Equine Internal Medicine 4th Ed

EQUINE
INTERNAL
MEDICINE
FOURTH EDITION
Stephen M. Reed, DVM, Dipl ACVIM

Rood & Riddle Equine Hospital • Lexington, Kentucky
Professor Emeritus, Department of Veterinary Clinical Sciences • The Ohio
State University • Columbus, Ohio
Warwick M. Bayly, BVSc, MS, PhD, Dipl ACVIM

Professor, Department of Veterinary Clinical Sciences
Washington State University • Pullman, Washington
Debra C. Sellon, DVM, PhD, Dipl ACVIM

Professor, Department of Veterinary Clinical Sciences • College of Veterinary Medicine,
Washington State University • Pullman, Washington
3251 Riverport Lane
St. Louis, Missouri
63043
EQUINE INTERNAL MEDICINE ISBN: 978-0-323-44329-6
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Library of Congress Cataloging-in-Publication Data
Names: Reed, Stephen M., editor. | Bayly, Warwick M., editor. | Sellon, Debra
C., editor.
Title: Equine internal medicine / [edited by] Stephen M. Reed, Warwick M.
Bayly, Debra C. Sellon.
Other titles: Equine internal medicine (Reed)
Description: Fourth edition. | St. Louis, Missouri : Elsevier, [2018] |
Includes bibliographical references and index.
Identifiers: LCCN 2017028516| ISBN 9780323443296 (hardback : alk. paper) |
ISBN 9780323443098 (Ebook)
Subjects: LCSH: Horses--Diseases. | Veterinary internal medicine. | MESH:
Horse Diseases
Classification: LCC SF951 .E565 2018 | NLM SF 951 | DDC 636.1/089--dc23 LC record available at
https://lccn.loc.gov/2017028516
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C HA P T E R 1
Mechanisms of Disease
and Immunity
Robert H. Mealey and Maureen T. Long*
nondisrupted skin surfaces. Even though horses inhabit an

The Microbiome environment heavily contaminated with fecal flora, normal
dermal flora in the horse is surprisingly devoid of members
Maureen T. Long of the Enterobacteriaceae.2 Normal inhabitants include mixed
populations of bacteria of species of Acinetobacter, Aerococ-
Dermal and mucosal surfaces provide a life-preserving pro- cus, Aeromonas, Bacillus, Corynebacterium, Flavobacterium,
tective barrier composed of physical, chemical, and microbial Micrococcus, Nocardia, coagulase-negative Staphylococcus,
defenses.1 In the past 5 years, the concept of normal flora has Staphylococcus aureus, Streptomyces, and nonhemolytic Strep-
been broadened to include the whole of “microbiota” that tococcus generae.3 Certain Staphylococcus spp. have been
colonizes skin, gut, and mucosal surfaces. The microbiome associated with skin disease in the horse, and these include
is the science of analyzing the total number of organisms in S. aureus, S. intermedius, and S. hyicus, whereas species such
an ecosystem, which in our case are animals. The practical as S. xylosus and S. sciuri were more associated with normal
application of this science to the clinician is that the microbi- skin. More than 30 species of fungi can inhabit the skin and
ome differs among many niches of the body, varies with indi- Alternaria, Aspergillus, Candida, Fusarium, Rhizopus, and
viduals, and has an interactive role with actual disease states. Trichophyton spp. are commonly present.2 Until recently the
Microbiota is the microbial population within the different presence of Malassezia yeast species has been considered
sites of the body. Commensal bacteria are those living on or pathogenic. Recent fungal culturing of the skin of normal,
within a host in a way such that both derive mutual benefit and healthy horses has confirmed colonization by a species of Mal-
in which interruption of this association results in abnormal assezia yeast that is novel to the horse (tentatively named M.
host development or overt disease. These represent that part equi). Colonized sites include the groin, axilla, and perineal
of the microbiome that has intimately coevolved with the dif- regions.4 To date there are no studies describing the microbi-
ferent niches of the body.1 ome of the skin of horses.
Environment is local, such as within different areas of the
gut, and also external, and these can have either positive or Oral Microbiome
negative effects on the microbiome. For instance, poor ven- The oral and pharyngeal mucosa is richly populated with
tilation in animal housing not only is a direct irritant, but many bacteria, including obligate aerobes, anaerobes, and
changes in pH, metabolism of particulates, and activation of facultative anaerobes.5 By culture, gram-positive and gram-
the immune system will dramatically alter the structure of the negative anaerobes are the predominant flora in the mouth
microbiome. and pharyngeal tonsils of the normal horse, with B. fragilis
Age is also an important factor. Colonization of skin and and Bacteroides spp. most commonly found. Genera consist-
mucosal surfaces occurs at birth and is highly variable in early ing of Fusobacterium spp., Eubacterium spp., Clostridium
life. Changes in management from birth to weaning are accom- spp., Veillonella spp., and Megasphaera spp. are also cul-
panied by changes in diet and husbandry for horses. They create tured. Aerobic and facultative anaerobic populations mostly
a highly dynamic environment that eventually can be used to include S. zooepidemicus, Pasteurella spp., E. coli, Actino-
predict best practices once data on the microbiome in healthy myces spp., and Streptococcus spp. In a 16S metagenomics
horses are obtained in a methodical and scientific manner. analysis of the subgingival sites of the horse, although highly
diverse, many similarities to human and other species were
Skin Microbiome observed.6 The most common bacterial phyla included Gam-
The combination of normal flora and mucosal immunity pro- maproteobacteria, Firmicutes, Bacteroidetes, Betaproteobac-
vides an effective barrier against infectious colonization of teria, Fusobacteria, Actinobacteria, Epsilonproteobacteria,
TM7, Deltaproteobacteria, Synergistetes, GN02, Tenericutes,
Spirochaetes, Chloroflexi, and Alphaproteobacteria. The
* The editors and authors acknowledge and appreciate the contributions of Gammaproteobacteria had the highest population of species,
J. Lindsay Oaks, Thomas R. Klei, D. Paul Lunn, and David W. Horohov as with Moraxella spp. and Pasteurellaceae spp. overrepresent-
previous contributors to this chapter. Some of their original work has been ing the population. In the former, Actinobacillus species and
incorporated into this edition. unclassified Pasteurellaceae were the most common bacteria.
3
4 PART 1 MECHANISMS OF DISEASE AND PRINCIPLES OF TREATMENT
The finding of Actinobacillus species is not unexpected; how- ascending colon and cecum, indicating highly specialized
ever, by comparison these taxa are relatively absent from digestive functions associated within the large intestine itself.16
cat and dog oral metagenomes. Of the highly abundant Yeasts and fungi of the order Mucorales have been identified
Firmicutes, many classes of Bacilli were detected; several in the cecum of normal horses and are capable of digesting cel-
Neisseria-like bacteria were detected. Of particular interest lulose and starch.18 By deep sequencing, Firmicutes and Bac-
is the population of oral spirochetes that reside in the equine teroidetes (or in another study, Verruccomicrobia) are the two
mouth because of its relationship to periodontal disease in must abundant phyla.19 The common bovine rumen bacteria
humans, and although there were Treponema, spirochetes, Ruminococcus flavefaciens is one of the most predominant
and leptospires present and abundant, “periodontopatho- cellulolytic bacteria of the equine cecum based on standard
gens” were present in low numbers. When healthy horses microbiologic techniques.15
were compared with horses with oral disease, Actinobacillus Since 2012 several studies have been published investi-
(Gammaproteobacteria) and the Neisseria-like Gemella sp. gating the equine microbiome, and these have been recently
(Firmicutes) predominated compared with Prevotella (Bac- reviewed.17 The techniques employed in each investigation
teroidetes) and Veillonella (Firmicutes).7 could highly bias study results. Fecal samples or samples from
specific gastrointestinal locations have been used. Most stud-
Pharyngeal and Respiratory Microbiome ies had a stated goal of attempting to define the flora of the
Because these same genera are also consistently found in hindgut of the horse.
horses with lower respiratory infections, opportunistic coloni- Routine surveillance demonstrates a relative lack of intesti-
zation by pharyngeal flora is the likely mechanism of disease.5 nal pathogens in the flora of normal horses. In the largest study
Contamination of the trachea of the horse is a frequent occur- to date, fecal shedding of Salmonella enteriditis as detected by
rence, as evidenced by the fact that transtracheal aspiration fecal culture in normal horses from farms without evidence of
yields positive bacterial cultures in approximately 30% of both salmonellosis was 0.8% in resident horses.20 Molecular diag-
normal adult horses and foals.8 As with skin flora, normal nostics, once hoped to provide a tool for understanding the
horses have multiple fungal species inhabiting conjunctival, incidence of Salmonella spp. in the clinically normal horse,
nasal, and oral mucosa.8 Stabling increases the frequency of has provided inconsistent information, and polymerase chain
ocular fungi in normal horses.9 reaction (PCR) is most useful for identification of subclinical
shedders and environmental contamination during an out-
Intestinal Microbiome break.21,22 On the basis of limited investigations, the carriage
In animal models and chronic human conditions, the pres- rates of C. difficile in normal horses and foals appear to be low
ence of normal flora is considered important for intestinal (less than 1.5%).23
maturity and containment of disease. Changes in cecal weight, Intestinal flora in the horse is an important source for
villus:crypt ratio, and volatile fatty acid (VFA) production and extraintestinal pathogens. In studies examining the car-
the development of gut immunoglobulin A (IgA) responses riage rate of Rhodococcus equi, all horses cultured carried
are all affected by suboptimal cecal colonization in germ-free the bacteria regardless of age.24,25 If a farm had endemic R.
animals.10 A relationship between severity of mucosal disease equi and respiratory isolates contain the 90-kDa plasmid
and normal flora has also been demonstrated in models of that is associated with disease, fecal isolates also contained
inflammatory bowel disease of humans.11 this plasmid. In a recent study, there was little difference
Bacteria are present in all parts of the intestinal tract of in the composition of the phyla of fecal bacteria measured
the horse, and the microbial fauna increases in complexity via deep sequencing between normal foals and those with
and density aborally.12 The stomach of the horse is not a ster- either subclinical or clinical R. equi.26 However, a striking
ile environment. A dense population of gram-positive bacte- difference in flora was observed over the first few weeks
rial rods, primarily composed of Lactobacillus spp., colonizes of life among all foals demonstrating the transition from
the nonsquamous portion of the equine stomach. Substantial a juvenile gut to that of the adult. Flora transitioned from
colonization of the duodenum is present with a large popula- equal abundance of Firmicutes to Bacteroidetes over this
tion of proteolytic bacteria, and this colonization increases by short interval.
tenfold in the ileum.13 The right dorsal colon contains the highest numbers
Microbial degradation and fermentation of plant material and the most diversity of protozoal species.17 Four classes
in the large intestine are important components of nutrient of protozoa species, Rhizopoda, Mastigophora, Cliata, and
acquisition in the equid. The consumption of cellulose and Suctoria, have been described based on relative prevalence
starch results in the production of VFAs.14 The major cellulo- in ascending and descending parts of the large colon. The
lytic bacterial strains in the horse produce arrays of fermenta- importance of protozoa for normal gastrointestinal func-
tion products that differ from those of cattle.15 Early genetic tion is debated, but these organisms are presumed to play
techniques also demonstrate that the predominant flora are the an important role in degradation of plant fiber. Despite this
low guanine-cytosine (GC)-content bacteria, which include presumption, one investigation demonstrated little effect of
Cytophaga-Flexibacter-Bacteroides and Clostridium bacteria; protozoa on the digestibility of dry matter with little effect
the actual species are completely novel.16 Standard microbio- on cellulose digestion.27
logic techniques specifically demonstrate Enterobacteriaceae,
Butyrivibrio spp., Streptococcus spp., Bacteroides spp., Lactoba- Urogenital Microbiome
cillus spp., Selenomonas spp., Eubacterium spp., Propionibacte- By far, most of the work that characterizes equine normal
rium spp., and Staphylococcus spp. in residence.17 In addition, flora has focused on urogenital flora to address infertility and
there are completely different compositions of bacteria among fetal loss. Although vaginal and vestibular mucosa of mares
the differing segments of the colon, especially between the should be colonized with normal mucosal flora, the uterus
CHAPTER 1 Mechanisms of Disease and Immunity 5
is considered sterile. However, typical culturing techniques receptor agonist resting in contraction of antral and duodenal
result in frequent isolation of what could be considered patho- smooth muscles.38 In the horse erythromycin results in a dose-
gens, and cytology and bacterial counts are essential supple- dependent increase in ileocecal emptying.39 Motility-enhanc-
mental tests for detecting true uterine infection. Counts less ing effects have also been observed in human patients treated
than 10 colony-forming units and lack of inflammatory cells with amoxicillin.37
indicate uterine or technical contamination.28 Occurrence of infectious lower respiratory disease in adult
Many bacteria inhabit the external genitalia of stallions, horses is an example of how contamination of a normally
including bacteria considered to be associated with metritis sterile site with several commensal bacteria results in disease.
in mares. The predominant aerobe isolated is coagulase- The tonsillar mucosa of the oropharynx is heavily colonized
negative Staphylococcus spp., followed by Corynebacterium with S. equi subsp. zooepidemicus, and necrosis of this tissue
spp., α-hemolytic Streptococcus spp., and Lactobacillus spp. occurring during viral infection is associated with spread to
Pathogens such as β-hemolytic Streptococcus spp., Pseu- the lower respiratory tract.5 Transport of horses (especially
domonas aeruginosa, and Klebsiella spp. can be frequently for distances greater than 500 miles) is a primary risk factor
found in servicing stallions.29,30 Pregnancy rates appear to for pleuropneumonia as demonstrated in a large retrospective
be the same in mares bred to stallions with P. aeruginosa– study.40 Elevation of the head for an extended period of time
infected semen.31 is likely a contributing factor. Horses normally feed from the
ground for most of the day, and this posture promotes effective
Fungal Microbiome tracheal clearance of inhaled debris and particulate matter.
Essentially the same principles apply regarding normal flora, Pasteurella, Actinobacillus, and Streptococcus spp. are the most
host immunity, and specific virulence factors for the patho- frequent and prolific colonizers of the trachea after prolonged
genesis of fungal infection. Fungal infections can be divided head elevation.41,42
into primary or opportunistic pathogens. True pathogens are Nosocomial infection (health care–associated infections)
less dependent on host status than opportunistic pathogens, is defined by the Centers for Disease Control and Prevention
although even a true pathogen may require some degree of as a localized/systemic condition resulting from an adverse
alteration of normal flora or host immunity to become estab- reaction to the presence of an infectious agent or its toxin.
lished. Long-term antibiotic use, immunosuppression, and There must be no evidence that the infection was present or
compromised organ function (especially involving the pul- incubating at the time of hospital admission.43 Nosocomial
monary or endocrine system) are three primary host factors infections are becoming a major problem for large animal
highly associated with the establishment of opportunistic veterinary teaching and private referral hospitals. Infections
fungal infection. Fungi in particular can adapt to the mam- with Serratia marcescens, Acinetobacter baumannii, S. aureus,
malian environment over a relatively short course in order to methicillin-resistant Staphylococcus spp., Enterococcus spp.,
become established. Establishment usually requires a change and various Salmonella enteritidis serovars have all been
in thermal range, oxygen requirements, and resistance to host reported in association with nosocomial infection in equine
defenses. patients.44,45 Surgical incision infection, joint sepsis, cath-
eter phlebitis, wounds, and diarrhea represent the common
Nosocomial Infections clinical syndromes reported in horses.44-46 When nosocomial
Development of colitis in the horse has been associated with infection involves the acquisition of isolates from the hospital
feed change, antibiotics, surgery, nonsteroidal inflammatory environment, these isolates are more difficult to treat because
drugs, and transport, all events that disrupt flora.32,33 Rapid they frequently undergo high-level antibiotic pressure and
change from a roughage diet to concentrate results in increased attain multiple-drug resistance (MDR). Nosocomially trans-
anaerobes, decreased cellulolytic bacteria, decreased cecal pro- mitted salmonellosis in equine hospital wards is increasingly
tozoa diversity, and decreased pH in the equine cecum.32 Iso- reported, with Salmonella enteritidis serotypes Krefeld, Saint
lation of Clostridium difficile is more likely from horses treated Paul, DT104, and Anatum all demonstrating attainment of
with antibiotics, and clinical disease has been associated with MDR over the course of the outbreak.47,48 Only one study of a
ampicillin, erythromycin, penicillin, and potentiated sulfon- nosocomially transmitted S. enteritidis (serotype Heidelberg)
amide administration in adult horses.34,35 In ponies infected did not demonstrate significant acquisition of MDR over
with Salmonella spp., transport and surgery reactivated infec- time.49
tion and diarrhea, and antibiotics (oxytetracycline) prolonged
shedding but did not induce recrudescence.33 In a case-control
study, use of potentiated sulfonamides was not significantly
associated with the development of diarrhea in hospitalized
Pathogenesis of Bacterial Infections
horses; however, overall antibiotic use was highly associated
with the occurrence of diarrhea.36
Antibiotics disrupt normal gastrointestinal flora and func- The ability of bacteria to gain entry and cause disease results
tion,37 and changes in carbohydrate metabolism are a large from a combination of factors possessed by the agent itself,
intestinal event secondary to reduced microbial reduction environmental conditions, and status of host defenses. Gen-
of carbohydrates to short-chain fatty acids (SCFAs). Because eral mechanisms that are specific to bacteria and enhance
SCFA metabolism and absorption result in fluid and electro- disease are virulence factors that enhance the entry, spread,
lyte absorption, a sudden decrease in SCFA leads to osmotic and damage to host tissues (Table 1.1). Major virulence fac-
diarrhea with an intraluminal accumulation of organic acids, tors are listed for specific equine pathogens. Protein secre-
cations, and carbohydrates. Erythromycin and amoxicillin tion systems (PSSs) are a structurally diverse complex of
directly affect colonic motility.37 Erythromycin is a motilin essential virulence factors for bacteria that allow specialized
interactions among cells.50 These main systems function to surface components recognizing adhesive matrix molecules.53,54
translocate various sized molecules and are important in the Gram-positive organisms possess afimbrial proteins on their
formation of adhesins on attachment to host cells. Fibrillar surfaces that presumably aid in binding to host cells. The
adhesins (FAs) and nonfibrillar adhesins (NFAs) are the most three most commonly studied afibrillar adhesins are those
important PSS subgroup not used for bacterial conjugation. that bind salivary glycoprotein, bind fibronectin, or are com-
They specifically target host cells and biofilms for enhance- posed of lipoteichoic acid.53,55 Salivary binding proteins are
ment of colonization and invasion. There are multiple types commonly found in pathogens and commensals of the oral
of FAs in both gram-positive and gram-negative bacteria, cavity. Both Streptococcus spp. and Actinomyces spp. possess
with gram-negative types the most well characterized (Table these proteins. Fibronectin binding protein (FBP) is neces-
1.2).51,52 Pili or fimbriae are rod-shaped structures composed sary for S. aureus invasion and binds both fibronectin and
of an orderly array of a single protein usually arranged in collagen to form a bridge between the FBP and the host cell
a helical fashion to form a cylinder. The tip of the fimbria integrin (integrin α5β1).56,57 Heterologs of FBP have been
mediates attachment to carbohydrate moieties on cell sur- demonstrated in S. pneumoniae of humans, S. equi subsp.
faces and is integral to bacterial invasion and colonization. equi, and S. equi subsp. zooepidemicus. Other potential equine
Bacteria can also contain multiple types of pili. Both the bac- pathogens that have FBPs on their surface include Actino-
terial pili themselves and the cellular pathways they use for myces spp., E. fecalis, and L. monocytogenes.55,58 Lipoteichoic
secretion and formation of pili are targets for pharmacologic acid, a common binding factor found in Streptococcus group
intervention, and there are multiple subclasses depending on A bacteria, is important in adhesion of bacteria to cells.59 This
their configuration.51 protein is also important in stimulation of cytokine secretion
Afimbrial adhesins are cell proteins that enhance the bind- from the cells during infection and has been demonstrated in
ing of bacteria to host cells. They are also called microbial group B Streptococcus, including S. equi subsp. equi.60 A less
commonly described afibrillar adhesin is composed of surface
TABLE 1.1 General Mechanisms of Bacterial Pathogenesis polypeptide chains in Corynebacterium that binds to lectin.61
Afibrillar adhesins are also present in gram-negative organ-
Action Mechanism Examples isms; the most commonly studied are conserved high-molec-
Entry of bacteria Adhesion Fibrillar adhesins ular-weight adhesion proteins of Haemophilus influenzae and
Entry Nonfibrillar adhesins Bordetella pertussis.59
Curli fimbriae Bacterial ecology has emphasized the importance of bio-
Lipoteichoic acid film for colonization of both biotic and abiotic surfaces of
Biofilm adhesion proteins bacteria.50 A requirement for biofilm formation is a tight
Membrane ruffling interaction of bacterial adhesins with surface receptors that
promote further bacterial aggregation. The most important
Enhancement of Immune resis- Capsule
family of biofilm adherence proteins is that of Staphylococ-
spread tance Lipopolysaccharide
cus aureus. These proteins have high molecular mass and
Host sub- Anticomplement
repetitive structures whose size and number can be varied
strate Resistance to
during the course of infection, possibly allowing for immune
utilization phagocytosis
evasion.
Phagolysosomal survival
The most common virulence proteins of both gram-pos-
Iron acquisition
itive and gram-negative organisms are bacteria lectins.53-62
Damage to host Toxins Exotoxin Although attachment is thought to be the primary role of
membranes Endotoxin these proteins, attachment itself results in an intracellular
Apoptosis change, including actin rearrangements, cell signaling reg-

ulation, or actual secretion of bacterial substances into the
TABLE 1.2 Major Types of Bacterial Adhesins

Adhesin Definition Example
Type 1 fimbriae Cell surface structure primarily on gram-negative bacteria that bind Escherichia coli
to the terminal mannose of glycoproteins on cells
Type 4 pili Cell surface structure primarily on gram-negative bacteria that func- Pseudomonas aeruginosa
tion in adhesion, twitching, and DNA uptake, which bind on CD46
and other glycolipids
Curli fimbriae Coiled aggregative fimbrial structures that bind to fibronectin, lam- Enterohemorrhagic Escherichia
inin, and plasminogen and function in adhesion, aggregation, and coli (EHEC)
biofilm formation Salmonella
Fibrils and flexible rods Short, thin rodlike adhesins that bind to fibronectin for adhesion to Streptococcus species
host tissues
Lipoteichoic acid Part of the peptidoglycan layer of cell walls Gram-positive bacteria
Biofilm Exopolysaccharide produced by bacteria that allows matrix forma- Gram-positive and gram-
tion of embedded material negative bacteria

host cell. These proteins are highly conserved in bacteria and in vitro phagocytosis can be abolished with treatment with
are important targets for immunoprophylaxis. Membrane hyaluronidase and induction of specific immunity against
transformation for uptake of intracellular bacteria such as M-protein of S. equi subsp. equi and S. equi subsp. zooepi-
Yersinia spp., Listeria monocytogenes, Salmonella spp., and demicus.80 The M-proteins of Streptococcus spp. are also essen-
Shigella flexneri can be either zipperlike or triggerlike. Alter- tial for resistance to phagocytosis blocking complement.66,81-83
natively, Salmonella and Shigella bacteria adhere and secrete This mechanism for complement resistance appears to be
proteins that are translocated into the host cell cytoplasm through enhancement of binding of fibrinogen to the bacteria
and trigger actin polymerization.63 In addition to mem- in the presence of M-protein.79,84,85
brane ruffling, Mycobacterium avium and Salmonella spp. Apoptosis is a distinctive morphologic process that results
also rely on activation of intracellular GTPases, leading to in cleavage of nuclear material and scavenging of unwarranted
phagocytosis.64,65 cells without immune activation. Apoptosis or programmed
Once colonization occurs, multiplication and spread of cell death is an important pathway for complex organisms
bacteria are enhanced through virulence factors. These fac- to deal with damaged and diseased tissue. Apoptosis avoids
tors assist bacteria in survival in the hostile host environ- the release of the tissue-damaging enzymes and nonspecific
ment and breakdown of tissue barriers. One of the most elimination of tissue that occurs in cellular necrosis. Several
common and potent strategies for avoidance of phagocytosis bacteria have modulated the host apoptotic pathways for
is the presence of a capsule. Despite the remarkable diver- enhancement of survival.86 Shigella flexneri, S. typhimurium,
sity of bacteria, capsule assembly and structure are remark- and toxins of S. aureus, Pseudomonas spp., and C. diphtheriae
ably similar across species. Early studies with S. equi subsp. have demonstrated programmed cell death as a consequence
equi demonstrated that resistance to phagocytosis was asso- of cellular infection or exposure.87,88 The protein of S. flex-
ciated with an increase in capsule and M-protein,66 and in neri, IpaB, induces apoptosis by binding to and activating the
a model of S. equi subsp. zooepidemicus infection in mice, cellular enzyme caspase 1, which induces apoptosis of mac-
enhancement of virulence was associated with increased rophages.89 Staphylococcus aureus α-toxin, which is similar
amount of capsule, which increased resistance to phagocy- to listeriolysin O, presumably escapes the macrophage after
tosis.67 Although colonization of the guttural pouch occurs engulfment and induces host cell apoptosis.90 The TSST toxin
with nonencapsulated S. equi subsp. equi strains, induction of S. aureus induces B-cell apoptosis and blocks immunoglob-
of lymphadenopathy is associated with capsular strains.68 In ulin production.91
more recent studies of S. equi subsp. equi infection, rapid
colonization in the lingual and pharyngeal tonsil is depen-
dent on genetically associated virulence factors that control
colony morphology, with the mucoid strain having enhanced
Pathogenesis of Fungal Infections
virulence.69 Maureen T. Long
Capsules of anaerobic bacteria are unique, and these
structures may directly account for the formation of Of the 250,000 species of fungi, fewer than 200 are true
abscesses within the host. The capsule of B. fragilis has two pathogens.1 Superficial mycoses affect the hair shaft and the
distinct polysaccharides composed of repeating subunits superficial epidermis. Cutaneous mycoses (dermatophytosis)
with oppositely charged groups (Zwitter ion).70 This poly- infect the epidermis, dermis, hair, and nails of animals, and
saccharide complex injected alone promotes the induction Microsporum, Trichophyton, and Epidermophyton spp. are
of abscess. Infection of rodents with the encapsulated form the most commonly associated pathogenic genera. Subcuta-
of Bacteroides and Fusobacterium spp. results in the forma- neous tissues can become infected with Sporothrix, Conid-
tion of intraperitoneal abscesses, whereas nonencapsulated iobolus, Basidiobolus spp., and members of the Dematiaceae
bacteria do not cause abscessation.71-73 Synergism of capsu- fungi, including the Chromoblastomycosis, Mycetoma, and
lar anaerobes with other bacteria occurs; nonencapsulated Phaeohyphomycosis spp. infections. Most of these infections
bacteria have enhanced survival in abscesses and produce are introduced by penetration through skin or opportunistic
capsule when cultured or inoculated with encapsulated invasion of damaged skin surfaces. Histoplasma capsulatum,
bacteria.72 Coccidioides immitis, Blastomyces dermatitidis, and Para-
Similar to and overlapping with capsule are structural pro- coccidioides brasiliensis are the four most important fungal
teins that block complement. The O side chain of lipopolysac- pathogens that can cause systemic infection. The most com-
charide (LPS) on gram-negative bacteria is an anticomplement mon opportunistic infections include Candida albicans,
factor.74 The longer the side chain, the greater the distance Aspergillus spp., Cryptococcus neoformans, Mucor spp., and
between phagocytes and bacteria. The capsular component, Pneumocystis carinii.
sialic acid, interacts with O antigen to prevent the formation Fungal virulence factors may be more complex than those
of C3 convertase.75 Bacterial enzymes are formed by Strepto- of bacteria because of the higher degree of opportunism that
coccus spp. and other organisms that damage the polymorph occurs with a change in host status. There may be subtle fac-
chemoattractant, C5a.76,77 Production of a protein in Salmo- tors that, combined with host status, result in a certain fungus
nella spp., encoded by the rck gene, prevents insertion of the attaining a virulent state. For instance, the typical fungal wall
C9 fragment of complement into the bacterial membrane.78 is composed of three major polysaccharides: mannose; β-1,3
The M-protein of S. equi subsp. equi appears to decrease depo- and β-1,6 linked glucans; and chitin. Chitin mutants in C.
sition of complement on the surface of bacteria.79 albicans are less virulent when tested in rodent models than
Recent studies of streptococci have shown that when are wild-type fungi.92 Further, a mutant C. albicans that can-
M-protein content is kept constant, the amount of capsule not synthesize complex mannose oligosaccharides does not
is correlated with resistance to phagocytosis.68 Resistance to adhere to other yeast and epithelial cells and has lost virulence
in a guinea pig model.93 Both of these mutants can proliferate

in vitro normally, and whether or not this is an actual viru- Pathogenesis of Viral Infections
lence factor is unclear.
As with bacteria, cellular adherence is an important pre-
requisite for infection and colonization of the host. Adhes-
ins have been identified in C. albicans and B. dermatitidis. Viral infections such as equine influenza (Orthomyxoviri-
Two genes have been associated with adhesion in C. albi- dae), rhinopneumonitis and abortion (Herpesviridae), Afri-
cans. The first is a glycoprotein that has sequences consis- can horse sickness (Reoviridae), equine infectious anemia
tent with agglutinating activity. Transformation of this gene (Retroviridae), and various encephalitides (Alphaviridae
into other nonadherent fungal species results in adhesion and Flaviviridae) are responsible for some of the most medi-
of the transformed yeast to cells.94 Candida albicans also cally and economically important diseases of horses. Specific
has integrin-like proteins, the disruption of which results therapy of viral infections remains a significant challenge
in diminished hyphal growth, adhesion to cells, and loss because antiviral drugs are generally ineffective, impractical,
of virulence in mice.95,96 The B. dermatitidis adhesin medi- or prohibitively expensive for the treatment of horses. Treat-
ates binding to human monocyte-macrophages through the ment of most viral infections focuses on supportive care of
CD14 receptor.97 the affected organ systems and control of secondary compli-
Many fungi have polysaccharide capsules that, like bac- cations such as bacterial infection. Currently control of most
teria, help resist phagocytosis and immune activation. The clinically significant viral diseases in horse populations relies
capsule of C. neoformans inhibits leukocyte accumula- on vaccination, quarantine, or even destruction of infected
tion, cytokine secretion, and macrophage phagocytosis.98 animals.
Mutants without capsule are highly infective and avirulent. Despite the great significance of some viral infections,
As indicated earlier, many fungi are engulfed by macro- recognizing that many equine viruses are ubiquitous,
phages, and intracellular survival is mediated by virulence weakly pathogenic, or not associated with any known dis-
factors. Macrophages are decimating cells for C. albicans,99 ease under normal circumstances is also important. Some
H. capsulatum,100 and B. dermatitidis. Histoplasma cap- examples include equine adenovirus, respiratory and
sulatum is primarily a yeast in vivo, and this form infects enteric reoviruses (the term reo is derived from the acro-
macrophages. Phagolysosomal fusion occurs at a normal nym for respiratory enteric orphan, indicating that these
rate,101 but blockage of acidification of the phagolysosome isolates have not been associated with disease), and equine
occurs.102 herpesvirus (EHV) type 2. Some host-virus relationships
Exposure to both pathogenic and saprophytic fungi is an may be mutualistic in that virally derived genetic elements
everyday occurrence. Respiratory contamination and infec- are theorized to benefit the host by facilitating genetic
tion are important for many pulmonary species, but skin pen- variability and evolution.116 Thus many viruses are of no
etration and dissemination from necrotic gut are important practical clinical significance, and no control efforts are
portals for large animals also. Dissemination after the initial warranted. For this reason, the veterinarian should never
infection is dependent on previous damage to host tissues, assume that the recovery of a virus from a clinical specimen
deeper mechanical penetration, or actual invasion of new tis- is significant without proof that the virus can cause the dis-
sues. C. albicans can actually grow through and replace cell ease in question.
membranes.99 True molds invade blood vessels and grow An in-depth discussion of viral structure, taxonomy, and
along the intima of the vessels. Fungi secrete many degradative replication is beyond the scope of this chapter, and the reader
enzymes, including proteinases, phosphatases, and DNAses, is referred to textbooks of veterinary or human virology for
to surmount structural barriers.103 A group of genes called more detailed information.117,118 A brief overview is presented
secreted aspartyl proteinase (SAP) genes allow more persistent to emphasize those features that have clinical relevance.
colonization of host surfaces and deeper penetration.104 The fundamental structure of all viruses is a DNA or RNA
When C. immitis invades the host, the fungi form endo- genome enclosed by a coat of protein called the capsid (Fig.
spores. These endospores secrete a proteinase and a urease 1.1). For viruses that are enveloped, the capsid is enclosed
that likely aid in the breakdown of pulmonary tissues.105-107 further by a host cell–derived lipid membrane into which
The two proteinases of A. fumigatus break down elastin, a viral proteins have been incorporated. In addition to protect-
major component of lung tissues.108,109 Phospholipase activity ing the viral genome, the capsid and other associated struc-
has been demonstrated in C. albicans, C. neoformans, and A. tural proteins (e.g., matrix proteins) are important for virus
fumigatus.110 Strains of Candida spp. with high amounts of this assembly, packaging the viral genome, releasing the genome
enzyme have higher virulence,111 and abolishing this activity into a target cell, and for nonenveloped viruses providing
results in decreased adherence of the organism.112 Host eico- receptors that bind to host cells. For enveloped viruses the
sanoids enhance fungal colonization. Recent evidence dem- receptors are incorporated into the lipid membrane. The pri-
onstrates production of eicosanoids by both dermatophytosis mary clinical significance of these features is that enveloped
and systemic fungi.113 viruses, because of their fragile lipid membrane, are highly
Fungi induce apoptosis, which may be due either to the susceptible to inactivation by heat, desiccation, or deter-
direct effect of a fungal toxin or secondary to host cell cyto- gents, and transmission typically requires direct exchange of
skeleton rearrangements.114 The gliotoxin of A. fumigatus can body fluids, short distance aerosols, or arthropod vectors. In
induce DNA fragmentation and apoptosis in macrophages.115 contrast, nonenveloped viruses (e.g., equine rotavirus) are
This toxin also has many other immunosuppressive qualities, resistant to physical inactivation, and environmental con-
which include inhibition of the neutrophil respiratory burst tamination is more likely to be a significant factor in their
and T-cell activation. transmission.
Herpesvirus Lipid envelope mutations are neutral or even deleterious, in the face of selective
(host cell derived) pressures such as the host immune response or antiviral drugs,
Capsid this genetic plasticity allows rapid development of resistant
(icosahedral) virus populations.120 Secondary structures or certain sequences
Genome in the viral genome may facilitate polymerase errors further at
Tegument
selected regions that are important for immune evasion, such as
in sequences that code for neutralizing epitopes.119 The genome
Surface viral of some viruses, such as influenza, comprise separate segments,
glycoproteins which allows reassortment of entire gene segments and sudden
(with receptors) and dramatic changes in antigenicity.121
All viruses are obligate intracellular parasites. Viral replica-
tion can occur only within living cells, and all viruses to some
extent depend on the host cell synthetic machinery. The life cycle
Rotavirus of all viruses includes the following steps: attachment to the tar-
get cell, entry into the cell, uncoating and release of the viral
genome, transcription and translation of viral proteins, replica-
Genome
tion of the viral genome, assembly of new virions, and release
(11 segments) of progeny virions117,118 (Fig. 1.4). Although the biochemistry of
these steps is beyond the scope of this discussion, recognizing
Capsid that they are all specific, energy-requiring interactions between
(2 layers of protein) the virus and the host cell is important. The inability of the virus
to interact appropriately with a cell at any of these steps prevents
Outer capsid proteins replication in that cell type and defines the tropism of the virus.
(with receptors) All of these steps are also important potential targets for antivi-
ral drugs and host immune responses.
Once the viral nucleocapsid gains entry to the cytosol of
FIG. 1.1 Schematic representations of basic viral structure. The basic struc- the cell, the viral genome is released through the process of
ture of an enveloped virus is shown by the drawing of a herpesvirus. The ba-
uncoating. After uncoating, the viral genome localizes to the
sic structure of a nonenveloped virus is shown by the drawing of a rotavirus.
appropriate regions of the cell for replication and mRNA tran-
scription. DNA viruses typically replicate genomes and tran-
scribe mRNA in the nucleus and then transport the mRNA to
the cytoplasm for translation. RNA viruses typically replicate,
The composition of the viral genome is an important basis transcribe mRNA, and translate viral proteins in the cyto-
for virus classification (Fig. 1.2). The type of viral genome also plasm. These sites of replication account, respectively, for the
determines the strategies required to replicate the genome and location of viral inclusion bodies that are diagnostically useful
transcribe messenger ribonucleic acid (mRNA; Fig. 1.3). Viral in histopathologic sections.
genomes may be single-stranded RNA, double-stranded RNA, Cells that replicate virus often are killed as a direct con-
single-stranded deoxyribonucleic acid (DNA), or double- sequence of infection. One mechanism by which viruses kill
stranded DNA. The genomes of single-stranded RNA viruses cells is lysis, often associated with the release of progeny viri-
may have positive polarity, in which the genome also serves ons. Insertion of viral proteins into cell membranes, budding,
directly as mRNA for translation of viral proteins. To replicate direct toxicity of viral proteins, and diversion of normal host
genomes, these viruses must first synthesize a strand of com- cell homeostatic processes to viral replication may result in
plementary RNA that can be used as a template to replicate death of the cell.117,118,122 Viruses also may activate the cellular
genomes and transcribe new mRNA. Retroviruses are a subset self-destruct mechanism of programmed cell death (apopto-
of single-stranded, positive-polarity RNA viruses that use their sis). Although cells may induce apoptosis in an attempt to pre-
RNA genomes as templates to produce double-stranded DNA, vent completion of the virus life cycle, viruses also may use this
which in turn is used for the transcription of mRNA and new mechanism to kill the cell and facilitate release of virions.123
viral genomes. Single-stranded RNA viruses may also have Viral infection can cause neoplastic transformation of
negative polarity, in which the genome is antisense to mRNA, infected cells. The most common examples in horses include
and synthesis of a complementary RNA strand is required to warts (equine papillomavirus) and sarcoids (bovine papillo-
serve as mRNA and as a template for new genomes. The clini- mavirus). Virally induced invasive neoplastic diseases such
cal significance of these types of replication strategies is that as leukemia or lymphosarcoma have not been recognized in
they require polymerases and other enzymes not normally the horse. Viral proteins that activate the cell cycle into the
found in eukaryotic host cells. These unique viral enzymes are growth and division phases may lead to neoplastic transfor-
important targets for antiviral drugs because they can be used mation if expressed in a cell that is not killed by the infection.
selectively to inhibit viral replication. Papillomavirus infections induce epithelial neoplasms (fibro-
Viral RNA polymerases are low fidelity and lack proofread- papillomata) using a virally encoded protein (E5 oncoprotein)
ing functions and thus randomly introduce errors into new that induces proliferation of normally quiescent cells and that
RNA at an average rate of about one nucleotide mismatch per presumably is needed for viral replication.124 Oncogenic retro-
10,000 bases copied.119 In a population of viruses, therefore, viruses, including leukemia and sarcoma viruses, induce neo-
virtually every individual virus differs slightly, and this popula- plastic transformation by integration into the host cell genome
tion is referred to as a quasi-species. Although many of these and activation of cellular oncogenes.125
ENVELOPED NONENVELOPED
dsDNA dsDNA
DNA Polyomaviridae
Iridoviridae Adenoviridae
Hepadnaviridae
Herpesviridae ssDNA
Poxviridae, Chordopoxviridae
Parvoviridae
ssRNA dsRNA
Reoviridae
Coronaviridae Paramyxoviridae Bunyaviridae Toroviridae
Birnaviridae
RNA Orthomyxoviridae Arenaviridae Togaviridae Flaviridae ssRNA
Piconaviridae
Retroviridae Rhabdoviridae
Caliviridae
Filoviridae
FIG. 1.2 Virus family classification based on genome composition and presence of envelope or absence
of envelope. The relative size of the viruses to each other is also shown.
At the host level viruses may use several mechanisms to infected animals serve as the reservoir of the virus.127-129 On
establish persistent infections and avoid immune clearance. reactivation viral nucleic acids are translocated across syn-
Virologic latency is defined as the presence of a viral genome apses to epithelial cells of the nasopharynx, which produce
that is not producing infectious virus.126 The genomes of infectious virus. The stimuli that induce reactivation are
latent viruses are transcriptionally suppressed and trans- poorly defined, but reactivation can be induced by immuno-
lationally silent so that no viral proteins are expressed that suppression (e.g., corticosteroids) and presumably by other
may identify the cell to the immune system as infected. The stressors, such as pregnancy, transport, and social stress.128,130
definition of latency also stipulates that on reactivation, viral The severity of disease in a virus-infected horse, or whether
gene expression and the production of infectious progeny infection even results in clinical disease at all, is the result
virions can be resumed, differentiating latently infected cells of a complex interaction among the triad of virus, host, and
from cells infected with defective viruses. In contrast, some environment. Critical factors include viral virulence, viral
persistent viral infections are characterized by continual rep- spread within the animal, the intensity of direct and immune-
lication despite the presence of antiviral immune responses. mediated pathologic response elicited by the virus, and the
Even in the absence of recognizable clinical signs, such infec- ability of the virus to avoid clearance by the host. Other than
tions are not truly latent. The classic latent infection is that the virulence of the virus, which is strictly a property of the
of the herpesviruses. For the α-herpesviruses, such as EHV1 virus, the other virus-host interactions can be influenced by
and EHV4, latent infections are established in the nuclei of the age and genetics of the host and by environmental fac-
sensory neurons and can be maintained indefinitely, and tors such as stress and nutrition. These factors account for
Protein Synthetic Replicative New Viral

Expression Intermediates Viral Genome Intermediates Genome
dsDNA
Adenoviridae
Asfarviridae
Herpesviridae
(+) mRNA Iridoviridae dsDNA
Papillomaviridae
Polyomaviridae
Poxviridae
ssDNA
(+) mRNA dsDNA Circoviridae (– or +) dsDNA ssDNA
Parvoviridae (– or +)
dsRNA
(+) mRNA Birnaviridae dsRNA
Reoviridae
ssRNA (+)
Arteriviridae
Astroviridae
Caliciviridae
(+) mRNA ssRNA (–) Coronaviridae ssRNA (–) ssRNA (+)
Flaviviridae
Picornaviridae
Togaviridae
dsDNA Retroviridae dsDNA
ssRNA (–)
Arenaviridae
Bornaviridae
Bunyaviridae
(+) mRNA Filoviridae ssRNA (+) ssRNA (–)
Orthomyxoviridae
Paramyxoviridae
Rhabdoviridae
FIG. 1.3 Summary of the main virus families that infect vertebrates and general strategies employed by
these viruses to produce mRNA for protein expression and to replicate genomes. Required intermediate mol-
ecules are indicated. White arrows indicate the need for unique viral polymerases, including RNA-dependent
RNA polymerase and RNA-dependent DNA polymerase (reverse transcriptase). Dark arrows indicate the use
of cellular polymerases or viral homologs of cellular polymerases. ds, Double-stranded; ss, single-stranded;
(+) for RNA = positive polarity, polarity of RNA used for protein translation; (+) for DNA = coding strand,
sequence same as for (+) RNA; (− or +) DNA = contains single strands of DNA of both polarities. (Modified
from Baltimore D: Expression of animal virus genomes, Bacteriol Rev. 35:235-241, 1971.)
the observation that considerable variation in disease signs in virulence, presumably because of the greater number of
can occur among a group of animals infected with the same infected cells and amount of tissue damage. The virulence
viral strain. of equine infectious anemia virus strains can be correlated
Certain strains of a virus may cause more severe disease directly to plasma virus titers and numbers of infected cells,
than other strains. The main properties of a virus that may without any changes in tropism.131,132 The molecular basis
affect virulence include host cell tropism and replication for the increased replication rate is not clear but most likely
rate. A tropism change that leads to involvement of addi- is caused by variation in viral regulatory sequences and
tional tissues or facilitates virus spread generally results in proteins.133,134
more severe disease. Outbreaks of EHV1 abortion or neu- Viral infections generally are regarded as localized or sys-
rologic disease strongly suggest that EHV1 strains exist temic. Localized viral infections are those that are restricted
that have a tropism for these tissues compared with EHV1 to a single organ system, often at the site of entry. Because
strains that cause respiratory disease. An increase in the infection of the tissue is direct, the incubation period for
viral replication rate is usually associated with an increase localized viral infections is usually short, often only a few
1 (Fig. 1.5). Localized viral replication first occurs at the site of

entry and in regional lymph nodes. Depending on the level
of replication, clinical disease may be present. The virus then
Cytoplasm enters the blood or lymphatics and spreads to other tissues,
2
such as spleen and liver, in which clinical disease may occur.
Virus is amplified and then released again for a second, usually
9 higher-titered, viremia that further disseminates the virus to
3 Nucleus
other organs. Each viremic episode is associated with a febrile
response and is the basis for the biphasic fever response asso-
4 6 ciated with some viral infections. Because systemic infections
6 4
require multiple steps, the incubation periods are longer than
5 for localized infections, typically 1 to several weeks. Infec-
10 tions in the horse by eastern, western, or Venezuelan equine
encephalitis virus closely follow this paradigm. Localized viral
7
7 11 replication occurs at the site of entry (mosquito bite) followed
by viremia and dissemination to the central nervous system.139
8 For most horses, even nonvaccinated horses, dissemination is
8 controlled before infection of the brain, and neurologic dis-
ease is a rare outcome of infection. A variation on the theme
is infection of horses with EHV1. The most common clini-
cal disease associated with EHV1 infection is rhinopneumo-
FIG. 1.4 Schematic representation of the general virus life cycle. Both nitis caused by a localized infection of the nasopharyngeal
RNA and DNA viruses share the initial steps, including attachment (1); entry/
mucosa.140 In almost all cases, a cell-associated viremia also
fusion (2); and uncoating and release of viral genome into the cell (3). Solid
occurs in lymphocytes, but in most infected horses this does
arrows indicate remaining steps for RNA viruses, which all occur in the cyto-
not result in disease. However, in some cases, viremia is asso-
plasm, including transcription of mRNA (4); translation of viral proteins (5);
ciated with infection of endothelial cells, and in the pregnant
replication of the viral genome (6); assembly of new virions (7); and release
mare vascular damage to the uterus and placenta may lead to
of progeny virions (8). Dashed arrows indicate steps for a DNA virus. The life
abortion.140,141 Similarly, infection of the vascular endothelium
cycle is similar except that the DNA genome is translocated to the nucleus (9)
in the central nervous system results in neurologic disease.142
for transcription (4) and replication of viral genomes (6). Viral mRNA is then
Some viruses also may spread in the host through nerves.
translocated back to the cytoplasm for translation (10), and newly synthesized
In the horse rabies is the best-known infection that relies on
viral proteins are translocated back to the nucleus (11) for assembly (7); new
neural spread. Following local replication in myocytes at the
virions are then released from both nuclear and cytoplasmic membranes (8).
site of entry, usually a bite wound, rabies virus ascends periph-
eral nerves into the central nervous system, where it repli-
cates in neurons and then egresses by way of cranial nerves
days. Many infections of the skin or mucosal surfaces are to the salivary gland.143 EHV1 and EHV4 establish latency in
localized, and examples in the horse include infections with the nuclei of sensory neurons that innervate the nasopharynx
enteric rotavirus and influenza. For influenza, virus is inhaled and reach the nucleus by ascending nerve axons. Similarly, on
into the nasopharynx and replicates in epithelial cells of the reactivation these viruses egress back down the axon to infect
upper respiratory tract and trachea. Virus is not present in epithelial cells.127,144
the blood or tissues outside of the respiratory tract. In gen- Once a virus reaches a target organ, virally mediated cell
eral, viruses remain localized because they lack the recep- death is the fundamental source of pathologic response,
tors to infect cells of other tissues or circulating cells, such as disease, and clinical signs observed by the veterinarian.
monocytes or lymphocytes, that can disseminate the virus. Despite the great complexity of virus-host interactions
Some viruses are temperature sensitive and remain local- and the many factors that influence the expression of clini-
ized because they are unable to replicate efficiently at core cal disease, in actuality viruses have a limited number of
body temperatures. EHV3, the cause of coital exanthema, is ways by which to cause pathology. Cells and tissues may be
restricted to the surface of the genitalia in horses because of destroyed directly by cytolytic viral infections or by infec-
its temperature sensitivity.135 EHV1 and EHV4 are not tem- tions that affect the differentiated function of target cells
perature sensitive, however, and systemic infection may occur (e.g., neoplasms and immunodeficiencies). Viral infections
with these viruses. Temperature sensitivity is also a means of organ systems with bacterial flora (e.g., intestinal and
by which some viruses, such as equine influenza and infec- respiratory tracts) can disrupt the normal barrier functions
tious bovine rhinotracheitis virus, may be attenuated for use of these organs and result in secondary bacterial infections
as modified-live intranasal vaccines. Infection by the vaccine and toxemia that may contribute significantly to the patho-
strain is limited to the cooler mucosal surfaces; the inability logic response. Cell death and pathologic response also may
to spread systemically prevents sequelae such as abortion and be caused by host immune responses specifically directed
pneumonia.136,137 against virally infected cells or by indiscriminate inflam-
Systemic infections are those in which virus is dissemi- matory responses. Virally induced autoimmune diseases
nated to multiple tissues by blood or lymph. This viremia may have not been described in horses but are another potential
exist in the form of cell-free virions in the plasma or lymph source of pathologic response that may be identified in the
or may be cell associated in circulating blood cells, usually future.
monocytes or lymphocytes. The classic paradigm for a sys- For most of the clinically important viral diseases of horses,
temic infection is infection of mice with ectromelia virus138 disease manifestation results from some combination of
DAY
Skin: Invasion
Multiplication
1 Regional lymph node:

Multiplication
2
Bloodstream:
Primary viremia
3
Incubation Spleen and liver:
period Multiplication necrosis
4
Bloodstream:
5 Viremia
Skin: Focal infection

6 Multiplication
Swelling of foot
(Primary lesion)
8
Early rash
Papules
Disease 9
10
Severe rash
Ulceration
11
FIG. 1.5 Schematic representation of the pathogenesis of mousepox (ectromelia), illustrating the classic
paradigm for the events in a systemic infection. (From Fenner F: The pathogenesis of the acute exanthems,
Lancet. 252:915, 1948.)
cytolytic infection and immune-mediated tissue destruction. apparent. EHV1 infections of the respiratory epithelium,
The relative contribution of these mechanisms is primarily a which has a large number of cells with a high turnover rate,
function of viral virulence and host factors that influence the produce mild clinical disease even with a high rate of infec-
type and intensity of immune responses. The predominant tion. On the other hand, much more significant clinical
mechanism of pathologic response also can vary with differ- manifestations of EHV1 infection such as abortion and neu-
ent stages of the same disease, as seen in acute versus chronic rologic disease are caused by infection of a few endothelial
equine infectious anemia. In acute disease most of the disease cells because minimal vascular damage can lead to thrombo-
manifestation is caused by direct viral damage and cytokines, sis, ischemic necrosis, and damage to large amounts of tissue.
whereas in chronic disease immune complex–mediated ane- If viral infection results in neoplastic transformation of a cell
mia and glomerulonephritis become more significant. type, disease may progress according to the characteristics of
The disease associated with a given viral infection is the neoplasm, whether or not the virus remains associated
related to the affected organ system(s), the number of cells with the tumor.
destroyed, and the sensitivity of the affected organ system to In most viral infections immune-mediated pathologic
dysfunction. If the number of infected cells is not sufficient response contributes significantly to disease and in some
to lead to clinically significant organ dysfunction, the result cases may be the predominant cause of disease manifestation.
is a subclinical infection. When enough cells are infected to Equine immune and inflammatory responses are covered else-
lead to overt organ dysfunction, clinical disease becomes where in this chapter.
Although not described in horses, viral infections in other in disease conditions. Immune responses leading to protective
species can induce immune-mediated responses to host cell resistance against reinfection occur, but the level of this resis-
antigens and autoimmune diseases. The best documented tance is most often incomplete. Mechanisms associated with
human autoimmune disease suspected to be initiated by viral these responses have not been investigated extensively in the
infections is Guillain-Barré syndrome, in which infection with horse, but information is available from other host-parasite
cytomegalovirus or Epstein-Barr herpesvirus elicits antinerve systems that may be relevant to equids. The purpose of this
ganglioside immune responses and demyelinating disease.145 section is to acquaint the reader with contemporary thoughts
Postinfluenza myocarditis is an occasional sequela in horses on host-parasite interactions. Because of their prevalence,
and human beings and is a potential autoimmune disease. major importance to equids, and information available, cover-
Although no direct evidence supports this theory, influenza age is limited to helminth parasites that occur in most devel-
virus is not identified consistently in affected heart muscle, oped and nontropical countries.
and the pathogenesis is not known.146 Infection with most metazoan parasites results in inflam-
A key requirement for viruses to be maintained in nature mation and structural and functional changes of the organs
is to persist successfully in a reservoir host (if the reservoir is invaded. The outcome of these changes is an alteration of the
an infected animal) and to be transmitted to another suscep- host’s physiologic state. The degree of alteration depends on
tible host. One of the most important obstacles to persistence the existing physiologic condition of the animal, which is dic-
and transmission is detection and elimination by the host tated to a great degree by its age, nutritional status, and previ-
immune system. Within the host rapidly replicating viruses ous immunologic experience with the parasite. The numbers
such as influenza may shed and transmit virus before the host of parasites introduced and the specific parasite also affect the
can mount specific antiviral immune responses. Herpesvi- degree of physiologic change that occurs. When these fac-
ruses avoid detection during latency by not expressing any tors favor major alterations, the results are readily identifiable
viral proteins. Immunodeficiency viruses may cripple antivi- clinical signs of infection. Subclinical infections, although less
ral immune responses by directly infecting immunoregulatory apparent, are potentially important to the general health of the
CD4+ T lymphocytes. One of the most important mechanisms animal and continued transmission of the agent. The patho-
of immunologic avoidance is antigenic variation in which neu- physiologic effects of infection by ectoparasites, helminths, and
tralizing viral antigens are altered so that they are no longer microorganisms are in many cases similar.150,151 Abnormalities
recognized or accessible by host immune responses. Antigenic in weight gain, skeletal growth, reproduction, and lactation may
variation is generated by nucleotide errors during transcrip- result from infections with any of these agents. These changes
tion or replication, which result in amino acid substitutions are often directly related to parasite-induced anorexia, disrup-
in the relevant epitopes. Other mechanisms by which some tion of metabolic processes, and anemia. An understanding of
viruses may modify their antigenicity is through intramolecu- the morphologic and biochemical lesions produced by specific
lar recombination/duplication or reassortment of segmented parasites clarifies the role of these agents in clinical and sub-
genomes (e.g., influenza and African horse sickness).120,121 For clinical conditions associated with the infections. Most detailed
reassortment, coinfection of a single cell with genetically dif- studies of the pathophysiology of parasitic infections have been
ferent virions may result in a progeny virion with segments conducted in laboratory animal models and domestic animal
derived from both virions and a major change in antigenicity. species other than the horse.151 However, the classical pathol-
In influenza these are called antigenic shifts, and the radical ogy of parasitic infections of the horse has been reviewed.149,152
change in the antigenicity of the virus may render preexisting The following discussion outlines some recent observations on
immunity in the host population ineffective at preventing out- host-parasite interactions that may be of significance to equine
breaks of disease with high morbidity and mortality rates.121 medicine. Examples of host-parasite interactions responsible
Genetic differences in susceptibility to disease have been for alterations in host homeostasis are presented as they relate
well documented. In an outbred population of animals, the to the gastrointestinal tract, lungs, and skin.
considerable variation in the type or severity of clinical dis-
ease is well recognized, even when animals are infected with Y GASTROINTESTINAL TRACT
the same virus strain and have no recognizable differences
in other factors such as age, challenge dose, nutrition, and Internal parasites are most important to equine health as
general health status. Conversely, highly inbred populations mediators of gastrointestinal problems, including colic and
may be more uniformly susceptible to a viral disease.147 Thus diarrhea. Although almost all internal parasites have been
inbreeding can pose problems for endangered species, such as inferentially implicated as causative agents of colic at some
Przewalski’s horse, or other populations with limited genetic time, significant evidence-based experimental or field obser-
variability, which may incur high rates of morbidity or mortal- vations have emerged to support this contention for some
ity if the animals are infected with a virulent virus. Host genet- parasites. The helminth parasites include large strongyles,
ics may affect the tropism of the virus and influence the type principally Strongylus vulgaris, Parascaris spp., Anoplocephala
and intensity of immune responses to a viral infection. perfoliata, and as a group the cyathostomins.
The pathogenesis of colic associated with migration of
Strongylus vulgaris through the mesenteric arteries and the
resultant thrombosis, infarctions, and necrosis of the intes-
Pathogenesis of Parasitic Infections tine have been described in detail elsewhere.149,152,153 Large
strongyles are easily controlled with currently available mac-
rocyclic lactone anthelmintics and are rare in horses kept on
Horses serve as hosts for numerous parasites, which induce well-managed farms in developed countries. Histologic stud-
a wide range of pathologic and immunologic responses.148,149 ies of experimentally infected parasite-free pony foals dur-
Many of the latter are of a hypersensitive nature and also result ing the initial stages of infection indicate that the severity of
lesions produced in the intestine cannot be attributed solely ruptures and intussusceptions of the cecum and colon asso-
to mechanical disruption caused by larval migrations and that ciated with these infections.160,161 Several case-control studies
these larval stages induce some biologic amplification system have documented an association between colics in the ileal
within the mucosa, which results in the degree of inflamma- region and A. perfoliata infection.162 These parasites inhabit
tion observed.154 Although the mechanisms involved in this the region of the ileocecal junction and produce ulcerated
response have not been investigated, the histologic nature of lesions of the mucosa and submucosal inflammation. Detailed
the lesion is characteristic of an Arthus reaction, suggesting experimental investigations of these infections have not been
an involvement of the immune response. Other experimental conducted, and thus specific details on the pathogenesis and
studies using the parasite-free pony–S. vulgaris system have relevance of these lesions are lacking. An association between
implicated a role for the immune response in the mediation severity of observed lesions and tapeworm burden has been
and regulation of the arterial lesions produced by this para- observed.163,164
site. Passive transfer of immune serum but not normal serum Cyathostomins (cyathostomes or small strongyles) have
reduced the severity of arteritis seen and clinical signs asso- not generally been considered to be of major importance,
ciated with experimental infections without reducing the particularly as causative agents of colic. In this regard,
numbers of parasites that develop in these ponies.155 However, Uhlinger’s field studies are of particular importance.165,166 In
treatment with immune serum also induced an anamnestic these controlled experiments different anthelmintic treatment
eosinophilia and marked perivascular infiltration of eosino- regimens were used to test their efficacy in reducing the inci-
phils in the cecum. The reduction in intravascular lesions may dence of colic. The more efficacious treatment programs sig-
have been associated with an inactivation of parasite-secreted nificantly reduced the incidence of colic by 2 to 13 times that
inflammatory factors either by antibody or serum enzymes seen in the same herds before implementation of the more
or circulating cytokines. This serum may also have contained efficacious treatment. Because of the management programs
nonspecific host-derived antiinflammatory substances. The used before the initiation of this study and the results of fecal
exacerbation of the eosinophil response may have been asso- cultures, it can be assumed that the primary parasites pres-
ciated with the formation of immune complexes. Although the ent in these horses were cyathostomins. These data strongly
mechanisms are unknown, the results suggest that the immune implicate a role for cyathostomins in a substantial proportion
response may simultaneously modulate and potentiate inflam- of colics observed under field conditions. The parasite or host
mation. It has been postulated that larvicidal treatment of S. factors involved in these colic cases are unknown but may be
vulgaris–infected horses and killing of intravascular larvae the dynamic turnover of parasites during the life cycle in the
may release a bolus of antigenic factors from these larvae mucosa and the related inflammatory responses seen that they
within the mesenteric vasculature, resulting in an exacerba- induce.
tion of arterial and intestinal lesions and colic. Experimen- Cyathostomins have been implicated in numerous case
tal testing of this hypothesis indicates that this phenomenon reports with seasonal diarrhea in adult horses, which is a con-
does not occur and further that viable larvae are necessary to dition called larval cyathostominiasis. These cases are charac-
maintain the arteritis and eosinophilia seen.156 Experimental terized by a sudden onset of diarrhea during the late winter
studies using parasite-free ponies that were immunized with or spring. Horses younger than 5 years of age are particularly
crude adult worm antigens and subsequently challenged with at risk, but mature horses can be affected as well, and a case-
S. vulgaris larvae showed an exacerbation of the pathologic fatality rate of 50% has been reported.167 These are difficult
responses seen in the mesenteric vasculature and including to diagnose, and the only consistent signs are weight loss,
an anamnestic eosinophilia, further suggesting a role for the hypoproteinemia, and diarrhea.166 Large numbers of larval
immune response in the development of these lesions.157 cyathostomins can be found in the feces or in intestinal con-
Colic associated with Parascaris spp. infection in foals has tents and within the mucosa of these horses. These symptoms
been related to intestinal impaction and rupture and is not are related to the synchronous emergence of fourth-stage
considered to be of major significance in adult horses.158 These larvae of these parasites from the mucosa. These larvae build
conditions in foals may become more important with the to potentially large numbers within the mucosa owing to the
widespread identification of Parascaris spp. resistance to iver- arrested development of infective larvae. The seasonality of
mectin.159 However, ascarid nematodes are particularly potent the occurrence of this condition at present does not appear
sources of allergens, and it is not inconceivable that the hyper- to vary in different climatic regions as does the analogous
sensitized mature horse may respond to low-level infections bovine condition of type II ostertagiasis. Specific parasite or
with this parasite. Observations made in the author’s labora- host factors associated with the regulation of the hypobiotic
tory are noteworthy in this regard. Two mature Parascaris-free state of the larvae or the inflammatory response initiated at
adult horses were inoculated intradermally with less than 90 parasite emergence have not been described. Other clinical
μg of saline-soluble somatic extract of adult Parascaris spp. reports have suggested that cyathostomin-related diarrhea
to test for immediate hypersensitivity to this antigen. Both and weight loss are not related to the seasonal presentation
horses experienced an immediate systemic response and colic. described previously.168 This is supported by experimental
One of the horses died within 3 hours of intradermal inocula- studies demonstrating that pathophysiologic effects occur as
tion. Necropsy results were consistent with the diagnosis of large numbers of parasites enter the intestine, as well as when
acute severe colitis. Because of the allergic potential of ascarid they leave.169
nematodes and the sensitivity of the equine gut to immediate In view of the paucity of specific mechanistic information
hypersensitivity reactions, this potential is worthy of further on the pathophysiologic effects of equine gastrointestinal par-
characterization and consideration. asites, a synopsis of relevant information gathered from other
Clinical observations have maintained an interest and model systems is warranted, particularly for nematodes.151,170
concern over the pathogenic potential of Anoplocephala per- Parasitic organisms may induce changes in gastrointestinal
foliata infections. Earlier case reports have described cecal function directly by mechanical disruption of tissues and cells
or by the release of factors that directly alter cell function. Parascaris spp. larval migrations in the lungs of yearling
Induction of the immune response serves as an anamnestic horses produce more severe clinical signs and inflammatory
amplification system. The result of these changes is an altera- responses than in foals that are reared parasite free. These
tion in function of the smooth muscle and epithelium of the infections in yearlings are accompanied by focal accumula-
bowel. tions of lymphoid tissue, indicating an induction of an active
A number of helminth parasites, including Parascaris local immune response. It is suggested that this is an age-
spp., stimulate intestinal smooth muscle hyperplasia. This related phenomenon.178 However, it is likely that more severe
response may be induced by intestinal inflammation or ste- reactions could be the result of previous sensitization to Par-
nosis associated with parasitism. Contractility of these mus- ascaris spp. antigens. Increased responses of this nature have
cles can be induced in a Schultz-Dale reaction by stimulation been described in the livers of pigs immunized with Ascaris
with parasite antigens. This response is mediated in rats suum antigens following challenge infections.
by mast-cell–derived 5-hydroxytryptamine (5-HT) and in Dictyocalus arnfieldi infections of donkeys rarely produce
guinea pigs by histamine. A regulatory relationship of myen- clinical signs, and it has been suggested that these equids are
teric neurons to these antigen-induced changes has also the natural host for this parasite. Infections of horses produce a
been demonstrated in this model system. These latter experi- more severe and prolonged bronchial inflammatory response
ments suggest that antigen-induced stimulation of smooth similar to Dictyocalus sp. infection in other hosts. The mecha-
muscle contractility may be correspondingly blocked by nisms associated with this differential response have not been
γ-aminobutyric acid similarly stimulated by mast cell prod- defined but are not uncommon in unadapted host-parasite
ucts. This complex system may be an adaptation by the host associations. It is possible that the more marked inflammatory
to maintain homeostasis in the face of continued antigenic reaction of the horse to these parasites is due to the absence of
stimulus. It is noteworthy that strongyle-induced altera- downregulatory mechanisms that are established in the more
tions in myoelectric activity of the equine small intestine and adapted natural host, the donkey.
colon have been demonstrated in vivo.171,172 In some of these
experiments, dead S. vulgaris larvae evoked an alteration of Y SKIN
the smooth muscle response in previously exposed ponies,
suggesting a role for the immune response in the stimulation Whereas Onchocerca cervicalis infections in horses are rare
of the hyperactivity.173 where macrocyclic lactone anthelmintics are regularly used,
There is a rapidly growing literature on the host-parasite reactions to the filarial nematode illustrate variations seen in
interactions of a number of mouse models of gastrointestinal responses to chronic parasite infection. Focal, alopecic, depig-
nematode infections.174-177 The mouse models include infec- mented, pruritic lesions are often seen in infected horses. Not
tions of Trichinella spiralis, Nippostrongylus brasiliensis, Helig- all infected horses react to this infection, and the appearance
mosomoides polygyrus, and Trichuris muris. Because of the of clinical signs is often seasonal. Detailed studies have not
use of the mouse the most contemporary of immunologic, been conducted on the pathogenesis of these lesions in horses.
genetic, molecular, and cell biologic techniques are available However, similar conditions occur in human onchocercia-
and may provide useful insights into potential explanations of sis,179 and it is likely that the host-parasite responses active in
immunologic and pathophysiologic responses of the horse to humans are also present in the horse. Lesion development is
nematode parasites, particularly the cyathostomins. Although associated with immune-mediated killing of microfilariae in
differences in specifics exist among these murine models, it is the skin. Parasites appear to be killed in an antibody-depen-
clear that these worms induce a type 2 T-helper cell cytokine dent cell-mediated reaction. In this response antimicrofilar-
response consisting of interleukins (ILs) IL-4, IL-5, IL-9, and ial surface IgG and IgE antibodies mediated adherence and
IL-13. IL-4 and IL-13 induction of the Stat6 pathway is cen- degranulation of granulocytes, which are predominantly
tral to most of the resulting responses. There is a consistent eosinophils. Major basic protein of eosinophils has been dem-
mastocytosis and eosinophil infiltration of the intestine. The onstrated in the tissues of patients with dermal lesions, and
resulting responses also involve goblet cells, the enteric ner- it has been suggested that eosinophil toxic enzymes and pro-
vous system, epithelial cells, and alternately activated macro- teins are responsible for many of the changes seen. The rea-
phages as effector cells. Cell junctions are disrupted, smooth son for the absence of these lesions in most horses is unclear.
muscle hypercontractility is stimulated, epithelial cell secre- Human onchocerciasis and filariasis are spectral diseases.
tion increased, and goblet cell production of mucus is stim- In these diseases regulation of immune responses has been
ulated. Although these mechanisms are used most often to associated with the lack of pathologic responses to the para-
explain expulsion of the nematodes in question, they could be sites.180,181 Immune regulatory mechanisms associated with
equally important in the disruption of the homeostasis seen in these infections include immune tolerance, anergy, induction
the parasitized equine intestine. of immune regulation involving Treg cells or macrophages,
and the production of IL-10 and transforming growth factor
Y RESPIRATORY SYSTEM beta (TGF-β)–altering Th-cell subsets and the production of
specific cytokines during different phases of the infections.
Several nematode parasites infect the equine lung. These Recent studies have also focused on the role of an intracellular
include migrating stages of Strongyloides westeri and Paras- commensal microorganism, Wolbachia, which is a parasite of
caris spp. en route to the small intestine. Migrating stages of Onchocerca and other filarial nematodes. These bacteria have
aberrant parasites, such as Habronema sp., Draschia megas- been shown to mediate type 1 inflammatory lesions in humans
toma, and Strongylus spp., which induce granulomatous foci in and mouse models.180
the lung parenchyma, and adults and larvae of the lungworm The presence of these types of parasite-associated immune
Dictyocalus arnfieldi, which inhabit the bronchi, also occur. regulatory events has yet to be critically studied in the horse.
Host responses to two of these are noted. However, the seasonal variability in skin responses to the
Onchocerca microfilariae by horses in some regions has been the migrating L3, which is effective in preventing reestablish-
investigated. In this instance the onset of ventral-midline der- ment of the intestinal infection but is ineffective against L3,
matitis during the summer may be related to a seasonal fluc- which are sequestered in the abdominal fat of the sow.184 Simi-
tuation in microfilarial burdens of the skin, which have been lar epidemiologic phenomena occur in S. westeri infection of
demonstrated to correspondingly peak at this time.182 Not only horses, and it may be implied that similar immunologic mech-
do total numbers increase, but microfilariae are also found anisms are also active.
more commonly in the surface layers of the skin. Interestingly, Immunologic mechanisms associated with protective resis-
this period of abundant microfilariae corresponds with the tance are presented primarily as they relate to parasites that
seasonal peak in numbers of the vector, Culicoides varripennis. inhabit the lumen of the gastrointestinal tract and secondarily
Although speculative, correlations in the peak availability of as those that undergo extraintestinal tissue migration.
microfilariae and vectors may be an evolutionary adaptation Immune responses directed toward gastrointestinal nema-
by these parasites to maximize transmission and survival of todes vary significantly among hosts and against different para-
this parasite species. site species within a given host. However, some generalities may
serve as a background for understanding these responses in the
Y PROTECTIVE RESISTANCE horse. A phenomenon termed self-cure has been described in
sheep, in which the ingestion of significant numbers of infec-
Resistance to infection may be innate or acquired. In some tive larvae induces the expulsion of existing adult parasites.
instances innate resistance to equine parasites has been attrib- This expulsion is initiated by a species-specific immediate-type
uted to age, with older individuals being resistant. Most equine hypersensitivity response that may cause the nonspecific expul-
helminth parasites develop only in the horse, and conversely sion of other nematode species. Although this phenomenon
the horse exhibits an innate resistance to most nonequine has not been examined in the horse, experimental infections of
parasites. Exceptions to this rule are parasites with a broader naturally parasitized ponies with large numbers of S. vulgaris
host range that occasionally infect horses, such as larvae of the L3 induced a dramatic decrease in preexisting strongyle fecal
tapeworm Echinococcus granulosus and the liver fluke Fasciola egg counts, suggesting that a self-cure–like reaction may occur
hepatica. Trichostrongylus axei, a parasite of ruminants, estab- under some conditions.
lishes readily in the equine stomach and produces significant More typically, establishment of primary infections results
lesions only when present in large numbers. In some cases at some time in spontaneous expulsions of these worms as a
parasites that develop in the horse induce more severe lesions result either of senility or, as demonstrated in laboratory ani-
and clinical signs than in their apparent normal host, as has mal model systems, of active acquired immune responses.
been described for D. arnfieldi. This phenomenon occurs experimentally in the absence of
Age resistance to Parascaris spp. and S. vulgaris has been reinfection and is thus separate from the self-cure phenom-
described in horses by comparing susceptibility of young and enon. A large number of immune effectors have been iden-
old ponies reared under parasite-free conditions. It is apparent tified with this phenomenon in various model systems, and
that the reaction of the lung to migrating Parascaris larvae is it is likely that some if not all are at some time active in the
more marked in mature horses and suggests that an immune equine intestine. The mechanisms involved are T-cell depen-
response occurs in this site.160,161 Initial reports on age-acquired dent. Antibodies may be involved but are not sufficient in
resistance to S. vulgaris infection183 have not been substanti- themselves to induce expulsion. T-cell–mediated mastocy-
ated, and experimental observations in our laboratory indicate tosis, eosinophilia, and goblet cell hyperplasia have all been
that this does not occur. demonstrated to be related to expression of expulsion in some
The occurrence of acquired resistance to equine parasites systems. These accessory cells are involved in the nonspecific
can be inferred from the observation that older chronically efferent arm of this response. Mediators of inflammation, such
exposed horses generally have lower burdens of parasites than as vasoactive amines, prostaglandins, and increased produc-
do similarly exposed young horses. On the basis of these cri- tion of mucus, have been linked to immune elimination of
teria, acquired resistance is apparent to infections of S. westeri, primary infections in some but not all model systems. The
Parascaris spp., Strongylus spp., and cyathostomin species. increased secretion and hyperreactivity of intestinal smooth
Extensive experiments are limited, however, to those on S. muscle associated with worm expulsion have been termed
vulgaris and to some degree cyathostomins. weep and sweep phenomena. It is likely that a number of spe-
Although S. vulgaris has been largely eliminated from well- cific immunologic events initiate several nonspecific effector
managed horse farms, examination of details of the immune mechanisms, resulting in this expulsion. These mechanisms
response to it illustrates some equine immune mechanisms. vary with the species of parasite involved. The elimination of
Resistance that is acquired to S. vulgaris in most cases is partial adult S. westeri and Parascaris spp. from maturing horses and
and of a concomitant type; that is, some stages of the para- the hypothetical seasonal turnover in Strongylus spp. and cya-
site, such as arterial larvae of S. vulgaris, may reside within the thostomin spp. may be mediated by such responses.
horse in the face of an active acquired resistance against newly In addition to immune responses that occur during tissue
acquired infective stages. migrations, protective resistance to reinfection by gastroin-
Resistance to infection with S. westeri adult parasites is testinal nematodes occurs at the surface of the epithelium.
inferred by the short duration of their life cycle within the This reaction, termed rapid expulsion or immune exclusion,
small intestine and the failure of subsequent exposures to is separate from self-cure or immune expulsion of primary
establish patent infections. Mares, however, remain infected infection. Infective larvae are expelled from the intestine in
with arrested third-stage larvae, which subsequent to foaling a matter of hours. Again, mechanisms of expulsion described
are transmitted to the foals in milk starting at 4 days postpar- vary between parasite and host species. However, anaphy-
tum. Similar phenomena occur in swine strongyloidosis. In lactic reactions and mucus entrapment have been observed.
these infections there is apparent protective resistance against Some experiments using the T. spiralis–rat system suggest
that alterations in the epithelial cells in immune animals are eosinophils are essential in this protective immune response,
directly involved in the exclusion of these parasites. Although an anamnestic eosinophilia is characteristic in immune ponies
immune-mediated damage of intestinal helminths such as but not nonimmune ponies following experimental S. vul-
decreased fecundity, reduced size, and morphologic alterations garis challenge.157 Because of its prominence and compelling
have been noted, infective larvae expelled by rapid expulsion in vitro and correlative in vivo data, the eosinophil is consid-
mechanisms remain viable and undamaged. It may be specu- ered a major effector in immune-mediated helminth killing.
lated that reactions of this nature are responsible, in part, for However, recent studies in murine parasite model systems in
resistance to reinfection of equines with cyathostomins. which eosinophilia was blocked by anti–IL-5 treatment sug-
Some specific observations have been made on the equine gest that this type of cell is not essential for protective resis-
acquisition of resistance to reinfection with cyathostomins.185 tance in some systems.190 Significant increases in equine IL-5
This resistance is acquired over time with continued exposure have been measured in ponies vaccinated against S. vulgaris.
to pasture L3; is incomplete; and, like other parasitic helminth It is possible, in vivo, that a number of cells function as effec-
infections, appears to be genetically regulated in that parasite tors and may overcome the absence of sufficient eosinophils
numbers are overdispersed within a given herd of adult ani- under some circumstances. Antibody reactivity with parasite-
mals. The limited number of experimental and field studies secreted enzymes and molting fluids, factors important in
completed to date suggests that immunity may be directed parasite homeostasis, has been demonstrated in vitro; similar
toward all stages of the parasite life cycle. Challenge infections reactions may be important in vivo.
of previously exposed and naive ponies with mixed strongyle T-cell responses are essential for the induction of protec-
infections indicate that a nonspecific self-cure–like phenom- tive resistance to tissue-migrating helminths in most systems
enon occurs, reducing numbers of adult and fourth-stage lar- studied, including the experimental S. vulgaris pony model.
vae (L4) in the lumen as well as within the mucosa.157 Fecal This dependency is likely due to the T-cell dependency of the
egg counts are significantly reduced in older animals com- antibody response and to the mediation of secondary effec-
pared with yearlings even when adult parasite numbers are tor cell responses. It is likely that antigenic substances secreted
similar. These observations suggest that immune responses or excreted (ES) by migrating nematodes are important in the
are directed at female fecundity or that the species of cyathos- induction of these responses. It is probable that a combina-
tomins present in the older animals are inherently less fecund. tion of immune responses elicited by a combination of specific
Numbers of early L3 (EL3) are reduced following challenge parasite antigens, including surface antigens and ES products,
infections of previously exposed adult ponies compared with is necessary to induce an immune response sufficient to pro-
previously exposed young animals or age-matched naive con- vide protective resistance.
trols.186 Other studies have suggested that acquired resistance
is important in the induction of hypobiosis.169,187 Resistance
to acquisition of EL3 was not seen when numbers were com- Y PARASITE-INDUCED REGULATORY
pared in young previously exposed and age-matched ponies RESPONSES
raised under parasite-free conditions. However, these previ-
ously exposed young animals demonstrated significantly fewer Helminth parasites have evolved elaborate mechanisms
developing larvae (DL) in the mucosa, suggesting that once to evade the host’s immune responses, live in the face of
the EL3 began to develop, they were susceptible to immune an active specific host response, and yet establish chronic
attack.186 This response is likely driven by cytokines produced infections. These immune evasion strategies include the
by T cells of the Th2 lineage with demonstrated increases in production and secretion of molecules such as proteases,
IL-4 and IL-5. This response mimics in some ways the results protease inhibitors, antioxidants, prostaglandins, and
described in studies of murine nematodes.177 phosphorylcholine-antigens, which disrupt host effector
A number of intestinal helminths, as well as others, migrate responses.191,192 Other molecules that mimic host immune
through extraintestinal tissues as part of their life cycle. regulatory factors, such as TGF-β and (macrophage migra-
These include parasites such as Parascaris spp., S. westeri, and tion inhibitory factor) MIF, have also been identified in
Strongylus spp., all of which stimulate an acquired immune parasitic helminth genomes.191 These mimics likely down-
response in the horse. During this migration these larvae regulate host-parasite–directed protective response and
are vulnerable to attack by immune effectors that may either add to immune evasion.
encapsulate them in an immune-mediated inflammatory Helminth parasites can induce a regulatory immune
response, disrupt their migrations by interfering with impor- response, which promotes their survival but also has bystander
tant metabolic or invasive processes, or inhibit molting from effects on host responses to other infectious agents, vaccines,
the L3 to L4 stages. The most studied phenomenon in this allergic responses, and autoimmune diseases. These observa-
regard is antibody-mediated adherence of inflammatory cells, tions have progressed to the point that helminth therapy is
which may result in killing of the larvae. This phenomenon being developed for the treatment of human inflammatory
involves many cell types and immunoglobulin isotypes in bowel disease and ulcerative colitis.193,194 In this situation
different host-parasite systems. In vitro studies of this nature infection with the swine whipworm T. suis impedes the regu-
have been conducted using S. vulgaris third-stage larvae and lation of type 1 inflammatory responses responsible for these
equine immune effectors.188 In these experiments an antibody- conditions and reduces disease activity. The generally accepted
dependent adherence of cells was demonstrated and shown to and simple model that has emerged for this type of helminth-
be parasite species specific. In vitro killing was mediated by induced regulation is that parasite factors stimulate dendritic
eosinophils and not by neutrophils or monocytes. Activated cells that activate regulatory T cells and alternately activated
eosinophils were necessary to mediate this response, and S. macrophages. These cells, through the production of TGF-β
vulgaris infections have been demonstrated to activate eosino- and IL-10, may suppress both Th1- and Th2-mediated inflam-
phils and neutrophils in vivo.189 Although it is not certain that matory responses.195-197
Detailed studies of the effects of equine helminths on the infectious diseases, and an important one is pneumonia
regulation of parasite-induced responses or to heterologous caused by Rhodococcus equi. Entry into the host can occur
immunogens have not been reported. The effects of dif- by ingestion, inhalation, or penetration through epithe-
ferent levels of gastrointestinal helminth infection on the lial barriers such as the skin or mucosal surfaces. Regard-
response of ponies to keyhole limpet hemocyanin immu- ing the entry of organisms, inoculum size is a key factor in
nization was measured.198 Antibody levels determined by determining whether or not disease will develop. Follow-
enzyme-linked immunosorbent assay showed that animals ing entry, microorganisms must spread from the entry site
with low levels of parasites had a trend toward increased to local tissues or disseminate to distant sites in the body.
KLH-specific total immunoglobulin, IgG(T), and IgA Bacteria such as Staphylococcus aureus produce enzymes
compared with heavily parasitized ponies. Moderately and such coagulase, protease, and hyaluronidase that facilitate
heavily parasitized ponies demonstrated a trend toward their ability to spread through tissues and cause disease.
reduced lymphoproliferative response to KLH that was not Substances produced by microorganisms that enhance their
restored after the addition of IL-2. Cells from these ponies ability to cause disease, as well as microbial structures that
also produced significantly lower levels of IL-4 compared do the same, are collectively referred to as virulence factors.
with lightly parasitized ponies. These data indicate that The next step in the development of disease is replication of
heavily parasitized animals have uniformly decreased cel- the infectious agent to levels that result in clinical signs. This
lular and humoral immune responses to soluble protein period of replication before the development of clinically
immunization. The mechanisms involved are unknown. A apparent disease comprises the incubation period. Micro-
recent study evaluated the inflammatory and immunologic organisms that cause disease by producing toxins, such as
response to three different antigens given simultaneously botulinum toxin produced by Clostridium botulinum, are an
to ponies concurrently dewormed with either ivermec- exception to this rule. Disease in the host ensues when the
tin or pyrantel pamoate or kept as untreated control. This infection results in tissue damage. There are many ways in
study found no difference in cytokine expression, acute- which damage can occur. Cell death caused by replication of
phase inflammatory markers, or antigen-specific antibody the agent, extracellular toxins produced by the agent, and,
titers between the anthelmintic treatment groups.199 Taken importantly, the host’s inflammatory and adaptive immune
together, the possible interaction between resident intesti- responses directed against the agent all result in tissue
nal nematodes and responses to vaccination in horses is in damage and disease. The systemic inflammatory response
need of further investigation. elicited by endotoxin during gram-negative bacterial infec-
tions is an excellent example of host-mediated damage. The
final outcome depends on the interplay between infectious
agent factors and host factors, which include the inoculum
Infection and Immunity size and virulence of the agent, as well as the immune sta-
Robert H. Mealey tus of the host. The host may mount a successful immune
response and clear the organism, as occurs with equine
influenza virus infection, or the immune response may
Y BASIC PRINCIPLES OF INFECTIOUS control replication of the agent such that disease resolves
DISEASE but the agent is not eliminated. This results in persistent
inapparent infection as occurs with equine infectious ane-
Equine clinicians devote tremendous effort to the preven- mia virus infection. Finally, highly virulent agents such as
tion, diagnosis, and treatment of infectious diseases. Detailed rabies virus and Hendra virus will kill the host, whereas less
and current information on specific infectious diseases in the pathogenic agents may kill hosts that are immunocompro-
context of organ systems is provided elsewhere in this book, mised in some way.
and in-depth discussions of infectious diseases of horses are Successful pathogens have developed efficient mechanisms
provided in a recent text200 and review.201 The field of equine for entry, spread, and replication, all of which enhance their
infectious disease research is growing rapidly, and modern ability to cause disease. Importantly, each one of these steps
genomics techniques such as massively parallel deep sequenc- requires breaching or avoiding host defense mechanisms,
ing have enabled the recent discovery of previously unknown which include physical barriers, innate immune responses, and
equine pathogens and potential pathogens.202,203 In addition, adaptive immune responses. These same immune responses
continued application of proteomics approaches204 will lead to ultimately control most infectious agents but also participate
a better understanding of infectious disease pathogenesis and in the pathogenesis of disease. Thus understanding how infec-
the discovery of novel vaccine and therapeutic targets, as well tious diseases develop and how they are controlled requires a
as improved diagnostics. fundamental knowledge of immunology, which is the primary
On a more basic level, the following events occur in all focus of this chapter.
infectious diseases: encounter, entry, spread, multiplication,
damage, and outcome.205 Encounter occurs when the host Y EQUINE IMMUNOLOGY
comes into contact with an infectious agent. The encounter
is endogenous when infections are caused by normal micro- Although our modern understanding of the immune sys-
bial flora. An example is pneumonia caused by Streptococcus tem is primarily based on humans and rodent models, the
zooepidemicus, a member of the normal flora of the equine horse has contributed significantly to our understanding of
nasopharynx. Exogenously acquired infections result from many immunologic processes. These contributions include
encounter with an infectious agent in the environment the earliest work on serotherapy and passive transfer of
or an agent transmitted from other animals or via insect antibodies, antibody structure and function, immunity to
or tick vectors. There are many examples of exogenous infectious agents, immunodeficiencies, and reproductive
immunology.206 Work in the horse continues in many of Proinflammatory Cytokines,

these areas from the standpoint of equine medicine and Acute Phase Proteins,
comparative immunology. With some exceptions, the over- and Complement
all organization and function of the equine immune sys-
tem is similar to other mammalian species. A number of After physical barriers have been breached, the innate immune
texts provide excellent in-depth reviews of basic and clini- system provides a variety of internal defenses to contain and
cal immunology, and much of the general information pro- eliminate the invading organisms. Inflammatory responses are
vided in this chapter is drawn from these resources.207-210 initiated either via the activation of plasma protease systems
This chapter will focus on aspects of the immune sys- directly, such as by bacterial cell wall components, or by the
tem that may be of most interest to equine clinicians and secretion of toxins or other proteins that can directly activate
researchers, with pertinent references to equine work pro- the inflammatory response.217 The cell walls and membranes
vided when possible. of bacteria contain various proteins and polysaccharides with
characteristic, often repeating, molecular structures. These
pathogen-associated molecular patterns (PAMPs) include
Innate Immunity and the Acute lipopolysaccharides (LPSs), peptidoglycans, lipoteichoic acid,
Inflammatory Response and flagellins.218 Other PAMPs include viral nucleic acids
Immune defenses include both innate responses and adap- and unmethylated bacterial cytosine-guanosine dinucleotides
tive responses, each mediated by cellular and soluble com- (CpG). PAMPs are recognized by pattern recognition receptors
ponents. Although fundamentally different, the innate and found on cells of the immune system, particularly those cells
adaptive immune systems are intimately related and share involved in the initial encounter with invading microbes. These
many of the same processes and components. Innate immu- “sentinel cells” include macrophages, dendritic cells, and mast
nity is rapid, is nonspecific, results in acute inflammation, cells, with macrophages being the most important for initiating
and has no memory. In contrast, adaptive immunity takes the inflammatory response. Pattern recognition receptors are
time to develop, is antigen specific, and has recall capability. located on the cell surface, as well as intracellularly, and include
It is both the specificity of adaptive responses and the capac- toll-like receptors (TLRs), retinoic acid–inducible gene–1
ity for immunologic memory that allow complete protection (RIG-1)–like receptors, and nucleotide-binding oligomeriza-
against a particular pathogen. However, innate responses tion domain–like receptors. The TLRs are particularly impor-
play key roles in both triggering the adaptive response and tant in the induction of inflammation. In addition, binding of
providing valuable time for specific adaptive responses to PAMPs leads to intracellular signaling events culminating in
develop. the expression of costimulatory signals for the developing adap-
The horse, like every other species, is under constant tive immune response. Injured cells release products collec-
assault from a variety of microbes that share its living space. tively termed damage-associated molecular patterns (DAMPs)
Although most of these organisms are thought to be harmless, that bind TLRs on macrophages and other cells leading to the
their disease-causing potential is evident when they cause production of proinflammatory cytokines that augment the
opportunistic infections in individuals with compromised inflammatory process. Resident macrophages that encounter
immune systems. In general, mammals have evolved a variety the invader initiate the inflammatory response through the
of defensive measures to prevent infections from occurring. production of proinflammatory cytokines such as interleu-
The first line of defense includes the physical barriers pro- kin-1 (IL-1), IL-6, and tumor necrosis factor–alpha (TNF-α).217
vided by the skin and the mucosal surfaces of the digestive, Cytokines are hormone-like proteins that mediate a variety of
respiratory, and urogenital tracts. In addition to providing a cellular responses. A vast number of cytokines are involved in
barrier to penetration, the surface of the skin contains vari- the regulation of innate and adaptive immune responses. IL-1,
ous enzymes, fatty acids, and oils that inhibit the growth of for example, is a pleiotropic mediator of the host response to
bacteria, fungi, and viruses. Mucous membranes and mucosal infections and tissue injury (Table 1.3). Many of the effects of
secretions contain bacteriolytic enzymes, bactericidal basic IL-1 are mediated through its capacity to increase the produc-
polypeptides, mucopolysaccharides, and antibodies that pre- tion of other cytokines, such as granulocyte colony-stimulating
vent colonization and penetration of these surfaces. Mucus factor (G-CSF), TNF-α, IL-6, and platelet-derived growth fac-
also provides a physical barrier that entraps invading organ- tor (PDGF). IL-6 is responsible for the increased production
isms and leads to their eventual disposal.211 Particles trapped of acute phase proteins by hepatocytes, including complement
in the mucus secretions of the respiratory tract, for example, proteins, C-reactive protein, and serum amyloid A (SAA).
are transported upward through the action of ciliary cells to
the trachea where they are swallowed.212 Once swallowed, TABLE 1.3 Biologic Activities of Interleukin-1
the acidic secretions and digestive enzymes of the stomach
destroy most organisms. Normal epithelial and tissue archi- Activates T cells Induces fever
tecture is essential for successful exclusion of bacteria, and Activates B cells Cytotoxic for some tumor cells
the disruption of this mechanism makes the host susceptible Enhances NK cell killing Cytostatic for other tumor cells
to infection by bacteria that normally colonize the upper Fibroblast growth factor Stimulates collagen production
airway.213,214 The protective role of gastric acidity against
Stimulates PGE synthesis Stimulates keratinocyte growth
gastrointestinal pathogens is supported by the observation
that acid-suppressive drugs increase the risk of diarrhea in Stimulates bone resorption Stimulates mesangial cell
neonatal foals treated in intensive care units.215 In humans, growth
administration of proton pump inhibitors in critically ill Chemotactic for neutrophils Activates neutrophils
patients increases the risk of Clostridium difficile–associated Activates osteoclasts Induces IL-6 production
diarrhea.216
Many of these proteins and the cytokines that elicited them are bound to the surface of a microbe. Bound C1q is proteolytic
responsible for the characteristic physical signs of inflamma- and cleaves other complement components activating the
tion, including increased blood flow and vascular permeability, pathway. The activation of complement via the alternate path-
migration of leukocytes from the peripheral blood into the tis- way does not involve antibodies. Instead, certain microbial
sues, accumulation of leukocytes at the inflammatory focus, and products stimulate the association of factor D, a proteolytic
activation of leukocytes to destroy any invading organisms.219 enzyme, with the complex of factor B and C3b leading to the
During viral infections, intracellular pattern recogni- formation of C3 convertase and its deposition on the micro-
tion receptors (such as RIG-1) bind to viral PAMPs (such as bial surface. All three pathways converge with the generation
double-stranded viral ribonucleic acid [RNA]) and induce the of C3 convertase and the cleavage of C3. Soluble C3a, pro-
production of type I interferons (IFNs), including IFN-α and duced by the cleavage of C3 by the C3 convertases, can bind
IFN-β. These are produced in virus-infected cells within hours to mast cells causing them to degranulate and is thus referred
and inhibit viral replication through various mechanisms. In to as an anaphylatoxin, as is C4a. C3b serves as an opsonin for
addition, natural killer (NK) cells are capable of lysing virus- C3b receptor-bearing phagocytic cells. C3b is also required for
infected cells via recognition of different types of receptors the formation of the membrane attack complex by the termi-
on the surface of infected cells, as well as recognizing cells nal complement components, C5 through C9. In this process
expressing fewer major histocompatibility complex molecules C5 is cleaved and C5a is generated, which, along with C3a, is a
(see later discussion), the expression of which can be down- chemoattractive factor for neutrophils and monocytes.221 C5b
regulated by viral infection. Finally, NK cells have surface Fc forms a complex with C6, C7, and C8 on cell surfaces. This
receptors (see later discussion) that can bind the Fc portion leads to the insertion and polymerization of C9 that forms a
of antibodies bound to the surface of infected cells and subse- pore in the membrane leading to cell lysis. A summary of the
quently kill the infected cell through the process of antibody- three complement pathways and the resultant effector mecha-
dependent cellular cytotoxicity. NK cells are of the lymphocyte nisms of microbial destruction is provided in Fig. 1.6.
lineage but do not possess antigen-specific receptors such as Lipid Mediators. Prostanoids are lipid mediators that regu-
T and B lymphocytes (discussed later) and thus act as innate late the inflammatory response.222,223 The prostanoids include
effector cells. the prostaglandins (PGs), leukotrienes (LTs), and prostacyclin
The complement system consists of over 30 different (PGI2), and they are the product of cyclooxygenase cleavage
plasma proteins that are produced primarily in the liver. This of arachidonic acid followed by endoperoxidation. The major
complex interacting series of proteases and their substrates sources of prostanoids in acute inflammation are the phago-
results in the production of physiologically active interme- cytes, endothelial cells, and platelets. Although prostanoids, in
diaries that can damage membranes, attract neutrophils and general, mediate the cardinal effects of pain, fever, and edema
other cells, increase blood flow and vascular permeability, and characteristic of the acute inflammatory response, their par-
opsonize bacteria and other particles for phagocytosis.220 The ticular roles are somewhat confounding and can be either pro-
complement cascade can be activated in three ways. The lectin inflammatory or antiinflammatory.224 Prostanoid production
pathway is initiated when soluble carbohydrate-binding pro- depends on the activity of the two isoforms of the cyclooxy-
teins (such as mannose-binding lectin) bind to carbohydrate genase (COX) enzymes within cells: COX-1, which is present
structures on microbial surfaces. Proteases associated with in most cells and its expression is generally constitutive, and
these carbohydrate binding lectins then initiate the cleavage of COX-2, for which expression is low or undetectable in most
complement components and activate the pathway. The classi- cells but its expression increases dramatically on stimulation,
cal pathway involves the binding of C1q to antibodies already particularly in cells of the immune system. Increased COX-
Lectin Pathway Classical Pathway Alternate Pathway

Lectins bind carbohydrates C1q binds antibody bound C3 convertase deposited
on microbial surface to microbial surface directly on microbial surface
Generation of C3 Convertase
C3 is cleaved, leaving C3b bound
to microbial surfaces and
releasing soluble C3a
Chemotaxis Opsonization Microbial Lysis

Soluble C3a and C5a recruit Phagocytic cells with C3b Assembly of components C5-C9
phagocytic cells to site of receptors engulf and destroy on the microbial surface leads to
infection and promote microbes with surface-bound formation of the membrane attack
inflammation C3b complex and lysis of the microbe
FIG. 1.6 Simplified pathways of complement activation and basic effector mechanisms of microbial de-
struction. See text for explanation.
2 expression by inflammatory stimuli likely accounts for the ous chemotactic factors by host cells, bacteria, and other in-
high levels of prostanoids found in inflammatory lesions and vaders causes various leukocytes to enter the circulation and
is the basis for the development of COX-2–selective nonsteroi- be carried to the site of the injury.238 Chemokines are chemo-
dal antiinflammatory drugs (NSAIDs).225 Because there are tactic cytokines. These are soluble proteins produced by host
species differences in the pharmacokinetics and COX selec- cells that induce the directional migration and activation of
tivity of NSAIDs, extrapolation of studies performed in other leukocytes, as well as other somatic cell types, and thus play
species should be interpreted with caution with respect to the major roles in the inflammatory response.239 The chemokine
potential COX selectivity and efficacy in the horse.226 Meloxi- CXCL8 (previously known as IL-8) plays a central role in the
cam has COX-2 selectivity and efficacy in the horse227-229 but migration of neutrophils, including equine neutrophils.240,241
at the time of this writing is not approved in the United States Other chemokines promote humoral and cell-mediated im-
for use in horses (but is approved in Europe). Firocoxib is a mune reactions; regulate cell adhesion, angiogenesis, leuko-
selective equine COX-2 inhibitor with documented safety and cyte trafficking, and homing; and contribute to lymphopoiesis
efficacy,210-236 and it is currently the only COX-2–selective in- and hematopoiesis.242
hibitor approved by the Food and Drug Administration for The specific trafficking of leukocytes from the blood to
use in horses in the United States. inflammatory sites is dependent on both the production of
Both COX isoforms produce PGH2, which is the common chemotactic factors and the interaction of specific receptors
substrate for a series of specific synthase enzymes that pro- on the leukocytes with corresponding adhesion molecules on
duce PGD2, PGE2, PGF2, PGI2, and TXA2. It is the differen- the endothelial surface of the blood vessels. Neutrophil adher-
tial expression of these enzymes within cells present at sites of ence is a two-step process first involving endothelial cell sur-
inflammation that determines the profile of prostanoid pro- face molecules known as selectins. Small venular endothelium
duction. Likewise, the biologic effect of a prostanoid depends overlying a site of inflammation and exposed to leukotrienes,
on binding to G protein–coupled cell surface receptors. platelet activating factor (PAF), IL-1, complement protein
Many cells of the immune system express multiple receptors C5a, histamine, LPSs, TNF-α, or other mediators released
that couple to apparently opposing pathways. The impact of by clotting, platelet activation, or mast-cell activation express
prostanoids present during an inflammatory response is thus P-selectin. P-selectin mediates the process in which neutro-
determined by the array of receptors the cells express and the phils initially interact with the endothelial surface in a pro-
intracellular pathways to which they are coupled. Activation cess known as “rolling” in which the circulating neutrophil
of these receptors, even when coupled to similar pathways, interacts with the endothelial cell before the actual adher-
might evoke different responses because of differences in the ence. P-selectin appears on the endothelial cell surface within
levels of expression (both constitutive and induced) or in the minutes of an inflammatory stimulus, followed by E-selectin
patterns of desensitization. The role of prostanoids in a given expression within a few hours. Endothelial selectins function
inflammatory response depends not only on the presence of by binding to carbohydrate ligands present on the leukocyte
the lipid mediators in the lesion but also the receptor profile surface. In the case of neutrophils, the ligand is sialyl-Lew-
on immune cells and the biochemical signaling pathways of isX, an oligosaccharide present on cell surface glycoproteins.
these receptors.237 Thus PGE2 is considered proinflammatory Equine P-selectin binds the sialyl-LewisX moiety on equine
because it promotes vasodilation by activating receptors on leukocytes, mediating adhesion and stimulating the produc-
vascular smooth muscle and increases vascular permeability tion of CXCL8.243 The second part of the adherence process
indirectly by enhancing the release of histamine and other is the tight binding of integrins on the neutrophil surface to
mediators from tissue leukocytes such as mast cells. PGE2 is intracellular adhesion molecules on the endothelial cell sur-
also the prostanoid responsible for fever production. However, face. Leukocyte integrins are heterodimeric proteins and
as inflammation progresses, PGE2 synthesis by macrophages include leukocyte functional antigen–1 (LFA-1, also called
is enhanced as a result of increased expression of COX-2 and CD11a:Cd18) and complement receptor type 3 (CR3, also
PGE-synthase, and the resulting increased levels of PGE2 called CD11b:Cd18). Neutrophils can be activated by a num-
inhibit leukocyte activation, inhibit mast cell degranulation, ber of soluble proteins present in bacterial but not eukaryotic
and relax smooth muscle contractions. In the lung, PGE2 pro- proteins. Host factors present at the site of inflammation can
motes bronchodilation. Thus in these situations PGE2 may be also activate neutrophils. These include complement proteins
considered antiinflammatory. (C5a, C3a), the chemokine CXCL8, cytokines (especially TNF-
Chemotaxis and Leukocyte Trafficking. One of the initial α), and immune complexes.244 Expression of integrins by the
and most crucial aspects of the acute inflammatory response activated neutrophil allows them to become tethered to the
is the recruitment of leukocytes (primarily neutrophils) to the endothelial surface. The migration of neutrophils through the
site of injury. Neutrophils constitute the first line of the cel- vascular wall is less well understood than these initial events
lular defense and are the initial cells involved in an inflam- leading to firm adhesion. Integrins LFA-1 and CR3, as well as
matory response. These phagocytic cells are derived from PECAM-1 (CD31), another cell adhesion molecule, appear to
multipotent stem cells located chiefly in the bone marrow. play a role in this process. Endothelial cell–produced CXCL8
Under the influence of a variety of signals provided from both also has a critical role in this process. Once through the endo-
within and outside of the bone marrow, these stem cells be- thelium, the phagocytes will follow chemotactic signals and
come committed to developing into cells of the granulocyte migrate toward the point of injury. They may adhere to other
lineage. The critical signal is provided by a family of growth cells during migration to the site of inflammation, and these
factors known as colony-stimulating factors (CSFs) that pro- interactions also are dependent on integrins.
vide both proliferative and differentiating signals leading to Neutrophils recruited and activated in this manner will
the development of granulocytes and other leukocytes. Once actively phagocytose microscopic invaders and attempt
released into the circulation these cells must find their way to to destroy them using reactive oxygen products gener-
the site of the inflammatory response. The production of vari- ated via a nicotinamide adenine dinucleotide phosphate
(NADPH)-oxidase–dependent respiratory burst. During Adaptive Immunity

this process, neutrophils release additional proinflammatory The adaptive immune response is initiated in response to
mediators, thus amplifying the response. Among those cells the encounter with a foreign agent and depends on antigen-
attracted to the area are NK cells, and the production of IFN- specific immune responses mediated by different divisions
α or IFN-β by macrophages and other cells enhances NK cell of the lymphocyte family (Fig. 1.7). In contrast to the non-
cytolytic activity. The NK cells themselves can be a source specific nature of the innate immune response, an important
of IFN-γ, another proinflammatory cytokine (discussed in characteristic of the adaptive immune response is the speci-
detail later). Depending on the magnitude of the initial insult ficity of this interaction. Thus exposure of the host to a par-
and the susceptibility of the invader to neutrophil-mediated ticular microbe or parasite results in the induction of immune
destruction, the inflammatory response may be either acute responses that are directed against specific components of the
or chronic. invading organism that do not affect unrelated organisms. The
Acute inflammation is thus a rapid response to an injury that specificity of the adaptive immune response is the result of the
is characterized by accumulations of fluid, plasma proteins, and interaction of specific molecular structures, or antigens, of the
neutrophils that rapidly resolves once the initial inflammatory invader with antigen-specific receptors on lymphocytes. All
stimulus is removed. Deactivation signals include PGE2, corti- types of chemical structures can serve as antigens, including
sol, IL-10, and transforming growth factor–β (TGF-β). Some of proteins, nucleic acids, lipids, and polysaccharides. However,
those chemotactic agents responsible for initiating the response foreign molecules that are large, complex, and stable are the
(CXCL8, FMLP, C5a, LTB4, and PAF) also serve to downregu- most antigenic. Large antigens, such as proteins, contain mul-
late its intensity by inducing the shedding of IL-1 receptors tiple antigenic determinants or epitopes that interact with lym-
from neutrophils.245 The shedding of this decoy receptor may phocytes via their antigen-specific receptors. Haptens consist
have antiinflammatory effects as it effectively binds and neutral- of single antigenic determinants and can effectively combine
izes this cytokine. Likewise many of the acute phase proteins with the binding site of antibody molecules. However, as they
are thought to have immunomodulatory activity downregulat- only consist of a single antigenic determinant, they cannot
ing neutrophil function.246 Acute inflammatory responses may cross-link B-cell receptors (antibody molecules), and they are
often be subclinical and resolve without complications. How- also unable to stimulate T-cell responses. Therefore haptens
ever, if the invader is resistant to neutrophil-mediated destruc- cannot stimulate an immune response unless multiple hap-
tion or the degree of injury is large, the response may become tens are physically attached to a larger molecule, known as a
more chronic with the added recruitment of macrophages, lym- carrier.
phocytes, and fibroblast growth. Like the innate response, the adaptive immune response to
The essential characteristic of the innate immune response a specific antigen consists of both humoral and cellular effector
is that it does not exhibit specificity for the invading organ- mechanisms. The humoral component is mediated by immu-
ism. Thus the induction of an innate immune response does noglobulins or antibodies found in plasma and tissue fluids.
not require prior exposure to the invading organism nor is Antibodies are produced by B lymphocytes, small lymphoid
it augmented by repeated exposure to the same organism. In cells characterized by the cell surface expression of immuno-
most instances these mechanisms are adequate for eliminating globulin molecules. B cells represent less than 15% of the cir-
casual invaders. However, pathogenic organisms have evolved culating peripheral blood mononuclear cells but are present
various methods for avoiding elimination. In response to these in higher proportions in lymph nodes and the spleen. B cells
organisms, the specialized cells and products of the adaptive are derived from the fetal liver and bone marrow of mammals
immune response are mobilized. and the bursa of Fabricius of birds. In the bone marrow, B
CD4 TH1 IFN-γ

Helper
TCR T cell
CD3 IL- 4, IL- 5
TH 2
IL -13, IL-10
T cell
CD8
TH17 IL-17, IL- 22
Lymphoid Cytotoxic
progenitor T cell
Treg TGF- β , IL-10
Plasma YY
sIgM sIgG /A/E cell Y
YY
B cell
Memory
B cell
Distinguished by cell surface molecules Functional distinctions
FIG. 1.7 Major divisions of the lymphocyte family. To the left of the diagram different populations of lymphocytes are distinguished by expression of
different cell surface molecules. To the right of the diagram the distinctions are functional.
Light chain
VL
CL Secretory piece
VH C 2
C 3
C 1
Heavy chain
J chain
Variable region Constant regions Fc region Fab region

(antigen (effector
recognition) functions)
FIG. 1.8 Molecular structure of secretory IgA. This schematic illustrates the major features of immunoglobu-
lin molecules. Whereas the illustrated IgA molecule is dimeric, with the two Ig units joined by a “J chain” and
a series of disulphide bonds, IgG molecules are monomeric. Each Ig unit consists of two heavy chains and
two light chains. The heavy chains have four subunits and the light chains two. One end of the Ig unit has a
highly variable protein structure and is involved in antigen recognition, and the remainder of the Ig unit has a
constant structure in each Ig class and subclass and determines the functional characteristics of the molecule,
such as binding complement, or recognition by macrophages or neutrophil Fc receptors. This specialized
dimeric IgA molecule also has a secretory piece that increases its stability in the harsh mucosal environment.
In this diagram, the Fc portion is depicted as a circular structure, consistent with actual x-ray crystal structure
determinations.
cells are the products of a putative lymphoid stem cell derived infection and/or disease (the basis of vaccination). Although
from the pluripotent stem cell. Under the influence of various this principle appears to be straightforward, vaccination
cytokines produced by bone marrow stromal cells, the B-cell does not always yield the expected result. Why some vac-
precursor undergoes its 3-day development into a mature B cines work and others fail is a complex issue, a major compo-
cell. On stimulation with a specific antigen, B cells differentiate nent of which is the nature of the antigen-specific receptors
into plasma cells that produce enormous quantities of a spe- of lymphocytes.
cific antibody. The activation, proliferation, and differentiation
of B lymphocytes into plasma cells is dependent on other cells, Immunoglobulin: Antigen-Specific Receptor
including T lymphocytes, which represent the cellular com- of B Lymphocytes
ponent of the adaptive immune response. The T lymphocyte The antigen-specific receptor of the B cell is cell surface bound
is also derived from the multipotent stem cell and lymphoid immunoglobulin, also known as antibody. An immunoglobu-
precursor in the bone marrow, though its subsequent devel- lin molecule is composed of two identical light chains and two
opment into the mature T cell occurs in the thymus. Within identical heavy chains that form a disulfide-linked Y-shaped
the thymic environment the prothymocyte undergoes a devel- molecule (Fig. 1.8). The light chain can be divided into two
opmental and selective process while emigrating through the domains, a conserved carboxy-terminal domain and a highly
cortex into the medullary region of the thymus. Less than 3% variable amino-terminal domain. Analysis of heavy chains
of all the immature thymocytes found in the cortex survive to reveals a similar domain structure with the amino-terminal
become peripheral T cells. domain being highly variable and the presence of three con-
Though the induction of an antibody response requires stant domains. The antigen-binding region of an immuno-
the interaction of B and T lymphocytes, these cells recognize globulin molecule is formed by the association of the amino
different epitopes on the same antigen. Indeed, antigen rec- ends of a light and a heavy chain, and the carboxyl end of the
ognition by B cells and T cells is fundamentally quite differ- heavy chain determines the isotype of the molecule. Similar to
ent. B cells, and antibodies, recognize antigens in solution or most species, five different immunoglobulin isotypes (classes)
on cell surfaces in their native conformation, whereas T cells have been identified in the horse: IgM, IgD, IgG, IgE, and IgA
only recognize antigen in association with self molecules (Table 1.4).247-250 Before the availability of genetic character-
known as major histocompatibility complex molecules found ization of the equine immunoglobulin heavy chain gene loci,
on most cells surfaces (see later discussion). The adaptive at least four IgG subclasses were identified by physicochemical
immune response thus differs from innate immunity in that means and defined serologically by monoclonal antibodies as
it is antigen driven, and those cells that mediate the adap- IgGa, IgGb, IgGc, and IgG(T).251 More recently, seven IgG sub-
tive immune responses, T and B lymphocytes, express spe- classes have been defined (IgG1–IgG7) and named based on
cific receptors for the antigen. Because the immune system the designation of the corresponding Ig heavy chain constant
will respond to the antigens of both live and killed patho- region genes.248,250 The original IgGa corresponds to IgG1,
gens, it is possible to stimulate immunity without causing IgGb to both IgG4 and IgG7, IgGc to IgG6, and IgG(T) to both
TABLE 1.4 Immunoglobulin Isotypes

Isotype Immunologic Function
IgM Surface IgM is found on naive, activated, and memory B cells. Secreted IgM is a pentamer and represents the major
antibody produced during a primary response. IgM efficiently mediates agglutination, neutralization, opsonization, and
complement activation.
IgD Antigen receptor of naive B lymphocytes. An IgD heavy chain gene has been identified in the horse, and it is expressed.
IgG The principal immunoglobulin found in plasma representing up to 80% of the total immunoglobulin concentration.
Seven subclasses of IgG have been identified (see text). The major functions of IgG include opsonization and neutral-
ization reactions. IgG1, IgG3, and IgG4/7 are effective in fixing complement, and IgG1, IgG4/7, and IgG3/5 bind Fc
receptors so they can function as opsonins and mediate antibody-dependent cellular cytotoxicity. IgG6 and IgG5 may
play an important role in exotoxin neutralization and immunity to parasites.
IgE Most IgE is found associated with the surface of mast cells and basophils and only very small amounts are present in
the plasma. The cross-linking of two IgE molecules with specific antigen results in the degranulation of the mast cells
and basophils. Thus IgE is the primary antibody responsible for type I hypersensitivity reactions and appears to play a
central role in immunity to parasites.
IgA The most abundant antibody in secretions (tears, mucus, saliva, colostrum, etc.) is a dimer composed of two IgA mol-
ecules joined by a J chain. IgA in the plasma is predominantly monomeric. IgA antibodies can be neutralizing but do
not fix complement efficiently nor do they have efficient opsonization activity.

IgG3 and IgG5.247,250 All seven IgG subclasses are expressed within the lymph nodes and spleen (and other secondary
and functional, with IgG1, IgG3, IgG4, IgG5, and IgG7 able to lymphoid organs) during a primary immune response and
elicit a respiratory burst in equine peripheral blood leukocytes requires interaction with T lymphocytes. Cytokines secreted
(predictive of binding to Fc receptors), whereas IgG1, IgG3, by these interacting helper T cells provide the signals driv-
IgG4, and IgG7 bind complement C1q and activate the clas- ing class switching. For example, IL-4 and IL-13 induce
sical complement pathway.247 Some functional discrepancies isotype switching to IgE, and interferon-gamma (IFN-γ)
exist between the new and original designations. For example, inhibits this induction and augments IgG production. IgA
IgG(T) does not fix complement and inhibits complement is produced in response to the combination of the cytokines
fixation by IgGa (IgG1) and IgGb (IgG4/7).252 This is not con- IL-4, IL-5, and transforming growth factor-β (TGF-β).
sistent with the complement fixing properties of IgG3, which, The antigen specificity of a particular antibody molecule
along with IgG5, corresponds to IgG(T).247 Perhaps new (and the B cell that produces it) is determined by the combi-
reagents will provide clarification. nation of the variable domains of the light and heavy chains.
Membrane-bound immunoglobulin serves as the anti- The association of these two domains results in the formation
gen-specific receptor for B lymphocytes (B-cell receptor of an antigen-binding cleft or pocket that contains regions of
[BCR]). Thus antibodies in serum are secreted soluble forms hypervariability that define the specificity of a particular anti-
of BCRs. Each BCR contains a membrane-spanning region body molecule. It has been estimated that over 108 different
near its carboxy end that is inserted into the mRNA dur- antibody specificities are possible. The generation of this tre-
ing differential splicing of the heavy chain exons. Membrane mendous amount of diversity in antibody specificity occurs
IgM and IgD comprise the BCRs on the surface of naive B during B-cell ontogeny in the bone marrow. Within a given
lymphocytes, although the function of IgD is unclear. The B cell, the genes encoding the heavy and light chains of an
IgD isotype is secreted in very small quantities, if at all, and antibody molecule are organized into specific gene segments.
is rarely detectable in the circulation. Once activated, B cells Thus the light chain is formed from variable (VL), joining (JL),
cease to express IgD but continue to express the membrane and constant (CL) gene segments, which together form the
form of IgM. Early on in an immune response the B cell variable and constant domains of the light chain. In the germ
secretes large amounts of the pentameric form of IgM. As the line of an undifferentiated human cell one finds several hun-
immune response proceeds, the B cell will switch the isotype dred different VL and several dozen JL gene segments. In the
of its heavy chain. Isotype switching involves the substitu- horse, there are 204 VL genes, 12 JL genes, and 8 CL genes.253
tion of one heavy chain constant region in place of another. Likewise the heavy chain of a B lymphocyte is composed of
In the horse, the genes encoding the 11 different constant VH, diversity (D), and JH segments, which form the variable
(C) regions (five primary isotypes including the seven IgG domain, and these join to the constant region genes (discussed
subclasses) of the heavy chain are sequentially arranged earlier) to form the complete heavy chain molecule. Similarly,
on chromosome 24 in the following order: Cμ(M), Cδ(D), in the germ line of humans one finds a large number of VH
Cγ1(G1), Cγ2(G2), Cγ3(G3), Cγ7(G7), Cγ4(G4), Cγ6(G6), gene segments and a smaller number of DH and JH segments.
Cγ5(G5), Cε(E), Cα(A).250 Initially, the first two constant There are 54 VH, 40 DH, and 8 JH genes in the horse.253 During
region genes encoding the M and D constant regions are the differentiation of a B cell (Fig. 1.9), there is the sequential
used to form the heavy chain. When switching occurs a new selection and rearrangement of a VL segment with a JL seg-
constant region segment is selected, and the intervening ment and the accompanying deletion of intervening VL and
genes are removed either by splicing or looping out. Isotype JL segments (Fig. 1.10). The VJ segment is joined with a C
switching only affects the heavy chain constant domains and gene, and the rearranged VJC sequence is then transcribed
has no effect on the antigen specificity of the immunoglobu- into mRNA and translated into the light chain. A somewhat
lin molecule. Isotype switching occurs in lymphoid follicles similar sequence follows for heavy chains except that two
Plasma
Lymphoid Pro-B Pre-B Immature Mature Activated cell
stem cell cell cell B cell B cell B cell
Ig gene rearrangement Antigen driven
cytoplasmic µ surface surface surface

IgM
(IgM heavy chain) IgM & D IgG/A/E
Memory
B cell
FIG. 1.9 B-cell differentiation. Different stages of B-lymphocyte development can be recognized by expression of immunoglobulin molecules. This
maturation requires a series of gene rearrangements to select the genes that will encode the antigen binding part of the immunoglobulin molecule (vari-
able region), and subsequently to select the genes that determine the class or subclass of the antibody molecule. Initially immature B cells express IgM
(the majority of peripheral blood B cells), but after antigen exposure the B cell becomes activated and may express any of the immunoglobulin classes or
subclasses. This decision depends in large part on cytokine signals from helper T cells. Activated B cells either mature into short-lived antibody-secreting
plasma cells or become long-lived memory B cells.
Variable region genes Constant region genes
IgGa ? IgG(T) IgGb IgGc IgG(T)

IgM IgD IgE IgA
V1 2 3 4 5 D1 2 3 J1 2 Cµ Cδ Cγ1 Cγ2 Cγ3 Cγ7 Cγ4 Cγ6 Cγ5 Cε Cα
Germline DNA
V1 2 3 4 5 D1 J2 Cµ Cδ Cγ1 Cγ2 Cγ3 Cγ4 Cγ5 Cγ6 Cγ6 Cε Cα

DJ joined rearranged DNA
V5 D1 J2 Cµ Cδ Cγ1 Cγ2 Cγ3 Cγ4 Cγ5 Cγ6 Cγ6 Cε Cα

VDJ rearranged DNA
V5 D1 J 2 Cγ4
VDJ, constant region rearranged DNA
Complete IgGb heavy chain polypeptide chain
Variable region Constant regions
FIG. 1.10 Immunoglobulin gene rearrangement: somatic recombination process for production of an
immunoglobulin heavy chain. The figure shows a hypothetical series of V, D, and J variable heavy chain
genes, positioned 5′ to the known equine heavy chain constant region gene loci. In the first step in somatic
recombination a D and a J gene segment are joined, and in the second step a V gene segment is joined to
complete the VDJ recombination and form a gene capable of encoding the variable region. Subsequently
one of the seven equine γ heavy chain constant regions, labeled with their corresponding IgG subclass,
was selected to complete the gene rearrangement. Because the Cγ4 heavy chain constant region gene was
selected, this leads to production of an IgG4 heavy chain.
rearrangements are necessary, a D to J rearrangement fol- of RAG-1 and RAG-2 components, encoded by recombina-
lowed by a V to DJ rearrangement. Once completed, the VDJ tion-activating gene–1 and recombination-activating gene–2.
segment is brought into proximity of the appropriate CH seg- To reconstitute the rearranged gene the cut ends of the DNA
ment and transcribed. During gene rearrangement, interven- must be rejoined, which requires the enzyme DNA-depen-
ing deoxyribonucleic acid (DNA) is looped out and excised, dent protein kinase (DNA-PK). Not all of the gene segment
which requires V(D)J recombinase. This enzyme is made up rearrangements produce functional genes. Because a B cell
has two sets of heavy chain genes, one on each chromosome, Analysis of the predicted amino acid sequences for the
and most species have two different sets of light chain genes, TCR proteins confirmed a structural similarity with antibody
including the horse,253-255 there are several chances to form molecules. One peculiarity in the structure of the TCR was
appropriate heavy and light chains. Once the heavy and light observed from the amino acid sequence analysis. Although
chain gene segments are successfully recombined, the genes both the α and β chains of the TCR contained a transmem-
on the sister chromosome neither recombine nor are they brane region, both proteins had very short cytoplasmic tails.
expressed. This process of allelic exclusion ensures that the However, the TCR heterodimer is noncovalently associated
B cell produces antibodies of a single specificity. Although with the CD3 complex of proteins. The five proteins of the
this random assortment of gene segments accounts for much CD3 complex are involved in signal transduction following
of the diversity in antibody specificity, additional mecha- TCR binding to antigen. Unlike the TCR α and β proteins,
nisms are also involved, including gene conversion (inser- the CD3 proteins have large intracellular domains, some of
tion of pseudogenes), junctional diversity (resulting from the which are phosphorylated in response to stimulation of the
imprecise joining of gene segments), and somatic mutations. TCR (see later discussion). In addition to providing a sig-
Somatic mutations are point mutations in the hypervariable naling mechanism for the TCR, the CD3 complex is also
region of either the heavy or light chain that occur during the required for the expression of the TCR heterodimer on the
proliferation of antigen-activated B lymphocytes within ger- cell surface.257
minal centers of lymph nodes and other secondary lymphoid The generation of diversity in the TCR during T-cell
organs and tissues. Such mutations play an important role in ontogeny employs a mechanism similar to that used to gen-
increasing antibody affinity for its antigen. Thus fewer than erate immunoglobulin diversity. The TCR α chains resemble
500 genes can give rise to over 108 molecules of the various immunoglobulin light chains in that they are composed of
specificities needed to recognize the vast number of antigens V, J, and C gene segments. The particular V, J, and C seg-
the host may encounter. ments used are selected from a germ line configuration con-
taining a few (C region) to several hundred (V region) gene
T-Cell Receptor and CD3 Complex: Antigen- segments. The selection and rearrangement of the gene seg-
Specific Receptor of T Cells ments are similar to those employed by the immunoglobu-
T lymphocytes can be differentiated from B lymphocytes lin light chain and appear to involve the same recombinases
in that they do not express surface immunoglobulins but and DNA-PK. Likewise the β chains resemble heavy chains,
instead express the T-cell receptor (TCR). T cells also each being composed of V, D, J, and C gene segments, and
express another surface molecule called CD3. (The desig- their selection and rearrangement from germ line genes also
nation CD stands for cluster of differentiation and is the parallels immunoglobulin heavy chain rearrangement. Thus
result of an international workshop to standardize the ter- the generation of diversity is the result of the combination
minology used to describe leukocyte surface antigens rec- of multiple gene segments and junctional diversity. However,
ognized by monoclonal antibodies.) The TCR and CD3 unlike immunoglobulins, the TCR genes do not undergo
form a multimeric complex on the T-cell surface, and this gene conversion or somatic mutations.
complex is involved in antigen-specific recognition. The
TCR was originally described as a heterodimer comprised T-Lymphocyte Subsets
of an α chain and a β chain. Peptide mapping studies of Mature T lymphocytes can be further divided into two dis-
the α and β chains from many different T-cell lines demon- tinct populations on the basis of their expression of either
strated that they contained variable and constant domains the CD4 or CD8 molecule.258 The expression of these surface
reminiscent of immunoglobulin structure. Further analy- molecules is directly correlated with the specificity of the T
sis indicated that, like immunoglobulin genes, TCR genes cell (see later discussion). The expression of either CD4 or
undergo gene rearrangements during T-cell development to CD8 also correlates with T-cell function. Thus those cells that
generate tremendous diversity in antigen specificity. Sub- express CD8 are typically cytotoxic effector cells (cytotoxic T
sequently, two additional TCR genes were identified, the γ lymphocytes [CTLs]), whereas those that express CD4 are
chain and δ genes corresponding to a second heterodimer. typically helper cells that produce cytokines that enhance
Thus two types of TCRs exist, an αβ heterodimer and a γδ antibody and cell-mediated immune responses. Whereas the
heterodimer. Although the percentages of T cells expressing T lymphocytes in the periphery express either CD4 or CD8,
the γδ receptor vary among mammalian species (ruminants cortical thymocytes (immature T cells in the thymus) express
and pigs have higher percentages of γδ T cells than other both antigens. During maturation in the thymus, these cells
species), most T cells are αβ T cells with fewer than 5% of convert to either CD4+ or CD8+ cells or they are eliminated
all T cells expressing the γδ receptor. The function of γδ T (Fig. 1.11). Within the cortex of the thymus, thymocytes are
cells is poorly understood. In general, γδ T cells generate exposed to thymic epithelial cells that present self peptides
less diversity in their TCRs, can recognize nonpeptide antiin the context of major histocompatibility complex (MHC)
gens such as lipids, do not require major histocompatibility molecules (see later discussion). The thymic selection pro-
complex presentation for antigen recognition (see later dis- cess involves both positive and negative selection. During
cussion), and participate in inflammatory responses. They positive selection, thymocytes with TCRs that bind self pep-
secrete cytokines and can have cytotoxic activity and may tide–MHC complexes with low avidity (weakly) are stimu-
be important for recognizing antigens frequently encoun- lated to survive. This ensures that the developing thymocyte
tered at mucosal surfaces and epithelial boundaries, at the has a functional TCR. During negative selection, thymocytes
interface between the host and the external environment.207 that bind self peptide–MHC complexes with high avidity
As such they are thought to play an important role in immu- (strongly) are deleted. The end result is that mature T lym-
nologic surveillance. In the horse, CD8+ T cells expressing phocytes leave the thymus with functional TCRs capable of
the γδ TCR have been identified in peripheral blood.256 binding self MHC molecules without autoreactivity.
{
Capsule
Immature CD4-/CD8- double negative

thymocytes proliferate and rearrange their
T-cell receptor genes
Cortex Immature CD4+/CD8+ thymocytes interact

with the network of thymic cortical epithelial
cells, which express MHC I & II molecules
{
Thymocytes with receptors with too high
an affinity for self-peptides or too low an
affinity for self-MHC molecules are
negatively selected and eliminated by
apoptosis
Medulla
CTL TH Mature single-positive (CD4 or CD8)
thymocytes reach the cortex and enter the
bloodstream as T cells
FIG. 1.11 T-cell maturation and selection in the thymus.
Major Histocompatibility Complex MHC I molecules are cell surface glycoproteins consisting
Molecules and Antigen Presentation of two noncovalently associated proteins, an MHC-encoded
Unlike B cells and antibodies, which recognize antigens in α chain (consisting of α1, α2, α3, transmembrane, and cyto-
solution or on cell surfaces in their native conformation, T plasmic domains) and β2-microglobulin, a protein encoded
cells only recognize processed antigen bound by antigen- outside of the MHC that stabilizes the molecule on the cell
presenting molecules on the surface of antigen-presenting surface (Fig. 1.12). The α1 and α2 domains are variable regions
cells (APCs). These antigen-presenting molecules are glyco- encoded by polymorphic genes and form the antigen bind-
proteins encoded by genes within a large gene cluster called ing cleft of the molecule. MHC I molecules are expressed on
the major histocompatibility complex (MHC), which also hap- the surface of most nucleated cells, with the highest level of
pens to be the most polymorphic gene region known in ver- expression on lymphoid cells and lower expression on fibro-
tebrates. The MHC was originally defined in terms of its role blasts, muscle cells, and neural cells. MHC I molecules are not
in allograft rejection. Following the rejection of a primary detectable on early embryonal cells, placental cells, and some
allograft, antibodies that reacted with the allograft could be carcinomas. The level of expression of MHC I molecules can
found in the recipient’s sera. These antibodies could be used to be modified by treatment with cytokines or infection with
identify or type tissues to determine the suitability of a donor viruses, including equine herpesvirus–1 (EHV-1), which
for transplantation. Genetic analysis of the MHC region downregulates expression.261 Interferons and TNF-α augment
demonstrated that there were a number of closely linked MHC I expression. This augmented expression is the result of
genes encoding several different, though related, molecules increased production of MHC I mRNA, and the regulatory
that were involved in allograft rejection. These closely related region of the MHC I genes has been shown to contain inter-
genes are collectively referred to as MHC class I (MHC I) feron and TNF-α–responsive elements that control the tran-
genes and their products as MHC I molecules. Similar to the scriptional activity of these genes.
anti–donor MHC antibodies found in allograft recipients, it The MHC I region of most species contains a large num-
was also demonstrated that multiparous mares had antibod- ber of polymorphic genes within several different loci (loca-
ies in their sera as a result of the exposure to paternal MHC tions on the chromosome). In humans there are three MHC
antigens on the fetus.259,260 These sera provided the earliest I loci (A, B, and C) with 2000 to 3000 expressed alleles iden-
means to serologically define MHC I haplotypes (the com- tified for each locus (Immuno Polymorphism Database;
plement of MHC alleles in a given individual) in horses.259 http://www.ebi.ac.uk/ipd). Comparably very few MHC I gene
Equine MHC I haplotypes are designated using the equine sequences are known in the horse. A recent BLAST query
leukocyte antigen (ELA) prefix, similar to the nomenclature (February 2016) returned approximately 100 equine MHC
used in humans and other species (i.e., “HLA” in humans). I sequences, and fewer have been published (approximately
In addition to the serologically defined MHC I molecules, 60).262-264 Although seven loci were identified in MHC I homo-
another group of molecules were identified within the MHC zygous horses (ELA-A3 haplotype),264 a more recent study in
that were involved in the stimulation of mixed lymphocyte horses representing 10 different haplotypes revealed that the
responses and the control of immune responsiveness. These number of loci differs by haplotype, with 4 confirmed and 3
MHC class II (MHC II) molecules are structurally and func- provisional loci identified.263 MHC I typing methods in horses
tionally distinct from the MHC I molecules, but both are include serologic typing,259 reverse transcriptase polymerase
involved in T-cell recognition of antigen. chain reaction (RT-PCR) cloning and sequencing to identify
Peptide
Antigen
α2 α1 β1 α1
α3 β2 α2
β2 -micro-
Trans- globulin
membrane
domain
Cell Surface
Cytoplasmic
domain
A B C
FIG. 1.12 MHC class I and II molecules . (A) Schematic depiction of an MHC molecule expressed on the cell
surface, with peptide bound in the cleft formed by the α1 and α2 domains. (B) Molecular model of equine
MHC class I molecule 7 to 6 (Eqca-N*00602) presenting the Rev-QW11 peptide, a known CTL epitope within
the Rev protein of equine infectious anemia virus. β2 microglobulin not shown. (C) Schematic diagram of an
MHC class II molecule expressed on the cell surface, with peptide bound in the cleft formed by the α1 and
β1 domains.
specific expressed alleles,263,265 and DNA microarray.63 Most Once in the ER, peptides are handed off to newly formed
recently, MHC haplotypes have been identified using micro- MHC I molecules and stabilize a trimolecular complex with
satellite markers.266,267 β2 microglobulin. This complex is then transported to the
MHC I polymorphism is primarily localized in the α1 and cell surface, where antigen presentation occurs. Because this
α2 domains, with the α3 domain being more conserved. The is a normal cellular process for eliminating degraded proteins
polymorphism of these two domains is related to their role in from the cell it is not surprising that MHC I molecules are nor-
presenting antigen to T cells. The physiologic role of MHC I mally loaded with these self-peptides. Indeed it is this encoun-
molecules was defined when it was discovered that CTL lysis ter with MHC I loaded with self-peptides in the thymus that
of virus-infected cells was restricted to target cells expressing is responsible for the deletion of autoreactive clones during
the same MHC I molecules as the CTL.268 This observation T-cell ontogeny. This unique peptide-binding characteristic of
led to the realization that T cells recognized the combination MHC I molecules has led to their use as immunologic reagents
of self-MHC and foreign antigen. Furthermore, those T cells (tetramers) for the identification and enumeration of antigen-
that recognized MHC I antigens invariably expressed the CD8 specific CD8+ T cells.271 In the horse, tetramers based on the
coreceptor. The nature of the association between MHC I and equine MHC I molecule 7-6 (Eqca-N*00602), associated with
the foreign antigen remained unclear until x-ray crystallo- the ELA-A1 haplotype, have been used to identify and quan-
graphic studies of human MHC I antigen were performed.269 tify equine infectious anemia virus (EIAV)-specific cytotoxic
In addition to revealing the structural organization of the T cells.272,273 Similar approaches are in development to analyze
domains of the MHC I antigen, the image also revealed a cleft CTL responses against other viruses and provide important
that lay between the α1 and α2 domains. It was proposed that information on the role these cells play in protection from
this cleft binds the processed peptide epitopes for presentation these infections.
to the T-cell receptor. Indeed, the cleft of the crystalized pro- Peptides that bind in the MHC I binding cleft are typically
tein used for the x-ray diffraction studies was found to contain 8 to 9 amino acids (aa) in length. Interestingly, three EIAV-
a contaminating peptide.269 Other experiments showed that specific CTL epitope peptides that bind to two closely related
the incubation of cells with purified viral peptides resulted equine MHC I molecules associated with ELA-A1 haplotype
in the lysis of the cells by virus-specific MHC I–restricted are 11 to 12 aa long.274 The two MHC I molecules, 7-6 (Eqca-
CTL.270 It is now known that the endogenous processing of N*00602) and 141 (Eqca-N*00601), differ in only one aa in the
viral antigens leads to the association of the viral peptides with α2 domain, yet present peptides to CTL differently, resulting
MHC I antigens on the surface of the infected cell, and this is in differential CTL recognition. Molecular modeling suggests
recognized by the TCR in association with CD8. How these that these peptides bind in a bulged conformation and pro-
viral antigens get to the cell surface is the result of a peptide vides an explanation for the experimentally observed differ-
transport system whose function is to transport processed ential recognition by CTL.274 Recently an independent group
peptides from the cytosol to the endoplasmic reticulum (ER). solved the crystal structures of these same MHC I molecules
Foreign and other cytosolic proteins are marked for degrada- with the bound peptides.275 This work confirmed the previ-
tion by covalent linkage to a small polypeptide called ubiqui- ous molecular modeling conclusions274 and has provided the
tin. These ubiquinated proteins are targeted for entry into a first crystal structures of equine MHC I–peptide complexes. In
proteasome, a cylindrical complex that degrades the protein addition, a shorter peptide (9 aa) with similar anchor residues
into small peptides. These are then transported into the ER bound the clefts of these molecules in a more typical confor-
by the transporter associated with antigen processing (TAP). mation.275 Despite MHC I binding, this 9 mer peptide may not
be a CTL epitope. The original study confirmed experimen- molecules play in antigen presentation to helper T cells (see
tally that although 1 of the 12 mer peptides bound the Eqca- later discussion), susceptibility to some diseases is associated
N*00601 molecule, there was no CTL recognition.274 Recent with particular MHC II haplotypes. For example, analysis
work with the Eqca-1*00101 MHC I molecule (associated of microsatellite markers and direct sequencing has demon-
with the ELA-A3 haplotype) has further defined equine MHC strated that the MHC II haplotype is a risk factor for insect bite
I peptide binding motifs and has demonstrated a narrow pep- hypersensitivity in defined populations of horses.286
tide binding repertoire.276 Moreover, CD8+ T-cell recognition Whereas intracellular antigens are processed via the endog-
of a large panel of EHV-1 peptides that bound this molecule enous pathway and are associated with MHC I molecules that
was restricted to a single 9 mer peptide. It will be of interest to present them to CD8+ cytotoxic T cells, extracellular antigens
determine whether any other equine MHC I molecules share are processed via the exogenous pathway and are associated
the limited peptide binding and TCR epitope recognition with MHC II molecules that present them to CD4+ helper
properties of Eqca-1*00101, as this would have implications T cells (Fig. 1.13). Here endocytosed antigens, such as that
for the control of intracellular infections in horses with some phagocytosed by a macrophage, are degraded into peptide
MHC I haplotypes. fragments within a phagolysosome compartment. Processed
MHC II molecules are heterodimeric, transmembrane gly- peptides then bind within the peptide binding cleft at the junc-
coproteins composed of an α chain and a β chain (see Fig. tion of the α1 and β1 domains of the MHC II molecule. This
1.12). A third chain, the invariant chain, has been shown to association of the epitope with the MHC II molecule protects
be associated with the MHC II molecule during assembly in it from further degradation. The MHC II molecule is then
the endoplasmic reticulum but is not expressed on the cell transported and expressed on the cell surface for subsequent
surface. Both the α and β polypeptides are encoded within presentation to the helper T cell. The immune system contains
the MHC region. Both polypeptides possess cytoplasmic, a distinct group of professional antigen-presenting cells called
transmembrane, and two extracellular domains (α1, α2 and dendritic cells that are specialized to capture antigens and ini-
β1, β2). The α1 and β1 domains comprise the peptide bind- tiate T-cell immunity and move freely from epithelial surfaces
ing cleft. The α chain has a single disulfide bond located in to adjoining lymph nodes. Dendritic cells can be found in a
its membrane proximal (α2) domain, and the β chain has a variety of locations in the body and are often named based
disulfide bond in both of its extracellular domains. Structur- on their microscopic appearance. Thus interdigitating cells
ally, the MHC II molecules resemble MHC I antigens and are found in lymph nodes, veiled cells in lymphatics, and Lang-
also members of the immunoglobulin superfamily, a group of erhans cells in skin are all dendritic cells. Immature dendritic
proteins that have structural similarities to immunoglobulin cells take up antigens by micropinocytosis using their exten-
molecules, including conserved domains and variable antigen sive cellular processes or by receptor-mediated phagocytosis.
binding domains. This results in activation and migration to a regional lymph
The MHC II genes are functionally and structurally distinct node where antigen presentation to T lymphocytes occurs.
from the MHC I genes. Unlike MHC I molecules, MHC II mol- Dendritic cells in the spleen capture blood-borne antigens and
ecules are restricted in their expression to certain cells of the similarly become activated, presenting antigens to T cells in
immune system: B lymphocytes, dendritic cells, macrophages, the periarteriolar lymphatic sheaths within white pulp. Mature
and activated T lymphocytes of some species. Other cells may dendritic cells have high levels of MHC II expression on their
also express MHC II molecules after treatment with various surface. Although no longer phagocytic, they are extremely
cytokines.277-279 Interferon-γ, TNF-α, 1,25-dihydroxyvitamin- efficient stimulators of both MHC I– and MHC II–restricted
D3, and granulocyte-macrophage colony-stimulating factor T-cell responses in the draining lymph node or other second-
can induce MHC II molecule expression on monocytes and ary lymphatic tissue (Fig. 1.14).
macrophages and other cells. IL-4 enhances MHC II expres- In a complex antigen, certain epitopes are particularly
sion on B cells. A number of agents have been shown to effective at stimulating an antibody response. These immuno-
downregulate MHC II expression, including glucocorticoids, dominant epitopes are often located at exposed areas of the
prostaglandins, and α-fetoprotein. Similar to MHC I, MHC II antigen such as in polypeptide loops. These types of structures
expression is regulated at the transcriptional level. The regu- are often quite mobile and may allow for easier access to the
latory regions are quite different, however, and this probably antibody binding site. T-cell epitopes have been shown to pos-
accounts for the differences in tissue distribution for these two sess a particular structural characteristic in that they involve
MHC molecules. the formation of amphipathic helices. However, structure
Like the MHC I genes, the MHC II region contains poly- alone does not determine the immunogenicity of a particu-
morphic genes encoding multiple MHC II molecules. There lar antigen, and T-cell recognition of foreign antigen requires
are loci for genes encoding the α chain (including DRA and more than just the expression of the processed antigen on
DQA loci) and β chain (including DRB and DQB loci), with the surface of the antigen-presenting cell. Additional signals
multiple alleles at most loci. In most species there is limited provided by the antigen-presenting cell are also required for
diversity in the α chain genes, with the β chain genes being the activation of the T lymphocytes. Among these are signals
the most polymorphic. For example, only two expressed provided by other accessory molecules found on the antigen
alleles occur at a single DRA locus in humans, whereas there presenting cell and various cytokines present in the extracel-
are multiple DRB loci containing over 1400 expressed alleles. lular environment.
Although the horse also has a single DRA locus, horses have
greater DRA allelic diversity than any other species.280-282 In Signaling through Antigen-Specific
addition, there are multiple DQA, DRB, and DQB loci, each Receptors
with multiple alleles contributing to the level of MHC II The binding of a specific antigen by either the TCR of a T
diversity in equids.282-285 Because of the critical role MHC II cell or the BCR of a B cell results in an intracellular signaling
Phagocytosis of
CTL TH extracellular antigen
3 1
Extracytoplasmic
Intracytoplasmic
KEY
MHC I molecule plus
chaperone molecules
MHC I molecule plus peptide

fragment of intracellular antigen
b MHC II molecule plus

invariant chain
Endoplasmic reticulum
MHC II molecule plus peptide
fragment of extracellular antigen
a
FIG. 1.13 Antigen processing pathways. This figure depicts MHC I antigen presentation to the left of the
diagram, and MHC II antigen presentation to the right. In MHC I antigen presentation (a) peptides generated
by degradation of proteins in the cytoplasm are transported into the endoplasmic reticulum by TAP (b). In
this location, MHC I molecules anchored by calnexin bind the antigenic peptides, which allows release of the
MHC I–peptide complex and transport through the Golgi to the cell surface (c). In MHC II antigen presenta-
tion, antigen is taken up by phagocytosis (1) into the endosome compartment that fuses with lysosomes for
degradation. Vesicles containing MHC II molecules produced in the endoplasmic reticulum fuse with the en-
dosomes (2), and the MHC II molecules bind with the degraded peptides for transport to the cell surface (3).
The MHC II molecules are prevented from binding the endogenous peptides in the endoplasmic reticulum
by the presence of an invariant chain, which is lost in the acidic endosomal environment.
cascade that eventually leads to the production of various Costimulatory Signals

cytokines and the proliferation of the stimulated cell. T-cell In addition to the interaction of TCR-CD3, CD4/CD8, and
recognition of antigen involves the engagement of a TCR- MHC-peptide antigen complexes, other cell surface molecules
CD4 or TCR-CD8 complex with processed peptide bound by are involved in signaling pathways. Of greatest importance is
an MHC II or MHC I molecule (Fig. 1.15). The engagement the interaction of CD28 on the T cell with B7 (CD80/86) on
of the TCR with the appropriate MHC-peptide complex also the antigen-presenting cell (APC). In the absence of CD28-
results in the binding of CD4 (or CD8) to a dedicated region CD80/86 costimulation, T cells are rendered functionally
of the MHC II (or MHC I). In doing so the lck protein tyrosine inactive or anergic. On restimulation, anergic T cells fail to
kinase associated with the cytoplasmic tail of CD4 (or CD8) proliferate or to produce cytokines such as IL-2 (a cytokine
phosphorylates the cytoplasmic regions of the CD3 proteins required for T-cell proliferation). The induction of anergy can
(associated with the TCR) in regions known as immunorecep- be prevented by either the addition of exogenous IL-2 or, more
tor tyrosine–based activation motifs (ITAM). A series of sub- important, by interaction of the CD28 cell surface antigen with
sequent phosphorylation events ultimately leads to the release its ligands (CD80/86). Stimulation of CD28 appears to be nec-
of stored Ca from the endoplasmic reticulum. The increase in essary for subsequent intracellular signaling events following
intracellular Ca levels and the activation of protein kinase C TCR stimulation as CD28 cross-linking enhances various bio-
leads to the phosphorylation of various transcriptional factors chemical events triggered by TCR-mediated signaling. Other
that regulate the expression of the genes for various cytokines molecules, including the TNF-receptor family member CD40,
and/or their receptors. The process is subsequently downregu- regulate T-cell growth and cell death. The engagement of CD40
lated by various phosphatases that are recruited to and subse- on the T cell with its ligand, CD40L (on APC), promotes cell
quently dephosphorylate the CD3 ITAMs. A similar process survival and cell cycle progression. The binding of other mem-
occurs in B cells when their surface immunoglobulin receptor bers of this family, notably TNF-α, to their receptors on acti-
is cross-linked on binding to specific antigen. The reader is vated T cells typically results in the activation of a biochemical
referred elsewhere for additional information regarding intra- cascade of caspases that leads to apoptosis (programmed cell
cellular signaling in lymphocytes.207,209 death). The cytocidal activity of these receptors is the result of
Pathogen invasion
Lymph node
Epithelial
surface
Paracortex
Follicle (T cell zone)
Dendritic cell Activation (B cell zone)
and migration
Antigen processing
and presentation
CTL
TH
FIG. 1.14 The role of professional antigen-presenting cells (APCs). In this figure pathogen invasion is fol-
lowed by antigen uptake by a dendritic cell, the most potent of the APC family. The dendritic cells become
activated and migrate to a local lymph node where they are extremely effective at stimulating naive T cells
in the paracortex, including both T-helper cells and CTLs.
TH CTL
T-cell receptor
Antigen
CD4 CD8
MHC II MHC I
Antigen presenting cell
FIG. 1.15 MHC class I and class II restricted T cell recognition: the role of T-cell CD4 and CD8 molecules.
T cells use their TCRs to recognize processed antigen presented in combination with either MHC I or MHC
II molecules. T cells exclusively express either CD4 (T-helper cells) or CD8 (cytotoxic T lymphocytes [CTLs]).
The CD4 molecule is required for interaction with MHC II molecules, and CD8 is required for MHC I interac-
tion. As a result, helper T cells only recognize antigen presented by MHC II molecules, and CTLs only recog-
nize antigen presented by MHC I molecules.
their intracytoplasmic portion of the receptor containing death Cytokines and Cell-Mediated Immunity
effector domains. By contrast, CD40 lacks the intracellular As indicated previously, cytokines are hormone-like proteins
death domains and instead has amino acid motifs that promote that mediate a variety of cellular responses. Over 100 differ-
activation. In addition to their role in promoting T-cell activa- ent cytokines and chemokines are known, and the reader is
tion and growth, both the CD28-CD80/86 and TNF-receptor referred elsewhere for comprehensive lists of their designa-
pathways may also play a dominant role in the induction of spe- tions and functions.207,209 Table 1.5 provides an abbreviated
cific T-helper cell subsets (see later discussion). list of cytokines with critical roles in innate and adaptive
TABLE 1.5 Selected Cytokines

Cytokine Biologic Activities and Source
IL-1 Multiple proinflammatory effects. Produced by macrophages. See Table 1.3.
TNF-α Multiple proinflammatory effects. Produced by macrophages.
IL-2 Stimulates growth and proliferation of T cells. Produced by activated CD4+ T cells, TH1 cells, and some CD8+ cells.
IL-4 Activates B cells and isotype switching to IgE and IgA. Produced by TH2 cells. Promotes differentiation of TH2 cells.
IL-5 Activates B cells and isotype switching to IgA. Recruits and stimulates eosinophil growth. Produced by TH2 cells.
IL-6 Proinflammatory. Induces fever and the production of acute phase proteins by hepatocytes. Produced by macrophages.
Also activates B cells and stimulates growth in stromal cells, fibroblasts, and a variety of other cell types.
IL-8 Now called CXCL8. A chemokine that is chemotactic for neutrophils. Produced by macrophages, endothelial cells, and
various other cells.
IL-10 Inhibits the production of IL-12 by dendritic cells and IFN-γ by TH1 cells. Suppresses macrophages and T-cell function.
Produced by TH2 cells and Tregs.
TGF-β Produced by Tregs and other cells. Promotes differentiation of Tregs. Inhibits cell growth. Antiinflammatory. Inhibits T-cell
proliferation and function. Promotes tissue repair. Induces isotype switching in B cells to IgA.
IL-12 Stimulates TH1 differentiation. Augments NK cell and CTL function. Produced by dendritic cells and macrophages.
IFN-γ Enhances phagocytosis and killing by macrophages. Produced by TH1 cells. Enhances MHC expression and antigen
presentation by APCs. Suppresses TH2 responses. Induces isotype switching in B cells to IgG.
IL-13 Produced by TH2 cells. Activates B cells and isotype switching to IgE. Inhibits TH1 cells.
IL-17 Proinflammatory. Produced by TH17 cells. Recruits neutrophils via induction of cytokine and chemokine production by
other leukocytes, epithelia, endothelia, and fibroblasts.
IL-21 Produced by TH17 cells and amplifies TH17 responses. Promotes B-cell and T-cell responses.
IL-22 Proinflammatory. Produced by TH17 cells. Induces chemokine production by epithelia and promotes epithelial barrier
function. Induces production of defensins.
IL-23 Promotes TH17 differentiation. Produced by dendritic cells and macrophages.

immune responses. A significant number of equine cyto- supports the stimulation, proliferation, and differentiation of
kines have been cloned and sequenced, and specific protocols all antigen-activated T cells very early in the immune response.
are available to measure their expression. Numerous studies Thus it is IFN-γ production that best characterizes TH1 cells.
confirming the role of cytokines in equine sepsis, joint dis- The primary function of TH1 cells is to activate macrophages
ease, airway diseases, and a variety of viral and bacterial dis- to phagocytose and kill invading pathogens and to support
eases emphasize the similarities between equine and human the activation of CTL responses. Thus TH1 cells are critical for
immune systems.206 As such, the potential for manipulating controlling intracellular infections. In addition to its primary
these responses using recombinant cytokines or anticyto- effect on activating macrophages to destroy microbes, IFN-γ
kine reagents is as applicable to equine medicine as it is for produced by TH1 cells enhances MHC antigen presentation
human medicine. The reader is referred to the U.S. Veterinary and costimulation by APC, promotes activation of CD8+ CTL,
Immune Reagent Network (http://www.umass.edu/vetimm promotes further differentiation of TH1 cells, inhibits the
/equine) for information and links regarding cloned equine differentiation of TH2 and TH17 cells, and acts on B cells to
cytokines and other equine immune reagents currently avail- promote isotype switching to IgG subclasses while it inhibits
able or in development. switching to TH2-type isotypes such as IgE (Fig. 1.16). Dur-
Cell-mediated immunity is the component of adaptive ing antigen activation, CD4+ T cells differentiate into TH1 cells
immune defense mediated by T lymphocytes. Helper T cells primarily during intracellular infections under the influence
are critical in these responses because depending on the cyto- of IL-12 produced by dendritic cells and macrophages, as well
kines they produce, they can activate macrophages to kill as IFN-γ produced by other TH1 cells and by NK cells.
phagocytosed microbes, promote CD8+ CTL responses, pro-
vide help for B cells in the production of antibodies, and, con- TH2 CD4+ Effector T Cells
versely, inhibit any of these responses. Helper T cells can be In contrast to TH1 cells, TH2 cells promote phagocyte-inde-
divided into distinct effector subsets based on the cytokines pendent immune responses, including those mediated by
they produce. These subsets include TH1, TH2, and TH17 cells, eosinophils and mast cells, and they provide help to B cells
as well as a regulatory T-cell subset (Treg), which has suppres- for the induction of antibody responses. These responses
sive functions (see Fig. 1.7). are important for the elimination of extracellular infections,
including parasitic infections and microbes infecting muco-
TH1 CD4+ Effector T Cells sal tissues. Detrimentally, TH2 responses are involved in the
The predominant cytokine produced by TH1 cells is IFN-γ, but development of allergic diseases. Antigen-activated CD4+ T
they also secrete IL-2 and TNF-α.287 Although classically con- cells differentiate into TH2 cells in the absence of IL-12 and
sidered a TH1 cytokine, IL-2 is produced transiently by CD4+ T IFN-γ, under the influence of IL-4 produced by other TH2
cells in general, within hours after their initial interaction with cells, and perhaps by mast cells or even the CD4+ T cell itself
the APC during recognition of antigen and costimulators. IL-2 during initial activation. Regardless, TH2 cells are best known
inhibits
inhibits
inhibits
FIG. 1.16 TH1 and TH2 regulation. TH1 lymphocytes provide help for macrophage activation, cytolytic activ-
ity, and production of a subset of IgG subclasses. TH2 lymphocytes promote antibody responses, including
IgA, IgE, and the remainder of the IgG subclasses. This is mediated by production of cytokines, which have
a regulatory effect on each other.
for their production of IL-4, IL-5, and IL-13.287 The com- caspases. In addition, IFN-γ secreted by TH1 cells enhances
bined effects of these cytokines include stimulation of isotype phagocytosis and destruction of microbial invaders by mac-
switching in B cells to produce IgE (IL-4 and IL-13), IgA (IL-4 rophages. Meanwhile, virus-specific B cells have also encoun-
and IL-5), and some IgG subclasses; further differentiation of tered antigen and, within the paracortical areas of the regional
TH2 cells and suppression of TH1 development (IL-4); recruit- lymph node, interact with the TH1 cells by presenting antigen
ment of eosinophils and increased production of mucus in the via MHC II molecules. The B cell and TH1 cell also interact
gastrointestinal tract and airways (IL-4 and IL-13); and sup- via costimulatory signals through CD28-CD80/86, as well as
pression of IFN-γ activation of macrophages and stimulation CD40-CD40L. This further stimulates the TH1 cell to secrete
of alternative activation of macrophages with an antiinflam- IFN-γ, inducing the B cell to undergo isotype switching to pro-
matory phenotype that promotes collagen synthesis and fibro- duce IgG. Within germinal centers of lymphoid follicles in the
sis (IL-4 and IL-13). lymph node cortex, activated B cells in the presence of antigen
undergo somatic hypermutation of their BCR variable region
T-Helper Paradigms genes as part of the affinity maturation process. This results in
The role of helper T-cell subsets and the cytokines they pro- selection and expansion of B-cell clones that produce antibod-
duce in promoting cell-mediated immune responses can best ies with the highest affinity for the viral antigen. Finally, these
be illustrated in two scenarios, the first involving the induc- B cells differentiate into high-affinity IgG-secreting plasma
tion of a TH1 immune response in response to viral infection, cells. This combination of high-affinity IgG antibodies and
and the second an allergic response to biting insect salivary CD8+ CTLs serves to eliminate the virus.
antigens. In the first scenario, viral antigen present at the site In the second scenario, the introduction of salivary antigens
of an ongoing infection in the lungs is processed by resident into the skin by the bites of blood-feeding Culicoides midges
dendritic cells via the endogenous pathway (cytosolic viral results in the exogenous processing of antigen by dendritic
proteins associated with intracellular infection), as well as the cells. However, in the absence of IL-12 and interferon-γ, and
exogenous pathway (endocytosed virus and/or viral particles likely in the presence of IL-4, there is the induction of TH2 cells
released by dead and dying infected cells). The exogenously that produce additional IL-4, IL-5, and IL-13. These cytokines
processed epitope is presented on the surface of the dendritic inhibit TH1 responses and cause antigen-specific B cells to iso-
cell in the context of an MHC II molecule to a naive CD4+ type switch to IgE antibodies that bind to mast cells. Subse-
T cell in a regional lymph node. The APC produces IL-12, quent exposure to antigen causes degranulation of these mast
which induces NK cells attracted to the site of the infection cells as the result of antigen cross-linking surface-bound IgE.
to produce IFN-γ that, along with antigen presentation and Mast cell release of vasoactive mediators such as histamine,
production of IL-12 by the APC, activates the T cell and lipid mediators such as PGE2, and additional production of
drives it toward a TH1 phenotype. Meanwhile, naive CD8+ IL-4, which exacerbates the response and leads to the accumu-
T cells encounter endogenously processed viral antigen on lation of eosinophils, further contributes to the inflammatory
the surface of the APC in the context of MHC I molecules process. The end result in some horses is a seasonally recurrent
and become activated. Newly activated CD4+ helper T cells allergic dermatitis known as insect bite hypersensitivity (IBH;
(including TH1 cells) produce IL-2, and differentiated TH1 see Hypersensitivity and Autoimmunity later in this chapter).
cells produce IFN-γ. The IL-2 drives the clonal proliferation of Strong evidence for this paradigm as it relates to susceptibility
the activated CD8+ T cells, and the IFN-γ stimulates CD8+ T to IBH is provided by a recent study in IBH-affected and unaf-
cells to become activated CTLs that produce additional IFN-γ. fected ponies.288 Following intradermal injection of Culicoides
These activated CTLs lyse virus-infected target cells through antigen, IL-4 expression was increased in skin biopsies from
the production of perforin and granzyme, which lead to apop- IBH-affected ponies, whereas IFN-γ expression increased
tosis of the infected target cell via the activation of cytoplasmic in those from unaffected ponies. Moreover, antigen-specific
stimulation of peripheral blood CD4+ T cells demonstrated tissues in response to particular antigens. These could be self
a higher percentage of IFN-γ producing CD4+ T cells in the or foreign antigens, and the antigen-specific peripheral Tregs
unaffected ponies. Finally, the serum of all ponies contained inhibit other T cells recognizing the same antigen. Develop-
similar levels of antigen-specific antibodies, but the affected ment of some Tregs requires TGF-β, and Tregs are dependent on
ponies had higher titers of antigen-specific IgE. These results IL-2 for survival and maintenance of function. Tregs suppress
indicate that IBH affected ponies are TH2 biased with respect immune responses by producing inhibitory cytokines (TGF-
to Culicoides antigen and that a TH1-biased response in unaf- β and IL-10), by reducing the ability of APCs to stimulate T
fected ponies is protective against IBH. cells (through CD80/86 interactions), by triggering apoptosis
In general, TH1 and TH2 responses along with their respec- of effector T cells, and by disrupting metabolic pathways.298
tive roles in immune protection and susceptibility to disease Although TGF-β has multiple effects on the immune system,
have been well described in horses.206,208,249,289,290 its suppressive effects are due to its ability to inhibit the pro-
liferation and function of T cells and inhibit the activation of
TH17 CD4+ Effector T Cells macrophages. IL-10 has several suppressive properties, includ-
The function of TH17 cells is to recruit neutrophils and induce ing inhibiting IL-12 production by dendritic cells and macro-
inflammation, primarily to destroy extracellular bacteria and phages and reducing expression of MHC and costimulatory
fungi. Therefore TH17 cells represent an interaction between molecules on APCs.
the adaptive and innate immune systems. Although TH17 A variety of human autoimmune diseases are associated
responses are important in resolving extracellular infec- with loss of Treg function, including systemic lupus erythema-
tions, they also significantly contribute to the pathogenesis of tosus, multiple sclerosis, type 1 diabetes, rheumatoid arthritis,
inflammatory diseases. As discussed earlier in the section on psoriasis, and inflammatory bowel disease.298 In the horse,
innate immunity, PAMPs associated with invading microbes reagents and methods are available for the identification of
bind pattern recognition receptors on macrophages and Tregs.299-301 Equine Tregs produce IL-10 and TGF-β and dem-
dendritic cells, leading to the production of proinflamma- onstrate suppressive function302 and may be involved in tro-
tory cytokines. During such an infection, the combination of phoblast T-cell tolerance during pregnancy in the mare.300
cytokines produced by dendritic cells, including IL-1, IL-6, In foals Tregs appear to have higher suppressive activity than
and IL-23, along with IL-21, promotes the differentiation of those derived from adult horses.303 Finally, failure of Treg
activated CD4+ helper T cells to the TH17 phenotype. Strong suppression could be involved in several inflammatory/allergic
TH1 and TH2 responses tend to inhibit TH17 differentiation. diseases in horses, including IBH,304-306 inflammatory bowel
Once differentiated, TH17 cells produce IL-17, an important disease,293 and possibly recurrent airway obstruction.307 Dur-
contributor to the strong acute inflammatory reaction that ing persistent infections, such as HIV-1 infection in humans,
sometimes occurs during T-cell responses (immune inflam- Tregs may promote persistence by suppressing virus-specific
mation). IL-17 induces neutrophilic inflammation by stimu- T cells.308 Whether this occurs during persistent infections in
lating the production of other cytokines and chemokines horses is under investigation.
(such as TNF-α and CXCL8) that attract neutrophils to the site
and also stimulates the production of antimicrobial substances Lymphocyte Trafficking Pathways
(defensins) by numerous other tissue cell types. TH17 cells also Leukocyte trafficking has been reviewed previously, with a
produce IL-22 and IL-21, which further promote inflamma- particular emphasis on the innate immune response and the
tion, stimulate production of defensins, and improve barrier migration of neutrophils into inflamed tissues. Lymphocytes
function in epithelial tissues. In humans, TH17 cells have been involved in adaptive immune responses differ in their migra-
implicated in a variety of autoimmune and inflammatory dis- tion from most other cells, in that they recirculate instead of
eases, including rheumatoid arthritis, multiple sclerosis, and making one-way trips. Memory and naive T lymphocytes,
inflammatory bowel disease.291,292 In horses, TH17 cells may be with their different capacities for response to antigens, dif-
involved in the pathogenesis of inflammatory bowel disease,293 fer also in their migration pathways through the body. Two
recurrent uveitis,294 and recurrent airway obstruction.295,296 general pathways of lymphocyte recirculation have been
Finally, peripheral blood mononuclear cells (PBMCs) and demonstrated. Naive T lymphocytes take the most common
bronchoaveolar lavage cells from foals within the first 3 weeks route, which involves entry into the lymph node by extrava-
of life increase expression of IL-17 mRNA in response to Rho- sation from the high endothelial venule (HEV) and return
dococcus equi stimulation in vitro.297 Whether TH17 cells play to the peripheral circulation via the efferent lymphatic. The
a role in the pathogenesis of R. equi pneumonia is currently endothelial cells of the HEV have a distinctive appearance,
speculative. have specialized receptors, and can support a lot of lympho-
cyte migration. This allows rapid repeated circulation of naive
Regulatory T Cells lymphocytes through lymph nodes where there is the greatest
Regulatory T cells (Treg) are a specialized subset of CD4+ T cells chance of exposure to their specific antigens. Memory lym-
that play important roles in suppressing immune responses phocytes, on the other hand, leave the bloodstream in periph-
and maintaining self tolerance. Tregs express high levels of the eral vascular beds, particularly in inflamed tissues, and return
IL-2 receptor α (CD25) and the transcription factor FoxP3, to lymph nodes via afferent lymphatics. This leads to the expo-
which is critical for their development and function. Thymic sure of primed memory lymphocytes to the most likely early
Tregs (also known as natural Tregs) are generated by self recog- sites of antigenic encounter and allows for an early response to
nition in the thymus. Although these cells are directed against recall antigens. Thus memory lymphocytes are most common
self antigens, they do not induce autoimmune responses. in inflammatory lesions and in the epithelial surfaces of the
Rather, they inhibit other T cells recognizing self antigens in lung and gut wall. Differing expression of the adhesion and
the same tissue. Peripheral Tregs (inducible Tregs) are generated homing molecules may play an important role in mediating
from naive CD4+ T cells in peripheral secondary lymphoid these different migration pathways.
For lymphocytes to follow the maturation and migration generated in one location are transferred throughout the
pathway outlined previously, the first step is for the naive lym- mucosal immune system by lymphocytes programmed to
phocyte to get into a lymph node so that it can meet its antigen home to regional effector sites. The principal immunoglob-
on a professional APC. To achieve this the T lymphocyte needs ulin produced by the mucosal immune system is secretory
to exit in the HEV. The naive lymphocyte expresses L-selec- IgA, which, in humans, is the most abundant immunoglobu-
tin, and this can bind to the vascular addressins GlyCAM-1, lin class in the body. Secretory IgA has unique adaptations
CD34, and MAdCAM-1, which are expressed on HEVs and that promote transport out onto mucosal surfaces, where it
promote rolling similar to that mediated by P- and E-selectin protects the body from bacteria and viruses principally by
when they bind to phagocytes. These molecules are expressed immune exclusion, that is, by physically preventing attach-
on a variety of tissues, but in HEVs they have specific patterns ment to mucosal surfaces. The importance of mucosal IgA
of glycosylation that make them bind L-selectin. These differ- has already been demonstrated in immunity to numerous
ences represent the key to the specificity of the migration of equine diseases.309 Secretory IgA (sIgA) is formed by dimer-
lymphocytes to HEVs. This weak interaction initiates the pro- ization of two IgA monomers, which are attached by means
cess of extravasation, promoted by locally bound chemokines of disulfide bonds to a J chain also produced by the same
(i.e., CXCL8), which increase the affinity of the lymphocyte plasma cell that secretes the IgA. This confers the advantage
integrins for their ligands. of increased valency to sIgA, which can bind up to four of its
Approximately 25% of lymphocytes passing through an targets, increasing its agglutinating ability. Immunoglobulin
HEV leave, and this could mean 1.4 × 104 cells in a single A is relatively “noninflammatory” (i.e., does not fix comple-
lymph node every second, and in the body 5 × 106 lympho- ment as effectively as IgG1 or IgG4/7), consistent with a role
cytes may extravasate through HEVs every second (human). in defense by immune exclusion. Similarly, although myeloid
The “sticking” process (rolling, activation, arrest) takes a few cells possess Fc receptors for IgA it is not clear that it func-
seconds, with transendothelial migration and passage through tions as an efficient opsonin or promotes phagocytosis.
the HEV basement membrane occurring in about 10 min- Coordination of the mucosal immune response depends
utes. Most T cells after leaving the blood travel through the on organized mucosal-associated lymphoid tissue (MALT),
lymph node uneventfully and leave via efferent lymphatics; principal examples of which are the pharyngeal tonsils and
however, in rare events a naive T cell recognizes its specific the intestinal Peyer’s patches. In the gastrointestinal tract
peptide/MHC complex and becomes activated, eventually MALT is distributed throughout the gut, but in the respira-
leading to formation of effector and memory T cells. That tory tract these tissues are only found in the nasopharynx and
process takes 4 to 5 days, and once activated the migration oropharynx. MALT consists of lymphoid follicles containing
pathway of memory T cells differs considerably from naive IgA-committed B cells, surrounded by interfollicular T-cell
cells. All activated T cells lose the L-selectin molecules that areas with APCs and HEVs, with an overlying follicle-asso-
mediated homing to lymph nodes and increase the expression ciated epithelium (FAE). Naive lymphocytes enter the MALT
of other adhesion molecules. The homing of individual lym- by extravasation from the HEVs (there are no afferent lym-
phocytes to specific sites is regulated by expression of specific phatics in MALT), and after antigen encounter in the MALT
adhesion molecules. Memory cells are specifically attracted to they leave through efferent lymphatics. The FAE is specialized
areas of inflammation because of the increased levels of adhe- for antigen sampling, by having reduced secretion of mucus,
sion receptor ligands expressed on vascular endothelium in and through the presence of specialized antigen uptake cells
these regions. This is typically a result of TNF-α production termed microfold or M cells. These M cells are typically closely
by regional macrophages encountering infections. Sometimes associated with underlying aggregates of lymphocytes, often
infections do not result in TNF-α production, but memory within large basolateral membrane pockets, and play a criti-
cells also migrate randomly throughout the body. When they cal role in mucosal immune surveillance. Adherent macro-
encounter their antigen, they can produce cytokines such as molecules or particles bound to the apical M-cell membrane
TNF-α themselves, which in turn causes local endothelial cells undergo endocytosis or phagocytosis and are released at the
to increase expression of E-selectins. This will subsequently pocket membrane, where antigen presentation is initiated by
recruit more effector and memory cells to the region. dendritic cells, resulting in activation of antigen-specific B
cells (Fig. 1.17). Subsequent trafficking and recirculation of
Mucosal Immunity memory IgA–positive B cells to the other components of the
The mucosal immune system comprises a series of distinct mucosal immune system (respiratory tract, intestinal tract,
compartments within the immune system, which are adapted etc.) are responsible for the dissemination of local mucosal
to immunologic responses in unique environments such as IgA responses throughout what is termed the common muco-
the gut, respiratory tract, or urogenital tract. The mucosal sal immune system. After homing of these B cells to effector
immune system is perhaps the most important component of sites such as the lamina propria of the gut and respiratory
the adaptive immune system, and the reader is referred else- tract, and extravasation into the lamina propria from HEVs,
where for an appropriately detailed description of its general further antigen encounter and second signals from APCs and
features209 and of its role in equine immunity in the context of from helper T cells result in further differentiation into IgA-
respiratory disease.309 The mucosal immune system may rep- producing plasma cells. The short half-life of IgA-secreting
resent the original vertebrate immune system, and it certainly plasma cells requires a constant generation of precursors in
protects the largest vulnerable area of the mammalian body induction sites and flow to effector sites. Antigen sampling
and comprises a very large proportion of the total lymphocyte and presentation are not restricted to organized MALT,
populations and immunoglobulin pool.310,311 as throughout the mucosal surfaces dendritic cells play a
The mucosal immune system consists of organized and key role in antigen uptake and presentation, subsequently
dispersed lymphoid tissues that are closely associated with migrating to local lymph nodes or MALT to initiate immune
mucosal epithelial surfaces, and mucosal immune responses responses.
FIG. 1.17 Initiation of mucosal immune responses. Respiratory mucosal immune responses typically origi-
nate after antigenic encounter at inductive sites, which are the tonsils of the nasopharynx and oropharynx in
the horse. Naive lymphocytes enter the inductive sites from high endothelial venules via the specialized cuboi-
dal endothelium of those vessels in response to specific molecular signals. Antigens, such as microbes, are
taken up by microfold or M cells, which are part of the highly specialized follicle-associated epithelium present
at these sites. Antigenic material is transported across the M cell, and antigen presentation to B and T lympho-
cytes is accomplished by dendritic cells in the underlying tissues. The underlying lymphoid follicle is composed
primarily of B lymphocytes, surrounded by areas of T lymphocytes. Antigen-specific B lymphocytes become
committed primarily to IgA production at these sites, although some IgG-producing B lymphocytes are also
generated. Subsequently, the primed lymphocyte populations exit the inductive site via efferent lymphatics,
eventually reaching the blood circulation through the thoracic duct. These cells traffic to HEVs of effector sites
throughout the respiratory epithelium and extravasate to make up the intraepithelial lymphocyte and lamina
propria lymphocyte population and to give rise to lymphoid aggregates. Subsequent antigen encounter results
in terminal differentiation to plasma cells, primarily IgA producing, although some IgG plasma cells are also
formed. IgG is largely restricted to tissues, but secretory IgA is transported to the respiratory epithelial surface
where it can agglutinate and neutralize infectious organisms. (From Lunn et al.,309 with permission.)
After release of secretory IgA by plasma cells into the intersti- the first lymphoid organ to develop, and mitogen-responsive
tium, it is bound by the polymeric Ig receptor on the abluminal cells can be identified there from day 80 of the 340-day gesta-
surface of epithelial cells. Subsequently the sIgA is transported tional period of the horse.314 Subsequently these cells appear
across the epithelial cell and released at the luminal surface in peripheral blood at 120 days, lymph nodes at 160 days, and
together with the secretory component formed by cleavage of the spleen at 200 days. Cells responsive in mixed lymphocyte
part of the polymeric Ig receptor. The secretory component reactions are detectable in the thymus from 100 days and the
can also be found in a free form in mucosal secretions. The spleen at 200 days. Immunoglobulin production is detectable
secretory component confers resistance to proteolytic enzymes before 200 days of gestation, and newborn foals have IgM and
found in the respiratory and gastroenteric environment, some IgG in their serum.314-317 Presuckle serum concentrations of
of which are secreted by pathogens, and prolongs the longev- these immunoglobulins in the newborn foal are low. The mean
ity of sIgA. During its transit through the epithelial cell sIgA concentration of IgM is 31.7 mg/dL, and that of IgG (com-
can neutralize intracellular infections encountered in the prised of IgG1 and IgG4/7) is 7.5 mg/dL.316 Overall it appears
endosomal compartments of cells. In addition, sIgA can bind that functional T lymphocytes are present by day 100 and B
antigens in the submucosa and transport or excrete them to lymphocytes by day 200 of gestation. Immunologic compe-
the mucosa by this mechanism. The majority of the IgA in the tence of the equine fetus has been assessed in terms of specific
mucosa is dimeric sIgA, whereas the bone-marrow–derived antibody responses. In utero immunization of foals in late ges-
IgA in circulation is predominantly monomeric. tation with keyhole limpet hemocyanin in an alum adjuvant
In the horse our understanding of the architecture and results in detectable specific antibody production and T-cell
functions of the mucosal lymphoid system is best developed responsiveness at the time of birth.318 In addition, the equine
for respiratory lymphoid tissues.309 Although lymphoid tis- fetus can respond to coliphage T2 at 200 days and Venezuelan
sues are distributed throughout the respiratory tract, the equine encephalitis virus at 230 days.319,320
greatest masses comprise the nodular lymphoid tissue of the Although detailed studies are few, some data regarding
nasopharynx and oropharynx, which can have an overlying the maturation of thymocytes in young horses are available.
lymphoepithelium specialized for antigen uptake and pro- As discussed, stem cells migrate into the thymus and mature
cessing as in the case of tonsillar tissues. Additional nodular into T cells under the influence of the epithelial microenviron-
lymphoid tissues are typically present at sites where antigen- ment. In this process different patterns of cell surface molecule
laden mucus and air currents converge throughout the tra- expression distinguish successive stages of thymocyte matu-
chea and bronchi and is called bronchus-associated lymphoid ration. In humans, the earliest thymic precursor cells express
tissue. Tonsils represent the most complex mucosal nodular low levels of CD4. This CD4 expression is lost as early thy-
lymphoid tissues. Horses possess all of the various tonsillar mocytes become double-negative CD4−CD8− cells and then
tissues that are recognized in other species, and they are ana- demonstrate their T-cell commitment by TCR-β gene rear-
tomically complex.309 The nasopharyngeal tonsil is the largest rangement, which is an essential trigger for subsequent events
mass of lymphoid tissue in the respiratory tract of horses of all and leads to low levels of expression of a cell surface TCR-β–
ages, and its epithelium has been extensively characterized.312 CD3 complex. Intermediate thymocytes are CD4loCD8lo, but
This epithelium has a classical FAE and is heavily folded, after TCR-α gene rearrangement and expression of cell surface
forming crypts, and also contains M cells. The nasopharyn- αβ TCR they rapidly become CD4hiCD8hiTCR–CD3hi. Subse-
geal tonsil exists in the dorsal recess of the nasopharynx and quently, thymocytes selected on the basis of productive TCR
extends ventrally toward the opercula on either side of the gene rearrangement and lack of self reactivity become mature
nasopharynx. Therefore it is ideally placed for the sampling T cells expressing either CD4 or CD8 (single positive) in com-
of antigens before entry to the airways or alimentary tract bination with high levels of TCR-CD3. Maturation of T cells
and may serve as an important target for intranasal vaccines. and similar patterns of T cell CD3, CD4, and CD8 expression
This tissue appears to be most abundant in young foals and can be demonstrated in the equine thymus.321-324
atrophies with age, although many lymphoid follicles remain Mature B and T cells are present in the equine fetal spleen
throughout the nasopharynx. and lymph nodes by 90 to 120 days of gestation.316 B cells are
The nasopharyngeal epithelium also contains numerous IgM+, consistent with their naive status, and do not occur in
lymphocytes. Immunohistochemical studies indicate that germinal centers. Both CD8+ and CD4+ T cells are present in
the majority of these lymphocytes are CD8+ T lymphocytes, these tissues. By the time foals are born, CD8+ and CD4+ T
although B lymphocytes are also present.312 The contribution cells are abundant in these secondary lymphoid tissues, as are
of these lymphocytes to mucosal cellular immune defenses of IgM+ B cells within well-developed germinal centers.316
the upper respiratory tract is poorly studied. However, follow-
ing intranasal challenge of yearling and 2-year-old horses with Immunocompetence in Foals
EHV-1, virus-specific cytotoxic activity is detectable in sev- Although normal foals are immunocompetent at birth they
eral mucosal lymphoid tissues of the upper respiratory tract, are immunologically naive, and infectious disease in neo-
as well as the local draining lymph nodes, and is particularly natal foals is associated with high morbidity and mortality.
evident in the nasopharyngeal lining.313 This cellular immune Although failure of passive transfer is a major cause of this
response is presumably mediated by CD8+ T lymphocytes problem, as discussed later, immaturity of the immune system
found in the nasopharyngeal epithelium and underlying lam- has also been considered a potential contributing factor. As a
ina propria and may provide an important contribution to the result numerous studies of neonatal immunocompetence have
clearance of infectious virus from the upper respiratory tract. been completed and reviewed.249,325,326
Ontogeny of the Equine Immune System Innate Immune Responses in Foals

There have been few studies of the prenatal development of Multiple studies indicate that expression of TLRs, proin-
the equine immune system. As in other species, the thymus is flammatory cytokines, and acute phase proteins in foals is
comparable to that of adults.326 A number of studies have foals were born to EIAV-negative dams and thus had no
reported neutrophils to be fully functional from birth,327-329 passive transfer of EIAV-specific antibodies. Seroconver-
but their function is significantly impaired before absorp- sion occurred later than in the adults, and antibody lev-
tion of colostral antibodies, which are required for opsoniza- els waned sooner than in the adults. Adult horse dendritic
tion.329,330 Killing by foal neutrophils is reduced in the first 2 cells stimulated with CpG-ODN (a PAMP that binds TLR-
weeks of life, as is phagocytic ability when assays are performed 9) increase IL-12 expression, but foal dendritic cells do
using autologous serum.331 However, when serum from adult not.340 This study further demonstrates that although foal
horses is used, neutrophil phagocytosis and oxidative burst dendritic cells express the costimulatory molecule CD86
capacity are normal and similar to those of adults from birth similar to adult levels, MHC II expression is reduced at
through 4 months of age.331,332 These studies indicate that neu- birth and does not reach adult levels until 3 months of age.
trophil function in foals depends on immunoglobulins and/or A follow-up study found that foal dendritic cells infected
complement with adequate opsonizing activity. Another study with R. equi produce IL-12 and express costimulatory mol-
of foals less than 7 days of age indicates that phagocytosis and ecules (CD40 and CD86) similar to adult levels, but as pre-
oxidative burst activity of neutrophils is reduced compared viously observed, MHC II molecule expression is limited.341
with adult levels, even when adult serum is used.333 Although Thus foal APCs can produce the costimulatory and IL-12
the assays were similar, these apparently disparate results may signals (albeit variably depending on stimulus) required
have been due to the procedures used. Regardless, the impor- for TH1 differentiation, but MHC II presentation may be
tance of complement in foals is illustrated by the finding that compromised.
the opsonic capacity of foal serum for bacteria is halved when Foals less than 1 week of age have significantly lower
complement is inactivated by heat.220 Interestingly, comple- whole blood basal expression of IFN-γ and IL-4 than adult
ment activity in the first week of life is considerably elevated horses and, unlike adults, fail to develop antigen-specific
in colostrum-deprived foals, possibly as an alternative defense lymphoproliferative responses following immunization with
mechanism.334 In bovine colostrum-fed foals, serum comple- a killed adjuvanted bovine vaccine.342,343 Similarly, foals less
ment levels reach adult levels by 1 to 3 weeks of age.335 Finally, than 1 week of age and foals between 3 and 6 months of age
alveolar macrophages recovered from bronchoalveolar lavages have a lower frequency of IFN-γ and IL-4 secreting PBMCs
may be low in number up to 2 weeks of age and have impaired than adult horses.344 Bronchial lymph node lymphocytes
chemotactic function.336 from R. equi–infected foals have significantly reduced R.
Taken together, available studies indicate that innate equi–specific proliferative responses than those from adult
immunity is intact in foals and leads to functional neutrophil horses but, interestingly, have lower IL-4 expression, higher
responses similar to those in adults but that adequate levels of IFN-γ expression, and higher IFN-γ/IL-4 ratios on R. equi
immunoglobulins and complement with opsonizing activity stimulation than those of adults.345 Although quantitatively
are critical. lower than adults, IFN-γ production by foal TH1 cells (and
by CD8+ T cells) following nonspecific stimulation is detect-
Adaptive Cell-Mediated Immunity in Foals able a few days after birth and increases with age, whereas
Several studies have measured lymphocyte numbers and sub- IL-4 production by TH2 cells is virtually absent during the
populations in foals.332,337,338 Foals are born with B and T lym- first 3 months.346 In addition, R. equi infection of BAL cells
phocytes, and with CD4+ and CD8+ T-lymphocyte subsets. from 10-day-old foals results in increased expression of
Lymphocyte counts rise in the first 4 months of life, and the IFN-γ and IL-4 and in PBMCs results in consistent IFN-γ
proportion of B lymphocytes increases. Although prolifera- expression during the first 3 weeks of age but decreased IL-4
tion of peripheral blood T and B lymphocytes is lower during expression at birth.297 Finally, foals orally inoculated with R.
the first few weeks of life, it rises to adult levels by 4 weeks of equi within the first 2 weeks of life develop R. equi–specific
age.332 During the first 3 months of life, follicular development CTL responses and IFN-γ expression by R. equi–stimulated
and the density of B- and T-cell zones increases in secondary PBMCs at similar levels as adult horses, with lower levels of
lymphoid tissues.336 In contrast, organized lymphoid tissue is IL-4 expression.347
not present in the lungs at birth, and very few lymphocytes are Taken together these observations indicate that foals
present in bronchoalveolar lavage (BAL) samples during the are capable of mounting T-cell responses, including TH1
first week of life.326,332 The appearance of organized lymphoid and CTL responses, and under some circumstances these
tissue in the lungs, along with T and B cells in BAL samples, responses can be similar to those of adult horses. Based on
gradually increases during the first 3 months. These factors the latter studies documenting lower IL-4 expression/produc-
likely increase the susceptibility of foals to respiratory infection relative to that of IFN-γ, foals appear to have a TH1 bias.
tions during the neonatal period. These observations challenge the view that foals are inher-
Compared with adult horses, foals exhibit reduced levels ently TH2 biased similar to mouse and human neonates.348
of IFN-γ production in stimulated BAL cells and PBMCs It should be noted that the equine studies evaluated different
throughout the first 6 months of life, and this reduced TH1 cell populations, different stimulation conditions, different
response might contribute to their susceptibility to Rho- methods to measure cytokine expression/production, and, in
dococcus equi and other intracellular pathogens.339 Adult the immunization studies, different immunogens and routes
horses immunized with an experimental EIAV plasmid of immunization, likely contributing to some of the disparate
DNA vaccine developed antigen-specific antibodies, lym- results. Nonetheless, these studies agree for the most part
phoproliferative, and CTL responses, whereas foals immu- that overall, helper T-cytokine expression/production and
nized within the first week of life with the same construct T-cell responses are quantitatively lower than those of adult
(and boosted at the same intervals as the adults) devel- horses. Although the precise mechanisms underlying these
oped antigen-specific antibody and lymphoproliferative differences between foals and adults are unclear, contributing
responses but failed to develop CTL responses.273 These factors likely involve the overall naivete of T cells in young
foals and the relative immaturity of APCs in terms of PAMP the antigenic stimulation. Overall, when foals are vaccinated
responses and MHC II presentation, all leading to inefficient with antigens against which they have no passively transferred
priming of naive T cells. antibody, normal antibody responses have been documented
from at least 3 months of age.352
Antibody-Mediated Immunity in Foals In colostrum-fed foals, serum IgG concentration falls to
Passive Transfer of Maternal Antibodies. As a result of epi- its lowest level at 1 to 2 months of age as a result of catabolism
theliochorial placentation in horses, transfer of maternal anti- of maternally transferred immunoglobulin, subsequently
bodies does not occur in utero, and foals are born essentially rising toward adult levels as a result of endogenous immu-
agammaglobulinemic. Foals therefore depend on the ingestion noglobulin production.331,332,338,353 A study of five Quarter
of colostrum and intestinal absorption of maternal antibodies Horse foals in the first 9 weeks of life showed that IgG (the
within the first 24 hours of life for protection against infectious equivalent of IgG1 plus IgG4/7) concentrations were low-
pathogens. See discussion of failure of transfer of passive immu- est at 1 month of age. However, the subsequent increase in
nity under Secondary Immunodeficiencies later in this chapter. IgG concentration was due to de novo IgG1 production, not
De Novo Antibody Production in Foals. Few studies of IgG4/7. At the end of this study (at 9 weeks of age) there was
de novo antibody production have been conducted in foals still no clear evidence of IgG4/7 production, although IgG1
without the effect of transferred maternal antibodies. In a and IgG3/5 concentrations had reached or exceeded adult
study of 10 pony foals fed only bovine colostrum, endogenous levels. In adult horse serum, IgG4/7 comprises greater than
equine antibody production measured by radial immunodif- 60% of total serum IgG and is by far the dominant subclass
fusion resulted in serum concentrations of IgG of 200 mg/dL in foal serum after passive transfer of immunity.249,317,326
by 2 weeks of age, 400 mg/dL by 1 month, and 1000 mg/dL IgG4/7 has also been shown to have a critical role in immu-
by 3 months.349 In a smaller study of two colostrum-deprived nity to a variety of pathogens,354,355 and it is possible that the
pony foals, comparing them to 18 colostrum-fed foals, and naturally late onset of endogenous production may be a fac-
measuring serum γ-globulin levels by immunoelectrophore- tor in the increased susceptibility of foals to bacterial respi-
sis, very similar results were obtained, although it was appar- ratory infections at this age.249,356,357 A study investigating
ent that the colostrum-deprived foals achieved higher serum this possibility during the first 42 days of life measured the
γ-globulin levels between 6 weeks and 3 months of age than opsonic capacity of foal serum against Escherichia coli and
colostrum-fed foals.350 In a third study, antibody concen- Actinobacillus equuli.220 No differences were detected over
trations in six colostrum-deprived foals were substantively time, and foal serum was as effective as adult horse serum.
higher than in five control foals between 3 and 5 months of Because IgG1, IgG4/7, and IgG3 all activate complement,
age.334 These three studies provide evidence for substantial bind Fc receptors, and bind bacterial cell walls,247 IgG1 and
endogenous production of IgG in the first month of life in IgG3 may functionally compensate for the slower onset
foals deprived of equine colostrum and suggest that the onset of IgG4/7 production in young foals. Finally, in a study of
of production is earlier and the rate is higher in foals deprived immunoglobulin concentrations in foals throughout the first
of colostrum. This observation is consistent either with non- year of life, serum levels of all measured isotypes decreased
specific immunosuppression in colostrum-fed foals or stimu- at 4 weeks of age, after which point all but IgG4/7 began to
lation of immunoglobulin production in colostrum-deprived rise. This pattern was the result of catabolism of maternal
foals. In another study of foals from mixed-breed horses fed antibody and the different times of onset and rates of endog-
only bovine colostrum, endogenous IgG production started enous antibody production as follows: (1) IgA and IgG3/5
later and was first detected at 1 month of age in the majority levels stabilized at 8 to 12 weeks of age; (2) IgG1 levels
of foals, reaching similar levels to foals fed equine colostrum peaked at 8 weeks of age and then slowly declined through-
by 2 months of age.351 Foals immunized with an experimen- out the duration of the study; and (3) IgG4/7 levels reached
tal EIAV plasmid DNA vaccine within the first week of life their nadir at 2 to 5 months of age and did not begin to rise
and boosted on days 15, 36, and 50 seroconverted between until after 16 weeks of age. These observations could provide
days 47 and 53.273 By comparison, three adult horses similarly a basis for reduced endogenous antibody-mediated immu-
immunized seroconverted on day 29. The foals were born nity during the first year of life. This study also showed that
to EIAV-negative dams and thus had no passive transfer of at 1 year of age serum immunoglobulin concentrations had
EIAV-specific antibodies. Vaccination of 3-day-old foals with still not reached adult levels.
a killed adjuvanted bovine vaccine, for which there was no A factor that significantly affects de novo immune responses
maternal antibody interference, resulted in considerably in foals is the suppressive effect of passively transferred anti-
decreased antibody responses compared with adults.343 Al- gen-specific maternal antibodies. The rate of decline of these
though 3-month-old foals had improved antibody responses, antibodies varies for both individuals and different infectious
the magnitude was less than in adults. In contrast, a similarly agents. The half-life for maternal IgG in foals is estimated at
designed study demonstrated that vaccination with bacillus 20 to 30 days.350 Studies of antigen-specific antibodies dem-
Calmette-Guérin (BCG; a modified live Mycobacterium bovis onstrate similar half-lives for anti-influenzavirus and anti–
vaccine) elicited robust antibody responses similar to those tetanus antibodies of 27 to 29 days for IgG1, 35 to 39 days
of 4-month-old foals and slightly less than adults, although for IgG4/7, and 35 days for IgG3/5.358 For many important
neither group of foals produced vaccine-specific IgG4/7.342 pathogens, the concentration of maternal antibodies in foals
The latter result was consistent with the findings of other stud- falls to nonprotective levels by 2 to 3 months of age.359,360
ies (see later discussion). Taken together, neonatal foals are However, the remaining antibody can still render the foal
clearly capable of endogenous antibody production in the ab- unresponsive to vaccination for weeks or even months to
sence of maternal antibody, although responses tend to be less come. In the case of equine influenzavirus361,362 and tetanus
robust than in older foals and adults. However, the magnitude toxoid, maternal antibodies can persist until 6 months of age
of the antibody response in neonates depends on the nature of and inhibit antibody responses in foals vaccinated before that
age.358 In contrast, a recent study indicates that 3-month-old immune-based strategies to prevent critical infectious dis-
foals immunized with a three-dose-series multivalent vaccine eases in foals such as R. equi pneumonia.
had similar antigen-specific antibody and T-cell responses as
foals initially vaccinated at 6 months of age.363 Based on this
study it is reasonable to begin vaccinating foals earlier than 6 Y HYPERSENSITIVITY AND
months of age in circumstances where the risk of infectious AUTOIMMUNITY
disease is high.
Hypersensitivity refers to an altered state of immunoreactiv-
Implications for Immunocompetence in Foals ity resulting in self-injury. Four different types of hypersen-
The evidence presented previously indicates that the sitivities can be defined by the type of immunologic process
immune system of the foal is competent in many ways, with underlying the tissue injury (Table 1.6). The most common
the innate immune system completely functional at least by and important type of hypersensitivity disease in most spe-
the second week of life, and with the full complement of cies is type I hypersensitivity, mediated by IgE. In these
lymphocytes present from birth. Antibody is entirely pro- diseases some individuals produce IgE antibodies against
vided by passive transfer at first, although endogenously a normally innocuous antigen, which is called an allergen.
produced immunoglobulin is detectable within a few weeks Exposure to the allergen triggers mast cell degranulation
of birth and predominates from 1 to 2 months of age. Nev- as described later, and a series of responses result that are
ertheless, there are some key features of the foal immune characteristic of allergy. Allergic diseases are so important
system that can limit its ability to defend against infection. that more is known about the function of IgE in hypersen-
A critical factor is maternal antibody interference, which sitivity than about its normal role in host defense. In this
inhibits the binding of antigens to BCRs of naive B cells definition, and throughout this chapter, the term allergy
in the foal, reducing endogenous antibody responses. As refers only to type I hypersensitivity diseases mediated by
foals age, a continuing immunomodulatory effect of mater- IgE, whereas in other definitions allergy can refer to the
nal antibody may limit foal immunoresponsiveness, while entire spectrum of hypersensitivity diseases.365 Other forms
no longer providing comprehensive protection itself. Of of hypersensitivity disease depend primarily on IgG anti-
similar importance is that although the adaptive immune bodies (type II and III hypersensitivities) or T cells (type IV
system is complete from the time of birth, it is naive. In hypersensitivity). Each of these disease processes can play
addition, APCs are immature.364 Neonates can mount nor- a role in the immunopathogenesis of autoimmune disease,
mal immune responses but require appropriate presentation in which the body mounts an adaptive immune response to
of antigen and costimulatory signals. Reduced antigen pre- self tissue antigens.
sentation by APCs, or antigen presentation in the absence Clinical hypersensitivity diseases, such as recurrent air-
of costimulatory signals, can result in a failure to mount way obstruction (RAO) or equine recurrent uveitis (ERU),
the appropriate immune response. This is particularly an can involve more than one type of hypersensitivity reaction
issue in neonates. The absence of memory responses and a simultaneously, which limits the utility of this classification for
well-developed repertoire of immune effectors is a serious clinical diagnosis. Alternative strategies for classifying these
handicap that only appropriate antigenic encounters can diseases may have greater clinical utility. For example, anti-
overcome. Despite the fact that humoral and cell-mediated body-mediated hypersensitivity diseases (types I, II, and III)
immune responses are less robust during the first year of are immediate in onset if preformed antibody exists in circula-
life, the majority of foals survive to adulthood. However, a tion or tissues, with some variation in time course dependent
better understanding of immune regulation in foals and the on the antibody isotype involved. Cell-mediated hypersensi-
precise mechanisms underlying the differences between foal tivity diseases (type IV) are delayed, even in sensitized indi-
and adult immune responses is needed to develop improved viduals, for 1 to 3 days, while effector cells are recruited to
TABLE 1.6 Hypersensitivity

Type I Type II Type III Type IV
Immune Mediator IgE IgG IgG, IgA TH1 TH2 CTL

Antigen Soluble antigen Cell or matrix as- Immune complex Soluble Soluble Cell-associat-
sociated antigen formation antigen antigen ed antigen
Effector Mast-cell Fc-receptor– Fc-receptor– Macrophage Eosinophil Cytotoxicity
mechanism degranuation positive cells positive cells, activation activation
(phagocytes of complement
reticuloendothelial
system)
Examples of Systemic Immune-mediated Purpura hemor- Equine Chronic Contact
hypersensitivity anaphylaxis, hemolytic rhagica, serum recurrent Culicoides dermatitis
reaction Culicoides anemia, neonatal sickness uveitis hypersensitivity
hypersensitivity isoerythrolysis

Note: The four types of hypersensitivities can be differentiated by the immune mediator involved, the form of antigen recognized, and the effector mechanism
elicited in producing pathology. Equine examples of each condition are given when available.
the site of antigen exposure.365 The goals of this section are as also results in CD40L expression and IL-4 secretion, which
follows: further promotes IgE production by B lymphocytes and sus-
• Review the classical hypersensitivity types to explain the tains allergic reactions.
immunopathogenesis of hypersensitivity diseases Some individuals are predisposed to IgE-mediated hyper-
• Describe antibody and cell-mediated hypersensitivities of activity to a wide variety of environmental allergens, and this
horses and their immunologic basis condition is termed atopy.370 Affected individuals have high
• Identify autoimmune conditions of horses with a known levels of IgE in the blood and increased eosinophil populations.
immunologic basis In humans this condition depends partly on genetic factors,
Detailed descriptions of clinical aspects of hypersensitivity including genetic variations in the IL-4 promoter sequence or
and autoimmune diseases, their diagnosis, and their manage- association with particular MHC II genes. Nevertheless, envi-
ment are presented elsewhere in this book. Detailed explana- ronmental factors are also important, as atopy is increasingly
tions of many immunologic mechanisms involved in these common in humans in economically developed parts of the
disease processes are provided previously in this chapter. world. Four potential explanations for this observation are
decreased exposure to infectious disease during childhood,
environmental pollution, allergen levels, and dietary change.
Classical Types of Hypersensitivity Reactions The first explanation, known as the “hygiene hypothesis,” is
Type I Hypersensitivity supported by epidemiologic and experimental evidence. The
As described, type I hypersensitivity, also known as immediate premise is that living in areas with poor sanitation, micro-
hypersensitivity or allergy, is mediated by IgE antibody specific bial exposure, and infectious diseases early in life biases the
for allergens, which are extrinsic antigens normally not rec- immune system toward TH1 responses and away from TH2
ognized by the healthy immune system. IgE is predominantly responses, thus reducing the later development of allergic dis-
found in tissues, where it is bound to mast cells through the eases. This is thought to be due in large part to the compo-
high-affinity IgE receptor, which is called FcεRI and has been sition of the intestinal microbiota, including the presence of
identified in the horse.366 When antigen binds to IgE on the helminths, and the resulting induction of Tregs that modulate
surface of mast cells, cross-linking two or more IgE molecules TH1/TH2 balance.371 In developed societies, decreased micro-
and their FcεRI receptors, this triggers the release of chemical bial exposure during early childhood and decreased preva-
mediators from the mast cells, which cause type I hypersen- lence of infectious diseases leads to a depleted microbiota
sitivity reactions. Basophils and eosinophils (when activated) and an increased tendency to mount TH2 responses, which
also possess FcεRI receptors and therefore can participate in may be the natural bias of the neonatal immune system.348 It
the same process. In addition to FcεRI receptors, there is an is unclear if atopy occurs in horses and whether or not the
unrelated low-affinity IgE receptor called CD23 that is present hygiene hypothesis applies. Interestingly, a recent study in 593
on many lymphocytes, monocytes, eosinophils, platelets, and Warmbloods in Switzerland found that some horses had mul-
follicular dendritic cells. The role of CD23 appears to be to tiple hypersensitivities.372 For example, horses with RAO had
enhance IgE responses to specific antigens when those anti- a 13.1 times higher odds ratio of being affected with IBH, and
gens are complexed with IgE. Thus CD23 on APCs can capture horses with IBH had a 7.1 times higher odds ratio of being
IgE-bound antigens. In the horse CD23 has been identified affected with urticaria. In addition, the multiple hypersensi-
and its expression is upregulated by equine IL-4.367 Monoclo- tivity phenotype was associated with the absence of nematode
nal antibodies against equine CD23 are now available and have eggs in the feces. Icelandic horses living in Iceland have high
been used to identify CD23 primarily on a subpopulation of B intestinal helminth burdens and low numbers of IL-4–produc-
cells.368 These reagents should be useful for further evaluating ing T cells along with significantly higher IL-10 and TGF-β
the role of this low-affinity receptor in IgE-mediated responses production by PBMCs than Icelandic horses living in Switzer-
in the horse. land.373 These horses do not develop IBH in Iceland because
The selective stimulation of IgE responses depends on Culicoides midges do not occur in Iceland, but they are prone
characteristics of the antigen (allergen), the individual affected to IBH when imported into countries where Culicoides spp.
(genetic factors such as MHC haplotype), and the mechanism are endemic. This susceptibility is associated with deworm-
of antigen presentation. The antigen must be capable of elic- ing before import, along with increased IL-4 production and
iting a TH2 immune response to stimulate IgE production. decreased regulatory cytokine production.373 Taken together,
Small, soluble proteins, frequently enzymes, containing pep- the results of these studies suggest that some horses are atopic
tides suitable for MHC II antigen presentation, and presented and that this might be associated with reduced intestinal nem-
to mucosal surfaces at low doses, are particularly efficient at atode exposure, consistent with the hygiene hypothesis.
generating IgE responses. Low doses of antigen specifically Effector Mechanisms in Type I Hypersensitivity Allergic
favor TH2 over TH1 responses, and exploiting this relationship Reactions. When triggered by antigen cross-linking of IgE
is the basis of some therapeutic hyposensitization strategies bound to FcεRI cell surface receptors, activated mast cells re-
(see under Immunomodulators). These processes are regulated lease chemical mediators stored in preformed granules and
by Tregs (discussed previously), which suppress TH2 cytokine synthesize leukotrienes and cytokines. In type I hypersensi-
production in healthy individuals. When Tregs are deficient, tivity reactions the outcome of this reaction can vary from
atopy can result. The process of TH2 differentiation is critical anaphylactic shock to minor localized inflammation. Mast cell
to promoting IgE responses and may be favored at enteric and degranulation causes an immediate allergic reaction within
respiratory mucosal surfaces, or skin, where parasite invasion seconds, but there is also a sustained late-phase response that
typically occurs. This makes teleologic sense, as IgE responses develops over up to 8 to 12 hours due to recruitment of TH2
are important for antiparasitic immunity.369 Dendritic cells at lymphocytes, eosinophils, and basophils.
such locations are frequently programmed to stimulate TH2 Mast cells are highly specialized cells of the myeloid lineage
responses. Cross-linking of FcεRI receptors on granulocytes that are common in mucosal and epithelial tissues near small
blood vessels. The range of inflammatory mediators released followed by a late-phase response several hours later. When
by degranulating mast cells is wide and includes enzymes that allergens are ingested and reach the skin from the blood-
can remodel connective tissues; toxic mediators such as hista- stream, a disseminated form of the wheal-and-flare reaction
mine and heparin; cytokines, including IL-4, IL-5, IL-13, and occurs that is termed urticaria or hives. Prolonged inflamma-
TNF-α; and lipid mediators, including leukotrienes and PAF. tion of the skin results in eczema or atopic dermatitis in some
Histamine causes an increase in local blood flow and capillary individuals. Ingestion of allergens causes activation of gas-
permeability. Enzymes activate matrix metalloproteinases, trointestinal mast cells resulting in fluid loss across the bowel
which cause tissue destruction, and TNF-α increases expres- and smooth muscle contraction. The clinical presentation is
sion of adhesion molecules and attracts inflammatory leuko- diarrhea and vomiting. Sometimes ingestion of allergens can
cytes. These reactions are all appropriate when the mast cell is lead to systemic anaphylaxis if they are absorbed rapidly, or
reacting to an invasive pathogen, but in allergy this is the basis urticaria, as is sometimes seen in humans after oral penicillin
of the immediate inflammatory response and also the initiat- administration.
ing step in the late-phase response.
The role of eosinophils in inflammation is tightly con- Type II Hypersensitivity
trolled at several levels. Synthesis in the bone marrow depends This form of hypersensitivity disease occurs when the causal
on IL-5 produced by TH2 cells in the face of infection or other antigen is associated with cells or tissue components of the
immune stimulation. Transit of the eosinophils to tissues body, and there is an IgG antibody response to this antigen.
depends on two chemokines, eotaxin 1 and eotaxin 2. Acti- Phagocytes, or other cells expressing Fcγ receptors, mediate
vation of eosinophils by cytokines and chemokines induces destruction of the affected tissue, or removal from the circu-
them to express FcεRI and complement receptors and primes lation by the reticuloendothelial system in the case of anti-
the eosinophil to degranulate if it encounters antigen that can body-positive erythrocytes or platelets. Additionally, antibody
cross-link IgE on its surface. Mast cell degranulation and TH2 bound to erythrocytes may activate complement resulting in
activation recruit and activate large numbers of eosinophils at hemolysis. Blood transfusion reactions and neonatal isoeryth-
the site of antigen encounter. Basophils are similarly recruited, rolysis are examples of type II hypersensitivities. Immune-
and together their presence is characteristic of chronic allergic mediated hemolytic anemia and thrombocytopenia are
inflammation. Eosinophils can trigger mast cells and basophil examples of drug-associated type II hypersensitivities. In the
degranulation by release of major basic protein. This late- case of the horse, penicillin is an established cause of hemolytic
phase response is an important cause of long-term illnesses anemia.375 Diagnosis can be accomplished using a Coombs test
such as chronic asthma in humans. (Fig. 1.18). Penicillin binds to the erythrocyte surface and is
Clinical Manifestations of Type I Hypersensitivity Reactions targeted by antipenicillin antibodies of the IgG isotype. Inter-
Depend on Their Site. The clinical outcome of type I hyper- estingly, quite large numbers of horses have antipenicillin anti-
sensitivity reactions depends on the amount of IgE present, bodies of the IgM isotype, but this does not lead to disease.
the dose of allergen, and the site of allergen introduction. Di-
rect introduction of allergen into the bloodstream or rapid Type III Hypersensitivity
enteric absorption can lead to widespread activation of con- In type III hypersensitivity the antigen is soluble and present
nective tissue mast cells associated with blood vessels. This in the circulation. Disease results from formation of antibody-
potentially disastrous event, termed systemic anaphylaxis, can antigen aggregates or immune complexes under certain spe-
cause catastrophic loss of blood pressure and airway obstruc- cific conditions. Although immune complexes are generated
tion resulting from bronchoconstriction and laryngeal swell- in all antibody responses, they are generally harmless. Large
ing. This leads to anaphylactic shock and can follow adminis- complexes fix complement and are removed from circulation
tration of drugs against which an individual has an established by the reticuloendothelial system. However, small complexes
IgE response. Treatment with epinephrine can control these can form at antigen excess (Fig. 1.19), and these can deposit
potentially fatal events. in blood vessel walls and tissues where they ligate Fc receptors
Penicillin is one example of a drug that can cause type I on leukocytes, causing an inflammatory response, increased
hypersensitivity reactions in humans, and it may induce this vascular permeability, and tissue injury. Complement activa-
type of hypersensitivity reaction in the horse.374 Penicillin tion also contributes to this process. Local injection of antigen
can act as a hapten (see under Equine Immunology). Penicil- can sometimes lead to a necrotizing skin lesion due to type III
lin alone can elicit antibody formation by B cells but cannot hypersensitivity, and this is termed an Arthus reaction.
elicit T-helper cell responses as it is not a protein. However, The classical example of a type III hypersensitivity reaction
the β-lactam ring of penicillin can react with amino groups on is serum sickness, which can be seen after administration of
host proteins to form covalent conjugates, and the modified horse antiserum in humans, such as in treating snakebites.
self peptides can generate TH2 responses in some individu- After an IgG response to the horse serum is generated (7–10
als. The TH2 cells can in turn release cytokines, which acti- days), signs of fever, urticaria, arthritis, and sometimes glo-
vate penicillin-binding B cells to produce IgE. In this scenario merulonephritis result. The foreign antigen is cleared as part
penicillin is a B-cell antigen and becomes a T-cell antigen by of this process, which makes this condition ultimately self-lim-
modifying self peptides. Intravenous penicillin results in pro- iting. Alternative scenarios for induction of type III hypersen-
tein modification and recognition and cross-linking of mast sitivity reactions include persistent infectious diseases where
cell IgE leading to anaphylaxis. pathogens (or their antigens) are not completely cleared from
Allergen inhalation, in contrast, induces local inflamma- tissues or autoimmune diseases in which antigen persists.
tion of the respiratory tract—for example, in the upper air- Glomerulonephritis in horses with chronic equine infectious
ways as in allergic rhinitis or in the lower airways in human anemia is one example of the former.376 Purpura hemorrhag-
asthma. Similarly allergen introduction into the skin causes ica following Streptococcus equi infection is another. Inhaled
local histamine release initially and a wheal-and-flare reaction, antigens associated with moldy hay that induce IgG responses
1) Wash patient RBCs

+ (anti-erythrocyte Ab) – (no anti-erythrocyte Ab)
2) Add anti-equine
immunoglobulin Ab
+ -
agglutination no agglutination
FIG. 1.18 Direct Coombs test. Ab, Antibody; RBCs, red blood cells.
equine IgE. Although equine IgE has long been known to

Antibody Antibody-antigen Antigen
excess equivalence excess
exist,377,378 and the genetic sequence has been known since
1995,379-381 the only reagents for studying it have historically
been conventional polyclonal antisera produced by vaccina-
tion with physicochemically purified IgE382,383 or made in
chickens after vaccination with recombinant fragments of the
IgE heavy chain.384 Although many valuable studies have been
performed using these reagents,385-388 the availability of well-
characterized monoclonal antibodies recognizing equine IgE
has moved the field forward.389,390 Passive transfer of maternal
FIG. 1.19 Antibody-antigen precipitation. Antibody can precipitate
IgE via colostrum occurs in equine neonates, and cross-link-
soluble antigen in the form of immune complexes. This is most efficient
ing of this maternal IgE on the surface of neonatal basophils
when concentrations of antibody and antigen reach equivalence, and
results in intracellular IL-4 production.391,392 This might help
large immune complexes are formed. However, when antigen is in excess
promote adaptive T-cell responses in newborn foals. However,
some immune complexes are too small to precipitate and can produce
the onset of endogenous IgE production in horses does not
pathologic changes such as are seen in type III hypersensitivities.
occur before 9 to 11 months of age and does not reach adult
levels before 18 months.391 This may help explain why hyper-
can lead to immune complex formation in the alveolar wall, sensitivity disease is uncommon in horses before puberty.
as occurs in cattle with hypersensitivity pneumonitis. This can The following section describes a series of equine diseases
also occur in humans and is known as farmer’s lung. Any such with characteristics of immediate hypersensitivity disease.
circumstance in which immune complexes are deposited in This is not an exhaustive list of equine hypersensitivity dis-
tissues can lead to this type of pathology. eases and additional examples can be found throughout this
book.
Type IV Hypersensitivity
Cell-mediated type IV hypersensitivities cause delayed Systemic Anaphylaxis
hypersensitivity reactions. A variety of cutaneous hyper- Systemic anaphylaxis is a severe immediate type I hypersensi-
sensitivity reactions are seen, such as the contact hyper- tivity reaction mediated by IgE. The incidence of true systemic
sensitivity seen after absorption of haptens such as anaphylaxis in horses is unknown, although the condition has
pentadecacatechol in poison ivy or the local TH1 response been reported in association with administration of a wide
seen in the diagnostic tuberculin reaction. When type IV range of compounds, including serum, vaccines, vitamin E–
hypersensitivity results in a TH2 response the principal out- selenium preparations, thiamine, iron dextrans, and antibiot-
comes are eosinophil activation and recruitment such as in ics, including penicillin.393,394 Target organs in experimental
chronic asthma in humans. equine anaphylaxis are the lung and the intestine.393 Sudden
dyspnea; hypotension, as evidenced by poor peripheral pulse
character; rapid onset of urticaria; and collapse are cardinal
Antibody-Mediated Hypersensitivity Diseases signs of the onset of systemic anaphylaxis.
in the Horse The therapeutic goals in treating systemic anaphylaxis
The study of hypersensitivity disease in the horse was ham- are to (1) prevent or reverse the complications caused by
pered in the past by the lack of reagents capable of detecting mediator release, (2) maintain respiratory integrity, and (3)
maintain cardiovascular stability. Not all anaphylactic reac- intestinal nematode burdens in Iceland,373 these observations
tions require therapy. However, rapid recognition of those are consistent with the hygiene hypothesis. Moreover, it has
that do is critical to patient survival. Intravenous access via an been shown that horses with IBH have reduced Treg responses
indwelling intravenous catheter and airway patency should be compared with unaffected horses.304-306,400
established immediately because cardiovascular collapse and
upper airway obstruction caused by angioedema can occur Recurrent Airway Obstruction
rapidly. The conscious horse does not tolerate tracheal intu- Recurrent airway obstruction (RAO) is a severe inflammatory
bation so emergency tracheotomy may be required. Oxygen disease of middle-aged and older horses induced by expo-
should be administered if available because bronchocon- sure of susceptible horses to inhaled organic dust, generally
striction and cardiovascular collapse result in hypoxemia. from hay, although a summer pasture–associated form is also
The fluid requirement of horses in anaphylactic shock is not observed in the southern United States and in Europe.296,401,402
known, but large volumes of balanced polyionic fluid should Hay dust contains a mixture of mold spores, forage mites, par-
be administered rapidly. ticulates, and endotoxins, which can induce and exacerbate
The principal therapeutic agent is epinephrine, which is airway inflammation. Removal of the hay dust by returning the
a potent sympathetic stimulant. Epinephrine administration horse to pasture leads to decreased inflammation within a few
may cause excitement in the horse. Epinephrine should be days. In RAO-susceptible horses, exposure to hay dust leads
administered intramuscularly (0.01–0.02 mg/kg, equiva- to invasion of the lungs and airways by neutrophils within 4
lent to 4.5–9 mL of 1:1000 dilution of epinephrine for a to 6 hours and concurrent airway obstruction resulting from
450-kg horse) if dyspnea and hypotension are not severe.395 bronchospasm, inflammation, and increased mucus viscosity,
Epinephrine should not be administered subcutaneously which principally affect the bronchioles. RAO-affected horses
because its potent vasoconstriction can lead to poor absorp- develop nonspecific airway hyperresponsiveness, which is a
tion and tissue necrosis. If dyspnea or hypotension is severe, bronchospasm in response to a wide variety of stimuli includ-
epinephrine should be administered slowly intravenously ing inflammatory mediators and neurotransmitters. Horses
at the same dose as above. If there is no venous access, 2 affected by RAO demonstrate increased histologic lesions and
times the above dose intramuscularly or 5 times the above worsening airway function with increasing age. In addition,
dose intratracheally can be administered.395 Epinephrine significant histopathologic changes are present before abnor-
doses can be repeated every 15 to 20 minutes until hypo- mal airway function can be detected.
tension improves. The side effects of epinephrine therapy The immunologic basis of RAO remains incompletely
are tachyarrhythmias and myocardial ischemia, which can understood. Two pieces of evidence suggest a role for type I
be life-threatening. Alternatively, an epinephrine or norepi- hypersensitivity in this disease. First, IgE levels are increased
nephrine drip can be instituted for cases of refractory hypo- in bronchoalveolar (BAL) fluid of RAO-affected horses,382
tension. Other therapeutic agents such as antihistamines, and second, allergen-specific IgE is increased in affected
β-agonists, or other pressors may be indicated, although horses.387,403,404 However, the immediate onset of airway
their value is less certain. Though its effects may be delayed, obstruction typical of type I hypersensitivity to exposure to
glucocorticoid therapy is indicated to help reverse persis- allergens is rarely observed, as clinical signs of RAO only
tent bronchospasm, reverse angioedema, and break the develop several hours after antigenic exposure.405 In addi-
cycle of mediator-induced inflammation triggered during tion, influx of eosinophils is not a feature of RAO. A study
hypersensitivity reactions. Ideally a rapid-acting glucocorti- of immunoregulatory cytokines in RAO demonstrated evi-
coid should be used such as prednisolone sodium succinate dence for a TH2 bias with increased levels of IL-4 and IL-5
(0.25–10.0 mg/kg intravenously), but dexamethasone may and decreased IFN-γ mRNA in BAL cells.406 However,
also be used (0.2–0.5 mg/kg intravenously). Glucocorticoid other investigators have documented increased IFN-γ lev-
therapy during the acute phase will aid in preventing the els in RAO and a lack of TH2 polarized responses.407,408
late-phase reaction. It seems likely that a number of complex immunologic
processes are involved in the pathogenesis of RAO,296,401
Insect Bite Hypersensitivity including a predominant TH2 response or at least a dys-
Insect bite hypersensitivity (IBH) occurs in response to salivary regulation of cytokine responses associated with a disrup-
allergens of Culicoides midges. It is the most common allergic tion in TH2/TH1 balance,206,409 IgE-mediated pathology, and
skin disease of horses and is characterized by intense seasonal TH17 responses295 accompanied by increased expression of
pruritus, alopecia, and excoriation.306,396 The clinical signs TLR-4 and CXCL8,410 leading to neutrophilic inflamma-
combined with increased numbers of IgE-positive cells in the tion. Neutrophil-mediated inflammation predominates in
skin along with high levels of Culicoides-specific IgE in serum RAO, and several studies suggest that IL-17 responses, and
provided evidence for immediate (type I) hypersensitivity in by extension TH17 responses, are involved in its pathogen-
the immunopathogenesis of IBH.385,386 This pathogenesis was esis.206,295,296 Finally, the percentage of Tregs in the airways of
further supported by studies using monoclonal antibodies horses with RAO increases, and this may be a mechanism to
against equine IgE390 and confirmed by transferring the intra- limit immunopathology.307
dermal allergic reaction to normal horses using IgE from IBH-
affected horses.397 In some breeds a genetic predisposition Neonatal Isoerythrolysis and Alloimmune
based on an MHC II linkage has been demonstrated.286,398,399 Thrombocytopenia
Interestingly, Icelandic horses, which are particularly affected, Neonatal isoerythrolysis (NI) is a common condition of foals
do not develop IBH in Iceland because Culicoides spp. do not and is extensively reviewed elsewhere in this text. The condi-
exist in Iceland. However, when these horses born in Ice- tion results from the passive transfer of maternal antibodies
land are exported later in life to Culicoides-endemic coun- in colostrum, which recognize allogeneic foal erythrocyte
tries, a high percentage develop IBH.306,400 In terms of lack antigens principally of the Aa and Qa blood group inher-
of exposure to Culicoides antigens early in life along with high ited from the sire. A similar condition occurs in mules due
1) Incubate foal (or sire) RBCs with mare's plasma (heat inactivated)
+ (anti-foal RBC Ab) – (no anti-foal RBC Ab)
2a) Add anti-equine immunoglobulin Ab
Endpoint: agglutination no agglutination
2b) Add complement
Endpoint: lysis no lysis
FIG. 1.20 Neonatal isoerythrolysis test. Ab, Antibody; RBCs, red blood cells.
to inheritance of a donkey-specific erythrocyte antigen.411,412 or infection but can also occur after Corynebacterium pseu-
A severe, potentially life-threatening, anemia results as the dotuberculosis infection or after vaccination with S. equi M
antibody-positive erythrocytes are removed by the reticulo- protein (SeM).418 Serum of affected horses contains immune
endothelial system or lysed by complement. A similar condi- complexes of S. equi–specific antigens (SeM) with IgA.416
tion causing severe neonatal thrombocytopenia in horses and These immune complexes become deposited on the walls
mules less commonly affects platelets.413-415 These conditions of small blood vessels, resulting in vasculitis, as discussed
are typical of type II hypersensitivities and are mediated by previously. The glomerulonephritis sometimes seen in asso-
circulating IgG recognizing cell surface antigens on erythro- ciation with purpura has been attributed to deposition of
cytes. For newborn foals at risk of NI, a jaundice foal aggluti- similar immune complexes containing streptococcal anti-
nation test can be performed before allowing the foal to nurse gens and IgG.419
by making 1-mL serial dilutions of the mare’s colostrum in
saline (1:2–1:128), adding 1 drop of the foal’s anticoagulated Cell-Mediated Hypersensitivity Diseases
(EDTA) whole blood to each tube and mixing, centrifuging at
medium speed (300–500 × g) for 2 to 3 minutes, then observ- in the Horse
ing for agglutination of the red blood cell pellet by inverting There are relatively few documented type IV (cell-mediated or
the tubes. If strong agglutination occurs at or above the 1:16 delayed) hypersensitivity conditions in the horse in which the
dilution (≥1:64 for mule foals), the foal should not be allowed immunologic mechanism has been confirmed, although con-
to nurse the mare. To prevent NI, the foal is muzzled and tact hypersensitivities have been reported.365 One exception is
not allowed to nurse during the first 36 hours. An alternative recurrent uveitis, which is a very well-characterized example
source of colostrum (or commercial equine immunoglobulin of type IV hypersensitivity in the horse.
product) is administered to the foal, and the mare is milked
out during this period and her colostrum discarded. Diagno- Equine Recurrent Uveitis
sis of NI can be confirmed using a variation of the Coombs Equine recurrent uveitis (ERU), also known as moon blind-
test (Fig. 1.20). ness or periodic ophthalmia, is the most important cause of
blindness in horses.420 The disease results in both acute and
Purpura Hemorrhagica chronic ocular inflammatory disease, and chronic sequelae
Purpura hemorrhagica is an uncommon acute type III include development of posterior and anterior synechiae,
hypersensitivity (immune complex) disease in horses char- cataracts, lens opacities, secondary glaucoma, and blindness.
acterized by edema of the head and limbs; leukocytoclastic Eyes of affected horses contain IgG antibodies and autoreac-
vasculitis; petechial hemorrhages in mucosae, musculature, tive T cells specific for retinal antigens.421 Although a spe-
and viscera; and sometimes glomerulonephritis.416,417 It is cific cause has not been identified, sensitization to a variety
most commonly associated with Streptococcus equi exposure of pathogens, and in particular to Leptospira spp.,422,423 is
thought to induce the immune-mediated pathology that to autoimmune disease. Well-described equine diseases with
is central to the disease.424 Early and aggressive treatment autoimmune components include those with characteristics
with corticosteroids and other antiinflammatory agents is of type II hypersensitivities such as immune-mediated hemo-
essential to avoid visual debility or blindness.425 Unfortu- lytic anemia in adults.431,432 Autoimmune diseases with skin
nately, treatment failures are common, and the disease fre- manifestations, including pemphigus foliaceus, pemphigus
quently recurs with further ocular damage months after the vulgaris, and systemic lupus erythematosus (SLE), have been
initial event, commonly leading to euthanasia.420 Of horses well characterized in humans and dogs. The pemphigus com-
with ERU, 56% become blind in one or both eyes, and 20% plex involves autoantibodies against skin adhesive proteins
become completely blind.426 (desmoglein 1 and desmoglein 3 for pemphigus foliaceus
The understanding of the immunologic basis of ERU has and pemphigus vulgaris, respectively) and thus is character-
been extended by studies of the immunoregulatory events in istic of type II hypersensitivity disease. SLE is multifactorial,
the eyes of affected horses. It has been shown that the T lym- involving autoantibodies and immune complexes, and thus
phocytes that invade the iris-ciliary body during this disease has characteristics of type II and type III hypersensitivity dis-
produce a pattern of IFN-γ cytokine production typical of eases. Although rare, pemphigus foliaceus and vulgaris433-436
a TH1 response.427 More recently, mononuclear cells in eyes and SLE435,437 have been described in horses. As discussed,
from horses with ERU were found to be positive for IL-17 and equine recurrent uveitis has features of type II and type IV
IL-23, strongly suggesting that TH17 cells are involved in the hypersensitivity, and there is some morphologic and immuno-
pathogenesis of ERU.294 Taken together, these studies indicate logic evidence for classifying polyneuritis equi (cauda equine
that type IV hypersensitivity mediated by TH1 and likely TH17 syndrome) as an autoimmune disease with immunopathology
cells contributes to the immunopathogenesis of ERU. consistent with type IV hypersensitivity.438-442
With the exception of a few conditions, including some of
Autoimmunity those discussed previously, there are few autoimmune diseases
Autoimmune diseases occur when T and/or B cells respond where the cause is well understood. One of the exceptions is
to self antigens resulting in tissue damage. The hypersensi- the anemia that can develop subsequent to administration of
tivity reactions discussed earlier comprise the mechanisms human recombinant erythropoietin to horses.443,444 There is
of this damage mediated by self reactive antibodies and/or substantial evidence that horses mount an antibody response
T cells. Autoimmune diseases are rare and only arise when to the exogenous human erythropoietin that cross reacts with
there is a break in self tolerance. A break in central toler- the endogenous equine hormone (molecular mimicry) and
ance occurs when self reactive B or T cells are not nega- results in erythroid hypoplasia. The lesson of this example may
tively selected during the maturation process in the bone be that in the modern world, with increasing availability of
marrow and thymus, as discussed previously under Equine recombinant drugs that mimic natural biologic compounds,
Immunology. When self reactive lymphocytes escape dele- we would do well to remember that the immune system has
tion in the primary lymphoid organs and are released into an exquisite ability to distinguish what is foreign and to reject
the circulation, peripheral tolerance mechanisms exist to it vigorously.
control autoreactivity. One of these peripheral tolerance
mechanisms is the downregulation of self reactive T cells by Y IMMUNODEFICIENCY
Tregs. Because B cells have additional mechanisms to gener-
ate receptor diversity (i.e., somatic hypermutation), B cells Immunodeficiencies occur in both primary and secondary
have a higher probability of developing self reactivity than T forms and have been extensively reviewed.325,445-448 Primary
cells. Thus many autoimmune diseases with known mecha- immunodeficiencies are congenital and have a genetic basis,
nisms involve autoantibodies. Autoreactive lymphocytes whereas secondary immunodeficiencies result from failure of
may respond to self antigens due to molecular mimicry, in transfer of passive immunity (FTPI) in foals, immunosuppres-
which foreign antigens are similar enough to self antigens sive infections or drug treatments, neoplasia, stress, or mal-
that the activated lymphocytes cross react with self antigen. nutrition. Immunodeficiencies can affect specific components
Molecular mimicry is involved in the thrombocytopenia of the immune system, such as the lymphoid or phagocytic
associated with HIV-1 infection in people where antibodies system. Typically immunodeficiency is suspected in any of the
against HIV-1 envelope proteins also react with surface gly- following circumstances:
coproteins on platelets.428 It is possible that a similar mecha- • Onset of infections in the first 6 weeks of life
nism contributes to thrombocytopenia in horses infected • Repeated infections that are poorly responsive to therapy
with EIAV. Autoreactive lymphocytes can also cause damage • Infections caused by commensal organisms or organisms
when they gain access to immunologically privileged sites of low pathogenicity
where they are normally excluded and in which self antigens • Failure to thrive
are normally sequestered. Examples of these sites include the • Familial history of immunodeficiency
central nervous system and the eye. The autoimmune basis • Disease resulting from the use of attenuated live vaccines
for ERU likely involves molecular mimicry between the Lep- • Failure to respond to vaccination
tospira LruA and LruB antigens and equine intraocular pro- • Marked neutropenia or lymphopenia that persists for sev-
teins,429 as well as self reactive T cells gaining access to the eral days
immunologically privileged intraocular location where they Equine immunodeficiency is most commonly suspected on
then cause damage. the basis of the first three reasons: increased susceptibility to
A number of equine diseases are considered to be autoim- infections. The most common immunodeficiency recognized
mune in etiology, but few have been extensively studied.430 in clinical practice is FTPI in foals.325,449-451 Other causes
Much of the explanation given earlier for the immunopa- of immunodeficiency vary from well-defined clinical enti-
thologies involved in hypersensitivity disease can be applied ties, such as severe combined immunodeficiency of Arabian
TABLE 1.7 Components of the Immune System That Can Be Evaluated in Horses and Appropriate Tests for Quantitative or Functional
Analyses of Each Component
Component Quantitative Tests Functional Tests
Immunoglobulin Radial immunodiffusion, membrane-ELISA, Response to vaccination
electrophoresis, precipitation/coagulation
testsa
Lymphocytes Complete blood cell count, DNA-PKcs and Response to vaccination, intradermal
SLA5A3 genetic evaluation,b flow cytometric PHA test, in vitro lymphoproliferation
evaluation of lymphocyte subsets assays
Neutrophils and macrophages Complete blood cell count Chemiluminesence and bactericidal
assays, flow cytometric evaluation of
phagocytosis and oxidative burst
Eosinophils and basophils Complete blood cell count No commonly available tests
Complement No commonly available tests No commonly available tests
Acute phase proteins SAA,c electrophoresis No commonly available tests

Note: The list of tests is not exhaustive but is restricted to tests of likely practical value for which normal data are available. Tests listed in bold are routinely
available to clinicians.
aZinc sulfate turbidity, glutaraldehyde coagulation.
bSee SCID and FIS for description of genetic testing.
cSerum amyloid A handheld test.
foals,452,453 to cases where immunodeficiency is suspected on (RID) assay. The disadvantages of this test are its cost and the
clinical grounds but the specific cause or nature of the prob- time required to perform the assay (24 hours or longer), which
lem is difficult or impossible to define. Regardless of their make it generally unsuitable for screening for FTPI in foals.
cause, immunodeficiencies result in increased susceptibility Nevertheless, this form of test remains the single most valu-
to infections, which are in turn poorly responsive to appro- able assay available to the clinician trying to measure total
priate therapy. Defects in antibody production tend to pre- antibody concentrations in the horse. Currently, test kits are
dispose to pyogenic bacterial infection, whereas deficiencies available for equine IgG and IgM (Triple J Farms, Belling-
in cell-mediated responses lead to infections with organisms ham, WA). The RID test is based on the ability of antigen and
normally nonpathogenic in horses such as Candida albicans, antibody to precipitate at equivalence when combined in pro-
Cryptosporidium spp., or adenovirus. When any immunode- portion in agar gel plates. The serum being tested is added to
ficiency is suspected, specific diagnostic tests are indicated to punched-out wells in agar, impregnated with antibody to the
define the deficiency. The aim of the next section is to iden- specific immunoglobulin class being measured, and allowed
tify tests clinicians can apply practically in such cases and to to diffuse outward and bind with the anti–class-specific anti-
explain their merits and limitations. sera. A precipitate forms when equivalence is reached and
the area within the precipitate ring is directly proportional
Tests of Equine Immune Function to the concentration of the patient’s immunoglobulin class.
Tests of components of the immune system (e.g., lymphocytes, Enzyme-linked immunosorbent assay (ELISA) test kits are
immunoglobulins) generally can either quantitate that compo- also available for quantitation of equine IgA, IgG3/5 (IgG[T]),
nent or measure its functional capacity. In Table 1.7 the com- and IgM (Bethyl Laboratories, Montgomery, TX). Although
ponents of the immune system that currently can be analyzed not commercially available, serum concentrations of the IgG
in this manner are identified, and corresponding quantitative subclasses (IgG1, IgG4/7, and IgG3/5) can be determined by
and functional tests are listed. The table also identifies those ELISA in equine immunologic research laboratories. Normal
tests that are likely to be commercially available, and it should ranges of serum immunoglobulin concentrations are typically
be noted that few of the functional tests are available unless provided with commercial kits, and normal serum, milk, and
the clinician is able to identify a capable equine immunologic colostrum concentrations of equine immunoglobulins have
research laboratory. Despite these limitations, the available been described in numerous published studies. These results
tests do permit the identification of many of the well-defined have been recently summarized and are available in tabular
causes of immunodeficiency in horses. form.249,326 One of these representative studies reported IgM,
IgG, and IgA concentrations in normal adult horse serum to
Tests of Antibody-Mediated Immunity be 103 ± 5 mg/dL, 1913 ± 754 mg/mL, and 225 ± 140 mg/dL,
Although some assays of B lymphocyte function and number respectively.316
are described later, the principal tests of humoral immunity By far the most common clinical question regarding
are quantitative assays of immunoglobulin concentration and immune status is whether a foal has achieved adequate trans-
measurements of specific antibody responses to vaccination. fer of passive immunity, which is defined as a serum IgG con-
The variety of classes of immunoglobulins in the horse is com- centration greater than 800 mg/dL. Serum IgG concentrations
plex, as reviewed earlier in this chapter. For practical purposes less than 400 mg/dL and between 400 and 800 mg/dL have
attention is generally focused on IgG, IgA, and IgM. defined complete and partial FTPI, respectively. Despite these
The current “gold standard” for measurement of concentra- traditional cutoff values, a recent study in a large number of
tions of immunoglobulin classes is the radial immunodiffusion hospitalized foals demonstrated that foals with serum IgG
Prepared SNAPTM unit

anti-equine IgG
1) Add foal serum
foal IgG
calibration spots
2) Add enzyme-conjugated
anti-equine IgG patient spot
FIG. 1.21 Membrane-based ELISA system (SNAP, Idexx) for measuring serum IgG concentration. The
diluted test equine serum sample is applied to a “patient spot” on a membrane impregnated with a capture
antibody recognizing equine IgG. Calibration spots corresponding to specific concentrations of equine IgG
(400 and 800 mg/dL) are adjacent to the patient spot. An enzyme-conjugated second antibody against
equine IgG is applied to the entire membrane, and finally the device is triggered to release an enzyme sub-
strate that produces a colored reaction corresponding to the amount of enzyme-conjugated antibody on the
membrane. By comparison with the calibration spots the test sample IgG concentration can be estimated.
concentrations below 800 mg/dL are more likely to die than An additional test that provides information about serum
foals with serum IgG concentrations above 800 mg/dL.454 The immunoglobulin content is serum protein electrophoresis.
distinction between complete and partial FTPI is therefore This test gives quantitative information about albumin, α- and
not particularly relevant in making therapeutic decisions, at β-globulins (acute inflammatory proteins), and γ-globulin
least in the hospitalized foal population. Tests used to deter- (immunoglobulin) concentrations (see Fig. 1.22). The utility
mine transfer of passive immunity status should be rapid to of protein electrophoresis is demonstrated when detecting
allow early initiation of therapy, which decreases the utility the monoclonal gammopathies that accompany plasma cell
of the RID test. A wide variety of other tests have been used myelomas.462 Hyperglobulinemia can occur during inflamma-
for this purpose, including zinc sulfate turbidity, latex bead tion with increased production of α- and β-globulins and dur-
agglutination, ELISA, turbidometric analysis, glutaraldehyde ing infections in normal horses with polyclonal production of
coagulation, and infrared spectroscopy.455-460 In the glutar- γ-globulins (immunoglobulins). Nevertheless in the diagnosis
aldehyde coagulation test (Gamma-Check E, Plasvacc USA, of immunodeficiencies, electrophoresis should be seen as an
Templeton, CA), glutaraldehyde forms insoluble complexes adjunct to RID assays, which are superior in terms of specific-
with basic proteins in the serum. Clot formation in 5 minutes ity and sensitivity.
or less is equated with a serum IgG concentration of 800 mg/
dL or greater. This test is good for initial screening because it Tests of Cellular Immunity
is simple, rapid, inexpensive, and accurate for confirming an The simplest test of the cellular arm of the immune response
IgG concentration ≥800 mg/dL (high sensitivity for ruling out is a complete blood count (CBC) to determine total and dif-
FTPI). However, the lack of clot formation within 5 minutes ferential leukocyte numbers, and this should be the start-
does not always indicate FTPI (can have low specificity), so ing point for any evaluation. Identification of an absolute
confirmatory testing is warranted.461 Although more expen- lymphopenia, for example, is a critical finding in a sus-
sive, the higher specificity and the ease of use and rapid results pected case of severe combined immunodeficiency (SCID)
make the membrane filter–based ELISA tests (e.g., SNAP, in an Arabian foal, although the result must be repeatable
Idexx Laboratories, Westbrook, ME) the preferred choice in a series of tests given the variability of blood lymphocyte
for many (see Fig. 1.21). Like the glutaraldehyde coagulation counts. Such a finding would logically lead to genetic test-
test, this test can be performed foal-side with whole blood. ing to confirm the diagnosis.463 The evaluation of a lymph
Although the membrane-filter ELISA is more specific in con- node biopsy for normal architecture, including the presence
firming FTPI, it is slightly less sensitive in detecting FTPI than or absence of cells in either the B- or T-lymphocyte–depen-
the glutaraldehyde coagulation test.461 dent areas, is another powerful test of the immune system.
Signals are typically displayed as either histograms or dual-

parameter correlated plots (dot plots), and statistical analysis
is completed by computer. Histograms are analyzed by set-
ting markers in particular channels and dot plots by drawing
rectangular or polygonal boxes around data points. The soft-
ware also allows the setting of “gates” for determining which
events are collected in the first instance or which events are to
be included in later analyses. Typically these gating techniques
are employed using forward and side scatter to differentiate cell
types, such as lymphocytes, monocytes, and granulocytes. The
final key characteristic of flow cytometers is their capacity to
analyze large numbers of cells in a short time, making it pos-
sible to analyze many thousands of cells in a matter of seconds.
An example of such an analysis is shown in Fig. 1.23. The
upper panels (A) show side- versus forward-scatter plots of
PBMCs isolated from a normal foal (left panel) and SCID
foal (right panel). A typical distribution of lymphocytes (red
gate), monocytes/blasting cells (blue gate), and granulocytes/
neutrophils (green gate) is observed in the normal foal. It
should be noted that the Ficoll centrifugation procedure for
PBMC isolation removes the vast majority of neutrophils.
In the SCID foal, there are very few cells in the normal lym-
phocyte gate, with the majority of cells being monocytes and
larger granular cells, which are most likely NK cells. Standard
two-color dot plots analyzing all cells within the lymphocyte
and monocyte/blasting cell gates are shown in the next panels
FIG. 1.22 Serum protein electrophoresis. The complex mixture of (B). In the normal foal, 43% of the PBMCs are labeled by the
serum proteins are separated by migration through an agarose gel slab fluorochrome-conjugated anti–equine CD3 monoclonal anti-
in response to an electric field. Proteins are stained and the intensity of body and are therefore T cells (upper and lower right quad-
staining of different bands is measured by densitometric scanning. These rants combined). Of these T cells, 26% (or 11.2% of all PBMCs
measurements are used to identify different types of globulins and albu- analyzed) are CD8+ T cells (upper right quadrant). These cells
min corresponding to stained bands. are double labeled with the anti–equine CD3 monoclonal
antibody and an anti–equine CD8 monoclonal antibody con-
jugated to a fluorochrome with a different color. The cells in
However, in profound immunodeficiencies such as SCID, the upper left quadrant are CD8+ but are not T cells and likely
lymphoid organs may be impossible to locate antemortem. represent CD8+ NK cells. Compared with the normal foal,
Beyond these readily available conventional techniques, the SCID foal has virtually no T cells but does have a similar
three other more complex types of analyses can be of value: percentage of CD8+ non–T cells (NK cells). Additional analy-
flow cytometric analysis (primarily of lymphocytes, although sis using fluorochrome-conjugated monoclonal antibodies
other cell types can be analyzed), lymphocyte function test- against equine B-cell and CD4+ T-cell markers would reveal a
ing, and functional analysis of phagocytic cells. similar absence of these lymphocyte populations in the SCID
Flow Cytometry. Flow cytometry provides additional cel- foal. Finally, the lower panels (C) show a standard single-color
lular information by using monoclonal antibodies conjugated dot plot and corresponding histogram analysis of CD8+ cells
to fluorochromes to differentiate morphologically identical in the normal foal.
lymphocytes into distinct subsets. Flow cytometers use la- Lymphocyte Function Testing. Unfortunately tests of lym-
sers to measure multiple parameters including light scatter phocyte function are generally limited in their availability in the
and fluorescence characteristics of cells. The fluidics system field. In vitro tests of lymphocyte function include lymphocyte
of the flow cytometer delivers cells one by one to a point in proliferation responses to mitogens such as pokeweed mito-
space intersected by a laser beam. The laser beam emits light gen, phorbol 12-myristate 13-acetate (PMA) with ionomycin,
of a defined wavelength to illuminate the cell, which results in phytohemagglutinin (PHA), or concanavalin A (ConA). These
both scattered light of the same wavelength and fluorescent assays are generally not commercially available, although they
light of a different wavelength that is collected by photode- are commonly performed by immunologic researchers. It is
tectors and converted into electronic signals. Optical filtra- essential to perform parallel studies on suitable age-matched
tion separates scattered light and fluorescent light to permit control horses. The endpoint of these tests is usually read by de-
their independent measurement. Side-scatter light is depen termining the incorporation of radioactive 3H-thymidine into
dent on the granularity of cells, whereas forward-scatter light the total population of proliferating cells.464 Nonradioactive
is dependent on the size of the cell. Fluorescent light can be alternatives exist, and one strategy utilizes the thymidine
detected independently for a number of fluorochromes of dif- analog 5-ethynyl-2′-deoxyuridine (EdU), which readily in-
ferent wavelengths, and typical examples are fluorescein and corporates into the DNA of replicating cells.465 The alkyne
phycoerythrin. High-end flow cytometers have multiple lasers group of EdU reacts with fluorescent azides in a Cu(I) catalyzed
with different wavelengths and can detect a large number of “Click” reaction, which can then be detected using flow cytom-
colors (e.g., 5 lasers with detection of 18 colors), as well as side etry. An EdU incorporation–Click assay kit is available to re-
and forward scatter. searchers (Click-iT EdU Imaging Kit, ThermoFisher Scientific),
Normal Foal SCID Foal
Side Scatter (granularity)
A Forward Scatter (size)
Normal Foal SCID Foal

4 4
10 10 3.6%
3.6% 11.2% 0.1%
3 3
10 10
2 2
10 10
CD8
1 1
10 10
53.5% 31.8% 96.1% 0.2%
0 0
10 0 1 2 3 4 10 0 1 2 3 4
10 10 10 10 10 10 10 10 10 10
B CD3
4
10 0.0% 0.0%
62
3
10
47
2
Count
10 31
1
10 16
84.4% 15.6%
0 0
10 0 1 2 3 4 0 1 2 3 4
10 10 10 10 10 10 10 10 10 10
C CD8
FIG. 1.23 Flow cytometric analysis of PBMCs from a normal foal and an SCID foal. See text for description.
and has shown utility for detecting equine lymphoprolifera- Response to vaccination has proven to be a potent means of
tive responses (see Fig. 1.24). Finally, flow cytometry can be identifying immunodeficiency in such conditions as juvenile
used to determine functional characteristics of various equine llama immunodeficiency syndrome.467 Similarly the equine
lymphocyte subsets by detecting intracellular production of immune response to a polyvalent inactivated bovine vaccine
cytokines following nonspecific stimulation with mitogens or has been used to document the immunosuppressive effects
antigen-specific stimulation (Fig. 1.24). of corticosteroid administration.468 For practical purposes,
Two tests that can be of value and are readily available response to rabies or tetanus vaccination may be the most suit-
in practice are response to vaccination, as measured by ris- able available tests provided that no routine vaccination had
ing serum titers, and response to intradermal PHA, which been administered in the immediate past. Equine rabies or
is dependent on a delayed-type hypersensitivity T lympho- tetanus antibody titer determination is typically commercially
cyte response and develops in normal animals without prior available, and the majority of available vaccines are sufficiently
sensitization.466 A 50-μg dose of PHA in 0.5 mL of phos- potent to provoke a fourfold increase in titer in normal horses.
phate-buffered saline is injected intradermally, and 0.5 mL Phagocyte Function Testing. Testing of equine neutro-
of phosphate-buffered saline is administered intradermally phil migration, phagocytic function, and bactericidal activ-
at a distant site. At the PHA site, an increase in wheal size of ity has been reported by several investigators,328,330,469,470 and
0.6 mm or less indicates a defect in cell-mediated immunity. more quantitative information has been obtained using flow
A
EdU
CD8
CD4
B IFN-γ
FIG. 1.24 Flow cytometric evaluation of lymphoproliferation and intracellular cytokine production. (A) Dot
plot (left panel) and histogram (right panel) showing 5-ethynyl-2′-deoxyuridine (EdU) incorporation by proliferat-
ing equine PBMCs following in vitro stimulation with antigen. In this case the PBMCs were isolated from a horse
infected with Theileria equi and stimulated with a T. equi sporozoite lysate for 4 days. (B) Two-color analysis
of CD4+ T cells (left panel) and CD8+ T cells (right panel) for IFN-γ production. Isolated PBMCs were stimulated
24 hours with PMA + ionomycin, then surface labeled with fluorochrome-conjugated monoclonal antibodies
against equine CD4 or CD8, followed by intracellular staining using a different fluorochrome-labeled monoclonal
antibody against equine IFN-γ. CD4+ cells (or CD8+ cells) producing IFN-γ appear in the upper right quadrants.
cytometric approaches.220,331,471 The techniques employed are 1977, the incidence of SCID among Arabian foals was at least
typically only available in research laboratories. 2% to 3%,487 suggesting a carrier prevalence rate between 25%
and 26%. However, in more recent studies conducted in the
Tests of Innate Immunity United States using a precise molecular diagnosis of the carrier
Components of the innate immune response that have been state, carrier prevalence was consistently 8%.488,489
measured in the horse include the numbers of granulocytes and Clinical Signs and Laboratory Findings. Affected foals
monocytes in peripheral blood (CBC) and their phagocytic are clinically normal at birth but develop signs of infection
function (see earlier discussion), natural cytotoxicity in terms during the first 1 to 3 months of life. The age of onset of
of lymphokine-activated killer (LAK) cell activity,469,472-474 and infection depends on the adequacy of transfer of passive
measurement of soluble factors including several acute phase immunity and degree of environmental challenge. As ma-
proteins.475-480 Serum amyloid A (SAA) is one acute phase ternal antibodies are catabolically eliminated SCID foals
protein that can serve as an early indicator of inflammation, are increasingly susceptible to infections with bacterial, vi-
and a rapid stall-side test is now available (StableLab, Sligo, ral, fungal, and protozoal agents. Bronchopneumonia is a
Ireland). Equine complement activity can be measured using prominent disease, often caused by adenovirus (the most
hemolytic or flow cytometric assays.481,482 With the exception significant pathogen of SCID foals, affecting two thirds of
of the CBC and SAA tests, tests of innate immune function them),490 Pneumocystis carinii, or Rhodococcus equi. En-
have very limited availability. teritis, frequently caused by Cryptosporidium parvum,491
arthritis, and omphalophlebitis are common. Adenoviral
infection frequently extends to the gastrointestinal and
Primary Immunodeficiencies urogenital systems and causes pancreatic disease leading to
Severe Combined Immunodeficiency loss of endocrine and exocrine tissue and possibly contrib-
Severe combined immunodeficiency (SCID) is a lethal pri- uting to the impaired growth and weight loss observed in
mary immunodeficiency affecting Arabian foals, character- SCID foals.445
ized by failure to produce functional B and T lymphocytes Clinical signs include nasal discharge, coughing, dys-
and resulting in the complete lack of adaptive immune pnea, diarrhea, fever, and weight loss. Although antibiotics,
responses.445,453,483,484 The vast majority of affected foals are plasma, and supportive care prolong the course of disease,
Arabians, in which the condition is inherited as an autosomal death invariably occurs before 5 months of age. The only
recessive trait485 and results from a lack of DNA protein kinase exception was a single foal experimentally treated with a bone
(DNA-PK) activity that prevents V(D)J recombination.452,486 marrow transplant from a histocompatible donor that lived
In studies conducted in the United States and reported in until 5 years of age before dying of an unrelated cause.492,493
A consistent hematologic finding is absolute lymphopenia (less also been identified in Dales pony foals and is now known as
than 1000/μl; usually less than 500/μl), with neutrophilia a foal immunodeficiency syndrome (FIS).496-498 Affected foals
variable finding resulting from bacterial infection. Total serum become ill within 2 to 3 weeks of birth and die by 3 months of
globulins and serum IgG can be normal in the first weeks of age. Affected animals have been described outside the United
life if transfer of passive immunity is adequate but decline as Kingdom499 and in the United States.500
maternal immunoglobulins are catabolized. Normal foals syn- Clinical Signs and Laboratory Findings. Clinical signs in-
thesize IgM from 180 days of gestation and have detectable clude ill thrift, anemia, respiratory infection, glossal hyper-
IgM at birth in presuckle samples, whereas SCID foals have keratosis, and diarrhea. Anemia can be severe and is normo-
no IgM.314 After colostral ingestion SCID foals also have IgM, chromic and normocytic to macrocytic, with small numbers
although with its relatively short half-life it is undetectable by of late erythroid precursors in bone marrow.495,501 Although
2 to 4 weeks of age.445 bone marrow erythroid precursors are present at birth, eryth-
Etiology and Pathogenesis. Normal maturation of T and roid hypoplasia develops rapidly and progresses to aplasia, re-
B lymphocytes requires rearrangement of germ line V, D, and sulting in severe progressive nonregenerative anemia.502 Some
J genes to encode the required wide diversity of TCRs and foals are affected by cryptosporidial enteritis and adenoviral
BCRs, through the process of V(D)J recombination (see under bronchopneumonia and pancreatitis. Plasma proteins and
Equine Immunology). This process depends on two groups of blood lymphocyte counts can be normal or low. Immunode-
enzymes, the recombinase activating gene (RAG) products, ficiency is due to profound B-cell lymphopenia,503,504 with a
which cut DNA, and DNA-PK, which is critical for DNA lack of B cells in the bone marrow and lymph nodes and very
double-stranded break repair. In equine SCID, the genetic de- few within germinal centers in the spleen.500,502 Concentra-
fect is a 5-base pair deletion in the gene encoding the catalytic tions of IgG subclasses are significantly lower in FIS foals
subunit of DNA-PK (DNA-PKcs).452 This frameshift mutation compared with age-matched controls, coinciding with reduc-
truncates the protein, resulting in a complete lack of DNA-PK tion of maternally derived antibodies and correlating with B-
activity.452,486 Because DNA-PK is required for DNA strand cell lymphopenia.503 Some studies have described normal IgG
break repair, V(D)J recombination does not occur.486 As a concentrations in FIS foals, although decreases would likely
consequence, developing T cells and B cells do not produce have been observed had the foals survived longer.500,502 IgM
functional TCRs and BCRs and thus fail the positive selection concentrations consistently decline in FIS foals compared with
process in the primary lymphoid organs. controls.502,503 Taken together these observations indicate an
Diagnosis. Previously antemortem diagnosis of SCID was absence of endogenous immunoglobulin production in FIS
suggested by appropriate clinical signs in a foal of Arabian foals caused by the lack of functional B cells. In contrast, T-
breeding with persistent marked lymphopenia (usually less cell subsets measured by flow cytometry are normal, and lym-
than 500/μL) and the absence of serum IgM by RID. If pre- phoproliferative responses are normal.500,505 However, MHC
suckle serum is unavailable for testing, serum IgM cannot be II expression is low,500,505 thymic hypoplasia is observed,495,500
used as a diagnostic aid until the foal is older than 3 weeks. All and T cells can be absent in the bone marrow.502 Thus it is
suspected cases required confirmation by the necropsy finding possible that an unidentified defect in T-cell function exists.
of hypoplasia of the spleen, thymus, and lymph nodes with the This is further suggested by the occurrence of opportunistic in-
absence of any normal lymphoid architecture. With the identi- fections in the face of adequate levels of maternally derived an-
fication of the genetic defect causing SCID, the current stand- tibodies. On necropsy, lymphoid organs can be small, and sec-
ard for definitive diagnosis is demonstrating that the foal is ondary lymphoid follicles and plasma cells are absent.495,500,502
homozygous for the defective SCID gene. This test depends on Neuronal changes are characterized by neuronal chromatolysis
PCR amplification of a specific region of the DNA-PKcs gene, in the cranial mesenteric, dorsal root, and trigeminal ganglia.495
and evaluation of the amplicon using probes specific for nor- Etiology and Pathogenesis. FIS is inherited as an auto-
mal and mutant sequences.463 This test is commercially avail- somal recessive trait,496 and a mutation in the sodium/myo-
able (VetGen, Ann Arbor, MI); can be performed on whole inositol cotransporter gene (SLA5A3) on chromosome 26 is
blood, pulled hair, or cheek swabs; and identifies homozygous- strongly associated with the syndrome.498 This is an osmotic
affected, heterozygous carrier, and normal animals. stress response gene that encodes a cell membrane transporter
Treatment. Supportive care may prolong the course of dis- protein that cotransports sodium ions and myo-inositol. De-
ease, but affected foals die by 5 months. Immunologic recon- spite the strong association, the specific role of this gene in
stitution is currently impractical and an ethically questionable erythrocyte and B-cell development is unknown, and formal
procedure. proof that the SLA5A3 mutation is the direct cause of FIS re-
Client Education. Arabian mares and stallions intended for quires additional functional studies.
breeding should be tested for SCID carrier status. When two Diagnosis. The presence of anemia, diarrhea, ill thrift, and/
heterozygous carriers are bred the progeny will include 25% or respiratory and other infections in young Fell and Dales
SCID foals, 50% carriers, and 25% homozygous normal foals. pony foals along with low IgM levels and B-cell lymphopenia
Therefore prevention of SCID requires identification of car- (as measured by flow cytometry) allows a presumptive diag-
riers and either their removal from the breeding population nosis. Confirmation of FIS can now be made by demonstrat-
or breeding exclusively with homozygous normal animals and ing that the foal is homozygous for the SLA5A3 mutation,
subsequent testing of progeny before their own breeding fu- using the available DNA test (Animal DNA Diagnostics, Cam-
ture is planned. bridge, UK). This PCR-based test is performed on pulled hair
and identifies homozygous-affected, heterozygous carrier, and
Foal Immunodeficiency Syndrome normal animals.
In the late 1990s a syndrome of anemia, immunodeficiency, Treatment. Treatment of specific secondary infections is of
and peripheral ganglionopathy was described in Fell pony limited efficacy in affected foals, particularly those affected by
foals and termed Fell pony syndrome.494,495 This syndrome has severe anemia and diarrhea, and all die by 3 months of age.
Client Education. The Fell and Dales pony breeds lost sig- Diagnosis, Treatment, and Client Education. CVID is rare
nificant genetic diversity during World War II, and the over- but should be suspected in adult horses with recurrent in-
use of a few popular sires likely resulted in the emergence of fections as described previously, hypogammaglobulinemia,
FIS, which until very recently affected up to 10% and 1% of B-cell lymphopenia, and failure to respond appropriately
Fell and Dales foals, respectively.498 Genetic testing results re- to vaccination. Affected horses with mild infections can be
ported in 2011 indicated that 38% of adult Fell ponies and 18% managed for variable lengths of time with continuous or in-
of adult Dales ponies were carriers of the FIS defect.497 Similar termittent oral antimicrobial therapy, but severe infections
to preventing SCID in Arabian horses, all Fell and Dales po- require aggressive intravenous antimicrobials and appropri-
nies used for breeding should be tested for FIS carrier status ate supportive therapy. Although regular immunoglobulin
so that carrier-carrier matings are avoided. This will eliminate replacement is used in human patients, this is not practical
the production of FIS-affected foals and will eventually reduce in affected horses. Affected horses are usually euthanized
the prevalence of the gene defect in the population. Imple- within 6 months of diagnosis because of financial considera-
mentation of this testing strategy has significantly decreased tions and poor quality of life.448
the number of FIS-affected foals, but it will take time to reduce
the mutant gene frequency in the population given the large Selective IgM Deficiency
number of carriers.506 Selective IgM deficiency is characterized by substantially
reduced or absent serum IgM with normal or increased
Common Variable Immunodeficiency concentrations of other immunoglobulins and no other evi-
In humans, common variable immunodeficiencies are a het- dence of immunodeficiency.445,512 Serum IgM concentrations
erogeneous group of disorders that do not become evident are more than 2 standard deviations below the mean of age-
until late childhood or adulthood and comprise the most com- matched control animals. All other immunologic parameters
mon forms of primary immunodeficiency.209 In horses, com- are normal, although a lack of response to the B-cell mitogen
mon variable immunodeficiency (CVID) is a rare adult-onset lipopolysaccharide was reported in an affected Standardbred
fatal disorder characterized by B-cell depletion and inadequate foal.513 The syndrome has been most frequently described in
antibody production caused by failure of B lymphocyte matu- Arabians and Quarter Horses, although the diagnosis has been
ration in the bone marrow.448 made in other breeds.
Clinical Signs and Laboratory Findings. Over 30 cases of Clinical Signs and Laboratory Findings. Two clinical syn-
CVID have been reported in recent years.507-511 Age of onset dromes have been described. The first condition affects foals 2
ranges from 2 to 23 years, there is no sex or breed predis- to 8 months of age, which develop severe pneumonia, arthritis,
position, and cases are sporadic. Hypogammaglobulinemia and enteritis with or without septicemia, and many die before
leads to recurrent infections, typically caused by Streptococ- 10 months of age. Gram-negative bacterial infections are com-
cus, Staphylococcus, Actinobacillus, and Klebsiella spp. Af- mon (especially with Klebsiella species), and age at onset of
fected horses can present with pneumonia, sinusitis, menin- signs is generally older than in foals with combined immu-
gitis, ataxia, diarrhea, peritonitis, gastrointestinal parasites, nodeficiency. Some affected foals survive but have a history
uveitis, conjunctivitis, skin infections, weight loss, and mus- of repeated bacterial infections that respond temporarily to
cle atrophy.448 Neutrophilia and hyperfibrinogenemia occur therapy but recur once antimicrobials are discontinued. These
during infections, and transient lymphopenia (less than 1200 foals grow poorly and generally die within 2 years. Rarely foals
cells/μL) is common. Serum IgG is uniformly low in affected can recover from IgM deficiency, suggesting that such cases
horses (less than 800 g/dL) as is IgM (less than 25 mg/dL), may actually be secondary rather than primary immunodefi-
and IgA concentrations tend to decrease as the disease pro- ciencies.514
gresses (less than 60 mg/dL). Flow cytometry reveals B-cell The second presentation involves horses between 2 and
lymphopenia (less than 2% of PBMCs) in all cases. Tetanus 5 years of age, many of which have or ultimately develop
toxoid vaccination does not result in a rise in antibody titer in lymphoma. These individuals may have external or internal
affected horses. Necropsy reveals lesions associated with infec- lymphadenopathy or both. Chronic weight loss, depression,
tion in the affected organ systems. Lymph nodes are small and and other nonspecific signs usually accompany lymphoma.
lack germinal centers, plasma cells are absent in lymphoid and In cases associated with lymphoma, the IgM deficiency
mucosal tissues, and B cells are typically absent in the bone is presumed to be a secondary rather than a primary
marrow and spleen.448,511 immunodeficiency.
Etiology and Pathogenesis. To maintain populations of Routine laboratory findings are not diagnostically specific.
B cells in secondary lymphoid tissues, hematopoietic stem Hematologic abnormalities consistent with chronic inflamma-
cells in the bone marrow must continuously generate B cells tory disease, such as anemia, neutrophilia, and hyperfibrino-
throughout an individual’s lifetime. Although the pathogen- genemia, are commonly present. The total plasma protein and
esis of CVID is still unclear, the progressive B-cell depletion serum globulins are usually normal.
indicates a failure of B-cell development in the bone marrow. Etiology and Pathogenesis. Although a genetic basis is
Early B-cell commitment genes, including E2A and PAX5, are suspected, the pathogenesis of selective IgM deficiency is un-
decreased in the bone marrow of CVID-affected horses.511 The known.445 It seems likely that there are primary and secondary
E2A gene encodes a transcription factor that initiates B-cell forms of this syndrome. The pathogenesis of IgM deficiency is
differentiation and PAX5 expression, which encodes the B- also unclear in humans but might involve decreased T-helper
cell-lineage–specific activator protein (BSAP) that is absent activity, increased isotype-specific suppressor T-cell activity,
in the bone marrow of affected horses.511 Thus disruption of and intrinsic B-cell defects.515
pro–B-cell development during the transition from pre–pro– Diagnosis. Definitive diagnosis of selective IgM deficiency
B cells could be the cause of CVID, and epigenetic gene silenc- is made by measuring the major serum immunoglobulins by
ing mechanisms may be involved.448,510,511 RID and determining the absolute lymphocyte count. Horses
with selective IgM deficiency have serum IgM concentrations Agammaglobulinemia is characterized by absence of B lym-
persistently less than 2 standard deviations below that of age- phocytes and failure to produce immunoglobulins in the pres-
matched controls (less than 15 mg/dL at 4–8 months; less than ence of normal cell-mediated immunity.445 The disease has
25 mg/dL at greater than 8 months) coupled with normal con- been described in five colts of Thoroughbred, Standardbred,
centrations of IgG (≥1000 mg/dL) and a normal lymphocyte or Quarter Horse breeds.514,519,520 Clinical signs commence
count. The normal IgM concentration in healthy fit horses is between 2 and 6 months of age and result from bacterial infec-
103 ± 40 mg/dL, and a cut-point for IgM deficiency has been tions such as pneumonia, enteritis, and arthritis. Multisystemic
defined as ≤23 mg/dL.516 Because seriously ill foals may have infections that respond poorly to therapy are common, and
transiently depressed serum IgM concentration, suspected laboratory changes reflect chronic inflammatory disease. The
cases should be tested at least twice to document that IgM con- fact that this syndrome has only been described in colts sug-
centrations remain low. All other immunoglobulin concentra- gests an X-linked mode of inheritance, as occurs in X-linked
tions are normal. agammaglobulinemia in humans, which is caused by a muta-
Treatment and Client Education. Other than supportive tion in a protein tyrosine kinase gene called Bruton’s tyrosine
care and antimicrobial therapy, there is no effective treat- kinase (btk).521 The lack of this kinase activity results in a fail-
ment for selective IgM deficiency. Transfused plasma con- ure of pre–B cells in the bone marrow to develop into mature
centrations of IgM are low and the half-life is quite short; B cells. A maturation defect from stem cells to B cells has been
thus any benefit would be only temporary. The prognosis suggested in affected horses.445 Affected foals have persistently
must be guarded; however, recovery has been reported.514 subnormal serum concentrations of all immunoglobulin
Because primary immunodeficiency is likely in foals affected classes and normal lymphocyte counts. Serum IgM and IgA
during the first year of life, it may be inadvisable to remate are generally absent at the time of evaluation, and maternally
the sire and dam. derived IgG and IgG3/5 decline with time. At 2 months of age,
IgG is less than 300 mg/dL, which declines to less than 100
Other Primary Immunodeficiencies mg/dL by 6 months. There is no serologic response to immu-
Transient hypogammaglobulinemia and agammaglobulinemia nization, and B lymphocytes, as determined by immunofluo-
are reported as established primary immunodeficiency syn- rescence, are absent. Tests of cell-mediated immune function
dromes in horses. However, these conditions have been infre- such as intradermal PHA and in vitro blastogenesis are nor-
quently reported and consequently remain poorly defined. mal. Plasma and antimicrobial therapy only result in transient
Available information is presented here. A further form of immu- improvement. Affected horses die of disseminated infection
nodeficiency affecting humoral immunity was described by Boy between 1 and 2 years of age.
and colleagues517 in a 10-month-old Arabian colt. The animal
exhibited an absence of serum of IgM, IgA, and IgG(T) and a
normal concentration of IgG. In vitro testing of PBMCs with Secondary Immunodeficiencies
T-cell mitogens elicited normal responses, whereas responses to Failure of Transfer of Passive Immunity
B-cell mitogens were weak. On postmortem examination there FTPI is the most common immunodeficiency disorder of
was generalized lymphocyte depletion of lymphoid organs. horses and has been extensively reviewed.325,446 It occurs in all
To increase our understanding of these and other cur- breeds secondary to inadequate absorption of colostral anti-
rently unidentified immunodeficiency syndromes of horses, bodies. FTPI is significantly correlated with increased suscep-
it is critical that every effort be made to identify such cases tibility to infectious disease and death in neonatal foals.522,523
and thoroughly investigate them. New immunologic resources The newborn foal is capable of mounting a normal immune
now available may make it possible to further define these dis- response, as described earlier in this chapter. However, neo-
eases and increase our diagnostic and prognostic resources, natal foals are immunologically naive and thus have not
provided the case material can be identified. developed memory responses or produced antigen-specific
Transient hypogammaglobulinemia has been reported antibody or T-cell responses.
in only two foals, an Arabian and a Thoroughbred, and is During the first 1 to 2 months of life, foals are dependent
characterized by delayed onset of immunoglobulin syn- on transfer of passive immunity for protection from infec-
thesis.514,518 Affected foals manifested signs consistent with tious disease. The diffuse epitheliochorial nature of the equine
bacterial and viral infections when passively acquired immu- placenta does not allow for in utero immunoglobulin transfer
noglobulins are catabolized to nonprotective concentrations. to foals. Although minor concentrations of IgM and IgG can
For unknown reasons, the onset of autologous immunoglob- be detected at birth, the foal is born essentially agammaglob-
ulin production, which generally occurs at birth, is delayed ulinemic and acquires passive immunity by the ingestion and
until these foals are approximately 3 months of age. Hemato- absorption of colostrum from the dam.350,353,522 Colostrum is
logic studies may be suggestive of chronic infection, although a specialized form of milk containing concentrated immuno-
total plasma protein is normal or reduced slightly. Diagnosis globulins that is produced during the last 2 weeks of gestation
is based on the presence of low serum IgG (less than 200 mg/ under hormonal influences. Colostrum contains primar-
dL) and IgG3/5 (less than 20 mg/dL) at 2 to 4 months of age, ily IgG4/7, along with IgG1 and IgG3/5, and lesser amounts
with low-normal serum IgM (greater than 15 mg/dL) and of IgA and IgM, all of which have been concentrated into
IgA (greater than 20 mg/dL). Lymphocyte counts are normal. mammary secretions from the mare’s blood.249,315,317,326,524
Antimicrobial therapy and plasma transfusions are neces- Although yet to be identified in foals, the neonatal Fc recep-
sary to minimize infections. Affected foals usually survive if tor (FcRn) transports maternal IgG from the intestinal lumen
they have not concomitantly suffered FTPI and they receive through enterocytes and into the systemic circulation in
appropriate support between 2 and 4 months of age. Because mice.525 This receptor has also been identified in the mam-
foals spontaneously recover from this condition, it may be a mary gland of cows and other species, but its functional role
secondary immunodeficiency. in transporting maternal IgG into colostrum has not been
confirmed.526-528 Whether FcRn is involved in this process in absorbed.249,531,535,536 At this time the significance of these vari-
the mare is unknown. Colostrum is only produced one time ous phenomena for the health of neonates and their immuno-
each pregnancy and is replaced by milk that contains negli- logic development is largely unknown. The one exception is
gible immunoglobulins within 24 hours of the initiation of the finding that colostral ingestion suppresses de novo anti-
lactation.350,524 This extremely rapid decline in immunoglob- body responses in foals in both a nonspecific and an antigen-
ulin concentrations in mammary secretions is consistent with specific manner.350,358
equine colostrum production ending at or even before par- Neonatal weakness, musculoskeletal problems, or lack of
turition.317 Intestinal absorption of immunoglobulins occurs maternal cooperation (maiden mares) are common reasons
in the small intestine, is greatest during the first 6 hours after for failure to ingest an inadequate volume of colostrum. If
birth, and then steadily declines until immunoglobulins can colostral ingestion is delayed beyond 6 hours, the absorption
no longer be absorbed when the foal is 24 hours old.529,530 of immunoglobulins is significantly reduced. Lactation before
Absorption is not selective for immunoglobulin as other parturition is another common reason for FTPI, because
macromolecules are absorbed,529,530 potentially along with colostrum is only produced one time each gestation. The caus-
maternal T cells present in colostrum.531 Thus the nonspecific ative factors for premature lactation are unknown at this time,
intestinal absorption of large molecules within the first 24 but foals from mares that “leak” milk hours to days before par-
hours in foals and other livestock species is the result of pino- turition are likely to suffer FTPI.534
cytosis by specialized enterocytes and is FcRn independent.526 Subnormal colostral immunoglobulin content (less than
This gut “closure” most likely results from the replacement of 3000 mg/dL) is rare in mares that do not prelactate,532 but
these specialized enterocytes by more mature cells within the wide individual variation in colostral concentration of
first day of life. immunoglobulins does occur.532,537-539 Poor-quality colos-
The incidence of FTPI is highly variable among groups of trum will undoubtedly cause FTPI. Colostral immunoglobu-
horses and seems to depend primarily on management fac- lin content can be estimated by specific gravity or quantitated
tors that ensure early colostral ingestion.532 The reported by RID.534 A Brix refractometer provides a quick and easy
prevalences of at least partial FTPI have ranged from 3% to stall-side method to accurately estimate colostral immuno-
37%.514,522,532,533 globulin content, with a reading of 20% to 30% equating to an
Clinical Signs and Laboratory Findings. FTPI does not di- IgG concentration between 5000 and 8000 mg/dL.540 A glu-
rectly cause any clinical signs of disease. FTPI is suspected taraldehyde coagulation test is also available for measuring
when signs of generalized or localized bacterial infections colostral IgG (Gamma-Check C, Plasvacc USA, Templeton,
such as septicemia, pneumonia, enteritis, and arthritis de- CA), with clot formation within 10 minutes indicating an
velop during the first 3 weeks of life. Routine laboratory IgG concentration of greater than 3800 mg/dL. Malabsorp-
findings may be suggestive of sepsis, but the presence of tion is implicated as a cause of FTPI when foals are known
infection in the neonatal period is not pathognomonic for to have ingested an adequate volume of good-quality colos-
FTPI. Common abnormalities include neutropenia or neu- trum within 12 hours of birth. Because glucocorticoids has-
trophilia, hypoglycemia, and hyperfibrinogenemia. The total ten the maturation of specialized enterocytes, stress-causing
plasma protein may be low, normal, or elevated in foals with endogenous corticosteroid release may be a cause of reduced
FTPI because of the wide variation in normal presuckle total immunoglobulin absorption. However, obvious stress factors
plasma protein and the confounding effects of dehydration are often not found in foals with apparent impaired ability to
secondary to sepsis. absorb IgG.205
Etiology and Pathogenesis. Causes for FTPI in foals in- Diagnosis. Subnormal serum IgG concentration 24
clude (1) failure of the foal to ingest an adequate volume of hours after birth is the basis for diagnosis of FTPI. Serum
colostrum in the early postpartum period; (2) loss of colos- IgG of less than 400 mg/dL is indicative of complete FTPI,
trum via premature lactation; (3) inadequate immunoglobulin and 400 to 800 mg/dL is considered partial FTPI. With the
content of the colostrum; and (4) insufficient immunoglobulin exception of hospitalized foals,454 many foals under good
absorption via the intestine.325,446,534 There is a highly nega- management conditions may remain healthy if the serum
tive correlation between foal serum IgG concentration and IgG concentration is at least 400 mg/dL, and consequently
the incidence of severe infections522; however, the minimum this cut-point is measured by several rapid diagnostic tests.
amount of IgG necessary for protection of a foal from infec- The most quantitatively accurate method to determine se-
tion varies with the amount and virulence of environmental rum IgG is by RID as discussed earlier. However, this assay
pathogens, concomitant stress factors, and colostral antibody is time-consuming and expensive and thus inappropriate for
titer against specific pathogens. Although a serum IgG con- the diagnosis of FTPI when timely therapeutic intervention
centration of at least 400 mg/dL has been considered evidence is paramount. Numerous field screening procedures for IgG
of adequate transfer of passive immunity, most normal foals have been evaluated.446,455-457,459-461,541 Criteria for selecting
attain values more than twice this high,522,532 and serum IgG a screening test for equine FTPI must include accuracy, the
greater than 800 mg/dL is likely required for adequate im- time necessary to perform the test, ease of performance, and
munity.523 A recent study in hospitalized foals supports this cost. The ease and reported accuracy of membrane-based
latter conclusion.454 Numerous other colostral factors may ELISA tests often make them the test of choice in many prac-
be important for the immune protection of foals. Colostrum tice situations. Because failure to diagnose and treat the con-
has been variously shown to regulate cell-mediated immunity, dition could result in the death of many foals, a sensitive test
activate granulocytes, promote intestinal absorption of mac- is required. However, specificity is also important, particu-
romolecules, decrease intestinal colonization by pathogens, larly given the cost of treatment and the fact that treatment
and contain constituents of innate immunity (e.g., lactofer- is not without its own inherent complications. Generally, all
rin, complement) and leukocytes that have a local protective the available immunoglobulin screening tests are relatively
role in the neonatal digestive tract and may be systemically accurate in identifying foals with complete FTPI; however,
there is variation in their ability to detect marginally defi- as a predictor of FTPI. As measured by specific gravity, a co-
cient foals.325,446,461 Individual clinician judgment is there- lostral IgG concentration of 3000 mg/dL is the minimum ac-
fore important in test selection. As discussed, the glutaralde- ceptable value, and when colostrum contains less than this
hyde coagulation test (Gamma-Check E) is good for initial amount, some degree of FTPI should be suspected in the foal
screening because it is simple, rapid, inexpensive, and sensi- and corrected.534 Brix refractometry542 or the Gamma-Check
tive for ruling out FTPI (IgG concentration ≥800 mg/dL). C test could also be used for this purpose. Routine screening
However, this test lacks specificity, so a diagnosis of FTPI of foal serum IgG at 24 to 48 hours after birth allows necessary
based on this test should be confirmed with a more specific plasma therapy before the onset of infections.
test, such as the membrane filter ELISA (SNAP).325,461 Over- Foals that are born prematurely, are weak, or are from pre-
all, the relatively good performance and the convenience of lactating mares should be provided with an alternative colos-
the semiquantitative SNAP test will continue to make it a tral source or commercial equine IgG product within 6 hours
popular first choice. of birth. A colostrum bank can be established by collecting and
Treatment. If FTPI is anticipated because of premature freezing (−20°C) 250 mL of colostrum from mares that have
lactation, neonatal weakness, dam death, or low-specific- not prelactated within 6 hours of foaling, once their own foals
gravity colostrum, an alternative source of colostrum or a have suckled. Ideally, banked colostrum should be screened
commercial concentrated equine IgG product (Seramune, for alloantibodies, although they are unlikely if the mare’s own
Sera, Inc., Shawnee Mission, KS) should be given orally. A foal remains healthy. The immunoglobulins in banked frozen
minimum of 2 L of equine colostrum given in 500-mL incre- colostrum are stable for at least 1 year.
ments during the first 8 hours after birth is optimal. Bovine
colostrum may be safely substituted if equine colostrum or Exercise
commercial equine IgG product is not available349,351; how- Exercise, when conducted at a stressful level, can signifi-
ever, foals given bovine colostrum may also require plasma cantly affect equine immune function.543 Strenuous exer-
transfusion because bovine immunoglobulins have a very cise significantly suppresses lymphoproliferative responses,
short half-life in foals and are not specifically directed against whereas lymphokine activated killer (LAK) cell activity
equine pathogens. increases.544,545 In racehorses, decreased lymphoproliferative
If the foal is more than 12 to 18 hours old when FTPI is responses can be demonstrated 12 to 16 hours after racing.546
suspected or diagnosed, an intravenous plasma transfusion is Protracted high-intensity training results in decreased phago-
indicated. The U.S. Department of Agriculture (USDA) has cytosis and oxidative burst activity in neutrophils and lym-
approved numerous commercial sources of equine plasma, phocytes, although pulmonary alveolar macrophage function
and use of these products is convenient, saves time, and is is unaffected.547 Other studies have demonstrated decreased
safe because donors are free of alloantibodies and negative for neutrophil and pulmonary alveolar macrophage function
infectious diseases. The only potential drawback to the use of in response to single bouts of intense exercise548,549 and
commercial plasma is that antibodies specific for pathogens in prolonged suppression of innate immunity after exercise of
the foal’s environment may be lacking. Optimal plasma would long duration.550 Incremental exercise in unfit Standardbred
be obtained from a local blood-typed donor known to lack mares results in an increase in inflammatory cytokine expres-
serum alloantibodies and alloantigens Aa and Qa. The volume sion in blood (IFN-γ, TNF-α, and IL-1) and in muscle tis-
of plasma necessary to bring serum IgG into an acceptable sue (IFN-γ, TNF-α, and IL-6).551 Strenuous exercise results in
range cannot be accurately predicted because it is dependent neutrophilia, increased apoptotic activity in leukocytes, and
on the severity of FTPI, the immunoglobulin content of the decreased leukocyte reactive oxygen species production in
plasma, and concomitant diseases, which may hasten immu- response to PMA stimulation, with some of these effects per-
noglobulin catabolism. Generally, 1 L of plasma will increase sisting for 72 hours after exercise.552 In unconditioned ponies
the serum IgG concentration of a 50-kg foal by 200 to 300 strenuous exercise increases susceptibility to experimental
mg/dL237; thus 2 to 4 L may be necessary to achieve serum infection with equine influenza, associated with alterations
IgG greater than 800 mg/dL. A therapeutic dose of plasma in the virus-specific cell-mediated immune response.553 In an
should be administered and then serum IgG concentration influenza infection study in trained horses, moderate exercise
reassessed. If the desired concentration has not been attained, led to increased signs of clinical disease, although duration of
more plasma is necessary. Some foals with partial FTPI (IgG disease was unaffected.554
greater than 400 and less than 800 mg/dL) may do well with- These various studies have demonstrated an immuno-
out plasma therapy if there are no preexisting infections and modulatory effect of exercise, with some specific evidence
exposure to pathogens is minimized. These foals should be for increased susceptibility to infectious disease. Some of
monitored closely for the development of infections. However, these effects are likely due to increases in plasma cortisol,
hospitalized foals with IgG concentrations in this range should which is correlated with the intensity and duration of exer-
receive plasma.454 cise and with alteration in immune function in horses.555 In
Client Education. The prognosis for foals with FTPI de- general, moderate exercise appears to be beneficial to the
pends on the degree of failure, the environment to which the immune system, whereas prolonged and intense exertion
foal is exposed, the foal’s age at the time of diagnosis, and the likely impairs immune function. The potentially immuno-
presence and severity of secondary infections. Management suppressive effect of high-intensity exercise, particularly of
factors that ensure the ingestion of at least 2 L of high-quality protracted duration or in unconditioned animals, should be
colostrum within 6 hours of birth are paramount in FTPI pre- recognized.
vention. Foaling should be witnessed so that any malpresen-
tations can be corrected, and foals that do not readily nurse Age
within 3 hours can be given colostrum or suitable substitute There is a high incidence of respiratory infections in foals and
via nasogastric tube. Colostral IgG concentration can be used weanlings, which frequently relapse on cessation of antibiotic
treatment.556 It is also possible that the normal level of immu- vaccination in old horses has been observed by others.544 A
nocompetence in this age group leads to increased susceptibil- recent study measured antibody and cell-mediated responses
ity to respiratory infections, particularly under group housing in old horses following vaccination with a canarypox recom-
conditions. Features of the foal’s immune system that pre- binant vector influenza vaccine.570 In young naive horses the
dispose to such infections have been discussed earlier in this vaccine induced antibody and cell-mediated responses as
chapter. measured by IFN-γ production and reduced viral shedding
Geriatric horses experience a general reduction of immune and protected against clinical disease following influenza
function similar to humans, a phenomenon called immu- virus challenge. The old horses in this study were not naive,
nosenescence. Also like humans, old horses tend to produce and vaccination slightly enhanced antibody titers whereas
exaggerated inflammatory responses, known as “inflamm- vaccine-elicited cell-mediated memory responses were not
aging.”557,558 Immunosenescence in humans is associated with detectable. Nonetheless, virus shedding was reduced, and
age-related defects in the thymic and bone marrow microen- clinical protection occurred in the old horses.
vironment and a predominance of memory T and B cells with The geriatric horse population is on the rise,557,558 requir-
limited repertoire diversity.559 In addition, increased cell death ing an increased appreciation for age-related diseases
in the elderly, along with hormonal dysregulation, increased and other problems unique to the older horse. Immune
oxidative stress, and the presence of chronic diseases, con- responses are diminished in old horses, and old horses are
tribute to a low-grade activation state in innate cells such as prone to produce inflammatory responses. Some vaccine
macrophages, which characterizes inflamm-aging.559 Many strategies that are effective in younger horses may result
of these effects are likely due to immune dysregulation, and in less robust immune responses in old horses, leading to
the underlying cause could involve age-related alterations in lower levels of protection and an increased need for boost-
the membrane composition and in critical signaling and regu- ing. Further studies in this area will hopefully improve the
latory molecules in immune cells such as neutrophils and T understanding of immune regulation and function in old
cells.560 horses to better inform immunoprophylactic and therapeu-
Horses greater than 20 years old have decreased total lym- tic approaches.
phocyte counts and reduced numbers of B cells and CD4+
and CD8+ T cells, as well as decreased lymphoproliferative Leukoproliferative Disease–Associated
responses to mitogens.561,562 In addition, old horses demon- Immunodeficiency
strate reduced immunologic responses during exercise.544 Lymphoma is often associated with IgM deficiency446,516,571
Although lymphoproliferative responses are decreased in old and can also be associated with decreased lymphocyte blas-
horses, T cells still produce IFN-γ and other inflammatory togenesis.572,573 Affected horses have been diagnosed with
cytokines, and elevated expression of inflammatory cyto- bacterial pneumonia in some instances, as well as pulmonary
kines occurs in peripheral blood along with elevated levels of aspergillosis in a horse with myelomonocytic leukemia.574
TNF-α in serum, consistent with inflamm-aging.563 Obesity These cases demonstrate the importance of considering leu-
likely contributes to the age-related proinflammatory state koproliferative disease, and particularly lymphoma, in cases of
as obese old horses have higher frequencies of lymphocytes persistent infections that are refractory to treatment.
and monocytes producing IFN-γ and TNF-α than old thin
horses.564 Interestingly, a proinflammatory bias may not Drug-Induced Immunodeficiency
occur in the lungs of old horses. As evidence, the frequency The most common iatrogenic cause of immunosuppression is
of IFN-γ producing lymphocytes in both PBMCs and BAL corticosteroid treatment, often administered with the aim of
cells is elevated in old horses, whereas age-related produc- treating a hypersensitivity disorder. The mode of action and
tion in TNF-α is only present in PBMCs.565 Moreover, an the immunosuppressive effects of corticosteroids are reviewed
age-related decrease in BAL cell proinflammatory cytokine in the next section, but there is evidence for the capacity of
expression has recently been documented in horses.566 Thus corticosteroids to induce recrudescence of viral diseases such
the process of inflamm-aging may be organ specific in the as equine infectious anemia575-577 or EHV-1 infection578 and
horse. to lead to development of life-threatening bacterial infec-
Telomeres protect the ends of chromosomes and contrib- tion.579 Based on the EIAV studies, dexamethasone admin-
ute to the stability of the genome; maintenance of telomere istration results in profound reduction of peripheral blood
length and telomerase activity inversely correlate with age, B- and T-cell numbers,575 and the recrudescence of viremia
and shorter telomeres are associated with age-related chronic is most likely due to the suppression of T-cell responses
diseases.567 Telomere length in PBMCs declines with age in because the virus-specific neutralizing antibody titers do not
horses and is inversely correlated with inflammatory cytokine change.576 There is also evidence that corticosteroid treatment
expression and positively correlated with lymphoprolifera- can bias adaptive immune responses to vaccination in horses,
tive responses and total immunoglobulin levels.568 Although specifically suppressing IgG1 and IgG4/7 responses with-
these observations suggest a role for telomere length in out affecting IgG3/5 responses.468 This phenomenon may be
equine immunosenescence and inflamm-aging, the associa- consistent with the capacity of corticosteroids to specifically
tions between telomere length and immune function do not suppress TH1 immune responses with minimal effect on TH2
apply in the oldest horses, indicating that other factors are also responses.580,581
involved.
Finally, old horses can mount a primary humoral immune Infectious Disease
response against a killed rabies vaccine similar to young Several infectious diseases have been associated with immu-
horses, but their memory response against a killed influenza nodeficiency in horses. The best-characterized example may
virus vaccine results in lower antibody titers than in young be perinatal EHV-1 infection.582 Foals that are infected late
horses.569 Lower antibody titers following influenzavirus in gestation with EHV-1 are often born weak with interstitial
pneumonia and develop a variety of bacterial diseases.583 network. Consequently, attempts to intervene with immuno-
Affected foals have profound lymphopenia and generally die, modulators are often nonspecific. Some of the information on
despite therapy. The immunodeficiency is thought to be due which the use of immunomodulators is based has come from
to viral-induced lymphoid damage, because necropsy reveals controlled experimental studies, some performed in vitro and
marked necrosis of lymphoid tissue in the thymus, spleen, others in vivo. In clinical patients, expectations based on these
and lymph nodes. Another example is EIAV infection. During types of studies are frequently not realized. Reasons for this
acute viremic episodes, reduction of peripheral blood CD4+ include the timing of the administration of the immunomodu-
and CD8+ T-cell numbers occurs as does suppression of lym- lator during the course of disease and the fact that observation
phoproliferative responses.584,585 of a single immunologic phenomenon resulting from use of an
immunomodulator—for example, an increase in lymphocyte
Undifferentiated Immunodeficiencies count or lymphoproliferative responses—does not necessarily
A group of foals with oral candidiasis and bacterial septice- translate into improved clinical performance in the face of an
mia between 2 weeks and 4 months of age were found to have infectious disease. Because of the complexity of the immune
laboratory or histologic evidence of immunodeficiency that network, the rational use of immunomodulators can be con-
did not fulfill diagnostic criteria for any of the recognized siderably more difficult than the use of antimicrobial agents.
primary immunodeficiencies.586 Oral lesions ranged from An example of the importance of timing in immunomodula-
focal white plaques on tongue margins to a generalized thick, tory intervention is the relative success of immunosuppressive
white pseudomembrane covering the tongue and gingiva. therapy in the context of organ allografts, compared with the
Affected foals showed bruxism, ptyalism, fever, and depres- frequent treatment failures experienced in treating autoim-
sion in addition to pneumonia, arthritis, or diarrhea, singly mune disease. In the former case therapy is planned in advance
or severally. The lymphocyte counts of the foals were usu- of the introduction of the allograft, whereas in the case of auto-
ally normal. Several foals had IgM deficiency coupled with immunity the immune response and resulting disease are well
depressed blastogenesis, suggesting cellular immune dys- established before they are detected and therapy is initiated.
function. Many of the foals had low or marginally reduced Immunomodulators have been embraced by clinicians,
serum IgG in addition to IgM deficiency or reduced blas- and the concept of their use remains appealing. The clini-
togenesis. It was not determined whether the immunologic cal value of immunosuppressive drugs such as corticoster
defects were primary or secondary. All foals died despite oids and the immunostimulant adjuvants used in vaccines
extensive therapy with parenteral antimicrobials, topical is clearly established. Although the body of work evaluat-
antimycotics, and intravenous plasma. ing immunostimulants has grown in recent years, the evi-
Acquired immunodeficiency was identified in a 7-year-old dence for the clinical value of many immunostimulants is
Appaloosa gelding that had no history of previous illness.587 still sparse and sometimes conflicting. It is important to
Clinical signs included lethargy, anorexia, and dyspnea. look critically at the immunomodulatory drugs on the mar-
Pneumonia and septicemia due to Rhodococcus equi were ket and make attempts to objectively evaluate the effects of
confirmed by tracheal wash and blood culture, respectively. therapy.
Immunologic evaluation revealed marked lymphopenia, sub- This discussion will be limited to drugs currently marketed
normal serum IgG and IgA with marginally low IgG concen- for use as immunomodulators or for which there is published
trations, failure to respond serologically to immunization, evidence of activity. Advances in molecular biology have made
and reduced in vitro lymphocyte blastogenesis. Histologic available recombinant forms of many cytokines with immu-
examination of lymph nodes and spleen revealed lymphoid nomodulatory potential, but only those with some established
atrophy. value will be discussed.
Y IMMUNOMODULATORS Immunosuppressors
Clinicians frequently seek to increase normal, restore deficient, Corticosteroids
and temper overexuberant host immune responses. For these Corticosteroids are classic examples of immunosuppres-
reasons, modulation of the immune system remains an area of sive agents. Corticosteroids exhibit an extensive range of
intense interest in clinical medicine. Both immunostimulants effects on elements of both the innate (inflammatory) and
and immunosuppressants are considered immunomodula- adaptive immune response. Corticosteroids are deriva-
tors. There are a variety of ways to classify immunomodula- tives of the glucocorticoid family of steroid hormones,
tors beyond this distinction, but for practical purposes they and after crossing the cell membrane they bind to cyto-
may be best classified based on their origin: that is, physi- plasmic glucocorticoid receptors. Once activated, gluco-
ologic products (actual normal components of the immune corticoid receptors are transported to the nucleus where
response), microbial products, and chemically defined agents. they bind to DNA and interact with other transcription
Immunomodulation can also result from modes of therapy factors, resulting in the regulation of as many as 20% of
not considered here, including bone marrow transplantation the genes expressed in leukocytes.209 The useful antiin-
and irradiation. flammatory effects of corticosteroids are summarized in
Although a scientific rationale for the use of immunomodu- Table 1.8. The effect on the adaptive immune response is
lators exists, a major limitation is the complexity of the immune complex.588 For example, in cases of autoimmune disease
response to be modulated. There are several major problems in such as autoimmune hemolytic anemia, corticosteroids may
the rational clinical application of immunomodulators. Com- act by reducing phagocytosis of antibody-coated cells by the
monly used diagnostic methods do not allow precise iden- reticuloendothelial system rather than decreasing antibody
tification of the in vivo defects, deficiencies, or excesses of production. Nevertheless corticosteroids have been shown
substances or regulators present within the immunoregulatory to have effects on antibody production, and in the horse
TABLE 1.8 Antiinflammatory Effects of Corticosteroid Therapy, Bacterial and Fungal Derivatives
Mediated by Regulation of Gene Transcription This class of drugs includes relatively nontoxic alternatives to
immunosuppressive cytotoxic drugs. Cyclosporine is a fungal
Action of Corticosteroids derivative and has emerged as a major immunosuppressive
Direct Effects Physiologic Effects agent for allograft survival. It selectively inhibits proliferation,
cytotoxicity, and lymphokine production of T cells by binding
↓ IL-1, TNF-α, GM-CSF, IL-3, ↓ Inflammation caused by to intracellular proteins known as immunophilins and inter-
IL-4, IL-5, CXCL8 cytokines fering with signaling pathways that are important for clonal
↓ Nitric oxide synthetase ↓ Nitric oxide expansion of lymphocytes.209 Cyclosporine is efficacious in
↓ Phospholipase A2, ↓ Protaglandins, leukotrienes suppressing specific immune responses with minimal nonspe-
cyclooxygenase type 2 cific toxic effects on polymorphonuclear leukocytes, mono-
↑ Annexin-1 cytes, and macrophages. Thus immunosuppressed patients
↓ Adhesion molecules ↓ Emigration of leukocytes suffer fewer severe secondary infections. The drug is not haz-
from vessels ard free, as in addition to suppressing lymphocyte responses in
↑ Endonucleases ↑ Apoptosis in lymphocytes general, it is also toxic to the kidneys and other organs.
and eosinophils In horses the use of cyclosporine has been limited to topi-
cal and intravitreal therapy for ocular inflammatory disease,
From Murphy KP, Janeway’s immunobiology, 8th edition, 2012. including keratitis603 and uveitis.604,605 In the treatment of
uveitis, numbers of infiltrating T lymphocytes and IL-2 and
IFN-γ levels were suppressed by cyclosporine treatment.606
they can suppress de novo antigen-specific IgG1 and IgG4/7 Use of a suprachoroidal cyclosporine implant results in
responses while sparing IgG3/5 responses.468 This may be long-term maintenance of vision in horses with recurrent
consistent with the action of corticosteroids to suppress uveitis.607
TH1 responses while sparing TH2 responses.580,581,589,590
Cell migration is significantly affected by corticosteroids,
and in the horse corticosteroids have been shown to sup- Y IMMUNOSTIMULANTS
press neutrophil migration, together with phagocytic and
bactericidal activity.591 The mechanism whereby migration
Physiologic Products
is decreased involves decreased expression of adhesion Cytokines
molecules including selectins and integrins.592 Experien- Given the central role of cytokines in immunoregulation (see
tially, high-dose dexamethasone (1.0 mg/kg intravenously under Equine Immunology), their potential as immunomod-
daily for 9 days) profoundly reduces the numbers of B and ulators is obvious, and a discussion of the possible use of cyto-
T lymphocytes in the peripheral blood of horses.575 Intra- kines as therapeutic agents in this regard would be extensive
venous administration of single lower doses of dexametha- although largely hypothetical. Therefore consideration will be
sone (0.05, 0.1, or 0.2 mg/kg) to a healthy horse results in limited to the two cytokines that have found clinical applica-
neutrophilia and reduction of peripheral blood CD4+ T-cell tion in horses to date.
numbers, with a corresponding increase in the numbers of Interferon-α. The clinical application of human interferon-
CD8+ T cells and B cells.593 α in the horse has been extensively reviewed.608-610 Interferon-
Although corticosteroids are powerful immunosuppressive α has antiviral and immunostimulant properties, and oral
agents, they may also predispose patients to life-threatening administration of interferon-α has been shown to reduce
opportunistic infections579 or recrudesence of viral infec- inflammatory airway disease611 in racehorses.612 The treat-
tion.575,576,594 Additional extensive undesirable side effects ment employed was low-dose (50–150 IU) natural human
include fluid retention, decreased wound healing, and the interferon-α, and it resulted in decreased BAL cell counts and
concern that their use can be associated with the develop- a noninflammatory cytologic profile.613 Higher doses (450 IU)
ment of laminitis in some circumstances.595-598 For this reason were less effective, consistent with results in other species.410
prolonged or high-dose corticosteroid therapy must be used The efficacy of oral therapy probably depends on effects medi-
judiciously. ated through oropharyngeal lymphoid tissue, as the agent is
destroyed in the stomach. Recombinant human interferon-α
Cytotoxic Drugs (Intron-A, Merck, Kenilworth, NJ) has similar therapeutic ef-
The two commonly used immunosuppressive cytotoxic fects as natural human interferon-α.614
drugs, azathioprine and cyclophosphamide, both interfere Granulocyte Colony-Stimulating Factor. The clinical appli-
with DNA synthesis and act primarily on dividing cells.209 cation of granulocyte colony-stimulating factor (G-CSF) in the
This activity is useful for treatment of cancer and for suppres- horse has been extensively reviewed.609,610 G-CSF treatment in
sion of dividing lymphocytes. Cyclophosphamide has been neonatal foals results in a sustained, dose-dependent increase
used along with prednisolone in a chemotherapeutic proto- in neutrophil count and a left shift,615,616 by increasing neutro-
col to achieve remission of thoracic lymphoma in a horse.599 phil production in the bone marrow and shortening the time
Toxicity limits the use of these drugs, although at lower doses to release into the circulation while the half-life remains un-
they can be used in combination with corticosteroids. These changed at 8 hours. Recombinant human G-CSF (Neupogen,
drugs have been used in horses to treat immune-mediated Amgen, Thousand Oaks, CA) has been effective for treating
hemolytic anemia or thrombocytopenia with success in some persistent neutropenia in foals with alloimmune neonatal neu-
cases600-602 and unsuccessfully for treatment of pemphigus tropenia.617,618 Canine recombinant G-CSF has been used to
vulgaris.436 treat sepsis and endotoxemia in foals with some success.609,610
Bacterial, Viral, and Plant Products Although P. acnes treatment had no effect on IFN-γ produc-
A variety of bacterial and fungal microorganisms or micro- tion by stimulated PBMCs or IFN-γ expression in peripheral
bial products have been identified that have immunomodulat- blood of neonatal foals less than 1 week of age, both were
ing effects. A common feature of many of these products is a increased following a second series of doses when the foals
nonspecific immunostimulant effect, purportedly due to mac- were 1 month old.625 Macrophages isolated from foals treated
rophage activation and release of cytokines including interfer- with P. acnes beginning at 1 week of age demonstrate less
ons, IL-1, TNF-α, or IL-6.609,619 Consequently mild fever and intracellular proliferation of R. equi when infected in vitro
malaise may be associated with this form of treatment. In the compared with macrophages from untreated control foals.626
horse these treatments are most commonly used in cases of Overall this agent is one of the most popular immunostimu-
respiratory infection or sarcoids. Extensive reviews of the use lants marketed for horses. Based on the published literature it
of these and other immunostimulants in the horse have been appears to be of therapeutic benefit in adult horses but likely
published.609,610,620 less so in neonatal foals.
Mycobacterial Products Parapoxvirus ovis

A wide range of mycobacterial fractions have been identified Parapoxvirus ovis is a DNA virus of small ruminants that
with immunomodulating ability.609,619 The minimal structure produces a variety of modulatory factors that are maintained
with immunologic (adjuvant) activity is muramyl dipeptide, after virus inactivation. As such, inactivated Parapoxvirus
which is a potent adjuvant.621 Preparations commercially avail- ovis (iPPVO) has been shown to activate APC, leading to
able for use in horses include bacillus Calmette-Guérin (BCG), upregulation of proinflammatory cytokines IL-6, TNF-α,
a modified live human tuberculosis vaccine, and protein-free and CXCL8; TH1-inducing IL-12; and T-cell production
mycobacterial cell wall extract (MCWE; Equimune, Immuno- of IL-2, IFN-α, and IFN-γ.610,620 Marketed under the trade
cidin, and Settle, NovaVive, Athens, GA). Efficacy is reported name Baypamun (Bayer Animal Health, DE), iPPVO was
for treatment of equine respiratory disease (Equimune; intrave- used extensively in Europe for prophylaxis and treatment of
nous), sarcoids (Immunocidin; intralesional), and endometritis infectious disease in companion animals, horses, and pigs.609
(Settle; intravenous or intrauterine). Intravenous administra- In the United States iPPVO was marketed as Zylexis (Zoetis,
tion of MCWE at the time of artificial insemination down- Florham Park, NJ) for enhancing immunity before stressful
regulates IL-1 expression in mares susceptible to postbreeding events or during disease, particularly to improve resolution
endometritis and thus might have therapeutic value in this of viral respiratory disease, including EHV-1 and EHV-4.620
population.622 Adverse hypersensitivity reactions have been At the time of this writing, however, Zylexis has been dis-
reported after multiple intravenous treatments in horses, result- continued and is not currently available. Efficacy has been
ing in interstitial lung infiltration and progressive pulmonary demonstrated against viral and bacterial disease in several
fibrosis. In horses, a successful application of these products species,609 and there is evidence in horses that prophylactic
has been in the intralesional treatment of sarcoids, particularly administration before weaning reduces signs of respiratory
periocular sarcoids,623 and this is discussed elsewhere in this disease after weaning.627 More recently, however, treatment
book. with iPPVO did not affect the decreased IFN-γ, TNF-α,
and IL-10 production by PBMCs associated with the stress
Propionibacterium acnes of abrupt weaning.628 In a model of transport stress, treat-
Propionibacterium acnes is a commensal gram-positive ment with Zylexis led to restoration of suppressed antibody
anaerobe, marketed for use in horses as a killed prepara- responses to influenzavirus infection in horses.629 More
tion under the trade name EqStim (Neogen, Lexington, recently, treatment with Zylexis was associated with a mod-
KY) for treatment of equine respiratory disease. It is recom- erate reduction in clinical signs and reduced shedding of
mended for use prophylactically before weaning, transport EHV-1 and S. equi.630 In healthy yearlings, iPPVO treatment
stress, or comingling, or for the therapy of chronic infec- resulted in increased IFN-γ expression in peripheral blood.631
tious respiratory disease. After intravenous administration, Neutrophils from foals treated with iPPVO at 1 week of age
P. acnes is taken up by macrophages in the liver and spleen had enhanced phagocytic and oxidative burst activity against
and degraded slowly, resulting in macrophage activation. In R. equi in vitro compared with baseline controls and with
addition, P. acnes CpG motifs (see later discussion) result in foals treated with P. acnes.626 In iPPVO-treated foals, TNF-
immune activation by binding TLR9 on macrophages, den- α induction was higher in monocyte-derived macrophages,
dritic cells, and NK cells.610,620 In healthy horses, P. acnes and IL-12 induction was higher in BAL macrophages infected
resulted in increased CD4+ T-lymphocyte numbers and LAK with R. equi in vitro compared with control foals. In a sepa-
cell activity in peripheral blood and BAL fluid, increased rate study using foals on an R. equi endemic farm, iPPVO
nonopsonized phagocytosis in peripheral blood leukocytes, treatment initiated within the first 2 days of life resulted in a
and decreased pulmonary cellularity.469 Treatment of horses higher number of PBMC producing IFN-γ by 1 to 2 weeks of
with P. acnes has also been shown to increase IFN-γ and anti- age compared with control foals, but there was no difference
microbial peptide expression in PBMCs.624 In adult horses, in the proportion of foals that developed R. equi pneumo-
two randomized controlled trials have demonstrated that nia.632 Finally, iPPVO has not shown efficacy for treatment
the addition of P. acnes treatment to conventional therapy of sarcoids.633
enhances clinical recovery or improvement of spontane-
ously occurring infectious respiratory disease.620 Several Imiquimod
other studies have shown that P. acnes treatment is beneficial Imiquimod (Aldara) is a synthetic imidazoquinoline immu-
in reducing the prevalence of respiratory disease associated nomodulating cream used for topical treatment of actinic
with longdistance transport and in resolving endometritis.620 keratosis and genital warts in humans and to successfully treat
sarcoids and aural plaques in horses.610,623 It acts as a TLR7 pathogens. Attenuated live vaccines have the potential to cause
agonist, resulting in increased proinflammatory cytokine disease in some individuals or to revert to virulence. Recom-
production, and has potent antiviral and antitumor activity. binant viral vector vaccines result in intracellular expression
Studies report that 56% to 82% of treated sarcoids achieve of antigens without the risk of causing disease or reversion to
complete remission, with 80% having at least a 75% reduction virulence. The success of all of these types of vaccines, sub-
in size. Mean treatment time is 3.7 months.623 unit and killed vaccines in particular, is frequently dependent
on use of an effective adjuvant.648 Adjuvants are compounds
Cytosine-Phosphate-Guanosine- capable of potentiating immune responses and include sub-
Oligodeoxynucleotides stances that result in depot formation, induce inflammatory
In recent years an extensive body of literature has developed cytokines, recruit leukocytes, enhance antigen uptake and pre-
describing the immunomodulatory effects of certain unmeth- sentation, or increase the expression of costimulatory mole-
ylated bacterial DNA motifs.634 The specific immunostimula- cules. As such, adjuvants are some of the most important types
tory DNA motifs are called CpG sequences, and appropriate of immunomodulating agents in use in equine medicine.
oligodeoxynucleotides (ODN) containing CpG motifs for Passive immunization is accomplished by administering
immunostimulation of domestic species have been identi- preformed antibodies either as a plasma transfusion or in
fied.635 Much work has been done on examining the efficacy of a concentrated form, as in commercially available tetanus
CpG-ODN as vaccine adjuvants,636 as immunomodulators for antitoxin. This strategy can be highly effective in diseases for
hyposensitization (see later discussion), or cancer therapy.637 which there is no available vaccine (e.g., R. equi) or in high-
The value of CpG-ODN in horses as both vaccine adjuvants638 risk situations when there is inadequate time for protection
and as potential nonspecific immunomodulators340,639,640 to be generated by active immunization. Although USDA-
has been demonstrated. Recently intramuscular administra- approved commercial equine plasma and serum products
tion of a CpG-ODN formulation to newborn foals resulted are derived from donors screened for routine blood-borne
in increased IFN-γ production by neutrophils and modulated pathogens, passive immunization carries a risk of transmit-
neutrophil degranulation.641 Although CpG-ODN hold prom- ting previously unidentified infectious agents. Examples
ise as immunomodulators, commercial products for clinical include the association with acute hepatic necrosis with a
use are not yet available. previous administration of tetanus antitoxin649 and more
recently an outbreak of liver disease associated with trans-
mission of Theiler’s disease–associated virus (TDAV) via
Chemically Defined Agents administration of botulinum antitoxin.202 Equine blood
Levamisole products could contain other newly reported viruses associ-
Levamisole is synthetic anthelmintic used for treatment of ated with hepatitis in horses, including equine hepacivirus
nematode infections, which has also been reported to restore and equine pegivirus.650 As was the case in the discovery
impaired host immune defenses.609 Levamisole appears to of TDAV,202 deep sequencing techniques may reveal other
have little effect on the normal immune system, but it appears infectious pathogens that could contaminate equine blood
to stimulate a subnormal response and suppress hyperac- products.
tive responses. The effects are dose related, and low doses are
reported to enhance whereas higher doses suppress responses. Hyposensitization
In cattle levamisole has been shown to enhance lymphoprolif- Because horses suffer from a number of hypersensitivity dis-
erative responses in vitro, although in vivo coadministration eases, attempts have been made to perform antigen-specific
with a vaccine had no immunostimulant effect.642 Similarly, immunosuppression. Examples include IBH and RAO.651 The
levamisole did not prevent corticosteroid-mediated immu- principle of this type of therapy is that the immune response
nosuppression in cattle643 or enhance postpartum lympho against an allergen can be redirected to reduce hypersensitiv-
proliferative responses in pigs.642 Other than anecdotal reports ity disease.652 For example, because type 1 hypersensitivity is
there are no published controlled studies of its value in horses. associated with a TH2-biased immune response, treatments
that cause a shift to a TH1 response could eliminate or con-
trol the hypersensitivity by changing the antibody response
Antigen-Specific Immunomodulation from one dominated by IgE to IgG.209 Typically hyposensiti-
Vaccination and Adjuvants zation treatments, also known as allergen-specific immuno-
Vaccination is a critically important tool in preventing infec- therapy (ASIT), use injections of the allergen itself, starting
tious disease in humans and animals, and both passive and with very small doses, and gradually increasing the dose
active vaccination are extensively employed in the horse. Spe- over time. This form of treatment depends on correct iden-
cific equine vaccination strategies are presented elsewhere tification of the allergen against which the hypersensitivity
in this book, and the scientific principles and the practice is directed, and the difficulty in identifying these allergens
of equine vaccination have been extensively reviewed.644-647 using intradermal or IgE ELISA-based serologic testing
Vaccination implies active immunization where an antigen- methodologies396,653 may provide an explanation for the
specific immune response is induced in the vaccinated animal mixed success of ASIT in horses.654,655 Prospects for ASIT
by administration of subunit, whole killed or attenuated live have been improved recently with the use of pure recom-
antigen, or DNA in a plasmid or a recombinant viral vector binant protein allergens, which are far superior in terms
capable of expressing protein antigens in vivo. Each of these of sensitivity (up to 89%) and specificity (up to 97%) for
strategies has advantages and disadvantages. For example, detection of allergen-specific IgE.656,657 A protein microar-
killed vaccines do not result in efficient MHC I processing ray containing a large panel of complex extracts along with
and presentation and thus do not elicit robust CTL responses, pure and recombinant proteins and analyzed using math-
limiting effectiveness against predominantly intracellular ematical modeling techniques has been recently described
that is capable of high-throughput detection of allergen- 8. Crane SA, Ziemer EL, Sweeney CR. Cytologic and bacteriologic
specific IgE.658 This microarray has yielded a sensitivity and evaluation of tracheobronchial aspirates from clinically normal
specificity of 100% and 97%, respectively, for the diagnosis foals. Am J Vet Res. 1989;50:2042–2048.
of IBH. Even when previous allergen identification methods 9. Moore CP, Heller N, Majors LJ, et al. Prevalence of ocular mi-
are used, ASIT can be effective for managing atopic skin dis- croorganisms in hospitalized and stabled horses. Am J Vet Res.
ease in horses as described in a recent retrospective study 1988;49:773–777.
10. Koopman JP, Kennis HM, Mullink JW, et al. “Normalization” of
involving 54 horses (1991–2008) treated for urticaria, pru-
germfree mice with anaerobically cultured caecal flora of “nor-
ritus, or both.659 Intradermal and/or serologic testing was mal” mice. Lab Anim. 1984;18:188–194.
used to identify allergens, and 84% of owners reported that 11. Blumberg RS, Saubermann LJ, Strober W. Animal models of
ASIT reduced clinical signs, with 59% able to manage clini- mucosal inflammation and their relation to human inflamma-
cal signs without the use of immunosuppressive drugs. The tory bowel disease. Curr Opin Immunol. 1999;11:648–656.
majority of owners (75%) discontinued ASIT after a mean 12. Mackie RI, Wilkins CA. Enumeration of anaerobic bacterial mi-
of 2.2 years, most because of resolution of clinical signs. The croflora of the equine gastrointestinal tract. Appl Environ Micro-
availability of increasingly sensitive and specific allergen biol. 1988;54:2155–2160.
testing strategies will undoubtedly further improve the suc- 13. Yuki N, Shimazaki T, Kushiro A, et al. Colonization of the strati-
cess of ASIT. Of considerable promise, a vaccine approach fied squamous epithelium of the nonsecreting area of horse stom-
ach by lactobacilli. Appl Environ Microbiol. 2000;66:5030–5034.
for potentially preventing IBH has recently been described
14. Davies MK. Studies on the microbial flora of the large intestine
in which small doses of recombinant Culicoides allergens are of the horse by continuous culture in an artificial colon. Vet Sci
inoculated along with a TH1-focusing adjuvant.660 Immuni- Communications. 1979;3:39–44.
zation results in induction of allergen-specific IgG without 15. Julliand V, de Vaux A, Millet L, et al. Identification of Rumi-
inducing IgE, does not produce IgE-mediated hypersensitiv- nococcus flavefaciens as the predominant cellulolytic bacte-
ity, and produces IgG that is capable of partially blocking the rial species of the equine cecum. Appl Environ Microbiol.
binding of IgE to the vaccine allergens. 1999;65:3738–3741.
Administration of CpG DNA has been evaluated for 16. Daly K, Stewart CS, Flint HJ, et al. Bacterial diversity within
hyposensitization because it promotes the TH1 immune the equine large intestine as revealed by molecular analysis of
responses.661-663 In horses with RAO, inhalation of CpG- cloned 16S rRNA genes. FEMS Microbiol Ecol. 2001;38:141–151.
17. Julliand V, Grimm P. Horse species symposium: the micro-
ODN nanoparticles resulted in reduced respiratory effort,
biome of the horse hindgut: history and current knowledge. J
nasal discharge, tracheal secretion, and viscosity; decreased Anim Sci. 2016;94:2262–2274.
tracheobronchial neutrophil percentage; and increased arte- 18. Orpin CG. Isolation of cellulolytic phycomycete fungi from the
rial oxygen pressure.664 Administration of CpG-ODN has caecum of the horse. J Gen Microbiol. 1981;123:287–296.
been evaluated for the potential to reduce vaccine-associated 19. Ericsson AC, Johnson PJ, Lopes MA, et al. A Microbiological
hypersensitivity reactions in horses. Administration of CpG- Map of the Healthy Equine Gastrointestinal Tract. PLoS One.
ODN along with a killed West Nile virus vaccine increased 2016;11:e0166523.
the differentiation of Tregs in response to bovine serum albu- 20. Traub-Dargatz JL, Garber LP, Fedorka-Cray PJ, et al. Fecal
min (BSA), and an inverse correlation between numbers of shedding of Salmonella spp by horses in the United States dur-
Tregs and BSA-specific IgE concentration was observed.665 ing 1998 and 1999 and detection of Salmonella spp in grain and
concentrate sources on equine operations. J Am Vet Med Assoc.
Taken together, the progress in this field indicates that new
2000;217:226–230.
and effective prophylactic strategies and therapies will likely 21. Alinovi CA, Ward MP, Couetil LL, et al. Detection of Salmo-
be developed in the future. nella organisms and assessment of a protocol for removal of
contamination in horse stalls at a veterinary teaching hospital. J
Am Vet Med Assoc. 2003;223:1640–1644.
REFERENCES 22. Ward MP, Alinovi CA, Couetil LL, et al. Evaluation of a PCR to
1. Sharp SE. Commensal and pathogenic organisms. In: Murray detect Salmonella in fecal samples of horses admitted to a vet-
PR, Barron EJ, Pfaller MA, et al., eds. Manual of Clinical Micro- erinary teaching hospital. J Vet Diagn Invest. 2005;17:118–123.
biology. 7th ed. Washington, D.C.: ASM Press; 1999:23–32. 23. Weese JS, Staempfli HR, Prescott JF. A prospective study of the
2. Scott DW. Structure and function of the skin. In: Scott DW, ed. roles of Clostridium difficile and enterotoxigenic Clostridium
Large Animal Dermatology. Philadelphia: W.B. Saunders Com- perfringens in equine diarrhoea. Equine Vet J. 2001;33:403–409.
pany; 1988:1–28. 24. Nakazawa M, Sugimoto C, Isayama Y. Quantitative culture of
3. Scott DW. Bacteria and yeast on the surface and within non- Rhodococcus equi from the feces of horse. Natl Inst Anim Health
inflamed hair follicles of skin biopsies from dogs with non-neo- Q (Tokyo). 1983;23:67–68.
plastic dermatoses. Cornell Vet. 1992;82:379–386. 25. Woolcock JB, Mutimer MD, Farmer AM. Epidemiology of
4. Nell A, James SA, Bond CJ, et al. Identification and distribu- Corynebacterium equi in horses. Res Vet Sci. 1980;28:87–90.
tion of a novel Malassezia species yeast on normal equine skin. 26. Bordin AI, Suchodolski JS, Markel ME, et al. Effects of adminis-
Vet Rec. 2002;150:395–398. tration of live or inactivated virulent Rhodococccus equi and age on
5. Bailey GD, Love DN. Oral associated bacterial infection the fecal microbiome of neonatal foals. PLoS One. 2013;8:e66640.
in horses: studies on the normal anaerobic flora from the 27. Moore BE, Dehority BA. Effects of diet and hindgut defauna-
pharyngeal tonsillar surface and its association with lower tion on diet digestibility and microbial concentrations in the
respiratory tract and paraoral infections. Vet Microbiol. cecum and colon of the horse. J Anim Sci. 1993;71:3350–3358.
1991;26:367–379. 28. Hinrichs K, Cummings MR, Sertich PL, et al. Clinical signifi-
6. Thompson H, Rybalka A, Moazzez R, et al. In vitro culture of cance of aerobic bacterial flora of the uterus, vagina, vestibule,
previously uncultured oral bacterial phylotypes. Appl Environ and clitoral fossa of clinically normal mares. J Am Vet Med Assoc.
Microbiol. 2015;81:8307–8314. 1988;193:72–75.
7. Kennedy R, Lappin DF, Dixon PM, et al. The microbiome as- 29. Madsen M, Christensen P. Bacterial flora of semen collected
sociated with equine periodontitis and oral health. Vet Res. from Danish Warmblood stallions by artificial vagina. Acta Vet
2016;47:49. Scand. 1995;36:1–7.
30. Platt H, Atherton JG, Orskov I. Klebsiella and Enterobacter or- 53. van der Flier M, Chhun N, Wizemann TM, et al. Adherence
ganisms isolated from horses. J Hyg (Lond). 1976;77:401–408. of Streptococcus pneumoniae to immobilized fibronectin. Infect
31. Newcombe JR. Comparison of the bacterial flora of three sites Immun. 1995;63:4317–4322.
in the genital tract of the mare. Vet Rec. 1978;102:169–170. 54. Wizemann TM, Moskovitz J, Pearce BJ, et al. Peptide methio-
32. Goodson J, Tyznik WJ, Cline JH, et al. Effects of an abrupt diet nine sulfoxide reductase contributes to the maintenance of
change from hay to concentrate on microbial numbers and adhesins in three major pathogens. Proc Natl Acad Sci U S A.
physical environment in the cecum of the pony. Appl Environ 1996;93:7985–7990.
Microbiol. 1988;54:1946–1950. 55. Gilot P, Andre P, Content J. Listeria monocytogenes possesses
33. Owen RA, Fullerton J, Barnum DA. Effects of transportation, adhesins for fibronectin. Infect Immun. 1999;67:6698–6701.
surgery, and antibiotic therapy in ponies infected with Salmo- 56. Sinha B, Francois P, Que YA, et al. Heterologously expressed
nella. Am J Vet Res. 1983;44:46–50. Staphylococcus aureus fibronectin-binding proteins are sufficient
34. Baverud V, Gustafsson A, Franklin A, et al. Clostridium difficile for invasion of host cells. Infect Immun. 2000;68:6871–6878.
associated with acute colitis in mature horses treated with anti- 57. Sinha B, Francois PP, Nusse O, et al. Fibronectin-binding
biotics. Equine Vet J. 1997;29:279–284. protein acts as Staphylococcus aureus invasin via fibronec-
35. Gustafsson A, Baverud V, Gunnarsson A, et al. The association tin bridging to integrin alpha5beta1. Cell Microbiol. 1999;1:
of erythromycin ethylsuccinate with acute colitis in horses in 101–117.
Sweden. Equine Vet J. 1997;29:314–318. 58. Rich RL, Kreikemeyer B, Owens RT, et al. Ace is a collagen-
36. Wilson DA, MacFadden KE, Green EM, et al. Case control and binding MSCRAMM from Enterococcus faecalis. J Biol Chem.
historical cohort study of diarrhea associated with administra- 1999;274:26939–26945.
tion of trimethoprim-potentiated sulphonamides to horses and 59. Wizemann TM, Adamou JE, Langermann S. Adhesins as targets
ponies. J Vet Intern Med. 1996;10:258–264. for vaccine development. Emerg Infect Dis. 1999;5:395–403.
37. Hogenauer C, Hammer HF, Krejs GJ, et al. Mechanisms and 60. Srivastava SK, Barnum DA. The role of lipoteichoic acids on the
management of antibiotic-associated diarrhea. Clin Infect Dis. adherence of Streptococcus equi to epithelial cells. Vet Microbiol.
1998;27:702–710. 1983;8:485–492.
38. Peeters T, Matthijs G, Depoortere I, et al. Erythromycin is a mo- 61. Colombo AV, Hirata Jr R, de Souza CM, et al. Corynebacterium
tilin receptor agonist. Am J Physiol. 1989;257:G470–G474. diphtheriae surface proteins as adhesins to human erythrocytes.
39. Lester GD, Merritt AM, Neuwirth L, et al. Effect of erythromy- FEMS Microbiol Lett. 2001;197:235–239.
cin lactobionate on myoelectric activity of ileum, cecum, and 62. Smyth CJ, Marron MB, Twohig JM, et al. Fimbrial adhesins:
right ventral colon, and cecal emptying of radiolabeled markers similarities and variations in structure and biogenesis. FEMS
in clinically normal ponies. Am J Vet Res. 1998;59:328–334. Immunol Med Microbiol. 1996;16:127–139.
40. Austin SM, Foreman JH, Hungerford LL. Case-control study of 63. Zhou D, Mooseker MS, Galan JE. An invasion-associated Sal-
risk factors for development of pleuropneumonia in horses. J monella protein modulates the actin-bundling activity of plas-
Am Vet Med Assoc. 1995;207:325–328. tin. Proc Natl Acad Sci U S A. 1999;96:10176–10181.
41. Raidal SL, Bailey GD, Love DN. Effect of transportation on low- 64. Reddy VM, Kumar B. Interaction of Mycobacterium avium
er respiratory tract contamination and peripheral blood neutro- complex with human respiratory epithelial cells. J Infect Dis.
phil function. Aust Vet J. 1997;75:433–438. 2000;181:1189–1193.
42. Raidal SL, Love DN, Bailey GD. Inflammation and increased 65. Sangari FJ, Goodman J, Bermudez LE. Mycobacterium avium
numbers of bacteria in the lower respiratory tract of horses enters intestinal epithelial cells through the apical membrane,
within 6 to 12 hours of confinement with the head elevated. but not by the basolateral surface, activates small GTPase Rho
Aust Vet J. 1995;72:45–50. and, once within epithelial cells, expresses an invasive pheno-
43. Gaynes R, Richards C, Edwards J, et al. Feeding back surveil- type. Cell Microbiol. 2000;2:561–568.
lance data to prevent hospital-acquired infections. Emerg Infect 66. Srivastava SK, Barnum DA, Prescott JF. Production and bio-
Dis. 2001;7:295–298. logical properties of M-protein of Streptococcus equi. Res Vet Sci.
44. Boerlin P, Eugster S, Gaschen F, et al. Transmission of oppor- 1985;38:184–188.
tunistic pathogens in a veterinary teaching hospital. Vet Micro- 67. Gilmour MI, Park P, Selgrade MK. Ozone-enhanced pulmo-
biol. 2001;82:347–359. nary infection with Streptococcus zooepidemicus in mice. The
45. Colahan PT, Peyton LC, Connelly MR, et al. Serratia spp infec- role of alveolar macrophage function and capsular virulence
tion in 21 horses. J Am Vet Med Assoc. 1984;185:209–211. factors. Am Rev Respir Dis. 1993;147:753–760.
46. Weese JS, Baird JD, Poppe C, et al. Emergence of Salmonella ty- 68. Anzai T, Timoney JF, Kuwamoto Y, et al. In vivo pathogenic-
phimurium definitive type 104 (DT104) as an important cause of ity and resistance to phagocytosis of Streptococcus equi strains
salmonellosis in horses in Ontario. Can Vet J. 2001;42:788–792. with different levels of capsule expression. Vet Microbiol.
47. Begg AP, Johnston KG, Hutchins DR, et al. Some aspects 1999;67:277–286.
of the epidemiology of equine salmonellosis. Aust Vet J. 69. Timoney JF, Kumar P. Early pathogenesis of equine Streptococ-
1988;65:221–223. cus equi infection (strangles). Equine Vet J. 2008;40:637–642.
48. Ikeda JS, Hirsh DC. Common plasmid encoding resistance to 70. Tzianabos AO, Kasper DL, Onderdonk AB. Structure and func-
ampicillin, chloramphenicol, gentamicin, and trimethoprim- tion of Bacteroides fragilis capsular polysaccharides: relation-
sulfadiazine in two serotypes of Salmonella isolated during an ship to induction and prevention of abscesses. Clin Infect Dis.
outbreak of equine salmonellosis. Am J Vet Res. 1985;46:769–773. 1995;20(suppl 2):S132–S140.
49. Amavisit P, Markham PF, Lightfoot D, et al. Molecular epide- 71. Brook I. Encapsulated anaerobic bacteria in clinical infections.
miology of Salmonella Heidelberg in an equine hospital. Vet Mi- Zentralbl Bakteriol. 1993;279:443–446.
crobiol. 2001;80:85–98. 72. Brook I. The role of encapsulated anaerobic bacteria in synergis-
50. Gerlach RG, Hensel M. Protein secretion systems and adhesins: tic infections. FEMS Microbiol Rev. 1994;13:65–74.
the molecular armory of Gram-negative pathogens. Int J Med 73. Patrick S, Lutton DA, Crockard AD. Immune reactions to Bacte-
Microbiol. 2007;297:401–415. roides fragilis populations with three different types of capsule in
51. Fernandez LA, Berenguer J. Secretion and assembly of regular a model of infection. Microbiology. 1995;141(Pt 8):1969–1976.
surface structures in gram-negative bacteria. FEMS Microbiol 74. Tomas JM, Ciurana B, Benedi VJ, et al. Role of lipopolysaccha-
Rev. 2000;24:21–44. ride and complement in susceptibility of Escherichia coli and
52. Wu H, Fives-Taylor PM. Molecular strategies for fimbrial ex- Salmonella typhimurium to non-immune serum. J Gen Micro-
pression and assembly. Crit Rev Oral Biol Med. 2001;12:101–115. biol. 1988;134:1009–1016.
75. Morrison DC, Brown DE, Vukajlovich SW, et al. Ganglioside 96. Kinneberg KM, Bendel CM, Jechorek RP, et al. Effect of INT1
modulation of lipopolysaccharide-initiated complement activa- gene on Candida albicans murine intestinal colonization. J Surg
tion. Mol Immunol. 1985;22:1169–1176. Res. 1999;87:245–251.
76. Hill HR, Bohnsack JF, Morris EZ, et al. Group B streptococci 97. Newman SL, Chaturvedi S, Klein BS. The WI-1 antigen of
inhibit the chemotactic activity of the fifth component of com- Blastomyces dermatitidis yeasts mediates binding to human
plement. J Immunol. 1988;141:3551–3556. macrophage CD11b/CD18 (CR3) and CD14. J Immunol.
77. Jagels MA, Travis J, Potempa J, et al. Proteolytic inactivation of 1995;154:753–761.
the leukocyte C5a receptor by proteinases derived from Porphy- 98. Fries BC, Taborda CP, Serfass E, et al. Phenotypic switching of
romonas gingivalis. Infect Immun. 1996;64:1984–1991. Cryptococcus neoformans occurs in vivo and influences the out-
78. Heffernan EJ, Reed S, Hackett J, et al. Mechanism of resistance come of infection. J Clin Invest. 2001;108:1639–1648.
to complement-mediated killing of bacteria encoded by the Sal- 99. Rotrosen D, Edwards Jr JE, Gibson TR, et al. Adherence of
monella typhimurium virulence plasmid gene rck. J Clin Invest. Candida to cultured vascular endothelial cells: mechanisms
1992;90:953–964. of attachment and endothelial cell penetration. J Infect Dis.
79. Boschwitz JS, Timoney JF. Inhibition of C3 deposition on Strep- 1985;152:1264–1274.
tococcus equi subsp. equi by M protein: a mechanism for sur- 100. Eissenberg LG, Goldman WE. Histoplasma capsulatum fails to
vival in equine blood. Infect Immun. 1994;62:3515–3520. trigger release of superoxide from macrophages. Infect Immun.
80. Chanter N, Ward CL, Talbot NC, et al. Recombinant hyalu- 1987;55:29–34.
ronate associated protein as a protective immunogen against 101. Eissenberg LG, Schlesinger PH, Goldman WE. Phagosome-
Streptococcus equi and Streptococcus zooepidemicus challenge lysosome fusion in P388D1 macrophages infected with Histo-
in mice. Microb Pathog. 1999;27:133–143. plasma capsulatum. J Leukoc Biol. 1988;43:483–491.
81. Hoe NP, Kordari P, Cole R, et al. Human immune response to 102. Eissenberg LG, Poirier S, Goldman WE. Phenotypic variation
streptococcal inhibitor of complement, a serotype M1 group A and persistence of Histoplasma capsulatum yeasts in host cells.
Streptococcus extracellular protein involved in epidemics. J In- Infect Immun. 1996;64:5310–5314.
fect Dis. 2000;182:1425–1436. 103. Woods JP, Heinecke EL, Luecke JW, et al. Pathogenesis of His-
82. Johnsson E, Berggard K, Kotarsky H, et al. Role of the hyper- toplasma capsulatum. Semin Respir Infect. 2001;16:91–101.
variable region in streptococcal M proteins: binding of a human 104. Hube B. Candida albicans secreted aspartyl proteinases. Curr
complement inhibitor. J Immunol. 1998;161:4894–4901. Top Med Mycol. 1996;7:55–69.
83. Mitchell TJ. Virulence factors and the pathogenesis of dis- 105. Resnick S, Pappagianis D, McKerrow JH. Proteinase production
ease caused by Streptococcus pneumoniae. Res Microbiol. by the parasitic cycle of the pathogenic fungus Coccidioides im-
2000;151:413–419. mitis. Infect Immun. 1987;55:2807–2815.
84. Boschwitz JS, Timoney JF. Characterization of the antiphago- 106. Yu JJ, Smithson SL, Thomas PW, et al. Isolation and charac-
cytic activity of equine fibrinogen for Streptococcus equi subsp. terization of the urease gene (URE) from the pathogenic fungus
equi. Microb Pathog. 1994;17:121–129. Coccidioides immitis. Gene. 1997;198:387–391.
85. Timoney JF, Artiushin SC, Boschwitz JS. Comparison of the 107. Yuan L, Cole GT. Isolation and characterization of an ex-
sequences and functions of Streptococcus equi M-like proteins tracellular proteinase of Coccidioides immitis. Infect Immun.
SeM and SzPSe. Infect Immun. 1997;65:3600–3605. 1987;55:1970–1978.
86. Gao LY, Kwaik YA. The modulation of host cell apopto- 108. Iadarola P, Lungarella G, Martorana PA, et al. Lung injury and
sis by intracellular bacterial pathogens. Trends Microbiol. degradation of extracellular matrix components by Aspergillus
2000;8:306–313. fumigatus serine proteinase. Exp Lung Res. 1998;24:233–251.
87. Feltis BA, Wiesner SM, Kim AS, et al. Clostridium difficile toxins 109. Rodriguez E, Boudard F, Mallie M, et al. Murine macrophage
A and B can alter epithelial permeability and promote bacte- elastolytic activity induced by Aspergillus fumigatus strains
rial paracellular migration through HT-29 enterocytes. Shock. in vitro: evidence of the expression of two macrophage-induced
2000;14:629–634. protease genes. Can J Microbiol. 1997;43:649–657.
88. Grassme H, Jendrossek V, Gulbins E. Molecular mechanisms of 110. Ghannoum MA. Potential role of phospholipases in virulence
bacteria induced apoptosis. Apoptosis. 2001;6:441–445. and fungal pathogenesis. Clin Microbiol Rev. 2000;13:122–143.
89. Schroeder GN, Jann NJ, Hilbi H. Intracellular type III secretion table of contents.
by cytoplasmic Shigella flexneri promotes caspase-1-dependent 111. Mitrovic S, Kranjcic-Zec I, Arsic V, et al. In vitro proteinase and
macrophage cell death. Microbiology. 2007;153:2862–2876. phospholipase activity and pathogenicity of Candida species.
90. Haslinger B, Strangfeld K, Peters G, et al. Staphylococcus aureus J Chemother. 1995;7(suppl 4):43–45.
alpha-toxin induces apoptosis in peripheral blood mononuclear 112. Prakobphol A, Leffler H, Hoover CI, et al. Palmitoyl carnitine,
cells: role of endogenous tumour necrosis factor-alpha and the a lysophospholipase-transacylase inhibitor, prevents Candida
mitochondrial death pathway. Cell Microbiol. 2003;5:729–741. adherence in vitro. FEMS Microbiol Lett. 1997;151:89–94.
91. Dinges MM, Orwin PM, Schlievert PM. Exotoxins of Staphy- 113. Noverr MC, Toews GB, Huffnagle GB. Production of prosta-
lococcus aureus. Clin Microbiol Rev. 2000;13:16–34. table of glandins and leukotrienes by pathogenic fungi. Infect Immun.
contents. 2002;70:400–402.
92. Bulawa CE, Miller DW, Henry LK, et al. Attenuated virulence 114. Mendes-Giannini MJ, Taylor ML, Bouchara JB, et al. Patho-
of chitin-deficient mutants of Candida albicans. Proc Natl Acad genesis II: fungal responses to host responses: interac-
Sci U S A. 1995;92:10570–10574. tion of host cells with fungi. Med Mycol. 2000;38(suppl 1):
93. Buurman ET, Westwater C, Hube B, et al. Molecular analysis 113–123.
of CaMnt1p, a mannosyl transferase important for adhesion 115. Golden MC, Hahm SJ, Elessar RE, et al. DNA damage by glio-
and virulence of Candida albicans. Proc Natl Acad Sci U S A. toxin from Aspergillus fumigatus. An occupational and environ-
1998;95:7670–7675. mental propagule: adduct detection as measured by 32P DNA
94. Fu Y, Rieg G, Fonzi WA, et al. Expression of the Candida radiolabelling and two-dimensional thin-layer chromatogra-
albicans gene ALS1 in Saccharomyces cerevisiae induces ad- phy. Mycoses. 1998;41:97–104.
herence to endothelial and epithelial cells. Infect Immun. 116. Bock M, Stoye JP. Endogenous retroviruses and the human ger-
1998;66:1783–1786. mline. Curr Opin Genet Dev. 2000;10:651–655.
95. Gale CA, Bendel CM, McClellan M, et al. Linkage of adhesion, 117. Flint SJ, Enquist LW, Krug RM, et al. Principles of Virology: Mo-
filamentous growth, and virulence in Candida albicans to a sin- lecular Biology, Pathogenesis, and Control. Washington, D.C.:
gle gene, INT1. Science. 1998;279:1355–1358. ASM Press; 1999.
118. Murphy FA, Gibbs EPJ, Horzinek MC, et al. Veterinary Virol- 142. Whitwell KE, Blunden AS. Pathological findings in horses dy-
ogy. 3rd ed. San Diego: Academic Press; 1999. ing during an outbreak of the paralytic form of equid herpesvi-
119. Preston BD, Dougherty JP. Mechanisms of retroviral mutation. rus type 1 (EHV-1) infection. Equine Vet J. 1992;24:13–19.
Trends Microbiol. 1996;4:16–21. 143. Green SL. Rabies. Vet Clin North Am Equine Pract. 1997;13:1–11.
120. Domingo E, Baranowski E, Ruiz-Jarabo CM, et al. Quasispe- 144. Baxi MK, Efstathiou S, Lawrence G, et al. The detection of laten-
cies structure and persistence of RNA viruses. Emerg Infect Dis. cy-associated transcripts of equine herpesvirus 1 in ganglionic
1998;4:521–527. neurons. J Gen Virol. 1995;76(Pt 12):3113–3118.
121. Scholtissek C. Molecular epidemiology of influenza. Arch Virol 145. Winer JB. Guillain Barré syndrome. Mol Pathol. 2001;54:381–385.
Suppl. 1997;13:99–103. 146. Nolte KB, Alakija P, Oty G, et al. Influenza A virus infection
122. Puvion-Dutilleul F, Besse S, Pichard E, et al. Release of viruses complicated by fatal myocarditis. Am J Forensic Med Pathol.
and viral DNA from nucleus to cytoplasm of HeLa cells at late 2000;21:375–379.
stages of productive adenovirus infection as revealed by elec- 147. Evermann JF, Heeney JL, Roelke ME, et al. Biological and path-
tron microscope in situ hybridization. Biol Cell. 1998;90:5–38. ological consequences of feline infectious peritonitis virus in-
123. Thomson BJ. Viruses and apoptosis. Int J Exp Pathol. fection in the cheetah. Arch Virol. 1988;102:155–171.
2001;82:65–76. 148. Jacobs DE. A Colour Atlas of Equine Parasites. Philadelphia: Lea
124. Carr EA, Theon AP, Madewell BR, et al. Expression of a trans- & Febiger; 1986.
forming gene (E5) of bovine papillomavirus in sarcoids ob- 149. Slocombe JO. Pathogenesis of helminths in equines. Vet Parasi-
tained from horses. Am J Vet Res. 2001;62:1212–1217. tol. 1985;18:139–153.
125. Burmeister T. Oncogenic retroviruses in animals and humans. 150. Fox MT. Pathophysiology of infection with gastrointestinal
Rev Med Virol. 2001;11:369–380. nematodes in domestic ruminants: recent developments. Vet
126. Garcia-Blanco MA, Cullen BR. Molecular basis of latency in Parasitol. 1997;72:285–297. discussion 297–308.
pathogenic human viruses. Science. 1991;254:815–820. 151. Symons LEA. Pathophysiology of endoparasitic infection com-
127. Borchers K, Wolfinger U, Lawrenz B, et al. Equine herpesvirus 4 pared with ectoparasitic infestation and microbial infection. Lon-
DNA in trigeminal ganglia of naturally infected horses detected don: Academic Press, Inc.; 1989.
by direct in situ PCR. J Gen Virol. 1997;78(Pt 5):1109–1114. 152. Herd RP. Epidemiology and control of parasites in northern tem-
128. Edington N, Bridges CG, Huckle A. Experimental reactivation perate regions. Vet Clin North Am Equine Pract. 1986;2:337–355.
of equid herpesvirus 1 (EHV 1) following the administration of 153. Nielsen MK, Jacobsen S, Olsen SN, et al. Nonstrangulating in-
corticosteroids. Equine Vet J. 1985;17:369–372. testinal infarction associated with Strongylus vulgaris in referred
129. Welch HM, Bridges CG, Lyon AM, et al. Latent equid herpes- Danish equine cases. Equine Vet J. 2016;48:376–379.
viruses 1 and 4: detection and distinction using the polymerase 154. McCraw BM, Slocombe JO. Strongylus vulgaris in the horse: a
chain reaction and co-cultivation from lymphoid tissues. J Gen review. Can Vet J. 1976;17:150–157.
Virol. 1992;73(Pt 2):261–268. 155. Klei TR. Recent observations on the epidemiology, pathogen-
130. Padgett DA, Sheridan JF, Dorne J, et al. Social stress and the re- esis and immunology of equine helminth infections. In: Pro-
activation of latent herpes simplex virus type 1. Proc Natl Acad ceedings of the 6th International Conference on Equine Infectious
Sci U S A. 1998;95:7231–7235. Diseases. Newmarket: R&W Publications; 1991:129–136.
131. Crawford TB, Wardrop KJ, Tornquist SJ, et al. A primary pro- 156. Klei TR, Turk MA, McClure JR, et al. Effects of repeated Stron-
duction deficit in the thrombocytopenia of equine infectious gylus vulgaris inoculations and concurrent ivermectin treat-
anemia. J Virol. 1996;70:7842–7850. ments on mesenteric arterial lesions in pony foals. Am J Vet Res.
132. Oaks JL, McGuire TC, Ulibarri C, et al. Equine infectious ane- 1990;51:654–660.
mia virus is found in tissue macrophages during subclinical in- 157. Monahan CM, Taylor HW, Chapman MR, et al. Experimental
fection. J Virol. 1998;72:7263–7269. immunization of ponies with Strongylus vulgaris radiation-at-
133. Belshan M, Baccam P, Oaks JL, et al. Genetic and biological tenuated larvae or crude soluble somatic extracts from larval or
variation in equine infectious anemia virus Rev correlates with adult stages. J Parasitol. 1994;80:911–923.
variable stages of clinical disease in an experimentally infected 158. Clayton HM. Ascarids. Recent advances. Vet Clin North Am
pony. Virology. 2001;279:185–200. Equine Pract. 1986;2:313–328.
134. Maury W, Perryman S, Oaks JL, et al. Localized sequence het- 159. Lyons ET, Tolliver SC, Ionita M, et al. Evaluation of parasiticidal
erogeneity in the long terminal repeats of in vivo isolates of activity of fenbendazole, ivermectin, oxibendazole, and pyrantel
equine infectious anemia virus. J Virol. 1997;71:4929–4937. pamoate in horse foals with emphasis on ascarids (Parascaris
135. Jacob RJ, Price R, Bouchey D, et al. Temperature sensitivity of equorum) in field studies on five farms in Central Kentucky in
equine herpesvirus isolates: a brief review. SAAS Bull Biochem 2007. Parasitol Res. 2008;103:287–291.
Biotechnol. 1990;3:124–128. 160. Barclay WP, Phillips TN, Foerner JJ. Intussusception associated
136. Cravens RL, Ellsworth MA, Sorensen CD, et al. Efficacy of a with Anoplocephala perfoliata infection in five horses. J Am Vet
temperature-sensitive modified-live bovine herpesvirus type-1 Med Assoc. 1982;180:752–753.
vaccine against abortion and stillbirth in pregnant heifers. J Am 161. Beroza GA, Barclay WP, Phillips TN, et al. Cecal perforation
Vet Med Assoc. 1996;208:2031–2034. and peritonitis associated with Anoplocephala perfoliata infec-
137. Youngner JS, Whitaker-Dowling P, Chambers TM, et al. Deri- tion in three horses. J Am Vet Med Assoc. 1983;183:804–806.
vation and characterization of a live attenuated equine influenza 162. Nielsen MK. Equine tapeworm infections: disease, diagnosis,
vaccine virus. Am J Vet Res. 2001;62:1290–1294. and control. Equine Vet Educ. 2016;28:388–395.
138. Fenner F. Mouse-pox; infectious ectromelia of mice; a review. J 163. Kjaer LN, Lungholt MM, Nielsen MK, et al. Interpretation of
Immunol. 1949;63:341–373. serum antibody response to Anoplocephala perfoliata in re-
139. Calisher CH. Medically important arboviruses of the United lation to parasite burden and faecal egg count. Equine Vet J.
States and Canada. Clin Microbiol Rev. 1994;7:89–116. 2007;39:529–533.
140. Walker C, Love DN, Whalley JM. Comparison of the pathogen- 164. Williamson RM, Gasser RB, Middleton D, et al. The distribu-
esis of acute equine herpesvirus 1 (EHV-1) infection in the horse tion of Anoplocephala perfoliata in the intestine of the horse and
and the mouse model: a review. Vet Microbiol. 1999;68:3–13. associated pathological changes. Vet Parasitol. 1997;73:225–241.
141. Edington N, Smyth B, Griffiths L. The role of endothe- 165. Uhlinger C. Effects of three anthelmintic schedules on the inci-
lial cell infection in the endometrium, placenta and foetus dence of colic in horses. Equine Vet J. 1990;22:251–254.
of equid herpesvirus 1 (EHV-1) abortions. J Comp Pathol. 166. Uhlinger C. Equine small strongyles: epidemiology, pathology
1991;104:379–387. and control. Compend Contin Educ Pract Vet. 1991;13:863–869.
167. Reid SW, Mair TS, Hillyer MH, et al. Epidemiological risk fac- 190. Finkelman FD, Pearce EJ, Urban Jr JF, et al. Regulation and bio-
tors associated with a diagnosis of clinical cyathostomiasis in logical function of helminth-induced cytokine responses. Im-
the horse. Equine Vet J. 1995;27:127–130. munol Today. 1991;12:A62–A66.
168. Love S, Murphy D, Mellor D. Pathogenicity of cyathostome 191. Maizels RM, Blaxter ML, Scott AL. Immunological genomics of
infection. Vet Parasitol. 1999;85:113–121. discussion 121-112, Brugia malayi: filarial genes implicated in immune evasion and
215-125. protective immunity. Parasite Immunol. 2001;23:327–344.
169. Murphy D, Love S. The pathogenic effects of experimental cy- 192. Maizels RM, Bundy DA, Selkirk ME, et al. Immunological
athostome infections in ponies. Vet Parasitol. 1997;70:99–110. modulation and evasion by helminth parasites in human popu-
170. Castro GA. Immunophysiology of enteric parasitism. Parasitol lations. Nature. 1993;365:797–805.
Today. 1989;5:11–19. 193. Elliott DE, Summers RW, Weinstock JV. Helminths and the
171. Bueno L, Ruckebusch Y, Dorchies P. Disturbances of digestive modulation of mucosal inflammation. Curr Opin Gastroenterol.
motility in horses associated with strongyle infection. Vet Para- 2005;21:51–58.
sitol. 1979;5:253. 194. Summers RW, Elliott DE, Weinstock JV. Is there a role for hel-
172. Lester GD, Bolton JR, Cambridge H, et al. The effect of Stron- minths in the therapy of inflammatory bowel disease? Nat Clin
gylus vulgaris larvae on equine intestinal myoelectrical activity. Pract Gastroenterol Hepatol. 2005;2:62–63.
Equine Vet J Suppl. 1989:8–13. 195. Hoerauf A, Satoguina J, Saeftel M, et al. Immunomodulation by
173. Berry CR, Merritt AM, Burrows CF, et al. Evaluation of the my- filarial nematodes. Parasite Immunol. 2005;27:417–429.
oelectrical activity of the equine ileum infected with Strongylus 196. Jackson JA, Friberg IM, Little S, et al. Review series on hel-
vulgaris larvae. Am J Vet Res. 1986;47:27–30. minths, immune modulation and the hygiene hypothesis:
174. Artis D. New weapons in the war on worms: identification of i
mmunity against helminths and immunological phenom-
putative mechanisms of immune-mediated expulsion of gastro- ena in modern human populations: coevolutionary legacies?
intestinal nematodes. Int J Parasitol. 2006;36:723–733. Immunology. 2009;126:18–27.
175. Finkelman FD, Shea-Donohue T, Goldhill J, et al. Cytokine 197. van Riet E, Hartgers FC, Yazdanbakhsh M. Chronic helminth
regulation of host defense against parasitic gastrointestinal infections induce immunomodulation: consequences and
nematodes: lessons from studies with rodent models. Annu Rev mechanisms. Immunobiology. 2007;212:475–490.
Immunol. 1997;15:505–533. 198. Edmonds JD, Horohov DW, Chapmat MR, et al. Altered
176. Maizels RM, Yazdanbakhsh M. Immune regulation by helminth immune responses to a heterologous protein in ponies
parasites: cellular and molecular mechanisms. Nat Rev Immunol. with heavy gastrointestinal parasite burdens. Equine Vet J.
2003;3:733–744. 2001;33:658–663.
177. Patel N, Kreider T, Urban Jr JF, et al. Characterisation of ef- 199. Nielsen MK, Rubinson EF, Chambers TM, et al. Interaction be-
fector mechanisms at the host:parasite interface during the im- tween anthelmintic treatment and vaccine responses in ponies
mune response to tissue-dwelling intestinal nematode parasites. naturally infected with cyathostomins. Vet Immunol Immuno-
Int J Parasitol. 2009;39:13–21. pathol. 2015;164:110–117.
178. Nielsen MK. Evidence-based considerations for control of Paras- 200. Sellon D, Long M. Equine Infectious Diseases. 2nd ed. Philadel-
caris spp. infections in horses. Equine Vet Educ. 2016;28:224–231. phia, PA: Saunders Elsevier; 2014.
179. Soulsby EJL. Immune Responses in Parasitic Infections: Immu- 201. Mealey RH. New perspectives in infectious diseases. Vet Clin
nology, Immunopathology and Immunoprophylaxis, Nematodes. North Am Equine Pract. 2014;30. xv-xvi.
Boca Raton: CRC Press; 1987. 202. Chandriani S, Skewes-Cox P, Zhong W, et al. Identification of
180. Allen JE, Adjei O, Bain O, et al. Of mice, cattle, and humans: the a previously undescribed divergent virus from the Flaviviridae
immunology and treatment of river blindness. PLoS Negl Trop family in an outbreak of equine serum hepatitis. Proc Natl Acad
Dis. 2008;2:e217. Sci U S A. 2013;110:E1407–E1415.
181. King CL, Nutman TB. Regulation of the immune response 203. Li L, Giannitti F, Low J, et al. Exploring the virome of diseased
in lymphatic filariasis and onchocerciasis. Immunol Today. horses. J Gen Virol. 2015;96:2721–2733.
1991;12:A54–A58. 204. Ceciliani F, Eckersall D, Burchmore R, et al. Proteomics in vet-
182. Foil LD, Klei TR, Miller RI, et al. Seasonal changes in density erinary medicine: applications and trends in disease pathogen-
and tissue distribution of Onchocerca cervicalis microfilariae esis and diagnostics. Vet Pathol. 2014;51:351–362.
in ponies and related changes in Culicoides variipennis popula- 205. Engleberg N, DiRita V, Dermody T. Schaechter’s Mechanisms of
tions in Louisiana. J Parasitol. 1987;73:320–326. Microbial Disease. 5th ed. Baltimore, MD: Lippincott Williams
183. Ogbourne CP. Studies on the epidemiology of Strongylus vul- & Wilkins; 2013.
garis infection of the horse. Int J Parasitol. 1975;5:423–426. 206. Horohov DW. The equine immune responses to infectious
184. Murrell KD. Induction of protective immunity to Strongyloides and allergic disease: a model for humans? Mol Immunol.
ransomi in pigs. Am J Vet Res. 1981;42:1915–1919. 2015;66:89–96.
185. Klei TR, Chapman MR. Immunity in equine cyathostome infec- 207. Abbas A, Lichtman A, Pillai S. Cellular and Molecular Immunol-
tions. Vet Parasitol. 1999;85:123–133. discussion 133-126, 215-125. ogy. 8th ed. Philadelphia, PA: Elsevier Saunders; 2015.
186. Monahan CM, Chapman MR, Taylor HW, et al. Experimental 208. Filippe M. Equine Clinical Immunology. Oxford, UK: John
cyathostome challenge of ponies maintained with or without Wiley & Sons, Inc.; 2016.
benefit of daily pyrantel tartrate feed additive: comparison of 209. Murphy K. Janeway’s Immunobiology. 8th ed. New York, NY:
parasite burdens, immunity and colonic pathology. Vet Parasi- Garland Science; 2012.
tol. 1998;74:229–241. 210. Tizard I. Veterinary Immunology. 9th ed. Philadelphia, PA: Else-
187. Chapman MR, French DD, Taylor HW, et al. One season of pas- vier Saunders; 2013.
ture exposure fails to induce a protective resistance to cyathos- 211. Coombs SL, Webbon PM. Tracheal mucus transport in
tomes but increases numbers of hypobiotic third-stage larvae. J the horse following equine influenza vaccination. Vet Rec.
Parasitol. 2002;88:678–683. 1986;119:601–602.
188. Klei TR, Chapman MR, Dennis VA. Role of the eosinophil in 212. Dixon PM. Respiratory mucociliary clearance in the horse in
serum-mediated adherence of equine leukocytes to infective health and disease, and its pharmaceutical modification. Vet
larvae of Strongylus vulgaris. J Parasitol. 1992;78:477–484. Rec. 1992;131:229–235.
189. Dennis VA, Klei TR, Chapman MR, et al. In vivo activation of 213. Oikawa M, Takagi S, Anzai R, et al. Pathology of equine res-
equine eosinophils and neutrophils by experimental Strongylus piratory disease occurring in association with transport. J Comp
vulgaris infections. Vet Immunol Immunopathol. 1988;20:61–74. Pathol. 1995;113:29–43.
214. Nordengrahn A, Rusvai M, Merza M, et al. Equine herpesvirus 235. Kvaternick V, Pollmeier M, Fischer J, et al. Pharmacokinetics
type 2 (EHV-2) as a predisposing factor for Rhodococcus equi pneu- and metabolism of orally administered firocoxib, a novel sec-
monia in foals: prevention of the bifactorial disease with EHV-2 ond generation coxib, in horses. J Vet Pharmacol Ther. 2007;30:
immunostimulating complexes. Vet Microbiol. 1996;51:55–68. 208–217.
215. Furr M, Cohen ND, Axon JE, et al. Treatment with histamine- 236. Letendre LT, Tessman RK, McClure SR, et al. Pharmacokinetics
type 2 receptor antagonists and omeprazole increase the risk of firocoxib after administration of multiple consecutive daily
of diarrhoea in neonatal foals treated in intensive care units. doses to horses. Am J Vet Res. 2008;69:1399–1405.
Equine Vet J Suppl. 2012:80–86. 237. Tilley SL, Coffman TM, Koller BH. Mixed messages: modula-
216. Buendgens L, Bruensing J, Matthes M, et al. Administration of tion of inflammation and immune responses by prostaglandins
proton pump inhibitors in critically ill medical patients is as- and thromboxanes. J Clin Invest. 2001;108:15–23.
sociated with increased risk of developing Clostridium difficile- 238. Hardy J, Bertone AL, Weisbrode SE, et al. Cell trafficking, me-
associated diarrhea. J Crit Care. 2014;29. 696.e611-695. diator release, and articular metabolism in acute inflammation
217. MacKay RJ. Inflammation in horses. Vet Clin North Am Equine of innervated or denervated isolated equine joints. Am J Vet Res.
Pract. 2000;16:15–27. v. 1998;59:88–100.
218. Netea MG, van der Graaf C, Van der Meer JWM, et al. Toll- 239. Gangur V, Birmingham NP, Thanesvorakul S. Chemokines in
like receptors and the host defense against microbial pathogens: health and disease. Vet Immunol Immunopathol. 2002;86:127–
bringing specificity to the innate-immune system. J Leukoc Biol. 136.
2004;75:749–755. 240. Cook VL, Neuder LE, Blikslager AT, et al. The effect of lido-
219. Petersen HH, Nielsen JP, Heegaard PM. Application of acute caine on in vitro adhesion and migration of equine neutrophils.
phase protein measurements in veterinary clinical chemistry. Vet Immunol Immunopathol. 2009;129:137–142.
Vet Res. 2004;35:163–187. 241. Brooks AC, Rickards KJ, Cunningham FM. CXCL8 attenuates
220. Grondahl G, Sternberg S, Jensen-Waern M, et al. Opsonic ca- chemoattractant-induced equine neutrophil migration. Vet Im-
pacity of foal serum for the two neonatal pathogens Escherichia munol Immunopathol. 2011;139:141–147.
coli and Actinobacillus equuli. Equine Vet J. 2001;33:670–675. 242. Marr KA, Lees P, Cunningham FM. Agonist-induced adherence
221. Camp CJ, Leid RW. Chemotaxis of radiolabeled equine neutro- of equine neutrophils to fibronectin- and serum-coated plastic
phils. Am J Vet Res. 1982;43:397–401. is CD18 dependent. Vet Immunol Immunopathol. 1999;71:77–
222. Higgins AJ, Lees P. The acute inflammatory process, arachidon- 88.
ic acid metabolism and the mode of action of anti-inflammato- 243. Xu J, Cai J, Anderson B, et al. Cloning and functional charac-
ry drugs. Equine Vet J. 1984;16:163–175. terization of recombinant equine P-selectin. Vet Immunol Im-
223. Gibson KT, Hodge H, Whittem T. Inflammatory mediators in munopathol. 2007;116:115–130.
equine synovial fluid. Aust Vet J. 1996;73:148–151. 244. Jones SL, Sharief Y, Chilcoat CD. Signaling mechanism for
224. Verburg KM, Maziasz TJ, Weiner E, et al. COX-2-specific in- equine neutrophil activation by immune complexes. Vet Immu-
hibitors: definition of a new therapeutic concept. Am J Ther. nol Immunopathol. 2001;82:87–100.
2001;8:49–64. 245. Re F, Muzio M, De Rossi M, et al. The type II “receptor” as a
225. Morton AJ, Campbell NB, Gayle JM, et al. Preferential and decoy target for interleukin 1 in polymorphonuclear leukocytes:
non-selective cyclooxygenase inhibitors reduce inflamma- characterization of induction by dexamethasone and ligand
tion during lipopolysaccharide-induced synovitis. Res Vet Sci. binding properties of the released decoy receptor. J Exp Med.
2005;78:189–192. 1994;179:739–743.
226. Lees P, Landoni MF, Giraudel J, et al. Pharmacodynamics and 246. Healy DP. New and emerging therapies for sepsis. Ann Pharma-
pharmacokinetics of nonsteroidal anti-inflammatory drugs in spe- cother. 2002;36:648–654.
cies of veterinary interest. J Vet Pharmacol Ther. 2004;27:479–490. 247. Lewis MJ, Wagner B, Woof JM. The different effector function
227. Beretta C, Garavaglia G, Cavalli M. COX-1 and COX-2 inhibi- capabilities of the seven equine IgG subclasses have implica-
tion in horse blood by phenylbutazone, flunixin, carprofen and tions for vaccine strategies. Mol Immunol. 2008;45:818–827.
meloxicam: an in vitro analysis. Pharmacol Res. 2005;52:302–306. 248. Wagner B, Miller DC, Lear TL, et al. The complete map of the Ig
228. Raidal SL, Edwards S, Pippia J, et al. Pharmacokinetics and safe- heavy chain constant gene region reveals evidence for seven IgG
ty of oral administration of meloxicam to foals. J Vet Intern Med. isotypes and for IgD in the horse. J Immunol. 2004;173:3230–3242.
2013;27:300–307. 249. Perkins GA, Wagner B. The development of equine immunity:
229. Walliser U, Fenner A, Mohren N, et al. Evaluation of the effi- current knowledge on immunology in the young horse. Equine
cacy of meloxicam for post-operative management of pain and Vet J. 2015;47:267–274.
inflammation in horses after orthopaedic surgery in a placebo 250. Wagner B. Immunoglobulins and immunoglobulin genes of the
controlled clinical field trial. BMC Vet Res. 2015;11:113. horse. Dev Comp Immunol. 2006;30:155–164.
230. Barton MH, Darden JE, Clifton S, et al. Effect of firocoxib on 251. Lunn DP, Holmes MA, Antczak DF, et al. Report of the Second
cyclooxygenase 2, microsomal prostaglandin E2 synthase 1, and Equine Leucocyte Antigen Workshop, Squaw valley, California,
cytosolic phospholipase A2 gene expression in equine mononu- July 1995. Vet Immunol Immunopathol. 1998;62:101–143.
clear cells. Am J Vet Res. 2015;76:1051–1057. 252. McGuire TC, Van Hoosier Jr GL, Henson JB. The complement-
231. Barton MH, Paske E, Norton N, et al. Efficacy of cyclo-oxyge- fixation reaction in eguine infectious anemia: demonstration of
nase inhibition by two commercially available firocoxib prod- inhibition by IgG (T). J Immunol. 1971;107:1738–1744.
ucts in horses. Equine Vet J. 2014;46:72–75. 253. Sun Y, Wang C, Wang Y, et al. A comprehensive analysis of ger-
232. Cook VL, Meyer CT, Campbell NB, et al. Effect of firocoxib or mline and expressed immunoglobulin repertoire in the horse.
flunixin meglumine on recovery of ischemic-injured equine je- Dev Comp Immunol. 2010;34:1009–1020.
junum. Am J Vet Res. 2009;70:992–1000. 254. Ford J, Home W, Gibson D. Light chain isotype regulation
233. Doucet MY, Bertone AL, Hendrickson D, et al. Comparison of in the horse. Characterization of Ig kappa genes. J Immunol.
efficacy and safety of paste formulations of firocoxib and phe- 1994;153:1099–1111.
nylbutazone in horses with naturally occurring osteoarthritis. J 255. Home W, Ford J, Gibson D. L chain isotype regulation in
Am Vet Med Assoc. 2008;232:91–97. horse. I. Characterization of Ig lambda genes. J Immunnol.
234. Hovanessian N, Davis JL, McKenzie 3rd HC, et al. Pharma- 1992;149:3927–3936.
cokinetics and safety of firocoxib after oral administration of 256. Tschetter JR, Davis WC, Perryman LE, et al. CD8 dimer usage
repeated consecutive doses to neonatal foals. J Vet Pharmacol on alpha beta and gama delta T lymphocytes from equine lym-
Ther. 2014;37:243–251. phoid tissues. Immunobiology. 1998;198:424–438.
257. Alcover A, Alarcon B. Internalization and intracellular fate of 279. Frayne J, Stokes CR. MHC Class II positive cells and T cells in
TCR-CD3 complexes. Crit Rev Immunol. 2000;20:325–346. the equine endometrium throughout the oestrous cycle. Vet
258. Kisielow P, Miazek A. Thymic selection and tolerance. Trans- Immunol Immunopathol. 1994;41:55–72.
plant Proc. 1996;28:3429–3430. 280. Albright-Fraser DG, Reid R, Gerber V, et al. Polymorphism of
259. Bailey E. Identification and genetics of horse lymphocyte al- DRA among equids. Immunogenetics. 1996;43:315–317.
loantigens. Immunogenetics. 1980;11:499–506. 281. Arbanasic H, Galov A, Ambriovic-Ristov A, et al. Extensive pol-
260. Antczak DF, Allen WR. Maternal immunological recognition ymorphism of the major histocompatibility complex DRA gene
of pregnancy in equids. J Reprod Fertil Suppl. 1989;37:69–78. in Balkan donkeys: perspectives on selection and genealogy.
261. Huang T, Lehmann MJ, Said A, et al. Major histocompatibility Anim Genet. 2013;44:711–716.
complex class I downregulation induced by equine herpesvirus 282. Kamath PL, Getz WM. Adaptive molecular evolution of the
type 1 pUL56 is through dynamin-dependent endocytosis. J Vi- Major Histocompatibility Complex genes, DRA and DQA, in
rol. 2014;88:12802–12815. the genus Equus. BMC Evol Biol. 2011;11:128.
262. Ramsay JD, Leib SR, Orfe L, et al. Development of a DNA 283. Fraser DG, Bailey E. Polymorphism and multiple loci for the
microarray for detection of expressed equine classical MHC horse DQA gene. Immunogenetics. 1998;47:487–490.
class I sequences in a defined population. Immunogenetics. 284. Fraser DG, Bailey E. Demonstration of three DRB loci in a do-
2010;62:633–639. mestic horse family. Immunogenetics. 1996;44:441–445.
263. Tallmadge RL, Campbell JA, Miller DC, et al. Analysis of MHC 285. Horin P, Matiasovic J. A second locus and new alleles in the
class I genes across horse MHC haplotypes. Immunogenetics. major histocompatibility complex class II (ELA-DQB) region in
2010;62:159–172. the horse. Anim Genet. 2002;33:196–200.
264. Tallmadge RL, Lear TL, Antczak DF. Genomic characteri- 286. Andersson LS, Swinburne JE, Meadows JR, et al. The same
zation of MHC class I genes of the horse. Immunogenetics. ELA class II risk factors confer equine insect bite hyper-
2005;57:763–774. sensitivity in two distinct populations. Immunogenetics.
265. Chung C, Leib SR, Fraser DG, et al. Novel classical MHC class I 2012;64:201–208.
alleles identified in horses by sequencing clones of reverse tran- 287. Raphael I, Nalawade S, Eagar TN, et al. T cell subsets and their
scription-PCR products. Eur J Immunogenet. 2003;30:387–396. signature cytokines in autoimmune and inflammatory diseases.
266. Tseng CT, Miller D, Cassano J, et al. Identification of equine Cytokine. 2015;74:5–17.
major histocompatibility complex haplotypes using polymor- 288. Meulenbroeks C, van der Lugt JJ, van der Meide NM, et al. Al-
phic microsatellites. Anim Genet. 2010;41(suppl 2):150–153. lergen-Specific Cytokine Polarization Protects Shetland Ponies
267. Brinkmeyer-Langford CL, Cai JJ, Gill CA, et al. Microsatellite against Culicoides obsoletus-Induced Insect Bite Hypersensi-
variation in the equine MHC. Anim Genet. 2013;44:267–275. tivity. PloS one. 2015;10:e0122090.
268. Zinkernagel RM, Doherty PC. Immunological surveilance 289. Horohov DW. Equine T-cell cytokines. Protection and pathol-
against altered self-components by sensitized T lymphocytes in ogy. Vet Clin North Am Equine Pract. 2000;16:1–14.
lymphocytic choriomeningitis. Nature. 1974;251:547–548. 290. Aggarwal N, Holmes MA. Characterisation of equine T helper
269. Bjorkman PJ, Saper MA, Samraoui B, et al. The foreign antigen cells: demonstration of Th1- and Th2-like cells in long-term
binding site and T cell recognition regions of class I histocom- equine T-cell cultures. Res Vet Sci. 1999;66:277–279.
patibility antigens. Nature. 1987;329:512–518. 291. Noack M, Miossec P. Th17 and regulatory T cell balance in
270. Braciale TJ, Morrison LA, Sweetser MT, et al. Antigen presenta- autoimmune and inflammatory diseases. Autoimmun Rev.
tion pathways to class I and class II MHC-restricted T lympho- 2014;13:668–677.
cytes. Immunol Rev. 1987;98:95–114. 292. Ueno A, Ghosh A, Hung D, et al. Th17 plasticity and its changes as-
271. Lechner F, Cuero AL, Kantzanou M, et al. Studies of human sociated with inflammatory bowel disease. World J Gastroenterol.
antiviral CD8+ lymphocytes using class I peptide tetramers. Rev 2015;21:12283–12295.
Med Virol. 2001;11:11–22. 293. Olofsson KM, Hjertner B, Fossum C, et al. Expression of T help-
272. Mealey RH, Sharif A, Ellis SA, et al. Early detection of dominant er type 17 (Th17)-associated cytokines and toll-like receptor 4
Env-specific and subdominant Gag-specific CD8+ lymphocytes and their correlation with Foxp3 positive cells in rectal biopsies
in equine infectious anemia virus-infected horses using major of horses with clinical signs of inflammatory bowel disease. Vet J.
histocompatibility complex class I/peptide tetrameric complex- 2015;206:97–104.
es. Virology. 2005;339:110–126. 294. Regan DP, Aarnio MC, Davis WS, et al. Characterization of
273. Mealey RH, Stone DM, Hines MT, et al. Experimental Rho- cytokines associated with Th17 cells in the eyes of horses with
dococcus equi and equine infectious anemia virus DNA vac- recurrent uveitis. Vet Ophthalmol. 2012;15:145–152.
cination in adult and neonatal horses: effect of IL-12, dose, and 295. Korn A, Miller D, Dong L, et al. Differential Gene Expression
route. Vaccine. 2007;25:7582–7597. Profiles and Selected Cytokine Protein Analysis of Mediastinal
274. Mealey RH, Lee JH, Leib SR, et al. A single amino acid dif- Lymph Nodes of Horses with Chronic Recurrent Airway Ob-
ference within the alpha-2 domain of two naturally occurring struction (RAO) Support an Interleukin-17 Immune Response.
equine MHC class I molecules alters the recognition of Gag and PloS one. 2015;10:e0142622.
Rev epitopes by equine infectious anemia virus-specific CTL. J 296. Bullone M, Lavoie JP. Asthma “of horses and men”—how can
Immunol. 2006;177:7377–7390. equine heaves help us better understand human asthma immu-
275. Yao S, Liu J, Qi J, et al. Structural Illumination of Equine MHC nopathology and its functional consequences? Mol Immunol.
Class I Molecules Highlights Unconventional Epitope Presenta- 2015;66:97–105.
tion Manner That Is Evolved in Equine Leukocyte Antigen Al- 297. Liu M, Bordin A, Liu T, et al. Gene expression of innate
leles. J Immunol. 2016;196:1943–1954. Th1-, Th2-, and Th17-type cytokines during early life of
276. Bergmann T, Moore C, Sidney J, et al. The common equine class neonatal foals in response to Rhodococcus equi. Cytokine.
I molecule Eqca-1*00101 (ELA-A3.1) is characterized by nar- 2011;56:356–364.
row peptide binding and T cell epitope repertoires. Immunoge- 298. Grant CR, Liberal R, Mieli-Vergani G, et al. Regulatory T-cells
netics. 2015;67:675–689. in autoimmune diseases: challenges, controversies and yet-un-
277. Crepaldi T, Crump A, Newman M, et al. Equine T lymphocytes answered questions. Autoimmun Rev. 2015;14:105–116.
express MHC class II antigens. J Immunogenet. 1986;13:349–360. 299. Wagner B, Hillegas JM, Brinker DR, et al. Characterization of
278. Lunn DP, Holmes MA, Duffus WP. Equine T-lymphocyte monoclonal antibodies to equine interleukin-10 and detection
MHC II expression: variation with age and subset. Vet Immunol of T regulatory 1 cells in horses. Vet Immunol Immunopathol.
Immunopathol. 1993;35:225–238. 2008;122:57–64.
300. de Mestre A, Noronha L, Wagner B, et al. Split immunological 322. Lunn DP, Holmes MA, Duffus WP. Three monoclonal anti-
tolerance to trophoblast. Int J Dev Biol. 2010;54:445–455. bodies identifying antigens on all equine T lymphocytes, and
301. Robbin MG, Wagner B, Noronha LE, et al. Subpopulations of two mutually exclusive T-lymphocyte subsets. Immunology.
equine blood lymphocytes expressing regulatory T cell markers. 1991;74:251–257.
Vet Immunol Immunopathol. 2011;140:90–101. 323. Wyatt CR, Davis WC, McGuire TC, et al. T lymphocyte devel-
302. Hamza E, Gerber V, Steinbach F, et al. Equine CD4(+) opment in horses. I. Characterization of monoclonal antibodies
CD25(high) T cells exhibit regulatory activity by close contact identifying three stages of T lymphocyte differentiation. Vet Im-
and cytokine-dependent mechanisms in vitro. Immunology. munol Immunopathol. 1988;18:3–18.
2011;134:292–304. 324. Perryman LE, Wyatt CR, Magnuson NS, et al. T lymphocyte devel-
303. Hamza E, Mirkovitch J, Steinbach F, et al. Regulatory T cells opment and maturation in horses. Anim Genet. 1988;19:343–348.
in early life: comparative study of CD4+CD25high T cells from 325. Giguere S, Polkes AC. Immunologic disorders in neonatal foals.
foals and adult horses. PloS one. 2015;10:e0120661. Vet Clin North Am Equine Pract. 2005;21:241–272.
304. Hamza E, Akdis CA, Wagner B, et al. In vitro induction of func- 326. Tallmadge R. The immune system of the young horse. In: Filippe
tional allergen-specific CD4+ CD25high Treg cells in horses M, ed. Equine Clinical Immunology. Oxford, UK: John Wiley &
affected with insect bite hypersensitivity. Clin Exp Allergy. Sons, Inc.; 2016.
2013;43:889–901. 327. Wichtel MG, Anderson KL, Johnson TV, et al. Influence
305. Hamza E, Steinbach F, Marti E. CD4+CD25+ T cells expressing of age on neutrophil function in foals. Equine Vet J.
FoxP3 in Icelandic horses affected with insect bite hypersensi- 1991;23:466–469.
tivity. Vet Immunol Immunopathol. 2012;148:139–144. 328. Morris DD, Gaulin G, Strzemienski PJ, et al. Assessment of
306. Schaffartzik A, Hamza E, Janda J, et al. Equine insect bite hy- neutrophil migration, phagocytosis and bactericidal capacity in
persensitivity: what do we know? Vet Immunol Immunopathol. neonatal foals. Vet Immunol Immunopathol. 1987;16:173–184.
2012;147:113–126. 329. Hietala SK, Ardans AA. Neutrophil phagocytic and serum op-
307. Henriquez C, Perez B, Morales N, et al. Participation of T regu- sonic response of the foal to Corynebacterium equi. Vet Immu-
latory cells in equine recurrent airway obstruction. Vet Immu- nol Immunopathol. 1987;14:279–294.
nol Immunopathol. 2014;158:128–134. 330. Bernoco M, Liu IK, Wuest Ehlert CJ, et al. Chemotactic and
308. Chevalier MF, Weiss L. The split personality of regulatory T phagocytic function of peripheral blood polymorphonuclear leu-
cells in HIV infection. Blood. 2013;121:29–37. cocytes in newborn foals. J Reprod Fertil Suppl. 1987;35:599–605.
309. Lunn DP, Breathnach C, Soboll G. Immunology and immuno- 331. Demmers S, Johannisson A, Grondahl G, et al. Neutro-
pathology. In: McGorum BC, Dixon PM, Robinson NE, Schu- phil functions and serum IgG in growing foals. Equine Vet J.
macher J, eds. Equine respiratory medicine and surgery. 1st ed. 2001;33:676–680.
Edinburgh: Sauders-Elsevier; 2007:71–81. 332. Flaminio MJ, Rush BR, Davis EG, et al. Characterization of pe-
310. Ganusov VV, De Boer RJ. Tissue distribution of lymphocytes ripheral blood and pulmonary leukocyte function in healthy
and plasma cells and the role of the gut: response to Pabst et al. foals. Vet Immunol Immunopathol. 2000;73:267–285.
Trends Immunol. 2008;29:209–210. 333. McTaggart C, Yovich JV, Penhale J, et al. A comparison of foal
311. Pabst R, Russell MW, Brandtzaeg P. Tissue distribution of lym- and adult horse neutrophil function using flow cytometric tech-
phocytes and plasma cells and the role of the gut. Trends Immu- niques. Res Vet Sci. 2001;71:73–79.
nol. 2008;29:206–208. 334. Bernoco MM, Liu IK, Willits NH. Hemolytic complement ac-
312. Kumar P, Timoney JF, Sheoran AS. M cells and associated lym- tivity and concentrations of its third component during matura-
phoid tissue of the equine nasopharyngeal tonsil. Equine Vet J. tion of the immune response in colostrum-deprived foals. Am J
2001;33:224–230. Vet Res. 1994;55:928–933.
313. Breathnach CC, Yeargan MR, Timoney JF, et al. Detection of 335. Lavoie JP, Spensley MS, Smith BP, et al. Complement activity
equine herpesvirus-specific effector and memory cytotoxic im- and selected hematologic variables in newborn foals fed bovine
munity in the equine upper respiratory tract. Vet Immunol Im- colostrum. Am J Vet Res. 1989;50:1532–1536.
munopathol. 2006;111:117–125. 336. Liu IKM, Walsh EM, Bernoco M, et al. Bronchalveolar lavage in
314. Perryman LE, McGuire TC, Torbeck RL. Ontogeny of the newborn foal. J Reprod Fert Suppl. 1987;35:587–592.
lymphocyte function in the equine fetus. Am J Vet Res. 337. Smith III R, Chaffin MK, Cohen ND, et al. Age-related chang-
1980;41:1197–1200. es in lymphocyte subsets of quarter horse foals. Am J Vet Res.
315. McGuire TC, Crawford TB. Passive immunity in the foal: meas- 2002;63:531–537.
urement of immunoglobulin classes and specific antibody. Am J 338. Flaminio MJ, Rush BR, Shuman W. Peripheral blood lympho-
Vet Res. 1973;34:1299–1303. cyte subpopulations and immunoglobulin concentrations in
316. Tallmadge RL, McLaughlin K, Secor E, et al. Expression of es- healthy foals and foals with Rhodococcus equi pneumonia. J Vet
sential B cell genes and immunoglobulin isotypes suggests ac- Intern Med. 1999;13:206–212.
tive development and gene recombination during equine gesta- 339. Breathnach CC, Sturgill-Wright T, Stiltner JL, et al. Foals are in-
tion. Dev Comp Immunol. 2009;33:1027–1038. terferon gamma-deficient at birth. Vet Immunol Immunopathol.
317. Sheoran AS, Timoney JF, Holmes MA, et al. Immunoglobu- 2006;112:199–209.
lin isotypes in sera and nasal mucosal secretions and their 340. Flaminio MJ, Borges AS, Nydam DV, et al. The effect of CpG-
neonatal transfer and distribution in horses. Am J Vet Res. ODN on antigen presenting cells of the foal. J Immune Based
2000;61:1099–1105. Ther Vaccines. 2007;5:1.
318. Hannant D, Rossdale PD, McGladdery AJ, et al. Immune re- 341. Flaminio MJ, Nydam DV, Marquis H, et al. Foal monocyte-de-
sponses of the equine foetus to protein antigens. Proceedings of rived dendritic cells become activated upon Rhodococcus equi
the Sixth International Conference on Equine Infectious Diseases; infection. Clin Vaccine Immunol. 2009;16:176–183.
1991:86. Cambridge, UK. 342. Sturgill TL, Giguere S, Berghaus LJ, et al. Comparison of anti-
319. Martin BR, Larson KA. Immune response of equine fetus to body and cell-mediated immune responses of foals and adult
coliphage T2. Am J Vet Res. 1973;34:1363–1364. horses after vaccination with live Mycobacterium bovis BCG.
320. Morgan DO, Bryans JT, Mock RE. Immunoglobulins produced by Vaccine. 2014;32:1362–1367.
the antigenized equine fetus. J Reprod Fertil Suppl. 1975:735–738. 343. Ryan C, Giguere S. Equine neonates have attenuated humoral
321. Blanchard-Channell M, Moore PF, Stott JL. Characterization of and cell-mediated immune responses to a killed adjuvanted
monoclonal antibodies specific for equine homologues of CD3 vaccine compared to adult horses. Clin Vaccine Immunol.
and CD5. Immunology. 1994;82:548–554. 2010;17:1896–1902.
344. Ryan C, Giguere S, Hagen J, et al. Effect of age and mito- 364. Merant C, Breathnach CC, Kohler K, et al. Young foal and
gen on the frequency of interleukin-4 and interferon gamma adult horse monocyte-derived dendritic cells differ by their
secreting cells in foals and adult horses as assessed by an degree of phenotypic maturity. Vet Immunol Immunopathol.
equine-specific ELISPOT assay. Vet Immunol Immunopathol. 2009;131:1–8.
2010;133:66–71. 365. Swiderski CE. Hypersensitivity disorders in horses. Vet Clin
345. Jacks S, Giguere S, Crawford PC, et al. Experimental infection of North Am Equine Pract. 2000;16:131–151. vii.
neonatal foals with Rhodococcus equi triggers adult-like gamma 366. McAleese SM, Halliwell RE, Miller HR. Cloning and sequenc-
interferon induction. Clin Vaccine Immunol. 2007;14:669–677. ing of the horse and sheep high-affinity IgE receptor alpha chain
346. Wagner B, Burton A, Ainsworth D. Interferon-gamma, interleu- cDNA. Immunogenetics. 2000;51:878–881.
kin-4 and interleukin-10 production by T helper cells reveals in- 367. Watson JL, Jackson KA, King DP, et al. Molecular cloning and
tact Th1 and regulatory TR1 cell activation and a delay of the Th2 sequencing of the low-affinity IgE receptor (CD23) for horse
cell response in equine neonates and foals. Vet Res. 2010;41:47. and cattle. Vet Immunol Immunopathol. 2000;73:323–329.
347. Harris SP, Hines MT, Mealey RH, et al. Early development of 368. Wagner B, Hillegas JM, Babasyan S. Monoclonal antibodies to
cytotoxic T lymphocytes in neonatal foals following oral in- equine CD23 identify the low-affinity receptor for IgE on sub-
oculation with Rhodococcus equi. Vet Immunol Immunopathol. populations of IgM+ and IgG1+ B-cells in horses. Vet Immunol
2011;141:312–316. Immunopathol. 2012;146:125–134.
348. Basha S, Surendran N, Pichichero M. Immune responses in 369. Klei TR. Equine immunity to parasites. Vet Clin North Am
neonates. Expert Rev Clin Immunol. 2014;10:1171–1184. Equine Pract. 2000;16:69–78. vi.
349. Holmes MA, Lunn DP. A study of bovine and equine immuno- 370. Fadok VA. Update on equine allergies. Vet Clin North Am
globulin levels in pony foals fed bovine colostrum. Equine Vet J. Equine Pract. 2013;29:541–550.
1991;23:116–118. 371. Brown EM, Arrieta MC, Finlay BB. A fresh look at the hy-
350. Jeffcott LB. Studies on passive immunity in the foal. 1. Gamma- giene hypothesis: how intestinal microbial exposure drives
globulin and antibody variations associated with the maternal immune effector responses in atopic disease. Semin Immunol.
transfer of immunity and the onset of active immunity. J Comp 2013;25:378–387.
Pathol. 1974;84:93–101. 372. Kehrli D, Jandova V, Fey K, et al. Multiple hypersensitivities
351. Lavoie JP, Spensley MS, Smith BP, et al. Absorption of bovine co- including recurrent airway obstruction, insect bite hypersensi-
lostral immunoglobulins G and M in newborn foals. Am J Vet Res. tivity, and urticaria in 2 Warmblood horse populations. J Vet
1989;50:1598–1603. Intern Med. 2015;29:320–326.
352. Wilson WD. Vaccination of foals. In: British Equine Veterinary 373. Hamza E, Torsteinsdottir S, Eydal M, et al. Increased IL-4 and
Association Conference. ; 2001. Harrogate. decreased regulatory cytokine production following relocation
353. Rouse BT. The immunoglobulins of adult equine and foal sera: of Icelandic horses from a high to low endoparasite environ-
a quantitative study. Vet J. 1971;127:45–51. ment. Vet Immunol Immunopathol. 2010;133:40–50.
354. Sheoran AS, Sponseller BT, Holmes MA, et al. Serum and mu- 374. Olsen L, Ingvast-Larsson C, Brostrom H, et al. Clinical signs
cosal antibody isotype responses to M-like protein (SeM) of and etiology of adverse reactions to procaine benzylpenicil-
Streptococcus equi in convalescent and vaccinated horses. Vet lin and sodium/potassium benzylpenicillin in horses. J Vet
Immunol Immunopathol. 1997;59:239–251. Pharmacol Ther. 2007;30:201–207.
355. Nelson KM, Schram BR, McGregor MW, et al. Local and 375. Blue JT, Dinsmore RP, Anderson KL. Immune-mediated
systemic isotype-specific antibody responses to equine influ- hemolytic anemia induced by penicillin in horses. Cornell Vet.
enza virus infection versus conventional vaccination. Vaccine. 1987;77:263–276.
1998;16:1306–1313. 376. Banks KL, Henson JB, McGuire TC. Immunologically mediated
356. Hoffman AM, Viel L, Juniper E, et al. Clinical and endoscopic glomerulitis of horses. I. Pathogenesis in persistent infection by
study to estimate the incidence of distal respiratory tract infection equine infectious anemia virus. Lab Invest. 1972;26:701–707.
in thoroughbred foals on Ontario breeding farms. Am J Vet Res. 377. Suter M, Fey H. Further purification and characterization of
1993;54:1602–1607. horse IgE. Vet Immunol Immunopathol. 1983;4:545–553.
357. Dawson TR, Horohov DW, Meijer WG, et al. Current under- 378. Matthews AG, Imlah P, McPherson EA. A reagin-like antibody
standing of the equine immune response to Rhodococcus equi. in horse serum: 1. Occurrence and some biological properties.
An immunological review of R. equi pneumonia. Vet Immunol Vet Res Commun. 1983;6:13–23.
Immunopathol. 2010;135:1–11. 379. Wagner B, Siebenkotten G, Radbruch A, et al. Nucleotide se-
358. Wilson WD, Mihalyi JE, Hussey S, et al. Passive transfer of ma- quence and restriction fragment length polymorphisms of
ternal immunoglobulin isotype antibodies against tetanus and the equine Cvarepsilon gene. Vet Immunol Immunopathol.
influenza and their effect on the response of foals to vaccina- 2001;82:193–202.
tion. Equine Vet J. 2001;33:644–650. 380. Navarro P, Barbis DP, Antczak D, et al. The complete cDNA
359. Gibbs E, Wilson J, All B. Studies on Passive Immunity and the and deduced amino acid sequence of equine IgE. Mol Immunol.
Vaccination of foals against Eastern Equine Encephalitis in 1995;32:1–8.
Florida. In: Equine infectious Disease V: Proceedings of the Fifth 381. Marti E, Szalai G, Bucher K, et al. Partial sequence of the equine
International Conferance. ;5. ; 1988:201–205. immunoglobulin epsilon heavy chain cDNA. Vet Immunol Im-
360. Galan JE, Timoney JF, Lengemann FW. Passive transfer of mu- munopathol. 1995;47:363–367.
cosal antibody to Streptococcus equi in the foal. Infect Immun. 382. Halliwell RE, McGorum BC, Irving P, et al. Local and systemic
1986;54:202–206. antibody production in horses affected with chronic obstructive
361. van Maanen C, Bruin G, de Boer-Luijtze E, et al. Interference pulmonary disease. Vet Immunol Immunopathol. 1993;38:201–
of maternal antibodies with the immune response of foals after 215.
vaccination against equine influenza. Vet Q. 1992;14:13–17. 383. Halliwell RE, Hines MT. Studies on equine recurrent uveitis. I:
362. Van Oirschot JT, Bruin G, de Boer-Luytze E, et al. Maternal anti- Levels of immunoglobulin and albumin in the aqueous humor
bodies against equine influenza virus in foals and their interference of horses with and without intraocular disease. Current Eye Re-
with vaccination. Zentralbl Veterinarmed [B]. 1991;38:391–396. search. 1985;4:1023–1031.
363. Davis EG, Bello NM, Bryan AJ, et al. Characterisation of im- 384. Marti E, Peveri P, Griot-Wenk M, et al. Chicken antibodies to
mune responses in healthy foals when a multivalent vaccine a recombinant fragment of the equine immunoglobulin epsilon
protocol was initiated at age 90 or 180 days. Equine Vet J. heavy-chain recognising native horse IgE. Vet Immunol Immu-
2015;47:667–674. nopathol. 1997;59:253–270.
385. van der Haegen A, Griot-Wenk M, Welle M, et al. Immunoglob- 406. Cordeau M-E, Joubert P, Dewachi O, et al. IL-4, IL-5 and IFN-g
ulin-E-bearing cells in skin biopsies of horses with insect bite mRNA expression in pulmonary lymphocytes in equine heaves.
hypersensitivity. Equine Vet J. 2001;33:699–706. Vet Immunol Immunopathol. 2004;97:87–96.
386. Wilson AD, Harwood LJ, Bjornsdottir S, et al. Detection of 407. Ainsworth DM, Grunig G, Matychak MB, et al. Recurrent
IgG and IgE serum antibodies to Culicoides salivary gland anti- airway obstruction (RAO) in horses is characterized by IFN-
gens in horses with insect dermal hypersensitivity (sweet itch). gamma and IL-8 production in bronchoalveolar lavage cells. Vet
Equine Vet J. 2001;33:707–713. Immunol Immunopathol. 2003;96:83–91.
387. Eder C, Crameri R, Mayer C, et al. Allergen-specific IgE levels 408. Kleiber C, McGorum BC, Horohov DW, et al. Cytokine profiles
against crude mould and storage mite extracts and recombinant of peripheral blood and airway CD4 and CD8 T lymphocytes
mould allergens in sera from horses affected with chronic bron- in horses with recurrent airway obstruction. Vet Immunol Im-
chitis. Vet Immunol Immunopathol. 2000;73:241–253. munopathol. 2005;104:91–97.
388. Eder C, Curik I, Brem G, et al. Influence of environmental and 409. Horohov DW, Beadle RE, Mouch S, et al. Temporal regulation
genetic factors on allergen-specific immunoglobulin-E levels in of cytokine mRNA expression in equine recurrent airway ob-
sera from Lipizzan horses. Equine Vet J. 2001;33:714–720. struction. Vet Immunol Immunopathol. 2005;108:237–245.
389. Wagner B, Radbruch A, Rohwer J, et al. Monoclonal anti-equine 410. Berndt A, Derksen FJ, Venta PJ, et al. Elevated amount of Toll-
IgE antibodies with specificity for different epitopes on the im- like receptor 4 mRNA in bronchial epithelial cells is associated
munoglobulin heavy chain of native IgE. Vet Immunol Immuno- with airway inflammation in horses with recurrent airway ob-
pathol. 2003;92:45–60. struction. Am J Physiol. 2007;292:L936–L943.
390. Wilson AD, Harwood L, Torsteinsdottir S, et al. Production of 411. Traub-Dargatz JL, McClure JJ, Koch C, et al. Neonatal isoeryth-
monoclonal antibodies specific for native equine IgE and their rolysis in mule foals. J Am Vet Med Assoc. 1995;206:67–70.
application to monitor total serum IgE responses in Icelandic 412. McClure JJ, Koch C, Traub-Dargatz J. Characterization of a red
and non-Icelandic horses with insect bite dermal hypersensitiv- blood cell antigen in donkeys and mules associated with neona-
ity. Vet Immunol Immunopathol. 2006;112:156–170. tal isoerythrolysis. Anim Genet. 1994;25:119–120.
391. Wagner B, Flaminio JB, Hillegas J, et al. Occurrence of IgE in 413. Buechner-Maxwell V, Scott MA, Godber L, et al. Neonatal allo-
foals: evidence for transfer of maternal IgE by the colostrum immune thrombocytopenia in a quarter horse foal. J Vet Intern
and late onset of endogenous IgE production in the horse. Vet Med. 1997;11:304–308.
Immunol Immunopathol. 2006;110:269–278. 414. Ramirez S, Gaunt SD, McClure JJ, et al. Detection and effects on
392. Wagner B, Stokol T, Ainsworth DM. Induction of interleukin-4 platelet function of anti-platelet antibody in mule foals with ex-
production in neonatal IgE+ cells after crosslinking of maternal perimentally induced neonatal alloimmune thrombocytopenia.
IgE. Dev Comp Immunol. 2010;34:436–444. J Vet Intern Med. 1999;13:534–539.
393. Hanna CJ, Eyre P, Wells PW, et al. Equine immunology 2: im- 415. Perkins GA, Miller WH, Divers TJ, et al. Ulcerative dermatitis,
munopharmacology—biochemical basis of hypersensitivity. thrombocytopenia, and neutropenia in neonatal foals. J Vet In-
Equine Vet J. 1982;14:16–24. tern Med. 2005;19:211–216.
394. Nielsen IL, Jacobs KA, Huntington PJ, et al. Adverse reac- 416. Galan JE, Timoney JF. Immune complexes in purpura hemor-
tion to procaine penicillin G in horses. Aust Vet J. 1988;65 rhagica of the horse contain IgA and M antigen of Streptococcus
:181–185. equi. J Immunol. 1985;135:3134–3137.
395. Orsini J, Divers T. Equine Emergencies Treatment and Proce- 417. Hunyadi L, Pusterla N. Purpura hemorrhagica. In: Filippe M,
dures. 4th ed. St. Louis, MO: Elsevier Saunders; 2014. ed. Equine Clinical Immunology. Oxford, UK: John Wiley &
396. Wagner B. Allergy. In: Filippe M, ed. Equine Clinical Immunol- Sons, Inc.; 2016.
ogy. Oxford, UK: John Wiley & Sons, Inc.; 2016. 418. Pusterla N, Watson JL, Affolter VK, et al. Purpura haemorrhag-
397. Wagner B, Miller WH, Morgan EE, et al. IgE and IgG antibodies ica in 53 horses. Vet Rec. 2003;153:118–121.
in skin allergy of the horse. Vet Res. 2006;37:813–825. 419. Divers TJ, Timoney JF, Lewis RM, et al. Equine glomerulone-
398. Lazary S, Marti E, Szalai G, et al. Studies on the frequency and phritis and renal failure associated with complexes of group-C
associations of equine leucocyte antigens in sarcoid and sum- streptococcal antigen and IgG antibody. Vet Immunol Immuno-
mer dermatitis. Anim Genet. 1994;25(suppl 1):75–80. pathol. 1992;32:93–102.
399. Marti E, Gerber H, Lazary S. On the genetic basis of equine al- 420. Hines MT. Immunologically mediated ocular disease in the
lergic diseases: II. Insect bite dermal hypersensitivity. Equine horse. Vet Clin North Am Large Anim Pract. 1984;6:501–512.
Vet J. 1992;24:113–117. 421. Deeg CA, Kaspers B, Gerhards H, et al. Immune responses to
400. Wilson AD. Immune responses to ectoparasites of horses, retinal autoantigens and peptides in equine recurrent uveitis.
with a focus on insect bite hypersensitivity. Parasite Immunol. Invest Ophthalmol Vis Sci. 2001;42:393–398.
2014;36:560–572. 422. Davidson MG, Nasisse MP, Roberts SM. Immunodiagnosis of
401. Bullone M, JP L. Recurrent airway obstruction and summer leptospiral uveitis in two horses. Equine Vet J. 1987;19:155–157.
pasture-associated obstructive pulmonart disease. In: Filippe 423. Faber NA, Crawford M, LeFebvre RB, et al. Detection of Lepto-
M, ed. Equine Clinical Immunology. Oxford, UK: John Wiley & spira spp. in the aqueous humor of horses with naturally ac-
Sons, Inc.; 2016. quired recurrent uveitis. J Clin Microbiol. 2000;38:2731–2733.
402. Leclere M, Lavoie-Lamoureux A, Lavoie JP. Heaves, an asthma- 424. Parma AE, Fernandez AS, Santisteban CG, et al. Tears and
like disease of horses. Respirology. 2011;16:1027–1046. aqueous humor from horses inoculated with Leptospira contain
403. Schmallenbach KH, Rahman I, Sasse HH, et al. Studies on antibodies which bind to cornea. Vet Immunol Immunopathol.
pulmonary and systemic Aspergillus fumigatus-specific IgE 1987;14:181–185.
and IgG antibodies in horses affected with chronic obstruc- 425. Gilger B. Recurrent uveitis. In: Filippe M, ed. Equine Clinical
tive pulmonary disease (COPD). Vet Immunol Immunopathol. Immunology. Oxford, UK: John Wiley & Sons, Inc.; 2016.
1998;66:245–256. 426. Dwyer AE, Crockett RS, Kalsow CM. Association of lepto-
404. Kunzle F, Gerber V, Van Der Haegen A, et al. IgE-bearing cells spiral seroreactivity and breed with uveitis and blindness
in bronchoalveolar lavage fluid and allergen-specific IgE levels in horses: 372 cases (1986–1993). J Am Vet Med Assoc.
in sera from RAO-affected horses. J Vet Med A Physiol Pathol 1995;207:1327–1331.
Clin Med. 2007;54:40–47. 427. Gilger BC, Malok E, Cutter KV, et al. Characterization of T-
405. Robinson NE, Derksen FJ, Olszewski MA, et al. The pathogen- lymphocytes in the anterior uvea of eyes with chronic equine
esis of chronic obstructive pulmonary disease of horses. Vet J. recurrent uveitis. Vet Immunol Immunopathol. 1999;71:
1995;152:283–306. 17–28.
428. Cines DB, Liebman H, Stasi R. Pathobiology of second- 452. Shin EK, Perryman LE, Meek K. A kinase-negative mutation of
ary immune thrombocytopenia. Semin Hematol. 2009;46: DNA-PK(CS) in equine SCID results in defective coding and
S2–S14. signal joint formation. J Immunol. 1997;158:3565–3569.
429. Verma A, Kumar P, Babb K, et al. Cross-reactivity of antibodies 453. McGuire TC, Poppie MJ, Banks KL. Combined (B- and T-lym-
against leptospiral recurrent uveitis-associated proteins A and phocyte) immunodeficiency: a fatal genetic disease in Arabian
B (LruA and LruB) with eye proteins. PLoS neglected tropical foals. J Am Vet Med Assoc. 1974;164:70–76.
diseases. 2010;4:e778. 454. Liepman RS, Dembek KA, Slovis NM, et al. Validation of IgG
430. McClure JJ. Equine autoimmunity. Vet Clin North Am Equine cut-off values and their association with survival in neonatal
Pract. 2000;16:153–164. foals. Equine Vet J. 2015;47:526–530.
431. Wilkerson MJ, Davis E, Shuman W, et al. Isotype-specific an- 455. Leblanc MM. Immunologic considerations. In: Koterba AM,
tibodies in horses and dogs with immune-mediated hemolytic Drummond WH, Kosch PC, eds. Equine clinical neonatology.
anemia. J Vet Intern Med. 2000;14:190–196. 1st ed. Philadelphia: Lea and Febiger; 1990:275–295.
432. Divers T. Immune-mediated cytopenias. In: Filippe M, ed. 456. Clabough DL, Conboy HS, Roberts MC. Comparison of
Equine Clinical Immunology. Oxford, UK: John Wiley & Sons, four screening techniques for the diagnosis of equine neona-
Inc.; 2016. tal hypogammaglobulinemia. J Am Vet Med Assoc. 1989;194:
433. Pfeiffer CJ, Spurlock S, Ball M. Ultrastructural aspects of equine 1717–1720.
pemphigus foliaceus-like dermatitis. Report of cases. J Submi- 457. McCue PM. Evaluation of a turbidimetric immunoassay for
crosc Cytol Pathol. 1988;20:453–461. measurement of plasma IgG concentration in foals. Am J Vet
434. Vandenabeele SI, White SD, Affolter VK, et al. Pemphigus folia- Res. 2007;68:1005–1009.
ceus in the horse: a retrospective study of 20 cases. Vet Derma- 458. Davis DG, Schaefer DM, Hinchcliff KW, et al. Measurement of
tol. 2004;15:381–388. serum IgG in foals by radial immunodiffusion and automated
435. Scott D, Miller W. Equine Dermatology. 2nd ed. Philadelphia, turbidimetric immunoassay. J Vet Intern Med. 2005;19:93–96.
PA: Elsevier Saunders; 2011. 459. Riley CB, McClure JT, Low-Ying S, et al. Use of Fourier-trans-
436. Winfield LD, White SD, Affolter VK, et al. Pemphigus vulgaris form infrared spectroscopy for the diagnosis of failure of trans-
in a Welsh pony stallion: case report and demonstration of an- fer of passive immunity and measurement of immunoglobulin
tidesmoglein autoantibodies. Vet Dermatol. 2013;24. 269–e260. concentrations in horses. J Vet Intern Med. 2007;21:828–834.
437. Geor RJ, Clark EG, Haines DM, et al. Systemic lupus erythema- 460. Pusterla N, Pusterla JB, Spier SJ, et al. Evaluation of the SNAP
tosus in a filly. J Am Vet Med Assoc. 1990;197:1489–1492. foal IgG test for the semiquantitative measurement of immuno-
438. Fordyce PS, Edington N, Bridges GC, et al. Use of an ELISA globulin G in foals. Vet Rec. 2002;151:258–260.
in the differential diagnosis of cauda equina neuritis and other 461. Davis R, Giguere S. Evaluation of five commercially available
equine neuropathies. Equine Vet J. 1987;19:55–59. assays and measurement of serum total protein concentration
439. Wright JA, Fordyce P, Edington N. Neuritis of the cauda equina via refractometry for the diagnosis of failure of passive transfer
in the horse. J Comp Pathol. 1987;97:667–675. of immunity in foals. J Am Vet Med Assoc. 2005;227:1640–1645.
440. Kadlubowski M, Ingram PL. Circulating antibodies to the neu- 462. Edwards DF, Parker JW, Wilkinson JE, et al. Plasma cell myelo-
ritogenic myelin protein, P2, in neuritis of the cauda equina of ma in the horse. A case report and literature review. [Review]. J
the horse. Nature. 1981;293:299–300. Vet Intern Med. 1993;7:169–176.
441. van Galen G, Cassart D, Sandersen C, et al. The composition of 463. Shin EK, Perryman LE, Meek K. Evaluation of a test for
the inflammatory infiltrate in three cases of polyneuritis equi. identification of Arabian horses heterozygous for the severe
Equine Vet J. 2008;40:185–188. combined immunodeficiency trait. J Am Vet Med Assoc.
442. Hahn CN. Polyneuritis equi: the role of T-lymphocytes 1997;211:1268–1270.
and importance of differential clinical signs. Equine Vet J. 464. Fraser DG, Mealey RH, McGuire TC. Selecting peptides to op-
2008;40:100. timize Th1 responses to an equine lentivirus using HLA-DR
443. Piercy RJ, Swardson CJ, Hinchcliff KW. Erythroid hypo- binding motifs and defined HIV-1 Th peptides. Immunogenet-
plasia and anemia following administration of recombinant ics. 2003;55:508–514.
human erythropoietin to two horses. J Am Vet Med Assoc. 465. Yu Y, Arora A, Min W, et al. U incorporation is an alternative
1998;212:244–247. non-radioactive assay to [(3)H]thymidine uptake for in vitro
444. Woods PR, Campbell G, Cowell RL. Nonregenerative anae- measurement of mice T-cell proliferations. J Immunol Methods.
mia associated with administration of recombinant human 2009;350:29–35.
erythropoetin to a Thoroughbred racehorses. Equine Vet J. 466. McClure JT, Lunn DP, McGuirk SM. Combined immunodefi-
1997;29:326–328. ciency in 3 foals. Equine Vet Educ. 1993;5:14–18.
445. Perryman LE. Primary immunodeficiencies of horses. Vet Clin 467. Hutchison JM, Garry FB, Belknap EB, et al. Prospective charac-
North Am Equine Pract. 2000;16:105–116. vii. terization of the clinicopathologic and immunologic features of
446. Sellon DC. Secondary immunodeficiencies of horses. Vet Clin an immunodeficiency syndrome affecting juvenile llamas. Vet
North Am Equine Pract. 2000;16:117–130. Immunol Immunopathol. 1995;49:209–227.
447. Crisman MV, Scarratt WK. Immunodeficiency disor- 468. Slack JA, Risdahl JM, Valberg S, et al. Effects of corticosteroids
ders in horses. Vet Clin North Am Equine Pract. 2008;24: on equine IgG sub-isotype responses to vaccination. Am J Vet
299–310. vi. Res. 1997;61:1530–1533.
448. Filippe M. Immunodeficiencies. In: Filippe M, ed. Equine Clini- 469. Flaminio MJ, Rush BR, Shuman W. Immunologic function in
cal Immunology. Oxford, UK: John Wiley & Sons, Inc.; 2016. horses after non-specific immunostimulant administration. Vet
449. Clabough DL, Levine JF, Grant GL, et al. Factors associated Immunol Immunopathol. 1998;63:303–315.
with failure of passive transfer of colostral antibodies in Stand- 470. Zink MC, Yager JA, Prescott JF, et al. In vitro phagocytosis and
ardbred foals. J Vet Intern Med. 1991;5:335–340. killing of Corynebacterium equi by alveolar macrophages of
450. Stoneham SJ, Digby NJ, Ricketts SW. Failure of passive trans- foals. Am J Vet Res. 1985;46:2171–2174.
fer of colostral immunity in the foal: incidence, and the ef- 471. Flaminio MJ, Rush BR, Davis EG, et al. Simultaneous flow cy-
fect of stud management and plasma transfusions. Vet Rec. tometric analysis of phagocytosis and oxidative burst activity in
1991;128:416–419. equine leukocytes. Vet Res Commun. 2002;26:85–92.
451. Raidal SL. The incidence and consequences of failure of passive 472. Hormanski CE, Truax R, Pourciau SS, et al. Induction of lym-
transfer of immunity on a thoroughbred breeding farm. Aust phokine-activated killer cells of equine origin: specificity for
Vet J. 1996;73:201–206. equine target cells. Vet Immunol Immunopathol. 1992;32:25–36.
473. Lunn DP, Schram BR, Vagnoni KE, et al. Positive selection of 494. Holliman A, Scholes SP. Possible immune deficiency in Fell po-
EqCD8+ precursors increases equine lymphokine-activated nies. Vet Rec. 1995;137:176.
killing. Vet Immunol Immunopathol. 1996;53:1–13. 495. Scholes SF, Holliman A, May PD, et al. A syndrome of anaemia,
474. Liu C, Betancourt A, Cohen DA, et al. Granzyme B-mRNA ex- immunodeficiency and peripheral ganglionopathy in Fell pony
pression by equine lymphokine activated killer (LAK) cells is foals. Vet Rec. 1998;142:128–134.
associated with the induction of apoptosis in target cells. Vet 496. Fox-Clipsham L, Swinburne JE, Papoula-Pereira RI, et al. Im-
Immunol Immunopathol. 2011;143:108–115. munodeficiency/anaemia syndrome in a Dales pony. Vet Rec.
475. Canisso IF, Ball BA, Cray C, et al. Serum amyloid A and hap- 2009;165:289–290.
toglobin concentrations are increased in plasma of mares with 497. Fox-Clipsham LY, Brown EE, Carter SD, et al. Population
ascending placentitis in the absence of changes in peripheral screening of endangered horse breeds for the foal immunodefi-
leukocyte counts or fibrinogen concentration. Am J Reprod Im- ciency syndrome mutation. Vet Rec. 2011;169:655.
munol. 2014;72:376–385. 498. Fox-Clipsham LY, Carter SD, Goodhead I, et al. Identification
476. Hooijberg EH, van den Hoven R, Tichy A, et al. Diagnostic and of a mutation associated with fatal Foal Immunodeficiency Syn-
predictive capability of routine laboratory tests for the diagnosis drome in the Fell and Dales pony. PLoS genetics. 2011;7:e1002133.
and staging of equine inflammatory disease. J Vet Intern Med. 499. Butler CM, Westermann CM, Koeman JP, et al. The Fell pony
2014;28:1587–1593. immunodeficiency syndrome also occurs in the Netherlands: a
477. Leclere M, Lavoie-Lamoureux A, Lavoie JP. Acute phase pro- review and six cases. Tijdschr Diergeneeskd. 2006;131:114–118.
teins in racehorses with inflammatory airway disease. J Vet In- 500. Gardner RB, Hart KA, Stokol T, et al. Fell Pony syndrome in a
tern Med. 2015;29:940–945. pony in North America. J Vet Intern Med. 2006;20:198–203.
478. Passamonti F, Vardi DM, Stefanetti V, et al. Rhodococcus equi 501. Richards AJ, Kelly DF, Knottenbelt DC, et al. Anaemia, diar-
pneumonia in foals: an assessment of the early diagnostic value rhoea and opportunistic infections in Fell ponies. Equine Vet J.
of serum amyloid A and plasma fibrinogen concentrations in 2000;32:386–391.
equine clinical practice. Vet J. 2015;203:211–218. 502. Tallmadge RL, Stokol T, Gould-Earley MJ, et al. Fell Pony syn-
479. Pihl TH, Scheepers E, Sanz M, et al. Influence of disease drome: characterization of developmental hematopoiesis failure
process and duration on acute phase proteins in serum and associated gene expression profiles. Clin Vaccine Immunol.
and peritoneal fluid of horses with colic. J Vet Intern Med. 2012;19:1054–1064.
2015;29:651–658. 503. Thomas GW, Bell SC, Carter SD. Immunoglobulin and periph-
480. Zabrecky KA, Slovis NM, Constable PD, et al. Plasma C-reac- eral B-lymphocyte concentrations in Fell pony foal syndrome.
tive protein and haptoglobin concentrations in critically ill neo- Equine Vet J. 2005;37:48–52.
natal foals. J Vet Intern Med. 2015;29:673–677. 504. Thomas GW, Bell SC, Phythian C, et al. Aid to the antemortem
481. Reis KJ. A hemolytic assay for the measurement of equine com- diagnosis of Fell pony foal syndrome by the analysis of B lym-
plement. Vet Immunol Immunopathol. 1989;23:129–137. phocytes. Vet Rec. 2003;152:618–621.
482. Grondahl G, Johannisson A, Jensen-Waern M, et al. Opsoniza- 505. Bell SC, Savidge C, Taylor P, et al. An immunodeficiency in Fell
tion of yeast cells with equine iC3b, C3b, and IgG. Vet Immunol ponies: a preliminary study into cellular responses. Equine Vet J.
Immunopathol. 2001;80:209–223. 2001;33:687–692.
483. McGuire TC, Poppie MJ. Hypogammaglobulinemia and thymic 506. Carter SD, Fox-Clipsham LY, Christley R, et al. Foal immuno-
hypoplasia in horses: a primary combined immunodeficiency deficiency syndrome: carrier testing has markedly reduced dis-
disorder. Infect Immun. 1973;8:272–277. ease incidence. Vet Rec. 2013;172:398.
484. Perryman LE. Molecular pathology of severe combined immu- 507. Pellegrini-Masini A, Bentz AI, Johns IC, et al. Common vari-
nodeficiency in mice, horses, and dogs. Veterinary pathology. able immunodeficiency in three horses with presumptive bacte-
2004;41:95–100. rial meningitis. J Am Vet Med Assoc. 2005;227:114–122. 187.
485. Perryman LE, Torbeck RL. Combined immunodeficiency of 508. Flaminio MJ, LaCombe V, Kohn CW, et al. Common vari-
Arabian horses: confirmation of autosomal recessive mode of able immunodeficiency in a horse. J Am Vet Med Assoc.
inheritance. J Am Vet Med Assoc. 1980;176:1250–1251. 2002;221:1296–1302.
486. Wiler R, Leber R, Moore BB, et al. Equine severe combined im- 509. Flaminio MJ, Tallmadge RL, Salles-Gomes CO, et al. Common
munodeficiency: a defect in V(D)J recombination and DNA- variable immunodeficiency in horses is characterized by B cell
dependent protein kinase activity. In: Proceedings of the Na- depletion in primary and secondary lymphoid tissues. J Clin Im-
tional Academy of Sciences of the United States of America. ;92. ; munol. 2009;29:107–116.
1995:11485–11489. 510. Tallmadge RL, Shen L, Tseng CT, et al. Bone marrow transcrip-
487. Poppie MJ, McGuire TC. Combined immunodeficiency in foals tome and epigenome profiles of equine common variable im-
of Arabian breeding: evaluation of mode of inheritance and es- munodeficiency patients unveil block of B lymphocyte differen-
timation of prevalence of affected foals and carrier mares and tiation. Clin Immunol. 2015;160:261–276.
stallions. J Am Vet Med Assoc. 1977;170:31–33. 511. Tallmadge RL, Such KA, Miller KC, et al. Expression of essential
488. Bernoco D, Bailey E. Frequency of the SCID gene among Ara- B cell development genes in horses with common variable im-
bian horses in the USA. Anim Genet. 1998;29:41–42. munodeficiency. Mol Immunol. 2012;51:169–176.
489. Ding Q, Bramble L, Yuzbasiyan-Gurkan V, et al. DNA-PKcs 512. Perryman LE, McGuire TC, Hilbert BJ. Selective immunoglobu-
mutations in dogs and horses: allele frequency and association lin M deficiency in foals. J Am Vet Med Assoc. 1977;170:212–215.
with neoplasia. Gene. 2002;283:263–269. 513. Weldon AD, Zhang C, Antczak DF, et al. Selective IgM defi-
490. Perryman LE, McGuire TC, Crawford TB. Maintenance of foals ciency and abnormal B-cell response in a foal. J Am Vet Med
with combined immunodeficiency: causes and control of sec- Assoc. 1992;201:1396–1398.
ondary infections. Am J Vet Res. 1978;39:1043–1047. 514. Perryman LE, McGuire TC. Evaluation for immune system failures
491. Bjorneby JM, Leach DR, Perryman LE. Persistent cryptosporid- in horses and ponies. J Am Vet Med Assoc. 1980;176:1374–1377.
iosis in horses with severe combined immunodeficiency. Infect 515. Louis AG, Gupta S. Primary selective IgM deficiency: an ignored
Immun. 1991;59:3823–3826. immunodeficiency. Clin Rev Allergy Immunol. 2014;46:104–111.
492. Bue CM, Davis WC, Magnuson NS, et al. Correction of equine 516. Perkins GA, Nydam DV, Flaminio MJ, et al. Serum IgM con-
severe combined immunodeficiency by bone marrow trans- centrations in normal, fit horses and horses with lymphoma or
plantation. Transplantation. 1986;42:14–19. other medical conditions. J Vet Intern Med. 2003;17:337–342.
493. Perryman LE, Bue CM, Magnuson NS, et al. Immunologic re- 517. Boy MG, Zhang C, Antczak DF, et al. Unusual selective im-
constitution of foals with combined immunodeficiency. Vet Im- munoglobulin deficiency in an arabian foal. J Vet Intern Med.
munol Immunopathol. 1987;17:495–508. 1992;6:201–205.
518. McGuire TC, Poppie MJ, Banks KL. Hypogammaglobuline- 542. Korosue K, Murase H, Sato F, et al. Correlation of serum IgG
mia predisposing to infection in foals. J Am Vet Med Assoc. concentration in foals and refractometry index of the dam’s
1975;166:71–75. pre- and post-parturient colostrums: an assessment for failure
519. Deem DA, Traver DS, Thacker HL, et al. Agammaglobulinae- of passive transfer in foals. J Vet Med Sci. 2012;74:1387–1395.
mia in a horse. J Am Vet Med Assoc. 1979;175:469–472. 543. Hines MT, Schott 2nd HC, Bayly WM, et al. Exercise and im-
520. Banks KL, McGuire TC, Jerrells R. Absence of B lymphocytes munity: a review with emphasis on the horse. J Vet Intern Med.
in a horse with primary agammaglobulinaemia. Clin Immunol 1996;10:280–289.
Immunopathol. 1976;5:282–290. 544. Horohov DW, Dimock A, Guirnalda P, et al. Effect of exercise
521. Vetrie D, Vorechovsky I, Sideras P, et al. The gene involved in on the immune response of young and old horses. Am J Vet Res.
X-linked agammaglobulinaemia is a member of the src family 1999;60:643–647.
of protein-tyrosine kinases. Nature. 1993;361:226–233. 545. Horohov DW, Keadle TL, Pourciau SS, et al. Mechanism of
522. McGuire TC, Crawford TB, Hallowell AL, et al. Failure of co- exercise-induced augmentation of lymphokine activated killer
lostral immunoglobulin transfer as an explanation for most (LAK) cell activity in the horse. Vet Immunol Immunopathol.
infections and deaths of neonatal foals. J Am Vet Med Assoc. 1996;53:221–233.
1977;170:1302–1304. 546. Nesse LL, Johansen GI, Blom AK. Effects of racing on lympho-
523. Koterba AM, Brewer BD, Tarplee FA. Clinical and clinico- cyte proliferation in horses. Am J Vet Res. 2002;63:528–530.
pathological characteristics of the septicaemic neonatal foal: 547. Raidal SL, Rose RJ, Love DN. Effects of training on resting pe-
review of 38 cases. Equine Vet J. 1984;16:376–382. ripheral blood and BAL-derived leucocyte function in horses.
524. Rouse BT, Ingram DG. The total protein and immuno- Equine Vet J. 2001;33:238–243.
globulin profile of equine colostrum and milk. Immunology. 548. Wong CW, Smith SE, Thong YH, et al. Effects of exercise
1970;19:901–907. stress on various immune functions in horses. Am J Vet Res.
525. Roopenian DC, Akilesh S. FcRn: the neonatal Fc receptor comes 1992;53:1414–1417.
of age. Nat Rev Immunol. 2007;7:715–725. 549. Wong CW, Thompson HL, Thong YH, et al. Effect of strenuous
526. Cervenak J, Kacskovics I. The neonatal Fc receptor plays a cru- exercise stress on chemiluminescence response of equine alveo-
cial role in the metabolism of IgG in livestock animals. Vet Im- lar macrophages. Equine Vet J. 1990;22:33–35.
munol Immunopathol. 2009;128:171–177. 550. Robson PJ, Alston TD, Myburgh KH. Prolonged suppression
527. Kacskovics I. Fc receptors in livestock species. Vet Immunol Im- of the innate immune system in the horse following an 80 km
munopathol. 2004;102:351–362. endurance race. Equine Vet J. 2003;35:133–137.
528. Mayer B, Doleschall M, Bender B, et al. Expression of the neo- 551. Liburt NR, Adams AA, Betancourt A, et al. Exercise-induced
natal Fc receptor (FcRn) in the bovine mammary gland. J Dairy increases in inflammatory cytokines in muscle and blood of
Res. 2005;72:107–112. Spec No. horses. Equine Vet J Suppl. 2010:280–288.
529. Jeffcott LB. Duration of permeability of the intestine to macro- 552. Donovan DC, Jackson CA, Colahan PT, et al. Assessment of
molecules in the newly-born foal. Vet Rec. 1971;88:340–341. exercise-induced alterations in neutrophil function in horses.
530. Jeffcott LB. Passive immunity and its transfer with special refer- Am J Vet Res. 2007;68:1198–1204.
ence to the horse. Biol Rev Camb Philos Soc. 1972;47:439–464. 553. Folsom RW, Littlefield-Chabaud MA, French DD, et al. Exercise
531. Perkins GA, Goodman LB, Wimer C, et al. Maternal T-lym- alters the immune response to equine influenza virus and in-
phocytes in equine colostrum express a primarily inflammatory creases susceptibility to infection. Equine Vet J. 2001;33:664–669.
phenotype. Vet Immunol Immunopathol. 2014;161:141–150. 554. Gross DK, Hinchcliff KW, French PS, et al. Effect of moderate
532. Morris DD, Meirs DA, Merryman GS. Passive transfer failure in exercise on the severity of clinical signs associated with influ-
horses: incidence and causative factors on a breeding farm. Am enza virus infection in horses. Equine Vet J. 1998;30:489–497.
J Vet Res. 1985;46:2294–2299. 555. Horohov DW. Is exercise bad for the immune system? Equine
533. McClure JT, DeLuca JL, Miller J. Comparison of five screen- Vet J. 2003;35:113–116.
ing tests for detection of failure of passive transfer in foals. J 556. Hoffman AM, Viel L, Prescott JF. Microbiologic changes during
Vet Intern Med: ACVIM 20th Annual Veterinary Medical Forum antimicrobial treatment and rate of relapse of distal respiratory
Abstract Program. 2002;16:336. tract infections in foals. Am J Vet Res. 1993;54:1608–1614.
534. LeBlanc MM, Tran T, Baldwin JL, et al. Factors that influence 557. Hansen S, Baptiste KE, Fjeldborg J, et al. A review of the equine
passive transfer of immunoglobulins in foals. J Am Vet Med As- age-related changes in the immune system: comparisons be-
soc. 1992;200:179–183. tween human and equine aging, with focus on lung-specific
535. Le Jan C. Cellular components of mammary secretions and immune-aging. Ageing Res Rev. 2015;20:11–23.
neonatal immunity: a review. Vet Res. 1996;27:403–417. 558. Horohov DW, Adams AA, Chambers TM. Immunosenescence
536. Xu RJ. Development of the newborn GI tract and its relation to co- of the equine immune system. J Comp Pathol. 2010;142(suppl
lostrum/milk intake: a review. Reprod Fertil Dev. 1996;8:35–48. 1):S78–S84.
537. Pearson RC, Hallowell AL, Bayly WM, et al. Times of appear- 559. Boraschi D, Italiani P. Immunosenescence and vaccine failure
ance and disappearance of colostral IgG in the mare. Am J Vet in the elderly: strategies for improving response. Immunol Lett.
Res. 1984;45:186–190. 2014;162:346–353.
538. Townsend HG, Tabel H, Bristol FM. Induction of parturition in 560. Fulop T, Le Page A, Fortin C, et al. Cellular signaling in the ag-
mares: effect on passive transfer of immunity to foals. J Am Vet ing immune system. Curr Opin Immunol. 2014;29:105–111.
Med Assoc. 1983;182:255–257. 561. Horohov DW, Kydd JH, Hannant D. The effect of aging on
539. Lavoie JP, Spensley MS, Smith BP, et al. Colostral volume and T cell responses in the horse. Dev Comp Immunol. 2002;26:
immunoglobulin G and M determinations in mares. Am J Vet 121–128.
Res. 1989;50:466–470. 562. McFarlane D, Sellon DC, Gibbs SA. Age-related quantitative al-
540. Knottenbelt D, Holdstock N, Madigan J. Equine Neonatology terations in lymphocyte subsets and immunoglobulin isotypes
Medicine and Surgery. Philadelphia, PA: Elsevier Saunders; 2004. in healthy horses. Am J Vet Res. 2001;62:1413–1417.
541. Rumbaugh GE, Ardans AA, Ginno D, et al. Measurement of 563. Adams AA, Breathnach CC, Katepalli MP, et al. Advanced age
neonatal equine immunoglobulins for assessment of colos- in horses affects divisional history of T cells and inflammatory
tral immunoglobulin transfer: comparison of single radial cytokine production. Mech Ageing Dev. 2008;129:656–664.
immunodiffusion with the zinc sulfate turbidity test, serum 564. Adams AA, Katepalli MP, Kohler K, et al. Effect of body
electrophoresis, refractometry for total serum protein, and condition, body weight and adiposity on inflammatory cy-
the sodium sulfite precipitation test. J Am Vet Med Assoc. tokine responses in old horses. Vet Immunol Immunopathol.
1978;172:321–325. 2009;127:286–294.
565. Hansen S, Sun L, Baptiste KE, et al. Age-related changes in in- 584. Newman MJ, Issel CJ, Truax RE, et al. Transient suppression
tracellular expression of IFN-gamma and TNF-alpha in equine of equine immune responses by equine infectious anemia virus
lymphocytes measured in bronchoalveolar lavage and periph- (EIAV). Virology. 1991;184:55–66.
eral blood. Dev Comp Immunol. 2013;39:228–233. 585. Murakami K, Sentsui H, Shibahara T, et al. Reduction of CD4+
566. Hansen S, Baptiste KE, Fjeldborg J, et al. A comparison of pro- and CD8+ T lymphocytes during febrile periods in horses ex-
inflammatory cytokine mRNA expression in equine bronchoal- perimentally infected with equine infectious anemia virus. Vet
veolar lavage (BAL) and peripheral blood. Vet Immunol Immu- Immunol Immunopathol. 1999;67:131–140.
nopathol. 2014;158:238–243. 586. McClure JJ, Addison JD, Miller RI. Immunodeficiency mani-
567. Franzke B, Neubauer O, Wagner KH. Super DNAging-New in- fested by oral candidiasis and bacterial septicemia in foals. J Am
sights into DNA integrity, genome stability and telomeres in the Vet Med Assoc. 1985;186:1195–1197.
oldest old. Mutat Res Rev Mutat Res. 2015;766:48–57. 587. Freestone JF, Hietala S, Moulton J, et al. Acquired immuno-
568. Katepalli MP, Adams AA, Lear TL, et al. The effect of age and deficiency in a seven-year-old horse. J Am Vet Med Assoc.
telomere length on immune function in the horse. Dev Comp 1987;190:689–691.
Immunol. 2008;32:1409–1415. 588. Wilckens T, De Rijk R. Glucocorticoids and immune function:
569. Muirhead TL, McClure JT, Wichtel JJ, et al. The effect of age on unknown dimensions and new frontiers. [Review] [74 refs]. Im-
serum antibody titers after rabies and influenza vaccination in munol Today. 1997;18:418–424.
healthy horses. J Vet Intern Med. 2008;22:654–661. 589. Blotta MH, DeKruyff RH, Umetsu DT. Corticosteroids inhibit
570. Adams AA, Sturgill TL, Breathnach CC, et al. Humoral IL-12 production in human monocytes and enhance their ca-
and cell-mediated immune responses of old horses fol- pacity to induce IL-4 synthesis in CD4+ lymphocytes. J Immu-
lowing recombinant canarypox virus vaccination and sub- nol. 1997;158:5589–5595.
sequent challenge infection. Vet Immunol Immunopathol. 590. Franchimont D, Louis E, Dewe W, et al. Effects of dexametha-
2011;139:128–140. sone on the profile of cytokine secretion in human whole blood
571. Perryman LE, Wyatt CR, Magnuson NS. Biochemical and cell cultures. Regul Pept. 1998;73:59–65.
functional characterization of lymphocytes from a horse with 591. Morris DD, Strzemienski PJ, Gaulin G, et al. The effects of
lymphosarcoma and IgM deficiency. Comp Immunol Microbiol corticosteroid administration on the migration, phagocytosis
Infect Dis. 1984;7:53–62. and bactericidal capacity of equine neutrophils. Cornell Vet.
572. Furr MO, Crisman MV, Robertson J, et al. Immunodeficiency 1988;78:243–252.
associated with lymphosarcoma in a horse. J Am Vet Med Assoc. 592. Burton JL, Kehrli Jr ME, Kapil S, et al. Regulation of L-selec-
1992;201:307–309. tin and CD18 on bovine neutrophils by glucocorticoids: ef-
573. Dopson LC, Reed SM, Roth JA, et al. Immunosuppression asso- fects of cortisol and dexamethasone. J Leukoc Biol. 1995;57:
ciated with lymphosarcoma in two horses. J Am Vet Med Assoc. 317–325.
1983;182:1239–1241. 593. Filippe M. Immunosupressive therapy. In: Filippe M, ed.
574. Buechner-Maxwell V, Zhang C, Robertson J, et al. Intravascu- Equine Clinical Immunology. Oxford, UK: John Wiley & Sons,
lar leukostasis and systemic aspergillosis in a horse with sub- Inc.; 2016.
leukemic acute myelomonocytic leukemia. J Vet Intern Med. 594. Gibson JS, Slater JD, Awan AR, et al. Pathogenesis of
1994;8:258–263. equine herpesvirus-1 in specific pathogen-free foals: pri-
575. Tumas DB, Hines MT, Perryman LE, et al. Corticosteroid im- mary and secondary infections and reactivation. Arch Virol.
munosuppression and monoclonal antibody-mediated CD5+ T 1992;123:351–366.
lymphocyte depletion in normal and equine infectious anaemia 595. Bathe AP. The corticosteroid laminitis story: 3. The clinician’s
virus-carrier horses. J Gen Virol. 1994;75(Pt 5):959–968. viewpoint. Equine Vet J. 2007;39:12–13.
576. Kono Y, Hirasawa K, Fukunaga Y, et al. Recrudescence of 596. Bailey SR, Elliott J. The corticosteroid laminitis story: 2. Science
equine infectious anemia by treatment with immunosuppres- of if, when and how. Equine Vet J. 2007;39:7–11.
sive drugs. Natl Inst Anim Health Q (Tokyo). 1976;16:8–15. 597. Dutton H. The corticosteroid laminitis story: 1. Duty of care.
577. Craigo JK, Leroux C, Howe L, et al. Transient immune suppres- Equine Vet J. 2007;39:5–6.
sion of inapparent carriers infected with a principal neutralizing 598. Johnson PJ, Slight SH, Ganjam VK, et al. Glucocorticoids
domain-deficient equine infectious anaemia virus induces neu- and laminitis in the horse. Vet Clin North Am Equine Pract.
tralizing antibodies and lowers steady-state virus replication. J 2002;18:219–236.
Gen Virol. 2002;83:1353–1359. 599. Saulez MN, Schlipf Jr JW, Cebra CK, et al. Use of chemo-
578. Gibson JS, Slater JD, Field HJ. The pathogenicity of Ab4p, the therapy for treatment of a mixed-cell thoracic lympho-
sequenced strain of equine herpesvirus-1, in specific pathogen- ma in a horse. J Am Vet Med Assoc. 2004;224:733–738.
free foals. Virology. 1992;189:317–319. 699.
579. Mair TS. Bacterial pneumonia associated with corticosteroid 600. Messer NTt, Arnold K. Immune-mediated hemolytic anemia in
therapy in three horses. Vet Rec. 1996;138:205–207. a horse. J Am Vet Med Assoc. 1991;198:1415–1416.
580. DeKruyff RH, Fang Y, Umetsu DT. Corticosteroids enhance the 601. Humber KA, Beech J, Cudd TA, et al. Azathioprine for treat-
capacity of macrophages to induce Th2 cytokine synthesis in ment of immune-mediated thrombocytopenia in two horses.
CD4+ lymphocytes by inhibiting IL-12 production. J Immunol. J Am Vet Med Assoc. 1991;199:591–594.
1998;160:2231–2237. 602. McGurrin MK, Arroyo LG, Bienzle D. Flow cytometric detec-
581. Ramierz F, Fowell DJ, Puklavec M, et al. Glucocorticoids pro- tion of platelet-bound antibody in three horses with immune-
mote a TH2 cytokine response by CD4+ T cells in vitro. J Im- mediated thrombocytopenia. J Am Vet Med Assoc. 2004;224:
munol. 1996;156:2406–2412. 83–87. 53.
582. Allen GP, Kydd JH, Slater JD, et al. Advances in understanding 603. Gratzek AT, Kaswan RL, Martin CL, et al. Ophthalmic cyclo-
of the pathogenesis, epidemiology, and immunological control of sporine in equine keratitis and keratouveitis: 11 cases. Equine
equid herpesvirus) abortion. In: Wernery U, Wade JF, Mumford Vet J. 1995;27:327–333.
JA, Kaaden O-R, eds. Equine infectious diseases VIII. Proceedings 604. Gilger BC, Wilkie DA, Davidson MG, et al. Use of an in-
of the Eighth International Conference. Dubai: 23rd-26th March, travitreal sustained-release cyclosporine delivery device for
1998, 1 ed. Newmarket: R & W Publications; 1999:129–146. treatment of equine recurrent uveitis. Am J Vet Res. 2001;62:
583. Bryans JT, Allen GP. Herpesviral diseases of the horse. In: Witt- 1892–1896.
mann G, ed. Herpesvirus diseases of cattle, horses, and pigs. Bos- 605. Gilger BC, Michau TM, Salmon JH. Immune-mediated keratitis in
ton: Kluwer Academic Publishers; 1989:176–229. horses: 19 cases (1998–2004). Vet Ophthalmol. 2005;8:233–239.
606. Gilger BC, Malok E, Stewart T, et al. Effect of an intravitreal 627. Ziebell KL, Steinmann H, Kretzdorn D, et al. The use of Baypa-
cyclosporine implant on experimental uveitis in horses. Vet Im- mun N in crowding associated infectious respiratory disease: ef-
munol Immunopathol. 2000;76:239–255. ficacy of Baypamun N (freeze dried product) in 4-10 month old
607. Gilger BC, Wilkie DA, Clode AB, et al. Long-term outcome after horses. Zentralbl Veterinarmedizin Reihe B J Vet Med Series B.
implantation of a suprachoroidal cyclosporine drug delivery device 1997;44:529–536.
in horses with recurrent uveitis. Vet Ophthalmol. 2010;13:294–300. 628. Adams AA, Horohov DW. The effect of an immunomodula-
608. Moore BR. Clinical application of interferons in large animal tor (parapoxvirus ovis) on cell-mediated immunity (CMI)
medicine. J Am Vet Med Assoc. 1996;208:1711–1715. in abruptly weaned foals. Vet Immunol Immunopathol.
609. Rush BR, Flaminio MJ. Immunomodulation in horses. Vet Clin 2013;153:118–122.
North Am Equine Pract. 2000;16:183–197. viii. 629. Lunn DP, Rush BR. Immunomodulation: Principles and
610. Davis E. Immunomodulators. In: Filippe M, ed. Equine Clinical Mechanisms. In: Proceeding of the 50th Annual Convention of
Immunology. Oxford, UK: John Wiley & Sons, Inc.; 2016. the American Association of Equine Practitioners. Denver: Colo-
611. Moore BR, Krakowka S, Robertson JT, et al. Cytologic evalu- rado; 2004:447–453.
ation of bronchoalveolar lavage fluid obtained from Standard- 630. Ons E, Van Brussel L, Lane S, et al. Efficacy of a Parapoxvirus
bred racehorses with inflammatory airway disease. Am J Vet ovis-based immunomodulator against equine herpesvirus type
Res. 1995;56:562–567. 1 and Streptococcus equi equi infections in horses. Vet Microbiol.
612. Moore BR, Krakowka S, Cummins JM, et al. Changes in airway 2014;173:232–240.
inflammatory cell populations in standardbred racehorses after 631. Horohov DW, Breathnach CC, Sturgill TL, et al. In vitro and
interferon-alpha administration. Vet Immunol Immunopathol. in vivo modulation of the equine immune response by parapox-
1996;49:347–358. virus ovis. Equine Vet J. 2008;40:468–472.
613. Moore BR, Krakowka S, McVey DS, et al. Inflammatory mark- 632. Sturgill TL, Giguere S, Franklin RP, et al. Effects of inactivated
ers in bronchoalveolar lavage fluid of standardbred racehorses parapoxvirus ovis on the cumulative incidence of pneumonia
with inflammatory airway disease: response to interferon-al- and cytokine secretion in foals on a farm with endemic infec-
pha. Equine Vet J. 1997;29:142–147. tions caused by Rhodococcus equi. Vet Immunol Immunopathol.
614. Moore I, Horney B, Day K, et al. Treatment of inflammatory 2011;140:237–243.
airway disease in young Standardbreds with interferon alpha. 633. Studer U, Marti E, Stornetta D, et al. [The therapy of equine sar-
Can Vet J. 2004;45:594–601. coid with a non-specific immunostimulator—the epidemiology
615. Zinkl JG, Madigan JE, Fridmann DM, et al. Haematological, and spontaneous regression of sarcoids]. Schweizer Archiv fur
bone marrow and clinical chemical changes in neonatal foals Tierheilkunde|Sat. Schweiz Arch Tierheilkd. 1997;139:385–391.
given canine recombinant granulocyte-colony stimulating fac- 634. Hacker G, Redecke V, Hacker H. Activation of the immune sys-
tor. Equine Vet J. 1994;26:313–318. tem by bacterial CpG-DNA. Immunology. 2002;105:245–251.
616. Madigan JE, Zinkl JG, Fridmann DM, et al. Preliminary studies 635. Rankin R, Pontarollo R, Ioannou X, et al. CpG motif identifica-
of recombinant bovine granulocyte-colony stimulating factor tion for veterinary and laboratory species demonstrates that se-
on haematological values in normal neonatal foals. Equine Vet J. quence recognition is highly conserved. Antisense Nucleic Acid
1994;26:159–161. Drug Dev. 2001;11:333–340.
617. Wong DM, Alcott CJ, Clark SK, et al. Alloimmune neonatal neu- 636. Sato Y, Roman M, Tighe H, et al. Immunostimulatory DNA se-
tropenia and neonatal isoerythrolysis in a Thoroughbred colt. quences necessary for effective intradermal gene immunization.
J Vet Diagn Invest. 2012;24:219–226. Science. 1996;273:352–354.
618. Davis EG, Rush B, Bain F, et al. Neonatal neutropenia in an Ara- 637. Whitmore MM, Li S, Falo Jr L, et al. Systemic administration of
bian foal. Equine Vet J. 2003;35:517–520. LPD prepared with CpG oligonucleotides inhibits the growth
619. Rush BR, Lunn DP. Immunomodulation in horses: indications of established pulmonary metastases by stimulating innate and
and preparations. In: Proceeding of the 50th Annual Convention acquired antitumor immune responses. Cancer Immunol Immu-
of the American Association of Equine Practitioners. Denver: nother. 2001;50:503–514.
Colorado; 2004:454–458. 638. Lopez AM, Hecker R, Mutwiri G, et al. Formulation with CpG
620. Paillot R. A systematic review of the immune-modulators Para- ODN enhances antibody responses to an equine influenza virus
poxvirus ovis and Propionibacterium acnes for the prevention of vaccine. Vet Immunol Immunopathol. 2006;114:103–110.
respiratory disease and other infections in the horse. Vet Immu- 639. Bordin AI, Liu M, Nerren JR, et al. Neutrophil function of neo-
nol Immunopathol. 2013;153:1–9. natal foals is enhanced in vitro by CpG oligodeoxynucleotide
621. Audibert FM, Lise LD. Adjuvants: current status, clini- stimulation. Vet Immunol Immunopathol. 2012;145:290–297.
cal perspectives and future prospects. Trends Pharmacol Sci. 640. Liu M, Liu T, Bordin A, et al. Activation of foal neutrophils at
1993;14:174–178. different ages by CpG oligodeoxynucleotides and Rhodococcus
622. Fumuso E, Giguere S, Wade J, et al. Endometrial IL-1beta, IL-6 equi. Cytokine. 2009;48:280–289.
and TNF-alpha, mRNA expression in mares resistant or sus- 641. Cohen ND, Bourquin JR, Bordin AI, et al. Intramuscular ad-
ceptible to post-breeding endometritis. Effects of estrous cycle, ministration of a synthetic CpG-oligodeoxynucleotide modu-
artificial insemination and immunomodulation. Vet Immunol lates functional responses of neutrophils of neonatal foals. PloS
Immunopathol. 2003;96:31–41. one. 2014;9:e109865.
623. Bergvall KE. Sarcoids. Vet Clin North Am Equine Pract. 642. Babiuk LA, Misra V. Levamisole and bovine immunity: in vitro
2013;29:657–671. and in vivo effects on immune responses to herpesvirus immu-
624. Davis EG, Rush BR, Blecha F. Increases in cytokine and antimi- nization. Can J Microbiol. 1981;27:1312–1319.
crobial peptide gene expression in horses by immunomodula- 643. Roth JA, Kaeberle ML. Effect of levamisole on lymphocyte blas-
tion with Propionibacterium acnes. Vet Ther. 2003;4:5–11. togenesis and neutrophil function in dexamethasone-treated
625. Sturgill TL, Strong D, Rashid C, et al. Effect of Propionibacteri- cattle. Am J Vet Res. 1984;45:1781–1784.
um acnes-containing immunostimulant on interferon-gamma 644. Lunn DP, Townsend HGG. Equine vaccination. Vet Clin North
(IFNgamma) production in the neonatal foal. Vet Immunol Im- Am Equine Pract. 2000;16:199–226.
munopathol. 2011;141:124–127. 645. Bordin A, Cohen N. Types of vaccines. In: Filippe M, ed. Equine
626. Ryan C, Giguere S, Fultz L, et al. Effects of two commercially Clinical Immunology. Oxford, UK: John Wiley & Sons, Inc.; 2016.
available immunostimulants on leukocyte function of foals fol- 646. Cohen N, Bordin A. Principles of vaccination. In: Filippe M, ed.
lowing ex vivo exposure to Rhodococcus equi. Vet Immunol Im- Equine Clinical Immunology. Oxford, UK: John Wiley & Sons,
munopathol. 2010;138:198–205. Inc.; 2016.
647. Wilson W, Pusturla N, Long M. Immunoprophylaxis. In: Sellon 657. van der Meide NM, Savelkoul HF, Meulenbroeks C, et al. Evalu-
D, Long M, eds. Equine Infectious Diseases. 2nd ed. Philadel- ation of a diagnostic ELISA for insect bite hypersensitivity in
phia, PA: Saunders Elsevier; 2014. horses using recombinant Obsoletus complex allergens. Vet J.
648. Horohov DW, Dunham J, Liu C, et al. Characterization of the 2014;200:31–37.
in situ immunological responses to vaccine adjuvants. Vet Im- 658. Marti E, Wang X, Jambari NN, et al. Novel in vitro diagnosis of
munol Immunopathol. 2015;164:24–29. equine allergies using a protein array and mathematical model-
649. Savage CJ. Diseases of the liver. In: Moore J, ed. Equine Medicine ling approach: a proof of concept using insect bite hypersensi-
and Surgery. 5th ed. St. Louis: Mosby Inc; 1999:816–833. tivity. Vet Immunol Immunopathol. 2015;167:171–177.
650. Ramsay JD, Evanoff R, Wilkinson Jr TE, et al. Experimental 659. Stepnik CT, Outerbridge CA, White SD, et al. Equine atopic
transmission of equine hepacivirus in horses as a model for skin disease and response to allergen-specific immunothera-
hepatitis C virus. Hepatology (Baltimore, Md). 2015;61:1533– py: a retrospective study at the University of California–Davis
1546. (1991–2008). Vet Dermatol. 2012;23:29–35. e27.
651. Marti E, Horohov DW, Antzak DF, et al. Advances in equine 660. Jonsdottir S, Hamza E, Janda J, et al. Developing a preventive
immunology: Havemeyer workshop reports from Santa Fe, immunization approach against insect bite hypersensitivity us-
New Mexico, and Hortobagy, Hungary. Vet Immunol Immuno- ing recombinant allergens: A pilot study. Vet Immunol Immuno-
pathol. 2003;91:233–243. pathol. 2015;166:8–21.
652. Crameri R. Allergy vaccines: dreams and reality. Expert Rev 661. Jahn-Schmid B, Wiedermann U, Bohle B, et al. Oligodeoxy-
Vaccines. 2007;6:991–999. nucleotides containing CpG motifs modulate the allergic TH2
653. Jose-Cunilleras E, Kohn CW, Hillier A, et al. Intradermal test- response of BALB/c mice to Bet v 1, the major birch pollen al-
ing in healthy horses and horses with chronic obstructive pul- lergen. J Allergy Clin Immunol. 1999;104:1015–1023.
monary disease, recurrent urticaria, or allergic dermatitis. J Am 662. Goodman JS, Van Uden JH, Kobayashi H, et al. DNA immu-
Vet Med Assoc. 2001;219:1115–1121. notherapeutics: new potential treatment modalities for allergic
654. Barbet JL, Bevier D, Greiner EC. Specific immunotherapy in the disease. Int Arch Allergy Immunol. 1998;116:177–187.
treatment of Culicoides hypersensitive horses: a double-blind 663. Broide D, Schwarze J, Tighe H, et al. Immunostimulatory DNA
study. Equine Vet J. 1990;22:232–235. sequences inhibit IL-5, eosinophilic inflammation, and airway
655. Ginel PJ, Hernandez E, Lucena R, et al. Allergen-specific im- hyperresponsiveness in mice. J Immunol. 1998;161:7054–7062.
munotherapy in horses with insect bite hypersensitivity: a dou- 664. Klier J, Lehmann B, Fuchs S, et al. Nanoparticulate CpG immu-
ble-blind, randomized, placebo-controlled study. Vet Dermatol. notherapy in RAO-affected horses: phase I and IIa study. J Vet
2014;25. 29–e10. Intern Med. 2015;29:286–293.
656. Peeters LM, Janssens S, Goddeeris BM, et al. Evaluation of an 665. Behrens NE, Gershwin LJ. Immune modulation of T regula-
IgE ELISA with Culicoides spp. extracts and recombinant sali- tory cells and IgE responses in horses vaccinated with West
vary antigens for diagnosis of insect bite hypersensitivity in Nile virus vaccine combined with a CpG ODN. Vaccine.
Warmblood horses. Vet J. 2013;198:141–147. 2015;33:5764–5771.
C HA P T E R 2
Pharmacologic Principles
Jennifer L. Davis*
and assumed to represent drug concentrations in the target

Introduction to Clinical Pharmacology tissues. Most cells in the body are perfused with tissue fluids
or plasma, and drug concentrations usually reach equilibrium
between tissue fluids and the blood. Therefore for most drugs
pharmacologic action correlates well with the plasma drug
Drug administration in equine practice relies on selection of concentration.
a safe and efficacious dosage regimen based on the individual
horse’s physiology and the nature and formulation of the drug.
It is the veterinarian’s responsibility to ensure that the selected Y VARIATION BETWEEN DRUG
drug is efficacious with minimal toxicity or adverse reactions DOSE AND PLASMA DRUG
in the patient. Individual animals of various ages and species CONCENTRATION
vary widely in their handling of an administered drug. A basic
understanding of pharmacokinetics and the effects of patho- Drug dosages needed for a therapeutic effect differ widely
physiology on drug disposition in the horse enables the clini- among individuals. The “usual” dose has no effect in some
cian to optimize therapy while minimizing the risk of adverse individuals, causes serious toxicity in others, and produces
drug effects. an optimal effect in a few. The relationship between the dos-
age of a drug and its concentration in plasma is affected by
Y PHARMACOKINETICS its bioavailability, the animal’s body size and fluid compo-
sition, variability in drug distribution within the body, and
Pharmacokinetics describes the effect the body has on a drug, variability in rates of metabolism and excretion. These fac-
including drug absorption and distribution throughout the tors are all influenced by genetic differences in metabolism
body, along with metabolism and excretion from the body. and excretion, environmental factors, disease alterations in
Basic pharmacokinetic studies are usually performed in healthy system function, and concurrent administration of other
animals. Unfortunately, however, veterinarians do not often drugs. Therefore the plasma concentration of a drug is not
administer drugs to normal, healthy animals. Dosage regimens a perfect index of pharmacologic response. However, phar-
derived from studies in healthy animals may not be accurate for macologic response is more closely related to plasma drug
diseased animals. Clinical pharmacokinetics is the study of the concentration than to drug dose, and knowledge of plasma
effects of disease states or other variables (age, sex, pregnancy) drug concentration should always be used in combination
on the pharmacokinetics of drugs. Clinical pharmacokinetics with careful medical observation and judgment to determine
guides veterinarians in adjusting dosage regimens determined optimal therapy.
in healthy animals to optimize treatment of diseased animals.
Y DEFINITIONS IN
Y PLASMA DRUG CONCENTRATIONS PHARMACOKINETICS
AS THERAPEUTIC GUIDELINES
Pharmacokinetic information is used to determine drug dos-
Most pharmacokinetic information is derived from plasma age regimens in clinical patients. An understanding of the way
drug concentrations, even though pharmacologic action in which drug dosage regimens are derived and how they can
depends on drug concentration at a particular effector site, be adjusted for different disease states requires knowledge of
which is often a specific drug receptor. In reality, measuring some basic pharmacokinetic terms. Mathematical models pro-
drug concentrations at the drug receptor site is not practical. vide equations to describe drug concentration as a function of
Instead, plasma (or serum) drug concentrations are measured time. With an open model the drug is eliminated from the body.
An open model describes the fate of most drugs. With a closed
* The editors and authors acknowledge and appreciate the contributions of model the drug is recirculated within the body (e.g., a drug that
Patricia M. Dowling as a previous contributor to this chapter. Some of her undergoes enterohepatic recirculation). In pharmacokinetic
original work has been incorporated into this edition. models the body is represented by a series of compartments that
79
communicate reversibly with one another. A compartment is a tis- Zero order elimination
sue or group of tissues with similar blood flow and drug affinity. 100
A drug is assumed to be uniformly distributed within a compart-
ment and can move dynamically in and out of compartments. 80
Rate constants represent the entry and exit of drugs from each
Conc (g/mL)
compartment. The central compartment is made up of the highly 60
perfused tissues that equilibrate rapidly with the drug. Overall
drug elimination occurs mainly from the central compartment,
because the kidneys and liver are well-perfused tissues. The 40
peripheral compartment is made up of less perfused tissues such
as muscle and connective tissues. The deep compartment consists 20
of slowly perfused tissues or depot tissues such as fat and bone.
The presence of a deep compartment for drug distribution is 0
important for toxins and drug residues. Most drugs in clinical use 0 10 20 30 40 50
are described by one- or two-compartment models. Models with Time
more than three compartments are usually not physiologically
relevant. Describing drug disposition with compartment models FIG. 2.1 Drug concentration versus time for a zero order reaction pro-
creates differential equations that describe drug concentration duces a straight line on regular graph paper.
changes in each compartment and provides a visual representa-
tion of the rate processes among compartments.
1st order elimination
100
Y RATES AND ORDERS OF REACTIONS 90
80
The drug absorption or elimination rate is the speed with
70
which it occurs. If the amount of drug in the body is decreas- Conc (g/mL) 60
ing over time, the elimination rate is expressed as follows:
50
ΔC/Δt 40
The absorption and elimination rate of a drug is determined 30
experimentally by measuring the plasma drug concentration 20
at given time intervals. Rate constants relate the observed rate 10
of a kinetic process to the drug concentration that controls the 0
process. The elimination rate constant (K) is equal to the rate 0 50 100 150
of drug elimination divided by the amount of drug in the body. Time (min)
The absorption rate constant (Ka) describes the rate of drug
absorption into the central compartment. Reaction order refers
to the way that drug concentration influences reaction rate. 1st order elimination
With a zero order reaction the amount of drug changes at a 100
constant time interval, regardless of the drug concentration.
The rate of drug elimination is as follows:
ΔC/Δt = − K0
Conc (g/mL)
where K0 is the zero order rate constant in mg/mL/min. A 10

graph of drug concentration versus time on regular graph
paper for a zero order reaction produces a straight line (Fig.
2.1), described by the following equation:
C = −K0 t + C0
1
where C is the drug concentration at any time t, and C0 is 0 50 100 150
the drug concentration at time zero. For most drugs zero Time (min)
order elimination occurs only when elimination mechanisms
become saturated. Renal tubular secretion and bile secre- FIG. 2.2 Drug concentration versus time for a first order reaction
tion of drugs are examples of potentially saturable processes. produces an exponential curve on regular graph paper but produces a
In veterinary medicine, drugs with well-known zero order straight line on semilogarithmic graph paper.
elimination include phenylbutazone in horses and deracoxib
in dogs. Once elimination processes are saturated, increased
dosages of such drugs result in wildly unpredictable plasma where K is the first order rate constant, is expressed in units of
concentrations and easily result in toxicity. time−1 (min−1 or hr−1), and defines the fraction of drug elimi-
With a first order reaction, the amount of drug changes at nated from the body per unit time; C is the plasma drug con-
a rate proportional to the amount of drug remaining. The first centration at any time t. Although K remains constant, the rate
order elimination rate is expressed as follows: (>C/>t) is always changing because C is always decreasing. A
graph of drug concentration versus time for a first order reac-
ΔC/Δt = −KC tion produces an exponential curve on regular graph paper
CHAPTER 2 Pharmacologic Principles 81
100
Drug concentration (g/mL)

Central
compartment 10
1
0 50 100 150
Time (min)
FIG. 2.3 Graphic representation of a one-compartment open model with IV administration and first order
elimination.
10.00
Ka Central
compartment 1.00
K
0.10
0 5 10 15 20 25 30 35 40
Time (hr)
FIG. 2.4 Plasma concentration versus time graph after intramuscular administration of long-acting OTC to
a horse, demonstrating a one-compartment open model with first order absorption and elimination.
but produces a straight line on semilogarithmic graph paper a two-compartment open model with IV injection and first
(Fig. 2.2) and is described by the following equation: order elimination, the model assumes the body acts as two
compartments: the central compartment (blood and highly
C = C0 e−Kt vascularized tissues) and a peripheral compartment (less vas-
where C is drug concentration at any time t, K is the first order cularized tissues). Many drugs administered in veterinary
rate constant in minutes or hours, and C0 is the drug concen- medicine are described by this model (Fig. 2.5). Elimination
tration at time zero (the moment of injection). Most drugs are is considered to occur only from the central compartment,
absorbed and eliminated by first order processes. Glomerular because the liver and kidneys are highly vascularized tissues.
filtration by the kidney is a first order process. The plasma concentration versus time graph does not produce
a straight line on semilogarithmic paper but can be broken
into two sections and described by the following biexponen-
Y CLINICAL APPLICATION OF tial equation:
COMPARTMENTAL MODELING,
C = Ae−αt + Be−βt
RATES, AND ORDERS OF REACTIONS
where C is the concentration at any time t, A is the y-intercept
The aforementioned concepts can be combined to mathemati- of the first portion of the curve extrapolated to zero, and α is
cally describe the changes in the drug concentration in the body the slope of the line; B is the y-intercept of the latter portion
over time. Drug disposition described by a one-compartment of the curve extrapolated to zero, and β is its slope. The move-
open model with intravenous (IV) injection and first order ment of drug between the central and peripheral compart-
elimination (Fig. 2.3) means that the body acts as one homoge- ments is described by the rate constants K12 and K21.
neous compartment. A drug’s concentration in one part of the For some concentration versus time data, the line can be
body is assumed to be proportional to its concentration in any broken into three or more straight lines and described mathe-
other part. The movement of drug into and out of the central matically with three or more exponential terms. Theoretically,
compartment is described by the rate constants K01 and K10. drug distribution in the body can be described by as many
Many drugs administered by routes other than IV, such as oral compartments as there are different tissues, but for practical
(PO), subcutaneous (SC), intramuscular (IM), or intradermal, purposes more than three-compartment models are not nec-
are described by a one-compartment open model with first essary. Drugs that are described by three-compartment mod-
order absorption (Ka) and elimination (K) (Fig. 2.4). With els usually have some tissue site where the drug is sequestered
K12 Dose 10 mg
Central Peripheral
compartment compartment
K 21
K
1L 1L
100.00
10.00
B
Conc 10 mg/L Conc 5 mg/L

1.00
0 2 4 6 8 10 Vd 1 L Vd 2 L
Time (hr)
FIG. 2.7 The beaker on the left represents a low Vd drug that is mainly
FIG. 2.5 Plasma concentration versus time graph after IV administration distributed to the extracellular fluid. A sample from the fluid will contain
of gentamicin to a horse, demonstrating a two-compartment open model a high concentration of drug and therefore will have a low value for Vd.
with first order elimination from the central compartment. The equation The beaker on the right represents a high Vd drug that readily crosses
of the line is biexponential, where C = A e–αt + Be–βt. membranes and moves out of the extracellular fluid into tissues. A sam-
ple from the fluid will contain a low concentration of drug and therefore
will have a high value for Vd.
Vdc
distribution calculated by the area method. Conceptually, the

Concentration
easiest demonstration of the volume of distribution is with

Vdarea Tissue
the volume of the central compartment (Vdc). Just after an
IV dose, plasma drug concentration is maximal (Fig. 2.6).
Plasma Assuming that the instant drug concentration (C0) results
from the drug mixing in the blood, the Vdc is the apparent
volume from which drug elimination occurs since the kidneys
and liver belong to the central compartment, and is calculated
Time
from the following equation:
Pseudoequilibrium
Vdc = Dose/C0
FIG. 2.6 Graphical representation of the difference between the volume where C0 is the concentration at time zero, extrapolated from
of the central compartment and the volume of distribution by area.
the plasma concentration versus time graph. To understand
what the Vdc for a drug represents, consider the body as
and slowly eliminated from the body, such as the aminoglyco- a beaker filled with fluid (Fig. 2.7). The fluid represents the
sides, which sequester in the renal tubular epithelial cells, and plasma and other components of extracellular water. If a drug
oxytetracycline, which sequesters in teeth and bone. is administered intravenously, it rapidly distributes in the
extracellular fluid (ECF). If the drug does not readily cross
lipid membranes, it will be confined mainly to the ECF, and
Y DISTRIBUTION OF DRUGS IN a plasma sample therefore will have a high drug concentra-
THE BODY tion. The higher the measured concentration in relation to the
original dose, the lower the numeric value for Vdc. Drugs such
The volume of distribution (Vd) of a drug is the mathematical as the β-lactam and aminoglycoside antibiotics are poorly
term used to describe the apparent volume of the body in which lipid soluble and therefore remain predominantly in the ECF
a drug is dissolved.1 The Vd is the parameter used to assess the and have low values for Vd. In contrast, some drugs read-
amount of drug in the body from the measurement of a “snap- ily cross lipid membranes and distribute into tissues. This is
shot” plasma concentration. The numeric value of Vd can give represented by the beaker on the right, where the stars at the
some indication of the distribution of the drug in the body. A bottom of the beaker represent drug molecules that have been
drug’s distribution is determined by its ability to cross biologic taken up by tissues. A plasma sample will have a low drug
membranes and reach tissues outside the vascular system. The concentration in proportion to the original dose and therefore
physical characteristics of the drug molecule, such as ionization, will have a high numeric value for Vdc. Given the limitations
lipid solubility, molecular size, and degree of protein binding, on measuring drug concentrations at “time zero” and using
determine its ability to cross biologic membranes. the aforementioned formula, the measured concentration of
Three volumes of distribution (Vd) are reported in the highly lipid-soluble drugs can be low enough to result in a
veterinary literature: the volume of the central compartment, value of Vdc that is greater than 1 L/kg, so it is often referred
the steady-state volume of distribution, and the volume of to as an apparent volume of distribution. In the example on
BOX 2.1 Volume of Distribution (Vd) of Various Drugs

Tissue
LOW-VD DRUGS (<0.3 L/KG)
Penicillins
Concentration Vdss Cephalosporins
Aminoglycosides
Nonsteroidal antiinflammatory drugs
Plasma
MEDIUM-VD DRUGS (>0.3–<1 L/KG)
Phenobarbital
Sulfonamides
Time Prednisolone
Steady-state equilibrium Rifampin
FIG. 2.8 Graphical representation of the volume of distribution when HIGH-VD DRUGS (>1 L/KG)
plasma concentrations are measured at steady-state conditions. Macrolides
Tetracyclines
the right, the “apparent” Vd is 2 L/kg even though the beaker Fluoroquinolones
contains only 1 L of fluid. Chloramphenicol
For most drugs after a single IV dose, the drug is distributed Metronidazole
and begins to be eliminated simultaneously. When concentra- Trimethoprim
tions are measured and the data graphed, there is a distribu- Dexamethasone
tion phase, wherein the plasma drug concentration that is due Furosemide
to elimination and not distribution increases until it reaches an Ketamine
asymptotic value at which pseudoequilibrium is achieved (see Diazepam
Fig. 2.6). When pseudoequilibrium is reached, the movement of Firocoxib
drug between the peripheral and central compartments reaches
equilibrium, and decreasing plasma concentrations are now due
only to irreversible elimination (described by the elimination large fraction of the drug is eliminated before pseudoequi-
rate constant, β). The applicable Vd value in this situation is the librium is reached.
volume of distribution by area (Vdarea): It is useful to compare a drug’s Vd to the distribution of
Vdarea = Dose ÷ AUC0 − ∞ /β water in the body to get an idea of its distribution. Drugs with
a Vd value of less than 0.3 L/kg are predominantly confined to
where AUC0–∞ is the area under the plasma concentration time the ECF, whereas drugs with a Vd value of greater than 1 L/kg
curve extrapolated to infinity. To be calculated accurately, the are highly lipid soluble and tend to distribute out of the ECF
amount of drug that enters the systemic circulation must be and into tissue compartments (Box 2.1). Although the value of
accurately known, and the terminal phase must be a pure elimi- Vd does not confirm penetration of a drug into specific tissues,
nation phase. An inaccurate Vdarea is frequently published for in general the higher the value of the Vd, the more likely it is
“long-acting” IM- or SC-administered drugs, where prolonged that the drug will reach sequestered sites such as the brain and
elimination is due to delayed absorption (flip-flop kinetics). cerebrospinal fluid (CSF), the prostate and other sex organs,
With an IV infusion or with a multiple-dose regimen, the the eye, and the mammary gland. Studies must be performed
rate of drug entry into the body is equal to its elimination rate, to confirm that therapeutic concentrations are achieved in
and the body becomes a closed system with no clearance. In such sites.
this situation the correct Vd to describe distribution is the Vd
at steady-state (Vdss; Fig. 2.8): Conditions That Affect Volume of Distribution
The Vd is constant for any drug and will change only with
Vdss = Drug in body at steady state/Concentration in plasma
physiologic or pathologic conditions that change the distribu-
tion of the drug. Drugs with high Vd are usually very lipid
Clinical Use of the Different Volume of soluble and typically are not significantly affected by changes
in body water status and do not require dosage adjustment.
Distribution Values However, there are many medical conditions that affect the
The Vdc is used to predict the initial plasma drug concen- disposition of low Vd drugs in a patient (e.g., nonsteroidal
tration after an IV bolus of a drug when a loading dose is antiinflammatory drugs and aminoglycosides), and these
needed to rapidly achieve a therapeutic drug concentration. drugs do require dosage adjustment because of their narrow
The Vdss is used to calculate a loading dose when it is clini- therapeutic index. Many conditions in horses, such as colic,
cally necessary to rapidly reach steady-state concentrations. are characterized by volume contraction and dehydration and
The Vdarea is used to predict the amount of drug remaining changes in acid-base balance, which affect the ECF volume.
in the body. For all drugs the value of Vdarea is greater than Neonatal foals have a higher percentage of body water than
Vdss, but generally the difference is small and the values are adult horses (80% vs. 60% total body water), and the extra 20%
used interchangeably. However, with the IV administration is primarily confined to the ECF, so the Vd values of drugs
of drugs that are rapidly eliminated into urine (e.g., amino- such as gentamicin are higher in neonatal foals than older foals
glycosides), Vdarea can be much larger than Vdss because a or adult horses.2 Therefore to achieve equivalent therapeutic
plasma concentrations of gentamicin in a neonatal foal, the
dose must be higher than that administered to the older foal BOX 2.2 Drugs Classified by pH
or adult horse.
Bioavailability ACIDIC DRUGS
Penicillins
Bioavailability (F) is a measure of the systemic availability of
Cephalosporins
a drug administered by a route other than IV.3 Bioavailability
Sulfonamides
is determined by comparing the area under the plasma drug
Nonsteroidal antiinflammatory drugs
concentration curve versus time (AUC) for the extravascular
formulation to the AUC for the IV formulation. The AUC is BASIC DRUGS
calculated by computer or by the trapezoidal method, wherein
Macrolides
the entire curve is divided into trapezoids, then the area of
Trimethoprim
each trapezoid is calculated and summed to give the AUC. For
Chloramphenicol
an orally administered drug, use the following equation:
Metronidazole
F = (AUCoral ÷ AUCIV ) × 100 = % bioavailable Aminoglycosides
If F is significantly less than 100%, the drug dose must be AMPHOTERIC DRUGS
increased to achieve systemic drug concentrations similar to
Fluoroquinonolones
the IV formulation:
Tetracyclines
Adjusted dose = DoseIV /F
If the oral formulation of a drug has a mean bioavailability of
50%, the drug dose must be doubled to achieve the same concen- Whereas the precise ratios of ionized versus nonionized
trations in plasma as achieved using the IV formulation. How- drug can be calculated from the Henderson-Hasselbalch
ever, the variability of the bioavailability in the population is more equations, the relevance of the equations can be understood
clinically significant than the mean. To make sure that the horse by simply remembering the sentence “like is nonionized in
with the poorest absorption is dosed appropriately, the dose must like.” For example, a weak acid will be most nonionized in
be increased according to the lowest bioavailability, not the mean. an acidic environment, so aspirin is most nonionized in the
For example, if a drug has a mean F of 50% with a range of 20% stomach and is readily absorbed. The fluid of most seques-
to 70%, then to achieve an exposure of 100% for all the treated tered sites in the body (CSF, accessory sex gland fluid, milk,
horses, the dose must be multiplied by 5, not just 2. However, if abscesses) has a pH more acidic than plasma. In cattle with
this is done, the horses with an F of 70% will be overdosed by a mastitis weak acid antibiotics are typically administered by
factor of 3.5. For a drug with a narrow therapeutic window and intramammary infusion, whereas weak bases are admin-
a poor bioavailability, there may be no dose that is ideal for all istered parenterally. This makes sense according to the
horses in the population. Low bioavailability of antimicrobials pH-partition concept. Weak bases in the plasma are highly
and anthelmintics is a major cause of subtherapeutic dosages that nonionized and readily cross into the mammary gland. Then,
promote drug resistance. Poor oral bioavailability is a major limi- as the equilibrium shifts, they become “ion trapped” in the
tation of many drugs administered to horses.4 more acidic milk, but the fraction of nonionized drug in the
mammary gland is available to cross the bacterial cell mem-
Lipid Solubility and Drug Ionization (the brane for antimicrobial action. Weak acids such as penicil-
pH-Partition Hypothesis) lins and cephalosporins are highly ionized in plasma and
therefore do not penetrate into the mammary gland very
The degree of lipid solubility determines how readily a drug will well, so these are most effective when administered by local
cross biologic membranes. Drugs are classified as lipid soluble infusion into the udder, where the extremely high local con-
(or nonpolar) versus water soluble (or polar). Highly lipophilic centrations negate local pH effects.
drugs diffuse easily across almost all tissue membranes. Most Typically, drugs that are weak acids will have low Vd val-
of the drugs used in equine practice exist as weak acids or weak ues and weak bases will have high values for Vd (Box 2.2).
bases. Their lipid solubility depends a great deal on their degree Amphoteric drugs such as the fluoroquinolones and tet-
of ionization (charged state). An ionized drug is hydrophilic and racyclines have acidic and basic groups on their chemical
poorly lipid soluble. A nonionized drug is lipophilic and can cross structures. These drugs have a pH range where they are max-
biologic membranes. The degree of ionization for a weak acid or imally nonionized. For example, enrofloxacin is most lipid
weak base depends on the pKa of the drug and the pH of the sur- soluble (nonionized) in the pH range of 6 to 8, so it is lipid
rounding fluid. At a given pH, there is an equilibrium between soluble at most physiologic pH levels. In acidic urine signifi-
the ionized and nonionized proportions of drug. When the pH cant ionization occurs, which reduces enrofloxacin’s antibac-
is equal to the pKa of the drug, the drug will be 50% ionized and terial activity. But this reduction in activity is offset by the
50% nonionized (log 1 = 0). As the pH changes, the proportion of extremely high concentrations of enrofloxacin achieved in
ionized to nonionized drug will change according to the Hender- urine, so it is of no clinical importance. Despite being weak
son-Hasselbach equations: bases, the aminoglycosides are very large, hydrophilic mole-
For a weak acid: cules and have high pKa values, so they are highly ionized at
pH = pKa + log (Ionized drug/Nonionized drug) physiologic pH levels. Therefore parenterally administered
aminoglycosides do not cross lipid membranes well and do
For a weak base: not achieve therapeutic concentrations in milk, accessory
pH = pKa + log (Nonionized drug/Ionized drug) sex gland fluids, abscesses, or CSF.
Elimination Half-life true interaction is from phenylbutazone-induced inhibition of

100 the hepatic metabolism of warfarin, which results in increased
plasma concentrations and increased anticoagulant effect.7
Therefore adjustments in dosing regimens because of hypo-
Concentration (g/mL)
1 Hr proteinemia or concurrent administration of highly bound

10 drugs are not necessary except in the rare case of a drug with
a high hepatic extraction ratio and narrow therapeutic index
1 Hr that is given parenterally (e.g., IV dosing of lidocaine).9
1
Y DRUG ELIMINATION FROM THE BODY
Drug elimination refers to the irreversible removal of drug
from the body by all routes of elimination. Elimination may be
0.1
0 2 4 6 8 10 12 divided into two major components: excretion and biotrans-
Time (hr)
formation. Drug excretion is the removal of the intact drug.
Most drugs are excreted by the kidney into the urine. Other
pathways include the excretion of drug into bile, sweat, saliva,
FIG. 2.9 For a drug with first order elimination, the plasma concentra-
or milk. Biotransformation (drug metabolism) converts the
tion decreases by 50% every hour, so the elimination half-life is 1 hour.
drug in the body to a metabolite that is more readily excreted,
usually by adding a chemical group to the molecule to make
it more water soluble. Enzymes involved in biotransformation
Drug Protein Binding are mainly located in the liver. Other tissues, such as the kid-
Protein binding can involve plasma proteins, extracellular tis- ney, lung, small intestine, and skin, also contain biotransfor-
sue proteins, or intracellular tissue proteins. Many drugs in mation enzymes.
circulation are bound to plasma proteins, and because bound
drug is too large to pass through biologic membranes, only
free drug is available for delivery to the tissues and to produce Y ELIMINATION RATE CONSTANT AND
the desired pharmacologic action. Therefore the degree of pro- ELIMINATION HALF-LIFE
tein binding can greatly affect the pharmacokinetics of drugs.
Acidic drugs such as nonsteroidal antiinflammatory drugs The rate of elimination for most drugs is a first order process.
(NSAIDs) tend to bind predominantly to albumin.5 Albumin The elimination rate constant (K) represents the sum of drug
is the most abundant plasma protein, and it is critical to main- elimination by excretion and metabolism. Drug elimination
taining the colloidal oncotic pressure in the vascular system. is considered always to occur from the central compart-
As a negative acute phase protein, albumin concentration ment, because the liver and kidney are well-perfused tissues.
decreases during inflammation. Hypoalbuminemia results The elimination rate constant is used to calculate the drug’s
from decreased production, seen with severe hepatic insuf- half-life (T½), or the time required for drug concentration to
ficiency, or by loss through increased rates of urinary excre- decrease by one half (Fig. 2.9). For first order reactions, T½ is
tion, such as in glomerulonephritis or with mucosal damage, constant across the plasma concentration versus time curve
as with protein-losing enteropathies. Basic drugs typically and is calculated from
bind to α-1 acid glycoprotein, which is an acute phase pro- T1/ = 0.693/K
2
tein, whose hepatic production increases significantly with
inflammatory conditions.6 Other proteins, including cortico- where 0.693 = ln2 (the natural logarithm of 2). Mean resi-
steroid binding globulin, are important for binding of some dence time (MRT) is roughly the equivalent of T½ when
specific drugs but are less important in overall drug-protein pharmacokinetics is calculated using statistical moment
binding.7 There is equilibrium between free and bound drug, theory. The MRT is an estimate of the average time a drug
however, just like the relationship of ionized and nonionized molecule spends in the body, which typically correlates to
drug molecules. Protein binding is most clinically significant the time it takes for drug concentration to decrease by 63.2%.
for antimicrobial therapy, where a high degree of protein bind- Therefore the MRT value should be slightly greater than T½.
ing serves as a drug “depot,” allowing for increased duration of If the calculated value for MRT is not longer than the T½,
the time the drug concentration remains above the bacterial there was likely an inadequate number of samples in the dis-
minimum inhibitory concentration, adding to antimicrobial tribution or elimination phase of the study. Although these
efficacy.8 For other drugs changes in plasma protein binding parameters are similar, it is the T½ that is used to determine
can influence individual pharmacokinetic parameters, but the drug dosage interval, how long a toxic or pharmaco-
changes in plasma protein binding usually do not influence the logic effect will persist, and drug withdrawal times for food
clinical exposure of the patient to a drug. Changes in protein animals or performance horses. Notice that it takes 10 T½
binding caused by drug interactions are assumed to instan- to decrease the plasma concentration by 99.9% (Table 2.1).
taneously change free drug concentrations and have been Knowing a drug’s plasma T½ can give the clinician some idea
frequently cited as a cause of adverse drug reactions. But the of the drug’s withdrawal time for food or performance ani-
increase in free drug concentration is only transient, because mals. However, for drugs that undergo hepatic metabolism
drug distribution and drug elimination change to compensate. (e.g., phenylbutazone) or drugs that sequester in specific tis-
The often-cited example of the concurrent administration of sues (e.g., aminoglycosides, isoxsuprine), simply multiplying
phenylbutazone and warfarin leading to bleeding caused by the T½ by a factor of 10 for a withdrawal time may not be suf-
increased free concentrations of warfarin is erroneous. The ficient to prevent violative residues. Also note that doubling
TABLE 2.1 Half-Life of Elimination of a Drug Clearance

Clearance is a measure of drug elimination from the body
Number of Fraction of Drug Fraction of Drug without reference to the mechanism of elimination. It is
Half-Lives Remaining (%) Eliminated (%) always reported in pharmacokinetic papers, but its signifi-
0 100 0 cance is rarely explained in pharmacokinetic studies in horses.
1 50 50 Clearance is the most important pharmacokinetic parameter
2 25 75 because it is the only parameter that controls overall drug
exposure, and it is used to calculate the dosage required to
3 12.5 87.5
maintain a specific average steady-state concentration.10
4 6.25 93.75 Clearance (Cl) is the total drug clearance and is the sum
5 3.125 96.875 of renal clearance (ClR), hepatic clearance (ClH), and all other
6 1.56 98.44 elimination mechanisms. By definition, Cl is the volume of
7 0.78 99.22 fluid containing drug that is cleared of drug per unit of time
8 0.39 99.61
(mL/kg/min). The most frequent technique for determining
plasma Cl is to administer a single IV dose of a drug and then
9 0.195 99.805 measure plasma concentrations over time. Then,
10 0.0975 99.9025
Cl = Dose/AUC
100 where AUC is the area under the plasma concentration time
curve.
Concentration (ppm)
10 If the body is considered as the whole system clearing the

drug, Cl can also be determined by the animal’s cardiac out-
1
put and the extraction ratio (E), where E is a numeric value
between 0 and 1 that is the percentage of the drug that is
cleared by a single pass through the clearing organ:
0.1
Cl = Cardiac output × E
0.01
0 10 20 30 40
For a drug with an extraction ratio of 1 (100% removal by the
liver and kidney on the first pass), the expected value of Cl is about
Time (days after dosing)
50% of the cardiac output, because blood flow to the liver and the
kidneys represents approximately half of the cardiac output.
FIG. 2.10 Doubling a drug dose adds only one half-life to its withdrawal In contrast to Vd values, Cl values have to be interpreted
time. For this drug with an elimination half-life of 24 hours, if the dose is according to the value of cardiac output for the species
doubled to reach a plasma concentration of 20 μg/mL, it will take 21 days involved. Given that most drugs are extracted primarily by
instead of 20 days to reach an acceptable threshold of 0.01 μg/mL. renal and hepatic mechanisms, the extraction ratio is consid-
ered high if E is greater than 0.7, medium if E equals 0.3, and
a drug dose does not double the withdrawal time; it merely low if E is less than 0.1. Because the liver and kidneys receive
adds 1 half-life to the time it takes to reach the acceptable about 50% of cardiac output, the overall E is high if it is greater
threshold concentration (Fig. 2.10). than 0.35, medium if it is about 0.15, and low if it is less than
0.05. From this and the cardiac output of the species, break-
Flip-Flop Kinetics point values can be determined to classify drugs as having
Long-acting drug formulations are often products whose high, medium, and low clearance. For the horse with a cardiac
carriers cause them to be slowly absorbed from the site output of 55 mL/kg/min, a high Cl value is 19 mL/min/kg,
of administration into the systemic circulation. In these medium Cl is 8.25 mL/min/kg, and low Cl is 3.6 mL/min/kg.
instances, the drug elimination rate is limited by the drug It is sometimes difficult to understand the difference
absorption rate. The value for K (the elimination rate con- between the elimination half-life and clearance. The relation-
stant) calculated from the plasma concentration versus ship is as follows:
time curve is actually the value for Ka (the absorption rate
constant). The easiest way to identify flip-flop kinetics is to Cl = (Vd) (K) or
compare the plasma concentration versus time curve for the ( )
extravascular route of administration to the curve after the Cl = (Vd) 0.693/T1/
2
drug is given intravenously (Fig. 2.11). If the elimination
phases of the curves are not parallel, delayed absorption is Consider the values for clearance and T½ for four antimi-
prolonging elimination and the flip-flop phenomenon has crobial drugs (Table 2.2). Note that the plasma clearance val-
occurred. Flip-flop kinetics is also one potential reason for ues are similar, but the elimination half-lives are very different.
a reported bioavailability greater than 100%. Because the T½ is influenced by the extent of drug distribu-
For a two-compartment model, β (from the equation C = tion, the drugs have similar clearance, but oxytetracycline has
Ae−αt + Be−βt) is the drug elimination rate constant from the the largest Vd and the longest T½. Because T½ is derived from
entire body once the drug has reached equilibrium between rate constants and does not have a physiologic basis, it is influ-
the two compartments. Therefore β is used to calculate the enced by the sensitivity of the analytic method and by many
elimination half-life: pharmacokinetic parameters, and it is a poor parameter alone
to evaluate physiologic (e.g., age, sex) or pathologic (e.g., renal
T1/ = 0.693/β
2 failure) changes that effect drug disposition.
TABLE 2.2 Comparison of Clearance to Elimination Half-Life TABLE 2.3 Renal Clearance (mL/min/kg) at Different Urinary pHs
Penicillin Gentamicin Oxytetracycline Tylosin Urine pH
Cl (mL/ 3.5 3.1 4.0 2.2
pKa 4.4 6.4 7.9
min/kg)
Penicillin Acid 2.4 0.001 0.1 3.0
T½ (min) 30 75 360 54
Oxytetracycline Base 10.4 1000 10 0.3

100 I.V. 6.6 mg/kg

tubular secretion, and FR is the fraction of drug reabsorbed
I.M. 6.6 mg/kg
from the tubule back to circulation.
Glomerular filtration occurs with small molecules (less than
10 T2 6 hr 300 molecular weight) of free (unbound) drug. Large molecules

T2 22 hr or protein-bound drugs do not get filtered at the glomerulus
because of size and electrical hindrance. The kidneys receive
approximately 25% of cardiac output, so the major driving force
1 for glomerular filtration is the hydrostatic pressure within the glo-
merular capillaries. Glomerular filtration rate (GFR) is estimated
by measuring a substance or drug that is eliminated only by glo-
merular filtration, such as creatinine or inulin.
0
If ClR is greater than ClF, some degree of tubular secretion is
0 12 24 36
Time (hr) occurring. Active tubular secretion is a carrier-mediated transport
system, located in the proximal renal tubule. It requires energy
FIG. 2.11 Plasma concentration versus time graph for long-acting oxy- input because the drug is moved against a concentration gradient.
tetracycline in horses, demonstrating “flip-flop” kinetics. The delayed ab-
Two active tubular secretion systems have been identified: anion
sorption from the intramuscular injection results in the slow elimination
secretion for acids and cation secretion for bases. Drugs with sim-
and triples the elimination half-life value.
ilar structures may compete with each other for the same trans-
port system. For example, probenecid competes with penicillin
or the fluoroquinolones for the same transport system, effectively
decreasing ClR of these antimicrobials. In patients with reduced
functional renal tissue, remaining transport systems become eas-
Free drug enters ily saturated and drug accumulation occurs.
glomerular filtrate
If ClR is less than the GFR, tubular reabsorption of drug
is occurring. Tubular reabsorption is an active process for
endogenous compounds (e.g., vitamins, electrolytes, glucose).
It is a passive process for the majority of drugs. It occurs along
Active secretion Proximal the entire nephron but primarily in the distal renal tubule. Fac-
tubule tors that affect reabsorption include the pKa of the drug and
urine pH, which in turn influence drug ionization. According
Loop of Henle to the Henderson-Hasselbach equation, a drug that is a weak
base will be mainly nonionized in alkaline urine, and a weak
Passive reabsorption
Distal acid will be mainly ionized in alkaline urine. The nonionized
of nonionized drug
down a concentration
tubule form of the drug is more lipid soluble and has greater reab-
gradient sorption (Table 2.3). The pKa of a drug is constant, but urinary
Collecting duct pH is highly variable in animals and varies with the diet, drug
intake, time of day, and systemic acidosis/alkalosis. Species
differences have a major influence on the renal excretion of
Ionized, polar drug eliminated in urine ionized drugs. Carnivores, with a urine pH of 5.5 to 7.0, will
have a greater renal excretion of basic drugs than herbivores,
with a urine pH of 7.0 to 8.0, and vice versa. Additional factors
FIG. 2.12 Movement of drugs in the renal tubule.
affecting drug reabsorption include lipid solubility, drug size,
and urine flow.
Renal Clearance of Drugs Hepatic Clearance of Drugs
Renal excretion is the major route of elimination from the Nonrenal drug elimination is assumed to be due primarily to
body for most drugs. Drug disposition by the kidneys includes biotransformation (hepatic metabolism) and biliary excretion.
glomerular filtration, active tubular secretion, and tubular Clearance of a drug by the liver is determined by hepatic blood
reabsorption (Fig. 2.12), such that renal drug clearance is flow (QH) and the intrinsic ability of the liver to extract the
defined by the following equation: drug (extraction ratio, or ERH):
ClR = ClF + ClS − FR ClH = (QH ) (ERH )
where ClR is total renal clearance, ClF is clearance attributed Drugs with a high extraction ratio (approaching 1) have
to glomerular filtration, ClS is clearance attributed to active ClH equal to the hepatic blood flow. These drugs are called high
Some drugs
directly enter BOX 2.3 Drugs That Affect Enzyme Function
phase II
metabolism ENZYME INDUCERS
Oxidation, Chlorinated hydrocarbons
reduction Conjugation Griseofulvin
Drug Phase I Phase II products
and/or Omeprazole
hydrolysis Phenobarbital
Phenytoin
Following phase I, Rifampin
the drug may be Conjugated
activated or, most drug is usually ENZYME INHIBITORS
often, inactivated inactive
Chloramphenicol
Cimetidine
FIG. 2.13 Hepatic metabolism increases the water solubility of drugs, Dexamethasone
facilitating excretion from the body. Erythromycin
Fluoroquinolones
Ketoconazole
clearance drugs. Examples of drugs with high ERH are lido- Phenobarbital
caine, propranolol, and isoproterenol. Clearance of drugs with Phenylbutazone
high ERH is highly influenced by changes in hepatic blood Prednisolone
flow. Drugs that are administered orally and are absorbed Quinidine
across the intestinal mucosa must first pass through the liver
via the portal circulation before being distributed to the rest of
the body. Most of a drug with a high ERH will be cleared in one pigs are deficient in sulfate conjugation, and dogs are relatively
pass through the liver; this is called the first pass effect, and it poor acetylators. Compared with other species, the metaboliz-
limits the oral administration of such drugs (e.g., morphine). ing pathways of the horse are relatively unknown.
Drugs that have a low hepatic extraction rate (ERH ≤ 0.2) are
not greatly affected by changes in hepatic blood flow. How- Induction and Inhibition of Metabolism
ever, their clearance will be affected by changes in the hepatic Metabolism of drugs can be substantially affected by
microsomal enzyme systems and protein binding. A first pass enzyme induction or inhibition by other drugs or chemicals
effect does not interfere with the systemic availability of these (Box 2.3). In some cases the drug itself may alter its own
drugs. Drugs with a low ERH include chloramphenicol, phen- metabolic fate by induction or inhibition. Many drugs are
ylbutazone, phenobarbital, and digoxin. capable of inducing enzyme activity, thereby increasing the
rate of metabolism and hepatic clearance of concurrently
Biotransformation (Hepatic Metabolism) administered drugs, which typically results in a decreased
pharmacologic effect. Enzyme induction usually occurs
of Drugs slowly, requiring several weeks to reach maximum effect.
Metabolism is necessary for removal of lipophilic drugs from Induction is accompanied by increased hepatic ribonucleic
the body (Fig. 2.13). Biotransformation depends on the chemi- acid (RNA) and protein synthesis and increased hepatic
cal composition of the liver, activity of major drug metabolism weight. Enzyme induction is important in the pathogenesis
enzymes, hepatic volume (perfusion rate), drug accessibility to of hepatotoxicity and therapeutic failure of many drugs.
and extraction by hepatic metabolic sites, and physicochemi- Phenobarbital is a potent enzyme inducer known for hepa-
cal properties of the drug. Biotransformation of a parent drug totoxicity and for inducing its own metabolism. Rifampin
results in metabolites that may be active or inactive themselves. induces the metabolism of azole antifungals; concurrent
A prodrug is a drug administered in an inactive form that must administration with itraconazole results in subtherapeutic
be biotransformed to its active form, such as prednisone to itraconazole concentrations.
prednisolone. Drug metabolic pathways are divided into phase Drug-induced enzyme inhibition also occurs and typically
I and phase II reactions. Phase I reactions (oxidation, reduc- results in prolonged clearance of a concurrently administered
tion, hydrolysis, hydration, dethioacetylation, isomerization) drug. The potential for toxicity or an exaggerated pharmaco-
typically add functional groups to the drug molecule necessary logic response is increased. In contrast to induction, inhibi-
for phase II reactions. Phase II reactions (glucuronidation, glu- tion occurs rapidly. Erythromycin and enrofloxacin are known
cosidation, sulfation, methylation, acetylation, amino acid con- inhibitors of the metabolism of theophylline; concurrent
jugation, glutathione conjugation, and fatty acid conjugation) administration can cause central nervous system toxicity and
typically include conjugation reactions that increase the water seizures.11,12
solubility of the drug, facilitating excretion from the body.
Among the reactions catalyzed by drug metabolism enzymes, Kinetics of Drug Metabolism
the cytochrome P450 mixed function oxidase system is the most The enzymes that catalyze drug metabolism typically obey
intensively studied. This reaction catalyzes the hydroxylation of Michaelis-Menten kinetics as a first order reaction:
hundreds of structurally diverse drugs, whose only common V = (Vmax [C] )/(Km + [C] )
characteristic is high lipid solubility. Species differences in drug
metabolic rate are the primary source of variation in drug activ- where V is the rate of drug metabolism, Km is the Michae-
ity and toxicity. Cats have a poor ability to glucuronidate drugs, lis constant, and C is the drug concentration. In most
Steady-state plasma concentration Steady-state plasma concentration

dosage interval (1 hr) = T1/2 (1 hr) dosage interval (0.5 hr) <T1/2 (1 hr)
210 410
Cmax
190 360

170
310
150
130 260
110 210
Cmin
90 160
70
110
50
30 60
10 10
0 1 2 3 4 5 6 7 8 9 10 0 1 2 3 4 5 6 7 8 9 10
Time (hr) Time (hr)
FIG. 2.14 Plasma concentration versus time graph for an IV drug that FIG. 2.15 Plasma concentration versus time graph for a drug with a
produces a peak plasma concentration of 100 μg/mL after a single dose. dosage interval (0.5 hour) less than the half-life (1 hour), demonstrating
After 6 hours (which equals 6 half-lives), the maximum and minimum significant drug accumulation at steady-state.
drug concentrations become constant, further drug accumulation does
not occur, and the drug is steady-state.
Clinical Consequences of Dosage Intervals Less
clinical situations the drug concentration is much less Than the Half-Life
than the Michaelis constant, so the equation reduces to the Drugs such as phenobarbital, potassium bromide, phenylbu-
following: tazone, and digoxin are commonly given at dosage intervals
much shorter than their T½ (Fig. 2.15). This results in drug
V = (Vmax [C] )/Km accumulation and a Cmax at steady-state that is greater than
That is, the rate of drug metabolism is directly proportional the peak concentration after a single dose. The predicted accu-
to the concentration of free drug, and first order kinetics are mulation ratio (RA) with multiple-dose administration can be
observed in that a constant fraction of drug is metabolized per estimated using the following equation:
unit of time. With a few drugs, such as phenylbutazone, etha-
nol, deracoxib, and phenytoin, or if very large doses of a drug RA = 1/1 − e−λzτ
are given, the drug concentrations achieved are much greater where λz is the slope of the elimination phase and τ is the dos-
than Km and the rate equation is as follows: age interval. There is minimal fluctuation between Cmax and
Cmin, and missing a single dose will not affect plasma concen-
V = (Vmax [C] )/ [C] = Vmax
trations greatly. There is a lag time to reach the desired plasma
The enzymes are saturated by the high free drug concentra- concentrations at steady-state, and there will be a lag time for
tions, and the rate of metabolism remains constant over time. plasma concentrations to change in response to a dose change.
This is termed zero order kinetics or nonlinear kinetics.
Clinical Consequences of Dosage Intervals
Y DRUG ACCUMULATION Greater Than the Half-Life
Drugs are often given in multiple-dose regimens. To pre- Drugs such as IV formulations of penicillin and cephalospo-
dict plasma drug concentrations, it is necessary to decide rins are administered at dosage intervals that are greater than
whether successive doses of a drug have any effect on the the T½ (Fig. 2.16). As the dosage interval increases, Cmax at
previous dose. The principle of superposition assumes that steady-state is closer in value to the peak concentration after
early doses of drug do not affect the pharmacokinetics of a single dose. If the dosage interval is greater than 10 T½ (the
subsequent doses. For most drugs, as equal doses are given time required to eliminate 99.9% of the previous dose), drug
at a constant dosage interval, the plasma concentration-time accumulation essentially does not occur. There is marked
curve plateaus and a steady-state is reached. At steady-state fluctuation between Cmax and Cmin (peak and trough), and
the plasma drug concentration fluctuates between a maxi- missing a dose will greatly affect plasma concentrations. How-
mum concentration (Cmax, or peak) and minimum concen- ever, there is minimal lag time to achieve the desired plasma
tration (Cmin, or trough). Once steady-state is reached, Cmax concentration.
and Cmin are constant and remain unchanged from dose to
dose (Fig. 2.14). The time to steady-state depends solely on
the elimination half-life. It takes approximately 5 to 6 T½ to Y DESIGNING DRUG DOSAGE
reach 99% steady-state levels. The drug dose and dosage fre- REGIMENS
quency influence the values of Cmax and Cmin at steady-state,
and the dosage frequency and T½ influence the fluctuation The success of drug therapy is highly dependent on the dosage
between Cmax and Cmin. regimen design. Not all drugs require rigid individualization
Steady-state plasma concentration TABLE 2.4 Age-Related Changes in Geriatric and Pediatric
dosage interval (4 hr) >T1/2 (1 hr) Patients
121
Body Part/Function
101 Affected Geriatric Pediatric
Organ blood flow Decreased Increased

81 Total body water Decreased Greatly increased
Body fat Increased Decreased
61
Serum proteins Decreased Decreased albumin
albumin
41
Increased Decreased
globulins globulins
21
Hepatic metabolism Decreased Greatly decreased

1
0 2 4 6 8 10 12 14 16
Time (hr) The definition of neonate also varies with species and age,
but the determinants of drug disposition may be altered as the
FIG. 2.16 Plasma concentration versus time graph for a drug with a foal matures.14 Blood flow to the heart and brain is greater and
dosage interval (4 hours) greater than the half-life (1 hour), resulting in no faster, making the foal more susceptible to drug-induced car-
significant drug accumlation at steady-state. diotoxicity and neurotoxicity. GI absorption may be decreased
as a result of decreased gastric emptying and decreased intes-
of the dosage regimen. In the case of antimicrobials with a tinal peristalsis. Absorption from the GI tract may also be
broad safety range, such as the penicillins and cephalosporins, affected by the differences in gastric pH between neonates
the dosage is not titrated precisely but rather determined on and adults. Gastric pH in foals is highly variable (pH 1.5–7.0)
the basis of the dose required to maintain an effective plasma and dependent on feeding status. Absorption from IM and SC
concentration above the minimum inhibitory concentration sites changes as muscle mass and blood flow change. Neonates
of the bacterial pathogen. For drugs with a narrow therapeu- have less fat and greater total body water (primarily ECF) than
tic margin, such as digoxin, the aminoglycosides, and the- adults. Therefore low-Vd drugs (e.g., gentamicin, ketoprofen)
ophylline, the individualization of the dosage regimen is very distribute into a larger volume, making it necessary to increase
important. The objective of the dosage regimen for these drugs the dose to avoid therapeutic failure. Because of low body fat
is to produce a safe, therapeutic plasma drug concentration stores, lipid-soluble drugs will have higher plasma concentra-
that does not exceed the minimum toxic concentration. Fac- tions in foals. For example, moxidectin is much more lipid sol-
tors that influence the concentration of drug attained at the uble than ivermectin, so it is more easily overdosed in foals.15
drug’s site of action include the dose administered, the route Drug elimination by both hepatic metabolism and renal excre-
of administration, release and absorption of drug from dos- tion is limited in neonates, so drug dosing intervals may need
age form, the extent of drug distribution, and the rate of drug to be increased for some drugs, such as aminoglycosides and
elimination. nonsteroidal antiinflammatory drugs. Not all drugs behave
The horse’s age may have a profound effect on drug dispo- this way, however, and differences in pharmacokinetics result
sition (Table 2.4).13 The definition of geriatric varies among in a shortened dosing interval for some drugs, such as firo-
species and may even vary among breeds. Aging may also coxib and meloxicam.
be influenced by genetics, environment, nutrition, basic Finally, disease states may alter drug pharmacokinetics. The
health care, and use. In general, horses greater than 18 to sick horse usually has impaired drug detoxifying and elimina-
20 years may be considered geriatric. Ponies often age bet- tion capability. Hepatic damage reduces drug metabolism and
ter than horses and can be considered geriatric between 25 may increase drug action, whereas renal damage and impaired
and 30 years and older. Body composition and regional blood excretion decrease drug clearance. Alterations in GI motility
flow change in geriatric horses. Cardiac output decreases, so affect drug absorption and are a concern in horses with post-
regional and organ blood flow also decrease. These changes operative ileus. Peripheral circulation is decreased in shock,
have an impact on drug absorption, distribution, and elimina- resulting in decreased absorption of intramuscularly and sub-
tion. Blood flow is preferentially redistributed to the brain and cutaneously administered drugs.
heart, so there is an increase in risk of drug toxicity in these
organs. Gastrointestinal (GI) motility and absorptive capacity Pharmacokinetic-Based Dosage Regimens
are reduced. Hepatocyte number and function decrease along A drug dose regimen is composed of a dose and a dosing fre-
with hepatic and splanchnic blood flow. As renal blood flow quency. Some drugs are given as single doses, so a specific
decreases, GFR and active secretory capacity of the nephron plasma concentration will be targeted. When multiple doses of
decrease, resulting in decreased renal clearance of drugs. Lean a drug are given, the dosage frequency and drug accumulation
body mass decreases while fatty tissues increase. The plasma must be considered. There are simple calculations that can be
concentrations of water-soluble (low volume of distribution) used to design a patient-specific dose regimen.
drugs tend to increase, whereas the plasma concentrations
of lipid-soluble (high volume of distribution) drugs tend to Single-Dose Regimen
decrease. Serum albumin decreases while gamma globulins A single drug dose has its duration of action determined by
increase, so total plasma protein concentrations essentially the size of the dose, its elimination rate, and the volume of
remain the same. distribution. To calculate a single dose of a drug, or when
assuming a once-a-day dosing, only the Vd and the desired the desired clinical effect or an adverse effect. It is particu-
plasma concentration are needed: larly helpful in horses with systemic diseases that may affect
pharmacokinetics. It is also useful when many drugs are being
Dose = (Vd)(C0 ) administered at the same time when interactions may occur.
For drugs administered other than intravenously, the dose Therapeutic drug monitoring (TDM) is often valuable for
must be corrected for bioavailability: regulating the dosage of drugs used chronically or prophy-
lactically. For those drugs in which plasma concentration and
Dose = (Vd)(C0 )/F clinical effect are not related, other pharmacodynamic param-
eters may be monitored. For example, clotting times may be
Continuous Rate Infusion measured in patients on anticoagulant therapy.
When the desired response needs to be constant, the drug may The drugs for which TDM is most commonly used are
be infused intravenously at a constant rate (R0) following the characterized by serious toxicity (e.g., digoxin, phenobarbi-
initial IV dose: tal, aminoglycosides); a steep dose-response curve, wherein a
small increase in dose can cause a marked increase or decrease
R = (C)(Vd)(K)
in response (e.g., theophylline); marked pharmacokinetic
This equation can also be written as variability among individual patients, so dose is poorly pre-
dictive of plasma drug concentration (e.g., cyclosporine); eas-
R0 = Css × Cl ily saturable elimination mechanisms that lead to nonlinear
The infusion rate is essentially the rate of drug loss from kinetics; or when the cost of therapy justifies confirming a
the body (mg/min or mg/hr). Therefore to maintain the estab- desired plasma drug concentration (Table 2.5).
lished concentration of drug in the body, it is necessary to
infuse drug at the rate equal to its loss (K = elimination rate). Performing Therapeutic Drug Monitoring
For example, the vasopressive drugs dopamine and dobuta- Samples for TDM should not be submitted until plasma drug
mine have extremely short elimination half-lives, so they must concentrations have reached steady-state in the patient (after
be administered by constant infusion. approximately 5–6 elimination half-lives have passed). For con-
ditions in which steady-state concentrations must be reached
Multiple-Dose Regimen immediately, administer a loading dose. The risk of adverse drug
Continuous IV infusion offers the most precise control of drug reactions is obviously increased, so TDM can be used to proac-
levels in the body and is essential for precise control of drugs tively determine the proper maintenance dose. When a loading
with a narrow safety margin or very rapid elimination, as well dose is being administered, TDM should be done after the load-
as for those drugs with a time-dependent effect (e.g., β-lactam ing dose to establish a baseline. The second TDM should be 1
antibiotics). This method is not feasible for most drugs in vet- drug half-life later to ensure that the maintenance dose is able
erinary medicine. It is possible to maintain an average desired to maintain the concentrations achieved by the loading dose.
plasma concentration by repeat dosing at constant dosing If the drug concentrations at the second sample do not match
intervals. Obviously, the highest plasma concentrations will those of the first sample, the maintenance dose can be adjusted
occur soon after drug administration, and the lowest concen- at this time rather than waiting for steady-state, with the risk of
trations will be just before the next dose is administered. As therapeutic failure or toxicity. The third time to do TDM is at
long as the lowest concentration is acceptable for therapy and steady-state to ensure an appropriate dosage regimen.
the highest concentration does not cause toxicity, these varia- The number of samples collected for TDM depends on
tions in plasma concentration are acceptable: the drug, its T½, and the reason for monitoring. To determine
optimal aminoglycoside therapy, peak and trough samples
(Cave )(Vd)(τ) are needed. To allow for the distribution phase, blood sam-
Dose =
(1.44) T1/ pling for the peak concentration is done 0.5 to 1 hour after
2
administration, and the trough sample is usually taken before
where τ = dosage interval and 1.44 is a constant to correct for the next dose. With very long elimination half-lives and twice-
log scale. daily dosing, there are no statistically significant differences
between Cmax and Cmin values for phenobarbital or potassium
bromide. Therefore a single sample can be collected for TDM
Loading Dose Followed by Maintenance at any time during the dosing interval. However, Cmax and Cmin
Dose Regimen samples should be collected in any horse that is not respond-
Drugs that have long elimination half-lives, such as phenobar- ing as expected to therapy in order to determine whether the
bital and fluconazole, have a long lag time to acceptable drug horse has a shorter- or longer-than-normal elimination time
concentrations and therefore are usually given by a large load- for the drug (Box 2.4).
ing dose (DoseL) followed by maintenance doses (DoseM).
Adjustment of Dosage Regimens
DoseM Adjustment of the dosage regimen is frequently required when
DoseL =
1 − e−K τ drugs are administered to diseased horses, due to the fact that
most dosage regimens have been established in a small num-
ber of normal horses. Adjustment is indicated when the drug’s
Y THERAPEUTIC DRUG MONITORING elimination or distribution is significantly altered in the ani-
mal. In general, the following rules are true:
Monitoring plasma drug concentrations is valuable if there • If the volume of distribution changes, change the drug
is a relationship between the plasma drug concentration and dose.
TABLE 2.5 Recommendations for Therapeutic Drug Monitoring

Drug Therapeutic Range Vd (L/kg) T½ Time to Steady State Sample Collection
Amikacin 40 μg/mL peek 0.25 1–2 hr 1 day Peak: 0.5–1 hr after administration
<3 μg/mL trough Trough: just before next dose or 8
hr after dosing if using once-daily
administration; collect in plastic
only
Bromide Monotherapy: 24 days 4 mo Any time
2–3 μg/mL
(20–30 mmol/L)
W/ phenobarb:
1–2 –g/mL
(10–20 mmol/L)
Digoxin 0.9–2.0 ng/mL 6.7 23 hr 7 days 2–5 hr after dose, collect in glass
only
Gentamicin 20 μg/mL peek 0.3 1 hr 1 day Peak: 0.5–1 hour after administra-
<2 μg/mL trough tion
Trough: just before next dose or 8
hr after dosing if using once-daily
administration; collect in plastic
only
Phenobarbital 15–40 μg/mL 0.96 24 hr 6 days Any time
(70–170 mmol/L)
Quinidine 2–6 μg/mL 3.10 6.65 hr 40 hr Trough
Theophylline 10–20 μg/mL 0.8 13 hr 3 days 1–2 hr after dose

BOX 2.4 Interpreting the Results of Therapeutic Drug Y DOSAGE ADJUSTMENTS IN

Monitoring RENAL FAILURE
PLASMA CONCENTRATIONS LOWER THAN ANTICIPATED Renal disease can have a profound impact on the disposition of
Poor compliance with regimen drugs administered to animals in renal failure. With reduced
Error in dosage regimen renal clearance, the parent drug, its metabolites, or both may
Wrong product (e.g., controlled release instead of immediate accumulate in the patient and cause toxicity. Loss of proteins
release) and electrolytes in urine and the alterations in acid-base bal-
Poor bioavailability ance associated with renal failure affect the pharmacokinetics
Rapid elimination and pharmacodynamics of drugs. Enhanced drug activity or
Increased apparent volume of distribution toxicity can occur as a result of synergy with uremic complica-
Poor timing of blood sample tions. Altogether, these effects make it difficult to determine
safe and effective drug dosages for veterinary patients in renal
PLASMA CONCENTRATIONS HIGHER THAN ANTICIPATED failure.
Poor compliance with regimen The goal of dosage adjustment is to provide a drug con-
Dose incorrect centration–time profile in the horse with renal failure that
Very rapid drug absorption is as similar as possible to that of a normal horse. The best
Decreased apparent volume of distribution approach to modifying drug therapy in horses with renal fail-
Slow elimination ure would be to carry out therapeutic drug monitoring and
adjust the dosage for each patient. This is possible with some
PLASMA CONCENTRATION CORRECT BUT POOR PATIENT drugs, such as phenobarbital and digoxin, but it is impracti-
RESPONSE TO THERAPY cal and cost prohibitive for most drugs used in veterinary
Diagnosis incorrect practice. The best approach for most drugs is to estimate a
Altered tissue receptor sensitivity (tolerance) corrected dose from available renal function tests and then
Drug interaction at receptor site to monitor the patient closely for evidence of efficacy or tox-
icity. For drugs that are eliminated primarily by renal mech-
anisms, creatinine (Cr) clearance correlates well with drug
• If the elimination of the drug changes, change the dosing clearance. Cr is an endogenous product of creatinine phos-
interval. phate metabolism in muscle. It is removed by glomerular
For drug dosage regimens determined by TDM, modifica- filtration, and serum concentrations are relatively constant
tions are made on a percentage basis: in healthy people and animals. The elimination half-life of a
New dose = Old dose × drug that is eliminated in urine remains stable until Cr clear-

(Target + Concentration ÷ Measured concentration) ance is reduced to 30% to 40% of normal, which is why drug
dosage regimens are typically not adjusted until two thirds of
Interval extension method

12
Drug concentration (µg/ml)

10
0
0 1 2 3 4 5 6
Time (hr)
FIG. 2.17 Comparison of an interval-extension dosage regimen (solid line) in a renal failure patient with a
normal dosage regimen in a healthy patient (dotted line). Normal elimination half-life was 15 minutes; in the
patient with renal failure, it increased to 8 hours.
renal function has been lost.16 In human patients Cr clear- periods of time during which drug concentrations may be
ance is quantified by determining urinary Cr excretion over subtherapeutic. This is the preferred method with amino-
a 24-hour period. The measured Cr clearance is then used in glycosides, which have a long postantibiotic effect and in
formulas to make drug dosage adjustments. Unlike in human which a low trough concentration is desirable to reduce
medicine, values for Cr clearance are not usually available for the risk of nephrotoxicity. Depending on the relationship
veterinary patients. When Cr clearance is not available, a sin- of the elimination half-life to the dosage interval, signifi-
gle value of the patient’s serum creatinine can be substituted cant drug accumulation may occur with the dose-reduc-
in the formulas. However, the relationship between serum tion method (Fig. 2.18), but at steady-state there are no
creatinine is not linear once serum creatinine is above 4 mg/ periods of time during which concentrations are subthera-
dL, so the adjustment formulas are even less accurate for pre- peutic. This is the preferred method for the penicillin and
dicting an ideal dose adjustment.16 These formulas do not cephalosporin antibiotics, wherein maintaining the plasma
account for changes in the volume of distribution, degree of concentration above the pathogen’s minimum inhibi-
protein binding, and nonrenal clearance mechanisms of the tory concentration (MIC) correlates with efficacy and the
drug that may be caused by the renal dysfunction. Therefore drugs are relatively nontoxic even if accumulation occurs.
these dosage adjustments must be regarded as preliminary To decide which method to use, the practitioner should
estimations to be followed by adjustments based on observed determine whether drug efficacy and toxicity are related to
clinical response. peak, trough, or average plasma concentrations and then
select the method that best balances efficacy against poten-
Dose-Reduction Method tial toxicity. The interval-extension method is more conve-
With the dose-reduction method the normal dosage regimen nient for the client because the normal recommended dose
is adjusted by reducing the drug dose and maintaining the is simply administered less frequently. In addition, if the
drug dosing interval. drugs are available only in fixed dosage forms (e.g., cap-
sules, unbreakable tablets), it is easier to adjust the dosage
Adjusted dose = Normal dose × interval.
(Patient's Cr clearance ÷ Normal Cr clearance) Because the elimination half-life is prolonged in patients
or with renal disease and it always takes 6 elimination half-lives
to reach 99% of steady-state concentrations, there is a delay
Adjusted dose = Normal dose × (Normal Cr ÷ Patient's Cr) in reaching steady-state in horses with renal failure compared
with horses with normal renal function. Therefore it may be
Interval-Extension Method necessary to administer a loading dose to rapidly achieve ther-
With the interval-extension method the drug dose is main- apeutic drug concentrations. If the dose-reduction method
tained and the drug dosing interval is extended. is used, this is achieved by giving the usual dose initially, fol-
lowed by the reduced dose at the next time. If the interval-
Adjusted interval = Normal interval extension method is used, this is accomplished by giving a
[1/(Patient's Cr clearance/Normal Cr clearance)] double dose initially.
or For renal failure patients in general, the practitioner must
consider the following:
Adjusted interval = Normal interval 1. Avoid using any drugs at all, unless there are definite thera-
[1/(Normal serum Cr/Patient's serum Cr)] peutic indications. If a drug is absolutely necessary, try to
select one that is hepatically metabolized and excreted in
Both methods attempt to keep the average plasma drug bile rather than eliminated by the kidneys (e.g., doxycy-
concentrations constant. The interval-extension method cline).
produces Cmax and Cmin values similar to those seen in 2. If therapeutic drug monitoring is available, tailor the drug
healthy patients (Fig. 2.17), but it does produce substantial dosage regimen to that specific patient.
Dose-reduction method
25
Drug concentration (µg/mL)

20
15
10
–5
0 1 2 3 4 5 6
Time (hr)
FIG. 2.18 Comparison of a dose-reduction dosage regimen in a renal failure patient (solid line) compared
with a normal dosage regimen in a healthy patient (dotted line). Normal elimination half-life was 15 minutes;
in the renal failure patient, it increased to 8 hours.
3. If therapeutic drug monitoring is unavailable, determine inflammatory diseases is irrational, expensive, and poten-
whether there are clinically proven, adjusted dosage regi- tially hazardous to the patient; it also encourages antimi-
mens for specific drugs. The package insert that accompa- crobial resistance. Clients have come to expect antimicro-
nies pharmaceuticals intended for human use often gives bials for trivial infections or in the event that an infection
guidelines for adjusting dosages. may develop. Equine practitioners must resist client pres-
4. If the drug has not been sufficiently studied to have dosage sure to use or prescribe unnecessary drugs.
adjustment recommendations, determine whether there 2. What organism(s) are likely to be involved? For many infec-
is sufficient information about its kinetics to estimate the tions the likely organism can be successfully predicted on
proper drug dose in renal failure. the basis of the history and clinical signs (e.g., Streptococcus
5. Carefully monitor treated patients for signs of efficacy and zooepidemicus and respiratory infections).
toxicity. 3. What is the in vitro antimicrobial susceptibility of the organ-
ism? For many pathogens the in vitro susceptibility can be
reliably predicted. For example, Streptococcus species are
typically susceptible to penicillin. However, many gram-
Antimicrobial Therapy negative bacteria have unpredictable susceptibilities, and
susceptibility testing is essential for determining appropri-
ate drug therapy.
Successful antimicrobial therapy relies on administering suffi- 4. In what part of the body or tissue is the infection located? Will
cient doses so that pathogens at the site of infection are killed or the antimicrobial penetrate to the infection? Consideration
suppressed to the extent that they can be eliminated by the host’s of the pathophysiology of the infection will help the practi-
immune system. There are complex pharmacokinetic (PK) and tioner select an effective therapy. Treatment of sequestered
pharmacodynamic (PD) relationships among the host, the infections such as mastitis or meningitis requires antimi-
bacteria, and the antimicrobial. Pharmacokinetics is what the crobials that readily cross membrane barriers. Antimicro-
body does to a drug; the processes of absorption, distribution bials characterized by low values for volume of distribution
to the various organs and tissues, metabolism, and elimination. (Vd) are unlikely to reach therapeutic concentrations in
Pharmacodynamics is what the antimicrobial does to the bac- such sites.
teria. It describes the drug action and responses of the bacteria. 5. Will the antimicrobial be effective in the local environment
Pharmacokinetics and pharmacodynamics are interrelated in of the organism? The local infection environment reduces
that PK effects determine the amount of drug that reaches the the efficacy of some antimicrobials. Sulfonamides are in-
site of action, and the intensity of a PD effect is associated with effective in purulent debris because para-aminobenzoic
the drug concentration at the site of action. New information acid (PABA) released from decaying neutrophils serves
on the PK/PD relationships of veterinary pathogens and anti- as a PABA source for bacteria and reduces the competi-
microbials is rapidly emerging and changing the way in which tive effect of the sulfonamide. Aminoglycosides are in-
the dosage of antimicrobials is determined in equine practice. effective in an abscess because of the acidic, anaerobic
environment along with the presence of nucleic acid ma-
terial from decaying cells, which inactivates this class of
Y RATIONAL USE OF ANTIMICROBIAL drug.
AGENTS 6. What drug formulation and dose regimen will maintain the
appropriate antimicrobial concentration for the proper du-
The following questions must be considered when developing ration of time? Label doses apply only to label pathogens.
an antimicrobial regimen: For off-label uses the dosage regimen must be adjusted de-
1. Does the diagnosis warrant antimicrobial therapy? Using pending on the antimicrobial susceptibility of the specific
antimicrobials to treat minor infections or purely viral or pathogen.
7. What adverse drug reactions or toxicities might be expected? transport mechanisms, and degree of protein binding. The
Do the benefits outweigh the risks? The risks of adverse re- relationship between bacteria and drug in the laboratory is
actions from antimicrobials are often underappreciated. A described by the following:
serious adverse reaction may complicate treatment of the
original problem and even be fatal. Failure to communicate MIC: The lowest drug concentration that inhibits bacterial
the risks of adverse drug reactions to clients is a common growth. Often expressed as the concentration that inhibits
cause of litigation. 50% (MIC50) or 90% (MIC90) of the bacterial growth.
8. Can you choose an approved product? If using an antimi- Minimum bactericidal concentration (MBC): The lowest drug
crobial in an off-label manner, can you determine appropri- concentration that kills 99.9% of bacteria.
ate withdrawal times for food animals? Can you determine Mutant prevention concentration (MPC): Threshold concen-
appropriate withdrawal times for performance horses? The tration above which the selective proliferation of resistant
antimicrobials used in horses are not approved for horses mutants is expected to occur only rarely.
intended for food, and information on appropriate with-
drawal times is lacking. Also, competitive horses are subject The MICs are used to determine the drug dose, in an
to the rules of the sport’s governing association regarding attempt to achieve blood and tissue concentrations that exceed
drugs, which vary according to the organization, state or the in vitro MIC for the pathogen.
province, and country. Understanding the principles of
drug elimination allows the practitioner to determine ap- Interpreting Minimum Inhibitory Concentrations
propriate withdrawal times for competitive or slaughter According to the Clinical Laboratory Standards Institute
horses. (CLSI; formerly called the National Committee for Clinical
Laboratory Standards [NCCLS]) definition, the MIC values
Documenting the Infection are derived as serially doubled concentrations (in μg/mL).
A diagnosis must be established before any therapy can be Susceptible (S), intermediate (I), and resistant (R) designations
administered. It is not always necessary to culture samples are derived from breakpoints assigned by laboratory-based
from all patients with infectious diseases to identify the organ- PK and PD data, pathogen population MIC distribution, and
ism involved. Often the practitioner can base a diagnosis on clinical trial results.17 A CLSI-approved breakpoint is specific
clinical experience from similar cases. The signs of some infec- for the animal species, disease, pathogen, antimicrobial, and
tious diseases are so obvious that the need for microbiologic dosage regimen. When a pathogen is reported as susceptible, it
identification is minimal; however, for those infectious dis- means that the recommended dosage of the antimicrobial will
eases of unknown cause or for those attributable to organisms reach plasma or tissue concentrations that will inhibit bacte-
with irregular antimicrobial susceptibility, there is no sub- rial growth in vivo. When a pathogen is reported as resistant,
stitute for isolation and identification of the causative agent. inhibitory antimicrobial concentrations are not safely attain-
For these organisms initial therapy while waiting for culture able in the patient. If the pathogen is reported as intermediate,
results must include an antimicrobial with a broad spectrum administering the antimicrobial at higher-than-recommended
of activity. doses may result in effective therapy.18 Pathogens with inter-
Whenever possible, the veterinarian should obtain a rep- mediate susceptibility may also be successfully treated if the
resentative sample of material from a clinical patient. Beware infection is located in an area of high drug concentration (e.g.,
of sampling grossly contaminated sites such as purulent nasal urine for renally excreted drugs) or by treatment with local
discharges. Treatment failure may also be related to sampling routes of administration (e.g., topical administration to the
of an inappropriate area. For instance, in cases of pleuropneu- eye for corneal infections).
monia, failure to culture both transtracheal wash fluid and Susceptibility testing results predict which bacteria have
pleural fluid may result in an inability to culture all associated intrinsic or acquired resistance mechanisms to a particular
organisms. An immediate Gram stain can be performed from antimicrobial. In vitro tests do this because bacterial suscepti-
a direct smear and will direct initial therapy. Samples are sub- bility usually clusters around a small range of MICs. In Fig. 2.19
mitted for appropriate culture and identification. If the iden- the bacterial inhibition of E. coli by amoxicillin has a bimodal
tified organism has unpredictable susceptibility patterns, the distribution. The large cluster of Escherichia coli inhibited by
practitioner should request a susceptibility test, such as Kirby- amoxicillin concentrations of 0.5 to 16 μg/mL are considered
Bauer, E test, or MIC method. the normal range and 16 μg/mL is considered the breakpoint
In some clinical cases identification of the pathogen may be of susceptibility. E. coli requiring an amoxicillin concentra-
made by serologic demonstration of antibodies (e.g., anaplas- tion of 16 μg/mL to be inhibited are likely to have intrinsic or
mosis, leptospirosis, brucellosis). acquired resistance mechanisms, and amoxicillin is unlikely
to be a successful treatment for patients infected with these
Antimicrobial Dosage Regimen Design isolates. In vitro susceptibility tests predict treatment outcome
The relationship among the host, the bacteria, and the drug fairly well, considering that many variables in the host-patho-
may be very complex. High plasma antimicrobial concentra- gen relationship are not taken into account.17 Antimicrobial
tions are assumed to be advantageous in that a large concentra- susceptibility data may not account for the following:
tion of drug will diffuse into the ECF of various tissues. Drug 1. Host defenses: The interaction between the host and the
concentration at the site of infection is assumed to be of major pathogen is complex and not predicted by in vitro tests.
importance in determining drug efficacy. In many infections Antimicrobial drug action takes place in concert with
the site of infection is the ECF; however, infections may also host defenses such as humoral and cell-mediated im-
occur within cells or other protected sites. Drug movement munity; complement components; and nonspecific anti-
from the plasma to extravascular tissues depends on molecu- bacterial factors such as lactoferrin, lactoperoxidase, and
lar size, lipid solubility, drug pKa, local pH, specific cellular lysozyme.19
2. Drug distribution in the body: The S, I, and R designa- administered systemically, it is rarely included in suscep-
tions assigned by the microbiology laboratory are typi- tibility testing. Bacitracin and mupirocin are other exam-
cally based on safely achievable plasma concentrations. ples of topical antimicrobials rarely tested by diagnostic
This does not necessarily take into account extremely laboratories.
high concentrations of antimicrobials achieved in organs 8. In vivo synergism may occur with antimicrobial combina-
and fluids of excretion (kidney, urine, bile) or with local tions: Despite predictions of resistance from susceptibility
administration of high drug concentrations (e.g., oph- testing, therapy may be successful because of synergistic
thalmic ointments). Macrolide antimicrobials are charac- combinations of antimicrobials. Synergism between peni-
terized by negligible plasma concentrations despite very cillins and aminoglycosides has been recognized for strep-
high lung and intracellular concentrations.20 Pathophysi- tococcal, enterococcal, and staphylococcal infections.24 The
ology may alter drug distribution, and some antimicrobi- synergism is attributed to increased cellular uptake of the
als, such as the tetracyclines, accumulate in pneumonic aminoglycoside after cell wall damage from the penicillin.
lung tissues.21 9. The CLSI breakpoints may be inappropriate: The CLSI
3. Growth rates and size of inoculum: The incubator of the breakpoints were originally established with bacterial iso-
microbiology laboratory is an ideal setting for bacterial lates from humans, using human PK data and clinical tri-
growth. Conditions are managed to promote rapid growth, als. A veterinary subcommittee was established in 1993 and
and rapidly dividing bacteria are more susceptible to an- has proposed veterinary-specific guidelines for susceptibil-
timicrobial drugs. Replication rates may be much slower ity tests for a limited number of antimicrobials.25 Currently,
at the infection site, and MICs are generally unreliable for only ceftiofur, ampicillin, amikacin, and gentamicin have
slow-growing bacteria. Standardized inoculums used in the CLSI-approved breakpoints for equine pathogens. Diag-
laboratory may overrepresent or underrepresent pathogen nostic laboratories use human-derived breakpoints for
numbers in infected tissues.19 other bacteria-drug combinations. It is important to know
4. Mixed infections: Separate susceptibility testing of patho- if your laboratory uses the equine-specific breakpoints,
gens in a mixed infection does not account for the patho- as these can differ widely among species. For example,
logic synergism between bacteria. The byproducts of one the amikacin breakpoint in humans is 16 μg/mL, in adult
bacterium may facilitate the establishment and growth of horses 4 μg/mL, and in foals 2 μg/mL.
another.22 Therefore the true relevance of any in vitro MIC in pre-
5. Infection environment: Many antimicrobials are inactive in dicting the in vivo results of drug therapy is questionable. The
purulent exudate, which is typically anaerobic, acidic, and MIC results are not a positive order to use a particular antimi-
hyperosmolar. Some antimicrobials have different activity crobial. Selection of the optimal antimicrobial must take into
in body fluids (e.g., plasma, milk, bile) than in nutrient- consideration other factors, such as the site of infection, phar-
rich laboratory media. Deposition of fibrin may alter tissue macokinetics of the drugs, and effect of underlying diseases.
penetration of antimicrobials. Many bacteria are capable of Considering all of these factors, most veterinarians determine
producing a polysaccharide slime capsule to protect them a drug dosage regimen that uses a target plasma drug concen-
from host factors. Mastitis pathogens typically increase tration based on a multiple of the in vitro MIC (usually 2–10).
their replication rate when incubated in mastitic milk.19
7. Topically administered antimicrobials are not tested: Vet- Bactericidal Versus Bacteriostatic Antimicrobials
erinary microbiology laboratories may not routinely do It is common to classify antimicrobials as bactericidal or bacte-
susceptibility testing for antimicrobials that are used riostatic (Box 2.5). If the ratio of the MBC to MIC is small (less
only topically. Polymixin B is one of the most effective than 4–6), a drug is considered bactericidal, and it is possible
antimicrobials for superficial Pseudomonas infections,23 to obtain drug concentrations that will kill 99.9% of the organ-
but because it causes neurotoxicity and nephrotoxicity if isms exposed. If the ratio of MBC to MIC is large, it may not be
% of Escherichia coli inhibited

30
25
20
% Inhibited
15
10
0
0.12 0.25 0.5 1 2 4 8 16 32 64 128 256
Amoxicillin (g/mL)
FIG. 2.19 The percentage of Escherichia coli inhibited by increasing concentrations of amoxicillin has a bi-
modal distribution. E. coli requiring more than 16 μg/mL of amoxicillin to be inhibited are likely to have intrinsic
or acquired resistance mechanisms. Amoxicillin therapy in patients with this pathogen is unlikely to be effective.
possible to safely administer dosages of the drug to kill 99.9% efficacy is concentration dependent, high plasma concentra-
of the bacteria, and the drug is considered bacteriostatic. tions relative to the MIC of the pathogen (Cmax:MIC) and the
For many drugs the distinction between bactericidal and area under the plasma concentration-time curve that is above
bacteriostatic is not exact and depends on the drug concentra- the bacterial MIC during the dosage interval (AUC0–24:MIC)
tion attained in the target tissue and the pathogen involved. are the major determinants of clinical efficacy. These drugs
Specific situations in which a bactericidal drug is preferred over also have prolonged PAEs, thereby allowing once-a-day dosing
a bacteriostatic drug include immunocompromised patients while maintaining maximum clinical efficacy. For fluoroquino-
such as neonates, life-threatening infections such as bacterial lones (e.g., enrofloxacin, orbifloxacin, marbofloxacin), clinical
endocarditis and meningitis, and surgical prophylaxis. efficacy is associated with achieving either an AUC0–24:MIC
greater than 100 to 125 for gram-negative organisms and
Postantibiotic Effect AUC0–24:MIC greater than 55 for gram-positive organisms or
For some bacteria-antimicrobial interactions, bacterial growth a Cmax:MIC greater than 10. For aminoglycosides (e.g., genta-
remains suppressed for a period after drug concentration has micin, amikacin), achieving a Cmax:MIC greater than 10 is con-
decreased below the MIC.26 This postantibiotic effect (PAE) sidered optimal for efficacy. Other antimicrobials that appear to
may be the reason that dosage regimens that fail to maintain have concentration-dependent activity include metronidazole
drug concentration above the MIC are still efficacious. The (Cmax:MIC > 10–25) and azithromycin (AUC0–24:MIC > 25).
PAE depends on the antimicrobial and the bacterial pathogen For some pathogens with very high MIC values, such as Pseu-
(Table 2.6). domonas aeruginosa, achieving the optimum PK/PD ratios may
be impossible with label or even higher-than-label dosages. In
such cases underdosing is ineffective and merely contributes to
Pharmacokinetic-Pharmacodynamic
antimicrobial resistance.
Relationships For antimicrobials with time-dependent efficacy, the drug
The PK-PD relationship between an antimicrobial and a patho- concentration at the site of infection must be maintained
gen determines the way that the dosage regimen is calcu- above the MIC for some portion of the dosing interval. How
lated.27 The PK parameters used in drug dosage design are the much above the MIC and for what percentage of the dosing
area under the plasma concentration versus time curve from interval concentrations should be above the MIC are still
0 to 24 hours (AUC0–24), the maximum plasma concentration being debated and are likely specific for individual bacteria-
(Cmax), and the time the antimicrobial concentration exceeds drug combinations. Typically, exceeding the MIC by 1 to 5
a defined PD threshold (T > MIC). In relating the PK and PD multiples for between 40% and 100% of the dosage interval
parameters to clinical efficacy, antimicrobial drug action is is appropriate for time-dependent antibiotics. The T > MIC
classified as either concentration dependent or time depen- should be closer to 100% for bacteriostatic antimicrobials and
dent (Box 2.6; Figs. 2.20 and 2.21). For antimicrobials whose in patients that are immunosuppressed. These drugs typically
require frequent dosing or constant rate infusions for appro-
priate therapy. In sequestered infections penetration of the
antimicrobial to the site of infection may require high plasma
BOX 2.5 Classification of Antimicrobials concentrations to achieve a sufficient concentration gradient.
In such cases the AUC0–24:MIC and/or Cmax:MIC may also be
BACTERICIDAL important in determining efficacy of otherwise time-depen-
Aminoglycosides dent antimicrobials.
β-lactams
Fluoroquinolones
Trimethoprim/sulfonamides Y DESIGNING THE DRUG
DOSAGE REGIMEN
BACTERIOSTATIC
Chloramphenicol When designing specific antimicrobial dosage regimens,
Macrolides the practitioner targets a specific plasma drug concen-
Sulfonamides tration. High plasma antimicrobial concentrations are
Tetracyclines assumed to be advantageous in that a large concentration
of drug will diffuse into various tissues and body fluids. In
TABLE 2.6 Length of Postantibiotic Effect for Selected Antimicrobials and Antibiotics
Microbe Long PAE (>3 hr) Intermediate PAE Short PAE (<1 hr)
Gram positive Fluoroquinolones Aminoglycosides —
Macrolides Penicillins —
Chloramphenicol Cephalosporins —
Tetracycline Carbapenems
Gram negative Fluoroquinolones Carbapenems Penicillins
Aminoglycosides — Cephalosporins
— — Trimethoprim/sulfonamides
Anaerobes Metronidazole — —

PAE, Postantibiotic effect.

light of the previous information, antimicrobial dosage reg- and if the volume of distribution (Vd) of the antimicrobial is
imens are designed in one of two ways: either to maximize known, a precise drug dosage regimen for the pathogen can be
plasma concentration or to provide a plasma concentration calculated from the following equation:
above the bacterial MIC for some percentage of the dosage
Dose = (Vd)(Desired plasma concentration)
interval.
For concentration-dependent antibiotics with a prolonged where the desired plasma concentration is some multiple of
PAE whose PK-PD relationship is to have an ideal Cmax:MIC, the MIC (usually 8–10) and once-daily dosing is assumed.
For concentration-dependent antibiotics whose PK-PD rela-
tionship is to have an ideal AUC0–24:MIC, the following equa-
BOX 2.6 C
lassification of Antimicrobials Based on Means tion can be used to calculate a daily dose:
of Effect
Dose = (AUC0−24 :MIC)(MIC)(Cl)(F)(24 hr)
CONCENTRATION-DEPENDENT ANTIMICROBIALS where AUC0–24:MIC is ≥ 100, Cl is clearance (volume
Aminoglycosides of blood cleared of drug per day in mL/kg/day), and F is
Fluoroquinolones bioavailability.
Metronidazole For time-dependent antibiotics the objective is to keep the
average plasma drug concentration above the pathogen’s MIC
TIME-DEPENDENT ANTIMICROBIALS for the duration of the dosage interval. Again, by using Vd and
Cephalosporins elimination half-life information, the practitioner can pre-
Chloramphenicol cisely calculate a dosing regimen:
Macrolides
Penicillins Dose = (Desired avg plasma concentration)
( )
Sulfonamides (Vd)(Dosage interval)1.44 T1/
Tetracyclines 2
Time-dependent antimicrobial activity

14
7 Hr
12
10
2 MIC = 2
0
0 1 2 3 4 5 6 7 8 9 10 11 12
Time (hr)
FIG. 2.20 For time-dependent antimicrobials the time during which the antimicrobial concentration ex-
ceeds the minimum inhibitory concentration of the pathogen determines clinical efficacy.
Dose-dependent antimicrobial activity

18
16
14
12
IQ Ratio 4:1
10
8
6
MIC = 4
4
2
0
0 1 2 3 4 5 6 7 8 9 10 11 12
Time (hr)
FIG. 2.21 For concentration-dependent antimicrobials, the inhibitory quotient (IQ) and the area under the
inhibitory curve are the major determinants of clinical efficacy.
Y CONCURRENT USE OF ADDITIONAL 4. Antimicrobial prophylaxis in adult horses with diarrhea

ANTIMICROBIALS is unlikely to be beneficial, unless suspicion of a specific
etiologic agent is extremely high based on prior use of anti-
Combination antimicrobial therapy is commonplace in veteri- microbials (Clostridium difficile/perfringens), season of the
nary medicine, but combination therapy has rarely been dem- year (Neorickettsia risiticii), and age (Lawsonia extracellula-
onstrated as superior to single-drug therapy through clinical ris).
trials. Use of multiple antimicrobial drugs should be limited to
the following cases:
1. Known synergism against specific organisms24 Y β-LACTAMS: PENICILLINS AND
2. Prevention of rapid development of bacterial resistance28 CEPHALOSPORINS
3. To extend antimicrobial spectrum of initial therapy of life-
threatening conditions29 The β-lactam antibiotics include the penicillins, cephalospo-
4. To treat known mixed bacterial infections30 rins, and carbapenems. They have excellent activity against
Multiple antimicrobial therapy is implicated as a cause of most gram-positive bacteria and very few associated side
diarrhea in horses, likely from the additive antibacterial effects effects. They are considered bactericidal and time dependent.
against normal GI flora.31 Antagonistic combinations such as Postantibiotic effects have been associated with some drugs in
chloramphenicol and a macrolide should be avoided; both this class. In general, the β-lactam antibiotics have low plasma
these classes of drugs competitively bind to the same binding protein binding, distribute well to the ECF in most tissues, and
site on bacterial ribosomes, thus effectively battling each other are excreted renally. With a few exceptions, they have a very
for the site of action. short half-life and require frequent dosing. β-Lactams do not
distribute well to protected sites, such as the central nervous
system, the eye, or the prostate.
Y PROPHYLACTIC USE OF
ANTIMICROBIALS Mechanism of Action
β-Lactam antibiotics act on enzymes called penicillin-bind-
There are few reports examining the efficacy of prophylactic ing proteins (PBPs) responsible for building the bacterial cell
antimicrobials in veterinary medicine in general and in horses wall.18 Therefore they are active only against rapidly multiply-
specifically.32 Because of the lack of controlled veterinary stud- ing organisms in which the binding of penicillin within the
ies, information on prophylaxis is largely extrapolated from cell wall interferes with production of cell wall peptidoglycans
human studies. The relative risk of infection must warrant the and results in cell lysis in a hypo-osmotic or iso-osmotic envi-
use of prophylactic antimicrobials. The risks of adverse effects ronment. There may be anywhere from two to eight PBPs in
from the prophylactic drug must be less than the risk of devel- a bacterium. When β-lactam antibiotics bind covalently and
opment of disease and its consequences. In veterinary medicine irreversibly to the PBPs, the bacterial cell wall is disrupted
most of the risk of infection depends on the skill of the surgeon and lysis occurs. Differences in the spectrum and activity of
and handling practices in the hospital.33 The organism or organ- β-lactam antibiotics are due to their relative affinity for differ-
isms that are likely to cause the infection and their antimicro- ent PBPs. To bind to the PBPs, the β-lactam antibiotic must
bial susceptibility should be known or accurately predicted. The first diffuse through the bacterial cell wall. Gram-negative
antimicrobial should be bactericidal and must be administered organisms have an additional lipopolysaccharide layer that
and distributed to the site of potential infection before the onset decreases antibiotic penetration. Therefore gram-positive bac-
of infection. The veterinarian should consider drugs that can teria are usually more susceptible to the action of β-lactams
be given intravenously and have a high volume of distribution. than gram-negative bacteria. Because the penicillins poorly
Drugs used prophylactically should not be those that would be penetrate mammalian cells, they are ineffective in the treat-
used therapeutically. The duration of antimicrobial prophylaxis ment of intracellular pathogens.
should be as abbreviated as possible. Most of the time a single
preoperative dose is sufficient and cost effective.34 Resistance Mechanisms
A comprehensive review of the subject has resulted in sev- Resistance mechanisms to the β-lactams include failure of
eral recommendations being made regarding the use of anti- the antibiotic to penetrate the outer bacterial cell layers and
microbials in the absence of culture and sensitivity data or a alteration of PBPs that decrease the affinity of the PBP for the
definitive diagnosis.35 These include the following: antibiotic.36-38 Alterations of the PBPs to a low-affinity PBP2a
1. Commonly used antimicrobial combinations remain the occur with methicillin-resistant staphylococci and are medi-
mainstay for treating purulent infections. Appropriate ated by the presence of the chromosomal gene mecA.39 The
choice of an antibiotic that is not inactivated in a purulent presence of this gene precludes therapy with any of the cur-
environment is recommended. rently available β-lactam antibiotics and predicts resistance to
2. Antimicrobial treatment for compromised foals should several classes of antibiotics. A third mechanism of resistance
be instituted until sepsis is proven or disproven; however, is from production of β-lactamase enzymes.40,41
treatment should not extend beyond recovery. Prophylac- There may be as many as 50 β-lactamase enzymes (penicil-
tic administration of antimicrobials to healthy foals is not linases, cephalosporinases, and carbapenemases) produced by
recommended. bacteria. These enzymes hydrolyze the cyclic amide bond of
3. Continuation of prophylactic antimicrobials for more than the β-lactam ring and inactivate the antibiotic. Staphylococcal
3 days is likely unnecessary after colic surgery; shorter du- β-lactamases are produced by coagulase-positive Staphylococ-
rations might be equally effective. Exceptions may include cus spp. The synthesis of these enzymes is plasmid encoded, and
large colon volvulus, where an increased risk of septic peri- the enzymes are exocellular. These enzymes typically do not
tonitis is present. inactivate cephalosporins and antistaphylococcal penicillins.
Most of these β-lactamases can be inactivated by inhibi- and are quickly absorbed from IM or SC sites of administra-
tors such as clavulanic acid and sulbactam. The β-lactamase tion.47 Procaine penicillin G is more slowly absorbed from IM
inhibitors are a specific class of drugs that inhibit bacterial administration than are the sodium or potassium salts and so
β-lactamase, so they are administered in combination with produces lower but more sustained plasma concentrations.
β-lactam antibiotics.42 These drugs combine with β-lactamase The rate of absorption from IM injections of procaine penicil-
enzymes produced by gram-negative and some gram-positive lin G varies depending on the injection site, with injections
bacteria. An inactive enzyme complex is formed, and the into the neck muscle producing more rapid absorption and
coadministered antibiotic is then able to exert its effect. New higher plasma concentrations than with injections into the
evidence suggests that β-lactamase inhibitors, once thought to hindquarters.48 Benzathine penicillin G is the least soluble of
have little antimicrobial activity of their own, bind to differ- the dosage forms; it is very slowly absorbed, producing sus-
ent PBPs, affecting autolysis and contributing to the activity tained but subtherapeutic plasma concentrations of penicillin
of the concomitantly administered β-lactam antibiotic.43 The G.47 Because the benzathine fraction is poorly absorbed and
majority of clinically isolated B. fragilis spp. are β-lactamase plasma concentrations are below the MICs of most pathogens,
producers. Most of the enzymes are chromosomally mediated use of these products is not recommended in horses.49
cephalosporinases, with activities against many narrow- and
broad-spectrum penicillins and cephalosporins. Distribution
The gram-negative β-lactamases are a diverse group of The Vd of sodium penicillin G is 0.7 L/kg,50 and there is a mod-
enzymes that can be chromosomal coded, plasmid coded, or erate degree of protein binding (52%–54%).35 After absorp-
both. Chromosomal-mediated lactamases hydrolyze penicil- tion penicillin is distributed mainly in ECF and may not reach
lin, cephalosporins, or both. In the past few decades, bacteria therapeutic concentrations in sequestered infections.49
(mainly E. coli and Klebsiella spp.) have been discovered that
produce what are known as extended-spectrum β-lactamases Elimination
(ESBLs). These enzymes hydrolyze the extended-spectrum Elimination of penicillin is primarily renal, with unchanged
cephalosporins that have an oxyimino side chain, which drug being excreted by glomerular filtration and active renal
include third- and fourth-generation drugs such as cefotax- tubular secretion. The elimination half-life of penicillin G is 1
ime, ceftriaxone, and ceftazidime. The expression of ESBLs is hour,49,51 and total clearance is 8.5 ± 1.33 mL/min/kg.50 Oral
plasmid mediated, and these plasmids often encode for other penicillin V has an elimination half-life of 3.7 hours.46
genes that infer resistance to antimicrobials of other classes
(i.e., aminoglycosides, trimethoprim-sulfamethoxazole, and
quinolones). ESBL-producing strains are particularly feared Adverse Effects and Drug Interactions
as they are resistant to all penicillins, cephalosporins, and Immune-Mediated Reactions
aztreonam. Penicillin is associated with immune-mediated hemolytic
anemia (type II hypersensitivity)52,53 and anaphylaxis (type I
Y PENICILLIN G (BENZYLPENICILLIN ) hypersensitivity) in horses.54 The immune-mediated anemia
usually resolves with discontinuation of penicillin therapy.
Penicillin G was the first antibiotic developed and remains one Anaphylaxis usually occurs after previous exposure to penicil-
of the most effective antibiotics available. It is still the initial lin and can be fatal. IV epinephrine and oxygen administration
drug of choice for many bacterial infections. and respiratory support are indicated. Although it is widely
assumed that penicillin and cephalosporins are cross-reactive
Spectrum of Activity in sensitive individuals, the actual incidence in humans is
Aerobic bacteria susceptible to penicillin G include most extremely low.55
β-hemolytic streptococci, β-lactamase–negative staphylococci,
Actinomyces spp., some Bacillus anthracis, Corynebacterium
spp., and Erysipelothrix rhusiopathiae.44 Most species of anaer- Procaine Reactions and Use in
obes are susceptible, excluding β-lactamase–producing Bacte- Performance Horses
roides spp.45 Penicillin G is easily inactivated by β-lactamases When procaine penicillin G products are accidentally admin-
and has little efficacy against organisms that can produce these istered intravascularly, they cause extreme central nervous
enzymes. In addition, penicillin G is ineffective against those system stimulation.56,57 Most horses will survive unless they
bacteria that are resistant by other mechanisms, such as hav- fatally traumatize themselves during the reaction. Diazepam
ing a relatively impermeable cell wall. Therefore penicillin G will attenuate the reaction if given before procaine administra-
has little activity against many staphylococci and most gram- tion but has no effect if given afterward.56 Veterinary formula-
negative bacteria.40 tions contain higher concentrations of procaine than human
formulations, and high temperatures increase the solubility
of procaine. Therefore penicillin procaine G should be kept
Pharmacokinetics refrigerated and administered by careful IM injection. Even
Absorption with careful IM injection, adverse reactions are still reported
Because penicillin is a weak acid with a pKa of 2.7, it is highly in horses. Repeated injections increase the chance of intravas-
ionized in plasma. Gastric absorption of penicillin G is poor cular administration and may increase the sensitivity to pro-
because it is rapidly hydrolyzed in the acid environment of caine as a result of neuronal sensitization. Once absorbed into
the stomach. Phenoxymethyl penicillin (penicillin V) can be the circulation, procaine is hydrolyzed by plasma esterases to
given orally to horses and has a half-life of absorption of 0.2 the nontoxic metabolites PABA and diethylaminoethanol.58
hours.46 The sodium and potassium salts of penicillin G are The presence of PABA may inactivate sulfonamide antibiot-
the only dosage forms that are suitable for IV administration ics.59 Horses that have had documented adverse reactions to
IM procaine penicillin G injections had significantly lower

procaine hydrolyzing capacity compared with horses that did Y AMINOPENICILLINS
not have a history of adverse reactions.60 Procaine is slowly
eliminated in urine, is easily detectable by regulatory labora- Spectrum of Activity
tories, and commonly causes violative residues in racehorses The aminopenicillins are able to penetrate the outer layer
and performance horses given penicillin procaine G.61 of gram-negative bacteria better than penicillin G; there-
fore they have activity against many of the gram-negative
Electrolyte Imbalances bacteria (E. coli, Salmonella, Pasteurella spp.) as well as
The sodium or potassium content of IV formulations can con- gram-positive bacteria.18 However, resistance to the amino-
tribute to electrolyte imbalances associated with congestive penicillins is easily acquired by gram-negative bacteria, so
heart failure and renal function impairment. A million units they are not usually effective against Klebsiella, Proteus, Pseu-
of potassium penicillin contain 1.7 mEq of potassium, so it domonas, and S. aureus. Most anaerobes are sensitive, except
should be administered by slow IV injection. Potassium peni- β-lactamase–producing strains of Bacteroides.45 Amoxicil-
cillin is not recommended for use in horses with hyperkalemic lin penetrates the gram-negative cell more easily than does
periodic paralysis (HYPP). ampicillin; therefore it has greater activity against gram-
negative bacteria.44
Phenylbutazone
Concurrent administration with phenylbutazone in horses
increases plasma concentrations of penicillin G but lowers tis- Pharmacokinetics
sue concentrations. The effect is likely due to a lower periph- Absorption
eral distribution.50 In horses ampicillin sodium is well absorbed after IM or
SC administration; however, oral dosage forms are poorly
Formulations absorbed by adult horses.63 The IM administration of ampi-
Only procaine penicillin G and combination procaine/ cillin trihydrate produces lower ampicillin blood concen-
benzathine penicillin products are currently labeled for use in trations that extend over a longer period of time than does
horses. These formulations are labeled for a dose of 3000 IU/ IM ampicillin sodium.63 Oral absorption of amoxicillin is
lb (6600 IU/kg), which is a much lower dose than that con- between 5.3% and 10.4% in adult horses64,65 but between
sidered to be therapeutic. Procaine penicillin products are 36% and 42% in foals.66 The ampicillin prodrugs are con-
labeled for IM dosing once daily. Combination products are verted to ampicillin as they are absorbed from the GI tract.
labeled for IM or SC dosing once every other day. Na+ and K+ Compared with the bioavailability of oral ampicillin (2%),
penicillin (also called crystalline penicillin) are human formu- the ampicillin esters have improved oral bioavailabilities in
lation drugs used off-label intravenously, intramuscularly, or adult horses: pivampicillin (31%), bacampicillin (39%), and
subcutaneously. They achieve rapid plasma concentrations but talampicillin (23%).51,67 The low oral bioavailability of ampi-
have very short elimination half-lives and therefore must be cillin esters is due to chemical hydrolysis in the high pH of
administered frequently or by continuous rate infusion. Potas- equine ileal contents.
sium penicillin is usually less expensive than sodium penicil-
lin but must be administered more carefully because rapid IV Distribution
administration can cause cardiac arrhythmias. Procaine peni- The aminopenicillins are rapidly and widely distributed into
cillin G is a poorly soluble salt that is slowly absorbed after most body fluids; distribution into CSF is low unless the
IM injection. It is the most commonly used formulation of meninges are inflamed. The Vd of amoxicillin in adult horses
penicillin in horses. Benzathine penicillin G is a very insoluble is 0.1968 and 0.27 L/kg in neonatal foals.66 The Vd of ampicillin
salt that is used in long-acting penicillin preparations, which in horses ranges from 0.18 to 0.7 L/kg.69,70 Peak serum concen-
contain a 50:50 mixture of procaine penicillin G and benza- trations of ampicillin are 6.2 to 9.7 μg/mL 16 minutes after an
thine penicillin G. IM dose of 10 mg/kg of ampicillin sodium.63 Penetration into
synovial fluid is high,63,71 and concentrations are increased
Clinical Use and persist in infected joints.72 In a subcutaneous tissue cham-
Penicillin is still the antimicrobial of choice for many diseases ber model in ponies, concentrations of IV ampicillin sodium,
in horses, such as streptococcal and anaerobic infections. oral pivampicillin, and IM procaine penicillin G remained
Traumatic wounds are frequently infected with Streptococcus above the MIC of S. zooepidemicus for 8, 12, and 24 hours,
zooepidemicus, which is routinely susceptible to penicillin.29 respectively.73 The protein binding of amoxicillin is moderate
However, iatrogenic wounds are frequently infected with pen- (37%–38%),74 whereas it is low for ampicillin (6%–8%).51
icillinase-producing Staphylococcus aureus or other staphylo-
cocci, so culture and susceptibility testing is necessary before Elimination
initiating penicillin therapy.29,62 Amoxicillin and ampicillin are primarily excreted unchanged
The dosage of penicillin G is typically 22,000 to 44,000 IU/ in the urine. The elimination half-life of amoxicillin is approxi-
kg. Dosage frequency varies greatly depending on the formu- mately 1 hour in horses and foals.65,66,72,74 The elimination half-
lation and on the disease being treated. Procaine penicillin G life of ampicillin ranges from 0.5 hour to 2.3 hours.63,69,70,75,76
should be administered every 12 to 24 hours. Every-24-hour
dosing is only recommended for treatment of streptococci. Adverse Effects and Drug Interactions
Potassium or sodium formulations are administered every 6 Amoxicillin and ampicillin have the same adverse effects as
hours, although every-3-hour or constant rate infusion can be penicillin G. Their spectrum of action is greatly enhanced
used in immunosuppressed patients or those with life-threat- when combined with β-lactamase inhibitors such as clavu-
ening sepsis. lanic acid and sulbactam.
Elimination
Formulations Ticarcillin CA demonstrates age-dependent elimination in
Sodium ampicillin is available as a human aqueous formula- foals. In neonatal foals the Vd and clearance of ticarcillin
tion for IV, IM, and SC injection. The reconstituted aque- were approximately double those reported for older foals and
ous formulations are unstable after more than a few hours. mares.79 The renal elimination mechanism of ticarcillin appears
Ampicillin trihydrate is a poorly soluble, slow-release aque- immature in a 3-day-old foal but near normal adult function by
ous suspension approved for use in large animals. Absorp- 28 days of age. In mares the elimination half-life of clavulanic
tion is erratic, and it produces prolonged but low plasma acid is 0.4 hour.81
concentrations.
Adverse Effects and Drug Interactions
Clinical Use When ticarcillin is administered intramuscularly into the
Indications for ampicillin or amoxicillin are few insofar as hindquarters at a concentration of 400 mg/mL with 13.2 mg/
they offer little advantage over benzylpenicillins because of mL CA, foals showed signs of significant local discomfort.79 A
acquired resistance in gram-negative bacteria. Based on a lower concentration of drug did not cause signs of discomfort
tissue cage inflammation model, an IM dosage of 15 mg/kg in neonatal foals.
of ampicillin sodium given every 6 hours would be required
to treat ampicillin-susceptible bacteria.70 Sodium ampicillin Formulations
may be substituted for potassium penicillin as a choice for Ticarcillin sodium is approved in horses as a 240-mg/mL solu-
surgical prophylaxis in horses with current hyperkalemia or tion for intrauterine infusion for the treatment of endometritis
HYPP. caused by β-hemolytic streptococci. Ticarcillin disodium–
clavulanic acid formulations are available for human use.
Y ANTIPSEUDOMONAL PENICILLINS Clinical Use
Because of its strong antipseudomonal activity, intrauterine
Spectrum of Activity administration of ticarcillin is used to treat endometritis in
Carbenicillin, ticarcillin, and piperacillin are the antipseu- mares. The ticarcillin β-lactamase inhibitor drugs can be used
domonal penicillins.18 This group of penicillins can pen- in combination with aminoglycosides for a synergistic effect
etrate the outer cell wall of Pseudomonas spp. and other against the pathogens commonly encountered in septicemic
gram-negative bacteria. They are susceptible to β-lactamase foals.82
inactivation by Klebsiella spp. For this reason, these drugs
are often combined with β-lactamase inhibitors. The drug
combination most frequently used in equine medicine is Y CEPHALOSPORINS
ticarcillin and clavulanic acid (CA). This group has activ-
ity against gram-negative bacteria at the expense of activity Spectrum of Activity
against gram-positive bacteria. They retain activity against The cephalosporins are a very large group of β-lactam antibi-
anaerobic bacteria and are synergistic when administered otics. They are most commonly grouped according to “gen-
with aminoglycosides. erations,” primarily on the basis of their antibacterial activity,
as well as their susceptibility to β-lactamases (Table 2.7).18 By
convention, cephalosporins discovered before 1975 are spelled
Pharmacokinetics with a ph and after 1975 with an f.
Absorption Cephalosporins are broad-spectrum antibiotics with a wide
Bioavailability of IM ticarcillin is 65%, and the elimination range of antimicrobial activity.18,83 They are usually active
half-life is less than 1 hour in horses.77,78 Absorption of ticar- against β-hemolytic streptococci and against β-lactamase–
cillin CA in foals is age dependent; neonatal foals have a higher producing staphylococci but not against methicillin-resis-
systemic bioavailability after IM administration than older tant (oxacillin-resistant) Staphylococcus aureus (MRSA) or
foals (100% and 88% vs. 100% and 27%, respectively).79 When mycobacteria. Most enterococci are resistant. In the absence
administered intramuscularly in combination with clavulanic of acquired resistance, E. coli and Salmonella are usually
acid, ticarcillin demonstrates flip-flop kinetics, wherein the susceptible, as are some Proteus and Klebsiella spp. Fourth-
elimination half-life is longer after IM than IV injection as a generation cephalosporins are effective against Enterobac-
result of slow absorption from the injection site.80 Systemic teriaceae and other gram-negative bacteria that are resistant
absorption of both ticarcillin and CA is poor after intrauterine to earlier generations of cephalosporins because of acquired
administration.81 β-lactamase resistance. Common gram-negative aerobic
respiratory pathogens such as Haemophilus and Pasteurella,
Distribution including β-lactamase producers, are usually susceptible to
Peak endometrial concentrations of ticarcillin after IV admin- cephalosporins. Although most corynebacteria are suscep-
istration were 12.9 μg/g but were greater than 150 μg/g when tible, Rhodococcus equi is usually resistant. Only antipseudo-
6 g were diluted in 250 mL of saline and infused into the monal cephalosporins (some third and fourth generation)
uterus.77 The Vd of ticarcillin in older foals was 0.24 L/kg, and are effective against P. aeruginosa. Activity against non–
the Vd of clavulanic acid was 0.48 L/kg. In neonatal foals the spore-forming anaerobic bacteria is variable and similar to
Vd was higher at 0.69 L/kg, as would be expected for a low-Vd that of the aminopenicillins. Cefoxitin is notably resistant to
drug in a neonate, with its increased ECF volume.79 In mares β-lactamase–producing anaerobes, including Bacteroides fra-
the Vd of ticarcillin was 0.13 L/kg, and the Vd of clavulanic gilis. Ceftiofur is active against respiratory pathogens such as
acid was 0.18 L/kg.81 streptococci, Pasteurella spp., and Histophilus spp. and most
TABLE 2.7 Pharmacokinetics of Cephalosporins in Horses

Classification of Cephalosporins
Characteristics Examples
First generation Effective against almost all gram-positive bacteria, Cephacetrile, cephaloridine, cephalothin,
including β-lactamase–positive staphylococci; entero- cephapirin, cefazolin,a cefadroxil,
cocci are resistant; effective against some gram-negative cephadrine, cephalexin
bacteria,a although sensitive to enterobacterial β-lactamase
Second generation Greater activity against gram-negative bacteria due to in- Cefaclor, cefotetan,b cefoxitin,b cefuroxime,
creased resistance to β-lactamasesb; similar gram-positive cefuroxime axetil, cefamandole,
spectrum to first-generation drugs cefmetazole, cefonocid, cefprozil
Third generation Greater activity against gram-negative organisms; some Cefoperazone,c cefsulodin, ceftazidime,c
drugs active against Pseudomonas aeruginosac; resistant cefotaxime,d ceftizoxime proxetil,
to many β-lactamases; less active against gram-positive ceftriaxone, ceftiofur,d cevofecin, cefdinir,
cocci, with a few exceptionsd latamoxef (moxalaxtam), cefetamet,
cefixime, cefpodoxime, cefovicin
Fourth generation Broad spectrum of activity against gram-positive and Cefepime, cefquinome, cefpirome
gram-negative bacteria; resistant to staphylococcal,
enterobacterial, and pseudomonal β-lactamases
Relative Activity of Cephalosporins against Common Bacteriae
E. coli, Klebsiella, Pseudomonas Other

Drug Generation S. aureusf Proteus Enterobacter aeruginosa Bacteroides Anaerobes
Cephalothin 1 +++ ++ − − − +
Cefuroxime 2 ++ +++ − − − +
Cefoxitin 2 + +++ + − ++ ++
Cefotaxime 3 ++ +++ + − + ++
Ceftriaxone 3 + +++ + − − +
Ceftazidime 3 + +++ ++ +++ − −
Ceftiofur 3 ++ ++ + − − +
Cefepime 4 ++ +++ +++ +++ − +
Protein Clearance
Drug Vd (L/kg) T½ or MRT (hr) Binding (%) (mL/min/kg) F (%) Dose (mg/kg)
FIRST GENERATION
Cefazolin111 0.19 0.6–0.8 8 5.51 IV: 11
Cephalothin112 0.15 0.25 18 13.6 IV: 11
Cephapirin113 0.17 0.9 10 95 IV, IM: 20
Cephradine114 0.4 1.6 6.7 IV, PO: 25
CEFADROXIL
Adults87 0.46 0.8 7 IV: 25
Foals86 0.52 1.4 37–100 IV: 5, PO: 5–20
SECOND GENERATION
Cefoxitin115 0.12 0.8 4.32 77 IV, IM: 20
THIRD GENERATION
Ceftriaxone98 0.15 0.81 2.81 IV: 14
Cefotaxime99 0.29 0.6 5.2 IV: 40
CEFTIOFUR
Adults116 0.43 5.11 99 42 IM: 2.2
Foals91 0.76 3
Cefoperazone117 0.68 IV: 0.77 12 42 IV, IM: 30
IM: 1.52
Continued
TABLE 2.7 Pharmacokinetics of Cephalosporins in Horses—cont’d

Protein Clearance
Drug Vd (L/kg) T½ or MRT (hr) Binding (%) (mL/min/kg) F (%) Dose (mg/kg)
FOURTH GENERATION
CEFEPIME
Adults100 0.23 2.1 100 IV, IM: 2.2
Foals118 0.18 1.65 1.33 IV: 14

aMost activity against gram-negative bacteria in this generation.
bMost activity against Bacteroides fragilis.
cMost activity against Pseudomonas aeruginosa.
dMost activity against gram-positive cocci in this generation.
e+++, Highly active; ++, moderately active; +, limited activity; −, no clinical activity. Susceptibilities for individual isolates may vary.
fMethicillin-susceptible Staphylococcus aureus.
IM, Intramuscular; IV, intravenous.
anaerobes but has less activity against S. aureus and Entero- through a combination of glomerular filtration and active tubu-
bacteriaceae than other third-generation drugs. Bacteroides lar secretion. Therefore it may be necessary to modify the dos-
spp. and Pseudomonas spp. are resistant to ceftiofur. When age regimen of most cephalosporins for patients in renal failure,
administered, ceftiofur is rapidly metabolized to the active although there is a low risk of adverse effects at high concentra-
metabolite desfuroylceftiofur. Desfuroylceftiofur is less active tions. For the cephalosporins that undergo hepatic metabolism,
than ceftiofur against S. aureus and Proteus spp.84 Diagnos- hepatic insufficiency may decrease metabolism and increase
tic laboratories use a ceftiofur disk for susceptibility testing drug accumulation.
because of the instability of desfuroylceftiofur, so susceptibil- The two most recent cephalosporins to be approved for
ity testing results for staphylococci and Proteus spp. may not veterinary use are exceptions to the general pharmacokinetic
reliably predict the efficacy of ceftiofur therapy. attributes of this drug class. Ceftiofur crystalline free acid
The broad-spectrum antibacterial activity of the cephalo- (CCFA) and cefovicin are sustained release formulations. Of
sporins may cause overgrowth (“superinfection”) by inher- these, CCFA is labeled for use in horses. This drug provides
ently resistant bacteria, including C. difficile, which no longer therapeutic concentrations (based on an MIC of ≤0.2 μg/mL
have to compete with the normal microbial flora. Nosoco- for streptococci) for up to 4 days following a single dose and
mial infection with vancomycin-resistant enterococci (VRE) for 10 days using a two-dose regimen. Compared with cef
has become a serious problem in human hospitals. One of tiofur sodium, it has a lower Cmax and a longer Tmax, with an
the highest risk factors for contracting a VRE infection in a absolute bioavailability of 100%.92 The half-life of CCFA is
human hospital is treatment with a cephalosporin.85 approximately 4 times longer than that of ceftiofur sodium (81
hours vs. 21.5 hours), which is consistent with flip-flop kinet-
ics. Pharmacokinetics are not significantly different when
Pharmacokinetics the dose is divided and administered in two different sites.93
Absorption, Distribution, and Elimination CCFA penetrates well into the endometrium and can be used
Numerous pharmacokinetic studies have been done on horses for treatment of endometritis caused by Streptococcus equi
using multiple different cephalosporin antibiotics (see Table subsp. zooepidemicus. However, it does not appear to cross
2.7). In general, IM and SC administration of cephalosporins the blood-placental barrier as administration to mares with
results in rapid drug absorption, but the extent varies with streptococcal placentitis did not improve foal survival or pre-
the drug and the species. Oral bioavailability is acceptable in vent septicemia in foals.94 Investigations in healthy neonatal
neonates but rapidly becomes too low to be practical for older foals showed that subcutaneous administration of CCFA had
foals or adults.86,87 An ester formulation of cefpodoxime, cef- a lower AUC, shorter observed time to maximum concentra-
podoxime proxetil, has been examined for use in horses. In a tion, and higher observed Cmax compared with adult horses.95
study in foals, oral absorption was good enough that a dose of Weanling age foals (4–6 months old) also exhibit different
10 mg/kg every 6 to 12 hours produced plasma concentrations pharmacokinetics, including higher peak plasma concentra-
that would potentially treat infections.88 The values for Vd in tions and AUC compared with adults; however, these differ-
horses for the cephalosporins are typically low (less than 0.3 L/ ences were not significant enough to necessitate a difference
kg), indicating distribution primarily to ECF. However, they in dosing regimen.96
have good distribution into the ECF of most tissues, including
pleural, pericardial, and synovial fluid. Penetration into corti- Adverse Effects and Drug Interactions
cal and cancellous bone is usually adequate.89 Cephalosporins In general cephalosporins have a high therapeutic index.
penetrate poorly into the ocular humor and, except for some The adverse effects of the cephalosporins are similar to
third-generation drugs, do not achieve therapeutic concen- those reported for the penicillins, including hypersensitiv-
trations in the central nervous system.18 In general the third- ity allergic reactions. Bleeding disorders have been reported
generation cephalosporins have an increased ability to in humans but not in animals.97 The reaction appears to be
penetrate the central nervous system.90 Higher Vd values for related to vitamin K antagonism and/or platelet dysfunc-
foals reflect the increased ECF compartment of the neonate.86,91 tion and is usually only an issue with drugs that contain
Most cephalosporins are rapidly eliminated as the unchanged an N-methylthiotetrazole side chain (cefoperazone, cefo-
drug in the urine. Renal excretion of cephalosporins occurs tetan, cefamandole). High doses of ceftiofur and cefotaxime
may cause anemia and thrombocytopenia. Ceftriaxone and CCFA will provide 10 days’ worth of therapeutic concen-
cefepime cause GI disturbances after administration to foals trations against streptococci (MIC < 0.2 μg/mL) following a
and horses.98-100 The currently available cephalosporins are two-dose regimen (6.6 mg/kg IM, repeated 96 hours later).
considered to be potentially nephrotoxic by way of depo- Extralabel dosing of the drug has been used in clinical prac-
sition of immune complexes in the glomerular basement tice, mainly through the use of prolonged dosing regimens.
membrane or from a direct toxic effect leading to acute tubu- For treatment of streptococci, the recommended dosing regi-
lar necrosis, although this does not seem to be an issue at men for CCFA is 6.6 mg/kg IM on day 1 and 4, then every 7
clinically relevant doses.101 Like the penicillins, cephalospo- days after.109 For more resistant bacteria (MIC ≤ 1 μg/mL), the
rins can be synergistic with aminoglycosides against many recommended dosing regimen is 6.6 mg/kg IM every 4 days.
pathogens.102 In human medicine it is recommended that Similar dosing regimens are recommended in weanling foals.
cephalosporins not be used in conjunction with aminogly- For neonatal foals, administration at a dose of 6.6 mg/kg body
cosides; however, animal studies demonstrate a protective weight SC every 72 hours would be expected to provide pro-
effect of the cephalosporins against nephrotoxicity.103 tection against bacteria isolated from neonatal foals, based on
Ceftiofur is associated with diarrhea caused by altered GI an MIC of 0.5 μg/mL.95
flora in horses.104,105 Toxicity studies have shown that horses
tolerate ceftiofur doses up to 11 mg/kg/day IM, with pain at Y CARBAPENEMS
the injection site and decreased feed consumption as the most
common adverse effect at the highest dose. The main adverse The carbapenems are the newest class of β-lactam antimicro-
effect associated with CCFA has been injection site reactions, bials. They have an extended spectrum of activity, including
which can be minimized by splitting the dose into two different many gram-negative bacteria. The only notable exceptions
injection sites, injecting no more than 10 mL per site, drawing include MRSA and resistant Enterococcus faecium. The high
up the drug with a separate needle and using a new needle activity of these drugs is due to the ability to withstand the
for each injection site, and using a 16-g, 1.5-in needle. Sub- β-lactamases (including ESBL) and the ability to penetrate
cutaneous administration of CCFA in adult horses appeared porin channels that usually exclude other drugs. Pharmacoki-
to increase the risk for injection site reactions, although netic properties are similar to other β-lactam drugs in horses,
this route is considered safe in neonatal foals.95,106 Reported including poor oral bioavailability, a short half-life, and low to
consequences of injection site reactions include fever (up to moderate Vd, although carbapenems have a long postantibi-
103.5°F), abscessation, and clostridial myositis. otic effect. Clinical use in horses is typically limited to septic
neonates because of cost and the need for appropriate antibi-
Formulations otic stewardship, as these are considered critically important
Cefadroxil is available as veterinary-formulated tablets or sus- drugs in human medicine. Drugs in this class include imipe-
pension for small animals. Cephalexin is available as human nem and meropenem.
tablets and suspensions for oral administration. Cefpodox- Imipenem has been used in neonatal foals at a dose of 5
ime proxetil is available as veterinary-formulated tablets (100 mg/kg IV infused over 20 minutes q6–8hr. A pharmacokinetic
or 200 mg) for dogs. Cefepime (human) and ceftiofur (food study in adult horses suggests a dose of 10 to 20 mg/kg imipe-
animal “ready to use”) are available as hydrochloride formula- nem by slow IV infusion q6hr would be necessary to maintain
tions. Ceftiofur sodium is labeled for horses and is available as adequate plasma concentrations.110 Imipenem is available in
a 1-g or 4-g sterile powder to be reconstituted in sterile water human injectable formulations in combination with cilastatin.
to a final concentration of 50 mg/mL. Once reconstituted, the Cilastatin inhibits renal brush border enzymes that would oth-
product is stable for up to 12 hours at room temperature, 7 erwise convert imipenem into a nephrotoxic metabolite. Pre-
days when refrigerated, and 6 months when frozen. CCFA vention of this metabolism not only decreases toxicity of the
is available as sterile suspension equivalent to 200 mg/mL of drug, but it also increases the concentration of active parent
ceftiofur in a caprylic/capric triglyceride and cottonseed oil drug into the urine.
base. Meropenem is a slightly less expensive than imipenem and
is less irritating when injected IM or SC. Pharmacokinetic
Clinical Use data on meropenem are lacking; however, based on therapeu-
Ceftiofur sodium is approved for treatment of respiratory dis- tic drug monitoring in clinical cases, the clearance was high
ease caused by S. equi subsp. zooepidemicus at a dose of 2.2 to (5.2 mL/min/kg) and the half-life was short (34.5 min). Due
4.4 mg/kg q24hr IM. Higher doses or more frequent intervals to its short half-life, a constant rate infusion of 10 μg/kg/min
have been recommended for treating gram-negative organ- (15 mg/kg/day) is recommended. This dose will be adequate
isms (e.g., Klebsiella, Enterobacter, Salmonella). Because these for bacteria with MICs ≤ 2 μg/mL. Pharmacokinetics appear
organisms are inherently more resistant, higher plasma concen- to be linear over a range of 10 to 30 μg/kg/min with no noted
trations are needed for efficacy. The susceptibility breakpoint adverse effects in the small number of clinical cases for which
for ceftiofur use in horses is very low (less than 0.25 μg/mL), it has been used.
and organisms other than streptococci may be classified
in vitro as resistant. In septic neonatal foals, doses as high as Y AMINOGLYCOSIDES
10 mg/kg IV q6hr have been used. However, more recent stud-
ies in foals have shown lower doses (5 mg/kg IV, SC q12hr) are The aminoglycoside antibiotics include streptomycin, neo-
sufficient for the treatment of most bacteria cultured from sep- mycin, gentamicin, amikacin, tobramycin, and kanamycin.
tic neonates (MIC90 < 0.5 μg/mL).107 Constant rate infusion of They have a chemical structure of amino sugars joined by a
ceftiofur has also been shown to be safe in foals at doses up to glycoside linkage. The importance of this group in veterinary
20 mg/kg/day.108 This dose rate is adequate for the treatment medicine is to treat serious infections caused by aerobic gram-
of bacteria with MICs up to 4 μg/mL. negative bacteria and staphylococci. Amikacin and tobramycin
have excellent activity against P. aeruginosa. Nevertheless, the spp. are intracellular pathogens and are often resistant. Some
aminoglycosides remain important drugs in the treatment of mycobacteria, spirochetes, and mycoplasma are susceptible.
severe gram-negative sepsis, although their highly cationic, Aminoglycosides are ineffective against anaerobic bacteria
polar nature means that distribution across membranes is lim- because aminoglycoside penetration into the bacteria requires
ited. Single daily dosing is now recommended for most dosage an oxygen-dependent transport mechanism. Amikacin was
regimens because it maximizes efficacy and reduces toxicity. developed from kanamycin and has the broadest spectrum of
activity of the aminoglycosides. It is effective against strains
Mechanism of Action not susceptible to other aminoglycosides because it is more
The aminoglycosides are large molecules with numerous resistant to bacterial enzymatic inactivation and is considered
amino acid groups, making them basic polycations that are the least nephrotoxic.
highly ionized at physiologic pHs. Aminoglycosides must
penetrate the bacteria to assert their effect. Susceptible, aero- Resistance Mechanisms
bic gram-negative bacteria actively pump the aminoglycoside Aminoglycoside resistance is primarily due to enzymes
into the cell. This is initiated by an oxygen-dependent interac- encoded by genes located on bacterial plasmids. These phos-
tion between the antibiotic cations and the negatively charged photransferases, acetyltransferases, and adenyltransferases act
ions of the bacterial membrane lipopolysaccharides. This internally to alter the aminoglycoside and prevent it from bind-
interaction displaces divalent cations (Ca++, Mg++), which ing to ribosomes.18 Amikacin is least susceptible to enzyme
affects membrane permeability.119 Once inside the bacterial inactivation. Plasmid-mediated resistance to the aminoglyco-
cell, aminoglycosides bind to the 30S ribosomal subunit and sides is transferable between bacteria. A single type of plasmid
cause a misreading of the genetic code, interrupting normal may confer cross-resistance to multiple aminoglycosides and
bacterial protein synthesis. This changes the cell membrane to other unrelated antimicrobials. Bacteria may also utilize
permeability, resulting in additional antibiotic uptake, further other methods that reduce the efficacy of aminoglycosides.
cell disruption, and ultimately cell death. Some strains of bacteria are less permeable to aminoglycosides,
Aminoglycoside action is bactericidal and concentration requiring much higher concentrations of aminoglycosides to
dependent. For example, concentrations of gentamicin in the kill them and therefore can be selected for during treatment.
range of 0.5 to 5.0 μg/mL are bactericidal for gram-positive Chromosomal-mediated resistance is minimal and develops
and some gram-negative bacteria. At 10 to 15 μg/mL, genta- slowly for most of the aminoglycosides, with the exception of
micin is effective against the more resistant bacteria such as streptomycin or dihydrostreptomycin; resistance to streptomy-
Pseudomonas aeruginosa, Klebsiella pneumoniae, and Proteus cin can occur from a single-step mutation.
mirabilis.120 The clinical implication is that high initial doses of
aminoglycosides increase ionic bonding, enhancing the initial First Exposure Adaptive Resistance
concentration-dependent phase of rapid antibiotic internal- Both subinhibitory and inhibitory aminoglycoside concentra-
ization, which leads to greater immediate bactericidal activ- tions produce resistance in bacterial cells surviving the initial
ity. Human clinical studies demonstrate that proper initial ionic binding.122 This adaptive resistance is due to decreased
therapeutic doses of aminoglycosides are critical in reducing aminoglycoside transport into the bacteria. Exposure to one
mortality from gram-negative septicemia. For antimicrobi- dose of an aminoglycoside is sufficient to produce resistant
als whose efficacy is concentration dependent, high plasma variants of an organism with altered metabolism and impaired
concentration levels relative to the MIC of the pathogen aminoglycoside uptake. In vitro animal and clinical studies
(Cmax:MIC ratio, also known as the inhibitory quotient, or IQ) show that the resistance occurs within 1 or 2 hours of the first
and the area under the plasma concentration–time curve that dose. The duration of adaptive resistance relates directly to the
is above the bacterial MIC during the dosage interval (area elimination half-life of the aminoglycoside. With normal ami-
under the inhibitory curve, AUIC = AUC/MIC) are the major noglycoside pharmacokinetics, the resistance may be maximal
determinants of clinical efficacy. For the aminoglycosides a for up to 16 hours after a single dose of aminoglycoside, fol-
Cmax:MIC ratio of 10 is suggested to achieve optimal efficacy.27 lowed by partial return of bacterial susceptibility at 24 hours
The aminoglycosides have a significant PAE, meaning the and complete recovery at approximately 40 hours.123 If the
period of time during which antimicrobial concentrations are aminoglycoside is dosed multiple times a day or the drug con-
below the bacterial MIC but the antimicrobial-damaged bac- centration remains constant, as with a continuous infusion,
teria are more susceptible to host defenses. The duration of the adaptive resistance persists and increases. Adaptive resistance
PAE tends to increase as the initial aminoglycoside concentra- is likely to persist in peripheral compartments, which are often
tion increases.121 the site of infection because of the persistence of aminoglyco-
Antimicrobial activity of aminoglycosides is enhanced in sides at these sites. Dose administration at 24-hour intervals,
an alkaline environment (pH of 6–8). They bind to and are or longer, may increase efficacy by allowing time for adaptive
inactivated by the nucleic acid material released by decaying resistance to reverse.122-124
white blood cells. Therefore they are usually ineffective in the
acidic, hyperosmolar, anaerobic environment of abscesses. Pharmacokinetics
Absorption. See Table 2.8 for the pharmacokinetics of gen-
Spectrum of Activity tamicin, amikacin, and tobramycin in horses. Amikacin and
The aminoglycosides are effective against most aerobic gram- gentamicin are rapidly and well absorbed from IM and SC
negative bacteria, including Pseudomonas.18 They are some- routes of administration but are not absorbed orally.119
what effective against staphylococci, although resistance Distribution. The aminoglycosides are polar antibiotics;
can occur. They are often effective against enterococci, but therefore distribution is limited to the ECF space. The Vd
therapy against streptococci is more effective when com- in most species ranges between 0.15 and 0.3 L/kg.125,126 Af-
bined with a β-lactam antibiotic. Salmonella and Brucella ter parenteral administration, effective concentrations are
TABLE 2.8 Pharmacokinetics of Aminoglycosides in Horses

Drug Volume of Distribution (L/kg) Half-Life or MRT (hr) Clearance (mL/min/kg) Dose (mg/kg)
AMIKACIN
Foals, 3-day-old2 0.42 2.7 1.92 7
Foals, premature, hypoxic161 0.60 5.4 1.9 7
Neonatal, high sepsis score126 0.34 4.10 1.17 IV: 6.6
Horses187 0.14–0.2 1.14–1.57 1.28–1.49 IV: 4.4, 6.6, 11
Horses188 0.13 1.34 1.25 IV: 10
GENTAMICIN
Foals, 1-day-old125 0.31 2.2 1.75 4
Foals, 1-month-old125 0.24 3.07 0.9 IV: 4
Mares, late pregnancy128 0.15 2.26 1.06 —
Horses130 0.17 1.66 1.41 IV: 3
Horses, endotoxic130 0.14 1.54 1.17 IV: 3
Horses158 0.12 0.78 — IV: 6.6
Horses127 0.27 2.17 1.56 IV: 2.2
Horses159 0.14 3.0 — IV, IM: 6.6
Ponies129 0.19 1.82 1.27 IV, IM: 5
Horses, intravenous fluids131 0.15 1.96 1.04 IV: 2.2
Horses, postoperative132 0.17 1.47 1.27 IV: 6.6
TOBRAMYCIN
Horses173 0.55 4.02 2.17 IV: 4
Horses174 0.18 4.61 1.18 IV, IM: 4

IM, Intramuscular; IV, intravenous; MRT, mean residence time.
obtained in synovial, perilymph, pleural, peritoneal, and peri- in animals with renal dysfunction.126 Renal accumulation
cardial fluid.127 Therapeutic concentrations are not achieved results in extended withdrawal times for food animals.
in bile, CSF, respiratory secretions, and prostatic and ocular
fluids.119 Gentamicin does not cross the placenta of late-term Foals
mares; however, endometrial tissue concentrations of gen- The pharmacokinetics of aminoglycosides in foals is different
tamicin were higher than plasma concentrations after 7 days from that in adults. The most consistent difference is in the Vd,
of IM therapy with a dose of 5 mg/kg every 8 hours.128,129 The which is higher in neonatal foals due to a larger volume of ECF.
predominant site of drug accumulation is the renal cortex Clearance is usually unaffected, except for slight increases in
in most species. In endotoxemia, gentamicin concentrations septic or compromised neonates. This results in an increased
increase in serum as a result of a fever-induced decrease in elimination half-life in animals less than 2 weeks of age.126 It
the volume of the ECF compartment.130 The administration also results in a Cmax lower than that in adult horses, necessi-
of therapeutic fluids, colic surgery, or peritoneal lavage does tating higher doses and possibly longer dosing intervals.
not significantly change the pharmacokinetics of concurrently
administered gentamicin.131-133
Gentamicin distributed into synovial fluid in normal Adverse Effects and Drug Interactions
horses and reached a peak of 6.4 μg/mL at 2 hours with a Nephrotoxicity
single 4.4-mg/kg IV dose.134 Intraarticular administration or The aminoglycosides enter the renal tubule after filtration
regional perfusion techniques are excellent methods to deliver through the glomerulus (Fig. 2.22). From the luminal fluid
aminoglycosides locally and prevent the adverse effects of sys- the cationic aminoglycoside molecules bind to anionic phos-
temic therapy.135-141 When intraosseous perfusion was com- pholipids on the proximal tubular cells.145 The aminoglycoside
pared with IV perfusion, each technique produced mean peak is taken into the cell by way of carrier-mediated pinocytosis
concentrations of amikacin ranging from 5 to 50 times that and translocated into cytoplasmic vacuoles, which fuse with
of recommended peak serum concentrations for therapeutic lysosomes.146 The drug is sequestered unchanged in the
efficacy.142 Gentamicin-impregnated polymethylmethacry- lysosomes. With additional pinocytosis drug continues to
late beads or collagen sponges may also be used to achieve accumulate within the lysosomes. The accumulated aminogly-
extremely high local concentrations of drug, while avoiding coside interferes with normal lysosomal function, and eventu-
systemic toxicity.143,144 ally the overloaded lysosomes swell and rupture. Lysosomal
enzymes, phospholipids, and the aminoglycoside are released
Elimination into the cytosol of the proximal tubular cell, disrupting other
The aminoglycosides are almost exclusively eliminated in organelles and causing cell death.147
urine by glomerular filtration.119 The plasma elimination half- The risk factors for aminoglycoside toxicity include pro-
lives range from 1 to 3 hours in adult animals but are increased longed therapy (longer than 7–10 days), acidosis and electrolyte
Tubular lumen If therapeutic drug monitoring is unavailable, then once-

Renal tubule epithelial cell daily high-dose therapy is recommended; the development
of nephrotoxicity is detected by an increase in urine gamma
glutamyl transferase (UGGT) enzyme and an increase in the
UGGT:urine creatinine (UCr) ratio. The UGGT:UCr may
increase to 2 to 3 times baseline within 3 days of a nephrotoxic
dose.148,163,164 If these tests are not available, the development
of proteinuria is the next best indicator of nephrotoxicity and
is easily determined in a practice setting.163,164 Elevations in
serum urea nitrogen and Cr confirm nephrotoxicity but are not
seen for 7 days after significant renal damage has occurred.126
Aminoglycoside molecules Lysosomes Elimination half-lives of 24 to 45 hours have been reported
in horses with renal toxicity, further prolonging the toxic
FIG. 2.22 Nephrotoxicity occurs from ionic binding of aminoglycoside exposure to the drug.151 Although peritoneal dialysis is use-
molecules to polysaccharide cations on the proximal tubular epithelium,
ful in lowering creatinine and serum urea nitrates, it may not
followed by pinocytosis and accumulation within lysosomes.
be effective in significantly increasing the elimination of the
accumulating aminoglycoside.151 The horse’s ability to recover
most likely depends on the type of medication exposure and
disturbances (hypokalemia, hyponatremia), volume depletion the amount of healthy renal tissue remaining to compensate.
(shock, endotoxemia), concurrent nephrotoxic drug therapy,
preexisting renal disease, and elevated plasma trough concen- Ototoxicity
trations.147-153 Calcium supplementation can reduce the risk Aminoglycoside ototoxicity occurs from the same accumula-
of nephrotoxicity.154 Administration of antioxidants such as tion mechanisms as nephrotoxicity. In the inner ear aminogly-
silymarin and vitamin E may decrease aminoglycoside neph- cosides appear to generate free radicals that subsequently do
rotoxicity.155 The risk of nephrotoxicity can also be decreased permanent damage to sensory cells and neurons.165 Gentami-
by feeding the patient a diet high in protein and calcium, such cin damages the cochlear division of the eighth cranial nerve,
as alfalfa hay, because protein and calcium cations compete resulting in vertigo, and amikacin damages the auditory divi-
with aminoglycoside cations for binding to renal tubular epi- sion of the eighth cranial nerve, resulting in permanent deaf-
thelial cells.156 High dietary protein also increases GFR and ness. This drug-specific toxicity may be due to the distribution
renal blood flow, reducing aminoglycoside accumulation.157 characteristics of each drug and concentration achieved in
Uptake and accumulation of aminoglycosides into renal each sensory organ.166
tubular epithelium demonstrate saturable kinetics. Because
nephrotoxicity is related to aminoglycoside accumulation in Neuromuscular Blockade
the renal proximal tubular cells, it is logical that peak concen- Neuromuscular blockade is a rare effect, related to blockade
trations are not related to toxicity and that longer dose inter- of acetylcholine at the nicotinic cholinergic receptor.167 It is
vals result in less total drug exposure to the renal brush border most often seen when anesthetic agents are administered con-
membrane. High-dose, once-daily dosing of aminoglycosides currently with aminoglycosides.168,169 Diseases that affect the
has now become common in human and veterinary medicine; neuromuscular junction, such as botulism, can also precipitate
it takes advantage of the concentration-dependent killing and blockade. Affected patients should be treated promptly with
long PAE of these drugs and prevents first exposure adaptive parenteral calcium chloride at 10 to 20 mg/kg intravenously or
resistance and toxicity.132,158-160 calcium gluconate at 30 to 60 mg/kg intravenously to reverse
Individual horses can differ widely in the serum concentra- dyspnea from muscle response depression. IV edrophonium at
tions produced by the same aminoglycoside dosage regimen. 0.5 mg/kg will also reverse neuromuscular blocking effects.168
There is a tendency to underdose neonatal patients, especially
those that are receiving aggressive fluid therapy.161 To maxi- Drug Interactions
mize efficacy and minimize toxicity, therapeutic drug moni- Aminoglycosides are inactivated if combined in vitro with
toring is recommended to ensure a Cmax:MIC ratio of 10 is other drugs because of pH incompatibilities. In vitro, penicil-
acheived.27,119,162 Because the trough concentration is asso- lins interact chemically with the aminoglycoside antibacteri-
ciated with nephrotoxicity, it is recommended that trough als to form biologically inactive amides by a reaction between
concentrations be less than 2 μg/mL for gentamicin and less the amino groups on the aminoglycosides and the β-lactam
than 5 μg/mL for amikacin before the next dose is adminis- ring on the penicillins, inactivating both antibacterials. In vivo
tered.119,162 To allow for the distribution phase, blood sampling however, the aminoglycosides are synergistic against strepto-
for the peak concentration is performed 0.5 to 1 hour after IV cocci, Pseudomonas, and other gram-negative bacteria if com-
administration, and the trough sample is usually taken before bined with β-lactam antibiotics as a result of the bacterial cell
the next dose. The peak and trough concentrations can then wall being disrupted by the β-lactam antibiotic. Halothane
be used to estimate the elimination half-life for the individual anesthesia causes significant changes in the pharmacokinetics
patient. An increase in the elimination half-life during therapy of gentamicin; total body clearance and volume of distribution
is a very sensitive indicator of early tubular insult.163 If a once- decrease, and half-life of elimination increases.169 A longer
daily regimen is used, a blood sample just before the next dose gentamicin dosing interval after anesthesia may help correct
will be well below the recommended trough concentrations for the changes, but the practitioner should seriously consider
and may even be below the limit of detection of the assay. For selecting another antimicrobial. Neuromuscular blocking
these patients an 8-hour postdose sample will provide a more agents or drugs with neuromuscular blocking activity should
accurate estimate of the elimination half-life. not be used concurrently with aminoglycosides because they
can increase the risk of neuromuscular blockade, particu- a single administration in mares, and bioavailability declines
larly during anesthesia.168 Other nephrotoxic drugs should be to 20% after five doses.177 Due to the high lipid solubility of
avoided when possible during aminoglycoside therapy. Con- CHPC, even topical administration in the eye can result in sig-
current administration of phenylbutazone with gentamicin nificant systemic absorption.
decreases the elimination half-life of gentamicin by 23% and
decreases the Vd by 26%; the pharmacokinetics of phenylbu- Distribution
tazone are not affected.170 Flunixin has no effect on the phar- Because of high lipid solubility and low protein binding, CHPC
macokinetics of gentamicin when administered concurrently is widely distributed throughout the body. Highest drug lev-
to adult horses.132 els are attained in the liver and kidney, but therapeutic drug
concentrations are attained in most tissues and fluids, includ-
Formulations ing abscesses, ocular humor, and synovial fluid.18 CHPC may
Gentamicin and amikacin are available as brand name and achieve CSF concentrations of up to 50% of plasma concentra-
generic solutions for intrauterine infusion in mares. Human tions when the meninges are normal, and more if inflamma-
and small animal labeled products for gentamicin, amikacin, tion is present.178 The Vd of CHPC is 2.83 L/kg in horses179
and tobramycin are administered by IV, IM, SC, intraarticular, and 1.6 L/kg in neonatal foals.160 The degree of protein bind-
and intraosseous routes to horses. Gentamicin is also avail- ing of CHPC in horses is 30%.180
able in ophthalmic formulations for the treatment of gram-
negative keratitis. Elimination
In most species CHPC is eliminated by renal excretion of par-
Clinical Use ent drug and by hepatic glucuronide conjugation and elimina-
Gentamicin and amikacin are commonly used to treat seri- tion in feces. The elimination half-life of CHPC in foals older
ous gram-negative infection in horses and septicemia in foals, than 7 days and adult horses is less than 1 hour.176,179-182 In
often combined with β-lactam antimicrobials. Amikacin or 1- and 3-day-old foals the elimination half-life is 5.3 and 1.4
tobramycin is used when antimicrobial resistance to gentami- hours, respectively, indicating the immaturity of the foal’s
cin has developed in gram-negative pathogens, but gentamicin hepatic metabolism capacity.181 The elimination half-life is
has greater activity against streptococci than amikacin.29 The greatly prolonged in premature foals, and this drug should be
use of aminoglycosides in horses had previously been limited used with caution.
because of toxicity concerns, but high-dose once-daily dosing
greatly reduces the risks. Use of the aminoglycosides is also Adverse Effects and Drug Interactions
limited by their poor penetration of cellular membranes and Insofar as these drugs are protein synthesis inhibitors, dose-
inactivation in purulent environments. related anemia and pancytopenia are associated with chronic
therapy (longer than 14 days), causing a decrease in protein
Y AMPHENICOLS synthesis in the bone marrow. FLF is more likely than CHPC
to cause reversible bone marrow suppression with chronic
Chloramphenicol (CHPC) was isolated in 1947 from a soil dosing or overdose.183 In humans an idiosyncratic aplas-
actinomycete from Venezuela. Florfenicol (FLF) is a fluori- tic anemia occurs with exposure to CHPC.184 The reaction
nated derivative of CHPC. Although CHPC is well tolerated is rare (1 in 30,000) and not dose related. Toxic effects are
by horses, FLF alters fecal consistency, enteric flora, and sus- related to the presence of the para-nitro group on the CHPC
ceptibility of Salmonella spp., E. coli, and Clostridium perfrin- molecule. If CHPC is dispensed for client use at home, appro-
gens, and its use is not recommended. priate client education should always accompany the pre-
scription, including dissolving the drug rather than crushing
Mechanism of Action tablets and wearing gloves during and washing hands after
Chloramphenicol is a bacteriostatic antibiotic that inhibits administration.
protein synthesis by binding to ribosomal subunits of suscep- CHPC is a hepatic microsomal enzyme inhibitor. It
tible bacteria, leading to the inhibition of peptidyl transferase decreases the clearance of other drugs metabolized by the
and thereby preventing the transfer of amino acids to growing same cytochrome P450 enzymes, including phenytoin, phe-
peptide chains and subsequent protein formation.175 There is a nobarbital, pentobarbital, phenylbutazone, xylazine, and
very wide spectrum of activity, including streptococci, staphy- cyclophosphamide.185,186
lococci (including many MRSA), anaerobes, Haemophilus, In general, CHPC should not be administered concurrently
Salmonella, Pasteurella, Mycoplasma, and Brucella spp., as well with penicillins, macrolides, aminoglycosides, or fluoroqui-
as rickettsia, chlamydia, and hemobartonella.2 nolones. CHPC may antagonize the activity of penicillins or
aminoglycosides, and they act on the same ribosomal site
Mechanisms of Resistance as the macrolides.187,188 Inhibition of protein synthesis by
Bacterial resistance to CHPC results from plasmid-mediated CHPC interferes with the production of autolysins neces-
bacterial production of acetylase enzymes. Acetylation of sary for cell lysis after fluoroquinolones interfere with DNA
hydroxyl groups prevents drug binding to the 50S ribosomal supercoiling.189
subunit.
Formulations
CHPC sodium succinate is a water-soluble formulation for IV
Pharmacokinetics use and is hydrolyzed to CHPC in the liver. CHPC free base
Absorption and CHPC-palmitate are available for oral administration.
CHPC is rapidly absorbed after oral administration. The oral The CHPC-palmitate is hydrolyzed in the GI tract to CHPC.
bioavailability of CHPC in foals is 83%176 but only 40% after Ophthalmic formulations of CHPC are also available.
include protozoa (Toxoplasma gondii, Sarcocystis neurona) and

Clinical Use coccidia. PYM is more effective than TMP against protozoa.191
CHPC is banned for use in any type of food animal because it The potentiated sulfonamides are formulated at a fixed ratio of
can lead to idiosyncratic aplastic anemia in humans. In coun- 1:5 of TMP to sulfonamide. The optimum concentration for
tries where its use is permitted in horses, it is used for a vari- bactericidal action is 1:20.190 When and where this optimum
ety of bacterial infections, especially when penetration into concentration is achieved are difficult to predict in vivo, but a
abscesses (e.g., umbilical abscesses) and the central nervous 1:20 ratio is used in susceptibility testing.193
system is desired, but appropriate precautions should be taken
in handling the product to prevent human exposure. Because Mechanisms of Resistance
of the short half-life, high doses administered frequently are Bacterial resistance to the sulfonamides is common and may be
recommended (50 mg/kg PO q6–8hr). from chromosomal mutations or mediated by plasmids. Chro-
mosomal mutations can lead to bacterial hyperproduction of
Y POTENTIATED SULFONAMIDES PABA, which overcomes the competitive substitution of the
sulfonamides. Plasmid-encoded resistance results in a bypass
The sulfonamides are a group of organic compounds with che- of the drug-sensitive step by production of altered forms of
motherapeutic activity (hence they are antimicrobials, not anti- the DPS enzyme with a lower affinity for sulfonamides. Resis-
biotics). They have a common chemical nucleus that is closely tance to TMP usually occurs by plasmid-encoded production
related to p-aminobenzoic acid, an essential component in the of TMP-resistant dihydrofolate reductase. Other resistance
folic acid pathway of nucleic acid synthesis. Sulfonamides are mechanisms include excessive bacterial production of dihy-
combined with diaminopyrimidines such as trimethoprim drofolate reductase (DHFR) and reduction in the ability of
(TMP) and pyrimethamine (PYM), which inhibit an essential the drug to penetrate the bacterial cell wall. Cross-resistance
step farther along the folate pathway. Because the potentiated among sulfonamides is considered complete and often occurs
sulfonamides are remarkably synergistic and nontoxic, they with pyrimidines.190 Resistance to the TMP-sulfonamide com-
are commonly used in equine medicine. Their use is compli- binations develops slowly but is now common among equine
cated by differences in pharmacokinetics among TMP and bacterial isolates.29,194
PYM and the various sulfonamides used in the combinations.
Pharmacokinetics
Mechanism of Action Pharmacokinetics of the potentiated sulfonamides are com-
The sulfonamides inhibit the bacterial enzyme dihydroptero- plicated by the distinct differences between disposition of
ate synthetase (DPS) in the folic acid pathway, thereby block- TMP and PYM and the various sulfonamides. When sulfon-
ing bacterial nucleic acid synthesis. Sulfonamides substitute amides and diaminopyrimidines are administered concur-
for PABA, preventing its conversion to dihydrofolic acid. rently to horses, the pharmacokinetics of each drug appears
Alone, this action is considered bacteriostatic. Because the to be unaffected by the presence of the other. Table 2.9 out-
activity is by competitive substitution, the sulfonamide tissue lines the pharmacokinetics of specific potentiated sulfon-
concentration must be kept high enough to prevent bacterial amide combinations in horses. Although the potentiated
access to PABA. Therefore the sulfonamides are ineffective in sulfonamides are frequently used interchangeably, pharma-
pus and necrotic tissue, which provide additional sources of cokinetic studies show that they are not bioequivalent in
PABA to the bacteria. The sulfonamides are nontoxic to mam- horses.
malian cells because they use dietary folate for synthesis of
dihydrofolic acid and do not require PABA. The addition of Absorption
TMP or PYM to a sulfonamide creates a bactericidal combi- In general, potentiated sulfonamides are readily absorbed
nation. TMP inhibits bacterial folic acid synthesis at the next from the GI tract of horses, but absorption may be affected
step in the folic acid sequence, inhibiting the conversion of by feeding.195-197 For TMP and sulfachlorpyridazine, peak
dihydrofolic acid to tetrahydrofolic acid by inhibiting dihy- plasma concentrations and bioavailabilities are significantly
drofolate reductase. This enzyme is present in both bacteria reduced when the drug is mixed with concentrate compared
and mammalian cells, but the bacterial enzyme is inhibited with nasogastric administration.198 Both drugs also dem-
at much lower concentrations than necessary to inhibit the onstrate a biphasic absorption pattern, and it appears that
mammalian enzyme.190 The MICs against specific susceptible this is due to a portion of the TMP and sulfachlorpyrida-
bacteria for each drug are generally lowered when the anti- zine dose binding to feed, with a second absorption phase
microbials are administered in the potentiated sulfonamide occurring in the large intestine.199 Bioavailability following
combination. The resistance developed to the potentiated sul- intrauterine administration was 23% to 43% for TMP and
fonamides is lower than that to each individual drug; this is an 29% to 34% for sulfadoxine, and both were detected in the
important benefit because resistance to sulfonamides is very milk of lactating mares.200 The oral bioavailability of PYM
common and resistance develops rapidly to diaminopyrimi- is 56% in horses.201
dines when used alone.191
The potentiated sulfonamides have a broad spectrum Distribution
of activity. The following bacteria are usually susceptible: Because the sulfonamides are weak acids and relatively hydro-
Streptococcus, Proteus, E. coli, Pasteurella, Haemophilus, and philic, they distribute well in ECF and typically have values
Salmonella spp. Staphylococci, anaerobes, Nocardia, Cory- for Vd of 0.3 to 0.7 L/kg. Concentrations of sulfonamides in
nebacterium, Klebsiella, and Enterobacter are susceptible but tissues are generally lower than those in plasma. The diamino-
may become resistant. Pseudomonas spp., Bacteroides spp., pyrimidines are lipophilic weak bases and penetrate intracel-
and enterococci are usually resistant.29,62,192 Other significant lularly better than sulfonamides, resulting in values for Vd of
organisms that are susceptible to potentiated sulfonamides 1.5 to 2.7 L/kg and higher tissue concentrations than plasma
TABLE 2.9 Pharmacokinetics of Trimethoprim, Pyrimethamine, and Sulfonamides in Horses

Volume of Distribution
Drug (L/kg) Half-Life or MRT (hr) Protein Binding (%) Clearance (mL/min/kg) Dose (mg/kg)
Trimethoprim — 2.4 — — PO: 5
Sulfadiazine196 7.4 PO: 25
Trimethoprim 2.0 2.8 35 8.8 IV: 2.5
Sulfadiazine218 0.5 4.6 20 1.5 IV: 12.5
Trimethoprim 1.5 3 50 — IV: 8
Sulfadoxine206 0.39 14 14–72 IV: 40
Trimethoprim 2.8 3.4 — 11 IV: 7.5
Sulfamethoxazole222 0.5 4.8 — 1.4 IV: 36.5
Trimethoprim 1.6 1.9 — 13 IV: 2.5
Sulfamethoxazole202 0.33 3.5 — 1.3 IV: 12.5
Trimethoprim 1.5 2.6 — 7.7 IV: 5
Sulfachlorpyrida- 0.26 3.8 — 2.6 IV: 25
zine198
Pyrimethamine201 1.5 12 — 1.6 IV, PO: 1
Sulfadiazine207 0.4 3.8 43 2.3 IV: 20
Sulfamerazine207 0.49 3.2 44 1.8 IV: 20
Sulfamethazine197 0.63 11.4 — 0.8 IV: 160
Sulfamethazine207 0.33 5.4 69 0.9 IV: 20

IV, Intravenous; MRT, mean residence time; PO, oral.
concentrations.190 Distribution of potentiated sulfonamides in the distal tubule by passive diffusion. Because most sulfon-
has been broadly investigated in the horse. Sulfadiazine and amides are weak acids, alkaline urine increases their ionization
TMP and sulfamethoxazole and TMP are all well distributed and elimination. Renal excretion of TMP occurs by glomeru-
into peritoneal fluid, CSF, synovial fluid, and urine.202-204 lar filtration, active tubular secretion, and reabsorption. In
Inflammation in the meninges or synovium does not sig- horses it appears that a large percentage of TMP is metabo-
nificantly affect distribution into the respective fluids. After lized before elimination in urine (46%) and feces (52%). The
repeated doses sulfamethoxazole, unlike TMP, accumulates clearance of the diaminopyrimidines is affected by urine pH,
in the CSF.202 CSF concentrations of PYR reach 25% to 50% plasma concentration, and extent of diuresis. In contrast to the
of serum concentrations but do not appear to accumulate in sulfonamides, alkaline urine increases the reabsorption of the
horses with daily dosing.205 basic TMP.206
Sulfonamides can be highly bound to plasma proteins, but
the extent of binding depends on species, drug, and concen- Adverse Effects and Drug Interactions
tration. In the horse the degree of protein binding varies from The potentiated sulfonamides are noted for their widely
33% for sulfaphenazole to 93% for sulfamethoxine.190 Approx- varying adverse effects. Crystalluria, hematuria, and renal
imately 50% of TMP is protein bound, and binding is indepen- tubular obstruction can result from poorly soluble sul-
dent of plasma concentration.206 fonamides, especially in dehydrated patients with acidic
urine.190 However, the lower doses of sulfonamide used in
Metabolism the potentiated sulfonamide combinations make crystal-
Diaminopyrimidines and sulfonamides are metabolized by lization less likely than with sulfonamides administered
the liver, usually by acetylation, aromatic hydroxylation, and alone. Local infusion of potentiated sulfonamides into the
glucuronidation.190 The acetylated, hydroxylated, and conju- uterus of mares caused irritation of the endometrium and
gated forms of the sulfonamides are significantly less micro- a decreased pregnancy rate.200 Intramuscular administra-
biologically active than their parent compounds. The precise tion is not recommended because of tissue irritation from
metabolic pathways for TMP or PYR have not been elucidated. the organic solvents, high concentration, and high pH of
Metabolites may compete with the parent drug for involve- the formulations. IV administration must be done by slow
ment in folic acid synthesis. They have little detrimental effect and careful injection. Rapid administration is associated
on bacteria, so their presence can decrease the activity of the with thrombophlebitis and anaphylaxis.190,209 The concur-
remaining parent drug.207,208 rent use of IV potentiated sulfonamides with detomidine
is contraindicated because it appears that the potentiated
Elimination sulfonamide sensitizes the myocardium and results in car-
Sulfonamides are primarily excreted in urine, but excretion diac dysrhythmias and hypotension that may be fatal.210,211
in feces, bile, milk, sweat, and tears also occurs. Renal excre- The procaine in procaine penicillin G is a PABA analog and
tion of unchanged drug and metabolites occurs by glomerular may reduce efficacy if used concurrently with potentiated
filtration and active tubular secretion.190 Reabsorption occurs sulfonamides.18
Folate Antagonism Effects that twice-daily dosing is better for attaining therapeutic
Anemia, thrombocytopenia, and even pancytopenia may be plasma concentrations.218,220 However, the newest formula-
seen in response to long-term, high-dose administration, such tion approved in the United States is a suspension labeled for
as in the treatment of equine protozoal myeloencephalitis dosing at 24 mg/kg PO q12hr. Pharmacokinetic data available
(EPM). Anemia may be related to folate deficiency due to inhi- from this product showed that this dosing strategy produced
bition of folate production by intestinal bacteria or inhibition free drug concentrations that exceeded the MIC90 for Strep-
of its conversion to tetrahydrofolate and dihydrofolate. Coad- tococcus equi subsp. zooepidemicus (SDZ-TMP: 4.75/0.25) for
ministration of TMP and PYR does not increase the efficacy the entire 24-hour dosing interval. Despite frequent clinical
against protozoa and is suspected to increase the incidence of use for equine streptococcal infections, even prophylactic
adverse effects caused by folate reduction. Supplementation administration failed to prevent abscessation caused by Strep-
with oral folic acid is often recommended for horses on long- tococcus equi subsp. zooepidemicus.221
term potentiated sulfonamide therapy.212 The administration
of oral folic acid to pregnant mares being treated for EPM may Y TETRACYCLINES
not protect the fetus from the effects of folate deficiency. Mares
have delivered foals with congenital defects after oral admin- Tetracycline was discovered after a team of workers examined
istration of potentiated sulfonamides, despite supplementa- 100,000 soil samples from around the world. Tetracycline
tion with oral folic acid during treatment.213 Treatment with derivatives include oxytetracycline, chlortetracycline, doxycy-
TMP-sulfamethoxazole and PYM does not affect semen qual- line, and minocycline. Oxytetracycline (OTC), doxycycline
ity, testicular volume, sperm production efficiency, erection, (DXC), and minocycline (MNC) are used in horses.
or libido of healthy stallions. However, treatment may induce
changes in copulatory form and agility and alter the pattern Mechanism of Action
and strength of ejaculation.214 Stallions that develop neu- The tetracyclines bind to the 30S ribosomal subunit and inter-
rologic signs during treatment should be bred with caution. fere with bacterial protein synthesis. They are bacteriostatic
TMP-sulfamethoxazole has been associated with immune- at usual therapeutic concentrations but bactericidal at high
mediated hemolytic anemia in a horse.215 concentrations. Drug entry into the bacteria is by an energy-
dependent mechanism. Mammalian cells do not possess the
Effects on GI Flora tetracycline transport mechanism. Tetracyclines are most
The effects of potentiated sulfonamides on normal GI flora are active at an acidic pH. The tetracyclines are broad-spectrum
controversial. In some studies potentiated sulfonamides alone in activity; they are effective against gram-positive and gram-
or with concurrent penicillin or aminoglycoside therapy are negative bacteria, as well as Chlamydia, Mycoplasma, and
associated with diarrhea in horses.216,217 Other studies show Rickettsia spp. and some protozoa (Haemobartonella, Ana-
little effect on fecal flora.218,219 The likelihood of any antimi- plasma spp.). Their activity against staphylococci is limited,
crobial therapy causing diarrhea in a horse depends on several and they are not active against enterococci. Pseudomonas, E.
factors, including the antibacterial spectrum of the drug and coli, Klebsiella, and Proteus are usually resistant. Most anaer-
the drug concentrations achieved in the GI tract. The presence obes are susceptible to DXC.18 In vitro concentrations of OTC
or absence of potential pathogens in the composition of the above 0.01 μg/mL effectively suppress growth of Neorickettsia
individual horse’s microflora and the presence of antimicro- risticii.223 Tetracyclines are also effective against intracellular
bial-resistant pathogens in the hospital or clinic environment pathogens of foals, such as Lawsonia intracellularis and Rhodo-
are also important factors in the incidence of GI disturbances. coccus equi.224 Multiple other actions have been attributed to
Despite the low incidence of colitis in horses treated with DXC and MNC, including anticollagenolytic activity through
potentiated sulfonamides, the client and clinician should be inhibition of matrix metalloproteinases (MMPs), antiinflam-
aware of the potential, as cases can be rapidly fatal. matory activity, and ability to enhance corneal repair.225,226
Formulations Mechanisms of Resistance
TMP-sulfadiazine is available as a 48% injectable solution for Widespread acquired resistance in many pathogens limits
IV administration in horses. It is also available as oral sus- the clinical usefulness of the tetracyclines. Resistance occurs
pension, paste and powder formulations for horses. Generic from plasmid-mediated failure in the active transport of the
tablets of TMP-sulfamethoxazole available for human use are drug into the bacterial cell and increased efflux from the cell.
commonly administered to horses. A commercially available Another major mechanism of resistance involves cytoplasmic
PYR-sulfadiazine formulation is marketed for the treatment of production of a protein that protects the ribosome from tetra-
equine protozoal myelitis in horses. cycline action.18
Clinical Use
It is very difficult to apply pharmacokinetic principles to deter-
Pharmacokinetics
mine drug dosage regimens for the potentiated sulfonamides. Absorption
Different pathogens have varying MIC values, and the opti- Oral absorption of OTC is erratic, and oral administration is
mal ratio of TMP or PYM to sulfonamide also varies among not recommended in horses because of its adverse effects on
bacteria and protozoa. The most important component of the GI flora.219 The long-acting formulation of OTC in polyeth-
formulation for efficacy appears to be the diaminopyrimidine, ylene glycol has a bioavailability of 83% after IM injection in
and the choice of sulfonamide may not be nearly as important. horses.227
Therefore there is considerable controversy regarding the dos- At an oral dose of 10 mg/kg in fed horses, DXC produced
age regimen of these combinations. Most veterinary products serum, synovial fluid, peritoneal fluid, and endometrial tissue
are labeled for once-daily administration, but studies indicate concentrations above 0.25 μg/mL, suggesting effective therapy
for gram-positive infections.228 At an oral dose of 20 mg/kg increased free fraction of drug may explain the better penetra-
in fasted horses DXC produced mean maximum plasma con- tion into the eye and CSF of MNC compared with DXC.
centration of 0.91 μg/mL following a single dose and 1.74 μg/
mL after multiple doses using a 12-hour dosing interval.229 Elimination
A precise bioavailability cannot be determined because IV The tetracyclines are not known to be biotransformed to any
administration of DXC causes cardiac toxicity.230 However, significant extent before elimination. OTC is eliminated in
using allometric scaling, the estimated systemic absorption urine unchanged primarily by glomerular filtration. Unme-
for DXC after oral administration in horses is only 2.7%.229 tabolized drug is also eliminated with bile into the GI tract
Oral absorption of DXC in foals is higher, with a single oral and may undergo enterohepatic recirculation, prolonging its
dose of 10 mg/kg producing mean maximum plasma concen- effects.18 DXC is primarily excreted into the feces by way of
trations of 2.54 μg/mL and 4.05 μg/mL after multiple doses nonbiliary routes in an inactive form. Therefore DXC does
using a 12-hour dosing interval.231 Steady-state mean plasma not accumulate in patients with renal insufficiency.239 The
concentrations of minocycline following administration of 4 clearance of OTC in foals is 3.3 mL/min/kg234 and 2.2 mL/
mg/kg PO q12hr were 0.67 μg/mL, and concentrations were min/kg in adult horses.227 When administered intravenously,
above the MIC50 and MIC90 for many gram-positive equine the elimination half-life is 7 hours in foals234 and 6 hours in
pathogens (0.25 μg/mL).232 Although it has not been studied horses.227 Because of flip-flop kinetics, the elimination half-
directly, based on data from different studies, MNC oral bio- life is 22 hours after IM administration of OTC in polyethy
availability is approximately 23%. lene glycol.227 DXC clearance cannot be accurately determined
from oral dosing.229 The half-life of MNC in adult horses is 8
Distribution to 11 hours, and the plasma clearance is 2.7 mL/kg/min.232,238
The tetracyclines are well distributed to most tissues,
except the central nervous system. Therapeutic levels may
be achieved, however, when the meninges are inflamed. Adverse Effects and Drug Interactions
Tetracyclines readily diffuse into milk.18 OTC reaches 50% GI Effects and Interactions
of plasma concentrations in synovial fluid and peritoneal Calcium-containing products (e.g., milk, antacids) or other
fluid. Urine OTC concentrations are relatively high, with divalent cations will chelate with tetracyclines and interfere
peak concentrations above 1500 μg/mL.233 The Vd of OTC with GI absorption.18 Because DXC is less likely than the older
in neonatal foals is 2 L/kg234 and 0.34 to 0.95 L/kg in adult tetracyclines to form chelation complexes with divalent and
horses.227,235 The apparent Vd of DXC in horses after oral trivalent metals, there is less interference with oral absorption
absorption is 25 L/kg, indicating the high lipid solubility by calcium or other substances.239
and tissue penetration of DXC. Synovial and peritoneal flu- The clinical use of OTC in horses is controversial because
ids achieve the same DXC concentrations as plasma, and of reports of adverse GI effects. However, adverse effects were
endometrial tissue concentrations are more than twice also associated with excessive dosage,240 concomitant use of
plasma concentrations. DXC is not detectable in CSF after other antimicrobials, and stressors such as surgery and trans-
oral administration.228 DXC concentrates intracellularly, port.241-244 Anecdotally, OTC therapy has been used suc-
with mean Cmax in polymorphonuclear cells approximately cessfully in equine practice, and recognition of the equine
17 times higher than concentrations found in plasma.229 In rickettsial diseases has increased OTC use in horses.245-247 In a
foals peritoneal fluid, synovial fluid, and bronchoalveolar chronic dosing study using a long-acting formulation of OTC,
lavage cell activity of DXC were similar to plasma con- no deleterious effects on fecal flora were detected, and treated
centrations; however, activity in the CSF was significantly horses remained clinically normal.248 DXC is less likely to
lower, and activity in pulmonary epithelial lining fluid cause adverse GI effects because it is bound in an inactive form
and urine was significantly higher.231 Minocycline has a in the intestines; however, at higher doses the risk of adverse
Vd of 1.53 L/kg in adults. Synovial fluid concentrations of effects may be increased. One study reported that doses of 20
minocycline were approximately 74% of the corresponding mg/kg orally twice daily produced signs of abdominal dis-
trough plasma concentrations. Minocycline penetrates the comfort in one horse and a severe enterocolitis in another.
CSF to a greater extent than OTC and DXC with a mean The other four horses in that study were unaffected.229 DXC
CSF concentration of 0.39 μg/mL at steady state, which was administered to foals at 10 mg/kg orally twice daily for 8 to 17
69.5% of the corresponding plasma concentration. days for treatment of Lawsonia intracellularis infection did not
Ocular penetration of systemic DXC and MNC has been produce any adverse effects.224 No adverse GI effects of mino-
studied. Vitreal drug concentrations of DXC were 0.17 μg/mL cycline have been reported, although clinical use has been lim-
after multiple doses of 10 mg/kg.236 Aqueous humor concen- ited compared with other drugs in this class.
trations were approximately 0.11 μg/mL after multiple doses
of 20 mg/kg, which represented 7.5% of corresponding plasma Renal Effects
concentrations.229 DXC was also detectable in the preocular Renal tubular necrosis caused by OTC is associated with high
tear film of horses without ocular disease after once-daily doses, outdated parenteral products, endotoxemia, dehydration
administration of 20 mg/kg.225 As with the CSF, MNC pen- and hypovolemia, and concurrent pigment nephropathy.18,249
etrated into the aqueous humor of horses to a greater extent, In normal foals single high-dose IV OTC administration for
with concentrations being 17% to 20% that of plasma concen- the correction of flexural deformities does not cause renal tox-
tration at steady-state.232 icity.250 Multiple doses administered at dosing intervals less
OTC is 50% protein bound in horses.237 Plasma protein than every 48 hours may increase the risk of nephrotoxicity in
binding of DXC is high (82%), which is similar to that of foals. Oliguric renal failure developed in a foal that had con-
other species.229 This impairs distribution of DXC into the current neonatal isoerythrolysis given 70 mg/kg of IV OTC for
ECF. Plasma protein binding of MNC is 68% in horses.238 The a flexural deformity.249
Cardiovascular Effects commonly used for treatment of proliferative enteropathy

Rapid IV administration of OTC results in hypotension caused by Lawsonia intracellularis. DXC is also used for the
and collapse. This is attributed to intravascular chelation of treatment of keratomalacic diseases in horses because it may
calcium, decreased blood pressure from the drug vehicle decrease corneal proteinases such as MMP-2 and MMP-9.225
(propylene glycol), or both. Pretreatment with IV calcium
borogluconate prevents collapse.251,252 Both rapid IV bolus and Y MACROLIDES AND AZALIDES
slow constant rate infusion of DXC to horses causes tachycar-
dia, arrhythmias, systemic arterial hypertension, collapse, and The macrolide antibiotics include erythromycin, clarithro-
death.230,253 It is suggested that this reaction is due to chelation mycin, tylosin, tilmicosin, and tiamulin. Azalides, such as
of intracellular calcium, resulting in neuromuscular blockade azithromycin and gamithromycin, have a similar mechanism
of the myocardium. Plasma total and ionized calcium concen- of action but have a methylated nitrogen in the macrocyclic
trations are not affected by IV DXC administration. ring. Triamilides, such as tulathromycin, are semisynthetic
macrolides prepared by fermentation followed by organic syn-
Musculoskeletal Effects thesis. Because of their adverse GI effects, these drugs are typi-
Intramuscular injection of long-acting OTC formulations cally contraindicated in adult horses; however, erythromycin,
causes localized pain and swelling at the injection site.18,248 clarithromycin, and azithromycin are commonly used in foals.
OTC causes flexor tendon relaxation; this effect has been used
to treat foals with flexural deformities.254,255 OTC induces a Mechanism of Action
dose-dependent inhibition of collagen gel contraction by The macrolides and their derivatives bind to the 50S ribo-
equine myofibroblasts. Inhibition of normal collagen organi- somal subunit in a manner similar to that of CHPC, and they
zation may provide the mechanistic explanation for the results interfere with protein synthesis. They are usually considered
seen after the pharmacologic treatment of flexural deformi- bacteriostatic but may be bactericidal at high concentrations.
ties by OTC administration.256 Because of the neuromuscular Macrolides are not effective against gram-negative bacteria,
blocking effects, tetracyclines are not recommended for the except some strains of Pasteurella and Haemophilus.18 Azithro-
treatment of diseases affecting the neuromuscular junction, mycin is more active than the macrolides against gram-nega-
such as botulism. tive bacteria and anaerobes.223,258 Susceptible bacteria include
staphylococci, streptococci, Campylobacter jejuni, Clostridium
spp., Rhodococcus equi, Lawsonia intracellularis, Mycoplasma
Doxycycline and Rifampin Combination spp., and Chlamydia spp.259Antimicrobial activity of these
Therapy weak bases is optimum at an alkaline pH; therefore they have
Doxycycline is a possible treatment for foals that develop reduced activity in acidic environments (e.g., pus, abscesses)
macrolide-resistant R. equi infections. However, a study exam- but may be clinically effective because of high concentra-
ining the use of DXC combined with rifampin in foals with tions due to ion trapping. Erythromycin has nonantimicrobial
naturally occurring clinical disease noted that some foals effects on host cell metabolism, inflammatory mediators, and
developed hemolytic anemia and icterus or increased liver GI motility.260,261
enzymes 17 to 20 days after initiating the treatment. The cause
of these reactions is unknown, and similar clinical findings Mechanisms of Resistance
have not been seen in foals treated with doxycycline alone or The routine use of the macrolides is limited because bacterial
with rifampin combined with macrolides.257 At this time, this resistance develops quickly after repeated exposure.262 Mecha-
combination should only be used with caution and not as a nisms of resistance include decreased drug entry into bacte-
first-line treatment for R. equi. ria, inability to bind to the bacterial 50S ribosomal subunit,
and plasmid-mediated production of esterases.18 Resistance to
Formulations erythromycin has been reported in 3.9% of R. equi isolates.263
Injectable OTC products are formulated as short- or long- Extensive cross-resistance occurs among the macrolides.18
acting products. The short-acting solutions are in propylene
glycol and have concentrations of 50 or 100 mg/mL. The long-
acting solutions are in 2-pyrrolidone or polyethylene glycol
Pharmacokinetics
and have a concentration of 200 mg/mL. The polyethylene Absorption
glycol formulation is less irritating than the 2-pyrrolidone for- Erythromycin is available for oral administration as enteric-
mulation. The long-acting formulations may be administered coated erythromycin base, erythromycin esters (ethylsuccinate
by slow IV injection, but the long-acting effect is lost.210 DXC or estolate), and erythromycin salts (phosphate or stearate).
and MNC tablets are available in multiple generic and propri- Because of expense, many practitioners administer the drug as
etary formulations. crushed enteric-coated tablets of erythromycin base. However,
erythromycin base is degraded in the stomach by gastric acid.
Clinical Use The esterified formulations are absorbed intact and must be
OTC is the drug of choice for treatment of Potomac horse hydrolyzed to the active erythromycin A. The erythromycin
fever (Neorickettsia risticii) and equine anaplasmosis (Ana- salts are absorbed unchanged.260 The oral bioavailability of
plasma phagocytophilum). It is also used to treat contracted erythromycin base is 17% in fasted foals, with most of the drug
flexor tendons in foals. Its use for other microbial infections in being degraded and absorbed as the microbiologically inac-
horses is controversial because of concerns related to adverse tive anhydroerythromycin A.264 Microencapsulation of the
GI effects and widespread antimicrobial resistance. DXC and base improves the oral bioavailability of erythromycin base to
MNC are also indicated for rickettsial diseases in horses and 26% in fasted foals, but it remains only 7.7% in fed foals.265 The
may be a suitable oral alternative to OTC. Tetracyclines are oral bioavailability of erythromycin estolate in fasted foals is
36% but only 16% for erythromycin phosphate.266 The estolate humans, and the active metabolite, 14-hydroxy-clarithro-
formulation appears to have the best pharmacokinetic profile mycin, is produced in foals, although the pharmacokinet-
in foals. Because of injection site irritation, IM administration ics have not been quantitated.269 The elimination half-life
of erythromycin is not recommended in horses. The reported of clarithromycin in foals is intermediate between erythro-
oral bioavailability of azithromycin in foals ranges between mycin and azithromycin at 5.4 hours.269 Tulathromycin has
39% and 56%.267,268 The oral bioavailability of clarithromycin the longest elimination half-life, reported at 117 hours in
in foals is similar (57%).269 Telithromycin, an oral ketolide foals.271 Gamithromycin also has an extended elimination
antibiotic used for treatment of macrolide-resistant R. equi in phase, with a half-life of 39.1 hours.272
humans, has also been studied in foals. Bioavailability has not
been determined; however, although absorption was adequate Adverse Effects and Drug Interactions
for treatment of susceptible R. equi isolates, it was not high The use of erythromycin in horses is associated with a number
enough for treatment of most macrolide-resistant R. equi iso- of adverse effects. Since erythromycin came into clinical use in
lates in foals.270 The bioavailability of tulathromycin has not the 1950s, it was apparent that therapy was frequently accom-
been determined; however, after IM administration the drug panied by adverse GI effects. Macrolide antibiotics, including
is rapidly detected in the plasma of foals, with maximum con- erythromycin and clarithromycin, are motilin receptor ago-
centrations of 0.41 μg/mL 4 hours after administration.271 nists. They also appear to stimulate motility via cholinergic
Gamithromycin has maximum concentrations of 0.33 μg/mL and noncholinergic neuronal pathways. At microbially inef-
1 hour after IM administration in foals.272 fective doses they stimulate migrating motility complexes and
antegrade peristalsis in the GI tract.261,276,278,279 When used at
Distribution antimicrobial doses, erythromycin is associated with poten-
The macrolides concentrate in leukocytes, making them very tially fatal colitis from Clostridium spp.280-282
effective against intracellular pathogens such as R. equi.273 Erythromycin is associated with acute respiratory distress
Concentrations of azithromycin and clarithromycin in bron- syndrome, gastroenteritis, and hepatotoxicity in foals.277,283,284
choalveolar lavage cells were significantly higher than erythro- Erythromycin also interferes with host cell metabolism and
mycin, and azithromycin had a significantly longer elimination decreases inflammatory responses in airways, but the clinical
half-life from the cells.274 Bronchoalveolar cell and pulmonary significance of this has not been determined.277
epithelial lining fluid concentrations of azithromycin are 15- Hyperthermia following administration of macrolides is
to 170-fold and 1- to 16-fold higher than concurrent serum most associated with erythromycin, although it also associ-
concentrations, respectively, and did not decrease for up to 48 ated with azithromycin and clarithromycin to a lesser degree.
hours after administration.267 Clarithromycin concentrations The mechanism of macrolide-induced hyperthermia has been
in bronchoalveolar cell and pulmonary epithelial lining fluid shown to be drug-induced anhidrosis, as evidenced by signifi-
are 91- to 105-fold and 324- to 585-fold higher than concur- cantly reduced sweating in response to an intradermal sweat
rent serum concentrations, respectively; however, in contrast tested in treated versus placebo control foals.285 Anhidrosis
to azithromycin, clarithromycin concentrations significantly begins shortly after initiation of treatment, partially recovers
decreased within 12 hours of administration.269 Tulathromy- during treatment, and can take at least 10 days after stopping
cin concentrates in bronchoalveolar cells, and concentrations treatment to fully recover. To minimize the risks of macrolide-
are detectable for at least 8 days after a single administration, induced hyperthermia, it is recommended to decrease access
although they are still lower than the MIC for R. equi (greater to direct sunlight, provide ample shade, avoid turnout during
than 64 μg/mL).271 The relative distribution of macrolide anti- the hottest parts of the day, and provide access to clean, fresh
biotics into bronchoalveolar cell and pulmonary epithelial lin- water at all times. Erythromycin is commonly administered in
ing fluid has been reviewed in depth.275 conjunction with rifampin to take advantage of antimicrobial
Because they are weak bases, macrolides are ion trapped in synergism and reduce the chance of resistance development.28
milk, CSF, and gastric fluids. The Vd for erythromycin is 2.7 Erythromycin may interact with other drugs metabolized
L/kg in foals.264 Azithromycin is known for its high degree of by the same cytochrome P450 enzyme system. Concurrent
lipid solubility, and the Vd of azithromycin in foals is 11.6 to administration of erythromycin with theophylline results in a
18.6 L/kg.267,268 Clarithromycin also exhibits a large volume of doubling of plasma theophylline concentrations and can result
distribution, with reported values of 10.4 L/kg.269 Peritoneal in seizures in foals.18
and synovial fluid concentrations of azithromycin and clar- Clarithromycin is also frequently administered in combina-
ithromycin parallel serum concentrations.269 The apparent Vd tion with rifampin due to synergistic effects against R. equi.286
for tulathromycin after IM administration is 15.2 L/kg.271 However, coadministration of rifampin reduces clarithromy-
cin bioavailability by as much as 90%, resulting in plasma
Elimination concentrations of clarithromycin that are below the MIC90 of
Erythromycin is extensively metabolized, with much of the R. equi.287 Bronchoalveolar lavage cell and pulmonary epithe-
parent drug and active metabolite excreted into the bile, lial lining fluid concentrations were also decreased, but they
resulting in an elimination half-life of 1 to 2 hours.264-266,276 remained above therapeutic concentrations. The exact cause of
Erythromycin inhibits the metabolism of a number of other the decrease is unknown. It does not appear to be due to induc-
drugs by interfering with cytochrome P450 enzymes.18 In tion of hepatic metabolism by rifampin, as the pharmacoki-
addition, the degradation product anhydroerythromycin A netics of clarithromycin and its metabolite remain unchanged.
is a potent inhibitor of cytochrome P450–mediated metabo- It is speculated that the decreased bioavailability is secondary
lism.277 Erythromycin undergoes enterohepatic cycling.18 to changes in oral absorption, likely through inhibition of an
Azithromycin is not highly metabolized and is primarily unknown intestinal uptake transporter.288 Concentrations of
eliminated in bile. The elimination half-life is 16 to 20.3 hours tulathromycin in the lung of foals was also significantly low-
in foals.267,268 Clarithromycin is extensively metabolized in ered by comedication with rifampin. Because tulathromycin
is only administered via the IM route, the mechanism of this therapy. Azithromycin alone has been shown to be as effective
interaction also remains unknown.289 as azithromycin and rifampin combined.295 Tulathromycin is
Azithromycin is associated with fewer adverse effects than not recommended for treatment of R. equi in foals, due to the
erythromycin in human beings. No adverse reactions were high MICs (greater than 64 μg/mL). Gamithromycin offers
detected during or after repeated intragastric administration more promise for treatment of R. equi. A once-weekly IM dos-
of azithromycin or clarithromycin in foals.273,275 A multiple- ing regimen (6 mg/kg) may provide a more affordable treat-
dose study of oral azithromycin in adults (10 mg/kg PO q24hr ment alternative, although adverse reactions may limit the use
for 5 days) showed mild decreases in appetite and alterations of this drug in horses.
in fecal consistency in some horses.290 There are anecdotal Although most frequently used for R. equi pneumonia, the
reports of antimicrobial-associated colitis in older weanlings, macrolide anitbiotics are also effective against Lawsonia intra-
particularly those treated with compounded formulations of cellularis, although the risk of adverse GI effects in weanling
azithromycin. age foals limits their use and tetracyclines have replaced them
In a study that evaluated the use of tulathromycin in foals in most cases. Some drugs in this class, including azithromy-
with evidence of pulmonary abscessation, self-limiting diar- cin and gamithromycin, have good activity against strepto-
rhea, fever, and injection site reactions were the only adverse cocci and may be useful for treatment of abscesses caused by
effects noted. In one foal in that study, the injection site reac- Streptococcus spp. in foals.
tion was severe and resulted in temporary lameness and
severe swelling.288 Injection site reactions and colic have been Y FLUOROQUINOLONES
reported following IM gamithromycin administration and
may limit the use of this antibiotic in foals.291 The quinolones are a group of synthetic antimicrobials. The
first was nalidixic acid, which was introduced in 1964. It had
Formulations good activity against gram-negative bacteria but had a low
Because the base of erythromycin is unstable in gastric acid, it Vd and numerous adverse effects and was limited to treat-
is formulated as enteric-coated erythromycin tablets. Eryth- ment of urinary tract infections. Further chemical manipula-
romycin stearate and erythromycin phosphate are insoluble tion resulted in development of the fluorinated quinolones,
salt formulations that disassociate in the intestine, allowing which had extended antimicrobial activity with improved
absorption of the free erythromycin base. Erythromycin eth- safety. Included in this group are ciprofloxacin, enrofloxacin,
ylsuccinate and erythromycin estolate are ester formulations danofloxacin, difloxacin, orbifloxacin, marbofloxacin, fleroxa-
that are absorbed intact from the intestine, and then plasma cin, moxifloxacin, and levofloxacin. No fluoroquinolones are
esterases release active drug. Erythromycin is available in an approved for use in horses, but because of their pharmacoki-
IM formulation approved for cattle. Because of its highly irri- netics and antimicrobial activity, they are commonly used for
tating nature, this formulation is not recommended for IM serious gram-negative infections.
use in horses, and it can be fatal if injected intravenously. A
human-labeled formulation of erythromycin lactobionate Mechanism of Action
is available for IV use. Tablet formulations are available for The fluoroquinolones have a unique mechanism of action for
azithromycin in 250-, 500-, and 600-mg strengths. Clarithro- bacterial killing. The fluoroquinolones inhibit bacterial deoxy-
mycin is available as an immediate and extended release tablet. ribonucleic acid (DNA) gyrase (also known as topisomerase
The extended release formulations have not been studied in II). Bacteria have a single chromosome consisting of double-
horses. Tulathromycin is available as a 100-mg/mL injectable stranded DNA. Within the bacterial cell the chromosome is
solution for cattle and swine. Gamithromycin is available as a folded around an RNA core, and each fold is supercoiled. DNA
150-mg/mL injectable solution for cattle. gyrase, which has been found in every organism examined, is
responsible for supercoiling the strand of bacterial DNA. The
Clinical Use DNA gyrase structure has four subunits: two A monomers and
On account of its association with potentially fatal adverse two B monomers. The enzyme forms a heart-shaped molecule,
effects, erythromycin is usually limited to treatment of R. equi with the A monomers forming the atria and the B monomers
infections in foals. It also has been shown to be an effective forming the ventricles. The bacterial DNA binds to the gyrase
therapy for Potomac horse fever292 and equine proliferative in the cleft between the A and B subunits. The DNA gyrase
enteropathy caused by Lawsonia intracellularis.293 Its motilin- nicks double-stranded DNA, introduces negative supercoils,
like activity is exploited for use as a treatment for adynamic and seals the nicked DNA. The fluoroquinolones bind to the
ileus in horses.261 Azithromycin has become an attractive DNA-DNA gyrase complex and inhibit the DNA resealing,
alternative to erythromycin for the treatment of R. equi infec- resulting in abnormal spatial DNA configuration, which leads
tions in foals because of its pharmacokinetic profile, which to DNA degradation by exonucleases.296
allows once-daily or every-other-day dosing and an apparent Fluoroquinolone activity is concentration dependent, and
reduced incidence of adverse effects.294 However, in a retro- clinical efficacy is most associated with achieving either an
spective study of 81 foals treated for naturally occurring R. AUC0–24:MIC greater than 125 or a Cmax:MIC greater than 10.
equi infection, the combination of clarithromycin (10 mg/kg These PK/PD relationships are related, insofar as increasing
q24hr) and rifampin was shown to be superior to combina- the dose to increase the peak plasma concentration will also
tions of azithromycin (7.5 mg/kg q12hr) and rifampin and increase the AUC value.18
erythromycin (25 mg/kg q6hr, 25 mg/kg q8hr, or 37.5 mg/ All of the fluoroquinolones are bactericidal, although
kg q12hr) and rifampin.273 Given the drug interactions noted these drugs have an optimum concentration for bacterial kill-
between clarithromycin and rifampin, further work is needed ing. Higher or lower drug concentrations result in reduced
to determine whether monotherapy with clarithromycin alone bactericidal activity. It is thought that the DNA-DNA gyrase
would be as effective as or more effective than combination complex has two binding sites for fluoroquinolones. At low
drug concentrations only one binding site is occupied, result- Since the fluoroquinolones have been used intensively in
ing in single-stranded nicks in the DNA. Reduced killing at human medicine in the past 3 decades, high-level resistance
high concentrations is thought to be due to dose-dependent has emerged in some pathogens. Chronic fluoroquinolone use
inhibition of RNA or protein synthesis. RNA and protein encourages the development of chromosomally mediated resis-
synthesis are required for production of bacterial autolysins, tance. In high-level resistant bacterial strains, one resistance
which are responsible for the fluoroquinolone-induced cell mechanism alone is usually not responsible; rather, two or three
lysis.18,296 mechanisms of resistance operate in conjunction. In resistant
The fluoroquinolones are broad spectrum in activity, with S. pneumoniae increased efflux is often coupled with a gyrase
activity against most gram-negative bacteria; some gram- mutation.301 In resistant E. coli gyrase mutations are usually
positive bacteria; and Mycoplasma, Chlamydia, and Rickettsia associated with changes in the outer membrane proteins.302
spp. They are particularly effective against the enteric gram-
negative pathogens, including some strains resistant to ami-
noglycosides and cephalosporins. Reported MICs are very Pharmacokinetics
low, and MBCs are 1 to 2 times the MIC for most pathogens. Absorption
They are usually active against staphylococci but have vari- The fluoroquinolones are rapidly and well absorbed from the
able activity against streptococci and are not effective against GI tract of monogastrics and preruminant calves. Enrofloxa-
enterococci. Most diagnostic laboratories use ciprofloxacin or cin is more lipid soluble than ciprofloxacin and has a higher
enrofloxacin to determine pathogen susceptibility; however, oral bioavailability than ciprofloxacin in horses and small ani-
MIC values vary among the fluoroquinolones. Ciprofloxacin mals. The oral bioavailability of ciprofloxacin is only 6.8% to
has the greatest activity against Pseudomonas spp. Orbifloxacin 10.5% in adult horses and ponies.303,304 The oral bioavailability
has lower MIC values than enrofloxacin for the gram-negative of enrofloxacin is approximately 60% in adult horses and 42%
bacteria Actinobacillus equuli, E. coli, Pasteurella spp., and Sal- in foals.305-307 The moderate oral absorption of enrofloxacin
monella spp. Enrofloxacin has lower MIC values for the gram- has been determined to be due to hepatic first pass effect.308
positive bacteria and Pseudomonas spp.18 Even with in vitro Oral absorption of enrofloxacin is not affected by feeding.309
evidence of susceptibility, however, enrofloxacin is not a good Antacids containing divalent cations (calcium, magnesium)
choice for Pseudomonas spp. as resistance develops rapidly. chelate fluoroquinolones and reduce oral bioavailability.18
Most fluoroquinolones are not active against anaerobic Oral bioavailability of marbofloxacin and orbifloxacin is 62%
bacteria.297 This susceptibility pattern may be a therapeutic and 68%, respectively.308,310 Administration of the injectable
advantage in the treatment of enteric infections in horses, formulation of danofloxacin intragastrically to horses had a
because GI anaerobes rarely cause disease and usually are pro- bioavailability of only 35.8%.311 Bioavailability from IM injec-
tective by competitively inhibiting colonization by pathogenic tion is nearly 100% for all fluoroquinolones, but IM injec-
aerobic organisms. tions of enrofloxacin are irritating to tissues.312 For economic
The fluoroquinolones concentrate within phagocytic cells. reasons and client convenience, practitioners have attempted
Uptake occurs by simple diffusion, and intracellular concen- to administer the bovine injectable solution of enrofloxacin
trations may be several times greater than plasma concentra- orally to horses. This results in a bioavailability of approxi-
tions. Intracellular drug is microbiologically active against mately 65% in horses when administered intragastrically.313
intracellular pathogens such as Brucella spp., Mycoplasma spp., Unfortunately, the injectable formulation is highly irritating
and Mycobacterium spp.18 Exposure of gram-negative bacteria to the oral mucosa and may cause ulceration with repeated
to fluoroquinolones at concentrations several times the MIC use. A methylcellulose gel formulation compounded from the
for 1 to 2 hours results in a PAE with a recovery period of 1 injectible liquid has better oral absorption but may also cause
to 6 hours. This effect suggests that fluoroquinolone dosage oral ulceration.314
regimens can tolerate plasma concentrations below the patho-
gen’s MIC for extended periods of time without a reduction in Distribution
efficacy.298 The fluoroquinolones are generally lipid soluble and well dis-
tributed to most tissues. The Vd of the fluoroquinolones stud-
Mechanisms of Resistance ied in horses ranges from 1.2 L/kg for marbofloxacin315 to
Microbial resistance to the fluoroquinolones is primarily due 4.9 L/kg for ciprofloxacin.304 Tissue concentrations typically
to chromosomal mutations that alter bacterial DNA gyrase, exceed plasma concentrations during therapy. Extremely high
decrease cell wall permeability, or increase fluoroquinolone concentrations are achieved in the kidney, urine, liver, and bile.
efflux from the cell. Plasmid-mediated resistance has only Therapeutic concentrations for gram-negative bacteria may be
recently been documented for the fluoroquinolones. Fluoro- achieved in cerebrospinal and ocular fluids.303,306,316,317 Aque-
quinolone-resistance plasmids can be transmitted horizontally ous humor concentrations of enrofloxacin after IV admin-
and provide low-level resistance that facilitates the emergence istration of 3 daily doses of 7.5 mg/kg were 0.32 μg/mL.318
of higher level resistance at therapeutic levels.299 The fluoro- Plasma protein binding of fluoroquinolones is low to moder-
quinolones must penetrate bacteria to reach the target DNA ate in most species. Protein binding data are available for cip-
gyrase. They do so by diffusing through porin channels in rofloxacin, enrofloxacin, orbifloxacin, and levofloxacon in the
the outer membrane of gram-negative bacteria. Pseudomonas horse. Binding is similar across drugs and ranges between 21%
spp. resistance is associated with alterations in a wide range of and 28%.310,319
outer-membrane proteins. From these mutations the increase
in the MICs of the fluoroquinolones is relatively low (2- to Elimination
32-fold). However, there is cross-resistance with unrelated The fluoroquinolones are predominantly excreted in the urine
antibiotics, most frequently TMP, tetracycline, CHPC, and by glomerular filtration and active tubular secretion.18 For
cefoxitin.300 marbofloxacin approximately 40% is excreted unchanged in
the urine, whereas with enrofloxacin only 3.4% is excreted activity.326 This can be prevented by slow injection or dilution
unchanged in the urine.308 Ciprofloxacin undergoes some sulf- of the dose. Dilution of the dose should be performed in sterile
oxidation, and its metabolites also have antimicrobial activity. saline solution, because the cations found in other fluids, such
Enrofloxacin is metabolized (de-ethylated) to ciprofloxacin in as lactated Ringer’s solution, may chelate and inactivate the
horses and donkeys,320 with serum ciprofloxacin concentra- drug. Photosensitivity reactions and Achilles tendon rupture
tions reaching 20% to 35% of enrofloxacin concentrations.312 have been associated with fluoroquinolone use in humans but
Metabolism of enrofloxacin to ciprofloxacin is negligible in have not been reported in animals.296
foals, and ciprofloxacin was not detected in the plasma of The fluoroquinolones have been used in combination with
foals in which IV or oral enrofloxacin was administered.305 other antimicrobial agents to expand the therapeutic spec-
The elimination half-life of ciprofloxacin in ponies is 2.5 hours trum, suppress emergence of drug-resistant bacterial popula-
and 5 hours in horses.303 Enrofloxacin has an elimination half- tions, or exploit inhibitory or bactericidal synergism against
life of 4.4 hours after IV administration and 10 hours after drug-resistant populations. Minimal synergy occurs between
IM administration, indicating flip-flop kinetics.312 With oral fluoroquinolones and β-lactams or aminoglycosides against
administration the elimination half-life of enrofloxacin is 8 gram-negative enteric bacteria because of the already high sus-
hours.317 The elimination half-lives of danofloxacin, orbifloxa- ceptibility of these organisms. Combinations with aminogly-
cin, and marbofloxacin are 8, 5.1, and 4.14 hours, respectively. cosides, β-lactams, or vancomycin are additive or indifferent
against staphylococci. Antagonism between fluoroquinolones
Adverse Effects and Drug Interactions and CHPC or rifampin appears to be due to the inhibition of
Toxicity of fluoroquinolones is mild in most species, and GI bacterial autolysin synthesis from concurrent administration
irritation is the most common side effect.18 Both ciprofloxa- of bacterial protein synthesis inhibitors.18
cin and moxifloxacin have been associated with GI effects in
horses.304,321 These effects with ciprofloxacin ranged from mild Formulations
transient diarrhea to severe colitis, endotoxemia, and laminitis Ciprofloxacin is available as human-labeled tablets, a diluted
necessitating euthanasia of three horses on humane grounds. solution for IV administration, and a solution for ophthalmic
Adverse effects were seen regardless of the route of adminis- use. Enrofloxacin is available as oral tablets and a 50-mg/mL
tration and the high incidence of adverse events precludes oral injectable solution for IM injection in dogs and as a 100-mg/
and rapid IV bolus administration of ciprofloxacin. mL injectable solution for the SC treatment of cattle. Both
The effect of most clinical concern with most fluoroqui- injectable solutions can be administered intravenously to
nolones is cartilage damage with subsequent arthropathy. horses. Orbifloxacin and marbofloxacin are available as oral
Arthropathies have been reported in humans, dogs, and foals, tablets for small animals. Danofloxacin is available as a 180-
but not calves, swine, or poultry.322-325 The risk of arthropathy mg/mL injectable formulation for cattle.
is age dependent, with younger animals being at higher risk.
Weight bearing and exercise are also associated with increased Clinical Use
severity of disease. Arthropathies have been documented in The use of fluoroquinolones in horses has been limited because
2-week-old foals after receiving 10 mg/kg of enrofloxacin of the risk of arthropathies; however, enrofloxacin has been
orally.325 Damage was characterized by synovial joint effusion successfully used in clinical cases, and fluoroquinolones may
and lameness and erosion and cleft formation in articular car- be the only viable option for treating some infections.328,331-333
tilage. Arthropathies were not seen in adult horses that were Informed consent from the client should always be obtained
given up to 25 mg/kg of IV enrofloxacin daily for 3 weeks or before using fluoroquinolones in young horses. Because the
15 mg/kg orally every 12 hours for 3 weeks.316,326 Although fluoroquinolones are concentration-dependent killers with a
they are not recommended for use in pregnant humans or long PAE, the ideal dosage regimen is once-daily high-dose
animals, the fluoroquinolones appear to have little effect on therapy. Enrofloxacin is commonly administered at doses of
the developing fetus.327 Enrofloxacin was successfully used to 7.5 to 10 mg/kg orally or intravenously, once daily.
treat chronic pleuritis in a pregnant mare with no apparent
detrimental effects on the foal.328
Ciprofloxacin and enrofloxacin interfere with the cyto- Y RIFAMPIN
chrome P450 system metabolism of methylxanthines such as
theophylline. Serum theophylline concentrations may double Mechanism of Action
and result in central nervous system and cardiac toxicity, so The rifamycins are antibiotics produced from Streptomyces
concentrations must be monitored during therapy.329 Coad- mediterranei. Rifampin inhibits DNA-dependent RNA poly-
ministration of nonsteroidal antiinflammatory drugs and merase in susceptible organisms, suppressing RNA synthe-
enrofloxacin may influence the pharmacokinetics of either sis. It has no effect on the mammalian enzyme. Its action
drug depending on the species studied and the specific drugs is bacteriostatic or bactericidal, depending on the suscep-
administered. Coadministration of firocoxib and enrofloxacin tibility of the bacteria and the concentration of the drug.
did not influence firocoxib concentrations in the horse.330 Rifampin is effective against a variety of mycobacterium
The fluoroquinolones may cause adverse central ner- species and S. aureus, Haemophilus, and R. equi. Rifampin
vous system effects in humans and animals as a result of a is considered especially active in the treatment of staphylo-
γ-aminobutyric acid (GABA) receptor antagonism. This has coccal and rhodococcal infections and in the eradication of
been associated with an increase in the incidence of seizures pathogens located in difficult-to-reach target areas, such as
in human beings and dogs. Administration of enrofloxacin to inside phagocytic cells. It is active at an acid pH, making it
human beings results in hallucinations.18 Rapid IV adminis- a rational choice for the treatment of septic foci and granu-
tration of high doses of enrofloxacin to horses causes tran- lomatous infections. It has moderate activity against Actino-
sient neurologic signs, including excitability and seizure-like bacillus suis, Actinobacillus equuli, Bordetella bronchiseptica,
and Pasteurella spp. Equine isolates of P. aeruginosa, E. coli, Microsomal enzyme induction from rifampin may shorten
Enterobacter cloacae, Klebsiella pneumoniae, Proteus spp., and the elimination half-life and decrease plasma drug concentra-
Salmonella spp. are resistant. The ability of rifampin to reach tions of CHPC, corticosteroids, theophylline, itraconazole,
intracellular bacteria can make it difficult to predict in vivo ketoconazole, warfarin, and barbiturates.342 Rifampin has a
therapy results on the basis of in vitro sensitivity tests.334 significant effect on clarithromycin bioavailability, decreasing
Because bacterial resistance to rifampin develops rapidly, clarithromycin plasma concentrations by 70% to 90%.288
it is usually administered with another antimicrobial.335
Although it is commonly combined with erythromycin for Formulations
the treatment of R. equi,28 resistance to the combination has Rifampin is available as human-labeled capsules or suspension
been reported.262,336 Rifampin is also commonly adminis- for oral administration or as a diluted solution for IV use.
tered with newer macrolide and macrolide derivative drugs,
such as clarithromycin and azithromycin.273 Clinical Use
Rifampin is primarily used in the treatment of pulmonary
abscess caused by R. equi and L. intracellularis proliferative
Pharmacokinetics enteropathy in foals in combination with a macrolide or a
Absorption macrolide derivative.
The oral bioavailability of rifampin varies from 70% in fasted
horses to 26% when administered with feed.48,334,337 Because
rifampin is usually administered with feed, recommended Y METRONIDAZOLE
dosages compensate for the decreased bioavailability. Bioavail-
ability after IM injection is 60%.338 In foals, maximum plasma Mechanism of Action
concentrations reach approximately 18 μg/mL at approxi- Metronidazole is rapidly taken up by bacteria, where it is
mately 3.5 hours. metabolized by a reduction process to cytotoxic derivatives
(short-lived free radical compounds). These cytotoxic com-
Distribution pounds damage DNA and other critical intracellular mac-
Rifampin is highly lipophilic and penetrates most tissues, as romolecules. Aerobic bacteria lack the reductive pathway
well as milk, bone, abscesses, and the central nervous system. necessary to produce the radical compounds.343 Metronida-
The Vd of rifampin in horses is 0.6 to 0.9 L/kg.337,338 Rifampin zole is highly effective against anaerobic bacteria, including
is 78% bound to plasma proteins.337 Bacteroides fragilis (penicillin resistant), Fusobacterium, and
Clostridium spp. Metronidazole-resistant C. difficile may cause
Elimination diarrhea in foals.344 Metronidazole has good activity against
In other species rifampin is deacetylated in the liver to a protozoa, including Giardia and Trichomonas spp.345 Metro-
metabolite that also has antibacterial activity. Desacetylri- nidazole has antiinflammatory effects in human beings, par-
fampin was not detected in equine serum samples after an ticularly in the GI tract, and has been used for the treatment of
IV dose of 10 mg/kg or oral doses of 10 mg/kg every 12 chronic inflammatory bowel diseases.346
hours for seven doses.337 Desacetylrifampin was measured
in urine, but rifampin was much more predominant. How-
ever, only 6.82% of the total dose was recovered in the urine Pharmacokinetics
as either rifampin or desacetylrifampin. In foals, metabolite Absorption
concentrations were no higher than 0.1 μg/mL in plasma Metronidazole is rapidly and well absorbed after oral admin-
following a single oral dose. The elimination half-life of istration in horses, with an oral bioavailability of 75% to
rifampin is 6 to 8 hours after IV administration and 12 to 85%.345,347 In horses with GI ileus, metronidazole may be
14 hours after oral administration.334,337 Because of imma- administered rectally and is rapidly absorbed; however, the
ture hepatic metabolism, elimination of rifampin is delayed bioavailability is only 30%.348 Bioavailability in foals 1 to 2.5
in very young foals.339,340 Plasma clearance ranges between days of age is 100%.349
1.14 and 1.34 mL/min/kg.337,338 As a hepatic enzyme
inducer, rifampin induces its own metabolism so that mul- Distribution
tiple oral dosing significantly decreases the elimination Metronidazole is lipophilic and widely distributed in tissues.
half-life. Enzyme induction is typically not seen with fewer It penetrates bone, abscesses, and the central nervous system.
than 5 days of therapy, but once it occurs, the increase in The Vd in mares is 0.7 to 1.7 L/kg.345,347 In foals less than 2
enzyme activity may last for more than 2 weeks after dis- weeks of age, the Vd is 0.87 L/kg.
continuation of treatment.341
Elimination
Adverse Effects and Drug Interactions Metronidazole is primarily metabolized in the liver. Both
Rifampin stains everything it touches red, and treated animals metabolites and unchanged drug are eliminated in urine and
may produce red urine, tears, sweat, and saliva. There are no feces. Plasma clearance is 2.8 mL/min/kg, and elimination
harmful consequences from this effect. Most horses object to half-life is 3 to 4 hours in horses.345,347,348,350 Age-related dif-
the taste of rifampin, so care must be taken to deposit a dose ferences in clearance have been noted in foals within the neo-
quite far back on the tongue and rinse the horse’s mouth after- natal period.349 At 1 to 2.5 days of age, clearance is 0.84 mL/
ward. Combination therapy of rifampin and doxycycline in min/kg and increases to 1.14 mL/min/kg in foals 10 to 12 days
foals with R. equi pneumonia resulted in adverse effects severe of age. This results in a significantly longer half-life in very
enough to warrant stopping treatment, including icterus and young foals, with values of 11.8 and 9.1 hours for foals 1 to 2.5
elevated liver enzymes. and 10 to 12 days old, respectively.
Adverse Effects and Drug Interactions Phospholipids

With clinical use in horses, anorexia and salivation are the
Steroids phospholipase
only adverse effects associated with the oral use of metroni- lipoxygenase
dazole.351 Histopathologic evidence of peripheral neuropathy Arachidonic acid 5-HPETE
and hepatopathy have been seen in horses administered high
doses for prolonged periods of time (30 mg/kg PO q12hr for NSAIDs cyclooxygenase
30 days). Metronidazole produces mutations in bacteria, and

carcinogenicity occurs in laboratory mice with prolonged PGG2 LTA4 LTB4
exposure. Therefore metronidazole is banned from use in
food animals. Because it has been implicated as a teratogen LTC4
in laboratory animals, use in pregnant animals is not recom- PGH2
mended.18 In neonatal foals, central nervous system excite-
ment can be seen with high or frequent dosing. If seen, dosing LTD4
should be stopped immediately. This appears to occur more
commonly with IV dosing, therefore slow administration over
30 minutes is recommended.
TXA2 PGE2 PGF2 PGD2 PGI2
Formulations (thromboxane) (prostacyclin)
Metronidazole is available only as human-labeled formula-
tions. It is most commonly administered orally as tablets and
TXB2
capsules. Because it is poorly soluble, the IV formulation must
be diluted in a large volume for administration, and it is cost
prohibitive in adult horses. FIG. 2.23 In the arachidonic acid cascade, cyclooxygenase works on
arachidonic acid to produce prostaglandins (PG), thromboxanes (TX), and
Clinical Use prostacyclin, whereas lipoxygenase works on arachidonic acid to produce
leukotrienes (LT). NSAIDs, Nonsteroidal antiinflammatory drugs; HPETE,
Metronidazole is used to treat anaerobic infections, espe-
hydroperoxyeicosatetraenoic acid.
cially pleuropneumonia and lung abscesses caused by
penicillin-resistant Bacteroides fragilis and clostridial entero-
colitis.30,351-353 Although rectal absorption is inferior to oral Unfortunately, this classification of “good” versus “bad”
absorption, it is a viable option for treatment when oral admin- COX proved too simplistic to explain the roles of the differ-
istration is not feasible. Metronidazole has also been used for ent forms of COX.358 COX-2 is produced constitutively in
the treatment of infiltrative bowel diseases in the horse.354 the brain, spinal cord, kidney, ovary, uterus, placenta, thy-
mus, bone, cartilage, synovia, endothelia, prostate, and lung.
Additionally, COX-2 is involved in cellular processes such as
gene expression, differentiation, mitogenesis, apoptosis, bone
Nonsteroidal Antiinflammatory Drugs remodeling, wound healing, and neoplasia359 but can also be
induced by hormones, nitric oxide, cytokines, and lipoxy-
genase products. The prostaglandins produced in the GI tract
and kidney that maintain mucosal integrity in the upper GI
The most commonly used drugs for treatment of pain and tract and renal perfusion, respectively, originally appeared to
inflammation in horses are the nonsteroidal antiinflammatory be derived only from COX-1. It is now widely accepted that
drugs (NSAIDs). NSAIDs inhibit the enzyme cyclooxygenase both COX-1 and COX-2 are involved in mucosal defense
(COX), which converts arachidonic acid to prostaglandins, in the GI tract.360 Likewise, both COX-1 and COX-2 are
thromboxane, and prostacyclin (Fig. 2.23). Blocking these involved in normal renal function, insofar as prostaglandins
ecosanoids results in antiinflammatory, analgesic, antipyretic, affect renal circulation through vasodilation, renin secretion,
and antithrombotic effects.355 and sodium and water excretion. As in the GI tract, it was
thought that COX-1–derived prostaglandins were involved
in regulating homeostatic functions and COX-2–derived
Y MECHANISM OF ACTION prostaglandins were involved only in inflammation or tissue
damage. However, constitutive expression has been demon-
Cyclooxygenase Inhibition strated for both isoforms in the kidney. NSAIDs also reduce
Two different, distinct forms of COX have been identified. A sodium excretion and may cause acute renal failure when
third form (COX-3) has been identified in other species, but maintenance of adequate renal perfusion is prostaglandin
its significance in the horse is currently unknown. Of the two dependent.361
forms known to exist in the horse, COX-1 is considered to be
the constitutively expressed form and is necessary for normal Nonselective Versus COX-2–Selective Inhibitors
homeostatic mechanisms in the body, whereas COX-2 is the Newer NSAID products have targeted selective inhibition
inducible form produced in response to injury.356 COX-1 is of COX-2 to supposedly increase the safety profile of these
found in platelets, the kidneys, and the GI tract; COX-2 is drugs. However, as previously stated, the theory behind
identified in fibroblasts, chondrocytes, endothelial cells, mac- this may be oversimplified. Either of the COX enzymes is
rophages, and mesangial cells. COX-2 is induced by exposure capable of producing any of the prostanoids. The profile of
to various cytokines, mitogens, and endotoxin and is upregu- the mediators produced depends mainly on the cell types
lated at sites of inflammation.357 present. Additionally, both enzymes are responsible in
some part for the inflammatory response. COX-1, because before endotoxin exposure without obscuring the signs of
it is constitutively expressed, is present in the early stages colic pain, and with a lesser risk of adverse effects. However,
of inflammation. Production of COX-2 will increase as the at low doses it does not alter endotoxin-induced leukopenia,
inflammatory process progresses, because it is an inducible and with ongoing inflammation there is little benefit in using
enzyme. COX-2 is also involved in mucosal healing, par- the low dose over the recommended dose.371-377 Flunixin and
ticularly in the case of gastric and colonic ulceration, and is phenylbutazone significantly inhibit movement of polymor-
constitutively expressed in some tissues, such as the kidney. phonuclear and mononuclear cells and antagonize the effects
Renal responses to furosemide, dobutamine, and exercise of endotoxin on bowel motility.368,378
were similar between meloxicam, a COX-2 preferential COX inhibition does not explain all of the antiinflamma-
agent, and phenylbutazone treatment, which suggested that tory activity of NSAIDs. NSAIDs are more lipophilic at a low
COX-2 was the mediator of prostanoid-induced changes to pH, such as is found in inflamed tissues. Some antiinflam-
renal function in horses.362 Therefore the safety of COX-2 matory action appears to be related to their ability to insert
selective inhibitors versus nonselective inhibitors has been into the lipid bilayer of cells and disrupt normal signals and
called into doubt.363,364 Nevertheless, there does appear to protein-protein interactions in cell membranes. In the cell
be a benefit to the use of these selective inhibitors in veteri- membrane of neutrophils, NSAIDs inhibit neutrophil aggre-
nary practice. gation, decrease enzyme release and superoxide generation,
COX-2 inhibitors exert their specificity by taking advan- and inhibit lipoxygenase.379,380
tage of the differences in protein structure between COX-1 The NSAIDs act as analgesics by inhibiting COX and pre-
and COX-2. There is a valine-leucine substitution in COX-2 venting the production of prostaglandins that sensitize the
that is not present in COX-1. This creates a side pocket in the afferent nociceptors at peripheral sites of inflammation. How-
tertiary structure of the molecule, and it is this side pocket ever, increasing evidence suggests that some NSAIDs have a
that COX-2 inhibitors preferentially bind to. The selectivity of central mechanism of action at the level of the spinal cord for
the drug for COX-2 versus COX-1 therefore depends on the analgesia unrelated to COX inhibition.381 This action is syn-
affinity a drug has for this site. Regardless of affinity, all COX ergistic with opioids and β2-receptor–adrenergic drugs.381,382
inhibitors bind both COX-1 and COX-2 to some extent; there- For managing pain and inflammation in horses, NSAIDs
fore there are no truly COX-2–specific drugs available at this are more effective as analgesics when inflammation is a part
time. Some drugs that have been described as COX-2 selec- of the pain process and when they are given before the onset
tive include etodolac, meloxicam, deracoxib, carprofen, and of the inflammatory process or insult. The time to onset and
firocoxib. Of these, firocoxib is the only drug labeled for use duration of analgesia of NSAIDs does not correlate well with
in the horse that has COX-2–selective activity at therapeutic their antiinflammatory properties. Because the analgesic effect
concentrations. has a more rapid onset and shorter duration of action than the
Affinity, or specificity, for COX-1 and COX-2 is generally antiinflammatory action, dosage regimens for effective analge-
assessed by in vitro techniques using whole blood assays. The sia may need to be different than those for antiinflammatory
activity against COX-1 is most commonly determined by mea- effects, or adjunct analgesics may need to be used.
surement of thromboxane B2 (TXB2), the stable metabolite of
TXA2, which is thought to be specific for COX-1 production in Y CHIRALITY
platelets. For COX-2 activity, macrophages are stimulated with
lipopolysaccharide (LPS), and production of prostaglandin E2 Many of the NSAIDs are stereoisomers. Stereoisomers consist
(PGE2) is measured. Enzyme-linked immunosorbent assays of enantiomers with the same molecular formula; however,
(ELISAs) are used for measurement of mediators. These tests due to asymmetrically oriented chemical groups on a central
are most valuable as comparative assays performed within the carbon, they form three-dimensional, nonsuperimposable
same laboratory, by the same investigators, within one class mirror images and are known as chiral compounds.383 For
of drugs, as a measure of the potency of the drugs against the the NSAIDs it is common to use the S (sinister) and R (rectus)
specific COX enzymes. designations for each of a pair of enantiomers.384 Although
each member of a pair of enantiomers differs in three-dimen-
Antiinflammatory and Analgesic Effects sional orientation, their physical properties (e.g., melting and
The NSAIDs are primarily antiinflammatory as a result of their boiling points, refractive index, solubility) are identical. Bio-
inhibition of prostaglandin production. Therefore NSAIDs do logic systems are highly chiral environments, and the phar-
not resolve inflammation but prevent its ongoing occurrence. macokinetics and pharmacodynamic effects of each of a pair
Whereas prostaglandin production will rapidly diminish, any of enantiomers may be very different. Stereospecificity may
previously present prostaglandin must be removed before occur in the pharmacokinetic processes of absorption, distri-
inflammation will subside. From tissue cage work, it has been bution, metabolism, and excretion, especially if the process
shown that phenylbutazone, ketoprofen, and carprofen have involves a carrier protein.385 If the fit of a drug molecule into
delayed peak concentrations at the site of inflammation and the binding site on a protein, enzyme, or receptor involves
persist in inflammatory exudates for long periods of time after the chiral center, the affinity for attachment will be differ-
plasma concentrations are negligible.365-367 This explains the ent for each of a pair of enantiomers. Therapeutic efficacy,
delayed onset and prolonged duration of antiinflammatory toxicity, or both may be related specifically to one enantio-
action that does not correlate with plasma pharmacokinetics mer. Work with the specific enantiomers of some NSAIDs
of the NSAIDs. has shown the S enantiomers to have good COX-inhibitory
The NSAIDs are commonly used in horses to attenuate the effects, whereas R forms can have weak activity against COX
prostaglandin-mediated effects of endotoxin.368-370 Flunixin yet still produce analgesia.383,386,387
meglumine administered at doses as low as one fourth the label Most chiral drugs are formulated as racemic mixtures,
dose will block prostaglandin production when administered containing equal amounts of each enantiomer, because pure
enantiomeric compounds are difficult and expensive to man- distribution and delayed elimination of gentamicin.395 Phen-
ufacture. All of the propionic acid NSAIDs (i.e., ketoprofen, ylbutazone also decreases urinary excretion of furosemide and
carprofen, vedoprofen, naproxen) are chiral compounds, attenuates furosemide-induced increases in urinary excretion
and, except for naproxen, they are formulated as racemic of sodium and chloride.396,397
mixtures. After administration, some enantiomers undergo
chiral inversion, as hepatic enzymes convert one form of the
enantiomer to the other form. When chiral inversion of the Y ADVERSE EFFECTS OF NONSTEROIDAL
propionic acid derivatives occurs, it is almost invariably uni- ANTIINFLAMMATORY DRUGS
directional, from R to S.383 The degree of chiral inversion
varies among species and cannot be predicted from one spe- The adverse effects of the NSAIDs are primarily related to
cies to another, making extrapolating dosages for NSAIDs COX inhibition in tissues where prostaglandins are beneficial
extremely hazardous. and protective. The NSAIDs have a higher incidence of toxic-
ity in neonates because kidney and liver function is not fully
Y PHYSICAL PROPERTIES developed.398-400 When indicated in neonates, NSAIDs should
be administered at the lowest possible doses and at extended
Almost all NSAIDs are weak acids and highly bound to dosing intervals. NSAIDs should be administered very cau-
plasma proteins such as albumin.355 Therefore they are well tiously to dehydrated animals.401,402 Because they mostly dis-
absorbed from the stomach, and most of the drug in the tribute in extracellular water, plasma concentrations will be
plasma is protein bound. Because of protein binding, they greater than normal in the dehydrated animal and more likely
are predominantly distributed in the ECF, and only low con- to cause toxicity. Decreased feed intake may also contribute to
centrations of NSAIDs are found in normal tissues and joint an increase in toxicity by increasing mucosal contact of drugs
fluid. In damaged tissues and joints, however, total (bound that may be directly cytotoxic. Common adverse drug reac-
and unbound) NSAID concentrations increase to thera- tions associated with NSAID use in the horse include renal
peutic levels because of increased blood flow, vascular per- papillary necrosis (medullary crest necrosis) and oral and GI
meability, and acute phase protein penetration into sites of ulceration.397,401-408
inflammation. Most NSAIDs undergo hepatic metabolism The renal toxicity of NSAIDs is a major concern, particu-
either through oxidation or glucuronide conjugation before larly in the perioperative period. NSAIDs typically have little
being eliminated in the urine.355 effect on renal function in normal adult animals.409 However,
they decrease renal blood flow and GFR in patients with con-
Y DRUG INTERACTIONS gestive heart failure, those that are hypotensive or hypovolemic
(especially during anesthesia and surgery), or those that have
The occurrence and potential hazards of drug interactions chronic renal disease.361 A more severe dose-dependent toxic-
must be considered before initiating therapeutic use of the ity associated most commonly with phenylbutazone is renal
NSAIDs. In general, any two NSAIDs administered together papillary necrosis.397,401,408 Although attributed to impaired
will be additive in their effect.388-391 The downside to this prac- renal blood flow, other mechanisms, such as direct nephrotox-
tice is the increased risk of toxicity that occurs when NSAIDs icity of the drug or its metabolites, also may be involved. Risk
are administered concurrently. Horses administered a combi- for nephrotoxicity is increased when NSAIDs are coadminis-
nation of phenylbutazone and flunixin at the recommended tered with other nephrotoxic drugs, such as polymyxin B or
doses for 5 days had a higher incidence of gastric ulceration, as aminoglycoside antibiotics.
well as a significant decrease in blood protein concentrations, Ulceration of the GI tract occurs most commonly in the
compared with placebo-treated horses and horses receiving oral cavity, gastric glandular mucosa, and duodenum. With
phenylbutazone alone.391 It is likely that the benefits of giving duodenal involvement, stricture formation is possible, and
two NSAIDs at once are far outweighed by the risks. Because surgical bypass of the proximal duodenum may be required
most NSAIDs act by similar mechanisms of COX inhibition, for successful treatment. Ulceration in the right dorsal colon
a higher dose of a single NSAID should produce the same may also occur and can result in severe disease. The treatment
response. of right dorsal colitis is intensive and mainly symptomatic.403
Antacids, mucoprotective agents, and adsorbent antidiar- The hypoproteinemia that results from loss of plasma proteins
rheal drugs can interfere with the absorption of NSAIDs.346 into the ulcerated GI tract can be corrected with IV infusions
Concurrent use of corticosteroids is generally contraindi- of plasma. The fluid and electrolyte losses that accompany the
cated because corticosteroids increase the secretion of gastric diarrhea are managed with commercially available IV fluids.
acid, pepsin, and trypsin; alter the structure of gastric mucin; Broad-spectrum antimicrobials are indicated when bacterial
and decrease mucosal cell proliferation. This action is syn- septicemia appears to exist. Pain must be managed with opioid
ergistic with NSAID-induced GI mucosal damage, but the analgesics. Antiulcer medications may be beneficial and speed
specific risks of concurrent NSAID and steroid administra- recovery. Surgical removal of damaged sections of the colon
tion are unknown.392 Several antibiotics have been shown to may be necessary in some cases.403 Recovery is usually slow,
alter phenylbutazone disposition. Chloramphenicol decreases and in severe cases the prognosis is always guarded.
the elimination rate, and rifampin significantly increases the Less common adverse drug reactions include hemostatic
elimination rate of phenylbutazone.393 Alternatively, phen- effects and altered proteoglycan synthesis. NSAIDs classi-
ylbutazone may affect the disposition of other antibiotics. cally inhibit platelet aggregation by preventing thromboxane
Coadministration of phenylbutazone and procaine penicillin production via the COX-1 pathway.355 Recovery of platelet
G results in higher serum concentrations of penicillin because function is dependent on the pharmacokinetics of the NSAID
of decreased tissue distribution.394 Concurrent administra- and the mechanism of COX inhibition.410-414 Aspirin perma-
tion of gentamicin and phenylbutazone results in increased nently modifies COX, so platelet function is restored only by
the production of new platelets.410,414 The effects of NSAIDs compared with flunixin or phenylbutazone.386,425 Despite this,
on proteoglycan synthesis should be considered in their clini- carprofen produces significant analgesia, probably owing to
cal use for equine joint disease. Many NSAIDs affect cartilage the central actions of the R enantiomer.425 Carprofen may also
anabolism in addition to their antiinflammatory actions.415,416 have other beneficial antiinflammatory effects, including inhi-
A few NSAIDs, such as carprofen, increase proteoglycan syn- bition of matrix metalloproteinases in cartilage explants and
thesis.415,417 Phenylbutazone does not affect proteoglycan inhibition of the activation of NfκB-dependent genes such as
synthesis or chondrocyte viability, but it is protective against inducible nitric oxide synthase.426,427
chondrocyte-mediated catabolism.416 The effects of NSAIDs
on bone healing are currently controversial, with some labo- Y DICLOFENAC
ratory animal studies showing detrimental effects and others
showing little or no effect on bone healing.418 Currently the Diclofenac is available as a 1% liposomal suspension cream
only NSAID that has shown negative bone healing effects in for topical application in horses. It is used to control pain and
horses is phenylbutazone.419 Clinicians should consider the inflammation associated with osteoarthritis in the tarsal, car-
clear benefits of analgesia in equine patients against the poten- pal, metacarpophalangeal, metatarsophalangeal, and proximal
tial adverse effects. interphalangeal joints in horses. A 5-inch ribbon of diclofe-
nac topical cream can be applied twice daily over the affected
Y ASPIRIN joint for up to 10 days. Owners should wear rubber gloves to
prevent absorption into the hands. A single topical applica-
Aspirin (sodium salicylate) is available only in oral forms. tion of diclofenac cream produced measurable concentrations
Because it is a weak acid, it is best absorbed in the acidic envi- of diclofenac in transudate within 6 hours and significantly
ronment of the upper GI tract, although overall bioavailability attenuated carrageenan-induced local production of PGE2.428
is low via the oral route (6%). Absorption is higher when given However, in an amphotericin B acute synovitis model, there
via the rectal route (17%).420 During absorption aspirin is was no overall difference between the diclofenac-treated group
partially hydrolyzed to salicylic acid and distributed through- and the control group.429 In a controlled field study in horses
out the body. The highest concentrations are attained in the with osteoarthritis, average lameness scores showed statisti-
liver, heart, lungs, renal cortex, and plasma. Protein binding is cally significant improvement after treatment with diclofenac
moderate (about 60%) and depends on species and drug and topical cream.430 Topical application over the sites of injection
albumin concentrations.355 Aspirin is hepatically metabolized for regional limb perfusion has also been found to decrease
by glycine and glucuronide conjugation. Salicylates and their inflammation at the site, as well as provide analgesia, poten-
metabolites are rapidly excreted in urine by way of glomer- tially allowing extended use of this procedure.431 The limited
ular filtration and active tubular excretion, with an elimina- systemic absorption of diclofenac makes it useful in the treat-
tion half-life in the horse of approximately 1 hour.420 In the ment of acute lameness in competitive horses.432 However, as
horse salicylic acid is the primary salicyl compound found a result of central sensitization and windup, locally adminis-
in urine.421 Significant tubular reabsorption occurs, which tered diclofenac will be less effective than systemically admin-
depends greatly on pH.355 istered NSAIDs for therapy of chronic pain. Topical diclofenac
Aspirin is the most effective NSAID for antiplatelet ther- can be used simultaneously with systemically administered
apy.410,422,423 Aspirin irreversibly acetylates the COX present NSAIDs for maximal effect.
in platelets, which inhibits the formation of thromboxane A2,
which is responsible for vasoconstriction and platelet aggrega- Y FIROCOXIB
tion. 410,422,423 Because platelets do not contain a nucleus, they
are incapable of synthesizing additional COX; therefore plate- Firocoxib is an NSAID in the coxib class introduced in the
let thromboxane production will be inhibited for the life of any United States in 2005. It is labeled for use in the horse as a
circulating platelets. Antiplatelet therapy may be beneficial in paste preparation for oral administration at a dose of 0.1 mg/
the management of equine laminitis, disseminated intravas- kg for 14 days for the treatment of osteoarthritis. In 2011 it
cular coagulation, and equine verminous arteritis. A precise was also approved as an injectable formulation for IV admin-
antiplatelet dose has not been established, but a dose of 12 mg/ istration at 0.09 mg/kg for 5 days. In clinical trials of horses
kg prolongs bleeding time for 48 hours.410 with naturally occurring osteoarthritis, overall clinical efficacy
of firocoxib was comparable to that of a paste formulation of
Y CARPROFEN phenylbutazone after 14 days of administration.433 A canine
tablet formulation is also available, and data suggest that the
Carprofen is a propionic acid derivative formulated as a race- canine formulation is absorbed in the horse and may also be
mic mixture that is currently available for use in horses in used as an effective antiinflammatory agent.434,435 The use of
Europe. The Vd is 0.1 L/kg for the R enantiomer and 0.29 L/kg the canine formulation is controversial, as it is often adminis-
for the S enantiomer.365 At the recommended dose of 0.7 mg/ tered because of the decreased cost compared with the paste.
kg, carprofen has a longer elimination half-life in horses than The American Veterinary Medical Association has stated that
most other NSAIDs, at 21 hours for the R enantiomer and 17 it will not support the practice and this extralabel use is not
hours for the S enantiomer following IV administration. The R justified.436
enantiomer predominates in plasma and exudates because of Firocoxib is highly COX-2 selective, with COX-1:COX-2
the hepatic stereospecificity for glucuronidation of the S enan- IC50 ratios of 263 to 643 demonstrated in vitro.437 Several
tiomer, leading to its more rapid clearance.424 Chiral inversion studies have confirmed this in ex vivo models of the horse,
of carprofen does not occur in the horse.424 Like other NSAIDs, with minimal to no COX-1 inhibition noted following oral or
carprofen accumulates in inflammatory exudate but produces IV administration.434,438 On the basis of in vitro whole blood
only modest reductions in the concentrations of ecosanoids experiments, the concentration of firocoxib that inhibits 50%
(IC50) or 80% (IC80) of COX-2 activity in LPS-stimulated readily partition into tissues, hence the relatively high volume
equine whole blood is approximately 30 ng/mL and 67 ng/ of distribution.449,450 The elimination half-life in inflammatory
mL, respectively.439 Adjusting for plasma concentrations by exudate is 16 hours.451 The onset of antiinflammatory action
assuming a plasma concentration that is 65% of whole blood, is within 2 hours, peak response occurs between 12 and 16
the IC80 equates to 103 ng/mL.435 Concentrations of 100 ng/ hours, and duration of action is 36 hours. Analgesic effects
mL firocoxib have been shown to reduce COX-2 and mPGES1 have a more rapid onset and shorter duration. Only 14% of a
gene expression in isolated equine peripheral blood mono- dose is excreted in urine, but otherwise little is known about
nuclear cells.440 When modeled using plasma concentration the metabolism of flunixin.355
profiles in ex vivo models, similar results were found, with an Flunixin is used in horses for a variety of inflammatory and
IC80 reported between 96 and 110 ng/mL.434,435 This IC80 is painful conditions, including colic, colitis, exertional rhabdo-
similar to what was achieved following IV administration of a myolysis, endotoxic shock, respiratory disease, ocular disease,
single dose434 and oral administration of multiple doses435 of general surgery, and laminitis.355 Flunixin is more effective
either the paste or tablet formulation in the other study. than phenylbutazone in preventing the clinical signs of endo-
In safety studies, oral ulcers were detected at 3× and 5× the toxemia but appears equivalent to ketoprofen.452 Flunixin may
label dose, but no other adverse effects were noted. However, prevent abortion in endotoxic mares.453 Flunixin is dosed at
adverse effects may still occur, particularly in patients with 1.1 mg/kg every 12 to 24 hours for musculoskeletal pain but
preexisting disease, or those that receive NSAID stacking. A may be administered more frequently at lower doses (0.5 mg/
study examining the effects of coadministration of firocoxib kg q6–12hr) for colic pain. Therapy at 0.25 mg/kg every 6 to 8
with phenylbutazone showed significantly increased serum hours is used as the lowest dose that will provide antiprosta-
creatinine, significantly decreased total protein, and a signifi- glandin effects, but this dose will not provide much analgesia.
cantly lower urine specific gravity after 10 days of treatment at Extremely high doses of flunixin may mask signs of surgical
commonly used doses.441 colic pain and interfere with treatment decisions.
In horses firocoxib is well absorbed, with an oral bioavail- Flunixin has a good safety profile, but high doses or chronic
ability of 79%, although the time to maximum concentration dosing can cause anorexia, depression, and GI ulcers.406,454 In
following the first dose is often prolonged. Firocoxib is slowly normal foals the label dose of flunixin administered for 5 days
eliminated, and Vd values are approximately 2 L/kg. Reported did not produce adverse effects, but 6 times the label dose
elimination half-lives are as long as 2 days.437,439 Based on the resulted in GI ulcers.400 In another study foals were adminis-
long half-life, it may take multiple days for steady concentra- tered flunixin at the label dose for 30 days, and all treated foals
tions and maximum efficacy to be reached. To overcome this, developed gastric ulcers.398 Area under the curve, clearance,
a loading dose of 0.3 mg/kg once has been recommended,442 and half-life of flunixin are significantly greater in newborn
which allows achievement of average steady-state drug con- foals compared with adult horses.448 The half-life increases
centrations within 24 hours. After the loading dose, mainte- from 1 to 2 hours in adults to 6 to 8 hours in neonates. Based
nance doses following label directions maintain a relatively on this, higher doses with prolonged dosing intervals should
constant average drug concentration that produces less vari- be used in neonatal foals.
ability in onset of action and efficacy. IM injections of flunixin are highly irritating to muscle
Foals 4 to 6 weeks of age have similar pharmacokinetics to and have been incriminated in cases of clostridial myonecro-
adult horses443; however, the pharmacokinetics differs signifi- sis in horses; they should therefore be avoided when possible,
cantly in neonatal foals. In neonates, firocoxib is more rapidly despite the label directions.455,456 If not treated promptly and
absorbed, with a higher maximum concentration but a shorter aggressively, clostridial myonecrosis causes severe tissue dam-
half-life, resulting in less drug accumulation.444 Steady-state age and may be rapidly fatal. Flunixin treatment of horses with
is achieved after approximately 3 doses. In healthy neonates, ischemic GI disease may cause prolonged permeability defects
no clinically apparent adverse effects were noted after 9 days in recovering mucosa.495
of oral firocoxib at 0.1 mg/kg. Intravenous data in neonates
suggest that the difference in pharmacokinetics is due to an Y KETOPROFEN
increased clearance. Even following multiple doses, IC80 lev-
els were not reached in neonates at horse label doses. Further Ketoprofen is a chiral propionic acid derivative approved
work is needed to determine the IC80 necessary for foals and for horses as a racemic solution for IV or IM injection. The
whether or not the use of higher doses or shorter dose inter- label dose is 2.2 mg/kg administered once daily. Oral and
vals is safe and effective; however, current clinical practice is to rectal bioavailability is too poor for these routes to be used
use 0.2 mg/kg PO or IV q12–24hr. clinically.367,457,458 Ketoprofen is 92.8% protein bound in
horses.459 Ketoprofen has a moderate Vd for both enantiomers
Y FLUNIXIN MEGLUMINE of approximately 0.5 L/kg and short plasma elimination half-
lives of 1 to 1.5 hours.367,387,451,459,460 Ketoprofen is hepatically
Flunixin meglumine is a very potent inhibitor of COX that is metabolized by conjugation reactions, with only 25% of a
approved for use in horses and is available in injectable and oral dose eliminated as unchanged drug in urine.459 The S enan-
formulations. Flunixin is rapidly absorbed after oral adminis- tiomer is associated with antiprostaglandin activity and toxic-
tration, with a bioavailability of 86% and peak serum levels ity, whereas the R enantiomer is associated with analgesia and
within 30 minutes.445 Absorption is delayed by feeding.446 The does not produce GI ulceration.367,461 Because of chiral inver-
Vd is 0.1 to 0.3 L/kg in horses, and the plasma elimination sion, the S enantiomer predominates in horses.367 Ketoprofen
half-life is 1 to 2 hours.445-447 In newborn foals the elimination accumulates in inflammatory exudates in the horse, where the
half-life is prolonged at 13.4 hours. The Vd is also increased elimination half-life of the S enantiomer is 23 hours and the
in the newborn foal, as is expected with a low-Vd drug in the R enantiomer is 20 hours. The maximum antiinflammatory
neonate.448 It is highly protein bound (86%) but appears to effects of ketoprofen occur at 4 hours after a dose and last for
24 hours, illustrating that the antiinflammatory effects are not albumin and protein concentrations, were not noted in foals
related to plasma concentrations.451 Similar to flunixin, keto- receiving meloxicam at these doses for 21 consecutive days.
profen pharmacokinetics are different in neonatal foals, and Another NSAID in this group, piroxicam, has received
higher doses with longer dosing intervals are recommended.462 some attention in equine medicine, not for treatment of lame-
In studies of noninfectious arthritis, endotoxemia, and colic, ness or colic, but for the treatment of squamous cell carcinoma
ketoprofen is clinically similar to flunixin meglumine in effi- (SCC). Some tumors, particularly SCC, have been shown to
cacy.451,452,461 In an experimentally induced synovitis model, produce COX-2.477 Treatment with piroxicam has produced
phenylbutazone was more effective in reducing lameness and long-term remissions of SCC in the bladder, urethra, and peri-
synovial fluid prostaglandin concentrations.463 In horses with ocular structures.478 Adverse effects, even at the low doses used
chronic laminitis, ketoprofen was more effective than phenyl- (0.2 mg/kg PO q24hr), have been noted, and include diarrhea
butazone at relieving pain but only at a higher-than-label dose and abdominal pain. It is not known at this time whether or
(3.63 mg/kg).464 In comparative toxicity studies in both horses not meloxicam would have a similar effect, with a higher safety
and donkeys, ketoprofen at the label dose had less potential for profile.
toxicity than flunixin meglumine or phenylbutazone.406,465 In
drug tolerance studies using 25 times the label dose for 5 days, Y PHENYLBUTAZONE
horses developed depression, icterus, nephritis, hepatitis, and
hemorrhagic necrosis of the adrenal glands.466 Phenylbutazone is the most widely used NSAID in the horse
and is available in many generic IV and oral formulations. After
Y MELOXICAM oral administration, phenylbutazone is well absorbed, but
time to peak concentration may be delayed by feeding.479-481
Meloxicam is an enolic acid belonging to the oxicam class of The Vd is 0.15 L/kg, with highest concentrations in the liver,
NSAIDs. It is slightly COX-2 selective in the horse with an heart, kidney, lungs, and plasma.482 The elimination half-life is
IC50 COX-1:IC50 COX-2 of 3.8.467 Meloxicam is labeled for use 3.5 to 7 hours.483 In neonatal foals the Vd is higher (0.27 L/kg)
in Europe as an antiinflammatory drug in the horse for both and the elimination half-life is longer (6.4–22.1 hours) than
oral and injectable formulations. Oral bioavailability is nearly in adult horses.484 Plasma protein binding in horses is greater
complete, and absorption is not affected by feeding.468 The than 99%.483 Phenylbutazone is metabolized in the liver to
Vd is 0.12 L/kg, with most drug eliminated unchanged in the oxyphenbutazone, an active metabolite that is eliminated more
urine. The elimination half-life is 5.2 to 8.5 hours.468,469 Clear- slowly from the body than phenylbutazone. Oxyphenbutazone
ance differs significantly between horses and donkeys, with inhibits the metabolism of phenylbutazone. Phenylbutazone
values of 34.7 mL/kg/hr and 187.9 mL/kg/hr, respectively.470 and its metabolite cross the placenta and are excreted in milk.
Pharmacokinetic-pharmacodynamic analysis has shown that Less than 2% is excreted in the urine as unchanged drug. The
a maximum effect is achieved at plasma concentrations of capacity of the liver to metabolize phenylbutazone becomes
approximately 0.2 μg/mL, which translates into a daily dose of overwhelmed at relatively low drug doses, resulting in dose-
0.6 mg/kg intravenously or orally. dependent kinetics.485 The elimination half-life increases with
This dose has proven effective in lameness models, as well increasing dose rates and increasing age.485-487 The elimination
as experimental models of colic and abdominal pain. Direct half-life from exudate is 24 hours.366 Therapeutic efficacy lasts
comparison of flunixin and meloxicam in postoperative for more than 24 hours as a result of the irreversible binding
cases of small intestinal strangulating obstructions showed of phenylbutazone to COX, slow elimination from inflamed
that meloxicam was as effective as flunixin when comparing tissues, and long elimination half-life of oxyphenbutazone.483
most major clinical variables, although more horses in the Therefore high or frequent doses of phenylbutazone result in
meloxicam group showed gross signs of pain.471 Additionally, disproportionately increasing plasma concentrations, which
meloxicam treatment did not impair mucosal recovery after easily result in toxicity.
ischemic injury in a small intestinal strangulation model.472 Phenylbutazone is used extensively in horses for a variety
Meloxicam also had no detectable difference in sucrose per- of musculoskeletal disorders. Although phenylbutazone also
meability following intragastric administration, indicating antagonizes the disruptive effects of endotoxin on bowel motil-
less compromise to gastric mucosal permeability compared ity, flunixin meglumine is generally preferred for treatment of
with phenylbutazone.473 However, chronic dosing with higher colic in horses.368 Phenylbutazone appears to inhibit prosta-
doses (1.8–3.0 mg/kg) was associated with dose-dependent glandin synthesis at low plasma concentrations in the horse
adverse effects typical of this class of drugs, including hypopro- (5–15 μg/mL), whereas much higher drug concentrations are
teinemia and hypoalbuminemia, GI disorders, renal damage, needed in human beings (50–150 μg/mL).483 This discrepancy
and bone marrow dyscrasias.474 Administration of meloxicam is probably due to a species difference in the structure of COX.
IV before surgery followed by once-daily oral administration An initial dose of 4.4 mg/kg every 12 hours on the first day
for 4 consecutive days is efficacious in controlling postopera- of therapy is followed by a decreased dose and increased dos-
tive pain and inflammation in horses undergoing orthopedic ing interval for subsequent therapy. Because of the accumu-
surgery.475 lation from the long elimination half-life of phenylbutazone
Meloxicam pharmacokinetics in neonatal foals differs from and oxyphenbutazone, chronic therapy should be at the lowest
adults.476 Similar to firocoxib, meloxicam exhibits a higher possible dose and the longest possible dosing interval that still
clearance in neonates, with an elimination half-life of approxi- controls pain.
mately 2.5 hours. Based on a multiple-dose study, 0.6 mg/kg Phenylbutazone has a narrow safety margin, especially in
orally q12hr to foals less than 7 weeks of age produced con- foals and ponies and dehydrated horses.400,401 Phenylbutazone
centrations thought to be effective for treatment of pain and toxicity most commonly results in adverse GI effects, includ-
inflammation. Adverse effects, including gastric ulceration, ing oral, esophageal, gastric, cecal, and right dorsal colonic
changes in white blood cell counts, and changes in serum ulcerations, and accompanying protein-losing enteropathy,
hypoproteinemia, leukopenia, and anemia.401-405,488 Renal REFERENCES

papillary necrosis (renal medullary crest necrosis) results
1. Toutain PL, Bousquet-Melou A. Volumes of distribution. J Vet
from inhibition of prostaglandins that maintain renal blood Pharmacol Ther. 2004;27:441–453.
flow and direct toxicity of phenylbutazone and metabo- 2. Baggot JD, Love DN, Stewart J, et al. Gentamicin dosage in foals
lites.408 Ulcerative cystitis associated with prolonged phen- aged one month and three months. Equine Vet J. 1986;18:113–116.
ylbutazone administration has also been reported489 and 3. Toutain PL, Bousquet-Melou A. Bioavailability and its assess-
may also relate to direct cytotoxic effects of drug secreted ment. J Vet Pharmacol Ther. 2004;27:455–466.
in the urine. Because phenylbutazone can mask symptoms 4. Baggot JD. Bioavailability and bioequivalence of veterinary
of lameness in horses for several days after therapy, it may drug dosage forms, with particular reference to horses: an over-
be used to disguise lameness during soundness examinations view. J Vet Pharmacol Ther. 1992;15:160–173.
or for competitive purposes.483 Extravascular administration 5. Bertucci C, Domenici E. Reversible and covalent binding of
drugs to human serum albumin: methodological approaches and
results in severe tissue necrosis. Phenylbutazone may have a
physiological relevance. Curr Med Chem. 2002;9:1463–1481.
negative effect on bone healing in horses.419 Phenylbutazone 6. Bailey DN, Briggs JR. The binding of selected therapeutic drugs
significantly suppresses total T4 and free T4 concentrations in to human serum alpha-1 acid glycoprotein and to human serum
horses for 10 days.490 albumin in vitro. Ther Drug Monit. 2004;26:40–43.
7. Toutain PL, Bousquet-Melou A. Free drug fraction vs free drug
Y VEDAPROFEN concentration: a matter of frequent confusion. J Vet Pharmacol
Ther. 2002;25:460–463.
Vedaprofen is structurally related to ketoprofen and carprofen 8. Craig WA, Ebert SC. Protein binding and its significance in an-
and also is formulated as a racemic mixture of S and R enan- tibacterial therapy. Infect Dis Clin North Am. 1989;3:407–414.
tiomers. It is available in some countries as an IV injectable 9. Benet LZ, Hoener BA. Changes in plasma protein binding have
little clinical relevance. Clin Pharmacol Ther. 2002;71:115–121.
solution and as a palatable gel for oral administration with a
10. Toutain PL, Bousquet-Melou A. Plasma clearance. J Vet Phar-
loading dose of 2 mg/kg followed by 1 mg/kg every 12 hours. macol Ther. 2004;27:415–425.
Oral bioavailability is approximately 100%, and it is highly 11. Intorre L, Mengozzi G, Maccheroni M, et al. Enrofloxacin-
protein bound (99%). Within 2 hours after IV administration, theophylline interaction: influence of enrofloxacin on theo-
the mean R:S plasma concentration ratio is 95:5. This is due phylline steady-state pharmacokinetics in the beagle dog. J Vet
to marked distribution and elimination differences between Pharmacol Ther. 1995;18:352–356.
the enantiomers, and not chiral inversion. The R enantiomer 12. von Rosensteil NA, Adam D. Macrolide antibacterials. Drug in-
has an elimination half-life of 2.2 hours and a Vd of 0.23 L/ teractions of clinical significance. Drug Saf. 1995;13:105–122.
kg, and the S enantiomer has an elimination half-life of 0.76 13. Boothe DM. Drug disposition and extrapolation of dosing regi-
hours and a volume of distribution of 0.5 L/kg.491 Both enan- mens. St. Louis: Saunders; 2001.
14. Baggot JD, Short CR. Drug disposition in the neonatal animal, with
tiomers accumulate in inflammatory exudate and are more
particular reference to the foal. Equine Vet J. 1984;16:364–367.
slowly cleared from exudate than from plasma. In an equine 15. Johnson PJ, Mrad DR, Schwartz AJ, et al. Presumed moxidectin
acute nonimmune inflammation model, vedaprofen produced toxicosis in three foals. J Am Vet Med Assoc. 1999;214:678–680.
significant inhibition of inflammatory swelling and partially 16. Riviere JE. Comparative pharmacokinetics: principles, techniques
inhibited leukocyte migration into the exudate. Inhibition of and applications. Hoboken, NJ: Wiley-Blackwell; 2003.
leukocyte migration was not seen in this model with other 17. Lorian V, Burns L. Predictive value of susceptibility tests for
NSAIDs.491 Based on in vitro models, vedaprofen is moder- the outcome of antibacterial therapy. J Antimicrob Chemother.
ately COX-1 selective. 1990;25:175–181.
18. Giguere S, Prescott JF, Baggot JD, et al. Antimicrobial therapy in
veterinary medicine. 4th ed. Ames: Blackwell Publishing; 2006.
Y OTHER DRUGS 19. Sandholm M, Kaartinen L, Pyorala S. Bovine mastitis: why does
antibiotic therapy not always work? An overview. J Vet Pharma-
Numerous other NSAIDs have been studied in the horse, col Ther. 1990;13:248–260.
although their clinical use is sporadic and no formulations 20. Clark C, Dowling PM, Ross S, et al. Pharmacokinetics of
are labeled for use in the horse. Etodolac is a relatively selec- tilmicosin in equine tissues and plasma. J Vet Pharmacol Ther.
tive COX-2 inhibitor in the horse. It has been used clini- 2008;31:66–70.
cally in horses with a previous history of gastric or colonic 21. Ames TR, Patterson EB. Oxytetracycline concentrations in
ulceration, as well as in a few horses with active GI disease, plasma and lung of healthy and pneumonic calves, using two
with apparent benefits. Doses of 20 mg/kg PO q12–24hr have oxytetracycline preparations. Am J Vet Res. 1985;46:2471–2473.
been reported, although the COX-2 selectivity may be lost 22. Kuriyama T, Nakagawa K, Kawashiri S, et al. The virulence of
at these high doses.492-495 Deracoxib is a moderately selec- mixed infection with Streptococcus constellatus and Fusobacte-
rium nucleatum in a murine orofacial infection model. Microbes
tive COX-2 inhibitor in the horse with a long elimination
Infect. 2000;2:1425–1430.
half-life and average maximum plasma concentration of 23. Hariharan H, McPhee L, Heaney S, et al. Antimicrobial drug
0.54 μg/mL following oral administration. Doses of 2 mg/ susceptibility of clinical isolates of Pseudomonas aeruginosa.
kg PO q12hr would maintain concentrations above the IC80 Can Vet J. 1995;36:166–168.
for COX-2.496 Acetaminophen, although not considered a 24. Fantin B, Carbon C. In vivo antibiotic synergism: contribution of
classic NSAID due to its weak inhibitory effects on COX-1 animal models. Antimicrob Agents Chemother. 1992;36:907–912.
and COX-2, is another drug occasionally used as an antiin- 25. Marshall SA, Jones RN, Wanger A, et al. Proposed MIC quality
flammatory, analgesic, and antipyretic in horses. It is well control guidelines for National Committee for Clinical Labo-
absorbed with a bioavailability of approximately 91%497 and ratory Standards susceptibility tests using seven veterinary
has been used successfully in laminitis cases with no spe- antimicrobial agents: ceftiofur, enrofloxacin, florfenicol, peni-
cillin G-novobiocin, pirlimycin, premafloxacin, and spectino-
cific adverse effects.498 Doses range from 20 to 25 mg/kg PO
mycin. J Clin Microbiol. 1996;34:2027–2029.
q12–24hr.
26. Vogelman BS, Craig WA. Postantibiotic effects. J Antimicrob 50. Firth EC, Nouws JF, Klein WR, et al. The effect of phenyl
Chemother. 1985;15:A37–46. butazone on the plasma disposition of penicillin G in the
27. McKellar QA, Sanchez Bruni SF. Jones DG: Pharmacokinetic/ horse. J Vet Pharmacol Ther. 1990;13:179–185.
pharmacodynamic relationships of antimicrobial drugs used in 51. Durr A. Comparison of the pharmacokinetics of penicillin G
veterinary medicine. J Vet Pharmacol Ther. 2004;27:503–514. and ampicillin in the horse. Res Vet Sci. 1976;20:24–29.
28. Prescott JF, Nicholson VM. The effects of combinations of se- 52. McConnico RS, Roberts MC, Tompkins M. Penicillin-induced
lected antibiotics on the growth of Corynebacterium equi. J Vet immune-mediated hemolytic anemia in a horse. J Am Vet Med
Pharmacol Ther. 1984;7:61–64. Assoc. 1992;201:1402–1403.
29. Clark C, Greenwood S, Boison JO, et al. Bacterial isolates 53. Wilkerson MJ, Davis E, Shuman W, et al. Isotype-specific an-
from equine infections in western Canada. Can Vet J. 1998- tibodies in horses and dogs with immune-mediated hemolytic
2003;2008(49):153–160. anemia. J Vet Intern Med. 2000;14:190–196.
30. Sweeney CR, Holcombe SJ, Barningham SC, et al. Aerobic and 54. Nielsen IL, Jacobs KA, Huntington PJ, et al. Adverse reaction to
anaerobic bacterial isolates from horses with pneumonia or procaine penicillin G in horses. Aust Vet J. 1988;65:181–185.
pleuropneumonia and antimicrobial susceptibility patterns of 55. Romano A, Mayorga C, Torres MJ, et al. Immediate allergic
the aerobes. J Am Vet Med Assoc. 1991;198:839–842. reactions to cephalosporins: cross-reactivity and selective re-
31. Cohen ND, Woods AM. Characteristics and risk factors for sponses. J Allergy Clin Immunol. 2000;106:1177–1183.
failure of horses with acute diarrhea to survive: 122 cases 56. Chapman CB, Courage P, Nielsen IL, et al. The role of procaine
(1990-1996). J Am Vet Med Assoc. 1999;214:382–390. in adverse reactions to procaine penicillin in horses. Aust Vet J.
32. Raidal SL, Taplin RH, Bailey GD, et al. Antibiotic prophylaxis of 1992;69:129–133.
lower respiratory tract contamination in horses confined with 57. Tobin T, Blake JW. The pharmacology of procaine in the horse:
head elevation for 24 or 48 hours. Aust Vet J. 1997;75:126–131. relationships between plasma and urinary concentrations of
33. Whittem TL, Johnson AL, Smith CW, et al. Effect of perio- procaine. J Equine Med Surg. 1977;1:188–194.
perative prophylactic antimicrobial treatment in dogs un- 58. Tobin T, Blake JW, Sturma L, et al. Pharmacology of procaine
dergoing elective orthopedic surgery. J Am Vet Med Assoc. in the horse: procaine esterase properties of equine plasma and
1999;215:212–216. synovial fluid. Am J Vet Res. 1976;37:1165–1170.
34. Haven ML, Wichtel JJ, Bristol DG, et al. Effects of antibiotic 59. Fischbach H, Welch H, King EQ, et al. Procaine penicillin and
prophylaxis on postoperative complications after rumenotomy sulfonamide antagonism. J Am Pharm Assoc Am Pharm Assoc.
in cattle. J Am Vet Med Assoc. 1992;200:1332–1335. 1949;38:544–546.
35. Dunkel B, Johns IC. Antimicrobial use in critically ill horses. 60. Olsen L, Ingvast-Larsson C, Brostrom H, et al. Clinical signs
J Vet Emerg Crit Care (San Antonio). 2015;25:89–100. and etiology of adverse reactions to procaine benzylpenicillin
36. Dever LA, Dermody TS. Mechanisms of bacterial resistance to and sodium/potassium benzylpenicillin in horses. J Vet Phar-
antibiotics. Arch Intern Med. 1991;151:886. macol Ther. 2007;30:201–207.
37. Gold HS, Moellering RC. Antimicrobial-drug resistance. N Engl 61. Stevenson AJ, Weber MP, Todi F, et al. Plasma elimination and
J Med. 1996;335:1445–1453. urinary excretion of procaine after administration of different
38. Ayala J, Quesada A, Vadillo S, et al. Penicillin-binding proteins products to standardbred mares. Equine Vet J. 1992;24:118–124.
of Bacteroides fragilis and their role in the resistance to imipe- 62. Adamson PJ, Wilson WD, Hirsh DC, et al. Susceptibility of
nem of clinical isolates. J Med Microbiol. 2005;54:1055–1064. equine bacterial isolates to antimicrobial agents. Am J Vet Res.
39. de Lencastre H, Oliveira D, Tomasz A. Antibiotic resistant 1985;46:447–450.
Staphylococcus aureus: a paradigm of adaptive power. Curr Opin 63. Firth EC, Klein WR, Nouws JF, et al. Effect of induced synovial
Microbiol. 2007;10:428–435. inflammation on pharmacokinetics and synovial concentration
40. Geddes AM, Klugman KP, Rolinson GN. Introduction: histori- of sodium ampicillin and kanamycin sulfate after systemic ad-
cal perspective and development of amoxicillin/clavulanate. Int ministration in ponies. J Vet Pharmacol Ther. 1988;11:556–562.
J Antimicrob Agents. 2007;30(suppl 2):S109–112. 64. Ensink JM, Moi A, Vulto AG, et al: Bioavailability of pivampi-
41. Essack SY. The development of beta-lactam antibiotics in cillin and ampicillin trihydrate administered as an oral paste in
response to the evolution of beta-lactamases. Pharm Res. horses. Vet Q 18:2s117–120.
2001;18:1391–1399. 65. Wilson WD, Spensley MS, Baggot JD, et al. Pharmacokinetics
42. Sandanayaka VP, Prashad AS. Resistance to beta-lactam antibi- and estimated bioavailability of amoxicillin in mares after intra-
otics: structure and mechanism based design of beta-lactamase venous, intramuscular, and oral administration. Am J Vet Res.
inhibitors. Curr Med Chem. 2002;9:1145–1165. 1988;49:1688–1694.
43. Finlay J, Miller L, Poupard JA. A review of the antimicrobial 66. Baggot JD, Love DN, Stewart J, et al. Bioavailability and dis-
activity of clavulanate. J Antimicrob Chemother. 2003;52:18–23. position kinetics of amoxicillin in neonatal foals. Equine Vet J.
44. Papich MG. The beta-lactam antibiotics: clinical pharmacol- 1988;20:125–127.
ogy and recent developments. Compend Contin Educ Pract Vet. 67. Ensink JM, Vulto AG, van Miert AS, et al. Oral bioavailability
1987;9:68–74. and in vitro stability of pivampicillin, bacampicillin, talampicil-
45. Falagas ME, Siakavellas E. Bacteroides, Prevotella, and Porphy- lin, and ampicillin in horses. Am J Vet Res. 1996;57:1021–1024.
romonas species: a review of antibiotic resistance and therapeu- 68. Ensink JM, Klein WR, Mevius DJ, et al. Bioavailability of oral
tic options. Int J Antimicrob Agents. 2000;15:1–9. penicillins in the horse: a comparison of pivampicillin and
46. Schwark WS, Ducharme NG, Shin SJ, et al. Absorption and dis- amoxicillin. J Vet Pharmacol Ther. 1992;15:221–230.
tribution patterns of oral phenoxymethyl penicillin (penicillin 69. Sarasola P, McKellar QA. Pharmacokinetics and applications of
V) in the horse. Cornell Vet. 1983;73:314–322. ampicillin sodium as an intravenous infusion in the horse. J Vet
47. Schipper IA, Filipovs D, Ebeltoft H, et al. Blood serum concen- Pharmacol Ther. 1993;16:63–69.
trations of various benzyl penicillins after their intramuscular 70. van den Hoven R, Hierweck B, Dobretsberger M, et al. Intra-
administration to cattle. J Am Vet Med Assoc. 1971;158:494–500. muscular dosing strategy for ampicillin sodium in horses, based
48. Baggot JD. Bioavailability and bioequivalence of veterinary on its distribution into tissue chambers before and after induc-
drug dosage forms, with particular reference to horses: an over- tion of inflammation. J Vet Pharmacol Ther. 2003;26:405–411.
view. J Vet Pharmacol Ther. 1992;15:160–173. 71. Bowman KF, Dix LP, Riond JL, et al. Prediction of pharmacoki-
49. Love DN, Rose RJ, Martin IC, et al. Serum concentrations of netic profiles of ampicillin sodium, gentamicin sulphate, and
penicillin in the horse after administration of a variety of peni- combination ampicillin sodium-gentamicin sulphate in serum
cillin preparations. Equine Vet J. 1983;15:43–48. and synovia of healthy horses. Am J Vet Res. 1986;47:1590–1596.
72. Errecalde JO, Carmely D, Marino EL, et al. Pharmacokinetics 94. Macpherson ML, Giguère S, Hatzel JN, et al. Disposition of desfur
of amoxycillin in normal horses and horses with experimental oylceftiofur acetamide in serum, placental tissue, fetal fluids, and fetal
arthritis. J Vet Pharmacol Ther. 2001;24:1–6. tissues after administration of ceftiofur crystalline free acid (CCFA)
73. Ensink JM, Klein WR, Barneveld A, et al. Distribution of peni- to pony mares with placentitis. J Vet Pharmacol Ther. 2013;36:59–67.
cillins into subcutaneous tissue chambers in ponies. J Vet Phar- 95. Hall TL, Tell LA, Wetzlich SE, et al. Pharmacokinetics of cefti-
macol Ther. 1996;19:439–444. ofur sodium and ceftiofur crystalline free acid in neonatal foals.
74. Montesissa C, Carli S, Sonzogni O, et al. Pharmacokinetics of J Vet Pharmacol Ther. 2011;34:403–409.
sodium amoxicillin in horses. Res Vet Sci. 1988;44:233–236. 96. Credille BC, Giguère S, Berghaus LJ, et al. Plasma and pul-
75. Beech J, Leitch M, Kohn CW, et al. Serum and synovial fluid monary disposition of ceftiofur and its metabolites after in-
levels of sodium ampicillin and ampicillin trihydrate in horses. tramuscular administration of ceftiofur crystalline free acid in
J Equine Med Surg. 1979;3:3503–3504. weanling foals. J Vet Pharmacol Ther. 2012;35:259–264.
76. Traver DS, Riviere JE. Ampicillin in mares: a comparison of in- 97. Strom BL, Schinnar R, Gibson GA, et al. Risk of bleeding and
tramuscular sodium ampicillin or sodium ampicillin-ampicillin hypoprothrombinaemia associated with NMTT side chain an-
trihydrate injection. Am J Vet Res. 1982;43:402–404. tibiotics: using cefoperazone as a test case. Pharmacoepidemiol
77. Spensley MS, Baggot JD, Wilson WD, et al. Pharmacokinetics Drug Saf. 1999;8:81–94.
and endometrial tissue concentrations of ticarcillin given to 98. Gardner SY, Aucoin DP. Pharmacokinetics of ceftriaxone in
the horse by intravenous and intrauterine routes. Am J Vet Res. mares. J Vet Pharmacol Ther. 1994;17:155–156.
1986;47:2587–2590. 99. Gardner SY, Sweeney RW, Divers TJ. Pharmacokinetics of cefo-
78. Sweeney CR, Soma LR, Beech J, et al. Pharmacokinetics of ticar- taxime in neonatal pony foals. Am J Vet Res. 1993;54:576–579.
cillin in the horse after intravenous and intramuscular adminis- 100. Guglick MA, MacAllister CG, Clarke CR, et al. Pharmacoki-
tration. Am J Vet Res. 1984;45:1000–1002. netics of cefepime and comparison with those of ceftiofur in
79. Wilson WD, Spensley MS, Baggot JD, et al. Pharmacokinetics horses. Am J Vet Res. 1998;59:458–463.
and bioavailability of ticarcillin and clavulanate in foals after in- 101. Fanos V, Cataldi L. Renal transport of antibiotics and nephro-
travenous and intramuscular administration. J Vet Pharmacol toxicity: a review. J Chemother. 2001;13:461–472.
Ther. 1991;14:78–89. 102. Miranda-Novales G, Leanos-Miranda BE, Vilchis-Perez M,
80. Sweeney RW, Beech J, Simmons RD, et al. Pharmacokinetics et al. In vitro activity effects of combinations of cephalothin,
of ticarcillin and clavulanic acid given in combination to adult dicloxacillin, imipenem, vancomycin and amikacin against
horses by intravenous and intramuscular routes. J Vet Pharma- methicillin-resistant Staphylococcus spp. strains. Ann Clin Mi-
col Ther. 1988;11:103–108. crobiol Antimicrob. 2006;5:25.
81. Van Camp SD, Papich MG, Whitacre MD. Administration of 103. Beauchamp D, Theriault G, Grenier L, et al. Ceftriaxone pro-
ticarcillin in combination with clavulanic acid intravenously tects against tobramycin nephrotoxicity. Antimicrob Agents
and intrauterinely to clinically normal oestrous mares. J Vet Chemother. 1994;38:750–756.
Pharmacol Ther. 2000;23:373–378. 104. Foreman JH: Does ceftiofur cause diarrhea? AAEP 44th Annual
82. Hoffman AM, Viel L, Muckle CA, et al. Evaluation of sulbactam plus Convention Proceedings. 1994;146–147.
ampicillin for treatment of experimentally induced Klebsiella pneu- 105. Mahrt CR. Safety of ceftiofur sodium administered intramuscu-
moniae lung infection in foals. Am J Vet Res. 1992;53:1059–1067. larly in horses. Am J Vet Res. 1992;53:2201–2205.
83. Hornish RE, Kotarski SF. Cephalosporins in veterinary medi- 106. Fultz L, Giguère S, Berghaus LJ, et al. Comparative pharma-
cine: ceftiofur use in food animals. Curr Top Med Chem. cokinetics of desfuroylceftiofur acetamide after intramuscular
2002;2:717–731. versus subcutaneous administration of ceftiofur crystalline free
84. Salmon SA, Watts JL, Yancey RJ. In vitro activity of ceftiofur and acid to adult horses. J Vet Pharmacol Ther. 2013;36:309–312.
its primary metabolite, desfuroylceftiofur, against organisms of 107. Meyer S, Giguère S, Rodriguez R, et al. Pharmacokinetics of in-
veterinary importance. J Vet Diagn Invest. 1996;8:332–336. travenous ceftiofur sodium and concentration in body fluids of
85. Rice LB. Emergence of vancomycin-resistant enterococci. foals. J Vet Pharmacol Ther. 2009;32:309–316.
Emerg Infect Dis. 2001;7:183–187. 108. Wearn JM, Davis JL, Hodgson DR, et al. Pharmacokinetics of
86. Duffee NE, Christensen JM, Craig AM. The pharmacokinetics of a continuous rate infusion of ceftiofur sodium in normal foals.
cefadroxil in the foal. J Vet Pharmacol Ther. 1989;12:322–326. J Vet Pharmacol Ther. 2013;36:99–101.
87. Wilson WD, Baggot JD, Adamson PJ, et al. Cefadroxil in the 109. Fultz L, Giguère S, Berghaus LJ, et al. Plasma and pulmonary
horse: pharmacokinetics and in vitro antibacterial activity. J Vet pharmacokinetics of desfuroylceftiofur acetamide after weekly
Pharmacol Ther. 1985;8:246–253. administration of ceftiofur crystalline free acid to adult horses.
88. Carrillo NA, Giguère S, Gronwall RR, et al. Disposition of Equine Vet J. 2014;46:252–255.
orally administered cefpodoxime proxetil in foals and adult 110. Orsini JA, Moate PJ, Boston RC, et al. Pharmacokinetics of
horses and minimum inhibitory concentration of the drug imipenem-cilastatin following intravenous administration in
against common bacterial pathogens of horses. Am J Vet Res. healthy adult horses. J Vet Pharmacol Ther. 2005;28:355–361.
2005;66:30–35. 111. Sams RA, Ruoff WW. Pharmacokinetics and bioavailability of
89. Lovering AM, Walsh TR, Bannister GC, et al. The penetration of cefazolin in horses. Am J Vet Res. 1985;46:348–352.
ceftriaxone and cefamandole into bone, fat and haematoma and 112. Ruoff WW, Sams RA. Pharmacokinetics and bioavailability of
relevance of serum protein binding to their penetration into cephalothin in horse mares. Am J Vet Res. 1985;46:2085–2090.
bone. J Antimicrob Chemother. 2001;47:483–486. 113. Brown MP, Gronwall RR, Houston AE. Pharmacokinetics and
90. Cunha BA. Third-generation cephalosporins: a review. Clin body fluid and endometrial concentrations of cephapirin in
Ther. 1992;14:616–652, discussion 615. mares. Am J Vet Res. 1986;47:784–788.
91. Meyer JC, Brown MP, Gronwall RR, et al. Pharmacokinetics of 114. Henry MM, Morris DD, Lakritz J, et al. Pharmacokinetics of
ceftiofur sodium in neonatal foals after intramuscular injection. cephradine in neonatal foals after single oral dosing. Equine Vet
Equine Vet J. 1992;24:485–486. J. 1992;24:242–243.
92. Collard WT, Cox SR, Lesman SP, et al. Pharmacokinetics of 115. Brown MP, Gronwall RR, Houston AE. Pharmacokinetics
ceftiofur crystalline-free acid sterile suspension in the equine. and body fluid and endometrial concentrations of cefoxitin in
J Vet Pharmacol Ther. 2011;34:476–481. mares. Am J Vet Res. 1986;47:1734–1738.
93. Giguère S, Sturgill TL, Berghaus LJ, et al. Effects of two methods 116. Jaglan PS, Roof RD, Yein FS, et al. Concentration of ceftiofur
of administration on the pharmacokinetics of ceftiofur crystal- metabolites in the plasma and lungs of horses following intra-
line free acid in horses. J Vet Pharmacol Ther. 2011;34:193–196. muscular treatment. J Vet Pharmacol Ther. 1994;17:24–30.
117. Soraci AL, Mestorino ON, Errecalde JO. Pharmacokinetics of 140. Errico JA, Trumble TN, Bueno AC, et al. Comparison of two
cefoperazone in horses. J Vet Pharmacol Ther. 1996;19:39–43. indirect techniques for local delivery of a high dose of an anti-
118. Gardner SY, Papich MG. Comparison of cefepime pharmacoki- microbial in the distal portion of forelimbs of horses. Am J Vet
netics in neonatal foals and adult dogs. J Vet Pharmacol Ther. Res. 2008;69:334–342.
2001;24:187–192. 141. Parra-Sanchez A, Lugo J, Boothe DM, et al. Pharmacokinetics
119. Brown SA, Riviere JE. Comparative pharmacokinetics of ami- and pharmacodynamics of enrofloxacin and a low dose of ami-
noglycoside antibiotics. J Vet Pharmacol Ther. 1991;14:1–35. kacin administered via regional intravenous limb perfusion in
120. Barclay ML, Begg EJ, Hickling KG. What is the evidence for standing horses. Am J Vet Res. 2006;67:1687–1695.
once-daily aminoglycoside therapy? Clin Pharmacokinet. 142. Butt TD, Bailey JV, Dowling PM, et al. Comparison of 2 tech-
1994;27:32–48. niques for regional antibiotic delivery to the equine forelimb:
121. Nestaas E, Bangstad HJ, Sandvik L, et al. Aminoglycoside ex- intraosseous perfusion vs. intravenous perfusion. Can Vet J.
tended interval dosing in neonates is safe and effective: a meta- 2001;42:617–622.
analysis. Arch Dis Child Fetal Neonatal Ed. 2005;90:F294–300. 143. Booth TM, Butson RJ, Clegg PD, et al. Treatment of sepsis in the
122. Barclay ML, Begg EJ. Aminoglycoside toxicity and relation to small tarsal joints of 11 horses with gentamicin-impregnated
dose regimen. Adverse Drug React Toxicol Rev. 1994;13:207–234. polymethylmethacrylate beads. Vet Rec. 2001;148:376–380.
123. Daikos GL, Jackson GG, Lolans VT, et al. Adaptive resistance 144. Ivester KM, Adams SB, Moore GE, et al. Gentamicin concentra-
to aminoglycoside antibiotics from first-exposure down-regula- tions in synovial fluid obtained from the tarsocrural joints of
tion. J Infect Dis. 1990;162:414–420. horses after implantation of gentamicin-impregnated collagen
124. Daikos GL, Lolans VT, Jackson GG. First-exposure adaptive sponges. Am J Vet Res. 2006;67:1519–1526.
resistance to aminoglycoside antibiotics in vivo with mean- 145. Kaloyanides GJ. Antibiotic-related nephrotoxicity. Nephrol Dial
ing for optimal clinical use. Antimicrob Agents Chemother. Transplant. 1994;9:4130–4134.
1991;35:117–123. 146. Tulkens PM. Nephrotoxicity of aminoglycoside antibiotics. Tox-
125. Cummings LE, Guthrie AJ, Harkins JD, et al. Pharmacokinet- icol Lett. 1989;46:107–123.
ics of gentamicin in newborn to 30-day-old foals. Am J Vet Res. 147. Kaloyanides GJ. Drug-phospholipid interactions: role in ami-
1990;51:1988–1992. noglycoside nephrotoxicity. Ren Fail. 1992;14:351–357.
126. Wichtel MG, Breuhaus BA, Aucoin D. Relation between phar- 148. van der Harst MR, Bull S, Laffont CM, et al. Gentamicin ne-
macokinetics of amikacin sulfate and sepsis score in clinically phrotoxicity—a comparison of in vitro findings with in vivo
normal and hospitalized neonatal foals. J Am Vet Med Assoc. experiments in equines. Vet Res Commun. 2005;29:247–261.
1992;200:1339–1343. 149. Molitoris BA, Meyer C, Dahl R, et al. Mechanism of ischemia-
127. Anderson BH, Firth EC, Whittem T. The disposition of gen- enhanced aminoglycoside binding and uptake by proximal tu-
tamicin in equine plasma, synovial fluid and lymph. J Vet Phar- bule cells. Am J Physiol. 1993;264:F907–916.
macol Ther. 1995;18:124–131. 150. Riviere JE, Coppoc GL, Hinsman EJ, et al. Species dependent
128. Santschi EM, Papich MG. Pharmacokinetics of gentamicin in gentamicin pharmacokinetics and nephrotoxicity in the young
mares in late pregnancy and early lactation. J Vet Pharmacol horse. Fundam Appl Toxicol. 1983;3:448–457.
Ther. 2000;23:359–363. 151. Sweeney RW, MacDonald M, Hall J, et al. Kinetics of gentamicin
129. Haddad NS, Pedersoli WM, Ravis WR, et al. Pharmacokinetics elimination in two horses with acute renal failure. Equine Vet J.
of gentamicin at steady-state in ponies: serum, urine, and endo- 1988;20:182–184.
metrial concentrations. Am J Vet Res. 1985;46:1268–1271. 152. Matzke GR, Frye RF. Drug administration in patients with re-
130. Wilson RC, Moore JN, Eakle N. Gentamicin pharmacokinetics nal insufficiency. Minimising renal and extrarenal toxicity. Drug
in horses given small doses of Escherichia coli endotoxin. Am J Saf. 1997;16:205–231.
Vet Res. 1983;44:1746–1749. 153. Thatte L, Vaamonde CA. Drug-induced nephrotoxicity: the
131. Jones SL, Wilson WD, Milhalyi JE. Pharmacokinetics of gen- crucial role of risk factors. Postgrad Med. 1996;100:83–84. 87–
tamicin in healthy adult horses during intravenous fluid admin- 88, 91 passim.
istration. J Vet Pharmacol Ther. 1998;21:247–249. 154. Brashier MK, Geor RJ, Ames TR, et al. Effect of intravenous cal-
132. Tudor RA, Papich MG, Redding WR. Drug disposition and dos- cium administration on gentamicin-induced nephrotoxicosis in
age determination of once daily administration of gentamicin ponies. Am J Vet Res. 1998;59:1055–1062.
sulfate in horses after abdominal surgery. J Am Vet Med Assoc. 155. Varzi HN, Esmailzadeh S, Morovvati H, et al. Effect of silymarin
1999;215:503–506. and vitamin E on gentamicin-induced nephrotoxicity in dogs. J
133. Easter JL, Hague BA, Brumbaugh GW, et al. Effects of postop- Vet Pharmacol Ther. 2007;30:477–481.
erative peritoneal lavage on pharmacokinetics of gentamicin in 156. Schumacher J, Wilson RC, Spano JS, et al. Effect of diet on
horses after celiotomy. Am J Vet Res. 1997;58:1166–1170. gentamicin-induced nephrotoxicosis in horses. Am J Vet Res.
134. Beech J, Kohn C, Leitch M, et al. Therapeutic use of gentamicin 1991;52:1274–1278.
in horses: concentrations in serum, urine, and synovial fluid and 157. Behrend EN, Grauer GF, Greco DS, et al. Effects of dietary pro-
evaluation of renal function. Am J Vet Res. 1977;38:1085–1087. tein conditioning on gentamicin pharmacokinetics in dogs. J
135. Lloyd KC, Stover SM, Pascoe JR, et al. Effect of gentamicin sulfate Vet Pharmacol Ther. 1994;17:259–264.
and sodium bicarbonate on the synovium of clinically normal 158. Godber LM, Walker RD, Stein GE, et al. Pharmacokinetics, ne-
equine antebrachiocarpal joints. Am J Vet Res. 1988;49:650–657. phrotoxicosis, and in vitro antibacterial activity associated with
136. Lescun TB, Adams SB, Wu CC, et al. Continuous infusion of single versus multiple (three times) daily gentamicin treatments
gentamicin into the tarsocrural joint of horses. Am J Vet Res. in horses. Am J Vet Res. 1995;56:613–618.
2000;61:407–412. 159. Magdesian KG, Hogan PM, Cohen ND, et al. Pharmacokinet-
137. Murphey ED, Santschi EM, Papich MG. Regional intravenous ics of a high dose of gentamicin administered intravenously or
perfusion of the distal limb of horses with amikacin sulfate. J Vet intramuscularly to horses. J Am Vet Med Assoc. 1998;213:1007–
Pharmacol Ther. 1999;22:68–71. 1011.
138. Whitehair KJ, Blevins WE, Fessler JF, et al. Regional perfu- 160. Magdesian KG, Wilson WD, Mihalyi J. Pharmacokinetics of
sion of the equine carpus for antibiotic delivery. Vet Surg. a high dose of amikacin administered at extended intervals to
1992;21:279–285. neonatal foals. Am J Vet Res. 2004;65:473–479.
139. Whitehair KJ, Bowersock TL, Blevins WE, et al. Regional limb 161. Green SL, Conlon PD, Mama K, et al. Effects of hypoxia and
perfusion for antibiotic treatment of experimentally induced azotaemia on the pharmacokinetics of amikacin in neonatal
septic arthritis. Vet Surg. 1992;21:367–373. foals. Equine Vet J. 1992;24:475–479.
162. Barclay ML, Begg EJ. Aminoglycoside adaptive resistance: im- 185. Burrows GE, MacAllister CG, Tripp P, et al. Interactions between
portance for effective dosage regimens. Drugs. 2001;61:713–721. chloramphenicol, acepromazine, phenylbutazone, rifampin and
163. Brown SA, Garry FB. Comparison of serum and renal gen- thiamylal in the horse. Equine Vet J. 1989;21:34–38.
tamicin concentrations with fractional urinary excretion 186. Grubb TL, Muir WW, Bertone AL, et al. Use of yohimbine to
tests as indicators of nephrotoxicity. J Vet Pharmacol Ther. reverse prolonged effects of xylazine hydrochloride in a horse
1988;11:330–337. being treated with chloramphenicol. J Am Vet Med Assoc.
164. Whiting PH, Brown PA. The relationship between enzymuria 1997;210:1771–1773.
and kidney enzyme activities in experimental gentamicin ne- 187. Asmar BI, Prainito M, Dajani AS. Antagonistic effect of chlo-
phrotoxicity. Ren Fail. 1996;18:899–909. ramphenicol in combination with cefotaxime or ceftriaxone.
165. Bates DE. Aminoglycoside ototoxicity. Drugs Today (Barc). Antimicrob Agents Chemother. 1988;32:1375–1378.
2003;39:277–285. 188. Ruiz NM, Ramirez-Ronda CH. Tetracyclines, macrolides, lin-
166. Selimoglu E, Kalkandelen S, Erdogan F. Comparative vestibulo- cosamides and chloramphenicol. Bol Asoc Med P R. 82:8–17.
toxicity of different aminoglycosides in the Guinea pigs. Yonsei 189. Neu HC. Synergy of fluoroquinolones with other antimicrobial
Med J. 2003;44:517–522. agents. Rev Infect Dis. 1989;11(suppl 5):S1025–1035.
167. Paradelis AG, Triantaphyllidis C, Giala MM. Neuromuscular 190. Van Duijkeren E, Vulto AG, Van Miert AS. Trimethoprim/
blocking activity of aminoglycoside antibiotics. Methods Find sulfonamide combinations in the horse: a review. J Vet Phar-
Exp Clin Pharmacol. 1980;2:45–51. macol Ther. 1994;17:64–73.
168. Hildebrand SV, Hill 3rd T. Interaction of gentamycin and atra- 191. van Miert AS. The sulfonamide-diaminopyrimidine story. J Vet
curium in anaesthetised horses. Equine Vet J. 1994;26:209–211. Pharmacol Ther. 1994;17:309–316.
169. Smith CM, Steffey EP, Baggot JD, et al. Effects of halothane an- 192. van Duijkeren E, van Klingeren B, Vulto AG, et al. In vitro suscep-
esthesia on the clearance of gentamicin sulfate in horses. Am J tibility of equine Salmonella strains to trimethoprim and sulfona-
Vet Res. 1988;49:19–22. mide alone or in combination. Am J Vet Res. 1994;55:1386–1390.
170. Whittem T, Firth EC, Hodge H, et al. Pharmacokinetic interac- 193. Grace ME, Bushby SR, Sigel CW. Diffusion of trimethoprim
tions between repeated dose phenylbutazone and gentamicin in and sulfamethoxazole from susceptibility disks into agar me-
the horse. J Vet Pharmacol Ther. 1996;19:454–459. dium. Antimicrob Agents Chemother. 1975;8:45–49.
171. Orsini JA, Soma LR, Rourke JE, et al. Pharmacokinetics of ami- 194. Marsh PS, Palmer JE. Bacterial isolates from blood and their
kacin in the horse following intravenous and intramuscular ad- susceptibility patterns in critically ill foals: 543 cases. J Am Vet
ministration. J Vet Pharmacol Ther. 1985;8:194–201. Med Assoc. 1991-1998;218:1608–1610. 2001.
172. Pinto N, Schumacher J, Taintor J, et al. Pharmacokinetics of 195. Bogan JA, Galbraith A, Baxter P, et al. Effect of feeding on the
amikacin in plasma and selected body fluids of healthy horses fate of orally administered phenylbutazone, trimethoprim and
after a single intravenous dose. Equine Vet J. 2011;43:112–116. sulphadiazine in the horse. Vet Rec. 1984;115:599–600.
173. Hubenov H, Bakalov D, Krastev S, et al. Pharmacokinetic studies 196. Sigel CW, Byars TD, Divers TJ, et al. Serum concentrations of
on tobramycin in horses. J Vet Pharmacol Ther. 2007;30:353–357. trimethoprim and sulfadiazine following oral paste administra-
174. Newman JC, Prange T, Jennings S, et al. Pharmacokinetics of tion to the horse. Am J Vet Res. 1981;42:2002–2005.
tobramycin following intravenous, intramuscular, and intra- 197. Wilson RC, Hammond LS, Clark CH, et al. Bioavailability and
articular administration in healthy horses. J Vet Pharmacol pharmacokinetics of sulfamethazine in the pony. J Vet Pharma-
Ther. 2013;36:532–541. col Ther. 1989;12:99–102.
175. Cannon M, Harford S, Davies J. A comparative study on the inhibi- 198. van Duijkeren E, Vulto AG, Sloet van Oldruitenborgh-Oosterbaan
tory actions of chloramphenicol, thiamphenicol and some fluori- MM, et al. Pharmacokinetics of trimethoprim/sulphachlorpyri-
nated derivatives. J Antimicrob Chemother. 1990;26:307–317. dazine in horses after oral, nasogastric and intravenous adminis-
176. Brumbaugh GW, Martens RJ, Knight HD, et al. Pharmacoki- tration. J Vet Pharmacol Ther. 1995;18:47–53.
netics of chloramphenicol in the neonatal horse. J Vet Pharma- 199. Van Duijkeren E, Kessels BG, Sloet van Oldruitenborgh-Ooster-
col Ther. 1983;6:219–227. baan MM, et al. In vitro and in vivo binding of trimethoprim and
177. Gronwall R, Brown MP, Merritt AM, et al. Body fluid con- sulphachlorpyridazine to equine food and digesta and their sta-
centrations and pharmacokinetics of chloramphenicol given bility in caecal contents. J Vet Pharmacol Ther. 1996;19:281–287.
to mares intravenously or by repeated gavage. Am J Vet Res. 200. Boyd EH, Allen WE. Absorption of two trimethoprim/
1986;47:2591–2595. sulphonamide combinations from the uterus of pony mares.
178. Nau R, Sorgel F, Prange HW. Pharmacokinetic optimisation J Vet Pharmacol Ther. 1989;12:438–443.
of the treatment of bacterial central nervous system infections. 201. Clarke CR, Burrows GE, MacAllister CG, et al. Pharmacokinet-
Clin Pharmacokinet. 1998;35:223–246. ics of intravenously and orally administered pyrimethamine in
179. Brown MP, Kelly RH, Gronwall RR, et al. Chloramphenicol so- horses. Am J Vet Res. 1992;53:2292–2295.
dium succinate in the horse: serum, synovial, peritoneal, and 202. Brown MP, Gronwall R, Castro L. Pharmacokinetics and
urine concentrations after single-dose intravenous administra- body fluid and endometrial concentrations of trimethoprim-
tion. Am J Vet Res. 1984;45:578–580. sulfamethoxazole in mares. Am J Vet Res. 1988;49:918–922.
180. Sisodia CS, Kramer LL, Gupta VS, et al. A pharmacologi- 203. Brown MP, Kelly RH, Stover SM, et al. Trimethoprim-sulfadi-
cal study of chloramphenicol in horses. Can J Comp Med. azine in the horse: serum, synovial, peritoneal, and urine con-
1975;39:216–223. centrations after single-dose intravenous administration. Am J
181. Adamson PJ, Wilson WD, Baggot JD, et al. Influence of age on Vet Res. 1983;44:540–543.
the disposition kinetics of chloramphenicol in equine neonates. 204. Brown MP, McCartney JH, Gronwall R, et al. Pharmacokinetics
Am J Vet Res. 1991;52:426–431. of trimethoprim-sulphamethoxazole in two-day-old foals after
182. Varma KJ, Powers TE, Powers JD. Single- and repeat-dose phar- a single intravenous injection. Equine Vet J. 1990;22:51–53.
macokinetic studies of chloramphenicol in horses: values and 205. Clarke CR, MacAllister CG, Burrows GE, et al. Pharmacoki-
limitations of pharmacokinetic studies in predicting dosage netics, penetration into cerebrospinal fluid, and hematologic
regimens. Am J Vet Res. 1987;48:403–406. effects after multiple oral administrations of pyrimethamine to
183. Tuttle AD, Papich MG, Wolfe BA. Bone marrow hypoplasia horses. Am J Vet Res. 1992;53:2296–2299.
secondary to florfenicol toxicity in a Thomson’s gazelle (Gazella 206. Rasmussen F, Gelsa H, Nielsen P. Pharmacokinetics of sulphadox-
thomsonii). J Vet Pharmacol Ther. 2006;29:317–319. ine and trimethoprim in horses. Half-life and volume of distribu-
184. Page SW. Chloramphenicol 1. Hazards of use and the current tion of sulphadoxine and trimethoprim and cumulative excretion
regulatory environment. Aust Vet J. 1991;68:1–2. of [14C]-trimethoprim. J Vet Pharmacol Ther. 1979;2:245–255.
207. Nouws JF, Firth EC, Vree TB, et al. Pharmacokinetics and renal 228. Bryant JE, Brown MP, Gronwall RR, et al. Study of intragas-
clearance of sulfamethazine, sulfamerazine, and sulfadiazine tric administration of doxycycline: pharmacokinetics including
and their N4-acetyl and hydroxy metabolites in horses. Am J body fluid, endometrial and minimum inhibitory concentra-
Vet Res. 1987;48:392–402. tions. Equine Vet J. 2000;32:233–238.
208. Nouws JF, Vree TB, Baakman M, et al. Disposition of sulfadimi- 229. Davis JL, Salmon JH, Papich MG. Pharmacokinetics and tissue
dine and its N4-acetyl and hydroxy metabolites in horse plasma. distribution of doxycycline after oral administration of single
J Vet Pharmacol Ther. 1985;8:303–311. and multiple doses in horses. Am J Vet Res. 2006;67:310–316.
209. Gray AK, Kidd AR, O’Brien J, et al. Suspected adverse reactions 230. Riond JL, Riviere JE, Duckett WM, et al. Cardiovascular effects
to medicines during 1988. Vet Rec. 1989;124:286–287. and fatalities associated with intravenous administration of
210. Dick IG, White SK. Possible potentiated sulphonamide-associ- doxycycline to horses and ponies. Equine Vet J. 1992;24:41–45.
ated fatality in an anaesthetised horse. Vet Rec. 1987;121:288. 231. Womble A, Giguere S, Lee EA. Pharmacokinetics of oral doxy-
211. Taylor PM, Rest RJ, Duckham TN, et al. Possible potenti- cycline and concentrations in body fluids and bronchoalveolar
ated sulphonamide and detomidine interactions. Vet Rec. cells of foals. J Vet Pharmacol Ther. 2007;30:187–193.
1988;122:143. 232. Schnabel LV, Papich MG, Divers TJ, et al. Pharmacokinetics
212. Fenger CK, Granstrom DE, Langemeier JL, et al. Epizootic of and distribution of minocycline in mature horses after oral ad-
equine protozoal myeloencephalitis on a farm. J Am Vet Med ministration of multiple doses and comparison with minimum
Assoc. 1997;210:923–927. inhibitory concentrations. Equine Vet J. 2012;44:453–458.
213. Toribio RE, Bain FT, Mrad DR, et al. Congenital defects in new- 233. Brown MP, Stover SM, Kelly RH, et al. Oxytetracycline hy-
born foals of mares treated for equine protozoal myeloencepha- drochloride in the horse: serum, synovial, peritoneal and
litis during pregnancy. J Am Vet Med Assoc. 1998;212:697–701. urine concentrations after single dose intravenous adminis-
214. Bedford SJ, McDonnell SM. Measurements of reproductive tration. J Vet Pharmacol Ther. 1981;4:7–10.
function in stallions treated with trimethoprim-sulfamethoxa- 234. Papich MG, Wright AK, Petrie L, et al. Pharmacokinetics of
zole and pyrimethamine. J Am Vet Med Assoc. 1999;215:1317– oxytetracycline administered intravenously to 4- and 5-day-old
1319. foals. J Vet Pharmacol Ther. 1995;18:375–378.
215. Thomas HL, Livesey MA. Immune-mediated hemolytic anemia 235. Horspool LJ, McKellar QA. Disposition of oxytetracycline in
associated with trimethoprim-sulphamethoxazole administra- horses, ponies and donkeys after intravenous administration.
tion in a horse. Can Vet J. 1998;39:171–173. Equine Vet J. 1990;22:284–285.
216. Ensink JM, Klein WR, Barneveld A, et al. Side effects of oral 236. Gilmour MA, Clarke CR, Macallister CG, et al. Ocular pen-
antimicrobial agents in the horse: a comparison of pivampicillin etration of oral doxycycline in the horse. Vet Ophthalmol.
and trimethoprim/sulphadiazine. Vet Rec. 1996;138:253–256. 2005;8:331–335.
217. Wilson DA, MacFadden KE, Green EM, et al. Case control and 237. Pilloud M. Pharmacokinetics, plasma protein binding and
historical cohort study of diarrhea associated with administra- dosage of oxytetracycline in cattle and horses. Res Vet Sci.
tion of trimethoprim-potentiated sulphonamides to horses and 1973;15:224–230.
ponies. J Vet Intern Med. 1996;10:258–264. 238. Nagata S, Yamashita S, Kurosawa M, et al. Pharmacokinetics
218. Gustafsson A, Baverud V, Franklin A, et al. Repeated admin- and tissue distribution of minocycline hydrochloride in horses.
istration of trimethoprim/sulfadiazine in the horse—pharma- Am J Vet Res. 2012;71:1062–1066.
cokinetics, plasma protein binding and influence on the intesti- 239. Shaw DH, Rubin SI. Pharmacologic activity of doxycycline.
nal microflora. J Vet Pharmacol Ther. 1999;22:20–26. J Am Vet Med Assoc. 1986;189:808–810.
219. White G, Prior SD. Comparative effects of oral administration 240. Andersson G, Ekman L, Mansson I, et al. Lethal complications
of trimethoprim/sulphadiazine or oxytetracycline on the faecal following administration of oxytetracycline in the horse. Nord
flora of horses. Vet Rec. 1982;111:316–318. Vet Med. 1971;23:9–22.
220. Bertone AL, Jones RL, McIlwraith CW. Serum and synovial flu- 241. Baker JR, Leyland A. Diarrhoea in the horse associated with
id steady-state concentrations of trimethoprim and sulfadiazine stress and tetracycline therapy. Vet Rec. 1973;93:583–584.
in horses with experimentally induced infectious arthritis. Am J 242. Cook W. Diarrhoea in the horse associated with stress and tet-
Vet Res. 1988;49:1681–1687. racycline therapy. Vet Rec. 1973;93:15–17.
221. Ensink JM, Bosch G, van Duijkeren E. Clinical efficacy of pro- 243. Owen R. Post stress diarrhoea in the horse. Vet Rec. 1975;96:
phylactic administration of trimethoprim/sulfadiazine in a 267–270.
Streptococcus equi subsp. zooepidemicus infection model in po- 244. Owen RA, Fullerton J, Barnum DA. Effects of transportation,
nies. J Vet Pharmacol Ther. 2005;28:45–49. surgery, and antibiotic therapy in ponies infected with Salmo-
222. Green SL, Mayhew IG, Brown MP, et al. Concentrations of tri- nella. Am J Vet Res. 1983;44:46–50.
methoprim and sulfamethoxazole in cerebrospinal fluid and 245. Palmer JE. Potomac horse fever. Vet Clin North Am Equine
serum in mares with and without a dimethyl sulfoxide pretreat- Pract. 1993;9:399–410.
ment. Can J Vet Res. 1990;54:215–222. 246. Palmer JE, Benson CE, Whitlock RH. Effect of treatment
223. Rikihisa Y, Jiang BM. In vitro susceptibilities of Ehrlichia with oxytetracycline during the acute stages of experimen-
risticii to eight antibiotics. Antimicrob Agents Chemother. tally induced equine ehrlichial colitis in ponies. Am J Vet Res.
1988;32:986–991. 1992;53:2300–2304.
224. Sampieri F, Hinchcliff KW, Toribio RE. Tetracycline therapy 247. Palmer JE, Whitlock RH, Benson CE. Equine ehrlichial colitis:
of Lawsonia intracellularis enteropathy in foals. Equine Vet J. effect of oxytetracycline treatment during the incubation pe-
2006;38:89–92. riod of Ehrlichia risticii infection in ponies. J Am Vet Med Assoc.
225. Baker A, Plummer CE, Szabo NJ, et al. Doxycycline levels in 1988;192:343–345.
preocular tear film of horses following oral administration. Vet 248. Dowling PM: Long-acting oxytetracycline in horses, 17th An-
Ophthalmol. 2008;11:381–385. nual ACVIM Forum 217–219, 1999.
226. Fortier LA, Motta T, Greenwald RA, et al. Synoviocytes are 249. Vivrette S, Cowgill LD, Pascoe J, et al. Hemodialysis for treat-
more sensitive than cartilage to the effects of minocycline and ment of oxytetracycline-induced acute renal failure in a neona-
doxycycline on IL-1alpha and MMP-13-induced catabolic gene tal foal. J Am Vet Med Assoc. 1993;203:105–107.
responses. J Orthop Res. 2010;28:522–528. 250. Wright AK, Petrie L, Papich MG, et al. Effect of high dose
227. Dowling PM, Russell AM. Pharmacokinetics of a long-acting oxytetracycline on renal parameteres in neonatal foals: recom-
oxytetracycline-polyethylene glycol formulation in horses. J Vet mended dose for treatment of flexural limb deformities. Proc
Pharmacol Ther. 2000;23:107–110. Am Assoc Equine Practitioners. 1993;38:297–298.
251. Gyrd-Hansen N, Rasmussen F, Smith M. Cardiovascular effects 271. Scheuch E, Spieker J, Venner M, et al. Quantitative determi-
of intravenous administration of tetracycline in cattle. J Vet nation of the macrolide antibiotic tulathromycin in plasma
Pharmacol Ther. 1981;4:15–25. and broncho-alveolar cells of foals using tandem mass spec-
252. Smith M, Gyrd-Hansen N, Rasmussen F. Tetracycline intra- trometry. J Chromatogr B Analyt Technol Biomed Life Sci.
venously to cattle: cardiovascular side-effects. Nord Vet Med. 2007;850:464–470.
1981;33:272–273. 272. Berghaus LJ, Giguère S, Sturgill TL, et al. Plasma pharmacoki-
253. Riond JL, Duckett WM, Riviere JE, et al. Concerned about in- netics, pulmonary distribution, and in vitro activity of gamith-
travenous use of doxycycline in horses. J Am Vet Med Assoc. romycin in foals. J Vet Pharmacol Ther. 2012;35:59–66.
1989;195(846):848. 273. Giguere S, Jacks S, Roberts GD, et al. Retrospective compari-
254. Kasper CA, Clayton HM, Wright AK, et al. Effects of high doses son of azithromycin, clarithromycin, and erythromycin for the
of oxytetracycline on metacarpophalangeal joint kinematics in treatment of foals with Rhodococcus equi pneumonia. J Vet In-
neonatal foals. J Am Vet Med Assoc. 1995;207:71–73. tern Med. 2004;18:568–573.
255. Madison JB, Garber JL, Rice B, et al. Effect of oxytetracycline on 274. Suarez-Mier G, Giguere S, Lee EA. Pulmonary disposition of
metacarpophalangeal and distal interphalangeal joint angles in erythromycin, azithromycin, and clarithromycin in foals. J Vet
newborn foals. J Am Vet Med Assoc. 1994;204:246–249. Pharmacol Ther. 2007;30:109–115.
256. Arnoczky SP, Lavagnino M, Gardner KL, et al. In vitro effects of 275. Villarino N, Martín-Jiménez T. Pharmacokinetics of macrolides
oxytetracycline on matrix metalloproteinase-1 mRNA expres- in foals. J Vet Pharmacol Ther. 2013;36:1–13.
sion and on collagen gel contraction by cultured myofibroblasts 276. Prescott JF, Hoover DJ, Dohoo IR. Pharmacokinetics of eryth-
obtained from the accessory ligament of foals. Am J Vet Res. romycin in foals and in adult horses. J Vet Pharmacol Ther.
2004;65:491–496. 1983;6:67–73.
257. Venner M, Astheimer K, Lämmer M, et al. Efficacy of mass antimi- 277. Lakritz J, Wilson WD, Watson JL, et al. Effect of treatment with
crobial treatment of foals with subclinical pulmonary abscesses as- erythromycin on bronchoalveolar lavage fluid cell populations
sociated with Rhodococcus equi. J Vet Intern Med. 2013;27:171–176. in foals. Am J Vet Res. 1997;58:56–61.
258. Neu HC. Clinical microbiology of azithromycin. Am J Med. 278. Steiner A, Roussel AJ. Drugs coordinating and restoring gas-
1991;91:12S–18S. trointestinal motility and their effect on selected hypodynamic
259. Jacks SS, Giguere S, Nguyen A. In vitro susceptibilities of Rho- gastrointestinal disorders in horses and cattle. Zentralbl Veteri-
dococcus equi and other common equine pathogens to azithro- narmed A. 1995;42:613–631.
mycin, clarithromycin, and 20 other antimicrobials. Antimicrob 279. Nieto JE, Rakestraw PC, Snyder JR, et al. In vitro effects of
Agents Chemother. 2003;47:1742–1745. erythromycin, lidocaine, and metoclopramide on smooth mus-
260. Lakritz J. Erythromycin: clinical uses, kinetics and mechanism cle from the pyloric antrum, proximal portion of the duode-
of action. 15th Annual ACVIM Forum. 1997:368–370. num, and middle portion of the jejunum of horses. Am J Vet
261. Lester GD, Merritt AM, Neuwirth L, et al. Effect of erythromy- Res. 2000;61:413–419.
cin lactobionate on myoelectric activity of ileum, cecum, and 280. Baverud V, Franklin A, Gunnarsson A, et al. Clostridium dif-
right ventral colon, and cecal emptying of radiolabeled markers ficile associated with acute colitis in mares when their foals are
in clinically normal ponies. Am J Vet Res. 1998;59:328–334. treated with erythromycin and rifampicin for Rhodococcus equi
262. Kenney DG, Robbins SC, Prescott JF, et al. Development of re- pneumonia. Equine Vet J. 1998;30:482–488.
active arthritis and resistance to erythromycin and rifampin in a 281. Gustafsson A, Baverud V, Gunnarsson A, et al. The association
foal during treatment for Rhodococcus equi pneumonia. Equine of erythromycin ethylsuccinate with acute colitis in horses in
Vet J. 1994;26:246–248. Sweden. Equine Vet J. 1997;29:314–318.
263. Giguère S, Lee E, Williams E, et al. Determination of the prev- 282. Larsen J, Dolvik NI, Teige J. Acute post-treatment enterocol-
alence of antimicrobial resistance to macrolide antimicrobials itis in 13 horses treated in a Norwegian surgical ward. Acta Vet
or rifampin in Rhodococcus equi isolates and treatment out- Scand. 1996;37:203–211.
come in foals infected with antimicrobial-resistant isolates of 283. Stratton-Phelps M, Wilson WD, Gardner IA. Risk of adverse effects
R equi. J Am Vet Med Assoc. 2010;237:74–81. in pneumonic foals treated with erythromycin versus other antibi-
264. Lakritz J, Wilson WD, Mihalyi JE. Comparison of microbiologic otics: 143 cases. J Am Vet Med Assoc. 1986-1996;217:68–73. 2000.
and high-performance liquid chromatography assays to deter- 284. Traub-Dargatz J, Wilson WD, Conboy HS, et al. Hyperthermia
mine plasma concentrations, pharmacokinetics, and bioavail- in foals treated with erythromycin alone or in combination with
ability of erythromycin base in plasma of foals after intravenous rifampin for respiratory disease during hot environmental con-
or intragastric administration. Am J Vet Res. 1999;60:414–419. ditions. Proc Am Assoc Equine Pract. 1996;42:243–244.
265. Lakritz J, Wilson WD, Marsh AE, et al. Effects of prior feed- 285. Stieler AL, Sanchez LC, Mallicote MF, et al. Macrolide-induced
ing on pharmacokinetics and estimated bioavailability after oral hyperthermia in foals: role of impaired sweat responses. Equine
administration of a single dose of microencapsulated erythro- Vet J. 2016;48:590–594.
mycin base in healthy foals. Am J Vet Res. 2000;61:1011–1015. 286. Berghaus LJ, Giguère S, Guldbech K. Mutant prevention concen-
266. Lakritz J, Wilson WD, Marsh AE, et al. Pharmacokinetics of eryth- tration and mutant selection window for 10 antimicrobial agents
romycin estolate and erythromycin phosphate after intragastric against Rhodococcus equi. Vet Microbiol. 2013;166:670–675.
administration to healthy foals. Am J Vet Res. 2000;61:914–919. 287. Peters J, Block W, Oswald S, et al. Oral absorption of clarithro-
267. Jacks S, Giguere S, Gronwall PR, et al. Pharmacokinetics of mycin is nearly abolished by chronic comedication of rifampi
azithromycin and concentration in body fluids and bronchoal- cin in foals. Drug Metab Dispos. 2011;39:1643–1649.
veolar cells in foals. Am J Vet Res. 2001;62:1870–1875. 288. Peters J, Eggers K, Oswald S, et al. Clarithromycin is absorbed
268. Davis JL, Gardner SY, Jones SL, et al. Pharmacokinetics of by an intestinal uptake mechanism that is sensitive to major in-
azithromycin in foals after i.v. and oral dose and disposition into hibition by rifampicin: results of a short-term drug interaction
phagocytes. J Vet Pharmacol Ther. 2002;25:99–104. study in foals. Drug Metab Dispos. 2012;40:522–528.
269. Womble AY, Giguere S, Lee EA, et al. Pharmacokinetics of 289. Venner M, Peters J, Höhensteiger N, et al. Concentration of the
clarithromycin and concentrations in body fluids and bron- macrolide antibiotic tulathromycin in broncho-alveolar cells
choalveolar cells of foals. Am J Vet Res. 2006;67:1681–1686. is influenced by comedication of rifampicin in foals. Naunyn
270. Javsicas LH, Giguère S, Womble AY. Disposition of oral tel- Schmiedebergs Arch Pharmacol. 2012;381:161–169.
ithromycin in foals and in vitro activity of the drug against 290. Leclere M, Magdesian KG, Cole CA, et al. Pharmacokinet-
macrolide-susceptible and macrolide-resistant Rhodococcus ics and preliminary safety evaluation of azithromycin in adult
equi isolates. J Vet Pharmacol Ther. 2010;33:383–388. horses. J Vet Pharmacol Ther. 2012;35:541–549.
291. Hildebrand F, Venner M, Giguère S. Efficacy of gamithromycin 313. Boeckh CBC, Boeckh A, Wilkie S, Davis C, Buchanan T, Boothe
for the treatment of foals with mild to moderate bronchopneu- D. Pharmacokinetics of the bovine formulation of enrofloxacin
monia. J Vet Intern Med. 2015;29:333–338. (Baytril 100) in horses. Vet Ther. 2001;2:129–134.
292. Palmer JE, Benson CE. Effect of treatment with erythromycin and 314. Epstein K, Cohen N, Boothe D, et al. Pharmacokinetics, sta-
rifampin during the acute stages of experimentally induced equine bility and retrospective analysis of use of an oral get formula-
ehrlichial colitis in ponies. Am J Vet Res. 1992;53:2071–2076. tion of the bovine injectable enrofloxacin in horses. Vet Ther.
293. Lavoie JP, Drolet R, Parsons D, et al. Equine proliferative en- 2004;5:155–167.
teropathy: a cause of weight loss, colic, diarrhoea and hypopro- 315. Carretero M, Rodríguez C, San Andrés MI, et al. Pharmacokinet-
teinaemia in foals on three breeding farms in Canada. Equine ics of marbofloxacin in mature horses after single intravenous and
Vet J. 2000;32:418–425. intramuscular administration. Equine Vet J. 2002;34:360–365.
294. Chaffin MK, Cohen ND, Martens RJ. Chemoprophylactic 316. Giguere S, Sweeney RW, Habecker PL, et al. Tolerability of oral-
effects of azithromycin against Rhodococcus equi–induced ly administered enrofloxacin in adult horses: a pilot study. J Vet
pneumonia among foals at equine breeding farms with en- Pharmacol Ther. 1999;22:343–347.
demic infections. J Am Vet Med Assoc. 2008;232:1035–1047. 317. Langston VC, Sedrish S, Boothe DM. Disposition of single-
295. Venner M, Credner N, Lämmer M, et al. Comparison of tu- dose oral enrofloxacin in the horse. J Vet Pharmacol Ther.
lathromycin, azithromycin and azithromycin-rifampin for the 1996;19:316–319.
treatment of mild pneumonia associated with Rhodococcus 318. Divers TJ, Irby NL, Mohammed HO, et al. Ocular penetration
equi. Vet Rec. 2013;173:397. of intravenously administered enrofloxacin in the horse. Equine
296. Brown SA. Fluoroquinolones in animal health. J Vet Pharmacol Vet J. 2008;40:167–170.
Ther. 1996;19:1–14. 319. Goudah A, Abo El-Sooud K, Shim JH, et al. Characterization
297. Appelbaum PC. Quinolone activity against anaerobes. Drugs. of the pharmacokinetic disposition of levofloxacin in stallions
1999;58(suppl 2):60–64. after intravenous and intramuscular administration. J Vet Phar-
298. Nicolau DP. Predicting antibacterial response from pharma- macol Ther. 2008;31:399–405.
codynamic and pharmacokinetic profiles. Infection. 2001;29 320. Sekkin S, Gokbulut C, Kum C, et al. Plasma disposition of enro-
(suppl 2):11–15. floxacin following intravenous and intramuscular administra-
299. Robicsek A, Jacoby GA, Hooper DC. The worldwide emergence tion in donkeys. Vet Rec. 2012;171:447.
of plasmid-mediated quinolone resistance. Lancet Infect Dis. 321. Gardner SY, Davis JL, Jones SL, et al. Moxifloxacin pharmacoki-
2006;6:629–640. netics in horses and disposition into phagocytes after oral dos-
300. Hooper DC. Mechanisms of fluoroquinolone resistance. Drug ing. J Vet Pharmacol Ther. 2004;27:57–60.
Resist Updat. 1999;2:38–55. 322. Alghasham AA, Nahata MC. Clinical use of fluoroquinolones in
301. Schmitz FJ, Perdikouli M, Beeck A, et al. Molecular surveillance children. Ann Pharmacother. 2000;34:344–413, 347–359; quiz.
of macrolide, tetracycline and quinolone resistance mechanisms 323. Burkhardt JE, Hill MA, Turek JJ, et al. Ultrastructural changes
in 1191 clinical European Streptococcus pneumoniae isolates. Int in articular cartilages of immature beagle dogs dosed with di-
J Antimicrob Agents. 2001;18:433–436. floxacin, a fluoroquinolone. Vet Pathol. 1992;29:230–238.
302. Webber M, Piddock LJ. Quinolone resistance in Escherichia coli. 324. Beluche LA, Bertone AL, Anderson DE, et al. In vitro dose-
Vet Res. 2001;32:275–284. dependent effects of enrofloxacin on equine articular cartilage.
303. Dowling PM, Wilson RC, Tyler JW, et al. Pharmacokinetics of Am J Vet Res. 1999;60:577–582.
ciprofloxacin in ponies. J Vet Pharmacol Ther. 1995;18:7–12. 325. Vivrette SL, Bostian A, Bermingham EC, et al. Quinolone-
304. Yamarik TA, Wilson WD, Wiebe VJ, et al. Pharmacokinetics induced arthropathy in neonatal foals. 47th Annual American
and toxicity of ciprofloxacin in adult horses. J Vet Pharmacol Association of Equine Practitioners Convention. 2001:376–377.
Ther. 2010;33:587–594. 326. Bertone AL, Tremaine WH, Macoris DG, et al. Effect of long-
305. Bermingham EC, Papich MG, Vivrette SL. Pharmacokinetics of term administration of an injectable enrofloxacin solution on
enrofloxacin administered intravenously and orally to foals. Am physical and musculoskeletal variables in adult horses. J Am Vet
J Vet Res. 2000;61:706–709. Med Assoc. 2000;217:1514–1521.
306. Giguere S, Belanger M. Concentration of enrofloxacin in equine 327. Larsen H, Nielsen GL, Schonheyder HC, et al. Birth outcome
tissues after long-term oral administration. J Vet Pharmacol following maternal use of fluoroquinolones. Int J Antimicrob
Ther. 1997;20:402–404. Agents. 2001;18:259–262.
307. Giguere S, Sweeney RW, Belanger M. Pharmacokinetics of enro- 328. Heath SE. Chronic pleuritis in a horse. Can Vet J. 1989;30:69.
floxacin in adult horses and concentration of the drug in serum, 329. Intorre L, Mengozzi G, Maccheroni M, et al. Enrofloxacin-
body fluids, and endometrial tissues after repeated intragastri- theophylline interaction: influence of enrofloxacin on theophyl-
cally administered doses. Am J Vet Res. 1996;57:1025–1030. line steady-state pharmacokinetics in the beagle dog. J Vet Phar-
308. Peyrou M, Bousquet-Melou A, Laroute V, et al. Enrofloxacin macol Ther. 1995;18:352–356.
and marbofloxacin in horses: comparison of pharmacokinetic 330. Cox S, Dudenbostel L, Sommardahl C, et al. Pharmacokinetics
parameters, use of urinary and metabolite data to estimate of firocoxib and its interaction with enrofloxacin in horses. J Vet
first-pass effect and absorbed fraction. J Vet Pharmacol Ther. Pharmacol Ther. 2012;35:615–617.
2006;29:337–344. 331. Dechant J. Combination of medical and surgical therapy for
309. Steinman A, Britzi M, Levi O, et al. Lack of effect of diet on pleuropneumonia in a horse. Can Vet J. 1997;38:499–501.
the pharmacokinetics of enrofloxacin in horses. J Vet Pharmacol 332. MacDonald DG, Bailey JV, Fowler JD. Arthrodesis of the scap-
Ther. 2006;29:67–70. ulohumeral joint in a horse. Can Vet J. 1995;36:312–315.
310. Davis JL, Papich MG, Weingarten A. The pharmacokinetics of 333. Rodger LD, Carlson GP, Moran ME, et al. Resolution of a left
orbifloxacin in the horse following oral and intravenous admin- ureteral stone using electrohydraulic lithotripsy in a thorough-
istration. J Vet Pharmacol Ther. 2006;29:191–197. bred colt. J Vet Intern Med. 1995;9:280–282.
311. Lopez BS, Giguère S, Berghaus LJ, et al. Pharmacokinetics of 334. Wilson WD, Spensley MS, Baggot JD, et al. Pharmacokinetics,
danofloxacin and N-desmethyldanofloxacin in adult horses bioavailability, and in vitro antibacterial activity of rifampin in
and their concentration in synovial fluid. J Vet Pharmacol Ther. the horse. Am J Vet Res. 1988;49:2041–2046.
2015;38:123–129. 335. Fines M, Pronost S, Maillard K, et al. Characterization of
312. Kaartinen L, Panu S, Pyorala S. Pharmacokinetics of enrofloxa- mutations in the rpoB gene associated with rifampin resist-
cin in horses after single intravenous and intramuscular admin- ance in Rhodococcus equi isolated from foals. J Clin Microbiol.
istration. Equine Vet J. 1997;29:378–381. 2001;39:2784–2787.
336. Takai S, Takeda K, Nakano Y, et al. Emergence of rifampin- 361. Giovanni G, Giovanni P. Do non-steroidal anti-inflammatory
resistant Rhodococcus equi in an infected foal. J Clin Microbiol. drugs and COX-2 selective inhibitors have different renal ef-
1997;35:1904–1908. fects? J Nephrol. 2002;15:480–488.
337. Kohn CW, Sams R, Kowalski JJ, et al. Pharmacokinetics of single 362. Raidal SL, Hughes KJ, Charman AL, et al. Effects of meloxi-
intravenous and single and multiple dose oral administration of cam and phenylbutazone on renal responses to furose
rifampin in mares. J Vet Pharmacol Ther. 1993;16:119–131. mide, dobutamine, and exercise in horses. Am J Vet Res.
338. Burrows GE, MacAllister CG, Beckstrom DA, et al. Rifampin in 2014;75:668–679.
the horse: comparison of intravenous, intramuscular, and oral 363. Wallace JL, Reuter BK, McKnight W, et al. Selective inhibitors
administrations. Am J Vet Res. 1985;46:442–446. of cyclooxygenase-2: are they really effective, selective, and GI-
339. Burrows GE, MacAllister CG, Ewing P, et al. Rifampin disposi- safe? J Clin Gastroenterol. 1998;27(suppl 1):S28–S34.
tion in the horse: effects of age and method of oral administra- 364. Wallace JL, Muscara MN. Selective cyclo-oxygenase-2 inhibi-
tion. J Vet Pharmacol Ther. 1992;15:124–132. tors: cardiovascular and gastrointestinal toxicity. Dig Liver Dis.
340. Castro LA, Brown MP, Gronwall R, et al. Pharmacokinetics 2001;33(suppl 2):S21–S28.
of rifampin given as a single oral dose in foals. Am J Vet Res. 365. Armstrong S, Tricklebank P, Lake A, et al. Pharmacokinet-
1986;47:2584–2586. ics of carprofen enantiomers in equine plasma and synovial
341. Burrows GE, MacAllister CG, Ewing P, et al. Rifampin disposi- fluid—a comparison with ketoprofen. J Vet Pharmacol Ther.
tion in the horse: effects of repeated dosage of rifampin or phe- 1999;22:196–201.
nylbutazone. J Vet Pharmacol Ther. 1992;15:305–308. 366. Higgins AJ, Lees P, Sedgwick AD. Development of equine mod-
342. Frank LA. Clinical pharmacology of rifampin. J Am Vet Med els of inflammation. The Ciba-Geigy Prize for Research in Ani-
Assoc. 1990;197:114–117. mal Health. Vet Rec. 1987;120:517–522.
343. Baggot JD, Wilson WD, Hietala S. Clinical pharmacokinetics of 367. Landoni MF, Lees P. Pharmacokinetics and pharmacodynam-
metronidazole in horses. J Vet Pharmacol Ther. 1988;11:417–420. ics of ketoprofen enantiomers in the horse. J Vet Pharmacol
344. Magdesian KG, Hirsh DC, Jang SS, et al. Characterization of Ther. 1996;19:466–474.
Clostridium difficile isolates from foals with diarrhea: 28 cases 368. King JN, Gerring EL. Antagonism of endotoxin-induced dis-
(1993-1997). J Am Vet Med Assoc. 2002;220:67–73. ruption of equine bowel motility by flunixin and phenylbuta-
345. Sweeney RW, Sweeney CR, Soma LR, et al. Pharmacokinetics of zone. Equine Vet J. 1989;21(suppl 7):38–42.
metronidazole given to horses by intravenous and oral routes. 369. Moses VS, Hardy J, Bertone AL, et al. Effects of anti-inflamma-
Am J Vet Res. 1986;47:1726–1729. tory drugs on lipopolysaccharide-challenged and unchallenged
346. Rubin DT, Kornblunth A. Role of antibiotics in the manage- equine synovial explants. Am J Vet Res. 2001;62:54–60.
ment of inflammatory bowel disease: a review. Rev Gastroen- 370. Danek J. Effects of flunixin meglumine on selected clinico-
terol Disord. 2005;5(suppl 3):S10–S15. pathologic variables, and serum testosterone concentration in
347. Steinman A, Gips M, Lavy E, et al. Pharmacokinetics of metro- stallions after endotoxin administration. J Vet Med A Physiol
nidazole in horses after intravenous, rectal and oral administra- Pathol Clin Med. 2006;53:357–363.
tion. J Vet Pharmacol Ther. 2000;23:353–357. 371. Dunkle NJ, Bottoms GD, Fessler JF, et al. Effects of flun-
348. Garber JL, Brown MP, Gronwall RR, et al. Pharmacokinetics of ixin meglumine on blood pressure and fluid compartment
metronidazole after rectal administration in horses. Am J Vet volume changes in ponies given endotoxin. Am J Vet Res.
Res. 1993;54:2060–2063. 1985;46:1540–1544.
349. Swain EA, Magdesian KG, Kass PH, et al. Pharmacokinetics of 372. Olson NC, Meyer RE, Anderson DL. Effects of flunixin me-
metronidazole in foals: influence of age within the neonatal pe- glumine on cardiopulmonary responses to endotoxin in po-
riod. J Vet Pharmacol Ther. 2015;38:227–234. nies. J Appl Physiol. 1985;59:1464–1471.
350. Specht TE, Brown MP, Gronwall RR, et al. Pharmacokinetics of 373. Semrad SD. Comparison of flunixin, prednisolone, dimethyl
metronidazole and its concentration in body fluids and endo- sulfoxide, and a lazaroid (U74389F) for treating endotoxemic
metrial tissues of mares. Am J Vet Res. 1992;53:1807–1812. neonatal calves. Am J Vet Res. 1993;54:1517–1522.
351. Sweeney RW, Sweeney CR, Weiher J. Clinical use of metroni- 374. Semrad SD, Hardee GE, Hardee MM, et al. Flunixin meglumine
dazole in horses: 200 cases (1984-1989). J Am Vet Med Assoc. given in small doses: pharmacokinetics and prostaglandin inhi-
1991;198:1045–1048. bition in healthy horses. Am J Vet Res. 1985;46:2474–2479.
352. Jones RL. Clostridial enterocolitis. Vet Clin North Am Equine 375. Semrad SD, Hardee GE, Hardee MM, et al. Low dose flunixin
Pract. 2000;16:471–485. meglumine: effects on eicosanoid production and clinical signs
353. McGorum BC, Dixon PM, Smith DG. Use of metronida- induced by experimental endotoxaemia in horses. Equine Vet J.
zole in equine acute idiopathic toxaemic colitis. Vet Rec. 1987;19:201–206.
1998;142:635–638. 376. Semrad SD, Moore JN. Effects of multiple low doses of flunixin
354. Barr BS. Infiltrative intestinal disease. Vet Clin North Am Equine meglumine on repeated endotoxin challenge in the horse. Pros-
Pract. 2006;22:e1–e7. taglandins Leukot Med. 1987;27:169–181.
355. Lees P, Higgins AJ. Clinical pharmacology and therapeutic uses 377. Templeton CB, Bottoms GD, Fessler JF, et al. Endotoxin-in-
of non-steroidal anti-inflammatory drugs in the horse. Equine duced hemodynamic and prostaglandin changes in ponies: ef-
Vet J. 1985;17:83–96. fects of flunixin meglumine, dexamethasone, and prednisolone.
356. Wallace JL. How do NSAIDs cause ulcer disease? Baillieres Best Circ Shock. 1987;23:231–240.
Pract Res Clin Gastroenterol. 2000;14:147–159. 378. Dawson J, Lees P, Sedgwick AD. Actions of non-steroidal
357. Wallace JL. Distribution and expression of cyclooxygenase anti-inflammatory drugs on equine leucocyte movement
(COX) isoenzymes, their physiological roles, and the categori- in vitro. J Vet Pharmacol Ther. 1987;10:150–159.
zation of nonsteroidal anti-inflammatory drugs (NSAIDs). Am 379. Pillinger MH, Capodici C, Rosenthal P, et al. Modes of action
J Med. 1999;107:11S–16S, discussion 16S-17S. of aspirin-like drugs: salicylates inhibit erk activation and inte-
358. Wallace JL, Ma L. Inflammatory mediators in gastrointestinal de- grin-dependent neutrophil adhesion. Proc Natl Acad Sci U S A.
fense and injury. Exp Biol Med (Maywood). 2001;226:1003–1015. 1998;95:14540–14545.
359. Wallace JL. Selective cyclooxygenase-2 inhibitors: after the 380. Weissmann G, Montesinos MC, Pillinger M, et al. Non-
smoke has cleared. Dig Liver Dis. 2002;34:89–94. prostaglandin effects of aspirin III and salicylate: inhibition of
360. Wallace JL. Prostaglandins, NSAIDs, and gastric mucosal integrin-dependent human neutrophil aggregation and inflam-
protection: why doesn’t the stomach digest itself? Physiol Rev. mation in COX 2- and NF kappa B (P105)-knockout mice. Adv
2008;88:1547–1565. Exp Med Biol. 2002;507:571–577.
381. Chambers JP, Waterman AE, Livingston A. The effects of opi- 404. Collins LG, Tyler DE. Experimentally induced phenylbuta-
oid and alpha 2 adrenergic blockade on non-steroidal anti- zone toxicosis in ponies: description of the syndrome and
inflammatory drug analgesia in sheep. J Vet Pharmacol Ther. its prevention with synthetic prostaglandin E2. Am J Vet Res.
1995;18:161–166. 1985;46:1605–1615.
382. Johnson CB, Taylor PM, Young SS, et al. Postoperative analgesia 405. Hough ME, Steel CM, Bolton JR, et al. Ulceration and stricture
using phenylbutazone, flunixin or carprofen in horses. Vet Rec. of the right dorsal colon after phenylbutazone administration in
1993;133:336–338. four horses. Aust Vet J. 1999;77:785–788.
383. Landoni MF, Soraci AL, Delatour P, et al. Enantioselective be- 406. MacAllister CG, Morgan SJ, Borne AT, et al. Comparison of
haviour of drugs used in domestic animals: a review. J Vet Phar- adverse effects of phenylbutazone, flunixin meglumine, and ke-
macol Ther. 1997;20:1–16. toprofen in horses. J Am Vet Med Assoc. 1993;202:71–77.
384. Landoni MF, Lees P. Chirality: a major issue in veterinary phar- 407. Meschter CL, Gilbert M, Krook L, et al. The effects of phe-
macology. J Vet Pharmacol Ther. 1996;19:82–84. nylbutazone on the morphology and prostaglandin concentra-
385. Lapicque F, Muller N, Payan E, et al. Protein binding and ste- tions of the pyloric mucosa of the equine stomach. Vet Pathol.
reoselectivity of nonsteroidal anti-inflammatory drugs. Clin 1990;27:244–253.
Pharmacokinet. 1993;25:115–123. 408. Read WK. Renal medullary crest necrosis associated with
386. Armstrong S, Lees P. Effects of R and S enantiomers and a race- phenylbutazone therapy in horses. Vet Pathol. 1983;20:
mic mixture of carprofen on the production and release of pro- 662–669.
teoglycan and prostaglandin E2 from equine chondrocytes and 409. Held JP, Daniel GB. Use of nonimaging nuclear medicine tech-
cartilage explants. Am J Vet Res. 1999;60:98–104. niques to assess the effect of flunixin meglumine on effective re-
387. Verde CR, Simpson MI, Frigoli A, et al. Enantiospecific pharma- nal plasma flow and effective renal blood flow in healthy horses.
cokinetics of ketoprofen in plasma and synovial fluid of horses Am J Vet Res. 1991;52:1619–1621.
with acute synovitis. J Vet Pharmacol Ther. 2001;24:179–185. 410. Cambridge H, Lees P, Hooke RE, et al. Antithrombotic actions
388. Brouwers JR, de Smet PA. Pharmacokinetic-pharmacodynamic of aspirin in the horse. Equine Vet J. 1991;23:123–127.
drug interactions with nonsteroidal anti-inflammatory drugs. 411. Hardee MM, Moore JN, Hardee GE. Effects of flunixin meglu-
Clin Pharmacokinet. 1994;27:462–485. mine, phenylbutazone and a selective thromboxane synthetase
389. Semrad SD, Sams RA, Harris ON, et al. Effects of concurrent inhibitor (UK-38,485) on thromboxane and prostacyclin pro-
administration of phenylbutazone and flunixin meglumine on duction in healthy horses. Res Vet Sci. 1986;40:152–156.
pharmacokinetic variables and in vitro generation of throm- 412. Heath MF, Evans RJ, Poole AW, et al. The effects of aspirin and
boxane B2 in mares. Am J Vet Res. 1993;54:1901–1905. paracetamol on the aggregation of equine blood platelets. J Vet
390. Keegan KG, Messer NT, Reed SK, et al. Effectiveness of admin- Pharmacol Ther. 1994;17:374–378.
istration of phenylbutazone alone or concurrent administration 413. Lees P, Ewins CP, Taylor JB, et al. Serum thromboxane in the
of phenylbutazone and flunixin meglumine to alleviate lame- horse and its inhibition by aspirin, phenylbutazone and flun-
ness in horses. Am J Vet Res. 2008;69:167–173. ixin. Br Vet J. 1987;143:462–476.
391. Reed SK, Messer NT, Tessman RK, et al. Effects of phenylbuta- 414. Baxter GM, Moore JN. Effect of aspirin on ex vivo generation of
zone alone or in combination with flunixin meglumine on blood thromboxane in healthy horses. Am J Vet Res. 1987;48:13–16.
protein concentrations in horses. Am J Vet Res. 2006;67:398–402. 415. Frean SP, Cambridge H, Lees P. Effects of anti-arthritic drugs
392. Peng S, Duggan A. Gastrointestinal adverse effects of non- on proteoglycan synthesis by equine cartilage. J Vet Pharmacol
steroidal anti-inflammatory drugs. Expert Opin Drug Saf. Ther. 2002;25:289–298.
2005;4:157–169. 416. Jolly WT, Whittem T, Jolly AC, et al. The dose-related effects of
393. Burrows GE, MacAllister CG, Tripp P, et al. Interactions be- phenylbutazone and a methylprednisolone acetate formulation
tween chloramphenicol, acepromazine, phenylbutazone, ri- (Depo-Medrol) on cultured explants of equine carpal articular
fampin and thiamylal in the horse. Equine Vet J. 1989;21:34–38. cartilage. J Vet Pharmacol Ther. 1995;18:429–437.
394. Firth EC, Nouws JF, Klein WR, et al. The effect of phenyl 417. Frean SP, Abraham LA, Lees P. In vitro stimulation of equine
butazone on the plasma disposition of penicillin G in the articular cartilage proteoglycan synthesis by hyaluronan and
horse. J Vet Pharmacol Ther. 1990;13:179–185. carprofen. Res Vet Sci. 1999;67:183–190.
395. Whittem T, Firth EC, Hodge H, et al. Pharmacokinetic interac- 418. Pountos I, Georgouli T, Blokhuis TJ, et al. Pharmacological
tions between repeated dose phenylbutazone and gentamicin in agents and impairment of fracture healing: what is the evi-
the horse. J Vet Pharmacol Ther. 1996;19:454–459. dence? Injury. 2008;39:384–394.
396. Dyke TM, Hinchcliff KW, Sams RA. Attenuation by phenyl 419. Rohde C, Anderson DE, Bertone AL, et al. Effects of phenyl
butazone of the renal effects and excretion of furosemide in butazone on bone activity and formation in horses. Am J Vet
horses. Equine Vet J. 1999;31:289–295. Res. 2000;61:537–543.
397. Hinchcliff KW, McKeever KH, Muir 3rd WW, et al. Pharmaco- 420. Broome TA, Brown MP, Gronwall RR, et al. Pharmacokinetics
logic interaction of furosemide and phenylbutazone in horses. and plasma concentrations of acetylsalicylic acid after intrave-
Am J Vet Res. 1995;56:1206–1212. nous, rectal, and intragastric administration to horses. Can J Vet
398. Carrick JB, Papich MG, Middleton DM, et al. Clinical and path- Res. 2003;67:297–302.
ological effects of flunixin meglumine administration to neona- 421. Murdick PW, Ray RS, Noonan JS. Salicylic acid concentration
tal foals. Can J Vet Res. 1989;53:195–201. in plasma and urine of medicated and nonmedicated horses.
399. Traub JL, Gallina AM, Grant BD, et al. Phenylbutazone toxico- Am J Vet Res. 1968;29:581–585.
sis in the foal. Am J Vet Res. 1983;44:1410–1418. 422. Judson DG, Barton M. Effect of aspirin on haemostasis in the
400. Traub-Dargatz JL, Bertone JJ, Gould DH, et al. Chronic flunixin horse. Res Vet Sci. 1981;30:241–242.
meglumine therapy in foals. Am J Vet Res. 1988;49:7–12. 423. Trujillo O, Rios A, Maldonado R, et al. Effect of oral administra-
401. Gunson DE, Soma LR. Renal papillary necrosis in horses tion of acetylsalicylic acid on haemostasis in the horse. Equine
after phenylbutazone and water deprivation. Vet Pathol. Vet J. 1981;13:205–206.
1983;20:603–610. 424. Soraci A, Benoit E, Jaussaud P, et al. Enantioselective glucuroni-
402. Karcher LF, Dill SG, Anderson WI, et al. Right dorsal colitis. dation and subsequent biliary excretion of carprofen in horses.
J Vet Intern Med. 1990;4:247–253. Am J Vet Res. 1995;56:358–361.
403. Cohen ND, Carter GK, Mealey RH, et al. Medical management 425. Lees P, McKellar Q, May SA, et al. Pharmacodynamics and
of right dorsal colitis in 5 horses: a retrospective study. J Vet pharmacokinetics of carprofen in the horse. Equine Vet J.
Intern Med. 1987-1993;1995(9):272–276. 1994;26:203–208.
426. Williams A, Smith JR, Allaway D, et al. Carprofen inhibits 446. Welsh JC, Lees P, Stodulski G, et al. Influence of feeding sched-
the release of matrix metalloproteinases 1, 3, and 13 in the se- ule on the absorption of orally administered flunixin in the
cretome of an explant model of articular cartilage stimulated horse. Equine Vet J. 1992;11(suppl 1):62–65.
with interleukin 1. Arthritis Res Ther. 2013;15:R223. 447. Coakley M, Peck KE, Taylor TS, et al. Pharmacokinetics of flu-
427. Bryant CE, Farnfield BA, Janicke HJ. Evaluation of the ability of nixin meglumine in donkeys, mules, and horses. Am J Vet Res.
carprofen and flunixin meglumine to inhibit activation of nu- 1999;60:1441–1444.
clear factor kappa B. Am J Vet Res. 2003;64:211–215. 448. Crisman MV, Wilcke JR, Sams RA. Pharmacokinetics of flun-
428. Caldwell FJ, Mueller PO, Lynn RC, et al. Effect of topical ap- ixin meglumine in healthy foals less than twenty-four hours old.
plication of diclofenac liposomal suspension on experimentally Am J Vet Res. 1996;57:1759–1761.
induced subcutaneous inflammation in horses. Am J Vet Res. 449. Galbraith EA, McKellar QA. Protein binding and in vitro se-
2004;65:271–276. rum thromboxane B2 inhibition by flunixin meglumine and
429. Schleining JA, McClure SR, Evans RB, et al. Liposome-based di- meclofenamic acid in dog, goat and horse blood. Res Vet Sci.
clofenac for the treatment of inflammation in an acute synovitis 1996;61:78–81.
model in horses. J Vet Pharmacol Ther. 2008;31:554–561. 450. Higgins AJ, Lees P, Sharma SC, et al. Measurement of flunixin
430. Lynn RC, Hepler DI, Kelch WJ, et al. Double-blinded placebo- in equine inflammatory exudate and plasma by high perfor-
controlled clinical field trial to evaluate the safety and efficacy mance liquid chromatography. Equine Vet J. 1987;19:303–306.
of topically applied 1% diclofenac liposomal cream for the relief 451. Landoni MF, Lees P. Comparison of the anti-inflammatory
of lameness in horses. Vet Ther. 2004;5:128–138. actions of flunixin and ketoprofen in horses applying PK/PD
431. Levine DG, Epstein KL, Neelis DA, et al. Effect of topical ap- modelling. Equine Vet J. 1995;27:247–256.
plication of 1% diclofenac sodium liposomal cream on inflam- 452. Jackman BR, Moore JN, Barton MH, et al. Comparison of the
mation in healthy horses undergoing intravenous regional limb effects of ketoprofen and flunixin meglumine on the in vitro re-
perfusion with amikacin sulfate. Am J Vet Res. 2009;70:1323– sponse of equine peripheral blood monocytes to bacterial endo-
1325. toxin. Can J Vet Res. 1994;58:138–143.
432. Anderson D, Kollias-Baker C, Colahan P, et al. Urinary and 453. Daels PF, Stabenfeldt GH, Hughes JP, et al. Effects of flun-
serum concentrations of diclofenac after topical application to ixin meglumine on endotoxin-induced prostaglandin F2 al-
horses. Vet Ther. 2005;6:57–66. pha secretion during early pregnancy in mares. Am J Vet Res.
433. Doucet MY, Bertone AL, Hendrickson D, et al. Comparison of 1991;52:276–281.
efficacy and safety of paste formulations of firocoxib and phe- 454. MacAllister CG, Sangiah S. Effect of ranitidine on healing of
nylbutazone in horses with naturally occurring osteoarthritis. experimentally induced gastric ulcers in ponies. Am J Vet Res.
J Am Vet Med Assoc. 2008;232:91–97. 1993;54:1103–1107.
434. Holland B, Fogle C, Blikslager AT, et al. Pharmacokinetics 455. Brehaus BA, Brown CM, Scott EA, et al. Clostridial muscle
and pharmacodynamics of three formulations of firocoxib in infections following intramuscular injections. Equine Vet Sci.
healthy horses. J Vet Pharmacol Ther. 2015;38:249–256. 1983;3:42–46.
435. Barton MH, Paske E, Norton N, et al. Efficacy of cyclo-oxyge- 456. Rebhun WC, Shin SJ, King JM, et al. Malignant edema in horses.
nase inhibition by two commercially available firocoxib prod- J Am Vet Med Assoc. 1985;187:732–736.
ucts in horses. Equine Vet J. 2014;46:72–75. 457. Corveleyn S, Deprez P, Van der Weken G, et al. Bioavailability
436. American Veterinary Medical Foundation: Clarification regard- of ketoprofen in horses after rectal administration. J Vet Phar-
ing substitution of Previcox® for Equioxx®. May 11, 2010. Avail- macol Ther. 1996;19:359–363.
able at https://www.avma.org/KB/Resources/Reference/Pages/ 458. Corveleyn S, Henrist D, Remon JP, et al. Bioavailability of race-
Previcox-for-Equioxx.aspx. mic ketoprofen in healthy horses following rectal administra-
437. Letendre LT, Tessman RK, McClure SR, et al. Pharmacokinetics tion. Res Vet Sci. 1999;67:203–204.
of firocoxib after administration of multiple consecutive daily 459. Sams R, Gerken DF, Ashcraft SM. Pharmacokinetics of keto-
doses to horses. Am J Vet Res. 2008;69:1399–1405. profen after multiple intravenous doses to mares. J Vet Pharma-
438. Duz M, Parkin TD, Cullander RM, et al. Effect of flunixin col Ther. 1995;18:108–116.
meglumine and firocoxib on ex vivo cyclooxygenase ac- 460. Landoni MF, Lees P. Influence of formulation on the pharma-
tivity in horses undergoing elective surgery. Am J Vet Res. cokinetics and bioavailability of racemic ketoprofen in horses. J
2015;76:208–215. Vet Pharmacol Ther. 1995;18:446–450.
439. Kvaternick V, Pollmeier M, Fischer J, et al. Pharmacokinet- 461. Landoni MF, Foot R, Frean S, et al. Effects of flunixin, tolfenam-
ics and metabolism of orally administered firocoxib, a novel ic acid, R(−) and S(+) ketoprofen on the response of equine
second generation coxib, in horses. J Vet Pharmacol Ther. synoviocytes to lipopolysaccharide stimulation. Equine Vet J.
2007;30:208–217. 1996;28:468–475.
440. Barton MH, Darden JE, Clifton S, et al. Effect of firocoxib on 462. Wilcke JR, Crisman MV, Scarratt WK, et al. Pharmacokinetics
cyclooxygenase 2, microsomal prostaglandin E2 synthase 1, and of ketoprofen in healthy foals less than twenty-four hours old.
cytosolic phospholipase A2 gene expression in equine mononu- Am J Vet Res. 1998;59:290–292.
clear cells. Am J Vet Res. 2015;76:1051–1057. 463. Owens JG, Kamerling SG, Stanton SR, et al. Effects of pretreat-
441. Kivett L, Taintor J, Wright J. Evaluation of the safety of a combi- ment with ketoprofen and phenylbutazone on experimentally
nation of oral administration of phenylbutazone and firocoxib induced synovitis in horses. Am J Vet Res. 1996;57:866–874.
in horses. J Vet Pharmacol Ther. 2014;37:413–416. 464. Owens JG, Kamerling SG, Stanton SR, et al. Effects of ketopro-
442. Cox S, Villarino N, Sommardahl C, et al. Disposition of firo- fen and phenylbutazone on chronic hoof pain and lameness in
coxib in equine plasma after an oral loading dose and a multiple the horse. Equine Vet J. 1995;27:296–300.
dose regimen. Vet J. 2013;198:382–385. 465. Mozaffari AA, Derakhshanfar A, Alinejad A, et al. A compara-
443. McConnico RS, Khodadad JL. Pharmacokinetics and clinical tive study on the adverse effects of flunixin, ketoprofen and phe-
safety of oral paste firocoxib, a COX-1 sparing NSAID, in foals. nylbutazone in miniature donkeys: haematological, biochemi-
J Vet Int Med. 2011;25:665. cal and pathological findings. N Z Vet J. 2010;58:224–228.
444. Hovanessian N, Davis JL, McKenzie 3rd HC, et al. Pharma- 466. Ketofen. In: Arrioja A, ed. Compendium of veterinary products.
cokinetics and safety of firocoxib after oral administration of 10th ed. Hensall, ON: North American Compendiums Ltd;
repeated consecutive doses to neonatal foals. J Vet Pharmacol 2007. p 1673.
Ther. 2014;37:243–251. 467. Beretta C, Garavaglia G, Cavalli M. COX-1 and COX-2 inhibi-
445. Soma LR, Behrend E, Rudy J, et al. Disposition and excretion of tion in horse blood by phenylbutazone, flunixin, carprofen and
flunixin meglumine in horses. Am J Vet Res. 1988;49:1894–1898. meloxicam: an in vitro analysis. Pharmacol Res. 2005;52:302–306.
468. Toutain PL, Reymond N, Laroute V, et al. Pharmacokinet- 484. Wilcke JR, Crisman MV, Sams RA, et al. Pharmacoki-
ics of meloxicam in plasma and urine of horses. Am J Vet Res. netics of phenylbutazone in neonatal foals. Am J Vet Res.
2004;65:1542–1547. 1993;54:2064–2067.
469. Toutain PL, Cester CC. Pharmacokinetic-pharmacodynamic 485. Tobin T, Blake JW, Valentine R. Drug interactions in the horse:
relationships and dose response to meloxicam in horses effects of chloramphenicol, quinidine, and oxyphenbutazone on
with induced arthritis in the right carpal joint. Am J Vet Res. phenylbutazone metabolism. Am J Vet Res. 1977;38:123–127.
2004;65:1533–1541. 486. Lees P, Maitho TE, Taylor JB. Pharmacokinetics of phenylbuta-
470. Sinclair MD, Mealey KL, Matthews NS, et al. Comparative zone in two age groups of ponies: a preliminary study. Vet Rec.
pharmacokinetics of meloxicam in clinically normal horses and 1985;116:229–232.
donkeys. Am J Vet Res. 2006;67:1082–1085. 487. Piperno E, Ellis DJ, Getty SM, et al. Plasma and urine lev-
471. Naylor RJ, Taylor AH, Knowles EJ, et al. Comparison of flun- els of phenylbutazone in the horse. J Am Vet Med Assoc.
ixin meglumine and meloxicam for postoperative management 1968;153:195–198.
of horses with strangulating small intestinal lesions. Equine Vet 488. Hunt JM, Lees P, Edwards GB. Suspected non-steroidal anti-in-
J. 2014;46:427–434. flammatory drug toxicity in a horse. Vet Rec. 1985;117:581–582.
472. Little D, Brown SA, Campbell NB, et al. Effects of the cyclooxy- 489. Aleman M, Nieto JE, Higgins JK. Ulcerative cystitis associated
genase inhibitor meloxicam on recovery of ischemia-injured with phenylbutazone administration in two horses. J Am Vet
equine jejunum. Am J Vet Res. 2007;68:614–624. Med Assoc. 2011;239:499–503.
473. D’Arcy-Moskwa E, Noble GK, Weston LA, et al. Effects of 490. Ramirez S, Wolfsheimer KJ, Moore RM, et al. Duration of effects
meloxicam and phenylbutazone on equine gastric mucosal per- of phenylbutazone on serum total thyroxine and free thyroxine
meability. J Vet Intern Med. 2012;26:1494–1499. concentrations in horses. J Vet Intern Med. 1997;11:371–374.
474. Noble G, Edwards S, Lievaart J, et al. Pharmacokinetics and 491. Lees P, May SA, Hoeijmakers M, et al. A pharmacodynamic
safety of single and multiple oral doses of meloxicam in adult and pharmacokinetic study with vedaprofen in an equine mod-
horses. J Vet Intern Med. 2012;26:1192–1201. el of acute nonimmune inflammation. J Vet Pharmacol Ther.
475. Walliser U, Fenner A, Mohren N, et al. Evaluation of the effi- 1999;22:96–106.
cacy of meloxicam for post-operative management of pain and 492. Davis JL, Papich MG, Morton AJ, et al. Pharmacokinetics of
inflammation in horses after orthopaedic surgery in a placebo etodolac in the horse following oral and intravenous adminis-
controlled clinical field trial. BMC Vet Res. 2015;11:113. tration. J Vet Pharmacol Ther. 2007;30:43–48.
476. Raidal SL, Edwards S, Pippia J, et al. Pharmacokinetics and safe- 493. Symonds KD, MacAllister CG, Erkert RS, et al. Use of force
ty of oral administration of meloxicam to foals. J Vet Intern Med. plate analysis to assess the analgesic effects of etodolac in horses
2013;27:300–307. with navicular syndrome. Am J Vet Res. 2006;67:557–561.
477. Thamm DH, Ehrhart 3rd EJ, Charles JB, et al. Cyclooxygenase-2 494. Morton AJ, Campbell NB, Gayle JM, et al. Preferential and
expression in equine tumors. Vet Pathol. 2008;45:825–828. non-selective cyclooxygenase inhibitors reduce inflamma-
478. Moore AS, Beam SL, Rassnick KM, et al. Long-term control of tion during lipopolysaccharide-induced synovitis. Res Vet Sci.
mucocutaneous squamous cell carcinoma and metastases in a 2005;78:189–192.
horse using piroxicam. Equine Vet J. 2003;35:715–718. 495. Tomlinson JE, Wilder BO, Young KM, et al. Effects of flun-
479. Rose RJ, Kohnke JR, Baggot JD. Bioavailability of phenylbuta- ixin meglumine or etodolac treatment on mucosal recovery of
zone preparations in the horse. Equine Vet J. 1982;14:234–237. equine jejunum after ischemia. Am J Vet Res. 2004;65:761–769.
480. Smith PB, Caldwell J, Smith RL, et al. The bioavailability of phe- 496. Davis JL, Marshall JF, Papich MG, et al. The pharmacokinetics
nylbutazone in the horse. Xenobiotica. 1987;17:435–443. and in vitro cyclooxygenase selectivity of deracoxib in horses.
481. Sullivan M, Snow DH. Factors affecting absorption of non- J Vet Pharmacol Ther. 2011;34:12–16.
steroidal anti-inflammatory agents in the horse. Vet Rec. 497. Neirinckx E, Vervaet C, De Boever S, et al. Species comparison
1982;110:554–558. of oral bioavailability, first-pass metabolism and pharmacoki-
482. Soma LR, Gallis DE, Davis WL, et al. Phenylbutazone kinetics netics of acetaminophen. Res Vet Sci. 2010;89:113–119.
and metabolite concentrations in the horse after five days of ad- 498. West E, Bardell D, Morgan R, et al. Use of acetaminophen
ministration. Am J Vet Res. 1983;44:2104–2109. (paracetamol) as a short-term adjunctive analgesic in a lami-
483. Tobin T, Chay S, Kamerling S, et al. Phenylbutazone in the nitic pony. Vet Anaesth Analg. 2011;38:521–522.
horse: a review. J Vet Pharmacol Ther. 1986;9:1–25.
C HA P T E R 3
Recognizing and Treating Pain
in Horses
Rachel C. Hector and Khursheed R. Mama
Y INTRODUCTION leukotrienes, neuropeptides, and nerve growth factors) that

sensitize peripheral nerve fibers and activate additional (silent)
Following a brief review of general concepts related to pain nociceptors at the terminal ends of Aδ and C fibers.2,3 Cen-
and its assessment in horses, this chapter will focus on avail- tral sensitization results from the cumulative effects of repeti-
able pharmacologic and to a lesser extent complementary tive and sustained nociceptive input on the dorsal horn of
therapeutic options. The intent is to provide information that the spinal cord and a subsequent release of glutamate and
veterinarians can directly apply to management of acute and neuropeptides (substance P and neurokinin A) that activate
chronic pain in horses. N-methyl-d-aspartate (NMDA) and tachykinin receptors,
resulting in a gradual “windup” of central neural pathways.2-4
Pathophysiology of Pain Visceral pain (e.g., pain from intestine, liver, spleen, kidney, or
The International Association for the Study of Pain defines bladder), unlike somatic pain, is transmitted by parasympathetic
pain as “an unpleasant sensory and emotional experience (principally vagal) and sympathetic splanchnic afferent nerve
associated with actual or potential tissue damage, or described fibers.5,6 The autonomic fibers involved in transmitting noxious
in terms of such damage” (Box 3.1).1 Nociception refers to the
activation of high threshold receptors (nociceptors) located at
the distal ends of unmyelinated (C) or poorly myelinated (Aδ)
nerve fibers. Electrical impulses conducted by these afferent BOX 3.1 Definitions of Terms Used to Describe Pain
fibers reach the dorsal horn of the spinal cord and via ascend-
ing pathways (spinothalamic and spinoreticular thalamic) are 1. Pain: Unpleasant sensory or emotional experience
transmitted to the brain in which they may be perceived or associated with actual or potential tissue damage or
recognized as painful (Fig. 3.1). Nociception may occur in described in terms of such damage.
the absence of perception (as in the anesthetized horse) and 2. Noxious stimulus: Stimulus (mechanical, chemical, and
can trigger neuroendocrine (cortisol and catecholamines), thermal) of sufficient intensity to threaten or overtly cause
metabolic (hyperglycemia), and physiologic (heart rate and tissue damage.
respiratory rate) responses. Perception, which is influenced 3. Nociception: Process of pain perception via pain recep-
by external and animal-related factors, will trigger similar tors (nociceptors) and transmission of noxious (painful)
responses and behaviors (e.g., avoidance, lameness) intended stimuli, including transduction, transmission, modulation,
to protect the horse from further insult. Comprehensive and perception.
assessment of these responses is useful when evaluating the 4. Hyperalgesia: Increased response (hypersensitivity) to a
severity, stress, and impact of pain on the horse’s quality of life. noxious stimulus, either at the site of injury (primary) or in
Acutely painful states may resolve with discontinuation of surrounding undamaged tissue (secondary).
the stimulus and appropriate intervention. Neuronal input 5. Hyperesthesia: Increased sensitivity to nonnoxious stimuli.
may also be modulated by descending inhibitory pathways 6. Hyperpathia: Greatly exaggerated pain sensation to
originating from the brain and by use of alternate nonpain- nociceptive stimuli.
ful afferent neural input (e.g., ice at the site of injury). In the 7. Allodynia: Pain produced by nonnoxious stimuli.
absence of these, continued nociceptive input can lead to 8. Preemptive analgesia: Prevention or minimization
chronic nervous system pathology resulting from peripheral of pain by the administration of analgesics before the
and central sensitization. Clinically these conditions are asso- production of pain or before the introduction of a noxious
ciated with hypersensitivity (or a reduction in the intensity of stimulus (surgery) if pain already exists. The goal of
the stimulus required to cause pain) and allodynia (in which a preemptive analgesia is to provide a therapeutic interven-
typically nonpainful stimulus is now perceived as pain). Exag- tion in advance of pain to prevent or minimize the central
gerated responses to a noxious stimulus (hyperalgesia) and nervous system response to a noxious stimulus.
persistence of pain after removal of a noxious stimulus (hyper- 9. Multimodal therapy: Administration of multiple drugs
pathia) may also occur. that act by different mechanisms of action to produce
Peripheral sensitization is caused by the local produc- the desired (analgesic) effect.
tion, release, and accumulation of chemicals (prostaglandins,
138
CHAPTER 3 Recognizing and Treating Pain in Horses 139
Central sensitization
Dorsal ,
horn , TrkB C fiber
neuron BDNF central
NMDA axon
Ca2+
Mg2+
Signaling molecules Glutamate
Perception
Cortex
AMPA/KAI
Sub P
Projection NK1
Transmission
Modulation
Peripheral sensitization
COX2
C fiber R Prostaglandins (PGE2)

peripheral
axon RHeat
H+ Histamine
R
+
K+ Serotonin (5HT)
Signaling molecules H+
K +
H Bradykinin
R
Proteases
Cytokines (TNF )
R Nerve growth factor Transduction
FIG. 3.1 Pain nociception and perception. Painful thermal, mechanical, and chemical stimuli are trans-
duced to electric potentials (action potentials) that are transmitted to the spinal cord, in which they are
modulated and then projected to the brain (perception). The major excitatory neurotransmitter in the spine
is glutamate, which normally activates α-amino-3-hydroxy-5-isoxazole proprionic acid (AMPA) and kainate
(KAI) receptors. NMDA, N-methyl-d-aspartate; NK1, neurokinin.
inputs from visceral organs are diffuse and overlap extensively, (e.g., gastrointestinal, orthopedic, dental). Additionally, it is
resulting in difficulty in localization of the site of pain. Neuro- recognized that the pain experience is likely to be influenced
pathic pain, which is yet another form of pain, may result from by animal and environmental factors.10-12 Among physiologic
injury to the peripheral or central nervous system. For addi- assessments, stress hormones (e.g., cortisol, β-endorphins),
tional details regarding the pathophysiology of pain the reader is and catecholamines (e.g., epinephrine, norepinephrine) have
referred to McMahon et al. (2013) and Almeida et al. (2004).7,8 been measured in both clinical and laboratory settings in an
attempt to correlate these “objective data” with pain states.10,13
Pain Assessment Their usefulness has, however, been mixed because shock,
Although horses will demonstrate a variety of behavioral stress, and medications influence them like they do other
indicators of pain (Box 3.2), assessment of pain in horses physiologic measurements, such as heart rate. Further, they
has historically been considered challenging.9 This could be are not contemporaneous to the pain assessment; thus, they
because horses, as prey animals, do not wish to appear vul- only have retrospective value. Measurement of inflammatory
nerable and so do not fully exhibit signs of pain in unfamil- mediators such as prostaglandin E2 and substance P from
iar or threatening environments until pain becomes severe or joints are similarly not consistently reliable as indicators of
unrelenting. Consequently, horses may not be appropriately pain, and results are not immediately available.14,15
treated for painful conditions by the inexperienced observer. In an attempt to overcome these challenges, there has been
Although early reports suggest an emphasis on physiologic significant recent work on the development of multifaceted
or limited behavioral parameters to assess pain, today there pain assessment tools that consider physiologic (e.g., heart
is the recognition that evaluation of pain requires a multi- rate, blood pressure) and behavioral (both spontaneous and
faceted approach and should be assessed in light of the cause in response to interaction) indices developed specifically for
repeatable, and consistent categorization of pain, such that

BOX 3.2 Potential Behavioral Indicators of Pain in Horses therapies can be both targeted and monitored. If multiple
individuals are to be involved in assessing the animal, train-
• onsiderable restlessness, agitation, and anxiety
C ing in use of the preferred pain scale or behaviors is helpful to
• Rigid stance and reluctance to move minimize interobserver variation on parameters that are open
• Lowered head carriage to interpretation. Accurate assessment of pain will allow vet-
• Fixed stare and dilated nostrils, clenched jaw erinarians to continue to improve analgesic efforts in horses.
• Aggression toward its own foal
• Aggression toward handlers, horses, objects, and self Development of a Treatment Plan
• Decreased interactions with handlers Given the multifaceted nature of pain, the many individual
• Vocalization (deep groaning and grunting) breeds of horses, and additional equid species (e.g., donkeys,
• Rolling mules), as well as consideration of a wide age range of individual
• Kicking at abdomen equids in which veterinarians may be faced with managing pain,
• Flank watching a systematic approach to developing and modifying a pain treat-
• Stretching ment plan should be considered. Because of the significance of
• Dullness and depression well-being, pain is considered the “5th vital sign” in human
• Weight-shifting among limbs patients. In addition to the potential emotional association
• Limb guarding and subsequent avoidance behavior horses exhibit to locations
• Abnormal weight distribution in which they may have experienced pain, physiologic conse-
• Pointing, hanging, and rotating limbs quences such as negative energy balance, poor wound healing,
• Abnormal movement and altered gastrointestinal motility may be significant.22
• Reluctance to move Management of nociceptive pain such as surgical pain or
• Arched back that associated with acute injury is a common scenario. Noci-
• Head shaking ceptive pain is considered an adaptive or protective strategy,
• Abnormal bit behavior and the associated inflammatory response is considered essen-
• Altered eating; anorexia, quidding tial to the healing process. The goal of therapy is to normalize
pain sensitivity and not allow it to progress to a maladaptive
state or one that is no longer proportional to the noxious
horses in different clinical scenarios (e.g., postarthroscopy, stimulus and healing tissue.23 Nonsteroidal antiinflammatory
colic). Each parameter on many of these scales is further cate- drugs (NSAIDs) help normalize the inflammatory response
gorized in an attempt to indicate severity of pain; for example, generated by tissue injury and are commonly used in horses.
the parameter “kicking at the abdomen” is characterized by Although there have been mixed reports of the overall advan-
frequency of the same over a fixed interval, with greater fre- tage of preemptive versus postprocedural use of NSAIDs, it
quency assigned a worse score (greater degree of pain). Hence, is most common to administer these preemptively to limit
these scales serve not only to assess the presence or absence of inflammation. Additionally, medications used in the horse for
pain but also the severity (two such scales are included in Figs. sedation (e.g., α2-adrenergic agonists) and general anesthesia
3.2 and 3.3).16-21 One of these—namely, the horse grimace (e.g., ketamine) are also analgesic and affect different sites in the
scale—presents a somewhat unique approach and is worth nociceptive pathway (e.g., α2-adrenergic agonist drugs medi-
highlighting. This scale, which was modeled after similar work ate their analgesia through descending inhibition), providing
in rodents, correlates six specific facial expressions with the a multimodal approach. Regional techniques (e.g., intraar-
degree of pain; for example, ears stiffly backward can indi- ticular, epidural, perineural) further facilitate this multimodal
cate a greater degree of pain versus none if ears face forward. approach to analgesia and minimize the adverse effects (e.g.,
Although this was developed in horses undergoing castration, gastrointestinal stasis) associated with systemic medications.
it may have applicability or provide a good adjunctive assess- Although foals are similarly deserving of a multimodal
ment tool in horses with other conditions.19 Photographic approach in treating pain, the safety of NSAIDs (e.g., gas-
examples of horses demonstrating facial expressions of pain trointestinal ulcers) and the cardiovascular side effects of
are included in Fig. 3.4. α2-adrenergic agents when used at doses similar to the adult
Note that the majority of these pain scales are targeted horse deserve consideration. Conversely, some regional tech-
toward acute or nociceptive pain in adult horses. Assessment niques (e.g., lumbosacral epidural) are more feasible, and cer-
of chronic pain may require additional and different tools (e.g., tain drugs (e.g., opioids) may not be limited by behavioral side
force plate, gait analysis), owner or trainer input, and greater effects to the same degree as in adult horses.
reliance on response to therapy. Similarly, the authors are not The goal in treating pain early and using a multimodal
aware of ethograms or pain scales for foals, but based on the approach is to minimize development of a chronic condition
author’s impressions and in talking with veterinarians who that can be more challenging to evaluate and treat. The subse-
routinely manage foals, additional behavioral signs should be quent text includes information on pain treatment modalities
considered. For example, grinding of the teeth is commonly and medications that the veterinarian may select to best man-
associated with pain from stomach ulcers in foals. Addition- age individual equine patients.
ally, unwillingness to lie down despite buckling the front limbs,
stamping hind feet toward the belly, and lying down in lateral Y DRUGS USED TO TREAT PAIN
recumbency with one or both legs cranially toward or over the
head has been associated with pain in foals. Almost all types of drugs used to treat pain in small ani-
Although methodology may need to vary based on the cir- mals have also been used in horses, although there are
cumstance, the goal of pain assessment is to provide objective, fewer controlled trials evaluating their efficacy. This may
Physiological Data Criteria Score

/12
Heart Rate (Compared to <10% increase 0
Baseline)
>11-30% increase 1
>31-50% increase 2
>50% increase 3
Respiratory Rate <10% increase 0
(Compared to
Baseline) >11-30% increase 1
>31-50% increase 2
>50% increase 3
Digestive Sounds Normal motility 0
Decreased motility 1
No motility 2
Hypermotility 3
Rectal Temperature <0.5°C variation 0
(Compared
to Baseline) <1°C variation 1
<2°C variation 2
>2°C variation 3
Response To Interaction Criteria Score
/6
Interactive Behavior Pays attention to people 0
Exaggerated response to auditory stimuli 1
Excessive to aggressive response to auditory stimuli 2
Stupor, prostration, no response to auditory stimuli 3
Response To Palpation Of No reaction to palpation 0
Painful Area Mild reaction to palpation 1
Resistance to palpation 2
Violent reaction to palpation 3
Behavior Criteria Score
/21
Appearance (reluctance to Bright, lowered head and ears, no reluctance to move 0
move, restlessness, agitation, Bright, alert, occasional head movement, no reluctance to move 1
anxiety) Restless, pricked up ears, abnormal facial expressions, dilated 2
pupils
Excited, continuous body movements, abnormal facial expression 3
Sweating No obvious signs of sweat 0
Damp to the touch 1
Wet to the touch, beads of sweat apparent over body 2
Excessive sweating, beads of sweat running off the animal 3
Kicking At Abdomen Quietly standing, no kicking 0
Kicking at abdomen 1 - 2 times/5 mins 1
Kicking at abdomen 3 - 4 times/5 mins 2
Kicking at abdomen >5 times/5 mins, intermittent attempts to roll 3
Pawing On Floor (includes Quietly standing, no pawing 0
pointing or hanging limb) Occasionally pawing (1 - 2 times/5 mins) 1
Frequent pawing (3 - 4 times/5 mins) 2
Excessive pawing (>5 times/5 mins) 3
Posture (weight distribution Stands quietly, normal walk 0
and comfort) Occasional weight shift, slight muscle tremors 1
Non-weight bearing, abnormal weight distribution 2
Analgesic posture, attempts to urinate, prostration, muscle tremors 3
Head Movement (lateral or No evidence of discomfort, head straight ahead mostly 0
vertical head movements) Intermittent head movement, looking at flanks or lip curl 1 - 2 times 1
/5 mins
Intermittent, rapid head movement, looking at flanks or lip curl >5 2
times/5 mins
Continuous head movements, looking at flanks or lip curl >5 3
times/5 mins
Appetite Eats hay readily 0
Hesitates to eat hay 1
Little interest in eating hay, takes hay but doesn’t chew or swallow 2
Neither shows interest in nor eats hay 3
Total CPS 39
FIG. 3.2 Multifactorial numeric rating composite pain scale for evaluating pain in horses. (Reprinted with
permission from Elsevier. Bussières G, Jacques C, Troncy E, et al. Development of a composite orthopedic
pain scale in horses. Res Vet Sci. 2008; 85:294.)
FIG. 3.3 A multidimensional, nonvalidated pain scale that is used at the authors’ institution.
A B
FIG. 3.4 Examples of equids demonstrating facial expressions of pain. (A) Note the horse has partially
closed eyes and drawn back upper lip. (B) The donkey shows ears pointed back and strained nostrils.
be one reason why there are limited validated pharmaco- housekeeping functions in the body and play a significant role
logic options for analgesia in horses compared with those in the development of pain, inflammation, and fever.
for dogs and cats. Practically, there may also be limitations There are at least two isoforms of cyclooxygenase, and the
to the use of certain drugs in horses with respect to drug most important ones are COX-1 and COX-2. COX-1 is con-
volume or cost. As in any species, analgesic drugs also have sidered constitutively expressed in most body tissues and plays
potential adverse effects that may limit their use. Pharma- an important role in maintaining renal blood flow, protecting
cologic approaches tend to provide the greatest benefit with gastric mucosa, and facilitating platelet aggregation (among
fewer or less severe adverse effects when drugs are selected other processes). The COX-2 isoform has a greater role in the
for a specific purpose, used preemptively, or as a part of a development of inflammation and pain, and traditionally thera-
multimodal approach, and the dose is scaled to the severity peutic effects of NSAIDs are attributed to inhibition of COX-2
of pain. effects.35,36 However, COX-2 can also have housekeeping func-
Classes of drugs most commonly used in the horse include tions in the gastrointestinal tract and kidney, with greater effects
antiinflammatories, opioids, α2-adrenergic agonists, and local in diseased states,37 and the traditional absolute separation into
anesthetics. There are, however, several additional drugs that constitutive with respect to COX-1 and inducible with respect
have a place in equine pain management, and these have been to COX-2 is an oversimplification of the roles of the COX iso-
included here. Greater detail about some of these drugs may forms.38,39 The existence of a COX-3 isoform, originally dis-
be found in Chapter 2 and numerous additional resources.24-26 covered as a variant of COX-1 in dogs, is reported in canine,
Dosing information is provided in Table 3.1. rodent, and human literature.40 COX-3 is the purported target
of acetaminophen (paracetamol), although considerable debate
Antiinflammatory Drugs exists regarding this topic.41,42 Whether a COX-3 isoform exists
Antiinflammatory drugs used in horses include cortico- in horses is unknown. Regardless, important species differences
steroids and NSAIDs. They are often the first-line choice in exist in the expression of different COX isoforms in various tis-
the management of pain related to inflammatory conditions sues, and extrapolation of what works in a dog or a human is not
(e.g., synovitis and osteoarthritis)27-29 and are administered uniformly applicable to the horse.43,44
by various routes, including systemically, intraarticularly, and The most common adverse effects associated with blocking
topically.30-32 Generally, NSAIDs are the most commonly used the COX pathways are seen in the gastrointestinal and renal
drugs in horses.33 They are readily available and relatively systems. In horses gastric ulceration, right dorsal ulcerative
inexpensive and do not require precise record keeping. colitis, and renal papillary/crest necrosis are reported with
Corticosteroids act on the enzyme phospholipase A2 to NSAID use.45-47 Renal effects may be worsened by concurrent
prevent the breakdown of membrane phospholipids to arachi- dehydration.48 The reader should be aware that although the
donic acid, which is the precursor to inflammatory prostaglan- practice of combining multiple NSAIDs or corticosteroids and
dins and leukotrienes.26 NSAIDs act to block cyclooxygenase NSAIDs may result in increased analgesia, this practice is also
(COX), the enzyme that produces prostaglandins from arachi- associated with increased frequency and severity of adverse
donic acid.34 Prostaglandins and leukotrienes have important effects.49-52 In circumstances in which pain is best managed by
TABLE 3.1 Drugs Used for Analgesia in Horses
Drug Route Dose Comments

NONSTEROIDAL ANTIINFLAMMATORY DRUGS
Phenylbutazone28 IV, PO 2.2–4.4 mg/kg q12–24 h Lower doses suggested for chronic use
Flunixin meglumine230 IV, PO 1.1 mg/kg q 12–24 h IM route on label but not recommended
because of potential for local tissue
irritation
Ketoprofen28,231 IV 1.1–2.2 mg/kg q 12–24 h —
Firocoxib57 IV 0.09 mg/kg q 24 h Nonaqueous solution should not be
mixed with aqueous flush solutions in
IV lines
PO Loading dose: 0.3 mg/kg —
Then: 0.1 mg/kg q 24 h
Meloxicam55,56 PO 0.6 mg/kg q 24 h Increased dose frequency may be re-
quired for foals (q 12 h)
Diclofenac32 Topical 1% liposomal cream applied to —
bare skin over area of interest
OPIOIDS
Can be combined with acepromazine, α2-adrenergic agonists. Dilute epidural dose to desired volume.
Butorphanol62,63,179,232-235 IV, IM, SC 0.01–0.22 mg/kg Common clinically used doses are lower
than reported analgesic doses
IV CRI CRI: 0.013–0.025 mg/kg/h Loading dose recommended
Nalbuphine236 IV, IM 0.02–0.15 mg/kg —
Buprenorphine83,237-239 IV, sublingual 0.005–0.01 mg/kg —
Epidural 0.005 mg/kg —
Morphine 87-89,91,93,240,241 IV, IM 0.05–0.2 mg/kg —
IV CRI 0.1 mg/kg/h Loading dose recommended
Epidural 0.1–0.2 mg/kg —
Intraarticular 0.1–0.2 mg/kg —
Fentanyl81,201,242 IV CRI Loading dose: 0.005 mg/kg Less effective analgesic in horses com-
CRI: 0.006 mg/kg/h pared with other species
Transdermal 20- to 30-mg adhesive patch As an adjunct to other analgesics
applied to bare skin per ap-
proximately 500-kg adult horse
Remifentanil 240,243,244 IV CRI Loading dose: 0.0005 mg/kg As an adjunct to general anesthesia
CRI: 0.002–0.006 mg/kg/h
Methadone133,245,246 IV, IM, PO 0.05–0.15 mg/kg —
Epidural 0.1 mg/kg —
Meperidine (pethi- IV, IM 1 mg/kg —
dine)62,247-249 Epidural 0.3–0.8 mg/kg —
Hydromorphone 250 Epidural 0.04 mg/kg —
α2-ADRENERGIC AGONISTS
Doses provided will cause sedation. Lower doses may be effective for analgesia, especially in combination with opioids.
CRI doses are used for standing procedures or as an adjunct to general anesthesia.
Xylazine251,252-255 IV, IM 0.2–1.1 mg/kg —
IV CRI 0.016–0.69 mg/kg/h —
Epidural 0.17–0.22 mg/kg Hind limb weakness/recumbency is a
possible side effect
Detomidine 93,244,252,256-258 IV, IM 0.01–0.03 mg/kg —
IV CRI 0.005–0.02 mg/kg/h —
Epidural 0.015–0.03 mg/kg Systemic absorption is likely
Romifidine235,252,259,260 IV, IM 0.02–0.08 mg/kg —
IV CRI 0.03–0.04 mg/kg/h —
Epidural 0.03–0.06 mg/kg —
TABLE 3.1 Drugs Used for Analgesia in Horses—cont’d
Drug Route Dose Comments

Dexmedetomi- IV, IM 0.003–0.005 mg/kg —
dine240,241,261,262 IV CRI 0.001–0.008 mg/kg/h —
Medetomidine251,263,264 IV, IM 0.007–0.01 mg/kg —
IV CRI 0.003–0.005 mg/kg/h —
LOCAL ANESTHETICS
Epidural doses may be combined with opioids or α2-adrenergic agonists; recommended volume when local anesthetics are used
is not to exceed 5–7 mL in an adult horse.
Lidocaine133,247,265,266 IV CRI Loading dose: 1.3–1.5 mg/kg Loading dose given over 10–20 min
CRI: 0.05 mg/kg/min
Sacrococcygeal 0.2–0.35 mg/kg —
epidural
Mepivacaine267,268 Sacrococcygeal 0.16–0.2 mg/kg —
epidural
Ropivacaine269,270 Sacrococcygeal 0.08–0.15 mg/kg —
epidural
Bupivacaine271,272 Sacrococcygeal 0.02–0.06 mg/kg —
epidural
OTHER DRUGS
Ketamine150-152 IV CRI 0.4–0.8 mg/kg/h In conscious horses higher doses can be
used as an adjunct to general anes-
thesia
Gabapentin160,161 IV, PO 5–20 mg/kg q 8–12 h Low oral bioavailability; higher dosing
may be needed; titrate dose to effect
Methocarbamol236 PO 40–60 mg/kg q 12–24 h —
N-butylscopolamine179 IV 0.3 mg/kg Lower doses may achieve desired clinical
effect

IV, Intravenously; PO, orally; IM, intramuscularly; SC, subcutaneously; CRI, constant rate infusion.
a combination of drugs within these two classes, concurrent pure μ-agonists (e.g., morphine, methadone, fentanyl), partial
use of gastrointestinal protectants is suggested. μ-agonists (e.g., buprenorphine), and κ-agonist/μ-antagonists
Most NSAIDs approved for use in horses (e.g., aspirin, phen- (e.g., butorphanol). Morphine is the prototypic μ-agonist with
ylbutazone, ketoprofen, flunixin meglumine, diclofenac) work which all other opioids are compared.59,60 Although tradition-
by inhibiting both COX-1 and COX-2. However, COX-2–selec- ally pure μ-agonist opioids are considered to provide the most
tive NSAIDs (firocoxib and meloxicam) have been developed potent analgesic effects, butorphanol is reported to be equally
for horses, with the primary goal of reducing gastrointestinal as or more effective (with potentially fewer adverse effects)
side effects,53-55 especially because NSAIDs may be used chron- than μ-agonists in the treatment of gastrointestinal pain in
ically in some horses. Meloxicam specifically may offer further horses.60-63 Opioids, especially morphine, produce profound
benefit in foals, in which traditional NSAIDs have a higher risk sedative effects when combined with α2-agonists. This is com-
of adverse effects because of prolonged clearance in foals commonly termed neuroleptanalgesia and can be useful in animals
pared with adult horses. Meloxicam is cleared more rapidly in that are refractory to analgesia or when standing interventions
foals than adults, which may result in improved tolerance to are necessary.64,65
longer treatment durations.56 Opioid use in horses is often limited by the potential for
The use of a canine chewable tablet formulation of firocoxib adverse effects. μ-Agonists in particular are known to cause
has become popular with horse owners because of low cost and excitement, agitation, and increased locomotor activity in
ease of use; however, the canine tablet has reduced bioavailabil- horses.58,66,67 This may be explained in part by the loca-
ity and reduced COX-2 inhibition in horses compared with the tion, density, and binding affinity of μ-opioid receptors in
oral equine formulation.57 Additionally, practitioners should be the equine brain.68 Although this effect is well documented,
aware that use of the canine formulation may represent extra- the clinical importance is confounded by multiple variables,
label drug use depending on their country of practice. The including potential bias in the studies because they were con-
same is true of the COX-2–selective NSAID carprofen, which is ducted using healthy, nonpainful horses. Dosages used in
licensed for dogs but has been administered to foals in place of investigational studies may also be higher than dosages used
phenylbutazone because of perceived efficacy and lower toxicity. clinically, contributing to excitatory effects.69 As mentioned
previously, coadministration with sedative drugs ameliorates
Opioids the potential excitatory effects of opioids and augments seda-
Opioids produce their effects by activating mu (μ), kappa tion.58,68 In painful horses, low to moderate doses of opioids
(κ), or delta (δ) opioid receptors.58 Available opioids include have a calming effect and in some studies are associated with
improved anesthesia recovery quality,70,71 but variability exists nervous system α2-receptors in areas of the brain that are
with respect to behavioral responses to opioids in horses. In responsible for awareness, arousal, and vigilance. Activation of
other species for which extensive research exists, differences α2-receptors in the brain and spinal cord decreases the release
have been attributed to opioid receptor polymorphisms. A of excitatory neurotransmitters and interferes with sensory
μ-opioid receptor polymorphism has recently been shown to processing and transmission, producing analgesia.94
significantly affect locomotor responses to fentanyl in adult α2-Adrenoceptor agonists are profound visceral analgesics.
horses.72 Continued research in this area may help to clarify This property is crucial in the management of moderate to
varying clinical observations regarding opioid use in this severe colic. The use of α2-adrenoceptor agonists can prevent
species. injury to both practitioner and horse and allow critical diag-
A further untoward effect of opioids is that they can delay nostic and treatment procedures to be performed. These drugs,
gastric emptying and prolong intestinal transit time. Because however, may also mask signs of clinical deterioration,95,96
of this, opioids can predispose horses to constipation and especially if higher doses or drugs with longer half-lives are
colonic impaction, because water is absorbed from the slow- administered (e.g., detomidine).97 Behavioral and possibly
moving contents of the intestinal lumen.73,74 Although it has analgesic effects may be improved when α2-adrenoceptor
been the authors’ experience that horses receiving large doses agonists are administered with opioids (e.g., butorphanol or
of opioids such as morphine can show gastrointestinal sta- morphine).63
sis necessitating passage of a nasogastric tube to relieve gas, The use of α2-adrenoceptor agonists is not without sig-
studies on the risk of colic associated with morphine use in nificant adverse effects. Clinically, the administration of α2-
horses undergoing general anesthesia are conflicting.69,75-77 agonists for the purpose of analgesia is accompanied by varying
Most show no relationship between the perioperative use of levels of sedation, which may be undesirable. α2-Adrenoceptor
morphine and gastrointestinal complications. In addition, agonists also cause peripheral vasoconstriction and subse-
pain itself may predispose horses to ileus.78,79 Although the quent baroreceptor-mediated reflex bradycardia and bradyar-
potential for adverse effects should not to be ignored, it should rhythmias (e.g., second degree atrioventricular block).98,99 The
be noted that complications are most likely when opioids are increase in afterload associated with α2-adrenoceptor agonist
used systemically at large doses. administration causes a profound reduction in cardiac out-
Experimental studies on the use of opioids in horses con- put,99-101 which may be detrimental in a horse with cardio-
tinue to emerge as potential clinical benefits of this class of vascular compromise. As the vasoconstrictive effect wanes, a
drugs are increasing recognized. Several new studies describe decrease in arterial blood pressure follows, which is caused by
the pharmacology of specific opioids in horses, but the need a decrease in central nervous system sympathetic output and
for additional evidence to support specific clinical treatment continued bradycardia.94,102 Decreases in cardiac output are
protocols is great. For example, intravenous fentanyl appears relatively independent of dose.103 In horses with severe hemo-
to be a relatively ineffective analgesic with undesirable behav- dynamic compromise (e.g., strangulating colic), the benefits of
ioral effects at the doses studied in adult horses,80,81 but it has a the use of α2-adrenoceptor agonists must be weighed carefully
sedative effect in foals at relatively low doses.82 Buprenorphine with the risk of cardiovascular collapse.
shows promise as an analgesic because of its long plasma half- Other adverse effects of α2-adrenoceptor agonists include
life in horses and its efficacy via sublingual administration.83 occasional paradoxic excitement or aggression, changes in
Reports of significant buprenorphine-induced excitement or respiratory rate and tidal volume, upper airway obstruction
increases in locomotor activity exist in adult horses and foals, caused by relaxation of pharyngeal muscles, hyperglycemia,
however, even when the drug is given in combination with a increased urine production, and immediate and pronounced
sedative.84-86 The use of systemic opioids in horses will, there- decreases in gastrointestinal tone and motility that can last
fore, continue to be challenged by the need for appropriate well beyond the duration of the drug.104-110 These effects are
case selection and dose titration such that clinical benefits are dose dependent but can be related to postoperative ileus and
achieved without undesired effects. colic.111 Increased urine production could exacerbate dehy-
Systemic adverse effects can be mitigated via the use of dration in a debilitated horse if supplemental fluids are not
alternative routes of administration. Routes that have been provided. Tachypnea is sometimes observed when febrile
studied in horses with promising results include intraarticular, horses receive any of this class of drugs.
transdermal, perineural, and epidural administration. Intraar- α2-Adrenoceptor agonists can be administered as bolus
ticular morphine, for example, has a profound and lasting doses or via constant rate infusion.110 Like opioids, they
analgesic and antiinflammatory effect and produces a more can also be administered intraarticularly, perineurally,
significant reduction in lameness than intravenous morphine and epidurally. Intraarticular use of α2-adrenoceptor ago-
in horses with synovitis.87-90 Epidural morphine provides nists provides analgesia by an undetermined mechanism;
useful and prolonged analgesia for a variety of surgical pro- regional and systemic effects (from drug absorption), how-
cedures,91-93 although dose-dependent decreases in gastroin- ever, are possible.112 The potential for chondrotoxic effects
testinal transit time are reported.79,91 of α2-adrenoceptor agonists are currently under investiga-
tion, with early reports indicating the potential for chon-
α2-Adrenoreceptor Agonists drotoxicity with some but not all drugs in this class.113,114
α2-Adrenoreceptor agonists (e.g., xylazine, detomidine, romif- α2-Adrenoceptor agonists have been shown to improve dura-
idine, medetomidine, dexmedetomidine) produce sedation, tion of analgesia provided by perineural local anesthetics.115
muscle relaxation, and analgesia via activation of central and Epidural administration of α2-adrenoceptor agonists pro-
peripheral α2-receptors. Although drug effects are broadly vides beneficial analgesia for surgical procedures.93,116 Some
the same, individual differences exist with respect to α1:α2- α2-adrenoceptor agonists (e.g., detomidine) demonstrate
receptor selectivity, chemical structure, drug metabolism, systemic effects, however, because they are rapidly absorbed
and elimination. Sedation is attributed to activation of central from the epidural space.116,117
The effects of α2-adrenoceptor agonists can be reversed the local anesthetic effect has worn off. Local anesthetic drugs
with α2-adrenoceptor antagonists (e.g., atipamezole, tolazo- can also cause respiratory paralysis when administered by
line, yohimbine, idazoxan).111,118 When using these reversal epidural or spinal (subarachnoid) routes. Although unlikely
agents, all α2 effects, including analgesia, are abolished. If unless excessive drug volume is administered inadvertently,
α2-adrenoceptor antagonists are used in a situation in which the migration of local anesthetic cranially to the cervical
pain is anticipated, the practitioner should plan to provide region can paralyze the diaphragm, resulting in hypoventila-
analgesia by an alternate method. The use of α2-adrenoceptor tion and apnea. To avoid these adverse effects of epidural local
antagonists has been associated with significant adverse effects anesthetics, the authors recommend these drugs generally not
in horses, including behavioral changes, tachycardia, hypoten- be placed in epidural catheters and that the volume of local
sion, and death. Adverse effects are more often associated with anesthetic drug when using the caudal epidural space be lim-
high doses and rapid (e.g., intravenous) administration.119 ited to 5 to 7 mL for an adult horse.
Assessment of peripheral α2-adrenoceptor antagonists that Intraarticular use of local anesthetics is common in equine
retain beneficial central effects and reduce the negative cardio- practice for the diagnosis and management of lameness and
vascular effects of α2-adrenoceptor agonists is ongoing.120,121 surgery of the joints. Of concern is the potential for local anes-
thetic-induced chondrotoxicity, which has been clinically rec-
Local Anesthetics ognized in humans with the use of bupivacaine.134 An in vitro
Local anesthetics (e.g., lidocaine, mepivacaine, bupivacaine, investigation in the horse showed chondrotoxicity associated
ropivacaine) are frequently used alone or in combination with with bupivacaine, lidocaine, and mepivacaine, with mepi-
other analgesic drugs to produce loss of sensation. They may vacaine considered the least toxic to cartilage and safest for
be administered topically, regionally (perineurally and epi- clinical use.135 A subsequent in vitro human study showed that
durally), or systemically. Analgesia results from a blockade chondrotoxic effects were worse in arthritic joints.136 In con-
of sodium ion channels, which prevents the initiation and trast, a single injection of bupivacaine and lidocaine produced
conduction of electrical activity (action potentials) in small- no increases in collagen degradation biomarkers in an in vivo
diameter (C, Aδ) sensory nerve fibers. Larger (clinical) doses study in healthy horses.137 More data are necessary before the
of local anesthetics also block conduction in large fibers (Aβ), issue is clarified in horses, and practitioners should weigh
and when administered at certain sites (e.g., epidural, perineu- potential risks with benefits in individual clinical scenarios.
ral to a mixed nerve) produce a loss of motor function and
result in temporary motor paralysis. Ketamine
The local anesthetic lidocaine when administered intrave- Ketamine is commonly used as an anesthetic induction and
nously produces mild central nervous depression and has anti- maintenance agent in horses and also possesses important
arrhythmic, antiinflammatory, free radical scavenging, and analgesic properties. NMDA receptor activation is critical
gastrointestinal promotility effects.122-127 It also provides anal- to the development of hyperalgesia and central sensitization
gesia, decreases the requirement for inhalant anesthetics, and mediated through interaction with a number of other recep-
potentiates the analgesic actions of opioids or α2-adrenoceptor tors.138,139 Ketamine’s antagonism at this receptor helps miti-
agonists.122,123,128,129 Because of variable cardiac toxicity, gate these effects. Analgesia may also be partly mediated via
administration of other local anesthetic agents by this route the monoaminergic pathway through ketamine-induced
is currently not recommended. Lidocaine produces minimal release of norepinephrine, dopamine, and serotonin.138
cardiovascular and respiratory effects in otherwise normal, At anesthetic doses, ketamine increases heart rate, cardiac
healthy horses but can decrease cardiac output, arterial blood output, and arterial blood pressure in horses.140 When used
pressure, and heart rate when administered intravenously with a goal of preventing central sensitization as an adjunct to
because of decreases in central nervous system sympathetic inhalant anesthesia, ketamine infusion both reduces inhalant
output, myocardial contractile force, and venous return.123,128 dose requirement and improves cardiac output.141 Beneficial
Lidocaine infusion does not improve cardiovascular function cardiovascular effects are attributed to increased circulating
in anesthetized horses despite decreases in inhalant anesthetic catecholamines, even though ketamine in isolation is a direct
dose, and in certain circumstances it may predispose horses myocardial depressant.142,143 Nonsystemic routes of ketamine
to a poorer quality of recovery from general anesthesia.129-131 administration have also been used with some success. For
Significant differences in metabolism, elimination, and the example, short-term local anesthesia is observed when used
potential to produce central nervous system toxicity (disori- perineurally in horses.144 Similarly when administered epi-
entation, ataxia, and seizures) are seen among different local durally, ketamine produces analgesia, but evidence of local-
anesthetics.125 Horses appear to be more sensitive to the neu- ized neuronal toxicity, especially with chronic use, limits its
rotoxic effects than some other species, with large doses pro- use in clinical patients.145,146
ducing central nervous stimulation typified by nervousness, Behavioral side effects associated with ketamine use in
agitation, sedation, ataxia, and collapse.132 Seizures have also horses must be considered. In humans, ketamine produces
been observed by the authors in clinical patients. Although hallucinations138; in horses, the potential for excitement or
less likely to occur in full-size adult horses, toxic doses may delirium during ketamine use in anesthesia is a reality mini-
also be reached when these drugs are administered locally or mized by the provision of other drugs (e.g., α2-adrenoceptor
regionally. agonists).140,147 Subanesthetic doses of ketamine used to pre-
Local anesthetics can be administered epidurally to decrease vent central sensitization do not seem to be associated with
the need for additional analgesics.133 However, as mentioned adverse behavioral effects in people, dogs, and cats.148,149 In
previously, they have the potential to produce a loss of motor horses, low-dose infusions can be used with minimal to no
function (paralysis), which can become problematic in an behavioral effects.150 Evidence of antinociceptive effect with
animal as large as a horse. The horse may injures itself while this dosing of ketamine in horses is conflicting and clinical
unable to control its limbs or may becomes recumbent until data are sparse, but subanesthetic infusions appear to be an
effective adjunct for the management of laminitic pain.150-153 in horses in multiple research models and caused excitement
Prolonged infusions of ketamine lead to an increase in gastro- with increases in dose.171-173 In clinical patients, tramadol was
intestinal transit time and decreased fecal output in healthy mildly effective at reducing pain in laminitic horses in multi-
horses,154 but similar data from clinical patients are lacking. modal approaches to pain control,151, 174 and no adverse effects
were seen when it was used as an adjunct to acepromazine,
Magnesium detomidine, ketamine, diazepam, and flunixin meglumine for
Like ketamine, magnesium owes its analgesic effects largely castration.175 Further study is necessary to determine the clin-
to its NMDA receptor blockade. Magnesium is also a calcium ical utility of tramadol in horses, but it is currently not promis-
channel blocker, and although this attribute has historically ing as a sole analgesic in this species.
been used in the treatment of hypertension and arrhythmias,
it is also an important mechanism by which systemic admin- Soluble Epoxide Hydrolase Inhibitors
istration of magnesium is used to help treat pain.155 Although Oxidative metabolism of polyunsaturated fatty acids is a
magnesium has not been studied as an analgesic in horses, it critical step in the production of mediators important to the
has been extensively studied in human medicine. Some data development of inflammation and pain associated with tis-
are conflicting, but overall it appears that magnesium reduces sue damage. The most well-known group of drugs blocking
postoperative pain and opioid requirements after a variety of this process is the NSAIDs, which prevent arachidonic acid
surgical procedures.156,157 In an experimental setting, mag- metabolism via COX inhibition, as discussed earlier. However,
nesium also potentiates analgesia provided by morphine and the COX pathway is only part of a much more complex set of
delays the development of morphine tolerance.158 Adverse processes responsible for inflammatory and neuropathic pain.
effects appear to be minimal with appropriate dosing but Recently inhibition of the cytochrome P450–mediated
include hypotension, bradycardia, and sedation.157 transformation of polyunsaturated fatty acids into epoxides
has been explored as a potential analgesic treatment for horses
Anticonvulsants with laminitis.176 Soluble epoxide hydrolase activity measured
Gabapentin is an anticonvulsant drug that also has analgesic in the digital laminae is increased in laminitic horses, and
effects, which is likely caused by its interaction with the α2δ- experimental treatment with the soluble epoxide hydrolase
subunit on voltage-gated calcium channels, which is upregu- inhibitor t-TUCB provided moderate improvement in clini-
lated in chronic and neuropathic pain. In humans, gabapentin cal signs (e.g., limb lifting) and pain scores in a small group of
is considered a first-line drug for the treatment of neuropathic laminitic horses in a recent clinical trial.177 The novel nature
pain.159 It has low oral bioavailability in horses.160 Oral gaba- of this treatment means that further research is needed before
pentin given for 2 weeks at common clinical dosages (5–10 widespread use is adopted, but it represents a promising addi-
mg/kg every 8 hours) failed to reduce the lameness level of tion to a multimodal approach to pain control in horses with
chronically lame horses compared with placebo treatment.161 laminitis.
However, a relatively low oral dose appeared effective for treat-
ing neuropathic pain in a horse in one case report.162 Acepromazine
When given intravenously, 20 mg/kg of gabapentin was Acepromazine is a phenothiazine tranquilizer that does not
associated only with very mild sedation,160 suggesting this have inherent analgesic properties.178,179 As such, it should not
higher dosage could be used without significant adverse be used as a sole agent with the intent to provide analgesia, nor
effects. In humans, appropriate dose titration may take several should its calming effects be interpreted as analgesic efficacy.
weeks to achieve.163 More clinical data are necessary to deter- Although not licensed for such use, acepromazine is used by
mine whether this is a factor in the efficacy of gabapentin in veterinarians in combination with α2-adrenoceptor agonists
horses. The primary dose-limiting adverse effect of gabapentin or opioids to augment sedation. The literature also suggests
in humans is somnolence.163 that acepromazine administration improves undesired loco-
Pregabalin is a similar drug with the same mechanism motor activity associated with the use of opioids in horses.58
of action used as both an anticonvulsant and analgesic in
humans. When given via nasogastric tube to healthy horses, N-Butylscopolamine
bioavailability was high and sedation was the most common Butylscopolamine is an anticholinergic and antispasmodic
adverse effect.164 Use of pregabalin in equine clinical patients drug that has a short duration of effect on gastrointestinal pain
has not been reported. and is used to treat spasmodic colic,179-181 and it can be given in
combination with other analgesic drugs. Because its duration
Tramadol of action is very short (20–30 minutes), a perceived benefit is
Tramadol is a synthetic weak μ-opioid receptor agonist and that it will not mask pain from a deteriorating, nonspasmodic
serotonin and norepinephrine reuptake inhibitor. Tramadol colic while still providing relief to horses with uncomplicated
is not a controlled drug in many countries. There are several colic pain. It should be noted that the anticholinergic effect of
metabolites of tramadol, but O-desmethyl-tramadol (M1) is this drug will increase the heart rate, which may complicate
considered the primary analgesic metabolite because it has physiologic assessment of pain.
increased affinity for the μ-receptor compared with the parent
compound.165,166 Methocarbamol
In pharmacokinetic studies, horses show wide individ- Methocarbamol is a skeletal muscle relaxant that has been
ual variability in production of M1, and this metabolite has used in horses for several years to treat discomfort associated
either not been detectable or measured in very low concen- with muscle spasms, and it is moderately orally bioavailable
trations.167-170 It is possible that horses efficiently glucuroni- in horses.182 Although there is considerable anecdotal evi-
date the M1 metabolite, affecting M1 concentrations.167 dence of its use to treat equine back pain, scientific data are
Regardless, tramadol did not have an antinociceptive effect lacking.
Bisphosphonates
Tiludronate and clodronate are bisphosphonate drugs used to
treat bone-related pain in horses. Bisphosphonates distribute
primarily to bone and inhibit bone resorption primarily via
negative effects on osteoclasts and macrophages.183,184 These
drugs are given intravenously and intramuscularly, respec-
tively, with a duration of effect of several months.
Small clinical studies with tiludronate have shown some
improvement in lameness caused by navicular disease and distal
hock arthritis,185 and a larger double-blind, placebo-controlled
trial for hock arthritis also demonstrated this drug’s efficacy.186
Tiludronate has also proven efficacious in the treatment of tho-
racolumbar vertebral pain in horses.187 Although it has been
administered during regional limb perfusion, its safety and the
efficacy of this technique are not known.188 Colic has been associ-
ated with the use of tiludronate in horses,185 and varying degrees
of renal damage have been demonstrated in humans with the use
of different bisphosphonates.189 Extensive clinical data regarding
renal toxicity in horses do not exist. However, the potential for
adverse effects should be strongly considered in horses before FIG. 3.5 An epidural catheter secured with a bandage, which prevents
treatment, because anecdotal reports of renal damage are increas- debris (such as straw or shavings) from contaminating the catheter.
ing. The practice of pretreating with flunixin meglumine to pre-
vent tiludronate-associated colic signs is discouraged because of
the concern for compounding nephrotoxicity.
Autologous Conditioned Serum (Interleukin-1

Receptor Antagonist Protein)
Interleukin-1 receptor antagonist protein (IRAP) is an antiin-
flammatory cytokine used in the treatment of equine osteo-
arthritis. Whole blood is collected and incubated with beads
that enhance the production of IRAP.190 Serum is then sepa-
rated and injected intraarticularly. Clinically, IRAP improves
lameness scores in horses with osteoarthritis compared with
placebo.191 Because the product is autologous and includes
no drugs, it can be used in performance horses before
competition.
Y SPECIFIC ANALGESIC TECHNIQUES

FIG. 3.6 Components of a commercially available epidural catheter kit,
Epidural Catheters including scalpel blade, catheter, connector, filter, plastic loss of resistance
Epidural catheters (Fig. 3.5) can be placed in horses to pro- syringe, and Tuohy needle for placement. (Photo courtesy Gregg Griffen-
vide a safe and efficient way to administer repeated doses of hagen, DVM, DACVAA.)
analgesic drugs (e.g., opioids, α2-adrenoceptor agonists) into
the epidural space. Epidural catheter kits that can be used in This technique involves continuous infusion (or intermittent,
horses are available commercially (Fig. 3.6). These catheters low-volume boluses) of local anesthetics in catheters placed
can be maintained successfully for several days to weeks. In adjacent to peripheral nerves. A significant advantage of this
clinical cases, patient-related complications (e.g., inflamma- technique is the ability to reduce or discontinue systemi-
tion at the catheter insertion site) appear to be very infrequent cally administered analgesics, thus avoiding the systemic side
when proper aseptic technique is used in the placement and effects of those drugs.194-197
maintenance of epidural catheters. The most common cath- In horses, this technique has been developed for use in the
eter-related complications in horses include dislodgement of distal limb, in which a perineural catheter can be placed in
the catheter or filter, loss of patency of the catheter, or catheter a standing, sedated patient and maintained under a bandage
leakage.192 Indwelling catheters do cause epidural inflamma- thereafter (Fig. 3.7). Possible complications include inadver-
tion and fibrosis, which may be responsible for loss of patency tent vascular or synovial structure puncture, local infection,
over time.192,193 These issues do not preclude replacement with nerve injury, and swelling or hematoma. Complications can
a new catheter but may make it more challenging. be avoided by adhering to proper landmarks and using strict
aseptic technique.194,198
Perineural Catheters
Continuous peripheral nerve block via the use of perineural Topical and Transdermal Drug Administration
catheters has been successfully used in human medicine for Topical administration of analgesic drugs offers advantages
a variety of applications, including postoperative analgesia. to systemic drug administration. Application is directed over
has not been associated with untoward side effects, and there
are promising reports of clinical efficacy in horses in pain.201
Pharmacologic data, however, show widely variable absorp-
tion in both adult horses and foals, in which effective plasma
concentrations were not reached in all individuals.202,203
Several factors may affect patch efficacy, including improper
patch placement and premature patch removal. Conditions
under which the patch is applied (e.g., whether hair is clipped
and the area cleaned) or anatomic location of the patch on the
horse might also affect absorption. Location-dependent dif-
ferences in absorption could be related to differences in the
thickness of the stratum corneum or differences in cutaneous
blood flow. In vitro work with horse skin suggests that absorp-
tion through the groin or thorax is superior to absorption
through skin on the distal limb.204
Y COMPLEMENTARY THERAPIES
Complementary techniques may play an important role in mul-
timodal analgesic management of horses. Acupuncture, chiro-
practic manipulations, massage, and extracorporeal shock wave
therapy have been adopted and successfully used by equine vet-
erinarians.205 At their introduction, these therapies were used
in horses with primarily anecdotal evidence, but scientific data
A B on these modalities are emerging, especially as they become
increasingly popular with horse owners.
FIG. 3.7 (A) Anatomic diagram showing proper placement of a distal Acupuncture
limb perineural catheter in the horse, 5 cm distal to the accessory car- Acupuncture is purported to act by restoration of energy flow
pal bone (ACB) on the medial aspect of the limb, and 7 cm distal to ACB via stimulation of certain points on channels or “meridians”
on the lateral aspect. Dotted lines between points A and B and D and E within the body.206 Points can be stimulated with needles
represent the intended path for subcutaneous tunneling of the catheter. alone, injected substances, or electrically (“electroacupunc-
Dashed lines between points B and C and E and F represent the intended ture”).207 Modern scientific research has shown that analge-
path for the subfascial placement of the catheter, ending distal to the com- sia is produced by the stimulation of specific (acupuncture)
municating branch (cb) between the medial and lateral palmar nerves and points and not produced by similar stimulation of other points
proximal to the proximal sesamoid bones (PSB). (B) Perineural catheter on the body.208 The analgesic effect results from modulation of
secured in place on the lateral aspect of the left front limb of a horse. (Re- nociceptive input at the level of the dorsal horn of the spinal
printed with permission from Elsevier. Driessen B, Scandella M, Zarucco cord through activation of antinociceptive pathways and the
L. Development of a technique for continuous perineural blockade of the release of endogenous opioids.209 Acupuncture is an appeal-
palmar nerves in the distal equine thoracic limb. Vet Anaesth Analg. 2008; ing modality because of its relative safety and lack of systemic
35:432.) drug levels, which allows its use in performance horses during
competition.
the desired site of action such that the dose (and therefore In horses, acupuncture and electroacupuncture have posi-
side effects) may be reduced. The NSAID diclofenac is avail- tive effects on endorphin release and cutaneous analgesia.207,210
able in the United States in a liposomal formulation that has Electroacupuncture has also been used to increase pain thresh-
been shown to reduce clinical signs of lameness in horses with old in an experimental rectal distention model.211 Clinical
osteoarthritis, providing beneficial disease-modifying effects results, however, have been inconsistent. In one study, elec-
compared with systemically administered phenylbutazone.199 troacupuncture may have provided clinical improvement in
This equine formulation is not available worldwide, and the horses with chronic lameness, but differences from controls
use of topical diclofenac products formulated for humans has were not significant.212 In a more recent study of naturally
thus been adopted in many places. These formulations, how- occurring palmar heel pain, acupuncture failed to consistently
ever, do not offer similar absorption and efficacy, which is affect pain in those horses.213 Further research into the use of
likely caused by differences between human and equine skin acupuncture as a clinical modality is needed to define which
for which these products were not designed.200 conditions might benefit the most from this treatment.
Transdermal drug administration offers a method for
continuously delivering systemic drugs over several hours or Extracorporeal Shock Wave Therapy
days. This is especially beneficial for drugs with a short dura- Extracorporeal shock wave therapy is used to treat a variety
tion of effect, such that multiple bolus doses can be avoided. of musculoskeletal injuries in horses, including osteoarthri-
The opioid fentanyl, for example, is widely available as a trans- tis, back pain, stress fractures, tendonitis, and desmitis.214
dermal patch designed to provide controlled fentanyl release Although the exact mechanism of action is not known, the
for 72 hours. Intravenous administration of fentanyl has been basic principle is that when focused, pulsed, high-energy
associated with adverse behavioral effects and questionable waves are applied to the injured area, they lead to neovascu-
analgesic efficacy in horses. In contrast, transdermal fentanyl larization and tissue remodeling.214,215 In some studies, shock
wave therapy produced acute local analgesia for 48 to 72 hours showing benefits of many different drugs and nontraditional
after treatment,216,217 which has raised concern about poten- analgesic techniques. In addition, the importance of treating
tial catastrophic injury in performance horses subjected to pain and the use of multimodal techniques is more and more
work after minor injury and subsequent treatment. However, widely accepted. Although pain management in the horse
in further studies with specific lesions, shock wave therapy did continues to be challenging, the increasing availability of
not reduce lameness in the immediate posttreatment period, pharmacologic and complementary options provides a reason
and its acute analgesic effect in these cases has been ques- for optimism.
tioned.15,218 Nevertheless, shock wave remains a viable poten-
tial adjunct therapy in a multimodal approach to analgesia. REFERENCES
Chiropractic Manipulations 1. Merskey HR, Bogduk N. Classification of chronic pain, descrip-
tions of chronic pain syndromes and definitions of pain terms.
Chiropractic manipulations rely on “high-velocity, low-ampli- 2nd ed. Seattle, WA: IASP Press; 1994.
tude” manual thrusts that attempt to restore normal joint 2. Muir WW, Woolf CJ. Mechanisms of pain and their therapeutic
motion and improve tissue function of the equine spine.219 implications. J Am Vet Med Assoc. 2001;219:1346.
These factors might be negatively altered by an underlying 3. Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in
pathologic condition, such as limb lameness.220 Addressing pain. Science. 2000;288:1765.
this additional potential source of pain could theoretically 4. Woolf CJ, Decosted I. Implications of recent advances in the
improve the overall clinical condition, especially if the under- understanding of pain pathophysiology for the assessment of
pain in patients. Pain Suppl. 1999;6:S141.
lying condition is also managed. Chiropractic manipulations 5. Blackshaw LA, Gabhart GF. The pharmacology of gastrointesti-
change the kinematics of horses with back pain, increase nal nociceptive pathways. Curr Opin Pharmacol. 2002;2:642.
mechanical nociceptive thresholds in healthy horses compared 6. Bueno L, Fioramonti J, Delvaux M, et al. Mediators and phar-
with controls, and reduce cervical muscle activity.219,221,222 The macology of visceral sensitivity: from basic to clinical investiga-
significance of these findings with respect to acute or chronic tions. Gastroenterology. 1997;112:1714.
pain control is unknown. 7. McMahon S, Koltzenburg M, Tracey I, et al. Wall and Melzack’s
textbook of pain. 6th ed. Philadelphia: Saunders; 2013.
Low-Level Laser Therapy 8. Almeida TF, Roizenblatt S, Tufik S. Afferent pain pathways: a
Low-level lasers (“cold lasers”) have become a popular thera- neuroanatomical review. Brain Res. 2004;1000:40.
peutic adjunct in the equine veterinary world. Cold lasers are 9. Love EJ, Taylor PM, Clark C, et al. Analgesic effect of butorpha-
nol in ponies following castration. Equine Vet J. 2009;41:552.
typically relatively low power and nonthermal, such that tis- 10. Bussières G, Jacques C, Troncy E, et al. Development of a com-
sue damage is avoided while beneficial effects are achieved. posite orthopaedic pain scale in horses. Res Vet Sci. 2008;85:294.
There is anecdotal support from performance horse owners 11. Ashley FH, Waterman-Pearson AE, Whay HR. Behavioural as-
regarding the use of laser therapy in the treatment of acute sessment of pain in horses and donkeys: application to clinical
and chronic musculoskeletal pain. Despite enthusiasm for this practice and future studies. Equine Vet J. 2005;37:565.
modality, strong scientific data supporting the use of lasers in 12. Van Loon JPAM, Back W, Hellebrekers LJ, et al. Application of
the horse are sparse.223 Evidence of laser therapy as an analge- a composite pain scale to objectively monitor horses with so-
sic, antiinflammatory, and aid to wound healing is emerging matic and visceral pain under hospital conditions. J Equine Vet
in human medicine and research models.224-226 Studies sug- Sci. 2010;30:641.
gest that possible mechanisms of action include modulation 13. Raekallio M, Taylor PM, Bennett RC. Preliminary investiga-
tions of pain and analgesia assessment in horses administered
of local inflammatory mediators (e.g., prostaglandins, tumor phenylbutazone or placebo after arthroscopic surgery. Vet Surg.
necrosis factor-α [TNF-α]) and reduction or alteration in 1997;26:150.
inflammatory cell infiltration or distribution.227 14. deGraue JC, van de Lest CH, van Weeren R, et al. Arthrogenic
A wide variety of cold lasers are marketed that can be sold lameness of the fetlock: synovial fluid markers or inflammation
directly to horse owners.228 Lasers are classified on a 1 to 4 and cartilage turnover in relation to clinical joint pain. Equine
scale by the U.S. Food and Drug Administration or by the Vet J. 2006;38:305.
International Electrotechnical Commission based on the level 15. Kirker-Head CA, Chandna VK, Agarwal RK, et al. Con-
of potential operating hazard, with higher classes being more centrations of substance P and prostaglandin E2 in synovial
powerful and also more likely to cause injury if improperly fluid of normal and abnormal joints of horses. Am J Vet Res.
operated.229 Lasers available for equine therapy come from 2000;61:714.
16. Taylor D, Hood DM, Wagner IP. Short-term effect of therapeu-
one of the two highest classes: class 3B or class 4. Class 4 lasers tic shoeing on severity of lameness in horses with chronic lami-
are typically more expensive, more powerful and more effi- nitis. Am J Vet Res. 2002;63:1629.
cient and can treat larger or deeper areas. Protocols and laser 17. Price J, Catriona S, Welsh EM, et al. Preliminary evaluation of
types used in human medicine vary across studies, and there is a behaviour-based system for assessment of post-operative pain
no scientific consensus as to the most appropriate laser or proin horses following arthroscopic surgery. Vet Anaesth Analg.
tocol for use in equine therapy. Positive results from human 2003;30:124.
studies, however, should encourage further research on laser 18. Graubner C, Gerber V, Doherr M, et al. Clinical application and
therapy in horses, which will help to clarify the place of cold reliability of a post abdominal surgery pain assessment scale
laser therapy in management of equine pain. (PASPAS) in horses. Vet J. 2011;188:178.
19. Dalla Costa E, Minero M, Lebelt D, et al. Development of the
Horse Grimace Scale (HGS) as a pain assessment tool in horses
Y SUMMARY undergoing routine castration. PLoS One. 2014;9:e92281.
20. van Loon JP, Jonckheer-Sheehy VSM, Back W, et al. Monitor-
Equine practitioners have more tools now than ever before to ing equine visceral pain with a composite pain scale score and
assess and manage pain. Detailed pain scales improve clinical correlation with survival after emergency gastrointestinal sur-
pain assessment, and promising clinical studies have emerged gery. Vet J. 2014;200:109.
21. Sutton GA, Dahan R, Turner D, et al. A behavior based pain 44. Marshall JF, Blikslager AT. The effect of nonsteroidal anti-
scale for horses with acute colic: scale construction. Vet J. inflammatory drugs on the equine intestine. Equine Vet J Suppl.
2013;196:394. 2011;39:140.
22. Taylor PM, Pascoe PJ, Mama KR. Diagnosing and treating pain 45. McConnico RS, Morgan TW, Williams CC, et al. Pathophysi-
in the horse. Where are we today? Vet Clin North Am Equine ologic effects of phenylbutazone on the right dorsal colon in
Pract. 2002;18:1. horses. Am J Vet Res. 2008;69:1496.
23. Woolf CJ. Pain: moving from symptom control toward mecha- 46. MacAllister CG, Morgan SJ, Borne AT, et al. Comparison of
nism-specific pharmacologic management. Ann Internal Med. adverse effects of phenylbutazone, flunixin meglumine, and ke-
2004;140:441. toprofen in horses. J Am Vet Med Assoc. 1993;202:71.
24. Riviere JE, Papich MG. Veterinary pharmacology and therapeu- 47. Read WK. Renal medullary crest necrosis associated with phe-
tics. 9th ed. Somerset: John Wiley & Sons; 2013. nylbutazone therapy in horses. Vet Pathol. 1983;20:662.
25. Cunningham FM. Comparative and veterinary pharmacology. 48. Gunson DE, Soma LR. Renal papillary necrosis in horses after
1st ed. Heidelberg: Springer; 2010. phenylbutazone and water deprivation. Vet Pathol. 1983;20:603.
26. Papich MG. Saunders handbook of veterinary drugs: small and 49. Keegan KG, Messer NT, Reed SK, et al. Effectiveness of admin-
large animal. 3rd ed. Philadelphia: Elsevier/Saunders; 2011. istration of phenylbutazone alone or concurrent administration
27. Owens JG, Kamerling SG, Stanton SR, et al. Effects of pretreat- of phenylbutazone and flunixin meglumine to alleviate lame-
ment with ketoprofen and phenylbutazone on experimentally ness in horses. Am J Vet Res. 2008;69:167.
induced synovitis in horses. Am J Vet Res. 1996;57:866. 50. Boston SE, Moens NMM, Kruth SA, et al. Endoscopic evalua-
28. Soma LR, Uboh CE, Maylin GM. The use of phenylbutazone in tion of the gastroduodenal mucosa to determine the safety of
the horse. J Vet Pharmacol Ther. 2012;35:1. short-term concurrent administration of meloxicam and dexa-
29. Hu HH, MacAllister CG, Payton ME, et al. Evaluation of the methasone in healthy dogs. Am J Vet Res. 2003;64:1369.
analgesic effects of phenylbutazone administered at a high or 51. Kivett L, Taintor J, Wright J. Evaluation of the safety of a combi-
low dosage in horses with chronic lameness. J Am Vet Med As- nation of oral administration of phenylbutazone and firocoxib
soc. 2005;226:414. in horses. J Vet Pharmacol Ther. 2014;37:413.
30. Soma LR, Uboh CE, Liu Y, et al. Pharmacokinetics of 52. Reed SK, Messer NT, Tessman RK, et al. Effects of phenyl
dexamethasone following intra-articular, intravenous, in- butazone alone or in combination with flunixin meglumine
tramuscular, and oral administration in horses and its ef- on blood protein concentrations in horses. Am J Vet Res.
fects on endogenous hydrocortisone. J Vet Pharmacol Ther. 2006;67:398.
2013;36:181. 53. Doucet MY, Bertone AL, Hendrickson D, et al. Comparison of
31. de Grauw JC, Visser-Meijer MC, Lashley F, et al. Intra-articular efficacy and safety of paste formulations of firocoxib and phe-
treatment with triamcinolone compared with triamcinolone nylbutazone in horses with naturally occurring osteoarthritis. J
with hyaluronate: a randomised open-label multicentre clinical Am Vet Med Assoc. 2008;232:91.
trial in 80 lame horses. Equine Vet J. 2016;48:152. 54. Orsini JA, Ryan WG, Carithers DS, et al. Evaluation of oral ad-
32. Levine DG, Epstein KL, Neelis DA, et al. Effect of topical ap- ministration of firocoxib for the management of musculoskel-
plication of 1% diclofenac sodium liposomal cream on inflam- etal pain and lameness associated with osteoarthritis in horses.
mation in healthy horses undergoing intravenous regional limb Am J Vet Res. 2012;73:664.
perfusion with amikacin sulfate. Am J Vet Res. 2009;70:1323. 55. D’Arcy-Moskwa E, Noble G, Weston L, et al. Effects of meloxi-
33. Goodrich LR, Nixon AJ. Medical treatment of osteoarthritis in cam and phenylbutazone on equine gastric mucosal permeabil-
the horse–a review. Vet J. 2006;171:51. ity. J Vet Intern Med. 2012;26:1494.
34. Lees P, May SA, McKellar QA. Pharmacology and therapeutics 56. Raidal SL, Edwards S, Pippia J, et al. Pharmacokinetics and safe-
of non-steroidal anti-inflammatory drugs in the dog and cat: 1. ty of oral administration of meloxicam to foals. J Vet Intern Med.
General pharmacology. J Small Anim Pract. 1991;32:183. 2013;27:300.
35. Brune K, Patrignani P. New insights into the use of currently 57. Holland B, Fogle C, Blikslager AT, et al. Pharmacokinetics
available non-steroidal anti-inflammatory drugs. J Pain Res. and pharmacodynamics of three formulations of firocoxib in
2015;8:105. healthy horses. J Vet Pharmacol Ther. 2015;38:249.
36. Lees P, Landoni MF, Giraudel J, et al. Pharmacodynamics 58. Combie J, Shults T, Nugent EC, et al. Pharmacology of narcotic
and pharmacokinetics of nonsteroidal anti-inflammatory analgesics in the horse: selective blockade of narcotic-induced
drugs in species of veterinary interest. J Vet Pharmacol Ther. locomotor activity. Am J Vet Res. 1981;42:716.
2004;27:479. 59. Combie J, Blake JW, Ramey BE, et al. Pharmacology of narcotic
37. DeMaria AN, Weir MR. Coxibs—beyond the GI tract: re- analgesics in the horse: quantitative detection of morphine in
nal and cardiovascular issues. J Pain Symptom Manage Suppl. equine blood and urine and logit-log transformations of this
2003;25:41. data. Am J Vet Res. 1981;42:1523.
38. Simmons DL, Botting RM, Hla T. Cyclooxygenase isozymes: 60. Combie J, Nugent TE, Tobin T. Pharmacokinetics and protein
the biology of prostaglandin synthesis and inhibition. Pharma- binding of morphine in horses. Am J Vet Res. 1983;44:870.
col Rev. 2004;56:387. 61. Kalpravidh M, Lumb WV, Wright M, et al. Effects of butorpha-
39. KuKanich B, Bidgood T, Knesl O. Clinical pharmacology of nol, flunixin, levorphanol, morphine, and xylazine in ponies.
nonsteroidal anti-inflammatory drugs in dogs. Vet Anaesth An- Am J Vet Res. 1984;45:217.
alg. 2012;39:69. 62. Muir WW, Robertson JT. Visceral analgesia: effects of xylazine,
40. Kis B, Snipes JA, Busija DW. Acetaminophen and the cyclooxy- butorphanol, meperidine, and pentazocine in horses. Am J Vet
genase-3 puzzle: sorting out facts, fictions, and uncertainties. J Res. 1985;46:2081.
Pharmacol Exp Ther. 2005;315:1. 63. Sellon DC, Roberts MC, Blikslager AT, et al. Effects of continu-
41. Botting R, Ayoub SS. COX-3 and the mechanism of action of ous rate intravenous infusion of butorphanol on physiologic
paracetamol/acetaminophen. Prostaglandins Leukot Essent Fat- and outcome variables in horses after celiotomy. J Vet Intern
ty Acids. 2005;72:85. Med. 2004;18:555.
42. Davies NM, Good RL, Roupe KA, et al. Cyclooxygenase-3: ax- 64. Robertson JT, Muir WW. A new analgesic drug combination in
iom, dogma, anomaly, enigma or splice error? Not as easy as 1, the horse. Am J Vet Res. 1983;44:1667.
2, 3. J Pharm Pharm Sci. 2004;7:217. 65. Muir WW, Skarda RT, Sheehan W. Hemodynamic and respira-
43. Radi ZA. Pathophysiology of cyclooxygenase inhibition in ani- tory effects of xylazine-morphine sulfate in horses. Am J Vet
mal models. Toxicol Pathol. 2009;37:34. Res. 1979;40:1417.
66. Mama KR, Pascoe PJ, Steffey EP. Evaluation of the interaction 88. Lindegaard C, Thomsen MH, Larsen S, et al. Analgesic efficacy
of mu and kappa opioid agonists on locomotor behavior in the of intra-articular morphine in experimentally induced radio-
horse. Can J Vet Res. 1993;57:106. carpal synovitis in horses. Vet Anaesth Analg. 2010;37:171.
67. Nugent TE, Combie JD, Weld JM, et al. Effects of enkephalins 89. van Loon JP, De Grauw JC, van Dierendonck M, et al. Intra-
versus opiates on locomotor activity of the horse. Res Commun articular opioid analgesia is effective in reducing pain and in-
Chem Pathol Pharmacol. 1982;35:405. flammation in an equine LPS induced synovitis model. Equine
68. Hellyer PW, Bai L, Supon J, et al. Comparison of opioid and al- Vet J. 2010;42:412.
pha-2 adrenergic receptor binding in horse and dog brain using 90. Lindegaard C, Frost AB, Thomsen MH, et al. Pharmacokinetics
radioligand autoradiography. Vet Anaesth Analg. 2003;30:172. of intra-articular morphine in horses with lipopolysaccharide-
69. Andersen MS, Clark L, Dyson SJ, et al. Risk factors for colic in induced synovitis. Vet Anaesth Analg. 2010;37:186.
horses after general anaesthesia for MRI or nonabdominal sur- 91. Martin-Flores M, Campoy L, Kinsley MA, et al. Analgesic and
gery: absence of evidence of effect from perianaesthetic mor- gastrointestinal effects of epidural morphine in horses after
phine. Equine Vet J. 2006;38:368. laparoscopic cryptorchidectomy under general anesthesia. Vet
70. Taylor PM. Effect of postoperative pethidine on the anaesthetic Anaesth Analg. 2014;41:430.
recovery period in the horse. Equine Vet J. 1986;18:70. 92. Van Hoogmoed LM, Galuppo LD. Laparoscopic ovariectomy
71. Clark L, Clutton RE, Blissitt KJ, et al. The effects of morphine on using the endo-GIA stapling device and endo-catch pouches
the recovery of horses from halothane anaesthesia. Vet Anaesth and evaluation of analgesic efficacy of epidural morphine sul-
Analg. 2005;35:22. fate in 10 mares. Vet Surg. 2005;34:646.
72. Wetmore L, Pascoe P, Shilo-Benjamini Y, et al. Effects of fentanyl 93. Goodrich LR, Nixon AJ, Fubini SL, et al. Epidural morphine
administration on locomotor response in horses with the G57C and detomidine decreases postoperative hindlimb lameness in
μ-opioid receptor polymorphism. Am J Vet Res. 2016;77:828. horses after bilateral stifle arthroscopy. Vet Surg. 2002;31:232.
73. Boscan P, Van Hoogmoed LM, Farver TB, et al. Evaluation of 94. England GCW, Clarke KW. Alpha2 adrenoceptor agonists in
the effects of the opioid agonist morphine on gastrointestinal the horse: a review. Br Vet J. 1996;152:641.
tract function in horses. Am J Vet Res. 2006;67:992. 95. Jochle W, Moore JN, Brown J, et al. Comparison of detomidine,
74. Sojka JE, Adams SB, Lamar CH, et al. Effect of butorphanol, butorphanol, flunixin meglumine and xylazine in clinical cases
pentazocine, meperidine, or metoclopramide on intestinal mo- of equine colic. Equine Vet J Suppl. 1989;7:111.
tility in female ponies. Am J Vet Res. 1988;49(4):527. 96. Lowe JE, Hilfiger J. Analgesic and sedative effects of detomidine
75. Senior JM, Pinchbeck GL, Dugdale AHA, et al. Retrospective compared to xylazine in a colic model using IV and IM routes
study of the risk factors and prevalence of colic in horses after of administration. Acta Vet Scand. 1986;82:85.
orthopaedic surgery. Vet Rec. 2004;155:321. 97. Lowe JE, Hilfiger J. Analgesic and sedative effects of detomidine
76. Nelson BB, Lordan EE, Hassel DM. Risk factors associated in a colic model: blind studies on efficacy and duration of ef-
with gastrointestinal dysfunction in horses undergoing elec- fects. Proc Annu Conv Am Equin. 1984;30:225.
tive procedures under general anaesthesia. Equine Vet J Suppl. 98. Muir WW, Skarda RT, Sheehan W. Hemodynamic and respira-
2013;45:8. tory effects of a xylazine-acetylpromazine drug combination in
77. Mircica E, Clutton RE, Kyles KW, et al. Problems associated horses. Am J Vet Res. 1979;40:1518.
with perioperative morphine in horses: a retrospective case 99. Wagner AE, Muir WW, Hinchcliff KW. Cardiovascular effects
analysis. Vet Anaesth Analg. 2003;30:147. of xylazine and detomidine in horses. Am J Vet Res. 1991;52:651.
78. Koenig J, Cote N. Equine gastrointestinal motility—ileus and 100. Still J, Serteyn D, Van der Merwe CA. Cardiovascular and respir-
pharmacological modification. Can Vet J. 2006;47:551. atory effects of detomidine in isoflurane-anaesthetised horses.
79. Sano H, Martin-Flores M, Santos LCP, et al. Effects of epidural J S Afr Vet Assoc. 1996;67:199.
morphine on gastrointestinal transit in unmedicated horses. Vet 101. Bettschart-Wolfensberger R, Freeman SL, Bowen I, et al. Car-
Anaesth Analg. 2011;38:121. diopulmonary effects and pharmacokinetics of i.v. dexmedeto-
80. Sanchez L, Robertson S, Maxwell L, et al. Effect of fentanyl on midine in ponies. Equine Vet J. 2005;37:60.
visceral and somatic nociception in conscious horses. J Vet In- 102. Kamerling SG, Cravens WMT, Bagwell CA. Dose-related ef-
tern Med. 2007;21:1067. fects of detomidine on autonomic responses in the horse. J Au-
81. Ohta M, Wakuno A, Okada J, et al. Effects of intravenous fenton Pharmacol. 1988;8:241.
tanyl administration on end-tidal sevoflurane concentrations in 103. Pypendop BH, Verstegen JP. Hemodynamic effects of medeto-
thoroughbred racehorses undergoing orthopedic surgery. J Vet midine in the dog: a dose titration study. Vet Surg. 1998;27:612.
Med Sci. 2010;72:1107. 104. Lester GD, Merritt AM, Neuwirty L, et al. Effect of α2-
82. Knych HK, Steffey EP, Casbeer HC, et al. Disposition, behav- adrenergic, cholinergic, and nonsteroidal anti-inflammatory
ioural and physiological effects of escalating doses of intra- drugs on myoelectric activity of ileum, cecum, and right ventral
venously administered fentanyl to young foals. Equine Vet J. colon and on cecal emptying of radiolabeled markers in clini-
2015;47:592. cally normal ponies. Am J Vet Res. 1998;58:320.
83. Messenger KM, Davis JL, LaFevers DH, et al. Intravenous and 105. Merritt AM, Burrows JA, Hartless CS. Effect of xylazine, deto-
sublingual buprenorphine in horses: pharmacokinetics and in- midine, and a combination of xylazine and butorphanol on
fluence of sampling site. Vet Anaesth Analg. 2011;38:374. equine duodenal motility. Am J Vet Res. 1998;59:619.
84. Davis JL, Messenger KM, LaFevers DH, et al. Pharmacokinetics 106. Sutton DGM, Preston T, Christley RM, et al. The effects of xy-
of intravenous and intramuscular buprenorphine in the horse. J lazine, detomidine, acepromazine and butorphanol on equine
Vet Pharmacol Ther. 2012;35:52. solid phase gastric emptying rate. Equine Vet J. 2002;34:486.
85. Potter JJ, MacFarlane PD, Love EJ, et al. Preliminary investi- 107. Nuñez E, Steffey EP, Ocampo L, et al. Effects of alpha2-adrener-
gation comparing a detomidine continuous rate infusion com- gic receptor agonists on urine production in horses deprived of
bined with either morphine or buprenorphine for standing food and water. Am J Vet Res. 2004;65:1342.
sedation in horses. Vet Anaesth Analg. 2016;43:189. 108. Valdes-Vazquez MA, Aguilera-Tejero E, Mayer-Valor R. Effect
86. Risberg ÅI, Spadavecchia C, Ranheim B, et al. Antinociceptive of xylazine during endoscopic evaluation of functional upper
effect of buprenorphine and evaluation of the nociceptive with- respiratory disorders in horses. J Equine Vet Sci. 1993;13:84.
drawal reflex in foals. Vet Anaesth Analg. 2015;42:329. 109. Ducharme NG, Hackett RP, Fubini SL, et al. The reliability of
87. Santos LCP, De Moraes AN, Saito ME. Effects of intraarticu- endoscopic examination in assessment of arytenoid cartilage
lar ropivacaine and morphine on lipopolysaccharide-induced movement in horses. Part II. Influence of side of examination,
synovitis in horses. Vet Anaesth Analg. 2009;36:280. reexamination, and sedation. Vet Surg. 1991;20:180.
110. Ringer SK, Schwarzwald CC, Portier KG, et al. Effects on 130. Valverde A, Gunkel C, Doherty TJ, et al. Effect of a constant rate
cardiopulmonary function and oxygen delivery of doses of infusion of lidocaine on the quality of recovery from sevoflu-
romifidine and xylazine followed by constant rate infusions in rane or isoflurane general anaesthesia in horses. Equine Vet J.
standing horses. Vet J. 2013;195:228. 2005;37:559.
111. Grubb TL, Muir WW, Bertone AL, et al. Use of yohimbine to re- 131. Schuhbeck MM, Kuhn M, Spadavecchia C, et al. Continuous
verse prolonged effects of xylazine hydrochloride in a horse being intravenous lidocaine infusion during isoflurane anaesthesia
treated with chloramphenicol. J Am Vet Med Assoc. 1997;210:1771. in horses undergoing surgical procedures. Pferdeheilkunde.
112. Di Salvo A, Della Rocca G, Bazzica C, et al. A pharmacokinetic/ 2012;28:252.
clinical approach to postulate a local action of intra-articular 132. Meyer GA, Lin HC, Hanson RR, et al. Effects of intravenous
xylazine administration in the horse: a preliminary study. J Vet lidocaine overdose on cardiac electrical activity and blood pres-
Pharmacol Ther. 2014;37:464. sure in the horse. Equine Vet J. 2001;33:431.
113. Ullmer J, Mama KR, Lee C, et al. The effects of xylazine on nor- 133. Olbrich VH, Mosing M. A comparison of the analgesic effects
mal and interleukin-1 conditioned equine articular cartilage ex- of caudal epidural methadone and lidocaine in the horse. Vet
plants. CA: Proc 38th Am College Vet Anesth San Diego; 2013. Anaesth Analg. 2003;30:156.
114. Mama KR, Ullmer J, King M, et al. The effects of xylazine, 134. Rapley JH, Beavis RC, Barber FA, et al. Glenohumeral chon-
dexmedetomidine and clonidine on normal and interleukin-1 drolysis after shoulder arthroscopy associated with continuous
conditioned equine cartilage explants. Japan: Proc 12th World bupivacaine infusion. Arthroscopy. 2009;25:1367.
Congress of Vet Anaesth Kyoto; 2015. 135. Park J, Sutradhar BC, Hong G, et al. Comparison of the cytotox-
115. Abdallah FW, Brull R. Facilitatory effects of perineural dexme- ic effects of bupivacaine, lidocaine, and mepivacaine in equine
detomidine on neuraxial and peripheral nerve block: a system- articular chondrocytes. Vet Anaesth Analg. 2011;38:127.
atic review and meta-analysis. Br J Anaesth. 2013;110(915):2013. 136. Breu A, Rosenmeier K, Kujat R, et al. The cytotoxicity of bupiv-
116. Skarda RT, Muir WW. Comparison of antinociceptive, cardiovas- acaine, ropivacaine, and mepivacaine on human chondrocytes
cular, and respiratory effects, head ptosis, and position of pelvic and cartilage. Anesth Analg. 2013;117:514.
limbs in mares after caudal epidural administration of xylazine and 137. Piat P, Richard H, Beauchamp G, et al. In vivo effects of a single
detomidine hydrochloride solution. Am J Vet Res. 1996;57:1338. intra-articular injection of 2% lidocaine or 0.5% bupivacaine on
117. Skarda RT, Muir WW. Caudal analgesia induced by epidural articular cartilage of normal horses. Vet Surg. 2012;41:1002.
or subarachnoid administration of detomidine hydrochloride 138. Mion G, Villevieille T. Ketamine pharmacology: an update
solution in mares. Am J Vet Res. 1994;55:670. (pharmacodynamics and molecular aspects, recent findings).
118. Hubbell JAE, Muir WW. Antagonism of detomidine sedation CNS Neurosci Ther. 2013;19:370.
in the horse using intravenous tolazoline or atipamezole. Equine 139. De Kock MF, Lavand’homme PM. The clinical role of NMDA
Vet J. 2006;38:238. receptor antagonists for the treatment of postoperative pain.
119. Carroll GL, Matthews NS, Hartsfield SM, et al. The effect of Best Pract Res Clin Anaesthesiol. 2007;21:85.
detomidine and its antagonism with tolazoline on stress-related 140. Muir WW, Skarda RT, Milne DW. Evaluation of xylazine and
hormones, metabolites, physiologic responses, and behavior in ketamine hydrochloride for anesthesia in horses. Am J Vet Res.
awake ponies. Vet Surg. 1997;26:69. 1977;38:195.
120. Pakkanen SAE, Raekallio MR, Mykkänen AK, et al. Detomidine 141. Muir WW, Sams R. Effects of ketamine infusion on halo-
and the combination of detomidine and MK-467, a peripheral thane minimal alveolar concentration in horses. Am J Vet Res.
alpha-2 adrenoceptor antagonist, as premedication in horses 1802;53:1992.
anaesthetized with isoflurane. Vet Anaesth Analg. 2015;42:527. 142. Lin HC, Passler T, Wilborn RR, et al. A review of the general
121. Vainionpää MH, Raekallio MR, Pakkanen SA, et al. Plasma pharmacology of ketamine and its clinical use for injectable an-
drug concentrations and clinical effects of a peripheral alpha- aesthesia in horses. Equine Vet Educ. 2015;27:146.
2-adrenoceptor antagonist, MK-467, in horses sedated with 143. Takki S, Nikki P, Jäättelä A, et al. Ketamine and plasma catecho-
detomidine. Vet Anaesth Analg. 2013;40:257. lamines. Br J Anaesth. 1972;44:1318.
122. Doherty TJ, Frazier DL. Effect of intravenous lidocaine on halo- 144. López-Sanromán FJ, Cruz JM, Santos M, et al. Evaluation of
thane minimum alveolar concentration in ponies. Equine Vet J. the local analgesic effect of ketamine in the palmar digital nerve
1998;30:300. block at the base of the proximal sesamoid (abaxial sesamoid
123. Robertson SA, Sanchez LC, Merritt AM, et al. Effect of systemic block) in horses. Am J Vet Res. 2003;64:475.
lidocaine on visceral and somatic nociception in conscious 145. Gómez de Segura IA, De Rossi R, Santos M, et al. Epidural in-
horses. Equine Vet J. 2005;37:122. jection of ketamine for perineal analgesia in the horse. Vet Surg.
124. Harkins JD, Mundy GD, Woods WE, et al. Lidocaine in the 1998;27:384.
horse: its pharmacological effects and their relationship to ana- 146. Braun S, Gaza N, Werdehausen R, et al. Ketamine induces apop-
lytical findings. J Vet Pharmacol Ther. 1998;21:462. tosis via the mitochondrial pathway in human lymphocytes and
125. Harkins JD, Stanley S, Mundy GD, et al. A review of the phar- neuronal cells. Br J Anaesth. 2010;105:347.
macology, pharmacokinetics, and regulatory control in the US of 147. Taylor PM, Bennett RC, Brearley JC, et al. Comparison of deto-
local anaesthetics in the horse. J Vet Pharmacol Ther. 1995;18:397. midine and romifidine as premedicants before ketamine and
126. Brianceau P, Chevalier H, Karas A, et al. Intravenous lidocaine halothane anesthesia in horses undergoing elective surgery. Am
and small-intestinal size, abdominal fluid, and outcome after J Vet Res. 2001;62:359.
colic surgery in horses. J Vet Intern Med. 2002;16:736. 148. Wagner AE, Walton JA, Hellyer P, et al. Use of low doses of
127. Guschlbauer M, Feige K, Geburek F, et al. Effects of in vivo li- ketamine administered by constant rate infusion as an ad-
docaine administration at the time of ischemia and reperfusion junct for postoperative analgesia in dogs. J Am Vet Med Assoc.
on in vitro contractility of equine jejunal smooth muscle. Am J 2002;221:72.
Vet Res. 2011;72:1449. 149. Carstensen M, Møller AM. Adding ketamine to morphine for
128. Rezende ML, Wagner AE, Mama KR, et al. Effects of intrave- intravenous patient-controlled analgesia for acute postopera-
nous administration of lidocaine on the minimum alveolar con- tive pain: a qualitative review of randomized trials. Br J Anaesth.
centration of sevoflurane in horses. Am J Vet Res. 2011;72:446. 2010;104:401.
129. Wagner AE, Mama KR, Steffey EP, et al. Comparison of the car- 150. Fielding CL, Brumbaugh GW, Matthews NS, et al. Pharma-
diovascular effects of equipotent anesthetic doses of sevoflurane cokinetics and clinical effects of a subanesthetic continu-
alone and sevoflurane plus an intravenous infusion of lidocaine ous rate infusion of ketamine in awake horses. Am J Vet Res.
in horses. Am J Vet Res. 2011;72:452. 2006;67:1484.
151. Guedes AGP, Matthews NS, Hood DM. Effect of ketamine hy- 172. Carregaro AB, Freitas GC, Ribeiro MH, et al. Physiological
drochloride on the analgesic effects of tramadol hydrochloride and analgesic effects of continuous-rate infusion of morphine,
in horses with signs of chronic laminitis-associated pain. Am J butorphanol, tramadol or methadone in horses with lipopol-
Vet Res. 2012;73:610. ysaccharide (LPS)-induced carpal synovitis. BMC Vet Res.
152. Peterbauer C, Larenza PM, Knobloch M, et al. Effects of a 2014;10:1.
low dose infusion of racemic and S-ketamine on the nocicep- 173. Milaré AS, De Oliveira FA, Luna SPL, et al. Intravenous trama-
tive withdrawal reflex in standing ponies. Vet Anaesth Analg. dol injection has no antinociceptive effect in horses undergoing
2008;35:414. electrical and thermal stimuli. J Equine Vet Sci. 2013;33:823.
153. Wagner AE, Mama KR, Contino EK, et al. Evaluation of seda- 174. Guedes A, Knych H, Hood D. Plasma concentrations, anal-
tion and analgesia in standing horses after administration of xy- gesic and physiological assessments in horses with chronic
lazine, butorphanol, and subanesthetic doses of ketamine. J Am laminitis treated with two doses of oral tramadol. Equine Vet J.
Vet Med Assoc. 2011;238:1629. 2016;48:528.
154. Elfenbein JR, Robertson SA, Corser AA, et al. Systemic effects of 175. Cagnardi P, Ferraresi C, Zonca A, et al. Clinical pharmacoki-
a prolonged continuous infusion of ketamine in healthy horses. netics of tramadol and main metabolites in horses undergoing
J Vet Intern Med. 2011;25:1134. orchiectomy. Vet Q. 2014;34:143.
155. Tramer MR, Schneider J, Marti RA, et al. Role of magnesium 176. Guedes A, Galuppo L, Hood D, et al. Soluble epoxide hydrolase
sulfate in postoperative analgesia. Anesthesiology. 1997;84:340. activity and pharmacologic inhibition in horses with chronic
156. Stomatology FM, Yan Q. Effects of systemic magnesium on severe laminitis. Equine Vet J. 2016.
post-operative analgesia: is the current evidence strong enough? 177. Guedes AG, Morrisseau C, Sole A, et al. Use of a soluble epoxide
Pain Physician. 2015;18:405. hydrolase inhibitor as an adjunctive analgesic in a horse with
157. Albrecht E, Kirkham KR, Liu SS, et al. Peri-operative intrave- laminitis. Vet Anaesth Analg. 2013;40:440.
nous administration of magnesium sulphate and postoperative 178. Love EJ, Taylor PM, Murrell J, et al. Effects of acepromazine,
pain: a meta-analysis. Anaesthesia. 2013;68:79. butorphanol and buprenorphine on thermal and mechanical
158. McCarthy RJ, Kroin JS, Tuman KJ, et al. Antinociceptive po- nociceptive thresholds in horses. Equine Vet J. 2012;44:221.
tentiation and attenuation of tolerance by intrathecal co-infu- 179. Sanchez LC, Elfenbein JR, Robertson SA. Effect of aceproma-
sion of magnesium sulfate and morphine in rats. Anesth Analg. zine, butorphanol, or N-butylscopolammonium bromide on
1998;86(830):1998. visceral and somatic nociception and duodenal motility in con-
159. Finnerup NB, Attal N, Haroutounian S, et al. Pharmacotherapy scious horses. Am J Vet Res. 2008;69:579.
for neuropathic pain in adults: a systematic review and meta- 180. Roelvink ME, Goossens L, Kalsbeek HC, et al. Analgesic and
analysis. Lancet Neurol. 2015;14:162. spasmolytic effects of dipyrone, hyoscine-N-butylbromide and
160. Terry RL, McDonnell SM, Van Eps AW, et al. Pharmacokinetic a combination of the two in ponies. Vet Rec. 1991;129:378.
profile and behavioral effects of gabapentin in the horse. J Vet 181. Boatwright CE, Fubini SL, Grohn YT, et al. A comparison of N-
Pharmacol Ther. 2010;33:485. butylscopolammonium bromide and butorphanol tartrate for
161. Caldwell FJ, Taintor J, Waguespack RW, et al. Effect of PO ad- analgesia using a balloon model of abdominal pain in ponies.
ministered gabapentin on chronic lameness in horses. J Equine Can J Vet Res. 1996;60:65.
Vet Sci. 2015;35:536. 182. Rumpler MJ, Colahan P, Sams RA. The pharmacokinetics of
162. Davis JL, Posner LP, Elce Y. Gabapentin for the treatment of methocarbamol and guaifenesin after single intravenous and
neuropathic pain in a pregnant horse. J Am Vet Med Assoc. multiple-dose oral administration of methocarbamol in the
2007;231:755. horse. J Vet Pharmacol Ther. 2014;37:25.
163. Dworkin RH, O’Connor AB, Backonja M, et al. Pharmacologic 183. Cremers S, Papapoulos S. Pharmacology of bisphosphonates.
management of neuropathic pain: evidence-based recommen- Bone. 2011;49:42.
dations. Pain. 2007;132:237. 184. Catterall JB, Cawston TE. Drugs in development: bisphos-
164. Mullen KR, Schwark W, Divers TJ. Pharmacokinetics of single- phonates and metalloproteinase inhibitors. Arthritis Res Ther.
dose intragastric and intravenous pregabalin administration in 2003;5:12.
clinically normal horses. Am J Vet Res. 2013;74:1043. 185. Kamm L, McIlwraith W, Kawcak C. A review of the efficacy of
165. Grond S, Sablotzki A. Clinical pharmacology of tramadol. Clin tiludronate in the horse. J Equine Vet Sci. 2008;28:209.
Pharmacokinet. 2004;43:879. 186. Gough MR, Thibaud D, Smith RKW. Tiludronate infusion in
166. Vettorato E, Zonca A, Cagnardi P, et al. Pharmacokinetics and the treatment of bone spavin: a double blind placebo-controlled
efficacy of intravenous and extradural tramadol in dogs. Vet J. trial. Equine Vet J. 2010;42:381.
2010;183:310. 187. Coudry V, Thibaud D, Riccio B, et al. Efficacy of tiludronate in
167. Knych HK, Corado CR, McKemie DS, et al. Pharmacokinet- the treatment of horses with signs of pain associated with osteo-
ics and selected pharmacodynamic effects of tramadol fol- arthritic lesions of the thoracolumbar vertebral column. Am J
lowing intravenous administration to the horse. Equine Vet J. Vet Res. 2007;68:329.
2013;45:490. 188. Hunter BG, Duesterdieck-Zellmer KF, Larson MK. Tiludronate
168. Stewart AJ, Boothe DM, Cruz-Espindola C, et al. Pharmaco concentrations and cytologic findings in synovial fluid after in-
kinetics of tramadol and metabolites O-desmethyltramadol travenous regional limb perfusion with tiludronate in horses.
and N-desmethyltramadol in adult horses. Am J Vet Res. Peer J. 2015;3:e889.
2011;72:967. 189. Body JJ, Pfister T, Bauss F, et al. Preclinical perspectives on bis-
169. Shilo Y, Britzi M, Eytan B, et al. Pharmacokinetics of tramadol phosphonate renal safety. Oncologist. 2005;10(suppl 1):3.
in horses after intravenous, intramuscular and oral administra- 190. Meijer H, Reinecke J, Becker C, et al. The production of anti-
tion. J Vet Pharmacol Ther. 2008;31:60. inflammatory cytokines in whole blood by physico-chemical
170. Giorgi M, Soldani G, Manera C, et al. Pharmacokinetics of induction. Inflamm Res. 2003;52:404.
tramadol and its metabolites M1, M2 and M5 in horses fol- 191. Frisbie DD, Kawcak CE, Werpy NM, et al. Clinical, biochemi-
lowing intravenous, immediate release (fasted/fed) and sus- cal, and histologic effects of intra-articular administration of
tained release single dose administration. J Equine Vet Sci. autologous conditioned serum in horses with experimentally
2007;27:481. induced osteoarthritis. Am J Vet Res. 2007;68:290.
171. Dhanjal JK, Wilson DV, Robinson E, et al. Intravenous trama- 192. Martin CA, Kerr CL, Pearce SG, et al. Outcome of epidural
dol: effects, nociceptive properties, and pharmacokinetics in catheterization for delivery of analgesics in horses: 43 cases
horses. Vet Anaesth Analg. 2009;36:581. (1998–2001). J Am Vet Med Assoc. 2003;222:1394.
193. Sysel AM, Pleasant RS, Jacobson JD, et al. Systemic and lo- 214. Waguespack RW, Burba DJ, Hubert JD, et al. Effects of extra-
cal effects associated with long-term epidural catheterization corporeal shock wave therapy on desmitis of the accessory liga-
and morphine-detomidine administration in horses. Vet Surg. ment of the deep digital flexor tendon in the horse. Vet Surg.
1997;26:141. 2011;40:450.
194. Zarucco L, Driessen B, Scandella M, et al. Continuous perineu- 215. Imboden I, Waldern NM, Wiestner T, et al. Short term analge-
ral block of the palmar nerves: a new technique for pain relief in sic effect of extracorporeal shock wave therapy in horses with
the distal equine forelimb. Clin Tech Equine Pract. 2007;6:154. proximal palmar metacarpal/plantar metatarsal pain. Vet J.
195. Chelly JE, Greger J, Casati A, et al. Continuous lateral sciatic 2009;179:50.
blocks for acute postoperative pain management after major 216. McClure SR, Sonea IM, Evans RB, et al. Evaluation of analgesia
ankle and foot surgery. Foot Ankle. 2002;23:749. resulting from extracorporeal shock wave therapy and radial
196. Ganesh A, Rose JB, Wells T, et al. Continuous peripheral nerve pressure wave therapy in the limbs of horses and sheep. Am J
blockade for inpatient and outpatient postoperative analgesia in Vet Res. 2005;66:1702.
children. Anesth Analg. 2007;105:1234. 217. Dahlberg JA, McClure SR, Evans RB, et al. Force platform
197. Boezaart AP. Perineural infusion of local anesthetics. Anesthesi- evaluation of lameness severity following extracorporeal shock
ology. 2006;104:872. wave therapy in horses with unilateral forelimb lameness. J Am
198. Driessen B, Scandella M, Zarucco L. Development of a tech- Vet Med Assoc. 2006;229:100.
nique for continuous perineural blockade of the palmar 218. Brown KE, Nickels FA, Caron JP, et al. Investigation of the
nerves in the distal equine thoracic limb. Vet Anaesth Analg. immediate analgesic effects of extracorporeal shock wave
2008;35:432. therapy for treatment of navicular disease in horses. Vet Surg.
199. Frisbie DD, McIlwraith CW, Kawcak CE, et al. Evaluation of 2005;34:554.
topically administered diclofenac liposomal cream for treat- 219. Gomez Alvarez CBG, L’ami JJ, Moffat D, et al. Effect of chiro-
ment of horses with experimentally induced osteoarthritis. Am practic manipulations on the kinematics of back and limbs in
J Vet Res. 2009;70:210. horses with clinically diagnosed back problems. Equine Vet J.
200. Andreeta A, Verde C, Babusci M, et al. Comparison of di- 2008;40:153.
clofenac diethylamine permeation across horse skin from five 220. Landman M, De Blaauw JA, Van Weeren PR, et al. Field study
commercial medical human formulations. J Equine Vet Sci. of the prevalence of lameness in horses with back problems. Vet
2011;31:502. Rec. 2004;155:165.
201. Thomasy SM, Slovis N, Maxwell LK, et al. Transdermal fentanyl 221. Langstone J, Ellis J, Cunliffe C. A preliminary study of the ef-
combined with nonsteroidal anti-inflammatory drugs for anal- fect of manual chiropractic treatment on the splenius muscle in
gesia in horses. J Vet Intern Med. 2004;18:550. horses when measured by surface electromyography. Equine Vet
202. Eberspächer E, Stanley SD, Rezende M, et al. Pharmacokinetics J. 2015;47(18):2015.
and tolerance of transdermal fentanyl administration in foals. 222. Sullivan KA, Hill AE, Haussler KK. The effects of chiroprac-
Vet Anaesth Analg. 2008;35:249. tic, massage and phenylbutazone on spinal mechanical noci
203. Orsini JA, Moate PJ, Kuersten K, et al. Pharmacokinetics of fen- ceptive thresholds in horses without clinical signs. Equine Vet J.
tanyl delivered transdermally in healthy adult horses–variabil- 2008;40:14.
ity among horses and its clinical implications. J Vet Pharmacol 223. Klide AM. Treatment of chronic back pain in horses stimulation
Ther. 2006;29:539. of acupuncture points with a low powered infrared laser. Vet
204. Mills PC, Cross SE. Regional differences in transdermal pene- Surg. 1987;16:106.
tration of fentanyl through equine skin. Res Vet Sci. 2007;82:252. 224. Hagiwara S, Iwasaka H, Okuda K, et al. GaAlAs (830 nm) low-
205. Hubbell JAE, Saville WJA, Bednarski RM, et al. The use of seda- level laser enhances peripheral endogenous opioid analgesia in
tives, analgesic and anaesthetic drugs in the horse: an electronic rats. Lasers Surg Med. 2007;39:797.
survey of members of the American Association of Equine 225. Ginani F, Soares DM, Barboza CAG. Effect of low-level laser
Practitioners (AAEP). Equine Vet J. 2010;42:487. therapy on mesenchymal stem cell proliferation: a systematic
206. Vincent CA, Richardson PH. The evaluation of therapeutic acu- review. Lasers Med Sci. 2015;30:2189.
puncture: concepts and methods. Pain. 1986;24:1. 226. Smoot B, Chiavola-Larson L, Lee J, et al. Effect of low-level la-
207. Skarda RT, Tejwani GA, Muir WW. Cutaneous analgesia, ser therapy on pain and swelling in women with breast cancer-
hemodynamic and respiratory effects, and beta-endorphin con- related lymphedema: a systematic review and meta-analysis. J
centration in spinal fluid and plasma of horses after acupunc- Cancer Surviv. 2014;9:287.
ture and electroacupuncture. Am J Vet Res. 2002;63:1435. 227. Bjordal JM, Johnson MI, Iversen V, et al. Low-level laser ther-
208. Takeshige C, Oka K, Mizuno T, et al. The acupuncture point apy in acute pain: a systematic review of possible mechanisms
and its connecting central pathway for producing acupuncture of action and clinical effects in randomized placebo-controlled
analgesia. Brain Res Bull. 1993;30:53. trials. Photomed Laser Surg. 2006;24:158.
209. Tobaldini G, Aisengart B, Lima MMS, et al. Ascending nocicep- 228. ColdLasers.org: A guide to equine lasers. http://www.coldlasers
tive control contributes to the antinociceptive effect of acupunc- .org/guide-to-equine-lasers; 2016.
ture in a rat model of acute pain. J Pain. 2014;15:422. 229. U.S. Food and Drug Administration. Laser products and instru-
210. Bossut DFB, Leshin LS, Stromberg MW, et al. Plasma cortisol ments. http://www.fda.gov/radiation-emittingproducts/radiati
and beta-endorphin in horses subjected to electro-acupuncture onemittingproductsandprocedures/homebusinessandentertain
for cutaneous analgesia. Peptides. 1983;4:501. ment/laserproductsandinstruments/default.htm; 2016.
211. Skarda RT, Muir WW. Comparison of electroacupuncture and 230. Lee CD, Maxwell LK. Effect of body weight on the pharmacoki-
butorphanol on respiratory and cardiovascular effects and rec- netics of flunixin meglumine in miniature horses and quarter
tal pain threshold after controlled rectal distention in mares. horses. J Vet Pharmacol Ther. 2014;37:35.
Am J Vet Res. 2003;64:137. 231. Landoni MF, Lees P. Pharmacokinetics and pharmacodynam-
212. Steiss JE, White NA, Bowen JM. Electroacupuncture in the ics of ketoprofen enantiomers in the horse. J Vet Pharmacol
treatment of chronic lameness in horses and ponies: a con- Ther. 1996;19:466.
trolled clinical trial. Can J Vet Res. 1989;53:239. 232. Spadavecchia C, Arendt-Nielsen L, Spadavecchia L, et al. Ef-
213. Robinson KA, Manning ST. Efficacy of a single-formula acu- fects of butorphanol on the withdrawal reflex using threshold,
puncture treatment for horses with palmar heel pain. Can Vet J. suprathreshold and repeated subthreshold electrical stimuli in
2015;56:1257. conscious horses. Vet Anaesth Analg. 2007;34:48.
233. Dias BP, Araújo MA, Deschk M, et al. Effects of a continuous 253. Neto PIN, Luna SP, Queiroz-Williams P, et al. Cardiorespiratory
rate infusion of butorphanol in isoflurane-anesthetized horses and antinociceptive effects of two different doses of lidocaine
on cardiorespiratory parameters, recovery quality, gastrointes- administered to horses during a constant intravenous infusion
tinal motility and serum cortisol concentrations. Acta Cir Bras. of xylazine and ketamine. BMC Vet Res. 2013;9:1.
2014;29:801. 254. Moens Y, Lanz F, Doherr MG, et al. A comparison of the
234. Chiavaccini L, Claude AK, Lee JH, et al. Pharmacokinetics and antinociceptive effects of xylazine, detomidine and romi-
pharmacodynamics comparison between subcutaneous and in- fidine on experimental pain in horses. Vet Anaesth Analg.
travenous butorphanol administration in horses. J Vet Pharma- 2003;30:183.
col Ther. 2015;38:365. 255. LeBlanc PH, Caron JP, Patterson JS, et al. Epidural injection of
235. Marly C, Bettschart-Wolfensberger R, Nussbaumer P, et al. xylazine for perineal analgesia in horses. J Am Vet Med Assoc.
Evaluation of a romifidine constant rate infusion protocol with 1988;193:1405.
or without butorphanol for dentistry and ophthalmologic pro- 256. Wilson DV, Bohart GV, Evans AT, et al. Retrospective analy-
cedures in standing horses. Vet Anaesth Analg. 2014;41:491. sis of detomidine infusion for standing chemical restraint in 51
236. Orsini JA. Equine emergencies: treatment and procedures. 4th ed. horses. Vet Anaesth Analg. 2002;29:54.
St. Louis: Elsevier/Saunders; 2014. 257. da Silva Serpa PB, Natalini CC, Cavalcanti RL, et al. Effects of
237. Cruz FSF, Carregaro AB, Machado M, et al. Sedative and car- detomidine constant rate infusion on blood glucose and lactate
diopulmonary effects of buprenorphine and xylazine in horses. in sevoflurane anesthetized horses. Acta Sci Vet. 2012;40:1051.
Can J Vet Res. 2011;75:35. 258. Serpa PB, Garbade P, Natalini CC, et al. Energy imbalance and
238. Taylor P, Coumbe K, Henson F, et al. Evaluation of sedation for physiological changes during detomidine hydrochloride constant
standing clinical procedures in horses using detomidine com- rate infusion in standing horses. J Equine Vet Sci. 2015;35:232.
bined with buprenorphine. Vet Anaesth Analg. 2014;41:14. 259. Ringer SK, Portier K, Torgerson PR, et al. The effects of a loading
239. Fischer BL, Ludders JW, Asakawa M, et al. A comparison of dose followed by constant rate infusion of xylazine compared
epidural buprenorphine plus detomidine with morphine plus with romifidine on sedation, ataxia and response to stimuli in
detomidine in horses undergoing bilateral stifle arthroscopy. horses. Vet Anaesth Analg. 2013;40:157.
Vet Anaesth Analg. 2009;36:67. 260. Devisscher L, Schauvliege S, Dewulf J, et al. Romifidine as a
240. Benmansour P, Husulak ML, Bracamonte JL, et al. Cardiopul- constant rate infusion in isoflurane anaesthetized horses: a clin-
monary effects of an infusion of remifentanil or morphine in ical study. Vet Anaesth Analg. 2010;37:425.
horses anesthetized with isoflurane and dexmedetomidine. Vet 261. Rezende ML, Grimsrud KN, Stanley SD, et al. Pharmacokinet-
Anaesth Analg. 2014;41:346. ics and pharmacodynamics of intravenous dexmedetomidine in
241. Gozalo-Marcilla M, Steblaj B, Schauvliege S, et al. Comparison the horse. J Vet Pharmacol Ther. 2015;38:15.
of the influence of two different constant-rate infusions (dex- 262. Marcilla MG, Schauvliege S, Segaert S, et al. Influence of a con-
medetomidine versus morphine) on anaesthetic requirements, stant rate infusion of dexmedetomidine on cardiopulmonary
cardiopulmonary function and recovery quality in isoflurane function and recovery quality in isoflurane anaesthetized horses.
anaesthetized horses. Res Vet Sci. 2013;95:1186. Vet Anaesth Analg. 2012;39:49.
242. Thomasy SM, Steffey EP, Mama KR, et al. The effects of iv fen- 263. Creighton CM, Lemke KA, Lamont LA, et al. Comparison of
tanyl administration on the minimum alveolar concentration of the effects of xylazine bolus versus medetomidine constant rate
isoflurane in horses. Br J Anaesth. 2006;97:232. infusion on cardiopulmonary function and depth of anesthe-
243. Benmansour P, Duke-Novakovski T. Prolonged anesthesia us- sia in horses anesthetized with isoflurane. J Am Vet Med Assoc.
ing sevoflurane, remifentanil and dexmedetomidine in a horse. 2012;240:991.
Vet Anaesth Analg. 2013;40:521. 264. Kempchen S, Kuhn M, Spadavecchia C, et al. Medetomidine
244. Lamuraglia R, Kirkby P, Funcia JP. Cardiopulmonary effects continuous rate intravenous infusion in horses in which sur-
and recovery quality of remifentanil–isoflurane anesthesia in gical anaesthesia is maintained with isoflurane and intrave-
horses. J Equine Vet Sci. 2015;35:271. nous infusions of lidocaine and ketamine. Vet Anaesth Analg.
245. Nilsfors L, Kvart C, Kallings P, et al. Cardiorespiratory and 2012;39:245.
sedative effects of a combination of acepromazine, xylazine and 265. Nannarone S, Cenani A, Gialletti R, et al. Clinical comparison
methadone in the horse. Equine Vet J. 1988;20:364. of two regimens of lidocaine infusion in horses undergoing
246. Linardi RL, Stokes AM, Keowen ML, et al. Bioavailability and laparotomy for colic. Vet Anaesth Analg. 2015;42:150.
pharmacokinetics of oral and injectable formulations of metha- 266. Peiró JR, Barnabe PA, Cadioli FA, et al. Effects of lidocaine in-
done after intravenous, oral, and intragastric administration in fusion during experimental endotoxemia in horses. J Vet Intern
horses. Am J Vet Res. 2012;73:290. Med. 2010;24:940.
247. DeRossi R, Medeiros U, de Almeida RG, et al. Meperidine pro- 267. Skarda RT, Muir WW. Segmental epidural and subarachnoid
longs lidocaine caudal epidural anaesthesia in the horse. Vet J. analgesia in conscious horses: a comparative study. Am J Vet
2008;178:294. Res. 1870;44:1983.
248. Foreman JH, Ruemmler R. Efficacy of intramuscular meperi- 268. Hendrickson DA, Wilson DG. Laparoscopic cryptorchid cas-
dine hydrochloride versus placebo in experimental foot lame- tration in standing horses. Vet Surg. 1997;26:335.
ness in horses. Equine Vet J Suppl. 2013;45:48. 269. Skarda RT, Muir WW. Analgesic, hemodynamic and respira-
249. Skarda RT, Muir WW. Analgesic, hemodynamic, and respiratory effects of caudal epidurally administered ropivacaine hy-
tory effects induced by caudal epidural administration of me- drochloride in mares. Vet Anaesth Analg. 2001;28:61.
peridine hydrochloride in mares. Am J Vet Res. 2001;62:1001. 270. van Loon JP, Menke ES, Doornenbal A, et al. Antinociceptive
250. Natalini CC, Linardi RL. Analgesic effects of epidural adminis- effects of low dose lumbosacral epidural ropivacaine in healthy
tration of hydromorphone in horses. Am J Vet Res. 2006;67:11. ponies. Vet J. 2012;193:240.
251. Yamashita K, Muir WW, Tsubakishita S, et al. Clinical compari- 271. DeRossi R, Módolo TJ, Pagliosa RC, et al. Comparison of anal-
son of xylazine and medetomidine for premedication of horses. gesic effects of caudal epidural 0.25% bupivacaine with bupiv-
J Am Vet Med Assoc. 2002;221:1144. acaine plus morphine or bupivacaine plus ketamine for analgesia
252. López-Sanromán FJ, Holmbak-Petersen R, Varela M, et al. Ac- in conscious horses. J Equine Vet Sci. 2012;32:190.
celerometric comparison of the locomotor pattern of horses se- 272. DeRossi R, Miguel GLS, Frazílio FO, et al. L-Bupivacaine 0.5%
dated with xylazine hydrochloride, detomidine hydrochloride, vs. racemic 0.5% bupivacaine for caudal epidural analgesia in
or romifidine hydrochloride. Am J Vet Res. 2013;74:828. horses. J Vet Pharmacol Ther. 2005;28:293.
C HA P T E R 4
Critical Care
Samuel D. Hurcombe*
Y INTRODUCTION horses admitted for gastrointestinal disease, administration of

antibiotics, and fasting are such examples.2
The development of critical care in equine medicine has truly In addition to dedicated stalls and personnel, some key
evolved over the past 20 years to deliver high-level care to the equipment for diagnostic and therapeutic purposes are neces-
sickest patients, both adult horses and foals. To this end, criti- sary to deliver optimal care. Fluid pumps, electrocardiographic
cal care has developed into a specialty stream of medicine in (ECG) capabilities, ultrasonography, and point-of-care clini-
its own right in which many of the leading hospitals and foun- copathologic testing capabilities are a few examples. However,
dation criticalists have pushed the envelope in advancing care there is no greater asset in an ICU than methodical, detail-
to our equine patients with improved outcomes. The develop- oriented personnel that serially evaluate their patients and are
ment of the American College of Veterinary Emergency and in tune with even subtle changes.
Critical Care (ACVECC) large-animal group was formed and There are no randomized, controlled studies that advocate
has somewhat legitimized equine critical care as a specialty for the provision of critical care medicine and improved sur-
in its own right. Both members of ACVECC, many of whom vival outcomes. The precedent has been set time and again in
are also specialists in internal medicine or surgery, and other human medicine where, in many instances, dedicated person-
like-minded clinicians around the world, are skilled to run an nel, personalized care, early goal-directed therapies, and novel
intensive care unit (ICU) and deliver urgent and immediate therapies result in greater survival, shorter duration of stay in
care. However, there are still significant challenges and clinical the hospital, decreased morbidity, and lower hospital costs.
obstacles to overcome, yet this exciting field of study is chang- More studies are needed in veterinary medicine to support
ing rapidly and will surely continue to do so. similar outcomes in equine practice.
Critical care is provided to an animal whose condition is The provision of critical care to horses is at the purview of
typically severe, life-threatening, and acute. Early recognition equine clinicians; however, certain criteria appear to be uni-
of a disease state or complex condition is needed to execute versal among specialists, which include horses with parenteral
a diagnostic or therapeutic plan, which oftentimes has a sig- fluid requirement to support the cardiovascular system, sys-
nificant impact on the outcome. For example, in human temic inflammatory response syndrome ([SIRS]; both septic
emergency departments, the administration of antimicrobials and nonseptic causes), (poly)trauma, hemorrhage, cardiovas-
within 60 to 180 minutes of sepsis diagnosis is significantly cular collapse, malignant dysrhythmia, respiratory distress
associated with improved survival.1 (notably lower respiratory dysfunction), acute abdominal dis-
Intensive care is a dynamic process. Patient condition ease (surgical and medical), seizure disorder, and acute neuro-
can change minute to minute, and oftentimes these patients logic decompensation, to name a few.
require fine-tuning of a therapeutic plan over several days. As Therapeutic goals for all patients include providing appro-
such, this is time-consuming, detail oriented, tiring, and often priate care for the primary problems, anticipating complications
physically demanding. Therefore a team of personnel includ- and initiating appropriate preventive therapy, and providing
ing clinicians, technicians, and barn staff is best suited to the appropriate supportive care for all vital body systems.
ICU setting to optimize patient care. In this chapter, salient features of the critically ill patient
Patients in the ICU setting are better suited segregated from profile, diagnostic options, and immediate life-saving thera-
a general hospital population. There is a twofold positive effect. peutics for specific body systems will be provided. Additional
First, ICU patients are often sick, immunocompromised, and specific information on select medical conditions will be cov-
may be at risk of developing opportunistic infection. Second, ered in Chapter 20.
certain ICU populations may be at higher risk of shedding
infectious organisms like salmonella. For example, juvenile Y EQUINE INTENSIVE CARE UNIT
*The editors and authors acknowledge and appreciate the contributions of J. Equine ICUs are becoming increasingly prevalent in clini-
Hardy, P. Marsh, P. Mooresey, B. Barr, B. Waldridge, and Y. Nout as previous cal practice. Common features include housing of patients
contributors to this chapter. Some of their original work has been incorpo- according to type or severity of illness with appropriate biose-
rated into this edition. curity precautions; readily available equipment for diagnosing,
158
CHAPTER 4 Critical Care 159
monitoring, and treating the seriously compromised horse; and

24-hour staffing with professionals who have the knowledge BOX 4.1
Equipment List for Different Levels of Equine
and experience to treat these patients. The goals of the ICU are Intensive Care Units
to provide comprehensive care and improve patient outcomes
while using tools and resources that promote efficiency. BASIC
Several studies describe the general case population and • Fluid administration system: coil sets and fluid hooks
commonly performed procedures and treatments of patients • Electrocardiogram
admitted on an emergency basis to large university referral • Centrifuge
centers.3,4 Because equine emergencies are relatively com- • Refractometer
mon among patients requiring critical care, such information • Glucose meter
provides an initial database for understanding population • Lactate meter
dynamics and the required expertise when staffing the ICU. • Urinalysis strips
Colic or acute abdominal pain is the most common type of • Microscope for cytologic examination/Gram stain
case encountered in emergency/critical care centers, and stud- • Ultrasound including Doppler capability
ies show that expertise is required that can handle both medi- • Oxygen tank and regulator
cal and surgical needs. However, the fact remains that a variety • Biosecurity equipment and personnal protective equipment
of other problems present as emergencies, and the required
skills to deal with these include experience with dysfunction INTERMEDIATE
of most all body systems. Each ICU population will reflect the • Blood gas/electrolyte/glucose analyzer
local horse population type, and regular review of hospital • Complete blood count capability
populations is useful to appropriately allocate resources (staff • Coagulation profile testing
and equipment) to meet the unique needs of the region. • Blood pressure monitor (direct and indirect)
Human ICU treatment requires a multidisciplinary team • Intravenous fluid pump delivery systems
that includes intensivists (i.e., physicians who specialize in criti- • Sling and hoist for down horses
cal illness care), nurses, respiratory care therapists, dieticians,
pharmacists, and other consultants from a broad range of spe- ADVANCED
cialties, such as surgery, internal medicine, and anesthesiology. • Pulse oximeter
Because of patient numbers, costs of therapy, and limitations of • Mechanical ventilator
certain aspects in equine practice, the range of specialists is often • Colloid osmometer
consolidated to fewer, multiskilled, broadly trained individuals. • Capnograph
Integral to the ICU are licensed veterinary technicians who • Continuous electrocardiogram telemetry
provide intensive and continuous care. Generally, good nurs- • Syringe infusion pumps
ing care is pivotal to successful outcomes. The technical staff
are the “eyes and ears” of the ICU and are trained to identify
early subtle changes in patient status and feel comfortable using and drug bags/packs strategically located around the hospital
a range of equipment. The ability to perform common tech- are advisable. Drug expiration dates should be regularly moni-
niques and to recognize changes in condition early is essential. tored and expired medications replaced. Table 4.1 lists several
Box 4.1 lists basic, intermediate, and advanced equipment emergency drugs and dosages used in adult horses. Having
that may be used in the ICU. Again, based on patient popula- emergency drug cheat sheets located in several key areas with
tions, if a practice rarely sees critically ill foals, purchase of a volumes, routes, and indications listed helps all ICU personnel
mechanical ventilator would be a poor economic choice. Regu- deliver safe, appropriate care in an emergency situation.
lar review of equipment to ensure it is in working order as well In addition, assembling packs for specific anticipated emer-
as training for all personnel on new equipment are essential. gency situations, such as all the necessary items for delivering
Commonly performed procedures include patient moni- supplemental oxygen or supplies to perform an urgent trache-
toring, fluid administration, and attention to and provision otomy, and placing these packs in key areas is recommended.
of appropriate analgesia. Monitoring includes close, astute Essential monitoring equipment commonly used in the ICU
observation and serial physical examinations. Use of diag- includes an ECG, a blood pressure monitor, a point-of-care glu-
nostic techniques and laboratory support are adjunctive mea- cometer and lactate meter, a point-of-care electrolyte and chem-
sures that complement competent observation to monitor istry analyzer, an ultrasound unit, a centrifuge for hematocrit
the systemic health of the patient. Parenteral fluid adminis- determination, a refractometer for determining total protein and
tration encompasses routine administration of a wide range urine specific gravity (SG), and urine test strips for urinalysis.
of products, including crystalloids, synthetic colloids, blood, Other monitoring tools to consider are a hemocytometer, micro-
and blood components. Choosing analgesia in the ICU will scope with 100× magnification, equipment for cytologic exami-
depend on the type and severity of pain experienced by the nation (including Gram stains), and a blood gas and electrolyte
patient (e.g., inflammatory pain versus neuropathic pain). The monitoring unit. A colloid osmometer is useful for determining
clinician needs to consider potential adverse effects that also colloid osmotic pressure (COP) in hypoproteinemic horses.
may influence the primary disorder (e.g., limiting morphine Advanced imaging is becoming more common, and the use
use in the abdominal patient to minimize ileus). Multimodal of ultrasound has become an essential component of diagnos-
analgesia techniques are being used that have the purported ing and monitoring critically ill patients. Ultrasound can be
benefits of analgesia being delivered through several mecha- used for identifying and monitoring effusions, intestinal dis-
nisms of action while using lower total doses to the patient. tention, and motility; identifying umbilical structures; moni-
Emergency drugs should be readily available and accessible toring pregnancy; and visualizing ocular structures, among
within seconds to minutes in any hospital. Mobile crash carts other anatomic areas. To enable imaging of a wide variety of
TABLE 4.1 Emergency Drugs Used for Adult Horses

Drug Dose Dose per 1000 lb Route Comment
Atropine 0.01–0.02 mg/kg 0.3–0.45 mL IV Bradycardia; rescue therapy for
severe bronchoconstriction
Dobutamine (positive 2–10 μg/kg/min (1 vial 900–4500 μg/min IV Use diluted solution within 24 h; it
inotrope) [250 mg] in 1000 mL = is compatible with most IV fluids;
250 μg/mL) do not mix with alkaline solution
calcium chloride/gluconate
Doxapram (respiratory 0.2 mg/kg 4.5 mL IV or topical Do not mix with alkaline drugs/
stimulant) under tongue fluid
Epinephrine 4.5–9 mL IV/IM/SC/ Do not give with bicarbonate, hy-
For anaphylaxis 0.01–0.02 mg/kg Intratracheal pertonic saline, or aminophylline
For asystole 0.1–0.5 mg/kg It does not need to be diluted
when given IV to adults
Double volumes when given
intratracheally
Furosemide 0.5–1.1 mg/kg 5–10 mL IV Pulmonary edema, diuresis,
congestive heart failure
Glycopyrrolate (for 0.001–0.005 mg/kg 2.25–11.25 mL IV/IM/SC Do not mix with alkaline drugs/
bronchodilation and fluids
bradycardia)
Lidocaine (treatment of 1.3 mg/kg loading Loading: 30 mL IV Ensure that product does not
ileus) slowly over 5 minutes Infusion: 67 mL/h contain epinephrine
0.05-mg/kg/min
infusion
Lidocaine (treatment of Bolus: 0.25–0.5 mg/kg Bolus: 5–10 mL IV Ensure that product does not
arrhythmias) (slowly) Infusion: 30–60 mL/h contain epinephrine
Infusion: 20–50 μg/kg/min
Aminophylline 5 mg/kg 2.5 g Nebulized

IV, Intravenously; IM, intramuscularly; SC, subcutaneously.
structures, access to a variety of transducers ranging from 2.5 be routine, large foaling stalls should be available. These stalls
to 10 MHz, as well as a rectal probe, is recommended. may feature mobile separators to facilitate treatment of foals
Oxygen provision for supplementation through nasal while allowing them access to their dams.
insufflation, demand valve access, or for mechanical venti- A central office facilitates oversight of the entire unit. A
lation should be available. Compressed gas cylinders can be central viewing station with either cameras or direct visual-
used but must be stored and handled appropriately to prevent ization of stalls is ideal. The ICU should have adequate stor-
injury. Oxygen cylinders can be fitted with a diameter index age and be uncluttered. Hand sanitizer, wash sinks, and boxes
safety system for connection to a demand valve. At peak flow, of gloves should be easily accessible. Hand washing between
a demand valve can provide up to 160 L/min of oxygen. For patients is essential to prevent spread of nosocomial infection.
each cylinder type, knowledge of the capacity of the cylinder Food preparation areas should be separate, and operators
and the flow rate enables calculation of the amount of time should be diligent in washing hands to prevent cross-contam-
provided. The small portable E cylinders contain 655 L of oxy- ination of pathogens in feed.
gen when full and can provide oxygen for 260 minutes when In the ICU, strict disinfection and isolation protocols
set at a flow rate of 5 L/min. Adult horses may require flow should be in place to prevent nosocomial infections and the
rates of 10 to 15 L/min to have any significant effect on the spread of infectious disease. In addition to hand washing,
fraction of oxygen inspired (Fio2). Larger G or H cylinders hand rubbing with an alcohol-based solution is more effec-
containing 5290 or 6910 L, respectively, allow oxygen supple- tive than hand washing with an antiseptic, probably because it
mentation for longer periods. does not require rinsing and drying of hands.5
The design of the ICU should accommodate the care of Guidelines and standard operating procedures (SOPs) can
horses with a wide variety of problems. All stalls should have the be applied to a variety of aspects of the ICU; for example,
equipment necessary for hanging large-volume fluid bags. Stalls guidelines for the use of antibiotics, guidelines on how to han-
should be free of objects that could cause injury. In addition, the dle multidrug-resistant pathogens, SOPs for personnel inju-
design should include one or two stalls for easy unloading of ries, and so forth. It is recommended that each ICU establish
down horses, and the structure must be able to withstand hoist- “best practice regimens” to optimize care, minimize complica-
ing. A track system to hoist horses off a trailer and transport to tions and mistakes, and maximize patient survival and per-
a surgical table or ICU stall would be a welcome feature. Com- sonnel safety.
mercially made glides are also essential to facilitate safe move- The overarching goal of critical care is to support and
ment of down horses. If care of neonatal patients is expected to treat the patient such that normal homeostatic mechanisms
become fully functional and independent of exogenous sup-

port. Treating and preventing shock, in all its various forms, is Adult Horse: Basic Procedures in
a common theme among patients. Provision of care that main- Critical Care
tains oxygen and cellular metabolic substrate delivery to meet
the unique demands of the patient is key. The clinician often Samuel D. Hurcombe
focuses on a specific disease process or even organ system.
However, because of the systemic consequences of several Expedient acquisition of important physiologic and physical
pathologic processes (e.g., inflammation, neoplasia), methodi- findings in the critically ill horse is essential to formulating
cal and serial evaluations of the entire patient are important. an initial diagnostic and/or therapeutic plan. Regardless of the
This allows the practitioner to identify problems early with nature of the particular condition presented to the clinician,
hopes of instituting early intervention and avoid morbidity. expertise in a variety of technical procedures is required to
Severely ill patients require special attention. Their condition facilitate diagnostic and therapeutic efforts.
is dynamic and can change quickly. These patients may require
rechecking key indices such as coagulation panels or ionized
electrolyte concentrations as frequently as each hour. Cardiac Y VASCULAR ACCESS AND
rhythm reassessment or direct blood pressure measurement ADMINISTRATION OF FLUIDS
may be required on a minute-by-minute basis (continuous
telemetry is particularly beneficial in these patients). Establishing venous access is often crucial in critical care.
Expected and unexpected problems can be encountered Generally, using large veins (i.e., jugular veins, lateral thoracic
in the ICU patient. Horses with focal disease (e.g., injection veins, cephalic veins, and rarely saphenous veins) for access
site abscess) that by itself is unlikely to be life-threatening makes it easier to catheterize and deliver medications, fluids,
can develop multisystemic consequences that jeopardize the parenteral nutrition (PN), and perform blood draws for clini-
patient (e.g., hemolytic anemia, fever, anemic hypoxia, and copathologic monitoring. IV catheters are available in vary-
pigment nephropathy). Oftentimes, the development of seri- ing materials, constructions, lengths, and diameters (Tables
ous problems can be a consequence of a ramped up immune 4.2 and 4.3). In choosing a catheter, the practitioner should
system and SIRS. In health, inflammatory pathways can be consider the desired fluid rate, fluid viscosity, the length of
regulated by antiinflammatory pathways. When the balance time the catheter will remain in the vein, the severity of the
tips in favor of inflammatory pathways, overwhelming acti- systemic illness, and the size of the animal. Determinants
vated systemic inflammation ensues and downstream effects of catheter flow rate follow the Poiseuille-Hagen law: larger
can be observed, such as coagulopathy or acute respiratory lumen diameter (r), shorter length (L), and higher pressure
distress syndrome (ARDS), which may be seemingly unrelated differences (ΔP) between flow into the catheter versus flow out
to the primary disease process. of the catheter result in greater volumes per unit time through
Medication mistakes can be categorized in two main cat- the catheter (Poiseuille-Hagen equation of flow through a tube
egories: therapeutic-related unexpected adverse effects in the [e.g., catheter]):
patient and administration mistakes made by the ICU staff. 4
An example of an adverse effect would be the development of Flow α Pressure gradient (ΔP) × radius (r) /viscosity (η)
antibiotic-associated colitis (AAC). Horses with acute gastroin- × length (L)
testinal disease represent the most common admission to the
ICU. In many instances, these patients are stressed, inappetent In cases in which volume provision is critical, placement of
(often forcibly), and often require intestinal surgery, all of which short, large-bore catheters using a pressurized fluid bag would
are considered to be selection pressures for intestinal dysbio- optimize fluid delivery. Viscosity (η) of the fluid administered
sis.2 These horses also are frequently treated with antibiotics in also modulates a flow rate in which higher viscosity fluids (i.e.,
the perioperative period, which, with preexisting pressures, can natural colloids, blood, blood products) result in slower rates
lead to life-threatening colitis. It is prudent for the clinician to of fluid administration. Cautious use of high flow rates may
exercise good judgment on antibiotic usage and try to institute be more traumatic to the vascular endothelium, increasing
early enteral feeding where possible to help avoid AAC. thrombotic risk.
Medication administration mistakes can also occur. A Catheters are generally made of Teflon or polyurethane. The
recent article highlighted that poor compliance to medication thrombogenic properties of each material should be taken into
recommendations occurs more frequently than anticipated.6 consideration with the patient’s clinical condition. Polyurethane
Mistakes can be minimized by having clear medical records catheters (i.e., MILA International) are considered to be less
that list the generic name of the medication, the dose (e.g., thrombogenic than Teflon; therefore, it is recommended to use
number of milligrams), the amount of units delivered (e.g., this material in patients with clinical coagulopathy or “at risk
milliliters), route of administration, and frequency of dos- for” clinical coagulopathy. Typically these patients are horses
ing: for example, gentamicin, 3000 mg (30 mL), intravenously with hypoproteinemia; SIRS; those requiring blood products,
(IV), q 24 h. PN provision, endotoxemic/hemorrhagic shock, septicemia/
ICU orders should be reviewed by a supervising clinician bacteremia; and horses with inherited or acquired coagulo-
and signed off on as a check and balance, especially when pathic disease. Teflon catheters should be changed every 3 days,
multiple users may be following and carrying out these orders. and polyurethane catheters can remain in the vein for up to 2
Daily rounds with ICU personnel on the patient condition, weeks. Regardless of the type of catheter, the site of vascular
current treatment and monitoring plan, and a discussion of access should be closely monitored several times daily for signs
potential complications is highly informative for ICU staff and of flow disturbance, thrombosis, and/or infection.
helps maintain an open line of communication to ensure that For most applications, over-the-needle catheters are easi-
the orders are clearly understood. est and faster to place and achieve therapeutic goals in adult
TABLE 4.2 List of Available Catheters (by Material Type)

Material Example Comment
Polypropylene Polyethylene tubing, Medicut Highly thrombogenic not recommended
Teflon Angiocath Less thrombogenic
Polyurethane MILA Much less thrombogenic
Silastic Centrasil Least thrombogenic

TABLE 4.3 Commercially Available Catheters (by Construction Type)

Type Description Advantage Disadvantage
Butterfly Needle attached to tubing Ease of use Laceration of vessel; vessel
puncture and extravascular
administration
Over-the-needle Stylet inside catheter for venipunc- Available in large diameter, ease of Limited length of catheter, not
ture insertion flexible, break at catheter and
hub junction
Through-the-needle Short needle inserted; catheter All lengths available, flexible, Technically more difficult to
threaded through needle peel-away needle insert
Over-the-wire Needle serving as guide to insert Flexible, long catheters avail- More technical expertise
wire, which serves as guide for able, ensures proper catheter required to place catheter,
catheter placement expensive

horses. Over-the-wire (OTW) catheters are more technically Provision of an antithrombotic such as clopidogrel (4 mg/kg
challenging to place; however, they are often better tolerated PO once, then 2 mg/kg PO every 24 hours) has been used
long term and are less traumatic to the vascular endothelium. to help prevent thrombotic catheter complications despite
OTW catheters come in single-lumen and multilumen models proven efficacy.
and are often placed in foals and adult horses at high risk for Injection caps should be changed daily or sooner if exces-
thrombotic complications or patients in which multiple solu- sively perforated with multiple injections. Before inserting a
tions may be administered, especially hyperosmolar/hyper- needle, injection caps should be wiped with 70% isopropyl
tonic solutions. OTW catheters are recommended for lateral alcohol and allowed to dry.
thoracic vein catheterization caused by the acute angulation Catheters and extension sets may be secured using adhe-
that the vessel travels into the thorax. Ultrasound guidance sive glue for short-term catheters or directly sutured to the
can assist in catheter placement at this location, particularly in skin using 2-0 nonabsorbable suture material. Care should be
obese and edematous horses. taken to ensure that no part of the catheter is exposed when
Short- and long-extension sets are available as well as being secured.
small-bore and large-bore diameters. Using an extension set Each line can be labeled and the utmost care should be
with a Luer lock that screws into the hub of the catheter is exercised to never break the circuit of any solution contain-
best to prevent dislodgment. In horses with low central venous ing glucose (e.g., supplemented crystalloid solutions or PN)
pressures (CVPs), disconnection of the line can result in sig- to help prevent catheter and line sepsis. Some practitioners
nificant aspiration of air and cardiovascular collapse, notably apply triple antibiotic ointment to insertion sites to prevent
from jugular venous catheters. Moreover, one-way hemostatic infection, although evidence is lacking about the efficacy of
valves are also available to help prevent backflow of blood and this practice. If infection is suspected, the catheter should be
aspiration of air. removed and the catheter tip should be cultured (aerobic and
Horses receiving multiple infusions (i.e., crystalloid flu- anaerobic).
ids and continuous rate infusions [CRI’s]), may benefit from Coil sets are used for stall-side fluid administration for
double extensions in which each fluid/medication type has most adult horses. These are advantageous because they allow
an individual port entering a central line catheter rather than the horse to move around, lie down, and eat without restraint.
“piggybacking” fluids into each other. An overhead pulley system with a rotating hook prevents fluid
lines from becoming tangled.
Catheter Maintenance and Care Solution administration sets are used for short-term fluid
Before using any placed catheter, drawing back on the cath- or drug administration and typically deliver 10 drops/mL.
eter to ensure intravascular placement is advised. Cath- Long coiled extension sets can then be used to connect fluids
eters should be flushed frequently with heparinized saline to the horse.
(10 units/mL) before and after each medication administered Calibrated pumps allow continuous even delivery of solu-
and every 4 to 6 hours after catheter placement. For some cath- tions at designated flow rates (CRI). When using a calibrated
eters that are infrequently used, a “heparin lock” comprised of fluid pump, one should take care to use the appropriate set cal-
20 units/mL heparinized saline instilled in the catheter, fol- ibrated for the brand of pump. These pumps have alarms that
lowed by line clamps, may help preserve the integrity of flow. signal air in the line, an empty fluid bag, or catheter problems.
TABLE 4.4 Parameters Used for Estimation of Dehydration in the Horse

Heart Rate (Beats
% Estimated Dehydration per Minute) CRT (Seconds) PCV/TP (%/g/dL) Creatinine (mg/dL)
6 40–60 2 40/7 1.5–2
8 61–80 3 45/7.5 2–3
10 81–100 4 50/8 3–4
12 >100 >4 >50/>8 >4

CRT, Capillary refill time; PCV, packed cell volume; TP, total protein.
The maximal fluid rate that most commercial pumps can of liters of enterogastric reflux) or estimates of ongoing fluid
deliver is 999 mL/h, which is insufficient for crystalloid deliv- losses to calculate a total volume deficit/requirement for the
ery in most adult horses. Infusion pumps are useful for PN, first 24 hours.
multimodal analgesia, prokinetic therapies, and cardiovascu- The rate of fluid administration depends on the severity of the
lar drugs, to name a few. Some clinicians advocate CRI antibi- critical illness. Horses with profound deficits and cardiovascular
otic administration for time-dependent drugs (i.e., β-lactams) compromise require expedient delivery of resuscitative fluids.
to minimize peak-trough pharmacodynamics and potential The type of fluid also varies, depending on the critical
periods of subtherapeutic (sub–minimum inhibitory concen- nature. Replacement crystalloids typically have higher sodium
tration) drug delivery. and chloride concentrations than maintenance solutions
For large-volume fluid delivery, peristaltic or oscillation that have lower sodium and higher calcium, potassium, and
infusion pumps are available that can deliver up to 40 L/h. One magnesium concentrations. Hyperosmolar solutions and/or
must supervise these pumps constantly when in use because colloid solutions may also be indicated, and, together with iso-
they continue to run even if fluids run out. Large-bore cath- tonic crystalloids, all three types should be considered.
eters should be used to prevent trauma resulting from the jet Special circumstances to consider when delivering fluid
effect on the endothelium of the vein. therapy include patients with renal failure. Both volume and
content of fluid choice should be considered depending on the
Y FUNDAMENTALS OF FLUID THERAPY clinical disease process—for example, anuric renal failure ver-
sus acute tubular necrosis of the proximal convoluted tubule
The provision of fluid therapy to adult horses is a pivotal (PCT) and abnormal fractional electrolyte clearances. Horses
modality in treating the critically ill equine patient. Dehydra- with decreased oncotic pressure may not tolerate high-volume
tion is detectable clinically when the deficit comprises 5% or crystalloid therapy without adjunctive colloid support.
greater. Fluids can be delivered in several methods but most Cardiopulmonary arrest, while dire in nature, is the ulti-
commonly enterally and IV. Intraperitoneal and intraosseous mate form of congestive heart failure, and judicious limited
delivery is less commonly used but possible with specific indi- fluid therapy to allow for enough circulation of cardioactive
cations. Parenteral fluids should be administered to horses who therapies is indicated without excess loading of the vascular
cannot tolerate enteral fluids (i.e., gastrointestinal obstruction, circuit.
esophageal trauma, dysphagia, and/or dehydration estimates
exceeding 5%). Enteral fluids are often more cost-effective and Maintenance Requirements
indicated in cases with mild volume deficits (≤5%) and may In the adult horse, maintenance fluid requirements have been
be more effective for certain conditions than parenteral fluid estimated at 40 to 60 mL/kg per day. This volume likely overes-
delivery (e.g., colonic impaction) and maintenance therapy. timates the actual needs of a resting, fasted animal but appears
to be safe in most situations. Smaller breeds may be more
Rational Fluid Therapy Planning appropriately dosed at 60 mL/kg per day, and heavier breeds
An understanding of fluid types and properties as well as the (e.g., draft horses) are more appropriately dosed at 40 mL/
needs of the patient are essential to design a fluid therapy plan. kg per day. In horses with renal failure, monitoring of body
The clinician should consider several key questions that facili- weight, CVP, and ideally urine output is indicated. If weight
tate developing a fluid regimen: gain, edema, or increased CVP (>12 mm Hg) is evident, the
1. What volume of fluid is required? fluid administration rate should be decreased if not stopped
2. What rate of fluid is required? and other renal replacement therapy (RRT) considered.
3. What type of fluid is required?
4. What specific circumstances (physical and physiologic) do Fluid Deficit
you need to consider? Practical evaluation of hypovolemia caused by dehydration is
The volume of fluid required is determined based on the a subjective estimate using both clinical and clinicopathologic
clinical and clinicopathologic data gleaned from a thorough findings. Table 4.4 lists useful parameters for evaluating acute,
clinical examination and minimum database laboratory work. extracellular dehydration.
Skin turgor, heart rate, mucous membrane color and texture, After obtaining an estimate of dehydration, the clinician
eye position, neurologic status, serum creatinine concentra- can calculate the amount of fluids to be given as follows
tion, and packed cell volume with total protein estimates help (Table 4.5):
the clinician determine a deficit, often expressed as a percent-
age of body weight. Maintenance fluid requirements should Volume (Liters) = Body Weight (kilograms)
be combined along with either quantification (i.e., number × Percent Dehydrated (expressed as a decimal)
TABLE 4.5 Commonly Used Equations in Critical Care normalize. Additional means of monitoring adequate fluid
delivery may include measurement of CVP, arterial blood
Maintenance fluids pressure, and urine output.
requirement (mL) 40–60 mL/kg/day The fundamental basic principle of establishing a fluid
Fluid deficit calculation Body weight (kg) × percent dehy- therapy regimen centers on choosing an appropriate volume
(L) drated (expressed as a decimal) as follows (see Table 4.5):
Electrolyte deficit for Body weight (kg) × 0.3 (ECF ∑
monovalent electro- coefficient) × ([Electrolyte]desired Fluid requirement (initial 24 hours) = (fluid deficit
lytes in abundance in − [Electrolyte]measured) + estimated losses + maintenance needs)
the ECF space (e.g.,
bicarbonate) This is a starting point and subject to change based on clinical
Shock rate of isotonic 80–100 mL/kg in the first 60–90 response of the patient.
crystalloid (mL) min
Fluid Choices
Blood transfusion ([PCVdesired − PCVpatient] × body
Isotonic crystalloid fluids almost always constitute the
volume (L) weight [kg] × 0.08 [blood vol-
foundation of any parenteral fluid therapy regimen. The
ume coefficient])/PCVdonor
type of crystalloid fluid to administer depends on the
Osmolarity (mOsm) 2 × [Na] + glucose/18 + BUN/2.8 results of a chemistry evaluation and disease of the patient.
(when glucose and BUN are Generally, an appropriate volume is most critical. How-
measured in mg/dL) ever, when several options are available, one should decide
Mean arterial pressure 1
⁄3 × (SAP − DAP) + DAP between a balanced electrolyte solution (BES) or isotonic
(mm Hg) saline (0.9% NaCl) as the baseline fluid. Additives can then
Pulse pressure (mm Hg) SAP − DAP be added à la carte to treat specific electrolyte and/or meta-
Cerebral perfusion pres- MAP − ICP bolic derangements.
sure (mm Hg) Table 4.6 lists the composition of various commercially
Abdominal perfusion MAP − IAP
available fluids. Generally, BESs are chosen when serum
pressure (mm Hg)
electrolytes are close to normal or when chemistry analysis
is unavailable, because BESs are generally considered more
Content of oxygen in (1.34 × [hemoglobin] × Sao2) + physiologic.
arterial blood (Cao2 (0.0031 × Pao2) Physiologic saline might be preferable in conditions in
[mL O2/dL]) which potassium restriction is indicated (e.g., hyperkalemic
Delivery of oxygen (mL/ Q (cardiac output) × Cao2 states, such as hyperkalemic periodic paralysis, uroperito-
minute) neum, renal failure) because BESs all contain some potassium.
Oxygen extraction ratio (Cao2 − Cvo2)/Cao2 or BESs, by their nature, also have buffering ability. Lactate in
(Sao2 − Svo2)/Sao2 lactated Ringer’s solution (LRS) requires hepatic metabolism;
Alveolar Po2 (Pao2) Fio2 × (Patmosphere − PH O) − thus, LRS may not be an ideal choice in horses with liver dys-
2
Paco2/0.8 function. In cases of long-term fluid maintenance therapy
A-a gradient PAo2 − Pao2 (greater than 4–5 days), if the oral route is not available, the
practitioner should consider half-strength basic fluids (e.g.,
ECF, Extracellular fluid; PCV, packed cell volume; BUN, blood urea nitrogen; 0.45% NaCl and 2.5% dextrose) to which potassium and cal-
SAP, systolic arterial pressure; DAP, diastolic arterial pressure; MAP, mean cium are added. Long-term fluid therapy with routine BESs
arterial pressure; ICP, intracranial pressure; IAP, intraabdominal pressure. can result in hypernatremia, hypokalemia, hypomagnesemia,
and hypocalcemia.
Routine electrolyte supplementation often includes cal-
Continued Ongoing Losses cium, potassium, and magnesium provision. This is particu-
Objective quantification of ongoing losses is ideal but sel- larly important when the horse receives limited or no enteral
dom truly reflective of all volume deficits. Even measuring intake (e.g., gastrointestinal disease). These electrolytes are
enterogastric reflux volume still does not account for the third important for smooth muscle function, vascular tone, and
spaced volume of fluid within the bowel that remains. This intestinal smooth muscle activity.7,8
remaining volume does not contribute to effective circulat- Suggested doses of calcium depend on ionized calcium
ing volume and, as such, quantification of reflux in the bucket concentrations. Routine supplementation with 10 mL of
underestimates the true volume deficit. Horses with high- 23% calcium gluconate per liter of fluids is used by the
volume diarrhea can also lose significant volumes as well as author as a starting point. Potassium chloride can be sup-
third space volume within the large reservoir of the large colon plemented at up to 0.5 mEq/kg per hour maximum paren-
and cecum. teral rate. The author starts at 0.05 mEq/kg per hour for
Regardless of the nature of ongoing losses, frequent clinical routine supplementation and 1 g magnesium sulfate per
and clinicopathologic reassessment of the patient is imperative liter of fluids.
to minimize further deterioration. Heart rate, measurement Horses with high anion gap metabolic acidosis (e.g.,
of packed cell volume, total protein, and l-lactate concentra- lactic acidosis) are often hypobicarbonatemic because of
tion are clinically useful every 2 to 6 hours, depending on the increased buffering of organic acid production. In most
nature of critical illness. instances, this represents a type A lactic acidosis, such as
Daily creatinine concentration assessment and urinalysis perfusion-mediated hyperlactatemia. As such, volume res-
are indicated in patients with azotemia until laboratory values toration to optimize systemic perfusion should be the first
TABLE 4.6 Crystalloid Solutions Available for Fluid Therapy

Product Approximate pH mOsm/L Na (mEq/L) K (mEq/L) Ca (mEq/L) Mg (mEq/L) Cl (mEq/L) Buffer (mEq/L)
Lactated Ringer’s 6.5 273 130 4 3 — 109 Lactate 28
solution
Lactated Ringer’s 5 525 130 4 3 — 109 Lactate 28
solution and 5%
dextrose
Plasma-Lyte A 7.4 294 140 5 — 3 98 Acetate 27
Gluconate 23
Plasma-Lyte 148 7.4 294 140 5 — 3 98 Acetate 27
Gluconate 23
Plasma-Lyte 148 5.5 294 140 5 — 3 98 Acetate 27
Gluconate 23
Plasma-Lyte 56 and 5 362 40 13 — 3 40 Acetate 16
5% dextrose
5% dextrose 4 252 — — — — — —
0.9% NaCl 5 308 154 — — — 154 —
7% NaCl — 2400 1196 — — — 1196 —
5% dextrose and 4 560 154 — — — 154 —
0.9% NaCl
5% dextrose and 4 280 77 — — — 77 —
0.45% NaCl
5% NaHCO3 8 1190 595 — — — 595 —
8.4% NaHCO3 — 2000 1000 — — — 1000 —
1.3% NaHCO3 (must — 308 154 — — — 1541 —
be mixed)

step in treating the acidosis; however, in extreme cases, option. The deficit is calculated and the number of milliequiv-
supplemental bicarbonate (NaHCO3) treatment may also alents converted to a weight (in grams):
be required.
Horses receiving bicarbonate therapy should have their 1 g NaHCO3 = 12 mEq NaHCO3
respiratory function assessed because carbon dioxide (CO2)
generated from carbonic anhydrase activity requires nor- The total number of grams is divided into several admin-
mal alveolar ventilation for effective CO2 removal. Respi- istrations per day. Orally administered NaHCO3 may cause
ratory compromise will result in worsening of acidemia minor caustic injury to the gingival mucosa. Mixing NaHCO3
caused by mixed metabolic and respiratory acidosis. with Karo syrup or molasses and washing the mouth after the
For horses with a pH ≤7.2 caused by metabolic derange- horse swallows may help prevent injury.
ments (nonrespiratory) following shock crystalloid dosing (80
mL/kg in 1 h), isotonic bicarbonate (1.3%) therapy is indi- Rate of Administration
cated. First, administer 50% of the bicarbonate deficit (see For patients in severe shock, the clinician should strive to
later) rapidly over 1 to 2 hours followed by the remaining 50% administer a shock dose of isotonic crystalloid fluids in the
over 12 to 24 hours. first hour (80 mL/kg), which can be done only with pressur-
Note that parenteral bicarbonate solutions are incompat- ized bags, a fluid pump, and/or multiple catheters.
ible with calcium-containing solutions. The 1.3% sodium In other situations, the volume calculated accounting for
bicarbonate solutions are isotonic, and 8.4% sodium bicar- losses, replacement, and maintenance represents a volume
bonate solutions are hypertonic (1 mEq/mL). To make a 1.3% for the 24-hour requirements and estimates as a volume per
NaHCO3 solution, remove 130 mL of water from a 1-L sterile hour. Accurate record keeping of a running tally of fluids
water bag. Add 130 mL (130 mEq) of 8.4% NaHCO3 to the provided is important to ensure that the correct amount is
sterile water bag. administered.
Bicarbonate de�cit = (Bicarbonatedesired − Bicarbonatemeasured ) Y ORALLY ADMINISTERED FLUIDS

× body weight (kilograms) × �.� (e�tracellular �uid
[ECF] compartment coeﬃcient; see Table 4.5) Oral fluids are indicated in horses with only mild volume
deficits and who can tolerate enteral fluids (e.g., no intes-
For ongoing losses of bicarbonate not associated with tinal obstruction or reflux). Oral fluid therapy should be
excessive plasma buffering (e.g., hypersecretory diarrhea, administered using the fluid composition shown in Table 4.7.
renal tubular acidosis), enteral supplementation is a suitable One should administer calcium separately because it causes
TABLE 4.7 Fluid Composition for Orally Administered Hypertonic Saline Solution (7.2% NaCl)
Fluid Therapy Hypertonic saline solution (HSS) is approximately eight times
the tonicity of plasma and ECF, and the immediate effect is
For Every L of Water, add: to rapidly expand the vascular volume by redistribution of
FOR EVERY 21 L OF WATER fluid from the interstitial and intracellular spaces. The rapid
increase in vascular volume improves cardiac output (CO)
Electrolyte Amount (g)
and tissue perfusion with rapid administration of only a rel-
NaCl 10 atively small volume of fluid. Initially, this is a roughly 1:3
NaHCO3 15 ratio—that is, for every liter of HSS administered, the patient
KCl 75 recruits up to 3 L of volume expansion. This effect is short-
K2HPO4 60 lived (estimated to be ∼20 minutes). Because the electrolytes
redistribute across the ECF, fluid redistribution occurs again
and the patient becomes hypovolemic again. Because the
principal effect is fluid redistribution, a total body deficit still
precipitation of the solution. This electrolyte solution meets exists and it must be replaced. For this reason, concurrent or
daily needs for an adult horse and can be given through a immediately following HSS administration, isotonic crystal-
small, preplaced nasogastric feeding tube or by intermittent loids must be provided to correct the total body volume defi-
intubation. cit. The duration of effect of hypertonic solutions is directly
proportional to the distribution constant, which is the indexed
Parenteral Fluids CO. The dose is 2 to 4 mL/kg, administered as rapidly as pos-
sible. Iatrogenic metabolic acidosis, hypernatremia, and hypo-
Crystalloids kalemia may occur after hypertonic saline administration;
The IV administration of isotonic crystalloids immediately therefore, plasma electrolyte concentrations should ideally be
reconstitutes effective circulating volume. Crystalloids (all evaluated in the patient before and after the administration of
types) rapidly redistribute out of the vascular space (VS) to hypertonic saline.
the entire ECF space. The ECF is roughly 30% of body weight,
and the VS is roughly 8% of body weight. As such, to maintain Maintenance Solutions
a desired expanded intravascular volume, 3 to 3.75 times as Crystalloid maintenance fluids are polyionic isotonic or hypo-
much volume is required to account for redistribution among tonic fluids formulated for long-term use in patients needing
the entire ECF. BESs are typically chosen such as LRS. Doses chronic fluid support beyond fluid volume resuscitation. They
of BESs for rapid volume expansion (not maintenance fluid contain lower sodium and higher potassium, calcium, and
requirements) are 70 to 90 mL/kg per hour with frequent magnesium concentrations. Examples include Plasma-Lyte
(every 20 minutes) reassessment of additional volume needs. 56, Normosol-M, and 0.45% NaCl/2.5% dextrose, and these
fluids should not be used for rapid volume expansion.
Replacement Solutions Colloids
Lactated Ringer’s Solution Colloid fluids contain large molecular weight particles that do
LRS has a lower sodium concentration and higher chloride not readily diffuse across healthy cellular barriers, maintaining
concentration than equine plasma. LRS should be avoided in or increasing COP within the intravascular space. These mole-
cases of hyperkalemia because of low levels of potassium and cules do redistribute to the ECF but at a much slower rate than
when administering products containing citrate or bicarbon- crystalloids; thus, the duration of effect is prolonged compared
ate, because the calcium in LRS may precipitate. Lactate in with that of crystalloids. Table 4.8 describes the different col-
LRS is metabolized by the liver and, in theory, may accumulate loids available. Critically ill patients often develop endothelial
and contribute to metabolic acidosis in patients with hepatic dysfunction, and the associated increased vascular permeabil-
dysfunction. ity may ameliorate some of the beneficial effects of colloids,
dependent, in part, on the average molecular size of the col-
Plasma-Lyte 148 and Normosol-R loid administered. For example, hetastarch (6% hydroxyethyl
Plasma-Lyte 148 and Normosol-R are similar to LRS but have starch) has an average molecular size of 450 kDa, and albu-
a more physiologic sodium:chloride ratio and contain mag- min in plasma has a molecular size of 70 kDa. Further, meta-
nesium rather than calcium. They may be administered con- analyses in humans failed to support the theory of improved
currently with blood products and bicarbonate but should be resuscitation through the use of colloids over crystalloids9;
avoided in cases where neuromuscular blockade is a concern however, colloids may be indicated in patients with hypopro-
(e.g., botulism). The alkalinizing agents in these fluids are ace- teinemia, severe blood loss, or those in need of clotting factors
tate and gluconate, respectively. or immunoglobulins.
A disadvantage of natural colloids (plasma or albumin)
Normal Saline (0.9% NaCl) is that they are more antigenic and can cause allergic reac-
Normal saline consists solely of sodium and chloride in con- tions. Synthetic colloids have a much lower antigenicity, but
centrations significantly higher than that of plasma. Saline they can cause bleeding disorders because of their tendency to
is acidifying and is useful in the treatment of patients with coat platelets or by causing a decrease in coagulation factors.
hyperkalemia and metabolic alkalosis. The use of normal In the horse Dextran 40 can cause anaphylactoid reactions.
saline in cases of hyponatremia is cautioned because overly Hetastarch administration can cause a decrease in coagula-
rapid correction of sodium concentrations may lead to exces- tion factors and prolong clotting times, particularly at high
sive osmotic draw of water from cells. doses (20 mL/kg).10
TABLE 4.8 Characteristics of Colloid Solutions Available for Fluid Therapy

Hetastarch Tetrastarch
Characteristics 5% Albumin 25% Albumin Dextran 40 Dextran 70 (600/0.75) 6% (130/0.4) 6%
Molecular weight (d) — — — — — —
Average 69,000 69,000 40,000 70,000 450,000 130,000
Number average 69,000 69,000 25,000 39,000 70,000
Range — — 10,000–80,000 15,000–160,000 10,000–3,400,000 110,000–
150,000
Solvent — — 0.9% saline or 5% 0.9% saline or 0.9% saline or 0.9% saline
dextrose 5% dextrose balanced
electrolyte solution
Maximum water 18 18 37 29 20 —
binding (mL/g)
Concentration (%) 5 25 10 6 6 6
Half-life 14–16 days 14–16 days 2.5 h 6h 25 h 12 h (human)
Plasma percentage — — 18 29 38 —
(after 24 h)
Extravascular per- — — 22 33 39 —
centage (after 24 h)
Overall survival in — — 44 h 4–6 weeks 17–26 weeks —
blood
Colloid osmotic 20 100 40 — 30 36
pressure (mm Hg)

Synthetic colloids do not register on a refractometer. Accu- of oncotic effect, the potential for adverse reactions (10%
rate evaluation of oncotic pressure requires the use of a colloid incidence),15 and the relatively high cost if given for large-
osmometer. If one is not available, the clinician must use clini- volume resuscitation.
cal evaluation (e.g., observing the presence of edema and poor
circulatory volume and pressure). Whole Blood
Whole blood can be considered the ultimate colloid replace-
Synthetic Colloids ment fluid when indicated in cases of hemorrhage.16 Blood
Hetastarch is a more cost-effective synthetic colloid. Advan- transfusion may restore circulating volume, improve oncotic
tages of hetastarch include maintenance of plasma oncotic activity, increase oxygen-carrying capacity, is a supply vehicle
effect for up to 24 hours following administration and the for therapeutic drug transport, and replenishes coagulation
ability to give as a rapid bolus.10,11 However, unlike plasma, factors. Whole blood is the ideal fluid for blood loss or plate-
there are no functional proteins present in hydroxyethyl let loss, provided that it is fresh blood and has been cross-
starch solutions and a negative effect on coagulation has matched. It is important to remember that stored blood loses
been demonstrated in healthy equids.10,12 Further, a 2013 its oxygen-carrying capacity and it can take several hours to
review of the use of colloids as volume replacement in criti- restore it after administration.
cally ill humans found an increased risk of mortality and Access to whole-blood donors that are free of erythrocyte
acute kidney injury in patients receiving hetastarch.13 As antigenic determinants, particularly Aa and Qa, and of isoan-
such, the use of hetastarch in horses with underlying renal tibodies are important hores to have available to ones practice.
insufficiency is cautioned, and its use is restricted to those The practitioner can perform a major and minor cross-match
with clinical signs of acute hypoproteinemia. Recently tet- to select an appropriate donor, provided that complement is
rastarch (6%) was evaluated and shown to have a more added to the test for hemolysin detection. Interpretation of
sustained effect on COP with fewer adverse coagulopathic the minor cross-match may be difficult if autoagglutination is
effects than hetastarch.14 Both hetastarch and tetrastarch present. If cross-matching is unavailable, use of a non-Thor-
can be dosed at 10 mL/kg. oughbred gelding is advised. Up to 20 mL/kg can be safely
collected every 3 weeks in adult horses, and whole blood can
Natural Colloids: Plasma be collected in sodium citrate using sterile technique provided
Plasma contains not only osmotically active albumin but the product will be used immediately.
a variety of essential proteins, including clotting factors, Commercial blood collection kits are also available. The
immunoglobulins, and antithrombin III. The advantage of reported incidence of transfusion reactions is 16%,17 and a
plasma over synthetic colloids is that these proteins provide recent study showed a marked decrease in transfused erythro-
carrier sites for exogenous (pharmaceuticals) and endog- cyte half-life with an incompatible cross-match (4.7 days ver-
enous (hormones) compounds. Disadvantages of plasma as sus 33.5 days).18 Complications of blood transfusion include
a resuscitation fluid in horses include the prolonged time acute anaphylactic reactions, allergic reactions, hemolysis,
required for administration, a relatively short duration fever, tachypnea, and hypocalcemia caused by citrate chelation.
Oxygen delivery to tissues depends on adequate perfusion

Critical Care Techniques of functional capillary density (FCD) of the tissues. FCD has
recently become a research interest in veterinary species in
Samuel D. Hurcombe which dark-field microscopy has been used to evaluate gin-
gival and colonic perfusion.19 Clinically, FCD quantification
techniques are impractical; thus, blood pressure is used to esti-
Y MONTORING ARTERIAL mate blood flow and tissue perfusion. MAP as a perfusion esti-
BLOOD PRESSURE mate does not account for local regulation of tissue bed blood
flow. Regional shunting, regional vasomotor tone differences,
The goal of blood pressure measurement is to identify hypo- microthrombi, and interstitial edema may all affect local blood
tension and follow the response to therapy after interventions. flow. Blood flow through a vessel is also dependent on the vis-
Mean arterial blood pressures (MAPs) of greater than 70 mm Hg cosity of the fluid (blood) and the radius of the vessel. At high
are targeted in the adult, and pressures greater than 60 mm Hg viscosity blood flow may be impaired. Severe vasoconstric-
are targeted in neonates. Table 4.9 shows expected blood pres- tion, although maintaining blood pressure, may impair flow.
sures in healthy conscious horses. Hypertension is uncommon
in horses. Pheochromocytoma, pain, and transient hypertensive Direct (Invasive) Blood Pressure Measurement
states associated with pressor agents have been described. A 20-gauge or 22-gauge over-the-needle catheter is most
Arterial blood pressure can be measured by direct catheter- commonly used to perform direct or invasive blood pressure
ization of a peripheral artery or by indirect measurements that measurement. Suitable sites for catheterization include the
depend on a cuff placed over an artery and cuff inflation until transverse facial, facial, and greater metatarsal arteries (Fig. 4.1).
blood flow is occluded. Blood pressure can also be calculated as In the standing horse the transverse facial or the facial artery
the product of CO and systemic vascular resistance (SVR). The are most practical. Catheters are placed toward the direction
MAP is a surrogate estimate of tissue perfusion but does not nec- of blood flow (i.e., toward the heart), and noncompliant tubing
essarily correlate with blood flow through the tissue. For example, filled with heparinized saline is used to connect the catheter to
a hypovolemic patient with high SVR may have a MAP within an a calibrated pressure transducer. It is important to flush all air
acceptable range; yet, the actual volume of blood per unit time from the circuit to avoid dampening of the waveform.
flowing through the tissue (e.g., perfusion volume) might be Blood pressures are measured in millimeters of mercury
inadequate. Horses can have low MAP as a result of hypovolemia, (mm Hg), which measures the force exerted by the blood
SIRS, heart failure, or any of a wide variety of disorders. against an area of the vessel wall to raise a column of mer-
Most monitoring equipment provides an estimation of sys- cury by a certain number of millimeters. Occasionally, cen-
tolic arterial pressure (SAP), diastolic arterial pressure (DAP), timeters of water (cm H2O) are used where 1 mm Hg = 1.36
and MAP. MAP is a calculated value determined by integrat- cm H2O. Continuous readings of blood pressure are most
ing the area under the pressure waveform and dividing this by useful clinically and can be graphically displayed using an
the duration of the cardiac cycle. MAP can also be calculated electronic transducer that converts a pressure signal to an
by MAP = 1⁄3 × (SAP − DAP) + DAP (see Table 4.5). electronic output. The transducer and flush device (Pressure
Pulse pressure is the difference between systolic and dia-
stolic pressure (SAP − DAP; see Table 4.5). A bounding
pulse pressure results from an increased systolic pressure, a
decreased diastolic pressure, or both. Conversely, a poor or
weak pulse quality indicates little difference between SAP and
DAP. Ultimately, pulse pressure is not a good surrogate of per-
fusion, and clinical markers of perfusion or quantitative meth-
ods of CO are required for improved accuracy.
TABLE 4.9 Hemodynamic Parameters in Adult Horses

Type of Pressure Blood Pressure Reading
Arterial pressure
Mean arterial pressure >60 mm Hg
(indirect) 106 ± 12 mm Hg
Mean arterial pressure
(direct)
Systolic (indirect) 111.8 ± 13.3 mm Hg
Systolic (direct) 142 ± 18 mm Hg
Diastolic (indirect) 67.7 ± 13.8 mm Hg
Diastolic (direct) 82 ± 12 mm Hg
Central venous pressure 8–12 mm Hg (6–18 cm H2O)

Data from Magdesian KG. Monitoring the critically ill equine patient. Vet Clin
North Am Equine Pract. 2004; 20:11-39; Hurcombe SD, Scott VHL. Direct
intraabdominal pressures and abdominal perfusion pressures in unsedated FIG. 4.1 Adult horse with an arterial catheter in the transverse facial
normal horses. J Vet Emerg Crit Care. 2012; 22(4):441-446. artery for direct blood pressure monitoring.
Monitoring Kit with TruWave disposable pressure trans- Doppler (Systolic Arterial Blood Pressure)
ducer; Edwards Lifesciences, Irvine, CA) then can be used Doppler uses a small ultrasound probe placed on a periph-
for continuous blood pressure measurement. The transducer eral artery, and a piezoelectric crystal within the probe con-
should be maintained at the level of the heart base, which is verts the pulse wave into an audible signal. The probe must be
estimated to be at the point of the shoulder. Pressure record- placed over a shaved area (usually under the tail of the horse)
ing systems should be zeroed to atmosphere before reading after application of a coupling gel. Doppler only measures sys-
from the patient. tolic arterial blood pressure.
When the waveform appears flat or dampened, the line and
catheter should be flushed to yield a “square wave.” When the Oscillometric Sphygmomanometry
flush is stopped, the arterial waveform should resume. This test Oscillometric sphygmomanometry relies on detecting changes
also evaluates the dampening status of the circuit. Immediately in oscillations generated by changes in blood flow during grad-
after flushing, wave oscillations are observed before beginning ual deflation of a cuff. Oscillations are initially detected once
the next arterial waveform. Two oscillations are considered the cuff pressure decreases to be equal to the systolic pressure.
normal. An overdamped system (e.g., clot in the catheter, air Maximal oscillations are detected when cuff pressure is equal
bubble in connection tubing) results in fewer oscillations and to the mean pressure and then disappear when the cuff reaches
lower magnitude. An underdamped system (e.g., long stiff diastolic pressure. The meter records and displays systolic, dia-
tubing) results in a greater number of oscillations. stolic, and mean pressures (Fig. 4.2).
Indirect (Noninvasive) Blood Pressure Photoplethysmography

Photoplethysmography relies on the detection of arterial vol-
Measurement ume by attenuation of infrared radiation. Photoplethysmogra-
Indirect blood pressure measurements depend on a cuff placed phy originally was designed for use in human fingers and has
around the tail (coccygeal artery) or the metatarsus (metatar- been validated for use in small dogs and cats but has not been
sal artery). The diameter of the cuff influences the accuracy evaluated for use in horses.
of the measurement, and cuffs that are too wide result in
underestimation of the blood pressure. An ideal cuff width-to-
circumference ratio of 0.25 to 0.35 has been recommended for Y CENTRAL VENOUS PRESSURE
use on the tail or limbs of horses. Cuff widths are available for
neonate, pediatric, and adult horses. Monitoring Central Venous Pressure
CVP is the hydrostatic pressure within a large central vein, typi-
cally the cranial vena cava, and is an estimate of right atrial fill-
ing pressure. The CVP is affected by vascular volume, venous
tone, and cardiac function. Monitoring CVP is most useful for
patients in which the veterinarian is attempting to maintain
adequate vascular volume without fluid overload. For example,
assessment of CVP may be useful in horses with oliguric or
anuric renal failure, horses with large-volume gastric reflux, and
horses predisposed to edema formation. The venous system has
high volume capacitance, which makes CVP quite insensitive to
subclinical volume overload. By the time CVP measurements
increase, transvenous fluid shifts, and interstitial edema and
volume overload have likely occurred.
Conversely, negative CVP values may reflect hypovolemia,
indicating a need for fluid therapy.20 As with measurements
of arterial blood pressure, the trend in CVP seen through
repeated monitoring is most informative.
CVP is measured by using an IV catheter placed in the
jugular vein and terminating in the intrathoracic portion of
the cranial vena cava. The catheter is attached via an extension
set to a water manometer positioned such that the pressure is
at the level of the base of the heart (point of the shoulder), or
it can be connected to an electronic transducer. The latter is
preferred by the author because the typical CVP waveform can
be visualized to confirm accurate location of the catheter tip.
Normal CVP in adult horses is 8 to 12 mm Hg (6–18 cm H2O).
Y EMERGENCY TRACHEOSTOMY
FIG. 4.2 Indirect oscillometric blood pressure cuff applied to the tail Acute respiratory distress referable to obstruction of the upper
(coccygeal artery) of this 27-year-old Miniature Horse. Lower left inset is a respiratory tract represents a true emergency and need to estab-
close-up of the tail cuff. Lower right inset is the electronic indirect blood lish a patent airway. It is important for the clinician to make
pressure reading. This horse had apparent blindness and was found to a rapid assessment of that patient to determine the anatomic
have hypertensive cardiomyopathy on echocardiography. location (upper versus lower respiratory tract) of obstruction
placement of chest tubes. Indwelling tubes used are typically

BOX 4.2
Materials Needed for an Emergency 20 to 32 Fr and sterile. The location for tube placement is ide-
Tracheostomy Pack ally identified by ultrasound; however, a rough guide for safe
placement is a hand span caudal to the olecranon and a hand
Local anesthetic (2% without epinephrine) span dorsal to the lateral thoracic vein. Where possible, the
20-gauge needle and 10-mL syringe most ventrally dependent location that minimizes trauma to
Sterile, disposable no. 10 surgical blade the heart and lateral thoracic vein is ideal.
Metzenbaum scissors The clinician clips and prepares the site with antiseptic,
Hemostats infiltrating it with 2% local anesthetic. An incision is made in
J-type tracheostomy tube or self-retaining tube the desensitized skin slightly cranial to the proposed point of
entry, and the trocar is inserted through the skin. The clinician
moves the incision in a caudal direction to the cranial mar-
and to decide if a tracheostomy is indicated. Box 4.2 shows the gin of the nearest rib. Using controlled pressure, the trocar is
typical equipment needed for a tracheostomy. advanced perpendicular to the chest wall and in a slight caudal
When possible, the clinician should clip and prepare the direction. Fluid is seen to fill the tube, and the tube is fed off
planned incision site and infiltrate it with 2% local anesthetic. In the trocar. A unidirectional flow apparatus should be placed
cases of true acute respiratory obstruction, the patient may be in on the free end of the tube (e.g., Heimlich valve, latex glove
such distress that surgical preparation is unnecessary. At this time, finger, condom) to allow egress of pleural fluid but preventing
the operator should not waste time and immediately perform the air entry into the chest. The tube is secured at the entry point
tracheostomy without preparation. The clinician makes an 8- using 0 or 2-0 suture with a purse-string and Chinese finger
to 10-cm longitudinal incision at midline at the junction of the trap pattern.
proximal and middle third of the neck, just above the V made by Normal pleural fluid has a protein concentration <2.5 g/dL
the junction of the sternothyrohyoideus muscles. Blunt dissection and total nucleated cell count <5000/μL.
with Metzenbaum scissors is used to expose the tracheal rings. Pneumothorax is classified as open (e.g., external wound)
Next, an incision is made between two tracheal rings, taking care or closed (e.g., bronchopleural fistula). As pleural pressure
not to damage the tracheal cartilages. This incision should be no equilibrates with atmospheric pressure, lung collapse occurs
more than 50% of the circumference of the trachea. In emergency and can be seen as a cranioventral retraction of the lung field
situations a J-type tracheostomy tube is used because of its ease of on radiographs. Tension pneumothorax develops when air
insertion. When the horse is calm, or if the situation is not critical, continuously enters the chest without evacuation and repre-
a metal self-retaining tube is preferable for maintenance because sents a most serious and life-threatening condition in which
J-tubes tend to fall out. Silicone-cuffed tubes are also available for supraatmospheric pleural pressures causes rapid cardiorespi-
closed-system ventilation. ratory demise.
The tracheostomy tube should be cleaned daily and With open pneumothorax, rapid recognition, sealing of
changed as needed. The surgical site should be cleaned with the open wound, and evacuation of air must occur. In open
dilute antiseptic, and saline with petroleum gel applied pneumothorax sealing of the chest must occur, followed by
around the incision prevents skin scalding. Generally, but evacuation of air. Clear plastic wrap (e.g., Saran wrap) makes
particularly in foals, tracheostomy tubes should be removed an ideal temporary sealant that conforms to the chest and can
as early as possible to avoid permanent tracheal deformity. be wrapped around the thorax. Application of silver sulfadia-
To help decide when to remove the tube, the clinician can zine cream around the wound before plastic wrap application
occlude the tube temporarily to see if the horse can breathe provides a secure air-tight seal.
without it. After the tube is removed, the site should be Pleural air is then evacuated via placement of a cannula
cleaned of exudate twice daily and allowed to heal by sec- or 14-gauge catheter in the caudodorsal lung field. The 12th
ond intention. It is the author’s opinion that broad-spectrum or 13th intercostal space is a suitable location. Air is gradu-
antibiotics, such as potentiated sulfonamides, should be ally removed using 60-mL syringes. Reexpansion pulmonary
administered to help prevent local cellulitis and dissecting edema is a concern and can be avoided by slow, gradual air
infection down fascial planes of the neck. The wound gener- evacuation with evacuation pressures <25 mm Hg. As the lung
ally closes in 10 to 14 days and heals in 3 weeks. expands, it begins to “tickle” the cannula end, which is seen
as a twitching of the cannula during inspiration. The cannula
Y THORACOCENTESIS is removed once the air has been evacuated satisfactorily. In
closed pneumothorax or tension pneumothorax, the catheter
Pleural fluid drainage is integral in cases of effusive disease must be kept in place until the source of air entry can be sealed.
and can be life-saving. Prolonged increased pleural pressures
can lead to pulmonary collapse; associated respiratory dys- Y NASOGASTRIC INTUBATION
function; dyspnea; and in severe cases, cardiac tamponade.
Auscultation and percussion of the chest, an increased field of Nasogastric intubation is an essential and possibly life-saving
cardiac auscultation, and transthoracic ultrasound can iden- procedure performed in cases of equine colic. Unless contra-
tify pleural effusion. Different tools can be used to facilitate indicated (e.g., dangerous patient; head, neck, or esophageal
drainage depending on the volume, shock status of the patient, trauma), failing to pass a tube may be construed as negligence.
quality and tenacity of the fluid, and likelihood of the need for The patient should be adequately restrained, with a twitch
continued drainage. Small volumes can be drained using a teat and sedation if needed. The clinician should stand on the
cannula or 14-gauge catheter with the stylet removed. Larger side of the horse, with the hand closest to the horse placed on
volumes, hyperechoic fluid (e.g., pyothorax), proteinaceous the nose, and the thumb in the nostril. With the other hand,
fluid, and horses with infectious pleuritis usually require the clinician passes the tube in the ventral meatus, using the
thumb to keep it directed ventromedially. If any resistance nephrosplenic entrapment of the large colon. Colonic dis-
is met or a hard structure is encountered (possibly ethmoid tention can exert extraluminal pressure on the stomach
turbinates), the user should stop, retract, and redirect ven- and/or duodenum.
trally. On reaching the pharynx, the practitioner should feel The clinician should note the amount of reflux obtained
a soft resistance. The tube can be turned 180 degrees to direct because this factors into ongoing losses, and the volume of
its curvature dorsally. The clinician stimulates the horse to fluids given IV must be adjusted accordingly. Horses with
swallow by gentle to-and-fro movement or by blowing in functional ileus need gastric decompression usually every
the tube. Keeping the head of the horse flexed at the poll is 2 to 4 hours. The nasogastric tube should be left in place
helpful to direct esophageal passage. Once the horse swal- only as long as required, because some horses develop pha-
lows, the clinician pushes the tube into the esophagus. Blow- ryngeal and laryngeal irritation associated with its pres-
ing into the tube to dilate the esophagus facilitates insertion. ence.22 These horses may show pain on swallowing when
If the horse coughs, the clinician withdraws the tube and they resume feeding. Sinusitis can also occur because of
repeats the procedure until the tube is positioned correctly. nasogastric tube placement.23 When tubes are left in place,
Determining correct anatomic placement in the esophagus a small-bore tube that still allows effective gastric emptying
and stomach is imperative. It is signaled by gentle suction, should be used.
which should elicit a negative pressure; shaking of the tra-
chea, which should not elicit a rattle; and visual confirmation Y ABDOMINOCENTESIS
of correct placement (typically just dorsal to the left jugular
furrow). Direct observation is the safest method. The tube is Abdominocentesis is important for evaluating abdominal dis-
advanced until it is in the stomach (14th rib). If the clinician ease, whether it is colic, weight loss, or postoperative prob-
encounters difficulty in passing the cardia, 60 mL of lido- lems. Box 4.3 provides the materials needed to perform this
caine may be injected into the tube. procedure.
Once placed, spontaneous egress of fluid may occur. If The clinician clips a 2 × 2-inch area approximately 3 cm
not, creation of a water siphon to empty the stomach can be caudal to the xiphoid and 1 to 2 cm to the right of midline
achieved by filling the tube with water using a pump or funnel or using transabdominal ultrasound to guide fluid localiza-
under gravity and then immediately directing the end of the tion.24 Various methods are described with different instru-
tube downward. One sign of an empty stomach is retrieving ments. Regardless, the procedure is performed under sterile
froth or foam that can sit on the surface of accumulated gastric technique. Use of a sterile 18-gauge 1.5-inch needle does not
fluid. It is not uncommon to lose fluid during the refluxing require local anesthetic infiltration of the skin and subcutis. If
process in horses in which no appreciable fluid accumulation a teat cannula or bitch catheter is used, local anesthesia infil-
is present. tration is necessary. The operator makes a stab incision with
Medication or intragastric fluids should never be admin- a no. 15 scalpel blade before cannula entry. Two points of
istered by nasogastric tube to a horse with colic with any net resistance will be encountered: as the device goes through the
positive volume of fluid accumulation. abdominal wall and as it goes through the peritoneum. Horses
To remove the tube, creating a fluid lock is achieved by may become agitated when the peritoneum is “tented” before
occluding the tube (putting a thumb on the end or folding it) penetration.
to prevent its contents from spilling out in the pharynx and Fluid should be collected into ethylenediaminetetraacetic
possibly the trachea as it is withdrawn. Gentle traction is then acid (EDTA) and sterile culture containers. Low-yield samples
applied in a direction parallel to the nose. If bleeding occurs, should be collected in EDTA tubes in which the anticoagu-
a towel can be placed over the horse’s nose. Epistaxis, even if lant is shaken out to avoid misinterpretation of fluid analysis.25
severe, is typically self-limiting. In rare cases of severe hem- Obtaining fluid from very dehydrated horses is often difficult,
orrhage, ε-aminocaproic acid administration, nasal packing, especially in cases of simple obstruction.
and intranasal phenylephrine (10 mg in 10 mL saline) can be Normal values and characteristics for abdominal fluid
used to help resolve bleeding. are as follows: clear, yellow in color (able to read newsprint
Nasogastric reflux is not normal. Occasionally, a small through), low turbidity, total protein concentration should
amount of reflux (≤1 L) is obtained if a horse has had a tube be less than 2.5 g/dL, and total white blood cell count
in place for a long time.21 When reflux occurs, the clinician should be less than 5000 cells/μL. On cytologic examina-
should note the amount, character, and timing in relation tion, neutrophils make up approximately 40% to 50% of
to the onset of colic. In addition, the clinician should note cells, with the remainder being lymphocytes, macrophages,
the response to gastric decompression. Reflux originating
from the small intestine is alkaline, whereas reflux com-
posed of gastric secretions is acidic. Typically, reflux refers BOX 4.3
Materials Needed for Abdominocentesis
to small intestinal ileus, functional or mechanical. Lesions
of the proximal small intestine produce large amounts of • 18-gauge, 1½-inch needle
reflux early in the onset of the colic. Inflammatory lesions • Local anesthetic (2% without epinephrine)
(e.g., duodenitis proximal jejunitis) are typically associated • Teat cannula
with copious volumes of reflux caused by the hypersecre- • Bitch catheter
tory nature of the disease process. With lesions of the distal • Peritoneal dialysis catheter
small intestine (ileum) and often mechanical obstructions, • Sterile gloves
one initially obtains no reflux, and as the condition per- • Ethylenediaminetetraacetic acid and culture tubes
sists, one obtains reflux but usually several hours after the • Sterile, disposable no. 15 scalpel blade
onset of the colic. Occasionally, large colon disease can be • Sterile gauze
associated with reflux, notably left dorsal displacement/
and peritoneal cells. l-Lactate concentration should be Subsequently, the white blood cell count remains elevated
equal to that of systemic circulation and in normal horses, for approximately 2 weeks, but on cytologic examination
with <2 mmol/L is appropriate. the neutrophils appear to be nondegenerate and no bacteria
With intestinal strangulation, total protein increases ini- are apparent. The total protein level remains elevated for 1
tially (in the first 1–2 hours) such that the fluid is clear but month after surgery.
more yellow. After 3 to 4 hours of strangulation, red blood cells
also leak, and the fluid is more orange or pink. After 6 hours or Y TROCARIZATION
more, white blood cells increase gradually, with the progres-
sion of intestinal necrosis. Serosanguineous fluid is indicative Trocarization of the cecum, or occasionally ascending colon,
of small bowel strangulation and, in concert with the rest of is useful to decompress the bowel and improve abdomi-
the examination, likely indicates a need for bowel resection if nal perfusion pressure ([APP]; see Table 4.5). By decreasing
possible. l-Lactate concentration in horses with strangulating intraabdominal pressure, APP can be improved in cases where
small bowel lesions is greater than systemic concentrations. obstructive disorders of the large intestine are diagnosed. Tro-
An l-lactate of ≥4 mmol/L or an increase in l-lactate concen- carization provides analgesic relief by reducing visceral dis-
tration on repeat assessment is highly associated with small tention and may relieve dyspnea where significant abdominal
bowel strangulation.26 bloating is apparent. Box 4.4 lists the materials needed for this
Inadvertent enterocentesis can occur, particularly in cases procedure.
with increased abdominal pressure and/or large bowel impac- Trocarization is only indicated for large bowel distention.
tions. Enterocentesis must be differentiated from intestinal Rectal palpation, abdominal auscultation and percussion, and
rupture. Cytologic features of enterocentesis include plant transabdominal ultrasound can help decipher which segment
material, bacteria, and debris but no polymorphonuclear of bowel is distended. Segments of large bowel adjacent to the
cells. Moreover, the clinical condition of the horse is not con- body wall are suitable cases. The right paralumbar fossa and
sistent with rupture (septic shock). With early rupture, clini- cecal trocarization are ideally suited because of the fixed loca-
cal evidence may not be evident for several hours. Cytologic tion of the cecal cupula in the right dorsal abdomen. Cecal
examination of abdominal fluid with intestinal rupture shows tympany commonly accompanies obstructions of the ascend-
neutrophils, bacteria, and bacteria that have been phagocy- ing colon because of cecal outflow obstruction. These are ideal
tized by neutrophils. candidates for trocarization.
Peritonitis can be classified as primary or secondary. Pri- The clinician clips and prepares the site with antiseptic,
mary peritonitis is often idiopathic or associated with Acti- infiltrating a 4 × 4-cm area of skin with a local anesthetic.
nobacillus equuli and covered in more detail elsewhere.27 With gloved hand, the clinician inserts a 14-gauge catheter
Secondary peritonitis is often associated with polymicrobial with an extension tube perpendicular to the skin. The clinician
species when fluid is evaluated cytologically and on Gram places the end of the extension in water so that gas bubbles
stain. Degenerate neutrophils (>90%), the presence of multiple are visible when the tip of the catheter is positioned correctly.
bacteria, and certainly gram-negative enteric species should When gas is obtained, the trochar part of the catheter should
alert the clinician to the possibility of compromised bowel and be withdrawn slightly or removed to keep from lacerating the
may warrant surgical exploration. bowel. It may be necessary to reposition the catheter several
Blood contamination must be differentiated from internal times when gas is not obtained. Connecting the catheter to an
hemorrhage or severely devitalized bowel. Blood from skin or extension set in water can help visualize gas egress (Fig. 4.3).
body wall vessels and inadvertent splenocentesis can cause a Occasionally, a second operator can apply gentle pressure per
bloody “tap.” When centrifuged, the sample often spins clear rectum to facilitate gas egress. After decompression, the clini-
with minor blood contamination from skin. Inadvertent sple- cian removes the trocar and infuses an antibiotic (e.g., genta-
nocentesis will result in a higher packed cell volume than micin or procaine penicillin) while withdrawing the catheter
peripheral blood, which is caused by the erythrocyte reservoir through the body wall.
of the spleen. All fresh blood contamination shows platelets, Complications with trocarization include peritonitis and
which are not present with blood older than 12 hours. In inter- local abscessation. The horse should be observed for 24 hours
nal hemorrhage blood is hemolyzed such that the supernatant for signs of peritonitis. If the practitioner suspects peritonitis,
is reddish after centrifugation; the sample has no platelets and confirmation is with abdominocentesis, and systemic broad-
shows erythrophagocytosis. Ultrasonography also reveals spectrum antibiotics should be administered to the horse until
fluid swirling in the abdomen, especially with acute internal the condition resolves. Serum amyloid A concentrations may
hemorrhage of various causes. be useful for monitoring the response to treatment and opti-
Excess EDTA in a low-volume sample will falsely increase mal time to cease therapy. If a local abscess develops, percu-
the total protein on refractometry (often by 0.9–1.0 g/dL taneous external drainage with local lavage of sterile fluids is
higher). When performing an abdominocentesis, the clinician recommended.
should shake out the EDTA from the tube to avoid this sam-
pling error.
Abdominal surgery increases the total protein level BOX 4.4
Materials Needed for Trocarization
and white blood cell count postoperatively.28 Typically, if
no enterotomy was performed, the white blood cell count 14-gauge, 5¼-inch catheter
increases for 4 to 7 days and returns to normal by 14 days. The Local anesthetic (2% without epinephrine)
total protein level may remain elevated for 3 to 4 weeks after Sterile gloves
surgery. Neutrophils appear to be nondegenerate. After an Extension tubing
enterotomy or an anastomosis, degenerate neutrophils and Small water container (syringe case works)
occasional bacteria may be seen in the first 12 to 24 hours.29
and nutrient requirements. When the cardiovascular sys-

tem fails to meet tissue oxygen demands, a state of shock
ensues. Support of cardiovascular function can be achieved
through the administration of intravenous fluids, antiar-
rhythmics, inotropes, and/or vasopressors, depending on
the nature of dysfunction.
The volume of blood, and therefore the amount of oxygen,
delivered to tissues depends on arterial oxygen content and
CO, which is defined as the amount of blood pumped out
of the heart per minute and is the product of heart rate and
stroke volume. Heart rate may be influenced by a number of
neurologic, endocrine, and physical factors. Stroke volume is
the amount of blood ejected from the heart with each contrac-
tion and is influenced by the venous return of blood to the
heart (preload), the force/duration of contraction of the heart
(inotropy), and the resistance to forward flow (afterload).
CO is not evenly distributed to all tissues in the body as a
result of varying resistance to arterial blood flow dependent on
tissue demands. Contraction of arteriole smooth muscle main-
FIG. 4.3 Cecal trocarization using a 14-gauge catheter connected to an tains a pressure gradient that allows blood to flow from arteri-
extension set in a syringe case of water. oles through tissue bed capillaries, to venules, and back to the
heart. SVR is related to blood pressure and is determined by
vasomotor tone, or degree of vessel constriction, in the systemic
Y URINARY CATHETERIZATION circulation. The greater the SVR, the less blood flow from the
heart through the systemic circulation and the greater the heart
Micturition disorders (lower motor neuron bladder, upper must work to achieve the same CO achieved at a lower SVR.
motor neuron bladder, and urethral detrusor dyssynergy)
may require manual evacuation to relieve the patient and
provide comfort. Measurement of urine output in adult Y CARDIOVASCULAR INSUFFICIENCY:
horses is indicated in horses with oliguric renal failure or SHOCK STATES
when 24-hour volumetric measurements are needed. Thor-
ough cleansing of the urethral fossa and glans penis in males When the cardiovascular system fails to supply sufficient oxy-
and the vulva and perineal region in mares is indicated gen to meet tissue demands, shock develops and cells shift
before catheter placement. Gentle soapy water or saline with to anaerobic metabolism. If left uncorrected, the shock state
roll cotton are suitable options. In mares, urine is easily col- can result in irreversible cellular dysfunction. There are four
lected by placing a Foley catheter connected to collection major categories of shock that are differentiated by underlying
tubing. A closed system can be fashioned by using a solution pathophysiology: hypovolemic, cardiogenic, obstructive, and
administration set and empty fluid bag. In geldings one can maldistributive.30
insert a male urinary catheter and suture it in place using a Hypovolemic shock is the most common type of shock rec-
Chinese finger trap pattern. If the horse is recumbent and ognized in equine patients and results from decreases in effective
thrashing, leaving as little as possible of the catheter protrud- circulating blood volume, which may occur through external
ing to keep it from being pulled out is important. Normal loss (e.g., diarrhea, reflux), third spacing of plasma volume,
horses produce 1 to 2 mL/kg per hour of urine. or hemorrhage. Decreased blood volume results in decreased
venous return to the heart (decreased preload), reduced stroke
volume, and decreased CO if heart rate cannot compensate.
Cardiovascular Critical Care The mainstay of intervention is through restoration of circulat-
ing volume via intravascular fluid administration.
Tiffany L. Hall Cardiogenic shock is associated with impaired ventricu-
lar function as a result of myocarditis, ventricular dysrhyth-
mias, or valvular pathology resulting in cardiac chamber
Y REVIEW OF CARDIOVASCULAR enlargement.31 A decrease in contractility (inotropy) results
PHYSIOLOGY in reduced stroke volume and decreased CO. Therapy is
directed at improving cardiac pumping through treatment of
The cardiovascular system functions to deliver oxygen the underlying condition and use of inotropes when indicated.
and nutrients to tissues throughout the body, as well as Obstructive shock results from lack of blood flow through
to deliver carbon dioxide to the lungs for elimination and the heart or great vessels as a result of thrombosis (atrial or
other wastes from the tissues for detoxification and excre- pulmonary), constrictive pericarditis, cardiac tamponade, or
tion from the body. It is comprised of the heart, the pul- pleural space disease (e.g., pneumothorax).32 This condition is
monary circulation, and the systemic circulation, which act characterized by decreased preload or increased afterload and
in coordination to deliver blood and its constituents to tis- results in circulatory failure.33 Therapy is directed at address-
sues. Through a complex interplay of neuroendocrine path- ing the underlying cause.
ways, the cardiovascular system is able to adapt to different Maldistributive (vasodilatory) shock is the result of abnor-
physiologic and disease states to meet the body’s oxygen mal shunting of blood through microcirculation in the face of
normal CO, leading to tissue hypoxia and metabolic derange- or dysoxic patients. If response to fluid resuscitation is inade-
ment. This may be caused by septic, anaphylactic, or neuro- quate, inotropes provide another means to increase tissue per-
genic causes.33 Central to the pathogenesis of maldistributive fusion; however, these medications increase cardiac oxygen
shock is endothelial dysfunction in response to neutrophil- consumption, so oxygenation should be monitored.31
generated cytokines, proteases, lipid mediators, and oxygen-
derived free radicals.34 Therapy is directed at addressing the Dobutamine
underlying cause, reducing systemic inflammation, and use of Dobutamine is a synthetic catecholamine that has primarily β1-
vasopressors to improve SVR. adrenergic agonist activity with weak α- and β2-affinity. Dobu-
Regardless of the inciting cause, if shock is prolonged and tamine is useful in patients with diminished CO or decreased
severe, the terminal physiologic disturbance will manifest central venous oxygen tension despite adequate fluid volume
as maldistributive shock.35 Successful management of shock restoration. Beneficial effects include increased stroke volume
depends on early recognition and aggressive intervention.36 and decreased heart rate with improved splanchnic perfusion
and urine output. Dobutamine administered to foals with
anesthesia-induced hypotension resulted in increased cardiac
Y CARDIOVASCULAR SUPPORT index, increased blood pressure, decreased oxygen consump-
THERAPIES tion, decreased oxygen extraction ratio, and apparent mainte-
nance of splanchnic perfusion.46
Principles of Management
The goal of therapy in patients with cardiovascular compro- Vasopressors
mise is to restore tissue perfusion and oxygen delivery. Thera- Vasopressors increase vasomotor tone (SVR), which is reflected
pies include fluid resuscitation to restore circulating blood as an increase in MAP. Further, decreased venous compliance/
volume, administration of vasoactive medications (inotropes/ capacitance increases venous return (preload), which improves
vasopressors) to improve CO and vascular tone, and directed CO.37,38 Careful monitoring and titration of these medications
therapies at the underlying disease condition. Fluid therapy must be performed to avoid excessive vasoconstriction, which
has been discussed earlier, and the remainder of this section would increase SVR (afterload), thus increasing cardiac work-
will focus on cardiovascular-specific therapies. load and potentially decreasing stroke volume and CO.
Vasoactive Drugs Norepinephrine
Vasoactive drugs (e.g., inotropes and/or vasopressors) may Norepinephrine (NE) has predominantly α1-adrenergic ago-
be administered if tissue perfusion is inadequate following nist activity, and it improves organ perfusion pressure during
IV fluid resuscitation. Desirable qualities of vasoactive drugs maldistributive and vasodilatory shock in patients nonre-
include a short onset of action and rapid metabolism, so they sponsive to fluid resuscitation and inotrope administration.
may be quickly titrated to effect in response to changes in Resulting vasoconstriction increases cardiac afterload, poten-
patient condition and administered as a CRI. Vasopressors tially decreasing CO; however, this effect is countered by its
and inotropes exert their effects through interaction with β1-effects, which facilitate increased stroke volume. Compared
adrenergic and nonadrenergic receptors. with dopamine, NE appears to have increased benefits in sep-
Adrenergic receptors targeted by vasoactive therapy include sis, demonstrating improved outcomes and increased splanch-
α1-, α2-, β1-, and β2-adrenergic receptors and dopamin nic perfusion in humans and increased urine output in septic
ergic receptors. α1-Adrenergic receptor stimulation results in foals when combined with dobutamine.47,48
peripheral arterial vasoconstriction and altered metabolism
as well as increased cardiac contractility.37-39 Postsynaptic α2- Epinephrine
receptor stimulation results in vasodilation.40 β1-Adrenergic Epinephrine is a strong α- and β-adrenergic agonist, mak-
receptor stimulation results primarily in cardiac effects with ing it a potent vasopressor. Splanchnic, renal, and coronary
increases in both heart rate (chronotropic effect) and con- blood flow is decreased compared with NE.49 Increased risk
tractility (inotropic effect). β2-Receptor stimulation results of dysrhythmia is associated with an increase in myocar-
in vasodilation of the arteries of coronary vessels, visceral dial irritability, and postresuscitation myocardial depres-
organs, and skeletal muscle. Slight chronotropic and inotropic sion with increased myocardial oxygen consumption is also
improvement after β2-stimulation is also seen.41 Dopaminergic reported.50
stimulation improves myocardial contractility, increases heart
rate, and results in peripheral vasoconstriction.42 Nonadren- Dopamine
ergic mechanisms include activation of vasopressin-specific Dopamine is active at adrenergic (α and β) and dopaminergic
receptors (chiefly V1) and effects on phosphodiesterase activ- receptors in a dose-dependent manner. High infusion rates of
ity.31 Vasopressin receptors (V1) are present throughout the dopamine tend to result in a predominance of α-adrenergic
vascular system and stimulation results in vasoconstriction, effects and marked vasopressor response, whereas β-adrenergic
especially at peripheral arterioles.43,44 During hypovolemic effects (inotropy) predominate at lower infusion rates. Con-
shock, markedly increased levels of V1 stimulation lead to sig- siderable controversy exists regarding the utility of dopamine,
nificant increases in vascular resistance, which is an important with mixed experimental evidence regarding its “renal protec-
mechanism for restoration of arterial blood pressure.45 tive” effects and meta-analysis data showing increased mortal-
ity in some subsets of patients.3,51-53
Inotropes
Inotropic drugs increase myocardial contractility, increasing Phenylephrine
stroke volume and CO. Cardiac workload and oxygen con- Phenylephrine is primarily an α-agonist resulting in increased
sumption are increased, which is of concern in hypoxemic SVR, MAP, and decreased CO. When phenylephrine is used as
a vasopressor, concurrent use of a β-agonist (e.g., NE, dobuta- parameters is observed or when limits to fluid resuscitation
mine) is often beneficial. (e.g., 60–80 mL/kg total volume, CVP >15 mm Hg, declin-
ing Pao2, peripheral edema) are reached. In most situations,
Vasopressin an increase in circulating volume to achieve subnormal val-
Vasopressin, or antidiuretic hormone, is a regulatory peptide ues for blood pressure are adequate to balance critical tissue
integral in regulating body water balance through promotion perfusion while limiting the risk of fluid overload, second-
of water conservation in the collecting tubule of nephrons (V2 ary compartment syndrome, and tissue edema. Once hypo-
receptor) in response to centrally mediated detection of dehy- volemia is corrected, fluids may be administered at 1 to 2
dration (osmoreceptors). In addition, vasopressin induces times maintenance to correct the remaining fluid deficits and
vasoconstriction via V1 receptors, particularly during sepsis, account for ongoing needs/losses. If limits of fluid resuscita-
and human research demonstrates beneficial effects of vaso- tion efforts are reached before perfusion parameters improve,
pressin when used concurrently with catecholamines, such as vasoactive medications may be administered to increase car-
NE.37,50,54,55 Vasopressin works through nonadrenergic mech- diac contractility or SVR.
anisms, even in the face of moderate acidosis. This is in stark
contrast to catecholamines that do not function as optimally Practical Use of Vasoactive Medications
under similar conditions. As with other vasopressors, V1 ago- When normalization of fluid volume fails to correct perfusion
nists may be unsuitable for use in horses that have not been abnormalities or limits to volume resuscitation are reached,
volume resuscitated before administration because of a reduc- the clinician should consider the use of vasoactive medica-
tion in splanchnic perfusion.56 Research in clinical equine tions (Table 4.10). Inotropes and vasopressors should not be
practice indicates that endogenous vasopressin concentrations administered in patients who are hypovolemic because of a
are increased in sick or septic animals compared with healthy risk of tachycardia, increased myocardial oxygen demand in
controls, and that nonsurvivors have higher concentrations at the face of decreased coronary perfusion, and marked vaso-
admission compared with survivors.55,57-62 constriction resulting in increased afterload and decreased
CO.53,65 The choice of which medication is most appropriate is
case dependent and sometimes patient dependent; however, all
Y CARDIOVASCULAR SUPPORT medications should be titrated to effect based on cardiovascu-
STRATEGIES lar monitoring, including serial heart rate/ECG, blood pressure,
urine volume, and, when possible, CO determination. Scientific
Practical Approach to Fluid Resuscitation data regarding inotrope/vasopressor use under clinical condi-
The goal of fluid resuscitation is the restoration of tissue per- tions is limited in horses; therefore, our knowledge is based on
fusion through increased stroke volume and improved blood human data and limited experimental research in horses.
pressure by correcting blood volume deficits. The key to fluid Administration of an inotrope, such as dobutamine, is cur-
resuscitation is, therefore, balancing rapid volume expansion rently the first-line choice of vasoactive medication in equine
with monitoring to prevent fluid overload and avoiding the patients, particularly when adequate CO cannot be confirmed.
negative effects of oversupplementation. Administration of a vasopressor in the face of inadequate car-
There is little evidence to support one fluid resuscitation diac function would result in a further decrease in CO associ-
protocol over another in horses. Therefore selection of fluid ated with increased SVR; however, if administration of low-dose
type is highly subjective in most situations, and recommenda- dobutamine (2–5 μg/kg/min) fails to improve perfusion indi-
tions are extrapolated from human critical care. Most clini- ces then a vasopressor may be added. Clinically, this situation
cians select a polyionic isotonic crystalloid fluid (e.g., LRS or is generally limited to neonatal foals with sepsis or adults with
Plasma-Lyte A) administered alone, or in combination with vasodilatory shock. NE appears to be the best vasopressor for
hypertonic saline in the presence of clinical shock symptoms. use in the horse based on the available data and clinical expe-
The use of hypertonic saline should be cautiously considered rience, and data would suggest that concurrent administration
or avoided in cases of uncontrolled hemorrhage or where with dobutamine has a favorable effect on blood pressure and
marked interstitial dehydration is likely; however, it has dem- renal perfusion while preserving splanchnic circulation.47,53,66
onstrated a more rapid return of normal heart rate and urina- If the patient’s cardiovascular status remains poor, administra-
tion in endurance horses requiring IV fluid support compared tion of vasopressin may be considered, especially in the case
with normal saline.63,64 Considering the risks/benefits of col- of septic shock, during which the body’s responsiveness to
loid administration, the concurrent administration of col- catecholamines may be reduced.37,67 Research regarding the
loids with crystalloids may be indicated where symptoms of administration of exogenous vasopressin in the equine patient
decreased plasma oncotic pressure (e.g., edema, effusions) are is limited, but preliminary data support its use.68
present or where a critical decrease in oxygen-carrying capac-
ity is detected. Therapeutic Goals and Monitoring
Ideally, volumes to be administered and administration The primary goal of the criticalist related to the cardiovascular
rates are based on estimates of fluid deficits; however, clini- system is to restore tissue perfusion and oxygen delivery. Early
cal interpretation of percentage dehydration and degree of goal-directed therapy (EGDT) outlines management proce-
hypovolemia is insensitive and may result in oversupplemen- dures to optimize global tissue perfusion and oxygenation
tation or undersupplementation. Therefore a fluid challenge in critical patients and was once considered revolutionary in
method is more commonly used in practice where a bolus human sepsis treatment to improved patient outcomes; how-
of 10 to 20 mL/kg of isotonic crystalloid is administered ever, recent clinical trials show no benefit over routine care.69
over 30 to 60 minutes with monitoring of perfusion param- Research related to EGDT in veterinary patients is limited.70,71
eters between sequential boluses. Administration of boluses Dysfunction of the cardiovascular system may be iden-
is stopped when normalization or plateau of perfusion tified clinically through abnormal mentation or weakness,
increased heart rate, weak peripheral pulse quality, cool the section Renal Critical Care later in this chapter for addi-
extremities, prolonged jugular refill time, altered mucous tional information.
membrane color or capillary refill time, and/or decreased
urine production. Clinicopathologic abnormalities reflect- l-Lactate
ing poor tissue perfusion include elevated l-lactate concen- l-Lactate is the terminal product of anaerobic glycolysis, and
trations, increases in cardiac troponin I activity, decreased increases in blood lactate concentration in the horse are most
central venous oxygenation, and increased urine SG. The often the result of inadequate delivery of oxygen to periph-
evaluation of each of these and other cardiac monitoring eral tissues resulting from hypovolemia, hypoxemia, anemia,
modalities are described in this section. or decreased perfusion pressure (type A lactic acidosis).74,75
Other causes of hyperlactatemia include abnormal tissue uti-
Physical Examination Parameters lization of oxygen, including mitochondrial dysfunction, or
Positive clinical response to therapies are indicated by abnormal clearance of lactate (type B lactic acidosis).
improved patient mentation and responsiveness to the Lactate measurement is useful clinically in monitoring the
environment, normalization of the heart rate, and the pres- response to fluid therapy and vasoactive drugs in patients with
ence of pink mucous membranes with a capillary refill time cardiovascular dysfunction. Decreases in plasma lactate con-
of 1 to 2 seconds. Further clinical indicators of adequate centration temporally follow improvements in cardiovascular
tissue perfusion include warming of the extremities, pal- performance; therefore, the trend in serial plasma lactate con-
pation of strong peripheral pulses, and improved jugular centration is most clinically useful. In situations of appropri-
refill. In the normal standing horse, the jugular vein should ate volume restoration in which lactate concentration remains
fill quickly in response to occlusion of the vein in the mid- increased, unresolved inflammatory stimulus or uncontrolled
dle of the neck. The presence of jugular pulsation may be sepsis should be considered.
a crude indicator of elevated CVP, and thus fluid overload,
when occlusion of the vein eliminates jugular pulsation.72 Arterial Blood Pressure
Other clinical evidence of fluid overload includes elevated Arterial blood pressure is the product of CO and SVR. Mean
respiratory rate, weight gain, and subcutaneous-dependent blood pressure, not systolic or diastolic blood pressure, is
edema. considered the driving perfusing pressure for tissue and
organs.73 Arterial blood pressure can be measured by direct
Urine Production (invasive) and indirect (noninvasive) means, as described
Urine production is considered a reflection of renal blood flow earlier in this chapter. Trends in arterial blood pressure, as
and hence CO and serves as an indication of adequate organ opposed to individual readings, combined with other indi-
and tissue perfusion.73 Therefore when urine production cators of perfusion (examination and urination) should be
remains low (< two thirds of fluid volume being administered) used to guide therapy.
in a euvolemic hypotensive horse, the administration of ino-
tropes/vasopressors should be considered. However, the urine Central Venous Pressure
output and glomerular filtration rate are unreliable indicators CVP is determined by central venous blood volume, muscular
of renal function in humans receiving vasopressors. Please see tone of the venous system, and the balance between venous
TABLE 4.10 Useful Drugs in Cardiovascular Critical Care

Type Dose Comments
Vasopressors
Norepinephrine 0.05–1 μg/kg/min IV —
Epinephrine 0.02–0.05 mg/kg IV —
Dopamine 1–5 μg/kg/min IV Renal dopaminergic-1 receptors
5–10 μg/kg/min IV β1-Adrenergic stimulation
>10 μg/kg/min IV α-Adrenergic stimulation
Phenylephrine 3 μg/kg/min IV over 15 min —
Vasopressin 0.4–0.8 units/kg IV —
Inotropes —
Dobutamine 1–20 μg/kg/min IV —
Plasma volume expansion —
Crystalloids
Isotonic 50–100 mL/kg IV —
Hypertonic saline (7.2%) 4–8 mL/kg IV —
Colloids —
Plasma 5–10 mL/kg IV —
Hetastarch 6% 5–10 mL/kg IV —
Tetrastarch 6%

IV, intravenously.
return and CO. CVP is an estimate of right atrial pressure and

cardiac preload. It is used to guide fluid therapy, because nor- Respiratory Critical Care
malization of CVP may reflect success of fluid volume resusci-
Tiffany L. Hall
tation, whereas elevations in CVP may reflect volume overload
and limits of fluid resuscitation. As with measurements of arte-
rial blood pressure, the trend in CVP seen through repeated
monitoring is most informative. Y REVIEW OF RESPIRATORY
PHYSIOLOGY
Venous Blood Gas
Arterial blood gas values are required to assess pulmonary gas The major function of the respiratory system is gas exchange
exchange, as described in the later section Respiratory Criti- and, in conjunction with the cardiovascular system, to deliver
cal Care; however, in patients with cardiovascular compromise oxygen to the tissues and facilitate carbon dioxide elimination.
in which severe hypoperfusion may be present, tissue level Table 4.11 shows expected arterial blood gas indices from nor-
hypoxemia, hypercapnia, and acidemia are more accurately mal horses. The respiratory control center maintains Pao2 and
represented in central venous blood. Central venous oxygen Paco2 within a narrow homeostatic range despite the body’s
saturation is a reflection of oxygen delivery and consumption wide variety of demands. Under normal conditions the pri-
by tissues and is used in monitoring the efficacy of the car- mary driving force of alveolar ventilation is changes in Paco2,
diovascular system. Decreases in venous oxygen saturation which are sensed by chemoreceptors in the brainstem.78
may reflect decreased respiratory function, decreased CO/ Changes in Pao2 are sensed by peripheral chemoreceptors
tissue perfusion, or increased oxygen demand. In goal- in the carotid and aortic bodies and also have an impact on
directed therapy, normalization of central venous oxygenation alveolar ventilation but typically alter respiratory rate or effort
serves as a therapeutic target. only in states of marked hypoxemia.78
The basic components of the respiratory system are the
Colloid Osmotic Pressure upper airways, the sequentially branching respiratory passage-
COP, also referred to as oncotic pressure, results from the ways, and the alveolar-capillary membrane. The upper airways
osmotic force created by macromolecules within the intravas- and respiratory passageways are not involved in gas exchange;
cular compartment and is essential to retaining appropriate therefore, they are referred to as anatomic dead space.78 The
intravascular volume. Proteins and colloid molecules are suf- alveolar-capillary membrane is the primary region that par-
ficiently large in mass to limit permeability across the vascular ticipates in gas exchange, although some areas may not be
endothelium and retain water within the vasculature by virtue equally perfused and ventilated, resulting in physiologic dead
of their osmotic draw. In addition, the Gibbs-Donnan effect, space.78 The alveolar-capillary membranes form a dense net-
in which sodium cations are attracted to negative residues on work within the alveoli, allowing for maximum exchange of
protein (albumin), adds further to the intravascular osmotic oxygen and carbon dioxide. Factors that affect the rate of gas
draw. diffusion include thickness and surface area of the membranes,
COP can be measured or calculated, with reasonable agree- diffusion coefficient of the gas, and the gas pressure difference
ment in healthy but not hospitalized horses. Because albumin between the two sides of the membrane.78,79
is the major contributor to COP, alterations in the albumin- In the body, oxygen diffuses down a pressure gradient
to-globulin ratio alter COP at any given total plasma protein from the alveolar space to the pulmonary capillaries to release
concentration. Direct measurement of COP is necessary after within tissue capillary beds. Oxygen in the blood is either
synthetic colloid (hetastarch) administration because these bound to hemoglobin (Sao2) in the erythrocyte or dissolved
starch molecules have considerable osmotic effect but are not (Pao2) in plasma, with approximately 97% of total blood
measurable by refractometry. oxygen content (Cao2) bound to hemoglobin under normal
conditions.78,79 The oxygen-hemoglobin dissociation curve
Electrocardiogram depicts the association between partial pressure of oxygen
Indications for ECG monitoring of equine patients with in the blood (Pao2) plotted on the x-axis and percentage (%)
cardiovascular compromise include dysrhythmias, marked oxygen saturation of hemoglobin (Sao2) on the y-axis. Fac-
electrolyte abnormalities (e.g., hyperkalemia), and during tors such as pH, temperature, carbon dioxide levels, and the
vasoactive drug therapy. The base-apex lead system is most concentration of 2,3-diphosphoglycerate alter the hemoglobin
commonly used in equine medicine, and telemetry units allow affinity for oxygen and, therefore, the ability of oxygen to be
remote monitoring of horses free in stalls. A more complete
review of the cardiovascular system and its monitoring is
TABLE 4.11 Normal Range of Arterial Blood Gas Values for
available in Chapter 9.
Adult Horses
Cardiac Output Measurements Variable Normal Range
The use of advanced technologies such as lithium dilution, indi-
pH 7.4 ± 0.2
cator dilution, bioimpedance, and pulse contour analysis for
assessment of CO has been extensively reviewed elsewhere.76 Paco2 40 ± 3 mm Hg
These techniques are impractical in the clinical setting or have Pao2 94 ± 3 mm Hg
not been validated for the horse; however, echocardiography Base excess 0 ± 1 mm Hg
(see Chapter 9) may be used in calculating CO. Volumetric Spo2 98–99%
determination (four-chamber and bullet methods) and right
ventricular outflow tract Doppler are reliable, accurate, and From Aguilera-Tejero E, Estepa JC, Lopez I, et al. Arterial blood gases and acid-
noninvasive means of determining CO in horses.77 base balance in healthy young and old horses. Equine Vet J. 1998;30:352.
carried to and unloaded at the tissue level.78,79 Disorders that If V/Q mismatch is severe, the result is a right-to-left intrapul-
affect the binding of oxygen to hemoglobin have a tremendous monary shunting of blood.78,79
impact on oxygen delivery to the tissues associated with a Hypoxemia is only one of several possible causes of oxy-
marked decrease in total oxygen content (Cao2). As such, Pao2 gen deficiency at the tissue level, such as a condition referred
is primarily an indicator of pulmonary gas exchange within to as hypoxia. Tissue hypoxia can occur in the face of normal
the lungs, whereas oxygen extraction ratios and venous oxy- respiratory function as a result of any condition that causes
gen indices are better predictors of tissue oxygenation. decreased oxygen delivery to the tissues or abnormal oxy-
gen utilization within the tissues, including decreased CO,
decreased blood oxygen-carrying capacity, peripheral arte-
Y RESPIRATORY INSUFFICIENCY: riovenous shunting, mitochondrial dysfunction, increased
HYPOXEMIA AND HYPERCAPNIA peripheral oxygen consumption, and/or hypermetabolic con-
ditions (e.g., hyperthermia, seizures, sepsis).78,79
Respiratory insufficiency leading to hypoxemia, a decrease
in oxygen content in arterial blood (low Pao2), occurs for
one of five reasons: decreased inspired oxygen content Y APPROACH TO THE PATIENT WITH
(Fio2), diffusion barrier impairment within the lungs, alveo- RESPIRATORY DISTRESS
lar hypoventilation, right-to-left shunting of blood, and/or
ventilation-perfusion (V/Q) mismatch. Hypercapnia (elevated Respiratory dysfunction may be the primary reason that a
Paco2) results from insufficient elimination of carbon dioxide veterinarian is consulted, or it may occur while a horse is
from the blood to the alveoli, or alveoli to the atmosphere, and treated for another problem. Respiratory distress is defined
is commonly observed in cases of hypoventilation and V/Q as an inappropriate degree of breathing effort based on an
mismatch. For practical purposes decreased inspired oxygen assessment of respiratory rate, rhythm, and character. Causes
is a very rare primary cause of hypoxemia because horses of respiratory distress may be respiratory or nonrespiratory
breathing room air inspire sufficient quantities of oxygen to in origin. The physiology of this condition is discussed else-
maintain adequate dissolved oxygen fractions. where (Chapter 8).
Diffusion impairment is an uncommon cause of hypox- Upper respiratory disorders that result in respiratory
emia or hypercapnia in horses at rest because pulmonary distress usually do so because of respiratory tract obstruc-
disease must be very severe before gas exchange is limited, tion (Box 4.5). Complete upper airway obstruction is a true
which is caused by a high functional residual capacity of the emergency because inspiration against a closed airway results
lungs. Diffusion is impaired because of decreased surface area in the inability to inspire and marked negative intratho-
or increased thickness of the alveolar-capillary membrane, racic pressures leading to pulmonary edema, which can be
as might occur in pulmonary fibrosis. Carbon dioxide dif- fatal.84 Diagnosis is usually based on physical examination
fuses more rapidly than oxygen (20-fold). Thus, hypoxemia is and endoscopy of the upper airway. Horses with upper air-
observed before hypercapnia. way obstruction may require an emergency tracheotomy and
Hypoventilation results in both hypoxemia and hyper- additional therapies, depending on the primary cause of the
capnia and occurs when there is a reduction in the volume obstruction.
of air entering and exiting the alveoli per minute (decreased Lower airway diseases that may be associated with respira-
alveolar ventilation), resulting in decreased gas exchange. tory distress are listed in Box 4.6. Diagnosis is based on a thor-
Metabolic production of CO2 is fairly constant under normal ough physical examination, thoracic imaging, transtracheal
metabolic circumstances, so Paco2 is primarily controlled aspirate, and arterial blood gas analysis. Treatment depends on
by its rate of elimination through the lungs and, therefore, the nature of the primary disorder and may include antimicro-
is an accurate reflection of alveolar ventilation. Hypoven- bial agents, antiinflammatory agents, oxygen administration,
tilation may occur with disorders of the central nervous or thoracic drainage as indicated. Diagnosis and treatment of
system ([CNS]; e.g., trauma, HIE, pharmaceutical drugs), specific disorders are described in Chapter 8.
thoracic cavity (e.g., pleural space disease, pain), respira- Nonpulmonary causes of respiratory distress include ane-
tory tract (e.g., obstruction), or neuromuscular disease (e.g., mia, compensation for metabolic acidosis, pain, anxiety, and
botulism).78,79 hyperthermia. Evaluation of nonpulmonary causes of respira-
Hypoxemia caused by a right-to-left shunt occurs when tory distress include a thorough history, physical examination,
blood bypasses the pulmonary circulation and is, therefore, and blood work. After the initial evaluation further diagnostic
not oxygenated within the lungs. This deoxygenated blood testing might include endoscopy, ultrasound, or radiographs.
mixes with oxygenated blood in the left heart resulting in
hypoxemia. Shunting may be extrapulmonary, such as a Oxygen Therapy
right-to-left cardiac shunt (e.g., tetralogy of Fallot), or intra- Nasopharyngeal administration of oxygen is the most common
pulmonary, such as occurs with severe V/Q mismatch (e.g., form of respiratory support in horses suffering from hypox-
ARDS). emia (Fig. 4.4). Oxygen supplementation is indicated when the
A V/Q mismatch is the most common cause of hypox- Pao2 falls below 60 mm Hg or Sao2 < 90%.80 Research demon-
emia in the horse and occurs when alveolar ventilation and strates a significant and dose-dependent increase in Pao2 and
blood flow are not closely matched, resulting in inefficient gas Sao2 with increasing flow rates of oxygen to a maximum of 10
exchange. V/Q mismatch may result from all forms of pulmo- to 20 L/min, beyond which airway irritation is observed.81,82
nary disease. A high V/Q mismatch occurs when regions of Although adequate delivery of oxygen to tissues is essential,
the lung are ventilated but not perfused, such as occurs with oxygen is also toxic when in excess through production of
pulmonary thromboembolism.78,79 Conversely, a low V/Q reactive oxygen species. Serial arterial blood gas measure-
mismatch occurs when regions of the lung are perfused but not ments will aide in determining the response to treatment and
ventilated, as with bronchopneumonia and consolidation.78,79 ability to decrease supplementation, with the goal of providing
BOX 4.5
Upper Airway Disorders That May Be Associated BOX 4.6
Lower Airway Disorders That May Be Associated
with Respiratory Distress in Adult Horses with Respiratory Distress in Adult Horses
NASAL DISORDERS PULMONARY DISORDERS

• Trauma, foreign body • Pulmonary edema (cardiogenic or neurogenic)
• Hemorrhage or hematoma • Acute interstitial pneumonia
• Neoplasia • Chronic interstitial pneumonia including equine multinod-
• Abscess ular pulmonary fibrosis (equine herpesvirus 5) infection
• Granuloma • Aspiration pneumonia
• Amyloidosis • Abscessing or coalescing bronchopneumonia
• Acute respiratory distress syndrome/acute lung injury
PHARYNGEAL DISORDERS • Silicosis
• Neoplasia • Smoke inhalation
• Subepiglottic or pharyngeal cyst • Tracheal/bronchial foreign body
• Persistent dorsal displacement of the soft palate
• Trauma, foreign body EXTRAPULMONARY DISORDERS
• Abscess • Pleural effusion (hydrothorax, pyothorax, chylothorax,
and hemothorax)
LARYNGEAL DISORDERS • Thoracic trauma
• Laryngeal paralysis • Pneumothorax (open, closed, and tension)
• Laryngeal hemiplegia
• Trauma, foreign body
• Edema
• Arytenoid chondritis
• Epiglottitis and epiglottic granuloma
MISCELLANEOUS
• Guttural pouch enlargement
• Empyema
• Tympany
• Mycosis and hemorrhage
• Head swelling: edema, cellulitis, anaphylactic shock,
bilateral jugular occlusion
the lowest flow rates (lowest Fio2) possible to achieve adequate

oxygenation.
Inhalational Therapy
Inhalational therapy is beneficial in respiratory disorders of the
lower airways, including bronchopneumonia and inflammatory
airway conditions. Mucolytics, bronchodilators, and antimicro-
bials (including amikacin, gentamicin, and sodium ceftiofur
[Naxcel]) may be administered by ultrasonic nebulization.83,84
Inhalers may be used for the administration of bronchodilators,
mast cell stabilizers, and corticosteroids (CSs) in horses with
inflammatory airway conditions such as inflammatory airway
disease or recurrent airway obstruction (RAO).85,86 Advantages FIG. 4.4 Horse with a nasal oxygen cannula. Suturing to the nostril and
of inhalation therapy include a localized delivery to the target affixing the tubing to the halter helps maintain the cannula in place.
site allowing for higher concentrations at lower doses adminis-
tered, as well as reduced incidence of adverse systemic effects.
compared with caffeine.87 Disadvantages of doxapram use
Pharmacologic Ventilation include an increase in myocardial oxygen consumption and
Hypoxemia and hypercapnia resulting from hypoventila- cost. Theophylline is similar to caffeine; however, it has a nar-
tion may respond to the administration of medications that row therapeutic index with adverse effects including colic, sei-
stimulate respiration centrally. Caffeine, doxapram, and the- zure, tachycardia, and sudden death.80
ophylline are three such medications that may benefit equine Acute bronchoconstriction and decompensation may be
patients with hypoventilation secondary to head trauma, seen with severe RAO, inhalation of noxious gases, or other
encephalitis, or hypoxic-ischemic encephalopathy. Caffeine chemical irritants and can be managed with bronchodilating
is most frequently used in practice because of ease of admin- agents. β2-Agonists (e.g., inhaled albuterol [720 μg per 450-
istration, cost, and wide therapeutic index. Doxapram has a kg horse]) and anticholinergics (e.g., intravenous glycopyrro-
short duration of action requiring frequent or CRI administra- late) are beneficial. Atropine may be used as a rescue therapy
tion, which limits use despite evidence of improved ventilation only. Bronchial inflammation can both trigger and perpetuate
bronchoconstriction and warrants the justified use of inhaled Paco2 indicates hyperventilation, the presence of which cannot
or systemic glucocorticoids in some cases. be accurately assessed based on physical examination alone.
Hypoventilation may be caused by central apnea (CNS disease),
Mechanical Ventilation obstructive apnea (upper respiratory tract disease), increased
Mechanical ventilation, when administered in a hospital set- dead space ventilation (shunt and decreased CO), reduced lung
ting by experienced clinicians, has resulted in improved out- compliance (low lung volume), respiratory muscle weakness
comes in foals80 and may be beneficial in adults.88 Indications or fatigue, poor control when mechanical ventilation is used,
for mechanical ventilation include marked hypoxemia or thoracic pain, or abdominal distention. Hyperventilation, with
hypoventilation (pHa <7.3 with Paco2 >65 mm Hg or Pao2 decreased Paco2, may result from pain, hypoxemia of any
<60 mm Hg) despite maximal medical therapy, and fatigue cause, pulmonary disease, or neurologic disease.
or excessive work of breathing. Clinical diagnoses in equine Oxygenation status is then determined by the assessment
patients that may benefit from mechanical ventilation include of Pao2 and Sao2 in light of the partial pressure of alveolar
botulism, hypoxemic-ischemic encephalopathy, or ARDS. oxygen (PAo2) and hemoglobin levels. PAo2 is influenced by
Long-term mechanical ventilation techniques in adult horses the fraction of inspired oxygen (Fio2), atmospheric pressure,
are poorly described and represent a significant challenge for and Paco2. Pao2 is typically five times the Fio2 in the healthy
equine critical care. standing horse; therefore, in a patient breathing room air at
sea level (Fio2 = 21%), expected Pao2 concentration is approx-
Therapeutic Goals and Monitoring imately 100 mm Hg with an Sao2 >93%.
The goals in supporting respiratory function are recognition Calculation of the alveolar-arterial oxygen gradient (A-a
of improved respiratory rate and effort, improved oxygen indi- gradient) is helpful in evaluating causes of hypoxemia and
ces, and normalization of oxygen and carbon dioxide blood hypercapnia.78,79 In the normal horse breathing room air,
concentrations. the Pao2 should be only slightly less than PAo2 with an A-a
difference of 5 to 10 mm Hg. In patients with a normal A-a
Blood Gas Analysis gradient, hypoxemia and/or hypercapnia are the result of alve-
Blood gas analysis is the most common method for assessment olar hypoventilation. Hypoxemia and hypercapnia in patients
of pulmonary function and acid-base status in horses that are with an increased A-a gradient may be associated with V/Q
critically ill. Arterial samples may be obtained from the facial mismatch, right-to-left shunt, or diffusion impairment; how-
artery, transverse facial artery, or lateral metatarsal artery.89 In ever, nonpulmonary causes may also be present, including an
the clinical setting, venous samples are best collected from a imbalance of oxygen demand and delivery, hypermetabolism,
catheter placed in the cranial vena cava or jugular vein. Cor- or overfeeding.
rect interpretation of the information obtained from blood The causes of hypoxemia can be further differentiated
gas analysis allows the clinician to make appropriate decisions through the administration of supplemental oxygen and eval-
regarding diagnosis, therapy, and prognosis related to respira- uation of oxygen saturation and extraction ratios. When the
tory function and acid-base status. administration of oxygen fails to increase Pao2 to 100 mm Hg,
Samples for blood gas analysis must be collected and han- right-to-left shunting or massive pulmonary thromboembo-
dled appropriately to ensure accurate results. A small amount of lism should be suspected and appropriate diagnostic testing
heparin is used to coat the hub of the needle before aspiration used. Improvement of Pao2 above 100 mm Hg with oxygen
of the sample, which should be stored anaerobically after collec- therapy suggests hypoxemia associated with V/Q mismatch or
tion by removing the needle and placing a syringe cap over the a diffusion disturbance. Venous blood gas analysis has limited
tip of the syringe. Prolonged exposure to air or bubbles in the usefulness for evaluation of respiratory tract disease; however,
syringe can result in a decrease in Paco2 and an increase in Pao2 Svo2 may be used in calculating the oxygen extraction ratio,
as the sample equilibrates with room air in the bubble.79,89 A which provides some information about tissue oxygenation
sample stored at room temperature should be analyzed within in the horse. Oxygen extraction ratios greater than 30% may
10 to 15 minutes. Delayed analysis may result in an increased reflect increased oxygen consumption (e.g., exercise, hyper-
Paco2, decreased pH, decreased glucose, and increased lactate metabolism) or inadequate oxygen delivery to tissues associ-
as blood cells continue to metabolize nutrients.90 ated with hypoxemia, anemia, or cardiovascular dysfunction.
Acid-Base Status
Blood Gas Interpretation An interpretation of blood gas analysis is not complete with-
Respiratory Function out assessment of the patient’s acid-base status. In a simpli-
A systematic evaluation of blood gas values includes consid- fied approach to acid-base status, the clinician first determines
eration of pH, Pao2, arterial and venous oxygen saturation of whether the blood pH is normal (approximately 7.40) or
hemoglobin (Sao2, Svo2), Paco2, and bicarbonate concentra- whether acidemia (pH <7.36) or alkalemia (pH >7.44) exist.
tion. The partial pressure of oxygen dissolved in arterial blood There are four primary acid-base disturbances that may occur
(Pao2) is a reflection of pulmonary oxygenating capability and in a patient based on interpretation of the blood gas: respira-
is not affected by hemoglobin-bound oxygen. Causes of low tory acidosis, resulting from hypoventilation and reflected by
Pao2 (hypoxemia) are discussed in the preceding sections. The increased Paco2; respiratory alkalosis, resulting from hyper-
partial pressure of CO2 dissolved in arterial blood (Paco2) is a ventilation and reflected by decreased Paco2; metabolic aci-
reflection of the balance between alveolar minute ventilation dosis (decreased HCO3−); and metabolic alkalosis (increased
and metabolic CO2 production.78,79,89 HCO3−). These may exist as sole disorders or in combination
The first step in interpreting the blood gas information with (mixed disorders). A complete discussion of acid-base disor-
respect to pulmonary function is to assess ventilatory status. ders and the approach to critically evaluating acid-base status
Increased Paco2 indicates hypoventilation, whereas decreased is beyond the scope of this text, and the reader is referred to
additional resources regarding the physiochemical approach mediators increase basal metabolic rate, contributing to the
to evaluation of acid-base status in animals.91,92 inefficient use of oxygen and calories, and may also modulate
the body’s response to starvation.94,95 Negative energy balance,
Pulse Oximetry in which nutritional intake does not meet the energy demands
A useful adjunct to arterial blood gas analysis is pulse oxim- of the body, depletes the body of structural and functional
etry, which is a technique that relies on the reflection of dif- proteins, impairing wound healing, decreasing immune func-
ferent wavelengths of light to differentiate oxygenated and tion, and altering many other normal physiologic functions.
deoxygenated hemoglobin reported as a percentage of oxy- The effects of an ongoing, profound negative energy balance
genated hemoglobin (Spo2). Generally, an Spo2 greater than may manifest in musculoskeletal weakness, disruption of the
91% is considered indicative of an arterial oxygen level within gastrointestinal barrier (villous blunting), sepsis, multiorgan
physiologically normal limits.79,93 Pulse oximetry has a lim- dysfunction, and even death.
ited sensitivity for determining changes in pulmonary gas
exchange at ranges above 90% hemoglobin saturation; how-
ever, Spo2 below 91% represents increasingly severe reduc- Y EVALUATION OF GASTROINTESTINAL
tions in arterial oxygen levels.79,93 The accuracy of Spo2 may FUNCTION
be influenced by several factors including pigmented skin,
hypoperfusion at the measurement site, anemia, hypothermia, Methods used to recognize gastrointestinal dysfunction in
and motion. False readings of Spo2 may occur in the presence the critically ill horse include changes in the physical exami-
of carboxyhemoglobin and methemoglobin, in which coox- nation, abdominal ultrasonography, and clinicopathologic
imetry is the preferred analytical method. Because of the limi- testing. Serial physical examinations will identify changes in
tations of pulse oximetry, response to treatment in a patient vital parameters, mentation, behavior, fecal production, and
with critical hypoxemia is best monitored with arterial blood abdominal size. Transabdominal ultrasound (2.5- to 3.5-mHz
gas analysis. transducer) can be used to evaluate the anatomic location,
contents, wall thickness, and motility of various regions of the
intestine. Classic patterns identified by ultrasound are useful
in narrowing a list of differential diagnoses for gastrointestinal
Gastrointestinal Critical Care disorders. The identification of peritoneal fluid by ultrasound
Tiffany L. Hall warrants abdominocentesis and fluid analysis to better evalu-
ate the disease process and can help guide therapy and deci-
The primary role of the gastrointestinal tract is digestion of sions regarding prognosis. Clinical pathologic abnormalities
food so that nutrients including proteins, vitamins, miner- are often nonspecific regarding gastrointestinal disorders but
als, and fluids may be absorbed into systemic circulation for may reflect the presence of systemic inflammation, major fluid
use throughout the body. Normal function of the gastroin- shifts or deficits, decreased tissue perfusion, acute protein loss,
testinal tract includes appropriate motility, balanced micro- negative energy balance (e.g., disorders of glucose and triglyc-
biota, digestion, and absorption through complex interactions erides), and/or electrolyte disturbances. See Chapter 12 for a
among the nervous system, enteric nervous system, endocrine more in-depth discussion of the use of complete blood count
system, and musculature of the gastrointestinal tract. The gas- (CBC), biochemistry, ultrasonography, and radiography for
trointestinal mucosa forms a barrier between the body and a disorders of the gastrointestinal tract.
luminal environment, which not only contains nutrients but Assessment of the nutritional status of the critically ill
also is laden with potentially hostile microorganisms and equine patient at presentation and at regular intervals dur-
toxins. Thus normal function also requires that nutrients be ing hospitalization is necessary to identify patients that would
transported across the epithelium while excluding passage of benefit from early nutritional support. The most practical
harmful molecules and organisms. methods for evaluation of nutritional status and body fat com-
position in horses are monitoring of body weight (e.g., scale
Y GASTROINTESTINAL DYSFUNCTION or weight tape) and body condition score (BCS), which is a
subjective, semiquantitative method of evaluating body fat
Complications related to the gastrointestinal tract are com- and muscle mass by visual inspection and palpation of certain
mon in the critically ill horse and include inappetence, pain, areas of the body. BCS is positively correlated to body fat but
endotoxemia/SIRS, ileus, enteritis or colitis, malassimilation not to weight or height. A nine-point scale was described by
(malabsorption/maldigestion), and protein-losing enteropa- Henneke in which 1 is extreme emaciation, 9 is obese, and 4
thy. The details of many of these conditions are discussed in to 6 are ideal.96 The appropriate assessment and monitoring
Chapter 12. Inappetence is probably the most common com- of nutritional status would include both the body weight and
plication in the critical equine patient and will be the focus of BCS.
the remainder of this section. Decreased feed intake may be
caused by a mechanical inability to eat (dysphagia) or a loss Y NUTRITIONAL SUPPORT
of appetite associated with a variety of conditions and diseases
including pain, stress, systemic infection, or loss of palatability Early nutritional support is indicated in underweight or obese
associated with medications. The regulation of appetite is an horses, those with highly catabolic disease states (e.g., pleu-
immensely complex process involving the gastrointestinal tract, ropneumonia), or in patients that are unable to eat (e.g., dys-
central and autonomic nervous systems, and many hormones. phagia, ileus). Healthy horses at rest may have feed withheld
Severe illness or injury has been associated with hyper- for 2 to 3 days without significant consequence; however, all
metabolism characterized by a pronounced catabolic state hospitalized horses may benefit from early nutritional inter-
that is made worse by a patient’s inappetence. Inflammatory vention. Numerous reports in human critical care document
the benefits of early nutritional support because it hastens with severe endotoxemia or SIRS. Hypokalemia can result
recovery, diminishes complications of the critically ill, and from decreased intake of food and the delivery of a high con-
decreases length of hospitalization.94,95,97 The goals of early centration of dextrose causing pancreatic insulin release; thus,
nutritional support are to maintain host defenses and preserve potassium should be supplemented in horses receiving PN.
lean body mass while avoiding oversupplementation.
The nutritional requirements of the critically ill adult horse
have not been determined and are influenced by size, age, dis- Y GASTROINTESTINAL MOTILITY
ease state, and metabolic stress. Maintenance requirements SUPPORT
for healthy adult horses at rest are estimated to be 30 to 40
kcal/kg per day.98-100 More research is available in critically ill The promotion of gastrointestinal motility and function in the
foals whose resting energy requirements are approximately postoperative patient is discussed elsewhere in this text (see
50 kcal/kg per day and increase as the foal’s clinical condition Chapter 12). However, maintenance of normal blood volume,
improves.101 physiologic electrolyte concentrations, and gastrointestinal
Enteral feeding is preferred to PN if the gastrointestinal blood flow will aide in maintaining gastrointestinal integrity
tract is even partially functional because local delivery of feed and function. The reader is referred to other sections of this
bulk and nutrients improves intestinal motility, maintains text for further information regarding support of normal gas-
mucosal integrity, protects against bacterial translocation, and trointestinal tract function.
supports organ and immune function.94,95,97 Even if a horse
cannot tolerate enteral feeding sufficient to meet mainte-
nance energy demands, lesser amounts of enteral nutrition are
shown to be beneficial while the remainder of energy require-
Renal Critical Care
ments are met through parenteral means (sometimes termed Samuel D. Hurcombe
trophic feeding). It can be difficult to determine caloric intake
for a horse on a voluntary feeding plan; however, weighing the Primary renal disease in horses may be underdiagnosed in
feed and hay offered compared with that left behind by the adult horses. Standard testing using blood work (blood urea
patient allows one to estimate the number of ingested calories. nitrogen [BUN] and creatinine concentrations) may only
If consumption is below 75% of the maintenance requirements increase once advanced or severe acute disease is established.
for 48 hours, or if the horse is anorexic or dysphagic, feeding Horses with critical illness are superb candidates for second-
by nasogastric tube is recommended.99,100 See Chapter 5 for a ary renal disease, which in many cases critically ill horses may
discussion of different enteral diet regimens and methods of be underperfused, in various shock states, and frequently
administration. It is recommended that enteral feeding begin administered nephrotoxic therapies.
gradually, with a goal of reaching maintenance requirements Horses with fluid deficits, severe myopathies, hemolysis,
over 3 to 7 days, because rapid changes may result in colic or and septic/endotoxemic shock are at high risk of renal disease.
diarrhea.99,100 Optimizing renal perfusion, glomerular perfusion, and tubu-
PN is indicated for aged animals off feed, pregnant or lac- lar flow should be of highest importance in supporting renal
tating mares off feed, horses with a BCS <4, critically ill breeds function. Electrolyte imbalances, acid-base disorders, urine
at risk for hyperlipidemia/hyperlipemia, and critical patients output volumes, and neurohormonal regulation of splanchnic
who cannot tolerate enteral feeding because of gastrointestinal blood flow should be evaluated and considered in the develop-
dysfunction.102-104 PN is a combination of nutrients designed ment of all fluid therapy strategies in the renal patient.
to meet the patient’s energy requirements through IV admin- Evaluation of renal function through clinicopathologic
istration and may consist of supplementation with dextrose testing of blood and urine are best performed before fluid
alone or in combination with amino acids and/or lipids. Other therapy. Provision of IV fluids may lead to changes in blood
components added to PN solutions include vitamins (A, D, E, electrolyte composition and SG findings.107
and B complex) and minerals. Macrominerals such as potas-
sium, calcium, and magnesium are best added to crystalloid Y GENERAL PRINCIPLES
fluids. The reader is referred to Chapter 5 for a complete dis-
cussion of PN. Horses with renal disease should be assessed for their ability
Complications associated with PN administration include to produce urine before fluid therapy. Low-volume resuscita-
hyperglycemia, hyperlipidemia, hypokalemia, hypophospha- tion (<40 mL/kg/day) should be used until it is known that
temia, hypomagnesemia, and thrombophlebitis.105,106 Hyper- the patient can tolerate maintenance and the previously men-
glycemia is the most common complication reported in horses tioned maintenance IV fluid rates. Monitoring body weight
and foals administered PN and may be avoided through slow and/or urine output volumes is the most practical method for
introduction of the fluid, beginning at 25% of the target rate. determining volume infusion tolerance.
This allows an appropriate endogenous insulin response to Caution should be exercised in the anuric patient and those
occur in response to dextrose supplementation. Blood glucose with low-volume oliguric renal failure. Patients with uremic
levels should be monitored every 4 to 6 hours to avoid hyper- encephalopathy and intolerance to IV fluids have a grave
glycemia, glucosuria, and osmotic diuresis. A sudden onset of prognosis.
hyperglycemia in a patient that had been tolerating PN can If the patient demonstrates volume tolerance, maintenance
indicate the presence of complications such as infection or rates (40–60 mL/kg/day) of isotonic crystalloids and/or bolus
sepsis. If hyperglycemia persists, exogenous insulin therapy infusions of hyperosmolar solutions (7.2% hypertonic saline
should be considered. Parenteral formulations containing lip- [2–4 mL/kg]; mannitol 20% solution [0.25–1 g/kg]) may be
ids should be avoided in horses with hyperlipidemia, hyperli- useful to promote renal perfusion, tubular flow, and nephron
pemia, or severe liver disease and used with caution in horses recruitment.
Specific treatment and diagnosis of acute and chronic renal Diagnostic samples to assess renal function would include
failure are discussed in greater detail elsewhere in this text. blood (CBC, serum chemistry, and leptospirosis microag-
glutination serology), urine (cytology, cast assessment, dark-
Y COMMON NEPHROTOXIC field microscopy, SG, and quantitative urine culture), and
renal tissue (histopathology with or without special stains
SUBSTANCES IN THE INTENSIVE and culture).
CARE UNIT Dilute urine (SG ≤1.012) concurrent with azotemia gen-
erally indicates decreased renal function. Azotemia with
Nonsteroidal Antiinflammatory Drugs isosthenuria (SG 1.008–1.012) indicates renal failure. Uri-
Nonsteroidal antiinflammatory drugs (NSAIDs) are com- nary indicators of tubular damage include granular casts
monly used in equine practice. Renal perfusion, notably to in urine, an increased urinary γ-glutamyl transferase-to-
the inner medulla and medullary pyramids, relies on perfu- creatinine ratio (>25), abnormal fractional clearance of
sion of the vasa recta. Intrinsic flow through the vasa recta electrolytes such as sodium and potassium,110 and increased
is affected by both volume status of the patient and vasomo- urinary glucose. The presence of white blood cells, bacteria,
tor tone. Vasomotor tone is regulated, in part, by prosta- and excess protein concentration as determined by dipstick
glandins. Prostaglandin E2 (PGE2) and prostacyclin (PGI2) or other methods as well as increased urine to protein ratio
promote vasodilation, perfusion, and health of the inner are abnormal findings in urine and should prompt more in-
tissues. These are constitutively produced via metabolism of depth investigation.
arachidonic acid shunting through cyclooxygenase-1 (COX- To understand and best prognosticate the severity of renal
1) activity.108 With the exception of firocoxib, other NSAIDs damage and chances of tissue restitution, ultrasound-guided
used in horses are not selective for COX-2, which is induced renal biopsy and histopathology are recommended.
by inflammatory stimuli.108 Therefore most NSAIDs inhibit A more complete discussion of laboratory methods of renal
activity of both enzymes to some degree, which blocks renal function assessment is found in Chapter 14.
production of prostaglandins and prevents the compensa-
tory increase in renal blood flow during dehydration, poten- Y THERAPY FOR RENAL DYSFUNCTION
tially leading to vasomotor nephropathy and renal papillary
necrosis (also termed renal ischemic necrosis). The mecha- Many cases of acute kidney injury respond favorably to
nism of action and toxicity for NSAIDs is discussed else- fluid therapy and avoidance of nephrotoxic drugs. In some
where in this text. instances, establishing a polyuric state can be beneficial when
horses are treated with the previously mentioned maintenance
Aminoglycoside Antibiotics fluid rates and can tolerate IV fluids. High tubular flow rate
Aminoglycoside antibiotics (e.g., gentamicin, amikacin) are is essential in establishing endogenous waste clearance (e.g.,
freely filtered at the glomerulus and excreted into the urine.109 creatinine) and other noxious substances (e.g., myoglobin).
In low tubular flow states (e.g., dehydration), aminoglycosides Diuresis may be induced through increased fluid rates above
are actively taken up by proximal convoluted tubular cells and the maintenance requirements (>60 mL/kg/day) of polyionic
stored in lysosomes. Drug accumulation exceeds drug disposi- isotonic solutions, administration of hypertonic solutions, and
tion and leads to rupture of PCT cells and acute tubular necro- use of diuretic therapies. Azotemia that decreases by ≥50% in
sis.109 Alternative drugs should be considered over systemic 24 hours in response to fluid therapy (usually at rates >80–100
aminoglycoside in the hypovolemic and/or azotemic patient. mL/kg/day) indicates prerenal azotemia.
If fluid therapy does not produce the expected increase in
Endogenous Toxins: Myoglobin and Hemoglobin urine output, then diuretics (furosemide, 1 mg/kg, IV) can be
Liberation of myoglobin (myopathies, e.g., rhabdomyoly- administered. Urination should be expected within 30 min-
sis, myositis) or hemoglobin (intravascular hemolysis, e.g., utes of furosemide administration. CRIs of furosemide may
immune-mediated hemolytic anemia, red maple leaf toxic- yield a more consistent diuretic response.111 Bags and infusion
ity) may lead to acute kidney injury via several mechanisms lines should be covered to prevent exposure to light because
including physical plugging of nephron tubules via polym- furosemide is light sensitive.
erization, reflexive renal vasoconstriction causing ischemia, Volume replacement should always be attempted before
and free radical injury via reduction-oxidation reactions from diuretic therapy because the resultant increase in urination
iron-containing pigments and genesis of reactive species (e.g., at blood volume expense will contribute to severe dehydra-
hydroxyl radical). free radicals. tion and reduce systemic perfusion and exacerbate renal
damage.
Y IDENTIFYING RENAL DYSFUNCTION Active treatment of refractory hypotension (hypotension
unresponsive to fluid therapy) is important to treat or prevent
Recognition of renal dysfunction is easily overlooked in criti- perfusion-mediated causes of acute kidney injury. Autoregula-
cal care patients. It is advisable to monitor serum BUN and tion begins to fail at a MAP <60 mm Hg. Maintaining an MAP
creatinine concentrations at least every 48 hours to assess ≥65 mm Hg is recommended to minimize reduced urine out-
glomerular filtration and renal function. Regular measure- put and kidney injury.53
ment of BUN and creatinine concentrations and assessment of Vasoactive therapies such as dobutamine (1–5 μg/kg/
results in light of physical examination findings (e.g., evidence min) have been advocated to improve blood pressure. Low-
of dehydration) and results of urinalysis are the most read- dose dopamine therapy (2–5 μg/kg/min) and fenoldopam
ily available methods for monitoring renal function in equine (0.04–0.4 μg/kg/min) have purported benefits in healthy sub-
critical care patients. Increases in serum creatinine concentra- jects on renal blood flow. The effects of dopamine or fenoldo-
tion as small as 0.3 mg/dL can be significant.110 pam on renal blood flow in critically ill equine patients is
unknown.110,53 Blood pressure should be measured in patients veterinary attention. Disorders of the forebrain (seizure activ-
at risk for hypotension and those that fail to produce urine ity and changes in behavior), spinal cord (ataxia and recum-
despite appropriate therapy. bency), peripheral nervous system (inability to ambulate or
In horses with oliguric renal dysfunction and certainly severe generalized weakness), and autonomic nervous sys-
anuric renal dysfunction, the CVP may be monitored to assess tem (urinary/fecal incontinence) may all require emergency
the potential for fluid overload and edema formation. Normal care. Extracranial causes of neurologic dysfunction can also
CVP in the standing horse is <12 mm Hg. Values >12 mm Hg be challenging and represent a multisystemic disorder (e.g.,
should prompt the clinician to reassess the patient’s’ tolerance hepatic and other metabolic encephalopathies).
to fluid therapy. Certain disorders may present as a neurologic disorder but
Aminoglycoside toxicity is best prevented by ensuring may be caused by other systemic causes. For example, cardio-
appropriate dosing regimens and limiting the use of amino- vascular or respiratory diseases and gait abnormalities caused
glycosides to hydrated animals without preexisting renal dys- by musculoskeletal diseases such as bone fractures, rhabdo-
function.111 Administering aminoglycoside antibiotics every 24 myolysis, or laminitis.
hours decreases the amount of time that renal tubular cells are Peripheral nerve damage in horses is not uncommon and
exposed to higher concentrations of aminoglycosides. The peak most often involves the suprascapular, radial, ulnar, femoral,
concentration (Cmax) dictates the efficacy of the drug; however, and selected cranial nerves. Occasionally, the brachial plexus
the trough concentration dictates the safety of the drug. Thera- can be injured after a collision accident. Peripheral nerve
peutic drug monitoring allows for the detection of elevated injury is commonly traumatic and associated with additional
trough (usually 24 hours after the previous dose) concentra- musculoskeletal abnormalities (e.g., fracture).
tions, which are more likely to cause toxicity. Drug-dosing Traumatic head injury with traumatic brain injury (TBI)
adjustments should be based on trough concentrations, either represents a dynamic neurologic emergency. Depending on
as a lower dose administered or a prolonged dosing interval.109 the nature of the injury, primary and secondary TBI can cause
the clinical presentation of the patient to change frequently as
Renal Replacement Therapy processes such as edema, inflammation, and changes in intra-
RRT such as peritoneal dialysis (PD) or hemodialysis is techni- cranial pressure (ICP) occur.
cally possible in horses. PD is technically easier but less effec- Abnormal neurologic function can cause secondary excite-
tive than hemodialysis. Recently venovenous hemodiafiltration ment, agitation, and stress in the patient and worry for the
was described in healthy adult horses and well tolerated.112 The owner or caretaker. Horses with alterations in the content of
need for specialized equipment and familiarity with creatinine consciousness and behavioral changes may be unpredictable,
clearance kinetics, etc., makes the application of hemodialysis in vacillating between somnolence and maniacal rage. It is pru-
clinical patients somewhat limited currently. dent to ensure safety of not only the patient to prevent addi-
PD has been described in horses as either intermittent or tional injury but also any handler or personnel. In cases of
continuous. The concept involves using the peritoneum as an unexplained neurologic deterioration, notably of inapparent
accessory kidney to dialyze blood. In one clinical report, con- causes, a thorough understanding of vaccination history of the
tinuous flow PD (CFPD) was more effective than intermittent patient and use of barrier protection strategies (e.g., medical
PD.113 LRS with 1.5% dextrose and 1 unit of unfractionated examination gloves, coveralls) should be performed. Taking
heparin per milliliter is an easy dialysate solution to obtain note of any “‘in-contact” personnel is important if potential
and use. For intermittent PD, 40 mL/kg of dialysate is infused zoonotic disease is suspected (i.e., rabies).
and left for 30 to 60 minutes and then allowed to drain. This
is repeated 2 to 6 times per day. With CFPD, an ingress cath- Y DIAGNOSTICS
eter is placed in the left flank and an egress catheter on ven-
tral midline connected to a closed bag collection system for Performing a thorough neurologic examination is critical. To
volumetric assessment. Dialysate fluid ingress is provided at come to a diagnosis, the practitioner performs a careful neu-
∼3 L/h. Eighty percent of ingress volume should be recovered rologic examination followed by appropriate ancillary diag-
in the collection system. Marked improvements in azotemia nostics. Ancillary diagnostics used in emergency situations
have been observed within the first 24 hours of starting CFPD, typically include hematology and serum chemistries, radio-
and it is continued based on creatinine clearance responses. graphs, and potentially cerebrospinal fluid analysis. When
RRT should be considered in cases where azotemia is unre- available, these patients may require further diagnostic tests,
sponsive to fluid therapy and/or diuretic medications or the notably imaging such as computed tomography, magnetic
horse is severely oliguric to anuric. Acute kidney injury would resonance imaging, endoscopy and electrodiagnostics, or a
likely yield potentially favorable outcomes using RRT com- combination of tests.
pared with chronic disease states. A neuroanatomic localization of the disease should be
made after a thorough examination,114,115 as described in
(Chapter 11). The neuroanatomic localization can be simpli-
fied by determining whether there is CNS, peripheral nerve,
Neurologic Critical Care or multifocal nerve disease. In the case of CNS disease, it is
Samuel D. Hurcombe helpful to determine whether the lesion is localized cranial or
caudal to the foramen magnum (i.e., whether there is brain
Any neurologic condition can represent a true emergency involvement). If there is brain involvement, it may be possible
requiring expedient assessment, stabilization, and targeted to further differentiate among cerebral, cerebellar, vestibular,
therapy. Severe manifestations of common diseases can be or brainstem disease. If disease is localized caudal to the fora-
challenging cases to treat, and horses that present acutely men magnum, the disease may be located in the cervical spi-
and/or deteriorate in the face of therapy require immediate nal cord or in the spinal cord caudal to T2.
Stabilization and symptomatic treatment are the primary spinal cord injury.117 Other potential beneficial effects of CSs
goals of emergency management of neurologic disease. A defin- include reduction in the spread of morphologic damage, pre-
itive diagnosis may not be known for several days following vention of the loss of axonal conduction and reflex activity,
the initial presentation of the emergent neurologic patient— preservation of vascular membrane integrity, and stabilization
for example, waiting for diagnostics for infectious agents (e.g., of white matter neuronal cell membranes in the presence of
protozoal myelitis, West Nile virus, etc.). As such, the clinician’s central hemorrhagic lesions. Furthermore, their antiinflam-
thorough neurologic examination provides a framework for a matory properties may be useful in reducing edema and fibrin
list of likely differential diagnoses. Empiric treatments, often deposition, as well as their ability to reverse sodium and potas-
for several differential diagnoses at once, are often provided sium imbalance caused by edema and necrosis.
until further testing supports a definitive diagnosis. Methylprednisolone sodium succinate (MPSS) is a syn-
thetic glucocorticoid with four times more antiinflammatory
Y TREATMENT activity and 0.8 times less mineralocorticoid action compared
with cortisol. Beneficial effects of MPSS on neural tissue
The goal of therapy should be to optimize CNS perfusion and include inhibition of lipid peroxidation, eicosanoid formation,
delivery of neurotropic substrates. Perfusion to the CNS is and lipid hydrolysis, including arachidonic acid release, main-
modulated by both the perfusing pressure (MAP) and local tenance of tissue blood flow and aerobic energy metabolism,
ICP. To promote global CNS perfusion, increasing MAP and/ improved elimination of intracellular calcium accumulation,
or decreasing ICP are desirable. reduced neurofilament degradation, and improved neuro-
Judicious use of sedation may be needed to facilitate safe nal excitability and synaptic transmission. The dose of MPSS
examination of the neurologic patient. Low-dose, short-acting used in human trials (30 mg/kg) exceeds that necessary for
drugs such as xylazine hydrochloride are recommended. How- activation of steroid receptors, which suggests that MPSS acts
ever, for more fractious and refractory patients, longer acting through mechanisms that are unrelated to steroid receptors.
continuous infusions and anesthetic agents may be required. Investigators have concluded that high-dose MPSS treatment
Stabilization of hemorrhagic and hypovolemic conditions is within 8 hours of spinal cord injury improved neurologic
necessary in trauma patients. Medical treatment of specific recovery.118,119 Controversy regarding the beneficial effects of
primary conditions is described in detail in Chapter 11. This MPSS and other steroids remains.120,121 A suggested dose for
section discusses select groups of drugs that are commonly horses is 25 mg/kg, IV bolus, then 5 to 8 mg/kg per hour for
used in horses with acute neurologic disease. 23 hours.
Analgesics Intracranial Pressure Reduction
Analgesic drugs are indicated if horses experience pain (e.g., Osmotic diuretics such as 20% mannitol (0.25–2.0 mg/kg,
in traumatic disease). NSAIDs are the mainstay drugs in administered IV over 20 minutes) and 7.2% hypertonic saline
equine medicine because of their antiinflammatory and anal- (2–4 mL/kg, administered IV as a bolus) are effective in com-
gesic properties. Flunixin meglumine (0.5–1 mg/kg, IV, every bating cerebral edema and increased ICP. These have a rapid
12–24 hours) is suitable. Opioids should be considered when onset of action (10–20 minutes) and are ideal therapies because
additional analgesia is required, or when analgesia is required they reduce ICP by drawing volume into the vascular com-
in situations of suspected NSAID toxicity, or when the risk partment and they increase MAP. Animals receiving osmotic
of developing NSAID toxicity is high (e.g., dehydration). diuretics should be adequately hydrated. Mannitol adminis-
Opioids do not have specific antiinflammatory effects and in tration is very effective in reducing ICP, although despite some
theory, κ-agonists over μ-agonists are advisable. Naloxone, technical limitations to the administration of this osmotic
μ-antagonist, has been shown to improve spinal cord blood diuretic, multiple doses of mannitol can lead to intravascular
flow. Multimodal analgesia, including the use of ketamine, dehydration, hypotension, reduction of cerebral blood flow
may offer advantages in blocking neuroexcitation through (CBF), and elevation of spinal fluid osmolarity.122,123
N-methyl-d-aspartate blockade. Hypertonic saline administered early in the treatment of
shock associated with head trauma may enhance the return of
Corticosteroids CBF and cell membrane function. Hypertonic saline may be
Corticosteroids (CSs) are potent antiinflammatory medi- the maintenance fluid of choice in head injury.124 It is associ-
cations and may be indicated in certain types of neurologic ated with significant decreases in ICP and cerebral water con-
diseases. Known inflammatory disease and acute trauma still tent compared with isotonic fluid treatment. Another study
appear to be indications for short-term corticosteroid therapy. comparing the effects of a hypertonic saline + solution and
Dexamethasone sodium phosphate is commonly adminis- mannitol on increased ICP found that the hypertonic saline
tered (0.05–0.1 mg/kg, IV, every 12–24 hours) for up to 48 hydroxyethyl starch reduced the ICP more effectively than
hours. A favorable response is expected within 4 to 8 hours mannitol alone.125 Induction of prolonged hypernatremia
after CS administration. Horses being given corticosteroid using 3% hypertonic saline administered as a continuous infu-
therapy should be monitored closely for the development of sion appears to be a promising therapy for the control of cere-
laminitis or secondary infection. If improvement in clini- bral edema.126
cal signs is observed, transition to oral prednisolone therapy Head and neck elevation at least 30 degrees above shoul-
(0.5–1.0 mg/kg, PO, daily tapered over 3–5 days) to decrease der height is also advised to minimize venous pooling in the
the chance of adverse effects is indicated. The neuroprotec- head. Increased venous pressures lead to increases in ICP via
tive effect of CSs is thought primarily to be mediated by free Queckenstedt’s phenomenon. Use of a wire and pulley system
radical scavenging.116 Recently, it has been shown that, similar connected to a halter is useful for the technique (Fig. 4.5).
to methylprednisolone, dexamethasone decreases apoptosis- Dimethyl sulfoxide (DMSO) 1 g/kg, administered IV as a
related cell death in rats that were subjected to traumatic 10% to 20% solution for 3 consecutive days, followed by three
penicillin (22,000 IU/kg, IV, every 6 hours) in combination

with gentamicin (6.6 mg/kg, IV, every 24 hours) can be used.
For anaerobic coverage, metronidazole (15 mg/kg, PO, every
8 hours) is indicated. Gentamicin and tetracyclines have poor
cerebrospinal fluid penetration.
Y SUPPORTING THE DOWN HORSE

Establishing venous access, controlling pain and anxiety of the
patient, and performing a thorough examination and frequent
repeat examinations should be done. Caution should be exer-
cised and safe handling practices are imperative when dealing
with a fractious patient and/or rabies is a concern. Manage-
ment of a recumbent horse requires intensive supportive care
and specific treatment aimed at the underlying or complicat-
ing disease processes.128,129 Supportive care is mainly directed
at protection of the animal and maintenance of adequate
hydration and nutritional status. Care of down horses is time-
consuming and more difficult if the horse is very large.
Down horses should be safely turned every 4 to 6 hours to
help prevent muscle compartmental injury, peripheral nerve
injury, and decubital ulcers. Treatment and prevention of
decubital ulcers are critical in recumbent animals,130 because
FIG. 4.5 This horse sustained head (and body) trauma. The head and prolonged or repeated unrelieved pressures to skin can result
neck are kept elevated to reduce central nervous system venous pooling in damage and ischemia to underlying tissues and subsequent
and intracranial pressure. tissue ulceration.131 Pressure ulcers usually occur over bony
prominences, and in horses the most common sites of decu-
bital ulcers are the tuber coxae, the points of the shoulder, and
treatments every other day may be of benefit in acute neuro- the caudal to the eye protuberance. Furthermore, pressure
logic disease. Reported benefits of DMSO include increased sores can occur along the distal extremities. For horses pre-
brain and spinal cord blood flow, decreased brain and spinal ventive strategies include appropriate padding and bedding,
cord edema, increased vasodilating PGE1, decreased platelet frequent changes in body positioning (i.e., turning), efforts to
aggregation, decreased PGE2 and PGF2, protection of cell mem- improve mobility, frequent examination of skin, maintenance
branes, and trapping of hydroxyl radicals. The exact mechanism of a well-balanced diet, and skin that is kept dry. Pressure
of DMSO remains unknown and remains controversial because sores generally heal well once the horse is able to stand. Rarely,
purported positive effects are unsubstantiated.127 Antioxidants infection of underlying bone can occur with prolonged severe
such as vitamin E and selenium have been shown to be benefi- decubitus and require debridement and local therapy.
cial in certain neurologic diseases. Their purported beneficial Surgical intervention may be required in some cases—for
effects include reduced lipid peroxidation and free radical scav- example, traumatic skull injury with unstable fragmentation.
enging116; however, they have not proved beneficial in cases of Successful treatment of such cases has been reported in horses.132
acute injury because of the length of time required to achieve Bedding should be absorbent, nonabrasive, and conform-
therapeutic concentrations in the CNS. able. It may be necessary to adjust the type of bedding when
the horse makes (successful) attempts to stand or is standing
Antibiotics in the sling. Once the patient begins to make attempts to stand,
Antimicrobial drugs may be required to treat the primary dis- bedding with good footing is helpful. Deep bedding in those
ease process (e.g., in bacterial meningitis) or to treat/prevent situations may hinder the horse’s attempts to stand or ambu-
secondary complications such as deep decubital ulceration, late, and straw may be slippery. Where possible, keeping the
pneumonia, and cystitis. Horses with prolonged recumbency down horse in sternal recumbency will help V/Q mismatch
or dysphagia are at high risk of aspiration pneumonia and and respiratory effort. Straw bales can assist in patient posi-
warrant broad-spectrum antibiotic therapy. tioning. Padded helmets and head bandages are advised to
Ideally, the choice of antibiotic should be based on culture help protect the head and eyes. Damage to the eyes can occur
and sensitivity testing; however, empiric coverage while await- directly by pressure to the eye or from bedding material. More-
ing results should include drugs that can penetrate the site of over, specific diseases may result in a horse’s inability to blink
action desired (e.g., meninges) and be tolerated by the patient (e.g., botulism, Horner’s syndrome, facial nerve paralysis).
(e.g., parenteral drugs in patients with dysphagia). The most common ophthalmic disorders seen in recumbent
For CNS penetration, parenteral fluoroquinolones (enro- horses are corneal ulcers and keratitis. Eyes should be exam-
floxacin 7.5 mg/kg, IV, every 24 hours) or enteral chloramphen- ined daily and assessed and treated carefully. Triple antibiotic
icol (50 mg/kg, PO, every 6 hours) appears to be a good choice. without steroid should be applied to the patients’ eyes daily to
Potentiated sulfonamides and third-generation cephalosporins help prevent keratopathy.
also achieve therapeutic cerebrospinal fluid concentrations. For
empiric therapy of secondary sites of infection, trimethoprim- Nutrition and Hydration Maintenance
sulfamethoxazole (20–30 mg/kg, PO, every 12 hours) or pro- Parenteral fluids are indicated in cases where swallowing is
caine penicillin (22 mg/kg, IM, every 12 hours) or crystalline impossible or the patient is in critical condition. Maintenance
fluids (40–60 mL/kg/day) are typically appropriate. Where REFERENCES

enteral therapy can be tolerated, intragastric fluids may be
1. Dellinger RP, Levy MM, Carlet JM, et al. Surviving sepsis cam-
preferable and more physiologic. Intermittent nasogastric paign: international guidelines for management of severe sepsis
tube passage or an indwelling small-bore enteral feeding tube and septic shock. Crit Care Med. 2008;36:296–327.
placement is a good choice. Depending on the dietary pro- 2. Ernst NS, Hernandez JA, MacKay RJ, et al. Risk factors associ-
tocol used, electrolytes and glucose may be added to the flu- ated with fecal Salmonella shedding among hospitalized horses
ids. Recumbent animals lose body condition rapidly when no with signs of gastrointestinal tract disease. J Am Vet Med Assoc.
nutrition is provided. Dramatic changes are often noticeable 2004;225:275–281.
within 1 week because of protein-calorie malnutrition. To pre- 3. Hardy J, Burkhardt HA, Beard W. Equine emergency and in-
vent weight loss and maintain muscle strength and immunity, tensive care: case survey and assessment of needs (1992–1994).
nutrition provision is essential. A more thorough discussion Proc Am Assoc Equine Pract. 1996;42:182–183.
4. Dolente B, Lindberg S, Russell G, et al. Emergency case admis-
of nutrition in the critically ill horse can be found in Chapters
sions at a large tertiary university referral hospital during a
5 and 20. 12-month period. J Vet Emerg Crit Care. 2008;18:298–305.
Down horses are prone to developing impactions of the 5. Girou E, Loyeau S, Legrand P, et al. Efficacy of handrubbing with
cecum, large colon, or small colon. Horses with botulism are alcohol based solution versus standard handwashing with anti-
notable cases. Reduced fecal output is an early sign, and judi- septic soap: randomized clinical trial. Br Med J. 2002;325:362.
cious use of laxatives (magnesium sulfate or sodium sulfate; 1 6. Dallap-Shaer BL, Linton JK, Aceto H: Antimicrobial use in
g/kg, intragastrically) and/or lubricants (mineral oil 2–4 L per horses undergoing colic surgery. J Vet Intern Med. 2012, Nov-
500-kg horse, intragastrically) is indicated. Dec; 26:1449–1456.
7. Sevinga M, Barkema HW, Hesselink JW. Serum calcium and
Additional Considerations magnesium concentrations and the use of a calcium-magnesium-
borogluconate solution in the treatment of Friesian mares with
Horses with autonomic dysfunction (i.e., urine and/or fecal
retained placenta. Theriogenology. 2002;57:941–947.
retention) require frequent emptying of the rectum and blad- 8. Garcia-Lopez JM, Provost PJ, Rush JE, et al. Prevalence and
der. Use of stool softeners and frequent manual rectal evacu- prognostic importance of hypomagnesemia and hypocalcemia
ation should be performed several times each day. Special in horses that have colic surgery. Am J Vet Res. 2001;62:7–12.
caution should be made when performing rectal evacua- 9. Perel P, Roberts I. Colloids versus crystalloids for fluid resus-
tion, especially in the down horse, to avoid traumatic rectal citation in critically ill patients. Cochrane Database Syst Rev.
tearing. 2012;13(6). CD000567.
An indwelling urinary catheter with either a one-way 10. Jones PA, Tomasic M, Gentry PA. Oncotic, hemodilutional, and
valve or closed collection system should be placed to assist hemostatic effects of isotonic saline and hydroxyethyl starch
bladder emptying. Closed systems are recommended to solutions in clinically normal ponies. Am J Vet Res. 1997;58:
541–548.
avoid ascending cystitis. Empiric use of potentiated sul-
11. Jones PA, Bain FT, Byars TD, et al. Effect of hydroxyethyl starch
fonamides can assist in preventing catheter-related urinary infusion on colloid oncotic pressure in hypoproteinemic horses.
bladder sepsis. J Am Vet Med Assoc. 2001;218:1130–1135.
Physiotherapy is advocated to facilitate the rehabilitative 12. Reickhoff K, Forster H, Weidhase R, et al. Administration of
process of injured horses. Physiotherapy can be provided in 10% hydroxyethyl starch 200/0.5 solution in normovolaemic
the recumbent animal by manipulating limbs, depending on horses, Scientific Proc. 7th International Equine Colic Research
the horse’s attitude, or assisting the horse to stand with a sling. Symposium. Manchester, UK. 2002.
Controlled exercise allows the unaffected parts of the nervous 13. Zarychanski R, About-Setta AH, Turgeon AF, et al. Association
system to compensate for the affected parts by increasing of hydroxyethyl starch administration with mortality and acute
strength and conscious proprioception. Exercise is especially kidney injury in critically ill patients requiring volume resusci-
tation: a systematic review and metanalysis. J Amer Med Assoc.
helpful in improving spinal cord deficits (e.g., weakness,
2013;309:678–688.
ataxia, and spasticity). 14. Epstein KL, Bergren A, Giguere S, et al. Cardiovascular, col-
Sling usage in the management of the down horse can loid osmotic pressure, and hemostatic effects of 2 formula-
be very helpful in reducing recumbency-related concerns. tions of hydroxyethyl starch in healthy horses. J Vet Intern Med.
Placing the neurologic patient with normal mentation may 2014;28:223–233.
be useful to facilitate a more thorough examination of indi- 15. Wilson EM, Holcombe SJ, Lamar A, et al. Incidence of trans-
vidual limb deficits. The presence of lameness, weakness, fusion reactions and retention of procoagulant and antico-
and ataxia as well as the number of affected limbs is much agulant factor activities in equine plasma. J Vet Intern Med.
more easily assessed when the horse is in an upright posi- 2009;23:323–328.
tion. In this position the horse may be able to stand freely 16. Mugde MC. Acute hemorrhage and blood transfusion in horses.
Vet Clin North Am Equine Pract. 2014;30:427–436.
and demonstrate clinical signs that may help in determining
17. Hurcombe SD, Mudge MC, Hinchcliff KW. Clinical and clin-
a diagnosis. icopathologic variables in adult horses receiving blood trans-
Deterioration or improvement of disease may be deter- fusions: 31 cases (1999–2005). J Am Vet Med Assoc. 2007;231:
mined relatively easily by daily sling assistance to provide 267–274.
short-term recommendations and prognosis. For long-term 18. Tomlinson JE, Taberner E, Boston RC, et al. Survival time of
management the sling can be useful, depending on the horse’s cross-match incompatible red cells in adult horses. J Vet Intern
primary disease and compliance. Horses may become used to Med. 2015;29:1683–1688.
using the sling and can be comfortably managed until they 19. Hurcombe SD, Welch BR, Williams JM, et al. Dark-field mi-
have regained sufficient control and strength to ambulate croscopy in the assessment of large colon microperfusion and
freely. Use of the sling may also help with physiotherapy dur- mucosal injury in naturally occurring surgical disease of the
equine large colon. Equine Vet J. 2014;46:674–680.
ing which periodic sessions of partial or assisted standing can
20. Fielding L. Crystalloid and colloid therapy. Vet Clin North Am
facilitate manipulation of limbs. Equine Pract. 2014;30:415–425.
21. Cruz AM, Li R, Kenney DG, et al. Effects of indwelling nasogas- 47. Corley KT, McKenzie HC, Amoroso LM, et al. Initial experi-
tric intubation on gastric emptying of a liquid marker in horses. ence with norepinephrine infusion in critically ill foals. J Vet
Am J Vet Res. 2006;67:1100–1104. Emerg Crit Care. 2000;10(4):267–276.
22. Hardy J, Stewart RH, Beard WL, et al. Complications of na- 48. Martin C, Viviand X, Leone M, et al. Effect of norepinephrine on
sogastric intubation in horses: nine cases (1987-1989). J Am Vet the outcome of septic shock. Crit Care Med. 2000;28(8):2758–
Med Assoc. 1992;201:483–486. 2765.
23. Nieto JE, Yamout S, Dechant JE. Sinusitis associated with na- 49. Woolsey CA, Coopersmith CM. Vasoactive drugs and the gut:
sogastric intubation in 3 horses. Can Vet J. 2014;55:554–558. is there anything new? Curr Opin Crit Care. 2006;12:155–159.
24. Beccati F, Nannarone S, Gialletti R, et al. Evaluation of transab- 50. Zhong JQ, Dorian P. Epinephrine and vasopressin during car-
dominal ultrasound as a tool for predicting the success of ab- diopulmonary resuscitation. Resuscitation. 2005;66:263–269.
dominocentesis in horses. Vet Rec. 2014;174:251. 51. Kellum JA, Pinsky MR. Use of vasopressor agents in critically ill
25. Estepa JC, Lopez I, Mayer-Valor R, et al. The influence of anti- patients. Curr Opin Crit Care. 2002;8:236–241.
coagulants on the measurement of total protein concentration 52. Smit AJ. Dopamine in heart failure and critical care. Clin Exp
in equine peritoneal fluid. ResVet Sci. 2006;80:5–10. Hypertens. 2000;22:269–276.
26. Peloso JG, Cohen ND. Use of serial measurements of peritoneal 53. Corley KTT. Inotropes and vasopressors in adults and foals. Vet
fluid lactate concentration to identify strangulating intestinal Clin North Amer. 2004;20:77–106.
lesions in referred horses with signs of colic. J Am Vet Med As- 54. Patel BM, Chittock DR, Russell JA, et al. Beneficial effects of
soc. 2012;240:1208–1217. short-term vasopressin infusion during severe septic shock. An-
27. Matthews S, Dart AJ, Dowling BA, et al. Peritonitis associ- esthesiology. 2002;96:576–582.
ated with Actinobacillus equuli in horses: 51 cases. Aust Vet J. 55. Malay MB, Ashton Jr RC, Landry DW, et al. Low-dose vaso-
2001;79:536–539. pressin in the treatment of vasodilatory septic shock. J Trauma.
28. Santschi EM, Grindem CB, Tate Jr LP, et al. Peritoneal fluid anal- 1999;47:699–703.
ysis in ponies after abdominal surgery. Vet Surg. 1988;17:6–9. 56. Asfar P, De Backer D, Meier-Hellmann A, et al. Clinical re-
29. Hanson RR, Nixon AJ, Gronwall R, et al. Evaluation of peri- view: influence of vasoactive and other therapies on intestinal
toneal fluid following intestinal resection and anastomosis in and hepatic circulations in patients with septic shock. Crit Care.
horses. Am J Vet Res. 1992;53:216–221. 2004;8:170–179.
30. Weil MH, Shubin H. Proposed reclassification of shock states 57. Wong DM, Vo DT, Alcott CJ, et al. Plasma vasopressin con-
with special reference to distributive defects. Adv Exp Med Biol. centrations in healthy foals from birth to 3 months of age. J Vet
1971;23:13–23. Intern Med. 2008;22:1259–1261.
31. Ellender TJ, Skinner JC. The use of vasopressors and inotropes 58. Hurcombe SD, Toribio RE, Slovis N, et al. Blood arginine vaso-
in the emergency medical treatment of shock. Emerg Med Clin pressin, adrenocorticotropin hormone, and cortisol concentra-
North Am. 2008;26:759–786. tions at admission in septic and critically ill foals and their as-
32. Rodgers KG. Cardiovascular shock. Emerg Med Clin North Am. sociation with survival. J Vet Intern Med. 2008;22:639–647.
1995;13:793–810. 59. Hollis AR, Boston RC, Corley KT. Plasma aldosterone, vaso-
33. Spaniol JR, Knight AR, Zebley JL, et al. Fluid resuscitation ther- pressin and atrial natriuretic peptide in hypovolaemia: a prelim-
apy for hemorrhagic shock. J Trauma Nurs. 2007;14:152–160. inary comparative study of neonatal and mature horses. Equine
34. Lefer AM, Lefer DJ. Pharmacology of the endothelium in Vet J. 2008;40:64–69.
ischemia-reperfusion and circulatory shock. Annu Rev Pharma- 60. Dembek KA, Hurcombe SD, Stewart AJ, et al. Association of
col Toxicol. 1993;33:71–90. aldosterone and arginine vasopressin concentrations and clini-
35. Landry DW, Oliver JA. The pathogenesis of vasodilatory shock. cal markers of hypoperfusion in neonatal foals. Equine Vet J.
N Engl J Med. 2001;345:588–595. 2016;48:176–181.
36. Tuite PK. Recognition and management of shock in the pediat- 61. Borchers A, Magdesian KG, Schenck PA, Kass PH. Serial plas-
ric patient. Crit Care Nurs Q. 1997;20:52–61. ma vasopressin concentration in healthy and hospitalized neo-
37. Holmes CL. Vasoactive drugs in the intensive care unit. Curr natal foals. Equine Vet J. 2014;46:306–310.
Opin Crit Care. 2005;11:413–417. 62. Ludders JW, Palos HM, Erb HN, et al. Plasma arginine vaso-
38. Ruffolo Jr RR, Nichols AJ, Stadel JM, et al. Pharmacologic and pressin concentration in horses undergoing surgery for colic. J
therapeutic applications of alpha 2-adrenoceptor subtypes. Vet Emerg Crit Care. 2009;19:528–535.
Annu Rev Pharmacol Toxicol. 1993;33:243–279. 63. Krausz MM. Controversies in shock research: hypertonic resus-
39. Nagashima M, Hattori Y, Akaishi Y, et al. Alpha 1-adrenoceptor citation-pros and cons. Shock. 1995;3:69–72.
subtypes mediating inotropic and electrophysiological effects in 64. Fielding CL, Magdesian KG. A comparison of hypertonic (7.2%)
mammalian myocardium. Am J Physiol. 1996;271:H1423–H1432. and isotonic (0.9%) saline for fluid resuscitation in horses: a
40. Huang L, Tang W. Vasopressor agents: old and new compo- randomized, double-blinded, clinical trial. J Vet Intern Med.
nents. Curr Opin Crit Care. 2004;10:183–187. 2011;25:1138–1143.
41. Steel A, Bihari D. Choice of catecholamine: does it matter? Curr 65. Corley KTT. Monitoring and treating hemodynamic distur-
Opin Crit Care. 2000;6:347–353. bances in critically ill foals. Equine Vet Educ. 2002;14:270–279.
42. Girault JA, Greengard P. The neurobiology of dopamine signal- 66. Hollis AR, Ousey JC, Palmer L, et al. Effects of norepineph-
ing. Arch Neurol. 2004;61:641–644. rine and a combined norepinephrine and dobutamine infusion
43. Holmes CL, Landry DW, Granton JT. Science review: vasopres- on systemic hemodynamics and indices of renal function in
sin and the cardiovascular system part 1: receptor physiology. normotensive neonatal thoroughbred foals. J Vet Intern Med.
Crit Care. 2003;7:427–434. 2006;20:1437–1442.
44. Vincent JL. Vasopressin in hypotensive and shock states. Crit 67. Landry DW, Levin HR, Gallant EM, et al. Vasopressin deficien-
Care Clin. 2006;22:187–197. cy contributes to the vasodilation of septic shock. Circulation.
45. Holmes CL, Landry DW, Granton JT. Science review: vasopres- 1997;95:1122–1125.
sin and the cardiovascular system part 2: clinical physiology. 68. Dickey EJ, McKenzie H, Johnson A, Furr MO. Use of pressor
Crit Care. 2004;8:15–23. therapy in 24 hypotensive critically ill neonatal foals. Aust Vet J.
46. Valverde A, Giguere S, Sanchez LC, et al. Effects of dobutamine, 2010;88:472–477.
norepinephrine, and vasopressin on cardiovascular function in 69. Rivers MD, Nguyen B, Havstad S, et al. Early goal-directed ther-
anesthetized neonatal foals with induced hypotension. Am J Vet apy in the treatment of severe sepsis and septic shock. N Engl J
Res. 2006;67(10):1730–1737. Med. 2001;345:1368–1377.
70. ARISE Investigators. Goal-directed resuscitation for patients 97. Heidegger CP, Darmon P, Pichard C. Enteral vs parenteral nu-
with early septic shock. N Engl J Med. 2014;371:1496–1506. trition for the critically ill patient: a combined support should
71. ProCESS Investigators. A randomized trial of protocol-based be preferred. Curr Opin Crit Care. 2008;14:408.
care for early septic shock. N Engl J Med. 2014;370:1683–1693. 98. National Research Council. Nutrient requirements of horses.
72. Corley KTT, Marr CM. Cardiac monitoring in the ICU patient. Washington, DC: National Academies Press; 2007.
Clin Tech Equine Pract. 2003;2:145–155. 99. Robinson NE, ed. Current therapy in equine medicine. 6th ed.
73. Magdesian KG. Monitoring the critically ill equine patient. Vet St. Louis, MO: Saunders; 2009.
Clin North Am Equine Pract. 2004;20:11–39. 100. Carr EA, Holcombe SJ. Nutrition of critically ill horses. Vet Clin
74. Magdesian KG, Fielding CL, Rhodes DM, et al. Changes in North Am Equine Pract. 2009;25:93–108.
central venous pressure and blood lactate concentration in 101. Jose-Cunilleras E, Viu J, Corradini I, et al. Energy expenditure
response to acute blood loss in horses. J Am Vet Med Assoc. of critically ill neonatal foals. Equine Vet J Supp. 2012;41:48–51.
2006;229:1458–1462. 102. Hansen TO, White NA, Kemp DT. Total parenteral nutrition in
75. Allen SE, Holm JL. Lactate: physiology and clinical utility. J Vet four healthy adult horses. Am J Vet Res. 1988;49:122.
Emer Crit Care. 2008;18:123–132. 103. Spurlock SL, Ward MV. Parenteral nutrition in equine pa-
76. Corley KT, Donaldson LL, Durando MM, et al. Cardiac out- tients: principles and theory. Compend Cont Educ Pract Vet.
put technologies with special reference to the horse. J Vet Intern 1991;13:461.
Med. 2003;17:262–272. 104. Furr M. Intravenous nutrition in horses: clinical applications.
77. McConachie E, Barton MH, Rapoport G, et al. Doppler and volu- Proc Am Coll Vet Intern Med. 2002;20:186.
metric echocardiographic methods for cardiac output measure- 105. Myers CJ, Magdesian KG, Kass PH, et al. Parenteral nutrition in
ment in standing adult horses. J Vet Intern Med. 2013;27:324–330. neonatal foals: clinical description, complications, and outcome
78. West JB. Respiratory physiology: the essentials. 8th ed. Baltimore, in 53 foals (1995-2005). Vet J. 2009;181:137–144.
MD: Lippincott Williams & Wilkins; 2008. 106. Krause JB, McKenzie HC. Parenteral nutrition in foals: a retrospec-
79. Wingfield WE, Raffe MR, eds. The veterinary ICU book. Jackson tive study of 45 cases (2000-2004). Equine Vet J. 2007;39:74–78.
Hole, WY: Teton New Media; 2002. 107. Dunkel B, Palmer JE, Olson KN, et al. Uroperitoneum in 32
80. Palmer JE. Ventilatory support of the critically ill foal. Vet Clin foals: influence of intravenous fluid therapy, infection, and sep-
North Am Equine Pract. 2005;21:457–486. sis. J Vet Intern Med. 2005;19:889–893.
81. Wong DM, Alcott CJ, Wang C, et al. Physiologic effects of na- 108. Doucet MY, Bertone AL, Hendrickson D, et al. Comparison of
sopharyngeal administration of supplemental oxygen at various efficacy and safety of paste formulations of firocoxib and phe-
flow rates in neonatal foals. Am J Vet Res. 2010;71:1081–1088. nylbutazone in horses with naturally occurring osteoarthritis.
82. Wilson DV, Schott HC, Robinson NE, et al. Response to naso- J Am Vet Med Assoc. 2008;232:91–97.
pharyngeal oxygen administration in horses with lung disease. 109. Brashier MK, Geor RJ, Ames TR, et al. Effect of intravenous cal-
Equine Vet J. 2006;38:219–223. cium administration on gentamicin-induced nephrotoxicosis in
83. McKenzie HC. Characterization of antimicrobial aerosols for ponies. Am J Vet Res. 1988;59:1055–1062.
administration to horses. Vet Ther. 2003;4:110–119. 110. Divers TJ. Urine production, renal function, and drug monitor-
84. McKenzie HC, Murray MJ. Concentrations of gentamicin in ing in the equine intensive care unit. Clin Tech Equine Pract.
serum and bronchial lavage fluid after intravenous and aerosol 2003;2:188–192.
administration to horses. Am J Vet Res. 2000;61:1185. 111. Johansson AM, Gardner SY, Levine JF, et al. Furosemide contin-
85. Duvivier DH, Votion D, Roberts CA, et al. Inhalation therapy of uous rate infusion in the horse: evaluation of enhanced efficacy
equine respiratory disorders. Equine Vet Educ. 1999;11:124. and reduced side effects. J Vet Intern Med. 2003;17:887–895.
86. Coutiel LL, Cardwell JM, Gerber V, et al. Inflammatory air- 112. Wong DM, Witty D, Alcott CJ, et al. Renal replacement therapy
way disease of horses–revised consensus statement. J Vet Intern in healthy adult horses. J Vet Intern Med. 2013;27:308–316.
Med. 2016;30(2):503–515. 113. Gallatin LL, Couteil LL, Ash SR. Use of continuous-flow perito-
87. Giguere S, Slade JK, Sanchez LC. Retrospective comparison neal dialysis for the treatment of acute renal failure in an adult
of caffeine and doxapram for the treatment of hypercapnia in horse. J Am Vet Med Assoc. 2005;226:756–759.
foals with hypoxic ischemic encephalopathy. J Vet Intern Med. 114. De Lahunta A, Glass EN. Veterinary neuroanatomy and clinical
2008;22:401–405. neurology. 3rd ed. St. Louis, MO: Saunders; 2009.
88. Taylor SD, Toth B, Townsend WM, et al. Mechanical ventilation 115. Matthews HK, Andrews FM. Performing a neurologic examination
and management of an adult horse with presumptive botulism. in a standing or recumbent horse. Vet Med. 1990;85:1229–1240.
J Vet Emerg Crit Care. 2014;24:594–601. 116. Olby N. Current concepts in the management of acute spinal
89. Aguilera-Tejero E, Estepa JC, Lopez I, et al. Arterial blood gases cord injury. J Vet Intern Med. 1999;13:399–407.
and acid-base balance in healthy young and old horses. Equine 117. Zurita M, Vaquero J, Oya S, Morales C. Effects of dexameth-
Vet J. 1998;30:352. asone on apoptosis-related cell death after spinal cord injury.
90. Picandet V, Jeanneret S, Jean-Pierre L. Effects of syringe type J Neurosurg. 2002;96:83–89.
and storage temperature on results of blood gas analysis in arte- 118. Bracken MB. Methylprednisolone in the management of acute
rial blood of horses. J Vet Intern Med. 2007;21:476. spinal cord injuries. Med J Austr. 1990;153:368.
91. Viu J, Armengou L, Rios J, Cesarini Latorre Carlota, Jose Cu- 119. Bracken MB. Treatment of acute spinal cord injury with methyl-
nilleras Eduardo. Acid base imbalances in ill neonatal foals and prednisolone: results of a multicenter, randomized clinical trial.
their association with survival. Equine Vet J. 2015;49(1):51–57. J Neurotrauma. 1991;1(suppl 8):S47–S50, discussion S51–S42.
92. Stampfli HR, Schoster A, Constable PD. Clinical utility of se- 120. Hugenholtz H. Methylprednisolone for acute spinal cord injury:
rum biochemical variables for predicting acid-base balance in not a standard of care. CMAJ. 2003;168:1145–1146.
critically ill horses. Vet Clin Pathol. 2014;43:547–556. 121. Hugenholtz H, Cass DE, Dvorak MF, et al. High-dose methyl-
93. Matthews NS, Hartke S, Allen Jr JC. An evaluation of pulse oxi- prednisolone for acute closed spinal cord injury—only a treat-
meters in dogs, cats and horses. Vet Anaesth Anal. 2003;30:3. ment option. Can J Neurol Sci. 2002;29:227–235.
94. Souba WW. Nutritional support. N Engl J Med. 1997;336:41. 122. Arai T, Tsukahara I, Nitta K, Watanabe T. Effects of mannitol on
95. Weissman C. Nutrition in the intensive care unit. Crit Care. cerebral circulation after transient complete cerebral ischemia
1999;3:R67. in dogs. Crit Care Med. 1986;14:634–637.
96. Henneke DR, Potter GD, Kreider JL, et al. Relationship between 123. Polderman KH, van de Kraats G, Dixon JM, et al. Increases in
condition score, physical measurements and body fat percent- spinal fluid osmolarity induced by mannitol. Crit Care Med.
ages in mares. Equine Vet J. 1983;15:371. 2003;31:584–590.
124. Qureshi AI, Suarez JI. Use of hypertonic saline solutions in 128. McConnico RS, Clem MF, DeBowes RM. Supportive medi-
treatment of cerebral edema and intracranial hypertension. Crit cal care of recumbent horses. Compend Cont Educ Pract Vet.
Care Med. 2000;28:3301–3313. 1991;13:1287–1295.
125. Schwarz S, Schwab S, Bertram M, et al. Effects of hypertonic 129. Nout YS, Reed SM. Management and treatment of the recum-
saline hydroxyethyl starch solution and mannitol in pa- bent horse. Equine Vet Educ. 2005;7:416–432.
tients with increased intracranial pressure after stroke. Stroke. 130. Thomas DR. Issues and dilemmas in the prevention and treat-
1998;29:1550–1555. ment of pressure ulcers: a review. J Gerontol A Biol Sci Med Sci.
126. Peterson B, Khanna S, Fisher B, Marshall L. Prolonged hyper- 2001;56:M328–M340.
natremia controls elevated intracranial pressure in head-injured 131. Thomas DR. Prevention and treatment of pressure ulcers: what
pediatric patients. Crit Care Med. 2000;28:1136–1143. works? what doesn’t? Cleve Clin J Med. 2001;68:704–722.
127. Hoerlein BF, Redding RW, Hoff EJ, et al. Evaluation of dexa- 132. Rayner SG. Traumatic cerebral partial lobotomy in a Thorough-
methasone, DMSO, mannitol and solcoseryl in acute spinal bred stallion. Austr Vet J. 2005;83:674–677.
cord trauma. J Am Anim Hosp Assoc. 1983;19:216.
C HA P T E R 5
Internal Medicine and
Clinical Nutrition
Raymond J. Geor*
Veterinarians are a primary source of nutritional information can be used to collect clinical data, including signalment, body
and advice for horse owners. Therefore it is reasonable to expect weight (BW) and condition, and details regarding the horse’s
equine practitioners to have some expertise in the clinical assess- current and recommended ration. Box 5.1 provides explana-
ment of the nutritional status and feeding programs so that tions for a number of nutritional terms used to describe feed
they may assist horse owners in the selection of rations for an nutrients and fractions, the knowledge of which is relevant to
individual horse or group of horses. Additionally, because diet the interpretation of feed analysis data.
composition can contribute to the pathophysiology and clini-
cal manifestations of certain chronic diseases (e.g., some forms Clinical Examination
of chronic exertional rhabdomyolysis), the veterinarian is often Body condition scoring (BCS) and measurement of BW are the
consulted to make recommendations for special diets. Special cornerstones of the clinical assessment of nutritional status.
dietary considerations are also required for sick neonatal foals In some situations laboratory analysis of blood or other tissue
or adult horses. This chapter provides an overview of the prin- samples may be indicated as part of the nutritional evaluation
ciples of clinical assessment of nutritional status and feeding (e.g., measurement of whole-blood selenium concentration).
programs, reviews carbohydrate nutrition for horses (includ- It must be recognized that no single laboratory value is a reli-
ing the types of carbohydrates in horse feeds, terminology and able indicator of nutritional status in an individual animal.
methods for analysis of carbohydrates in feeds, and strategies Nonetheless, blood or tissue measurements may be valuable
for mitigation of gastrointestinal disturbances associated with for the evaluation of herd problems, in which samples should
carbohydrate nutrition), and summarizes current recommen- be obtained from a representative number of animals.
dations for the nutritional support of neonatal or adult horses BW and BCS, which assesses subcutaneous fat deposition,
with acute illness. Other topics are feeding management of thin are indicators of long-term energy balance, or energy (calorie)
and starved horses and dietary recommendations for the man- intake relative to the horse’s needs. Generally, horses that receive
agement of obesity, which is becoming a significant problem in inadequate dietary energy will lose BW and condition, whereas
equine medicine. The reader is referred to the most recent edi- weight gain and the development of overconditioning (high
tion of the National Research Council’s Nutrient Requirements BCS) signify energy intake in excess of requirements. Although
of Horses for a complete discussion of equine nutrition.1 a number of systems have been used to determine BCS, the
most widely applied method is that developed by Henneke.3
The Henneke system uses a 1- to 9-point scale and requires the
Y EVALUATION OF NUTRITIONAL assessment of subcutaneous fat deposition in six areas: over the
STATUS AND FEEDING PROGRAMS crest of the neck, withers, behind the shoulder, over the ribs,
along the back, and around the tailhead. Considerable varia-
Clinical assessment of a feeding program for an individual or tion may exist in the pattern of fat deposition among horses; for
group of horses involves three basic elements: assessment of example, some horses have little fat deposited over the ribs even
general health and dietary history, clinical examination, and when other areas of the body are well covered. In addition, fat
evaluation of current diet and feeding method (i.e., types and deposits are sometimes asymmetrically distributed. Therefore it
amounts of feeds and how they are fed). The physiologic state is important to evaluate all six areas of the body on both sides.
and intended use of the horse (e.g., pregnant, lactating, in ath- A score between 1 and 9 is assigned, in which 1 indicates severe
letic work) affect its nutritional requirements; therefore, they emaciation and 9 indicates extreme fatness (Table 5.1). Body
are vital to the evaluation of the feeding program and when condition scores of 4 to 6 are regarded as ideal depending on
making any necessary adjustments. It also is useful to inspect use of the horse. Studies of weight gain and loss in moderately
housing and feeding facilities, including feed bins, hay storage, conditioned (BCS = 4–7) Thoroughbred, Quarter, and Arabian
and the watering system. Commercial software programs are horses indicate that one BCS unit represents approximately 25
available to assist with ration evaluation in relation to nutrient to 35 kg of BW.4,5 The BW associated with each unit of body
requirements.2 Fig. 5.1 shows an example of a simple form that condition may be higher in fat or thin horses.
The Henneke BCS system, originally developed for use in
*The editors and authors acknowledge and appreciate the contributions of Quarter Horse broodmares,3 is most appropriate for use in
Debra K. Rooney as a previous contributor to this chapter. Some of her original light breeds such as Thoroughbreds, Arabians, and Standard-
work has been incorporated into this edition. breds. This system may not be suitable for ponies and larger
191
NUTRITIONAL STATUS AND FEEDING PROGRAM EVALUATION FORM
HORSE INFORMATION Date ________
Owner _____________________________ Horse Name ________________________
Description _________________________________________________
(e.g., age, gender, breed)
Use/physiological state ______________________________________________________________
Housing/environment _______________________________________________________________
Medical history________________________________________________________________
_____________________________________________________________________________
PHYSICAL ASSESSMENT
Dentition _______ Normal _________ Poor
Hooves _______ Normal _________ Founder lines (laminitic)
Hair Coat _______ Normal _________ Long _________Other
Current Body Condition Score _________
(1 = very thin; 5 = moderate; 9 = very obese)
Notes:_______________________________________________________________________
(e.g., abnormal fat deposits)
Optional: Neck Circumference (cm or inches)_____________
ESTIMATED ENERGY INTAKE ON CURRENT DIET
Forage Consumption
Excellent hay (1.1 Mcal/lb) × __________ lb/d = ________________ Mcal digestible energy (DE)
Very good hay (0.9 Mcal/lb) × __________ lb/d = ________________ Mcal
Average hay (0.8 Mcal/lb) × __________ lb/d = ________________ Mcal
Below-average hay (0.7 Mcal/lb) × __________ lb/d = _______________ Mcal
Concentrate Consumption
Oat grain (1.3 Mcal/lb) × _____________ lb/d = ________________ Mcal
Sweet feed (1.4 Mcal/lb) × __________ lb/d = ________________ Mcal
High-fat sweet feed (1.5 Mcal/lb) × ________ lb/d = ________________ Mcal
Other Feeds (e.g., protein supplements, beet pulp)

____________ (_____ Mcal/lb) × ________ lb/d = _________________ Mcal
____________ (_____ Mcal/lb) × ________ lb/d = _________________ Mcal
____________ (_____ Mcal/lb) × ________ lb/d = _________________ Mcal
Current Total Energy Intake __________________ Mcal/d

(NOTE: Other nutrient intakes should also be checked for adequacy)
FIG. 5.1 Worksheet for evaluation of nutritional status and feeding program. (Adapted from Dr. Laurie
Lawrence, University of Kentucky, Lexington, Kentucky.)
CHAPTER 5 Internal Medicine and Clinical Nutrition 193
ESTIMATING THE APPROPRIATE DAILY ENERGY INTAKE

Target Body Condition Score (BCS) _________________
Recommended Change in BCS ____________________

(+1, +2, –1, –2, etc.)
Current Horse Weight _____________ Target Horse Weight _____________
Guide: For an 1100- to 1200-lb horse, change in 1 BCS unit = 45 to 70 lb, but greater weight change
may be necessary to alter BCS in very thin or very obese horses. Also, note that altering feed intake
can have a rapid effect on body weight by increasing or decreasing gut fill. Thus, a change in gut fill
can affect body weight by 10 to 20 lb, without a concomitant change in body condition score.
Recommended Energy Intake for Target Weight ___________________ Mcal/d

(see Box 2)
Suggested Adjustments for Weight Change (estimates)

Increase BCS 1 unit in 60 days (add 6 to 7 Mcal/d)
Increase BCS 2 units in 90 days (add 9 to 10 Mcal/d)
Decrease BCS 1 unit in 60 days (subtract 6 to 7 Mcal/d)
Decrease BCS 2 units in 120 days (subtract 6 to 7 Mcal/d)
Adjusted Recommended Daily Energy Intake ______________ Mcal/d
RECOMMENDED DIET
Current Level of Dietary Energy

Adequate _______ Insufficient _________ Excessive __________
Current Diet Could Include Minor Modifications: ______________________
Current Diet Should Be Adjusted as Follows:
Suggestions:
For weight loss: concentrate amounts should be reduced first
For weight gain: hay intake and quality should be adjusted first
ENERGY INTAKE WITH SUGGESTED DIET

Forage Consumption
Excellent hay (1.1 Mcal/lb) × __________ lb/d = ________________ Mcal DE
Very good hay (0.9 Mcal/lb) × __________ lb/d = ________________ Mcal
Average hay (0.8 Mcal/lb) × __________ lb/d = ________________ Mcal
Below-average hay (0.7 Mcal/lb) × __________ lb/d = _______________ Mcal
Concentrate Consumption
Oat grain (1.3 Mcal/lb) × _____________ lb/d = ________________ Mcal
Sweet feed (1.4 Mcal/lb) × ___________ lb/d = ________________ Mcal
FIG. 5.1, cont’d

Continued
High-fat, sweet feed (1.5 Mcal/lb) × ________ lb/d = ________________ Mcal
Other Feeds (e.g., protein supplements, beet pulp)

___________ (_____ Mcal/lb) × ________ lb/d = _________________ Mcal
___________ (_____ Mcal/lb) × ________ lb/d = _________________ Mcal
___________ (_____ Mcal/lb) × ________ lb/d = _________________ Mcal
Total Energy Intake ___________________ Mcal/d
FIG. 5.1, cont’d
BOX 5.1
Nutritional Terminology Relevant to the Interpretation of Feed Composition Data
Moisture: Percentage of feed that is water Ethanol-soluble carbohydrates (ESCs): Part of the non-
Dry matter (DM): 100% minus the water in feed structural carbohydrate fraction. The ESC fraction contains
Most hays and concentrates are approximately 90% water. mostly simple sugars (disaccharides). Some laboratories
Fresh pasture can contain 60% to 80% water. categorize this fraction as sugars.
Feed compositions are usually compared on a DM basis Starch: Contains amylose and amylopectin. The starch analy-
(100% DM), but feeds with similar concentrations of sis does not separate easily digested starch and starch
DM can be compared on an as-fed basis. resistant to small intestinal digestion.
Crude protein (CP): Also called total protein; this value is Nonstructural carbohydrate (NSC): Previously, the NSC
calculated by measuring total nitrogen. fraction included all carbohydrates not included in NDF,
Acid detergent fiber (ADF): A chemically determined fraction but today it is commonly defined as starch plus ESC.
that contains cellulose and lignin. ADF is inversely related Therefore the NSC in a feed represents the carbohydrates
to digestibility and is used to estimate the digestible energy that are expected to be digested and absorbed from the
content of horse feeds. small intestine as glucose or other simple sugars.
Neutral detergent fiber (NDF): A chemically determined Water-soluble carbohydrates (WSCs): This fraction includes
fraction that contains cellulose, lignin, and hemicellu- the simple carbohydrates that appear in the ESC fraction
lose. NDF contains most of the structural carbohydrates as well as some longer chain carbohydrates, including
in plants. As plants mature, they contain more stem fructans. Fructans are storage carbohydrates synthesized
(more structure); therefore, DF increases with maturity. by some plants, especially cool season grasses. Some nu-
The NDF fraction includes the ADF fraction. There is a tritionists calculate fructan as the difference between WSC
general inverse relationship between NDF in forages and and ESC, but this estimate has not been validated.
voluntary forage intake by horses; in other words, when Digestible energy (DE): This is not a measured value. DE is
two hays of similar variety are compared, the forage calculated from other analyzed fractions, including ADF and
with lower NDF will be consumed in higher amounts by CP. The amount of fat in the feed affects the true DE value of
horses. a feed, but if crude fat was not a requested item on the feed
Nonfiber carbohydrates (NFCs): This is not a measured analysis, the DE might be calculated using an average value
fraction. NFC is determined by calculating the difference for crude fat. For common forages (e.g., hay and pasture),
between total DM and the sum of NDF, crude fat, ash, the DE value calculated by a laboratory is a relatively accu-
and CP. Types of carbohydrates that are included in the rate assessment of the true DE value. For concentrate feeds
NFC fraction are true nonfiber carbohydrates, such as the calculated DE value may not represent the true DE value.
monosaccharides and starch, but it also includes some Adjusted CP, % total digestible nutrients (TDN), net
carbohydrates that are resistant to mammalian enzymatic energy of lactation (NEL), net energy of maintenance
digestion such as pectin (found in beet pulp and alfalfa (NEM), net energy of gain (NEG), relative feed value: Not
hay) and fructan (found in some grasses). relevant to horse diet analyses.
breed horses (e.g., drafts) that have a different pattern of fat adiposity is more closely linked than generalized obesity to
distribution. A 9-point BCS system for Warmblood horses the risk for diabetes and cardiovascular disease, and mea-
was developed to account for differences in conformation and surement of waist circumference is a better indicator of
patterns of fat deposition in this breed compared with Quar- abdominal fat accumulation than is body mass index.7 In
ter Horses.6 For example, fat begins to cover the hip bones of horses and ponies there may be a similar association between
Quarter Horses at a BCS of 4, whereas the hip bones of Warm- regional adiposity and disease risk. In studies of horses and
blood horses remain prominent at a BCS of 6 (using the sys- ponies with a predisposition to pasture-associated laminitis,
tem developed for Warmbloods). some affected animals are not obese on the basis of BCS (i.e.,
It also should be noted that the BCS system does not BCS <7) and have no external evidence of regional adipos-
register differences in regional adiposity that may signify ity, but others have enlarged fat deposits on the neck (“cresty
increased risk of disease. In humans visceral (abdominal) neck”) and thoracic and tailhead regions; these fat deposits
TABLE 5.1 Description of Body Condition Scores in Horses

Condition General
Score Condition Neck Shoulder Withers Ribs Loin Tailhead
1 Very poor Individual bone Bone structure Bones easily Ribs very Spine bones Tailhead and
structure vis- very visible visible; no visible and visible; ends hips very
ible; feels very and sharp to fat; razor-like skin furrows feel pointed visible
bony touch between ribs
Animal extremely emaciated; no fatty tissue can be felt
2 Very thin Bones just Possible to Withers obvi- Ribs promi- Slight fat cover- Tailhead and hip
visible; animal outline bone ous, very nent, slight ing other bones obvious
emaciated structure minimal fat depression vertical and flat to the eye
covering between ribs spin projec-
tions; ends feel
rounded
3 Thin Thin, flat muscle Shoulder ac- Withers thin Slight fat Fat buildup Tailhead
covering, no centuated; and accen- cover over halfway on prominent;
raised muscle some fat tuated with ribs; rib out- vertical spines, hip bones
or fat cover but some, al- line obvious but easily vis- rounded but
thinner than though little, to the eye ible; flat spinal easily visible;
desirable fat cover bones not felt pin bones
covered
4 Moderately Neck with some Shoulder not Withers not Faint outline Slight outward Fat palpable
thin fat; horse not obviously thin obviously visible to the ridge along
obviously thin with some fat thin, smooth eye back
cover edges but
prominent
5 Moderate Neck blends Shoulder Withers Ribs cannot Back level Fat around
smoothly blends smoothly be seen but tailhead begin-
into body smoothly into rounded can be easily ning to feel
with some fat body over top felt spongy
cover
6 Moderately Fat easily pal- Fat layer pal- Fat palpable Fat over ribs May have slight Fat around tail-
fleshy pable pable feels spongy inward crease head soft and
palpable
7 Fleshy Visible fat Fat buildup be- Fat covering Individual ribs May have slight Fat around tail-
deposits or hind shoulder withers is still palpable inward crease head soft and
lumps along firm down back rounded off
neck
8 Fat Noticeable Area behind Area along Difficult to feel Crease down Tailhead fat very
thickening of shoulder withers filled ribs back evident soft and flabby
neck filled in flush with fat
with body
Fat deposited along inner buttocks
9 Extremely Bulging fat Bulging fat Bulging fat Patchy fat Obvious deep Building fat
fat over ribs crease down around tail-
back head
Fat along inner buttocks may rub together; flank filled in flush

are sometimes asymmetrically distributed.8,9 Neck crest adi- 15%, depending on hydration and feeding status and on gas-
posity, assessed by the ratio of mean neck circumference to trointestinal fill. Accordingly, it is important to standardize
height at the withers (NCHR), is negatively associated with the time of feeding relative to measurement of BW. BW may
insulin sensitivity in horses and ponies.9,10 Although cutoff be measured directly by use of a platform scale or, in mature
values for NCHR in relation to obesity and disease risk have horses, estimated from body measurements such as heart girth
not been defined, the repeated measurement of mean neck circumference and body length.11,12 Heart girth is measured
circumference is useful for monitoring the effectiveness of a immediately behind the elbows, and body length is measured
weight loss program. from the point of the shoulder to the tuber ischii:
Knowledge of a horse’s BW is needed for accurate calcula- 2
tion of nutrient and feed requirements. It is important to note BW ( kg) = Heart girth ( cm) × length ( cm) /11, 800
that the BW of an individual horse can vary between 5% and
BW also can be estimated from measurement of heart girth The clinician also should evaluate feeding management,
circumference by use of a weight tape calibrated for horses. particularly when a problem under investigation may be
Measurements should be taken in a consistent manner, with due to poor feeding practices (e.g., weight loss, colic). For
the horse standing on a flat surface, and care must be taken example, what are the relative proportions of forage and
not to pull the tape too tightly. Clinicians are advised to take grain/concentrate? Does the ration contain adequate high-
the average of several (e.g., three or four ) measurements. quality forage? How many times a day is the horse fed? How
Accuracy of these measurements is affected by a number of frequently is the diet changed, and are these changes made
factors, including breed, conformation, level of fitness, thick- gradually (ideally over 7–10 days) or suddenly? Several epi-
ness of hair coat, gastrointestinal fill, and pregnancy status.12 demiologic studies have reported that changes in diet (grain/
BW based on heart girth is most accurate when this method concentrate or hay, even when switching to hay of the same
is applied to mature horses with an average BCS (i.e., 5–7). type) significantly increase the risk of colic.14-16 The risk of
Underestimation or overestimation of BW may occur when gastrointestinal problems also increases when horses are fed
weight tapes are used to estimate the BW of horses with low or large quantities of starch-rich grain and concentrate feeds or
high condition scores. inadequate long-stem roughage.14,16 As a general guide, all
horses should receive a minimum of 1.0% of BW per day as
Diet and Ration Evaluation hay or the equivalent; forage at 1.5% of BW per day is pre-
It is useful to first examine the physical characteristics of feeds ferred. For a 450- to 500-kg horse, grain or concentrate meals
(i.e., visual appearance [color, presence of foreign material should be no more than 2.5 kg (approximately 5 lb) to reduce
such as mold and dust] and odor). Preserved forages (e.g., hay) risk of hindgut disturbances associated with the cecal delivery
should be evaluated for type (grass vs. legume), leaf-to-stem of undigested starch. If the daily ration includes more than
ratio, and presence of seed heads. Hays with good nutritional 5.0 kg of grain or concentrate, it should be provided in more
value are characterized by a large proportion of leaf; compared than two feedings per day (see the section Carbohydrates in
with stems, leaves have higher nonstructural carbohydrates Equine Nutrition).16
(NSCs; starches, sugars, and fructans), lower structural car- Information on the nutrient content of the diet is needed
bohydrates (SCs; hemicellulose, cellulose, and lignin), and to determine the adequacy of the ration. Several approaches
higher protein.1 Therefore second- and third-cutting hays, can be used to estimate the nutrient contents of feeds. The feed
which often have a higher stem-to-leaf ratio, tend to provide tags on commercial feeds provide some nutritional informa-
higher nutritional value than first-cutting hay. The latter is tion, including a list of ingredients and data on some nutrients.
usually harvested at a more mature stage. The presence of seed However, feed manufacturers are required to guarantee only
heads and a stemmy, coarse appearance are also indications of that minimums were met and maximums were not exceeded;
advanced maturity at cutting. Some studies have reported an in other words, the actual content of listed nutrients is not pro-
inverse relationship between the neutral detergent fiber (NDF; vided. An alternative source of data on the nutrient content
the fraction that contains cellulose, hemicellulose, and lignin) of feeds is published databases (e.g., National Research Coun-
and voluntary hay intake (i.e., the voluntary intake of stemmy cil [NRC] publications, feed company websites). Although
hays with high NDF content will be lower compared with that the nutrient profiles available from these databases provide
of hays with high leaf-to-stem ratio).1,13 a useful guide, these data may not correspond exactly to the
The next step in the evaluation is to estimate daily feed feedstuff provided to the horse under evaluation because of
intake. Owners or stable managers should be questioned to differences in geography, growing and harvesting conditions,
determine the amounts of hay, concentrates, and supplements and other factors. The ideal, although not always practical,
provided (and whether the horse regularly refuses any of approach is to submit samples of feed and forages (core hay
these feedstuffs). All feeds, including several flakes or biscuits samples and pasture clippings) for laboratory analysis of nutri-
of hay, should be weighed to estimate the actual amounts of ent content. At least two samples (approximately 250 g each)
feed provided to the horse. Significant errors may occur when of each grain or concentrate should be taken; these should be
volume (e.g., “a coffee can–full”) rather than weight is used mixed thoroughly with the composite sample submitted for
to estimate feed provision because grains, concentrates, and analysis. Approximately 10% of the hay store should be sam-
hays vary markedly in weight per unit volume. A handheld pled by use of a hay probe. Again, these samples should be well
fish scale or similar scale works well for this task. It is difficult mixed, with the composite sample shipped to the laboratory
to measure actual feed intake, particularly when forage is fed in a sealable plastic bag. Garden shears can be used to obtain
on the ground, where wastage can be as high as 25%, or fed pasture clippings, which should be sampled in a Z-pattern
to groups of horses. The other challenge is estimation of pas- and cut to grazing height. It may be necessary to sample clip-
ture forage intake, which is generally taken as the difference pings taken from several pastures to determine the range of
between the mean intake of digestible energy (DE) for horses, nutrients on the farm. The basic nutrient profile from analysis
with consideration given to their weight, age, and physiologic includes dry matter (DM), DE, crude protein (CP), acid deter-
condition, minus actual daily intakes of hay and grains. As gent fiber, NDF, fat (ether extract), ash, calcium, magnesium,
previously mentioned, regular assessment of BW and BCS phosphorus, sodium, and potassium (see Box 5.1). Trace ele-
over time will provide the best guide to the adequacy of energy ment and vitamin analyses are available depending on need
intake. Reported values for daily dry matter intake (DMI) by and expense. Some laboratories will perform additional analy-
horses, ponies, and donkeys range between 0.8% and 5.2% of ses and calculations to provide estimates of some of the carbo-
BW.1 Young and mature horses appear to have a maximal daily hydrate fractions. For example, Equi-Analytical Laboratories
DMI of 3% to 3.2% of BW, but intakes in the range of 2.0% to (Ithaca, NY; www.equianalytical.com) analyzes starch and
2.5% of BW are more typical (this includes horses maintained ethanol-soluble carbohydrates (ESCs; which are mostly simple
on an all-hay diet). Some evidence suggests that ponies may sugars). More information on dietary carbohydrates is pre-
have higher daily DMI than horses.1 sented later in this chapter.
With data on feed composition (and estimated intake of Classification and Nomenclature
feeds), it is possible to formally evaluate the ration against pub- Plant carbohydrates in equine feeds can be subdivided into the
lished feeding standards (e.g., NRC 20071). The NRC devel- SCs, which largely make up the fibrous portion of the diet and
oped a simple Web-based program that calculates nutrient originate from the plant cell wall, and the NSCs, which origi-
requirements derived from the 2007 Nutrient Requirements of nate from the cell content. Diets for horses, whether based on
Horses (http://nrc88.nas.edu/nrh/); this program can also be pasture, conserved forage, concentrates, or a combination of
downloaded to a personal computer. The user is first required all three, contain both SCs and NSCs.26
to enter basic information such as age, BW, and physiologic All dietary carbohydrates contain similar amounts of gross
state (e.g., stallion, lactating mare, working horse) and then energy. However, when used by the horse, they provide variable
data on the horse’s ration, specifically, the amount and nutri- amounts of DE, metabolizable energy, and net energy.27 Car-
ent profile of each feed and supplement fed to the horse. The bohydrates digested and absorbed as monosaccharides in the
program uses these data to calculate nutrient requirements, small intestine yield more energy than carbohydrates digested
dietary supply, and the difference between the two amounts. by microbial action (predominantly fermentation), and a gly-
Unfortunately, only a limited number of nutrients are evalu- cemic response to the ingestion of such carbohydrates tends
ated: DE, CP, lysine, Ca, P, Na, Cl, and K. The NRC recommen- to occur.28 The type of linkage between the monosaccharide
dations are also based on minimum nutrient requirements, residues in the carbohydrate also affects the site of digestion of
whereas many nutritionists favor feeding standards based on these compounds and thus their nutritional value. Hydrolysis
optimal ranges. Several nutrition companies have developed of the α1-6 and the α1-4 linkages of starch and maltose, for
more comprehensive computer software programs. For exam- example, can occur in the equine small intestine, but horses
ple, MicroSteed, developed by Kentucky Equine Research, Inc. do not produce the enzymes necessary to digest the β1-4 link-
(Versailles, Kentucky), can evaluate the ration against both ages found in cellulose or the mixed linkages found in hemi-
the NRC minimums and a set of optimums recommended by cellulose.28 Therefore digestion of cellulose and hemicellulose
company nutritionists.17 must occur as a result of microbial fermentation, which does
The process outlined in the preceding paragraphs will facil- not result in a pronounced glycemic response. Stachyose, raf-
itate decisions regarding the adequacy of the current ration. finose, β-glucans, fructooligosaccharides (or fructans), and
If gross deficiencies or excesses are identified, adjustments pectin are also thought to be resistant to enzymatic hydrolysis.
can be recommended and implemented. Another important Thus an understanding of the various carbohydrate fractions
aspect is the need for follow-up monitoring, particularly if a in plants (including means of digestion) is needed to deter-
goal has been set for weight loss or gain. Fig. 5.1 outlines a mine the potential for a feed to result in a glycemic–insulin-
simple way to estimate energy needs and intake and calculate emic response.
ration adjustments necessary to facilitate weight loss or gain.
A more detailed discussion of dietary management of thin or Simple Sugars
obese horses is presented later in this chapter. This fraction comprises monosaccharides and disaccharides
(i.e., glucose, fructose, sucrose). The simple sugar content of
these plants is low; the sugars produced by way of photosyn-
Y CARBOHYDRATES IN EQUINE thesis can be used immediately by the plant to supply energy
NUTRITION for metabolism, protein synthesis, and growth, or they can be
elaborated into more complex oligosaccharides (e.g., raffinose
Carbohydrates are the primary source of energy in the diet of and stachyose) or the structural polysaccharides of the plant
horses. As nonruminant herbivores, horses evolved to utilize cell wall (e.g., cellulose, hemicellulose, pectin). When sugar
forages high in SCs, with bacterial fermentation and produc- production exceeds the immediate requirements for metabo-
tion of volatile fatty acids (VFAs) in a highly developed large lism, the excess sugars are polymerized to form “storage,” or
intestine. However, modern horses, particularly those in ath- “reserve,” carbohydrates. Storage carbohydrates mostly are in
letic training, are often fed cereal grains or other starch-rich the form of starch or fructan. Starches and fructans, together
feeds to meet energy requirements. For example, some sur- with the simple sugars and the oligosaccharides, make up the
vey studies indicate that racehorses weighing 450 to 550 kg NSC fraction of the diet.26
typically receive 3 to 6 kg of feed per day, with some horses
receiving more than 8 kg per day.18,19 Such high grain intakes Oligosaccharides
by horses (or a low forage-to-grain ratio such as 30:70) have The raffinose family of oligosaccharides are α-galactosyl deriv-
been implicated in the development of gastrointestinal prob- atives of sucrose. The most common are the trisaccharide raf-
lems, particularly colic associated with disturbances to hindgut finose (composed of galactose, fructose, and glucose) and the
function20,21 and gastric ulcer disease.22,23 Additionally, diets tetrasaccharide stachyose. These oligosaccharides are found in
rich in starch and sugar contribute to the clinical expression sugar beet molasses and whole grains. Soybean oligosaccha-
of chronic muscle diseases (polysaccharide storage myopathy rides make up approximately 5% of DM in whole beans and up
and recurrent exertional rhabdomyolysis) in genetically sus- to 8% of DM in soybean meal. Together raffinose and stachy-
ceptible horses24 and likely exacerbate insulin resistance and ose rank second only to sucrose in abundance as water-soluble
susceptibility to laminitis in horses and ponies with the meta- carbohydrates (WSCs). However, raffinose and stachyose can-
bolic syndrome phenotype.25 Therefore equine veterinarians not be directly digested by the horse because of the absence of
should have working knowledge of carbohydrate digestion and the enzyme α-galactosidase.
metabolism and methods for assessment of the carbohydrate
fractions in feeds. This information can be used in the formula- Structural Polysaccharides
tion of diets and feeding programs that control intake of certain This fraction includes dietary fiber that is composed of cel-
carbohydrates and potentially mitigate risk of these conditions. lulose, pectin, and hemicelluloses, along with mannans,
galactans, and xyloglucans.26 Total nonstarch polysaccharides to understand what the different terms mean and to recognize
(NSPs) are the sum of the water-soluble and water-insoluble the variation among laboratories with respect to analytical
NSPs and include cellulosic and noncellulosic polysaccha- methods and definitions (see Box 5.1).
rides. Although some of the NSPs are water soluble, these are
not digestible by mammalian enzymes; therefore, digestion Water-Soluble Carbohydrates
can occur only through fermentation, which may occur proxi- The WSC fraction includes the simple (glucose, sucrose, and
mal to the cecum. fructose) and more complex (oligosaccharides and fructans)
sugars. Although not all of these components can be digested
Starch by mammalian enzymes, most can be rapidly fermented by
Starch is the main storage polysaccharide in a number of gram-positive bacteria, resulting in the production of lactic
higher plants, including the forage legumes (e.g., clover, acid. However, it is important to note that starch, which also
alfalfa). Starch is stored in both the vegetative tissues (i.e., can be fermented in this way, is not included in this category.
nonreproductive tissues such as leaves and stems) and the Some commercial laboratories measure WSC (i.e., free sug-
reproductive tissues (i.e., flowers, seeds). The starch content of ars plus oligosaccharides and fructans) but report it simply as
grass seed ranges from approximately 300 to 400 g starch/kg sugar, whereas others use the term sugar to describe the free
seed DM, whereas oats, barley, and corn contain approxi- sugar fraction only.
mately 400, 550, and 700 g starch/kg DM, respectively.26 The
amount of starch stored in the leaves of legumes rarely exceeds Ethanol-Soluble Carbohydrates
75 g starch/kg DM. The term ethanol-soluble carbohydrates (ESCs) refers to the
Starch consists of polymers of glucose, which occur in two component of the WSC that is digestible by mammalian
forms: amylose and amylopectin. Amylose is a linear α-(1–4) enzymes and elicits a glycemic response (i.e., simple sugars).
linked molecule, and amylopectin is a larger, highly branched The difference between the WSC and ESC fractions has been
molecule containing both α-(1–4) and α-(1–6) linkages. The used to approximate the amount of fructan in a particular
ratio of amylose to amylopectin largely depends on the botani- feedstuff, although the accuracy of this calculation has not
cal origin of the starch. For example, in wheat flour amylose is been verified.
around 30% of the total starch, whereas corn can contain up
to 70% amylose. The extent to which starch is digested pre- Nonstructural Carbohydrates
cecally depends on many factors, including the availability of The NSC fraction includes the monosaccharides and disac-
the starch to mammalian enzymes (e.g., the extent to which charides, oligosaccharides (including fructan), fructan
any outer husk or hull has been broken down), the ratio of polysaccharides, and starch. Several methods have been
amylose to amylopectin within the starch granule, the effect used to estimate the NSC content of feeds. The system
of processing (thermal treatment, for example, improves the developed by Van Soest31 estimates NSC by difference, in
digestibility of corn and barley starch), and intestinal passage which the feed is partitioned into neutral detergent solubles
rate.29 Glucose availability in the small intestine tends to be and NDF. The NDF fraction contains cellulose, most of the
higher for starches with high amylopectin content. As dis- hemicellulose, and lignin. Until recently, the NSC content
cussed in more detail later, the ingestion of excessive levels of of a feed was determined on the basis of feed analysis and
starch may exceed the relatively limited amylolytic capacity of the “by-difference method,” according to the following
the equine foregut. Any undigested starch (including resistant equation:
starch) that has not been fermented in the stomach and small
intestine by resident microbes will pass into the large intestine, NSC = 100 − ( CP % + NDF % + moisture %
where it will be fermented and yield less net energy than when + fat % + ash %
(
it is absorbed as glucose.29
This estimate was taken to represent the combined sugar,
Fructan starch, and fructan content of the feed. However, it also
Fructan is the major storage carbohydrate of the vegetative tis- includes pectins, gums, and mucilages that, unlike starch,
sues of temperate grasses. Depending on the number of fruc- sugar, and fructan, are not subject to very rapid fermentation;
tose molecules, fructans can be described as oligosaccharides therefore, they do not induce the marked changes in lactic acid
(<10 monosaccharide units) or polysaccharides (>10 units). concentrations and pH within the hindgut that can occur with
High levels of fructan can accumulate in the vegetative tissues excess intake of sugars, starch, or fructan. Therefore the NSC
of pasture grasses, with implications for the development of by-difference fraction is now referred to as nonfiber carbohy-
pasture-associated laminitis.26 In a 3-year northern European drate, or NFC. The quantitative difference between measured
study of the WSC (sugar plus fructan) components in the vege- NSC and NFC is small for some feeds (e.g., cereal grains) but
tative structures of temperate grasses, fructan contents of up to can be quite large for other feeds (e.g., feeds with substantial
279 g/kg DM were recorded.26 Fructan accumulation (unlike pectin, such as sugar beet pulp; Table 5.2).
that for starch) can occur below the temperature threshold for Most commercial feed analysis laboratories do not com-
plant growth (approximately 6°C).30 Therefore cold, bright pletely fractionate the carbohydrates that make up the NSC,
days that result in high rates of photosynthesis but minimal but in most feeds the amount of NSC can be approximated
plant growth may lead to the production of large quantities of by summing the amount of starch and WSC. The extent
excess sucrose and, in turn, substantial fructan accumulation. to which the sum of starch and WSC accounts for all NSC
depends on the analytic procedures used to measure these
Evaluation of the Carbohydrate Content in Feeds fractions. This determination probably more accurately
A number of analytical techniques and terms have been used reflects the potential for a feed to be rapidly fermented to
to describe the carbohydrate fractions in feeds. It is important produce lactic acid.
TABLE 5.2 Neutral Detergent Fiber, Nonfiber Carbohydrate, and Nonstructural Carbohydrate Composition of Selected Feedstuffs on a
Dry Matter Basisa
Feedstuff % NDF % NFCb % NSCc
Alfalfa hay 43.1 22.0 12.5
Beet pulp 47.3 36.2 19.5
Corn gluten meal 7.0 17.3 12.0
Mixed, mostly grass hay 60.9 16.6 13.6
Soybean meal (48% CP) 9.6 34.4 17.2
Soyhulls 66.6 14.1 5.3

aThe values shown here may vary from those shown elsewhere in this chapter. They are provided to illustrate differences among feeds and carbohydrate
categories. Actual values for individual feeds may vary by stage of maturity, variety, and source.
b%NFC = (100% − %CP − %EE − %ash − %NDF).
c%NSC determined by direct measurement.
CP, Crude protein; EE, ether extract; NDF, neutral detergent fiber; NFC, nonfiber carbohydrate; NSC, nonstructural carbohydrate.
Carbohydrate Nutrition and Colic in the spring.39 In reviewing the results of available epidemio-
Colic is caused by many conditions, each of which may be logic studies, Cohen estimated that approximately one third of
related to specific risk factors, such as changes in diet, feeding colic cases had a history of a recent change in diet.40 The inges-
practices, exercise patterns, and housing or inappropriate par- tion of high-concentrate and low-forage diets has also been
asite control programs. An association between feeding prac- implicated in the development of gastric ulcers, which in turn
tices and disturbances in gastrointestinal function has long may result in signs of colic.23
been hypothesized,32,33 but the mechanisms linking diet with These observations raise several questions regarding the
the development of intestinal dysfunction are poorly under- effects of diet composition and dietary change on gastroin-
stood. Indeed, the exact relationship between diet and colic is testinal function, including the capacity of the equine diges-
difficult to determine because of the variety of feeds and feed- tive tract for grain (starch) digestion, possible reasons for
ing practices used throughout the world as well as differences increased colic risk with high levels of grain feeding, and the
in study populations. Furthermore, it is often difficult to sepa- effect of a sudden change in diet (grain or forage) on gastroin-
rate the effects of diet and feeding schedule from other man- testinal function.
agement practices, which often depend on the horse’s breed
and use. Nonetheless, the results of recent epidemiologic stud- Carbohydrate Digestion and Hindgut Function
ies support the proposition that diet composition and recent From a digestive viewpoint carbohydrates in horse feedstuffs
changes in diet are important risk factors for the development can be divided into three main fractions: (1) hydrolyzable
of colic.34-39 Tinker et al.37 prospectively examined the risk for carbohydrates (CHO-H), which can be digested in the small
colic at 31 horse farms over a 1-year period. Both a change intestine by mammalian enzymes (or they can be fermented,
in concentrate feeding (odds ratio [OR] = 3.6 relative to no both in the foregut and hindgut); (2) rapidly fermented car-
colic) and the feeding of high levels of concentrate (>2.5 kg/ bohydrates (CHO-FR), which cannot be broken down by
day DM, OR = 4.8, >5 kg/day DM, OR = 6.3, relative to feed- mammalian digestive enzymes but are readily available for
ing no concentrate) were identified as risk factors for colic. In microbial fermentation; and (3) slowly fermentable carbohy-
addition, colic risk increased when processed feeds such as drates (CHO-FS). The hydrolyzable fraction includes hexoses,
pellets were fed. Hudson et al.36 reported that a recent (within disaccharides, some oligosaccharides, and the nonresistant
2 weeks) change in type of grain or concentrate fed (OR = 2.6), starches. Although some fermentation of these compounds
the feeding of more than 2.7 kg of oats per day (OR = 5.9), may occur in the stomach, the primary products of diges-
and a change in the batch of hay fed (OR = 4.9) were signifi- tion of these compounds are monosaccharides that can be
cant risk factors for an episode of colic. In another prospective absorbed in the small intestine, with a relatively high energy
case-control study, neither the amount nor type of concentrate yield. The rapidly fermentable fraction included pectin, fruc-
fed was associated with the colic risk, although the research- tan, and some oligosaccharides not digested in the small intes-
ers did conclude that horses at pasture may have a decreased tine. Resistant starch and neutral detergent hemicellulose
risk of colic.38 On the other hand, a recent (within 2 weeks) could also be included in the rapidly fermentable fraction. The
change in diet, in particular the type of hay fed (including hay slowly fermentable carbohydrate fraction includes cellulose,
from a different source or cutting of the same type of hay) was hemicellulose, and lignocellulose that result primarily in the
a significant risk factor for colic.38 In this study feeding hay production of acetate in the large intestine.
other than coastal/Bermuda or alfalfa significantly increased
the colic risk, but this finding may have reflected hay quality Foregut Digestion
and digestibility rather than type of hay per se. Changing to Carbohydrate digestion begins in the stomach, which in the
a poorer quality, less digestible hay or feeding wheat straw or horse is relatively small and inelastic (capacity 9–15 L for a
cornstalks may predispose horses to large colon impaction.38 500-kg horse). Bacterial fermentation of ingested feed is initi-
In a practitioner-based colic study in the United Kingdom, a ated in the cranial (squamous) portion of the stomach, with
recent change in management was associated with at least 43% conversion of some of the available simple sugars or starches
of the cases of spasmodic or mild undiagnosed colic. The most to lactic acid.41 This microbial activity and starch/sugar deg-
common management change was turnout onto lush pasture radation slows when the gastric contents pass to the fundic
gland region and are mixed with gastric secretions contain- controlling proliferation, apoptosis, and differentiation of gut
ing pepsinogen. Horse saliva contains minimal amylase activ- epithelial cells.50
ity, and little enzymatic carbohydrate digestion occurs in the The rate of fermentation and the microbial and biochemi-
stomach. cal contents of the large intestine are affected by diet compo-
The small and large intestines are the primary sites of car- sition and feeding pattern (i.e., continuous grazing, or small,
bohydrate digestion. Starch digestion in the small intestine frequent meals, versus large meals administered twice daily).
first involves degradation by α-amylase into disaccharide A change from forage only to a forage and concentrate diet
(maltose), trisaccharide (maltotriose), and α-dextrin units. will result in an increased rate of fermentation and marked
Subsequently, there is hydrolysis of maltose, maltotriose, and changes in the microbial population, luminal pH, and the con-
α-dextrin units by small intestine brush border glycanases, tents of VFA and lactate.51 The extent of these changes is likely
primarily amyloglucosidase, to form free glucose.42 The disac- dependent on the nature and abruptness of the dietary change.
charidases sucrase, lactase, and maltase are expressed along With a sudden increase in grain (i.e., starch) feeding, a por-
the length of the small intestine.43 d-Glucose and d-galactose tion of the ingested starch passes into the cecum undigested,
are transported across the equine intestinal brush border in which it undergoes rapid fermentation with increased pro-
membrane by a Na+/glucose cotransporter type 1 isoform duction of lactate and gas and a decrease in cecal–colonic pH.
(SGLT1),43 and fructose is absorbed by way of an equine- Increasing proportions of grain result in decreased acetate and
specific GLUT-5 transporter.15 The activity of both transport increased propionate and lactate contents of the cecum and
proteins is highest in the duodenum and lowest in the ileum.15 colon.51 Other biochemical changes with the rapid fermenta-
Sugars taken up by enterocytes are transported down concen- tion of starch (or other CHO-FR, such as fructan) in the hind-
tration gradients into the circulation by way of the GLUT-2 gut may include an increase in the production of vasoactive
transporter. Preliminary studies have demonstrated upregula- monoamines (e.g., tyramine, tryptamine), endotoxins, and
tion of small intestinal SGLT1 expression with an increase in exotoxins, all of which have been implicated in the pathogen-
dietary starch content.44 esis of laminitis.52
It has been proposed that starch digestion in the small intes- After an increase in starch feeding, the numbers of lac-
tine is limited by amylolytic activity (e.g., the availability and tobacilli and total anaerobic bacteria increase, whereas the
activity of α-amylase). The activity of α-amylase in the pan- numbers of xylanolytic and pectinolytic bacteria decrease.53
creatic tissue of horses is low relative to that of other species,45 Overall, there is an increase in amylolytic, lactic acid–
although the activities of brush border glycanases appear to be producing bacteria and decreases in the proportions of
comparable to those observed in humans, pigs, and dogs.46,47 acid-utilizing (particularly lactate) and cellulolytic (i.e.,
The activity of α-amylase in the pancreatic tissue of horses fiber-degrading) bacteria. Reduced efficiency of fiber utiliza-
fed either hay or hay and concentrate for at least 8 weeks was tion and decreased energy yield may result from the decline
unaffected by diet.46 However, in a related study, the amylase in cellulolytic bacteria with high grain feeding. In horses fed
activity of jejunal chyme was modestly higher in horses that forage only, pH within the cecum and colon is in the range
received a diet with added corn, oats, or barley compared with of 6.7 to 7.0. The feeding of increasing amounts of corn or
only hay.47 barley starch is associated with proportionate decreases in
The extent of starch digestion in the small intestine is cecal pH, with values approaching 6.0 when 3 to 4 g/kg BW
affected by the type and amount of starch digested (see the is fed as a single meal.51,54,55 A similar dose of oat starch was
section Recommendations for Minimizing Digestive Distur- not associated with a significant decrease in pH, consistent
bances).48 At low levels of starch intake (<100 g/100 kg BW with other data demonstrating higher prececal digestibility
from oats, barley, or corn as a single meal), approximately 80% of oat starch versus barley and corn starch.55 Some nutrition-
of the starch was digested in the small intestine. When starch ists have suggested that a cecal pH of 6.0 represents subclini-
feeding was doubled (250–270 g/100 kg BW), prececal starch cal acidosis and that the risk of clinically apparent intestinal
digestibility decreased to between 50% and 55%.49 Therefore dysfunction (e.g., increased permeability) is substantially
most nutritionists recommend that an individual grain or increased when hindgut pH is less than 6.0.2,55 Similar dis-
concentrate meal should contain no more than 2 g starch/ ruptions to the hindgut environment probably occur with
kg BW. For example, if a grain concentrate is 50% starch, no the delivery of other rapidly fermentable substrate, such as
more than 4 g/kg BW or approximately 2 kg for a 500-kg horse fructan, which can compose 5% to 40% of grass DM,26 par-
should be fed. At higher intakes in a single meal, particularly ticularly temperate species such as perennial ryegrass and
when unprocessed corn or barley is fed, there is the risk of Timothy grass. In vitro experiments have demonstrated that
substantial starch overflow into the hindgut, where it will fructan induces a more rapid decrease in the pH of cecal
undergo rapid fermentation. contents compared with corn starch,56 and one type of fruc-
tan (Raftilose) has been used to induce carbohydrate over-
Hindgut Digestion load and laminitis.57
The equine large intestine (cecum and colon) is an enlarged These disturbances to the hindgut environment put the
fermentative chamber that contains an extremely abundant horse at greater risk for digestive disturbances such as colic,
and highly complex community of microorganisms. Although osmotic diarrhea, and laminitis.32,33 Scenarios favoring the
some fermentation of feedstuffs occurs in the stomach and presentation of large loads of rapidly fermentable substrate to
small intestine, most fermentation occurs in the hindgut. The the hindgut include (1) a sudden introduction to grain feeding
microbial hydrolysis of dietary plant fiber within the large or an abrupt increase in the amount of grain concentrate; (2)
intestine leads to the release of soluble sugars that are subse- the feeding of large grain meals that, even in horses adapted to
quently fermented to the VFAs acetate, propionate, and buty such feeds, overwhelm the hydrolytic or absorptive capacity of
rate, which are an important source of energy. In addition, the the small intestine; and (3) the grazing of lush pasture or for-
VFAs (particularly butyrate) regulate the expression of genes age with high contents of rapidly fermentable substrate such as
fructan and simple sugars. It is therefore apparent that feeding

Limiting Delivery of Rapidly Fermented
strategies designed to minimize hindgut disturbances must Substrate to the Hindgut
focus on reducing the flow of rapidly fermented substrate to Size of Grain-Concentrate Meals. The feeding of large meals
the cecum and large colon. rich in starch and sugar can overwhelm the digestive capac-
ity of the small intestine and destabilize the hindgut because
of rapid fermentation of these substrates. No more than 2 g
Recommendations for Minimizing Digestive starch/kg BW should be fed in a single meal. For a grain or
Disturbances sweet feed mix that is 40% to 50% starch, this upper limit
Feeding Frequency equates to approximately 2.0 kg per meal for a 500-kg horse.
Ideally, feeding strategies for horses kept under intensive con- Feed Starch Sources with High Prececal Digestibility. Prececal
ditions would mimic the pattern of a grazing animal; that is, starch digestibility varies with the type of grain and the nature of
an almost continuous feeding pattern that minimizes fluctua- any mechanical or thermal processing. Although oat starch has a
tions in the rate of delivery of substrate to the large intestine prececal digestibility of around 80% to 90%, approximately 35%
and, when forage makes up the bulk of the diet, ensures some of equivalent doses of barley or corn starch (from unprocessed
stability of the hindgut ecosystem. A more continuous feed- grains) reaches the cecum undigested. The higher prececal di-
ing pattern also may minimize fluctuations in gastric acid- gestibility of oat starch may relate to the small size of the starch
ity and therefore be of benefit in horses at risk for squamous granules compared with other grains, providing a large surface
mucosal ulcer disease. For stabled horses fed two large meals area for exposure to intestinal amylase. Milling, grinding, and
daily, foraging behavior should be encouraged by increasing various heat treatments (e.g., steam flaking, micronization, ex-
the availability of hay (or even a variety of different forages) trusion) improves the prececal starch digestibility of oats, barley,
and pasture or dry lot turnout (with forage available). Pro- and corn. In one study the preileal digestibility of ground oats was
vision of more frequent (e.g., thrice daily rather than twice 97% compared with 83% for whole oats. Rolling or breaking did
daily), smaller concentrate meals throughout the day is also not improve the preileal digestibility of oats. For corn and bar-
recommended to minimize delivery of undigested hydrolyz- ley preileal starch digestibility is substantially increased after heat
able carbohydrate to the hindgut. Extending eating time by (e.g., steam-flaked corn, micronized barley) but not mechanical
diluting the energy density of the meal (e.g., chopped hay treatment. Overall, oats appear to be the safest source of starch for
mixed with concentrates) or feeding forage before grain or horses, although barley and corn are acceptable if they are sub-
concentrate may be helpful. For some greedy eaters place- jected to some form of heat treatment.
ment of several large stones in the feeder trough may slow Use Alternative Sources of Energy. The energy demands
the rate of intake. of growth, lactation, and performance can be readily met
by provision of alternative energy sources such as vegetable
Adequate Forage and Fiber oil (fat) and nonstarch carbohydrates (e.g., sugar beet pulp,
For hard-working horses with high DE requirements, the pro- soya hulls). Commercial concentrates made with these in-
vision of roughage is often restricted in favor of grain concen- gredients contain varying amounts of starch and sugar, but
trates to ensure adequate DE intake within limits of typical generally amounts are substantially lower compared with
DM consumption. However, there is considerable circumstan- straight cereals or sweet feed mixes. Compared with more
tial evidence associating low-roughage diets with digestive traditional fiber sources such as hay, soya hulls and beet pulp
disturbances (e.g., hindgut acidosis, colic, gastric ulcers) and contain lower indigestible material (e.g., lignin) and higher
behavioral problems. There also is evidence that the adverse amounts of NSPs, pectins, and gums, which can be digested
effects of high starch intake on hindgut function are mitigated to a large extent within the time period that they remain
when the ration is at least 50% NDF.58 Accordingly, there is within the gastrointestinal tract. This translates to a higher
rationale for feeding programs that promote higher roughage energy yield. A variety of vegetable oils (e.g., corn, soy, saf-
intake. An absolute fiber requirement has not been defined, flower, or flaxseed) and other sources of fat (e.g., stabilized
but a minimum of 1.0 kg long-stem forage per 100 kg BW rice bran; approximately 20% fat) are suitable for inclusion
(i.e., 5.0 kg for a 500-kg horse, as-fed basis) has been recom- in equine diets. Corn oil tends to be the most palatable oil,
mended. Some nutritionists have suggested that a rate of 1.5 but most types have acceptable palatability provided that
kg per 100 kg BW is preferable. Alternatively, fiber intake can they are fresh and not rancid. One recommendation is to
be increased by feeding other sources such as sugar beet pulp feed up to 100 g oil/100 kg BW daily. For reference pur-
or soya hulls, both of which are highly digestible (i.e., the DE poses, 450 mL of oil (approximately 420 g) provides about
yield is higher compared with that of hay) and are now com- 3.4 megacalories (Mcal) of DE. This daily amount should be
monly added to energy supplements for horses. This approach divided into two or three meals and introduced gradually
also facilitates a decrease in reliance on grain or sweet feed for (e.g., starting at 50 mL/day). Vitamin E (100–200 IU/100 mL
energy, decreasing the risk of digestive disturbances associated of oil) should be added to the ration if supplemental vegeta-
with high starch intake. ble oil is provided.
Forage quality is another important consideration. The Pasture Grazing. An unresolved problem is management
feeding of highly lignified fiber sources (e.g., straw), which are of the intake of rapidly fermentable substrate (e.g., fructan)
poorly degraded in the large intestine, may increase the risk by horses on pasture, particularly animals with a history of
of impaction colic. High intake of straw is possible when it is pasture-associated laminitis or those with recognized risk
used for bedding, particularly when an inadequate amount of factors for this disease (i.e., obesity, insulin resistance). The
hay (or roughage with low palatability) is offered. An increase most obvious avoidance strategy is to prevent access to pas-
in the provision of palatable forage or a change in bedding can ture and feed-preserved forage with a low NSC content (e.g.,
be helpful in these situations. Moldy forage should not be fed <10% NSC). Alternative approaches are to restrict access to
to equids. pasture at certain times of the day, avoiding peaks in forage
NSC content that may increase risk of laminitis, or to apply probiotic. However, in a randomized controlled clinical trial
a grazing muzzle that limits forage intake (but allows water of 153 neonatal foals (24–48 hours old), the administration of
intake). Several factors affect the accumulation of fructans and freeze-dried L. pentosus WE7 for 7 days was significantly asso-
other forms of NSC in pasture plants, including plant growth ciated with the development of signs of depression, anorexia,
rate, temperature, and light intensity. There also is marked di- and colic and more days with diarrhea compared with the pla-
urnal variation, with peak concentrations in the afternoon and cebo treatment.60 On the other hand, supplementation with
a nadir during the night and early morning, and it has been S. boulardii reduced significantly the duration of diarrhea in
suggested that horses grazing in the afternoon may ingest two- horses with enterocolitis.61
fold to fourfold quantities of NSC compared with that ingested The feeding of a protected sodium bicarbonate product has
during night or early morning grazing. These observations are been reported to moderate the decrease in fecal pH associ-
the basis for the recommendation to restrict grazing to late ated with grain feeding in horses,62 perhaps as a result of the
night and early morning, with removal of the horse or pony buffering of lactic acid produced in the cecum and colon. This
from pasture by midmorning. approach may be useful for mitigation of hindgut disturbances
associated with grain feeding or the grazing of lush pasture.
Gradual Dietary Changes
The increased risk of colic in the 2-week period after a change
in hay or grain feeding suggests that all changes in diet and Y NUTRITIONAL SUPPORT
pattern of feeding should be gradual. Horses should receive OF SICK HORSES
a blend of old and new hays during the transition between
hay batches (e.g., over a 7- to 10-day period, with a gradual There are few data on the effects of different feeding practices
increase in the proportion of the new forage) and a conserva- on short- and long-term outcomes of sick horses, and many
tive introduction to concentrate feeding or changes in type of recommendations regarding nutritional management are
grain or concentrate. One suggestion is to start at about 0.5 kg/ based on anecdotal evidence or clinician experience rather
day (split into two feedings) for a 450- to 500-kg horse, with than the results of controlled studies. In human medicine
increasing increments of no more than 0.5 kg/day until attain- nutritional status is an independent determinant of morbid-
ment of the target feeding rate. ity in hospital patients.63,64 Nutrient deprivation is associated
with immunosuppression and alterations in gastrointestinal
Efficacy of Probiotic Supplements and function, including decreased motility, villous atrophy, and a
decrease in gut barrier function resulting from an increase in
Feed Additives Purported to Stabilize intestinal permeability, particularly in patients with preexist-
the Hindgut Environment ing malnutrition.65 Consequently, nutritional support is stan-
There is considerable interest in the use of feed additives such dard practice in the care of sick people.
as live yeast culture, probiotics (bacterial species), and buffers Healthy adult horses can tolerate 2 to 3 days of feed with-
(e.g., sodium bicarbonate) as a strategy to minimize the negative drawal without ill effect. Starvation invokes neuroendocrine
effects of cereal-based diets. Yeast cultures might be beneficial responses that lower metabolic rate, conserve lean tissues (i.e.,
for stabilization of the hindgut environment in the face of high skeletal muscle), and promote use of fat stores to meet energy
cereal feeding. In horses fed high-starch meals (3.4 g/kg BW demands.66 This strategy prolongs life in the face of nutrient
per meal, as barley), daily supplementation with 10 g of a live deprivation. The metabolic response to critical illness (e.g.,
yeast (Saccharomyces cerevisiae) culture preparation attenuated sepsis) contrasts with that of simple starvation. Increased
postfeeding decreases in cecal and colonic pH and alterations sympathetic nervous system activity, inflammatory cytokines
in hindgut microbial populations.59 Thus supplementation with (e.g., interleukin-1[IL-1], IL-2, IL-6, tumor necrosis factor-α
live yeast culture may be beneficial in horses fed a high grain [TNF-α]), and catabolic hormones (catecholamines, cortisol,
ration. From a practical standpoint it may be more important and glucagon) combine to increase metabolic rate and induce
to ensure adequate fiber in the diet, decrease the quantity of a state of hypercatabolism.67 Stimulation of proteolytic path-
grain, and emphasize use of nonstarch energy sources that do ways in skeletal muscle provides amino acids for hepatic glu-
not adversely affect the hindgut environment. coneogenesis and synthesis of acute phase proteins. Amino
Probiotics have been defined as live microorganisms that, acids (from catabolism of lean tissues) rather than fatty acids
when ingested or administered orally, provide a beneficial are the primary source of energy substrate. There also is dis-
effect beyond that of their nutritional value.60 Many probiot- ruption of glucose regulation with the development of marked
ics are marketed for use in horses; the primary rationale is the insulin resistance. Unabated, this hypercatabolic state results
treatment or prevention of gastrointestinal diseases (e.g., as an in large nitrogen losses, severe muscle wasting, and compro-
adjunct therapy in the management of acute or chronic diar- mise of immune function and tissue healing.66-68
rhea) or prophylactic administration for prevention of colic Severe hyperlipidemia has been described in horses with
associated with disturbances to gut microflora (e.g., for horses colic, colitis, or both that had clinical and laboratory evidence
fed a high-cereal ration). Anecdotal data suggest that the use of systemic inflammatory response syndrome (SIRS).69 The
of probiotics in horses is widespread; however, as with many increase in circulating lipids likely reflects both an increase
nutritional supplements, there is a dearth of scientific data in the mobilization of fat reserves (lipolysis) and a decrease
regarding safety and efficacy. An effective probiotic organism in lipid clearance from blood, with both processes poten-
must be resistant to destruction by gastric acid, pancreatic tially modulated by SIRS, endotoxemia, or both. Studies in
secretions, and bile salts and be able to colonize the intestinal other species have demonstrated that the activity of endo-
tract. Weese and Rousseau60 have screened equine intestinal thelial lipoprotein lipase, the enzyme responsible for tissue
microflora for organisms meeting these criteria and initially uptake of circulating lipids, is decreased by TNF-α, whereas
identified Lactobacillus pentosus (WE7) as a potential equine the activity of hormone-sensitive lipase is increased during
endotoxemia.68,70,71 In horses with severe hypertriglyceride- horses kept at pasture or in similar circumstances that require
mia, treatment with intravenous dextrose solution or partial them to engage in some voluntary activity. Pagan and Hintz78
parenteral nutrition (PN) resulted in a decrease in serum reported that the DE requirement of healthy horses kept in
triglyceride concentrations to reference limits, and appetite stalls was approximately 22 to 23 kcal/kg BW per day, or 30%
improved coincident with the decrease in circulating lipids.69 lower than the DE required by horses kept at pasture. This stall
maintenance caloric requirement can be estimated by the fol-
Candidates for Nutritional Support lowing equation:
Several factors affect the decision to provide nutritional sup- RER = [21 kcal × BW (kg)] + 975 kcal
port to a sick horse, including the duration of inappetence or
anorexia, the nutritional state before illness (e.g., poor versus where RER is resting energy requirement. Energy require-
good body condition), physiologic state (e.g., growing ani- ments are also affected by the level of feed intake. Thermo-
mals, last trimester of pregnancy, lactation), and the presence genesis associated with the digestion, fermentation, and
of clinical indicators of a hypercatabolic state (e.g., hyperlip- metabolism of feed can account for 15% to 25% of daily energy
idemia or lipemia).72,73 As a general guide, horses that have expenditure. Because horses recovering from illness generally
not eaten for 48 to 72 hours are candidates for nutritional consume less feed, some reduction in the energy losses associ-
support. However, earlier intervention should be considered ated with digestion and nutrient processing is to be expected.
when there is evidence of compromised nutritional status, Another consideration in the estimation of energy require-
such as horses in thin body condition (BCS <3); those with ments is the effect of disease or surgical intervention on meta-
a history of weight loss, poor feed intake, or both for more bolic rate. There is conflicting evidence from human studies
than 48 hours before examination; and those with evidence regarding the effects of surgery, injury, or illness (e.g., sepsis)
of sepsis, SIRS, or severe hyperlipidemia (e.g., triglycerides on metabolic rate and energy requirements. Some studies have
>500 mg/dL). Aggressive nutritional support also is indicated demonstrated that abdominal surgery increases energy needs
for obese (BCS >7) animals, particularly pony breeds, Minia- by as much as 30%, whereas others have reported minimal
ture Horses, donkeys, and lactating mares, all of which are at change in energy requirements after gastrointestinal surgery,
high risk for development of hyperlipemia and hepatic lipido- perhaps a reflection of the decrease in physical activity dur-
sis during periods of negative energy balance. Old horses or ing hospitalization.79,80 On balance, it appears that energy
those with evidence of endocrine (pituitary pars intermedia needs are minimally altered by surgery or injury unless there
dysfunction, equine Cushing’s disease) and metabolic disease are major complications, such as generalized burns or sepsis,
(equine metabolic syndrome) also are candidates for early in which case energy requirements may increase by 40% to
nutritional intervention. 100%.80 The potential effects of underlying disease (e.g., endo-
toxemia or SIRS) on the energy requirements of horses are
Estimating Nutrient and Feed Requirements unknown. However, in sick neonatal foals the resting meta-
The nutritional requirements of sick horses have not been bolic rate and energy requirements were considerably lower
determined, so recommendations are largely based on data compared with those of healthy foals of the same age,81,82 and
from healthy horses, with some extrapolation from data in horses that underwent resection of the small intestine gained
other species. As for healthy animals, however, the first con- weight when fed at true maintenance (i.e., 32–33 kcal/kg/day)
sideration is energy (calories). As discussed, negative energy during the postoperative period.83 This author recommends
balance caused by starvation or underfeeding can compromise that the caloric requirements of sick horses initially be based
immune function, delay wound healing, and result in a marked on the RER or stall maintenance equation (i.e., 22–23 kcal/
decrease in lean mass (e.g., skeletal muscle), the latter resulting kg/day). Thereafter there should be a gradual increase in the
from the breakdown of endogenous protein for use in energy- ration, although true maintenance DE may not be required
requiring processes. On the other hand, studies in humans until the horse returns to normal management (e.g., field
and other species have shown that an oversupply of energy turnout). Practitioners should keep in mind that regular mea-
(hyperalimentation) is also detrimental, with complications surement of BW or assessment of BCS should be undertaken
such as hyperglycemia, hyperinsulinemia, hypertriglyceride- during convalescence to judge the adequacy of energy provi-
mia, insulin resistance, and increased risk of septic complica- sion and provide a basis for adjustments in feeding.
tions.74 A proposed mechanism of increased complications Protein serves an important role in tissue maintenance,
induced by hyperalimentation is an increase in the expression immune function, wound healing, and the slowing of endog-
of TNF receptors associated with an increase in nuclear factor enous protein catabolism. Protein requirements must be
κB binding to the nucleus.75 Furthermore, in septic animals considered in light of caloric intake and underlying disease
high caloric intake results in an increase in mortality.76,77 For process. When energy supply from carbohydrate and fat is lim-
these reasons, the current thinking in human medicine is to ited, endogenous protein will be used for energy, contributing
underfeed nonprotein calories (15–25 kilocalories [kcal]/kg to a loss of lean body mass. Therefore the practitioner should,
daily or no more than 66% of calculated energy requirements) when developing a nutritional plan, first ensure that minimal
to minimize risk of septic complications.74 energy needs are met and then calculate protein requirements.
The sixth edition of Nutrient Requirements of Horses1 For humans suggested protein requirements range between
reported that the DE needs of mature horses at maintenance 1.2 and 2.0 g protein/kg per day, with the higher end of this
range between 30.3 and 36.3 kcal/kg BW daily. The lower end range recommended for patients undergoing major intestinal
of this range is suitable for minimally active animals with a surgery.84 The CP requirement of healthy adult horses at main-
tendency to gain weight (“easy keepers”), and the high value tenance is approximately 1.25 g CP/kg BW per day, and this
should be applied to animals with a nervous temperament value is an appropriate starting point in the development of
(“hard keepers”). For healthy horses confined to a stall, daily a nutritional plan for sick horses: As the efficiency of diges-
energy requirements are probably 25% to 40% lower than in tion for most dietary proteins in horse feeds is about 70%, this
level of CP will provide approximately 0.9 g available protein fiber, which is an advantage because it facilitates administra-
per kilogram BW. For parenteral feeding a slight lowering of tion through a small-diameter nasogastric tube, but there is
protein feeding is reasonable given the higher metabolic avail- also a disadvantage: it may lead to the development of diarrhea
ability of amino acids administered by the intravenous route. when these products are fed to horses. There also have been
In recent reports of parenteral feeding of horses, 0.6 to 0.8 g anecdotal reports of laminitis in horses fed these diets. Risk of
protein/kg per day (1 g per 40–50 kcal) was administered (as a these complications may be mitigated by gradually introducing
balanced amino acid solution).83,85 There may be justification the liquid diet over a 3- to 4-day period, but diarrhea remains
for higher levels of dietary protein (e.g., 2 g CP/kg/day), par- common, perhaps indicating the importance of dietary fiber
ticularly for horses in poor body condition (BCS <3) or those for maintenance of normal hindgut function. It also should
with SIRS, hypoproteinemia, or hypoalbuminemia. be recognized that the mix of energy substrates in these fiber-
free enteral formulas for human use differs from that in typi-
Modes of Nutritional Therapy cal equine rations. Osmolite contains approximately 29% of
The mode of nutritional therapy will depend on the underly- calories from lipid and 54% of calories from hydrolyzable
ing disease, the horse’s appetite, and complications that arise carbohydrate (mostly sugars), and Vital HN provides about
during convalescence. The popular phrase in human clinical 10% of calories from lipids and 74% from carbohydrates. The
nutrition “if the gut works, use it” is used when discussing the high lipid content of Osmolite may contribute to digestive dis-
pros and cons of enteral nutrition (EN) versus PN support. turbances in horses not adapted to fat-supplemented rations,
Historically, PN has been associated with several complica- and use of a high-carbohydrate diet such as Vital HN may be
tions, including intestinal atrophy, failure of gut barrier func- contraindicated for horses with abnormal glucose metabolism
tion, bacterial translocation, increased incidence of sepsis, (insulin resistance). Collectively, these considerations argue
and hyperglycemia. In rodent models intestinal villous atro- against using fiber-free enteral products intended for human
phy develops within a few days of the start of PN, and with- use in horses. Diets containing a moderate amount of fiber
drawal of enteral feeding has been associated with bacterial (10%–20% crude fiber [CF], DM basis) appear to be a more
translocation, systemic inflammation, and sepsis.86-88 Early suitable choice for AEF in horses.
human studies also suggested that complication rates (partic- A simple approach is to use a commercially available pel-
ularly sepsis) and mortality were higher in patients receiving leted feed that contains a source of fiber, such as Equine Senior
PN compared with those who received EN. However, critical (Land O’ Lakes-Purina Feed, St. Louis, MO) or similar “com-
review of human studies has indicated that PN (i.e., complete plete feeds” that contain added fiber and can be fed without
bowel rest) is not associated with intestinal atrophy, whereas hay. These products contain about 14% to 25% CF and pro-
the incidence of bacterial translocation is the same in patients vide 2.6 to 3.1 Mcal DE/kg diet (as fed). Therefore 3.5 to 4.0
receiving PN and those receiving EN.74 Although EN is prefer- kg of diet would be needed to meet the stall energy require-
able when the gastrointestinal tract is functional, the weight of ments of a 500-kg horse. Vegetable oils (75–375 mL per day)
evidence from human studies indicates that PN is an impor- can be added to increase the caloric density of the diet (Table
tant alternative to EN when a risk of malnutrition is present 5.3). One standard cup (approximately 225 mL [210 g]) of oil
and EN is not tolerated or not possible because of poor gas- provides about 1.7 Mcal of DE. Vitamin E (100–200 IU per
trointestinal function. These same principles can be applied 100 mL of oil) should be added to the ration if supplemental
when developing a plan for the nutritional management of vegetable oil is provided. When providing supplemental fat to
sick horses. PN should be considered for horses with ileus and a sick horse (450–500 kg BW), 75 to 125 mL/day (¼ to ½ cup)
other intestinal conditions that prevent voluntary or enteral should be given initially and then gradually increased if no
feeding, particularly when the withholding of oral feeding is adverse response is seen (e.g., diarrhea, steatorrhea, lipemia).
expected to exceed 48 hours. Feeding vegetable oil may be contraindicated in horses and
ponies with hypertriglyceridemia (triglyceride concentration
Assisted Enteral Feeding >40–500 mg/dL) or hepatic lipidosis.
Assisted enteral feeding (AEF) is accomplished by the infu- Variations on the alfalfa/dextrose/casein enteral formula-
sion of a liquid diet through a nasogastric tube. Diet options tion first described by Naylor et al.90 also can be used for AEF
for AEF include human-marketed enteral products, commer- (Table 5.4). The recipe designed by Naylor et al.90 provides
cial pelleted horse feeds, and homemade recipes.89,90 Formu- about 3 Mcal DE/kg diet and is 33% CP and 12% CF. The higher
lations marketed for humans that have been administered to protein content, compared with that of typical equine diets,
adult horses include Vital HN and Osmolite HN (Ross Labo- may be beneficial for debilitated or hypoproteinemic horses.
ratories, Columbus, Ohio). Both formulations are devoid of In healthy horses this diet reportedly maintained BW and
TABLE 5.3 Enteral Formulation Based on a Complete Pelleted Ration and Recommended Feeding Schedule for a 500-kg Horsea
Ingredient Day 1 (¼ Ration) Day 2 (½ Ration) Day 3 (¾ Ration) Day 4 (Full Ration)
Complete pelleted horse feed (g)b 885 1770 2650 3530
Vegetable oil (mL) 100 177 265 354
Water (L) 8 16 24 24
Digestible energy (Mcal) 3 6 9 12

aEnergy requirements are at stall maintenance for a 500-kg horse (∼12 Mcal DE/day). These allowances should be divided and administered into a minimum
of four feedings daily.
bEquine Senior (Land O’Lakes-Purina Feed, St. Louis, Missouri), 2.6 Mcal DE/kg (as fed).
serum biochemical parameters within reference limits. How- for infusion of fiber-containing diets. After administration of
ever, diarrhea and laminitis were occasional complications. the diet, the tube should be flushed with approximately 1 L of
Suggested feeding protocols for a complete pelleted feed water followed by a small volume of air to ensure that no feed
with supplemental vegetable oil and for the alfalfa/dextrose/ material remains in the tube. The end of the tube should be
casein formulation are presented in Tables 5.3 and 5.4, respec- capped with a syringe case between feedings.
tively. The rate of diet administration should be gradually Close clinical monitoring, particularly of gastrointestinal
increased over a 3- to 5-day period. A suggested rate of intro- function, is imperative for horses receiving AEF. Repeated
duction is to administer ¼ of the final target volume of feed on ultrasonographic examinations can be useful for the evalua-
day 1, ½ total volume on day 2, ¾ total volume on day 3, and tion of gastric distention and intestinal motility. The presence
the total volume on day 4 or 5. Clinical signs of intolerance to of residual gastric fluid should be assessed (i.e., by siphon-
enteral feeding will dictate a slower rate of introduction. In ing) before each feeding. Substantial gastric reflux (>1–2 L)
hospital settings the enteral diet should be administered in is an indication to withhold enteral feeding for at least 1 to
a minimum of four and preferably six feedings per day, with 2 hours, with reevaluation before recommencement of diet
no more than 6 to 8 L per feeding for a 450- to 500-kg horse administration. Persistent gastric reflux indicates intolerance
(including volume of water used to flush the tube). This vol- to enteral feeding and the need for parenteral feeding. Simi-
ume should be administered over a 10- to 15-minute period. larly, signs of colic, ileus, abdominal distention, and increased
In field settings a more practical approach is to administer two digital pulses suggest intolerance to enteral feeding and are
treatments daily, although it will not be possible to meet stall an indication to discontinue therapy or decrease the volume
maintenance nutritional requirements with this treatment and frequency of feedings. The passage of loose feces is not
regimen. uncommon in horses receiving AEF and of minimal concern if
Pelleted feeds should be soaked in warm water to soften not accompanied by clinical signs of depression, dehydration,
before mixing in a blender (ratio of 1 kg pelleted feed to 6 L of ileus, or colic. It is important to measure the total volume of
water). A fresh batch of diet should be made before each feed- water administered through the nasogastric tube. Daily water
ing. A tube with a ½-inch (12-mm) inner diameter is suitable requirements (approximately 50 mL/kg/day) can generally be
for most enteral diets that contain fiber. The end of the tube met during AEF if the horse is fed four to five times daily. Fre-
should be open ended, rather than fenestrated, to prevent the quent measurements of hematocrit and plasma total protein
tube from becoming clogged. Intermittent nasogastric intu- concentration also are useful for monitoring hydration status
bation or placement of an indwelling nasogastric tube can be and the adequacy of water administration. Hypokalemia, ion-
used to facilitate feeding. In hospitalized horses feeding tubes ized hypomagnesemia, and ionized hypocalcemia can occur
can be left in place for up to 8 days, although nasopharyn- in horses with gastrointestinal disease. Accordingly, frequent
geal irritation and mucoid nasal discharge are expected out- measurements of serum electrolytes and ionized calcium and
comes (when longer term AEF is anticipated, placement of magnesium are recommended during AEF in these patients.
the tube through cervical esophagostomy is recommended). Supplementation with potassium, calcium, magnesium, or
Softer silicon tubes are less irritating compared with tubes both may be necessary. Horses also should be monitored for
made of polyvinylchloride, do not tend to harden when left development of complications associated with repeated or
in place, and are generally recommended for horses requiring indwelling nasogastric intubation, including rhinitis, phar-
AEF for a number of days. Before placing the tube, the clini- yngitis, and esophageal ulceration. BW should be measured
cian should establish that the diet solution flows adequately daily to assess the adequacy of nutritional support, although
through the tube. It may be necessary to add more water or changes in BW may reflect alterations in fluid balance rather
to mix the feed in a blender a second time. The tube should than the effect of feeding.
be positioned in the stomach rather than the distal esopha-
gus to minimize risk of reflux of feed around the tube. The Parenteral Nutritional Support
tube should be secured to the halter; between feedings appli- PN is indicated for horses with gastrointestinal tract dys-
cation of a muzzle may be necessary to prevent the horse from function (e.g., ileus, gastric reflux) or conditions that man-
dislodging the tube. A marine bilge pump is recommended date complete bowel rest (e.g., small intestinal resection,
TABLE 5.4 Alfalfa/Dextrose/Casein Enteral Formulation and Recommended Feeding Schedule for a 500-kg Horsea
Day
Parameter 1 2 3 4 5 6 7
Electrolyte mixture (g)b 230 230 230 230 230 230 230
Water (L) 21 21 21 21 21 21 21
Dextrose (g) 300 400 500 600 800 800 900
Dehydrated cottage cheese or casein (g) 300 450 600 750 900 900 900
Dehydrated alfalfa meal (g) 2000 2000 2000 2000 2000 2000 2000
Digestible energy (Mcal) 7.4 8.4 9.4 10.4 11.8 11.8 12.2

aThese allowances should be divided and administered into three or four feedings daily. Stall maintenance requirements for a 500-kg horse are 12 Mcal DE/
day.
bComposition of electrolyte mixture: sodium chloride (NaCl) 10 g; sodium bicarbonate (NaHCO ) 15 g; potassium chloride (KCl) 75 g; potassium phosphate
3
(dibasic anhydrous, K2HPO4) 60 g; calcium chloride (CaCl2·2H2O) 45 g; magnesium oxide (MgO) 25 g.
Adapted from Naylor JM, Freeman DE, Kronfeld DS. Alimentation of hypophagic horses. Compend Cont Educ Pract Vet. 1984;6:S93-S99.
duodenitis-proximal jejunitis). Durham et al.83,85 examined soybean oil, egg yolk phospholipid, and glycerin. These emul-
the effects of postoperative PN in 15 horses (vs. 15 control sions provide mainly unsaturated fatty acids (linoleic, 44%–
horses) recovering from resection and anastomosis of stran- 62%; oleic, 19%–30%; linolenic, 4%–11%; palmitic, 7%–14%).
gulated small intestine and reported no beneficial effect of PN PN solutions with and without lipid can be used (i.e., dex-
on time to first oral feeding, duration of hospitalization, costs trose/amino acid or dextrose/lipid/amino acid mixtures).
of treatment, or short-term survival (up until 5 months after The addition of lipids to the PN formula results in a solution
discharge). The PN protocol did confer improved nutritional with lower osmolarity compared with a dextrose/amino acid
status, as reflected by lower serum concentrations of triglycer- mixture of similar caloric density. Hence the lipid-containing
ides and total bilirubin and higher concentrations of glucose. solution should be less irritating to peripheral veins. Lipid
However, the duration and volume of postoperative gastric solutions must be included in the formula if target calorie
reflux were longer in the PN group than in the control horses, provision approaches true maintenance (32–33 kcal/kg/day)
perhaps as a result of alterations in gastric or small intestinal because this level of calorie delivery from a dextrose/amino
motility, and there was an insignificant trend for catheter- acid PN solution often results in marked hyperglycemia and
site complications in the PN group.83 The authors concluded glucosuria. However, when the target daily energy provision
that further study of a larger number of horses is necessary is 20 to 22 kcal/kg per day, dextrose/amino acid mixtures can
to determine the clinical benefits and possible harmful side be used. In human medicine this approach is referred to as
effects of PN in horses recovering from small intestinal sur- a partial PN and is often used in postoperative patients who
gery. Studies of the effects of PN in human patients also have require only a few days of intravenous nutritional support;74
yielded equivocal findings. Several studies have demonstrated similarly, partial PN is recommended for horses requiring
that perioperative PN is associated with reduced morbid- short-term (3–7 days) intravenous feeding. Lipid administra-
ity and mortality in malnourished patients.91-93 In contrast, tion is not recommended for patients at high risk for severe
perioperative PN in well-nourished human patients has been hypertriglyceridemia or hyperlipemia (e.g., ponies, Minia-
associated with increased morbidity, particularly septic com- ture Horses, donkeys). Serum triglyceride concentrations
plications.94,95 Nonetheless, as previously discussed, the cur- should be monitored on a regular basis if lipid solutions are
rent consensus in human clinical nutrition is that PN is an administered to these patients. As discussed previously, the
important component of overall case management, particu- provision of amino acids (protein) at a rate of 0.6 to 0.8 g/kg
larly in patients with evidence of malnourishment, gut failure, BW daily is one guideline for meeting protein requirements
and increased nutritional requirements (e.g., pregnancy, lacta- in adult horses, although some authors have recommended
tion, growth). 1 to 1.5 g/kg per day, and provision of amino acids at 0.6 to
The following paragraphs provide a brief overview of 2 g/kg per day has been used in sick horses without apparent
the composition of PN solutions, methods for delivery, and complications.
potential complications. As with EN support, the goal of PN is A suggested PN formula (Table 5.5) comprises 1 L of 50%
to administer calories and amino acids such that loss of body dextrose (0.5 g/mL dextrose × 3.4 kcal/g × 1000 mL = 1700
protein (and lean body mass) is minimized.73 Carbohydrates, kcal), 1 L of a 10% amino acid solution (0.1 g/mL of amino
in the form of a 50% dextrose solution (3.4 kcal/g or 1.7 kcal/ acids × 4 kcal/g × 1000 mL = 400 kcal), and 500 mL of 20%
mL; osmolarity 2525 mOsm/L), and lipid, as a 10% to 20% lipid emulsion (0.2 g/mL lipid × 9 kcal/g × 500 mL = 900
emulsion (20% emulsion: 9 kcal/g or 2 kcal/mL; osmolarity kcal). These components are diluted with 4 L of isotonic
260 mOsm/L), are the primary sources of energy used in PN fluid, yielding a final volume of 6.5 L and a caloric density
solutions, whereas an amino acid solution (e.g., Travasol 8.5% of approximately 0.45 kcal/mL. A multivitamin supplement
or 10%; Baxter Health Care Corporation, Deerfield, IL) is used may be added to this mixture. This solution can be prepared
to meet protein requirements (e.g., protein synthesis, immune up to 24 hours before administration, with storage at 4°C
function). Commercial lipid emulsions (e.g., Intralipid 20%; until use. Administration of PN solutions should be through
Baxter Health Care Corporation, Deerfield, IL) consist of a dedicated intravenous catheter (i.e., do not administer
TABLE 5.5 Parenteral Nutrition Formula and Recommended Administration Rate for a 500-kg Horsea
Formula Variable First 12 hours Second 12 hours Day 2
Dextrose 50% 1000 mL 1000 mL 1000 mL
Lipid 20% 500 mL 500 mL 500 mL
Amino acids 10% 1000 mL 1000 mL 1000 mL
Isotonic fluids 4000 mL 4000 mL 4000 mL
Total volume 6500 mL 6500 mL 6500 mL
Kcal per bag 3000 3000 3000
Kcal/h 210 333 480
Rate (mL/h) — 470 740
Bags required 0.90 per 12 h 1.4 per 12 h 4.0 per 24 h
Kcals per day — — 11,500

aForparenteral nutrition, daily energy needs are estimated at 23 kcal/kg per day (11.5 Mcal per day for a 500-kg horse).
Adapted from Robinson NE, Sprayberry K, eds. Current Therapy in Equine Medicine. 6th ed. St. Louis, MO: Saunders; 2009.
other medications with this catheter), preferably one inserted Y NUTRITIONAL MANAGEMENT OF
into a large vein such as the jugular, to minimize the risk of
complications associated with the infusion of hyperosmotic THE ORPHANED OR SICK FOAL
solutions. Alternatively, a double-lumen catheter can be
used, allowing the PN solution to be given through one port Foal Metabolism and Nutrient Requirements
and medications and other fluids through the other port. To The foal’s nutritional requirements and dietary composition
minimize the risk of thrombophlebitis, nonthrombogenic change substantially during the gradual transition from neonate
catheters such as those made from polyurethane are recom- to weanling. At birth the foal must transition from a continuous
mended. Meticulous attention to sterile technique is needed supply of nutrients provided by the dam by way of the placenta to
during catheter placement to further minimize the risk of intermittent absorption of ingested nutrients. At the same time,
thrombophlebitis and other septic complications. The fluid the metabolism of the neonate is no longer able to depend on the
lines used for delivery of the PN solution should be changed maternal glucose concentration to maintain normoglycemia,
every 24 hours. An infusion pump is required to ensure accu- and the pancreas assumes responsibility for regulating glucose
rate delivery of the PN solution. The bag containing the PN homeostasis.97 These dramatic alterations in energy metabolism
solution should be covered with a brown bag during adminis- may not always occur smoothly, and the neonatal foal possesses
tration to protect it from light, which can degrade the amino limited energy reserves in the form of glycogen and fat. The
acids within the solution. result is that hypoglycemia occurs frequently in even the normal
Table 5.5 provides a recommended rate of parenteral neonatal foal, and the sick foal is at risk for profound hypoglyce-
feeding for a 500-kg horse. The initial rate of PN solution mia if deprived of energy intake for even a few hours.97
administration should be approximately 35% of target calo- The neonatal foal has a high metabolic rate and requires
rie provision, increasing to 60% to 65% after 12 hours and frequent ingestion of high volumes of milk to meet its energy
100% (23 kcal/kg/day) at 24 hours, provided that there are requirements for maintenance and growth. In light breeds
no complications, such as the development of marked hyper- the average rate of daily gain over the first month of life is 1
glycemia, glucosuria, or hyperlipemia. Hyperglycemia and to 1.5 kg/day. During the first week of life, calorie needs are
hyperlipemia were the most common complications of post- as follows: approximately 150 kcal/kg per day, with a gradual
operative PN in horses after intestinal surgery. In one report decrease to approximately 120 kcal/kg per day at 3 weeks of
hyperglycemia was observed in 52 of 79 horses receiving age, and then to 80 to 100 kcal/kg per day by 1 to 2 months
PN,96 perhaps because of insulin resistance, an excessive of age.81,82 Healthy neonatal foals (<7 days of age) have up to
rate of administration, or both. Blood glucose concentra- seven nursing bouts per hour, most lasting for 1 to 2 minutes.
tions should be measured every 4 to 8 hours in horses receiv- Subsequently, there is a gradual decrease in the frequency
ing PN, and the rate of dextrose administration should be of nursing but an increase in the duration of each nursing
decreased if glucose concentrations exceed renal threshold bout. During the first 24 hours of life, foals consume approxi-
(approximately 180–200 mg/dL). A constant-rate insulin mately 15% BW as milk (i.e., 8 L in a 50-kg foal), increasing
infusion (e.g., regular insulin at a starting dose of 0.05–0.1 to between 23% and 25% BW (15 L) by day 3 or day 4.98 On
IU/kg/h) can be instituted if the reduction in dextrose a DM basis, mare’s milk averages about 64, 22, and 13% sugar
administration rate fails to correct the hyperglycemia. Blood (as lactose), protein, and fat, respectively, compared with cow’s
glucose concentrations must be closely monitored (e.g., every milk, which contains 38, 26, and 30% sugar, protein, and fat,
2–6 hours). Adjustments in insulin dose may be required to respectively. As a result, glucose (from lactose) is the primary
achieve glycemic control. Serum blood urea nitrogen (BUN), source of energy for the foal.
triglycerides, and electrolytes should be monitored at least Starting as early as the second day of life, foals begin ingest-
daily. Hypokalemia, hypocalcemia, and hypomagnesemia ing small amounts of hay, grass, and grain while also ingesting
have been reported in horses receiving PN, and it may be maternal feces, which likely provides the initial microbial flora
necessary to supplement these nutrients if parenteral feed- required to support digestion of these feedstuffs. It is unlikely
ing is used for more than 48 hours. Finally, BW should be that grain and roughage are well digested until at least sev-
recorded daily or every other day. eral weeks of age, at which point the foal begins the gradual
transition from a milk-based diet to a forage-based diet. The
Transition to Voluntary Feeding amount of milk produced by the mare peaks after approxi-
A decrease in AEF or PN is indicated when appetite returns mately 2 months of lactation and then begins a steady decline,
(or when voluntary oral feeding is no longer contraindicated). which continues until the time of weaning, when the foal must
Initially, small amounts of palatable (e.g., fresh grass or leafy begin relying on solid feed for an increasing proportion of its
hay) feed should be offered. If these feedings are tolerated, the nutritional requirements. Full maturation of hindgut function
level of tube or parenteral feeding can be gradually reduced as may occur by 3 to 4 months of age.
the provision of feed for voluntary consumption is increased.
Nutritional support can be withdrawn when voluntary feed Nutritional Support of Orphan Foals
intake provides at least 75% of stall maintenance DE and pro- The primary options for management of orphan foals are to raise
tein requirements. As with any feeding program, all changes in by hand or foster to a nurse mare.98,99 Fostering is the best option
diet should be gradual. Hay should be the primary, if not sole, for a foal younger than 6 to 8 weeks of age. Draft or Draft-cross
component of the convalescent diet, preferably leafy hay with mares that are mild in temperament make good nurse mares.
a fresh aroma. Grain or commercial grain-concentrate feeds Any disparity between the stage of lactation and age of the foal
should be offered only if hay alone does not meet require- should be noted. A mare that is 4 to 6 weeks into lactation may
ments. An alternative to grain is to feed 1 to 2 lb/day of a high- not have the quality of milk needed to sustain a neonate; it may
protein product (approximately 20%–25% CP, usually with be necessary to provide the neonatal foal with a mineral supple-
added minerals and vitamins) as a supplement to hay. ment when fostered to a mid- to late-lactation mare.
Hand rearing has several disadvantages, including the need approach to nutritional support may prevent complications
for high labor input, the expense of milk substitute, and a associated with overfeeding, such as hyperglycemia and glu-
high incidence of behavioral problems. The risk of behavioral cosuria, particularly in foals with sepsis in which the systemic
problems can be mitigated by ensuring that the foal is raised inflammatory response contributes to insulin resistance and
with an equine companion (e.g., a quiet horse or pony or even carbohydrate intolerance. Neonatal foals require approxi-
another orphan foal). Teaching a foal to drink from a bucket is mately 1.5 g protein/kg BW per day.
preferable to bottle feeding because it is less labor intensive for The adage, “if the gut works, use it”, also applies to the
the owner and allows the foal to drink milk on demand. Feed- nutritional support of sick neonatal foals. Milk contains tro-
ing from a bucket also helps prevent some of the behavioral phic substances that promote growth and development of the
problems that develop in foals that have bonded to people. gastrointestinal tract. Additionally, enteral feeding is believed
Bottle feeding may be the only option in newborn foals, but a to lower the risk of sepsis associated with bacterial translo-
quick transition to bucket feeding is recommended. It is also cation. However, parenteral feeding is required in foals with
important to ensure adequate colostral intake (and acquisition poor gastrointestinal tract function.
of passive immunity) in foals that are orphaned at birth.
Fortified cow’s milk (by the addition of 20 g/L dextrose to Enteral Nutrition
2% part skimmed milk); goat milk; and calf, lamb, and kid Thorough assessment of gastrointestinal function is needed
milk substitutes have been used to rear foals, but a high-qual- before institution of EN support, including abdominal aus-
ity mare-milk formula is preferred. On a DM basis foal milk cultation and evaluation of abdominal distention and the
replacers should contain approximately 15% fat and 22% CP, presence of gastric reflux. Abdominal radiographs and ultra-
with a fiber content of less than 0.5%.99 Milk replacers should sonographic examination for evaluation of bowel dimensions
be fed as a 10% to 15% solution when diluted with water and and motility also may be indicated. Foals with evidence of
generally provide about 500 kcal/L when mixed according to gastrointestinal dysfunction such as gastric reflux, bowel dis-
the manufacturer’s instructions. The volume of milk should tention, increased bowel wall thickness, and ileus are unlikely
be fed over a 7- to 10-day period. One recommendation is to to tolerate enteral feeding. A conservative approach to enteral
start at 5% to 10% of BW, increasing to 20% to 25% BW by feeding is also indicated for premature or immature foals in
day 10. Intake of 20% to 25% BW/day as milk replacer will which the gastrointestinal tract may not be completely devel-
meet energy and nutrient requirements for growth. As a gen- oped. Foals with perinatal asphyxia syndrome or severe sepsis
eral guide, most light-breed foals need 14 to 17.5 L (4–5 gal- may be intolerant of enteral feeding as a result of intestinal
lons) of milk substitute each day during the first 2 to 3 weeks ischemic injury.
of life, and draft foals require 21 to 28 L (6–8 gallons). Foals Mare’s milk is the preferred substrate for enteral feeding; it
may be fed as infrequently as two to four times daily, although is highly digestible and obviously provides the correct balance
more frequent feedings (six to nine daily) are recommended of nutrients for normal growth and development. Commercial
for young foals and during the initial phase of hand rearing to mare milk replacers can be used, but practitioners should bear
keep from overwhelming the digestive tract. Feeding buckets in mind that these products are bovine in origin and have lower
should be thoroughly cleaned on a daily basis. Similarly, strict digestibility compared with mare’s milk. This may increase the
hygiene is required during the preparation of the milk substi- risk of intestinal dysfunction associated with enteral feeding.
tute. Fresh water should be available at all times. Part skimmed (2% fat) cow’s milk to which 20 g/L dextrose
BW or linear measures that predict weight and height (corn sugar) is added can be used if mare’s milk (or a mare’s
gain100 should be monitored on a regular (e.g., weekly) basis. milk replacer) is unavailable. Foals that are unable to nurse
Expected rates of growth and weight gain are available for the mare (or when no mare is available) may be fed through
some horse breeds. Studies of hand-reared foals have demon- a bottle, bowl, or nasogastric feeding tube. Bottle feeding is
strated growth rates similar to those observed in foals reared recommended when the foal is expected to be transitioned to
with their dams.101 Solid feed should be introduced as early as a mare within a short period of time. The practitioner should
2 to 3 weeks of age (e.g., small amounts of high-quality hay, remember, however, that bottle feeding is very labor intensive
milk-based pellets, or both). Up to 1 kg of milk pellets per day and does carry some risk of milk aspiration if the milk flow
can be fed with a concomitant reduction in liquid milk feed- rate from the bottle exceeds the foal’s capacity to nurse prop-
ing. Orphan foals can be weaned from milk at 10 to 12 weeks erly. The risk of aspiration is lower with bowl feeding because
of age, with a transition to a diet of forage and a balanced foal the head is positioned with the nose down during drinking.
feed (16%–18% CP). Many sick, recumbent foals have a weak or uncoordinated
suck reflex and are at risk of milk aspiration and pneumo-
Nutrition of the Sick Neonatal Foal nia. Milk should be administered to these patients through a
The energy (calorie) requirements of sick, recumbent foals are feeding tube. Use of small-bore, indwelling nasogastric feed-
less than those of healthy foals, in part because of their lower ing tubes (e.g., NG1243–12Fr × 108 cm [43 inches], MILA
physical activity and a temporary decrease in growth rate com- International, Erlanger, KY) and feeding of small volumes at
pared with healthy neonates. In one study the metabolic rate of frequent intervals (e.g., every 20 minutes) are preferred over
healthy foals was 130 to 140 kcal/kg BW per day, whereas met- repeated passage of a nasogastric tube at 1- to 2-hour intervals.
abolic rate in immature foals and foals with perinatal asphyxia Large-bolus feedings may overwhelm digestive capacity, and
syndrome was approximately 62 to 69 kcal/kg BW per day.81 repeated passage of a stomach tube is an unnecessary stress on
It is possible that sepsis and endotoxemia increase metabolic the foal. Another advantage of the small-bore indwelling tubes
rate, although studies in neonatal humans indicate that critical is that they do not interfere with the suckle response. There-
illness is not accompanied by a hypermetabolic state. Currently fore the tube may be left in place as the foal is transitioned to
providing critically ill, recumbent foals approximately 45 to 50 feeding from the mare. The feeding tube should be inserted
kcal/kg BW per day is recommended.98,102 This “hypocaloric” with the foal in sternal recumbency, and correct placement
TABLE 5.6 Feeding Recommendations for Neonatal and Growing Foals

Foal Age (days) Energy Requirement Volume of Mare’s Milk or Milk Replacer Percentage of Body Weight Fed
0–1 150 kcal/kg/day 2–3 mL/kg/h 5%–7%
2–3 150 kcal/kg/day 4–5 mL/kg/h 10%–12%
4–7 150 kcal/kg/day 6–8 mL/kg/h 14%–20%
8–30 120 kcal/kg/day 9–10 mL/kg/h 22%
30–weaning 80–100 kcal/kg/day Gradually decreasing and replaced with solid feed —

within the esophagus should be confirmed by radiography or solution with 5% dextrose, 0.45% saline with 5% dextrose),
endoscopy. The tube should be fastened to the external nares and hypotonic maintenance electrolyte solutions containing
by sutures or may be retained using a circumferential elastic 5% dextrose.97 Fluids containing dextrose should not be used
bandage around the muzzle. It is important to check at each for initial large-volume fluid resuscitation because this often
feeding that the tube is still in place and there is no gastric results in profound hyperglycemia. After initial fluid resusci-
reflux. The foal should be in sternal recumbency or standing tation the solutions containing electrolytes as well as dextrose
when it is fed. Milk should be administered by gravity flow and may be used as the primary fluids for maintenance therapy
followed by a small amount of clean water to flush the tube. in foals with minimal ongoing fluid losses. As a maintenance
The tube should be capped between feedings to prevent aspira- solution, D5W is not a good choice because it lacks electro-
tion of air. Feeding tubes should be replaced every 1 or 2 days lytes; it is primarily useful in providing free water to patients
to reduce the risk of gastrointestinal tract infection. suffering from hyperosmolar conditions. The caloric content
A suggested initial rate of milk delivery is 2 to 3 mL/kg BW of a 5% dextrose solution is 0.17 kcal/mL, so an infusion rate
per hour or 100 to 150 mL/h for a 50-kg foal, which will proof 10 mL/kg per hour would be required to deliver approxi-
vide 2.4 to 3.6 L of milk to a 50-kg foal during the first 24 hours mately 40 kcal/kg per day (0.17 kcal/kg/h × 24 h/day = 41 kcal/
of enteral feeding (Table 5.6). Dextrose-containing fluids can kg/day). However, this rate of infusion is more than twice the
be administered intravenously to provide additional calories maintenance fluid requirements of neonatal foals (4–5 mL/
during the transition to an adequate level of enteral feeding. kg/h). Therefore an infusion rate of 5 mL/kg per hour (provid-
The feeding rate can be gradually increased over the next 2 ing approximately 20 kcal/kg/day) is a more appropriate target
to 3 days (e.g., increase to 4–5 mL/kg/h on day 2 and then to for partial caloric support using 5% dextrose solutions.97 Cau-
6–8 mL/kg/h on day 3), which represents a total daily intake of tion is required when adjusting the infusion rate in response
10% to 15% BW. As the rate of enteral feeding increases, intra- to changes in hydration state to prevent excessive dextrose
venous caloric support (dextrose) can be gradually withdrawn. administration, especially in premature or very sick foals that
This feeding level will likely meet the maintenance energy may be glucose intolerant.
requirements of hospitalized foals. Depending on the rate of An alternative approach involves the administration of
clinical improvement and the length of hospitalization, it may a 50% dextrose solution by use of an infusion pump, pro-
be possible to increase the volume of feeding to 22% to 23% vided that isotonic fluids are administered concurrently to
BW per day, which approximates the milk intake of healthy minimize the risk of vascular endothelial injury caused by
neonatal foals. Clinical monitoring should include frequent the hyperosmolar 50% dextrose solution. Use of 50% dex-
assessments of gastrointestinal function, including gastric trose solution is not recommended unless an infusion pump
reflux, intestinal sounds, abdominal distention, and quantity is available. The caloric content of 50% dextrose solution is
and quality of feces. Gastric reflux, bloating, colic, diarrhea, 1.7 kcal/mL; therefore, an infusion rate of 1 mL/kg per hour
or constipation can indicate intolerance to enteral feeding and will provide about 40 kcal/kg per day (1.7 kcal/kg/h × 24 h/
the need for adjustments to the feeding program. Adjustments day = 41 kcal/kg/day). At this low rate of infusion, the pri-
may involve a decrease in the volume or frequency of enteral mary fluid needs of the patient can be met with a dextrose-
feedings. Foals fed milk replacers appear to be more likely to free isotonic electrolyte-containing fluid, the infusion rate of
develop loose feces than foals fed mare’s milk. In some cases which can be altered in response to changes in patient fluid
clinical improvement is observed after supplementation with status without concerns related to the requirements of the
6000 units of lactase (Lactaid; McNeil Nutritionals, LLC, Ft. nutritional plan.97
Washington, PA) per 50-kg foal every 3 to 8 hours, mixed into Two approaches have been used for formulation of PN
the milk replacer before feeding.103 solutions for foals.97,98,104 The first involves the exact determi-
nation of the anticipated metabolic needs of the patient, fol-
Parenteral Nutrition lowed by the development of a formulation that will meet all
PN support is indicated for foals with poor gastrointestinal of these needs using a mixture of dextrose, amino acids, and
function and intolerance to enteral feeding. Short-term par- lipids. The second approach is simpler and more practical and
enteral supplementation (less than 24 hours) does not require uses one of two basic PN formulas (Table 5.7):
the use of a balanced PN solution that contains sources of car- 1. Solution I: A mix of equal volumes of 50% dextrose and
bohydrate, amino acids, and lipids. However, if PN is expected 8.5% amino acid solutions, intended for short-term use
to be administered for a longer period, then a more complete (caloric density = 1.02 kcal/mL)
formula should be used. 2. Solution II: A mix of three parts 50% dextrose, four parts
Short-term caloric supplementation can be accomplished 8.5% amino acid, and one part 20% lipid solutions; this so-
by administrations of an intravenous fluid containing 5% lution is preferred for foals that are poorly tolerant of in-
dextrose (e.g., 5% dextrose in water [D5W], lactated Ringer’s fused dextrose (caloric density = 1.08 kcal/mL)
TABLE 5.7 Formulation of Parenteral Nutrition Solutions for Neonatal Foals

Formulation Composition Caloric Density (kcal/mL) Nonprotein Calories/g Nitrogen
Formula I 1500 mL 50% dextrose, 1500 mL 8.5% amino acids 1.02 125
Formula II 1500 mL 50% dextrose, 500 mL 20% lipids, 2000 mL 1.08 131
8.5% amino acids

As previously discussed, protein degradation in muscle tis- BW should be assessed on a daily basis to ensure that the foal
sue occurs during critical illnesses such as sepsis. Thus pro- is at least maintaining BW while on PN support.
vision of adequate energy and amino acids to counter this Some critically ill foals are intolerant of even a conser-
catabolic response is an important goal of PN support. The vative rate of dextrose administration because of insulin
recommended ratio for nonprotein calories to nitrogen is 100 resistance. The administration of insulin is needed to con-
to 200 nonprotein calories per gram of nitrogen.105 In one trol hyperglycemia and allow attainment of the goal level of
report the amount of protein provided affected weight gain of PN support.97 Use of continuous rate infusion (CRI) for the
neonatal foals, with a negative association between the non- administration of insulin is preferred to intermittent bolus
protein nitrogen calories: grams nitrogen ratio (NPC/g N) and dosing. An initial insulin infusion rate of 0.07 IU/kg per
the rate of weight gain.106 Solution I provides 125 NPC/g N, hour is generally well tolerated. If possible, simultaneous
and Solution II contains 131 NPC/g N. alterations in both the insulin and PN infusion rate should
The inclusion of lipids in the PN formulation allows for be avoided, because this can result in marked fluctuations
the provision of a larger number of calories per unit volume in blood glucose concentrations. Blood glucose monitor-
compared with solutions containing only dextrose. Another ing should be performed at least hourly for the first 2 to 3
advantage of lipid emulsions is that they are isotonic, moder- hours after initiation of the insulin CRI, and if hyperglyce-
ating the hypertonicity of the PN formulation and potentially mia (blood glucose >150 mg/dL) is persistent beyond the
decreasing the risk of thrombophlebitis. In a recent report the first 2 hours of insulin therapy, then the insulin infusion rate
use of lipid-containing PN solutions allowed for the provision may be increased by 50%, followed by hourly blood glucose
of 40 to 92 kcal/kg per day (mean = 63 kcal/kg/day) to foals, monitoring for an additional 2 or 3 hours. This procedure
compared with 25 to 66 kcal/kg per day (mean = 41 kcal/kg/ for increasing the insulin infusion rate may be repeated if
day) with a dextrose-based solution.104 hyperglycemia persists. Conversely, if hypoglycemia (blood
Methods for delivery of PN solutions have been dis- glucose <60 mg/dL) is noted, then a bolus of 0.25 to 0.5 mL/
cussed (see the previous section Nutritional Support of kg of 50% dextrose solution should be administered intrave-
Sick Horses). The catheter and catheter site should be mon- nously over 3 to 5 minutes. The blood glucose level should
itored at least twice daily for heat, swelling, or exudation. then be reassessed every 30 minutes for at least 90 minutes.
Increased resistance to fluid flow in the catheter may be an If hypoglycemia recurs, a second bolus of dextrose should be
indication of thrombosis deeper within the vasculature and administered and the insulin infusion rate decreased by 50%.
will often necessitate the placement of a catheter in an alter- Close monitoring will then be required for an additional 60
native site, such as the opposite jugular vein, a cephalic vein, to 90 minutes to assess the stability of blood glucose concen-
or a lateral thoracic vein. The rate of infusion (in mL/h) is tration. Further changes to the insulin infusion rate are not
calculated on the basis of the desired kcal/kg per day to be usually necessary once a steady state has been achieved, in
administered. A reasonable initial goal is 40 to 50 kcal/kg which the blood glucose level is stable and the desired rate of
per day; higher rates of energy administration often result PN administration has been achieved.
in hyperglycemia and hyperlipidemia. The initial infusion When PN support is to be discontinued, it is recom-
rate of PN solutions should be 50% of the calculated final mended that the infusion rate be gradually reduced by 25%
rate, and the rate should be gradually increased every 1 to 3 to 50% increments every 4 to 6 hours while gradually intro-
hours after monitoring of the blood glucose concentration ducing enteral feeding. The monitoring of blood glucose
to ensure that hyperglycemia (blood glucose >180 mg/dL) must continue during this weaning process to prevent severe
is not present. hypoglycemia.
Rectal temperature should be closely monitored during
PN support because fever is a common early manifestation of Y MANAGEMENT OF OBESITY
systemic infection. Blood glucose concentrations should be
closely monitored, the frequency of which depends on the sta- Obesity is an emergent problem in companion animal equid
bility of blood glucose concentrations. Blood glucose should populations. It has been associated with insulin resistance in
be maintained between 90 and 180 mg/dL. Although the renal horses and ponies, and both obesity and insulin resistance
threshold for glucose is not well described in foals, glucosuria have been associated with increased risk of laminitis, particu-
and diuresis will be observed in many when blood glucose larly the pasture-associated form of this disease.8,9,107 There
levels exceed 180 mg/dL. Urine output should be monitored is no universal definition of obesity in horses and ponies.
continuously, in combination with intermittent monitoring According to the Henneke system, horses with a BCS of 8 (fat)
of urine glucose concentration, because of the risk of hyper- or 9 (extremely fat) can be defined as obese, and animals with
glycemia-induced diuresis and glucosuria. Additional clinico- a BCS of 7 might be considered overweight, if not obese. Few
pathologic monitoring should consist of daily complete blood studies have examined the prevalence of obesity in horse and
counts and serum chemistry profiles in the critical case; these pony populations. The 1998 National Animal Health Monitor-
can be performed every 48 to 72 hours in more stable patients. ing System (NAHMS) study estimated that 4.5% of the horse
TABLE 5.8 Recommended Digestible Energy Intake by Mature Horses (Mcal/day)a

Target Body Weight
Type of Horse 400 kg (880 lb) 500 kg (1100 lb) 600 kg (1320 lb)
Adult sedentaryb
Minimum voluntary activity 12.1 15.2 18.2
Average voluntary activity 13.3 16.7 20.0
Elevated voluntary activity 14.5 18.2 21.8
Adult light exercise 16.0 20.3 24.0
Adult moderate exercise 18.6 23.3 28.0
Adult heavy exercise 21.3 26.6 32.0
Adult very heavy exercise 27.6 35.6 41.4
Pregnant: 0–4 months 13.3 16.7 20.0
5 months 13.7 17.1 20.5
6 months 13.9 17.4 20.9
7 months 14.3 17.9 21.5
8 months 14.8 18.5 22.2
9 months 15.4 19.2 23.1
10 months 16.2 20.2 24.2
11 months 17.1 21.4 25.7
Lactating: 1st month 25.4 31.7 38.1
2nd month 25.3 31.7 38.0
3rd month 24.5 30.6 36.7
4th month 23.6 29.4 35.3
5th month 22.7 28.3 34.0
6th month 21.8 27.2 32.7

aRecommended intakes for stallions and growing horses can be found in the NRC publication.
bSedentary adults: Minimum = very inactive in stall/paddock, easy keeper; elevated = very active in stall/paddock, hard keeper. Light exercise: 1 to 3 h/week;
walking, trotting. Moderate exercise: 3 to 5 h/week; walking, trotting, some canter; easy skills. Heavy exercise: 4 to 5 h/week; trotting, cantering; hard skills.
Very heavy: racing; elite 3-day; endurance racing.
From Committee on Nutrient Requirements of Horses, National Research Council. Nutrient Requirements of Horses. 6th ed. rev. Washington, DC: National
Academies Press; 2007.
population in the United States was overweight or obese.108 maintained at pasture year round and were not used for any
However, the accuracy of this estimate may be questioned type of riding activity.109
because it was based on owner reports, not the results of physi- Maintenance DE requirements for horses range between 30
cal examination. Anecdotal observations by equine veterinari- and 36 kcal/kg BW (Table 5.8), with variation among horses
ans suggest that the prevalence of obesity is far higher than the resulting from differences in dietary composition, age, breed,
NAHMS estimate. In support of this contention, a recent cross- environment, and body composition, among other factors.1
sectional, prospective study of 300 mature horses (ponies were Thus for a 500-kg (1100-lb) horse, minimum maintenance
excluded) in southwestern Virginia reported obesity (BCS of 8 energy needs are 15.2 Mcal DE/day. This requirement can be
or 9) in 56 animals (i.e., a prevalence of 19%).109 In a study of met by about 7 kg (15 lb) of high-quality hay (i.e., no sup-
319 pleasure riding horses in Scotland, 32% were obese and a plemental grain is required). To illustrate the impact of even
further 35% were considered fat.110 moderate overfeeding on BW, consider the effect of adding
The cause of obesity in horses and ponies is likely multi- 1 kg of grain or sweet feed per day to this horse’s ration for a
factorial. However, overfeeding and lack of physical activity 1-year period (i.e., an additional 3 Mcal/day or >1000 Mcal
are likely contributing factors. Many horses are kept in con- over the 1-year period); if it is assumed that 20 to 25 Mcal of
finement (e.g., stall, small pen) for much of the day, and even DE over maintenance is required for 1 kg of weight gain, the
if used for riding activities 2 or 3 days per week, they may horse in this example will gain upward of 40 kg BW during
not require any more than maintenance energy intakes. Nev- this period (with a 1- to 1½-unit increase in BCS).
ertheless, many of these horses are fed much more than the Genetics may be another factor in the predisposition to
maintenance energy requirement, which is a problem that is obesity. Horse owners and veterinarians often use the term
compounded by the provision of grains, sweet feeds, and other easy keeper to describe a horse or pony that has a tendency to
feeds with high caloric density. Obesity also can be a prob- be overweight and appears to require fewer calories than most
lem in some horses and ponies given unrestricted access to horses to maintain condition. Ponies and certain horse breeds
pasture, particularly during the spring and fall, when pasture (e.g., Morgans, Arabians, Paso Finos) appear to fit this descrip-
forage is actively growing, plentiful, and energy rich. In a study tion. One hypothesis is that certain lines of horses and ponies
by Thatcher et al., more than 60% of the surveyed horses were have inherited genetic traits that have facilitated survival on
poor-quality forages or in the face of limited feed availability: may result from a decrease in abdominal fat or abdominal
the so-called thrifty genotype.8,111 When these animals are sup- fat mass, and further weight loss may be required before
plied with abundant feed, particularly grains or pasture forage noticeable changes in BCS occur. BW and body condition
rich in NSC, weight gain and obesity result. should be assessed regularly (e.g., every 2–4 weeks) during
Obesity in horses and ponies is a risk factor for laminitis. the weight reduction program so that progress can be moni-
Mechanical trauma caused by increased load on the feet is tored and the program adjusted accordingly.
one possible reason that obesity is linked with laminitis. How- • Make all dietary changes gradually and avoid prolonged
ever, the increased risk of laminitis in obese equids is more periods of feed withholding. Abrupt starvation in obese
likely related to the attendant insulin resistance. In one recent ponies, donkeys, and Miniature Horses carries the risk of
study of ponies, a phenotype characterized by generalized hyperlipemia and hepatic and renal lipidosis.
or regional adiposity (especially a cresty neck), hyperinsu- • Develop an appropriate weight maintenance program once
linemia, and hypertriglyceridemia was associated with 10-fold the target weight and body condition have been achieved.
higher risk for development of pasture-associated laminitis. This includes monthly assessment of BW and condition to
The clustering of these risk factors for laminitis is termed ensure that the feeding program is appropriate to the cur-
prelaminitic syndrome.8 Similar associations between obesity, rent level of physical activity and other environmental in-
insulin resistance, and laminitis have been observed in horses, fluences on energy requirements (e.g., ambient conditions).
leading to the use of the term equine metabolic syndrome.112 In obese people the combination of caloric restriction and
Obese ponies, donkeys, and Miniature Horses are prone to the regular physical activity can result in more substantial weight
development of hyperlipemia during times of stress or nega- loss than either strategy alone. However, studies in humans
tive energy balance (e.g., concurrent disease, lactation). Other also have demonstrated that physical activity is beneficial even
proposed effects of obesity include impaired thermoregulation when weight loss does not occur, as demonstrated by improve-
in hot weather, reduced athletic performance, and increased ments in insulin resistance, blood lipid profile, and markers of
risk of joint injuries, but evidence is lacking. In broodmares inflammation, all of which are risk factors for cardiovascular
obesity and insulin resistance have been associated with pro- disease. Similarly, a study in a small number of obese mares
longed luteal phase and lengthened interovulatory intervals,112 demonstrated improvements in insulin sensitivity without a
but the impact of these alterations in the estrous cycle on change in BW after 7 days of round pen exercise (15–20 min/
reproductive performance has not been extensively studied. day).113 Accordingly, a program of regular exercise is likely to
be beneficial in the management of obese (but sound) horses
Weight Management Programs and ponies. In the author’s experience, weight reduction and
In horses, as in humans, eating less and exercising more are subsequent control are improved when dietary restriction is
the key strategies for improving BW and condition. Important combined with a program of riding or longeing. A suggested
steps in the development of a weight management program exercise regimen is to start with two or three exercise sessions
include the following: per week (20–30 min per session), subsequently building to 4
• Owner/trainer recognition that the horse or pony is over- or 5 times per week, with a gradual increase in the intensity
weight or obese: As the old adage states, “beauty is in the eye and duration of exercise.
of the beholder,” and different equestrian disciplines and
breeds have adopted different standards to evaluate body Feeding Obese Horses
condition. Nonetheless, the effectiveness of any weight loss Caloric restriction is of paramount importance in the manage-
program is critically dependent on the willingness of the ment of obese equids; creation of a state of negative energy bal-
owner or caregiver to comply with the plan. ance is needed to achieve loss of BW. Several different dietary
• Evaluation of the current feeding program and housing: strategies can be applied depending on the horse’s present and
This includes a thorough evaluation of the type of feed desired body condition and other individual circumstances. A
that is being provided (including supplementary feed, hay, certain amount of trial and reassessment is invariably required
pasture quality, and time allowed for grazing) and in what to achieve the goal weight and condition in an individual ani-
quantities. mal. Key considerations are the quantity and composition of
• Assessment of the weekly workload and soundness for ex- the ration. Removal from pasture (e.g., to a large dry lot) is nec-
ercise: Is the horse or pony engaged in structured physical essary for adequate control of dietary intake. Some nutritionists
activity (e.g., being ridden)? If so, how much? Many obese and veterinarians have recommended restrictive grazing as a
equids receive little structured exercise. Information on means to decrease caloric intake in overweight equids. However,
current activity level and soundness for exercise forms the a study in obese pony mares reported no change in BW when
basis for recommendations regarding physical activity. ponies were allowed access to pasture for 12 hours daily (either
• Set realistic goals for weight loss and regularly monitor pro- during day or night),114 perhaps because of increased forage
gress: In this author’s experience, there is wide variation in consumption during the restricted grazing period. In another
the response of obese horses and ponies to weight loss treat- study it was estimated that ponies could consume 40% of their
ment programs. Some undergo a substantial loss of BW and daily DM intake during 3 hours of pasture turnout.115 Strate-
adiposity after 2 to 3 months of diet restriction and increased gies that allow turnout while minimizing forage intake include
physical activity. In others, progress can be frustratingly application of grazing muzzles, strip grazing behind other
slow, and further adjustments to diet and the level of physi- horses, mowing the pasture and removing clippings before pro-
cal activity may be needed for satisfactory improvement. As viding access, putting a deep layer of wood chips over a small
a guide, an effective weight loss regimen should result in the paddock, and using dry lots or indoor arenas. It is important
loss of approximately 25 to 30 kg over a 4- to 6-week pe- to ensure that horses wearing grazing muzzles are able to con-
riod. This decrease in BW may be accompanied by the loss sume water. In some obese horses and ponies, a return to less
of approximately 1 unit of BCS. However, initial weight loss restricted pasture access is possible after attainment of goal BW
and condition. Even then, however, reduced grazing may be development of hyperlipemia. This risk is increased at times of
justified during periods of rapid growth (i.e., spring and fall) stress, such as during transportation, lactation, pregnancy, and
given the likelihood for weight gain and exacerbation of insulin management changes. As mentioned previously, the target dura-
resistance, with attendant increased risk of laminitis. tion for weight loss should be weeks to months rather than days.
Generally, rations for overweight and obese horses should be Additional factors should be considered when planning
high in fiber and low in NSC. Horses at maintenance require a weight reduction program, including strategies to extend
approximately 2% BW as forage or forage plus supplement to feeding time and relieve boredom in the face of limited feed
meet daily nutrient requirements. As a first step toward calo- provision, the need for individual rather than group feeding,
rie restriction and weight loss, grain and other concentrated the potential need for a change in the type of bedding, and
sources of calories (e.g., commercial sweet feeds, feeds contain- the potential use of pharmacologic agents (e.g., levothyroxine)
ing added fats) should be reduced (for overweight animals) or purported to enhance weight loss or mitigate comorbidities
totally removed (for obese animals) from the diet. Excessive such as insulin resistance. Recent studies have demonstrated
feeding of other treats, such as carrots and apples, also should that levothyroxine sodium (48 mg/day for an adult horse) can
be curtailed. Forage (as hay or hay substitute such as chop, chaff, enhance weight loss in healthy horses.117
or haylage) should be the primary, if not sole, energy-provid- Use of hay nets with small openings or double hay nets
ing component of the ration. In some areas forage-based, low- can extend feeding time in some horses. The size of the
calorie feeds complete with vitamins and minerals are available meal and duration of feeding can be increased by mixing
commercially; this type of feed is convenient and may be used the feed with chaff or chopped straw. In group housing
as a substitute for hay or fed as a component of the ration along situations it may be necessary to separate the obese horse
with hay. In a study of obese ponies provided a free-choice for- or pony to allow strict control of feed intake. For animals
age (chaff) diet during winter and summer, voluntary intake housed in stalls, dietary restriction can promote intake of
(DM basis) was about 2% of BW, and BCS was unchanged dur- bedding. Because some straws retain some of the cereal
ing the study period.116 As a general guide, therefore, hay or hay heads, ingestion of bedding can substantially increase daily
substitute should initially be provided at no more than 1.5% of caloric intake (and possibly the risk of colic). In this situa-
current BW per day (clients should be instructed to weigh the tion use of shavings, paper, or other nonstraw alternatives
ration), with subsequent further reductions in feed depending for bedding is recommended.
on the extent of weight loss (e.g., 1% of target BW). It is prefer-
able not to decrease forage provision below 1% of BW; feeding Y FEEDING THIN AND STARVED
smaller amounts of forage can increase the risk of hindgut dys- HORSES
function, stereotypical behaviors (e.g., wood chewing), inges-
tion of bedding, and coprophagy. The ration should be divided Failure to meet a horse’s energy (DE) requirements will result
into three to four feedings per day. in weight loss. Prolonged nutritional restriction (energy and
Mature grass hay (i.e., with visible seedheads and a high protein) will result in emaciation and, in severe cases, death.
stem-to-leaf ratio) has higher fiber and lower energy and NSC Chronically starved horses have low body condition (BCS of
than immature hay and is suitable forage for the obese horse or 2 or lower), with minimal subcutaneous fat and reduced mus-
pony. Alfalfa hay or other legumes, such as clover, are less pre- cle mass. The hair coat is often unthrifty in appearance, and
ferred because, on average, these forages have higher energy muscle weakness may result in recumbency. Healthy horses
and NSC content than grass hay. Ensiled forages generally starved of feed take approximately 60 to 90 days to become
have lower NSC contents than hay made from the same crop. recumbent. After 36 to 48 hours of recumbency, horses are
However, despite the generally lower NSC content of haylage often in lateral recumbency, may not be able to raise their
compared with hay, the high palatability of some haylages may heads, and can display seizure-like activity. The prognosis for
result in higher total NSC intake. Ideally, the results of proxi- survival is very poor in horses recumbent for more than 72
mate nutrient analysis, including direct measurement of starch hours, even when appropriate nutritional support and nursing
and ESC, should be reviewed before selection of the hay. An care are instituted.118
NSC content of less than 10% is recommended. Poorly digest- Laboratory findings in chronically starved horses may include
ible, highly silicated forages should be used with caution; anemia, hypertriglyceridemia, hyperbilirubinemia (especially
according to anecdotal reports, this practice increases the risk unconjugated bilirubin), high nonesterified fatty acid concentra-
of impaction colic in some animals. tions, lymphopenia, hypophosphatemia, and hypomagnesemia.
Forage-only diets do not provide adequate protein, minerals, Protein deficiency may result in hypoalbuminemia and low BUN
or vitamins. It is possible that the lack of protein over the long concentration. When presented with a thin or emaciated horse,
term could lead to the loss of muscle mass rather than fat. There- the clinician first must determine the cause (e.g., feed restriction
fore the forage diet should be supplemented with a low-calorie versus medical problems such as intestinal parasites, malabsorp-
commercial ration balancer product that contains sources of tion syndromes, poor dentition, old age). Thorough clinical eval-
high-quality protein and a mixture of vitamins and minerals to uation is therefore required to identify the cause of weight loss
balance the low vitamin E, vitamin, copper, zinc, selenium, and and emaciation. If the horse has been neglected, obtaining an
other minerals typically found in mature grass hays. These prod- accurate history of its diet and feeding program may be difficult.
ucts are often designed to be fed in small quantities (e.g., 0.5–1.0 However, observation of the environment and other horses on
kg/day); they can be mixed with chaff (hay chop) to increase the the farm may indicate feed restriction as the cause of thin body
size of the meal and extend feeding time, which may alleviate condition or starvation. Herdmates also may be in poor body
boredom in animals provided a restricted diet. condition, pastures overgrazed, and hay quality poor or fed in
Ponies, donkeys, and Miniature Horses must not be abruptly quantities insufficient to meet the requirements of the individual
starved to reduce their BW or prevented from eating for pro- or herd. Harsh environmental conditions (e.g., dry summer, cold
longed periods; these strategies have been associated with the winter) can contribute to feed restriction in horses kept at pasture.
Recommendations for feeding management of thin and refeeding syndrome have been observed in starved horses pro-
emaciated horses vary depending on the severity and chronic- vided a diet rich in starches and sugars (i.e., high NSC). There-
ity of starvation and appetite. Severely debilitated horses with fore some experts recommend restricting dietary NSC in the
poor appetite may require AEF with a slurry made from com- ration provided to chronically starved horses, specifically less
mercial complete feeds or PN support (as described earlier in than 20% NSC in the total diet.73 One study evaluated the
this chapter). For horses in moderately poor body condition metabolic responses of chronically starved horses refed one
(BCS 3 or 4) with good appetite, a simple increase in energy of three diets: alfalfa hay, oat hay, or a diet of half oat hay and
intake will result in weight gain. The first step is to thoroughly half an extruded (commercial) feed.120 The diets were initially
evaluate the current ration, with particular reference to the offered at 50% of estimated daily DE requirements and, over
adequacy of DE and protein intake (see Fig. 5.1 and Table the subsequent 10-day period, gradually increased to 100% of
5.8). Requirements for weight gain can then be estimated. The daily needs. There were minimal differences among treatments
relationships among energy intake, change in BW, and change regarding metabolic responses (e.g., blood glucose, nonesteri-
in BCS have not been well described. However, in light-breed fied fatty acid, mineral concentrations), but serum insulin con-
horses it appears that each unit of body condition increase centrations were higher in horses fed hay in addition to extruded
requires at least 20 kg of weight gain. Some experts suggest feed. Weight gain over the 10-day period did not differ among
that 16 to 24 Mcal of DE are required per kilogram of gain in treatments. Another study compared starved horses fed a diet
mature horses of about 500-kg (1100-lb) BW.1 Using an average of alfalfa alone and those fed alfalfa and corn oil.121 Phosphorus
value of 20 Mcal DE/kg weight gain, a 1-unit increase in BCS intake was lower in horses fed the alfalfa and corn oil diet, which
(20-kg gain) will require 400 Mcal of DE over maintenance is associated with lower serum phosphorus concentrations.
requirements, or an additional 6 to 7 Mcal per day for the 500- Generally, a diet consisting mostly of forage (e.g., hay) is
kg horse over a 60-day period. Using similar assumptions, a recommended during the rehabilitation of chronically starved
2-unit increase in BCS (approximately 40 kg) may be achieved horses. Grass or legume hay (or a mixture of the two) should
over a 90-day period by feeding an additional 9 to 10 Mcal of be fed. The NSC content of these forages is generally less than
DE per day (see Fig. 5.1). Note that these estimates have been 15% DM. Alfalfa hay is a good choice for initial refeeding
derived from limited data, and individual responses are likely because it has a higher mineral content than grass hay. Grains
to vary. Also bear in mind that the efficiency of conversion of (e.g., oats, corn, barley) and sweet feeds are not recommended
DE to usable energy for tissue deposition (net energy) varies because of their high NSC content. It is advisable to supple-
among energy sources; less DE may be needed per unit of gain ment the hay ration with a vitamin and mineral supplement
if a high-fat feed is provided compared with a high-fiber feed or balancer pellet. The energy density of the ration may be
such as grass hay. The addition of 3 kg of good-quality hay increased by adding vegetable oil (e.g., ¼ to 1 cup per day,
(e.g., alfalfa, DE 2.4 Mcal/kg on DM basis) or sugar beet pulp starting at the low end of this range) or providing a commercial
(2.8 Mcal DE/kg DM) to the ration will provide the extra DE fat-supplemented feed (8%–12% fat, as fed with NSC <20%).
required for a 1-unit increase in BCS over a 60-day period. As previously mentioned, thiamine deficiency is thought to
Alternatively, a smaller amount of additional hay or beet pulp contribute to the pathophysiology of refeeding syndrome in
may be combined with vegetable oil (1.7 Mcal DE per standard humans. Accordingly, the administration of a B-vitamin prep-
cup [225 mL]). The provision of 2 to 2.5 kg/day of a commer- aration may be justified.
cial fat-supplemented feed (8%–10% fat; typical DE of 3–3.5 The DE (caloric) requirements should be calculated on the
Mcal/kg) is another option. basis of RERs at the current BW (22–23 kcal/kg/day) and the
A more conservative approach is indicated for the initial true maintenance requirements at the ideal BW (30–36 kcal/
nutritional support of starved horses. In malnourished human kg/day; see Table 5.8). Starved, emaciated horses may have
patients aggressive refeeding can result in potentially fatal shifts lost 25% to 30% of BW; therefore, maintenance DE needs for
in fluids and electrolytes as a result of hormonal and metabolic ideal BW will be based on 125% to 130% of BW measured
responses to rapid refeeding, whether enteral or parenteral; this at the time of first examination. A gradual increase in daily
problem has been named refeeding syndrome. The hallmark DE intake has been recommended,73 starting at 25% to 50% of
biochemical feature of refeeding syndrome is hypophosphate- resting requirements at current BW, building to 100% of rest-
mia, but other electrolyte abnormalities may occur, including ing requirements over the next 2 to 3 days, and followed by
hypokalemia and hypomagnesemia.119 Thiamine deficiency is a gradual (over 7–10 days) transition to maintenance energy
another possible feature of refeeding syndrome. During pro- requirements for the ideal BW. Energy provision should not
longed starvation the intracellular concentrations of these exceed 100% of resting requirements if AEF is used for provi-
substances become severely depleted, although serum concen- sion of the ration, with transition to true maintenance after
trations may remain within reference limits. With refeeding, the start of voluntary feed consumption. Regardless of feeding
glycemia leads to an increase in circulating insulin, which stim- method (voluntary vs. AEF), the ration should be divided into
ulates glycogen, and fat and protein synthesis. These processes four to six feedings daily during the first 10 to 14 days of reha-
require cofactors such as phosphate, magnesium, and thiamine. bilitation. Subsequently, the ration can be provided into two to
Insulin stimulates cellular uptake of potassium, and magne- three meals per day.
sium and phosphate also move into the cells. Water follows by Regular (every 1–2 days) measurement of blood glucose,
osmosis. Consequently, there can be marked decreases in serum serum magnesium, phosphorus, and potassium is advised
phosphate, magnesium, and potassium, with potential develop- during the first 7 to 10 days of refeeding. Frequent assessment
ment of cardiac dysfunction (e.g., arrhythmias, cardiac arrest) of hydration status and gastrointestinal function (e.g., borbo-
and neuromuscular complications. rygmi, quantity and character of feces) is also recommended.
The incidence of refeeding syndrome in chronically starved Administration of intravenous fluids, oral electrolyte-mineral
horses is unknown. Anecdotally, however, metabolic and elec- preparations, or both may be necessary to correct electrolyte
trolyte derangements similar to those observed in humans with imbalances.
REFERENCES 23. Reese RE, Andrews FM. Nutrition and dietary management of
equine gastric ulcer syndrome. Vet Clin Nth Am Equine Pract.
1. National Research Council. Nutrient requirements of horses. 6th 2009;25:79–92.
ed. Washington, DC: National Academies Press; 2007. 24. McKenzie EC, Valberg SJ, Godden SM, et al. Effect of dietary
2. Pagan JD, Geor RJ, eds. Advances in equine nutrition II. Not- starch, fat and bicarbonate content on exercise responses and
tingham, UK: Nottingham University Press; 2001. serum creatine kinase activity in equine recurrent exertional
3. Henneke DR, Potter GD, Kreider JL, et al. Relationship between rhabdomyolysis. J Vet Intern Med. 2003;17:693–701.
condition score, physical measurements and body fat percent- 25. Geor RJ. Metabolic predispositions to laminitis in horses and
age in mares. Equine Vet J. 1983;15:371–372. ponies: obesity, insulin resistance and metabolic syndromes. J
4. Pratt SE, Geor RJ, McCutcheon LJ. Effect of dietary energy Equine Vet Sci. 2008;28:753–759.
source and physical conditioning on insulin sensitivity and glu- 26. Longland AC. Starch, sugar and fructans, what are they and
cose tolerance in standardbred horses. Equine Vet J. 2006;(suppl how important are they in diets for horses. In: Proceedings of the
36):579–584. 1st WALTHAM-RVC Laminitis Conference. 2007:7–14.
5. Suagee JK, Burk AO, Quinn JK, et al. Effects of diet and weight 27. Harris PA. Energy requirements of the exercising horse. Ann
gain on body condition scoring in Thoroughbred geldings. Rev Nutr. 1997;17:185–210.
J Equine Vet Sci. 2008;28:156–166. 28. Harris PA, Geor RJ. Primer on dietary carbohydrates and util-
6. Kienzle E, Schramme S. Body condition scoring and prediction ity of the glycemic index in equine nutrition. Vet Clin Nth Am
of bodyweight in adult warm-blooded horses. Pferdeheilkunde. Equine Pract. 2009;25:23–37.
2004;20:517–524. 29. de Fombelle A, Veiga L, Drogoul C, et al. Effect of diet composi-
7. Lee S, Bacha F, Gungor N, et al. Waist circumference is an in- tion and feeding pattern on the prececal digestibility of starches
dependent predictor of insulin resistance in black and white from diverse botanical origins measured with the mobile nylon
youths. J Pediatr. 2006;148:188–194. bag technique. J Anim Sci. 2004;82:3625–3634.
8. Treiber KH, Kronfeld DS, Hess TM, et al. Evaluation of genetic 30. Pollock CJ, Lloyd EJ. The effect of low temperature upon starch,
and metabolic predispositions and nutritional risk factors for sucrose and fructan synthesis in leaves. Ann Bot. 1987;60:231–
pasture-associated laminitis in ponies. J Am Vet Med Assoc. 235.
2006;228:1538–1545. 31. Van Soest PJ. Nutritional ecology of the ruminant. 2nd ed. Ithaca,
9. Carter RA, Treiber KH, Geor RJ, et al. Prediction of incipient NY: Comstock Publishing; 1995.
pasture-associated laminitis from hyperinsulinemia, hyperlep- 32. Argenzio RA. Functions of the equine large intestine and their
tinemia, and generalized and localized obesity in a cohort of interrelationship in disease. Cornell Vet. 1979;65:303–330.
ponies. Equine Vet J. 2009;41:171–178. 33. Clarke LL, Roberts MC, Argenzio RA. Feeding and digestive
10. Frank N, Elliott SB, Brandt LE, et al. Physical characteristics, problems in horses. Physiologic responses to a concentrated
blood hormone concentrations, and plasma lipid concentra- meal. Vet Clin North Am Equine Pract. 1990;6:433–450.
tions in obese horses with insulin resistance. J Am Vet Med As- 34. Cohen ND, Gibbs PG. Dietary and other management fac-
soc. 2006;228:1383–1390. tors associated with colic in horses. J Am Vet Med Assoc.
11. Caroll C, Huntington P. Body condition scoring and weight es- 1999;215:53–60.
timation of horses. Equine Vet J. 1988;20:41–45. 35. Hillyer MH, Taylor FGR, Proudman CJ, et al. Case control
12. Ellis JM, Hollands T. Accuracy of different methods of estimat- study to identify risk factors for simple colonic obstruction and
ing the weight of horses. Vet Rec. 1998;143:335–336. distension colic in horses. Equine Vet J. 2002;34:55–463.
13. St. Lawrence AC, Lawrence LM, Coleman R. Using an empirical 36. Hudson JM, Cohen ND, Gibbs PG, et al. Feeding practices asso-
equation to predict the voluntary intake of grass hays by mature ciated with colic in horses. J Am Vet Med Assoc. 2001;219:1419–
equids. In: Proceedings of the 17th Equine Nutrition and Physi- 1425.
ological Society Symposium. 2001:99–100. 37. Tinker MK, White NA, Lessard P, et al. Retrospective study of
14. Archer DC, Proudman CJ. Epidemiological clues to preventing equine colic risk factors. Equine Vet J. 1997;29:454–458.
colic. Vet J. 2006;172:29–39. 38. Cohen ND, Peloso JG. Risk factors for history of previous colic
15. Shirazi-Beechey SP. Molecular insights into dietary induced and for chronic, intermittent colic in a population of horses. J
colic. Equine Vet J. 2008;40:414–421. Am Vet Med Assoc. 1995;208:607–703.
16. Geor RJ, Harris PA. How to minimize gastrointestinal disease 39. Proudman CJ. A two year, prospective survey of equine colic in
associated with carbohydrate nutrition in horses. In: Proceed- general practice. Equine Vet J. 1992;24:90–93.
ings of the 53rd Annual Convention of the American Association 40. Cohen ND. The John Hickman Memorial Lecture: colic by
of Equine Practitioners. 2007:178–185. numbers. Equine Vet J. 2003;35:343–349.
17. Pagan JD, Jackson S, Duren S. Computing horse nutrition: 41. Varloud M, Goachet AG, de Fombelle A, et al. Effect of the diet
how to properly conduct an equine nutrition evaluation using on prececal digestibility of dietary starch measured in horses
MicroSteed equine ration evaluation software. World Equine with acid insoluble ash as an internal marker. In: Proceedings of
Vet Rev. 1996;1:11–17. the 18th Equine Nutrition and Physiological Society Symposium.
18. Gallagher K, Leech J, Stowe H. Protein, energy and dry matter 2003:117–118.
consumption by racing Thoroughbreds: a field study. J Equine 42. Cummings JH, Englyst HN. Gastrointestinal effects of food car-
Vet Sci. 1988;12:43–47. bohydrate. Am J Clin Nutr. 1995;(suppl 61):S938–S945.
19. Southwood LL, Evans DL, Bryden WL, et al. Nutrient intake of 43. Dyer J, Fernandez-Castano E, Salmon KS, et al. Molecular char-
horses in Thoroughbred and Standardbred stables. Aust Vet J. acterisation of carbohydrate digestion and absorption in equine
1993;70:164–168. small intestine. Equine Vet J. 2002;34:349–358.
20. White NA. Equine colic. II. Causes and risk factors for colic. 44. Dyer J, Al Rammahi M, Waterfall L, et al. Adaptive response
In: Proceedings of the 52nd Annual Convention of the American of equine intestinal Na(+)/glucose co-transporter (SGLT1)
Association of Equine Practitioners. 2006:115–119. to an increase in dietary soluble carbohydrate. Pflugers Arch.
21. Richards N, Hinch GN, Rowe JB. The effect of current grain feed- 2009;458:419–430.
ing practices on hindgut starch fermentation and acidosis in the 45. Lorenzo-Figueras M, Morisset SM, Morriset J, et al. Digestive
Australian racing Thoroughbred. Aust Vet J. 2006;84:402–407. enzyme concentrations and activities in healthy pancreatic tis-
22. Nadeau JA, Andrews FM, Mathew AG, et al. Evaluation of diet sue. Am J Vet Res. 2007;68:1070–1072.
as a cause of gastric ulcers in horses. Am J Vet Res. 2000;61:784– 46. Kienzle E. Small intestinal digestion of starch in the horse. Re-
790. vue Med Vet. 1993;145:199–204.
47. Kienzle E, Radicke S, Wilke W, et al. Activity of amylase in 68. Leverve X. Inter-organ substrate exchanges in the critically ill.
the gastrointestinal tract of the horse. J Anim Physiol Am Nutr. Curr Opin Clin Nutr Metab Care. 2001;4:137–142.
1994;72:234–241. 69. Dunkel B, McKenzie HC. Severe hypertriglyceridemia in clini-
48. Meyer H, Radicke S, Kienzle E, et al. Investigations on preileal cally ill horses: diagnosis, treatment and outcome. Equine Vet J.
digestion of oats, corn and barley starch in relation to grain pro- 2003;35:590–595.
cessing. In: Proceedings of the 13th Equine Nutrition and Physi- 70. Gelfand RA, Mathews DE, Bier D, et al. Role of counter-regulatory
ological Society Symposium. 1993:92–97. hormones in the catabolic response to stress. J Clin invest. 1984;
49. Potter GD, Arnold FF, Householder DD, et al. Digestion of 74:2238–2248.
starch in the small or large intestine of the equine. Pferde- 71. Langhans W. Peripheral mechanisms involved with catabolism.
heilkunde. 1992;1:107–111. Curr Opin Clin Nutr Metab Care. 2002;5:419–426.
50. Bugaut M, Bentejec M. Biological effects of short chain fatty acids 72. Magdesian KG. Nutrition for critical gastrointestinal ill-
in nonruminant mammals. Annu Rev Nutr. 1993;13:217–241. ness: feeding horses with diarrhea or colic. Vet Clin Equine.
51. De Fombelle A, Julliand V, Drogoul C, et al. Feeding and micro- 2003;19:617–644.
bial disorders in horses: part 1—effects of an abrupt incorpora- 73. Robinson NE, Sprayberry K, eds. Current therapy in equine
tion of two levels of barley in a hay diet on microbial profile and medicine. 6th ed. St. Louis, MO: Saunders; 2009.
activities. J Equine Vet Sci. 2001;21:439–445. 74. Jeejeebhoy KN. Enteral and parenteral nutrition: evidence-
52. Bailey SR, Marr CM, Elliott J. Current research and theo- based approach. Proc Nutr Soc. 2001;60:399–402.
ries on the pathogenesis of acute laminitis in the horse. Vet J. 75. Raina N, LaMarre J, Liew C-C, et al. Effect of nutrition on the
2004;167:129–142. expression of plasma soluble tumor necrosis factor (TNF) re-
53. Goodson J, Tyznik WJ, Cline JH, et al. Effects of an abrupt diet ceptors, membrane TNF receptors and MRNA of TNF recep-
change from hay to concentrate on microbial numbers and tors in rats receiving oral and parenteral nutrition. Am J Physiol.
physical environment in the cecum of the pony. Appl Environ 1999;277:E464–E473.
Microbiol. 1988;54:1946–1950. 76. Yamazaki K, Maiz A, Moldaver LL, et al. Complications as-
54. Willard JG, Willard JC, Wolfram SA, et al. Effect of diet on cecal sociated with overfeeding of infected animals. J Surg Res.
pH and feeding behavior of horses. J Anim Sci. 1977;45:87–93. 1986;40:152–158.
55. Radicke S, Kienzle E, Meyer H. Preileal apparent digestibility 77. Matsui J, Cameron RG, Kurian R, et al. Nutritional, hepatic, and
of oat and corn starch and consequences for cecal metabolism. metabolic effects of cachetin/tumor necrosis factor in rats receiv-
In: Proceedings of the 13th Equine Nutrition and Physiological ing parenteral nutrition. Gastroenterology. 1993;104:235–243.
Society Symposium. 1991:43–48. 78. Pagan JD, Hintz HF. Equine energetics. I. Relationship between
56. Bailey SR, Rycroft A, Elliott J. Production of amines in equine body weight and energy requirements in horses. J Anim Sci.
cecal contents in an in vitro model of carbohydrate overload. J 1986;63:815–821.
Anim Sci. 2002;51:1930–1934. 79. Stapleton RD, Jones N, Heyland KD, et al. Feeding critically ill
57. French KR, Pollitt CC. Equine laminitis: loss of hemides- patients: what is the optimal amount of energy? Crit Care Med.
mosomes in hoof secondary epidermal lamellae correlates to 2007;35:S535–S540.
dose in an oligofructose induction model: an ultrastructural 80. Jeejeebhoy KN. Permissive underfeeding of the critically ill pa-
study. Equine Vet J. 2004;(suppl 36):230–235. tient. Nutr Clin Pract. 2004;19:477–480.
58. Drogoul C, de Fombelle A, Julliand V. Feeding and microbial 81. Ousey JC, Holdstock NB, Rossdale PD, et al. How much energy
disorders in horses. 2: effect of three hay:grain ratios on di- do sick neonatal foals require compared to healthy foals? Pfer-
gesta passage rate and digestibility in ponies. J Equine Vet Sci. deheilkunde. 1996;12:231–237.
2001;21:487–490. 82. Ousey JC, Prandi S, Zimmer J, et al. Effects of various feeding
59. Medina B, Girard ID, Jacotot E, et al. Effect of preparation of regimens on the energy balance of equine neonates. Am J Vet
Saccharomyces cerevisiae on microbial profiles and fermenta- Res. 1997;58:1243–1251.
tion patterns in the large intestine of horses fed a high fiber or a 83. Durham AE, Phillips TJ, Walmsley JP, et al. Study of the clini-
high starch diet. J Anim Sci. 2002;80:2600–2609. cal effects of postoperative parenteral nutrition in 15 horses. Vet
60. Weese JS, Rousseau J. Evaluation of Lactobacillus pentosus WE7 Rec. 2003;153:493–498.
for prevention of diarrhea in neonatal foals. J Am Vet Med As- 84. Adam S, Forrest S. ABC of intensive care. Br Med J.
soc. 2005;226:2031–2034. 1999;319:175–178.
61. Desrochers AM, Dolente BA, Roy MF, et al. Efficacy of Saccha- 85. Durham AE, Phillips TJ, Walmsley JP, et al. Nutritional and
romyces boulardii for treatment of horses with acute enterocol- clinicopathological effects of post operative parenteral nutrition
itis. J Am Vet Med Assoc. 2005;227:954–959. following small intestinal resection and anastomosis in the ma-
62. Pagan JD, Lawrence TJ. LA: Feeding protected sodium bicar- ture horse. Equine Vet J. 2004;36:390–396.
bonate attenuates hindgut acidosis in horses fed a high-grain 86. Frost P, Bihari D. The role of nutritional support in the criti-
ration. In: Proceedings of the 54th Annual Convention of the cally ill: physiological and economic considerations. Nutrition.
American Association of Equine Practitioners. 2007:530–533. 1997;(suppl 13):58–63.
63. Heyland DK. Nutritional support in the critically ill pa- 87. Miura S, Tanaka S, Yoshioka M, et al. Changes in intestinal ab-
tient: a critical review of the evidence. Critical Care Clinics. sorption of nutrients and brush border glycoproteins after total
1998;14:423–440. parenteral nutrition in rats. Gut. 1992;33:484–489.
64. Silk DBA, Gow NM. Postoperative starvation after gastrointesti- 88. Mosenthal AC, Xu D, Deitch EA. Elemental and intravenous
nal surgery: early feeding is beneficial. Br Med J. 2001;323:761– total parenteral nutrition diet-induced gut barrier failure is in-
766. testinal site specific and can be prevented by feeding nonfer-
65. Shukla VK, Roy SK, Kumar J, Vaida MP. Correlation of immune mentable fiber. Crit Care Med. 2002;30:396–402.
and nutritional status with wound complications in patients un- 89. Buechner-Maxwell VA, Elvinger F, Thatcher CD, et al. Physi-
dergoing abdominal surgery. Ann Surg. 1985;51:442–445. ologic response of normal adult horses to a low residue liquid
66. Hasselgren PO, Fischer JE. Counter-regulatory hormones and diet. J Equine Vet Sci. 2003;23:310–317.
mechanisms in amino acid metabolism with special reference 90. Naylor JM, Freeman DE, Kronfeld DS. Alimentation of hy-
to the catabolic response in skeletal muscle. Curr Opin Clin Nutr pophagic horses. Comp Cont Educ Pract Vet. 1984;6:S03–S99.
Metab Care. 1999;2:9–14. 91. Detsky AS, Baker JP, O’Rouke K, Goel V. Perioperative paren-
67. Romijn JA. Substrate metabolism in the metabolic response to teral nutrition: a meta-analysis. Ann Intern Med. 1987;107:195–
injury. Proc Nutr Soc. 2000;59:447–449. 203.
92. Silk DB, Green CJ. Perioperative nutrition: parenteral versus 108. United States Department of Agriculture. NAHMS Equine ‘98.
enteral. Curr Opin Clin Nutr Metab Care. 1998;1:21–27. Part III. Management and health of horses. https://www.aphis
93. Bozzetti F, Gavazzi C, Miceli R, et al. Perioperative total paren- .usda.gov/animal_health/nahms/equine/downloads/equine98/
teral nutrition in malnourished gastrointestinal cancer patients: Equine98_dr_PartIII.pdf; accessed 28 March 2017.
a randomized, clinical trial. J Parenter Enteral Nutr. 2000;24: 109. Thatcher C, Pleasant RS, Geor RJ, et al. Prevalence of overcon-
7–14. ditioning in mature horses in southwest Virginia during the
94. Klein S, Kinney J, Jeejeebhoy K, et al. Nutrition support in clini- summer. J Vet Intern Med. 2012;26:1413–1418.
cal practice: review of published data and recommendations for 110. Wyse CA, McNie KA, Tannahil VJ, et al. Prevalence of obesity
future research directions. J Parenter Enteral Nutr. 1997;21:133– in riding horses in Scotland. Vet Rec. 2008;162:590–591.
156. 111. Treiber KH, Kronfeld DS, Geor RJ. Insulin resistance in equids:
95. Farinas-Alvarez C, Farinas MC, Fernandez-Mazarrasa C, et al. possible role in laminitis. J Nutr. 2006;136:S2094–S2098.
Analysis of risk factors for nosocomial sepsis in surgical pa- 112. Johnson PJ. The equine metabolic syndrome: peripheral
tients. Br J Surg. 2000;87:1076–1081. Cushing’s syndrome. Vet Clin N Am Equine Pract. 2002;
96. Lopes MA, White NA. Parenteral nutrition for horses with gas- 18:271–293.
trointestinal disease: a retrospective study of 79 cases. Equine 113. Powell DM, Reedy SE, Sessions DR, et al. Effect of short-term
Vet J. 2002;34:250–257. exercise training on insulin sensitivity in obese and lean mares.
97. McKenzie III HC, Geor RJ. Feeding management of sick neona- Equine Vet J. 2002;(suppl 34):81–84.
tal foals. Vet Clin North Am Equine Pract. 2009;25:109–119. 114. Buff PR, Johnson PJ, Wiedmeyer CE, et al. Modulation of lep-
98. Stoneham S. How to feed the sick neonatal foal. In: Proceedings tin, insulin and growth hormone in obese pony mares under
of the 1st British Equine Veterinary Association and Waltham chronic nutritional restriction and supplementation with racto-
Nutrition Symposia. Suffolk, UK: Equine Veterinary Journal pamine hydrochloride. Vet Ther. 2007;7:64–72.
Limited; 2005:33–37. 115. Ince JC, Longland AC, Moore-Colyer M, et al. A pilot study to
99. Naylor JM, Bell R. Raising the orphan foal. Vet Clin N Am estimate the intake of grass by ponies with restricted access to
Equine Pract. 1985;1:169–178. pasture. In: Proceedings of the British Society of Animal Science.
100. Staniar WB, Kronfeld DS, Hoffman RM, et al. Weight predic- 2005:109.
tion from linear measures of growing thoroughbreds. Equine 116. Dugdale AHA, Curtis GC, Knottenbelt DC, et al. Changes in
Vet J. 2004;36:149–154. body condition and fat deposition in ponies offered an ad li-
101. Cymbaluk NF, Smart ME, Bristol F, et al. Importance of milk bitum chaff-based diet. In: Proceedings of the 12th Congress of
replacer intake and composition in rearing orphan foals. Can the European Society of Veterinary Clinical Nutrition. 2008:39.
Vet J. 1993;34:479–486. [abstract].
102. Ousey JC. Feeding the newborn foal in health and disease. 117. Frank N, Elliott SB, Boston RC. Effects of long-term oral ad-
Equine Vet Educ. 2003;6:50–54. ministration of levothyroxine sodium on glucose dynamics in
103. Magdesian KG. Neonatal foal diarrhea. Vet Clin N Am Equine healthy adult horses. Am J Vet Res. 2008;69:76–81.
Pract. 2005;21:295–312. 118. Whiting TL, Salmon RH, Wruck GC. Chronically starved horses:
104. Krause JB, McKenzie III HC. Parenteral nutrition in foals: a predicting survival, economic, and ethical considerations. Can
retrospective study of 45 cases. Equine Vet J. 2000-2004;(39): Vet J. 2005;46:320–324.
74–78. 119. Stanga Z, Brunner A, Leuenberger M, et al. Nutrition in clini-
105. Koterba AM, Drummond WH, Kosch PC, eds. Equine clinical cal practice: the refeeding syndrome: illustrative cases and
neonatology. Philadelphia: Saunders; 1990. guidelines for prevention and treatment. Eur J Clin Nutr.
106. Spurlock SL, Donaghue S. Weight gains in foals on parenteral 2008;62:687–694.
nutrition. In: Proceedings of the 2nd Conference of the Interna- 120. Witham CL, Stull CL. Metabolic responses of chronically
tional Society of Perinatology. 1990:61. starved horses to refeeding with three isoenergetic diets. J Am
107. Geor R, Frank N. Metabolic syndrome: from human organ dis- Vet Med Assoc. 1998;212:691–696.
ease to laminar failure in equids. Vet Immunol Immunopathol. 121. Stull CL. Nutrition for rehabilitating the starved horse. J Equine
2009;129:151–154. Vet Sci. 2003;23:456–459.
C HA P T E R 6
Clinical Epidemiology and
Evidence-Based Medicine
Kenneth W. Hinchcliff
Y INTRODUCTION The emerging practice in human medicine is more holis-

tic and includes a consideration of the evidence and its qual-
Contemporary veterinary clinical practice is the art and sci- ity in the context in which the evidence will be used. This
ence of providing optimal care for the animal in a context that approach, which is captured in the Grading of Recommen-
is consistent with the informed consent of the person respon- dations Assessment, Development and Evaluation (GRADE)
sible (owner) for the care, well-being, and use of that animal. process explicitly acknowledges that good clinical practice
These are two important considerations: the provision of opti- is complex and not solely based on the use of high-quality
mal care, which implies knowledge of what is best practice, evidence. Good clinical practice includes a consideration of
and provision of this care in a context in which the wishes and multiple factors such as the seriousness of the outcome, risk
resources of the owner are considered. Best practice increas- of adverse events, and preferences of the owner or trainer (or,
ingly relies on an awareness of the scientific and clinical litera- in human medicine, the patient; see later). GRADE provides a
ture on a specific topic and the ability to evaluate the reliability conceptual framework that involves a systematic and transpar-
of this information. This process has been called “evidence- ent approach to moving from the evidence to a recommen-
based veterinary medicine” (EBVM), and it underlies much of dation or decision while recognizing that the high quality of
modern veterinary clinical practice. This topic was previously evidence is a fundamental, but not the sole, basis for making
discussed in earlier editions of this textbook. strong recommendations for clinical practice.8,9
EBVM can be defined broadly as the dispassionate assess-
ment of the evidence underlying our approaches to diagnosis, Evidence-Based Veterinary Medicine: Arriving at
treatment, and control of diseases or conditions. This consid-
eration of the evidence is scientifically based and is intended a Recommendation
to provide objective assessment of the evidence leading to a There are three key components and five steps to arriving at
finding of the best intervention, diagnostic method, or means a recommendation using EBVM.1 The fundamental compo-
of control of a disease. The term evidence-based medicine nents of EBM are identifying and clearly stating the question,
(EBM) was proposed in human medicine in the early 1990s, assembling and evaluating the evidence through a systematic
and the concept was soon extended to veterinary medicine review, and considering the evidence in making a recommen-
including equine medicine. There is now a substantial body dation.10 These aims can be divided into five steps.1
of literature on human EBM and a smaller, but still impor-
tant, amount of literature on veterinary evidence-based Ask the Pertinent Question
medicine.1-7 All EBVM begins with asking the right question. The start of
The basis of EBM and EBVM is scientific in that both the any search for evidence must begin with a clear and concise
evidence and the method of assessing it are grounded in sci- response to “What is the question?” A common method of
ence. EBVM is an evaluation of the scientific evidence, as formulating the question is the PICO method: patient (animal
available in the published literature, using prescribed and pre- including species, age, sex, disease, and other demographi-
determined methodologies and criteria, as discussed further in cally or clinically defining characteristics), intervention (or
this chapter. What is often not clear is the role of clinical expe- diagnostic method or prophylaxis), comparator (the situation
rience in evaluating this scientific evidence. Early definitions to which the intervention is being applied, such as a placebo,
of EBM in human medicine explicitly included consideration different surgical or diagnostic technique), and the outcome of
of individual clinical expertise, but a definition of veterinary interest.10 A relevant question must include a consideration of
EBM referred to the “use of current best evidence,” imply- the setting (primary practice or referral hospital), the popula-
ing that individual, or collective, clinical experience is not a tion of interest (e.g., foals <5 months of age on a stud farm
basis for the application of the evidence.7 Although perhaps with endemic Rhodococcus (Prescottella) equi pneumonia), the
not the intended approach, exclusion of clinical experience intervention being applied (e.g., administration of azithromy-
would appear to be a limitation of the purely evidence-based cin), the comparator (e.g., administration of a placebo), and
approach to practice, and this is recognized in more current well-defined and measurable outcomes (e.g., survival at 300
definitions.1 days of age).11
218
CHAPTER 6 Clinical Epidemiology and Evidence-Based Medicine 219 219
The question should be framed in a very utilitarian con- This chapter will consider what represents evidence in vet-
text: the population, intervention, comparator, and outcomes erinary practice, how the quality of this evidence is assessed,
should all be practicable and available to the person seeking to and how this evidence can be used to inform the practice.
apply the recommendations arising from the evidence in their
particular setting. In particular, the outcome should be impor- What Is Evidence and What Is Quality of
tant to the patient, owner, or trainer. An irrelevant or trivial
outcome yields only low-grade evidence and at best enables Evidence?
recommendations that are weak or ineffectual. Evidence is an observation, fact, or organized body of infor-
mation offered to support or justify inferences or beliefs in
Acquire the Evidence the demonstration of some proposition or matter at issue.14
There are essentially two ways of sourcing evidence with which Evidence evaluated in EBVM is usually in written format and
to answer the question being considered: find evidence that is commonly in the form of a scientific article or report. How-
someone else has generated or generate the evidence (i.e., ever, it could be contained in a database, such as online colla-
do research) yourself. The latter approach is usually, but not tions of,15 or in hospital records or similar clinical databases.
always, restricted to academic institutions or large practices Not all evidence has the same usefulness (evidentiary value)
and often has a time frame of months to years. The former in informing our decision, and an important aspect of EBM is
approach involves going to the literature to find evidence that deciding on the evidentiary value of evidence in the context
someone else has created. This approach can be very efficient, in which you need it. High-quality evidence exists in publi-
compared with actually doing a research study yourself, but cations that describe studies of high quality and in which we
involves finding the relevant literature, evaluating its applica- have higher degrees of confidence that the results of the study
bility to your situation, and making an assessment of its quality. accurately reflect our reality. High-quality evidence gives con-
fidence that the results are repeatable, provides estimates of
Appraise the Quality of Evidence the effect of the intervention that are usefully narrow, and is
Generally, the strength of a recommendation for a particular consistent with other high-quality studies addressing the same
intervention is strongly correlated to the quality of the evi- question. Most important, information of high evidentiary
dence used to develop the recommendation.12 High-quality value is relevant to the practice situation and the question we
evidence (as defined later in this chapter) provides clear indi- are seeking to answer. For this reason, even the highest qual-
cations of the magnitude of the effect of the intervention on ity evidence of efficacy of an intervention in, for example,
the key outcome in the population of interest.10 It should also humans, dogs, or cats, has limited evidentiary value in equids.
include high-quality evidence of adverse effects or outcomes.
This then allows formulation of strong recommendations. Veterinary Scientific Literature
Weak or equivocal evidence or evidence from a population Perhaps the greatest single advance in veterinary medicine has
that is not relevant to the question does not provide the confi- been the increase in the amount of information and, presum-
dence to make strong recommendations. ably, the proportionate increase in knowledge. This increase
in the amount of information is most clearly demonstrated by
Apply the Evidence to Practice the 2.3-fold increase in the number of articles published each
Taking evidence and converting it to a practice situation is not year in the veterinary scientific literature (from 8815 in 1996
quite as easy as one might first think. For any particular ques- to 20,549 in 2014).16,17 Not only did the number of articles
tion there might be a body of evidence, some of it conflicting, and increase, but so did the number of veterinary journals indexed
often the body of evidence will have important gaps. These com- by Scopus (from 109 in 1996 to 211 in 2014), although this
plexities mean that rather than relying on the results of one study does not include all journals that publish veterinary mate-
(a much less than ideal situation), one must consider a diversity of rial.16-18 These increases are representative of the increase
evidence in formulating an answer to the question. The author’s in information available for equine veterinary science, with
answer, the recommendation, must be a synthesis of the evidence 123,146 equine-related articles published between 1996 and
and ideally considers factors other than just the quality of the 2014, rising from 2534 in 1996 to 7722 in 2014.19 There is
evidence. For instance, the recommendation should also include clearly an abundance of scientific literature in which we can
consideration of the cost of the intervention, its availability for seek answers to important clinical questions.
use in the population in question, the preferences of owners and The large increase in the volume of information creates
trainers, and the risk and severity of adverse effects or outcomes. some important challenges for practitioners and veterinarians
Systematic reviews of evidence do not, or should not, make seeking to use this information. These challenges include the
recommendations. A process that is additional to evaluating following:
the quality of evidence is needed to make recommendations • Identifying that the information exists: how does one find
applicable to clinical practice. This process has been formal- out that the relevant publications exist?
ized as the GRADE process in which the quality of evidence is • Sourcing the information: having identified that the infor-
considered along with a number of other factors (see later) in mation exists, how does one then access these publications?
arriving at a recommendation about an intervention.13 • Evaluating the information: is the information reliable, is it
valid, and does it apply to this particular circumstance?
Assessing the Efficacy of the Intervention • Using the information: how does one make sense of and ap-
A key component of any evidence-based approach to clinical ply the information that is related to a particular problem?
practice is evaluating if the intervention, diagnostic technique,
or prophylaxis was effective. This should ideally be done pro- Identifying That the Information Exists
spectively with metrics that provide evidence of the effect of The first challenge facing a veterinarian is to locate current
the intervention on the outcome of interest. information about the topic. There are various ways of doing
so, including sourcing information from colleagues, continu- Databases that index journals that publish articles relevant
ing education events or notes, scientific or clinical journals, to veterinary medicine include the following21,22:
textbooks, and Internet sources.20 • Agricola: Indexes the agricultural literature including top-
When presented with a difficult case, 44% of veterinarians ics such as animal science, cytology, feed science, microbi-
in the United Kingdom first sought advice from a colleague ology, and parasitology. Agricola is open access.25
(not a specialist), and 23% consulted a textbook.20 Accessing • Biological Abstracts: As the major index for life sciences
information in publications was less important to veterinar- literature, Biological Abstracts covers bioengineering, bio-
ians, with fewer than 5% seeking information in scientific technology, microbiology, and other areas of biology.26
articles. Equine veterinarians in the United Kingdom most • CAB Abstracts: Indexes the veterinary medical literature
frequently read the journal In Practice (81%), which publishes more completely than any other database.18 CAB Abstracts
only commissioned, peer-reviewed articles; the peer-reviewed contains records from more than 8000 journals, conference
Veterinary Record (75%) and Equine Veterinary Education proceedings, and books. It can be accessed through the fol-
(43%); and nonpeer-reviewed material in the Veterinary Times lowing platforms: CAB Direct (Center for Biosciences and
(79%) and UK Vet (49%). This usage is likely a reflection of Agriculture International [CABI]’s own platform), Dialog,
the availability of these publications, with the Veterinary Times Dimdi, EBSCO, OvidSP, STN International, and Thomson
and UK Vet being free resources, the Veterinary Record and Web of Knowledge. In 2012 CAB Abstracts indexed almost
In Practice included as part of membership of the British Vet- all the principal veterinary journals (98%) and 90% of jour-
erinary Association (BVA), and Equine Veterinary Education nals that include any veterinary content.18,27
included as part of membership of the British Equine Veteri- • CONSULTANT: This is a database of animal diseases in-
nary Association.20 Uncertainty about how to identify suitable dexed and searchable by diagnosis or clinical signs. Out-
information through Internet-based searches, limited access comes of a search include citations of selected scientific
to publications, and esoteric content (for practitioners) of articles. CONSULTANT is open access.28
many scientific articles could be reasons for limited uptake of • Embase: This an Elsevier product that offers additional
information from scientific journals. tools for compiling systematic reviews. As of 2012 it in-
dexed 85% of the principal veterinary journals and 38% of
Veterinary Literature Database journals that publish any veterinary content.18,29
Until late in the last century, sourcing information in the • Google Scholar: This is a search engine provided by Google
scientific or peer-reviewed clinical literature was only that searches the scholarly literature. It, and Google, are
achieved by physically visiting scholarly libraries and pour- frequently used sources of information for veterinary stu-
ing through printed indices (Index Veterinarius), consult- dents and veterinarians in practice.20,30 Google Scholar
ing specialized textbooks or tomes, and scouring the index searches provide different results from PubMed searches in
of scientific journals. Sourcing of information has changed the human literature, often missing the “gray” literature of
markedly with the availability of specialized veterinary abstracts and conference proceedings.31-35 Use of Google
electronic databases and almost universal access to the Scholar is free, but there is no information about the pro-
Internet and search engines. However, access to special- portion of veterinary journals that it indexes or locates.
ized databases and many scientific journals is limited to Google Scholar is open access.36
academics and those who choose and have the financial • MEDLINE: Indexes roughly 100 veterinary medical jour-
resources to subscribe to these resources. Although there is nals, but overall coverage of veterinary science is mediocre
greater availability of open access journals, which make the with the database covering approximately 82% of the prin-
articles they publish available without payment by readers, cipal veterinary journals and only 37% of journals that pub-
most veterinarians rely on nonspecialized sources identi- lish any veterinary content.18 Notable journals not covered
fied using search engines.20 For instance, 71% of veterinar- by MEDLINE include Advances in Veterinary Dermatology,
ians in the United Kingdom rely on Google searches as Equine Veterinary Education, Veterinary Economics, and
their primary source of electronic veterinary information, Veterinary Medicine.37
although not surprisingly veterinarians in academia prefer • PubMed: The overlap between PubMed and MEDLINE is
PubMed (which is also available to the public).20 The con- roughly 98% with PubMed including life science journals
cern with accessing information from the Internet is that that submit full text to PubMed Central and additional arti-
the source, while ostensibly authoritative, might not be cles in journals that are selectively indexed by MEDLINE.21
so. This is balanced with the ease with which the informa- PubMed Central is a free online archive of the biomedical
tion can be accessed. Finding the answer will involve using and life sciences literature.38
information sources that provide reliable, contemporary, • Scopus: This database, owned by Elsevier, in 2012 covered
and current information or guidance. almost all the principal veterinary journals (98%) but only
There are a number of databases that cover topics in 58% of journals that publish any veterinary content.18,39
veterinary medicine and related fields.21,22 Many of these • SPORTDiscus: This is the major database for sports medi-
databases restrict access by requiring a subscription, such cine. It covers horse biomechanics, medicine, and physiology.
as through a university library or institution, and are not • VetMed Resource: Produced by CABI Abstracts, this data-
readily accessible to veterinarians in practice. However, a base and resource center includes all CAB Abstracts of [?]
number of professional organizations, such as the American veterinary-related records for journals and conference pro-
College of Veterinary Internal Medicine,23 have agreements ceedings. The VetMed Resource is marketed to practicing
that provide access to these databases by their members. veterinarians and includes an attractive and useful landing
Access to relevant databases by practicing veterinarians is an page, continuous alerts to recent articles, ready access to full
impediment to use for EBVM in clinical practice outside of text sources, information about continuing education, and
universities.24 the capacity to create user profiles (as do some other sites).40
• V etSRev: This is a database of systematic reviews of the 21 veterinary conferences including the American College of
veterinary literature. It is useful for identifying reviews on Veterinary Internal Medicine (ACVIM) Forum. VIN is a com-
particular topics.41 mercial product marketed to practicing veterinarians.48
• Web of Science: Indexes the major journals in biomedicine, A list of libraries holding collections of veterinary literature
the sciences, and engineering including, as of 2012, 93% of is available from Veterinary Medical and Related Libraries: An
principal veterinary journals and 53% of journals that pub- International Directory (http://vmls.mlanet.org/libraries).
lish any veterinary content.18,42
• Wikipedia: This also contains articles that address veteri- Evaluating the Quality of Evidence
nary topics. The articles are not primary source research Confidence in an evidence-based approach to veterinary prac-
articles, do not have an identified single author or identified tice depends on our assessment of the quality (evidentiary
groups of authors, and are sometimes unreliable or asser- value) of the available evidence.49 The higher the quality of
tions are not verified. The articles are publicly curated.43 evidence, the greater confidence we have in recommendations
derived from this evidence. Assessing the quality of evidence
Searching the Literature is not simple and must involve the consideration of a combi-
Regardless of the database used, key to identifying relevant lit- nation of factors including the design of the study, with some
erature is formulating an effective search strategy. Briefly, an study designs being considered more likely to provide high-
effective search strategy involves clearly defining the purpose quality evidence (e.g., a randomized, controlled trial [RCT]
of the search, which can usually be framed in terms of PICO.22 compared with a case report); the rigor of the design, conduct
For instance, searching for articles on the effectiveness of the and reporting of individual studies, with studies that are con-
use of ponazuril compared with pyrimethamine in treatment sidered likely to provide high-quality evidence being “rated
of horses with clinical signs consistent with equine protozoal down” because of flaws in the design of the individual study;
myeloencephalitis can be framed as P, equine; I, ponazuril; and the journal or format in which the study is published, with
C, pyrimethamine; and O, protozoal myeloencephalitis. This some scientific journals being of higher reputational value
search yields four articles dealing with the use of ponazuril than others and, by implication, publishing articles that are of
to treat equine protozoal myeloencephalitis. Further details higher evidentiary value.
on effective search strategies in veterinary medicine are avail- Grading Quality of Evidence. There are a number of meth-
able in publications dealing with this important topic.1,2,7,22,44 odologies, and reporting scales, that are used to categorize
Search techniques useful for identifying evidence in human the quality of evidence. All scales are ordinal; thus, they rank
medical literature are not sufficiently sensitive (detect a the quality of evidence. A relatively simple but effective series
sufficient proportion of the articles) for use in veterinary of definitions of varying quality of evidence is provided by
medicine.45 GRADE13:
• High: Further research is very unlikely to change our confi-
Sourcing the Information dence in the estimate of the effect (i.e., the magnitude, pre-
Accessing information in scientific publications can be chal- cision, and direction of the effect of an intervention).
lenging for veterinarians who are not associated with univer- • Moderate: Further research is likely to have an impact on
sities or similar institutions that have subscriptions to large our confidence in the estimate of the effect (magnitude,
numbers of veterinary and other journals. Most scientific precision, and direction) and might change the estimate.
journals require a subscription to access articles that they pub- • Low: Further research is very likely to have an important
lish or they provide access to individual articles at a cost per impact on our confidence in the estimate of effect and is
article (often $25 or more). Other journals charge authors to likely to change the estimate.
publish and then make their articles freely available to read- • Very low: Any estimate of the effect is very uncertain.
ers (so-called open access publishing). The availability of jour- This methodology for ranking the quality of evidence is par-
nals publishing open access articles of interest to practicing ticularly important in conducting systematic reviews and
veterinarians is increasing, and a catalog of journals that pro- forming guidelines for practice.
vide free access to readers is available at the Directory of Open Journal Reputation and Article-Level Metrics. Veterinary
Access Journals.46 scientific journals do not all have the same reputational value;
Journals that publish veterinary topics and provide open some are considered to commonly publish articles of higher
access to articles include Acta Vet Scandinavica, BMC Vet- scientific merit. This reputational value has been based on the
erinary Research, Equine Disease Quarterly, Frontiers in Vet- “impact factor” developed and reported annually by Thom-
erinary Science, Irish Veterinary Journal, Journal of Veterinary son Reuters as Journal Citation Reports.50-52 Scopus provides
Internal Medicine, PLoS One, Veterinary Record Open, and a similar ranking of journal impact factor (journal analytics)
Veterinary Research, among others. Articles that are available using slightly different methods of calculating impact.53 Im-
through open access can be accessed through searches of data- pact factor is calculated by dividing the number of citations
bases, including using VetSRev or CONSULTANT. PubMed to articles that were published in a 2-year, 3-year, or 5-year
Central is a repository of open access articles that contains period by a journal by the number of articles published by
many veterinary articles.38 that journal during a defined period. For example, if a jour-
The International Veterinary Information Service (IVIS) is nal received 800 citations to articles it published during a
an online publisher of veterinary books and proceedings. The 2-year period, and during that time the journal published
IVIS website currently includes 1673 book chapters and pro- 400 articles, the impact factor would be 800/400 = 2. This is
ceeding articles and access is free.47 It does not publish articles the average number of citations per article published in that
describing primary scientific research. Similarly, the Veteri- journal and is considered to be a metric of the influence of
nary Information Network (VIN) indexes more than 150 core the journal; it is not a measure of the impact of individual
veterinary journals and publishes the proceedings of at least articles or of each article’s evidentiary value. Other, more
sophisticated indices take into account the quality of journals comment it attracts, and the number of links to online ref-
that cite articles in a particular journal (assessing quality of erencing services provide other metrics that could indicate
a journal by the company it keeps), whereas others attempt the influence of an article.50 However, the link between these
to normalize or account for variations in citation rates across article-level metrics and the quality of evidence is unknown;
disciplines. The usefulness of these metrics as surrogates for more frequently downloaded or commented on articles might
the quality of individual or particular articles in a journal is not provide higher quality of evidence.
quite limited. Appraising the Evidentiary Value of an Individual Article.
There are a number of shortcomings in using the impact Articles are considered to have a certain evidentiary value
factor to assess the quality of evidence of individual articles. by virtue of their overall study design (see the later section
Importantly, articles in clinical areas in human medicine, and “Study Design and Evidentiary Value”). This initial rating of
especially those describing therapeutic interventions, receive evidentiary value is based on the assumption that the indi-
fewer citations than do articles describing basic biomedi- vidual article conforms with the highest standards in terms
cal research or diagnostic testing.54 Citation counts are not of conduct and reporting of the study and that the study pa-
evidence of research impact on clinical applications, public tients, intervention, comparator, and outcomes are those of
health outcomes, or meaningful health outcomes in human interest to the person seeking the evidence. Unfortunately,
medicine, nor do high citation counts provide evidence of a this is frequently, indeed mostly, not the case, and the evi-
higher quality of research or greater influence.50 It is likely dentiary value of individual articles must be considered in
that a similar situation exists in veterinary medicine and that the context of the features of that study. This usually involves
articles with high clinical utility and providing high quality of decreasing the evidentiary value of an article, although
evidence for clinically important topics are not always more GRADE provides for a mechanism for increasing the value
frequently cited. Furthermore, for articles in veterinary jour- of some very well-conducted and reported observational
nals there is no association between the number of citations studies.
to an article and the level of evidence of the study design of Critical appraisal of an article is a systematic process that
that article.55 The impact factor ranking of the journal and the aims to identify the strengths and weaknesses of the publica-
number of citations to an individual article are generally not tion.56 Critical appraisal is the basis for deciding on the use of
important factors to consider when determining the eviden- the article by clinicians. Evaluation of the quality of an indi-
tiary value of an article. vidual article often requires some expertise or understanding
Article level metrics, such as the number of times an article of experimental design and statistics and the recognition that
is downloaded or viewed online, the amount of social media different study designs are prone to particular weaknesses
TABLE 6.1 Summary of Strengths and Limitations of Various Types of Studies Included in the Veterinary Literature
Study Type Strengths Limitations
Systematic Involves use of the full body of literature to estimate Restricted to combining studies with a similar design and
review or the direction and magnitude of effect of potential duration of follow-up (meta-analysis)
meta-analysis risk factors, protective factors, and interventions Findings subject to publication bias
of randomized, Provides analytic methods to estimate magni-
controlled trials tude of effect and degree of certainty
Randomized, Allows good control for bias and confounding Involves restrictive study population and environment that
controlled trials Provides the strongest evidence for cause-and- can limit generalizability of results to real-word settings.
effect relationships Allows testing of few variables
Often involves a brief follow-up period between interven-
tions and outcome assessment
Involves experimentally induced (not naturally occurring)
disease in some situations
Retrospective Involves use of real-world population and envi- Can be prone to selection bias, information bias, and
or prospective ronment confounding
cohort study Able to test a large number of risk factors pro- Can be expensive to conduct prospectively because of the
vided the study population is sufficiently large long follow-up period between factors or exposures and
Able to test for effect of uncommon risk factors outcomes
Allows prolonged follow-up period between fac- Subjects can be lost to follow-up when conducted
tors or exposures and outcomes prospectively
Dependent on quality of case records
Case-control Involves use of subjects from real-world popula- Highly prone to selection bias, information bias, and con-
study tions and environments founding
Can be used to investigate risk factors for un- Relies on accuracy and completeness of historical records
common diseases while involving few animals Does not provide evidence for causation because timing
Less expensive to conduct than randomized, of exposure to risk factors is different from that of the out-
controlled trials and prospective cohort studies come of interest
Can generate questions that can be investigated Occurrence of risk factors and outcomes is unclear
by use of study types with better control for
bias and confounding
TABLE 6.1 Summary of Strengths and Limitations of Various Types of Studies Included in the Veterinary Literature—cont’d
Study Type Strengths Limitations
Cross-sectional Involves use of subjects from real-world popula- Can be prone to selection bias, information bias, and
study tions and environments confounding
Often inexpensive to perform Does not provide evidence of causation because chronol-
Results can be used to generate hypotheses ogy of exposure to the risk factor(s) differs to that of the
or objectives that can be investigated in other outcome
studies
Case reports or Useful for reporting rare diseases or novel A descriptive account of clinical findings
series potential treatments or interventions Inconsistent format results in variable quality of reporting
Inexpensive Does not control for bias or confounding
Results can generate questions that can be Do not provide evidence of proof; the intervention might
studied in other formats involving larger popu- not have had the effect that was observed
lations or more controlled study conditions.
Induced disease Demonstrates clinical signs and diagnostic fea- Does not replicate full range of conditions occurring in the
in species of tures of the disease naturally occurring disease that might affect efficacy of
interest Enables testing of accuracy of diagnostic tests treatment, disease progression, or accuracy of diagnostic
or efficacy of therapeutic interventions in con- tests
trolled conditions Expensive to conduct
Concerns about animal welfare
Physiologic Provide understanding of mechanisms of dis- Do not provide evidence of risk factors or outcomes for
studies or in ease naturally occurring disease
vitro studies Usually high quality with internal validity (good Require cautious and considered extrapolation to naturally
experimental design) occurring disease
Readily reproduced
Consensus Useful for providing narrative summary of a topic Variable quality of reporting of methodology; hence, they
statement and compiled by a panel of experts provide evidence or recommendations of variable quality
guidelines Provides guidance on topics that are conten- Expert panel is often self-appointed
tious Subject to group think bias
Provides best assessment of available evidence Often do not differentiate between systematic reviews, which
should not provide recommendations, and guidelines
Expert opinion Provides considered opinion of an expert, or Unreliable or unknown evidence base and subject to bias
self-appointed expert, in the field Not subject to peer review or critique by peers

Modified from Larson RL, White BJ. Importance of the role of the scientific literature in clinical decision making. J Am Vet Med Assoc. 2015;247:58–64.
(Table 6.1). A series of “filters” can be applied when deciding if the quality of studies are available including a comprehensive
an individual article is likely to be useful and are based on the set of tool kits and guides from the Critical Appraisal Skills
following questions: (1) Is the study valid?, (2) What are the Programme (CASP).59
results?, and (3) Are the results of use to me?57-59: Quality of Reporting of Studies. Fundamental to the eval-
1. Decide on the question, preferably using the PICO format, uation of the quality of the study described in an article is that
and conduct the literature search. the details of the study are reported in sufficient detail that the
2. Review each article’s title and abstract to decide if the topic reader can evaluate the validity of the study. This realization
of the article is relevant to your question. If the topic is rel- has led to the development and use of reporting guidelines.
evant, proceed to the next step; if not, discard the article. These guidelines, which are tailored to particular study de-
3. Review the results of the study. If correct, will they change signs, provide advice and direction on optimal reporting of the
your current practice or inform your decision in a mean- study. There is evidence in the veterinary literature that inade-
ingful way? If not, discard the article. If so, proceed to the quate, or poor, reporting of the details of studies is significant-
next step. ly associated with reports of positive outcomes in the study.60
4. Review the materials and methods for appropriate study This result implies that imperfectly or inadequately reported
design (controls, randomization, interventions, blinding, studies are more likely to report positive effects or estimates
etc.) and control of bias and confounding factors. If these that are not reliable. Guidelines for reporting are useful to edi-
are not adequate, discard the article. If they are of accept- tors, reviewers, and readers in assessing the completeness of
able standards, proceed to the next step. reporting and, therefore, the quality of the article and evidence
5. Review statistical handling and reporting of data. If they it contains.61,62 For example, the CONSORT checklist provides
are adequate, proceed to the next step. a means of assessing quality and completeness of reporting
6. Interpret the findings of the study in the light of your par- of randomized clinical trials (Table 6.4),63 and the Preferred
ticular clinical context. Reporting Items for Systematic Reviews and Meta-Analysis
The previous six points provide a rudimentary guide to evalu- (PRISMA) guidelines provide a structure for conducting and
ating a single article. More detailed guidelines for appraising reporting systematic reviews (Fig. 6.1).64
Identification
Records identified through Additional records identified
database searching through other sources
(n = ) (n = )
Records after duplicates removed

(n = )
Screening
Records screened Records excluded

(n = ) (n = )
Eligibility
Full-text articles assessed Full-text articles excluded,

for eligibility with reasons
(n = ) (n = )
Studies included in
qualitative synthesis
(n = )
Included
FIG. 6.1 Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) flow diagram for
inclusion of articles in systematic reviews.74
There are a large number of reporting guidelines (>317) RCTs are initially categorized as “high quality,” and obser-
with a small number tailored for the veterinary literature vational studies are initially categorized as “low quality.”67
(REFLECT65 and STROBE-vet). Guidelines are available at the The categorization of an RCT can be decreased by at least
EQUATOR network site.66 one level (to “moderate”) if there are particular methodo-
Study Design and Evidentiary Value. The design of logical problems with the RCT and that of an observational
studies reported in the veterinary literature varies, but they study increased by up to two levels (to “high”) if the evi-
can be grouped broadly into one of nine categories (see dence from the observational study is particularly strong.
Table 6.1). The conventional view is that not all study de- Using the GRADE approach, some observational stud-
signs are of equal merit or utility and that the type of study ies might provide higher quality evidence than do some
design should be considered when evaluating the quality RCTs.
of the evidence derived from that article. This view, which The Oxford hierarchy of evidence has been modified and
is held steadfastly by some authorities, provides for a hier- revised by numerous authors to fit the veterinary context and
archy of quality of evidence based on overall study design can be restated as follows1,7:
(Table 6.2).7 Others contend that evidence can be under- • Systematic review including meta-analysis
stood not as being ordered by methodology but rather in • Systematic review of RCTs
the context of its use and method of its production.14 An • RCTs performed under field conditions
intermediate view is presented by the GRADE process, • Nonrandomized trials, cohort studies, or models of in-
which while allocating an a priori ranking (high, moderate, duced disease in the species of interest
low, and very low) based on the design of studies, allows • Case-control or cross-sectional studies
for the quality of evidence of a particular study, or group of • Case reports and case series
studies, to be revised up or down (Table 6.3). For instance, • Expert opinion/editorials
TABLE 6.2 Levels of Quality of Evidence TABLE 6.3 Methodology for Assigning the Grade of Quality of
Evidence for Individual or Groups of Studies13
Level of Evidence Method
1a Systematic review (with homogeneity A priori evidence grade based on study design:
of outcomes and narrow confidence • Randomized trial = high
intervals around consistent effects of the • Observational study = low
intervention) of RCTs • All others = very low
1b Individual RCT (with narrow confidence in- Decrease grade of evidence if the following are evident in
terval about the effect of the intervention) the study:
• Serious (−1 grade) or very serious (−2) limitations to
1c All or none: met when all patients died
study quality
before the intervention became available,
• Important inconsistency with other studies (−1)
but some now survive on it, or when
• Some (−1) or important (−2) uncertainty about directness
some patients died before the intervention
• Imprecise or sparse data
became available, but none now die on it
• High probability of reporting bias (−1)
2a Systematic review of cohort studies dem-
Increase evidence grade if
onstrating homogeneity of outcomes or
• There is evidence of a strong association–significant
effect measures
relative risk of >2 or <0.5 based on two or more observa-
2b Individual cohort study or low-quality RCT tional studies with no plausible confounding (+1)
2c “‘Outcomes”’ research such as audit • Evidence of very strong association–significant relative
studies risk of >5 or <0.2 based on direct evidence with no major
3a Systematic review of case-control studies threats to validity (+2)
demonstrating homogeneity of out- • An evident dose:response gradient (+1)
comes or effect measures • All plausible confounders would have reduced the effect (+1)

3b Individual case-control study
Notes: Inconsistency refers to lack of similarity of estimates across a number
4 Case-series or poor quality cohort and of studies, which then reduces confidence in estimates of effect for that
case-control studies outcome. Directness refers the extent that patients, interventions, and
5 Expert opinion without explicit critical ap- outcomes are similar to those of interest.13
praisal, or based on physiology, bench
research, or “first principles” studies do not include numeric or statistical analysis and can-

not report on formal assessments of risk factors or effects of
RCT, Randomized, controlled trial.
Modified slightly from the evidence hierarchy of the Oxford Centre For Evidence- interventions. Examples of descriptive studies include case
Based Medicine. Anon. Oxford Centre for Evidence-Based Medicine: levels reports and case series and some types of cross-sectional
of evidence (March 2009). http://www.cebm.net/oxford-centre-evidence- studies.
based-medicine-levels-evidence-march-2009/; 2016. Accessed 9 May 2017. Descriptive Observational Studies (Case Reports and Case
Series). Case reports provide a detailed description of a small
number (usually 1–3) of cases with no attempt to formally
• A nimal models of the disease of interest (induced disease identify common characteristics of the cases beyond one fac-
in species other than the species in which the disease oc- tor (such as the diagnosis or presenting signs). Reports of a
curs naturally, e.g., mouse model of a disease in horses) series of cases (usually >3) can attempt to subjectively identify
• In vitro studies with an appropriate control group common characteristics, such as breed, sex, predisposition to
The characteristics and evidentiary value of publications in vet- the disease, or outcome, in a series of nonrandomly selected
erinary medicine and veterinary science vary and can be catego- cases. These reports can be useful in identifying new diseases
rized as described in Table 6.1. They can be further differentiated or rare adverse effects with treatments but without providing
as being of either experimental or observation study designs.7,68 definitive evidence of these associations.
The shortcomings of observational descriptive studies are
Observational Studies the high risk of selection bias or confounding caused by the
Observational studies are those in which there is no interven- nonrandom availability of cases and case records. Selection
tion by the investigators. Data are obtained by simply observ- bias occurs because the investigators cannot take measures to
ing and recording events without any attempt to impose increase the likelihood that cases included in the study reflect
interventions that could alter the course of events. There is no the larger population of cases. For instance, reports of out-
experimental aspect to observational studies in that there is comes of cases treated at a referral hospital might have little
no testing of a hypothesis. These studies are solely based on similarity to outcomes of cases of the same disease treated in
observing details about a case or series of cases, or groups ambulatory practice. The quality of observational studies can
of animals, and summarizing associations among variables. also be impaired by the quality of record keeping, especially
Observational studies can be descriptive or analytic. in retrospective studies, and the often high frequency of miss-
Descriptive studies are useful in providing information on ing data. Results of case reports or case series are usually not
the presentation of disease including such information as clin- generalizable to a larger, or different, population of animals
ical signs, outcomes, or simply that the disease occurs. They and have limited external validity. Indeed, the characteristics
do so by observing events and recording facts, often in a ret- of the case or cases might not be representative of the more
rospective fashion using medical or other case records or, less common or important manifestations or outcomes of the
frequently, in prospective studies. Observational descriptive disease.
TABLE 6.4 CONSORT Checklist for Reporting of Randomized, Controlled Clinical Trials63
Reported on
Section/Topic Number Checklist Item Page Number
TITLE
Title 1 Identify the report as a systematic review, meta-analysis, or both
ABSTRACT
Structured 2 Provide a structured summary including, as applicable, background; objectives; data
summary sources; study eligibility criteria, participants, and interventions; study appraisal and
synthesis methods; results; limitations; conclusions and implications of key findings;
and systematic review registration number
INTRODUCTION
Rationale 3 Describe the rationale for the review in the context of what is already known
Objectives 4 Provide an explicit statement of questions being addressed with reference to partici-
pants, interventions, comparisons, outcomes, and study design (PICOS)
METHODS
Protocol and 5 Indicate if a review protocol exists, if and where it can be accessed (e.g., web ad-
registration dress), and, if available, provide registration information including registration number
Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteris-
tics (e.g., years considered, language, publication status) used as criteria for eligibility,
giving rationale
Information 7 Describe all information sources (e.g., databases with dates of coverage, contact with
sources study authors to identify additional studies) in the search and date last searched
Search 8 Present full electronic search strategy for at least one database, including any limits
used, such that it could be repeated
Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic
review, and, if applicable, included in the meta-analysis)
Data collection 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in
process duplicate) and any processes for obtaining and confirming data from investigators
Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources)
and any assumptions and simplifications made
Risk of bias 12 Describe methods used for assessing risk of bias of individual studies (including
in individual specification of whether this was done at the study or outcome level) and how this
studies information is to be used in any data synthesis
Summary mea- 13 State the principal summary measures (e.g., risk ratio, difference in means)
sures
Synthesis of 14 Describe the methods of handling data and combining results of studies, if done,
results including measures of consistency (e.g., I2) for each meta-analysis
Risk of bias 15 Specify any assessment of risk of bias that may affect the cumulative evidence (e.g.,
across studies publication bias, selective reporting within studies)
Additional 16 Describe methods of additional analyses (e.g., sensitivity or subgroup analyses,
analyses metaregression), if done, indicating which were prespecified
RESULTS
Study selection 17 Give numbers of studies screened, assessed for eligibility, and included in the review,
with reasons for exclusions at each stage, ideally with a flow diagram
Study charac- 18 For each study, present characteristics for which data were extracted (e.g., study size,
teristics PICOS, follow-up period), and provide the citations
Risk of bias 19 Present data on risk of bias of each study and, if available, any outcome level assess-
within studies ment (see Item 12)
Results of indi- 20 For all outcomes considered (benefits or harms), present, for each study (a) simple
vidual studies summary data for each intervention group, (b) effect estimates and confidence inter-
vals, ideally with a forest plot
Synthesis of 21 Present the main results of the review
results If meta-analyses are done, include for each confidence intervals and measures of
consistency
Risk of bias 22 Present results of any assessment of risk of bias across studies (see Item 15)
across studies
Additional 23 Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses,
analysis metaregression [see Item 16])
TABLE 6.4 CONSORT Checklist for Reporting of Randomized, Controlled Clinical Trials63—cont’d
Reported on
Section/Topic Number Checklist Item Page Number
DISCUSSION
Summary of 24 Summarize the main findings including the strength of evidence for each main out-
evidence come; consider their relevance to key groups (e.g., health care providers, users, and
policy makers).
Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias) and at review level
(e.g., incomplete retrieval of identified research, reporting bias)
Conclusions 26 Provide a general interpretation of the results in the context of other evidence and
implications for future research
FUNDING
Funding 27 Describe sources of funding for the systematic review and other support (e.g., supply
of data) and role of funders for the systematic review

A particular type of observational study is a cross-sectional controls. As with other retrospective observational studies,
description of cases in a population at a single point in time. data quality can be limiting.
These studies provide a one point in time estimate of preva-
lence and can attempt to identify risk factors if both cases and Experimental Studies
controls are included in the study; however, there is consid- Experimental study designs are those in which the investigator
erable risk of selection bias and of confounding (in which a chooses the animals being studied and assigns the interven-
third, perhaps unidentified, variable influences the effect of tion to a proportion of the study population. By manipulat-
another variable on the outcome of interest). Cross-sectional ing one variable, the aim is to establish a causal relationship
studies can be inexpensive to undertake. Surveys are a form of by measuring the outcome or dependent variable. Typically,
cross-sectional study.7 experimental studies involve a group of animals to which the
Analytic Observational Studies. This type of study design new intervention is applied, a control group that might receive
is often useful when studying naturally occurring diseases. an alternative intervention, or no active intervention (placebo)
Common designs in veterinary medicine are cohort and case- with random assignment of animals to each group. This design
control studies.7 attempts to minimize the effect of known or unknown factors,
A cohort study is a type of longitudinal study that is commonly other than that of the interventions, on the outcome. The best
used to study associations between naturally occurring exposure justification for placing RCTs at the top of evidence hierarchies
to a putative risk factor for disease and subsequent development for individual studies is that RCTs minimize certain forms of
of disease. Another variation is to look at responses to different bias, especially selection bias, therefore producing the best evi-
therapeutic interventions. In either case, an initial population dence of a treatment effect or of causation.
of animals is identified and then animals in that population are RCTs in equids can be conducted under laboratory condi-
categorized as exposed to the particular risk factor of interest tions, usually with induced disease, or as clinical trials using
or not and their progression to disease determined. Similarly, a animals with naturally occurring disease.7 When evaluating
population of animals with a particular disease might be divided an RCT for quality of evidence, it is important to consider
in two or more groups, each of which receives a different treat- the relevance of the intervention, the population being stud-
ment. The outcomes of each group are then compared. Cohort ied (especially if the study uses induced rather than naturally
studies can be retrospective or prospective. occurring disease), and the setting (field service versus refer-
Prospective cohort studies can require long time periods to ral clinic). RCTs using experimental animals are efficient and
complete if there is a delay between exposure and appearance of effective to perform and provide for strict control of poten-
disease. Retrospective cohort studies are relatively inexpensive tially confounding factors. Such experimental trials might not
to conduct because they use already collected data, often in the mimic or replicate the condition or disease in the field, and
form of medical records. However, a disadvantage of retrospec- care should be taken extrapolating results of these studies to
tive cohort studies is that the data were collected for purposes animals with naturally occurring disease. Conversely, RCTs
other than research; thus, information relevant to the study may conducted in the field are often highly relevant to animals with
not have been recorded. Cohort studies do not permit blinding, naturally occurring disease but are more challenging to per-
and matching of animals in each group of factors other than the form than laboratory studies.7
risk factor of interest can be difficult. Prospective cohort study RCTs should include blinding (masking) of those investi-
results should be reported as relative risk, and retrospective gators who determine which treatment an animal receives, of
cohort studies should be reported as odds ratios. those administering the treatments, and those evaluating the
The case-control study is retrospective in that cases are iden- outcomes of the intervention to minimize the likelihood of
tified and then matched with animals that did not develop the conscious or unconscious bias.
disease. The records of each group are then examined to iden- RCTs are also parsimoniously powered to get answers
tify risk factors that differ between cases and controls. Case- related to the efficacy of the intervention on the outcome,
control studies are relatively inexpensive and easy to perform, which is usually treatment of a disease. As a result, RCTs and
but they do not usually allow for control of confounding vari- meta-analyses that use them are often underpowered to detect
ables because of the difficulty in closely matching cases and infrequent or rare adverse effects.69
Synthesis of Evidence: Reviews A systematic review therefore provides a dispassionate assess-

The wealth and volume of veterinary scientific literature have ment of the published evidence on an issue. It makes an assess-
both prompted and enabled individuals or groups to attempt ment about the quality of evidence and, in doing so, enables
to provide a considered synthesis of information on a par- readers to weigh the use of the evidence as they decide on the
ticular topic. The purpose of such reviews is to take the pri- answer to their clinical question. Systematic reviews consider
mary literature and create a generalizable understanding of only the quality of the evidence and do not provide a meth-
the disease or intervention on the assumption that compiling odology for taking the next step, which is that of making a
information from a number of studies will provide more reli- recommendation on use of the evidence.
able information than that from one study alone. Although
there are at least 14 forms of review identified in the library From Evidence to Recommendation:
literature, most reviews in the veterinary literature are nar-
rative (integrative) or systematic (aggregative) reviews or Practice Guidelines
meta-analyses.70,71 The most common form of this informa- The approach of using evidence to guide clinical decision
tion synthesis in veterinary medical literature is the narrative making has been formalized in the past two decades in
(integrative) review. Detailed descriptions of these types of human medicine and is gaining traction in veterinary prac-
reviews, including strengths and weaknesses, are available tice. As veterinary clinicians we have ethical and legal obli-
elsewhere.70 gations to use methods and practices that are most likely to
Narrative Review. Narrative, or otherwise known as in- provide the “best” outcomes for the animals we treat and
tegrative, reviews seek to bring together the literature on a their owners. A traditional approach to deciding on the
particular topic, not with the intention of answering a specific “best” treatments, diagnostic tests or methods, and preven-
question or questions but rather to provide a commentary on tive measures has been to identify the highest quality evi-
the results of the available primary studies on the topic. These dence of effectiveness and to adopt the approach with the
types of reviews, which are typical of textbooks or review strongest evidence of efficacy. The Cochrane collaboration
articles in journals, are often useful summaries of a body of and the Cochrane reviews exemplify and lead this approach
literature. Such reviews do not typically include an explicit in human medicine.76
methodology, such as how the literature search was conduct- This “evidence-based” approach has the implicit assump-
ed, how evidence was appraised, and how articles were includ- tion that one should rely on the highest quality evidence and
ed or excluded. As such, narrative reviews might not consider that high-quality evidence of efficacy necessarily leads to the
all the available literature on a topic. Lack of a predetermined adoption of that treatment, diagnostic test, or prophylaxis.
methodology also increases the possibility of conscious or However, this approach falls short when formulating recom-
unconscious bias in the inclusion of primary studies in the mendations for use in clinical practice. What practitioners
review or the interpretation of results. Authors of narrative re- need are recommendations that are based on the available
views are often self-selected and might, or might not, be expert evidence but that also take into account the other factors that
in the topic of the review. The author’s reasons for writing the must be considered when advising an owner or trainer on the
review might not be revealed to readers. “best” approach to dealing with their animal’s (and their) prob-
Systematic Reviews. The highest quality evidence is pro- lem. Clinical practice guidelines are statements that include
vided by systematic reviews, which might include a meta- recommendations intended to optimize patient care that are
analysis. Systematic reviews differ from narrative reviews, informed by a systematic review of evidence and an assess-
which have much lower evidentiary value, in that systematic ment of the benefits and harms of alternative care options.77
reviews are approached in a manner and with methodology Importantly, development of practice guidelines (recommen-
designed to ensure the validity of the conclusions.70 System- dations) includes both a systematic review and consideration
atic reviews should be based on a clearly defined question of the trade-offs between benefits and harms.77
and prespecified criteria for inclusion and evaluation of the Although an analysis of the quantitative literature, such as
literature, among other factors. Criteria and methodology RCTs, is important, it is also important to consider the litera-
for performing systematic reviews are available.44,72,73 The ture describing more qualitative outcomes. This literature can
PRISMA statement provides a widely, although not univer- be evaluated according to four criteria, each of which has five
sally, used methodology for reporting systematic reviews, grades (Table 6.5). The criteria are feasibility, appropriateness,
including a recommended flowchart and reporting checklist meaningfulness, and effectiveness.78
(see Fig. 6.1).64,74,75 The recognition that systematic reviews of the literature are
Systematic reviews should be methodologically rigorous an essential but not the sole, or best, means for making recom-
assessments of the literature and should not make recommen- mendations for interventions resulted in the development of
dations on clinical practice.12 The fundamental characteristics the GRADE process.79 GRADE works by providing a frame-
of systematic reviews are as follows76: work to determine a final recommendation on an intervention
1. A clearly stated set of objectives with predefined eligibility through use of the following:
criteria for inclusion of studies 1. Quality of evidence (Cochrane and similar evaluations of
2. An explicit and reproducible methodology quality of evidence stop here)
3. Use of a systematic and thorough search that attempts to iden- 2. Seriousness of the outcome
tify all reports of studies that meet with eligibility criteria 3. Magnitude of the treatment effect
4. A systematic assessment of the validity of the findings of 4. Precision of the treatment effect
studies that are included in the review 5. Risk of the target event (how frequent)
5. A systematic assessment of the characteristics and findings 6. Risk of adverse events associated with the intervention
of the included studies and a systematic presentation of 7. Cost of the intervention
those findings 8. Values and preferences of the end users
TABLE 6.5 Example of Elements of Qualitative Assessment and Review Instrument Levels of Applicability of Evidence
Feasibility Appropriateness Meaningfulness Effectiveness
Immediately practicable Acceptable and justifiable and Provides a rationale for prac- Effectiveness established to a
within ethical guidelines tice development degree that merits application
in clinical practice
Practicable with limited Acceptable after minor revision Provides a rationale for local, Effectiveness established to a
local training or modest regional, or national reform degree that suggests applica-
additional resources tion in some clinical situations
Practicable with extensive Acceptable after major revision Provides a rationale for Effectiveness established to a
additional training or practice-relevant research degree that warrants consid-
resources eration of applying the findings
Practicable with Acceptable after development of Provides a rationale for Effectiveness established to a
significant national or new ethical guidelines advocating change limited degree and benefits are
regulatory reforms unclear
Impracticable to practi- Ethically unacceptable Evidence unlikely to make Effectiveness not established
tioners sense

Modified from Pearson A. Balancing the evidence: incorporating the synthesis of qualitative data into systematic reviews. JBI Rep. 2004;2:45–64.
All of these criteria have at least some applicability in veteri- • “ Do not do it”: There is high-quality evidence of harm
nary medicine. Briefly, judgments about the quality of recom- clearly exceeding benefits, the cost is too great compared
mendations require consideration of the following: with benefits, or the baseline risk is very low (i.e., the prob-
• The quality of evidence on which the recommendation is lem is not important).
based: The quality of evidence is assessed on the type of study The GRADE guidelines, although not well established for vet-
imprecision of the results over a number of studies, inconsist- erinary medicine, have been used and provide the opportunity
ency of the studies, indirectness, reporting bias, magnitude to make evidence-based recommendations to practitioners.84
of the effect, biologic plausibility, and strength of associa-
tion.67,80-83 Systematic reviews of the literature are fundamen- Y CONCLUSIONS
tal to the development of appropriate recommendations.
• The balance between benefits and harms: Will the interven- The techniques underlying EBVM are useful as we seek answers
tion do more good than harm? What is the extent of the to problems in equine medicine. The techniques allow us to ask
benefit and of the potential harm? the relevant question, seek out the information, and assess its
• Feasibility of translating the evidence into the circumstance quality. We can then decide how best to apply this information
in which the intervention will be made: Can I apply this in to the problem. This final step involves more than just an evalu-
my practice? Is it affordable? ation of the quality of evidence; it requires that we consider a
• Certainty of the baseline risk (i.e., How important is the number of other factors in arriving at a recommendation and
problem?) deciding on the strength of that recommendation. This final step
• Cost (both monetary and in terms of resources) is crucial to the sensible application of the principles of EBVM.
The balance between benefit and harm (the trade-off) can
be categorized as follows: REFERENCES
• Net benefits: The intervention clearly does more good than 1. Anon. Evidence-based veterinary medicine. Nottingham, UK:
harm. University of Nottingham.
• Trade-off: There are important trade-offs between the ben- 2. Cockcroft P, Holmes M. Evidence-based veterinary medicine 2.
efits and harms. Identifying information needs and finding the evidence. In Prac-
• Uncertain trade-offs: It is unclear whether the intervention tice. 2004;26:96–102.
does more good than harm. 3. Holmes M, Cockcroft P. Evidence-based veterinary medicine 3.
• No net benefits: The intervention clearly does more harm Appraising the evidence. In Practice. 2004;26:154–164.
than benefit. 4. Holmes M, Cockcroft P. Evidence-based veterinary medicine
Finally, these considerations can be distilled down to the 1. Why is it important and what skills are needed? In Practice.
2004;26:28–33.
following recommendations being “a judgment that most 5. Malynicz G. Evidence-based medicine. Vet Rec. 1998 Nov 28;
well-informed people would make”12: 143(22):619.
• “Do it”: There is high-quality evidence of net benefits with- 6. More SJ. Evidence is at the core of scientific method: a challenge
in appropriate resource constraints (costs) for a problem for clinicians. Vet J. 2012;191:11–12.
that has significant importance (a judgment that most well- 7. Cockcroft P, Holmes MA. Handbook of evidence-based veterinary
informed people would make). medicine. Oxford: Blackwell Publishing; 2003.
• “Probably do it”: When the strength of evidence is mod- 8. Guyatt GH, Oxman AD, Schuenemann HJ, et al. GRADE guide-
erate or when the benefit:harm trade-off is unclear or lines: a new series of articles in the Journal of Clinical Epidemiol-
marginal. ogy. Journal of Clinical Epidemiology. 2011;64:380–382.
• “Probably do not do it”: When the strength of evidence is 9. Djulbegovic B, Kumar A, Kaufman RM, et al. Quality of evi-
dence is a key determinant for making a strong GRADE guide-
low or very low, when the benefit:harm trade-off is unclear lines recommendation. Journal of Clinical Epidemiology. 2015;68:
or marginal, or when the baseline risk is low. 727–732.
10. Larson RL, White BJ. First steps to efficient use of the scientific 35. Shariff SZ, Bejaimal SAD, Sontrop JM, et al. Retrieving clinical
literature in veterinary practice. Javma-Journal of the American evidence: a comparison of PubMed and Google Scholar for quick
Veterinary Medical Association. 2015;247:254–258. clinical searches. Journal of Medical Internet Research. 2013 Aug 15;
11. Guyatt GH, Oxman AD, Kunz R, et al. GRADE guidelines: 2. 15(8).
Framing the question and deciding on important outcomes. 36. Google Scholar: https://scholar.google.com; 2016.
Journal of Clinical Epidemiology. 2011;64:395–400. 37. MEDLINE: https://www.nlm.nih.gov/bsd/pmresources.html; 2016.
12. Guyatt GH, Oxman AD, Kunz R, et al. GRADE: going from 38. Pubmed Central: https://www.ncbi.nlm.nih.gov/pmc/; 2016.
evidence to recommendations. British Medical Journal. 39. Scopus: https://www.elsevier.com/solutions/scopus; 2016.
2008;336:1049–1051. 40. VetMed Resource: www.cabi.org/vetmedresource/; 2016.
13. Atkins D, Best D, Briss PA, et al. Grading quality of evidence 41. VetSRev: http://webapps.nottingham.ac.uk/refbase/index.php;
and strength of recommendations. British Medical Journal. 2016.
2004;328:1490–1494. 42. Web of Science: http://thomsonreuters.com/en/products-services/
14. Upshur REG, VanDenKerkhof EG, Goel V. Meaning and mea scholarly-scientific-research/scholarly-search-and-discovery/
surement: an inclusive model of evidence in health care. Journal web-of-science.html; 2016.
of Evaluation in Clinical Practice. 2001;7:91–96. 43. Wikipedia: https://www.wikipedia.org; 2016.
15. Nicholas F, Online Mendelian Inheritance in Animals (OMIA). 44. O’Connor AM, Anderson KM, Goodell CK, et al. Conducting
Online Mendelian Inheritance in Animals (OMIA). Faculty of Vet- systematic reviews of intervention questions I: writing the review
erinary Science, University of Sydney; 2012. protocol, formulating the question and searching the literature.
16. Christopher MM, Marusic A. Geographic trends in research Zoonoses and Public Health. 2014;61:28–38.
output and citations in veterinary medicine: insight into global 45. Murphy SA. Research methodology search filters: are they effec-
research capacity, species specialization, and interdisciplinary re- tive for locating research for evidence-based veterinary medi-
lationships. BMC Veterinary Research. 2013:9. cine in PubMed? Journal of the Medical Library Association.
17. Anon. SJR–SCImago Journal & Country Rank: SCImago. (2007), 2003;91:484–489.
2016. 46. Directory of Open Access Journals: https://doaj.org; 2016.
18. Grindlay DJC, Brennan ML, Dean RS. Searching the veterinary 47. International Veterinary Information Service: www.ivis.org/home
literature: a comparison of the coverage of veterinary journals by .asp; 2016.
nine bibliographic databases. Journal of Veterinary Medical Edu- 48. Anon. Veterinary Information Network. http://www.vin.com; 2016.
cation. 2012;39:404–412. 49. Sargeant JM, Kelton DF, O’Connor AM. Study designs and sys-
19. Anon. Web of Science: Thomson Reuters, 2016. tematic reviews of interventions: building evidence across study
20. Nielsen TD, Dean RS, Massey A, et al. Survey of the UK veteri- designs. Zoonoses and Public Health. 2014;61:10–17.
nary profession 2: sources of information used by veterinarians. 50. Carpenter CR, Cone DC, Sarli CC. Using publication metrics to
Veterinary Record. 2015 Aug 15;177(7):172. highlight academic productivity and research impact. Academic
21. Buchanan RA, Wooldridge AA. Staying current by searching the Emergency Medicine. 2014;21:1160–1172.
veterinary literature. Journal of Veterinary Medical Education. 51. Neylon C, Wu S. Article-level metrics and the evolution of scien-
2011;38:10–15. tific impact. PLoS Biol. 2009 Nov;7(11).
22. Murphy SA. Searching for veterinary evidence: strategies and re- 52. Christopher MM. Weighing the impact (factor) of publish-
sources for locating clinical research. Veterinary Clinics of North ing in veterinary journals. Journal of Veterinary Cardiology.
America-Small Animal Practice. 2007;37:433ff. 2015;17:77–82.
23. ACVIM. Access to information: American College of Veterinary 53. Lab S. Scimago Journal and Country Rank: SCOPUS, 2016.
Internal Medicine. http://www.acvim.org/Diplomates/Members 54. van Eck NJ, Waltman L, van Raan AFJ, et al. Citation analysis
hip; 2016. may severely underestimate the impact of clinical research as
24. Vandeweerd JM, Kirschvink N, Clegg P, et al. Is evidence- compared to basic research. PLoS One. 2013 Apr 24;8(4).
based medicine so evident in veterinary research and prac- 55. Giuffrida MA, Brown DC. Association between article citation
tice? History, obstacles and perspectives. Veterinary Journal. rate and level of evidence in the companion animal literature.
2012;191:28–34. journal of veterinary internal medicine. 2012;26:252–258.
25. AGRICOLA: https://www.ebscohost.com/academic/agricola; 2016. 56. Young JM, Solomon MJ. How to critically appraise an arti-
26. Biological Abstracts: http://thomsonreuters.com/en/products- cle. Nature Clinical Practice Gastroenterology & Hepatology.
services/scholarly-scientific-research/scholarly-search-and- 2009;6:82–91.
discovery/biosis-citation-index.html; 2016. 57. White BJ, Larson RL. Systematic evaluation of scientific research
27. CABI Abstracts: www.cabi.org/publishing-products/online-infor appropriateness of data analysis to improve clinical decision
formation-resources/cab-abstracts/; 2016. making. Javma-Journal of the American Veterinary Medical As-
28. White ME. CONSULTANT, 2016. sociation. 2015;247:759–762.
29. Embase: www.elsevier.com/solutions/embase-biomedical-research; 58. White BJ, Larson RL. Systematic evaluation of scientific research
2016. for clinical relevance and control of bias to improve clinical deci-
30. Weiner SA, Stephens G, Nour AYM. Information-seeking be- sion making. Javma-Journal of the American Veterinary Medical
haviors of first-semester veterinary students: a preliminary Association. 2015;247:496–500.
report. Journal of Veterinary Medical Education. 2011;38: 59. CASP. Critical Appraisal Skills Programme. http://www.casp-
21–32. uk.net/; 2013.
31. Anders ME, Evans DP. Comparison of PubMed and Google 60. Sargeant JM, Thompson A, Valcour J, et al. Quality of reporting
Scholar literature searches. Respiratory Care. 2010;55:578–583. of clinical trials of dogs and cats and associations with treatment
32. Boeker M, Vach W, Motschall E. Google Scholar as replace- effects. Journal of Veterinary Internal Medicine. 2010;24:44–50.
ment for systematic literature searches: good relative recall and 61. Grindlay D. Reporting guidelines: how can they be implemented by
precision are not enough. BMC Medical Research Methodology. veterinary journals? Equine Veterinary Journal. 2015;47:133–134.
2013:13. 62. Grindlay DJ, Dean RS, Christopher MM, Brennan ML. A sur-
33. Haddaway NR, Collins AM, Coughlin D, Kirk S, et al. The role of vey of the awareness, knowledge, policies and views of veterinary
Google Scholar in evidence reviews and its applicability to Grey journal editors-in-chief on reporting guidelines for publication
literature searching. PLoS One. 2015 Sep 17;10(9). of research. BMC Vet Res. 2014 Jan 10;10:10.
34. Nourbakhsh E, Nugent R, Wang HL, et al. Medical literature 63. Schulz KF, Altman DG, Moher D, et al. CONSORT 2010 state-
searches: a comparison of PubMed and Google Scholar. Health ment: updated guidelines for reporting parallel group randomised
Information and Libraries Journal. 2012;29:214–222. trials. Journal of Clinical Epidemiology. 2010;63:834–840.
64. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, et al. 74. Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group,
The PRISMA statement for reporting systematic reviews and et al. Preferred reporting items for systematic reviews and meta-
meta-analyses of studies that evaluate health care interventions: analyses: the PRISMA statement. PLoS Med. 2009 Jul 21;6(7).
explanation and elaboration. PLoS Med. 2009 Jul 21;6(7). 75. Tao KM, Li XQ, Zhou QH, Moher D, Ling CQ, Yu WF, et al.
65. O’Connor AM, Sargeant JM, Gardner IA, et al. The REFLECT From QUOROM to PRISMA: A survey of high-impact medical
statement: methods and processes of creating reporting guide- journals’ instructions to authors and a review of systematic re-
lines for randomized controlled trials for livestock and food safe- views in anesthesia literature. PLoS One. 2011;6(11).
ty. Journal of Veterinary Internal Medicine. 2010;24:57–64. 76. Higgins JPT, Green S. Cochrane handbook for systematic reviews
66. Network E. EQUATOR network: enhancing the quality and of interventions. 1st ed. Hoboken: Wiley; 2008.
transparency of health research, www.equator-network.org; 77. Sox HC. Do clinical guidelines still make sense? Yes. The Annals
2016. of Family Medicine. 2014;12:200–201.
67. Guyatt GH, Oxman AD, Sultan S, et al. GRADE guidelines: 9. 78. Pearson A. Balancing the evidence: incorporating the synthe-
Rating up the quality of evidence. Journal of Clinical Epidemiol- sis of qualitative data into systematic reviews. JBI REPORTS.
ogy. 2011;64:1311–1316. 2004;2:45–64.
68. Institute TJB. Joanna Briggs Institute reviewers’ manual: 2014 79. Guyatt G, Oxman AD, Akl EA, et al. GRADE guidelines: 1.
edition. The University of Adelaide, South Australia 5005: The Introduction—GRADE evidence profiles and summary of
Joanna Briggs Institute; 2014. findings tables. Journal of Clinical Epidemiology. 2011;64:
69. Upshur REG. Looking for rules in a world of exceptions–reflec- 383–394.
tions on evidence-based practice. Perspectives in Biology and 80. Guyatt GH, Oxman AD, Kunz R, et al. GRADE guidelines 6. Rat-
Medicine. 2005;48:477–489. ing the quality of evidence—imprecision. Journal of Clinical Epi-
70. O’Connor A, Sargeant J. Research synthesis in veterinary science: demiology. 2011;64:1283–1293.
Narrative reviews, systematic reviews and meta-analysis. Veteri- 81. Guyatt GH, Oxman AD, Kunz R, et al. GRADE guidelines: 8.
nary Journal. 2015;206:261–267. Rating the quality of evidence—indirectness. Journal of Clinical
71. Grant MJ, Booth A. A typology of reviews: an analysis of 14 re- Epidemiology. 2011;64:1303–1310.
view types and associated methodologies. Health Information 82. Guyatt GH, Oxman AD, Kunz R, et al. GRADE guidelines: 7.
and Libraries Journal. 2009;26:91–108. Rating the quality of evidence—inconsistency. Journal of Clinical
72. O’Connor AM, Sargeant JM, Wang C. Conducting systematic re- Epidemiology. 2011;64:1294–1302.
views of intervention questions III: synthesizing data from inter- 83. Guyatt GH, Oxman AD, Vist G, et al. GRADE guidelines: 4. Rat-
vention studies using meta-analysis. Zoonoses and Public Health. ing the quality of evidence—study limitations (risk of bias). Jour-
2014;61:52–63. nal of Clinical Epidemiology. 2011;64:407–415.
73. Sargeant JM, O’Connor AM. Conducting systematic reviews of 84. Hinchcliff KW, Couetil LL, Knight PK, et al. Exercise induced
intervention questions II: relevance screening, data extraction, pulmonary hemorrhage in horses: American College of Veteri-
assessing risk of bias, presenting the results and interpreting the nary Internal Medicine consensus statement. Journal of Veteri-
findings. Zoonoses and Public Health. 2014;61:39–51. nary Internal Medicine. 2015;29:743–758.
C HA P T E R 7
Clinical Approach to Commonly
Encountered Problems
Melissa T. Hines*
Y CHANGES IN BODY TEMPERATURE degree of vasoconstriction and thus the amount of blood flow,
with increases in temperature resulting in cutaneous vasodi-
Assessment of body temperature is an essential part of every lation and increased skin blood flow. Heat is lost from body
physical examination. As with all mammalian species, horses surfaces to the surroundings by several physical mechanisms,
normally maintain their core body temperatures within a nar- including radiation, conduction, and convection. Evaporation
row range despite extremes in environmental conditions.1,2 is also an important mechanism of heat loss in horses.5 To some
The core temperatures may vary by approximately 1°C (2°F) extent, the amount of evaporative heat loss is controlled by the
between individuals. In adult horses the normal body tem- rate of sweating. However, even when the animal is not sweating,
perature ranges from 37.2° to 38.3°C (99.0°–101.0°F), whereas water evaporates insensibly from the skin and lungs, resulting
in neonatal foals the temperature tends to be slightly higher, in continual heat loss. In horses, evaporative heat loss, primarily
ranging from 37.8° to 38.9°C (100.0°–102.0°F). Diurnal varia- through increased sweating but also through increased respira-
tion of up to 1°C (2°F) may occur, with the low point typically tion, becomes more important as the ambient temperature rises
occurring in the morning and the peak in the late afternoon. and during exercise.5,6 In addition to increased heat loss when
the body temperature rises, the horse also decreases tempera-
Mechanisms Controlling Body Temperature ture further by inhibiting means of heat production, such as
The set-point, which is the crucial temperature that the body shivering, and by behavioral responses, such as seeking shade
attempts to maintain, is regulated primarily via neuronal con- and wind currents and wading into water.6-8
trol operating through temperature centers in the hypothala- Mechanisms that increase body temperature are triggered
mus.3-5 Both peripheral and central thermoreceptors sense when the body temperature is too low.2 Heat is conserved by
changes in ambient and core body temperatures and activate stimulation of the posterior hypothalamic sympathetic centers,
feedback mechanisms that bring the temperature back to the leading to cutaneous vasoconstriction and piloerection. Heat
set-point. Specifically, peripheral thermoreceptors, which are production also increases and may occur through increased
generally most sensitive to low temperatures, are located in the muscle activity ranging from inapparent contractions to gen-
skin and around certain great veins, as well as in some deep eralized shivering. Shivering may increase heat production by
tissues, such as the spinal cord and abdominal viscera. Central 4 to 5 times baseline. The primary motor center for shivering is
thermoreceptors include large numbers of heat-sensitive neu- in the posterior hypothalamus, which normally is stimulated by
rons and lower numbers of cold-sensitive neurons in the pre- cold signals from the peripheral receptors and to some extent
optic area of the anterior hypothalamus (POA). In response to central receptors in the POA. Digestion of food also contrib-
changes in temperature, the peripheral and central thermore- utes to total body heat. Sympathetic stimulation may increase
ceptors transmit signals into the posterior hypothalamic area, the rate of cellular metabolism, increasing heat production by
subsequently activating autonomic and behavioral effector chemical thermogenesis. Cooling also increases the produc-
responses to regulate body temperature. These responses affect tion of thyrotropin-releasing hormone, ultimately increas-
the balance between heat loss and heat production. ing thyroid hormones and cellular metabolism and further
There are multiple mechanisms for cooling in response to contributing to chemical thermogenesis. In addition to these
elevations in body temperature, which include both means of physiologic adaptations, behavioral responses to conserve heat
increasing heat loss and decreasing heat production.3-5 One also occur, such as adopting a huddled stance, aggregating in
means of increasing heat loss is by transferring heat from the groups, and seeking shelter.9-11 It has been demonstrated that
body core to the surface by increasing blood flow to the skin. horses voluntarily select shelter, especially under wet, windy
Changes in core body temperature and environmental tem- conditions and that shelter selection is affected by breed, body
perature cause the sympathetic nervous system to regulate the condition score, and hair coat weight.9
Increased Body Temperature: Hyperthermia and

*The editors and authors acknowledge and appreciate the contributions of
Bonnie R. Rush, Kenneth W. Hinchcliff, and Siddra A. Hinesas as previous
Fever
contributors to this chapter. Some of their original work has been incorpo- Elevation of the body temperature above normal is one of the
rated into this edition. most common clinical problems encountered, and although
232
CHAPTER 7 Clinical Approach to Commonly Encountered Problems 23332
classically associated with infection, a variety of disorders may Heat Stroke. Heat stroke occurs when the body tempera-
cause increased body temperature.3-5 Veterinarians should ture rises above a critical temperature, leading to multisystem-
distinguish between conditions of hyperthermia, in which the ic problems. In horses signs of heat stroke may develop when
temperature set-point is unaltered, and true fever, in which the the body temperature is above 41.5°C (107°F), which most
set-point actually increases. often occurs in association with exercise in environmentally
stressful conditions.13,15 Although horses can acclimatize to
Hyperthermia various weather conditions to some extent, the efficiency of
Mechanisms of Hyperthermia. The body temperature may evaporative heat loss may be compromised significantly in hot,
become elevated without an increase in the set-point when humid weather.6,12,13,15 Susceptibility to heat stroke may in-
there is a loss of equilibrium in the heat balance equation.4 crease if sweating leads to dehydration and electrolyte imbal-
Increased heat production or absorption of heat beyond the ances. Once the body temperature reaches the critical point,
ability of the body to dissipate heat may occur. In some condi- the homeostatic mechanisms of thermoregulation fail, result-
tions impaired heat loss also may occur. ing in peripheral vasoconstriction, decreased cardiac output,
Conditions Associated with Hyperthermia. Hyperthermic and decreased blood pressure. Affected horses are lethargic
conditions include problems such as exercise-related hyper- with weak, flaccid muscles. Prostration, circulatory shock, dis-
thermia, heat stroke, anhidrosis, malignant hyperthermia, seminated intravascular coagulation, multiple organ failure,
central nervous system disorders, and reactions to certain and death may occur.
toxins or drugs (Box 7.1). In general, these conditions do not Anhidrosis. Anhidrosis is an inappropriate response to
respond to treatment with antipyretic drugs. prolonged climatic stress characterized by a partial or total
Exercise-Related Hyperthermia. During sustained or loss of the ability to sweat.16-18 This condition occurs primarily
high-intensity exercise, increased heat production is associ- in horses living in hot, humid environments and has been doc-
ated with muscular activity.5,6,12,13 The heat produced may umented in about 2% to 6% of horses living in Florida.16,19 The
exceed the ability of the body to lose heat, resulting in an impaired sweating results in diminished heat loss, frequently
increased core body temperature. Typically, the temperature resulting in hyperthermia. Other clinical signs include tachy-
returns to normal with rest as heat loss mechanisms remain pnea, poor performance, and poor hair coat.
activated. There is some evidence that ageing compromises Malignant Hyperthermia. Malignant hyperthermia (MH)
the ability of horses to thermoregulate during exercise.14 El- encompasses a group of inherited skeletal muscle disorders in
evated temperature also may occur with the intense muscle which calcium metabolism is altered. Although the condition
activity associated with generalized seizures. is most common in human beings and pigs, it has been re-
ported in several species, including dogs and horses.20-23 MH
is characterized by a hypermetabolic state of muscle that gen-
erally is induced by halogenated inhalation anesthetics, depo-
larizing skeletal muscle relaxants, and occasionally local anes-
BOX 7.1
Causes of Changes in Body Temperature thetics or stressors such as heat or vigorous exercise. Clinical
signs include a rapid increase in core body temperature, skel-
HYPERTHERMIA etal muscle rigidity, and tachycardia. Affected animals may de-
Exercise-related hyperthermia velop significant acidosis and muscle necrosis, and the condi-
Heat stroke tion can be fatal. MH is most often associated with a defect in
Anhidrosis the ryanodine receptor.20,23 In Quarter Horses and American
Malignant hyperthermia Paint Horses, MH is inherited as an autosomal dominant trait
Central nervous system disorders that is linked to a single point mutation in the skeletal muscle
Toxins or drugs ryanodine receptor 1 (RyR1) gene at nucleotide C7360G.23,24
Macrolide-induced hyperthermia This mutation can be identified by genetic testing. Horses with
polysaccharide storage myopathy tend to have a more severe
FEVER clinical phenotype if they are concurrently affected with the
Infection MH mutation.24
Neoplasia Central Nervous System. Alterations in body temperature
Immune-mediated disease have been documented with a variety of conditions affecting
Other areas of the hypothalamus involved in thermoregulation, with
Toxic hepatopathy hyperthermia being more common than hypothermia.1,3,4,25
Inflammatory bowel disease Central hyperthermia has been associated with conditions
Other such as hemorrhage, traumatic brain injury, neoplasms or ab-
scesses, infectious/inflammatory changes, and degenerative
HYPOTHERMIA disorders. It is usually characterized by a lack of diurnal varia-
Accidental Hypothermia tion, absence of sweating, resistance to antipyretic drugs, and
Exposure to harsh environmental conditions excessive response to external cooling. In some cases, dam-
Surgical procedures/anesthesia age to the hypothalamus results in a disruption in the hypo-
thalamic set-point temperature, resulting in neurogenic fever
Pathologic Hypothermia rather than true hyperthermia.25
Sepsis/inflammation (maladaptive response) Toxins or Drugs. Hyperthermia has occasionally been as-
Intracranial disease sociated with some toxins or drugs.26-28 Exposure to com-
Hypothyroidism (neonates) pounds that uncouple oxidative phosphorylation, such as
the wood preservative pentachlorophenol, could potentially
cause a significant rise in body temperature.27 Foals treated hypothalamic neurons to influence the febrile response.34,35
with macrolide antibiotics are at risk of developing hyperther- Other mediators, such as orexin, may also play a role in ther-
mia.28,29 Erythromycin causes a drug-induced anhidrosis that moregulation.36,37
is the likely cause of the hyperthermia.29 Because the sweat re- The substance most often used in experimental studies of
sponse of treated foals is impaired, these foals are at particular the febrile response is bacterial lipopolysaccharide (LPS).38-40
risk of hyperthermia when exposed to hot, humid environ- Like many microbial products acting as exogenous pyrogens,
ments and direct sunlight. LPS initiates fever by activation of the innate immune system,
specifically via the complement cascade and Toll-like receptors
Fever (TLRs). The response is generally biphasic, with early and late
Mechanisms of Fever. In true fever the set-point for the phases. In the early phase of fever, LPS taken up by the Kupffer
desired core body temperature increases and then is main- cells of the liver activates the complement cascade, with C5a
tained by the same mechanisms that maintain the normal rapidly stimulating the Kupffer cells to produce PGE2. This
body temperature. Fever is a part of the acute phase response peripherally produced PGE2 may then act primarily via two
to infection or inflammation. The pathogenesis of fever is pathways to affect thermoregulation. First, this PGE2 may
complex, and multiple integrative signaling pathways come be transported by the bloodstream to the ventromedial POA
into play3,4,30,31 (Fig. 7.1). Currently it is thought that both where it acts on thermoregulatory neurons to increase the set-
neuronal and humoral mechanisms are involved in the induc- point. Second, it may interact with receptors on hepatic vagal
tion of fever. Neuronal mechanisms in part involve stimula- afferents, leading to activation of pathways projecting to the
tion of vagal afferents, whereas humoral mechanisms involve medulla oblongata and then to the POA via the ventral nor-
several proinflammatory cytokines that act as endogenous adrenergic bundle. Consequently, norepinephrine is secreted,
pyrogens.32,33 Prostaglandin E2 (PGE2), which may be pro- which then stimulates α1-adrenoreceptors on thermoregula-
duced peripherally or centrally, is regarded as the principal tory neurons, evoking a rise in core temperature. In the late
downstream mediator of fever, acting on thermosensitive phase of fever, there is further production of PGE2 following
Conditions of Increased Body Temperature
Animal attempts Animal attempts

to dissipate heat to conserve/produce heat
Non-febrile hyperthermia True fever
History and environmental evaluation Physical examination and

minimum database
Exercise
Heat stroke
Anhidrosis
Malignant hyperthermia Localizing signs No abnormalities
Drugs/toxins
Pursue diagnostic work-up Review history,

repeat physical examination
Serology (esp. EIA)

Evaluation of respiratory tract
Evaluation of abdomen
Cardiac evaluation
Blood culture (esp. neonates)
Fecal parasitology
Immunologic testing
Exploratory laparoscopy/laparotomy
Conditions of Decreased Body Temperature

(Hypothermia)
Accidental hypothermia Pathologic hypothermia
Cold, damp environment Sepsis

Surgery Hypothyroidism (neonates)
Intracranial disease
FIG. 7.1 Approach to changes in body temperature.

both direct induction of its synthesizing enzymes via TLR sig- during fever.31,46-50 Some of the antipyretic effects occur via
naling and the production of endogenous pyrogens resulting an inhibitory influence on the formation or action or endog-
in the central production of PGE2. enous pyrogens or via effects on neuronal thermoregula-
Endogenous pyrogen was initially assumed to be a single tory circuits that are activated during fever. The interactions
molecule produced by leukocytes, thus the name leukocytic between pyrogens and cryogens are complex, and some cyto-
or granulocytic pyrogen. Currently, at least 11 cytokines have kines function as either depending on the circumstance. Some
been shown to be intrinsically pyrogenic.30,32,33 These cyto- endogenous antipyretic substances include glucocorticoids,
kines are produced predominantly by monocytes and macro- neuropeptides/hormones (arginine vasopressin, adrenocorti-
phages. Among the most potent of the endogenous pyrogens cotropic hormone, α-melanocyte-stimulating hormone MSH,
are interleukin-1 (IL-1) α and β and tumor necrosis factor– γ-MSH), cytokines (TNF-α, IL-10), lipocortin, nitric oxide,
alpha (TNF-α). Others include TNF-β, IL-6, and interferon-α. and epoxyeicosanoids.31,47,49 One of the major antipyretics
The precise means by which these cytokines influence ther- is IL-10. Following induction by pyrogenic cytokines, IL-10
moregulation are complex and remain to be fully elucidated. inhibits further production of IL-1 and TNF. Also, α-MSH has
It appears that endogenous pyrogens have both peripheral and significant antipyretic effects, being more effective in control-
central mechanisms of action that include stimulation of affer- ling fever than acetaminophen when administered to human
ent neuronal pathways, induction of PGE2 synthesis in endo- beings.49 Nitric oxide also has an antipyretic role, mediated by
thelial cells in both the periphery and brain, and direct action cyclic guanosine monophosphate in the POA.50 Even PGE2,
in the brain via neuronal cytokine receptors. whose role is primarily in the induction of fever, may pro-
The organum vasculosum laminae terminalis (OVLT) is duce hypothermic responses when interacting with the EP4
a rich vascular network associated with neurons of the POA receptor.45
that plays an important role in the generation of fever.33,35,41,42 The cytokines that act as endogenous pyrogens are gen-
This region is part of the circumventricular organs, which are erally proinflammatory, with a variety of biologic effects in
unique structures of the brain with extensive vasculature and addition to fever.1,4,30,33,40,51 Thus fever is usually accompa-
a minimal blood-brain barrier. As such, endothelial cells lin- nied by additional hematologic, immunologic, and meta-
ing this region may allow direct movement of exogenous or bolic changes referred to as the acute phase response. Among
endogenous pyrogens and peripherally produced PGE2 into these effects is the synthesis of acute phase proteins by
the brain. Also, exogenous and endogenous pyrogens may hepatocytes, including fibrinogen, C-reactive protein, hap-
interact with specific receptors on endothelial cells of the toglobin, serum amyloid A, and others. Also, hypoferremia,
OVLT to further produce PGE2. Ablation of the OVLT pre- hypozincemia, and hypercupremia are cytokine mediated,
vents fever after a peripheral injection of endogenous pyro- as is the activation of lymphocytes, which in turn produce
gens but has no effect when endogenous pyrogens are injected additional cytokines.
directly into the brain tissue.42 Prostaglandins induced by endogenous pyrogens stimulate
The production of both peripheral and central PGE2 is key the muscle catabolism associated with fever and induce colla-
in the pathogenesis of fever. PGE2 is basically synthesized in genase synthesis from synovial cells, contributing to the mus-
three steps involving phospholipase A2, cyclooxygenase, and cle and joint pain often seen with fever. Local tissue responses
terminal PGE synthetase. These enzymes are upregulated to IL-1β and TNF-α may stimulate afferent neural impulses
in fever.34 The cyclooxygenase 2 (COX-2) pathway is clearly that lead to behavioral responses associated with fever, such
important in the pathogenesis of fever because COX inhibi- as lethargy and anorexia. As expected, treatment with COX
tors, and specifically COX-2 inhibitors, effectively reduce inhibitors can diminish many of the signs of fever.
the febrile response but have no effect on the normal body Fever is a host defense mechanism that has been pre-
temperature.43,44 At the same time that there is upregulation served within the animal kingdom. Although much attention
of proteins involved in prostaglandin production, there is is focused on the adverse effects of fever, including patient
transcriptional downregulation of proteins involved in PGE2 discomfort, there is evidence that fever can be beneficial.52-58
inactivation, such as 15-hydroxy-prostaglandin dehydro- Some studies have demonstrated an association between a
genase. Once produced, PGE2 interacts with E type prosta- rise in body temperature and a decrease in mortality and
glandin receptors (EP receptors), of which there are currently morbidity during infection. Although the elevation in tem-
four identified subtypes with differential expression in vari- perature may directly impair organism growth in some cases,
ous areas of the hypothalamus and brainstem.45 It appears the beneficial effects are thought to be primarily associated
that the EP3 receptor in the median preoptic nucleus within with enhanced host defenses.40,52-57 Fever has beneficial
the POA of the hypothalamus is particularly important in the effects on multiple aspects of both the innate and adap-
febrile response. The interaction of prostaglandins with their tive immune response. As part of the acute phase response
receptors initiates neuronal signaling by producing a cascade associated with fever, the concentration of iron, which is
of changes in cyclic nucleotides, calcium, and monoamines required by many bacteria for multiplication, decreases.59-61
leading to a higher set-point in the hypothalamic thermoregu- The beneficial effects of fever, however, are not universal, and
latory center. For example, interaction with the EP3 receptor many of the positive effects of fever are reversed when tem-
mediates decreases in intracellular cyclic adenosine mono- perature becomes extremely high.43,62 In rabbits experimen-
phosphate (cAMP), which results in decreased firing of warm- tally infected with Pasteurella multocida, the survival rate
sensitive neurons, increased firing of cold-sensitive neurons, increased in association with elevations in body temperature
and ultimately fever. up to 2.25°C (4.5°F) above normal but decreased with eleva-
Feedback mechanisms exist to prevent an excessive rise tions above this level.63 The increased catabolism, variable
in body temperature. A number of antipyretic substances, anorexia, and increased metabolic rate can lead to muscle
sometimes referred to as either endogenous or autogenous wasting and weakness when fever is prolonged. Although
cryogens, may be liberated systemically or within the brain seizures induced by fever are uncommon in horses, they
can be seen in neonates when the temperature is above 42°C Fever. Multiple conditions may result in fever. Infectious
(108°F).2 In debilitated animals, prolonged fever has been diseases remain the most common cause, although other in-
associated with cardiovascular failure. flammatory conditions such as neoplasia and immune-me-
Conditions Associated with Fever. Fever is part of the diated disease may also cause fever. Often localizing clinical
physiologic response to infection and inflammation (see Box signs such as nasal discharge or diarrhea aid in determining
7.1). It is considered a cardinal sign of infection and has been the specific etiology. If the underlying condition responsible
associated with infections caused by essentially all types of for the fever is not readily apparent, additional diagnostic
organisms. Although there is considerable variation, viral in- tests are warranted.
fections are often associated with high fevers. In addition to Documentation of Fever. It may be useful to have the body
infection, fever can be a prominent component of many in- temperature taken twice daily over a period of time to docu-
flammatory, neoplastic, and immunologic conditions. In in- ment fever and identify any pattern. Fevers can be categorized
tensive care units in human hospitals, the incidence of fever as intermittent, remittent, biphasic, or sustained, although
ranges from 23% to 70% and is related to an infectious process some inconsistencies in the precise definitions of these pat-
in approximately half of the cases.64,65 terns exist. In general, intermittent fevers are characterized
Fever of Unknown Origin. Fever of unknown origin in by recurring paroxysms of elevated temperature followed by
human medicine is defined specifically as a fever that oc- periods of normal temperature, such as those fevers that dem-
curs on several occasions over at least 3 weeks in which the onstrate diurnal variation. In most cases of intermittent fever
diagnosis remains unclear after an initial diagnostic workup. the temperature tends to peak in the late afternoon or evening.
In veterinary medicine, the term fever of unknown origin is Intermittent fevers most often are associated with infectious
often used more loosely, referring to any prolonged, unex- causes, particularly viral infections, although they may be seen
plained fever. In many cases, the cause of a fever of unknown with a variety of other conditions. Remittent fevers are those
origin is a common disease with an unusual presentation. in which diurnal variation is exaggerated without a return to
In a review of 63 cases of fever of unknown origin in the normal body temperature or those with a cyclic pattern in
horse, the specific criteria used to define fever of unknown which the temperature elevation lasts for several days, such
origin included (1) illness of at least 3 weeks’ duration as- as may be seen with equine infectious anemia virus. Biphasic
sociated with nonspecific signs, (2) body temperature of at fevers, in which an initial rise in body temperature precedes
least 38.6°C (101.5°F) on several occasions, and (3) no clear a period of normal temperature and then a second rise, are
diagnosis after an initial complete blood count and serum characteristic of certain diseases such as equine neorickettsio-
biochemical profile.66 The most common cause was found sis (Potomac horse fever). Sustained fevers are those in which
to be infection, which was responsible for 43% of the cases. the elevation of temperature is consistent.
Other causes included neoplasms in 22% of cases; immune- Signalment and History. The signalment and history
mediated diseases in 6.5%; and miscellaneous diseases such should be considered when investigating fever. Some causes
as toxic hepatopathy, parasitism, and others in 19%. In 9.5% of fever may be more common in certain age groups. For ex-
of cases no diagnosis was made. Specifically, the most com- ample, although not a consistent finding, fever is often seen in
mon conditions identified were abdominal infections (peri- neonatal foals in association with septicemia, omphalophle-
tonitis/abdominal abscessation) and lymphosarcoma, each bitis, or septic arthritis. Rhodococcus equi is predominantly
accounting for approximately 16% of cases. Pneumonia, seen in foals 1 to 6 months of age and is often associated with
pleuropneumonia, or both were found in 11% of cases. Three fever. Young horses, especially those that have been recently
horses (approximately 5%) were found to have bacterial en- exposed to new horses, may be particularly at risk for respi-
docarditis, and in each case a murmur was not identified ini- ratory tract infections. Any exposure to Streptococcus equi
tially but developed within several weeks of the onset of ill- subspecies equi (strangles) may be significant because of the
ness. Thus the diagnosis of fever of unknown origin requires association of this organism with internal abscessation. Geo-
a systematic approach with emphasis on the evaluation of graphic location and travel history may be relevant, as some
infectious disease. diseases, such as equine neorickettsiosis, piroplasmosis, and
coccidioidomycosis, are more common in certain geographic
Diagnostic Approach to Elevations in locations.
Body Temperature Physical Examination. A thorough physical examination,
Increased body temperature is a common clinical sign with including auscultation of the thorax with a rebreathing bag
diverse causes. Fortunately, in many cases the cause may be and rectal palpation, is indicated in the evaluation of fever. Re-
readily apparent on the basis of the signalment, history, and peating the physical examination may yield new information.
physical examination. In other cases, additional diagnostic A neurologic examination can also be useful as disorders of
testing may be required (see Fig. 7.1). the central nervous system may cause aberrations in tempera-
Hyperthermia. Many causes of hyperthermia, such as ex- ture through pyrogenic cytokines or in some cases through
ercise-related hyperthermia and malignant hyperthermia, can direct effects on thermoregulatory centers.
be distinguished from fever based largely on the signalment Ancillary Diagnostic Aids. Ancillary diagnostic tests are
and history of the patient. Older horses may be more suscep- commonly used in the diagnosis of fever, particularly in cases
tible to exercise-related hyperthermia.14 Treatment with mac- of fever of unknown origin. Localizing signs may help direct
rolide antibiotics is significant due to the potential for mac- selection of the most appropriate tests but are not always
rolides to cause hyperthermia.28,29 A sweat test, such as the present.
quantitative intradermal terbutaline sweat test, can be useful CLINICAL PATHOLOGY/LABORATORY TESTING. A database,
in confirming anhidrosis.18,67 Genetic testing is available for including complete blood count (CBC), fibrinogen, biochemi-
detection of the RyR1 mutation in cases of suspect malignant cal profile with bile acids, and urinalysis, should be obtained.
hyperthermia.23,24 Hemoparasites may occasionally be seen on the blood smear,
but the apparent absence of organisms does not rule out a Corynebacterium pseudotuberculosis, equine piroplasmosis,
parasitemia that is below detectable limits. Abnormalities brucellosis, and coccidioidomycosis, among others.
consistent with chronic infection or inflammation, including Immune-mediated disorders such as immune-mediated
anemia, hyperfibrinogenemia, hyperglobulinemia, and throm- hemolytic anemia, immune-mediated thrombocytopenia,
bocytosis, are common but nonspecific findings. Although in- systemic lupus erythematosis, vasculitides, and rheumatoid
flammation is the most common cause of hyperglobulinemia, arthritis have been implicated as causes of fever of unknown
further assessment by serum protein electrophoresis and spe- origin but more commonly in human beings and small ani-
cific immunoglobulin quantitation may be indicated in some mals than in horses. Appropriate diagnostic tests, such as the
cases. A monoclonal gammopathy is characteristic of plasma Coombs’ test, skin biopsy, and antinuclear antibody testing,
cell myeloma but may also be seen with other tumors of the may be useful in some patients.
reticuloendothelial system and occasionally other conditions. ENDOSCOPY. Endoscopy is commonly used for evaluation
Immunodeficiencies, which in some cases are associated with of the respiratory tract, especially the upper respiratory tract
low lymphocyte counts or low immunoglobulin concentra- including the guttural pouches. Pleuroscopy allows direct vi-
tions, can predispose affected horses to chronic infections. In sual examination of the pleural space and may facilitate biopsy
cases of hypoalbuminemia, gastrointestinal or renal loss, third of any masses. Also, endoscopy can be useful in evaluation of
space loss, and decreased production associated with signifi- the esophagus, stomach, and urinary tract.
cant hepatic disease should be investigated. The presence of DIAGNOSTIC IMAGING. Ultrasound is a practical, noninva-
hypercalcemia can be helpful in the diagnosis of disease, as it is sive means of assessing the thorax and parts of the abdomen.
most often linked with either renal disease or certain neoplasms It can help identify abnormalities that need further evaluation,
in horses. Bone marrow aspiration may be useful, particularly such as consolidated lung, abdominal masses, or pathologic
in those horses with persistent abnormalities in circulating cell liver and kidney conditions. It may also help identify fluid for
populations. collection. Echocardiography can aid in the diagnosis of bac-
Infections of the respiratory tract and abdomen frequently terial endocarditis.
are associated with fever in the horse, and therefore these Radiographs of the thorax are helpful in the evaluation of
systems should be thoroughly evaluated. In many cases this pulmonary disease. Although the practicality and utility of
includes cytologic evaluation and culture and/or polymerase abdominal radiographs are limited, especially in adult horses,
chain reaction (PCR) of samples from the respiratory tract and they may be of value in individual cases, especially in neonates.
abdomen. The upper airway is often sampled by nasal swabs, Nuclear imaging using labeled white blood cells may identify a
nasal washes, or guttural pouch lavage, and the lower airway site of infection or inflammation.
can be sampled by bronchoalveolar lavage or transtracheal OTHER. Exploratory laparoscopy or laparotomy is indicat-
aspiration. Thoracocentesis may be considered because abnor- ed when abdominal involvement is suspected or the animal
malities of pleural fluid are occasionally present even without is becoming progressively debilitated. In horses for which a
increases in the volume of fluid. Similarly, abnormalities in specific diagnosis has not been made, therapeutic trials with
peritoneal fluid can be found without increases in fluid vol- antimicrobials may help, and in cases of suspected immune-
ume, and abdominocentesis should be considered as part of mediated disease, corticosteroids may help.
the diagnostic plan. It should be remembered that neoplastic
cells often do not exfoliate into fluid; therefore neoplasia can-
not be ruled out based on cytologic evaluation of fluid. Decreased Body Temperature: Hypothermia
Although only occasionally associated with fever, the pres- Mechanisms of Hypothermia
ence of gastrointestinal parasites is so common that feces from Hypothermia occurs when the core body temperature drops
horses with fever of unknown origin should be examined for below accepted normal values.4 Clinically, hypothermia can be
parasite ova. In cases of suspected gastrointestinal protein characterized as either accidental or pathologic. In accidental
loss, diarrhea, or melena, one should consider diagnostic pro- hypothermia the body’s ability to produce heat is overwhelmed,
cedures such as fecal culture and analysis for clostridial tox- often in association with harsh environmental conditions. There
ins, culture and PCR for Salmonella, rectal mucosal biopsy, or is a spontaneous decrease in the core body temperature inde-
absorption tests. pendent of actual disruption to the thermoregulatory system.
Blood cultures are generally most useful in neonates but Pathologic causes of hypothermia should be considered
can yield valuable information in adult horses with fever as when no clear reason for accidental hypothermia is evident.
well. Ideally, three to five samples should be collected at least Pathologic hypothermia occurs in association with disorders
45 minutes apart when the horse is not on a regimen of anti- that decrease metabolic activity or directly affect the thermo-
biotic therapy. Sampling just before and during a temperature regulatory center, such as endocrine disorders, sepsis, and
rise is most likely to yield a positive culture. intracranial disease. When hypothermia is seen with systemic
Serologic evaluation can be useful in the assessment of inflammation, it is often considered a maladaptive thermo-
fever, and specific tests can be prioritized based on the patient regulatory response. The mechanisms involved in producing
and the geographic area. Due to variability in the clinical pre- hypothermia are not fully understood, but several cytokines
sentation and regulatory concerns, equine infectious anemia (including TNF-α, interleukins, and interferon-gamma [IFN-
should be considered as a differential diagnosis for horses with γ]) are involved.69 Some of these same cytokines may also act
fever of unknown origin, and testing should be performed. A as pyrogens under other conditions.
serologic test for detection of antibodies to the M protein of The ability to generate heat through shivering is impaired
Streptococcus equi ssp. equi has been developed and may be a or lost once the body temperature becomes too low. The ani-
useful aid in the diagnosis of metastatic abscessation associ- mal experiences a decrease in the metabolic rate of most tis-
ated with the strangles organism.68 Serologic tests for several sues. Heart rate, cardiac output, glomerular filtration, and
other infectious diseases are also available, including tests for blood pressure may decrease.
Conditions Associated with Hypothermia cause, can result in starvation and the accompanying signs of
Accidental Hypothermia. Accidental hypothermia is most marked weakness and wasting, known as inanition. Ultimately
often associated with cold or cold, damp, windy environments starvation can lead to organ failure and death. Obesity appears
(see Box 7.1). Occasionally extreme situations occur, such as to be increasing in prevalence in the horse population and has
an animal falling through ice. Mild accidental hypothermia been linked to serious health concerns, particularly lamini-
sometimes occurs with surgical procedures. Accidental hypo- tis.75-78 Some horses that are prone to obesity (“easy keepers”)
thermia is particularly common in neonates and geriatric or have an endocrinologic disorder known as equine metabolic
debilitated adult horses. Although central thermoregulation syndrome (EMS).79-81
through the hypothalamus is normal in neonates, foals have a The most accurate means of assessing body weight and moni-
large ratio of surface area to body weight, enhancing heat loss.2 toring changes in weight is to use a scale, but this has practical
Sick or debilitated animals often have decreases in activity and limitations. Thus a variety of weight tapes and equations based on
nutritional intake and alterations in circulation that can con- morphometric measurements have been developed to estimate
tribute to hypothermia. Severe hypothermia may result in sig- body weight.82,83 To account for differences in body type between
nificant metabolic changes and death. breeds, some breed-specific equations are available.82 The ideal
Pathologic Hypothermia. Pathologic hypothermia can be body weight depends on the type and use of the horse, and equa-
associated with sepsis, neurologic disorders, and endocrine tions have been developed to calculate the ideal body weight for
disorders (see Box 7.1). Hypothermia has been observed with horses of certain breeds. Several online tools are available to aid in
septicemia and shock, especially in neonates, in which 24% of the calculation of actual and ideal body weight.
septic foals were found to have a decreased body temperature.2 Weight alone does not necessarily reflect the body condi-
Hypothyroidism is an uncommon clinical problem in tion of the horse. Because muscle weighs more than fat, ath-
horses; however, impaired thermoregulation has been seen in letic horses may be heavier than nonathletic horses of similar
foals with congenital hypothyroidism.70,71 Hypothermia may size. To better evaluate body condition, a number of scoring
be more common in donkeys than horses. In one study, histo- systems have been developed to estimate the extent of adi-
logic lesions of the thyroid gland were identified in four of five posity.83-87 One commonly used system to determine a body
hypothermic donkeys.72 condition score (BCS) is the Henneke system, which uses a
scale of 1 to 9, with 1 representing an extremely emaciated
Approach to Hypothermia horse, 9 representing an extremely fat one, and 5 being close
Accidental Hypothermia. Accidental hypothermia can to ideal86,87 (Table 7.1). A BCS system that ranges from 0 to
generally be identified from the signalment and history (see 5 is also occasionally used, with 0 being emaciated, 3 good,
Fig. 7.1). It is important to assess environmental conditions to and 5 very fat. In addition to body condition scoring, a num-
determine whether environmental stress, especially cold, wet, ber of morphometric measurements can be used to help esti-
and windy conditions, is contributing to the hypothermia. mate adiposity, some of which may be particularly useful in
Neonatal, geriatric, and debilitated patients are at high risk. evaluating localized adiposity.83,88,89 The girth-to-height ratio
Pathologic Hypothermia correlates well with the BCS and is a suitable morphometric
SIGNALMENT AND HISTORY. The signalment and history measure for assessment of overall adiposity.83 The cresty neck
should be considered when assessing cases of potential patho- score, which ranges from 0 to 5, can be used to evaluate adi-
logic hypothermia (see Fig. 7.1). It is important to consider en- posity in the neck, with a score of 3 or greater being consid-
vironmental conditions, as in some cases both accidental and ered a cresty neck (Table 7.2). Some additional measurements
pathologic causes may contribute to the hypothermia, such as used to assess neck adiposity include crest height, neck cir-
in septic neonates born in cold, damp environments. cumference, and neck circumference–to–height ratio. It has
PHYSICAL EXAMINATION. A thorough physical examination been demonstrated in ponies that measures of generalized and
should be performed in horses with hypothermia. Patients localized obesity, including a BCS of 7 or greater, a cresty neck
should be assessed for potential underlying conditions such as score of 4 or greater, and a neck circumference–to–height ratio
sepsis or inflammation and neurologic or endocrine disorders. greater than 0.71, are useful in the prediction of laminitis.88 A
A neurologic examination may be useful. more quantitative means of measuring adiposity is by ultra-
ANCILLARY DIAGNOSTIC TESTS. A CBC, serum biochemi- sound.90 One method is to take a measurement 5 cm lateral
cal profile, fibrinogen, and urinalysis can be useful in deter- from the midline at the midpoint of the pelvic bone and the
mining the underlying cause of hypothermia. Blood cultures percent body fat is calculated by the following equation: %
are indicated in cases of potential sepsis. Hypothyroidism is body fat = 2.47 + 5.47 (rump fat in cm). Most lean horses are
uncommon, but if suspected, diagnostic testing may include approximately 8% to 14% body fat, whereas overconditioned
a thyroid-stimulating hormone or thyrotropin-releasing hor- horses are 16% to 30%. Ultrasound can also be used to assess
mone (TRH) response test. Ultrasound and aspiration or bi- retroperitioneal fat. A topline score can be used to evaluate
opsy of the thyroid may also be useful, especially in foals with epaxial musculature. Body condition scoring is also valuable
suspected congenital or nutritional hypothyroidism. in evaluating thin horses and is often used to assess horses in
animal welfare cases.
Y CHANGES IN BODY WEIGHT Mechanisms Controlling Body Weight
Changes in body weight and condition are common clinical The stability of body weight and body composition is related
problems in horses. Both weight loss and obesity have the to the balance of energy intake and energy expenditure.73
potential to adversely affect the health of the horse. Weight loss Dietary carbohydrates, fats, and proteins provide energy to
can range from mild physiologic weight loss, such as that seen support the body’s metabolic needs. When the energy intake
with increased exercise, to dramatic, life-threatening weight exceeds the expenditure, the excess energy is stored, primar-
loss.73,74 Severe malnutrition, regardless of the underlying ily as fat, resulting in an increase in body weight. When the
TABLE 7.1 Horse Body Condition Scores on the Henneke Scale86 energy intake is insufficient to meet metabolic needs, energy
stores are used and there is a loss of body weight. Both weight
Score Description loss and obesity can be serious clinical problems.
1. Poor Extremely emaciated; no fatty tissue;
vertebrae, ribs, tail head, and bones of Weight Gain/Obesity
withers, shoulder, and neck are visible Obesity is being increasingly recognized in the equine popu-
2. Very thin Emaciated; slight tissue cover over bones; lation. In the 1990s, a study by the National Animal Health
vertebrae, ribs, tail head, and bones of Monitoring System of the U.S. Department of Agriculture
withers, shoulder, and neck are visible (USDA) estimated that approximately 5% of the horse popu-
3. Thin Slight fat cover over body; individual lation was obese. Several more recent studies in the United
vertebrae and ribs no longer visibly States and Europe have found that 45% to 50% of horses are
discernible; withers, shoulders, and overconditioned, with 10% to 35% being obese.75-78,91-93 Breed
neck do not appear overly thin has been shown to be strongly associated with the risk of
obesity. In many cases, owners do not recognize their horse
4. Moderately Ridge of spine and outline of ribs are visible;
as obese. Horses that are not ridden or used for pleasure rid-
thin tail head may or may not be visible de-
ing rather than competition appear to be at increased risk of
pending on the breed; withers, shoulders,
obesity.75,76 In a study of outdoor-living horses in the United
and neck do not appear overly thin
Kingdom, seasonal variation in BCS was documented, with
5. Moderate Spine and ribs cannot be seen, but ribs the prevalence of obesity increasing from 27% at the end of
can be felt; tail head is spongy; withers, winter to 35% at the end of summer.76 In this study, provid-
shoulders, and neck are rounded and ing supplementary feed was not a strong predictor of obesity,
smooth supporting the belief that grass consumption is an important
6. Moderately Slight crease down spine; ribs and tail factor influencing obesity in outdoor-living horses.
fleshy head feel spongy; fat deposits along Obesity has been linked to adverse health effects in many
withers and neck and behind shoulders species. In horses, the increased risk of laminitis associated
7. Fleshy Crease down spine; ribs have fat filling with obesity is a major concern.81,94 Other potential problems
between them; tail head spongy; fat seen with obesity include thermoregulatory inefficiency, exer-
deposits along withers and neck and cise intolerance, altered reproductive performance, hyperlipe-
behind shoulders mia syndrome, and the development of lipomas in mesenteric
8. Fat Apparent crease down spine; ribs difficult adipose.
to feel; soft fat surrounding tail head; fat
deposits along withers, behind shoulders, Mechanisms of Weight Gain
and on inner thighs; neck is large Weight gain occurs when energy intake exceeds energy expen-
9. Extremely Obvious crease down spine; patchy fat
diture. Although this is a fairly straightforward concept, the
fat on ribs; bulging fat on tail head, withers,
actual etiology of obesity can be complex, involving interac-
behind shoulders, and on neck; fat fills
tions between genetics, hormones, and management. In many
in flank and on inner thighs
cases, management factors including diets high in sugar and

starch coupled with a lack of sufficient exercise contribute to
obesity. Even when horses are ridden regularly as pleasure
horses, the relatively low-intensity exercise provided often
TABLE 7.2 Cresty Neck Score Used in the Assessment of does not use significant energy.75,76
Regional Adiposity83 Some horses are particularly susceptible to obesity. At one
time, it was proposed that this was due to hypothyroidism, but
Score Description evidence did not support this. In 2002 EMS was introduced
0 No palpable crest as a metabolic and endocrine disorder contributing to obe-
1 No visual appearance of a crest but slight filling sity.79 EMS is a complex problem that shares some character-
felt with palpation istics with metabolic syndrome in people.79-81,94,95 The major
phenotypic features of EMS include obesity and/or regional
2 Noticeable appearance of a crest
adiposity, insulin resistance, and a predisposition for laminitis.
Fat deposited fairly evenly from poll to withers
The pathophysiologic mechanisms involved in both obe-
Crest easily cupped in one hand and bent from
sity in general and EMS are complex, involving interactions
side to side
between multiple factors including genetics. It appears that
3 Crest enlarged and thickened some individuals may inherit traits that facilitate survival in
Fat deposited most heavily in middle of neck harsh environments, making them especially thrifty. EMS can
giving a mounded appearance be recognized in any breed of horse, but an increased suscep-
Crest fills cupped hand and begins losing side-to- tibility has been recognized in certain breeds, including several
side flexibility pony breeds, Morgan Horses, Paso Finos, Arabians, Saddle-
4 Crest grossly enlarged and thickened breds, Spanish Mustangs, and Warmblood breeds.81 Studies are
May have wrinkles perpendicular to the topline ongoing to help better define the role of genetics in EMS.
Crest can no longer be cupped in one hand or Insulin dysregulation is a key factor in the diverse physi-
easily bent from side to side ologic processes that contribute to EMS.79-81,96,97 Insulin
5 Crest is so large it falls to one side dysregulation refers collectively to abnormalities of insulin
metabolism including excessive insulin responses to sugars,
fasting hyperinsulinemia, and insulin resistance (IR). The

relationship between IR and obesity might be described as a BOX 7.2
Causes of Weight Gain/Obesity
vicious circle, as each may promote the other. In one study
that demonstrated differences in the insulin response to glu- PHYSIOLOGIC WEIGHT GAIN
cose between ponies and horses, all animals were in moderate Growth
body condition, suggesting that the breed-related differences Pregnancy
in insulin dynamics were independent of obesity.98 In addi-
tion to genetics, EMS, and obesity itself, some factors that can MANAGEMENT
potentially cause IR include physiologic responses to stress or Overfeeding/excessive grass consumption
pregnancy, systemic inflammation, and pituitary pars inter- Lack of exercise
media dysfunction (PPID).
There is increasing awareness of the role fat itself plays in ENDOCRINOLOGIC/METABOLIC DISORDERS
the development of metabolic disease and inflammation.99-101 Equine metabolic syndrome
Previously, adipose tissue was considered simply an energy Pituitary pars intermedia dysfunction
storage depot with a fixed number of adipocytes. Any increase Often causes weight loss
in adipose mass was thought to occur due to increased fat
storage within existing cells resulting in hypertrophy. How-
ever, it is now recognized that adipose tissue is a complex and insulin dysregulation is under investigation in multiple
endocrine organ that contains a large pool of stem cells and species, including horses.110-112
preadipocytes that can be recruited once existing adipocytes An increased risk of laminitis is an important feature of
reach a critical level of hypertrophy. Thus in obesity there is EMS.79-81,113 The mechanisms involved in the relationship of
generally both hypertrophy and proliferation of adipocytes. obesity and insulin dysregulation to laminitis are not fully
The adipocytes are biologically active and influence multiple understood, and this remains an active area of research. The
physiologic processes including energy metabolism, cardio- pathogenesis is likely multifactorial, and some proposed
vascular function, reproductive function, inflammation, and mechanisms include impaired glucose uptake by epidermal
immunity. The cells secrete a wide variety of cell-signaling laminar cells, altered function of epidermal cells, endothe-
proteins, or cytokines, known as adipokines, that function in lial cell dysfunction within the vasculature of the foot, digital
both an autocrine/paracrine and endocrine fashion.100 Due vasoconstriction, and activation of metalloproteinase by glu-
to local influences, adipocytes from differing anatomic loca- cose deprivation or reactive oxygen species.
tions may vary in their specific pattern of expression of these
adipokines. Currently at least 100 substances are thought to Conditions Associated with Weight Gain
be secreted by adipocytes. Some important adipose-derived An increase in body weight occurs when the energy intake is
hormones include leptin, adiponectin, resistin, visfatin, and greater than the energy expenditure. Being overweight should be
angiotensinogen. Adipokines that act as proinflammatory distinguished from the normal physiologic weight gain associ-
cytokines and inflammatory mediators include TNF-α, IL-1α ated with pregnancy and from pathologic conditions that cause
and IL-1β, IL-6, and IL-8, as well as monocyte chemotactic abdominal distention, such as ascites or peritonitis (Box 7.2).
protein–1 and plasminogen activator inhibitor. The altered Overconditioning and obesity are often related to manage-
expression of adipokines in obesity can influence a number of ment problems associated with supplemental feed or excessive
metabolic processes and contribute to EMS.101-107 Adipokines grass consumption, often combined with a lack of significant
may inhibit insulin signal transduction pathways contribut- exercise. Horses with EMS are particularly susceptible to
ing to insulin resistance. Leptin, which is involved in satiety weight gain, and EMS is an important cause of obesity and
and regulation of obesity, is elevated in horses with IR, sug- regional adiposity. PPID can have variable effects on body
gesting leptin resistance. Adiponectin, an insulin-sensitizing weight. Whereas many horses with PPID may experience
hormone, can be decreased in obese horses. In humans and weight loss and muscle wasting, others may exhibit obesity or
rodents, obesity is linked with an upregulation of proinflam- regional adiposity, especially if they have concurrent IR.
matory cytokines secreted by adipocytes. This results in a
chronic inflammatory state and contributes to insulin dys- Diagnostic Approach to Weight Gain
regulation. Studies in horses, however, have yielded variable Signalment and History. Any breed may develop EMS, but
results regarding the expression of inflammatory mediators in some appear to be at increased risk, including pony breeds,
obese horses, and further investigation is needed to under- Morgan Horses, Paso Finos, Arabians, Saddlebreds, Spanish
stand their role in EMS.95,104-106 Mustangs, and Warmblood breeds.81 The condition has also
Several other factors may influence the development of been commonly recognized in American Miniature Horses,
obesity in addition to insulin dysregulation and the action of draft breeds, and Norwegian Fjords, as well as donkeys and
adipokines. The mechanisms of central control of body weight mules. It appears to be less common in Thoroughbreds and
remain somewhat obscure, and it has been proposed that there Standardbreds. The prevalence of PPID increases with age.
is a set-point for body weight regulated through a region of A thorough history is important. Particular attention
the hypothalamus.108 Myostatin, a myokine and negative regu- should be given to the feeding practices as well as the amount
lator of skeletal muscle mass, has been implicated in obesity and type of exercise that the horse receives. Previous episodes
in other species, and limited data in the horse suggest a pos- of laminitis may point to an increased likelihood of EMS or
sible role for myostatin and its receptor in equine obesity.109 PPID. A history of abnormal shedding or polyuria/polydipsia
Recently, the central role of the intestinal microbiota in the increases the suspicion of PPID. The breeding history should
progression and prevention of metabolic dysfunction has be established. In some cases, the breeding history may be
become apparent, and the role of the gut microbiota in obesity unknown, especially if the horse has changed ownership.
Physical Examination. A complete physical examination muscle atrophy, in which case the muscle loss may be inde-
should be performed in cases of weight gain. This may help to pendent of generalized weight loss.
rule out medical conditions that may cause abdominal disten- Causes of Decreased Energy Intake
tion such as ascites, bloat, uroperitoneum, hemoabdomen, or 1. Limited access to feed or poor quality feed: The most direct
peritonitis. Palpation per rectum may be indicated to rule out cause of protein-calorie malnutrition and weight loss is an
pregnancy, especially in horses that have an unknown breed- inadequate volume or quality of feed to meet the dietary
ing history. requirements of the animal. This can result from actual un-
The body weight and BCS should be assessed, and the horse derfeeding or from other factors such as excessive competi-
should be evaluated for regional adiposity.82-87 Several morpho- tion between horses or lameness preventing the horse from
metric measurements can be useful in the evaluation of body accessing the feed easily.117 Also, the nutritional value of
weight and condition. It is important to palpate carefully over feed, particularly forage, can vary widely, and poor quality
the shoulder, elbow, ribs, withers, sternum, loin, and tailhead. feed can be a significant factor in malnutrition.
The girth:height ratio can be useful in the assessment of overall 2. Dysphagia: Dysphagia, difficulty with prehension, masti-
adiposity.83 A cresty neck score, as well as the neck crest height cation, or swallowing, can occur in horses for many rea-
and neck circumference–to–height ratio, are useful in the assess- sons with resultant decreased feed intake and weight loss.
ment of neck adiposity.83 In many cases, careful evaluation for One common cause of difficulty eating, especially in older
lameness, increased digital pulses, and sensitivity to hoof testers horses, is abnormal dentition.
is warranted due to the association of obesity with laminitis. 3. Malabsorption/malassimilation: Malabsorption is the inad-
Ancillary Diagnostic Tests. Routine blood work is often un- equate assimilation of dietary substances due to defects in
remarkable in cases of weight gain. As normal values may vary digestion, absorption, or transport.118 Both macronutrients
among laboratories, it is ideal to use reference ranges specific (carbohydrates, fats, and proteins) and micronutrients (vi-
for the laboratory being used, especially when evaluating IR tamins and minerals) can be affected. Normal absorption is
and PPID. Also, any significant ongoing pain or stress should a complex process involving multiple organs, enzymes, and
be taken into account as these conditions can affect glucose hormones, as well as transport and secretory mechanisms.
and insulin dynamics, as well as adrenocorticotropic hormone Impairment of any of the steps in this process can result in
(ACTH) and cortisol. Horses with both suspected EMS and malabsorption. Rapid gastrointestinal transit time can also
PPID should be screened for IR. Current tests for evaluating IR contribute to malabsorption. In horses, malabsorption is
focus primarily on measurements of glucose and insulin.80,81 often associated with conditions that damage the intesti-
It is generally recommended to limit feed before sampling to nal wall, such as inflammatory bowel diseases, infiltrative
one flake of grass hay low in nonstructural carbohydrates per neoplasms, parasitism, and certain gastrointestinal infec-
500 kg of body weight given no later than 10 pm the night be- tions.119 In foals, both primary and secondary lactase defi-
fore. As IR is often well compensated, baseline concentrations ciency have been identified as causes of malabsorption.120
of glucose and insulin may be normal or in many cases the Depending on the underlying cause of the malabsorption,
glucose is normal whereas the insulin is elevated. Occasionally weight loss may occur in the face of normal dietary intake.
horses will develop diminished glycemic control and become 4. Anorexia: Anorexia, which is a loss of appetite, frequently
hyperglycemic (greater than 150 mg/dL) consistent with type contributes to weight loss, especially when prolonged. An-
2 diabetes mellitus. There are several mathematical calcula- orexia may be either partial or complete, and occasionally
tions such as the glucose:insulin ratio and reciprocal inverse the term hyporexia is used to describe partial anorexia. A
square of insulin (RISQI) that are occasionally used to help wide variety of diseases are associated with anorexia, and
assess insulin sensitivity.114 Because resting concentrations of in many cases, the decreased desire for feed is combined
both glucose and insulin can be normal in IR, dynamic test- with increased energy expenditure, resulting in significant
ing is often indicated. Practical dynamic tests include the oral weight loss. The pathophysiologic mechanisms involved in
sugar test (OST) and the combined intravenous glucose-insu- anorexia are not fully understood, but it appears that there
lin test (CGIT). Other diagnostic tests that may be useful in are disturbances of hypothalamic pathways controlling
assessing IR include measurement of triglyceride and leptin energy homeostasis and that multiple mediators including
concentrations, both of which may be elevated in IR. hormones, neuropeptides, and cytokines such as IL-1 and
Evaluation for PPID should be considered in horses with TNF-α are involved.121,122
weight gain or regional adiposity, as well as in those with loss Causes of Increased Energy Demand. In general, causes of
of body condition.115,116 There are several options for diagnos- increased energy demand can be categorized as physiologic or
tic testing. Currently, frequently recommended tests include pathologic.
measurement of baseline ACTH, a low-dose dexamethasone 1. Physiologic causes of increased energy demand: Physiolog-
suppression test, and a TRH stimulation test with measure- ic weight loss may be seen with conditions requiring in-
ment of ACTH. creased energy, such as late pregnancy, early lactation, and
intense exercise. Environmental stress, especially decreased
ambient temperature, can also have a significant impact on
Weight Loss caloric requirements.123-125 In adult horses, the lower criti-
Mechanisms of Weight Loss cal temperature, which is the temperature below which the
Weight loss occurs when the energy intake is exceeded by the horse must increase metabolic heat production to maintain
expenditure. Thus there are basically two general mechanisms normal body temperature, ranges from 5°C (4°F) to −15°C
of weight loss, decreased energy intake and increased energy (5°F) depending on the horse’s adaptation to the environ-
demand. In many horses with weight loss, both of these mech- ment. The digestible energy requirements are estimated to
anisms come into play. Muscle loss often occurs with weight increase by 2.5% for every degree Celsius below the low-
loss but can also occur as a result of neurogenic or disuse er critical temperature. Energy requirements are further
increased by wet, windy conditions. It is estimated that 5. Aging in multiple species has been associated with
in cold temperatures when the hair coat is wet the main- unintentional weight loss and sarcopenia, which is a
tenance digestible energy requirement may increase by as loss in muscle mass, quality, and strength associated
much as 50%. specifically with aging. The mechanisms behind this
2. Pathologic causes of increased energy demand: Many dis- structural and functional decline in skeletal muscle are
ease processes will result in weight loss, not only because complex.137 In horses, aging alone has been associated
anorexia is common, but because there is frequently a con- with a loss of weight and muscles.138,139 Horses affect-
comitant increase in energy expenditure.126 Fever itself ed with PPID may be particularly susceptible to mus-
appears to increase energy needs. In human patients, the cle loss due to atrophy of type 2A and 2B muscle fibers
resting energy requirement is estimated to increase by ap- and loss of type 2B fibers.115,140 Proposed mechanisms
proximately 14% for each degree C increase in body tem- of steroid-related myopathy in horses with PPID include
perature. However, the increase in energy requirement as- myocyte apoptosis, negative regulation of nuclear factor
sociated with disease is not consistent. For example, it was kappa B (NF-κΒ) activation and function, and oxidative
determined that the resting energy requirement of critically stress.
ill neonatal foals (40–50 kcal/kg body weight per day) was 6. It is not uncommon for weight loss to involve multiple
less than that of control foals (60–80 kcal/kg body weight mechanisms at the same time. Not only may decreased en-
per day).127 The regulation of energy requirements in dis- ergy intake and increased energy demand be present con-
ease is complex and remains poorly understood. currently, but there may be multiple mechanisms contrib-
3. Cachexia is a specific multifactorial syndrome associated uting to the decreased intake and increased demand. For
with underlying illness that is defined by the loss of skeletal example, in recurrent airway obstruction there may be in-
muscle with or without the loss of fat mass.128-130 Cachexia creased demands from both the work of breathing and the
is characterized by a negative protein and energy balance presence of inflammatory cytokines. In parasitism, there is
driven by a variable combination of reduced feed intake competition for nutrients within the gastrointestinal tract,
and abnormal metabolism, and it cannot be fully reversed as well as damage to the gastrointestinal wall resulting in
by nutritional support. The pathophysiology of this syn- inflammation and malabsorption of both macronutrients
drome involves multiple mechanisms.130-133 It is in part me- and micronutrients.
diated by cytokines, including TNF-α, IL-6, IL-1β, IFN-γ,
and proteolysis inducing factor. TNF-α was originally des- Conditions Associated with Weight Loss
ignated as cachectin due to its catabolic effects. In human A wide variety of problems can be associated with weight
patients, muscle catabolism has been associated with TNF- loss (Box 7.3). An inadequate amount or quality of feed
α in a variety of conditions such as cancer, congestive heart for the age and use of the horse is an important cause that
failure, and chronic obstructive pulmonary disease. Based should not be overlooked. In some cases, adequate feed is
on studies in cultured muscle cells, it appears the increased provided, but the horse is unable to eat a sufficient amount
muscle catabolism associated with TNF-α is mediated by due to factors such as competition with other horses or the
reactive oxygen species and nuclear factor-κβ, which up- presence of a gait deficit that limit’s the horse’s ability to
regulate ubiquitin/proteasome activity.134 There are several access feed readily. Also, actual dysphagia can contribute
additional mechanisms of cytokine mediated cachexia, in- to weight loss if prolonged. Some of the more common
cluding activation of the hypothalamic melanocortin sys- problems causing dysphagia include dental disorders, oral
tem and upregulation of the cytokine-activated transcrip- or pharyngeal foreign bodies, esophageal disorders, mas-
tion factor STAT3.128,129,132-134 The endocrine system also seter myopathy, and several neurologic conditions such as
has a role in cachexia. There is often a reduction in circu- neuropathy associated with guttural pouch disease, nigro-
lating anabolic hormones associated with disease. In can- pallidal encephalomalacia, equine protozoal myelitis, and
cer patients, tumor-derived parathyroid hormone–related botulism.
protein (PTHrP) appears to play a role in cachexia.131 In Almost any disease process, including parasitism, infec-
chronic disease states such as congestive heart failure and tious diseases, neoplasms, immunologic disorders, toxici-
chronic kidney disease, it appears that the renin-angioten- ties, chronic organ dysfunction, and endocrinopathies, can
sin system has a major role in producing cachexia.133 An- result in weight loss. In some instances the underlying cause
giotensin II concentrations are often elevated in chronic of weight loss is readily apparent, such as in cases of pleuro-
disease, and treatment with angiotensin converting enzyme pneumonia or diarrhea. Weight loss is common with many
inhibitors can improve weight loss. gastrointestinal diseases, particularly protein losing enter-
4. Several additional mechanisms may contribute to increased opathies. In a retrospective study of 40 horses presented for
energy requirements during systemic disease.126,128-130 The weight loss despite a good appetite, a definitive diagnosis was
stress associated with disease may alter metabolism due to in- established in 24 of 40 cases (60%), and 16 of 40 cases (40%)
creases in sympathetic and hormonal activity. Chronic pain were idiopathic.141 The most common diagnoses were inflam-
may also result in elevated systemic catecholamine and corti- matory bowel disease (13 of 40, 32.5%) and intestinal lym-
sol concentrations, resulting in a catabolic state. In recurrent phosarcoma (4 of 40, 10%). Hypoalbuminemia was identified
airway obstruction, the work of breathing can increase energy in 58% of the total cases, and the severity of hypoalbumin-
requirements. An increase in nutrient demand can be seen in emia was related with nonsurvival. A review of inflammatory
association with protein loss in conditions such as peritonitis, bowel diseases of the horse identified cases of granulomatous
pleuritis, colitis, inflammatory bowel disease, and burns. Also, enteritis, multisystemic eosinophilic epitheliotropic disease,
although thyroid disease is uncommon in horses, weight loss lymphocytic-plasmacytic enterocolitis, and idiopathic eosino-
has been recognized in association with hyperthyroidism and philic enterocolitis.142 Some other potential gastrointestinal
the accompanying increase in basal metabolic rate.135,136 causes of weight loss and hypoproteinemia in horses include
parasitism, right dorsal colitis, and proliferative enteropathy

BOX 7.3
Mechanisms and Selected Differential Diagnoses due to Lawsonia intracellularis.
for Decreased Body Weight Other important causes of weight loss include inter-
nal abscessation, neoplasia, and chronic organ dysfunc-
Mechanism Differential Diagnoses tion.141,143-149 Internal abscesses can be difficult to diagnose.
Lack of access to Unappetizing or inappropriate types Although a multitude of organisms may be involved, Strepto-
appropriate food of feed coccus equi subspecies equi (strangles) and Corynebacterium
Poor-quality feed pseudotuberculosis (pigeon fever) are particularly important.
Insufficient quantity of feed Weight loss is a common clinical finding in horses with either
Inability to access the available feed: chronic hepatic or renal disease, and weight loss has also been
Lameness, other musculoskeletal recognized with heart failure. In some cases, recurrent airway
abnormality obstruction can also be associated with significant weight loss.
Social factors within the herd Several neoplastic conditions can cause weight loss, and in
(“pecking order”) horses, lymphosarcoma is particularly common.
Endocrine disorders have also been associated with changes
Lack of ingestion of Lack of appetite
in body weight. In horses, PPID is a common disorder that can
available nutrients Inadequate prehension
be associated with either abnormal fat deposition or weight
Nigropallidal encephalomalacia
loss and muscle wasting.115,140 Although uncommon, hyper-
Masseter myodegeneration
thyroidism has been documented in horses, with weight loss
Abnormal mastication
being a major feature.135,136,150,151 Rarely, diabetes mellitus has
Poor dentition
been identified in horses.152
Masseter myodegeneration
Weight loss can be a component of a variety of other condi-
Abnormal swallowing
tions. Persistent infection with equine infectious anemia virus
Dysphagia
can result in weight loss, although many cases are subclinical.153
Abnormal esophageal transit
Several toxins have been associated with weight loss through a
Esophageal abnormalities
variety of mechanisms. For example, yellow star thistle toxicity
Abnormal digestion, Gastrointestinal dysfunction causes significant dysphagia, and pyrollizidine alkaloids and
absorption, or Gastrointestinal ulceration alsike clover cause hepatic disease. Some other potential toxic
metabolism of Inflammatory bowel disorder causes of weight loss include selenium, lead, wild jasmine (Ces-
nutrients Neoplasia trum diurnum), and hairy vetch (Vicia villosa), among others.
Parasitism Chronic pain may also result in weight loss.
Hepatic dysfunction Muscle atrophy may occur either as a component of gener-
Toxicities alized weight loss, as in starvation and cachexia, or as a separate
Inadequate delivery Cardiovascular disease entity. Muscle loss is often prominent in association with aging
of nutrients to Heart failure and PPID. Some direct causes of muscle atrophy include dis-
peripheral tissues Respiratory disease use and neurogenic muscle atrophy. Progressive muscle wast-
Recurrent airway obstruction ing and weight loss are prominent features of equine motor
(chronic obstructive pulmonary neuron disease, which is a neurodegenerative disorder linked
disease) to vitamin E deficiency.154 Other signs include weakness, mus-
Hepatic disease cle fasciculations, shifting weight, and increased recumbency.
Increased rate of Unusual levels of physical activity
Also, rapid muscle atrophy affecting primarily the epaxial and
protein and energy Late gestation, early lactation
gluteal muscles has been associated with immune-mediated
use or loss Adaptation to environmental
myositis, particularly in Quarter Horses.155
conditions (e.g., cold)
Diagnostic Approach to Weight Loss
Neoplasia
Infection, inflammation
Signalment and History. The signalment and history
Pneumonia
should be considered when evaluating a horse with weight
Pleuritis
loss. Some conditions, such as certain dental disorders and
Peritonitis
PPID, are more common in older horses. Lawsonia intracel-
Equine infectious anemia
lularis primarily affects weanling-age foals.
Pain
An accurate diet history is particularly important. The
Heart failure
type, amount, and quality of feed should be documented,
Endocrine disorder
and it should be determined whether additional micronutri-
Pituitary pars intermedia dysfunc-
ents or supplements are being fed. It is important to ensure
tion
that assessment of the amount is accurate by weight, because
Gastrointestinal disease
many owners feed by volume. The age, use, and condition of
Renal disease
the horse should be considered when evaluating the feeding
program because these may affect nutritional requirements.
Primary muscle Neurogenic muscle atrophy The feed should be evaluated for the presence of mold or toxic
wasting disorders Primary muscle disease plants. The potential availability of vitamin E in the diet should
Equine motor neuron disease be considered. Feed analysis can often be beneficial in assess-
Immune-mediated myopathy ing feed quality. The particulars of the feeding management
Polysaccharide storage myopathy should be determined, such as the feeding schedule, the types
of feeders, potential access to sand, and the water source. It Additional diagnostic testing, such as serum or whole
should be established if there are other horses on the property blood trace mineral analysis, determination of vitamin E
and if so whether there is competition among horses for feed concentrations, thyroid testing, and testing for PPID, may
and if the weight loss affects more than one individual. Also, be indicated for some horses with weight loss, determina-
the appetite of the horse should be determined. tion of vitamin E concentrations, thyroid testing, and testing
General historical information is also important when eval- for PPID. Baseline concentrations of thyroid hormones often
uating weight loss. This includes the history of deworming, do not accurately reflect thyroid status due to the number
dental care, and any use of medications, such as nonsteroidal of confounding variables, and additional testing is generally
antiinflammatory drugs. Any history of abnormal shedding, recommended.150,151,156-158
as well as any history of previous disease, such as strangles, ENDOSCOPY. Endoscopic evaluation may aid in the evalua-
pigeon fever, or laminitis, can be relevant. tion of pharyngeal function and guttural pouch disease. It can
Physical Examination. A complete general physical ex- also be helpful in assessing the esophagus and examining the
amination should be performed. The BCS and, if possible, stomach for equine gastric ulcer syndrome or gastric squa-
the body weight should be determined. Observing the animal mous cell carcinoma.
while eating can be important to establish whether it can pre- DIAGNOSTIC IMAGING. Imaging of the thorax by ultrasound
hend, masticate, and swallow normally. Neonatal foals should and radiographs can be useful in the evaluation of thoracic
be observed suckling and evaluated for milk coming from the disease. Ultrasound can be used to assess the abdomen and
nostrils. The mare’s udder and the milk should be examined. can help to assess fluid volume and character, intestinal wall
The clinical examination should include a thorough oral ex- thickness, and abdominal masses. Abdominal radiographs
amination, rebreathing examination, and rectal palpation. A may be useful in foals, but in adult horses they are often im-
neurologic examination may also yield useful information. practical, and the diagnostic utility is generally limited to the
The presence of concurrent clinical signs, such as fever, diar- identification of enteroliths or excessive sand accumulation.
rhea, cough, nasal discharge, a heart murmur, polyuria/poly- Echocardiography may be indicated especially in cases where
dipsia, icterus, and abnormal shedding or hypertrichosis, can a murmur or arrhythmia is identified on physical examina-
point more quickly to a specific cause of weight loss and help tion.
direct additional testing. OTHER. Oral absorption tests using either D(+)-xylose or
Ancillary Diagnostic Tests. A number of ancillary tests can glucose to identify malabsorption can be useful in the evalu-
be useful in the diagnosis of weight loss, and tests should be ation of unexplained weight loss.142,159,160 Although xylose
prioritized based on the signalment, history, and physical ex- is less affected by metabolic factors, glucose absorption is a
amination findings. valid, practical means of assessing malabsorption. Intestinal
CLINICAL PATHOLOGY/LABORATORY TESTING. A CBC, fi- biopsy is often necessary to identify the specific cause of the
brinogen, and serum chemistry can be useful and is gener- malabsorption.
ally part of the minimum database. The white blood cell count
and fibrinogen may be elevated with active infection. Several Y COUGH
parameters may support a diagnosis of chronic inflammation
including anemia, hyperfibrinogenemia, hyperglobulinemia, Cough is a sudden, forceful expulsion of air through the glot-
and thrombocytosis. These changes may support internal ab- tis that generates a characteristic sound. Although cough is a
scessation. Hypoproteinemia, and particularly hypoalbumin- normal reflex mechanism that is important in protection of
emia, is seen with protein losing conditions, such as gastroin- the airways, it is also a common sign of disease in multiple
testinal or renal disease and third space loss, or with decreased species. Cough promotes ciliary activity and generates the
protein production, which can be seen with significant liver high air flows necessary to shear mucus from the airway walls,
disease. A common cause of hypoalbuminemia in horses with thus acting to remove secretions and foreign particles from the
weight loss is protein losing enteropathy. The serum chemis- respiratory tract and prevent pulmonary aspiration. Specific
try may support a diagnosis of renal or hepatic disease, and data related to the importance of an intact cough mechanism
a urinalysis can help in the evaluation of renal disease. The in horses are limited, but in human patients an inefficient
presence of hypercalcemia may indicate possible renal disease, cough reflex has been associated with atelectasis and recurrent
hyperparathyroidism, or neoplasia. However, it should be re- pneumonia.161-163 Although cough is an important protective
membered that hypercalcemia of malignancy is an inconsis- mechanism, excessive cough is a common sign of disease and
tent finding in horses with neoplasia. can have deleterious effects. In human medicine, cough has
Parasitism can contribute to weight loss even if it is not the been estimated to account for up to 40% of outpatient prac-
primary problem. Assessment of parasite status should include tice.164-166 Cough is also a common clinical problem in horses.
fecal flotation with a fecal egg count; a Baermann analysis and Even when not associated with significant systemic disease,
tapeworm enzyme-linked immunosorbent assay (ELISA) cough can be performance limiting in the equine athlete.
should be considered. Feces should also be assessed for the
consistency and fiber length, as well as the presence of sand. Mechanisms of Cough
Sampling of the airway via transtracheal aspirate or bron- Cough is a highly coordinated reflex action that can be mod-
choalveolar lavage can be useful in evaluating pulmonary dis- ulated by voluntary input. All mammalian species that have
ease. Culture and cytology of pleural or peritoneal fluid can been studied either cough or display a similar respiratory
also be useful; however, it should be remembered that many reflex.167 Despite the prevalence and clinical importance of
neoplastic conditions do not exfoliate significant numbers of cough, the precise mechanisms involved are not fully under-
cells, making diagnosis of neoplasia often challenging. Aspira- stood. Much of the information reported regarding the mech-
tion or biopsy of appropriate tissues may be indicated when anism of cough in horses has been extrapolated from other
possible. species. Some species-related differences, however, are known
to exist.167 Age and gender are also known to influence cough. Afferent Pathways Regulating Cough. Cough is initiated
The cough reflex can be poorly developed in neonates and can by the activation of sensory vagal afferent nerves that pri-
be compromised in association with aging.168,169 These age- marily innervate the respiratory tract, although they may be
related differences may contribute to an increased susceptibil- found in additional sites such as the ear in some species.178-182
ity to aspiration and respiratory infections in these age groups. Though all vagal in origin, this population of afferent nerves
Interestingly, in humans an increased sensitivity of the cough is not homogeneous, and several subtypes have been identi-
reflex has been recognized in females following puberty, and fied. Some of the differences between subtypes include their
women are more likely to develop chronic cough.170-172 distribution within the respiratory tract as well as the pres-
ence of myelination, the receptor type and sensitivity to vari-
Cough Cycle ous stimuli, and the location of the cell bodies, which can be
There are three phases of the cough cycle: inspiratory, com- within either the nodose and/or jugular ganglia. In general,
pressive, and expiratory.173-175 These phases are generally these nerves respond to chemical and/or mechanical stimuli,
followed by a period of relaxation. In the inspiratory phase, with different thresholds for the various stimuli. There is no
inhalation essentially generates the volume necessary for an single classification scheme, but the subtypes are often func-
effective cough. A variable amount of air is inhaled and serves tionally classified broadly as being either primarily sensi-
to lengthen the expiratory muscles, optimizing the length- tive to mechanical stimuli (mechanosensors) or to chemical
tension relationship. This expansion of lung volume allows stimuli (chemosensors, sometimes referred to as nociceptors).
for an increase in the subsequent velocity of expiratory air- Although both types can be located throughout the airways,
flow due to greater force of contraction from the lengthened mechanosensors tend to predominate in the larynx and large
muscles and greater elastic recoil pressure. airways. Among the most studied subtypes of sensory affer-
The compressive phase of cough consists of a very brief (200 ents are the rapid-adapting receptors (rapidly adapting stretch
msec) closure of the glottis to maintain lung volume as isomet- receptors), slow-adapting receptors (slowly adapting stretch
ric contraction of the expiratory muscles occurs. Muscles of the receptors), and C-fibers. Several other receptors, including a
chest wall, diaphragm, and abdominal wall contract against the possible specific cough receptor, have been described. Overall,
closed glottis, resulting in a rapid rise in intrathoracic pressure. the relative contribution of the various subtypes in the genera-
The expiratory phase starts with opening of the glottis as tion of cough is still uncertain and may be species dependent.
the expiratory muscles continue to contract, resulting in the These nerves often contribute to other functions within the
release of air. There is a brief period of supramaximal expi- respiratory tract, such as enhancing mucus secretion, initiat-
ratory flow, sometimes referred to as the cough spike, which ing bronchoconstriction, and influencing the rate and depth
is then followed by lower expiratory flows. Due to relative of respiration.
changes in pleural and airway pressures there is dynamic com- RAPID-ADAPTING RECEPTORS AND SLOW-ADAPTING RECEP-
pression of the larger airways during expiration, which helps TORS. Rapid-adapting receptors (RARs) and slow-adapting
to maximize the velocity of airflow by decreasing the airway receptors (SARs) are myelinated nerves that originate pri-
diameter. The high-velocity turbulent airflow results in airway marily in the nodose ganglion.178-181 RARs are present in
vibration, which is largely responsible for the sound recog- both extrapulmonary and intrapulmonary airways, whereas
nized as cough. Importantly, the high flows generated in the SARs are predominantly within the intrapulmonary airways
expiratory phase dislodge mucus and facilitate the removal and lung parenchyma and are sparse in extrapulmonary air-
of mucus and debris from the tracheobronchial tree. At the ways. Although there are some differences in the exact stimuli
end of cough, expiratory muscles relax, intrapleural pressure they respond to, they are both predominantly low threshold
decreases and transient bronchodilation may occur. mechanosensors that may respond to a variety of stimuli such
The specific pattern of cough can vary and is sometimes as changes in lung volume and changes in airway diameter
broadly categorized into two types.173 Laryngeal cough, due to smooth muscle constriction, airway wall edema, or the
which functions primarily to protect the airway from aspi- presence of mucus.
ration, is triggered by mechanical stimulation of laryngeal C-FIBERS. The majority of vagal airway afferent nerves
receptors and is a true reflex, sometimes referred to as the are unmyelinated C-fibers that originate primarily in the
expiratory reflex. The inspiratory phase is minimal, and expi- jugular ganglion.178-181 They innervate the epithelial layer
ration occurs rapidly. Tracheobronchial cough is stimulated throughout the extrapulmonary and intrapulmonary respi-
primarily by receptors distal to the larynx and has a more ratory tract. A type of nociceptor, C-fibers are predominant-
prominent inspiratory phase in order to generate the greater ly chemosensors that respond to a wide variety of stimuli
airflows necessary to remove secretions and debris from the including both high and low temperatures, nonisotonicity,
tracheobronchial tree. It may occur either as a reflex or by low pH, irritants, and inflammatory mediators. They can
voluntary control. have multiple receptors, including neuronal transient recep-
tor potential (TRP) channels such as ankyrin 1 (TRPA1) and
Neurophysiology of Cough vanilloid 1 (TRPV1).183,184 Most C-fibers are known to re-
Coughing is a complex visceral reflex that can be both vol- act with capsaicin, and it appears that this occurs primarily
untarily and involuntarily regulated.176-179 The neurologic through the TRPV1 receptor. Also, the TRP receptors may
control of cough is still under investigation, and an improved be important in disease states as they can be activated by
understanding has therapeutic implications for the control of reactive oxygen species generated during inflammation, and
cough. Basically, cough can be compartmentalized into three TRP channel antagonists are being investigated as potential
components: (1) stimulation of sensory afferent nerves, (2) antitussive agents.185-187 PGE2, which is released in associa-
integration of the information in the brainstem and higher tion with airway inflammation, acts directly on pulmonary
brain centers, and (3) activation of efferent pathways to the C-fibers to increase their sensitivity and lower the cough
muscles involved in the generation of cough176-179 (Fig. 7.2). threshold.188
Peripheral Afferent Pathway Cough Stimulus
Airway Receptors
RARs, SARs, C-fibers, other
Vagus Nerve
Central Pathway Brainstem Cortex

Nucleus tractus solitarius
Cough pattern generator
Peripheral Efferent Pathway Efferents to Laryngeal & Respiratory Muscles, Pelvic
Sphincters
Cough
FIG. 7.2 Simplified schematic of the neurophysiology of cough.
The initiation of cough is a complex activity with multiple is centrally integrated primarily within the nucleus tractus
interactions between the afferent nerve subtypes.178-181,189 For solitarius (nTS) of the medulla oblongata in the brainstem.
example, activated C-fibers release neuropeptides including Neurons within the nTS communicate with other brainstem
substance P, neurokinin A, and calcitonin gene–related pep- neurons as part of a multifunctional, dynamic neural network
tide. These neuropeptides can cause bronchospasm, edema that functions in both generation of the normal breathing pat-
formation, and mucus secretion, which in turn can lead to tern and cough. This neural network has been referred to as
activation of the RARs. Without the activity of the RARs and the cough pattern generator as well as the respiratory pattern
SARs, C-fibers are limited in their ability to evoke cough. generator or central controller. When cough occurs, there is
Bronchoconstriction and cough are closely interrelated but reshaping of the discharge patterns of respiratory neurons
can also have distinct pathways.190,191 Some, but not all, stim- within this neural network resulting in discharges being trans-
uli for cough will also cause reflex bronchoconstriction, which mitted to the motor neurons involved in cough. Projections
generally has a slower onset and longer duration than cough. between the brainstem and cortical centers add complexity
Bronchoconstriction itself can be a stimulus for cough and, to the regulation of both breathing and cough. Due to corti-
up to a point, can improve the efficiency of cough by decreas- cal modulation, some cough can be voluntarily initiated and
ing airway diameter and thus increasing airflow velocity. Some suppressed. Among the receptors involved in the generation
therapies affect either bronchoconstriction or cough, whereas of cough in the brainstem are N-methyl-d-aspartate (NMDA)
others affect both. For example, some bronchodilator drugs receptors, and in several species antagonists of NMDA-type
can also decrease cough by desensitizing airway receptors that glutamate receptors such as dextromethorphan have been ef-
initiate cough. fective antitussives.195,196
Central Regulation of Cough. The mechanisms controlling Activation of Efferent Pathways. Signals from the brain-
the central regulation of cough are complex, involving both stem and cerebral cortex are transmitted via a number of effer-
the brainstem and higher brain centers.177,179,192-194 The af- ent nerves to the muscles involved in cough.173,178 Important
ferent sensory nerve input arising from the respiratory tract efferent nerves include the vagus, phrenic, intercostal, and
lumbar nerves. In addition to the vagus, several other cranial

nerves play a role, including the trigeminal, facial, hypoglos- BOX 7.4
Causes of Cough with Fever
sal, and accessory nerves. The efferent nerves involved in
cough supply the muscles of the larynx and tracheobronchial Common Causes Major Diagnostic Test(s)
tree, the diaphragm, and the intercostal, abdominal, and pel- Viral respiratory tract disease Nasal or nasopharyngeal
vic muscles, as well as secretory glands of the respiratory tract. Equine influenzavirus swab
The coordinated activity of these muscles results in cough. Equine herpesviruses Polymerase chain reaction
Cough Efficiency/Adverse Effects. The effectiveness of Equine rhinitis viruses A (PCR)
cough is dependent on the ability to generate high flow veloc- and B Viral isolation
ities and the interaction of the flowing air with airway secre- Equine viral arteritis Viral antigen detection
tions.173 In general, cough is more effective in clearing large Adenovirus Serology
airways as opposed to smaller peripheral airways. Cough ef- Other
ficiency is affected by the integrity of the neurophysiologic Bacterial pneumonia/ Radiographs/ultrasound
pathway of cough as well as physical aspects, such as respira- pleuropneumonia (includ- Transtracheal aspirate/
tory muscle strength and mucus quality. Normal mucus acts ing aspiration pneumonia, thoracocentesis
to improve airway clearance and protect receptors from ir- pulmonary abscesses) Cytology
ritants, and changes in the amount or tenacity of mucus can Culture and sensitivity
both mechanically stimulate cough receptors and cause flow PCR
limitation.173,197,198 Cough is often less effective as a clear-
ance mechanism when airway disease is present. Less Common Causes Major Diagnostic Test(s)
Not only does cough lose its defensive function is some dis- Fungal pneumonia Radiographs/ultrasound
ease conditions, but it may even have deleterious effects.173,199 Transtracheal aspirate/
Lung expansion during the inspiratory phase may allow for thoracocentesis
the spread of infectious agents and particulate matter into the Cytology
smaller airways. Paroxysmal or persistent coughing can cause Fungal culture
fatigue and may decrease feed intake, particularly in foals. Serology
Chronic cough can result in bronchial muscle hypertrophy.
Interstitial pneumonia Radiographs
Cough can also have significant cardiovascular effects due to
Equine multinodular PCR—EHV 5
changes in abdominal and intrathoracic pressures.199,200 Dur-
pulmonary fibrosis Lung biopsy
ing the expiratory phase of cough there is an initial rise in sys-
Syndromes of acute lung
temic arterial blood pressure and a concurrent rise in cerebral
injury, acute respiratory
venous and cerebrospinal fluid pressures. This is followed by a
distress
period of hypotension, which can reduce the effective perfu-
sion pressure of the brain, especially when there is high cere- Neoplasia Radiographs/ultrasound
bral venous pressure. The resulting cerebral hypoperfusion Endoscopy
and anoxia have been associated with cough-induced syncope Transtracheal aspirate/
in dogs as well as people.201,202 Some other potential adverse thoracocentesis
effects of cough that have been reported in small animals and Cytology (often low yield)
people include pneumothorax, pneumomediastinum, and Biopsy
lung lobe torsion, as well as rib and vertebral fractures.199,202 Smoke inhalation History
Conditions Associated with Cough Other—parasitic pneumoni-

tis, cardiogenic cough
The potential causes of cough are diverse, as the cough recep-
tors can respond to a wide variety of mechanical and irritant
stimuli.173-181,183,203 Some general stimuli of cough include
inhaled particles or irritants, inflammatory mediators, bron- from the upper or lower airway. Categorizing cough can be
choconstriction, excessive mucus, exposure to cold or hot air, useful in establishing a list of differentials for cough, although
sloughing of airway epithelial cells, and pulmonary edema. there can be considerable overlap between the categories. The
Intramural or extramural tension on the airways, such as that presence or absence of fever may be particularly useful when
seen in association with masses or decreased pulmonary com- considering the causes of cough (Box 7.4).
pliance, can result in cough. The sensitivity of cough receptors
is influenced by a number of factors, such as genetics, age, and Causes of Cough Associated with Fever
the presence of disease. Most often, the cough reflex becomes Cough in conjunction with fever is most often associated
hyperresponsive once respiratory disease is established due to with infection of the respiratory tract, although some non-
both increased exposure of the cough receptors due to a loss infectious conditions such as neoplasia can also occasionally
of the integrity of the epithelial lining and increased sensitivity present with fever. Infection of the respiratory tract may be
of the receptors in response to inflammation. It is important to primary or may be secondary to an underlying condition
remember, however, that significant respiratory disease can be such as inflammation of the airways. Viral infections of the
present without cough. respiratory tract are a common cause of cough in horses
The specific causes of cough have been categorized in and are particularly important as they can cause outbreaks
a number of ways, such as the duration of signs (acute or of respiratory disease.203,204 Affected horses often present
chronic), the presence or absence of fever, whether the cough with an acute onset of a dry cough in conjunction with fever,
is productive or not (wet or dry), and whether it originates lethargy, and anorexia. Some important equine respiratory
viruses include equine influenzavirus, equine herpesviruses obstructive pulmonary disease, SPAOPD) is a subset of RAO
(EHVs), equine rhinitis A and B, and equine viral arteritis. in which signs occur after exposure to pasture in warm sum-
With regard to the equine herpesviruses, EHV-4 and EHV-1 mer months. RAO primarily affects horses over 7 years of age.
are the major pathogens associated with acute respiratory The prevalence of RAO is approximately 10% to 20%, and a
disease in the domestic horse population.204,205 Respiratory familial predisposition has been identified.219-222 Affected
viruses frequently cause exposure and sensitization of cough horses typically have frequent coughing, increased respiratory
receptors, along with injury to epithelial cells and decreased effort at rest, and exercise intolerance. With IAD, horses may
mucociliary clearance, which can predispose the affected be affected at any age, and the clinical signs are more subtle.
horse to secondary bacterial infection. In addition to viruses, Both RAO and IAD are characterized by increased mucus in
both bacterial and fungal agents can cause infection of the the airways. With regard to the specific cytologic abnormali-
respiratory tract, and are often associated with a periodic ties in the bronchoalveolar lavage fluid (BALF), RAO is typi-
wet cough due to increased mucus production and neutro- cally characterized by pronounced neutrophilia (greater than
phil accumulation. Bacterial infection is particularly com- 25%), whereas in IAD the abnormalities tend to be milder
mon in the lower respiratory tract and can cause bronchitis, and more variable. Other conditions that can resemble equine
pneumonia, or pleuropneumonia.206,207 A variety of organ- asthma clinically include silicosis, lungworm infection, and
isms have been isolated and polymicrobial infections may idiopathic eosinophilic pneumonia.223-226
occur. Some common pathogens include Streptococcus equi It is not uncommon for horses to cough occasionally, espe-
subspecies zooepidemicus, Pasteurella, Actinobacillus spp., cially at the beginning of exercise. These coughs are sometimes
Escherichia coli, and Klebsiella pneumoniae. Rhodococcus referred to as arena cough, warm-up cough, or nuisance cough
equi is an important cause of pneumonia in foals. Anaerobic depending on the exact circumstances. This type of cough may
organisms, such as Bacteroides fragilis and Peptostreptococ- reflect cough’s function as part of the normal defense mecha-
cus anaerobius, may also infect the lower airways of horses. nisms of the respiratory tract, as it is not uncommon for clini-
Mycobacterium and Mycoplasma spp. are occasionally iso- cally normal horses to have some mucus accumulated behind
lated from horses with respiratory tract disease.206,208 Fungal the larynx waiting to be expelled. Also, horses breathe more
respiratory disease in horses is uncommon and is most often deeply during exercise, and the environment in some riding
recognized in the paranasal sinuses, guttural pouches, and arenas can be dusty. Although this type of cough is gener-
lungs.209,210 Some primary fungal pathogens that have been ally relatively innocuous, it may indicate poor air quality and
identified in association with respiratory disease in the horse may also be a sign of early disease. Thus all horses with cough
include Coccidioides immitis, Cryptococcus neoformans, His- should be monitored closely.
toplasma capsulatum, Blastomyces dermatitidis, and Conid- Parasitic pneumonitis is another cause of cough that is
iobolus coronatus. Opportunistic fungi, such as Aspergillus generally afebrile, although occasionally fever may be seen. In
spp., Candida spp., and Pneumocystis carinii, can also cause foals, the larvae of Parascaris equorum migrate through the
respiratory tract disease. Following recovery from infectious lungs and can occasionally cause a significant inflammatory
respiratory tract disease of any cause, horses will often have response resulting in cough and nasal discharge.203 Horses
a persistent wet or dry cough as the cough receptors remain infected with the lungworm Dictyocaulus arnfeldi can have
hypersensitive. chronic cough and mucoid nasal discharge.224,225 Affected
Interstitial pneumonia has been reported in horses of all horses often have a history of contact with donkeys or mules.
ages in association with both acute and chronic respiratory In donkeys and mules, infection is generally asymptomatic but
disease.211,212 Horses with interstitial pneumonia frequently is patent, providing a source of eggs in the feces. In horses and
have marked tachypnea with increased respiratory effort, and ponies, infection often results in an inflammatory response
cough and fever can be present as well. Some specific types and cough and is typically not patent, with larval development
of interstitial pneumonias include equine multinodular pul- arrested in the lungs.
monary fibrosis and syndromes of acute lung injury and acute Exercise-induced pulmonary hemorrhage (EIPH) is defined
respiratory distress. Although interstitial pneumonia has been by the presence of hemorrhage in the airways of a horse after
linked to a variety of causes, in many cases an underlying cause exercise.227,228 It is common in Thoroughbred and Standard-
is not identified. Equine multinodular pulmonary fibrosis has bred racehorses and in other horses performing strenuous
been linked to EHV-5 infection.212 exercise, such as barrel racing horses. The clinical abnor-
Other conditions may occasionally present with cough malities seen with EIPH are not consistent but may include
in association with fever. Thoracic neoplasia is uncommon epistaxis, increased respiratory rate, poor performance, and
in horses and presents with variable clinical signs that may coughing.
include cough with or without fever.213 Smoke inhalation may Congestive heart failure, although not common in horses,
cause a significant inflammatory response and edema result- can result in cough.229,230 In particular, in left-sided heart fail-
ing in tachypnea, cough, and fever.214 Fever may occasionally ure, blood is not effectively pumped from the left side of the
be present with parasitic or cardiogenic cough. heart, leading to increased blood in the pulmonary circulation
and increased pulmonary vascular pressure. Vascular conges-
Causes of Cough Without Fever tion and pulmonary edema follow, and cough receptors are
Among the most common causes of cough without fever in stimulated. In a study of 14 horses with congestive heart fail-
horses is a spectrum of chronic inflammatory airway dis- ure, all horses presented with a heart murmur and tachycar-
ease that is now referred to as equine asthma syndrome.215-218 dia.229 Other common clinical signs included cough, crackles,
Included in this syndrome are inflammatory airway disease tachypnea, ventral edema, and either jugular distention or
(IAD, mild to moderate equine asthma) and recurrent air- pulsation. The underlying causes for heart failure included
way obstruction (RAO, severe equine asthma). Summer pas- congenital defects, traumatic vascular rupture, pericarditis,
ture-associated RAO (SPARAO, summer pasture-associated pulmonary hypertension secondary to RAO, and valvular
dysplasia. Fever is not generally associated with cardiogenic increase the suspicion of infectious respiratory disease. The
cough but may be present in some horses, especially those risk of lungworm infection is increased by exposure to don-
with pericarditis or endocarditis. keys or mules.224,225 EIPH is associated with strenuous exer-
A number of disorders of the upper airway can result in cise.227 The geographic area may raise the suspicion of some
cough. Pharyngitis, also referred to as pharyngeal or follicu- conditions such as silicosis, which has been reported primarily
lar lymphoid hyperplasia, is a relatively common disorder that in California, and certain mycotic infections, such as Coccidi-
is recognized primarily in young horses.203,231,232 It is most oides immitis, which is found primarily in the southwestern
likely the result of the lymphoid response to a variety of irri- United States.209,210,223 Any history of previous disease, as well
tant or infectious stimuli. Although many cases are subclinical, as a history of signs such as stridor or exercise intolerance, can
coughing, nasal discharge, and mild submandibular lymph- also be important.
adenopathy may be present. Dynamic or static compression The historical aspects of the cough itself can be helpful in
of the upper airway such as may be seen with dorsal displace- the evaluation of horses with cough. These include whether
ment of the soft palate, fourth branchial arch defect (rostral the cough is acute or chronic, any seasonal pattern, the fre-
displacement of the palatopharyngeal arch, laryngeal dyspla- quency of the cough, and any association with feeding or exer-
sia), aryepiglottic fold entrapment, subepiglottic cyst, aryte- cise. It can be helpful to establish if the cough is nonproductive
noid chondritis/chondrosis, and laryngeal hemiplegia, may or productive, although this can be difficult to discern.
also be associated with cough, which is often dry in nature.203
Although clinical signs vary, these disorders are often charac- Physical Examination
terized by abnormal breath sounds such as stridor or stertor A complete physical examination, including a detailed exami-
at rest or during exercise as well as normal lung sounds and nation of the respiratory system, should be performed in horses
absent or minimal mucopurulent discharge. Soft palate prob- presented for evaluation of cough. The character of any nasal
lems, including soft palate paresis, dorsal displacement of the discharge should be noted. The presence of a fever increases
soft palate and cleft palate, and other causes of dysphagia, can the likelihood of infectious respiratory tract disease, although
result in cough that is often associated with eating. In some noninfectious conditions may occasionally be associated with
cases, disorders such as sinusitis and guttural pouch mycosis fever. It should be remembered that fever can be intermittent
or empyema will result in cough due to the presence of exudate and can be suppressed by the administration of nonsteroidal
in the upper airways. antiinflammatory drugs. Careful auscultation of the thorax
Tracheal abnormalities may also result in cough. These should be performed. The presence of a heart murmur and
include tracheal stenosis, collapse, and partial obstruction tachycardia may suggest congestive heart failure, especially if
such as may be seen with a foreign body or neoplasia. Tra- there is jugular distention or pulsation.229 If the horse can tol-
cheal collapse is typically associated with an inspiratory honk- erate it, a rebreathing examination should be performed, espe-
ing sound. It is most often diagnosed in American Miniature cially if there are no obvious abnormal sounds during quiet
Horses but may be seen in other horses as well and has been breathing. The rebreathing examination, which is performed
reported in association with pneumonia.233-235 by loosely placing a plastic bag over the nostrils, will cause the
horse to increase tidal volume, accentuating breath sounds.
Diagnostic Approach to Cough Cough may be induced, especially if there is exudate in the
Cough is a common clinical problem that can be associ- airways. The presence of crackles and/or wheezes on ausculta-
ated with a number of diverse disorders. The diagnosis of tion suggests pulmonary parenchymal disease. With pulmo-
the specific cause of cough is based on consideration of the nary consolidation, atelectasis, or pleural fluid, breath sounds
signalment, history, and clinical signs, as well as the use of are typically decreased or absent ventrally, although occasion-
appropriate diagnostic aids. ally sounds may be accentuated due to referral of sounds from
aerated lung. Percussion can be used to identify areas of dull-
Signalment and History ness. In horses with significant RAO, percussion can be used
The signalment can help to prioritize the differential diag- to identify a shift of the caudal lung border.236
noses in a horse presented for cough. Pneumonia caused by
Rhodococcus equi is most common in foals 1 to 6 months of Ancillary Diagnostic Tests
age.207 Although viral respiratory diseases can be seen in any Clinical Pathology. A CBC and fibrinogen are frequently
age horse, they are particularly common in weanling and indicated in the assessment of horses with cough, and in some
yearling horses.204 Pharyngitis is also most common in young cases a serum chemistry may also be useful. Acute viral infec-
horses.231,232 Horses with RAO are typically over 7 years of age, tion can be associated with leukopenia characterized primar-
and a familial predisposition has been identified.215-218 The risk ily by lymphopenia.204 A transient anemia may be seen as well.
of developing RAO is threefold when one parent is affected Neutrophilia and hyperfibrinogenemia are seen with many
and almost fivefold when both parents are affected.221,222 inflammatory conditions, especially bacterial or fungal pneu-
Several components of the history are important in the monia.206 Inflammatory conditions may also be associated with
assessment of a horse with cough. Routine management fac- anemia, hyperglobulinemia, and thrombocytosis, especially if
tors such as vaccination, deworming, stabling, and bedding chronic. Hematologic values are usually unremarkable in horses
type, as well as the feed type, feed quality, and feeding prac- with uncomplicated equine asthma.216 Although not consistent,
tices, are of particular importance. Risk factors for infectious peripheral eosinophilia may be seen with idiopathic eosinophil-
respiratory disease include exposure to new horses, either at ic pneumonia, parasitic pneumonitis, and occasionally eosino-
an event or through new arrivals to the farm, and stress, such philic IAD.216,224-226 Hypercalcemia can be seen in some horses
as recent transport, surgery, weaning, or strenuous activity. with malignancy.
A history of other clinical signs such as fever, lethargy, and An arterial blood gas evaluates air exchange and helps to
anorexia, as well as the involvement of other horses, may monitor the severity of respiratory disease. In some horses
with chronic or recurrent infectious disease, measurement of performed without sedation if possible. Endoscopy can iden-
immunoglobulin concentrations may help identify an under- tify exudate, anatomic or functional abnormalities, mass le-
lying immunodeficiency. There has been a growing interest in sions, and airway obstruction. On occasion, lungworm lar-
the use of biomarkers to evaluate disease states. Although find- vae may be seen in the trachea. Pleuroscopy can be used to
ings are often nonspecific, serum amyloid A and fibrinogen evaluate the pleural space.
are two biomarkers commonly used to evaluate inflammatory An endoscopic mucus scoring system has been developed
disease.237 In racehorses with IAD, increased concentrations to quantify mucus in the trachea (0—no visible mucus, 1—
of surfactant protein D (SP-D) have been described, and in single to multiple small blobs of mucus, 2—larger but non-
horses with RAO, soluble CD14 concentrations are increased confluent blobs, 3—confluent or stream forming mucus,
compared with controls.238,239 4—pool forming mucus, 5—profuse amounts of mucus).247
Airway Cytology. Several techniques have been described Normal horses tend to be either grade 0 or 1, whereas those
for sampling the respiratory tract of horses.240-246 The pri- with equine asthma are 2 to 5.216,248 Studies have shown asso-
mary means of sampling the lower respiratory tract include ciations between the amount of mucus present in the airways
bronchoalveolar lavage and tracheal wash. Tracheal wash is with coughing and poor performance.232,249-251
often used for the diagnosis of infectious pneumonia. Anal- Diagnostic Imaging. Radiographs and ultrasound are use-
ysis of BALF is recommended for the diagnosis of equine ful in the evaluation of horses with either suspected upper
asthma.215,216 RAO is characterized by a moderate to severe or lower airway cough.246 Radiographs of the upper airway
neutrophilia (greater than 25%), whereas in IAD the changes can demonstrate fluid accumulation, soft tissue masses, and
are more varied and may include a mild to moderate increase abnormalities of pharyngeal and laryngeal structures. Ultra-
in neutrophils (greater than 10%), eosinophils (greater than sound can be used to evaluate laryngeal problems such as left
5%), and/or mast cells (greater than 5%). BALF fluid cytology laryngeal hemiplegia, laryngeal dysplasia, arytenoid chondri-
is also useful in the diagnosis of EIPH, which is characterized tis, and congenital malformations. Thoracic ultrasonography
by the presence of erythrocytes and hemosiderophages. is a practical means of assessing the thorax and can provide
Assessment of Infection. Currently a nasal or nasopharyn- diagnostic information about the pleural cavity, lung, and me-
geal swab is the preferred sample for diagnosis of most viral diastinum. The presence and character of pleural fluid can be
respiratory infections.204 A Dacron or rayon swab is preferred determined, and abnormalities such as consolidation and ab-
compared with cotton. Detection of genetic material by PCR is scessation in the periphery of the lung can be identified. In
a common means of virus identification, although virus isola- addition, the caudal lung borders can be determined. If con-
tion can be performed as well. There are also several means of gestive heart failure is suspected, the heart can be evaluated by
viral antigen detection. For example, direct immunofluores- echocardiography. Thoracic radiography can identify abnor-
cence can be used to demonstrate EHV antigens and several malities of the pleural space, pulmonary parenchyma, medi-
enzyme-linked immunosorbent assays are available for the astinum, and diaphragm. In the lungs, pulmonary consolida-
detection of influenza-virus nucleoprotein. tion, abscesses, peribronchial disease, and interstitial disease
Appropriate samples for the identification of bacterial or may be evident.
fungal agents in respiratory tract disease depend on the sus- Other Diagnostic Aids. Several additional diagnostic tests
pected site of infection and organism. Common techniques for can be helpful in the evaluation of equine asthma, especially
sampling the upper airways include nasal or nasopharyngeal pulmonary function testing.215-218,249,252 Other tests that may
swab, nasal wash, guttural pouch wash, and sinus trephina- be useful include a hay challenge to induce disease, histamine
tion. Transtracheal aspiration is commonly used for sampling provocation tests to assess airway reactivity, and bronchodi-
the lower airway in cases of suspected pneumonia. Other lator response testing, typically with atropine, N-butylscopol-
techniques include endoscopic tracheal aspiration or brushing ammonium bromide, or albuterol. Although allergen testing
and sterilely performed BAL. Pleural fluid can be sampled by has limitations in horses, it may be useful in some cases to
thoracocentesis. Cytology and Gram stain of the samples can identify specific triggers. Endobronchial biopsy specimens
support the presence of infection. Culture and PCR are used have also been used in the evaluation of horses with asthma.253
for identification of specific pathogens. Many laboratories now Percutaneous lung biopsy, although not commonly per-
offer diagnostic panels for respiratory disease that test for mul- formed, can be used to evaluate respiratory disease.254 Both
tiple common pathogens. histologic and microbiologic evaluation of tissue may be use-
Serologic testing is available to detect the host response to ful. Lung biopsy may be particularly helpful in the diagnosis of
several infectious agents. Depending on the organism, however, pulmonary neoplasia, equine multinodular pulmonary fibro-
it may be difficult to distinguish active infection from exposure sis, and silicosis.
or vaccination. Serology can be useful in the diagnosis of sev-
eral fungal infections, such as cryptococcosis, coccidiomycosis, Y RESPIRATORY DISTRESS
blastomycosis, and conidiobolomycosis.209,210
The Baermann fecal flotation technique can be used in Respiratory distress is defined as labored breathing and is
horses with suspected lungworm infection. However, as infec- characterized by an inappropriate degree of effort to breathe
tions in horses are often not patent, a negative Baermann does based on rate, rhythm, and subjective evaluation of respiratory
not rule out the presence of lungworms.224,225 Routine fecal effort.255 Dyspnea refers to the sensation of arduous, uncom-
flotation can be used to detect Parascaris equorum in foals fortable, or difficult breathing that occurs when the demand for
with suspected parasitic pneumonitis, but in some cases the ventilation exceeds the patient’s ability to respond.256 Because
infection may not yet be patent. dyspnea describes a subjective feeling, it is technically a symp-
Endoscopy. Endoscopic examination is particularly valu- tom rather than a clinical sign and thus not strictly applicable
able in evaluation of the upper airways and trachea. Be- in veterinary medicine although the term is often used. The
cause sedation can alter airway function, endoscopy is best clinical signs of respiratory distress vary with the severity and
origin of impaired gas exchange. Clinical signs commonly CENTRAL AND PERIPHERAL ARTERIAL CHEMORECEPTORS. The
observed in horses with respiratory distress include flared major chemoreceptors include the central chemoreceptors in the
nostrils, exercise intolerance, inactivity, exaggerated abdomi- ventral medulla of the brainstem and the peripheral chemorecep-
nal effort, abnormal respiratory noise (stertor or stridor), tors in the arterial vasculature.256 These chemoreceptors identify
anxious expression, extended head and neck, and synchro- changes in metabolism and oxygenation, providing feedback to
nous pumping of the anus with the respiratory cycle.255,257,217 the central controller and thus influencing ventilation.
In severe cases, cyanosis may be seen. Horses with chronic The central chemoreceptors monitor alterations in the pH
respiratory distress may develop a heave line resulting from of intracerebral interstitial fluid and cerebrospinal fluid. As the
hypertrophy of the cutaneous trunci and abdominal muscles, blood-brain barrier is impermeable to bicarbonate and hydro-
which assist during forced expiration.257,217 Weight loss may gen ions but is freely permeable to carbon dioxide, acidification
be seen in association with decreased feed intake and a high of the intracerebral interstitial fluid and thus stimulation of the
energy demand for respiration. In fact, it has been shown that central chemoreceptors occur predominantly in response to
in horses with recurrent airway obstruction (RAO), which is hypercapnia and respiratory acidosis. The severity of acidosis
part of the syndrome of equine asthma, the work of breathing in the intracerebral interstitial fluid caused by hypercapnia is
has the potential to approximate the energy expenditure of a amplified by two features of the central nervous system: (1)
horse trotting for 12 hours a day.258,216 hypercapnia produces cerebral vasodilation, increasing the
delivery of CO2 to the central nervous system, and (2) cere-
Mechanisms of Respiratory Distress brospinal fluid has poor buffering capacity because of low total
Problems with both ventilation, which is the process of mov- protein concentrations.256
ing air into and out of the lungs, and respiration, which is the Peripheral chemoreceptors include the carotid bodies,
process of gas exchange, can impair the efficient exchange of situated at the bifurcation of the common carotid artery, and
oxygen and carbon dioxide leading to respiratory distress. the aortic bodies, which are located near the aortic arch.256
Common causes of respiratory distress include primary pul- Carotid bodies are generally considered the primary periph-
monary disease, airway obstruction, or impairment of the eral chemoreceptor, but the aortic bodies can also influence
muscles and supporting structures necessary for ventila- ventilation. These receptors relay information to the central
tion.255,256,259 In some horses, respiratory distress can occur controller regarding arterial gas tensions via the glossopha-
in the absence of impaired gas exchange in response to pain, ryngeal and vagus nerves. Their responsiveness to alterations
metabolic acidosis, or high environmental temperature. Famil- in Paco2 is less consequential than the central chemorecep-
iarity with the mechanics of breathing and control of ventila- tors. They also can have a slight response to metabolic aci-
tion in healthy and diseased lungs facilitates the diagnosis and dosis. The peripheral chemoreceptors are highly sensitive
treatment of respiratory distress.217,257 to changes in the partial pressure of oxygen, however, and
are solely responsible for the hypoxic ventilatory drive. The
Control of Ventilation peripheral chemoreceptors demonstrate a nonlinear response
The partial pressure of oxygen (Pao2) and the partial pres- to low arterial oxygen tension. They are insensitive to altera-
sure of carbon dioxide (Paco2) in arterial blood are main- tions in Pao2 above 100 mm Hg, exhibit moderate response to
tained within a narrow range through rigid control of gas arterial O2 tensions between 50 and 100 mm Hg, and demon-
exchange.256 The control of ventilation is complex but essen- strate a dramatic increase in responsiveness when the partial
tially involves three components: (1) stimulation of sensory pressure of oxygen falls below 50 mm Hg in the arterial cir-
afferents via chemoreceptors and mechanoreceptors, (2) inte- culation.256 The respiratory pattern elicited by hypoxia differs
gration of the information in the brainstem, and (3) efferent from that stimulated by hypercapnia.265,266 Hypoxia evokes
signals to the muscles of respiration256,260-262 (Fig. 7.3). Within an increase in respiratory frequency, whereas hypercapnia
the brainstem, ventilation is controlled by a complex neuronal triggers an elevation in tidal volume. In addition, hypoxia
network known as the central controller or respiratory pat- stimulates recruitment of the inspiratory muscles, whereas
tern generator, which is the same neuronal network involved hypercapnia potentiates the activity of inspiratory and expira-
in the cough reflex. In response to afferent signals, the central tory muscles.
controller alters the rate and depth of respiration via efferent The sensitivity of peripheral chemoreceptors should be con-
signals to the muscles of respiration. The central controller sidered in the treatment of patients with complex acid-base and
therefore adjusts alveolar ventilation to the metabolic rate of blood-gas abnormalities. A patient suffering simultaneously
the individual. Although this process is involuntary, higher from impaired gas exchange caused by pulmonary disease and
brain centers can influence ventilation, and there can be vol- metabolic acidosis resulting from shock can manifest respira-
untary, conscious control of ventilation. tory distress in response to hypoxemia, hypercapnia, and aci-
Neuromuscular Physiology of Ventilation dosis. Oxygen supplementation likely will improve the patient’s
SENSORY AFFERENTS. Afferent input into the central re- arterial oxygen tension; however, such treatment may abolish
spiratory centers in the brainstem arises primarily from three the hypoxic ventilatory drive and consequently slow the venti-
groups of neural receptors: (1) peripheral arterial chemo- latory rate. This decreased ventilation could exacerbate respira-
receptors, (2) central chemoreceptors in the brainstem, and tory acidosis and result in decompensation of the patient.259
(3) chemoreceptors and mechanoreceptors in the respiratory Although treatment of metabolic acidosis may be indicated,
tract260-264 (see Fig. 7.3). In addition, mechanoreceptors in the it can also contribute to respiratory acidosis by ultimately
diaphragm and thoracic wall have some influence on the level increasing CO2. Thus to prevent life-threatening acidemia,
and timing of ventilatory activity in response to changes in treatment of respiratory acidosis, often by assisted ventilation,
length, tension, or movement. All of these receptors collec- may be indicated depending on the specifics of the case.
tively provide information to the central controller, resulting Respiratory Tract Receptors. Receptors located in the up-
in the modification of ventilation. per and lower respiratory tract respond to mechanical and
Chemical and Higher brain

CO2 O2 pH
mechanical stimuli centers
Mechano-and
Central Peripheral
chemoreceptors in the
chemoreceptors chemoreceptors
respiratory tract
(medulla) (carotid and aortic)
(RARs, SARs, CFRs)
Afferent sensory Afferent sensory

neurons neurons
Central control
Medullary respiratory center
Pontine respiratory center
Somatic motor neurons
Muscles of respiration
intercostals, diaphragm, abdominal muscles
FIG. 7.3 Simplified schematic outlining the control of ventilation. CFRs, C-fiber receptors; RARs, rapid-
adapting receptors; SARs, slow-adapting receptors.
chemical stimuli and relay afferent information to the central mechanosensors and are stimulated in part by pulmonary
controller of respiration via the vagus nerve.255,256,263,264 Vagal inflation, inhibiting further inflation of the lung (Hering-
blockade abolishes tachypnea in horses with pulmonary dis- Breuer reflex). Conversely, at end expiration these receptors
ease; therefore these receptors are likely to play an important stimulate inspiratory activity. These receptors are considered
role in development of respiratory distress associated with pri- to be partially responsible for controlling the depth and rate
mary pulmonary disease.267-269 of respiration.
As discussed earlier, some of the major respiratory tract The RARs are found in and under the epithelium of the
receptors influencing ventilation are the slow-adapting recep- respiratory tract from the nasopharynx to the bronchi, and
tors (SARs, slowly adapting stretch receptors), rapid-adapt- their pattern of response varies with their location.256,264
ing receptors (RARs, rapidly adapting stretch receptors), Although they are highly sensitive to mechanical stimuli, those
and C-fiber receptors (CFRs).261,263,264 These receptors also in the bronchi are more chemosensitive and are sometimes
function in mucus secretion, bronchoconstriction, and the referred to as irritant receptors. The wide variety of stimuli they
generation of cough.180 The SARs, also known as pulmonary may respond to include exogenous agents such as smoke, irri-
stretch receptors, are located primarily within smooth muscle tant gases, and dust, as well as endogenously produced inflam-
fibers in the walls of the trachea and bronchi and are sparse matory mediators, including histamine and prostaglandins.
in extrapulmonary airways.256,259,263 The SARs are primarily RARs are not likely to function in regulation of breathing in
a normal resting horse.259 Stimulation of these receptors by The pneumotaxic center, also in the pons, inhibits the inspira-
noxious stimuli triggers bronchoconstriction, cough, tachy- tory centers and helps to regulate the volume and rate of res-
pnea, mucus production, and release of inflammatory media- piration. The pneumotaxic center is not required to maintain
tors.255,256,180 In horses with RAO (severe equine asthma), the a normal respiratory rhythm; instead, this center functions to
production of histamine, prostaglandins, and other inflam- fine-tune the respiratory rhythm, receiving afferent input from
matory mediators increases, and the resulting stimulation of the vagus nerve regarding Pao2, Paco2, and pulmonary infla-
RARs by these inflammatory mediators may be in part respon- tion.
sible for the bronchoconstriction, mucus production, and Input of Higher Brain Centers. Ventilation is primarily under
tachypnea observed in horses with this disorder.217,270-272 In involuntary control via the brainstem, but higher brain centers
addition to their role as chemoreceptors, the RARs or irritant can also play a role.260-262 Conditions that influence ventilation
receptors also function as mechanoreceptors throughout the via higher brain centers include the emotional state, via input
airways.263,264 An abrupt change in end-expiratory lung vol- from the limbic system, and temperature, via input from the
ume, such as occurs with pneumothorax or pleural effusion, hypothalamus, as well as conscious control. Conscious or vol-
can produce tachypnea in response to stimulation of these untary control of ventilation, which is centered in the cerebral
receptors. Increased negative pressure (upper airway obstruc- cortex, can be overridden by the chemoreceptor reflex.
tion) within the airway stimulates the mechanoreceptors of the EFFECTORS OF VENTILATION. The muscles required for ven-
larynx and produces prolongation of inspiratory time and acti- tilation include the diaphragm, the external and internal inter-
vation of upper airway dilator muscles.273,274 costal muscles, and the abdominal muscles.256 Horses have a
Unmyelinated C-fibers innervate receptors found in the somewhat unique biphasic inspiratory and expiratory airflow
epithelial layer throughout the intrapulmonary and extra- pattern in which there is both a passive and an active phase to
pulmonary respiratory tract.256,263 C-fiber receptors are pre- inspiration and expiration.277 The single most important mus-
dominantly chemosensors, although they may also respond cle required for the inspiratory phase of the respiratory cycle is
to hyperinflation of the lung. These receptors respond to pul- the diaphragm.278 The relaxation volume is the static equilib-
monary edema, congestion, and inflammatory mediators, and rium volume of the relaxed respiratory system at which the net
stimulation activates tachypnea. In addition, C-fiber receptors elastic recoil pressure is zero. In horses, the first part of inhala-
may stimulate the release of pulmonary neuropeptides, which tion following exhalation is passive until the relaxation volume
produce bronchoconstriction, vasodilation, protein extrava- is reached, at which point the diaphragm and external inter-
sation, and cytokine production. C-fiber receptors located costal muscles complete the inspiratory phase. Contraction of
within the alveolar walls in juxtaposition to pulmonary cap- the diaphragm forces the abdominal contents back, increas-
illaries are sometimes referred to as juxtacapillary receptors. ing the length of the thoracic cavity, and pulls the ribs abaxi-
Information from other species suggests that these receptors ally, increasing the width of the abdominal cavity. In addition,
can respond to increased interstitial fluid volume and may be the external intercostal muscles participate in inspiration by
involved in the sensation of difficult breathing.256 pulling the ribs abaxially to increase the width of the thoracic
CENTRAL CONTROL OF VENTILATION cavity. The net effect is an increase in the size of the thoracic
Brainstem Control. The mechanisms involved in the cen- cavity, producing subatmospheric intrathoracic pressure that
tral control of ventilation are still not completely understood. drives inspiration and pulmonary inflation. In most species,
The central controller of the brainstem integrates signals from expiration at rest is a passive process and relies on elastic recoil
the sensory afferent neurons and then initiates phasic activ- of the lung to create positive intrathoracic pressure.256 This is
ity of the diaphragmatic, intercostal, and abdominal respira- the case during the first portion of expiration in horses, which
tory muscles.256 Although it is a complex neuronal network, relies on elastic recoil to the point of relaxation volume, when
the central controller consists of two basic regions with sev- the tendency for pulmonary collapse equals the tendency for
eral subregions: (1) the medullary respiratory center in the expansion by the thoracic wall. Horses then further decrease
reticular formation, which includes the ventral and dorsal lung volume by active compression of the chest wall through
respiratory groups, and (2) the pontine respiratory center, contraction of the internal intercostal muscles and muscles
which includes the pneumotaxic and apneustic centers. The of the abdominal wall.278 The passive phase of inhalation fol-
medullary respiratory center controls the rhythmic pattern lows. Dysfunction of the diaphragm and intercostal muscles
of respiration. The dorsal respiratory group helps to coordi- due to either mechanical (abdominal distention, trauma to
nate inspiratory activity by assimilating afferent information the thoracic wall) or neuromuscular (botulism, phrenic nerve
from the glossopharyngeal and vagus nerves and transmitting damage, nutritional myodegeneration) problems prevents ex-
efferent signals to the muscles of inspiration and neurons in pansion of the thoracic wall and can produce hypoventilation,
the ventral respiratory group. The ventral respiratory group hypoxemia, and respiratory distress.255,257 Horses with torsion
consists of inspiratory and expiratory motor neurons. One of the large colon can develop significant abdominal disten-
subregion, the pre-Botzinger complex, appears to have a major tion and respiratory distress, and respiratory failure caused by
role in generating the basic breathing rhythm.260-262,275 Closely impaired diaphragmatic function can play an important role
associated neurons in the retrotrapezoid nucleus and para- in the pathophysiology and mortality associated with this in-
facial respiratory group are important in regulating expira- testinal accident.
tion.275,276 The ventral respiratory group also helps to regulate
ventilation during exercise. In the pontine respiratory center, Control of Airway Diameter
the apneustic center provides stimulatory input to inspiratory The diameter of the conducting airways, which is primarily
motor neurons, activating and prolonging inhalation.260-262 controlled by the autonomic nervous system, is an impor-
Damage to this region, which can result from problems such tant determinant of the degree of pulmonary resistance and
as trauma or neonatal encephalopathy, results in prolonged in- work of breathing.256 The control of airway diameter by the
spiratory gasps interrupted by transient expiratory efforts.259 autonomic nervous system involves both sympathetic and
parasympathetic innervation with activation of adrenergic right-to-left shunting of blood, diffusion impairment, and
and muscarinic receptors, respectively.256,279-281 The receptors reduced inspired oxygen concentration.256 The degree of associ-
are generally widely expressed in the lung, although the pat- ated hypercapnia and the response to oxygen supplementation
tern of specific receptor expression can vary among species. vary depending on the mechanism of impaired gas exchange,
The control of normal airway function and airway diameter is and determination of these two parameters is useful in defining
complex, requiring interactions or “crosstalk” between recep- the pathophysiologic process predominantly responsible for the
tors. Vagal-mediated parasympathetic stimulation is impor- development of hypoxemia.256
tant in the regulation of airway smooth muscle tone, and Hypoventilation. Alveolar hypoventilation is defined as in-
stimulation can cause bronchoconstriction as well as mucus sufficient ventilation leading to hypercapnia.256 The elevation
secretion and bronchial vasodilation. Specifically, broncho- in Paco2 is inversely proportional to the reduction in alveolar
constriction can occur due to the action of acetylcholine from ventilation; halving alveolar ventilation doubles Paco2.256 The
parasympathetic fibers on M3 muscarinic receptors located on reduction in arterial oxygen tension is almost directly propor-
airway smooth muscle. This mechanism of bronchoconstric- tional to the increase in CO2. For instance, if Paco2 increases
tion has been associated with allergic airway disease in several from 40 to 80 mm Hg, the Pao2 decreases from 100 to 60 mm
species. The administration of anticholinergics such as atro- Hg. Therefore hypoxemia resulting from hypoventilation is
pine or N-butylscopolammonium bromide can result in rapid rarely life threatening. In addition, oxygen supplementation
relief of bronchoconstriction in some horses with RAO, dem- easily abolishes hypoxemia caused by pure hypoventilation.
onstrating the important role of parasympathetic bronchocon- Acidosis caused by hypercapnia is the most clinically signifi-
striction in the pathogenesis of this disorder.257,259,282,283 With cant feature of hypoventilation and may be life threatening.256
regard to sympathetic effects, both α- and β-adrenergic recep- Metabolic alkalosis or central nervous system depression (e.g.,
tors are found in the lung.28-30 However, direct sympathetic from head trauma, encephalitis, narcotic drugs) can produce
innervation of airway smooth muscle is minimal to none, and hypoventilation; however, horses with these disorders may not
thus stimulation of the adrenergic receptors is primarily via demonstrate clinical signs of respiratory distress. Disorders
circulating catecholamines.279-281 β2-Adrenergic receptors are that can cause alveolar hypoventilation that are often associ-
abundant throughout the lung on multiple cell types, includ- ated with clinical signs of respiratory distress include dysfunc-
ing bronchial smooth muscle, bronchial epithelial cells, and tion of the respiratory muscles from mechanical (abdominal
several immune cells, and thus activation can have multiple distention, trauma to the thoracic wall) or neuromuscular
effects. The stimulation of β2-receptors on airway smooth (botulism, phrenic nerve damage, nutritional myodegenera-
muscle can cause smooth muscle relaxation and bronchodilation) conditions, restrictive pulmonary disease (silicosis, pul-
tion. Airways must be constricted for β2-receptor stimulation monary fibrosis, pneumothorax, pleural effusion), and upper
or the anticholinergic action of atropine to increase airway airway obstruction.255,257,259
diameter.284,285 β2-Receptors appear to be present in normal Ventilation-Perfusion Mismatch. Ventilation-perfusion (V-
or increased numbers on asthmatic airway smooth muscle Q) mismatch is the most common cause of hypoxemia and is
but appear to be hyporesponsive, thus allowing bronchocon- characterized by unequal distribution of alveolar ventilation
striction.281,286 β1-Adrenergic receptors are less abundant than and blood flow.256,259 Either a low or high V-Q ratio can re-
β2-receptors in the airways. The effects of both β1- and α1- sult in hypoxemia. Pulmonary regions that are overperfused
adrenergic receptors in the regulation of airway diameter in in relation to ventilation (low V-Q ratio) contribute dispro-
horses appear to be minimal.285-287 portionate amounts of blood with low arterial oxygen content
Nonadrenergic-noncholinergic (NANC) innervation, to the systemic circulation.256 Respiratory diseases character-
including both excitatory and inhibitory components, also ized by low V-Q ratios include RAO, pulmonary atelectasis,
contributes to large airway diameter.288,289 Stimulation of and consolidation.259 If ventilation exceeds perfusion (high
excitatory NANC nerves initiates a process of neurogenic V-Q ratio), the ventilated pulmonary units are inefficient
inflammation that involves bronchoconstriction, mucus for CO2 elimination and O2 uptake. Ventilation of poorly or
secretion, increased vascular permeability, vasodilation, and nonperfused units is wasted ventilation, termed alveolar dead
cough. Inhibitory NANC nerves appear to be important neu- space.256 Conditions associated with high V-Q ratios include
ral pathways for bronchodilation, and activation results in pulmonary thromboembolism and shock (low pulmonary ar-
the relaxation of smooth muscles of the trachea and bronchi. tery pressure). Patients with V-Q mismatch often have a nor-
Dysfunction of the NANC system may play a role in asthma mal arterial Pco2. The ventilatory drive to maintain normal
in both people and horses, although the precise role remains Paco2 is powerful, and as the CO2 dissociation curve is basi-
to be elucidated. In RAO-affected horses with clinical signs of cally a straight line (direct relationship), increased ventilation
airway obstruction, inhibitory NANC function is absent.290 efficiently decreases Paco2 at high and low V-Q ratios. How-
Failure of the inhibitory NANC system may result from the ever, also due to the nearly flat shape of the O2 dissociation
inflammatory response during acute RAO or may be an inher- curve, increasing ventilation is inefficient for proportionally
ent autonomic dysfunction of the conducting airways of RAO- increasing the arterial Po2. Only pulmonary units with mod-
affected horses. erate to low V-Q ratios benefit from increased ventilation.
Therefore the increased ventilatory effort to maintain nor-
Role of Hypoxemia and Hypercapnia in mal Paco2 is wasted and unnecessarily increases the work of
Respiratory Distress breathing. Oxygen supplementation tends to increase Paco2
Respiratory distress most often originates from inadequate pul- in patients with a V-Q mismatch. Also, elevation in arterial O2
monary gas exchange to meet the metabolic demands of the is delayed compared with hypoventilation and in some cases
individual, resulting in hypoxemia and hypercapnia. Hypox- may be incomplete.256 Compensatory mechanisms are present
emia results from one or more of five basic pathophysiologic to minimize unequal distribution of ventilation and perfusion
mechanisms: hypoventilation, ventilation-perfusion mismatch, in diseased lungs to prevent the development of hypoxemia
until the pulmonary pathologic condition is severe.256 Reflex ventilation with a low oxygen concentration are the most com-
pulmonary arterial constriction (hypoxic vasoconstriction) mon circumstances in which hypoxemia is attributed to re-
prevents perfusion of unventilated alveolar units and attempts duction of inspired oxygen content.256
to redirect blood flow to alveoli that are ventilated adequately. Most pulmonary diseases in horses incorporate more than
Airway hypocapnia causes bronchoconstriction of airways one of these pathophysiologic mechanisms for the devel-
that conduct to unperfused alveolar units, redirecting air flow opment of hypoxemia. Horses with pleuropneumonia, for
to better perfused alveoli. example, may develop hypoxemia caused by hypoventilation
Shunt. Shunt is defined as blood that is not exposed to ven- (extrapulmonary restriction by pleural effusion), V-Q mis-
tilated areas of the lung and is added to the arteries of the sys- match (accumulation of exudate and edema within alveoli and
temic circulation.256 Shunting can occur as an extreme form of conducting airways), and diffusion impairment (exudate and
V-Q mismatch or with direct addition of unoxygenated blood edema within the interstitial spaces).
to the arterial system. Physiologic shunting is defined as per-
fusion of nonventilated or collapsed regions of the lung and Role of Obstructive Disease in
occurs with pulmonary consolidation, atelectasis, and edema. Respiratory Distress
Certain congenital heart diseases, such as tetralogy of Fallot Airway obstruction can limit air flow and contribute to respi-
and some cardiac septal defects, are examples of direct right- ratory distress. The location (intrathoracic or extrathoracic)
to-left shunts wherein unoxygenated blood from the right side and nature (fixed or dynamic) of airway obstruction deter-
of the heart is added to oxygenated blood from the left side of mine whether impedance to air flow occurs during inspira-
the heart. Right-to-left shunting may also contribute to hypox- tion, expiration, or both.257 The phase of the respiratory cycle
emia in some cases of persistent pulmonary hypertension. In that is affected by air flow obstruction is prolonged and may
these conditions hypoxemia cannot be abolished by increas- be associated with a respiratory noise (stertor, stridor, or
ing the oxygen content of inspired air. The shunted blood is wheeze).256,257,291
never exposed to the higher concentration of inspired oxygen The horse is an obligate nasal breather and can breathe
in the alveolus, and the addition of a small amount of shunted efficiently only through the nares.259 Therefore upper airway
blood with its low O2 content greatly reduces the Po2 of arte- obstruction within the nasal passages cannot be bypassed by
rial blood. Compared with breathing room air, the decrement mouth breathing. In addition, approximately 80% of the total
in Po2 is much greater at Po2 levels associated with the inhala- airway resistance to air flow is located in the upper airway.291
tion of O2-enriched air because the O2 dissociation curve is so A 50% decrease in the radius of an airway increases its resis-
flat at high Po2 levels. Only hypoxemia caused by right-to-left tance by 16 times (Poiseuille’s law).256 Therefore small changes
shunting behaves in this manner when the patient is permit- in the upper airway diameter dramatically affect the overall
ted to inspire high percentages of oxygen (70%–100%). Shunts resistance to air flow and work of breathing for the horse.
do not usually cause hypercapnia.256 Chemoreceptors detect Extrathoracic airway pressures are subatmospheric during
excess arterial CO2, and ventilation increases to reduce the inspiration; therefore poorly supported structures in the upper
content of CO2 in unshunted blood until arterial Pco2 reaches airway narrow or collapse during inspiration (dynamic col-
the normal range. In some cases of shunt the arterial Pco2 is lapse). There are several causes of upper airway obstruction in
below normal because of hyperventilation stimulated by the horses, the most common being laryngeal hemiplegia.
hypoxemic ventilatory drive. Of the total airway resistance 20% is attributable to the
Diffusion Impairment. Gas exchange between the alveo- small airways.291 Although the radius of individual bronchi-
lus and the capillary occurs by passive diffusion, which is oles is small, many of them exist and the sum or collective
driven by the property of molecules to move randomly from radius is large, with the result that their overall contribution
an area of high concentration to one of low concentration.256 to pulmonary resistance is low.256 Because the resistance of the
Factors that determine the rate of gas exchange include the bronchioles is low, advanced disease must be present for rou-
concentration gradient between the alveolus and capillary tine measurements of airway resistance to detect an abnormal-
blood, solubility of the gas, surface area available for diffu- ity, and obstruction of these airways must be extensive before
sion, and width of the air-blood barrier. Diseases character- a horse would suffer from respiratory distress. During pul-
ized by pure diffusion impairment are rare in veterinary med- monary inflation intrathoracic pressures are subatmospheric.
icine.259 However, some degree of diffusion impairment can Small airways are pulled open by negative intrathoracic pres-
occur with disorders such as pulmonary fibrosis, interstitial sure and stretched parenchymal attachments at high lung vol-
pneumonia, silicosis, or pulmonary edema and is most often umes. Thus resistance to air flow in small airways is low during
associated with increased width of the barrier or decreased the inspiratory phase of respiration.256 During exhalation
surface area available for gas exchange. Although the major intrathoracic pressure is positive and the diameter of small air-
component of hypoxemia in these conditions is a V-Q mis- ways is decreased, and bronchioles may even close at low lung
match, diffusion impairment can contribute to the severity of volumes. Therefore resistance to air flow in small airways is
hypoxemia. Supplemental oxygen therapy is effective in treat- greatest during the expiratory phase. In horses with RAO the
ing hypoxemia caused by diffusion impairment because it airway diameter is reduced by inflammatory exudate, edema,
creates a more favorable concentration gradient and increases and bronchoconstriction.257,259,290 As lung volume decreases
the driving pressure of oxygen to move from the alveolus into during expiration, the narrowed bronchioles are compressed
the blood. Transport of CO2 is less affected by diseases of dif- shut (dynamic airway collapse) and trap air distal to the site of
fusion impairment because of its greater solubility compared closure.259 This is an example of severe flow limitation, which
with O2.256 may lead ultimately to the development of emphysema. Flow
Reduction of Inspired Oxygen. Hypoxemia resulting from limitation forces horses with RAO to breathe at higher lung
decreased inspired oxygen content is uncommon and occurs volumes and maintain a higher functional residual capacity
only under special circumstances. High altitude and iatrogenic to reduce or prevent dynamic airway collapse. Affected horses
attempt to reduce the end-expiratory lung volume by recruit- rhabdomyolysis and laminitis are painful musculoskeletal
ing abdominal muscles to increase the intrathoracic pressures conditions that may produce tachypnea.257 Marked respira-
during expiration. However, the greater the end-expiratory tory distress is observed frequently in horses with abdominal
pressure, the greater is the likelihood of small airway com- pain; however, the respiratory distress is not caused solely by
pression and collapse. Hypertrophy of the cutaneous trunci pain and is exacerbated by abdominal distention, shock, aci-
and expiratory abdominal muscles, especially the external dosis, and endotoxemia.
abdominal oblique, produces the characteristic “heave line” Elevations in body temperature caused by fever or hyperther-
associated with RAO.259 Because dynamic airway narrowing mia associated with exercise, heat stroke, anhidrosis, or mac-
and collapse occur during exhalation, wheezes are typically rolide-induced hyperthermia can produce respiratory distress
loudest at end expiration in horses with RAO.257,259 in horses. Hyperpnea is an effective means of heat dissipation
in human beings, dogs, and ruminants.257 Unfortunately, in
Role of Restrictive Disease in Respiratory horses increased ventilation is an inefficient mechanism for
Distress heat dissipation.257,259
Restrictive disease is less common than obstructive pulmo-
nary disease in horses.259 By definition, restrictive disease Conditions Associated with Respiratory Distress
inhibits pulmonary expansion and leads to inspiratory respi- A number of conditions, both respiratory and nonrespira-
ratory distress.256 The vital capacity and compliance (pulmo- tory in origin, can cause some degree of respiratory distress
nary or chest wall) decrease, expiratory flow rates and elastic in horses (Box 7.5). Among the more common respiratory
recoil increase, and airway resistance is normal. The character- causes are infectious conditions. In particular, bacterial infec-
istic respiratory pattern in horses with restrictive pulmonary tions of the respiratory tract such as bacterial pneumonia,
disease is rapid, shallow respiration at low lung volumes.259 aspiration pneumonia, pleuropneumonia, pleuritis, and pul-
This strategy takes advantage of high pulmonary compliance monary abscessation can result in respiratory distress.206,207
at low lung volumes and decreases the work of breathing. This Strangles can result in respiratory distress in association with
respiratory pattern has the disadvantage of increased ventila- airway obstruction from lymph node abscessation and less
tion of anatomic dead space.256 Restrictive diseases may be frequently due to pneumonia. Viral respiratory tract infec-
classified as intrapulmonary (pulmonary fibrosis, silicosis, and tions, which are common in horses, may sometimes result in
interstitial pneumonia) and extrapulmonary (pleural effusion, respiratory distress.204 Fungal pneumonia can result in signifi-
pneumothorax, mediastinal mass, botulism, and nutritional cant respiratory distress in some patients but is uncommon in
myodegeneration).255,259 Hypoxemia observed in horses with horses.209,210 Respiratory distress is often a prominent feature
intrapulmonary restrictive disease is largely attributed to V-Q of syndromes of interstitial pneumonia, including acute lung
mismatch and diffusion impairment, although hypoventila- injury, acute respiratory distress, and equine multinodular
tion may also have a role. Stimulation of juxtacapillary recep- pulmonary fibrosis.211,212,292,293 In neonatal foals, immature
tors may contribute to respiratory distress observed in these lungs and lack of surfactant can contribute to respiratory dis-
patients.256 The pathophysiologic mechanism for hypoxemia tress.294 Idiopathic or transient tachypnea has been reported
in horses with extrapulmonary restriction is hypoventila- in neonatal foals, especially in Clydesdales, Thoroughbreds,
tion.259 In horses with pleural effusion and pneumothorax, and Arabians.294 RAO is a common condition in horses that
respiratory distress is likely to be exacerbated by thoracic pain. has the potential to cause significant respiratory distress,
both in association with acute exacerbations of the condition
Nonpulmonary Respiratory Distress and with chronic disease.215,216,217,218,290 Some other respira-
Respiratory distress does not always originate from dysfunc- tory problems that can be associated with respiratory distress
tion of the pulmonary system and its supporting structures. include exercise-induced pulmonary hemorrhage, eosino-
Nonpulmonary respiratory distress can occur because of inad- philic pulmonary disease, silicosis, smoke inhalation, and
equate oxygen-carrying capacity of the blood, pain, hyper- neoplasia.213,214,223,226,227,295-297
thermia, or compensation for metabolic acidosis.255-257 Upper airway obstruction is another important cause of
Impaired oxygen-carrying capacity of the blood may respiratory distress in horses, especially when oxygen demand
occur because of anemia (blood loss, hemolytic, or aplastic) is increased by exercise.255,257,259 The most common cause of
or dysfunction of red blood cells (methemoglobinemia, car- non–fixed upper airway obstruction in horses is laryngeal
bon monoxide toxicity). In these cases the arterial Po2 tension hemiplegia, which produces inspiratory stridor during exer-
(quantity of dissolved oxygen) is normal; however, the total cise.257,298-300 Intraluminal masses and arytenoid chondritis
oxygen content of the blood is reduced greatly.256 Tachypnea cause fixed upper airway obstruction and produce inspira-
and respiratory distress occur in response to impaired oxygen tory and expiratory respiratory distress.257 Several other upper
delivery and tissue hypoxia. airway abnormalities have been documented, such as fourth
The respiratory system can compensate for metabolic aci- branchial arch defect, subepiglottic cyst, aryepiglottic fold
dosis by increasing ventilation to lower Paco2 and attenu- entrapment, and dorsal displacement of the soft palate.257,301
ate acidemia.256 The ventilatory drive increases in response Laryngeal and pharyngeal dysfunction has been reported in
to stimulation by peripheral chemoreceptors by circulat- horses that are homozygous for hyperkalemic periodic paraly-
ing hydrogen ions. Hypocarbic compensation for mild to sis.302,303 Infrequently, laryngeal paralysis has been associated
moderate metabolic acidosis is effective in returning blood with hepatic dysfunction.304 A wide variety of other condi-
pH to normal until renal compensatory mechanisms can be tions have been associated with respiratory distress such as
established.256 pneumothorax, diaphragmatic hernia, choanal atresia, naso-
Pain and anxiety are physiologic causes of tachypnea and pharyngeal cicatrix syndrome, tracheal collapse, and oth-
hyperpnea. Horses with musculoskeletal pain are unlikely ers.233-235,305,306 Although heart disease is relatively uncommon
to demonstrate significant respiratory distress; however, in horses, it may result in respiratory distress via pulmonary
BOX 7.5
Causes of Respiratory Distress
RESPIRATORY CAUSES Cardiac disease

Respiratory tract infection Pulmonary edema
Bacterial pneumonia, pleuropneumonia (including Left-to-right shunting
aspiration, pulmonary abscesses) Other
Strangles Silicosis
Viral respiratory tract infection Smoke inhalation
Fungal respiratory tract infection Neoplasia
Interstitial pneumonia Eosinophilic pulmonary disease
Equine multinodular pulmonary fibrosis Crotolaria equorum—pyrrolizidine alkaloid toxicity
Syndromes of acute lung injury, acute respiratory distress Additional causes in foals
Recurrent airway obstruction (severe asthma) Inadequate surfactant, pulmonary immaturity
Upper airway obstruction Idiopathic tachypnea (transient)
Left laryngeal hemiplegia
Arytenoid chondritis NONRESPIRATORY CAUSES
Fourth branchial arch defect Systemic inflammatory response syndrome
Subepiglottic cyst Pain
Dorsal displacement of the soft palate Elevated body temperature
Aryepiglottic fold entrapment Fever
Intraluminal masses, abscessation (strangles, other) Hyperthermia
Laryngeal and pharyngeal dysfunction associated with HYPP Exercise-related hyperthermia
Choanal atresia Heat stroke
Nasopharyngeal cicatrix syndrome Anhidrosis
Exercise-induced pulmonary hemorrhage CNS disorders
Pneumothorax Macrolide-induced hyperthermia
Diaphragmatic hernia Anemia
Tracheal abnormalities Monensin
Tracheal collapse, stenosis Snake envenomation
Foreign body Neuroborreliosis
Intraluminal mass
edema or right-to-left shunting.229,230 Respiratory distress is a pulmonary hypertension, and meconium aspiration are prob-
prominent sign of a rare form of pyrollizidine alkaloid toxicity lems unique to neonatal foals.294 Congenital problems such as
associated with Crotolaria equorum.307 choanal atresia and cardiac defects should also be considered
Several nonrespiratory conditions can also cause respira- in neonates. Rhodococcal pneumonia is primarily a disease of
tory distress. Respiratory distress is often a feature of the sys- foals 1 to 6 months of age.207 Horses affected with RAO are
temic inflammatory response syndrome.255,257 Pain, fever, or generally over 7 years of age, and a familial predisposition has
hyperthermia may lead to respiratory distress. Tachypnea and been identified.215,216
elevation in body temperature are the most prominent clinical Some important historical considerations include environ-
signs in horses with anhidrosis.16 Other nonrespiratory causes mental conditions such as heat and humidity and relocation
of respiratory distress include disorders that cause anemia, to high altitude. A history of recent transport may raise the
such as blood loss, autoimmune hemolytic activity, neonatal index of suspicion for pleuropneumonia. Useful information
isoerythrolysis, and red maple toxicosis. In addition to red can also be obtained from specifics related to the respiratory
maple, other toxins that can affect respiration include monen- distress such as the speed of onset, progression of signs, his-
sin and snake envenomization. Episodic respiratory distress tory of previous episodes, and association with exercise or
was seen in 5 of 16 horses diagnosed with neuroborreliosis.308 specific locations/housing. Any history of recent trauma or
potential exposure to toxins should be determined. A history
of any other problems such as cough, nasal discharge, dyspha-
Approach to Respiratory Distress gia, anorexia, or lethargy can also be important.
Signalment and History In neonatal foals, the circumstances of gestation and par-
Both breed and age have been linked with specific causes of turition can help to establish the likelihood of problems such
respiratory distress. For example, American Miniature Horses as immaturity, rib fractures, meconium aspiration, and sepsis.
are at increased risk of tracheal collapse.233 Idiopathic laryn-
geal hemiplegia is more common in large, long-necked horses Physical Examination
such as draft horses, Thoroughbreds, and Warmbloods.298,299 A thorough physical examination is essential to determine
In Quarter Horses and related breeds, some foals affected with the origin of respiratory distress, identify concurrent disease,
hyperkalemic periodic paralysis will show signs of respira- and direct further diagnostic testing. Prolonged inspiration is
tory stertor usually within the first week of life as a result of consistent with restrictive or extrathoracic, nonfixed, obstruc-
laryngeal dysfunction, especially if homozygous.302,303 Inad- tive disease, whereas horses with intrathoracic airway obstruc-
equate lung development, surfactant deficiency, persistent tion exhibit expiratory difficulty.256,257 Respiratory distress
associated with inspiration and expiration may indicate an infections, the most common means of diagnosis is detection
extrathoracic fixed obstruction. Stertor is a low-pitched, of viral genetic material by PCR from a nasal or nasopharyn-
“snoring” respiratory noise caused by partial obstruction geal swab. For strangles, PCR and/or culture of a nasal or naso-
above the larynx and is inspiratory. In comparison, stridor pharyngeal swab, nasal wash, guttural pouch wash, or abscess
is a more musical sound that is generated by obstruction of can be diagnostic. Several techniques have been described for
the larynx and less frequently the trachea or bronchi. Stridor sampling the lower airways of horses including transtracheal
can be heard during inspiration and/or expiration but is most aspiration, bronchoalveolar lavage, and various transendo-
often audible during inspiration.257 scopic procedures. Thoracocentesis can be useful in cases of
Thoracic auscultation identifies abnormal respiratory sounds suspected pleuropneumonia and in some cases of suspected
(crackles and wheezes) or regions of decreased breath sounds neoplasia. For the diagnosis of RAO, cytologic analysis of
caused by pleural effusion, pneumothorax, or pulmonary con- bronchoalveolar lavage fluid is recommended and is typically
solidation.259,308 Percussion of the thoracic wall generates a reso- characterized by a significant increase in neutrophils (greater
nant and hollow sound when performed over regions of normal than 25%). Bronchoalveolar lavage can also be helpful in the
lung. Pleural effusion and pulmonary consolidation sound dull evaluation of suspected EIPH.
and flat during thoracic percussion, whereas pneumothorax Endoscopy. An endoscopic examination of the upper air-
produces a hyperresonant sound.246,259 way is indicated in horses with stertor or stridor and suspect-
Normal air flow occurs in laminar flow; therefore normal ed upper airway obstruction.246,259 Endoscopy can be used to
horses at rest do not generate easily audible sounds.259 If the evaluate the trachea and can help to identify tracheal collapse,
horse is not in significant distress, auscultation with a rebreath- foreign bodies, mucus, or hemorrhage. Horses with extreme
ing bag can help enhance sounds by increasing tidal volume. respiratory distress may resent endoscopic examination, and
Respiratory sounds are generated from vibration in tissue forced examination may precipitate a respiratory crisis.
and sudden changes in pressure of gas moving within the air- Diagnostic Imaging. The findings during thoracic auscul-
way lumen. Airway narrowing and exudate generate audible tation and percussion are valuable in determining whether
sounds by creating disturbances in laminar flow, turbulence, ultrasonography rather than radiography is indicated.246,259
and sudden changes in pressure of moving gas.256 Crackles Pulmonary consolidation, abscessation, fibrosis, interstitial
are intermittent or explosive sounds, generated by bubbling pneumonia, peribronchial infiltration, and mediastinal mass-
of air through secretions or by equilibration of airway pres- es are typically imaged best via thoracic radiography. Thoracic
sures after sudden opening of collapsed small airways. The ultrasonography is superior to radiography in detecting and
generation of crackles requires an air-fluid interface, and these characterizing pleural fluid and peripheral pulmonary absces-
abnormal lung sounds occur in horses with pneumonia, inter- sation and consolidation in horses.309 Air reflects the ultra-
stitial fibrosis, RAO, pulmonary edema, and atelectasis.246,259 sound beam; therefore ultrasonography does not image deep
Wheezes are continuous, musical sounds that originate from pulmonary lesions if the overlying lung is aerated.
oscillation of small airway walls before complete closing (expi- Other Diagnostic Aids. The administration of atropine or
ratory wheeze) or opening (inspiratory wheeze).256 Expiratory N-butylscopolammonium bromide in horses with RAO may
wheezes are the hallmark of obstructive pulmonary disease.256 provide rapid relief of respiratory distress if the major com-
Horses with nonpulmonary respiratory distress demon- ponent of airway obstruction is reversible bronchoconstric-
strate increased rate and/or depth of respiration without pro- tion.282 The bronchodilatory properties of N-butylscopolam-
ducing abnormal respiratory noise. Stertor and stridor are monium bromide appear to be similar to those of atropine,
absent, and auscultation of the thorax is normal. although of shorter duration and associated with fewer sys-
temic side effects.283 Horses that respond to an atropine or N-
Ancillary Diagnostic Tests butylscopolammonium bromide challenge likely will respond
Clinical Pathology favorably to bronchodilator therapy. Incomplete response to
BLOOD WORK. A CBC and fibrinogen can help to evaluate these bronchodilators in horses with RAO indicates that exu-
hemoconcentration, anemia, and the presence of inflamma- date or fibrosis is contributing to airway obstruction, and lim-
tion. Serum amyloid A can also be used in the assessment of ited response to bronchodilator therapy is anticipated.257,259
inflammation. Other tests that may be of value in the assessment of equine
Arterial blood gas analysis provides a quantitative eval- asthma include a hay challenge, histamine provocation test,
uation of pulmonary function, alveolar ventilation, and and pulmonary function testing.
acid-base status and may identify the origin of respiratory Both endobronchial and percutaneous lung biopsies may be
distress (hypercapnia, hypoxemia, or acidemia).256 The cli- used in the diagnosis of respiratory disease but are not com-
nician may determine the pathophysiologic mechanism of monly performed.253,254 In horses with suspected anhidrosis,
hypoxemia by examining the Paco2 level and by investigat- a terbutaline sweat test can be used to evaluate the patient’s
ing the response of Pao2 to supplemental oxygen therapy. ability to sweat.67
In addition, serial blood gas monitoring can determine
response to bronchodilator, parasympathomimetic, or anti- Y EDEMA
inflammatory therapy.
Airway Cytology/Assessment of Infection. Appropriate Edema is defined as the excessive and abnormal accumulation
samples for cytologic evaluation and culture can be obtained of fluid in the interstitium, which is the intercellular connective
from the respiratory tract depending on the primary differ- tissue that lies between the cellular elements of tissues.310,311
ential diagnoses.240,241,246 The degree of respiratory distress Interstitial fluid accumulates as a result of imbalances between
should be considered, as some diagnostic procedures can the rates at which fluid enters and exits the interstitium. Fac-
be stressful in horses with significant respiratory distress, tors that either increase the rate of fluid flux from the capillary
especially foals. Currently, for most viral respiratory tract or impair reabsorption and lymph drainage to the extent that
normal compensatory mechanisms are overwhelmed result edema include the endothelial glycocalyx layer, the endothe-
in the accumulation of fluid in the interstitial space and the lial basement membrane, and selective water channels known
development of edema. as aquaporins.312,316-319
Edema is often classified according to the anatomic loca-
tion. The most frequently recognized type of edema in horses The Starling Equation
is peripheral edema, which is often seen in the limbs or along The net rate of ingress of fluid from capillaries into the inter-
the ventrum. Most peripheral edema is “pitting,” which means stitium is determined by a number of factors acting across the
that an indentation persists after pressure is applied to an area capillary membrane, the effects of which are related by Star-
and released—for example, using the tip of a finger to indent ling’s equation:
( [ ])
the fluid. Occasionally nonpitting peripheral edema will be J = Kf [Pc − Pt ] − σ πp − πt
recognized, which in horses is most often associated with
lymphedema, which is fluid retained in the interstitium as a in which J equals the volume flow across the capillary wall; Kf
result of impaired lymphatic drainage. Organ-specific edema, equals the filtration coefficient of the capillary wall (volume
such as cerebral, pulmonary, and corneal edema, also occurs flow per unit time per 100 g of tissue per unit pressure); Pc
and is often clinically important. Generalized edema occurs equals capillary hydrostatic pressure; Pt equals interstitial fluid
when edema is present both peripherally and in multiple hydrostatic pressure; σ equals the osmotic reflection coeffi-
organs. cient; πp equals the colloid osmotic (oncotic) pressure of the
plasma; and πt equals the colloid osmotic (oncotic) pressure of
General Physiology of Fluid Movement the interstitial fluid.315 Although all these factors act in concert
The volume of interstitial fluid and lymph fluid in the nor- to determine the rate of net fluid efflux from the capillary, con-
mal horse is 8% to 10% of body mass,310 or 36 to 45 L in sidering them individually is conceptually easier.
a 450-kg horse. Interstitial fluid consists largely of water, Filtration (Kf) and Reflection (σ) Coefficients. Together the
protein, and electrolytes. Compared with plasma, intersti- filtration and reflection coefficients describe the properties of
tial fluid has a slightly lower concentration of cationic elec- the capillary membrane that determine the ease with which
trolytes, a slightly higher concentration of chloride, and a water, protein, and other plasma constituents move from the
much lower concentration of protein (1.2 vs. 0.2 mOsm/L vascular space to the interstitium. The filtration coefficient,
of water).311 The overall amount and function of the pro- which is the product of the hydraulic permeability and sur-
teins within the interstitial space are not inconsequential. A face area of the capillary, is a measure of the ease with which
constant circulation of plasma proteins occurs between the water crosses the capillary membrane. The reflection coeffi-
vascular and interstitial spaces, with about half of the pro- cient is a mathematical expression of the capillary permeabil-
tein circulating every 24 hours in human beings. More than ity to a particular substance and ranges from 0, indicating the
half of the plasma protein content of the body is contained substance crosses the membrane as easily as water, to 1, in-
within the interstitial space at any one time. Plasma proteins dicating that the substance does not cross the membrane.
within the interstitial space are important in the transport of The reflection coefficient is dependent on both the substance
water-insoluble substances from the vascular space and in in question and the tissue bed.311,320,321 For example, in lung
resistance to infection.312 endothelium, the reflection coefficients for urea, glucose and
The extracellular tissue of the interstitium, except in the albumin are approximately 0.3, 0.5, and 0.7. Reflection coeffi-
case of bone, consists of a three-dimensional collagen fiber cients for albumin vary among tissues, being 0.1 in the hepatic
network embedded in a proteoglycan gel matrix.313 Normally sinusoids, 0.9 in muscle, and 0.99 in brain.
most of the interstitial water is contained within the proteo- The filtration and reflection coefficients together partially
glycan interstitial gel, with a small proportion existing as free determine the rate of fluid flux across the capillary wall and the
water. However, in edematous states, the proportion of fluid as composition of the fluid. For a given hydrostatic and oncotic
free water within the interstitium increases.311 pressure difference, tissues with higher filtration coefficients
The source of interstitial fluid is the intravascular space. (whether because of a larger capillary surface area or more
The volume of interstitial fluid is determined by the functional porous capillaries) will have a greater fluid flux. Conversely,
relationships of three major anatomic structures: the capillary, under the same circumstance, increases in the reflection coef-
the interstitial space, and the lymphatics.314 Functionally, the ficient will reduce solute movement across the capillary wall,
volume of fluid that accumulates in the interstitium is deter- affecting the osmotic pressure gradient and reducing fluid
mined by the rate of ingress of fluid from the vascular space, flux. The differential permeability of the capillary membrane
the compliance of the interstitium, and the rate at which fluid to water and protein has important consequences in the main-
is evacuated from the interstitium. tenance of the oncotic pressure difference between plasma and
Traditionally the fundamental principle guiding micro- interstitial fluid. Multiple factors influence the movement of
vascular filtration and transcapillary fluid shifts has been fluid and solutes across the endothelium, including the con-
defined by the Starling equation, first introduced in 1896. centration of the solutes on either side of the membrane, sol-
In this model, fluid movement is passive and dependent on ute charge and interaction with other solutes, and capillary
pressure gradients across the endothelium, which are deter- pore configuration.322
mined by hydrostatic and colloid osmotic pressures.311,315 Hydrostatic and Colloid Osmotic Pressures (Starling’s
However, it is now recognized that the regulation of fluid Forces). Transcapillary fluid flow results from an imbalance
flux is not simply governed by transcapillary hydrostatic and between the hydraulic forces favoring movement of water
oncotic pressure differences but is much more complex. The from the capillary into the interstitium and the forces favor-
role of non-Starling mechanisms of barrier regulation and ing movement of water in the reverse direction. The forces
fluid movement are an area of active investigation. Important contributing to fluid movement out of the capillary are the
factors that mediate processes central to the development of intracapillary hydrostatic pressure and the interstitial colloid
Capillary Interstitium
Hydrostatic pressure Hydrostatic pressure Total hydrostatic pressure

favoring filtration
17.0 mm Hg 22.3 mm Hg
–5.3 mm Hg
Oncotic pressure Oncotic pressure

Total oncotic pressure
opposing filtration
28.0 mm Hg
22.0 mm Hg
6.0 mm Hg
Total pressure favoring
filtration = 0.3 mm Hg
FIG. 7.4 Basic Starling’s forces—mean forces influencing fluid movement into or out of the capillary.
(From Guyton AC, Hall JE: The microcirculation and the lymphatic system: capillary fluid exchange, intersti-
tial fluid and lymph flow. The body fluid compartments: extracellular and intracellular fluids; interstitial fluid
and edema. In Guyton AC, Hall JE, editors: Textbook of medical physiology, ed 11, Philadelphia: Elsevier/
Saunders; 2006.)
osmotic pressure, whereas those forces favoring movement of from the capillary occurs at its arteriolar end, where capillary
fluid from the interstitium to the capillary are the interstitial hydrostatic forces are greatest and the oncotic gradient is least,
hydrostatic pressure (if it is positive) and the plasma colloid whereas a net flux of fluid into the capillary occurs toward its
osmotic pressure323 (Fig. 7.4). venous end, where capillary hydrostatic forces are least and the
The principal force favoring fluid efflux from the capil- oncotic pressure gradient favoring reabsorption is greatest fol-
lary is the hydrostatic pressure within the capillary. Capil- lowing dilution of protein in the interstitium (Fig. 7.5).
lary hydrostatic pressure varies among different tissues The small imbalance in filtration forces results in a net
and decreases along the length of the capillary. Hydrostatic efflux of fluid from the capillary into the interstitial tissue.
pressure within a capillary is determined by the arterial and Normally this fluid does not accumulate in the interstitium, as
venous pressures and by the precapillary and postcapillary it is removed by the lymphatics.
resistances.324 Specifically, capillary pressure (Pc) is deter-
mined by the ratio of the postcapillary resistance (Ra) to Other Factors Influencing Fluid and
the precapillary resistance (Rv), and by the arterial (Pa) and Solute Movement
venous (Pv) pressures: Vascular Endothelium. The endothelium forms a dynamic
Pc = [(Rv/Ra) Pa + Pv] / [1 + (Rv/Ra)] barrier between the blood and the tissue. Although endothe-
lial cells can have distinct morphologies and functions de-
Thus although an increase in either arterial or venous pres- pending on the tissue and even the specific vessel, in general
sure will increase capillary pressure, a small increase in venous one function is to restrict the extravasation of larger molecules
pressure has a much greater effect than does an increase in and cells from the vasculature to the interstitium.325 The en-
arterial pressure. For this reason the hydrostatic pressure is dothelial glycocalyx, which is a layer of macromolecules at the
greater in capillaries below the heart (e.g., legs) than in those luminal surface of the vascular endothelium, plays an impor-
above the heart (e.g., head). tant role in fluid homeostasis and solute exchange.317,325,326
The colloid osmotic pressure of the plasma is the prin- The composition of the endothelial glycocalyx is dynamic,
cipal force minimizing fluid efflux from the capillary. The but the major constituents are hyaluronic acid and the nega-
colloid osmotic pressure is generated both because the tively charged heparin sulfate proteoglycans. Changes in the
plasma and interstitial fluid are separated by a semiperme- endothelial glycocalyx appear to play a key role in endothelial
able membrane, the endothelium, and because they vary dysfunction and the formation of edema. Also, endothelial
slightly, but significantly, in composition. As noted previ- permeability is in part regulated by the dynamic opening and
ously, the interstitial fluid has a lower protein concentration closing of cell-cell adherens junctions that are composed pri-
than does plasma but has an essentially identical electro- marily of vascular endothelial-cadherin.318,327,328
lyte concentration. The difference in protein concentra- Aquaporins. Aquaporins are a diverse family of membrane
tion across the semipermeable endothelium generates an proteins that are expressed predominantly in tissues in which
osmotic force that tends to draw water from the intersti- edema and fluid imbalances are of major concern.319,329 Water
tium into the plasma. movement across cell membranes is driven by osmotic and hy-
In addition to the capillary hydrostatic pressure, the col- drostatic forces, but the speed of this process can be influenced
loid osmotic pressure and negative hydrostatic pressure of the by the presence of specific aquaporin channels. These channels
interstitial fluid favor fluid movement out of the capillary. Fluid are primarily water channels, although some are also permea-
flux across the capillary results from the summation of these ble to small solutes. Aquaporin-4 water channels play a central
forces (see Fig. 7.4). These figures should be recognized as rep- role in brain water regulation in neurologic disorders.330-332
resenting the forces at the midpoint of an idealized capillary; The pharmacologic modulation of the expression and activity
the forces are dynamic, changing between tissues and even of various aquaporins potentially could provide novel treat-
along the length of the capillary. In fact, a large net flux of fluid ments for a variety of disorders, including brain edema.
Interstitium
Lymphatics
+ 10 mm Hg ~ 0 mm Hg – 7 mm Hg
net filtration pressure
Capillary bed
Arteriole Venule
FIG. 7.5 Schematic of normal fluid movement in a capillary bed. Filtration occurs at the arterial end where
capillary hydrostatic pressure is highest, and absorption occurs at the venous end where capillary hydro-
static pressure is lower, allowing plasma colloid oncotic pressure to predominate. Excess fluid is removed
by the lymphatics.
Lymphatics. The lymphatics drain the interstitium of fluid

and substances, notably proteins, that are not absorbed by BOX 7.6
Mean Forces (mm Hg) Influencing Fluid Movement
the capillaries.311 The lymphatics represent the only means into or out of the Capillary
by which interstitial protein is returned to the circulation. In-
terstitial fluid (and, with it, protein) moves down a pressure Type of Pressure Mean Force
gradient into lymphatic capillaries through clefts between the HYDROSTATIC PRESSURES
lymphatic endothelial cells. Lymphatic endothelial cells are Mean capillary pressure 17.0
supported, and the lymphatic capillaries maintained patent, Interstitial pressure –5.3
by anchoring filaments that attach the endothelial cells to sur-
rounding connective tissue. Lymphatic fluid progresses cen- Total hydrostatic pressure favoring filtration 22.3
tripetally through progressively larger vessels before draining COLLOID ONCOTIC PRESSURES
into the great veins of the chest. Lymphatic valves prevent the Plasma oncotic pressure 28.0
retrograde flow of fluid from the lymphatics. Lymph is pro- Interstitial oncotic pressure 6.0
pelled by factors extrinsic to the lymphatics, including muscle
activity, active and passive motion, posture, respiration, and Total oncotic pressure opposing filtration 22.0
blood vessel pulsation. Exercise increases lymph flow, at least Total pressure favoring filtration 0.3
in part because of the increase in tissue pressure that is as-
sociated with muscle contraction, although passive motion Data from Guyton AC: Textbook of medical physiology, ed 11, Philadelphia,
also increases lymph flow. In human beings, standing results Saunders, 2005.
in significant diminution or cessation of lymph flow from the
lower extremities, which can result in the accumulation of Alterations in Starling’s Forces
interstitial fluid and edema. In addition to the extrinsic fac- Perturbations of one or more of the forces that affect filtra-
tors affecting lymph flow, coordinated contractions of lym- tion across the capillary alter the rate at which fluid enters the
phatic vessels contribute substantially to the centripetal flow interstitium.311,312 Increases in capillary hydrostatic pressure,
of lymph.313 decreases in plasma oncotic pressure, and increases in inter-
stitial oncotic pressure all favor increased fluid filtration. Con-
Mechanisms of Edema Formation versely, increased interstitial hydrostatic pressure and decreased
Simply stated, accumulation of excessive fluid in the intersti- interstitial oncotic pressure act to inhibit fluid filtration.
tial spaces—edema—results from an imbalance of the rates of There are several fundamental mechanisms by which exces-
fluid filtration from the capillaries and drainage by the lym- sive interstitial fluid can accumulate (Box 7.6). Increases in cap-
phatics. The exact pathophysiologic mechanisms involved in illary hydrostatic pressure, which occur with venous obstruction
edema formation are complex and involve some tissue-specific or arteriolar dilation, such as that associated with inflammation,
mechanisms. Basic mechanisms of edema include alterations increase net fluid efflux. The edema that occurs with congestive
in Starling’s forces, changes in vascular permeability, and heart failure likely has an increase in capillary hydrostatic pres-
impaired lymph drainage. sure as one of its causes, although the mechanism is complex.313
Posture also affects capillary hydrostatic pressure; capillaries oncotic pressure causes fluid to accumulate in the interstitium,
below the level of the heart have higher hydrostatic pressures thus exacerbating the edema.
than do capillaries above the level of the heart.
A decrease in the oncotic gradient across the capillary endo- Compensatory Mechanisms Limiting
thelium, which occurs with a decreased plasma oncotic pressure Edema Formation
or an increased interstitial oncotic pressure, results in an increase Alterations in the magnitude of one or more of Starling’s forces
in efflux of fluid from the capillary. A decrease in plasma oncotic can be offset by compensatory changes in lymph flow and other
pressure decreases the oncotic gradient that favors movement of of Starling’s forces.311 In concert Starling’s forces and lymph flow
fluid into the capillary. Consequently, the capillary hydrostatic act as “edema safety factors” to prevent the excess accumulation
pressure, which favors filtration, predominates and fluid accu- of interstitial fluid and development of frank edema. For exam-
mulates in the interstitium. Plasma oncotic pressure decreases ple, lymph flow increases with the increased filtration associated
when plasma protein concentration declines. Albumin is the with increased capillary hydrostatic pressure. Thus a larger vol-
plasma protein that exerts the preponderance of the oncotic force ume of fluid enters and is removed from the interstitial space.
and edema often is associated with hypoalbuminemia.311,321 The interstitial protein concentration decreases as increased
fluid flow washes protein out of the interstitial space. Reduced
Changes in Vascular Permeability interstitial space protein concentration minimizes oncotic forces
An increase in the permeability of the capillary membrane drawing fluid from the capillary to the interstitial space.315
can increase fluid and protein transport into the interstitium
and decrease the ability of the membrane to maintain a differ- Conditions Associated with Edema
ence in oncotic pressure between the plasma and the intersti- Edema is not in itself a disease; rather, it is a sign of a disease
tium.314 Thus changes in vascular permeability can affect fluid process. Therefore the identification of conditions leading to
flux both directly and via changes in Starling’s forces. the accumulation of edema is based on an understanding of
The regulation of vascular permeability is complex with the pathogenesis of edema. The most common form of edema
multiple pathophysiologic triggers contributing to increased recognized in horses is peripheral edema, and multiple causes
permeability.325-327 The microvasculature is sensitive to dam- have been identified (Table 7.3). Some specific causes of
age via several mechanisms including mechanical forces, peripheral edema are discussed later.
ischemia-reperfusion injury, sepsis, and inflammation. Vaso- A nonpainful edema of the limbs is often seen in horses
dilation and increased blood flow alone can increase vascular in association with immobility. This condition, commonly
permeability. Numerous molecular regulators affect vascular referred to as “stocking up,” is apparently associated with
permeability, including hormones, inflammatory cytokines, venous congestion and decreased lymph flow. It can affect all
and other plasma constituents. Vascular endothelial growth four limbs but is most common in the hindlimbs.
factor is a potent angiogenic factor that can affect regulation of Hypoproteinemia, particularly hypoalbuminemia, is an
the vascular barrier.325,333,334 Also, a number of inflammatory important cause of edema.311 In horses, the most common
cytokines contribute to vasculitis. Among these are histamine cause of hypoalbuminemia is protein loss, particularly through
and bradykinin, both of which can ultimately increase the the gastrointestinal tract. In addition to acute colitis, some
generation of nitric oxide.325 specific gastrointestinal conditions that are frequently associ-
The precise means by which vascular permeability is ated with protein loss include right dorsal colitis, proliferative
increased after stress to the endothelium are complicated and enteropathy due to Lawsonia intracellularis, and inflammatory
still under investigation. Inflammatory mediators and hor- bowel disease.142.335,336 Other potential causes of protein loss
mones can affect the integrity and function of the endothelial include renal disease, especially chronic renal failure, amyloi-
glycocalyx layer, and the changes in this layer frequently result dosis, extensive skin wounds (burns), and third space loss as
in increased permeability and edema.317,325,326 The organization is seen in some cases of pleuritis or peritonitis. Occasionally
and function of vascular endothelial-cadherin and other pro- hypoalbuminemia can be seen in association with decreased
teins at the adherens junctions can also be affected.318,325,327,328 albumin production due to liver disease.337 Severe burn inju-
In addition, changes in the transcriptional, translational, and ries can induce generalized edema independent of protein
posttranslational regulation of transporters and ion and water loss, likely secondary to endothelial injury.214,338
channels, including aquaporins, occur.325,329-332 The complex- Vasculitis is another important cause of edema in
ity of the regulation of vascular permeability and other factors horses.339-343 Some infectious diseases in which vasculitis is
contributing to edema can in part explain some of the limita- often prominent include equine viral arteritis, equine infec-
tions of colloid therapy. Improved understanding of the mech- tious anemia virus, African horse sickness, and equine granu-
anisms controlling vascular permeability might lead to the locytic anaplasmosis (Anaplasma phagocytophilum). Purpura
formulation of pharmacologic strategies to control the barrier hemorrhagica is an immune-mediated vasculitis that is often
function of the endothelium. associated with marked edema.343 Many, but not all, horses
affected with purpura hemorrhagica have been exposed to or
Impaired Lymph Drainage infected with Streptococcus equi subspecies equi.
Lymphatic obstruction prevents the removal of interstitial Several other causes of edema have been recognized in
fluid and protein.311 Filtration of fluid and passage of small horses. Congestive heart failure is relatively uncommon in
amounts of protein into the interstitial space continues in horses, but when it does occur ventral edema is among the
the presence of lymphatic obstruction. The interstitial fluid most common clinical signs along with a heart murmur
is reabsorbed by the capillaries, but the protein is not. Con- accompanied by either jugular distention or pulsation, tachy-
sequently, the protein content of the interstitial fluid gradu- cardia, and tachypnea.229 Lymphangitis is an inflammation of
ally increases, with a resultant increase in interstitial oncotic the lymphatic vessels that often results in impaired lymphatic
pressure that favors filtration of fluid. The increased interstitial drainage and swelling. The condition can occur in any limb
TABLE 7.3 Common Causes of Peripheral or Ventral Edema any different from that for any other sign of disease. A clini-
in Horses cal examination, including history and physical examination,
permits the development of a list of potential diagnoses and
CONGESTIVE HEART FAILURE dictates the appropriate subsequent steps in confirming the
Valvular disease diagnosis. The reader is referred to those sections of the text
Myocarditis that deal with specific diseases for a more in-depth description
Monensin toxicosis of the conditions and their diagnosis.
VASCULITIS
Equine viral arteritis Signalment and History
Equine ehrlichiosis The signalment can be important when considering specific
Purpura hemorrhagica conditions associated with edema. For example, Lawsonia
Equine infectious anemia intracellularis is primarily a disease of weanling-age horses.335
VENOUS OBSTRUCTION AND CONGESTION Chronic progressive lymphedema is particularly common
Catheter-related thrombophlebitis in certain draft breeds, including Shires, Clydesdales, and
Disseminated intravascular coagulation Belgians.229
Tight bandages When taking the history of a horse that has edema, the vet-
Tumors erinarian should focus on acquiring facts that have the great-
Immobility est diagnostic use in differentiating among those diseases that
have edema as a sign. The veterinarian should consider the fol-
CELLULITIS
lowing aspects: housing, season, and geographic region; vac-
Staphylococcal
cine and parasiticide administration; exposure to other horses
Clostridial
and diseases present within the herd; the duration of the
Counterirritant application
edema and its distribution; and the presence of any other clini-
LYMPHATIC OBSTRUCTION cal signs. The veterinarian should investigate the remainder of
Ulcerative lymphangitis the history depending on the responses to initial questions.
Lymphadenitis (Streptococcus equi, Corynebacterium
pseudotuberculosis) Physical Examination
Lymphosarcoma The physical examination should begin with a visual evalu-
Tumors ation of the attitude and physical condition of the horse.
HYPOALBUMINEMIA The temperature, pulse rate, and respiratory rate should be
Parasitism recorded. Although the physical examination should be com-
Pleural and peritoneal effusions plete, particular attention should be paid to those body sys-
Protein loss (gastrointestinal, renal, or wounds) tems that the preliminary examination indicates might be
Inadequate production (starvation) involved in the disease process. The physical examination
Hemodilution (subsequent to hemorrhage) reveals the distribution and severity of edema. Edema that is
SHOCK localized to one extremity or is not bilaterally symmetric is
Hemorrhagic more likely to be caused by local factors (e.g., lymphangitis,
Endotoxic venous obstruction) than by systemic disease. Conversely,
edema that involves several areas of the body and has a sym-
PLEURITIS metric distribution is likely to be associated with systemic dis-
Late-term pregnancy ease, such as the ventral edema of congestive heart failure. It is
Prepubic tendon rupture important to note that distribution of edema associated with
Starvation (inadequate intake; malabsorption) hypoproteinemia can vary and can be widespread or limited to

the ventrum, limbs, or submandibular area.
but is more common in the hindlimbs. It is usually caused Ancillary Diagnostic Tests
by a bacterial infection, although culture is frequently unre- The clinician will have developed an ordered list of potential
warding. Some cases of Corynebacterium pseudotuberculosis diagnoses after the initial clinical examination, and this list
infection manifest as an ulcerative lymphangitis.344 Chronic will help direct the most appropriate ancillary diagnostic tests.
progressive lymphedema is a condition recognized in some Confirmation or elimination of the potential diagnoses may
draft horse breeds including Clydesdales, Shires, and Bel- depend on the subsequent diagnostic procedures, including
gians.345 The condition is thought to be caused by altered the response to therapy. A CBC and serum biochemical pro-
elastin metabolism leading to impaired lymphatic function. file are often useful as part of a minimum database and will
Affected horses have chronic lymphedema with swelling of establish whether hypoproteinemia is present. Sections of this
the distal limbs and development of fibrosis. Massive enven- text deal with the specific disease processes and appropriate
omation by bees (bee stings) causes generalized edema in diagnostic procedures.
horses.346 Snake envenomation can also cause edema.347
Diagnostic Approach to the Patient with Edema Y COLLAPSE IN HORSES: SYNCOPE,
The diagnostic approach to the patient with edema is depen- SEIZURES, AND SLEEP DISORDERS
dent on an understanding of the mechanisms of edema forma-
tion and a knowledge of the diseases likely to be involved. The Collapse is characterized by a loss of postural tone with or
diagnostic approach to an animal with edema should not be without progression to recumbency and with or without loss
of consciousness. Collapse in horses is uncommon, but it has been recognized in people include carotid sinus syndrome,
serious implications for both horse welfare and human safety. postmicturition syncope, and swallow syncope.
In horses, it appears that collapse most often occurs at rest, but Syncope is common in people, with approximately one third
episodes can occur during exercise.348 of the population experiencing syncope at least once during
Collapse can be categorized as syncopal or nonsyncopal. their lifetime.350,351 In humans, presyncopal signs such as weak-
Syncopal collapse, which is sometimes referred to as faint- ness, blurred vision, and nausea frequently precede the collapse.
ing, is a self-limiting loss of consciousness and postural tone Recovery is spontaneous, and following the episode people can
resulting from cerebral hypoperfusion.349,350 Nonsyncopal experience persistent drowsiness, dizziness, headache, or nausea
collapse includes a number of disorders that can be further but typically not confusion. In horses, signs such as stumbling,
subdivided into those that are associated with some degree head elevation, or anxiousness can precede collapse, but in most
of loss of consciousness, including seizures, sleep disorders, cases there are little or no premonitory warning signs.355 The
and hypoglycemia, and those with no loss of consciousness, collapse is associated with a transient comatose state followed
including musculoskeletal and metabolic problems, such as by recovery. Horses may struggle during recovery but are nor-
hyperkalemic periodic paralysis. mal thereafter unless they sustain significant trauma during the
episode. A syndrome of convulsive syncope that is difficult to
differentiate from seizure activity has been described in people,
Mechanisms of Collapse but it is uncertain if this occurs in horses.356,357
Syncope
Syncope is defined as a temporary interruption of cerebral per- Seizures
fusion resulting in a sudden and transient loss of conscious- Seizures are the manifestation of the excessive and/or hyper-
ness and postural tone.349,350 The brain has a high metabolic synchronous discharge of neurons in the cerebral cortex that
demand and is highly sensitive to changes in perfusion. Nor- leads to voluntary alterations of motor activity, consciousness,
mally cerebral blood flow is tightly regulated by a complex sys- and autonomic or sensory functions.349,355,358-360 Normal neu-
tem of cerebral autoregulation involving metabolic, myogenic, ronal function reflects a balance between excitatory and inhib-
and neurologic components. This system maintains cerebral itory activity. When intracranial neurons experience either
blood flow despite changes in blood pressure, and syncope excessive excitation or loss of inhibition (disinhibition) the
can occur when this system fails. As syncope is uncommon in resulting excessive depolarization can result in seizure activity.
horses, much of the information regarding syncope is extrapo- The seizure threshold reflects the level of neuronal inhibition
lated from other species. that must be exceeded for uncontrolled discharge of a popula-
The causes of syncope can be broadly classified as cardio- tion of neurons to occur.
vascular, noncardiovascular, and unknown.350,351 Cardiovas- Normally there are sporadic low-frequency spontaneous
cular syncope is due to reduced cardiac output and has been depolarizations within the brain that are contained by a pro-
associated with structural heart disease, arrhythmias, and, in cess known as surround inhibition. However, in some cases,
people, coronary heart disease. Causes of noncardiovascular groups of cells will depolarize with recurrent high-frequency
syncope include primarily neurologic and metabolic disorders. bursts of action potentials that can manifest as focal seizure
One cause of noncardiogenic syncope in people is orthostatic activity. Depolarizations of sufficient magnitude can overcome
or postural hypotension, which is defined as a decrease of 20 the surrounding inhibitory zone and be conducted to a more
mm Hg in systolic blood pressure or 10 mm Hg in diastolic widespread area via normal anatomic connections between
blood pressure within 3 minutes of changing position from neurons, thus propagating seizure activity and potentially
sitting or supine to standing.350-352 It results from an inade- involving the entire cortex. Although occasionally depolar-
quate physiologic response to postural changes and has been izations in the brainstem and thalamus can result in seizures,
associated with an impairment of peripheral vasoconstriction these depolarizations are projected to the cortex. The mecha-
or reduction of intravascular volume. Specific causes of syn- nisms of seizure termination are not fully understood, but
cope related to orthostatic hypotension include dehydration factors that may be involved include metabolic exhaustion
or blood loss, as well as a variety of neurologic, cardiovascu- of neurons and the activity of extracortical inhibitory cen-
lar, and endocrine disorders. Another type of noncardiogenic ters within the cerebellum. Other regions of the brain, such
syncope is neurally mediated syncope, which is associated as the caudate and reticular formation, may also affect seizure
with disturbances of reflex cardiovascular control.350,351,353,354 activity.
Some cases of neurally mediated syncope are associated with Multiple factors may trigger the uncontrolled synchro-
pain, stresss, or specific triggers. Although the pathogenesis of nous neuronal activity involved in the generation of seizures,
this phenomenon is not fully understood, it is characterized reflecting the complexity of the neuronal environment.358-361
by peripheral vasodilation and/or transient bradycardia that is Among the factors influencing this environment are the neu-
associated with inappropriate triggering of neural reflexes. In ronal lipoprotein cell membrane with its associated ion chan-
some but not all cases, neurally mediated syncope is associated nels and enzymes. Also, neuronal function is influenced by
with concurrent cardiac disease. The most common form of the ionic environment, including concentrations of sodium,
neurally mediated syncope is neurocardiogenic or vasovagal chloride, calcium, and potassium. A variety of neurotrans-
syncope, in which there is an increase in vagal parasympa- mitters are present, including both excitatory neurotransmit-
thetic tone and a decrease in sympathetic tone that results in ters such as glutamate, aspartate, and acetylcholine, and also
bradycardia and hypotension associated with peripheral vaso- inhibitory neurotransmitters such as γ-aminobutyric acid,
dilation.353,354 In two cases of presumptive neurocardiogenic glycine, taurine, and norepinephrine. Several hormones and
syncope in horses, no bradycardia was noted before collapse, neurosteroids can influence epileptogenesis, having variable
suggesting a purely vasodepressor response in those cases.348 effects depending on the substance.361 Any alterations in the
Some other forms of neurally mediated syncope that have complex neuronal environment can potentiate seizures. For
example, hypoglycemia can result in a loss of energy substrate rigidity or a loss of muscle tone. Postictal signs have also been
for the Na+-K+ ATPase pump, causing cells to move toward reported in horses. In the study of 104 horses with seizures,
lower positivity and allowing excessive excitation. In hepa- 31% of horses affected by complex focal or generalized seizures
toencephalopathy, there may be a decrease in the function of had postictal signs typically lasting from minutes to hours.364
inhibitory neurotransmitters, resulting in a lack of inhibition These signs included ataxia, disorientation, lethargy, agitation,
and unregulated depolarization. Multiple factors contribute to blindness, hypersensitivity, and shallow breathing.
the development of seizures associated with traumatic brain
injury, infection, or neoplasia including neuronal loss, altered Sleep Disorders
cellular metabolism and blood flow, and neuroinflammation, Sleep is defined as unconsciousness from which one can be
among others.358-362 aroused by sensory or other stimuli.349,355 Sleep has been
Seizures can present with a variety of forms and severities, investigated in domestic horses, and four stages of vigilance
and the classification and terminology can be confusing. In have been identified: wakefulness, drowsiness, slow wave
humans, the Commission on Classification and Terminology sleep (SWS), and rapid eye movement (REM) sleep, also
of the International League Against Epilepsy has developed known as paradoxic or desynchronized sleep.366-369 REM sleep
a comprehensive scheme for the classification of seizures to appears to be an important regenerative part of the sleep cycle.
more accurately describe seizures and develop a systematic Adult horses typically require 3 to 5 hours per day of sleep
approach to their diagnosis and treatment.363 Efforts have with approximately 0.5 hour per day of that being REM sleep.
been made to similarly classify seizures in horses.364,365 The The majority of REM sleep in horses appears to occur dur-
term epilepsy is defined as two or more seizures that occur in ing recumbency, although occasionally REM sleep has been
more than 24 hours regardless of the cause. Seizures can be observed in standing horses that are not habituated to their
described as either focal or generalized, both of which have environment.368
been described in horses. Focal seizures, which have previ- One cause of excessive drowsiness and possible collapse in
ously been referred to as partial, represent a focal area of abnor- horses is recumbent sleep deprivation. The level of tolerance
mal discharge within the brain and result in localized motor for sleep deprivation among individual horses appears to vary
signs or sensations. Focal seizures can be further categorized widely, with some horses being able to tolerate weeks of being
as simple, if alertness and normal mentation are maintained, unable to lie down to sleep whereas others will show signs of
and complex, if impairment of consciousness is present. Gen- sleep deprivation after just several days.355,368,370
eralized seizures involve the entire cerebral cortex and typi- Narcolepsy is a sleep disorder that is primarily character-
cally result in generalized bilateral motor activity and loss of ized by excessive drowsiness and sleep attacks with or without
consciousness. Generalized seizures can be primary, meaning cataplexy, which is a sudden loss of muscle tone and somatic
they are generalized from the outset, or secondary, meaning areflexia.355,371,372 In people, disturbed nocturnal sleep, hyp-
they progress from a focal seizure. Seizures can also be clas- nagogic hallucinations, and sleep paralysis can also be seen in
sified by the cause. Reactive seizures are those in which the association with narcolepsy. The sleep cycle is disrupted, and
seizure is a result of a temporary systemic disease with normal people with narcolepsy frequently enter REM sleep at the onset
brain function such as seizures seen in association with acute of sleep rather than later in the sleep cycle. Both sporadic and
hemorrhage or hypoglycemia. Other causes of seizures have familial forms of narcolepsy have been identified in humans,
been grouped as follows: (1) symptomatic, in which there is a dogs, and horses.370-379 The pathophysiology of narcolepsy
documented structural brain disorder such as brain damage remains unclear and may vary among species and individu-
from trauma or hypoxia, congenital anomalies, neoplasia, and als. It appears to be a complex biochemical disorder affecting
infection, including meningitis, encephalitis, and abscessation; several regions of the brain (brainstem, hypothalamus, limbic
(2) cryptogenic, in which symptomatic causes are suspected system, and possibly the striatum and cortex) with dysfunc-
but cannot be documented; and (3) idiopathic, in which there tion of dopaminergic, cholinergic, and noradrenergic neu-
are no underlying structural or metabolic abnormalities and rotransmitters.372,381 Defective hypocretin signaling has been
there is a suspected genetic predisposition. described in both familial and sporadic narcolepsy in some
The clinical presentation of seizures in horses is similar to species.371-373,382 Hypocretin 1 and 2, also known as orexins,
that seen in other species.355,364 In a study of 104 horses over are neuropeptides that appear to be specifically expressed in
3 weeks of age with seizures, precipitating factors were iden- certain hypothalamic neurons. They appear to have an impor-
tified in approximately 11% of cases and included xylazine, tant role in the regulation of sleep and arousal states, as well as
noise, trimming the mane, touching the neck, and estrus.364 appetite. In some dog breeds, a familial form of narcolepsy has
Prodromal or preictal signs are not consistently recognized been identified in association with a mutation in hypocretin-2
but can be seen in some horses with either focal or generalized receptor gene.374 In these dogs, hypocretin concentration in
seizures and include anxious behavior, isolation from other the cerebrospinal fluid (CSF) is normal. In humans, narco-
horses, standing in a corner, swishing of the tail, and changes lepsy is only rarely associated with mutations in the hypocre-
in personality. Focal seizures may involve the face or body and tin receptor gene. In both humans and dogs, the sporadic form
some of the more common signs include ear or lip twitching, of narcolepsy has been associated with decreased hypocretin
tongue prolapse, opening and closing of jaw, compulsive kick- concentration in the CSF. Many cases of narcolepsy in people
ing, head turning to one side, and tremors.364 In some cases, are linked to the human leukocyte antigen, and an autoim-
impaired consciousness and behavior changes have also been mune component may play a role in the development of dis-
reported. Generalized seizures are typically characterized by ease. It has been postulated that there is an immune-mediated
tonic-clonic motor activity. Eye globe deviation and nystag- destruction of hypothalamic neurons producing hypocretin,
mus are common. Vocalization and autonomic disturbances resulting in a progressive decline in the concentration of hypo-
such as mydriasis, urination, defecation, and profuse sweating cretin. The role of hypocretin in equine narcolepsy is currently
have also been reported. Affected horses may have generalized uncertain. The concentration of hypocretin in the CSF of an
Icelandic foal with narcolepsy without cataplexy was similar to monitoring. Polycythemia and upper airway obstruction have
controls, although it was speculated that concentrations could also been reported to cause syncopal episodes.387,388
decrease over time.377 Occasionally secondary narcolepsy may
develop after disease or organic insult to the brain, such as fol- Seizures
lowing traumatic brain injury.383,384 A number of disorders have been associated with seizures in
Most cases of narcolepsy in horses have been diagnosed horses. The clinical presentation of the seizure appears to be
in foals, but sporadic cases have been seen in adults.355,374-380
Given the difficulties in diagnosing narcolepsy, some of these
cases may represent recumbent sleep deprivation or idiopathic BOX 7.7
Causes of Collapse
hypersomnia, which is another disorder of the central nervous
system characterized by excessive sleepiness. Better character- SYNCOPE
ization of sleep disorders in horses is needed. Cardiovascular
Sleep disorders in horses are often characterized by drowsi- Arrhythmia
ness, with gradual lowering of head and buckling, which most 3° atrioventricular (AV) block
often occurs in the forward direction. In some cases there is Atrial tachycardia with 2° AV block
complete collapse. In cases of narcolepsy with cataplexy there Atrial fibrillation
will be limb atonia and areflexia. Occasionally swaying and Other
stumbling when walking have been described in narcoleptic Right-sided heart failure
horses. In cases of narcolepsy in other species, cataplexy can Ruptured chordae tendinae
sometimes be induced by play or feeding, and similar triggers Myocardial infarction, myocardial fibrosis
have been described occasionally in equine cases of narcolepsy. Endocarditis
Many normal newborn foals can be induced into a sleeplike Pericarditis
cataplectic state by firm, whole-body restraint or squeezing.355 Noncardiovascular
Conditions Causing Collapse Neurocardiogenic (vasovagal) syncope
Polycythemia
Several conditions have been reported in association with col- Airway obstruction
lapse in horses, but information is somewhat limited (Box 7.7). Undetermined
It can be challenging to make a definitive diagnosis for the
cause of collapse. In a retrospective study of 25 horses with epi- SEIZURES
sodic collapse, a final diagnosis was established in 11 cases and Reactive (no structural brain lesion)
a presumptive diagnosis was made in 8, with 6 being undiag- Hepatoencephalopathy
nosed.348 Overall, the most common cause of collapse in this Hemorrhage
series of cases was syncope, which accounted for 63% of the Electrolyte abnormalities
cases in which a definitive or presumptive diagnosis was made. Hypoglycemia
In the 11 horses with a specific final diagnosis, causes included Symptomatic
cardiac disease (5 of 11), generalized seizures (2 of 11), hypo- Traumatic brain injury (skull fracture, cerebral hemorrhage)
glycemia secondary to neoplasia (2 of 11), and sleep disorders Cerebral edema
(2 of 11). In the 8 horses with a presumptive diagnosis, causes Neonatal encephalopathy
included neurocardiogenic syncope (5 of 8), syncope associated Neoplasia
with severe EIPH (2 of 8), and seizures (1 of 8). Cholesterol granuloma (can be incidental)
Vasculitis
Syncope Viral, bacterial, or verminous meningoencephalitis
Syncope in horses has been associated with cardiovascular, Abscessation
noncardiovascular, and unexplained causes, with cardio- Equine protozoal myeloencephalitis
vascular and presumed neurocardiogenic syncope being the Intracranial vascular events
most common. Specific cardiovascular problems that have Leukoencephalomalacia
been reported in association with syncope in horses include Congenital anomalies
cardiac arrhythmias, including third-degree atrioventricular Ear ticks
(AV) block, atrial tachycardia with advanced second-degree Cryptogenic
AV block, and atrial fibrillation.348,355,385,386 Right-sided heart Lesion suspected but cannot be identified
failure, ruptured chordae tendineae, myocardial infarction, Idiopathic
myocardial fibrosis, aortic endocarditis, and pericarditis have Juvenile idiopathic epilepsy of Arabian foals
also been associated with syncope.355,385,386 In some cases, a
definitive cardiac disease can be hard to confirm. Depending SLEEP DISORDERS
on the underlying problem some horses with cardiovascular Recumbent sleep deprivation
syncope may have other signs of cardiac failure, but this is not Narcolepsy
consistent. Presumptive neurocardiogenic syncope has been
diagnosed in horses in which there are no abnormal findings OTHER
on clinical, neurologic, or cardiac examinations.348,355 In gen- Hyperkalemic periodic paralysis
eral, collapse was reported to occur without warning at rest, Hypoglycemia
and horses were described to sink abruptly or to raise their Hyperthermia
heads and fall backward to the ground. Confirmation of neu- Undetermined
rocardiogenic syncope would require ECG and blood pressure
independent of the underlying cause, reflecting the area and disorders that can be result in collapse include trauma to the
extent of the cerebral cortex involved.364 In the study evaluating motor pathways, botulism, and hyperthermia.355
104 horses with seizures, 2 horses were found to have reactive sei-
zures not associated with abnormal brain function. These horses Diagnostic Approach to Collapse
were diagnosed with liver failure and severe acute systemic hem- The diagnosis of the cause of collapse can be challenging,
orrhage. The remaining 102 horses were felt to have underlying and in many cases a definitive cause is not determined. Often
brain disease, although a specific diagnosis was not always pos- the clinician is unable to witness the episode, and although
sible. Of these, 28% had a single seizure episode and 70% had accounts by the owner can be helpful, they can also be inaccu-
two or more seizures and were diagnosed with epilepsy. Of those rate and may omit key information if the owner is unaware of
horses with a single seizure episode, an underlying structural the significance. A final diagnosis was found to be more likely
brain lesion was confirmed or suspected in 16 of 29 horses, with in horses that experienced multiple episodes of collapse than
acute head trauma being the most common (6 of 16). In those in horses that were observed to collapse only once.348 This may
horses with epilepsy, the condition was categorized as symptom- be because they may be more likely to have ongoing signs of
atic in 35.6% of cases and cryptogenic in 54.8%, and 2 foals were disease and also because the sensitivity of diagnostic proce-
diagnosed with idiopathic epilepsy. Overall there was no breed, dures may be improved by carrying them out either during
age, or gender association in horses with epilepsy, although juve- or immediately after a collapsing episode. For example, some
nile idiopathic epilepsy is seen in Arabian foals. Specific causes cardiac arrhythmias are paroxysmal and may not be present
of symptomatic seizures that were identified included skull frac- between episodes.
ture, cerebral hemorrhage, cerebral edema, neoplasia, choles-
terol granuloma, vasculitis, meningoencephalitis, abscessation, Signalment and History
intracranial vascular events, leukoencephalomalacia, congenital There are some age, breed, and sex associations with some
abnormalities, and equine protozoal myeloencephalitis (EPM). causes of collapse. In general, neonatal foals are more suscepti-
The presence of ear ticks has rarely been associated with sei- ble to seizures than adult horses and may seize in response to a
zures.355 Meningoencephalitis due to infection with the nema- number of metabolic and systemic diseases.355,390-392 Juvenile
tode Halicephalobus gingivalis has been associated with multiple idiopathic epilepsy is a disease of Egyptian Arabian foals with
neurologic deficits, including seizures.389 Neonatal foals have an age of onset ranging from 2 days to 6 months.355,393 Familial
a lower seizure threshold than adults, and seizures have been forms of narcolepsy have been identified in American Min-
reported in association with sepsis, neonatal encephalopathy, iature Horses, Shetland Ponies, and Lipizzaners.355,375,376,378
and electrolyte abnormalities, including hyponatremia.355,390-392 Hyperkalemic periodic paralysis should be considered as
Hypoglycemia may cause seizures but is more often associated a possible cause of collapse in Quarter Horses and related
with weakness and lethargy. Hyperbilirubinemic encephalopa- breeds.302 In the study of 104 horses with seizures, seizure type
thy (kernicterus) may rarely occur in foals. was significantly associated with gender, with females being
more prone to generalized seizures and one mare demonstrat-
Sleep Disorders ing generalized seizures during estrus.364 Estrogen and pro-
Sleep deprivation can be induced by preventing horses from gesterone concentrations are related to alterations in seizure
being able to lie down, such as when horses are kept on a threshold in women and female dogs, and a similar risk factor
tie-line to prevent them from exacerbating a musculoskel- may be present in horses.361,394
etal injury by getting up and down.355,370 Other conditions in A detailed history should be obtained, including a perfor-
which horses do not lie down to sleep include musculoskeletal, mance history and the occurrence of any other problems, such
abdominal, thoracic, or neurologic problems that either creas EIPH or lameness. With regard to the episodes of collapse,
ate pain or mechanical difficulties on attempt at recumbency the onset and duration as well as any specific triggers and the
or rising to stand. Environmental insecurity, including such features of the episode should be determined. Possible rea-
things as herd dynamics, stall size, and excessive noise, may sons for recumbent sleep deprivation should be investigated,
prevent horses from feeling comfortable enough to lie down. It including underlying medical problems and management
has also been proposed that monotony, such as being in cross- changes such as moving the horse to a new environment with
ties for an extended time, may cause horses to exhibit drowsi- different horses, excessive noise, or limited space.
ness, with the head lowering to the point of near collapse as
the horse begins to transition from SWS to REM sleep. Physical Examination
Familial narcolepsy has been identified in American Min- A thorough physical examination should be performed. In
iature Horses, Shetland Ponies, and Lipizzaners.355,375,376,378 some cases, additional clinical signs may be present depend-
At this time the precise genetics have not been determined. ing on the underlying disease. For example, fever and lethargy
Sporadic narcolepsy, generally without cataplexy, has been may be present in horses with viral or bacterial encephali-
identified in several breeds including Warmbloods, Icelandic tis and icterus, and weight loss may be seen in horses with
Horses, and Thoroughbreds.355,378 hepatoencephalopathy. Horses with sleep disorders may have
abrasions on the fetlocks from repeatedly buckling forward.
Other Particular attention should be focused on the cardiovascular
A number of other disorders can occasionally result in collapse. and neurologic systems. In some cases of potential cardiac dis-
Hyperkalemic periodic paralysis can cause weakness, muscle fas- ease, evaluating the horse after exercise may be useful.
ciculations, and collapse without alterations in consciousness.302 Video surveillance may be needed to allow observation of
Other electrolyte abnormalities in addition to hyperkalemia may the actual episode of collapse. Although differentiation of the
result in collapse including hypocalcemia, hyponatremia, and conditions can be difficult, clinical features can vary among
hypokalemia.355 Hypoglycemia can be associated with weakness syncope, seizures, and sleep disorders. Generalized seizures
and collapse, and in some cases seizures may occur. Some other generally differ from syncope in that they involve tonic-clonic
convulsive activity and may be associated with opisthotonos evaluation of narcolepsy, but at this time the value of hypocre-
or nystagmus, as well as urination and defecation. Seizures are tin testing in horses is uncertain.377,382
also often followed by a postictal phase that is not seen in syn-
cope or narcolepsy. In horses with sleep disorders, the collapse Y DYSPHAGIA
is often preceded by a gradual lowering of the head, and the
horse most often falls forward. Eye movement may be seen Dysphagia is defined as difficulty swallowing. Normal swal-
in association with REM sleep during a sleep attack, but this lowing, or deglutition, occurs as a complex sequence of events
appears to be uncommon in horses. with three phases: oral, pharyngeal, and esophageal.401 In
equine medicine, dysphagia is often used in the broad sense
Ancillary Diagnostic Aids to include any difficulty in the prehension and uptake of feed,
Clinical Pathology. A CBC, fibrinogen, and serum chem- as well as in actual swallowing. The clinical signs of dyspha-
istry can be helpful in identifying metabolic or systemic ab- gia vary depending on the cause but frequently include drop-
normalities, such as sepsis, liver disease, or electrolyte abnor- ping feed or packing feed between the cheek teeth and buccal
malities. In some horses, such as those with hyperkalemic mucosa, ptyalism, extension of the neck, gagging, coughing,
periodic paralysis (HYPP), the abnormality may only be and the presence of feed-tinged nasal discharge. Dysphagia
present during the episode. Measurement of cardiac tropo- can be a significant problem for the patient due to the risk of
nin can be useful to identify cardiac disease.395,396 Analysis aspiration and the potential compromise in nutritional and
of CSF and testing for EPM can provide useful information. hydration status.
Electrodiagnostic Testing. An electrocardiogram (ECG)
is valuable in evaluating the cardiac rhythm in horses with Mechanisms of Dysphagia
episodes of collapse. As some arrhythmias are intermittent, Normal eating and drinking are complex neuromuscular
continuous ECG monitoring may be necessary to identify the activities that are initiated with the uptake of material into the
arrhythmia. This is most often done with a 24-hour Holter oral cavity.401-403 The process of swallowing allows the trans-
monitor. An insertable cardiac monitor, also known as insert- port of this material from the oral cavity to the stomach while
able or implantable loop recorder, has been used in horses to protecting the airway. The initial stage of swallowing is the oral
record an ECG during the collapse episodes and can improve phase, which encompasses the formation and positioning of a
the diagnostic yield.348 Blood pressure monitoring during an feed bolus, which is defined as feed that is of suitable size and
episode could be useful but has not been done in horses. consistency to be swallowed. Mastication and moistening by
An electroencephalogram (EEG) assesses electrical brain saliva lead to formation of the bolus and also initiate diges-
activity and can be helpful in the identification of seizures. tion by mechanical breakdown of the feed and addition of
However, due to the paroxysmal nature of epileptiform activ- digestive enzymes from saliva. The bolus is moved to the base
ity, a normal EEG does not rule out the presence of seizures, of the tongue, where coordinated movements of the tongue
especially if performed during the interictal period. In Arabian and pharynx initiate the pharyngeal phase of swallowing.
foals with juvenile idiopathic epilepsy, epileptiform activity The oropharynx relaxes and the soft palate elevates to seal the
was found on EEG in 9 of 13 foals.393 Continuous EEG moni- palatopharyngeal arch and nasopharynx. As the bolus enters
toring improves the chance of detecting abnormal brain activ- the oropharynx, the hyoid apparatus moves rostrodorsally,
ity. A device for ambulatory EEG has been used in horses for drawing the larynx and common pharynx forward while at
long-duration EEG recording and has been shown to identify the same time the epiglottis tips caudally to prevent the bolus
abnormal brain acitivity.397,398 EEG can also evaluate electrical from entering the larynx. The bolus is moved through the
activity in the sleep cycle and may be useful in the assessment pharynx by sequential contraction of the pharyngeal constric-
of narcolepsy. tor muscles along with some driving force from the tongue.
Diagnostic Imaging. Echocardiography can be useful in The lower portion of the inferior pharyngeal constrictor mus-
the evaluation of cardiac disease. It can also be used to evalu- cle, known as the cricopharyngeus, is the major muscle in the
ate the liver in horses with suspected hepatic disease and hepa- upper esophageal sphincter. At the end of the pharyngeal stage
toencephalopathy. of the swallow, this muscle relaxes, allowing the bolus to enter
Radiographs, computed tomography (CT), and magnetic the esophagus, and then contracts to prevent oroesophageal
resonance imaging (MRI) can all be useful in the diagnostic reflux and aerophagia. As the bolus enters the esophagus, the
evaluation of horses with collapse, especially with suspected esophagus, including the lower esophageal sphincter, relaxes
seizure activity.348,364,399,400 Skull radiographs and CT are and the bolus is propelled toward the stomach by primary
particularly useful in horses with skull trauma.400 CT can be peristaltic waves. Gravity can assist in moving a liquid bolus
used to identify other lesions as well but has some limita- toward the stomach. After the bolus enters the stomach, the
tions in identifying inflammatory disease and small or diffuse lower esophageal sphincter contracts to prevent gastroesoph-
parenchymal lesions. MRI has been shown to be a valuable ageal reflux. Any minor reflux that does occur is typically
diagnostic tool, especially in the evaluation of symptomatic cleared by secondary peristaltic waves, which are waves that
epilepsy.364,399 There has been a good correlation between occur in the thoracic esophagus without an associated pha-
MRI findings and intraoperative or postmortem results. It is ryngeal contraction. Active antiperistalsis does not normally
important to remember, however, that it is not uncommon for occur in horses, and thus horses generally do not actively
seizures to occur in the absence of a structural brain lesion. vomit. All of the activity involved in swallowing occurs rela-
Additional Testing. Challenge testing has been used in the tively rapidly. In herbivores, breathing can continue uninter-
assessment of possible narcolepsy in horses, but results have rupted during swallowing.
not been consistent.374-377 Physostigmine may induce narco- Several anatomic structures and at least 30 muscles, includ-
leptic episodes, and atropine may eliminate signs. In humans ing both striated and smooth muscles, are involved in the pro-
and dogs, hypocretin concentration in CSF can be used in the cess of eating and drinking.401,402 Among the muscles used
are the masseter, temporalis, and medial and lateral ptery-

goid muscles, often referred to as the muscles of mastication. BOX 7.8
Morphologic Causes of Dysphagia
Also muscles within the lips, oral cavity, pharynx, larynx,
and esophagus are involved. Sophisticated integration among Anatomic abnormalities
these muscles and the peripheral and central nervous systems Cleft palate
is required for normal swallowing to occur. Wry nose, severe malocclusions
Each phase of swallowing is under complex neurologic Branchial remnant cysts
control, with both voluntary (somatic) and involuntary (auto- Subepiglottic cysts
nomic) input into the process.401-403 Cranial nerves (CNs) that Dental conditions
play a major role in prehension and swallowing include the tri- Points, hooks
geminal (CN V), facial (CN VII), glossopharyngeal (CN IX), Retained deciduous premolars
vagus (CN X), spinal accessory (CN XI), and hypoglossal (CN Wave, step, or shear mouth
XII). The activity of these six CNs is mediated centrally via the Periodontitis
medulla oblongata of the brainstem, where a network of sen- Fractured teeth
sory and motor nuclei and interneurons form the swallowing Equine odontoclastic tooth resorption and
center. In addition to the brainstem, the cortical and subcorti- hypercementosis
cal regions of the brain play an integral part in mediating the Other
swallow, especially the oral phase. Temporomandibular joint disease
Both sensory and motor function play a role in the uptake Oral ulceration
of feed, as well as throughout swallowing.403 With regard Dental problems
to the uptake of feed, sensory input from the olfactory and Vesicular stomatitis virus
optic nerves is important in providing smell and sight while Plant awns
the trigeminal nerve provides sensation to the rostral oral Caustic substances, medications
mucosa and lips. Once feed is in the oral cavity and orophar- Cantharidin toxicosis
ynx, peripheral receptors stimulate the trigeminal, facial, and Trauma
glossopharyngeal nerves providing sensory input to the brain- Fractures of skull, mandible, or maxilla
stem, which leads to activation of the swallowing reflex. Pat- Tongue lacerations
terned discharges of excitation and inhibition are sent from Foreign bodies
neurons in the swallowing center to motor nuclei of the cra- Neoplasia
nial nerves, resulting in swallowing. Swallowing can also be Oral, esophageal—squamous cell carcinoma, dental
initiated by stimulation of cortical neurons, and often corti- Epiglottitis
cal and peripheral inputs act together in eliciting swallowing. Retropharyngeal masses causing compression
Once swallowing is initiated, continuing sensory input modu- Abscesses
lates motor activity. Guttural pouch enlargement
A variety of problems, either congenital or acquired, can Empyema, mycosis
disrupt swallowing.404-406 Problems causing dysphagia may Tympany
be grouped by the anatomic location as oral, pharyngeal, or Hemorrhage associated with rupture of the longus
esophageal. Also, general mechanisms of dysphagia may be capitus
classified as either morphologic or functional. Morphologic Neoplasia
causes include pain and inflammatory conditions, as well as Septic sialoadenitis
mechanical problems, such as anatomic abnormalities and Esophageal disorders
obstruction. Functional causes include a variety of neurologic, Obstruction (choke)
neuromuscular, and muscular disorders that can interfere Esophagitis
with the highly regulated activity of swallowing. Functional Perforation, fistula
disorders may affect any phase in the process of eating and Stricture
drinking, but most often affect the oral and pharyngeal phases Diverticula, megaesophagus
of swallowing. Some disorders, such as guttural pouch empy- Congenital abnormalities—cysts
ema, have the potential to cause both physical obstruction and Neoplasia
neurologic impairment. Snakebite
Conditions Associated with Dysphagia syndrome (EOTRH). Problems such as retained deciduous
Morphologic Causes premolars, as well as a wave, step, or shear mouth, and occa-
Several morphologic causes of dysphagia have been identified sionally severe malocclusions may make it mechanically dif-
in horses (Box 7.8). Anatomic abnormalities that have been ficult to chew effectively. Oral ulceration causing discomfort
recognized in association with dysphagia include a cleft palate, may be seen with plant awns, vesicular stomatitis virus, can-
wry nose, branchial remnant cysts, and subepiglottic cysts.405-408 tharidin toxicosis, and exposure to caustic substances or some
Pain and inflammation from a number of underlying causes medications, such as phenylbutazone or enrofloxacin.404-406
often contribute to dysphagia. Dental problems can cause both Dysphagia has been reported in a foal with equine herpesvirus
pain and mechanical problems with mastication.409,410 Some 2–associated oral and esophageal ulceration.411 Other painful
painful dental conditions include ulcerations from points or conditions include epiglottitis, foreign bodies, temporoman-
hooks, periodontitis, infundibular caries, fractured teeth, and dibular joint disease, mandibular or maxillary fractures, and
equine odontoclastic tooth resorption and hypercementosis other traumatic injuries, such as hyoid bone injury or tongue
lacerations.405,406,412,413 Although uncommon, septic sialo-

adenitis involving either the parotid or mandibular salivary BOX 7.9
Functional Causes of Dysphagia
gland can be a significant cause of pain, inappetance, and
dysphagia.414 PERIPHERAL NERVE DISEASE
The most common obstructive problem causing dyspha- Guttural pouch disease affecting the cranial nerves
gia is esophageal obstruction, or choke.404-406,415 This most Empyema, mycosis
often results from a feed impaction, although esophageal Tympany
foreign bodies may occur as well. In addition to obstruc- Hemorrhage associated with rupture of the longus
tion, other esophageal conditions that can result in dyspha- capitus
gia include esophagitis, esophageal rupture, fistula, strictures, Neoplasia
diverticula, megaesophagus, and congenital disorders, such Temporohyoid osteoarthropathy
as esophageal cysts.415,416 Esophageal tumors are uncom- Lead poisoning
mon, but primary esophageal squamous cell carcinoma has Polyneuritis equi
been reported.415,417-419 Both squamous cell carcinoma and
leiomyosarcoma have been seen to extend from the stomach CENTRAL NEUROLOGIC DISEASE
into the esophagus. Idiopathic muscular hypertrophy of the Viral encephalitis/encephalomyelitis
distal esophagus has been recognized but in many cases is of Rabies
no clinical significance.420 Eastern, western, and Venezuelan encephalitis
External compression of the pharynx or esophagus may (EEE, WEE, VEE)
also result in obstruction. Pharyngeal collapse may be seen West Nile virus (WNV)
with enlargement of the retropharyngeal lymph nodes, most Equine herpes myeloencephalopathy
often due to abscessation associated with Streptococcus equi Equine protozoal myeloencephalitis
subspecies equi, as well as with severe guttural pouch disease, Toxicity
including empyema, mycosis, or tympany, and occasionally Nigropallidal encephalomalacia
neoplasia.405,406,421-424 Pharyngeal collapse is often associated Leukoencephalomalacia
with dyspnea, as well as dysphagia. Oral neoplasms of either Trauma
dental or nondental origin are relatively uncommon but can Tetanus
cause pain or act as a space-occupying mass resulting in dys- Migrating parasites
phagia.405,406,425,426 A number of dental tumors, as well as Equine grass sickness
osteogenic tumors of nondental origin, such as osteomas, ossi- Affects central, peripheral, and enteric nervous systems
fying fibromas, and osteochondromas, have been described. Pharyngeal dysfunction in neonatal foals
Squamous cell carcinoma is the most common soft tissue
neoplasm reported in the oral cavity, but others have been NEUROMUSCULAR DISEASE
identified, including melanoma and lymphosarcoma. Adeno- Botulism
carcinoma of the tongue and epiglottis has been reported as a Tetanus
cause of severe dysphagia in a horse.427 Snakebite may cause Organophosphate toxicity
severe edema of the head and dysphagia.347,428 Primarily acute cholinergic signs, dysphagia rare
Tick paralysis
Functional Causes
Guttural pouch diseases affecting the cranial nerves within the MUSCLE DISEASE
pouch are one of the more common functional problems caus- Nutritional myodegeneration (white muscle disease)
ing dysphagia404-406,424,429-431 (Box 7.9). The dorsolateral wall Hyperkalemic periodic paralysis
of the medial compartment of the guttural pouch contains
several nerves, including the glossopharyngeal (IX); branches
of the vagus (X), spinal accessory (XI), and hypoglossal nerves nerves occur, resulting in dysphagia.432,433 Lead toxicity may
(XII); and the cranial cervical ganglion. In addition, a small result in a peripheral neuropathy with dysphagia.434 Some
portion of the facial nerve (VII) is located in the dorsal wall horses with polyneuritis equi, an inflammatory condition
of the lateral compartment. Thus guttural pouch disease can affecting primarily the cauda equina, will have involvement of
result in pharyngeal dysfunction, dysphagia, and occasionally the cranial nerves and present with cranial nerve signs includ-
other neurologic signs such as laryngeal paralysis, Horner’s ing dysphagia, occasionally even before the development of
syndrome, and facial paralysis.404-406,424,429-431 Important dis- signs related to cauda equina dysfunction.435,436
eases of the guttural pouch causing dysphagia include guttural Central neurologic diseases and neuromuscular or muscle
pouch empyema and guttural pouch mycosis. Skull trauma disorders that can result in dysphagia often have other concur-
resulting in rupture of the longus capitus muscle at the site of rent signs in addition to problems eating. Some important cen-
attachment to the basisphenoid bone may result in significant tral neurologic diseases that can be associated with dysphagia
hemorrhage into the pouch, potentially affecting the cranial include viral encephalitis (rabies, eastern and western enceph-
nerves.429 Occasionally flushing of the guttural pouch and sur- alitis, West Nile virus, equine herpesvirus), equine protozoal
gical correction of guttural pouch tympany results in damage myeloencephalitis, toxic neuropathies (leukoencephaloma-
to the cranial nerves coursing through the pouch with conse- lacia and nigropallidal encephalomalacia), tetanus, cerebral
quent neurologic dysfunction.405,406,431 Although temporohy- trauma, and rarely migrating parasites.404-406,437-441 Dysphagia
oid osteoarthropathy most often results in deficits of the facial is a relatively common finding in horses affected with rabies.404
(CN VII) and vestibulocochlear (CN VIII) nerves, occasion- Horses with nigropallidal encephalomalacia have lesions of
ally deficits of the glossopharyngeal (CN IX) and vagus (X) the basal ganglia and can swallow but are unable to prehend
feed as they lack coordination of the lips and tongue. Tetanus A thorough general history is important in the evaluation
toxin acts at several sites within the nervous system, including of dysphagia. The history may help to differentiate dysphagia
the inhibitory interneurons in the central nervous system and from a decrease in appetite. The diet, dental history, and any
the neuromuscular junction, causing muscle paralysis.442 It recent disease and treatment should be determined. A history
typically results in increased tonus of the masticatory muscles, of dropping feed during mastication, or quidding, may sug-
known as trismus, and dysphagia. The mouth may be difficult gest dental disease. The potential for exposure to toxins such
to open, thus the term lockjaw. Some cases of marked hypocal- as lead, organophosphates, or yellow star thistle and Russian
cemia may result in tetany and dysphagia. A syndrome of dys- knapweed should be assessed. The vaccination status of the
phagia related to presumed pharyngeal dysfunction has been horse should be established, especially with regard to teta-
reported in neonatal foals.443 Although the pathogenesis is not nus, West Nile virus, eastern equine encephalitis virus (EEE),
fully understood, some affected foals were premature and/or western equine encephalitis virus (WEE), equine herpesvirus,
diagnosed with neonatal encephalopathy. Other central neu- and rabies. It should be determined whether other animals on
rologic problems that may potentially cause dysphagia include the farm are having problems as certain conditions, such as
bacterial or fungal meningitis and intracranial masses. strangles and botulism, may affect more than one individual.
Neuromuscular problems that can result in dysphagia Trauma is often associated with a history of an acute onset of
include organophosphate toxicity, tick paralysis, botulism, dysphagia. In some cases there is a known history of a trau-
and to some extent tetanus, which also has a central compo- matic event such as a fall or kick, but in other cases the cause
nent.404-406,442,444,445 One of the early signs of botulism can be of the trauma in unknown. Occasionally trauma may occur
that the horse eats slowly. Equine grass sickness (EGS), also during the administration of medication or passage of a naso-
referred to as equine dysautonomia, is a largely fatal neurode- gastric tube. In addition, a history of flushing the guttural
generative disease affecting the peripheral, central, and enteric pouch can be of significance as the procedure may rarely cause
nervous systems of grazing equids.446-448 The gastrointestinal inflammation and tissue damage.
tract is the most severely affected body system, with the pre-
dominant clinical signs being colic, weight loss, and dysphagia. Physical Examination
Although the disease primarily occurs within Great Britain, Biosecurity procedures should be followed during the initial
cases have been identified in regions of mainland Europe and assessment of horses with dysphagia as rabies is a potential
rarely in other locations including the United States. A pos- differential. Ideally, veterinarians and assistants should have
sible link to Clostridium botulinum types C and D has been an adequate rabies antibody titer.
proposed, but the cause of EGS remains unclear.446 A complete physical examination should be performed.
The primary muscle disease resulting in dysphagia is The presence of a fever suggests an infectious or inflamma-
nutritional myodegeneration (nutritional muscular dystro- tory process. Observing the horse while eating, and if pos-
phy, white muscle disease) associated with selenium defi- sible drinking, can be valuable. Some horses can continue
ciency.449-451 Although reported more frequently in foals, to drink despite difficulty swallowing feed whereas oth-
nutritional myodegeneration can affect horses of any age. ers cannot. Offering feed may help distinguish dysphagia
Although multiple muscles can be affected, myodegeneration from anorexia. Depending on the underlying cause, many
may be limited to the masseter muscle and/or tongue in some dysphagic horses are hungry and will attempt to eat. Some
cases, making dysphagia the predominant sign. Foals affected horses, such as those with retropharyngeal abscessation due
with HYPP may have dysphagia, particularly when they are to strangles, may have both dysphagia and a decreased appe-
homozygous.302 tite. Observation of eating can also help determine the phase
of eating affected, which can help in prioritizing differentials.
Diagnostic Approach to Dysphagia In cases where prehension is primarily affected, nigropalli-
The evaluation of dysphagia focuses on determining whether dal encephalomalacia should be considered in areas where
morphologic and/or functional abnormalities are present. The yellow star thistle or Russian knapweed is present. Dropping
initial assessment should include consideration of the sig- feed while chewing is consistent with abnormal mastication,
nalment and history and a thorough physical examination, which is often associated with dental disease. The regurgita-
including observation of the horse eating. Additional tests tion of feed through the nares while eating is generally asso-
such as a neurologic examination and ancillary diagnostic aids ciated with pharyngeal or esophageal disorders rather than
are often indicated. oral cavity problems. Those horses with feed in the nares are
at increased risk of aspiration of feed material, and coughing
Signalment and History or increased respiratory rate and effort may be seen. Careful
Some age and breed associations have been associated with auscultation of the thorax, including a rebreathing evalua-
dysphagia. Anatomic abnormalities such as a cleft palate or tion, should be performed.
wry nose are generally apparent at an early age. Some dental A thorough oral examination using a mouth speculum
disorders can be age related.409,410 The deciduous premolars are is usually indicated. The teeth should be examined for the
lost between 2 and 5 years of age and may be retained as caps. presence of problems such as retained deciduous caps, sharp
Older horses are more are more likely to have a severe wave points or hooks, wave mouth or step mouth, missing teeth,
mouth, missing teeth, or EOTRH and can be at increased risk diastema, periodontitis, infundibular caries, dental fractures,
of esophageal obstruction. Dysphagia associated with pharyn- and EOTRH.409,410 The oral cavity and tongue should be
geal dysfunction may be seen in neonatal foals, sometimes in examined for the presence of ulcers or other abnormalities,
association with prematurity or neonatal encephalopathy.443 such as lacerations, foreign bodies, and masses. Foreign bodies
In foals with Quarter Horse breeding, HYPP can be a cause of may become wedged between the molars or under the tongue,
dysphagia.302 Friesian horses have an increased prevalence of and wire foreign bodies or awns may become embedded in
esophageal disorders, specifically megaesophagus.452 the tissue. The submandibular and throat latch area should
be examined for evidence of lymphadenopathy or guttural signs along with the exclusion of other diseases.444,445 Several
pouch enlargement. Occasionally an esophageal obstruction tests are available for definitive diagnosis, including testing for
can be palpated in the neck. An esophageal perforation should toxin by mouse bioassay or PCR in feed, manure, gastroin-
be considered if there is heat or swelling in the neck. If ptya- testinal contents, serum, or wound exudate. The antemortem
lism is observed without dysphagia, ingestion of clover that diagnosis of polyneuritis equi can be difficult, but a biopsy of
is contaminated with Rhizoctonia leguminicola, a fungus that skeletal muscle innervated by nerves arising from the cauda
produces the mycotoxin slaframine, should be considered.453 equina may demonstrate extensive cellular infiltrates in intra-
Excess salivation stops once the horse is no longer exposed to muscular nerve fibers.435,436
the toxin. Endoscopy. Endoscopic examination allows visualization
of the nasal passageways, nasopharynx, pharynx, larynx, and
Nasogastric Intubation guttural pouches. Pharyngeal and laryngeal function can be
A complete esophageal obstruction can be ruled out if a naso- assessed, although the use of sedation should be taken into
gastric tube can be passed into the stomach. Common sites for account as it may affect function. Endoscopic examination of
esophageal obstruction to occur are the proximal esophagus the guttural pouch can identify the presence of empyema or
just distal to the larynx, at the thoracic inlet, and at the base guttural pouch mycosis, as well as other less common condi-
of the heart. tions such as trauma-related hemorrhage and neoplasia. The
stylohyoid bone should be carefully evaluated. In temporohy-
Neurologic Examination oid osteoarthropathy there is often osseous proliferation pri-
A complete neurologic examination is often indicated in the marily affecting the proximal portion of the stylohyoid.432,433
evaluation of dysphagia, especially when morphologic causes Depending on the length of the endoscope, the esophagus
have been ruled out. The neurologic examination helps estab- may also be evaluated for evidence of esophagitis, obstruction,
lish a neuroanatomic localization. In general, horses with dys- strictures, diverticula, perforations, or other abnormalities.
phagia due to peripheral neurologic disease may exhibit only Diagnostic Imaging. Diagnostic imaging can provide useful
dysphagia, whereas those with central neurologic or neuro- information in the evaluation of dysphagia. Skull radiographs,
muscular disease tend to have additional deficits. For example, CT, or MRI can help in the diagnosis of fractures, dental dis-
the presence of generalized weakness in association with dys- ease, temporohyoid osteoarthropathy, temporomandibular
phagia often suggests a neuromuscular problem, such as botu- joint disease, guttural pouch disease, and retropharyngeal
lism or organophosphate toxicity.404-406,444,445 Equine motor masses.405,406,409,410,412,421 Radiopaque foreign bodies, such as a
neuron disease results in generalized weakness and muscle wire in the oral cavity, pharynx, or esophagus, can be identified
atrophy; however, affected horses do not exhibit cranial nerve on radiographs.413 In cases of esophageal perforation, extralu-
deficits and are not dysphagic.454 Tetanus causes spastic paral- minal radiolucencies consistent with subcutaneous air may be
ysis and can present with a variety of signs, including dyspha- visualized. Contrast radiography with the use of barium sulfate
gia, hyperesthesia, and prolapse of third eyelid, in addition to can be useful in the diagnosis of certain esophageal disorders
a stiff gait, which may progress to recumbency.442 Spinal ataxia such as strictures, diverticula, or megaesophagus.415 Due to the
associated with dysphagia suggests a diffuse or multifocal dis- risk of aspiration in horses with dysphagia, radiographs and ul-
ease affecting the spinal cord and brainstem, such as equine trasound of the thorax are often indicated, especially in horses
protozoal myelitis, rabies, equine herpes myeloencephalopa- with abnormal thoracic auscultation, nasal discharge, cough,
thy, or a migrating parasite.437-440 Viral encephalitis should increased respiratory rate, or increased respiratory effort as
be considered in dysphagic horses with mentation changes, evidenced by increased abdominal effort or nasal flare. Ultra-
especially if the horse is febrile. Horses with polyneuritis equi sound may also be useful in the detection of foreign bodies and
occasionally have cranial nerve involvement in addition to in evaluation of swelling in the throatlatch region.
the classic signs of cauda equina involvement, which include
slowly progressive paralysis of the tail, rectum, anus, and blad- Y COLIC
der.435,436 Affected horses may also have ataxia and weakness
of the hindlimbs. Colic is defined as the manifestation of abdominal pain. In
horses colic is a serious medical and economic problem world-
Ancillary Diagnostic Aids wide. In the United States the annual incidence of equine colic
Clinical Pathology/Laboratory Testing. A CBC, fibrinogen, has been reported to be anywhere between 3.5% and 26%.455-458
and serum chemistry may be helpful in documenting an in- A study performed by the National Animal Health Monitor-
flammatory process. In cases of suspected nutritional myode- ing System in 1998 assessed the annual incidence of colic to
generation, measurement of selenium and glutathione peroxi- be 4.2% with an estimated total cost of approximately $115
dase can help in evaluating the selenium status of the patient. million.455 In this study only 1.4% of colic episodes resulted in
Further diagnostic tests are often indicated in cases of surgery, but the overall fatality rate for all colic was 11%. When
suspected neurologic disease. These may include an evalua- evaluating general causes of mortality in horses over 6 months
tion of CSF for cytologic and biochemical abnormalities, as of age, including euthanasia, colic was found to be responsi-
well as specific testing for antibodies to Sarcocystis neurona ble for 22.2% of equine deaths in 1998 and 15.2% in 2005.459
or Neospora hughsei.440 In cases of suspected West Nile virus This makes colic among the most common causes of death in
infection, the immunoglobulin M (IgM) capture ELISA can horses along with old age (24.8% and 30.4% of deaths) and
be used. Cranial nerve involvement is infrequent with equine injury (12.7% and 16.0% of deaths). Even in less serious cases,
herpesvirus myeloencephalopathy, but testing by PCR or virus colic can be associated with a significant loss of use. In a study
isolation on nasal swabs and/or blood should be considered if of working horses in Egypt, the prevalence of colic was found
appropriate.438,439 Botulism can be a difficult disease to diag- to be 54.6%.460 These numbers illustrate the enormous impact
nose, and diagnosis is often based on the history and clinical that colic has on the equine population.
Horses express clinical signs of colic in a variety of process in the gastrointestinal tract is similar to that of other
ways.461,462 Often the first sign recognized by owners is inap- body systems. Almost all cells in the intestine can play a role
petence, but other early signs may include general restlessness in the development of inflammation by either cytokine pro-
and extended periods of lying down. More overt signs, such as duction or cell activation. Some specific cell types involved in
kicking or biting at the abdomen, pawing, and stretching out the initiation of intestinal inflammation include mucosal cells,
as if to urinate, may also be observed. Bruxism is occasionally endothelial cells, fibroblasts, neutrophils, macrophages, neu-
seen. As the level of discomfort increases, horses may repeat- rons, eosinophils, and mast cells.463 Cytokines, growth factors,
edly get up and down and try to roll, sometimes violently.461 and adhesion molecules produced by these cells are important
In some cases, the horse may acutely have much pain. The in the initiation of inflammation. Some important cytokines
level of stoicism varies widely among individual horses, and include IL-1, TNF-α, platelet activating factor, complement,
the severity of signs does not always correlate to the severity interferon, and histamine.463
of the lesion. Endothelial cells are stimulated by ischemia or macrophage
cytokines to attract neutrophils, which subsequently migrate
Mechanisms of Colic to the affected tissue facilitated by adhesion molecules. Vas-
The precise pathophysiologic mechanisms involved in cases of cular permeability is also increased, resulting in the forma-
colic can vary because of the myriad causes for colic in the tion of edema and facilitating the migration of inflammatory
horse. Most cases of colic, sometimes referred to as “true” col- cells. Neurons, fibroblasts, and muscle cells detect and release
ics, are gastrointestinal in origin. However, disorders of other other cytokines, leading to the activation of many effector cell
body systems, such as cholelithiasis and uterine torsion, may types.463,464
also manifest as colic. True colic can be classified on the basis Eventually the intestinal barrier is compromised to the
of small intestinal versus large intestinal disorders, physical extent that endotoxin begins to leak into systemic circula-
versus functional disorders, obstructive versus nonobstructive tion. Endotoxemia (discussed in detail in Chapter 12) is most
lesions, and strangulating versus nonstrangulating lesions. In common with colitis and to a lesser extent with strangulat-
all of these colic classifications, the simplest basic etiologies ing lesions. The response to endotoxin is complex, involv-
for damage to the gastrointestinal tract are inflammation and ing a massive release of cytokines and mediators that results
ischemia.462-464 Gastrointestinal distention, ileus, mesenteric in systemic inflammation and fever. Classical endotoxemia
tension, and endotoxemia also play a role in the development has more recently been described as systemic inflammatory
of disease in many cases. response syndrome (SIRS), because it likely involves more
Ischemia of the intestine can result from a strangulat- than just endotoxin as an initiating factor.463 The result is
ing lesion or even from a simple obstruction. Strangulat- hemodynamic responses that include both vasodilation
ing lesions cause acute direct occlusion of vessels leading to and vasoconstriction, platelet aggregation, and eventual
rapid tissue hypoxia, ischemia, and ultimately necrosis. With development of a hypercoagulable state and consumptive
obstructions significant pressure within the distended intes- coagulopathy.462,463
tine may lead to venous collapse, which over time may result Finally, ileus should be addressed as an important com-
in ischemia as the intestinal vasculature becomes increas- ponent of the pathophysiology of colic. Ischemic bowel has
ingly compromised.462-464 The mucosa is the layer most decreased motility, although bowel more proximal to the
sensitive to hypoxia because of its high metabolic activity. lesion tends to have an increase in motility until it becomes so
Damage to the mucosa can be assessed on a scale of Grade distended that it can no longer contract normally. Postopera-
I through Grade V, with Grade V being the most severe.462 tive ileus appears to involve both dopaminergic and adrener-
The villous tips are especially sensitive to ischemia, and gic stimulation. It has also been suggested that prostaglandins
damage typically begins there. Crypt cells are affected later E1 and E2, as well as nitric oxide, play a role in disrupting intes-
as the ischemia becomes more complete and longer in dura- tinal motility patterns.462
tion. In the equine colon complete ischemia leads to necro- Owners often question why horses have colic, and several
sis and detachment of surface epithelial cells and most likely studies have attempted to identify risk factors for colic with
to capillary thrombosis and occlusion.462 Smooth muscle is varying results.465-473 Some factors that may increase the risk
less sensitive to hypoxia, and therefore it is destruction of of colic in horses include stall confinement, feeding of exces-
the mucosa that is the main factor leading to the pathologic sive concentrate, infrequent large meals, recent feed changes,
changes associated with colic. decreased water consumption or lack of access to water even
Prolonged intestinal distention proximal to an obstruc- during turnout, feeding of Coastal Bermuda grass hay, and
tive lesion can eventually lead to tissue ischemia. Distention off-the-ground feeding. Other risk factors include inadequate
also results in edema and additional secretion of fluid into the deworming or dentistry, exposure to sand, transport, changes
lumen of the gut as venous collapse occurs.462-464 As veins are in activity, previous colic episodes, and the use of nonsteroi-
occluded, hydrostatic pressure within the capillaries increases, dal antiinflammatory drugs (NSAIDs). Colic has also been
causing increased filtration. Lymphatic drainage is also often linked to stereotypic behaviors such as crib-biting, which has
impaired, and the resultant excess fluid becomes edema and been shown in some studies to be associated with an increased
secreted intestinal fluid. Distention is one of the main causes risk of both colic in general and epiploic foramen entrap-
of pain associated with colic, as stretch pain receptors are trig- ment.470,474-476 It is important to remember that colic can
gered within the wall of the intestine.462 occur regardless of management practices.
Inflammation plays a major role in almost every type of
colic and often occurs secondary to ischemia. The inflamma- Conditions Associated with Colic
tory response is generally meant to protect the intestine against Colic encompasses a wide variety of conditions, both gastroin-
long-term damage. The pathophysiology of inflammation is testinal and nongastrointestinal in origin (Table 7.4). The actual
complex and beyond the scope of this section, but the basic incidence of specific disorders causing colic in the general
TABLE 7.4 Gastrointestinal Causes of Colic Disorders of several body systems other than the gastro-
intestinal tract can present with signs of colic.480-484 Causes
Gas and spasmodic of colic involving the reproductive tract include uterine tor-
Impactions Pelvic flexure sion or tears in mares and testicular torsion in stallions. Occa-
Feed Large colon sionally ovarian activity may cause transient colic in mares.
Sand (primarily pelvic Cecum Some other potential nongastrointestinal causes of colic
flexure, large colon) Small colon include cholelithiasis, liver lobe torsion, urolithiasis, and
Other intraluminal Ileal pheochromocytoma.
obstructions Gastric
Meconium impaction (foals) Diagnostic Approach to Colic
Enteroliths Colic can be caused by a number of different conditions. Sev-
Fecaliths eral other clinical problems may be confused with colic, such as
Foreign body pleuritis, exertional rhabdomyolysis, laminitis, hyperkalemic
Large colon displacements Right dorsal displacement periodic paralysis, renal disease, and even neurologic abnor-
Left dorsal displacement malities.485 When a horse presents with colic, it is important
(nephrosplenic entrapment) to determine that the horse is exhibiting signs of abdominal
Other pain and then arrive at a specific diagnosis if possible. In some
Large colon torsion and cases the evaluation of a horse with colic may be straightfor-
volvulus ward, but other cases may be more challenging. Fortunately,
Small intestinal volvulus although a specific diagnosis may not be made, many cases
Strangulating lipoma of colic either resolve spontaneously or with minimal inter-
vention. However, in some horses, the condition can be life
Entrapment of small Epiploic foramen
threatening, and a delay in surgical exploration can result in
intestine Mesenteric rent
increased mortality. Thus the initial goal in the assessment of
Intussusception a horse with colic is often to determine whether the case is an
Ulceration Gastric uncomplicated one, such as a gas or spasmodic colic, rather
Right dorsal colitis than one requiring either extensive medical management or
Enteritis/colitis Duodenitis/proximal jejunitis surgical exploration. Signalment, history, physical examina-
Inflammatory bowel (anterior enteritis) tion, clinicopathologic data, imaging findings, and endos-
disease Colitis copy may all contribute to the evaluation of a patient with
Parasites Ascarid impactions colic.485,486 A number of studies have focused on identifying
Tapeworms means to aid in the early classification of colic cases as medical
Strongylus vulgaris or surgical and to determine a prognosis. Most of these studies
Cyathostomes have assessed a number of physical examination and labora-
tory variables.486-492
Herniation Inguinal
Umbilical Signalment and History
Diaphragmatic
The signalment of the horse can provide information that may
Peritonitis increase the degree of suspicion for a specific cause of colic.
Abdominal abscessation Weanling-age foals are more prone to ascarid impactions,
Hemoperitoneum whereas younger foals are at higher risk for small intestinal
Toxins Cantharidin volvulus or intussusception.485,486,493,494 Older horses have a far
Monensin greater likelihood of developing strangulating lipomas.462,477
Other Colic may affect horses of any breed, but some breed pre-
Other Ileus dispositions have been recognized. An increased incidence
Overo lethal white syndrome of colic has been recognized in Arabians and Thorough-
Congenital anomalies breds.455,457,485,495 Arabians are specifically predisposed to ileal
Neoplasia impaction, small colon impaction, and enterolith formation.
Miniature horses, especially when young, are prone to small
colon impactions and fecaliths.462,485 Standardbred, Tennessee
Walking Horse, and Warmblood stallions have a higher risk
equine population is not known, partially because a definitive of developing inguinal hernias than stallions of other breeds,
diagnosis is not always established. In general, most colics are which is felt to be related to increased size of the inguinal
gastrointestinal in origin, with simple gas or spasmodic colics rings.462,485 Overo lethal white syndrome is a fatal, recessive
being most common.456,477-479 Other common causes include genetic condition that causes ileocolonic aganglionosis in neo-
large colon impaction and large colon displacement. In one natal foals.496 Affected foals are white or predominantly white
study of 604 horses that were referred for evaluation of colic, with small dark markings and generally develop signs of colic
327 cases were medical (54.1%) and 277 cases were surgical shortly after birth. The defective gene is found predominantly
(45.9%).479 Of the medical cases, the most common prob- in American Paint Horses but has also been found in horses of
lems were large colon impaction (39.6%) and spasmodic colic other breeds with overo coloring, such as American Miniature
(20.8%). Of the surgical cases, the most common problems Horses and half-Arabians.
were large colon displacement (24.5%), followed by large colon Gender is also important to consider in cases of colic. In
torsion (14.3%) and strangulating lipoma (13.5%).479 addition to inguinal hernias, testicular torsion can be a cause
of colic in stallions.462 Postpartum mares are predisposed to of the inguinal region must be performed to identify an ingui-
torsion of the large colon, whereas colic in a late-gestation nal hernia or testicular torsion. Severe abdominal distention
mare may be associated with normal parturition or dysto- may markedly increase the respiratory effort and eventually
cia.462,485 Pregnant mares exhibit signs of colic with uterine lead to respiratory distress. Auscultation of abdominal quad-
torsion.480,485 Nonpregnant mares can have mild transient rants (left dorsal, left ventral, right dorsal, right ventral) can
signs of colic associated with ovarian activity. give an estimation of gastrointestinal motility.485,486 Assessing
The history of the patient can provide vital clues as to the the abdomen for pings can help to localize gas. Auscultation
severity and possible etiology of the colic.485,486 With regard of the most ventral part of the abdomen should also be per-
to the current episode, it is important to determine the dura- formed to assess for the presence of sand.499 Although not
tion and severity of pain, recent defecation and character of always present, a characteristic “waves on the beach” sound
feces, appetite, previous treatment, and response to treatment. can sometimes be heard, indicating the presence of sand in
Previous history of colic, including colic surgery, history of the colon. If feces can be collected from the horse, it can be
other surgeries, recent management changes, geographic area, useful to evaluate for the presence of sand. A simple way to
breeding history, and pregnancy status, are all important com- do this is to mix a few fecal balls with warm water in a rectal
ponents in the medical history of a colicky horse. Addition- sleeve and hang the sleeve with the fingers down. After about
ally, specific details as to feed, access to sand, water source, 5 minutes any sand in the feces should sediment into the ends
deworming, dentistry, history of medications (e.g., NSAIDs, of the glove fingers.485
antibiotics), activity level, and stereotypic behavior such as Additional diagnostics for horses with colic include rec-
crib-biting/windsucking may also provide valuable diagnostic tal palpation, nasogastric intubation, and, in many cases,
information. abdominocentesis. Adequate restraint is important for these
procedures because not only is the veterinarian at increased
Physical Examination risk of injury with an uncooperative horse, but the horse also
A thorough physical examination is essential to the evaluation is at increased risk of rectal tears, significant epistaxis, and
of colic. It is important to assess the degree of pain, and in some abdominocentesis complications such as enterocentesis or
cases the horse may be so uncomfortable initially that sedation contamination of the collection site. The most appropriate
will be necessary for safe completion of the examination. If means of restraint is dependent on the individual patient and
possible, heart rate, respiratory rate, and auscultation of gut may include sedation and/or the application of a nose twitch.
sounds should be evaluated before sedation because these can When selecting the method of restraint the safety of the exam-
change significantly in response to sedation.497,498 Because rec- iner and the horse must be considered, while at the same time
tal temperature can also be significantly decreased after rectal it is important to not further compromise an unstable patient
palpation, it is advisable to obtain the body temperature before or dramatically affect assessment of the horse’s level of pain.
palpation.461 A finding of pyrexia may increase suspicion of Use of xylazine hydrochloride intravenously at 0.2 to 0.5 mg/
colitis, enteritis, peritonitis, or intraabdominal abscessation kg (typically 100–250 mg for a 500-kg horse) is often adequate,
in the patient, although previous administration of an NSAID but butorphanol tartrate at 0.01 to 0.08 mg/kg intravenously
may mask this clinical finding.462,485,486 Tachycardia can be an can be added when necessary.461 Use of detomidine is usually
indicator of pain, hypovolemia, tachyarrhythmia, or endo- discouraged in the initial management of colic because of its
toxemia, and rates of greater than 80 beats per minute gener- long duration of action and heightened ability to mask more
ally indicate serious disease.462,485,486 During auscultation the significant pain that may affect determination of the horse’s
patient should be evaluated for the presence of any cardiac treatment.465,466 However, if indicated, detomidine can be
abnormalities that would put the horse at increased risk under administered at 0.01 to 0.04 mg/kg intravenously or intramus-
sedation. Respiratory rate may be increased in horses with cularly.461 It is most commonly used when a longer duration
colic as a response to some combination of pain, fever, and/ of sedation is required to keep a horse quiet during transport
or metabolic acidosis. Mucous membranes and capillary refill to a referral center.
time (CRT) give a rough assessment of cardiovascular status Nasogastric intubation should be performed as a part of a
and peripheral perfusion. Normal mucous membranes should complete colic examination. If a horse is exhibiting significant
be pink and moist with a CRT of less than 2 seconds. Tacky pain or has a heart rate greater than 60 beats per minute on
mucous membranes are generally observed with dehydration initial evaluation, nasogastric intubation should be performed
of at least 5% to 7%.485,486 Prolonged CRT and either grayish or before other diagnostic procedures because it may have both
dark red mucous membranes indicate impaired cardiovascu- diagnostic and therapeutic value. If a horse has significant gas-
lar status and poor perfusion. With poor perfusion, there may tric distention, gastric decompression may help prevent gas-
also be cool extremities and reduced jugular fill. Significant tric rupture and decrease pain, allowing for a more thorough
changes in mucous membrane color, often with a dark “toxic” physical examination. The nasogastric tube can be left in place
line adjacent to the teeth, may accompany endotoxemia, which if a significant amount of net reflux is obtained to allow for
is common in gastrointestinal disease, particularly in horses repeated decompression. If no reflux is obtained and a simple
with colitis, proximal enteritis, and strangulating lesions. colic is suspected, oral fluids with or without electrolytes or
Icterus is relatively common in horses that have been off feed magnesium sulfate (Epsom salt) can be administered via the
for more than 48 hours due to equine fasting hyperbilirubine- tube. Although mineral oil has long been considered a part of
mia. However, icterus may also be seen with hepatobiliary dis- standard colic treatment, its use is controversial. Mineral oil
ease or hemolysis. Other important considerations during the may be valuable as a diagnostic tool, providing an estimate of
physical examination include assessment of hydration status, gastrointestinal transit time. In a normal horse mineral oil can
attitude, abdominal distention, and the presence of injuries be observed in the feces and on the perineum and tail in 12 to
that indicate self-trauma, which often reflects the degree of 24 hours.500 The absence of mineral oil after this period may
pain. As previously mentioned, in stallions careful palpation indicate delayed gastrointestinal transit. However, mineral
oil can sometimes pass around an impaction that is present, Electrolyte abnormalities, especially hypokalemia and
thereby falsely suggesting adequate gastrointestinal transit hypocalcemia, are relatively common abnormalities observed
when in fact digesta is not moving normally.500 In addition, if on a chemistry panel in horses with colic.505 Anorexia, dehy-
a horse ultimately requires abdominal surgery, the presence of dration, diarrhea, and excessive nasogastric reflux can all con-
mineral oil can complicate an enterotomy.501 tribute to derangement of electrolytes. In addition to calcium
Palpation per rectum can be important in the assess- and potassium, sodium, chloride, magnesium, and bicarbon-
ment of colic. Even with the use of appropriate sedation, ate can be lost with diarrhea or significant gastric reflux.472
some horses remain resistant to rectal examination, placing Leakage from damaged cells may result in elevated serum
them at increased risk for rectal tears. To potentially improve phosphate. Metabolic acidosis caused by elevation of lactate,
the quality and safety of palpation per rectum, intrave- loss of bicarbonate, or both may also be observed. Hypergly-
nous administration of N-butylscopolammonium can help cemia is relatively common in horses with acute gastroin-
to decrease rectal pressure and peristalsis.502 Application testinal disease in association with dysregulation of glucose
of lidocaine within the rectal lumen has also been used to homeostasis. Significant elevations in glucose have been asso-
facilitate palpation. Although rectal palpation can provide ciated with a worse prognosis for hospital discharge.506 Occa-
valuable diagnostic information, the presence or absence of sionally, hepatic enzyme activities are increased, especially
a particular lesion cannot always be definitively determined. γ-glutamyltransferase (GGT). This most commonly occurs
For instance, although a pelvic flexure or cecal impaction with right dorsal displacement of the large colon or proximal
may be palpable, if no impaction is palpated, it cannot be enteritis.507,508 In a study of horses with large colon displace-
ruled out. Additionally, gas distention might be palpable in ments, 49% of horses with right dorsal displacements had
gas colic, but it may also reflect a more serious problem, such concentrations of GGT above the reference range compared
as a displacement or torsion. Rectal palpation therefore can with 1% of horses with left dorsal displacements.508 Dehydra-
provide evidence to support a diagnosis but is often not diag- tion often results in elevations in creatinine and serum urea
nostic in itself. Nephrosplenic entrapment may be suspected nitrogen, and these parameters should be monitored, espe-
if the spleen is displaced medially or the gut is palpated cially when NSAIDs or aminoglycoside antibiotics are used.
between the spleen and kidney.485,486 Another useful finding Elevations in muscle enzymes are common in horses with
is the identification of distended small intestine. Although colic. In a study of horses undergoing celiotomy for acute
small intestinal distention may occasionally occur second- gastrointestinal pain, elevations in creatine kinase (CK) and
ary to a large intestinal problem such as a displacement, it is aspartate aminotransferase (AST) activity were significantly
most often an indication of small intestinal disease. Although associated with the presence of lesions resulting in intestinal
rectal palpation cannot differentiate a surgical small intesti- ischemia.509
nal problem such as a strangulating lesion from a medical Abdominocentesis can be performed both in the field and
problem such as proximal enteritis, small intestinal disease in a referral setting. Most often the procedure is performed
is almost always an indication for referral.485,486,503 Therefore with either an 18-g, 1.5-inch needle or a teat cannula for the
palpable loops of distended small intestine are a significant collection of fluid. The typical location in which the procedure
finding on rectal examination. Rectal palpation can also be is performed is to the right of midline (to avoid splenocente-
useful for identifying masses in the abdomen, which may be sis) on the most ventral point of the abdomen at least several
a cause of chronic colic. inches caudal to the xiphoid.462,485 However, occasionally other
locations, such as on the ventral midline, will be used. Also,
Ancillary Diagnostic Tests ultrasound of the abdomen can be used to identify pockets of
Clinical Pathology. A packed cell volume (PCV) and total fluid, but it should be remembered that fluid can often still be
protein should ideally be evaluated to assist with assessment obtained even when a significant volume of fluid is not appar-
of hydration status and possible protein loss. These values can ent on ultrasound. If severe gas distention or small intestinal
be affected by stress, which can increase the PCV, anemia, distention is present, or if a sand enterocolitis is suspected, it
protein loss, or hyperproteinemia, confounding the effects of may be advisable to forego abdominocentesis to avoid punc-
dehydration.462,504 Therefore these values must be evaluated ture of a distended compromised viscus or a heavy sand-filled
in the context of the history and physical examination of the viscus that is sitting flush with the ventral body wall. Although
patient, as well as their relationship to each other. In general, a practitioner may not have access to a full fluid analysis and
the greatest negative indicator is a significantly increased PCV cytology, a basic assessment of abdominal fluid can be made
(i.e., greater than 65%) coupled with a significantly low plasma by visual evaluation for color and clarity, and total protein can
protein concentration (i.e., less than 4 g/dL), especially if serial be evaluated with a refractometer. Normal fluid should be
values are trending toward these extremes.462,485,486,504 odorless, nonturbid, and a clear to pale yellow color.462,510,511
Although further blood work usually is not performed on a Increased turbidity can indicate increased protein, increased
standard simple colic, a CBC and serum chemistry can provide total nucleated cell count, or both. Total protein should be less
valuable information if a colic goes beyond simple treatment than 2.5 g/dL. A normal cell count is typically less than 5000
and requires more advanced care.504,505 In acute colic CBC cells/μL, although it may be normal up to 10,000/μL.458,475
values will typically be normal or reflect stress, but in more Serosanguineous fluid usually reflects a strangulating obstruc-
chronic conditions nonspecific signs of inflammation such as tion or significant compromise to the bowel wall. With a rup-
leukocytosis and hyperfibrinogenemia can develop, as well as tured gastrointestinal structure, the fluid is generally dark and
a possible normochromic normocytic anemia of inflamma- smells of ingesta. These results should be confirmed, however,
tion and chronic disease. If significant colon wall compromise because an accidental enterocentesis will appear the same.462
occurs, leukopenia with neutropenia and a left shift with toxic If the spleen is accidentally punctured, the fluid will look like
changes can occur as a result of endotoxemia.461,485,504 Throm- frank blood and will usually have a PCV equal to or greater
bocytopenia may also be present with endotoxemia. than the peripheral PCV.511
Measurement of lactate concentrations in both the cir- intestinal obstruction, left dorsal displacement of the large
culation and peritoneal fluid is useful in the assessment of colon (nephrosplenic entrapment), and large colon torsion in
colic.512-516 Several point-of-care analyzers are available, the long axis, but was less sensitive than rectal examination in
making measurement of lactate practical.516,517 In general, horses with impactions and most large colon displacements.521
in horses with colic, an elevation in lactate concentration in It was concluded that although ultrasonography is advisable in
either the circulation or peritoneal fluid suggests intestinal evaluation of the equine acute abdomen, it should not replace
hypoperfusion and correlates with more severe disease. Eleva- traditional rectal palpation.
tions in peritoneal fluid lactate, especially if higher than the Radiographs of the abdomen are of limited usefulness but
simultaneously measured blood lactate, as well as increases in may be diagnostic for two problems associated with colic in
peritoneal fluid lactate over time, are predictors of intestinal the adult horse: sand accumulation and enterolithiasis.529,530
ischemia secondary to a strangulating obstruction.512,515,516 Sand is usually visualized best in the ventral large colon. It
There is some evidence that pony and miniature breeds pre- is important to keep in mind that some sand can be visual-
senting for gastrointestinal disease have higher blood lactate ized in many normal horses, so the presence of sand in and of
concentrations compared with large-breed horses, suggesting itself has no diagnostic relevance. Radiographs may, however,
that different cutoff values should be used when determining provide some information as to the volume of sand present.504
the necessity of surgery and the prognosis in these breeds.518 Enteroliths represent the other main lesion identifiable by
Diagnostic Imaging. Ultrasound examination of the abdo- radiographs, although, depending on the location, they may
men is often useful in the evaluation of horses with colic.519-525 be difficult to visualize. In a study of 141 horses evaluated for
Adequate transabdominal ultrasound examination is most enterolithiasis, abdominal radiography had a sensitivity of
easily performed with a 2.5- to 5-MHz curved linear trans- 76.9% and a specificity of 94.4%.530 The abdomen can be more
ducer; however, an examination can also be performed using thoroughly assessed via radiography in a neonate as opposed
a transrectal probe.519,520,525 A protocol for fast localized ab- to an adult horse, although results still cannot be considered
dominal sonography of horses admitted for colic (FLASH) has conclusively diagnostic. Radiographs of a foal’s abdomen can
been developed.524 This protocol allows for rapid evaluation identify gas distention of the stomach, small intestine, or large
of specific abdominal regions of particular importance in the colon, which are nonspecific but generally pathologic find-
assessment of colic. On the left side of the horse the regions ings.494,531 Radiographs can aid in the diagnosis of meconium
evaluated include the ventral abdomen, gastric window, spl- impaction. A radiographic pattern known as pneumatosis
enorenal window, and left middle third of the abdomen, and intestinalis, characterized by linear radiolucencies within the
on the right side the regions evaluated include the duodenal bowel wall, is typical for necrotizing enterocolitis.494 Excessive
window, right middle third of the abdomen, and cranial ven- peritoneal fluid and pneumoperitoneum can also be identified.
tral thorax. Endoscopy/Other. Gastroscopy is important in cases of
Ultrasonography is particularly valuable in the evaluation colic where equine gastric ulcer syndrome is suspected. Ideally
of small intestinal distention and motility.519,520,522,524 Small the squamous and glandular regions of the stomach, as well as
intestine can most reliably be found in the inguinal region or the pyloric antrum, should be examined.
on the ventral abdomen, and it should normally be collapsed Evaluation for parasites may be indicated for some patients.
or have a very small diameter with frequent peristalsis. Small Ideally both fecal flotation and a fecal egg count should be per-
intestine can be evaluated for dilation, motility, and thicken- formed. Because standard flotation and fecal egg count meth-
ing of the intestinal wall. The presence of dilated turgid small ods are unreliable in the diagnosis of tapeworm infestation,
intestinal loops is highly sensitive and specific (80% and however, a tapeworm ELISA, which detects antibody to tape-
96.15%) for small intestinal obstruction, although enteritis worms, should be considered.
cannot entirely be ruled out. An intussusception may be iden- An underlying cause is not found in some horses with
tified as a target-shaped lesion on cross-sectional view.519,520,526 chronic colic after routine diagnostic evaluation. In these cases,
Ultrasound can also be used to identify a left dorsal displace- an exploratory laparotomy or laparoscopy may be indicated.
ment of the large colon, also referred to as a nephrosplenic
entrapment.519,520,527 With this condition, the spleen cannot Referral Indications
be visualized against the body wall, or the kidney cannot be Referral to a secondary care center is indicated when there is
visualized on the left side because of the interference of large a strong likelihood that the horse will require surgery or more
colon. Visualization of colonic mesenteric vasculature on the extensive medical care is necessary. The most common basis
right side of the abdomen can be a predictor of right dorsal for referral is severe or persistent pain with a lack of response
displacement of the large colon, a 180° large colon volvulus, or to analgesics.485,486,503 If a horse demonstrates intractable pain
both, although this change is not present in all cases.528 Ultra- or requires repeated doses of analgesics to remain comfort-
sonographic assessment of peritoneal fluid volume and char- able, referral is warranted. Referral is also indicated when a
acter may be useful in assessing the patient and in identifying horse has not resolved the signs of colic in 24 to 48 hours after
pockets of representative fluid for abdominocentesis.519,520 onset, or if a 1.1-mg/kg dose of flunixin meglumine does not
The thickness of intestinal wall should be evaluated at numer- maintain comfort for at least 8 to 12 hours.503 A persistently
ous locations, especially the right dorsal colon, which may be elevated heart rate can be a good indicator of pain or endotox-
extraordinarily thickened with right dorsal colitis.519,520 Inves- emia and necessitates referral. Other indications of endotox-
tigation for abdominal masses also is often undertaken using emia or impaired cardiovascular status include weak pulses,
ultrasound, coupled with rectal palpation. abnormal mucous membrane color (pale, hyperemic, injected,
A study comparing the findings of rectal examination purple, or cyanotic), and delayed capillary refill time. Rectal
and ultrasonographic findings in horses with colic demon- palpation of a potentially surgical lesion or small intestinal
strated that ultrasonography was a more sensitive diagnos- distention, an abnormal abdominocentesis, net nasogastric
tic technique than rectal examination in horses with small reflux of greater than 2 to 3 L, or significant depression are
all findings that would also support referral.485,486,503 In addi- to compensate for increased fecal losses. Protein loss may be
tion, significant dehydration may require extensive treatment seen with both acute and chronic diarrhea.
with intravenous or oral fluids or both because dehydration
has the potential to exacerbate even apparently simple colic Mechanisms of Diarrhea
problems and affects the patient’s systemic health. Dehydra- Several basic mechanisms of diarrhea have been described,
tion can result in worsening of an impaction that is already and in many diarrheal diseases more than one mechanism is
present or contribute to development of an impaction when involved. Inflammation within the bowel often plays a central
coupled with ileus and an inciting primary colic problem such role in the pathogenesis of diarrhea and may contribute to
as colonic displacement. diarrhea via multiple mechanisms. Basic mechanisms of diar-
rhea include the following:
Y DIARRHEA 1. Malabsorption: Malabsorption results from a decrease in
the functional absorptive surface area of the gastrointes-
Diarrhea, defined as an increase in the fluidity, frequency, or tinal tract. In the small intestine, villus atrophy, such as
volume of feces, is a commonly encountered clinical problem that seen with rotaviral enteritis, equine proliferative en-
in the horse. It is often the result of a primary gastrointestinal teropathy (Lawsonia intracellularis), and infiltrative bowel
disease but may also occur as a secondary response to another disease, can result in malabsorption because of the loss
disease process, such as sepsis, endotoxemia, or hepatic dis- of functional epithelium and maldigestion caused by de-
ease. In some cases, diarrhea may rapidly develop into a life- creased production of digestive enzymes.142,535,539-577 In the
threatening condition. colon, a number of insults can result in inflammation and
The function of the equine gastrointestinal tract is com- disruption of absorptive cells and tight junctions, leading
plex and involves maintenance of normal fluid balance and to decreased absorptive capacity and decreased ability to
digestion and absorption.532-534 As a result of dietary intake retain absorbed fluid (i.e., increased loss). Several inflam-
and endogenous secretions, a large volume of fluid normally matory mediators, such as TNF-α, histamines, and pros-
enters the gastrointestinal tract, most of which is reabsorbed. taglandins, can contribute to the colonic inflammation.
In the adult horse absorption occurs predominantly in the These mediators are produced primarily by inflammatory
large bowel, where a volume of water approximately equal to cells in the lamina propria and inhibit absorption through
the total extracellular fluid volume of the animal, or about 100 a variety of mechanisms.542-546
L, is recovered during the course of the day. Because the large 2. Increased secretion: The increased secretion of solutes and
colon is the primary site of water resorption, most significant water by the inflamed colon can contribute significantly to
diarrheal disease in the adult horse involves the colon. In the development of diarrhea. Although the precise mecha-
young foals, however, small intestinal disorders such as rotavi- nisms of secretion in the equine colon are not understood
ral infection also may result in diarrhea.535 fully, active secretion and passive fluid loss occur.542-549
A second critical function of the large bowel is that of Control of active secretion is complex, involving two pri-
microbial digestion of carbohydrates and, to some extent, pro- mary pathways: first, the activation of adenyl cyclase, re-
tein or nonprotein nitrogen.532-534 Microbial fermentation of sulting in an increase of intracellular cyclic adenosine
carbohydrates in the cecum and colon results primarily in the monophosphate concentrations, and second, the activation
production of volatile fatty acids (VFAs), which are absorbed of calcium channels, leading to increased intracellular cal-
readily, providing up to 75% of the energy requirement of the cium concentrations.547,548 Cyclic adenosine monophos-
horse. The intestinal microbiome is a complex polymicrobial phate and calcium stimulate specific secretory activities,
ecosystem that appears to play an important role in the main- primarily through chloride channels. In some cases of
tenance of health.534,536,537 Therefore maintaining a stable envi- diarrhea, bacterial enterotoxins such as those produced
ronment for the microbial population is important. In general, by certain strains of Escherichia coli and Salmonella spp.
efficient function of the large bowel requires mechanisms that stimulate adenyl cyclase activity, thus increasing active se-
limit the rate of digesta passage, provide optimal conditions cretion. This is true hypersecretory diarrhea. Also, a num-
for microbial digestion, and allow for efficient transport of sol- ber of inflammatory mediators produced by the inflamed
utes and water. colon, particularly prostaglandin E2, increase intracellular
The characteristics of normal equine feces and the fre- concentrations of cyclic adenosine monophosphate and to
quency of defecation can vary somewhat with diet, age, and some extent calcium, thereby increasing active secretion
sex.538 On average, adult horses defecate approximately 8 to by mucosal cells.547-549 Inflammation also enhances pas-
10 times daily. The frequency of defecation tends to be slightly sive fluid loss through a number of factors, such as changes
higher in stallions and foals. Generally, equine feces are tan, in hydrostatic pressure in the colonic capillaries, mucosal
brown, or greenish, and, although approximately 75% water, damage, and loss of tight junctions. In horses with severe
they are well formed. An average size adult horse on a typical mucosal injury, the loss of protein can decrease vascular
diet of grass hay and grain produces about 20 to 28 g of feces oncotic pressure and further potentiate fluid exchange
per kilogram of body weight per day, or about 11 to 13 kg of across the endothelium.
feces per day.538 In cases of diarrhea the amount of feces may 3. Decreased transit time (abnormal motility): Sufficient re-
increase up to tenfold, with some horses producing more than tention time and thorough mixing are required for diges-
200 g/kg/day, which can equate to more than 90 L of diarrhea. tion and absorption of nutrients and fluid to occur, and
As a result, diarrhea can cause significant losses of electrolytes thus decreased intestinal transit time can contribute to
and water. Especially in cases of acute diarrhea, these losses diarrhea.532-534,550 Primary motility disorders causing diar-
may result in severe dehydration, electrolyte imbalances, and rhea are not well recognized, although diarrhea associated
acid-base abnormalities. However, horses with chronic diar- with stress or excitement may represent this phenomenon.
rhea seldom develop these abnormalities as they are often able However, it appears that secondary motility disorders are
common in response to a variety of gastrointestinal prob- TABLE 7.5 Differential Diagnoses for Acute Diarrhea
lems, although the exact role that these changes in motilin Adult Horses
ity play in the pathogenesis of diarrhea is not entirely clear.
Both inflammatory and infectious conditions may influ- Common Causes Major Diagnostic Test(s)
ence motility in addition to potentially altering absorption Salmonellosis Fecal culture or polymerase
and secretion. Absorption of endotoxin and the release of chain reaction (PCR),
inflammatory mediators, including prostaglandins, dis- culture of rectal mucosal
rupts normal motility patterns.551 In general, these changes biopsy
result in hypermotility and decreased intestinal transit Potomac horse fever PCR (feces, peripheral blood),
time, although hypomotility has been recognized as well. (Neorickettsia risticii) paired serologic tests
Some progressive motility must be present for diarrhea Clostridiosis (Clostridium Fecal culture, toxin analysis
to occur. In some cases of acute colitis, a period of ileus difficile, C. perfringens)
may occur without diarrhea. This is usually transient and
Antibiotic-associated diarrhea History
diarrhea develops, although occasionally ileus may persist.
With diarrheal diseases, the elimination of gastrointestinal Nonsteroidal antiinflammatory History and supportive
contents is part of the normal host defense mechanism, and toxicity (primarily right dorsal clinicopathologic findings,
thus treatments specifically aimed at decreasing motility colitis) ultrasonography, explor-
are not indicated in most cases. atory surgery with biopsy
4. Osmotic overload: Any increase in osmotically active par- Undiagnosed Other conditions ruled out
ticles within the intestinal lumen can result in diarrhea.
Less Common
The increase can be associated with the administration or
ingestion of osmotically active substances such as mag- Cantharidin toxicity
nesium sulfate. The increase also may be associated with Parasitism (strongylosis, cya-
overloading of the intestine with carbohydrates or occa- thostomiasis, other)
sionally lipids beyond the amount that can be digested and Aeromonas, Campylobacter
absorbed. Therefore sudden dietary changes that result in spp.
significant shifts in gut flora and changes in fermentation Sand
or gastrointestinal diseases that result in malabsorption Carbohydrate overload
or maldigestion also may result in an osmotic diarrhea. In Arsenic toxicity, other toxicities
foals the loss of villous epithelial cells in the small intestine Thromboembolic disease
associated with disorders such as rotavirus infection and Anaphylaxis

clostridiosis may lead not only to malabsorption but also to
maldigestion caused by the decreased production of lactase
and secondary lactose intolerance.535,539,552 Although un- and chronic diarrhea have been identified (Tables 7.5, 7.6, and
common, primary lactose intolerance has also been report- 7.7). In some cases, rapid dietary changes or stress can result
ed in foals.553 Lactose intolerance allows excess lactose to in diarrhea that is generally mild and transient. Also, although
enter the large intestine, increasing the osmotic load. sand ingestion is frequently associated with impactions, it may
5. Increased hydraulic pressure from the blood to the lumen: The also result in diarrhea due to mechanical irritation to the gas-
pressure change may result in increased fluid movement to trointestinal tract.
the lumen and decreased net fluid absorption. This mecha- Several infectious agents are associated with diarrhea in
nism of diarrhea is more common in chronic conditions, horses. Salmonella and Clostridium species are among the most
such as congestive heart failure or inflammatory bowel common causes of infectious diarrhea in horses of any age.554,555
disease. The condition may result from decreased oncotic Salmonella is of particular importance because under certain
pressure associated with hypoproteinemia, increased capil- circumstances it can be highly contagious, leading to signifi-
lary hydrostatic pressure (as in heart failure), or decreased cant outbreaks of disease, especially in hospitalized patients.556
lymphatic drainage associated with inflammation of lym- Clostridium difficile and Clostridium perfringens are the most
phatics and lymph nodes. common clostridia associated with colitis in horses, although
The normal equine fecal microbiota is very complex. In occasionally other species may be involved.552,557-561 In certain
horses with diarrhea, the bacterial diversity of the gut micro- geographic areas equine neorickettsiosis (Potomac horse fever)
biota may be lower than in horses with normal feces.537 This caused by Neorickettsia risticii is also common.562 Lawsonia
microbial imbalance, referred to as microbiome dysbiosis, may intracellularis can cause equine proliferative enteropathy result-
be both a result and a cause of intestinal disease and diarrhea. ing in diarrhea, colic, edema, and weight loss.335,601-565 Lawso-
Characterization of the microbiome and its role in health and nia intracellularis can potentially affect horses of any age, but it
disease is a very active area of research. is most common in weanling-age foals. Although primarily a
Understanding the mechanisms of diarrhea can be helpful respiratory pathogen, Rhodococcus equi also can cause diarrhea,
in directing therapy. It is important to remember that most particularly in foals 2 to 4 months of age.566 Escherichia coli is
disorders that cause diarrhea, whether infectious or noninfec- an uncommon cause of diarrhea in foals, unlike in calves and
tious, do so through inflammatory mechanisms resulting in piglets. However, enterotoxigenic strains, characterized by the
multiple functional alterations. presence of virulence factors, have been identified in foals.567
Other, less common bacterial agents potentially associated with
Conditions Associated with Diarrhea diarrhea include Campylobacter spp. and Aeromonas spp.568,569
Diarrhea is a common, and sometimes fatal, clinical problem Both equine rotavirus and coronavirus can be important
of adult horses and foals. A number of specific causes for acute enteropathogens. Rotaviral infection is a common cause of
TABLE 7.6 Differential Diagnoses for Chronic Diarrhea TABLE 7.7 Differential Diagnoses for Diarrhea in Foals
in Adult Horses
Cause of Diarrhea Major Diagnostic Test(s)
Cause of Diarrhea Major Diagnostic Test(s) Salmonellosis Fecal culture or PCR
Chronic salmonellosis Fecal culture or polymerase Clostridiosis (Clostridium Fecal culture, toxin analysis
chain reaction, culture difficile, C. perfringens)
Sand Fecal sedimentation Endotoxemia, gram-negative Blood culture, physical ex-
Parasitism (strongylosis, Fecal egg count, empirical septicemia amination, complete blood
cyathostomiasis) deworming count, sepsis score
Nonsteroidal antiinflammatory History and supportive Antibiotic-associated diar- History
toxicity (primarily right dorsal clinicopathologic findings, rhea
colitis) ultrasonography, explor- Foal heat diarrhea History, physical examination
atory surgery with biopsy
Viral: rotavirus; rarely coro- Electron microscopy, enzyme
Inflammatory or infiltrative Histopathologic examina- navirus or adenovirus immunoassay
disorders tion, absorption tests (sup-
Protozoan: cryptosporidiosis Fecal analysis
Inflammatory bowel disease portive but nonspecific)
(granulomatous, lymphocytic- Secondary lactose intoler- Oral lactose tolerance test,
plasmacytic, or eosinophilic ance therapy response to
enterocolitis) Rhodococcus equi Culture, PCR
Mucosal lymphosarcoma Lawsonia intracellulare Fecal PCR, serologic testing
Amyloidosis Gastric ulcer disease Gastric endoscopy
Dietary: abnormal fermentation History syndrome
Neoplasms: lymphosarcoma, Histopathologic examina- Strongyloides westeri Fecal egg count
squamous cell carcinoma tion Sand Fecal sedimentation
Peritonitis, abdominal absces- Peritoneal fluid analysis,
sation ultrasound, exploratory PCR, Polymerase chain reaction.

surgery
Nongastrointestinal causes Physical examination, clini-
(chronic liver disease, con- copathologic findings being antibiotics and NSAIDs. Potentially any systemic antibi-
gestive heart failure, renal otic may cause diarrhea, but the risk appears to be higher with
disease) certain antibiotics such as trimethoprim-potentiated sulfon-
amides and erythromycin.28,583,584 Although the mechanisms of
antibiotic-associated diarrhea may be multifactorial, an impor-
tant factor is that the use of systemic antimicrobials leads to
diarrhea in foals and is most often recognized in foals from 1 changes in the intestinal microbiota.585,586 The use of NSAIDs
to 4 weeks of age.535,539,570,571 Equine coronavirus, also some- has been linked to adverse gastrointestinal effects including
times referred to as equine enteric coronavirus, has been gastric ulcers, right dorsal colitis, and inhibition of mucosal
recognized in both foals and adult horses.571-575 Since 2011 barrier healing.336,587,588,589,626 Phenylbutazone causes changes
several outbreaks of equine coronavirus have been identified in right dorsal colon arterial blood flow and changes in VFA
in adult horses, causing it to be named as an emerging patho- production.589
gen. The most common signs include anorexia, lethargy, and Diarrhea is a component of the clinical syndrome associ-
fever; diarrhea and colic are less common. ated with several toxins. Cantharidin (blister beetle toxin) can
The signs associated with internal parasites can vary cause severe colitis in horses.590 Some plants associated with
depending on the type and severity of infestation, but diar- diarrhea include alfalfa dodder (Cuscuta campestris), acorns,
rhea may occur. Often it is a chronic diarrhea, but acute diar- and oleander.591-593 Other toxins that may result in diarrhea
rhea may be seen. Encysted cyathosomin larvae are ubiquitous include lead, selenium, and arsenic.594,595
in grazing horses, but large numbers of encysted larvae place Cellular infiltrative disorders such as inflammatory bowel
the horse at risk for developing larval cyathostominosis.576,577 disease and neoplasia can cause diarrhea, which is generally
This condition occurs when there is a mass emergence of the chronic in nature. Alimentary lymphosarcoma is the most
larvae, resulting in acute typhlocolitis. The inflammatory common intestinal neoplasia of horses, and it can cause sig-
responses trigger diarrhea, especially in individuals with high nificant cellular infiltration of the intestine and associated
parasite burdens. The case fatality rate may be as high as 50%. lymph nodes.596 It has been recognized across a broad age
The majority of infections with Strongyloides westeri are sub- range, including relatively young horses. Several inflamma-
clinical, but occasionally diarrhea can occur in foals with high tory bowel diseases have been recognized in horses, including
worm burdens.578,579 A 2014 study in Thoroughbred foals in granulomatous enteritis, lymphocytic-plasmacytic enterocoli-
central Kentucky found a mean prevalence of S. westeri infec- tis, eosinophilic enterocolitis, and multisystemic eosinophilic
tion of 30%, which was greater than previous reports from epitheliotropic disease.142
the area.579 Cryptosporidium spp. are coccidian parasites that Some additional causes of diarrhea occur in neonatal foals.
have been linked to diarrhea in foals and occasionally adult Foal heat diarrhea is a normal physiologic diarrhea that occurs
horses.580-582 typically between 5 and 15 days of age.597 Foals are otherwise
Medications may be involved in the pathogenesis of diarrhea, healthy and the diarrhea is generally mild and self-limiting.
with the two classes of drugs most commonly incriminated With respect to infectious agents, coinfections appear to be
Signalment and History

BOX 7.10
Outline of Diagnostic Approach to Diarrhea The veterinarian should consider the signalment and his-
tory carefully when evaluating a patient with diarrhea. Age
I. SIGNALMENT, HISTORY, AND PHYSICAL EXAMINATION is particularly important because several disorders, such as
II. CLINICAL PATHOLOGY foal heat diarrhea, rotaviral diarrhea, and equine prolifera-
1. Minimum database: complete blood count, fibrinogen, tive enteropathy, are age related. The genetic background
and serum chemistry profile also may be significant because diarrhea has been associ-
a. Assess hydration, acid-base status, electrolyte abnor- ated with certain heritable immunodeficiencies, and granu-
malities, and protein status lomatous bowel disease has been identified in three sibling
b. Assess renal and hepatic function horses.600-602 Establishing whether the diarrhea is acute or
c. Assess endotoxemia chronic is important. Other historical questions of particu-
2. Serum protein electrophoresis and immunoglobulin lar relevance include the type and source of feed, as well
quantitation as any dietary changes; deworming program; involvement
3. Serologic testing: Neorickettsia risticii and Lawsonia of single versus multiple animals; exposure to sand; and
intracellulare the use of medications, especially antibiotics and NSAIDs.
4. Peritoneal fluid analysis Other concurrent diseases, stress, possible exposure to tox-
ins, weight loss, water consumption, and salt availability
III. EVALUATION OF FECES also may be significant. The information obtained helps
1. Gross appearance: severity, hemorrhage, odor, and the veterinarian prioritize differential diagnoses and direct
presence of sand further testing.
2. Direct smear: evaluation of protozoan populations and
presence of leukocytes and epithelial cells
Physical Examination
3. Parasite evaluation: including evaluation for Crypto- The clinician should perform a complete physical examina-
sporidium parvum, especially in foals tion. Attention should be given to good biosecurity measures,
4. Evaluation of bacterial pathogens especially as some causes of equine diarrhea are potentially
a. Gram stain and spore stain zoonotic in addition to being transmissible among horses.
b. Aerobic and anaerobic culture (culture of multiple The body condition of the horse and the presence of any
samples or rectal mucosal biopsy for Salmonella edema should be noted. The presence of fever, dehydration,
spp.) or signs of endotoxemia may help in assessing the sever-
c. Clostridial toxin analysis ity of the disease and differentiating the cause because some
d. Polymerase chain reaction: Salmonella spp., N. risticii, causes of diarrhea are not typically associated with systemic
and L. intracellulare signs of illness. The presence of oral ulcers and synchronous
5. Foals: evaluation of viral pathogens, primarily rotavirus diaphragmatic flutter increase the likelihood of cantharidin
(electron microscopy and enzyme immunoassay) toxicity especially in horses being fed alfalfa.590 In horses pre-
sented for diarrhea with a concurrent arrhythmia, oleander
IV. DIAGNOSTIC IMAGING: RADIOGRAPHY AND ULTRA- toxicity should be considered if exposure is possible.593 Care-
SONOGRAPHY ful evaluation of the abdomen should be performed. Visible
V. ENDOSCOPIC EXAMINATION: STOMACH, RECTUM, AND abdominal distention is often an indication of large intesti-
DESCENDING COLON nal distention, which may occur in association with acute
VI. ABSORPTION TESTS (GLUCOSE OR XYLOSE ABSORPTION): colitis. However, distention also may be visible with extreme
PRIMARILY FOR CHRONIC PROTEIN-LOSING ENTEROPATHY dilation of multiple loops of small intestine. Careful auscul-
tation of the abdomen can be useful in assessing motility.
VII. HISTOPATHOLOGIC EXAMINATION
Although the frequency of borborygmi in horses is variable,
VIII. TOXIN EVALUATION: CANTHARIDIN IN URINE OR GASTRO- horses with normal motility generally have 1 to 3 borborygmi
INTESTINAL CONTENTS, ARSENIC IN LIVER, OR OTHER in a 60-second time period. Auscultation behind the xiphoid
IX. RESPONSE TO THERAPY process may help identify the presence of sand or gravel if
particles can be heard grinding together during contractions
of the colon.499 Percussion of the abdomen while ausculting
may help to identify high-pitched resonant sounds associ-
ated with gas-distended bowel. Particularly in foals, transab-
common in neonatal foals.571 Secondary lactose intolerance dominal palpation and ballottement may be useful to identify
has been documented in foals with gastrointestinal infec- increased abdominal fluid or large masses near the body wall.
tions, and primary lactose intolerance has been reported as Transrectal palpation can be helpful in assessing the size of
well.539,552,553 Diarrhea has been seen in neonatal foals in asso- intestinal segments, consistency of contents, and wall thick-
ciation with hypoxic-ischemic gastrointestinal damage, sepsis, ness, as well as in identifying masses, enlarged lymph nodes,
and rarely acute pancreatitis.598 or mesenteric arteritis.
Diagnostic Approach to Diarrhea Ancillary Diagnostic Tests
A comprehensive evaluation may help in establishing a diag- Clinical Pathology. Routine analysis of blood work typi-
nosis and developing a treatment plan in cases of diarrhea cally does not identify a specific cause of diarrhea, although
(Box 7.10). However, even in severe cases a definitive diag- occasionally N. risticii can be found in circulating monocytes.
nosis often is not made, making the problem particularly However, blood work is often important in directing ap-
frustrating.554,555,568,571,599 propriate supportive care and may help to establish whether
diarrhea is caused by another condition, such as hepatic or also can assess the feces for the presence of occult blood, which
renal disease. Some important parameters to evaluate include indicates bleeding from any source. Although excess sand in the
the presence of leukopenia, particularly neutropenia with feces is readily apparent in some cases, other cases require mixing
a left shift, and toxic changes in the white blood cells. These the feces in a rectal sleeve with water and allowing the sand to set-
abnormalities suggest a systemic inflammatory response, of- tle. Acorn husks may be present in the feces of horses with acorn
ten associated with endotoxemia. Thrombocytopenia and toxicity. Less commonly used tests include evaluation of fecal os-
coagulopathies may also be present. The clinician also should molality and electrolyte concentrations (sodium and potassium).
evaluate the concentration of protein, as well as the albumin- If the concentration of sodium plus potassium is much less than
to-globulin ratio. Both acute and chronic diarrhea can cause the osmolality, the result indicates the presence of osmotically ac-
significant protein loss, resulting in hypoproteinemia and par- tive nonelectrolytes, confirming an osmotic diarrhea.
ticularly hypoalbuminemia. Hyperglobulinemia may indicate Microscopic examination of the feces for evidence of parasit-
a chronic inflammatory condition. Disturbances in acid-base ism and evaluation of viable protozoal populations also may be
balance, especially metabolic acidosis, and electrolyte abnor- useful. A direct smear of fresh feces allows for observation of
malities frequently occur in horses with acute diarrhea but are the motility of ciliates and can be used as a screen for the pres-
uncommon with chronic diarrhea. Although hypocalcemia is ence of ova and oocysts. Ideally evaluation of parasitism should
relatively common in horses with colitis, marked hypocalce- include fecal flotation and a quantitative method that allows
mia may be suggestive of possible cantharidin toxicity.63 Be- for estimation of the number of eggs per gram of feces, such
cause of the dehydration frequently seen with acute diarrhea, as McMaster’s or Stolley’s. Cryptosporidial oocysts are typi-
prerenal azotemia is common and is important to recognize cally difficult to identify on routine fecal flotation, but detec-
because some therapies, especially NSAIDs, may worsen the tion can be improved by acid-fast or acridine orange staining as
condition. In a study of 122 horses with acute diarrhea, horses well as immunofluorescent staining or flow cytometry.579-582 It
with azotemia and clinicopathologic findings consistent with is important to remember that fecal examination for parasites
hemoconcentration and hypoproteinemia were less likely to sometimes can be misleading, giving false-negative results.
survive.599 Fecal samples also can be examined microscopically for leu-
The diagnostic and prognostic value of serum protein electro- kocytes and epithelial cells. In general, the cellularity increases
phoresis has been evaluated in horses with chronic diarrhea.603 with the severity of diarrhea. Fecal leukocytes and epithelial
Significantly higher levels of β1-globulin were found in horses cells are increased in salmonellosis but are not specific for this
with larval cyathostominosis than in other horses, and such disorder.605 The presence of more than 10 leukocytes per high-
values in conjunction with a decreased albumin were helpful in power field has been associated with salmonellosis.
diagnosing intestinal parasitism. However, a normal β1-globulin Evaluation of the feces for infectious agents is essential in the
concentration was not a reliable indicator of the absence of the diagnostic evaluation of horses with diarrhea. Gram stain and
disease. Significantly lower albumin concentrations and signifi- spore stain of fecal smears can help to identify and quantitate
cantly higher α2-globulin concentrations were found in horses the bacterial populations present, particularly clostridial species.
that did not survive, suggesting that these parameters are non- However, although large numbers of gram-positive rods or spores
specific indicators of the severity of inflammatory changes within have been identified in horses with clostridial enterocolitis, the
the intestinal wall. Parasitic infections, particularly strongylosis, results of direct staining may be misleading.557-561 Clostridium
also may be associated with elevated serum concentrations of the perfringens has been cultured from 59% of samples in which no
immunoglobulin G (IgG) isotype IgG(T).604 gram-positive rods were visible. Some clostridial strains also are
Because immunodeficiencies are infrequently associated likely parts of the normal microflora.561,606 Large numbers of
with diarrhea,600,601 further evaluation of immune status may yeast in the feces should alert the clinician to the possibility of
be indicated in some horses. This evaluation may include candidiasis, especially in compromised neonatal foals.
specific immunoglobulin quantitation, evaluation of specific Fecal culture is used commonly to establish a diagno-
lymphocyte subsets, or functional assays. The clinician should sis in horses with bacterial diarrhea. When culturing feces,
consider genetic testing for severe combined immunodefi- especially if an outside laboratory is used, the clinician must
ciency in sick foals of Arabian breeding. consider proper sample handling, particularly for anaerobic
Analysis of peritoneal fluid may be useful in some horses clostridia.607 Salmonella spp. are one of the most significant
with diarrhea. Abnormalities in the peritoneal fluid may bacterial pathogens in equine feces.556 Although the number
reflect the severity of inflammation and in some cases may of Salmonella organisms isolated from the feces of horses with
help to establish a specific diagnosis. Increases in protein and clinical salmonellosis is generally greater than from horses
sometimes nucleated cell count may be seen in association with asymptomatic infections, the volume of feces in horses
with ulcerative colitis. In horses with bacterial peritonitis, the with profuse diarrhea may decrease the likelihood of posi-
veterinarian may find organisms on cytologic examination or tive culture. Culture of multiple fecal samples, typically five,
culture. Occasionally, the veterinarian may identify neoplastic is recommended to increase the sensitivity.608 Culture of a
cells in the peritoneal fluid, although their absence does not rectal mucosal biopsy or rectal scraping is an alternative to
rule out the presence of neoplasia. fecal cultures and may increase sensitivity because Salmonella
Evaluation of Feces. Evaluation of the feces may yield im- spp. are intracellular organisms. Identifying clostridial species
portant information in horses with diarrhea. Even the gross ap- requires anaerobic culture. However, evaluating the presence
pearance of the feces can be helpful. For example, profuse, watery of toxin in cases of suspected clostridial diarrhea also is critical
diarrhea is not generally consistent with a diagnosis of right dor- because Clostridium spp., particularly C. perfringens type A,
sal colitis, which is most often associated with soft, poorly formed may be present in normal equine feces.557-561,606 Depending on
feces. Frank blood in the feces suggests bleeding into the distal co- the clostridial species and the laboratory, toxin can be assessed
lon from mucosal damage. Hemorrhagic, foul-smelling feces of- by detecting preformed toxin in the feces, toxin being pro-
ten are seen in association with clostridial diarrhea. The clinician duced by the isolate in culture, or the toxin gene in the isolate.
An increasing number of polymerase chain reaction (PCR) metabolism as well as absorption from the gastrointestinal
assays are available for detecting causative agents of equine tract, the assay is reliable in the diagnosis of significant malab-
diarrhea. In comparing a PCR with microbial culture for sorptive conditions. Xylose is influenced less by the metabolic
detection of salmonellae in equine feces and environmental status of the horse, but the compound is more expensive than
samples, the PCR method was found to be more sensitive and glucose, and the assay is not available in many laboratories. Re-
more rapid and required submission of fewer samples.609,610 sults of both assays are nonspecific, but abnormal results sup-
For diagnosis of equine neorickettsiosis (Potomac horse fever), port malabsorption and may indicate the necessity of biopsy.
PCR is currently recommended for detection of Neorickettsia Diagnosing neoplasms and chronic inflammatory or infil-
risticii in feces and peripheral blood.562,611,612 Fecal PCR analy- trative disorders often requires histopathologic examination.
sis is also useful in documenting Clostridium, Lawsonia intra- A rectal mucosal biopsy is easy to collect and can be cultured,
cellularis, and Cryptosporidium spp., as well as both equine but the area that can be reached for biopsy is limited. Lapa-
rotavirus and equine coronavirus.335,539,563,572,613,614 Both rota- roscopy allows for visualization of the abdomen and certain
virus and coronavirus can also be identified in the feces by biopsies. The veterinarian can obtain a full-thickness intestinal
electron microscopy.539,572,615 A number of commercial assays biopsy during exploratory celiotomy.
are also available for the detection of rotavirus antigen.539,616 The diagnosis of cantharidin toxicity can be made in sus-
Serologic methods, evaluating the presence of antibodies, pect cases by the identification of blister beetles in the feed
have been used in the diagnosis of Neorickettsia risticii and Law- source and detection of cantharidin in urine or gastrointes-
sonia intracellularis.562-564,612,614 In the case of N. risticii, the sero- tinal contents.590 If a heavy metal or trace mineral toxicity is
logic tests are of limited value in the diagnosis of disease.562 For L. suspected, lead and selenium can be measured in the blood
intracellularis, it is recommended to use both PCR and serologic and liver or arsenic can be measured in the blood, urine, liver,
diagnostic testing as these assays have high analytic specificity or kidney as appropriate.594,595 Oleandrin is detectable in urine
but variable sensitivity depending on the circumstances.563,614 and gastrointestinal contents.593
Coinfections have been documented in both adult horses
and foals with diarrhea. In a study of neonatal foals, coinfec- Evaluation of Response to Therapy
tions were significantly associated with the risk of gastroin- Evaluating the response to empirical therapy may be helpful in
testinal disease.571 The use of diagnostic panels rather than some horses with undiagnosed diarrhea, especially in chronic
individual tests in combination with quantitative toxin gene cases. Dietary changes may decrease diarrhea in some cases,
analysis may be helpful in the diagnosis of coinfections. and often a diet of grass hay alone is recommended. In cases in
Diagnostic Imaging. Diagnostic imaging, although particu- which right dorsal colitis is suspected but cannot be confirmed,
larly useful in foals, also can be valuable in adult horses. In foals using pelleted feed and the addition of psyllium mucilloid and
radiographs can detect gas distention in the lumen of the gas- corn oil to the diet may be beneficial. Psyllium mucilloid also has
trointestinal tract, and the gas pattern may help to differentiate been used for treatment of horses in which sand was suspected
ileus from mechanical obstruction. Occasionally, gas may be as contributing to the diarrhea. Any medications that the horse
seen within the bowel wall in severe cases of clostridial necro- has been receiving, especially NSAIDs or antibiotics, should be
tizing enterocolitis. In adult horses abdominal radiography is discontinued in case they are contributing to the diarrhea.
limited somewhat by having the proper facilities and equipment Fecal microbiota transplant (FMT), also known as trans-
to perform the procedure safely. However, radiographs can be faunation, can be used in an attempt to restore normal flora.620
effective in identifying radiodense material, such as enteroliths Although not a new concept, there has been renewed interest in
and sand. Ultrasonography can be used in horses of all ages FMT due in part to increased awareness of the importance of
to evaluate the amount and character of the peritoneal fluid, the microbiota and the success of FMT in the management of
masses, small intestinal motility, intestinal distention, and wall Clostridium difficile infection in humans. Currently, data regard-
thickness. In horses with right dorsal colitis the diagnosis has ing FMT in horses are limited. Some guidelines for the use of
been supported by ultrasonographic evidence of an increase in FMT in horses, including case selection and FMT procedure,
mural thickness of the right dorsal colon.617 The right dorsal have been proposed.620 Several commercial prebiotics and pro-
colon may have a prominent hypoechoic layer most likely as- biotics are available, and their efficacy is under investigation.621
sociated with submucosal edema and inflammatory infiltrates. The yeast Saccharomyces boulardii may decrease the severity and
Although isotope-labeled white blood cell scintigraphic scans duration of clinical signs in horses with acute enterocolitis.622
also may help identify colonic ulcerations, the availability and A course of corticosteroids can be tried in cases of chronic
sensitivity of the procedure are limited.618 In cases of L. intracel- diarrhea in which infectious causes have been ruled out. Treat-
lularis, ultrasonography may reveal thickened small intestinal ment with a larvicidal anthelmintic may be beneficial in some
loops and possibly excess free abdominal fluid.335,563 cases and sometimes is used with corticosteroids. Some horses
Endoscopy. Endoscopic examination of the stomach and with chronic diarrhea have responded to iodochlorhydroxyquin
proximal duodenum may reveal the presence of neoplasms (10 g/450 kg/day for 2 weeks). This drug sometimes has been
or ulceration. Diarrhea and inappetence can be seen in symp- used concurrently with trimethoprim-sulfa. Occasionally, trans-
tomatic foals with ulceration of the squamous gastric mucosa. fusion with plasma seems to suppress diarrhea in young horses.
Endoscopy also can be used for inspection of the mucosa of
the rectum and descending colon, allowing for evaluation of Y POLYURIA AND POLYDIPSIA
mural masses or mucosal inflammation.
Additional Diagnostic Tests. Absorption tests are used pri- Polyuria and polydipsia are infrequently reported clinical
marily in horses with chronic diarrhea or weight loss to evalu- problems in the horse that can be a source of inconvenience to
ate the small intestinal absorptive capacity. Oral glucose and owners, may indicate a major abnormality in the mechanisms
oral xylose absorption tests have been used.160,619 Although controlling water balance, and can be associated with sig-
the plasma concentration of glucose may reflect glucose nificant disease. As water intake and urine output are closely
linked, polydipsia and polyuria generally occur together. TABLE 7.8 Causes of Polyuria and Polydipsia
Establishing whether the primary problem is polyuria or poly-
dipsia can be helpful in developing a management strategy SOLUTE DIURESIS
and providing an accurate prognosis. Primary renal insufficiency or failure
Normal fluid intake and urine production in horses are Glucosuria (PPID)
influenced by a number of factors, including age, diet, physi- Psychogenic salt consumption
ologic demands such as exercise or lactation, environmental Diabetes mellitus
temperature and humidity, and gastrointestinal water absorp- Postobstructive diuresis
tion.623-630 In adult horses, water requirements range from 25 WATER DIURESIS
to 70 mL/kg per day. These requirements are proportional to Insufficient antidiuretic hormone (central diabetes insipidus)
metabolic body size rather than body mass, with larger horses PPID
requiring less water per kilogram than smaller horses or Head trauma
ponies. Because fat is low in water content compared with lean (Potassium depletion)a
body tissue, horses with significant body fat require less water Insufficient response of collecting ducts to antidiuretic
than lean horses. Fluid requirements are higher in neonatal hormone
foals than adult horses due to their high total body water. Acquired nephrogenic diabetes insipidus
Water is obtained from three sources: drinking water, water Hyperadrenocorticism (glucocorticoid excess with PPID)
in feed, and metabolic water from the catabolism of fats, car- Endotoxemia
bohydrates, and protein. Water is lost in urine and feces as (Drugs: gentamicin, lithium, methoxyflurane, amphotericin
well as through evaporation across the skin and respiratory B, propoxyphene, etc.)
tract. In adult horses, normal water intake through drinking (Congenital nephrogenic diabetes insipidus)
is approximately 50 to 60 mL/kg per day (20–30 L/day for an Renal medullary solute washout
average adult horse) and normal urine production is approxi- Chronic diuresis of any cause
mately 15 to 30 mL/kg per day (5–15 L/day for an average adult Inappropriate renal tubular sodium handling
horse).623-627 Diet is a major influence on drinking and urine Apparent psychogenic polydipsia
output. In neonatal foals on a milk diet, fluid intake is approxi- (Chronic liver disease)
mately 250 mL/kg per day to meet their caloric needs.631-633 As (Polycythemia)
a result, the kidneys actively excrete water and the urine output (Pyometra)
approaches 148 mL/kg per day, which is almost 5 times that of (Hypercalcemia)
adults. In adult horses, water intake correlates with dry mat- (Potassium depletion)
ter intake.628,629 Depending on weather conditions, water con- IATROGENIC
sumption may be minimal in horses on good quality pasture Intravenous fluid therapy
due to the high moisture content of grass. Water requirements Excess dietary salt
are higher for horses consuming hay compared with pasture Drugs
or grain-based rations and vary with the type of hay. Horses Diuretics
on legume hay have significantly higher urine production than Glucocorticoids
those on grass hay. Voluntary water intake is also affected by (Drugs causing acquired diabetes insipidus)
ambient temperature, increasing when temperatures are high
and water losses in sweat are increased623,625,634,635 (Table 7.8). aNot reported in horses.
Water consumption may increase significantly in heavily exer- Modified from Fenner WR: Quick reference to veterinary medicine, ed 3,
cised horses such as endurance horses to replace the addi- Philadelphia, Wiley-Blackwell, 2001.
PPID, Pituitary pars intermedia dysfunction.
tional fluid lost in sweat.634,635 Horses with diarrhea may also
have significantly increased water consumption.
Polyuria and polydipsia may be clearly evident in some essential for normal cellular function. Under normal condi-
affected horses but in others may be more subtle. The conditions, plasma osmolality remains relatively constant, varying
tions are sometimes hard for owners to recognize, particularly only by approximately 2%.636 Body water is controlled by two
in horses housed at pasture and especially if they are with other general mechanisms: (1) fluid intake, which is regulated by
horses. Some owners may misinterpret frequent urination, or factors that influence thirst, and (2) renal excretion of water,
pollakiuria, as polyuria. Objective documentation of polyuria which is regulated by factors that affect glomerular filtration
and polydipsia requires measurement of water consumption and tubular reabsorption. In normal horses, glomerular filtra-
and 12- to 24-hour urine production. In adult horses, poly- tion exceeds 1000 L/day, but 99% is reabsorbed in the renal
dipsia has been defined as water intake greater than 100 mL/ tubules and collecting ducts. Normal urine is 3 to 4 times more
kg per day and polyuria as urine output greater than 50 mL/kg concentrated than plasma with an osmolality of 900 to 1200
per day. Consideration of factors that can influence water con- mOsm/kg and a specific gravity of 1.025 to 1.050. The ability
sumption and urine production, such as diet, climatic condi- to concentrate urine is dependent primarily on three factors:
tions, and level of exercise, should be taken into consideration (1) the production of arginine vasopressin (AVP), also known
when documenting polyuria and polydipsia. as antidiuretic hormone (ADH); (2) the presence of a sufficient
number of nephrons that are sensitive to AVP; and (3) the
presence of a hyperosmotic renal medullary interstitium.636,637
Mechanisms of Polyuria and Polydipsia Role of Arginine Vasopressin. Arginine vasopressin is
Maintenance of Normal Water Balance an important peptide hormone that is highly conserved
The maintenance of adequate body water that has a relatively among species.636-639 Initially, AVP was recognized as hav-
constant concentration of electrolytes and other solutes is ing two functions, antidiuresis and vasoconstriction. It is
The higher the osmolarity of the Sodium is actively pumped from

ECF, the more water leaves the descending the ascending limb, increasing the
limb by osmosis. osmolarity of the ECF.
As water leaves the descending limb, the concentration

of solute in the tubule increases.
FIG. 7.6 Simplified schematic of the countercurrent multiplier in the loop of Henle. ECF, Extracellular fluid,
concentrations in mOsm/L.
now known to have diverse effects, some of which include kidney.638 Extrarenal V2 receptors are present in the endothe-
modulation of pituitary functions, as well as immune re- lium. Within the kidney, one mechanism of action of AVP is to
sponses and behavior. A small peptide of nine amino acids, influence aquaporins, which are integral membrane proteins
AVP is synthesized primarily in the supraoptic and paraven- that can form pores in the cell membrane that act primar-
tricular nuclei of the hypothalamus, with smaller quantities ily as water channels. Binding of AVP to the renal V2 recep-
produced by various tissues outside the hypothalamus. It tor increases aquaporin-2 synthesis and leads to aquaporin-2
is produced as a precursor, prepro-vasopressin, which is water channel insertion into the apical membrane. This aqua-
packaged into neurosecretory granules and transported ax- porin channel then allows water to move down the osmotic
onally via the pituitary stalk (infundibulum) to the posteri- gradient and out of the nephron, increasing water reabsorp-
or pituitary (neurohypophysis). During transport, prepro- tion by the kidney. AVP also acts to increase urea permeability
vasopressin is processed into the active hormone, which is in the terminal inner medullary collecting duct by regulating
stored for secretion in the posterior pituitary. urea transporters, increasing the concentration of urea in the
AVP is primarily released in response to signals from medullary interstitium.641 Also, the V2 receptors are active in
osmoreceptors located in the anterior hypothalamus near the loop of Henle, where activation stimulates the reabsorption
the supraoptic nuclei and in the anteroventral region of the of sodium.
third ventricle.636-639 These osmoreceptors rapidly respond Role of the Renal Hyperosmotic Medullary Interstitium.
to small increases in the osmolarity of the extracellular fluid, The osmolarity of the interstitial fluid in the medulla of the
which is primarily determined by the sodium concentra- kidney is approximately 1200 to 1400 mOsm/L compared with
tion. Once stimulated, osmoreceptors send signals to nerve about 300 mOsm/L for interstitial fluid in other locations.
cells in the supraoptic nuclei, which relay the signals down This high osmolarity of the renal medullary interstitium sur-
the pituitary stalk to the posterior pituitary stimulating the rounding the collecting ducts provides the osmotic gradient
release of AVP from secretory granules in the nerve endings. necessary for water reabsorption to occur when AVP concen-
Although the exact threshold for AVP release in the horse is trations are high. The primary mechanism maintaining the
unknown, in healthy ponies, an increase of approximately 8 hyperosmolar interstitium is countercurrent multiplication,
mOsm/kg in plasma osmolality (about 3%) following water which depends on the structure and function of the loop of
deprivation was associated with an increase in plasma AVP Henle636 (Fig. 7.6). Essentially, the ongoing active reabsorp-
concentration from 1.53 ± 0.36 pg/mL to 4.32 ± 1.12 pg/ tion of ions from the thick ascending loop of Henle combined
mL.640 When the extracellular fluid becomes hypo-osmolar, with the continued flow of new ions into the loop of Henle
less AVP is released, causing less water to be reabsorbed. ultimately multiplies the medullary solute concentration. Due
Although changes in osmolarity are the major stimulus for to the presence of aquaporin channels, the descending loop
AVP release, the stimulation of arterial and cardiopulmonary of Henle is permeable to water, but it is relatively imperme-
baroreceptors by a reduction in circulating volume and hypo- able to solute. Thus as tubular fluid enters the descending loop
tension can also result in AVP release.636,638 Other stimuli for and moves toward the inner medulla, it gradually becomes
AVP release that have been reported in some species include more hypertonic as water moves out into the interstitium. In
stress, pain, nausea, hypoglycemia, and certain drugs such as the thin ascending loop of Henle, ions begin to move into the
morphine. interstitium by passive diffusion. Once fluid enters the thick
There are three different receptors for AVP, V1a, V1b, and ascending loop of Henle, sodium, potassium, and chloride
V2, with V2 being the receptor found on the epithelial cells are actively reabsorbed via the apical Na+/K+/2Cl− cotrans-
of the distal convoluted tubule and collecting duct of the porter. This active transport of ions, combined with the
impermeability of this section to water, results in an increased the collecting ducts less permeable to water, increasing urine
osmolarity in the renal medullary interstitium. This creates an output.
osmotic pressure gradient, drawing water from the descend- Polyuria as the Primary Problem. Polyuria can result
ing limb and increasing the osmolarity of the tubular fluid. from renal disease or several systemic disorders. Although
This process is repeated as fluid continues to flow through the polyuria is commonly associated with renal failure, the pre-
tubules, with the net effect of continuing to add sodium to the cise mechanisms are not fully understood and are most like-
medullary interstitium until the osmolarity reaches 1200 to ly multiple.643 With primary renal insufficiency or failure,
1400 mOsm/L. The collecting ducts also contribute to the hy- there is a decrease in functional nephrons. This can result
perosmolar interstitium through the active transport of ions in solute diuresis, as increasing amounts of glomerular fil-
and the facilitated diffusion of urea into the interstitium. The trate are presented to the remaining tubules, often exceeding
relatively low blood flow in the renal medulla and the unique their reasborptive capacity. The resultant increase in urinary
characteristics of the vasa recta help to maintain the hyperos- solute is accompanied by an increase in water loss. Also, the
molar interstitium. increased tubular flow rate in the remaining tubules may
Countercurrent multiplication and maintenance of the simply allow less time for the reabsorption of water. In addi-
hyperosmolar interstitium play important roles in the concen- tion, diuresis may result from decreased hypertonicity of the
tration of urine. When luminal fluid enters the thick ascend- medullary interstitium associated with decreased transport
ing loop of Henle, approximately 80% of the glomerular of sodium and chloride out of the loop of Henle when there
filtrate has been reabsorbed. The active resorption of NaCl in is renal compromise. Another factor that may contribute to
the thick ascending loop of Henle, which is impermeable to polyuria in renal failure is acquired nephrogenic diabetes in-
water, causes the fluid entering the distal tubule in the renal sipidus due to an inability of the diseased collecting ducts to
cortex to be hypotonic. Water is then reabsorbed from the dis- respond to AVP.
tal tubules and cortical portions of the collecting ducts under The syndrome of diabetes insipidus, which is characterized
the action of AVP. Reabsorbed water is transported rapidly out by the excretion of large volumes of dilute urine associated
of the interstitium by the extensive cortical capillary network, with abnormalities related to AVP, has several fundamental
and interstitial hypertonicity is preserved. causes.644,645 In primary polydipsia, AVP secretion is sup-
Thirst. Adequate fluid intake, which is regulated by thirst, pressed by excessive fluid intake. Also, in human patients,
contributes to the maintenance of water balance along with gestational diabetes insipidus can occur due to degradation
the renal excretion of water.630,634,636,642 The thirst center in of AVP by a placental enzyme. Central or neurogenic dia-
the hypothalamus consists of osmoreceptors in the antero- betes insipidus occurs when there is inadequate production
ventral wall of the third ventricle and anterolateral preoptic or secretion of AVP. This form of diabetes, or inflammatory
nucleus that are in close proximity to those that regulate AVP disease involves the hypothalamus or posterior pituitary. In
secretion. A major stimulus for thirst is increased osmolarity nephrogenic diabetes insipidus there is insensitivity of the
of the extracellular fluid, which causes intracellular dehydra- renal collecting duct epithelial cells to AVP, and the condition
tion in the thirst centers, stimulating the sensation of thirst. may be primary or acquired. Primary nephrogenic diabetes
In human beings the threshold for stimulation of thirst is ap- insipidus implies isolated dysfunction of the response to AVP
proximately 2 to 5 mOsm/kg greater than that for stimulation not associated with actual structural or metabolic problems
of AVP release. Also, decreases in extracellular fluid volume of the kidney. In people this occurs as a familial disorder with
and arterial pressure can stimulate thirst via mechanisms an X-linked autosomal semirecessive mode of inheritance,
that are distinct from osmolarity. These mechanisms include and there is some evidence this may occur as a familial prob-
neural input from cardiopulmonary and systemic barorecep- lem in horses as well. Acquired nephrogenic diabetes insipi-
tors and the release of angiotensin II, which can both stim- dus can be associated with renal disease or altered sensitivity
ulate thirst and decrease renal fluid excretion. Peripherally, of nephrons to AVP due to endotoxemia or cortisol excess.
mechanoreceptors in the oropharynx can sense dryness of Also, in some species, hypercalcemia, potassium depletion,
the mouth, stimulating thirst. Following experimental water and the administration of certain drugs such as gentamicin
deprivation, ponies drank when their plasma osmolalities in- have been reported to cause insensitivity of the collecting
creased by 3%, when plasma Na concentrations increased by duct receptors to AVP.
approximately 5%, and after induction of a plasma volume Renal medullary washout is a syndrome in which the rela-
deficit of 6%.8 tive hypertonicity of the renal medulla is reduced, typically
from prolonged diuresis of any cause.636,643 The increased
General Mechanisms of Polyuria tubular flow rates during diuresis may result in an inability to
and Polydipsia resorb sufficient sodium and urea from the tubular lumen. The
General mechanisms of polyuria and polydipsia include water resulting decrease in medullary hypertonicity leads to impair-
or solute diuresis, and in some cases both mechanisms may ment of renal concentrating ability and polyuria with second-
contribute.625,630,634,636 Water diuresis is caused by either ary polydipsia. Enhanced medullary blood flow may deplete
decreased water absorption in the collecting tubules or exces- medullary solute further.
sive voluntary water intake. In water diuresis, either polyuria Polyuria as a result of solute diuresis can occur in associa-
or polydipsia may be primary. Solute diuresis is caused by tion with excessive salt consumption and hyperglycemia in
excessive renal excretion of a nonreabsorbed solute such as addition to renal failure.643,646-649 When blood glucose concen-
glucose or sodium, resulting in primary polyuria. trations increase above the renal threshold of approximately
Polydipsia as the Primary Problem. Excessive water intake 150 to 200 mg/dL in the horse, the resultant glucosuria results
results in water diuresis.636 By expanding the extracellular flu- in increased urine flow. Solute diuresis may also occur follow-
id volume and decreasing plasma osmolarity, excessive fluid ing obstructive urinary tract disease, but this is not commonly
intake causes a suppression of AVP secretion. This then makes reported in horses.
Conditions Associated with Polyuria not completely understood and most likely involves multiple
factors. As some horses with PPID are hyperglycemic, osmotic
and Polydipsia diuresis associated with glucosuria may play a role. Although
There are several potential specific causes of polyuria and it has not been documented, the enlarged pars intermedia may
polydipsia in horses.650,651 The most common causes include impinge on the posterior pituitary and/or hypothalamus, po-
renal failure, PPID, and primary psychogenic polydipsia. tentially causing secondary neurogenic diabetes insipidus by
Other less common causes include excessive salt consump- interfering either with the production or release of AVP or
tion, central and nephrogenic diabetes insipidus, and diabetes possibly with osmoreceptors involved in thirst. Also, an in-
mellitus. Polyuria and polydipsia may also occur secondary to crease in plasma cortisol associated with PPID may result in
sepsis and endotoxemia or may be iatrogenic following the use antagonism of the action of AVP at the renal tubule.
of α2-agonists, corticosteroids, or diuretics.650-652 Diabetes Insipidus. Neurogenic diabetes insipidus appears
to be rare in the horse, with two cases reported in the litera-
Polydipsia ture.661,662 In both cases, the horses were unable to concentrate
The most common reason for excessive water intake in horses urine in response to water deprivation but responded to the
is psychogenic water drinking. The extent of polydipsia and administration of exogenous vasopressin with a decrease in
therefore polyuria seen with psychogenic water drinking can urine volume and increase in urine concentration. In one case
be substantial. Psychogenic water drinking can be a stable vice the condition was felt to be idiopathic, and in the other it was
associated with confinement and boredom.642,653 The behav- felt to be acquired secondary to encephalitis.
ior has also been associated with changes in environmental Primary nephrogenic diabetes insipidus also appears to
conditions, stabling, and diet. It has been suggested that pri- be rare in horses, having been reported in three colts and
mary polydipsia is particularly common in horses residing in a 14-year-old gelding.663-665 Two of the colts were sibling
the southern United States when ambient temperature and Thoroughbreds, suggesting that an inherited form of neph-
humidity are high. rogenic diabetes insipidus similar to what is seen in people
Excessive salt consumption may also result in increased may occur in horses.664 In addition to signs of polyuria and
thirst, although a significant amount of salt needs to be con- polydipsia, two of the three colts were underweight. Fol-
sumed to stimulate thirst in horses.648 In human patients, lowing water deprivation, affected colts could not increase
polydipsia has been reported in association with conditions urine concentration although plasma AVP concentrations
affecting the osmoreceptors involved in the regulation of increased. In addition, affected horses had minimal response
thirst, such as neurologic disease affecting the hypothalamic to the administration of exogenous vasopressin, confirming
thirst center.654,655 This could potentially occur in horses. For resistance of the collecting ducts to the antidiuretic action of
example, the enlarged pituitary gland in horses with PPID vasopressin.
could compress the hypothalamus. Nephrogenic diabetes insidipus has been recognized in
The ability to concentrate urine is retained in cases of pri- horses with some frequency as a secondary problem in which
mary polydipsia. However, occasionally the long-standing there is an acquired decrease in renal responsiveness to AVP.645
diuresis can result in medullary washout and a decrease in This acquired nephrogenic diabetes insipidus has been associ-
concentrating ability. ated with a variety of conditions, including renal disease. It
has also been described following drug therapy, as well as with
Polyuria a variety of endocrine, metabolic, infectious, neoplastic, and
Important causes of primary polyuria in horses include postobstructive disorders.
renal failure and pituitary pars intermedia dysfunc- Diabetes Mellitus. Diabetes mellitus is characterized by
tion.650,651 Diabetes insipidus and diabetes mellitus are less chronic hyperglycemia. In type 1 or insulin-dependent dia-
common causes. betes mellitus, there is a lack of insulin, whereas in type 2 or
Renal Failure. In the acute stage of renal failure there is fre- non–insulin-dependent diabetes mellitus, insulin is adequate
quently a period of oliguria or anuria, which is then followed but tissue sensitivity to insulin is impaired. Although it is a
by polyuria.643,646 The repair of tubules following an acute in- relatively common cause of hyperglycemia and glucosuria in
sult may take several weeks, and in some cases the repair may other species, type 1 diabetes mellitus has been infrequently
not be complete, resulting in chronic renal failure and per- diagnosed in the horse.152, 666-671 Type 2 diabetes mellitus has
sistently diminished concentrating ability.643,647 Some poten- been recognized in horses in association with several condi-
tial causes of renal failure in horses include failure to recover tions, especially PPID and equine metabolic syndrome.80, 672-676
from ischemic renal damage, pigmenturia, chronic infection, Diabetes mellitus has also been reported in a horse with bilat-
urinary obstruction, and exposure to nephrotoxins such as eral granulosa cell tumors.672
nonsteroidal antiinflammory drugs, gentamicin, and poly- Other. Medullary washout may result from chronic di-
mixin.646,647,656,657 Other possible causes include immune- uresis of any cause and may be a more common complica-
mediated disease, glomerulonephritis, congenital abnormali- tion of primary diseases and their therapy in horses than
ties, renal helminthiasis, and amyloidosis. In some horses, the has been reported to date. Polyuria and polydipsia have oc-
inciting cause of chronic renal failure may be hard to identify. casionally been reported in association with sepsis and en-
Pituitary Pars Intermedia Dysfunction. Polyuria and poly- dotoxemia in multiple species, including horses. The mech-
dipsia are recognized in approximately 30% of horses with pi- anisms are unclear but may involve endotoxin-induced
tuitary pars intermedia dysfunction (PPID), although numbers production of PGE2, which can cause renal vasodilation and
vary among studies.658-660 Other clinical signs that are com- inhibit the actions of AVP. Although infrequently reported
monly associated with PPID include hypertrichosis, laminitis, in horses, polyuria and polydipsia have been recognized in
muscle atrophy, abnormal fat deposition, and recurrent infec- association with severe liver disease. Some conditions that
tions. The pathogenesis of polyuria and polydipsia in PPID is have been associated with polyuria and polydipsia in other
species include primary polycythemia, hypercalcemia, and without other laboratory abnormalities. As hyposthenuria in-
potassium depletion. dicates that renal diluting ability is intact, horses with renal
failure or complete medullary washout are unlikely to have hy-
posthenuria, although it may occasionally be present in horses
Diagnostic Approach to Polyuria and Polydipsia recovering from acute renal failure. Chronic renal failure is
Signalment and History suggested by the presence of isothenuria (USG 1.008–1.014
The signalment and history can be valuable in the assessment and osmolality 260–300 mOsm/kg) with concurrent azote-
of polyuria and polydipsia. Congenital problems such as renal mia.681-683 Other laboratory abnormalities that may be seen
anomalies are generally recognized in young animals, whereas with chronic renal failure include mild anemia, hypoalbumin-
PPID increases in prevalence with age. Primary nephrogenic emia, hyponatremia, hypochloridemia, hyperkalemia, hyper-
diabetes insipidus has been described in two related Thor- calcemia, and hypophosphatemia. Some additional laboratory
oughbred colts. A detailed history should be obtained with tests that may be used to assess renal function include frac-
particular emphasis on the duration of signs, any management tional excretion of electrolytes, urinary protein–to–urinary
changes, diet including any supplements, and any current or creatinine ratio, creatinine clearance, and measurement of
previous medication use. In some horses, iatrogenic causes of urinary enzymes. Measurement of glomerular filtration rate
polyuria and polydipsia can be ruled out by assessment of the is a sensitive indicator of renal dysfunction but is infrequently
history and return to normal urine output and water intake performed primarily for practical reasons. Measurement of
after discontinuing medications, intravenous fluids, or excess symmetric dimethylarginine, a methylated form of arginine
dietary salt. that is eliminated primarily by renal excretion, is useful in the
evaluation of renal function in small animals and is under in-
Physical Examination vestigation in horses.684
A complete physical examination should be performed with There are no consistent laboratory abnormalities in horses
careful attention to hydration status. Palpation per rectum with PPID, although neutrophilia, lymphopenia, hyperglyce-
can be useful in evaluation of the urinary tract. Horses with mia, and glucosuria may be present.658-660 Additional endo-
psychogenic polydipsia are generally normal on physical crine testing is required to confirm the presence of PPID.
examination. Chronic renal insufficiency is often associated Some recommended tests include measurement of baseline
with a poor body condition, and in some cases, appetite may ACTH concentration, measurement of ACTH concentra-
be decreased. The clinical signs of PPID can be quite vari- tion following the administration of thyrotropin-releasing
able depending on the individual and the stage of disease, but hormone, or a low-dose dexamethasone suppression test.
commonly recognized signs include hypertrichosis, muscle Hyperglycemia and glucosuria may also be seen with equine
atrophy, abnormal fat deposition, chronic infections, and metabolic syndrome, underlying systemic disease and diabe-
laminitis. tes mellitus.
Water Deprivation Testing. Water deprivation evalu-
Measurement of Water Intake and Urine ates the ability to conserve water and is most often used to
Volume differentiate psychogenic polydipsia from diabetes insipi-
The measurement of 24-hour water intake and urine produc- dus.624,685,686 It is most clearly indicated in horses that are
tion can be helpful in confirming the problem, especially in hyposthenuric rather than isossthenuric. Water deprivation
those cases in which polyuria and polydipsia are less obvi- testing is contraindicated in horses that are dehydrated or
ous.677-680 It can also establish the severity, which can help azotemic. In normal animals, the increase in plasma os-
to prioritize differentials. In general, the degree of polydipsia molality that occurs with water deprivation results in the
and polyuria tends to be more pronounced with psychogenic release of AVP, which acts on the renal tubules and collect-
polydipsia and diabetes insipidus than with renal failure or ing ducts to conserve water, increasing USG. Before initi-
PPID. Several means of urine collection have been devised. ating the test, baseline values for USG, serum urea nitro-
Generally close observation and cross-tying are required to gen, creatinine, and body weight should be obtained and
ensure the device stays in place and measurements are accu- the bladder emptied by catheterization. After water is re-
rate. In general water intake over 100 mL/kg per day and urine moved, USG and body weight should be monitored every
output over 50 mL/kg per day are consistent with polydipsia 6 to 12 hours. Serum urea nitrogen and creatinine may be
and polyuria in adult horses. Factors that can influence water monitored as well. In response to 24 to 72 hours of water
intake and urine production, such as diet and environmental deprivation, normal horses will increase their USG over
conditions, should be taken into consideration. When mea- 1.045 with an osmolality over 1500 mOsm/kg. For practical
suring water consumption, behavioral tendencies to spill or purposes, if USG increases above 1.025 within 24 hours or
play in the water should be taken into account. by the time that 5% of body weight is lost, concentrating
ability is adequate and the test can be discontinued. The
Ancillary Diagnostic Aids test should be terminated if there is a loss of more than
Clinical Pathology. A hemogram, serum biochemistries, 5% of the body weight or if clinical signs of dehydration
and urinalysis should be assessed in horses presented for poly- or azotemia develop. Typically, horses with psychogenic
uria and polydipsia. Urine specific gravity (USG) is decreased polydipsia can concentrate their urine in response to water
in horses with polyuria and polydipsia. The extent of the de- deprivation whereas those with diabetes insipidus cannot.
crease in USG, along with the presence or absence of other Occasionally horses with psychogenic polydipsia will have
abnormalities on laboratory tests, can help prioritize differen- incomplete concentrating ability due to medullary wash-
tial diagnoses and may direct additional testing. Horses with out and loss of the medullary interstitial osmotic gradient.
psychogenic polydipsia tend to present with hyposthenuria These horses may respond to a modified water deprivation
(USG less than 1.008 and osmolality less than 260 mOsm/kg) test where water intake is gradually restricted for several
days allowing for restoration of the medullary interstitial potentially impair performance either by direct effects on the
osmotic gradient.687 Horses with either central or nephro- individual’s health or by increasing the likelihood of the indi-
genic diabetes insipidus cannot effectively concentrate their vidual developing secondary problems. For example, heritable
urine in response to water deprivation, and to distinguish muscle disorders can directly affect performance, and poor
these conditions additional testing such as measurement of structural conformation can increase the risk of injury.3,4 Sim-
endogenous AVP concentrations and evaluation of the re- ilarly, it has been suggested that Warmblood horses that must
sponse to exogenous AVP is indicated. work in top gear to achieve the speeds required for upper lev-
Measurement of Arginine Vasopressin and Response to els of 3-day eventing are more prone to injury.692
Exogenous Arginine Vasopressin or Analogs. The plasma
concentration of AVP can be measured during water depriva- Locomotion
tion testing or following the administration of 7.5% sodium Movement is a key component of athletic performance, and
chloride solution to increase plasma osmolality. In normal therefore musculoskeletal, neurologic, and neuromuscular
ponies, AVP concentrations increased from baseline values of disorders can all have a negative impact on performance.691-695
1.53 ± 0.36 pg/mL to 4.32 ± 1.12 pg/mL after 24 hours of water The mechanisms by which they affect performance are multi-
deprivation.13 Plasma concentrations of AVP will increase in ple and include pain, mechanical restrictions, incoordination,
horses with psychogenic polydipsia or nephrogenic diabetes and weakness. Pain can make the horse reluctant to exercise
insipidus, but any increase will be minimal with central diabe- and can also limit the amount of training so that the horse
tes insipidus. In nephrogenic diabetes insipidus, the elevation is unable to achieve the level of fitness required for optimal
in AVP is not accompanied by an increase in USG. performance. Any gait deficit can potentially make efficient
The ability of renal tubules to respond to AVP can be movement mechanically difficult. Also, lameness at one site
assessed by a challenge test.688 USG is monitored following can contribute to the development of secondary problems
the administration of either exogenous synthetic vasopressin such as back pain or chronic myopathy that can further impair
or desmopressin acetate, a synthetic vasopressin analog. USG performance. Neurologic disease can cause ataxia and weak-
is expected to increase over 1.020, and failure to do so is con- ness, adversely affecting performance.
sistent with a diagnosis of nephrogenic diabetes insipidus if Physical activity requires muscles to generate and sustain
medullary washout is not present. the power for movement. Horses are generally considered to
be a highly athletic species, and there are several adaptations
Diagnostic Imaging in equine skeletal muscle that contribute to this athletic ability,
Transabdominal and transrectal ultrasound examination can including an increased muscle mass relative to body weight,
be useful in evaluation of the urinary tract. Although not con- high locomotor efficiency based on muscle-tendon architec-
sistent, changes in the size and/or architecture of the kidneys ture, high intrinsic shortening velocities, and efficient muscle
may be present in both acute and chronic renal failure. Ultra- energetics.696,697 In horses, muscle tissue comprises about 45%
sound can also be helpful in the diagnosis of urolithiasis. of body weight in most equine breeds and up to 55% of body
weight in Thoroughbreds, compared with 30% to 40% in many
Y POOR PERFORMANCE other species. Horses that have the ability to run fast tend to
have a large overall skeletal muscle mass, longer muscle fas-
Poor performance is the inability of an individual to perform cicles, a high percentage of fast-twitch muscle fibers, and a low
at a level that can be reasonably expected based on the individ- percentage of body fat.90 Any change in muscle mass, architec-
ual’s physical characteristics, level of training, and/or previous ture, or function can have a profound impact on performance.
performance. Any decrease in performance may be critical If muscle fatigues prematurely or is painful, such as with rhab-
to the equine athlete. In some cases, poor performance may domyolysis, the horse may not be able to generate the neces-
be easily documented, such as when the problem is severe or sary power for efficient movement.
when there is a drop in performance that can be objectively
measured (e.g., in a discipline such as racing). However, in Oxygen Uptake and Transport
other cases, poor performance may be subtle and difficult to Any process that impairs the uptake or transport of oxy-
document. gen can limit the ability to produce the energy required for
optimal performance. Thus diseases of both the upper and
Mechanisms Affecting Performance lower respiratory tract, and less frequently the cardiovas-
Numerous factors influence performance, including genetics, cular system, are important causes of poor performance. A
training, desire, body composition, and overall health. Peak number of upper airway obstructive disorders have been
athletic performance requires optimal function of all body recognized that restrict the movement of air into and/or out
systems, particularly those involved in locomotion and oxy- of the lung.301,698-,699-702,739 Disease of the lower respiratory
gen transport. tract may increase the work of breathing and impede normal
gas exchange in the lung. For example, inflammatory airway
Genetic Factors disease (IAD) has been shown to alter pulmonary mechan-
Genetic factors play a role in several aspects of performance. ics through changes in lung compliance, greater viscous lung
In multiple species, genetics are known to influence athletic resistance, and rate of dynamic work of breathing.703 Due
potential. As the knowledge of equine genomics expands, to the increase in ventilatory load, the energy required for
understanding of the heritability of specific traits associated breathing is significantly higher in affected horses, which may
with elite athletic performance will increase.689-691 For exam- limit their performance. Also, a higher neutrophil percent-
ple, variation at the myostatin gene locus has been found to age in the bronchoalveolar lavage fluid of horses with poor
be associated with a horse’s best racing distance.690 In addi- racing performance has been correlated with significantly
tion to influencing inherent athletic ability, genetic traits can lower relative gas flows during inspiration and expiration.704
Although the effects of exercise-induced pulmonary hem-

orrhage (EIPH) on performance are not entirely clear, in BOX 7.11
Causes of Poor Performance
a study of 132 horses with a history of poor performance,
exercise-induced hypoxemia was seen in horses with IAD SYSTEMIC DISEASE
and EIPH.705 Gas exchange was most significantly impaired BODY CONDITION
in those horses with concurrent EIPH and upper airway Overconditioned
obstruction. Once oxygen is taken up into the circulation Underconditioned
from the lung, it must be delivered to the tissue, especially
working muscle, for optimal performance. Thus cardiovascu- TRAINING
lar disease can impair performance by decreasing the effec- Inadequate
tiveness of oxygen delivery to the tissues. Overtraining
Other MUSCULOSKELETAL
Almost any systemic disease or source of pain has the poten- Lameness
tial to make the horse reluctant to work. For example, poor Back pain
performance has been reported in association with equine Neck pain
gastric ulcer syndrome and possibly dental disease.700,706,707 Muscle disorders
Also, in horses with anhidrosis, their decreased ability to Sporadic exertional rhabdomyolysis
maintain normal body temperature can limit performance in Subclinical exertional rhabdomyolysis
warm environmental conditions.708 Polysaccharide storage myopathy
Recurrent exertional rhabdomyolysis
Conditions Associated with Poor Performance
Vitamin E myopathy
It is not possible to list all potential causes of poor perfor- Muscle injury/strain
mance as so many factors influence performance (Box 7.11). Mitochondrial myopathy
Certainly almost any systemic disease, as well as desire and Myofibrillar myopathy
training, can affect performance. When evaluating horses
presented specifically for the complaint of poor performance, NEUROLOGIC DISEASE
the conditions most often identified have been abnormalities RESPIRATORY TRACT DISEASE
of the respiratory and musculoskeletal systems.695,699,700,709,710
Upper airway obstruction
It is not uncommon for multiple problems to occur concur-
Dorsal displacement of the soft palate
rently. In a study of 275 racehorses with a history of poor
Recurrent laryngeal neuropathy
racing performance, 84% were found to have more than one
Axial deviation of the aryepiglottic folds
abnormality.699 Similarly, in a study of 27 endurance horses
Dynamic pharyngeal collapse
with poor performance, 66.7% had multiple concomitant
Epiglottic entrapment
disorders.710
Subepiglottic cyst
Locomotor Disorders Rostral displacement of the palatopharyngeal arch
Redundant alar folds
A surprising number of horses presented for poor perfor-
Lower airway disease
mance are found to be lame even when lameness has not
Inflammatory airway disease; recurrent airway obstruction
been reported by the owner or trainer.692,695,699,700,709,710
Exercise-induced pulmonary hemorrhage
Although some horses may compete successfully with low-
grade lameness, any degree of lameness has the potential to CARDIOVASCULAR DISEASE
impair performance. A wide variety of musculoskeletal condi-
Cardiac arrhythmia
tions have been identified in association with poor perfor-
Myocardial dysfunction
mance.692,695,699,700,709-712 In addition to those horses with
Murmurs (often not clinically significant)
forelimb or hindlimb lameness, horses with other sites of mus-
culoskeletal pain, such as neck, back, or sacroiliac joint pain, OTHER
may also have poor performance.693,694,712 Neurologic deficits
Dental disorders
also have the potential to adversely affect performance.
Equine gastric ulcer syndrome
Several muscle disorders have been linked to poor per-
Anhidrosis
formance, including both sporadic and recurrent rhabdomy-
Saddle fit; horse-saddle-rider interaction
olysis (tying-up).698,700,713,714 In many cases, affected horses
Disease in early neonatal period
do not exhibit the classic clinical signs of rhabdomyolysis but
have increased muscle enzymes in response to exercise. In one
study, 53 of 348 horses examined for poor performance had
this form of subclinical myopathy identified only by increased
creatine kinase concentrations after exercise, and 10 of 348 breed, and the clinical presentation of affected horses ranges
had clinical exertional rhabdomyolysis.700 from being asymptomatic to exhibiting muscle atrophy and
Polysaccharide storage myopathy (PSSM) is an inherited progressive weakness, muscle soreness, and gait abnormali-
glycogen storage disorder that is an important cause of muscle ties, or acute rhabdomyolysis. In Quarter Horses and related
disease in a number of breeds, including Quarter Horses and breeds it appears there is a second mutation, malignant hyper-
related breeds, many draft and Warmblood breeds, and oth- thermia, that potentially worsens the signs of PSSM in affected
ers.714 Clinical signs vary depending on the individual and horses.24
Several other muscle disorders have been identified in infection significantly affects performance, but the role of sub-
horses. Recurrent exertional rhabdomyolysis (RER) is a clinical infections is less clear. Studies in Standardbred trotters
heritable abnormality of intramuscular calcium regulation have not found an association between subclinical viral infec-
seen primarily in Thoroughbreds and to a lesser extent in tion and poor performance.723,724
Standardbreds and possibly Arabians.715 A skeletal muscle
mitochondrial myopathy has been described in an Arabian Cardiovascular Disorders
in association with impaired oxidative energy metabolism; Cardiovascular disease can also cause poor performance,
muscle stiffness and exercise intolerance due to a suspected although it is less common than either musculoskeletal or
myofibrillar myopathy have also been reported in Arabian respiratory disease.699,700,709,710 The prevalence and clinical
horses.716,717 Vitamin E deficiency has been associated with relevance of cardiac arrhythmias have varied between stud-
several clinical problems, one of which is a myopathy.718 ies.699,700,709,710,725-727 In the study of 348 horses evaluated for
Horses affected with myopathy related to vitamin E deficiency poor performance, a clinically significant cardiac arrhythmia
may present with signs of muscle atrophy, weakness, toe drag- was the sole abnormality found in 33 horses, and an arrhythmia
ging, and muscle fasciculations, as well as poor performance. in conjunction with dynamic airway obstruction was found in
Muscle strain or soreness can also be a cause of decreased 22 horses.700 The most frequent arrhythmias observed were
performance.698 Equine activities can often be athletically atrial and ventricular premature depolarizations. However, in
challenging and may require either high intensity or pro- the study of 275 racehorses, arrhythmias were noted in just
longed effort. Some disciplines require a combination of activ- two horses.699 Isolated premature depolarizations were com-
ities and may require sudden moves or maintaining a precise mon in a study of 88 Thoroughbreds with poor performance,
body position. In some cases, the horse is not adequately con- with 55 horses having at least one premature ventricular or
ditioned, making the risk of muscle injury greater. Any muscle supraventricular premature depolarization.727 The clinical sig-
group may be affected, and clinical signs vary depending on nificance of these depolarizations was uncertain. Ventricular
the muscle involved and the severity of the injury. tachycardia and paroxysmal atrial fibrillation have also been
identified in horses with poor performance. Changes in the
Respiratory Disorders T wave, once thought to be related to poor performance, and
Respiratory disease has been the most common cause of poor second-degree atrioventricular block have been found to have
performance in several studies. Among the most common no effect on exercise capacity.728
respiratory problems associated with poor performance in the Many horses have murmurs that are of little clinical signifi-
equine athlete is dynamic airway obstruction, affecting both cance.699,700,709,710,729,730 In the study of 348 horses with poor
racing and nonracing performance horses.300,699,700,702,709,719 In performance, 102 were found to have murmurs, the most
the study of 275 racehorses evaluated for poor performance, 110 common being mitral regurgitation.700 In all cases the mur-
(40%) were found to have dynamic airway obstruction.699 Simi- mur was determined to be clinically unimportant. Similarly,
larly, in the study of 348 racehorses and show horses with poor in the study of endurance horses, neither the prevalence nor
performance, 148 (42.6%) had dynamic airway obstruction.700 the grade of valvular regurgitation was significantly different
Of these 148 affected horses, 39 were found to have multiple between well-performing horses and those with a decreased
airway abnormalities, and an additional 22 were found to have a performance level.710 Although many murmurs appear to be
concurrent cardiac arrhythmia. The most common conditions clinically unimportant, in some individual cases a murmur
causing airway obstruction include dorsal displacement of the may be associated with more significant cardiac disease and
soft palate and idiopathic left laryngeal hemiplegia with aryte- poor performance.
noid collapse, also referred to as recurrent laryngeal neuropa- Echocardiography has been used to evaluate cardiac func-
thy. Other conditions diagnosed have included axial deviation tion in cases of poor performance. In the study of 348 horses,
of the aryepiglottic folds, dynamic pharyngeal collapse, epiglot- decreased fractional shortening indicating left ventricular
tic entrapment, subepiglottic cyst, fourth branchial arch defect myocardial dysfunction after exercise was found in 19 horses,
(rostral displacement of the palatopharyngeal arch, laryngeal only 8 of which had echocardiographic changes at rest.700 Six
dysplasia), and redundant alar folds. Horses of Quarter Horse of the 19 horses had what was felt to be a clinically significant
breeding with hyperkalemic periodic paralysis (HYPP) may ventricular arrhythmia.
suffer dynamic collapse of the airway when exercising.720
Disease of the lower respiratory tract is also a common Other
cause of decreased performance.227,251,755,710,721,722 In the study A wide variety of other disorders have been linked to poor
of 27 endurance horses with poor performance, respiratory performance. Body condition plays a role in performance,
tract abnormalities, specifically tracheal fluid neutrophilia and and horses that are both overconditioned and undercondi-
IAD, were the most commonly identified problems.710 IAD tioned may have suboptimal performance.90,697,731,732 A study
was identified in 70% of national hunt horses presented for in endurance horses demonstrated that body condition score
poor athletic performance.721 Excess mucus accumulation in at the start of the ride had a significant effect on performance,
the airway has been associated with poor willingness to per- with horses with lower scores being less likely to complete the
form in sport horses.251,721 In addition to IAD, other subtypes ride.732 Some other problems potentially associated with poor
of equine asthma, including recurrent airway obstruction performance include dental disease, gastric ulcers, anhidrosis,
(RAO) and summer-pasture–associated obstructive pulmo- and both undertraining and overtraining.706-708,733 Poor saddle
nary disease, can limit athletic performance. The effects of fit may cause focal areas of increased pressure resulting in an
EIPH on performance have been difficult to measure because unwillingness to work. The dynamic interaction between the
there are so many confounding factors, but current evidence horse, saddle, and rider may not be optimal.734 Some foals that
suggests that moderate to severe EIPH adversely affects ath- were sick within the first 18 hours of birth may have decreased
letic capacity.227,722 Clinical bacterial or viral respiratory tract performance as an adult.735
Diagnostic Approach to Poor Performance disease, respiratory noise, cough, or respiratory distress
Determining the cause of poor performance in those horses associated with exercise. Any change in gait also may be
without overt clinical disease often is challenging.695,698,699-701 significant. Establishing the housing environment, feeding
In the study of 348 cases of poor performance, a definitive practices, changes in appetite or body condition, the type of
diagnosis was established in 73.5% of cases after in-depth tack used, and whether sweating is appropriate is important.
examination, which included the use of a high-speed tread- The clinician should determine the response to any medica-
mill.700 Multiple factors can contribute to the difficulty in tions that have been used, such as phenylbutazone or furo-
establishing a definitive diagnosis. First, it can even be hard semide. The information obtained in the history may help
to determine whether the horse has actual poor performance direct the investigation.
or if it is simply not performing up to expectations that are
unrealistic for the individual’s inherent ability or current level Physical Examination
of training. Medical conditions can certainly influence the The clinician should perform a complete physical examination
willingness to work, but there may also be a behavioral com- in all cases. The body condition score should be determined.
ponent that can be difficult to assess. The abnormalities that In-depth assessment of the gait, as well as the respiratory and
are sufficient to impair performance can be quite subtle and cardiovascular systems, is generally indicated.
may be evident only during exercise. Multiple problems may Respiratory Examination. The examination should in-
be present concurrently, which can make it hard to determine clude evaluation of air flow from the nares and percussion of
the actual clinical significance of any given problem. the sinuses, as well as assessment of any cough or nasal dis-
Equine athletes presented for poor performance should charge. Careful palpation of the larynx may reveal an increase
undergo a comprehensive evaluation, the basic components in prominence of the muscular process of the left arytenoid
of which include a history, detailed physical examination, and cartilage resulting from a loss of mass of the left dorsal crico-
laboratory screening. The clinician should emphasize exami- arytenoid muscle associated with idiopathic hemiplegia. The
nation of the respiratory, musculoskeletal, and cardiovascular clinician can use the laryngeal adductor response test, or slap
systems because these systems most often are linked to perfor- test, to evaluate adduction of the arytenoid cartilages by slap-
mance problems. In many cases standardized exercise testing, ping the withers during expiration and evaluating movement
generally on a high-speed treadmill, is critical in identifying of the contralateral arytenoid by endoscopy or palpation. It
the problem. Endoscopic examination of the upper airways is important to note that many of the horses with airway ob-
during exercise has proven particularly useful. It may also be struction did not have a history of abnormal respiratory noise
helpful to evaluate the horse while it’s being ridden. and did not have abnormalities at rest.300,699,700,702,709,719 At the
same time, not all abnormalities observed at rest caused ob-
Signalment and History struction. These findings emphasize the importance of video-
The signalment may be helpful in the assessment of some cases endoscopy during exercise as a component of a performance
of poor performance. Horses that present at a young age may evaluation.
be more likely to have a congenital or heritable condition or Thorough auscultation of the trachea and lungs should
may have limited genetic potential. Diseases with a heritable be performed. Having the horse rebreathe from a plastic bag
basis are more often seen in certain breeds. PSSM is found placed over the nostrils increases the respiratory rate and tidal
in a wide variety of breeds but is common in Quarter Horses volume, thus accentuating sounds. In addition to auscultation,
and related breeds as well as some draft horse and Warmblood the clinician should note the character and pattern of respi-
breeds, whereas RER is primarily seen in Thoroughbreds and ration, including the presence of any abdominal component,
to a lesser extent Standardbreds and possibly Arabians.713-715 and the recovery time. Percussion of the thorax may be useful
RER is more common in females and in horses with a nervous in establishing the lung border and any dull or hyperresonant
temperament. Recurrent laryngeal neuropathy appears to be areas, as well as in detecting pleural pain.
more common in large, long-necked horses especially of Thor- Cardiovascular Examination. Any decrease in cardiac
oughbred or draft horse breeding.736 output potentially can limit performance, making thorough
Obtaining a complete history is a fundamental part of evaluation of the cardiovascular system essential. On basic
evaluating poor performance. The clinician should establish physical examination the clinician should evaluate the mucous
the use of the horse, the time in training, and the specifics of membrane color, capillary refill time, and arterial and venous
the training program. Determining whether the horse has peripheral pulses, although finding abnormalities in these
never performed as expected or has experienced a decline in parameters in horses presented for decreased performance is
the level of performance is crucial. If the horse has never per- uncommon. The clinician should perform careful auscultation
formed as expected, the veterinarian should consider a lack of the heart on both sides of the thorax to evaluate the cardiac
of ability, congenital abnormalities, and training problems. rhythm and murmurs. Electrocardiography can be used to
A change in performance, either sudden or insidious, often further evaluate the cardiac rhythm and ideally should be per-
is associated with an acquired problem. The clinician should formed before, during, and after exercise using radiotelemetry.
characterize specifically the decline in performance, includ- Musculoskeletal and Neurologic Examination. A lame-
ing the intensity of exercise at which signs are observed and ness examination should be performed in all horses presented
whether performance is abnormal from the onset of exercise for evaluation of poor performance both because lameness is
or declines during an exercise bout. In those cases in which a common cause of poor performance and because it is im-
performance drops off during exercise, the clinician should portant to establish that the horse is sound enough to safely
determine whether the decline is acute or gradual and whether perform an exercise test if indicated. In some horses presented
any other signs, such as stridor, are associated with it. for poor performance, the gait asymmetry may be subtle and
Other elements of the history with particular relevance only discernible at high speed, making diagnosis by traditional
to athletic performance include any previous respiratory methods difficult. In these cases use of a sensor-based motion
analysis system, gait analysis on the treadmill, and advanced techniques can vary, in most cases cytologic evaluation of
diagnostic techniques such as nuclear scintigraphy, thermog- bronchoalveolar lavage fluid is used to aid in the diagnosis of
raphy, and CT or MRI may be useful. In some cases it can be EIPH and forms of equine asthma such as IAD and RAO.
helpful to perform a ridden evaluation. Careful palpation of Endoscopy. Endoscopic examination of the upper airway
the muscles should be performed to identify any heat, swell- is an important part of the evaluation of poor performance. As
ing, or reactivity. In many cases a neurologic examination is many of the abnormalities associated with poor performance
indicated to identify any neurologic deficits that could con- are related to dynamic airway obstruction, either treadmill or
tribute to poor performance. overground videoendoscopy is generally indicated regardless
of the history and physical examination findings.300,719,743-745
Ancillary Diagnostic Aids Endoscopy also can be useful in identifying respiratory prob-
Clinical Pathology/Selected Laboratory Tests. Hematologic lems other than dynamic airway collapse. For example, the
testing and a biochemical profile are indicated, although in clinician can identify narrowing of the ventral nasal meatus
most horses presented for poor performance without obvious associated with sinusitis, nasal masses, and pharyngitis. In
clinical abnormalities, routine evaluation of a single sample is some cases evidence of inflammation and retropharyngeal
within normal limits. Because exercise can induce some chang- lymphadenopathy on endoscopic examination of the guttural
es in laboratory parameters, such as an increase in the packed pouches has been associated with dorsal displacement of the
cell volume and neutrophil count, considering the time of sam- soft palate, which may result from neuropathy of the pharyn-
ple collection relative to exercise is important.737-739 Potentially geal branch of the vagus nerve.746
significant findings include changes consistent with chronic in- Tracheal injury and secretions in the lower respiratory tract
flammation, such as anemia, hyperglobulinemia, and possibly can be visualized if the endoscope is sufficiently long. Airway
hyperfibrinogenemia or thrombocytosis. Subclinical infections secretions may be sampled via the endoscope or via a bron-
may have only slight alterations in the leukocyte count and dif- choalveolar lavage catheter. Endoscopy can also be useful in
ferential. Viral infections, especially in the early stages, may diagnosing equine gastric ulcer syndrome.
be associated with a leukopenia and neutropenia. A decrease Diagnostic Imaging. Diagnostic imaging can be useful in
in the neutrophil-to-lymphocyte ratio has been associated the evaluation of horses with poor performance. Radiographs
with overtraining, although this is not a reliable correlation.739 and ultrasound are routinely used in the evaluation of muscu-
Changes in the hormonal response to exercise have been re- loskeletal problems. In some cases, additional imaging tech-
ported with overtraining, primarily a decrease in cortisol.740 niques may be indicated such as nuclear scintigraphy, ther-
Horses at rest normally maintain a significant proportion of mography, CT, or MRI.
red blood cells and hemoglobin in the splenic reserve.737,738,741 Radiographs and ultrasound can also be helpful in evalu-
Although total body hemoglobin increases in response to ation of the respiratory tract. Thoracic ultrasound and radio-
training and may correlate with performance, this cannot be graphs are often used in the evaluation of lower respiratory
determined from a resting sample. Special techniques must tract disease but may be normal in conditions commonly
be used to document total red cell mass or hemoglobin.741,792 associated with poor performance such as IAD. Radiographs
Anemia can decrease the oxygen-carrying capacity during of the upper airways can allow for the evaluation of soft tis-
exercise, resulting in suboptimal performance. sue masses or fluid accumulations. In addition, abnormalities
Signs of organ dysfunction in horses presented for poor of the pharyngeal and laryngeal structures such as thickening
performance are not common findings but are occasionally of the soft palate or hypoplasia of the epiglottis may be seen.
present. Much attention has been paid to the importance of Upper airway ultrasonography can also be helpful, particu-
electrolytes and exercise; however, abnormalities seldom are larly in the assessment of recurrent laryngeal neuropathy.747
found. In general, circulating electrolyte concentrations are The denervated laryngeal muscles are hyperechoic and more
regulated tightly and may not reflect closely the total body homogeneous than normal muscle. Other conditions that
electrolyte status.628 However, a concentration of potassium can be diagnosed by ultrasound include arytenoid chondritis,
consistently below 3 mEq/L may suggest a potassium deficit. laryngeal dysplasia, and congenital malformations of the lar-
Performing renal fractional excretion of electrolytes can help ynx. CT and MRI have also been used to evaluate the upper
in detecting chronic electrolyte deficiencies. airway.
Myopathy can lead to decreased performance, and muscle Echocardiography can be used in addition to electrocardi-
enzymes may be elevated, although many cases of myopathy ography for further assessment of the heart.698,748 In assessing
are subclinical and require evaluation of muscle enzymes after cardiac function, it is ideal to measure indices such as percent-
exercise.700,713 Creatine kinase is measured before exercise age fractional shortening and wall motion indices, both before
and ideally 4 to 6 hours after an exercise bout consisting of 15 and after exercise. It should be taken into account that there is
to 30 minutes at the trot. In normal horses this light exercise considerable normal variation in postexercise indices.749
rarely causes more than a threefold increase in creatine kinase. Exercise Testing. Exercise testing provides a mechanism
An increase of fivefold or more indicates exertional rhabdo- for evaluating a range of body systems under standard exercise
myolysis. Genetic testing, muscle biopsies, and measurement conditions.695,698,750,751 In particular, measurements of cardio-
of vitamin E and selenium can also be helpful in defining respiratory and metabolic function taken during an exercise
myopathies. test provide information about the capacity and efficiency
Myocardial disease may contribute to left ventricular dys- of key body systems involved in energy production. From a
function and arrhythmias. Elevations in myocardial fractions clinical standpoint exercise testing is generally most useful in
of creatine kinase, lactate dehydrogenase, and troponin sup- assessing the significance of abnormalities found on a physi-
port myocardial disease but are not present in all cases. cal examination; however, testing may also help to establish
Analysis of fluid from the lower airways is important in the the reason for reduced athletic capacity in horses that have no
diagnosis of lower airway disease. Although exact sampling abnormalities on basic examinations. Exercise testing can be
done in the field, which mimics the condition in which the Heart rate measurements are helpful in determining the
horse actually performs. However, most testing is currently actual significance of cardiac abnormalities such as murmurs
done on a treadmill, which provides more consistent condi- and arrhythmias. In horses with functional cardiac disease, the
tions and an opportunity to perform a greater range of mea- reduced stroke volume necessitates higher heart rates to main-
surements. The specific protocol used for exercise testing may tain adequate cardiac output. It should be taken into account
vary somewhat.695,698,750-752 Occasionally a high-speed test is that a high heart rate does not always indicate a cardiac prob-
performed in which the horse is accelerated rapidly to maxi- lem. For example, studies in Standardbred racehorses have
mal speed and run to fatigue. However, the most common type suggested that horses with musculoskeletal problems have an
of test is an incremental test in which the speed increases every increased V200 and that monitoring the V200 may help to iden-
1 to 2 minutes until the horse reaches fatigue, allowing for the tify subclinical lameness.
generation of data during submaximal and maximal exercise. Blood or Plasma Lactate Measurement. Exercising mus-
In most cases the test is performed with the treadmill at a slope cles produce lactate to some extent during all intensities of
of 10%. This slope is not so steep as to be completely unrep- exercise, but production increases exponentially with the in-
resentative of normal exercise, yet it ensures that maximum- tensity of exercise.756-758 As exercise becomes more intense,
intensity exercise can be performed without reaching speeds the aerobic energy contribution becomes insufficient to meet
that may be too fast for horse safety. Some parameters that can total energy requirements, and increased anaerobic metabo-
be assessed in an exercise test include heart rate, blood lactate lism results in increased lactate production. Lactate diffuses
level, arterial blood gases, total red cell volume, stride length, from muscle to blood, and therefore blood or plasma concen-
and oxygen uptake. Various spirometers, which are masks for trations of lactate reflect muscle lactate. Some evidence sug-
measuring pulmonary ventilation, can be used to measure pa- gests that whole blood concentrations most accurately mea-
rameters such as air flow rates, tidal volume, and the durations sure lactate accumulation because red blood cells actively take
of phases of the respiratory cycle.698 As previously discussed, up lactate.758-761
treadmill videoendoscopy is often valuable. The rate of increase of lactate in the blood may be used as
Heart Rate during Exercise. Evaluation of the heart rate an indirect indicator of cardiovascular and metabolic capacity.
during exercise provides an indirect index of cardiovascular Horses with the highest aerobic capacities because of a high
capacity and function. Several heart rate monitors are avail- maximal cardiac output tend to have lower lactate values at
able.753 Radiotelemetry also can be used to evaluate the heart submaximal exercise intensities than those with lower aerobic
rate and rhythm, particularly at the end of exercise. Because capacities. Lactate values can be used to compare horses or to
the stroke volume does not change greatly with increasing evaluate training in the same horse. The treadmill speed at which
exercise speed, the heart rate provides a guide to changes in a plasma lactate of 4 mmol/L (VLA4) is reached is one measure of
cardiac output. In general, a linear increase in heart rate oc- lactate production, and a high value reflects good aerobic capac-
curs with increasing exercise speed up to the point at which ity. The VLA4 has been used to monitor changes in fitness. In fit
the maximal heart rate is reached.752,754-756 The maximal heart Thoroughbred horses 3 years of age and older, values for VLA4
rate (HRmax) is identified when no further increase in heart range from 8.0 to 9.5 m/sec. Horses that are not fit or that have
rate occurs despite an increase in exercise speed. The HRmax respiratory disease have lower values. Another useful reference
does not change with training state, although the speed at is the blood or plasma lactate at conclusion of the 10-m/sec exer-
which it is reached increases with increasing fitness. cise step of the incremental test, and highly fit, athletic horses
One reference point for comparison of cardiovascular usually have values below 5 mmol/L. High-quality sprint horses,
capacity is the treadmill speed at a heart rate of 200 beats per which perform largely under anaerobic conditions and have a
minute (V200). At a heart rate of 200 beats per minute, most high anaerobic capacity, may have high peak lactate values.
horses are close to the point of onset of blood lactate accu- Oxygen Uptake. The measurement of oxygen uptake
mulation. The V200 can be calculated by linear regression (VO2) is critical to assessing athletic performance.754,755 The
analysis or plotted using measurements taken at three to four VO2max has been used as a key indicator of exercise capacity
submaximal exercise speeds, without the horse reaching maxi- in human athletes since the 1950s. As the VO2 increases lin-
mal exercise. The clinician should take care when using the early with increasing treadmill speed, VO2max can be identified
V200 to assess exercise capacity because at a heart rate of 200 when VO2 reaches a plateau despite an increase in speed. The
beats per minute, horses may be exercising at different pro- Thoroughbred horse has VO2max values that are higher than
portions of their HRmax and therefore their maximal oxygen those of many other mammalian species when expressed on a
uptake (VO2max). In general, however, horses with the highest mass-specific basis. The major factor responsible for the high
cardiovascular and metabolic capacities have the highest V200 VO2max in athletic horses is their high oxygen-carrying capac-
values; that is, the better horses reach a heart rate of 200 beats ity, which arises from a high maximum stroke volume and to
per minute at higher speeds than those with a lower exercise some extent a large arteriovenous oxygen content difference.
capacity. The V200 increases with training and can be useful The VO2max is a good index of changes in fitness and a mea-
for monitoring changes in fitness. The better quality Thor- surement of exercise capacity in performance horses.
oughbreds have a V200 of 8 to 9 m/sec in an exercise test with Maximum Oxygen Pulse. The oxygen pulse is defined
the treadmill set at a 10% slope. Values less than 7 m/sec are as the VO2/heart rate and is expressed as mL/kg/beat. This
abnormal and if found in a fit horse indicate decreased cardiac value provides an indication of the maximum stroke volume,
capacity. and in high-quality horses values range from 0.66 to 0.76
Another measurement of cardiovascular capacity is the mL/kg/beat. Those horses with cardiac problems resulting in
treadmill speed at which the horse reaches HRmax, known as low cardiac outputs and individuals with low VO2max values
VHRmax. This value correlates with VO2max and exercise capac- usually have values in the range of 0.5 to 0.56 mL/kg/beat.
ity but requires the horse to exercise up to maximal speeds so The maximum oxygen pulse also has been shown to correlate
that a plateau in heart rate can be identified. with treadmill total run time.
Arterial Blood Gas Analysis during Exercise. Arterial blood 5. Guthrie AJ, Lund RJ. Thermoregulation: base mechanisms and
gas analysis during exercise may be indicated, especially in hyperthermia. Vet Clin North Am Equine Pract. 1998;14:45.
horses in which respiratory disorders are the suspected cause 6. Marlin DJ, Schroter RC, White SL, et al. Recovery from trans-
of poor performance. For an accurate blood gas analysis, the port and acclimatisation of competition horses in a hot humid
environment. Equine Vet J. 2001;33:371.
clinician should take into account the temperature of the
7. Holcomb KE, Tucker CB, Stull CL. Preference of domes-
blood because it may reach 42°C during maximal exercise. tic horses for shade in a hot, sunny environment. J Anim Sci.
At exercise intensities above 65% VO2max, athletic horses be- 2014;92:1708.
come hypoxemic, although the extent varies among individu- 8. Holcomb KE, Stull CL. Effect of time and weather on prefer-
als.762-765 Horses with low VO2max values do not necessarily ence, frequency and duration of shade use by horses. J Anim Sci.
have a significant decrease in arterial oxygen tension. 2016;94:1653.
Additional Pulmonary Function Evaluation. Assessment 9. Jorgensen GH, Aanensen L, Mejdell CM, et al. Preference for
of pulmonary ventilation can be facilitated by measurements shelter and additional heat in horses exposed to Nordic win-
of respiratory resistance, air flow rates, tidal volume, and the ter conditions. Equine Vet J. 2015. http://dx.doi.org/10.1111/
durations of phases of the respiratory cycle. Tests can be per- evj.12522.
10. Stachurska A, Robovsky J, Bocian K, et al. Changes of coat cover
formed during and after exercise. This testing generally re-
in primitive horses living on a reserve. J Anim Sci. 2015;93:1411.
quires specialized equipment such as spirometers and ergo- 11. Brinkmann L, Gerken M, Hambly C, et al. Saving energy during
spirometers, which may become more widely available for use. hard times: energetic adaptations of Shetland pony mares. Exp
Hematocrit and Total Red Cell Volume during Exercise. The Biol. 2014;217(Pt 24):4320.
total volume of red cells is a major determinant of oxygen-car- 12. Geor RJ, McCutcheon LJ, Ecker GL, et al. Heat storage in horses
rying capacity, and therefore measurement of red cell volume during submaximal exercise before and after humid heat accli-
can give some index of exercise capacity. A postexercise packed mation. J Appl Physiol. 2000;89:2283.
cell volume test is not a reliable indicator of total red cell vol- 13. Geor RJ, McCutcheon LJ. Thermoregulatory adaptations asso-
ume primarily because of plasma volume variations, but it does ciated with training and heat acclimation. Vet Clin North Am
provide a rough estimate of total circulating red cells. Equine Pract. 1998;14:97.
14. McKeever KH, Eaton TL, Geiser S, et al. Age related decreases
The clinician can make an accurate determination of red
in thermoregulation and cardiovascular function in horses.
cell volume by techniques that use dye dilution after mobili- Equine Vet J Suppl. 2010;38:220.
zation of the splenic erythrocyte pool to measure the plasma 15. Lindinger MI. Exercise in the heat: thermoregulatory limita-
volume. Although total red cell volume increases with train- tions to performance in humans and horses. Can J Appl Physiol.
ing, some evidence indicates that Standardbred racehorses 1999;24:152.
with overtraining syndrome may develop an abnormal red cell 16. Mayhew IG, Ferguson HO. Clinical, clinicopathological, and
hypervolemia that contributes to poor performance.792 epidemiological features of anhidrosis in central Florida Thor-
Peak Running Speed and Total Run Time. The peak tread- oughbred horses. J Vet Intern Med. 1987;1:136.
mill running speed and the total run time may indicate ex- 17. McEwan Jenkinson D, Elder HY, Bovell DL. Equine sweat-
ercise capacity. In some studies of human athletes, the peak ing and anhidrosis part 1—equine sweating. Vet Dermatol.
2006;17:361.
treadmill running speed during an exercise test was shown to
18. McEwan Jenkinson D, Elder HY, Bovell DL. Equine sweating
be a predictor of performance. Athletic Thoroughbred race- and anhidrosis part 2: anhidrosis. Vet Dermatol. 2007;18:2.
horses can complete 60 seconds at 13 m/sec during an incre- 19. Johnson EB, MacKay RJ, Hernandez JA. An epidemiologic
mental exercise test at a 10% slope. study of anhidrosis in horses in Florida. J Am Vet Med Assoc.
Stride Length. Athletic horses are thought to have better 2010;236:1091.
stride characteristics.701,766 Some studies have shown a cor- 20. Fujii J, Otsu K, Zorzato F, et al. Identification of a mutation in
relation between maximum stride length and the treadmill porcine ryanodine receptor associated with malignant hyper-
run time. An accelerometric device has been used to provide thermia. Science. 1991;253:448.
quantitative information about locomotor variables that may 21. Manley SV, Kelly AB, Hodgson D. Malignant hyperthermia-
be useful in evaluating performance.766 like reactions in three anesthetized horses. J Am Vet Med Assoc.
1983;183:85.
It is important to remember that although exercise testing
22. Smyth GB. Spinal cord decompression and stabilization of a com-
can be useful in the evaluation of poor performance, a diag- minuted axis fracture complicated by intraoperative malignant
nosis usually cannot be made based on a single measurement. hyperthermia-like reaction in a filly. Aust Equine Vet. 1992;10:133.
An integrative approach taking into account the history, clini- 23. Aleman M, Nieto JE, Magdesian KG. Malignant hyperthermia
cal findings, and all ancillary diagnostic testing is generally associated with ryanodine receptor 1 (C7360G) mutation in
required. Quarter Horses. J Vet Intern Med. 2009;23:329.
24. McCue ME, Valberg SJ, Jackson M, et al. Polysaccharide storage
REFERENCES myopathy phenotype in quarter horse-related breeds is modi-
fied by the presence of an RYR1 mutation. Neuromuscul Disord.
1. Klein BG. Thermoregulation. In: Klein BG, ed. Cunningham’s 2009;19:37.
textbook of veterinary physiology. 5th ed. St. Louis: Elsevier; 25. Agrawal A, Timothy J, Thapa A. Neurogenic fever. Singapore
2012. Med. 2007;48:492.
2. Koterba AM. Physical examination, neonatal infection. In: 26. Cuddy ML. The effects of drugs on thermoregulation. AACN
Koterba AM, Drummond WH, Kosch PC, eds. Equine clinical Clin Issues. 2004;15:238.
neonatology. Philadelphia: Lea and Febiger; 1990. 27. Exon JH. A review of chlorinated phenols. Vet Hum Toxicol.
3. Dinarello CA. Thermoregulation and the pathogenesis of fever. 1984;26:508.
Infect Dis Clin North Am. 1996;10:433. 28. Stratton-Phelps M, Wilson WD, Gardner IA. Risk of adverse
4. Guyton AC, Hall JE. Body temperature, temperature regula- effects in pneumonic foals treated with erythromycin versus
tion, and fever. In: Guyton AC, Hall JE, eds. Textbook of medical other antibiotics: 143 cases (1986–1996). J Am Vet Med Assoc.
physiology. 11th ed. Philadelphia: Elsevier/Saunders; 2006. 2000;68:217.
29. Stieler AL, Sanchez LC, Mallicote MF, et al. Macrolide-induced 55. Jiang Q, Cross AS, Singh IS, et al. Febrile core temperature is
hyperthermia in foals: role of impaired sweat responses. Equine essential for optimal host defense in bacterial peritonitis. Infect
Vet J. 2015. http://dx.doi.org/10.1111/evj.12481. Immun. 2000;68:1265.
30. Dinarello CA. Infection, fever, and exogenous and endoge- 56. Weinstein MP, Iannini PB, Stratton CW, Eickhoff TC. Sponta-
nous pyrogens: some concepts have changed. J Endotoxin Res. neous bacterial peritonitis: a review of 28 cases with emphasis
2004;10:201. on improved survival and factors influencing prognosis. Am J
31. Kozak W, Kluger MJ, Tesfaigzi J, et al. Molecular mecha- Med. 1978;64:592.
nisms of fever and endogenous antipyresis. Ann N Y Acad Sci. 57. Banet M. Fever and survival in the rat: the effect of enhancing
2000;917:121. fever. Pflugers Arch. 1979;381:35.
32. Dinarello CA. Cytokines as endogenous pyrogens. J Infect Dis. 58. Launey Y, Nesseler N, Malledant, et al. Clinical review: fever
1999;179(suppl 2):S294. in septic ICU patients—friend or foe? Critical Care. 2011;15:222.
33. Luheshi GN. Cytokines and fever: mechanisms and sites of action. 59. Grieger TA, Kluger MJ. Fever and survival: the role of serum
Ann N Y Acad Sci. 1998;856:83. iron. J Physiol. 1978;279:187.
34. Ivanov AI, Romanovsky AA. Prostaglandin E2 as a mediator of 60. Kluger MJ, Rothenburg BA. Fever and reduced iron: their inter-
fever: synthesis and catabolism, Front Biosci. 1977;9:2004. action as a host defense response to bacterial infection. Science.
35. Simm B, Ott D, Pollatzek E, et al. Effects of prostaglandin E2 on 1979;203:374.
cells cultured from the rat organum vasculosum laminae termi- 61. Ballantyne GH. Rapid drop in serum iron concentrations as a
nalis and median preoptic nucleus. Neuroscience. 2016;28:313. host defense mechanism: a review of experimental and clinical
36. Rusyniak DE, Zaretsky DV, Zaretskaia, et al. The role of Orexin-1 evidence. Am Surg. 1984;50:405.
receptors in physiologic responses evoked by microinjection of 62. Mackowiak PA, Plaisacne KI. Benefits and risks of antipyretic
PgE2 or muscimol into the medial preoptic area. Neurosci Lett. therapy. Ann N Y Acad Sci. 1998;856:214.
2011;498:162. 63. Kluger MJ, Vaughn LK. Fever and survival in rabbits infected
37. Kozak W, Fraifeld V. Non-prostaglandin eicosanoids in fever with Pasteurella multocida. J Physiol. 1978;282:243.
and anapyrexia. Front Biosci. 2004;9:3339. 64. Laupland KB. Fever in the critically ill medical patient. Crit
38. Roth J, Blatteis CM. Mechanisms of fever production and lysis: Care Med. 2009;37:S273.
lessons learned from experimental LPS fever. Compr Physiol. 65. Circiumara B, Baldock G, Cohen J. A prospective study of fever
2014;4:1563. in the intensive care unit. Intensive Care Med. 1999;25:668.
39. Blatteis CM, Li S, Feleder C, et al. Cytokines, PGE2 and endo- 66. Mair TS, Taylor FG, Pinsent PJ. Fever of unknown origin in the
toxic fever: a re-assessment. Prostglandins Other Lipid Mediat. horse: a review of 63 cases. Equine Vet J. 1989;21:260.
2005;76:1. 67. MacKay RJ. Quantitative intradermal terbutaline sweat test in
40. Evans SS, Repasky EA, Fisher DT. Fever and the thermal regu- horses. Equine Vet J. 2008;40:518.
lation of immunity: the immune system feels the heat. Nature 68. Sheoran AS, Sponseller BT, Holmes N, et al. Serum and mu-
Reviews Immunol. 2015;15:335. cosal antibody isotype responses to M-like protein (SeM) of
41. Still JT. Evidence for the involvement of the organum vasculo- Streptococcus equi in convalescent and vaccinated horses. Vet
sum laminae terminalis in the febrile response of rabbits and Immunol Immunopathol. 1997;59:239.
rats. J Physiol. 1985;368:501. 69. Leon LR. Hypothermia in systemic inflammation: role of cy-
42. Blatteis CM, Bealer SL, Hunter WS, et al. Suppression of fever tokines. Front Biosci. 1877;9:2004.
after lesions of the anteroventral third ventricle in guinea pigs. 70. Irvine CH. Hypothyroidism in the foal. Equine Vet J. 1984;16:302.
Brain Res Bull. 1983;11:519. 71. Murray MJ. Hypothyroidism and respiratory insufficiency in a
43. Plaisacne KI, Mackowiak PA. Antipyretic therapy: physiologic neonatal foal. J Am Vet Med Assoc. 1990;197:1635.
rationale, diagnostic implications and clinical consequences. 72. Stephen JO, Baptiste KE, Townsend HG. Clinical and patholog-
Arch Intern Med. 2000;160:449. ic findings in donkeys with hypothermia: 10 cases (1988–1998).
44. Aronoff DM, Neilson EG. Antipyretics: mechanisms of action J Am Vet Med Assoc. 2000;216(725).
and clinical use in fever suppression. Am J Med. 2001;111:304. 73. Guyton AC, Hall JE. Dietary balances; regulation of feeding;
45. Lazarus M. The differential role of prostaglandin E2 receptors EP3 obesity and starvation; vitamins and minerals. In: Guyton AC,
and EP4 in regulation of fever. Mol Nutr Food Res. 2006;50:451. Hall JE, eds. Textbook of medical physiology. 11th ed. Philadel-
46. Tatro JB. Endogenous antipyretics. Clin Infect Dis. 2000;5 phia: Elsevier/Saunders; 2006.
(suppl):S190. 74. Kronfeld DS. Starvation and malnutrition of horses: recogni-
47. Roth J. Endogenous antipyretics. Clinica Chimica Acta. tion and treatment. J Equine Vet Sci. 1993;13:298.
2006;371:13. 75. Robin CA, Ireland JL, Wylie CE, et al. Prevalence of and risk
48. Catania A, Lipton JM. Peptide modulation of fever and inflam- factors for equine obesity in Great Britain based on owner-
mation within the brain. Ann N Y Acad Sci. 1998;856:62. reported body condition scores. Equine Vet J. 2015;47:196.
49. Lipton JM, Catania A. Anti-inflammatory actions of the neuro- 76. Giles SL, Rands SA, Nicol CJ, et al. Obesity prevalence and asso-
immunomodulator alpha-MSH. Immunol Today. 1997;18:140. ciated risk factors in outdoor living domestic horses and ponies.
50. Steiner AA, Antunes-Rodrigues J, McCann SM, et al. Antipy- PeerJ. 2014;2:e299.
retic role of the NP-cGMP pathway in the anteroventral pre- 77. Ireland JL, Wylie CE, Collins SN, et al. Preventive health care
optic region of the rat brain. Am J Physiol Regul Integr Comp and owner-reported disease prevalence of horses and ponies in
Physiol. 2002;282:R584. Great Britain. Res Vet Sci. 2013;95:418.
51. Morimota A, Sakata Y, Watanabe N, et al. Charactistics of fever 78. Thatcher CD, Pleasant RS, Geor RJ, et al. Prevalence of over-
and acute-phase response induced in rabbits by IL-1 and TNF. conditioning in mature horses in southwest Virginia during the
Am J Physiol. 1989;256:R35. summer. J Vet Intern Med. 2012;26:1413.
52. Soszynski D. The pathogenesis and adaptive value of fever. 79. Johnson PJ. The equine metabolic syndrome peripheral
Postepy Hig Med Dosw. 2003;57:531. Cushing’s syndrome. Vet Clin North Am Equine Pract.
53. Repasky EA, Evans SS, Dewhirst MW. Temperature matters! 2002;18:271.
And why it should matter to tumor immunologists. Cancer Im- 80. Johnson PJ, Wiedmeyer CE, LaCarrubba A, et al. Diabetes, in-
munol Res. 2013;1:210. sulin resistance and metabolic syndrome in horses. J Diabetes
54. Lee CT, Zhong L, Mace TA, et al. Elevation in body temperature Sci Technol. 2012;6:534.
to fever range enhances and prolongs subsequent responsiveness 81. Frank N, Geor RJ, Bailey SR, et al. Equine metabolic syndrome.
of macrophages to endotoxin challenge. PLoS One. 2012;7:e30077. J Vet Intern Med. 2010;24:467.
82. Martinson KL, Coleman RC, Rendahl AK, et al. Estimation 105. Suagee JK, Corl BA, Geor RJ. A potential role for pro-inflam-
of body weight and development of a body weight score for matory cytokines in the development of insulin resistance in
adult equids using morphometric measurements. J Anim Sci. horses. Animals (Basel). 2012;2:243.
2014;92:2230. 106. Holbrook TC, Tipton T, McFarlane D. Neutrophil and cytokine
83. Carter RA, Geor RJ, Burton Staniar W, et al. Apparent adipos- dysregulation in hyperinsulinemic obese horses. Vet Immunol
ity assessed by standardized scoring systems and morphometric Immunopathol. 2012;145:283.
measurements in horses and ponies. Vet J. 2009;179:204. 107. Tadros EM, Frank N, Donnell RL. Effects of equine metabolic
84. Hallebeek JM. The body condition score in horses. Tijdschr syndrome on inflammatory responses of horses to intravenous
Diergeneeskd. 2014;139:30. lipopolysaccharide infusion. Am J Vet Res. 2013;74:1010.
85. Dugdale AH, Grove-White D, Curtis GC, et al. Body condition 108. Farr OM, Li CS, Mantzoros CS. Central nervous system regula-
scoring as a predictor of body fat in horses and ponies. Vet J. tion of eating: insight from human brain imaging. Metabolism.
2012;194. 2016;65:699.
86. Henneke DR, Potter GD, Kreider JL, et al. Relationship between 109. Morrison PK, Bing C, Harris PA, et al. Preliminary investigation
condition score, physical measurements and body fat percent- into a potential role for myostatin and its receptor (ActRIIB) in
age in mares. Equine Vet J. 1983;15:371. lean and obese horses and ponies. PLos One. 2014;9:e112621.
87. Mottet R, Onan G, Hiney K. Revisiting the Henneke body 110. Raoult D. Microbiota, obesity and malnutrition. Microb Pathog.
condition scoring system: 25 years later. J Equine Vet Sci. 2016. doi: 10.1016.
1983;29:417. 111. Shepherd ML, Ponder MA, Burk AO, et al. Fibre digestibility,
88. Carter RA, Treiber KH, Geor RJ, et al. Prediction of incipient abundance of faecal bacteria and plasma acetate concentrations
pasture-associated laminitis from hyperinsulinaemia, hyperlep- in overweight adult mares. J Nutr Sci. 2014;3:e10.
tinaemia and generalized and localized obesity in a cohort of 112. Patterson E, Ryan PM, Cryan JF, et al. Gut microbiota, obesity
ponies. Equine Vet J. 2009;41:171. and diabetes. Postgrad Med J. 2015. http://dx.doi.org/10.1136/
89. Giles SL, Nicol CJ, Rands SA, et al. Assessing the seasonal prev- ppostgrad medj.
alence and risk factors for nuchal crest adiposity in domestic 113. Treiber KH, Kronfeld DS, Hess TM, et al. Evaluation of genetic
horses and ponies using the cresty neck score. BMC Vet Res. and metabolic predispositions and nutritional risk factors for
2015;11:13. pasture-associated laminitis in ponies. J Am Vet Med Assoc.
90. Kearns CF, McKeever KH, Kumagai K, et al. Fat-free mass is 2006;228:1538.
related to one-mile race performance in elite Standardbred 114. Treiber KH, Kronfeld DS, Hess TM, et al. Use of proxies and
horses. Vet J. 2002;163:260. reference quintiles obtained from minimal model analysis for
91. Wyse CA, McNie KA, Tannahill VJ, et al: Prevalence of obesity determination of insulin sensitivity and pancreatic beta-cell re-
in riding horses in Scotland. 162:590, 2008. sponsiveness in horses. Am J Vet Res. 2005;66:2114.
92. Thatcher CD, Pleasant RS, Geor RJ, et al. Prevalence of obe- 115. Schott HC. Pituitary pars intermedia dysfunction: challeng-
sity in mature horses: an equine body condition study. J Anim es of diagnosis and treatment. Proc Am Assoc Equine Pract.
Physiol Anim Nutr. 2008;92:222. 2006;52:60.
93. Stephenson HM, Green MJ, Freeman SL. Prevalence of obesity 116. Beech J, Boston R, Lindborg S. Comparison of cortisol and
in a population of horses in the UK. Vet Rec. 2011;168:131. ACTH responses after administration of thyrotropin releasing
94. Johnson PJ, Wiedmeyer CE, Messer NT, et al. Medical implica- hormone in normal horses and those with pituitary pars inter-
tions of obesity in horses—lessons for human obesity. J Diabetes media dysfunction. J Vet Intern Med. 2011;25:1431.
Sci Technol. 2009;3:163. 117. Giles SL, Nicol CJ, Harris PA, et al. Dominance rank is asso-
95. Ertelt A, Barton AK, Schmitz RR, et al. Metabolic syndrome: is ciated with body condition in outdoor-living domestic horses
equine disease comparable to what we know in humans? Endocr (Equus caballus). Appl Anim Behav Sci. 2015;166:71.
Connect. 2014;3:R81. 118. Kiela PR, Ghishan FK. Physiology of intestinal absorption and
96. de Graaf-Roelfsema E. Glucose homeostasis and the enteroin- secretion. Best Pract Res Clin Gastroenterol. 2016;30:145.
sular axis in the horse: a possible role in equine metabolic syn- 119. Roberts MC. Malabsorption syndromes in the horse. Compend
drome. Vet J. 2014;199:11. Cont Educ Pract Vet. 1985;7:S637.
97. Frank N, Tadros EM. Insulin dysregulation. Equine Vet J. 120. Sloet van Oldruitenborgh-Oosterbaan MM. Lactose intoler-
2014;46:103. ance in foals. Equine Vet Educ. 2008;20:252.
98. Bamford NJ, Potter SJ, Harris PA, et al. Breed differences in 121. Laviano A, Inui A, Marks DL, et al. Neural control of the an-
insulin sensitivity and insulinemic responses to oral glucose in orexia-cachexia syndrome. Am J Physiol Endocrinol Metab.
horses and ponies of moderate body condition score. Domest 2008;295:E1000–E1008.
Anim Endocrinol. 2014;47:101. 122. Ramos EJ, Suzuki S, Marks D, et al. Cancer anorexia-cachexia
99. Fischer-Posovszky P, Wabitsch M, Hochberg Z. Endocrinology syndrome: cytokines and neuropeptides. Curr Opin Clin Nutr
of adipose tissue—an update. Horm Metab Res. 2007;39:314. Metab Care. 2004;7:427.
100. Radin MJ, Sharkey LC, Holycross BJ. Adipokines: a review of 123. Cymbaluk NE, Christison GI. Environmental effects on ther-
biological and analytical principles and an update in dogs, cats, moregulation and nutrition of horses. Vet Clin North Am Equine
and horses. Vet Clin Pathol. 2009;38:136. Pract. 1990;6:355.
101. Bamford NJ, Potter SJ, Harris PA, et al. Effect of increased adi- 124. Morgan K. Thermoneutral zone and critical temperatures of
posity on insulin sensitivity and adipokine concentrations in horses. J Thermal Biol. 1998;23:59.
horses and ponies fed a high fat diet, with or without a once daily 125. Ott EA. Influence of temperature stress on the energy and pro-
high glycaemic meal. Equine Vet J. 2015. doi: 10:111/evj.12434. tein metabolism and requirements of the working horse. Live-
102. Kearns CF, McKeever KH, Roegner V, et al. Adiponectin and stock Proc Sci. 2005;92:123.
leptin are related to fat mass in horses. Vet J. 2006;172:460. 126. Plank LD, Hill GL. Energy balance in critical illness. Proc Nutr
103. Pleasant RS, Suagee JK, Thatcher CD, et al. Adiposity, plasma Soc. 2003;62:545.
insulin, leptin, lipids, and oxidative stress in mature light breed 127. Jose-Cunilleras E, Viu J, Corradini I, et al. Energy expenditure
horses. J Vet Intern Med. 2013;27:576. of critically ill neonatal foals. Equine Vet J Suppl. 2012;41:48.
104. Suagee JK, Corl BA, Crisman MV, et al. Relationships between 128. Evans WJ, Morley JE, Argiles J, et al. Cachexia: a new definition.
body condition score and plasma inflammatory cytokines, insu- Clin Nutr. 2008;27:793.
lin, and lipids in a mixed population of light-breed horses. J Vet 129. Fearon K, Strasser F, Anker SD, et al. Definition and classifica-
Intern Med. 2013;27:157. tion of cancer cachexia. The Lancet. 2011;12:489.
130. Anker SD, Morleoy JE. Cachexia: a nutritional syndrome? J Ca- 156. Meredith TB, Dobrinski I. Thyroid function and pregnancy sta-
chexia Sarcopenia Muscle. 2015;6:269. tus in broodmares. J Am Vet Med Assoc. 2004;224:892.
131. Kir S, Komaba H, Garcia AP, et al. PTH/PTHrP receptor medi- 157. Breuhaus BA. Thyroid-stimulating hormone in adult euthyroid
ates cachexia in models of kidney failure and cancer. Cell Metab. and hypothyroid horses. J Vet Intern Med. 2002;16:109.
2015. http://dx.doi.org/10.1016/jcmet. 158. Morris DD, Garcia M. Thyroid-stimulating hormone response
132. Burfeind KG, Michaelis KA, Marks DL. The central role of hy- test in healthy horses, and effect of phenylbutazone on equine
pothalamic inflammation in the acute illness response and ca- thyroid hormones. Am J Vet Res. 1983;44:503.
chexia. Semin Cell Dev Biol. 2015. doi: 10:1016/jsemcbd. 159. Jacobs KA, Bolton JR. Effect of diet on the oral D-xylose absorp-
133. Yoshida T, Delafontaine P. Mechanisms of cachexia in chronic tion test in the horse. Am J Vet Res. 1856;43:1982.
disease states. Am J Med Sci. 2015;350:250. 160. Mair TS, Hillyer MH, Taylor FG, et al. Small intestinal malab-
134. Reid MB, Yi-Ping L. Tumor necrosis factor-α and muscle wast- sorption in the horse: an assessment of the specificity of the oral
ing: a cellular perspective. Respir Rec. 2001;2:269. glucose tolerance test. Equine Vet J. 1991;23:334.
135. Ramirez S, McClure JJ, Moore RM, et al. Hyperthyroidism asso- 161. Perrin C, Unterborn JN, Ambrosio CD, Hill NS. Pulmonary
ciated with a thyroid adenocarcinoma in a 21-year-old gelding. complications of chronic neuromuscular diseases and their
J Vet Intern Med. 1998;12:475. management. Muscle Nerve. 2004;29:5.
136. Frank N, Sojka J, Messer NT. Equine thyroid dysfunction. Vet 162. Schramm CM. Current concepts of respiratory complica-
Clin North Am Equine Pract. 2002;18:305. tions of neuromuscular disease in children. Curr Opin Pediatr.
137. Rygiel KA, Piccard M, Turnbull DM. The ageing neuromuscular 2000;12:203.
system and sarcopenia—a mitochondrial perspective. J Physiol. 163. Niimi A, Matsumoto H, Ueda T, et al. Impaired cough reflex in
2016. doi: 10.1113. patients with recurrent pneumonia. Thorax. 2003;58:152.
138. Lehnhard KA, McKeever KH, Kearns CF, et al. Myosin heavy 164. Irwin RS, Curley FJ, French CL. Chronic cough. The spectrum
chain profiles and body composition are different in old versus and frequency of causes, key components of the diagnostic
young Standardbred mares. Vet J. 2004;167:59. evaluation, and outcome of specific therapy. Am Rev Respir Dis.
139. Kim J, Hinchcliff KW, Yamaguchi M, et al. Age-related changes 1990;141:640.
in metabolic properties of equine skeletal muscle associated 165. Irwin RS, Baumann MH, Bolser DC, et al. Diagnosis and man-
with muscle plasticity. Vet J. 2005;169:397. agement of cough executive summary: ACCP evidence-based
140. Aleman M, Watson JK, Williams DC, et al. Myopathy in horses clinical practice guidelines. Chest. 2006;129:1S.
with pituitary pars intermedia dysfunction (Cushing’s disease). 166. Schappert SM, Burt CW. Ambulatory care visits to physicians’
Neuromusc Disord. 2006;16:737. offices, hospital outpatient departments, and emergency de-
141. Metcalfe LVA, More SJ, Duggan V, et al. A retrospective study partments: United States, 2001–02. Vital Health Stat. 2006;13:1.
of horses investigated for weight loss despite a good appetite 167. Canning BJ. The cough reflex in animals: relevance to human
(2002–2011). Equine Vet J. 2013;45:340. cough research. Lung. 2008;186:S23.
142. Schumacher J, Edwards JF, Cohen ND. Chronic inflammatory 168. Chang AB, Widdicombe JG. Cough throughout life: children,
bowel diseases of the horse. J Vet Intern Med. 2000;14:258. adults and the senile. Pulm Pharmacol Ther. 2007;20:371.
143. Traub JL, Bayly WM, Reed SM, et al. Intra-abdominal neoplasia 169. Chang AB. Pediatric cough: children are not miniature adults.
as a cause of chronic weight loss in the horse. Compend Cont Lung. 2010;1:S33.
Educ Pract Vet. 1983;5:S526. 170. Fujjimura M, Sakamoto S, Kamio Y, et al. Female gender as a
144. Rumbaugh GE, Smith BP, Carlson GP. Internal abdominal ab- determinant of cough threshold to inhaled capsaicin. Eur Resp
scesses in the horse: a study of 25 cases. J Am Vet Med Assoc. J. 1996;9:1624.
1978;172:304. 171. Kavlcikova-Bogdanova N, Buday T, Plevkova J, Song WJ. Chron-
145. Foreman JH, Weidner JP, Parry BA, et al. Pleural effusion sec- ic cough as a female gender issue. Adv Exp Med Biol. 2016;905:69.
ondary to thoracic metastatic mammary adenocarcinoma in a 172. Morice AH. Chronic cough hypersensitivity syndrome. Cough.
mare. J Am Vet Med Assoc. 1990;197:1193. 2013;9:14.
146. McGorum BC, Murphy D, Love S, et al. Clinicopathological 173. Chang AB. The physiology of cough. Paed Resp Rev. 2006;7:2.
features of equine primary hepatic disease: a review of 50 cases. 174. McCool FD. Global physiology and pathophysiology of cough.
Vet Rec. 1999;145:134. Chest. 2006;129:48S.
147. Moore BR, Abood AS, Hinchcliff KW. Hyperlipemia in 9 175. Robinson NE. Pathophysiology of coughing. Proceedings of the
miniature horses and miniature donkeys. J Vet Intern Med. thirty-second convention of the American Association of Equine
1994;8:376. Practitioners. Nashville. 1986;291.
148. West HJ. Clinical and pathological studies in horses with he- 176. Canning BJ, Chang AB, Bolser DC, et al. Anatomy and neuro-
patic disease. Equine Vet J. 1996;28:146. physiology of cough: CHEST guideline and expert panel report.
149. McLeland S. Diseases of the equine urinary system. Vet Clin Chest. 2014;146:1633.
North Am Equine Pract. 2015;31:377. 177. Canning BJ. Encoding of the cough reflex. Pulm Pharmacol
150. Tan RH, Davies SE, Crisman MV, et al. Propylthiouracil for Ther. 2007;20:396.
treatment of hyperthyroidism in a horse. J Vet Intern Med. 178. Polverino M, Polverino F, Fasolino, et al. Anatomy and neuro-
2008;22:1253. pathophysiology of the cough reflex arc. Multidisciplinary Resp
151. Alberts MK, McCann JP, Woods PR. Hemithyroidectomy in a Med. 2012;7:5.
horse with confirmed hyperthyroidism. J Am Vet Med Assoc. 179. Canning BJ. Anatomy and neurophysiology of the cough re-
2000;217:1051. flex: ACCP evidence-based clinical practice guidelines. Chest.
152. Johnson PJ, Scotty NC, Wiedmeyer C, et al. Diabetes melli- 2006;129:33S.
tus in a domesticated Spanish Mustang. J Am Vet Med Assoc. 180. Canning BJ, Mori N, Mazzone SB. Vagal afferent nerves regulat-
2005;226:584. ing the cough reflex. Respir Physiol Neurobiol. 2006;152:223.
153. Clabough DL. Equine infectious anemia: the clinical signs, trans- 181. Mazzone SB. An overview of the sensory receptors regulating
mission, and diagnostic procedures. Vet Med. 1990;85:1007. cough. Cough. 2005;1:2.
154. Divers TJ, Mohammed HO, Hintz HF, et al. Equine motor neu- 182. Bloustine S, Langston L, Miller T. Ear-cough (Arnold’s) reflex.
ron disease: a review of clinical and experimental studies. Clin Ann Otol Rhinol Laryngol. 1976;85:496.
Techniques Equine Pract. 2006;5:24. 183. Zholos AV. TRP channels in respiratory pathophysiology: the
155. Lewis SS, Valberg SJ, Nielsen IL. Suspected immune-mediated role of oxidative, chemical irritant and temperature stimuli.
myositis in horses. J Vet Intern Med. 2007;21:495. Curr Neuropharmacol. 2015;13:279.
184. Geppetti P, Patacchini R, Nassini R, et al. Cough: the emerging 214. Marsh PS. Fire and smoke inhalation injury in horses. Vet Clin
role of the TRPA1 channel. Lung. 2010;1:S63. North Am Equine Pract. 2007;23:19.
185. Taylor-Clark TE. Role of reactive oxygen species and TRP chan- 215. Couetil LL, Hoffman AM, Hodgson J, et al. Inflammatory air-
nels in the cough reflex. Cell Calcium. 2016. doi.org/10.1016. way disease of horses. J Am Vet Intern Med. 2007;21:356.
186. Bonvini SJ, Birrell MA, Smith JA, Belvisi MG. Targeting TRP 216. Couetil LL, Cardwell JM, Gerber V, et al. Inflammatory airway
channels for chronic cough: from bench to bedside. Naunyn disease of horses—revised consensus statement. J Vet Intern
Schmiedebergs Arch Pharmacol. 2015;388:401. Med. 2016;30:503.
187. Grace MS, Dubuis E, Birrell MA, Belvisi MG. TRP channel an- 217. Mazan MR. Update on noninfectious inflammatory diseases of
tagonists as potential antitussives. Lung. 2012;190:11. the lower airway. Vet Clin North Am Equine Pract. 2015;31:159.
188. Lee LY, Kwong K, Lin YS, et al. Hypersensitivity of bronchopul- 218. Pirie RS. Recurrent airway obstruction: a review. Equine Vet J.
monary C-fibers induced by airway mucosal inflammation: cel- 2014;46:276.
lular mechanisms. Pulm Pharmacol Ther. 2002;15:199. 219. Ireland JL, Christley RM, McGowan CM, et al. Prevalence of
189. Canning BJ. Interactions between vagal afferent nerve subtypes and risk factors for recurrent airway obstruction in geriatric
mediating cough. Pulm Pharmacol Ther. 2002;15:187. horses and ponies. Equine Vet J. 2015;47:25.
190. Karlsson JA, Sant’Ambrogio G, Widdicombe J. Afferent neu- 220. Hotchkiss JW, Reid SW, Christley RM. A survey of horse owners
ronal pathways in cough and reflex bronchoconstriction. J Appl in Great Britain regarding horses in their care. Part 2: risk factors
Physiol. 1988;65:1007. for recurrent airway obstruction. Equine Vet J. 2007;39:301.
191. Pounsford J. Cough and bronchoconstriction. Bull Eur Physi- 221. Gerber V, Swinburne JE, Blott SE, et al. Genetics of recur-
opathol Respir. 1987;23(S10):37s. rent airway obstruction (RAO). Dtsch Tierarztl Wochenschr.
192. Pantaleo T, Bongianni F, Mutolo D. Central nervous mecha- 2008;115:271.
nisms of cough. Pulm Pharmacol Ther. 2002;15:227. 222. Gerber V, Tessier C, Marti E. Genetics of upper and lower air-
193. Haji A, Kimura S, Ohi Y. A model of the central regulatory sys- way diseases in the horse. Equine Vet J. 2015;47:390.
tem for cough reflex. Biol Pharm Bull. 2013;36:501. 223. Schwartz LW, Knight HD, Whittig LD, et al. Silicate pneumo-
194. Shannon R, Baekey DM, Morris KF, et al. Production of reflex coniosis and pulmonary fibrosis in horses from the Monterey-
cough by brainstem respiratory networks. Pulm Pharmacol Carmel peninsula. Chest. 1981;80:82.
Ther. 2004;17:369. 224. Lyons ET, Tolliver SC, Drudge JH, et al. Lungworms (Dictyo-
195. Canning BJ. Central regulation of the cough reflex: therapeutic caulus arnfeldi): prevalence in live equids in Kentucky. Am J Vet
implications. Pulm Pharmacol Ther. 2009;22:75. Res. 1985;46:921.
196. Allain H, Bentue-Ferrer D, Daval G, et al. Mechanisms of 225. Goetz TE. Dictyocaulus arnfeldi as a possible cause of chronic
chronic cough pathophysiology. Rev Mal Respir. 2004;21:763. cough in 14 horses. Equine Pract. 1984;6:33.
197. Foster WM. Mucociliary transport and cough in humans. Pulm 226. Bell SA, Drew CP, Wilson WD, Pusterla N. Idiopathic chron-
Pharmacol Ther. 2002;15:277. ic eosinophilic pneumonia in 7 horses. J Vet Intern Med.
198. Rubin BK. Secretion properties, clearance and therapy in airway 2008;22:648.
disease. Transl Respir Med. 2014;2:6. 227. Hinchcliff KW, Couetil LL, Knight PK, et al. Exercise induced
199. Irwin RS. Complications of cough: Evidence-based clinical pulmonary hemorrhage in horses: American College of Veteri-
practice guidelines. Chest. 2006;129:55S. nary Internal Medicine consensus statement. J Am Vet Intern
200. Johansson AM, Gardner SY, Atkins CE, et al. Cardiovascular Med. 2015;29:743.
effects of acute pulmonary obstruction in horses with recurrent 228. Leguillette R, Steinmann M, Bond SL, Stanton B. Tracheobron-
airway obstruction. J Vet Intern Med. 2007;21:302. choscopic assessment of exercise-induced pulmonary hemor-
201. Dicpinigaitis PV, Lim L, Farmakidis C. Cough syncope. Respir rhage and airway inflammation in barrel racing horses. J Vet
Med. 2014;108:244. Intern Med. doi:10.1111/jvim. 2016;13959.
202. Nelson RW, Couto CG, eds. Essentials of small animal internal 229. Davis JL, Gardner SY, Schwabenton B, et al. Congestive heart
medicine. 2nd ed. St. Louis: Mosby; 1992. failure in horses: 14 cases (1984–2001). J Am Vet Med Assoc.
203. Clayton H, Murphy J. The coughing horse. In Practice. 1980;2:25. 2002;220:1512.
204. Gilkerson JR, Bailey KE, Diaz-Mendez A, Hartley CA. Update 230. Leroux AA, Detilleux J, Sandersen CF, et al. Prevalence and risk
on viral diseases of the equine respiratory tract. Vet Clin North factors for cardiac diseases in a hospital-based population of
Am Equine Pract. 2015;31:91. 3,434 horses (1994–2011). J Vet Intern Med. 2013;27:1563.
205. Ma G, Azab W, Osterrieder N. Equine herpes viruses type 1 231. Auer DE, Wilson RG, Groenendyk S. Pharyngeal lymphoid hy-
(EHV-1) and 4 (EHV-4)—masters of co-evolution and a con- perplasia in Thoroughbred racehorses in training. Aust Vet J.
stant threat to equids and beyond. Vet Microbiol. 2013;167:123. 1985;62:124.
206. Reuss SM, Giguere S. Update on bacterial pneumonia and pleu- 232. Christley RM, Hodgson DR, Rose RJ, et al. Coughing in Thor-
ropneumonia in the adult horse. Vet Clin North Am Equine oughbred racehorses: risk factors and tracheal endoscopic and
Pract. 2015;31:105. cytological findings. Vet Rec. 2001;148:99.
207. Reuss SM, Cohen ND. Update on bacterial pneumonia in the 233. Aleman M, Nieto JE, Benak J, et al: Tracheal collapse in Ameri-
foal and weanling. Vet Clin North Am Equine Pract. 2015;31:121. can Miniature Horses: 13 cases (1985–2007). 2008;233:1302.
208. Ogilvie TH, Rosendal S, Blackwell TE, et al. Mycoplasma 234. Tetens J, Hubert JD, Eddy AL, et al. Dynamic tracheal collapse
felis as a cause of pleuritis in horses. J Am Vet Med Assoc. as a cause of exercise intolerance in a Thoroughbred. J Am Vet
1983;192:1374. Med Assoc. 2000;216:722.
209. Stewart AJ, Cuming RS. Update on fungal respiratory disease in 235. Fenger CK, Kohn CW. Tracheal obstruction from tracheal col-
horses. Vet Clin North Am Equine Pract. 2015;31:43. lapse associated with pneumonia in a horse. J Am Vet Med As-
210. Cafarchia C, Figueredo LA, Otranto D. Fungal diseases of soc. 1992;200:1698.
horses. Vet Microbiol. 2013;167:215. 236. Bakos Z, Voros K, Kellokoski H, Reiczigel J. Comparison of the
211. Wilkins PA, Lascola KM. Update on interstitial pneumonia. Vet caudal lung borders determined by percussion and ultrasonog-
Clin North Am Equine Pract. 2015;31:137. raphy in horses with recurrent airway obstruction. Acta Vet
212. Williams KJ, Maes R, Del Piero F, et al. Equine multinodular Hung. 2003;51:249.
pulmonary fibrosis: a newly recognized herpesvirus-associated 237. Kusano K, Hobo S, Ode H, Ishikawa Y. Tracheal endoscopic
fibrotic lung disease. Vet Pathol. 2007;44:849. and cytologic findings and blood examination results in Thor-
213. Scarrett WK, Crisman MV. Neoplasia of the respiratory tract. oughbred racehorses suspected to have lower respiratory tract
Vet Clin North Am Equine Pract. 1998;14:451. disease. J Equine Sci. 2008;19:97.
238. Richard EA, Pitel PH, Christmann U, et al. Serum concentra- 258. Mazan MR, Deveney EF, DeWitt S, et al. Energetic cost of
tion of surfactant protein D in horses with lower airway inflam- breathing, body composition, and pulmonary function in h orses
mation. Equine Vet J. 2012;44:277. with recurrent airway obstruction. J Appl Physiol. 2004;97:91.
239. Wagner B, Ainsworth DM, Freer H. Analysis of soluble CD14 259. Beech J, ed. Equine respiratory disorders. Philadelphia: Lea &
and its use as a biomarker in neonatal foals with septicemia and Febiger; 1991.
horses with recurrent airway obstruction. Vet Immunol Immu- 260. Garcia AJ, Zanella S, Koch H, et al. Chapter 3—networks within
nopathol. 2013;155:124. networks: the neuronal control of breathing. Prog Brain Res.
240. Hoffman AM, Viel L. Techniques for sampling the respiratory 2011;188:31.
tract of horses. Vet Clin North Am Equine Pract. 1997;13:463. 261. Dempsey JA, Smith CA. Pathophysiology of human ventilatory
241. Hoffman AM. Bronchoalveolar lavage: sampling technique and control. Eur Respir J. 2014;44:495.
guidelines for cytologic preparation and interpretation. Vet Clin 262. McCrimmon DR, Ramirez JM, Alford S, Zuperku EJ. Unrave-
North Am Equine Pract. 2008;24:423. ling the mechanism for respiratory rhythm generation. Bioes-
242. Wysocka B, Klusinski W. Cytological evaluation of tracheal assays. 2000;22:6.
pirate and broncho-alveolar lavage fluid in comparison to en- 263. Widdicombe J. Reflexes from the lungs and airways: historical
doscopic assessment of lower airways in horses with recurrent perspective. J Appl Physiol. 2006;102:268.
airways obstruction or inflammatory airway disease. Pol J Vet 264. Widdicombe J. Functional morphology and physiology of pul-
Sci. 2015;18:587. monary rapidly reacting receptors (RARs). Anat Rec A Discov
243. Sweeney CR, Sweeney RW, Benson CE. Comparison of bacteria Mol Cell Evol Biol. 2003;270:2.
isolated from specimens obtained by use of endoscopic guard- 265. Ainsworth DM, Ducharme NG, Hackett RP. Regulation of
ed tracheal swabbing and percutaneous tracheal aspiration in equine respiratory muscles during acute hypoxia and hypercap-
horses. J Am Vet Med Assoc. 1989;195:1225. nia. Am Rev Respir Dis. 1993;147:A700.
244. Moore BR, Dradowka S, Robertson JT, et al. Cytologic evalu- 266. Muir WW, Moore CA, Hamlin RL. Ventilatory alterations in
ation of bronchoalveolar lavage fluid obtained from Standard- normal horses in response to changes in inspired oxygen and
bred racehorses with inflammatory airway disease. Am J Vet carbon dioxide. Am J Vet Res. 1975;36:155.
Res. 1995;56:562. 267. Derksen FJ, Robinson NE, Slocombe RF. Ovalbumin induced
245. Rossier Y, Sweeney CR, Ziemer EL. Bronchoalveolar lavage allergic lung disease in the pony: role of vagal mechanisms. J
fluid cytologic findings in horses with pneumonia or pleuro- Appl Physiol. 1982;53:719.
pneumonia. J Am Vet Med Assoc. 1991;198:1001. 268. Derksen F, Robinson N, Slocombe R. 3-Methylindole-induced
246. Hewson J, Arroyo LG. Respiratory disease: diagnostic ap- pulmonary toxicosis in ponies. Am J Vet Res. 1982;43:603.
proaches in the horse. Vet Clin North Am Equine Pract. 2015; 269. Derksen FJ, Robinson NE, Stick JA. Technique for reversible
31:307. vagal blockade in the standing conscious pony. Am J Vet Res.
247. Gerber V, Straub R, Marti E, et al. Endoscopic scoring of mucus 1981;42:523.
quantity and quality: observer and horse variance and relation- 270. McGorum BC. Quantification of histamine in plasma and pul-
ship to inflammation, mucus viscoelasticity and volume. Equine monary fluids from horses with chronic obstructive pulmonary
Vet J. 2004;36:576. disease, before and after “natural” (hay and straw) challenges.
248. Koblinger K, Nicol J, McDonald K, et al. Endoscopic assess- Vet Immunol Immunopathol. 1993;36:223.
ment of airway inflammation in horses. J Vet Intern Med. 271. Watson E, Sweeney C, Steensma K. Arachidonate metabolites
2011;25:1118. in bronchoalveolar lavage fluid from horses with and without
249. Rettmer H, Hoffman AM, Lanz S, et al. Owner-reported cough- COPD. Equine Vet J. 1992;24:379.
ing and nasal discharge are associated with clinical findings, 272. Grunig G, Hermann M, Winder C, et al. Procoagulant activity
arterial oxygen tension, mucus score and bronchoprovocation in respiratory tract secretions from horses with chronic pulmo-
in horses with recurrent airway obstruction in a field setting. nary disease. Am J Vet Res. 1988;49:705.
Equine Vet J. 2015;47:291. 273. Sant’Ambrogio G, Mathew OP, Fisher JT. Laryngeal receptors
250. Holcombe SJ, Robinson NE, Derksen FJ, et al. Effect of tracheal responding to transmural pressure, airflow, and local muscle
mucus and tracheal cytology on racing performance in Thor- activity. J Appl Physiol. 1983;65:317.
oughbred racehorses. Equine Vet J. 2006;38:300. 274. Sant’Ambrogio G, Mathew OP. Laryngeal receptors and their
251. Widmer A, Doherr MG, Tessier C, et al. Association of in- reflex responses. Clin Chest Med. 1986;7:211.
creased tracheal mucus accumulation with poor willing- 275. Feldman JL. Chapter 14—Looking forward to breathing. Prog
ness to perform in show-jumpers and dressage horses. Vet J. Brain Res. 2011;188:213.
2009;182:430. 276. Silva JN, Tanabe FM, Moreira TS, Takura AC. Neuroanatomical
252. Bedenice D, Mazan MR, Hoffman AM. Association between and physiological evidence that the retrotrapezoid nucleus/par-
cough and cytology of bronchoalveolar lavage fluid and pulmo- afacial region regulates expiration in adult rats. Respir Physiol
nary function in horses diagnosed with inflammatory airway Neurobiol. 2016;227:9.
disease. J Vet Intern Med. 2008;22:1022. 277. Koterba AM, Kosch PC, Beech J. The breathing strategy
253. Bullone M, Helie P, Joubert P, Lavoie JP. Development of a of the adult horse (Equus caballus) at rest. J Appl Physiol.
semiquantitative histological score for the diagnosis of heaves 1988;64:337.
using endobronchial biopsy specimens of horses. J Vet Intern 278. Lessa TB, de Abreu DK, Bertasoli BM, Ambrosio CE. Dia-
Med. 2016;14556. http://dx.doi.org/10.111/jvim. phragm: a vital respiratory muscle in mammals. Ann Anat.
254. Venner M, Schmidbauer S, Drommer W, Deegen E. Percutane- 2016;205:122.
ous lung biopsy in the horse: comparsion of two instruments 279. Nijkampf FP. β-adrenergic receptors in the lung: an introduc-
and repeated biopsy in horses with induced acute interstitial tion. Life Sci. 1993;52:2073.
pneumopathy. J Vet Intern Med. 2006;20:968. 280. Proskocil BJ, Fryer AD. Beta2-agonist and anticholinergic
255. Ainsworth DM, Davidow E. Respiratory distress in large ani- drugs in the treatment of lung disease. Proc Am Thorac Soc.
mals. Proc Forum ACVIM. 1994;12:589. 2005;3:395.
256. West JB. Respiratory physiology: the essentials. 9th ed. Baltimore: 281. Bai TR. Beta 2 adrenergic receptors in asthma: a current per-
Lippincott, Williams & Wilkins; 2012. spective. Lung. 1992;170:125.
257. Wilson WD, Lakritz J. Alterations in respiratory function. In: 282. Couetil L, Hammer J, Miscovis Feutz M, et al. Effects of N-bu-
Smith BP, ed. Large animal internal medicine. 5th ed. St. Louis: tylscopolammonium bromide on lung function in horses with
Elsevier Mosby; 2015. recurrent airway obstruction. J Vet Intern Med. 2012;26:1433.
283. De Lagarde M, Rodrigues N, Chevigny M, et al. N-butylsco- 305. Norman TE, Chaffin MK, Bisset WT, Thompson JA. Associa-
polammonium bromide causes fewer side effects than atropine tion of clinical signs with endoscopic findings in horses with
when assessing bronchoconstriction reversibility in horses with nasopharyngeal cicatrix syndrome: 118 cases (2003–2008). J
heaves. Eq Vet J. 2014;46:474. Am Vet Med Assoc. 2012;240:734.
284. Derksen FJ, Scott JS, Slocombe RF, et al. Effect of clenbuterol on 306. James FM, Parente EJ, Palmer JE. Management of bilateral cho-
histamine-induced airway obstruction in ponies. Am J Vet Res. anal atresia in a foal. J Am Vet Med Assoc. 2006;229:1784.
1987;48:423. 307. Botha CJ, Lewis A, du Plessis EC, et al. Crotalariosis equo-
285. Scott J, Broadstone R, Derksen F, et al. Beta-adrenergic block- rum (“jaagsiekte”) in horses in southern Mozambique, a rare
ade in ponies with recurrent obstructive pulmonary disease. J form of pyrrolizidine alkaloid poisoning. J Vet Diagn Invest.
Appl Physiol. 1988;64:2324. 2012;24:1099.
286. Scott JS, Berney CE, Derksen FJ, Robinson NE. Beta-adrenergic 308. Johnstone LK, Engiles JB, Aceto H, et al. Retrospective evalu-
receptor activity in ponies with recurrent obstructive pulmo- ation of horses diagnosed with neuroborreliosis on postmor-
nary disease. Am J Vet Res. 1991;52:1416. tem examination: 16 cases (2004–2015). J Vet Intern Med.
287. Scott JS, Garon HE, Broadstone RV, et al. Alpha 1 adrenergic 2016;30:1350.
induced airway obstruction in ponies with recurrent pulmo- 309. Reimer JM. Diagnostic ultrasonography of the equine thorax.
nary disease. J Appl Physiol. 1988;65:686. Compend Cont Educ Pract Vet. 1990;12:1321.
288. van der Veldenr VH, Hulsmann AR. Autonomic innervation 310. Carlson GP. Blood chemistry, body fluids, and hematology. In:
of human airways: structure, function, and pathophysiology in Gillespie JR, Robinson NE, eds. Equine exercise physiology. 2nd
asthma. Neuroimmunomodulation. 1999;6:145. ed. Davis, CA: ICEEP Publications; 1987.
289. Andersson RG, Grundstrom N. Innervation of airway smooth 311. Guyton AC, Hall JE. The microcirculation and the lymphatic
muscle. Efferent mechanisms. Pharmacol Ther. 1987;32:107. system: capillary fluid exchange, interstitial fluid and lymph
290. Robinson NE, Derksen FJ, Olszewski MA, et al. The pathogen- flow. The body fluid compartments: extracellular and intracel-
esis of chronic obstructive pulmonary disease of horses. Br Vet lular fluids; interstitial fluid and edema. In: Guyton AC, Hall
J. 1996;152:283. JE, eds. Textbook of medical physiology. 11th ed. Philadelphia:
291. Macklem PT, Mead J. Resistance of central and peripher- Elsevier/Saunders; 2006.
al airways measured by retrograde catheter. J Appl Physiol. 312. Renkin EM. Some consequences of capillary permeability to
1967;22:395. macromolecules: Starling’s hypothesis revisited. Am J Physiol.
292. Buergelt CD, Hines SA, Cantor G, et al. A retrospective study 1986;250:H706.
of proliferative interstitial lung disease of horses in Florida. Vet 313. Staub NC, Taylor AE, eds. Edema. New York: Raven Press; 1984.
Pathol. 1986;23:750. 314. Demling RH. Effect of plasma and interstitial protein content
293. Lakritz J, Wilson WD, Berry CR, et al. Bronchointerstitial on tissue edema formation. Curr Stud Hematol Blood Transfus.
pneumonia and respiratory distress in young horses: clinical, 1986;53:36.
clinicopathologic, radiographic, and pathological findings in 23 315. Taylor AE. Capillary fluid filtration: Starling forces and lymph
cases. J Vet Intern Med. 1984–1989;7(277):1993. flow. Circ Res. 1981;49:557.
294. Wilkins PA. Lower respiratory problems of the neonate. Vet 316. Levick JR, Michel CC. Microvascular fluid exchange and the re-
Clin North Am Equine Pract. 2003;19:19. vised Starling principle. Cardiovasc Res. 2010;87:198.
295. Berry CR, O’Brien TR, Madigan JE, et al. Thoracic radio- 317. Collins SR, Blank RS, Deatherage LS, et al. The endothelial
graphic features of silicosis in 19 horses. J Vet Intern Med. glycocalyx: emerging concepts in pulmonary edema and acute
1991;5:248. lung injury. Anesth Analg. 2013;117:664.
296. Marques FJ, Hehenberger E, Dickinson R, et al. Respiratory 318. Dejana E, Orsenigo F, Lampugnani MG. The role of adherens
distress due to retropharyngeal and neck swelling in a horse junctions and VE-cadherin in the control of vascular perme-
with mediastinal lymphosarcoma. Compend Contin Educ Vet. ability. J Cell Sci. 2008;121:2115.
2012;34:E5. 319. Frigeri A, Nicchia GP, Svelto M. Aquaporins as targets for drug
297. Singh K, Holbrook TC, Gilliam LL, et al. Severe pulmonary dis- discovery. Curr Pharm Des. 2007;13:2421.
ease due to multisystemic eosinophilic epitheliotropic disease 320. Renkin EM, Michel CC, eds. Handbook of physiology. New York:
in a horse. Vet Pathol. 2006;43:189. Oxford University Press; 1984.
298. Brakenhoff JE, Holcombe SJ, Hauptman JG, et al. The preva- 321. Raj JU, Anderson J. Regional differences in interstitial fluid al-
lence of laryngeal disease in a large population of competition bumin concentration in edematous lamb lungs. J Appl Physiol.
draft horses. Vet Surg. 2006;35:579. 1992;72:699.
299. Dixon PM, McGorum BC, Railton DI, et al. Laryngeal paraly- 322. Costanzo L, ed. Physiology. 3rd ed. St. Louis: Saunders; 2006.
sis: a study of 375 cases in a mixed-breed population of horses. 323. Michel CC. Microvascular permeability, venous stasis and
Equine Vet J. 2001;33:452. oedema. Inter Angiol. 1984;8:9–13.
300. Davidson EJ, Martin BB, Boston RC, et al. Exercising upper 324. Green JF. Fundamental cardiovascular and pulmonary physiol-
respiratory videoendoscopic evaluation of 100 nonracing per- ogy. Philadelphia: Lea & Febiger; 1987.
formance horses with abnormal respiratory noise and/or poor 325. Claesson-Welsh L. Vascular permeability—the essentials. Ups J
performance. Equine Vet J. 2011;43:3. Med Sci. 2015;120:135.
301. Franklin SH, Naylor JR, Lane JG. Effect of dorsal displacement 326. Golden MH. Nutritional and other types of oedema, albumin,
of the soft palate on ventilation and airflow during high-inten complex carbohydrates and the interstitium—a response to Mal-
sity exercise. Equine Vet J Suppl. 2002;34:379. com Coulthard’s hypothesis: oedema in kwashiorkor is caused
302. Naylor JM, Nickel DD, Trimino G, et al. Hyperkalemic periodic by hypoalbuminemia. Paediatr Int Child Health. 2015;35:90.
paralysis in homozygous and heterozygous horses: a co-domi- 327. Trani M, Dejana E. New insights in the control of vascular
nant genetic condition. Equine Vet J. 1999;31:153. permeability: vascular endothelial-cadherin and other players.
303. Carr EA, Spier SJ, Kortz GD, Hoffman EP. Laryngeal and phar- Curr Opin Hematol. 2015;22:267.
yngeal dysfunction in horses homozygous for hyperkalemic pe- 328. Vestweber D. VE-cadherin: the major endothelial adhesion
riodic paralysis. J Am Vet Med Assoc. 1996;209:798. molecule controlling cellular junctions and blood vessel forma-
304. Hughes KJ, McGorum BC, Love S, Dixon PM. Bilateral lation. Arterioscler Thromb Vasc Biol. 2008;28:223.
ryngeal paralysis associated with hepatic dysfunction and he- 329. Verkman AS. Mammalian aquaporins: diverse physiological
patic encephalopathy in six ponies and four horses. Vet Rec. roles and potential clinical significance. Expert Rev Mol Med.
2009;164:142. 2008;10:e13.
330. Stokum JA, Kurland DB, Gerzanich V, et al. Mechanisms of as- 357. Kanjwal K, Karabin B, Kanjwal Y, et al. Differentiation of con-
trocyte-mediated cerebral edema. Neurochem Res. 2015;40:317. vulsive syncope from epilepsy with an implantable loop record-
331. Stokum JA, Gerzanich V, Simard JM. Molecular pathophysiol- er. Int J Med Sci. 2009;6:296.
ogy of cerebral edema. J Cereb Blood Flow Metab. 2016;36:513. 358. Jefferys JGR. Advances in understanding basic mechanisms of
332. Hsu Y, Tran M, Linninger AA. Dynamic regulation of aqua- epilepsy and seizures. Seizure. 2010;19:638.
porin-4 water channels in neurological disorders. Croat Med J. 359. McNamara JO. Cellular and molecular basis of epilepsy. J Neu-
2015;56:401. rosci. 1994;14:3413.
333. Sun Z, Li X, Massena S, et al. VEGFR2 induces c-Src signaling 360. Staley K. Molecular mechanisms of epilepsy. Nature. 2015;
and vascular permeability in vivo via the adaptor protein TSAd. 18:367.
J Exp Med. 2012;209:1363. 361. Reddy DS. Role of hormones and neurosteroids in epileptogen-
334. Eliceiri BP, Paul R, Schwartzberg PL, et al. Selective require- esis. Front Cell Neurosci. 2013;7:115.
ment for Src kinases during VEGF-induced angiogenesis and 362. Lucke-Wold BP, Nguyen L, Turner RC, et al. Traumatic brain
vascular permeability. Mol Cell. 1999;4:915. injury and epilepsy: underlying mechanisms leading to seizure.
335. Page AE, Slovis NM, Horohov DW. Lawsonia intracellularis Seizure. 2015;33:13.
and equine proliferative enteropathy. Vet Clin North Am Equine 363. Engel J. A proposal diagnostic scheme for people with epileptic
Pract. 2014;30:641. seizures and with epilepsy: report of the ILAE Task Force on
336. Galvin N, Dillon H, McGovern F. Right dorsal colitis in the classification and terminology, ILAE Commission Report. Epi-
horse: minireview and reports on three cases in Ireland. Ir Vet J. lepsia. 2001;42:796.
2004;57:467. 364. Lacombe VA, Mayes M, Mosseri S, et al. Distribution and
337. Parraga ME, Carlson GP, Thurmon M. Serum protein concen- predictive factors of seizure types in 104 cases. Equine Vet J.
trations in horses with severe liver disease: a retrospective study 2013;46:441.
and review of the literature. J Vet Intern Med. 1995;9:154. 365. Lacombe VA, Mayes M, Mosseri S, et al. Epilepsy in horses:
338. Demling RH. The burn edema process: current concepts. J Burn aetiological classification and predictive factors. Equine Vet J.
Care Rehabil. 2005;26:207. 2012;44:646.
339. Morris DD. Cutaneous vasculitis in horses: 19 cases (1978– 366. Zepelin H. Mammalian sleep. In: Kryger MH, Roth T, Dement
1985). J Am Vet Med Assoc. 1987;191:460. WC, eds. Principles and practice of sleep medicine. 3rd ed. Phila-
340. White SD, Affolter VK, Dewey J, et al. Cutaneous vasculitis delphia: WB Saunders Co; 2000.
in equines: a retrospective study of 72 cases. Vet Dermatol. 367. Ruckebusch Y. The relevance of drowsiness in the circadian cy-
2009;20:600. cle of farm animals. Anim Behav. 1972;20:637.
341. Balasuriya UB. Equine viral arteritis. Vet Clin North Am Equine 368. Williams DC, Aleman M, Holliday TA, et al. Qualitative and
Pract. 2014;30:543. quantitative characteristics of the electroencephalogram in nor-
342. Cook RF, Leroux C, Issel CJ. Equine infectious anemia and mal horses during spontaneous drowsiness and sleep. J Vet In-
equine infectious anemia virus in 2013: a review. Vet Microbiol. tern Med. 2008;22:630.
2013;29:167. 369. Hendricks JC, Morrison AR. Normal and abnormal sleep in
343. Pusterla N, Watson JL, Affolter VK, et al. Purpura haemorrhag- mammals. J Am Vet Med Assoc. 1981;178:121.
ica in 53 horses. Vet Rec. 2003;153:118. 370. Bertone JJ. Excessive drowsiness secondary to recumbent sleep
344. Kilcoyne I, Spier SJ, Carter CN, et al. Frequency of Corynebac- deprivation in two horses. Vet Clin North Am Equine Pract.
terium pseudotuberculosis infection in horses across the United 2006;22:157.
States during a 10-year period. J Am Vet Med Assoc. 2014;245:309. 371. Mignot EJ, Dement WC. Narcolepsy in animals and man.
345. Affolter VK. Chronic progressive lymphedema in draft horses. Equine Vet. 1993;25:476.
Vet Clin North Am Equine Pract. 2013;29:589. 372. Scammell TE. Narcolepsy. N Engl J Med. 2015;373:2654.
346. Lewis N, Racklyeft DJ. Mass envenomation of a mare and foal 373. Ripley B, Fujiki N, Okura M, et al. Hypocretin levels in spo-
by bees. Aust Vet J. 2014;92:141. radic and familial cases of canine narcolepsy. Neurobiol Dis.
347. Fielding CL, Pusterla N, Magdesian KG, et al. Rattlesnake en- 2001;8:525.
venomation in horses: 58 cases (1992–2009). J Am Vet Med As- 374. Lin L, Faraco J, Li R, et al. The sleep disorder canine narcolepsy
soc. 2011;238:631. is caused by a mutation in the hypocretin (orexin) receptor 2
348. Lyle CH, Turley G, Blissitt KJ, et al. Retrospective evaluation of gene. Cell. 1999;98:365.
episodic collapse in the horse in a referred population: 25 cases 375. Lunn DP, Cuddon PA, Shaftoe S, et al. Familial occurrence of
(1995–2009). J Vet Intern Med. 2010;24:1498. narcolepsy in miniature horses. Equine Vet J. 1993;25:483.
349. Guyton AC, Hall JE. Textbook of medical physiology. 11th ed. 376. Ludvikova E, Nishino S, Sakai N, et al. Familial narcolepsy in
Philadelphia: Elsevier; 2006. the Lipizzaner horse: a report of three fillies born to the same
350. Gauer RL. Evaluation of syncope. Am Fam Physician. sire. Vet Q. 2012;32:99.
2011;84:640. 377. Bathen-Nothen A, Heider C, Fernandez AJ, et al. Hypocretin
351. Hilz MJ, Marthol H, Neundorfer B. Syncope—a systematic measurement in an Icelandic foal with narcolepsy. J Vet Intern
overview of classification, pathogenesis, diagnosis and manage- Med. 2009;23:1299.
ment. Fortschr Neurol Psychiatr. 2002;70:95. 378. van Nieuwstadt RA, van der Want CJ, Binkhorst GJ. Narcolepsy
352. Lanier JB, Mote MB, Clay EC. Evaluation and management of in horses. Tijdschr Diergeneeskd. 1993;118:765.
orthostatic hypotension. Am Fam Physician. 2011;84:527. 379. Dreifuss FE, Flynn DV. Narcolepsy in a horse. J Am Vet Med
353. Benditt DG. Neurally mediated syncopal syndromes: patho- Assoc. 1984;184:131.
physiological concepts and clinical evaluation. Pacing Clin Elec- 380. Sweeney CR, Hendricks JC, Beech J, et al. Narcolepsy in a horse.
trophysiol. 1997;20:572. J Am Vet Med Assoc. 1983;183:126.
354. Gatzoulis KA, Toutouzas PK. Neurocardiogenic syncope: aeti- 381. Faull KF, Guillemainault C, Berger PA, et al. Cerebrospinal
ology and management. Drugs. 2001;61:1415. fluid monoamine metabolites in narcolepsy and hypersomnia.
355. Mayhew J. Large animal neurology. 2nd ed. Sussex, UK: Wiley Ann Neurol. 1983;13:258.
Blackwell; 2009. 382. Mignot E, Lammers GJ, Ripley B, et al. The role of cerebrospinal
356. Sabu J, Regeti K, Mallappallil M, et al. Convulsive syncope in- fluid hypocretin measurement in the diagnosis of narcolepsy
duced by ventricular arrhythmia masquerading as epileptic sei- and other hypersomnias. Arch Neurol. 2002;59:1553.
zures: case report and review of the literature. J Clin Med Res. 383. Viola-Saltzman M, Watson MD. Traumatic brain injury and
2016;8:610. sleep disorders. Neurol Clin. 2012;30:1299.
384. Baumann CR, Bassetti CL, Scammell TE. Loss of hypocre- 408. Nolen-Walston RD, Parente EJ, Madigan JE, et al. Branchial
tin (orexin) neurons with traumatic brain injury. Ann Neurol. remnant cysts of mature and juvenile horses. Equine Vet J.
2010;66:555. 2009;41:918.
385. Jesty SA, Reef VB. Evaluation of the horse with acute cardiac 409. Dixon PM, Dacre I. A review of equine dental disorders. Vet J.
crisis. Clin Tech Equine Pract. 2006;5:93. 2005;169:165.
386. Reef VB, Clark ES, Oliver JA, et al. Implantation of a permanent 410. Staszyk C, Bienert A, Kreutzer R. Equine odontoclastic tooth
transvenous pacing catheter in a horse with a complete heart resorption and hypercementosis. Vet J. 2008;178:372.
block and syncope. J Am Vet Med Assoc. 1986;189:449. 411. Vengust M, Baird JD, van Dreumel T, et al. Equid herpesvirus
387. Hay WP, Baskett A, Abdy MJ. Complete upper airway obstruc- 2-associated oral and esophageal ulceration in a foal. J Vet Diag
tion and syncope caused by a subepiglottic cyst in a horse. Invest. 2008;20:811.
Equine Vet J. 1997;29:75. 412. Baker GJ. Equine temporomandibular joints (TMJ): morphol-
388. Steiger R, Feige K. Case report: polycythemia in a horse. Sch- ogy, function, and clinical disease. Proc Am Assoc Equine Pract.
weiz Arch Tierheilkd. 1995;137:306. 2002;48:442.
389. Bryant UK, Lyons ET, Bain FT, et al. Halicephalobus gingivalis- 413. Pusterla N, Latson KM, Wilson WD, et al. Metallic foreign bod-
associated meningoencephalitis in a Thoroughbred foal. J Vet ies in the tongues of 16 horses. Vet Rec. 2006;159:485.
Diagn Invest. 2006;18:612. 414. Kilcoyne I, Watson JL, Spier SJ, et al. Septic sialoadenitis in
390. Hardefeldt LY. Hyponatremic encephalopathy in azotaemic equids: a retrospective study of 18 cases (1998–2010). Equine
neonatal foals: four cases. Aust Vet J. 2014;92:488. Vet J. 2010;47:54.
391. Viu J, Monreal L, Jose-Cunilleras E, et al. Clinical findings in 415. Bezdekova B. Esophageal disorders in horses—a review of the
10 foals with bacterial meningoencephalitis. Equine Vet J Suppl. literature. Pferdeheilkunde. 2012;28:187.
2012;41:100. 416. Broekamn LE, Kuiper D. Megaesophagus in the horse. A short
392. Wong D, Wilkins PA, Bain FT, et al. Neonatal encephalopathy review of the literature and 18 own cases. Vet Q. 2002;24:199.
in foals. Compend Contin Educ Vet. 2011;33:E5. 417. Booth TM, Marmion WJ, Cullimore AM, et al. Esophageal ob-
393. Aleman M, Gray LC, Williams DC, et al. Juvenile idiopathic struction in an aged pony associated with squamous cell carci-
epilepsy in Egyptian Arabian foals: 22 cases (1985–2005). J Vet noma. Equine Vet Educ. 2008;20:627.
Intern Med. 2006;20:1443. 418. Brazil TJ. Recurrent esophageal obstruction caused by gastro-
394. Berendnt M, Gredal H, Pedersen LG, et al. A cross-sectional esophageal squamous cell carcinoma: a diagnostic challenge?
study in Danish Labrador Retrievers: prevalence and selected Equine Vet Educ. 2008;20:633.
risk factors. J Vet Intern Med. 2002;16:262. 419. Green S, Green EM, Aronson E. Squamous cell carcinoma: an
395. Cornelisse CJ, Schott HC, Olivier NB, et al. Concentration of unusual case of esophageal choke in a horse. Mod Vet Pract.
cardiac troponin I in horse with a ruptured aortic regurgita- 1986;65:870.
tion jet lesion and ventricular tachycardia. J Am Vet Med Assoc. 420. Benders NA, Velduis Kroez EJ, van der Kolk JH. Idiopathic
2000;217:231. muscular hypertrophy of the esophagus in the horse: a retro-
396. Nath LC, Anderson GA, Hinchcliff KW, et al. Serum cardiac spective study of 31 cases. Equine Vet J. 2004;36:46.
troponin I concentrations in horses with cardiac disease. Aust 421. Todhunter RJ, Brown CM, Stickle R. Retropharyngeal infec-
Vet J. 2012;90:351. tions in five horses. J Vet Med Assoc. 1985;187:600.
397. Wijnberg ID, van der Ree M, van Someren P. The applicabil- 422. Sweeney CR, Timoney JF, Newton JR, et al. Streptococcus equi
ity of ambulatory electroencephalography (AEEG) in healthy infections in horses: guidelines for treatment, control and pre-
horses and horses with abnormal behavior or clinical signs of vention of strangles. J Vet Intern Med. 2005;19:123.
epilepsy. Vet Q. 2013;33:121. 423. McCue PM, Freeman DE, Donawick WJ. Guttural pouch tym-
398. van der Ree M, Wijnberg I. A review on epilepsy in the horse pany: 15 cases (1977–1986). J Am Vet Med Assoc. 1989;12:1761.
and the potential of ambulatory EEG as a diagnostic tool, 424. Greet TRC. Outcome of treatment in 35 cases of guttural pouch
332:159, 2012. mycosis. Equine Vet J. 1987;19:483.
399. Manso-Diaz G, Dyson SJ, Dennis R, et al. Magnetic resonance 425. Tremaine WH: Oral cavity neoplasia, ivis.org. AAEP Focus
imaging characteristics of equine head disorders: 84 cases Meeting, Indianapolis, 2006.
(2000–2013). Vet Radiol Ultrasound. 2015;56:176. 426. Casey M. A new understanding of the oral and dental pathol-
400. Sogaro-Robinson C, Lacombe VA, Reed SM, et al. Factors pre- ogy of the equine cheek teeth. Vet Clin North Am Equine Pract.
dictive of abnormal results for computed tomography of the 2013;29:301.
head in horses affected by neurologic disorders. J Am Vet Med 427. Laus F, Rossi G, Paggi E, et al. Adenocarcinoma involving the
Assoc. 2009;235:176. tongue and epiglottis in a horse. J Vet Med Sci. 2014;76:467.
401. Goyal RK, Mashimo H. Physiology of oral, pharyngeal, and 428. Anlen KG. Effects of bites by the European adder (Vipera berus)
esophageal motility. GI Motility online. 2006. http://dx.doi in seven Swedish horses. Vet Rec. 2008;162:652.
.org/10.1038/gimo1. 429. Sweeny CR, Freeman DE, Sweeny RW, et al. Hemorrhage into
402. Shaw S, Martino R. The normal swallow: muscular and the guttural pouch (auditory tube diverticulum) associated with
neurophysiological control. Otolaryngol Clin N Am. 2013; rupture of the longus capitis muscle in three horses. J Am Vet
46:937. Med Assoc. 1993;202:1129.
403. Steele CM, Miller AJ. Sensory input pathways and mechanisms 430. Dobesova O, Schwarz B, Velde K, et al. Guttural pouch my-
in swallowing: a review. Dysphagia. 2010;25:323. cosis in horses: a retrospective study of 28 cases. Vet Rec.
404. Aleman M. Dysphagia of neurogenic origin. In: Robinson NE, 2012;171:561.
Sprayberry KA, eds. Current therapy in equine medicine 6. St. 431. Bell C. Pharyngeal neuromuscular dysfunction associated
Louis: Saunders/Elsevier; 2009. with bilateral guttural pouch tympany in a foal. Can Vet J.
405. Baum KH, Modransky PD, Halpern NE, et al. Dysphagia in 2007;48:192.
horses: the differential diagnosis, part I. Compend Cont Educ 432. Koch C, Witte T. Temporohyoid osteoarthropathy in the horse.
Pract Vet. 1988;10:1301. Equine Vet Ed. 2014;26:121.
406. Baum GH, Halpern NE, Banish LD, et al. Dysphagia in horses: 433. Walker AM, Sellon DC, Cornelisse CJ, et al. Temporohyoid os-
the differential diagnosis, part II. Compend Cont Educ Pract Vet. teoarthropathy in 33 horses. J Vet Intern Med. 2002;16:697.
1988;10:1405. 434. Burrows GE, Borchard RE. Experimental lead toxicosis in po-
407. Stick JA, Boles C. Subepiglottic cyst in three foals. J Am Vet Med nies: comparison of the effects of smelter effluent-contaminated
Assoc. 1980;177:62. hay and lead acetate. Am J Vet Res. 1982;43:2129.
435. Yvorchuk-St. Jean K. Neuritis of the cauda equina. Vet Clin 461. Orsini JA, Divers TJ, eds. Equine emergencies: treatment and
North Am Equine Pract. 1987;3:421–426. procedures. St. Louis: Saunders; 2008.
436. Hahn CN. Polyneuritis equi: the role of T-lymphocytes and im- 462. Mair T, Divers T, Ducharme N, eds. Manual of equine gastroen-
portance of differential clinical signs. Equine Vet J. 2008;40:100. terology. St. Louis: Saunders; 2002.
437. Long MT. West Nile virus and equine encephalitis viruses: new 463. White NA. II: Intestinal response to injury. Proc Ann Conv
perspectives. Vet Clin North Am Equine Pract. 2014;30:523. AAEP. 2006;52:115.
438. Pusterla N, Hussey GS. Equine herpesvirus 1 myeloencepha- 464. Snyder JR. The pathophysiology of intestinal damage: effects
lopathy. Vet Clin North Am Equine Pract. 2014;30:489. of luminal distention and ischemia. Vet Clin North Am Equine
439. Kohn CW, Fenner WR. Equine herpes myeloencephalopathy. Pract. 1989;5:247.
Vet Clin North Am Equine Pract. 1987;3:405. 465. Kaya G, Sommerfeld-Stur I, Iben C. Risk factors of col-
440. Howe DK, MacKay RJ, Reed SM. Equine protozoal myeloen- ic in horses in Austria. J Anim Physiol Anim Nutr (Berl).
cephalitis. Vet Clin North Am Equine Pract. 2014;30:659. 2009;93:339.
441. Uhlinger C. Clinical and epidemiologic features of an epizo- 466. Cohen ND, Gibbs PG, Woods AM. Dietary and other manage-
otic of equine leukoencephalomalacia. J Am Vet Med Assoc. ment factors associated with colic in horses. J Am Vet Med As-
1991;198:126. soc. 1999;215:53.
442. van Galen G, Delguste C, Sandersen C, et al. Tetanus in the 467. Tinker MK, White NA, Lessard P. Prospective study of equine
equine species: a retrospective study of 31 cases. Tijdschr Dier- colic risk factors. Equine Vet J. 1997;29:454.
geneeskd. 2008;133:512. 468. Hudson JM, Cohen ND, Gibbs PG, et al. Feeding practices asso-
443. Holcombe SJ, Hurcombe SD, Barr BS, et al. Dysphagia associat- ciated with colic in horses. J Am Vet Med Assoc. 2001;219:1419.
ed with presumed pharyngeal dysfunction in 16 neonatal foals. 469. Archer DC, Proudman CJ. Epidemiological clues to preventing
Equine Vet J Suppl. 2012;41:105. colic. Vet J. 2006;172:29.
444. Swerczek TW. Toxicoinfectious botulism in foals and adult 470. Scantlebury CE, Archer DC, Proudman CJ, et al. Management
horses. J Am Vet Med Assoc. 1980;176:217. and horse-level risk factors for recurrent colic in the UK general
445. Wilkins PA, Palmer JE. Botulism in foals less than 6 months of equine practice population. Equine Vet J. 2015;47:202.
age: 30 cases (1989–2002). J Vet Intern Med. 2003;17:702. 471. Suthers JM, Pinchbeck GL, Proudman CJ, et al. Risk factors for
446. Doxey DL, Milne EM, Gilmour JS, et al. Clinical and biochemi- large colon volvulus in the UK. Equine Vet J. 2013;45:558.
cal features of grass sickness (equine dysautonomia). Equine Vet 472. Scantlebury CE, Archer DC, Proudman CJ, et al. Recurrent col-
J. 1991;23:360. ic in the horse: incidence and risk factors for recurrence in the
447. Wylei CE, Proudman CJ. Equine grass sickness: epidemiology, general practice population. Equine Vet J Suppl. 2011;39:81.
diagnosis, and global distribution. Vet Clin North Am Equine 473. White NA. II: Causes and risks for colic. Proc Ann Conv AAEP.
Pract. 2009;25:381. 2006;52:115.
448. McGorum BC, Scholes S, Milne EM, et al. Equine grass sickness, 474. Malamed R, Berger J, Bain MJ, et al. Retrospective evaluation of
but not botulism, causes autonomic and enteric neurodegenera- crib-biting and windsucking behaviours and owner-perceived
tion and increases soluble N-ethylmaleimide-sensitive factor behavioural traits as risk factors for colic in horses. Equine Vet J.
attachment receptor protein expression within neuronal peri- 2010;42:686.
karya. Equine Vet J. 2016. http://dx.doi.org/10.1111/evj.13543. 475. Escalona EE, Okell CN, Archer DC. Prevalence of and risk fac-
449. Moore RM, Kohn CW. Nutritional muscular dystrophy in foals. tors for colic in horses that display crib-biting behavior. BMC
Compend Cont Educ Pract Vet. 1991;13:476. Vet Res. 2014;1:S3.
450. Step DL, Divers TJ, Cooper B, et al. Severe masseter myonecro- 476. Archer DC, Pinchbeck GK, French NP, et al. Risk factors for
sis in a horse. J Am Vet Med Assoc. 1991;198:117. epiploic foramen entrapment colic: an international study.
451. Pearson EG, Snyder SP, Saulez MN. Masseter myodegenera- Equine Vet J. 2008;40:224.
tion as a cause of trismus or dysphagia in adult horses. Vet Rec. 477. Proudman CJ. A two year, prospective study of equine colic in
2005;156:642. general practice. Equine Vet J. 1992;24:90.
452. Komine M, Langohr IM, Kiupel M. Megaesophagus in Frie- 478. Voigt A, Saulex MN, Donnellan CM, et al. Causes of gastro-
sian horses associated with muscular hypertrophy of the caudal intestinal colic at an equine referral hospital in South Africa
esophagus. Vet Pathol. 2014;51:979. (1998–2007). J S Afr Vet Assoc. 2009;80:92.
453. Sockett DC, Baker JC, Stowe CM. Slaframine (Rhizoctonia 479. Abutarbush SM, Carmalt JL, Shoemaker JL. Causes of gastro-
leguminicola) intoxication in horses. J Am Vet Med Assoc. intestinal colic in horses in western Canada: 604 cases (1992–
1982;181:606. 2002). Can Vet J. 2005;46:800.
454. Divers TJ, Mohammed HO, Cummings JR, et al. Equine lower 480. Yorke EH, Caldwell FJ, Johnson AK. Uterine torsion in
motor neuron disease: findings in 28 horses and proposal of a mares. Compend Contin Educ Vet. 2012;34:E2.
pathophysiological mechanism. Equine Vet J. 1994;26:409. 481. Duesterdieck-Zellmer KF. Equine urolithiasis. Vet Clin North
455. USDA-APHIS: Incidence of colic in U.S. horses. Available at Am Equine Pract. 2007;23:613.
http://www.aphis.usda.gov/vs/ceah/ncahs/nahms/equine/equi 482. Johnston JK, Divers TJ, Reef VB, et al. Cholelithiasis in horses:
ne98/colic.PDF. Accessed Mar 4, 2009. ten cases (1982–1986). J Am Vet Med Assoc. 1989;194:405.
456. Tinker MK, White NA, Lessard P, et al. Prospective study of 483. Tennent-Brown BS, Mudge MC, Hardy J, et al. Liver lobe tor-
equine colic incidence and mortality. Equine Vet J. 1997;29:448. sion in six horses. J Am Vet Med Assoc. 2012;241:615.
457. Traub-Dargatz JL, Kopral CA, Seitzinger AH, et al. Estimate of 484. Luethy D, Habecker P, Murphy B, et al. Clinical and pathologi-
the national incidence of and operation-level risk factors for cal features of pheochromocytoma in the horse: a multi-center
colic among horses in the United States, spring 1998 to spring retrospective study of 37 cases (2007–2014). J Vet Intern Med.
1999. J Am Vet Med Assoc. 2001;219:67. 2016;30:309.
458. Uhlinger C. Investigations into the incidence of field colic. 485. Moore BR, Moore RM. Examination of the equine patient with
Equine Vet J. 1992;13:11. gastrointestinal emergency. Vet Clin North Am Equine Pract.
459. USDA-APHIS: Trends in equine mortality, 1998–2005. Avail- 1994;10:549.
able at http://www.aphis.usda.gov/animal_health/nahms/equin 486. Cook VL, Hassel DM. Evaluation of the colic in horses: decision
e/download/equine05/Equine05_ is_Mortality.PDF for referral. Vet Clin North Am Equine Pract. 2014;30:383.
460. Salem SE, Scantlebury CE, Ezzat E, et al. Colic in a working 487. Furr MO, Lessard P, White 2nd NA. Development of a colic
horse population in Egypt: prevalence and risk factors. Equine severity score for predicting the outcome of equine colic. Vet
Vet J. 2016. http://dx.doi.org/10.1111/wvj.12573. Surg. 1995;24:97.
488. Ebert R. Prognostic parameters in equine colic. Tiearztl Prax. 513. Radcliffe RM, Divers TJ, Fletcher DJ, et al. Evaluation of L-
1994;22:256. lactate and cardiac troponin I in horses undergoing emer-
489. Orsini JA, Elser AH, Galligan DT, et al. Prognostic index for acute gency abdominal surgery. J Vet Emerg Crit Care (San Antonio).
abdominal crisis (colic) in horses. Am J Vet Res. 1969;49:1988. 2012;22:313.
490. Parry BW, Anderson GA, Gay CC. Prognosis in equine colic: 514. Yamout SZ, Nieto JE, Beldomenico PM, et al. Peritoneal and
a study of individual variables used in case assessment. Equine plasma D-lactate concentrations in horses with colic. Vet Surg.
Vet J. 1983;15:337. 2011;40:817.
491. Parry BW, Anderson GA, Gay CC. Prognosis in equine colic: a 515. Latson KM, Nieto JE, Beldomenico PM, et al. Evaluation of per-
comparative study of variables used to assess individual cases. itoneal fluid lactate as a marker of intestinal ischemia in equine
Equine Vet J. 1983;15:211. colic. Equine Vet J. 2005;37:342.
492. Parry BW, Gay CC, Anderson GA. Assessment of the necessity 516. Tennent-Brown BS. Interpreting lactate measurement in criti-
for surgical intervention in cases of equine colic: a retrospective cally ill horses: diagnosis, treatment, and prognosis. Compend
study. Equine Vet J. 1983;15:216. Contin Educ Vet. 2012;34:E2.
493. Cribb NC, Cote NM, Boure LP, et al. Acute small intestinal 517. Nieto JE, Dechant JE, le Jeune SS, et al. Evaluation of 3 handheld
obstruction associated with Parascaris equorum infection in portable analyzers for measurement of L-lactate concentrations
young horses: 25 cases (1985–2004). N Z Vet J. 2006;54:338. in blood and peritoneal fluid of horses with colic. Vet Surg.
494. Chaffin MK, Cohen ND. Diagnostic assessment of foals with 2015;44:366.
colic. Proc Ann Conv AAEP. 1999;45:235. 518. Dunkel B, Kapff JE, Naylor RJ, et al. Blood lactate concentra-
495. Cohen ND, Matejka PL, Honnas CM, et al. Case-control study tions in ponies and Miniature Horses with gastrointestinal dis-
of the association between various management factors and ease. Equine Vet J. 2013;45:666.
the development of colic in horses. Texas Equine Colic Study 519. Freeman SL. Diagnostic ultrasonography of the mature equine
Group. J Vet Med Assoc. 1995;206:667. abdomen. Equine Vet Educ. 2003;15:319.
496. Santschi EM, Purdy AK, Valberg SJ, et al. Endothelin receptor 520. le Jeune S, Whitcomb MB: Ultrasound of the equine acute ab-
B polymorphism associated with lethal white foal syndrome in domen. Vet Clin North Am Equine Pract. 2014;30:353.
horses. Mamm Genome. 1998;9:306. 521. Scharner D, Bankert J, Brehm W. Comparison of the find-
497. Wagner AE, Muir 3rd WW, Hinchcliff KW. Cardiovascular ings of rectal examination and ultrasonographic findings in
effects of xylazine and detomidine in horses. Am J Vet Res. horses with colic. Tieraztl Prax Ausg G Grosstiere Nutztiere.
1991;52:651. 2015;43:278.
498. Daunt DA, Steffey EP. Alpha-2 adrenergic agonists as analgesics 522. Cavalleri JM, Biernert-Zeit A, Feige K. Examination of horses
in horses. Vet Clin North Am Equine Pract. 2002;18:39. with acute colic—clinical pathology and diagnostic imaging.
499. Ragle CA, Meagher DM, Schrader JL, et al. Abdominal auscul- Tierarztl Prax Ausg G Grosstiere Nutztiere. 2013;41:124.
tation in the detection of experimentally induced gastrointesti- 523. Beccati F, Pepe M, Gialletti R, et al. Is there a statistical cor-
nal sand accumulation. J Vet Intern Med. 1989;3:12. relation between ultrasonographic findings and definitive diag-
500. Tillotson K, Traub-Dargatz JL. Gastrointestinal protectants and nosis in horses with acute abdominal pain? Equine Vet J Suppl.
cathartics. Vet Clin North Am Equine Pract. 2003;19:599. 2011;39:98.
501. White NA, ed. The equine acute abdomen. Malvern: Lea & Fe- 524. Busoni V, De Busscher V, Lopez D, et al. Evaluation of a proto-
biger; 1990. col for fast localized abdominal sonography of horses (FLASH)
502. Luo T, Bertone JJ, Greene HM, et al. A comparison of N-butyl admitted for colic. Vet J. 2011;188:77.
scopolammonium and lidocaine for control of rectal pressure in 525. Bradecamp EA. How to image the adult equine abdomen and
horses. Vet Ther. 2006;7:243. thorax in ambulatory practice using a 5-mHz rectal probe. Proc
503. White NA. Equine colic: how to make the decision for surgery. Ann Conv AAEP. 2007;53:537.
In: AAEP Focus Proceedings. Philadelphia; 2005. 526. Bernard WV, Reef VB, Reimer JM, et al. Ultrasonographic di-
504. Parry BW. Use of clinical pathology in evaluation of horses with agnosis of small-intestinal intussusception in three foals. J Am
colic. Vet Clin North Am Equine Pract. 1987;3:529. Vet Med Assoc. 1989;194:395.
505. Navarro M, Monreal L, Segura D, et al. A comparison of tradi- 527. Santschi EM, Slone DE, Frank WM. Use of ultrasound in
tional and quantitative analysis of acid-base and electrolyte im- horses for diagnosis of left dorsal displacement of the large
balances in horses with gastrointestinal disorders. J Vet Intern colon and monitoring its nonsurgical correction. Vet Surg.
Med. 2005;19:871. 1993;22:281.
506. Hassel DM, Hill AE, Rorabeck RA. Association between hyper- 528. Ness SL, Bain FT, Zantingh AJ, et al. Ultrasonographic visuali-
glycemia and survival in 228 horses with acute gastrointestinal zation of colonic mesenteric vasculature as an indicator of large
disease. J Vet Intern Med. 2009;23:1261. colon right dorsal displacement or 180° volvulus (or both) in
507. Davis JL, Blikslager AT, Catto K, et al. A retrospective analysis horses. Can Vet J. 2012;53:378.
of hepatic injury in horses with proximal enteritis (1984–2002). 529. Keppie NJ, Rosensein DS, Holcombe SJ, et al. Objective radio-
J Vet Intern Med. 2003;17:896. graphic assessment of abdominal sand accumulation in horses.
508. Gardner RB, Nydam DV, Mohammed HO, et al. Serum gamma Vet Radiol Ultrasound. 2008;49:122.
glutamyl transferase activity in horses with right or left dorsal 530. Yarbrough TB, Langer DL, Snyder JL, et al. Abdominal radiog-
displacements of the large colon. J Vet Intern Med. 2005;19:761. raphy for diagnosis of enterolithiasis in horses: 141 cases (1990–
509. Krueger CR, Ruple-Czerniak A, Hackett ES. Evaluation of plas- 1992). J Am Vet Med Assoc. 1994;205:592.
ma muscle enzyme activity as an indicator of lesion character- 531. Gerhards H, Klein HJ, Offeney F. Radiographic diagnosis of ab-
istics and prognosis in horses undergoing celiotomy for acute dominal diseases in foals and ponys. II. Pathologic findings in
gastrointestinal pain. BMC Vet Res. 2014;1:S7. 60 cases. Tierarztl Prax. 1990;18:383.
510. Fischer Jr AT. Advances in diagnostic techniques for horses 532. Argenzio RA, Lowe JE, Pickard DW, et al. Digesta passage
with colic. Vet Clin North Am Equine Pract. 1997;13:203. and water exchange in the equine large intestine. Am J Physiol.
511. Cowell RL, Tyler RD, eds. Diagnostic cytology and hematology of 1974;226:1035.
the horse. 2nd ed. St. Louis: Mosby; 2007. 533. Argenzio RA, Stevens CE. Cyclic changes in ionic composi-
512. Peloso JG, Cohen ND. Use of serial measurements of peritoneal tion of digesta in the equine intestinal tract. Am J Physiol.
fluid lactate concentration to identify strangulating intestinal 1975;228:1224.
lesions in referred horse with signs of colic. J Am Vet Med Assoc. 534. Argenzio RA. Functions of the large intestine and their inter-
2012;240:1208. relationship with disease. Cornell Vet. 1975;65:303.
535. Conner ME, Darlington RW. Rotavirus infection in foals. Am J 560. Magdesian KG, Hirsh DC, Jang SS, et al. Characterization of
Vet Res. 1980;41:1699. Clostridium difficile isolates from foals with diarrhea: 28 cases
536. Costa MC, Stampfli HR, Allen-Vercoe E, et al. Development of (1993–1997). J Am Vet Med Assoc. 2002;220:67.
the faecal microbiota in foals. Equine Vet J. 2015. doi: 10.1111. 561. Tillotson K, Traub-Dargatz JL, Dickinson CE, et al. Population-
537. Rodriguez C, Taminiau B, Brevers B, et al. Faecal microbiota based study of fecal shedding of Clostridium perfringens in
characterization of horses using rdna barcoded pyrosequenc- broodmares and foals. J Am Vet Med Assoc. 2002;220:342.
ing, and carriage rate of Clostridium difficile at hospital admis- 562. Berlin FR, Reising A, Slovis NM, et al. Clinical and clinico-
sion. BMC Microbiol. 2015;15:181. pathological findings associated with survival in 44 horses with
538. Holland JL, Kronfeld DS, Sklan D, et al. Calculation of fecal equine neorickettsiosis (Potomac horse fever). J Vet Intern Med.
kinetics in horses fed hay or hay and concentrate. J Anim Sci. 2013;27:1528.
1934;76:1998. 563. Pusterla N, Gebhart CJ. Equine proliferative enteropathy—a re-
539. Bailey KE, Gilkerson JR, Browning GF, et al. Equine rotavi- view of recent developments. Equine Vet J. 2013;45:403.
ruses—current understanding and continuing challenges. Vet 564. Platell JL, Gibson JS. Proliferative enteropathy in foals: disease,
Microbiol. 2013;167:135. diagnostics and transmission. Vet J. 2013;195:135.
540. Vannucci FA, Gebhart CJ. Recent advances in understand- 565. Lavoie JP, Drolet R, Parsons D, et al. Equine proliferative en-
ing the pathogenesis of Lawsonia intracellularis infections. Vet teropathy: a cause of weight loss, colic, diarrhoea and hypopro-
Pathol. 2014;51:465. teinemia in foals on three breeding farms in Canada. Equine Vet
541. Wong DM, Alcott CJ, Sponseller BA, et al. Impaired intestinal J. 2000;32:418.
absorption of glucose in 4 foals with Lawsonis intracellularis in- 566. Cimprich RE, Rooney JR. Corynebacterium equi enteritis in
fection. J Vet Intern Med. 2009;23:940. foals. Vet Pathol. 1977;14:95.
542. O’Louglin EV, Scott RB, Gall DG. Pathophysiology of infec- 567. Holland RE, Sriranganathan N, Dupont L. Isolation of entero-
tious diarrhea: changes in intestinal structure and function. J toxigenic Escherichia coli from a foal with diarrhea. J Am Vet
Pediatr Gastroenterol Nutr. 1991;12:5. Med Assoc. 1989;194:389.
543. Rachmilewitz D. Prostaglandins and diarrhea. Dig Dis Sci. 568. Hurcombe SD, Fox JG, Kohn CW. Isolation of Campylobacter fetus
1980;25:897. subspecies fetus in a 2-year-old quarter horse with chronic diar-
544. Hardcastle J, Hardcastle PT. Involvement of prostaglandin in rhea of an undetermined etiology. J Vet Diagn Invest. 2009;21:266.
histamine-induced fluid and electrolyte secretion by rat colon. 569. Hathcock TL, Schumacher J, Wright JC, et al. The prevalence of
J Pharm Pharmacol. 1988;40:106. Aeromonas species in feces of horses with diarrhea. J Vet Intern
545. Wang YZ, Su HC, Cooke, et al. Histamine augments colonic Med. 1999;13:357.
secretion in guinea pig distal colon. Am J Physiol. 1990;258: 570. Browning GF, Chalmers RM, Snodgrass DR, et al. The preva-
G432. lence of enteric pathogens in diarrhoeic Thoroughbred foals in
546. Clarke LL, Argenzio RA. NaCl transport across equine proxi- Britain and Ireland. Equine Vet J. 1991;23:397.
mal colon and the effect of endogenous prostaglandins. Am J 571. Slovis NM, Elam J, Estrada M, et al. Infectious agents associated
Physiol. 1990;259:G62. with diarrhoea in neonatal foals in central Kentucky: a compre-
547. Halm DR, Rechkemmer GR, Schoumache RA, et al. Apical hensive molecular study. Equine Vet J. 2014;46:311.
membrane chloride channels in a colonic cell line activated by 572. Pusterla N, Mapes S, Wademan C, et al. Emerging outbreaks as-
secretory agonists. Am J Physiol. 1988;254:C505. sociated with equine coronavirus in adult horses. Vet Microbiol
548. Cliff WH, Frizzell RA. Separate Cl− conductances activated 2013;162:228.
by cAMP and Ca2 in Cl(−)-secreting epithelial cells. Proc Natl 573. Fielding CL, Higgins JK, Higgins JC, et al. Disease associated
Acad Sci USA. 1990;87:4956. with equine coronavirus infection and high case fatality rate.
549. Ling BN, Kokko KE, Eaton DC. Prostaglandin E2 activates J Vet Intern Med. 2015;29:307.
clusters of apical Cl− channels in principal cells via a cyclic 574. Oue Y, Morita Y, Kondo T, et al. Epidemic of equine coronavi-
adenosine monophosphate-dependent pathway. J Clin Invest. rus at Obihiro Racecourse, Hokkaido, Japan in 2012. J Vet Med
1994;93:829. Sci. 2013;75:1261.
550. Guirl MJ, Hogenauer C, Santa Ana CA, et al. Rapid intestinal 575. Guy JS, Breslin JJ, Breuhaus B, et al. Characterization of a
transit as a primary cause of severe chronic diarrhea in patients coronavirus isolated from a diarrheic foal. J Clin Microbiol.
with amyloidosis. Am J Gastroenterol. 2003;98:2219. 2000;38:4523.
551. King JN, Gerring EL. The action of low dose endotoxin on 576. Corning S. Equine cyathostomins: a review of biology, clinical
equine bowel motility. Equine Vet J. 1991;23:11. significance and therapy. Parasit Vectors Suppl. 2009;2:S1.
552. Weese JS, Parsons DA, Staempfli HR. Association of Clostridi- 577. Nielsen MK, Loynachan AT, Jacobsen S, et al. Local and sys-
um difficile with enterocolitis and lactose intolerance in a foal. temic inflammatory and immunologic reactions to cyathos-
J Am Vet Med Assoc. 1999;214:229. tomin larvicidal therapy in horses. Vet Immunol and Immuno-
553. Roberts VLH, Knottenbelt DC, Williams A, et al. Suspected pathol. 2015;168:203.
primary lactose intolerance in neonatal foals. Equine Vet Educ. 578. Netherwood T, Wood JL, Townsend HG, et al. Foal diarrhoea
2008;20:249. between 1991 and 1994 in the United Kingdom associated with
554. Larsen J. Acute colitis in adult horses. A review with emphasis Clostridium perfringens, rotavirus, Strongyloides westeri and
on aetiology and pathogenesis. Vet Q. 1997;19:72. Cryptosporidium spp. Epidemiol Infect. 1996;117:375.
555. Stewart MC, Hodgson JL, Kim H, et al. Acute febrile diarrhoea 579. Lyons ET, Tolliver SC. Prevalence of patent Strongyloides wes-
in horses: 86 cases (1986–1991). Aust Vet J. 1995;72:41. teri infections in Thoroughbred foals in 2014. Parasitol Res.
556. Smith BP. Salmonella infection in horses. Compend Cont Educ 2014;113:4163.
Pract Vet. 1981;3:S4. 580. Galuppi R, Piva S, Castagnetti C, et al. Cryptosporidium parvum:
557. Jones RL. Clostridial enterocolitis. Vet Clin North Am Eq from foal to veterinary students. Vet Parasitol. 2016;219:53.
Pract16. 2000;471. 581. Liu A, Zhang J, Zhao, et al. The first report of Cryptosporidium
558. Diab SS, Songer G, Uzal FA. Clostridium difficile infection in andersoni in horses with diarrhea and multilocus subtype anal-
horses: a review. Vet Microbiol. 2013;167:42. ysis. Parasit Vectors. 2015;8:483.
559. East LM, Savage CJ, Traub-Dargatz JL, et al. Enterocolitis asso- 582. Cole DJ, Cohen ND, Snowden K, et al. Prevalence of and risk
ciated with Clostridium perfringens infection in neonatal foals: factors for fecal shedding of Cryptosporidium parvum oocysts in
54 cases (1988–1997). J Am Vet Med Assoc. 1998;212:1751. horses. J Am Vet Med Assoc. 1998;213:1296.
583. Wilson DA, MacFadden KE, Green EM, et al. Case control and 607. Weese JS, Staemplfi HR, Prescott JF. Test selections and inter-
historical cohort study of diarrhea associated with administra- pretation in the diagnosis of Clostridium difficile–associated
tion of trimethoprim-potentiated sulphonamides to horses and colitis. Proc Ann AAEP Conv. 1999;45:502.
ponies. J Vet Intern Med. 1996;10:258. 608. Hyatt DR, Weese JS. Salmonella culture: sampling procedures
584. Baverud V, Franklin A, Gunnarson A, et al. Clostridium diffi- and laboratory techniques. Vet Clin North Am Equine Pract.
cile associated with acute colitis in mares when their foals are 2004;20:577.
treated with erythromycin and rifampin for Rhodococcus equi 609. Cohen ND, Neibergs HL, Wallis DE, et al. Genus-specific
pneumonia. Equine Vet J. 1998;30:482. detection of salmonellae in equine feces by use of the polymer-
585. Costa MC, Stampfli HR, Arroyo LG, et al. Changes in the equine ase chain reaction. Am J Vet Res. 1994;55:1049.
fecal microbiota associated with the use of systemic antimicro- 610. Cohen ND, Martin LJ, Simpson RB, et al. Comparison of poly-
bial drugs. BMC Vet Res. 2015;11:19. merase chain reaction and microbiological culture for detection
586. Harlow BE, Lawrence LM, Flythe MD. Diarrhea-associated of salmonellae in equine feces and environmental samples. Am
pathogens, lactobacilli and cellulolytic bacteria in equine feces: J Vet Res. 1996;57:780.
responses to antibiotic challenge. Vet Microbiol. 2013;166:225. 611. Barlough JE, Rikihisa Y, Madigan JE. Nested polymerase chain
587. Karcher LF, Dill SG, Anderson WI, et al. Right dorsal colitis. J reaction for detection of Ehrlichia risticii genomic DNA in in-
Vet Intern Med. 1990;4:247. fected horses. Vet Parasitol. 1997;68:367.
588. Marshall JF, Blikslager AT. The effect of nonsteroidal anti- 612. Mott F, Rikihisa T, Zhang Y, et al. Comparison of PCR and
inflammatory drugs on the equine intestine. Equine Vet J Suppl. culture to the indirect fluorescent-antibody test for diagnosis of
2011;39:140. Potomac horse fever. J Clin Microbiol. 1997;35:2215.
589. McConnico RS, Morgan TW, Williams CC, et al. Pathophysi- 613. Magdesian KG, Leutenegger CM. Real-time PCR and typing
ologic effects of phenylbutazone on the right dorsal colon in of Clostridium difficile isolates colonizing mare foal pairs. Vet J.
horses. Am J Vet Res. 2008;69:1496. 2011;190:119.
590. Schmitz DG. Cantharidin toxicosis in horses. J Vet Intern Med. 614. Page AE, Slovis NM, Gebhart CJ, et al. Serial use of serologic
1989;3:208. assays and fecal PCR assays to aid in identification of subclini-
591. Abutarbush SM. Alfalfa dodder (Cuscuta campestris) toxicity cal Lawsonia intracellularis infection for targeted treatment
in horses: clinical, haematological and serum biochemical find- of Thoroughbred foals and weanlings. J Am Vet Med Assoc.
ings. Vet Rec. 2013;173:95. 2011;238:1482.
592. Smith S, Naylor RJ, Knowles EJ, et al. Suspected acorn toxicity 615. Ellis GR, Daniels E. Comparison of direct electron microscopy
in nine horses. Equine Vet J. 2015;47:568. and enzyme immunoassay for the detection of rotaviruses in
593. Renier AC, Kass PH, Magdesian KG, et al. Oleander toxi- calves, lambs, piglets and foals. Aust Vet J. 1988;65:133.
cosis in equids: 30 cases (1995–2010). J Am Vet Med Assoc. 616. Mino S, Kern A, Barrandeguy M, et al. Comparison of two com-
2013;242:540. mercial kits and an in-house ELISA for the detection of equine
594. Pace LW, Turnquist SE, Casteel SW, et al. Acute arsenic toxico- rotavirus in foal feces. J Virol Methods. 2015;222:1.
sis in five horses. Vet Pathol. 1997;34:160. 617. Jones SL, Davis J, Rowlingson K. Ultrasonographic findings in
595. Casteel SW. Metal toxicosis in horses. Vet Clin North Am Equine horses with right dorsal colitis: five cases (2000–2001). J Am Vet
Pract. 2001;17:517. Med Assoc. 2003;222:1248.
596. Taylor SD, Pusterla N, Vaugan B, et al. Intestinal neoplasia in 618. East LM, Trumble TN, Steyn PF, et al. The application of
horses. J Vet Intern Med. 2006;20:1429. technetium-99m hexamethylpropyleneamine oxime (99mTc-
597. Gianini M, Sutter O, Burger D, et al. Gastrointestinal and en- HMPAO) labeled white blood cells for the diagnosis of right
docrine function during “foal heat diarrhea” in healthy foals. J dorsal ulcerative colitis in two horses. Vet Radiol Ultrasound.
Reprod Fertil Suppl. 2000;56:717. 2000;41:360.
598. Olivett TL, Divers TJ, Cushing T, et al. Acute pancreatitis in two 619. Roberts MC, Norman P. A re-evaluation of the D (+) xylose
5-day-old Appaloosa foals. Equine Vet J Suppl. 2012;41:96. absorption test in the horse. Equine Vet J. 1979;11:239.
599. Cohen ND, Woods AM. Characteristics and risk factors for fail- 620. Mullen KR, Yasuda K, Divers TJ, et al. Equine faecal microbiota
ure of horses with acute diarrhea to survive: 122 cases (1990– transplant: current knowledge, proposed guidelines and future
1996). J Am Vet Med Assoc. 1999;214:382. directions. Equine Vet Educ. 2016. http://dx.doi.org/10.1111/
600. Mair TS, Taylor FG, Harbour DA, Pearson GR. Concurrent eve. 12559.
cryptosporidium and coronavirus infections in an Arabian 621. Schoster A, Weese JS, Guardabassi L. Probiotic use in horses—
foal with combined immunodeficiency syndrome. Vet Rec. what is the evidence for their clinical efficacy? J Vet Intern Med.
1990;126:127. 2014;28:1640.
601. Richards AF, Kelly DF, Knottenbelt DC, et al. Anaemia, diar- 622. Desrochers AM, Dolente BA, Roy MF, et al. Efficacy of Saccha-
rhoea and opportunistic infections in Fell ponies. Equine Vet J. romyces boulardii for treatment of horses with acute enterocol-
2000;32:386. itis. J Am Vet Med Assoc. 2005;227:954.
602. Sweeney RW, Sweeney CR, Saik J, et al. Chronic granuloma- 623. Groenendyk S, English PB, Abetz I. External balance of water
tous bowel disease in three sibling horses. J Am Vet Med Assoc. and electrolytes in the horse. Equine Vet J. 1988;20:189.
1986;188:1192. 624. Rumbaugh GE, Carlson GP, Harrold D. Urinary production in
603. Mair TS, Cripps PJ, Ricketts SW. Diagnostic and prognostic the healthy horse and in horses deprived of feed and water. Am
value of serum protein electrophoresis in horses with chronic J Vet Res. 1982;43:735.
diarrhoea. Equine Vet J. 1993;25:324. 625. Tasker JB. Fluid and electrolyte studies in the horses. III. Intake
604. Patton S, Mock RE, Drudge JH, et al. Increase of immunoglobulin and output of water, sodium and potassium in normal horses.
T concentrations in ponies as a response to experimental infection Cornell Vet. 1967;57:649.
with the nematode Strongylus vulgaris. Am J Vet Res. 1978;39:19. 626. Morris DD, Divers TJ, Whitlock RH. Renal clearance and frac-
605. Morris DD, Whitlock RH, Palmer JE. Fecal leukocytes and epi- tional excretion of electrolytes over a 24-hour period in horses.
thelial cells in horses with diarrhea. Cornell Vet. 1983;73:265. Am J Vet Res. 1984;45:2431.
606. Schoster A, Arroyo LG, Staempfli HR, et al. Presence and 627. Kohn CW, Strasser SL. 24-hour renal clearance and excretion of
molecular characterization of Clostridium difficile and Clostrid- endogenous substances in the mare. Am J Vet Res. 1986;47:1332.
ium perfringens in intestinal compartments of healthy horses. 628. Rose RJ. Electrolytes: clinical application. Vet Clin North Am
BMC Vet Res. 2012;8:94. Equine Pract. 1990;6:281.
629. Cymbaluk NF. Water balance of horses fed various diets. Equine 658. McGowan TW, Pinchbeck GP, McGowan CM. Prevalence, risk
Pract. 1989;11:19. factors and clinical signs predictive for equine pituitary pars in-
630. Sufit E, Houpt KA, Sweeting M. Physiological stimuli of thirst termedia dysfunction in aged horses. Equine Vet J. 2013;45:74.
and drinking patterns in ponies. Equine Vet J. 1985;17:12. 659. McFarlane D. Equine pituitary pars intermedia dysfunction. Vet
631. Brewer BD, Clement SF, Lotz WS, et al. Renal clearance, uri- Clin North Am Equine Pract. 2011;27:93.
nary excretion of endogenous substances and urinary diagnos- 660. Schott HC. Pituitary pars intermedia dysfunction: equine Cush-
tic indices in healthy neonatal foals. J Vet Intern Med. 1991;5:28. ing’s disease. Vet Clin North Am Equine Pract. 2002;18:237.
632. Edwards DJ, Brownlow MA, Hutchins DR. Indices of renal 661. Breukink HJ, Van Wegen P, Schotman AJH. Idiopathic diabetes
function; values in eight normal foals from birth to 56 days. insipidus in a Welsh pony. Equine Vet J. 1983;15:284.
Aust Vet J. 1990;67:251. 662. Filar J, Ziolo T, Szalecki J. Diabetes insipidus in the course of
633. Martin RG, McMeniman NP, Dowsett KF. Milk and water in- encephalitis in the horse. Med Weter. 1971;27:205.
takes of foals sucking grazing mares. Equine Vet J. 1992;24:295. 663. Morgan RA, Malalana F, McGowan CM. Nephrogenic diabetes
634. Rose BD. Clinical physiology of acid-base and electrolyte disor- insipidus in a 14-year-old gelding. N Z Vet J. 2012;60:254.
ders. New York: McGraw-Hill Information Services; 1989. 664. Schott HC, Bayly WM, Reed SM, et al. Nephrogenic diabetes
635. McCutcheon LJ, Geor RJ. Sweat fluid and ion losses in horses dur- insipidus in sibling colts. J Vet Intern Med. 1993;7:68.
ing training and competition in cool vs. hot ambient conditions: 665. Brashier M. Polydipsia and polyuria in a weanling colt caused
implications for ion supplementation. Equine Vet J. 1996;22(S):54. by nephrogenic diabetes insipidus. Vet Clin North Am Equine
636. Guyton AC, Hall J. Regulation of extracellular fluid osmolarity Pract. 2006;22:219.
and sodium concentration. In: Textbook of medical physiology. 666. Corke MJ. Diabetes mellitus: the tip of the iceberg. Equine Vet J.
Philadelphia: Elsevier Saunders; 2006. 1986;18:87.
637. Jamison RL, Maffly RH. The urinary concentrating mechanism. 667. Menzies-Gow N. Diabetes in the horse: a condition of increas-
N Engl J Med. 1976;295:1059. ing clinical awareness for differential diagnosis and interpreta-
638. Rotondo F, Butz H, Syro LV, et al. Arginine vasopressin (AVP): tion of tests. Equine Vet J. 2009;41:841.
a review of its historical perspectives, current research and mul- 668. Collobert C, Gillet JP, Sorel P, Minnelo J. Chronic pancreatitis
tifunctional role in the hypothalmo-hypophysial system. Pitui- associated with diabetes mellitus in a Standardbred racehorse: a
tary. 2016;19:345. case report. J Eq Vet Sci. 1990;10:58.
639. Boone M, Deen PM. Physiology and pathophysiology of the 669. Giri JK, Magdesian KG, Gaffney PM. Insulin-dependent diabe-
vasopressin-regulated renal water reabsorption. Pflugers Arch. tes mellitus associated with presumed autoimmune polyendo-
2008;456:1005. crine syndrome in a mare. Can Vet J. 2011;52:506.
640. Houpt KA, Thornton SN, Allen WR. Vasopressin in dehydrated 670. Navas de Solis C. Foreman JH: Transient diabetes mellitus
and rehydrated ponies. Physiol Behav. 1989;45:659. in a neonatal Thoroughbred foal. J Vet Emerg Critical Care.
641. Sands JM, Blount MA, Klein JD. Regulation of renal urea trans- 2010;20:611.
port by vasopressin. Trans Am Clin Climatol Assoc. 2011;122:82. 671. Jeffrey JR. Diabetes mellitus secondary to chronic pancreatitis
642. Houpt KA. Thirst in horses: the physiological and psychological in a pony. J Am Vet Med Assoc. 1968;153:1168.
causes. Equine Pract. 1987;9:28. 672. McCoy DJ. Diabetes mellitus associated with bilateral granulosa
643. Guyton AC, Hall J. Kidney diseases and diuretics. In: Textbook cell tumors in a mare. J Am Vet Med Assoc. 1986;188:733.
of Medical Physiology. Philadelphia: Elsevier Saunders; 2006. 673. Ruoff WW, Baker DC, Morgan SJ. Type II diabetes mellitus in a
644. Robertson GL. Diabetes insipidus: differential diagnosis and horse. Equine Vet J. 1986;18:143.
management. Best Pract Red Clin Endocrinol Metab. 2016;30:205. 674. Baker JR, Ritchie HE. Diabetes mellitus in the horse: a case re-
645. Schott HC. Water homeostasis and diabetes insipidus in horses. port and review of the literature. Equine Vet J. 1974;6:7.
Vet Clin North Am Equine Pract. 2011;27:175. 675. Durham AE, Hughes KJ, Cottle HJ, et al. Type 2 diabetes mel-
646. Geor RJ. Acute renal failure in horses. Vet Clin North Am Equine litus with pancreatic beta cell dysfunction in 3 horses confirmed
Pract. 2007;23:577. with minimal model analysis. Equine Vet J. 2009;41:924.
647. Schott HC. Chronic renal failure in horses. Vet Clin North Am 676. Muylle E, van den Hende C, et al. Non–insulin dependent dia-
Equine Pract. 2007;23:593. betes mellitus in a horse. Equine Vet J. 1986;18:145.
648. Buntain BJ, Coffman JR. Polyuria and polydipsia in a horse in- 677. Sneddon JC, Colyn P. A practical system for measuring water
duced by psychogenic salt consumption. Equine Vet J. 1981;13:266. intake in stabled horses. Equine Vet Sci. 1991;11:141.
649. Taylor FGR, Hillyer MH. The differential diagnosis of hypergly- 678. Harris P. Collection of urine. Equine Vet J. 1988;20:86.
caemia in horses. Equine Vet Educ. 1992;4:135. 679. van den Berg IS. Modified apparatus for collection of free-flow
650. Knottenbelt DC. Polyuria-polydipsia in the horse. Equine Vet urine from mares. J S Afr Vet Assoc. 1996;67:214.
Educ. 2000;12:179. 680. Tasker JB. Fluid and electrolyte studies in the horse. II. An
651. McKenzie EC. Polyuria and polydipsia in horses. Vet Clin North apparatus for the collection of total daily urine and feces from
Am Equine Pract. 2007;23:641. horses. Cornell Vet. 1966;56:77.
652. Rye SH, Kim BS, Lee CW, et al. Glucocorticoid-induced 681. Kohn CW, Chew DJ. Laboratory diagnosis and characteriza-
laminitis with hepatopathy in a Thoroughbred filly. J Vet Sci. tion of renal disease in horses. Vet Clin North Am Equine Pract.
2004;5:271. 1987;3:585.
653. Browning AP. Polydipsia and polyuria in two horses caused by 682. Bickhardt K, Deegen E, Espelage W. Kidney function tests in
psychogenic polydipsia. Equine Vet Educ. 2000;12:175. horses—methods and reference values in healthy animals.
654. Andersson B, Rundgren M. Thirst and its disorders. Ann Rev Dtsch Tierarztl Wochenschr. 1996;103:117.
Med. 1982;33:231. 683. Satoh H, Abe S, Kato M, et al. Optimum conditions for serum
655. Robertson GL. Abnormalities of thirst regulation. Kidney Inter- clearance of iodixanol, applicable to the estimation of glomeru-
national. 1984;25:460. lar filtration rate in horses. Vet Res Commun. 2011;35:463.
656. Sturgeon BP, Bassett H. Polydipsia in a foal with renal helmin- 684. Nabity MB, Lees GE, Boggess MM, et al. Symmetric dimethyl
thiasis. Vet Rec. 2000;147:23. arginine assay validation, stability and evaluation as a marker
657. Wooldridge AA, Seahorn TL, Williams J, et al. Chronic renal for the early detection of chronic kidney disease in dogs. J Vet
failure associated with nephrolithiasis, ureterolithiasis, and re- Intern Med. 2015;29:1036.
nal dysplasia in a 2-year-old Quarter Horse gelding. Vet Radiol 685. Brobst DF, Bayly WM. Responses of horses to a water depriva-
Ultrasound. 1999;40:361. tion test. J Equine Vet Sci. 1982;2:51.
686. Genetzky RM, Loparco FV, Ledet AE. Clinical pathologic al- 708. Hubert JD, Beadle RE, Norwood G. Equine anhidrosis. Vet Clin
terations in horses during a water deprivation test. Am J Vet Res. North Am Equine Pract. 2002;18:355.
1987;48:1007. 709. Richard EA, Fortier GD, Pitel PH, et al. Sub-clinical diseases af-
687. Brown CM. Problems in equine medicine. Philadelphia: Lea & fecting performance in Standardbred trotters: diagnostic meth-
Febiger; 1989. ods and predictive parameters. Vet J. 2010;184:282.
688. Zimmer EL. Water deprivation test and vasopressin challenge. 710. Fraipont A, Van Erck E, Ramery E, et al. Subclinical diseases
In: Equine medicine and surgery. Goleta, CA: American Veteri- underlying poor performance in endurance horses: diagnostic
nary Publications; 1991. methods and predictive tests. Vet Rec. 2011;169:154.
689. Velie BD, Hamilton NA, Wade CM. Heritability of racing per- 711. Dabareiner RM, Cohen ND, Carter GK, et al. Lameness and
formance in the Australian Thoroughbred racing population. poor performance in horses used for team roping: 118 cases
Anim Genet. 2015;46:23. (2000–2003). J Am Vet Med Assoc. 2005;226:1694.
690. Hill EW, McGivney BA, Gu J, et al. A genome-wide SNP- 712. Gorgas D, Luder P, Lang J, et al. Scintigraphic and radio-
association study confirms a sequence variant (g.66493737C>T) graphic appearance of the sacroiliac region in horses with gait
in the equine myostatin (MSTN) gene as the most powerful abnormalities or poor performance. Vet Radiol Ultrasound.
predictor of optimum racing distance for Thoroughbred race- 2009;50:208.
horses. BMC Genomics. 2010;11:552. 713. Aleman M. A review of equine muscle disorders. Neuromuscul
691. Jonsson L, Egenvall A, Roepstorff L, et al. Associations of health Disord. 2008;18:277.
status and conformation with longevity and lifetime competi- 714. McCue ME, Valberg SJ, Lucio M, et al. Glycogen synthase
tion performance in young Swedish Warmblood riding horses. (GYS1) mutation in diverse breeds with polysaccharide storage
J Am Vet Med Assoc. 2014;244:1449. myopathy. J Vet Intern Med. 2008;22:1228.
692. Dyson S. Lameness and poor performance in the sports horse: 715. Fritz KL, McCue ME, Valberg SJ, et al. Genetic mapping of
dressage, show jumping and horse trials (eventing). AAEP Pro- recurrent exertional rhabdomyolysis in a population of North
ceedings. 2000;46:308. American Thoroughbreds. Anim Genet. 2012;43:730.
693. Dyson SJ. Lesions of the equine neck resulting in lameness or 716. Valberg SJ, Carlson GP, Cardinet GH, et al. Skeletal muscle
poor performance. Vet Clin North Am Equine Pract. 2011;27:417. myopathy as a cause of exercise intolerance in a horse. Muscle
694. Girodroux M, Dyson S, Murray R. Osteoarthritis of the thora- Nerve. 1994;17:305.
columbar synovial intervertebral articulations: clinical and 717. Valberg SJ, McKenzie EC, Eyrich LV, et al. Suspected myofi-
radiographic features in 77 horses with poor performance and brillar myopathy in Arabian horses with a history of exertional
back pain. Equine Vet J. 2009;41:130. rhabdomyolysis. Equine Vet J. 2015. http://dx.doi.org/10.1111/
695. Rose RJ. Poor performance: a clinical and physiological per- evj.12493.
spective. Proceedings of the 19th American College of Veterinary 718. Bedford HE, Valberg SJ, Firshman AM, et al. Histopathologic
Internal Medicine Forum. 2001;224. findings in the sacrocaudalis dorsalis medialis muscle of horses
696. Rivero JL, Hill EW. Skeletal muscle adaptations and muscle with vitamin E–responsive muscle atrophy and weakness. J Am
genomics of performance horses. Vet J. 2016;209:5. Vet Med Assoc. 2013;242:1127.
697. Kearns CF, McKeever KH, Abe T. Overview of horse body 719. Tan RH, Dowling BA, Dart AJ. High-speed treadmill videoen-
composition and muscle architecture: implications for perfor- doscopic examination of the upper respiratory tract in the
mance. Vet J. 2002;164:224. horse: the results of 291 clinical cases. Vet J. 2005;170:243.
698. Evans DL. Physiology of equine performance and associated 720. Maxson-Sage A, Parente EJ, Beech J, et al. Effect of high-intensity
tests of function. Equine Vet J. 2007;39:373. exercise on arterial blood gas tensions and upper airway and
699. Morris EA, Seeherman HJ. Clinical evaluation of poor perfor- cardiac function in clinically normal Quarter Horses and horses
mance in the racehorse: the results of 275 evaluations. Equine heterozygous and homozygous for hyperkalemic periodic paraly-
Vet J. 1991;23:169. sis. Am J Vet Res. 1998;59:615.
700. Martin BB, Reef VB, Parente EJ, et al. Causes of poor perfor- 721. Allen KJ, Tremaine WH, Franklin SH. Prevalence of inflam-
mance of horses during training, racing or showing: 348 cases matory airway disease in national hunt horses referred for
(1992–1996). J Am Vet Med Assoc. 2000;216:554. investigation of poor athletic performance. Equine Vet J Suppl.
701. Seeherman HJ, Morris E, O’Callaghan MW. The use of sports 2006;36:529.
medicine techniques in evaluating the problem equine athlete. 722. Salz RO, Ahern BJ, Boston R, et al. Association of tracheal mu-
Vet Clin North Am Equine Pract. 1991;7:259. cus or blood and airway neutrophilia with racing performance
702. Brown JA, Hinchcliff KW, Jackson MA, et al. Prevalence of in Thoroughbred horses in an Australian racing yard. Aust Vet
pharyngeal and laryngeal abnormalities in Thoroughbreds rac- J. 2016;94:96.
ing in Australia, and their association with performance. Equine 723. Back H, Penell J, Pringle J, et al. A longitudinal study of poor
Vet J. 2005;37:397. performance and subclinical respiratory viral activity in Stand-
703. Pirrone F, Albertini M, Clement MG, et al. Respiratory mechan- ardbred trotters. Vet Rec Open. 2015;2:e000107.
ics in Standardbred horses with sub-clinical inflammatory air- 724. Back H, Ullman K, Treiberg Berndtsson L, et al. Viral load of
way disease and poor athletic performance. Vet J. 2007;173:144. equine herpesviruses 2 and 5 in nasal swabs of actively rac-
704. Evans DL, Kiddell L, Smith CL. Pulmonary function measure- ing Standardbred trotters: temporal relationship of shedding
ments immediately after exercise are correlated with neutrophil to clinical findings and poor performance. Vet Microbiol.
percentage in tracheal aspirates in horses with poor racing per- 2015;179:142.
formance. Res Vet Sci. 2011;90:510. 725. Barbesgaard L, Buhl R, Meldgaard C. Prevalence of exercise-
705. Sanchez A, Couetil LL, Ward MP, et al. Effect of airway dis- associated arrhythmias in normal performing dressage horses.
ease on blood gas exchange in racehorses. J Vet Intern Med. Equine Vet J Suppl. 2010;38:202.
2005;19:87. 726. Buhl R, Meldgaard C, Barbesgaard L. Cardiac arrhythmias
706. Tamzali Y, Marguet C, Priymenko N, et al. Prevalence of gastric in clinically healthy showjumping horses. Equine Vet J Suppl.
ulcer syndrome in high-level endurance horses. Equine Vet J. 2010;38:196.
2011;43:141. 727. Jose-Cunilleras E, Young LE, Newton JR, et al. Cardiac ar-
707. Leahy ER, Burk AO, Greene EA, et al. Nutrition-associated rhythymias during and after treadmill exercise in poorly
problems facing elite level three-day eventing horses. Equine performing Thoroughbred racehorses. Equine Vet J Suppl.
Vet J Suppl. 2010;38:370. 2006;36:163.
728. King CM, Evans DL, Rose RJ. Significance for exercise capacity 747. Chalmers HJ, Cheetham J, Yeager AE, et al. Ultrasonography of
of some electrocardiographic findings in racehorses. Aust Vet J. the equine larynx. Vet Radiol Ultrasound. 2006;47:476.
1994;71:200. 748. Meyer C, Gerber R, Guthrie AJ. The use of the standard exer-
729. Kriz NG, Hodgson DR, Rose RJ. Prevalence and clinical im- cise test to establish the clinical significance of mild echocardio-
portance of heart murmurs in racehorses. J Am Vet Med Assoc. graphic changes in a Thoroughbred poor performer. J S Afr Vet
2000;216:1441. Assoc. 2004;75:100.
730. Zucca E, Ferrucci F, Stancari G, et al. The prevalence of cardiac 749. Durando MM, Reef VB, Birks EK. Right ventricular pressure
murmurs among Standardbred racehorses presented with poor dynamics during exercise: relationship to stress echocardiogra-
performance. J Vet Med Sci. 2010;72:781. phy. Equine Vet J Suppl. 2002;34:472.
731. Leleu C, Cotrel C. Body composition in young Standardbreds 750. Seeherman HJ, Morris EA. Methodology and repeatability of
in training: relationships to body condition score, physiologic a standardized treadmill exercise test for clinical evaluation of
and locomotor variables during exercise. Equine Vet J Suppl. fitness in horses. Equine Vet J Suppl. 1990;9:20.
2006;36:98. 751. Seeherman HJ. Treadmill exercise testing: treadmill installation
732. Garlinghouse SE, Burrill MJ. Relationship of body condi- and training protocols used for clinical evaluations of equine
tion score to completion rate during 160 km endurance races. athletes. Vet Clin North Am Equine Pract. 1991;7:259.
Equine Vet J Suppl. 1999;30:591. 752. Leleu C, Cotrel C, Courouce-Malblanc A. Relationships be-
733. McGowan CM, Golland LC, Evans DL, et al. Effects of pro- tween physiological variables and race performance in French
longed training, overtraining and detraining on skeletal muscle Standardbred trotters. Vet Rec. 2005;156:339.
metabolites and enzymes. Equine Vet J Suppl. 2002;34:257. 753. Evans DL, Rose RJ. Method of investigation of the accuracy
734. Greve L, Dyson S. The horse-saddle-rider interaction. Vet J. of four digital-display heart rate meters suitable for use in the
2013;195:275. exercising horse. Equine Vet J. 1986;18:129.
735. Hemberg E, Kindahl H, Lundeheim N, et al. Relationships be- 754. Evans DL, Rose RJ. Cardiovascular and respiratory responses
tween early foal health, future performance and their dams in Thoroughbred horses during treadmill exercise. J Exp Biol.
reproductive health. Reprod Domest Anim. 2010;45:817. 1988;134:397.
736. Boyko AR, Brooks SA, Behan-Braman A, et al. Genomic as- 755. Evans DL, Rose RJ. Determination and repeatability of maxi-
sociation establishes correlation between growth and laryngeal mum oxygen uptake and other cardiorespiratory measurements
neuropathy in Thoroughbreds. BMC Genomics. 2014;15:259. in the exercising horse. Equine Vet J. 1988;20:94.
737. Rose RJ, Allen JR, Hodgson DR, et al. Response to submaximal 756. Rose RJ, Hendrickson DK, Knight PK. Clinical exercise testing
treadmill exercise and training in the horse: changes in haema- in the normal Thoroughbred racehorse. Aust Vet J. 1990;67:345.
tology, arterial blood gas and acid base measurements, plasma 757. Evans DL, Harris RC, Snow DH. Correlation of racing perfor-
biochemical values and heart rate. Vet Rec. 1983;113:612. mance with blood lactate and heart rate after exercise in Thor-
738. Rose RJ, Allen JR. Hematologic responses to exercise and train- oughbred horses. Equine Vet J. 1993;25:441.
ing. Vet Clin North Am Equine Pract. 1985;1:461. 758. Rasanen, Lampinen KF, Poso AR. Responses of blood and plas-
739. Tyler-McGowan CM, Golland LS, Evans DL, et al. Haemato- ma lactate and plasma purine concentrations to maximal exer-
logical and biochemical responses to training and overtraining. cise and their relation to performance in Standardbred trotters.
Equine Exerc Physiol Suppl. 1999;30:621. Am J Vet Res. 1995;56:1651.
740. Hamlin MJ, Shearman JP, Hopkins WG. Changes in physiolog- 759. Vaihkonen LK. Hyyppa, Poso AR. Factors affecting accumula-
ic parameters in overtrained Standardbred racehorses. Equine tion of lactate in red blood cells. Equine Vet J Suppl. 1999;30:443.
Vet J. 2002;34:383. 760. Rainger JE, Evans DL, Hodgson DR, et al. Distribution of lac-
741. McKeever KH, Hinchcliff KW, Reed SM, et al. Role of decreased tate in plasma and erythrocytes during and after exercise in
plasma volume in hematocrit alterations during incremental horses. Br Vet J. 1995;151:299.
treadmill exercise in horses. Am J Physiol. 1993;265:R404. 761. Poso AR, Lampinen KJ, Rasanen LA. Distribution of lactate be-
742. Persson SGB, Osterberg I. Racing performance in red blood tween red blood cells and plasma after exercise. Equine Vet J
cell hypervolaemic Standardbred trotters. Equine Vet J Suppl. Suppl. 1995;18:231.
1999;30:617. 762. Bayly WM, Shultz DA, Hodgson DR, et al. Ventilatory r esponses
743. Dart AJ, Dowling BA, Hodgson DR, et al. Evaluation of high- of the horse to exercise: effect of gas collection systems. J Appl
speed treadmill videoscopy for diagnosis of upper respiratory Physiol. 1987;63:1210.
tract dysfunction in horses. Aust Vet J. 2001;79:109. 763. Christley RM, Evans DL, Hodgson DR, et al. Blood gas c hanges
744. Christley RM, Hodgson DR, Evans DL, et al. Cardiorespiratory during incremental and sprint exercise. Equine Vet J Suppl.
responses to exercise in horses with different grades of idiopath- 1999;30:24.
ic laryngeal hemiplegia. Equine Vet J. 1997;29:6. 764. Bayly WM, Hodgson DR, Schulz DA, et al. Exercise-induced
745. King CM, Evans DL, Rose RJ. Cardiorespiratory and metabolic hypercapnia in the horse. J Appl Physiol. 1989;67:958.
responses to exercise in horses with various abnormalities of the 765. Christley RM, Hodgson DR, Evans DL, et al. Effects of training
upper respiratory tract. Equine Vet J. 1994;71:200. on the development of exercise-induced arterial hypoxemia in
746. Holcombe SJ, Derksen FJ, Stick JA, et al. Pathophysiology of horses. Am J Vet Res. 1997;58:653.
dorsal displacement of the soft palate in horses. Equine Vet J 766. Barrey E, Evans SE, Evans DL, et al. Locomotion evaluation for
Suppl. 1999;30:45. racing in Thoroughbreds. Equine Vet J Suppl. 2001;33:99.
C HA P T E R 8
Disorders of the Respiratory System
Elizabeth Davis*
Equine respiratory disease is the second most common dis- The combination of turbulence and anatomic organization
order that limits performance in horses, ranked only behind effectively removes particles as small as 5 μm, so that only
musculoskeletal disease in importance.1,2 Specifically, the particles less than this dimension reach the alveoli.
metabolic requirements of the pulmonary system include Once the material has passed this level of protection and
the transfer of oxygen from inspired air to the arterial system has gained entrance to the proximal trachea the mucocili-
for delivery to the tissues. Concurrently, the carbon diox- ary escalator mechanism will offer protection through trap-
ide generated during cellular metabolism must be delivered ping, the coughing reflex, and expulsion of material from the
to the lungs by the venous system and exhaled. Pulmonary airways. Respiratory system mucous secretion is a continual
functional requirements increase dramatically during exer- process that aids with the removal of airway debris and par-
cise, which is why horses are recognized as elite athletes, as ticles. Mucous flow moves from the bronchioles in a rostral
evidenced by wide fluctuations in gas exchange capabilities direction toward the bronchi and trachea due to the wavelike
during exercise. Even though the respiratory system is highly motion of the ciliated respiratory epithelium, and a similar
integrated with other body systems such as the musculoskel- but opposite movement of material passes from the nasal pas-
etal, central nervous, and endocrine systems, the respira- sages toward the pharynx. The mucociliary escalator is highly
tory system has been well recognized as the limiting factor effective based on the composition of the double layer of
in determining athletic performance. For this reason, even mucus that extends from the pharynx to the bronchioles. The
early, mild, or subclinical respiratory disease will reduce particle-laden mucus is swallowed and presumably digested in
the performance capacity of horses. Therefore, it is ideal to the intestinal tract.
identify horses that suffer from respiratory disease early in Respiratory mucous secretions are produced by airway
the course of events so that the clinician can provide specific goblet cells that line the airway mucosa. The mucous gel is
and effective care that will enable a favorable prognosis to be highly effective at adsorption of soluble host molecules, which
given. This is facilitated by the fact that, from a diagnostic include host defensin peptides, cathelicidins, lactoferrin, lyso-
standpoint, many aspects of the equine respiratory tract are zyme, and surfactant proteins.3,4 The majority of microbial
highly accessible and easily evaluated, and, when pathology organisms that encounter this barrier are rapidly destroyed.
is present, these conditions are often responsive to a variety Those particles that escape the mucociliary clearance mecha-
of therapeutic modalities. nism will reach the alveoli and be cleared via phagocytosis by
The primary defense of the respiratory tract includes a alveolar macrophages, which will also enter the mucociliary
combination of nonspecific, generalized, and highly spe- clearance mechanism.
cialized protective mechanisms. Nonspecific protection is There are four major surfactant proteins produced by
offered by anatomic organization, microbial, and nonspecific alveolar type II cells in pulmonary fluid secretions: surfac-
immunologic mechanisms. Anatomic protection is provided tant protein (SP)-A, SP-B, SP-C, and SP-D. SP-B and SP-C
by the organization of the upper respiratory tract, nasal pas- are highly hydrophobic, which provides for low surface ten-
sages, lymphoid tissue, and pulmonary clearance mecha- sion within the alveoli, preventing lung collapse. In contrast,
nisms. For instance, when particulate material is inhaled, SP-A and SP-D are antimicrobial because of their hydrophilic
anatomic upper respiratory tract barriers provide a valuable nature. These proteins belong to the collectin family of anti-
mechanism for removal via local trapping at the level of the microbial peptides and provide an innate defense mechanism
nasal respiratory mucosa. Particles that are suspended in the against pathogen challenge.5 Their hydrophilic nature enables
inhaled air are largely removed by turbulent air flow that them to bind to the surface of pathogens via their carbohy-
redirects their movement toward the mucus-covered epithe- drate moieties and act as opsonins. Additional immunologic
lial surface. Turbulence created in the airstream results from properties provided by SP-A and SP-D include macrophage
the conformation of the turbinates, trachea, and bronchi. activation, facilitation of chemotaxis, enhancement of respi-
ratory burst activity, and inflammatory cytokine expression.
* The editors and authors acknowledge and appreciate the contributions of SPs facilitate apoptotic cell removal from lower airways, which
Dorothy M. Ainsworth and Jonathan Cheetham as previous contributors is particularly important for the resolution of pulmonary
to this chapter. Some of their original work has been incorporated into this inflammation. Failure of effective macrophage phagocytosis
edition. leads to the persistence of degraded or apoptotic neutrophils
313
314 PART 2 DISORDERS OF SPECIFIC BODY SYSTEMS
and cellular debris, which can serve as a nidus for persistent

airway inflammation.
The respiratory tract contains an abundant arrangement of
lymphoid structures with lymphocytes diffusely distributed
throughout the lung and along the airways. Mucosa in the
proximal larynx contains a large repertoire of T lymphocytes.
Microfold (M) cells are located along lymphoid nodules as well
as in association with nasal lymphoid tissues. The predominant
immunoglobulin (Ig) molecule in this location is secretory
IgA, with the greatest concentrations in the upper respiratory
tract. Secretory IgA is bound to the mucous layer through the
secretory component, which facilitates the clearance of adher-
ent bacteria. More distal regions of the respiratory tract contain
greater concentrations of IgG, particularly in the bronchioles
and alveoli. An additional antibody molecule present in the
upper respiratory tract includes IgE. Notably, IgA facilitates host
protection through the process of immune exclusion, which
prevents the entry of potential pathogens through the respira-
tory epithelium. In contrast, other antibodies typically provide
effective immunity through the process of immune elimination,
which aims to target the pathogen for destruction and removal
through the process of opsonization.
Many resident cells can be found in the lower airways. In FIG. 8.1 A 7-year-old Saddlebred mare presented for 2-year history of
upper airway noise. Endoscopy revealed a subepiglottic cyst.
healthy horses approximately 50% of the cells in bronchoal-
veolar lavage fluid (BALF) are macrophages, whereas approxi-
mately 40% are lymphocytes and <5% are neutrophils. Based contribute to colonization of the lower airways with commen-
on this cellular composition (i.e., a preponderance of pulmo- sals from the upper respiratory tract and oral cavity include
nary T lymphocytes and alveolar macrophages), cell-mediated stress, long-distance transport, esophageal obstruction, and
immune activation may be induced in the lower airways under prolonged head elevation.5-7
certain stimulatory conditions. Also, horses are a species that
expresses pulmonary intravascular macrophages (PIMs),
which provide the equine host with the capacity for clearance Y PATIENT ASSESSMENT
of blood-borne pathogens, resulting in the lung potentially
serving as a shock organ. For instance, if marked bacteremia Signalment
or other pathogen challenges occur as blood passes through
pulmonary capillary beds, PIM activation can contribute to Specific patient details may provide insightful information
marked systemic inflammatory response mechanisms. regarding the potential for certain diseases. Congenital or
Although the respiratory tract may be considered as a rela- developmental disorders are more likely to manifest as clini-
tively sterile environment, in reality it contains abundant flora or cal disorders in young animals. Examples of such congeni-
a microbiome that provides an important endogenous protection tal abnormalities include choanal atresia, subepiglottic cysts
barrier. Similar to other surfaces, the mucosa of the respiratory (Fig. 8.1), hypoplastic lungs, or expression of upper airway
tract is far from a sterile surface because of the presence of the disorders associated with hyperkalemic periodic paralysis
extensive microflora, which provides beneficial microbes aimed (HYPP). Acquired disorders such as infections with Rhodo-
at maintaining microbial homeostasis. The symbiotic relationship coccus (Prescottia8) equi or S. equi subsp. zooepidemicus are
provided by the diverse microflora or microbiota is well main- generally evident at 2 to 3 months of age.
tained in the healthy host. Disruption of this microbial popula- Similarly, performance-associated disorders such as
tion, damage to the normal clearance mechanisms, or mechanical epistaxis with short-burst breezing or barrel racing may
epithelial damage may, however, result in altered microbial popu- increase the index of suspicion for exercise-induced pulmo-
lations leading to pathogen proliferation or invasion. nary hemorrhage (EIPH), whereas having historical infor-
The upper respiratory tract contains an abundant micro- mation that includes awareness of indoor patient housing
flora of aerobic and anaerobic bacteria, which provides an during adverse weather conditions in association with the
essential competitive barrier to pathogen colonization.3 When development of cough in a riding horse will make allergic
horses suffer from lower airway infection it is typically caused airway inflammation more likely.
by colonization with an opportunistic organism from the
upper airways. Bacterial isolates associated with the healthy Diagnostic Considerations
flora of the upper respiratory tract include Streptococcus spp., When the initial examination is conducted it is imperative
Pasteurella spp., Escherichia coli, and Actinomyces spp. In addi- that the clinician collect a complete and pertinent history,
tion to common aerobic isolates, anaerobic bacteria predomi- although there may be extraneous factors that influence the
nate in the healthy equine oral cavity, including Bacteroides presenting complaint. Historical information combined with
fragilis, Fusobacterium spp., Eubacterium spp., Clostridium a thorough evaluation at the time of presentation should aid
spp., Veillonella spp., and Megasphaera spp.4 Although patho- the clinician in determining the source of the problem. Diag-
genetic mechanisms associated with lower airway disease nostic examination of the respiratory tract can be achieved
are complex and commonly multifactorial, risk factors that with a variety of modalities that include (but are not limited
CHAPTER 8 Disorders of the Respiratory System 315
Classification of Equine
Respiratory Disease
Lower
Upper
Cough ± Increase in respiratory effort
Nasal discharge Fever
Fever Lethargy
Lethargy Nasal discharge
Lymphadenopathy + History
Cough
Yes No Yes No, No

other signs exercise other signs
impairment
Infectious/ Non-contagious Infectious Inflammatory Other

contagious
Bacterial Arytenoid Bacterial Inflammatory EIPH

chondritis Bronchopneumonia/ Airway
S. equi Neoplasia:
Pleuropneumonia Disease
Lyphoid primary or
Viral pharyngeal Recurrent metastatic
Parasitic
hyperplasia pneumonitis Airway
EIV Obstruction
EHV-1/4 Neoplasia
EHV-2 Other:
Guttural pouch EMPF/EHV5 Parasitic,
EVA mycosis
AdVA/B MEED/IEPz
FIG. 8.2 Flowchart diagram differentiating various classifications of equine respiratory diseases. EHV,
Equine herpesvirus; EIV, equine influenza virus; EMPF, equine multinodular pulmonary fibrosis; EVA, equine
virus arteritis.
to) endoscopy, ultrasound, radiography, and respiratory head and neck. The phase of respiration that is abnormal typi-
secretion evaluation using transtracheal aspiration and/or cally aids the clinician with insight into the origin of the respira-
bronchoalveolar lavage (BAL) for the collection of samples tory tract disorder. Obstructive and restrictive airway diseases
for culture or cellular analysis, respectively. Advanced imag- can generally be distinguished by differences in respiratory
ing techniques include computed tomography (CT) or mag- efforts. Marked inspiratory difficulty, particularly in combina-
netic resonance imaging (MRI), which may be used for the tion with an audible noise, is consistent with obstructive upper
examination of the upper respiratory tract in adult horses or airway disease. The very low airway pressure of the upper respi-
the entire respiratory tract in small horses/ponies or foals. ratory tract is exacerbated during inspiration, which is caused
Respiratory diseases in horses are typically categorized as by the movement of soft tissue structures into the lumen in a
upper or lower airway diseases and infectious or noninfectious. dynamic manner, exacerbating airway obstruction of the upper
Some authors prefer to categorize these conditions according to respiratory tract. Conversely, a prolonged expiratory phase of
those that are contagious and noncontagious, as well as infec- respiration, combined with a marked expiratory respiratory
tious and inflammatory or other independent disorders. One effort, provides the clinician with evidence of lower airway
way of classifying these disorders is reflected in Fig. 8.2. obstruction. During expiration, intrathoracic pressure is posi-
tive, which narrows the diameter of small airways. If disease
Physical Examination includes smooth muscle contraction, mucous production, and
Physical examination should commence with the examina- increased airway cellularity, these conditions collectively con-
tion of respiratory rate, effort, and pattern at rest. The clinician tribute to the development of lower airway obstruction.
should observe the horse in a natural, relaxed environment. It is Physical examination of the respiratory tract begins with
ideal if the clinician can observe the horse from various angles the head. Observation of the character, frequency, and lateral-
to specifically observe the inspiratory and expiratory efforts, ization of nasal discharge may reflect the origin of the disease.
evidence of nostril flare, abdominal push, or other alteration Inspiratory noise is characteristic of upper airway obstruc-
from normal respiratory parameters. The normal respiratory tion. Maxillary sinusitis may present with unilateral discharge,
rate is 8 to 12 breaths per minute. Anxiety, pain, acidosis, hyper- facial deformity, and/or epiphora. Rostral components of the
thermia, and stress are among the more common reasons that respiratory tract should be carefully examined for nostril flare,
horses can have an increase in respiratory rate. Therefore, the nasal discharge, and appropriate air flow. Nostril flare is not
clinician must examine all facets of the patient’s status before specific for any condition because it may be observed in asso-
making the diagnosis of primary respiratory disease. ciation with either upper or lower airway disease. However,
Clinical signs consistent with respiratory distress in horses nostril flare observed in combination with prolonged inspi-
include flared nostrils, anxious facial expression, and extended ration and audible noise justifies concern regarding possible
upper airway obstruction. Sounds originating from the upper sudden equalization of pressure in two compartments after
respiratory tract are classified as stridor, roar, or snore. Strid- airways have reopened. Crackles are often audible in horses
ulous respiratory sounds are characterized by high-pitched with pneumonia, pulmonary edema, or recurrent airway
inspiratory noise. Diseases characterized by inspiratory stri- obstruction (RAO). Breathing 100% oxygen also may produce
dor include bilateral laryngeal paralysis, a marked pharyngeal crackles because the nitrogen stent maintaining alveolar dis-
or retropharyngeal mass or lymphadenopathy/abscess, aryte- tention is eliminated.10 Crackles are also audible in horses with
noid chondritis, and pharyngeal collapse as observed in cases subcutaneous emphysema. Wheezes are high-pitched musical
of Quarter Horses with HYPP. Roaring is a very distinctive sounds thought to arise from the vibration of airway walls or
noise that occurs when exercising horses suffering from left tissue masses in close contact with the airway walls and may be
laryngeal hemiplegia make a low-pitched noise. These horses audible during inspiration or expiration. Pleuritic friction rubs
do not make any audible noise at rest. Unilateral nasal pas- are sandpaper-like sounds generated by visceral and parietal
sage obstructions lead to the development of snoring noise. pleural movement. Percussion of the thorax is accomplished
On physical examination, these horses will be noted to have by evaluating the types of sounds produced as one system-
asymmetric airflow through their nostrils and accordingly atically taps the intercostal spaces (ICS) of the thorax using a
develop a low-pitched noise that originates from the obstruc- plexor and pleximeter (foals) or a large spoon and neurologic
tion in the nasal passages. An exercise-associated low-pitched hammer (adults). Aerated tissues produce a resonant sound,
fluttering sound can be heard with dorsal displacement of the whereas fluid-filled structures (bowel, heart, lung abscesses,
soft palate (DDSP). This might be associated with exercise and consolidated lung) produce a dull sound. The examiner
intolerance, particularly in horses like Thoroughbreds that should identify the transitional site in which the sound quality
work at high speed. In the majority of cases, the origin of the changes during percussion to establish the boundaries of lung
airway noise can be successfully identified with standing and/ fields. Defining caudal lung borders with thoracic percussion
or dynamic endoscopy. is consistent with limits identified by thoracic ultrasonogra-
phy.11 Under normal conditions performing thoracic percus-
sion should not result in pain or discomfort to the patient; if
Y EXAMINATION OF THE LOWER the horse appears uncomfortable or distressed this may indi-
RESPIRATORY TRACT cate pleural pain or the presence of rib fractures. Percussion
that reveals ventral dullness suggests pleural effusion, pleural
Examine the horse during eupneic and hyperpneic (by use thickening, lung consolidation, masses, or pericardial effu-
of a rebreathing bag) breathing. Normal breath sounds are sion. Occasionally, caudal borders may be expanded, suggest-
those produced by turbulent air movement through the tra- ing alveolar overinflation, which may accompany recurrent
cheobronchial tree and vary in intensity and quality depend- airway disease.
ing on the portion of the lung field auscultated. Vesicular
sounds, heard over the middle and diaphragmatic lung lobes, Endoscopy
are the quietest. Bronchial sounds, which are audible over Endoscopic examination is a cost -efficient diagnostic modality
the trachea and the base of the lung, are the loudest. In the that enables the clinician to visualize many critical structures
healthy horse, one can hear breath sounds more easily on of the upper and lower respiratory tract. Horses are tolerant of
the right side than on the left. Considerable variation exists endoscopic examination and in some instances do not require
among healthy patients in the intensity of the breath sounds. sedation, which may be highly desirable when examining laryn-
For example, vesicular sounds are often barely audible dur- geal function. In some clinical settings light to moderate sedation
ing normal breathing, whereas in the obese patient they have provides the clinician with the ability to effectively complete a
been described as soft rustling sounds. One may hear breath thorough endoscopic examination. Endoscopic examination of
sounds more easily in a thin or young animal because of less the respiratory tract provides a diagnostic tool that can be easily
attenuation of lung sounds by the chest wall. The intensity adapted to a variety of equine patients, regardless of size or age.
of breath sounds also increases with increased airflow. Thus The broad utility of endoscopy is extremely helpful to equine
breath sounds are accentuated in febrile or excited animals clinicians to diagnose DDSP, epiglottic entrapment, rostral
or in animals hyperpneic from a variety of causes (exercise, displacement of the palatopharyngeal arches, arytenoid chon-
hypoxia, and pain). However, auscultatory findings do not dritis (Fig. 8.3), tracheal collapse or stenosis, and pharyngeal
always correlate well with the degree of alveolar ventilation.9 disease that may include narrowing (Fig. 8.4). Developmental
For example, in horses with pulmonary consolidation, air or congenital abnormalities may be identified with upper air-
movement through large airways adjacent to areas of pathol- way endoscopy such as cleft palate, subepiglottic cyst (see Fig.
ogy inappropriately gives the examiner the indication that a 8.1), or choanal atresia. When exudate or hemorrhage is pres-
particular pulmonary region is well ventilated. Breath sounds ent, endoscopy can help determine its origin. Examples include
also may become more difficult to hear in cases of alveolar guttural pouch mycosis, guttural pouch empyema, progressive
overinflation in which the aerated tissue of the lung is a poor ethmoidal hematoma, retropharyngeal lymphadenopathy, pul-
conduction medium for sound or pneumothorax and pleural monary hemorrhage (Fig. 8.5), or exudate or mucus (Fig. 8.6).
effusions in which the sound is reflected at the pleural surface Examination should include tracheal examination and a
(acoustic impedance).9 Adventitious pulmonary sounds are thorough examination of the lower airways; particular areas
abnormal sounds superimposed on the normal breath sounds of interest will include the mucosa and the presence of exu-
and are described as crackles or wheezes. Crackles are short, date or masses. Diagnostic sampling may include a collection
explosive, and discontinuous sounds that are consistent with of tracheal or bronchial secretions, depending on the purpose
the sound of cellophane being crumpled. They are usually of of sampling. Tracheal secretion collection is most appropriate
low intensity and are audible during the inspiratory phase for culture purposes, whereas BAL washing of distal airways
of respiration. Their production has been attributed to the can be performed for examination of lower airway cellularity.
FIG. 8.3 A 24-year-old Paint mare presented for respiratory distress FIG. 8.5 Marked tracheal hemorrhage originating from the lower air-
characterized by an increased inspiratory effort. Upper airway endoscopy way in a horse suffering from exercise-induced pulmonary hemorrhage.
revealed arytenoid chondritis. Right-sided chondritis is present with right-
sided paralysis. Note the exudate exiting from the right arytenoid. Airway
distress resulted from severe airway inflammation and near complete
airway obstruction. (Video is available in this textbook’s website video
library.)
FIG. 8.6 A 5-year-old Holsteiner mare presented for the complaint of

cough at the beginning of exercise. Airway endoscopy revealed marked
tracheal exudate along the length of the trachea.
Videoendoscopic examination of the upper respiratory

tract while on a high-speed treadmill and the use of dynamic
endoscopy while the horse is ridden under saddle have become
common methods to evaluate a variety of airway disorders.
Although many abnormalities associated with the upper respi-
FIG. 8.4 Upper airway endoscopy of this 14-year-old Thoroughbred ratory tract can be identified at rest, some conditions are ide-
gelding presenting for abnormal whinny and roaring noise with exer-
ally diagnosed with the use of dynamic evaluation while under
cise. Marked lymphoid hyperplasia was identified and determined to be
saddle or on a high-speed treadmill.12,13
caused by neoplastic lymphoid tissue diagnosed as B-cell lymphoma.
Radiography
In instances where endoscope sterility is in question, transtra- Conventional radiography of the equine skull can be diagnos-
cheal wash (TTW) is ideally performed using a midcervical, tic under routine conditions of dental disease, the presence
percutaneous approach to avoid the potential for inadvertent of a mass, fluid lines, or fracture. However, equine skull radi-
bacterial contamination (the TTW procedure is described ography may be challenging to interpret because of the mul-
later). tiple interfaces of radiographic densities and highly complex
A B
FIG. 8.7 A 31-year-old Arabian gelding presented for a left-sided mass that was rapidly progressive in na-
ture. Although a dorsoventral radiographic imaging provides substantial evidence for a soft tissue mass (A),
CT imaging with reconstruction provides remarkable detail regarding the nature and extent of the mass (B).
anatomy of detailed structures. Although examination and Y LOWER RESPIRATORY TRACT

conventional radiography may provide some insight into dis-
ease origin, additional imaging modalities are often required DIAGNOSTIC SAMPLING
to fully assess structures in the equine head. CT is a modality
that lends itself to detailed imaging of complex structures, par- Tracheobronchial Aspiration
ticularly when pathology is present.14 From a methodological Transtracheal aspiration is a routine diagnostic proce-
standpoint, CT uses a rotated highly collimated radiographic dure performed in equine respiratory disease workup. The
x-ray beam to generate digital cross-sectional images.15 Col- primary indication for performing transtracheal aspiration
lectively, these serial cross-sectional images provide the cli- is to identify pathogenic bacteria colonizing the airway in
nician with greater information and detail compared with horses suffering from bronchopneumonia. Following routine
conventional radiography alone (Fig. 8.7). (Note: Video is sedation and sterile preparation, local subcutaneous anes-
available of this series.) Some limitations of advanced imaging thetic infiltration is administered to facilitate the procedure.
include cost and requirement for general anesthesia. However, A 3- to 5-mm stab incision is made vertically through the
CT imagining of the equine head continues to become more skin and subcutaneous tissue using a no. 15 surgical blade. A
common, and in many instances the actual image capture TTW trocar is inserted perpendicular to the skin between the
time is shorter than compared with conventional radiographic tracheal rings, while manually stabilizing the trachea. After
imaging. Additional evidence to support the use of CT for the penetration of the tracheal lumen, the trocar is removed from
equine skull includes complex structures such as nasal turbi- the sheath, and the sheath is inserted down the trachea. A
nates, paranasal sinuses, dentition,16 nasopharynx, larynx, and lavage catheter is introduced through the sheath into the air-
guttural pouches. way to the level of the thoracic inlet. Approximately 30 to 50
MRI is an additional imaging modality that can be used to mL of warmed, isotonic crystalline solution is instilled into
investigate upper respiratory tract disorders. Magnetic reso- the tracheal lumen and immediately aspirated. Samples can
nance images represent a map of tissue protons that, under be used for Gram stains and prepared for aerobic and anaero-
the influence of a magnetic field, are excited by brief pulses bic culturing.
of radiofrequency waves.15 As the magnetized excited protons
relax back to their original magnetized state, a signal is emit- Bronchoalveolar Lavage Sampling
ted, the intensity of which is converted to a grayscale image. BAL can be performed through a 3-m endoscope or using a
MRI provides excellent cross-sectional evaluations of soft tis- Bivona (equine BAL) cuffed tube designed specifically to sam-
sue structures, although it also provides useful information ple the equine lower airway. Routine sedation is administered
about bony structures. Contrast enhancement can be achieved in combination with appropriate restraint procedures. The
by injecting an intravenous (IV) derivative of gadolinium dur- BAL tube is initially primed with sterile 0.9% saline containing
ing the T1-weighted scans.15 Recent evidence supports the 2% lidocaine. After entering the nasal passage, the BAL tube
utility of MRI for use in horses. There is a favorable correla- is placed in the ventral meatus and moved caudally into the
tion with imaging studies and those identified with surgery trachea and passed to the lower airways until it is wedged into
or postmortem examination. The increasing availability pro- place at approximately the third- to fourth-generation bron-
vides support for the application of this diagnostic modality in chi. Once wedged into the third- to fourth-generation bron-
equine patients with structural diseases involving the head.17 chi, the cuff is fully inflated and the tube is instilled with 200 to
TABLE 8.1 Differential Counts in Bronchoalveolar Lavage Fluid*

Neutrophils Macrophages Lymphocytes Eosinophils Mast Cells Epithelial Cells
A 8.9 ± 1.2 45.0 ± 2.8 43.0 ± 2.7 ± 1.0 1.2 ± 0.3 3.5 ± 0.7
B 5.0 ± 4.0 72 ± 10 18 ± 3.0 2.0 ± 4.0 1.0 ± 1.4 —
C 6.2 ± 5.0 70.3 ± 15.2 7.6 ± 3.9 1.0 ± 1.4 0.6 ± 1.4 14.3 ± 13.4
D 6.2 ± 2.4 48.5 ± 2.5 35.3 ± 2.5 2.5 ± 0.9 5.2 ± 0.8 2.3 ± 1.4

*Percent of total white blood cell count plus-or-minus standard error or standard deviation.
Data from (A) Derksen FJ, Brown CM, Sonea I, et al.: Comparison of transtracheal aspirate and bronchoalveolar lavage cytology in 50 horses with chronic lung
disease, Equine Vet J. 21:23, 1989; (B) Fogarty U: Evaluation of a bronchoalveolar lavage technique, Equine Vet J. 22:174, 1990; (C) Mair TS, Stokes CR,
Bourne FJ: Cellular content of secretions obtained by lavage from different levels of the equine respiratory tract, Equine Vet J. 19:458, 1987; (D) Deegan E,
Beedle RE, editors: Lung function and respiratory diseases in the horse. Stuttgart, Germany, 1986, Hippiatrika.
500 mL of sterile, physiologic solution. After instillation, fluid

is aspirated with gentle but constant pressure. Marked suc-
tion should be avoided to minimize the chance for iatrogenic
trauma and associated blood contamination, because blood
contamination into the BAL fluid can complicate cytologic
interpretation. In addition, horses with marked lower airway
inflammation will be more likely to collapse their bronchi;
thus care should be taken to avoid exuberant aspiration.18,19
After completion of the sample collection (approximately
50%–70% recovery of instilled fluid) the cuff is deflated and
the tube removed. Sample collection of BALF provides valu-
able diagnostic information in horses suffering from lower
airway inflammation. Representative cytologic findings from
bronchoalveolar lavage studies of normal horses are shown in
Table 8.1
Thoracocentesis
Pleural fluid accumulation occurs in horses with pleuropneu-
monia, penetrating wounds that enter into the thoracic cavity,
thoracic neoplasia, and hydatid cysts.20 Percutaneous sam-
pling of pleural fluid is performed for diagnostic and thera-
peutic purposes. Ideally the anatomic location selected for
thoracocentesis is based on ultrasonographic identification
of the largest and most ventral location of pleural fluid accu-
mulation. Ventral location is particularly important when an
indwelling thoracic drain is being placed, so that the greatest
volume of fluid can be evacuated from the pleural space. Care
should be taken to identify the location of the diaphragm and FIG. 8.8 The use of a one-way Heimlich valve placed on the end of an
heart, noting that large-volume fluid can sometime result in indwelling thoracotomy tube to provide effective elimination of pleural
caudal displacement of the heart. Skin preparation generally fluid while concurrently avoiding ascending contamination of the pleural
involves routine clipping and aseptic preparation. The skin and space with room air or microbial contaminants.
periosteum of the rib are locally blocked with 2% lidocaine.
A small stab incision is made for placement of a teat cannula
or indwelling thoracic drain. Following placement of the stab because horses do not have a complete mediastinum. How-
incision, a thoracic tube with trocar can be placed to facilitate ever, with marked fibrin accumulation, it is unlikely that fluid
drainage of pleural fluid. When fluid is drained from the pleu- evacuation from an individual side will successfully remove
ral space, large-volume fluid should be removed slowly with fluid from the contralateral hemithorax, necessitating bilateral
concurrent administration of IV, isotonic fluid therapy. Rapid indwelling thoracic tube placement. Ultrasonographic exami-
and large-volume pleural fluid drainage may lead to patient nation will enable the clinician to determine the necessity and
decompensation caused by re-expansion hypotension and frequency of fluid evacuation and thoracic tube placement.
potential development of pulmonary edema.21,22 Concurrent Once the indwelling thoracic tube has been placed, a one-
IV fluid therapy will aid with maintenance of physiologic sta- way (Heimlich) valve can be placed on the end to facilitate
tus. If the patient appears weak or anxious, it is recommended one-way flow of fluid from the pleural space with protection
to periodically clamp off the chest tube while continuing to avoid ascending introduction of microorganisms into the
to administer IV fluids to facilitate a stable patient status. pleural space (Fig. 8.8).
When evacuating pleural fluid early in the course of disease If ultrasound imaging is not available and a blind approach
or in conditions with low fibrin accumulation, fluid may be to thoracocentesis is selected, landmarks should include the
removed unilaterally yet effectively from both hemithoraces sixth or seventh ICS on the right hemithorax and the seventh
or eighth ICS on the left hemithorax. Sampling should be per- successfully obtain diagnostic-quality images.27 A series
formed approximately 10 cm dorsal to the olecranon, dorsal to of three to four overlapping lateral projections are gener-
the location of the costochondral junction. ally required to successfully obtain the entire thorax. The
routine focal spot to film distance is approximately 100 cm.
Thoracic Ultrasonographic Examination The thoracic cavity of foals may be successfully imaged with
Ultrasonographic imaging of the equine thorax is a routine portable radiographic equipment. Thoracic radiography
diagnostic procedure. Thoracic ultrasonography reveals valu- provides superior diagnostic information compared with
able information about the lung and pleural cavity. Examina- ultrasound when the aim of diagnostic testing is to examine
tion will aid the clinician with the assessment for potential pulmonary parenchymal lesions, mediastinal structures,
pulmonary consolidation, atelectasis, pleuropneumonia, and thoracic wall abnormalities. Specific clinical indica-
abscess formation, masses, and integrity of the diaphragm. tions for thoracic radiographic imaging include patients
Patient preparation should include cleaning the surface of with pulmonary disease that is not responsive to standard
the hair coat; ideally the area to be imaged should be shaved therapy; severe respiratory distress; thoracic trauma; respi-
with surgical no. 40 clipper blades.23 In some instances this is ratory disease in combination with weight loss, aspira-
not conducive to patient management or the horse may have tion, or other forms of bronchopneumonia; intrathoracic
a very fine hair coat, and application of coupling gel or topical esophageal disease; or suspected diaphragmatic rupture.27
isopropyl alcohol will be sufficient to allow image acquisition. Pulmonary abscesses, pulmonary consolidation, interstitial
In a healthy horse, pulmonary fields can be imaged from pneumonia, pneumothorax, mediastinal lymphadenopathy,
both sides of the thorax from just below the epaxial muscu- and pulmonary fibrosis are conditions in which thoracic
lature to the area in which the lung fields join the diaphragm. radiography is indicated and will provide additive diagnos-
The ventral border of the lung field is usually identified as a tic information when combined with thoracic ultrasonog-
sloping line that originates at the level of the tuber coxae at raphy.26,27 Structures located deeper than the superficial
the 17th ICS, then at the level of the ischial tuberosity at the pulmonary surface and those that involve the pulmonary
15th ICS, and at approximately the level of the point of the parenchyma cannot be examined in complete detail with
olecranon at the 5th ICS.24 Lung fields can easily be imaged ultrasound alone.
from the 5th to the 16th to the 17th ICS, bilaterally. Pulmo- Four radiographic patterns are described for thoracic
nary fields can also be imaged in the more cranial lung fields radiographic imaging and include interstitial, alveolar, bron-
at the third and fourth ICS, but in these locations the triceps chiolar, and vascular. Although classification of radiographic
musculature is superficial to the lung fields, so probe depth pattern can provide the clinician with insight as to the primary
must be adjusted to account for the focal point of interest. The disease etiology, none of the radiographic patterns are pathog-
initial lung scan should be performed with a 5-mHz probe, nomonic for specific disease, and many times overlapping
with the depth set at approximately 10 to 15 cm.25 If more patterns are observed. Finding characteristic radiographic
superficial imaging is required, then a 7.5- to 10-mHz probe changes will aid in formulating and possibly narrowing the
is indicated to improve image clarity. The depth setting for a list of differential possibilities. Among the patterns observed
higher frequency probe will need to be adjusted to approxi- in equine patients, similar to other species, the interstitial pat-
mately 5 to 10 cm. Higher frequency probes are most appro- tern is the most commonly identified. Changes within the
priate for imaging the foal thorax, including young neonates interstitial tissue lead to an increased background opacity
through weanling-aged individuals.26 Adult full-sized horses identified on radiographs. Although an increased interstitial
with a particularly thick body wall may require a lower fre- pattern is characteristic for older horses and for this reason
quency setting to obtain a diagnostic quality image, and probe is sometimes considered a normal finding, marked change or
selection settings may be ideal at the 2.5- to 3.5-mHz range. interstitial disease in a young horse is abnormal. An intersti-
Additionally, horses with severe pulmonary disease, such as tial pattern is often identified in the early course of disease
a marked pleuropneumonia, may require an increased depth and is very non-specific. Interstitial changes may be observed
setting at 25 to 35 cm so that the full area of pathology can early in the course of infectious pneumonia, pulmonary neo-
be effectively examined. Typically sector scanners will provide plasia, cardiogenic-associated pulmonary disease, and allergic
optimal imaging ability, because the head of the transducer is airway diseases. Nodular interstitial disease represents cellu-
small and can be placed in the ICS of most horses. Limitations lar infiltrative disease, with the most severe form represented
exist when using linear-array transducers because the depth by metastatic neoplasia or fungal pneumonia (Fig. 8.9). An
is fixed at 10 cm with some instruments and the entire probe alveolar radiographic pattern is seen as patchy and often with
is not in contact with the skin surface, limiting the quality of soft tissue dense areas that impair the ability to see vascu-
the examination. The lung fields should be scanned in the 3rd lar structures and airways. The characteristic feature of the
(right side) or 4th (left side) through the 17th ICS, moving alveolar pattern is the presence of air bronchogram(s), which
in a dorsal to ventral direction and moving cranial to caudal characterize small airways. An air bronchogram is seen as a
to ensure that all areas of the lung fields have been examined branching lucency in which the airway walls are not visible,
thoroughly.26 The probe should be carefully placed in the ICS yet the pulmonary fields are opaque because of the presence of
to avoid inadvertent acoustic shadowing from ribs as this will fluid-filled alveoli. Air bronchograms are observed in patients
impair image assessment. with pulmonary edema, hemorrhage, consolidation, or atel-
ectasis. Identification of an air bronchogram in a particular
Thoracic Radiography distribution will aid in establishing the differential diagno-
Thoracic radiography is a valuable component of patient sis with a cranioventral distribution identified in association
evaluation often used in combination with other diagnos- with bronchopneumonia (Fig. 8.10), whereas a caudodorsal
tic modalities such as thoracic ultrasound. Standard tho- distribution may represent cardiogenic pulmonary edema,
racic radiography will require a 1000-mA, 150-kV unit to hemorrhagic disease, or hematogenous dissemination and
A B
FIG. 8.9 A 15-year-old Thoroughbred gelding with the complaint of weight loss and the diagnosis of
equine multinodular pulmonary fibrosis. (A) Nodular interstitial radiographic pattern in a ventral thoracic
radiograph centered over the caudal cardiac silhouette. (B) Caudodorsal view of the nodular interstitial ra-
diographic pattern.
FIG. 8.10 A 20-year-old Arabian gelding with the complaint of respira-

tory distress with acute onset following the administration of mineral oil
for colic signs. Note the cranioventral alveolar pattern represented by air
bronchograms caused by marked pulmonary fluid accumulation in asso-
ciation with severe mineral oil aspiration pneumonia.
sepsis. Thickening of the airway results in the identification FIG. 8.11 A 15-year-old Arabian mare with the complaint of respiratory
of a bronchiolar pattern (Fig. 8.11). This represents severe dis- distress evidenced by nasal flare and increased expiratory effort. Note the
ease of the airways, resulting in thickening of the bronchiolar marked bronchointerstitial pattern diffusely present in all lung fields. A
structures with increased visibility of the bronchi. Increased marked bronchiolar component is consistent with the presence of chronic
opacity of the bronchial walls may result from peribron- peribronchiolar inflammation in association with recurrent airway ob-
chiolar infiltration or from intraluminal exudate, which is struction.
sometimes referred to as a diphtheritic membrane. Classifi- An alternative and less invasive technique for measuring
cation of a bronchiolar pattern can be categorized based on pulmonary function uses the forced-oscillation method (or
sharply defined bronchi or more ill-defined thickened walls its modification, the impulse-oscillation method). For this
termed a peribronchiolar pattern. A bronchiolar pattern rep- method of testing, the horse is fitted with an airtight face mask
resents chronic disease with mineralized changes within the while an external test signal is imposed on the horse’s breath-
bronchiolar wall. In contrast, a peribronchiolar pattern indi- ing efforts that generate pressure-flow responses from the
cates inflammatory disease that surrounds the bronchi, which respiratory system. The mechanical properties derived from
may develop early in the course of bronchopneumonia or this technique over a wide range of frequencies include total
following chronic allergic airway disease such as RAO. The respiratory system impedance (Zrs), respiratory system resis-
least common pattern is the vascular pattern characterized by tance (Rrs), and respiratory system reactance (Xrs).30,31 The
a pronounced vascular pattern that mainly occurs following impedance represents the impediment that the system presents
pulmonary overcirculation in association with a left-to-right to oscillatory flow and consists of Rrs (resistive properties of
shunt. the respiratory system) and Xrs (elastic and inertive properties
of the respiratory system).
Pulmonary Function Testing Measurements of airway hyperresponsiveness are obtained
Measurements of mechanical properties of the respiratory in combination with pulmonary function testing.32-35 This
system, airway reactivity, and arterial blood gas determi- technique uses a dose of a nebulized bronchoconstrictor
nations have been used to determine pulmonary function agent, such as histamine or methacholine, which causes a
in horses and are generally available only at select referral 35% increase in baseline Rrs or a 35% decrease in baseline
centers. Conventional techniques of pulmonary function lung compliance. The dose to achieve this value in a horse
testing require the horse to wear a breathing apparatus that with inflammatory airway disease (IAD) or RAO is consider-
measures airflow, and pleural pressure changes are measured ably less than the dose needed to induce airway reactivity in a
by an esophageal balloon, which is connected to a pressure healthy horse. Histamine bronchoprovocation testing requires
transducer. The integration of overall airflow as it relates to that the horse be sedated and outfitted with an airtight breath-
time provides a flow rate that aids in the measurement of ing mask. Laboratory assistants must wear protective masks
inspiratory and expiratory volume. Additional parameters to prevent inadvertent inhalation of the bronchoconstricting
obtained using this method of pulmonary function assess- agent, which could cause harm to personnel.
ment provide inspiratory and expiratory time, respiratory Pulmonary function testing of exercising horses and its
frequency, and peak airflow. From a practical standpoint, the use in assessing poor athletic performance remains a valu-
simple measurement of tidal volume, breathing frequency, able diagnostic approach offered at select referral centers.
or minute volume (= tidal volume × breathing frequency) With the availability of high-speed treadmills and the ability
provides limited information regarding the pulmonary func- to measure airflow during exercise,36 analysis of tidal volume,
tion because these values are extremely well maintained breathing frequency, dynamic compliance, lung resistance,
until severe respiratory disease leads to marked pulmonary end-expiratory lung volume, and flow-volume and pressure-
impairment.28,29 volume loops continue to provide additional insights into the
Measurements of lung movement defined as compliance cause of the poor performance, the recognition of expiratory
and airway obstruction characterized by pulmonary resistance flow limitation, and the influence of EIPH on respiratory
provide meaningful information regarding overall pulmonary mechanics.
function. Dynamic compliance (Cdyn) is calculated by divid-
ing the tidal volume by the change in pleural pressure occur- Lung Biopsy
ring at the initiation and completion of inhalation. Pulmonary A histopathologic diagnosis may prove useful in the thera-
resistance can be measured by several different techniques, peutic management of certain lung disorders. Percutaneous
depending on whether the measurement is resistance at peak lung biopsy has been used to investigate disorders charac-
airflow or at specific ventilatory volumes (i.e., isovolumetric; terized radiographically by a pulmonary miliary pattern and
e.g., 50% tidal volume), which is then divided by the change disorders for which radiographic or ultrasonographic results
in pleural (esophageal balloon) pressure over the same inter- are compatible with pulmonary neoplasia or granuloma. A
val. Changes in these measurements can provide information percutaneous approach was originally described,37 although
regarding the physiologic impact of the pulmonary disease. methods used have been modified because of the routine
Horses that suffer from obstructive airway disease of the tra- use of ultrasound during sample collection. Following rou-
cheobronchial tree have reduced dynamic compliance with tine sedation biopsy locations are selected after ultrasono-
increased pulmonary resistance. Reduced dynamic compli- graphic confirmation of landmarks (heart and diaphragm)
ance without a change in pulmonary resistance indicates that and assessment of tissue accessibility. The biopsy instrument
the pulmonary parenchyma is stiffened by alveolar disease or is aseptically advanced through the ICS (cranial to the rib) to
by obstruction of the peripheral bronchioles. Notably, because the depth of the desired tissues, and samples are obtained for
of the marked surface area of peripheral bronchioles, there will culture and for fixation in 10% formalin. In a study compar-
be little change in overall lower airway function until severe, ing biopsy instruments (manual Tru-Cut versus automated
end-stage disease is present. The remarkably large cross- biopsy needle), the investigators found airway bleeding
sectional area has minimal impact on the overall resistance developed in approximately one third of the cases sampled
of breathing until the disorder is well advanced. Conversely, with the manual device and one tenth of the cases biopsied
increased pulmonary resistance without a change in dynamic using the automated instrument.38 This technique is not rec-
compliance indicates that the obstruction exists in the respira- ommended in patients that are tachypneic, are in respiratory
tory tract, but is does not make a distinction between upper distress, exhibit uncontrollable coughing, or have bleed-
airway, trachea, or bronchus.28 ing disorders. It is not indicated in horses with pulmonary
abscess formation, pleuropneumonia, or pneumonia.39 In agent with enhanced bioavailability such as fluconazole may
a review of percutaneous lung biopsies performed in 66 be an appropriate consideration if the susceptibility profile
horses, this technique yielded a definitive antemortem his- indicates drug efficacy.
tologic diagnosis of pulmonary disease in 82% of cases.40 In Sinonasal disease is very common in horses and likely
the same study, no complications were recognized in 91% of results from the extensive network of six pairs of sinuses
horses sampled. The most common complications observed including the conchal sinuses that exchange air with the nasal
with lung biopsy are coughing, epistaxis, pulmonary hem- airway. The frontal sinuses may be affected with granuloma-
orrhage, tachypnea, and respiratory distress. Hemothorax or tous masses with fungal or parasitic etiologies or bacterial
accidental sampling of abdominal organs (liver and stom- empyema. The most common bacterial isolates are Strepto-
ach) may occur.38,40 When horses in respiratory distress are coccus spp., which include S. equi subsp. zooepidemicus and
sampled using an automated instrument, epistaxis occurred S. equi subsp. equi. Staphylococcus spp. are the next most
in 13%, airway bleeding in 39%, and pneumothorax in 4% of frequent isolates.48 Polymicrobial infection is also identified
patients.38 among sinus disease in horses. C. neoformans and Coccidioi-
des immitis also may cause granuloma formation within the
Thoracoscopy paranasal sinuses.49,50 In a study of 277 horses with sinusitis,
Thoracoscopy or pleuroscopy is a diagnostic technique 24% of the horses had primary sinusitis with no history of
used in the standing sedated horse to visualize the intratho- predisposing trauma or dental infection.51 Dental disease of
racic structures that include the aorta, esophagus, intercos- the third to sixth maxillary cheek teeth was the most common
tal vessels, sympathetic trunk, vagus nerves, lymph nodes, predisposing factor for secondary sinusitis (22% of horses) fol-
mainstem bronchi, pulmonary and azygous veins (right lowed by sinus cysts, neoplasia, progressive ethmoidal hema-
hemithorax), diaphragm, and dorsal and lateral surfaces of toma, trauma, mycotic infection, sinonasal polyps, and nasal
the lungs. The procedure is used to sample thoracic masses epidermal inclusion cysts. Primary infection of a rostral max-
or nodules, to transect pleural adhesions, to place drains for illary cheek root infection was identified in only 4% of cases,
the treatment of pleural abscesses, to repair diaphragmatic although CT evaluation was not used for diagnosis of many of
hernias, and to resect lung segments either for therapeu- these cases. Nasal discharge (most commonly unilateral but
tic or diagnostic purposes. Thoracoscopy provides a supe- occasionally bilateral) and facial swelling were the most com-
rior method to obtain larger biopsy samples and therefore mon clinical signs associated with sinusitis in horses. Nasal
more accurately assess parenchymal and peripheral airway discharge may be mucopurulent to serosanguineous. A fetid
morphology. odor is often present and typically attributed to the presence
of anaerobic bacteria. Clinical signs commonly persist over
several weeks, an initial favorable response to broad-spectrum
Y DISEASES OF THE UPPER antibiotics is often only transient. Once antibiotic therapy is
RESPIRATORY TRACT discontinued, clinical signs frequently return. Other signs
of frontal and maxillary sinus involvement may include lac-
Sinusitis rimal discharge and exophthalmia. Headshaking syndrome
Nasal airways can be infected with a variety of viral, bac- is an uncommon clinical manifestation of fungal sinusitis in
terial, fungal, and parasitic agents with resultant sinusitis horses.52
and/or rhinitis. Rhinitis is defined as infection of the nasal Diagnostic techniques that may facilitate identification of
passage independent of the sinus. Infection may include the the characterization of sinusitis in horses include endoscopy,
nasal concha but does not involve the conchal sinuses unless radiography, CT, and MRI.53-55 Endoscopy can detect changes
caused by viral agents. Specific viral agents include equine in airway structure (84% of cases) and rule out ethmoidal
influenza virus (EIV), equine herpesvirus 1 and 4 (EHV-1 hematoma.51,56 Sinuscopy can also be performed through
and EHV-4), equine rhinoviruses, and adenovirus. Bacte- a space created in the skull by trephination in the standing
rial rhinitis is not common and usually occurs secondary to horse.44,51,56,57
trauma or foreign body. Mycoplasma spp. have been isolated Radiography is essential for the identification of fluid and
at postmortem examination from horses with rhinitis.41 A masses within sinuses and for preliminary assessment of den-
variety of mycotic agents such as Aspergillus spp., Conid- tition (Fig. 8.12). Currently available high-detail computed
iobolus spp. (usually C. coronatus), and Cryptococcus neo- radiography images provide the clinician with a remarkable
formans may cause rhinitis in horses.42 The most common level of radiographic detail that may provide valuable diag-
cause of parasitic rhinitis is myiasis caused by Habronema; nostic information for the identification of sinus or dental dis-
Draschia; and the Russian gadfly, Rhinoestrus purpureus. ease.58 It is not uncommon that the first molar is involved in
Enzootic lymphangitis or glanders caused by Burkholderia association with the development of sinusitis. CT and MRI59
mallei causes a specific granuloma within the sinus cavity.43,44 are exceptionally valuable for detection of tooth root involve-
Horses with sinusitis most commonly have unilateral disease ment and boney changes, which often involve the maxillary
unless the infection is viral or there is extensive involve- bone and facial crest.
ment of the nasal septa. Most horses present with respira- Appropriate and effective treatment of sinusitis requires
tory stridor and nasal discharge with diminished airflow on that underlying or predisposing conditions be accurately
the affected side.41,45-47 Therapy is usually aimed at surgical identified and treated, that debris be removed from the sinus,
debridement, debulking of nasal granuloma, and local ther- and that associated infectious agents are properly identi-
apy for the specific agent.47 Orally administered itraconazole fied. When fluid is present within a sinus, medical treatment
has been described for treatment of recurrent nasal myco- with antibiotics alone is unlikely to be successful. Trephi-
ses.46 Although successful in this case, the pharmacokinet- nation and flushing or surgical debridement and drainage
ics of this agent are variable, suggesting that an antifungal through a sinus flap are indicated.60 Establishment of ventral
reveals a variably green-colored, smooth glistening mass

originating from the ethmoid region. The mass may pro-
trude beyond the nasal septum (and in such cases may cause
a bilateral nasal discharge). Radiographs reveal a space-
occupying soft tissue density with smooth margins and may
demonstrate extension into the paranasal sinuses. Confir-
mation of the diagnosis is by histopathologic study of the
removed tissue,58 although the clinical appearance is highly
suggestive.
Treatment
Treatment options include formalin injection, surgical
resection, and laser ablation. Smaller lesions (<10 cm in
diameter) can be treated effectively by the intralesional
injection of 4% to 10% formalin.68 Most cases require mul-
tiple injections to achieve full resolution.68a,68b This pro-
cedure can be performed in the standing horse, has a low
complication rate, and is associated with 60% resolution
after a median of five injections.64 However, severe neu-
FIG. 8.12 Skull radiographs can be diagnostic for the identification rologic complications can occur if the cribriform plate is
of dental disease and associated potential sinus disease. This 5-year-old fenestrated by the chronic pressure of a large PEH.69 CT
Quarter Horse mare presented with the complaint of facial deformity just may be indicated to determine the extent of the lesion
rostral to the right facial crest. Radiography demonstrates evidence of before treatment.67
periodontal disease, particularly in the region of the right fourth premolar. Surgical removal via a frontal sinus flap is associated with
extensive hemorrhage and may require preoperative or post-
operative blood transfusions.64,70 A preoperative crossmatch
drainage of the affected sinuses may be required. Local flush- is warranted, and the horse may also require a postoperative
ing is likely to be the most important component of therapy, tracheotomy if extensive packing of the nasal cavity is nec-
although systemic antimicrobial therapy may be indicated for essary to effect hemostasis. After surgical removal, approxi-
any horse with signs of osteomyelitis. Prognosis is guarded mately 20% to 50% of ethmoidal hematomas recur.70,71
for complete resolution of clinical signs, especially when Postoperative complications may include facial incisional
apical dental disease is present. Frequently, tooth removal dehiscence, suture periostitis, facial bone sequestration,
is indicated. Recurrence is most common with ethmoidal persistent nasal discharges, fungal sinus plaque formation,
hematoma and neoplasia.61 and encephalitis.63,64 Laser excision has also been used to
treat PEH, with a recurrence rate of 20% described in one
Y PROGRESSIVE ETHMOIDAL report.72 Recurrence is higher in bilateral PEH than other
forms.
HEMATOMA
Definition and Epidemiology Y GUTTURAL POUCH ANATOMY
Progressive ethmoidal hematoma (PEH) is characterized The paired guttural pouches are diverticula of the external
by encapsulated, expansive masses that usually arise from auditory tubes. Some investigators have suggested that the
the submucosa of the ethmoidal labyrinth.62,63 The mass is pouches play a role in cooling the arterial blood supply to
composed of blood and fibrous tissue, is encapsulated by the brain.73 Each pouch has a capacity of about 475 mL and
respiratory epithelium, and may extend into the paranasal is divided into medial and lateral compartments by the sty-
sinuses.64 lohyoid bone.74 Each pouch fills on inspiration via the plica
This condition occurs in 4% to 6% of horses with diseases salpingopharyngeus. The mucosal lining of each pouch is
of the nose and sinus.50,65 The inciting factor in their devel- secretory and covered by ciliated pseudostratified epithe-
opment is not known, although they have been hypothesized lium with goblet cells and glands.74 The medial compart-
to be associated with repeated episodes of submucosal hem- ment is three times bigger than the lateral compartment and
orrhage. PEH appears bilaterally in 50% of cases and is more contains the internal carotid artery and a fold that encloses
prevalent in older horses.66 cranial nerves IX, XI, and XII. The pharyngeal branch
of the vagus nerve (cranial nerve X) traverses the floor of
Clinical Signs the medial pouch, and the cranial sympathetic ganglia are
The most common clinical sign caused by PEH is intermittent, also found within it. The rectus capitis ventralis and longus
serosanguineous discharge from the affected nasal passage. capitis muscle run just medially to the guttural pouch, and
Other clinical signs include facial swelling, halitosis, respira- tearing of these muscles after a poll injury can be identified
tory distress, and coughing.58,64 endoscopically as blood in the associated pouch. The lateral
compartment of the guttural pouch contains the external
Diagnosis carotid and maxillary artery. Branches of the facial nerve
Diagnosis is based on the clinical signs, endoscopic exami- (VII), vestibulocochlear (VIII), and mandibular branch of
nation, radiographic evaluation,51 and, in some cases, CT the trigeminal nerve (V) run close to the wall of the lateral
findings to determine the extent of the lesion.67 Endoscopy compartment.
Guttural Pouch Tympany Treatment

Guttural pouch tympany is defined as distention of the gut- If upper airway inflammation is identified on endoscopy
tural pouches with pressurized air. In some instances air as lymphoid pharyngeal lymphoid hyperplasia, then medi-
accumulation is accompanied by fluid accumulation. Most cal therapy may be initially implemented as a conservative
commonly the condition affects an individual pouch, but management scheme. Therapy may include nonsteroidal
it may occur bilaterally. Several reports have described antiinflammatory therapy with flunixin meglumine com-
increased frequency of disease in fillies compared with bined with broad-spectrum antibiotic therapy, trimethoprim-
colts.75-78 Additionally, a breed predilection has been sulfamethoxazole, doxycycline, or minocycline. Therapy should
observed for Arabians and Paint foals.76 Among the affected be maintained for 10 to 14 days. If unsuccessful or disease pro-
Arabian foals, many had close genetic relationships. Heri- gression is observed, surgical options may be considered.
tability testing revealed polygenic and mixed monogenic to Surgical approaches include needle decompression and
polygenic models that best described the condition in Ara- surgical fenestration. Regarding the intricate network of vas-
bian foals.79 Interestingly and consistent with these previ- culature and nerves in the affected region, an experienced sur-
ous observations, whole genome-wide scanning for guttural geon is best suited to manage affected patients.81
pouch tympany in Arabian and German Warmblood horses Overall, with surgical management, the prognosis remains
revealed a gender-specific quantitative trait locus, which is favorable for recovery and return to function. In some cases,
completely consistent with the observation that fillies are individual surgical decompression is not successful, and
more commonly affected than colts.80 repeated surgery is indicated. Nonetheless, when properly
applied, even if repeated surgery is required, the prognosis for
Clinical Signs recovery remains favorable.76
Guttural pouch tympany is most commonly diagnosed in Medical conditions that may occur secondarily to the
young foals, although it can occur at any time in the first condition of guttural pouch tympany include guttural pouch
year of life. Characteristic clinical findings include a mark- empyema and aspiration pneumonia. Resolution of the pri-
edly enlarged area in the throatlatch region. This area can be mary condition of guttural pouch tympany is the central focus
markedly enlarged and is most commonly unilateral, although of disease resolution, but medical management with antibiot-
bilateral involvement is possible. In cases with severe unilateral ics and guttural pouch lavage may be required postoperatively.
involvement, it may be somewhat challenging to determine In some instances, the surgical procedure may result in per-
whether one or both sides are involved because the area of manent nerve damage resulting in aspiration caused by per-
enlargement can be large enough to cross the ventral midline, sistent dysphagia. In such cases, the prognosis for complete
giving the impression of bilateral disease. The affected area is recovery is guarded.75
not painful to palpation, and additional clinical signs may not
be apparent. In cases where severe guttural pouch enlargement Y GUTTURAL POUCH MYCOSIS
is present, airway obstruction or dysphagia may be observed.
When neurologic deficits are present (e.g., in cases of dyspha- Guttural pouch mycosis is a life-threatening disease that can
gia) complete examination should be performed to determine lead to fatal hemorrhage in horses. Mycotic plaques are typi-
whether evidence of aspiration pneumonia is present. cally located on the roof of the medial compartment associ-
ated with the internal carotid artery, and are less commonly
Pathogenesis on the lateral wall of the lateral compartment of the pouch
Although the exact etiopathogenesis is incompletely under- associated with the external carotid or external maxillary
stood, anatomic and physiologic factors must be considered artery. There is no apparent age, gender, breed, or geographic
for disease development. It is thought that a mucosal flap predisposition to this condition. The etiopathogenesis of
(plica salpingopharyngeus) may serve as a one-way valve that this disorder remains elusive, but Aspergillus (Emericella)
prevents the release of air and/or fluid from the affected gut- fumigatus is the most frequently identified pathogen, which
tural pouch.81 Other proposed etiologies include upper airway is more readily identified on biopsy versus fungal culture.83
(viral or bacterial) infection, persistent coughing, or metabolic The fungal plaque is reported to contain a diphtheritic mem-
dysfunction.82 In most cases there is no obvious anatomic brane that contains necrotic debris, a multitude of bacterial
abnormality that can be identified in association with the isolates, and fungal organisms. Although this is typically a
affected guttural pouch or opening.76 condition of more intensely managed horses living in North
America, guttural pouch mycosis has also been defini-
Diagnosis tively diagnosed in horses living on pasture in the Southern
Signalment, history, and clinical findings often provide strong Hemisphere.84
evidence for the diagnosis of guttural pouch tympany in foals.
Upper airway endoscopy will provide the clinician with the Clinical Signs
ability to thoroughly examine the upper airway, nasal pas- Horses most commonly present with the complaint of epi-
sages, guttural pouches, and entire laryngeal region. Although staxis, which may be severe. The hemorrhage originates from
the guttural pouch openings may appear normal, dorsal pha- the site of fungal plaque localization, which is most com-
ryngeal compression is commonly observed secondary to monly over the internal carotid artery, but may involve the
the trapping of air within the pouch. Additional diagnostic maxillary artery in approximately one third of the cases.73,85-88
options include skull radiographs, which reveal an enlarged, Alternate clinical signs many include dysphagia evidenced by
gas-filled guttural pouch. Although radiographs may be diffi- feed and saliva containing material exiting from the nostrils,
cult to interpret in foals with bilateral disease, the combination recurrent laryngeal neuropathy (RLN) resulting in turbulent
of endoscopy and radiographs will aid the clinician in making airflow and altered airway mechanics, Horner’s syndrome,
an accurate diagnosis. head extension, parotid enlargement, paralysis of cranial
nerve VII (facial), mycotic encephalitis, and atlantooccipital For these reasons, medical therapy may not be the preferred
joint infections.87,89-92 Even though guttural pouch mycosis therapeutic option for guttural pouch mycosis. Potential anti-
is most commonly observed in adult horses, foals have also fungal therapeutic protocols have been provided for select
been reported to develop this disease.93,94 Epistaxis may be cases in which this therapy may be considered.73 Ampho-
recurrent in nature and can be fatal in approximately 48% tericin has been administered for up to 40 days, but lack of
of horses; therefore, immediate surgical management is confirmed efficacy combined with safety concerns limit appli-
indicated.87,95 cation of this therapy.100,101 Itraconazole (5 mg/kg PO daily)
can reach plasma concentrations greater than the minimum
Pathogenesis inhibitory concentration in horses and, although itraconazole
The etiopathogenesis of guttural pouch mycosis remains elu- has a similar spectrum of activity as fluconazole, it is effec-
sive. It has been postulated that aneurysmal dilations of the tive against Aspergillus spp.102 In a separate report, a combina-
vasculature provide a suitable environment for fungal organ- tion of systemically administered itraconazole in combination
isms to proliferate.96 Fungal colonization of the guttural pouch with topical enilconazole (60 mL of 33.3 mg/mL solution daily
mucosa and underlying vascular and neural structures results flush) provided successful therapy in an individual case of gut-
in marked inflammation, necrosis, and erosion, which leads to tural pouch mycosis.103 Ketoconazole and fluconazole have
the clinical manifestation of hemorrhage and potential neu- been considered as potential therapeutic options, but because
ropathy. Clinical signs will reflect the severity of disease and of a lack of efficacy and absorption, respectively, these drugs
specific anatomic structures that are colonized by the fungal are not recommended for the treatment of guttural pouch
organism. mycosis. In a separate report of topical therapy, guttural pouch
lavage with 0.08% clotrimazole emulsion in 500 mL water for
Diagnosis 14 days prevented recurrence of a solitary lesion in an individ-
Diagnostic confirmation of guttural pouch mycosis is based ual report. It has been suggested that a 3-day depot treatment
on endoscopic observation of a fungal plaque within the of clotrimazole providing residual antimycotic activity within
appropriate anatomic location. Notably, in some cases com- the pouch may be a superior option.
plete examination of the guttural pouch may not be possible Additional medical therapy must also include patient
because of the severity of hemorrhage and obstruction of view. needs. Complete assessment for severity of anemia, hydration
In such cases, endoscopic examination provides confirma- status, and degree of discomfort must be addressed accord-
tory diagnostic evidence regarding the area of hemorrhage, ingly. Patients that are dysphagic will require nutritional
even though the exact site of the fungal plaque might not be support. An indwelling feeding tube may be required to pro-
observed upon initial examination. Based on clinical signs and vide support until disease resolution is sufficient to result in
endoscopic findings the diagnosis of guttural pouch hemor- improved neurologic function.
rhage can be established, which will allow a therapeutic plan to
be established. An important consideration when performing Surgical Therapy
endoscopy is to avoid dislodgement of an existing clot over a Commonly, guttural pouch mycosis is only effectively man-
hemorrhagic lesion. For this reason, caution should be used aged with intensive medical therapy to address blood loss and
when performing upper airway endoscopy in patients with systemic disease manifestation in combination with surgical
suspected guttural pouch mycosis.97 occlusion of the affected vessel or vessels. Current interven-
Neuropathy may result in dysphagia or laryngeal paralysis. tional therapies of choice use a coil or nitinol plug to occlude
Fungal plaque formation involving the pharyngeal branches of arterial flow proximal and distal to the fungal lesion.81 The
the vagus and glossopharyngeal nerves results in dysphagia and placement of transarterial coils, via an incision in the com-
potential aspiration pneumonia,73,98 whereas a mycotic lesion mon carotid artery under fluoroscopic guidance, is associ-
located in the medial compartment of the guttural pouch may ated with 84% survival and 71% return to performance.99,99a
cause damage to the cranial cervical ganglion, which can lead Historically, fluoroscopic guidance has been an important
to signs of Horner’s syndrome on the ipsilateral side. Changes procedural component to ensure accurate coil placement.
in vocalization or respiratory noise may result from RLN or More recent reports describe transarterial coil embolization in
pharyngeal paresis.87 The presence of laryngeal paralysis or standing horses with the use of fluoroscopy.104 An increased
dysphagia should be documented at the initial examination risk of complication is associated with the presence of aberrant
because both are associated with a more guarded prognosis.99 vessels, and for this reason fluoroscopic guidance provides the
A more favorable prognosis is provided in horses that have optimal imaging capability when vascular occlusion is per-
evidence of dysphagia. Recovery has been observed to occur formed.105,106 Correct placement can be difficult in the pres-
over a 6- to 18-month period. Horses may also recover from ence of aberrant vessels.105,106
facial nerve paralysis and Horner’s syndrome. Radiographs of
the guttural pouch may show evidence of fluid accumulation Prognosis
or osteolytic changes in the stylohyoid bone or may suggest Horses that present with moderate to severe hemorrhage and
mycotic plaque formation. receive occlusional procedures are likely to have an improved
prognosis for survival. Although original reports suggested an
Treatment approximate 50% survival rate, this was reported before the
Current options for medical management of fungal disease application of widespread and routine application of interven-
in horses are hampered by not having a cost-effective, bio- tional therapies.73 Recovery from guttural pouch mycosis is
available drug that can be effectively administered. When typically prolonged, and for this reason deficits may persist for
hemorrhage is marked, having an efficient therapy is para- extended periods and in some cases may be permanent. Laryn-
mount. Regardless of the medical therapy selected, it generally geal paralysis is commonly a residual complication of this
requires weeks of therapy for treatment benefit to be achieved. disease,99 but it has been reported to resolve in some cases.89
Dysphagia is one of the more serious long-term complicating developed into chondroids. The horse should be routinely
factors, and, although some horses partially improve, the final sedated to facilitate a low head position, which will improve
outcome may not be apparent for up to 18 months.87,89 Neu- drainage of lavage fluid. In acute cases, daily lavage with ster-
ropathy that involves the facial nerve or cranial cervical gan- ile physiologic or 0.9% saline is generally effective for removal
glion leading to facial nerve paralysis or Horner’s syndrome, of exudate.108 Administration of local penicillin may improve
respectively, often resolves completely.73,107 treatment success.110 A gelatin-penicillin mixture can be
instilled through a catheter inserted either through an endo-
Y GUTTURAL POUCH EMPYEMA scope or using endoscopic guidance into the guttural pouch.111
A 50-mL mixture is prepared by first heat dissolving 2 g of
Guttural pouch empyema results from accumulation of gelatin in 40 mL of sterile water and then cooling to 45°C to
purulent material within one or both guttural pouches. 50°C. Then add 10 million units of sodium benzylpenicillin
Accumulated exudate can accumulate and become inspis- that have been reconstituted with 10 mL of sterile water. The
sated and form chondroids.108 Most commonly empyema mixture is ideally stored overnight at 4°C to allow the gel to
results following upper airway infection with S. equi subsp. set. Approximately 25 mL of the mixture is instilled for each
equi. Abscess formation of the retropharyngeal lymph nodes pouch that requires treatment.
leads to rupture and drainage into one or both guttural When chondroids are present, their removal may be
pouches. Persistence of purulent material may lead to the attempted with an endoscopic snare, which prevents the
development of chondroids, which occurs in approximately risk of surgical complications and minimizes treatment
20% of horses that develop guttural pouch empyema.108 Less costs. However, complete removal of chondroids can be
commonly, empyema may be a complicating factor result- challenging, particularly if they are numerous.111,112 When
ing from traumatic injury to the stylohyoid bone, potentially endoscopic removal is unsuccessful or chondroids are
resulting in fracture. Iatrogenic infusion of irritating materi- numerous, surgical removal may be performed through a
als or trauma secondary to inadvertent placement of a naso- modified Whitehouse approach or by using a transendo-
esophageal tube may result in trauma to the guttural pouch. scopic laser to establish a permanent pharyngeal fistula into
Rarely, congenital or acquired stenosis of the guttural pouch the guttural pouch.81,113,114
opening may lead to impaired drainage, resulting in fluid
and exudate accumulation.82,109
Y PHARYNGEAL LYMPHOID
Clinical Signs HYPERPLASIA
Horses with guttural pouch empyema often have intermit-
tent, chronic nasal discharge.108 Additionally, submandibular Pharyngeal lymphoid hyperplasia is a common condition
lymphadenopathy and parotid enlargement may be observed. involving the upper respiratory tract of 2- and 3-year-old race-
Increased respiratory noise is commonly heard resulting from horses. Most mild cases respond favorably to reduced athletic
increased upper airway resistance caused by pharyngeal com- activity in combination with systemic and topical antiinflam-
pression. Neuropathy and dysphagia are uncommon but may matory therapy. Dexamethasone can be administered at a dose
develop if guttural pouch inflammation is severe. Occasionally of 0.02 to 0.05 mg/kg orally daily for 1 week, followed by half
hemorrhage or serosanguineous discharge will accompany of the original dose given orally for 1 week, then the same dose
guttural pouch empyema.73 administered orally every other day for an additional week. A
throat spray comprised of nitrofurazone, dexamethasone, and
Diagnosis dimethyl sulfoxide is reported to be of benefit when admin-
Upper airway endoscopy will provide diagnostic confirma- istered topically.115 Systemic immune modulation is reported
tion for the presence of exudate within the guttural pouches. to be effective for the treatment of horses with lower airway
Examination will enable the clinician to determine the extent inflammation and may also have some benefit in horses suf-
of fluid and exudate accumulation and definitively determine fering from upper airway inflammation.115-117 Occasionally,
whether disease is unilateral or bilateral. Diagnostic testing on chronic disease occurs; reports have suggested that these
samples collected endoscopically generally includes microbio- horses may respond favorably to cautery of the dorsal roof of
logical culture and polymerase chain reaction (PCR) testing the pharynx.118
for the presence of S. equi subsp. equi. Radiography will also Organisms associated with a more prolonged course of
provide the clinician with diagnostic examination of other pharyngeal hyperplasia include S. equi subsp. equi; equine
structures in the upper airway. Fluid lines within the gut- influenza; and EHV-1, EHV-2, and EHV-4. The condition
tural pouch suggest the presence of fluid and exudate within is thought to result from chronic inflammation of the local-
the guttural pouch. Ultrasonographic examination can pro- ized lymphoid tissues, particularly because these structures
vide additional diagnostic evaluation of peripheral soft tissue have a diffuse distribution within the mucosa in this species.
structures and the extent of lymph node enlargement. Although some investigators have cultured the oropharynx of
affected horses, no consistent etiologic agent has been identi-
Treatment fied. Normal inhabitants of the equine upper respiratory tract
Based on the likelihood that S. equi subsp. equi is associated such as S. equi subsp. zooepidemicus, Bordetella bronchiseptica,
with the development of guttural pouch empyema, appropri- and Moraxella have been isolated; however, the direct asso-
ate biosecurity protocols should be adopted to reduce the risk ciation with the condition has not been determined. A grad-
of bacterial dissemination to instruments or personnel. Spe- ing system has been established for this condition (Table 8.2).
cific management protocols generally include medical therapy Horses with more severe inflammation have greater numbers
for the physical removal of exudate, preferably while material of bacterial organisms isolated from their upper respiratory
is liquid rather than when firm mucoid accumulations have tract.119
TABLE 8.2 Grading Scheme for Pharyngeal Lymphoid TABLE 8.3 Function and Innervation of Muscles Controlling the
Hyperplasia Tone of the Equine Soft Palate
GRADE 1: Small number of inactive white follicles scattered Muscle Function Innervation
over the dorsal pharyngeal wall. The follicles are small Tensor veli Tenses the rostral Mandibular branch
and inactive; this appearance is normal in horses of all palatini aspect of the soft of the trigeminal
ages. palate nerve
GRADE 2: Many small inactive white follicles over the dorsal
Levator veli Elevates the palate Pharyngeal branch
and lateral walls of the pharynx to the level of the guttural
palatini during swallow- of the vagus
pouches. Numerous follicles are larger, pink, edematous
ing and closes the
and interspersed throughout.
nasopharynx
GRADE 3: Many large pink follicles and some shrunken
white follicles are distributed over the dorsal and lateral Palatinus Shortens and Pharyngeal branch
walls of the pharynx. In some individuals the follicles depresses the of the vagus
extend onto the dorsal surface of the soft palate and into palate
the dorsal pharyngeal diverticula. Palatopharyn- Shortens and Pharyngeal branch
GRADE 4: More numerous pink and edematous follicles geus depresses the of the vagus
packed close together covering the entire pharynx, the palate
dorsal surface of the soft palate, epiglottis, and lining
the guttural pouches. Large accumulations appear as

polyps.
muscles results in DDSP.132 This cause is closely linked to pha-
Adapted from: Raker CW: The nasopharynx. In Mansmann RA, McAllister ryngeal lymphoid hyperplasia in young horses because the
ES, editors: Equine medicine and surgery. Santa Barbara, CA, 1982 pharyngeal branch of the vagus nerve runs through the floor
Veterinary Publications.
of the guttural pouch, which is also the roof of the pharynx.
Transection of the tensor veli palatini tendon alone destabi-
lizes the rostral aspect of the soft palate, leading to inspiratory
Y DORSAL DISPLACEMENT OF THE airway obstruction but not DDSP.133 Dysfunction of the cau-
SOFT PALATE dal stylopharyngeus muscle destabilizes the nasopharynx but
does not cause DDSP.131
DDSP results in an upper airway expiratory obstruction with Extrinsic causes are related to the musculature that controls
exercise. It is a common cause of poor performance in race- the position of the larynx and hyoid apparatus. Transection of
horses and has a prevalence of 10% to 20%.120-123 Most affected the paired thyrohyoid muscles produces DDSP134 presumably
horses make a loud, vibratory respiratory noise, known as because these muscles, innervated by the hypoglossal nerve,
choking down,124,125 although a proportion are silent during prevent caudal retraction of the larynx at exercise. Partial
displacement.11,125 Endoscopic examination of the upper air- resection of the sternothyroid and sternohyoid tendons pro-
way at rest is a poor predictor of DDSP.126 A definitive diag- duces an inspiratory airway obstruction but not DDSP.135
nosis is made, during high-speed treadmill examination, if the Investigation targeting the role of the rostral hyoid muscles
caudal border of the soft palate is seen dorsal to the epiglottis (geniohyoid, stylohyoid, and styloglossus) in horses is lacking,
for more than 8 seconds.127 but in humans these muscles are critical to pharyngeal stabil-
ity.136,137 Indirectly, tongue-tie devices, which are designed to
Anatomy prevent caudal retraction of the hyoid apparatus at exercise,
The horse is an obligate intranasal breather, and the epiglottis have been shown to prevent DDSP in some horses.138 In addi-
is usually positioned dorsal to the caudal border of the soft tion to these neuromuscular dysfunctions, structural abnor-
palate. A common analogy is a button through a buttonhole.128 malities such as masses or granulomas associated with the
The anatomy of this area is complex. The larynx is suspended epiglottic cartilage or the soft palate can induce DDSP.139
from the petrous part of the temporal bone by a chain of
paired hyoid bones, the stylohyoid, ceratohyoid, single basi- Treatment
hyoid bone, and thyrohyoid, which articulates with the rostral Surgical techniques aimed at preventing caudal retraction of
aspect of the thyroid cartilage. The strap muscles (sterno- the larynx, such as strap muscle resection and the Llewellyn
hyoid, sternothyroid, and omohyoid) contract during exer- procedure (transection of the tendon of insertion of the ster-
cise and pull the larynx caudally. Similarly, the genioglossus, nothyroid muscle), are associated with success rates ranging
geniohyoid, and styloglossus muscles (through their direct or between 58% and 73%.125,140,141 Treatments aimed at intrinsic
indirect attachments to the hyoid apparatus) pull the larynx causes include staphylectomy141 and soft tissue stiffening tech-
rostrally.129,130 The tone of the soft palate is determined by four niques such as rostral palatoplasty.142 Conservative manage-
pairs of muscles (Table 8.3). The stylopharyngeus muscle is ment of DDSP, incorporating rest, improvement of fitness, use
innervated by the glossopharyngeal nerve and tenses the dor- of a tongue tie, or any combination, has also been reported,
sal wall of the nasopharynx.131 with a success rate of up to 61%.138,143 A case-controlled study
demonstrated that composite surgery including staphylec-
Etiology tomy, sternothyrohyoideus myectomy, and ventriculocor-
The etiologic factors of DDSP are not completely understood dectomy produced increased race earnings in 60% of horses
and can be divided into intrinsic and extrinsic causes. Intrin- compared with 40% in controls.124
sic dysfunctions are seen with decreased tone in muscles of Surgical advancement of the larynx (laryngeal tie-forward
the palate. Dysfunction of the palatinus and palatopharyngeus procedure) demonstrated a success rate of 80% to 82% in
TABLE 8.4 Grading System for Laryngeal Function Performed in TABLE 8.5 Grading System for Laryngeal Function Performed
the Standing Unsedated Horse152 During Treadmill Endoscopy153
Grade Description Grade Description
I All arytenoid cartilage movements are synchronous A Full abduction of the arytenoid cartilages during
and symmetrical, and full arytenoid abduction can inspiration
be achieved and maintained. B Partial abduction of the left arytenoid cartilage
II Arytenoid cartilage movements are asynchronous (between full abduction and the resting position)
at times, but full arytenoid abduction can be C Abduction less than resting position, including
achieved and maintained. collapse into the contralateral half of the rima glot-
III Arytenoid cartilage movements are asynchronous tidis during inspiration
or asymmetrical (or both). Full arytenoid cartilage
abduction cannot be achieved and maintained.

IV Immobility of the arytenoid cartilage and vocal fold
the lateral cricoarytenoid muscle using ultrasound has been
is complete.

described, and this technique is a good predictor of arytenoid
Grades II and III contain several subgrades. Readers should consult the function at exercise.156 It is especially useful if a high-speed
referenced monograph152 for further information. treadmill examination cannot be performed.
Anatomy and Etiology
racehorses.144 The proposed mechanism of this procedure The left recurrent laryngeal nerve curves medially around
is that it replaces the action of the thyrohyoid muscles and the aortic arch during development and is approximately
prevents ventral descent and caudal retraction of the larynx 1 m long.157 In contrast, the right recurrent laryngeal nerve
during exercise. This procedure is well described elsewhere.144 courses around the right subclavian artery and is approxi-
Horses undergoing this procedure are as likely to race post- mately 25% shorter.157 The high prevalence of chronic demy-
operatively as matched controls. The procedure restores elinating peripheral neuropathy in the left recurrent laryngeal
race earnings to preoperative baseline levels and to those of nerve has been attributed to its length.158,159 The myelin loss
matched controls. is most severe distally160,161 and is associated with axonal
In addition, an external device (Cornell Collar, Vet-Aire, loss.161a,161b RLN results in progressive atrophy of the left dorsal
Inc., Ithaca, NY) that applies forward and upward pressure to cricoarytenoid muscle and associated loss of arytenoid carti-
the hyoid apparatus and incorporates a figure-eight noseband lage abduction.158,160,162 The right recurrent laryngeal nerve is
also prevents experimentally induced DDSP during strenuous rarely affected, although direct trauma to the nerve can induce
exercise.145 dysfunction.
During exercise, arytenoid dysfunction narrows the
rima glottidis and increases inspiratory impedance and
Y RECURRENT LARYNGEAL noise.163,164 This circumstance, in turn, results in airflow
NEUROPATHY limitation and increased driving pressure during inhalation,
leading to severe exercise-induced hypoxemia and decreased
RLN is a major cause of poor performance in racehorses and performance.163,165-167
affects 1.6% to 8% of Thoroughbreds.146-149 The prevalence in
draft horses is nearly 42%,150 and the risk of RLN increases Treatment
with increasing height in Belgians and Percherons but not in The current gold standard for treatment of RLN in horses
Clydesdales.150 Horses as young as 6 months may be affected.151 is prosthetic laryngoplasty, with or without vocal cordec-
The condition produces an inspiratory noise at exercise, which tomy or ventriculectomy.168-171 This technique involves the
has been described as both roaring and sawing. The term recur- placement of a nonabsorbable suture to create arytenoid
rent laryngeal neuropathy is preferred to idiopathic laryngeal abduction. One limitation of this technique is the frequent
hemiplegia.152 and significant loss of abduction of the arytenoid cartilage
seen in the immediate postsurgical period.171,172 This loss of
Diagnosis abduction leads to a reduction in the cross-sectional area of
A diagnosis can be made in most horses based on a resting the rima glottidis and the return of exercise intolerance and
endoscopic examination of the arytenoid cartilages. Some abnormal respiratory noise.171-173 Loss of abduction may also
confusion has arisen from different grading systems used to contribute to the modest postoperative success rate of 48%
diagnose the degree of arytenoid dysfunction present at this to 68% observed in racehorses.168,169,174-177 A much higher
examination. A recent meeting of investigators reached a success rate (73%–91%) is reported in horses performing at
consensus on a four-level grading system (Table 8.4).152 This submaximal exercise.171
resting grading system is most useful in its ability to predict In draft breeds, the degree of abduction required at laryn-
arytenoid function at high-speed exercise. Arytenoid position goplasty is lower than that for a racehorse, given that the goal
at exercise is shown in Table 8.5.153 is to prevent dynamic collapse of the arytenoid rather than
All grade 1 horses are normal (grade A) at exercise, and to achieve a normal cross-sectional area of the rima glotti-
all grade 4 horses show dynamic collapse (grade C).154 During dis. Some clinicians recommend vocal cordectomy alone for
exercise, 4% of grade 3 horses are normal (grade A), 19% are draft breeds. For racehorses and nonracehorses, the major
grade B, and 77% are grade C.155 For grade 2 horses, 4% are complications are exercise intolerance, respiratory noise, and
grade B or C at exercise.154 Recently a technique for examining coughing.169,170,177
Restoration of physiologic function through reinnervation Y ROSTRAL DISPLACEMENT OF THE

and nerve–muscle pedicle transplant techniques has also pro- PALATOPHARYNGEAL ARCH
duced positive results,178-180 although a delay of several months
occurs before any improvement in arytenoid function is seen. In the horse, the soft palate terminates caudally at the conflu-
Partial arytenoidectomy is associated with a fair prognosis ence of the caudal pillars to form the palatopharyngeal arch
for the treatment of RLN in horses174,181 and is not generally that covers the esophageal orifice.193 With rostral displace-
recommended as a first-line surgical option. ment of the palatopharyngeal arch, this fold of tissue appears
to be displaced forward, overlying the apices of the arytenoid
Y EPIGLOTTIC ENTRAPMENT cartilages. The condition is uncommon, with a number of
small case series and individual cases being reported.120,194-197
The aryepiglottic fold is the mucous membrane that extends The displacement of the palatopharyngeal arch may be asso-
from the lateral aspect of the arytenoid cartilages to the ven- ciated with malformation of the laryngeal cartilages and the
trolateral aspect of the epiglottis, where it blends with the sub- cricopharyngeal and cricothyroid muscles.120 The condition
epiglottic mucosa and the glossoepiglottic fold. In epiglottic may be present from birth. In most cases, abnormal respi-
entrapment, this membrane envelops the free border of the ratory noise and poor athletic performance are the pre-
epiglottis.182 Billowing of the entrapping membranes during senting complaints. Abnormal pharyngeal conformation
respiration decreases the cross-sectional area of the phar- prevents normal deglutition, predisposing horses to develop
ynx and effectively obstructs the airflow, particularly during aspiration pneumonia. In severe cases, horses may exhibit
expiration. dysphagia, nasal discharge of food material, and persistent
The cause of epiglottic entrapment is not understood com- coughing.128,196 The diagnosis is based on the clinical signs
pletely. In most cases, the epiglottic cartilage and associated and history and confirmed with endoscopic examination.
soft tissues appear normal. In occasional cases, congenital The rostrally displaced palatopharyngeal arch obscures the
epiglottic hypoplasia or inflammation of the upper respiratory normal view of the apices of the arytenoid cartilages. Ros-
tract structures appears to contribute to entrapment. Epiglot- tral displacement of the palatopharyngeal arch represents a
tic entrapment is responsible for 1% to 3% of upper airway major deformation of the laryngeal structures and is associ-
obstructive problems in horses.121,149 ated with a guarded prognosis. Resection of the arch by con-
ventional surgery or laser surgery has not enabled successful
Clinical Signs athletic performance.194
Most horses exhibit exercise intolerance and respiratory ster-
tor. Horses may occasionally cough during exercise or while Y NASOPHARYNGEAL CICATRIX
eating.
Nasopharyngeal cicatrix is a condition of upper airway
Diagnosis inflammation and subsequent scarring of the pharynx. Addi-
The diagnosis is based on endoscopic examination. The mem- tional structures that are commonly affected include the
brane obscures the normal serrated margin of the epiglottis openings to the guttural pouches, the epiglottis, and the ary-
and its dorsal vasculature. In contrast to DDSP, the shape of tenoid cartilages. A very specific geographic region is associ-
the epiglottis can still be seen. Ulceration of the free margin ated with the development of this condition, specifically in the
of the fold and erosion of the entrapped epiglottis may be Gulf Coast region of central and southeastern Texas.198-201 The
apparent.183 disease has also been reported in Mississippi, Louisiana, and
Florida, but rarely.183,198 This is an upper airway condition that
Treatment has been recognized for approximately three decades, but for
Entrapment requires surgical correction. Several different equine referral clinics this condition has become one of the
approaches have been used and include transoral182,184-186 most commonly diagnosed disorders among horses requiring
or transnasal187 axial division with a hooked bistoury and permanent tracheostomy.200 Clinical signs commonly include
transendoscopic division with a laser.188-190 The prognosis is upper respiratory noise, exercise intolerance, and rarely, dys-
good after surgery, although re-entrapment and DDSP may phagia. During acute stages of disease, nasal discharge may
occur after surgery.182,190,191 be observed.202 Horses that present with the complaint of
respiratory distress are more likely to be in the acute stages
Y ARYTENOID CHONDRITIS of disease. Airway obstruction of >50% leads to marked
increase in airway resistance, which increases by 16-fold (or
Arytenoid chondritis is a progressive inflammatory condition more) depending on the severity of scarring and pharyngeal
of the arytenoid cartilages in adult horses, originating as an narrowing. Consistent with the fact that disease is localized
infectious condition. Most commonly, upper airway dysfunc- to the upper airway and dysphagia is uncommon, coughing
tion is reflected in poor athletic performance and respiratory is not usually reported in association with nasopharyngeal
stridor. Diagnosis is based on upper airway endoscopy. One cicatrix.202
manifestation of chondritis is the development of granulo- Upper airway endoscopy will provide a confirmatory diag-
mas on the axial surface of the arytenoid cartilages. Clinical nosis. Early diagnosis is important so that environmental fac-
management of affected patients involves medical or surgi- tors can be modified to limit disease progression. Removal
cal therapy. Although broad-spectrum antibiotic therapy has from pasture and movement to a stall or dry lot is associated
been attempted in many cases, it is rarely curative. Also of with limited disease progression. Although various surgi-
importance in management of some of these cases is place- cal procedures have been used to remove scar tissue forma-
ment of a tracheostomy tube. Several techniques are described tion, the currently recommended procedure is permanent
for placement of a permanent tracheostomy.192 tracheostomy.199
A recent retrospective case-control investigation aimed at between these organisms can provide diagnostic information
determining risk factors for the development of nasopharyn- regarding DNA sequence data that are unique to S. equi, which
geal cicatrix evaluated 242 horses, 121 with nasopharyngeal provides the clinician with improved diagnostic sensitivity.110
cicatrix and 121 control horses. In toto, 1236 horses were Ideally, PCR testing should be performed using primers based
examined with the reported affected and control horses meet- on the nucleotide sequence of the gene encoding the S. equi
ing inclusion criteria for investigation. Risk factors associated M-like (SeM) protein.205
with disease development included horses living on pasture Molecular evaluation with multilocus enzyme electro-
exclusively or access to pasture and age of the horse.202 There phoresis has confirmed a strong genetic relationship of S.
was no breed or gender association with disease develop- equi subsp. equi and S. equi subsp. zooepidemicus, indicating
ment, which was in contrast to a previous investigation that that the former is actually a clone derived from the more
suggested mares may have an increased risk of disease.198 The genetically diverse S. equi subsp. zooepidemicus.206 This
age-associated component of disease development is believed finding has led to the recommendation that S. equi subsp.
to be associated with chronic progression of the disease or equi be reclassified as a biovar of S. equi subsp. zooepi-
that the disease results from repeated bouts of exposure to demicus.207 Even though isolates of these two organisms
an allergen or irritant located in the pasture. The repeated show greater than 92% DNA homology (similarity), immu-
bouts of exposure are believed to result in continued bouts nity is species specific; immunization with S. equi subsp.
of inflammation and fibrous remodeling of the upper airway zooepidemicus does not protect against challenge by S. equi
of affected horses.202 Based on the available published data subsp. equi. However, from an immunologic perspective,
reporting this disease, it appears that the proportion of cases host response to this pathogen may be complex because of
have remained steady since the original reports were pro- antigen cross-reactivity against these two very similar bac-
vided, with the overall proportion being 0.64% of the cases terial organisms.
seen in high-risk geographic regions.198,202 Disease was rec- Because S. equi is a primary pathogen of the equine upper
ognized to have a seasonality, with affected horses presented respiratory tract, unlike S. zooepidemicus, which is pathologic
for examination in summer months. Acute flare-up of dis- only as a secondary invader, S. equi does not require airway epi-
ease was more likely to occur in the spring, summer, or fall thelial disruption or prior viral infection for effective bacterial
months, suggesting that exposure to an irritant such as pol- colonization and subsequent infection.208 Three colony types
len or algal toxin was more likely to occur during warmer exist for S. equi, with morphologic differences directly asso-
months. ciated with bacterial virulence. The most widely recognized
Overall, it appears that this condition is more likely to strain that demonstrates marked pathogenicity in horses pro-
occur in older horses that live predominantly on pasture, duces colonies that are heavily encapsulated and light golden
particularly during warmer months in southeastern and cen- color on blood agar, whereas atypical S. equi colonies exhibit
tral Texas. The exact etiology remains elusive, which makes a matt appearance within 24 hours of incubation in culture
prevention challenging. In horses diagnosed with nasopha- conditions and are nonencapsulated colonies that are dry and
ryngeal cicatrix resulting in marked airway narrowing and small.209 Morphologic differences are observed among S. equi
distress, permanent tracheostomy is the treatment of choice, strains as a result of variability in the hyaluronic acid content
with a favorable prognosis (89%) for outcome and return to of the bacterial capsule.
function.200
Epidemiology
Infection with S. equi is most commonly observed in young
Y STREPTOCOCCUS EQUI SUBSP. EQUI horses, typically aged from 1 to 5 years of age, but can occur
INFECTION (STRANGLES) in horses of any age, particularly if antigen-specific immunity
is not present or challenge is marked. Foals up to 3 months
Bacterial infections involving the upper respiratory tract of age born from immune mares are known to be resistant to
commonly involve S. equi subsp. equi. S. equi subsp. equi is the development of strangles.210 Therefore in endemic areas
a gram-positive β-hemolytic coccoid bacterium that is cat- foals will have increased susceptibility to infection after wan-
egorized within Lancefield group C and has been responsible ing of maternal antibodies, generally at the time of weaning
for causing primary respiratory disease in horses for centu- or later in the first year of life. Immunologically naive indi-
ries.203 S. equi is a highly contagious primary upper respiratory viduals are highly susceptible to infection with morbidity
tract bacterial pathogen and is the causative agent of stran- rates of approximately 100%, whereas mortality is low (up
gles, which is one of the most common infectious diseases to 10%).211 It has been estimated that following infection
of horses. S. equi is easily grown on blood agar and produces approximately 75% of horses maintain protective immunity
mucoid, nonpigmented (honeydew) colonies that appear in against challenge for greater than 5 years.212,213 Interestingly,
pairs or chains that are surrounded by a prominent zone of however, the remaining 25% of these horses fail to maintain
β-hemolysis. Although highly similar genetically, this organ- pathogen-specific immunity; therefore, they are susceptible
ism is distinct from S. equi subsp. zooepidemicus, which is a to reinfection within months of challenge, which may rep-
normal inhabitant of the upper respiratory tract of healthy resent a failure to produce or maintain an adequate level of
horses. Although colony morphology may be indistinguish- protective mucosal and systemic antibodies.213 In one study of
able, S. equi is typically differentiated from S. zooepidemicus young horses that had been affected with clinical strangles as
by its inability to ferment carbohydrate sugars, specifically foals, researchers found that 83% were resistant to comingling
lactose, sorbitol, or trehalose.204 Typical S. equi isolates fail to exposure 6 months later.214 As would be expected, however,
ferment sugars, whereas atypical S. equi isolates may ferment immunity is not lifelong. Historical epidemiologic studies
lactose or trehalose but not sorbitol.205 In addition to bio- report attack rates in horses greater than 3 years of age at 18,
chemical characteristics, DNA-based tests that discriminate 29, and 35%.211,215,216
from the guttural pouches. It has been proposed that incom-

plete emptying of the guttural pouches leads to retention of
material that develops into chondroid material; the persistent
presence of this material in the guttural pouch may maintain a
perpetual cycle of inflammation in a relatively closed-off ana-
tomic site. Carrier animals maintained in the general popu-
lation play a critical role in harboring the bacteria between
apparent disease outbreaks.222 Identification of the carrier
animal is paramount to abate future disease outbreak.
Although large-scale controlled field studies aimed at
documenting survivability of environmental S. equi have
not been conducted, there has been a long-standing suspi-
cion that S. equi may persist in the environment for extended
periods of time.223 Recommendations for the management of
contaminated environments were based on original investi-
gations aimed at determining survival of environmental S.
equi that suggested that long-term bacterial persistence may
FIG. 8.13 A 12-year-old Quarter Horse gelding with the history of Strep- be a substantial risk for up to 63 days.224 However, and in con-
tococcus equi infection approximately 6 months previously. Intermittent trast to these original observations, more contemporary evi-
unilateral mucopurulent nasal discharge was observed since the original dence suggests more limited survival of S. equi in an outdoor
infection. Upper airway endoscopy revealed marked chondroid develop- environment.225 In this study, sunlight was associated with
ment in the left guttural pouch. survival of less than 24 hours, whereas overall survival was
less than 72 hours.225 The implications from this investiga-
tion should not be overinterpreted; however, it is noteworthy
S. equi subsp. equi can be transmitted by direct contact with than in an outdoor environment, particularly in which ample
an infected horse with purulent discharge associated with sunlight exists, long-term sequestering of facilities is unlikely
disease or via contamination of fomites such as horse han- to be necessary. When cleansing of nonporous surfaces is
dlers, grooming equipment, tack, feed areas, water sources, implemented, the organism is susceptible to a 1:200 dilu-
or other items that may be contaminated with bacterial-laden tion of phenol, and disinfectants such as povidone-iodine,
mucous secretions from an infected horse. Not uncommonly, chlorhexidine, and glutaraldehyde kill the organism within
introduction of a horse that is recovering from infection into 90 minutes.
a group of naive horses can lead to an outbreak. Although S. equi has traditionally been defined as a pathogen
horses can resolve the clinical manifestation of disease in restricted to the equine host. However, fatal pneumonia attrib-
approximately 14 days, bacterial shedding typically contin- uted to the organism was reported and characterized at the
ues for 4 to 6 weeks. In some instances, disease outbreak can molecular level in a dromedary camel.226,227 Although S. equi
occur as a result of an apparently healthy horse serving as an infection may occur in humans and descriptions of S. equi
asymptomatic chronic carrier animal. Horses can maintain bacteremia and meningitis exist, infections in humans are
the organism within the guttural pouches for extended peri- rare and may be associated with overwhelming challenge or
ods within inspissated purulent material in the form of chon- impaired host immunity.228
droids (Fig. 8.13). In a recent report it was recommended that
guttural pouch endoscopy may provide the clinician with the Pathogenesis
most efficient and accurate method of diagnosis in an inap- After infective droplets are inhaled or ingested, the organism
parent carrier horse. This case-control study included 8308 adheres to the epithelial cells of the buccal and nasal mucosa
horses over an 8-year period that were examined by the ambu- of the horse, but it does not colonize the mucosal surface of
latory service of a major teaching hospital. Overall there were tonsillar tissues of the nasopharynx. The incubation period
108 (1.3%) strangles cases, and 215 (2.6%) of the horses pre- for bacterial exposure to clinical manifestation of lymph
sented with pyrexia but did not suffer from S. equi infection node abscess formation is approximately 10 to 14 days. Inter-
and therefore served as control animals. The study confirmed estingly, S. equi cannot be detected by bacterial culture or
previous observations217-219 that horses with bilateral muco- nasopharyngeal swabs obtained 24 hours after infection or
purulent nasal discharge (Fig. 8.14A–B) and external abscess challenge. The mechanism of bacterial adherence remains
formation in the pharyngeal region were likely suffering from incompletely understood but may involve exposed bacterial
S. equi infection.220 Additionally it was determined that not all surface proteins such as SzPSe, Se73.0, and Se51.9.223 What
horses demonstrated clinical evidence to support S. equi infec- makes S. equi unique when compared with S. zooepidemicus
tion and that on examination of suspect horses upper airway has been suggested to relate to the genetic sequence of S.
endoscopy may provide a more efficient and accurate method equi, which results in the ability of this bacterial organism
for examination of the upper airway and sample collection for to rapidly translocate the mucosal epithelium and create
microbial culture and molecular diagnostic testing. Previous marked lymph node abscess formation. Of particular rel-
reports have provided evidence that horses may harbor the evance to the molecular structure of S. equi is the fact that
organism in the guttural pouches for extended periods, with the genome encodes 29 surface proteins that are character-
one report indicating 39 months in the absence of clinical ized by the presence of a specific LPXTG motif, which under
signs.216,221 The etiopathogenesis of the carrier state for horses the influence of sortase enzymes results in the attachment of
with chondroids is incompletely understood but is believed to this protein to the peptidoglycan cell wall.222,229 Similarly, S.
develop as a result of incomplete drainage of mucoid material zooepidemicus also encodes sortase processed proteins with
A B
FIG. 8.14 Yearling Quarter Horse cross filly with evidence of submandibular lymphadenopathy and bilat-
eral mucopurulent nasal discharge consistent with microbiological culture of Streptococcus equi subsp. equi
(A). (B) Subsequent rupture of submandibular lymph nodes.
one strain, termed H70, which encodes 39 proteins. These ribose, lactose, and sorbitol.204,222 Mucosal colonization is
proteins are defined as pili loci; pili are hairlike projections directly related to carbohydrate metabolism, and it is believed
that extend from the bacterial surface and are believed to that although S. zooepidemicus has maintained this capacity, S.
play an important role regarding epithelial attachment to equi has lost this through the process of evolution.
host tissues.222 Because S. equi expresses a more limited rep- Similar to many strains of bacteria, S. equi produces a hyal-
ertoire of these proteins, this may limit the diversity of host uronic acid capsule. This capsule provides the bacteria with
attachments by this bacterial strain, leading to more rapid an immune evasion mechanism that limits host destruction of
epithelial translocation. bacterial challenge. This capsule mimics the host molecule that
Among the characteristics of S. equi is the ability of this bac- is present in mammalian tissues, conferring a protective shield
teria to evade host defense mechanisms. The sortase-processed for the bacterial organism. Nonencapsulated S. equi has been
M protein of streptococci confer antiphagocytic properties. compared with a medium capsule-producing strain referred
Specifically, acid-resistant fibrillar molecules that project from to as the matt strain in addition to a heavily encapsulated
the bacterial surface are expressed in pairs that twine around or mucoid strain. When compared in vitro, the strains were
one another into a tight surface coil structure. S. equi subsp. similar with respect to their M-protein expression, cytotoxin
equi–expressed M proteins are approximately 58 kDa in size. activity, and mitogen expression. However, the nonencap-
The C-terminal region of SeM is predicted to have an α-helical sulated strain did not demonstrate any resistance to in vitro
coiled-coil structure with a high degree of sequence similarity phagocytosis by neutrophils, independent of the presence of
to SzM expressed by S. zooepidemicus. In contrast, however, opsonins. In contrast, strains with matt or mucoid levels of
the N-terminal portion of SeM is not coiled, and single strands capsule formation demonstrated near-complete resistance to
are expressed that are unique to S. equi. Regarding evasion of phagocytosis. In addition, when considering the influence of
host immunity, antiphagocytic activity is associated with the the capsule on pathogenicity in the equine host, the nonencap-
fibrinogen binding capacity of these individual protein moi- sulated strain did not result in clinical disease following chal-
eties in addition to the binding capacity with Ig isotypes, IgG4 lenge, yet seroconversion was observed, whereas encapsulated
and IgG7. With the presence of fibrinogen and Ig binding on strains of S. equi repeatedly resulted in disease consistent with
the bacterial surface C3b-binding sites are blocked, which S. equi infection.230
inhibits the activity of the alternate complement cascade of C3 Within hours of adhesion, the organism translocates
and C5 convertases. There is a large degree of diversity of this below the mucosa to gain access to the local lymphatics and
region of SeM. lymph nodes, in which replication occurs extracellulary.222,231
Although it is recognized that there are many differences Complement-derived chemotactic factors generated after
among S. equi and S. zooepidemicus, one of the major differ- interaction of C1 with bacterial peptidoglycan attract large
ences pertains to fermentation of carbohydrates—namely, numbers of neutrophils that contribute to the lymphadenitis
and abscess formation.213 Metastatic bacterial spread to sites to induce nonspecific T-cell stimulation, proliferation, and
other than the upper respiratory tract lymphoid tissue may cytokine release. As a result, an acute phase response ensues,
occur by hematogenous or lymphatic pathways. Although characterized by release of interleukin-1 (IL-1), tumor necro-
uncommon and reported in an isolated investigation, S. equi sis factor-α (TNF-α), and IL-6 from mononuclear cells that
may be cultured from the blood 6 to 12 days after intranasal contribute to the production of fever, malaise, neutrophilia,
inoculation.232 and hyperfibri-nogenemia.213,232a
Numerous virulence factors of S. equi contribute to its Humoral immune responses to many of these virulence fac-
pathogenicity, a few of which include the hyaluronic acid tors are apparent in infected horses. During the initial stages of
capsule, the SeM protein, an antiphagocytic protein (Se18.9), infection, serum IgGa to the SeM protein is induced, followed
a leukocidal toxin (streptolysin S–like [SLS] toxin), and cell by the appearance of IgA and IgGb to SeM on the mucosal
membrane lipoproteins.205,232a-c, Synthesis of the hyaluronic surfaces.232e During convalescence, strong IgGb responses
acid capsule is controlled by the has operon, which consists appear to SeM, as well as to other surface-exposed proteins
of hasA (encodes hyaluronate synthase), hasB (encodes UDP- (Se44.2, Se46.8, Se45.5, and Se42.0).213
glucose dehydrogenase), and hasC (encodes UDP-glucose
pyrophosphorylase). The capsule is antiphagocytic, ultimately Clinical Signs
reducing the number of bacteria that are subsequently ingested The incubation period for typical S. equi infection ranges
and killed. The capsule, by virtue of its negative charge and between 2 and 12 days. Generally, horses are febrile (103°F
hydrophilicity, also produces a localized reducing environ- or higher), exhibit lethargy, may have reduced appetite, and,
ment that protects the activity of oxygen-labile proteases and although initially have serous nasal discharge, with the dis-
toxins (SLS). Finally, the capsule is required for the activity ease progressing, the material becomes mucopurulent. Ocu-
of SeM. In nonencapsulated strains of S. equi, SeM aggregate lar and nasal mucosal membranes are commonly hyperemic,
and fail to achieve the three-dimensional structure required and a mucopurulent ocular discharge may ensue. Mandibu-
for their function.213 Although nonencapsulated strains of lar and retropharyngeal lymph nodes are initially firm but
S. equi are able to colonize the surface of the upper respira- become fluctuant before rupturing 7 to 14 days after the onset
tory tract and stimulate production of the serum antibody, of signs. Retropharyngeal lymph nodes may rupture into the
they are unable to induce detectable pathologic changes in guttural pouches, causing neuropathy (dysphagia), empy-
the retropharyngeal and mandibular lymph nodes. The sec- ema, and chondroid formation. Lymphadenopathy, one of
ond virulence factor, the SeM protein, is a 58-kDa cell wall the major signs of S. equi infections, may be asymmetric and
antigen that is also antiphagocytic. At its N-terminal end, SeM may become so severe that dysphagia, stridor, and respiratory
binds to fibrinogen; at its central region, it binds to IgG. In distress ensue. Swelling of the throatlatch area or of Viborg’s
doing so, it masks the C3b binding surface on the bacterial triangle may be apparent, and palpation of this area may elicit
cell wall and inhibits the alternative C3 and classical C5 con- pain. The affected horse may stand with its neck stretched out
vertase.213 Sequencing of the SeM gene between codons 38 and be reluctant to swallow. A soft moist cough may be heard.
and 143 from 142 S. equi strains has identified 43 alleles of The average course of the syndrome is 23 days.208 In atypical S.
SeM, with each allele characteristic of a particular outbreak in equi infections, a mild inflammation of the upper respiratory
a geographic location.232d Thus SeM sequence analysis can be tract occurs and is characterized by a slight nasal discharge,
used to complement epidemiologic investigations of strangles cough, and fever. Lymph node abscess formation occurs only
outbreaks. The loss of SeM expression leads to a loss of viru- in a small number of the cases.209,233,234 In the majority of
lence but not to a decrease in the infectivity of the organism. horses, clinical signs resolve, and bacterial shedding ceases by
Another M-like protein of S. equi, SzPSe, exhibits antigenic 4 to 6 weeks. In an estimated 10% of affected horses, continued
cross reactivity with the M-like proteins of S. zooepidemicus, intermittent shedding of S. equi may occur for several addi-
but its contribution to the virulence of S. equi is unknown.206 tional weeks.
Recently, a protein unique to S. equi, Se18.9, was found to also
possess antiphagocytic properties.232c The net effect of Se18.9 Clinical Pathology
is to decrease deposition of C3 (and hence opsonic C3b) on Neutrophilic leukocytosis, hyperfibrinogenemia, hyperglobu-
the bacterial surface, reducing phagocytosis. SLS protein linemia, and anemia of chronic infection are characteristic
is thought to represent a fourth virulence factor by its cyto- findings with typical strangles cases. In cases complicated by
toxic properties. It damages host macrophages and neutro- concurrent pneumonia (aspiration), a left shift and the pres-
phils enabling immune evasion, as well as access to released ence of neutrophils with toxic signs may be noted. In horses
essential nutrients.205 A fifth virulence factor resides in the with purpura hemorrhagica, moderate to marked elevations
lipoprotein components of the S. equi cell membrane. When in muscle enzymes occur. Horses that suffer from infarctive
mutants of a specific lipoprotein are synthesized (PrtM) and purpura hemorrhagica may have marked elevations of muscle
the organisms are administered to susceptible ponies, clinical enzymes.235
signs are markedly attenuated (0 of 5 infected ponies devel-
oped signs compared with controls). These data suggest that Diagnosis
this lipoprotein is an important virulence factor and might be Diagnosis of strangles in an equine patient is based on clini-
targeted for vaccine development.232b Additional factors that cal signs and the isolation (culture) or detection (via PCR) of
contribute to the pathogenicity of S. equi include extracel- S. equi from a lymph node, nasal passage swab, nasopharyn-
lular proteins or exotoxins that are mitogenic for peripheral geal lavage, or lavage fluid from the guttural pouches. Identi-
blood mononuclear cells.230 These mitogenic factors (SePE- fication of S. equi via culture or PCR testing can generally be
H, SePE-I, SePE-K, and SePE-L) bind simultaneously to class achieved 2 to 3 days after the onset of fever. Bacterial shed-
II major histocompatibility complex (MHC) molecules on ding can typically be detected for several weeks, often even
antigen-presenting cells and to the T-cell receptor of T cells following resolution of clinical signs. Because S. equi does
not colonize the upper airway mucosa culture, PCR testing Treatment
of an acutely affected horse may initially be negative.110 Naso- In most cases of S. equi infection supportive care provided by
pharyngeal lavage samples are more likely to yield positive soft palatable feed, NSAID therapy, and maintenance of hydra-
results compared with swab samples. The lavage fluid will tion will be all the medical care that is required. However,
contact an increased surface area, increasing the likelihood there are some differences of opinion regarding the adminis-
of detecting bacteria if present. Following routine sedation, tration of antibiotics in horses with strangles.223 Treatment is
the wash is accomplished by instilling approximately 50 mL a function of the stage of the disease, and the general recom-
of warmed, 0.9% sterile saline into the nasal cavity via a mendations listed here are those included in the American
15-cm soft rubber tubing that has been inserted to the level College of Veterinary Internal Medicine (ACVIM) Consensus
of the medial canthus. Fluid is collected by gravity, placed Statement.223 The reader is referred to this excellent review. In
into a 50-mL conical tube, and centrifuged; the pellet can be treating horses with S. equi, penicillin is the drug of choice,
used for culture. Guttural pouch lavage is ideally performed although the organism is sensitive to oxytetracycline and the
endoscopically, allowing inspection of the medial and lateral potentiated sulfonamides.211,231
compartments for evidence of lymphadenopathy, empyema,
or (in more chronic infections) chondroid formation. For the Clinical Management of Streptococcus
lavage, approximately 50 mL of warmed, sterile 0.9% saline
is instilled through the biopsy chamber and gently aspirated
equi–Infected Horses and Prevention of
for culture, PCR, or (commonly) both. When endoscopy Disease Progression
is not feasible, a guttural pouch lavage may yet be possible Horses exhibiting early clinical signs of infection (initial fever
by advancing a Chambers catheter blindly into the guttural spike and lethargy) in the absence of lymph node abscess for-
pouch of the sedated horse and lavaging the compartments. mation should receive penicillin G therapy for 5 days, which
In unusual instances blood cultures may become positive for can arrest the progression of the disease. One should isolate
S. equi on days 6 to 12 after infection.232 PCR testing is based the horses during their treatment protocol. Treated horses are
on the SeM DNA sequence and is used in conjunction with likely to remain susceptible to infection because sufficient bac-
bacterial culture in diagnostic workups. PCR has greater terial antigen to elicit a protective immune response may not
diagnostic sensitivity compared with bacterial culture and have been produced as a result of treatment. No evidence has
may detect SeM DNA for weeks in guttural pouch lavages been found that the use of antibiotics during this stage will
after the disappearance of live organisms.236 Upper airway promote the development of metastatic strangles.240
endoscopy has become commonplace in field settings and For alert and otherwise clinically stable horses exhibiting
may provide superior diagnostic capability for examination lymph node abscess formation, administration of penicillin
and sample collection, particularly when the goal is to iden- slows the progression of lymph node abscess formation and
tify carrier animals.220 It is useful in detecting asymptom- is generally contraindicated. Hot-packing the area or areas
atic carriers, in establishing S. equi infection status before or promotes maturation of the abscess. Once achieved, the cli-
after transport or commingling, and in establishing success nician should lance the abscess and flush it with a 3% to 5%
of treatment.223 povidone-iodine solution and, if desirable, then institute anti-
Screening of horses suspected to be suffering from com- biotic therapy. Horses may benefit from phenylbutazone or
plications of S. equi infection includes serologic assessment flunixin meglumine administration, which will reduce fever,
of the SeM-specific antibody. Horses identified to have an lessen pharyngeal discomfort associated with the lymphad-
SeM titer in excess of 1:12,800 are suspected to suffer from enitis, and improve demeanor. Horses with S. equi infection
complicating factors of S. equi infection, such as purpura should be maintained in an isolation area with strict adher-
hemorrhagica or metastatic dissemination of S. equi.223 ence to biosecurity.
Serologic testing can also be helpful in determining the Horses that are systemically ill or that develop complica-
need for vaccination or in identifying horses that may be tions such as dysphagia, aspiration pneumonia, or respira-
hyperresponders and predisposed to the development of tory distress (particularly if tracheostomy is needed), require
purpura hemorrhagica (SeM-specific antibodies >1:1600). supportive care in addition to high levels of IV penicillin and
An enzyme-linked immunosorbent assay (ELISA) based on broad-spectrum antimicrobials effective against gram-nega-
SeM-specific antibodies is commercially available through tive organisms (aminoglycosides) and/or anaerobes (metroni-
two commercial laboratories (Equine Diagnostic Solutions dazole). Horses may also require IV fluid therapy, nonsteroidal
[EDS] Lexington, KY, and IDEXX Laboratories, Westbrook, antiinflammatory drugs, and enteral nutritional support.
ME). Serology may not reliably detect subclinical carriers
because of the overlap in the breakpoints between normal Sequelae
and convalescent horses.237,238 The overall complication rate in horses with strangles is esti-
Upper airway endoscopy is an important component of the mated to be 20%; most frequently, complications result from
examination of horses suffering from S. equi infection. Visual metastasis of the organism to other organ systems with the
inspection of the guttural pouches will provide the clinician formation of purulent foci.241 Complications are detailed in
with the opportunity to identify evidence of lymphadenopa- the following sections.
thy, empyema, or chondroids, which can be instrumental in
the diagnosis of S. equi infections. It can also aid in the identifi- Internal Abscessation of the Mesentery or
cation of asymptomatic carriers, given that endoscopic abnor- of Parenchymatous Organs
malities are often still present in these horses.220,221 Notably, The exact pathogenesis for the development of internal abscess
the absence of visible pathology in an asymptomatic carrier formation is not known.242 Although anecdotal reports sug-
emphasizes the need to still obtain samples for concurrent cul- gest that antibiotic therapy early in the course of infection may
ture and standard (direct) PCR analysis.110,220,239 predispose horses to the development of metastatic disease,
there is no evidence to support this suggestion. Additionally, which is a deviation of the larynx potentially with drainage of
because the treatment protocols for horses that suffer from purulent material into the nasopharynx when external pres-
internal abscess formation include long-term and in some sure is applied to the parotid region.248 Skull radiographs typi-
cases high-dose antibiotic therapy, it is counterintuitive to cally demonstrate a soft tissue opacity in the retropharyngeal
consider that antibiotics are a risk factor for the development area; thickening of the roof of the pharynx; reduction in the
of metastatic disease. The prevalence of metastatic abscess for- diameter of the pharyngeal airway; and distortion or compres-
mation is low, with estimates of 28% based on outbreaks on sion of the guttural pouches, pharynx, and trachea.249 Ultra-
two farms.243 sonographic evaluation of the affected region caudal to the
mandible, dorsal to the trachea, and between the linguofacial
Purpura Hemorrhagica vein and maxillary vein can be used to identify the position
Immune-mediated type III hypersensitivity leading to vascu- of the abscessed retropharyngeal lymph nodes.250,251 Abscess
litis may occur after re-exposure to S. equi by natural infection maturation and rupture will occur into the pharynx, which
or following vaccination. Most commonly, purpura hemor- may result in secondary pneumonia, or abscess rupture may
rhagica develops during the recovery phase of the disease, 2 occur dorsally into the guttural pouches, which when associ-
to 4 weeks following severe disease manifestation. Immune ated with marked inflammation may lead to neuritis and sub-
complex deposition of the vascular intima results in marked sequent dysphagia.241,248,249
edema and necrosis. Clinical manifestation of purpura hem-
orrhagica involves the development of ventral edema that Abscess Formation Resulting in Respiratory
may be asymmetric in origin. The prevalence of this disorder and Systemic Complications
after natural outbreaks is not known. In a retrospective study Laryngeal hemiplegia has been reported to occur when
of 53 horses diagnosed with purpura hemorrhagica at a uni- abscessed lymph nodes impair normal conduction of the
versity teaching hospital,244 17 horses had confirmed expo- recurrent laryngeal nerve resulting in laryngeal paralysis.252
sure or infection with S. equi, and 5 had been vaccinated with In the same report an additional complicating factor involved
SeM protein. Horses that are hypersensitive to S. equi are at tracheal compression caused by abscess formation in the
greater risk for developing purpura hemorrhagica defined region of the cranial mediastinal lymph nodes.252
as having an SeM protein titer of >1:1600.110 Specifically, the
deposition of IgA-containing immune complexes is associ- Other Complications
ated with clinical manifestation of purpura hemorrhagica, Other complications of S. equi infection can also include
whereas an increase in S. equi–specific IgG was observed in endocarditis, myocarditis, or cardiac conduction abnormali-
the clinical recovery stage of purpura hemorrhagica in one ties. These conditions may result from primary colonization
report.171,172 Horses with clinical evidence of purpura hem- or secondary immune-mediated, inflammatory disorders.
orrhagica demonstrated markedly elevated IgA titers against An additional complication that can occur in periparturi-
SeM-like proteins and culture supernatant compared with ent mares is a condition of agalactia. Although not a result
IgA titers in horses with uncomplicated strangles.245 The iso- of primary bacterial infection, systemic illness and negative
lation of immune complexes consisting of IgA and SeM-like energy balance may play a role for mares reducing or elimi-
proteins in the sera of horses with purpura hemorrhagica nating their lactogenic capacity. Brood mares suffering from
has led to the suggestion that IgA is directly involved in the S. equi infection, that are intended to be raising a foal, should
development of purpura.245,246 The immunologic basis for be monitored closely for proper lactation so that foals can be
the increase in serum IgA levels is not known, but possible appropriately nutritionally supplemented, as indicated.
explanations include clonal expansion of S. equi–specific IgA
secreting plasma cell populations, impaired IgG production, Central Nervous System Disease
neutralization, or IgG utilization. Equine purpura hemor-
rhagica has some similarity with pathogenesis and disease Disorder243,253,254
manifestation and is therefore sometimes compared with Clinical manifestation of CNS disease will depend on the loca-
Henoch-Schönlein purpura, an IgA-mediated immune tion of S. equi abscess formation. Cerebral cortical lesions may
complex–mediated disease of people.246 present with the clinical complaint of circling, altered behav-
ior, cortical blindness, marked lethargy, and/or reduced feed
Guttural Pouch Empyema and Chondroids intake. Patients presenting with clinical signs that suggest CNS
This has been described earlier (see page 327). involvement may benefit from advanced imaging. In a previ-
ous report T2-weighted MRI images provided valuable diag-
Septicemia and the Development of nostic information regarding lesion location and severity. In
Infectious Arthritis and Pneumonia addition to imaging acquisition in the cranium, imaging also
These conditions warrant a poor prognosis.247 defined lesion severity in the region of retropharyngeal lymph
nodes and sinus involvement. The use of MRI in this report
Retropharyngeal Abscess Formation in two of four confirmed positive cases revealed high-quality
Bacterial translocation across the pharyngeal epithelium images that involved soft tissue of the CNS. Lesions that were
with S. equi results in lymphadenitis and abscess formation identified with MRI correlated well with lesions identified
of a variety of regional lymph nodes. Involvement of the ret- at postmortem. MRI is an excellent diagnostic tool that may
ropharyngeal lymph nodes can result in marked pharyngeal be considered for the characterization of lesions in affected
compression and airway obstruction. Lymphadenopathy and patients.243 In a case of S. equi meningoencephalomyelitis in a
inflammation in the guttural pouches may result in neuropa- 4-month-old foal, cerebrospinal fluid (CSF) analysis revealed
thy and associated dysphagia, potentially with aspiration. marked elevated total nucleated cell count and total protein
Upper airway endoscopy will reveal nasopharyngeal collapse, concentration and was PCR positive for S. equi.254
Streptococcus-Associated Myopathy. Myositis may devel- designated as such (“dirty” or “strangles cases”). This
op as a complication of S. equi infection. A serious and poten- will allow caregivers to have major areas for horse han-
tially fatal form of myositis has been called infarctive purpura dling and “clean” and “affected” areas.
hemorrhagica. In this disease horses may initially demonstrate 2. Determine whether recovering horses are infectious.
clinical signs of purpura hemorrhagica, but in addition to • Three nasopharyngeal lavages (preferably) collected at
lethargy, fever, and asymmetric edema, clinical signs of pain weekly intervals for 3 weeks; samples should be tested
evidenced by reluctance to move, marked ventral edema, and using microbiological culture and PCR testing.
colic signs often develop. Complete blood count and serum • Test-negative horses are “clean” of infection.
chemistry analysis reveals neutrophilic leukocytosis with left 3. Determine whether apparently healthy horses are S. equi
shift, and hyperproteinemia and hypoalbuminemia are char- positive.
acteristic findings. Most notably marked elevation of creatine • Upper airway endoscopy to determine whether there is
(phospho)kinase and aspartate aminotransferase are identified the presence of disease.
on serum chemistry evaluation. When clinical presentation is 4. Eliminate S. equi from guttural pouches of affected horses.
consistent with infarctive purpura hemorrhagica and marked • Endoscopically guided guttural pouch lavage with iso-
muscle involvement is identified, these findings should alert tonic, sterile fluid to remove mucous or chondroid ac-
the clinician to the likelihood of extensive muscle damage and cumulation; manual removal of chondroids may be re-
necrosis. Postmortem examination reveals muscle infarctions, quired if lavage alone is unsuccessful.
as well as infarcts in the skin, gastrointestinal tract, pancreas, • Systemic and local antibiotic therapy to eliminate S. equi
and pulmonary thromboembolism of the lungs; collectively all infection.
findings are compatible with infarctive purpura hemorrhagica. 5. Establishment of an isolation area and protocols to prevent
The prognosis is guarded, and affected horses require intense indirect cross-infection of S. equi to clean areas.
medical management: pain management, IV fluids, penicillin, • Caretakers should have dedicated barrier clothing and
and high-dose corticosteroid therapy.235 instruments. Avoid simultaneous contact with horses.
Immune-mediated myositis has been reported to occur Manage affected horses after clean horses and clean ar-
in horses.255 Among horses diagnosed with this disease the eas.
most common breed included Quarter Horses or closely re- • After removal of organic debris, all areas should be
lated breeds.255 The presenting complaint for affected horses cleaned and disinfected.
is rapid with marked muscle atrophy (usually symmetric), • Manure and general waste should be composted in an
particularly over the epaxial and gluteal muscles. Additional isolated area.
clinical signs include lethargy, reluctance to move, weak- • Water troughs should be cleaned daily.
ness, and fever. Muscle enzymes creatine kinase and aspar- • Horse transportation vehicles should be cleaned after
tate aminotransferase are typically elevated. Histopathologic every use.
evaluation of affected muscle groups reveals macrophages
and lymphocytes within myofibers. Phenotypic classification Disease Prevention
of lymphocytes revealed them to predominantly be CD4+ Among the currently manufactured vaccines there is an inac-
cells with few B cells, plasma cells, and CD8+ lymphocytes. tivated M-protein subunit vaccine and an attenuated live S.
Although 39% of the horses in the original report had recent equi vaccine. The subunit vaccine is a protein-rich acid- and
exposure to Streptococcus spp. organisms, a specific trigger enzyme-extract product that is administered parenterally
was not determined in all cases.255 The diagnosis of immune- (e.g., Strepvax II, BIVI). The attenuated live S. equi vaccine
mediated myositis is based on characteristic clinical findings is administered intranasally (Pinnacle I.N., Zoetis Inc.). In
of marked muscle atrophy in combination with supportive Europe, deletion mutant vaccine is approved as a submuco-
histopathologic findings of lymphocytic myositis obtained sally administered vaccine. Injection is recommended in the
from affected muscle tissue. Treatment involves a com- upper lip (Equilis StrepE, Intervet). Among the currently
bination therapy of penicillin and corticosteroid therapy. available vaccines, there is no guarantee for the prevention of
Response to therapy is rapid and marked in most cases, but strangles in vaccinated horses.
a tapering dose of corticosteroids may be needed for several Parenterally administered inactivated vaccines induce
weeks to achieve complete resolution in lymphocytic infil- serum bactericidal activity, but circulating antibodies are not
trates within muscle tissue. Rarely, a poor or incomplete re- necessarily protective because local mucosal immunity plays
sponse to therapy is observed.255 a significant role in the resistance to infection.256 Naive adult
horses and foals should receive two to three vaccine doses at
Outbreak Management 2- to 3-week intervals, followed by annual boosters while they
The primary goal when managing an outbreak of S. equi is remain at risk for S. equi exposure. Vaccine administration is
to effectively manage affected horses and minimize disease not recommended in horses with high SeM titers (>1:1600)
spread to naive individuals in an effort to minimize the risk because of the potential for an adverse event such as the devel-
of further disease outbreak and potential complicating fac- opment of purpura hemorrhagica.223
tors.223,256 The reader is referred to the ACVIM223 consensus The attenuated live intranasally administered S. equi vac-
statement for complete management guidelines, but a sum- cine is aimed at mimicking the natural exposure to S. equi,
mary of outbreak management is provided here: inducing endogenous local immunity with systemic and
1. Immediate quarantine of premises that halts equine trans- locally produced immunoglobulins, notably IgA, aimed at
port on or off the affected premises to eliminate further dis- this problematic pathogen. Vaccine manufacturer claims
ease spread. report a significant reduction in the number of horses devel-
• Horses that are identified to have confirmed S. equi dis- oping clinical signs of disease following challenge when vac-
ease must be located in an isolation area that is properly cinates are compared with control animals. Approximately
40% of vaccinees develop clinical signs of strangles, whereas new arrivals should be monitored for any evidence of conta-
approximately 60% of nonvaccinated control animals develop gious infectious disease, which includes overall health status,
disease. Although intranasal vaccines are expected to pro- presence of nasal discharge, lymphadenopathy, and rectal tem-
duce fewer adverse reactions than parenteral vaccines, leth- perature monitoring one to two times daily. Comprehensive
argy, inappetence, fever, lymphadenopathy, lymph node monitoring of potential S. equi carriers should include upper
abscess formation, purpura hemorrhagica, and intramuscu- airway endoscopy with guttural pouch lavage. Collection of
lar abscesses have occurred after vaccination.213 Additionally, fluid for S. equi PCR testing will aid with the determination
clinicians may consider whether to administer the attenuated of S. equi carrier horses. Measures should be implemented to
live vaccine to young horses (<1 year of age). In one report it prevent animal or personnel contact between the new addi-
was suggested that in this age group the potential for disease tions and resident horses.
manifestation exists following vaccination and was observed, Although previous reports have provided suggestions that
yet it should be noted that the sample size was small in this S. equi is a pathogen that may be eradicated, this has not been
investigation.257 successfully achieved. Factors that favor eradication include
Submucosal vaccines have also been associated with the an individual host for infection, poor survival in the environ-
production of adverse reactions, including neck and mandibu- ment, minimal antigenic variability, PCR diagnostic availabil-
lar lymph node abscess formation.258 ity, and low level of carrier individuals.259 The primary caveat
Attenuated live vaccines should be administered to healthy is that although S. equi vaccines are available they are not
afebrile animals free of evidence of disease. For the intranasal universally protective. It is anticipated that with the advent of
vaccine, it is recommended that two doses at 2-week intervals more efficacious vaccine(s), eradication of the serious bacte-
followed by an annual booster be administered. Foal vaccina- rial pathogen may be achievable. If successful, strangles would
tion should be considered in light of the mare’s vaccine status become a reportable disease with stringent regulatory control
at the time of parturition. In foals born to unvaccinated mares measures implemented to prevent the reintroduction of this
that are in high-risk situations vaccination may be initiated at pathogen.
1 to 2 months of age, but the risk of vaccination is that disease-
like manifestations may occur. Y EQUINE INFLUENZA (EIV)
For the submucosal vaccine available in Europe (Equilis
StrepE), two doses (0.2 mL) of vaccine are injected at 4-week EIV is classified as an orthomyxovirus with a single-stranded
intervals in healthy horses older than 4 months of age. Because segmented RNA genome.260 Influenza viruses are classified on
the duration of immunity by the submucosal vaccine is lim- the basis of surface and internal protein antigens into three
ited, it is recommended that high-risk horses receive a booster types (A, B, and C); only type A influenza is reported to infect
every 3 months, although boosting of horses vaccinated up horses. Major viral antigens include neuraminidase and hem-
to 6 months previously in the setting of an outbreak was sug- agglutinin (HA). Two type A viral subtypes are known to cause
gested in one report.237 disease in horses: H7N7 and H3N8.260 The strain H7N7 was
When administering any form of an attenuated live vac- initially isolated in 1956 in Prague and designated A/equine/
cine (intranasal or submucosal vaccines) caution should be Prague/56. This H7N7 variant, termed equine-1 influenza,
used regarding health status and any invasive procedures has not been isolated since 1980 and is believed to have disap-
implemented at the time of S. equi vaccination. Specifically, peared from the equine population.119 The H3N8 EIV, called
care should be implemented if other vaccines are concurrently equine-2, is a strain that was initially isolated in Miami in 1963
administered because potential abscess formation at the site and designated A/equine/Miami/63.261-263 Antigenic drift has
of concurrent intramuscular vaccines may occur. Handling subsequently resulted in many subtypes of variant equine-2
the vaccine should be followed by thorough hygiene measures among horses, including A/equine/Fontainebleau/79, A/
that include careful handwashing to minimize the transfer of equine/Kentucky/81, A/equine/Saskatoon/90, and A/equine/
bacteria to other sites or instruments. Newmarket 2/93. Although antigenic drift has been observed
Additional areas of concern regarding S. equi vaccination for many years, a larger scale change in the antigenic nature of
include the risk of complications such as purpura hemor- the EIVs has not been documented.
rhagica. For this reason, vaccination at the time of disease out- Equine influenza is endemic in Europe, North and South
break is controversial and should be carefully considered. The America, North Africa, the Middle East, and Asia. Because of
only horses that should be vaccinated are those that have not the highly contagious nature of this virus, susceptible equine
had a chance for bacterial exposure and those with an SeM populations are at risk for major outbreaks if virus is intro-
titer of <1:1600. An appropriate amnestic immune response duced. This scenario occurred in 2007 when breeding stallions
requires approximately 10 days to occur, so exposure to at-risk from Japan were introduced into Australia and were infected
individuals should not occur before this immunity is expected with a Florida Clade I lineage H3N8 equine influenza strain
to be present. No S. equi vaccines have any claim to provide of the virus.264,265 Australia was influenza free at the time of
protection against S. zooepidemicus–associated respiratory (or introduction, and disease outbreak resulted in 76,000 horses
otherwise) disease. developing the viral infection. The outbreak occurred over an
18-week period. Rapid control measures were implemented,
General Control Measures including vaccination; the outbreak was successfully managed;
Introduction of new arrivals to an equine establishment and Australia is once again influenza negative.
should include careful biosecurity protocols that include a Influenza is most common in horses commingled under
quarantine period of 3 to 4 weeks. Quarantine areas should be stressful conditions such as race training. Viral spread occurs
designed so that there is no direct contact of new arrivals with through aerosolization of viral particles from a contaminated
resident horses and that personnel use proper hygiene after horse to susceptible individuals. Fomites can play a role as
working with new arrivals. During this period of quarantine well; contamination of personnel can also contribute to viral
spread.266 Infection occurs via inhalation of viral particles. The the prevention of influenza is an achievable goal in many set-
virus infects respiratory ciliated epithelium, leading to loss of tings. Commercially available vaccines include live attenuated,
the mucociliary escalator for pathogen and particle clearance. cold-adapted, inactivated, and recombinant vectored vaccines.
Therefore, viral infection predisposes affected individuals to The majority of investigation into vaccine efficacy is based on
secondary bacterial infection. relatively small-scale investigations that consistently identify
a correlation between protection from disease and antibody
Clinical Signs levels, particularly when there is strong similarity between
Clinical characteristics of equine influenza include a short vaccine strain and challenge isolate. In most performance
incubation period of 1 to 3 days, high fever, depression, and horse populations, regardless of discipline, vaccination prac-
paroxysmal coughing, which can be severe. Nasal discharge tices are applied to aid with enhanced host immunity. In some
may begin as serous fluid and change to a more mucopurulent instances, racing authorities have mandated vaccine protocols
character with disease progression and bacterial contamina- aimed at providing support for vaccination to enhance immu-
tion. Submandibular lymphadenopathy is commonly asso- nity. A recent investigation aimed at determining the optimal
ciated with viral disease. Myositis, anorexia, and persistent vaccine administration interval compared different intervals
cough are not uncommon signs observed in association with aimed at stimulating protocols established by various racing
influenza infection. Immune status and previous vaccination authorities. It was concluded that longer vaccine intervals may
will directly influence disease course; unvaccinated horses or result in periods of susceptibility, in which vaccine-induced
those not previously exposed to the virus typically demon- immunity may not be protective, but when needed shortened
strate the most severe clinical evidence of disease. Horses with intervals may be protective when risk of exposure is high.273 At
influenza are at risk of secondary bacterial infection that may the time of this writing, the United States Equine Federation
progress to bronchopneumonia and/or pleuropneumonia. has implemented a requirement for all horses competing in
sanctioned events or shows to demonstrate proof of vaccina-
Diagnosis and Treatment tion for EIV and EHV in the previous 6 months. Accelerated
The recognition of a rapidly spreading respiratory infection vaccine protocols with the recombinant canary pox–vectored
in a group of horses is characterized by rapid onset, high influenza vaccine have been demonstrated to increase serum
fever, depression, and particularly cough, which is strongly antibody levels using the single radial hemolysis assay. In
presumptive of the equine influenza infection.267 Vaccinated this investigation, time from initial vaccine to second dose
horses may not demonstrate clinical manifestation of disease, was 14 days, followed by a booster vaccine at 105 days.274 In
which was illustrated with an outbreak of racehorses in Hong situations where an accelerated vaccine protocol is needed to
Kong that displayed a variety of clinical signs that delayed enhance viral-specific immunity, accelerated protocols should
definitive diagnosis in this group of horses.268,269 Addition- be considered. Implementation of a protocol with the canary
ally, based on experimental challenge data, there is an inverse pox–vectored vaccine during the Australian outbreak not only
relationship regarding the level of challenge and time course provided enhanced host protection, but this strategy used a
for clinical manifestation of disease.270 Collectively, a variety vaccine with differentiation of infected and vaccinated indi-
of factors that include host immunity and health, pathogen- vidual capacity, which is an added advantage to this protocol
specific immunity, and pathogen dose can impact the presence in this setting.268
and severity of clinical manifestation of the disease. For these
reasons, all factors should be considered when evaluating a Y EQUINE HERPESVIRUS INFECTION
potential outbreak with appropriate diagnostic testing per-
formed to determine the specific etiologic agent responsible Herpesviruses are enveloped, double-stranded DNA viruses
for disease outbreak. that are ubiquitous in nature and are well recognized for infect-
A variety of diagnostic tests have been developed to deter- ing a variety of hosts. Equids have been reported to have the
mine the presence of this virus in the equine host and include potential to be infected with nine different herpesviruses.275
virus isolation, influenza A antigen detection, HA inhibition Among the viruses with clinical relevance to the equine host
(paired baseline and convalescent), and real-time quantita- are alphaherpesviruses (EHV-1, EHV-3, and EHV-4) and
tive PCR (qPCR). Definitive diagnosis in an outbreak is based gammaherpesviruses (EHV-2 and -5).
on viral detection with nasopharyngeal secretions or by an Among alphaherpesviruses EHV-1 and EHV-4 are most
increasing virus neutralization (VN) titer. Notably, evidence widely recognized for morbidity in horses.276 Both EHV-1
supports that optimal sample collection with improved test and EHV-4 are well recognized for induction of upper respira-
sensitivity should be based on nasopharyngeal lavage sam- tory disease in horses, whereas EHV-1 is also associated with
pling rather than just nasal swab sampling, particularly in abortion and in rare instances may induce severe neurologic
surveillance situations that will lead to quarantine of test- disease. EHV-1 viral infection is associated with cell-associ-
positive individuals.271 Sample collection with a synthetic ated viremia, in which infected host leukocytes effectively
swab submitted for PCR testing provides a cost-effective and disseminate virus throughout the infected horse. Differences
efficient method of diagnostic testing under most routine clin- in these somewhat similar viruses are believed to influence
ical settings.268,272 clinical manifestation of the disease. Although both are capa-
Even though specific antiviral treatment for the manage- ble of viral replication in the upper respiratory tract, EHV-1
ment of influenza-positive humans has become commonplace, is well adapted to translocate across the respiratory epithe-
the same cannot be said for equine patients. The primary goal lium, whereas EHV-4 appears to be restricted to the upper
of prevention through application of effective biosecurity mea- airways supported by an airway explant model system,277
sures and vaccine strategies remains the focus for disease avoid- which is believed to have a direct influence on this virus being
ance in horses. Among the American Association of Equine restricted in anatomic location resulting in rhinopharyngi-
Practitioners risk-based vaccine guidelines, vaccination for tis and/or tracheobronchitis.268 However, as a result of viral
dissemination, EHV-1 is recognized for not only upper respi- may include severe pneumonitis, icterus in association with
ratory disease but also abortion, neonatal illness, and neuro- hepatic involvement, and commonly marked neutropenia as
logic disease.278,279 Abortion and myelitis are a direct result a reflection of severe bone marrow necrosis and destruction.
of vasculitis that is induced by systemic spread of the virus. Among the viral strains of EHV-1 that have been iden-
Because EHV is neurotropic, latency is likely and associated tified, in some instances there is a mutation in the open
with the trigeminal (cranial nerve V) ganglion or lymphoid reading frame for the DNA polymerase (DNApol) gene.
tissue.280 During times of severe stress or immune suppression Specifically, the mutation has been identified as a single
disease viral recrudescence and shedding are possible when nucleotide polymorphism (SNP) at the nucleotide level
latent virus is reactivated. Although EHV-1–associated disease (A2254 > G2254),290 which is associated with increased
has been reported in a variety of situations that include west- virulence and the potential for neurologic disease mani-
ern performance events and a racetrack setting, horses evalu- festation.291 Following signs of upper respiratory disease
ated in a veterinary hospital setting for the potential of EHV-1 and fever, affected horses may progress with signs of mild
viral shedding were not found to be shedding virus.281 incoordination, posterior paresis, posterior paralysis, and
recumbency. Commonly clinical signs will include urinary
Pathogenesis emptying defects that result in marked urine dribbling.
Herpesviruses are well recognized for viral maintenance Attenuated sensation in the perineal region may also be
within the host as a latent virus, and this holds true for present. Prognosis is influenced by disease severity and
EHV-1/4.282 A continued cycle of viral latency and recrudes- progression to recumbency.
cence likely plays an important role in the viral maintenance Postmortem examination on foals from aborted mares
within groups of horses. Immunosuppression is associated reveals interlobar pulmonary edema, pleural effusion, and
with attenuated cell-mediated immunity, which leads to viral necrosis of lymphoreticular tissues that includes liver, bone
shedding among latently infected individuals.283,284 Horses marrow, and thymus. Petechiation of the myocardium, adre-
that are latently infected are viral carriers for life.268 In a nal glands, and spleen are commonly observed lesions. His-
small-scale investigation aimed at viral detection in a group topathologic examination will reveal intranuclear inclusions,
of experimentally infected horses, it was determined that particularly from the liver, lung, and adrenal glands.
horses challenged 5 years previously were later determined Adult horses that succumb to EHV-1–associated myelitis
to have maintained the same viral strain as the primary chal- may have no apparent gross lesions, or they may have mild
lenge strain.285 hemorrhage in the meninges, brain, and spinal cord. Histo-
pathology will reveal lymphocytic vasculitis with endothelial
Clinical Signs damage and perivascular cuffing, thrombus formation, hem-
Clinical signs of disease associated with EHV-1/4 typically orrhage, and possibly malacia. Lesions are most commonly
include pyrexia, marked serous nasal discharge, and occa- observed in the spinal cord but may be observed in the brain
sionally cough. Secondary bacterial colonization will result and brainstem.
in nasal secretions changing from mucoid to mucopurulent
in nature. Lymphadenopathy and serous ocular discharge Diagnosis and Treatment
may also be observed in association with EHV-1/4 infec- Horses suffering from contagious infectious respiratory dis-
tion. Disease spread is typically not as rapid as with equine ease should be maintained in an isolation-type environment.
influenza, but morbidity among susceptible horses can be In most cases diagnostic confirmation requires days or longer.
very high.286,287 Clinical manifestation of respiratory disease Because of the inherent nature of respiratory pathogens, horses
tends to be worse in younger horses compared with mature should be restricted from contact with other horses, particu-
adults, with reports commonly including disease outbreak larly in a hospital environment or farm with high-risk individ-
in recently weaned foals. This may in part be influenced by uals such as breeding animals and animals that are traveling
the level of immunity in young horse populations. Diagnosis frequently for performance-related activities. Because of the
in affected horses more commonly reveals EHV-4 as the pri- similarity in clinical signs, viral respiratory disease requires
mary pathogen associated with disease.276,288 EHV-1/4 is well diagnostic confirmation for pathogen identification. Serologic
recognized to cause respiratory disease in adult horses. One testing for virus-neutralizing antibodies collected during the
report described an EHV-1 outbreak among a group of race- acute and convalescent (4 weeks) sampling with a fourfold rise
horses in training during the winter months, whereas EHV-4 in antibody supports the diagnosis of recent EHV infection.
did not have an apparent age or season association with dis- However, when considering the frequency of latently infected
ease outbreak.289 adult horses, serologic testing can be challenging to interpret.
When pregnant mares are infected, abortion occurs Additionally, mares that abort their fetus have had a serologic
approximately 2 to 12 weeks following infection, typically dur- response to viral infection long before delivery of the fetus,
ing the final months of gestation. Aborted fetuses are typically further complicating this diagnostic method. Definitive diag-
fresh or demonstrate minimal autolysis while the placenta is nosis (gold standard) is based on virus isolation from samples
passed shortly after abortion. Mares that are infected with obtained from upper respiratory nasopharyngeal lavage sam-
EHV-1 rarely demonstrate clinical evidence of illness, par- pling or leukocyte buffy coat isolation early in the course of
ticularly before expulsion of the fetus. There is no evidence of infection. PCR testing has become the diagnostic test of choice
damage to the reproductive tract of the mare and no problems because of its high analytic sensitivity and specificity. Positive
with subsequent fertility. Abortions may be individual cases PCR test results may be obtained when culture techniques are
or observed as an abortion storm within a herd. Mares that are not successful because of low-level viral shedding. Samples
virally infected during late gestation might successfully deliver can be collected from that respiratory tract and include nasal
a live foal, yet the foal will have marked disease caused by swab sampling or nasopharyngeal lavage collection. Addition-
viral infection. Clinical signs observed in EHV–infected foals ally, because of the leukocyte-associated nature of the virus,
whole blood (anticoagulated) buffy coat sampling will provide Foals infected in utero with EHV-1 are unlikely to survive
an additional sample for viral PCR testing. In index cases, nasal despite intensive care therapy. Antiviral therapy with acyclo-
swab and whole blood samples should be tested simultaneously vir or valacyclovir may be considered for virally infected foals.
(in parallel) to further enhance diagnostic sensitivity.292 Nasal Adult horses that demonstrate clinical manifestation of neuro-
swab sampling is recommended over pharyngeal lavage sam- logic disease consistent with EHM are appropriate candidates
pling because of greater diagnostic sensitivity.293 Contempo- for antiviral therapy with valacyclovir. Additional nursing care
rary molecular diagnostic tests have been designed to test for for EHM-affected horses often requires intensive nursing care
the presence of EHV-1 and the presence of the DNApol SNP that may include indwelling urinary catheter placement to
at the amino acid level (D752/N752), with D752 more com- avoid urinary bladder rupture. Satisfactory recovery can be
monly associated with neurologic disease manifestation.290 achieved although mild persistent neurologic deficits might
Diagnostic testing requires careful interpretation as outlined still be discernible 6 to 12 months later. Even so, these horses
in the 2009 ACVIM consensus statement on this pathogen are often capable of competitive activity. Horses that remain
and disease process, and the interested reader is referred to recumbent for extended periods of time have a more guarded
this particularly valuable reference for a more detailed diag- prognosis for survival.
nostic outline.292 Careful patient examination is the initial step
to determine the course of diagnostic evaluation. In patients Gammaherpesviruses
suspected to suffer from EHV-1–associated disease, appropri- EHV-2 is ubiquitous among the equine population even
ate diagnostic samples should be collected for PCR analysis. though the exact significance of this virus as a primary respi-
In samples that test positive for the EHV-1 sequence, an addi- ratory pathogen remains to be fully elucidated. Select clinical
tional step in molecular characterization will be determining signs and conditions that have been implicated with EHV-2
the presence of the mutated EHV-1 biovar. If present in the infection include pulmonary inflammation, keratoconjunc-
appropriate clinical setting, proper biosecurity and quarantine tivitis, fever, pharyngitis, inappetence, immunosuppression,
measures should be implemented immediately. In contrast, lymphoma. and lymphadenopathy.294,295 EHV-2 has been
identification of this EHV-1 D752 biovar in an asymptomatic identified within circulating leukocytes, nasal secretions and
individual (healthy horse with no signs of respiratory or other nasopharyngeal swabs, kidney, bone marrow, spleen, and
disease) should not be overinterpreted. Recall that horses are reproductive and ocular tissues.296-298 In addition, EHV-2 has
often latently infected with EHV-1, and simply identifying this been positively identified in lymphoid and neural tissue col-
virus in an otherwise healthy horse does not confirm the pres- lected from naturally infected horses. In one investigation of
ence of future disease manifestation, particularly neurologic equine respiratory disease tracheal aspirates were infrequently
disease. There is insufficient evidence to determine the sub- positive for EHV-2 (1/20 foals; 5%) when collected from
sequent implications of an individual being infected with this healthy horses compared with those with clinical respiratory
virus. Additionally, the absence of EHV-1 D752 does not pre- disease (20/30; 67%).299 Notably, in the same investigation
clude the development of equine herpesvirus myeloencepha- EHV-2 was identified within circulating leukocytes collected
lopathy (EHM) in a horse that has clinical signs of respiratory from both groups of foals. A subsequent investigation aimed
or neurologic disease. Recommendations regarding diagnos- at demonstrating a causal relationship of this viral agent and
tic testing for horses that demonstrate clinical signs suggesting disease used respiratory secretions collected from a clinically
EHV-1 and provided in the EHV-1 ACVIM consensus state- affected EHV-2–infected horse. These were then administered
ment include292: to two immunosuppressed ponies that subsequently developed
• Uncoagulated (ethylenediaminetetraacetic acid) whole respiratory disease (coughing and nasal secretions), conjunc-
blood sample and nasal swab (synthetic material) for quan- tivitis, viral shedding, and a demonstrable humoral antibody
titative real-time PCR testing. response to EHV-2.296 In addition to primary respiratory dis-
• Uncoagulated blood and nasal swab for virus isolation of ease, it has been suggested that EHV-2 may play an important
EHV-1 when strongly suspect disease-positive horse based role regarding the disease pathogenesis of other respiratory
on clinical signs and PCR testing. pathogens, such as EHV-1. It is plausible that altered immune
• Paired serum samples collected 12 to 21 days apart for VN function infection induced by EHV-2 infection may promote
and ELISA for specific virus antigen when possible. recrudescence of EHV-1, resulting in notable clinical respira-
• Avoid diagnostic testing in healthy horses that have no risk tory disease.298
for disease manifestation; screening in healthy horses is not
recommended. Equine Herpesvirus-5 and Equine Multinodular
There is no specific antiviral treatment recommended for the
treatment of horses with respiratory disease associated with Pulmonary Fibrosis
EHV-1/4 infection. Rest and proper nursing supportive care Initial investigations into the relevance of EHV-5 in asso-
are indicated to facilitate disease recovery. High-quality, pal- ciation with interstitial pneumonia in adult horses resulted
atable feeds are recommended to facilitate proper nutritional from the identification of asinine herpesvirus-5 (AHV-5) and
intake. Horses should be maintained in a comfortable, shel- AHV-2 in cases of interstitial pneumonia in donkeys.300 In
tered environment to minimize the risk of secondary disease addition to the identification of AHV-2/5 in donkeys suffer-
manifestation such as bacterial colonization. Horses that dem- ing from pulmonary inflammation and fibrosis, adult horses
onstrate marked pyrexia, fever >103°F will benefit from the suffering from poor exercise tolerance and multinodular
administration of nonsteroidal antiinflammatory therapy in pulmonary fibrosis have been identified to harbor EHV-5.301
the euhydrated individual. Antibiotic therapy is indicated if Subsequent to initial observations, numerous reports support
clinical signs are consistent with bacterial colonization such the finding that in nearly all cases of equine multinodular pul-
as mucopurulent oculonasal discharge or pulmonary disease monary fibrosis (EMPF) EHV-5 has been identified. In addi-
is evident. tion to the identification of EHV-5 in EMPF-affected horses,
Williams et al. administered EHV-5 via bronchial instilla- horses have chronic progressive disease, systemic inflam-
tion to six healthy horses that subsequently demonstrated an mation, and a poor or incomplete response to corticosteroid
increase in total lung collagen and the appearance of myofi- therapy.
broblasts, which supported the suggestion that EHV-5 is the Postmortem examination of EMPF-affected horses reveals
causative agent for EMPF.302 It is possible that infection with evidence of primary pulmonary disease characterized by
EHV-5 independently results in the development of pulmo- enlarged lungs that fail to collapse, diffuse pleural thicken-
nary fibrosis, although it is also reasonable to consider that a ing, and the presence of numerous fibrous nodules of vari-
synergistic effect may occur in horses that are coinfected with able size, in some cases up to 5 cm (or more) in diameter.
EHV-5 and EHV-2 or AHV-5. Further support regarding the Bronchial and mediastinal lymphadenopathy is commonly
synergism of EHV-2/5 comes from the observation that both associated with the presence of pulmonary granulomas (Fig.
gammaherpesviruses have been identified in approximately 8.15D–E). There have been two types of pulmonary granu-
30% of the cases of EMPF.298 lomas described in EMPF patients based on lesion size and
Equine patients that suffer from EMPF are typically adult- distribution. The more common form is referred to as a dis-
aged horses (Fig. 8.15A). Clinical signs often include weight seminated nodular form in which multifocal, coalescing
loss, poor overall condition, and increased respiratory rate fibrotic nodules are present throughout all lung fields with
and effort. Physical examination will localize disease to the lesions ranging from 1 to 5 cm. In this form of EMPF there
respiratory tract characterized by fever, abnormal pulmo- is often minimal healthy pulmonary parenchyma present,
nary sounds including tracheal rattle, and increased bron- and approximately 80% of the lungs are composed of fibrous
chovesicular sounds with wheezes. Additional clinical signs granulomas. Alternatively, a discrete nodular form has been
include lymphadenopathy, reluctance to ambulate normally described in which large discreet nodules are separated by
(pain), oral cavity ulcerations, and keratoconjunctivitis.303-305 normal-appearing pulmonary parenchyma. The nodules in
Hematologic examination will often reveal leukocytosis, this form of disease are much larger, sometimes measuring
neutrophilia, lymphopenia, anemia, hyperfibrinogenemia, 8 to 10 cm in diameter. Regardless of the form of disease
hypoxemia, and hypoalbuminemia.302 Consistent with the on histologic examination, the lesions are characterized by
pronounced inflammatory response in affected individuals, marked interstitial fibrosis with type 2 pneumocyte hyper-
elevation of serum amyloid A can also be expected in EMPF plasia. Alveoli are often filled with neutrophils, fewer alveolar
patients. A number of investigators suspect that in some cases macrophages, multinucleated giant cells, and eosinophilic
of infection there is an immune-mediated destruction of proteinaceous material. Intranuclear inclusions, consistent
mature cells in the peripheral circulation and possible destruc- with herpes viral infection, may be observed within macro-
tion of hematopoietic precursors located within the bone phages and/or epithelial cells.302,307
marrow, which can result in notable cytopenia.306 Although Definitive diagnosis of EMPF is based on histopathologic
this mechanism remains to be fully elucidated, this author has evidence of pulmonary tissue obtained by lung biopsy or
most commonly observed elevation of leukocyte cell counts sample collection at postmortem. Diagnosis is often strongly
in EMPF cases, although in rare individuals marked cytope- suspected based on clinical history, ultrasonographic evalua-
nia has been observed. EHV-5 has been conclusively identi- tion, thoracic radiographic findings, and pulmonary airway
fied in the bone marrow of one affected individual that had cytology, particularly if cells with intranuclear inclusions are
pancytopenia.306 identified. Additional supportive evidence for the diagnosis
of EMPF is based on the presence of EHV-5 detected with
Diagnosis molecular testing such as PCR and preferably with the qPCR
Diagnostic evaluation of suspect EHV-5 cases should include method. Ideal samples for testing include BAL fluid and/or
a complete evaluation of the respiratory tract. Physical exam- lung tissue. Additional samples that should be tested in par-
ination followed by thoracic ultrasound will provide the cli- allel include peripheral blood (leukocytes) and nasal swab
nician with evidence of primary pulmonary disease. Severity secretions (synthetic, nylon or Dacron swab). Testing should
of ultrasonographic abnormalities will relate to chronicity of also include evaluation for additional viruses such as EHV-2
pulmonary disease demonstrated by pleural irregularity and and AHV-5. Although they may not serve a primary role,
thickening, peripheral nodules, and abscess that can often their presence may potentiate disease development in affected
be visualized in non-acute cases (Fig. 8.15B). Subsequent horses.
respiratory system examination will often include thoracic
radiographs, which reveal moderate to severe interstitial pul- Treatment
monary nodules (Fig. 8.15C). Radiographic appearance of Therapeutic management of EMPF patients is targeted at
pulmonary nodules may resemble those resulting from meta- clearance of pathogen challenge and provision of appropriate
static neoplasia or fungal granulomas; therefore, additional supportive care. Specifically, therapy should include broad-
diagnostic testing will be needed to definitively diagnose spectrum antimicrobials, antiinflammatories that include
EMPF. Additional diagnostic testing includes BAL, which will dexamethasone, and intranasal oxygen therapy in hypoxic
allow the clinician to examine pulmonary cellularity of the individuals. Antiviral therapy is recommended as a compo-
lower airways. Characteristic findings include neutrophilic nent of therapy; although acyclovir308 has poor bioavailability,
inflammation with marked mucous accumulation. In some valacyclovir has been demonstrated to have improved plasma
instances, the cytologic characteristics may resemble RAO levels following oral administration.309 The dosing protocol
(heaves). Clinical distinction of the conditions is important. should be at the higher end of the dosing range, based on
EMPF should be suspected in an equine patient diagnosed limited evidence for successful management of such cases.
with RAO that does not respond to appropriate therapy and Valacyclovir should be administered at 30 to 40 mg/kg PO
environmental management. In addition, EMPF-affected three times daily.310 Although this treatment protocol remains
A
B
C D
FIG. 8.15 (A) A 15-year-old Thoroughbred gelding presenting for weight loss and poor appetite was diag-
nosed with equine herpesvirus 5 (EHV-5) associated equine multinodular pulmonary fibrosis. (B) Thoracic
ultrasound revealed multiple peripherally located nodular lesions ranging from approximately 2 to 4 cm in
diameter. (C) Thoracic radiographs confirmed the presence of a diffuse nodular interstitial radiographic pat-
tern. (D) Failure to respond to therapy necessitated euthanasia, which revealed gross pulmonary changes
consistent with those identified antemortem on thoracic ultrasound and radiograph. (E) Cross section of
nodular pulmonary fibrosis associated with EHV-5 infection.
under investigation for this particular viral infection, there occurs within a month of exposure and occurs during late
is evidence to support this dose for this particular condition. clinical disease or early convalescence. Typically the fetus is
A serious and potentially fatal complicating factor for horses nonviable at the time of abortion and is autolyzed by the time
suffering from EMPF includes the development of pulmonary of expulsion. Rarely, neonatal foals infected with the virus
hypertension, which may be suspected based on ultrasono- demonstrate respiratory difficulty and rarely recover from
graphic and radiographic evaluation. The presence of pulmo- viral infection.313-315 Hematologic evidence of EVA includes
nary hypertension is considered a poor prognostic indicator leukopenia characterized by a lymphopenia, and thrombocy-
for EMPF-affected horses and was observed postmortem in topenia, which may be severe.
one EMPF-affected horse.311 EAV is spread by aerosolization of respiratory secretions
In cases suspected to have elevated pulmonary arterial and venereal transmission. Virus-laden droplets can be dis-
pressure, pulmonary artery diameter should be measured seminated in the environment for up to 2 weeks following
and compared with aortic diameter during echocardiographic recovery from disease. Immunologically naive intact stal-
evaluation to aid in the establishment of pulmonary hyperten- lions exposed to the virus following sexual maturity maintain
sion.311 In addition, pulmonary artery pressure should be mea- the virus in the ampulla of the vas deferens. Carrier stallions
sured in such cases whenever possible. An individual report remain seropositive, and their semen contains live virus
of management of an EMPF-affected horse with associated whether used for natural breeding, artificial insemination, or
pulmonary hypertension involved administration of the phos- frozen semen. The virus can be maintained for many years in
phodiesterase type V inhibitor sildenafil with furosemide.312 frozen semen with little negative influence on fertility.
Additional therapies that have been included in the treat- Susceptible mares bred to EAV-positive stallions com-
ment protocol for EMPF include nebulized N-acetylcysteine, monly develop respiratory disease (80%–100% cases) and suf-
pentoxifylline, and doxycycline. fer from early embryonic death but do not sustain a persistent
Based on the current body of literature regarding EHV-5 in EVA infection. Most cases of EVA are self-limiting with low
horses, this appears to be an important pathogen that at least risk of complicating factors. Standardbred horses have a high
in part plays a role in the development of pulmonary fibrosis frequency for seropositivity and carrier infection compared
in horses, whereas AHV-5 appears to play a similar role in dis- with other horse breeds.
ease development among donkeys. EMPF is a distinct disease
process that results in nodular pulmonary disease of equids; Prevention
there is marked remodeling of the pulmonary architecture The greatest challenge for disease prevention is the presence of
with eosinophilic intranuclear viral inclusion bodies that may a persistently infected stallion. Prevention from infection and
be present within intraluminal macrophages.304 Early diagno- induction of the carrier state can be achieved through care-
sis and aggressive therapeutic management provide the most ful vaccination. Once determined to be serologically negative
favorable prognosis. When severe or advanced, EMPF remains (requirement for international equine transport), stallions
a serious infectious disease of horses. can be successfully vaccinated with the commercially avail-
able MLV vaccine to prevent the carrier state. Colts should be
Y EQUINE ARTERITIS VIRUS INFECTION vaccinated <280 days of age and isolated for approximately 21
days to minimize the risk of viral shedding in the vaccinated
Although most commonly recognized for its association with individual and to allow for immunity to develop and prevent
the equine reproductive tract, equine arteritis virus (EAV) viral exposure before the immunity is maximally induced.
causes a mild to moderate vasculitis and associated respira- All vaccinated horses should be separated from nonvacci-
tory disease termed equine viral arteritis (EVA). The virus is nated horses for approximately 21 days following vaccina-
maintained in equine populations in carrier stallions because tion. Infected horses should be separated from herdmates
testosterone is required for persistence and maintenance of the for approximately 3 weeks following infection to reduce the
virus in vivo. Carrier stallions maintain the virus within the risk of viral spread. Similarly, any individual that has been
ampulla and vas deferens. infected with the virus should not have contact with young
horses or broodmares. All at-risk individuals should be vac-
Clinical Signs and Viral Transmission cinated annually to minimize the risk of disease. Broodmares
Clinical manifestations of EVA are similar to those of other should be vaccinated before breeding; the modified live vac-
viral respiratory tract diseases. Variations in the severity of cine is not recommended to be administered to pregnant
clinical signs result from strain differences in virulence, broodmares.
pathogen dose, and host immune function. Incubation
requires several days to 2 weeks, with a more rapid course Y EQUINE PICORNAVIRUS INFECTION
of disease after venereal transmission. Clinical signs associ-
ated with respiratory tract infection include serous nasal The equine picornaviruses are categorized into two sero-
discharge, submandibular lymphadenopathy, mild to moder- groups: equine rhinitis virus A and B (ERAV and ERBV).
ate cough, and ventral edema. Vasculitis is evident based on Former classification referred to these viruses as rhinovi-
clinical signs of edema and occurs secondary to viral damage ruses. ERAV (formerly equine rhinovirus 1) is grouped in
of the tunica media of small arteries and venules. Edema of the Aphthovirus genus based on genotype and similarity
the prepuce, scrotum, and limbs is commonly observed. The with other members of this genus, such as foot and mouth
two most important consequences of EVA infection include virus, as well as the characteristic viremia and persistent
abortion of the pregnant mare and induction of the carrier shedding that occurs following infection with the virus.316,317
status in a breeding stallion. Clinical signs may persist for 2 to Equine rhinitis B virus ERBV1 (formerly equine rhinovirus
9 days. Most infections are self-limiting, although edema may 2), ERBV2 (formerly equine rhinovirus 3), and ERBV3 (for-
be severe and respiratory distress evident. Abortion typically merly acid-stable picornavirus) are members of the genus
Erbovirus.318,319 Both ERAV and ERBV have been implicated As stated previously, disease manifestation is a reflection of
in association with respiratory disease in horses.268,320,321 host immunity. The peracute syndrome is the pulmonary form
Most recent investigations have provided evidence for the with a mortality rate of approximately 95%. With this, there is
virus-neutralizing capability of antibodies against these a brief incubation period that may last up to 5 days. Clinical
viruses and their impact on clinical respiratory disease in signs include fever and hemorrhagic pulmonary fluid exudate
horses.322 Persistent shedding has been identified in respira- characteristic of pulmonary edema. Postmortem examination
tory and urinary secretions.323 reveals evidence of marked pulmonary edema and hydrotho-
Viral detection of picornaviruses has been identified in rax. Acute or mixed AHS is a more common manifestation
horses with respiratory disease and healthy horses.324,325 It has with pulmonary and cardiac abnormalities. The incubation
been suggested that infection happens early in life via aero- period is slightly longer and may be up to 7 days. Mortality
sol transmission. Notably ERAV is shed in respiratory secre- for the acute form is 50% to 95%. Clinical signs reveal a com-
tions and urine,326 whereas ERAB1 and ERAB2 appear to be bination of cardiac (edema of head and neck) and pulmonary
restricted to the respiratory tract (secretions) only. Experi- disease (cough, respiratory distress, and pulmonary edema)
mentally induced respiratory disease with ERAV resulted in manifestations. Postmortem examination reveals marked
upper and lower airway disease and viremia, which lasted 4 subcutaneous edema of the head and neck. Subacute AHS
to 5 days.268 Additional clinical signs following experimental demonstrates clinical signs of myocardial dysfunction, fever,
challenge included pyrexia, lymphadenopathy, changes on edema, and lethargy. Edema of the supraorbital fossa is highly
thoracic auscultation, evidence of airway inflammation with characteristic of AHS. Incubation of the subacute form is 50%.
mucosal hyperemia, and tracheal mucous accumulation that Horse sickness fever is the mildest form of the disease, and this
persisted for 21 days.327 manifestation is displayed by horses with preexisting immu-
Clinical manifestations of disease typically include pyrexia, nity and those species with inherent resistance to disease such
serous to seromucous nasal discharge, coughing, depression, as donkeys and zebras. Mortality tends to be low for this form
anorexia, pharyngitis, and submandibular lymphadenopa- of the disease.
thy.327 Mild lymphopenia and increased plasma fibrinogen Diagnosis is based on serology and virus isolation.332 An
concentrations have been reported in affected horses.319,328 inactivated vaccine is available and is used in endemic regions
Diagnosis is based on serology or molecular detection of to minimize loss in high-risk regions.333 During an epidemic,
the virus. The application of PCR and real-time PCR have the primary goal is to eradicate disease though implemen-
become more commonplace because of the variability in sero- tation of quarantine, vector control,334 and euthanasia of
logic titers and prolonged turnaround time for virus isolation. exposed horses. If these efforts fail, perimeter vaccination is
Preventative strategies have primarily focused on hygiene implemented to limit the spread of the disease.13
and overall health maintenance. Recently, a commercially
available ERAV vaccine was approved for use in horses and Y HENDRA VIRUS INFECTION
may be considered for high-risk situations.
Hendra virus, formerly referred to as equine morbillivi-
Y AFRICAN HORSE SICKNESS rus, was first identified in Hendra, Australia, in 1995 and
was recognized as a zoonotic disease of horses.335 Hendra
African horse sickness (AHS) is a foreign animal disease that virus causes fatal pneumonia and encephalitis in horses
has never been reported in the United States. From a global and humans.336 Clinical signs of Hendra virus are similar
perspective the disease has major implications on the equine to AHS. Fruit bats are the reservoir of infection. Disease
industry. Historically this is a viral disease affecting horses in transmission requires close contact with infected horses or
Sub-Saharan Africa, but outbreaks in India and the Middle bat excrement. Hendra virus is classified as a Hazard Group
East were reported in the mid-1950s,329 and cases in Spain 4 pathogen, which requires the highest level of biosecurity
were reported in the 1980s.330 procedures.
The primary vector for viral transmission is Culicoides imi- In an initial outbreak involving Hendra virus, 14 of 21
cola. This is a serious worldwide pathogen because morbidity horses died.337 Two primary caregivers for the horses became
and mortality remain high in naive equine populations. Dis- ill, and one did not survive.338 Morbillivirus was identified
ease manifestation ranges from fulminant pulmonary edema, from renal tissue from one of the nonsurviving humans,
subcutaneous edema, and myocardial failure to horse sickness which was identical to the virus cultured from the lungs of
depending on the level of host immunity at the time of viral five affected horses.339 All human cases have been reported in
challenge. association with equine cases. Although Hendra virus is not
There are four clinical syndromes: peracute, acute, sub- considered directly contagious, very close contact with horses,
acute, and mild. AHS is caused by a virus within the family particularly in the environment in which they were infected,
Reoviridae, genus Orbivirus (double-stranded RNA virus), increases the risk of human disease. Among 157 humans
and is related to the causative agent of bluetongue. that had casual contact with infected horses and humans,
Although endemic in parts of Africa, all equidae are sus- there was no evidence of seroconversion. Gray-headed fruit
ceptible, with horses having the greatest sensitivity to the bats seroconvert and demonstrate mild clinical disease when
virus, followed by mules, donkeys, and zebras.331 experimentally infected.340 However, subclinical disease or
Viral spread is directly influenced by the insect vector C. seroconversion have not been identified in horses exposed to
imicola. This biting midge prefers claylike moisture-retaining the virus. Horse are exposed via the upper respiratory or oral
soils. In years with abundant rainfall midge numbers increase cavity and once infected will excrete virus in their urine, saliva,
dramatically. The vector is moving northward, which is why and respiratory secretions.341 The virions are highly labile and
there has been movement into the Middle East and parts of can be destroyed by heat, lipid solvents, detergents, formalde-
Europe. hydes, and oxidizing agents.
Horses that are infected with virus develop severe and typi- the primary pleuritis is not effectively managed. The clinical
cally fatal respiratory disease that is characterized by dyspnea, approach to equine patients with marked pleural effusion
vasculitis, and severe pulmonary edema. Nonspecific signs should include consideration for septic, traumatic (hemor-
include lethargy, anorexia, fever, respiratory distress, ataxia, rhage), neoplastic causes; secondary to congestive heart fail-
tachycardia, and frothy nasal discharge. Encephalitic and ure; and parasitic disease (hydatid cyst). In North America,
marked subcutaneous edema may be observed in some cases. pleuropneumonia remains the most common cause of pleuro-
The incubation period is 8 to 12 days, with clinical progres- pneumonia, whereas in other parts of the world reduced fre-
sion characterized as peracute. Death typically occurs 1 to 3 quency of this disease is observed. Notably, in the UK, some
days after the onset of clinical signs. Clinical manifestation is reports indicate that pleuropneumonia only makes up approx-
similar to AHS, and diagnosis is based on serology aimed at imately 30% of the cases of infectious lower airway disease.
detecting virus-neutralizing antibodies and immunofluores- At the time of diagnosis of pneumonia or pleuropneumo-
cence. Virus isolation is performed in Vero cell culture with nia, relevant history includes information that may support
immunofluorescence used to detect viral antigens within the primary etiology, such as recent viral respiratory infection,
infected tissues. Because of the extreme danger and zoonotic long-distance transport, strenuous exercise, immunosuppres-
potential of this virus, sample collection should be performed sive therapy, exercise-induced pulmonary hemorrhage, severe
under Biosafety Level (BSL)-4 conditions; this is the highest esophageal obstruction, or marked age. Endogenous pulmo-
level of biosecurity implementation. nary defense mechanisms include cough, mucociliary clear-
ance, respiratory (or bronchial)-associated lymphoid tissue,
and alveolar macrophages.
Y BACTERIAL PNEUMONIA AND The mucociliary escalator provides an active mechanism
PLEUROPNEUMONIA for removal of particulate material from the respiratory tract
and is an important component of the nonspecific endog-
Bacterial pneumonia is not usually a spontaneous disease in enous host mechanisms for clearance of pathogen challenge.
adult horses. Most often it is a primary disease or risk factor The mucociliary escalator is present from the level of the phar-
that leads to bronchopneumonia in the adult horse. Events that ynx to the respiratory bronchioles. Particles that accumulate
lead to suppressed endogenous immunity may result in bacte- on the epithelial surface are moved in an oral direction under
rial colonization of the lower respiratory tract. A primary viral the action of ciliary waves moving the double layer of super-
upper respiratory tract infection may lead to loss of the muco- ficial sol-gel mucus. Once in the pharynx the constituents are
ciliary clearance mechanism leading to bacterial colonization swallowed. Anatomic airway division or size impacts respira-
of the lower airways or marked aspiration, potentially in com- tory clearance efficiency as ciliary beating frequency is greater
bination with some of the previously mentioned mechanisms. in the larger airways compared with the lower bronchioles;
General anesthesia may contribute to immunosuppression host benefit from this effect is prevention of excessive mucous
and in some cases may result in low-grade (or marked) aspira- accumulation in the trachea and larger conducting airways.
tion. Long-distance transport, particularly with head elevation This also contributes to the impact of head position on mucous
for extended periods of time or esophageal obstruction can clearance; prolonged head elevation is a known impediment to
all result in various levels of aspiration into the lower airways. respiratory clearance mechanisms primarily mediated by the
Although anatomic and immunoprotective mechanisms are mucociliary escalator. In the larger airways mucus originates
likely to aid in protection from lower airway colonization, in from goblet cells, whereas in the bronchioles mucus is pro-
some instances bacterial challenge overwhelms the host produced in the nonciliated Clara cells. In the bronchi, submu-
tective mechanisms, and bronchopneumonia may result. cosal bronchial glands produce serous and mucous secretions.
The importance of risk factors cannot be overemphasized Mucous secretion is under autonomic regulation; importantly,
because bacterial pathogens isolated from the lower respira- transepithelial water and electrolyte constituents may fluctu-
tory tract are opportunistic, environmental, or commensal ate, resulting in changes in mucus composition. Changes in
organisms that are unable to initiate primary invasion. The volume and composition of mucus can lead to respiratory
most frequently isolated organism from horses suffering from disease or may be the result of pathogen or toxin exposure.
primary pneumonia is S. equi subsp. zooepidemicus. Initial Cough is an important clearance mechanism mediated in part
colonization involves the primary airways, resulting in bron- by stimulation of the subepithelial irritant or stretch recep-
chitis, whereas disease progression leads to extension beyond tors, which are located with the greatest density in the larger
the airways to the surrounding pulmonary parenchyma. Fur- bronchi. Cough is an effective way to clear mucoid secretions
ther disease dissolution leads to the most advanced progres- from the intrathoracic trachea and large bronchi but not from
sion of bacterial colonization with extension to the pleural peripheral bronchi and bronchioles. Alveolar macrophages
space and associated structures and is termed pleuropneumo- provide an essential layer of protection within the alveoli.
nia. In mild or early cases of airway colonization, frequently Alveolar macrophages will either move up the mucociliary
disease resolution can be achieved with broad-spectrum anti- system or leave the alveoli and enter lymphatics. Once in lym-
biotic administration and general supportive care to facilitate phoid tissues, these macrophages play an important role in
optimal immune function. However, when disease is severe or antigen presentation. Physiologic factors that impair macro-
chronic or involves marked immunosuppression the progno- phage function include a hypoxic environment brought about
sis may be guarded. Identification of risk factors and severity by disease or reduced Fc receptor expression and subsequent
of disease will aid the clinician in determining the ideal diag- phagocytosis secondary to therapeutically administered corti-
nostic and therapeutic options. costeroids. Alveolar function is suppressed by viral infection.
Primary pleuritis is a rare event in horses. Traumatic pene- Therefore, in addition to viral respiratory disease leading to
trating wounds that contaminate the pleural cavity commonly impaired mucociliary clearance mechanisms, viral challenge
result in septic pleuritis. Pneumonia is not a common second- also impairs direct killing by alveolar macrophages and anti-
ary event to traumatic wounds but may occur in the event that gen presentation.
Etiologic Agents on ultrasound examination. Advantages of ultrasonography

Because the majority of cases of equine bacterial pneumonia are that location and approximate quantity (depth) of pleural
result from aspiration, the bacterial flora of the upper respira- fluid can be identified. Additionally, ultrasonography provides
tory tract is commonly involved with lower airway coloniza- the clinician with the ability to thoroughly examine peripheral
tion. Notably, S. equi subsp. zooepidemicus remains the leading lung fields. If fluid is present, once the pleural fluid has been
bacterial pathogen of the lower airways of adult horses suffer- removed thoracic radiography will provide additional imaging
ing from pneumonia.342,343 In addition to S. equi subsp. zooepi- information to aid with patient assessment of disease severity.
demicus, other pathogens may co-colonize the lower airways. Axial disease, such as abscess formation or lymphadenopathy,
As mentioned previously, a variety of stress and physiology will not be apparent with ultrasonography alone.
factors may put horses at risk for lower airway infection. Thoracic ultrasound will enable identification of not only
Classification of pathogens that may colonize the lower air- fluid accumulation but also gas echoes, fibrin, loculation, or
ways include gram-positive and gram-negative aerobes and highly cellular fluid, which will provide prognostic informa-
anaerobes. In addition to S. equi subsp. zooepidemicus, Staphy- tion regarding the severity of disease. Pleural fluid with high
lococcus spp. may lead to bronchopneumonia. In rare instances, protein content and low cellularity will appear anechoic (Fig.
typically in association with immunodeficiency, Rhodococcus 8.16), whereas fluid containing greater cellularity will have a
equi may be identified. Human pathogens are uncommonly greater degree of echogenicity. The identification of gas echoes
identified in the airways of horses, with Streptococcus pneu- within the pleural space may be identified in patients with
moniae more commonly being identified among racehorses in anaerobic-containing fluid, rupture of a bronchopleural fistula,
the UK and occasionally in the United States.344,345 Because or following iatrogenic introduction of air, which may result
of the pathogenesis of equine bronchopneumonia, aspiration during thoracocentesis. Pulmonary atelectasis, consolidation,
may result in the colonization with mixed isolates. Anaerobic or abscess formation may be identified if located in peripheral
bacteria may include Bacteroides fragilis, Prevotella heparino- lung fields. Ultrasound waves are unable to penetrate gas; there-
lytica, Clostridium spp., Peptostreptococcus spp., and Fusobac- fore, air-filled lung or lung overlapping areas of disease will not
terium spp. Historically, anaerobic bacteria have been reported be visible with ultrasound imaging alone. Marked pulmonary
to compose approximately 30% of the isolates identified in consolidation identified in combination with serosanguineous
horses with pneumonia.346,347 Identification of the bacterial pleural fluid, particularly when combined with the identifica-
population present can provide prognostic information, with tion of epistaxis, suggests the presence of pulmonary infarc-
the identification of anaerobes yielding a higher overall mor- tion, which carries a guarded prognosis.349 Added benefits of
tality, particularly if there has been a delay from the onset of thoracic ultrasound include the ability to determine whether
disease to the time of diagnosis and treatment.348 pleural adhesions are present. The clinical importance of iden-
tifying where adhesions are located is so they can be avoided
Clinical Manifestation of Disease if thoracentesis is performed or if indwelling thoracic drains
Clinical manifestation of lower airway infection frequently are going to be placed. Pneumothorax can be diagnosed with
indicates severe systemic infection. Although somewhat non- thoracic ultrasonography, but the extent of disease cannot be
specific, when combined with relevant history, signalment, fully determined. Once the diagnosis of pneumothorax is made
and examination findings, the diagnosis is generally not over- with ultrasound, further patient assessment should be com-
whelmingly challenging. Clinical signs often include lethargic pleted with thoracic radiography. Cranial thoracic imaging
attitude, reduced appetite, fever, and increased respiratory should be completed to determine whether mediastinal fluid or
effort. Cough may be present but may be blunted as a result abscess formation are present. Imaging through the triceps can
of the thoracic pain experienced on induction of the cough be performed with most 3- to 5-mHz imaging probes. When
reflex. examination of the equine patient with pleuropneumonia is
Diagnosis
Equine patients suffering from pleuropneumonia commonly
have a fever and lethargic mentation. Variation in clinical
signs at presentation will be influenced by severity and chro-
nicity of disease. Early in the course of infection, in addition
to pyrexia and lethargy, horses may experience pleural pain
demonstrated by forelimb abduction at the level of the elbow.
Physical examination should include complete thoracic aus-
cultation, and particular attention should focus on the identi-
fication of breath sounds in all lung fields. If lung sounds are
attenuated, particularly in ventral pulmonary fields, exami-
nation should include thoracic ultrasonography. Although
rebreathing examination may be a reasonable approach, the
procedure is contraindicated if there is any evidence of respi-
ratory distress or impairment.
Thoracic ultrasonography should be performed in a thor-
ough and comprehensive manner with particular attention
paid to the evaluation of the entire thorax, bilaterally. Exami- FIG. 8.16 A 25-year-old Arabian gelding with severe pleuropneumonia
nation should be performed from dorsal to ventral either cra- following esophageal obstruction and associated aspiration pneumonia.
nial to caudal or vice versa. The region of the mediastinum can Thoracic ultrasound examination with a 3.5-mHz probe revealed the pres-
be imaged through the triceps and is an important aspect to ence of marked anechoic pleural effusion that surrounds consolidated
examine, particularly if abundant fluid and fibrin are identified pulmonary parenchyma measuring greater than 10 cm in depth.
completed, the advantage of ultrasound is to not only determine thoracic tube can be placed, which is generally sized between
the presence and character of pleural fluid but also to determine 16 and 32 Fr. Pleural fluid collection will provide a diagnostic
the ideal location for performing pleurocentesis and potential sample for Gram stain and aerobic and anaerobic culture. If an
indwelling chest tube placement. The goal of sample collection indwelling tube is placed, fluid evacuation provides improved
and tube placement is to determine the area of greatest depth patient stability in addition to diagnostic sample collection
(volume) and a safe location that will minimize the potential for (Fig. 8.18). Large-volume fluid removal should be completed
adverse outcome such as diaphragmatic or cardiac puncture. with caution over a period of 30 to 45 minutes with concurrent
Subsequent to making the diagnosis of pleuropneumonia and isotonic crystalloid fluid administration. Rapid fluid removal
evacuation of pleural fluid, daily thoracic ultrasound is a main- from the pleural space can lead to re-expansion pulmonary
stay of patient monitoring. Daily ultrasound examinations will edema and hypotension.
allow the clinician to determine evidence of disease progression Normal equine pleural fluid is transparent with a clear to
or resolution, based on volume of fluid present, effectiveness pale yellow color. It is odorless and has a protein concentra-
of indwelling thoracic tubes, the presence and extent of pleural tion of <2.5 g/dL with a nucleated cell count of <8000/μL.350
fibrin production, and the assessment of peripheral pulmonary Bacterial pleuropneumonia commonly leads to an increase in
parenchymal disease. protein concentration and nucleated cell concentration. As
Once fluid has been identified within the pleural space, if previously mentioned, pulmonary infarction results in sero-
the volume measures greater than 3 cm in depth, then thora- sanguineous pleural fluid. Cytologic examination of pleural
cocentesis is indicated for therapeutic and diagnostic purposes fluid is typically represented by a large percentage (>80%) of
(Fig. 8.17). Location for fluid collection should be determined neutrophils, which are characterized by degenerate changes.
based on the most ventrally accessible location. Anatomic Often intracellular and extracellular bacteria are visible. Addi-
locations may be altered by large-volume fluid accumula- tional evidence for septic disease will include an elevated
tion, and this should be considered when planning the site pleural fluid lactate concentration (greater than found in circu-
for thoracocentesis or tube placement. The procedure for lation), pH <7.1, and low glucose concentration (<40 mg/dL).
thoracocentesis should be performed using sterile technique. Pleural fluid with a fetid odor often suggests the presence of
Once the location has been determined, subcutaneous infiltra- anaerobic bacteria. A recent report that described five cases of
tion of 2% lidocaine is performed. A no. 15 blade is an ideal intrathoracic esophageal rupture leading to the development
choice for making a small skin incision, which is generally 0.5 of severe fibrinous pleuropneumonia351 highlights the impor-
cm in length. A blunt teat cannula is an ideal instrument for tance of a thorough examination of pleural fluid cytology.
fluid collection. If large-volume fluid is present an indwelling The presence of feed material in pleural fluid is not a normal
FIG. 8.18 Indwelling thoracic tube placement should be determined

FIG. 8.17 Teat cannula placement with a polyethylene extension set with ultrasound as indicated by tube placement in this individual with a
for evacuation of purulent pleural fluid associated with pleuropneumonia dorsally located loculated pocket of pleural fluid accumulation. Note the
that developed in a 13-year-old Arabian mare that had recently been trans- unusually dorsal location of tube placement in this individual. Abundant
ported over approximately 1600 miles. septic pleural fluid can be observed to fill this thoracic tube.
finding and should alert the clinician to potential esophageal susceptibility patterns. Fibrin and cellular debris may occlude
damage and rupture. Particular case details that may provide the end of the thoracic drainage tube, and ultrasound can aid
the clinician with evidence to support a possible esophageal in determining the efficacy of thoracic tube drainage based on
rupture includes a history inconsistent with the development the amount of fluid exiting the tube and the amount of fluid
of pleuropneumonia, such as a horse that has not had recent remaining in the pleural space. If needed, a 60-mL catheter-
long-distance transport or esophageal obstruction. Examina- tip syringe can be used in a sterile fashion to remove debris
tion of pleural fluid should also include Gram stain, which is from the indwelling tube. In addition sterile isotonic fluid
beneficial to determine the class of bacterial organisms pres- can be introduced into the thoracic tube to lavage the pleural
ent, which can direct initial therapeutic strategies until bacte- space. Approximately 5 to 10 L of warm sterile fluid can be
rial culture results are available. introduced and removed by gravity flow. When fluid is intro-
In addition to pleural fluid culture for aerobic and anaero- duced patient monitoring should be continued throughout
bic bacterial pathogens, percutaneous transtracheal aspira- instillation. If at any time the patient appears uncomfortable
tion should be performed. Although pleural fluid is a readily or anxious the fluid should be allowed to drain and relieve any
accessible sample, based on the pathogenesis of disease result- built-up pressure. If during the instillation of fluid any fluid is
ing from aspiration, sampling from the primary site is likely noted to exit from the nostrils, coughing observed, or pleural
to provide superior diagnostic information, which may differ fluid exiting from the nostrils, lavage should be immediately
from pleural fluid analysis.13 Cytologic examination will pro- discontinued, and consideration should be given to the pres-
vide supportive evidence of septic inflammation character- ence of a bronchopleural fistula. Continued pleural lavage in
ized by a predominance of degenerate neutrophils. Gram stain the presence of a bronchopleural fistula can lead to dissemina-
evaluation will provide diagnostic information that may aid tion of septic material to previously healthy regions of lung. If
with therapeutic decision making while waiting for final cul- suspected, a bronchopleural fistula can be confirmed by the
ture results to be returned. instillation of fluorescein dye into the pleural space. The pres-
Etiologic agents associated with equine pleuropneumo- ence of dye at the level of the nostrils will confirm open com-
nia commonly originate from the upper respiratory tract, munication between the septic pleural space and the central
with polymicrobial infection as a predominant and consis- airways. Additional complications that may develop include
tent feature of equine pneumonia.280,342,348,352 Although the kinking of the indwelling tube or cellulitis surrounding the
most common isolate remains S. equi subsp. zooepidemicus, site in which the tube is located. In instances where cellulitis
gram-negative pathogens such as Escherichia coli are also develops locally, applied warm compress material can aid with
recognized.353 When a Klebsiella spp. is isolated from the reduced swelling and inflammation. Marked pain or swelling
lower airways of adult horses with pneumonia, a particularly indicate more severe disease necessitating tube removal.
guarded prognosis may be indicated and likely reflects the Thoracic ultrasonography is an essential diagnostic modal-
high degree of antibiotic resistance that has been reported.354 ity for the ongoing management of an equine patient with
Obligate anaerobes are normal inhabitants of the oral cav- pleuropneumonia. In addition to establishing a diagnosis,
ity and intestinal tract of horses and for this reason may be determining an optimal site(s) for pleural drainage by thoracic
isolated from the lower airways of horses with aspiration ultrasound is essential for the ongoing evaluation and assess-
pneumonia. A recent investigation that used a novel molecu- ment of patient progress and response to therapy. In addition
lar method of detection (referred to as the 16S rRNA gene to thoracic ultrasound thoracic radiography is an important
sequencing) recognized that Bacteroides spp. and Prevotella imaging modality for determining disease severity. It is para-
spp. are dominant anaerobes of the lower airways with anti- mount that pleural fluid is drained effectively before thoracic
biotic susceptibility patterns that include metronidazole, radiography so there is optimal visualization of pulmonary
imipenem, and clindamycin.355 parenchymal disease. Thoracic radiography will provide addi-
Pleuropneumonia may be effectively managed with evacua- tional information to patient assessment because radiographs
tion of the pleural space via teat cannula placement followed by are better able to detect central disease such as mediastinal
primary closure of the entrance made into the thoracic cavity. lymphadenopathy or abscess formation, deep parenchymal
Alternatively and particularly with large-volume pleural fluid, lesions, mediastinal disease, and the presence and sever-
indwelling thoracic drains are commonly left in place until ity of pneumothorax. Serial imaging studies will provide the
marked improvement or complete resolution of the septic pro- clinician with diagnostic information regarding response to
cess. Once placed the chest tube can be maintained in place by therapy and disease progression. Disease distribution will dif-
using a snare-type suture pattern along the 3 to 5 cm of thoracic fer based on the etiology of pneumonia because most cases
tube that is exiting from the body wall. A one-way (Heimlich) of bronchopneumonia are a consequence of aspiration. Cra-
valve is required to provide a mechanism for fluid evacuation nioventral pulmonary alveolarization is typically identified.
and reduce the potential for introduction of air or additional In contrast, disease that resulted from hematogenous delivery
pathogens into the pleural space. Patient assessment should will be evidenced by a caudodorsal pulmonary distribution.
include daily thoracic ultrasound examination to determine
the effectiveness of pleural drainage and identify any changes Treatment
that may develop, such as the production of fibrin accumula- Clinical management of pleuropneumonia requires effective
tion within the pleural cavity. Loculated parapneumonic effu- antibiotic therapy, pleural drainage, ideal supportive patient
sion with fibrin deposition has been reported to have a more management, and in some cases surgical intervention for the
guarded prognosis in horses with pleuropneumonia and is an removal of necrotic pulmonary foci.
important characteristic that should be carefully monitored Broad-spectrum antibiotic therapy is the mainstay of
through the course of disease management.356 A sampling of patient management because of the frequency of polymicro-
pleural fluid should be cultured every 10 to 14 days to identify bial infection. In addition to antimicrobial therapy frequent
changes in microbial populations and associated antimicrobial patient monitoring is essential to determine patient status
and response to therapy. Patient status is typically dynamic, TABLE 8.6 Antibiotic Therapy
particularly early in the course of disease. For this reason
changes in patient status should be addressed quickly to mini- Antimicrobial Dose
mize further complications and morbidity. In many instances Amikacin 10–185 mg/kg, IV, q 24 h
fibrin deposition will lead to marked flocculation of pleural Ampicillin sodium 11–22 mg/kg, IV or IM, q 6–8 h
fluid. Thoracocentesis may be efficacious in particular regions Ceftiofur sodium 2.2 mg/kg, IV or IM, q 12 h
of disease and should be modified to address current patient
Ceftiofur crystalline-free 6.6 mg/kg IM, q 96 h
status. It is not uncommon that several thoracic drains may be
acid
required to effectively drain an individual hemithorax caused
by the presence of fibrin loculations and the organization of Chloramphenicol 50 mg/kg, PO, q 6 h
numerous fluid pockets. In addition to antibiotic therapy and Doxycycline 10 mg/kg, PO, q 12 h
effective pleural drainage, it is paramount that the clinician Enrofloxacin 7.5 mg/kg, PO or IV, q 24 h
provide excellent supportive care in the form of maintenance 5.0 mg/kg, PO or IV, q 12 h
of euhydration with IV fluid therapy, assessment of acid-base Gentamicin 6.6 mg/kg, IV or IM, q 24 h
status, supplemental oxygen therapy in severe cases, provision Metronidazole 15–25 mg/kg, PO, q 6–8 h
of adequate nutritional support, and analgesic antiinflamma-
tory therapy commonly through the judicious administration Minocycline 4 mg/kg, PO, q 12 h
of NSAIDs. In cases where medical management alone pro- Oxytetracycline 6.6 mg/kg, IV, q 12–24 h
vides incomplete disease resolution, surgical intervention may Potassium penicillin G 22,000 IU/kg, IV, q 6 h
be indicated for the removal of necrotic pulmonary tissue as Procaine penicillin G 22,000 IU/kg, IM, q 12 h
well as to facilitate drainage that may be impaired by the use of Rifampin 5–10 mg/kg, PO, q 12 h
thoracic tubes alone.
Sodium penicillin G 22,000 IU/kg, IV, q 6 h
When horses suffering from pleuropneumonia are identi-
fied and properly diagnosed early in the course of the disease, Trimethoprim-sulfonamide 15–30 mg/kg, PO or IV, q 12 h
effective therapeutic management may lead to disease reso-
IM, Intramuscularly; IV, intravenous; PO, orally; q, every.

lution with limited or individual thoracocentesis to facilitate
pleural drainage. More commonly, disease progression is
present at the time of presentation, and pleural drainage is TABLE 8.7
required multiple times for management of an individual or
multiples, and at times bilateral indwelling thoracic drainage Non-specific COX inhibitors
tubes are required. Flunixin meglumine 0.5-1.1 mg/kg, IV or PO, q
Combined thoracic drainage and systemic antibiotic ther- 12-24 hr
apy are the mainstay treatments required for the resolution Phenylbutazone 2.2-4.4 mg/kg, IV or PO, q
of pleuropneumonia in horses. Effective medical therapy for 12-24 hr
the management of pleuropneumonia required knowledge
Selective COX-2 specific
about the microorganism(s) present and susceptibility to inhibitors
various antimicrobial agents. Broad-spectrum antibiotic cov-
Firocoxib 0.1 mg/kg, IV, q 24 hr
erage is required for the various classes of bacterial patho-
gens that may be present. A rational approach for initial Meloxicam 0.6 mg/kg, PO, q 24 h
treatment includes the combination of penicillin (or other
Dosages of non-steroidal antiinflammatory drugs (NSAID) used in the treat-

β-lactam agent), gentamicin, and metronidazole. This comment of pleuropneumonia and other severe pulmonary infections in which
bination will provide a broad level of antibiotic protection the administration of corticosteroids might be contraindicated.
against gram-positive (e.g., Streptococcus spp.), gram-nega-
tive enteric organisms, and anaerobic bacteria, respectively.
Although penicillin has good efficacy against many anaero- have evidence of hypovolemia, renal impairment, or loss of
bic organisms, the synthesis of β-lactamase by Bacteroides gastrointestinal epithelial integrity. Even though NSAIDs are a
spp. warrants the addition of metronidazole for more com- mainstay of clinical management of equine patients suffering
plete coverage. Adverse events or reduced patient stability from a variety of inflammatory and painful disorders, the risk
may require modification to this initial protocol. Once bacte- for an adverse drug event should be recognized. Renal pap-
rial isolate(s) have been identified and antibiotic susceptibil- illary necrosis, gastric ulceration, and right dorsal ulcerative
ity profiles provided, informed changes in antibiotic coverage colitis have been well reported as consequent events that can
can be made (Table 8.6). develop in equine patients.362 Particular attention should be
An essential adjunct therapy in horses suffering from pleu- paid to medications that may have been administered before
ropneumonia involves analgesic and antiinflammatory ther- veterinary evaluation to minimize the potential for concurrent
apy. In the early stages of disease management, NSAID therapy NSAID agent administration, which could potentiate adverse
is indicated to address the issues of systemic inflammation events.363,364
and fever, pain of disease and thoracic tube placement, and Nutritional support should be carefully monitored in
endotoxemia that may ensue because of infection with gram- horses suffering from marked pleuropneumonia. It is not
negative pathogens and subsequent lipopolysaccharide (LPS) uncommon for horses that suffer from pain and sepsis to
liberation. Commonly selected NSAID agents aimed at pro- enter into a negative energy balance, which can be poten-
viding analgesia in horses with pleuropneumonia include flu- tiated with reduced feed intake. Monitoring body weight
nixin meglumine, phenylbutazone, firocoxib, and meloxicam at routine intervals will aid the clinician to determine a
(Table 8.7).357-361 Caution should be exercised in horses that decline in condition. In addition, monitoring certain clinical
chemistry parameters can also aid with the determination been established (by 7–10 days) postoperatively nonsterile
of overall nutritional status. Monitoring of blood glucose, fluids (tap water) can be used for ongoing pleural drainage.
electrolyte concentrations, and serum triglyceride levels will Drainage should continue until sepsis is resolved and the sur-
help determine whether the horse is entering into a negative gical site has closed. The convalescent period following surgery
energy balance. Particular attention should be paid to horses will depend on the surgical procedure selected and degree of
that are among breeds at risk for lipid mobilization such as ongoing sepsis at the time of surgery. Generally, horses com-
ponies, Miniature horses, or those with evidence (or risk) of plete tissue healing and resolution of sepsis within 60 days of
insulin resistance or pituitary pars intermedia dysfunction. thoracotomy.
Palatable feeds and fresh grass can often help to encourage Complicating factors may prolong or prevent disease reso-
feed intake in sick horses. When indicated additional nutri- lution. Primary pulmonary conditions that may complicate
tional supplementation can be achieved with the addition of disease management include the development of pneumotho-
dextrose to IV fluids or the introduction of parenteral nutri- rax, pleural adhesions, pulmonary abscess formation, pulmo-
tion (partial or complete). Enteral nutrition can be achieved nary infarction, bronchopleural fistula, or cranial mediastinal
by offering commercial supplementation with high-protein abscess formation. Pneumothorax is a relatively common
amino acid products (Purina Well Gel, Purina Mills, Inc. St. complication that develops with pleuropneumonia. Causes
Louis, MO). include iatrogenic introduction of air at the time of thoraco-
Complicated, refractory disease often requires surgical centesis or indwelling chest tube placement or secondary to
thoracotomy to facilitate removal of fibrinous material and development of a bronchopleural fistula. Mild pneumothorax
necrotic lung to facilitate pleural drainage. Evidence that a is commonly well tolerated and may not have clinical con-
horse is suffering from refractory disease includes lack of pleu- sequences. However, more severe pneumothorax requires air
ral fluid resolution over the course of several weeks despite evacuation to reestablish adequate pulmonary function and
appropriate antimicrobial therapy and repeated pleural drain- oxygen delivery. Clinical signs that support the necessity of
age. Case selection for thoracotomy is a critical component of air evacuation in a patient with pneumothorax include respi-
case outcome. Timing for thoracotomy in equine pleuropneu- ratory distress and elevated respiratory rate and effort. Place-
monia cases was reported to have a mean time of 60 days since ment of an indwelling thoracic tube in the caudodorsal lung
disease development in one report. Surgical intervention too field following the confirmation of pneumothorax via radi-
early in the course of disease may result in complications that ography will provide the clinician with the ability to remove
include bilateral pneumothorax, hemorrhage, and/removal pleural air to reestablish negative intrathoracic pressure.
of viable lung, which can result in catastrophic case outcome. Pulmonary infarction has been reported to occur following
When case selection is made, timing for thoracotomy should strenuous exercise and is associated with severe pulmonary
be based on several factors that include patient stability and disease characterized by epistaxis, pulmonary consolidation,
approximately 45 to 60 days of medical therapy. In an ideal and fetid serosanguineous pleural fluid.349 Bronchopleu-
setting pleural abscess will become walled off so that a pleural fistulae can develop in horses with extensive pulmonary
ral to parietal pocket is completely formed and separate from necrosis, which result in an open communication between
other regions of the thorax. At a minimum, it is important the pleural cavity and central airways. The presence of a bron-
to determine that the mediastinum is complete based on the chopleural fistula does not impair the prognosis for survival,
ability of the patient to handle air introduction into the pro- but it will prevent thoracic lavage and may impact future
posed surgical hemithorax. The indwelling thoracic drain athletic performance. Occasionally septic pleural disease can
should be left open without a one-way valve for a minimum have cranial dissemination leading to the organization of a
of 2 hours to determine whether the patient is able to physi- mediastinal abscess. Clinical signs that suggest a mediastinal
ologically handle a unilateral pneumothorax. If the patient is abscess may be present include apparent preference to stand
noted to become anxious and have altered respiratory rate and with forelimbs in a pointed position, evidence of jugular vein
pattern or other signs of distress the site should be closed, air occlusion with pronounced jugular pulsation, and marked
removed, and the procedure delayed until the patient is ana- pectoral edema. Imaging with ultrasound and thoracic radi-
tomically prepared with a closed mediastinum for the surgical ography may provide additional evidence of mediastinal
intervention. abscess based on cranial fluid accumulation located cranial
The procedure for thoracostomy can be performed using to the heart. In such cases, there is also evidence of caudal
two different methods: an intercostal approach that opens displacement of the cardiac silhouette. Mediastinal abscess
an area in an ICS or a partial rib resection, which removes formation can be particularly challenging to manage, often
a section of rib adjacent to the abscessed material. An inter- requiring general anesthesia to facilitate effective drainage
costal approach has the advantage of using a smaller window cranial to the heart.
of approach, which limits postoperative discomfort. In mild Extrathoracic complications can develop in association
cases intercostal thoracotomy can provide a functional area with pleuropneumonia and include laminitis, jugular vein
for pleural drainage and removal of fibrin and necrotic pulmo- thrombophlebitis, and antibiotic-associated colitis. Similar to
nary tissue. In more severe cases, partial rib resection has the other manifestations of laminitis, depending of the severity
advantage of a larger surgical window in which larger, more of laminar damage, recovery may be prolonged and athletic
advanced necrotic lung and debris can be removed. Patient performance limited following recovery despite resolution of
recovery in the postoperative period is further delayed with pulmonary disease. Horses suffering from pleuropneumo-
rib resection because of the size and extent of tissue removal, nia are commonly critically ill at the time of diagnosis, and
which delays wound healing. In the immediate postoperative hematologic parameters may indicate the onset of dissemi-
period daily lavage should be performed with warmed sterile nated intravascular coagulopathy (DIC). Whether clinical or
isotonic fluids. Lavage will help facilitate the removal of debris subclinical, DIC will place patients at greater risk for throm-
and blood clots following surgery. After tissue granulation has bophlebitis. In some cases catheter site cellulitis may progress
to thrombophlebitis, and for these reasons catheter selection Y PULMONARY ABSCESS FORMATION
should be aimed at materials with a low likelihood of throm-
bogenicity with placement and maintenance a clinical prior- Pulmonary abscess formation most commonly occurs in
ity. Inadvertent or frequent jugular venipuncture should be weanling age foals in association with R. equi infection (Chap-
avoided in horses at high risk for thrombotic disorders. In ter 20). S. equi subsp. zooepidemicus is the organism most
most instances, if a timely identification of jugular vein dis- commonly cultured from the lungs of horses with generalized
ease is established recovery can be favorable with an alternate pneumonia and rarely results in abscess formation. Complica-
placement site, and thrombosis is not severe. Antibiotic-asso- tions from S. equi infection include metastatic spread to vari-
ciated colitis is an ever-present potential in horses receiving ous organs including possible pulmonary abscess formation.
antibiotic therapy. Based on the nature and severity of disease, Aspiration is another cause of focal pulmonary infection and
this should be monitored throughout the course of therapy. abscessation. Aspiration pneumonia is a potential complica-
If evidence of gastrointestinal disturbance is noted, hydration of esophageal obstruction or dysphagia in horses. Neona-
tion, acid-base status, and electrolyte concentrations should tal foals may suffer from dysphagia in association with hypoxic
be corrected. Antibiotic therapy will be required throughout ischemic encephalopathy or nutritional muscular dystrophy,
the course of management for pleuropneumonia, so alternate whereas adult horses may develop aspiration pneumonia after
therapy should be selected to target the primary pulmonary complete esophageal obstruction.
pathogen(s).
Prognosis and Outcome Y INTERSTITIAL PULMONARY DISEASE
The overall prognosis for horses to recover and resume ath- Interstitial pneumonia is a pulmonary disorder that may affect
letic performance has improved over the past three decades. horses of various age groups. Adult horses with interstitial
Evidence to suggest a more guarded prognosis includes the pneumonia have a more guarded prognosis for recovery and
presence of marked fibrin accumulation with an overall sur- survival280 compared with foals and weanlings. Horses less
vival of 68%. In horses that did not have fibrin accumulation than a year of age that are provided with appropriate therapy
survival was 100%, whereas horses that had fibrinous accumu- and supportive care tend to have a favorable prognosis for
lation survival was only 62%.21 It was noted that in this popu- complete recovery.368
lation, the nonfibrinous group only had 18% of the patients
identified as having necrotic pulmonary parenchyma, whereas Etiology
60% of the patients with fibrinous disease exhibited necrotic Some cases of interstitial pneumonia result from a primary
pulmonary parenchyma. Bacterial isolates in this report were toxic or infectious insult, but at the time of presentation deter-
similar to previous reports, with the most common pathogen mination of the exact etiology can be challenging.300,368-370
being S. equi subsp. zooepidemicus followed by E. coli, Acti- Toxic pulmonary disease has been associated with ingestion
nobacillus equuli, Enterococcus, and Klebsiella. The most com- of crofton weed, pyrrolizidine alkaloids (Crotalaria, Trich-
mon anaerobes were Prevotella spp. and Bacteroides spp.21 In odesma, and Senecio), perilla ketones, silicosis, and prolonged
a previous report, horses that had pleuropneumonia or pneu- oxygen therapy. Hepatic metabolites of pyrrolizidine alkaloids
monia had an overall survival rate of 75%.342 In that report cause cellular damage and death in the pulmonary endothe-
38% of the horses with anaerobic bacteria cultured from the lium.370,371 Inhaled irritants or toxins may contribute to direct
lower airways survived, which is similar to 35% survival in pulmonary damage such as occurs after inhalation of smoke
the recent report, regardless of the presence of marked fibrin or agrichemicals.372-374 Silicosis is a highly specific chronic
accumulation.21,346 In a report that looked at pneumonia as granulomatous pneumonia of horses and should be consid-
secondary to penetrating thoracic wounds, the association of ered in horses with compatible clinical signs that originate
reduced survival with the presence of anaerobic bacteria was from the Carmel Valley in California.280
not found. This finding may have resulted, in part, because The most recent evidence for an infectious etiology asso-
of the different pathogenesis of disease rather than the lack ciated with interstitial disease in horses is EHV-5–associated
of association with anaerobic bacteria, resulting in a more multinodular pulmonary fibrosis. Supportive evidence for
guarded prognosis.365 Among the published reports regarding the association was recently described in which investiga-
the prognosis for horses with pleuropneumonia the range is tors characterized findings of 24 adult horses that suffered
43.3% to 95.7%.353,366,367 Not only is there a favorable over- from progressive nodular fibrotic lung disease associated
all prognosis for the horse to survive pleuropneumonia, the with EHV-5.302 Herpes viral DNA was identified in 79.2% of
likelihood of returning to the previous performance level is affected individuals compared with 8.7% of the control ani-
also favorable. With appropriate treatment the prognosis is mals.302 Similarly, a case series of five horses suffering from
approximately 90% with about 60% returning to performance. respiratory distress with clinical evidence of interstitial dis-
As mentioned previously a delay in therapy, the presence of ease were all confirmed to have EHV-5 in pulmonary tissue
anaerobic bacteria, and the presence of marked fibrin locula- or secretions, supporting previous findings associated with
tions are associated with a more guarded prognosis. Horses this disorder and multinodular pulmonary fibrosis second-
that are at risk for the development of lower airway disease and ary to viral disease.311 An additional report of two horses also
bacterial colonization should be treated appropriately with confirmed similar clinical manifestation of disease, radio-
antimicrobial therapy, monitored closely, and have therapy graphic and histopathologic evidence of multinodular granu-
modified as indicated by the bacteria isolated from the lower lomatous disease, and the presence of EHV-5.304 It should be
airways. Complicating factors such as pneumothorax, lamini- noted that the exact association of viral involvement remains
tis, or colitis may prolong hospitalization and owner expense, speculative in some circumstances. In a prospective investiga-
which may also limit the ability of the horse to recover from tion of mares and foals in central Kentucky, up to 88% of the
its primary disease. foals were positive for the virus in peripheral blood yet they
remained clinically healthy.375 Although EHV-5 has been iso-

lated from the upper respiratory tract of horses with respira-
tory disease, similar to a related gammaherpesvirus EHV-2,
clinical disease associated with EHV-5 has been suggested to
result in lymphadenopathy, immunosuppression, depression,
and primary respiratory tract disease. Adult onset of severe
respiratory disease characterized by multinodular granulo-
matous pulmonary lesions should be strongly suspected to be
associated with EHV-5 infection.
The initial infectious or toxic agent causes alveolar dam-
age resulting in cell death and increased permeability at the
level of the alveoli. Pulmonary congestion, interstitial edema,
erythrocyte extravasation, and alveolar edema occur dur-
ing the exudative phase of the disease. Subsequently, alveo-
lar infiltrates with inflammatory leukocytes and fibrin and
increased permeability lead to fluid accumulation, impairing
normal gas exchange mechanisms, hyaline membrane forma-
tion, and clinical respiratory distress. Acutely affected patients
typically demonstrate respiratory distress, injected mucous
membranes, and impaired pulmonary function. Subacute to FIG. 8.19 A 19-year-old Quarter Horse mare presented with a 5-day
chronic disease results in alveolar regeneration with alveolar history of fever, anorexia, and respiratory distress. The mare failed to re-
type II pneumocyte proliferation to replace damaged type I spond to antibiotic and nonsteroidal antiinflammatory drug therapy. Tho-
pneumocytes. Fibroplasia leads to cellular proliferation and racic radiographs were diagnostic for generalized interstitial pneumonia.
septal thickening, fibrous development, and ultimately to
reduced pulmonary compliance. (dexamethasone 0.05–0.1 mg/kg IV daily), with transition
to aerosolized corticosteroids (beclomethasone 1500 μg
Clinical Findings intranasally three times a day to twice a day)376 as clinical
Horses presenting with interstitial pneumonia are typically improvement is observed. Corticosteroid therapy should be
in severe respiratory distress with labored breathing, dark continued until clinical resolution is observed or no further
mucous membranes, poor pulse quality, and tachycardia. improvement is noted with therapy. Prolonged corticosteroid
Some patients are mistakenly considered to have an obstruc- therapy of several weeks to months should be anticipated
tive disease like heaves, yet interstitial pneumonia is char- because of the severity of lower airway inflammation asso-
acterized by a restrictive rapid, shallow breathing pattern. ciated with this condition. Bronchodilator therapy is indi-
Additional clinical features of disease include hypoxemia, a cated when severe bronchoconstriction exists. β2-adrenergic
stress or inflammatory leukogram, hyperfibrinogenemia, and receptor agonists are the drugs of choice for immediate bron-
hypoxemia that may be severe. More chronic disease may be chodilation and subsequent improvement of air movement
observed in mildly affected individuals with exercise intoler- to the lower airways (albuterol 360–720 mg/kg every 3–12
ance and chronic cough. hours).377,378 Enteral bronchodilator therapy with clenbuterol
0.8 to 3.0 μg/kg orally every 12 hours (Ventipulmin, BIVI)
Diagnosis can provide additional support in cases with marked bron-
Definitive diagnosis of interstitial pneumonia in horses is choconstriction. Following initial stabilization, an additional
based on histopathologic evaluation of a pulmonary biopsy. therapeutic option is the use of a combined parasympatho-
Examination for EHV-5 viral DNA can be performed on a tis- lytic agent (ipratropium 360–470 μg/kg every 6–12 hours)379
sue sample or BALF. Thoracic radiographs can be helpful in with a β2-adrenergic receptor agonist (albuterol; Combi-
establishing a preliminary diagnosis of interstitial pneumo- vent, 3M Pharmaceuticals, and Boehringer Ingelheim) to
nia. Two patterns of interstitial disease have been described improve oxygen delivery to the lower airways with the added
in horses with interstitial pneumonia: as discrete or diffuse advantage of having an increased half-life compared with β2-
nodules suggestive of neoplasia or mycotic disease or as a dif- adrenergic agonist therapy alone.
fuse increase in radiographic interstitial pattern (Fig. 8.19). In addition to supportive care and antiinflammatory
Serum titers may indicate recent exposure or infection with therapy, specific antiviral therapy may be selected for cases
viral respiratory disease. Histopathologic evaluation of lung of EHV-5–associated multinodular pulmonary fibrosis, typi-
biopsies or specimens obtained at postmortem will confirm cally in combination with antiinflammatory therapy. Valacy-
the diagnosis of interstitial pneumonia. If silicosis remains a clovir has the greatest oral bioavailability with a protocol that
differential, diagnosis is based on x-ray diffraction techniques includes 27 mg/kg orally every 8 hours for 48 hours followed
on lung tissue preparations.280 by 20 mg/kg every 12 hours thereafter.309,380,381 Duration of
therapy should be based on clinical response to treatment.
Treatment In some circumstances, this therapeutic protocol may be cost
The prognosis for adult horses with interstitial pneumo- prohibitive or only possible for a limited time. Investigations
nia remains guarded. In horses that present with mild to are ongoing regarding the optimization of antiviral therapeu-
moderate disease, treatment should be aimed at improving tic protocols for horses that suffer from herpes viral infection.
oxygenation. Intranasal insufflation of oxygen is warranted Supportive evidence is provided by the use of such agents in
for patients that are severely hypoxemic. Antiinflammatory human patients that are at risk for serious cytomegalovirus
therapy should initially include systemic corticosteroids infection post organ transplantation.382,383
Prognosis administration of corticosteroid therapy, pituitary pars inter-

The prognosis for return to function is guarded for adult media dysfunction, or other overwhelmingly debilitating
horses and favorable for foals that are managed appropriately. disease. Some invasive fungal pathogens may cause primary
Supportive and antiinflammatory therapy may improve clini- disease and do not require a predisposing host factor as a
cal status, yet high-level athletic activity may be impaired. precedent for colonization, which includes Blastomyces der-
matitidis, Coccidioides immitis, Histoplasma capsulatum, and
Y FUNGAL PNEUMONIA Cryptococcus neoformans.
Direct inhalation of B. dermatitidis conidia can result in
Respiratory fungal disease is most commonly a result of pulmonary colonization. These are dimorphic saprophytic
inhalation of aerosolized fungal pathogens. After inhalation fungi that can be detected on cytologic examination of airway
the causative organisms are able to penetrate into the lower secretions. Infection has been reported to result in pulmo-
pulmonary airways and alveoli as a result of their small par- nary abscess formation, peritonitis, subcutaneous abscesses,
ticle size. Interestingly, more than 90% of the particles pres- and mastitis.393-395 Histoplasma capsulatum is most commonly
ent in stable air samples that are visible with light microscopy associated with moist regions, particularly those contaminated
are spores of fungi or Actinomyces.384,385 However, in some with bird or bat fecal waste. The characteristic appearance of
cases of fungal pneumonia penetration may occur through yeast includes a 2- to 4-μm organism with a definitive circular
a compromised gastrointestinal tract in an immunocompro- halo surrounding the centrally located crescent-shaped cyto-
mised patient. In one report 86% of the horses diagnosed with plasm. Although horses are considered resistant to infection,
mycotic pneumonia developed disease secondary to gastroin- disease associated with H. capsulatum has included pulmonary
testinal disease with disruption of epithelial integrity.386 For granuloma,396 pneumonia, and abortion.397 Coccidioidomyco-
this reason, in addition to horses that demonstrate evidence of sis is an uncommon pathogen of horses, but among horses that
pulmonary disease and have appropriate risk factors such as live in regions of sandy, alkaline soils disease may occur fol-
gastrointestinal disease, particularly if immunocompromised lowing inhalation. Marked pulmonary inflammation develops
(marked neutropenia is present), fungal pneumonia should be initially, followed by pulmonary and lymphoid localization.
considered. Nonspecific clinical signs may involve multiple organ systems
The most common isolate from horses with fungal pneu- including liver, lung, kidney, or spleen and warrant a particu-
monia is Aspergillus spp., which are commonly present in the larly guarded prognosis. Horses with severe pulmonary disease
equine environment,387 particularly in moldy feed and bed- associated with C. immitis similarly are unlikely to survive.
ding materials, such as straw. Predisposing factors that lead
to disease development in horses include immunosuppres- Immunosuppressed Patients
sion because Aspergillus spp. are opportunistic pathogens. Candida albicans is an uncommon opportunistic pathogen
Adequate anatomic and immunologic function provides the that has been observed as a complicating factor in septic neo-
healthy individual with effective protection against coloniza- natal foals, which rarely can be identified on diagnostic evalu-
tion and disease. Immunosuppression may result from endog- ation of the respiratory tract. In suspect cases, fungal culture of
enous disease that alters effective immunity or is secondary to transtracheal aspirate samples may be indicated. Pneumocystis
the administration of immunosuppressive therapy.388-392 jirovecii is currently classified as a saprophytic fungus based on
the DNA sequence information from the 16S-like ribosomal
Pathogenesis subunit. Clinical signs of P. jirovecii infection typically include
Enteritis, colitis, and typhlocolitis are proposed to predispose an interstitial pneumonia that fails to respond to conventional
horses to the development of systemic fungal dissemina- therapeutics. Historical reports have described Arabian foals
tion. Gastrointestinal inflammation results in the disruption with severe combined immunodeficiency as the most likely
of the epithelial barrier, allowing for translocation of fungal to succumb to infection. Similarly, in humans, this is a dis-
organisms and subsequent systemic dissemination. Lesions ease of immunosuppressed individuals that commonly suffer
have been described to center around large blood vessels, from HIV infection that have progressed to develop AIDS.
which then lead to systemic spread of organisms. Among the Diagnosis is based on cytologic examination of lower airway
reported retrospective cases of invasive pulmonary aspergillo- secretions obtained by BAL sampling. This organism cannot
sis nearly 84% were associated with enterocolitis.388,392 Hema- be cultured.
togenous dissemination leads to fungal deposition in the lung.
Among the risk factors for mycotic distribution from the Clinical Signs
gastrointestinal tract, NSAID therapy may contribute to epi- Clinical signs of equine fungal pneumonia include tachypnea,
thelial disruption, enhancing mucosal permeability to luminal fever, nasal discharge, epistaxis, nasal plaques or erosions, abnor-
microorganisms. Additionally, neutropenia is an important mal lung sounds, and pleural friction rubs. Most horses have a
risk factor for humans to develop mycotic pneumonia. Simi- history of progression of respiratory disease despite aggressive
larly in horses, the majority of cases are reported to suffer from antimicrobial therapy. Inspection of the nasal passages may
neutropenia even though the exact role that neutropenia plays reveal nasal plaque formation or ulceration. Although these
regarding disease manifestation is not fully elucidated. Dis- lesions may be detected in the minority of cases, estimated in
semination of disease is an important component of disease 10% of horses, this is highly predictive of concomitant or subse-
pathogenesis; 40% of the horses with fungal pneumonia have quent invasive pulmonary aspergillosis.
evidence of invasive fungal disease in other organs including
the kidney and brain.347,388 Diagnosis
Overwhelming exposure to inhaled spores may result in Low-volume pleural effusion may be detected by thoracic
pulmonary fungal disease, particularly in immunosuppressed ultrasound, and fibrin plaques may occur on visceral and pari-
individuals. Altered immunity may result from iatrogenic etal pleural surfaces. If pleural effusion is identified, pleural
fluid samples should be submitted for cytologic evaluation and on clinical pathologic findings of abundant fungal organisms
culture. Observation of fungal spores on cytologic evaluation in the presence of marked inflammation characterized by
and/or culture of fungal elements from transtracheal aspi- abundant (>20%) and typically degenerate neutrophils pres-
rate samples are not strong indicators of a diagnosis of fun- ent. Clinically relevant findings typically also include intracel-
gal pneumonia in horses. Culture and histologic evaluation lular and extracellular organisms in the presence of marked
of lung biopsy samples provide definitive evidence of fungal inflammation.
pneumonia and differentiation from neoplasia. Fungal medi- In vitro growth of fungal organisms can be lengthy because
astinal granuloma appears similar to mediastinal lymphoma of their naturally fastidious growth kinetics. Suspect samples
on radiographic examination.398 The site is difficult to biopsy should be applied to prepared culture media and transported
percutaneously and is best identified via thoracoscopy. to a microbiology laboratory at room temperature. Routine
The radiographic appearance of fungal pneumonia can culture media includes Sabouraud dextrose agar, inhibitory
be similar to disseminated pulmonary neoplasia. A mili- mold agar, or a mycobiotic containing cycloheximide and
ary or reticulonodular interstitial pattern is common with chloramphenicol, which enhance the potential for positive
multifocal, coalescing nodules visualized in peripheral lung fungal growth. Test interpretation should carefully consider
fields in both fungal pneumonia and metastatic neoplasia patient status because of the frequency of fungal organisms
(see Fig. 8.9). in the equine environment. Similar to airway cytology find-
Patient examination will provide the clinician with the ings test specificity is reduced and false positive samples can
opportunity to determine optimal sample collection for diag- occur.385,400
nostic examination. Thoracocentesis may be performed in Serologic diagnostic testing can provide the clinician
cases with evidence of pleural fluid. However, in cases of lower with valuable diagnostic information and the opportunity to
airway disease, with an absence of pleural fluid accumula- monitor disease progression and response to antifungal ther-
tion, transtracheal aspiration will be a preferred diagnostic apy. Currently available options include immunodiffusions,
sample for collection. Cytologic examination of pleural fluid radioimmunoassays, complement fixation, and ELISA test-
or tracheal aspirate reveals the presence of fungal organisms. ing. These tests will aid with the quantification of circulating
Aspergillus spp. are characterized by having broad septate antifungal antibody titers. For this reason they have diagnos-
hyphae with parallel sides and discrete 90-degree branches tic and patient-monitoring benefits. Immunohistochemis-
that can be identified on cytologic or histopathologic exami- try, fluorescence in situ hybridization, and DNA probes are
nation. Sample collection should include fungal culture antigen-detection testing methods. Additionally, a commer-
analysis in suspect cases. Serologic assessment may provide cial comprehensive real-time PCR assay can be used to detect
supportive evidence, but specificity is influenced by the fre- fungal DNA in biological samples. This can be followed by a
quency of fungal exposure among horses. Sample staining species-specific real-time PCR test to determine the particular
may provide more efficient diagnostic evidence; immunohis- inciting pathogen.401
tochemistry and immunofluorescence are available diagnos- Although not all fungal pathogens are opportunistic in
tic options. nature, based on the potential for attenuation of endogenous
Lesions involving the upper respiratory tract may be sam- immune activity, suspect cases that fail to demonstrate an
pled using standard biopsy techniques. Uterine biopsy instru- appropriate risk for fungal disease may benefit from immune
ments are useful tools for sample acquisition because in some assessment testing. Overall lymphocyte concentrations can be
cases sample size can make definitive diagnosis challenging. ascertained on compete blood count analysis, but lymphocyte
For lesions involving sinus structures, sample acquisition is subset testing and functional analysis can provide the clinician
generally accomplished with a sinus flap. Fungal pneumonia with an improve assessment of host immune function. Testing
may be diagnosed via TTW or BAL sampling or lung biopsy should include lymphocyte subset immunophenotyping and
acquisition. Risk of pulmonary vascular damage is a poten- immunoglobulin concentration assessment.402-407
tial risk associated with biopsy collection and should be care-
fully monitored with ultrasound and physical examination Treatment and Prognosis
(epistaxis) to determine whether hemorrhage is present.385 Amphotericin B deoxycholate is a polyene antibiotic that
Routine staining with hematoxylin and eosin may not provide combines with ergosterol in the fungal cell wall to enhance
diagnostic information for all fungal organisms, particularly membrane permeability. The hazards of drug administra-
when chronic lesions contain marked fibrosis; therefore, in tion are numerous, and caution should be exercised when
suspect cases special staining for fungal organisms should be administering to equine patients. When administered intrave-
requested. Staining techniques may include periodic acid– nously the drug is nephrotoxic and quite irritating, potentially
Schiff, Gridley fungus stain, and Grocott-Gomori methena- leading to phlebitis. Additional adverse events may include
mine silver nitrate staining.385 anorexia, anemia, cardiac arrhythmias, hepatic dysfunction,
The presence of fungal elements may be identified in cyto- and hypersensitivity reactions.408 Despite the potential for
logic fluid samples or impression smears obtained from tis- adverse events in some instances, this is considered a reason-
sue biopsy samples, although interpretation of such findings able treatment choice and has been used with success to treat
should be carefully considered. The direct association of fun- systemic diseases such as histoplasmosis, pulmonary asper-
gal elements in biologic samples should correlate with the gillosis, cryptococcosis, and topically for nasal Conidiobolus
presenting complaint and patient status. Tracheal aspirate and coronatus.100,387,409-412
lower airway samples commonly contain Alternaria spp. (non- Benzimidazole derivative drugs classified among the azoles
pathogenic barn fungus), yet this does not correlate with clini- provide an effective antimicrobial therapy against fungal
cal disease, and they are found in combination with normal pathogens by inhibiting ergosterol synthesis in the cell mem-
cytologic findings in healthy horses.399 If diagnosis is based brane. These drugs have been used with success topically and
on cytologic examination, ideally this finding should be based as systemically administered drugs (Table 8.8).
TABLE 8.8 Antifungal Agents for Consideration in Equine Patients

Drug Dose Comments
Amphotericin B 0.3–0.6 mg/kg in 1 L 5% dextrose1 Nephrotoxicity, phlebitis, hypersensitivity
Use caution
AZOLE DRUGS
Miconazole 2% topical Topical2 Guttural pouch mycosis
Enilconazole Topical3 Guttural pouch mycosis
Nebulization for fungal pneumonia, Scopulariopsis
spp.
Ketoconazole 30 mg/kg NG tube, daily4,5 Acidify with 0.2 N HCl
Itraconazole (Sporonox) 5 mg/kg PO, daily6 Aspergillus spp., Histoplasma spp., Blastomyces
spp.
Compounded formulation not recommended
Fluconazole Load 14 mg/kg PO Not effective against Aspergillus spp. and Fusarium
spp.
Then 5 mg/kg PO, daily7–9 Compounded formulation is stable
Voriconazole 4 mg/kg PO, daily10 Drug of choice for human invasive Aspergillus spp.
pneumonia
IODIDE THERAPY Do not administer to pregnant mares, congenital
hypothyroidism
Sodium iodide (20%) 20–40 mg/kg/day 7–10 days11–13 Monitor for signs of iodonism: lacrimation, dermatitis
Oral formulations
Inorganic potassium iodide 10–40 mg/kg/day 12,13 Chemical grade only, unstable in light, heat, humidity
Organic ethylenediamine 0.86–1.72 mg/kg/day13 Commercially available

dihydriodide
NG, Nasogastric; PO, orally.
References
1. Begg LM, Hughes KJ, Kessell A et al., Successful treatment of cryptococcal pneumonia in a pony mare, Aust Vet J. 2004;82:686–692.
2. Davis PR, Meyer GA, Hanson RR et al., Pseudallescheria boydii infection of the nasal cavity of a horse, J Am Vet Med Assoc. 2000;217, 674, 707-709.
3. Stewart AJ, Cuming RS, Update on fungal respiratory disease in horses, Vet Clin North Am Equine Pract. 2015;31:43-62.
4. Weinstein WL, Moore PA, Sanchez S et al., In vitro efficacy of a buffered chelating solution as an antimicrobial potentiator for antifungal drugs against
fungal pathogens obtained from horses with mycotic keratitis, Am J Vet Res. 2006;67:562-568.
5. Ziemer EL, Pappagianis D, Madigan JE et al., Coccidioidomycosis in horses: 15 cases (1975-1984), J Am Vet Med Assoc. 1992;201:910-916.
6. Davis JL, Salmon JH, Papich MG, Pharmacokinetics and tissue distribution of itraconazole after oral and intravenous administration to horses, Am J Vet
Res. 2005;66:1694-1701.
7. Davis JL, Little D, Blikslager AT et al., Mucosal permeability of water-soluble drugs in the equine jejunum: a preliminary investigation, J Vet Pharmacol
Ther. 2006;29:379-385.
8. Latimer FG, Colitz CM, Campbell NB, et al., Pharmacokinetics of fluconazole following intravenous and oral administration and body fluid concentrations
of fluconazole following repeated oral dosing in horses, Am J Vet Res. 2001;62:1606-1611.
9. Reilly LK, Palmer JE, Systemic candidiasis in four foals, J Am Vet Med Assoc. 1994;205:464-466.
10. Davis JL, Salmon JH, Papich MG, Pharmacokinetics of voriconazole after oral and intravenous administration to horses, Am J Vet Res. 2006;67:1070-1075.
11. French DD, Haynes PF, Miller RI, Surgical and medical management of rhinophycomycosis (conidiobolomycosis) in a horse, J Am Vet Med Assoc.
1985;186:1105-1107.
12. Zamos DT, Schumacher J, Loy JK, Nasopharyngeal conidiobolomycosis in a horse, J Am Vet Med Assoc. 1996;208:100-101.
13. Scott DW. Fungal skin diseases. In: Saunders-Elsevier ed. Equine Dermatology. 2nd ed. St. Louis (MO), 2003;311-312.
Although iodide-containing agents have limited evidence disease may demonstrate a positive response to appropriate
to demonstrate efficacy against fungal pathogens, they have therapeutics, but because of the multitude of factors that may
apparent effectiveness against some granulomatous diseases be involved with host status these must also be considered.
and are thought to provide benefit through antiinflammatory In cases where disease is advanced, complicating factors are
properties. Advantages of iodide therapy include that these are marked and/or therapeutic options are limited, prognosis for
cost-effective agents and for this reason are often administered disease resolution may be more guarded.
to equine patients with fungal disease, commonly in combina-
tion with other therapies (Table 8.8). Y PARASITIC PNEUMONITIS
The overall prognosis for horses suffering from fungal
disease involving the respiratory system is dependent on a Parasitic pneumonia is a condition that may affect foals or
variety of factors that include infecting agent, host immune adult horses. Parasites associated with this condition include
status, primary disease process, the stage of the disease at the Parascaris equorum larvae or the adults of Dictyocaulus arn-
time of diagnosis, and owner commitment to invest in newer fieldi. Clinically affected horses have obvious evidence of
generation antifungal agents when indicated. Collectively, respiratory disease that includes exercise intolerance and
in some instances horses suffering from mycotic pulmonary coughing that may be accompanied by nasal discharge, fever,
and depression, particularly when secondary bacterial infec- equorum infection include an initial low dose of fenbendazole
tion has occurred. P. equorum infection is most common in (5 mg/kg). Careful monitoring for approximately 24 hours is
foals and weanlings, particularly those raised on breeding recommended to observe the foal for evidence of deterioration
farms in which the parasite resides in the environment and or gastrointestinal distress. Laxative therapy may be required
soil. Dictyocaulus infection may occur in horses of any age, but if gastrointestinal ascarid impaction is suspected. After the
this parasite requires a donkey as a primary host to complete foal has received an initial low dose of fenbendazole without
its life cycle. complication, the dose can be increased (10 mg/kg PO daily)
and this therapy can be repeated daily for 5 days. This therapy
Clinical Findings will be effective in killing adult and migrating larvae. Because
Chronic coughing, mucoid to mucopurulent nasal discharge, this is a farm problem, other individuals on the same property
respiratory distress, and poor overall body condition proof similar age should be managed appropriately, even if clini-
vide nonspecific evidence of parasitic disease in foals. Poor cal evidence of disease is not apparent. Other anthelmintics
body condition, abnormal pulmonary sounds represented that have been used include pyrantel pamoate (6.6 mg/kg) and
by increased bronchovesicular sounds, crackles, and wheezes ivermectin (200 μg/kg). D. arnfieldi infection can be success-
are common findings on thoracic auscultation of horses with fully treated with ivermectin (200 μg/kg), moxidectin (adult
parasitic pneumonia. Poor body condition is a common find- horses only, 400 μg/kg), thiabendazole 440 (mg/kg/day twice),
ing because of intestinal involvement of parasitic infection. or levamisole (10 mg/kg).
Colic may be a component of the history or may result fol- Benzimidazole anthelmintic agents inhibit microtubule
lowing therapeutic anthelmintic treatment in severely affected formation, which impairs the parasite’s ability to move and
individuals. Frequently the history also includes a poor ingest food. Energy metabolism is also impaired because
response to appropriate antimicrobial therapy for suspected of the inhibition of fumarate reductase.414 Although many
bronchopneumonia. benzimidazoles are efficacious against intestinal larvae, they
are not uniformly effective at killing migrating parasite larvae;
Diagnosis however, at higher doses fenbendazole is safe and effective at
Hematologic evaluation commonly reveals an inflammatory killing intestinal and tissue larvae. Anecdotal and personal
leukogram consisting of a mature neutrophilia, hyperfibrino- observations have suggested this anthelmintic to be highly
genemia, and hyperglobulinemia. In some instances, partic- efficacious, particularly in cases where ivermectin resistance
ularly early in the course of disease, hematologic evaluation is suspected.
may reveal few abnormalities. Hepatic parasitic migration Pyrantel pamoate is an acetylcholine agonist that results
(P. equorum) may result in mild to moderate hepatic enzyme in parasite paralysis.415 At the recommended dose this agent
elevation.413 Thoracic radiography is a useful diagnostic test in is effective at killing intestinal larvae but not migrating lar-
affected individuals. A moderate to severe bronchointerstitial vae.413,414 Avermectins are effective because they bind gluta-
pattern is a common finding, whereas granuloma or abscess mate-gated chloride channels, and this class is effective against
formation may be detected by radiographs with advanced dis- both P. equorum and D. arnfieldi adults and migrating lar-
ease. Thoracic ultrasonographic examination will allow the vae. Ivermectin has a reported efficacy of 76.9% for removal
clinician to detect the presence of pleural fluid or peripheral of intestinal P. equorum and is 100% effective for removal of
pulmonary consolidation. pneumonic larvae.414,416 Overall, ivermectin and moxidectin
Cytologic examination of a sterile tracheobronchial aspi- have similar efficacy as effective anthelmintics in horses for
rate will often reveal abundant eosinophils (5–50%, normal many gastrointestinal parasites other than Anoplocephala per-
<2%), and neutrophilic inflammation may exist concurrently, foliata.417 Based on these reports regarding anthelmintic effi-
particularly when secondary bacterial infection is present. cacy, recommendations include combining therapeutic agents
Microorganisms are apparent with significant bacterial infec- to maintain maximal efficacy. Initial treatment with fenbenda-
tion; culture is recommended to determine the presence of zole (10 mg/kg orally daily for 5 days) followed in 14 days with
bacterial infection and to determine the antimicrobial sensi- an avermectin product at the appropriate dose should clear the
tivity pattern for pathogens of concern. Fecal flotation is indi- individual of both intestinal and pneumonic parasites.
cated to determine the presence of parasite ova being shed
from the host. D. arnfieldi requires a donkey or mule host for Prognosis
life cycle completion; therefore, parasite eggs will only infre- Foals or adult horses with primary parasitic pneumonia and
quently be detected in adult horses with lungworm infection. secondary bacterial infection will require concurrent anti-
It is difficult to diagnose P. equorum infection on fecal flotation biotic and anthelmintic therapy. The prognosis is excellent
because tissue migration occurs during the prepatent period. for recovery from parasitic pneumonitis. It is important to
Therefore, diagnosis is based on clinical signs, lack of evidence emphasize the need for complete deworming, including don-
of bacterial infection, and tracheal wash cytology indicating keys and mules, because they harbor the adult Dictyocaulus
eosinophilic pneumonitis. Response to therapy is supportive parasites that serve as a source for parasite contamination and
of the diagnosis, although antibiotic therapy may be required infection of horses in the immediate environment.
in combination with anthelmintic therapy.
Therapy Y RECURRENT AIRWAY OBSTRUCTION
Severely hypoxemic patients may require oxygen insufflation.
Severe pulmonary inflammation is induced by eosinophilic Clinical Presentation
infiltrates necessitating bronchodilator and potentially aero- Equine RAO (heaves and severe equine asthma418) causes a
solized corticosteroid therapy (see previous recommenda- reproducible series of clinical signs in affected horses. RAO is
tions on aerosol therapy). Oral anthelmintics used to treat P. a common cause of performance impairment characterized by
a chronic cough, serous to mucoid nasal discharge, and epi- BAL cytology will provide diagnostic confirmation of
sodic respiratory distress. Clinical signs are often seasonal and pulmonary inflammation in horses with mild to moderate
more intense when horses are housed indoors and exposed to disease. BAL is recommended as the appropriate diagnostic
dust, poor-quality hay, ammonia fumes, fungal spores, and method to obtain samples for cytologic analysis. Compared
other nonspecific stimuli.418-420 Horses with RAO are typically with samples obtained with TTW aspiration, BAL sampling
mature adults, and the average age of horses with RAO is >7 provides more representative diagnostic information regard-
years of age.421 ing the status of cellular infiltrate into the lower airway secre-
There is no breed or gender predilection, but there is an tions. There is poor correlation using the criteria for RAO
apparent heritable component to disease development, partic- diagnosis of >5% neutrophils in a BAL sample compared
ularly in certain lines of breeds such as Warmblood horses in with >20% neutrophils in a tracheal aspirate sample. It is
Europe.422-424 Although these studies have demonstrated that well recognized that a great deal of variability can be identi-
in some lines the heritability of RAO is more clearly defined, fied in the cellular composition of tracheal fluid, which is in
the overall mode of inheritance for RAO is not completely contrast to samples from the lower airways obtained by BAL
understood and is presumed to be complex. A question that sampling.426 When sampling is performed using the BAL
has challenged equine clinicians for many years has involved protocol, specifically when marked inflammation is present,
the potential relationship between pulmonary inflammation there may be a reduction in sample volume obtained result-
in the form of IAD leading to the subsequent development ing from airway collapse distal to the tube or endoscope.17
of RAO. Additional information that may contribute to the In such instances, low aspiration pressures should be applied
complexity and understanding of these conditions relates to in an effort to reduce distal airway collapse. In addition to
the current terminology of equine airway inflammation classi- difficulty with sample collection, the quality of sample col-
fied as mild to moderate asthma in horses suffering from IAD lected should be inspected. In horses where airway collapse
and severe equine asthma in horses with RAO. An incomplete has occurred the amount and quality of surfactant collected
understanding of disease pathophysiology may lead an indi- may be reduced. Interpretation of cytologic findings support
vidual to assume that these conditions are directly linked. In RAO when neutrophilic inflammation (>5% neutrophils) is
reality, there is insufficient evidence to provide a direct rela- found on BALF cytology. Cellular morphology is generally
tionship that a horse with IAD will develop RAO in later life. normal and classified as nondegenerate without evidence of
Current evidence supports that horses with cough associated sepsis. Mucus is commonly abundant in cytologic analysis
with pulmonary mucus and inflammatory cell accumulation of horses suffering from RAO and deeply stained casts of
are at risk for the development of RAO,425 and there is insuf- inspissated mucus (classified as Curschmann’s spirals) may
ficient evidence to demonstrate that there is a clear transition be reported. However, mucus may be identified with other
from IAD to RAO.418 Summer pasture-associated obstructive conditions that can lead to pulmonary inflammation, reduc-
pulmonary disease (SPAOPD) is a syndrome similar to heaves ing the specificity of this independent finding. The diagno-
or severe equine asthma; however, the clinical signs are trig- sis of RAO is more difficult when clinical signs are mild and
gered by exposure to late summer pollens in the southeast- exhibited by an occasional cough or minimal abdominal
ern United States. The primary difference between heaves and effort. Rebreathing is a simple procedure that will enhance
summer-associated disease is the local climate with expo- pulmonary sounds on auscultation, but in horses with less
sure to specific allergens that induce clinical signs of airway severe disease, ancillary diagnostics are required. When pul-
obstruction. The presenting complaint for horses with severe monary function testing is performed on horses with severe
equine asthma varies but often includes a chronic cough. Exer- equine asthma, they typically demonstrate an increased
cise intolerance, respiratory distress, mucopurulent nasal dis- change in pleural pressure ΔPLmax (>15 cm H2O), increased
charge, abnormal pulmonary sounds, and an enlarged field of pulmonary resistance (RL), and decreased dynamic lung
percussion may also be identified. compliance (Cdyn).427-430 Although standard pulmonary test-
ing is not sensitive enough to detect mild airway obstruction
Diagnosis when RAO patients are in remission, horses with RAO have
Typically the diagnosis of RAO is based on supportive histori- histologic evidence of pulmonary disease. These findings
cal information and physical examination findings. Complete indicate that although clinical signs are recurrent, and the
blood count and serum chemistry analysis are generally unre- patient may be in remission, pulmonary disease is perma-
markable in horses without comorbid disease. Thoracic radi- nent and pulmonary function is negatively impacted, par-
ography is not indicated for routine diagnosis of heaves, but if ticularly when exacerbation is present.
a horse fails to demonstrate expected clinical improvement to Therapeutic goals of horses suffering from RAO include
appropriate pharmacologic therapy and environmental modi- improved pulmonary function through the attenuation of
fication, then additional diagnostics should include thoracic airway inflammation and bronchial wall hyperresponsiveness
radiography. Thoracic radiography is an important diagnos- leading to marked bronchoconstriction. The central factor
tic modality to determine whether marked interstitial disease for disease control is environmental modification that limits
exists. Therefore, in horses suspected to have bronchointersti- (preferably eliminates) allergen exposure. The removal of the
tial pneumonia or multinodular pulmonary fibrosis, thoracic environmental allergen is a key feature to achieving disease
radiography is indicated. Characteristics of the respiratory remission in horses suffering from heaves. Medical therapy
pattern should provide the clinician with evidence of marked aimed at attenuation of clinical signs associated with pul-
fibrosis or interstitial disease resulting in restrictive pulmo- monary inflammation and bronchoconstriction will provide
nary disease, which would be characterized by marked inspi- temporary clinical benefit. If environmental modification is
ratory distress compared with the RAO-affected horse that insufficient, disease exacerbation will occur once drug dos-
demonstrates marked expiratory effort caused by air trapping ages are reduced. Synthetic corticosteroid administration
and expanded pulmonary fields. will aid with reduction in pulmonary inflammation, and
bronchodilator therapy will open airways, improving pulmo- improves pulmonary function in horses with RAO. Triam-
nary function as a rescue therapy, and should be continued cinolone acetonide (0.09 mg/kg intramuscularly) as a single
concurrently with corticosteroid therapy until bronchodila- dose relieves lower airway obstruction for up to 4 weeks.
tion is achieved. However, this protocol also results in adrenal suppression for
The goal of therapy is to reduce airway inflammation and up to 4 weeks.437 Triamcinolone has also been demonstrated
bronchoconstriction while enhancing mucociliary clearance to induce hyperglycemia and hypertriglyceridemia for up
mechanisms. Corticosteroids and bronchodilator therapy to 4 days following drug administration.438 Dexametha-
are used regularly for treatment of RAO. The most common sone (0.1 mg/kg IV q 24 h) reduces airway obstruction and
environmental allergens leading to exacerbation of RAO signs inflammation within 3 to 7 days with clinical benefit evident
include airborne particulate material that is in extraordinarily for up to 7 days.439 Administration of dexamethasone also
high concentrations in most stable environments. Apparently produces adrenal suppression; however, this effect lasts for
clean and fresh hay typically contains mold spores such as approximately 3 days after discontinuation of treatment.18
Aspergillosis fumigatus, Faenia rectivirgula, and Thermoacti- Oral prednisolone has favorable bioavailability and improves
nomyces vulgaris.419,431 In addition to environmental molds, clinical signs of airway inflammation, but compared with IV
environmental endotoxin and ammonia are recognized to dexamethasone does not provide the same antiinflammatory
contribute to induction of airway inflammation.432,433 Round effect based on BALF cytologic examination.440 Oral pred-
bale hay is exposed to repeated environmental moisture and nisone demonstrates limited efficacy for resolution of clini-
contains high levels of airway allergens when fed to RAO- cal signs associated with RAO. Nor does this therapy reduce
affected horses maintained on pasture. Horses that are stabled pulmonary inflammation in horses with moderate to severe
will have an improved local environment if provided with disease.441 NSAIDs and antihistamines are ineffective for
ample ventilation, a clean stall with low-dust bedding material, treatment of RAO.442
and commercial pelleted feed (low dust) that contains mini- Inhaled corticosteroids provide an effective treatment
mal allergens and particulate materials. Moistened hay pellets, alternative for mild to moderately affected RAO horses.
cubes, or silage may provide alternate roughage sources for Beclomethasone (500–1500 μg b.i.d.) reduces pulmonary
horses with airway-related inflammation. Commercial rough- inflammation, improves pulmonary function, and improves
age products such as hydration hay are becoming increasingly ventilation imaging of horses suffering from RAO.443 In con-
available with the advent of small-sized baled hay that can be trast to rescue bronchodilator therapy, no immediate drug
soaked and fed from a 5-gallon bucket. These products have effect is observed with aerosolized corticosteroids.18 Aero-
the advantage of high-quality roughage with the introduc- solized medications can effectively be administered with
tion of limited allergens and airborne particles. Soaking of a spacer device such as the Equine Haler (Jorgensen Labs,
long-stem hay is an option for management of mildly affected Inc.) or the AeroHippus (Trudell Medical International).
horses but will not provide sufficient reduction of allergen Investigations aimed at comparison of delivery systems have
exposure for highly sensitive individuals. Management of revealed similar efficacy.444 Clinical improvement is appar-
heaves-affected horses should take into account all triggers. ent approximately 24 hours following initiation of therapy.
Although dust particles are not a specific allergen, horses with Administration of beclomethasone (3200 μg b.i.d.) using
airway inflammation will benefit from a low-particle environ- the Equine Haler device improves parameters of pulmonary
ment.434 Avoidance of indoor arenas, housing near a rock or function and arterial oxygen tension approximately 3 to 4
dirt road, or maintenance in a dry lot pen should be avoided days after initiation of therapy.1 Among the variety of avail-
in an effort to remove all particles from the breathing zone of able inhaled corticosteroid preparations, fluticasone is the
affected horses. most potent with the advantage of lowest adrenosuppressive
effects.9,11,13 Reduced pulmonary neutrophilia, improved pul-
Antiinflammatory Therapy monary function, and reduced airway hyperresponsiveness
The cornerstone of remission of clinical signs in horses suf- are significantly improved following fluticasone administra-
fering from RAO is reduced inflammation. It is well recog- tion (2000 μg t.i.d.).445-447 Although inhaled corticosteroids
nized that the inflammatory cytokines released by activated are particularly useful for resolution of airway obstruction,
T lymphocytes increase the pulmonary concentration of IL-4 unless environmental modification is implemented, clinical
and IL-8.435,436 The recruitment of neutrophils, particularly in signs of obstructive disease will return within 2 to 4 days after
response to the potent chemokine IL-8, maintains a height- discontinuation of therapy.
ened level of immune reactivity in this environment, con- Aerosolized corticosteroids are effective in horses with
tributing to enhanced mucous production, bronchospasm, mild to moderate airway obstruction, with clinical signs rang-
and coughing. Corticosteroids act as direct inhibitors of this ing from exercise intolerance to respiratory distress while at
inflammatory cycle, resulting in improved clinical signs. The rest. Aerosolized drugs provide the benefit of drug delivery
combination of corticosteroids with bronchodilator therapy is directly to the respiratory tract but represent a more substan-
the most effective method to induce disease remission. It is tial financial investment and may be reserved for valuable or
important to consider that long-acting potent corticosteroids performance horses. Currently, there are three aerosolized
are more likely to produce detrimental effects such as laminitis corticosteroid preparations available in metered dose inhaler
and immunosuppression. Therefore, therapeutic recommen- preparations: beclomethasone dipropionate, fluticasone pro-
dations include using the lowest effective dose and avoiding pionate, and flunisolide. The relative potency of these surface-
prolonged therapeutic administration. In many cases, a course acting corticosteroids are fluticasone > beclomethasone >
of therapy for approximately 2 weeks is sufficient to induce flunisolide = triamcinolone. When considering dexametha-
clinical remission. sone as a standard of 1, flunisolide = 1.9, triamcinolone = 2.0,
Systemic administration of potent corticosteroids beclomethasone = 13.5, and fluticasone = 18.0. When com-
improves clinical signs, reduces airway inflammation, and paring the commercially available corticosteroid products,
fluticasone is the most potent and the most expensive. Fluti- change in pleural pressure observed in heaves-affected horses
casone is highly lipophilic, which results in the longest pul- treated with bronchodilator therapy.2,5,19 The most consistently
monary residence time. Because fluticasone has extremely effective bronchodilators are β2-adrenergic agonists and anti-
low oral bioavailability (<2%) and extensive first pass metabo- cholinergic agents. Methylxanthines are less reliable for pro-
lism (99%), fluticasone has the advantage of the least poten- viding positive results and have a narrow therapeutic index.
tial for adverse systemic side effects and the most favorable Heaves-affected horses stabled in a dust-free environment
therapeutic index of the commercially available aerosolized demonstrate a positive response to bronchodilator therapy,
corticosteroids. Horses suffering from RAO and receiving suggesting that environmental management alone will not
fluticasone (2000 μg t.i.d.) demonstrate reduced pulmonary completely resolve the bronchoconstrictive component of
neutrophilia, improved pulmonary function assessment, and heaves.15
reduced responsiveness to histamine challenge during epi- The pathogenesis of bronchospasm in horses with recur-
sodes of airway obstruction.29 When healthy horses are evalu- rent airway disease appears to be primarily vagally mediated
ated following administration of fluticasone, serum cortisol and may involve soluble mediators such as serotonin, hista-
levels are reduced by 40% following 1 day of therapy and 65% mine, and leukotriene D4.12,15 Defective inhibitory pathways
following 1 week of treatment. Serum cortisol concentrations of airway smooth muscle have been suggested to play a role
return to pretreatment levels approximately 24 to 48 hours fol- in the development of bronchospasm. β-Adrenergic agonists
lowing discontinuation of drug therapy. Beclomethasone is serve as inhibitors of smooth muscle contraction through the
the first line of aerosolized corticosteroid therapy for moder- release of nitric oxide from inhibitory nonadrenergic noncho-
ate to severe allergic airway disease in human patients. Beclo- linergic (iNANC) nerves and release of inhibitory prostanoids
methasone (500–1500 μg t.i.d.) results in reduced pulmonary such as prostaglandin 2 (PGE2) from the airway mucosa. Dur-
inflammation, improved parameters of pulmonary function, ing episodes of acute RAO, iNANC-mediated relaxation is not
and improved ventilation imaging of horses with RAO.1,11,13,18 present, and the prostanoid profile shifts from an inhibitory
Although immediate effects are not observed following one to a stimulatory one.15
administration of beclomethasone, clinical signs and pulmo- Smooth muscle contraction, smooth muscle hypertro-
nary function begin to improve within 24 hours of adminis- phy, and mucosal thickness all contribute to airway narrow-
tration. Administration of beclomethasone (3750 μg t.i.d.) ing and subsequent air trapping. Pulmonary remodeling in
improves pulmonary function and arterial oxygen tension for heaves-affected horses includes mucous cell hyperplasia and
about 2 weeks. When housed in an allergen-rich environment, metaplasia that contributes to the cascade of smooth muscle
pulmonary function parameters return to pretreatment val- contraction leading to luminal contraction and narrowing.
ues within 3 to 7 days following discontinuation of drug ther- Bronchodilator therapy has remained a mainstay of heaves
apy.18 Subsequently, it can be concluded that if environmental treatment, and resolution of severe airway distress requires
management is not addressed, clinical resolution will not be administration of rapid-acting bronchodilators.9,11,13
maintained when beclomethasone treatment is used without Increasing luminal diameter should not be the only focus
environmental modification. of therapy. Antiinflammatory therapy is required to reduce
Despite the fact that human asthma patients remain on exudate and prevent bronchoconstriction. Inflammation is
inhaled corticosteroids for extended periods without the det- recognized to be the underlying pathophysiological process
riment of adrenosuppression, horses have increased sensitiv- in all cases of bronchoconstriction, and daily antiinflamma-
ity to the adrenosuppressive effects of inhaled corticosteroids. tory therapy will mitigate potential disease exacerbation and
Endogenous cortisol production is reduced in horses treated reduce the requirements for bronchodilator therapy. Corti-
with beclomethasone (>1000 μg b.i.d.)18 or fluticasone (2000 costeroids are recognized to be the only drug class to dem-
μg b.i.d.)29 with the threshold for beclomethasone of approxi- onstrate substantial modification of allergic airway disease
mately 500 μg b.i.d. The adrenosuppressive effects have been in human asthmatic patients. Chronic administration of β2-
observed to last for approximately 2 days following discontin- adrenergic agonists alone produce deterioration in pulmonary
uation of drug therapy. Interestingly, the therapeutic efficacy function, increased airway responsiveness, and more frequent
of beclomethasone (500 μg b.i.d.) is approximately equal to exacerbations of bronchoconstriction.
larger doses, suggesting that horses can be treated at an effec- Aerosolized, short-acting β2-adrenergic agonists (albuterol,
tive dose with the least adrenal suppression being induced pirbuterol, and fenoterol) are rapidly effective bronchodila-
when environmental modification is implemented.18 tors indicated for “rescue therapy” for horses demonstrating
respiratory difficulty at rest.2,5,19,24 Albuterol sulfate (360 μg)
Bronchodilator Therapy improves pulmonary function by 70% within 5 minutes of
Pulmonary bronchoconstriction associated with RAO requires administration.5,19 When severe airway obstruction is pres-
specific therapy for immediate relief of smooth muscle con- ent, drug administration at 15-minute increments for up to
traction in the lower airways. Symptomatic bronchodilator 2 hours may be implemented for sequential bronchodilation.
therapy will improve clinical signs; however, lower airway Beneficial effects from short-acting β2-adrenergic agonists last
inflammation is not altered by bronchodilator administration. approximately 1 hour in severely affected horses, resulting in
Bronchodilator therapy is primarily indicated for immediate the need for longer acting preparations. Combination therapy
relief of bronchoconstriction (rescue therapy).2,5,19,24 The rapid with corticosteroids will reduce the tolerance that develops to
onset of action of an aerosolized bronchodilator consistently these agents in addition to enhancing β2-adrenergic receptor
provides immediate relief of bronchoconstriction. The most protein expression.11,13,18
effective agents available for bronchodilation are β2-adrenergic Long-acting bronchodilator preparations are ineffective
agonists and parasympatholytic agents. for use as rescue treatment in patients suffering from severe
Clinical improvement associated with bronchodilator airway obstruction caused by delayed onset of activity and
treatment is characterized by reduced pulmonary resistance, slightly reduced peak activity compared with albuterol sul-
increased pulmonary compliance, and decreased maximal fate.10,20 Salmeterol xinafoate is a chemical analog of albuterol
with an elongated side chain providing a longer duration of SPAOPD is a condition similar to RAO regarding clini-
action. Salmeterol xinafoate (210 μg) improves pulmonary cal signs and management; however, a marked difference in
function by 55% within 60 minutes of administration with disease development involves the triggering aeroallergen
efficacy lasting for up to 8 hours, even in severely affected involving molds and pollens from pasture grasses. Disease
horses.10,11 Ipratropium bromide is a surface-acting antimus- development of SPAOPD is similar with respect to the devel-
carinic agent that exhibits little to no systemic absorption opment of hypersensitivity; however, the antigenic stimulus
(quaternary ammonium structure) from the respiratory or involves pasture forage pollens that have been recognized in
gastrointestinal system. Ipratropium (90–180 μg) improves the Gulf Coast states in the United States and in England.450,451
pulmonary function by 50% within 1 hour, and the duration Weather conditions that favor exacerbation for sensitized
of the effect is approximately 4 to 6 hours in severely affected horses include hot, humid weather that most commonly
patients. Oral clenbuterol (0.8 μg/kg, PO, b.i.d.) is a systemic occurs in late summer.452,453 Evidence has demonstrated that
alternative to the aerosolized, long-acting bronchodilators for specific environmental conditions that contribute to the exac-
management of RAO-affected horses. Clenbuterol is prepared erbation of SPAOPD include not only temperature but also
for oral administration as a syrup (Ventipulmin, BIVI). A sig- humidity, which affect concentration of fungal spores, sea-
nificant advantage to clenbuterol is a longer duration of action sonal vegetative growth, and pollination of plants in the pas-
(12 hours). Clenbuterol is approved by the Food and Drug ture environment.453,454
Administration (FDA) in the United States for use in horses Bronchodilator and antiinflammatory therapy are rec-
with airway constriction. It should be noted that clenbuterol ommended in combination with relocation to a clean,
is illegal for use in food-producing animals.1,2 Dosing proto- low-dust environment. Eliminating or reducing access
cols for clenbuterol should be followed carefully and in accor- to an antigen commonly requires a well-ventilated stable
dance with manufacturer recommendations. Initial therapy at environment. Clinical signs are similar to those associ-
the lower end of the dosing range is generally well tolerated, ated with traditional RAO. The clinical management of
and incremental dose increases may be tolerated. However, SPAOPD involves removal from pasture, whereas in tradi-
inadvertent initial high-dose therapy (3.2 μg/kg) may result tional RAO the preferred environment is full-time pasture
in tachycardia, tremors, sweating, and apparent anxiety. Clen- access. Interestingly, some horses manifest airway obstruc-
buterol administration is indicated for temporary smooth tion under specific environmental conditions such as tra-
muscle airway relaxation in association with airway disease; ditional RAO in which a closed barn environment favors
prolonged therapy is not indicated and may result in adverse disease exacerbation, whereas in the southeastern United
effects. States a warm humid outdoor environment results in clini-
cal signs of respiratory distress. The particularly challeng-
Alternate Bronchodilatory Options ing component of managing any horse with allergic airway
N-butylscopolammonium bromide (NBB; Buscopan) is a disease is to specifically determine the inciting cause of
quaternary ammonium that serves as a peripherally acting disease so antigen avoidance can be used. In horses that
antimuscarinic, anticholinergic agent similar in action to atro- react to a multitude of environments with clinical signs of
pine. This formulation is marketed by BIVI as Buscopan for airway obstruction, maintaining a horse in a state of consis-
administration to horses. NBB is FDA approved in the United tent disease remission can be particularly challenging. The
States for use in horses that demonstrate colic signs result- similarity among disease development and the recognition
ing from gas, spasms, or mild impactions. Recent work has that SPAOPD may also demonstrate sensitivity to allergens
focused on the potential utility of NBB administration for the in a confined environment such as hay and straw dust and
treatment of marked airway obstruction that may occur with molds support the suggestion that minimizing these expo-
conditions of airway inflammation such as RAO. Current evi- sures should also be avoided.
dence provides support for the use of NBB as an immediate
bronchodilator.429,448 Although tachycardia and reduced gas-
trointestinal motility are valid considerations, based on the Y INFLAMMATORY AIRWAY DISEASE
short duration of activity and evidence to support improved
ventilatory function it is considered an appropriate therapeu- Clinical Presentation
tic option when managing equine patients with severe airway IAD (mild to moderate equine asthma418) can develop in
obstruction. Additional evidence to support the use of NBB horses of all ages. In contrast to RAO, clinical signs of IAD
in horses suffering from airway obstruction is supported be a are typically subtle, particularly at rest. Horses with IAD tend
crossover investigation in RAO-affected horses in which atro- to be younger horses compared with horses that suffer from
pine and NBB provided similar bronchodilatory effects, yet RAO, but clinical signs of IAD are dependent on the extent of
the systemic effects, such as pupillary dilation and one horse physiologic exertion. The presenting complaint may include
developing colic signs, were only observed following atropine poor performance, particularly at exertion, with occasional
administration.449 From this study it was concluded that NBB cough. Frequency of cough in horses with IAD is variable. In
bromide was associated with fewer systemic side effects and is some reports cough has been used as a measure of inclusion
therefore a preferred treatment for reversible airway obstruc- criteria,455 which complicates the determination of the over-
tion in horses. Atropine (0.005–0.01 mg/kg horse, IV) is a all frequency of cough in horses with confirmed IAD.419 At
rapid and powerful bronchodilator in horses suffering from rest, horses with IAD do not demonstrate any discernable evi-
heaves. Because several adverse effects (ileus, CNS toxicity, dence of respiratory dysfunction. Pulmonary inflammation in
tachycardia, increased viscosity of mucous secretions, and horses that suffer from IAD is mild, requiring advanced pul-
impaired mucociliary clearance) may develop following the monary function testing to detect alteration in gas exchange
administration of atropine, use of this agent is recommended mechanisms. However, similar to RAO, horses with IAD typi-
as a rescue therapy for severe and life-threatening airway cally have airway mucus accumulation, which can be marked
obstruction. in severe cases. Current recommendations have focused on
the identification of lower airway cytologic characteristics that examination, and findings on airway endoscopic examination
define the inflammatory milieu of the lower airway in combi- in combination with the cytologic analysis.
nation with pulmonary function testing.418 Collectively these It is important to note that the interpretation of cytologic
criteria provide the clinician with direct evidence with respect findings should be carefully considered in association with the
to the origin of reduced exercise performance.32,456-458 Differ- patient. It has been long recognized that age, vocation, and
ent phenotypes of airway inflammation have been described environment can play a role regarding cellular changes in the
for horses with IAD and have apparent correlation with dis- respiratory tract. In a recent study young horses transition-
ease severity. Mast cell inflammation has been observed ing to a race-training environment were recognized to have
in association with airway hyperreactivity459 and subclini- abnormal BALF cytologic analysis after 4 weeks in race train-
cal airway obstruction, whereas airway neutrophilia has ing.433 Although the horses were not tested for pulmonary
been observed in association with cough and airway mucus function changes, the actual clinical implications for these
accumulation.418,459 cellular changes cannot be made. This investigation high-
lights the importance of environment, particularly in young
Diagnosis horses entering race training that may not have any measur-
Diagnosis of IAD (mild to moderate equine asthma) is based able changes in training performance but may have cytologic
on clinical signs, airway inflammation with excess mucus, changes occurring in their lower airways. In other words,
abnormal lower airway cytologic evaluation, or abnormal looking at lower airway BALF cytology independent of other
pulmonary function. It must be confirmed that horses with factors may lead to overinterpretation of clinical association.
IAD do not suffer from RAO or infectious pulmonary dis- Sample collection is also an important consideration, which
ease. Identification of clinical signs consistent with lower has been well reported in the literature. When examination of
airway inflammation are characterized by reduced athletic a suspect IAD horse is performed, sample collection must be
performance and mild cough and airway mucus identified on restricted to the use of BALF analysis. Although in some set-
endoscopy (Table 8.9). Other consideration should be given tings collection of a transtracheal aspirate may provide greater
to causes for poor performance such as upper airway disease ease and efficiency of collection, based on the lack of correla-
or musculoskeletal disease or injury. tion between TTW and BALF cytology,426,464,465 TTW sample
BALF cytology is the diagnostic test sampling procedure of collection for cytologic analysis for the diagnosis of IAD is not
choice for a confirmatory diagnosis of IAD. Although the cyto- recommended.418
logic profile of BALF analysis in horses with RAO is markedly Additional diagnostics that may be completed for a
neutrophilic, horses with IAD typically have a cytologic pro- horse with suspect IAD may include complete hematologic
file characterized by mild to moderate increase in neutrophil, and serum chemistry profile analysis, pulmonary func-
eosinophil, and/or mast cell percentages.418,457,460 Variability tion testing, and thoracic imaging to include ultrasound
among sampling techniques and instrumentation prevents the and radiography. Hematologic changes are rarely abnormal
application of universal cutoff limits for the classification of in horses with IAD with the exception of horses suffering
IAD. Based on the availably body of literature, when 250 mL of from eosinophilic IAD, which may also be associated with
sterile saline is infused the approximate findings should include peripheral eosinophilia,466 particularly if the horse is suf-
a total cell count of ≤530 cell/μL, neutrophils ≤5%, eosinophils fering from idiopathic eosinophilic pneumonia, although
≤1%, and metachromatic (mast) cells ≤2%. When interpreta- circulating changes in eosinophilic concentrations are not
tion of cytologic values are based on total percentages, regard- always present in horses with airway eosinophilia.433 Sensi-
less of volume of fluid instilled, findings consistent with IAD tive pulmonary function testing that includes forced expira-
include neutrophils >10%, mast cells >5%, and eosinophils tion and impulse oscillometry provides evidence that horses
>5%.418,460-463 Collectively the interpretation of BALF cytology with IAD suffer from airway obstruction.33,460 Because
needs to be based on the patient history, clinical signs, physical advanced pulmonary function testing requires specialized
instrumentation and training, diagnostic testing is limited
to specialty services that provide such testing. Reproducible
TABLE 8.9 Tracheal Mucus Grading Scale1,2 characteristics of eosinophilic and mast cell–associated IAD
include clinical evidence of airway hyperresponsiveness to
Grade Mucus Accumulation
airway particles. Clinical manifestation of airway reactivity
0 None includes bronchoconstriction, airway reactivity, and cough,
1 Multiple small which represent the physiologic response to irritants that
2 Moderate larger, non-confluent alter pulmonary homeostasis, resulting in reduced pulmo-
3 Marked mucus nary function, particularly at speed. Based on the recogni-
tion that there are similarities and differences between IAD
Marked - confluent
and RAO, clinically practical observations can be made to
Marked - stream forming aid the clinicianin discriminating between these two airway
4 Large pool-forming disorders.418 Specifically, a horse with evidence of airway dis-
5 Extreme, profuse amounts ease can be placed in a challenge environment of moldy hay
and observed for evidence of respiratory distress or difficulty.
1. Gerber V, Lindberg A, Berney C, et al., Airway mucus in Although horses that suffer from IAD will have cytologic
recurrent airway obstruction—short-term response to envi- changes and increased mucous production in their lower
ronmental challenge, J Vet Intern Med. 2004;18: 92-97. airways, they will not demonstrate evidence of respiratory
2. Couetil LL, Cardwell JM, Gerber V, et al., Inflammatory air- distress. In contrast, a horse that suffers from severe equine
way disease of horses-revised consensus statement, J Vet asthma will demonstrate increased expiratory effort, cough,
Intern Med. 2016; and nostril flare when placed in the challenge environment.
Treatment clinical signs, BALF cytology, and pulmonary function. Sys-

Clinical management of horses suffering from IAD has some temically administered dexamethasone appears to provide
similarities to the management of horses with RAO. Interest- superior antiinflammatory effects as evidenced by improve-
ingly, published evidence to support therapeutic protocols are ment in pulmonary cellular infiltrate compared with pred-
more limited when demonstrated efficacy for the management nisolone468 in an antigen-controlled investigation. In an
of IAD is compared with the efficacy of therapy for RAO.418,419 independent investigation aimed at determining drug effi-
As stated, IAD is a milder condition; horses do not demonstrate cacy in an antigen-rich environment, oral prednisolone and
respiratory distress and appear normal at rest. For these reasons dexamethasone were compared with improved clinical signs
disease characterization can be more challenging; therefore, observed in all treated horses; however, dexamethasone-
objective measures that define disease outcome and response to treated horses demonstrated improvement in pulmonary
therapy are limited. Nonetheless, clinical management is aimed function. Although prednisolone has historically been a treat-
at reducing pulmonary inflammation through the use of antiin- ment of choice because of the ease of oral administration,
flammatory therapy and environmental management. response to therapy has not been consistently observed and
Once the diagnosis of IAD has been established, antiin- likely relates to variability in bioavailability among horses.
flammatory therapy combined with environmental manage- Adverse events appear to be more common with systemically
ment467 is aimed at reducing pulmonary cellular infiltrates and administered triamcinolone, and for this reason this agent is
airway hyperresponsiveness.467 not recommended for the management of airway inflamma-
Treatment goals of horses suffering from IAD include imme- tion. An investigation that demonstrated similar clinical effi-
diate control of horses that demonstrate evidence of broncho- cacy when dexamethasone was compared with isoflupredone
constriction and cough that impairs performance, reduced also demonstrated hypokalemia, making this a less than ideal
mucous production and associated airway obstruction, and drug selection as well.469
sustained pulmonary quiescence to allow for continued ath- Use of aerosolized corticosteroids has become common-
letic performance. Despite the limited evidence to support the place for the management of equine patients with lower air-
efficacy of corticosteroids for improvement of IAD in horses, way inflammation (Table 8.10). In most clinical settings when
anecdotal reports support recommendations that antiinflam- treating a patient for airway inflammation associated with
matory therapy is an important component of therapy in IAD (similar to the management of RAO), in all but the most
horses with performance limitation caused by IAD. Systemi- mild of cases initial therapy will include systemically admin-
cally administered corticosteroids have a profound and global istered medication; once airway inflammation is believed to
effect on inflammation and associated eicosanoid expression. be reduced drug administration will typically include aerosol-
The decision for route of drug delivery for systemically admin- ized therapy. As stated, finances may impact the ability of the
istered drug compared with aerosolized medication is based clinician to use the airway for drug delivery. Options for the
on factors that include severity of disease and financial avail- administration of synthetic corticosteroid delivery are beclo-
ability, because aerosolized medications can be cost prohibitive methasone and fluticasone. Available spacer devices include
in some settings. Additionally, potential consequences associ- the AeroHippus and Equine Haler devices, with drug delivery
ated with corticosteroid administration must be factored into and efficacy among the two devices being similar.444
the decision-making process. Systemic responses following Efficacy of aerosolized corticosteroid therapy in horses with
corticosteroid administration include some degree of immu- RAO was evidenced by the administration of fluticasone pro-
nosuppression, altered protein synthesis, and reduced adrenal pionate (2000 μg q 12 h) with improvement of clinical signs
responsiveness. Unpredictable idiosyncratic reactions may have and pulmonary function without evidence of impairment of
deleterious patient effects, such as the development of laminitis. immune system function.446 Beclomethasone when adminis-
Using RAO as a model to determine drug efficacy, several tered at moderate dosages (≥500 μg) results in adrenosuppres-
studies have been designed to assess drug efficacy based on sion.470 Similarly, fluticasone (1500 μg b.i.d.) administration
TABLE 8.10 Systemically Administered Therapeutic Agents Used for the Treatment of Non-Infectious Airway Disease1
Medication Dose
Corticosteroids
Dexamethasone 0.04-0.1 mg/kg, IV or IM, q 24 h
0.05 mg/kg, PO, q 24-48 h2
Prednisone 1-2 mg/kg, PO, q 24 h
Bronchodilators
Clenbuterol 0.8-3.2 μg/kg, PO, q 12 h3
Aminophylline 2-5 mg/kg, IV, q 12 h
5-10 mg/kg, PO, q 12 h
Theophylline 5-10 mg/kg, PO, q 12 h
Other
Interferon alpha 50-150 U, PO, q 24 h x 5 days4
Omega-3 polyunsaturated fatty acids 1.5 g DHA, PO, q 24 h x 60 days5
Continued
TABLE 8.10 Systemically Administered Therapeutic Agents Used for the Treatment of Non-Infectious Airway Disease1—cont’d
Aerosolized medications for the management of non-infectious airway disease1
Medication Device Dose
Corticosteroids
Fluticasone AeroHippus, Equine Haler 1-6 μg/kg, q 12 h6–11
Beclomethasone AeroHippus, Equine Haler 1-8 μg/kg, q 12 h12–17
Bronchodilators
Albuterol AeroHippus, Equine Haler 1-2 μg/kg, q 1–3 h18,19
Ipratropium AeroHippus, Equine Haler 0.2-0.4 μg/kg, q 8–12 h18,20,21
Ultrasonic nebulizer 2-3 μg/kg 0.02% solution for nebulization, q 24 h
Chromones
Cromolyn sodium Jet nebulizer 200 mg 0.02% solution for nebulization, q 12 h22–26
Ultrasonic nebulizer 80 mg 0.02% solution for nebulization, q 24 h

1. Couetil LL, Cardwell JM, Gerber V, et al., Inflammatory Airway Disease of HorsesRevised Consensus Statement, J Vet Intern Med. 2016.
2. Grady JA, Davis EG, Kukanich B et al., Pharmacokinetics and pharmacodynamics of dexamethasone after oral administration in apparently healthy
horses, Am J Vet Res. 2010;71:831-839.
3. Erichsen DF, Aviad AD, Schultz RH, et al., Clinical efficacy and safety of clenbuterol HCl when administered to effect in horses with chronic obstructive
pulmonary disease (COPD), Equine Vet J. 1994;26:331-336.
4. Moore BR, Krakowka S, Cummins JM, et al., Changes in airway inflammatory cell populations in standardbred racehorses after interferon-alpha
administration, Vet Immunol Immunopathol. 1996;49:347-358.
5. Nogradi N, Couetil LL, Messick J, et al., Omega-3 fatty acid supplementation provides an additional benefit to a low-dust diet in the management of
horses with chronic lower airway inflammatory disease, J Vet Intern Med. 2015;29:299-306.
6. Couetil LL, Chilcoat CD, DeNicola DB, et al., Randomized, controlled study of inhaled fluticasone propionate, oral administration of prednisone, and
environmental management of horses with recurrent airway obstruction, Am J Vet Res. 2005;66:1665-1674.
7. Couetil LL, Chilcoat CD, DeNicola DB, et al., Randomized, controlled study of inhaled fluticasone propionate, oral administration of prednisone, and
environmental management of horses with recurrent airway obstruction, Am J Vet Res. 2005;66:1665-1674.
8. Dauvillier J, Felippe MJ, Lunn DP, et al., Effect of long-term fluticasone treatment on immune function in horses with heaves, J Vet Intern Med. 2011;25:549-557.
9. Giguere S, Viel L, Lee E et al., Cytokine induction in pulmonary airways of horses with heaves and effect of therapy with inhaled fluticasone propionate, Vet
Immunol Immunopathol. 2002;85:147-158.
10. Laan TT, Westermann CM, Dijkstra AV, et al., Biological availability of inhaled fluticasone propionate in horses, Vet Rec. 2004;155:361-364.
11. Robinson NE, Berney C, Behan A et al., Fluticasone propionate aerosol is more effective for prevention than treatment of recurrent airway obstruction, J
Vet Intern Med. 2009.
12. Couetil LL, Art T, de MB, et al., Effect of beclomethasone dipropionate and dexamethasone isonicotinate on lung function, bronchoalveolar lavage fluid
cytology, and transcription factor expression in airways of horses with recurrent airway obstruction, J Vet Intern Med. 2006;20:399-406.
13. Rush BR, Raub ES, Thomsen MM, et al., Pulmonary function and adrenal gland suppression with incremental doses of aerosolized beclomethasone
dipropionate in horses with recurrent airway obstruction, J Am Vet Med Assoc. 2000;217:359-364.
14. Rush BR, Trevino IC, Matson CJ, et al., Serum cortisol concentrations in response to incremental doses of inhaled beclomethasone dipropionate, Equine
Vet J. 1999;31:258-261.
15. Rush BR, Worster AA, Flaminio MJ, et al., Alteration in adrenocortical function in horses with recurrent airway obstruction after aerosol and parenteral
administration of beclomethasone dipropionate and dexamethasone, respectively, Am J Vet Res. 1998;59:1044-1047.
16. Rush BR, Raub ES, Rhoads WS, et al., Pulmonary function in horses with recurrent airway obstruction after aerosol and parenteral administration of
beclomethasone dipropionate and dexamethasone, respectively, Am J Vet Res. 1998;59:1039-1043.
17. Rush BR, Flaminio MJ, Matson CJ, et al., Cytologic evaluation of bronchoalveolar lavage fluid from horses with recurrent airway obstruction after aerosol
and parenteral administration of beclomethasone dipropionate and dexamethasone, respectively, Am J Vet Res. 1998;59:1033-1038.
18. Bayly WM, Slocombe RF, Schott HC, et al., Effects of inhalation of albuterol sulphate, ipratroprium bromide and frusemide on breathing mechanics and
gas exchange in healthy exercising horses, Equine Vet J. 2001;33:302-310.
19. Bertin FR, Ivester KM, Couetil LL, Comparative efficacy of inhaled albuterol between two hand-held delivery devices in horses with recurrent airway ob-
struction, Equine Vet J. 2011;43:393-398.
20. Bayly WM, Duvivier DH, Votion D, et al., Effects of inhaled ipratropium bromide on breathing mechanics and gas exchange in exercising horses with
chronic obstructive pulmonary disease, Equine Vet J. 2002;34:36-43.
21. Robinson NE, Derksen FJ, Berney C, et al., The airway response of horses with recurrent airway obstruction (heaves) to aerosol administration of
ipratropium bromide, Equine Vet J. 1993;25:299-303.
22. Beech J, Principles of therapy, Vet Clin North Am Large Anim Pract. 1979;1:73-88.
23. Hare JE, Viel L, O’Byrne PM, et al., Effect of sodium cromoglycate on light racehorses with elevated metachromatic cell numbers on bronchoalveolar
lavage and reduced exercise tolerance, J Vet Pharmacol Ther. 1994;17:237-244.
24. Murphy JR, McPherson EA, Lawson GH, The effects of sodium cromoglycate on antigen inhalation challenge in two horses affected with chronic obstruc-
tive pulmonary disease (COPD), Vet Immunol Immunopathol. 1979;1:89-95.
25. Soma LR, Beech J, Gerber NH, Jr., Effects of cromolyn in horses with chronic obstructive pulmonary disease, Vet Res Commun. 1987;11:339-351.
26. Thomson JR, McPherson EA, Prophylactic effects of sodium cromoglycate on chronic obstructive pulmonary disease in the horse, Equine Vet J.
1981;13:243-246.
attenuated serum cortisol concentrations following 1 week of Current protocol recommendations from a recent review
therapy.471 Notably, there are no reports that describe clini- suggest that treatment is ideally initiated with systemically
cal manifestation of Addisonian crisis or evidence of adrenal administered corticosteroid therapy using a tapering dose
dysfunction in horses following treatment, but it should be protocol for approximately 4 weeks.419 Drug dosages are typi-
advised that because of systemic effects judicious drug admin- cally reduced at 25% increments at weekly intervals or as clini-
istration should implemented. cal response to therapy is observed. Clinical improvement of
IAD can subjectively be difficult to determine because clinical that has similar activity to atropine. Low to negligible bio-
signs are typically mild, particularly at rest. Therefore, a proto- availability provides the advantage of not inducing unwanted
col aimed at systemically administered corticosteroids tapered side effects of systemically administered parasympatholytic
over 4 weeks and followed by aerosolized therapy is a rational agents. Horses suffering from mast cell IAD may benefit from
approach aimed at improved pulmonary inflammation. Tran- the administration of sodium cromoglycate, which blocks
sition from systemically administered medications to fluti- calcium channels, resulting in mast cell stabilization rather
casone or beclomethasone is determined by disease severity than degranulation, inhibiting the release of histamine and
and response to therapy. Some individuals apparently respond tryptase, which potentiate leukotriene and PGE expression
more favorably to one preparation over another, and this fac- and bronchoconstriction. Client compliance is essential
tor should be considered with drug selection and follow-up because the drug must be administered for 1 to 2 weeks to
examination to determine response to therapy. produce clinical benefit. For some caregivers this therapeutic
The overall goal of therapy for horses suffering from airway protocol is not practical.
hyperresponsiveness is the reduction in pulmonary inflamma- Although mild to moderate equine asthma is not nearly
tion as well as attenuation of tissue airway remodeling, which as debilitating as severe equine asthma, consideration must
is a consequence of chronic airway inflammation. Application be made for environmental influences that may potentiate
of environmental modification used in combination with anti- airway reactivity and hyperresponsiveness. Low-dust envi-
inflammatory therapy with fluticasone in combination will ronments and avoidance of any feeding from hay nets or
provide the greatest likelihood of achieving these therapeutic elevated mangers should be practiced. Areas in which dust
goals. is present should be wet down before cleaning and when-
Bronchodilator therapy is aimed at improving airway ever possible, horses removed from the environment before
mechanics and airflow, particularly with severe airway cleaning. Use low-dust bedding material, avoid stabling in
obstruction. Therapeutic agents available to provide benefit an area with an indoor arena, and avoid overhead storage of
include β-adrenergic type 2 receptor agonists and parasym- hay or straw.
patholytic agents. Among the β-adrenergic receptor type 2
agonists, aerosolized albuterol, and oral clenbuterol syrup
(Ventipulmin, BIVI) are the agents of preference. Among
Y EXERCISE-INDUCED PULMONARY
drugs that target muscarinic receptors, aerosolized ipratro- HEMORRHAGE
pium or IV NBB429,449 (Buscopan, BIVI) are the agents of
preference. Atropine used at low dosages provides broncho- Definition
dilation but carries the potential risk of iatrogenically induced EIPH is defined as the presence of blood in the airways fol-
ileus, and for that reason it is not recommended for routine lowing strenuous exercise. Hemorrhage originates from the
use. Albuterol is indicated for immediate rescue treatment of pulmonary capillary vasculature into the alveolar spaces. The
bronchoconstriction, whereas clenbuterol is indicated for pro- predominant regions of hemorrhage are localized in the cau-
longed bronchodilation. Chronically administered clenbuterol dodorsal lung fields. At the microscopic level, tissue changes
(0.8 μg/kg, PO, b.i.d.) was reported to lead to tachyphylaxis include edema, pulmonary capillary hemorrhage, and alveolar
evidenced by an investigation that determined 21 days of hemorrhage.
clenbuterol therapy resulted in increased airway hypersen- Blood may be identified by gross examination with airway
sitivity and impaired bronchodilatory activity.472 As stated, tracheobronchoscopy or by the identification of erythrocytes
clenbuterol administration is indicated for temporary bron- or hemosiderophages on tracheal or BAL cytologic examina-
chodilation; prolonged therapy is not recommended. tion. EIPH may result in occult hemorrhage, in which blood
Aerosolized albuterol is indicated for bronchoconstriction is not obviously visible on examination but can be identified
observed in horses with severe airway disease. Although res- with airway endoscopy or may be evidenced by epistaxis fol-
cue therapy is not commonly required for the management lowing exertional exercise. A recent systematic review was
of patients with IAD, in some instances airway obstruction compiled on this subject and published as an ACVIM consen-
may benefit from bronchodilatory therapy. In addition to sus statement and serves as a valuable reference on this par-
bronchodilation, therapeutic strategies must also incorporate ticular disease process.474
corticosteroid therapy and environmental modification to
reduce dust and aeroallergen materials. Albuterol is gener- Epidemiology
ally cost-effective and is readily available for use in equine EIPH is a disease the affects all disciplines of horses that work
patients. Uncommon events such as paradoxical broncho- at intensity. The characterization of the frequency of EIPH
constriction may result in patient responsiveness to the race- among performance horses is somewhat hindered by the use
mic mixture of albuterol preparations. In instances where of different criteria to define the disease. When the diagnosis
an alternate approach is desired, the (R)-enantiomer can be was made with tracheobronchoscopy within 2 hours of racing,
administered solely in the form of levalbuterol. Although approximately 43% to 75% of racing Thoroughbreds were iden-
levalbuterol has historically been cost prohibitive for use in tified with blood within the tracheal lumen.475-478 However,
equine patients, current costs have come down consider- when horses have been repeatedly examined the frequency of
ably. Longer acting β2-adrenergic agonist therapy is available disease increases to 85%.478,479 The dramatic changes in pul-
in the form of salmeterol. With a modification of molecular monary pressure are a direct effect of cardiac output generated
design, this agonist can sustain longer activity compared during the high-intensity exercise of athletic horses. Perfor-
with albuterol. Frequency of administration is approximately mance events other than racing have variable prevalence of
every 8 hours.473 Additional classes of aerosolized bronchodi- disease ranging from 10% to 70%, with the greatest frequency
lator therapy may provide added benefit for patients that have in horses that work at speed such as racing Quarter Horses
diminished sensitivity to β2-adrenergic receptor agonists. and those with the lowest frequency on horses that work at
Ipratropium is a surface-acting parasympatholytic agent lesser intensity such as pleasure ponies. The relevance of use is
associated with the intensity of exercise rather than the dura- for leukocyte infiltration, specifically macrophages that will
tion of work. In one investigation, polo ponies were examined provide the phagocytic capacity needed for clearance of
for the presence of tracheal hemorrhage, with approximately erythrocytic debris, there is no evidence to demonstrate that
11% to 46% of the horses demonstrating evidence of pul- this inflammation was the proximal mediator in the cascade
monary hemorrhage.480 The primary lesion associated with that induced the primary event of hemorrhage. Instillation of
pulmonary hemorrhage is pulmonary capillary stress failure. whole blood into the airways will consistently induce inflam-
More severe grades (3–4) of EIPH are associated with reduced mation and associated alveolar macrophage activation to
racing career length. clear erythrocyte byproducts evidenced by the presence of
hemosiderophages, which will clear the region of hemor-
Pathogenesis rhage within 14 days.489,490 Further supportive evidence for
The pathophysiologic mechanism leading to stress failure is a the lack of primary inflammation serving as an initiating fac-
result of high pulmonary capillary pressure and very low inspi- tor for the development of EIPH is based on the recognition
ratory alveolar pressures that occur during intense exercise.481 that when a model system using the instillation of blood to
Consequently, the pulmonary capillary transmural pressure determine clearance mechanisms was investigated, not only
is extreme at times of intense, strenuous exercise leading to was there efficient and effective removal of blood, there were
tissue failure and hemorrhage. Pulmonary capillary pres- no caudodorsal pulmonary lesions characteristic of horses
sure at rest is very low, yet with high-intensity exercise pres- with EIPH.491,492 Although some investigations have exam-
sures may exceed 95 mm Hg during maximal exercise.482,483 ined the role of experimentally induced airway inflamma-
The critical point at which stress failure occurs appears to be tion with the propensity for pulmonary hemorrhage to occur,
when capillary pressure exceeds 75 to 100 mm Hg. There is there is insufficient evidence from larger scale investigations
good indirect evidence that these numbers are exceeded by that have examined racehorses to make a direct correlation
most galloping horses.484 Ultrastructural pulmonary capillary between cough as a measure of inflammation and the pres-
stress failure and changes have been identified in horses tested ence of hemosiderophages493 or between endoscopic scoring
using a treadmill challenge and in a perfused lung model sys- of tracheal mucus and tracheal hemorrhage.494 Collectively,
tem. Characteristic changes that are identified in association when considering pathogenic events that my lead a horse to
with EIPH include disruption of the capillary endothelium experience pulmonary hemorrhage with intense exercise, the
and alveolar epithelium, with resulting erythrocytes within current understanding is that the level of evidence to support
the alveoli and pulmonary interstitial spaces and subsequent inflammation of the airways or pulmonary parenchyma as a
erythrocytes, platelets, and macrophages in the region of tis- cause of EIPH is low.474
sue failure. A characteristic change occurring in some horses
that suffer from EIPH involves the development of venooc- Clinical Signs
clusive remodeling associated with pulmonary veins. This Identification of a horse that has suffered a bout of EIPH will
remodeling takes place in the intralobar pulmonary veins with most consistently be determined with airway endoscopy. In a
the presence of collagen deposition, smooth muscle hyper- small proportion of racehorses (approximately 5%) epistaxis
trophy, and intimal hyperplasia within the pulmonary veins. may be observed.475,476,495,496 Physical examination of horses
The end result of this venoocclusive remodeling is increased with EIPH is within normal limits for most parameters evalu-
stiffness with reduced vascular compliance. It is believed that ated; in one small-scale investigation (n = 10) there were
these changes are the physiologic consequence to repeated changes identified with thoracic percussion in 50% of the
bouts of strenuous exercise. The pathologic effect on the horse horses with EIPH but no auscultable abnormalities in the cau-
with continued high-intensity exercise is that with increased dodorsal lung fields.497 The recent systematic review provided
cardiac output and continued high pressure from the pul- that there was no evidence of changes in examination param-
monary arterial vasculature, tissue failure can continue and eters, such as changes in respiratory rate, respiratory effort, or
potentially worsen over time, leading to propagation of tissue evidence of distress, or changes in behavior to provide clini-
failure and hemorrhage into the alveolar spaces and surround- cal evidence of EIPH following exercise. The quality of evi-
ing interstitium. Evidence to support this postulated series of dence suggesting that consistent clinical abnormalities can be
events is in part a reflection of the finding that racehorses that detected in horses with EIPH (with the exception of epistaxis
have suffered from EIPH can have increased fibrosis in their following exercise) is also low.474
caudodorsal lung fields.485 The specific amount of exercise Although epistaxis is an uncommon finding, when pres-
required to lead to these tissue changes has not been defined. ent it is an indication of the severity of hemorrhage. The cli-
The complete understanding of the impact that venoocclusive nician may consider differential possibilities for the presence
remodeling has on the development and propagation of EIPH of epistaxis following exercise, but current evidence supports
continues to be under investigation. the suggestion that when epistaxis is observed soon after exer-
Among the historical proposed risk factors for the develop- cise, EIPH is the likely cause.474 Several retrospective studies
ment of EIPH, lower airway inflammation has been suggested have further characterized the frequency of epistaxis among
to play a role in disease development. The suggested pathway performance horses with EIPH. In Japan, when horses were
has included persistent pulmonary inflammation with asso- examined 30 minutes following race completion that included
ciated bronchoconstriction leading to increased negative both flat and steeplechase racehorses, epistaxis was identified
alveolar pressure that would further potentiate pulmonary in 0.13% of the Thoroughbreds examined and 0.10% of Anglo-
hemorrhage.486,487 More recent investigations, however, do Arabs.498 A similar frequency of epistaxis has been identified
not support this suggestion,488 and airway inflammation as in South African Thoroughbred racehorses.499 Once a horse
a proposed mechanism for EIPH disease development is not suffers from epistaxis, the recurrence rate was reported to be
supported. Although it is clear that following an episode of 13%, supporting the persistent nature of the disease. In one
pulmonary hemorrhage there is an indication and recruitment study, there was an apparent association with horses that were
TABLE 8.11 Grading Scale for EIPH Endoscopic Examination1 observers.477 Commonly, tracheobronchoscopic examination
following intense exercise will provide confirmatory evidence
0 No blood in pharynx, larynx or anywhere along the of pulmonary hemorrhage. However, the absence of blood
tracheal lumen does not eliminate the possibility of pulmonary hemorrhage.
1 Few specs of blood, fever than 2 short areas The presence of hemorrhage will be evident following exercise,
2 Specs throughout, < 10% tracheal surface stream but the clearance of erythrocyte constituents may not be com-
3 Multiple distinct streams, covers > 30% tracheal plete for up to 14 days. Because of this, BAL can be valuable for
surface, but not pooling at thoracic inlet the diagnosis of EIPH.
BAL cytologic assessment can aid with the diagnosis of
4 Multiple coalescing streams, covers > 90% trache-
EIPH. Although total nucleated cell counts in BALF are simi-
al surface with obvious pooling at thoracic inlet

lar among horses in race training and yearlings that have not
1. Hinchcliff KW, Jackson MA, Brown JA, et al., Tracheobronchoscopic entered training,505 erythrocytes and hemosiderophages in the
assessment of exercise-induced pulmonary hemorrhage in horses, Am BALF are greater in horses in training compared with horses
J Vet Res. 2005;66:596-598. not being trained. Although the identification of erythrocytes
within the BALF is used to provide the diagnosis of EIPH,
variability among samples has led to the concern that enu-
older and that raced over jumps. The evidence to support an meration of BALF erythrocytes alone may not provide accu-
age-associated phenomenon is lacking. Although age may play rate evidence to allow the clinician to classify the severity of
a role with the development of disease, the number of races EIPH.506 When horses confirmed with EIPH are compared
that horses have competed in needs to be recognized because with healthy horses, total hemosiderin score (cytoplasmic cal-
this directly impacts the number of high-intensity events that culation of iron within alveolar macrophages) correlates with
a horse has endured and therefore, the degree of pulmonary EIPH status. Total hemosiderin score >75 has a reported sensi-
vasculature remodeling that exists. tivity and specificity of 94% and 88%, respectively.507 Notably,
Some early indicators suggested that acute death may be hemosiderin scores should be carefully interpreted because
associated with EIPH in racehorses. However, the overall fre- pulmonary hemorrhage, regardless of etiology, such as trau-
quency of EIPH is notably high among racehorses at 85% or matic pneumonia/pleuropneumonia or abscess formation will
higher in some populations. In contrast, the development of increase the hemosiderin score.
acute death among racehorses is remarkably low at 0.08 to 0.29 Thoracic radiographs obtained from horses with EIPH
horses per 1000 starts.500 Although some reports suggest that will have characteristic changes in the caudodorsal pulmo-
pulmonary hemorrhage may account for up to 35% of acute nary fields. Radiographic changes may include alveolar or
deaths in which postmortem was successful with the confir- mixed interstitial opacities in the caudodorsal lung fields.
matory cause of death,501 other reports do not consistently Clinical management of EIPH-affected horses is unlikely to
provide evidence to support this finding. Currently, the level be impacted by the identification of radiographic changes.
of evidence to support that EIPH is causally associated with Lesions can be identified with radiography and have been con-
acute death in racehorses is low.474 sistently identified in horses at postmortem.
The overall influence of EIPH on the performance level of
horses has long been questioned. Although the standards for Treatment
athletic performance differ among breeds, when racehorses Furosemide is the recommended therapy for the prophy-
are examined for their racing career longevity the evidence laxis of hemorrhage associated with EIPH. Although hem-
demonstrates that horses with low to moderate (grades 1–3/4) orrhage is not eliminated, it is evident that furosemide
level EIPH do not have shortened race careers.502 In contrast, administration (0.5–1.0 mg/kg, IV) approximately 4 hours
racehorses with severe EIPH are likely to have shortened race before exertion reduces the severity of pulmonary hemor-
careers.474 When considering the impact that EPIH has on rac- rhage in racehorses.477 Efficacy of furosemide to reduce the
ing performance using finishing position as a measure of rac- severity of pulmonary hemorrhage is believed to be an effect
ing performance,477,503 horses that are EIPH grade 1 or less (no of reduced pulmonary arterial pressure and left atrial (pulmo-
blood) as defined by endoscopic examination are more likely nary wedge) pressures.508-515 The effect of lowering pulmonary
to win or at least finish in the top three finishing positions.504 arterial pressure is a reduction in capillary and transmural
With the currently available and analyzed evidence, the con- pressure during exercise, which reduces the impact on the
sensus is that horses with more severe EIPH will have inferior capillary alveolar interface and associated tissue stress failure
performance compared with horses that have minimal to no and disruption. There is strong evidence that furosemide is an
pulmonary hemorrhage.474 Horses with more severe forms of effective mitigating therapy for horses that suffer from EIPH.
EIPH have reduced career utility compared with horses that In addition to the administration of furosemide as a pro-
have lower levels of hemorrhage associated with EIPH. phylactic treatment for the attenuation of pulmonary hem-
orrhage associated with EIPH, additional therapeutic agents
Diagnosis have been tested for their efficacy as a prophylactic agent or
The diagnosis of EIPH is based on the identification of hemor- treatment for pulmonary hemorrhage. Agents have included
rhage within the airways. Although tracheobronchial endos- antiinflammatory therapeutics, bronchodilators, phosphodi-
copy can be performed between 30 and 90 minutes following esterase inhibitors, procoagulants (synthetic and herbal rem-
exertional exercise and will identify frank hemorrhage in edies), and application of nasal dilator strips.
most EIPH-affected horses, BAL remains a valuable diagnos- Two independent investigations aimed to determine
tic technique. An endoscopic scoring system reflecting the the effectiveness of aminocaproic acid for the treatment of
presence of tracheal blood following exercise has been estab- EIPH. Both were randomized, controlled studies that used
lished (Table 8.11) and has consistent interpretation among a treadmill model to induce high-intensity exercise. These
investigations failed to identify the difference between ami- Primary Thoracic Neoplasia
nocaproic acid administration and saline placebo administra- Primary lung tumors are less common than metastatic pulmo-
tion 2 to 4 hours before high-intensity exercise. No difference nary neoplasms and constitute less than 10% of all pulmonary
in BALF erythrocyte number was identified between treat- tumors.528 Granular cell tumor is the most frequently reported
ment groups. These were low-powered investigations based primary pulmonary tumor of horses.529 Despite being the most
on sample size and methods applied for outcome assess- common type, only approximately 30 cases have been reported
ment.516,517 There is insufficient evidence to support the rec- in the literature.530-537 These tumors have been described as
ommendation for the use of aminocaproic acid in horses myoblastomas and appear to originate from Schwann cells.538
with EIPH.474 Alternate agents that have been considered They occur as single or multiple masses adjacent to the bron-
for the treatment of EIPH include bronchodilators for the chi and bronchioles and are locally invasive with no reports
potential of subclinical bronchoconstriction that may further of metastasis. The mass typically extends into a large-caliber
reduce negative alveolar pressure. Clenbuterol administered airway, resulting in partial or complete occlusion of the lumen.
independently (intravenously) or in combination with furo- Although some authors suggest an increased frequency for the
semide failed to influence hemodynamics among study sub- right hemithorax, there is no apparent predisposition to right-
jects.508,518 Additionally, clenbuterol was investigated for the sided or left-sided lesions.537 Bilateral disease is uncommon
potential beneficial effect of enhancing pulmonary clearance and occurs in less than 20% of the case reports. There is no
of red blood cell debris following experimental inoculation, breed predilection, yet mares more commonly develop these
but no benefit was observed in clenbuterol-treated horses.519 tumors. Despite their size and propensity to occlude large air-
Atropine and ipratropium have also been investigated for ways, granular cell tumors may result in minimal clinical signs
their potential benefit in EIPH patients, but no clear benefit and represent an incidental necropsy finding in some horses.
has been identified.520 Based on these investigations without In clinically affected horses, the presenting complaints are
any demonstrated benefit, bronchodilators are not recom- chronic cough, exercise intolerance, tachypnea, and weight
mended for the treatment of EIPH-affected horses. Among loss. Horses with advanced disease demonstrate an increased
the potential treatments that may provide benefit, intuitively effort of respiration during expiration. Depending on tumor
corticosteroids have been reasonably considered for the ther- size, auscultation may reveal decreased breath sounds over one
apeutic benefit of reduced potential inflammation and subse- hemithorax. Based on age (mean age at onset = 13 years old)
quent remodeling that may contribute to the development of and clinical signs, horses with granular cell tumor are often
lower airway stiffness. Limited numbers of studies have been assigned a presumptive diagnosis of recurrent airway disease
undertaken to test dexamethasone, beclomethasone, or oral (heaves).537 Failure to respond to appropriate therapy results
prednisolone, but among the outcomes examined there was in further diagnostic testing. Focal pneumonia may develop
no evidence of benefit or improvement of EIPH severity.519,521 in the pulmonary parenchyma distal to the mass because of
Nonsteroidal agents have similarly been investigated in poor clearance of respiratory secretions and inhaled particu-
small-scale treadmill investigations; neither phenylbutazone late material. Horses with focal pneumonia present with fever,
with furosemide nor flunixin meglumine has demonstrated depression, abnormal lung sounds, and leukocytosis, in addi-
any improvement with the presence of blood on endoscopic tion to coughing. There are no reports of pleural effusion,
examination.514,522 Vasodilator therapy and modification of epistaxis, or mediastinal lymphadenopathy in horses with
erythrocyte rheologic properties have been postulated to granular cell tumor. Hypertrophic osteopathy (HO) has been
potentially influence the severity of EIPH, resulting in two reported as a paraneoplastic complication of granular cell
treadmill investigations testing the efficacy of pentoxifylline tumor in some horses.535,539-541
as a potential treatment strategy for EIPH. When adminis- Routine blood work provides little evidence to advance the
tered alone or in combination with furosemide there was no diagnosis of granular cell tumor. Thoracic radiography identi-
evidence of change in pulmonary hemodynamics.511,523 Using fies a single, large mass or multiple pulmonary masses near
nasal dilator strips for the prevention of pulmonary hemor- or caudal to the hilus.529 Evaluation of magnification in left
rhage has been tested in several investigations. One treadmill and right radiographic projections can identify the hemitho-
study found that there was no benefit from using nasal dila- rax affected by the tumor. Rarely, the tumor cannot be visu-
tor strips on the amount of blood in the airways following alized via thoracic radiography. In some cases, the mass may
exercise. Four additional investigations with a limited number be obscured by focal pneumonic lung. Focal pneumonia in an
of horses revealed that there was a reduction in the number of atypical pulmonary location (i.e., central or dorsal lung fields)
BALF erythrocytes following exercise with the application of should trigger a suspicion of tumor or inhaled foreign body.
nasal strips.524-527 These data show low-quality evidence to Using a tracheobronchial map of the lung,542 the approximate
support the efficacy of nasal dilator strips for the prevention location of the tumor in the pulmonary tree can be deter-
of EIPH.474 mined for endoscopic examination.
There is no report of visualization of the tumor mass via
ultrasonographic examination; however, decreased movement
Y TUMORS OF THE RESPIRATORY of the pleural surface over the affected hemithorax has been
SYSTEM reported in horses with large granular cell masses.537
Gross assessment of granular cell tumors reveals them to be
Equine patients suffering from pulmonary neoplasia present smooth pink to white in color and occludes or nearly occludes
with nonspecific signs that may not clearly indicate the pri- a large-caliber airway. A mainstem bronchus is the most com-
mary disease process. Careful history and physical exami- monly affected airway.543 Biopsy confirmation is difficult
nation combined with thorough diagnostic assessment will and may not be necessary because the endoscopic appear-
enable the clinician to establish the diagnosis of pulmonary ance of the tumor is distinctive. The external surface of the
neoplasia. mass consists of normal respiratory epithelium; therefore, a
biopsy sample obtained via endoscopy may be non-diagnostic Malignant thymoma has rarely been reported to affect
because of insufficient size and depth.537,544 To obtain a larger horses.499,547,549 A mediastinal mass, associated lymphade-
tissue sample, with a greater chance of achieving a diagnosis, nopathy, and marked pericardial involvement was reported
a biopsy instrument (such as uterine biopsy forceps) can be in one case.499 In addition to cranial thoracic disease, the
passed through a tracheotomy incision at the level of the tho- affected Percheron mare had evidence of pulmonary lymph
racic inlet.544 node involvement, extensive parenchymal pulmonary dis-
On histopathological examination, neoplastic cells are ease, and abdominal and retroperitoneal lesions. A separate
benign and appear rounded to polyhedral with hyperchro- report described a mixed-breed mare affected by a squamous
matic nuclei, numerous eosinophilic cytoplasmic granules, cell thymoma that demonstrated a markedly more aggressive
and indistinct cytoplasmic margins.537,543 Histochemical nature.549 This latter report described the lesions to extend
and immunohistochemical staining results of these tumors from the intermandibular space to the thoracic inlet. Post-
are well described and suggest they are composed primarily mortem examination revealed the mass to involve the medias-
of neural crest cells, which are likely myelinating Schwann tinum and pericardial sac. Pulmonary nodules were diffusely
cells.538 Morphologic features of the equine pulmonary granu- present and confirmed on histopathology.
lar cell tumors are similar to those of endobronchial granular A recent report describes an 18-year-old Tennessee Walk-
cell tumors of humans.538,543 In other species (dogs, cats, and ing Horse that suffered from acute death during a trail ride.547
humans), granular cell tumors are reported to occur at many Postmortem examination revealed that the pleural cavity and
other sites along with the thoracic cavity, including the oral pericardial sac contained a combined volume of 300 to 500 mL
cavity and CNS. of serosanguineous fluid. A large mass was found to occupy
Granular cell tumors are presumably slow growing and may the cranial thoracic cavity and was adherent to the thoracic
be an incidental finding at postmortem examinations. Conser- wall. The architecture of the right atrium was significantly
vative treatment may produce an acceptable clinical outcome distorted, which also involved the tricuspid valve. Histopatho-
for years in horses with stable clinical signs.537 The presenting logical evaluation of the mass revealed few characteristics of
complaint for the horse is indicative of focal pneumonia and neoplasia consistent with previous reports of thymic tumors in
includes cough, fever, and depression. The granular cell tumor horses. This tumor was classified in accordance with the WHO
obscured a third-generation bronchus and compressed only a classification system as a type A thymoma with proliferation
small portion of pulmonary parenchyma. The mare was treated of spindle-shaped cells with oval to elongated nuclei, lack
with a 2-week course of broad-spectrum antibiotics and man- of nuclear atypia, and a lack of neoplastic lymphocytes with
aged for several years with minimal clinical signs. Ohnesorge inconspicuous nuclei. A predominant feature of this neoplasm
et al.545 removed the intraluminal portion of a granular cell and the findings in this reported case is the lack of a neoplastic
tumor mass via transendoscopic electrosurgery. The remain- nature identified on histopathology, yet there was aggressive
ing tumor surface was irradiated using an Nd-YAG laser to behavior of the tumor in the host. In the reported case, car-
coagulate and kill residual tumor cells. In most cases, the tumor diac invasion was attributed to lymphatic drainage or direct
observed in the airway represents only a small proportion of the local invasion, yet hematogenous spread was also considered
total tumor mass. Horses with large tumor masses require more a possibility.547
aggressive therapy. Facemire et al.544 removed the entire right
lung, which was affected by multiple large masses. In the reports Other Tumor Types
by Ohnesorge et al.545 and Facemire et al.,544 there was no tumor Additional primary thoracic neoplasms originate from
recurrence after a 2-year period of follow-up. various pulmonary tissues and are primarily reported as
Necropsy examination reveals a single large mass or, more single case reports: pulmonary and bronchial carcinoma
commonly, a large mass with multiple small nodular masses, and adenocarcinoma,550-554 bronchogenic squamous cell
which compress the surrounding parenchyma and invade the carcinoma,555 bronchial myxoma,556 pulmonary chondro-
lumen of a large airway. There are no reports of metastasis to sarcoma,557 pulmonary leiomyosarcoma,558 and pleuropul-
other organs, primary neoplasia originating from other sites, monary blastoma.559
metastasis to regional lymph nodes, or invasion of nonpulmo- Clinical signs of primary pulmonary neoplasms are
nary tissue.529 dependent on the tumor type and location. Chronic cough,
weight loss, anorexia, fever, and respiratory difficulty are
Thymic Tumors common clinical findings in horses with pulmonary neopla-
Thymic tumors are classified as benign or metastatic, based on sia regardless of the tissue of origin. Ventral edema, pleural
evidence of tissue invasiveness, even though they uniformly effusion, and epistaxis are not unusual in horses with pulmo-
appear benign histologically. These tumors are derived from nary neoplasia. Most case reports involve aged horses (>12
epithelial reticular cells of the thymus. Tumor classification years of age), although pleuropulmonary blastoma has been
has historically included those with a lymphocytic compo- reported in a neonate and a young adult horse.559 Similar
nent, epithelial, or mixed composition. More recently, the to humans, this tumor is characterized by mixed epithelial
World Health Organization (WHO) has provided classifica- and mesenchymal elements and aggressive malignancy. The
tion recommendations to include A, AB, B1, B2, and B3.546 clinical presentation of pulmonary leiomyosarcoma is simi-
The equine case report that used this classification scheme lar to granular cell tumor, with the exception of the presence
describes a type A tumor characterized by the proliferation of of epistaxis.558
spindle cells without nuclear atypia that contain no more than Mesothelioma is a rare primary pleural tumor arising
a few nonneoplastic lymphocytes and inconspicuous nuclei. 547 from the mesothelium of the pleura, pericardium, and perito-
Thymic tumors are rare in horses. In an original report of two neum. In humans, this malignancy is associated with asbestos
cases, they were described as incidental postmortem findings exposure. The clinical presentation in horses includes weight
without evidence of metastasis.548 loss, respiratory difficulty, and large-volume pleural effusion.
Differentiation of neoplastic mesothelial cells from reactive diagnostic information regarding lymph node architecture
mesothelial cells can be challenging based on cytologic exami- and are difficult to cytologically differentiate from reactive
nation of pleural effusion. Ultrasonographically, the tumor is lymph nodes.
observed as multiple small nodules on a thick serosal surface, Peripheral lymphadenopathy is an uncommon clinical fea-
and pleural biopsy is diagnostic. There is no treatment and the ture of disease,577 yet when lymphadenopathy develops, the
prognosis is grave.560-567 prescapular or submandibular nodes are usually enlarged.
Most cases of primary thoracic neoplasia have an extended Postmortem examination typically reveals conclusive evidence
history of cough and nonspecific signs of weight loss and of lymphoid pathology. When examining a patient with sus-
anorexia.529 The most common first-opinion diagnosis in pected lymphoma, rectal palpation is an important component
horses with pulmonary neoplasia is heaves, followed by low- of the physical examination to determine whether abdominal
grade pneumonia and pleuropneumonia. In some cases, the lymphadenopathy is present. A recent report of lymphoma
definitive diagnosis is not identified for months to years. With described an 18-year-old mare with a presenting complaint of
the exception of granular cell tumor, there are limited options severe pruritus, alopecia, pyrexia, mammary gland enlarge-
for therapeutic intervention, and the prognosis is grave at the ment, and lymphadenopathy.578 This mare was determined
time of diagnosis.528 to be suffering from primary T-cell lymphoma that primar-
ily affected the mammary gland. Hematologic dyscrasias that
Metastatic Pulmonary Neoplasia may be present in lymphoma cases include hyperglobulin-
Equine lymphoma is the most common hematopoietic neo- emia, hypercalcemia, and anemia. Rarely leukemia may be
plasm in horses and can present with a variety of the clinical identified, which typically represents bone marrow involve-
signs that have been previously described.554,568-573 Classifica- ment. The mare of the previously mentioned report suffered
tion involves four main manifestations of lesions: mediastinal, from pyrexia and anemia, which resulted from paraneoplas-
multicentric, alimentary, and cutaneous. When present in the tic complications. Pruritus has been previously described to
thoracic cavity, this manifestation of lymphoma is not consid- occur as a paraneoplastic condition in horses579 and has been
ered a true primary neoplasm because it originates from an identified in approximately 25% of human patients suffering
extrathoracic site.554 Lymphoma is usually a disease of adult from Hodgkin’s lymphoma.
horses without a specific breed or gender predilection.572 A recent report described a mare with significant sub-
Clinical signs of lymphoma typically relate to the primary mandibular lymphadenopathy and respiratory distress that
organ system involvement. Common clinical features of was later diagnosed with lymphomatoid granulomatosis.580
the disease include chronic weight loss, lethargy, anorexia, Although the mare had clinical findings to suggest a more
subcutaneous edema, lymphadenopathy, colic, bleeding typical case of lymphoma, this mare had evidence of marked
tendency, and diarrhea.574-576 Although the disease has an lymphocytosis on hematologic examination. Morphologic
insidious progression, it is not uncommon for cases to pre evaluation of these cells revealed that approximately 98% of
sent with a relatively acute change or deterioration in condi- the cells were classified as atypical T cells. Additional clinical
tion. It is likely that the time of presentation relates to a stage findings included anemia and thrombocytopenia. On post-
of disease in which the clinical manifestation has become mortem examination unencapsulated nodules were scattered
pronounced. throughout all the lung lobes, without obvious involvement
Ventral edema, particularly when in the pectoral region, of other organs. However, microscopic examination of the
is a common clinical finding in association with lymphoma, skin revealed perivascular and mural infiltrates of neoplastic
resulting from lymphatic obstruction. Coughing and labored mononuclear cells closely associated with an affinity for vascu-
respiratory effort are often apparent in individuals suffering lar elements. Neoplastic cells were characterized to have oval
from mediastinal masses. In such instances, pleural effusion or cleaved nuclei with characteristics of neoplasia represented
may result in severe pulmonary atelectasis, and pulmonary by multiple nucleoli and evidence of mitosis among cells.
function is significantly compromised. Lymphomatoid granulomatosis is a rare form of lymphoma
Hematologic and serum biochemical testing are nonspe- that has been previously identified in humans,581 dogs,582-586
cific regarding the provision of diagnostic evidence for the and cats.587 The findings in this mare were supportive of this
presence of thoracic lymphoma. Thoracic radiography may diagnosis for the first time in a horse. Interestingly, her lesions
identify a pleural fluid line, and in some instances it reveals involved primarily the submandibular lymph nodes, pulmo-
the presence of a mediastinal mass. Thoracic ultrasonography nary tissue, and skin. The leukemic nature of disease in this
provides specific evidence regarding the presence, depth, and horse was believed to represent a consequence of the angio-
character of pleural fluid. Thoracocentesis is an important invasive progression of the disease. This differential consider-
diagnostic procedure that will provide the clinician with evi- ation should be considered for clinical disease that presents in
dence of the nature of fluid. Cytologic examination provides a similar fashion with clinical and histopathologic findings to
evidence of lymphoma, when the tumor is exfoliative. In some support this diagnosis.
instances concurrent sepsis may be identified. Therefore, care- Classification of tumor type has become a routine com-
ful examination of lymphocyte morphology should be per- ponent of the clinical evaluation of lymphoma. Specifically,
formed. When overlapping conditions exist, such as sepsis diagnostic modalities used for tumor classification include
with mediastinal lymphoma, a lack of response to appropriate immunophenotypic examination with flow cytometry and
medical therapy should alert the clinician to the potential for immunohistochemical staining on tissue samples. Immuno-
complicating factors rather than a primary pleuropneumo- phenotypic evaluation of pleural fluid can be performed to
nia. Thoracoscopy may be particularly helpful in these cases. determine lymphocyte surface marker expression, which can
When enlarged peripheral lymph nodes are present, biopsy aid with the characteristic nature of neoplasia. Flow cytometry
is strongly recommended to aid in diagnostic confirmation of fluid effusions is analyzed for surface expression of MHC
of lymphoma. Fine-needle aspirates typically do not provide II, CD4, CD5, CD8α, or CD8/α/β.588 When tissue samples
are available, immunohistochemistry is used to establish cell- epistaxis; and subcutaneous, cutaneous, or intramuscular
surface expression, which provides criteria for tumor classi- masses.596 Anemia, thrombocytopenia, and neutrophilia are
fication.577,589 Cellular staining provides diagnostic evidence the most common abnormalities on routine blood work.592
for the distinction between T- and B-cell lineage neoplasms. A large volume of hemorrhagic pleural effusion is present
Standard staining protocols involve identification of CD3 for in approximately 20% of the cases, accompanied by ven-
T-cell lesions and CD20, CD21, and/or CD79α for B-lym- tral edema and marked respiratory distress. Thoracocentesis
phocyte surface marker. Several veterinary laboratories offer provides relief for horses with large-volume pleural effusion.
diagnostic services that can aid in the specific identification Pleural fluid is typically serosanguineous in color and may be
of tumor type. Examination of DNA ploidy may aid in char- characterized as hemothorax. Cytologic examination may or
acterization of neoplastic cell populations in some clinical may not reveal neoplastic cells. Trauma is the most common
investigations.403,590 first-opinion diagnosis in horses with hemothorax caused by
Classification of equine lymphoma has been hindered by hemangiosarcoma.592
the documentation of relatively few cases. An original report Antemortem diagnosis is uncommon592 but has been
examined 31 horses with diagnostic confirmation of lym- achieved via cytologic evaluation of pleural fluid and pleu-
phoma. Among these cases, 24 (77%) horses had lymphoma roscopic-guided biopsy.595 Biopsy of a hemangiosarcoma-
derived from B lymphocytes with an infiltration of nonneo- tous mass can result in further hemorrhage. Plans to manage
plastic T lymphocytes and is termed T-cell–rich B-cell lym- hemostasis should be considered before completing a biopsy
phoma (TCRBCL).589 This investigation concluded that not all in cases of suspected hemangiosarcoma. At postmortem
equine lymphomas can be classified; however, among equine examination, neoplastic tissue is widely distributed to many
tumors that can be classified, there is an apparent tendency tissues including the heart, spleen, kidney, skeletal muscle,
toward TCRBCL. and CNS. The spleen is the most common organ of origin,
In contrast, a more recent investigation that used immu- although many other tissues have been reported to be the site
nophenotyping classified 37 cases of equine lymphoma.577 of primary tumor formation. Occasionally, the thoracic cavity
Among all tumors, 34 (91%) of the neoplasms involved mul- is considered the primary tumor with disseminated metastasis
tiple lymphoid tissues in addition to abdominal or thoracic to distant sites.
organs. Twenty-six (70%) of the cases were identified to be Disseminated hemangiosarcoma should be differentiated
of T-cell origin, 7 cases B-cell origin, and 4 cases were not from focal hemangiosarcoma of the distal limb in horses less
able to be classified. Immunophenotyping was performed on than 3 years of age.597 These tumors do not demonstrate the
effusions and was found to be consistent with the immuno- same aggressive biological activity and are unlikely to metas-
histochemical findings in six tumors.577 The investigation of tasize at the same rate. Surgical resection can be curative, and,
this population concluded that most horses had large T-cell in some cases, the tumor may resolve spontaneously.
tumors, a concurrent inflammatory response was common, Other tumor types that metastasize to the thoracic cavity
and many horses had mediastinal masses. This population include adenocarcinoma,598,599 squamous cell carcinoma,600
of affected horses was uncharacteristically young, less than 5 fibrosarcoma,601 metastatic melanoma,602,603 mastocytoma,604
years old. Anemia was the most common cytopenia and was or undifferentiated sarcoma.528,554 The clinical features of these
frequently associated with agglutination and hyperglobulin- tumors are generally nonspecific and often relate more to the
emia. Thrombocytopenia and neutropenia were identified primary site of tumor formation. Some metastatic tumors will
in association with myelophthisis.577 Although equine lym- produce neoplastic effusion and/or damage to intrathoracic
phoma is relatively uncommon, an effort to establish a diagno- structures.601,602 Cytologic evaluation may or may not identify
sis early in the course of disease would be expected to enhance neoplastic cells. Thoracoscopy is an important diagnostic tool
the chance for a favorable case outcome should chemotherapy to obtain a tissue sample to confirm neoplasia and identify the
be a therapeutic option. tissue type.605,606
Postmortem examination typically reveals large-volume
pleural effusion and associated ventral pulmonary atelectasis. Paraneoplastic Disease
Cranial mediastinal masses are commonly present and are Paraneoplastic conditions develop in association with neo-
often composed of coalescing enlarged lymph nodes. Such plasia yet are often unrelated to the primary site of tumor
masses may occlude the thoracic inlet contributing to obstruc- development. Recent reviews will provide the reader with a
tion of blood flow and lymphatic drainage. Regional and local comprehensive understanding of this condition and specific
lymph nodes are commonly enlarged. In some instances, the manifestations in equine patients.607
pulmonary parenchyma may be infiltrated with neoplastic Fever is a common paraneoplastic disorder observed in
lesions as well as other organs that may be involved including association with equine lymphoma resulting from cytokine
liver, kidney, spleen, and potentially gastrointestinal tract.554,591 production by the tumor. IL-1, IL-6, and TNF are pyrogens
Hemangiosarcoma appears to be the second most common that are believed to increase PGE production by hypothalamic
metastatic thoracic neoplasm in horses. In a series of 35 cases, endothelial cells. When pyrexia is identified in combination
pulmonary parenchyma and pleura were involved in 77% of with anemia, the differential list must include potential infec-
the horses.592 The age distribution of affected horses is clus- tious etiologies such as equine infectious anemia and piroplas-
tered around middle-aged adults (mean age 12 years, range mosis. Immune-mediated disorders should also be considered
3–27 years). Pulmonary hemangiosarcoma is not unusual in as a primary disease or manifestation of paraneoplastic disease
6- to 7-year-old horses.593-595 Disseminated hemangiosarcoma that may also involve intermittent or persistent fevers.
is aggressive and rapidly progressive. Most horses present in Pruritus has been clearly demonstrated to develop as a
good body condition with an abbreviated history of anorexia paraneoplastic condition associated with equine lymphoma.579
and depression. The clinical presentation often includes tach Altered T-cell function is believed to result in modified cyto-
ypnea; pale or icteric mucous membranes; respiratory distress; kine synthesis and secretion. Additional etiologies for pruritus
include nerve entrapment or compression, tumor growth, and that describes the clinical features of 24 cases.540 In this report,
hepatic involvement leading to bile duct obstruction.607 71% of the horses were ultimately diagnosed with pulmonary
Anemia may result from immune-mediated mechanisms disease. Among those with pulmonary lesions, 40% were neo-
or reduction of bone marrow production, such as with myelo- plastic in origin. In cases with a treatable pulmonary condi-
phthisis. Anemia of chronic disease is well recognized and tion, resolution of HO occurred following clearance of the
occurs secondary to a variety of inflammatory conditions. primary pulmonary disease. Limb swellings were present on
Changes in bone marrow function occur secondary to altered all four limbs and typically occurred in a bilaterally symmet-
cytokine synthesis. Cytokines that have been implicated in this ric fashion. In some instances, the limbs were cool and com-
mechanism include transforming growth factor B, IL-11, IL-6, fortable, whereas in others they were warm and sensitive to
and interferon gamma, which upregulate hepcidin synthesis. palpation. Head lesions were present in two of the cases that
Hepcidin will antagonize gastrointestinal iron uptake and uti- involved the mandible and maxilla.540 Stiffness and pain were
lization. In addition, erythropoietin antagonism results from commonly reported in affected individuals. When intratho-
TNF affecting bone marrow production and function.607 racic disease was present, clinical signs also included cough
Hypercalcemia (calcium >14 mg/dL) may result from a and dyspnea. The radiographic findings associated with HO
paraneoplastic syndrome, although the clinician should con- included periosteal new bone formation in a palisade fashion.
sider other differential possibilities as well such as chronic Similar to findings in humans and canine patients, in those
renal failure, iatrogenic hypervitaminosis D, consumption individuals with a treatable condition, clinical signs resolved
of wild or day-blooming jasmine (Estrum diurnum) particu- on resolution of the primary disorder. Interestingly, in this
larly in the southeastern United States, rapid administra- report three cases were not identified to have a primary disor-
tion of calcium-containing solutions, laboratory error, and der, yet clinical signs resolved following symptomatic therapy
hyperparathyroidism. with phenylbutazone. In humans, indomethacin is an NSAID
The mechanisms of hypercalcemia occurring in patients that has been reported to provide clinical benefit when used as
suffering from neoplastic disease may include lytic bone the primary therapy for the management of HO.619
metastases, malignant hyperparathyroidism, ectopic tumor
production of parathyroid hormone-like hormone (PTHLH, Other Considerations
PTHLP), tumor-produced PGEs (PGE1 and PGE2), and Differentiating a thoracic tumor from a number of infectious
tumor-produced osteoclast activating factor.608-610 The cDNA conditions of the thorax can be surprisingly difficult. Middle-
sequence for equine PTHLP has been reported (Accession aged and aged horses with solid pulmonary tumors are often
NP_001157453). Although this protein has been clearly mistaken as affected with heaves. Hydatid cysts and fungal
defined to result in hypercalcemia associated with canine pneumonia are less common conditions that may mimic signs
tumors such as with lymphoma and anal sac adenocarci- of thoracic neoplasia.
noma,611 further investigations are required to more clearly Equine cases of hydatid cyst may present with a large vol-
define the relationship of PTHLH in the horse. Reported cases ume of pleural effusion. In Europe, hydatidosis (Echinococcus
of hypercalcemia in equine patients suffering from neoplasia equinus) is generally well tolerated in horses, and cysts in the
are somewhat limited to include disseminated lymphoma and liver and lung may be an incidental finding at postmortem
lymphoid leukemia.579,612,613 examination.19 In the United States Echinococcus spp. and
Hypertrophic osteopathy (aka Marie’s disease) has been an unidentifiable aberrant, acephalic metacestode have been
reported in domestic species and is most commonly associ- identified in the liver and lungs of horses. Occasionally the
ated with primary and metastatic pulmonary tumors.614-616 cyst will rupture, resulting in clinical respiratory difficulty
The pathogenesis of HO remains incompletely understood. caused by large-volume pleural effusion. In the United States,
The primary syndrome involves periosteal proliferation on the this clinical syndrome has been associated with the acephalic
cortices of long bones. The condition is classically described metacestode.
to occur secondary to an intrathoracic mass yet may develop Affected horses may have intermittent fever, depression,
secondary to extrathoracic lesions as well. Although HO is rapid shallow respiration, pectoral edema, and nonspecific
more common in humans and dogs, it also occurs in horses. laboratory findings indicative of inflammation.19 A large vol-
In horses, it has been reported in association with a variety ume of pleural effusion is a consistent finding in horses with
of pulmonary conditions including infection, neoplasia, and pulmonary and pleural metacestode infection. The effusion
trauma.540,617 Thoracic neoplasia is an uncommon disease in has low to moderate cellularity (5000–80,000 cells/μL), 20%
horses, with HO being rarely reported in affected individu- to 80% neutrophils, and markedly increased protein concen-
als. This finding is in contrast to the findings in humans in tration (5.0–8.0 g/dL) and may be difficult to differentiate
which up to 10% of patients with thoracic neoplasia develop from neoplastic effusion.529 Bacterial and fungal culture of the
HO, often characterized by clubbing of the fingers, dermal pleural fluid is negative. Ultrasound examination may reveal
changes, limb swelling, and arthropathy.616 In canine patients a large fluid-filled cyst within the pulmonary parenchyma, on
suffering from HO, the most common predisposing factor is the surface of the diaphragm, and/or within the hepatic paren-
consistently pulmonary neoplasia.614 The presence of HO in chyma. Metacestodes may be attached to a thickened pleural
an equine patient should alert the clinician to be aware of the surface, or hypoechoic cysts (1 × 4 mm) may be seen floating
potential for intrathoracic disease. within the pleural or peritoneal fluid.
Although HO is a relatively uncommon condition in Treatment of a horse with an unidentified aberrant, ace-
horses, it has been described to occur in association with phalic metacestode utilized albendazole (10 mg/kg, PO, s.i.d.
pulmonary and extrapulmonary disease. Previous retrospec- × 30 days), thoracic drainage, and surgical debridement of the
tive reports that described HO in horses include a total of 42 pleura and cyst (10 × 10 × 17) on the surface of the diaphragm.
cases.540,617,618 These reports are divided among individual case Disruption of a cyst by centesis or surgery may result in an
reports that date back to 1944 and a more recent retrospective anaphylactic reaction or seeding of daughter metacestodes
within the thoracic cavity. Surgical intervention was per- 21. Perricone G, Mazzarelli C. Images in clinical medicine. Reex-
formed in this case after 2 weeks of antiparasitic therapy. The pansion pulmonary edema after thoracentesis. N Engl J Med.
horse was asymptomatic 6 weeks after treatment and returned 2014;370:e19.
to athletic performance for several years. 22. Tomlinson JE, Reef VB, Boston RC, et al. The Association of
Fibrinous Pleural Effusion with Survival and Complications
in Horses with Pleuropneumonia (2002-2012): 74 Cases. J Vet
REFERENCES Intern Med. 2015;29:1410–1417.
1. Rossdale PD, Hopes R, Digby NJ, et al. Epidemiological study 23. Reef VB. Advances in diagnostic ultrasonography. Vet Clin
of wastage among racehorses 1982 and 1983. Vet Rec. 1985;116: North Am Equine Pract. 1991;7:451–466.
66–69. 24. Reef VB, Whittier M, Allam LG. Thoracic ultrasonography.
2. Perkins NR, Reid SWJ, Morris RS. Profiling the New Zealand Clin Tech Equine Pract. 2004;3:284–293.
Thoroughbred racing industry. 2. Conditions interfering with 25. Reef VB. Thoracic ultrasonography. Equine Diagnostic Ultra-
training and racing. New Zeal Vet J. 2005;53:69–76. sound. Philadelphia: W. B. Saunders; 1998:187–214.
3. Long MT. Mechanisms of Infectious Disease. In: Reed SM 26. Reef VB. Thoracic ultrasonography: noncardiac imaging. In:
BW, Sellon DC, eds. Equine Internal Medicine. 2nd ed. St. Reef VB, ed. Equine Diagnostic Ultrasound. Philadelphia: W. B.
Louis: Saunders; 2004:59–74. Saunders; 1998:187–214.
4. Bailey GD, Love DN. Oral associated bacterial infection in 27. Dunkel B, Gibbs C, Weller R. A fresh approach to equine tho-
horses: studies on the normal anaerobic flora from the pharyn- racic radiography. In Practice. 2013;35:589–596.
geal tonsillar surface and its association with lower respiratory 28. Robinson NE. Tests of equine airway function. in Proc Am Coll
tract and paraoral infections. Vet Microbiol. 1991;26:367–379. Vet Intern Med Forum. 1992:284.
5. Raidal SL, Love DN, Bailey GD. Inflammation and increased 29. Robinson NE. The physiologic basis of pulmonary function
numbers of bacteria in the lower respiratory tract of horses tests. Proc Am Coll Vet Intern Med. 1992:403.
within 6 to 12 hours of confinement with the head elevated. 30. Young SS, Hall LW. A rapid, non-invasive method for meas-
Aust Vet J. 1995;72:45–50. uring total respiratory impedance in the horse. Equine Vet J.
6. Raidal SL, Love DN, Bailey GD. Effect of a single bout of high 1989;21:99–105.
intensity exercise on lower respiratory tract contamination in 31. van EE, Votion D, Art T, et al. Measurement of respiratory
the horse. Aust Vet J. 1997;75:293–295. function by impulse oscillometry in horses. Equine Vet J.
7. Raidal SL, Love DN, Bailey GD. Effects of posture and accu- 2004;36:21–28.
mulated airway secretions on tracheal mucociliary transport 32. Hare JE, Viel L. Pulmonary eosinophilia associated with in-
in the horse. Aust Vet J. 1996;73:45–49. creased airway responsiveness in young racing horses. J Vet In-
8. Jones AL, Sutcliffe IC, Goodfellow M. Prescottia equi gen. nov., tern Med. 1998;12:163–170.
comb. Nov.: a new home for an old pathogen Antonie Van Leeu- 33. Hoffman AM, Mazan MR, Ellenberg S. Association between
wenhoek. Int J Gen Microbiol Biotechnol. 2013;103:655–671. bronchoalveolar lavage cytologic features and airway reactivity
9. Kotlikoff MI, Gillespie JR. Lung sounds in veterinary medicine in horses with a history of exercise intolerance. Am J Vet Res.
part II. Deriving clinical information from lung sounds. Com- 1998;59:176–181.
pend Contin Educ Pract Vet. 1984;6:462. 34. Couetil LL, Rosenthal FS, DeNicola DB, et al. Clinical signs,
10. Forgacs P. Lung Sounds. London: Bailliere Tindall; 1978. evaluation of bronchoalveolar lavage fluid, and assessment of
11. Bakos Z, Voros K. Thoracic percussion to determine the cau- pulmonary function in horses with inflammatory respiratory
dal lung border in healthy horses. J Vet Intern Med. 2007;21: disease. Am J Vet Res. 2001;62:538–546.
504–507. 35. Mazan MR, Hoffman AM, Manjerovic N. Comparison of
12. Allen KJ, Franklin SH. Comparisons of overground endosco- forced oscillation with the conventional method for histamine
py and treadmill endoscopy in UK Thoroughbred racehorses. bronchoprovocation testing in horses. Am J Vet Res. 1999;60:
Equine Vet J. 2010;42:186–191. 174–180.
13. Franklin SH, Naylor JR, Lane JG. Videoendoscopic evaluation 36. Art T, Anderson L, Woakes AJ. Mechanics of breathing dur-
of the upper respiratory tract in 93 sport horses during exer- ing strenuous exercise in Thoroughbred horses. Respir Physiol.
cise testing on a high-speed treadmill. Equine Vet J Suppl. 2006: 1990;82:279.
540–545. 37. Raphel CF, Gunson DE. Percutaneous lung biopsy in the
14. Morrow KL, Park RD, Spurgeon TL, et al. Computed tomo- horse. Cornell Vet. 1981;71:439–448.
graphic imaging of the equine head. Vet Radiol Ultrasound. 38. Venner M, Schmidbauer S, Drommer W, et al. Percutaneous
2000;41:491–497. lung biopsy in the horse: comparison of two instruments and
15. Kraft SL, Gavin PR. Physical principles and technical consid- repeated biopsy in horses with induced acute interstitial pneu-
erations for equine computed tomography and magnetic reso- mopathy. J Vet Intern Med. 2006;20:968–973.
nance imaging of equine musculoskeletal conditions. Vet Clin 39. Savage CJ, Traub-Dargatz JL, Mumford EL. Survey of the large
North Am Equine Pract. 2001;17:115–121. animal diplomates of the American College of Veterinary In-
16. Barakzai SZ, Barnett TP. Computed tomography and scintig- ternal Medicine regarding percutaneous lung biopsy in the
raphy for evaluation of dental disease in the horse. Equine Vet horse. J Vet Intern Med. 1998;12:456–464.
Educ. 2015;27:323–331. 40. Pusterla N, Watson JL, Madigan JE. Technique and diagnostic
17. Manso-Diaz G, Dyson SJ, Dennis R, et al. Magnetic resonance value of percutaneous lung biopsy in 66 horses with diffuse
imaging characteristics of equine head disorders: 84 cases pulmoanry diseases using an automated biopsy device. Equine
(2000-2013). Vet Radiol Ultrasound. 2015;56:176–187. Vet Educ. 2007;19:157–202.
18. Koblinger K, Hecker K, Nicol J, et al. Bronchial collapse dur- 41. Moorthy AR, Spradbrow PB. Isolation of mycoplasmas from
ing bronchoalveolar lavage in horses is an indicator of lung the respiratory tract of horses in Australia. Vet Rec. 1976;98:
inflammation. Equine Vet J. 2014;46:50–55. 235–237.
19. Koblinger K, Nicol J, McDonald K, et al. Endoscopic assess- 42. Tan RM, DeFrancisco AL, Singh K. Pathology in practice. Se-
ment of airway inflammation in horses. J Vet Intern Med. vere chronic diffuse pyogranulomatous, necrohemorrhagic and
2011;25:1118–1126. eosinophilic rhinitis caused by Conidiobolus. J Am Vet Med As-
20. Blutke A, Hamel D, Huttner M, et al. Cystic echinococcosis soc. 2010;236:831–833.
due to Echinococcus equinus in a horse from southern Ger- 43. Arun S, Neubauer H, Gurel A, et al. Equine glanders in Turkey.
many. J Vet Diagn Invest. 2010;22:458–462. Vet Rec. 1999;144:255–258.
44. Malik P, Singha H, Goyal SK, et al. Incidence of Burkholderia 68. Marriott MR, Dart AJ, Hodgson DR. Treatment of progressive
mallei infection among indigenous equines in India. Vet Rec ethmoidal haematoma using intralesional injections of forma-
Open. 2015;2:e000129. lin in three horses. Aust Vet J. 1999;77:371–373.
45. Greet T. Differential diagnosis of nasal discharge in the horse. 68a Blazyczek I, Hamann H, Ohnesorge B, et al. Population genetic
In Practice. 1986;8:49–57. analysis of the heritability of gutteral pouch tympany in Arabian
46. Korenek NL, Legendre AM, Andrews FM, et al. Treatment of purebred foals. Dtsch Tierarztl Wochenschr. 2003;110:417–419.
mycotic rhinitis with itraconazole in three horses. J Vet Intern 68b Dixon PM, Rowlands AC. Atlanto-occipital joint infection as-
Med. 1994;8:224–227. sociated with guttural pouch mycosis in a horse. Equine Vet J.
47. Cruz VC, Sommardahl CS, Chapman EA, et al. Successful 1981;13:260–262.
treatment of a sinonasal cryptococcal granuloma in a horse. 69. Frees KE, Gaughan EM, Lillich JD, et al. Severe complication
J Am Vet Med Assoc. 2009;234:509–513. after administration of formalin for treatment of progres-
48. Deegen E. The causes of rhinorrhea in horses. Tierarztl Prax. sive ethmoidal hematoma in a horse. J Am Vet Med Assoc.
1973;1:169–176. 2001;219:950–952. 939.
49. Riley CB, Bolton JR, Mills JN, et al. Cryptococcosis in seven 70. Specht TE, Colahan PT, Nixon AJ, et al. Ethmoidal hematoma
horses. Aust Vet J. 1992;69:135–139. in nine horses. J Am Vet Med Assoc. 1990;197:613–616.
50. Ziemer EL, Pappagianis D, Madigan JE, et al. Coccidioido- 71. Hanselka DV, Young MF. Ethmoidal hematoma in the horse.
mycosis in horses: 15 cases (1975-1984). J Am Vet Med Assoc. Vet Med Small Anim Clin. 1975;70:1289–1291.
1992;201:910–916. 72. Schumacher J, Yarbrough T, Pascoe J, et al. Transendoscopic
51. Tremaine WH, Dixon PM. A long-term study of 277 cases chemical ablation of progressive ethmoidal hematomas in
of equine sinonasal disease. Part 1: details of horses, histori- standing horses. Vet Surg. 1998;27:175–181.
cal, clinical and ancillary diagnostic findings. Equine Vet J. 73. Freeman DE. Update on disorders and treatment of the gut-
2001;33:274–282. tural pouch. Vet Clin North Am Equine Pract. 2015;31:63–89.
52. Fiske-Jackson AR, Pollock PJ, Witte TH, et al. Fungal sinusi- 74. Dyce KM, Sack WO, Wensing T. The head and ventral neck of the
tis resulting in suspected trigeminal neuropathy as a cause of horse: the guttural pouch. In Textbook of Veterinary Anatomy.
headshaking in 5 horses. Equine Vet Educ. 2012;24:126–133. 2nd ed. Philadelphia: W. B. Saunders; 1996:501–504.
53. Henninger W, Frame EM, Willmann M, et al. CT features 75. McCue PM, Freeman DE, Donawick WJ. Guttural pouch
of alveolitis and sinusitis in horses. Vet Radiol Ultrasound. tympany: 15 cases (1977-1986). J Am Vet Med Assoc.
2003;44:269–276. 1989;194:1761–1763.
54. Probst A, Henninger W, Willmann M. Communications of 76. Blazyczek I, Hamann H, Deegen E, et al. Retrospective anal-
normal nasal and paranasal cavities in computed tomography ysis of 50 cases of guttural pouch tympany in foals. Vet Rec.
of horses. Vet Radiol Ultrasound. 2005;46:44–48. 2004;154:261–264.
55. Swor TM, Skirpstunas RT, Hines MT, et al. What is your diagno- 77. Blazyczek I, Hamann H, Ohnesorge B, et al. Population genetic
sis? Soft tissue opacification of the right maxillary sinus and lysis analysis of the heritability of gutteral pouch tympany in Arabian
of the maxillary bone. J Am Vet Med Assoc. 2001;218:347–348. purebred foals. Dtsch Tierarztl Wochenschr. 2003;110:417–419.
56. Freeman DE. Sinus disease. Vet Clin North Am Equine Pract. 78. Blazyczek I, Hamann H, Ohnesorge B, et al. Gutteral pouch
2003;19:209–243. viii. tympany in German warmblood foals: influence of sex, in-
57. Davis PR, Meyer GA, Hanson RR, et al. Pseudallescheria boy- breeding and blood proportions of founding breeds as well as
dii infection of the nasal cavity of a horse. J Am Vet Med Assoc. estimation of heritability. Berl Munch Tierarztl Wochenschr.
2000;217:707–709. 674. 2003;116:346–351.
58. Dixon PM, Parkin TD, Collins N, et al. Equine paranasal sinus 79. Blazyczek I, Hamann H, Ohnesorge B, et al. Inheritance of gut-
disease: a long-term study of 200 cases (1997-2009): ancillary tural pouch tympany in the arabian horse. J Hered. 2004;95:
diagnostic findings and involvement of the various sinus com- 195–199.
partments. Equine Vet J. 2012;44:267–271. 80. Zeitz A, Spotter A, Blazyczek I, et al. Whole-genome scan for
59. Tessier C, Bruhschwein A, Lang J, et al. Magnetic resonance guttural pouch tympany in Arabian and German warmblood
imaging features of sinonasal disorders in horses. Vet Radiol horses. Anim Genet. 2009;40:917–924.
Ultrasound. 2013;54:54–60. 81. Freeman DE, Hardy J. Guttural Pouch. In: Auer JA, Stick JA,
60. Perkins JD, Windley Z, Dixon PM, et al. Sinoscopic treatment eds. Equine Surgery. 4th ed. St. Louis: Elsevier Saunders; 2012:
of rostral maxillary and ventral conchal sinusitis in 60 horses. 623–642.
Vet Surg. 2009;38:613–619. 82. Cook W. Diseases of the Ear, Nose and Throat in the Horse.
61. Dixon PM, Parkin TD, Collins N, et al. Historical and clinical Bristol, UK: John Wright and Sons; 1971:12.
features of 200 cases of equine sinus disease. Vet Rec. 83. Ludwig A, Gatineau S, Reynaud MC, et al. Fungal isolation
2011;169:439. and identification in 21 cases of guttural pouch mycosis in
62. Sullivan M, Burrell MH, McCandlish IA. Progressive haematoma horses (1998-2002). Vet J. 2005;169:457–461.
of the maxillary sinus in a horse. Vet Rec. 1984;114:191–192. 84. Archer RM, Knight CG, Bishop WJ. Guttural pouch mycosis
63. Laing JA, Hutchins DR. Progressive ethmoidal haematoma in in six horses in New Zealand. N Z Vet J. 2012;60:203–209.
horses. Aust Vet J. 1992;69:57–58. 85. Caron JP, Fretz PB, Bailey JV, et al. Balloon-tipped catheter
64. Greet TR. Outcome of treatment in 23 horses with progressive arterial occlusion for prevention of hemorrhage caused by gut-
ethmoidal haematoma. Equine Vet J. 1992;24:468–471. tural pouch mycosis: 13 cases (1982-1985). J Am Vet Med Assoc.
65. Tremaine WH, Dixon PM. A long-term study of 277 cases 1987;191:345–349.
of equine sinonasal disease. Part 2: treatments and results of 86. Church S, Wyn-Jones G, Parks AH, et al. Treatment of guttural
treatments. Equine Vet J. 2001;33:283–289. pouch mycosis. Equine Vet J. 1986;18:362–365.
66. Dixon PM, Parkin TD, Collins N, et al. Equine paranasal sinus 87. Cook WR, Campbell RS, Dawson C. The pathology and aetiol-
disease: a long-term study of 200 cases (1997-2009): ancillary ogy of guttural pouch mycosis in the horse. Vet Rec. 1968;83:
diagnostic findings and involvement of the various sinus com- 422–428.
partments. Equine Vet J. 2012;44:267–271. 88. Freeman DE, Ross MW, Donawick WJ, et al. Occlusion of the ex-
67. Tucker R, Windley ZE, Abernethy AD, et al. Radiographic, ternal carotid and maxillary arteries in the horse to prevent hem-
computed tomographic and surgical anatomy of the equine orrhage from guttural pouch mycosis. Vet Surg. 1989;18:39–47.
sphenopalatine sinus in normal and diseased horses. Equine 89. Greet TR. Outcome of treatment in 35 cases of guttural pouch
Vet J. 2016;48:578–584. mycosis. Equine Vet J. 1987;19:483–487.
90. Freeman DE, Long-term. follow-up on a large number of 113. Gehlen H, Ohnesorge B. Laser fenestration of the mesial sep-
horses that underwent transarterial coil embolisation (TCE) tum for treatment of guttural pouch chondroids in a pony. Vet
for guttural pouch mycosis (GPM). Equine Vet J. 2006;38:271. Surg. 2005;34:383–386.
91. Walmsley JP. A case of atlanto-occipital arthropathy follow- 114. Hawkins JF, Frank N, Sojka JE, et al. Fistulation of the auditory
ing guttural pouch mycosis in a horse. The use of radioisotope tube diverticulum (guttural pouch) with a neodymium: yttri-
bone scanning as an aid to diagnosis. Equine Vet J. 1988;20: um-aluminum-garnet laser for treatment of chronic empyema
219–220. in two horses. J Am Vet Med Assoc. 2001;218:405–407. 361.
92. Dixon PM, Rowlands AC. Atlanto-occipital joint infection as- 115. Holcombe SJ. Medical Treatment of Upper Airway Dysfunc-
sociated with guttural pouch mycosis in a horse. Equine Vet J. tion. In: Robinson NE, ed. Current Therapy in Equine Medi-
1981;13:260–262. cine. 5th ed. Philadelphia: Saunders; 2003:398–400.
93. Millar H. Guttural pouch mycosis in a 6-month-old filly. Can 116. Moore BR, Krakowka S, Cummins JM, et al. Changes in air-
Vet J. 2006;47:259–261. way inflammatory cell populations in standardbred racehorses
94. Ryan JA, Modransky PD, Welker B. Guttural pouch mycosis in after interferon-alpha administration. Vet Immunol Immuno-
a 3-month old foal. Equine Practice. 1992;14:21–22. pathol. 1996;49:347–358.
95. Cook WR. The clinical features of guttural pouch mycosis in 117. Moore BR. Clinical application of interferons in large animal
the horse. Vet Rec. 1968;83:336–345. medicine. J Am Vet Med Assoc. 1996;208:1711–1715.
96. Colles CM, Cook WR. Carotid and cerebral angiography in 118. Palmer SE. The use of lasers for treatment of upper res-
the horse. Vet Rec. 1983;113:483–489. piratory tract disorders. Vet Clin North Am Equine Pract.
97. Lane JG. The management of guttural pouch mycosis. Equine 2003;19:245–263.
Vet J. 1989;21:321–324. 119. Ainsworth D, Hackett RP. Disorders of the respiratory system.
98. Eichentopf A, Snyder A, Recknagel S, et al. Dysphagia caused In: Fathman L, Merchant T, eds. Reed, Bayly and Sellon: Equine
by focal guttural pouch mycosis: mononeuropathy of the phar- Internal Medicine. 2nd ed. St. Louis: Saunders; 2004:289–353.
yngeal ramus of the vagal nerve in a 20-year-old pony mare. Ir 120. Lane JG, Bladon B, Little DR, et al. Dynamic obstructions of
Vet J. 2013;66:13. the equine upper respiratory tract. Part 1: observations during
99. Lepage OM, Piccot-Crezollet C. Transarterial coil embolisa- high-speed treadmill endoscopy of 600 Thoroughbred race-
tion in 31 horses (1999-2002) with guttural pouch mycosis: a horses. Equine Vet J. 2006;38:393–399.
2-year follow-up. Equine Vet J. 2005;37:430–434. 121. Tan RH, Dowling BA, Dart AJ. High-speed treadmill videoen-
99a. Holcombe SJ. Medical Treatment of Upper Airway Dysfunc- doscopic examination of the upper respiratory tract in the
tion. In: Robinson NE, ed. Current Therapy in Equine Medi- horse: the results of 291 clinical cases. Vet J. 2005;170:243–248.
cine. 5th ed. Philadelphia: Saunders; 2003:398–400. 122. Ducharme NG. Larynx. Equine Surgery. 3rd ed. St. Louis
100. McMullan WC, Joyce JR, Hanselka DV, et al. Amphotericin B (MO): Elsevier Saunders; 2006:592–622.
for the treatment of localized subcutaneous phycomycosis in 123. Dart AJ, Dowling BA, Hodgson DR, et al. Evaluation of
the horse. J Am Vet Med Assoc. 1977;170:1293–1298. high-speed treadmill videoendoscopy for diagnosis of upper
101. Davis JL. The use of antifungals. Comp Equine. 2008;3:128–133. respiratory tract dysfunction in horses. Aust Vet J. 2001;79:
102. Davis JL, Salmon JH, Papich MG. Pharmacokinetics and tissue 109–112.
distribution of itraconazole after oral and intravenous admin- 124. Barakzai SZ, Johnson VS, Baird DH, et al. Assessment of the
istration to horses. Am J Vet Res. 2005;66:1694–1701. efficacy of composite surgery for the treatment of dorsal dis-
103. Davis EW, Legendre AM. Successful treatment of guttural placement of the soft palate in a group of 53 racing Thorough-
pouch mycosis with itraconazole and topical enilconazole in a breds (1990-1996). Equine Vet J. 2004;36:175–179.
horse. J Vet Intern Med. 1994;8:304–305. 125. Parente EJ, Martin BB, Tulleners EP, et al. Dorsal displacement
104. Benredouane K, Lepage O. Trans-arterial coil embolization of the soft palate in 92 horses during high-speed treadmill ex-
of the internal carotid artery in standing horses. Vet Surg. amination (1993-1998). Vet Surg. 2002;31:507–512.
2012;41:404–409. 126. Lane JG, Bladon B, Little DR, et al. Dynamic obstructions
105. Freeman DE, Staller GS, Maxson AD, et al. Unusual internal ca- of the equine upper respiratory tract. Part 2: comparison of
rotid artery branching that prevented arterial occlusion with a endoscopic findings at rest and during high-speed treadmill
balloon-tipped catheter in a horse. Vet Surg. 1993;22:531–534. exercise of 600 Thoroughbred racehorses. Equine Vet J. 2006;38:
106. Bacon MC, Wilson DA, Martin DD, et al. Complications of 401–407.
balloon catheterization associated with aberrant cerebral arte- 127. Rehder RS, Ducharme NG, Hackett RP, et al. Measurement of
rial anatomy in a horse with guttural pouch mycosis. Vet Surg. upper airway pressures in exercising horses with dorsal dis-
1998;27:450–453. placement of the soft palate. Am J Vet Res. 1995;56:269–274.
107. Lepage OM, Piccot-Crezollet C. Transarterial coil embolisa- 128. Cook WR. Some observations on form and function on the
tion in 31 horses (1999-2002) with guttural pouch mycosis: a upper airway in health and disease. Proc Am Assoc Eq Pract.
2-year follow-up. Equine Vet J. 2005;37:430–434. 1981:355–392.
108. Judy CE, Chaffin MK, Cohen ND. Empyema of the guttural 129. Fogel RB, Trinder J, White DP. The effect of sleep onset on up-
pouch (auditory tube diverticulum) in horses: 91 cases (1977- per airway muscle activity in patients with sleep apena versus
1997). J Am Vet Med Assoc. 1999;215:1666–1670. controls. J Physiol. 2005;564:549.
109. Rashmir-Raven AM, DeBowes RM, Gift LJ. What’s your diag- 130. Gumery PY, Roux-Buisson H, Meignen S, et al. An adaptive
nosis? Upper airway obstruction in a horse caused by pharyn- detector of genioglossus EMG reflex using Berkner transform
geal perforation during nasogastric intubation. J Am Vet Med for time latency measurement in OSA pathophysiological
Assoc. 1991;198:1991–1992. studies. IEEE Trans Biomed Eng. 2005;52:1382–1389.
110. Sweeney CR, Timoney JF, Newton JR, et al. Streptococcus equi 131. Tessier C, Holcombe SJ, Derksen FJ, et al. Effects of stylo-
infections in horses: guidelines for treatment, control, and pre- pharyngeus muscle dysfunction on the nasopharynx in exer-
vention of strangles. J Vet Intern Med. 2005;19:123–134. cising horses. Equine Vet J. 2004;36:318–323.
111. Verheyen K, Newton JR, Talbot NC, et al. Elimination of gut- 132. Holcombe SJ, Derksen FJ, Stick JA, et al. Effect of bilateral
tural pouch infection and inflammation in asymptomatic carri- blockade of the pharyngeal branch of the vagus nerve on soft
ers of Streptococcus equi. Equine Vet J. 2000;32:527–532. palate function in horses. Am J Vet Res. 1998;59:504–508.
112. Seahorn TL, Schumacher J. Nonsurgical removal of chondroid 133. Holcombe SJ, Derksen FJ, Stick JA, et al. Effect of bilateral
masses from the guttural pouches of two horses. J Am Vet Med tenectomy of the tensor veli palatini muscle on soft palate
Assoc. 1991;199:368–369. function in horses. Am J Vet Res. 1997;58:317–321.
134. Ducharme NG, Hackett RP, Woodie JB, et al. Investigations 156. Chalmers HJ, Cheetham J, Yeager AE, et al. Ultrasonogra-
into the role of the thyrohyoid muscles in the pathogenesis of phy of the equine larynx. Vet Radiol Ultrasound. 2006;47:
dorsal displacement of the soft palate in horses. Equine Vet J. 476–481.
2003;35:258–263. 157. Quinlan TJ, Goulden BE, Barnes GR, et al. Innervation of the
135. Holcombe SJ, Beard WL, Hinchcliff KW, et al. Effect of sterno- equine intrinsic laryngeal muscles. N Z Vet J. 1982;30:43–45.
thyrohyoid myectomy on upper airway mechanics in normal 158. Duncan ID, Griffths IR, McQueen A, et al. The pathology
horses. J Appl Physiol (1985). 1994;77:2812–2816. of equine laryngeal hemiplegia. Acta Neuropathol. 1974;27:
136. Malhotra A, Pillar G, Fogel RB, et al. Pharyngeal pressure and 337–348.
flow effects on genioglossus activation in normal subjects. Am 159. Gunn HM. Histochemical observations on laryngeal skeletal
J Respir Crit Care Med. 2002;165:71–77. muscle fibers in “normal” horses. Equine Vet J. 1972;4:144.
137. Brennick MJ, Ogilvie MD, Margulies SS, et al. MRI study of re- 160. Cahill JI, Goulden BE. The pathogenesis of equine laryngeal
gional variations of pharyngeal wall compliance in cats. J Appl hemiplegia—a review. N Z Vet J. 1987;35:82–90.
Physiol (1985). 1998;85:1884–1897. 161. Dattilo DJ, Drooger SA. Outcome assessment of patients un-
138. Franklin SH, Naylor JR, Lane JG. The effect of a tongue-tie in dergoing maxillofacial procedures for the treatment of sleep
horses with dorsal displacement of the soft palate. Equine Vet J apnea: comparison of subjective and objective results. J Oral
Suppl. 2002;34:430–433. Maxillofac Surg. 2004;62:164–168.
139. Ducharme NG. Pharynx. Equine Surgery. 3rd ed. St. Louis 161a. Ducharme NG, Horney FD, Partlow GD, et al. Attempts to
(MO): Elsevier Saunders; 2006:569–591. restore abduction of the paralyzed equine arytenoid cartilage.
140. Harrison IW, Raker CW. Sternothyrohyoideus myectomy in I. Nerve-muscle pedicle transplants. Can J Vet Res. 1989;53:
horses: 17 cases (1984-1985). J Am Vet Med Assoc. 1988;193: 202–209.
1299–1302. 161b. Fulton IC, Derksen FJ, Stick JA, et al. Treatment of left laryn-
141. Anderson JD, Tulleners EP, Johnston JK, et al. Sternothyrohy- geal hemiplegia in standardbreds, using a nerve muscle pedicle
oideus myectomy or staphylectomy for treatment of intermit- graft. Am J Vet Res. 1991;52:1461–1467.
tent dorsal displacement of the soft palate in racehorses: 209 162. COLE CR. Changes in the equine larynx associated with la-
cases (1986-1991). J Am Vet Med Assoc. 1995;206:1909–1912. ryngeal hemiplegia. Am J Vet Res. 1946;7:69–77.
142. Ahren TJ. Oral palatopharyngoplasty. J Equine Vet Sci. 1993; 163. Derksen FJ, Stick JA, Scott EA, et al. Effect of laryngeal hemi-
13:670–672. plegia and laryngoplasty on airway flow mechanics in exercis-
143. Barakzai SZ, Dixon PM. Conservative treatment for thorough- ing horses. Am J Vet Res. 1986;47:16–20.
bred racehorses with intermittent dorsal displacement of the 164. Brown JA, Derksen FJ, Stick JA, et al. Laser vocal cordectomy
soft palate. Vet Rec. 2005;157:337–340. fails to effectively reduce respiratory noise in horses with la-
144. Woodie JB, Ducharme NG, Kanter P, et al. Surgical advance- ryngeal hemiplegia. Vet Surg. 2005;34:247–252.
ment of the larynx (laryngeal tie-forward) as a treatment for 165. Shappell KK, Derksen FJ, Stick JA, et al. Effects of ventriculec-
dorsal displacement of the soft palate in horses: a prospective tomy, prosthetic laryngoplasty, and exercise on upper airway
study 2001-2004. Equine Vet J. 2005;37:418–423. function in horses with induced left laryngeal hemiplegia. Am
145. Woodie JB, Ducharme NG, Hackett RP, et al. Can an external J Vet Res. 1988;49:1760–1765.
device prevent dorsal displacement of the soft palate during 166. Tetens J, Derksen FJ, Stick JA, et al. Efficacy of prosthetic lar-
strenuous exercise? Equine Vet J. 2005;37:425–429. yngoplasty with and without bilateral ventriculocordectomy as
146. Goulden BE, Anderson LG. Equine laryngeal hemiplegia. Part treatments for laryngeal hemiplegia in horses. Am J Vet Res.
III. Treatment by laryngoplasty N Z Vet J. 1982;30:1–5. 1996;57:1668–1673.
147. Lane JG, Ellis DR, Greet TR. Observations on the examination 167. Ehrlich PJ, Seeherman HJ, Morris E, et al. The effect of revers-
of Thoroughbred yearlings for idiopathic laryngeal hemiple- ible left recurrent laryngeal neuropathy on the metabolic cost
gia. Equine Vet J. 1987;19:531–536. of locomotion and peak aerobic power in thoroughbred race-
148. Dixon PM, McGorum BC, Railton DI, et al. Laryngeal paraly- horses. Vet Surg. 1995;24:36–48.
sis: a study of 375 cases in a mixed-breed population of horses. 168. Kidd JA, Slone DE. Treatment of laryngeal hemiplegia in
Equine Vet J. 2001;33:452–458. horses by prosthetic laryngoplasty, ventriculectomy and vocal
149. Brown JA, Hinchcliff KW, Jackson MA, et al. Prevalence of cordectomy. Vet Rec. 2002;150:481–484.
pharyngeal and laryngeal abnormalities in Thoroughbreds 169. Hawkins JF, Tulleners EP, Ross MW, et al. Laryngoplasty with
racing in Australia, and their association with performance. or without ventriculectomy for treatment of left laryngeal
Equine Vet J. 2005;37:397–401. hemiplegia in 230 racehorses. Vet Surg. 1997;26:484–491.
150. Brakenhoff JE, Holcombe SJ, Hauptman JG, et al. The preva- 170. Kraus BM, Parente EJ, Tulleners EP. Laryngoplasty with ven-
lence of laryngeal disease in a large population of competition triculectomy or ventriculocordectomy in 104 draft horses
draft horses. Vet Surg. 2006;35:579–583. (1992-2000). Vet Surg. 2003;32:530–538.
151. Harrison GD, Duncan ID, Clayton MK. Determination of the 171. Dixon PM, McGorum BC, Railton DI, et al. Long-term sur-
early age of onset of equine recurrent laryngeal neuropathy. 1. vey of laryngoplasty and ventriculocordectomy in an older,
Muscle pathology. Acta Neuropathol. 1992;84:307–315. mixed-breed population of 200 horses. Part 2: owners’ assess-
152. Dixon P, Robinson NE, Wade JF. Workshop summary Pro- ment of the value of surgery. Equine Vet J. 2003;35:397–401.
ceedings of a workshop on Equine Recurrent Laryngeal Neu- 172. Brown JA, Derksen FJ, Stick JA, et al. Effect of laryngoplasty
ropathy. Stratford-upon-Avon, United Kingdom, R & W Pub- on respiratory noise reduction in horses with laryngeal hemi-
lications (Newmarket) Ltd; 2003. plegia. Equine Vet J. 2004;36:420–425.
153. Rakestraw PC, Hackett RP, Ducharme NG, et al. Arytenoid 173. Schumacher J, Wilson AM, Pardoe C, et al. In vitro evaluation
cartilage movement in resting and exercising horses. Vet Surg. of a novel prosthesis for laryngoplasty of horses with recurrent
1991;20:122–127. laryngeal neuropathy. Equine Vet J. 2000;32:43–46.
154. Ducharme NG. Four-grade system of equine laryngeal function. 174. Radcliffe CH, Woodie JB, Hackett RP, et al. A comparison of
Proceedings of a Workshop on Equine Recurrent Laryngeal laryngoplasty and modified partial arytenoidectomy as treat-
Neuropathy. Stratford-upon-Avon, United Kingdom R & W ments for laryngeal hemiplegia in exercising horses. Vet Surg.
Publications (Newmarket) Ltd; 2003. 2006;35:643–652.
155. Hammer EJ, Tulleners EP, Parente EJ, et al. Videoendoscopic 175. Davenport CL, Tulleners EP, Parente EJ. The effect of recur-
assessment of dynamic laryngeal function during exercise in rent laryngeal neurectomy in conjunction with laryngoplasty
horses with grade-III left laryngeal hemiparesis at rest: 26 cas- and unilateral ventriculocordectomy in thoroughbred race-
es (1992-1995). J Am Vet Med Assoc. 1998;212:399–403. horses. Vet Surg. 2001;30:417–421.
176. Strand E, Martin GS, Haynes PF, et al. Career racing perfor- 198. Schumacher J, Hanselka DV. Nasopharyngeal cicatrices in hors-
mance in Thoroughbreds treated with prosthetic laryngoplasty es: 47 cases (1972-1985). J Am Vet Med Assoc. 1987;191:239–242.
for laryngeal neuropathy: 52 cases (1981-1989). J Am Vet Med 199. Chesen AB, Whitfield-Cargile C. Update on diseases and
Assoc. 2000;217:1689–1696. treatment of the pharynx. Vet Clin North Am Equine Pract.
177. Russell AP, Slone DE. Performance analysis after prosthetic 2015;31:1–11.
laryngoplasty and bilateral ventriculectomy for laryngeal 200. Chesen AB, Rakestraw PC. Indications for and short- and
hemiplegia in horses: 70 cases (1986-1991). J Am Vet Med As- long-term outcome of permanent tracheostomy performed in
soc. 1994;204:1235–1241. standing horses: 82 cases (1995-2005). J Am Vet Med Assoc.
178. Ducharme NG, Horney FD, Partlow GD, et al. Attempts to restore 2008;232:1352–1356.
abduction of the paralyzed equine arytenoid cartilage. I. Nerve- 201. Dean PW, Cohen ND. Arytenoidectomy for advanced uni-
muscle pedicle transplants. Can J Vet Res. 1989;53:202–209. lateral chondropathy with accompanying lesions. Vet Surg.
179. Fulton IC, Derksen FJ, Stick JA, et al. Treatment of left laryn- 1990;19:364–370.
geal hemiplegia in standardbreds, using a nerve muscle pedicle 202. Norman TE, Chaffin MK, Bisset WT, et al. Association of clin-
graft. Am J Vet Res. 1991;52:1461–1467. ical signs with endoscopic findings in horses with nasopharyn-
180. Fulton IC, Derksen FJ, Stick JA, et al. Histologic evaluation geal cicatrix syndrome: 118 cases (2003-2008). J Am Vet Med
of nerve muscle pedicle graft used as a treatment for left la- Assoc. 2012;240:734–739.
ryngeal hemiplegia in standardbreds. Am J Vet Res. 1992;53: 203. Slater JD. Strangles, bastard strangles, vives and glanders: ar-
592–596. chaeological relics in a genomic age. Equine Vet J. 2003;35:118–
181. Barnes AJ, Slone DE, Lynch TM. Performance after partial ar- 120.
ytenoidectomy without mucosal closure in 27 Thoroughbred 204. Bannister MF, Benson CE, Sweeney CR. Rapid species iden-
racehorses. Vet Surg. 2004;33:398–403. tification of group C streptococci isolated from horses. J Clin
182. Russell T, Wainscott M. Treatment in the field of 27 horses Microbiol. 1985;21:524–526.
with epiglottic entrapment. Vet Rec. 2007;161:187–189. 205. Harrington DJ, Sutcliffe IC, Chanter N. The molecular basis
183. McClure SR, Schumacher J, Snyder JR. Transnasal incision of of Streptococcus equi infection and disease. Microbes Infect.
restrictive nasopharyngeal cicatrix in three horses. J Am Vet 2002;4:501–510.
Med Assoc. 1994;205:461–463. 206. Timoney JF, Artiushin SC, Boschwitz JS. Comparison of the
184. Perkins JD, Hughes TK, Brain B. Endoscope-guided, transoral sequences and functions of Streptococcus equi M-like proteins
axial division of an entrapping epiglottic fold in fifteen stand- SeM and SzPSe. Infect Immun. 1997;65:3600–3605.
ing horses. Vet Surg. 2007;36:800–803. 207. Jorm LR, Love DN, Bailey GD, et al. Genetic structure of pop-
185. Lumsden JM, Stick JA, Caron JP, et al. Surgical treatment for ulations of beta-haemolytic Lancefield group C streptococci
epiglottic entrapment in horses: 51 cases (1981-1992). J Am from horses and their association with disease. Res Vet Sci.
Vet Med Assoc. 1994;205:729–735. 1994;57:292–299.
186. Ross MW, Gentile DG, Evans LE. Transoral axial division, un- 208. Sweeney CR, Whitlock RH. Streptococcus equi infection in
der endoscopic guidance, for correction of epiglottic entrap- horses: part I. Compend Contin Educ Pract Vet. 1987;9:689.
ment in horses. J Am Vet Med Assoc. 1993;203:416–420. 209. Prescott JF, Srivastava SK, deGannes R, et al. A mild form of
187. Greet TR. Experiences in treatment of epiglottal entrapment strangles caused by an atypical Streptococcus equi. J Am Vet
using a hook knife per nasum. Equine Vet J. 1995;27:122–126. Med Assoc. 1982;180:293–299.
188. Tate LP, Sweeney CL, Bowman KF, et al. Transendoscopic Nd: 210. Galan JE, Timoney JF, Lengemann FW. Passive transfer of
YAG laser surgery for treatment of epiglottal entrapment and mucosal antibody to Streptococcus equi in the foal. Infect Im-
dorsal displacement of the soft palate in the horse. Vet Surg. mun. 1986;54:202–206.
1990;19:356–363. 211. Sweeney CR, Benson CE, Whitlock RH, et al. Description of
189. Tulleners EP. Correlation of performance with endoscopic an epizootic and persistence of Streptococcus equi infections
and radiographic assessment of epiglottic hypoplasia in race- in horses. J Am Vet Med Assoc. 1989;194:1281–1286.
horses with epiglottic entrapment corrected by use of contact 212. Todd TG. Strangles. J Comp Pathol Ther. 1910;23:212.
neodymium: yttrium aluminum garnet laser. J Am Vet Med As- 213. Timoney JF. The pathogenic equine streptococci. Vet Res. 2004;
soc. 1991;198:621–626. 35:397–409.
190. Tulleners EP. Transendoscopic contact neodymium: yttrium 214. Hamlen HJ, Timoney JF, Bell RJ. Epidemiologic and immuno-
aluminum garnet laser correction of epiglottic entrapment in logic characteristics of Streptococcus equi infection in foals. J
standing horses. J Am Vet Med Assoc. 1990;196:1971–1980. Am Vet Med Assoc. 1994;204:768–775.
191. Ross MW, Gentile DG, Evans LE. Transoral axial division, un- 215. Piche CA. Clinical observations on an outbreak of strangles.
der endoscopic guidance, for correction of epiglottic entrap- Can Vet J. 1984;25:7–11.
ment in horses. J Am Vet Med Assoc. 1993;203:416–420. 216. George JL, Reif JS, Shideler RK, et al. Identification of carriers
192. Kemper T, Spier S, Barratt-Boyes SM, et al. Treatment of Streptococcus equi in a naturally infected herd. J Am Vet
of smoke inhalation in five horses. J Am Vet Med Assoc. Med Assoc. 1983;183:80–84.
1993;202:91–94. 217. Whelchel DD, Chaffin MK. Sequelae and complications of
193. Haynes PF. Dorsal displacement of the soft palate and epi- Streptococcus equi subspecies equi infections in the horse.
glottic entrapment: diagnosis, management and interrelation- Equine Vet Educ. 2009;21:135–141.
ships. Compend Contin Educ Pract Vet. 1983;5:379. 218. Lindahl S, Baverud V, Egenvall A, et al. Comparison of sam-
194. Blikslager AT, Tate LP, Tudor R. Transendoscopic laser treat- pling sites and laboratory diagnostic tests for S. equi subsp.
ment of rostral displacement of the palatopharyngeal arch in equi in horses from confirmed strangles outbreaks. J Vet Intern
four horses. J Clin Laser Med Surg. 1999;17:49–52. Med. 2013;27:542–547.
195. Klein HJ, Deegen E, Stockhofe N, et al. Rostral displacement of 219. Taylor SD, Wilson WD. Streptococcus equi subsp. equi (stran-
the palatopharyngeal arch in a seven-month-old Hanoverian gles) infection. Clin Tech Equine Pract. 2006;5:211–217.
colt. Equine Vet J. 1989;21:382–383. 220. Duffee LR, Stefanovski D, Boston RC, et al. Predictor varia-
196. Goulden BE, Anderson LJ, Davies AS, et al. Rostral displace- bles for and complications associated with Streptococcus equi
ment of the palatopharyngeal arch: a case report. Equine Vet J. subsp equi infection in horses. J Am Vet Med Assoc. 2015;247:
1976;8:95–98. 1161–1168.
197. Crabill M, Schumacher J, Walker M. What is your diagnosis? 221. Newton JR, Wood JL, Dunn KA, et al. Naturally occurring per-
Rostral displacement of the palatopharyngeal arch. J Am Vet sistent and asymptomatic infection of the guttural pouches of
Med Assoc. 1994;204:1347–1348. horses with Streptococcus equi. Vet Rec. 1997;140:84–90.
222. Waller AS, Sellon DC, Sweeney CR, et al. Streptococcal infec- 238. Davidson A, Traub-Dargatz JL, Magnuson R, et al. Lack of cor-
tions. In: Sellon DC, Long MT, eds. Equine Infectious Diseases. relation between antibody titers to fibrinogen-binding protein
2nd ed. St. Louis: Elsevier; 2014:265–277. of Streptococcus equi and persistent carriers of strangles. J Vet
223. Sweeney CR, Timoney JF, Newton JR, et al. Streptococcus Diagn Invest. 2008;20:457–462.
equi infections in horses: guidelines for treatment, con- 239. Boyle AG, Rankin SC, Duffee L, et al. Streptococcus equi
trol, and prevention of strangles. J Vet Intern Med. 2005;19: Detection Polymerase Chain Reaction Assay for Equine Na-
123–134. sopharyngeal and Guttural Pouch Wash Samples. J Vet Intern
224. Jorm LR. Factors affecting the survival of Streptococcus equi Med. 2016;30:276–281.
subsp equi on surfaces. Proc 6th Intnatl Conf Equine Infectious 240. Ramey D. Does early antibiotic use in horses with “strangles”
Diseases. 1991:39–43. cause metastatic Streptococcus equi bacterial infections?
225. Weese JS, Jarlot C, Morley PS. Survival of Streptococcus equi Equine Vet Educ. 2007;19:14.
on surfaces in an outdoor environment. Can Vet J. 2009;50: 241. Sweeney CR, Benson CE, Whitlock RH. Streptococcus equi
968–970. infection in horses. Part 2. Compend Contin Educ Pract Vet.
226. Sechi LA, Roger F, Diallo A, et al. Molecular characterization 1987;9:845–850.
of Streptococcus equi subspecies equi isolated from an Ethio- 242. Rumbaugh GE, Smith BP, Carlson GP. Internal abdominal ab-
pian camel by ribotyping and PCR-ribotyping. New Microbiol. scesses in the horse: a study of 25 cases. J Am Vet Med Assoc.
1999;22:383–387. 1978;172:304–309.
227. Yigezu LM, Roger F, Kiredjian M, et al. Isolation of Strepto- 243. Spoormakers TJ, Ensink JM, Goehring LS, et al. Brain abscesses
coccus equi subspecies equi (strangles agent) from an Ethio- as a metastatic manifestation of strangles: symptomatology
pian camel. Vet Rec. 1997;140:608. and the use of magnetic resonance imaging as a diagnostic aid.
228. Breiman RF, Silverblatt FJ. Systemic Streptococcus equi in- Equine Vet J. 2003;35:146–151.
fection in a horse handler—a case of human strangles. West J 244. Pusterla N, Watson JL, Affolter VK, et al. Purpura haemor-
Med. 1986;145:385–386. rhagica in 53 horses. Vet Rec. 2003;153:118–121.
229. Holden MT, Heather Z, Paillot R, et al. Genomic evidence for 245. Heath SE, Geor RJ, Tabel H, et al. Unusual patterns of serum
the evolution of Streptococcus equi: host restriction, increased antibodies to Streptococcus equi in two horses with purpura
virulence, and genetic exchange with human pathogens. PLoS hemorrhagica. J Vet Intern Med. 1991;5:263–267.
Pathog. 2009;5:e1000346. 246. Galan JE, Timoney JF. Immune complexes in purpura hemor-
230. Anzai T, Sheoran AS, Kuwamoto Y, et al. Streptococcus equi rhagica of the horse contain IgA and M antigen of Streptococ-
but not Streptococcus zooepidemicus produces potent mito- cus equi. J Immunol. 1985;135:3134–3137.
genic responses from equine peripheral blood mononuclear 247. Yelle MT. Clinical aspects of Streptococcus equi infection.
cells. Vet Immunol Immunopathol. 1999;67:235–246. Equine Vet J. 1987;19:158–162.
231. Timoney JF. Strangles. Vet Clin North Am Equine Pract. 248. Todhunter RJ, Brown CM, Stickle R. Retropharyngeal infec-
1993;9:365–374. tions in five horses. J Am Vet Med Assoc. 1985;187:600–604.
232. Evers WD. Effect of furaltadone on strangles in horses. J Am 249. Golland LC, Hodgson DR, Davis RE, et al. Retropharyngeal
Vet Med Assoc. 1968;152:1394–1398. lymph node infection in horses: 46 cases (1977-1992). Aust Vet
232a. Muhktar MM, Timoney JF. Chemotactic response of equine J. 1995;72:161–164.
polymorphonuclear leucocytes to Streptococcus equi. Res Vet 250. De CD, van LG, Nollet H, et al. Percutaneous puncture tech-
Sci. 1988;45:225. nique for treating persistent retropharyngeal lymph node infec-
232b. Hamilton A, Robinson C, Sutcliffe IC, et al. Mutation of the tions in seven horses. Vet Rec. 2003;152:169–172.
maturase lipoprotein attenuates the virulence of Streptococcus 251. Todhunter RJ, Brown CM, Stickle R. Retropharyngeal infec-
equi to a greater extent than does loss of general lipoprotein tions in five horses. J Am Vet Med Assoc. 1985;187:600–604.
lipidation. Infect Immun. 2006;74:6907. 252. Rigg DL, Ramey DW, Reinertson EL. Tracheal compression
232c. Tiwari R, Qin A, Artiushin S, et al. Se18.9, an anti-phagocytic secondary to abscessation of cranial mediastinal lymph nodes
factor H binding protein of Streptococcus equi. Vet Microbiol. in a horse. J Am Vet Med Assoc. 1985;186:283–284.
2007;121:105. 253. Bell RJ, Smart ME. An unusual complication of strangles in a
232d. Kelly C, Bugg M, Robinson C, et al. Sequence variation of the pony. Can Vet J. 1992;33:400–401.
SeM gene of Streptococcus equi allows discrimination of the 254. Finno C, Pusterla N, Aleman M, et al. Streptococcus equi
source of strangles outbreaks. J Clin Microbiol. 2006;44:480. meningoencephalomyelitis in a foal. J Am Vet Med Assoc.
232e. Sheoran AS, Sponseller BT, Holmes MA, et al. Serum and mu- 2006;229:721–724.
cosal antibody isotype responses to M-like protein (SeM) of 255. Lewis SS, Valberg SJ, Nielsen IL. Suspected immune-mediated
Streptococcus equi in convalescent and vaccinated horses. Vet myositis in horses. J Vet Intern Med. 2007;21:495–503.
Immunol Immunopathol. 1997;59:239. 256. Galan JE, Timoney JF. Mucosal nasopharyngeal immune
233. Grant ST, Efstratiou A, Chanter N. Laboratory diagnosis of responses of horses to protein antigens of Streptococcus equi.
strangles and the isolation of atypical Streptococcus equi. Vet Infect Immun. 1985;47:623–628.
Rec. 1993;133:215–216. 257. Borst LB, Patterson SK, Lanka S, et al. Evaluation of a com-
234. Timoney JF, Timoney PJ, Strickland KL. Lysogeny and the im- mercially available modified-live Streptococcus equi subsp
munologically reactive proteins of Streptococcus equi. Vet Rec. equi vaccine in ponies. Am J Vet Res. 2011;72:1130–1138.
1984;115:148. 258. Kemp-Symonds J, Kemble T, Waller A. Modified live Strep-
235. Kaese HJ, Valberg SJ, Hayden DW, et al. Infarctive purpura hem- tococcus equi (‘strangles’) vaccination followed by clinically
orrhagica in five horses. J Am Vet Med Assoc. 2005;226:1893–1898. adverse reactions associated with bacterial replication. Equine
1845. Vet J. 2007;39:284–286.
236. Newton JR, Verheyen K, Talbot NC, et al. Control of strangles 259. Prescott JF, Timoney JF. Could we eradicate strangles in
outbreaks by isolation of guttural pouch carriers identified using equids? J Am Vet Med Assoc. 2007;231:377–378.
PCR and culture of Streptococcus equi. Equine Vet J. 2000;32: 260. Timoney JF, Gillespie JH, Scott FW, et al. The Orthomyxoviri-
515–526. dae. In: Timoney JF, Gillespie JH, Scott FW, et al., eds. Hagan
237. Waller AS, Jolley KA. Getting a grip on strangles: recent and Bruner’s Microbioloby and Infectious Diseases of Domes-
progress towards improved diagnostics and vaccines. Vet J. tic Animals. 8th ed. Ithaca: Comstock Publishing Associates;
2007;173:492–501. 1988:775–789.
261. Wood JM. Antigenic variation of equine influenza: a stable 284. Slater JD, Borchers K, Thackray AM, et al. The trigeminal gangli-
virus. Equine Vet J. 1988;20:316–318. on is a location for equine herpesvirus 1 latency and reactivation
262. Morley PS, Townsend HG, Bogdan JR, et al. Descriptive ep- in the horse. J Gen Virol. 1994;75:2007–2016.
idemiologic study of disease associated with influenza virus 285. Allen GP. Antemortem detection of latent infection with neu-
infections during three epidemics in horses. J Am Vet Med ropathogenic strains of equine herpesvirus-1 in horses. Am J Vet
Assoc. 2000;216:535–544. Res. 2006;67:1401–1405.
263. Newton JR, Verheyen K, Wood JL, et al. Equine influenza in 286. Gilkerson JR, Whalley JM, Drummer HE, et al. Epidemiology
the United Kingdom in 1998. Vet Rec. 1999;145:449–452. of EHV-1 and EHV-4 in the mare and foal populations on a
264. Sovinova O, Tumova B, Pouska F, et al. Isolation of a virus Hunter Valley stud farm: are mares the source of EHV-1 for un-
causing respiratory disease in horses. Acta Virol. 1958;2:52–61. weaned foals. Vet Microbiol. 1999;68:27–34.
265. Waddell GH, Teigland MB, Sigel MM. A new influenza virus 287. Gilkerson JR, Whalley JM, Drummer HE, et al. Epidemiologi-
associated with equine respiratory disease. J Am Vet Med As- cal studies of equine herpesvirus 1 (EHV-1) in Thoroughbred
soc. 1963;143:587–590. foals: a review of studies conducted in the Hunter Valley of New
266. Mumford JA, Hannant D, Jessett DM. Experimental infection South Wales between 1995 and 1997. Vet Microbiol. 1999;68:
of ponies with equine influenza (H3N8) viruses by intrana- 15–25.
sal inoculation or exposure to aerosols. Equine Vet J. 1990;22: 288. Burrows R, Goodridge D. Experimental studies on equine her-
93–98. pesvirus type 1 infections. J Reprod Fertil Suppl. 1975:611–615.
267. Willoughby R, Ecker G, McKee S, et al. The effects of equine 289. Foote CE, Gilkerson JR, Whalley JM, et al. Seroprevalence
rhinovirus, influenza virus and herpesvirus infection on tra- of equine herpesvirus 1 in mares and foals on a large Hunter
cheal clearance rate in horses. Can J Vet Res. 1992;56:115–121. Valley stud farm in years pre- and postvaccination. Aust Vet J.
268. Gilkerson JR, Bailey KE, Diaz-Mendez A, et al. Update on vi- 2003;81:283–288.
ral diseases of the equine respiratory tract. Vet Clin North Am 290. Nugent J, Birch-Machin I, Smith KC, et al. Analysis of equid
Equine Pract. 2015;31:91–104. herpesvirus 1 strain variation reveals a point mutation of
269. Livesay GJ, O’Neill T, Hannant D, et al. The outbreak of equine the DNA polymerase strongly associated with neuropatho-
influenza (H3N8) in the United Kingdom in 1989: diagnostic genic versus nonneuropathogenic disease outbreaks. J Virol.
use of an antigen capture ELISA. Vet Rec. 1993;133:515–519. 2006;80:4047–4060.
270. Mumford JA, Rossdale PD. Virus and its relationship to the 291. Perkins GA, Goodman LB, Tsujimura K, et al. Investigation of
“poor performance” syndrome. Equine Vet J. 1980;12:3–9. the prevalence of neurologic equine herpes virus type 1 (EHV-
271. Kirkland PD, Davis RJ, Gu X, et al. Application of high- 1) in a 23-year retrospective analysis (1984-2007). Vet Micro-
throughput systems for the rapid detection of DNA and RNA biol. 2009;139:375–378.
viruses during the Australian equine influenza outbreak. Aust 292. Lunn DP, vis-Poynter N, Flaminio MJ, et al. Equine herpesvi-
Vet J. 2011;89(suppl 1):38–39. rus-1 consensus statement. J Vet Intern Med. 2009;23:450–461.
272. Quinlivan M, Dempsey E, Ryan F, et al. Real-time reverse 293. Pusterla N, Mapes S, Wilson WD. Diagnostic sensitivity of na-
transcription PCR for detection and quantitative analysis of sopharyngeal and nasal swabs for the molecular detection of
equine influenza virus. J Clin Microbiol. 2005;43:5055–5057. EHV-1. Vet Rec. 2008;162:520–521.
273. Cullinane A, Gildea S, Weldon E. Comparison of primary 294. Browning GF, Bulach DM, Ficorilli N, et al. Latency of equine
vaccination regimes for equine influenza: working towards herpesvirus 4 (equine rhinopneumonitis virus). Vet Rec. 1988;
an evidence-based regime. Equine Vet J. 2014;46:669–673. 123:518–519.
274. El-Hage CM, Savage CJ, Minke JM, et al. Accelerated vac- 295. Palfi V, Christensen LS. Analyses of restriction fragment pat-
cination schedule provides protective levels of antibody and terns (RFPs) and pathogenicity in baby mice of equine herpes-
complete herd immunity to equine influenza. Equine Vet J. virus 1 and 4 (EHV-1 and EHV-4) strains circulating in Dan-
2013;45:235–239. ish horses. Vet Microbiol. 1995;47:199–204.
275. Davison AJ, Eberle R, Ehlers B, et al. The order Herpesvirales. 296. Borchers K, Wolfinger U, Ludwig H, et al. Virological and
Arch Virol. 2009;154:171–177. molecular biological investigations into equine herpes virus
276. Allen GP, Bryans JT. Molecular epizootiology, pathogenesis, type 2 (EHV-2) experimental infections. Virus Res. 1998;55:
and prophylaxis of equine herpesvirus-1 infections. Prog Vet 101–106.
Microbiol Immunol. 1986;2:78–144. 297. Craig MI, Barrandeguy ME, Fernandez FM. Equine herpesvi-
277. Vandekerckhove AP, Glorieux S, Gryspeerdt AC, et al. Equine rus 2 (EHV-2) infection in thoroughbred horses in Argentina.
alphaherpesviruses (EHV-1 and EHV-4) differ in their efficien- BMC Vet Res. 2005;1:9.
cy to infect mononuclear cells during early steps of infection in 298. Johnson PJ. An emerging role for the equine and asinine gam-
nasal mucosal explants. Vet Microbiol. 2011;152:21–28. ma-herpesviruses? 2013.
278. Patel JR, Heldens J. Equine herpesviruses 1 (EHV-1) and 4 299. Murray MJ, Eichorn ES, Dubovi EJ, et al. Equine herpesvirus
(EHV-4) - epidemiology, disease and immunoprophylaxis: a type 2: prevalence and seroepidemiology in foals. Equine Vet J.
brief review. Vet J. 2005;170:14–23. 1996;28:432–436.
279. O’Keefe JS, Alley MR, Jones D, et al. Neonatal mortality 300. Kleiboeker SB, Schommer SK, Johnson PJ, et al. Associa-
due to equid herpesvirus 4 (EHV-4) in a foal. Aust Vet J. tion of two newly recognized herpesviruses with interstitial
1995;72:353–354. pneumonia in donkeys (Equus asinus). J Vet Diagn Invest.
280. Wilkins PA. Lower airway diseases of the adult horse. Vet Clin 2002;14:273–280.
North Am Equine Pract. 2003;19:101–121. vii. 301. Fortier G, van EE, Fortier C, et al. Herpesviruses in respiratory
281. Carr E, Schott H, Pusterla N. Absence of equid herpesvirus-1 liquids of horses: putative implication in airway inflamma-
reactivation and viremia in hospitalized critically ill horses. J tion and association with cytological features. Vet Microbiol.
Vet Intern Med. 2011;25:1190–1193. 2009;139:34–41.
282. Foote CE, Love DN, Gilkerson JR, et al. Detection of EHV- 302. Williams KJ, Maes R, Del PF, et al. Equine multinodular pul-
1 and EHV-4 DNA in unweaned Thoroughbred foals from monary fibrosis: a newly recognized herpesvirus-associated
vaccinated mares on a large stud farm. Equine Vet J. 2004;36: fibrotic lung disease. Vet Pathol. 2007;44:849–862.
341–345. 303. Wong D, Scarratt WK. Equine herpes myeloencephalopathy
283. Slater JD, Borchers K, Field HJ. Equine herpesvirus-1: a neu- in a 12-year-old American quarter horse. Vet Clin North Am
rotropic alphaherpesvirus. Vet Rec. 1994;135:239–240. Equine Pract. 2006;22:177–191.
304. Niedermaier G, Poth T, Gehlen H. Clinical aspects of multi- 327. Klaey M, Sanchez-Higgins M, Leadon DP, et al. Field case
nodular pulmonary fibrosis in two warmblood horses. Vet Rec. study of equine rhinovirus 1 infection: clinical signs and clin-
2010;166:426–430. icopathology. Equine Vet J. 1998;30:267–269.
305. Vengust M, Wen X, Bienzle D. Herpesvirus-associated neuro- 328. Diaz-Mendez A, Viel L, Shewen P, et al. Genomic analysis of a
logical disease in a donkey. J Vet Diagn Invest. 2008;20:820– Canadian equine rhinitis A virus reveals low diversity among
823. field isolates. Virus Genes. 2013;46:280–286.
306. Hart KA, Barton MH, Williams KJ, et al. Multinodular pul- 329. Howell PG. The 1960 epizootic of African Horse Sickness in the
monary fibrosis, pancytopenia and equine herpes virus 5 in Middle East and S. W. Asia. J S Afr Vet Assoc. 1960;31:329–334.
the Thoroughbred gelding. Equine Verterinary Education. 330. Lubroth J. African horse sickness and the epizootic in Spain
2008;20:470–475. 1987. Equine Practice. 1988;10:26–33.
307. Marenzoni ML, Passamonti F, Lepri E, et al. Quantification of 331. Mellor PS, Hamblin C. African horse sickness. Vet Res.
Equid herpesvirus 5 DNA in clinical and necropsy specimens 2004;35:445–466.
collected from a horse with equine multinodular pulmonary 332. Rubio C, Cubillo MA, Hooghuis H, et al. Validation of ELISA
fibrosis. J Vet Diagn Invest. 2011;23:802–806. for the detection of African horse sickness virus antigens and
308. Bentz BG, Maxwell LK, Erkert RS, et al. Pharmacokinetics of antibodies. Arch Virol Suppl. 1998;14:311–315.
acyclovir after single intravenous and oral administration to 333. Lelli R, Molini U, Ronchi GF, et al. Inactivated and adjuvanted
adult horses. J Vet Intern Med. 2006;20:589–594. vaccine for the control of the African horse sickness virus se-
309. Maxwell LK, Bentz BG, Bourne DW, et al. Pharmacokinetics rotype 9 infection: evaluation of efficacy in horses and guinea-
of valacyclovir in the adult horse. J Vet Pharmacol Ther. pig model. Vet Ital. 2013;49:89–98.
2008;31:312–320. 334. Lincoln VJ, Page PC, Kopp C, et al. Protection of horses
310. Schwarz B, Schwendenwein I, van den Hoven R. Successful against Culicoides biting midges in different housing systems
outcome in a case of equine multinodular pulmonary fibrosis in Switzerland. Vet Parasitol. 2015;210:206–214.
(EMPF) treated with valacyclovir. Equine Vet Educ. 2012;2:1–4. 335. Middleton D. Hendra virus. Vet Clin North Am Equine Pract.
311. Wong DM, Belgrave RL, Williams KJ, et al. Multinodular 2014;30:579–589.
pulmonary fibrosis in five horses. J Am Vet Med Assoc. 336. Mahalingam S, Herrero LJ, Playford EG, et al. Hendra virus:
2008;232:898–905. an emerging paramyxovirus in Australia. Lancet Infect Dis.
312. Wilkins PA. Equine multinodular pulmonary fibrosis. 2012;12:799–807.
2004;178–180. 337. Tulsiani SM, Graham GC, Moore PR, et al. Emerging tropi-
313. Timoney PJ, McCollum WH. Equine viral arteritis. Vet Clin cal diseases in Australia. Part 5. Hendra virus. Ann Trop Med
North Am Equine Pract. 1993;9:295–309. Parasitol. 2011;105:1–11.
314. Timoney PJ. Equine viral arteritis: a disease of emerging sig- 338. Playford EG, McCall B, Smith G, et al. Human Hendra virus
nificance? Equine Vet J. 1986;18:166–168. encephalitis associated with equine outbreak, Australia, 2008.
315. Del Piero F, Wilkins PA, Lopez JW, et al. Equine viral arteritis Emerg Infect Dis. 2010;16:219–223.
in newborn foals: clinical, pathological, serological, microbio- 339. Field H, Schaaf K, Kung N, et al. Hendra virus outbreak
logical and immunohistochemical observations. Equine Vet J. with novel clinical features, Australia. Emerg Infect Dis.
1997;29:178–185. 2010;16:338–340.
316. Li F, Browning GF, Studdert MJ, et al. Equine rhinovirus 1 is 340. Field H, de JC, Melville D, et al. Hendra virus infection dy-
more closely related to foot-and-mouth disease virus than to namics in Australian fruit bats. PLoS One. 2011;6:e28678.
other picornaviruses. Proc Natl Acad Sci U S A. 1996;93:990–995. 341. Martin G, Plowright R, Chen C, et al. Hendra virus survival
317. Hartley CA, Ficorilli N, Dynon K, et al. Equine rhinitis A virus: does not explain spillover patterns and implicates relatively
structural proteins and immune response. J Gen Virol. 2001;82: direct transmission routes from flying foxes to horses. J Gen
1725–1728. Virol. 2015;96:1229–1237.
318. Diaz-Mendez A, Viel L, Hewson J, et al. Surveillance of equine 342. Sweeney CR, Holcombe SJ, Barningham SC, et al. Aerobic and
respiratory viruses in Ontario. Can J Vet Res. 2010;74:271–278. anaerobic bacterial isolates from horses with pneumonia or
319. Diaz-Mendez A, Hewson J, Shewen P, et al. Characteristics of pleuropneumonia and antimicrobial susceptibility patterns of
respiratory tract disease in horses inoculated with equine rhini- the aerobes. J Am Vet Med Assoc. 1991;198:839–842.
tis A virus. Am J Vet Res. 2014;75:169–178. 343. Davis E, Rush BR, Herr LG, et al. Enrofloxacin use in a long-
320. Quinlivan M, Maxwell G, Lyons P, et al. Real-time RT-PCR distance transport model of equine respiratory disease. Vet
for the detection and quantitative analysis of equine rhinitis Ther. 2006;7:232–242.
viruses. Equine Vet J. 2010;42:98–104. 344. Wood JL, Newton JR, Chanter N, et al. Association between
321. Plummer G. An equine respiratory virus with enterovirus respiratory disease and bacterial and viral infections in British
properties. Nature. 1962;195:519–520. racehorses. J Clin Microbiol. 2005;43:120–126.
322. Black WD, Wilcox RS, Stevenson RA, et al. Prevalence of se- 345. Blunden AS, Hannant D, Livesay G, et al. Susceptibility of
rum neutralising antibody to equine rhinitis A virus (ERAV), ponies to infection with Streptococcus pneumoniae (capsular
equine rhinitis B virus 1 (ERBV1) and ERBV2. Vet Microbiol. type 3). Equine Vet J. 1994;26:22–28.
2007;119:65–71. 346. Sweeney CR, Holcombe SJ, Barningham SC, et al. Aerobic and
323. Dynon K, Varrasso A, Ficorilli N, et al. Identification of equine anaerobic bacterial isolates from horses with pneumonia or
herpesvirus 3 (equine coital exanthema virus), equine gam- pleuropneumonia and antimicrobial susceptibility patterns of
maherpesviruses 2 and 5, equine adenoviruses 1 and 2, equine the aerobes. J Am Vet Med Assoc. 1991;198:839–842.
arteritis virus and equine rhinitis A virus by polymerase chain 347. Sweeney CR, Divers TJ, Benson CE. Anaerobic bacteria
reaction. Aust Vet J. 2001;79:695–702. in 21 horses with pleuropneumonia. J Am Vet Med Assoc.
324. Fukunaga Y, Kumanomido T, Imagawa H, et al. Isolation of 1985;187:721–724.
picornavirus from horses associated with Getah virus infec- 348. Racklyeft DJ, Love DN. Bacterial infection of the lower res-
tion, Nihon Juigaku. Zasshi. 1981;43:569–572. piratory tract in 34 horses. Aust Vet J. 2000;78:549–559.
325. Fukunaga Y, Kumanomido T, Kamada M. Equine Picornavi- 349. Carr EA, Carlson GP, Wilson WD, et al. Acute hemor-
rus Isolation of Virus from the Oral Cavity of Healthy Horses. rhagic pulmonary infarction and necrotizing pneumonia in
1983;20:103–109. Bulletin of Equine Research Institute. horses: 21 cases (1967-1993). J Am Vet Med Assoc. 1997;210:
326. Lynch SE, Gilkerson JR, Symes SJ, et al. Persistence and chron- 1774–1778.
ic urinary shedding of the aphthovirus equine rhinitis A virus. 350. Wagner AE, Bennett DG. Analysis of equine thoracic fluid. Vet
Comp Immunol Microbiol Infect Dis. 2013;36:95–103. Clin Pathol. 1982;11:13–17.
351. Hepworth-Warren KL, Wilgenbusch CM, Wong DM, et al. 373. Donaldson MT, Beech J, Ennulat D, et al. Interstitial pneumo-
Intrathoracic oesophageal perforation and secondary pleuro- nia and pulmonary fibrosis in a horse. Equine Vet J. 1998;30:
pneumonia: five cases. Equine Vet Educ. 2015;27:283–290. 173–175.
352. Sweeney CR, Divers TJ, Benson CE. Anaerobic bacteria 374. Dungworth DL. Interstitial pulmonary disease. Adv Vet Sci
in 21 horses with pleuropneumonia. J Am Vet Med Assoc. Comp Med. 1982;26:173–200.
1985;187:721–724. 375. Bell SA, Balasuriya UB, Gardner IA, et al. Temporal detection
353. Reuss S, Giguere S. Update on Bacterial Pneumonia and of equine herpesvirus infections of a cohort of mares and their
Peuropneumonia in the Adult Horse. Vet Clin North Am foals. Vet Microbiol. 2006;116:249–257.
Equine Pract. 2015;31:105–120. 376. Rush BR, Raub ES, Thomsen MM, et al. Pulmonary function
354. Estell KE, Young A, Kozikowski T, et al. Pneumonia Caused by and adrenal gland suppression with incremental doses of aero-
Klebsiella spp. in 46 Horses. J Vet Intern Med. 2016;30:314–321. solized beclomethasone dipropionate in horses with recurrent
355. Kinoshita Y, Niwa H, Katayama Y. Use of loop-mediated iso- airway obstruction. J Am Vet Med Assoc. 2000;217:359–364.
thermal amplification to detect six groups of pathogens caus- 377. Derksen FJ, Olszewski MA, Robinson NE, et al. Aerosolized
ing secondary lower respiratory bacterial infections in horses. albuterol sulfate used as a bronchodilator in horses with recur-
Microbiol Immunol. 2015;59:365–370. rent airway obstruction. Am J Vet Res. 1999;60:689–693.
356. Tomlinson JE, Reef VB, Boston RC, et al. The Association of 378. Rush BR, Hoskinson JJ, Davis EG, et al. Pulmonary distribu-
Fibrinous Pleural Effusion with Survival and Complications tion of aerosolized technetium Tc 99m pentetate after adminis-
in Horses with Pleuropneumonia (2002-2012): 74 Cases. J Vet tration of a single dose of aerosolized albuterol sulfate in hors-
Intern Med. 2015;29:1410–1417. es with recurrent airway obstruction. Am J Vet Res. 1999;60:
357. Knych HK, Stanley SD, Arthur RM, et al. Detection and phar- 764–769.
macokinetics of three formulations of firocoxib following mul- 379. Leguillette R. Recurrent airway obstruction—heaves. Vet Clin
tiple administrations to horses. Equine Vet J. 2014;46:734–738. North Am Equine Pract. 2003;19:63–86, vi.
358. Kvaternick V, Pollmeier M, Fischer J, et al. Pharmacokinetics and 380. Garre B, Baert K, Nauwynck H, et al. Multiple oral dosing
metabolism of orally administered firocoxib, a novel second gen- of valacyclovir in horses and ponies. J Vet Pharmacol Ther.
eration coxib, in horses. J Vet Pharmacol Ther. 2007;30:208–217. 2009;32:207–212.
359. Vander Werf KA, Davis EG, Kukanich B. Pharmacokinetics 381. Garre B, Gryspeerdt A, Croubels S, et al. Evaluation of orally
and adverse effects of oral meloxicam tablets in healthy adult administered valacyclovir in experimentally EHV1-infected
horses. J Vet Pharmacol Ther. 2013;36:376–381. ponies. Vet Microbiol. 2009;135:214–221.
360. Vivancos M, Barker J, Engbers S, et al. Pharmacokinetics and 382. Razonable RR. Cytomegalovirus infection after liver trans-
bioequivalence of 2 meloxicam oral dosage formulations in plantation: current concepts and challenges. World J Gastroen-
healthy adult horses. Can Vet J. 2015;56:730–736. terol. 2008;14:4849–4860.
361. Foreman JH, Ruemmler R. Phenylbutazone and flunixin me- 383. Razonable RR, Emery VC. Management of CMV infection
glumine used singly or in combination in experimental lame- and disease in transplant patients. 27-29 February 2004. Her-
ness in horses. Equine Vet J Suppl. 2011:12–17. pes. 2004;11:77–86.
362. McConnico RS, Morgan TW, Williams CC, et al. Pathophysi- 384. Clarke AF. A review of environmental and host factors in
ologic effects of phenylbutazone on the right dorsal colon in relation to equine respiratory disease. Equine Vet J. 1987;19:
horses. Am J Vet Res. 2008;69:1496–1505. 435–441.
363. Reed SK, Messer NT, Tessman RK, et al. Effects of phenylb- 385. Stewart AJ, Cuming RS. Update on fungal respiratory disease
utazone alone or in combination with flunixin meglumine on in horses. Vet Clin North Am Equine Pract. 2015;31:43–62.
blood protein concentrations in horses. Am J Vet Res. 2006;67: 386. Sweeney CR, Habecker PL. Pulmonary aspergillosis in horses:
398–402. 29 cases (1974-1997). J Am Vet Med Assoc. 1999;214:808–811.
364. Keegan KG, Wilson DA, Wilson DJ, et al. Evaluation of mild 387. Guillot J, Sarfati J, de BM, et al. Comparative study of sero-
lameness in horses trotting on a treadmill by clinicians and in- logical tests for the diagnosis of equine aspergillosis. Vet Rec.
terns or residents and correlation of their assessments with kin- 1999;145:348–349.
ematic gait analysis. Am J Vet Res. 1998;59:1370–1377. 388. Slocombe RF, Slauson DO. Invasive pulmonary aspergillo-
365. Collins MB, Hodgson DR, Hutchins DR. Pleural effusion asso- sis of horses: an association with acute enteritis. Vet Pathol.
ciated with acute and chronic pleuropneumonia and pleuritis 1988;25:277–281.
secondary to thoracic wounds in horses: 43 cases (1982-1992). 389. Blomme E, Del Piero F, La Perle KM. Aspirgillosis in horses: a
J Am Vet Med Assoc. 1994;205:1753–1758. review. Equine Vet Educ. 1998;10:86–93.
366. Raphel CF, Beech J. Pleuritis secondary to pneumonia or lung 390. Johnson PJ, Moore LA, Mrad DR, et al. Sudden death of
abscessation in 90 horses. J Am Vet Med Assoc. 1982;181:808– two horses associated with pulmonary aspergillosis. Vet Rec.
810. 1999;145:16–20.
367. Seltzer KL, Byars TD. Prognosis for return to racing after 391. Tunev SS, Ehrhart EJ, Jensen HE, et al. Necrotizing mycotic
recovery from infectious pleuropneumonia in thorough- vasculitis with cerebral infarction caused by Aspergillus ni-
bred racehorses: 70 cases (1984-1989). J Am Vet Med Assoc. ger in a horse with acute typholocolitis. Vet Pathol. 1999;36:
1996;208:1300–1301. 347–351.
368. Nout YS, Hinchcliff KW, Samii VF, et al. Chronic pulmonary 392. Sweeney CR, Habecker PL. Pulmonary aspergillosis in horses:
disease with radiographic interstitial opacity (interstitial pneu- 29 cases (1974-1997). J Am Vet Med Assoc. 1999;214:808–811.
monia) in foals. Equine Vet J. 2002;34:542–548. 393. Toribio RE, Kohn CW, Lawrence AE, et al. Thoracic and
369. Britton AP, Robinson JH. Isolation of influenza A virus from a abdominal blastomycosis in a horse. J Am Vet Med Assoc.
7-day-old foal with bronchointerstitial pneumonia. Can Vet J. 1999;214:1357–1360, 1335.
2002;43:55–56. 394. Dolente BA, Habecker P, Chope K. Disseminated blastomyco-
370. Buergelt CD, Hines SA, Cantor G, et al. A retrospective study sis in a miniature horse. Equine Vet Educ. 2003;15:139–142.
of proliferative interstitial lung disease of horses in Florida. Vet 395. Wilson JH, Olson EJ, Haugen EW, et al. Systemic blastomyco-
Pathol. 1986;23:750–756. sis in a horse. J Vet Diagn Invest. 2006;18:615–619.
371. Nobre D, Dagli ML, Haraguchi M. Crotalaria juncea intoxica- 396. Katayama Y, Kuwano A, Yoshihara T. Histoplasmosis in the
tion in horses. Vet Hum Toxicol. 1994;36:445–448. lung of a race horse with yersiniosis. J Vet Med Sci. 2001;63:
372. Buergelt CD. Interstitial pneumonia in the horse: a fledgling 1229–1231.
morphological entity with mysterious causes. Equine Vet J. 397. Rezabek GB, Donahue JM, Giles RC, et al. Histoplasmosis in
1995;27:4–5. horses. J Comp Pathol. 1993;109:47–55.
398. Rush Moore B, Reed S, Kowalski JJ, et al. Aspergillosis gran- 421. Couetil LL, Ward MP. Analysis of risk factors for recurrent airway
uloma in the mediastinum of a nonimmunocompromised obstruction in North American horses: 1,444 cases (1990-1999). J
horse. Cornell Vet. 1993;83:97–104. Am Vet Med Assoc. 2003;223:1645–1650.
399. Sweeney CR, Humber KA, Roby KA. Cytologic findings of tra- 422. Gerber V, Bailey E. Genetics and disease in the horse. Equine
cheobronchial aspirates from 66 thoroughbred racehorses. Am Vet J. 1995;27:400–401.
J Vet Res. 1992;53:1172–1175. 423. Marti E, Gerber H, Essich G, et al. The genetic basis of equine
400. Sweeney CR, Beech J, Roby KA. Bacterial isolates from tra- allergic diseases. 1. Chronic hypersensitivity bronchitis. Equine
cheobronchial aspirates of healthy horses. Am J Vet Res. Vet J. 1991;23:457–460.
1985;46:2562–2565. 424. Gerber V, Baleri D, Klukowska-Rotzler J, et al. Mixed inherit-
401. Pusterla N, Holmberg TA, Lorenzo-Figueras M, et al. Acremo- ance of equine recurrent airway obstruction. J Vet Intern Med.
nium strictum pulmonary infection in a horse. Vet Clin Pathol. 2009;23:626–630.
2005;34:413–416. 425. Bosshard S, Gerber V. Evaluation of coughing and nasal dis-
402. Flaminio MJ, Rush BR, Cox JH, et al. CD4+ and CD8+ T-lym- charge as early indicators for an increased risk to develop
phocytopenia in a filly with Pneumocystis carinii pneumonia. equine recurrent airway obstruction (RAO). J Vet Intern Med.
Aust Vet J. 1998;76:399–402. 2014;28:618–623.
403. Davis EG, Wilkerson MJ, Rush BR. Flow cytometry: clinical 426. Derksen FJ, Brown CM, Sonea I, et al. Comparison of tran-
applications in equine medicine. J Vet Intern Med. 2002;16: stracheal aspirate and bronchoalveolar lavage cytology in
404–410. 50 horses with chronic lung disease. Equine Vet J. 1989;21:
404. Perron Lepage MF, Gerber V, Suter MM. A case of interstitial 23–26.
pneumonia associated with Pneumocystis carinii in a foal. Vet 427. Tesarowski DB, Viel L, McDonell WN. Pulmonary function
Pathol. 1999;36:621–624. measurements during repeated environmental challenge of
405. Franklin RP, Long MT, MacNeill A, et al. Proliferative inter- horses with recurrent airway obstruction (heaves). Am J Vet
stitial pneumonia, Pneumocystis carinii infection, and immu- Res. 1996;57:1214–1219.
nodeficiency in an adult Paso Fino horse. J Vet Intern Med. 428. Robinson NE, Olszewski MA, Boehler D, et al. Relationship
2002;16:607–611. between clinical signs and lung function in horses with recur-
406. MacNeill AL, Alleman AR, Franklin RP, et al. Pneumonia in a rent airway obstruction (heaves) during a bronchodilator trial.
Paso-Fino mare. Vet Clin Pathol. 2003;32:73–76. Equine Vet J. 2000;32:393–400.
407. Perryman LE, McGuire TC, Crawford TB. Maintenance of 429. Couetil L, Hammer J, Miskovic FM, et al. Effects of N-butyl-
foals with combined immunodeficiency: causes and control of scopolammonium bromide on lung function in horses with
secondary infections. Am J Vet Res. 1978;39:1043–1047. recurrent airway obstruction. J Vet Intern Med. 2012;26:
408. Chandna VK, Morris E, Gliatto JM, et al. Localised subcutane- 1433–1438.
ous cryptococcal granuloma in a horse. Equine Vet J. 1993;25: 430. Couetil LL, Rosenthal FS, Simpson CM. Forced expiration:
166–168. a test for airflow obstruction in horses. J Appl Physiol (1985).
409. Begg LM, Hughes KJ, Kessell A, et al. Successful treatment 2000;88:1870–1879.
of cryptococcal pneumonia in a pony mare. Aust Vet J. 431. Pirie RS, McLachlan G, McGorum BC. Evaluation of nebu-
2004;82:686–692. lised hay dust suspensions (HDS) for the diagnosis and inves-
410. Cornick JL. Diagnosis and treatment of pulmonary histoplasmo- tigation of heaves. 1: preparation and composition of HDS.
sis in a horse. Cornell Vet. 1990;80:97–103. Equine Vet J. 2002;34:332–336.
411. French DD, Haynes PF, Miller RI. Surgical and medical man- 432. Pirie RS, Dixon PM, McGorum BC. Endotoxin contamination
agement of rhinophycomycosis (conidiobolomycosis) in a contributes to the pulmonary inflammatory and functional re-
horse. J Am Vet Med Assoc. 1985;186:1105–1107. sponse to Aspergillus fumigatus extract inhalation in heaves
412. Zamos DT, Schumacher J, Loy JK. Nasopharyngeal con- horses. Clin Exp Allergy. 2003;33:1289–1296.
idiobolomycosis in a horse. J Am Vet Med Assoc. 1996;208: 433. Ivester KM, Couetil LL, Moore GE, et al. Environmental expo-
100–101. sures and airway inflammation in young thoroughbred horses.
413. Burks BS. Parastitic Pneumonitis in Horses. Compend Contin J Vet Intern Med. 2014;28:918–924.
Educ Pract Vet. 1998;20:378–383. 434. Millerick-May ML, Karmaus W, Derksen FJ, et al. Local air-
414. Austin SM, DiPietro JA, Foreman JH, et al. Comparison of the borne particulate concentration is associated with visible
efficacy of ivermectin, oxibendazole, and pyrantel pamoate tracheal mucus in Thoroughbred racehorses. Equine Vet J.
against 28-day Parascaris equorum larvae in the intestine of 2013;45:85–90.
pony foals. J Am Vet Med Assoc. 1991;198:1946–1949. 435. Ainsworth DM, Grunig G, Matychak MB, et al. Recurrent
415. Pardridge WM. Blood-brain barrier drug targeting enables airway obstruction (RAO) in horses is characterized by IFN-
neuroprotection in brain ischemia following delayed intra- gamma and IL-8 production in bronchoalveolar lavage cells.
venous administration of neurotrophins. Adv Exp Med Biol. Vet Immunol Immunopathol. 2003;96:83–91.
2002;513:397–430. 436. Cordeau ME, Joubert P, Dewachi O, et al. IL-4, IL-5 and
416. DiPietro JA, Todd Jr KS. Anthelmintics used in treatment of IFN-gamma mRNA expression in pulmonary lymphocytes in
parasitic infections of horses. Vet Clin North Am Equine Pract. equine heaves. Vet Immunol Immunopathol. 2004;97:87–96.
1987;3:1–14. 437. Chen CL, Goldberg J, Gronwall RR. Pharmacokinetics of in-
417. Costa AJ, Barbosa OF, Moraes FR, et al. Comparative efficacy travenously administration of prednisolone in the horse as
evaluation of moxidectin gel and ivermectin paste against inter- determined by radioimmunoassay. Chin J Physiol. 1995;38:
nal parasites of equines in Brazil. Vet Parasitol. 1998;80:29–36. 1–6.
418. Couetil LL, Cardwell JM, Gerber V, et al. Inflammatory Air- 438. French K, Pollitt CC, Pass MA. Pharmacokinetics and meta-
way Disease of Horses-Revised Consensus Statement. J Vet In- bolic effects of triamcinolone acetonide and their possible re-
tern Med. 2016;30:503–515. lationships to glucocorticoid-induced laminitis in horses. J Vet
419. Mazan MR. Update on noninfectious inflammatory dis- Pharmacol Ther. 2000;23:287–292.
eases of the lower airway. Vet Clin North Am Equine Pract. 439. Rush BR, Worster AA, Flaminio MJ, et al. Alteration in adren-
2015;31:159–185. ocortical function in horses with recurrent airway obstruction
420. Davis E, Rush BR. Equine recurrent airway obstruction: after aerosol and parenteral administration of beclomethasone
pathogenesis, diagnosis, and patient management. Vet Clin dipropionate and dexamethasone, respectively. Am J Vet Res.
North Am Equine Pract. 2002;18:453–467, vi. 1998;59:1044–1047.
440. Courouce-Malblanc A, Fortier G, Pronost S, et al. Comparison 459. Bedenice D, Mazan MR, Hoffman AM. Association between
of prednisolone and dexamethasone effects in the presence cough and cytology of bronchoalveolar lavage fluid and pul-
of environmental control in heaves-affected horses. Vet J. monary function in horses diagnosed with inflammatory air-
2008;175:227–233. way disease. J Vet Intern Med. 2008;22:1022–1028.
441. Peroni DL, Stanley S, Kollias-Baker C, et al. Prednisone per 460. Richard EA, Fortier GD, Denoix JM, et al. Influence of subclini-
os is likely to have limited efficacy in horses. Equine Vet J. cal inflammatory airway disease on equine respiratory function
2002;34:283–287. evaluated by impulse oscillometry. Equine Vet J. 2009;41:384–389.
442. Gray PR, Derksen FJ, Robinson NE, et al. The role of cyclooxy- 461. Robinson NE, Berney C, Eberhart S, et al. Coughing, mucus
genase products in the acute airway obstruction and airway accumulation, airway obstruction, and airway inflammation
hyperreactivity of ponies with heaves. Am Rev Respir Dis. in control horses and horses affected with recurrent airway
1989;140:154–160. obstruction. Am J Vet Res. 2003;64:550–557.
443. Rush BR, Raub ES, Rhoads WS, et al. Pulmonary function in 462. Fogarty U, Buckley T. Bronchoalveolar lavage findings in horses
horses with recurrent airway obstruction after aerosol and with exercise intolerance. Equine Vet J. 1991;23:434–437.
parenteral administration of beclomethasone dipropionate 463. Moore BR, Krakowka S, Robertson JT, et al. Cytologic evalu-
and dexamethasone, respectively. Am J Vet Res. 1998;59:1039– ation of bronchoalveolar lavage fluid obtained from standard-
1043. bred racehorses with inflammatory airway disease. Am J Vet Res.
444. Bertin FR, Ivester KM, Couetil LL. Comparative efficacy of 1995;56:562–567.
inhaled albuterol between two hand-held delivery devices 464. Fraipont A, van EE, Ramery E, et al. Subclinical diseases under-
in horses with recurrent airway obstruction. Equine Vet J. lying poor performance in endurance horses: diagnostic meth-
2011;43:393–398. ods and predictive tests. Vet Rec. 2011;169:154.
445. Couetil LL, Chilcoat CD, DeNicola DB, et al. Randomized, con- 465. Malikides N, Hughes KJ, Hodgson DR, et al. Comparison of
trolled study of inhaled fluticasone propionate, oral administra- tracheal aspirates and bronchoalveolar lavage in racehorses.
tion of prednisone, and environmental management of horses 2. Evaluation of the diagnostic significance of neutrophil per-
with recurrent airway obstruction. Am J Vet Res. 2005;66:1665– centage. Aust Vet J. 2003;81:685–687.
1674. 466. Hare JE, Viel L. Pulmonary eosinophilia associated with in-
446. Dauvillier J, Felippe MJ, Lunn DP, et al. Effect of long-term creased airway responsiveness in young racing horses. J Vet
fluticasone treatment on immune function in horses with Intern Med. 1998;12:163–170.
heaves. J Vet Intern Med. 2011;25:549–557. 467. Ivester KM, Couetil LL. Management of chronic airway in-
447. Giguere S, Viel L, Lee E, et al. Cytokine induction in pulmo- flammation in the horse: a systematic review. Equine Vet Educ.
nary airways of horses with heaves and effect of therapy with 2014;26:647–656.
inhaled fluticasone propionate. Vet Immunol Immunopathol. 468. Courouce-Malblanc A, Fortier G, Pronost S, et al. Comparison
2002;85:147–158. of prednisolone and dexamethasone effects in the presence
448. Couetil L, Hammer J, Miskovic FM, et al. Effects of N-butyl- of environmental control in heaves-affected horses. Vet J.
scopolammonium bromide on lung function in horses with 2008;175:227–233.
recurrent airway obstruction. J Vet Intern Med. 2012;26:1433– 469. Picandet V, Leguillette R, Lavoie JP. Comparison of efficacy
1438. and tolerability of isoflupredone and dexamethasone in the
449. de LM, Rodrigues N, Chevigny M, et al. N-butylscopolammo- treatment of horses affected with recurrent airway obstruction
nium bromide causes fewer side effects than atropine when (‘heaves’). Equine Vet J. 2003;35:419–424.
assessing bronchoconstriction reversibility in horses with 470. Rush BR, Worster AA, Flaminio MJ, et al. Alteration in adren-
heaves. Equine Vet J. 2014;46:474–478. ocortical function in horses with recurrent airway obstruction
450. Seahorn TL, Beadle RE, McGorum BC, et al. Quantification after aerosol and parenteral administration of beclomethasone
of antigen-specific antibody concentrations in tracheal lavage dipropionate and dexamethasone, respectively. Am J Vet Res.
fluid of horses with summer pasture-associated obstructive 1998;59:1044–1047.
pulmonary disease. Am J Vet Res. 1997;58:1408–1411. 471. Laan TT, Bull S, van Nieuwstadt RA, et al. The effect of
451. Mair TS. Obstructive pulmonary disease in 18 horses at sum- aerosolized and intravenously administered clenbuterol and
mer pasture. Vet Rec. 1996;138:89–91. aerosolized fluticasone propionate on horses challenged with
452. Seahorn TL, Groves MG, Harrington KS, et al. Chronic ob- Aspergillus fumigatus antigen. Vet Res Commun. 2006;30:
structive pulmonary disease in horses in Louisiana. J Am Vet 623–635.
Med Assoc. 1996;208:248–251. 472. Read JR, Boston RC, Abraham G, et al. Effect of prolonged
453. Costa LR, Johnson JR, Baur ME, et al. Temporal clinical exac- administration of clenbuterol on airway reactivity and sweat-
erbation of summer pasture-associated recurrent airway ob- ing in horses with inflammatory airway disease. Am J Vet Res.
struction and relationship with climate and aeroallergens in 2012;73:140–145.
horses. Am J Vet Res. 2006;67:1635–1642. 473. Henrikson SL, Rush BR. Efficacy of salmeterol xinafoate in
454. Ward MP, Couetil LL. Climatic and aeroallergen risk factors horses with recurrent airway obstruction. J Am Vet Med Assoc.
for chronic obstructive pulmonary disease in horses. Am J Vet 2001;218:1961–1965.
Res. 2005;66:818–824. 474. Hinchcliff KW, Couetil LL, Knight PK, et al. Exercise induced
455. Christley RM, Hodgson DR, Rose RJ, et al. A case-control pulmonary hemorrhage in horses: American College of Vet-
study of respiratory disease in Thoroughbred racehorses in erinary Internal Medicine consensus statement. J Vet Intern
Sydney, Australia. Equine Vet J. 2001;33:256–264. Med. 2015;29:743–758.
456. Sanchez A, Couetil LL, Ward MP, et al. Effect of airway dis- 475. Pascoe JR, Ferraro GL, Cannon JH, et al. Exercise-induced
ease on blood gas exchange in racehorses. J Vet Intern Med. pulmonary hemorrhage in racing thoroughbreds: a prelimi-
2005;19:87–92. nary study. Am J Vet Res. 1981;42:703–707.
457. Couetil LL, Rosenthal FS, DeNicola DB, et al. Clinical signs, 476. Raphel CF, Soma LR. Exercise-induced pulmonary hemor-
evaluation of bronchoalveolar lavage fluid, and assessment of rhage in Thoroughbreds after racing and breezing. Am J Vet
pulmonary function in horses with inflammatory respiratory Res. 1982;43:1123–1127.
disease. Am J Vet Res. 2001;62:538–546. 477. Hinchcliff KW, Jackson MA, Morley PS, et al. Association
458. Couetil LL, DeNicola DB. Blood gas, plasma lactate and bron- between exercise-induced pulmonary hemorrhage and per-
choalveolar lavage cytology analyses in racehorses with res- formance in Thoroughbred racehorses. J Am Vet Med Assoc.
piratory disease. Equine Vet J Suppl. 1999:77–82. 2005;227:768–774.
478. Hinchcliff KW, Morley PS, Guthrie AJ. Efficacy of furosemide 498. Takahashi T, Hiraga A, Ohmura H, et al. Frequency of and risk
for prevention of exercise-induced pulmonary hemorrhage factors for epistaxis associated with exercise-induced pulmo-
in Thoroughbred racehorses. J Am Vet Med Assoc. 2009;235: nary hemorrhage in horses: 251,609 race starts (1992-1997). J
76–82. Am Vet Med Assoc. 2001;218:1462–1464.
479. Sweeney CR, Soma LR, Maxson AD, et al. Effects of furo- 499. Furuoka H, Taniyama H, Matsui T, et al. Malignant thymoma
semide on the racing times of Thoroughbreds. Am J Vet Res. with multiple metastases in a mare, Nippon Juigaku. Zasshi.
1990;51:772–778. 1987;49:577–579.
480. Voynick BT, Sweeney CR. Exercised-induced pulmonary 500. Boden LA, Charles JA, Slocombe RF, et al. Sudden death in
hemorrhage in polo and racing horses. J Am Vet Med Assoc. racing Thoroughbreds in Victoria, Australia. Equine Vet J.
1986;188:301–302. 2005;37:269–271.
481. West JB, Mathieu-Costello O, Jones JH, et al. Stress failure 501. Lyle CH, Uzal FA, McGorum BC, et al. Sudden death in rac-
of pulmonary capillaries in racehorses with exercise-induced ing Thoroughbred horses: an international multicentre study
pulmonary hemorrhage. J Appl Physiol (1985). 1993;75: of post mortem findings. Equine Vet J. 2011;43:324–331.
1097–1109. 502. Sullivan SL, Anderson GA, Morley PS, et al. Prospective
482. Manohar M, Goetz TE. Pulmonary vascular pressures of study of the association between exercise-induced pulmonary
strenuously exercising Thoroughbreds during intravenous in- haemorrhage and long-term performance in Thoroughbred
fusion of nitroglycerin. Am J Vet Res. 1999;60:1436–1440. racehorses. Equine Vet J. 2015;47:350–357.
483. Manohar M, Goetz TE. Pulmonary vascular pressures of ex- 503. de Mello Costa MF, Thomassian A, Gomes TS. Study of ex-
ercising thoroughbred horses with and without endoscopic ercise induced pulmonary hemorrhage (EIPH) in flat racing
evidence of EIPH. J Appl Physiol (1985). 1996;81:1589–1593. Thoroughbred horses through 1889 respiratory endoscopies
484. Birks EK, Mathieu-Costello O, Fu Z, et al. Very high pressures after races. Rev Bras Cien Vet. 2005;12:89–91.
are required to cause stress failure of pulmonary capillaries 504. Hinchcliff KW, Jackson MA, Brown JA, et al. Tracheobron-
in thoroughbred racehorses. J Appl Physiol (1985). 1997;82: choscopic assessment of exercise-induced pulmonary hemor-
1584–1592. rhage in horses. Am J Vet Res. 2005;66:596–598.
485. Stack A, Derksen FJ, Sordillo LM, et al. Effects of exercise on 505. McKane SA, Canfield PJ, Rose RJ. Equine bronchoalveolar lav-
markers of venous remodeling in lungs of horses. Am J Vet Res. age cytology: survey of thoroughbred racehorses in training.
2013;74:1231–1238. Aust Vet J. 1993;70:401–404.
486. O’Callaghan MW, Pascoe JR, Tyler WS, et al. Exercise-induced 506. Hinchcliff KW. Counting red cells—is it an answer to EIPH?
pulmonary haemorrhage in the horse: results of a detailed Equine Vet J. 2000;32:362–363.
clinical, post mortem and imaging study. VIII. Conclusions 507. Doucet MY, Viel L. Alveolar macrophage graded hemosiderin
and implications. Equine Vet J. 1987;19:428–434. score from bronchoalveolar lavage in horses with exercise-in-
487. O’Callaghan MW, Hornof WJ, Fisher PE, et al. Exercise- duced pulmonary hemorrhage and controls. J Vet Intern Med.
induced pulmonary haemorrhage in the horses: results of a 2002;16:281–286.
detailed clinical, post mortem and imaging study. VII. Ventila- 508. Manohar M, Goetz TE, Rothenbaum P, et al. Clenbuterol
tion/perfusion scintigraphy in horses with EIPH. Equine Vet J. administration does not enhance the efficacy of furosemide
1987;19:423–427. in attenuating the exercise-induced pulmonary capillary hy-
488. Williams KJ, Derksen FJ, De Feijter-Rupp H, et al. Regional pertension in Thoroughbred horses. J Vet Pharmacol Ther.
pulmonary veno-occlusion: a newly identified lesion of 2000;23:389–395.
equine exercise-induced pulmonary hemorrhage. Vet Pathol. 509. Manohar M, Goetz TE, Sullivan E, et al. Pulmonary vascu-
2008;45:316–326. lar pressures of strenuously exercising Thoroughbreds after
489. Derksen FJ, Williams KJ, Uhal BD, et al. Pulmonary response administration of varying doses of frusemide. Equine Vet J.
to airway instillation of autologous blood in horses. Equine Vet 1997;29:298–304.
J. 2007;39:334–339. 510. Manohar M. Furosemide attenuates the exercise-induced in-
490. McKane SA, Slocombe RF. Sequential changes in bronchoal- crease in pulmonary artery wedge pressure in horses. Am J Vet
veolar cytology after autologous blood inoculation. Equine Vet Res. 1993;54:952–958.
J Suppl. 1999:126–130. 511. Manohar M, Goetz TE, Rothenbaum P, et al. Intravenous pen-
491. McKane SA, Slocombe RF. Alveolar fibrosis and changes in toxifylline does not enhance the pulmonary haemodynamic
equine lung morphometry in response to intrapulmonary efficacy of frusemide in strenuously exercising thoroughbred
blood. Equine Vet J Suppl. 2002:451–458. horses. Equine Vet J. 2001;33:354–359.
492. Williams KJ, Derksen FJ, Defeijter-Rupp HL, et al. Repeated 512. Magid JH, Manohar M, Goetz TE, et al. Pulmonary vascular
blood instillation into the airway of the horse does not cause pressures of thoroughbred horses exercised 1, 2, 3 and 4 h af-
pulmonary fibrosis. Equine Vet J. 2011;43:354–358. ter furosemide administration. J Vet Pharmacol Ther. 2000;23:
493. Christley RM, Hodgson DR, Rose RJ, et al. Coughing in thor- 81–89.
oughbred racehorses: risk factors and tracheal endoscopic and 513. Gleed FD, Ducharme NG, Hackett RP, et al. Effects of frusem-
cytological findings. Vet Rec. 2001;148:99–104. ide on pulmonary capillary pressure in horses exercising on a
494. Chapman PS, Green C, Main JP, et al. Retrospective study of treadmill. Equine Vet J Suppl. 1999:102–106.
the relationships between age, inflammation and the isolation 514. Manohar M. Pulmonary vascular pressures of strenuously ex-
of bacteria from the lower respiratory tract of thoroughbred ercising thoroughbreds after administration of flunixin meglu-
horses. Vet Rec. 2000;146:91–95. mine and furosemide. Am J Vet Res. 1994;55:1308–1312.
495. Speirs VC, van Veenendaal JC, Harrison IW, et al. Pulmonary 515. Olsen SC, Coyne CP, Lowe BS, et al. Influence of furosemide
haemorrhage in standardbred horses after racing. Aust Vet J. on hemodynamic responses during exercise in horses. Am J
1982;59:38–40. Vet Res. 1992;53:742–747.
496. Hillidge CJ, Whitlock TW. Sex variation in the prevalence of 516. Buchholz BM, Murdock A, Bayly WM, et al. Effects of intrave-
exercise-induced pulmonary haemorrhage in racing quarter nous aminocaproic acid on exercise-induced pulmonary haem-
horses. Res Vet Sci. 1986;40:406–407. orrhage (EIPH). Equine Vet J Suppl. 2010:256–260.
497. Doucet MY, Viel L. Clinical, radiographic, endoscopic, bron- 517. Epp TS, Edwards KL, Poole DC. Effects of conjugated
choalveolar lavage and lung biopsy findings in horses with oestrogens and aminocaproic acid upon exercise induced
exercise-induced pulmonary hemorrhage. Can Vet J. 2002;43: pulmonary hemorrhage (EIPH). Compative Exerc Physiol.
195–202. 2008;5:95–103.
518. Manohar M, Goetz TE, Rothenbaum P, et al. Clenbuterol ad- 541. Heinola T, Heikkila M, Ruohoniemi M, et al. Hypertrophic
ministration does not attenuate the exercise-induced pulmo- pulmonary osteopathy associated with granular cell tumour in
nary arterial, capillary or venous hypertension in strenuously a mare. Vet Rec. 2001;149:307–308.
exercising Thoroughbred horses. Equine Vet J. 2000;32:546–550. 542. Smith BL, Aguilera-Tejero E, Tyler WS, et al. Endoscopic
519. Walker HJ, Evans DL, Slocombe RF, et al. Effect of corticos- anatomy and map of the equine bronchial tree. Equine Vet J.
teroid and bronchodilator therapy on bronchoalveolar lavage 1994;26:283–290.
cytology following intrapulmonary blood inoculation. Equine 543. Kelley LC, Hill JE, Hafner S, et al. Spontaneous equine pulmonary
Vet J Suppl. 2006:516–522. granular cell tumors: morphologic, histochemical, and immuno-
520. Sweeney CR, Soma LR, Bucan CA, et al. Exercise-induced pul- histochemical characterization. Vet Pathol. 1995;32:101–106.
monary hemorrhage in exercising Thoroughbreds: prelimi- 544. Facemire PR, Chilcoat CD, Sojka JE, et al. Treatment of gran-
nary results with pre-exercise medication. Cornell Vet. 1984;74: ular cell tumor via complete right lung resection in a horse.
263–268. J Am Vet Med Assoc. 2000;217:1522–1525.
521. Manohar M, Goetz TE, Hassan AS, et al. Anti-inflammatory 545. Ohnesorge B, Gehlen H, Wohlsein P. Transendoscopic elec-
agent, dexamethasone, does not affect exercise-induced ar- trosurgery of an equine pulmonary granular cell tumor. Vet
terial hypoxemia in Thoroughbreds. J Appl Physiol (1985). Surg. 2002;31:375–378.
2002;93:99–106. 546. Dadmanesh F, Sekihara T, Rosai J. Histologic typing of thymo-
522. Manohar M, Goetz TE, Griffin R, et al. Pulmonary vascular ma according to the new World Health Organization classifica-
pressures of strenuously exercising thoroughbreds after admin- tion. Chest Surg Clin N Am. 2001;11:407–420.
istration of phenylbutazone. Am J Vet Res. 1996;57:1354–1358. 547. Shahriar F, Moore J. Thymic epithelial tumor with heart me-
523. Manohar M, Goetz TE, Rothenbaum P, et al. Intravenous tastasis in a horse. Vet Med Int. 2010;2010.
pentoxifylline does not affect the exercise-induced pulmonary 548. Migaki G. Hematopoietic neoplasms of slaughter animals.
arterial, capillary or venous hypertension in Thoroughbred Natl Cancer Inst Monogr. 1969;32:121–151.
horses. J Vet Pharmacol Ther. 2000;23:317–322. 549. Whiteley LO, Leininger JR, Wolf CB, et al. Malignant squa-
524. Geor RJ, Ommundson L, Fenton G, et al. Effects of an exter- mous cell thymoma in a horse. Vet Pathol. 1986;23:627–629.
nal nasal strip and frusemide on pulmonary haemorrhage in 550. Dill SG, Moise NS, Meschter CL. Cardiac failure in a stallion
Thoroughbreds following high-intensity exercise. Equine Vet J. secondary to metastasis of an anaplastic pulmonary carcino-
2001;33:577–584. ma. Equine Vet J. 1986;18:414–417.
525. Kindig CA, McDonough P, Fenton G, et al. Efficacy of nasal 551. Uphoff CS, Lyncoln JA. A primary pulmonary tumour in a
strip and furosemide in mitigating EIPH in Thoroughbred horse. Equine Pract. 1987;9:19–20.
horses. J Appl Physiol (1985). 2001;91:1396–1400. 552. van Rensburg IB, Stadler P, Soley J. Bronchiolo-alveolar ad-
526. Kindig CA, Poole DC, McDonough P, et al. Nasal strips and enocarcinoma in a horse. J S Afr Vet Assoc. 1989;60:212–214.
EIPH in the exercising Thoroughbred racehorse. J Appl Physiol 553. Anderson JD, Leonard JM, Zeliff JA, et al. Primary pulmonary
(1985). 2001;91:1908–1910. neoplasm in a horse. J Am Vet Med Assoc. 1992;201:1399–1401.
527. Valdez SC, Nieto JE, Spier SJ, et al. Effect of an external nasal 554. Mair TS, Brown PJ. Clinical and pathological features of
dilator strip on cytologic characteristics of bronchoalveolar thoracic neoplasia in the horse. Equine Vet J. 1993;25:220–223.
lavage fluid in Thoroughbred racehorses. J Am Vet Med Assoc. 555. Schultze AE, Sonea I, Bell TG. Primary malignant pulmonary
2004;224:558–561. neoplasia in two horses. J Am Vet Med Assoc. 1988;193:477–480.
528. Sweeney CR, Gillette DM. Thoracic neoplasia in equids: 35 556. Murphy JR, Breeze RG, McPherson EA. Myxoma of the equine
cases (1967-1987). J Am Vet Med Assoc. 1989;195:374–377. respiratory tract. Mod Vet Pract. 1978;59:529–532.
529. Mair T, Rush BR, Tucker RL. Clinical and diagnostic features of 557. Clem MF, O’Brien TD, Christopher MM. Pulmonary chon-
thoracic neoplasia in the horse. Equine Vet Educ. 2004;16:30–36. drosarcoma in a horse. Compend Contin Educ Pract Vet.
530. Misdorp W, Nauta-van Gelder HL. Granular-cell myoblastoma’ 1986;8:964–969.
in the horse. A report of 4 cases Pathol Vet. 1968;5:385–394. 558. Rossdale PD, Greet TR, McGladdery AJ. Pulmonary leiomyo-
531. Parker GA, Novilla MN, Brown AC, et al. Granular cell tu- sarcoma in a 13-year-old Thoroughbred stallion presenting as
mour (myeloblastoma) in the lung of a horse. J Comp Pathol. a differential diagnosis recurrent airway obstruction (RAO).
1979;89:421–430. Equine Vet Educ. 2004;16:21–28.
532. Nickels FA, Brown CM, Breeze RG. Myoblastoma. Equine 559. Perez-Ecija RA, Mendoza FJ, Zafra R, et al. Clinical, pathologi-
granular cell tumor. Mod Vet Pract. 1980;61:593–596. cal and immunohistochemical features of a pulmonary blas-
533. Turk RHH, Breeze RG. Histochemical and ultrastructural fea- toma in a horse. Vet Rec. 2009;164:182–183.
tures of an equine pulmonary granular cell tumour. J Comp 560. Straub R, von TC, Pauli B, et al. Pleural mesothelioma in a
Pathol. 1981;91:471–481. horse. Schweiz Arch Tierheilkd. 1974;116:207–211.
534. Scarratt WK, Crisman MV, Sponenberg DP, et al. Pulmonary 561. Kramer JW, Nickels FA, Bell T. Cytology of diffuse mesothe-
granular cell tumour in 2 horses. Equine Vet J. 1993;25:244–247. lioma in the thorax of a horse. Equine Vet J. 1976;8:81–83.
535. Sutton RH, Coleman GT. A pulmonary granular cell tumour 562. Carnine BL, Schneider G, Cook JE, et al. Pericardial mesothe-
with associated hypertrophic osteopathy in a horse. N Z Vet J. lioma in a horse. Vet Pathol. 1977;14:513–515.
1995;43:123. 563. Wallace SS, Jayo MJ, Maddux JM, et al. Mesothelioma in a
536. Goodchild LM, Dart AJ, Collins MB, et al. Granular cell tu- horse. Compend Contin Educ Pract Vet. 1987;9:210–216.
mour in the bronchus of a horse. Aust Vet J. 1997;75:16–18. 564. Colbourne CM, Bolton JR, Mills JN, et al. Mesothelioma in
537. Pusterla N, Pesavento PA, Smith P, et al. Idiopathic granuloma- horses. Aust Vet J. 1992;69:275–278.
tous pneumonia in seven horses. Vet Rec. 2003;153:653–655. 565. Mair T, Hillyer MH, Brown PJ. Mesothelioma of the pleu-
538. Bouchard PR, Fortna CH, Rowland PH, et al. An immuno- ral cavity in a horse: diagnostic features. Equine Vet Educ.
histochemical study of three equine pulmonary granular cell 1992;4:59–61.
tumors. Vet Pathol. 1995;32:730–734. 566. Frye FL, Knight HD, Brown SI. Hemangiosarcoma in a horse.
539. Alexander JE, Keown GH, Palotay JL. Granular cell myoblas- J Am Vet Med Assoc. 1983;182:287–289.
toma with hypertrophic pulmonary osteoarthropathy in a 567. Fry MM, Magdesian KG, Judy CE, et al. Antemortem diag-
mare. J Am Vet Med Assoc. 1965;146:703–708. nosis of equine mesothelioma by pleural biopsy. Equine Vet J.
540. Mair TS, Dyson SJ, Fraser JA, et al. Hypertrophic osteopathy 2003;35:723–727.
(Marie’s disease) in equidae: a review of twenty-four cases. 568. Cotchin E. A general survey of tumours in the horse. Equine
Equine Vet J. 1996;28:256–262. Vet J. 1977;9:16–21.
569. East LM, Savage CJ. Abdominal neoplasia (excluding urogeni- 596. Jean D, Lavoie JP, Nunez L, et al. Cutaneous hemangiosarco-
tal tract). Vet Clin North Am Equine Pract. 1998;14:475–4vi. ma with pulmonary metastasis in a horse. J Am Vet Med Assoc.
570. Neufeld JL. Lymphosarcoma in a mare and review of cases at 1994;204:776–778.
the Ontario Veterinary College. Can Vet J. 1973;14:149–153. 597. Johns I, Stephen JO, Del PF, et al. Hemangiosarcoma in 11
571. Neufeld JL. Lymphosarcoma in the horse: a review. Can Vet J. young horses. J Vet Intern Med. 2005;19:564–570.
1973;14:129–135. 598. Prater PE, Patton CS, Held JP. Pleural effusion resulting from
572. Platt H. Observations on the pathology of non-alimentary malignant hepatoblastoma in a horse. J Am Vet Med Assoc.
lymphomas in the horse. J Comp Pathol. 1988;98:177–194. 1989;194:383–385.
573. van den Hoven R, Franken P. Clinical aspects of lymphosar- 599. East LM, Steyn PF, Dickinson CE, et al. Occult osseous me-
coma in the horse: a clinical report of 16 cases. Equine Vet J. tastasis of a colonic adenocarcinoma visualized with techne-
1983;15:49–53. tium tc 99m hydroxymethylene diphosphate scintigraphy in a
574. Reef VB, Dyson SS, Beech J. Lymphosarcoma and associated horse. J Am Vet Med Assoc. 1998;213:1167–1173.
immune-mediated hemolytic anemia and thrombocytopenia 600. Ford TS, Vaala WE, Sweeney CR, et al. Pleuroscopic diagnosis
in horses. J Am Vet Med Assoc. 1984;184:313–317. of gastroesophageal squamous cell carcinoma in a horse. J Am
575. Rebhun WC, Bertone A. Equine lymphosarcoma. J Am Vet Vet Med Assoc. 1987;190:1556–1558.
Med Assoc. 1984;184:720–721. 601. Jorgensen JS, Geoly FJ, Berry CR, et al. Lameness and pleural
576. Adams R, Calderwood-Mays MB, Peyton LC. Malignant lym- effusion associated with an aggressive fibrosarcoma in a horse.
phoma in three horses with ulcerative pharyngitis. J Am Vet J Am Vet Med Assoc. 1997;210:1328–1331.
Med Assoc. 1988;193:674–676. 602. Murray MJ, Cavey DM, Feldman BF, et al. Signs of sympa-
577. Meyer J, DeLay J, Bienzle D. Clinical, laboratory, and his- thetic denervation associated with a thoracic melanoma in a
topathologic features of equine lymphoma. Vet Pathol. horse. J Vet Intern Med. 1997;11:199–203.
2006;43:914–924. 603. MacGillivray KC, Sweeney RW, Del PF. Metastatic melanoma
578. Mendes LCN, de Araujo MA, Bovino F, et al. Clinical, histo- in horses. J Vet Intern Med. 2002;16:452–456.
logical and immunophenotypic findins in a mare with amma- 604. Tan RH, Crisman MV, Clark SP, et al. Multicentric mastocy-
ry lymphoma associated with anemia and pruritis. Equine Vet toma in a horse. J Vet Intern Med. 2007;21:340–343.
Educ. 2011;23:177–183. 605. Peroni JF, Robinson NE, Stick JA, et al. Pleuropulmonary and
579. Finley MR, Rebhun WC, Dee A, et al. Paraneoplastic pruritus cardiovascular consequences of thoracoscopy performed in
and alopecia in a horse with diffuse lymphoma. J Am Vet Med healthy standing horses. Equine Vet J. 2000;32:280–286.
Assoc. 1998;213:102–104. 606. Vachon AM, Fischer AT. Thoracoscopy in the horse: diag-
580. Keen JA, Swain JM, Rhind SM, et al. Lymphoproliferative dis- nostic and therapeutic indications in 28 cases. Equine Vet J.
ease resembling lymphomatoid granulomatosis in a thorough- 1998;30:467–475.
bred mare. J Vet Intern Med. 2004;18:904–906. 607. Hollis AR. Paraneoplastic syndromes. Equine Vet Educ.
581. Liebow AA, Carrington CR, Friedman PJ. Lymphomatoid 2011;23:184–185.
granulomatosis. Hum Pathol. 1972;3:457–558. 608. Blackman MR, Rosen SW, Weintraub BD. Ectopic hormones.
582. Lucke VM, Kelly DF, Harrington GA, et al. A lymphoma- Adv Intern Med. 1978;23:85–113.
toid granulomatosis of the lungs in young dogs. Vet Pathol. 609. Dascanio JJ, Zhang CH, Antczak DF, et al. Differentiation of
1979;16:405–412. chronic lymphocytic leukemia in the horse. A report of two
583. Postorino NC, Wheeler SL, Park RD, et al. A syndrome resem- cases. J Vet Intern Med. 1992;6:225–229.
bling lymphomatoid granulomatosis in the dog. J Vet Intern 610. Weir EC, Burtis WJ, Morris CA, et al. Isolation of 16,000-dalton
Med. 1989;3:15–19. parathyroid hormone-like proteins from two animal tumors
584. Berry CR, Moore PF, Thomas WP, et al. Pulmonary lympho- causing humoral hypercalcemia of malignancy. Endocrinology.
matoid granulomatosis in seven dogs (1976-1987). J Vet Intern 1988;123:2744–2751.
Med. 1990;4:157–166. 611. Weir EC, Norrdin RW, Barthold SW, et al. Primary hyper-
585. Leblanc B, Masson MT, Andreu M, et al. Lymphomatoid gran- parathyroidism in a dog: biochemical, bone histomorphomet-
ulomatosis in a beagle dog. Vet Pathol. 1990;27:287–289. ric, and pathologic findings. J Am Vet Med Assoc. 1986;189:
586. Fitzgerald SD, Wolf DC, Carlton WW. Eight cases of canine 1471–1474.
lymphomatoid granulomatosis. Vet Pathol. 1991;28:241–245. 612. Jaeschke G, Rudolph R. Clinical diagnostic keys and spe-
587. Valentine BA, Blue JT, Zimmer JF, et al. Pulmonary lym- cial manifestations in equine leukosis. Berl Munch Tierarztl
phomatoid granulomatosis in a cat. J Vet Diagn Invest. Wochenschr. 1991;104:303–307.
2000;12:465–467. 613. Jaeschke G, Rudolph R. Clinical chemistry in leukosis of horses
588. Roberts MC. Equine lymphoma: What are the prospects for (review). Berl Munch Tierarztl Wochenschr. 1992;105:114–122.
cellular differentiation, early daignosis and intervention strate- 614. Brodey RS. Hypertrophic osteoarthropathy in the dog: a
gies? Equine Vet Educ. 2008;20:464–466. clinicopathologic survey of 60 cases. J Am Vet Med Assoc.
589. Kelley LC, Mahaffey EA. Equine malignant lymphomas: mor- 1971;159:1242–1256.
phologic and immunohistochemical classification. Vet Pathol. 615. Brodey RS, Craig PH, Rhodes WH. Hypertrophic osteoar-
1998;35:241–252. thropathy in a dog with pulmonary metastases arising from
590. Ross JS. DNA ploidy and cell cycle analysis in cancer diagnosis a renal adenocarcinoma. J Am Vet Med Assoc. 1958;132:
and prognosis. Oncology (Williston Park). 1996;10:867–882, 887. 232–237.
591. Scarratt WK, Crisman MV. Neoplasia of the respiratory tract. 616. Fawthrop FW, Russell RGG. Hypertrophic pulmonary osteo-
Vet Clin North Am Equine Pract. 1998;14:451–473, v. arthropathy. In: Nordin BEC, Need AG, Morris HA, eds. Met-
592. Southwood LL, Schott HC, Henry CJ, et al. Disseminated abolic Bone and Stone Disease. 3rd ed. Edinburgh: Churchill
hemangiosarcoma in the horse: 35 cases. J Vet Intern Med. Livingstone; 1993;330.
2000;14:105–109. 617. Mair TS, Tucker AL. Hypertrophic osteopathy (Marie’s dis-
593. Valentine BA, Weinstock D. Metastatic testicular embryonal ease) in horses. Equine Vet Educ. 2004;16:308–311.
carcinoma in a horse. Vet Pathol. 1986;23:92–96. 618. Sweeney CR, Stebbins KE, Schelling CG, et al. Hypertrophic
594. Johnson JE, Beech J, Saik JE. Disseminated hemangiosarcoma osteopathy in a pony with a pituitary adenoma. J Am Vet Med
in a horse. J Am Vet Med Assoc. 1988;193:1429–1431. Assoc. 1989;195:103–105.
595. Rossier Y, Sweeney CR, Heyer G, et al. Pleuroscopic diagnosis 619. Leung FW, Williams AJ, Fan P. Indomethacin therapy for
of disseminated hemangiosarcoma in a horse. J Am Vet Med hypertrophic pulmonary osteoarthropathy in patients with
Assoc. 1990;196:1639–1640. bronchogenic carcinoma. West J Med. 1985;142:345–347.
C HA P T E R 9
Disorders of the
Cardiovascular System
Colin C. Schwarzwald*
Cardiovascular (CV) system function is critical to exercise, group of experts in the field of equine CV medicine summa-
thermoregulation, and the blood flow–dependent functions of rizes the current recommendations for management of equine
the brain, heart, lungs, kidneys, gut, and reproductive system. athletes with CV abnormalities.68 These recommendations are
Heart and vascular diseases are common in horses, but for- included in the respective sections later in this chapter.
tunately the underlying lesion is often minor and well toler- Heart murmurs and arrhythmias are commonly detected
ated. However, clinically significant CV disease can develop in in horses, even in the absence of clinical signs of CV dis-
horses with clinical signs that can include arrhythmia, exercise ease.69-82 A variety of studies describe the prevalence of CV
intolerance, congestive heart failure, weakness or collapse, sys- disease in horses, indicating that mitral regurgitation, aortic
temic infection, or sudden death. regurgitation, tricuspid regurgitation, and atrial fibrillation
The clinical evaluation of the equine CV system is often are the most common cardiac abnormalities detected.33,83,84
perplexing. Horses are renowned for a variety of physiologic Else and Holmes noted myocardial fibrosis in 14.3% of horses
murmurs and arrhythmias. Furthermore, the equine CV sys- examined at necropsy and evidence of chronic valvular disease
tem has an enormous compensatory capacity, and the limits in approximately 25% of the hearts examined.27-29 Various CV
of normal CV function can only be reached by horses under- lesions were considered important in 8.5% of 480 consecu-
going exercise at the highest levels. Clinical assessment is best tive losses in a necropsy study conducted by Baker and Ellis.85
served by an awareness of normal variation, the appreciation of Cardiovascular diseases are probably the third most common
relevant diseases, diagnostic studies and prognostic indicators, cause of poor performance following musculoskeletal and
and an understanding of available management options. Com- respiratory diseases.86-90 Occult heart disease, cardiac arrhyth-
munication of these issues constitutes the focus of this chapter. mias, and vascular lesions are considered important reasons
Equine cardiology has advanced from a study of physi- for unexplained sudden death.85,91-106 Certainly, CV abnor-
ologic variation and speculation to one of accurate diagnosis malities are clinically relevant, and most clinicians encounter
and focused therapy, though many clinical issues are unre- manifestations of CV disease or dysfunction on a regular basis.
solved. Much of the important groundwork in clinical equine The assessment of CV disease in a horse is predicated on a
cardiology can be attributed to the studies of Detweiler and competent clinical examination, the clinician’s knowledge, and
colleagues,1-4 Hamlin, Smith, and Smetzer,5-20 and Holmes the ability to order and evaluate diagnostic studies. Incomplete
and his trainees.21-51 The initial information provided by these information may impede an accurate diagnosis, foster mis-
cardiologists regarding normal CV physiology, cardiac cath- communication of risks to the client, or delay the proper course
eterization, pathology, cardiac auscultation, and electrocardi- of management. Fundamentals of CV anatomy, physiology,
ography was pivotal, and we still make clinical decisions based and electrophysiology are reviewed elsewhere.9,20,53,57,107-117
on data these groups provided. There has been steady prog- This chapter offers a framework for understanding the lesions,
ress in cardiac assessment by many other investigators over pathophysiology, diagnosis, and management of important
the past decades. Many of these advances relate to the various congenital and acquired conditions of the heart and major
modalities of echocardiography, which (along with ausculta- vessels. Clinical aspects of circulatory shock are described in
tion) is the most important of available diagnostic studies. this volume. The reader is referred elsewhere for the manage-
Other examinations of importance to CV assessment include ment of cardiopulmonary arrest.58,118
ambulatory electrocardiography, functional exercise testing,
and biochemical tests of cardiac injury. Appropriate selection
and interpretation of these tests allows the clinician to identify Y ANATOMIC CORRELATES OF
and quantify most diseases of the heart and circulation. CARDIOVASCULAR DISEASES
A variety of sources are available providing a compre-
hensive overview of the current knowledge of CV diseases Most diagnostic techniques, including cardiac auscultation,
in horses.52-67 A recent consensus statement formulated by a electrocardiography, cardiac catheterization, and echocardiog-
raphy, are predicated on an understanding of cardiac anatomy
* The editors and authors acknowledge and appreciate the contributions of and physiology. The CV system is divided into two separate
John D. Bonagura and Virginia B. Reef as previous contributors to this chap- circulations—systemic and pulmonary. The systemic circula-
ter. Some of their original work has been incorporated into this edition. tion has a greater venous capacitance, ventricular pumping
387
pressure, arterial pressure, and vascular resistance.57,110,112-114,116

Despite these differences, the functions of these two circula- BOX 9.1
Cardiac Diagnoses
tions are interdependent as the following examples illustrate.
Systemic and pulmonary circulations are arranged in series; ANATOMIC DIAGNOSIS
therefore cardiac output (CO) from the left ventricle (LV) and Cardiac malformation
the right ventricle (RV) must be equivalent. Accordingly, fail- Valvular (endocardial) disease
ure of either ventricle limits CO. Isolated left ventricular fail- Myocardial disease
ure, as with severe mitral regurgitation, can cause right-sided Pericardial disease
failure. This is explained by the increased pulmonary venous Cor pulmonale (pulmonary disease leading to secondary
pressure causing pulmonary vascular remodeling and pulmo- heart disease)
nary hypertension and imparting a pressure load on the RV. Disorder of the impulse-forming or conduction system
A third example is the case of isolated RV failure with marked Vascular disease
right ventricular dilation. Here the leftward bulging of the
ventricular septum impairs filling of the LV. This last situation PHYSIOLOGIC DIAGNOSIS
also can develop in chronic pericarditis. Arrhythmias also Systemic: pulmonary shunting
affect both sides of the heart, so that the development of atrial Left to right
fibrillation (AF) in the setting of severe structural heart dis- Right to left
ease often promotes biventricular heart failure. Valvular insufficiency
The heart consists of unique active and passive components, Valvular stenosis
and different diagnostic methods are needed to evaluate these Myocardial (systolic) dysfunction
structures and associated functions. Normal heart action requires Diastolic dysfunction
coordination of electrical activity, muscular contraction and Cardiac rhythm disturbance
relaxation, and valve motion. When reviewing heart anatomy, and Cardiac-related syncope
subsequently cardiac pathology, it is useful to consider the ana- Heart insufficiency or failure (limited cardiac output)
tomic integrity of the pericardium, myocardium, endocardium Congestive heart failure
and valves, specialized impulse-forming and conduction systems, Shock
and blood vessels.107,109,111 Using this approach, the causes of CV Sudden cardiac death
disease can be conveniently subdivided into anatomic, physi- Cardiopulmonary arrest
ologic (functional), and etiologic diagnoses (Boxes 9.1 and 9.2).
ETIOLOGIC DIAGNOSIS
Pericardial Disease Malformation (genetic)
The pericardium limits cardiac dilation, acts as a barrier against Degenerative disease
contiguous infection, and contributes to the diastolic properties Metabolic or endocrine disease
of the heart. The pericardial space is formed by the reflection Neoplasia
of the two major pericardial membranes, the parietal pericar- Nutritional disorder
dium and the visceral pericardium (epicardium), and normally Inflammatory disease
contains such a small amount of serous fluid that it cannot be Infective or parasitic
seen by echocardiography. Pericardial effusion leading to car- Noninfective
diac compression (tamponade) impairs ventricular filling and • Immune-mediated
diastolic function, typically causing right-sided congestive heart • Idiopathic
failure (CHF). Some cases of pericarditis progress to constric- Ischemic injury
tive pericardial disease, which severely limits ventricular filling. Idiopathic disorder
Pericardial effusion can develop as a primary disorder or Iatrogenic disease
secondary to pleuropneumonia. Infective pericarditis can Toxic injury
produce an effusion sufficient to cause cardiac tamponade or Traumatic injury
eventual constriction of the heart.88,119-137 Sterile, idiopathic
pericardial effusion also has been reported in horses. The
volume of effusion can be substantial and can lead to cardiac the atrial septum. The LA is dorsal to the LV through which it
decompensation.126 Cardiac mass lesions and intrapericardial communicates across the left AV (mitral) valve. The LV is circular
tumors have been reported sporadically.128,131,138,139 Cranial in cross section when viewed by echocardiography and separated
mediastinal tumors (lymphosarcoma) or abscesses secondary from the RV by the ventricular septum. The septum and free
to pleuropneumonia also can compress the heart and mimic walls are thicker than the RV free wall (by approximately 2.5–3
pericardial disease.140 Clinical aspects of pericardial disease times). Persistent embryologic openings in the cardiac septa are
are discussed later in this chapter. known as septal defects, with the ventricular septal defect (VSD)
representing the most common cardiac anomaly in most equine
Myocardial Disease practices (see Box 9.2). The LV is functionally V shaped, with an
The myocardium forms the bulk of the atrial and ventricular inlet and outlet separated by the cranioventral (septal or accord-
muscular walls. The right atrium (RA) communicates with the ing to the human nomenclature “anterior”) leaflet of the mitral
RV inlet through the right atrioventricular (AV) or tricuspid valve (Fig. 9.1). The aorta originates in the LV outlet, continuous
valve. The RV appears crescent shaped on cross-sectional echo- with the ventricular septum cranially and in fibrous continuity
cardiographic examination and is functionally U shaped. The RV with the septal mitral leaflet caudally. This great vessel exits from
inlet is located in the right hemithorax and the outlet, pulmonary near the center of the heart and to the right of the main PA.
valve, and main pulmonary artery (PA) on the left side of the The myocardium may dilate or hypertrophy in response
chest. The left atrium (LA) is caudal to the RA and separated by to exercise,141,142 in response to increased work caused by
CHAPTER 9 Disorders of the Cardiovascular System 389
BOX 9.2
Causes of Cardiovascular Disease
CONGENITAL CARDIAC MALFORMATION Myocardial ischemia/hypoxia

Simple systemic-to-pulmonary shunts (left to right) Toxic injury (e.g., ionophores, plant toxins, cantharidin,
Atrial septal defect snake venom)
Ventricular septal defect Nutritional deficiencies (e.g., vitamin E, selenium)
• Paramembranous defect Atypical myopathy
• Ventricular inlet defect Trauma
• Subarterial (subpulmonic) defect Infiltrative myocardial disease (e.g., myocardial neoplasia,
• Muscular defect amyloidosis)
Patent ductus arteriosus Tachycardia-induced cardiomyopathy
Patent foramen ovale (permitting right-to-left shunting) Chronic hypertension (e.g., chronic pain, laminitis, metabolic
Valvular dysplasia syndrome, chronic kidney disease)
Mitral stenosis/atresia
Pulmonary atresia (leading to a right-to-left shunt) PERICARDIAL DISEASE
Tricuspid stenosis/atresia (leading to a right-to-left shunt) Pericardial effusion with or without cardiac tamponade
Aortic stenosis/insufficiency (bicuspid or quadricuspid valve) Infective: bacterial, viral, or fungal
Subaortic rings with stenosis Immune-mediated
Tetralogy of Fallot Trauma
Pulmonary atresia with ventricular septal defect (pseudotruncus Neoplasia
arteriosus) Idiopathic pericardial effusion
Double-outlet right ventricle Constrictive pericardial disease
Subaortic stenosis Mass lesion (intrapericardial or extrapericardial) compressing
Hypoplastic left side of the heart the heart
Other complex malformations
PULMONARY HYPERTENSION AND COR PULMONALE
VALVULAR HEART DISEASE CAUSING VALVE INSUFFICIENCY Pulmonary hypertension following left-sided heart disease
OR STENOSIS Pulmonary vascular disease following left-to-right shunt
Congenital valve malformation Immature pulmonary circulation
Semilunar valve fenestrations causing valve insufficiency Primary bronchopulmonary or pulmonary vascular disease
Degenerative (fibrosis) or myxomatous disease causing valve Alveolar hypoxia with reactive pulmonary arterial vasoconstriction
insufficiency Severe acidosis
Valvular prolapse Pulmonary thromboembolism
Bacterial endocarditis causing valve insufficiency with or
without stenosis CARDIAC ARRHYTHMIAS (see Box 9.12)
Rupture of a chorda tendinea causing mitral or tricuspid Atrial arrhythmias
valve insufficiency Junctional (nodal) arrhythmias
Rupture of a valve leaflet causing flail leaflet and valve Ventricular arrhythmias
insufficiency Conduction disturbances
Noninfective valvulitis
Valvular regurgitation following dilation of the heart or a great VASCULAR DISEASES
vessel Congenital vascular lesions
Papillary muscle dysfunction causing valvular insufficiency Rupture of the aorta, pulmonary artery, or systemic artery
Aneurysm of the aortic sinus of Valsalva
MYOCARDIAL DISEASE Aortopulmonary fistula
Idiopathic dilated cardiomyopathy: ventricular dilation and Aortic or aortoiliac degenerative disease
myocardial contractility failure Arteritis
Myocarditis Infective
Myocardial fibrosis Immune-mediated
Ischemic (embolic?) myocardial fibrosis (Jugular) venous thrombosis/thrombophlebitis
Parasitic (Strongylus) embolization Pulmonary embolism
Myocardial degeneration/necrosis Mass lesion or tumor obstructing blood flow
structural cardiac disease, or as a consequence of a noncardiac in response to exercise, severe anemia, and infections. In these
disorder. Ventricular or atrial dilation is recognized echocar- situations, compensatory increases in CO, sympathetic acti-
diographically or at necropsy by distention and rounding of the vation, and peripheral vasodilation occur to maintain oxygen
affected chambers, including a “double-apex” sign when there delivery to the tissues.57,110,112-114,116,117,144
is marked RV enlargement. Lesions causing systolic pressure The overall prevalence of myocardial disease is unknown;
overload lead to concentric hypertrophy.143 More common in however, multifocal areas of fibrosis are commonly found at
horses are lesions such as incompetent valves or shunts that necropsy.28,29,97,145-150 Whether these areas indicate prior inflam-
cause ventricular volume overload with dilation and eccentric mation, toxic injury, or ischemic necrosis caused by intramu-
ventricular hypertrophy. Increased cardiac work also occurs ral coronary disease is uncertain. Cases of multifocal or diffuse
Pulmonary
veins
Pulmonary
artery
Great coronary
vein
Anterior
vena cava Left coronary artery
(circumflex branch)
Bicuspid valve
Chordae tendineae
Musculus
pectinatus Musculus papillaris
Moderator band
Right coronary
artery Left ventricle
Tricuspid
valve
Chordae
tendineae
Moderator
band
Right
ventricle Left coronary
artery
FIG. 9.1 Sagittal view of the equine heart. The thicknesses of the ventricles, the position of the atria
relative to the ventricles, and the relationship of the left ventricular (LV) inlet and outlet are evident. The
bicuspid valve referred to in this figure is the mitral valve. The circular appearance of the left atrium (LA) and
the relationship of the septal cusp of the mitral valve to the LV inlets and outlets are notable. These aspects
are important when examining the heart by echocardiography. v.a., Segment of aortic valve. (From Sisson
S, Grossman JD: Anatomy of the domestic animals, ed 4, Philadelphia, 1953, WB Saunders.)
myocarditis have been observed. Myocardial inflammation and flow of blood through the heart by preventing significant regur-
myocardial failure can lead to cardiac arrhythmias and heart gitation of blood from higher to lower pressure zones. The AV
failure.4,151,152 Idiopathic dilated cardiomyopathy develops spo- inlet valves—the tricuspid and the mitral—are anchored by the
radically and is recognized echocardiographically as a dilated, collagenous chordae tendineae and papillary muscles and are
hypokinetic left or right ventricle.129 As in other species, echo- supported by a valve annulus and the caudal atrial walls (Fig.
cardiographic features of dilated cardiomyopathy can also be 9.2; also see Fig. 9.1).107,109,111 The mitral valve consists of two
tachycardia induced and may resolve following successful con- major cusps and several accessory cusps.45 The tricuspid valve
trol of heart rate (HR) and heart rhythm.153 Ingestion of monen- is the largest valve and consists of three well-defined leaflets.
sin or other ionophores can cause mild to severe myocardial Lesions of any portion of the AV valve apparatus or dilation of
injury.154-163 Vitamin E and selenium deficiency have been the ventricle can lead to valvular insufficiency (see Box 9.2). The
described as causes of myocardial degeneration and dysfunc- aortic and pulmonary valves each consist of three semilunar
tion.164,165 Neoplastic infiltration is considered rare.93,138,139,166 leaflets that close during diastole to protect the ventricles from
Impaired myocardial function as a consequence of regional the higher arterial blood pressure (BP). Aortic valvular tissue
ischemia has been sought using stress echocardiography imme- in horses is not simply passive, and it will contract in response
diately following treadmill exercise or pharmacologic stress, but to a number of adrenergic and vascular agonists, such as angio-
this diagnosis requires further definition167,168 (see later discus- tensin II and endothelin.169 The left and right main coronary
sion). Myocardial contraction is dictated by electrical activity of arteries originate within the aortic valve sinuses (of Valsalva).
the myocardium; accordingly, cardiac arrhythmias—especially Valvular disorders in horses are common. Congenital valve
atrial fibrillation or ventricular tachycardia (VT)—can limit CO stenosis, dysplasia, or atresia are recognized sporadically in
and cause exercise intolerance in performance animals (see later foals.4,151,170-190 Degenerative diseases of the aortic, mitral, and tri-
discussion). Clinical aspects of myocardial disease are discussed cuspid valves are very common in mature horses,4,123,148,151,191,192
later in this chapter. and endocarditis can develop on any cardiac valve4,31,129,151,191,193-206
(see Box 9.2). Valvular lesions of obscure etiology, including
Valvular and Endocardial Diseases nonseptic valvulitis, have been recognized sporadically. Tricus-
The cardiac chambers are lined by the endocardium, which also pid and mitral regurgitation, of unspecified etiology, is often
covers the four cardiac valves and is continuous with the endo- detected in high-performance animals, including Standard-
thelium of the great vessels. Normal valves govern the one-way bred and National Hunt horses.70,72,75,207-211 Mitral regurgitation
Bachman’s bundle
N
SA
RA LA
AVN
H
RV LV
Purkinje fibers
P 130 ms QRS 130 ms
PQ 300 ms
FIG. 9.2 Anatomy of the left atrioventricular (mitral) valve. Opened left Sympathetic Vagus
atrium (LA) and LV viewed from the caudal perspective. The large ante-
rior (cranioventral or septal) leaflet in the center of the figure is notable.
Chordae tendineae attach the valve to the papillary muscles. The ventricle
–
has been cut so that the multiple cusps of the posterior (caudodorsal or + N
mural) leaflet are visible to the left and the right of the anterior leaflet. A
S
–
(MR) due to rupture of a chorda tendineae is recognized in both + AVN
foals and mature animals.38,212-214 Clinical aspects of valvular
heart disease are discussed later in this chapter.
Disease of the Impulse-Forming and

Conduction Systems
The specialized cardiac tissues consist of the sinoatrial (SA) node, FIG. 9.3 Impulse-forming and conduction systems of the heart. The im-
internodal pathways, AV node, bundle of His, bundle branches, pulse originates in the sinoatrial node (SAN) and is propagated across the
fascicles, and Purkinje system (Fig. 9.3). The SA node, a rela- right atrium (RA) and left atrium (LA), generating the P wave. Specialized in-
tively large, crescent-shaped structure, is located subepicardially ternodal and interatrial (Bachmann’’s bundle) pathways facilitate impulse con-
at the junction of the right auricle and cranial vena cava. Well- duction. The impulse is delayed in the atrioventricular node (AVN) and rap-
documented sinus node disease, although suggested,215 is rare; in idly conducted through the bundle of His (H), bundle branches and Purkinje
contrast, vagally induced sinus arrhythmias are common.9,215-217 network (top). Electrical activation of ventricular myocytes generates the QRS
The equine atrial muscle mass is large and predisposes the horse complex. The automaticity of the SA node and conduction across the AV
to development of reentrant rhythms and fibrillatory conduc- node are modulated by the autonomic nervous system (bottom). (Courtesy
tion.218 The AV node, situated in the ventral atrial septum, and Dr. Robert L. Hamlin. From Schwarzwald CC, Bonagura JD, Muir WW: The
the bundle of His, which continues on into the bundle branches, cardiovascular system. In Muir WW, Hubbell JA, editors: Equine anesthesia:
are sites for AV block, both physiologic (vagal) and, infrequently, monitoring and emergency therapy, ed 2, St. Louis, 2009, WB Saunders.)
pathologic in nature. Conduction is slow across the normal AV
node.112,219-221 The His-Purkinje system in the ventricular septum a minor extent. Vagal influence generally depresses HR (chro-
and ventricular myocardium can act as substrates for junctional notropism), AV conduction (dromotropism), excitability (bath-
and ventricular ectopic impulses and tachycardias. Because the motropism), and myocardial contractile state (inotropism).
horse has relatively complete penetration of Purkinje fibers in However, because vagotonia also shortens the action potential
the ventricles—except for a small portion of the LV free wall— and refractory period of atrial myocytes, high vagal activity is
the substantial equine ventricles are electrically activated in a a predisposing factor in the development of AF.112,229 Innerva-
relatively short time (approximately 110 msec).7 tion of the stimulatory sympathetic nervous system is exten-
The autonomic nervous system extensively innervates sive throughout the heart and has effects generally opposite to
the heart and influences cardiac rhythms.4,151,222-227 Interplay those of the parasympathetic system. β1-Adrenergic receptors
between the sympathetic and parasympathetic branches nor- dominate in the equine heart,230 but presumably there are other
mally controls HR and heart rhythm in response to changes autonomic subtype receptors, including α-adrenergic recep-
in arterial BP.9,228 The vagus innervates supraventricular tissues tors and small numbers of β2-adrenoceptors.112,231 The notable
extensively and probably affects proximal ventricular tissues to increase in HR that attends exercise is related to increased
sympathetic efferent activity and withdrawal of parasympa- Cardiac Cycle

thetic tone.9 Increases in HR to 220 to 240 beats/min are not The association between electrical and mechanical events of the
uncommon with maximal exercise.232-236 The exact role of dys- heart first described by Wiggers has been reviewed in standard
autonomia in the genesis of cardiac arrhythmias has not been physiology textbooks (Fig. 9.4).57,110,112-115 From a study of this
determined; however, infusion of autonomic receptor agonists cycle, it is evident that cardiac electrical activity precedes pres-
and antagonists can be associated with direct or baroreceptor- sure and volume changes; therefore arrhythmias can exert dele-
induced changes in HR and rhythm.237-247 Cardiac arrhythmias terious hemodynamic effects, especially during exercise, illness,
are discussed later in this chapter. or anesthesia. Relevant aspects of this cycle are now considered.
The P wave of the electrocardiogram (ECG) stems from
Vascular Diseases electrical activation of the atria, late in ventricular diastole, and
There are three major subdivisions of the circulation: sys- after the ventricles have been largely filled. During the ensuing
temic, coronary, and pulmonary. The arteries and veins con- atrial contraction the atrial sound (fourth heart sound or S4) is
sist of three layers: adventitia, media, and intima. The overall generated and the ventricle is filled to its end-diastolic volume.
structure and function of each layer vary with the vessel and The increase in atrial pressure, the atrial a wave, is reflected as
location. Vascular receptors20,112,114,116 and anatomic lesions a normal jugular pulse in the ventral cervical region. The mag-
influence vascular resistance and blood flow. α-Adrenoceptors nitude of the atrial contribution to ventricular filling generally
dominate in the systemic vasculature, and BP is generally placed at 15% to 20% at rest but increases dramatically during
raised by vasoconstriction following stimulation of postsyn- high HRs. Therefore atrial tachyarrhythmias such as AF have
aptic α-adrenergic receptors by norepinephrine, epinephrine, the greatest impact on CO during exercise or tachycardia.
or infused α-adrenergic receptor agonists such as phenyleph- The QRS complex heralds ventricular systole. After depolar-
rine.246,248-254 The presence of vasodilator β2-adrenergic recep- ization of the ventricular myocytes, calcium enters the cell to
tors is clinically relevant, insofar as infused β2-agonists cause trigger release of calcium stores in the sarcoplasmic reticulum.
vasodilation in circulatory beds that contain high β-agonist Increased cytosolic calcium interacts with the cardiac troponin
adrenergic receptor density. Many vascular beds also dilate complex on actin and myosin filaments to shorten the myofila-
following the production of local vasodilator substances, such ments and develop tension. These events are enhanced by sym-
as nitric oxide, released during exercise, stress, or metabolic pathetic activity or drugs such as digoxin or dobutamine and
activity.112,114,116 Dopaminergic receptors, when present in vas- depressed by anesthetics and drugs that impair calcium entry
cular walls, may be stimulated, causing vasodilation, provided into cells. The abrupt increase in ventricular wall tension and
vasoconstricting α-adrenergic activity does not dominate. chamber pressure closes the AV valves (coinciding with the
Stimulation of histamine (H1) receptors or serotonin (5-HT) vibrations of the first heart sound; S1) and increases intraven-
receptors causes arteriolar dilation, venular constriction, and tricular pressure (isovolumic period) until the semilunar valves
increased capillary permeability.112,114,116 Infusion of endothe- open.23,25 At this instant the ventricular walls move inward and
lin255-257 or of calcium salts causes arterial vasoconstriction,258 blood is ejected into the great vessel as the ventricular pressure
whereas administration of calcium channel antagonists (e.g., increases to peak value and creates a similar peak arterial BP
verapamil, diltiazem) causes vasodilation of vascular smooth (Figs. 9.4A, 9.5C and D, and 9.6). The contracting heart twists
muscle.259 during systole, and the left ventricle strikes the chest wall caudal
Various vascular lesions have been reported in horses (see to the left olecranon causing the cardiac impulse or apex beat.
Box 9.2). Rupture of the aorta, PA, or middle uterine artery is This early systolic movement, coincident with opening of the
devastating and often lethal.4,34,92,151,260-262 The aorta may also aortic valve, is a useful timing clue for cardiac auscultation and
rupture into the heart, creating an aortic to cardiac fistula.263,264 for identifying the mitral valve area for auscultation. The delay
Aortopulmonary fistulation in conjunction with aortic rupture between the onset of the QRS and the opening of the semilu-
is relatively common in Friesians, possibly caused by a connec- nar valves, termed the preejection period, can be measured by
tive tissue disorder.265,266 Although parasitic arteritis may pre- Doppler echocardiography and is an index of ventricular myo-
dispose to vascular injury, the cause of most vascular lesions, cardial contractility such that sympathetic activation and posi-
including aortoiliac thrombosis, is unknown.267-272 Causes of tive inotropic drugs shorten the preejection period.46,241,274-279
vasculitis include Strongylus vulgaris infestation of the cranial Blood is ejected into the aorta and PA with an initial velocity
mesenteric artery, infective thrombophlebitis of the jugular that generally peaks near 1 m/sec and can be measured by Dop-
veins, equine viral arteritis, and suspected immune-mediated pler echocardiography (see Fig. 9.5D).280,281 The aortic ejection
disease.145,147,273 Neoplasms can obstruct blood flow by exter- time usually exceeds 400 msec in a horse at rest, and reduc-
nal compression or through invasion, more often affecting the tions of either ejection velocity or ejection time are suggestive
right side of the circulation. Examples include obstruction of of reduced LV function. A functional systolic ejection murmur
the PA by a lung tumor and obstruction of venous return by is often heard during ejection (Fig. 9.4A). Such murmurs, by
neoplastic compression or invasion of the vena cava. Clinical definition, must begin after the first sound and end before the
features of vascular disease are discussed later in this chapter. second sound. The difference between the diastolic and sys-
tolic pressure (pulse pressure) and rate of rise of pressure con-
tribute to a palpable arterial pulse during midsystole (see Figs.
Y CLINICAL CARDIOVASCULAR 9.4A and 9.6). The precise timing of the pulse depends on the
PHYSIOLOGY proximity of the palpation site relative to the heart. At the end
of the ejection period, as ventricular pressures fall below those
The clinician must appreciate elementary aspects of normal of the corresponding arteries, the semilunar valves close coin-
heart function in order to perform a clinical CV examina- cident with the high-frequency second heart sound (S2) and
tion and understand the abnormalities associated with heart the incisura of the arterial pressure curves (see Figs. 9.4A and
disease and CHF. Central to this are the electrical-mechanical 9.6).19,23,25 The pulmonary valve may close either after or before
correlates of Wiggers’ cardiac cycle. the aortic valve.3,4,282 Asynchronous valve closure may lead to
Time (sec)
Phase
Pressure (mm Hg)
ECG
Heart
sounds
A
FIG. 9.4 A, The cardiac (Wiggers) cycle of the horse. This drawing integrates the electrical, pressure, me-
chanical, and flow events of diastole and systole and demonstrates the origins of the heart sounds. Electrical
activity precedes mechanical events. See the text for a full description. AVC, Closure of the mitral (atrioven-
tricular) valve; AVO, opening of the mitral (atrioventricular) valve; SLO, opening of the aortic (semilunar)
valve; SLC, closure of the aortic (semilunar) valve. B, Determinants of cardiac output (CO) and blood pressure
(BP). (A, Modified from Detweiler DK, Patterson DF: The cardiovascular system. In Cattcott EJ, Smithcors JF,
editors: Equine medicine and surgery, ed 2, Santa Barbara, CA, 1972, American Veterinary Publications. B,
From Muir WW, Hubbell JA: Equine anesthesia, ed 2, St. Louis, 2009, Saunders.)
audible splitting of S2, which is normal but can be extreme in c wave of the atrial pressure curve, and is accompanied by a
some horses with lung disease and pulmonary hypertension. downward motion of the mitral and tricuspid annulus toward
During the ejection period the ventricular volume is markedly the apex, causing the subsequent x descent of the atrial pressure
reduced from the end-diastolic volume: this volume ejected is curve and a brief systolic collapse of the jugular vein. Subse-
defined as the stroke volume. The ratio of the stroke volume to quent to atrial filling during ventricular systole, a positive pres-
the end-diastolic volume is the ejection fraction, a commonly sure wave, the v wave, occurs in the atrial and venous pressure
used index of systolic heart function and correlated to the often- curves. Severe TR accentuates this wave and may lead to patho-
used shortening fraction of the M-mode echocardiogram (see logic systolic pulsations extending up the jugular furrow. Finally
Fig. 9.5C). Contraction of the ventricles causes the AV valves to there is a decline in ventricular pressure (isovolumic relaxation)
bulge toward the atrium, leading to the early-systolic positive related to off-loading of calcium from the troponin apparatus
TW RV
RVW VS
RV
S
AV AO
LV LV S
D
AMV
PMV LA
LVW W
A C P
1 2 3 4
EKG P T
Thoracic wall
RV RS
S
AMV AV
LS LV AO
PMV
EN LA
LVW
PER
B Lung
1 2 3 4
FIG. 9.5 Ventricular function and echocardiography. A, Derivation of the M-mode echocardiogram. The
lines demonstrate typical paths of M-mode recording planes (1, ventricular/papillary muscle; 2, chordae
tendineae; 3, anterior mitral valve [AMV]; 4, aortic root and left atrium [LA]/auricle; TW, thoracic wall; RVW,
right ventricular wall; RV, right ventricle; S, septum; LV, left ventricle; AV, aortic valve; AO, aortic outflow
tract; LVW, left ventricular wall; PMV, posterior mitral valve; LA, left atrium). B, The drawing demonstrates
the appearance of the M-mode echocardiogram at each level (PER, pericardium; RS, LS, right and left sides of
the ventricular septum; EN, endocardium). C, M-mode echocardiogram demonstrating the method of mea
suring left ventricular shortening fraction (LVSF), in which D is diastolic dimension and S is systolic dimension
(LVSF = D − S/D). The prominent thickening of the walls during systole is notable. The end-systolic excursion
of the LV wall is visible (arrow). In practice, the systolic dimensions of the ventricular septum and the LV wall
generally are measured along the same line as demonstrated for the LV lumen in systole (S) (W, LV wall;
VS, ventricular septum). D, Left: Doppler echocardiographic recordings of LV filling (left) and ejection (right).
Transmitral inflow is characterized by an early diastolic rapid-filling wave (E), low-velocity middiastolic filling
(diastasis), and a presystolic atrial filling wave (A). Right: The velocity profile of aortic ejection is characterized
by a roughly triangular appearance with rapid acceleration of blood flow into the ascending aorta in early to
midsystole and termination of flow at the time of aortic valve closure. The area under the velocity spectrum
curve (velocity-time-integral) correlates directly with ventricular stroke volume. The preejection period (the
time between the start of the QRS and beginning of ejection) and the ejection times (ET, arrows) are load-
dependent indices of LV function.
and resequestration into the sarcoplasmic reticulum. This active have relaxed and the atrial pressure exceeds the correspond-
ventricular relaxation is associated initially with closure of the ing ventricular pressure, the AV valves open. At that instant,
semilunar valves and eventually by opening of the AV valves rapid filling ensues, with a peak velocity of about 0.5 to 1 m/
(see Fig. 9.4A). Relaxation in healthy hearts is enhanced by sym- sec but varying directly with the HR.280 The ventricular pres-
pathetic activity. Conversely, myocardial ischemia can impair sures increase only slightly during this phase, whereas the ven-
active relaxation, and it is likely that subendocardial ischemia tricular volume curves change dramatically from the venous
combined with reduced diastolic filling time contributes to the return. Rapid filling may be associated with a functional proto-
marked elevations in left atrial pressures observed during gal- diastolic murmur, which is concluded by the third heart sound
loping or other high-intensity exercise.283,284 (S3), the low-frequency vibrations occurring near the termi-
Ventricular filling commences just as the AV valves open. nation of rapid ventricular filling (see Fig. 9.4A). The loss of
As shown in Fig. 9.5D, ventricular diastole can be subdi- atrial volume and corresponding decline in the atrial pressure
vided into three general phases: rapid ventricular filling, (the y descent) is reflected in the jugular furrow as the vein
diastasis, and atrial contraction.110,112,113,115 These phases are collapses. Following rapid filling, a period of greatly reduced
readily observed using pulsed-wave Doppler echocardiogra- low-velocity filling, diastasis, ensues. This period may last for
phy or Doppler tissue imaging.168,285-287 Once the ventricles seconds during vagal arrhythmias such as sinus bradycardia,
pronounced sinus arrhythmia, or second-degree AV block.
With markedly exaggerated pauses, the jugular vein may begin
ECG
to fill prominently. The last phase of diastole is the contribu-
tion to ventricular filling caused by the atrial contraction. A
functional presystolic murmur has been associated with this
period between the fourth and first heart sounds.
ABP During the cardiac cycle the atrium functions as a reservoir
for blood (ventricular systole), a conduit for venous return
(early to middiastole), and as a pressure pump (atrial sys-
tole).288 Mechanical atrial function of the LA can be studied
using two-dimensional (2D) echocardiography and advanced
Doppler echocardiographic methods. Impaired electrical and
FIG. 9.6 Compressed electrocardiogram (ECG) with simultaneous arte- mechanical function of the atria may predispose to recurrent
rial blood pressure (ABP) recording in a horse with second-degree atrio- atrial arrhythmias such as AF.218,287,289-291
ventricular block. The progressive increase in ABP triggers a baroreceptor
reflex leading to atrioventricular conduction block (upper arrows) and a Ventricular Function
corresponding fall in the ABP (lower arrows). Presumably this mecha- The ability of the ventricles to eject blood depends on both sys-
nism, along with sinus arrhythmia and sinus arrest, represents vagally tolic and diastolic ventricular function as well as HR and heart
induced mechanisms for controlling ABP in the standing horse. rhythm (Box 9.3; see also Fig. 9.4B). The most commonly used
BOX 9.3
Determinants of Cardiac Function
SYSTOLIC FUNCTION: DETERMINANTS OF VENTRICULAR DIASTOLIC FUNCTION: DETERMINANTS OF VENTRICULAR

STROKE VOLUME (see also Fig. 9.4B) FILLING
Preload [+]—ventricular end-diastolic volume Pleural/mediastinal factors
• Plasma (blood) volume • Intrapleural pressure (ventilation, effusion)
• Determinants of diastolic function (see below) • Mass lesions
Contractility [+]—intrinsic myocardial ability to Pericardial function
contract • Intrapericardial pressure (effusion)
• Sympathetic activity • Constriction
• Loading conditions Myocardial recoil (passive elastic properties)
• Myocardial perfusion (ischemia) Myocardial relaxation (active process)
• Myocardial disease • Myocardial perfusion (ischemia)
• Drugs (positive or negative inotropic agents) Ventricular wall distensibility (chamber and myocyte compliance)
Afterload [−]—wall tension required to eject Venous pressure and venous return (must be matched with
blood compliance)
• Aortic impedance • Plasma volume
• Vascular resistance • Venous capacitance
• Ventricular volume (tension increases with Diastolic filling time
dilation) • Heart rate
• Ventricular wall thickness (thin walls have higher Atrial contribution to filling (“booster pump”)
tension) • Heart rate
Cardiac lesions increasing workload [−] • Cardiac arrhythmias (atrial fibrillation)
• Valvular regurgitation (common) Atrioventricular contraction sequencing
• Valvular stenosis (rare) • Cardiac arrhythmias
• Septal defects and shunts Atrioventricular valve function
• Stenosis
measurements of overall ventricular performance and circula- atrial stunning after AF) and certain tachyarrhythmias (by short-
tory function are HR, invasively or noninvasively determined ening filling time and disturbing the atrioventricular conduction
arterial BP, rate of ventricular pressure change (dp/dt), car- sequence) all reduce ventricular filling and decrease SV. Increased
diac output (CO), stroke volume (SV), LV ejection fraction, preload can be observed in horses with heart disease as a conse-
LV shortening fraction, systolic time intervals, central venous quence of impaired pump function and fluid retention second-
pressure, PA and pulmonary capillary wedge pressures, and ary to activation of the renin-angiotensin-aldosterone system.117
arteriovenous oxygen difference (A-V DO2).57 Moderate to severe valvular insufficiency increases ventricular
Cardiac output, the amount of blood pumped by the left (or filling pressures and preload.144,352-355 The increased ventricular
right) ventricle in 1 minute (L/min), is the product of ventricu- diastolic dimensions serve as a compensatory mechanism that
lar SV (mL/beat) multiplied by HR (beats/min) (see Fig. 9.4B). maintains forward stroke volume in the early setting of a failing
Cardiac index refers to the CO divided by (indexed to) the body ventricle or regurgitant heart valve. Ventricular preload can be
surface area (or body mass). Cardiac output coupled to systemic estimated by determining ventricular end-diastolic dimensions
vascular resistance determines the mean arterial BP; an increase (volume, area, or diameter) using echocardiography168,344,345,355
in either variable raises mean arterial pressure. Values for CO or by measuring venous filling pressures using intracardiac cath-
vary widely with the size and activity of the horse and are often eters.353,354 The measurement of venous filling pressures (central
influenced by drug therapy or anesthesia.292,293 Ventricular venous pressure, pulmonary diastolic, or pulmonary capillary
stroke volume depends on myocardial contractility, preload, and wedge pressure)353-358 provides an accurate gauge of preload
afterload (see Fig. 9.4B and Box 9.3).24,26,110,112-115 Although tra- provided that HR and ventricular compliance (distensibility) are
ditionally considered independent determinants of myocardial normal and ventilation is relatively stable. Myocardial ischemia,
function, these three variables are all interconnected and influ- which impairs myocardial relaxation, and pericardial diseases,
ence force, velocity, and duration of ventricular contraction and which constrict the ventricles, both reduce ventricular compli-
thereby SV.110,112,114 Invasive and noninvasive estimates of SV and ance; in such cases, the venous filling pressures may not accu-
CO can be obtained in standing and anesthetized horses using rately reflect chronic changes in ventricular preload.
a large variety of methodologies.276,294-318 In clinics, SV is often Ventricular afterload relates to the forces impeding ejection
estimated noninvasively by 2D and Doppler echocardiography of blood and is closely related to the aortic pressure.110,112-115 Vas-
(see later discussion).168,297,306,307,309,311-313 cular impedance during ejection is determined by the elastic,
Myocardial contractility (inotropy) is defined as the maxi- resistive, and dynamic properties of the connected great vessel
mum velocity of fiber shortening at zero load.110,112-115 Ulti- and vascular tree. However, afterload is not solely determined
mately, it is determined by the availability of calcium to the by blood pressure. Ejection against a pressure load causes wall
sarcomere and the sensitivity of troponin C for calcium, which stress, which according to Laplace’s law is proportionate to pres-
are modulated by the autonomic input, the initial myocardial sure (P) × radius (r) and inversely proportionate to wall thick-
stretch (preload; see later discussion), and the HR (Bowditch ness (h). Afterload can be expressed as LV wall stress during
“treppe” effect) (see Fig. 9.4B). Contractility is increased by ejection. While the exact equation depends on cardiac chamber
catecholamines, calcium, digitalis glycosides, and phospho- shape, which is subject to changes during the cardiac cycle, the
diesterase inhibitors.* True contractility is difficult to mea- above simplified relationship highlights how pressure, radius,
sure in the clinical setting because of the influence of HR and and wall thickness contribute to afterload. Peak wall stress
loading conditions on clinical measurements of systolic ven- occurs immediately before aortic valve opening. Afterload is
tricular function. Overall systolic ventricular function can be difficult to measure clinically, and although BP is not identical to
estimated noninvasively by observing directional changes in afterload, it may be used to estimate directional changes in after-
load-dependent preejection or ejection phase indices of ven- load. Additionally, relative LV wall thickness can be measured
tricular function. These include LV shortening and ejection by echocardiography and should be taken into account.168,344
fractions by M-mode and 2D echocardiography; preejection Increases in ventricular chamber size, thinning of ventricular
period, ejection time, flow acceleration, velocity time integral walls, aortic stenosis, arterial stiffness or resistance (leading to
of aortic or pulmonic ejection, and peak myocardial velocity increased pressures), as well as marked increases in hematocrit,
by tissue Doppler echocardiography; and myocardial defor- increase the impedance to ventricular ejection and reduce SV.
mation (strain) or strain rate by computerized analysis of 2D Ventricular hypertrophy, by increasing relative wall thickness,
echocardiograms or tissue Doppler studies (see Fig. 9.5).† can be thought of as a mechanism that reduces wall stress at a
Measured variables will be influenced by physiologic state, given pressure and radius.114 The failing heart is characterized
altered mildly by day-to-day variation350,351 or sedatives,274 by poor myocardial contractility, an exhausted preload reserve,
and affected markedly by exercise168 and general anesthesia.292 and an increased sensitivity to ventricular afterload. Arterial
Ventricular sarcomere length before contraction or preload vasodilators such as acepromazine, hydralazine, and angioten-
is a positive determinant of ventricular systolic function that sin-converting enzyme inhibitors decrease afterload and are
depends on ventricular filling (Box 9.3). The healthy ventricle is important components of heart failure treatment.55,58,359-363
highly preload dependent such that increases in preload increase Ventricular synergy refers to the normal method of ventric-
SV. This ability of the heart to change its force of contraction ular activation and contraction. Normal electrical activation
and therefore SV in response to changes in preload is called the causes a burst of activation of great mechanical advantage.
Frank-Starling mechanism (or Starling’s law of the heart).110,112-115 Cardiac arrhythmias, especially ventricular rhythm distur-
Dehydration, venous pooling, impairment of ventricular relax- bances, can cause dyssynergy (dyssynchrony) with a resultant
ation and compliance, increased intrapleural or intrapericardial decrease in SV. Coronary occlusions leading to transient myo-
pressures, loss of atrial booster pump function (e.g., with AF or cardial ischemia or ischemic myocardial necrosis also cause
dyssynergy but are considered relatively rare.91,147,364
* References 237, 238, 241, 246, 249-251, 253, 258, 277, 319-339. Structural and functional competency of the cardiac valves
† References 49-51, 56, 168, 279, 286, 340-349. and the ventricular septa influence ventricular systolic function.
Valvular insufficiency (or the rare stenosis) reduces ventricu- demand.112 Persistent ST-segment depression or elevation,
lar stroke volume unless there is adequate compensation from especially at rest and normal HRs, suggests deficient myo-
ventricular dilation and hypertrophy. Ventricular remodeling, cardial perfusion. However, marked ST-segment and T-wave
combined with HR reserve, often allows small septal defects or changes are normal in horses examined during treadmill exer-
mild to moderate valvular lesions to be well tolerated even dur- cise and are therefore difficult to interpret.
ing exercise. However, large defects or severe valvular lesions
can create significant volume overload of the left side of the Y CARDIOVASCULAR EXAMINATION
heart, progressive myocardial dysfunction, and heart failure.
Development of CHF is particularly likely when an arrhythmia OF THE HORSE
such as AF is superimposed on a serious structural lesion.
Ventricular diastolic function determines ventricular fill- General Approach
ing and preload.110,112-115 Factors that affect diastolic function A general approach to the recognition and diagnosis of heart
are indicated in Box 9.3. When diastolic function is abnormal, disease and an assessment of its severity is summarized in
there is often greater HR and higher venous pressure dependen- Box 9.4.61,62 Undoubtedly, history and physical examination
cies for maintenance of CO. A well-recognized cause of diastolic are the most important initial evaluation procedures in the CV
dysfunction is constriction or compression of the heart due to examination of the horse. With the exception of mild abnor-
pericardial disease. Marked ventricular chamber dilation or malities in cardiac structure and function, normal physical
hypertrophy also decreases ventricular compliance and requires examination and cardiac auscultation in a horse with good
higher ventricular distending pressures for filling. Left ventricu- exercise tolerance practically precludes clinically relevant heart
lar diastolic dysfunction as a consequence of severe RV dilation disease. The initial CV physical examination should include
or hypertrophy can be explained by bulging of the ventricular recording of an accurate resting HR and respiratory rate,
septum into the left ventricle, which impedes left-sided filling. evaluation of the arterial pulses (head and limbs), inspection
This impact of ventricular interdependence is observed clinically of the veins (mostly jugular veins), evaluation of the mucous
with chronic pericardial disease and severe pulmonary hyper- membranes for pallor, refill time, and cyanosis (which may
tension. Ventricular diastolic function also is affected by arrhyth- develop secondary to a right-to-left cardiac shunt or severe
mias. Persistent tachycardia shortens diastole, cardiac filling respiratory disease), evaluation for abnormal fluid accumula-
time, and coronary perfusion. With AF, the atrial contribution to tion, inspection for abnormal ventilatory patterns, palpation
filling is lost. Junctional and ventricular arrhythmias lead to AV of the precordium, a thorough auscultation of the heart at all
dissociation preventing normal AV sequencing and can also cre- valve areas, and auscultation of both lung fields. Noninvasive
ate marked dyssynchrony of ventricular contraction. Objective BP measurement can serve to objectify palpatory findings on
measures of diastolic function are very complicated, and no good arterial pulses and identify widening of pulse pressure.52,68
clinical indicator of diastolic function is currently available for It is worth emphasizing that most serious cardiac disorders
horses. However, diastolic dysfunction may be assumed when can be detected initially by physical examination and a stetho-
one of the aforementioned conditions is recognized. It is pos- scope. The presence of a cardiac murmur is the essential find-
sible to measure transmitral and tricuspid inflow using Doppler ing that leads one to suspect degenerative or infective valvular
techniques, but these methods are unreliable, are crude, and also disease or a congenital heart malformation. Sustained or recur-
depend on atrial pressure.280,281,287,344,365 Assessment of diastolic rent cardiac arrhythmias are easily discovered through cardiac
wall motion velocities by tissue Doppler imaging also may pro- auscultation and palpation of the arterial pulse. Pericarditis and
vide more insight into diastolic cardiac function.161,164,286,349,366 cardiac tamponade are characterized by muffled heart sounds
Imbalance between myocardial oxygen demand and deliv- or pericardial friction rubs, jugular distention, and often RV
ery can reduce both ventricular systolic and diastolic func- failure. Significant myocardial disease is usually associated
tion and may affect cardiac rhythm as well. This relationship with heart failure, arrhythmias, or a cardiac murmur, especially
is also relevant when there is airway obstruction or broncho- when ventricular dilation or dysfunction causes insufficiency of
pulmonary disease, which can reduce arterial oxygenation.90 the mitral or tricuspid valves. Mild, subtle, or occult CV disease
Myocardial oxygen demand is augmented by increasing myo- may be subclinical at rest and require a detailed examination,
cardial inotropic state, HR, and ventricular wall stress (related including exercise testing, before abnormalities can be objec-
to preload and afterload).110,112-115 Oxygen delivery depends tively detected. Laboratory studies, electrocardiography, echo-
on coronary anatomy and vasomotion (degree of vessel con- cardiography, and cardiac catheterization are additional tests
striction), diastolic arterial BP, diastolic (coronary perfusion) that are particularly useful in recognizing or confirming the
time, and metabolic activity of the myocardium.10,367-373 Nor- underlying basis of CV disease and assessing its severity.
mal coronary flow is highest to the LV myocardium in the
ventricular septum and LV wall.373 The immediate subendo- History
cardial layer of myocardium is probably most vulnerable to CV disease may be suspected from the history or a seren-
ischemic injury,367 and altered ventricular depolarization may dipitous finding during the course of a routine examina-
develop secondary to an imbalance in oxygen delivery. This tion. The horse with CHF may be presented for generalized
probably accounts in part for the ST-T depression and changes venous distention, jugular pulsations, edema, or rarely, in the
in the T waves observed in hypotensive animals and in nor- case of acute left-sided heart failure, respiratory distress and
mal horses during sinus tachycardia. Coronary vasomotion is pulmonary edema.148,374 Conversely, other cardiac problems
effective in augmenting coronary perfusion even at high HRs such as arrhythmias or murmurs can be incidental findings,
(up to 200/min in ponies); however, coronary autoregulation detected during a routine physical, prepurchase, or insurance
is not as effective if diastolic perfusing pressure decreases in examination. The horse with clinically apparent CV disease
the aorta.368,369 The clinician may use the “double product” of may have subtle performance problems that are only appar-
arterial BP × HR as a general estimate of myocardial oxygen ent at peak performance levels. In many cases, performance
BOX 9.4
Diagnostic Studies for the Evaluation of Heart Disease
HISTORYa THORACIC AND ABDOMINAL ULTRASONOGRAPHY

• Signalment, presenting complaints, general medical • Evaluation of abnormal fluid accumulation: pleural effu-
history, past illnesses, past and current medications, sion, ascites
weight loss, work history, and exercise tolerance
CLINICAL LABORATORY TESTS
PHYSICAL EXAMINATIONa • Complete blood count, serum amyloid A (SAA), and
• Body condition fibrinogen to identify anemia and inflammation
• Heart rate and rhythm • Serum biochemical tests including electrolytes
• Arterial and venous pulses, venous distention, venous refill (particularly K+, Mg2+, Ca2+), renal function tests, and
• Mucous membrane color and capillary refill time muscle enzymes: these studies can be useful for
• Evaluation for abnormal fluid accumulation: subcutane- assessment of arrhythmias, identification of low cardiac
ous edema, pleural effusion (by thoracic percussion) output (azotemia), and recognition of myocardial cell
• Auscultation of the heart (heart sounds, heart murmurs, injury (CK and AST, unspecific)
rhythm) and lungs • Cardiac troponin T or I (cTnT, cTnI): Can be measured
• Measurement of arterial blood pressure and pulse pres- at rest and after exercise testing to identify myocardial
sure (noninvasive) damage
• Serum proteins to identify hypoalbuminemia and
ELECTROCARDIOGRAPHY hyperglobulinemia
• Resting electrocardiogram—heart rate, rhythm, • Arterial blood gas analysis to evaluate pulmonary
P-QRS-T configuration, conduction sequence, associa- function (alternatively: pulse oximetry)
tion of P and QRS-T, ECG time intervals, and electrical • Venous (or preferably mixed venous) blood gas analysis
axis (axis has limited value in horses) to assess acid-base status, oxygen delivery, and
• Exercise and postexercise electrocardiographyb oxygen extraction in the tissues
• 24-Hour ambulatory (Holter) electrocardiographyb • Blood lactate to identify anaerobic metabolism associ-
ated with poor tissue oxygenation or impaired oxygen
ECHOCARDIOGRAPHY utilization in the tissues
• Two-dimensional echocardiography—cardiac anatomy, • Blood cultures in cases of thrombophlebitis or
chamber size, and vessel dimensions; valve anatomy suspected endocarditis
and motion; systolic atrial and ventricular function; • Cytology and culture of pericardial effusates
identification of cardiac lesions or free fluid; estimation • Urinalysis to identify renal injury from heart failure or
of cardiac output endocarditis
• M-mode echocardiography—ventricular dimensions • Serum/plasma assays for digoxin, quinidine,
and systolic ventricular function; cardiac anatomy and and other cardioactive drugs (therapeutic drug
valve motion; estimation of cardiac output monitoring)
• Doppler echocardiography—identification of normal
and abnormal flow; estimation of intracardiac pressures CARDIAC CATHETERIZATION AND ANGIOCARDIOGRAPHYc
and pressure gradients; estimation of cardiac output; • Diagnosis of abnormal blood flow and identification
assessment of systolic and diastolic ventricular function of abnormal intracardiac and intravascular
• Postexercise echocardiographyc—identification of pressures
regional or global wall dysfunction or valve dysfunction
exacerbated by exercise RADIONUCLIDE STUDIESc
• Detection of abnormal blood flow or lung perfusion;
THORACIC RADIOGRAPHY assessment of ventricular function
• Evaluation of pleural space, pulmonary parenchyma,
lung vascularity
• Estimation of heart size
a Most important part of the cardiac evaluation.
b May be needed to identify paroxysmal arrhythmias.
c Not routinely performed.
may only deteriorate slightly. In other horses, particularly in horses with heart disease. Cardiovascular disease must always
cases of AF, racing performance may decline greatly by 20 to be considered along with musculoskeletal, respiratory, meta-
30 seconds or more throughout a race. Horses with sudden- bolic, and neurologic problems in the differential diagnosis
onset AF or with malignant ventricular tachycardia (VT) may of poor performance (Box 9.5).87-90,375-377 Other performance-
stop abruptly or even fall. Horses with CV disease also may related problems with CV disease can include weakness,
demonstrate excessively high heart and respiratory rates dur- ataxia, collapse, and sudden death (Box 9.6).85,91-106,261
ing and after exercise or may take a longer than normal time Once an abnormality has been found, a complete CV
to return to a resting rate (or “cool out”). Coughing, either at examination is aimed at determining the lesion and the clini-
rest or during exercise, tachypnea, and exercise-induced pul- cal relevance of disease in terms of horse and rider safety, per-
monary hemorrhage are respiratory signs reported in some formance capabilities, and expected longevity.
BOX 9.5
Cardiovascular Disorders Associated With Poor BOX 9.6
Causes of Sudden Cardiovascular Death
Performance
DISORDERS OF THE HEART (ARRHYTHMIAS)
ARRHYTHMIAS Ventricular tachycardia, flutter, or fibrillation
Atrial premature complexes Complete atrioventricular block
Ventricular premature complexes Asystole
Atrial fibrillation
Supraventricular tachycardia HEMORRHAGE
Ventricular tachycardia Rupture of the heart (with cardiac tamponade)
Advanced second-degree atrioventricular block Rupture of the aorta or pulmonary artery (with or without
Complete third-degree atrioventricular block cardiac tamponade)
Arterial rupture
CONGENITAL, VALVULAR, MYOCARDIAL, OR PERICARDIAL Middle uterine artery
HEART DISEASES ASSOCIATED WITH MURMURS Mesenteric, omental, or other large arteries
Ventricular septal defects or other congenital malformations Severe pulmonary hemorrhage
Mitral regurgitation Rupture of the spleen or liver
Tricuspid regurgitation Brain hemorrhage
Aortic regurgitation
Cardiomyopathy with secondary atrioventricular valvular ACUTE MYOCARDIAL FAILURE
regurgitation Acute decompensation of chronic heart failure
Pericardial disease causing friction rubs Acute onset of severe valvular insufficiency
Acute myocardial ischemia/necrosis (rare)
OCCULT HEART DISEASE
Pericardial disease TOXIC INJURY TO THE HEART
Myocardial disease Drug- or toxin-induced arrhythmia
Anesthetics
VASCULAR DISORDERS Toxic plants
Aortoiliac thrombosis Myocardial toxins
Jugular vein thrombosis/thrombophlebitis (bilateral) Systemic toxin secondarily affecting the heart
Aortic root rupture (aortocardiac fistula)
Peripheral vein thrombosis/thrombophlebitis CARDIAC TAMPONADE
Bacterial pericarditis
Idiopathic pericarditis
Auscultation Viral pericarditis
Trauma
Clinical Method
Cardiac auscultation is the systemic examination of the heart EMBOLISM
using a stethoscope. Auscultation is expedient and relatively Carotid air embolism
sensitive for detection of serious heart disease when per- Coronary embolism or thrombosis
formed by a knowledgeable and experienced examiner. It
provides information about HR, persistent arrhythmias, and ELECTROCUTION
presence or absence of congenital and acquired heart diseases. Lightning
Auscultation should be conducted within the context of a Alternating current electrocution
medical history and general physical examination.
Effective auscultation requires an understanding of anat- CARDIAC TRAUMA
omy, physiology, pathophysiology, and sound. There is exten- Cardiac catheterization or needle puncture of a ventricle
sive clinical experience regarding cardiac auscultation in the leading to ventricular fibrillation
horse,* and experience with Doppler echocardiography has Penetrating thoracic wound
refined the clinician’s understanding of heart sounds and mur-
murs.71,208,209,211,390,391 Experience and training are also significant
factors in effective cardiac auscultation,392,393 and this examina- sufficiently studied, but most certainly depends on the clinician’s
tion method should be considered an acquired skill that can be knowledge and experience,392 as well as one’s opinion related to
constantly honed. The overall sensitivity of auscultation is high the physiologic versus pathologic nature of valvular regurgitation
for identification of congenital heart diseases, significant valvular in some high-performance horses.
disease, and persistent cardiac arrhythmias. Sensitivity is lower A prerequisite for auscultation is an appreciation of the
for primary myocardial or pericardial diseases, unless there are normal heart sounds, the genesis of which has already been
obvious associated abnormalities such as a murmur, arrhythmia, described (see Clinical Cardiovascular Physiology). The
or prominent friction rub. The specificity of auscultation in the examiner must be familiar with the causes and clinical fea-
horse (e.g., the ability to distinguish a functional from a patho- tures of arrhythmias and murmurs (Tables 9.1 through 9.3)
logic murmur or identify a specific flow disturbance) has not been and the areas for auscultation (Fig. 9.7).* Auscultation is best
* References 3, 16, 19, 23, 25, 57, 72, 73, 75, 152, 223, 282, 378-389. * References 3, 19, 57, 73, 379-382, 385, 386, 393, 394.
TABLE 9.1 Identification of Heart Sounds and Common Cardiac Murmurs

°S—systole, the interval between S1 and S2; D—diastole, the interval between S2 and S1 (see Figs. 9.8 and 9.9).
*Only typical features are considered; “apex” refers to the ventral part of the heart, at the point of the palpable cardiac impulse (apex beat); “base” refers to the
craniodorsal part of the heart over the outlet valves (aortic, pulmonic) where the second heart sound is most intense (see Fig. 9.7).
†The exact causes of functional (flow) murmurs have not been proven. The systolic ejection murmur, which begins after the first heart sound and ends before
the second heart sound, is the most commonly identified murmur in the horse; the protodiastolic murmur extends from the second to the third heart sound;
the presystolic murmur is quite short, spanning the fourth and first heart sounds. Functional murmurs may be musical.
‡Ventricular inlets refer to the parts of the thorax overlying the ventricular inflow tracts. These include the areas just dorsal to the mitral and tricuspid valve areas
and extend ventrally to the apical regions of the ventricles.

§Murmurs of AV valve insufficiency are generally heard over the affected valve, project prominently toward the respective ventricular apex, and also radiate
dorsally, following the regurgitant jet into the atrium. Occasionally, murmurs of tricuspid valve disease are prominent at the extreme left, cranial heart border.
Valve regurgitation murmurs are evident throughout systole or diastole and extend into the second heart sound (holosystolic or pansystolic) or first heart sound
(holodiastolic or pandiastolic); however, late systolic murmurs, which may be related to valve prolapse, have been identified with mitral or tricuspid valve insuf-
ficiency, and the murmur of aortic insufficiency may not always be holodiastolic. Documented reports of valve stenosis are quite rare.
‖Murmurs caused by defects in the right ventricular inlet septum (paramembranous VSD, common) are heard best above the right sternal border; murmurs from
defects in the RV outlet septum (subpulmonic VSD, rare) may be loudest over the pulmonic valve; increased flow across the pulmonic valve can cause left-basilar
systolic murmurs of relative pulmonic stenosis in the absence of pulmonic valve pathology; flow across very large nonrestrictive defects can be relatively soft.
From Schwarzwald, C.C., Bonagura, J.D., and Muir, W.W.: The cardiovascular system. In: Equine Anesthesia—Monitoring and Emergency Therapy (Ed. W.W.
Muir), 2nd ed. Saunders Elsevier, p. 65.
carried out in a very quiet area because extraneous noise region of cardiac dullness can be used effectively by practiced
makes detection of soft to moderate murmurs quite difficult. examiners to identify heart size.395
The horse or foal should be sufficiently restrained so the exam- The stethoscope examination generally commences on
iner can concentrate on listening. The venous pulse should the left side. Both stethoscope chest pieces—the diaphragm
be inspected and then the arterial pulse and the precordium (applied tightly, for high-frequency sounds and murmurs) and
palpated before commencing auscultation. Although uncom- the bell (applied lightly, for low-frequency sounds and mur-
monly used today, percussion of precordial area to identify the murs)—should be used. When using a single-piece tunable
TABLE 9.2 Auscultation of Cardiac Arrhythmias

Rhythm Heart Rate per Minute Heart Soundsa Auscultation
SINUS RHYTHMS
Sinus rhythm Variable S4–S1–S2 (S3) Rate and rhythm dependent on autonomic tone
Sinus arrest/block <26 S4–S1–S2 (S3) Irregular, long pauses
Sinus bradycardia <26 S4–S1–S2 (S3) Generally regular unless escape rhythm develops
Sinus arrhythmia 25–50 S4–S1–S2 (S3) Irregular, cyclic change in heart rate; often interval varying between S4
and S1; often associated with second-degree atrioventricular block or
sinus bradycardia
Sinus tachycardia >50 S4–S1–S2 (S3) Typically regular, but second-degree atrioventricular block may develop
if sympathetic tone decreases (e.g., during recovery from exercise)
SUSTAINED ATRIAL TACHYARRHYTHMIAS
Atrial tachycardia >30 S1–S2 (S3) Ventricular regularity and rate dependent on atrioventricular conduc-
and atrial flutter tion sequence and sympathetic tone; consistent S4 absent; variable-
intensity S1; may detect independent atrial sounds
Atrial fibrillation >30 S1–S2 (S3) Ventricular response irregular; rate related to sympathetic tone; heart
rates consistently above 60 beats/min suggestive of significant un-
derlying heart disease or heart failure; absence of consistent S4
ECTOPIC RHYTHMS
Junctional rhythm 26–200 S1–S2 (S3) Heart rate usually regular with idionodal rhythms or junctional tachycar-
dia; heart rate dependent on the mechanism and sympathetic tone;
inconsistent independent S4 at lower rates possibly audible
Ventricular rhythm 26–200 S1–S2 (S3) Heart rate possibly regular during monomorphic, uniform ectopic
rhythm or irregular during polymorphic or multiform ectopic activity;
heart rate dependent on the mechanism (e.g., escape rhythm versus
ventricular tachycardia); variable intensity and split heart sounds pos-
sibly audible
Premature atrial Varies Early S1–S2 Intensity of S1 may be louder or softer than normal; the sounds are not
and junctional usually split; less than compensatory pause often follows premature
beats beat; nonconducted atrial premature complexes result in pauses but
not premature first heart sounds
Premature ven- Varies Early S1–S2 Intensity of S1 often variable and ventricular beats possibly softer than
tricular beats normal; heart sounds possibly split from asynchronous ventricular
activation heart sounds; compensatory pause typically following a
premature beat
ATRIOVENTRICULAR BLOCKS
Incomplete (first- <50 S4–S1–S2 (S3) Heart rate variable; cyclic arrhythmia, variable S4–S1 interval; some
and second- Isolated S4 variation in heart sounds; isolated S4 with second-degree AV block
degree block)
Complete (third- <26 S4/S1–S2 (S3) Ventricular escape rhythm, usually regular; independent atrial (S4)
degree block) sounds; variable-intensity heart sounds

aHeart sounds in parentheses may not be audible.
TABLE 9.3 Causes of Cardiac Murmurs

Cardiac Murmur Lesion Identified by Echocardiography, Cardiac Catheterization, or Necropsy
Functional murmursa No identifiable lesions; occasionally markedly turbulent systolic blood flow identified in great vessels on
color Doppler echocardiography
Congenital heart Defect(s) in the atrial or ventricular septa; patent ductus arteriosus; atresia/stenosis of tricuspid or pul-
disease murmurs monic valve; valve stenosis; complex malformations of the heart
Mitral regurgitationb No identifiable lesion (high-level training); degenerative thickening of the valve; bacterial endocarditis;
mitral valve prolapse into left atrium; rupture of a chorda tendinea; dilated, hypokinetic ventricle (dilated
cardiomyopathy, severe aortic regurgitation); papillary muscle lesion or dysfunction; noninfective valvuli-
tis; malformation
Continued
TABLE 9.3 Causes of Cardiac Murmurs—cont’d
Cardiac Murmur Lesion Identified by Echocardiography, Cardiac Catheterization, or Necropsy
Tricuspid regurgita- Same as mitral regurgitation; also pulmonary hypertension from severe left-sided heart failure or chronic
tionb respiratory disease
Aortic regurgitationb Degenerative thickening and/or prolapse of the valve; congenital fenestration of the valve; bacterial en-
docarditisc; aortic prolapse into a ventricular septal defect; flail aortic valve leaflet; noninfective valvulitis;
malformation; ruptured aorta or aortic sinus of Valsalva
Pulmonary regurgi- No identifiable lesion; bacterial endocarditisc; pulmonary hypertension; flail pulmonary leaflet; noninfective
tationb valvulitis; malformation; rupture of the pulmonary artery

aFunctional murmurs may be innocent (unknown cause) or physiologic (suspected physiologic cause); functional murmurs are very common in foals, trained
athletes (athletic murmur), and horses with high sympathetic nervous system activity (pain, stress, sepsis); are associated with fever; and are often heard in
anemic horses. Functional murmurs are very dependent on physiologic state and can be altered (accentuated or abated) by changing the heart rate. Such
dynamic auscultation is very useful in detecting functional murmurs.
b“Silent” trivial or mild regurgitation across right-sided (most common) or left-sided (less common) cardiac valves can be identified in some horses by Doppler
echocardiography; this is probably a normal finding of no clinical relevance provided that no other findings indicate the presence of cardiac disease. Pulmonary
insufficiency is often silent. Many trained athletes have audible murmurs of tricuspid and/or mitral regurgitation that are not associated with poor performance
or signs of heart disease (by physical examination and echocardiography) and are not considered clinically relevant.
cLarge vegetations may result in anatomic stenosis causing a systolic murmur, which is usually associated with a diastolic murmur of valve insufficiency;
increased flow across a normal valve may generate a murmur of relative valve stenosis (e.g., with aortic regurgitation, there may be a systolic ejection murmur
resulting from an increased stroke volume).
A
P M
T
A B
FIG. 9.7 Cardiac auscultation areas in the horse from the left (A) and the right (B) side of the thorax. Note
the size and anatomic position of the heart within the thorax. The cardiac apex (apical area) is usually located
slightly above the level of the olecranon and can be identified by palpation of the apical beat. The cardiac
base (basilar area) is located more cranially and at the level of the scapulohumeral joint. The shaded areas
represent the respective valve areas (P, pulmonic; A, aortic; M, mitral; T, tricuspid). The right atrium (RA)
(above T), tricuspid valve, and right ventricular (RV) inlet (inflow region, below T) are located on the right
side of the thorax. Paramembranous ventricular septal defects (VSDs) that communicate with the RV inlet
(below the tricuspid valve) are usually heard best along the lower right hemithorax (below T) and typically
radiate from the right ventricle (RV) into the pulmonary artery (left hemithorax). Most (but not all) murmurs
of tricuspid valve disease are heard best over the right chest wall, usually heard best more dorsally as they
radiate into the RA (above T). The RV outlet projects to the left side of the thorax and continues into the
pulmonary artery, which is located at the left dorsal cardiac base (above P). Thus murmurs originating in
the RV outlet (e.g., murmurs from subpulmonic VSDs), systolic murmurs of relative pulmonic stenosis (from
cardiac shunting), murmurs of pulmonic insufficiency (rare), and functional pulmonary arterial murmurs are
heard best over the left chest wall (P). The aortic valve is located centrally, and diastolic murmurs of aortic in-
sufficiency may be heard at either hemithorax, although they are usually loudest on the left (A). Functional
murmurs generated in the ascending aorta are heard over the cranial basilar region of the heart. The systolic
murmur of mitral regurgitation (MR) radiates to the left apex and is usually heard across the left ventricular
(LV) inlet (area caudoventral of M). The regurgitant mitral jet can be directed craniodorsal or caudodorsal
into the left atrium (LA) and can account for variability in murmur radiation. The functional protodiastolic
murmurs associated with ventricular filling are usually evident over the ventricular inlets and may be heard
on either side of the thorax. (From Reef VB: Cardiovascular system. In Orsini JA, Divers TJ, editors: Manual
of equine emergencies: treatment and procedures, ed 2, Philadelphia, 2003, WB Saunders.)
diaphragm, the pressure on the chest piece should be gradu- b-lub dup-uh b-lub dup-uh
S1 S2 S1 S2
ally increased to optimize the sounds of interest. A variety of Phono S4 S3 S4 S3
digital stethoscopes are available today that are able to amplify
heart sounds and murmurs across selected frequency ranges,
reduce or eliminate external noise and artifacts, record sound, ECG P QRS T
and display phonocardiograms on a computer or a smart-
phone. These devices can be helpful for diagnostic and teach-
ing purposes. However, the clinician should be aware that ABP
digitally processed sound quality is different compared with
traditional stethoscopes. The diagnostic agreement may only
be moderate, and the sensitivity to detect abnormal sounds
and murmurs may not necessarily be improved with digital FIG. 9.8 Schematic diagram of the normal heart sounds (Phono) in rela-
techniques.396,397 It is therefore advisable to use digital stetho- tion to a surface electrocardiogram (ECG) and an arterial blood pressure trac-
scopes complementary to and not in place of conventional ing (ABP) recorded from the transverse facial artery. S1, First (systolic) heart
stethoscopes. sound; S2, second (diastolic) heart sound; S3, third heart sound; S4, fourth
All auscultatory areas should be examined (see Fig. 9.7). (atrial) heart sound. B-lub dup-uh describes the sounds heard on ausculta-
The locations of the cardiac valve areas can be identified using tion. Note the timing of the heart sounds and the (peripheral) pulse pressure
the following method: wave relative to the ECG. (From Orsini JA, Divers TJ, editors: Manual of equine
• The left apical impulse located at the left thoracic wall is adja- emergencies: treatment and procedures, ed. 2, Philadelphia, 2003, Saunders.)
cent to or under the olecranon near the fifth intercostal space;
this location identifies the ventral region of the LV inlet.
The mitral valve is dorsal to the cardiac impulse, but mitral which occurs with second-degree AV block and with noncon-
sounds and murmurs often project well to the apex while also ducted atrial premature complexes, causes a pause in which the
radiating dorsally into the left atrium. The first heart sound first and second heart sounds are absent. The heart sounds and
(S1) is best heard at this location and the ventricular filling or precordial movements often can be palpated, especially over the
third heart sound (S3) is also heard well over this point. left thoracic wall. Frequently the cardiac movements and low-
• The aortic valve area is located one (or two) intercostal spaces frequency vibrations corresponding to the atrial contraction (S4),
cranially and is dorsal to the left apical impulse. The second onset of ventricular contraction (S1), and closure of the semilunar
sound (S2) is loudest at this point, and aortic valve murmurs valves (S2) can be detected. With ventricular volume overloading
are heard best over this valve. The murmur of mitral regur- or vigorous normal filling, an accentuated apex beat and third
gitation may also radiate dorsally and cranially to this area. sound (S3) will be palpable. Cardiac enlargement or displacement
Because of the central location of the aortic valve and the of the heart by an intrathoracic mass may lead to an abnormal
orientation of the ascending aorta to the right, aortic flow location of the cardiac impulse. A loud cardiac murmur is often
murmurs and the murmur of aortic regurgitation generally associated with a palpable vibration or precordial thrill.
can be heard bilaterally, just medial to the triceps muscles.
• The pulmonic valve is located slightly cranioventral (generally Heart Sounds
one intercostal space) to the aortic valve, and the pulmonary Heart sounds should be readily heard on each side of the tho-
component of S2 is loudest at this point. This is also the loca- rax, although there is some variability based on body type, and
tion where splitting of the second sound is most obvious. The sounds are louder over the left thoracic wall. All four heart
main PA extends dorsally from the pulmonic valve, high on the sounds can be detected in healthy horses, but all may not be
left-cranial base. Murmurs that radiate into the PA are heard present or evident at the same location (Figs. 9.8 and 9.9; see
best at this location, including some functional murmurs and Table 9.1).3,23,25,382 The intensity of the heart sounds should be
the murmur of patent ductus arteriosus. The murmur associ- consistent when the rhythm is regular, but variation of heart
ated with a subarterial (subpulmonic) VSD, as well as the rare sound intensity occurs with arrhythmias (irregular cardiac fill-
murmurs of an atrial septal defect or pulmonic stenosis, are ing). Muffled heart sounds are heard with pericardial effusions
typically loudest over the pulmonary valve and PA. or pericardial abscesses (the muffling may only be on one side
• The tricuspid valve area is located over a wide area on the of the thorax) but also occur in some horses with large pleural
right hemithorax, dorsal to the sternum and just cranial to effusions and cranial mediastinal masses. Accentuation of all
the mitral valve; sounds and murmurs associated with tri- heart sounds, especially the third sound, may be detected with
cuspid valve disease are usually heard best over the right volume-loaded ventricles or with marked sympathetic activ-
hemithorax. Murmurs of paramembranous VSDs are often ity. Projection of heart sounds over a wider area is some-
detected ventral and slightly cranial to the tricuspid valve times evident in cases of pleuropneumonia with pulmonary
area, dorsal to the sternum. consolidation.
It is worthwhile to concentrate first on the individual heart The first heart sound (S1) varies with arrhythmias and often
sounds when assessing the heart rhythm, because the generation becomes louder (or sometimes softer) after prolonged dia-
of cardiac sounds depends on the underlying electrical rhythm stolic periods. This in itself is not diagnostic of an abnormality.
and heart murmurs are timed relative to the heart sounds (Fig. Splitting of the first heart sound, if pronounced, may indicate
9.8). The atrial sound (S4) is heard after the P wave. The first and abnormal ventricular electrical activation or ventricular pre-
second heart sounds (S1 and S2) encompass systole, indicating mature complexes.3,282 Close splitting of the first sound may
the presence of a QRS complex. A murmur detected between the be more obvious when there is AF, and in the absence of an
first and second sounds is termed systolic. In contrast, a murmur atrial sound (S4), the split S1 may be misinterpreted as a closely
heard after S2 is designated as diastolic. The distinctive atrial sound timed S4–S1 complex.
(S4) is absent in AF. Normal variation in the PR interval causes The second sound (S2) is loudest normally over the aortic
gradual changes in the S4–S1 interval. Absence of a QRS complex, valve area and may be audibly split over the pulmonic valve
area.3,282 This sound can be very soft or absent following a area may be a marker for mitral valve disease or prolapse of the
premature beat, and it may be obscured by a holosystolic valve into the left atrium. Constrictive pericardial disease can
murmur. Audible splitting of S2 occurs commonly in normal create a loud early diastolic ventricular filling sound, a ventricu-
horses, varies with HR or respiration, and only infrequently lar “knock,” indicating abrupt termination of rapid filling under
is associated with pulmonary hypertension. The relative clo- high venous pressures. In addition to muffling of sounds, peri-
sure of the semilunar valves probably varies with the HR and carditis is often associated with a pericardial friction rub. These
PA pressure,3,282 although the pulmonic component is most rubs are classically detected during three portions of the cardiac
often detected after the aortic component in the healthy, rest- cycle (systole, early diastole, late diastole). These sounds must be
ing horse. If the pulmonic component of the second sound distinguished from pleural friction rubs or respiratory mediated
develops a tympanic quality, becoming equal to or louder than sounds, which are occasionally associated with the cardiac cycle.
the aortic component of S2, the clinician should suspect pul- Pleural and pulmonary rubs tend to be heard only during one
monary hypertension. Identification of a loud pulmonic S2 is or two phases of the cardiac cycle and may not correlate closely.
a useful clinical finding in cases of right-sided heart failure
because it often indicates that a lesion on the left side of the Heart Rate and Rhythm
heart has led to pulmonary hypertension and right-sided CHF. HR can change rapidly and dramatically, varying with auto-
Diastolic transient sounds are normal.3,16,17,19,387 The atrial nomic efferent traffic and level of physical activity. Changes in
sound (S4) should be detected in virtually all horses, and this the rate and rhythm are reflected in cardiac auscultation and
sound may be quite loud in some cases. Isolated atrial sounds palpation of the pulse (see Table 9.2). The normal arterial pulse
are commonly auscultated at slow resting HRs due to second- and cardiac rhythm are regular or cyclically irregular. HR in
degree AV block; however, multiple isolated S4 sounds indicate mature horses varies between 28 and 44 beats/min, although
high-grade AV block. The ventricular filling sound (S3) is most slightly slower HRs can be detected in some very fit racehorses,
localized and variable and may be difficult to detect unless the and higher HRs are often present in foals,386 yearlings, draft
bell is placed lightly over the left apex. This sound is normal horses,398 ponies,399 and healthy but nervous horses. An elevated
and has a low-pitched sound that often increases transiently resting HR is commonly detected with late pregnancy, fever,
when there is sinus tachycardia and enhanced rapid filling. This pain, hypovolemia, severe anemia, infection, or shock. Persis-
sound also achieves greater intensity when there is ventricular tent, otherwise unexplained tachycardia is also typical of heart
dilation and elevated filling pressures as with heart failure. failure wherein the standing HR usually exceeds 60 beats/min.
Other sounds may be detected with heart disease. Systolic Physiologic arrhythmias associated with high resting vagal
clicks are uncommonly heard over the great vessels where they tone must be differentiated from pathologic arrhythmias. Vagal
are thought to be benign. A systolic click loudest over the mitral induced arrhythmias are most often observed in healthy relaxed
A B
S2 Aortic regurgitation
Diastolic murmur
T T
P QRS
FIG. 9.9 Phonocardiograms (PCG). A, The four normal heart sounds (S1 through S4) are evident in this
recording. (The numbers 1 through 4 indicate the various components of the first heart sound; ECG, electro-
cardiogram.) B, Systolic murmur recorded from a yearling with a ventricular septal defect (VSD) (P waves on
the ECG are negative in this tracing). C, Decrescendo, musical, holodiastolic murmur recorded from a horse
with aortic regurgitation (AR). The murmur begins in early diastole (after the T wave) and ends at the QRS
complex. (A, Recording courtesy D. Smetzer, R.L. Hamlin, and C.R. Smith.)
horses. The most common of these are sinus arrhythmia and Junctional or nodal tachycardia and ventricular tachycar-
second-degree AV block (see Fig. 9.6), which is reported in 15% dia (VT) are usually manifested by a rapid regular rhythm,
to 18% of normal horses at rest and has been detected in up to although some VTs (particularly polymorphic or multiform
44% of normal horses with 24-hour continuous electrocardio- VT) cause an irregular rhythm. Owing to concomitant AV dis-
graphic monitoring.222,227,400 This arrhythmia is most common sociation or abnormal ventricular activation, the heart sounds
in fit racehorses or in other high-performance animals and dis- may sound split or variable in intensity.
appears with stimulation of sympathetic nervous system activ-
ity. Sinus arrhythmia also occurs regularly in horses and is often Cardiac Murmurs
associated with sinus bradycardia and resting HRs of 24 to 28 Cardiac murmurs are prolonged audible vibrations develop-
beats/min. Sinus arrhythmia may wax and wane with respira- ing in a usually quiet portion of the cardiac cycle. In general,
tion; however, synchronization with ventilation is not a consis- murmurs are manifestations of either normal (functional)
tent finding in the horse, and it is more likely related to changes or abnormal (pathologic) blood flow in the heart and blood
in baroreceptor activity. Sinoatrial block and SA arrest occur vessels. Although many heart murmurs are functional (physi-
sporadically in fit horses. Because these physiologic arrhythmias ologic, athletic, innocent), other murmurs provide evidence of
are associated with high vagal tone, it is typical for the HR to heart disease and may require further investigation (see Tables
range from a low-normal value to overt bradycardia. Maneuvers 9.1, 9.3, and 9.4). One of the challenges of physical diagnosis is
that reduce vagal activity and increase sympathetic tone can be determination of the cause and clinical relevance of a cardiac
undertaken to ensure that the rhythm becomes normal. Suc- murmur. With knowledge and experience the clinician can
cessful methods include leading the horse through three or four accurately determine the likelihood that a murmur is physi-
tight circles, jogging, or lunging. It should be recognized, how- ologic or pathologic in origin, and efficiently select animals
ever, that some horses redevelop physiologic AV block within requiring additional studies. The clinician should describe the
10 to 60 seconds following such maneuvers. If the arrhythmia timing, duration, quality or pitch, grade, point of maximal mur-
persists after exercise, or if the auscultatory findings suggest mur intensity, and radiation of a murmur (Box 9.7), as well as
another arrhythmia, an ECG should be obtained (Table 9.4; also the effect of changing HR on the sounds. Determination of
see Table 9.2). timing is made relative to the heart sounds so that murmurs
The arrhythmias associated with heart disease occur most are designated as systolic, diastolic, or continuous. When the
often with normal to increased HRs, with the exception of overall timing is not obvious, the clinician can either palpate
advanced second-degree and complete (third-degree) AV the apical impulse, which occurs in early systole, or the systolic
block.33,84,383,401,402 Atrial premature beats are characterized pulse in the brachial or median artery to identify the timing of
by a regular cardiac rhythm, which is suddenly interrupted the murmur (consider the slight time delay between ventricu-
by earlier than normal beats. Because the sinus node is reset lar contraction and occurrence of a peripheral pulse wave). It
during an atrial premature beat, the following pause is usually is also helpful to remember that at a normal (low) HR, ven-
incomplete or less than compensatory (provided the underly- tricular diastole (i.e., the time interval between S2 and the fol-
ing sinus rhythm is regular). Premature atrial beats can also lowing S1) is markedly longer than ventricular systole (i.e., the
be blocked in the AV node, leading to a sudden pause in the time interval between S1 and the following S2) (see Fig. 9.8).
rhythm without a premature first heart sound. A ventricu- Hence, long-lasting murmurs or brief murmurs occurring
lar premature beat is often followed by a fully compensatory during the long S2–S1 interval are likely to be diastolic mur-
pause unless the extrasystole is interpolated between two nor- murs. Skilled auscultators subdivide the timing of murmurs
mal sinus beats. Pulse deficits (more first heart sounds than into proto- (early), meso- (middle), or tele- (late) systole or
arterial pulses) are common with premature beats due to inad- diastole because the timing and duration of the murmur often
equate ventricular filling and subsequent low stroke volume. correlate with specific flow disturbances. Shorter murmurs,
Atrial fibrillation is characterized by an irregularly irregu- especially those occurring in early systole or protodiastole,
lar pulse and ventricular rhythm, with some beats occurring are more likely to be functional, although this is not always
sooner than expected, and with pauses in the rhythm demon- the case. Experience also teaches that relatively loud or long
strating no consistent diastolic interval. The atrial contraction murmurs are more likely to be associated with cardiac pathol-
and hence the fourth sound (S4) are absent in AF. Infrequently, ogy, but again there are exceptions. The pitch or quality of
AF develops with recurring periodicity of cycle lengths that the murmur provides additional insight. For example, mixed
can cause difficulty in distinguishing this from second-degree frequency (harsh or blowing) murmurs are typical of cardiac
AV block.219,221,229,403 At higher rates, such as during exercise disease. A brief vibratory or musical murmur is typically func-
or in a horse in heart failure, the cycle lengths shorten and the tional; however, a prolonged musical murmur is suggestive of
rhythm appears to become (more) regular. However, when lis- a valvular lesion. Applying the characteristics of murmurs to
tening carefully, an irregularly irregular rhythm is still evident, the clinical setting requires study, an organized scheme (see
distinguishing AF from second-degree AV block. Another Table 9.4), and practice.
diagnostic pitfall can be the presence of a split first sound, Functional, innocent, or physiologic heart murmurs are
because the clinician may mistake this for a closely timed very common and are not attributed to cardiac pathology.
S4–S1 complex. Such murmurs may be related to the large size and tremen-
Atrial tachycardia can be conducted with patterns leading dous inflow and outflow volumes of the equine heart. They
to a rapid but regular heart rhythm. However, most horses are caused by vibrations that attend the ejection of blood
with atrial tachycardia develop irregular rhythms owing to from the heart during systole or the rapid filling of the ven-
frequent block of atrial impulses in the AV node, especially at tricles during early diastole.* Physiologic causes of functional
rest. HRs are usually higher than normal at rest. Auscultation murmurs include fever, high sympathetic activity (e.g., colic,
of the horse in a quiet area may reveal isolated audible fourth
heart sounds associated with the second-degree AV block. * References 3, 18, 19, 32, 72, 207, 223, 380, 382, 384, 388, 404-407.
406
TABLE 9.4 Diagnostic Algorithm for Cardiac Auscultation in the Horse
Auscultation Considerations Further Observations Probable Assessment Other Tests
PART 2 DISORDERS OF SPECIFIC BODY SYSTEMS

Irregular rhythm → Vagally mediated or abnor- ⇒ Induce increased sympathetic
mal rhythm tonea
⇓
↑ Rate and regular rhythm → Vagally mediated (physiologic) → None
rhythmb
↑ Rate and irregular rhythm → Abnormal cardiac rhythm (see → ECG, ± echo,
Table 9.2 for details) electrolyes, cardiac tropo-
nin I (cTnI)
Regular tachycardia → Sympathetic activation ⇒ Manage underlying disorder
<90 beats/minc (stress/anxiety, pain, vol- ⇓
ume depletion, infection,
anemia, heart failure, etc.)
or ectopic cardiac rhythm
Appropriate HR reduction with → Physiologic sinus tachycardia → None

normal heart sounds
Persistent tachycardia, abnormal → Persistent sinus or ectopic → ECG, ± echo,
heart sounds or murmurs tachycardia,d underlying or- electrolyes, cardiac tropo-
ganic heart disease nin I (cTnI)
Loud cardiac murmur → Organic heart disease ⇒ Determine timing and PMI (see → Congenital or acquired heart → Echo
with a precordial below) disease
thrill
Systolic murmur PMI: → Functional or organic ⇒ PMI: pulmonic or aortic valve
left thorax Crescendo-decrescendo
Grade: 1–3/6e → Functional ejection murmur → Noneg
Grade: 4–6/6 → Congenital heart defectf → Echo
PMI: mitral valve or left apex → Mitral regurgitation → Echog,h
Any grade or configuration
Systolic murmur PMI: → Organic murmur ⇒ PMI: tricuspid valve → Tricuspid regurgitation → Echog,h
right thorax Any grade or configuration
PMI: cranioventral thorax → Ventricular septal defect (VSD) → Echo
Holosystolic
Diastolic murmur → Functional or organic ⇒ Brief (protodiastolic or presystolic) → Functional murmur (or trivial AR) → Noneg
PMI: left or right
thorax
PMI: aortic or pulmonic valve → Aortic regurgitation (AR) or → Echog,h
Holodiastolic pulmonic regurgitation with
pulmonary hypertension
Continuous murmur → Organic murmur ⇒ PMI: pulmonary artery → Patent ductus arteriosus (PDA) → Echo
PMI: left or right Foal or other signs of CHD or a systemic to pulmonary
thorax shunt
Mature horse → Aortic to cardiac fistula or aortic → Echo
to pulmonary artery fistula
Pericardial friction → Organic murmur ⇒ Systolic or multiphasic → Pericarditis → Echo
rubi Distant (muffled) heart sounds
Jugular venous distention

aEndogenous sympathetic activity can be transiently increased by suddenly leading the horse in four or five tight circles or through trotting or lunging; the horse should be examined immediately after the activity has
stopped.
bVagally induced rhythms include sinus bradycardia, pause or arrest, sinoatrial block, sinus arrhythmia, and second-degree atrioventricular block.
cResting tachycardia exceeding 90/min should be evaluated with an ECG to qualify the rhythm; the cutoff rate is arbitrary but clinically useful.
dEctopic rhythms include ectopic atrial tachycardia, junctional (nodal) tachycardia, and ventricular tachycardia.
eFunctional murmurs due to ejection of blood into the great vessels often become transiently louder following an increase in sympathetic activity.
fLoud ejection murmurs over the semilunar valves and great vessels may indicate pulmonic stenosis or complex defects such as tetralogy of Fallot.
gJudgment should be exercised regarding the need for echocardiography. An echocardiogram might be indicated in the prepurchase examination of any valuable foal or horse with a cardiac murmur; however, echo-
CHAPTER 9 Disorders of the Cardiovascular System

cardiography may not be indicated in an older horse with a soft murmur of aortic regurgitation with normal arterial pulses or in a fit racehorse with a typical murmur of tricuspid regurgitation.
hAccording to the 2014 Joint ACVIM/ECEIM Consensus Statement on Recommendations for Management of Equine Athletes with Cardiovascular Abnormalities (Reef VB, et al., J Vet Intern Med 28:749-761, 2014),
an echocardiogram is specifically indicated if a left-sided murmur compatible with mitral regurgitation or aortic regurgitation is of grade 3–6/6 or a right-sided systolic murmur compatible with tricuspid regurgitation is
of grade 4–6/6.
iClassic pericardial friction rubs are heard during systole, early diastole, and late diastole. Occasionally a functional presystolic murmur exhibits a frequency quality similar to a brief friction rub.
Abbreviations and Terminology:

Configuration = the phonocardiographic “shape” of a murmur; for example, a “plateau-shaped” murmur that extends from the first sound through the second sound is termed holosystolic or pansystolic (e.g., MR or
VSD); a “diamond-shaped” murmur is crescendo-decrescendo in configuration (e.g., functional ejection); a “blowing” murmur that starts suddenly but dissipates gradually is decrescendo (e.g., aortic regurgitation);
and a murmur that becomes progressively louder and then stops is crescendo in configuration (e.g., MR from mitral valve prolapse)
ECG = perform an electrocardiogram to determine heart rhythm
Echo = perform an echocardiogram to identify abnormal structure, cardiac size, or function; Doppler studies are added to assess normal and abnormal blood flow patterns and are optimal for evaluating horses with
cardiac murmurs; Doppler studies must be interpreted relative to auscultatory findings
Grade = intensity of the murmur on a 1 through 6 scale; in most systems a grade 5 or 6 murmur is accompanied by a precordial thrill
HR = heart rate
Organic = related to a structural lesion in the heart or great vessels
PMI = point of maximal murmur intensity
Precordial thrill = the palpable thoracic vibration associated with a loud cardiac murmur
Troponin I = serum/plasma concentration of inhibitory cardiac troponin or cTnI, a biomarker used to detect cardiomyocyte injury or necrosis
Valve = refers to the general valve area of auscultation (see text for details)
407
of this is the varying murmurs identified in some horses with

BOX 9.7
Characterization of Heart Murmurs emergent colic. Because a loud functional murmur can radi-
ate caudally, it may be confused with mitral regurgitation. In
TIMING AND DURATION (see Figs. 9.8 and 9.9 and Tables 9.1 terms of diagnostic considerations, the clinician should not
and 9.4) mistake a functional ejection murmur for that of aortic or
• Systolic, diastolic, or continuous pulmonic stenosis. Pulmonic stenosis is rare in the horse and
• Early, mid, or late systolic or diastolic aortic stenosis even less common. Accordingly, these valvular
• Holosystolic (S1 to S2), holodiastolic (S2 to S1) malformations are rarely entertained in the differential diag-
nosis. The murmurs resulting from subpulmonic (subarterial)
QUALITY VSDs or the stenosis associated with tetralogy of Fallot may be
• Frequency of sound—high pitch, low pitch, mixed-pitch loudest over the great vessels, but such murmurs are usually
• Character of murmur—harsh, coarse, rumbling, very loud and prompt echocardiographic investigation.
musical, honking, blowing Functional diastolic murmurs are also common, especially
in young horses and in the Thoroughbred breed. These mur-
GRADE murs are generally soft and are detected over the LV or RV
• Grade 1/6—very quiet, only heard over a very local- inlets—from the dorsal atrium to the ventricular apex. The
ized area after careful auscultation in quiet environ- functional protodiastolic murmur is an early diastolic mur-
ment, may be inconsistent mur detected between S2 and S3. The murmur may be musical,
• Grade 2/6—quiet, heard consistently over the point of vibratory, or “squeaky” and typically accentuates with increased
maximal intensity HR.3 It most reasonably represents the rapid early filling of the
• Grade 3/6—moderately loud, heard immediately and ventricles. The presystolic functional murmur is heard between
consistently, small area of radiation S4 and S1, and the vibrations may sound like a “rub” or long
• Grade 4/6—loud, radiating over a wider area, no heart sound following the atrial contraction. It can be confused
palpable thrill with an early systolic murmur or a friction rub.
• Grade 5/6—very loud, radiating over widespread Causes of abnormal (pathologic) murmurs include struc-
area, palpable precordial thrill tural or organic heart disease such as incompetent cardiac
• Grade 6/6—extremely loud, also heard with the valves, septal defects, vascular lesions, and (very rarely) valvu-
stethoscope held just above the skin surface lar stenosis. The continuous murmur of patent ductus arterio-
• Variations in grade can be described as crescendo (in- sus is a normal finding in full-term foals for up to 3 days after
creasing in grade), decrescendo (decreasing in grade), parturition but occasionally persists for almost a week after
or crescendo-decrescendo (“diamond-shape”) foaling.382,386,408,409 The most commonly detected pathologic
murmurs in horses are those generated by tricuspid regurgita-
POINT OF MAXIMAL INTENSITY tion, mitral regurgitation, aortic regurgitation, and ventricu-
• Apical—location of the thoracic wall cardiac impulse lar septal defect. Typical causes and auscultatory features of
(apical beat), approximately at or slightly above the level these murmurs are indicated in Tables 9.1, 9.3, and 9.4 and
of the elbow (ventral region of the left ventricular inlet) described in detail later in this chapter.
• Basilar—area above the elbow and slightly more cra- When a murmur is believed to represent underlying car-
nial, below the triceps muscle (region of the ventricu- diac pathology, further investigation is required. The overall
lar outflow tracts, semilunar valves, and great vessels) relevance of the hemodynamic abnormality should include
• Mitral, aortic, pulmonic, tricuspid valve area (see Fig. 9.7) consideration of the work history, general physical exami-
nation, presence or absence of heart enlargement or cardiac
RADIATION failure, and results of ancillary tests such as echocardiogra-
• Dorsal-ventral, cranial-caudal, left-right phy, electrocardiography, and exercise performance (or test-
ing). Certainly, the history should be considered, because the
horse with excellent performance and good exercise tolerance
exercise, pain), moderate to severe anemia, and peripheral is unlikely to have serious heart disease. Auscultation, how-
vasodilation. These murmurs are typically soft (grades 1–3/6), ever, is insufficient to distinguish trivial from significant heart
localized, relatively short, crescendo-decrescendo in timing, disease in the poorly performing horse or in a horse with a
and labile. Increasing HR usually increases the intensity and cardiac arrhythmia. Echocardiography is helpful in these cases
duration of a functional murmur, although in some horses to quantify heart size and objectively assess ventricular func-
the murmur becomes less intense. Functional murmurs are tion. Underlying lesions such as a valve vegetation, a ruptured
neither holosystolic nor holodiastolic, and therefore the heart valve chorda tendineae, or dilated cardiomyopathy can be
sounds should still be evident. identified or discounted. Although there are no well-defined
The most common functional murmur is the systolic ejec- echocardiographic or Doppler correlates to functional heart
tion murmur heard over the aortic and pulmonic valves and murmurs, these studies can document abnormal blood flow
projecting into their respective arteries at the left cardiac base and can pinpoint the cause of a pathologic murmur.
(see Fig. 9.7 and Table 9.1).3 The functional ejection murmur
is generated by flow into the great vessels and by definition Pulmonary Auscultation
must start after S1 and end before S2. Nonetheless, in some Auscultation of the lungs should reveal normal breath sounds
horses, the functional ejection murmur can achieve substan- with the horse at rest, while ventilating into a rebreathing
tial intensity (rarely, a grade 4–5/6) and may seem holosystolic bag, and after exercise. Decreased or absent airway sounds or
at higher HRs. At times there is a remarkable change in func- large airway sounds in the ventral portions of the thorax indi-
tional murmur intensity from one day to another. An example cate a pleural effusion, a common finding in biventricular or
therefore may be detected in CHF and in diseases associ-

ated with volume depletion or profuse hemorrhage. Thready
arterial pulses may also be detected only in the hindlimbs
with aortoiliac thrombosis. The pulse in septic animals may
be weak, owing to reduced pulse pressure, or normal to rap-
idly declining if there is peripheral vasodilation. Bounding,
hyperkinetic arterial pulses are palpable with clinically rel-
evant aortic regurgitation, patent ductus arteriosus, and aortic
to pulmonary or aortic to right-sided heart fistulas. Marked
variation in the intensity of the pulse usually occurs with
arrhythmias, particularly AF and rapid or multiform VT. A
pulse deficit (first heart sound without palpable pulse) occurs
when developed LV pressure does not exceed aortic pressure.
Deficits are likely to be palpated in association with pathologic
arrhythmias, particularly premature beats or following very
short diastolic periods of tachyarrhythmias when ventricular
filling is insufficient to generate a significant stroke volume.
FIG. 9.10 Peracute pulmonary edema in a horse with a ruptured chorda Arterial pressure is determined by the interplay among SV,
tendinea. The photo was taken immediately after euthanasia. An impor-
HR, and vascular resistance (see Box 9.3 and Fig. 9.4B). Palpa-
tant note is that tracheal froth is often a postmortem artifact, particularly
tion of the arterial pulse mainly provides information on pulse
when observed hours after death.
pressure but cannot quantify the actual arterial BP, which
(if required) must be measured directly by arterial puncture
right-sided heart failure. Moist or bubbling (fluid) sounds or or cannulation (invasive blood pressure [IBP]) or indirectly
crackles (i.e., rales) are uncommonly auscultated in the lungs using various auscultatory, Doppler, or oscillometric tech-
of horses with pulmonary edema and left-sided heart failure. niques (noninvasive blood pressure [NIBP]).259,410-440 Percuta-
Instead, tachypnea associated with harsh bronchovesicular neous placement of an arterial catheter in the facial, transverse
breath sounds is usually heard, as horses with chronic left- facial, transverse tibial, or metatarsal artery is frequently used
sided CHF seem to develop more interstitial than alveolar to monitor pressure invasively in critically ill or anesthetized
pulmonary edema. When alveolar edema does develop, respi- horses and foals. Indirect methods have been used successfully
ratory distress may be severe, crackles may become evident, to monitor pressure in the coccygeal, metacarpal, metatarsal,
and free fluid may be auscultated in the trachea. On rare occa- and median artery. However, NIBP measurements are less
sion, primarily with peracute left-sided heart failure, froth will reliable compared with IBP measurements. Although different
be visible at the nares and the horse will cough and expel large study designs (including varying patient populations, hemo-
quantities of pulmonary edema (Fig. 9.10). Such horses dem- dynamic interventions, devices, cuff sizes and placements, and
onstrate severe respiratory distress (marked tachypnea and correction factors) make direct comparison difficult, overall
dyspnea), anxiety, and agitation. agreement between IBP and NIBP measurements tends to
be better in anesthetized animals compared with standing
Examination of the Peripheral Vasculature and conscious horses. The mean arterial pressure (MAP), which
is derived from the maximum oscillation amplitude, is more
Blood Pressure Measurement accurately detected by oscillometric monitors than the algo-
An evaluation of the peripheral vasculature is part of a CV rithm-dependent systolic arterial pressure (SAP) and diastolic
workup and should include examination of the arteries and arterial pressure (DAP).441,442 No information is available
veins in the head, forelimbs, and hindlimbs and assessment of on the accuracy and reliability of noninvasive pulse pressure
the mucous membranes. When the equipment is available, arte- measurements, although in clinical practice quantification of
rial BP also should be measured. The genesis of the arterial and pulse pressures is considered very useful to detect or confirm
venous pulses has been described previously. The heart sounds hyperkinetic pulses, particularly in horses with AR (see later
should be correlated with both the jugular and arterial pulses. discussion).406
Attention must be directed to placement and diameter
of the occluding cuff when indirect methods are used.427
Arterial Pulses and Blood Pressure A cuff width to tail circumference ratio of 0.4 to 0.6 is often
Measurement recommended by the manufacturers and has been used in
Normal quality arterial pulses should be palpable in the facial, horses when measuring pressure in the middle coccygeal
median, carotid, great metatarsal, coccygeal, and digital arter- artery.412,436,437,439,440 However, a large range of ratios from 0.2
ies. The arterial pulse represents the pulse pressure (i.e., the to 0.9 have been described in the literature,412,434-440,443 and
difference between peak systolic and diastolic pressures), the some authors recommend an optimal cuff width between 0.2
rate of rise of arterial pressure, and the physical characteristics to 0.35 of the circumference of the tail.421,425,444 Generally, if
of the artery and surrounding tissues. HR and heart rhythm, wide cuffs tend to cause underestimation then small cuffs tend
as well as altered hemodynamic states, may be identified by to cause overestimation of NIBP.427,443
palpating the facial artery pulse. The arterial pulse can be The effect of gravity and the vertical distance between site
described as normal, hypokinetic (weak), hyperkinetic, or of cuff placement and the heart base also need to be consid-
variable. Irregularity often indicates a cardiac arrhythmia. ered. Measurements of NIBP in standing horses using a tail
Thready or hypokinetic arterial pulses are associated with cuff will underestimate true pressures because the coccygeal
reduced stroke volume and peripheral vasoconstriction and artery is located above the heart base. Generally, a correction
factor of 0.77 mm Hg/cm of vertical distance between the base blood pressure, peripheral vasomotor tone, PCV and hemo-
of the tail and the point of the shoulder is applied or, if not, globin concentrations, and plasma bilirubin concentrations.
measurements should be described as “uncorrected” values.427 Although assessment is largely subjective, normal mucous
NIBP measurements may be less sensitive in hypoten- membranes should be moist and pink, with a CRT of less
sive animals and may lag in response during rapid changes than 2 seconds. Dry, congested membranes suggest dehydra-
in BP.413,415,417 The slow HR in horses may represent another tion and CV disturbance. Pale membranes indicate anemia or
source of inaccuracy for NIBP measurements, because the rate poor peripheral perfusion and vasoconstriction, and dark red
of the cuff deflation can be a source of error if the deflation (injected) or gray-bluish membranes may indicate septicemia
rate is too rapid or the HR is too slow.445 The arterial pulse or endotoxemia and peripheral vasodilation or vasoconstric-
wave itself varies, depending on the site of measurement, due tion, respectively. Capillary refill time is prolonged with poor
to the wave reflection when the pulse wave is entering from CO, hypovolemia, hypotension, or peripheral vasoconstric-
central to the periphery. The distal arterial systolic pressure tion; conversely, it may be shortened when there is vasodi-
may be higher, and the diastolic pressure lower, than the cor- lation. Cyanosis because of right-to-left cardiac or vascular
responding central aortic pressures. However, due to compen- shunting is a rare finding. It is important to realize that the
sation of the increase in peak systolic pressure by narrowing detection of hypoxemia by inspection of the mucous mem-
of the pressure wave, the MAP is usually unaffected by wave branes is influenced by the blood hemoglobin concentration,
reflection.444,446 because the bluish color of the mucous membranes directly
Arterial BP monitoring includes determination of SAP, relates to the absolute concentration of deoxygenated hemo-
DAP, MAP, and pulse pressures (difference between SAP and globin. Hence, anemic horses may be hypoxemic without
DAP). Normal reported values for NIBP in conscious stand- showing any cyanosis, whereas polycythemic horses might
ing adult horses (corrected for vertical distance of cuff posi- appear cyanotic without being markedly hypoxemic.
tion above heart base) are around 135 ± 15, 110 ± 15, and 90
± 15 mm Hg (average ± standard deviation [SD]) for SAP, Peripheral Veins
MAP, and DAP, respectively, with a calculated pulse pressure The cutaneous veins should be examined for distensibility,
of approximately 45 ± 6 mm Hg.423,431,436,439 BP is lowest in refill, thrombosis, and estimated venous pressure. The jugular
neonates and rises during the first month of life to the normal veins in normal horses are collapsed, but the veins of the limbs
adult range.409,415,426 There is some variation among breeds. and torso are visible and somewhat filled. Venous pressure in
Draft breeds tend to have lower pressures than racehorses, and the jugular vein is normally less than 10 cm of water above the
Standardbreds have lower pressures than Thoroughbreds.431 phlebostatic point (i.e., 0 [zero] reference point, usually taken
Posture imposes a significant influence on arterial pressure, to be the right atrium), and jugular pulsations are normally
because raising the head from the feeding position necessi- confined to the thoracic inlet and the ventral one third (10
tates a higher aortic pressure to maintain cerebral perfusion. cm) of the neck. These pulsations are reflections of the right
Obviously, when the head is lowered, the hydrostatic pressure atrial pressure changes that range from positive to subatmo-
imposed by an elevated head position is minimized. MAP spheric over the cardiac cycle (discussed previously). Pulsa-
measured in the middle coccygeal artery can vary approxi- tions are normally visible along the entire length of the jugular
mately 20 mm Hg with the changing head position.428 Marked vein when the head is lowered below the level of the heart and
increases in CO can lead to significant increases in arterial BP, should not be misinterpreted. A pathologic jugular pulse also
with systolic pressures exceeding 200 mm Hg.447-449 Sedatives, can be misdiagnosed if there is transmission of carotid arterial
anesthetics, and adrenergic drugs cause significant dose- and pressure into the jugular furrow. Occluding the jugular vein
time-dependent increases or decreases in systemic BPs.292 ventrally can demonstrate if the pulses are actually originating
The systolic arterial pressure is generated by the left ventri- within the right atrium or not, because venous pulse transmis-
cle and is consequently affected by the interplay between the sion, or prominent collapse, will be prevented by light digi-
stroke volume, HR, aortic compliance, and previous diastolic tal pressure over the vein. Pronounced jugular pulsations are
BP.46 Arterial pulse pressure is highly dependent on stroke vol- observed occasionally in excited but otherwise normal horses
ume and the peripheral arteriolar resistance that determines with high sympathetic tone. This might be due to either vig-
the runoff of diastolic pressure. Ventricular failure or reduced orous right atrial contraction. Alternatively, an exaggerated
venous return reduces pulse pressure, creating a hypokinetic venous collapse can create a “jugular pulse” that is simply a
pulse, whereas abnormal diastolic runoff (aortic regurgitation, reflection of normal venous refilling during periods of positive
generalized vasodilation) widens the pulse pressure, produc- right atrial pressure. When there is doubt, this finding can be
ing a stronger peripheral pulse. Diastolic and mean pressures verified by simple ultrasound imaging of the ventral portion
are better estimates of perfusion pressure in anesthetized or of the vein.
critical equine patients; these variables are increased by arte- Jugular abnormalities include abnormal pulses or elevated
riolar vasoconstriction or by higher CO.57 Arterial pressures venous pressure. An abnormal jugular pulse is one that extends
fluctuate slightly with ventilation and significantly under posi- proximally up the jugular vein for more than 10 cm in systole
tive pressure ventilation or during cyclic changes in HR (see (with the horse’s head held in a normal position) or that dem-
Fig. 9.6) related to variation in ventricular filling. However, onstrates retrograde filling from the heart when the vein is
marked differences can be associated with cardiac tamponade, occluded dorsally. Duplex Doppler studies of the jugular vein
and the dramatic fall in pressure during inspiration is termed can distinguish a prominent pulse caused by retrograde flow
pulsus paradoxus. from an apparent pulse caused by prominent collapse and nor-
mal filling. Abnormal jugular pulses are observed with arrhyth-
Mucous Membranes mias causing AV dissociation (nonconducted atrial premature
The color of the mucous membranes and the capillary refill beats, junctional tachycardia, VT); with diseases of the tricus-
time (CRT) are determined by cardiac output, systemic pid valve (moderate to severe tricuspid regurgitation; tricuspid
stenosis); and with RV failure from any cause including cardiac disorders in horses with exercise intolerance or poor perfor-
tamponade or constrictive pericardial disease. Elevated jugu- mance. In horses with clinically important structural lesions,
lar venous pressure generally indicates right-sided CHF, peri- intermittent premature complexes, or AF, exercise testing can
cardial disease, or hypervolemia. Generalized venous determine whether the HR is appropriate for the work per-
distention, particularly when accompanied by subcutaneous formed or if an arrhythmia deteriorates over the course of
edema, is characteristic of CHF (Figs. 9.11 and 9.12). Isolated the test.53,54,61,68,459 Exercise testing is also indicated during a
distention of the veins cranial to the thoracic inlet is suggestive prepurchase examination when a nonfunctional heart mur-
of a cranial mediastinal or pulmonary mass (or abscess) with mur or sporadic arrhythmia is identified. Having advanced
obstruction of the cranial vena cava.140 Prolonged refill of the this recommendation, it must be acknowledged that the reli-
saphenous vein indicates the possibility of aortoiliac thrombo- ability and overall sensitivity, specificity, and predictive values
sis and decreased arterial supply to the affected limb.267-272,450-455 of exercise testing (as it pertains to detection of arrhythmia
A distended vein that is firm to palpation and associated with and organic heart disease) are incompletely defined, and more
marked distention of associated veins indicates probable data and information are needed to establish the clinical value
venous thrombus. Pain or heat associated with venous swelling of such studies relative to CV disease. Contraindications for
is suggestive of thrombophlebitis.456-458 an exercise test include CHF; severe valvular regurgitation
with secondary AF, PHT, or severely reduced systolic func-
tion; or presence of a ventricular arrhythmia of dangerous
Diagnostic and Laboratory Studies complexity.68
Exercise Testing High-speed treadmill exercise and various forms of field
Because most horses function as athletes, exercise testing rep- exercise testing are increasingly used to detect subtle clinical
resents an important method for identifying CV and other abnormalities that limit peak performance or may lead to col-
lapse, syncope, or sudden death.53,460,461 Treadmill exercise is
particularly useful when evaluating the horse at risk of col-
lapse, because the cardiac response to exercise can be evalu-
ated without risk to a rider. Although an exercise test at lower
levels of work effort (e.g., lunging exercise) might still provide
some valuable information, the work intensity during an exer-
cise test should generally be at or slightly exceeding the horse’s
customary or anticipated activities. This is particularly impor-
tant when the history indicates performance problems only at
the peak of exercise. Some method of inducing unexpected
sympathetic stimulation should be included in the exercise
test to identify an inappropriate HR, aberrant conduction, or
ectopy associated with adrenergic stimulation.68 If the animal
is too young to perform a regular exercise test, evaluation after
a period of free exercise is recommended.
The exercise examination provides valuable information
about musculoskeletal diseases, airway diseases, and cardio-
FIG. 9.11 Jugular venous distention in a Shire foal with biventricular vascular disorders. There are a number of components to a
congestive heart failure (CHF) caused by congenital heart disease. standardized treadmill examination, which should include
continuous recording of an ECG using a device that has per-
manent storage and playback capabilities.54,68,462 Specific
cardiac assessments include (1) the effects of exercise on aus-
cultation (rate, rhythm, and murmurs); (2) peak HR during
exercise; and (3) HR and heart rhythm during the different
phases of the exercise test and during recovery. Optionally,
echocardiography can be performed before and after exer-
cise (stress echocardiogram). Additional tests that might be
indicated are gait analyses, assessment of airway dynamics by
videoendoscopy, evaluation of pulmonary function by arterial
blood gas analyses, and clinical laboratory tests such as preex-
ercise and postexercise serum creatine kinase (CK) activities
to identify subclinical myopathy. The “standardized” exercise
test may not be identical across equine medical centers so it
may be difficult to compare results. The examiner’s own ref-
erence for normal variation further qualifies the examination
results.
Changes in HR and ECG with exercise have been well
studied.* The normal horse develops sinus tachycardia, short-
ening of conduction intervals, and marked ST-T alterations
FIG. 9.12 Ascites, ventral edema, and weight loss are evident in this associated with exercise. The maximal HR achieved depends
mare with right-sided congestive heart failure (CHF). The distended lateral
thoracic vein (arrow) is evident caudal to the triceps. * References 53, 54, 61, 233, 448, 459-461, 463-471.
on the level of exercise performed. At HRs of less than 100 to demonstrate marked fluctuations in sympathetic and para-
120 beats/min, SA node discharge is very labile and subject to sympathetic tone during the recovery period following exer-
psychological influences. Once exercise has commenced, the cise, often termed autonomic instability.471,475-478 Arrhythmias
HR should accelerate and then stabilize at a level appropriate are especially common during this time,* even if the resting
for the work being performed. As a general guideline: on the and peak exercise heart rhythms were normal. Marked sinus
flat, HRs of 70 to 140 beats/min are normal at the trot, 120 to arrhythmia, second-degree AV block, supraventricular ectopy,
160 beats/min at the canter, 150 to 180 beats/min at the gal- and ventricular premature complexes can be evident in the
lop, and more than 180 beats/min when galloping hard. When immediate postexercise period. With the exception of vagally
exercising on slopes, the highest rates associated with each gait mediated arrhythmias, postexercise arrhythmias should be
increase, and it is possible to approach maximal rates at the considered suspicious. Atrial fibrillation, ectopic supraventric-
trot when on gradients of greater than 20%. The maximal HR ular tachycardias, and ventricular tachycardias are considered
for most horses is between 210 and 240 beats/min, although abnormal at any point in the exercise test. However, the impor-
some younger horses develop higher rates, and aged horses tance of single (isolated) ectopic complexes identified only in
can have maximum rates below 210 beats/min. There is a lin- the immediate postexercise phase is less certain,* which is
ear relationship between HR and the velocity or work effort not surprising considering similar issues persist in assess-
of exercise when the HR is between 120 and 210 beats/min. ing human athletes. In assessing these horses, attention also
HR usually recovers rapidly and falls to less than 100 beats/ should be directed to baseline auscultation and echocardio-
min within 2 to 5 minutes of cessation of exercise. The recov- graphic examinations, the heart rhythm during exercise, and
ery of HR to the resting level is influenced by many factors, measurements of plasma cardiac troponin I (cTnI) concen-
including the humidity, ambient temperature, training fitness, trations before and after exercise. The presence of coexisting
work performed, psychological factors, and state of CV health. respiratory disease and associated arterial hypoxemia needs to
After maximal work, such as a race, an hour may pass before be considered, because it creates the potential for secondary
the HR completely recovers to the resting rate. An inappropri- rhythm disturbances, unrelated to primary cardiac disease.90
ately high HR for a given level of exercise may simply denote Echocardiography immediately following the stress
a healthy, but unfit, horse; however, this finding can also of exercise (the so-called stress echo) may be used in an
indicate the presence of pulmonary, musculoskeletal, or CV attempt to identify global and regional myocardial dysfunc-
disease.68,472 Information about the HR is particularly useful tion.90,167,168,459,480-482 This examination must occur within
when a horse has the HR monitored routinely during exercise. 2 to 3 minutes after high-intensity exercise and with the HR
Exercise-induced arrhythmias may be observed during or in excess of 100 beats/min.168 However, the optimal HRs and
after exercise. An exercising ECG is necessary to determine the influence of rapidly decreasing HRs on echocardiographic
whether an arrhythmia is present during exercise. An HR measurements such as shortening fraction require better defi-
monitor may provide some indication regarding arrhythmias nition.168 Dynamic changes can be viewed from the short-axis
during exercise; however, the detectable maximum HR (or tomograms, and prominent thickening of the ventricular
shortest RR interval) might be limited by inherent filtering septum and LV free-wall identified from long-axis images.
algorithms, and the detection of erratic heart “blips” or “beeps” Persistent abnormalities in regional myocardial contraction
does not adequately characterize the rhythm disturbance. are suggestive of vascular disease with ischemia, preexistent
Exercise may induce supraventricular premature complexes, myocardial fibrosis, or a localized conduction disturbance.
AF, ventricular premature complexes, or VT. Exercise-induced Left ventricular shortening fraction and LV fractional area
(paroxysmal) AF should be included in the differential diag- change—two estimates of LV systolic function—are com-
nosis of horses with poor performance during high-intensity monly measured during stress echocardiography but have
exercise.39,54,68,88,472-474 Exercise-induced ventricular arrhyth- recently been shown to poorly track stress-induced changes
mias (VAs) are a particular concern because ventricular in LV function.168 Errors in cursor placement (e.g., too dorsal)
rhythm disturbances can lead to poor performance, sudden or inconsistent orientation of the M-mode cursor placement
stopping, or even falling and have been suspected as a com- between examinations can produce misleading results. Volu-
mon cause of sudden death.* Repetitive ventricular activity metric estimates of stroke volume and LV ejection fraction by
(paroxysmal ventricular tachycardia) with short R-R inter- 2D echocardiography are more reliable to assess global LV sys-
vals or R-on-T phenomenon is particularly worrisome and tolic function after exercise.168 Other methods used for stress
may indicate preexisting myocardial disease or myocardial echocardiographic assessment of LV function are the manual
ischemia with altered cardiac electrical activity. Although AF tracking of endocardial motion and subjective evaluation of
per se is not a fatal rhythm, sudden-onset AF during maximal regional wall motion. Newer echocardiographic modalities
exercise may rarely cause a horse to collapse. One recent study such as 2D strain imaging (2D speckle tracking) may have
further showed that the prevalence of QRS broadening and some advantages over conventional methods and could prove
R-on-T phenomenon was high in horses with AF even at lower useful for quantitative assessment of regional and global LV
levels of exercise, indicating that some horses with AF might function during stress echocardiography.168 However, the
in fact be at risk for fatal ventricular rhythms.472 AF associated quantitative and objective detection of stress-induced hypoki-
with exercise-induced VA resulting in sudden cardiac death nesia, akinesia, and dyssynchrony in diseased horses requires
has been documented in at least one horse.54 additional investigations, and more data and standardizations
Undoubtedly, CV disorders can be induced or worsened are needed before methods can be widely accepted. Finally,
by the stress of exercise, and the likelihood of detecting dis- the assessment of cardiac valve function following exercise
ease is increased. However, there are challenges to this assess- requires much better definition before any conclusions can be
ment because physiologic variability is also magnified. Horses made.
* References 54, 94, 96-99, 104, 106, 150, 475. * References 54, 77-80, 82, 90, 475, 478, 479.
Although the standardized treadmill examination is the 1

2
0
most commonly used cardiac “stress test” at equine centers,
some attention has been directed on performing pharma-
cologic stress testing. This examination involves increasing mV 0
3
the HR and myocardial contractile force with dobutamine,
either with or without atropine or glycopyrrolate, followed 90
4 4
by echocardiographic assessment of ventricular contrac-
tion.243,247,481,483,484 Pharmacologic stress echocardiography is gNa
used to identify regions of reduced myocardial perfusion or
ischemic myocardial injury in human patients with coronary gCa
heart disease; the study is used in people who cannot perform
physical exercise to stress the heart and increase myocardial
gK
oxygen demand. Whether this form of stress testing should be
used in horses is subject to debate. First, it must be emphasized
that there is no compelling evidence from pathology stud- FIG. 9.13 The cardiac action potential. The diagram demonstrates the
ies that horses develop significant coronary arterial disease. phases of depolarization and repolarization, as well as membrane con-
Admittedly, myocardial fibrosis is found in some horses at ductance (g) to important ions (see the text for details). (From Berne RM,
necropsy29,485; however, the pathogenesis or clinical relevance Levy MN: Cardiovascular physiology, St. Louis, 1986, CV Mosby.)
of these often microscopic lesions is unresolved. In human
patients, the diagnostic target is well-defined extramural coro- potassium, and chloride are responsible for the processes
nary artery disease, and stress echocardiography generally of depolarization, muscular contraction, and repolariza-
predicts normal or abnormal findings at coronary arteriogra- tion (see Fig. 9.13). These processes, in turn, are affected by
phy. There is no evidence at this time for a similar situation in serum electrolyte concentration, acid-base status, autonomic
horses, and this represents a major contextual issue when con- traffic, myocardial perfusion and oxygenation, heart disease,
sidering “stress echo” with either exercise- or pharmacologic- and drugs. The basic processes of cell depolarization, calcium
induced cardiac work. Furthermore, pharmacologic stress influx, and cell repolarization form the basis for, respectively,
testing may not achieve the identical exercise endpoints in the P and QRS complexes of the ECG, myocardial contraction,
terms of HR or altered vascular resistances. The combination and the ST-T wave of the ECG.
of dobutamine and atropine involves the use of proarrhythmic The resting membrane potential is determined primar-
drugs, making the heart rhythm assessment—a pivotal com- ily by the partitioning of potassium ions and proteins across
ponent of the exercise test—quite problematic. Pharmacologic the cell membrane and the relative impermeability of the
stress testing does not provide an opportunity for dynamic membrane to sodium. Depolarization of atrial and ventricu-
assessment of the gait and airways.482 Last, assessment of left lar myocytes and Purkinje fibers is caused by the rapid influx
heart valve function is complicated by changes in systemic of extracellular sodium into the cell.57,110,112-114,116 This current
arterial BP that may develop during drug-induced tachycardia is represented by phase 0 of the cardiac cell action potential
(but have been poorly characterized in studies thus far). Thus, recording. Normal cardiac tissues depolarized in this manner
although pharmacologic stress testing carries the benefit of a conduct electrical impulses at high velocity. In contrast, the
stationary diagnostic setup not requiring a treadmill, a num- cells of the SA and AV nodes, as well as ischemic cells, dem-
ber of outstanding issues must be addressed before this exami- onstrate less negative diastolic membrane potentials. Nodal
nation can be advocated for wider use. cells depend on a slow-inward current of depolarization that is
carried mainly by calcium ions across the transient and long-
Electrocardiography lasting calcium channels. In ischemic cells, due to the less neg-
Normal Cardiac Cell Electrical Activity. Cardiomyocytes are ative resting potential, some sodium channels remain in the
excitable and capable of responding to electrical stimuli re- inactivated state and thus are unavailable for activation and
gardless of extrinsic innervation. Specialized cardiac tissues membrane depolarization during phase 0. Therefore cells in
such as those in the sinoatrial node and the His-Purkinje sys- the SA node, AV node, and ischemic tissue conduct electrical
tem demonstrate spontaneous depolarization and can serve as impulses very slowly and can be involved in blocks, abnor-
pacemakers for the heart. The electrical processes responsible mal automatic mechanisms, or reentrant pathways that pro-
for the ECG are caused by ion fluxes across the cell membrane mote cardiac arrhythmias. Antiarrhythmic drugs and calcium
(Fig. 9.13).57,110,112-114,116 A general understanding of cellular ac- channel blockers act differently on tissues that are “fast” versus
tivity, generation, and spread of the cardiac electrical impulse; “slow” current dependent (see Cardiac Arrhythmias later in
effects of autonomic innervation; and electrocardiographic this chapter).
lead systems is required to interpret the equine ECG. The influx of extracellular calcium into the cell during
The partially selective nature of the cardiac cell mem- the plateau phase (phase 2) of the action potential triggers
brane and the presence of various cell membrane pumps the release of intracellular calcium from the sarcoplasmic
lead to an unequal partitioning of ions across the cell mem- reticulum. Increases in cytosolic calcium cause myocardial
brane.57,110,112-114,116 This results in very high potassium and contraction. Hypoxia, acidosis, anesthetics, and many other
relatively low sodium concentrations intracellularly compared drugs can affect myocardial contractility by interfering with
with the extracellular fluid. Other ions including chloride and calcium entry into cells, with the release of calcium from the
magnesium, but most notably calcium, are important to cel- sarcoplasmic reticulum, or with the binding of calcium to
lular electrical activity. Calcium also is essential for contrac- contractile filaments.57,110,112-114,116 Conversely, digitalis glyco-
tion of the cardiomyocytes. Sudden changes in cardiac cell sides and dobutamine increase calcium influx and myocardial
membrane permeability or conductance to sodium, calcium, contractility.
Cellular repolarization is initiated by decreases in the cell

membrane conductance to sodium and to calcium coincident
with increased conductance to potassium. As intracellular
potassium moves out of the cell, along its concentration gra-
dient, phase 3 of the cardiac action potential occurs. Repolar-
ization is complex, involves a number of ion currents,486 and
is affected by genetics and drugs such as quinidine or amioda-
rone. Sympathetic stimulation may activate currents that facili-
tate repolarization at higher HRs, explaining the shortening of FIG. 9.14 A normal equine base-to-apex lead electrocardiogram (ECG)
(25 mm/sec; 1 cm = 1 mV). The waveforms are indicated. The normal P
the action potential under sympathetic drive. Paradoxically,
wave in this lead is positive and notched (bifid), and a depression occurs in
vagotonia also enhances repolarization by opening potassium
the baseline after the P wave that indicates atrial repolarization (Ta wave).
channels, an effect that is very prominent in the atria and may
The QRS complex often lacks an R wave in this lead (QS complex). The
predispose to development of AF. Hypoxia and abnormalities in
T wave is labile and may be negative, biphasic, or positive. Increases in
serum potassium or calcium also alter repolarization. Hyper-
heart rate or sympathetic tone usually lead to positive T waves in this lead.
kalemia accelerates repolarization and shortens the ST-T wave
of the ECG. This occurs because hyperkalemia increases mem-
brane permeability to potassium, and the high intracellular under general anesthesia. When the principal abnormality
potassium (exceeding 100 mmol/L) is more than adequate to resides in depression of SA node function or blockage of the
drive potassium out of the cell (because extracellular potassium impulse in the AV node, the slow discharge of a subsidiary
rarely exceeds 10 mmol/L). pacemaker is termed an escape mechanism. The purpose of
Spontaneous depolarization or automaticity is a property these latent cardiac pacemakers is to rescue the heart from
of select cardiac tissues. Such activity is most prominent in the extreme bradycardia or asystole. However, ectopic pacemak-
SA node but may also be encountered in cells around the AV ers also can be enhanced abnormally by drugs, inflammatory
node and in the His-Purkinje network. Normal automaticity mediators, abnormal sympathetic activity, electrolyte distur-
is observed in these cells during phase 4 of the cardiac action bances, or ischemia, leading to ectopic rhythms that manifest
potential. Spontaneous pacemaker activity is generated in as premature complexes or tachycardias. Additional abnormal
normal pacemaker tissues by the background inward sodium electrophysiologic mechanisms, including abnormal auto-
current and a time-related decrease in membrane permeabil- maticity in tissues other than nodal and conduction tissues
ity to potassium ion efflux, and a transient inward calcium (i.e., ischemic myocardium), afterdepolarizations, and reentry
current.57,110,112-114,116 Once membrane threshold is reached, account for the development of other arrhythmias.57,110,112-114,116
ion flow across the long-lasting calcium channels (“slow cur- Genesis of the Electrocardiogram. The SA node is located
rent”) predominates and leads to cell depolarization (phase near the right auricle; therefore initial cardiac muscle depolar-
0). Spontaneous depolarization is modified markedly by auto- ization crosses the right atrium (see Fig. 9.3). Activation waves
nomic traffic. Vagal activity opens potassium channels and spread through the atrial myocardial cells to the left atrium
hyperpolarizes the membrane, depressing automaticity. With and also in the direction of the AV node. Specialized atrial
sympathetic stimulation or membrane hyperpolarization, the muscle cells comprising internodal pathways and Bachman’s
depolarizing “funny current” (IF) becomes activated, enhanc- bundle facilitate transmission of current across the atria.8,488
ing pacemaker activity. These specialized pathways—as well as the SA node—are rela-
Autonomic innervation has profound effects on electrical tively resistant to high serum potassium concentrations and
activity9,217,487 but is not distributed equally through the heart. may function during hyperkalemia to cause a sinoventricular
The right and left vagus have preferential innervation to SA rhythm, even while normal atrial myocytes are inexcitable
and AV nodes, and parasympathetic traffic is more extensive in (atrial standstill).
supraventricular than ventricular myocardium. Sympathetic Conduction continues across the AV tissues by first enter-
activity derived from paired ganglia are also not bilaterally ing the AV node. Current transmission across the AV nodal
symmetric but do innervate both atria and ventricles exten- cells is especially slow because this tissue depends on inward
sively. Parasympathetic activity depresses SA nodal activity, calcium currents and is subject to physiologic blockade from
enhances intraatrial conduction by shortening atrial action vagal efferent traffic.220 Conduction proceeds at a greater
potential duration, and slows AV nodal conduction. Con- velocity through the bundle of His and bundle branches. Prop-
versely, sympathetic efferent traffic increases HR and shortens agation of the impulse through the ventricles is enhanced by a
AV conduction time.112 Sympathetic activity also increases rapidly conducting Purkinje system that penetrates relatively
cellular excitability, predisposes to some cardiac arrhythmias, completely through the ventricular myocardium.6,7
and increases myocardial oxygen consumption by augment- The ECG graphs the time-voltage activity of the heart. The
ing the HR, force of myocardial contraction, and myocardial average electrical potential generated by the heart muscle is
wall tension. Parasympathetic efferent traffic dominates in the recorded throughout the phases of the cardiac cycle with time
resting, standing horse and frequently fluctuates with changes displayed along the X-axis and electrical potential inscribed
in BP. The pronounced sinus arrhythmia, sinoatrial block, and vertically (Fig. 9.14). The normal waveforms are the P wave
second-degree AV block so often encountered in the normal (atrial depolarization), the PR (or PQ) interval that is due
horse are caused by changing vagal tone and serve to regulate mostly to slow AV nodal conduction, the QRS complex (ven-
arterial BP at rest (see Fig. 9.6).108 tricular depolarization), and the ST-T wave (ventricular repo-
Depression of normal SA automaticity or increased activity larization). A prominent atrial repolarization wave (Ta wave)
in other tissues in the atria, in the Purkinje system, or in cells is often noted in the PR segment of the equine ECG, particu-
around the AV node may lead to an abnormal or “ectopic” car- larly at faster HRs. The QT interval represents total electrical
diac rhythm. This situation is often observed in healthy horses activation-repolarization time.
P T P′
BOX 9.8
Electrocardiographic Leads
BASE-APEX MONITOR LEAD (MOST COMMONLY USED)

P R T
[+] Electrode over the left apex (left chest, at the level of the
olecranon)
[−] Electrode over the right jugular furrow
The most common method to obtain the base-apex lead
is to place the left arm (LA) electrode over the left P T
apex, the right arm (RA) electrode over the jugular
furrow, and select “lead I” on the electrocardiograph.
This lead is the preferred choice for monitoring cardiac
rhythm.
BIPOLAR LEADS (EINTHOVEN)a

Lead I = Left foreleg (LA) [+] − Right foreleg (RA) [−]
Lead II = Left rear leg (LL) [+] − Right foreleg (RA) [−]
FIG. 9.15 Examples of extrasystoles. Atrial (P′ at top) and ventricular
(at bottom) extrasystoles in a mare with heart failure, sinus tachycardia,
Lead III = Left rear leg (LL) [+] − Left foreleg (LA) [−]
and premature beats. The recordings are from a 24-hour tape-recorded
UNIPOLAR AUGMENTED LIMB LEADS (GOLDBERGER)a (Holter) electrocardiogram (ECG). Two transthoracic leads recorded si-
multaneously. The waveforms are indicated. The dark circles indicate the
Lead aVR = Right foreleg [+] − Left foreleg and Left rear leg [−]
premature complexes. The P-R interval of the APC is longer because of
Lead aVL = Left foreleg [+] − Right foreleg and Left rear leg [−]
physiologic refractoriness in the atrioventricular node. The ventricular ec-
Lead aVF = Left rear leg [+] − Right foreleg and Left foreleg [−]
topic follows the sinus P wave (late diastolic) but discharges the ventricle
UNIPOLAR PRECORDIAL CHEST LEADS before the sinus impulse can cause a normal QRS complex. The T wave
of the ventricular extrasystole is abnormal (secondary T-wave change).
[+] Electrode over selected precordial site
Paper speed is 25 mm/sec.
[−] Electrode composed of a compound electrode of left
and right foreleg and left rear leg (Wilson central terminal)
The lead is named based on the location of the exploring monitoring can be performed with self-adhesive contact elec-
(V or C) electrode. trodes using a bipolar lead system similar to that used for the
V10 = [+] over the dorsal spine. Precordial leads other equine HR monitors. Electrodes are often placed over the left
than V10 are not commonly used. saddle area (positive [right arm] electrode), sternum (negative
[left arm] electrode), and right thorax (neutral [left leg] elec-
MODIFIED ORTHOGONAL LEAD SYSTEM trode), with the ground (right leg) electrode placed anywhere
Lead X = Lead I, right [−] to left [+] around the girth area. However, alternative electrode placements
Lead Y = Lead aVF, cranial [−] to caudal [+] might be used to record an ambulatory ECG of diagnostic quality
Lead Z = Lead V10, ventral [−] to dorsal [+] (e.g., right arm, right saddle area; left arm and left leg, left thorax
a Frontal
20 cm and 5 cm, respectively, above olecranon; right leg (neutral),
plane leads.
left saddle area). To facilitate ECG pattern reading and optimize
the ECG for automated processing using dedicated software, the
Clinical Electrocardiography. The clinical application of electrode arrangement should provide an ECG with a distinct
electrocardiography to the horse has been studied extensively.* negative QRS complex and positive P and T waves (see Fig. 9.14).
The principles of recording and interpreting the equine ECG If ECG recordings are analyzed using human Holter analysis sys-
are similar to those used for humans, dogs, and other species. tems, it may be beneficial to record an ECG with positive QRS
The lead systems employed are identical, although some mod- complexes. In any case, the T waves should not be bigger than
ified leads, such as the base-to-apex lead, are most useful for the QRS complexes. Clipping may not be necessary as long as the
monitoring the cardiac rhythm. A number of semiorthogonal hair coat is not too long and the self-adhesive electrodes can be
lead systems have been evaluated experimentally but are rarely kept moist (e.g., by additionally adding a drop of 0.9% saline or
used in clinical practice. The modified Einthoven’s lead sys- electrode contact gel onto the contact area) and in tight contact
tem, consisting of leads frontal planes I, II, III, aVR, aVL, and with the horse using a surcingle and padding material. This type
aVF, and the precordial lead V10, is quite applicable for ECG of continuous 24-hour rhythm monitor can be useful to evaluate
studies of horses (Box 9.8). The base-apex lead or chest leads the horse with a history of syncope or an arrhythmia but in which
are most often used for rhythm analysis. an arrhythmia cannot be induced during resting, exercise, and
The value of continuous, ambulatory (Holter) ECG monitor- postexercise ECG examinations. An alternative is an ECG event
ing is obvious for identification of infrequent rhythm distur- recorder that continuously records the rhythm and stores the
bances, quantifying the severity of an arrhythmia, or objectively ECG following an observed event, such as a sudden fall. These
evaluating drug therapy (Fig. 9.15). In one study it was observed event recorders can be worn for longer periods of time.
that many horses that were historically and clinically without Telemetry-based ECG recordings are commonly used in exer-
evidence of cardiac disease had supraventricular or (less often) cise testing (see Exercise Testing earlier in this chapter) and in
ventricular arrhythmias on Holter ECG.400,541 Ambulatory monitoring of critical patients in hospital settings.58,90,459,534 The
lead systems used are often similar to those employed for Holter
* References 1, 6-8, 11, 30, 35, 40, 43, 44, 57, 77-79, 82, 216, 222, 224, 378, 383, ECG recordings. However, the degree of artifact that occurs
399, 426, 470, 479, 489-541. during exercise is considerable. Those interested in consistent
stress ECG recordings must experiment with various electrode

BOX 9.9
Evaluation of the Electrocardiogram positions and lead systems. One proven possibility is placement
of the right arm and ground electrodes next to each other on
TECHNICAL ASPECTS the left dorsum above the scapula, cranial to the saddle or the
• Paper speed—standard: 25 or 50 mm/sec lunging girth, and the left arm and left leg electrodes next to
• Calibration—standard: 1 cm/mV each other on the left ventral thorax, caudal to the saddle girth
• Lead(s)—see Box 9.8 or lunging girth. The electrodes should be place sufficiently dis-
tant to the tack and the rider’s legs to minimize motion artifacts.
ARTIFACTS The orientation, amplitude, and duration of the ECG wave-
• Electrical, motion, twitching, muscle tremor, equipment forms depend on many factors, including the age and size of
(ventilator) the horse,386,399,519 the lead examined, the size of the cardiac
chambers, the degree of training, and even the phase of ventila-
HEART RATE tion.492,493 The principal use of the ECG is to diagnose the heart
• Atrial and ventricular rate rhythm, because in horses this examination is insensitive for
detecting cardiomegaly, especially in horses with mild to mod-
CARDIAC RHYTHM erate heart enlargement. A normal ECG does not exclude heart
• Regular, regularly irregular, irregularly irregular disease; moreover, the ECG is not a test of myocardial function.
• Atrial, AV conduction sequence, ventricular, ventricular A systematic approach to ECG analysis should be undertaken
conduction (Box 9.9) and compared with reference values (see Table 9.5).
• Arrhythmias Although the magnitude of absolute differences may be small,
• Site or chamber of abnormal impulse formation, body weight needs to be considered when comparing HR and
myocardial fibrillation, or conduction disturbance ECG time intervals to reference values, because small equine
• Rate of abnormal impulse formation breeds have slightly faster HRs and shorter ECG time intervals
• Conduction of abnormal impulses (i.e., PR interval, QRS duration, QT interval) compared with
• Patterns or repeating cycles larger equine breeds (Fig. 9.16).399 Furthermore, the HR depen-
dence of repolarization needs to be considered when measuring
WAVES AND COMPLEXES QT intervals,399,536,537,539 acknowledging that the best method
• P wave—morphology, duration, amplitude, variation for QT correction in individual horses is ill defined.
• PQ (PR) interval—duration, variation, conduction block Atrial depolarization generates the P wave. Normal activa-
(of P wave) tion proceeds from right to left and craniad to caudad, leading
• QRS—morphology, duration, amplitude, frontal plane to positive P waves in left-right lead I and also in craniocaudal
mean electrical axis leads II and aVF.8,11 The normal P wave is notched or bifid;
• ST segment—depression or elevation however, single peaked, diphasic, and polyphasic P waves may
• T wave—changes in morphology or size be encountered in normal horses. A negative/positive P wave
• QT interval—duration (consider heart rate) is often recorded if the focus of pacemaker activity shifts to the
caudal right atrium near the coronary sinus (Fig. 9.17). The
MISCELLANEOUS initial peak of the common bifid P wave is reportedly caused
• Electrical alternans, synchronous diaphragmatic by depolarization of the middle and caudal one third of the
contraction right atrium.6,8 The second peak represents activation of the
atrial septum and the medial surface of the left atrium. The
P wave peaks can be subdivided, with P1 reported to be as
TABLE 9.5 Normal Heart Rates and ECG Time Intervals for Horses at Rest
Breed HR (beats/min) PQ (msec)a QRS (msec)b QT (msec)c
ADULTS399,470,499,500,512,532,533
Large breeds 26–50 200–500 80–140 360–600
Small breeds, ponies 30–54 160–320 60–120 320–560
FOALS426,519,546
Large breeds 100–140 100–180 50–80 200–350
1–7 d 80–130 100–190 60–80 230–350
14 d
Ponies 70–145 90–130 25–70 180–370
1–30 d 60–95 110–150 30–70 220–420
60 d 50–85 130–170 50–80 310–390
90 d

aAlso termed PR, because the Q wave is often not visible. Interval varies with autonomic input, longer when vagal tone is high.
bQRS duration is often difficult to determine due to the normal slur in the ST segment. Duration can vary with size of the heart and lead positioning (often
longer in the base-apex lead).
cInversely related to heart rate.
FIG. 9.16 Scatter plots showing the relationship between body weight (BWT), heart rate (HR), and ECG
time intervals in healthy adult horses of different breeds (n = 250). Reference intervals for HR and ECG time
intervals for a specific BWT can be estimated based on the prediction band (dotted line). HR15″, mean HR
calculated over 15 sec; RR, RR interval; PQ, PQ (PR) interval; QRS, QRS duration; QT, QT interval; QTcf, rate-cor-
rected QT interval, Fridericia’s correction. (Modified from Schwarzwald CC, et al.: Relationship of heart rate
and electrocardiographic time intervals to body mass in horses and ponies. J Vet Cardiol 2012, 14:343-350.)
FIG. 9.17 P waves of the horse are demonstrated. On the left is a normal, bifid P wave morphology with
two distinct peaks (designated as P1 and P2) and also a physiologic second-degree atrioventricular block (ar-
row). The center panel demonstrates a negative/positive P wave of coronary sinus origin. This is a normal
variation. The right panel shows increased amplitude P waves recorded in a horse after conversion from
atrial fibrillation (AF). The second peak is particularly large and may indicate atrial enlargement; however,
such voltage criteria correlate poorly with cardiomegaly in horses. Echocardiography is a more accurate
method for evaluating atrial size. Lead 2 paper speed is 25 mm/sec.
1 aVR RV1
Following ventricular activation, repolarization of the ven-
tricles is recorded. This period is measured from the end of the
QRS complex (the “J point”) and extends to the end of the T
wave.35,505,543 The T wave vector is most often directed toward the
right caudal quadrant, resulting in a positive T wave in lead III
and a negative or isoelectric T wave in lead I in resting horses
(Fig. 9.18).499 Although some clinical surveys have suggested
that abnormalities of the ST-T indicate cardiac dysfunction in
performance animals, marked deviation of the ST segment and
2 aVL V3 increased amplitude of the T wave are anticipated in healthy
horses during exercise or even with excitement-induced tachy-
cardia. There is simply no compelling evidence that T-wave
abnormalities can be interpreted consistently. Progressive J-point
or ST-segment deviation in the horse with hypovolemia or shock
may indicate myocardial ischemia, whereas enlargement of the
3 aVF V10 T wave may develop with myocardial hypoxia or hyperkalemia.
Diagnosis and management of cardiac arrhythmias are dis-
cussed later in this chapter.
Thoracic Radiography
There are severe limitations to the use of thoracic radiography
FIG. 9.18 Multiple lead recordings in a normal horse. The varying con- in the evaluation of the equine heart because of the large size
figuration of the P-QRS-T complexes across the leads is notable. of the mature horse and the ability to obtain only a standing
lateral thoracic radiograph in all except the smallest foals.544
high as 0.25 mV (mean of 0.14 mV) and the second peak, P2, Although recumbent lateral and on occasion ventrodorsal or
reported to be as high as 0.5 mV (mean of 0.28 mV).499 There dorsoventral projections can be obtained on neonatal foals,
are even subtle differences among breeds of horses. The P-wave the stress of restraint or requirement for heavy sedation can
morphology can change cyclically with waxing and waning of make such positioning contraindicated in foals with cardiac
vagal tone during sinus arrhythmia. During tachycardia, the disease. Thoracic radiographs may be useful to identify areas
P wave shortens, becomes more peaked, and is followed by a of pulmonary or pleural disease and assist in the differential
prominent atrial repolarization (Ta) wave that deviates the PQ diagnosis of respiratory problems.
segment downward. Such features make the diagnosis of atrial Gross changes in cardiac size and shape may be detected in a
enlargement by electrocardiography very difficult. lateral thoracic radiograph of a foal or horse with significant car-
The time required for conduction across the AV node and diomegaly.544-548 A normal thoracic radiograph does not neces-
His-Purkinje system is estimated by measuring the PR inter- sarily indicate that the heart is normal in size. Mild to moderate
val. Because physiologic AV block is so common, there is increases in the size of the cardiac chambers may go undetected,
significant variation in the PR interval even within the same particularly in adult horses. Generalized enlargement of the
horse; thus, normal maximal values for the PR interval are dif- cardiac silhouette is observed in cases of significant pericardial
ficult to state. Values that persistently exceed 0.5 seconds are effusion or with CHF (Fig. 9.19). Dorsal displacement of the tra-
probably abnormal (see Table 9.5). Variation in the PR interval chea may be detected in some horses with left atrial (LA) and LV
is not usually related to changes in ventilation42 but is often enlargement. In some horses with LA enlargement, the caudodor-
correlated with changes in BP and baroreceptor activation.108 sal border of the cardiac silhouette bulges caudally. Increased
The morphology of the QRS complex is variable. The rela- contact between the ventral border of the heart and the sternum
tively complete penetration of the conduction system into the may be detected with RV enlargement but is usually difficult to
free walls of the ventricle causes these chambers to be activated appreciate. A 50% decrease in the spinotracheal angle (the angle
simultaneously with a burst of depolarization, which cancels between the dorsal border of the trachea and the ventral border
much of the divergent electromotive forces.6,7 Consequently, of the adjacent thoracic vertebrae) was demonstrated in young
the normal electrical axis may vary, and the amplitude of the horses with cardiomegaly caused by congenital cardiac disease.544
QRS complex can be quite small in the frontal plane leads. A Evaluation of the pulmonary vasculature and pulmonary
substantial dorsally oriented vector causes a prominent posi- parenchyma is also difficult and very dependent on radio-
tive terminal deflection in lead V10, while the (− electrode) graphic technique. Enlarged pulmonary vessels associated
right base to (+ electrode) left apex lead exhibits a prominent with pulmonary overcirculation can occasionally be observed
S-wave (Figs. 9.14 and 9.18). The normal slur in the ST seg- in left-to-right shunts; the opposite is also true in congenital
ment makes determination of QRS duration difficult in many right-to-left shunts. Pulmonary edema causes generalized
horses.6,35,542 The mean amplitude for the R wave in lead II for increased radiopacity, particularly in the hilar regions; the
normal racehorses is about 0.8 to 1.1 mV.1,4,151,499-501,522 Clinical characteristic air bronchograms are more readily identified
experience suggests that R wave amplitudes exceeding 2.2 mV there when alveolar edema is present.
in lead II or 1.7 mV in lead I are often abnormal. But occa- Angiocardiography is only practical in foals less than about
sionally, the R wave amplitude in a normal horse exceeds even 115 kg and usually requires general anesthesia, which may
these limits. The frontal plane leads can be inspected to esti- be contraindicated in the foal with a severely compromised
mate the mean electrical axis of depolarization, the “average” cardiovascular system. Both selective and nonselective posi-
wave of depolarization. Abnormal axis deviations have been tive contrast angiocardiograms have been performed in foals
observed with cardiomegaly, cor pulmonale, conduction dis- and adult horses (see Fig. 9.19D),171,545,549 but these techniques
turbances, and electrolyte imbalance.522 have been almost exclusively replaced by echocardiography.
A B
C D
FIG. 9.19 Thoracic radiography. A, Significant cardiomegaly in a Quarter Horse foal with complex con-
genital heart disease, including multiple ventricular septal defects (VSDs). B, Cardiomegaly and alveolar
pulmonary edema in a filly with mitral regurgitation (MR) and left-sided congestive heart failure (CHF). C,
Increased pulmonary density and pleural effusion in a Standardbred gelding with atrial fibrillation (AF), atrio-
ventricular valvular regurgitation, myocardial failure, and biventricular CHF. D, Angiocardiogram obtained
from an Arabian foal with pulmonary atresia and a large VSD (pseudotruncus arteriosus). Contrast medium
was injected in the left ventricle (LV), and this medium opacifies a dilated, overriding aorta. Right-to-left
shunting across the VSD results in dilution of contrast medium. The right arrow shows the subaortic LV
outflow tract; the widened aorta is delineated by the arrows at the left. Ao, Aorta; LA, left atrium; LV, left
ventricle; RCA, right coronary artery.
Nuclear medicine imaging has been developed in some and nature of heart lesions, and the relevant hemodynamics
equine referral institutions and has been used to assess car- of a cardiac lesion.* Transesophageal echocardiography (TEE)
diac function. First-pass nuclear angiocardiography permits has been used in horses241,276,277,309,312,566 but (except in foals)
the visualization of the cardiac chambers during sequential requires custom-made transducers and is only practical in
phases of the cardiac cycle.544 Application of first pass studies anesthetized or heavily sedated horses due to the fragile (and
may be useful for identification of cardiac shunting, but again, expensive) nature of the TEE probe.
this diagnosis is more simply attained by echocardiography. Despite the recent technical advances that allowed great
improvement of image quality and temporal resolution of
Echocardiography echocardiographic images, accurate and reliable assessment
Over the past 35 years, echocardiography has evolved to of chamber dimensions and mechanical function of the heart
become the most important diagnostic study currently avail- remains challenging and is limited by a variety of technical,
able for evaluation of the equine heart. Transthoracic echo- anatomic, and physiologic issues that need to be considered
cardiography, including 2D, M-mode, and Doppler studies,
provides the basis for comprehensive evaluation of internal * References 14, 49, 51, 56, 70, 71, 74-76, 122, 124, 129, 130, 142, 148, 161, 167,
cardiac structures, chamber and vessel dimensions, blood flow 168, 209, 211, 243, 244, 274, 276, 280, 281, 285-287, 289, 297, 306, 311-313,
characteristics, mechanical function of the heart, presence 340-350, 365, 390, 391, 426, 481, 484, 550-593.
when performing echocardiographic examinations.344,594,595 (Box 9.10).68 Furthermore, ultrasound can also identify other
Knowledge of the technical principles of ultrasonography, lesions of the lung, pleural space, or mediastinum that may
technical skills with imaging and instrumentation, strict masquerade as heart disease.140,598
adherence to a routine protocol in order to obtain high-quality A complete echocardiographic study should address mor-
standard sonographic images, comprehensive knowledge of phologic lesions, motion abnormalities, cardiac chamber and
normal cardiac anatomy and physiology, and thorough appre- great vessel size, cardiac valve function, blood flow distur-
ciation of equine cardiac diseases are prerequisites to the suc- bances, global and regional ventricular systolic function, esti-
cessful use of echocardiography. mates of hemodynamic variables including pressure gradients
The echocardiographic examination should take place in a and volumetric flow, and ventricular diastolic function and
location where the horse can be safely restrained. If possible, filling pressures (realizing that these two are challenging to
the patient should not be sedated before the examination, measure in mature horses).68 A normal echocardiogram and
because cardiac dimensions, indices of cardiac function, and Doppler study in a horse with a cardiac murmur is a favorable
color Doppler signals of regurgitant flow or shunt flow might finding, suggesting a functional basis for the murmur. Con-
be altered because of drug effects on preload, afterload, conversely, identification of an abnormal flow pattern with asso-
tractility, HR, and rhythm.274,584,587,596 However, some horses ciated cardiomegaly or abnormal ventricular function may
do not tolerate the echocardiographic procedure and require indicate a high risk or limitation for work. As with all diag-
sedation to allow conducting the examination safely, with suf- nostic studies, there can be ambiguous results, particularly
ficient quality, and at normal HRs. regarding the tricuspid valve, because physiologic tricuspid
Examination findings are relatively consistent when per- regurgitation, silent to auscultation, is detectable by Doppler
formed by experienced examiners, but there is day-to-day, studies in many clinically normal horses. Box 9.11 provides an
subject, and examiner variation that can be significant (greater overview on interpretation of echocardiographic and Doppler
than 10%) for some variables and must be considered when studies. Clinical applications of echocardiography are illus-
performing serial examinations.* Unfortunately, an imaging trated later in this chapter.
standard for equine echocardiography that is unanimously Technical Considerations. The ultrasonographic equip-
acknowledged and followed by all centers and clinicians is ment should include a phased-array sector transducer work-
currently lacking. Most clinicians follow some kind of stan- ing at frequencies between 1.5 and 3.5 MHz. Tissue harmonic
dard, but the methods differ. Similarly, the methods described imaging often improves the image quality, particularly in the
in the literature vary and are often not sufficiently described far field and in large horses, by providing a higher signal-to-
when it comes to technical details, machine settings, imaging noise ratio, better contrast, and higher spatial resolution.
planes, exact anatomic landmarks, and—importantly—tim- The depth of penetration should reach at least 25 to 30 cm
ing of measurements. Reference values for echocardiographc to scan the heart of an adult horse. The image is usually
measurements are often insufficiently defined and are based displayed, by convention, with that part of the heart closest
on individual papers or small studies in selected populations. to the transducer at the top of the screen. Simultaneous
Some representative data are provided in Table 9.6. recording of a surface ECG is required and allows exact tim-
A recent survey showed that despite the large number of ing of flow events and echocardiographic measurements.
publications and the great amount of collective experience Modern echocardiography systems offer digital raw data
among experts, there is hardly anything in equine echocar- storage of still frames and cine loop recordings. This is ex-
diography everybody does entirely the same way when it tremely useful because it reduces the contact time with the
comes to modalities, imaging planes, landmarks, timing, and patient and allows postprocessing and off-line analysis of the
scaling for differences in body mass.597 It will be important in stored data.
the near future to define standard imaging guidelines based on Two imaging modalities, the motion-mode (M-mode) and
expert consensus, better characterize repeatability and repro- two-dimensional (2D, B-mode, or cross-sectional) formats, are
ducibility of echocardiographic methods and measurements, in widespread use. When Doppler studies or contrast echocar-
and provide normal reference intervals for echocardiographic diography are added, blood flow can be detected relative to the
measurements considering differences in breed, size, and body 2D and M-mode images (Box 9.11, Figs. 9.20–9.25; see also
weight. This said, it is important to realize that despite the Fig. 9.5).56,344,590,591
availability of quantitative imaging methods, subjective assess- The M-mode echocardiogram is a single-crystal icepick
ment of recordings is a cornerstone of echocardiography and image of the heart (see Figs. 9.5, 9.20, and 9.23).56,344,590,591 The
must not be neglected. Finally, independent of the methods movement of the cardiac structures (vertical axis) is displayed
used, the findings obtained during echocardiography must be over time along the horizontal axis. The ECG is recorded to
critically assessed in the light of medical history and clinical provide a timing reference, and the depth of the cardiac struc-
findings. tures from the transducer is displayed in centimeters. Visual-
Indications and Clinical Use of Echocardiography in Horses. ization of the characteristic movements of cardiac structures
Echocardiography can be used to identify cardiac disorders, permits the experienced viewer to evaluate and quantify
assess hemodynamic and structural consequences of disease, cardiac anatomy and function. The high sampling rate of
and monitor response to treatment and progression of dis- the M-mode study makes it excellent for visualizing rapidly
ease. Echocardiography is primarily indicated in horses with vibrating structures, such as the oscillating mitral leaflet in
heart murmurs and allows differentiation of physiologic flow aortic regurgitation (see Fig. 9.23D).554
murmurs from pathologic murmurs and assessment of their The two-dimensional echocardiogram (2DE) generates an
clinical relevance. However, there are other clinical situations image by sweeping an ultrasound beam across the heart to pro-
when echocardiography also provides valuable information duce sector frames (see Figs. 9.20–9.22).56,344,590,591 In conven-
tional transthoracic echocardiography, the operator hand-directs
* References 286, 287, 340, 341, 346, 350, 351, 567, 569, 577, 592, 593. the imaging probe to achieve a suitable tomographic plane.
TABLE 9.6 Reference Values of Selected Echocardiographic Measurements in Adult Horses
Normal Values
Measurement Mode BWT (kg)
Timing View Mean ± SD Interval Population N Mean ± SD or Min-Max Ref.
LV STUDY—SHORT-AXIS LINEAR MEASUREMENTS
LVIDd (cm) M-mode 11.2 ± 0.9 (9.9–13.4)a WB Jump/Dress 15 589 ± 47 19
LV internal diameter at end-diastole Right para- 11.6 ± 0.7 WB Dressage 15 602 ± 38 1
sternal 12.1 ± 1.0 WB Jumping 14 587 ± 40 1
short-
11.5 ± 0.7 WB Untrained 15 549 ± 44 1
axis
view— 11.6 ± 1.0 (10.3–12.5)a WB Eventing 5 529 ± 48 16
chordal 11.1 ± 0.9 (9.3–12.9)c WB 31 500§ 20
level (9.9–12.9)d WB 13 550 ± 59 22
12.0 ± 0.9 (9.7–13.4)c WB 30 570 ± 53 23
11.2 ± 0.7 (9.8–12.6)b 30 WB, 1 THB, 1 STB 32 563 ± 49 26
12.6–14.0f TBH (trained, var. levels) 483 446–497 9
11.9 ± 0.7 (10.5–13.4)a THB and THB cross 21 432–648 2
11.3 ± 1.4 (8.0–14.0)a THB and THB cross 18 482 ± 45 3

11.9 ± 0.8 (9.7–13.1)a THB 37 420–617 4
11.5 ± 0.7 (10.3–13.0)a THB (untrained/trained) 8 560 ± 50 7
(10.9–13.6)d THB 7 548 ± 59 22
11.5 ± 0.9 (9.8–13.2)b THB 26 n/a 11
11.5 ± 0.7 (10.1–12.9)b STB (untrained) 8 477–540 5
10.9 ± 0.8 (9.4–12.4)b STB (untrained) 103 441 ± 42 6
12.2 ± 0.8 (10.6–13.8)b STB (trained) 103 481 ± 36 6
11.5 ± 1.1 (10.0–13.3)a STB (untrained) 9 510 ± 37 7
11.7 ± 0.6 (10.8–12.4)a STB (trained) 7 490 ± 33 7
(10.2–13.2)d STB 15 539 ± 31 22
11.8 ± 0.7 (10.4–13.1)b STB (in training) 13 411 ± 10 27
10.5 ± 0.5 (9.6–11.5)b STB (deconditioned) 13 411 ± 10 27
10.7 ± 0.9 (8.9–12.5)b Arabian Endurance 24 423 ± 31 25
Continued
421
422
TABLE 9.6 Reference Values of Selected Echocardiographic Measurements in Adult Horses—cont’d
Normal Values
LVIDs (cm) 6.8 ± 0.9 (5.9–9.2)a WB Jump/Dress 15 589 ± 47 19
LV internal diameter at peak systole 8.2 ± 0.6 WB Dressage 15 602 ± 38 1
8.6 ± 0.8 WB Jumping 14 587 ± 40 1
8.2 ± 0.7 WB Untrained 15 549 ± 44 1
7.4 ± 1.5 (5.9–8.9)a WB Eventing 5 529 ± 48 16
6.7 ± 0.8 (5.0–8.4)c WB 31 500§ 20
(5.5–8.3)d WB 13 550 ± 59 22
6.9 ± 1.1 (4.7–9.1)c WB 30 570 ± 53 23
6.4 ± 0.8 (4.8–8.0)b 30 WB, 1 THB, 1 STB 32 563 ± 49 26
7.5 ± 0.6 (5.8–8.8)a THB 37 420–617 4
(6.6–8.7)d THB 7 548 ± 59 22
7.2 ± 0.7 (5.7–8.9)b THB 26 n/a 11
7.7 ± 0.6 (6.5–8.8)b STB (untrained) 8 477–540 5
7.5 ± 1.2 (5.4–8.8)a STB (untrained) 9 510 ± 37 7
7.5 ± 0.7 (6.9–8.7)a STB (trained) 7 490 ± 33 7
(5.3–8.9)d STB 15 539 ± 31 22
8.1 ± 0.7 (6.7–9.5)b STB (in training) 13 411 ± 10 27
IVSd (cm) 3.2 ± 0.4 (2.6–4.1)a WB Jump/Dress 15 589 ± 47 19
Interventricular septal thickness at 3.5 ± 0.4 WB Dressage 15 602 ± 38 1
end-diastole 3.0 ± 0.3 WB Jumping 14 587 ± 40 1
3.3 ± 0.5 WB Untrained 15 549 ± 44 1
3.4 ± 0.3 (2.9–3.6)a WB Eventing 5 529 ± 48 16
3.0 ± 0.3 (2.3–3.7)c WB 31 500§ 20
(2.7–3.8)d WB 13 550 ± 59 22
3.0 ± 0.3 (2.4–3.5)c WB 30 570 ± 53 23
2.9 ± 0.3 (2.3–3.4)a THB 38 420–617 4
(3.0–3.7)d THB 7 548 ± 59 22
2.6 ± 0.3 (2.0–3.2)b THB 26 n/a 11
2.6 ± 0.1 (2.3–2.8)b STB (untrained) 8 477–540 5
3.1 ± 0.3 (2.4–3.5)a STB (untrained) 9 510 ± 37 7

3.3 ± 0.5 (2.5–3.8)a STB (trained) 7 490 ± 33 7
(2.5–3.8)d STB 15 539 ± 31 22
3.2 ± 0.3 (2.5–3.9)b STB (in training) 13 411 ± 10 27
Continued
423
424
Normal Values
IVSs (cm) 4.4 ± 0.4 (3.6–5.2)a WB Jump/Dress 15 589 ± 47 19
Interventricular septal thickness at 4.3 ± 0.7 WB Dressage 15 602 ± 38 1
peak systole 4.0 ± 0.5 WB Jumping 14 587 ± 40 1
4.0 ± 0.6 WB Untrained 15 549 ± 44 1
4.5 ± 0.7 (3.5–5.2)a WB Eventing 5 529 ± 48 16
4.4 ± 0.4 (3.5–5.2)c WB 31 500§ 20
(4.5–5.2)d WB 13 550 ± 59 22
4.5 ± 0.4 (3.6–5.4)c WB 30 570 ± 53 23
4.2 ± 0.5 (3.2–5.2)a THB 38 420–617 4
(4.0–5.2)d THB 7 548 ± 59 22
4.0 ± 0.3 (3.4–4.5)b THB 26 n/a 11
3.5 ± 0.3 (2.9–4.1)b STB (untrained) 8 477–540 5
4.3 ± 0.4 (3.5–4.9)a STB (untrained) 9 510 ± 37 7
4.4 ± 0.5 (3.4–5.0)a STB (trained) 7 490 ± 33 7
(3.8–5.5)d STB 15 539 ± 31 22
4.3 ± 0.3 (3.7–5.0)b STB (in training) 13 411 ± 10 27
LVFWd (cm) 2.5 ± 0.4 (1.6–3.0)a WB Jump/Dress 15 589 ± 47 19
LV free wall at end-diastole 3.0 ± 0.3 WB Dressage 15 602 ± 38 1
2.6 ± 0.4 WB Jumping 14 587 ± 40 1
2.7 ± 0.6 WB Untrained 15 549 ± 44 1
2.7 ± 0.2 (2.4–2.8)a WB Eventing 5 529 ± 48 16
2.5 ± 0.3 (1.9–3.1)c WB 30 500§ 20
(1.9–2.9)d WB 13 550 ± 59 22
2.6 ± 0.4 (1.8–3.4)c WB 30 570 ± 53 23
2.5 ± 0.3 (1.8–3.1)b 30 WB, 1 THB, 1 STB 32 563 ± 49 26
2.3 ± 0.4 (1.7–3.4)a THB 37 420–617 4
(2.2–2.7)d THB 7 548 ± 59 22
2.0 ± 0.2 (1.6–2.4)b THB 26 n/a 11
2.4 ± 0.1 (2.1–2.7)b STB (untrained) 8 477–540 5
2.3 ± 0.2 (2.0–2.5)a STB (untrained) 9 510 ± 37 7
2.8 ± 0.4 (2.2–3.2)a STB (trained) 7 490 ± 33 7

(1.7–3.1)d STB 15 539 ± 31 22
2.5 ± 0.3 (1.9–3.2)b STB (in training) 13 411 ± 10 27
Continued
425
426
Normal Values
LVFWs (cm) 4.5 ± 0.6 (3.0–5.7)a WB Jump/Dress 15 589 ± 47 19
LV free wall at peak systole 3.6 ± 0.5 WB Dressage 15 602 ± 38 1
3.2 ± 0.5 WB Jumping 14 587 ± 40 1
3.2 ± 0.6 WB Untrained 15 549 ± 44 1
4.4 ± 0.3 (4.1–4.8)a WB Eventing 5 529 ± 48 16
4.4 ± 0.4 (3.7–5.1)c WB 31 500§ 20
(3.5–4.9)d WB 13 550 ± 59 22
4.7 ± 0.5 (3.6–5.8)c WB 30 570 ± 53 23
4.5 ± 0.5 (3.4–5.5)b 30 WB, 1 THB, 1 STB 32 563 ± 49 26
3.9 ± 0.4 (3.0–4.6)a THB 37 420–617 4
(3.9–4.7)d THB 7 548 ± 59 22
3.7 ± 0.4 (3.0–4.2)b THB 26 n/a 11
3.5 ± 0.3 (2.9–4.0)b STB (untrained) 8 477–540 5
3.8 ± 0.4 (3.1–4.4)a STB (untrained) 9 510 ± 37 7
4.2 ± 0.4 (3.7–4.9)a STB (trained) 7 490 ± 33 7
(2.7–4.3)d STB 15 539 ± 31 22
3.7 ± 0.5 (2.7–4.8)b STB (in training) 13 411 ± 10 27
LVIDd/AAD 1.7 ± 0.1 (1.5–1.9)a WB Jump/Dress 15 589 ± 47 19
LVIDd normalized to aortic annular 1.7 ± 0.2 (1.4–2.1)c WB 31 574 ± 58 20
diameter 1.7 ± 0.2 (1.3–2.0)c WB 30 570 ± 53 23
RWTd 0.51 ± 0.07 (0.35–0.63)a WB Jump/Dress 15 589 ± 47 19
Relative LV wall thickness at end- 0.53 ± 0.05 (0.49–0.61)a WB Eventing 5 529 ± 48 16
diastole = (LVFWd + IVSd)/LVIDd 0.51 ± 0.05 (0.40–0.62)c WB 31 574 ± 58 20
(0.41–0.63)d WB 13 550 ± 59 22
0.49 ± 0.06 (0.36–0.62)c WB 29 570 ± 53 23
0.40 ± 0.05 THB (untrained) 7 463 ± 28 8
0.45 ± 0.08 THB (trained) 7 461 ± 22 8
(0.40–0.56)d THB 7 548 ± 59 22
0.43 ± 0.04 (0.35–0.51)b STB (untrained) 8 477–540 5
0.40 ± 0.04 (0.32–0.48)b STB (untrained) 103 441 ± 42 6
0.40 ± 0.04 (0.32–0.48)b STB (trained) 103 481 ± 36 6
0.46 ± 0.02 (0.43–0.50)a STB (untrained) 9 510 ± 37 7
0.53 ± 0.07 (0.42–0.62)a STB (trained) 7 490 ± 33 7
(0.39–0.56)d STB 15 539 ± 31 22
0.5 ± 0.1 Arabian Endurance 24 423 ± 31 25

MWTd (cm) 2.9 ± 0.3 (2.1–3.2)a WB Jump/Dress 15 589 ± 47 19
Mean LV wall thickness at end- 2.9 ± 0.3 (2.3–3.5)b WB Eventing 5 529 ± 48 18
diastole 2.8 ± 0.2 (2.4–3.2)c WB 31 500§ 20
= (LVFWd + IVSd)/2
(2.4–3.2)d WB 13 550 ± 59 22
2.8 ± 0.2 (2.3–3.3)c WB 30 570 ± 53 23
2.4 ± 0.2 THB (untrained) 7 463 ± 28 8
2.7 ± 0.1 THB (trained) 7 461 ± 22 8
(2.7–3.2)d THB 7 548 ± 59 22
2.2 ± 0.2 (1.8–2.6)b STB (untrained) 103 441 ± 42 6
2.4 ± 0.2 (2.1–2.8)b STB (trained) 103 481 ± 36 6
2.7 ± 0.2 (2.2–2.9)a STB (untrained) 9 510 ± 37 7
3.1 ± 0.4 (2.4–3.4)a STB (trained) 6 490 ± 33 7
(2.2–3.5)d STB 15 539 ± 31 22
Continued
427
428
Normal Values
LV Mass (g) 3575 ± 677 (2539–5225)a WB Jump/Dress 15 589 ± 47 19
LV mass 4087 ± 727 (3175–4878)a WB Eventing 5 529 ± 48 16

= 1.04 × [(LVIDd + LVFWd + IVSd)3 (2482–4649)d WB 13 550 ± 59 22
− LVIDd3] − 13.6
3567 ± 490 (2546–4589)c WB 29 570 ± 53 23
(see Ref. 9)
3358–4322f TBH (trained, var. levels) 483 446–497 9
2866 ± 333 THB (untrained) 7 463 ± 28 8
3783 ± 240 THB (trained) 7 461 ± 22 8
(3262–4733)d THB 7 548 ± 59 22
2350 ± 383 (1584–3116)b STB (untrained) 103 441 ± 42 6
3263 ± 478 (2307–4219)b STB (trained) 103 481 ± 36 6
(2100–5477)d STB 15 539 ± 31 22
LV FS (%) 40 ± 5 (32–49)a WB Jump/Dress 15 589 ± 47 19
LV fractional shortening 29 ± 5 WB Dressage 15 602 ± 38 1
= (LVIDd − LVIDs)/LVIDd 29 ± 5 WB Jumping 14 587 ± 40 1
28 ± 5 WB Untrained 15 549 ± 44 1
36 ± 9 (24–46)a WB Eventing 5 529 ± 48 16
40 ± 5 (40–50)c WB 31 574 ± 58 20
(33–46)d WB 13 550 ± 59 22
40 ± 6 (27–54)c WB 30 570 ± 53 23
43 ± 6 (31–55)b 30 WB, 1 THB, 1 STB 32 563 ± 49 26
39 ± 5 (29–47)a THB and THB cross 21 432–648 2
36 ± 4 (26–44)a THB and THB cross 18 482 ± 45 3
37 ± 4 (29–45)a THB 37 420–617 4
40 ± 9 THB (untrained) 7 463 ± 28 8
31 ± 3 THB (trained) 7 461 ± 22 8
39 ± 6 (33–50)a THB (untrained/trained) 8 560 ± 50 7
(32–42)d THB 7 548 ± 59 22
37 ± 4 (30–45)b THB 26 n/a 11
34 ± 5 (24–44)b STB (untrained) 103 441 ± 42 6
31 ± 4 (23–39)b STB (trained) 103 481 ± 36 6
36 ± 6 (29–47)a STB (untrained) 9 510 ± 37 7
35 ± 4 (30–39)a STB (trained) 7 490 ± 33 7
(31–49)d STB 15 539 ± 31 22
31 ± 4 (24–39)b STB (in training) 13 411 ± 10 27
33 ± 4 (24–42)b STB (deconditioned) 13 411 ± 10 27
37 ± 5 (25–49)b Arabian Endurance 24 423 ± 31 25
LV STUDY—SHORT-AXIS AREA MEASUREMENTS
LVIsxAd (cm2) 2DE 102 ± 18 (66–137)b WB Eventing 5 529 ± 48 18
LV internal area at end-diastole Right para- 95 ± 12 (70–119)c WB 28 570 ± 53 23
sternal 94 ± 12 (70–119)b 30 WB, 1 THB, 1 STB 32 563 ± 49 26
short-
97–120f TBH (trained, var. levels) 483 446–497 9
axis
view— 101 ± 11 (81–124)a THB 37 420–617 4
chordal 102 ± 13 (77–127)b THB 26 n/a 11
level 84 ± 9 (67–101)b STB (in training) 13 411 ± 10 27
LVIsxAd/AAD2 2.00 ± 0.35 (1.27–2.73)c WB 29 570 ± 53 23
LVIsxAd normalized to the second
power of aortic annular diameter
LVIsxAs (cm2) 33 ± 11 (12–54)b WB Eventing 5 529 ± 48 18
LV internal area at peak systole 32 ± 8 (15–49)c WB 28 570 ± 53 23
33 ± 8 (18–48)b 30 WB, 1 THB, 1 STB 32 563 ± 49 26
68 ± 10 THB and THB cross 18 482 ± 45 3
41 ± 7 (29–57)a THB 37 420–617 4

38 ± 9 (21–55)b THB 26 n/a 11
37 ± 7 (24–51)b STB (in training) 13 411 ± 10 27
LVsxMyoAd (cm2) 107 ± 9 (89–125)b WB Eventing 5 529 ± 48 18
LV myocardial area at end-diastole 116 ± 9 (97–134)c WB 28 570 ± 53 23
223 ± 15 (193–260)a THB 37 420–617 4
137 ± 10 (113–158)b STB (in training) 13 411 ± 10 27
LVsxMyoAs (cm2) 148 ± 7 (135–161)b WB Eventing 5 529 ± 48 18
LV myocardial area at peak systole 152 ± 11 (129–176)c WB 29 570 ± 53 23
191 ± 17 (157–244)a THB 37 420–617 4
142 ± 12 (118–166)b STB (in training) 13 411 ± 10 27
RWTsxAd 0.44 ± 0.05 (0.34–0.54)b WB Eventing 5 529 ± 48 18
Area-based relative LV wall thickness 0.50 ± 0.06 (0.37–0.63)c WB 30 570 ± 53 23
at end-diastole
= [√(LVEsxAd/π) −
√(LVIsxAd/π)]/√(LVIsxAd/π)
MWTsxAd 2.5 ± 0.1 (2.3–2.7)b WB Eventing 5 529 ± 48 18
Area-based mean LV wall thickness
at end-diastole 2.7 ± 0.2 (2.3–3.2)c WB 30 570 ± 53 23
= √(LVEsxAd/π) − √(LVIsxAd/π)
429
Continued
430
Normal Values
LVsx FAC (%) 69 ± 6 (56–81)b WB Eventing 5 529 ± 48 18
LV fractional area change 67 ± 6 (54–79)c WB 30 570 ± 53 23
= (LVIsxAd − LVIsxAs)/LVIsxAd 65 ± 7 (51–78)b 30 WB, 1 THB, 1 STB 32 563 ± 49 26
60 ± 5 (47–69)a THB 37 420–617 4
63 ± 6 (51–75)b THB 26 n/a 11
LV STUDY—LONG-AXIS AREA MEASUREMENTS AND VOLUME ESTIMATES
LVIAd (cm2) 2DE 159 ± 16 (127–191)b 8 WB, 2 STB 10 541 ± 49 17
LV internal area at end-diastole Right para- 145 ± 20 (106–185)b 30 WB, 1 THB, 1 STB 32 563 ± 49 26
sternal 167 ± 12 (149–197)a WB Jump/Dress 13 589 ± 47 19
long-axis
184 ± 15 (152–216)c WB 29 570 ± 53 23
4-cham-
LVIAd/AAD2 ber view 3.75 ± 0.47 (3.07–4.69)a WB Jump/Dress 13 589 ± 47 19
LV Aread normalized to the second optimized 3.86 ± 0.49 (2.85–4.87)c WB 30 570 ± 53 23
power of aortic annular diameter for the LV
LVIAs (cm2) 76 ± 14 (48–104)b 8 WB, 2 STB 10 541 ± 49 17
LV internal area at peak systole 68 ± 12 (43–93)b 30 WB, 1 THB, 1 STB 32 563 ± 49 26
72 ± 10 (58–102)a WB Jump/Dress 13 589 ± 47 19
81 ± 12 (57–106)c WB 29 570 ± 53 23
LV FAC (%) 57 ± 4 (48–66)a WB Jump/Dress 13 589 ± 47 19
LV fractional area change 55 ± 5 (45–66)c WB 30 570 ± 53 23
= (LVIAd − LVIAs)/LVIAd 53 ± 6 (41–66)b 30 WB, 1 THB, 1 STB 32 563 ± 49 26
LVIVd (cm3) 2DE 1195 ± 52 (1091–1299)b 8 WB, 2 STB 10 541 ± 49 17
LV internal volume at end-diastole Right para- 1288 ± 229 (829–1746)b WB Eventing 5 529 ± 48 18
sternal 1283 ± 176 (1041–1729)a WB Jump/Dress 13 589 ± 47 19
long-axis
1475 ± 201 (1057–1893)c WB 29 570 ± 53 23
4-cham-
ber view 1108 ± 134 (840–1376)b Arabian Endurance 26 423 ± 31 25
LVIVd/AAD3 optimized 4.30 ± 0.75 (3.26–5.58)a WB Jump/Dress 13 589 ± 47 19
LVIVd normalized to the third power for the LV 4.50 ± 0.89 (2.65–6.36)c WB 30 570 ± 53 23
of aortic annular diameter Simpson’s
LVIVs (cm3) method 318 ± 101 (116–520)b 8 WB, 2 STB 10 541 ± 49 17
LV internal volume at peak systole of disks, 337 ± 87 (162–511)b WB Eventing 5 529 ± 48 18
single
352 ± 86 (278–615)a WB Jump/Dress 13 589 ± 47 19
plane
412 ± 82 (241–582)c WB 28 570 ± 53 23
LV EF (%) 68 ± 2 (64–72)b 8 WB, 2 STB 10 541 ± 49 17
LV ejection fraction 74 ± 4 (67–81)b WB Eventing 5 529 ± 48 18
= (LVIVd − LVIVs)/LVIVd 73 ± 4 (64–79)a WB Jump/Dress 13 589 ± 47 19
71 ± 5 (61–81)c WB 30 570 ± 53 23

LV SV (mL) 838 ± 123 (592–1084)b 8 WB, 2 STB 10 541 ± 49 17
LV stroke volume = LVIVd − LVIVs 951 ± 159 (633–1269)b WB Eventing 5 529 ± 48 18
931 ± 120 (711–1139)a WB Jump/Dress 13 589 ± 47 19
1065 ± 139 (774–1356)c WB 28 570 ± 53 23
CO (L) 32.9 ± 3.2 (26.5–39.3)b WB Eventing 5 529 ± 48 18
Cardiac output 40.0 ± 11.2 (25.2–59.3)a WB Jump/Dress 13 589 ± 47 19
= (LVIVd − LVIVs) × HR 41.8 ± 7.9 (25.1–58.4)c WB 25 570 ± 53 23
Continued
431
432
Normal Values
Timing View Mean ± SD Interval Modeº Population N Mean ± SD or Min-Max Ref.
LV STUDY—SYSTOLIC TIME INTERVALS
LVPEP (msec) Refs. 11, 15, 22, 27: (37–61)d MM WB 8 550 ± 59 22

Preejection period M-mode 76 ± 18 (40–112)b MM THB and THB cross 24 n/a 11
Ref. 11: = time (R–O) Right parasternal 75 ± 18 (40–110)a PWD THB and THB cross 40 428–648 12
R—peak of the electrocardio- short-axis view—
70 ± 10 (50–90)b PWD THB 7 490–600 13
graphic R wave aortic valve level
O—point at which aortic valve Refs. 12, 13, 15: 71 ± 10 (50–90)a MM THB and THB cross 112 308–480 14
fully opened PWD 68 ± 9 (58–88)a PWD THB and THB cross 112 308–480 14
Others: = time (Q—valve Left-parasternal (52–104)d MM THB 4 548 ± 59 22
opening) or time (Q—onset long-axis view— (50–110)d MM STB 4 539 ± 31 22
flow) aortic outflow MM
44 ± 13 STB 13 411 ± 36 15
Q—Onset of electrocardio- Ref. 14:
35 ± 6 PWD STB 13 411 ± 36 15
graphic Q wave M-mode and PWD
44 ± 12 MM STB (in training) 13 411 ± 10 27
Left-parasternal
75 ± 7 MM STB (deconditioned) 13 411 ± 10 27
LVET (msec) (388–532)d MM WB 8 550 ± 59 22
Ejection time 407 ± 30 (347–467)b MM THB and THB cross 24 n/a 11
Ref. 11: 467 ± 31 (410–550)a PWD THB and THB cross 40 428–648 12
= time (O–C)
480 ± 19 (442–518)b PWD THB 7 490–600 13
O—point at which aortic valve
fully opened 532 ± 97 (550–790)a MM THB and THB cross 112 308–480 14
C—closure point 527 ± 76 (400–700)a PWD THB and THB cross 112 308–480 14
Others: (458–538)d MM THB 4 548 ± 59 22
= time (valve opening-closing) (386–547)d MM STB 4 539 ± 31 22
or time (onset–end of flow) MM
448 ± 16 STB 13 411 ± 36 15
467 ± 25 PWD STB 15 411 ± 36 15
448 ± 14 MM STB (in training) 13 411 ± 10 27
432 ± 17 MM STB (deconditioned) 13 411 ± 10 27
LVPEP/LVET (0.07–0.13)d MM WB 8 550 ± 59 22
LVPEP:LVET ratio 0.19 ± 0.04 (0.11–0.27)b MM THB and THB cross 24 n/a 11
0.14 ± 0.03 (0.09–0.24)a MM THB and THB cross 112 308–480 14
0.13 ± 0.01 (0.09–0.31)a PWD THB and THB cross 112 308–480 14
(0.10–0.23)d MM THB 4 548 ± 59 22
(0.10–0.29)d MM STB 4 539 ± 31 22
0.10 ± 0.03 MM STB 13 411 ± 36 15
0.08 ± 0.01 PWD STB 13 411 ± 36 15
0.10 ± 0.03 MM STB (in training) 13 411 ± 10 27
0.17 ± 0.00 MM STB (deconditioned) 13 411 ± 10 27
LV STUDY—TISSUE DOPPLER IMAGING
PEPm (msec) PW TDI 96 ± 15 (72–123)a WB 14 589 ± 47 19
Preejection period Right parasternal short-
axis view—chordal
level—LV free wall (radial
motion)
121 ± 14 (96–149)e WB 30 570 ± 53 21
127 ± 25 STB, THB 6 517–606 24
IVCTm (msec) 88 ± 18 (58–123)a WB 14 589 ± 47 19
Isovolumic contraction 87 ± 16 (65–107)e WB 30 570 ± 53 21
time 91 ± 25 STB, THB 5 517–606 24
ETm (msec) 420 ± 28 (365–482)a WB 14 589 ± 47 19
Ejection time 421 ± 25 (374–475)e WB 30 570 ± 53 21
404 ± 19 STB, THB 6 517–606 24
PEPm/ETm 0.23 ± 0.03 (0.17–0.29)a WB 14 589 ± 47 19
PEPm:ETm ratio 0.29 ± 0.03 (0.24–0.36)e WB 30 570 ± 53 21
0.32 ± 0.07 STB, THB 6 517–606 24
IVCTm/ETm 0.21 ± 0.04 (0.15–0.28)a WB 14 589 ± 47 19

IVCTm:ETm ratio 0.21 ± 0.03 (0.15–0.26)e WB 30 570 ± 53 21
0.23 ± 0.07 STB, THB 5 517–606 24
IVRTm (msec) 60 ± 19 (29–92)a WB 14 589 ± 47 19
Isovolumic relaxation time 52 ± 15 (36–90)e WB 30 570 ± 53 21
48 ± 17 STB, THB 6 517–606 24
IMPm 0.35 ± 0.07 (0.24–0.47)a WB 14 589 ± 47 19
Index of myocardial perfor- 0.33 ± 0.05 (0.25–0.42)e WB 30 570 ± 53 21
mance (Tei) 0.35 ± 0.09 STB, THB 5 517–606 24
S1 (cm/sec) 9±2 (5–15)a WB 14 589 ± 47 19
Wall motion velocity during 9±3 (6–18)e WB 30 570 ± 53 21
isovolumic contraction 10 ± 1 STB, THB 5 517–606 24
Sm (cm/sec) 12 ± 2 (10–14)a WB 14 589 ± 47 19
Wall motion velocity during 12 ± 1 (10–15)e WB 30 570 ± 53 21
LV ejection 12 ± 2 STB, THB 6 517–606 24
E1 (cm/sec) 7±2 (4–10)a WB 14 589 ± 47 19
Wall motion velocity during 8±2 (4–13)e WB 30 570 ± 53 21
isovolumic relaxation 7±1 STB, THB 6 517–606 24
Continued
433
434
Normal Values

Em (cm/sec) 33 ± 6 (25–44)a WB 14 589 ± 47 19
Wall motion velocity during 33 ± 4 (24–41)c WB 28 574 ± 58 20
early diastole (passive 35 ± 6 (27–45)e WB 30 570 ± 53 21
filling)
29 ± 3 STB, THB 6 517–606 24
Am (cm/sec) 11 ± 3 (4–18)a WB 14 589 ± 47 19
Wall motion velocity dur- 11 ± 2 (7–14)c WB 28 574 ± 58 20
ing late diastole (atrial 12 ± 3 (8–20)e WB 30 570 ± 53 21
contraction)
10 ± 2 STB, THB 6 517–606 24
Em/Am 3.4 ± 1.4 (1.6–7.1)a WB 14 589 ± 47 19
Em:Am ratio 3.1 ± 0.8 (1.4–4.7)c WB 28 574 ± 58 20
3.1 ± 0.8 (2.0–4.6)e WB 30 570 ± 53 21
3.0 ± 0.8 STB, THB 6 517–606 24
LA STUDY—LINEAR AND AREA MEASUREMENTS
LAllxDmin (cm) 2DE 11.0 ± 0.8 (9.4–12.3)a THB and THB cross 18 482 ± 45 3
LA diameter at end- Left parasternal long-axis 12.8 ± 0.8 (11.3–14.5)a THB 36 420–617 4
diastole view 12.4 ± 0.7 (10.0–13.8)b THB 26 n/a 11
Midatrium
max. 13.5 THB and STB n/a n/a 10
max. 14.0 Larger horses n/a n/a 10
LAllxDmax (cm) 13.6 ± 1.1 (11.6–14.6)a WB Jump/Dress 15 589 ± 47 19
LA diameter at end-systole 13.1 ± 0.5 (12.7–13.6)a WB Eventing 5 529 ± 48 16
12.9 ± 0.5 (11.8–14.0)c WB 31 500§ 20
12.9 ± 0.8 (11.2–14.5)a THB 28 420–617 4
LADmax (cm) 2DE 12.3 ± 0.7 (10.9–13.5)a WB Jump/Dress 15 589 ± 47 19
LA diameter at end-systole Right parasternal long- 12.7 ± 0.9 (11.4–13.8)a WB Eventing 5 529 ± 48 16
(before opening of mitral axis 4-chamber view, 11.9 ± 0.7 (10.5–13.2)c WB 31 500§ 20
valve) optimized for LA
12.7 ± 0.7 (11.4–14.1)c WB 29 570 ± 53 23
Midatrium
max = end-systole (before
opening of mitral valve) 12.1 ± 0.9 (10.8–13.7)a STB (untrained, old) 9 510 ± 37 7
a = onset of atrial 12.4 ± 1.4 (10.4–13.8)a STB (trained, young) 5 490 ± 33 7
contraction (P wave) 11.3 ± 0.8 (9.7–12.9)b Arabian Endurance 21 423 ± 31 25
min = end-diastole
(closure of mitral valve)
LADmax/AAD 1.8 ± 0.1 (1.7–2.0)a WB Jump/Dress 15 589 ± 47 19
LADmax normalized to aor- 1.9 ± 0.2 (1.7–2.1)a WB Eventing 5 529 ± 48 16
tic annular diameter 1.9 ± 0.1 (1.6–2.1)c WB 31 574 ± 58 20
1.8 ± 0.1 (1.6–2.1)c WB 29 570 ± 53 23
1.9 ± 0.2 (1.7–2.1)a STB (untrained, old) 9 510 ± 37 7
1.9 ± 0.2 (1.6–2.1)a STB (trained, young) 5 490 ± 33 7
LADmax/LVIDd 1.1 ± 0.1 (1.0–1.3)a WB Jump/Dress 15 589 ± 47 19
LADmax:LVIDd ratio 1.1 ± 0.1 (0.9–1.3)c WB 31 574 ± 58 20
1.1 ± 0.1 (0.9–1.3)c WB 30 570 ± 53 23
LAAmax (cm2) 102.8 ± 8.5 (90.6–117.4)a WB Jump/Dress 15 589 ± 47 19
Left-atrial area at end- 103.5 ± 13.4 (82.1–117.6)a WB Eventing 5 529 ± 48 16
systole (before opening 92.8 ± 5.0 (82.3–103.2)c WB 31 500§ 20
of mitral valve)
109.7 ± 7.1 (94.7–124.6)c WB 29 570 ± 53 23

LAAmax/AAD2 2.7 ± 0.4 (2.2–3.4)a WB Jump/Dress 15 589 ± 47 19
LAAmax normalized to the 2.6 ± 0.4 (2.1–3.1)a WB Eventing 5 529 ± 48 16
second power of aortic 2.3 ± 0.3 (1.7–2.8)c WB 30 574 ± 58 20
annular diameter
2.3 ± 0.2 (1.8–2.8)c WB 29 570 ± 53 23
LAAmax/LVIAd 0.61 ± 0.05 (0.53–0.70)a WB Jump/Dress 15 589 ± 47 19
LAAmax:LVIAd ratio 0.59 ± 0.06 (0.47–0.72)c WB 30 570 ± 53 23
Passive LA FAC (%) 25 ± 5 (15–32)a WB Jump/Dress 15 589 ± 47 19
Passive LA fractional area 24 ± 5 (18–30)a WB Eventing 5 529 ± 48 16
change = (LAAmax − 23 ± 5 (13–33)c WB 31 574 ± 58 20
LAAa)/LAAmax
27 ± 5 (17–32)a STB (untrained, old) 9 510 ± 37 7
20 ± 5 (11–24)a STB (trained, young) 5 490 ± 33 7
Continued
435
436
Normal Values
Active LA FAC (%) 18 ± 7 (10–29)a WB Jump/Dress 15 589 ± 47 19
Active LA fractional area 15 ± 5 (9–21)a WB Eventing 5 529 ± 48 16
change = (LAAa − 20 ± 7 (6–33)c WB 31 574 ± 58 20

LAAmin)/LAAa
Total LA FAC (%) 39 ± 4 (33–48)a WB Jump/Dress 15 589 ± 47 19
Total LA fractional area 35 ± 5 (29–42) WB Eventing 5 529 ± 48 16
change = (LAAmax − 38 ± 3 (35–43)a THB (untrained/trained) 7 560 ± 50 7
LAAmin)/LAAmax
Active:total LA AC 0.35 ± 0.13 (0.18–0.60)a WB Jump/Dress 15 589 ± 47 19
Ratio of active to total LA 0.33 ± 0.11 (0.17–0.48)a WB Eventing 5 529 ± 48 16
area change 0.39 ± 0.12 (0.13–0.65)c WB 31 574 ± 58 20
LA RI (%) 64 ± 12 (48–92)a WB Jump/Dress 15 589 ± 47 19
LA reservoir index 55 ± 11 (40–72)a WB Eventing 5 529 ± 48 16
= (LAAmax − LAAmin)/LAAmin 62 ± 11 (39–86)c WB 30 574 ± 58 20
72 ± 12 (55–96)a STB (untrained, old) 9 7
47 ± 4 (44–53)a STB (trained, young) 5 7
LAsxAmax (cm2) 2DE 123.6 ± 19.3 (92.4–149.5)a WB Jump/Dress 15 589 ± 47 19
LA area at end-systole Right parasternal short- 113.4 ± 18.1 (95.0–138.8)a WB Eventing 5 529 ± 48 16
(closure of aortic valve) axis view—aortic level, 108.8 ± 12.2 (83.5–134.1)c WB 31 500§ 20
optimized for the left
atrium and left-atrial
appendage 106.2 ± 17.5 (65.5–125.0)a STB (untrained, old) 9 510 ± 37 7
LAsxAmax/AosxA 2.6 ± 0.3 (2.1–3.0)a WB Jump/Dress 15 589 ± 47 19
LAsxAmax normalized to 2.3 ± 0.3 (2.1–2.7)a WB Eventing 5 529 ± 48 16
aortic area 2.5 ± 0.3 (2.0–3.2)c WB 31 574 ± 58 20
GREAT VESSELS
AAD (cm) 2DE 6.8 ± 0.5 (6.1–8.0)a WB Jump/Dress 15 589 ± 47 19
Aortic annular diameter Right parasternal long-axis 6.7 ± 0.6 (6.0–7.6)a WB Eventing 5 529 ± 48 16
during systole LVOT view 6.4 ± 0.4 (5.6–7.2)c WB 31 500§ 20
6.9 ± 0.4 (6.1–7.7)c WB 29 570 ± 53 23
6.4 ± 0.5 (5.4–6.9)a STB (untrained) 9 510 ± 37 7
6.5 ± 0.2 (6.2–6.8)a STB (trained) 5 490 ± 33 7
AoD (cm) 8.0 ± 0.7 (7.1–9.0)a WB Jump/Dress 15 589 ± 47 19
Diameter of the aortic 7.8 ± 0.7 (7.2–9.0)a WB Eventing 5 529 ± 48 16
sinus (sinus Valsalva) at 7.6 ± 0.5 (6.5–8.7)c WB 31 500§ 20
end-diastole
8.7 ± 0.5 (7.8–9.9)a THB 37 420–617 4
8.3 ± 0.7 (6.9–9.7)b THB 25 n/a 11
7.4 ± 0.7 (6.2–8.4)a STB (untrained) 9 510 ± 37 7
7.5 ± 0.6 (7.2–8.5)a STB (trained) 5 490 ± 33 7
7.7 ± 0.3 (7.1–8.3)b STB (in training) 13 411 ± 10 27

AosxA (cm2) 2DE 44.8 ± 5.5 (33.5–56.2)c WB 31 500§ 20
Internal aortic area at end- Right parasternal short-
systole (closure of aortic axis view—aortic level
valve)
PAD (cm) 2DE 6.9 ± 0.5 (6.0–7.7)a WB Jump/Dress 15 589 ± 47 19
Diameter of the pulmonary Right parasternal long-axis 6.6 ± 0.6 (5.9–7.4)a WB Eventing 5 529 ± 48 16
sinus at end-diastole RVOT view 6.5 ± 0.4 (5.6–7.4)c WB 30 500§ 20
6.1 ± 0.5 (5.2–6.9)a THB 37 420–617 4
6.1 ± 0.4 (5.6–6.8)a STB (untrained) 9 510 ± 37 7
6.5 ± 0.5 (5.9–6.9)a STB (trained) 5 490 ± 33 7
PADann (cm) 2DE 5.5 ± 0.3 (4.9–6.1)b STB (untrained) 8 477–540 5
Annular diameter of the Right parasternal long-axis
pulmonary artery (at RVOT view
insertion of the PV) in late
systole
Continued
437
438
Normal Values
AoD/PAD 2DE 1.2 ± 0.1 (1.0–1.3)a WB Jump/Dress 15 589 ± 47 19
AoD:PAD ratio Right parasternal long-axis 1.2 ± 0.1 (1.0–1.3)a WB Eventing 5 529 ± 48 16
views 1.2 ± 0.1 (1.0–1.4)c WB 31 574 ± 58 20
1.2 ± 0.1 (1.0––1.5)a STB (untrained) 9 510 ± 37 7
1.2 ± 0.1 (1.1–1.4)a STB (trained) 5 490 ± 33 7
AoD/PADsx 2DE 1.6 ± 0.2 (1.4–1.8)a WB Jump/Dress 15 589 ± 47 19
Ratio of AoD to short-axis Right-parasternal long-axis 1.5 ± 0.1 (1.3–1.8)c WB 31 574 ± 58 20
PAD measured in same LVOT view
LVOT imaging plane at

end-diastole
Reference intervals:
arange (min-max)
b(mean − 2SD) − (mean + 2SD)
cLower and upper limit reference interval (Reference Value Advisor v2.1, National Veterinary School, Toulouse, France; using standard methods)
d2.5th–97.5th percentile
e5th–95th percentile
fRange of means
BWT, Body weight; 2DE, two-dimensional echocardiography; LA, left atrium; LV, left ventricle; MM, M-mode; N, number of horses; PWD, pulsed-wave Doppler; PW TDI, pulsed-wave tissue Doppler imaging; STB,
Standardbred; THB, Thoroughbred; WB, Warmblood.
§Values are allometrically scaled to a body weight of 500 kg.
Note: This summary does not provide a systematic review of the current literature. It is intended to serve as a general guide for assessment of some of the most commonly used echocardiographic indices of cardiac
dimensions and cardiac function in horses. Individual measurements may differ depending on echocardiographic techniques and breed, age, body weight, and athletic condition of the animal.
References:
1. Stadler P, Rewel A, Deegen E: M-mode echocardiography in dressage- and show-jumping horses of class “S” and in untrained horses. J Vet Med A 1993;40:292-306.
2. Long K, Bonagura JD, Darke PGG: Standardized imaging technique for guided M-mode and Doppler echocardiography in the horse. Equine Vet J 1992;24:226-235.
3. Voros K, Holmes JR, Gibbs C: Measurement of cardiac dimensions with two dimensional echocardiography in the living horse. Equine Vet J 1991;23:461-465.
4. Patteson MW, Gibbs C, Wotton PR, et al: Echocardiographic measurements of cardiac dimensions and indices of cardiac function in normal adult Thoroughbred horses. Equine Vet J 1995;Suppl 19:18-27.
5. Buhl R, Ersboll AK, Eriksen L, et al: Sources and magnitude of variation of echocardiographic measurements in normal standardbred horses. Vet Radiol Ultrasound 2004;45:505-512.
6. Buhl R, Ersboll AK, Eriksen L, et al: Changes over time in echocardiographic measurements in young Standardbred racehorses undergoing training and racing and association with racing performance. J Am
Vet Med Assoc 2005;226:1881-1887.
7. Schwarzwald CC: Unpublished data. 2006. Techniques see: Schwarzwald CC, Schober KE, Bonagura JD. Methods and reliability of echocardiographic assessment of left atrial size and mechanical function in
horses. Am J Vet Res 2007;68:735-747.
8. Young LE: Cardiac responses to training in 2-year-old thoroughbreds: an echocardiographic study. Equine Vet J Suppl 1999;30:195-198.
9. Young LE, Rogers K, Wood JL: Left ventricular size and systolic function in Thoroughbred racehorses and their relationships to race performance. J Appl Physiol 2005; 99:1278-1285.
10. Reef VB. Cardiovascular ultrasonography. In: Reef VB, ed. Equine diagnostic ultrasound, 1st ed. WB Saunders, Philadelphia, 1998:215-272.
11. Patteson MW, Gibbs C, Wotton PR, et al: Effects of sedation with detomidine hydrochloride on echocardiographic measurements of cardiac dimensions and indices of cardiac function in horses. Equine Vet J
Suppl 1995:33-37.
12. Blissitt KJ, Bonagura JD: Pulsed wave Doppler echocardiography in normal horses. Equine Vet J Suppl 1995:38-46.
13. Young LE, Scott GR: Measurement of cardiac function by transthoracic echocardiography: day to day variability and repeatability in normal Thoroughbred horses. Equine Vet J 1998;30:117-122.
14. Lightowler C, Piccione G, Fazio F, et al: Systolic time intervals assessed by 2-D echocardiography and spectral Doppler in the horse. Animal Science Journal 2003;74:505-510.
15. Kriz NG, Rose RJ: Repeatability of standard transthoracic echocardiographic measurements in horses. Aust Vet J 2002;80:362-370.
16. Schwarzwald CC, et al: Unpublished data, 2008. Techniques see: Schefer KD, Bitschnau C, Weishaupt MA, Schwarzwald CC. Quantitative analysis of stress echocardiograms in healthy horses with 2-dimen-
sional (2D) echocardiography, anatomical M-mode, tissue Doppler imaging, and 2D Speckle Tracking. J Vet Int Med 2010;24:918-931.
17. Gehlen H, Marnette S, Stadler P: The influence of adrenaline on echocardiographic parameters of left ventricular function in the horse. Equine and Comparative Exercise Physiology 2005;2:89-96.
18. Schefer KD, Bitschnau C, Weishaupt MA, Schwarzwald CC. Quantitative analysis of stress echocardiograms in healthy horses with 2-dimensional (2D) echocardiography, anatomical M-mode, tissue Doppler
imaging, and 2D Speckle Tracking. J Vet Int Med 2010;24:918-931.
19. Trachsel DS, Schwarzwald CC, Bitschnau C, et al: Atrial natriuretic peptide and cardiac troponin I concentrations in healthy WB horses and in WB horses with mitral regurgitation at rest and after exercise. J Vet
Cardio 2013;15:105-121 (supplementary unpublished data included).
20. Huesler IM, Mitchell KM, Schwarzwald CC: Echocardiographic assessment of left atrial size and function in WB horses: reference intervals, allometric scaling and agreement of different echocardiographic vari-
ables. J Vet Intern Med 2016;30:1241-1252.
21. Koenig TR, Mitchell KM, Schwarzwald CC: Echocardiographic assessment of left ventricular function in healthy horses and in horses with heart disease using pulsed-wave tissue Doppler imaging. J Vet Intern
Med 2016, submitted.
22. Grenacher PA, Schwarzwald CC: Assessment of left ventricular size and function in horses using anatomical M-mode echocardiography. J Vet Cardio 2010;12:111-121.
23. Berthoud DJ, Schwarzwald CC: Echocardiographic assessment of left ventricular size and systolic function in horses using linear measurements and area-based volume estimates. 2016, in progress.
24. Schwarzwald CC, Bonagura JD, Schober KE: Methods and reliability of tissue Doppler imaging for assessment of left ventricular radial wall motion in horses. J Vet Intern Med 2009;23:643-652.

25. Flethoj M, Schwarzwald CC, Haugaard MM, et al: Left ventricular function after prolonged exercise in equine endurance athletes. J Vet Intern Med 2016;30:1260-1269.
26. Ven S, Decloedt A, Van Der Vekens N, et al: Assessing aortic regurgitation severity from 2D, M-mode and pulsed wave Doppler echocardiographic measurements in horses. Vet J 2016;210:34-38.
27. Kriz NG, Hodgson DR, Rose RJ: Changes in cardiac dimensions and indices of cardiac function during deconditioning in horses. Am J Vet Res 2000;61:1553-1560.
439
detailed analysis. 2D echocardiography allows assessment of

BOX 9.10
Indications for Echocardiography cardiac anatomy, detection of macroscopic structural lesions,
subjective evaluation and measurement of chamber and ves-
EVALUATION OF HEART MURMURS sel dimensions, and evaluation of left atrial and left ventricu-
• Previously diagnosed “functional” murmur that is lar function.
louder on serial examinationsa Contrast echocardiography,599 whereby saline is used to
• Grade 3–6/6 left-sided murmur compatible with mitral delineate the path of blood flow, is especially useful for the
regurgitation (MR) or aortic regurgitation (AR)a detection of right-to-left shunts in foals, including patent fora-
• Grade 4–6/6 right-sided systolic murmur compatible men ovale (see Fig. 9.24D).
with tricuspid regurgitation (TR)a Doppler echocardiography relies on the Doppler princi-
• Suspected ventricular septal defect (VSD) or other ple to measure the direction and velocity of red blood cells
congenital heart lesion (RBCs) moving through the heart (see Figs. 9.5 and 9.25).*
• Continuous or combined systolic-diastolic murmurs In Doppler echocardiography, a portion of the ultrasound
• Murmur associated with poor performance emitted by the transducer strikes moving RBCs. These tar-
• Murmur detected on prepurchase examination gets cause ultrasound to be reflected back to the transducer.
Because the RBCs constitute a moving “source” of (reflected)
EVALUATION OF ARRHYTHMIAS ultrasound, the returning sound waves attain a frequency
• Clinically important arrhythmias, whether a murmur is that is slightly different from that originally transmitted (the
present or not “carrier frequency”). When the echocardiograph unit records
the Doppler frequency shift, calculation of RBC velocity and
OTHER INDICATIONS direction relative to the transducer is possible. The informa-
• Suspected myocardial disease (unexplained tachycardia, tion is displayed as a Doppler spectrum showing time along
supraventricular or ventricular ectopy, increased cardiac the horizontal axis, flow direction relative to the transducer as
troponin I concentrations) above (toward) or below (away from) a zero baseline, and cal-
• Unexplained exercise intolerance, poor performance, culated RBC velocity along the vertical axis. Disturbed flow, as
collapse, or episodic weakness might be recorded across a regurgitant orifice or ventricular
• Fever of unknown origin or specific suspicion for septal defect, results in a high-velocity and broadened veloc-
endocarditis or pericarditis ity spectrum. With all Doppler modalities, parallel alignment
• Muffled heart sounds (to detect effusion) with the direction movement of the target is crucial, because
• Suspicion of CHF excessive angle of interrogation (i.e., greater than 20 degrees)
• Severe respiratory disease (to detect pulmonary hyper- will lead to an underestimation of velocities. Therefore tech-
tension) nically, velocities can only be accurately measured for blood
aBecause
flowing parallel to the ultrasound beam (i.e., toward or away
of the high prevalence of heart murmurs in the healthy horse
population, an echocardiographic examination is not strictly recommended
from the transducer) but not for blood moving perpendicular
in all horses with murmurs. Acknowledging the fact that murmur grade to the ultrasound beam. Most echocardiography units offer
might not be directly related to clinical relevance or severity of disease, the digital angle correction that can be applied live or during post-
current recommendations are based on murmur grades, on the assumption processing to mathematically correct the measured velocities.
that murmurs of grade 1–2/6 are less likely to be clinically relevant. In case However, this function should not be applied for Doppler
of doubt, an echocardiogram is always indicated in horses with murmurs.
measurements of intracardiac blood flow because the exact
true direction of flow in the cardiac chambers is unknown and
cannot be derived from the Doppler signals, and angle correc-
The pie-shaped image obtained has both depth and breadth but tion may lead to overestimation of true velocity and severity
has no significant thickness. Accordingly, different image planes of the lesion.
must be used to interrogate the three-dimensional heart. These Pulsed-wave (PW) Doppler methods measure direction and
imaging planes are designated long-axis (sagittal), short-axis velocity of RBCs within a discrete area of the heart or circula-
(coronal), apical (when the transducer is near the left apex), and tion, which can be determined by the observer when placing
angled (hybrid) views. Because of anatomic restrictions, apical the sample volume within the cardiac chambers or vessels.
images are difficult or impossible to obtain except in foals. By Color-coded Doppler imaging is a more refined example of
convention, in long-axis and short-axis recordings, the dorsal pulsed-wave technology whereby flow toward the transducer
regions of the heart (atria, heart base) and the cranial regions of is coded in red and flow away is represented in blue. Calcu-
the heart (right ventricular outflow tract), respectively, are dis- lated velocity is displayed in relative shades of these colors,
played to the right of the screen. and green or yellow are added to the flow mapping to identify
The 2D field is constantly updated to visualize cardiac “turbulence.” Color coding permits superimposition of flow
motion in real time, and this is done at typical sampling information onto the 2D or M-mode image (see Fig. 9.25).
rates (frame rates) of 20 to 40 frames/sec, with the update Although there are substantial technical challenges in terms of
rate inversely related to penetration depth and angle of penetration and frame rate, color Doppler imaging is useful in
field. Fully digital echocardiographs can display much faster horses because a large area of the heart can be screened for flow
frame rates, often exceeding 60/sec. Newer applications such disturbances; this is also called “color flow mapping” (CFM).
as 2DE-based anatomic M-mode345 or 2D speckle track- For example, it is much easier to find a jet of mitral regurgi-
ing161,168,346-348 demand a frame rate between 40 and 90 Hz tation using color Doppler imaging than with other Doppler
to achieve sufficient temporal resolution. Human interpreta-
tion is generally limited to 32 frames/sec, so that recordings * References 56, 71, 208, 279-281, 285, 297, 311, 313, 340, 344, 391, 558, 560,
made at higher frame rates require slow motion playback for 563, 590, 591, 600-602.
BOX 9.11
Interpretation of Echocardiographic and Doppler Studies
GENERAL PRINCIPLES OF INTERPRETATION • Examine the atrioventricular groove for dilated vascular
• Evaluate the electrocardiogram relative to cardiac motion structure: Rule out dilated coronary sinus and left cranial
and cardiac rhythm disturbances; arrhythmias can alter vena cava.
measures of ventricular function, cause aortic valvular • 2D echocardiography and tissue Doppler can be used to
regurgitation, and alter flow and pressure gradients. evaluate atrial wall motion and function.
• Remember that persistent tachyarrhythmias can lead to
reversible form of dilated cardiomyopathy (tachycardia- MITRAL VALVE
induced cardiomyopathy). • Identify two valve leaflets and cusps in long- and short-axis
• Determine the initial image planes needed for examination planes; if evidence of mitral regurgitation, also examine
based on clinical examination and your standard operating mitral valve from left caudal imaging windows in two or
procedures. more imaging planes.
• Identify the general situs of the heart and cardiac struc- • Observe motion during cardiac cycle by 2D and M-mode
tures; identify the atria, ventricles, cardiac septa, great echocardiogram.
vessels, and cardiac valves. • Examine the support apparatus (chordae tendineae,
• Note any dilation, attenuation, or absence of the aorta or papillary muscles).
pulmonary artery, and identify their origins and relationships • Increased valve echogenicity: Rule out degenerative
to the atrioventricular valves and to the ventricles. thickening, valvulitis, vegetation (infective endocarditis),
• Note the presence of unanticipated or lack of expected malformation (rare).
structures. • Cleft or common septal leaflet: Rule out endocardial
• Identify pleural effusion. cushion defect/primum atrial septal defect (rare
• Rule out extrapericardial mass lesions of the lung or defects).
thorax. • M-mode: Reduced diastolic (E-F) slope suggests
decreased transvalvular flow.
PERICARDIUM AND PERICARDIAL SPACE • Lack of diastolic separation or increased mitral E point to
• Rule out pericardial effusion and pericardial mass lesion. septal distance: Rule out aortic regurgitation (regurgitant
• Mixed echoic effusions or shaggy tags may indicate highly jet impinging on the valve), left ventricular dilation with
cellular or inflammatory effusate. left ventricular failure (reduced transmitral flow), or mitral
• In pericardial effusion: Identify diastolic collapse of the stenosis/tethering (rare defects or acquired from
right atrium or right ventricle indicating cardiac tamponade endocarditis).
or a large bilateral pleural effusion; protracted collapse • Prolapse of mitral leaflet into left atrium: Rule out
or ventricular or atrial inversion are more reliable signs of degenerative disease, elongated or ruptured chordae
tamponade. Exuberant swinging of heart may be seen. tendineae, lesion of papillary muscle.
• In pericardial effusion: Identify any heart-related lesions • Flail leaflet: Rule out ruptured chordae tendineae or
using multiple complementary planes. avulsion of papillary muscle.
• If there is concern about constrictive pericardial disease, • Double line of mitral closure (mobile): Rule out ruptured
evaluate the motion of the ventricular septum (for accen- chordae tendineae (flail leaflet).
tuated flutter or ‘septal bounce’), and perform Doppler • Diastolic mitral valve fluttering: Rule out aortic regurgitation.
studies of the left and right sides of the ventricular inlets; • Systolic mitral fluttering: Rule out mitral regurgitation
large E waves with abrupt termination of filling may be ob- (musical).
served; evaluate the effects of ventilation because marked • Chaotic valve motion: Rule out arrhythmia (atrial flut-
variation may be observed in E waves; tissue Doppler may ter, premature ventricular complexes), ruptured chordae
also be instructive in cases of constrictive disease. tendineae.
• Premature (diastolic) closure: Rule out severe semilunar
LEFT ATRIUM, PULMONARY VEINS, AND ATRIAL SEPTUM valve insufficiency, long P-R interval, or atrioventricular
• Identify pulmonary veins and pulmonary venous entry. block.
• Examine for attenuation or small size: Rule out volume • Delayed (systolic) closure (B-shoulder): Rule out left
depletion, right-to-left shunt, or low cardiac output. ventricular failure and elevated atrial pressure.
• Examine for enlargement or rounding/turgid appearance: • Systolic anterior motion of the mitral valve (systolic anterior
Rule out left-to-right shunt, mitral valve disease, left ven- motion, systolic mitral–septal contact): Rule out dynamic
tricular systolic or diastolic failure, chronic arrhythmia (e.g., left ventricular outflow tract obstruction due to valve
atrial fibrillation). malformation, subaortic stenosis, volume depletion,
• Measure left atrial diameter and/or left atrial area by 2D pulmonic stenosis, or hypertrophic or infiltrative cardio-
imaging. myopathy (all very rare).
• Examine the atrial septum for abnormal bowing to the left • Doppler studies can be used to interrogate the mitral valve
or right atrium (high atrial pressure). for regurgitation or abnormal flow; multiple planes should
• Examine the atrial septum for septal defects or patent be obtained including short-axis images at the level of the
foramen ovale (perform Doppler and ‘bubble’ contrast left atrium immediately dorsal to the mitral valve.
studies if necessary). • Mitral regurgitation is common. Eccentric jets are often
• Examine the blood pool for spontaneous contrast. observed. Do not confuse ‘backflow’ color noise with true
Continued
BOX 9.11
Interpretation of Echocardiographic and Doppler Studies—cont’d
regurgitation. Horses can develop mid-to-late systolic • Thickened leaflets (diffuse or nodular): Rule out degenera-
mitral regurgitation (as with mitral prolapse). Multiple jets of tion, endocarditis.
mitral regurgitation are common. • Prolapse of aortic valve into the left ventricle: Rule out de-
• Always time flow events of mitral regurgitation (color M- generative semilunar valve disease (common), ventricular
mode and spectral Doppler); do not misdiagnose dias- septal defect, or bacterial endocarditis with torn leaflet.
tolic mitral regurgitation. Do not overemphasize receiving • Diastolic fluttering of the aortic valve: Rule out aortic insuf-
chamber color coding in mitral regurgitation because red ficiency.
blood cell entrainment and a ‘spray effect’ can result in • Systolic fluttering or the aortic valve: Normal or high flow
overestimation of mitral regurgitation severity, whereas state.
wall-hugging jets underestimate severity of mitral regurgi- • Lack of systolic separation: Rule out valvular cardiac out-
tation. Attempt to measure jet width at origin and correlate put, arrhythmia, stenosis (rare).
to left atrial and left ventricular chamber size. • Decreased aortic diameter: Low cardiac output, hypotension.
• Aortic dilation: Rule out aortic regurgitation tetralogy of
LEFT VENTRICLE Fallot, pulmonary artery atresia, truncus arteriosus, patent
• Evaluate from long- and short-axis tomograms; inspect ductus arteriosus (rare).
contour and walls; dorsal septum is normally slightly • Aortic sinus of Valsalva aneurysm (focal dilation or balloon-
thicker than left ventricle free wall. ing of affected sinus): Evaluate for rupture into ventricular
• Echogenic smoke/contrast: Some spontaneous contrast septum or right atrium.
may be normal; rule out low output states, bradycardia, • Doppler studies may be used to identify blood flow pat-
systemic inflammation (?). terns in the left ventricle outflow tract, aortic regurgitation,
• Evaluate left ventricle dimensions (internal dimensions, paramembranous ventricular septal defect, and rare cases
thickness of interventricular septum and free wall) and left of aortic stenosis. Doppler studies also can identify abnor-
ventricle systolic function (fractional shortening, ejection mal blood flow paths in rare cases of aortic sinus ruptured
fraction) using M-mode or 2D imaging. into the heart.
• Left ventricular dilation: Rule out causes of volume over-
load or left ventricular failure, including mitral or aortic VENTRICULAR SEPTUM
valvular regurgitation, dilated cardiomyopathy, myocarditis, • Septal hyperkinesis: As per the left ventricle.
left-to-right shunt, persistent tachyarrhythmia. • Septal hypokinesis: As per left ventricle; also rule out right
• Left ventricular wall thinning: Rule out infarct, prior myocar- ventricular pressure or volume overload.
ditis, congenital aneurysm (rare). • Paradoxic ventricular septal motion: Rule out moderate to
• Left ventricular wall thickening: Consider “athletic heart”; severe right ventricular volume overload such as atrial sep-
rule out pseudohypertrophy from volume depletion, acute tal defect, severe tricuspid regurgitation, severe pulmonary
myocarditis (necrosis/edema; viral, bacterial, toxic, idio hypertension with tricuspid regurgitation.
pathic), infiltrative cardiomyopathy (amyloid, lymphoma, • Flat ventricular septum: Rule out right ventricular volume
other neoplasia), chronic systemic hypertension (chronic overload (diastolic flattening) or right ventricular pressure
kidney disease, metabolic syndrome, laminitis, chronic overload (systolic flattening).
pain), chronic digitalis (foxglove, oleander, yew) poisoning, • Exaggerated and disparate ventricular filling rates with
or left ventricular outflow obstruction (very rare). diastolic septal fluttering: Rule out constrictive pericardial
• Hyperkinesis of left ventricle: Rule out mitral or aortic insuf- disease.
ficiency, bradycardia, sympathetic stimulation. • Examine for ventricular septal defects in both long-axis
• Hypokinesis or dyskinesis of the left ventricle: Rule and short-axis image planes (perform Doppler studies if
out cardiomyopathy or other myocardial disease, necessary).
ischemia, infarct, arrhythmia, regional wall infiltration, • Echocardiogram dropout or discontinuity of the ventricular
or myocarditis. septum: Rule out ventricular septal defect (peri/paramem-
• Hyperechoic myocardium or subendocardium: Rule out branous adjacent to right/noncoronary cusps of the aortic
recurrent ischemia, fibrosis, infiltration, infarction, myocar- valve and septal leaflet of tricuspid valve; inlet septal ven-
ditis, amyloidosis. tricular septal defect (ventral to tricuspid valve); muscular or
• Tissue Doppler and 2D speckle tracking (2D strain) may trabecular ventricular septal defect; subpulmonic ventricular
be used to evaluate regional and global left ventricular septal defect (also termed outlet, supracristal, subarte-
function; tissue Doppler (Em/Am ratio) is useful for assess- rial, or doubly committed ventricular septal defect; directly
ment of left ventricular diastolic function; transmitral flow underneath pulmonic and aortic valves); tetralogy of Fallot;
can also be obtained but is limited with respect to evalua- pulmonary artery atresia; truncus arteriosus; or a false defect
tion of left ventricular diastolic function. caused by angle of the ascending aorta or aortic dilation.
• Malalignment of the ventricular septum and anterior aortic
LEFT VENTRICULAR OUTLET, AORTIC VALVE, AND AORTA root: Examine for tetralogy of Fallot, malalignment-type
• Identify aortic valve leaflets and motion during cardiac ventricular septal defect.
cycle: Identify abnormal leaflet morphology (e.g., thicken- • Examine for dissection or “track” that may suggest rupture
ings, fenestrations) or motion. Examine in both long-axis of the aorta into the ventricular septum with subsequent
and short-axis image planes to see all leaflets. fistula.
BOX 9.11
Interpretation of Echocardiographic and Doppler Studies—cont’d
• High-frequency fluttering of the ventricular septum: Rule • Doppler studies can interrogate the tricuspid valve for ab-
out aortic regurgitation. normal flow or regurgitation; most horses have some small
• Doppler studies, especially color Doppler, are useful for jets of tricuspid regurgitation by color Doppler evaluation;
recognizing ventricular septal defects; continuous-wave use color M-mode and spectral Doppler to evaluate timing
Doppler should be used to measure velocity across shunts and peak velocity. High-velocity tricuspid regurgitation (>3.2
to evaluate for “restrictive” versus unrestrictive septal de- m/sec): Also rule out pulmonary hypertension, large ven-
fects. High-velocity flow across a ventricular septal defect tricular septal defect, right ventricular outflow obstruction.
(>4.5 m/sec) generally suggests a restrictive defect more
likely to be well tolerated. RIGHT VENTRICLE
• Dilation: Rule out severe tricuspid insufficiency, chronic
RIGHT ATRIUM AND ATRIAL SEPTUM right ventricular pressure overload, biventricular congestive
• Examine for attenuation: If small, rule out volume deple- heart failure, atrial septal defect, large ventricular septal
tion, external compression, or mass lesion impairing defect, severe pulmonary insufficiency, persistent tachyar-
venous return. rhythmia.
• Examine for enlargement: If enlarged, rule out tricuspid • Hypertrophy: Rule out large (unrestrictive) ventricular
regurgitation, tricuspid stenosis or atresia (rare), right- septal defect, pulmonary hypertension, pulmonic stenosis
sided heart failure, atrial septal defect, moderate to severe (rare), tetralogy of Fallot (rare), or complex congenital heart
anemia, or chronic arrhythmia. disease.
• Examine the atrial septum for abnormal bowing into the • Midventricular bands: Rule out double-chambered right
left or right atrium (high atrial pressure). ventricle (examine for ventricular septal defect); remem-
• Examine the atrial septum for septal defects or patent ber that the right ventricular moderator band can be very
foramen ovale (double mobile lines in foals). prominent in horses.
• Doppler studies can be used to identify atrial septal defect, • Hyperechoic tissue: Rule out myocardial fibrosis.
but streaming of normal flow patterns (i.e., caudal vena
cava flow) is confusing. RIGHT VENTRICULAR OUTLET, PULMONARY VALVE, AND
• “Bubble studies” (by injecting agitated normal saline into PULMONARY ARTERY
the jugular vein) should be used to identify right-to-left • Identify valve leaflets and motion during cardiac cycle; if
shunting of blood. Caution: Similar to Doppler studies, pulmonary valve lesion is suspected, also interrogate from
streaming of normal blood from the caudal vena cava may a left cranial transducer position.
produce negative contrast in the right atrium, falsely sug- • Thick, fused, or hypoplastic leaflets: Rule out congenital
gesting left-to-right shunting of blood. stenosis or dysplasia (rare).
• Diastolic fluttering of pulmonic valve: Rule out valvar insuf-
TRICUSPID VALVE ficiency.
• Identify valve leaflets and cusps in long- and short-axis • Systolic fluttering of pulmonic valve: Normal or high flow state.
image planes. • Lack of systolic separation of the pulmonic valve: Rule out
• Observe motion during cardiac cycle. low cardiac output, arrhythmia, stenosis.
• Identify support apparatus (chordae tendineae, papillary • Pulmonary artery, absence or attenuation: Rule out pulmo-
muscles). nary atresia or pulmonary artery hypoplasia.
• Increased valve echogenicity: Rule out degenerative thick- • Pulmonary artery, dilation of: Rule out pulmonary hyper-
ening, vegetation, malformation, thrombus on valve. tension, left-to-right shunt, poststenotic dilation of pulmo-
• Common septal leaflet: Rule out endocardial cushion nic stenosis (rare); rupture of the aorta into the right side of
defect/primum atrial septal defect (rare). the heart or pulmonary artery (rare).
• Flail leaflet: Rule out ruptured chordae tendineae or avul- • Doppler studies can be used to identify abnormal flow in
sion of papillary muscle; rule out infective endocarditis. the pulmonary artery, including the rare pulmonic stenosis
• Chaotic valve motion: Rule out arrhythmia, ruptured chor- (high velocity), increased velocity flow from a left-to-right
dae tendineae. shunt, and patent ductus arteriosus in equine neonates.
• Premature (diastolic) closure: Rule out severe pulmonic Pulmonary regurgitation is normal; high-velocity pulmonary
insufficiency, long P-R interval, or atrioventricular block. regurgitation indicates pulmonary hypertension.
methods. A pivotal limitation of color Doppler regards tem- normal “backflow” signals related to valve closure or diagnos-
poral resolution. Depending on the system used, the frame ing a diastolic flow event as systolic.
rates of interrogation can be very slow (often less than 10/sec). PW spectral and color Doppler techniques can provide
Thus it is mandatory to time flow events using either spectral accurate information about the location of flow disturbances
Doppler or by invoking the M-mode cursor and recording the but cannot measure high-velocity flow faithfully. High-veloc-
event by color-M-mode echocardiography. In many cases, the ity flow is encountered as RBCs are ejected from high to lower
color M-mode examination is simpler and provides excellent pressure zones across incompetent valves, stenotic valves,
temporal resolution, reducing interpretation errors. This tim- and intracardiac and extracardiac shunts (provided that there
ing of blood flow prevents the clinician from misinterpreting is a pressure difference across the defect). In general, once
A B
C D
FIG. 9.20 Standard echocardiographic views for assessment of left ventricular size and function. A, Right-
parasternal long-axis 4-chamber view centered on the left ventricle (LV). The transducer is positioned in the
right 4th intercostal space at a level slightly above the olecranon, angled caudally and rotated clockwise to
the 1 o’clock position. Slight changes in transducer placement may be necessary to optimize the image
plane. This view is best suited to assess the structures, dimensions, and mechanical function of the LV. Be-
cause this image is centered on the LV, the left atrium (LA) may not be imaged in its entirety throughout the
cardiac cycle. Assessment of the right side of the heart is limited due to its anatomic position, its complex
geometry, and its visualization in the narrow near field of the imaging sector. B, Right-parasternal short-axis
view of the LV at the level of the chordae tendineae (arrowheads). This view is obtained by rotating the
transducer 90 degrees clockwise from a 4-chamber view. It is commonly used for measurement of the di-
ameter and the area, respectively, of the LV and evaluation of LV systolic function. C, Right-parasternal short-
axis view (top) and corresponding M-mode recording (bottom) of the LV at the chordal level. The motion of
the interventricular septum (IVS) and the left-ventricular free wall (LVFW) is displayed over time. The right
ventricle (RV) and the right-ventricular free wall are displayed in the near field. A small amount of spontane-
ous echo contrast is frequently seen in the ventricular lumen (arrowheads). Measurement of LV wall thick-
ness and internal dimensions, evaluation of septal motion, and calculation of LV fractional shortening allow
assessment of LV size and systolic function. D, Anatomic M-mode (AMM) image of the LV (bottom), recon-
structed from a digitally stored 2D cineloop recording obtained from a right-parasternal short-axis view at the
chordal level (top). Notice that the AMM cursor (green line) can be freely positioned on the 2D image, inde-
pendent of the sector apex, to bisect the IVS, the LV cavity, and the LVPW into two equal parts throughout
the cardiac cycle. (From Schwarzwald CC: Ultrasonography of the heart. In: Kidd JA, Lu KG, Frazer ML, et al.:
Atlas of equine ultrasonography, Wiley, Oxford, UK, 2014. Reproduced with permission of John Wiley &
Sons, Ltd.)
velocities exceed about 2.5 m/sec in either direction, part of In recent years, more advanced echocardiographic meth-
the returning signal is displayed in the incorrect direction. This ods such as tissue Doppler imaging* and 2D speckle tracking
problem is called signal “aliasing” (see Fig. 9.25).56,344,590,591 To (2D strain) imaging161,168,346-348,575,603 (which is based on con-
quantify high-velocity flow, a third modality must be invoked, ventional 2DE cineloop recordings and independent of the
either high pulse-repetition-frequency (HPRF) Doppler or con- Doppler principle) have been investigated in horses to comple-
tinuous-wave (CW) Doppler. Continuous-wave Doppler has ment the traditional 2D, M-mode, and Doppler echocardio-
virtually unlimited ability to record very high velocity but graphic methods and to overcome some of their limitations.
does not provide the spatial discrimination found in PW Dop-
pler modalities. * References 161, 168, 286, 289, 349, 572, 574, 575, 603, 604.
A B
C D
FIG. 9.21 Standard echocardiographic views for assessment of left atrial size and function. A and B, Right-
parasternal 4-chamber view centered on the left atrium (LA), to image the LA in its entirety throughout the
cardiac cycle. At an imaging depth of 30 cm, this view is best suited to assess the mitral valve (MV) appara-
tus, LA dimensions, and LA mechanical function. Only in rare cases (e.g., giant draft breeds, horses with
severe cardiomegaly) the LA cannot be displayed in its entirety from this window. A, Image recorded at the
end of ventricular systole, 1 frame before opening of the MV, when the LA is at its maximum dimensions.
Chordae tendineae are seen in the left ventricular (LV) cavity (arrowheads). B, Image recorded at the end of
diastole, immediately after closure of the MV, when the LA is at its minimum dimensions. Note the obvious
change in LA dimensions within a single cardiac cycle (i.e., between A and B), indicating that timing of
measurements of LA dimensions is critical. Generally, LA dimensions should be assessed at the end of ven-
tricular systole (A). C, Right-parasternal short-axis view at the level of the aortic valve. This view is obtained
by rotating the transducer 90 degrees clockwise from a right-parasternal left-ventricular outflow tract view
(Fig. 9.22A). In this view, the aortic valve (AV) with its three cusps is visible in the center of the image. The
surrounding structures include right atrium (RA), tricuspid valve, right ventricle (RV), right-ventricular out-
flow tract (RVOT), LA, and left atrial appendage (LAA). The apparent triangular separation (at the 12 o’clock
position) evident between the noncoronary cusp (NCC) and the right coronary cusp (RCC) is a normal finding
and does not represent an anomaly. In this view, the end-systolic size of the LA and LAA can be measured
and compared with the aortic area. D, Left-parasternal long-axis view of the LA, MV, and LV. The transducer
is positioned in the 5th intercostal space slightly above the olecranon, oriented perpendicular to the chest
wall and angled dorsally. This view has traditionally been used for assessment of LA dimensions. However,
as opposed to the right-parasternal views (A, B), this view often does not allow imaging of the LA in its en-
tirety due to interference with the ventral lung border. Nonetheless, imaging LA and MV from a left thoracic
window provides additional information and should complement the right-parasternal views. LCC, Left-cor-
onary cusp of the aortic valve; PV, pulmonary vein; TV, tricuspid valve. (From Schwarzwald CC: Ultrasonog-
raphy of the heart. In: Kidd JA, Lu KG, Frazer ML, et al.: Atlas of equine ultrasonography, Wiley, Oxford, UK,
2014. Reproduced with permission of John Wiley & Sons, Ltd.)
These modalities allow quantitative assessment of myocardial function in horses. Tissue Doppler imaging is a promising
motion velocity, deformation (strain), deformation rate (strain tool for assessment of LV diastolic function,164,366,575 and 2D
rate), displacement, and rotation in longitudinal, radial, and speckle tracking may be helpful for detection and quantifi-
circumferential imaging planes and may provide more sen- cation of LV systolic dysfunction in horses with myocardial
sitive methods for assessing regional or global myocardial disease (see Fig. 9.49 later in this chapter)161,164,575 and for
A B
C D
FIG. 9.22 Standard echocardiographic views for assessment of the great vessels. A, Right-parasternal
long-axis view of the left ventricular outflow tract (LVOT). Starting from a 4-chamber view, the transducer is
angled more cranially, tilted dorsally, and rotated to the 2 o’clock position to obtain this view. It is best suited
to assess the structures, dimensions, and function of the aortic valve, the sinus of Valsalva, and the ascend-
ing aorta (Ao) and the pulmonary artery (PA). The size of the PA should be smaller than the diameter of the
aorta. B, Right-parasternal long-axis view of the right ventricular outflow tract (RVOT). Starting from an LVOT
view (A), the transducer is angled more cranially to obtain this view; occasionally the transducer will have to
be moved one intercostal space more cranially. The right atrium (RA), the tricuspid valve, the right ventricle
(RV), the RVOT, the pulmonic valve, the pulmonary artery (PA), and across section through the right coronary
artery (arrow) can be visualized. C, Left-parasternal long-axis view of the LVOT. The transducer is positioned
in the 5th or 4th intercostal space at a level slightly above the olecranon and angled slightly cranially. D, Left-
parasternal long-axis view of the RVOT. Starting from the LVOT view (C), the transducer is moved one inter-
costal space more cranially to obtain this image. LA, Left atrium; LV, left ventricle. (From Schwarzwald CC:
Ultrasonography of the heart. In: Kidd JA, Lu KG, Frazer ML, et al.: Atlas of equine ultrasonography, Wiley,
Oxford, UK, 2014. Reproduced with permission of John Wiley & Sons, Ltd.)
quantification of stress echocardiograms.168 However, clinical short-axis view or from a right-parasternal four-chamber
applications and the added value over traditional echocardio- view using 2DE or M-mode recordings (see Fig. 9.20).344
graphic methods need further definition. Linear measurements of the LV minor dimension may not
Assessment of Chamber Dimensions. One of the main well describe true LV size and geometry, as asymmetric LV
goals of echocardiography is the detection of cardiac chamber dilation and dimensional changes along the major axis of
dilation or hypertrophy and the grading of the enlargement (if the ventricle are neglected. Similarly, linear measurement of
present) as mild, moderate, or severe. Chamber dimensions wall thickness may not be accurate estimates of LV mass, par-
provide important information on hemodynamics, chamber ticularly asymmetric thickening is present or if the M-mode
remodeling, and severity of cardiac disease. Assessment of cursor crosses a papillary muscle or fails to sample the thick-
left atrial (LA) and left ventricular (LV) dimensions should be est part of the wall. Furthermore, standardized placement
based on an integrative approach combining subjective evalu- of the M-mode cursor can be challenging and is difficult to
ation and assessment of multiple measurements based on 2D verify in all three dimensions. This limitation may be par-
and M-mode echocardiography (see Figs. 9.20–9.23).* tially overcome by use of anatomic M-mode technology,
Left-ventricular internal dimensions and LV wall thickness, which allows free orientation of the cursor line within the
respectively, are usually measured from a right-parasternal imaging plane independent of the apex of the imaging sector
(see Fig. 9.20D).345 Measures that consider the short-axis area
* References 168, 287, 289, 344, 345, 576, 591, 595. (instead of diameter) and the length of the LV (i.e., various
LV D S
T
C
A P
QRS R T
RV m
100
2
1
AO C
LV D S
200
O
FIG. 9.23 M-mode echocardiography. A, M-mode tracing demonstrating a hyperdynamic left ventricle
(LV) in a horse with acute mitral regurgitation (MR). The significant change in LV dimensions from diastole (D)
to systole (S) is notable and is typical of volume overloading with preserved ventricular function. Further-
more, the reduced resistance to ejection of blood into the left atrium (LA) enhances ventricular shortening.
Depth calibration in millimeters is shown on the left. B, Recording through the ventricles demonstrating
decreased systolic function with a reduced LV shortening fraction. This pattern of contraction can be caused
by myocarditis, myocardial injury (e.g., monensin), idiopathic dilated cardiomyopathy, chronic volume over-
load, protracted ventricular tachycardia (VT), or administration of negative inotropic drugs. Depth calibration
in millimeters is shown on the left (RV, right ventricle). C, M-mode echocardiogram across the ventricles re-
corded from a horse with cardiac amyloidosis. Global LV systolic function is mildly reduced. The IVS and
LVPW are thickened. The IVS also appears hyperechoic relative to the RV wall. The LVPW in the far field is
less echogenic owing to attenuation of echoes in the far field. The right ventricle (RV) contained spontane-
ous echocontrast. Depth calibration in millimeters is shown on the left (RV, right ventricle; IVS, interventricu-
lar septum; LV, left ventricle; LVPW, left ventricular peripheral wall). D, Recording from a horse with aortic
regurgitation (AR) and atrial fibrillation (AF), demonstrating fine diastolic fluttering of an aortic valve leaflet
(small arrows). The aortic root (AO), valve opening (O), and valve closing (C) are indicated. The murmur (m)
of AR is evident in the previous phonocardiogram. First (1) and second (2) heart sounds are labeled. Diastolic
fluttering of the mitral valve (most common), aortic valve, ventricular septum, or walls of the aortic root may
be observed in horses with this hemodynamic abnormality. The M-mode sampling rate (approximately 1000
pulses/sec) is ideal for detecting these high-frequency events.
area-length models and the Simpson’s method of disks) may to error. Nonetheless, in addition to conventional linear mea-
be more accurate estimates of internal LV dimensions and surements one should consider using area measurements and
LV mass (see Fig. 9.20A and B).168,297,306,344 The accuracy of volume estimates for quantification of chamber dimensions,
these methods, on the other hand, is limited by the fact that particularly in cases where the subjective evaluation and con-
true LV long axis may be difficult to measure by 2DE because ventional measurements provide equivocal results.
of the LV shape and the translational motion of the LV dur- Assessment of LA size has traditionally been limited to sub-
ing contraction and relaxation. Furthermore, all conventional jective evaluation and measurement of the LA diameter from a
volumetric indices are calculated based on several geometric left-parasternal long-axis view (see Fig. 9.21D). However, this
assumptions and approximations and may therefore be prone view often does not allow imaging of the LA in its entirety due
A B
C D
FIG. 9.24 Two-dimensional (2D) echocardiograms. A, Long-axis image from the right thorax in a 12-year-
old Quarter Horse gelding demonstrating significant right ventricular (RV) and right atrial (RA) dilation after
tricuspid regurgitation (TR) and elevated pulmonary artery pressure. In this case a tumor that obstructed
flow in the main pulmonary artery caused the pulmonary hypertension. The ventricular septum is flat and
bulges slightly into the left ventricle (LV). B, Images of the ascending aorta and pulmonary artery obtained
from the right hemithorax (left panel) and left cranial hemithorax. An evaluation of the pulmonary artery
diameter relative to the aorta is useful when identifying pulmonary hypertension. C, Biatrial dilation in a
Thoroughbred colt with mitral regurgitation (MR), pulmonary hypertension, atrial fibrillation (AF), and con-
gestive heart failure (CHF). Both atria are rounded and appear turgid. The cause of mitral disease in this case
was idiopathic lymphocytic-plasmacytic mitral valvulitis (RA, right atrium; LV, left ventricle; LA, left atrium).
D, Contrast echocardiogram demonstrating right-to-left shunting at the level of the foramen ovale in a foal
with severe respiratory disease. The saline generates echocontrast, opacifies the right atrium (RA) and right
ventricle (RV), and visibly fills the left atrium (LA) (arrows), although the LV has not yet been opacified. This
technique is easy and practical for demonstrating right-to-left shunts across the cardiac septa.
to interference with the ventral lung border; this often results Objective quantification of the right atrial (RA) and right
in measurements of the LA diameter that are not parallel to the ventricular (RV) dimensions is difficult, because the geomet-
mitral valve annulus or that are made too close to the annulus ric shape of the right heart is complex and the internal dimen-
and thereby underestimate the true maximum atrial diameter. sions of the RA and the RV cavity largely depend on transducer
Also, the timing of LA measurements is often not specified in placement and imaging plane. Subjective assessment of the right
the equine literature, leading to uncertainties when comparing heart chambers in multiple image planes is therefore important.
results from different studies. With contemporary echocardio- Assessment of Systolic Left Ventricular Function. The
graphic systems, right-parasternal long-axis and short-axis echocardiographic detection of myocardial failure and deteri-
views (Fig. 9.21A–C) are preferred because they allow visual- oration of systolic function has great prognostic implications.
ization of the LA in its entirety and provide sufficient anatomic Most of the indices used in clinical practice serve to evaluate
landmarks for consistent and reliable measurement of LA global systolic LV function. It is important to realize that the
dimensions.287,289,576 In addition to LA diameter, assessment echocardiographic indices of systolic ventricular function gen-
of LA area should be considered because enlargement may not erally do not reflect contractility per se but are (to a variable
occur in a uniform fashion and LA geometry may change over extent) influenced by preload, afterload, HR, and heart rhythm
time. The LA size is best measured at the end of the ventricular (see Fig. 9.4).344 595 Generally, it is advised to use a variety of
systole, one frame before mitral valve opening, when the LA echocardiographic variables to assess LV systolic function and
chamber is at its greatest dimension. to interpret them in the context of the clinical findings.
A B
C D
FIG. 9.25 A–C, Black-and-white representations of color Doppler echocardiograms demonstrating map-
ping of blood through the heart. A, Perimembranous ventricular septal defect (VSD) in a foal (arrow). The
flow pattern was coded red and aliased as the velocity increased across the defect. B, Wide spray of mitral
regurgitation (MR) with flow moving from left ventricle (LV) into the left atrium (LA) in a horse with mitral
valve prolapse (RV, right ventricle; RA, right atrium). C, Color M-mode study from a horse with tricuspid re-
gurgitation (TR). The bright systolic flow pattern, following the QRS of the electrocardiogram (ECG), was
mapped as turbulence in the color study. This is an excellent method for timing abnormal flow events. D,
Example of continuous-wave (CW) spectral Doppler echocardiogram obtained from a horse with a VSD and
mild aortic regurgitation (AR). Time and the ECG waveforms are shown along the x-axis and velocity of flow
along the y-axis with a meters per second scale (m/sec). Direction of flow relative to the transducer is also
shown; flow toward the transducer is displayed as a positive signal (relative to the zero velocity baseline)
and away from the transducer as a negative signal. A low-velocity flow pattern is evident in diastole related
to diastolic shunting across the VSD, aortic regurgitant flow moving across the cursor line ‘off angle’ (with
parallel alignment, the AR velocity would be higher [i.e., >3.75 m/sec]), or contaminated transtricuspid flow.
In systole a high positive velocity signal is recorded (>5 m/sec) compatible with a small (restrictive) left-to-
right shunting VSD. However, the maximum velocity is not evident because the signal reaches the upper
limit of the velocity scale (arrow). The negative signal (lower arrow) is either an aliased signal (if antialiasing
filters are off) or VSD turbulence in the other direction. Moving the baseline down or increasing the velocity
scale would have allowed for faithful recording of the peak velocity.
The 2D ejection phase indices are based on measurements of a single measurement of LV function may be problematic.168
LV dimensions. Left ventricular ejection fraction (LV EF = SV/ The LV FS actually represents the relative shortening of the LV
LVEDV × 100, where SV is stroke volume and LVEDV is LV short axis in only one single dimension, disregarding the fact
end-diastolic volume) is based on geometric estimates of LV vol- that the LV contracts in all three dimensions. Also, it may lack
umes and has traditionally been the standard index of LV systolic accuracy when the IVS and the LVFW do not contract synchro-
function. The LV fractional shortening (LV FS = [LVIDd − nously or when the cursor line is not placed optimally. In horses
LVIDs]/LVIDd × 100; where LVIDd and LVIDs are the LV with mitral regurgitation and normal myocardial function, the
internal short-axis diameters at end-diastole and at peak sys- LV FS can actually be increased due to the increased preload
tole, respectively), is an approximation of the LV EF and is the and decreased afterload. Conversely, a normal LV FS in the pres-
most commonly used index of LV systolic function in horses. ence of severe MR may indicate (but does not necessarily prove)
In fact, often it is the only one used in routine echocardiogra- myocardial failure.
phy, because it can be easily calculated from M-mode record- Area-based measurements such as the LV fractional area
ings (see Fig. 9.23).306,344,595 However, reliance on this index as change (LV FAC) may be less sensitive to asynchronous wall
motion and allow assessment of shortening in two dimensions. filling results from the dynamic interplay of active ventricular
Volume-based measurements (LV EF, stroke volume, cardiac relaxation, ventricular compliance, filling pressures, pericar-
output) can be calculated based on estimates of LV volume as dial restraint, ventricular interaction, and atrial function (see
described earlier.168 They are generally considered more accu- earlier discussion). Afterload and contractility will further
rate and less affected by altered chamber geometry. However, influence diastolic function. Therefore the echocardiographic
there are differences and limitations related to the geometric assessment of diastolic ventricular function and filling pres-
model used.297,306,344,595 As stated, area- and volume-based sures (which are commonly assessed together) is difficult. In
measurements of LV systolic function should be considered in horses, diastolic ventricular dysfunction may certainly play
cases where the subjective evaluation and conventional mea- a role in pericardial and myocardial disease,161,164,366 but the
surements give equivocal results. clinical relevance of diastolic dysfunction in other types of car-
Doppler-based estimates of stroke volume (SV) and cardiac diseases is not clear, and the prevalence of diastolic heart
diac output (CO) are also indices of global ventricular func- failure is unknown.
tion. The SV is calculated by multiplying the velocity-time Doppler-derived transmitral flow velocities (E wave, A
integral (VTI) of the aortic or pulmonic flow signal by the wave, E/A ratio, E-wave deceleration time and deceleration
cross-sectional area of the respective vessel.297,306,307,311,313,344 slope) are commonly used in humans and small animals for
There are many limitations of this echocardiographic assessment of diastolic LV function and filling pressures. How-
estimate of SV, including the angle-dependency of Dop- ever, the usefulness of transmitral flow velocities is limited,
pler-based flow measurements, inaccuracies in the determi- because impaired relaxation coexisting with increased filling
nation of the flow area, and uncertainties as where exactly pressures may lead to “pseudonormalization” of filling pat-
to measure flow and cross-sectional area (or diameter) of terns.594 Furthermore, PW Doppler recordings of transmitral
the vessel.311 In adult horses, adequate alignment of the flow velocities strongly depend on alignment with blood flow
Doppler beam with blood flow by transthoracic echocar- and are sensitive to placement of the sample volume relative
diography is difficult, and Doppler estimates of SV are con- to the position of the mitral valve. Transmitral flow velocity
sidered neither very accurate nor reliable. Transesophageal profiles can be recorded in horses, but optimal alignment with
echocardiography (TEE) allows parallel alignment between blood flow from an apical window is not possible in adults.
Doppler beam and aortic blood flow in adult horses, and Transmitral flow velocity measurements in horses are relatively
CO measurements by TEE in adult, anesthetized horses unreliable and may not be suitable to detect minor changes in
have been shown to be in better agreement with thermodi- diastolic LV function.281,287,289 Nonetheless, if marked decrease
lution CO than CO measurements by transthoracic echo- or reversion of the E/A ratio is present, diastolic dysfunction
cardiography.309,311,312 In foals, alignment of the ultrasound must be suspected.164 Tissue Doppler imaging may provide
beam with blood flow can be achieved using apical imaging additional velocity-based and time interval–based indices that
planes. Although this may improve the accuracy of CO mea- are easier to obtain and that can be helpful for assessment of
surements by Doppler echocardiography, volumetric 2DE LV diastolic function in horses.161,164,286,366
measurements using the bullet method have been shown to Assessment of Left Atrial Function. LA function is rarely
provide better agreement with CO by lithium dilution than considered during routine echocardiography, and the clini-
Doppler estimates of CO.306 Generally, measurements of cal relevance of LA dysfunction is not well known in horses.
CO by echocardiography may be more accurate for detect- However, LA function is impaired in horses with atrial fibril-
ing acute changes in CO over time than for obtaining abso- lation (AF), and persistent LA contractile dysfunction can be
lute measurements of CO. Assessment of SV and CO by detected in horses after conversion from AF to sinus rhythm,
Doppler is not routinely performed in horses with cardiac likely attributed to AF-induced atrial remodeling.289-291 LA size
disease. In fact, myocardial dysfunction generally must be and LA mechanical function can easily be assessed in horses
severe for blood flow indices to be affected, because cardiac by use of 2DE variables, including LA area and LA fractional
output is maintained in the failing heart until the compen- area changes (see Fig. 9.21).287,289-291Additional studies will be
satory mechanisms are overwhelmed. Therefore estimates required to determine the clinical relevance of LA mechanical
of SV and CO may be of limited relevance in most horses dysfunction in the presence of cardiac disease in horses.576
with heart disease. Assessment of Valvular Regurgitation. The Doppler tech-
Systolic time intervals (STIs), including LV preejection nology of current echocardiographic systems is very sensitive
period (PEP), LV ejection time (LVET), and LV preejection to detect valvular regurgitation, and care must be taken not
period-to-ejection time ratio (PEP/LVET), can be measured to overinterpret the echo findings, particularly in otherwise
from M-mode images of aortic valve motion and from Doppler healthy animals without abnormal clinical findings and in the
tracings of aortic blood flow, respectively.344,605 The STIs may absence of heart murmurs. Assessment of valvular regurgita-
serve as alternative indicators of LV function that are inde- tion should be achieved using an integrated qualitative and
pendent of ventricular shape and geometry and that may be quantitative approach, combining clinical examination (in-
superior to the calculation of the LV FS. However, they are also cluding auscultation of a typical murmur) and echocardio-
variably influenced by HR and loading conditions.344 Accu- graphic findings. Measurement of cardiac chamber dimen-
rate time intervals may be difficult to obtain due to inability to sions provides information on the hemodynamic relevance
clearly identify the onset and the end of ejection on M-mode of chronic valvular regurgitation. Abnormal timing and di-
or Doppler tracings. This limitation may be overcome by use rection of transvalvular flow as well as flow turbulences can
of tissue Doppler imaging for measurement of STIs.164,286 The be detected by 2D color Doppler, color M-mode, and spec-
clinical value of STIs has not been well established in horses tral Doppler echocardiography. The regurgitant signal in the
with cardiovascular disease. “receiving chamber” can be interrogated in multiple imag-
Assessment of Diastolic Function. Diastolic ventricular ing planes to identify origin, extent, timing, and duration of
function is more complex than systolic function. Ventricular the regurgitation.74 However, it is important to realize that
color Doppler echocardiography only describes blood flow from horses with heart disease.* Normal published data relate
direction and velocity but not absolute volumetric flow. The in part to population and study methods; accordingly, refer-
Doppler-derived regurgitant signal is largely influenced by ence intervals vary considerably.57 Normal values also depend
gain settings, direction of flow, orifice size and shape, driving on the head and body positions of the horse, the influence of
pressure, and characteristics of the receiving chamber. Quan- administered tranquilizers, sedatives, or anesthetic agents,
tification of regurgitation by assessing signal strength of the and the size of the animal. Hemodynamic variables that can
spectral Doppler regurgitant signal or measuring the area of be measured or calculated by catheterization techniques
regurgitation within the receiving chamber is therefore nei- include systolic, diastolic, and mean BP in the systemic and
ther very accurate nor reliable. pulmonary circulations, PA occlusion (or pulmonary capillary
Hemodynamic Assessment. The hemodynamic load wedge) pressure, central venous pressure (in the venae cavae,
placed on the heart by cardiac disorders can be estimated by near the right atrium), intracardiac (atrial and ventricular)
combining echocardiographic information on chamber size, pressures, CO, systemic and pulmonary vascular resistances,
wall thickness, myocardial motion, LV systolic and diastolic and arteriovenous oxygen difference.633
function, and intracardiac blood flow. Doppler studies can Cardiac catheterization in the clinical setting has largely
be used to assess intracardiac pressures and pressure gradi- been replaced by Doppler echocardiography. However, indica-
ents. Normal pressure gradients driving blood flow through tions for cardiac catheterization persist, especially for research
heart, valves, and large vessels range from 0.25 to 1.5 m/sec. purposes or in clinical practice, when accurate measurement
Abnormally high velocities can be found in many cardiac con- of PA pressure is needed, the origin of pulmonary hyperten-
ditions, including ventricular septal defects and valvular re- sion cannot be determined, or the diagnosis of occult con-
gurgitations, in which pressure gradients drive blood across a strictive pericardial disease is entertained. Knowledge of the
restrictive orifice. The pressure gradients are either reflections general principles of hemodynamics and catheterization data
of normal intracardiac pressures or consequences of patholog- in health and disease creates a useful framework for under-
ically increased pressures. Pressure gradients can be estimated standing clinical assessment of the CV system.
using Doppler echocardiography by employing the simplified Pressures on the left side of the circulation include systemic
Bernoulli equation (dp = 4 × vmax2, where dp is the pressure arterial, left ventricular, and left atrial pressures. Measurement
gradient in mm Hg and vmax is the peak velocity in m/sec). The of systemic arterial BP has been described earlier in this chap-
main indications to measure pressure gradients in horses are ter. Left ventricular pressures can be measured by percutane-
the assessment of ventricular septal defects (by interrogation ous retrograde catheterization of the LV via the carotid artery,
of shunt flow) and the diagnosis of pulmonary hypertension aorta, and aortic valve.47,259,449,634,635 Carotid catheterization
(by interrogation of regurgitant flow at the tricuspid valve and can be facilitated using ultrasound guidance. For research
the pulmonic valve). purposes, subcutaneous translocation of the carotid artery has
If, for example, a peak velocity of 4.8 m/sec is recorded been described to allow for repeated catheter procedures.636
across a ventricular septal defect, and if the systolic systemic Left ventricular pressures are typically measured using micro-
arterial BP is determined noninvasively to be 125 mm Hg, the tip pressure-sensing catheters to avoid artifacts that commonly
estimated RV systolic pressure would be calculated as follows: arise when using fluid-filled catheter systems.47,259,449,635 Left
• Pressure drop across defect = 4 × 4.82 = 92 mm Hg atrial pressure is rarely measured directly but can be estimated
• Estimated LV systolic pressure = 125 mm Hg during right-sided heart catheterization by a pulmonary capil-
• Estimated RV systolic pressure = 125 − 92 = 33 mm Hg lary wedge pressure as described later.
These findings indicate a restrictive septal defect, a lesion Systemic arterial pressure is related in a directly positive
unlikely to cause difficulties for the horse except at highest lev- manner to left ventricular systolic function, impedance to
els of performance. blood flow in the aorta, systemic vascular resistance, and HR.
A similar quantitative approach is used to estimate the pres- Systolic pressures in the aorta and left ventricle in the standing
ence or absence of pulmonary hypertension when tricuspid horse generally peak at approximately 110 to 130 mm Hg (with
regurgitation is identified in the absence of right ventricular individual variation).57,259 Diastolic aortic pressure is usually
outflow tract obstruction (i.e., PA ejection velocity of less than near 75 mm Hg. An increase in HR as small as 10 beats per
1.5 m/sec). Assuming the jet can be interrogated at nearly par- minute can increase systemic BP by 20 mm Hg or more over
allel to flow, peak regurgitant velocities exceeding 3.2 to 3.4 m/ these values. A peak systolic pressure gradient between the LV
sec are suggestive of elevated PA systolic pressure. For this cal- and central aorta indicates an obstruction to left ventricular
culation, peak right atrial pressure must be estimated (around outflow, a very rare condition in horses. Left ventricular dia-
10 mm Hg in horses without CHF). For example, a peak stolic pressure reflects diastolic ventricular function and fill-
regurgitant velocity of 3.8 m/sec would results in calculated ing pressures as well as ventricular emptying during systole.
pressure drop from RV to RA of 4 × 3.82 = 58 mm Hg. When The diastolic pressure most often reported is the LV end-
the RA pressure estimate (10 mm Hg) is added, estimated PA diastolic pressure (LVEDP), which is higher than the early
systolic pressure is 68 mm Hg. In cases of right-sided CHF, the (often subatmospheric) minimal diastolic LV pressure. The
RA pressure can be assumed to be at least 20 mm Hg or more LVEDP typically ranges between 12 and 24 mm Hg in standing
accurately measured by a catheter. horses and ponies and is higher than the LVEDP of either peo-
ple or dogs.21,24,57,259,449,615 Exercise increases both left atrial and
ventricular end-diastolic pressures.53,283,284,370,608,610,637 Patho-
Intravascular Pressures and Cardiac logic elevation of resting LVEDP indicates either reduced myo-
Catheterization cardial contractility, ventricular failure, LV volume overload
There is a large body of literature derived from catheterization
studies of the healthy standing, exercising, and anesthetized * References 42, 46, 47, 248, 259, 298, 304, 308, 309, 311-314, 317, 318, 321,
horse and pony along with limited catheterization data derived 352, 354, 355, 367-370, 409, 410, 414, 418, 419, 428, 561, 606-632.
(large VSD, mitral regurgitation, or aortic regurgitation),

myocardial infiltration (lymphoma, amyloid), pericardial con-
straint, or increased ventricular wall stiffness.
Detailed computer-based analysis of a LV pressure tracing
allows derivation of several indices of LV systolic and diastolic
function. The maximum rate (i.e., the first derivative) of posi-
tive pressure change during isovolumetric contraction (+dp/
dtmax) is a classical invasive index of ventricular systolic func-
tion. Similarly, the maximum rate of negative pressure change
during the isovolumetric relaxation phase (−dp/dtmax) and the
time constant of isovolumetric relaxation (τ) are considered
the most reliable and least load-dependent indices of ven-
FIG. 9.26 Recording of intravascular pressure during cardiac catheteri-
tricular relaxation.57,259,633,638 Although these indices are not
zation. Right ventricular (RV) pressure recordings from a Thoroughbred
routinely obtained in clinical cases, they are often used for
yearling with atrial fibrillation (AF), pulmonary hypertension, and biven-
research purposes.
tricular congestive heart failure (CHF). The pressure waveforms vary be-
A right-sided heart catheterization is easily performed in
cause of ventilation and the arrhythmia. Peak pressures exceed 70 mm
most horses using a percutaneous technique involving local
Hg. In the absence of pulmonic stenosis or a large ventricular septal de-
anesthesia, placement of an 8-Fr introducer sheath into the
fect (VSD), this indicates pulmonary hypertension. The ventricular end
jugular vein, and insertion of a 7-Fr balloon-tipped (Swan-
diastolic pressure also is elevated and is compatible with heart failure.
Ganz) catheter of 110 to 120 cm in length through the jugu-
lar vein and the cranial vena cava into the RA, RV, and PA.
Longer catheters are required to consistently measure pul- proximal pulmonary artery during systole in normal animals
monary capillary wedge pressures in large-sized horses, but and relates in part to gravitational influences. The RV end-
these have to be custom made for use in horses and are not diastolic pressure is usually between 10 and 14 mm Hg, but val-
commercially available on the market. Pressures within the ues as high as 20 to 28 mm Hg have been reported.52,57,484,585,642
RA, RV, and PA can be obtained by advancing the catheter Hydrostatic effects can affect the RA and the RV end-diastolic
slowly from the jugular vein into a lobar branch of the PA. pressure if the horse’s head is raised or lowered.427 As with
This is typically performed in standing horses and guided by the left ventricle, depression of contractility reduces the rate
pressure measurements and sometimes with 2D ultrasound of systolic pressure development (+dp/dtmax).352 Elevated RV
imaging. Catheter placement in the RV and the PA is consid- systolic pressure is recorded in pulmonary hypertension from
erably more difficult in recumbent (e.g., anesthetized) horses, any cause, with a large VSD, and with RV outflow obstruction
and if intracardiac pressures are to be measured during anes- as with pulmonic stenosis, tetralogy of Fallot, or obstructive
thesia, it is advised to place all catheters before induction of pulmonary valve vegetation.200 Pathologic elevations in RV
anesthesia. Once the catheter tip is located in the PA, it may diastolic pressure are encountered with pericardial disease,
be possible to inflate the balloon tip briefly to occlude PA flow pulmonary hypertension, severe right-sided valvular disease,
and “wedge” the distal catheter tip. This pulmonary capillary and CHF (Fig. 9.26).
wedge pressure (PCWP, sometimes also referred to as pulmo- Pulmonary artery pressures in standing mature horses
nary artery occlusion pressure) can be used to estimate LV are considerably lower than values recorded from the aorta
filling pressures that are referred into the pulmonary veins because of the lower resistance encountered in the pulmo-
and left atrium.355,356,409,633,637,639 nary vascular tree. The PA pressure is higher in the newborn
Mean RA and central venous pressures estimate the pres- foal and decreases significantly during the first 2 weeks of
sures filling the RV and are influenced by plasma volume, life as pulmonary arteriolar resistance falls.409 Systolic PA
venomotor tone, body position, and heart function. Central pressures in healthy horses and ponies are approximately
venous pressure is typically about 5 to 10 mm Hg but increases 35 to 45 mm Hg (but can be higher or lower depending on
significantly in recumbent horses, especially during general CO). Mean PA pressures range around 25 to 30 mm Hg, and
anesthesia.57,259 Values frequently double from the stand- diastolic PA pressures are approximately 20 to 25 mm Hg,
ing preanesthetic measurement, and central venous pres- but again showing some variation.52,57,259 Pulmonary vas-
sure determinations of 20 mm Hg are not uncommon.612,640 cular pressures increase dramatically with increased CO
A single measurement of the central venous pressure or of as encountered during sinus tachycardia, and mean PAP
pressure in the RA is difficult to interpret unless the value is can reach (or even exceed) 80 to 90 mm Hg during high-
severely elevated. Trends are most important in assessment of intensity exercise.* The pressure that is developed in the PA
plasma volume status and cardiac function. Markedly elevated depends not only on CO and pulmonary arteriolar resistance
RA pressures are observed with cardiac tamponade, constric- but (unlike the systemic circulation) on the pulmonary capil-
tive pericardial disease (along with an abrupt “y” descent; see lary resistance and on the compliance and pressure in the left
Fig. 9.4A), and in right-sided CHF. The “x” descent of the RA atrium. Pulmonary disease can influence these variables; in
pressure waveform may be replaced by a positive “c-v” wave in addition to structural vascular and parenchymal changes,645
the setting of severe tricuspid regurgitation; this pressure wave alveolar hypoxia and acidosis can induce reactive vasocon-
corresponds to a prominent jugular pulsation observed during striction, raising PA pressures.646 Left ventricular function
inspection of the neck. also directly influences PA pressures because elevation of LA
The peak RV systolic pressure is lower than that of the left and pulmonary venous pressure places a direct burden on the
ventricle and is usually around 40 mm Hg (to up to 60 mm PA and right ventricle.449 Left ventricular failure generally
Hg) in standing horses.52,57,641 A small gradient (usually 10–15
mm Hg) may be measured between the ventricular apex and * References 53, 414, 448, 608, 610, 637, 643, 644.
leads to secondary pulmonary hypertension that can be very cooled to approximately 4°C or, in foals, at room tempera-
severe. In other cases, the cause of pulmonary hypertension ture. The resultant change in blood temperature is detected
may not be evident.647 Accordingly, elevated PA pressures by the thermistor downstream of the heart, and the CO can
must be assessed in light of HR, CO, and pulmonary capil- be calculated from the area under the curve of temperature
lary wedge, LA, or LV end-diastolic pressure.352,353 When PA change over time.
pressure is increased, RV systolic pressure is also elevated to The PA catheter can also be used for sampling of mixed-
meet the pressure load. If pulmonary hypertension is chronic, venous blood. The mixed-venous oxygen content ( CvO2 in mL
right sided cardiac enlargement, tricuspid regurgitation, and oxygen/dL blood), which is determined by hemoglobin con-
right-sided heart failure can ensue. Further details on pul- centration (Hb), mixed-venous hemoglobin saturation (SvO2 ),
monary hypertension can be found later in this chapter. and mixed-venous partial pressure of oxygen (PvO2), can be
The origin of pulmonary hypertension generally can be used as an indirect estimate of CO.57,307,628,630 As CO increases,
determined by conducting a thorough cardiorespiratory the tissues extract less oxygen from each aliquot of blood as it
examination that includes echocardiographic and Doppler passes through the capillaries; consequently, the CvO2 , SvO2 ,
assessment of the left and right sides of the heart. However, and PvO2 increase. As CO decreases, the tissue extraction of
catheterization of the PA can be instructive in confusing cases, oxygen increases, CvO2 , SvO2 , and PvO2 decrease, and the
especially if left-sided heart failure cannot be excluded. The systemic-to-venous O2 difference widens.
PCWP estimates LV filling pressure and should approximate Systemic and pulmonary vascular resistances strongly influ-
LVEDP, as long as there are no obstructions in the pulmo- ence the mean pressures in their respective vascular systems.
nary veins or across the mitral valve. The PA diastolic pres- Vasoconstriction increases arterial BP. However, resistances
sure also can estimate PCWP, provided that HR is normal and cannot be measured directly in the intact animal and are gener-
pulmonary vascular resistance is not increased. Increases in ally calculated using a variation of Poiseuille’s or Ohm’s laws. The
PCWP (or pulmonary diastolic pressure) are measured during general formula for calculation of static vascular resistance is as
exercise as left atrial pressure increases,283,356,637 in left-sided follows: Vascular resistance = (Mean arterial pressure − Mean
CHF,353,639 with moderate to severe MR,354,355 and in some atrial pressure)/CO, where pressure is measured in mm Hg and
horses with AF.357 Overinfusion of crystalloid solutions or CO is measured in mL/min. The pressures used are mean aortic
marked depression of LV function are other causes of elevated pressure and mean right atrial pressure for calculation of sys-
PCWP; conversely, the wedge pressure is reduced in hypovole- temic vascular resistance and mean PA pressure and mean pul-
mia. When pulmonary hypertension is not caused by left heart monary wedge pressure for calculation of pulmonary vascular
failure, a near-normal wedge pressure is recorded in the set- resistance. The units for vascular resistance are mm Hg × min
ting of elevated PA diastolic pressure. This indicates increased × mL−1, sometimes abbreviated as peripheral resistance units
vascular resistance across the small arteries due to pulmonary (PRU). Alternatively, resistance is often expressed in centime-
vasoconstriction or pulmonary vascular lesions. One caveat is ter-gram-second (cgs) units as dynes × sec × cm−5, where 1 mm
that a pressure gradient between the PA diastolic and PCWP Hg = 1330 dynes/cm2 and CO is expressed as cm3/sec. The resis-
may be observed in normal horses in the setting of resting tance value in PRU can be multiplied by 80 for conversion to a
tachycardia. corresponding cgs value.114 It is important to note that SVR can
Cardiac output (CO) is the volume of blood pumped be calculated from pressures and CO, but it is not determined
by the left (or right) ventricle in 1 minute. This can be by either of these variables. Physiologically, SVR and CO are the
divided by body weight or body surface area to calculate independent variables, and MAP is the dependent variable.114
the cardiac index. The CO can be measured by thermodi- Normal systemic vascular resistance in average-size (500-kg)
lution techniques, lithium dilution, arteriovenous oxygen adult horses averages about 265 dynes × sec × cm−5. It is con-
difference (Fick methodology), 2D echocardiographic and siderably higher in smaller horses, ponies, and foals, because
Doppler studies (see earlier discussion), and other meth- the total length of the circulation and the total cross-sectional
ods.168,276,294-318,409,628 Cardiac output in standing adult area of the resistance vessels, which according to Poiseuille’s
average-size (500-kg) horses is around 30 to 40 L/min, law determine vascular resistance, are directly related to body
with reported values for cardiac index in standing horses size.57,259 This explains the fact that systemic blood pressures are
or ponies ranging between 60 and 80 mL/min/kg.57 Mea- largely independent of body size despite the differences in CO
surement of CO is most often done clinically when moni- between larger and smaller individuals. Pulmonary vascular
toring the effects of anesthetic agents or during fluid and resistance should be about one fifth that of the systemic value,
drug therapy of the circulation in critical care situations but reported values vary more widely than that.57 Mechanisms
wherein CO relates to tissue oxygen delivery.57 However, that increase systemic vascular resistance include sympathetic
invasive methods involving cardiac catheterization are activation, activation of the renin-angiotensin system, and the
largely limited to research purposes. Traditionally, the release of other vasoactive hormones into the blood, including
thermodilution technique has been the most commonly arginine vasopressin (antidiuretic hormone) and epinephrine.
used method for invasive measurement of cardiac output in The pulmonary vascular resistance is tied to pulmonary vascu-
horses.* Thereby, a thermistor-tipped Swan-Ganz catheter lar anatomy, age, total lung capillary resistance, left atrial pres-
is placed in the pulmonary artery. A cold indicator solution sure, and degree of pulmonary vascular constriction. The latter
is injected into the right atrium or vena cava either through is controlled by the tension of alveolar oxygen and local media-
the proximal injection port of the Swan-Ganz catheter tors, including nitric oxide and endothelin.57,110,112-117,255-257
(in foals) or through a second injection catheter placed
through the jugular vein into the RA (in larger animals). Laboratory Studies
The indicator solution is usually 5% dextrose or saline Cardiovascular disorders may develop as a consequence of sys-
temic or metabolic diseases such as electrolyte disturbances or
* References 259, 296, 301, 304, 307-309, 311, 312, 314, 317, 648. septicemia. Conversely, CV infections, myocardial damage, or
circulatory failure may alter routine laboratory tests. Therefore Y PULMONARY HYPERTENSION AND
laboratory studies might be indicated during the workup of COR PULMONALE
horses with CV disorders. An overview of the laboratory studies
useful in assessment and management of CV diseases is found Pulmonary hypertension (PHT) is hemodynamically charac-
in Box 9.4. terized by pulmonary artery pressures exceeding the upper
A complete blood count, measurement of SAA and fibrin- normal limit by more than 10 mm Hg.692 Current human clas-
ogen concentrations, assessment of a biochemical profile, sifications of pulmonary hypertension include (1) pulmonary
and urinalysis are indicated in horses with arrhythmias, arterial hypertension (including idiopathic, drug and toxin
heart failure, or when there is clinical evidence or suspicion induced, and persistent PHT of the newborn); (2) PHT caused
of endocarditis, pericarditis, vasculitis, myocardial disease by left-sided heart disease (including congenital and acquired
or pleural effusion. Prerenal azotemia and electrolyte dis- heart disease); (3) PHT caused by lung disease and/or hypoxia;
turbances (hyponatremia, hypokalemia, hypomagnesemia) (4) chronic thromboembolic PHT; and (5) PHT with unclear
may be detected in the horse with CHF, especially following multifactorial mechanisms (including hematologic, systemic,
diuretic therapy. Additional studies including arterial and metabolic, and other disorders).693,694
venous blood gas tensions and oxygen saturation, blood lac- In horses, clinically relevant PHT most commonly results
tate concentrations, blood cultures, and cytology and culture from severe mitral valve disease, pulmonary overcirculation
of pericardial effusates are indicated in selected cases. Moni- caused by congenital left-to right shunts (e.g., VSD), or chronic
toring of serum or plasma drug concentrations, especially left-sided heart failure. In these cases, PHT can be very severe,
quinidine and digoxin, are appropriate when these drugs are with systolic pulmonary artery pressures exceeding 80 mm
administered. Hg. Presumably, factors such as reactive vasoconstriction or
Cardiac troponins are sensitive and tissue-selective diag- anatomic changes (structural remodeling) in the pulmonary
nostic biomarkers of myocardial damage in mammals.649,650 vascular tree must develop as a consequence of elevated left
Troponins may be released in the circulation from primary or atrial pressures in order to sustain such high pressures at rest.
secondary cardiac muscle injury, as might occur with myocar- Pulmonary hypertension is occasionally diagnosed in foals
dial infarction, myocarditis, cardiomyopathy, toxic or nutri- and adult horses with severe respiratory disease.695-699 In addition
tional myocardial injury, mechanical or electrical myocardial to structural vascular and parenchymal changes,645 low alveolar
damage, hypotension, ischemia, endothelial injury, DIC, oxygen tension is considered a very potent trigger of (reversible)
endotoxemia, and septicemia.161-164,575,651-668 High-intensity or pulmonary vasoconstriction leading to an increase in pulmonary
prolonged exercise also induces a small rise in plasma cTnI vascular resistance.700,701 Hypoxia was found to be a contribut-
but does not necessarily indicate underlying structural heart ing factor leading to (relatively mild) pulmonary hypertension
disease and can be observed in healthy horses.355,484,669-673 in horses with recurrent airway obstruction.646,697-699 Hypoxic
Both cardiac troponin I (cTnI) and cardiac troponin T (cTnT) vasoconstriction may also be particularly important in newborn
are useful for detection of myocardial injury in horses674-677 foals, in which vascular resistance is already high.409
and have replaced the less specific LDH and CK-MB isoen- Persistent pulmonary hypertension of the newborn foal
zymes in clinical practice. Troponin concentrations can be (also called persistent fetal circulation or reversion to fetal
obtained from most commercial laboratories or using hand- circulation) results from failure to successfully make the car-
held point-of-care analyzers.650,656 Normal plasma cardiac diorespiratory transition to extrauterine life or from reversion
troponin concentrations vary depending on assay and labora- to fetal circulatory patterns in response to hypoxia or acido-
tory but are often near or below the limit of detection of the sis.609,702,703 The fetal circulatory pattern with PHT and right-
respective assay.656,674,676-679 The average half-life of cTnI in to-left shunting of blood through the patent foramen ovale
horses is less than 1 hour.680 Failure to observe a decline in (PFO) and the ductus arteriosus are maintained in these cases,
plasma cTnI concentrations over several hours therefore sug- and affected foals are in hypoxemic respiratory failure. Fac-
gests ongoing myocardial damage as opposed to acute, tran- tors contributing to persistent PHT in newborns are chronic
sient myocardial injury. in utero hypoxia or acidosis, asphyxia, and meconium aspira-
Natriuretic peptides are released in the blood in response tion, but often the precipitating trigger is unknown.702
to a variety of stimuli, including myocardial stretch due Pulmonary thromboembolism is rarely diagnosed in
to volume overload and increases in intracardiac pres- horses,193,704-709 but it is possible that the condition is in fact
sures.110,112-114,116,664,681 Plasma atrial natriuretic peptide (ANP) underrecognized in clinical practice and that its incidence
concentrations increase during exercise,355,682-687 and they can might be higher than supposed.705 Idiopathic pulmonary
be elevated in horses with cardiac disease, particularly in the hypertension has been reported as a cause of AF in horses;
presence of LA enlargement or LA dysfunction.355,688-690 To however, left-sided heart dysfunction was not completely
date, no assays are available for accurate and reliable measure- excluded in the reported cases.96
ment of ANP in equine blood in routine clinical practice.664,691 Exercise-induced PHT, with mean pulmonary artery pres-
Therefore the use of ANP as a cardiac biomarker is currently sures exceeding 80 to 90 mm Hg, is a unique feature in horses
limited to experimental settings, and more work needs to be and ponies. It is likely caused by the massive (up to tenfold)
done to elucidate its clinical value in horses with heart disease. increase in pulmonary blood flow, in association with high
A variety of other cardiac biomarkers potentially indicating LV filling pressures (necessary to ensure rapid ventricular fill-
myocyte stress, myocyte injury, neurohormonal activation, ing at maximal HRs), compression of pulmonary vessels dur-
myocardial remodeling, inflammation, or oxidative stress are ing forced expiration and inspiration, greater blood viscosity
known but are currently not used for routine diagnostic pur- related to the exercise-induced rise in packed cell volume, and
poses in horses with heart disease.664 Further application of possibly arteriolar vasoconstriction.* Elevated pulmonary
laboratory studies is discussed under specific diseases later in
this chapter. * References 53, 414, 448, 608, 610, 637, 643, 644, 710-716.
vascular pressures during strenuous exercise are thought to VSD (4.00%)

be one of the major factors contributing to capillary stress Pericarditis (4.00%)
failure and the occurrence of exercise-induced pulmonary Tachyarr (12.00%)
DCM (8.00%)
hemorrhage.53,210,644,717
Pulmonary hypertension increases afterload on the RV
VHD + AF (28.00%)
and results in elevated end-diastolic and central venous pres-
VHD (32.00%)
sures. Acute PHT may result in RV dilation, because there is
not enough time for adaptive mechanisms (e.g., RV hypertro- Vasc Dz (4.00%)
phy) to develop. If pulmonary hypertension is chronic, RV Mass (8.00%)
hypertrophy will develop over time. Increased RV pressures
and alterations in RV geometry often result in tricuspid regur- FIG. 9.27 Graph demonstrating the overall causes of congestive heart
gitation. In severe cases, the interventricular septum bulges failure (CHF) in 25 horses at a referral teaching hospital as a percentage
into the LV, interfering with filling and thus causing diastolic of the total number of cases of equine CHF. Tachyarr, Tachyarrhythmia;
LV dysfunction. Right-sided or biventricular heart failure can VSD, ventricular septal defect; DCM, dilated cardiomyopathy; VHD, val-
ensue. vular heart disease; Mass, mass lesion; Vasc Dz, vascular disease; VHD
Cor pulmonale is characterized by right ventricular + AF, valvular heart disease and atrial fibrillation. Data from Ohio State
enlargement secondary to PHT due to pulmonary paren- University Veterinary Hospital.
chymal or vascular disease, in the absence of left ventricular
failure, a congenital malformation (e.g., VSD), or an acquired
valvular disorder. Diagnosis of cor pulmonale requires evi- or a combination of the two, limited CO in the setting of
dence of pulmonary hypertension and exclusion of a pri- normal to high venous pressures, increased neurohormonal
mary cardiac disease.57,692 Cor pulmonale is uncommon in activity, renal sodium retention, accumulation of edema in
horses.374,695,718-721 Although both acute and chronic airway tissues, and transudation of fluid into serous body cavities.
obstruction can negatively affect right heart and overall car- The neurohormonal and renal abnormalities that character-
diac function,646,696,720,721 there is no compelling evidence at ize heart failure have not been extensively studied in horses
this time to incriminate cor pulmonale as a common cause of but are probably similar to those reported in other species
clinically important heart disease in horses. and include increase in sympathetic tone, activation of the
On physical examination, a split-second heart sound with renin-angiotensin-aldosterone system, and increased release
a loud pulmonic component and a right-sided systolic heart of antidiuretic hormone (vasopressin) and atrial natriuretic
murmur consistent with TR may be detected in horses with peptide.* The most sensitive sign of heart failure is impaired
pulmonary hypertension. In cases of severe PHT, signs of exercise capacity, but this is hardly specific in horses. The most
right-sided congestive heart failure including distended jug- characteristic clinical features of heart failure are tachycardia,
ular veins and peripheral edema will be evident. Pulmonary increased venous pressures, and fluid accumulation. The typi-
artery pressures can be estimated echocardiographically by cal horse with cardiac failure is recognized in the overtly con-
Doppler flow imaging of tricuspid or pulmonic regurgitation gested phase termed congestive heart failure (CHF) (see Figs.
velocities. Enlargement of the pulmonary artery (exceeding 9.11 and 9.12).
the aortic root diameter) is considered a fairly specific (but However, most cardiac lesions in horses are insufficient
not sensitive) indicator of pulmonary hypertension. Cardiac to cause CHF, and this syndrome is not common in equine
catheterization allows invasive measurement of pulmonary practice. Nevertheless, CHF does develop in foals and mature
artery pressures and pulmonary capillary wedge pressures horses as a consequence of diverse disorders, including the
and may aid in the diagnosis of pulmonary hypertension and following: congenital malformation, severe degenerative
cor pulmonale. Further details on the diagnostic procedures valvular disease, chordal rupture, valvulitis, bacterial endo-
required to diagnose PHT have been discussed earlier in this carditis, dilated or infiltrative cardiomyopathy, myocarditis,
chapter. myocardial necrosis, pericardial disease, vascular rupture,
Horses with PHT are considered unsafe to ride or drive.68 pulmonary hypertension, artery obstruction, or persistent
Treatment of PHT should include alleviation of hypoxia and tachyarrhythmia.* The most common cause of CHF in horses
acidosis to minimize functional hypoxic vasoconstriction. is valvular heart disease—often complicated by atrial fibrilla-
Elimination of the underlying cause may be possible in horses tion, the onset of which can trigger transition from the com-
and foals with severe but treatable lung disease. Horses with pensated to the decompensated phase of heart failure (Fig.
PHT secondary to severe left heart disease require symp- 9.27). In addition to structural lesions of the heart and blood
tomatic treatment of heart failure (see later discussion). Note vessels, primary electrical disturbances, particularly sustained
that diuretics may be harmful in horses with cor pulmonale AV dissociation caused by intractable junctional or ventricu-
because small decreases in preload often worsen clinical lar tachycardia, can cause tachycardia-induced cardiomy-
signs. Nitric oxide (NO) is a potent, selective vasodilator of mopathy, reduce myocardial function, decrease CO, and lead
the pulmonary circulation, and inhaled NO may have value as to CHF.736 This is especially likely when the HR exceeds 100
a therapeutic agent in foals with PHT.702,722 The use of other beats/min for many days. Resolution of CHF in such cases
pulmonary vasodilators or of endothelin receptor blockers has may be possible if antiarrhythmic therapy and rate control are
not been established for treatment of PHT in horses. successful.153
Y CONGESTIVE HEART FAILURE

* References 57, 110, 112-114, 115, 144, 355, 688-690, 723.
Heart failure is a clinical syndrome characterized by cardiac * References 83, 125-127, 144, 148, 152, 192, 204, 212, 213, 262, 265, 352, 374,
disease leading to systolic dysfunction, diastolic dysfunction, 546, 563, 724-735.
Clinical Recognition of Heart Failure mediastinal lymphoma and cranial thoracic masses including
Congestive heart failure may develop suddenly or gradually. large pulmonary abscesses must be distinguished from RV
Peracute heart failure can occur following acute-onset mitral failure.140,737 Differential diagnosis is facilitated by examina-
regurgitation due to chordal rupture or papillary muscle tion with 2D echocardiography and thoracic ultrasonography.
ischemia or infarction, consequent to acute endocarditis of The recognition of isolated left-sided heart failure, which
a heart valve, or as a result of acute vascular rupture leading causes pulmonary venous congestion and pulmonary intersti-
to an aortocardiac fistula.262,265,374 Heart failure may progress tial or, uncommonly, alveolar edema, is more difficult in
rapidly in a foal with a large ventricular septal defect as the horses. Tachypnea and respiratory distress are predominant
pulmonary vascular resistance falls in the weeks following clinical signs. In these cases, heart sounds and murmurs may
birth.117,728 Chronic valvular regurgitation can after many be difficult to identify owing to loud airway sounds or even
years lead to CHF, although only a small number of horses pulmonary crackles. If a cardiac murmur is present but missed,
with degenerative valvular disease develop CHF.583 Some an erroneous diagnosis of pneumonia or severe equine asthma
lesions, which might otherwise be well tolerated, can cause (recurrent airway obstruction) may be entertained. Again,
heart failure if there are increased demands for CO. Examples resting tachycardia and loud third heart sound are typical in
include strenuous work, severe anemia, or persistent fever. these cases, and echocardiographic examination of the horse
Pregnancy is another example: the volume expansion and will be particularly useful. Typical findings in acute left-sided
increased demands for CO in the latter stages of gestation may CHF are dilation and rounding of the left atrium and ventricle
precipitate CHF in a mare with previously compensated heart and often dilation of the PA caused by pulmonary hyperten-
disease. Development of AF in a horse with underlying struc- sion. Careful examination may demonstrate anatomic lesions
tural disease, such as severe mitral or aortic regurgitation, can of the aortic root, ventricular septum, left heart valves, papil-
precipitate CHF. Such cases are distinguished from the more lary muscles, or chordae tendineae. Fulminant left-sided CHF
typical case of AF by the presence of persistent, resting tachy- can lead to coughing and expectoration of edema—a grave
cardia and identification of structural lesions and cardiomeg- sign in most horses (see Fig. 9.10).
aly during echocardiography. Biventricular CHF is most commonly observed when severe
The clinical features of CHF are easily recognized,724 but left-sided disease results in chronic CHF and is complicated by
determination of the underlying cause of heart disease may be AF. The clinical signs of advanced biventricular heart failure
more difficult. The etiology can be established if careful aus- include resting tachycardia (usually >60 beats/min), loud ven-
cultation is combined with echocardiography, ECG, labora- tricular filling sound, subcutaneous edema, tachypnea (from
tory tests, and ultrasound examination of other body cavities.* pulmonary congestion or pleural effusion), varying amounts
Presenting clinical signs can vary but often include exercise of ascites and pleural effusion, a small pericardial effusion,
intolerance, poor recovery after exercise, lethargy, anorexia, jugular distention, and abnormal jugular pulsations. Chronic
weight loss, loss of body condition, coughing, tachypnea, ven- biventricular CHF is frequently characterized by lethargy and
tral edema, and colic-like signs. loss of body condition. In most cases there will be a left-sided
The clinical features of right-sided CHF include resting heart murmur typical of mitral or aortic valve regurgitation
tachycardia (generally at 60/min or greater) and prominent and a murmur of tricuspid regurgitation on the right, which in
third (ventricular) sound along with generalized ventral, pre- advanced cases may become more prominent than the left-sided
putial, pectoral, and limb edema. Scrutiny of the jugular and murmurs. Infrequently, biventricular CHF is due to congenital
other superficial veins generally makes the recognition of heart disease such as a VSD or a complex malformation.
right-sided CHF straightforward, because affected horses It is important to understand that chronic left-sided CHF
demonstrate elevated venous pressure and pathologic jugular in the horse is likely to cause interstitial lung edema and pul-
pulses and filling (see Figs. 9.11 and 9.12). Isolated limb monary hypertension in the absence of overt clinical signs of
edema, which is common in hospitalized horses, or ventral left-sided heart failure. The magnitude of pulmonary hyper-
edema in the absence of generalized venous distention are not tension is often impressive, with systolic PA pressures exceed-
a sign of CHF and should prompt consideration of other dis- ing 80 mm Hg in many cases. The mechanisms by which the
orders causing edema including hypoproteinemia, vasculitis, lung accommodates such severe and chronic elevations in
or severe pleural or abdominal effusion. pulmonary venous pressures without development of alveolar
The most common causes of “isolated” right-sided CHF are edema is speculative. It is likely that pulmonary arterial resis-
tricuspid or pulmonic valve lesions as with valvular endocardi- tance increases, possibly related to remodeling in pulmonary
tis, diffuse pulmonary vascular disease, and pericardial disease. arteries from chronic elevation of LA pressure. Chronic pul-
In most cases a prominent murmur of tricuspid regurgitation monary hypertension subsequently leads to RV dilation and
will be evident over the right thorax. When there is pulmo- hypertrophy, tricuspid regurgitation, and RV failure, which
nary hypertension underlying right-sided failure, the tricuspid limits CO and results in predominant clinical signs of right-
murmur may be especially loud and the pulmonic component sided CHF. Thus the clinician should anticipate signs of right-
of the second heart sound tympanic. Because right-sided heart sided CHF even when the primary cardiac lesion is located
failure often develops consequent to pulmonary hypertension on the left side of the heart. Clinical findings of severe pulmo-
caused by left-sided heart failure, concurrent left-sided mur- nary hypertension caused by left-sided CHF include a loud,
murs are not uncommon. Another common association of tympanic, pulmonary component of the second heart sound
right-sided CHF is persistent cardiac arrhythmia, such as AF, (heard cranioventral to the aortic valve area), a systolic mur-
superimposed on structural heart disease of any form. Cranial mur and jugular pulse of tricuspid insufficiency, and dilation
of the PA, which can be identified by 2D echocardiography.
* References 83, 125-127, 144, 148, 152, 192, 204, 212, 213, 262, 265, 352, 374,
Thoracic radiographs may demonstrate increased pulmonary
546, 563, 725-735. vascularity, pulmonary infiltration near the hilus, pleural
effusion, and rounding or enlargement of the cardiac silhou- sulfate solution, quinidine, procainamide, propafenone,
ette. Further scrutiny of the echocardiogram identifies LA sotalol, or amiodarone may be effective for treatment of some
dilation and lesions affecting the LV and usually the mitral of these arrhythmias,55,58 and with resumption of normal
valve, aortic valve, or aorta. Doppler echocardiography can rhythm, CHF may be reversed.153
document abnormal flow patterns such as valvular regurgita- Horses in CHF should be brought to a quiet environment,
tion and predict PA pressures (using the Bernoulli relationship and any type of stress should be avoided or at least minimized
discussed previously). An ECG is needed to evaluate cardiac as much as possible. This also means that diagnostic interven-
arrhythmias. tions, although necessary, should be limited to those that are
required to make an initial decision about the most appropri-
Therapy for Congestive Heart Failure ate initial treatment.
Therapy for CHF is realistic for potentially reversible disorders Diuretics are used in the treatment of CHF not associated
such as acute papillary muscle ischemia/dysfunction, myocar- with cardiac tamponade in order to reduce volume overload
ditis, pericarditis or sustained ventricular tachyarrhythmia. It and edema and prevent their recurrence. Loop diuretics such
may also be feasible for valuable breeding stallions and mares, as furosemide are preferred due to their superior fluid clear-
mares that develop CHF during gestation, or horses and ance and dose-dependent effects. They act by inhibiting the
ponies kept as pets.724,727 The goal of treatment is to reduce the Na+/K+/2 Cl− cotransporter in the ascending limb of the loop
hemodynamic consequences of heart failure, restore cardiac of Henle.743 Furosemide is administered to horses with CHF
output, and reduce congestion. Before therapy can commence, at initial dosages of 1 to 2 mg/kg IV, given as repeated boluses
an accurate diagnosis is needed. For example, pericardiocen- to effect.55,58,327,744-748 Because the site of action is reached
tesis (not cardiac drugs) would be the appropriate initial man- intraluminally after excretion of furosemide by the proximal
agement of cardiac tamponade; thereafter, surgical drainage of tubule, higher or more frequent doses might be required when
the effusion (using drainage tubes) or a pericardiectomy could renal function is impaired.743 Bolus administration followed
be considered.125-127,133,137,738-742 Antibiotics would be essential by constant rate infusion is thought to be more effective than
in the treatment of bacterial endocarditis or infective pericar- intermittent bolus administration and can be chosen when
ditis. Sustained junctional and ventricular tachyarrhythmias profound diuresis is needed747 (Table 9.7). Respiratory effort
may lead to low CO and a potentially reversible dilated cardio- should improve when pulmonary edema is evident, and doses
myopathy. Antiarrhythmic therapy with lidocaine, magnesium should be adapted as dictated by respiratory rate and effort.
Text continued on page 461
TABLE 9.7 Drug Therapy of Heart Disease

Comments
Therapeutic Drug Monitoring Indications (I)
Drug Dose Recommendations Adverse/Toxic Effects Contraindications (CI)
ANTIARRHYTHMICS
Sodium Channel Blocker (Class IA)
Quinidine sulfate 22 mg/kg quinidine sulfate PO IV administration for AF of recent onset I: AF, SVT (ventricular arrhyth-
(PO) or gluco- by NGT q 2 h for 4 (–6) doses (<2 weeks) without underlying structural mias).
nate (IV) until converted, adverse or toxic heart disease or AF occurring during CI: Ventricular tachyarrhyth-
effects, or plasma quinidine anesthesia. mias, torsades de pointes,
concentration >4 μg/mL. Do not PO administration preferred for long- untreated heart failure,
exceed 6 doses PO q 2 h. standing AF (>2–4 weeks). preexisting prolonged QRS
Continue q 6 h until converted, Therapeutic drug monitoring: therapeutic or QT interval, complete AV
adverse or toxic effects, or total range: 2–5 μg/mL [6.2–15.4 μmol/L] block, digitalis intoxication.
dose of 180 mg/kg. 1–2 h after PO administration. Use with caution in patients
1–2.2 mg/kg quinidine gluconate Adverse effects: Commonly depression, with uncorrected hypoka-
IV q 10 min or 0.1–0.22 mg/kg/ diarrhea, colic, nasal mucosal swell- lemia, hypomagnesemia,
min CRI up to 12 (–24*) mg/kg ing, and ataxia. Rarely paraphimosis, hypoxia, or acid-base
total dose (*Caution: Can result urticaria, and laminitis. Cardiovascular disorders.
in severe adverse effects!) effects include acceleration of AV con-
duction and tachycardia (most com-
mon), prolonged QRS and QT interval,
VT or torsades de pointes, hypotension,
neg. inotropism, exacerbation of heart
failure, cardiovascular collapse, sudden
death.
Procainamide 25–35 mg/kg PO q 8 h Adverse effects: Hypotension, QRS and I: Ventricular and supraven-
1 mg/kg/min IV, up to 20 mg/kg QT prolongation, neg. inotropism, ar- tricular arrhythmias.
total dose rhythmias, GI and neurologic disorders. CI: See quinidine.
Similar but generally less severe than
with quinidine.
Continued
TABLE 9.7 Drug Therapy of Heart Disease—cont’d

Comments
Sodium Channel Blocker (Class IB)
Lidocaine 0.25–0.5 mg/kg slow IV, repeat Adverse effects: Low incidence at thera- I: Ventricular arrhythmias,
in 5–10 min to effect, up to 1.5 peutic doses. Occasionally depression (potentially vagally sustained
mg/kg total dose; followed by and muscle fasciculations. Overdoses AF).
0.03–0.05 mg/kg/min CRI may lead to ataxia, CNS excitement, CI: SA, AV, or intraventricular
seizures, hypotension, VT, collapse, and block, bradycardia.
sudden death. Caution with hypovolemia,
liver disease, shock, and
heart failure.
Phenytoin 20 mg/kg PO q 12 h for 3–4 Maintenance dose varies considerably. I: Digoxin-induced arrhyth-
doses or until signs of sedation, Therapeutic drug monitoring: therapeutic mias, other ventricular
followed by 10–15 mg/kg PO q range 5–10 μg/mL [19.8–39.6 μmol/L]. arrhythmias.
12 h maintenance dose Adverse effects: Sedation, lip and facial CI: SA or AV block, sinus
5–10 mg/kg IV, followed by 1–5 twitching, gait deficits, excitation bradycardia.
mg/kg IM q 12 h or 10–15 mg/ seizures, arrhythmias. Hepatotoxicity
kg PO q 12 h with chronic therapy. Hypotension and
respiratory depression at high doses.
Sodium Channel Blocker (Class IC)
Flecainide 1–2 mg/kg IV, infused at a rate of Use with caution. I: Acute AF, supraventricular
0.2 mg/kg/min Not generally recommended for treat- and ventricular arrhythmias
4 mg/kg PO q 2 h for 4–6 doses, ment of AF. Not considered effective for resistant to other treatments.
followed by 4 mg/kg PO q 4 h; chronic AF. CI: Structural heart disease,
adjust dose intervals if signs of Adverse effects: depression, colic, neu- heart failure, SA or AV node
toxicity occur rologic signs, negative inotropism, QRS dysfunction.
and QT prolongation, severe ventricular
arrhythmias, sudden death.
Propafenone 0.5–2.0 mg/kg in 5% dextrose Not commonly used. I: Supraventricular and ven-
slowly IV over 10–15 min Adverse effects: GI and neurologic tricular arrhythmias resistant
2 mg/kg PO q 8 h disorders, bronchospasm, negative ino to other treatments.
tropism, exacerbation of heart failure, CI: Structural heart disease,
AV block, QRS and QT prolongation, heart failure, SA or AV node
arrhythmias. dysfunction.
β-Adrenoceptor Blocker (Class II)
Propranolol 0.03–0.16 mg/kg slow IV q 12 h Unspecific β1/β2-blocker. I: SVT and AF (rate control,
0.38–0.78 mg/kg PO q 8 h Variable oral bioavailability. often in combination with
Dosage should be individually adjusted. digoxin), catecholamine-
Adverse effects: Depression, lethargy, induced arrhythmias, unre-
weakness, bradycardia, AV block, sponsive supraventricular
hypotension, neg. inotropism, exacer- and ventricular arrhythmias.
bation of heart failure, bronchoconstric- CI: Bradycardia, high-degree
tion (aggravation of recurrent airway AV block, untreated heart
obstruction). failure, bronchopulmonary
disease.
Potassium Channel Blocker (Class III)
Sotalol 1 mg/kg PO q 12 h for 1 d, con- Also class II effects. I: Prevention of recurrent AF,
tinue at 2–3 mg/kg PO q 12 h Good oral bioavailability. supraventricular and ven-
Generally well tolerated, even with tricular arrhythmias
chronic oral administration. CI: Preexisting QT prolonga-
Dosage should be gradually reduced tion. Use with caution in
before discontinuing medication. patients with uncorrected
Adverse effects: QT prolongation, ven- hypokalemia or hypomag-
tricular arrhythmias. nesemia.

Comments
Amiodarone 5 mg/kg/h IV for 1 h, followed Also class I, II, and IV effects. I: AF, ventricular arrhythmias
by 0.83 mg/kg/h for 23 h, and Poor and variable oral bioavailability, long (not investigated).
subsequently 1.9 mg/kg/h for half-life (16 days). CI: Sinus node dysfunction,
30 h or to effect Adverse reactions: Hindlimb weakness, bradycardia, AV block, car-
weight shifting, torsades de pointes diogenic shock.
(supposedly low incidence), SA and AV
nodal inhibition, bradycardia, hypoten-
sion. Prolonged treatment may affect
lungs, liver, heart, thyroid gland, GI
tract, eyes, skin, and nerves.
Bretylium tosy 3–5 mg/kg IV, repeat up to 10 Also indirect antiadrenergic effects. I: Refractory, life-threatening
late mg/kg Adverse effects: Excitement, GI dis- ventricular tachycardia,
orders, hypotension, tachycardia, ventricular fibrillation.
arrhythmias.
Calcium Channel Blocker (Class IV)
Diltiazem 0.125 mg/kg over 2 min IV, re- Titrate to effect. Use diltiazem doses I: Supraventricular arrhythmias
peated q 10 min to effect, up to >0.5–1.0 mg/kg with caution. (ventricular rate control in AF
1.25 mg/kg total dose Adverse effects: Hypotension, tachy- and interruption of SA/AV
Verapamil 0.025–0.05 mg/kg IV q 30 min, cardia, sinus arrhythmia, bradycardia, nodal-dependent SVT).
up to 0.2 mg/kg total dose sinus arrest, high-grade AV block, CI: Hypotension, bradycardia,
negative inotropism, exacerbation of SA or AV block, ventricular
heart failure (unless secondary to SVT systolic dysfunction, severe
or AF with rapid ventricular response heart failure, cardiogenic
rate). shock, β-blocker.
Physiologic Calcium Channel Blocker, Activator of Membrane Na+/K+-ATPase
Magnesium 2–6 mg/kg/min IV to effect, up 55 Adverse effects: Overdoses (rare) may I: Ventricular arrhythmias (esp.
sulfate (–100) mg/kg total dose lead to CNS depressant effects, weak- torsades de pointes and
ness, trembling, bradycardia, hypoten- refractory VT), hypomag-
sion. Very high doses lead to neuro- nesemia associated with
muscular blockade with respiratory cardiovascular disease.
depression and cardiac arrest. CI: Bradycardia, SA and AV
block, renal failure.
DIGITALIS GLYCOSIDES
Digoxin IV loading dose: 0.0022 mg/kg IV Therapeutic drug monitoring: peak (1–2 I: Heart failure, ventricular rate
q 12 h, for 2 doses h) and trough (12h) concentrations at control in SVT or AF.
IV maintenance dose: 0.0022 mg/ steady state should fall within 0.8–1.2 CI: AV block, diastolic ventric-
kg IV q 24 h (2.0) ng/mL (1–1.5 [2.6] nmol/L). ular dysfunction, preexisting
PO maintenance dose: 0.011 mg/ Adverse effects: Depression, anorexia, digitalis toxicity, myocarditis,
kg PO q 12 h colic, diarrhea, sinus bradycardia, AV ventricular arrhythmias.
block, supraventricular and ventricular
arrhythmias (bigeminy).
ADRENERGIC (SYMPATHOMIMETIC) AGENTS
Inotropes
Dopamine 1–5 μg/kg/min CRI, titrate to ef- β1-adrenergic, also dose-dependent I: Hypotension, acute heart
fect or adverse reactions dopaminergic and α1-adrenergic. failure, cardiogenic shock,
Adverse reactions: Tachycardia, ventricu- noncardiogenic shock (after
lar arrhythmias, vasoconstriction and adequate fluid loading),
hypertension can occur at doses >4–5 sinus arrest, bradycardia,
μg/kg/min. high-grade or complete
Dobutamine 1–5 μg/kg/min CRI, titrate to ef- β1-adrenergic, also β2- and α1- AV block, vagally induced
fect or adverse reactions adrenergic. bradyarrhythmias.
Preferred over dopamine. CI: Ventricular arrhythmias,
Adverse reactions: Tachycardia, ventricu- tachycardia, atrial fibrillation
lar arrhythmias, vasoconstriction. (risk of severe tachycardia
due to accelerated atrioven-
tricular conduction).
Continued

Comments
Epinephrine 0.01–0.05 mg/kg IV β-adrenergic, α1-adrenergic at higher I: Ventricular asystole, cardio-
0.1–0.5 mg/kg IT doses. pulmonary resuscitation.
Note different concentrations: Adverse effects: Tremor, excitability, CI: Nonanaphylactic shock,
1:1,000 = 1 mg/mL arrhythmias, ventricular fibrillation. arrhythmias, hypertension.
1:10,000 = 0.1 mg/mL Overdoses can lead to hypertension,
arrhythmias, renal failure, pulmonary
edema, cerebral hemorrhage.
Vasopressors
Norepinephrine 0.05–1 μg/kg/min CRI, titrate to α1-adrenergic, norepinephrine also exerts I: Hypotension and shock
effect some β1-adrenergic effects. associated with excessive
Phenylephrine 0.1–1 μg/kg/min CRI, titrate to Usually administered in conjunction with peripheral vasodilation (i.e.,
effect fluid therapy and dobutamine. septic or endotoxic shock,
Adverse effects: Hypertension, reflex quinidine toxicity; after ad-
bradycardia, reduction in cardiac output equate volume loading).
due to increased afterload, CNS ef- CI: Hypertension, bradycardia,
fects (excitement, restlessness), rarely poor cardiac output, cardiac
arrhythmias. Overdosage can lead to disease, ventricular tachy-
seizures, ventricular arrhythmias, cere- cardia.
bral hemorrhage.
ANTICHOLINERGIC (VAGOLYTIC) AGENTS
Atropine 0.01–0.02 mg/kg IV, IM Adverse effects: Constipation, ileus, I: Vagally induced bradyar-
Glycopyrrolate 0.005–0.01 mg/kg IV colic, bradycardia (initially or at very low rhythmias, sinus bradycar-
doses), tachycardia, arrhythmias, CNS dia, sinus arrest, high-grade
effects (stimulation, drowsiness, ataxia, or complete AV block.
seizures, respiratory depression). Glyco- CI: Tachycardia, tachyar-
pyrrolate is slightly less arrhythmogenic rhythmias, heart failure, GI
and rarely results in CNS effects. disease, colic.
ANGIOTENSIN-CONVERTING ENZYME (ACE) INHIBITORS
Benazepril 0.5–1.0 mg/kg PO q 24 h Potential effects include vasodilation, I: Cardiovascular protection in
Ramipril 0.05–0.2 mg/kg PO q 24 h reduction of volume overload, blunting cases with AR or MR, treat-
Quinapril 0.25 mg/kg PO q 24 h of mechanism leading to diuretic resis- ment of heart failure.
tance, cardioprotection by decreasing CI: Severe renal failure,
Enalapril 0.5 mg/kg PO q 12 h
myocardial remodeling and fibrosis. hyperkalemia, hypotension,
Optimal doses, safety, and efficacy in pregnancy.
horses largely unknown.
Benazepril appears most effective at
inhibiting serum ACE activity.
Monitor renal function and serum potas-
sium concentration.
Adverse effects: Cough, impairment of
renal function, hypotension, hyperka-
lemia.
VASODILATORS AND INODILATORS
Acepromazine 0.02–0.06 mg/kg IM q 6–8 h, Sedative/tranquilizer, anxiolytic, anti- I: Management of CHF
titrate to effect arrhythmic, vasodilator (decreases CI: Hypotension, hypovole-
0.3–1.0 mg/kg PO q 12 h, titrate afterload). mia, use cautiously and in
to effect Start at lower dose and titrate up to ef- smaller doses in animals
fect. with hepatic dysfunction.
Monitor systemic blood pressure.
Adverse effects: Hypotension, protrusion
of penis (very low risk of permanent pe-
nile dysfunction in intact male horses).

Comments
Hydralazine 0.5–1.5 mg/kg PO q 12 h Arterial vasodilator (reduces afterload). I: CHF, mitral regurgitation.
0.5 mg/kg IV q 12 h Adverse effects: Transient weakness, CI: Hypotension, hypovole-
lethargy, hypotension, tachycardia, mia, severe renal disease.
sodium/water retention (unless given
with diuretics).
Nitroglycerine 5–20 μg/kg/min CRI, titrate to Venous vasodilator (reduces preload). I: Acute management of CHF.
effect Tolerance with long-term treatment CI: Hypotension, hypovole-
(12–24 h). mia.
Adverse effects: Severe hypotension,
reflex tachycardia, weakness.
Milrinone 0.2 μg/kg IV bolus, followed by 10 Phosphodiesterase inhibitor (inodilator). I: Acute management of CHF.
μg/kg/min CRI Adverse effects: Arrhythmias, hypoten- CI: Normal or low filling pres-
0.5–1.0 mg/kg PO q 12 h sion, tachycardia, accelerated AV sures, severe renal failure.
conduction.
DIURETICS
Furosemide Initial dose for CHF: 1.0–3.0 mg/ Start at higher/more frequent doses and I: Congestive heart failure,
kg IV or IM q 8–12 h as needed reduce to minimal effective dose, as edema.
to produce diuretic effect dictated by respiratory rate and effort. CI: Dehydration, severe elec-
Alternatively: 1–2 mg/kg IV load- Oral administration not effective. trolyte disturbances.
ing dose, followed by 0.12 mg/ Adverse effects: At high doses risk of
kg/h CRI hypovolemia, renal failure, electrolyte
Maintenance dose: 1 mg/kg IV or and acid-base imbalances.
IM q 12 h

AF, Atrial flutter/fibrillation; AR, aortic regurgitation; AV, atrioventricular; CHF, congestive heart failure; CRI, constant rate infusion; HF, heart failure; IT, intratra-
cheal; MR, mitral regurgitation; NGT, nasogastric tube; RAAS, renin-angiotensin-aldosterone system; SA, sinoatrial; SVT, supraventricular tachycardia; VT,
ventricular tachycardia.
Volume depletion, azotemia, and electrolyte imbalances are can be administered as a continuous rate infusion (CRI),
the most common adverse effects of furosemide treatment. taking its proarrhythmic and vasoconstrictive effects into
Renal function should be followed and the dosage controlled account (see Table 9.7).55,57,58,743 For chronic inotropic sup-
to minimize prerenal azotemia. Diuretic therapy can eventu- port, digoxin is commonly used. Digoxin therapy is indicated
ally be discontinued in some horses, but others will require for CHF not associated with pericardial disease or serious
once- or twice-daily administration on the farm to prevent ventricular ectopy. It is particularly beneficial when there is
fluid retention. Systemic availability of orally administered concurrent AF superimposed on structural valvular heart dis-
furosemide is poor and variable,745 and therefore oral treat- ease, because in addition to its inotropic effects it also causes
ment is not recommended. Prolonged diuresis may lead to loss baroreceptor sensitization and increases vagal tone, thereby
of diuretic potency and diuretic resistance, which can poten- reducing HR (negative chronotropic effects) and control-
tially be counteracted by coadministration of angiotensin- ling ventricular response rate to AF (negative dromotropic
converting enzyme inhibitors.743 effects).743 Treatment is initiated by the intravenous route,
Short-term therapy with intranasal oxygen therapy, if avail- with most (450–550 kg) horses receiving a total dose of about
able, at a rate of 5 to 10 L/min using one or two nasal cannulas 1 mg IV (see Table 9.7). The reported elimination half-life of
might be useful for horses with respiratory distress. digoxin has not been consistent (7.2–28 hours) and probably
Horses in CHF can be cautiously sedated using aceproma- relates to the clinical state of the animals studied.* Long-term
zine to minimize stress. In addition to its anxiolytic effects, digoxin therapy involves once- or twice-daily oral adminis-
acepromazine also acts as an antiarrhythmic and a potent tration. Oral doses of digoxin are relatively higher because
vasodilator. As such, it reduces afterload, thereby decreasing of lower bioavailability (20%).320,330,331,334 Chronic digoxin
valvular regurgitant fraction and facilitating ventricular ejec- therapy is monitored by measuring the serum digoxin con-
tion. Acepromazine should be titrated to effect, and if possible, centration (drawn 8–12 hours after the previous dose). Tar-
systemic blood pressures should be monitored to avoid severe get therapeutic values range between 0.8 and 1.2 (2.0) ng/mL
hypotension (see Table 9.7).58 Note that α2-adrenergic agonists (1–1.5 [2.6] nmol/L), depending on the time of the blood sam-
such as xylazine and detomidine should not be used for seda- ple, and drug therapy achieving these serum concentrations is
tion in horses with CHF, because they act as vasoconstrictors usually well tolerated in terms of appetite and heart rhythm.
that increase afterload and result in increased regurgitant frac- Periodic cardiac examinations, measurements of serum bio-
tion and workload of the heart. chemistries (creatinine, electrolytes), and recordings of ECG
If acute positive inotropic support is required for stabiliza-
tion of CHF or treatment of cardiogenic shock, dobutamine * References 319, 320, 322, 327, 328, 330-332, 334, 727, 749-752.
rhythm strips are warranted during any long-term course of contraindicated in humans during pregnancy; therefore until
therapy. appropriately studied, all ACE inhibitors should be considered
The use of acepromazine as a sedative and afterload reducer as contraindicated in pregnant mares because of potential ill
in horses with CHF has been described earlier in this chapter. effects on the fetus.
There is limited published experience using other vasodilators Pimobendan is a calcium-sensitizing agent with phospho-
in horses with CHF (see Table 9.7). Hydralazine359,743 might be diesterase inhibitory effects similar to milrinone. Owing to its
considered in the initial management of severe MR caused by positive inotropic and vasodilatory effects, it is increasingly
ruptured chordae tendineae or endocarditis, because systemic used for treatment of heart failure in small animals.762-767 A
arterial dilation can reduce the mitral regurgitant fraction. recent study in five healthy mature horses indicated that pimo-
Nitroglycerin is a venous vasodilator that reduces preload and bendan administered intravenously at 0.25 mg/kg of body
can be effective as an adjunctive treatment in hospital therapy weight has positive chronotropic and inotropic effects without
of severe congestive heart failure and pulmonary edema.743,753 apparent adverse reactions. There are currently not enough
However, clinical experience with the use of nitroglycerin in data to allow the clinical use of pimobendan in horses, but this
horses is limited, and the drug should be used with caution. drug warrants further investigation for the treatment of heart
Ointment, sublingual tablets, or transdermal patches have not failure in horses.339
been used in horses for treatment of heart failure to date. Mil- For horses with valvular disease or cardiomyopathy, the
rinone is a phosphodiesterase III inhibitor that increases myo- development of AF may precipitate CHF. Furosemide and
cardial contractility and causes systemic vasodilation.328,336,743 digoxin can effectively control CHF in many of these cases,
It can be used in the acute management of heart failure to with ACE inhibitors often being added to the treatment pro-
provide inotropic support and reduce afterload. Although tocol. Quinidine is generally contraindicated in such cases,
occasionally recommended for horses, its costs are often pro- although horses may sometimes convert to sinus rhythm after
hibitive and the pharmacology, effects, and adverse effects in the resolution of CHF by medical therapy. Reasonable long-
horses with heart failure are not well studied. term control of clinical signs may be achieved in some cases
Heart failure leads to an activation of the renin-angio- of chronic CHF, thus permitting a comfortable existence for
tensin-aldosterone system (RAAS). Angiotensin-converting the horse and—in the case of breeding animals—continued
enzyme (ACE) inhibitors act on the RAAS by inhibiting the reproductive service.
angiotensin-converting enzyme (ACE), which is responsible Prognosis in CHF is at best guarded when irreversible
for conversion of angiotensin-I to angiotensin-II (AT-II). structural heart disease is the cause of failure; thus the long-
Therefore ACE inhibitors decrease renal sodium and water term outcome for life is poor. Of course, the horse with CHF
reabsorption, reduce volume overload, blunt the mecha- requires rest to reduce demands on the heart and should never
nisms leading to diuretic resistance, and cause vasodilation be worked or ridden owing to the risk of PA rupture, syn-
and decrease in myocardial oxygen demand. Furthermore, cope, or fatal arrhythmia.68 Valuable horses may be used for
they are considered cardioprotective by decreasing myocar- breeding; however, pregnant mares are likely to be difficult to
dial remodeling and fibrosis.743 In humans, ACE inhibitors control in the later stages of gestation related to the volume
have been shown to reduce mortality in heart failure. How- expansion that accompanies the latter stages of pregnancy.
ever, the benefits of ACE inhibitors have not been well stud-
ied in equine heart failure. There are some data available in Y CONGENITAL HEART DISEASE
horses regarding enalapril,360,754-757 ramipril,361,363,756,758,759
quinapril,362,363,756,760 perindopril,363 and benazepril (see Table The prevalence of congenital heart disease (CHD) in the over-
9.7).363,756,761 Although effective intravenously,360 oral enal- all equine population is unknown. In one survey of causes for
april at 0.5 mg/kg PO q 12 h does not demonstrate signifi- neonatal death or euthanasia in 608 cases, the prevalence of
cant availability, pharmacodynamic effect, or suppression of congenital heart disease was 3.5%.176 Congenital heart disease
ACE activity.754-757 Ramipril administered at 0.1 to 0.3 mg/kg is often considered when a foal, weanling, or immature horse
PO daily363,756,758,759 and quinapril at doses ranging between is identified with a prominent cardiac murmur, cyanosis, or
0.125 and 0.5 mg/kg PO363,756,760 suppress ACE activity and signs of congestive heart failure.405 Some defects are lethal
reduce indirect BP in healthy horses at rest and during exer- to the neonate, whereas other malformations are compatible
cise. Ramipril has been used in a horse to treat CHF,361 and with life but limit performance or reproductive value.
an open-label clinical study of quinapril in horses with MR A wide variety of cardiac malformations have been
but without CHF showed some evidence for increased stroke identified.* Theoretically, a great number of cardiac malforma-
volume and reduced regurgitation fraction.362 The currently tions could occur, including anomalies of (1) venous drainage,
available data suggest that oral benazepril at doses of 0.5 to (2) atrial situs or septation, (3) atrioventricular connection, (4)
1.0 mg/kg PO in healthy horses results in significantly greater atrial or ventricular development (including formation of the
serum ACE inhibition compared with the other ACE inhibi- two atrioventricular valves and the septum), (5) ventricular
tors.363,756,761 Pharmacokinetics is not affected by feeding, and outflow tracts, (6) semilunar valves, and (7) great vessels.797-800
administration of multiple doses does not result in a cumu- Furthermore, abnormal segmental connections might occur,
lative effect of the drug on serum ACE inhibition. Unfor- leading to “discordance” in the path of systemic or pulmonary
tunately, the use of benazepril is cost-prohibitive in some venous return relative to the pulmonary artery or aorta. These
countries. Additional studies will be required to assess the abnormalities include transposition of the great vessels and
pharmacodynamics, clinical efficacy, and safety of benazepril double-outlet ventricle, wherein both great vessels exit the
and other ACE inhibitors in horses with volume overload or right or left ventricular cavity.
signs of CHF. Cough, impairment of renal function, hypoten-
sion, and hyperkalemia are potential adverse effects of ACE * References 27, 28, 59, 170-186, 188, 408, 546, 552, 556, 563, 599, 728,
inhibitors that must be considered. Most ACE inhibitors are 731-733, 768-796.
Hence, complex congenital malformations are often char- stenosis or incompetency are uncommon. Rare lesions such
acterized by an unusual arrangement of the cardiac chambers as double-outlet right ventricle,769,803,804 transposition of the
and great arteries and by a markedly altered topographic car- great vessels,173,182,805,806 persistent right aortic arch,807-809 aor-
diovascular anatomy. Echocardiographic diagnosis of complex ticopulmonary septal defect,810 bicuspid pulmonary valve,772
congenital cardiac malformations is perceived as a difficult pulmonic stenosis,173,184,188,772 subaortic stenosis,780 mitral valve
task by many clinicians and may be challenging even for the malformation,187,793 persistent fetal circulation,811 hypoplastic
most experienced cardiologists. Even at necropsy, the cor- left heart syndrome,174,175 endocardial fibroelastosis,95,812 total
rect and complete diagnosis of congenital heart disease often anomalous pulmonary venous return,813 aortic origin of the
appears difficult and requires considerable effort. Sequential pulmonary artery,731 double-inlet left ventricle,814 and others
segmental analysis offers a systematic approach to complex have been reported but will not be discussed further. Some of
congenital malformations of the heart, facilitating their in vivo the more frequently recognized defects59,176,546 are described
diagnosis (using echocardiography, angiography, computed later in the chapter.
tomography, or magnetic resonance imaging) and postmor-
tem description.797,799-802 Pathogenesis of Congenital Heart Disease
Despite the wide variety of potential congenital defects, The underlying genetic or other etiologic factors responsible
practically speaking, the most common cardiac malformations for cardiac malformations in horses have not been studied.
in horses involve shunting of blood at the atrial or ventricular Potential but unproven causes include drugs, viral infection,
levels, with the ventricular septal defect (VSD) most often rec- environmental toxins, and nutritional disorders. Breed pre-
ognized (Fig. 9.28). Isolated malformations leading to valvular dispositions have been suspected for ventricular septal defects
in Arabian horses, Welsh Mountain ponies, and Standard-
breds.190,405,563 Cardiac morphogenesis is complicated, but it is
helpful to understand elementary aspects of cardiac develop-
ment, especially as these pertain to CHD.802,815-819 Among the
fundamentals are septation of the atria, the anatomic compo-
nents forming the ventricular septum, separation of the great
vessels, and the normal fetal circulation.
The right and left atria are separated by incorporation of
the right horn of the sinus venosus and through development
and fusion of two prominent membranes, septum primum,
and septum secundum. The endocardial cushions close the
gap between the atrial and ventricular septa. These tissues
also contribute to the atrioventricular septum, the septal seg-
ment spanning the point of mitral valve septal insertion on
the left to the tricuspid valve insertion on the right. The fora-
men ovale, a normal atrial structure, is located approximately
in the middle of the atrial septum, continues almost directly
from the entry of the caudal vena cava, and creates a passage-
way for blood to flow from right to left atrium in the normal
fetus.820 The equine foramen ovale resembles a fenestrated
finger cot and can be observed echocardiographically as a
mobile septal membrane even in healthy full-term foals. This
interatrial path may persist in foals with pulmonary hyper-
tension and elevated right atrial pressures. Failure of normal
development can lead to an atrial septal defect (ASD), which
is typically designated by the location of the defective mem-
brane (Fig. 9.28).
The ventricular septum is a complicated partition that
includes a small membranous portion located adjacent to the
aortic root and the tricuspid valve, an inlet septum imme-
FIG. 9.28 Drawing showing the common locations of atrial septal de- diately below the septal tricuspid leaflet, an apically located
fects (ASDs) and ventricular septal defects (VSDs). Defects located in the muscular or trabecular septum, and a dorsal outflow segment
region of the oval fossa are called ostium secundum ASDs or oval fossa that separates the subaortic and the subpulmonic infundibu-
defects (a). Other possible locations of interatrial communications include lum (see Fig. 9.28). The ventral atrial septum connects to the
ostium primum (b), sinus venosus, and coronary sinus defects. The most dorsal ventricular septum by growth and differentiation of
common interventricular communications in horses are the perimembra- endocardial cushions. These swellings also form major parts
nous (also called membranous or paramembranous) VSDs (c), located in of the atrioventricular valves. Insufficient development of any
the membranous area of the ventricular septum, adjacent to the aortic of these embryonic components can lead to a ventricular sep-
root and the tricuspid valve. Less commonly, VSDs can be located in the tal defect (VSD), the most common cardiac malformation in
subpulmonic region adjacent to the pulmonic and aortic valves (d, termed horses. Defective differentiation of the endocardial cushions
subpulmonic, subarterial, supracristal, or doubly committed VSDs) or in causes various combinations of an ostium primum (ventral)
the inlet, apical, and outlet portions of the septum (muscular VSDs). ASD, an inlet VSD, malformation of the atrioventricular
(Drawing: Matthias Haab, Equine Department, Vetsuisse Faculty, Univer- valves, or common atrium with a single atrioventricular valve
sity of Zurich, Switzerland.) (see Fig. 9.32B later in this chapter).
During cardiac morphogenesis, the aorta and pulmonary to pulmonary (left-to-right) shunting is the expected conse-
artery begin as a single vessel in the conus arteriosus. This quence of an ASD, VSD, and PDA as long as systemic pres-
common trunk, or truncus arteriosus, is eventually partitioned sures and resistances exceed those on the right side and there
by migration of the conus and development of the conotrun- is no stenosis limiting PA flow. Even in cases of abnormal
cal and spiral septa. Twisting of the spiral septum produces ventricular-arterial development, as with persistent truncus
appropriate alignment (concordance) of the great vessels with arteriosus, double-outlet right ventricle, or univentricular
their respective ventricular chambers. The descending aorta heart, the clinical findings of a left-to-right shunt may pre-
and pulmonary artery are connected by the ductus arteriosus dominate unless there is obstruction to blood flow or elevated
Botalli, which carries fetal blood from the pulmonary artery pulmonary vascular resistance.
to the descending aorta. Maldevelopment of conotruncal or The actual shunt volume carried to the lungs depends on
spiral septal tissues leads to complicated congenital heart the caliber (or “restrictive” nature) of the lesion orifice and
defects that can occasionally be seen in the horse, including the relative vascular resistances between systemic and pulmo-
persistent truncus arteriosus,181,785,792,821,822 double-outlet right nary circulations. Shunting may not be significant for some
ventricle,769,803,804 transposition of the great vessels,173,182,805,806 weeks after foaling because pulmonary vascular resistance is
and aorticopulmonary septal defect.810 Persistence of the right relatively high, and systemic arterial and left ventricular pres-
aortic arch807-809 and persistent patency of the ductus arterio- sures are relatively low. Eventually left-to-right shunts cause an
sus (PDA)408,731,768,774,809 are both rare in horses. increase in pulmonary arterial flow and augment pulmonary
There are two fetal circulations, one serving the fetus and venous return. Small shunts are easily handled at the expense
the other communicating with the placenta.816 However, of mild left-sided dilation and hypertrophy. When the pulmo-
unlike the sequentially arranged systemic and pulmonary nary-to-systemic flow ratio (Qp:Qs) exceeds about 1.8:1, the
circulations in the fully developed postpartum organism, the shunt is usually considered clinically relevant, and the conse-
fetal circulations are not completely separate. Functionally quences are obvious volume overload of the LA and LV. The
there are two right-to-left shunts: one across the foramen ovale greater the shunt volume, the higher is the potential for left-
and the other across the ductus arteriosus. The fetal lungs are sided or biventricular CHF from ventricular dysfunction. Pul-
collapsed, pulmonary vascular resistance is high, and pulmonary hypertension can occur in the setting of left-to-right
monary blood flow is minimal. Desaturated blood returning shunting from combinations of increased PA flow, remodeling
from the fetal tissues is collected in the cardinal venous sys- of the small pulmonary arteries, and left ventricular failure.
tem and enters the sinus venosus and right atrium. This blood Thus consequences of significant left-to-right shunting may
is largely earmarked for the right ventricle and pulmonary include any of the following: exercise intolerance, tachypnea,
artery. Most pulmonary arterial flow is diverted through the pulmonary edema, respiratory distress, pulmonary hyperten-
ductus arteriosus to the descending aorta, umbilical arteries, sion, AF, pleural effusion, jugular venous distention, or ven-
and placenta, where it is oxygenated. Well-saturated blood tral edema. The foal may be smaller than expected and may
returning across the umbilical veins is delivered by the caudal have a history of antibiotic therapy for presumed bouts of
vena cava to the right atrium where it preferentially crosses “pneumonia.”
the foramen ovale to enter the left atrium, left ventricle, and Right-to-left shunting produces a different clinical presen-
ascending aorta, from where it is delivered to the fetal tissues. tation. When a shunt is complicated by a right-sided obstruc-
Note that well-oxygenated blood from the ascending aorta is tion downstream from the defect, right-to-left shunting will
delivered to the heart (through the coronary arteries) and the develop once right-sided pressures exceed those on the left.
brain (through the brachiocephalic trunk), whereas the tissues This can occur in a foal with tricuspid valve atresia and ASD
in the caudal parts of the body receive a mixture of oxygen- or with pulmonary valve atresia and VSD. Conversely, elevated
ated blood from the ascending aorta and desaturated blood right-sided resistance can develop more chronically from pul-
entering the descending aorta through the ductus arteriosus. monary vascular disease or vascular remodeling. For example,
These patterns change dramatically with foaling. As the lungs a large left-to-right shunt can induce medial hypertrophy and
expand, pulmonary vascular resistance falls and pulmonary intimal thickening of small pulmonary arteries that elevate
blood flow increases. The resultant increase in left atrial pres- pulmonary vascular resistance.645 Though very uncommon,
sure functionally closes the foramen ovale within the first 24 to the resultant pulmonary hypertension may become severe
48 hours of life.820 Similarly, inhibition of local prostaglandins and reverse the shunt to right to left (Eisenmenger’s physiol-
leads to functional closure of the ductus arteriosus within 72 ogy). In these cases the left heart chambers are small, and the
hours after birth in most full-term foals.408 Persistence of the right ventricle is hypertrophied to generate systemic BP. The
right-to-left shunts, especially at the level of the foramen ovale, entrance of desaturated blood into the left side of the circu-
can occur in premature foals or those suffering from severe lation causes arterial hypoxemia with potential consequences
pulmonary disease with associated pulmonary hypertension. of tissue hypoxia, cyanosis, exercise intolerance, mild to mod-
In these cases, shunting across the foramen ovale represents erate polycythemia, hyperviscosity of blood, and stunting of
an additional mechanism for arterial desaturation and tissue growth. CHF is rare, but sudden death can occur, presumably
hypoxia. from arrhythmia. The degrees of hypoxemia and cyanosis in
a right-to-left shunt depend on overall pulmonary blood flow
Clinical Pathophysiology of Shunts and the degree of blood mixing between the circulations. Thus
Fundamental to understanding of cardiac malformations if pulmonary flow is markedly diminished, as with tricuspid
is an appreciation of shunt physiology and the responses of atresia, severe cyanosis is likely. However, the impact of right-
the heart and circulation to a shunt.59,816,817 Shunting can to-left shunting can be mitigated by overall increases in pul-
be defined as an abnormal deviation of blood flow between monary blood flow as with truncus arteriosus or double-outlet
systemic (left) and pulmonary (right) circulations. Shunting right ventricle without pulmonary obstruction. These lesions
can be left-to-right, right-to-left, and bidirectional. Systemic cause less hypoxemia because the volume of oxygenated blood
A B
FIG. 9.29 Pathologic evaluation of ventricular septal defects (VSDs). A, Opened right ventricle (RV) from a
mare demonstrating a perimembranous septal defect opening just beneath the septal leaflet of the tricuspid
valve. Aortic valve cusps are visible through the defect. Congestive heart failure (CHF) occurred late in life,
after the development of atrial fibrillation (AF). B, A large VSD in a horse. A probe runs through the defect.
The dorsal location immediately beneath the right and the noncoronary cusps of the aortic valve are nota-
ble. Ostia of both coronary arteries are also evident.
reaching the left ventricle is increased. The location or “com- paramembranous defect also can extend under the tricuspid
mitment” of a VSD relative to the subaortic or subpulmonic valve toward the inlet septum or advance across the supra-
region also influences clinical signs because oxygenated blood ventricular crest toward the outlet septum. The (conotrun-
from the LV can actually stream preferentially through a VSD cal) septal defects associated with tetralogy of Fallot (see Fig.
into the aorta. In these situations, cyanosis related to any mix- 9.34 later) and with pulmonary atresia are usually very large
ing of blood in the RV may be negligible and the clinical con- and fall into the latter appellation. Sometimes the aortic root
dition predominated by left-sided or biventricular CHF. If the is displaced ventrocranially and straddles (or “overrides”) the
increased pulmonary flow is sufficient to minimize arterial defect, creating a “malalignment” VSD. This is characteristic of
hypoxemia but not create heart failure, survival even beyond 5 the tetralogy of Fallot but also can be seen with large, isolated
years of age is possible. paramembranous defects. A less common location for a VSD
is immediately ventral to the septal tricuspid valve within the
Ventricular Septal Defects muscular septum. Such “inlet” VSDs are typical of a complete
Ventricular septal defect (VSD) is the most important CHD of endocardial cushion defect and commonly related to a sep-
horses.* A genetic basis is likely in the Arabian breed190,563 and tum primum ASD, common atrioventricular valve leaflet, or
in Welsh Mountain ponies.405 In the authors’ experience, VSD persistent atrioventricular canal, which creates a gap between
is also encountered regularly in Standardbred horses563 and in all four cardiac chambers (see Fig. 9.32B later).773,829,830 A
Quarter Horses. The VSD often accompanies more compli- subaortic VSD that communicates with the outlet portion of
cated heart malformations.† the ventricular septum directly below the pulmonic valve is
The location of a VSD depends on the embryogenesis of variably referred to as a “subpulmonic,” “subarterial,” “supra-
the lesion and influences the designation and even the clini- cristal,” or “doubly committed” VSD. This lesion also places
cal manifestations of the defect. The nomenclature of VSDs the aortic valve at risk for prolapse. Finally, apical muscular
is confusing but can be remembered by considering the main (trabecular) defects or multiple VSDs are rare but have been
components of the normal ventricular septum (Figs. 9.28, 9.29, observed in horses. Some of these are small, whereas others
and 9.30). In most cases, a VSD is located dorsally (“high”) have been enormous.
on the ventricular septum, below the right and noncoronary Many VSDs close spontaneously in people. This has also
cusp of the aortic valve on the left side, cranial to the septal been observed in horses, but whether or not this is common in
tricuspid leaflet on the right, and encompassing or contigu- this species is unknown.826 However, the flow across a VSD can
ous with the fibrous part of the ventricular septum.563,782 Such be diminished by imposition of a cardiac valve. For example,
defects are generally referred to as “perimembranous,” “mem- the rim or even a major portion of a VSD may be occluded
branous,” or perhaps more correctly, “paramembranous.” Most by fibrotic tissue that ensnares the septal tricuspid leaflet,
of these holes are also “subcristal” because the VSD is located rendering the defect functionally smaller and possibly creat-
caudoventral to the supraventricular crest, separating the ing a hyperechoic aneurysm on the right septal surface. Large
right ventricular inlet from the outlet. However, a very large defects associated with malalignment of the ascending aorta to
the upper border of the remaining septum are often associated
* References 59, 68, 178, 190, 390, 405, 552, 556, 563, 732, 775, 782, 794, and with prolapse of the right or noncoronary cusp of the aortic
823-827. valve (or of the aortic root) into the defect. Aortic prolapse can
† References 171-173, 178, 182, 190, 556, 772, 773, 784-787, 803, 806, 809, effectively close even a large VSD, but at the risk of permitting
814, 828. chronic aortic valve insufficiency over time (see Fig. 9.30B).563
A B
FIG. 9.30 Echocardiograms demonstrating ventricular septal defects (VSDs). A, This subaortic VSD is not
evident from the long-axis image (left panel) but is visible in the short-axis tomogram (arrows). This Quarter
Horse gelding also had pulmonic stenosis. The elevated right ventricular (RV) pressures have led to signifi-
cant RV enlargement with bulging of the septum toward the left ventricle (LV). B, Malalignment and a per-
imembranous septal defect associated with prolapse of an aortic valve leaflet across the defect (arrow)
(RVW, right ventricular wall). C, Continuous-wave Doppler study recorded from a foal with a small, restrictive
VSD. The maximal velocity of nearly 6 m/sec (arrow) predicts a pressure difference of up to 144 mm Hg
between left and right ventricles.
The pathophysiology of the uncomplicated VSD is that of incidental finding. A mature horse may be presented for poor
a left-to-right shunt as described previously (Fig. 9.31). Much performance or with AF. Foals may be symptomatic for pul-
of the shunt volume pumped by the left ventricle is ejected monary edema or biventricular heart failure. Commonly, a
immediately into the pulmonary artery. As pulmonary flow murmur is detected incidentally during the physical examina-
increases, there is increased venous return to the left atrium tion for another problem or during a prepurchase examination
and left ventricle, causing left atrial enlargement and left (see Fig. 9.7B and Tables 9.1 and 9.4). As most defects com-
ventricular dilation and hypertrophy that can be recognized municate near the tricuspid valve, the most consistent physi-
by echocardiography. Thus the left (not the right) ventricle cal examination finding is a harsh holosystolic or pansystolic
performs most of the extra volume work. This is made more murmur that is loudest just below the tricuspid valve region
severe if there is aortic valve prolapse with aortic regurgita- and above the right sternal border. A slightly less intense ejec-
tion or if mitral regurgitation develops owing to left ventricu- tion murmur due to increased flow across the RV outlet is
lar enlargement. If the shunt is large and pulmonary arteriolar usually evident over the left base (see Fig. 9.31). The second
resistance does not increase significantly, left ventricular fail- heart sound may be split more widely than normal owing to
ure can develop. This is most likely to occur early in life, as disparate ventricular ejection times; the pulmonic component
the high fetal pulmonary vascular resistance declines, but late of S2 will be tympanic if there is pulmonary hypertension. In
cases of CHF (with AF) also have been observed. The degree contrast, the murmur of a subpulmonic (subarterial or supra-
of RV hypertrophy and enlargement varies, depending on the cristal) VSD is loudest over the left cranial base as the high-
location and size of the septal defect and pulmonary vascu- velocity flow enters the main PA. When a VSD is associated
lar resistance. Large nonrestrictive defects create a functional with a complex cardiac malformation, the murmur is likely to
common chamber, allowing ventricular pressures to equili- be loud over each side of the thorax. The severity of the defect
brate and leading to marked RV hypertrophy as well as pul- cannot be judged based on murmur intensity. In some cases a
monary hypertension. small defect may be quite loud, whereas a large, less restrictive
The clinical features of VSD are variable.59,190,563,775,782,827 defect may cause a murmur related entirely to the increased
Clinical signs may be absent and the defect identified as an flow (relative pulmonic stenosis). A holodiastolic murmur of
↑ Pulmonary
flow
↑ O2 sat.
↑ Venous return
↑ LA
L → R shunt
S1 S2 RA
↑ LVDP
Ventricular
septal defect
RV
VSD
+/– DRVH
S1 S2
FIG. 9.31 Pathophysiology of ventricular septal defects (VSDs). See text for details. LA, Left atrium; RA,
right atrium; LVDP, left ventricular diastolic pressure; RV, right ventricle; RVH, right ventricular hypertrophy.
(From Bonagura JD: Congenital heart disease. In Bonagura JD, editor: Cardiology, New York, 1987, Churchill
Livingstone.)
aortic regurgitation indicates prolapse of an aortic cusp and the horse is relatively large and may be confused with a sub-
increases the likelihood that the lesion is relatively large. Sub- pulmonic VSD in short-axis image planes. It also should be
stantial aortic regurgitation is associated with a hyperdynamic noted that a true inlet VSD of an endocardial cushion defect,
arterial pulse and an increased pulse pressure. If there is sig- located immediately ventral to the septal tricuspid valve, might
nificant left ventricular volume overload, the mitral valve may not be easily seen in standard planes. Tipped or oblique views
become incompetent, and a holosystolic murmur of mitral that show both AV valves may be required. Similarly, finding
regurgitation may be evident over the left apex. The rare tra- a muscular, apical, or small subpulmonic defect requires more
becular (muscular) VSD may also create a systolic murmur imaging experience and nonstandard imaging planes and is
over the left or right apex. The VSD associated with pulmo- greatly assisted by color Doppler studies.
nary atresia or persistent truncus arteriosus may not create Attempts should be made to identify the largest diameter of
a substantial murmur, but the increased flow through the the defect in complementary planes and compare this with the
dilated single vessel usually generates a loud ejection murmur size of the aortic root, as orifice size is an important prognostic
over each side of the chest. If significant cardiomegaly devel- factor. Note that the size of the VSD is often underestimated
ops, atrial and ventricular premature complexes, or even AF, with 2D echocardiography and overestimated with color-flow
may be recognized. Doppler echocardiography. Although there are limitations to
Diagnostic studies are needed to confirm the lesion and echocardiographic sizing of the VSD, a defect exceeding 2.5 cm
determine the severity. The performance history is a useful in diameter or a VSD-to–aortic root diameter ratio of greater
overall indicator of impact, and the horse with an excellent than 0.4 identifies a large defect with greater likelihood of clin-
work history is unlikely to have a large defect. The ECG is ical signs.563 There is usually some enlargement of the left side
unreliable for diagnosing cardiomegaly in horses but is indi- of the heart, but cardiac dimensions fall within the normal
cated in the setting of an arrhythmia. Thoracic radiography range if the shunt is small. However, 2D or M-mode evidence
can be useful in foals to demonstrate cardiomegaly (see Fig. of left-sided cardiac dilation, right ventricular enlargement,
9.19A), the pulmonary circulation, the lungs, and the pleu- or marked dilation of the main PA suggests a hemodynami-
ral space. 2D echocardiography and color Doppler imaging cally relevant VSD and one more likely to affect performance
establish the diagnosis, and spectral Doppler examinations or survival. Moderate to severe enlargement of the LA and LV
are useful for assessing the hemodynamic burden of the is concerning and increases the risk for AF, PHT, and CHF.
defect.344,552,563,590,819 Complex congenital disease must be Noticeable systolic enlargement of PA indicates pulmonary
excluded. overcirculation, whereas marked PA enlargement during both
2D echocardiography successfully delineates the VSD systole and diastole suggests PHT.
in almost every case provided sufficient imaging planes are Identification of shunting across a VSD is confirmed using
obtained (see Figs. 9.25 and 9.30). It is important to collect color Doppler studies. There will typically be a region of flow
long-axis images of the left ventricular outflow tract and aortic acceleration proximal to the defect and a high-velocity, turbu-
valve, as well as short-axis images at the level of the left ven- lent flow entering the right ventricle distal to the defect dur-
tricular outflow tract, at and just ventral to the aortic leaflets. ing systole, with low-velocity, uniform color shunting noted
The typical paramembranous defect appears under the aortic during diastole. Color Doppler imaging is extremely helpful
valve and adjacent to the septal leaflet of the tricuspid valve. for identifying a very small VSD or one with an atypical loca-
A true defect is characterized by a relatively echogenic tissue tion. Aortic regurgitation is identified in some horses, and the
interface, whereas an area of false echo dropout tends to be regurgitant flow is often directed into the VSD, resulting in
gradual. Most defects can be imaged in orthogonal (long-axis/ high-velocity diastolic shunting. Continuous-wave Doppler
short-axis) planes. The ostium of the right coronary artery of is used to estimate the pressure difference between the two
ventricles, as velocity (in meters per second) is proportional by echocardiography or angiography are now possible, though
to the instantaneous pressure difference across the ventricles perhaps not practical in the majority of affected patients. Med-
(by the modified Bernoulli equation: Δp = 4 × vmax2; see Figs. ical management of CHF or of arrhythmias associated with
9.25D and 9.30C). A relatively small VSD is “restrictive” to CHD can be considered. However, even if the response to
flow, and the peak shunt velocity will generally exceed 4.5 m/ treatment is good, the horse should not be used.
sec, assuming proper alignment to shunt flow.563 With good
alignment, peak velocities greater than 5 m/sec (correspond- Atrial Septal Defects
ing to a left-to-right pressure gradient of greater than 100 mm Atrial septal defects, including endocardial cushion defects,
Hg) are expected. Lower shunt velocities (less than 4 m/sec), are quite uncommon in foals.* As indicated earlier, an ASD
along with higher pulmonary artery ejection and mitral inflow may involve different portions of the atrial septum (see Fig.
velocities, indicate a greater shunt volume. In the setting of 9.28) and is more likely to be observed with complex congeni-
pulmonary hypertension, pulmonic stenosis, or systemic tal cardiac defects, particularly with tricuspid or pulmonary
hypotension, the velocity of left-to-right shunting will also be atresia. An isolated ASD may be clinically irrelevant, with no
lower; when pulmonary hypertension is present, a tricuspid significant murmur or clinical signs. Moderate to good exer-
regurgitation jet of greater than 3.4 m/sec may be identified. cise capacity may be expected because left-to-right shunting
Potential outcomes of the isolated VSD include the fol- decreases as the systemic to pulmonary vascular resistance
lowing: (1) tolerance of the lesion; (2) partial or complete ratio declines with exercise. In the case of a large ASD, left-to-
closure of a VSD by adherence of the septal tricuspid leaflet, right shunting leads to right-sided volume overload and pul-
fibrous tissue, right ventricular hypertrophy, or aortic valve monary overcirculation and potentially to pulmonary vascular
prolapse; (3) progressive aortic regurgitation; (4) progressive injury. Atrial fibrillation has been observed in conjunction
mitral regurgitation owing to left-sided chamber enlargement; with ASD. Large defects are visible echocardiographically
(5) atrial fibrillation; (6) left-sided or biventricular CHF; (7) (Fig. 9.32A), but thinning, billowing, or flailing of the atrial
pulmonary hypertension (with left-to-right shunting); or (8) septum in the region of the oval fossa can lead to an incorrect
reversal of the shunt with development of arterial hypoxemia diagnosis of an ASD, particularly in cases with smaller defects
and cyanosis. The last situation is rare and would be caused and suboptimal image quality.344,819 Doppler echocardiogra-
by either severe pulmonary vascular disease (Eisenmenger’s phy and saline contrast studies (by injection of agitated saline
physiology) or fibromuscular obstruction in the right ventric- into the jugular vein) can confirm the presence and direction
ular outlet leading to subpulmonic stenosis. of the shunt and estimate its severity. Thereby, it must be con-
The horse with a relatively small-diameter paramembra- sidered that physiologic blood flow entering the RA from the
nous defect, high-velocity left-to-right shunt, mild cardio- caudal vena cava and the LA from the pulmonary veins can
megaly, relatively normal right ventricular cavity, and normal easily be mistaken for transseptal flow on color Doppler
heart rhythm probably has a restrictive VSD that will be well recordings. Similarly, streaming of vena cava flow in the RA
tolerated. Most of these animals can perform sufficiently in can cause a distinct negative contrast pattern within the RA
the show ring, as a hunter-jumper, or even as an endurance during saline contrast studies, mimicking left-to-right trans-
horse or racehorse. Moderate defects are often well tolerated septal flow.344,831
at rest, but performance in high-intensity sports might be Complete endocardial cushion defects are rarely seen but
affected. Large defects that are associated with echocardio- are serious, usually leading to CHF or AF at an early age. Com-
graphic evidence of moderate to severe cardiomegaly, right ponents of this defect typically include a large ASD involving
ventricular hypertrophy, aortic root prolapse, aortic malalign- the primum and the atrioventricular septa, a common atrio-
ment, marked valvular regurgitation (AR, MR, TR), evidence ventricular valve leaflet, and often an inlet VSD (see Figs.
of pulmonary hypertension, atrial fibrillation, or presence of 9.28 and 9.32B). The ventricles may be partitioned normally,
other comorbidities are prone to complications and carry a unequally with one rudimentary ventricular chamber, or not
less favorable prognosis for performance or life regardless of at all, creating a single ventricle. In the most severe cases there
current clinical signs. is a common atrioventricular canal, a single common atrio-
According to the 2014 American College of Veterinary ventricular valve, and a single ventricle from which both great
Internal Medicine (ACVIM) consensus statement on the vessels exit. The clinical signs of a complete endocardial cush-
management of equine athletes with CV abnormalities,68 ion defect are variable. The foal with two ventricles and an
horses with VSDs should be examined annually. Horses with unobstructed outlet to the pulmonary arteries will be hemo-
an isolated small (restrictive) VSD and minimal cardiomeg- dynamically similar to one with a large VSD. When a com-
aly can be considered safe to compete, whereas horses with mon ventricle is present, varying degrees of cyanosis may be
larger defects should be evaluated on a case-by-case basis in observed. A systolic murmur is typical and may reflect flow
consultation with a specialist experienced in equine cardiol- across the VSD, ventricular outflow, or atrioventricular valve
ogy. Exercise (ECG) testing is recommended in horses with regurgitation. A 2D echocardiogram can reveal the lesions
moderate to large VSDs, in prepurchase situations, or when and Doppler echocardiography the intracardiac shunts and
performance is suboptimal. Breeding of affected animals gen- AV valvular regurgitation. CHF may supervene, and the prog-
erally should be discouraged, especially in Arabian horses and nosis is poor.
Section A Welsh Mountain ponies.
Definitive therapy for VSD would involve cardiopulmonary Patent Ductus Arteriosus
bypass surgery that is impractical in horses. Surgical banding Patent ductus arteriosus (PDA) is rare as an isolated con-
of the PA elevates right ventricular pressures and reduces left- genital cardiac defect in foals and is detected most frequently
to-right shunting; however, this procedure also limits CO and in combination with other, more complex malformations
is not advised. New “hybrid” procedures involving catheter
devices delivered by a transventricular approach and guided * References 175, 177, 180, 599, 733, 773, 784, 829, 830.
FIG. 9.33 A postmortem demonstration of the ductus arteriosus (ar-

row) between the descending aorta and the pulmonary artery in a foal
with complex congenital heart disease.
persistent pulmonary hypertension, and foals whose dams

have been given prostaglandin inhibitors might be more sus-
ceptible to the development of a PDA.
The clinical signs depend on the magnitude of the shunt-
ing through the PDA, which is determined by ductal diameter
and vascular resistance in the pulmonary circulation. Physi-
cal examination findings (with a left-to-right PDA) include
a continuous machinery murmur and thrill, usually loudest
over the main PA (craniodorsal to the aortic valve area), and
B bounding arterial pulses. Differential diagnosis includes other
systemic-to-pulmonary shunts in association with complex
FIG. 9.32 A, Echocardiogram demonstrating a primum atrial septal de-
congenital heart disease.
fect (ASD) in a foal with complex congenital heart disease that included a
Echocardiography will reveal volume overload of the PA,
common (left) ventricle, rudimentary (right) ventricle, and double-outlet
LA, and LV.344,819 The severity of these findings depends on
ventricle. The septal defect is evident between the four cardiac chambers.
the magnitude of the shunt. Direct visualization of the PDA
The dorsal secundum septum (right) is present, as well as the apical ven-
is not always possible by 2D echocardiography because the
tricular septum (left). B, Long-axis image from a foal with a complete en-
ductus arteriosus may be obscured by overlying lung. Ductal
docardial cushion defect. The primum ASD is evident in the ventral atrial
flow is best identified from the left cranial thorax by Doppler
septum (arrow), and an inlet ventricular septal defect (VSD) component
echocardiographic examination of the main PA, which reveals
(arrowhead) is observed below the closed common (or straddling) atrio-
continuous, high-velocity, turbulent flow directed toward the
ventricular valve. Normal mitral and tricuspid septal leaflets would insert
pulmonary valve. Cardiac enlargement and increased pul-
into the septum at slightly different levels (with tricuspid septal leaflet in-
monary vascularity may be detected in neonatal foals with a
serting more ventrally than the mitral septal leaflet.)
PDA, as well as radiographic evidence of pulmonary edema
if the foal has developed CHF. Cardiac catheterization reveals
elevated PA and pulmonary capillary wedge pressures and
(Fig. 9.33).* The ductus arteriosus is a fetal vessel, derived increased PA oxygen saturation. The heart should be evaluated
from the left sixth aortic arch, that permits shunting from carefully for other congenital cardiac defects before surgical or
the PA to the descending aorta in the fetus. At birth the duc- catheter-based intervention is considered as complex cardiac
tus arteriosus normally constricts in response to increased malformations are likely in a foal with PDA. Late complica-
local oxygen tension and inhibition of prostaglandins. It is tions of this lesion include rupture of the PA.
functionally closed 72 hours after birth in the vast major-
ity of foals. If the ductus arteriosus does not close, a left- Tetralogy of Fallot
to-right shunt from the aorta to PA occurs. Although there The tetralogy of Fallot is one of the more common congenital
may be some hereditary predisposition to PDA in other spe- cardiac anomalies in foals responsible for right-to-left shunt-
cies, this lesion is so rare as an isolated congenital defect that ing, arterial desaturation, and cyanosis.171,178,183,190,833-837 The
this is not a significant concern. Premature foals, foals with four lesions are (1) large paramembranous-outlet VSD, (2)
cranial and rightward (dextro-) positioning of the aorta with
* References 171, 175, 182, 184, 408, 409, 731, 768, 774, 809, 832. overriding of the septal defect, (3) right ventricular outflow
tract obstruction, and (4) right ventricular hypertrophy. Echocardiographic evaluation is diagnostic and reveals a
Outflow obstruction can be due to subvalvular fibromuscu- large, unrestrictive VSD, malalignment and overriding of the
lar obstruction, valvular pulmonic stenosis, or hypoplasia of aortic root, right ventricular outflow tract obstruction, and
the PA. Ventricular hypertrophy is caused by right ventricu- right ventricular hypertrophy (Fig. 9.34).344,819 Shunting can
lar outflow obstruction and the large, unrestrictive, VSD that be identified by color Doppler or saline contrast echocardiog-
functionally creates a “common ventricle.” Blood leaves the raphy initiated by injection of agitated saline into the jugular
heart along the path of least resistance such that pulmonary vein. Both studies will demonstrate a right-to-left or bidirec-
flow depends on the severity of right ventricular outflow tract tional shunt. Conventional spectral Doppler studies can be
stenosis. As previously discussed, the degree of cyanosis and used to delineate the shunt (typically bidirectional, low-veloc-
severity of clinical signs depend on the volume of blood tra- ity flow of less than 2 m/sec) and right ventricular outflow
versing the lungs. In some horses, a PDA is also present (pen- obstruction (high-velocity flow exceeding 4 m/sec).
talogy of Fallot), and this defect reduces signs by increasing Although it is possible for horses to live for a number of years
pulmonary flow, left heart filling, and systemic arterial hemo- with tetralogy of Fallot, most affected animals are humanely
globin saturation. Tetralogy of Fallot must be distinguished destroyed due to the poor prognosis for life. Affected horses
from other causes of cyanotic heart disease, including tri- should not be used or bred if they survive to maturity.
cuspid atresia, pulmonary atresia with VSD, transposition of
the great vessels, double-outlet right ventricle with pulmonic Pulmonary Atresia with Ventricular Septal Defect
stenosis, truncus arteriosus, and total anomalous pulmonary Pulmonary atresia with VSD is rare, having been observed
venous connection.816,817 most often in Arabian foals (see Fig. 9.34C).171,172,186,790 This
Affected foals are usually smaller than normal, lethargic, malformation represents the exaggerated form of tetralogy of
and intolerant of exercise. Cyanosis is most evident after activ- Fallot, with these findings: (1) the right ventricular outlet does
ity and is variably present at rest. Arterial blood gas analysis not connect into the pulmonary artery, (2) the right ventricle
demonstrates hypoxemia with normal or reduced partial pres- is hypertrophied, (3) a large malalignment VSD is present (in
sure of carbon dioxide (Pco2). Auscultation is typically char- most cases), and (4) the fetal truncus arteriosus has been par-
acterized by a loud systolic murmur over the pulmonic valve titioned so unequally that the aorta is markedly dilated and
area on the left side caused by (sub-) pulmonic stenosis. The the pulmonary trunk atretic or severely hypoplastic. Without
second heart sound is usually unremarkable. Although poly- careful ultrasound studies (or necropsy dissection) of the pul-
cythemia can be significant, it is usually mild, even when arte- monary circulation, the dilated aorta can be mistaken for a per-
rial oxygen tensions fall to 50 to 70 mm Hg. sistent truncus arteriosus, hence the moniker “pseudotruncus
DAo
RV - 0 m/s
PT
AV
VSD
AV
PV
RV
- 3 m/s LV
Pulmonary
PA artery
A B C
FIG. 9.34 Tetralogy of Fallot. A, Echocardiogram from a filly with tetralogy of Fallot. The image plane
shows the right ventricle (RV), right ventricular outlet with stenotic (hypoplastic) pulmonary valves (PV),
and poststenotic dilation of the pulmonary artery (PA). There is a very large ventricular septal defect (VSD;
arrows) connecting the base of the dilated aorta with the right ventricle. Two aortic valve leaflets (AV) are
evident in this off-angle plane. B, Continuous-wave Doppler echocardiogram from a horse with tetralogy of
Fallot. The Doppler study demonstrates pulmonary stenosis. High-velocity systolic flow is evident, exceed-
ing 4 m/sec. Velocity scale is to the right; ECG at the top. C, Left lateral view of a heart obtained from a foal
that died from pulmonary atresia, the “exaggerated” form of tetralogy of Fallot. Because of unequal septa-
tion of the truncus arteriosus, a markedly dilated aorta (PT, pseudotruncus arteriosus), and a rudimentary,
imperforate main pulmonary artery (lower arrow) are present. Atresia of the pulmonary valve was evident
on opening the heart. Pulmonary artery flow was derived from the ductus arteriosus (upper arrow), which
serves two underdeveloped pulmonary arteries. DAo, Descending aorta; RV, right ventricle; LV, left ventricle.
(From Bonagura JD: Congenital heart disease. In Robinson N, editor: Current therapy in equine practice, ed 5,
Philadelphia, 2003, WB Saunders.)
arteriosus.” Owing to the atretic pulmonary valve, pulmonary ovale. Because all venous return must mix in the left atrium,
blood flow must be derived either from a PDA or the aorta. this malformation generally causes marked hypoxemia with
In the latter instance, the systemic collaterals are usually from cyanosis. Affected foals rarely survive to weanling age unless
bronchial arteries. Pulmonary atresia with an intact ventricu- there is also a left-to-right shunting VSD into a functional
lar septum has been diagnosed rarely.791,832 right ventricular outflow tract that provides good pulmonary
The diagnosis of pulmonary atresia is usually stimulated by flow. Otherwise, pulmonary flow must come from a ductus
clinical findings of cyanosis, cardiac murmur, and stunting in arteriosus or systemic collaterals (e.g., bronchial arteries).
a foal or weanling. Diagnosis is confirmed by echocardiogra- Most foals are stunted, nurse poorly, and exhibit severe exer-
phy.344,819 Careful imaging can identify the main lesions out- cise intolerance and cyanosis at rest. Arterial oxygen tension
lined previously. Of diagnostic importance is the inability to can be very low (40–60 mm Hg). Echocardiography reveals a
identify the pulmonic valve in the rudimentary right ventricu- markedly dilated right atrium and coronary sinus, atretic tri-
lar outflow tract (though a small pouch may be seen). Careful cuspid valve, and rudimentary right ventricle (larger if there is
ultrasound examination of the ascending aorta and aortic arch a functional left-to-right shunting VSD). Atrial shunting that
from the right and left sides of the thorax will fail to reveal a allows systemic venous return to empty into the left atrium
normal origin for the pulmonary trunk or an origin of the PA must be observed. Abnormal flow patterns can be verified by
directly from a truncus arteriosus. The bifurcation of the PA saline contrast or color Doppler echocardiography. The prog-
may be found from a cranial imaging position, and continuous nosis is grave.
flow into that vessel documented by Doppler echocardiogra-
phy suggests that pulmonary blood flow is derived from the Y VALVULAR HEART DISEASE
ductus arteriosus or a collateral systemic artery.
Healthy cardiac valves maintain normal antegrade flow in the
heart and prevent significant regurgitation of blood. Diseased
Truncus Arteriosus Communis (Common cardiac valves, which can be stenotic or incompetent, limit
Arterial Trunk) cardiac output and place an increased workload on the heart.
The failure of the fetal truncus arteriosus to partition into the Stenotic valvular lesions in horses are typically congenital in
aorta and PA represents a rare anomaly of the equine nature and are extremely rare; however, acquired valvular
heart.181,785,792,821,822,838 In this condition, the fetal truncus never regurgitation (also called valvular insufficiency or valvular
partitions, and both ventricles continue to develop, communi- incompetency) is common.* The majority of valvular insuf-
cating with the truncus arteriosus across a large malalignment- ficiencies in horses are caused by degenerative valve disease
type VSD. Systemic, coronary, and PA flows each arise from or are related to high-level training.† Infective (bacterial)
the truncus, which is guarded by a truncal valve (that can be endocarditis,‡ noninfective valvulitis, and ruptured chordae
incompetent or stenotic). Pulmonary blood flow originates tendineae38,212-214,845 are infrequent causes of valvular disease.
from one or more pulmonary arteries connected directly to the Box 9.2 summarizes important causes of valvular dysfunction.
truncus arteriosus or indirectly from systemic to pulmonary Degenerative valvular disease and infective endocarditis are
collateral vessels.802,816,817 the valvular problems most often encountered by the equine
The pathophysiology and clinical findings of this malforma- practitioner, and are the focus of this section.
tion depend largely on the magnitude of pulmonary blood flow. The clinical relevance of a valvular lesion depends largely
If the PA origins are not stenotic and if pulmonary vascular on the severity of regurgitation across the valve. It is clear that
resistance remains relatively low, the clinical condition resem- many horses adapt to trivial, mild, or even moderate valvular
bles a left-to-right shunt, except for right-to-left mixing of blood regurgitation with no apparent consequence on performance.*
across the VSD. However, the degree of arterial hypoxemia may The severity of valvular regurgitation is related to the dynamic
not be severe, and cyanosis may not be obvious. Conversely, cross-sectional area of the regurgitant orifice, the pressure
high pulmonary vascular resistance or obstruction to flow at the gradient driving blood across the valve, and the time allowed
truncal origin of the PA is associated with arterial desaturation for regurgitation, because not all incompetent valves leak
and findings similar to pulmonary atresia. throughout systole or diastole.74 Regardless of the volume, the
Clinical examination usually indicates a systolic cardiac movement of blood from a high-pressure to a low-pressure
murmur. The mucous membranes may be pink or cyanotic. If chamber is associated with a high-velocity jet that is pro-
there is marked left-to-right shunting, CHF may occur. With portional to the pressure drop between source and sink. The
careful ultrasound examination, the truncus and origin of the production of high-velocity jets leads to disturbed flow (with
pulmonary arteries may be identified, allowing the condition turbulence) and in many cases an audible cardiac murmur, the
to be distinguished from pulmonary atresia with VSD.344,819 hallmark clinical feature of valvular heart disease (Fig. 9.35;
Furthermore in some cases an abnormal truncal valve (with also see Figs. 9.9 and 9.23D).
four leaflets) may be evident, further supporting the diagno- Valvular incompetency can be diagnosed by ausculta-
sis. Management is best accomplished by consultation with a tion† or with Doppler echocardiography.‡ Doppler studies are
cardiac specialist.
* References 5, 18, 38, 45, 48, 65, 71, 72, 74, 75, 83, 148, 171, 173, 179, 184,
Tricuspid Atresia 188, 190, 207-212, 214, 355, 390, 391, 406, 407, 554, 557, 583, 602, 772, 793,
Another differential diagnosis for cyanotic heart disease is atre- 843-851.
sia of the tricuspid valve.* This malformation dictates right- † References 28, 65, 70, 75, 148, 191, 208-211, 586.
to-left shunting of systemic venous blood at the atrial level. ‡ References 31, 191, 193-197, 199-206, 824, 852-860.
* References 70, 71, 75, 208-211, 355, 407, 586.
The atrial shunt may be across a true ASD or a patent foramen
† References 3, 69, 70, 74-76, 207, 379, 381, 385, 389, 390, 392, 393, 406, and
861.
* References 171, 180, 182, 186, 190, 786, 828, 839-842. ‡ References 71, 75, 124, 208, 209, 211, 214, 344, 390, 391, 560, 601.
prevalence of tricuspid and mitral regurgitant murmurs

increased significantly over a 9-month training period to an
incidence of 25.5% and 21.8%, respectively. Similarly, stud-
ies on young Standardbreds and Thoroughbreds in training
revealed an increase in the prevalence of valvular regurgita-
tion detected by echocardiography without noticing effects on
racing performance.70,208,211 The causes of these changes and
A the interpretation of these findings are problematic, especially
when referenced to the clinical benchmark of “normal.” It is
possible that high-level training induces changes in ventricu-
lar geometry (i.e., physiologic cardiac hypertrophy, athlete’s
heart)208,211,588 or in valvular thickness related to cardiovas-
cular work, elevations of BP during training, or other factors.
B Nevertheless, whether these murmurs are actually “normal”
or not, it is clear that the clinical importance of a regurgitant
murmur in a horse must be interpreted with caution and cer-
tainly with the perspective of clinical and imaging findings.
The most practical evaluations for assessing the clinical
relevance of a heart murmur are the age, work history, physi-
C cal examination findings, and echocardiography. Other stud-
ies such as electrocardiography and exercise testing provide
FIG. 9.35 Phonocardiograms of cardiac murmurs caused by valvular further information by which to judge the importance of a
heart disease. A, A holosystolic murmur of mitral regurgitation (MR) in a murmur. As a general rule, significant regurgitant murmurs
horse with chronic valvular degeneration. B, A variable, late systolic mur- tend to be loud and long. However, the intensity of an insuf-
mur of MR related to mitral valve prolapse. The murmur has a crescendo ficiency murmur is related not only to the regurgitant volume
and peaks at end systole (arrow). Heart sounds are indicated. The mur- but also to the driving pressures of blood and the physical
mur obscures the second sound. C, A holodiastolic, vibratory murmur of characteristics of the thorax. Therefore although the intensity
aortic regurgitation (AR) with presystolic accentuation. The accentuation of a heart murmur can be graded by the examiner (see ear-
probably is related to atrial contraction, altered ventricular volume and lier in this chapter), it is not possible to grade the severity of
pressure, and an incremental increase in regurgitant volume. regurgitation by auscultation alone. Relatively loud murmurs
may be associated with regurgitant volumes that are inconse-
quential to an individual horse, especially when the murmur
highly sensitive for identification of valvular incompetency is high-pitched, vibratory, or musical in quality. Thus although
and represent the gold standard for identification of valvular clinically significant valvular heart disease is best identified by
dysfunction. However, many horses with normal auscultation auscultation (see Tables 9.1, 9.3, and 9.4), the clinical relevance
findings also demonstrate valvular regurgitation by Doppler of a valvular regurgitation must be assessed in other ways.*
examination. Most cardiologists consider these “silent” valvu- This approach is emphasized below. A recent consensus state-
lar leaks as normal,71,74 especially when observed on the right ment formulated by a group of experts in the field of equine
side of the heart. Even on the left side silent regurgitation is cardiovascular medicine summarizes the current recommen-
often observed by color Doppler examination. dations for management of equine athletes with valvular heart
Some of these flow signals are brief, representing “back- disease, and the reader is referred to this statement for addi-
flow” or valve closure signals; these are easily misinterpreted tional information.68
unless carefully timed by spectral Doppler or color M-mode
examinations. Certainly some cases of silent regurgitation Mitral Regurgitation
represent the earliest signs of degenerative valvular disease. Mitral regurgitation (MR) is commonly detected in
But there is no clinical benefit to screening horses by Doppler, horses.68,83,407,843 The etiopathologic basis of mitral valve
nor is the approach practical or even predictive of future out- incompetency may involve any of the following: high-level
come. Thus cardiac auscultation remains the most clinically training, degenerative thickening, prolapse of the valve, rup-
important method for identifying clinically relevant valvular tured chordae tendineae, bacterial endocarditis, noninfective
disease. Echocardiography including Doppler studies is used valvulitis, primary or ischemic myocardial disease leading to
to verify the source of a pathologic murmur, identify underly- papillary muscle dysfunction, severe LV dilation, congenital
ing structural heart lesions, assess atrial and ventricular func- malformation of the valve, and idiopathic disease (Figs. 9.36,
tion, and quantify the degree of cardiac remodeling that has 9.37, and 9.38; also see Box 9.2).† Degenerative, fibrotic thick-
developed in response to the lesion. It is also emphasized that ening of the mitral valve has been observed at necropsy in
usually there is no echocardiographic or Doppler correlate to mature horses and is probably the basis for most cases of mild
the functional ejection murmur. to moderate MR, including those with “normal” 2D echocar-
Although examiners usually discount “silent” regurgita- diographic imaging. The basis of mitral valve prolapse is
tion, the clinical relevance of audible valvular regurgitation uncertain but could involve connective tissue disease of the
also must be placed in context. For example, examination leaflets, stretched chordae tendineae, minor chordal ruptures,
of high-performance athletes will demonstrate murmurs of or injury to a papillary muscle. Ruptured mitral valve chordae
tricuspid, mitral, or aortic valvular insufficiency in many of
these horses.70,75,208-211,586 These findings are readily verifi- * References 70, 71, 73, 75, 208-211, 390, 391, 406, 560, 586, 602, 849.
able by Doppler imaging. In one study of 2-year-olds,75 the † References 28, 29, 48, 57, 148, 191, 406, 557, 591.
A B
FIG. 9.36 A, Postmortem images from a horse with mitral regurgitation (MR) and congestive heart failure
(CHF) caused by severe degenerative valvular disease. The left ventricle (LV) is opened and the septal or
anterior mitral valve leaflet (AMV) is shown. The free edges of the valve or cusps are slightly thickened for an
equine valve. The body of the valve is very irregular and thick, changes most evident when viewed in close-
up (see inset at lower left). The cut surface of a papillary muscle (PM) and intact chordal attachments to the
valves are evident (arrows). The arrowheads point to the LV moderator band or trabeculae septomarginalis,
part of electrical conduction system. Myxomatous degeneration of the valve was evident on histopathol-
ogy. The cause was unknown. B, Chronic suppurative valvulitis caused by chronic endocarditis has led to
scarring, thickening, and distortion of the mitral valve. This horse developed severe left-sided CHF. Noninfec-
tive valvulitis also is recognized sporadically in horses, particularly in younger animals.
A B
FIG. 9.37 Rupture of the mitral valve chordae tendineae. A, Acute rupture of a chorda tendinea in a horse
with lymphocytic plasmacytic valvulitis. The flail mitral cusp actually has twisted because of loss of support.
The ventral portion of the tear is obvious adjacent to intact chords. B, Chronic rupture of a chorda tendinea
in a horse. The contraction of the scarred segments (arrow) is notable.
tendineae with flail mitral leaflet can occur in animals of any endocarditis is involved. Although uncommon, infective
age, including foals.38,212-214,845 Chordal ruptures, which often endocarditis can lead to ulceration, vegetation, or chordal
involve the accessory mitral cusps, may lead to severe MR with injury and substantial MR (see later). The authors have
fulminant acute CHF. Necropsy findings in these cases often observed MR due to severe mitral scarring and thickening in
show degenerative thickening of the ruptured strand; rarely weanlings and young horses. The cause of these lesions is
FIG. 9.38 Echocardiograms recorded from horses with mitral regurgitation (MR). A, M-mode study dem-
onstrating significant thickening of the anterior mitral valve (AMV) leaflet (arrows). This would be compatible
with endocarditis or severe valvulitis (RVW, right ventricular wall; RV, right ventricle; IVS, intraventricular
septum; LV, left ventricle; LVW, left ventricular wall). B, Flail mitral leaflet (right arrow) in a horse with multi-
ple chordae ruptures. The prolapsed portion of the mitral valve forms a curved echodense line in the dilated
left atrium (LA), whereas the other valve portions are to the left of this echocardiogram. A normal chord is
evident (left arrow). C, Pulsed-wave Doppler study recorded from the LA demonstrating a turbulent, high-
velocity, aliased systolic jet of MR in a Thoroughbred horse. The duration of the event is shown (arrows).
unknown, but the nonsuppurative valvulitis identified might exercise-induced pulmonary hemorrhage, or overt CHF. Tol-
be related to an immune-mediated process. Severe aortic erance of the lesion depends largely on whether the horse is
insufficiency, nonrestrictive ventricular septal defects, or rarely used for vigorous work. Some horses with MR also develop
myocarditis, cardiomyopathy, or myocardial infarction can AF, which can further impair cardiac output. When a mur-
lead to mitral insufficiency through dilation of the mitral mur of MR is identified within the setting of fever, weight loss,
annulus or loss of papillary muscle support. polyarthritis, or systemic inflammation, infective endocarditis
The clinical presentation of the horse with MR varies. should be considered. Mitral regurgitation related to chordal
Mitral regurgitation is often an incidental finding detected rupture is a rare but well-recognized cause of CHF, including
during a routine examination. In other situations, MR might peracute disease with fulminating pulmonary edema (see Fig.
be identified in a horse with suboptimal performance or overt 9.10). Chronic, hemodynamically relevant MR from any cause
clinical signs of heart failure. As indicated previously, rela- can lead to pulmonary hypertension, AF, and biventricular
tively soft murmurs of MR are common in high-performance CHF, with clinical signs of right-sided CHF dominating the
horses.70,75,208-211,586 When MR is only mild to moderate, sig- clinical presentation (see earlier in this chapter).48,148
nificant left atrial dilation and LV volume overload are not evi- The physical examination of the horse with MR typically
dent, left atrial pressure (as estimated by pulmonary capillary reveals a grade 2 to 5/6 holosystolic murmur that is detected
wedge pressure) increases little compared with healthy con- most intensely at or dorsal to the palpable left apical impulse
trols,354,355,639 and the horse often performs satisfactorily.355 and over the mitral valve area (see Figs. 9.7 and 9.35 and Table
Two recent retrospective studies also suggest a good long-term 9.1). Often the murmur is loud at the aortic valve, probably
prognosis for cases of mild MR in sport and pleasure horses583 related to the proximity of the septal mitral leaflet to the aor-
and in middle-aged to older horses and ponies407 with left- tic valve or to cranial projection of the regurgitant jet. Loud
sided valvular regurgitation. With moderate to severe MR, MR murmurs often project quite dorsally and to the right. The
clinical signs are more likely, including poor performance, typical murmur of MR is long (holosystolic or pansystolic),
extending into the second sound. This timing may cause the a complete and thorough examination of the mitral valve that
listener to misinterpret the third sound as the second, thus involves multiple image planes. When color-flow Doppler
preventing a full appreciation of the significance of the mur- demonstrates both a wide origin of the regurgitant jet and
mur. When the third sound is very loud, the clinician should a pattern of diffuse distribution of turbulence deep into the
suspect significant volume overload or increased LV diastolic left atrium, the likelihood of hemodynamically relevant MR
pressure. Because many horses with MR also have concomi- is greater. However, receiving chamber (i.e., left atrial) color
tant tricuspid regurgitation, echocardiographic examination coding in MR should not be overemphasized because red
and Doppler studies may be needed to differentiate bilateral blood cell entrainment and “spray effects” can result in over-
atrioventricular valve insufficiency from isolated MR with estimation of MR severity, whereas wall-hugging jets underes-
radiation to the right. Finally, the murmur of MR can be mod- timate severity of MR. Therefore quantitation of cardiac size
ified by second-degree AV block, AF, or premature beats. is instrumental in assessing MR severity. With severe MR and
Two variants of holosystolic MR murmur are the early- LV volume overload there will be rounding of the LV apex and
to-mid-systolic decrescendo murmur and the mid-to-late increased end-diastolic LV dimension. Global LV function
systolic crescendo murmur. A decrescendo murmur may be may appear normal to exuberant (hyperdynamic) because ven-
detected with mild MR because coaptation of the leaflets can tricular preload is increased and afterload decreased in severe
occur as the ventricular volume decreases during late systole. MR. However, when MR is both severe and chronic, or if the
This type of murmur can be easily confused with a functional underlying basis for MR is cardiomyopathy, the ventricular
ejection murmur, unless the point of maximal murmur inten- systolic function is normal to decreased. The left atrium often
sity is centered near the left apex. Conversely, severe MR with assumes a more circular, almost turgid, appearance when MR
CHF could conceivably cause a decrescendo murmur because is hemodynamically important, and the 2D echocardiographic
atrial and ventricular pressures may equilibrate in late systole. measure of maximum internal LA dimensions measured from
However, this is not a common finding and would be associ- a right-parasternal long-axis view at end-systole often exceed
ated with CHF. The other variant of MR, the mid-to-late sys- 13.5 cm (for the widest LA diameter parallel to the mitral valve
tolic crescendo murmur (see Fig. 9.35B), presumably is caused annulus) and 105 cm2 (for maximum LA area), respectively,
by mitral valve prolapse as it starts after the left ventricle has in large-breed 500-kg horses.355,576,689 With acute or chronic
begun ejection. Decreasing LV volume predisposes to leaflet MR, the lobar and main PA may be dilated as a consequence
prolapse and initiates midsystolic regurgitation that builds of pulmonary hypertension, presumably related to increased
through the second heart sound. The resultant murmur can be LA pressure, interstitial lung edema, vascular remodeling, or
harsh or musical, and the novice often confuses this flow event other factors.
with an early diastolic murmur. The prognosis for horses with MR is variable and, as dis-
Echocardiography including Doppler examinations play cussed earlier, is related to clinical findings, work history,
a pivotal role in the assessment of the horse with MR* (see exercise testing, and results of echocardiographic studies.68 In
Fig. 9.38) and is indicated to examine the anatomy of the valve one study, MR was the most common valvular disease asso-
apparatus (including papillary muscles, chordae tendineae, ciated with AF, clinically important ventricular arrhythmias,
annulus, and leaflets), estimate the severity of MR, measure and CHF.83 Abnormalities observed during echocardiography,
the size of the atria, ventricles, and great vessels, and quan- including lesions of the mitral valve leaflets, the degree of LA
tify left atrial and ventricular systolic function. The underly- and LV volume overload, global LV function, and Doppler
ing cause of MR may be obvious from the echocardiographic findings, should be considered when formulating the progno-
examination. Mild to moderate valvular thickening, although sis. Certainly, when MR is associated with CHF, AF, endocar-
admittedly subjective, is compatible with degeneration or ditis, chordal rupture, marked cardiomegaly, severe valvular
noninfective valvulitis. Prolapse of the mitral valve cusps has thickening, dilated cardiomyopathy, or pulmonary hyperten-
been observed in horses with MR, but the limits of “normal” sion, the prognosis for life and performance is poor.148 In the
prolapse require further definition. Lesions due to vegetative absence of right-sided heart catheterization, increased TR
endocarditis cause the valves to appear irregularly thickened velocity and PA dilation are used as surrogates for the iden-
or shortened. In cases of acute endocarditis, there can be evi- tification of PHT. The detection of PA dilation indicates sig-
dence of valve thrombus, and a high-frame-rate real-time nificant pulmonary hypertension and the low but concrete
examination may show oscillation of this tissue. Small, focal possibility of PA rupture associated with exercise. Fortunately,
lesions are more commonly observed on the atrial surface of the vast majority of horses with MR appear to perform very
the valve that is facing blood flow (see Fig. 9.45B later in this well, indicating that MR in most cases is not severe enough
chapter). In chronic endocarditis, the valve may be more ech- to be clinically important.74,355,583 Whether progressive exer-
odense or even appear calcified. Chordal rupture is recognized cise intolerance will develop in a particular case depends
by observing chaotic flutter of a mitral structure (a flail leaflet), on the horse’s use and on the progression of the underlying
prolapse of a large portion of the valve into the atrium, or the lesion. Generally, when MR is caused by valve degenera-
contracted chordal remnant flipping into the atrium during tion and the heart size is normal, the progression is gradual,
systole (see Fig. 9.38B). High-frequency systolic vibrations of the prognosis for life is favorable, and performance is main-
the mitral valve may be seen on the M-mode study in horses tained.74,390,407,583,862 When MR is detected in an untrained
with a musical murmur of MR. Pulsed- or continuous-wave colt or filly, the prognosis is less encouraging. The presence
or color Doppler studies can identify the mitral regurgitant of even mild to moderate cardiac dilation in a case of MR rec-
jet (see Fig. 9.38C). The Doppler examination should be per- ommends a more guarded prognosis, though this assessment
formed from both the right- and left-sided thoracic windows. is best made by serial examinations. In any case, LA dilation
High-velocity or turbulent jets may be difficult to find without increases the risk for AF. The clinical relevance of trivial to
mild MR in the high-performance horse or racehorse is uncer-
* References 56, 71, 74, 75, 148, 208, 344, 390, 391, 560, 576. tain. In some animals, treadmill exercise is normal whereas
A B
FIG. 9.39 Postmortem lesions of aortic regurgitation (AR; see also Fig. 9.43B). A, A segment of the left
ventricular (LV) outflow tract and the ascending aorta. Linear bands are evident on the two valves shown,
and a large jet lesion also is visible below the valves between the arrows. The lesion is typical in aged
horses. B, The aortic valve (arrow) viewed from the ascending aorta. Noninfective valvulitis and scarring
have caused severe thickening.
others may demonstrate a higher HR for a given level of work In most cases, AR is an incidental finding encountered dur-
than might otherwise be expected. The latter finding may be ing a routine physical, prepurchase, or insurance examination.
suggestive of a cardiac limitation to performance. Most horses with this murmur are older than 10 years of age,
Regardless of cause or the severity of the condition, the and the murmur is especially common in aged horses, a testa-
horse diagnosed with MR merits follow-up examinations ment to the degenerative nature of the lesion. Careful auscul-
at least yearly, if not more often, to evaluate progression of tation in a quiet area may identify a very soft diastolic murmur
the hemodynamic burden and to detect the development of in a younger horse. Silent AR may also be considered physi-
CHF, pulmonary hypertension, or cardiac arrhythmias such ologic or trivial, and it is not uncommon to identify a trivial
as atrial fibrillation (see later discussion).68 HR and heart jet of AR by Doppler studies in horses with no identifiable dia-
rhythm should be monitored on a regular basis with moder- stolic murmur.71 Poor performance is an infrequent present-
ate to severe MR. Exercise testing including stress ECG to ing complaint in horses with AR, and most will continue at
assess HR response to exercise and occurrence of exercise- their prior performance level, provided that no other clinical
induce arrhythmias should be performed (1) in all horses or cardiac abnormalities are present. Intermittent fever, weight
with moderate to severe MR; (2) if AF becomes established loss, or lameness should prompt consideration of endocardi-
(see later discussion); or (3) if MR progresses more rapidly tis. CHF is infrequently observed in conjunction with isolated
than expected, in the absence of signs of CHF.68 Treatment AR but may develop in the horses when AR occurs in combi-
of MR involves management of complications of advance nation with MR or AF.
disease such as heart failure, endocarditis, or arrhythmias. Clinically important AR is identified by cardiac aus-
Limited data have been published about the use of ACE cultation, which reveals a holodiastolic murmur, with the
inhibitors in horses (see Therapy for Congestive Heart Fail- point of maximal intensity over the aortic valve area, and
ure), and no consensus exists among experts regarding their strong radiation to the right and toward the left cardiac
use in MR in the absence of CHF.68 These topics are covered apex in many instances (see Table 9.1). The murmur may
elsewhere in this chapter. vary greatly in intensity and character.18,72,868 The quality is
typically harsh and decrescendo with a blowing nature (see
Aortic Regurgitation Fig. 9.9C), but there may be presystolic accentuation (see
Aortic regurgitation (AR) is a common valvular insufficiency Fig. 9.35C). The character can be vibratory, musical, cooing,
in horses.68,83,407 Degeneration of the aortic valve is by far the buzzing, or “dive-bomber” in quality. A precordial thrill is
most common reason for AR.* The degenerative nodular palpable over the aortic valve area when the murmur is loud.
lesions and fibrous bands responsible for AR in older horses A variant of the typical AR murmur is that associated with
have been well described5 (Fig. 9.39A). Prolapse of the aortic rupture of an aortic sinus into the right atrium, ventricular
valve is a common echocardiographic finding and probably septum, or pulmonary artery. An aortic-cardiac fistula leads
represents another manifestation of connective tissue degen- to a holodiastolic or continuous murmur that is louder over
eration affecting the valve.194,577 Small fenestrations of the valve the right side of the thorax.262-264 However, in the majority of
also have been identified at necropsy but have uncertain clini- horses with an aortic-cardiac fistula, a continuous machin-
cal relevance. Other potential causes of AR in horses include ery-type murmur is detected. A systolic ejection murmur is
infective endocarditis,† congenital valvular disease,179,189,794 often present in addition to the typical diastolic murmur of
VSD (see earlier in this chapter), noninfective valvulitis, leaflet AR, particularly when the regurgitant volume is large, and
tearing, and ruptured aortic sinus aneurysm.34,262-264,777,864-867 is explained by ejection of a large stroke volume across the
aortic valve. It should be emphasized that there is no evi-
* References 5, 28, 29, 57, 83, 169, 191, 406, 843, 850, 863. dence for anatomic stenosis due to degenerative aortic valve
† References 194, 195, 205, 554, 852, 853, 855. disease.
The quality of the arterial pulses is a good indicator of the an uncommon but ominous finding of severe AR with ele-
severity of the isolated AR.406, 554 Bounding, hyperkinetic arte- vated ventricular end-diastolic pressure.
rial pulses, usually corresponding to increased pulse pressures The flow disturbance of AR is confirmed by Doppler stud-
(greater than 60 mm Hg), indicate moderate to severe AR and ies. The color Doppler examination shows one or more central
significant (but compensated) LV volume overload.406 If the or eccentric diastolic jets of AR. The timing of the flow distur-
myocardium is failing, the arterial pulses will become weak, bance can be verified by spectral Doppler or color-M-mode
the pulse pressure will decrease, and tachycardia will develop. studies. Assessing the severity of AR by Doppler studies is
A complete echocardiographic examination including ripe with pitfalls, and the examiner should use multiple 2DE,
Doppler echocardiography is useful for further evaluation M-mode, and Doppler findings to assess severity. Importantly,
of horses with AR, particularly when a louder (i.e., grade a wide jet area in the LV outflow tract does not always indi-
3–6/6) murmur is identified, the arterial pulse is abnormal, or cate severe AR. The finding of a small, central perivalvular jet,
cardiac-related clinical signs are suspected.* The most com- with a small cross-sectional area, suggests trivial AR. Often
mon abnormality observed by 2D echocardiography is mild these leaks are confined to mid-to-late diastole. Conversely, a
valvular thickening in association with prolapse of one or strong spectral signal, holdodiastolic timing, and wide-origin
more aortic leaflets (Fig. 9.40). Fibrous bandlike lesions color Doppler signal suggests more significant regurgitation.
appearing as an echoic line parallel to the free edge of the left Examination of the short-axis jet area in cross-sectional stud-
coronary leaflet or, less often, nodular thickening or a gen- ies of the aortic root is especially instructive because a wide
eralized increase in echogenicity of the leaflet’s free edge are ventricular spray is often associated with a small origin jet: this
detected.68,554 These findings are compatible with degenerative suggests mild AR. The CW Doppler spectrum can be assessed
valvular disease. Care should be taken not to overdiagnose the for a short pressure half-time (steep AR slope), which indi-
presence of aortic valve prolapse, because prolapse can eas- cates LV diastolic pressure is rapidly increasing and that AR is
ily be mimicked by ultrasound probe malignment.577 High- severe. However, the examiner must be certain the ultrasound
frequency fluttering or vibration of the aortic valve leaflets or beam has remained in good and consistent alignment with the
aortic walls may be seen, most commonly in horses with musi- regurgitant jet before this assessment can be made.
cal or vibratory murmurs. The 2D echocardiographic exami- The clinical relevance and prognosis of AR is most accu-
nation also assists with the differential diagnosis. In cases of rately based on the performance history, physical examination,
endocarditis, the leaflets may appear thickened, irregular, and and echocardiogram. As most cases of AR are associated with
more highly echogenic. The valve may appear to oscillate if a slow degeneration of the aortic valve leaflets, and this occurs
there is fresh thrombus within the vegetation. Other rare 2D in older horses without other cardiac problems, the prognosis
echocardiographic findings related to AR include fenestra- for life and performance is usually good. Such animals typi-
tions of the aortic valve leaflets, flail aortic leaflet, aortic sinus cally have minimal echocardiographic abnormalities or only
aneurysm, and aortic root prolapse into a VSD. Dilation of the mild echocardiographic signs of volume overload that are
aortic root (exceeding 10 cm) may be observed in some horses unchanged at follow-up examinations. Epidemiologic studies
with AR. A recent study described echocardiographic assess- suggest that in general AR is mild in most cases and, when
ment of the rate of diastolic decrease in aortic diameter, which taking age into account, is not an independent predictor of
is associated with the rate of diastolic runoff of blood from the mortality.407 However, when AR is moderate to severe or first
aorta and may serve as an indicator of AR severity.602 recognized in a younger horse (less than 10 years of age), the
Left ventricular volume overload that develops with AR risks for reduced performance life and longevity are higher.68
can be detected on 2D and M-mode echocardiography and The detection of hyperkinetic arterial pulses or a pulse pres-
is characterized by increased end-diastolic LV dimensions, sure of greater than 60 mm Hg suggests that progression of
decreased relative wall thickness, and increased stroke vol- AR is likely.68,406 The findings of flail aortic valve leaflet, endo-
ume.554,576,602,849 An exaggerated or swinging septal motion carditis, moderate to severe LV volume overload, or myocar-
on 2D or M-mode examination indicates a hyperkinetic LV dial failure indicate a poor prognosis for life and performance.
and represents another subjective observation of compen- Concurrent MR and LA enlargement should be anticipated in
sated volume overload (see Fig. 9.40). Left-ventricular short- horses with severe volume overload and increase the risk of
ening fraction and ejection fraction might be high-normal or atrial fibrillation, pulmonary hypertension, and CHF.
increased.554,576,602,849 If myocardial failure develops, septal Ventricular dilation can predispose to ventricular arrhyth-
motion will diminish, shortening fraction and ejection frac- mias. Sudden cardiac death associated with fatal ventricular
tion will decrease, and the end-systolic LV dimensions will arrhythmias has been observed in horses with moderate to
increase. Inspection of the mitral valve often reveals high- severe AR and can occur in isolation, without a history of poor
frequency diastolic vibrations of the septal (anterior) leaflet performance or CHF.68 Therefore an exercising ECG and exer-
related to an eccentric high-velocity AR jet directed across cise test should be obtained when moderate to severe AR and
the LV outflow tract to the left and caudally. Similar vibrations volume overload are present or when performance issues are
may also be detected on the interventricular septum when evident, to determine whether the horse remains safe to ride.68
the regurgitant jet is oriented in a right or cranial direction. Electrocardiographic evaluation should be focused on identi-
Increased mitral valve E-point to septal separation (EPSS) can fying exercise-induced premature ventricular complexes and
indicate that the regurgitant jet is impinging on the valve or appropriateness of the exercising HR. A Holter ECG can be
herald LV dilation and failure. In the latter case, other markers considered as a potential test to further identify and quantitate
of severe insufficiency will be evident, including ventricular ventricular ectopy at rest.68
dilation, rounding of the LV apex, and a wide origin jet of AR Follow-up examinations including echocardiography and
on Doppler studies. Premature (presystolic) mitral closure is ECG exercise test are indicated for the horse with moderate
to severe AR. Affected horses should be reexamined twice
* References 68, 344, 391, 406, 554, 576, 602, 849, 869. yearly and at least annually thereafter if progression has been
A B
C D
E F
G H
minimal. Longer follow-up intervals are appropriate for horses tendineae, pulmonary hypertension (caused by left-sided fail-
with mild AR after the first reevaluation.68 If AF develops in a ure or severe respiratory disease), myocardial disease with sec-
horse with mild to moderate AR, a reexamination is indicated ondary cardiomegaly, chronic tachyarrhythmia, and congenital
at that time, including an ECG exercise test. HR and heart malformation of the valve. Degenerative, fibrotic thickening of
rhythm should be monitored on a regular basis in cases of the tricuspid valve in mature horses may lead to mild to moder-
moderate to severe AR; an increased resting HR or an irregu- ate TR. Endocarditis of the tricuspid valve is in many cases
larly irregular rhythm suggesting atrial fibrillation or frequent associated with septic thrombophlebitis secondary to jugular
ventricular arrhythmias indicates progression of disease.68 venipunctures or catheterization. Compared with the mitral
The detection of exercise-induced ventricular arrhythmias is condition, ruptured tricuspid valve chordae tendineae are
considered an important negative prognostic indicator; these uncommon and better tolerated unless associated with endo-
horses are considered less safe to ride or drive than their age- carditis. Pulmonary hypertension, cardiomyopathy, and myo-
matched peers.68 Generally, horses with severe AR should carditis can lead to secondary dilation of the tricuspid annulus
not be ridden or driven by a child, be used as a lesson horse, or alteration of papillary muscle support, permitting valvular
or participate in a high-risk sport owing to a risk for sudden insufficiency. Tricuspid malformation does occur but seems
cardiac death.68 Limited data have been published about the more commonly associated with stenosis or atresia of the valve
use of ACE inhibitors in horses (see Therapy for Congestive (see earlier in this chapter).†
Heart Failure) and no consensus exists among experts regard- Auscultation of the horse with TR typically reveals a grade
ing their use in AR in the absence of CHF.68 These topics are 2/6 to 5/6 holosystolic murmur with the point of maximal
covered elsewhere in this chapter. intensity over the right hemithorax at the tricuspid valve area
(see Table 9.1). The murmur can be holosystolic, decrescendo,
Tricuspid Regurgitation or mid to late systolic. Although the timing and intensity
Tricuspid regurgitation (TR) may be the most frequently may at times remind the examiner of a functional murmur,
detected flow disturbance and murmur in the horse.* The the location of greatest murmur intensity argues against that
prevalence and color Doppler severity of TR increases with possibility. The murmur usually radiates dorsally and if loud
age, training, and subtle physiologic increases in RV dimen- to the extreme left cranioventral thorax. The intensity of the
sions, and murmurs consistent with TR are common in horses TR murmur in many cases does correlate well to the regurgi-
of racing age.70,75,208,209 However, the anatomic correlate to this tant volume, but loudness also depends on PA and RV systolic
incompetency is uncertain, and there is little information con- pressures. A soft, grade 2 to 3/6 systolic murmur of TR is most
firming the etiopathogenesis of this condition aside from often an incidental finding detected during a routine examina-
speculation that it might be related to recurrent physiologic tion. The majority of horses with a soft TR murmur perform
pulmonary hypertension of high-intensity exercise. Tricuspid well; therefore the clinician should first exclude other likely
valve incompetency can further result from any of the follow- reasons for poor performance before incriminating the tricus-
ing causes: degenerative thickening, prolapse, noninfective pid valve. The murmur is usually more problematic when it
tricuspid valvulitis, bacterial endocarditis, ruptured chordae is loud. In general, a grade 4 or louder murmur is anticipated
* References 69, 71, 72, 75, 83, 191, 208, 209, 280, 281, 391. † References 171, 177, 178, 180, 182, 405, 786, 828, 839.
FIG. 9.40 Aortic regurgitation. A, Right-parasternal long-axis view obtained from a 15-year-old Thoroughbred gelding with aortic regurgitation. Nodular
thickening of the aortic valve cusps is evident (arrow). B, Color Doppler echocardiogram in a right-parasternal long-axis view obtained from a 15-year-old
Warmblood mare with aortic regurgitation. The diastolic regurgitant jet is visible as an area of turbulent flow that appears to be directed toward the inter-
ventricular septum. Based on receiving chamber analysis, the severity of the regurgitation would be graded as mild. C, Color M-mode echocardiogram
in a right-parasternal long-axis view obtained from a horse with aortic regurgitation. The cursor line is placed immediately below the aortic valve (top).
An ECG is recorded simultaneously for timing. This imaging mode is particularly useful for timing of flow events and identifying brief regurgitant signals
or normal valve closure noise. In this case an aortic regurgitant jet is visible as a turbulent flow pattern, starting at the beginning of diastole (i.e., after the
T wave) and ending at the onset of systole (i.e., immediately after the QRS complex). Notice the absence of turbulent flow during the PQ-interval (arrow).
This can be explained by a change in left ventricular pressure occurring after atrial contraction or a reorientation of the regurgitant jet relative to the cur-
sor owing to translational movement of the heart. D, Continuous-wave Doppler recording of a diastolic aortic regurgitant jet from a right-parasternal
long-axis view. The absolute velocities are not accurate in this recording because of lack of adequate alignment with blood flow. However, this recording
can be used for timing of flow events (an ECG is recorded simultaneously for timing). Furthermore, the change in jet velocity (which can be expressed as
“pressure half-time”) reflects the rate of decline in pressure gradient between the aorta and the left ventricle and may be useful to assess the severity of
regurgitation as long as ventricular relaxation is normal; a relatively flat or gradual slope of the velocity envelope (white line) indicates mild aortic regur-
gitation (AR), a steep slope indicates severe AR. E–H, Echocardiogram of a 21-year-old Hanoverian Warmblood gelding with severe aortic regurgitation
and left ventricular volume overload. E, B-mode (left) and color Doppler (right) echocardiogram of the left ventricular outflow tract in a right-parasternal
long-axis view. The aortic valve cusps are irregularly thickened, and aortic valve prolapse is evident during diastole (arrow). A large regurgitant jet is vis-
ible in the left ventricular outflow tract during diastole (right panel). F, M-mode echocardiogram of the left ventricle (LV) in a right-parasternal short-axis
view demonstrating LV enlargement and hyperdynamic motion of the interventricular septum (IVS). The LV fractional shortening was 46%. G, M-mode
echocardiogram of the aortic valve in a left-parasternal long-axis view. Notice the high-frequency vibrations of the aortic cusps during diastole (arrows)
caused by the regurgitant blood flow. H, Two-dimensional (left), M-mode (middle), and color M-mode (right) echocardiogram of the mitral valve in a
right-parasternal short-axis view. Notice the prolapse (arrows) and the high-frequency vibrations (arrowheads) of the septal leaflet of the mitral valve,
caused by rapid, turbulent regurgitant flow in the left ventricular outflow tract during diastole. Ao, Aorta; LA, left atrium; LV, left ventricle; LVFW, left
ventricular free wall; PA, pulmonary artery; RA, right atrium. (From Schwarzwald CC: Ultrasonography of the heart. In: Kidd JA, Lu KG, Frazer ML, et al.:
Atlas of equine ultrasonography, Wiley, Oxford, UK, 2014. Reproduced with permission of John Wiley & Sons, Ltd.)
A B
FIG. 9.41 Tricuspid regurgitation (TR) and pulmonary hypertension (PHT) in a 6-year-old Friesian mare
with severe mitral regurgitation and congestive heart failure. A, Two-dimensional (2D) color flow Doppler
echocardiogram demonstrating marked tricuspid regurgitation (arrow). The right atrium (RA), the right ven-
tricle (RV), and the pulmonary artery (PA) appear enlarged compared with the left ventricle (LV) and the
aorta (Ao). B, Continuous-wave Doppler recording of the TR jet. The maximum jet velocity is 4.8 m/sec,
corresponding to an RV-to-RA pressure gradient of 92 mm Hg (modified Bernoulli equation: dp = 4 × vmax2).
In the absence of RV outflow tract obstruction, the high-velocity TR jet indicates severe pulmonary hyper-
tension. TR jets associated with normal RV pressures are typically less than 3.2 m/sec. An ECG is recorded
simultaneously for timing.
when there is moderate to severe TR or when TR is related at the origin and directed toward the aorta. However, when
to pulmonary hypertension. Atrial fibrillation or atrial pre- the jet is wide at its origin, occupies a larger area in the RA,
mature beats are present in some horses with TR, particularly or projects centrally or laterally into the right atrium, car-
when the right atrium is dilated or the regurgitant jet is large. If diomegaly is more likely to be present, and the heart should
chronic, hemodynamically significant TR has developed, peak be examined carefully. The RV (and PA) systolic pres-
work effort will suffer and even right-sided CHF may develop. sure can be estimated by faithfully recording the peak jet
The latter is very uncommon unless the TR is severe, related velocity. This requires the examiner to align the CW Dop-
to pulmonary hypertension or infective endocarditis, or com- pler cursor parallel to regurgitant flow and may demand a
plicated by AF. Prominent jugular pulses (giant c-v waves; see ventral or dorsal placement of the transducer with steep
Fig. 9.4) are typical of horses with TR associated with CHF. beam angulation. When the jet velocity is less than 2.5 m/
Echocardiographic examination is mainly indicated in sec, pulmonary hypertension is not present. Jets exceeding
horses with a grade 4 to 6/6 right-sided systolic murmur com- 3.2 to 3.4 m/sec are indicative of pulmonary hypertension
patible with TR in the setting of poor performance, concurrent (provided that there is no right ventricular outflow obstruc-
thrombophlebitis, or fever of unknown origin.68 However, an tion or VSD; see Fig. 9.41B). The identification of pulmo-
echocardiogram may also be performed in horses with softer nary hypertension should prompt careful examination of
murmurs in the setting of a prepurchase examination or if the the left side of the heart, because the main cardiac lesion
cause or clinical relevance of the murmur is unclear. The tri- may be centered over the mitral valve, aortic valve, or LV
cuspid valve is typically examined from the right side of the cavity and the right-sided heart changes simply a second-
thorax, because the tricuspid valve and RV inlet are closer to ary consequence. If left-sided heart disease can be excluded
the right thoracic wall (Fig. 9.41). However, an extreme left as a cause for pulmonary hypertension, severe pulmonary
cranial transducer location with caudal angulation can also disease must be considered, and appropriate diagnostics
be successful for examining the tricuspid valve. Because there should be performed.
are a number of potential reasons for tricuspid incompetency, The prognosis for horses with TR is generally very favor-
careful attention must be directed to the valve and its support able. A soft murmur of TR in a trained athlete is disregarded
apparatus, the size of the PA, and the left side of the heart. In as clinically irrelevant; however, defining such a disturbance
the vast majority of cases, with benign or training-related TR, as purely “functional” would be imprecise. The presence of TR
a clear-cut lesion of the tricuspid valve leaflet is not evident, is more likely to cause concern if right-sided cardiomegaly,
and the RA and RV are normal in size. With clinically signifi- severe MR, pulmonary hypertension, or AF is evident. Visu-
cant TR, there might be structural or motion abnormalities alization of a vegetation or chordal rupture or clinical signs of
of the TV originating from valve thickening, prolapse, vegeta- CHF would indicate a poor prognosis for performance and a
tions, chordal rupture, regurgitation secondary to RV dilation, guarded to poor prognosis for life. The width of the regurgi-
and pulmonary hypertension. As with mitral regurgitation, tant jet at its origin, recent performance history, and results
moderate to severe TR leads to RA and RV volume overload; of exercise testing are useful in developing a prognosis for life
however, it is more difficult to quantify these chamber vol- and future work. When TR is judged to be moderate or severe,
umes owing to their complex geometry.70,344,573 annual reexaminations are indicated to follow the progression
Doppler studies can identify the tricuspid regurgitant of the lesion and to detect cardiomegaly or cardiac arrhyth-
jet. In trivial or “silent” TR, this jet is typically very narrow mias if they develop.68
A B
FIG. 9.42 Pulmonic insufficiency and pulmonary hypertension. A, Right-parasternal view of the left ven-
tricular outflow tract obtained from an 11-year-old Paint gelding with severe mitral regurgitation, atrial fibril-
lation, and congestive heart failure. Enlargement of the right atrium (RA) and severe pulmonary artery (PA)
dilation are evident, consistent with pulmonary hypertension. Notice also the marked spontaneous echo
contrast (SEC) in the right atrium. B, Continuous-wave Doppler recording of pulmonic insufficiency in a left-
parasternal long-axis view of the right ventricular outflow tract, showing diastolic regurgitant flow. The vary-
ing peak velocities can be explained by differences in cycle lengths (due to atrial fibrillation), motion of the
heart (and the regurgitant jet) relative to the cursor line, and possibly respiratory variations. The highest
maximum early-diastolic velocity in this spectral Doppler recording was 3.5 m/sec, corresponding to a trans-
valvular pressure gradient of 49 mm Hg (modified Bernoulli equation: dp = 4 × vmax2). Assuming a right
atrial pressure of 5 mm Hg, the estimated mean pulmonary artery pressure (MPAP) would be at least 54 mm
Hg, indicating marked pulmonary hypertension. Ao, Aorta; LV, left ventricle.
Pulmonic Regurgitation pathogenesis may differ in younger animals or in those that

Trivial and clinically silent, physiologic pulmonic regurgita- are immunosuppressed. In two reports, the mean age of
tion (PR) can often be detected by Doppler studies; however, affected horses was 2.1 and 4.8 years, respectively.205,855
this is a normal finding.71,209,280,281,391,560 Clinically relevant PR Numerous bacteria have been associated with bacterial endo-
is rare and occurs most frequently with pulmonary hyperten- carditis. The offending microorganism likely depends on the
sion associated with left-sided heart failure or severe respira- environment, portal of entry (e.g., respiratory tract, gastroin-
tory disease. Infective endocarditis, congenital abnormalities testinal tract, skin, oral cavity, joint, surgical wound, or intra-
of the valve leaflets (bicuspid or quadricuspid valve), and rup- venous catheter), and the effects of prior antimicrobial therapy
ture of the pulmonic valve are rare causes of pulmonic insuf- that may select for resistant strains. Streptococcus spp., Actino-
ficiency.200,730 Murmurs of PR are usually undetectable unless bacillus equuli, and Pasteurella spp. have been isolated most
the regurgitant volume is large or is driven by pulmonary frequently, but Pseudomonas spp., Escherichia coli, Corynebac-
hypertension; however, the regurgitant flow can be easily iden- terium spp., Bacillus spp., Rhodococcus equi, Erysipelothrix
tified using pulsed-wave and color-flow Doppler echocardiog- rhusiopathiae, meningococci, Staphylococcus spp., Candida
raphy (Fig. 9.42). Dilation of the PA may be detected parapsilosis, and other organisms (including aspergillosis)
echocardiographically when pulmonic insufficiency is caused have also been reported, with no organism appearing more
by pulmonary hypertension (see Fig. 9.42A). prevalent than the others.872
When severe pulmonic regurgitation does develop, it is gen- The pathogenesis involves bacterial invasion from the
erally a consequence of left-sided heart failure with pulmonary bloodstream and colonization of the heart valve or endocar-
hypertension and accompanied by clinical signs of biventricular dial surfaces. Bacteremia is a prerequisite for development of
failure. Signs of right-sided CHF typically stem from the combi- this condition. Direct invasion of a previously normal valve
nation of pulmonary hypertension, pulmonic regurgitation, RV by virulent bacteria, or in the context of overwhelming sepsis,
volume overload, and TR. If a murmur of pulmonic regurgitation represents the most likely pathogenic mechanism involved in
is detected, it is usually holodiastolic and a decrescendo murmur, foals with infective endocarditis. Disruption of the endocar-
with the point of maximal intensity at the pulmonic valve area, dial surface by jet lesions associated with congenital intracar-
radiating toward the right cardiac apex (see Table 9.1). The prog- diac shunts may also predispose to endocarditis, although this
nosis for life and performance is usually poor in these cases. mechanism is not well established in horses. Preexisting val-
vular heart disease with endocardial changes or high-velocity
Infective Endocarditis jets may represent risk factors for bacterial colonization in
Infective (bacterial) endocarditis is caused by invasion of the older horses, but again this is completely unproven.
heart valves or endocardium by bacteria. Endocarditis is not The most common sites of infective endocarditis are the
common in horses but occurs sporadically in most aortic and mitral valves, although endocarditis lesions have
populations.* Horses of any age may be affected, although the been reported on all cardiac valves. Mural and chordal endo-
carditis lesions have also been reported but occur much less
* References 31, 191, 193-206, 824, 852-860, 870, 871. frequently. The combination of bacterial injury, exposure of
valve collagen, thrombosis, and host leukocyte response con- Clinical features of endocarditis are variable.205, 855 Affected
tributes to development of the vegetation (Fig. 9.43), which horses usually have a history of intermittent fever, weight loss,
consists microscopically of bacteria, platelets, fibrin, leuko- depression, anorexia, lethargy, and often intermittent lameness
cytes, and varying degrees of granulation or fibrosis. Bacte- (Fig. 9.44). Synovial distention may be noted. A predisposing
ria may not be evident at necropsy, especially if antimicrobial condition or a concurrent infection may be evident, includ-
therapy has sterilized the vegetation. ing jugular vein thrombophlebitis, strangles, septic joint, or an
The pathophysiology of endocarditis in horses is prob- abscess. In most horses there is no history of previous illness
ably similar to that in other species. A host response, as well and no evidence of concurrent infection. The physical exami-
as the primary cardiac lesions, contributes to the morbidity nation often reveals fever, and some horses may be tachypneic.
of this disease. Cardiac manifestations include valvular injury The fever is often intermittent. Murmurs of mitral or aortic val-
leading to regurgitation, chordal rupture, or rarely to steno- vular insufficiency are most commonly detected; those of TR
sis; secondary cardiomegaly; myocarditis from extension of are less common. Systolic murmurs caused by valve destruc-
the infection or through coronary embolization; myocardial tion must be differentiated from the physiologic flow murmurs
infarction if emboli are shed to the coronary arteries; arrhyth- that are heard so often in febrile horses. Murmurs of valvular
mias from cardiomegaly, myocarditis, or infarction; and myo- stenosis may also be detected with bacterial endocarditis but
cardial depression from bacteremia. Recurrent or chronic occur rarely.200 Some horses with bacterial endocarditis have
bacteremia, and hence fever, is characteristic of endocarditis. no auscultable murmur initially. The quality or intensity of the
Metastatic infection, distant thrombosis and infarction, and murmur may change over a number of days. Atrial fibrillation,
immune-mediated host responses can occur. Distant infec- atrial or ventricular premature depolarizations, and ventricular
tion or immune complex disease can lead to multisystemic tachycardia have been observed with endocarditis.199
clinical signs, including polyarthritis, osteomyelitis, vasculi- Laboratory studies obtained from horses with infective
tis, or nephritis. Right-sided thrombi can lead to pulmonary endocarditis may reveal anemia (related to chronic inflam-
thrombi and/or abscessation of the lungs (see Fig. 9.43).193, 200 matory disease), hyperproteinemia (hyperglobulinemia with
A B
C D
FIG. 9.43 Bacterial endocarditis: postmortem lesions. A, Severe mitral valve endocarditis in a yearling.
B, Focal aortic valve endocarditis is evident in this view of the left ventricular (LV) outlet and the ascending
aorta. The septal mitral leaflet is at the lower right, and a jet lesion (arrow) is visible in the LV outflow tract.
Above the mitral leaflet, in the center of the left coronary cusp, is a raised, irregular vegetation (arrowhead)
that caused aortic regurgitation (AR). C, Tricuspid valve vegetation in a weanling. Although less common
than mitral or aortic vegetations, right-sided endocarditis is a definite risk in horses, particularly in animals
subjected to repeated jugular venous catheterization. D, A lung abscess in a horse after pulmonary valve
endocarditis. The center of the abscess is incised and reveals caseous exudate. Systemic embolization and
metastatic infection are recognized complications of valvular infections.
hypoalbuminemia), elevated plasma fibrinogen concentra- Diagnosis of infective endocarditis may be definitive in
tions, and leukocytosis with a mature neutrophilia.205,855 the setting of a compatible clinical history with positive
Multiple blood cultures should be performed when bacterial blood cultures or clear echocardiographic demonstration
endocarditis is suspected. The result of blood cultures may be of a vegetation. In the absence of these, the relative likeli-
negative, however, particularly after antimicrobial therapy. A hood of endocarditis is based on combinations of clinical
positive blood culture may be more likely if multiple samples findings and laboratory tests. Major and minor diagnostic
are drawn at different times of the day during or near febrile criteria (Duke criteria) have been used for assessment of
episodes. Antibiotic removal system media might also be of human patients,873 and these principles are probably appli-
value when culturing blood from horses that have received cable to horses. Endocarditis should be considered in any
antibiotics recently, and it can be helpful to consult with a horse that presents with a fever of unknown origin and
clinical microbiologist regarding optimal broth media used one or more of the aforementioned clinical signs, particu-
for blood culturing. larly in association with synovial distention and lameness.
Endocarditis becomes more likely when the cause of fever
cannot be isolated to another body system and concurrent
cardiac disease is identified. The diagnosis is confirmed
with positive blood cultures in the setting of compatible
clinical findings or by echocardiographic detection of veg-
etative lesions on the valve leaflets or endocardial surface
(Fig. 9.45).
Vegetative lesions usually appear echocardiographically as
thickened, echogenic to hyperechoic masses with irregular or
“shaggy” edges. The valve leaflet often demonstrates diffuse
thickening as well. Discrete lesions are generally on the valve
surface facing the normal path of blood flow. The typical endo-
carditis lesion adheres to the valvular endocardium (and there-
fore moves with the valve). When a fresh thrombus is attached
to the vegetation, an oscillatory appearance may be evident
with high-frame-rate, real-time imaging. Chronic lesions may
contract, calcify, or develop a smooth contour. Rupture of the
chordae tendineae or avulsion of a valve leaflet may also be
detected echocardiographically, and this complication is not
uncommon in mitral or tricuspid valve endocarditis. Pulsed-
FIG. 9.44 Weight loss, loss of condition, and ventral edema in this wave and color-flow Doppler echocardiography can be used
weanling with endocarditis and right-sided congestive heart failure (CHF; to confirm that the valve is incompetent or (rarely) stenotic.
see also Fig. 9.43C). Valvular regurgitation often progresses because of continued
A B
FIG. 9.45 A, Right parasternal long-axis two-dimensional (2D) image from a horse with infective endocar-
ditis affecting multiple valves. Marked thickening of the tricuspid valve (TV) is evident, with spontaneous
contrast (C) surrounding the valve. The right leaflet of the aortic valve is markedly thickened (arrows) be-
tween the left ventricular outflow tract (LVOT) and ascending aorta (Ao). Pulmonary artery (PA) and right
atrium (RA) are seen in the far and near fields. B, Focal vegetation (arrow) is observed on a closed mitral
valve in a long-axis image from the right thorax (RV, right ventricle; LA, left atrium; LV, left ventricle).
A B
FIG. 9.46 A, Proliferative epicardial reaction in a horse with idiopathic, fibrinopurulent pericarditis. The
heart is covered by a layer of organizing fibrin and inflammatory debris creating a shaggy appearance
typical of inflammatory pericarditis. B, Two-dimensional (2D) long-axis echocardiogram from another
horse demonstrating a moderate pericardial effusion. The effusion (PE) appears more prominent behind
the left ventricle (LV) but is also evident (arrow) cranial to the right ventricle (RV). OT, Left ventricular
outflow tract.
damage to the valve leaflets associated with ongoing bacterial bacterial isolate, clinical response, cost, and potential toxico-
infection or subsequent to fibrosis or calcification associated sis of the antimicrobial therapy must all be weighed in these
with a bacteriologic cure. decisions.
Early diagnosis and aggressive, prolonged treatment are The expectation for long-term survival is poor in most
important for successful treatment of infective endocarditis. cases of infective endocarditis causing severe valvular injury.
Treatment should consist of adequate doses of bactericidal anti- Even in the absence of significant valvular regurgitation, there
biotics, ideally based on culture and sensitivity patterns of blood may be difficulty in achieving a bacteriologic cure, or valvu-
culture isolates. Initial therapy should be broad spectrum, until lar damage may progress as the vegetation heals and scars the
the results of the blood culture are known or when a positive valve. Although some horses have been treated successfully
blood culture cannot be obtained. Intravenous therapy is pre- for endocarditis,31,197,199,205 overall there is a low likelihood of
ferred in the initial stages of treatment. Drugs that penetrate long-term survival with continued use of the horse as a per-
fibrin well, particularly potassium penicillin (22,000–44,000 formance animal or in breeding. The absence of an obvious
IU/kg, IV every 6 hours), are reasonable initial choices because echocardiographic lesion or signs of systemic inflammatory
bacteria may be sequestered in fibrin and may be unavailable response creates a more favorable situation, provided that a
to leukocytes. To extend the antimicrobial spectrum, penicil- bacteriologic cure can be obtained. Progressive cardiomegaly,
lin is usually combined with gentamicin sulfate (9 mg/kg, IV CHF, rupture of the PA, development of AF, thromboembolic
every 24 hours) or amikacin sulfate (20 mg/kg, IV every 24 complications, and sudden death have been reported in horses
hours for adults; 25 mg/kg, IV every 24 hours for foals). Eryth- affected with endocarditis. Accordingly, periodic follow-up
romycin estolate (25 mg/kg, PO every 6–8 hours) combined examination, including echocardiograms, should be per-
with rifampin (5–10 mg/kg, PO every 12 hours) may be useful formed in successfully treated cases.
in some cases. Nonsteroidal antiinflammatory drugs (flunixin
meglumine 1.1 mg/kg, IV q 12 h) may be beneficial to reduce Y PERICARDIAL DISEASE
systemic and local inflammatory reactions. Aspirin (10–20 mg/
kg, PO every 24–48 hours) and heparin (sodium heparin: 40 Pericardial diseases occur uncommonly and are usually asso-
IU/kg, SC every 8–12 hours; dalteparin 50–100 IU/kg, SC every ciated with pericardial effusion and fibrinous pericarditis (Fig.
24 hours; or enoxaparin 40–80 IU/kg [0.4–0.8 mg/kg], SC every 9.46).* Approximately one third of the cases can be attributed
24 hours) are used by some clinicians to prevent platelet adhe- to bacterial infection,872 and an infectious etiology should be
sion, diminish growth of the vegetation, and reduce the risk of assumed until proven otherwise. Actinobacillus spp. have most
thrombotic complications, although the benefits of antithrom- frequently been reported with pericarditis,872 but Streptococ-
botic therapy are uncertain. cus spp., Escherichia coli, Enterococcus spp., Pseudomonas
With effective antimicrobial therapy, the fever should aeruginosa, Pasteurella spp., Corynebacterium pseudotubercu-
resolve within 5 to 7 days. Response to treatment should be losis, Mycoplasma, and other microorganisms, including fun-
assessed by repeated examinations, including clinical assess- gal agents, have also been isolated.126,133-135,739,872,880,881
ment, laboratory analyses, and serial echocardiograms. Outbreaks of pericarditis with largely sterile inflammatory
Therapy should extend to at least 4 to 8 weeks or until body effusates have been described as part of the mare reproductive
temperature, plasma fibrinogen concentration, and leukocyte
counts have been normal for at least 2 weeks. The duration and * References 67, 119-121, 125-128, 131-137, 140, 191, 738-742, 796, 870, 872,
type of long-term therapy depend on various factors, and the 874-883.
Right ventricular pressure curve fever, pericardial friction rub, muffled heart sounds, tachy-
pnea, pleural effusion, jugular and generalized venous dis-
tention, ventral edema, thready pulses, and ascites. In acute
100 cases, clinical signs of depression and weakness may predomi-
nate, whereas in chronic cases signs of right-sided CHF are
evident. Arterial BP may be decreased in cardiac tamponade,
and a pronounced inspiratory fall in BP (pulsus paradoxicus)
may be identified by palpation of the pulse or through careful
measurement of arterial BP. In chronic disease, BP is normal,
owing to fluid retention, elevated venous pressures, vasocon-
striction, and tachycardia.
Laboratory studies are contributory to the diagnosis. Clini-
cal laboratory abnormalities are not specific, but the most
0 frequently detected abnormalities include anemia, hyperpro-
teinemia, hyperfibrinogenemia, and a neutrophilic leuko-
FIG. 9.47 Pressure tracing demonstrating elevated right ventricular cytosis. Other hematologic abnormalities may be observed
(RV) end-diastolic pressure in a horse with constrictive pericarditis and related to inflammation, CHF, or organ hypoperfusion. Tho-
heart failure. A quick rise occurs from the nadir of pressure (lower arrow) racic radiographs usually reveal a globoid cardiac silhouette
to a plateau (upper arrow), which is typical of constrictive disease and or pleural effusion and may reveal interstitial pulmonary infil-
ventricular filling that is limited to early diastole. trates and enlarged pulmonary vessels. The ECG usually dem-
onstrates decreased amplitude of the QRS complexes. If the
effusion is large and the heart is swinging, electrical alternans
loss syndrome, first recognized in Kentucky and subsequently may be observed. Pericarditis may elevate the ST segment in
also in other areas.134,136,884-886 Exposure to eastern tent cater- multiple leads, but this change may occur simply as a result
pillars was identified as the greatest risk factor in these out- of tachycardia. Sinus tachycardia is typical, but ventricular or
breaks, and Actinobacillus spp. were the principal isolates atrial premature complexes may be detected.
obtained from necropsy and clinical cases.134,885 It was pro- The echocardiographic examination is diagnostic, dem-
posed that caterpillar-related toxins or hairs of the caterpillars onstrating an anechoic or hypoechoic fluid space between
breached the gastrointestinal mucosal integrity and led to sec- the pericardium and epicardial surface of the heart (see Fig.
ondary opportunistic invasion of commensal bacteria of the 9.46B) while excluding an extracardiac mass lesion, which can
mucosal surfaces that appeared to be pericardiotrophic in mimic pericardial disease.140 Fibrin tags frequently are evi-
horses.885 In many cases, idiopathic pericarditis might in fact dent on the parietal and visceral pericardial surfaces. Findings
be viral in origin, either directly or through immune-medi- of protracted diastolic collapse of the right ventricle or sys-
ated mechanisms.872 Equine influenza, equine viral arteritis, tolic collapse of the right atrium are compatible with a clinical
and equine herpes virus infections have been associated with diagnosis of cardiac tamponade. Inflammatory processes may
pericarditis, and horses with pericarditis sometimes have a eventually lead to adhesions between the parietal and visceral
recent or current history of respiratory disease; nonetheless, pericardial layers, causing constrictive pericarditis with mini-
evidence for a viral etiology is scarce.872 External thoracic mal or no obvious effusion. Associated pleural effusion is a
trauma or penetration by a gastric foreign body may lead to common ultrasound finding. Echocardiographic diagnosis of
bacterial inoculation of the pericardial space.741,874,877 The constrictive disease without effusion is more challenging but
pathogenesis of noninfective pericarditis is unknown but typically reveals thickened pericardium, atrial dilation, sys-
might be immune mediated in some situations.133 Finally, car- temic venous dilation, exuberant movement of the ventricu-
diac or pericardial neoplasia can cause pericardial effusion, lar septum, and exaggerated inspiratory filling of the heart as
with mesothelioma and lymphosarcoma being the most com- documented by pulsed-wave Doppler studies.121,125 In some
mon neoplasms affecting the pericardium in horses. Pericar- cases right-sided heart catheterization is needed to establish
dial hernias have also been seen but are rare. the diagnosis. Typical findings are increased central venous
The pathophysiology of pericardial disease in most cases pressure, elevated RV diastolic pressure, and possibly a dia-
is ascribed to impaired cardiac filling resulting from either stolic dip and plateau appearance to the RV waveform (see
external compression (cardiac tamponade) or pericardial con- Fig. 9.47).125
striction.117 There is typically marked elevation in the venous, Cytologic evaluation of the pericardial effusion is essential
atrial, and ventricular end-diastolic pressures (Fig. 9.47). to distinguish septic, aseptic, or neoplastic pericardial effu-
Occasionally a mass lesion compresses the heart or obstructs sion. Fluid can be obtained in the course of needle pericar-
venous drainage or ventricular outflow and mimics findings of diocentesis or during the placement of an indwelling tube for
pericardial disease. Other clinical signs may be referable to the pericardial lavage and drainage. Bacterial culture and sensitiv-
underlying cause as with infection or neoplasia. ity of the aspirated fluid should be performed so that antimi-
The clinical syndrome of pericardial effusion with tam- crobial therapy can be guided in cases of septic pericarditis.
ponade is characterized by reduced cardiac filling despite The treatment of pericardial diseases varies, depending
increases in ventricular filling pressures. The history usu- on the cause and clinical situation. Even when signs of right-
ally includes systemic signs of illness, such as fever, lethargy, sided CHF dominate the clinical picture, the use of furose-
depression, anorexia, tachypnea, ventral edema, colic, and mide is generally contraindicated, because aggressive diuresis
weight loss. A recent history of an upper or lower respira- results in lowered filling pressures, reduced ventricular filling,
tory tract infection is not uncommon. Physical examination decreased cardiac output, and possibly syncope. Instead, peri-
abnormalities include various combinations of tachycardia, cardiocentesis or catheter drainage should be considered as
first-line therapeutic procedure in all cases of pericardial effu- regarding these disorders.* There is certainly a potential for
sion with cardiac tamponade. Because the development of car- myocardial injury or inflammation related to drugs and toxins
diac tamponade depends not only on the volume of pericardial (e.g., ionophore antibiotics, poisonous plants, cantharidin,
fluid but also on the rate at which it accumulates, the clinician’s snake venom), ischemia, hypoxia, infective agents (bacterial,
urgency should be guided by BP, clinical signs, magnitude of viral, parasitic, fungal), heavy metals, trauma, metabolic dis-
pleural effusion, and echocardiographic evidence of cardiac ease, or nutritional deficiencies (e.g., vitamin E, selenium).
tamponade. Tamponade is an indication for immediate drain- Myocardial injury also can derive from extension of a preexist-
age of the pericardial sac. Echocardiography can be used to ing infection (pericarditis, pericardial abscess, or endocardi-
localize a site for pericardiocentesis and choose an appropriate tis) or related to sepsis.652 Infiltrative cardiomyopathies can
length of needle, catheter, or drainage tube. Pericardiocentesis occur consequent to neoplasia (lymphoma, melanoma,
should be performed after locally anesthetizing the intercostal lipoma, hemangioma/hemangiosarcoma, mesothelioma, pul-
muscles and pleura. Electrocardiographic monitoring should monary carcinoma)138,139,166,843,848,907-911 or the very rare amy-
be performed continuously during the procedure to moni- loidosis735 (Fig. 9.48; see also Box 9.2). Left ventricular
tor for cardiac puncture or in case ventricular arrhythmias hypertrophy and dysfunction may also develop secondary to
develop. Pericardiocentesis is usually performed within the systemic hypertension associated with chronic pain, laminitis,
left fifth intercostal space, above the level of the lateral tho- chronic kidney disease, or potentially metabolic syn-
racic vein, although it can also be performed at the right hemi- drome.143,903 Three cases of suspected arrhythmogenic right
thorax. Drainage is achieved using a large-bore catheter, teat ventricular cardiomyopathy have recently been described as a
cannula, or chest tube; the latter is recommended for repeated cause of episodic collapse and cardiac death.668,899 Dilated car-
drainage and lavage of the pericardial sac and is most success- diomyopathy (DCM) phenotype has been recognized in the
ful for aggressive management of septic or idiopathic fibrin- horse, but the underlying cause is generally unknown and the
ous pericarditis. After insertion of an indwelling catheter, local condition is usually considered to be idiopathic. Relentless
therapy is administered that includes pericardial lavage and junctional or ventricular tachycardia developing at a high rate
direct instillation of antimicrobials and possibly anticoagu- (greater than 100–120 beats/min) and persisting over days can
lants such as heparin. Combined with systemic antimicrobials cause tachycardia-induced cardiomyopathy that resembles
this therapy has been effective in the treatment of septic peri- DCM and is characterized by chamber dilation and systolic
carditis.133,738 Pericardial lavage should be continued for sev- dysfunction; control of HR and heart rhythm may lead imme-
eral days, until there is little accumulation of pericardial fluid diately to more normal LV function, and the cardiomyopathy
(less than 1 L over 12 hours), clinical signs have improved, and may resolve following conversion to sinus rhythm.153
the cytologic character of the fluid becomes less inflammatory.
Initially, broad-spectrum antibiotics should be used and the Clinical Features of Myocardial Diseases
antibiotic regimen should then be adapted according to the The general manifestations of myocardial disease, regardless
results of bacterial cultures and antibiotic sensitivity patterns. of the underlying injury, can be attributed to the following
Nonsteroidal antiinflammatory drugs are indicated to fight pathophysiologic processes: (1) reduced myocardial contrac-
inflammation and to reduce the risk of constrictive pericardi- tility and ventricular ejection fraction; (2) diastolic dysfunc-
tis. If the cytologic analysis and culture are negative for bacte- tion with impaired ventricular filling; (3) mitral or tricuspid
ria, antiinflammatory doses of dexamethasone may be used for valve incompetency caused by cardiac dilation or papillary
treatment of idiopathic, nonseptic, effusive pericarditis.126,133 muscle dysfunction; or (4) the development of arrhythmias.
Exudative pericarditis may not respond in all cases to conser- The overall cardiac disability engendered by myocardial dis-
vative treatment or even to drainage. Surgery is a rarely used ease varies greatly. Some horses have no detectable clinical
option for treatment of pericardial disease but would be most signs; others demonstrate exercise intolerance, life-threaten-
appropriate for constrictive or constrictive-effusive pericar- ing arrhythmias, low-output CHF, or sudden death.
ditis.125 Presumably introduction of minimally invasive tho- Persistent ventricular premature depolarizations or ven-
racoscopic surgical techniques to management of pericardial tricular tachycardia can be observed in horses with myocar-
diseases in horses might prove useful. dial disease.162,164,651,900,912 Atrial premature depolarizations,
The prognosis for survival and maintenance of perfor- atrial tachycardia, and AF are more often primary electrical
mance in horses affected by pericardial disease is guarded. disturbances; however, these arrhythmias also can develop
The prognosis for cardiac or pericardial neoplasia is quite in horses with cardiomyopathies. Although it is tempting
poor. Caution also must be expressed regarding inflammatory to diagnose “myocardial disease” in the setting of any car-
pericarditis because the condition may become chronic, but diac rhythm disturbance, it should be appreciated that many
very good results have been obtained in some reports.133 The rhythm abnormalities are “functional,” without a gross ana-
potential of eventual constrictive or fibrotic pericardial dis- tomic substrate. This point is especially germane to horses
ease is also greatest with inflammatory pericardial conditions suffering from electrolyte or other metabolic imbalances, high
so that early success may be tempered by later complications sympathetic tone, sepsis or toxemia, hypoxemia, or ischemia.
of the disease.126 The best prognosis of horses with fibrinous In horses examined for sudden death at a racetrack, gross or
pericarditis is when treatment includes repeated drainage and microscopic myocardial lesions were relatively uncommon
lavage. Treated horses should be followed and reevaluated by findings compared with pulmonary lesions.103,106
echocardiography. The onset of clinical signs may lag behind the initial myo-
cardial insult, especially in cases of myocarditis or chronic
Y MYOCARDIAL DISEASE myocardial injury. For example, a horse that has apparently
Myocardial diseases are probably underrecognized in clinical * References 28, 29, 66, 97, 138, 145, 149, 150, 154, 155, 160-162, 164, 166, 191,
practice although a variety of reports have been published 485, 575, 651, 658, 660, 661, 734, 735, 777, 870, 882, 887-906.
RV
LV
A B
C D
FIG. 9.48 Myocardial diseases. A, An opened left ventricle (LV) revealing a (incised) large, oval area of
subendocardial and myocardial fibrosis in a mare. No causative agent was found. B, Significant LV dilation
and subendocardial fibrosis in a horse with idiopathic dilated cardiomyopathy. The white discoloration of
the LV and left atrium (LA) may result from chronic distention or represent fibrosis after another injury. The
opened right ventricle (RV) (to the left) is dilated but is not discolored. C, Myocardial lymphoma. A substan-
tial myocardial infiltration is evident in this photomicrograph. D, Close-up of a left ventricular subepicardial
myocardial infarct (arrow) of undetermined cause.
recovered from an illness may develop problems once rig- remains persistently high after exercise is discontinued (note
orous training is begun. The trainer may complain that the that exercise testing should not be performed in horses with
horse is unable to achieve faster speeds or may stop or sud- persistent resting tachycardia or tachyarrhythmia that may be
denly slow during hard training. The affected horse may take attributed to myocardial disease).
a long time to “cool out” after a workout. In more severe cases, An ECG may demonstrate sinus tachycardia or atrial or
marked exercise intolerance, weakness, ataxia, or even col- ventricular arrhythmias. An exercise ECG, in addition to
lapse may occur. Respiratory distress, pulmonary edema, cya- potential exercise-induced arrhythmias, typically records an
notic mucous membranes, prolonged capillary refill time, and inappropriately high HR for the level of work undertaken.
a rapid thready pulse may be detected after exercise. In case of Resting echocardiography usually reveals a low normal or
severe myocardial injury, signs such as fever, persistent tachy- unambiguously reduced ventricular systolic function, as dem-
cardia, arrhythmia, murmur, pulmonary or ventral edema, or onstrated by low LV shortening fraction or ejection fraction.
respiratory distress may be observed. Sudden death may occur Novel echocardiographic methods such as tissue Doppler
without premonitory signs. imaging (TDI) or 2D speckle tracking might be more sensitive
Results of the clinical examination in horses with myo- to detect LV systolic dysfunction compared with conventional
cardial disease are inconsistent. Resting physical examina- 2DE or M-mode echocardiography161,164 and could be par-
tion findings can be normal or signs of heart disease may be ticularly useful to detect subtle myocardial disease in horses
evident. These can include persistent tachycardia, tachypnea, (Fig. 9.49). Furthermore, Doppler interrogation of transmitral
frequent premature beats, sustained arrhythmias, systolic blood flow (E and A wave) and LV wall motion analysis using
murmurs of AV valvular insufficiency, or CHF. A postexercise TDI (Em and Am wave, isovolumic relaxation time) can reveal
examination often detects an abnormally rapid HR, which significant LV diastolic dysfunction in the presence of normal
A B
E
or impaired systolic function,164 strongly suggesting myocar- echocardiogram, ECG, and clinical laboratory tests. Definitive
dial disease (see Fig. 9.49). Depending on the type of myocar- diagnosis of myocarditis requires transvenous endomyocardial
dial disease, the (relative) LV wall thickness can be increased biopsy,913 but this test is currently limited to research purposes
(i.e., infiltrative or hypertensive cardiomyopathy) or decreased and may not identify piecemeal inflammation, degeneration,
(i.e., dilated or tachycardia-induced cardiomyopathy; see Fig. infiltration, or necrosis.
9.23). Postexercise echocardiography may demonstrate a par- Treatment of horses affected by myocardial disease is pri-
adoxic reduction of LV shortening fraction or regional dys- marily supportive. Prognosis depends on the cause and sever-
function characterized by LV wall motion abnormalities.167,168 ity of myocardial injury and the hemodynamic consequences
Marked increases in left ventricular or left atrial spontaneous of myocardial disease. All horses should be rested, preferably
contrast may be observed with very poor myocardial function, in a stall, until myocardial function, ECG, and plasma tropo-
although this is not a specific finding (see Fig. 9.49). Abnor- nin concentrations return to normal or at least remain stable
mal areas of myocardial echogenicity have been observed, but for several weeks. A minimum rest of 1 month (and usually
myocardial tissue characterization by echocardiography is not more) should be instituted before a horse is returned to work.
well established in horses, and grayscale also depends on tech- Supplementation with vitamin E and selenium may be benefi-
nical factors. cial, particularly in cases with suspected nutritional deficien-
Clinical laboratory tests may be useful in the identification cies. Antiarrhythmic therapy is administered when indicated
of myocardial damage but may not necessarily distinguish for potentially life-threatening arrhythmias (see later in this
myocarditis from myocardial cell injury induced by a toxin or chapter). Theoretically, an ACE inhibitor will reduce myocar-
by ischemia. Elevated plasma or serum creatine kinase activ- dial remodeling and unload the ventricle, assuming the drug
ity (CK), myocardial fractions of creatine kinase (CK-MB), or can be sufficiently absorbed and biotransformed to an active
lactate dehydrogenase (LDH1-2) suggest myocardial injury.352 state; however, efficacy of this treatment is currently unknown.
A more specific marker of myocardial is elevation of plasma When CHF has developed, diuretics, peripheral vasodilators,
cardiac troponin I (cTnI) or troponin T (cTnT).* Although and positive inotropic agents may be prescribed as previously
normal values or mild elevations do not exclude cardiomy- discussed in the section on CHF. Digitalization should be
opathy or myocardial infiltration, markedly elevated values undertaken with caution in horses with ventricular extrasysto-
(i.e., cTnI greater than 1 ng/mL) point to recent cardiac mus- les, as the arrhythmia may be aggravated and it is not indicated
cle damage. Persistently elevated plasma cTnI concentrations in ionophore toxicosis (see later). For a suspected bacterial eti-
indicate ongoing damage, because plasma half-life of cTnI is ology, antibiotic treatment is indicated. If noninfective myo-
short.680 carditis is believed to be the cause of the arrhythmia or clinical
Diagnosis of myocardial disease requires clinical suspi- signs, corticosteroid therapy may be indicated, although its
cion and integration of findings from clinical and laboratory value is unsubstantiated. When the principal manifestation of
examinations. Because of the extreme variability of find- myocardial disease is electrical (arrhythmias with otherwise
ings, the presumptive diagnosis of myocardial disease can be normal myocardial function), the prognosis is fair to good for
made only after reviewing the history, physical examination, resolution of the arrhythmias. Horses with decreased myocar-
dial function by echocardiography or those with CHF must
* References 162, 163, 575, 651, 653, 658, 659, 661, 662, 665, 667. be given a guarded prognosis for life and a poor prognosis for
FIG. 9.49 Nutritional myocardial damage. Echocardiographic examination in a 22-year-old Arabian mare suffering from nutritional masseter myopathy
with concurrent myocardial damage (cardiac troponin I concentration 11.6 ng/mL; normal <0.06 ng/mL). This case study demonstrates the clinical use
of novel echocardiographic indices for the assessment of systolic and diastolic LV function in horses with myocardial disease. A, B-mode recording of
the left ventricle in right-parasternal long-axis 4-chamber view. Left atrial (LA), left ventricular (LV), and right ventricular (RV) dimensions appear normal.
There is marked spontaneous echo contrast in the LV (arrows). This can be found in healthy horses but may become more distinct with low-output
states, bradycardia, and possibly systemic inflammation. B, M-mode recording of the LV in a right-parasternal short-axis view. Notice the flat motion of
the interventricular septum (IVS) and the LV free wall (LVFW), suggesting poor LV systolic function (LV fractional shortening 22%; normal 30%–45%).
Marked spontaneous echo contrast is evident (arrows). C, Two-dimensional speckle tracking (2DST) analyses of an LV long-axis recording. Trace screens
of the 2DST software are shown, displaying the following information: top left, 2D image with the segmented ROI and parametric color coding at the time
of aortic valve closure. Bottom left, M-mode with parametric color coding. Right, Trace display for longitudinal segmental strain (i.e., relative myocardial
deformation). The horizontal axis represents the time in msec, the vertical axis represents radial strain in %. The colors of the trace correspond to the
colors of the segmented ROI. An ECG is superimposed for timing. The start and the end of the cycle (R waves) are marked on the ECG with yellow dots.
Time of aortic valve closure (AVC) is indicated by a green vertical line, dividing the cycle in its systolic and diastolic component. The dotted line indicates
the instantaneous average over all segments at the respective time of the cardiac cycle (global strain). Note that peak longitudinal strain in this case
(left) is reduced compared with the healthy control (right), indicating depressed LV systolic function. D, 2DST analyses of an LV short-axis recording. Trace
screens of the 2DST software are shown, displaying longitudinal segmental strain (for further explanations see C). Note that peak radial strain (left) in this
case is reduced compared with the healthy control (right), indicating depressed LV systolic function. E, Pulsed-wave tissue Doppler (PW TDI) analysis of
the LV free wall recorded at the level of the chordae tendineae in a right-parasternal short-axis view. The horizontal scales of the spectral tracings indicate
the time in seconds, the vertical scales indicate the velocity in cm/sec. The Em/Am inversion (left) indicates diastolic dysfunction and impaired ventricular
relaxation. Notice the normal Em/Am ratio in the healthy control (right) for comparison. S1, Peak radial wall motion velocity during isovolumic contraction;
Sm, peak radial wall motion velocity during ejection; E1, peak radial wall motion velocity during isovolumic relaxation; Em, peak radial wall motion veloc-
ity during early diastole; Am, peak radial wall motion velocity during late diastole. (From Schwarzwald CC: Ultrasonography of the heart. In: Kidd JA, Lu
KG, Frazer ML, et al.: Atlas of equine ultrasonography, Wiley, Oxford, UK, 2014. Reproduced with permission of John Wiley & Sons, Ltd.)
future performance. It is notable, however, that some horses caused myocardial injury and death in horses.928,944-946 Iono-
with LV hypertrophy and dysfunction and some with acute phores react with polar cations to form lipid-soluble com-
onset of CHF have recovered completely and returned to their plexes, leading to cation transport across myocardial cell
prior performance level. Such horses most likely suffered from membranes. Various ionophores demonstrate particular
acute myocarditis that resolved spontaneously or following affinities for different cations, though lasalocid may complex
antiinflammatory therapy. Other horses may achieve a less with a variety of ions. Exposure of horses to the ionophore
spectacular recovery but still serve successfully as breeding antibiotics usually stems from accidental contamination of
animals. equine feedstuffs at the mill or through accidental delivery of
poultry or cattle feed to horses. In most outbreaks, a recently
Myocarditis acquired ration was fed.
Myocardial inflammation, or myocarditis, is difficult to diag- Clinical signs of horses with ionophore toxicity vary with
nose. The diagnosis is often entertained in horses with cardiac the specific type, quantity, and concentration of ionophore
arrhythmias, concentric LV hypertrophy (supposedly acute ingested and the preexisting health and body condition of
myocarditis with cell infiltration and myocardial edema) or the exposed horses. A wide range of clinical signs has been
severe LV dilation (supposedly chronic or later stages), and observed in exposed horses ranging from none to clinical signs
abnormal myocardial function, particularly when cardiac involving almost all body systems.156,157,160,162,163,915 Weakness,
signs occur after another illness and are associated with ele- lethargy, depression, anorexia, ataxia, colic, diarrhea, profuse
vated cardiac isoenzymes or plasma cTnI or cTnT concentra- sweating, and recumbency have been seen. The cardiac find-
tions. Often the prior disorder is a viral, influenza-type ings are similar to those previously described for myocardial
condition or an infection caused by Streptococcus spp., but diseases. If sudden death occurs, it is usually within 12 to 36
parasitic migration, fungal infections, or toxic insults can also hours of ingestion of the contaminated feed. A single dose may
result in inflammatory myocardial lesions that may not obvi- lead to peracute death from cardiac arrhythmias before the
ously be associated with preceding clinical disease.* It is logi- development of myocardial necrosis and associated with only
cal that immune-mediated myocarditis is operative in many of mild signs of colic or neurologic deficits.901
these cases, but definitive cause-and-effect proof is lacking. Sublethal toxicosis may be well tolerated by some but not
Myocarditis may also follow pericarditis or infective endocar- all horses, and plasma cTnI concentrations, echocardiogra-
ditis. Hematogenous spread to the heart may be another phy, and exercise testing may help to identify horses affected
mechanism for myocarditis. The signs, prognosis, and treat- more severely.160-163,656 Polyuria and hematuria are other
ment of myocarditis are similar to that described in the pre- signs that have been reported in ponies following ionophore
ceding section. exposure.
A diagnosis of ionophore toxicity is based on the detection
Toxic Injury of the Myocardium of the ionophore in the feed or stomach contents of exposed
A number of chemicals and plant toxins are potentially horses. Various clinicopathologic abnormalities are observed
injurious to the myocardium. Ionophore antibiotics are with monensin toxicity, including decreased serum calcium,
among the most notorious causes of myocardial necrosis in potassium, magnesium, and phosphorus and increases in
horses.154-163,656,901,902,915 Toxic myocardial injury also can serum urea, creatinine, unconjugated bilirubin, aspartate
occur following ingestion of glycoside-containing yew aminotransferase, and muscle enzymes. Elevated concentra-
plants (Taxus spp.), oleander (Nerium oleander), foxglove tions of plasma cardiac troponin (cTnI, cTnT) and isoenzyme
(Digitalis spp.), and summer pheasant’s eye (Adonis aesti- patterns of CK and LDH have indicated cardiac, skeletal, and
valis)897,898,912,916-920 or from eating feed contaminated by RBC damage. Elevated packed cell volume and total solids
Epicauta species (blister beetles), which contain the toxic ele- have been associated with dehydration. Echocardiographic
ment cantharidin.889,891,921-928 Atypical myopathy (AM) and evaluation of affected horses has revealed marked decreases in
seasonal pasture myopathy (SPM) that are caused by inges- shortening fraction with segmental wall motion abnormalities
tion of hypoglycin A–containing seeds of maple trees (Acer that range from mild to severe.161
spp.)575,674-676,929-938 and marshmallow (Malva parviflora) Prognostically, horses that exhibit decreased shortening
toxicosis,904 through different mechanisms, can cause severe fraction and dyskinesis shortly after exposure to monensin
generalized myopathy with myocardial involvement/damage. generally are unlikely to survive. Horses with mild decreases
Myocardial necrosis has also been observed in association in shortening fraction survive and may be useful breeding ani-
with clostridial infection and following endotoxemia, particu- mals, but most do not return to previous performance levels.
larly with salmonellosis and torsion of the large colon. Venom Horses with normal echocardiograms typically survive and
of rattlesnakes (Crotalus spp.) and of other members of the may return to work at their previous level. The magnitude of
family of vipers (Viperidae) has been associated with cardiac increase in plasma cTnI or cTnT concentrations and rate of
injury and arrhythmias.659,900,939 decrease over time likely has some prognostic implications;
however, even in surviving animals concentrations can remain
Ionophore Toxicity increased for several months, likely because of ongoing release
Horses are uniquely sensitive to ionophore antibiotics, which from damaged myocytes.162 Postmortem findings range from
are used as a coccidiostat in poultry production and as a no visible lesions to myocardial pallor and signs of CHF. Severe
growth promoter in cattle. Monensin toxicosis (acute oral myocardial necrosis and fibrosis has been observed in horses
LD50 2–3 mg/kg) has occurred most frequently,154-160,163,901,940 with decreased shortening fraction or ventricular dyskinesis
but salinomycin (acute oral LD50 0.6 mg/kg)915,941,942 and on echocardiography.
lasalocid (acute oral LD50 21.5 mg/kg)161,162,943 also have Treatment for affected horses is largely symptomatic (see
earlier), unless very recent exposure is known. Vitamin E has
* References 149, 658, 870, 900, 902, 905, 914. been suggested to have a protective effect in other species
and may be beneficial in affected horses. Digoxin and cal- Y VASCULAR DISEASES
cium channel blockers are contraindicated in acutely affected
horses. If ingestion of the contaminated feedstuff is recent, Acquired disorders of blood vessels include a variety of con-
treatment with activated charcoal or mineral oil is indicated ditions that vary in etiology and range from subclinical to
to reduce absorption of the ionophore. Intravenous fluid and devastating.* Jugular vein thrombosis or thrombophlebitis is
electrolyte replacement therapy may be indicated, as well as probably the most common vascular problem encountered in
antiarrhythmic drugs, for any life-threatening arrhythmias. clinical practice (Fig. 9.50).456,458,957-962 Catheter fragmenta-
Stall rest in a quiet environment for up to 8 weeks after expo- tion and embolization are observed periodically and have been
sure is most important, because echocardiograms recorded amenable to surgical and percutaneous catheter retrieval.963-967
after trivial exercise or excitement can reveal residual disease Venous aneurysms, vascular and lymphatic malformations,
characterized by marked decreases in fractional shortening and angiomatous lesions are rare.952,968-974
and myocardial dyskinesis. Rupture of the aorta or pulmonary artery is usually a life-
threatening event or leads to severe sequelae.768 Aortic aneu-
Dilated Cardiomyopathy rysms, rupture of aortic sinus aneurysm into the ventricular
Idiopathic dilated cardiomyopathy is a disorder of the myocar- septum or right heart chambers (Figs. 9.51 and 9.52), aortic
dium characterized by global reduction of LV systolic function rupture into the pericardium, and acquired aortic-pulmonary
that cannot be explained by valvular, vascular, coronary, or fistula have been reported.34,63,92,261-266,866,975-977 Rupture of the
congenital heart disease. The inciting cause of dilated cardio- PA is a potential consequence of long-standing pulmonary
myopathy is generally undetermined, although myocarditis hypertension and left-sided heart failure. Periparturient rup-
or prior toxic injury is often suspected. Relentless junctional ture of the middle uterine artery260,978-982 and rupture of the
or ventricular tachycardia also can lead to a DCM state that internal carotid artery, external carotid artery, or maxillary
is reversible with control of the tachyarrhythmia (see earlier artery with guttural pouch mycosis983-985 are well recognized
discussion).153 The clinical signs of cardiomyopathy are simi- and may lead to fatal events. Arteriovenous communica-
lar to those described earlier for other myocardial diseases. tions occur rarely and may develop after rupture of smaller
Echocardiography is diagnostic, revealing cardiomegaly with arteries or subsequent to growth of vascular tumors. Degen-
biatrial and biventricular dilation and depressed shortening erative lesions (see Fig. 9.52A) including calcification may be
fraction (see Fig. 9.23B). Symptomatic therapy with digoxin observed in the great or peripheral arteries.947,978,986,987 Degen-
and diuretics may temporarily stabilize CHF and lead to tran- erative and calcific lesions affecting the bifurcation of the right
sient improvement, but most horses deteriorate in the 3 to 12 and left pulmonary arteries also have been reported,988,989
months after diagnosis and are humanely destroyed. Neither although the clinical importance of these is not well defined.
the history nor the postmortem examination reveals the cause, Arteriosclerosis and arterial thrombosis may be caused by
and generally only diffuse or multifocal myocardial degenera- parasite migration in the mesenteric arteries990 and possibly at
tion, necrosis, and fibrosis are observed. the terminal aortic quadrifurcation (Figs. 9.53 and 9.54). Aor-
A form of dilated cardiomyopathy also can be caused by tic inflammation of unknown cause has been observed.784,991
vitamin E and selenium deficiency and is observed primarily Pulmonary vascular disease and pulmonary structural remod-
in fast-growing foals from mares with a marginal or deficient eling due to pressure loading (e.g., left-sided heart failure) or
selenium status raised in selenium-deficient areas.178 Affected increased pulmonary flow (e.g., left-to-right shunting through
foals are usually younger than 6 months of age and present a VSD) can result in pulmonary hypertension with resulting
with an acute onset of weakness, recumbency, respiratory dis- right heart failure or cor pulmonale (see earlier discussion).
tress, pulmonary edema, tachycardia, murmurs, and arrhyth- Tumors of the great arteries and veins are rare,952 but neo-
mias. The prognosis for foals affected with the myocardial plasms can compress or invade arteries and veins, including
manifestations of white muscle disease is poor, and most die the PA and vena cavae.
within 24 to 48 hours after the onset of clinical signs. Labora- The ultrasonographic observation of spontaneous echo
tory abnormalities in affected foals include marked elevations contrast within blood vessels and cardiac chambers has been
of CK (including the MB fraction in foals with myocardial suggested to indicate CV or rheologic disease,992,993 as well as
involvement), aspartate aminotransferase (AST), and LDH, a normal phenomenon caused by rouleaux formation or plate-
as well as hyperkalemia, hyponatremia, and hypochloremia. let aggregates. This observation is common during ultrasound
Myoglobinuria may occur. Echocardiography demonstrates examinations, and contrast may be observed in a variety of
the severity of myocardial involvement. Whole blood sele- vessels, as well as in the heart (see Figs. 9.42, 9.49, and 9.50).
nium, RBC glutathione peroxidase, and vitamin E concentra- Pronounced spontaneous echo contrast is especially likely
tions may be helpful in the diagnosis; however, tissue samples when there is actual obstruction to blood flow in vessels or
provide a more accurate indication of selenium stores. Treat- when there are low flow rates due to bradycardia, arrhythmia,
ment with vitamin E and selenium might be successful, but or myocardial failure. Contrast is often prominent in valvu-
typically the myocardial necrosis is extensive and incompat- lar endocarditis. Lesions, thrombosis, or even venipuncture
ible with life. Postmortem findings reveal pale streaking of the of the jugular vein can lead to spontaneous echo contrast in
myocardium with intramuscular edema, myodegeneration, systemic veins and in blood flow entering the right side of the
myocardial necrosis, and fibrosis or calcification.165 Preven- heart, often becoming become more obvious if venous return
tion of white muscle disease is important in selenium-deficient suddenly increases. The identification of spontaneous contrast
areas. Supplementation of pregnant mares should occur dur- is also dependent on the operator with respect to transducer,
ing gestation based on individual blood and tissue selenium gain, and grayscale contrast settings. The clinical significance
concentrations and should be continued during lactation,
because more selenium is passed to the foal through the milk * References 34, 63, 64, 85, 91, 92, 96, 100, 145-147, 260-262, 264, 267-273,
than across the placenta. 364, 450, 451, 456, 458, 549, 768, 771, 864, 866, 867, 947-956.
of isolated intravascular contrast cannot be stated with cer- or rupture—over the affected artery or obvious hemorrhage if
tainty, and it has been observed in healthy horses as well as a superficial the vessel has ruptured. Ultrasound and Doppler
those with CV disease. examination can demonstrate serious arterial disease provided
Serious vascular disease often can be suspected from the there is an acoustic window for examination. Rarely angiogra-
clinical examination, although it may not be obvious until phy or nuclear scintigraphy is required to demonstrate arterial
a catastrophic vessel rupture or fatal hemorrhage occurs. In thrombosis or disruption. In major venous disease, the typical
general, significant arterial disease reduces perfusion to the sign is swelling of soft tissues drained by the affected vessel.
affected vascular bed, impairing tissue metabolism and func- Palpable evidence of local inflammation and thrombosis may
tion. If severe or complete, ischemia may lead to tissue necro- be found in superficial venous disease. Right-sided endocardi-
sis (infarction) and even perforation of a hollow organ. There tis, embolic pneumonia, and pulmonary embolism are poten-
may be a bruit—auscultatory evidence of vascular narrowing tial consequences of systemic venous disease.
FIG. 9.50 A, Postmortem specimen of a thrombosed jugular vein in cross section. B and C, Ultrasono-
graphic images obtained form a horse with jugular vein thrombosis in a cross-sectional (B) and a longitudinal
(C) plane. The images show a mixed echogenic thrombus within the jugular vein (arrowheads). The com-
mon carotid artery (CCA) is displayed adjacent to the jugular vein. Residual blood flow through the affected
area can be evaluated using duplex Doppler ultrasonography or newer vascular imaging technologies that
directly visualize blood reflectors (e.g., red blood cells [RBCs]) in a grayscale display.
Thrombophlebitis
Thrombus formation results from an interplay of multiple
factors, including vessel injury or intrinsic vessel wall
lesions, blood hypercoagulability, and low-flow states or
venous stasis (Virchow’s triad).957 Thrombophlebitis, the
inflammation and thrombosis of a vein, in horses is most
commonly caused by intravenous catheterization or injec-
tion (see Fig. 9.50),456,458,957-962,994,995 suggesting that local
trauma seems to be the most important factor.959 The jugular
veins are most often affected, but cephalic, lateral thoracic,
and saphenous veins are sometimes also used for permanent
venous access and therefore can be affected as well. The
degree of vessel injury and therefore the risk of thrombo-
phlebitis depends on a variety of factors, including tech-
nique of catheter placement, stability of the catheter, catheter
hygiene and maintenance, training of personnel, and dwell
time of the catheter.457,959,967,996 Catheter material, length,
and diameter likely determine the risk of thrombosis or
thrombophlebitis. Longer catheters made of materials that
FIG. 9.51 Aortic to cardiac fistula. Off-angle long-axis image of the are less stiff or rigid are preferable over short, rigid catheters.
proximal aorta (Ao) shows the origin (arrow) of a ruptured sinus of Val-
Polyurethane over-the-wire catheters are thought to carry
salva aneurysm. This channel communicated with the right atrium (RA)
the least risk of thrombosis and are commonly used for
in another plane. The right ventricle (RV) and pulmonary artery (PA) are
long-term indwelling venous catheterization in horses and
slightly dilated because of left-to-right shunting.
foals. Polyurethane over-the-needle catheters are thought to
A B
FIG. 9.52 Aortic disease. A, Severe atheromatous change with secondary Streptococcus spp. infection of
the proximal aorta. The intimal and subintimal change begins just distal to the coronary ostia. Representa-
tive sections of the ascending aorta are shown. Strongylus vulgaris was not found. The most distal segment
was necrotic and severely narrowed flow across the region. B, Dissecting lesion communicating the root
of the aorta (top panel, arrow) to the right side of the heart across the intraventricular septum (IVS). The
distorted tricuspid valve is retracted to demonstrate the lesion on the right (arrow).
A B
FIG. 9.53 Aortoiliac thrombosis. A, Postmortem image showing the thrombus in the terminal aorta (Ao)
and the iliac arteries. B, Images obtained by rectal ultrasonographic examination in cross-sectional (left)
and longitudinal (right) direction. The thrombus is evident as a hyperechoic mass within the vessel (arrow).
contamination of catheter or catheter hub by contact with

hands, contaminated fluids, or devices or when getting dis-
connected (e.g., when the horse is moving or rolling in the
stall); hematogenous infection from another infectious focus;
or contamination of the infusate can result in septic inflamma-
tion and thrombosis.996
Clinical signs of phlebitis are straightforward, including
swelling over the affected vein and pain on palpation of the
involved tissues. There is frequently a cellulitis associated with
the catheter entrance site causing swelling, pain, and exuda-
tion. Note that phlebitis is not always associated with venous
thrombosis. Conversely, venous thrombosis can occur with-
out obvious signs of inflammation. Smaller mural thrombi
may not cause any obvious clinical signs as long as residual
FIG. 9.54 Verminous arteritis and thrombosis in the cranial mesenteric (or collateral) blood flow is sufficient to allow adequate venous
artery caused by Strongylus vulgaris. drainage. One study showed that approximately 30% of sick
horses with long-term indwelling catheters may develop sub-
have a slightly higher risk, and polytetrafluoroethylene clinical catheter-related disease.1001 Partial or complete venous
(PTFE, Teflon) catheters likely carry the greatest risk of occlusion through a larger thrombus results in distention of
thrombosis.967,997-999 Some catheters are coated with anti- the veins and possibly subcutaneous edema adjacent to the
bacterial substances to inhibit bacterial growth, but proof of affected area. Unilateral complete jugular occlusion is usually
efficacy to prevent catheter-related infection is lacking in well tolerated, but bilateral jugular vein thrombosis can lead to
horses. The source (i.e., commercially versus locally pro- marked head edema and possibly result in poor performance.
duced), pH, and osmolality of intravenously administered Marked swelling, heat, and pain on palpation, combined
fluids and the method and rate of IV fluid administration with fever, hyperfibrinogenemia, increased concentrations of
(determining the amount of turbulent blood flow and irrita- serum amyloid A, or a neutrophilic leukocytosis, indicates
tion to the vascular endothelium at the catheter tip) further infection of the thrombus.
influence the risk for venous thrombosis or thrombophlebi- The diagnosis and assessment of phlebitis, thrombosis, or
tis.456,457,967,998,1000 The pharmaceuticals most frequently thrombophlebitis is based on the detection of the previously
associated with the development of thrombophlebitis described clinical signs and examination by duplex Doppler
include glyceryl guaiacolate, thiopental, calcium gluconate, ultrasonography (see Figs. 9.50B and 9.50C).458,591,1001 In case
oxytetracycline, and phenylbutazone.957 of thrombosis, imaging of the affected vein reveals filling of
Patient factors, including presence of fever, large intestinal the lumen with an anechoic, hypoechoic, hyperechoic (if gas
disease, hypoproteinemia, salmonellosis, endotoxemia, and filled), or mixed echogenic material that partially or com-
other diseases characterized by a hypercoagulable state, are pletely occludes the vessel. Ultrasonographic evaluation may
significantly associated with development of catheter-related also reveal thickening of the vessel wall (phlebitis), perivas-
thrombophlebitis in horses.457,958,959,967,998,1001 Critically ill cular swelling, tracts extending from the vein to the subcu-
patients often stand with their head and neck in a low posi- taneous tissues or skin, or subcutaneous abscesses. Septate
tion, promoting increased turbulence and stagnation of blood appearance or cavitation in the center of a thrombus is sug-
flow, which further increases the risk of jugular thrombosis.998 gestive of infection and represents a target for aspiration and
Thrombophlebitis can be nonseptic or septic. Migration bacterial culture. Anaerobic bacterial infections often result
of skin organisms into the cutaneous catheter tract; direct in gas production, creating multiple hyperechoic areas and
an acoustic shadow. Stagnant or turbulent flow may be mani- from the head such that if adequate collateral circulation does
fested by increased spontaneous venous contrast. Flow across not develop, impaired venous drainage of the head and neck
the affected zone may be evaluated by contrast venography may limit performance or reduce the chance of returning to
using agitated saline as a contrast agent, with pulsed-wave or the previous level of activity in high-level athletes.961 Bilateral
color-coded Doppler studies, or with newer vascular imaging occlusion of the jugular veins with insufficient collateral vascu-
technologies that directly visualize blood reflectors (such as larization may cause swelling of the head and cervical region,
red blood cells) in a grayscale or color-coded display. Venous leading to dysphagia and airway obstruction that might be per-
drainage proximal and distal to the area of thrombosis also formance limiting or even life threatening.1007,1008
should be assessed as collateral circulation may still enter When jugular vein thrombophlebitis is refractive to medi-
the vein distally. A careful evaluation of the communicating cal treatment or causing severe performance-limiting or even
large veins and of the heart and lungs should be performed in life-threatening clinical signs, surgical techniques including
horses with infective thrombophlebitis, particularly if clinical phlebotomy, thrombectomy with Fogarty’s catheter, or venous
signs of systemic disease develop. Bacterial endocarditis may grafts may be performed to restore blood flow.994,995,1009 Alter-
develop secondary to embolization of infective thrombus or natively, an expert in interventional radiology or medicine can
bacteremia (see earlier discussion). Rarely, embolization of be consulted regarding other options, such as intravascular
septic thrombi may also lead to pulmonary thromboembo- stenting.
lism, pleuropneumonia, and other conditions associated with Prophylaxis for venous thrombosis or thrombophlebitis
metastasis of septic thrombi.961,962 includes minimizing all of the aforementioned risk factors.
Early detection and management of phlebitis, thrombosis, Administration of a nonsteroidal antiinflammatory drug
or thrombophlebitis are crucial and significantly influence while the catheter is in place has been shown to reduce the
severity and outcome. Therefore at least twice daily careful risk of catheter-related complications.1001 Antithrombotic
monitoring of catheter and catheter site is mandatory for all prophylaxis is commonly performed using anticoagulants or
indwelling catheters. Catheter caps and fluid lines should be antiplatelet drugs, but clear evidence of its efficacy is currently
changed regularly to minimize the risk of bacterial contami- lacking.
nation. If a catheter is still in place when a thrombosis or
thrombophlebitis is discovered, the catheter should be care- Aortoiliac Thrombosis
fully withdrawn and the tip cultured. If possible, the opposite Aortoiliac thrombosis is an uncommon, but potentially serious,
jugular vein should be preserved to avoid the risk of bilateral disorder. The gross appearance, histologic features, and clini-
thrombophlebitis, and alternative options for fluid and drug cal findings of this vaso-occlusive disorder have been reviewed
administration should be sought. extensively in the literature.89,267-272,450-455,950,955,1010-1017 The
Local therapy including hot compresses and topical terminal aorta and the iliac arteries, including their proximal
ichthammol (ammonium bituminosulfonate), nonsteroi- branches, are the focus of involvement in this disease (see
dal antiinflammatory drugs (diclophenac sodium), hepa- Fig. 9.53A). Vessels become partially to completely occluded
rinoids (chondroitin polysulfate), or dimethyl sulfoxide by multifocal ingrowths of fibrous tissue, laminated thrombi,
(DMSO) may be helpful in the treatment of thrombophle- or fibrous plaques.267 Histologic lesions include organized,
bitis. Heparin therapy (unfractionated heparin, 40–100 IU/ fibrous connective tissue, hemosiderin-laden macrophages,
kg of body weight, SC, q 6 h; dalteparin, 50–100 IU/kg of irregular vascular channels, and disruption of the intima and
body weight, SC, q 24 h) may be beneficial to decrease pro- internal elastic lamina. The lesions are generally devoid of fat.
gressive thrombosis, particularly if the thrombotic lesion Arteriosclerotic and atherosclerotic aortic lesions have also
is associated with a generalized coagulopathy.982,1002,1003 been observed at other sites as well (see Fig. 9.52A). Suggested
Furthermore, early regional thrombolytic therapy may be etiologies of these arterial disorders include Strongylus vul-
used in an attempt to resolve jugular vein thrombosis and to garis infection, systemic infections, embolization, and vasculi-
achieve recanalization.957,1004-1006 However, clear evidence of tis. There is no convincing evidence that aortoiliac thrombosis
the efficacy of antithrombotic and thrombolytic treatment is consistently caused by Strongylus infection, and some have
is lacking. Infections with multiple organisms should be refuted this contention.269,271
anticipated in cases of infective thrombophlebitis, and high Although aortoiliac thrombosis is uncommon, it can be
doses of broad-spectrum antimicrobials should be admin- associated with severe performance problems. The typical fea-
istered until culture and sensitivity results of the aspirate tures include exercise-associated, typically (but not uniformly)
are obtained. Metronidazole (15 mg/kg PO every 6 hours unilateral, hindlimb lameness, ataxia, or collapse.267,269,271,272
or 25 mg/kg PO q 12 h) should be considered if anaerobic Aortoiliac thrombosis has also been diagnosed as a cause of
infection is suspected. Flunixin meglumine (1 mg/kg every breeding failure in stallions.271,272,955 Physical examination
12 hours) may be added to reduce inflammation. If anti- of an affected horse at rest may reveal weak metatarsal arte-
microbial therapy is unsuccessful, surgical resection of the rial pulses or delayed saphenous refill in the affected limb.
affected tissue or drainage of abscesses may be indicated. The temperature of the limb in the resting animal is usually
Recanalization of an affected vein often occurs and can be normal, unless complete arterial occlusion has occurred,
documented by Doppler or contrast ultrasound studies demon- in which case the limb is cold and painful and may become
strating blood flow between the vessel wall and the thrombus. edematous. Exercise in affected animals results in an exercise-
Recovery often requires 4 to 8 weeks or longer. Occasionally, associated gait abnormality (lameness, ataxia, or weakness)
loculation may be detected within the ends of the thrombus. with a decreased or absent metatarsal and digital pulse and
Such loculation may result in persistent fibrous webs within delayed or absent saphenous refill. This intermittent claudica-
the vein that restrict venous return. Venous stricture also tion may cause the horse to become very uncomfortable and
may occur due to long-standing thrombophlebitis. Complete reluctant to bear weight on the affected limb. Marked hyper-
fibrous occlusion of the jugular vein may impede venous return pnea, other signs of distress, and profuse, generalized sweating
are often present with trembling of the affected limb. A rectal evaluation of the cranial mesenteric artery is possible and can
examination may reveal fremitus, a weak or absent pulse, or be used to confirm the diagnosis of thrombosis in these ves-
aneurysmal dilation of the affected artery or arteries. These sels.954,1010,1021 Treatment should consist of larvicidal deworm-
abnormalities may be more evident after exercise and may ing, combined with a rigorous individual and environmental
help to confirm the diagnosis. parasite control program.
The diagnosis can be confirmed by ultrasonographic
evaluation of the terminal aorta and iliac arteries (see Fig. Arteriovenous Fistulas
9.53B) with a high-frequency (5–10 MHz) rectal trans- Arteriovenous fistulas occur uncommonly and are most often
ducer268,270,451,1016 or by nuclear techniques.1011,1018 Doppler detected with large vascular tumors (hemangiomas, heman-
studies may indicate abnormal blood flow in the femoral giosarcomas) or as a rare congenital defect or posttraumatic
arteries.1019 Essential abnormalities include a hypoechoic to sequelae.953,956,969,972 Classic features include a continuous
echogenic mass protruding into the arterial lumen. An esti- thrill and murmur over the affected area, localized edema,
mation of the degree of obstruction can be made based on slowing of the HR after occlusion of the shunt, and signs of
the percentage of the artery occluded. Many cases are long- increased CO if the shunt flow is great. Clinically important
standing, and hyperechoic areas, even tissues sufficiently ech- fistulas are more likely to develop where large arteries and
odense to cast acoustic shadows, may be imaged within the veins run in parallel, as with the jugular vein and carotid artery.
aortic or iliac thrombus. These findings suggest mature scar A diagnosis can be made with Doppler ultrasound, including
tissue and calcification. pulsed-wave and color-flow Doppler to demonstrate continu-
The prognosis for this disorder is guarded. No controlled ous and pulsatile flow from the artery, through the associated
studies have evaluated therapy for this condition. A case sur- communication, into the distended veins. A complete cardio-
vey1010 suggests no treatment consistently improves outcome, vascular examination should be performed because a large
but there is potential benefit of surgical or catheter-based arteriovenous communication could lead to cardiac failure.
thrombectomy or anticoagulation. Early diagnosis likely is Treatment depends on the underlying cause, and an experi-
essential if therapy is to be beneficial. Treatment is aimed at enced surgeon should be consulted. No treatment may be
improving collateral circulation and preventing additional indicated with small, uncomplicated arteriovenous communi-
thrombus formation. Various medical treatments have been cations. Large vascular neoplasms are usually inoperable at the
reported including intravenous sodium gluconate, larvicidal time when they are diagnosed or complicated by the possibil-
dewormings, phenylbutazone, low-molecular-weight dextran, ity of metastasis.
anticoagulants,455 and a controlled exercise program. There
are no reports of successful thrombolytic therapy at this time. Vascular Rupture
Ultrasound-guided balloon thrombectomy has been described Rupture of the aorta or its branches or of the PA are reported
and is probably most useful in cases of active thrombosis where sporadically and often are catastrophic events, with diagnoses
the obstruction can be partially relieved.950,1012,1013,1017,1020 In made at the necropsy floor. Ruptures of the extrapericardial
one study, 65% of the horses regained athletic activity, and aorta or other blood vessels leading to fatal hemorrhage or a
53% of the operated horses performed at their previous level systemic to pulmonary shunt have been reported.*
after surgical thrombectomy.1020 Postoperative complications Rupture of the middle uterine artery can cause severe peri-
included severe myopathy (24% of cases), acute thromboem- parturient hemorrhage into the broad ligament (hematoma
bolism on the contralateral limb, wound healing problems, formation) or into the abdomen (acute hemoabdomen). It
and reocclusion. is more common in older, multiparous mares and is charac-
terized by postpartum colic, tachycardia, anemia, and often
Parasitic Vascular Lesions sudden death.260,978-982 Mycotic disease within the guttural
The migrating larval forms, particularly L4, of S. vulgaris pouch is a well-recognized cause of arteritis and rupture of
are known causes of arterial disease, particularly involving the affected arteries.983-985 Uterine artery rupture and arterial
the aorta and the cranial mesenteric artery and its branches rupture secondary to guttural pouch mycosis are covered in
(see Fig. 9.54). Lesions have been described as far forward as Chapters 19 and 9, respectively.
the bulbous aorta and the aortic sinuses in infected horses.
Rounded fibrous plaques and mural thrombi have been Aortocardiac and Aortopulmonary Fistula
reported in the thoracic and cranial abdominal aorta in 9.4% Rupture of the aortic root has been commonly reported in
of horses examined immediately after death.145 These inves- older horses, usually older breeding stallions, but it may also
tigators reported a statistical association between the occur- occur in older mares or in younger horses.63,92,262-264,864,866,975
rence of proximal aortic S. vulgaris lesions and the presence of Rupture typically involves the right aortic sinus of Valsalva
focal ischemic lesions in the myocardium. They hypothesized (see Figs. 9.51 and 9.52B). The aortic root can rupture into the
that these lesions were consequent to microembolism from right atrium, right ventricle, interventricular septum, or peri-
parasitic lesions. With the advent of ivermectin and other cardial space. Dystrophic changes in the media of the aorta,
new anthelmintics, and aggressive deworming programs cur- degenerative changes associated with chronic aortic insuffi-
rently recommended by practicing veterinarians, heavy S. ciency, and the hypertension associated with breeding all have
vulgaris larval migration damage occurs much less frequently. been implicated as potential causes of aortic root rup-
However, migration of S. vulgaris L4 larvae must be consid- ture.92,263,864,1023 Aneurysms of the right sinus of Valsalva have
ered in horses with poor deworming histories, high potential also been reported and are related to congenital or acquired
of exposure, high fecal egg counts, and palpable abnormali- defects in the media of the aorta near the right coronary
ties on rectal examination, or when fremitus or aneurysmal sinus.34,262,864-867,1024
dilation of the aorta is found, particularly in the region of the
cranial mesenteric artery or iliac system. An ultrasonographic * References 85, 91, 93, 94, 96, 98-103, 106, 1022.
Rupture of the more distal aorta into the pulmonary artery Y CARDIAC ARRHYTHMIAS
also can occur.34 Aortopulmonary fistulation has been mostly
reported in Friesian horses.261,265,266,976,977 The rupture is usu- Cardiac arrhythmias are disturbances in HR, rhythm, or con-
ally located close to the arterial ligament and concurrent with duction and can be classified based on atrial and ventricu-
a circumferential cuff of perivascular hemorrhage.265 Recent lar rate, anatomic origin of the impulse, method of impulse
histologic studies suggest a connective tissue disorder affect- formation, and conduction sequence. Arrhythmias can
ing elastin or collagen in the aortic media as a potential under- develop as isolated electrical disorders or secondary to other
lying cause of aortic rupture in Friesian horses.266,976 etiologic factors, including (1) structural heart disease; (2)
Not all aortic ruptures are immediately fatal. Many horses metabolic and endocrine disorders; (3) systemic inflamma-
present with acute onset of poor performance, exercise intol- tion; (4) hypotension, hemorrhage, anemia, and ischemia;
erance, sustained tachycardia, and pain that is often perceived (5) autonomic influences; (6) toxicosis/envenomations; and
as colic. When aortic rupture or rupture of a sinus of Valsalva (7) drugs.68 A wide variety of cardiac arrhythmias have been
aneurysm communicates with the right atrium, right ventricle, recognized.54,60,736,1027,1028 Of principal concern to the clinician
or pulmonary artery, right-sided heart failure can occur. Car- are the hemodynamic consequences of arrhythmias (reduced
diac arrhythmias (usually ventricular tachycardia) may also pressure, flow, perfusion) and the potential for further electri-
develop, especially if dissection progresses into the interven- cal instability (myocardial fibrillation, sudden death).
tricular septum.263A continuous machinery murmur loudest The electrophysiologic basis of cardiac arrhythmias will not
on the right side of the thorax with bounding arterial pulses be discussed here, and the interested reader is referred else-
is characteristic of a horse with an aortocardiac fistula.68,263,264 where for descriptions of abnormal automaticity, reentry, and
Friesian horses with aortopulmonary fistulation present with triggered activity (early and late afterdepolarizations) as mecha-
bounding arterial pulses, tachycardia, and a grade 1 to 3/6 nisms of arrhythmogenesis.57,112,113,117 Cardiac arrhythmias are
holosystolic and early to middiastolic murmur loudest dorsal classified based on the anatomic origin of the manifest ECG
to the aortic valve; ventricular arrhythmias are rare.68,265,1025 mechanism (Box 9.12). The reader should be aware that some
Antemortem diagnosis of an aortic sinus of Valsalva aneu- arrhythmias, especially those originating in the AV junction,
rysm or aortocardiac fistula is possible by echocardiography may mimic either atrial rhythm disturbances or “high” ventric-
and Doppler interrogation (see Fig. 9.51). Because of the more ular rhythms. For purpose of discussion we have elected to dis-
distal location of aortopulmonary fistulas in Friesian horses, tinguish “atrial” from “junctional”; however, “supraventricular”
echocardiographic imaging is more challenging and requires may also be applied to these rhythm disturbances.
nonstandard, tilted imaging planes obtained from the left third The clinical evaluation of the horse with an arrhythmia is
or fourth intercostal space in order to visualize the aortic rup- reviewed in Box 9.13. Routine electrocardiography, clinical
ture and fistula; in addition, right heart and pulmonary artery chemistry, hematology, echocardiography, exercising electro-
dilation, tricuspid regurgitation, and pleural and pericardial cardiography, and continuous 24-hour electrocardiographic
effusion can be found.265,1025,1026 Transesophageal ultrasound (Holter) monitoring can all play a role in the complete eval-
may allow for better visualization of the aortopulmonary uation of a horse suspected of having intermittent cardiac
region and for diagnosing aortic rupture in Friesian horses, arrhythmias.68 These points are discussed further later in the
but the lack of appropriate equipment usually precludes this chapter. A recent consensus statement formulated by a group
option in horses.1026 If echocardiography does not allow defin- of experts in the field of equine cardiovascular medicine sum-
itive diagnosis of an aortopulmonary fistula, cardiac catheteri- marizes the current recommendations for management of
sation may serve to document increased right heart and PA equine athletes with cardiac arrhythmias, and the reader is
pressures with increased oxygen partial pressures and satu- referred to this statement for additional information.68
ration in the distal pulmonary artery indicating left-to-right
shunting of blood.1025 Sinus Rhythms
Aside from breeding, horses with diagnosed aortic aneu- A number of physiologic sinus rhythms are recognized. These
rysms should not be used for athletic endeavor, because rup- can be explained by the impact of autonomic nervous system
ture of the aneurysm could occur at any time. The prognosis for traffic on the SA node (Fig. 9.55). Normal horses at rest dem-
life in horses with aortic rupture is generally guarded to poor, onstrate vagal-mediated sinus bradycardia, sinus arrhythmia,
depending on the site and size of the communication. Some sinus block, and sinus arrest; however, fear or a sudden stimulus
horses survive and others may require supportive treatment for may provoke sympathetically driven sinus tachycardia. Exercise
CHF. Fatal ventricular arrhythmias can develop any time and leads to pronounced sinus tachycardia, with HRs often exceed-
lead to sudden cardiac death. Therefore horses with aortocar- ing 200 beats/min.53,54 Atrioventricular (AV) conduction, as a
diac or aortopulmonary fistulas are not considered safe to use.68 general rule, tends to follow sinus activity. During sinus tachy-
cardia, the PR interval shortens, whereas during periods of pro-
Pulmonary Artery Rupture gressive sinus node slowing the PR interval generally prolongs.
Pulmonary artery rupture is most often caused by chronic Mobitz type I second-degree AV block (Wenckebach periodic-
pulmonary hypertension and PA dilation.148,768 This is most ity) often follows a progressive prolongation of the PR inter-
commonly detected in conjunction with severe MR and pul- val. Sinus rate and AV conduction usually change in parallel;
monary hypertension. The potential for PA rupture should be however, some horses appear to control BP during high sinus
considered whenever a large dilated main PA or left and right tachycardia by blocking impulses in the AV node (see Fig. 9.6).
PA is detected echocardiographically. Affected horses should Second-degree AV block is more likely in a standing horse, in a
be considered unsafe for riding or driving and should not be horse that has suddenly stopped submaximal exercise, or after a
used, except for breeding, due to the possibility of sudden brief surge of sinus tachycardia in an anxious animal.
death. Focal medial calcification of the PA is not uncommon Sinus rate and rhythm should be carefully monitored in
at necropsy947,989 but is of uncertain clinical significance. the critically ill or anesthetized horse because HR is a major
BOX 9.12
Cardiac Rhythms in the Horse BOX 9.13
Evaluation of the Horse with a Cardiac Arrhythmia
PHYSIOLOGIC RHYTHMS General medical history, past illnesses, past and current
Sinus Rhythmsa medications
Normal sinus rhythm Work history and exercise tolerance
Sinus arrhythmia General physical examination
Sinoatrial block/arrest Physical examination: evidence of congestive heart failure
Sinus bradycardia Subcutaneous edema
Sinus tachycardia Jugular venous distention and pulsations
Pulmonary edema
Conduction Disturbancesa Pleural and peritoneal effusion
Atrioventricular block (AV block) Weight loss, poor condition
First-degree (long PQ or PR interval) Auscultation of the heart
Second-degree (P wave not followed by a QRS complex; Assessment of heart sounds (rhythm, third heart sound)
commonly Mobitz type I, Wenckebach) Assessment of heart murmurs
Resting electrocardiogram
PATHOLOGIC RHYTHMS Heart rate and cardiac rhythm
Atrial Rhythm Disturbances Analysis of P-QRS-T waveforms
Exercise (or treadmill) electrocardiogram
Atrial escape complexesb
Clinical laboratory studies
Atrial premature complexesa
Complete blood count (rule out anemia, infection)
Atrial tachycardia, nonsustained and sustained
Blood culture (in cases of suspected endocarditis)
Reentrant supraventricular tachycardia
Serum electrolytes (particularly potassium and possibly
Atrial flutter, atrial fibrillationa
magnesium)
Junctional Rhythm Disturbances Serum biochemical tests (especially renal function)
Skeletal muscle enzymes (cardiac isoenzymes)
Junctional escape complexesb
Serum troponin concentration
Junctional escape rhythmb (idionodal rhythm)
Red blood cell potassium
Junctional premature complexesa
Fractional excretion of potassium
Junctional (“nodal”) tachycardia
Echocardiogram/Doppler echocardiogram
Reentrant supraventricular tachycardia
Examine for cardiomegaly or reduced myocardial function
Ventricular Rhythm Disturbances Identify predisposing cardiac lesions and abnormal flow
Serum/plasma concentrations of cardioactive drugs
Ventricular escape complexesb
Serum digoxin concentration
Ventricular escape rhythmb (idioventricular rhythm)
Plasma quinidine concentration
Ventricular premature complexesa
Response to medications
Accelerated idioventricular rhythm (idioventricular tachycar-
dia, slow ventricular tachycardia)*
anesthesia, pain, hypotension, hypovolemia, hypercarbia and
Ventricular tachycardia
hypoxemia, anemia, endotoxemia or sepsis, pyrexia, systemic
Ventricular flutter
inflammatory response syndrome (SIRS), anaphylaxis, or exces-
Ventricular fibrillation
sive catecholamine administration. Specific therapy for sinus
Conduction Disturbances tachycardia is rarely required because it represents a physiologic
response to stress. However, when sinus tachycardia is identi-
Sinoatrial block (high grade or persistent)
fied, the cause must be sought and treated as appropriate.
Atrial standstill (sinoventricular rhythm caused by hyperkalemia)
Sinus bradycardia is generally a benign rhythm in stand-
Atrioventricular block (AV block)
ing horses; however, when encountered during sedation or
Second degree (high grade or persistent)
anesthesia this rhythm can lead to hypotension. Treatment
Third degree (complete, with AV dissociation)
of symptomatic sinus bradycardia can include the infusion of
Ventricular conduction disturbances
catecholamines (dobutamine, dopamine, epinephrine) or the
Ventricular preexcitation
administration of anticholinergic drugs (atropine, glycopyr-
aMost common rhythms and arrhythmias. rolate). Dopamine or dobutamine can be infused to increase
bEscape complexes develop secondary to another rhythm disturbance. HR, contractility, and arterial BP; however, reflex AV block
may develop in some horses.237,246,278,327 Excessive administra-
tion of catecholamines causes sinus tachycardia and ectopic
determinant of CO and arterial BP (Fig. 9.4B). Sedative drugs beats. Anticholinergic drugs may not be effective in the setting
and anesthetics can cause sinus bradycardia or sinus arrest. of anesthetic-induced depression of SA function, particularly
Anesthetic drugs, hypoxia, traction on an abdominal viscus, if vagal efferent traffic is low. Gastrointestinal complications
ocular manipulation, hypothermia, increased intracranial including ileus and colic may develop after anticholinergic drug
pressure, and hypertension can depress sinus node function. therapy; thus it should not be chosen for trivial rate problems.
Concurrent depression of the sinus node with stimulation of
latent pacemakers in the coronary sinus or AV junction can Atrial Arrhythmias
lead to ectopic rhythms in the anesthetized horse. Conversely, Rhythms originating in the atria are common. These dis-
an increasing sinus rate may indicate inadequate depth of turbances often develop as “functional” disorders with
FIG. 9.55 Sinus rhythms. A, Sinus bradycardia (top) and tachycardia (bottom). Base-apex lead recorded at
25 mm/sec. B, Sinus arrhythmia with sinus arrest/sinus block recorded at 25 mm/sec paper speed. C, Sinus
arrhythmia with second-degree atrioventricular block (arrows). An ambulatory electrocardiogram (ECG) is
shown; transthoracic leads recorded at 25 mm/sec. Whereas two consecutively blocked P waves are con-
sidered normal on a 24-hour ECG, these phenomena are observed infrequently (in approximately 1% of
normal horses).
no overt structural cardiac lesion. Autonomic imbalance tone present in most horses serves to shorten the duration
(including high sympathetic activity or high vagal tone), of the action potential of atrial myocytes and also facilitates
hypokalemia, drugs (e.g., catecholamines, anesthetics), development of sustained atrial tachyarrhythmias, which
infections, fever, anemia, hypoxia, and colic can be associ- probably depend on reentry.
ated with atrial premature complexes. Atrial rhythm dis- Atrial arrhythmias are the most common abnormal rhythms
turbances are also very common in the setting of structural detected in horses (Figs. 9.56 and 9.57).60,77-84,479,538,1029 Atrial
lesions of the heart valves, myocardium, and pericardium. premature complexes are the least complex of these rhythm
Cardiac conditions known to predispose to atrial arrhyth- disturbances; these can be clinically irrelevant or associated
mias include mitral or tricuspid insufficiency, endocardi- with exercise intolerance or other signs of cardiac disease.
tis, myocarditis, cardiac (atrial) enlargement, myocardial In contrast, atrial tachycardia, atrial flutter, and AF are more
fibrosis, and myocardial ischemia. Atrial premature com- likely to become clinically important. The overall importance
plexes can precipitate sustained atrial arrhythmias, includ- of atrial premature complexes is often difficult to ascertain.
ing atrial tachycardia, atrial flutter, and atrial fibrillation. Interpretation of routine ECG rhythm strips recorded from
The large size of the equine atria and the frequent presence over 950 horses indicated that atrial arrhythmias, overall, were
of microscopic atrial fibrotic lesions likely predispose the present in less than 3% of the horses studied (personal com-
horse to these sustained arrhythmias. The high resting vagal munication, JD Bonagura). However, when clinically normal
FIG. 9.56 Electrocardiograms (ECGs) with atrial rhythm disturbances (recorded at 25 mm/sec). A, Prema-
ture atrial complexes (arrows). The premature P waves of different morphology, the slightly prolonged P-R
interval indicating atrioventricular nodal refractoriness, and the normal-appearing QRS complex indicating a
supraventricular origin are notable. A slight conduction aberrancy is evidence in the second premature QRS
complex (see also Fig. 9.15). B, Premature atrial complexes occurring during the QT interval of the preceding
complexes. The first premature complex is nonconducted (arrow), the second premature complex is con-
ducted with first-degree AV block (arrowheads). C, Sustained atrial tachyarrhythmias. The top picture shows
atrial tachycardia with rapid, regular P waves (P′) and a variable ventricular rate response to conducted P
waves. The base-apex lead recorded at 25 mm/sec. The lower trace shows atrial flutter (F) with variable
ventricular response (S). Lead 3 recorded at 25 mm/sec.
horses were examined by Holter monitor, atrial premature reveals a regular sinus rhythm that is interrupted by an obvi-
complexes were recorded in 28% of the horses (personal com- ously premature beat or—in case of a blocked APC—by an
munication, VB Reef). The prevalence of atrial arrhythmias abnormal pause (see Fig. 9.56A and B). Premature atrial com-
during and after exercise has been reported as 29% to 89% plexes may be fully interpolated (there is continuation of the
and 46% to 62%, respectively,77-79 with the reservation that it regular sinus rhythm after the premature atrial contraction),
may be difficult to differentiate between supraventricular and or there may be a pause, if the sinus node is reset or the prema-
ventricular premature beats on exercise ECGs. Thus it appears ture complex is not conducted. The ECG is characterized by a
that the incidence of atrial arrhythmias depends not only on premature (usually narrow) QRS complex, which is preceded
the population examined but also on the methods used for by an abnormal, premature P wave (P′ wave) that is often
identification. These rhythm disturbances should be assessed buried within the preceding T wave (see Fig. 9.56B). If the
in light of other clinical findings. impulse arrives in the AV node before complete repolariza-
tion, the PR interval is longer than normal (physiologic first-
Atrial Premature Complexes degree AV block; see Fig. 9.56A). If the ectopic P′ wave is not
Atrial premature complexes (APCs) are detected by auscul- conducted (physiologic second-degree AV block) a pause will
tation and are documented by an ECG. Auscultation usually be evident in the ventricular rhythm (see Fig. 9.56). Premature
F
FIG. 9.57 Atrial arrhythmias. A and B, Successful conversion of atrial fibrillation (AF) using a combination of digoxin and quinidine (see text for details).
A, Incomplete conversion of AF to atrial tachycardia with rapid, regular atrial activity (arrows). B, Conversion to normal sinus rhythm during combination
therapy. Notice the high amplitude of the second part of the P wave, indicating possible atrial enlargement. C, Quinidine toxicosis can be manifested as
abnormalities on the electrocardiogram (ECG). In this horse, AF (top; base-apex lead recorded at 25 mm/sec) was not converted. The lower recording
shows persistent AF with a rapid atrioventricular conduction response, electrical alternans, and widening of the QRS complex (lead 2 recorded at 25 mm/
sec; right panel, at 50 mm/sec). The rapid rate response is related to the vagolytic effect of quinidine. The electrical alternans is common with regular
supraventricular tachycardias with rapid ventricular response rates; this finding indicates varying conduction into the ventricle. The widened QRS is a sign
of quinidine toxicosis. An idiosyncratic reaction leading to polymorphous ventricular tachycardia (VT) also has been recognized (see Figs. 9.58 and 9.61).
D, Hemodynamic consequences of increasing ventricular response rate in AF. The short QRS-QRS intervals do not generate effective arterial pulsations
recorded in the arterial blood pressure (ABP) tracing, which is related to inadequate ventricular filling time during short cycles. Pulse deficits are detectable
by physical examination. E, Atrial fibrillation with occasional QRS-T complexes of different morphology (base-apex lead recorded at 25 mm/sec). Note
that the large and slightly wider QRS complexes always occur when a short cycle follows a long cycle. These QRS complexes are most likely caused by
aberrant ventricular conduction, and this phenomenon is called Ashman’s phenomenon (or phase 3 aberrancy). F, Atrial fibrillation in a 14-year-old Ap-
paloosa with dilated cardiomyopathy and heart failure (base-apex lead recorded at 25 mm/sec). The heart rate is 132 beats/min. Three ventricular ectopic
beats are evident, characterized by different QRS-T morphology.
atrial impulses can also be conducted aberrantly through the in horses after conversion of AF to sinus rhythm in order to
ventricle as a result of incomplete repolarization or persistent prevent recurrent AF (see Table 9.7).1030 However, the effec-
refractoriness of ventricular conducting tissues; this causes tiveness of sotalol and of other antiarrhythmics has not been
the QRS-T complex to be wider than normal or atypical in formally established for this indication. Maintenance of nor-
configuration. Care must be taken not to overdiagnose atrial mal serum potassium and magnesium may be important in
premature complexes. Sinus arrhythmia and sinus bradycardia suppressing atrial ectopic activity. In cases of suspected myo-
often lead to variations in the P-P intervals, and there is often a carditis, antiinflammatory doses of dexamethasone might be
“wandering atrial pacemaker” that gradually alters the P wave considered as empiric therapy with consideration of adverse
morphology. Exercise or excitement will abolish such physi- effects of such treatment.
ologic rhythms.
A continuous 24-hour ECG and an exercising ECG are rec- Atrial Tachycardia
ommended to assess frequent APCs. Atrial premature com- Atrial tachycardia can be defined as a series of ectopic atrial
plexes are not considered a safety issue. Horses with occasional premature complexes. Atrial tachycardia may be sustained or
APCs that are overdriven during exercise and those with occa- nonsustained (paroxysmal) and is generally precipitated by a
sional APCs during exercise are considered as safe to use as single atrial premature complex. The atrial rate is rapid and
their age-matched peers.68 The greatest concern about APCs regular; however, because ectopic P′ waves can be blocked
relates to their potential to incite atrial flutter and AF. Atrial physiologically in the AV node, an irregular ventricular rate
premature complexes, as a general rule, are more likely to be response often results (see Fig. 9.56C). Atrial rates of 120 to
clinically relevant in the following circumstances: when they (1) 250 beats/min are typical in horses with sustained atrial tachy-
are frequent at rest, (2) are associated with runs of atrial tachycardia. At lower atrial rates, 2:1 AV conduction may yield a
cardia, (3) are related to poor performance (if other causes are regular, relentless HR. At the higher atrial rates, the rhythm
excluded), (4) precipitate paroxysmal atrial flutter or fibrilla- may be indistinguishable from atrial flutter. Differentiation
tion, or (5) develop in conjunction with structural cardiac dis- of atrial tachycardia from flutter is not critical because both
ease. Documentation of atrial arrhythmias during exercise may arrhythmias carry the same clinical significance and are
be critical for determining whether paroxysmal atrial tachycar- treated identically. Sustained atrial tachycardia is most often
dia, flutter, or fibrillation is likely to be the cause of poor perfor- recognized during treatment of horses with quinidine sulfate.
mance.474 Clinical judgment must be used, however, because Before conversion of AF to sinus rhythm, atrial tachycardia
supraventricular premature complexes are likely to occur in the may be observed (see Fig. 9.57A); thus in this setting rhythm
immediate postexercise period, probably associated with auto- indicates a partial therapeutic effect of quinidine on the atrial
nomic imbalance.77-79,479 If these postexercise arrhythmias are myocardium. When this atrial tachycardia occurs as an iso-
not associated with clinical signs and are not detected during lated finding, structural or underlying myocardial disease
exercise, they are unlikely to be clinically relevant. should be suspected and the horse should be considered pre-
Isolated atrial premature complexes generally are not disposed to the development or recurrence of AF. Treatment is
treated. The hemodynamic consequences of these rhythm the same as that described for AF. If the ventricular response
disturbances are minor, unless sustained abnormal activity rate is especially rapid (greater than 120 per minute) consid-
develops. Consideration of antiarrhythmic therapy might be eration can be given to administration of either digoxin to
appropriate if frequent atrial extrasystoles are documented block AV nodal conduction or possibly to diltiazem if digoxin
to precipitate AF or if they occur after conversion of AF to is ineffective (see Table 9.7). Arterial BP should be monitored
sinus rhythm and pose the horse at a risk of recurrent AF (see carefully if diltiazem is administered.1031-1033
later discussion). Unfortunately, neither quinidine nor pro-
cainamide is practical for chronic use. Oral administration of Atrial Flutter
sotalol has recently been advocated for chronic antiarrhyth- Atrial flutter is even less common than atrial tachycardia and
mic treatment to reduce the number of APCs, particularly represents a form of atrial circuit movement or macroreentry.
The clinical circumstances and assessment of this rhythm tone that both can favor development of reentry arrhythmias.
disturbance are identical to those of atrial tachycardia. The Vagosympathetic imbalances during exercise and transient
ECG in atrial flutter is characterized by a very rapid, abnor- potassium depletion, particularly in horses treated with furo-
mal, but regular atrial activity that is usually manifested as semide or bicarbonate solutions, may further increase the risk
a “saw-toothed” ECG baseline. The atrial frequency often of AF. Moreover, ultrastructural and functional myocardial
ranges between 170 and 275 per minute.68 The RR intervals pathology (e.g., focal myocarditis, fibrosis, channelopathies),
are usually irregular due to variable AV conduction, and there which cannot be detected using routine diagnostic tests, may
are fewer QRS and T complexes than flutter waves (see Fig. be present to promote the substrate that facilitates onset and
9.56C). The ventricular rate depends on the refractory period perpetuation of AF.1050,1067 Some, often older horses with AF
of the AV node and on the rate and the strength of the atrial present with underlying structural heart disease that is evi-
stimulus. Treatment of atrial flutter is similar to that for horses dent on physical and echocardiographic examination. Left
with AF.1034 atrial enlargement, most commonly caused by moderate to
severe MR, is considered the most important predisposing
Atrial Fibrillation factor for AF, but RA enlargement or other atrial pathology
Atrial fibrillation (AF) is the most common atrial arrhythmia can contribute in some horses as well.83,729 Atrial premature
associated with poor performance and exercise intolerance in complexes likely act as triggers for AF if an adequate substrate
horses. There is a large body of literature describing different for reentry arrhythmias is present.1050,1067,1068 Finally, once the
aspects of this important arrhythmia in horses.* Atrial fibril- arrhythmia is established, AF itself can induce atrial electrical,
lation is most common in adult horses82-84,88,1051 and has been structural, and functional remodeling that may be responsible
reported infrequently in foals,199,524,733,1065 weanlings, year- for the self-perpetuating, progressive, and recurrent nature
lings, or ponies. Several reports indicate a higher incidence of AF.289,290,1050,1062,1067 The duration of AF should be deter-
in Standardbreds, draft horses, and Warmblood horses com- mined when possible because it likely determines the degree
pared with the general hospital population,84,729 and in some of AF-induced atrial remodeling and affects the prognosis
Standardbred racehorses it has been identified as a heritable for successful conversion and the likelihood of recurrence.729
lesion.1052 Remodeling changes are more likely to be reversible if AF is
Cardiac output at rest is normal in most horses with treated promptly. Recurrent episodes of AF are not uncom-
AF621,1045,1066; however, maximal CO during exercise is limited mon and are more likely in the presence of remodeling and
because the atrial contribution to filling is most important at concurrent structural or functional cardiac disease.291,729,1062
higher HRs. As expected, exercise intolerance is most com- Horses with AF generally have a normal resting HR,
mon in high-performance horses (e.g., racehorses, advanced though the rate tends to decrease (and stroke volume tends
combined training horses, polo ponies, eventers, and some to increase) following successful conversion of AF to normal
Grand Prix jumpers) and less common in show hunters and sinus rhythm.621,1048,1066 The presence of resting tachycardia in
in pleasure, dressage, and endurance horses. The high LA a horse with AF should give the clinician pause to consider
pressures present in heavily exercising horses284,637 is further intercurrent cardiac lesions (including marked structural
exacerbated by the loss of active atrial transport function357 disease or the rare case of an accessory AV conduction path-
and may contribute to exercise intolerance or other associated way1069) or a disorder that increases sympathetic tone such as
signs. Exercise-induced pulmonary hemorrhage, respiratory pain, anemia, fever, or infection. A number of factors interact
distress, CHF, ataxia, collapse, and myopathy have all been in the prognosis of a horse with AF. Of these, the presence
reported with AF; conversely, the arrhythmia is often detected of CHF represents the overall worst prognostic indicator and
as an incidental finding in horses with no overt clinical signs.84 is invariably associated with resting tachycardia. Severe struc-
Atrial fibrillation can be acute or chronic, and it can be tural heart disease, recurrent bouts of AF, long-standing AF,
paroxysmal, persistent, or permanent. Paroxysmal AF is often and failure to convert with therapeutic serum concentrations
associated with a single episode of poor performance, with the of quinidine represent negative prognostic factors inasmuch
horse often decelerating suddenly during a race. The arrhyth- as affected horses can be more difficult to convert to sinus
mia usually disappears spontaneously within 24 to 48 hours. rhythm or more likely to revert back to AF even when therapy
Persistent or permanent AF may be less common than parox- is successful.291,729,1049,1062
ysmal AF but is easier to diagnose because the arrhythmia is Diagnostic Workup of Atrial Fibrillation. The diagnosis of
sustained. Persistent AF is terminating only after treatment, AF is initiated by recognition of an irregularly irregular heart
whereas permanent AF is sustained and resistant to therapy. rhythm, variable intensity heart sounds, and an absent fourth
Many horses with paroxysmal and some with sustained AF heart sound during cardiac auscultation. Arterial pulses vary
have no evidence of significant underlying cardiac disease in intensity, and pulse deficits may be present, especially when
when undergoing physical examination and echocardiogra- the ventricular rate is high (see Fig. 9.57D). The ECG is char-
phy. In these cases, a diagnosis of “lone AF” is often made, acterized by an absence of P waves; instead, fibrillation or “f ”
implying that AF is the only abnormality present and the etiol- waves are seen in the baseline (see Figs. 9.26, 9.57C, and 9.59).
ogy of the arrhythmia is purely functional. However, the fact These “f ” waves may be coarse (large) or fine (small). The
that AF appears to be “lone” in these cases may simply reflect number of atrial impulses per minute cannot be easily count-
our inability to identify the underlying pathology leading to ed but usually ranges between 275 and 500 per minute (when
arrhythmia. Intrinsic factors that are thought to contribute to analyzed on intracardiac electrograms).68,572,1062,1063 The QRS-
the risk of developing AF in the horse in general include the T complexes are normal in morphology and duration, but
(physiologically) large atrial mass and the high resting vagal ventricular rate response is irregularly irregular (chaotic). In-
frequently, periodicity leading to a patterned AV conduction
* References 2, 33, 39, 84, 218, 219, 221, 229, 289-291, 357, 401-403, 472, 572, sequence may be observed,219,403 which must be distinguished
621, 647, 721, 729, 1035-1064. from second-degree AV block. Although AF often sounds
more regular at higher HRs (e.g., immediately after exercise), Although uncommon, horses may collapse after sudden
the rhythm remains irregular and careful auscultation will re- onset of AF during exercise, most likely because of the sud-
veal this. Occasional QRS-T complexes of different morphol- den decrease in CO following the abrupt loss of atrial booster
ogy may be found, representing aberrant ventricular conduc- pump function. Recently it was shown that the prevalence of
tion (e.g., a wide QRS complex following a short RR interval QRS broadening and R-on-T phenomenon is high in horses
that is preceded by a long RR interval, also called Ashman’s with AF even at lower levels of exercise. These events are con-
phenomenon) or concurrent ventricular premature beats (see sidered risk factors for the development of ventricular arrhyth-
Fig. 9.57E and F). mias and might also explain some of the episodes of weakness
As for all atrial tachyarrhythmias, the ultimate ventricular and the rare case of collapse or sudden death that have been
rate response (and examination HR) depends on the refrac- reported in horses with AF.472 Atrial fibrillation associated
tory period of the AV node and the frequency and strength with exercise-induced ventricular arrhythmia resulting in
of the atrial stimuli.403 In the otherwise healthy horse in AF, sudden cardiac death has been documented by ECG in at least
vagal tone will be high and sympathetic tone low when stand- one horse.54 An exercise test including an exercise ECG should
ing; consequently, the ventricular rate will be close to normal therefore be performed when a horse is used for any type of
or only slightly increased. If sympathetic activity is increased performance activity and cardioversion is not an option or
for any reason, or if vagal activity is blocked (as occurs with could not be attained. The clinician should turn his or her
quinidine sulfate therapy), the ventricular rate response will attention to the HR response and maximum HR achieved dur-
increase as the AV nodal refractory period shortens. This ing exercise and to the occurrence of concurrent ventricular
explains the clinician’s simple, but very useful, dependence on arrhythmias.472 Horses in AF usually have a slightly higher HR
measuring pretreatment resting HR in horses with AF.84,729 during exercise compared with horses in sinus rhythm. How-
Because the horse with structural heart disease will be more ever, the average maximal HR during exercise at an intensity
likely to require sympathetic support to maintain CO and that is at or slightly exceeding the horse’s normal activities
arterial BP, persistent resting tachycardia, higher than 60 to 70 should not be greater than 220 beats/min. Markedly higher
beats/min, indicates underlying cardiac disease and is associ- maximal HRs might suggest an increased risk of collapse. Fur-
ated with a poorer prognosis. Horses with AF also should be thermore, ventricular ectopy during exercise or during sym-
examined critically for relevant murmurs that might indicate pathetic nervous system stimulation indicates a possible risk
the presence of valvular regurgitation, atrial enlargement, and for sudden cardiac death, particularly when short RR intervals
remodeling, creating a substrate for AF. or R-on-T phenomena are observed. Note that conventional
Laboratory studies in horses with AF, including plasma HR monitors (as opposed to telemetric ECG devices) may not
cardiac troponin concentrations, are usually normal. Infre- be able to track HRs above 200 to 220 beats/min and cannot
quently, a horse is found to have low serum potassium, urinary detect arrhythmias and differentiate among different types of
fractional excretion of potassium, or RBC potassium. Chest arrhythmias (i.e., atrial vs. ventricular). They are therefore not
x-rays are usually normal unless there is concurrent pulmo- considered suitable for diagnostic workup of horses in AF.
nary disease, and this study is not a high-yield procedure in Treatment of Atrial Fibrillation. Cardioversion is generally
horses without compatible signs of lung disease or structural not performed for the first 24 to 48 hours of a documented,
heart disease. recent onset of AF because spontaneous cardioversion might
A complete echocardiogram including Doppler studies occur. The most common treatment for AF involves conver-
should be performed to identify underlying structural heart sion to normal sinus rhythm, unless there is concurrent CHF
disease. The echocardiogram is often normal, unless there is or the horse is aged and therapy is deemed of little benefit. As
concurrent valvular, congenital, or ventricular myocardial a general principle, when AF occurs in the setting of CHF, the
disease. Horses in AF often demonstrate a mildly dilated treatments should be aimed at controlling CHF and resting
left atrium, even in the absence of significant MR or other HR with furosemide, digoxin, and possibly an ACE inhibitor,
structural disease. Significant LA enlargement is usually as opposed to conversion back to sinus rhythm.
associated with moderate to severe MR and reduces the like- The level of intended activity influences clinical decision
lihood of successful cardioversion and increases the risk for making, as sustained AF is likely to limit rigorous athletic work
recurrence. Assessment of LV function might be hampered and occasionally also impairs performance at mid to low levels
during AF because of ventricular dyssynchrony, tachycardia- of activity. Other horses with persistent AF are able to per-
induced LV dysfunction and preload, and HR dependence form successfully when used for less intense work. In any case,
of many of the echocardiographic indices used to assess treatment of AF is recommended for all horses that are still in
LV function.68,344 It is not uncommon for an otherwise use for any type of athletic activity when the average maximal
normal horse in AF to demonstrate a slightly reduced LV HR during sustained maximal exercise exceeds 220 beats/min
shortening fraction (usually in the 24%–32% range), which or when concurrent ventricular arrhythmias are observed (see
returns to normal once the horse has been converted to earlier discussion).54,68,472 If treatment is not an option in such
sinus rhythm.1070,1071 This decrease in fractional shortening cases, they should be retired due to safety concerns.68
is probably multifactorial in origin and probably related in Treatment of AF should only be performed in a controlled
part to decreased preload from loss of the atrial contribution setting with continuous (ECG) monitoring, regardless of the
to ventricular filling and irregular cardiac cycle. Evidence of treatment method.68 Conversion of AF to sinus rhythm usu-
persistent left ventricular dysfunction, even after the AF has ally is accomplished using the type IA sodium channel blocker
been successfully corrected, might indicate underlying myo- quinidine* or through electrical cardioversion, generally
cardial disease in the horse with AF; these horses often fail delivered by intracardiac catheters (transvenous electrical
to return to their previous level of performance. Echocardio- cardioversion [TVEC]).655,1038,1062,1084-1094 There have been no
graphic evidence of severe volume overload or PHT suggests
a grave prognosis. * References 58, 401, 729, 752, 1027, 1031, 1034, 1041, 1049, 1070, 1072-1083.
prospective, randomized studies comparing the two methods, Reef and colleagues an excellent prognosis for quinidine con-
and both quinidine and electrical cardioversion are generally version (greater than 95% conversion rate) may be given for
safe and effective treatments. Indications for quinidine treat- horses with HRs of less than or equal to 60 beats/min, murmurs
ment include lone AF, AF with mild LA enlargement, and less than or equal to grade 3/6, and AF of less than 4 months’
comorbidities in which general anesthesia or TVEC is not duration.729,1070 Recurrences affect approximately 25% of these
an option. TVEC can be used to treat lone AF, AF with mild horses. In a study of transvenous electrical cardioversion, the
LA enlargement, and horses either intolerant of or unrespon- results were also very positive, with a greater than 98% conver-
sive to quinidine treatment or horses in which quinidine is sion rate (71 of 72 episodes in 63 horses).1089 Overall, success
contraindicated.68 rates of 65% to 90% have been reported for both treatment
Quinidine conversion to sinus rhythm represents the stan- modalities.68 Young racehorses with lone AF probably have
dard therapy for most equine practices and has been used for a better prognosis for successful cardioversion, independent
the longest period of time. Hence, quinidine sulfate is the stan- of treatment modality. Horses with longer duration of AF, a
dard drug against which other drug treatments should be com- shorter fibrillation cycle length, or significant structural car-
pared, though this agent is becoming more difficult to obtain diac disease may be more difficult to convert to sinus rhythm
in some countries. Quinidine cardioversion of AF is successful using quinidine or electrical cardioversion and are more likely
in many horses, and a number of different treatment plans can to have a higher recurrence rate independent of the treatment
be followed (Box 9.14; also see Table 9.7). Based on studies of modality.729,1062 In one recent study, a recurrence rate of 36%
BOX 9.14
Quinidine Treatment of Atrial Fibrillation (AF)
PREPARATION BEFORE TREATMENT effects (hypotension, proarrhythmic effects including

• Intravenous catheter for rapid venous access in case of an ventricular tachycardia and torsades de pointes)
emergency
• Nasogastric tube/transnasal feeding tube for quinidine HORSE WITH HEART FAILURE
administration • Cardioversion using quinidine is usually not attempted;
• (Telemetric) ECG for continuous monitoring of heart rate, goals of treatment are stabilization of congestive heart
rhythm, and conduction times failure and ventricular rate control; treat with digoxin to
• Ensure adequate hydration and correct electrolyte and control heart rate and improve myocardial function, furo-
acid-base disturbances semide to control edema, and possibly an ACE inhibitor
• Prepare emergency drugs and protocols
MONITORING
HORSE WITHOUT HEART FAILURE • Monitor for response to treatment and adverse/toxic
Quinidine sulfate PO (by nasogastric tube or feeding tube): effects
• 22 mg/kg q 2 h until (1) conversion to sinus rhythm, (2) • Ensure adequate fluid intake during prolonged quinidine
adverse or toxic effects occur, or (3) a total of 4 (to 6) treatment
doses have been administered • Monitor serum electrolytes and BUN/creatinine during
• If possible, plasma quinidine concentration should be prolonged treatment
measured if (1) conversion has not occurred 1 hour
after the fourth dose, or (2) the patient exhibits adverse MANAGEMENT OF QUINIDINE-INDUCED ADVERSE AND
or toxic effects TOXIC EFFECTS
• Therapeutic concentration: 2–5 μg/mL, toxic concen- • Accelerated ventricular response rate—may occur within
tration: >5 μg/mL therapeutic range:
• Treatment intervals should be increased to every 6 • If rate is <100 beats/min and horse is hemodynamically
hours if (1) plasma quinidine concentration is >4 μg/mL stable, continue treatment with close monitoring
or (2) after the fourth dose if concentrations cannot be • If rate is persistently >100 beats/min, administer
measured digoxin (0.0022 mg/kg IV, may repeat dose once)
• Treatment every 6 hours can be continued, until (1) • If rate is sustained in excess of 150 beats/min or severe
conversion to sinus rhythm, (2) adverse or toxic effects systemic hypotension develops, administer digoxin and
occur, (3) a total cumulative dose of 180 mg/kg is NaHCO3 (1 mEq/kg IV)
reached • Other options for rate control include diltiazem (see
• If conversion to sinus rhythm has not occurred after 24 Table 9.7) or alpha-2 agonists; administer to effect,
hours, digoxin at 0.0055–0.011 mg/kg PO q 12 h may monitor ECG and direct blood pressures
be added for 24–48 hours • Prolongation of QRS (>25%)—indication of toxicity, dis-
Quinidine gluconate IV: continue quinidine
• As an alternative to oral treatment if the arrhythmia is • Severe hypotension—administer phenylephrine (0.1–0.2
recent (<2 weeks) or occurred during anesthesia μg/kg/min to effect, up to 0.01 mg/kg total dose)
• 1–2.2 mg/kg IV as a slow bolus every 10 min or • Ventricular arrhythmia (ventricular tachycardia, torsades
0.1–0.22 mg/kg/min CRI; to effect de pointes)—discontinue quinidine, administer lidocaine
• Total doses exceeding 12 mg/kg are usually not recom- (0.25–0.5 mg/kg slow IV, repeat in 5–10 min, up to 1.5
mended; higher doses (up to 24 mg/kg) may be neces- mg/kg total dose) and MgSO4 (2–6 mg/kg/min IV to effect,
sary for conversion but can result in severe adverse up to a total dose of 55 [up to 100] mg/kg)
after first AF episode and an overall recurrence rate of 43% phenylephrine drip to restore BP if there is critical hypoten-
were reported.291 Long-term recurrence rates after TVEC and sion (see Table 9.7 and Box 9.14). Ventricular arrhythmias
quinidine cardioversion are believed to be similar.68 (torsades de pointes, multiform VT, and ventricular premature
Quinidine is typically administered by nasogastric tube complexes) have also been detected with quinidine toxicosis
or feeding tube because of its irritating effects on the mucous (Fig. 9.58) and in the rare case may lead to sudden cardiac
membranes. Intravenous quinidine gluconate can be successful death during treatment. Intravenous sodium bicarbonate is
in conversion of horses with AF of recent onset or when naso- also indicated in these horses, whereas intravenous magne-
gastric delivery is not feasible,1075,1079,1082 but failure to respond sium sulfate (up to 25 g in a 450- to 500-kg horse) is the treat-
does not predict the response to oral treatment (see Box 9.14). ment of choice for quinidine-induced ventricular arrhythmias
Many successful approaches have been used to convert AF (see Table 9.7). Lidocaine may also be used if needed, starting
in horses, and the clinician should appreciate that the mean with an intravenous bolus of 0.5 to 1.5 mg/kg, slowly IV. Con-
quinidine elimination half-life after an oral dose is about 6.7 versely, administration of digoxin is contraindicated in horses
hours.327,1082 One treatment approach for AF involves admin- with ventricular arrhythmias induced by quinidine.
istration of a loading dose of 22 mg/kg quinidine sulfate by Clinical markers of quinidine toxicosis include ataxia,
nasogastric tube every 2 hours for two to four doses, followed colic, and nasal edema causing upper respiratory tract stri-
by every-6-hour dosing until the horse converts or develops dor. Most toxic reactions to quinidine sulfate are associated
initial signs of toxicosis. Aggressive q 2 h dosing exceeding 88 with higher serum concentrations of the drug (greater than
to 132 mg/kg is especially likely to induce adverse effects.1070 5 μg/mL) and can be avoided with careful clinical and elec-
Therapeutic serum quinidine concentrations for conversion trocardiographic monitoring. Some of the adverse effects of
from AF to sinus rhythm are 2 to 5 μg/mL (6.2–15.4 μmol/L) quinidine administration, particularly polymorphic ventricu-
and should be measured if a horse fails to convert following lar tachycardia (see Fig. 9.58), are likely an idiosyncratic reac-
an appropriate dosing regimen. If conversion to sinus rhythm tion. These adverse effects should prompt discontinuation of
has not occurred after 24 hours of therapy, digoxin at 0.0055 therapy or altering treatment intervals. Depression and para-
to 0.011 mg/kg orally twice a day may be added to the treat- phimosis occur in most horses treated with quinidine but dis-
ment regimen for 24 to 48 hours. As in other species, there is appear with the discontinuation of the drug. Diarrhea often
a digoxin-quinidine interaction that can effectively double the develops with the administration of higher doses of quinidine,
serum concentration of digoxin.752 Thus combination therapy but this sign also disappears with discontinuation of the drug.
beyond 24 hours should be continued only with monitoring Convulsions, hypotension due to vasodilation, CHF, laminitis,
of the serum digoxin concentrations (see Table 9.7) and con- urticaria, and sudden death have rarely been reported associ-
sideration of using the lower end of the digoxin dosage range. ated with quinidine sulfate administration. A ventricular rate
Even horses that do not convert on the “standard” administra- response in excess of 100 beats/min is an adverse reaction that
tion regimen may convert after the combined use of quinidine may be more common in nervous horses, horses that show an
with digoxin. The value of using such a treatment plan every 6 excessive ventricular response during exercise, or those prone
hours is that steady-state levels are reached, there is sufficient to the vagolytic effects of quinidine. These horses may benefit
time to attain myocardial concentrations, and quinidine toxic- from administration of digoxin to blunt the ventricular rate
ity is less frequent compared with the every-2-hour regimen. response, particularly if there are no other signs of quinidine
When prolonged treatment over more than 12 to 24 hours is toxicosis (that would indicate an excessive serum concentra-
necessary, adequate hydration and electrolyte balance (par- tion). If an increased ventricular response rate is anticipated,
ticularly potassium and magnesium) must be ensured by oral one may even consider pretreatment with digoxin before ini-
or intravenous administration of crystalloid solutions, because tiation of quinidine therapy. Alternatively, alpha-2 agonists
most horses undergoing oral quinidine treatment will become (e.g., detomidine)1063 or diltiazem259,1031-1033 could be used for
depressed and inappetent, will show reduced water intake, and ventricular rate control during quinidine treatment, provided
may develop mild diarrhea. that blood pressures can be closely monitored (see Table 9.7).
Careful clinical and continuous electrocardiographic moni- The clinical experience with the use of diltiazem is limited,
toring should be performed on horses with AF during conver- and doses should be carefully titrated to effect.
sion to sinus rhythm. The QRS duration should be monitored Other drugs have been studied for treatment of AF in
and compared with the pretreatment QRS duration before each horses. These might be considered mainly for cases of resistant
additional treatment is administered. Prolongation of the QRS or recurrent AF or in situations where quinidine or electro-
duration to greater than 25% of the pretreatment value is an cardioversion are unavailable. Procainamide may potentially
indication of quinidine toxicity and should prompt discontin- be effective and could be used at a dose of 1 mg/kg/min IV
uation of therapy. The simplest ECG change is an acceleration (up to a maximum of 20 mg/kg) when AF occurs during anes-
of AV nodal conduction related to the vagolytic effect of quini- thesia.327,1095 Based on recent discoveries in dogs, the use of
dine (see Fig. 9.57C). Rapid supraventricular tachycardias with lidocaine could also be attempted to treat acute vagally asso-
ventricular rate responses of up to 300 beats/min have been ciated AF that might develop during anesthesia.1096,1097 How-
seen in several horses receiving quinidine sulfate. These horses ever, efficacy of lidocaine for conversion of AF is unknown,
have been treated with intravenous digoxin at 0.002 mg/kg to and it is certainly not considered the drug of choice for routine
slow the ventricular response rate, intravenous replacement treatment of AF in horses. Amiodarone administered as a con-
fluids to improve perfusion, intravenous sodium bicarbonate stant rate infusion has been used for treating experimentally
at 1 mEq/kg to reverse the sodium channel–blocking effects of induced and natural AF in horses, but treatment may last up to
quinidine (probably by a combined effect of increasing extra- 54 hours and is expensive, and success rates are considerably
cellular sodium concentration and alkalinization, leading to lower than those reported for quinidine and TVEC.1098-1101
increased protein binding of quinidine and decreased extra- Therefore amiodarone cannot be recommended as a first-line
cellular concentrations of ionized calcium), and if needed, a therapy at this time. Pharmacokinetics of flecainide, a class IC
FIG. 9.58 Polymorphic ventricular tachycardia (VT) after administration of quinidine sulfate for attempted
conversion of atrial fibrillation (AF). In this case normal sinus rhythm was established (lower tracing) after
treatment with lidocaine, bicarbonate (to reverse sodium channel–blocking effects of quinidine), and phe-
nylephrine (administered to maintain arterial blood pressure [ABP]).
antiarrhythmic drug, have been studied in horses, and it has within the left PA and the other within the right atrial cavity.
been administered for treatment of experimentally induced Catheter placement is done in the standing position under seda-
and naturally occurring AF and atrial tachycardia.1102-1109 Early tion and local anesthesia. The catheters are guided by pressure
studies suggested that flecainide might be a safe and effective monitoring through the catheter lumen, 2D echocardiographic
alternative to quinidine for treatment of AF. However, intra- imaging, and interrogation of the intracardiac electrogram
venous administration of flecainide was not found to be effec- recorded through the catheter electrodes (Fig. 9.59). Radiogra-
tive to treat chronic naturally occurring AF,1102,1109 and in an phy is used to verify the placement of the catheters either before
experimental model it failed to show protective properties or preferably after induction of general anesthesia. General
against immediate reinduction of AF after conversion.1104 Fur- anesthesia is required because electrical cardioversion is very
thermore, flecainide administration caused widening of the painful and the shock results in a sudden jolt of the body and
QRS complex and was associated with potentially dangerous limbs. Electrical cardioversion involves a timed shock delivery
arrhythmias and sudden death.1103,1109 Therefore the use of on the R wave. Proper synchronization of the shock is crucial to
flecainide is currently not recommended in horses. Intrave- avoid shocking on the T wave, which represents the vulnerable
nous propafenone also has been suggested for conversion of period and is susceptible for inducing fatal ventricular arrhyth-
chronic AF1110,1111 but has recently been shown to be ineffective mias. A more detailed description of the specific procedure
at a dose of 2 mg/kg IV in horses with naturally occurring and used for TVEC is beyond the scope of this textbook, and the
pacing-induced AF, respectively. Therefore the current knowl- reader is referred to the respective literature.655,1038,1062,1084-1094
edge does not support the use of this class Ic antiarrhythmic The complications associated with electrocardioversion
drug for treatment of AF. Potentially, combination therapy appear to be quite low but are finite related to general anesthesia
using a variety of antiarrhythmic drugs at lower doses might or electrical shock.1088,1091,1093 A case of transient complete AV
prove useful for treatment of AF in the future. Furthermore, block has been reported,1092 and depending on catheter posi-
novel ion channel targets and new atrial-selective antiarrhyth- tion (i.e., placement of the RA catheter close to the AV node)
mic agents are currently under investigation for treatment of this complication might not be uncommon. Furthermore,
AF in horses and other species.1112,1113 However, more funda- fatal arrhythmias can be induced by unsynchronized shock
mental research has to be conducted before any of the newer delivery.1114 The immediate recurrence of AF (IRAF) within
strategies can be investigated in clinical studies. the first 24 hours after cardioversion, although infrequent, is
Transvenous electrical cardioversion of AF to sinus rhythm more likely than with quinidine cardioversion.68 Pretreatment
has been used at a number of referral centers as either the pri- with antiarrhythmic drugs before TVEC or administration
mary method of treatment or for management of horses who of an antiarrhythmic drug during and after anesthesia might
respond adversely or inadequately to quinidine therapy. As minimize the likelihood of IRAF.1038,1090Amiodarone and
stated, TVEC is a very effective therapy, but it requires special sotalol have been used for this purpose (see Table 9.7).
equipment and well-trained, experienced personnel. The proce- Follow-up Care after Conversion of Atrial Fibrillation. Af-
dure involves percutaneous placement of two specialized elec- ter spontaneous cardioversion, an evaluation is still in-
trode catheters transvenously with one catheter tip located dicated, including measurement of serum K+ and Mg++
A
A
FIG. 9.59 A, Electrocardioversion procedure in a Thoroughbred horse. The horse is under general anes-
thesia. Two specialized electrode catheters (arrows) were previously placed percutaneosly under local anes-
thesia into the right atrium (RA) and left pulmonary artery under guidance from two-dimensional (2D) echo-
cardiography and intravascular pressure monitoring. The biphasic cardioverter (top, center of image) is
connected to the catheters and is used to deliver the synchronized cardioversion shock, as well as monitor
electrocardiogram (ECG) rhythm, invasive blood pressure (BP), and pulse oximetry. Inset: 2D image showing
short-axis image at base of heart. The catheter inserted into the left pulmonary artery (LPA) is indicated (ar-
rows) (RA, right atrium; RV, right ventricle; Ao, aorta; RPA, right pulmonary artery). B, Transvenous electrical
cardioversion for treatment of atrial fibrillation (AF) in an 2-year-old Standardbred racehorse under general
anesthesia. A surface ECG (25 mm/sec) and an arterial blood pressure (ABP) tracing are displayed. The QRS
complexes are automatically detected by the defibrillator unit and marked by small triangles. Biphasic elec-
trical shocks (larger triangles on top) are applied at increasing energy levels. Delivery of the shocks is syn-
chronized to the QRS complex to avoid the vulnerable period (T wave) and prevent induction of ventricular
arrhythmias. (A) Unsuccessful attempt at an energy level of 125 J. (B) Successful cardioversion at an energy
level of 225 J. Immediately after the shock, the baseline flattens and normal sinus rhythm resumes. No fur-
ther treatment is required at this point. From Schwarzwald CC, Bonagura JD, Muir WW: The cardiovascular
system. In Muir WW, Hubbell JAE, editors: Equine anesthesia: monitoring and emergency therapy, ed 2, St.
Louis, 2009, WB Saunders.
concentrations, fractional excretion of K+ (in racehorses), long as the expected level of performance can be achieved and
echocardiography, continuous 24-hour ECG, and optimally the results of exercise testing do not suggest an increased risk
an exercising ECG test to identify atrial triggers or other ar- of collapse or sudden death; see earlier discussion). Alterna-
rhythmias. These tests are also appropriate in a horse with tively, they can be kept as breeding animals or pasture horses.
normal sinus rhythm if paroxysmal AF is suspected from the Importantly, horses with persistent AF should only be rid-
clinical history.68 den or driven by an informed adult and limited to an exercise
A continuous 24-hour ECG to detect recurrent atrial level considered relatively safe based on an exercising ECG
arrhythmias is recommended after successful conversion (see previous discussion). The use of an HR monitor might be
of AF to sinus rhythm. However, the optimal timing of this helpful to track HR during exercise and modify the rigor of the
examination, the influence of premature atrial complexes on work performed.68
long-term prognosis, and the best approach to management
of recurrent atrial ectopy are unknown.68 A complete echocar- Junctional and Ventricular Arrhythmias
diogram after cardioversion can evaluate LV and LA mechani- Cardiac arrhythmias that originate within the AV conduct-
cal function and reassess heart size and valvular function. ing tissues, the ventricular specialized conducting tissues, or
Left ventricular function should return to normal within 3 ventricular myocardium are classified as “junctional” (AV
days.1048 Recovery of LA contractile function can occur within node and parts of the bundle of His) or ventricular in origin.
a few days or might take several weeks when AF has been Unlike sinus or atrial arrhythmias, these arrhythmias are not
long-lasting.287,289,1038 Persistent LA contractile dysfunction preceded by a conducted P wave. When sustained, junctional
can be caused by AF-induced atrial remodeling or underlying and ventricular rhythms often lead to dissociation between the
primary cardiomyopathy and might portend an increased risk sinoatrial activity (P wave) and that of the ventricle (QRS-T
of recurrent AF.291,1038 complex), resulting in AV dissociation.57,60,502 In these cases,
Oral sotalol at an initial dose of 1 mg/kg PO and a main- an independent atrial rhythm is superimposed on the ectopic
tenance dose of 2 to 3 mg/kg PO q 12 h (see Table 9.7)1030 is rhythm (Fig. 9.60C and D). Note that AV dissociation in these
currently used by some clinicians, including the author, in cases develops because the premature AV junctional or ven-
an attempt to suppress atrial ectopy after cardioversion and tricular depolarization causes interference to the conduction
reduce the risk of recurrent AF. Sotalol is usually weaned of normal SA impulses. It is important to realize that escape
before reinitiation of normal training, and only rarely chronic rhythms (see later discussion) also cause AV dissociation
long-term treatment is elected. Although sotalol seems to through a different mechanism. Hence, “AV dissociation” is a
be well tolerated, its efficacy is currently not well studied. purely descriptive term of an ECG finding and neither char-
Other antiarrhythmic drugs that, based on human studies or acterizes the type and pathophysiologic mechanism of the
experimental animal models, might potentially be effective arrhythmia nor determines the therapeutic approach.
against atrial arrhythmias include propafenone,1110,1111 amioda- With sustained junctional or ventricular tachycardias, P
rone,1100,1101 and phenytoin.1115 However, efficacy and safety of waves may be identified that are not conducted and therefore
these treatments are currently unknown and further studies not consistently associated with a QRS complex (see Fig. 9.60).
are needed.68 Drugs known to predispose to ectopic impulse Some of these P waves may be buried in the ectopic QRS-T
formation should be avoided, including furosemide, supple- complexes (especially at higher rates of ventricular activation),
ments containing sodium bicarbonate, and thyroid hormones. making their identification difficult. The use of ECG calipers
Potassium chloride supplementation is indicated in most helps determine the P-P interval and can greatly facilitate the
horses administered furosemide before racing or in those with identification of P waves. Occasionally, atrial impulses may be
low fractional urinary excretion of potassium.68 normally conducted, leading to capture beats or fusion beats.
Horses can usually be returned to training within 1 week Capture beats are characterized by a normal P-QRS-T configu-
after conversion with paroxysmal AF or short-duration lone ration, resulting from normal ventricular activation occurring
AF, if follow-up examinations after cardioversion are normal. before the ectopic focus discharges (see Fig. 9.60D). Fusion
However, horses with long-standing AF or with persistent beats are seen when both the conducted impulse and an ecto-
sinus tachycardia, recurrent atrial premature complexes, or pic impulse cause simultaneous ventricular activation. The
persistent LA dysfunction observed after successful conver- QRS-T morphology of a fusion beat represents the summation
sion of AF to NSR should be given 4 to 6 weeks to recover.68 of a normal and an ectopic beat (see Fig. 9.60C).
Ideally, rest is enforced until atrial electrical and contractile It may be difficult to distinguish between junctional and ven-
function has normalized or is nearly normal. tricular arrhythmias and to determine the exact location of the
Conversion of horses with AF generally results in a return abnormal impulse formation. The differentiation of junctional
to their previous performance level.84,729 Horses with repeated and ventricular rhythms can sometimes be made by inspec-
episodes of AF are often converted numerous times with tion of the QRS complex. Junctional impulses are more likely
quinidine sulfate or electrocardioversion. Most horses that to result in a narrow, relatively normal-appearing QRS complex
experience a recurrence of AF do so within 1 year of initial with normal initial activation and electrical axis, because they
conversion,291,1038,1070 but much longer intervals have occurred originate above the ventricular myocardium. Complexes of
between episodes of AF in some horses. If the duration of ventricular origin, by contrast, are conducted abnormally and
sinus rhythm becomes shorter, repeated treatments may no more slowly, resulting in a widened QRS, an abnormal QRS
longer be practical and a career change may be indicated. orientation, and abnormal T waves. However, junctional tachy-
Some horses eventually become refractory to drug or electri- cardias also may be conducted aberrantly, resulting in a bizarre
cal cardioversion, probably due to progressive atrial fibrosis or and wide QRS complex. When sustained, both types of rhythms
underlying myocardial disease. However, in the absence of sig- cause AV dissociation with an independent atrial rhythm super-
nificant, detectable cardiac disease, horses with persistent or imposed on the ectopic ventricular rhythm. Advanced echocar-
permanent AF may still be used at lower levels of exercise (as diographic methods that identify the sequence of ventricular
E
FIG. 9.60 Ventricular arrhythmias. A, The ectopic complex (arrow) is premature and abnormal in morphology. A compensatory pause follows the
extrasystole because the next sinus P wave is blocked in the atrioventricular node. The effect of the premature complex on arterial blood pressure (ABP)
in the lower tracing (arrow) is noticeable. B, Base-apex lead electrocardiogram (ECG) recorded from a 15-year-old Arab mare with ventricular bigeminy.
Normal sinus beats alternate with slightly larger and wider ventricular ectopic beats. SA node discharge is not affected by the ectopic beats, as indicated
by the presence of nonconducted P waves immediately before the ectopic beats (arrowheads) (paper speed 25 mm/sec). C, Base-apex lead ECG recorded
from an 18-year-old Arab mare recovering from acute diarrhea and endotoxemia. The ECG shows an intermittent accelerated idioventricular rhythm at
a rate of 50 beats/min. P wave intervals are indicated (arrowheads). The recording demonstrates that the ectopic focus is suppressed at higher rates of
SA node discharge. The ventricular rhythm only becomes manifest when the sinoatrial (SA) rate drops below the rate of the ventricular pacemaker. SA
node discharge is not affected by the ectopic rhythm, resulting in AV dissociation. A fusion beat is present (arrow), resulting from summation of a con-
ducted sinus impulse with an ectopic ventricular beat (paper speed 25 mm/sec, voltage calibration 0.5 cm/mV). D, Base-apex lead ECG recorded from a
3-year-old Clydesdale gelding. The top recording shows a regular tachycardia at a rate of 120 beats/min. The appearance of the QRS-T complexes does
not allow conclusive distinction between a supraventricular rhythm with rapid ventricular response and a ventricular rhythm. However, as the rate slows
down (bottom strip), AV dissociation because of a ventricular tachycardia (VT) becomes apparent. P waves (arrowheads) and a capture beat (arrow) are
indicated (paper speed 25 mm/sec, voltage calibration 0.25 cm/mV). E, Base-apex ECG recorded from a 5-year-old Clydesdale stallion with acute myocar-
dial necrosis of unknown cause. The serum cardiac troponin I concentrations were severely elevated (404 ng/mL; normal <0.15 ng/mL). The ECG shows
multiform VT at a rate of 120 beats/min (paper speed 25 mm/sec, voltage calibration 0.5 cm/mV). (B to E, From Schwarzwald CC, Bonagura JD, Muir WW:
The cardiovascular system. In Muir WW, Hubbell JAE, editors: Equine anesthesia: monitoring and emergency therapy, ed 2, St. Louis, 2009, WB Saunders.)
activation and allow detection of ventricular dyssynchrony and manifest during periods of sinus bradycardia or AV block,
advanced electrophysiologic studies may be of value in dis- creating escape complexes or escape rhythms (see Fig. 9.62B
tinguishing ventricular origin complexes from those starting later). Escape rhythms are characterized by slow ventricular
above the ventricle and using the normal conduction system, rates, often in the realm of 15 to 25 beats/min. Specific antiar-
but these methods are not established in horses. rhythmic drug suppression of escape rhythms is generally not
necessary and is contraindicated because these rhythms serve
Junctional Arrhythmias as rescue mechanisms for the heart. Instead management of
Junctional complexes that arise early relative to the normal escape rhythms should be aimed at resolving the underlying
cardiac cycle are designated as premature junctional complexes. cause of sinus bradycardia or AV block.
These complexes may occur as single or repetitive events and
can resemble ectopic rhythms that might originate in the Accelerated Idioventricular
atria but without being related to a P wave. Repetitive ecto- (Idionodal) Rhythms
pic complexes that occur in short bursts or runs are termed Occasionally, the subsidiary nodal or ventricular pacemak-
nonsustained or paroxysmal junctional tachycardias. Sustained ers may be enhanced and discharge at a rate that is equal to
junctional tachycardias may also occur and can lead to cardio- or slightly above the sinoatrial rate (usually between 60 and
myopathy and CHF, which are reversible with control of the 80 beats/min). The resulting rhythm is commonly referred to
tachyarrhythmia (see earlier discussion). as accelerated idioventricular (idionodal) rhythm or slow ven-
The clinical relevance of an occasional junctional prema- tricular tachycardia (see Fig. 9.60C). Conditions that favor the
ture complex is difficult to ascertain. Persistent or repetitive development of these rhythms include gastrointestinal disease
junctional rhythms are indicative of heart disease, systemic (possibly due to a combination of endotoxemia, autonomic
disease, or a drug-induced abnormality of cardiac rhythm. imbalance, acid-base disturbances, and electrolyte abnormali-
The best management choice, besides treatment of the under- ties)504 and administration of anesthetics or catecholamines.
lying disorder, is uncertain inasmuch as some junctional When the independent atrial and ventricular pacemaker foci
rhythms behave more like atrial tachyarrhythmias, whereas discharge at similar rates, the P waves may appear to “march
others cause AV dissociation and appear to act like ventricu- in and out” of the QRS complex. This phenomenon is called
lar ectopic impulses. Because the mechanism responsible for isorhythmic AV dissociation and is occasionally observed in
junctional tachycardias can be either abnormal automaticity adult horses during inhalation anesthesia. Accelerated idio-
or reentry (circuit) movement using the AV node, empiric ventricular rhythms are often quite regular and may be mis-
therapy is usually required to control sustained arrhythmias. diagnosed as sinus tachycardia on auscultation or palpation
If there is obvious AV dissociation, lidocaine, procainamide, of peripheral pulses. Persistent, unexplained mild to moderate
quinidine, or sotalol would seem reasonable choices (see Table tachycardia should therefore prompt an electrocardiographic
9.7). If the mechanism is uncertain but is clearly supraventric- examination to ascertain a correct rhythm diagnosis. How-
ular, intravenous digoxin or intravenous diltiazem may either ever, accelerated idioventricular rhythms generally are of little
silence the rhythm or slow the rate. clinical (electrophysiologic and hemodynamic) relevance and
resolve spontaneously with appropriate treatment of potential
Escape Rhythms underlying conditions and reduction of anesthetic dosages.
The normal heart contains potential cardiac pacemakers Electrolyte supplementation (potassium, magnesium) and
within the AV junctional and ventricular specialized tissues correction of fluid deficits and acid-base disturbances may be
that are usually overdrive suppressed by the sinus node, which beneficial. Lidocaine (see Table 9.7) is sometimes adminis-
discharges at a faster rate than these subsidiary pacemakers. tered as an intraoperative adjunct to general anesthesia, or it is
The automaticity of the subsidiary pacemakers may become used as an analgesic, antiinflammatory, and prokinetic drug in
FIG. 9.61 Sustained, rapid ventricular tachycardia (VT) (top) of varying rate that develops into a poly-
morphic ventricular rhythm with varying morphology complexes (torsades de pointes). The horse died of
cardiac arrest (lower right panel). The arrows indicate QRS complexes of varying polarity (25 mm/sec).
the management of postoperative ileus. In these situations, its may be problematic to separate primary from secondary causes
antiarrhythmic effects may provide some additional preven- of cardiac troponin elevations. An echocardiogram is specifi-
tive or therapeutic benefits. cally recommended for horses with ventricular tachycardia or
In some cases, accelerated idioventricular (idionodal) complex VA, when VA is recurrent or persistent, or when VA is
rhythms can be sustained in an otherwise healthy horse. If the associated with poor performance, collapse, a clinically relevant
abnormal rhythm is overdriven by exercise, affected horses can cardiac murmur, or a marked increase in cardiac troponin con-
be used with caution by an informed adult. However, because centration.68 Further workup of a horse with VA should include
of concerns about underlying myocardial or electrical disease an exercising ECG, unless underlying systemic or myocardial
and potentially increased risks of exercise-associated collapse disease, VT, or complex VA is present.68
and sudden cardiac death, these horses should not be used by As opposed to atrial arrhythmias, safety of the horse and
a child or as a lesson horse.68 the rider or driver is more of a concern with VAs, and defining
the safety risks is paramount in cases of ventricular ectopy.68
Ventricular Arrhythmias The complexity of a ventricular arrhythmia (see later discus-
Ventricular arrhythmias (VAs) are less common than atrial sion) likely relates to the risk of hemodynamic compromise,
arrhythmias but are more likely to be associated with underly- electrical deterioration, and sudden cardiac death. Although
ing structural cardiac disease, lesions of the myocardium, or risk stratification for VA is imperfect, recommendations
a multisystemic disorder, including infections.* VAs may be should be biased toward safety as opposed to maintaining
observed with severe toxemia or sepsis or primary gastroin- athletic activity.68 A history of collapse, presence of important
testinal disorders including proximal enteritis and large bowel structural heart disease (and cardiomegaly), or detection of
disorders. Altered potassium, magnesium, and calcium con- systemic hypotension during a documented run of ventricu-
centrations can affect myocardial electrophysiology,1125 and lar tachycardia raises great concern in a horse with VA. In the
electrolyte and acid-base disorders can induce ventricular absence of clinical signs or of serious structural heart disease,
ectopy. Other potential causes of VAs include metabolic dis- the risk of ventricular ectopy is usually defined by electrocar-
orders, ischemia, hypoxia, drugs, toxins, and systemic inflam- diographic characteristics (see later discussion), accepting the
mation. Primary heart diseases, including severe valvular limitations of this analysis.68
regurgitation, cardiomyopathy, myocarditis, endocarditis, and
pericarditis, can induce VAs. This said, VAs are also frequently Ventricular Premature Complexes
encountered in apparently healthy athletic horses at rest and Ventricular premature complexes (VPCs) are characterized
during and after exercise.77-79,82,475,478,479 by premature, widened complexes, often followed by a com-
Ventricular ectopic rhythms are classified as indicated in Box pensatory pause. The pause occurs because the next sinus
9.12. The approach to the horse with VAs should emphasize rul- impulse is blocked by the refractory AV conduction system.
ing out the noncardiac causes, correcting them (if possible), If the sinus rate is slow or the ventricular premature complex
and then following if necessary with a complete CV examina- is closely coupled to the preceding normal sinus beat, it may
tion, including electrocardiography, echocardiography, and be interpolated between two normal beats. Ventricular ectopic
clinical laboratory studies.68 Plasma troponin concentrations impulses are characterized by QRS and T waves that are wide
should be measured to identify myocardial injury, although it and often bizarre in appearance (Fig. 9.61; see also Fig. 9.60).
The premature QRS bears no relationship to any preceding
* References 57, 77-79, 80, 81, 82, 83, 97, 149, 150, 153, 161, 227, 263, 383, 400, P waves, although the induction of ventricular ectopics may
472, 475, 478, 479, 485, 502, 524, 575, 651, 653, 654, 662, 665, 667, 736, 864, be dependent on underlying cardiac cycle length or HR. The
907, 917, 1028, 1029, 1103, 1116-1124. morphology of the VPCs may be uniform (monomorphic) or
multiform (polymorphic) as shown in Fig. 9.60E. The relation- Ventricular Tachycardia

ship of a ventricular extrasystole to the preceding sinus QRS-T Ventricular tachycardia (VT) is an ectopic ventricular rhythm
is expressed by the “coupling interval” between them. Often the characterized by three or more repetitive or linked VPCs
coupling interval is fixed, although it may vary minimally1120 either at a regular or irregular ventricular rate (see Figs. 9.60
or markedly. A very short coupling interval may place the and 9.61).68 Ventricular tachycardia is recognized clinically by
ectopic QRS on the preceding T wave, a phenomenon called an increased HR, often exceeding 100 beats/min. Auscultation
“R-on-T” and related to increased ventricular vulnerability for of VT is often characterized by a regular rhythm, with variable
fibrillation. Horses with repetitive ectopic activity with short intensity and often booming heart sounds. Lack of discern-
coupling intervals are therefore considered at a higher risk of ible rhythm irregularity on auscultation may cause the pos-
collapse or sudden cardiac death.68 sible existence of VT to be overlooked. Because of intermittent
Ventricular premature complexes are generally considered aortic valve opening, the rhythm can also sound irregular on
abnormal, except for possibly those occurring immediately auscultation, and an intermittent pulse deficit could be pres-
after exercise (see Exercise Testing earlier in this chapter).* ent. Arterial pulses are typically weak or variable in intensity.
However, ventricular ectopy was identified in 14% of clinically Multiform VT is characterized by an irregular rhythm (see
normal horses during routine 24-hour continuous electrocar- Fig. 9.60E). With multiform ventricular tachycardia, heart
diographic monitoring.400 The distributional pattern of ven- sounds are more likely to vary in intensity, and arterial pulses
tricular ectopic beats may include haphazard distribution of are likely to be abnormal. Jugular pulsations may be detected
single complexes, bigeminy (VPCs following normal beats in due to AV dissociation. Syncope is associated with higher
an alternating pattern), couplets (pairs of VPCs), triplets, or rates of ventricular tachycardia (180 beats/min or higher).
runs (four or more) of ventricular ectopic beats. Runs of accel- Respiratory distress and pulmonary edema may develop from
erated idioventricular rhythm (see earlier discussion), usually impaired ventricular function. Protracted junctional or ven-
developing at relatively slow HRs, are not uncommon. Runs of tricular tachycardias (greater than 120 beats/min) may lead
ventricular ectopic beats at a rapid rate—ventricular tachycar- to CHF due to reversible myocardial failure (tachycardia-
dia—are more likely to be hemodynamically and electrically induced cardiomyopathy).149 Torsades de pointes represents a
unstable, particularly when they develop at rates higher than specific form of polymorphic ventricular tachycardia, charac-
100 beats/min (see later discussion). terized by progressive changes in QRS direction leading to a
When premature beats are identified by auscultation, an steady undulation in the QRS axis (see Fig. 9.61). Ventricular
ECG should be obtained, and a workup similar to that out- tachycardias can progress to ventricular flutter and ventricu-
lined in Box 9.4 should be undertaken. Occasional premature lar fibrillation, characterized by chaotic ventricular activation
ventricular complexes, as with occasional supraventricular patterns leading to uncoordinated undulations of the electri-
premature complexes, may be clinically irrelevant and do cal baseline. These rhythms often represent terminal rhythms
not require treatment. Occasional monomorphic VPCs over- and usually result in cardiac arrest (see Fig. 9.61).
driven with exercise or only detected in the immediate postex- Ventricular tachycardia may be life threatening, and in
ercise period are not usually a cause of poor performance, but general, the following are features of complex or potentially
the importance of these arrhythmias and the risk of sudden “malignant” ventricular arrhythmias: severe hemodynamic
cardiac death requires further investigation.68 VPCs occurring compromise (systemic hypotension, poor pulse quality, pro-
during exercise are more concerning, although their relation- longed capillary refill time, weakness, collapse), sustained
ship with poor performance is also uncertain and requires VT, rapid ventricular rate (greater than 120 beats/min), short
further investigation. Generally, horses with occasional VPCs coupling intervals (particularly with R-on-T complexes),
at rest or during exercise can be used with caution by an and multiform or polymorphic QRS morphology (including
informed adult. However, because of concerns about under- torsades de pointes).68 Immediate treatment of CV collapse
lying myocardial or electrical disease and increased risks of may be required.1027 Intravenous therapies for VT include
exercise-associated collapse and sudden cardiac death, these lidocaine, procainamide, quinidine, magnesium salts, and
horses should not be used by a child or as a lesson horse.68 amiodarone (see Table 9.7). Administration of antiarrhyth-
Rest is highly recommended for horses with frequent ven- mic drugs can be associated with adverse effects, including
tricular premature complexes. In the majority of horses with proarrhythmia, seizures, and sudden death. Lidocaine, if
premature ventricular complexes occurring in the absence of administered too fast or at doses exceeding the recommended
significant structural heart disease, the arrhythmia seems to therapeutic doses, causes central nervous system excitation,
resolve spontaneously after 4 to 8 weeks of rest. The horse may but boluses and infusions can be well tolerated in horses, and
then be able to return successfully to its prior performance the drug causes minimal hemodynamic or electrophysiologic
level. Antiarrhythmic therapy (see Table 9.7) is usually suc- alterations at therapeutic, nontoxic doses.* Quinidine may be
cessful in abolishing ventricular premature complexes, but used for treatment of ventricular arrhythmias but is a myo-
most return when the antiarrhythmic agent is discontinued, cardial depressant and vagolytic drug.55,153,327,328,1082 Procain-
unless the underlying problem has been resolved. Chronic amide55,327,328,1095 has been studied to a limited degree but is
administration is usually not practical. Dexamethasone and generally well tolerated when given in graded doses. It has
other antiinflammatory drugs have been used to treat ven- similar electrophysiologic effects to quinidine but seems less
tricular arrhythmias, particularly in the presence of myocar- vagolytic and possibly has fewer gastrointestinal side effects.
dial damage as demonstrated by increased plasma troponin Cumulative doses of up to 10 mg/kg are generally well tol-
concentrations, but their use is controversial and they should erated; additional dosing should be guided by ECG, QRS
certainly not be administered to horses with a recent or cur- duration, and arterial BP. Magnesium sulfate is an alternative
rent infection.68 antiarrhythmic that can be effective in both normomagnesemic
* References 54, 77-80, 82, 90, 475, 478, 479. * References 55, 327, 328, 797, 798, 1126, 1127.
and hypomagnesemic horses and is generally well tolerated at third-degree (or complete) block. First-degree AV block occurs
therapeutic doses.55,1128 Amiodarone has been evaluated in a when the PR (or PQ) interval exceeds a certain value (approxi-
small number of horses1100,1101,1124 and can be considered as a mately 400–450 msec in large-breed horses and 250–350 msec
second-line drug for serious, drug-resistant VT. Other antiin small breeds and ponies; see Fig. 9.16) while the atrial
arrhythmics, including propafenone,1111 or phenytoin916,1129-1131 impulse still transmits through the AV conduction system and
may be tried in refractory ventricular arrhythmias. The use of activates the ventricle, causing a QRS complex. Some P waves
steroids in horses with ventricular tachycardia is empiric and are not conducted to the ventricles during second-degree AV
controversial but may be indicated if there is evidence of acute block, which results in occasional P waves not followed by a
myocardial damage in the absence of a recent or current infec- QRS-T complex (see Fig. 9.62A).* Second-degree AV block
tion (see earlier discussion).68 following progressive prolongation of the PQ interval is classi-
A substantial number of horses suffering from VT can be fied as Mobitz type I (Wenckebach) block. Conversely, the AV
successfully returned to performance after treatment with block is termed Mobitz type II if the PQ interval is constant.
antiarrhythmics and rest, as long as there is not significant Occurrence of two or more consecutive second-degree AV
and untreatable structural heart disease evident. A period blocks in the presence of a normal or slow sinoatrial rate is
of rest (4–8 weeks) followed by echocardiographic and elec- termed high-grade (advanced) AV block.68, 1151 Third-degree or
trocardiographic reevaluation (including a 24-hour Holter complete AV block is characterized by an absence of atrial to
ECG) once sinus rhythm is restored is indicated for horses ventricular conduction. P waves are not followed by or related
with sustained VT.68 An exercising ECG should be performed to QRS complexes, and to prevent ventricular asystole a junc-
before the horse may be returned to normal work, if the pre- tional or ventricular escape rhythm must develop below the
ceding echocardiogram and the 24-hour Holter ECG are nor- level of the AV block (see Fig. 9.62B).1092,1138,1141
mal; another exercising ECG should be performed once the First- and second-degree AV blocks are considered nor-
horse has returned to full work.68 Horses diagnosed with a mal variations. These rhythms are most often associated with
single episode of sustained monomorphic VT generally have a high vagal tone and may be seen with sinus bradycardia or
favorable prognosis, although recurrent VT is possible.68 The sinus arrhythmia. Auscultation is characterized by an irregu-
safety of horses with a history of symptomatic or complex VA lar rhythm with a repetitive pattern. In some horses, fourth
remains uncertain, and these horses should only be used by an (atrial) heart sounds that are not followed by first and second
informed adult. Strenuous athletic work is not recommended heart sounds are audible within the pauses, allowing a defini-
for horses that showed VA in the setting of moderate or severe tive diagnosis without ECG.3,68,72,381,383,384,388 Second-degree
structural heart disease, including myocardial fibrosis or scar AV block can usually be abolished with exercise, stress, or
and moderate to severe AR. These horses should only be rid- vagolytic drugs such as atropine or glycopyrrolate (though
den or driven by an informed adult because of the risk of pos- exercise is preferred and drugs are rarely needed).1132,1152 Note
sible recurrence of VT. These horses are not safe for use by that the AV blocks are likely to resume quickly after exercise.
a child or as a lesson horse. For horses with a history of VT High-grade (advanced) and third-degree AV blocks are
that remain in work follow-up 24-hour and exercising ECGs considered abnormal, and high-grade AV block may pro
should be performed at least annually.68 gress into complete AV block over time. They are indicative of
organic heart disease, severe drug toxicity, or abnormally high
Conduction Disturbances vagal activity. An exercising ECG should be performed if pos-
Once a cardiac electrical impulse is formed, it is conducted sible to evaluate the degree of contribution of high vagal tone.
rapidly throughout the heart. The sequence of cardiac electric A continuous 24-hour Holter ECG with simultaneous video
activation is usually dictated by the specialized conducting tis- recording should be obtained when there is a history of col-
sues in the atria, the AV node, the bundle of His, the bundle lapse.68 Horses with high-grade AV block that disappears with
branches, and the Purkinje fiber system (see Fig. 9.3). This exercise should only be used by an informed adult, and the
conduction system permits orderly activation of atrial and HR and heart rhythm should be frequently monitored. Horses
ventricular muscle and facilitates effective mechanical activ- with high-grade AVB that persists during exercise or after
ity of the heart.57,110,112-115,220 A variety of conduction disorders atropine administration should be rested and reevaluated;
are recognized, including SA nodal exit block, atrial stand- they are considered less safe to use than their age-matched
still (usually resulting from hyperkalemia), AV block, bundle peers. Horses with symptomatic bradyarrhythmias generally
branch block, and ill-defined ventricular conduction distur- have a poor prognosis and are not safe to use.68
bances (Figs. 9.62 and 9.63).* Sudden development of high-grade or complete AV block
Rarely, accelerated conduction occurs in the heart, which may require the administration of atropine or a catecholamine
involves a pathway around the normally slow-conducting AV or temporary transvenous pacing. Chronic third-degree AV
node and results in early excitation of the ventricles.1069,1147 block requires treatment with a permanent pacemaker. Pace-
These syndromes are termed preexcitation and have various makers have been successfully placed epicardially and trans-
associated labels related to similar human disorders (e.g., venously in several horses and in a number of Miniature
Wolff-Parkinson-White). A shortened P-R interval is typically Donkeys with possible congenital complete AV block (Fig.
found. 9.64; see also Fig. 9.62C).198,1134,1153-1156
Atrioventricular Conduction Block Intraventricular Conduction Blocks

Delays in AV conduction are the most common conduc- Intraventricular conduction blocks, such as bundle branch
tion blocks. These delays are classified as first-, second-, and block, are less common and more difficult to diagnose. Wid-
ening of the QRS complex and axis deviation are typical
* References 43, 60, 198, 215, 220, 223, 224, 226, 240, 383, 488, 525, 1028, 1033,
1092, 1132-1146. * References 43, 226, 487, 525, 541, 1028, 1133, 1135, 1137, 1140, 1148-1150.
FIG. 9.62 Conduction disturbances. A, Second-degree atrioventricular block. Nonconducted P waves and
varying P-R intervals are evident (base-apex lead recorded at 25 mm/sec). B, The tracings are from a horse
with third-degree atrioventricular block. The upper strip demonstrates multiple blocked P waves. The lower
tracing shows nonconducted P waves and ventricular escape complexes (base-apex lead recorded at 25
mm/sec). C, Permanent transvenous ventricular pacing in a Miniature Donkey with a complete atrioventricu-
lar block. A pacemaker spike (arrow) precedes each paced ventricular complex.
features (see Fig. 9.63B).1133,1136 As opposed to ventricular explain the high number of complexes currently classified as
premature beats, the aberrantly conducted QRS complex VPCs recorded on exercise ECGs,54,77-80,82,90,479 because dif-
is preceded by a P wave. These abnormalities may also be ferentiation between ventricular ectopic beats and aberrantly
found after atrial premature complexes, from overdosage conducted beats originating from the sinus node is very dif-
with quinidine sulfate, from severe hyperkalemia, or second- ficult and often impossible at high HRs, when distinct P waves
ary to supraventricular tachycardias with rapid ventricular are not present and motion artifacts hamper interpretation of
response. the ECG.
A recent study indicated a high prevalence of QRS broaden-
ing in horses with AF during exercise and suggested that QRS Preexcitation
broadening may originate from ventricular ectopic foci or Ventricular preexcitation, or accelerated AV conduction, in
from aberrant intraventricular conduction due, for example, humans and in dogs is often due to an anomalous conduct-
to bundle branch block.472 In fact, intraventricular conduc- ing pathway around the AV node, which serves as a path
tion blocks leading to aberrant ventricular conduction might for reentrant supraventricular tachycardias. These rhythm
FIG. 9.63 Conduction disturbances. A, Ventricular preexcitation. The short P-R interval (arrow) and small
deflection in the PR segment (delta wave) indicate an accessory pathway around the atrioventricular node
with premature activation of a portion of the ventricle (delta wave and initial portion of the QRS). The large
QRS and secondary T wave changes can be explained by the loss of normal cancellation of ventricular
electrical forces. B, A sinus arrhythmia and intraventricular conduction disturbance. The sudden change and
widening of the ventricular conduction pattern are notable, despite the consistent P-R interval and probably
represent a bundle branch block, although this diagnosis is difficult to make in horses (base-apex lead re-
corded at 25 mm/sec). C, Hyperkalemia in a foal with a ruptured bladder. The top strip demonstrates atrial
standstill (no P waves), significant widening of the QRS complexes, and large T waves with a shortened ST
segment. The lower tracing shows the effects after initial medical therapy for hyperkalemia, which included
treatment with saline and sodium bicarbonate. The normalization of the QRS complexes and the appearance
of low-amplitude P waves (arrows) are notable. (Tracing courtesy of Ron Hilwig, DVM, PhD.)
disturbances may cause hypotension and syncope. Whether Hyperkalemia

preexcitation syndromes are important in horses has yet Hyperkalemia can cause significant depression of atrial, AV,
to be determined. Nevertheless, ECG traces occasionally and ventricular conduction and can shorten ventricular repo-
show evidence of ventricular preexcitation and are charac- larization. Serum potassium is most likely to be markedly
terized by a P-QRS-T relationship but with an extremely elevated in foals with ruptured bladder or ureter and uro-
short PR interval, early excitation of the ventricle charac- peritoneum, following renal failure oliguria, during shock,
terized by a slurring of the initial QRS complex (a delta with severe metabolic acidosis, or after excessive intravenous
wave), and an overall widening of the QRS complex (see potassium replacement.226,1143-1146 Hyperkalemia also occurs in
Fig. 9.63A).1069,1147,1157 Quarter Horses with hyperkalemic periodic paralysis.1158,1159
is adequate) at a dose of 1 to 2 mEq/kg IV over 15 minutes or

depending on the base excess obtained by blood gas analyses
(mEq Na bicarbonate = 0.3 [−0.5] × BE × kg of body weight).
However, in the absence of severe acidosis, the use of sodium
bicarbonate is not recommended because of the associated
risks of sodium and fluid overload1160,1161 and its effect to lower
ionized calcium concentrations that might further destabilize
the rhythm. In cases of severe arrhythmias with QRS broaden-
ing, 0.2 to 0.4 mL/kg calcium gluconate 23% can be adminis-
tered over a 10-minute period to effect to stabilize the resting
cardiac membrane potential.
REFERENCES
1. Detweiler DK. Electrocardiogram of the horse. Fed Proc.
1952;11:34.
2. Detweiler DK. Auricular fibrillation in horses. J Am Vet Med
Assoc. 1955;126:47.
FIG. 9.64 A lateral radiograph of a permanent transvenous pacing sys- 3. Patterson DF, Detweiler DK, Glendenning SA. Heart sounds and
tem in a Miniature Donkey. The pacemaker is evident at the upper left of murmurs of the normal horse. Ann N Y Acad Sci. 1965;127:242.
the radiograph. The thin transvenous pacing wire extends from the device 4. Detweiler DK, Patterson DF. The cardiovascular system. In:
through the jugular vein and vena cava and into the right ventricular (RV) Catcott EJ, Smithcors JF, eds. Equine medicine and surgery.
apex. Santa Barbara: American Veterinary Publications; 1972.
5. Bishop SP, Cole CR, Smetzer DL. Functional and morphologic
pathology of equine aortic insufficiency. Pathol Vet. 1966;3:137.
Alterations in the ECG are usually evident at serum potas- 6. Hamlin RL, Smetzer DL, Smith CR. Analysis of QRS complex
sium concentrations greater than 6 mEq/L, with severe changes recorded through a semiorthogonal lead system in the horse.
evident when serum concentrations are between 8 and 10 Am J Physiol. 1964;207:325.
mEq/L. Broadening and flattening of the P wave are the most 7. Hamlin RL, Smith CR. Categorization of common domestic
consistently observed change. Prolongation of the PQ inter- mammels based on their ventricular activation process. Ann N
val and bradycardia develop, excitability decreases, and atrial Y Acad Sci. 1965;127:195.
standstill (sinoventricular rhythm) characterized by com- 8. Hamlin RL, Smetzer DL, Senta T, et al. Atrial activation paths
plete absence of P waves may be observed. Either inversion and P waves in horses. Am J Physiol. 1970;219:306.
or enlargement (tenting) of the T waves is also likely. Marked 9. Hamlin RL, Klepinger WL, Gilpin KW, et al. Autonomic con-
trol of heart rate in the horse. Am J Physiol. 1972;222:976.
widening of the QRS complex may be noted as near-lethal
10. Hamlin RL, Levesque MJ, Kittleson MD. Intramyocardial
concentrations of potassium are approached (see Fig. 9.63C). pressure and distribution of coronary blood flow during sys-
Ventricular asystole or fibrillation can develop. The QT interval tole and diastole in the horse. Cardiovasc Res. 1982;16:256.
is not a reliable indicator of induced hyperkalemia, and other 11. Illera JC, Illera M, Hamlin RL. Unipolar thoracic electrocar-
electrolyte and acid-base alterations, including serum calcium diography that induces QRS complexes of relative uniformity
and sodium concentrations, influence the effect of hyperkale- from male horses. Am J Vet Res. 1987;48:1700.
mia on the heart. 12. McKeever KH, Hinchcliff KW, Reed SM, et al. Splenectomy al-
Therapy for hyperkalemia includes correction of the under- ters blood pressure response to incremental treadmill exercise
lying problem; infusion of isotonic crystalloid solutions, dex- in horses. Am J Physiol. 1993;265:R409.
trose, and insulin; and possibly administration of β2 agonists, 13. Pipers FS, Hamlin RL. Echocardiography in the horse. J Am
Vet Med Assoc. 1977;170:815.
calcium salts, and sodium bicarbonate. Lactated Ringer’s
14. Pipers FS, Hamlin RL, Reef V. Echocardiographic detection
solution (LRS; 10–40 mL/kg/hr IV) can be used in patients of cardiovascular lesions in the horse. J Equine Med Surg.
with hyperkalemia. The small amount of potassium contained 1979;3:68.
in LRS is generally not considered problematic, as the ben- 15. Senta T, Smetzer DL, Smith CR. Effects of exercise on certain
eficial effects of volume replacement and treatment of meta- electrocardiographic parameters and cardiac arrhythmias in
bolic acidosis largely outweigh the potential negative effects the horse. A radiotelemetric study. Cornell Vet. 1970;60:552.
of additional potassium supply. Alternatively, NaCl or NaCl/ 16. Smetzer DL, Smith CR, Hamlin RL. The fourth heart sound in
dextrose solutions may be used, but maintenance solutions the equine. Ann N Y Acad Sci. 1965;127:306.
should not be used because of their relatively high potassium 17. Smetzer DL, Smith CR. Diastolic heart sounds of horses. J Am
content. Dextrose (or glucose) can be administered as a bolus Vet Med Assoc. 1965;146:937.
18. Smetzer DL, Bishop S, Smith CR. Diastolic murmur of equine
of 0.25 to 0.5 g/kg IV over 15 minutes. The administration of
aortic insufficiency. Am Heart J. 1966;72:488.
regular insulin (0.1 IU/kg) in conjunction with dextrose infu- 19. Smetzer DL, Hamlin RL, Smith CR. Cardiovascular sounds.
sion (0.5–1 g/kg IV over 15 minutes) should be considered in In: Swenson MJ, ed. Dukes’ Physiology of Domestic Animals.
cases of severe hyperkalemia and is considered most effective. Ithaca: Comstock Publishing Company, Inc; 1970.
β2-Adrenoceptor agonists (e.g., clenbuterol, albuterol/salbu- 20. Smith CR, Hamlin RL. Regulation of the heart and blood ves-
tamol) administered intravenously or by inhalation might sels. In: Swenson MJ, ed. Dukes’ Physiology of Domestic Ani-
augment the effects of intravenous insulin and glucose by pro- mals. Ithaca: Comstock Publishers; 1970.
moting potassium movement into cells,1160,1161 but this has not 21. Brown CM, Holmes JR. Haemodynamics in the horse: 2. In-
been investigated in horses. Sodium bicarbonate may be used tracardiac, pulmonary arterial and aortic pressures. Equine Vet
in cases of severe metabolic acidosis (provided that ventilation J. 1978;10:207.
22. Brown CM, Holmes JR. Haemodynamics in the horse: 1. Pres- 50. Voros K, Holmes JR, Gibbs C. Anatomical validation of two-
sure pulse contours. Equine Vet J. 1978;10:188. dimensional echocardiography in the horse. Equine Vet J.
23. Brown CM, Holmes JR. Phonocardiography in the horse. 1. 1990;22:392.
The intracardiac phonocardiogram. Equine Vet J. 1979;11: 51. Voros K, Holmes JR, Gibbs C. Measurement of cardiac dimen-
11. sions with two-dimensional echocardiography in the living
24. Brown CM, Holmes JR. Assessment of myocardial function in horse. Equine Vet J. 1991;23:461.
the horse. 2. Experimental findings in resting horses. Equine 52. Marr CM, Bowen M. Cardiology of the Horse. 2nd ed. Edin-
Vet J. 1979;11:248. burgh: Saunders Elsevier; 2010.
25. Brown CM, Holmes JR. Phonocardiography in the horse: 2. 53. Poole DC, Erickson HH. Heart and vessels: function during
The relationship of the external phonocardiogram to intracar- exercise and training adaptations. In: Hinchcliff KW, Kaneps
diac pressure and sound. Equine Vet J. 1979;11:183. AJ, Geor RJ, eds. Equine Sports Medicine and Surgery. Edin-
26. Brown CM, Holmes JR. Assessment of myocardial function in burgh: Saunders Elsevier; 2014.
the horse. 1. Theoretical and technical considerations. Equine 54. Young LE, van Loon G. Diseases of the heart and vessels. In:
Vet J. 1979;11:244. Hinchcliff KW, Kaneps AJ, Geor RJ, eds. Equine Sports Medi-
27. Else RW, Holmes JR. Cardiac pathology in the horse. III: clini- cine and Surgery. Edinburgh: W.B. Saunders; 2014.
cal correlations. Equine Vet J. 1972;4:195. 55. Schwarzwald CC. Cardiovascular pharmacology. In: Robinson
28. Else RW, Holmes JR. Cardiac pathology in the horse. 1. Gross NE, Sprayberry KA, eds. Current Therapy in Equine Medicine
pathology. Equine Vet J. 1972;4:1. 6. St. Louis: Saunders Elsevier; 2009.
29. Else RW, Holmes JR. Cardiac pathology in the horse. II: mi- 56. Schwarzwald CC. Ultrasonography of the heart. In: Kidd
croscopic pathology. Equine Vet J. 1972;4:57. JA, Lu KG, Frazer ML, eds. Atlas of Equine Ultrasonography.
30. Gattland L, Holmes JR. ECG recording at rest and during exer- Chichester, UK: John Wiley & Sons, Ltd; 2014.
cise in the horse. Equine Vet Educ. 1990;2:28. 57. Schwarzwald CC, Bonagura JD, Muir III WW. The cardiovas-
31. Hillyer MH, Mair TS, Holmes JR. Treatment of bacterial endo- cular system. In: Muir III WW, Hubbell JAE, eds. Equine Anes-
carditis in a Shire mare. Equine Vet Educ. 1990;2:5. thesia: Monitoring and Emergency Therapy. St. Louis: Saunders
32. Holmes JR. The equine heart: problems and difficulties in as- Elsevier; 2009.
sessing cardiac function on clinical examination. Equine Vet J. 58. Jesty SA. Cardiovascular system. In: Divers TJ, ed. Equine
1968;1:10. Emergencies. St. Louis: W.B. Saunders; 2014.
33. Holmes JR, Darke PGG, Else RW. Atrial fibrillation in the 59. Bonagura JD. Congenital heart disease. In: Robinson NE, ed.
horse. Equine Vet J. 1969;1:212. Current Therapy in Equine Medicine 5. St. Louis: W.B. Saun-
34. Holmes JR, Rezakhani A, Else RW. Rupture of a dissecting ders; 2003.
aortic aneurysm into the left pulmonary artery in a horse. 60. Bowen IM. Cardiac dysrhythmias. In: Robinson NE, ed. Cur-
Equine Vet J. 1973;5:65. rent Therapy in Equine Medicine 5. St. Louis: W.B. Saunders;
35. Holmes JR, Rezakhani A. Observations on the T wave of the 2003.
equine electrocardiogram. Equine Vet J. 1975;7:55. 61. Durando MM. Evaluation of cardiovascular function in the
36. Holmes JR. Prognosis of equine cardiac conditions. Equine Vet performance horse. In: Robinson NE, ed. Current Therapy in
J. 1977;9:181. Equine Medicine 5. St. Louis: W.B. Saunders; 2003.
37. Holmes JR. Sir Frederick Smith Memorial Lecture. A superb 62. Durando MM, Young LE. Cardiovascular examination and di-
transport system—the circulation. Equine Vet J. 1982;14:267. agnostic techniques. In: Robinson NE, ed. Current Therapy in
38. Holmes JR, Miller PJ. Three cases of ruptured mitral valve Equine Medicine 5. St. Louis: W.B. Saunders; 2003.
chordae in the horse. Equine Vet J. 1984;16:125. 63. Leroux A. Aortic root disease. In: Robinson NE, ed. Cur-
39. Holmes JR, Henigan M, Williams RB, et al. Paroxysmal atrial rent Therapy in Equine Medicine 5. St. Louis: W.B. Saunders;
fibrillation in racehorses. Equine Vet J. 1986;18:37. 2003.
40. Holmes JR. Electrocardiography in the diagnosis of common 64. Leroux A. Vascular diseases. In: Robinson NE, ed. Current
cardiac arrythmias in the horse. Equine Vet Educ. 1990;2:24. Therapy in Equine Medicine 5. St. Louis: W.B. Saunders;
41. Holmes JR. The development of clinical cardiology. Equine Vet 2003.
J Suppl. 1995;2. 65. Reef VB. Acquired valvular heart disease. In: Robinson NE, ed.
42. Miller PJ, Holmes JR. Effect of cardiac arrhythmia on left ven- Current Therapy in Equine Medicine 5. St. Louis: W.B. Saun-
tricular and aortic blood pressure parameters in the horse. Res ders; 2003.
Vet Sci. 1983;35:190. 66. Sleeper MM. Myocardial disease. In: Robinson NE, ed. Current
43. Miller PJ, Holmes JR. Beat-to-beat variability in QRS poten- Therapy in Equine Medicine 5. St. Louis: W.B. Saunders; 2003.
tials recorded with an orthogonal lead system in horses with 67. Sleeper MM. Acquired pericardial disease. In: Robinson NE,
second degree partial A-V block. Res Vet Sci. 1984;37:334. ed. Current Therapy in Equine Medicine 5. St. Louis: W.B. Saun-
44. Miller PJ, Holmes JR. Interrelationship of some electrocardio- ders; 2003.
gram amplitudes, time intervals and respiration in the horse. 68. Reef VB, Bonagura J, Buhl R, et al. Recommendations for
Res Vet Sci. 1984;36:370. management of equine athletes with cardiovascular abnor-
45. Miller PJ, Holmes JR. Observations on structure and function malities. J Vet Intern Med. 2014;28:749.
of the equine mitral valve. Equine Vet J. 1984;16:457. 69. Kriz NG, Hodgson DR, Rose RJ. Prevalence and clinical im-
46. Miller PJ, Holmes JR. Relationships of left side systolic time portance of heart murmurs in racehorses. J Am Vet Med Assoc.
intervals to beat-by-beat heart-rate and blood pressure vari- 2000;216:1441.
ables in some cardiac arrhythmias of the horse. Res Vet Sci. 70. Lightfoot G, Jose-Cunilleras E, Rogers K, et al. An echocar-
1984;37:18. diographic and auscultation study of right heart responses to
47. Miller PJ, Holmes JR. Computer processing of transaortic training in young national hunt thoroughbred horses. Equine
valve blood pressures in the horse using the first derivative of Vet J Suppl. 2006;153.
the left ventricular pressure trace. Equine Vet J. 1984;16:210. 71. Marr CM, Reef VB. Physiological valvular regurgitation in
48. Miller PJ, Holmes JR. Observations on seven cases of mitral clinically normal young racehorses: prevalence and two-di-
insufficiency in the horse. Equine Vet J. 1985;17:181. mensional colour flow Doppler echocardiographic character-
49. Voros K, Holmes JR, Gibbs C. Left ventricular volume deter- istics. Equine Vet J Suppl. 1995;56.
mination in the horse by two- dimensional echocardiography: 72. Patteson MW, Cripps PJ. A survey of cardiac auscultatory
an in vitro study. Equine Vet J. 1990;22:398. findings in horses. Equine Vet J. 1993;25:409.
73. Reef VB. The significance of cardiac auscultatory findings 98. Lucke VM. Sudden death (editorial). Equine Vet J. 1987;19:85.
in horses—insight into the age-old dilemma. Equine Vet J. 99. Brown CM, Kaneene JB, Taylor RF. Sudden and unexpected
1993;25:393. death in horses and ponies: an analysis of 200 cases. Equine Vet
74. Young LE, Rogers K, Wood JL. Heart murmurs and valvu- J. 1988;20:99.
lar regurgitation in thoroughbred racehorses: epidemiology 100. Allen JR, Heidel JR, Hodgson DR, et al. Spontaneous rupture
and associations with athletic performance. J Vet Intern Med. of the great coronary vein in a pony. Equine Vet J. 1987;19:145.
2008;22:418. 101. Leblond A, Villard I, Leblond L, et al. A retrospective evalu-
75. Young LE, Wood JL. Effect of age and training on murmurs ation of the causes of death of 448 insured French horses in
of atrioventricular valvular regurgitation in young thorough- 1995. Vet Res Commun. 2000;24:85.
breds. Equine Vet J. 2000;32:195. 102. Schiff P, Knottenbelt DC. Sudden death in a 11-year-old Thor-
76. Zucca E, Ferrucci F, Stancari G, et al. The prevalence of car- oughbred stallion. Equine Vet Educ. 1990;2:8.
diac murmurs among Standardbred racehorses presented with 103. Boden LA, Charles JA, Slocombe RF, et al. Sudden death in
poor performance. J Vet Med Sci. 2010;72:781. racing Thoroughbreds in Victoria, Australia. Equine Vet J.
77. Barbesgaard L, Buhl R, Meldgaard C. Prevalence of exercise- 2005;37:269.
associated arrhythmias in normal performing dressage horses. 104. Navas de Solis C. Exercising arrhythmias and sudden cardiac
Equine Vet J. 2010;42:202. death in horses: review of the literature and comparative as-
78. Buhl R, Meldgaard C, Barbesgaard L. Cardiac arrhythmi- pects. Equine Vet J. 2016;48:406.
as in clinically healthy showjumping horses. Equine Vet J. 105. Lyle CH, Blissitt KJ, Kennedy RN, et al. Risk factors for race-
2010;42:196. associated sudden death in Thoroughbred racehorses in the
79. Buhl R, Petersen EE, Lindholm M, et al. Cardiac arrhythmias UK (2000-2007). Equine Vet J. 2012;44:459.
in Standardbreds during and after racing-possible association 106. Lyle CH, Uzal FA, McGorum BC, et al. Sudden death in racing
between heart size, valvular regurgitations, and arrhythmias. J Thoroughbred horses: an international multicentre study of
Equine Vet Sci. 2013;33:590. post mortem findings. Equine Vet J. 2011;43:324.
80. Jose-Cunilleras E, Young LE, Newton JR, et al. Cardiac arrhyth- 107. Sisson S, Grossman JD. Anatomy of the Domestic Animals. 4th
mias during and after treadmill exercise in poorly performing ed. Philadelphia: W.B. Saunders; 1953.
thoroughbred racehorses. Equine Vet J Suppl. 2006;163. 108. Geddes LA, Hoff HE, McCrady JD. Some aspects of the car-
81. Morgan RA, Raftery AG, Cripps P, et al. The prevalence and diovascular physiology of the horse. [Baylor Univ College of
nature of cardiac arrhythmias in horses following general an- Medicine] Cardiovascular Res Center Bull. 1965;3:80.
aesthesia and surgery. Acta Vet Scand. 2011;53:62. 109. Schummer A, Wilkens H, Vollmerhaus B, et al. The circulatory
82. Slack J, Boston RC, Soma LR, et al. Occurrence of car- system, the skin, and the cutaneous organs of the domestic mam-
diac arrhythmias in Standardbred racehorses. Equine Vet J. mals, the anatomy of the domestic animals. In: Nickel R, Schum-
2015;47:398. mer A, Seiferle E, eds. vol. 3. Berlin: Verlag Paul Parey; 1981.
83. Leroux AA, Detilleux J, Sandersen CF, et al. Prevalence and risk 110. Berne RM, Levy MN. Cardiovascular Physiology. 8th ed. St.
factors for cardiac diseases in a hospital-based population of Louis: C.V. Mosby; 2001.
3,434 horses (1994–2011). J Vet Intern Med. 2013;27:1563. 111. Dyce KM, Sack WO, Wensing CJG. The cardiovascular sys-
84. Deem DA, Fregin GF. Atrial fibrillation in horses: a review of tem. In: Dyce KM, Sack WO, Wensing CJG, eds. Textbook of
106 clinical cases, with consideration of prevalence, clinical Veterinary Anatomy. Philadelphia: Elsevier Saunders; 2002.
signs, and prognosis. J Am Vet Med Assoc. 1982;180:261. 112. Opie LH. Heart Physiology: From Cell to Circulation. Philadel-
85. Baker JR, Ellis CE. A survey of post mortem findings in phia: Lippincott Williams & Wilkins; 2004.
480 horses 1958 to 1980: (1) causes of death. Equine Vet J. 113. Katz AM. Physiology of the Heart. 5th ed. Philadelphia: Wolters
1981;13:43. Kluwer; 2010.
86. Pipers FS. Applications of diagnostic ultrasound in veterinary 114. Klabunde RE. Cardiovascular Physiology Concepts. 2nd ed.
medicine. Equine Vet J. 1982;14:341. Philadelphia, PA: Lippincott Williams & Wilkins/Wolters Klu-
87. Morris EA, Seeherman HJ. Clinical evaluation of poor perfor- wer; 2012.
mance in the racehorse: the results of 275 evaluations. Equine 115. Hall JE. The heart. In: Hall JE, ed. Guyton and Hall: Textbook of
Vet J. 1991;23:169. Medical Physiology. Philadelphia: Saunders Elsevier; 2016.
88. Mitten LA. Cardiovascular causes of exercise intolerance. Vet 116. Hall JE. The circulation. In: Hall JE, ed. Guyton and Hall: Text-
Clin North Am Equine Pract. 1996;12:473. Book of Medical Physiology. Philadelphia: Saunders Elsevier;
89. Reef VB. Clinical approach to poor performance in horses. 2016.
Proc Am Coll Vet Internal Med San Diego. 1989;566. 117. Lilly LS. Pathyophysiology of Heart Disease. 6th ed. Philadel-
90. Martin Jr BB, Reef VB, Parente EJ, et al. Causes of poor perfor- phia, PA: Wolters Kluwer; 2016.
mance of horses during training, racing, or showing: 348 cases 118. Muir WW, Hubbell JAE. Cardiopulmonary resuscitation. In:
(1992-1996). J Am Vet Med Assoc. 2000;216:554. Muir WW, Hubbell JAE, eds. Equine Anesthesia—Monitoring
91. Cronin MTL, Leader GH. Coronary occlusion in a thorough- and Emergency Therapy. St. Louis: Saunders Elsevier; 2009.
bred colt. Vet Rec. 1952;64:8. 119. Rainey JW. A specific arthritis with pericarditis affecting
92. Rooney JR, Prickett ME, Crowe MW. Aortic ring rupture in young horses in Tasmania. Aust Vet J. 1944;20:204.
stallions. Pathol Vet. 1967;4:268. 120. Ryan AF, Rainey JW. A specific arthritis with pericarditis af-
93. Pascoe RR, O’Sullivan BM. Sudden death in a Thoroughbred fecting horses in Tasmania. Aust Vet J. 1945;21:146.
stallion. Equine Vet J. 1980;12:211. 121. Wagner P, Miller R, Merritt F, et al. Constrictive pericarditis in
94. Platt H. Sudden and unexpected deaths in horses: a review of the horse. J Equine Med Surg. 1977;1:242.
69 cases. Br Vet J. 1982;138:417. 122. Reef VB. Advances in echocardiography. Vet Clin North Am
95. Hughes PE, Howard EB. Endocardial fibroelastosis as a cause Equine Pract. 1991;7:435.
of sudden death in the horse. Equine Pract. 1984;6:23. 123. Rantanen NW. Diseases of the heart. Vet Clin North Am
96. Gelberg HB, Zachary JF, Everitt JI, et al. Sudden death in Equine Pract. 1986;2:33.
training and racing Thoroughbred horses. J Am Vet Med As- 124. Marr CM. Equine echocardiography—sound advice at the
soc. 1985;187:1354. heart of the matter. Br Vet J. 1994;150:527.
97. Kiryu K, Nakamura T, Kaneko M, et al. Cardiopathology of 125. Hardy J, Robertson JT, Reed SM. Constrictive pericarditis in a
sudden cardiac death in the race horse. Heart Vessels Suppl. mare: attempted treatment by partial pericardiectomy. Equine
1987;2:40. Vet J. 1992;24:151.
126. Freestone JF, Thomas WP, Carlson GP, et al. Idiopathic effu- 151. Fregin GF. The cardiovascular system. In: Mansmann RA,
sive pericarditis with tamponade in the horse. Equine Vet J. McCallister ES, Pratt PW, eds. Equine Medicine and Surgery.
1987;19:38. Santa Barbara: American Veterinary Publications Inc; 1982.
127. Dill SG, Simoncini DC, Bolton GR, et al. Fibrinous pericarditis 152. Bonagura JD. Equine heart disease. An overview. Vet Clin
in the horse. J Am Vet Med Assoc. 1982;180:266. North Am Equine Pract. 1985;1:267.
128. Carnine BL, Schneider G, Cook JE, et al. Pericardial mesothe- 153. Stern JA, Reina Doreste Y, Barnett S, et al. Resolution of sus-
lioma in a horse. Vet Pathol. 1977;14:513. tained narrow complex ventricular tachycardia and tachycar-
129. Bonagura JD, Herring DS, Welker F. Echocardiography. Vet dia-induced cardiomyopathy in a Quarter Horse following
Clin North Am Equine Pract. 1985;1:311. quinidine therapy. J Vet Cardiol. 2012;14(3):445–451.
130. Bonagura JD, Blissitt KJ. Echocardiography. Equine Vet J Sup- 154. Doonan GR, Brown CM, Mullaney TP, et al. Monensin
pl. 1995;5. poisoning in horses—an international incident. Can Vet J.
131. Birks EK, Hultgren BD. Pericardial haemangiosarcoma in a 1989;30:165.
horse. J Comp Pathol. 1988;99:105. 155. Mollenhauer HH, Rowe LD, Witzel DA. Effect of monensin on
132. Wijnberg ID, Vink-Nooteboom M, Sloet van Oldruiten- the morphology of mitochondria in rodent and equine striated
borgh-Oosterbaan MM. Idiopathic pericardial effusion with muscle. Vet Hum Toxicol. 1984;26:15.
tamponade in a Friesian gelding. Tijdschr Diergeneeskd. 156. Amend JF, Mallon FM, Wren WB, et al. Equine monensin
1997;122:216. toxicosis: some experimental clinicopathologic observations.
133. Worth LT, Reef VB. Pericarditis in horses: 18 cases (1986- Compend Cont Educ Pract Vet. 1980;2:S172.
1995). J Am Vet Med Assoc. 1998;212:248. 157. Amend JF, Nichelson RL, Freeland LR, et al. Clinical toxi-
134. Bolin DC, Donahue JM, Vickers ML, et al. Microbiologic and cology of an antibiotic ionophore (monensin) in ponies and
pathologic findings in an epidemic of equine pericarditis. J Vet horses; diagnostic markers and therapeutic considerations. In:
Diagn Invest. 2005;17:38. Miert ASJPAMV, Bogaert MG, Debackere M, eds. Compara-
135. Perkins SL, Magdesian KG, Thomas WP, et al. Pericarditis and tive Veterinary Pharmacology, Toxicology and Therapy. Nether-
pleuritis caused by Corynebacterium pseudotuberculosis in a lands: Springer; 1986.
horse. J Am Vet Med Assoc. 2004;224:1133. 158. Bezerra PS, Driemeier D, Loretti AP, et al. Monensin poison-
136. Seahorn JL, Slovis NM, Reimer JM, et al. Case-control study ing in Brazilian horses. Vet Hum Toxicol. 1999;41:383.
of factors associated with fibrinous pericarditis among horses 159. Bila CG, Perreira CL, Gruys E. Accidental monensin toxicosis
in central Kentucky during spring 2001. J Am Vet Med Assoc. in horses in Mozambique. J S Afr Vet Assoc. 2001;72:163.
2003;223:832. 160. Hughes KJ, Hoffmann KL, Hodgson DR. Long-term assess-
137. Armstrong SK, Raidal SL, Hughes KJ. Fibrinous pericarditis ment of horses and ponies post exposure to monensin sodium
and pericardial effusion in three neonatal foals. Aust Vet J. in commercial feed. Equine Vet J. 2009;41:47.
2014;92:392. 161. Decloedt A, Verheyen T, Sys S, et al. Tissue Doppler imag-
138. Baker D, Kreeger J. Infiltrative lipoma in the heart of a horse. ing and 2-dimensional speckle tracking of left ventricular
Cornell Vet. 1987;77:258. function in horses exposed to lasalocid. J Vet Intern Med.
139. Dill SG, Moise NS, Meschter CL. Cardiac failure in a stallion 2012;26:1209.
secondary to metastasis of an anaplastic pulmonary carcino- 162. Decloedt A, Verheyen T, De Clercq D, et al. Acute and long-
ma. Equine Vet J. 1986;18:414. term cardiomyopathy and delayed neurotoxicity after ac-
140. Byars TD, Dainis CM, Seltzer KL, et al. Cranial thoracic masses cidental lasalocid poisoning in horses. J Vet Intern Med.
in the horse: a sequel to pleuropneumonia. Equine Vet J. 2012;26:1005.
1991;23:22. 163. Divers TJ, Kraus MS, Jesty SA, et al. Clinical findings and se-
141. Evans DL. Cardiac respones to exercise and training. In: Marr rum cardiac troponin I concentrations in horses after intragas-
CM, ed. Cardiology of the Horse. London: WB Saunders; tric administration of sodium monensin. J Vet Diagn Invest.
1999. 2009;21:338.
142. Buhl R, Ersboll AK, Eriksen L, et al. Changes over time in 164. Schefer KD, Hagen R, Ringer SK, et al. Laboratory, electro-
echocardiographic measurements in young Standardbred cardiographic, and echocardiographic detection of myocardial
racehorses undergoing training and racing and association damage and dysfunction in an Arabian mare with nutritional
with racing performance. J Am Vet Med Assoc. 2005;226:1881. masseter myodegeneration. J Vet Intern Med. 2011;25:1171.
143. Rugh KS, Garner HE, Sprouse RF, et al. Left ventricular hy- 165. Barigye R, Dyer NW, Newell TK. Fatal myocardial degenera-
pertrophy in chronically hypertensive ponies. Lab Anim Sci. tion in an adult Quarter Horse with vitamin E deficiency. J
1987;37:335. Equine Vet Sci. 2007;27:405.
144. Braunwald E, Bonow RO. Braunwald’s Heart Disease: A Text- 166. Sweeney RW, Hamir AN, Fisher RR. Lymphosarcoma with
Book of Cardiovascular Medicine. 9th ed. Philadelphia: Saun- urinary bladder infiltration in a horse. J Am Vet Med Assoc.
ders; 2012. 1991;199:1177.
145. Cranley JJ, McCullagh KG. Ischaemic myocardial fibrosis and 167. Reef VB. Stress echocardiography and its role in performance
aortic strongylosis in the horse. Equine Vet J. 1981;13:35. assessment. Vet Clin North Am Equine Pract. 2001;17:179.
146. Dudan F, Rossi GL, Luginbuhl H. Cardiovascular study of the 168. Schefer KD, Bitschnau C, Weishaupt MA, et al. Quantitative
horse: relationships between vascular and tissue lesions in the analysis of stress echocardiograms in healthy horses with
myocardium. II. Schweiz Arch Tierheilkd. 1984;126:527. 2-dimensional (2D) echocardiography, anatomical M-mode,
147. Dudan F, Rossi GL, Luginbuhl H. Cardiovascular study in the tissue Doppler imaging, and 2D speckle tracking. J Vet Intern
horse: relationship between vascular and myocardial lesions. Med. 2010;24:918.
3. Schweiz Arch Tierheilkd. 1985;127:319. 169. Bowen IM, Marr CM, Chester AH, et al. In-vitro contraction
148. Reef VB, Bain FT, Spencer PA. Severe mitral regurgitation in of the equine aortic valve. J Heart Valve Dis. 2004;13:593.
horses: clinical, echocardiographic and pathological findings. 170. Rooney JR, Franks WC. Congenital cardiac anomalies in horses.
Equine Vet J. 1998;30:18. Vet Pathol. 1964;1:454.
149. Traub-Dargatz JL, Schlipf Jr JW, Boon J, et al. Ventricular 171. Bayly WM, Reed SM, Leathers CW, et al. Multiple congeni-
tachycardia and myocardial dysfunction in a horse. J Am Vet tal heart anomalies in five Arabian foals. J Am Vet Med Assoc.
Med Assoc. 1994;205:1569. 1982;181:684.
150. Kiryu K, Machida N, Kashida Y, et al. Pathologic and electro- 172. Vitums A, Bayly WM. Pulmonary atresia with dextroposi-
cardiographic findings in sudden cardiac death in racehorses. tion of the aorta and ventricular septal defect in three Arabian
J Vet Med Sci. 1999;61:921. foals. Vet Pathol. 1982;19:160.
173. McClure JJ, Gaber CE, Watters JW, et al. Complete transpo- 200. Nilsfors L, Lombard CW, Weckner D, et al. Diagnosis of
sition of the great arteries with ventricular septal defect and pulmonary valve endocarditis in a horse. Equine Vet J.
pulmonary stenosis in a Thoroughbred foal. Equine Vet J. 1991;23:479.
1983;15:377. 201. Ewart S, Brown C, Derksen F, et al. Serratia marcescens endo-
174. Tadmor A, Fischel R, Tov AS. A condition resembling hypo- carditis in a horse. J Am Vet Med Assoc. 1992;200:961.
plastic left heart syndrome in a foal. Equine Vet J. 1983;15:175. 202. Ball MA, Weldon AD. Vegetative endocarditis in an Appaloosa
175. Musselman EE, LoGuidice RJ. Hypoplastic left ventricular gelding. Cornell Vet. 1992;82:301.
syndrome in a foal. J Am Vet Med Assoc. 1984;185:542. 203. Pace LW, Wirth NR, Foss RR, et al. Endocarditis and pulmo-
176. Crowe MW, Swerczek TW. Equine congenital defects. Am J nary aspergillosis in a horse. J Vet Diagn Invest. 1994;6:504.
Vet Res. 1985;46:353. 204. Travers CW, van den Berg JS. Pseudomonas spp. associ-
177. Physick-Sheard PW, Maxie MG, Palmer NC, et al. Atrial sep- ated vegetative endocarditis in two horses. J S Afr Vet Assoc.
tal defect of the persistent ostium primum type with hypo- 1995;66:172.
plastic right ventricle in a Welsh pony foal. Can J Comp Med. 205. Maxson AD, Reef VB. Bacterial endocarditis in horses: ten
1985;49:429. cases (1984-1995). Equine Vet J. 1997;29:394.
178. Reef VB. Cardiovascular disease in the equine neonate. Vet 206. Church S, Harrigan KE, Irving AE, et al. Endocarditis caused
Clin North Am Equine Pract. 1985;1:117. by Pasteurella caballi in a horse. Aust Vet J. 1998;76:528.
179. Clark ES, Reef VB, Sweeney CR, et al. Aortic valve insufficien- 207. Patteson MW, Blissitt KJ. Evaluation of cardiac murmurs in
cy in a one-year-old colt. J Am Vet Med Assoc. 1987;191:841. horses. 1. Clinical Examination, In Pract. 1996;18:367.
180. Reef VB, Mann P. Echocardiographic diagnosis of tricuspid 208. Buhl R, Ersboll AK, Eriksen L, et al. Use of color Doppler echo-
atresia in two foals. J Am Vet Med Assoc. 1987;191:225. cardiography to assess the development of valvular regurgita-
181. Sojka JE. Persistent truncus arteriosus in a foal. Equine Pract. tion in Standardbred trotters. J Am Vet Med Assoc. 2005;227:
1987;9:19. 1630.
182. Zamora CS, Vitums A, Nyrop KA, et al. Atresia of the right 209. Buhl R, Ersboll AK. Effect of light exercise on valvular regurgi-
atrioventricular orifice with complete transposition of the tation in Standardbred trotters. Equine Vet J Suppl. 2006;178.
great arteries in a horse. Anat Histol Embryol. 1989;18:177. 210. Young LE, Helwegen MM, Rogers K, et al. Associations be-
183. Cargile J, Lombard C, Wilson JH, et al. Tetralogy of Fallot and tween exercise-induced pulmonary haemorrhage, right ven-
segmental uterine aplasia in a three-year-old Morgan filly. Cor- tricular dimensions and atrioventricular valve regurgitation
nell Vet. 1991;81:411. in conditioned national hunt racehorses. Equine Vet J Suppl.
184. Hinchcliff KW, Adams WM. Critical pulmonary stenosis in a 2006;193.
newborn foal. Equine Vet J. 1991;23:318. 211. Buhl R, Ersboll AK. Echocardiographic evaluation of changes
185. deGroot J, Sloet van Oldruitenborgh-Oosterbaan MM, van in left ventricular size and valvular regurgitation associated
der Linde Sipman JS, et al. Heart diseases in foals. A literature with physical training during and after maturity in Standard-
review exemplified by 2 case reports. Tijdschr Diergeneeskd. bred trotters. J Am Vet Med Assoc. 2012;240:205.
1996;121:382. 212. Brown CM, Bell TG, Paradis MR, et al. Rupture of mitral chor-
186. Meurs KM, Miller MW, Hanson C, et al. Tricuspid valve atre- dae tendineae in two horses. J Am Vet Med Assoc. 1983;182:281.
sia with main pulmonary artery atresia in an Arabian foal. 213. Reef VB. Mitral valvular insufficiency associated with rup-
Equine Vet J. 1997;29:160. tured chordae tendineae in three foals. J Am Vet Med Assoc.
187. Schober KE, Kaufhold J, Kipar A. Mitral valve dysplasia in a 1987;191:329.
foal. Equine Vet J. 2000;32:170. 214. Marr CM, Love S, Pirie HM, et al. Confirmation by Dop-
188. Gehlen H, Bubeck K, Stadler P. Valvular pulmonic stenosis pler echocardiography of valvular regurgitation in a horse
with normal aortic root and intact ventricular and atrial septa with a ruptured chorda tendinea of the mitral valve. Vet Rec.
in an Arabian horse. Equine Vet Educ. 2001;13:286. 1990;127:376.
189. Taylor SE, Else RW, Keen JA. Congenital aortic valve dysplasia 215. Kiryu K, Kaneko M, Kanemaru T, et al. Cardiopathology of
in a Clydesdale foal. Equine Vet Educ. 2007;19:463. sinoatrial block in horses. Nihon Juigaku Zasshi. 1985;47:45.
190. Hall TL, Magdesian KG, Kittleson MD. Congenital cardiac de- 216. Matsui K, Sugano S, Amada A. Heart rate and ECG response
fects in neonatal foals: 18 cases (1992-2007). J Vet Intern Med. to twitching in Thoroughbred foals and mares. Nihon Juigaku
2010;24:206. Zasshi. 1986;48:305.
191. Brown CM. Acquired cardiovascular disease. Vet Clin North 217. Matsui K, Sugano S. Relation of intrinsic heart-rate and au-
Am Equine Pract. 1985;1:371. tonomic nervous tone to resting heart-rate in the young
192. Sage AM. Cardiac disease in the geriatric horse. Vet Clin North and the adult of various domestic-animals. Jpn J Vet Sci.
Am Equine Pract. 2002;18:575. 1989;51:29.
193. Innes JR, Berger J, Francis J. Subacute bacterial endocarditis 218. Moore EN, Spear JF. Electrophysiological studies on atrial
with pulmonary embolism in a horse associated with Shigella fibrillation. Heart Vessels Suppl. 1987;2:32.
equirulis. Br Vet J. 1950;106:245. 219. Meijler FL, Kroneman J, van der Tweel I, et al. Nonrandom
194. Bonagura JD, Pipers FS. Echocardiographic features of aortic ventricular rhythm in horses with atrial fibrillation and its sig-
valve endocarditis in a dog, a cow, and a horse. J Am Vet Med nificance for patients. J Am Coll Cardiol. 1984;4:316.
Assoc. 1983;182:595. 220. Meijler FL. Atrioventricular conduction versus heart size from
195. Buergelt CD, Cooley AJ, Hines SA, et al. Endocarditis in six mouse to whale. J Am Coll Cardiol. 1985;5:363.
horses. Vet Pathol. 1985;22:333. 221. Meijler FL, van der Tweel I. Comparative study of atrial fibril-
196. McCormick BS, Peet RL, Downes K. Erysipelothrix rhusiopathiae lation and AV conduction in mammals. Heart Vessels Suppl.
vegetative endocarditis in a horse. Aust Vet J. 1985;62:392. 1987;2:24.
197. Dedrick P, Reef VB, Sweeney RW, et al. Treatment of bacterial 222. Raekallio M. Long term ECG recording with Holter monitor-
endocarditis in a horse. J Am Vet Med Assoc. 1988;193:339. ing in clinically healthy horses. Acta Vet Scand. 1992;33:71.
198. Hamir AN, Reef VB. Complications of a permanent 223. Mill J, Hanak J. Diagnosis of heart valve defects, arrhyth-
transvenous pacing catheter in a horse. J Comp Pathol. mia and functional disorders of cardiac conduction in com-
1989;101:317. petition horses and racehorses. Arch Exp Veterinarmed.
199. Collatos C, Clark ES, Reef VB, et al. Septicemia, atrial fi- 1985;39:319.
brillation, cardiomegaly, left atrial mass, and Rhodococcus 224. Tschudi P. Electrocardiography in the horse. (2). Disorders
equi septic osteoarthritis in a foal. J Am Vet Med Assoc. of impulse formation and impulse conduction. Tierarztl Prax.
1990;197:1039. 1985;13:529.
225. Reef VB. Heart murmurs irregularities and other cardiac ab- 248. Hardy J, Bednarski RM, Biller DS. Effect of phenylephrine on
normalities. In: Brown C, ed. Problems in Equine Medicine. hemodynamics and splenic dimensions in horses. Am J Vet
New York: Lea & Febiger; 1992. Res. 1994;55:1570.
226. Bonagura JD, Miller MS. Common conduction disturbances. 249. Hollis AR, Ousey JC, Palmer L, et al. Effects of norepinephrine
[ECG in the horse]. J Equine Vet Sci. 1986;6:23. and a combined norepinephrine and dobutamine infusion
227. Reef VB. Twenty-four hour rhythm monitoring. In: Mayhew I, on systemic hemodynamics and indices of renal function in
ed. Equine Medicine and Surgery IV. Santa Barbara: American normotensive neonatal thoroughbred foals. J Vet Intern Med.
Veterinary Publications; 1991. 2006;20:1437.
228. Slinker BK, Campbell KB, Alexander JE, et al. Arterial barore- 250. Valverde A, Giguere S, Sanchez LC, et al. Effects of dobu-
flex control of heart rate in the horse, pig, and calf. Am J Vet tamine, norepinephrine, and vasopressin on cardiovascular
Res. 1926;43:1982. function in anesthetized neonatal foals with induced hypoten-
229. Meijler FL. Atrial fibrillation—a new look at an old arrhyth- sion. Am J Vet Res. 2006;67:1730.
mia. J Am Coll Cardiol. 1983;2:391. 251. Craig CA, Haskins SC, Hildebrand SV. The cardiopulmonary
230. Horn J, Bailey S, Berhane Y, et al. Density and binding char- effects of dobutamine and norepinephrine in isoflurane-anes-
acteristics of beta-adrenoceptors in the normal and failing thetized foals. Vet Anaesth Analg. 2007;34:377.
equine myocardium. Equine Vet J. 2002;34:411. 252. Hollis AR, Ousey JC, Palmer L, et al. Effects of norepineph-
231. Badino P, Odore R, Re G. Are so many adrenergic receptor rine and combined norepinephrine and fenoldopam infusion
subtypes really present in domestic animal tissues? A pharma- on systemic hemodynamics and indices of renal function in
cological perspective. Vet J. 2005;170:163. normotensive neonatal foals. J Vet Intern Med. 2008;22:1210.
232. Evans DL, Rose RJ. Determination and repeatability of maxi- 253. Ohta M, Kurimoto S, Ishikawa Y, et al. Cardiovascular
mum oxygen uptake and other cardiorespiratory measure- effects of dobutamine and phenylephrine infusion in sevo-
ments in the exercising horse. Equine Vet J. 1988;20:94. flurane-anesthetized Thoroughbred horses. J Vet Med Sci.
233. Evans DL, Rose RJ. Cardiovascular and respiratory responses 2013;75:1443.
in Thoroughbred horses during treadmill exercise. J Exp Biol. 254. Fantoni DT, Marchioni GG, Ida KK, et al. Effect of ephedrine
1988;134:397. and phenylephrine on cardiopulmonary parameters in horses
234. Landgren GL, Gillespie JR, Fedde MR, et al. O2 transport undergoing elective surgery. Vet Anaesth Analg. 2013;40:367.
in the horse during rest and exercise. Adv Exp Med Biol. 255. Benamou AE, Marlin DJ, Lekeux P. Equine pulmonary and
1988;227:333. systemic haemodynamic responses to endothelin-1 and a se-
235. Littlejohn A, Snow DH. Circulatory, respiratory and metabolic lective ET(A) receptor antagonist. Equine Vet J. 2001;33:337.
responses in Thoroughbred horses during the first 400 meters 256. Benamou AE, Marlin DJ, Lekeux P. Endothelin in the equine
of exercise. Eur J Appl Physiol Occup Physiol. 1988;58:307. hypoxic pulmonary vasoconstrictive response to acute hypox-
236. Marsland WP. Heart rate response to submaximal exercise in ia. Equine Vet J. 2001;33:345.
the Standardbred horse. J Appl Physiol. 1968;24:98. 257. Benamou AE, Marlin DJ, Callingham BC, et al. Spasmogenic
237. Donaldson LL. Retrospective assessment of dobutamine thera- action of endothelin-1 on isolated equine pulmonary artery
py for hypotension in anesthetized horses. Vet Surg. 1988;17:53. and bronchus. Equine Vet J. 2003;35:190.
238. Swanson CR, Muir 3rd WW, Bednarski RM, et al. Hemody- 258. Gasthuys F, De Moor A, Parmentier D. Cardiovascular effects
namic responses in halothane-anesthetized horses given infu- of low dose calcium chloride infusions during halothane an-
sions of dopamine or dobutamine. Am J Vet Res. 1985;46:365. aesthesia in dorsally recumbent ventilated ponies. Zentralbl
239. Trim CM, Moore JN, White NA. Cardiopulmonary effects of Veterinarmed A. 1991;38:728.
dopamine hydrochloride in anaesthetised horses. Equine Vet J. 259. Schwarzwald CC, Bonagura JD, Luis-Fuentes V. Effects of
1985;17:41. diltiazem on hemodynamic variables and ventricular function
240. Whitton DL, Trim CM. Use of dopamine hydrochloride dur- in healthy horses. J Vet Intern Med. 2005;19:703.
ing general anesthesia in the treatment of advanced atrio- 260. Rooney JR. Internal hemorrhage related to gestation in the
ventricular heart block in four foals. J Am Vet Med Assoc. mare. Cornell Vet. 1964;54:11.
1985;187:1357. 261. van der Linde-Sipman JS, Kroneman J, Meulenaar H, et al. Ne-
241. Young LE, Blissitt KJ, Clutton RE, et al. Temporal effects of an crosis and rupture of the aorta and pulmonary trunk in four
infusion of dobutamine hydrochloride in horses anesthetized horses. Vet Pathol. 1985;22:51.
with halothane. Am J Vet Res. 1998;59:1027. 262. Roby KA, Reef VB, Shaw DP, et al. Rupture of an aortic sinus
242. Weil AB, Keegan RD, Greene SA. Effect of low-dose atropine aneurysm in a 15-year-old broodmare. J Am Vet Med Assoc.
administration on dobutamine dose requirement in horses 1986;189:305.
anesthetized with detomidine and halothane. Am J Vet Res. 263. Marr CM, Reef VB, Brazil TJ, et al. Aorto-cardiac fistulas in
1997;58:1436. seven horses. Vet Radiol Ultrasound. 1998;39:22.
243. Sandersen CF, Detilleux J, Delguste C, et al. Atropine reduces 264. Sleeper MM, Durando MM, Miller M, et al. Aortic root dis-
dobutamine-induced side effects in ponies undergoing a phar- ease in four horses. J Am Vet Med Assoc. 2001;219:491.
macological stress protocol. Equine Vet J. 2005;37:128. 265. Ploeg M, Saey V, de Bruijn CM, et al. Aortic rupture and aor-
244. Sandersen CF, Detilleux J, de Moffarts B, et al. Effect of at- to-pulmonary fistulation in the Friesian horse: characterisa-
ropine-dobutamine stress test on left ventricular echocardio- tion of the clinical and gross post mortem findings in 24 cases.
graphic parameters in untrained warmblood horses. J Vet Intern Equine Vet J. 2013;45:101.
Med. 2006;20:575. 266. Ploeg M, Saey V, Delesalle C, et al. Thoracic aortic rupture and
245. Light GS, Hellyer PW. Effects of atropine on the arrhythmo- aortopulmonary fistulation in the Friesian horse: histomor-
genic dose of dobutamine in xylazine-thiamylal-halothane- phologic characterization. Vet Pathol. 2015;52:152.
anesthetized horses. Am J Vet Res. 1993;54:2099. 267. Maxie MG, Physick-Sheard PW. Aortic-iliac thrombosis in
246. Hinchcliff KW, McKeever KH, Muir 3rd WW. Hemodynam- horses. Vet Pathol. 1985;22:238.
ic effects of atropine, dobutamine, nitroprusside, phenyle- 268. Reef VB, Roby KAW, Richardson DW, et al. Use of ultra-
phrine, and propranolol in conscious horses. J Vet Intern Med. sonography for the detection of aortic-iliac thrombosis in
1991;5:80. horses. J Am Vet Med Assoc. 1987;190:286.
247. Frye MA, Bright JM, Dargatz DA, et al. A comparison of dobu- 269. Azzie MAJ. Clinical diagnosis of equine aortic iliac thrombosis
tamine infusion to exercise as a cardiac stress test in healthy and its histopathology as compared with that of the strongyle
horses. J Vet Intern Med. 2003;17:58. aneurysm. Proc Am Assoc Equine Pract. 1972. San Francisco.
270. Edwards GB, Allen WE. Aorto-iliac thrombosis in two horses: 293. Hinchcliff KW, Kaneps AJ, Geor RJ. Equine Sports Medicine
clinical course of the disease and use of real-time ultrasonog- and Surgery. 2nd ed. Edinburgh: Saunders Elsevier; 2014.
raphy to confirm diagnosis. Equine Vet J. 1988;384:1988. 294. Kutter AP, Bettschart-Wolfensberger R, Schwarzwald CC,
271. Azzie MAJ. Aortic/iliac thrombosis of Thoroughbred horses. et al. Evaluation of the non-calibrated pulse contour cardiac
Equine Vet J. 1969;1:113. output monitor FloTrac/Vigileo against thermodilution in
272. Physick-Sheard PW, Maxie MG. Aortoiliofemoral arterioscle- standing horses. Vet Anaesth Analg. 2016;43:153.
rosis. In: Robinson NE, ed. Current Therapy in Equine Medi- 295. Shih AC, Queiroz P, Vigani A, et al. Comparison of cardiac
cine 1. Phildelphia: W.B. Saunders; 1983. output determined by an ultrasound velocity dilution cardiac
273. Reef VB. Vasculitis. In: Robinson NE, ed. Current Therapy in output method and by the lithium dilution cardiac output
Equine Medicine 3. Philadelphia: WB Saunders; 1992. method in juvenile horses with experimentally induced hypo-
274. Patteson MW, Gibbs C, Wotton PR, et al. Effects of sedation volemia. Am J Vet Res. 2014;75:565.
with detomidine hydrochloride on echocardiographic mea 296. Shih A. Cardiac output monitoring in horses. Vet Clin North
surements of cardiac dimensions and indices of cardiac func- Am Equine Pract. 2013;29:155.
tion in horses. Equine Vet J Suppl. 1995;33. 297. McConachie E, Barton MH, Rapoport G, et al. Doppler and
275. Raisis AL, Young LE, Blissitt KJ, et al. A comparison of the volumetric echocardiographic methods for cardiac output
haemodynamic effects of isoflurane and halothane anaesthesia measurement in standing adult horses. J Vet Intern Med.
in horses. Equine Vet J. 2000;32:318. 2013;27:324.
276. Young LE, Blissitt KJ, Clutton RE, et al. Feasibility of transoe- 298. Ambrisko TD, Coppens P, Kabes R, et al. Lithium dilution,
sophageal echocardiography for evaluation of left ventricu- pulse power analysis, and continuous thermodilution cardiac
lar performance in anaesthetised horses. Equine Vet J Suppl. output measurements compared with bolus thermodilution in
1995;63. anaesthetized ponies. Br J Anaesth. 2012;109:864.
277. Young LE, Blissitt KJ, Clutton RE, et al. Temporal effects of an 299. Shih AC, Giguere S, Sanchez LC, et al. Determination of car-
infusion of dopexamine hydrochloride in horses anesthetized diac output in anesthetized neonatal foals by use of two pulse
with halothane. Am J Vet Res. 1997;58:516. wave analysis methods. Am J Vet Res. 2009;70:334.
278. Young LE, Blissitt KJ, Clutton RE, et al. Haemodynamic effects 300. Shih A, Giguere S, Sanchez LC, et al. Determination of cardiac
of a sixty minute infusion of dopamine hydrochloride in hors- output in neonatal foals by ultrasound velocity dilution and its
es anaesthetised with halothane. Equine Vet J. 1998;30:310. comparison to the lithium dilution method. J Vet Emerg Criti-
279. Lightowler C, Piccione G, Fazio F, et al. Systolic time intervals cal Care (San Antonio, Tex : 2001). 2009;19:438.
assessed by 2-D echocardiography and spectral Doppler in the 301. Lepiz ML, Keegan RD, Bayly WM, et al. Comparison of Fick
horse. Animal Science Journal. 2003;74:505. and thermodilution cardiac output determinations in standing
280. Reef VB, Lalezari K, De Boo J, et al. Pulsed-wave Doppler horses. Res Vet Sci. 2008;85:307.
evaluation of intracardiac blood flow in 30 clinically normal 302. Durando MM, Corley KTT, Boston RC, et al. Cardiac output
Standardbred horses. Am J Vet Res. 1989;50:75. determination by use of lithium dilution during exercise in
281. Blissitt KJ, Bonagura JD. Pulsed wave Doppler echocardiogra- horses. Am J Vet Res. 2008;69:1054.
phy in normal horses. Equine Vet J Suppl. 1995;38. 303. Valverde A, Giguere S, Morey TE, et al. Comparison of nonin-
282. Welker FH, Muir WW. An investigation of the second heart vasive cardiac output measured by use of partial carbon diox-
sound in the normal horse. Equine Vet J. 1990;22:403. ide rebreathing or the lithium dilution method in anesthetized
283. Smith BL, Jones JH, Pascoe JR, et al. Why are left atrial pres- foals. Am J Vet Res. 2007;68:141.
sures high in exercising horses? Physiologist. 1992;35. 304. Wilkins PA, Boston RC, Gleed RD, et al. Comparison of ther-
284. Jones JH, Smith BL, Birks EK, et al. Left atrial and pul- mal dilution and electrical impedance dilution methods for
monary arterial pressures in exercising horses. FASEB J. measurement of cardiac output in standing and exercising
1992;6:A2020. horses. Am J Vet Res. 2005;66:878.
285. Long KJ. Doppler echocardiography in the horse. Equine Vet 305. Hallowell GD, Corley KTT. Use of lithium dilution and pulse
Educ. 1990;2:15. contour analysis cardiac output determination in anaesthetized
286. Schwarzwald CC, Schober KE, Bonagura JD. Methods and horses: a clinical evaluation. Vet Anaesth Analg. 2005;32:201.
reliability of tissue Doppler imaging for assessment of left 306. Giguere S, Bucki E, Adin DB, et al. Cardiac output measure-
ventricular radial wall motion in horses. J Vet Intern Med. ment by partial carbon dioxide rebreathing, 2-dimensional
2009;23:643. echocardiography, and lithium-dilution method in anesthe-
287. Schwarzwald CC, Schober KE, Bonagura JD. Methods and re- tized neonatal foals. J Vet Intern Med. 2005;19:737.
liability of echocardiographic assessment of left atrial size and 307. Corley KT, Donaldson LL, Durando MM, et al. Cardiac output
mechanical function in horses. Am J Vet Res. 2007;68:735. technologies with special reference to the horse. J Vet Intern
288. Pagel PS, Kehl F, Gare M, et al. Mechanical function of the Med. 2003;17:262.
left atrium: new insights based on analysis of pressure-vol- 308. Corley KT, Donaldson LL, Furr MO. Comparison of lithium
ume relations and Doppler echocardiography. Anesthesiology. dilution and thermodilution cardiac output measurements in
2003;98:975. anaesthetised neonatal foals. Equine Vet J. 2002;34:598.
289. Schwarzwald CC, Schober KE, Bonagura JD. Echocardio- 309. Linton RA, Young LE, Marlin DJ, et al. Cardiac output mea
graphic evidence of left atrial mechanical dysfunction after sured by lithium dilution, thermodilution, and transesophageal
conversion of atrial fibrillation to sinus rhythm in 5 horses. J Doppler echocardiography in anesthetized horses. Am J Vet
Vet Intern Med. 2007;21:820. Res. 2000;61:731.
290. DeClercq D, VanLoon G, Tavernier R, et al. Atrial and ventric- 310. Pascoe JR, Hiraga A, Hobo S, et al. Cardiac output measure-
ular electrical and contractile remodeling and reverse remod- ments using sonomicrometer crystals on the left ventricle at
eling owing to short-term pacing-induced atrial fibrillation in rest and exercise. Equine Vet J Suppl. 1999;30:148.
horses. J Vet Intern Med. 2008;22:1353. 311. Blissitt KJ, Young LE, Jones RS, et al. Measurement of cardiac
291. Decloedt A, Schwarzwald CC, De Clercq D, et al. Risk factors output in standing horses by Doppler echocardiography and
for recurrence of atrial fibrillation in horses after cardioversion thermodilution. Equine Vet J. 1997;29:18.
to sinus rhythm. J Vet Intern Med. 2015;29:946. 312. Young LE, Blissitt KJ, Bartram DH, et al. Measurement of car-
292. Muir WW, Hubbell JAE. Equine Anesthesia—Monitoring diac output by transoesophageal Doppler echocardiography in
and Emergency Therapy. 2nd ed. St. Louis: Saunders Elsevier; anaesthetized horses: comparison with thermodilution. Br J
2009. Anaesth. 1996;77:773.
313. Mizuno Y, Aida H, Hara H, et al. Comparison of methods 336. Muir WW. The haemodynamic effects of milrinone HCl in
of cardiac output measurements determined by dye dilution, halothane anaesthetised horses. Equine Vet J Suppl. 1995;108.
pulsed Doppler echocardiography and thermodilution in 337. de Vries A, Brearley JC, Taylor PM. Effects of dobutamine on
horses. J Vet Med Sci. 1994;56:1. cardiac index and arterial blood pressure in isoflurane-anaes-
314. Dunlop CI, Hodgson DS, Chapman PL, et al. Thermodilu- thetized horses under clinical conditions. J Vet Pharmacol
tion estimation of cardiac output at high flows in anesthetized Ther. 2009;32:353.
horses. Am J Vet Res. 1991;52:1893. 338. Vitale V, Sgorbini M, Briganti A, et al. Evaluation of echo-
315. Wetmore LA, Derksen FJ, Blaze CA, et al. Mixed venous oxy- cardiographic parameters during increasing infusion rates of
gen tension as an estimate of cardiac output in anesthetized dobutamine in isoflurane-anesthetized horses. J Equine Vet
horses. Am J Vet Res. 1987;48:971. Sci. 2013;33:1110.
316. Ward DS, Fessler JF, Bottoms GD. In vitro calibration and sur- 339. Afonso T, Giguère S, Rapoport G, et al. Cardiovascular ef-
gical implantation of electromagnetic blood flow transducers fects of pimobendan in healthy mature horses. Equine Vet J.
for measurement of left coronary blood flow and cardiac out- 2016;48:352.
put in the pony. Am J Vet Res. 1987;48:1120. 340. Long-Blissitt KJ, Bonagura JD, Darke PGG. Standardised im-
317. Muir WW, Skarda RT, Milne DW. Estimation of cardiac out- aging technique for guided M-mode and Doppler echocardi-
put in the horse by thermodilution techniques. Am J Vet Res. ography in the horse. Equine Vet J. 1992;24:226.
1976;37:697. 341. Patteson MW, Gibbs C, Wotton PR, et al. Echocardiographic
318. Hillidge CJ, Lees P. Cardiac output in the conscious and anaes- measurements of cardiac dimensions and indices of cardiac
thetised horse. Equine Vet J. 1975;7:16. function in normal adult thoroughbred horses. Equine Vet J
319. Brumbaugh GW, Thomas WP, Enos LR, et al. A pharma- Suppl. 1995;18.
cokinetic study of digoxin in the horse. J Vet Pharmacol Ther. 342. Slater JD, Herrtage ME. Echocardiographic measurements of
1983;6:163. cardiac dimensions in normal ponies and horses. Equine Vet J
320. Button C, Gross DR, Johnston JT, et al. Digoxin pharmacoki- Suppl. 1995;28.
netics, bioavailability, efficacy, and dosage regimens in the 343. Bakos Z, Voros K, Jarvinen T, et al. Two-dimensional and
horse. Am J Vet Res. 1980;41:1388. M-mode echocardiographic measurements of cardiac dimen-
321. Dyson DH, Pascoe PJ. Influence of preinduction methoxam- sions in healthy standardbred trotters. Acta Vet Hung. 2002;
ine, lactated Ringer solution, or hypertonic saline solution 50:273.
infusion or postinduction dobutamine infusion on anesthetic- 344. Boon JA. Veterinary Echocardiography. 2nd ed. Oxford: Wiley-
induced hypotension in horses. Am J Vet Res. 1990;51:17. Blackwell; 2011.
322. Francfort P, Schatzmann HJ. Pharmacological experiments as 345. Grenacher PA, Schwarzwald CC. Assessment of left ventric-
a basis for the administration of digoxin in the horse. Res Vet ular size and function in horses using anatomical M-mode
Sci. 1976;20:84. echocardiography. J Vet Cardiol. 2010;12:111.
323. Gasthuys F, De Moor A, Parmentier D. Influence of digoxin 346. Schwarzwald CC, Schober KE, Berli AS, et al. Left ventricular
followed by dopamine on the cardiovascular depression dur- radial and circumferential wall motion analysis in horses using
ing a standard halothane anaesthesia in dorsally recumbent, strain, strain rate, and displacement by 2D speckle tracking. J
ventilated ponies. Zentralbl Veterinarmed A. 1991;38:585. Vet Intern Med. 2009;23:890.
324. Grubb TL, Foreman JH, Benson GJ, et al. Hemodynamic ef- 347. Decloedt A, Verheyen T, Sys S, et al. Quantification of left ven-
fects of calcium gluconate administered to conscious horses. J tricular longitudinal strain, strain rate, velocity, and displace-
Vet Intern Med. 1996;10:401. ment in healthy horses by 2-dimensional speckle tracking. J
325. Keen P. The use of drugs in the treatment of cardiac disease in Vet Intern Med. 2011;25:330.
the horse. Equine Vet Educ. 1990;2:81. 348. Decloedt A, Verheyen T, Sys S, et al. Two-dimensional speckle
326. Meijler FL, van der Tweel I. Digitalis and atrial fibrillation in tracking for quantification of left ventricular circumferential
1985. Ned Tijdschr Geneeskd. 1985;129:729. and radial wall motion in horses. Equine Vet J. 2013;45:47.
327. Muir WW, Mcguirk SM. Pharmacology and pharmacokinet- 349. Decloedt A, Verheyen T, Sys S, et al. Evaluation of tissue Dop-
ics of drugs used to treat cardiac disease in horses. Vet Clin pler imaging for regional quantification of radial left ventricu-
North Am Equine Pract. 1985;1:335. lar wall motion in healthy horses. Am J Vet Res. 2013;74:53.
328. Muir WW, Mcguirk S. Cardiovascular drugs—their pharma- 350. Kriz NG, Rose RJ. Repeatability of standard transthoracic
cology and use in horses. Vet Clin North Am Equine Pract. echocardiographic measurements in horses. Aust Vet J. 2002;
1987;3:37. 80:362.
329. Muir 3rd WW. Cardiovascular effects of dopexamine HCl in 351. Gehlen H, Marnette S, Rohn K, et al. Precision-controlled echo-
conscious and halothane-anaesthetised horses. Equine Vet J cardiographic left ventricular function parameters by repeated
Suppl. 1992;24:24. measurement on three consecutive days in trained and untrained
330. Pedersoli WM, Belmonte AA, Purohit RC, et al. Pharmacoki- warmblood horses. Dtsch Tierarztl Wochenschr. 2005;112:48.
netics of digoxin in the horse. J Equine Med Surg. 1978;2:384. 352. Nuytten J, Deprez P, Picavet T, et al. Heart-failure in horses—
331. Pedersoli WM, Ravis WR, Belmonte AA, et al. Pharmacokinet- hemodynamic monitoring and determination of Ldh1 con-
ics of a single, orally administered dose of digoxin in horses. centration. J Equine Vet Sci. 1988;8:214.
Am J Vet Res. 1981;42:1412. 353. Fruhauf B, Stadler P, Deegen E. Evaluation of pulmonary
332. Staudacher G. Individual glycoside treatment by means of se- wedge pressure in horses with and without left heart abnor-
rum concentration determination in cardiac insufficiency in malities detected by echocardiography. Pferdeheilkunde.
horses. Berl Munch Tierarztl Wochenschr. 1989;102:1. 1996;12:544.
333. Swanson CR, Muir III WW. Dobutamine-induced augmen- 354. Gehlen H, Bubeck K, Stadler P. Pulmonary artery wedge pres-
tation of cardiac output does not enhance respiratory gas ex- sure measurement in healthy warmblood horses and in warm-
change in anesthetized recumbent healthy horses. Am J Vet blood horses with mitral valve insufficiencies of various degrees
Res. 1986;47:1573. during standardised treadmill exercise. Res Vet Sci. 2004;77:257.
334. Sweeney RW, Reef VB, Reimer JM. Pharmacokinetics of di- 355. Trachsel DS, Schwarzwald CC, Bitschnau C, et al. Atrial
goxin administered to horses with congestive heart failure. Am natriuretic peptide and cardiac troponin I concentrations in
J Vet Res. 1993;54:1108. healthy Warmblood horses and in Warmblood horses with
335. Trim CM. Inotropic agents and vasopressors in equine anes- mitral regurgitation at rest and after exercise. J Vet Cardiol.
thesia. Comp Cont Educ Pract. 1991;13:118. 2013;15:105.
356. Milne DW, Muir III WW, Skarda RT. Pulmonary artery wedge 378. Fregin GF. Medical evaluation of the cardiovascular system.
pressure blood gas tensions and pH in the resting horse. Am J Vet Clin North Am Equine Pract. 1992;8:329.
Vet Res. 1975;36:1431. 379. Gerring EL. Auscultation of the equine heart. Equine Vet Educ.
357. Gehlen H, Bubeck K, Rohn K, et al. Pulmonary artery wedge 1990;2:22.
pressure during treadmill exercise in warmblood horses with 380. Littlejohn A, Button C. When is a murmur not a murmur. J S
atrial fibrillation. Res Vet Sci. 2006;81:134. Afr Vet Assoc. 1982;53:130.
358. Gehlen H, Groner U, Rohn K, et al. Day-to day variability of 381. Littlewort MCG. The clinical auscultation of the equine heart.
cardiac pressure values in horses measured with right heart Vet Rec. 1962;74:1247.
catheterization on 3 consecutive days. Berl Munch Tierarztl 382. Machida N, Yasuda J, Too K. Auscultatory and phonocardio-
Wochenschr. 2006;119:400. graphic studies on the cardiovascular system of the newborn
359. Bertone JJ. Cardiovascular effects of hydralazine HCl adminis- thoroughbred foal. Jpn J Vet Res. 1987;35:235.
tration in horses. Am J Vet Res. 1988;49:618. 383. McGuirk SM, Muir WW. Diagnosis and treatment of cardiac
360. Muir 3rd WW, Sams RA, Hubbell JA, et al. Effects of enal- arrhythmias. Vet Clin North Am Equine Pract. 1985;1:353.
aprilat on cardiorespiratory, hemodynamic, and hematologic 384. Reef VB. Evaluation of the equine cardiovascular system. Vet
variables in exercising horses. Am J Vet Res. 2001;62:1008. Clin North Am Equine Pract. 1985;1:275.
361. Guglielmini C, Giuliani A, Testoni S, et al. Use of an ACE 385. Reimer J. Performing cardiac auscultation on horses. Vet Med.
inhibitor (ramipril) in a horse with congestive heart failure. 1993;88:660.
Equine Vet Educ. 2002;14:297. 386. Rossdale PD. Clinical studies on the newborn thoroughbred
362. Gehlen H, Vieht JC, Stadler P. Effects of the ACE inhibitor foal. II. Heart rate, auscultation and electrocardiogram. Br Vet
quinapril on echocardiographic variables in horses with mi- J. 1967;123:521.
tral valve insufficiency. J Vet Med A Physiol Pathol Clin Med. 387. Vanselow B, McCarthy M, Gay CC. A phonocardiographic
2003;50:460. study of equine heart sounds. Aust Vet J. 1978;54:161.
363. Afonso T, Giguere S, Rapoport G, et al. Pharmacodynamic 388. Blissitt KJ. Auscultation. In: Marr CM, Bowen M, eds. Cardiol-
evaluation of 4 angiotensin-converting enzyme inhibitors in ogy of the Horse. Edinburgh: Saunders Elsevier; 2010.
healthy adult horses. J Vet Intern Med. 2013;27:1185. 389. Naylor JM, Wolker RE, Pharr JW. An assessment of the termi-
364. Rugh KS, Garner HE, Hatfield DG, et al. Ischaemia induced nology used by diplomates and students to describe the char-
development of functional coronary collateral circulation in acter of equine mitral and aortic valve regurgitant murmurs:
ponies. Cardiovasc Res. 1987;21:730. correlations with the physical properties of the sounds. J Vet
365. Stadler P, Weinberger T, Deegen E. Pulsed Doppler-echo- Intern Med. 2003;17:332.
cardiography in healthy Warm-blooded horses. J Vet Med A. 390. Reef VB. Heart murmurs in horses: determining their signifi-
1993;40:757. cance with echocardiography. Equine Vet J Suppl. 1995;71.
366. Koenig TR, Mitchell KM, Schwarzwald CC. Echocardiographic 391. Blissitt KJ, Bonagura JD. Colour flow Doppler echocardi-
assessment of left ventricular function in healthy horses and in ography in horses with cardiac murmurs. Equine Vet J Suppl.
horses with heart disease using pulsed-wave tissue Doppler imag- 1995;82.
ing (PW TDI). J Vet Intern Med. 2017 Mar-Apr; 31(2): 556–567. 392. Naylor JM, Yadernuk LM, Pharr JW, et al. An assessment of
367. Parks CM, Manohar M. Distribution of blood flow during the ability of diplomates, practitioners, and students to de-
moderate and strenuous exercise in ponies (Equus caballus). scribe and interpret recordings of heart murmurs and arrhyth-
Am J Vet Res. 1861;44:1983. mia. J Vet Intern Med. 2001;15:507.
368. Parks C, Manohar M, Lundeen G. Regional myocardial blood flow 393. Abbott J. Auscultation: what type of practice makes perfect? J
and coronary vascular reserve in unanesthetized ponies during Vet Intern Med. 2001;15:505.
pacing-induced ventricular tachycardia. J Surg Res. 1983;35:119. 394. Kammerer H. Auscultation of the horse’s heart, using a new
369. Parks CM, Manohar M. Transmural coronary vasodilator re- stethoscope. Dtsch Tierarztl Wochenschr. 1983;90:521.
serve and flow distribution during severe exercise in ponies. J 395. Bakos Z, Voros K. Comparative examination of percussional
Appl Physiol. 1983;54:1641. and echocardiographic determination of the cardiac dullness
370. Manohar M. Transmural coronary vasodilator reserve and area in healthy horses. Acta Vet Hung. 2007;55:277.
flow distribution during maximal exercise in normal and sple- 396. Vörös K, Bonnevie A, Reiczigel J. Comparison of conven-
nectomized ponies. J Physiol. 1987;387:425. tional and sensor-based electronic stethoscopes in detect-
371. Parks CM, Manohar M. Transmural distribution of myocar- ing cardiac murmurs of dogs. Tierärztliche Praxis Kleintiere.
dial blood flow during graded treatmill exercise in ponies. In: 2012;40:103.
Persson SGB, Rose RJ, eds. Equine Exercise Physiology. Cam- 397. Blass KA, Schober KE, Bonagura JD, et al. Clinical evaluation
bridge, England: Granta; 1983. of the 3M Littmann Electronic Stethoscope Model 3200 in 150
372. Parks CM, Manohar M. Regional blood flow changes in re- cats. J Feline Med Surg. 2013;15:893.
sponse to near maximal exercise in ponies: a review. Equine 398. Hintz HF, Collyer C, Brant T. Resting heart rates in draft horses.
Vet J. 1985;17:311. Equine Pract. 1989;11:7.
373. Reddy VK, Kammula RG, Graham TC, et al. Regional coro- 399. Schwarzwald CC, Kedo M, Birkmann K, et al. Relationship
nary blood flow in ponies. Am J Vet Res. 1976;37:1261. of heart rate and electrocardiographic time intervals to body
374. Davis JL, Gardner SY, Schwabenton B, et al. Congestive heart mass in horses and ponies. J Vet Cardiol. 2012;14:343.
failure in horses: 14 cases (1984-2001). J Am Vet Med Assoc. 400. Reef VB. Frequency of cardiac arrhythmias and their signifi-
2002;220:1512. cance in normal horses. ACVIM forum. 1989. San Diego.
375. Fraipont A, Van Erck E, Ramery E, et al. Subclinical diseases 401. Bertone JJ. Atrial fibrillation in the horse: diagnosis, progno-
underlying poor performance in endurance horses: diagnostic sis, treatment. Equine Pract. 1984;6:6.
methods and predictive tests. Vet Rec. 2011;169:154. 402. Bertone JJ, Wingfield WE. Atrial fibrillation in horses. Comp
376. Kobluk CN, Gross GM. Exercise intolerance and poor per- Cont Educ Pract. 1987;9:763.
formance in western performance and sprint horses. Vet Clin 403. Gelzer ARM, Moise NS, Vaidya D, et al. Temporal organiza-
North Am Equine Pract. 1996;12:581. tion of atrial activity and irregular ventricular rhythm during
377. Martin BB, Davidson EJ, Durando MM, et al. Clinical exercise spontaneous atrial fibrillation: an in vivo study in the horse. J
testing: overview of causes of poor performance. In: Hinchcliff Cardiovasc Electrophysiol. 2000;11:773.
KW, Kaneps AJ, Geor RJ, eds. Equine Sports Medicine and Sur- 404. Li JK. Laminar and turbulent flow in the mammalian aorta:
gery. Edinburgh: Saunders Elsevier; 2004. reynolds number. J Theor Biol. 1988;135:409.
405. Marr CM. Cardiac murmurs: congenital heart disease. In: 429. Parry BW. Resting blood pressure values in various equine
Marr CM, ed. Cardiology of the Horse. Edinburgh: Saunders clinical cases. J Equine Vet Sci. 1984;4:49.
Elsevier; 2010. 430. Parry BW, Anderson GA. Importance of uniform cuff appli-
406. Marr CM. Cardiac Murmurs: Valvular regurgitation and in- cation for equine blood pressure measurement. Equine Vet J.
sufficiency. In: Marr CM, ed. Cardiology of the Horse. Edin- 1984;16:529.
burgh: Saunders Elsevier; 2010. 431. Parry BW, McCarthy MA, Anderson GA. Survey of resting
407. Stevens KB, Marr CM, Horn JNR, et al. Effect of left-sid- blood pressure values in clinically normal horses. Equine Vet J.
ed valvular regurgitation on mortality and causes of death 1984;16:53.
among a population of middle-aged and older horses. Vet Rec. 432. Taylor PM. Techniques and clinical application of arte-
2009;164:6. rial blood pressure measurement in the horse. Equine Vet J.
408. Machida N, Yasuda J, Too K, et al. A morphological study on 1981;13:271.
the obliteration processes of the ductus arteriosus in the horse. 433. Wagner AE, Brodbelt DC. Arterial blood pressure monitoring
Equine Vet J. 1988;20:249. in anesthetized animals. J Am Vet Med Assoc. 1997;210:1279.
409. Thomas WP, Madigan JE, Backus KQ, et al. Systemic and pul- 434. Nout YS, Corley KTT, Donaldson LL, et al. Indirect oscil-
monary haemodynamics in normal neonatal foals. J Reprod lometric and direct blood pressure measurements in anes-
Fertil Suppl. 1987;35:623. thetized and concious neonatal foals. J Vet Emerg Crit Care.
410. Andersson B, Augustinsson O, Bademo E, et al. Systemic and 2002;12:75.
centrally mediated angiotensin II effects in the horse. Acta 435. Giguere S, Knowles Jr HA, Valverde A, et al. Accuracy of in-
Physiol Scand. 1987;129:143. direct measurement of blood pressure in neonatal foals. J Vet
411. Bailey JE, Dunlop CI, Chapman PL, et al. Indirect Doppler ul- Intern Med. 2005;19:571.
trasonic measurement of arterial blood-pressure results in a 436. Heliczer N, Lorello O, Casoni D, et al. Accuracy and precision
large measurement error in dorsally recumbent anesthetized of noninvasive blood pressure in normo-, hyper-, and hypo-
horses. Equine Vet J. 1994;26:70. tensive standing and anesthetized adult horses. J Vet Intern
412. Branson KR. A clinical evaluation of an oscillometric blood Med. 2016;30:866.
pressure monitor on anesthetized horses. J Equine Vet Sci. 437. Hatz LA, Hartnack S, Kummerle J, et al. A study of measure-
1997;17:537. ment of noninvasive blood pressure with the oscillometric de-
413. Ellis PM. The indirect measurement of arterial blood pressure vice, Sentinel, in isoflurane-anaesthetized horses. Vet Anaesth
in the horse. Equine Vet J. 1975;7:22. Analg. 2015;42:369.
414. Erickson BK, Erickson HH, Coffman JR. Pulmonary artery, 438. Tearney CC, Guedes AG, Brosnan RJ. Equivalence between
aortic and oesophageal pressure changes during high intensity invasive and oscillometric blood pressures at different ana-
treadmill exercise in the horse: a possible relation to exercise- tomic locations in healthy normotensive anaesthetised horses.
induced pulmonary haemorrhage. Equine Vet J Suppl Supple- Equine Vet J. 2015.
ment. 1990;9:47. 439. Olsen E, Pedersen TLS, Robinson R, et al. Accuracy and pre-
415. Franco RM, Ousey JC, Cash RSG, et al. Study of arterial blood- cision of oscillometric blood pressure in standing conscious
pressure in newborn foals using an electronic sphygmoma- horses. J Vet Emerg Crit Care. 2016;26:85.
nometer. Equine Vet J. 1986;18:475. 440. Tünsmeyer J, Hopster K, Feige K, et al. Agreement of high def-
416. Fritsch R, Bosler K. Monitoring circulation in the horse during inition oscillometry with direct arterial blood pressure mea
sedation and anesthesia by indirect blood pressure measure- surement at different blood pressure ranges in horses under
ment. Berl Munch Tierarztl Wochenschr. 1985;98:166. general anaesthesia. Vet Anaesth Analg. 2015;42:286.
417. Fritsch R, Hausmann R. Indirect blood pressure determina- 441. Geddes LA, Voelz M, Combs C, et al. Characterization of the
tion in the horse with the Dinamap 1255 research monitor. oscillometric method for measuring indirect blood pressure.
Tierarztl Prax. 1988;16:373. Ann Biomed Eng. 1982;10:271.
418. Gasthuys F, De Moor A, Parmentier D. Haemodynamic chang- 442. Kittleson MD, Olivier NB. Measurement of systemic arte-
es during sedation in ponies. Vet Res Commun. 1990;14:309. rial blood pressure. Vet Clin North Am Small Anim Pract.
419. Will JA, Bisgard GE. Cardiac catheterization of unanesthetized 1983;13:321.
large domestic animals. J Appl Physiol. 1972;33:400. 443. Magdesian KG. Monitoring the critically ill equine patient. Vet
420. Gay CC, McCarthy M, Reynolds WT, et al. A method for indi- Clin North Am Equine Pract. 2004;20:11.
rect measurement of arterial blood pressure in the horse. Aust 444. Muir WW, Wade A, Grospitch B. Automatic noninvasive sphyg-
Vet J. 1977;53:163. momanometry in horses. J Am Vet Med Assoc. 1983;182:1230.
421. Geddes LA, Chaffee V, Whistler SJ, et al. Indirect mean blood 445. Ramsey 3rd M. Blood pressure monitoring: automated oscil-
pressure in the anesthetized pony. Am J Vet Res. 1977;38:2055. lometric devices. J Clin Monit. 1991;7:56.
422. Glen JB. Indirect blood pressure measurement in anesthetised 446. O’Rourke MF, Yaginuma T. Wave reflections and the arterial
animals. Vet Rec. 1970;87:349. pulse. Arch Intern Med. 1984;144:366.
423. Johnson JH, Garner HE, Hutcheson DP. Ultrasonic measur- 447. Bayly WM, Gabel AA, Barr SA. Cardiovascular effects of
ment of arterial blood pressure in conditioned Thorough- submaximal aerobic training on a treadmill in Standard-
breds. Equine Vet J. 1976;8:55. bred horses, using a standardized exercise test. Am J Vet Res.
424. Kvart C. An ultrasonic method for indirect blood pressure 1983;44:544.
measurement in the horse. J Equine Med Surg. 1979;3:16. 448. Physick-Sheard PW. Cardiovascular response to exercise
425. Latshaw H, Fessler JF, Whistler SJ, et al. Indirect measurement and training in the horse. Vet Clin North Am Equine Pract.
of mean blood pressure in the normotensive and hypotensive 1985;1:383.
horses. Equine Vet J. 1979;11:191. 449. Rugh KS, Garner HE, Miramonti JR, et al. Left ventricular
426. Lombard CW, Evans M, Martin L, et al. Blood pressure, elec- function and haemodynamics in ponies during exercise and
trocardiogram and echocardiogram measurements in the recovery. Equine Vet J. 1989;21:39.
growing pony foal. Equine Vet J. 1984;16:342. 450. Tillotson PJ, Kooper PH. Treatment of aortic thrombus in a
427. Parry BW, McCarthy MA, Anderson GA, et al. Correct occlu- horse. J Am Vet Med Assoc. 1966;149:766.
sive bladder width for indirect blood pressure measurement in 451. Tithof PK, Rebhun WC, Dietze AE. Ultrasonographic diagno-
horses. Am J Vet Res. 1982;43:50. sis of aorto-iliac thrombosis. Cornell Vet. 1985;75:540.
428. Parry BW, Gay CC, McCarthy MA. Influence of head height 452. Mouchot E, Desbrosse F. Aorto-iliac thrombosis in a horse.
on arterial blood pressure in standing horses. Am J Vet Res. Clinical examination and use of ultrasonography as a diagnos-
1980;41:1626. tic aid. Pratique Vétérinaire Équine. 1994;26:147.
453. Moore LA, Johnson PJ, Bailey KL. Aorto-iliac thrombosis in a 478. Physick-Sheard PW. Seek and ye shall find: cardiac arrhyth-
foal. Vet Rec. 1998;142:459. mias in the horse. Equine Vet J. 2013;45:270.
454. Barrelet A. Aorto-iliac thrombosis in a breeding stallion and 479. Ryan N, Marr CM, McGladdery AJ. Survey of cardiac arrhyth-
an eventer mare. Equine Vet Educ. 1993;5:86. mias during submaximal and maximal exercise in Thorough-
455. Trachsel D, Cohausz O, Scharf G, et al. Aorto-iliac thrombosis bred racehorses. Equine Vet J. 2005;37:265.
in a gelding treated with the anticoagulant phenprocoumon 480. Reef VB. Ambulatory and exercise electrocardiography and
(Marcoumar (R). Schweiz Arch Tierheilkd. 2008;150:613. post-exercise echocardiography. In: Marr CM, ed. Cardiology
456. Dickson LR, Badcoe LM, Burbidge H, et al. Jugular thrombo- of the Horse. London: WB Saunders; 1999.
phlebitis resulting from an anesthetic induction technique in 481. Sandersen C, Detilleux J, Art T, et al. Exercise and pharmaco-
the horse. Equine Vet J. 1990;22:177. logical stress echocardiography in healthy horses. Equine Vet J
457. Traub-Dargatz JL, Dargatz DA. A retrospective study of vein Suppl. 2006;159.
thrombosis in horses treated with intravenous fluids in a vet- 482. Durando M. Diagnosing cardiac disease in equine athletes: the
erinary teaching hospital. J Vet Intern Med. 1994;8:264. role of stress testing. Equine Vet J. 2005;37:101.
458. Gardner S, Reef VB, Spencer PA. Ultrasonographic evaluation 483. Gehlen H, Marnette S, Rohn K, et al. Stress echocardiography
of horses with thrombophlebitis of the jugular vein: 46 cases in warmblood horses: comparison of dobutamine/atropine
(1985-1988). J Am Vet Med Assoc. 1991;199:370. with treadmill exercise as cardiac stressors. J Vet Intern Med.
459. Durando M. Exercise and stress testing. In: Marr CM, ed. Car- 2006;20:562.
diology of the Horse. Edinburgh: Saunders Elsevier; 2010. 484. Durando MM, Slack J, Reef VB, et al. Right ventricular pressure
460. Franklin S, Allen K. Laboratory exercise testing. In: Hinchcliff dynamics and stress echocardiography in pharmacological and
KW, Kaneps AJ, Geor RJ, eds. Equine Sports Medicine and Sur- exercise stress testing. Equine Vet J Suppl. 2006;183–192.
gery. Edinburgh: Saunders Elsevier; 2014. 485. Coudry V, Jean D, Desbois C, et al. Myocardial fibrosis in a
461. Couroucé-Malblanc A, van Erck-Westergren E. Exercise test- horse with polymorphic ventricular tachycardia observed dur-
ing in the field. In: Hinchcliff KW, Kaneps AJ, Geor RJ, eds. ing general anesthesia. Can Vet J. 2007;48:623.
Equine Sports Medicine and Surgery. Edinburgh: Saunders El- 486. Finley MR, Li Y, Hua F, et al. Expression and coasso-
sevier; 2014. ciation of ERG1, KCNQ1, and KCNE1 potassium channel
462. Verheyen T, Decloedt A, De Clercq D, et al. Electrocardiogra- proteins in horse heart. Am J Physiol Heart Circ Physiol.
phy in horses—part 1: how to make a good recording. Vlaams 2002;283:H126.
Diergen Tijds. 2010;79:331. 487. Kuwahara M, Hiraga A, Kai M, et al. Influence of training on
463. Rose R. Symposium on exercise physiology—foreword. Vet autonomic nervous function in horses: evaluation by power
Clin North Am Equine Pract. 1985;1:437. spectral analysis of heart rate variability. Equine Vet J Suppl.
464. Poggenpoel DG. Measurements of heart rate and riding speed 1999;30:178.
on a horse during a training programme for endurance rides. 488. Glomset DJ, Glomset ATA, Moines D. A morphologic study
Equine Vet J. 1988;20:224. of the cardiac conduction system in ungulates, dog, and man.
465. Thornton JR. Exercise testing. Vet Clin North Am Equine Pract. Part I: the sinoatrial node. Am Heart J. 1940;20:389.
1985;1:573. 489. Gross DR. Practical electrocardiography in the equine subject.
466. Evans DL, Rose RJ. Dynamics of cardiorespiratory function in J Am Vet Med Assoc. 1971;159:1335.
Standardbred horses during different intensities of constant- 490. Grauerholz H, Jaeschke G. Construction of main and refer-
load exercise. J Comp Physiol B. 1988;157:791. ence vectors from limb leads in the ECG of the horse. Berl
467. Foreman JH, Bayly WM, Grant BD, et al. Standardized exer- Munch Tierarztl Wochenschr. 1988;101:376.
cise test and daily heart rate responses of thoroughbreds un- 491. Grauerholz H, Jaeschke G. Training-induced changes of refer-
dergoing conventional race training and detraining. Am J Vet ence vectors in the QRS complex of the EKG of young trotting
Res. 1990;51:914. horses. Berl Munch Tierarztl Wochenschr. 1990;103:329.
468. Rose RJ, Hendrickson DK, Knight PK. Clinical exercise testing 492. Grauerholz H. Influence of respiration on the QRS complex
in the normal Thoroughbred racehorse. Aust Vet J. 1990;67:345. of the ECG in clinically healthy horses and in horses with
469. Seeherman HJ, Morris EA. Comparison of yearling, two-year- respiratory problems. Berl Munch Tierarztl Wochenschr.
old and adult Thoroughbreds using a standardised exercise 1990;103:293.
test. Equine Vet J. 1991;23:175. 493. Grauerholz H, Jaeschke G. Alterations induced by training in
470. Reinhard HJ, Zichner M. Evaluation of telemetrically derived reference vectors of the electrocardiographic QRS complex
stress electrocardiograms of the horse using an electronic of young trotting horses. Berl Munch Tierarztl Wochenschr.
computer. Dtsch Tierarztl Wochenschr. 1970;77:211. 1990;103:329.
471. Physick-Sheard PW, Marlin DJ, Thornhill R, et al. Frequency 494. Grauerholz H, Jaeschke G. The construction of the main and
domain analysis of heart rate variability in horses at rest and reference vectors from the limb circuits in the ECG of the
during exercise. Equine Vet J. 2000;32:253. horse. Berl Munch Tierarztl Wochenschr. 1988;101:376.
472. Verheyen T, Decloedt A, van der Vekens N, et al. Ventricular 495. Hartley JW, Hahn AW, DeLorey M, et al. Digital processing
response during lungeing exercise in horses with lone atrial of equine exercise electrocardiograms. Biomed Sci Instrum.
fibrillation. Equine Vet J. 2013;45:309. 1990;26:11.
473. Amada A, Kurita H. Five cases of paroxysmal atrial fibrillation 496. Hilwig RW. Cardiac Arrhythmias in the horse. J Am Vet Med
in the racehorse. Exp Rep Equine Health Lab. 1975;12:89. Assoc. 1977;170:153.
474. Hiraga A, Kubo K. Two cases of paroxysmal atrial fibrillation 497. Hanak J, Zert Z. Some ECG characters in Thoroughbred horses,
during exercise in horses. Equine Vet Educ. 1999;11:6. common to parents and their offspring. Vet Med (Praha).
475. Physick-Sheard PW, McGurrin MK. Ventricular arrhyth- 1982;27:87.
mias during race recovery in Standardbred Racehorses 498. Hanak J, Jagos P. Electrocardiographic lead system and its vec-
and associations with autonomic activity. J Vet Intern Med. tor verification. Acta Veterinaria Brno. 1983;52:67.
2010;24:1158. 499. Fregin GF. The equine electrocardiogram with standardized
476. Hada T, Ohmura H, Mukai K, et al. Utilisation of the time body and limb positions. Cornell Vet. 1982;72:304.
constant calculated from heart rate recovery after exercise for 500. Fregin GF. Electrocardiography. Vet Clin North Am Equine
evaluation of autonomic activity in horses. Equine Vet J Suppl. Pract. 1985;1:419.
2006;141. 501. Bonagura JD, Miller MS. Electrocardiography. In: Jones WE,
477. Thayer JF, Hahn AW, Pearson MA, et al. Heart rate variability ed. Equine Sports Medicine. Philadelphia: Lea and Febiger;
during exercise in the horse. Biomed Sci Instrum. 1997;34:246. 1985.
502. Bonagura JD, Miller MS. Electrocardiography. What is your 527. Verheyen T, Decloedt A, De Clercq D, et al. Oesophageal elec-
diagnosis? Junctional and ventricular arrhythmias. J Equine trocardiography in healthy horses. Equine Vet J. 2012;44:640.
Vet Sci. 1985;5:347. 528. Verheyen T, Decloedt A, De Clercq D, et al. Electrocardiog-
503. Clark DR, McCrady JD. Clinical use of the electrocardiogram raphy in horses—part 2: how to read the equine ECG. Vlaams
in animals. I. Fundamentals of ECG examination. Vet Med Diergen Tijds. 2010;79:337.
Small Anim Clin. 1966;61:751. 529. Vibe-Petersen G, Nielsen K. Electrocardiography in the
504. Cornick JL, Seahorn TL. Cardiac arrhythmias identified in horse (A report of findings in 138 horses). Nord Vet Med.
horses with duodenitis/proximal jejunitis: six cases (1985- 1980;32:105.
1988). J Am Vet Med Assoc. 1990;197:1054. 530. Gross DR. Practical electrocardiography in the horse. J Am Vet
505. Costa G, Illera M, Garcia-Sacristan A. Electrocardiographi- Med Assoc. 1972;160:672.
cal values in non-trained horses. Zentralbl Veterinarmed A. 531. Banister EW, Purvis AD. Exercise electrocardiography in the
1985;32:196. horse by radiotelemetry. J Am Vet Med Assoc. 1968;152:1004.
506. Illera JC, Illera M. Physiological electrocardiograms as the ba- 532. Deegen E, Reinhard HJ. Electrocardiographic time patterns
sis for diagnosis of heart diseases in horses. Medicina Veteri- in the healthy Shetland pony. Dtsch Tierarztl Wochenschr.
naria. 1986;3:239. 1974;81:257.
507. Illera JC, Illera M. Electrocardiography and heart score of 533. Buss DD, Rwalings CA, Bisgard GE. The normal electrocar-
horses competing in an endurance ride. Aust Vet J. 1987;64:88. diogram of the domestic pony. J Electrocardiol. 1975;8:167.
508. Illera JC, Illera M. Precordial heart score. Aust Vet J. 534. Zucca E, Ferrucci F, Di Fabio V, et al. The use of electrocar-
1988;65:355. diographic recording with Holter monitoring during treadmill
509. Irie T. A study of arrhythmias in Thoroughbred newborn foals exercise to evaluate cardiac arrhythmias in racehorses. Vet Res
immediately after birth. Jpn J Vet Res. 1990;38:57. Commun. 2003;27:811.
510. Kuwahara M, Hashimoto S, Ishii K, et al. Assessment of au- 535. Reef VB. Electrocardiography and echocardiography in the
tonomic nervous function by power spectral analysis of heart exercising horse. In: Robinson NE, ed. Current Therapy in
rate variability in the horse. J Auton Nerv Syst. 1996;60:43. Equine Medicine 4. Philadelphia: WB Saunders; 1997.
511. Landgren S, Rutqvist L. Electrocardiogram of normal cold 536. Pedersen PJ, Kanters JK, Buhl R, et al. Normal electrocardio-
blooded horses after work. Nord Vet Med. 1953;5:905. graphic QT interval in race-fit Standardbred horses at rest and
512. Lannek N, Rutqvist L. Normal area of variation for the electro- its rate dependence during exercise. J Vet Cardiol. 2013.
cardiogram of horses. Nord Vet Med. 1951;3:1094. 537. Pedersen PJ, Karlsson M, Flethoj M, et al. Differences in the
513. Matsui K. Fetal and maternal heart rates in a case of twin pregnan- electrocardiographic QT interval of various breeds of athletic
cy of the Thoroughbred horse. Nihon Juigaku Zasshi. 1985;47:817. horses during rest and exercise. J Vet Cardiol. 2016.
514. Miller MS, Bonagura JD. Genesis of the equine electrocardio- 538. Trachsel DS, Bitschnau C, Waldern N, et al. Observer agree-
gram and indications for electrocardiography in clinical prac- ment for detection of cardiac arrhythmias on telemetric ECG
tice. J Equine Vet Sci. 1985;5:23. recordings obtained at rest, during and after exercise in 10
515. Polglaze K, Evans DL. The relationship between racing perfor- Warmblood horses. Equine Vet J. 2010;42:208.
mance and electrocardiographic findings in the Standardbred 539. Pedersen PJ, Moeller SB, Flethoj M, et al. Diurnal modulation
racehorse. Aust Equine Vet. 1992;10:88. and sources of variation affecting ventricular repolarization in
516. Rose RJ, Davis PE. The use of electrocardiography in the di- Warmblood horses. J Vet Cardiol. 2014;16:265.
agnosis of poor racing performance in the horse. Aust Vet J. 540. Hiraga A, Sugano S. History of research in Japan on electrocar-
1978;54:51. diography in the racehorse. J Equine Sci. 2015;26:1.
517. Stewart JH, Rose RJ, Davis PE, et al. A comparison of elec- 541. Scheffer CW, Robben JH. Sloet van Oldruitenborgh-Ooster-
trocardiographic findings in racehorses presented either for baan MM: continuous monitoring of ECG in horses at rest
routine examination or poor racing performance. In: Persson and during exercise. Vet Rec. 1995;137:371.
SGB, Rose RJ, eds. Equine Exercise Physiology. Cambridge, 542. Persson SGB, Forssbergy P. Exercise tolerance in Standard-
England: Granta; 1983. bred trotters with T-wave abnormalities. In: Gillespie JR, Rob-
518. Studzinski T, Czarnecki A. Relationship between the QRS du- inson NE, eds. Equine Exercise Physiology. Davis, CA: ICEEP
ration (heart score) and ventricular weight in horses, Annales publications; 1987.
Universitatis Mariae Curie Sklodowska. DD Medicina Veteri- 543. Matsui K, Sugano S. Species differences in the changes in heart
naria 35/36. 1980;33. rate and T-wave amplitude after autonomic blockade in Thor-
519. Tovar P, Escabias MI, Santisteban R. Evolution of the ECG oughbred horses, ponies, cows, pigs, goats and chickens. Ni-
from Spanish bred foals during the post natal stage. Res Vet hon Juigaku Zasshi. 1987;49:637.
Sci. 1989;46:358. 544. Koblik PD, Hornof WJ. Diagnostic-radiology and nuclear
520. Tschudi P. Electrocardiography in the horse (1). Principles cardiology—their use in assessment of equine cardiovascular-
and normal picture. Tierarztl Prax. 1985;13:181. disease. Vet Clin North Am Equine Pract. 1985;1:289.
521. Tschudi P. Electrocardiography in the horse. (3). Tierarztl 545. Carlsten J, Kvart C, Jeffcott LB. Method of selective and
Prax. 1986;14:365. non-selective angiocardiography for the horse. Equine Vet J.
522. White 2nd NA, Rhode EA. Correlation of electrocardiograph- 1984;16:47.
ic findings to clinical disease in the horse. J Am Vet Med Assoc. 546. Lombard CW. Cardiovascular diseases. In: Koterba AM, ed.
1974;164:46. Equine Clinical Neonatology. Malvern, PA: Lea & Febiger; 1990.
523. Yamamoto K, Yasuda J, Too K. Electrocardiographic findings 547. Marr CM. Ancillary diagnostic aids in equine cardiology.
during parturition and blood gas tensions immediately after Equine Vet Educ. 1990;2:18.
birth in Thoroughbred foals. Jpn J Vet Res. 1991;39:143. 548. O’Brien RT, Biller DS. Field imaging of the respiratory tract.
524. Yamamoto K, Yasuda J, Too K. Arrhythmias in newborn thor- Radiology and ultrasonography. Vet Clin North Am Equine
oughbred foals. Equine Vet J. 1992;24:169. Pract. 1997;13:487.
525. Yamaya Y, Kubo K, Amada A, et al. Intrinsic atrioventricular 549. Scott EA, Chaffee A, Eyster GE, et al. Interruption of aortic
conductive function in horses with a 2nd- degree atrioventric- arch in two foals. J Am Vet Med Assoc. 1978;172:347.
ular-block. J Vet Med Sci. 1997;59:149. 550. Stewart JH, Rose RJ, Barko AM. Echocardiography in foals
526. Ayala I, Montes A, Benedito JL, et al. Modifications of the form from birth to three months old. Equine Vet J. 1984;16:332.
and amplitude of the electrocardiographic QRS complex dur- 551. O’Callaghan MW. Comparison of echocardiographic and
ing growth in the Spanish-bred Horse. Zentralbl Veterinarmed autopsy measurements of cardiac dimensions in the horse.
A. 1998;45:309. Equine Vet J. 1985;17:361.
552. Pipers FS, Reef V, Wilson J. Echocardiographic detection of 577. Hallowell G, Bowen M. Reliability and identification of aortic
ventricular septal defects in large animals. J Am Vet Med Assoc. valve prolapse in the horse. BMC Vet Res. 2013;9:9.
1985;187:810. 578. Slack J, Durando MM, Belcher CN, et al. Intraoperator, in-
553. Bertone JJ, Paull KS, Wingfield WE, et al. M-mode echocar- traobserver and interoperator variability of echocardiographic
diographs of endurance horses in the recovery phase of long- measurements in healthy foals. Equine Vet J. 2012;44:69.
distance competition. Am J Vet Res. 1987;48:1708. 579. Underwood C, Norton JL, Nolen-Walston RD, et al. Echocar-
554. Reef VB, Spencer P. Echocardiographic evaluation of equine diographic changes in heart size in hypohydrated horses. J Vet
aortic insufficiency. Am J Vet Res. 1987;48:904. Intern Med. 2011;25:563.
555. Reef VB. Echocardiographic examination in the horse—the 580. Collins NM, Palmer L, Marr CM. Two-dimensional and M-
basics. Comp Cont Educ Pract. 1990;12:1312. mode echocardiographic findings in healthy Thoroughbred
556. Reef VB. Echocardiographic findings in horses with congeni- foals. Aust Vet J. 2010;88:428.
tal cardiac disease. Comp Cont Educ Pract. 1991;13:109. 581. Rovira S, Munoz A. Two-dimensional- and M-mode echocardi-
557. Stadler P, Weinberger T, Kinkel N, et al. B-mode-, M-mode- ographic measurements and indices of cardiac function in Span-
and Doppler sonographic findings in mitral valve insufficiency ish colts and fillies of different age. J Vet Med Sci. 2009;71:957.
(MVI) in horses. J Vet Med. 1992;39:704. 582. Rovira S, Muñoz A, Rodilla V. Allometric scaling of echocar-
558. Long KJ. Doppler echocardiography—clinical applications. diographic measurements in healthy Spanish foals with differ-
Equine Vet Educ. 1993;5:161. ent body weight. Res Vet Sci. 2009;86:325.
559. Bonagura JD. Echocardiography. J Am Vet Med Assoc. 1994; 583. Imhasly A, Tschudi PR, Lombard CW, et al. Clinical and echo-
204:516. cardiographic features of mild mitral valve regurgitation in
560. Blissitt KJ, Bonagura JD. Colour flow Doppler echocardiogra- 108 horses. Vet J. 2010;183:166.
phy in normal horses. Equine Vet J Suppl. 1995;47. 584. Menzies-Gow NJ. Effects of sedation with acepromazine on
561. Tucker RL, Wickler SJ, London C, et al. Echocardiographic echocardiographic measurements in eight healthy thorough-
and right-sided cardiac pressure comparison of the mule and bred horses. Vet Rec. 2008;163:21.
horse. J Equine Vet Sci. 1995;15:404. 585. Durando MM, Reef VB, Birks EK. Right ventricular pressure
562. Darke PGG, Bonagura JD, Kelly DF. Colour Atlas of Veterinary dynamics during exercise: relationship to stress echocardiog-
Cardiology. 1st ed. London: Mosby; 1996. raphy. Equine Vet J Suppl. 2002;472.
563. Reef VB. Evaluation of ventricular septal defects in horses us- 586. Helwegen MM, Young LE, Rogers K, et al. Measurements of
ing two-dimensional and Doppler echocardiography. Equine right ventricular internal dimensions and their relationships
Vet J Suppl. 1995;86. to severity of tricuspid valve regurgitation in national hunt
564. Lescure F, Tamzali Y. Reference values for echocardiography Thoroughbreds. Equine Vet J Suppl. 2006;171.
applied to sport horses (English Thoroughbreds and French 587. Buhl R, Ersboll AK, Larsen NH, et al. The effects of detomi-
riding horses). Rev Med Vet (Toulouse). 1984;135:405. dine, romifidine or acepromazine on echocardiographic mea
565. Lord PF, Croft MA. Accuracy of formulae for calculating left surements and cardiac function in normal horses. Vet Anaesth
ventricular volumes of the equine heart. Equine Vet J Suppl Analg. 2007;34:1.
Supplement. 1990;9:53. 588. Young LE, Rogers K, Wood JL. Left ventricular size and sys-
566. Young L. Transoesophageal echocardiography. In: Marr CM, tolic function in Thoroughbred racehorses and their relation-
ed. Cardiology of the Horse. London: WB Saunders; 1999. ships to race performance. J Appl Physiol. 2005;99:1278.
567. Buhl R, Ersboll AK, Eriksen L, et al. Sources and magnitude 589. Brown DJ, Rush JE, MacGregor J, et al. M-mode echocardio-
of variation of echocardiographic measurements in normal graphic ratio indices in normal dogs, cats, and horses: a novel
standardbred horses. Vet Radiol Ultrasound. 2004;45:505. quantitative method. J Vet Intern Med. 2003;17:653.
568. Zucca E, Ferrucci F, Croci C, et al. Echocardiographic mea 590. Marr CM, Patteson M. Echocardiography. In: Marr CM, ed.
surements of cardiac dimensions in normal Standardbred Cardiology of the Horse. Edinburgh: Saunders Elsevier; 2010.
racehorses. J Vet Cardiol. 2008;10:45. 591. Reef VB. Cardiovascular ultrasonography. In: Reef VB, ed.
569. Al Haidar A, Farnir F, Deleuze S, et al. Comparison of the re- Equine Diagnostic Ultrasound. Philadelphia: W.B. Saunders;
peatability of echocardiographic measurements from differ- 1998.
ent modes and views in horses of various breeds and sizes. J 592. Young LE, Scott GR. Measurement of cardiac function by tran-
Equine Vet Sci. 2010;30:287. sthoracic echocardiography: day to day variability and repeata-
570. Al Haidar A, Farnir F, Deleuze S, et al. Effect of breed, sex, age bility in normal Thoroughbred horses. Equine Vet J. 1998;30:117.
and body weight on echocardiographic measurements in the 593. Sampson SN, Jacobson RL, Sande RD, et al. Reproducibil-
Equine species. Res Vet Sci. 2013;95:255. ity and repeatability of M-mode echocardiographic measure-
571. Al Haidar A, Leroux A, Borde L, et al. Relationship between ments collected from 25 normal horses. J Equine Vet Sci.
echocardiographic measurements and body size in horses. J 1999;19:51.
Equine Vet Sci. 2013;33:107. 594. Otto CM. Textbook of Clinical Echocardiography. 5th ed. Phila-
572. Decloedt A, de Clercq D, van der Vekens N, et al. Noninvasive delphia: Elsevier Saunders; 2013.
determination of atrial fibrillation cycle length by atrial colour 595. Lang RM, Badano LP, Mor-Avi V, et al. Recommendations for
tissue Doppler imaging in horses. Equine Vet J. 2014;46:174. cardiac chamber quantification by echocardiography in adults:
573. Decloedt A, De Clercq D, Ven Sofie S, et al. Echocardiographic an update from the American Society of Echocardiography
measurements of right heart size and function in healthy horses. and the European Association of Cardiovascular Imaging. J
Equine Vet J. 2016. Am Soc Echocardiogr. 2015;28:1.
574. Decloedt A, Verheyen T, Sys S, et al. Influence of atrioven- 596. Gehlen H, Kroker K, Deegen E, et al. Influence of detomidine
tricular interaction on mitral valve closure and left ventricular on cardiac function and hemodynamic in horses with and
isovolumic contraction measured by tissue Doppler imaging. without heart murmur. Schweiz Arch Tierheilkd. 2004;146:119.
Circ Cardiovasc Imaging. 2013;6:109. 597. Underwood C, Schwarzwald CC. Equine Echocardiography:
575. Verheyen T, Decloedt A, De Clercq D, et al. Cardiac changes in Do We All Know What We All Do? Results of a Recent Survey
horses with atypical myopathy. J Vet Intern Med. 2012;26:1019. (unpublished data). Switzerland: University of Queensland,
576. Huesler IM, Mitchell KJ, Schwarzwald CC. Echocardiograph- Australia and University of Zurich, Switzerland.; 2013.
ic assessment of left atrial size and function in Warmblood 598. Rantanen NW. Diseases of the thorax. Vet Clin North Am
horses: reference intervals, allometric scaling, and agreement Equine Pract. 1986;2:49.
of different echocardiographic variables. J Vet Intern Med. 599. Bonagura JD, Pipers FS. Diagnosis of cardiac lesions by con-
2016;30:1241. trast echocardiography. J Am Vet Med Assoc. 1983;182:396.
600. Young LE, Long KJ, Clutton RE, et al. The use of two dimen- 622. Schatzmann U, Battier B. Factors influencing central venous
sional and Doppler echocardiography for haemodynamic pressure in horses. Dtsch Tierarztl Wochenschr. 1987;94:147.
monitoring during general anaesthesia: preliminary find- 623. Sheridan V, Zeller R, Deegen E. Central venous pressure
ings in halothane-anaesthetised horses. Vet Anaesth Analg. (C.V.P.) measurements during halothane anesthesia in horse.
1993;20:42. Vet Rec. 1972;90:149.
601. Guglielmini C, Pietra M, Bernardini D, et al. Colour-coded 624. Sinha AK, Gleed RD, Hakim TS, et al. Pulmonary capillary
Doppler echocardiography in the horse. Part II: abnormal pressure during exercise in horses. J Appl Physiol. 1996;80:1792.
findings. Ippologia. 2001;12:15. 625. Spörri H, Denac M. The ventricular pressure increase velocity
602. Ven S, Decloedt A, Van Der Vekens N, et al. Assessing aor- as a parameter of myocardial strength development. Schweiz
tic regurgitation severity from 2D, M-mode and pulsed wave Arch Tierheilkd. 1969;111:239.
Doppler echocardiographic measurements in horses. Vet J. 626. Staddon GE, Weaver BM, Webb AI. Distribution of cardiac
2016;210:34. output in anaesthetised horses. Res Vet Sci. 1979;27:38.
603. Stoylen A. Strain Rate Imaging: Cardiac Deformation Imaging 627. Stadler P, Kinkel N, Deegen E. Evaluation of systolic heart
by Ultrasound/Echocardiography—Tissue Doppler and Speckle function of the horse with PW- Doppler-echocardiography
Tracking; 2016. Available from: http://folk.ntnu.no/stoylen/str compared with thermodilution. Dtsch Tierarztl Wochenschr.
ainrate/. 1994;101:312.
604. Sepulveda MF, Perkins JD, Bowen IM, et al. Demonstration of 628. Weber JM, Dobson GP, Parkhouse WS, et al. Cardiac output
regional differences in equine ventricular myocardial velocity and oxygen consumption in exercising Thoroughbred horses.
in normal 2-year-old Thoroughbreds with Doppler tissue im- Am J Physiol. 1987;253:R890.
aging. Equine Vet J. 2005;37:222. 629. West JB, Mathieucostello O. Stress failure of pulmonary capil-
605. Atkins CE, Snyder PS. Systolic time intervals and their de- laries as a mechanism for exercise-induced pulmonary hemor-
rivatives for evaluation of cardiac function. J Vet Intern Med. rhage in the horse. Equine Vet J. 1994;26:441.
1992;6:55. 630. Wetmore LA, Derksen FJ, Blaze CA, et al. Mixed venous
606. Amend JF, Garner HE, Rosborough JP, et al. Hemodynamic oxygen-tension as an estimate of cardiac-output in anesthe-
studies in conscious domestic ponies. J Surg Res. 1975;19:107. tized horses. Am J Vet Res. 1987;48:971.
607. Bove AA. Effects of strenuous exercise on myocardial blood 631. Ringer SK, Schwarzwald CC, Portier KG, et al. Effects on
flow. Med Sci Sports Exerc. 1985;17:517. cardiopulmonary function and oxygen delivery of doses of
608. Davis JL, Manohar M. Effect of splenectomy on exercise-in- romifidine and xylazine followed by constant rate infusions in
duced pulmonary and systemic hypertension in ponies. Am J standing horses. Vet J. 2013;195:228.
Vet Res. 1988;49:1169. 632. Nollet H, Van Loon G, Deprez P, et al. Use of right ventricu-
609. Drummond WH, Sanchez IR, Kosch PC, et al. Pulmonary lar pressure increase rate to evaluate cardiac contractility in
vascular reactivity of the newborn pony foal. Equine Vet J. horses. Am J Vet Res. 1999;60:1508.
1989;21:181. 633. Moscucci M. Grossman & Baim’s Cardiac Catheterization, An-
610. Erickson BK, Erickson HH, Coffman JR. Pulmonary artery giography, and Intervention. 8th ed. Philadelphia, PA: Wolters
and aortic pressure changes during high intensity treadmill Kluwer; 2014.
exercise in the horse: effect of frusemide and phentolamine. 634. Button K. Application of percutaneous technique to equine
Equine Vet J. 1992;24:215. vascular catheterization. J Equine Med Surg. 1979;3:320.
611. Gasthuys F, Muylle E, de Moor A, et al. Influence of premedi- 635. Manohar M. Left ventricular oxygen extraction during sub-
cation and body position during halothane anaesthesia on maximal and maximal exertion in ponies. J Physiol. 1988;
intracardial pressures in the horse. Zentralbl Veterinarmed A. 404:547.
1988;35:729. 636. Butler HC. Subcutaneous relocation of the carotid artery for
612. Hall LW, Nigam JM. Papers and articles measurement of cen- experimental purposes. Am J Vet Res. 1962;23:165.
tral venous pressure in horses. Vet Rec. 1975;97:66. 637. Manohar M. Pulmonary artery wedge pressure increases with
613. Hall LW. Cardiovascular and pulmonary effects of recumben- high-intensity exercise in horses. Am J Vet Res. 1993;54:142.
cy in two conscious ponies. Equine Vet J. 1984;16:89. 638. Constable P, Muir 3rd W, Sisson D. Clinical assessment of left
614. Hellyer PW, Dodam JR, Light GS. Dynamic baroreflex sen- ventricular relaxation. J Vet Intern Med. 1999;13:5.
sitivity in anesthetized horses, maintained at 1.25 to 1.3 639. Stadler P, Fruhauf B, Deegen E. Echocardiographic determi-
minimal alveolar concentration of halothane. Am J Vet Res. nation of diastolic heart function and measurement of pulmo-
1991;52:1672. nary wedge pressure in horses. Pferdeheilkunde. 1995;11:109.
615. Hillidge CJ, Lees P. Influence of general anaesthesia on pe- 640. Klein L, Sherman J. Effects of preanesthetic medication, anes-
ripheral resistance in the horse. Br Vet J. 1977;133:225. thesia, and position of recumbency on central venous pressure
616. Hinchcliff KW, McKeever KH, Schmall LM, et al. Renal and in horses. J Am Vet Med Assoc. 1977;170:216.
systemic hemodynamic responses to sustained submaximal 641. Bergsten G. Blood pressure, cardiac output, and blood-gas
exertion in horses. Am J Physiol. 1990;258:R1177. tension in the horse at rest and during exercise. Acta Vet Scand
617. Manohar M. Right heart pressures and blood-gas tensions in Suppl. 1974;48:1.
ponies during exercise and laryngeal hemiplegia. Am J Physiol. 642. Grubb TL, Constable PD, Benson GJ, et al. Techniques for
1986;251:H121. evaluation of right ventricular relaxation rate in horses and ef-
618. Manohar M, Goetz TE, Hutchens E, et al. Atrial and ventricu- fects of inhalant anesthetics with and without intravenous ad-
lar myocardial blood flows in horses at rest and during exer- ministration of calcium gluconate. Am J Vet Res. 1999;60:872.
cise. Am J Vet Res. 1994;55:1464. 643. Goetz TE, Manohar M. Pressures in the right side of the heart
619. Manohar M. Pulmonary vascular pressures of strenuously ex- and esophagus (Pleura) in ponies during exercise before and
ercising Thoroughbreds after administration of flunixin meg- after furosemide administration. Am J Vet Res. 1986;47:270.
lumine and furosemide. Am J Vet Res. 1994;55:1308. 644. Art T, Bayly W. Lower airway function: response to exercise
620. Manohar M, Goetz TE, Hutchens E, et al. Effects of graded- and training. In: Hinchcliff KW, Kaneps AJ, Geor RJ, eds.
exercise on pulmonary and systemic hemodynamics in horses. Equine Sports Medicine and Surgery. W.B. Saunders; 2014.
Equine Pract. 1995;17:17. 645. Edwards WD. Pathology of pulmonary hypertension. Cardio-
621. Muir WW, McGuirk SM. Hemodynamics before and after vasc Clin. 1988;18:321.
conversion of atrial fibrillation to normal sinus rhythm in 646. Bisgard GE, Orr JA, Will JA. Hypoxic pulmonary hyperten-
horses. J Am Vet Med Assoc. 1984;184:965. sion in the pony. Am J Vet Res. 1975;36:49.
647. Gelberg HB, Smetzer DL, Foreman JH. Pulmonary hyperten- 668. Raftery AG, Garcia NC, Thompson H, et al. Arrhythmogenic
sion as a cause of atrial fibrillation in young horses: four cases right ventricular cardiomyopathy secondary to adipose infiltra-
(1980-1989). J Am Vet Med Assoc. 1991;198:679. tion as a cause of episodic collapse in a horse. Ir Vet J. 2015;68:1.
648. Long KJ, Young LE, Utting JE, et al. Determination of cardiac 669. Durando MM, Reef VB, Kline K, et al. Acute effects of short
output in the standing horse by Doppler echocardiography duration, maximal exercise on cardiac troponin I in healthy
and thermodilution. Proc 30th British Equine Vet Assoc Con- horses. Equine Comp Exerc Physiol. 2006;3:217.
gress 30. 1991. 670. Holbrook TC, Birks EK, Sleeper MM, et al. Endurance exer-
649. O’Brien PJ, Dameron GW, Beck ML, et al. Differential reactiv- cise is associated with increased plasma cardiac troponin I in
ity of cardiac and skeletal muscle from various species in two horses. Equine Vet J Suppl. 2006;27.
generations of cardiac troponin-T immunoassays. Res Vet Sci. 671. Nostell K, Haggstrom J. Resting concentrations of cardiac
1998;65:135. troponin I in fit horses and effect of racing. J Vet Cardiol.
650. Rossi TM, Pyle WG, Maxie MG, et al. Troponin assays in 2008;10:105.
the assessment of the equine myocardium. Equine Vet J. 672. Slack J, Boston RC, Soma L, et al. Cardiac troponin I in racing
2014;46:270. standardbreds. J Vet Intern Med. 2012;26:1202.
651. Schwarzwald CC, Hardy J, Buccellato M. High cardiac tro- 673. Flethoj M, Kanters JK, Haugaard MM, et al. Changes in heart
ponin I serum concentration in a horse with multiform ven- rate, arrhythmia frequency, and cardiac biomarker values in
tricular tachycardia and myocardial necrosis. J Vet Intern Med. horses during recovery after a long-distance endurance ride. J
2003;17:364. Am Vet Med Assoc. 2016;248:1034.
652. Slack JA, McGuirk SM, Erb HN, et al. Biochemical markers 674. Van Der Vekens N, Decloedt A, Ven S, et al. Cardiac troponin
of cardiac injury in normal, surviving septic, or nonsurviving I as compared to troponin T for the detection of myocardial
septic neonatal foals. J Vet Intern Med. 2005;19:577. damage in horses. J Vet Intern Med. 2015;29:348.
653. Cornelisse CJ, Schott 2nd HC, Olivier NB, et al. Concentration 675. Van Der Vekens N, van Dievoet MA, De Puydt H, et al. Ana-
of cardiac troponin I in a horse with a ruptured aortic regur- lytical validation of a high-sensitivity cardiac troponin T assay
gitation jet lesion and ventricular tachycardia. J Am Vet Med in horses. J Vet Diagn Invest. 2015;27:504.
Assoc. 2000;217:231. 676. Van Der Vekens N, Decloedt A, Sys S, et al. Evaluation of as-
654. Diana A, Guglielmini C, Candini D, et al. Cardiac arrhythmias says for troponin I in healthy horses and horses with cardiac
associated with piroplasmosis in the horse: a case report. Vet J. disease. Vet J. 2015;203:97.
2007;174:193. 677. Shields E, Seiden-Long I, Massie S, et al. Analytical validation
655. Jesty SA, Kraus MS, Gelzer AR, et al. Effect of transvenous elec- and establishment of reference intervals for a ‘high-sensitivity’
trical cardioversion on plasma cardiac troponin I concentrations cardiac troponin-T assay in horses. BMC Vet Res. 2016;12:104.
in horses with atrial fibrillation. J Vet Intern Med. 2009;23:1103. 678. Begg LM, Hoffmann KL, Begg AP. Serum and plasma cardiac
656. Kraus MS, Jesty SA, Gelzer AR, et al. Measurement of plasma troponin I concentrations in clinically normal Thoroughbreds
cardiac troponin I concentration by use of a point-of-care ana- in training in Australia. Aust Vet J. 2006;84:336.
lyzer in clinically normal horses and horses with experimen- 679. Phillips W, Giguere S, Franklin RP, et al. Cardiac troponin I in
tally induced cardiac disease. Am J Vet Res. 2010;71:55. pastured and race-training Thoroughbred horses. J Vet Intern
657. Serra M, Papakonstantinou S, Adamcova M, et al. Veterinary Med. 2003;17:597.
and toxicological applications for the detection of cardiac in- 680. Kraus MS, Kaufer BB, Damiani A, et al. Elimination half-life
jury using cardiac troponin. Vet J. 2010;185:50. of intravenously administered equine cardiac troponin I in
658. Durando MM, Birks EK, Hussey SB, et al. Cardiac troponin healthy ponies. Equine Vet J. 2013;45:56.
I concentrations in ponies challenged with equine influenza 681. Mifune H, Richter R, Forssmann WG. Detection of immu-
virus. J Vet Intern Med. 2011;25:339. noreactive atrial and brain natriuretic peptides in the equine
659. Gilliam LL, Holbrook TC, Ownby CL, et al. Cardiotoxicity, atrium. Anat Embryol (Berl). 1995;192:117.
inflammation, and immune response after rattlesnake enveno- 682. McKeever KH, Hinchcliff KW, Cooley JL, et al. Arterial-
mation in the horse. J Vet Intern Med. 2012;26:1457. venous difference in atrial natriuretic peptide concentration
660. Nath LC, Anderson GA, Hinchcliff KW, et al. Clinicopatho- during exercise in horses. Am J Vet Res. 1992;53:2174.
logic evidence of myocardial injury in horses with acute ab- 683. Kokkonen UM, Hackzell M, Rasanen LA. Plasma atrial natriu-
dominal disease. J Am Vet Med Assoc. 2012;241:1202. retic peptide in standardbred and Finnhorse trotters during
661. Nath LC, Anderson GA, Hinchcliff KW, et al. Serum cardiac and after exercise. Acta Physiol Scand. 1995;154:51.
troponin I concentrations in horses with cardiac disease. Aust 684. McKeever KH, Hinchcliff KW. Neuroendocrine control of
Vet J. 2012;90:351. blood volume, blood pressure and cardiovascular function in
662. Nostell K, Brojer J, Hoglund K, et al. Cardiac troponin I and horses. Equine Vet J. 1995;27:77.
the occurrence of cardiac arrhythmias in horses with experi- 685. Nyman S, Kokkonen UM, Dahlborn K. Changes in plasma
mentally induced endotoxaemia. Vet J. 2012;192:171. atrial natriuretic peptide concentration in exercising horses
663. Radcliffe RM, Divers TJ, Fletcher DJ, et al. Evaluation of L- in relation to hydration status and exercise intensity. Am J Vet
lactate and cardiac troponin I in horses undergoing emergen- Res. 1998;59:489.
cy abdominal surgery. J Vet Emerg crit care (San Antonio, TX: 686. Kokkonen UM, Hyyppa S, Poso AR. Plasma atrial natriuretic
2001). 2012;(22):313. peptide during and after repeated exercise under heat expo-
664. van der Vekens N, Decloedt A, De Clercq D, et al. The use sure. Equine Vet J Suppl. 1999;30:184.
of cardiac biomarkers in veterinary medicine: the equine per- 687. McKeever KH, Malinowski K. Endocrine response to exercise
spective. Vlaams Diergen Tijds. 2012;81:319. in young and old horses. Equine Vet J Suppl. 1999;561.
665. Peters ST, Hopkins A, Stewart S, et al. Myocardial contusion 688. Trachsel DS, Grenacher B, Weishaupt MA, et al. Plasma atrial
and rib fracture repair in an adult horse. J Vet Emerg Crit Care. natriuretic peptide concentrations in horses with heart dis-
2013;23:663. ease: a pilot study. Vet J. 2012;192:166.
666. Seco Diaz OM, Durando MM, Birks EK, et al. Cardiac tro- 689. Trachsel DS, Grenacher B, Schwarzwald CC. Plasma atrial/A-
ponin I concentrations in horses with colic. J Am Vet Med As- type natriuretic peptide (ANP) concentration in horses with
soc. 2014;245:118. various heart diseases. J Vet Cardiol. 2015.
667. Navas de Solis C, Dallap Schaer BL, Boston R, et al. Myocardial 690. Leroux AA, Al Haidar A, Remy B, et al. Atrial natriuretic pep-
insult and arrhythmias after acute hemorrhage in horses. J Vet tide as an indicator of the severity of valvular regurgitation and
Emerg Crit Care. 2015;25:248. heart failure in horses. J Equine Vet Sci. 2014;34:1226.
691. Trachsel DS, Schwarzwald CC, Grenacher B, et al. Analytic 716. Kindig CA, Erickson HH, Poole DC. Dissociation of exer-
validation and comparison of three commercial immunoas- cise-induced pulmonary hemorrhage and pulmonary artery
says for measurement of plasma atrial/A-type natriuretic pep- pressure via nitric oxide synthase inhibition. J Equine Vet Sci.
tide concentration in horses. Res Vet Sci. 2014;96:180. 2000;20:715.
692. Oh JK, Seward JB, Tajik AJ. Pulmonary hypertension. In: Oh 717. Langsetmo I, Meyer MR, Erickson HH. Relationship of pul-
JK, Seward JaB, Tajik AJ, eds. The Echo Manual. Philadelphia: monary arterial pressure to pulmonary haemorrhage in exer-
Lippincott Williams & Wilkins; 1999. cising horses. Equine Vet J. 2000;32:379.
693. Rosenkranz S. Pulmonary hypertension 2015: current defini- 718. Spörri H, Schlatter C. Blutdruckerhöhungen im Lungenkreis-
tions, terminology, and novel treatment options. Clin Res Car- lauf. Schweiz Arch Tierheilkd. 1959;101:525.
diol. 2015;104:197. 719. Slater J. Cor pulmonale and respiratory disease: unique fea-
694. Simonneau G, Gatzoulis MA, Adatia I, et al. Updated clinical tures of the equine cardiopulmonary system. Equine Vet Educ.
classification of pulmonary hypertension. J Am Coll Cardiol. 2006;18:188.
2013;62:D34. 720. Sage AM, Valberg S, Hayden DW, et al. Echocardiography in a
695. Schwarzwald CC, Stewart AJ, Morrison CD, et al. Cor pulmo- horse with cor pulmonale from recurrent airway obstruction.
nale in a horse with granulomatous pneumonia. Equine Vet J Vet Intern Med. 2006;20:694.
Educ. 2006;18:182. 721. Hanka J, van den Hoven R, Schwarz B. Paroxysmal atrial fibril-
696. Johansson AM, Gardner SY, Atkins CE, et al. Cardiovascular lation and clinically reversible cor pulmonale in a horse with
effects of acute pulmonary obstruction in horses with recur- complicated recurrent airway obstruction. Tierarztl Prax Ausg
rent airway obstruction. J Vet Intern Med. 2007;21:302. G Grosstiere Nutztiere. 2015;43:109.
697. Dixon PM, Nicholls JR, McPherson EA, et al. Chronic obstruc- 722. Lester GD, DeMarco VG, Norman WM. Effect of inhaled ni-
tive pulmonary disease anatomical cardiac studies. Equine Vet tric oxide on experimentally induced pulmonary hypertension
J. 1982;14:80. in neonatal foals. Am J Vet Res. 1999;60:1207.
698. Littlejohn A, Bowles F. Studies on the physiopathology of 723. Gehlen H, Sundermann T, Rohn K, et al. Aldosterone plasma
chronic obstructive pulmonary disease in the horse. II. Right concentration in horses with heart valve insufficiencies. Res
heart haemodynamics. Onderstepoort J Vet Res. 1980;47:187. Vet Sci. 2008;85:340.
699. Dixon PM. Pulmonary artery pressures in normal horses and 724. Marr CM. Heart failure. In: Marr CM, Bowen M, eds. Cardiol-
in horses affected with chronic obstructive pulmonary disease. ogy of the Horse. Edinburgh: Saunders Elsevier; 2010.
Equine Vet J. 1978;10:195. 725. Belgrave JOS. A case of atrial fibrillation with congestive heart
700. Atkins CE. The role of noncardiac disease in the development failure. Equine Vet Educ. 1990;2:2.
and precipitation of heart failure. Vet Clin North Am Small 726. Bonagura JD. Clinical evaluation and management of heart
Anim Pract. 1991;21:1035. disease. Equine Vet Educ. 1990;2:31.
701. Rhodes J. Comparative physiology of hypoxic pulmonary hy- 727. Brumbaugh GW, Thomas WP, Hodge TG. Medical manage-
pertension: historical clues from brisket disease. J Appl Physiol. ment of congestive heart failure in a horse. J Am Vet Med As-
2005;98:1092. soc. 1982;180:878.
702. Wilkins PA. Lower respiratory problems of the neonate. Vet 728. Glazier DB. Congestive heart failure and congenital cardiac
Clin North Am Equine Pract. 2003;19:19. defects in horses. Equine Pract. 1986;8:20.
703. Drummond WH. Neonatal pulmonary hypertension. Equine 729. Reef VB, Levitan CW, Spencer PA. Factors affecting prognosis
Vet J. 1987;19:169. and conversion in equine atrial fibrillation. J Vet Intern Med.
704. Schoster A, Anderson ME. Caudal vena cava thrombosis-like 1988;2:1.
syndrome in a horse. Can Vet J. 2010;51:891. 730. Reimer JM, Reef VB, Sommer M. Echocardiographic detec-
705. Norman TE, Chaffin MK, Perris EE, et al. Massive pulmonary tion of pulmonic valve rupture in a horse with right-sided
thromboembolism in six horses. Equine Vet J. 2008;40:514. heart failure. J Am Vet Med Assoc. 1991;198:880.
706. Long PH, Payne JW. Red maple-associated pulmonary throm- 731. Reimer JM, Marr CM, Reef VB, et al. Aortic origin of the right
bosis in a horse. J Am Vet Med Assoc. 1984;184:977. pulmonary artery and patent ductus arteriosus in a pony foal
707. Jones RS, Payne-Johnson CE, Seymour CJ. Pulmonary micro- with pulmonary hypertension and right-sided heart failure.
embolism following orthopaedic surgery in a Thoroughbred Equine Vet J. 1993;25:466.
gelding. Equine Vet J. 1988;20:382. 732. Seahorn TL, Hormanski CE. Ventricular septal defect and
708. Bryan J, Puggioni A, McAllister H, et al. Thrombosis of the atrial fibrillation in an adult horse—a case report. J Equine Vet
pulmonary artery in a yearling Thoroughbred colt. J Vet Intern Sci. 1993;13:36.
Med. 2009;23:215. 733. Taylor FG, Wotton PR, Hillyer MH, et al. Atrial septal defect
709. Carr EA, Carlson GP, Wilson WD, et al. Acute hemorrhagic and atrial fibrillation in a foal. Vet Rec. 1991;128:80.
pulmonary infarction and necrotizing pneumonia in horses: 734. Wijnberg ID, van der Kolk JH, van Garderen E, et al. Atrial
21 cases (1967-1993), J Am Vet Med Assoc. 1997;210:1774. fibrillation associated with central nervous symptoms and
710. Wagner PD, Gillespie JR, Landgren GL, et al. Mechanism colic in a horse: a case of equine cardiomyopathy. Vet Q.
of exercise-induced hypoxemia in horses. J Appl Physiol. 1998;20:73.
1989;66:1227. 735. Nout YS, Hinchcliff KW, Bonagura JD, et al. Cardiac amyloi-
711. Manohar M, Coney E, Hutchens E. Pulmonary vascular dosis in a horse. J Vet Intern Med. 2003;17:588.
pressure in near-maximally exercised horses. Equine Pract. 736. Bonagura JD. Diagnosis of cardiac arrhythmias. In: Robinson
1993;15:16. NE, ed. Current Therapy in Equine Medicine 4. Philadelphia:
712. Manohar M, Goetz TE. Pulmonary vascular pressures of ex- W.B. Saunders; 1997.
ercising Thoroughbred horses with and without endoscopic 737. Garber JL, Reef VB, Reimer JM. Sonographic findings in horses
evidence of EIPH. J Appl Physiol. 1996;81:1589. with mediastinal lymphosarcoma: 13 cases (1985-1992). J Am
713. Fedde MR, Erickson HH. Increase in blood viscosity in the Vet Med Assoc. 1994;205:1432.
sprinting horse: can it account for the high pulmonary arterial 738. Reef VB, Gentile DG, Freeman DE. Successful treatment of
pressure? Equine Vet J. 1998;30:329. pericarditis in a horse. J Am Vet Med Assoc. 1984;185:94.
714. Fedde MR, Wood SC. Rheological characteristics of horse 739. Bernard W, Reef VB, Clark ES, et al. Pericarditis in horses: six
blood: significance during exercise. Respir Physiol. 1993;94:323. cases (1982-1986). J Am Vet Med Assoc. 1990;196:468.
715. Kindig CA, Gallatin LL, Erickson HH, et al. Cardiorespiratory 740. Malalana F, Bardell D, McKane S. Idiopathic aseptic pericar-
impact of the nitric oxide synthase inhibitor L-NAME in the dial effusion with cardiac tamponade in a horse. Equine Vet
exercising horse. Respir Physiol. 2000;120:151. Educ. 2011;23:64.
741. Voros K, Felkai C, Szilagyi Z, et al. Two-dimensional echocar- 764. Reina-Doreste Y, Stern JA, Keene BW, et al. Case-control
diographically guided pericardiocentesis in a horse with trau- study of the effects of pimobendan on survival time in cats
matic pericarditis. J Am Vet Med Assoc. 1991;198:1953. with hypertrophic cardiomyopathy and congestive heart fail-
742. Edem E, Kahyaoglu B, Cakar MA. Acute effusive pericar- ure. J Am Vet Med Assoc. 2014;245:534.
ditis due to horse chestnut consumption. Am J Case Rep. 765. Vollmar AC, Fox PR. Long-term outcome of Irish wolfhound
2016;17:305. dogs with preclinical cardiomyopathy, atrial fibrillation,
743. Opie LH, Gersh BJ. Drugs for the Heart. 8th ed. Philadelphia, or both treated with pimobendan, benazepril hydrochloride,
PA: Elsevier Saunders; 2013. or methyldigoxin monotherapy. J Vet Intern Med. 2016;
744. Hinchcliff KW, Muir 3rd WW. Pharmacology of furosemide 30:553.
in the horse: a review. J Vet Intern Med. 1991;5:211. 766. Haggstrom J, Lord PF, Hoglund K, et al. Short-term hemo-
745. Johansson AM, Gardner SY, Levine JF, et al. Pharmacokinetics dynamic and neuroendocrine effects of pimobendan and
and pharmacodynamics of furosemide after oral administra- benazapril in dogs with myxomatous mitral valve disease
tion to horses. J Vet Intern Med. 2004;18:739. and congestive heart failure. J Vet Intern Med. 2013;27:1452.
746. Rivas LJ, Hinchcliff KW. Effect of furosemide and subsequent 767. Haggstrom J, Boswood A, O’Grady M, et al. Longitudinal
intravenous fluid administration on right atrial pressure of analysis of quality of life, clinical, radiographic, echocardio-
splenectomized horses. Am J Vet Res. 1997;58:632. graphic, and laboratory variables in dogs with myxomatous
747. Johansson AM, Gardner SY, Levine JF, et al. Furosemide mitral valve disease receiving pimobendan or benazepril: the
continuous rate infusion in the horse: evaluation of en- QUEST study. J Vet Intern Med. 2013;27:1441.
hanced efficacy and reduced side effects. J Vet Intern Med. 768. Buergelt CD, Carmichael JA, Tashjian RJ, et al. Spontaneous
2003;17:887. rupture of the left pulmonary artery in a horse with patent
748. Abbott LM, Kovacic J. The pharmacologic spectrum of furo- ductus arteriosus. J Am Vet Med Assoc. 1970;157:313.
semide. J Vet Emerg Crit Care. 2008;18:26. 769. Chaffin MK, Miller MW, Morris EL. Double outlet right
749. Baggot JD. The pharmacological basis of cardiac drug selec- ventricle and other associated congenital cardiac anoma-
tion for use in horses. Equine Vet J Suppl. 1995;97. lies in an American miniature horse foal. Equine Vet J.
750. Pearson EG, Ayres JW, Wood GL, et al. Digoxin toxicity in a 1992;24:402.
horse. Comp Cont Educ Pract. 1987;9:958. 770. Cottrill CM, Rossdale PD. A comparison of congenital heart
751. Marr CM. Treatment of cardiac arrhythmias and cardiac fail- disease in horses and man. Equine Vet J. 1992;24:338.
ure. In: Robinson NE, ed. Current Therapy in Equine Medicine 771. Cox VS, Weber AF, de Lima A. Left cranial vena cava in a
4. Philadelphia: WB Saunders; 1997. horse. Anat Histol Embryol. 1991;20:37.
752. Parraga ME, Kittleson MD, Drake CM. Quinidine adminis- 772. Critchley KL. An interventricular septal defect, pulmonary
tration increases steady state serum digoxin concentration in stenosis and bicuspid pulmonary valve in a Welsh pony foal.
horses. Equine Vet J Suppl. 1995;114. Equine Vet J. 1976;8:176.
753. Manohar M. Effects of glyceryl trinitrate (nitroglycerin) on pul- 773. Ecke P, Malik R, Kannegieter NJ. Common atrioventricular
monary vascular pressures in standing thoroughbred horses. canal in a foal. N Z Vet J. 1991;39:97.
Equine Vet J. 1995;27:275. 774. Glazier DB, Farrelly BT, Neylon JF. Patent ductus arteriosus in
754. Gardner SY, Atkins CE, Sams RA, et al. Characterization of an eight-month-old foal. Irish Vet J. 1974;28:12.
the pharmacokinetic and pharmacodynamic properties of the 775. Glazier DB, Farrelly BT, O’Connor J. Ventricular septal defect
angiotensin-converting enzyme inhibitor, enalapril, in horses. in a 7-year-old gelding. J Am Vet Med Assoc. 1975;167:49.
J Vet Intern Med. 2004;18:231. 776. Greene HJ, Wray DD, Greenway GA. Two equine congenital
755. Sleeper MM, McDonnell SM, Ely JJ, et al. Chronic oral cardiac anomalies. Irish Vet J. 1975;29:115.
therapy with enalapril in normal ponies. J Vet Cardiol. 777. Guarda F, Rattazzi C, Appina S. Pathology of cardiac aneu-
2008;10:111. rysms in horses. Pferdeheilkunde. 1992;8:241.
756. Muñoz A, Esgueva M, Gómez-Díez M, et al. Modulation of 778. Huston R, Saperstein G, Leipold HW. Congenital-defects in
acute transient exercise-induced hypertension after oral ad- foals. J Equine Med Surg. 1977;1:146.
ministration of four angiotensin-converting enzyme inhibi- 779. Johnson JW, DeBowes RM, Cox JH, et al. Diaphragmatic
tors in normotensive horses. Vet J. 2016;208:33. hernia with a concurrent cardiac defect in an Arabian foal. J
757. Gomez-Diez M, Munoz A, Caballero JM, et al. Pharmacoki- Equine Vet Sci. 1984;4:225.
netics and pharmacodynamics of enalapril and its active me- 780. King JM, Flint TJ, Anderson WI. Incomplete subaortic sten-
tabolite, enalaprilat, at four different doses in healthy horses. otic rings in domestic animals—a newly described congenital
Res Vet Sci. 2014;97:105. anomaly. Cornell Vet. 1988;78:263.
758. Luciani A, Civitella C, Santori D, et al. Haemodynamic effects 781. Kvart C, Carlsten J, Jeffcott LB, et al. Diagnostic value
in healthy horses treated with an ACE-inhibitor (Ramipril). of contrast echocardiography in the horse. Equine Vet J.
Vet Res Commun. 2007;31(suppl 1):297. 1985;17:357.
759. Serrano-Rodriguez JM, Gomez-Diez M, Esgueva M, et al. 782. Lombard CW, Scarratt WK, Buergelt CD. Ventricular septal
Pharmacokinetics and pharmacodynamics of ramipril and defects in the horse. J Am Vet Med Assoc. 1983;183:562.
ramiprilat after intravenous and oral doses of ramipril in 783. Reef VB. Equine pediatric ultrasonography. Comp Cont Educ
healthy horses. Vet J. 2016;208:38. Pract. 1991;13:1277.
760. Davis JL, Kruger K, LaFevers DH, et al. Effects of quinapril on 784. Reppas GP, Canfield PJ, Hartley WJ, et al. Multiple congenital
angiotensin converting enzyme and plasma renin activity as cardiac anomalies and idiopathic thoracic aortitis in a horse.
well as pharmacokinetic parameters of quinapril and its active Vet Rec. 1996;138:14.
metabolite, quinaprilat, after intravenous and oral administra- 785. Steyn PF, Holland P, Hoffman J. The angiocardiographic di-
tion to mature horses. Equine Vet J. 2014;46:729. agnosis of a persistent truncus arteriosus in a foal. J S Afr Vet
761. Afonso T, Giguere S, Rapoport G, et al. Attenuation of the Assoc. 1989;60:106.
blood pressure response to exogenous angiotensin I after oral 786. Wilson RB, Haffner JC. Right atrioventricular atresia and ven-
administration of benazepril to healthy adult horses. Equine tricular septal defect in a foal. Cornell Vet. 1987;77:187.
Vet J. 2016. 787. Zamora CS, Vitums A, Foreman JH, et al. Common ventricle
762. Fuentes VL. Use of pimobendan in the management of heart with separate pulmonary outflow chamber in a horse. J Am Vet
failure. Vet Clin North Am Small Anim Pract. 2004;34:1145. Med Assoc. 1985;186:1210.
763. Macgregor JM, Rush JE, Laste NJ, et al. Use of pimobendan in 788. Zamora CS, Vitums A, Sande RD, et al. Multiple cardiac mal-
170 cats (2006-2010). J Vet Cardiol. 2011;13:251. formation in a horse. Anat Histol Embryol. 1988;17:95.
789. Patterson-Kane JC, Harrison LR. Giant right atrial diverticu- 813. Seco DO, Desrochers A, Hoffmann V, et al. Total anomalous
lum in a foal. J Vet Diagn Invest. 2002;14:335. pulmonary venous connection in a foal. Vet Radiol Ultrasound.
790. Anderson RH. The pathological spectrum of pulmonary atre- 2005;46:83.
sia. Equine Vet Educ. 1997;9:128. 814. Sedacca CD, Bright JM, Boon J. Doppler echocardiographic
791. Young LE, Blunden AS, Bartram DH, et al. Pulmonary atre- description of double-inlet left ventricle in an Arabian horse. J
sia with an intact ventricular septum in a Thoroughbred foal. Vet Cardiol. 2010;12:147.
Equine Vet Educ. 1997;9:123. 815. Cottrill CM, Ho SY, O’Connor WN. Embryological develop-
792. Stephen JO, Abbott J, Middleton DM, et al. Persistent trun- ment of the equine heart. Equine Vet J Suppl. 1997;14.
cus arteriosus in a Bashkir Curly foal. Equine Vet Educ. 816. Rudolph A. Congenital Diseases of the Heart: Clinical-Physio-
2000;12:251. logical Considerations. New York: Blackwell; 2011.
793. McGurrin MK, Physick-Sheard PW, Southorn E. Parachute 817. Edwards JE, Edwards BS, Jesse E. Edwards’ Synopsis of Con-
left atrioventricular valve causing stenosis and regurgitation in genital Heart Disease. New York: Futura Publishing Company;
a Thoroughbred foal. J Vet Intern Med. 2003;17:579. 2000.
794. Michlik KM, Biazik AK, Henklewski RZ, et al. Quadricuspid 818. Michaëlsson M, Ho SY. Congenital Heart Malformations in
aortic valve and a ventricular septal defect in a horse. BMC Vet Mammals: An Illustrated Text. London: Imperial College Press;
Res. 2014;10:142. 2000.
795. Spiro I. Hematuria and a complex congenital heart defect in a 819. Ho SY, Rigby ML, Anderson RH. Echocardiography in Con-
newborn foal. Can Vet J. 2002;43:375. genital Heart Disease Made Simple. London: Imperial College
796. Tabaran AF, Nagy AL, Catoi C, et al. Congenital diaphragmat- Press; 2005.
ic hernia with concurrent aplasia of the pericardium in a foal. 820. MacDonald AA, Fowden AL, Silver M, et al. The foramen
BMC Vet Res. 2015;11:309. ovale of the foetal and neonatal foal. Equine Vet J. 1988;20:255.
797. Anderson R. Nomenclature and classification: sequential seg- 821. Rang H, Hurtienne H. Persistent truncus arteriosus in a 2-year
mental analysis. In: Moller JH, HJ, eds. Pediatric Cardiovascu- old horse. Tierarztl Prax. 1976;4:55.
lar Medicine. New York: Churchill Livingstone; 2003. 822. Jesty SA, Wilkins PA, Palmer JE, et al. Persistent truncus arte-
798. Van Praagh R. Nomenclature and classification: morphologic riosus in two Standardbred foals. Equine Vet Educ. 2007;19:307.
and segmental approach to diagnosis. In: Moller JH, Hoff- 823. Koblik PD, Hornof WJ. Use of first-pass nuclear angiocardi-
man JIE, eds. Pediatric Cardiovascular Medicine. New York: ography to detect left-to- right cardiac shunts in the horse. Vet
Churchill Livingstone; 2003. Radiology. 1987;28:177.
799. Shinebourne EA, Macartney FJ, Anderson RH. Sequential 824. Froehlich W, Wlaschitz S, Riedelberger K, et al. Tricuspid
chamber localization—logical approach to diagnosis in con- valve endocarditis in a horse with a ventricular septal defect.
genital heart disease. Br Heart J. 1976;38:327. Equine Vet Educ. 2006;18:172.
800. Schwarzwald CC. Sequential segmental analysis—a systematic 825. Gehlen H, Stadler P. Advantages and disadvantages of inva-
approach to the diagnosis of congenital cardiac defects. Equine sive and non-invasive examination techniques in 11 horses
Vet Educ. 2008;20:305. with ventricular septal defects. Tierarztl Prax Ausg Grosstiere
801. Tynan MJ, Becker AE, Macartney FJ, et al. Nomenclature Nutztiere. 2001;29:234.
and classification of congenital heart disease. Br Heart J. 826. Short DM, Seco OM, Jesty SA, et al. Spontaneous closure
1979;41:544. of a ventricular septal defect in a horse. J Vet Intern Med.
802. Ezon D, Goldberg J, Kyle W. Atlas of Congenital Heart Disease 2010;24:1515.
Nomenclature: An Illustrated Guide to the Van Praagh and An- 827. Hughes KJ. Diagnostic challenge: lethargy and weakness in an
derson Approaches to Describing Congenital Cardiac Pathology. Arabian foal with cardiac murmurs. Ventricular septal defect
Houston, TX: CreateSpace Independent Publishing Platform; (VSD). Aust Vet J. 2006;84:209.
2015. 828. Button C, Gross DR, Allert JA, et al. Tricuspid atresia in a foal.
803. Fennell LC, Church S, Tyrell D, et al. Double-outlet right ven- J Am Vet Med Assoc. 1978;172:825.
tricle in a 10-month-old Friesian filly. Aust Vet J. 2009;87:204. 829. Kutasi O, Voros K, Biksi I, et al. Common atrioventricular ca-
804. Vitums A. Origin of the aorta and pulmonary trunk from the nal in a newborn foal—Case report and review of the litera-
right ventricle in a horse. Pathol Vet. 1970;7:482. ture. Acta Vet Hung. 2007;55:51.
805. Vitums A, Grant BD, Stone EC, et al. Transposition of the aor- 830. Kraus MS, Pariaut R, Alcaraz A, et al. Complete atrioventricu-
ta and atresia of the pulmonary trunk in a horse. Cornell Vet. lar canal defect in a foal: clinical and pathological features. J
1973;63:41. Vet Cardiol. 2005;7:59.
806. Sleeper MM, Palmer JE. Echocardiographic diagnosis of trans- 831. Steininger Berli, Jud, et al. Echocardiography in Saanen-goats:
position of the great arteries in a neonatal foal. Vet Radiol Ul- normal findings, reference intervals in awake goats, and the ef-
trasound. 2005;46:259. fect of general anesthesia. Schweiz Arch Tierheilkd. 2011;153:553.
807. Petrick SW, Roos CJ, van Niekerk J. Persistent right aortic arch 832. Krüger MU, Wünschmann A, Ward C, et al. Pulmonary atre-
in a horse. J S Afr Vet Assoc. 1978;49:355. sia with intact ventricular septum and hypoplastic right ven-
808. Butt TD, MacDonald DG, Crawford WH, et al. Persistent right tricle in an Arabian foal. J Vet Cardiol. 2016.
aortic arch in a yearling horse. Can Vet J. 1998;39:714. 833. Prickett ME, Reeves JT, Zent WW. Tetralogy of fallot in a
809. van der Linde-Sipman JS, Goedegebuure SA, Kroneman J. Thoroughbred foal. J Am Vet Med Assoc. 1973;162:552.
Persistent right aortic arch associated with a persistent left 834. Reynolds DJ, Nicholl TK. Tetralogy of Fallot and cranial mes-
ductus arteriosus and an interventricular septal defect in a enteric arteritis in a foal. Equine Vet J. 1978;10:185.
horse. Tijdschr Diergeneeskd. 1979;104(suppl). 835. Borst GH. Tetralogy of Fallot in a Belgian foal (author’s transl).
810. Valdes-Martinez A, Eades SC, Strickland KN, et al. Echocar- Tijdschr Diergeneeskd. 1978;103:968.
diographic evidence of an aortico-pulmonary septal defect 836. Keith Jr JC. Tetralogy of Fallot in a quarter horse foal. Vet Med
in a 4-day-old thoroughbred foal. Vet Radiol Ultrasound. Small Anim Clin. 1981;76:889.
2006;47:87. 837. Schmitz RR, Klaus C, Grabner A. Detailed echocardiographic
811. Cottrill CM, O’Connor WN, Cudd T, et al. Persistence of findings in a newborn foal with tetralogy of Fallot. Equine Vet
foetal circulatory pathways in a newborn foal. Equine Vet J. Educ. 2008;20:298.
1987;19:252. 838. Tschudi PR, Staufenbiel B, Ueltschi G. Echocardiographical
812. Coumbe KM. Cardiac disease: endocardial fibroelastosis. documentation of a truncus arteriosus communis in a colt.
Equine Vet Educ. 2002;14:81. Pferdeheilkunde. 1997;13:387.
839. Honnas CM, Puckett MJ, Schumacher J. Tricuspid-atresia in a 865. Reef VB, Klumpp S, Maxson AD, et al. Echocardiographic de-
quarter horse foal. Southwest Vet. 1987;38:17. tection of an intact aneurysm in a horse. J Am Vet Med Assoc.
840. van Nie CJ, van der Kamp JS. Congenital tricuspid atresia in a 1990;197:752.
premature foal. Tijdschr Diergeneeskd. 1979;104:411. 866. Shirai W, Momotani E, Sato T, et al. Dissecting aortic aneu-
841. van der Linde-Sipman JS, van den Ingh TS. Tricuspid atresia in rysm in a horse. J Comp Pathol. 1999;120:307.
a foal and a lamb. Zentralbl Veterinarmed A. 1979;26A:239. 867. Stadler P, Wohlsein P, Gratopp M, et al. Echocardiographic
842. Gumbrell RC. Atresia of the tricuspid valve in a foal. N Z Vet J. and radiographic imaging of aortic root and aortic arch aneu-
1970;18:253. rysm in the horse. Pferdeheilkunde. 1996;12:91.
843. Marr CM. Cardiac and respiratory disease in aged horses. Vet 868. Spörri H. Two clinical types of aortic insufficiency in horses.
Clin North Am Equine Pract. 2016;32:283. Ann N Y Acad Sci. 1965;127:358.
844. Cipone M, Pietra M, Guglielmini C, et al. Aortic insuffi- 869. Stadler P, Hoch M, Fruhauf B, et al. Echocardiography in
ciency in horses. Results of electrophonocardiography, ultra- horses with and without heart murmurs in aortic regurgita-
sonic cardiography and carotid pulsed-wave Doppler echo- tion. Pferdeheilkunde. 1995;11:373.
cardiography in two cases. Obiettivi e Documenti Veterinari. 870. Jesty SA, Reef VB. Septicemia and cardiovascular infections in
1995;16:37. horses. Vet Clin North Am Equine Pract. 2006;22:481.
845. Deprez P, Sustronck B, Vanroy M, et al. A case of mitral-valve 871. Guidi EE, Thomas A, Cadore JL, et al. Citrobacter freundii in-
insufficiency due to a ruptured chorda tendinea in a horse. duced endocarditis in a yearling colt. Can Vet J. 2016;57:767.
Vlaams Diergen Tijds. 1993;62:180. 872. Marr CM. Cardiovascular infections. In: Sellon DC, Long MT,
846. Littlewort MC. Cardiological problems in equine medicine. eds. Equine Infectious Diseases. St. Louis: Saunders Elsevier;
Equine Vet J. 1977;9:173. 2014.
847. Yamaga Y, Shibui I, Yasuda J, et al. Echocardiographic and ul- 873. Haldar SM, O’Gara PT. Infective endocarditis: diagnosis and
trasonographic observations in a horse with mitral regurgita- management. Nat Clin Pract Cardiovasc Med. 2006;3:310.
tion and “intrahepatic cholangiocellular fibroadenomatosis.” 874. Bertone JJ, Dill SG. Traumatic gastropericarditis in a horse. J
Advances in Animal Cardiology. 1985;18:65. Am Vet Med Assoc. 1985;187:742.
848. Buergelt CD. Equine cardiovascular pathology: an overview. 875. Wagner PC. Pericarditis. In: Robinson NE, ed. Current Thera-
Anim Health Res Rev. 2003;4:109. py in Equine Medicine 1. Philadelphia: W.B. Saunders; 1983.
849. Patteson MW. Echocardiographic evaluation of horses with 876. Robinson JA, Marr CM, Reef VB, et al. Idiopathic, aseptic, ef-
aortic regurgitation. Equine Vet Educ. 1994;6:159. fusive, fibrinous, nonconstrictive pericarditis with tamponade
850. Young L. Equine aortic valve regurgitation: a disease worthy of in a standardbred filly. J Am Vet Med Assoc. 1992;201:1593.
further consideration. Equine Vet Educ. 2007;19:469. 877. Bradfield T. Traumatic pericarditis in a horse. Southwestern
851. Shaftoe S, Mcguirk SM. Valvular insufficiency in a horse with Vet. 1970;23:145.
atrial fibrillation. Comp Cont Educ Pract. 1987;9:203. 878. Orsini JA, Koch C, Stewart B. Peritoneopericardial hernia in a
852. Frohlich W, Wlaschitz S, Riedelberger K, et al. Case report: horse. J Am Vet Med Assoc. 1981;179:907.
aortic valve endocarditis in a horse. Dtsch Tierarztl Wochen- 879. Buergelt CD, Wilson JH, Lombard CW. Pericarditis in horses.
schr. 2004;111:370. Comp Cont Educ Pract. 1990;12:872.
853. Afonso T, Verheyen T, Saey V, et al. Severe aortic regurgi- 880. Morley PS, ChirinoTrejo M, Petrie L, et al. Pericarditis and
tation due to endocarditis in a horse. Vlaams Diergen Tijds. pleuritis caused by Mycoplasma felis in a horse. Equine Vet J.
2011;80:49. 1996;28:237.
854. Muñoz A, Riber C, Trigo P, et al. Bacterial endocarditis in 881. May KA, Cheramie HS, Howard RD, et al. Purulent pericardi-
two Spanish foals after neonatal septicemia. J Equine Vet Sci. tis as a sequela to clostridial myositis in a horse. Equine Vet J.
2012;32:760. 2002;34:636.
855. Porter SR, Saegerman C, Galen Gv, et al. Vegetative endocardi- 882. Guarda F, Rattazzi C, Appino S. Ventricular myocardium and
tis in equids. J Vet Intern Med. 2008;22:1411. pericardium disease in horses. Ippologia. 1993;4:43.
856. Roussel AJ, Kasari TR. Bacterial endocarditis in large animals. 883. Wilson JH, Olson EJ, Haugen EW, et al. Systemic blastomyco-
Part II. Incidence, causes, clinical signs, and pathologic find- sis in a horse. J Vet Diagn Invest. 2006;18:615.
ings. Comp Cont Educ Pract. 1989;11:769. 884. Sebastian M, Gantz MG, Tobin T, et al. The mare reproductive
857. Sponseller BT, Ware WA. Successful treatment of staphylo- loss syndrome and the eastern tent caterpillar: a toxicokinetic/
coccal endocarditis in a horse. Equine Vet Educ. 2001;13:289. statistical analysis with clinical, epidemiologic, and mechanis-
858. Verdegaal EJMM, de Heer N, Meertens NM, et al. A right- tic implications. Vet Ther. 2003;4:324.
sided bacterial endocarditis of dental origin in a horse. Equine 885. Sebastian MM, Bernard WV, Riddle TW, et al. Review paper:
Vet Educ. 2006;18:191. mare reproductive loss syndrome. Vet Pathol. 2008;45:710.
859. Verdegaal EJMM. Sloet van Oldruitenborgh-Oosterbaan MM. 886. Donahue JM, Sells SF, Bolin DC. Classification of Actinobacil-
Clinical commentary: endocarditis in the horse. Equine Vet lus spp isolates from horses involved in mare reproductive loss
Educ. 2006;18:196. syndrome. Am J Vet Res. 2006;67:1426.
860. Aalbaek B, Ostergaard S, Buhl R, et al. Actinobacillus equuli 887. Marcus LC, Ross Jr JN. Microscopic lesions in the hearts of
subsp. equuli associated with equine valvular endocarditis. aged horses and mules. Pathol Vet. 1967;4:162.
Acta Pathol Microbiol Scand. 2007;115:1437. 888. King JM, Roth L, Haschek WM. Myocardial necrosis second-
861. Blissitt KJ, Patteson MW. Evaluation of cardiac murmurs in ary to neural lesions in domestic animals. J Am Vet Med Assoc.
horses. 2. Echocardiography, In Pract. 1996;18:416. 1982;180:144.
862. Gehlen H, Goltz A, Rohn K, et al. A survey of the frequency 889. Shawley RV, Rolf Jr LL. Experimental cantharidiasis in the
and development of heart disease in riding horses—Part 2: horse. Am J Vet Res. 1984;45:2261.
Clinical and echocardiographic follow-up examination. Pfer- 890. Hulland TJ. Leptomeric fibrils in the myocardial fibers of a
deheilkunde. 2007;23:378. foal. Vet Pathol. 1988;25:175.
863. Spörri H, Leemann W. Pathophysiology of aortic valve in- 891. Schmitz DG. Cantharidin toxicosis in horses. J Vet Intern Med.
sufficiency in horses. Berl Munch Tierarztl Wochenschr. 1989;3:208.
1972;85:441. 892. Freestone JF, Williams MM, Norwood G. Thoracic haeman-
864. Lester GD, Lombard CW, Ackerman N. Echocardiographic giosarcoma in a 3-year-old horse. Aust Vet J. 1990;67:269.
detection of a dissecting aortic root aneurysm in a Thorough- 893. Guarda F, Rattazzi C. Pathology of cardiac ventricular aneu-
bred stallion. Vet Radiol Ultrasound. 1992;33:202. rysms in the horse. Schweiz Arch Tierheilkd. 1994;136:76.
894. Reef VB. Myocardial disease. In: Robinson NE, ed. Current Ther- 921. Beasley VR, Wolf GA, Fischer DC, et al. Cantharidin toxicosis
apy in Equine Medicine 3. Philadelphia: W.B. Saunders; 1992. in horses. J Am Vet Med Assoc. 1983;182:283.
895. Weldon AD, Step DL, Moise NS. Lymphosarcoma with myo- 922. Schoeb TR, Panciera RJ. Blister beetle poisoning in horses. J
cardial infiltration in a mare. Vet Med. 1992;87:595. Am Vet Med Assoc. 1978;173:75.
896. Ferrari JJF, Leme MCM, Macruz R. Occurrence of non-physi- 923. Schoeb TR, Panciera RJ. Pathology of blister beetle (Epicauta)
ological cardiac hypertrophy in a racehorse. Arquivos do Insti- poisoning in horses. Vet Pathol. 1979;16:18.
tuto Biologico Sao Paulo. 1989;56:54. 924. Ray AC, Post LO, Hurst JM, et al. Evaluation of an analyti-
897. Galey FD, Holstege DM, Plumlee KH, et al. Diagnosis of ole- cal method for the diagnosis of cantharidin toxicosis due to
ander poisoning in livestock. J Vet Diagn Invest. 1996;8:358. ingestion of blister beetles (Epicauta lemniscata) by horses and
898. Tiwary AK, Puschner B, Kinde H, et al. Diagnosis of Taxus sheep. Am J Vet Res. 1980;41:932.
(yew) poisoning in a horse. J Vet Diagn Invest. 2005;17:252. 925. Ray AC, Kyle AL, Murphy MJ, et al. Etiologic agents, inci-
899. Freel KM, Morrison LR, Thompson H, et al. Arrhythmogenic dence, and improved diagnostic methods of cantharidin toxi-
right ventricular cardiomyopathy as a cause of unexpected car- cosis in horses. Am J Vet Res. 1989;50:187.
diac death in two horses. Vet Rec. 2010;166:718. 926. Helman RG, Edwards WC. Clinical features of blister beetle
900. Hoffman A, Levi O, Orgad U, et al. Myocarditis following poisoning in equids: 70 cases (1983-1996). J Am Vet Med As-
envenoming with Vipera palaestinae in two horses. Toxicon. soc. 1997;211:1018.
1993;31:1623. 927. Edwards WC, Edwards RM, Ogden L, et al. Cantharidin con-
901. Peek SF, Marques FD, Morgan J, et al. Atypical acute mon- tent of two species of Oklahoma blister beetles associated with
ensin toxicosis and delayed cardiomyopathy in Belgian draft toxicosis in horses. Vet Hum Toxicol. 1989;31:442.
horses. J Vet Intern Med. 2004;18:761. 928. Whitlock RH. Feed additives and contaminants as a cause of
902. Van Vleet JF, Ferrans VJ. Myocardial diseases of animals. Am equine disease. Vet Clin North Am Equine Pract. 1990;6:467.
J Pathol. 1986;124:98. 929. Cassart D, Baise E, Cherel Y, et al. Morphological alterations
903. Navas de Solis C, Slack J, Boston RC, et al. Hypertensive car- in oxidative muscles and mitochondrial structure associated
diomyopathy in horses: 5 cases (1995–2011). J Am Vet Med with equine atypical myopathy. Equine Vet J. 2007;39:26.
Assoc. 2013;243:126. 930. McKenzie RK, Hill FI, Habyarimana JA, et al. Detection of hy-
904. Bauquier J, Stent A, Gibney J, et al. Evidence for marshmallow poglycin A in the seeds of sycamore (Acer pseudoplatanus) and
(Malva parviflora) toxicosis causing myocardial disease and box elder (A. negundo) in New Zealand; the toxin associated
myopathy in four horses. Equine Vet J. 2016. with cases of equine atypical myopathy. N Z Vet J. 2016;64:182.
905. Headley SA, de Carvalho PH, Cunha Filho LF, et al. Equine 931. Westermann CM, van Leeuwen R, van Raamsdonk LW, et al.
pulmonary aspergillosis with encephalitic, myocardial, and re- Hypoglycin a concentrations in maple tree species in the
nal dissemination. Mycopathologia. 2014;177:129. Netherlands and the occurrence of atypical myopathy in
906. Haaland MA, Davidson JP. Spontaneous left atrial rupture horses. J Vet Intern Med. 2016;30:880.
with associated chronic fibrotic myocarditis in a stallion. Vet 932. Baise E, Habyarimana JA, Amory H, et al. Samaras and seed-
Med Small Anim Clin. 1983;78. lings of Acer pseudoplatanus are potential sources of hypogly-
907. Delesalle C, van Loon G, Nollet H, et al. Tumor-induced cin A intoxication in atypical myopathy without necessarily
ventricular arrhythmia in a horse. J Vet Intern Med. 2002; inducing clinical signs. Equine Vet J. 2016;48:414.
16:612. 933. Zuraw A, Dietert K, Kuhnel S, et al. Equine atypical myopathy
908. Reef VB, Dyson SS, Beech J. Lymphosarcoma and associated caused by hypoglycin A intoxication associated with ingestion
immune-mediated hemolytic anemia and thrombocytopenia of sycamore maple tree seeds. Equine Vet J. 2016;48:418.
in horses. J Am Vet Med Assoc. 1984;184:313. 934. Gonzalez-Medina S. Update on the cause of equine atypical
909. Southwood LL, Schott 2nd HC, Henry CJ, et al. Disseminated myopathy. Vet Rec. 2015;176:143.
hemangiosarcoma in the horse: 35 cases. J Vet Intern Med. 935. Unger L, Nicholson A, Jewitt EM, et al. Hypoglycin A con-
2000;14:105. centrations in seeds of Acer pseudoplatanus trees growing on
910. Hamir AN, Habecker P, Tulleners E. Equine intrapericardial atypical myopathy-affected and control pastures. J Vet Intern
lipoma. Vet Rec. 1994;135:235. Med. 2014;28:1289.
911. Penrose LC, Brower A, Kirk G, et al. Primary cardiac lympho- 936. Valberg SJ, Sponseller BT, Hegeman AD, et al. Seasonal pas-
ma in a 10-year-old equine gelding. Vet Rec. 2012;171:20. ture myopathy/atypical myopathy in North America associ-
912. Renier AC, Kass PH, Magdesian KG, et al. Oleander toxi- ated with ingestion of hypoglycin A within seeds of the box
cosis in equids: 30 cases (1995–2010). J Am Vet Med Assoc. elder tree. Equine Vet J. 2013;45:419.
2013;242:540. 937. Westermann CM, Dorland L, Votion DM, et al. Acquired mul-
913. Decloedt A, de Clercq D, Ven S, et al. Right atrial and right tiple Acyl-CoA dehydrogenase deficiency in 10 horses with
ventricular ultrasound-guided biopsy technique in standing atypical myopathy. Neuromuscul Disord. 2008;18:355.
horses. Equine Vet J. 2016;48:346. 938. Sponseller BT, Valberg SJ, Schultz NE, et al. Equine multiple
914. Peet RL, McDermott J, Williams JM, et al. Fungal myocarditis acyl-CoA dehydrogenase deficiency (MADD) associated with
and nephritis in a horse. Aust Vet J. 1981;57:439. seasonal pasture myopathy in the midwestern United States. J
915. Aleman M, Magdesian KG, Peterson TS, et al. Salinomycin Vet Intern Med. 2012;26:1012.
toxicosis in horses. J Am Vet Med Assoc. 2007;230:1822. 939. Dickinson CE, Traub-Dargatz JL, Dargatz DA, et al. Rattle-
916. Wijnberg ID, van der Kolk JH, Hiddink EG. Use of phenytoin snake venom poisoning in horses: 32 cases (1973-1993). J Am
to treat digitalis-induced cardiac arrhythmias in a miniature Vet Med Assoc. 1996;208:1866.
Shetland pony. Vet Rec. 1999;144:259. 940. Bautista AC, Tahara J, Mete A, et al. Diagnostic value of tissue
917. Hughes KJ, Dart AJ, Hodgson DR. Suspected Nerium oleander monensin concentrations in horses following toxicosis. J Vet
(Oleander) poisoning in a horse. Aust Vet J. 2002;80:412. Diagn Invest. 2014;26:423.
918. Smith PA, Aldridge BM, Kittleson MD. Oleander toxicosis in 941. Rollinson J, Taylor FG, Chesney J. Salinomycin poisoning in
a donkey. J Vet Intern Med. 2003;17:111. horses. Vet Rec. 1987;121:126.
919. Cortinovis C, Caloni F. Epidemiology of intoxication of do- 942. Nicpon J, Czerw P, Harps O, et al. Salinomycin poisoning in
mestic animals by plants in Europe. Vet J. 2013;197:163. a Polish stud horse. Tierarztl Prax Ausg G Grosstiere Nutztiere.
920. Woods LW, Filigenzi MS, Booth MC, et al. Summer pheasant’s 1997;25:438.
eye (Adonis aestivalis) poisoning in three horses. Vet Pathol 943. Kronfeld DS. Lasalocid toxicosis is inadequately quantified for
Online. 2004;41:215. horses. Vet Hum Toxicol. 2002;44:245.
944. Novilla MN. The veterinary importance of the toxic syndrome 968. Hilbert BJ, Rendano VT. Venous aneurysm in a horse. J Am
induced by ionophores. Vet Hum Toxicol. 1992;34:66. Vet Med Assoc. 1975;167:394.
945. Oehme FW, Pickrell JA. An analysis of the chronic oral tox- 969. Guglielmini C, Bernardini D. Echo-Doppler findings of
icity of polyether ionophore antibiotics in animals. Vet Hum a carotid-jugular fistula in a foal. Vet Radiol Ultrasound.
Toxicol. 1999;41:251. 2003;44:310.
946. Kamphues J, Meyer H, Liebler EM, et al. Animal nutrition for 970. Jabara AG, Hazard GH, O’Shea JD. A congenital vascular nae-
veterinarians—recent cases of clinical disorders in horses after vus in a foal. Aust Vet J. 1984;61:286.
intake of ionophore-containing feed. Dtsch Tierarztl Wochen- 971. Miller LM, Reed SM, Gallina AM, et al. Ataxia and weakness
schr. 1990;97:537. associated with fourth ventricle vascular anomalies in two
947. Cranley JJ. Focal medial calcification of the pulmonary artery: horses. J Am Vet Med Assoc. 1985;186:601.
a survey of 1066 horses. Equine Vet J. 1983;15:278. 972. Schott 2nd HC, Barbee DD, Hines MT, et al. Clinical vignette.
948. Harrington DD, Page EH. Acute vitamin D3 toxicosis in Renal arteriovenous malformation in a quarter horse foal. J Vet
horses: case reports and experimental studies of the com- Intern Med. 1996;10:204.
parative toxicity of vitamins D2 and D3. J Am Vet Med Assoc. 973. Trope GD, Steel CM, Bowers JR, et al. Distensible superficial
1983;182:1358. venous orbital malformations involving the lower eyelid in
949. Lombardo de Barros CS. Aortic body adenoma in a horse. two horses. J Am Vet Med Assoc. 2010;237:943.
Aust Vet J. 1983;60:61. 974. Campbell-Beggs CL, Johnson PJ, Wilson DA, et al. Chyloab-
950. Knezevic PF, Fessl L. Thrombectomy of the descending aorta domen in a neonatal foal. Vet Rec. 1995;137:96.
in the horse. Tierarztl Prax Suppl. 1985;1:94. 975. Rooney JR. Rupture of the aorta. Mod Vet Pract. 1979;60:391.
951. Spier S. Arterial thrombosis as the cause of lameness in a foal. 976. Saey V, Ploeg M, Delesalle C, et al. Morphometric properties
J Am Vet Med Assoc. 1985;187:164. of the thoracic aorta of Warmblood and Friesian horses with
952. Platt H. Vascular malformations and angiomatous lesions in and without aortic rupture. J Comp Pathol. 2016;154:225.
horses: a review of 10 cases. Equine Vet J. 1987;19:500. 977. Saey V, Famaey N, Smoljkic M, et al. Biomechanical and biochemi-
953. Parks AH, Guy BL, Rawlings CA, et al. Lameness in a mare cal properties of the thoracic aorta in warmblood horses, Friesian
with signs of arteriovenous fistula. J Am Vet Med Assoc. horses, and Friesians with aortic rupture. BMC Vet Res. 2015;11:285.
1989;194:379. 978. Ueno T, Nambo Y, Tajima Y, et al. Pathology of lethal peripar-
954. Wallace KD, Selcer BA, Tyler DE, et al. In vitro ultrasono- tum broad ligament haematoma in 31 Thoroughbred mares.
graphic appearance of the normal and verminous equine aor- Equine Vet J. 2010;42:529.
ta, cranial mesenteric artery, and its branches. Am J Vet Res. 979. Pascoe RR. Rupture of the utero-ovarian or middle uterine ar-
1989;50:1774. tery in the mare at or near parturition. Vet Rec. 1979;104:77.
955. McDonnell SM, Love CC, Martin BB, et al. Ejaculatory failure 980. Dechant JE, Nieto JE, Le Jeune SS. Hemoperitoneum in horses:
associated with aortic-iliac thrombosis in two stallions. J Am 67 cases (1989-2004). J Am Vet Med Assoc. 2006;229:253.
Vet Med Assoc. 1992;200:954. 981. Pusterla N, Fecteau ME, Madigan JE, et al. Acute hemoperito-
956. Welch RD, Dean PW, Miller MW. Pulsed spectral Doppler neum in horses: a review of 19 cases (1992-2003). J Vet Intern
evaluation of a peripheral arteriovenous fistula in a horse. J Med. 2005;19:344.
Am Vet Med Assoc. 1992;200:1360. 982. Orsini JA, Divers TJ. Equine Emergencies: Treatment and Pro-
957. Dias DP, de Lacerda Neto JC. Jugular thrombophlebitis in cedures. 4th ed. St. Louis: W.B. Saunders; 2014. ed. Divers TJ.
horses: a review of fibrinolysis, thrombus formation, and clini- 983. Lepage OM, Piccot-Crezollet C. Transarterial coil embolisa-
cal management. Can Vet J. 2013;54:65. tion in 31 horses (1999-2002) with guttural pouch mycosis: a
958. Dolente BA, Beech J, Lindborg S, et al. Evaluation of risk fac- 2-year follow-up. Equine Vet J. 2005;37:430.
tors for development of catheter-associated jugular thrombo- 984. Freeman DE. Long-term follow-up on a large number of
phlebitis in horses: 50 cases (1993-1998). J Am Vet Med Assoc. horses that underwent transarterial coil embolisation (TCE)
2005;227:1134. for guttural pouch mycosis (GPM). Equine Vet J. 2006;38:271.
959. Lankveld DP, Ensink JM, van Dijk P, et al. Factors influencing author reply 271.
the occurrence of thrombophlebitis after post-surgical long- 985. Dobesova O, Schwarz B, Velde K, et al. Guttural pouch my-
term intravenous catheterization of colic horses: a study of 38 cosis in horses: a retrospective study of 28 cases. Vet Rec.
cases. J Vet Med A Physiol Pathol Clin Med. 2001;48:545. 2012;171:561.
960. Matsuda K, Suzuki H, Tsunoda N, et al. Jugular thrombophle- 986. Fales-Williams A, Sponseller B, Flaherty H. Idiopathic arterial
bitis developed from buccal ulcer in a thoroughbred horse. J medial calcification of the thoracic arteries in an adult horse. J
Vet Med Sci. 2010;72:913. Vet Diagn Invest. 2008;20:692.
961. Moreau P, Lavoie JP. Evaluation of athletic performance in 987. Martinez J, Montgomery DL, Uzal FA. Vascular mineraliza-
horses with jugular vein thrombophlebitis: 91 cases (1988- tion in the brain of horses. J Vet Diagn Invest. 2012;24:612.
2005). J Am Vet Med Assoc. 2009;235:1073. 988. Imaizumi K, Nakamura T, Kiryu K, et al. Morphological
962. Ryu SH, Kim JG, Bak UB, et al. A hematogenic pleuropneu- changes of the aorta and pulmonary artery in Thoroughbred
monia caused by postoperative septic thrombophlebitis in a racehorses. J Comp Pathol. 1989;101:1.
Thoroughbred gelding. J Vet Sci. 2004;5:75. 989. Arroyo LG, Hayes MA, Delay J, et al. Arterial calcification in
963. Hoskinson JJ, Wooten P, Evans R. Nonsurgical removal of a race horses. Vet Pathol. 2008;45:617.
catheter embolus from the heart of a foal. J Am Vet Med Assoc. 990. Guglick MA, MacAllister CG, Ewing PJ, et al. Thrombosis re-
1991;199:233. sulting in rectal perforation in a horse. J Am Vet Med Assoc.
964. Lees MJ, Read RA, Klein KT, et al. Surgical retrieval of a bro- 1996;209:1125.
ken jugular catheter from the right ventricle of a foal. Equine 991. Diaz OS, Sleeper MM, Reef VB, et al. Aortitis in a Paint geld-
Vet J. 1989;21:384. ing. Equine Vet J. 2000;32:354.
965. Little D, Keene BW, Bruton C, et al. Percutaneous retrieval of a 992. Mahony C, Rantanen NW, DeMichael JA, et al. Spontaneous
jugular catheter fragment from the pulmonary artery of a foal. echocardiographic contrast in the Thoroughbred: high preva-
J Am Vet Med Assoc. 2002;220:212. lence in racehorses and a characteristic abnormality in bleed-
966. Scarratt WK, Moll HD, Pleasant RS. Fragmentation of intrave- ers. Equine Vet J. 1992;24:129.
nous catheters in three horses. J Equine Vet Sci. 1997;17:608. 993. Rantanen NW, Byars TD, Hauser ML, et al. Spontaneous con-
967. Barakzai S, Chandler K. Use of indwelling intravenous cath- trast and mass lesions in the hearts of race horses: ultrasound
eters in the horse. In Pract. 2003;25:264. diagnosis-preliminary data. J Equine Vet Sci. 1984;4:220.
994. Russell TM, Kearney C, Pollock PJ. Surgical treatment of 1017. Swanson TD. Aortic-iliac thrombosis in horses. Compend
septic jugular thrombophlebitis in nine horses. Vet Surg. Contin Educ Vet. 2011;33:E1.
2010;39:627. 1018. Ross MW, Maxson AD, Stacy VS, et al. First-pass radionuclide
995. Rijkenhuizen AB, van Swieten HA. Reconstruction of the jug- angiography in the diagnosis of aortoiliac thromboembolism
ular vein in horses with post thrombophlebitis stenosis using in a horse. Vet Radiol Ultrasound. 1997;38:226.
saphenous vein graft. Equine Vet J. 1998;30:236. 1019. Warmerdam EP. Ultrasonography of the femoral artery in six
996. O’Grady NP, Alexander M, Burns LA, et al. Guidelines for the normal horses and three horses with thrombosis. Vet Radiol
prevention of intravascular catheter-related infections. Clin In- Ultrasound. 1998;39:137.
fect Dis. 2011;52:e162. 1020. Rijkenhuizen AB, Sinclair D, Jahn W. Surgical thrombectomy
997. Spurlock SL, Spurlock GH, Parker G, et al. Long-term jug- in horses with aortoiliac thrombosis: 17 cases. Equine Vet J.
ular vein catheterization in horses. J Am Vet Med Assoc. 2009;41:754.
1990;196:425. 1021. Voortman O, Binkhorst GJ, Walvoort HC. An unusual com-
998. Divers TJ. Prevention and treatment of thrombosis, phlebitis, plication in a case of verminous aneurysm (author’s transl).
and laminitis in horses with gastrointestinal diseases. Vet Clin Tijdschr Diergeneeskd. 1980;105:87.
North Am Equine Pract. 2003;19:779. 1022. Fio L. Sudden death on the racetrack—major causes revealed
999. Tan RHH, Dart AJ, Dowling BA. Catheters: a review of the by racehorse necropsy program. ERL Update. 1994;1.
selection, utilisation and complications of catheters for periph- 1023. Halper J. Connective tissue disorders in domestic animals.
eral venous access. Aust Vet J. 2003;81:136. Adv Exp Med Biol. 2014;802:231.
1000. Herschl MA, Trim CM, Mahaffey EA. Effects of 5% and 10% 1024. Stadler P. Echocardiographic findings in ruptured sinus of
guaifenesin infusion on equine vascular endothelium. Vet Valsalva aneurysm. Tierarztl Prax Suppl. 1993;29.
Surg. 1992;21:494. 1025. van Loon G, De Clercq D, de Bruijn CM, et al. Clinical Find-
1001. Geraghty TE, Love S, Taylor DJ, et al. Assessment of subclini- ings and Diagnosis of Aortopulmonary Fistula in Four Friesian
cal venous catheter-related diseases in horses and associated Horses. Birmingham, United Kingdom: British Equine Veteri-
risk factors. Vet Rec. 2009;164:227. nary Association Congress; 2010.
1002. Schwarzwald CC, Feige K, Wunderli-Allenspach H, et al. 1026. de Bruijn M, van Loon G, Ploeg M, et al. Use of Transoesopha-
Comparison of pharmacokinetic variables for two low-molec- geal Ultrasound to Visualise the Aortopulmonary Region in Two
ular-weight heparins after subcutaneous administration of a Normal Friesian Horses and Three Friesians With Aortic Rup-
single dose to horses. Am J Vet Res. 2002;63:868. ture or Aortopulmonary Fistulation. Manchester, United King-
1003. Feige K, Schwarzwald CC, Bombeli T. Comparison of unfrac- dom: British Equine Veterinary Association Congress; 2013.
tioned and low molecular weight heparin for prophylaxis of 1027. Reef VB. Dysrhythmias: assessment and medical manage-
coagulopathies in 52 horses with colic: a randomised double- ment. In: Marr CM, ed. Cardiology of the Horse. Edinburgh:
blind clinical trial. Equine Vet J. 2003;35:506. Saunders Elsevier; 2010.
1004. Tomlinson JE, Byrne E, Pusterla N, et al. The use of recombi- 1028. Gabriel F, Lekeux P. Cardiac arrhythmias encountered in 159
nant tissue plasminogen activator (rTPA) in the treatment of Belgian riding horses. Ann Med Vet. 1986;130:205.
fibrinous pleuropneumonia in horses: 25 cases (2007-2012). 1029. Hesselkilde EZ, Almind ME, Petersen J, et al. Cardiac arrhyth-
J Vet Intern Med. 2015;29:1403. mias and electrolyte disturbances in colic horses. Acta Vet
1005. Baumer W, Herrling GM, Feige K. Pharmacokinetics and Scand. 2014;56:58.
thrombolytic effects of the recombinant tissue-type plasmino- 1030. Broux B, De Clercq D, Decloedt A, et al. Pharmacokinetics of
gen activator in horses. BMC Vet Res. 2013;9:158. intravenously and orally administered sotalol hydrochloride
1006. Whelan MF, O’Toole TE. The use of thrombolytic agents. in horses and effects on surface electrocardiogram and left
Compendium. 2007;476. ventricular systolic function. Vet J. 2016;208:60.
1007. Spurlock SL, Spurlock GH. Risk factors of catheter-related 1031. Schwarzwald CC, Hamlin RL, Bonagura JD, et al. Atrial, SA
complications. Compend Contin Educ Pract Vet. 1990;12:214. nodal, and AV nodal electrophysiology in standing horses:
1008. Bayly WM, Vale BH. Intravenous catheterization and associ- normal findings and electrophysiologic effects of quinidine
ated problems in the horse. Compend Contin Educ Pract Vet. and diltiazem. J Vet Intern Med. 2007;21:166.
1982;4:S227. 1032. Schwarzwald CC, Sams RA. Determination of plasma protein
1009. Wiemer P, Gruys E, van Hoeck B. A study of seven different binding of diltiazem in horses by ultrafiltration. J Vet Pharma-
types of grafts for jugular vein transplantation in the horse. col Ther. 2006;29:579.
Res Vet Sci. 2005;79:211. 1033. Schwarzwald CC, Sams RA, Bonagura JD. Pharmacokinetics
1010. Dyson SJ, Worth L. Aortoiliacofemoral thrombosis. In: Rob- of the calcium-channel blocker diltiazem after a single intrave-
inson NE, ed. Current Therapy in Equine Medicine 4. Philadel- nous dose in horses. J Vet Pharmacol Ther. 2006;29:165.
phia: WB Saunders; 1997. 1034. van Loon G, Jordaens L, Muylle E, et al. Intracardiac over-
1011. Duggan VE, Holbrook TC, Dechant JE, et al. Diagnosis of aor- drive pacing as a treatment of atrial flutter in a horse. Vet Rec.
to-iliac thrombosis in a quarter horse foal using Doppler ultra- 1998;142:301.
sound and nuclear scintigraphy. J Vet Intern Med. 2004;18:753. 1035. Amada A, Kiryu K. Atrial fibrillation in the race horse. Heart
1012. Hilton H, Aleman M, Textor J, et al. Ultrasound-guided bal- Vessels Suppl. 1987;2:2.
loon thrombectomy for treatment of aorto-iliac-femoral 1036. Belloli C, Zizzadoro C. Atrial fibrillation in horses: difficult di-
thrombosis in a horse. J Vet Intern Med. 2008;22:679. agnosis for a therapeutic orphan. Vet J. 2006;172:8.
1013. Brama PAJ, Rijkenhuizen ABM, vanSwieten HA, et al. 1037. Bentz BG, Erkert RS, Blaik MA. Evaluation of atrial fibrillation
Thrombosis of the aorta and the caudal arteries in the horse; in horses. Comp Cont Educ Pract. 2002;24:734.
additional diagnostics and a new surgical treatment. Vet Q. 1038. Decloedt A, Verheyen T, Van Der Vekens N, et al. Long-term
1996;18:S85. follow-up of atrial function after cardioversion of atrial fibril-
1014. Mayhew IG, Kryger MD. Aortic-iliac-femoral thrombosis in a lation in horses. Vet J. 2013;197:583.
horse. Vet Med Small Anim Clin. 1975;70:1281. 1039. Dukes-Mcewan J. Atrial fibrillation: onset and perpetuation.
1015. Moffett FS, Vaden P. Diagnosis and treatment of thrombosis of Vet J. 2002;164:87.
the posterior aorta or iliac arteries in the horse. Vet Med Small 1040. Else RW, Holmes JR. Pathological changes in atrial fibrillation
Anim Clin. 1978;73:184. in the horse. Equine Vet J. 1971;3:56.
1016. Schmidt AR. Transrectal ultrasonography of the caudal por- 1041. Fenton FH, Cherry EM, Kornreich BG. Termination of equine
tion of abdominal and pelvic cavities in horses. J Am Vet Med atrial fibrillation by quinidine: an optical mapping study. J Vet
Assoc. 1989;194:365. Cardiol. 2008;10:87.
1042. Glazier DB, Nicholson JA, Kelly WR. Atrial fibrillation in the 1065. Machida N, Yasuda J, Too K. Three cases of paroxysmal atrial
horse. Irish Vet J. 1959;13:47. fibrillation in the Thoroughbred newborn foal. Equine Vet J.
1043. Kiryu K, Amada A, Kaneko M, et al. Atrial fibrillation in 1989;21:66.
the horse: clinical and histopathological studies of two 1066. Gehlen H, Stadler P. Comparison of systolic cardiac function
cases. II. Formal pathogenesis. Exp Rep Equine Health Lab. before and after treatment of atrial fibrillation in horses with
1974;11:70. and without additional cardiac valve insufficiencies. Vet Res
1044. Kiryu K, Kaneko M, Oikawa M, et al. Histopathogenesis of Commun. 2004;28:317.
atrial fibrillation in the horse: cardiopathology of an additional 1067. Nattel S. New ideas about atrial fibrillation 50 years on. Nature.
case. Exp Rep Equine Health Lab. 1977;14:54. 2002;415:219.
1045. Kubo K, Senta T, Sugimoto O. Changes in cardiac output with 1068. Haissaguerre M, Jais P, Shah DC, et al. Spontaneous initiation
experimentally induced atrial fibrillation in the horse. Exp Rep of atrial fibrillation by ectopic beats originating in the pulmo-
Equine Health Lab. 1975;12:101. nary veins. N Engl J Med. 1998;339:659.
1046. Kuwahara M, Hiraga A, Nishimura T, et al. Power spectral 1069. Jesty SA, Kraus MS, Johnson AL, et al. An accessory bypass
analysis of heart rate variability in a horse with atrial fibrilla- tract masked by the presence of atrial fibrillation in a horse. J
tion. J Vet Med Sci. 1998;60:111. Vet Cardiol. 2011;13:79.
1047. Manohar M, Smetzer DL. Atrial fibrillation. Comp Cont Educ 1070. Reef VB, Reimer JM, Spencer PA. Treatment of atrial fi-
Pract. 1992;14:1327. brillation in horses: new perspectives. J Vet Intern Med.
1048. Marr CM, Reef VB, Reimer JM, et al. An echocardiographic 1995;9:57.
study of atrial fibrillation in horses: before and after conver- 1071. Stadler P, Deegen E, Kroker K. Echocardiography and thera-
sion to sinus rhythm. J Vet Intern Med. 1995;9:336. py of atrial fibrillation in horses. Dtsch Tierarztl Wochenschr.
1049. Morris DD, Fregin GF. Atrial fibrillation in horses: factors as- 1994;101:190.
sociated with response to quinidine sulfate in 77 clinical cases. 1072. Bentz BG, Erkert RS, Blaik MA. Atrial fibrillation in horses:
Cornell Vet. 1982;72:339. treatment and prognosis. Comp Cont Educ Pract. 2002;24:
1050. Nattel S, Harada M. Atrial remodeling and atrial fibrillation: 817.
recent advances and translational perspectives. J Am Coll 1073. Bertone JJ, Traub-Dargatz JL, Wingfield WE. Atrial fibrillation
Cardiol. 2014;63:2335. in a pregnant mare: treatment with quinidine sulfate. J Am Vet
1051. Ohmura H, Hiraga A, Takahashi T, et al. Risk factors for atrial Med Assoc. 1987;190:1565.
fibrillation during racing in slow-finishing horses. J Am Vet 1074. Blissitt KJ. Diagnosis and treatment of atrial fibrillation.
Med Assoc. 2003;223:84. Equine Vet Educ. 1999;11:11.
1052. Physick-Sheard P, Kraus M, Basrur P, et al. Breed predisposition 1075. Gerber H, Chuit P, Schatzmann HJ. Treatment of atrial fibril-
and heritability of atrial fibrillation in the Standardbred horse: a lation in the horse with intravenous dihydroquinidine gluco-
retrospective case-control study. J Vet Cardiol. 2014;16:173. nate. Equine Vet J. 1971;3:110.
1053. Senta T, Kubo K. Experimental induction of atrial fibrillation 1076. Gerber H, Chuit P, Schatzmann HJ, et al. Intravenous treat-
by electrical stimulation in the horse. Exp Rep Equine Health ment of atrial fibrillation in the horse. Schweiz Arch Tierheilkd.
Lab. 1978;15:37. 1972;114:57.
1054. Senta T, Kubo K, Sugimoto O, et al. Induction of atrial fibril- 1077. Glendinning SA. The use of quinidine sulfate for the treatment
lation by electrical stimulation in the horse. Exp Rep Equine of atrial fibrillation in horses. Vet Rec. 1965;77:951.
Health Lab. 1975;12:109. 1078. Matsuda H. Treatment of atrial fibrillation in horses. Jpn J Vet
1055. navasvan Loon G. Atrial Pacing and Experimental Atrial Fi- Res. 1992;40:44.
brillation in Equines, in Department of Large Animal Internal 1079. Muir 3rd WW, Reed SM, McGuirk SM. Treatment of atrial
Medicine. Gent: Faculty of Veterinary Medicine, University of fibrillation in horses by intravenous administration of quini-
Gent; 2001:268. dine. J Am Vet Med Assoc. 1990;197:1607.
1056. Van Loon G, Duytschaever M, Tavernier R, et al. An equine 1080. Rose RJ, Davis PE. Treatment of atrial fibrillation in three race-
model of chronic atrial fibrillation: methodology. Vet J. horses. Equine Vet J. 1977;9:68.
2002;164:142. 1081. Young L, van Loon G. Editorial: atrial fibrillation in horses:
1057. Van Loon G, Tavernier R, Duytschaever M, et al. Pacing in- new treatment choices for the new millennium? J Vet Intern
duced sustained atrial fibrillation in a pony. Can J Vet Res. Med. 2005;19:631.
2000;64:254. 1082. McGuirk SM, Muir WW, Sams RA. Pharmacokinetic analysis
1058. Wachtell K, Greve AM, Structural, Cardiac Functional. Changes of intravenously and orally administered quinidine in horses.
are target organ damage that increases risk of atrial fibrillation. Am J Vet Res. 1981;42:938.
J Am Coll Cardiol. 2014;63:2014. 1083. Cipone M, Venturoli M. Atrial fibrillation in five horses. Changes
1059. Wyse DG, Van Gelder IC, Ellinor PT, et al. Lone atrial fibrilla- in the ECG during quinidine therapy. Summa. 1986;3:53.
tion: does it exist? J Am Coll Cardiol. 2014;63:1715. 1084. Frye MA, Selders CG, Mama KR, et al. Use of biphasic electri-
1060. Navas de Solis C, Reef VB, Slack J, et al. Evaluation of coagula- cal cardioversion for treatment of idiopathic atrial fibrillation
tion and fibrinolysis in horses with atrial fibrillatio. J Am Vet in two horses. J Am Vet Med Assoc. 2002;220:1039.
Med Assoc. 2016;248:201. 1085. McGurrin MK, Physick-Sheard PW, Kenney DG, et al. Trans-
1061. Asano K, Suzuki K, Chiba M, et al. Relationship between trace venous electrical cardioversion in equine atrial fibrillation:
elements status in mane hair and atrial fibrillation in horse. J technique and successful treatment of 3 horses. J Vet Intern
Vet Med Sci. 2006;68:769. Med. 2003;17:715.
1062. De Clercq D, Decloedt A, Sys SU, et al. Atrial fibrillation cycle 1086. McGurrin MK, Physick-Sheard PW, Kenney DG. How to per-
length and atrial size in horses with and without recurrence form transvenous electrical cardioversion in horses with atrial
of atrial fibrillation after electrical cardioversion. J Vet Intern fibrillation. J Vet Cardiol. 2005;7:109.
Med. 2014;28:624. 1087. McGurrin MK, Physick-Sheard PW, Kenney DG, et al.
1063. Decloedt A, de Clercq D, van der Vekens N, et al. Influence of Transvenous electrical cardioversion of equine atrial fi-
detomidine on atrial fibrillation cycle length measured by in- brillation: technical considerations. J Vet Intern Med.
tracardiac electrogram recording and by colour tissue Doppler 2005;19:695.
imaging in horses. Equine Vet J. 2016;48:21. 1088. Bellei MH, Kerr C, McGurrin MK, et al. Management and
1064. Mullen KR, Kraus MS, Divers TJ. ECG of the month. Atrial complications of anesthesia for transvenous electrical cardio-
fibrillation due to hypokalemia in a horse. J Am Vet Med Assoc. version of atrial fibrillation in horses: 62 cases (2002-2006). J
2014;244:657. Am Vet Med Assoc. 2007;231:1225.
1089. McGurrin MK, Physick-Sheard PW, Kenney DG. Transvenous 1109. van Loon G, Blissitt KJ, Keen JA, et al. Use of intravenous fle-
electrical cardioversion of equine atrial fibrillation: patient fac- cainide in horses with naturally-occurring atrial fibrillation.
tors and clinical results in 72 treatment episodes. J Vet Intern Equine Vet J. 2004;36:609.
Med. 2008;22:609. 1110. DeClercq D, VanLoon G, Tavernier R, et al. Use of propafenone
1090. DeClercq D, VanLoon G, Schauvliege S, et al. Transvenous for conversion of chronic atrial fibrillation in horses. Am J Vet
electrical cardioversion of atrial fibrillation in six horses using Res. 2009;70:223.
custom made cardioversion catheters. Vet J. 2008;177:198. 1111. Puigdemont A, Riu JL, Guitart R, et al. Propafenone kinetics
1091. Schauvliege S, van Loon G, De Clercq D, et al. Cardiovas- in the horse. Comparative analysis of compartmental and non-
cular responses to transvenous electrical cardioversion of compartmental models. J Pharmacol Methods. 1990;23:79.
atrial fibrillation in anaesthetized horses. Vet Anaesth Analg. 1112. Haugaard MM, Hesselkilde EZ, Pehrson S, et al. Pharmaco-
2009;36:341. logic inhibition of small-conductance calcium-activated po-
1092. VanLoon G, DeClercq D, Tavernier R, et al. Transient complete tassium (SK) channels by NS8593 reveals atrial antiarrhythmic
atrioventricular block following transvenous electrical cardio- potential in horses. Heart Rhythm. 2015;12:825.
version of atrial fibrillation in a horse. Vet J. 2005;170:124. 1113. Hancox JC, James AF, Marrion NV, et al. Novel ion chan-
1093. Marly-Voquer C, Schwarzwald CC, Bettschart-Wolfensberger nel targets in atrial fibrillation. Expert Opin Ther Targets.
R. The use of dexmedetomidine continuous rate infusion for 2016;20:947.
horses undergoing transvenous electrical cardioversion—A 1114. Estrada AH, Pariaut R, Moise NS. Avoiding medical error dur-
case series. Can Vet J. 2016;57:70. ing electrical cardioversion of atrial fibrillation: prevention of
1094. Preiss EE, Kenney DG, McGurrin MK, et al. Influence of elec- unsynchronized shock delivery. J Vet Cardiol. 2009;11:137.
trode position on cardioversion energy requirements during 1115. Dicken M, Gordon SJ, Mayhew IG. The use of phenytoin in
transvenous electrical cardioversion in horses. Am J Vet Res. two horses following conversion from atrial fibrillation. N Z
2011;72:1193. Vet J. 2012;60:210.
1095. Ellis EJ, Ravis WR, Malloy M, et al. The pharmacokinetics and 1116. Cornick JL, Hartsfield SM, Miller M. ECG of the month. Pre-
pharmacodynamics of procainamide in horses after intrave- mature ventricular complexes in an anesthetized colt. J Am Vet
nous administration. J Vet Pharmacol Ther. 1994;17:265. Med Assoc. 1990;196:420.
1096. Moïse NS, Pariaut R, Gelzer ARM, et al. Cardioversion with 1117. Marr CM, Reef VB. ECG of the month. [Multifocal ventricular
lidocaine of vagally associated atrial fibrillation in two dogs. J tachycardia in a horse]. J Am Vet Med Assoc. 1991;198:1533.
Vet Cardiol. 2005;7:143. 1118. Miller PJ, Rose RJ, Hoffman K, et al. Idioventricular tachycar-
1097. Pariaut R, Moise NS, Koetje BD, et al. Lidocaine converts acute dia in a horse. Aust Vet J. 1987;64:55.
vagally associated atrial fibrillation to sinus rhythm in German 1119. Nielsen IL. Ventricular tachycardia in a Thoroughbred race-
Shepherd dogs with inherited arrhythmias. J Vet Intern Med. horse. Aust Vet J. 1990;67:140.
2008;22:1274. 1120. Reimer JM, Reef VB, Sweeney RW. Ventricular arrhyth-
1098. DeClercq D, VanLoon G, Baert K, et al. Intravenous amiodar- mias in horses: 21 cases (1984-1989). J Am Vet Med Assoc.
one treatment in horses with chronic atrial fibrillation. Vet J. 1992;201:1237.
2006;172:129. 1121. Vrins A, Doucet M, DeRoth L. Paroxysmal ventricular tachy-
1099. DeClercq D, VanLoon G, Baert K, et al. Effects of an adapted cardia in a horse. Medecin Veterinaire du Quebec. 1989;19:79.
intravenous amiodarone treatment protocol in horses with 1122. Pfister R, Seifertalioth C, Beglinger R. Location of the ectopic
atrial fibrillation. Equine Vet J. 2007;39:344. focus of ventricular extrasystoles in the horse. Schweiz Arch
1100. Trachsel D, Tschudi P, Portier CJ, et al. Pharmacokinetics and Tierheilkd. 1984;126:165.
pharmacodynamic effects of amiodarone in plasma of ponies 1123. Johnson AL, Jesty SA, Gelzer AR, et al. ECG of the month.
after single intravenous administration. Toxicol Appl Pharma- Ventricular tachycardia in a horse. J Am Vet Med Assoc.
col. 2004;195:113. 2007;231:706.
1101. De Clercq D, Baert K, Croubels S, et al. Evaluation of the phar- 1124. DeClercq D, VanLoon G, Baert K, et al. Treatment with ami-
macokinetics and bioavailability of intravenously and orally odarone of refractory ventricular tachycardia in a horse. J Vet
administered amiodarone in horses. Am J Vet Res. 2006;67:448. Intern Med. 2007;21:878.
1102. Birettoni F, Porciello F, Rishniw M, et al. Treatment of chronic 1125. Garcia-Lopez JM, Provost PJ, Rush JE, et al. Prevalence and
atrial fibrillation in the horse with flecainide: personal obser- prognostic importance of hypomagnesemia and hypocalcemia
vation. Vet Res Commun. 2007;31(suppl 1):273. in horses that have colic surgery. Am J Vet Res. 2001;62:7.
1103. Dembek KA, Hurcombe SD, Schober KE, et al. Sudden death 1126. Meyer GA, Lin HC, Hanson RR, et al. Effects of intravenous li-
of a horse with supraventricular tachycardia following oral docaine overdose on cardiac electrical activity and blood pres-
administration of flecainide acetate. J Vet Emerg Crit Care. sure in the horse. Equine Vet J. 2001;33:434.
2014;24:759. 1127. Mullen KR, Gelzer AR, Kraus MS, et al. ECG of the month.
1104. Haugaard MM, Pehrson S, Carstensen H, et al. Antiarrhyth- Cardiac arrhythmias in a horse after lidocaine administration.
mic and electrophysiologic effects of flecainide on acutely J Am Vet Med Assoc. 2009;235:1156.
induced atrial fibrillation in healthy horses. J Vet Intern Med. 1128. Stewart AJ. Magnesium disorders in horses. Vet Clin North Am
2015;29:339. Equine Pract. 2011;27:149.
1105. Ohmura H, Hiraga A, Aida H, et al. Influence of quinidine 1129. Kowalczyk DF, Beech J. Pharmacokinetics of phenytoin (di-
and flecainide on autonomic nervous activity in Thoroughbred phenylhydantoin) in horses. J Vet Pharmacol Ther. 1983;6:133.
horses. Vet Rec. 2003;152:114. 1130. Soma LR, Uboh CE, Guan F, et al. Disposition, elimination,
1106. Ohmura H, Hiraga A, Aida H, et al. Determination of oral and bioavailability of phenytoin and its major metabolite in
dosage and pharmacokinetic analysis of flecainide in horses. J horses. Am J Vet Res. 2001;62:483.
Vet Med Sci. 2001;63:511. 1131. Wijnberg ID, Ververs FF. Phenytoin sodium as a treatment
1107. Ohmura H, Nukada T, Mizuno Y, et al. Safe and efficacious for ventricular dysrhythmia in horses. J Vet Intern Med.
dosage of flecainide acetate for treating equine atrial fibrilla- 2004;18:350.
tion. J Vet Med Sci. 2000;62:711. 1132. Gasthuys F, Parmentier D, Goossens L, et al. A preliminary
1108. Risberg AI, McGuirk SM. Successful conversion of equine study on the effects of atropine sulphate on bradycardia and
atrial fibrillation using oral flecainide. J Vet Intern Med. heart blocks during romifidine sedation in the horse. Vet Res
2006;20:207. Commun. 1990;14:489.
1133. Kroneman J. Heart arrhythmias in horses caused by delays of 1148. Asano K, Suzuki K, Chiba M, et al. Correlation between 25
conduction in the atrioventricular nodes and in the bundle of element contents in mane hair in riding horses and atrioven-
His. Berl Munch Tierarztl Wochenschr. 1991;104:351. tricular block. Biol Trace Elem Res. 2005;108:127.
1134. Reef VB, Clark ES, Oliver JA, et al. Implantation of a perma- 1149. Smetzer DL, Smith CR, Senta T. Second-degree atrioventricu-
nent transvenous pacing catheter in a horse with complete lar block in the horse. Am J Vet Res. 1969;30:933.
heart block and syncope. J Am Vet Med Assoc. 1986;189:449. 1150. Kiryu K, Kaneko M, Satoh H. Cardiopathological observations
1135. Matsui K, Amada A, Sawazaki H. Second-degree atrioventric- on histopathogenesis of incomplete atrioventricular block in
ular block observed in a Thoroughbred foal on 2.5 months of horses. Nihon Juigaku Zasshi. 1977;39:425.
age. Nihon Juigaku Zasshi. 1985;47:175. 1151. Smetzer DL, Senta T, Smith CR, et al. High-grade second-
1136. Glazier DB, Littledike ET, Cook HM. The electrocardiographic degree atrioventricular block in a horse. Am J Vet Res. 1969;
changes in experimentally induced bundle-branch block in the 30:337.
equine heart. Ir Vet J. 1983;37:71. 1152. Ohmura H, Hiraga A, Aida H, et al. Effects of repeated atropine
1137. Suzuki K, Yamaya Y, Asano K, et al. Relationship between hair injection on heart rate variability in Thoroughbred horses. J Vet
elements and severity of atrioventricular block in horses. Biol Med Sci. 2001;63:1359.
Trace Elem Res. 2007;115:255. 1153. Nihouannen JC, Sevestre J, Dorso Y, et al. Implantation of a
1138. Lawler JB, Frye MA, Bera MM, et al. Third-degree atrioven- cardiac pacemaker into horses. I. Equipment and techniques.
tricular block in a horse secondary to rattlesnake envenoma- Rev Med Vet (Toulouse). 1984;135:91.
tion. J Vet Intern Med. 2008;22:486. 1154. Nihouannen JC, Sevestre J, Dorso Y, et al. Implantation of a
1139. Meijler FL. Comparative pathophysiology of the atrioventricu- cardiac pacemaker into horses. II. Postoperative monitoring
lar node. Verh K Acad Geneeskd Belg. 1990;52:127. of a pacemaker with epicardial and myocardial electrodes in a
1140. Rezakhani A, Godarzi M. Tabatabei Naeini I: a combination of pony. Rev Med Vet (Toulouse). 1984;135:165.
atrioventricular block and sinoatrial block in a horse. Acta Vet 1155. van Loon G, Laevens H, Deprez P. Temporary transvenous
Scand. 2005;46:173. atrial pacing in horses: threshold determination. Equine Vet J.
1141. Sugiyama A, Takeuchi T, Morita T, et al. Mediastinal lympho- 2001;33:290.
ma with complete atrioventricular block in a horse. J Vet Med 1156. van Loon G, Fonteyne W, Rottiers H, et al. Dual-chamber
Sci. 2008;70:1101. pacemaker implantation via the cephalic vein in healthy
1142. Yamashita K, Tsubakishita S, Futaok S, et al. Cardiovascular equids. J Vet Intern Med. 2001;15:564.
effects of medetomidine, detomidine and xylazine in horses. J 1157. Kaese S, Frommeyer G, Verheule S, et al. The ECG in cardi-
Vet Med Sci. 2000;62:1025. ovascular-relevant animal models of electrophysiology. Her-
1143. Hardy J. ECG of the month. Hyperkalemia in a mare. J Am Vet zschrittmacherther Elektrophysiol. 2013;24:84.
Med Assoc. 1989;194:356. 1158. Naylor JM. Hyperkalemic periodic paralysis. Vet Clin North
1144. Epstein V. Relationship between potassium administration, Am Equine Pract. 1997;13:129.
hyperkalaemia and the electrocardiogram: an experimental 1159. Meyer TS, Fedde MR, Cox JH, et al. Hyperkalaemic periodic
study. Equine Vet J. 1984;16:453. paralysis in horses: a review. Equine Vet J. 1999;31:362.
1145. Castex AM, Bertone JJ. ECG of the month. Sinus tachycardia and 1160. Batterink J, Cessford TA, Taylor RAI, et al. Pharmacological
hyperkalemia in a horse. J Am Vet Med Assoc. 1989;194:654. interventions for the acute management of hyperkalaemia in
1146. Glazier DB, Littledike ET, Evans RD. Electrocardiographic adults. Cochrane Database of Systematic Reviews Art. 2015;
changes in induced hyperkalemia in ponies. Am J Vet Res. No.: CD010344.
1934;43:1982. 1161. Maxwell AP, Linden K, O’Donnell S, et al. Management of
1147. Muir WW, McGuirk SM. Ventricular preexcitation in two hyperkalaemia, J R Coll Physicians Edinb. 43:246.
horses. J Am Vet Med Assoc. 1983;183:573.
C HA P T E R 10
Disorders of the Musculoskeletal
System
Stephanie J. Valberg
Y MUSCLE FORM AND FUNCTION Diagnostic Approach

History and physical examination remain the cornerstones of
Skeletal muscle is the most plastic tissue in the body, con- the diagnostic approach. Goals are to (1) determine whether
stantly remodeling in response to exercise, diet, and the hor- the clinical signs represent a primary or secondary muscle
monal milieu. The primary components of muscle are water disorder; (2) assess the contributions of fasciculations, weak-
(80%), protein (10%–15%), and glycogen (1%–2%), with the ness, atrophy, muscle pain, or exercise intolerance to the
proteins largely comprising contractile proteins. The type of primary presenting complaint; (3) generate a logical list of
contractile protein, more specifically the isoforms of myosin differential diagnoses; and (4) select the most appropriate
heavy chains, determines the speed with which the fiber con- diagnostic tests to further characterize and identify the cause
tracts and the muscle fiber type. The speed of contraction var- of the muscle disorder. The requisite systematic approach
ies from slowest to fastest through type 1, type 2a, and type 2x begins with the history, is followed by inspection and palpa-
fibers. tion of every possible aspect of the musculature, and includes
Most equine locomotor muscles are comprised of a mosaic assessment of movement using both neurologic and lame-
of type 1 and type 2 muscle fibers, but the exact composi- ness examinations.
tion depends on the muscle’s function and use. For example,
digital flexor muscles that support the fetlock joint consist of History
50% type 1 and 50% type 2a muscle fibers, whereas proximal A thorough history is particularly important with myopathies
locomotor muscles that power the hind end consist of less because many disorders are intermittent in nature and are
than 25% type 1 and 75% or more type 2a and type 2x fibers not necessarily apparent on initial physical examination. In
in proportions that vary among individuals, breeds, and state addition, many myopathies are triggered by certain environ-
of training (Fig. 10.1).1 The contractile fiber types have dis- mental stimuli, and identifying those stimuli can help both to
tinctive metabolic properties that also vary with the state of diagnose the disorder and to formulate a management plan
training. Type 1 fibers generally have lower glycogen and gly- to prevent further episodes in the future. In particular, it is
colytic capacity and higher lipid and oxidative capacity than important to determine from the history whether clinical
type 2 fibers. Type 2a fibers have intermediate properties signs are associated with exercise. Horses, unlike many other
whereas type 2x fibers have higher glycogen, higher glyco- animals, are athletes, and forced exercise is routine. Riders
lytic, and lower lipid and oxidative capacity than type 1 and readily note subtle clinical signs of pain, weakness, or exercise
2a fibers. intolerance under saddle, and careful note of the rider’s com-
A motor unit consists of a subset of myofibers supplied by plaints aids in the identification of specific exertional myopa-
the branches of one nerve. Tonic motor neurons with a slow thies. Temperament, diet, supplements, current medications,
discharge rate supply type 1 fibers and fast discharging phasic exercise regimens, level of performance, changes in exercise
motor neurons supplying type 2a and 2x fibers. At slow exer- tolerance, vaccinations, other animals affected, and any rela-
cise intensities, type 1 and a small number of type 2a muscle tionships among those animals are documented. Details of the
fibers are activated, and as the speed or duration of exercise onset, progression of clinical signs, frequency, severity, and
increases, more muscle fibers will be recruited in the order duration are recorded. Every effort is made to characterize
type 1 to type 2a to type 2x. possible eliciting factors such as recent alterations in diet, tack,
Peripheral neuropathies usually affect both fast- and slow- exercise schedule, level of fitness, type and duration of exer-
twitch motor units, causing weakness and muscle atrophy. cise, or behavior. The environment, pasture access and quality,
Specific myopathies often affect one particular fiber type and size of turnout facilities, footing, and general horsemanship
a specific cellular pathway within that myofiber. The disrup- are noted.
tion in that cellular pathway often produces typical clinical
signs for that disease. Wherever possible the goal of internists Inspection
and researchers is to define the pathway that is dysfunctional Before beginning the physical examination, it is important to
in order to provide the most accurate diagnosis and targeted assess muscle mass, symmetry, stance, and behavior. Inspec-
treatments. tion is best done at a distance with the horse quietly standing
542
CHAPTER 10 Disorders of the Musculoskeletal System 345 543
FIG. 10.1 Cross section of equine gluteus medius muscle stained with myosin ATPase (pH 4.6) showing
a normal mosaic pattern of type 1 (slow-twitch), type 2A (fast-twitch oxidative), and type 2X (fast-twitch
glycolytic) fibers. (20×)
square. If signs of anxiety are present the horse may need to be thoracolumbar muscles or pain associated with the thoraco-
reevaluated in calm surroundings. The horse is viewed from lumbar spine or sacroiliac joints.
all sides, comparing left to right, and the tail is moved to assess In animals with spontaneous muscle activity, muscle
adductor muscles. Each athletic discipline results in hypertro- groups should also be percussed with a percussion hammer.
phy of specific muscle groups. The veterinarian performing The triceps, pectoral, and semitendinosus muscles are easily
the examination should be familiar with the ideal muscle mass accessed for percussion. A positive percussion sign occurs
present in a horse of that discipline and fitness and should when the muscle holds a contracture for several seconds,
compare the patient at that level of training with the ideal to creating a dimpled appearance below the contracted muscle
determine regions of underdevelopment (Fig. 10.2). Notes are (percussion myotonia). This occurs as the result of abnor-
made regarding tropic changes, atrophy, alterations in symme- mal mechanical irritability and sustained contraction of the
try of particular muscle groups, and any observed spontane- percussed fibers.
ous muscle activity.
Locomotor and Neurologic Examination
Physical Examination A locomotor examination is performed to characterize the
Following a standard general physical examination, each impact of a primary neuromuscular disorder on gait and
muscle should be palpated, beginning with the temporal and determine whether muscle pain is a secondary consequence
masseter muscles and working caudally to the tail. Where of orthopedic lameness. Horses are observed for evidence
possible, left and right sides are palpated simultaneously and of lameness, pain, asymmetry, decreased range of joint
compared. Impressions of muscle tone, consistency, swelling, motion, stiffness, or muscle cramping at a walk and trot and
atrophy, and heat are compared between left and right sides flexion tests performed where appropriate. If necessary to
and documented. Sensitivity to superficial followed by deep elicit the abnormality noted by the owner, the horse can be
palpation of each muscle group is noted. The temperament of observed under saddle. For neurologic assessment horses
the horse and level of comfort with the examiner needs to be are observed at a walk on a straight line, serpentines, and
considered when interpreting results of palpation. Some ani- spiraled circles, as well as when backing. A tail pull exami-
mals are tense and demonstrate apparent evidence of myalgia nation while the horse is standing still and walking is used to
when palpation is first performed or when performed by cer- assess stability and hindlimb weakness. Any atrophy, spas-
tain individuals. However, given time and patience or another ticity, weakness, or ataxia should trigger a full neurologic
examiner, some horses will relax and muscles or muscle examination to determine whether clinical signs are asso-
groups that at first appeared to be very sensitive or hypertonic ciated with the central nervous system, peripheral nerves,
may in reality be normal. Palpation is repeated to ensure the or muscle. Severe weakness can be difficult to differentiate
response is consistent. A blunt instrument such as a needle from ataxia. In such cases, horses are observed for other
cap or a pen can be run over the lumbar and gluteal muscles to signs of muscle/peripheral nerve weakness such as muscle
ensure that the horse shows extension (swayback) followed by fasciculations, knuckling at the walk, frequent recumbency
flexion (hogback) of the spine and sacroiliac joints. Guarding with difficulty rising, and shifting of weight because of an
against movement may reflect abnormalities in the pelvic or inability to fix the stifles.
FIG. 10.2 Rear view of two age-matched Quarter Horses. The horse on the right demonstrates normal
hindquarter muscle development. The horse on the left has a generalized decrease in muscle mass particu-
larly affecting the biceps femoris and semitendinosus muscles. The horse on the left was diagnosed with
myotonia dystrophica by electromyography.
Classification of Muscle Disorders

BOX 10.1
Exertional Myopathy
Findings from the muscle evaluation should be analyzed
to determine the following: (1) whether the complaint is
1. Rhabdomyolysis
a primary or secondary muscle disorder; (2) whether the
a. Extrinsic (sporadic) tying-up
complaint is focal or generalized; (3) whether it is exercise
• Dietary imbalances, vitamins, minerals, electrolytes
associated or not exercise associated; (4) if rhabdomyolysis
• Exercise in excess of training
is present; and (5) if clinical signs are primarily associated
• Exhaustion syndrome
with pain, atrophy, weakness, abnormal electrical conductiv-
b. Intrinsic (chronic) tying-up
ity, or exercise intolerance. A classification scheme for muscle
• Recurrent exertional rhabdomyolysis
disorders with differential diagnoses is provided in Box 10.1.
• Malignant hyperthermia
The first principal divisions are based on the presence of an
• Type 1 polysaccharide storage myopathy
exertional or nonexertional disorder and whether the condi-
• Type 2 polysaccharide storage myopathy
tion is characterized by rhabdomyolysis, atrophy, or muscle
• Idiopathic chronic exertional rhabdomyolysis
fasciculations.
2. Normal creatine kinase
Pathophysiology of Rhabdomyolysis a. Focal muscle strain
b. Type 2 polysaccharide storage myopathy
A variety of extrinsic (trauma, toxins, nutritional deficiency)
c. Vitamin E–deficient myopathy
and intrinsic (errors of metabolism, excitation-contraction
d. Mitochondrial myopathy
coupling) insults can cause rhabdomyolysis; however,
they often share a final common pathway that leads to cell
death—aberrant calcium cycling.2 If the energy pathways
that generate adenosine triphosphate for the calcium pump radicals, activating proteases and phospholipases, and gen-
are impaired, if the calcium pump or channels are not func- erating inflammatory cytokines, all of which combine to
tioning properly, or if the cell membrane is damaged, exces- disrupt cellular architecture and function within the dam-
sive calcium accumulates in the sarcoplasm. Mitochondria aged segment of the myofiber (Fig. 10.3). Fortunately, muscle
sequester excessive calcium but quickly become overloaded, is a highly plastic tissue and capable of complete repair as
disrupting oxidative metabolism, generating oxygen free long as the basal lamina of the cell is left intact and damaged
Normal Abnormal
Mitochondria Membrane
DHP disruption
by lipases,
RYR Ca++ proteases
Ca++
SR Ca++ ADP Ca++ Ca++ Energy
SERCA disruption
ATP Ca++
Ca++ Ca++ Contracture
|______ ______|____ ____| Ca++
Mitochondria | ____________| ______ |
|______ ______|______| A
| ____________| _______ |
Contraction
FIG. 10.3 (A) The normal course of excitation-contraction coupling

where depolarization of the cell membrane activates the dihydropyri-
dine receptor (DHPR), which triggers release of calcium ions from the
terminal cisternae into the sarcoplasm by opening the ryanodine re-
ceptor (RYR) in the terminal cisternae of the SR membrane is depicted
on the left. This raises myoplasmic calcium concentrations and causes
contraction of the myofilaments. Calcium, is actively resequestered
in the SR through the calcium pump (SERCA), which utilizes ATP and
causes relaxation of the contraction. Excessive release of calcium via
the RYR1 can raise myoplasmic calcium, resulting in uptake by mito-
chondria. Past a threshold, excessive calcium release can alter en-
ergy metabolism and cause muscle contracture without relaxation B
and activation of lipases and proteases, which destroy muscle cell
membranes. FIG. 10.4 (A) Cross section of equine gluteus medius muscle stained
with myosin ATPase (pH 4.6) showing myogenic atrophy in which type
segments can locate their corresponding end. Both ends 2A or type 2B fibers are smaller in cross-sectional area than type 1 muscle
of the damaged muscle fiber segment are sealed off within fibers and have lost their normal rounded shape and have an anguloid
hours of damage, and macrophage infiltration and phagocy- appearance (arrow). (40×) (B) Cross section of equine sacrocaudalis dor-
tosis of necrotic debris begin within 16 to 48 hours of the salis medialis muscle stained with myosin ATPase (pH 4.6) showing neu-
muscle injury. Progenitor cells called satellite cells migrate rogenic atrophy defined by the presence of angular atrophy of both type
along the remaining basal lamina and form regenerative 1 and type 2 muscle fibers (arrows). (40×)
myotubes within 3 to 4 days of injury, connecting damaged
ends, and mature muscle fibers are observed within a month
of the original damage. Diagnostic Tools
Muscle disorders characterized by rhabdomyolysis disrupt
Pathophysiology of Atrophy cellular homeostasis to the point that the muscle cell mem-
Atrophy can be the result of overt muscle cell damage or brane (sarcolemma) ruptures, resulting in leakage of cytoplas-
activation of ubiquitin-proteasome or autophagy-lyso- mic contents from the muscle cell into the bloodstream and
some machinery within a muscle cell, so-called myogenic urine. The activity of muscle enzymes within the serum and
atrophy. Atrophy can also be due to damage to the motor the presence of myoglobin in urine are used as diagnostic indi-
nerve supplying that muscle, so-called neurogenic atrophy. cators of rhabdomyolysis.
Myogenic atrophy usually produces anguloid atrophy of
fast-twitch muscle fibers (Fig. 10.4A) whereas neurogenic
Serum Creatine Kinase and Aspartate
atrophy usually involves both type 1 and type 2 muscle Transaminase Activities
fibers and is characterized by small angular atrophied fibers Serum activities of the skeletal muscle enzymes creatine kinase
(Fig. 10.4B). (CK), aspartate aminotransferase (AST), and lactate dehydro-
genase (LDH) are commonly used to detect rhabdomyolysis.3
Pathophysiology of Fasciculations Optimal information can be obtained by not only assessing
Muscle fasciculations can be due to abnormal recruitment the activity of the enzymes in serum but also by evaluating
of motor nerves causing cramping and fasciculations. This the respective activities of the enzymes relative to the onset
occurs with nerve root irritation, electrolyte abnormalities, of muscle disease. Note that it is the activity of the enzyme in
weakness, fatigue, anxiety, cold, and many other causes. Less serum expressed in units per liter (U/L) that is assessed rather
often, fasciculations can be due to ion channel defects within than the concentration of proteins.
the sarcolemma that cause abnormal propagation of muscle Serum CK is both sensitive and specific for skeletal and
cell depolarization. cardiac muscle damage. Serum CK activity increases within
hours of a muscle insult, peaks within 4 to 6 hours after injury, followed by 12 minutes of trotting should not normally induce
and usually declines to the normal range within 48 hours of elevations in serum CK. If signs of stiffness develop during the
an insult (longer if activities were greater than 100,000 U/L). test, exercise should be concluded. A normal response would
Persistently elevated CK activity indicates ongoing muscle be less than a threefold increase from basal CK; however, most
degeneration. Normal ranges vary among laboratories but healthy horses show no change in CK activity with this exer-
are generally less than 430 U/L. Elevations from several thou- cise test.
sand to hundreds of thousands of U/L occur with moderate to
severe rhabdomyolysis. Minor elevations in CK activity can Electrolytes
occur with training, transport, and strenuous exercise likely In horses with muscle fasciculations or moderate to severe
due to increased sarcolemmal permeability rather than mus- rhabdomyolysis serum sodium, potassium, calcium, chlo-
cle cell damage. Endurance rides or the cross-country phase ride, and phosphorus concentrations and potentially mea-
of a 3-day event can result in CK activity greater than 1000 sures of blood pH are essential parts of the diagnostic
U/L but usually less than 4000 U/L with CK rapidly return- profile. Hypocalcemia and hypophosphatemia, especially
ing to baseline.4 CK activity can increase by in general less in alkalotic horses, can contribute to marked muscle fascic-
than 3000 U/L as a result of prolonged recumbency without ulations or synchronous diaphragmatic flutter. With severe
an underlying myopathy. rhabdomyolysis, damage to muscle cell membranes results
Serum AST activity is not specific for skeletal and cardiac in movement of electrolytes and water from areas of high
muscle damage because it is also present in liver, red blood concentration to lower concentration. Following damage
cells, and other tissues. Elevated AST can result from hemo- to muscle cell membranes as occurs with rhabdomyolysis,
lysis, muscle, liver, or other organ damage, and measures of plasma concentration of extracellular electrolytes (sodium,
hemolysis and liver necrosis, as well as CK activity, are used chloride, and calcium) may be lower than normal as ions
to assess the significance of elevated serum AST. One of the move out of blood and into muscle. Conversely, plasma
main utilities of assessing AST in muscle disease is that it per- concentrations of electrolytes that are typically higher
sists in serum following muscle damage longer than CK and is intracellularly (e.g., potassium and phosphorus) may be
therefore a good means to assess the chronicity of muscle cell increased.8
necrosis. AST activity rises more slowly following damage to
muscle cell membranes than CK, often peaking 24 hours after Renal Parameter
the insult, and the half-life of AST is much longer than that of In horses with myoglobinuria and marked elevations in serum
CK. By comparing serial activities of CK and AST the progres- CK and AST, blood urea nitrogen (BUN) and creatinine should
sion and chronicity of muscle degeneration can be assessed. be monitored because myoglobinuria is associated with renal
Concurrent elevations in CK and AST reflect relatively recent tubular necrosis and renal failure.
or active degeneration. If AST activity is elevated accompanied
by decreasing or normal CK, activite muscle degeneration is Urinalysis
not ongoing. Urinalysis can be the fastest means to detect severe rhabdomy-
Elevations in serum LDH activity are not specific to skel- olysis and myoglobinuria. Myoglobinuria can be detected by
etal muscle and can occur with rhabdomyolysis, myocardial visual inspection of urine color and a positive urine Hemastix
necrosis, and/or hepatic necrosis. Because it is not specific for test in the absence of hemolysis or hematuria. Urine pH can
skeletal muscle and because it has a half-life intermediate to be a valuable first screen for hypoglycin A myopathy as equine
CK and AST, it is not used as often as CK and AST for moni- urine is normally alkaline but is acidic with this condition.
toring muscle damage. Urine can be screened for organic acids to diagnose hypogly-
cin A myopathy.9
Serum CK Exercise Response Test
If serum CK and AST activities are normal at rest but exer- Selenium and Vitamin E
tional rhabdomyolysis (ER) is suspected based on history, Selenium should be assessed in foals with severe rhabdo-
an exercise response test can be a useful adjunct to diagnose myolysis and α-tocopherol assessed in horses with gener-
an underlying predisposition to ER.5 The goal of an exercise alized muscle atrophy. Selenium concentrations are best
challenge test is to provoke subclinical rather than clinical ER. measured in whole blood (anticoagulated with ethylenedi-
Quantifying the extent of subclinical rhabdomyolysis during aminetetraacetic acid, [EDTA]) because selenium is incor-
mild exercise assists in determining the intensity and rapidity porated into red blood cell glutathione peroxidase. Serum
with which to put a horse back into training. Blood samples or plasma for assessment of α-tocopherol concentrations
are taken before exercise and about 4 to 6 hours after exer- should be chilled as soon as possible after obtaining a sample
cise to evaluate peak changes in serum CK. Serum CK activ- and protected from light by wrapping in aluminum foil. If
ity measured immediately after exercise will not reflect the analysis is delayed, serum/plasma samples should be stored
amount of damage occurring during the exercise test. Small frozen (−21°F [−70°C]) because α-tocopherol deteriorates
fluctuations in serum CK activity may occur with exercise due rapidly.
to enhanced muscle membrane permeability, particularly if
exercise is prolonged or strenuous and the horse is untrained. Genetic Testing
A submaximal exercise test provides more consistent evidence Genetic testing of hair roots or EDTA blood is currently avail-
of subclinical rhabdomyolysis than maximal exercise tests.6,7 able for definitive diagnosis of muscle disorders, including
With unfit horses alternating 2-minute intervals of walking hyperkalemic periodic paralysis (HYPP), glycogen branching
and trotting for a maximum of 15 minutes is often sufficient enzyme deficiency (GBED), malignant hyperthermia (MH),
to induce abnormal elevations in serum CK activity in horses and type 1 polysaccharide storage myopathy (PSSM1). The
susceptible to chronic ER. In fit horses 3 minutes of walking decision to perform testing should be based on the prevalence
of the mutation within a breed and whether clinical signs fit

with the genetic disease. Type 1 PSSM, for example, has such a
low prevalence in Thoroughbred horses that genetic testing for
PSSM1 is unlikely to yield valuable information.10 In contrast,
PSSM1 is present in over 50% of Percherons, and therefore the
significance of a positive PSSM1 test result must be correlated
with clinical signs of a myopathy.10 It is important to note that
commercially available genetic tests determine if one specific
mutation previously associated with the disease is present in
the sample submitted. Commercial tests do not detect any
other alterations in DNA sequence within that disease gene,
and such a question would require sequencing of the gene of
interest.
Muscle Biopsy A
Muscle histopathology can reveal the underlying basis for dis-
orders characterized by weakness, atrophy, rhabdomyolysis,
and exercise intolerance. The underlying basis for myopathies
primarily characterized by muscle fasciculations is often not
apparent in muscle biopsies unless there are underlying dys-
trophic changes. It is imperative that the most appropriate
muscle is selected for biopsy based on the differential diag-
noses; that an adequate amount of muscle is obtained; that
the specimen is handled appropriately; that the proper fixa-
tion is used; and that the most appropriate tinctorial, histo-
chemical, and immunohistochemical stains are used to obtain
a diagnosis.
In general, open biopsies of the semimembranosus
muscle (Fig. 10.5A) or percutaneous 6-mm needle biopsies
of the middle gluteal muscle (Fig. 10.5B) are optimal for
exertional myopathies. For Quarter Horses with suspected
B
immune-mediated myositis, a gluteal or lumbar muscle
biopsy obtained temporal to the onset of atrophy is best
whereas for focal atrophy a sample of that specific muscle FIG. 10.5 (A) Site of the open surgical biopsy of the semimembranosus
group is indicated.11 Equine motor neuron disease or vita- muscle. (B) Site of the percutaneous needle biopsy of the middle gluteal
min E–deficient myopathy is optimally diagnosed through muscle.
biopsy of the sacrocaudalis dorsalis medialis muscle.12,13
Samples of the diaphragm or deep postural muscles are most
likely to reveal excessive lipid storage in hypoglycin A myop- investigated, small muscle pieces can be excised and placed
athy.14 Deep pelvic muscles such as the iliopsoas should be directly in appropriate EM fixative.
obtained postmortem when examining a horse with recum-
bency from severe rhabdomyolysis. Electromyography
A limited amount of information restricted to cellular Fine-needle electromyography (EMG) is very useful for dif-
infiltrates and fiber sizes is obtained from standard hema- ferentiating myogenic and neurogenic atrophy and identifying
toxylin and eosin stains of formalin fixed paraffin embed- electrical disturbances of sarcolemmal sodium and chloride
ded skeletal muscle. Fresh samples frozen in a particular channels.16,17 EMG in horses is usually done under sedation to
fashion in isopentane suspended in liquid nitrogen can avoid painful reactions to insertion of the fine EMG needles.
be stained with a battery of tinctorial and histochemical EMG of normal skeletal muscle shows temporary insertional
stains to fully characterize a neuromuscular disorder. Such activity—a brief burst of electrical activity—when the needle
stains will highlight muscle fiber sizes, shapes, fiber type is inserted in muscle and then quiescence. If motor units are
distribution, mitochondrial distribution, polysaccharide recruited (motor unit action potentials) in the muscle exam-
and lipid staining pattern, vacuolar content, neuromus- ined or the needle is very close to a motor end plate (miniature
cular junctions, nerve branches, connective tissue, and end plate potentials), normal regular wave patterns are briefly
blood vessels.15 In addition, frozen samples can be used for observed. Horses with denervation of motor units have abnor-
immunohistochemistry and biochemical analysis of sub- mal spontaneous electrical activity in the form of fibrillation
strate concentrations and enzyme activities, as well as DNA potentials and positive sharp waves. Horses with abnormali-
isolation. Fresh samples can be shipped in a watertight hard ties in the electrical conduction system of muscle demonstrate
container on ice packs to specialized laboratories. Samples forms of complex repetitive discharges or myotonic discharges
for electron microscopy (EM) require appropriate fixation in numerous muscles. A more detailed EMG analysis evaluates
in glutaraldehyde. Ideally, thin sections of muscle for EM amplitude, duration, phase, and number of phases of motor
should be clamped in vivo to maintain fibers at a resting unit action potentials to identify myopathic features, as well as
length before they are excised. However, if pathology other neuropathic features.16 Myopathic changes include a decrease
than the alignment of thick and thin myofilaments is to be in duration and amplitude of motor unit action potentials.
FIG. 10.6 Ultrasonographic appearance of a horse with an acute onset of a stiff short-strided gait on the
right hind gait. The depth of the semimembranosus on the right side is much greater than at the correspond-
ing site on the left side (arrow), indicating swelling of the right semimembranosus muscles. There is no
evidence of tearing or hemorrhage in the muscle.
Imaging on correction, exertional muscle pain resolves. When muscle

Ultrasonography. Diagnostic ultrasonography can be of pain and cramping with exercise are associated with elevations
value to map the extent of muscle trauma, atrophy, and fibro- in serum CK and AST activity, the muscle disorder is classi-
sis. The typical striated echogenic pattern of skeletal muscle fied as exertional rhabdomyolysis (ER). Overt ER can arise as
varies among muscle groups, and ultrasonographic evalua- a sporadic event due to extrinsic factors such as exercise in
tion requires that comparisons are made between similar sites excess of training, exercise during illness, or nutritional imbal-
in contralateral muscles in both transverse and longitudinal ances. ER can also occur as a chronic disease due to intrinsic
views. It is important that the horse is standing squarely and abnormalities in muscle function.
bearing weight evenly as these can alter the ultrasonographic Exertional myopathies can present with exercise intoler-
image. Muscle fiber disruption with an acute injury appears as ance or exercise-induced pain and poor performance without
relatively hypoechoic areas and loss of the normal muscle fiber elevations in serum CK and AST activities or very infrequent
striation. The jagged edge of the margin of the torn muscle elevations. These myopathies are more difficult to accurately
may be increased in echogenicity. Minor trauma may only be diagnose than ER. Evaluation of these cases requires that other
apparent as an increase in the depth of the muscle relative to orthopedic, respiratory, cardiovascular, and behavioral causes
the muscle on the other side (Fig. 10.6). Relatively hyperechoic of decreased performance be critically assessed relative to his-
regions can represent fibrous scarring, whereas hyperechoic topathologic abnormalities in muscle biopsies.
regions causing shadowing artifacts can reflect mineraliza- The critical steps necessary to diagnose the basis for exer-
tion.18 tional myopathies include a detailed history, thorough lame-
Nuclear Scintigraphy. Nuclear scintigraphy is useful for ness evaluation, measurement of serum CK and AST activities,
identification of forms of muscle damage that may not be ap- genetic testing, and muscle biopsy. An exercise challenge test
parent on physical examination because of depth or location and 4-hour postexercise serum CK activity can be of value
and to assess horses with persistent gait abnormalities and in diagnosing ER if not immediately apparent on first evalu-
poor performance. Technetium-99m methylene diphospho- ation. These procedures are described in detail previously in
nate (MDP) is taken up in damaged muscle fibers in the horse this chapter.
and is best seen in the bone phase images (i.e., 3 hours after
injection).19 The mechanism of MDP binding is unknown, but Sporadic Exertional Rhabdomyolysis
the exposure of calcium binding sites on protein macromol- Sporadic forms of ER develop because of an extrinsic event
ecules in the damaged muscle may be responsible. or recurring extrinsic events that induce muscle damage with
exercise. Causes of sporadic ER include focal or generalized
Y EXERTIONAL MYOPATHIES trauma to muscle, dietary imbalances that affect muscle func-
tion, and exercise performed beyond any training adaptation
There are numerous reasons for horses to develop muscle pain or to the point of exhaustion.
with exercise. In many cases mild to moderate muscle sore-
ness can be secondary to extrinsic factors such as orthopedic Signalment, History, and Diagnosis
disease, trauma, ill-fitting saddles, and suboptimal training. A Horses with sporadic ER may be of any age, breed, or sex; may
detailed history, physical examination, and lameness examina- be involved in a wide variety of athletic disciplines; and may
tion will often identify the underlying primary disorder and, have a history of adequate performance before onset of ER.20
A diagnosis is made on the basis of history, clinical signs, and ele- with 15 to 25 g of light salt containing potassium chloride are
vations of serum muscle enzymes. A reasonable period of rest, a recommended for horses exercising in hot, humid conditions
balanced diet, and a gradual introduction of a training program and sweating extensively. In addition, the entire diet should
matched with performance will result in resolution of clinical be adequately balanced with calcium and phosphorus (ratio
signs and a successful return to performance. If over time ER of 2:1 Ca:P is ideal). Assessing total body electrolyte balance
recurs despite reasonable management, a diagnosis of chronic is difficult to accurately perform. One suggested means is to
ER becomes more likely, warranting further diagnostic testing. measure urinary fractional excretion of electrolytes28; how-
ever, marked variation can occur in electrolyte excretion
Focal or Generalized Trauma depending on the diet, exercise, and sampling technique, as
Horses that strain a particular muscle may be very reluctant well as between and within individuals from day to day.29 Fur-
to move and show signs resembling more generalized ER. thermore, the high calcium crystal concentration of alkaline
This is particularly true when lumbar, gluteal, psoas, adduc- equine urine requires acidification to accurately assess cal-
tor, semimembranosus, or semitendinosus muscles are acutely cium and magnesium content.
involved.18 Further, horses that struggle when cast, are caught
in a fence, or are thrashed by another horse may have acute Vitamin E and Selenium Concentrations
signs of rhabdomyolysis caused by severe exertion or trauma. Whole blood selenium concentrations measured in EDTA
A diagnosis of focal trauma is established by history, physical or heparin tubes are of value in assessing selenium status
examination, and serum muscle enzymes. Rectal examination in animals housed in areas where soil and therefore diet
of deep pelvic muscles and ultrasonography may help to local- is deficient in selenium. In cases where selenium has been
ize the extent of muscle damage for focal lesions. On occasion administered before blood collection, glutathione peroxi-
scintigraphy may help to identify specific muscle involvement.21 dase activity can be used to assess potential selenium defi-
ciency. Vitamin E concentration should be measured in
Overexertion serum samples kept chilled and protected from light; how-
A training imbalance as a cause of ER is usually suspected based ever, variability in serum levels can be quite large, and repeat
on a history of an increase in work intensity without a foun- sampling is recommended if marginal levels are identified
dation of consistent training for this level of exercise. Signs of in the first sample tested. Horses with ER are infrequently
muscle stiffness and gait changes range from mild to severe, and deficient in selenium and vitamin E, and alone it may not be
severity is reflected by the magnitude of elevations of serum CK responsible for ER30; however, anecdotal reports suggest that
activity. Overexertion is a well-described cause of ER in polo in some cases supplementation may help to further prevent
horses with 81% of cases of ER attributed to overexertion and episodes of ER.
30% of cases occurring after a day of rest.22 The incidence of ER
is as high as 9% in U.S. polo horses, with most of these horses Treatment of Acute Rhabdomyolysis
only having one episode of ER early in the polo season.22 Hand walking horses with acute rhabdomyolysis is contra-
Pathologic changes are often not evident in light micro- indicated as it exacerbates muscle damage. If ER occurs at a
scopic evaluation of muscle biopsies from individuals per- distance from home, a trailer should be brought to the horse
forming unaccustomed exercise, but electron microscopy and a tranquilizer administered to assist the horse in mov-
shows significant disruption of the alignment of muscle coning to the trailer and loading. During a competition, the
tractile proteins within muscle fibers. In more severe cases horse is treated for rhabdomyolysis on site, and transport
overt segmental damage to myofibers may be apparent in home over a long distance should be delayed for at least 24
muscle biopsy. Repetitive overuse of muscles, such as occurs to 48 hours.
with overtraining, may result in exercise intolerance and is The objectives of treatment are to relieve anxiety and mus-
associated with pathologic changes such as increased muscle cle pain, as well as to correct fluid and acid-base deficits.31
fiber size variation and centrally displaced myonuclei in mus- Acepromazine (0.04–0.07 mg/kg), an α-adrenergic antago-
cle biopsies.23 nist, is helpful in relieving anxiety and may increase muscle
blood flow. Dehydrated horses may become hypotensive and
Exhaustion recumbent if given acepromazine. Alternatively, xylazine
Exhaustion occurs most commonly in endurance horses or (0.4–0.8 mg/kg) may provide short-term relief from anxiety.
racehorses exercising in hot, humid weather. Signs of heat In horses in more pain, detomidine (0.02–0.04 μg/kg) com-
exhaustion include weakness, ataxia, rapid breathing, muscle bined with butorphanol (0.01–0.04 mg/kg) provides excellent
fasciculations, sweating, and in severe cases collapse. The body sedation and analgesia. Nonsteroidal antiinflammatory drugs
temperature may be elevated to 105° to 108°F. Muscles are fre- (NSAIDs) such as ketoprofen (2.2 mg/kg), phenylbutazone
quently not firm on palpation, although serum CK activity can (2.2–4.4 mg/kg), or flunixin meglumine (1.1 mg/kg) provide
be markedly elevated and myoglobinuria may be noted.24,25 additional pain relief. Analgesic treatment is continued to
effect, but most horses are relatively pain free within 18 to 24
Dietary Imbalances hours. For horses with extreme pain and distress a constant
Diets with a high nonstructural carbohydrate (NSC) content rate infusion of detomidine (0.22 μg/kg intravenously followed
and low forage content,26,27 deficient in electrolytes, or inade- by 0.1 μg/kg/min IV) or lidocaine (1.3 mg/kg intravenously
quate in selenium and vitamin E may exacerbate episodes of ER. followed by 0.05 mg/kg/min intravenously) or butorphanol
(13 μg/kg/hr) can make the difference between adequate time
Electrolyte Imbalances for recovery and euthanasia.
It is important to ensure that horses receive sodium chloride in Intravenous (IV) or intragastric dimethyl sulfoxide (as a
the diet, especially horses that compete in hot, humid weather. less than 20% solution) can be used as an antioxidant, antiin-
Between 30 and 50 g per day of sodium chloride combined flammatory, and osmotic diuretic in severely affected horses.
Some veterinarians administer corticosteroids in the acute the necessary additional sodium chloride, with the amount
stage. If the horse is recumbent methylprednisolone succinate fed depending on the heat, humidity, and intensity of exercise.
(2–4 mg/kg intravenously) can be given once. Muscle relax- Once serum CK returns to normal, training can be resumed
ants such as methocarbamol (5–22 mg/kg, slow IV adminis- gradually. A regular exercise schedule, beginning with 20
tration) seem to produce variable results possibly depending minutes or less of exercise per day, is gradually increased to
on the dosage used. Dantrolene sodium (Dantrium) (2–4 mg/ eventually match the expected amount of daily exercise to the
kg orally) is administered to decrease release of calcium from underlying state of conditioning.
the sarcoplasmic reticulum and further aggravation of muscle
contractures and necrosis. This can be repeated in 4 to 6 hours. Chronic Exertional Myopathies
Caution is advised when administering Dantrium to horses Several inherent disorders of equine skeletal muscle can
with HYPP as it can elevate serum K concentrations and pre- cause repeated episodes of ER or exertional myopathy:
cipitate an episode. recurrent exertional rhabdomyolysis, malignant hyperther-
Severe rhabdomyolysis can lead to renal compromise due mia, type 1 polysaccharide storage myopathy, type 2 poly-
to ischemia and the combined nephrotoxic effects of myoglo- saccharide storage myopathy, idiopathic chronic exertional
binuria, dehydration, and NSAIDs. The first priority in horses rhabdomyolysis, and mitochondrial myopathy. There are
with hemoconcentration, or myoglobinuria, is to reestablish likely many other causes yet to be identified. In these forms
fluid balance and induce diuresis. In mild cases administration of chronic exertional myopathies, there are specific environ-
of fluids via a nasogastric tube may be adequate, but generally mental stimuli that are necessary to trigger muscle pain in
fluids are better given intravenously. Balanced polyionic elec- susceptible horses. Horses cannot be cured of their suscepti-
trolyte solutions are best. If severe rhabdomyolysis is present, bility to this condition, but if the specific form of exertional
isotonic saline or 2.5% dextrose in 0.45% saline may be neces- myopathy is identified, changes in management may help to
sary because horses often have hyponatremia, hypochloremia, minimize episodes of muscle pain.
and hyperkalemia.8 If hypocalcemia is present, supplementing
IV fluids with 100 to 200 mL of 24% calcium borogluconate Recurrent Exertional Rhabdomyolysis
is recommended, but serum calcium should not exceed a low The term recurrent exertional rhabdomyolysis (RER)
normal range. Affected animals are usually alkalotic, making describes a subset of ER that is believed to be due to an
bicarbonate therapy inappropriate. abnormality in the regulation of muscle contraction and
The total fluid replacement is based on an estimation relaxation.5,32-34 Research into RER has primarily been
of the degree of dehydration and the clinical response: 10 performed in Thoroughbreds and, to a lesser extent, Stan-
L of fluids may be given rapidly. If the adult horse is 5% dardbred horses.32,35-37 Scientific studies of RER have used
dehydrated an additional 15 L may be given over the next a small number of horses that share common clinical signs
4 hours; if dehydration is severe (20%) an additional 50 L of and have abnormal muscle contracture tests.32,34,38 Broader
polyionic fluids may be required at 4 L per hour. Ideally, the epidemiologic and genetic studies have assumed that the
need for further IV fluids is guided by reassessment of the same pathophysiologic basis for ER exists in the majority of
packed cell volume, total plasma protein, and serum electro- Thoroughbred and Standardbred horses with similar clinical
lytes after the initial period of therapy. In severely affected signs. Whether this is true or not will require more research.
horses, regular monitoring of blood urea nitrogen and/or There are reports of some Arabian and Warmblood horses39
serum creatinine is advised to assess the extent of renal dam- with ER that may also suffer from RER based on the over-
age. Diuretics are usually contraindicated unless the horse is lapping histories, clinical signs, muscle biopsy findings, and
in oliguric renal failure. response to management.
Good nursing care is important with recumbent animals. Rhabdomyolysis is triggered suddenly during exercise in
This involves deep bedding, prevention or minimization of RER horses resulting in a sharp increase in serum myoglobin
trauma around the eyes, and appropriate care of decubital and CK activity.6 Clinically, the triggering event is often asso-
sores. Recumbent animals require frequent turning to allow ciated with excitement in a horse that already has an under-
reperfusion of compressed muscle. The use of slings to assist lying nervous temperament.35,40 Segmental necrosis in single
recumbent animals to rise is highly beneficial. fibers or small clusters of necrotic fibers scattered throughout
Following treatment of an acute ER episode, after stiffness fascicles may be apparent in fewer than 5% of type 2a and 2x
resolves, rest with regular access to a paddock and weekly muscle fibers in a gluteus medius muscle biopsy.36,37 Serum
monitoring of serum CK activity are recommended. Horses cortisol concentrations are higher in RER horses than normal
are much more susceptible to a second episode of ER in the horses before exercise and increase during an episode of ER.6
2 weeks following an acute episode, and allowing horses the Serum concentrations of epinephrine and norepinephrine are
ability to calmly determine their own exercise through turn- normal before an episode but increase dramatically in horses
out often avoids exacerbating rhabdomyolysis. If that is not with marked elevations in serum CK activity.6
feasible, hand walking needs to be performed with caution Exercise. In Standardbreds, ER commonly begins after 15
and limited to no more than a few minutes initially. While to 30 minutes of jogging at 5 m/sec, although clinical signs
the horse is rested, the diet can be assessed to ensure that the may not be apparent until after exercise.36 In Thoroughbreds
ration is fed in an amount recommended by the manufacturer exercising on the treadmill, ER most commonly develops
for the corresponding level of exercise. This will ensure that the with intervals of walk, trot, and canter and is less common if
proper balance of vitamins and minerals is provided. If exces- horses are allowed to gallop.41,42 At the racetrack, ER occurs
sive calories are provided when fed according to the manu- commonly when RER horses are held back to a paced gallop.35
facturer’s recommendations, the diet should be switched to a During eventing, RER commonly occurs after the excitement
less calorie-dense vitamin/mineral-balanced diet. A salt block of the steeplechase or early in the cross-country phase when
or 30 to 50 g (1–3 tablespoons) of salt per day will provide horses are held to a predetermined speed.43 ER rarely occurs
when horses are allowed to achieve maximal exercise speeds or contractility whose basis is yet to be defined. Alternatively,
such as racing. A day or more of rest before this type of exer- the increased sensitivity of RER horses in contracture test-
cise results in higher postexercise serum CK activity. ing may be a nonspecific indicator of an abnormality in other
Lactic Acid. There is no basis for an association between pathways governing muscle contraction.
RER and lactic acidosis. Thoroughbreds and Standardbreds Prevalence and Risk Factors. Assuming that the majority
rarely develop ER during near-maximal exercise42,44 when of cases of ER at racetracks are due to RER, the prevalence in
muscle lactates reach 240 mmol/kg45 and plasma lactates are Thoroughbred racehorses is remarkably similar around the
as high as 25 mM. Standardbred horses experience ER dur- world, with estimates of 4.9% in the United States,35 5.4% in
ing jogging when muscle lactate concentrations are less than Australia,21 and 6.7% in the United Kingdom.40,43 The an-
24 mmol/kg.46 Similarly, plasma lactate concentrations in RER nual incidence of ER in Standardbred racehorses in Sweden
Thoroughbred horses are less than 1.5 mM when performing is 6.4%.52 Exercise obviously increases the prevalence of RER
the walk, trot, and canter treadmill exercise that induces high in horses, and episodes are observed more frequently once
serum CK activity.41 Thus rhabdomyolysis in RER horses is horses achieve a level of fitness.
not due to lactic acidosis. In Standardbreds and Thoroughbreds, mares more com-
Intracellular Calcium Regulation. Research suggests that monly have RER than males; however, no general correlation
horses with RER may have an inherent abnormality in intra- has been observed between episodes of rhabdomyolysis and
muscular calcium regulation that is intermittently manifested stages of the estrous cycle.53 There is an interaction between
during exercise.34,47 Myoplasmic calcium concentrations are age and gender in RER Thoroughbred horses such that the
tightly controlled by channels and pumps in the sarcoplasmic proportion of affected females to males is much higher in
reticulum and usually are unaffected by normal serum cal- young horses compared with older age groups.35 Swedish
cium concentrations. Basal muscle intracellular calcium con- Standardbreds with RER, which do not begin racing until
centrations in RER horses are similar to healthy horses based 3 years of age, did not show the same age association with
on assays in muscle cell cultures.47 Higher intracellular calci- RER as Thoroughbreds.53 Temperament has a strong effect
um concentrations have been measured in horses of unspeci- on the expression of RER in both Standardbreds and Thor-
fied breeds during an episode of ER; however, this also could oughbreds, with nervous horses, particularly fillies, having a
be secondary to any insult that impairs energy generation or higher incidence of rhabdomyolysis than calm horses.35,43,52
cell membrane integrity.48 To specifically study shuttling of Young fillies are more likely to have a nervous temperament
calcium between the sarcoplasmic reticulum and myoplasm than mares or male horses. Diet also has an impact, with
within the muscle cell, technically complex procedures such Thoroughbred horses, fed more than 2.5 kg of grain being
as muscle contracture testing, calcium imaging in muscle cell more likely to show signs of RER.41 One study also found a
cultures, and calcium release by isolated muscle membrane higher prevalence of rhabdomyolysis among Thoroughbred
preparations have been evaluated. Results are reported as the horses with lameness.35 A few days of rest before exercise
threshold at which a significant increase in muscle tension oc- increases the degree of elevation on serum CK activity with
curs above baseline levels. Caffeine and halothane are most the next exercise session and in practice predisposes horses
frequently used to trigger the release of calcium from the sar- to an episode of ER.42
coplasmic reticulum to the myoplasm via the ryanodine re- Although there is a familial tendency for RER, its genetic
ceptor. This test remains an experimental procedure because basis has not yet been defined. A genetic susceptibility appears
of the difficulty in obtaining accurate and timely results. Early to exist in Thoroughbred horses, and RER-afflicted Thorough-
studies by Hildebrand et al38 suggested that some but not all breds may pass the trait to their offspring.54,55 The difficulty in
horses with ER showed a lower threshold for caffeine- and establishing a specific phenotype, the variable penetrance of
halothane-induced muscle contractures than healthy horses. the disease, and the possible existence of potential modifying
Waldron-Mease et al49 and Beech et al32 found that caffeine genes have made this hard to firmly establish. Of note is the
contracture thresholds were lower in semimembranosus finding that Standardbred trotters with a history of RER have
muscle from Thoroughbreds and Standardbreds susceptible faster racing times from a standstill start than those without a
to RER versus breed-matched controls. Lentz et al34,50 studied history of RER, suggesting that the trait may have beneficial as
intact external intercostal muscle fibers and found that Thor- well as deleterious effects.52
oughbreds with RER had a lower contracture threshold for Diagnosis. A presumptive diagnosis of RER is based on
triggering agents such as potassium, caffeine, and halothane clinical signs of muscle pain and the presence of risk factors
but not 4 chloro-m-cresol compared with control horses. An commonly associated with RER. Serum CK and AST activi-
abnormality in intracellular calcium regulation was also sup- ties serve as the basis for detecting muscle degeneration, and
ported by a muscle cell culture study of RER Thoroughbred they often show intermittent abnormal elevations that return
horses.47 Thus all of these studies support an abnormality in to normal relatively quickly during the course of training.
intracellular calcium regulation in most of the Thoroughbred If CK elevations are mild there are a number of factors to
or Standardbred horses studied. Isolated sarcoplasmic reticu- consider. Timing of the sample with regard to the onset of
lum membrane studies, however, have not conclusively iden- ER and exercise is important. Reliability is improved by ob-
tified any abnormalities in intracellular calcium regulation, taining blood samples at a standardized time after exercise,
indicating that there are distinct differences between RER and preferably 4 to 6 hours when CK peaks, and consistently
disorders such as malignant hyperthermia.32,51 Genetic link- with regard to exercise on the preceding day, because serum
age analysis has failed to associate RER with the genes RYR1 CK activity is higher on exercise days that are preceded by
(ryanodine receptor), SERCA (SR ATPase), or DHPR1 (dihy- a day or more of rest.56 In addition, normal values need to
dropyridine receptor), all of which are involved in intramus- be adjusted for the age and sex of horses. Two-year-old fil-
cular calcium regulation. Thus RER could be a novel defect in lies generally have greater fluctuations in serum CK activ-
muscle excitation-contraction coupling, calcium regulation, ity during race training than 3-year-old fillies or geldings.56
Muscle histopathology is nonspecific in RER horses; either their nervous temperament they may be more discriminating
no abnormalities or evidence of centrally located nuclei in in their eating habits or prone to gastric ulcers. Of the total
mature fibers and potentially waves of myofiber degenera- daily calories required by RER horses, research suggests that
tion or regeneration are found.5 There is a notable absence less than 20% DE should be supplied by nonstructural car-
of abnormal amylase-resistant polysaccharide, although in- bohydrates (NSC = starch and sugar), and at least 20% of DE
creased subsarcolemmal amylase-sensitive glycogen may be should be supplied by fat.41,42
present.57 The value of a muscle biopsy as a diagnostic tool in SELECTION OF FORAGE. Thoroughbred horses do not ap-
horses with suspected RER is largely confined to particularly pear to show the same significant increase in serum insulin
recurrent unmanageable cases where a need arises to rule in concentrations in response to consuming hay with an NSC
or out other forms of ER. of 17% as seen in Quarter Horses (Borgia L, 2010, PhD the-
Management. Prevention of rhabdomyolysis in horses sis, University of Minnesota). This fact combined with the
susceptible to RER is complex, and multiple factors need to be high caloric requirements of racehorses may mean that it is
changed to decrease episodes. These factors include the envi- not as important to select hay with very low NSC content
ronment, the exercise regimen, and diet. Medication may be in RER Thoroughbreds as it is in PSSM horses. Anecdotally
needed at times to prevent further episodes of muscle damage. some trainers find that horses with RER have more frequent
ENVIRONMENT. Because excitement and nervousness of- episodes on alfalfa hay. The nervous disposition of some
ten trigger rhabdomyolysis, stressful situations in the envi- RER horses may predispose them to gastric ulcers, and thus
ronment that can be modified need to be identified. This may frequent provision of hay with a moderate NSC and mixed
involve a change to a smaller barn with fewer horses and few- alfalfa content may be indicated.
er handlers, compatible companions, and a more consistent LOW-STARCH, HIGH-FAT CONCENTRATES. When RER Thor-
daily routine. Many stressed RER-susceptible horses respond oughbreds are fed a moderate caloric intake (24 MCal/day)
to a regular routine including feeding before other horses and in the form of high-starch concentrates (2.5 kg of corn/oats/
training before other horses, especially if the horse becomes wheat middlings/molasses), they show very little elevation
impatient while waiting. Other horses respond to being in serum CK activity with exercise.41 Most Thoroughbred
housed in a quiet area of the barn next to calm companion- racehorses, however, are fed at least 5 kg of high-starch con-
able horses. The use of hot walkers, exercise machines, and centrate per day at 30 MCal or more per horse per day, and
swimming pools should be evaluated on an individual basis, at this level of feeding, postexercise serum CK activity rises
as some horses develop rhabdomyolysis when using this type significantly.35 The discovery that substitution of fat for starch
of equipment. Horses that develop rhabdomyolysis at specific in a high-calorie ration significantly reduces muscle damage
events, such as horse shows, may need to be reconditioned to in exercising RER horses was a major advance in nutritional
decrease the stress level associated with such events or tran- management of RER.42 Practically, however, it was difficult to
quilized as part of the accommodation process. Providing achieve the desired caloric intake of racehorses because the
daily turnout with other horses seems to be very beneficial for maximum amount of fat that finicky Thoroughbreds will hap-
RER horses and may decrease anxiety and thereby the likeli- pily consume is often limited to 600 mL for vegetable oil or
hood of rhabdomyolysis. 5 lb/day of balanced rice bran. Management of RER horses
EXERCISE. Although for sporadic forms of ER a period of was significantly improved when a palatable means to provide
rest is recommended until serum CK normalizes, it is not rec- the amount of fat required by fit finicky RER Thoroughbreds
ommended for horses with RER.18 Daily exercise is important was developed. A controlled trial using a specialized feed de-
in preventing episodes of rhabdomyolysis, and when serum veloped for RER (Re-Leve 13% fat by weight and 9% NSC)
CK is less than about 3000 U/L horses should be returned to determined that NSC should be no greater than 20% of daily
regular daily exercise. Horses with more severe episodes of DE, and 20% to 25% of daily DE should be provided by fat
rhabdomyolysis may require additional time off in a paddock for optimal management of RER horses fed 30 MCal or more
before gradually resuming exercise. Once back in training, per day.42 No beneficial effect on serum CK activity occurred
some form of daily exercise is recommended. Avoiding fight- when sodium bicarbonate (4.2% of the pellet) was added to a
ing to hold racehorses to slower speeds during galloping may high-starch pellet feed.42 The amount of fat in the diet of an
decrease rhabdomyolysis in RER-susceptible Thoroughbreds. RER horse depends on its caloric requirements. If an affected
Interval training and reduction of jog miles to no more than horse being fed hay at 1.5% to 2% of body weight and 2.5 kg
15 minutes per session will benefit Standardbreds. For horses of grain daily requires additional caloric intake to maintain
under saddle, a relaxed warm-up with intermittent periods of body weight, additional calories should be supplied by adding
long low stretching may be of benefit, and continued breaks a source of fat to the diet.
to stretch between episodes of collection are recommended. The benefit of a fat-supplemented diet does not appear to
Event horses may require training that incorporates calm ex- be a change in muscle metabolism. Preexercise and postexer-
posure to speeds achieved during the steeplechase or cross- cise muscle glycogen and lactate concentrations are the same
country phase especially when used in an interval training in RER horses fed a low-starch, high-fat diet compared to a
program. high-starch diet.44 Low-starch, high-fat diets in RER horses
DIET. A nutritionally balanced diet with appropriate ca- may decrease muscle damage by assuaging anxiety and excit-
loric intake and adequate vitamin and mineral intake are the ability, which are tightly linked to developing rhabdomy-
core elements of managing RER. For RER Thoroughbreds and olysis in susceptible horses. High-fat, low-starch diets fed to
Standardbreds in training, the challenge is usually supply- fit RER horses produce lower glucose, insulin, and cortisol
ing enough calories in a highly palatable form to meet their responses and lead to a calmer demeanor and lower preex-
daily energy demands. This is in part because they often re- ercise heart rates. Neurohormonal changes may develop in
quire greater than 30 MCal of digestible energy (DE) a day response to high serum glucose, insulin, and cortisol concen-
(5 kg sweet feed, 1.5% of body weight in hay) and because of trations, resulting in an anxious demeanor.58 Although a calm
demeanor is desired during training, some racehorse trainers increments every 3 to 4 days. Phenytoin is a monoaminoxi-
feeding low-starch, high-fat feeds prefer to supplement with dase activator and can affect plasma concentrations of other
a titrated amount of high-starch grain 3 days before a race medications. Unfortunately, long-term treatment with Dant-
to potentially increase liver glycogen and increase a horse’s rium or phenytoin is expensive, and these drugs must be with-
energy during the race. drawn before competition.
Studies in RER horses show that significant reductions or HORMONE THERAPY. Various hormones, ranging from thy-
normalization of postexercise serum CK activity occurs within roxine to progesterone and testosterone, have been given to
a week of commencing a low-starch, fat-supplemented diet.42 horses with RER. Initial studies linking low T3 and T4 con-
Days off training in a stall are discouraged because postexer- centrations in horses with ER have not been substantiated.64,65
cise CK activity is higher following 2 days of rest compared to Some mares appear to exhibit signs of rhabdomyolysis during
values taken when performing consecutive days of the same estrus, and it may well be of benefit in these horses to suppress
amount of submaximal exercise.42,59 estrous behavior using progesterone injections. Testosterone
SUPPLEMENTS. Horses require daily dietary supplementa- and anabolic steroids have been used at racetracks to prevent
tion with sodium and chloride either in the form of loose salt signs of RER, but their use is no longer permitted.
(30–50 g/day) or a salt block. Additional electrolyte supple- ADJUNCT THERAPIES. Massage, myofascial release, me-
mentation is indicated in hot, humid conditions. A myriad of sotherapy, stretching, aqua-treadmill therapy, and hot/cold
supplements are sold that are purported to decrease lactic acid therapy performed by experienced therapists may be of ben-
buildup in skeletal muscle of RER horses. These include so- efit in individual horses.66 Their use may promote relaxation,
dium bicarbonate, B vitamins, branched chain amino acids, promote normal muscle tension, and build muscle strength.
and dimethylglycine. Given that lactic acidosis is no longer
implicated as a cause for rhabdomyolysis, it is difficult to find
a rationale for their use. Malignant Hyperthermia
MEDICATIONS. Low doses of tranquilizers, such as Pathogenesis
acepromazine, before exercise have been used in RER horses Malignant hyperthermia (MH) occurs in Quarter Horses and
prone to excitement.60 A dose of 7 mg intravenously 20 min- Paint Horses as a result of an autosomal dominant mutation
utes before exercise is reported to make horses more relaxed in exon 46 of the skeletal muscle ryanodine receptor 1 gene
and manageable. Reserpine and fluphenazine, which have a (RYR1).67,68 The mutation lowers the activation and heightens
longer duration of effect, have also been used for this purpose. the deactivation threshold of the ryanodine receptor, which
Horses given fluphenazine may occasionally exhibit extrapy- intermittently can result in a dramatic efflux of calcium from
ramidal adverse effects with prolonged bizarre behavior. Use the sarcoplasmic reticulum, increasing myoplasmic calcium
of tranquilizers may only be necessary when horses are in their and producing a contracture.69 Anaerobic glycogen metabo-
initial phase of training and accommodation to a new envi- lism is activated, lactate is produced, excessive heat is gener-
ronment. Horses obviously cannot compete on these medica- ated, and massive muscle necrosis ensues.
tions, and withdrawal times must be observed.
Dantrolene sodium (Dantrium) acts to decrease release of Prevalence and Risk Factors
calcium from the ryanodine receptor in skeletal muscle and is MH affects less than 1% of Quarter Horses and Paint Horses,
used to treat malignant hyperthermia. Studies of intact equine particularly affecting halter and pleasure horse lines. Rhabdo-
intercostal muscle from ER horses show that Dantrium lowers myolysis with MH can be induced by exercise or anesthesia
already elevated myoplasmic calcium concentrations.48 Con- and is exacerbated by the presence of the GYS1 mutation for
trolled and field studies have also shown that oral Dantrium type 1 PSSM. In many horses, clinical signs are completely
can significantly decrease signs of rhabdomyolysis in RER unapparent or very intermittent in nature.68
horses.59,61 One study indicated that horses need to be fasted
to achieve measurable blood levels of Dantrium,59 but more Clinical Signs
recent controlled trials suggest that absorption of Dantrium Clinical signs of hyperthermia (104.9°F [40.5°C]), hypercap-
is superior in fed versus fasted horses.62 Administration of 4 nia (PaCO2 of 274 mm Hg), and acidosis (pH of 6.72) were
mg/kg of Dantrium PO 1 hour before exercise to RER-suscep- reported in an experimental protocol approximately 60 min-
tible horses fed high-grain diets resulted in significantly lower utes after anesthesia was induced by delivering halothane via
serum CK activity 4 hours after exercise compared with pla- a face mask without premedication.70 Death occurred from
cebo.59 A dose of 800 mg of Dantrium was given to Thorough- cardiopulmonary arrest and was preceded by profound rigor
bred horses in the United Kingdom 1 hour before exercise and mortis. Hematologic changes present 2 minutes after death
resulted in significantly lower postexercise CK activity than a included hemoconcentration, hyperkalemia, hypercalce-
placebo.61 mia, hyperphosphatemia, hyperglycemia, and elevated cre-
Phenytoin (1.4–2.7 mg/kg PO b.i.d.) has been reported atinine. Serum CK activity was mildly increased at 843 U/L,
to be effective in preventing rhabdomyolysis in horses with and myoglobin was 10 times higher than the reference range
RER.33,63 Phenytoin acts on a number of ion channels within in this horse.
muscle and nerves, including sodium and calcium channels. Horses with the RYR1 mutation may intermittently show
Therapeutic levels vary, so oral doses are adjusted by monitor- signs of ER and high body temperatures.68 Some MH-affected
ing serum levels to achieve 8 μg/mL and not to exceed 12 μg/ horses have died suddenly after an episode of ER. Horses with
mL.33,63 Drowsiness and ataxia are evidence that the dose of the MH mutation may also have the GYS1 mutation associated
phenytoin is too high and the dose should be decreased by with type 1 PSSM.71 Such horses have more severe episodes
half. Initial dosages start at 6 to 8 mg/kg orally twice a day of ER, higher serum CK activity after exercise, and a more
for 3 to 5 days. If the horse is still experiencing rhabdomyoly- moderated response to the diet and exercise regimens recom-
sis but is not drowsy, the dose can be increased by 1-mg/kg mended for type 1 PSSM.71
Diagnosis of PSSM1 appears to occur in draft horses derived from Con-

Genetic testing is recommended in Quarter Horses and Paint tinental European breeds.79 In fact, many Continental Europe-
Horses with severe ER or ER associated with elevated body tem- an drafts are homozygous for the dominant PSSM1 trait (90%
perature. Muscle biopsy is not particularly useful for diagnosing prevalence of PSSM in Trekpaards with 40% of tested Belgian
MH. Biopsies may contain mild myopathic changes, including Trekpaards homozygous).79 North American Belgians and
increased variation in fiber sizes, centrally located nuclei, fiber Percherons also have a high prevalence of PSSM1 at 36% and
necrosis, glycogen depletion, and ringbinden fibers. 54% of horses affected.10 In contrast, the prevalence of PSSM
is very low in UK-derived breeds such as Shires and Clydes-
Treatment dales, but PSSM1 is present in other UK horse breeds such as
Horses with suspected MH should be treated with oral Dan- Irish Drafts, Cob, and Connemara.10,79 Horses of more than
trium (4 mg/kg) 30 to 60 minutes before anesthesia.70 The 20 other breeds may have the GYS1 mutation responsible for
exception to this rule may be horses with MH and hyperkale- PSSM1.80-82 Prevalence estimates of PSSM1 in Quarter Horses
mic periodic paralysis because Dantrium can cause an exces- range from 6% to 10% of the breed and 6% to 8% for Ameri-
sive rise in serum potassium that can trigger an episode of can Paint and Appaloosa horses.83 The highest frequency of
muscle paralysis.72 There is no cost-effective means to deliver PSSM1 occurs in halter Quarter Horses (28% affected) and
Dantrium to horses intravenously once an episode of MH has the lowest frequency in racing Quarter Horses.83 The GYS1
begun. The nature of ER with horses positive for MH is so mutation has been identified in approximately 72% of Quarter
intermittent that it is hard to justify premedication with Dan Horses diagnosed with PSSM by muscle biopsy and in 18%
trium before exercise. of Warmbloods of a variety of types diagnosed with PSSM by
muscle biopsy.84 The prevalence of PSSM1 is very low to non-
Polysaccharide Storage Myopathy existent in light horse breeds such as Arabians, Standardbreds,
Polysaccharide storage myopathy (PSSM) was first recognized and Thoroughbreds.10
as a specific myopathy in Quarter Horse–related breeds in Risk Factors. Some horses with PSSM1 are asymptomatic,
1992,73 but reports of abnormal polysaccharide inclusions in whereas other horses routinely show stiffness with exercise.
equine muscle of individual horses date back to 1979.74 The In a family of Warmbloods sired by a stallion with the GYS1
remarkable feature of the first horses reported to have PSSM mutation, the mutation resulted in a sevenfold higher risk
was twofold higher muscle glycogen concentrations than nor- of developing ER, with owners reporting that 66% of horses
mal horses and abnormal granular amylase-resistant inclu- with the GYS1 mutation had clinical signs of ER.85 The rea-
sions in histologic sections.73 Similar biopsy findings were son for variability in clinical signs of PSSM1 probably lies in
reported in Belgian and Percheron draft horses.74 the influence of diet, exercise, other environmental factors,
and other genes on the expression of the disease. There is no
Terminology significant temperament, body type, or gender predilection
PSSM has also been referred to as equine polysaccharide myopathy for PSSM1.86,87 The most common trigger for clinical signs
(EPSM or EPSSM). 27,75 Considerable controversy existed as to of PSSM1 is less than 20 minutes of exercise. Clinical signs
whether these acronyms encompassed one muscle condition.7,27,76 occur most commonly at a walk and trot, particularly if the
In 2008 a mutation in the glycogen synthase 1 gene (GYS1) was horse has been rested for several days before exercise or is
found to be highly associated with the presence of amylase-resis- unfit.86 Diets high in NSC also increase the risk of muscle
tant polysaccharide in skeletal muscle.77 Genetic testing of hun- pain and stiffness in PSSM1 horses.88 About 40% of own-
dreds of horses previously diagnosed with PSSM by muscle biopsy ers feel there is a seasonal incidence to the development of
revealed that the majority of cases of PSSM characterized by clinical signs, which some have attributed to quality of grass
amylase-resistant polysaccharide in skeletal muscle had the GYS1 available at the time.82 Although exercise is by far the most
genetic mutation. However, some cases previously diagnosed with common trigger for PSSM, Quarter Horse and Paint Horse
PSSM by muscle biopsy, particularly those with excessive amylase- foals and weanlings may develop rhabdomyolysis in con-
sensitive glycogen, did not possess the genetic mutation. This sug- junction with a systemic illness.89
gested that there are at least two forms of PSSM.77,78 For clarity, the Diagnosis. Persistent elevations in serum CK and AST
form of PSSM caused by an H309G GYS1 mutation is now termed activities are common in symptomatic horses with PSSM1
type 1 (PSSM1) whereas the form or forms of PSSM not caused (Fig. 10.7). If horses have normal serum muscle enzymes at
by the GYS1 mutation and whose origins are yet unknown are rest, an exercise test consisting of a maximum of 15 min-
termed type 2 (PSSM2).78 PSSM1 is likely to be the same disorder utes lunging at a walk and trot may help to determine if sub-
that was called “azoturia” or “Monday morning disease” in work clinical ER is present.5 Supportive evidence would include
horses in the nineteenth and twentieth centuries. a minimum of a threefold elevation in CK activity 4 hours
after exercise.
Type 1 PSSM The gold standard for diagnosis of PSSM1 is genetic testing
Genetics. PSSM1 is caused by an autosomal dominant mis- for the GYS1 mutation performed on whole blood or hair root
sense mutation in GYS1 that results in an arginine substitution samples. It is important to note that in draft horses of con-
for histidine at codon 309 in glycogen synthase.77 The effect of tinental European origin, the very high prevalence of PSSM
this amino acid substitution is a higher than normal activity of in essence means that there is a high chance that any clinical
glycogen synthase both at basal states and when activated by sign could be falsely associated with the disease PSSM1.79,87
glucose-6-phosphate. Clinical judgment is required to determine whether the clini-
Prevalence. PSSM1 is estimated to have emerged approxi- cal signs of the animal could reasonably be associated with a
mately 1600 years ago when the great horse was being de- myopathic process. Muscle biopsy provides a means to diag-
veloped from European draft and light horse breeds to carry nose PSSM; however, to classify PSSM as type 1 a genetic test
knights with heavy armor into battle.77 The highest prevalence is required. The distinctive features of PSSM1 in muscle biopsy
This results in particularly severe signs of ER and a limited

response to diet and exercise changes. During an episode of
ER, excessively high body temperatures may develop and sud-
den death can occur in horses with the RYR1 mutation. This
combination occurs most often in halter and pleasure horses.
DRAFT HORSES AND DRAFT CROSSES. The average age of
draft horses diagnosed with PSSM is about 6 years.87 Many
draft horses with PSSM are asymptomatic. Draft horses ho-
mozygous for the PSSM mutation have higher serum muscle
enzymes than healthy or heterozygous horses.94 Signs of se-
vere rhabdomyolysis and myoglobinuria may occur in horses
fed high-grain diets, exercised irregularly with little turnout,
or horses that undergo general anesthesia.91,95 Rhabdomyoly-
sis can be so severe that it leads to recumbency and death.91,95
Other signs of PSSM in draft horses include progressive weak-
FIG. 10.7 Serum creatine kinase (CK) activity obtained 4 hours after ness and muscle loss resulting in difficulty rising in horses
exercise in three Quarter Horses with type 1 polysaccharide storage myo- with normal serum CK activity. Pronounced weakness is more
pathy (PSSM1) over a 3-week period of training for 20 minutes or less each prevalent in horses homozygous for the GYS1 mutation. Gait
day. Note that these severely affected PSSM horses have persistent eleva- abnormalities, such as excessive limb flexion, fasciculations,
tions in serum CK activity that do not return to normal reference range. and trembling, are also reported in draft horses. Although the
condition “shivers” was previously attributed to PSSM, studies
found no causal association between these two conditions.87
samples are numerous subsarcolemmal vacuoles and dense, There is no evidence of impaired myocardial function in hors-
crystalline periodic acid–Schiff (PAS)–positive and amylase- es with PSSM1.96 In Belgian draft horses mean (± standard
resistant inclusions in fast-twitch fibers (Fig. 10.8). A diagno- deviation [SD]) AST activity was 502 ± 116 U/L for PSSM1
sis can be made irrespective of diet and proximity of sampling homozygotes, 357 ± 92 U/L for heterozygotes, and 311 ± 64
to recent episodes of rhabdomyolysis. A false-negative diag- U/L for controls, with significant differences among groups.94
nosis of type 1 PSSM by muscle biopsy may occur if biopsy The median serum CK and AST activities in draft horses from
samples are small or if horses are less than 1 year of age.90 which biopsies were sent to the University of Minnesota were
Acute Clinical Signs. Horses with the GYS1 mutation be- 459 and 537 U/L, respectively.93
gin to show clinical signs of muscle disease between 1 and 14 Pathophysiology. The GYS1 mutation causes a gain of
years of age, with an average age at onset of signs of 5 years. function in glycogen synthase both in basal states and when
Acute clinical signs occur when horses are calm and include activated by insulin and glucose-6-phosphate, and horses with
tucking up of the abdomen, fasciculations in the flank, mus- PSSM1 have on average 1.8-fold higher muscle glycogen con-
cle stiffness, sweating, reluctance to move forward, and overt centrations.77 The abnormal polysaccharide in PSSM1 is less
firm muscle contractures (Fig. 10.9).86 The hindquarters are branched than normal glycogen as a result of chronically en-
frequently most affected, but back, abdominal, and forelimb hanced glycogen synthase enzyme activity in the presence of
muscles may also be involved. Signs of pain can last for more elevated glucose-6-phosphate and insulin without the same
than 2 hours, and about 10% of cases become recumbent.86 relative activation of branching enzyme.97 Foals and yearlings
Less common signs of PSSM in Quarter Horses include gait with the GYS1 mutation rarely have abnormal polysaccharide
abnormalities, mild colic, and muscle wasting. During an in skeletal muscle yet they have rhabdomyolysis.09 Thus ab-
acute episode of ER, horses with PSSM1 often have markedly normal polysaccharide itself is an indicator of PSSM1 but not
elevated serum CK activity of greater than 35,000 U/L, and the direct cause for rhabdomyolysis.
myoglobinuria may be present. Severe colic-like pain after ex- The vast majority of horses that develop rhabdomyolysis
ercise and myoglobinuric renal failure are less common pre- with PSSM1 do so with aerobic exercise when blood lactate
senting complaints.91,92 concentrations are unchanged from preexercise samples at 1.0
Chronic Clinical Signs mmol/L.7 Although elevated serum CK activity occurs with
LIGHT BREEDS. Chronic signs of PSSM1 in riding horses in- near-maximal exercise on occasion, the degree of elevation is
clude a lack of energy when under saddle, reluctance to move often less than with submaximal exercise.7 A deficit in energy
forward, stopping and stretching out as if to urinate, and a sour metabolism represented by high myofiber inosine monophos-
attitude toward exercise.39,86 Horses may have a combination phate (IMP) occurs after light exercise in individual muscle
of low-grade reluctance to exercise, poor performance, and fibers of horses with PSSM1 in association with high serum
repeated episodes of ER.81 PSSM1 may also present in dres- CK activity. 99
sage and show jumpers as chronic back pain, failure to round A high-NSC diet increases the propensity to develop mus-
over fences, and fasciculations or pain on palpation of lumbar cle pain with aerobic exercise in PSSM1 horses.86 A high-NSC
muscles.57 The range of severity of clinical signs of PSSM1 can versus a low-NSC, high-fat diet results in higher muscle lactate
be wide with complete incapacitation in rare cases. Serum CK and citrate concentrations, lower glucose-6-phosphate, and
activities are often elevated in unmanaged horses, even when similar muscle pyruvate concentrations with aerobic exercise
horses are rested.92 The median CK and AST activity for all in PSSM1 horses.98 This suggests that the enhanced glycogen
PSSM1 Quarter Horses with muscle biopsies submitted to the synthase activity in PSSM horses may impair oxidative metab-
University of Minnesota was 2809 and 1792 U/L, respectively.93 olism of substrates such as pyruvate and fatty acids. Although
A small number of Quarter Horses and Paint Horses have the exact mechanism for this is not known, it may involve a
both the GYS1 mutation and the genetic mutation for MH.71 link between glycogen synthase or glycogen concentrations
FIG. 10.8 (A) Cross section of semimembranosus muscle showing accumulation of granular periodic
acid–Schiff (PAS) inclusions (arrow) in a horse with PSSM1. (B) Serial section of the same muscle preincu-
bated in amylase before PAS staining. Note that the abnormal granular material is amylase resistant. (20×)
and metabolic switches and nutrient sensors. One of the key increase plasma free fatty acid concentrations, which may
sensors and regulators of substrate flux in skeletal muscles facilitate muscle fat metabolism in PSSM1 horses.98,103
is AMP kinase.100,101 When energy supply is deemed to be
insufficient (↓ [ATP]/[ADP]), activation of AMP kinase leads Type 2 PSSM
to the increased transcription of genes involved in oxidative Much less is known about type 2 PSSM, because previous con-
metabolism, stimulation of fatty acid oxidation, and activation trolled research trials on PSSM have largely involved horses
of pyruvate dehydrogenase, which increases carbohydrate oxi- with PSSM1 (Valberg, unpublished data). The term type 2
dation.100-102 Nutrient sensors in the cell could interpret exces- PSSM refers to those horses that have altered staining for mus-
sive stimulation of glycogen synthesis (arising from the GYS1 cle glycogen that do not possess the GYS1 mutation.78 As such
mutation and stimulated by insulin) as an indication not to it should not be interpreted to necessarily indicate one spe-
activate glycogenolysis and lipolysis. PSSM horses fed high- cific disease. Furthermore, because PSSM2 is not consistently
NSC diets may be unable to generate sufficient acetyl CoA defined by the presence of amylase-resistant polysaccharide
from either carbohydrate or fat metabolism to fuel muscle but rather includes abnormal appearance of amylase-sen-
contraction during submaximal exercise. The common occur- sitive glycogen, there is considerable room for overlap of a
rence of clinical signs during the first 20 minutes of exercise diagnosis with RER or for false-positive diagnoses in trained
may be because at this stage of exercise, muscles rely heav- animals.75,76,80
ily on glycogen/glucose for energy. Low dietary starch and fat Much of the current knowledge of managing PSSM2 is
supplementation decrease muscle citrate concentrations and based on extrapolation of what works for PSSM1, retrospective
FIG. 10.10 Cross section of semimembranosus muscle (20×) from a

horse showing increased accumulation of subsarcolemmal periodic acid–
Schiff (PAS) material (arrows). The horse was negative for the GYS1 muta-
tion, establishing a diagnosis of PSSM2. Note the myopathic finding of
centrally displaced myonuclei in some fibers.
are usually related to an exertional myopathy with few or

rare occasions of a postexercise increase in serum CK activ-
ity. Clinical complaints usually relate to poor performance, an
undiagnosed lameness, sore muscles, and decreased energy
level. Warmbloods with PSSM2 may also have painful firm
back and hindquarter muscles, reluctance to collect and en-
FIG. 10.9 Horse with PSSM1 showing acute clinical signs of rhabdomy- gage the hindquarters, poor rounding over fences, poor canter
olysis that include anxiety, sweating, muscle stiffness, and reluctance to departs, and slow onset of atrophy, particularly if taken out of
move. work. The mean age of onset of clinical signs in Warmbloods
is between 8 and 11 years of age, with median CK and AST
activities of 323 and 331 U/L, respectively.
evaluation of cases diagnosed with PSSM2 by muscle biopsy,39 Diagnosis. PSSM2 is diagnosed by muscle biopsy where
and a few years of prospective clinical data. increased or abnormal PAS-positive material that is usually
Prevalence. Approximately 28% of Quarter Horses with amylase-sensitive is apparent (Fig. 10.10).78 Determination
PSSM diagnosed by muscle biopsy do not have the GYS1 of what constitutes an abnormal amount of amylase-sensitive
mutation and therefore have PSSM2.77,93 PSSM2 seems to glycogen is subjective, the specificity of the diagnosis is low,
be common in both high-performance Quarter Horse types and false-positive diagnoses occur. Highly trained horses have
such as barrel racing, reining, and cutting horses as well as increased glycogen storages as a normal response to training,
pleasure and halter horses. In the United Kingdom approxi- and this should be considered when histopathologic interpre-
mately 35% of PSSM cases diagnosed by muscle biopsy have tations are made. Glycogen is commonly found near capillar-
PSSM2.80 PSSM2 is also documented in Paint, Appaloosa, and ies in normal horses, and PAS-positive sarcoplasmic masses
Morgan horses. About 80% of Warmblood horses diagnosed can be found in 60% of healthy horses, so the presence of these
with PSSM by muscle biopsy have PSSM2.84 Other breeds di- structures should not be diagnostic criteria for PSSM2.104
agnosed with PSSM2 include Dutch Warmbloods, Swedish Type of fixation is also a consideration as formalin-fixed sec-
Warmbloods, Selle Francais, Hanoverians, Friesians, West- tions show a greater deposition of subsarcolemmal glycogen
falians, Canadian Warmbloods, Irish Sport Horses, Gerdland- and precipitation of glycogen in one area of a fiber even in
ers, Hussiens, Standardbreds, Thoroughbreds, and Arabians.77 healthy horses, and these should not be considered diagnostic
Pathogenesis. The cause or causes of PSSM2 are currently criteria for PSSM2.105 Other histopathologic features that may
unknown. Muscle glycogen concentrations are not as high as be present with PSSM2 include centrally located nuclei, sub-
those found in horses with PSSM1, and glycogenolytic enzyme sarcolemmal vacuoles, muscle necrosis, macrophage infiltra-
defects have not been identified in the few cases where enzymes tion of myofibers, regenerative fibers, and anguloid myofiber
were measured (Valberg, unpublished data). To date, the only atrophy.78 Some laboratories grade polysaccharide accumula-
reported abnormality in muscle ultrastructure is an increase in tion as mild, moderate, and severe where mild accumulation
normal β-glycogen particles.78 It may be that there are a group represents a category that has a higher chance of being a false-
of conditions currently captured under the term type 2 PSSM positive diagnosis. Mild PSSM cases in particular should re-
that have separate etiologies but share common findings of fo- ceive a full physical and lameness examination to ensure that
cal glycogen accumulation and poor performance. there are no other underlying causes for poor performance.
Clinical Signs. In adult Quarter Horses, ER is the predom-
inant clinical sign of PSSM2. In Quarter Horses less than 1 Management of Type 1 and Type 2 PSSM
year of age an inability to rise or a stiff hindlimb gait is re- Horses diagnosed with PSSM will always have an underly-
ported with PSSM2.78 In Warmblood Horses, signs of PSSM2 ing tendency for muscle soreness. Affected horses should
be managed appropriately to minimize clinical signs. With rhabdomyolysis and repeated frustration for the owner. Work
adherence to both diet and exercise recommendations pro- can usually begin under saddle after 3 weeks of ground work
vided below, at least 70% of horses with PSSM show notable and can gradually be increased by adding 2-minute intervals
improvement in clinical signs, and many return to acceptable of collection or canter to the initial relaxed warm-up period
levels of performance.27,39,86 There is, however, a wide range at a walk and trot. Unless a horse shows an episode of overt
in the severity of clinical signs, shown by horses with PSSM; rhabdomyolysis during the initial first 4 weeks of exercise, re-
those horses with severe or recurrent clinical signs will require evaluating serum CK activity is not helpful for the first month.
more stringent adherence to diet and exercise recommenda- This is because it is very common to have subclinical eleva-
tions in order to regain muscle function. tions in CK activity when exercise is reintroduced, and a re-
Rest. PSSM horses that are confined for days to weeks fol- turn to normal levels often requires 4 to 6 weeks of gradual
lowing an episode of rhabdomyolysis often have persistently exercise.92 Keeping horses with PSSM fit seems the best pre-
elevated serum CK activity. In contrast, PSSM horses kept on vention against further episodes of rhabdomyolysis.
pasture with little grain supplementation often show few clini- Diets for PSSM. The basis for designing PSSM diets is the
cal signs of rhabdomyolysis and have normal serum CK ac- belief that lowering the daily starch and sugar intake and
tivity. After an episode of rhabdomyolysis, horses with PSSM increasing dietary fat content will decrease the glucose load,
should be confined to a stall for only a brief time (less than increase the availability of nonesterified free fatty acids for
48 hours) followed by turnout in paddocks of gradually in- muscle metabolism, and lower serum insulin concentra-
creasing size. Providing horses with as much free exercise as tions. It is important to note that the dietary recommenda-
possible on pasture appears to be beneficial in the long term. tions provided here were tested in horses with PSSM1, and
If pasture is lush a grazing muzzle may be needed.81 Follow- there are no controlled trials to indicate whether these are
ing an acute episode, excitable horses may require tranquiliza- beneficial for PSSM2 horses. Quarter Horses naturally have
tion before turnout to avoid excessive galloping. Hand walking very little lipid stored within muscle fibers. The end result
horses for more than 5 to 10 minutes at a time when initially would thus be decreased uptake of glucose into muscles
recovering from an episode of PSSM may trigger another epi- cells, less substrate available for—and stimulation of—gly-
sode of rhabdomyolysis. cogen synthesis, and normalization of substrate flux. Own-
Exercise. The beneficial response to low-starch, fat-sup- ers report that this type of diet improves clinical signs of
plemented diets only occurs if it is instituted in conjunction muscle pain, stiffness, and exercise tolerance in draft horses,
with a regular incremental exercise program.88 Regular daily Warmbloods, Quarter Horses, and other breeds.27,39,81,86,88
exercise in PSSM horses over a 3-week period results in a dra- Dietary change appears to have less impact on alleviating
matic decrease in serum CK responses to exercise, whereas gait changes such as shivers.39
stall confinement is associated with elevations in serum CK CALORIC BALANCE. The horse’s caloric requirements at an
activity after exercise.88,98 One common adaptation to daily ideal body weight are the most important considerations in
training is an increase in oxidative capacity in skeletal muscle. designing the diet for PSSM. This is because many horses with
The oxidative capacity of skeletal muscle in PSSM Quarter PSSM are easy keepers and may be overweight at the time of
Horses was very low based on markers such as citrate syn- diagnosis. Adding excessive calories in the form of fat to an
thase activity and β–fatty acid oxidative marker HAD.88 The obese horse may result in equine metabolic syndrome and is
activity of these enzymes, however, was equally low in control contraindicated. If necessary, caloric intake should be reduced
Quarter Horses. Whether the beneficial effect of daily exer- by using a grazing muzzle during turnout, feeding hay with
cise on PSSM horses is a result of improved oxidative enzyme a low NSC content at 1% to 1.5% of body weight, providing
capacities or enhanced substrate flux or both has not been a low-calorie ration balancer, and gradually introducing dai-
elucidated. ly exercise. Rather than provide dietary fat to an overweight
EXERCISE REGIMENS. Important principles to follow when horse, fasting for 6 hours before exercise can be used to elevate
starting exercise programs in PSSM horses include the fol- plasma free fatty acids before exercise and alleviate any restric-
lowing: (1) provide adequate time for adaptation to a new diet tions in energy metabolism in muscle.
before commencing exercise; (2) recognize that the duration SELECTION OF FORAGE. Quarter Horses develop a signifi-
of exercise, not the intensity, is of primary importance; (3) en- cant increase in serum insulin concentrations in response
sure that the program is gradually introduced and consistently to consuming hay with an NSC of 17%, whereas insulin
performed; and (4) minimize any days without some form of concentrations are fairly stable when hay with 12% or 4%
exercise. If horses have experienced a moderate to marked NSC content is fed.106 Because insulin stimulates the al-
episode of rhabdomyolysis recently, 2 weeks of turnout and ready overactive enzyme glycogen synthase in the muscle of
diet change are often beneficial before recommencing exer- PSSM1 horses, selecting hay with 12% or less NSC is advis-
cise. Exercise should be very relaxed, and the horse should able. The degree to which the NSC content of hay should be
achieve a long, low frame without collection. For many horses restricted below 12% NSC depends on the caloric require-
this is most readily done in a round pen or on a lunge-line ments of the horse. Feeding a low-NSC hay of 4% provides
but can be done under saddle if needed. Successive daily ad- room to add an adequate amount of fat to the diet of easy
dition of 2-minute intervals of walk and trot beginning with keepers without exceeding the daily caloric requirement and
only 4 minutes of exercise and working up to 30 minutes after inducing excessive weight gain. For example, a 500-kg horse
3 weeks is often recommended.18,92 If horses had minor eleva- on a routine of light exercise generally requires 18 MCal per
tions in 4-hour postexercise CK with the 15-minute exercise day of digestible energy (DE). Fed at 2% of body weight, a
test, horses may begin at 15 minutes of exercise. Owners of- 12% NSC mixed grass hay almost meets their daily caloric
ten do not recognize that walking the horse for 10 minutes requirement by providing 17.4 MCal per day. Thus with a
or more initially can trigger muscle soreness in PSSM horses. 12%-NSC hay there is only room for 0.6 MCal of fat per
Advancing the horse too quickly often results in an episode of day (72 mL of vegetable oil) to achieve 18 MCal of energy.
In contrast, a 4%-NSC blue grama hay would provide 13.5 high-fat commercial diets are suitable for horses with PSSM.
MCal per day, which would allow a reasonable addition of Some commercial feeds meet the recommended nutritional
4.5 MCal of fat per day (538 mL of vegetable oil). needs of PSSM horses in one pelleted ration. These feeds
SELECTION OF FAT SOURCE. High-fat diets increase plasma typically contain at least 10% to 15% fat by weight and less
free fatty acid concentrations and thus the availability of fats than 20% NSC by weight. Some feed companies offer similar
for oxidation in skeletal muscle.98 The major sources of dietary nutritional content by blending two or more manufactured
fat for horses are vegetable-based fat, including vegetable oils feeds or by supplementing with oils or rice bran. At present,
and rice bran, or animal-based fat (tallow, lard, fish oil). Veg- the NSC content of equine feed products is not consistently
etable oils are highly unsaturated, very digestible (90%–100%), listed on the feed tag, and consultation with the feed manu-
and very energy dense. Suitable forms include soybean, corn, facturer is necessary to obtain this information. Nutritional
safflower, canola, flaxseed, linseed, peanut, and coconut. Con- support is available through most feed manufacturers in de-
trolled research studies in exercising PSSM horses have shown signing an appropriate diet. There is a great deal of variation
a decrease in muscle pain and serum CK in response to the in individual tolerance to dietary starch; however, horses
addition of corn oil and also a product containing soy hulls, with more severe clinical signs of PSSM appear to require the
soybean oil, and rice bran (RE•LEVE®).86,98 The amount of oil greatest restriction in starch intake.
added in these trials constituted at least 13% of daily DE. Some EXPECTATIONS. The beneficial effect of low-starch, high-fat
veterinarians have advocated as much as 25% of DE be fed in diets requires that horses are trained daily to enhance enzymes
the form of fat to PSSM horses.27 As discussed, the principal involved in fat and glucose metabolism. With adherence to
consideration here should be whether this provides excessive both the diet and exercise recommendations 70% to 75% of
calories and additional weight gain because feeding 13% DE as Quarter Horses and Warmbloods show notable improvement
fat may well be effective in reducing muscle pain. in clinical signs, and many return to acceptable levels of per-
Limited research has been performed on the form of oil to formance.28,39,81,90 There is, however, a wide range in the sever-
feed PSSM horses. An odd carbon 7 chain fat (triheptanoin) ity of clinical signs shown by horses with PSSM; those horses
fed to PSSM horses had a detrimental effect on muscle pain, with severe or recurrent clinical signs will require more strin-
exercise tolerance, and serum CK activity whereas long-chain gent adherence to diet and exercise recommendations in or-
fats fed in the form of corn oil or a rice bran/soy oil–supple- der to regain muscle function. PSSM horses that also have the
mented feed had a beneficial effect on lowering serum CK mutation for MH do not respond as well to diet and exercise
activity.98 Whether there is any direct beneficial effect on skel- recommendations and may continue to develop ER with the
etal muscle of providing energy in the form of omega-3 ver- possibility of a fatal episode.93
sus omega-6 fatty acids has yet to be determined. Corn oil, SUPPLEMENTS. There are no specific supplements that have
sunflower oil, and safflower oil are high in omega-6 and lower been shown to benefit horses with PSSM. Chromium, which
in omega-3, whereas soybean and canola oils are moderately is reported to increase glucose absorption, may be contraindi-
high in omega-6 and omega-3. Flax seed, linseed, and fish cated in PSSM horses. Carnitine is a dietary supplement that
oils contain more omega-3 than omega-6. It is usually cost- may replenish muscle carnitine stores if depleted and assist in
prohibitive to provide sufficient energy to a PSSM horse each transport of fat into the mitochondria. A deficiency of plasma
day in the form of dense omega-3 fat supplements. Soybean carnitine has not been identified in PSSM1 horses. Plasma free
and canola oils provide a relatively affordable alternative with carnitine concentrations ranged from 10.24 to 27.11 μM in
moderately high omega-6 or a mix of these oils and flax or fish PSSM1-affected horses and from 13.20 to 25.63 μM in normal
oil can be provided. Due to the potential additional oxidant horses (Valberg, unpublished data). Plasma carnitine does not
stress of fats, vitamin E (1000–5000 U/day) is recommended always reflect muscle carnitine concentrations.
for horses receiving oil-supplemented diets.
LOW-STARCH, HIGH-FAT CONCENTRATES. Although oils are Myofibrillar Myopathy
energy dense and inexpensive, they have the disadvantages of One recent addition to potential causes of exertional myopa-
being messy, unpalatable to some horses, prone to rancidity thies includes a suspected myofibrillar myopathy (MFM) that
in warm temperatures, and difficult to feed in large amounts. was identified in Arabian endurance horses with a history
As such a number of concentrates have been developed that of intermittent elevations in serum CK activity (greater than
contain fats. The important principle to be met by such feeds 10,000 U/L after endurance rides).107 The Arabian horses did
is that the starch and sugar components are low enough and not necessarily show the same degree of clinical signs of reluc-
fat supplementation high enough to ensure that in the total tance to move, muscle stiffness, and pain that is frequently
diet, the calories supplied by NSC comprise no more than seen with cases of ER. Muscle biopsies resembled those of
10% to 15% of the daily DE and the calories supplied by fat PSSM2 with increased aggregates of cytoplasmic glycogen,
comprise about 12% to 15% of daily DE. Common fat sourc- amylase-resistant polysaccharide in a few myofibers of some
es used in such concentrates include, in addition to the oils horses, and centrally located myonuclei in mature myofi-
mentioned above, stabilized rice bran or animal fats. Rice bers. Muscle glycogen concentrations in horses with MFM
bran and its products are palatable to most horses, have a were similar to controls. The distinguishing feature of muscle
moderate NSC content (about 25% by weight), contain ap- biopsies in these horses was disrupted myofibrillar alignment
proximately 20% fat by weight, and are excellent sources of and large desmin- and αβ crystallin-positive cytoplasmic
vitamin E and phosphorus. The NSC component of rice bran aggregates found in horses without a recent episode of ER.
can vary if the manufacturing process is not careful to ex- The ectopic accumulation of cytoskeletal proteins and Z-disc
clude the white rice grain. Commercial rice bran products degeneration identified on electron microscopy had features
occur as powder or an extruded pellet and are considerably of a myofibrillar myopathy. Many of these horses were previ-
more stable in warm temperatures compared to animal fat ously diagnosed with type 2 PSSM likely because pools of gly-
and vegetable oils. A number of well-balanced, low-starch, cogen forming within disrupted myofibrils appeared to give
the false appearance of a glycogen storage disorder. MFM may

represent a specific myopathy formerly grouped under the BOX 10.2
Nonexertional Rhabdomyolysis
diagnosis of type 2 PSSM.
1. Metabolic myopathy
Mitochondrial Myopathy a. Glycogen branching enzyme deficiency in Quarter
A deficiency of mitochondrial respiratory chain function was Horses
identified in a 3-year-old Arabian filly that presented with b. Type 1 and type 2 polysaccharide storage myopathy
profound exercise intolerance and normal serum CK activ- c. Malignant hyperthermia
ity 4 hours after exercise.108 Over the course of years the filly 2. Inflammatory myopathies
developed significant muscle atrophy. During exercise at a a. Immune mediated
trot, the horse would be unable to continue after 7 minutes, • Infarctive hemorrhagic purpura
becoming stiff and sweating profusely. Venous pH and bicar- • Immune-mediated myopathy
bonate concentrations dropped abnormally after 6 minutes of 3. Infectious
trotting, lactic acidosis was present (20 mM), and the horse a. Clostridial myositis
had dramatically reduced maximum oxygen consumption b. S. equi myositis
(maximal VO2 0.5 mL/kg/sec; normal 2.5 mL/kg/sec). A c. Anaplasma myositis
deficiency of complex I (nicotinamide adenine dinucleotide d. Viral myositis
[NADH]:ubiquinone reductase) in the respiratory chain was e. Sarcocystis myositis
identified in muscle samples. 4. Nutritional myopathy
a. Vitamin E and selenium deficiency
Idiopathic Chronic Exertional Myopathies 5. Toxic myopathy
Many horses develop chronic ER for which no known cause a. Ionophore toxicity
is apparent. More research needs to be done to further define b. Pasture myopathies
causes of exertional myopathies in horses. • Hypoglycin A myopathy
• Rayless goldenrod/white snakeroot
Fibrotic Myopathy • Cassia occidentalis
Fibrotic myopathy affects semimembranosus/semitendinosus 6. Traumatic myopathy
muscles and is usually a consequence of trauma to these mus- a. Compressive anesthetic myopathy
cles. Horses have a classic gait abnormality where the anterior b. Trauma
phase of the stride ceases abruptly, causing the leg to be pulled
back before the foot suddenly slaps the ground rather than
continuing its forward motion. In acute cases these muscles codon in exon 1 of the GBE1 gene.109 Branching enzyme activ-
may feel warm and painful on deep palpation. Chronically, ity is minimal in skeletal and cardiac muscle as well as liver.
hardened areas within the muscle may represent fibrosis and
ossification. Prevalence
The extent of tearing can be determined by ultrasonogra- Nine percent of the breed is a carrier of this autosomal reces-
phy, providing the muscle is within the depth of penetration sive mutation, and 3% of abortions are attributed to this
of the ultrasound machine. Acute injuries are treated with disease in Quarter Horses.110 The prevalence of carriers is par-
cold therapy and stretching once the limb is no longer acutely ticularly high in pleasure horses, with 26% carrying the GBE1
painful. Deep heating ultrasound may be of help in promoting mutation.83
healing. For more subtle strain, intermittent electrical stimu-
lation of focal areas within a muscle may be beneficial. The Clinical Signs
strength of stimulus necessary to induce contraction can be Clinical signs of GBED include abortion in second or third
incrementally assessed and compared between left and right trimester, stillbirth, hypothermia at birth, mild flexural defor-
sides. Damaged muscle tends to respond with a greater degree mities, intermittent seizures, skeletal and respiratory muscle
of pain and contraction at lower stimulus strength. Underwa- weakness, and sudden death (Fig. 10.11).109-111 Most foals
ter treadmill exercises to strengthen the muscles once healing diagnosed with GBED have presented with transient flexural
is apparent on ultrasound can help restore normal limb func- contractures at 1 day of age. Persistent leukopenia, intermit-
tion. Horses with a fibrotic band within the muscle or ossifi- tent hypoglycemia, and moderately high serum CK (1000–
cation of the muscle have a much poorer prognosis. Surgical 15,000 U/L), AST, and γ-glutamyltransferase (GGT) activities
resection of fibrotic muscle is attempted, but full restoration of are usually present in affected foals.
function is unlikely to occur.18
Diagnosis
Y NONEXERTIONAL MYOPATHIES A diagnosis is best obtained by confirming the presence of
the GBE1 genetic mutation in blood, hair, or tissue samples
Specific causes of nonexertional rhabdomyolysis are listed in or by identifying typical PAS-positive inclusions in muscle or
Box 10.2. cardiac samples.109-111 Gross postmortem changes are not evi-
dent, and routine hematoxylin and eosin stains of tissues may
be normal or show basophilic inclusions in skeletal muscle
Glycogen Branching Enzyme Deficiency and cardiac tissues. Frozen sections of muscle, heart, and liver
Pathogenesis show a notable lack of normal PAS staining for glycogen, as
Glycogen branching enzyme deficiency (GBED) occurs in foals well as abnormal PAS-positive globular or crystalline intracel-
of Quarter Horse–related breeds caused by a premature stop lular inclusions (see Fig. 10.11).
certain situations, deficiencies of both selenium and vitamin E

are necessary for disease to occur. In other animals NMD can
occur when a deficiency of only one of the nutrients is present
and the other is normal in blood and tissues.
Clinical Signs
Some foals present with a cardiorespiratory syndrome char-
acterized by dyspnea, a rapid irregular heartbeat, profound
weakness, recumbency, and sudden death.8,112 Other foals
have primary skeletal muscle involvement with signs of weak-
ness, trembling, stiffness, and inability to stand for more than
short periods. Affected muscle groups are firm and painful to
palpation. Dysphagia due to necrosis in the tongue may be the
only sign in some affected foals and is frequently accompanied
by aspiration pneumonia. The tongue, gastrocnemius, semi-
tendinosus, semimembranosus, biceps femoris, lumbar, glu-
teal, and neck musculature are often affected.
Clinical Pathology
Serum CK and AST activities are usually in the thousands to
hundreds of thousands of U/L. Myoglobinuria is common.
Hyperkalemia, hyperphosphatemia, hyponatremia, hypo-
chloremia, and hypocalcemia can occur with severe rhabdo-
myolysis when the normal distinction between extracellular
and intracellular compartments is destroyed by massive tissue
necrosis.8 Neutrophilia is common due to the high incidence
of aspiration pneumonia.
Diagnosis
FIG. 10.11 Foal with glycogen branching enzyme deficiency (GBED).
Foals with GBED are often born with slight forelimb flexural limb deformi-
Whole blood selenium (normal range 0.07 to greater than
ties and appear mentally less alert and less active than healthy foals.
0.1 ppm) or plasma α-tocopherol (normal range 1.1–2 ppm)
(Photo courtesy Dr. Alicia Foley.)
concentrations below the normal range in conjunction with
appropriate clinical signs are considered diagnostic. Selenium-
dependent GSH-Px formed in the red cells during erythro-
Treatment poiesis could also provide an index of body selenium status.
Although foals initially respond to treatment in neonatal Adequate GSH-Px activities are greater than 20 to 50 U/mg of
intensive care, all foals with GBED have died. Death occurs hemoglobin per minute in horses. However, GSH-Px reference
as sudden collapse, with the longest survivor being 18 weeks values are only specific to the laboratory where the analysis is
of age. performed and must be validated by comparison with blood
selenium concentration. Plasma samples for α-tocopherol
Nutritional Myodegeneration analysis need to be put on ice immediately, protected from the
Nutritional myodegeneration (NMD) (white muscle disease, light by wrapping in aluminum foil, and stored frozen (−21°F
nutritional muscular dystrophy) is an acute degenerative dis- [−70°C]) if analysis is to be delayed. Tissue specimens can be
ease affecting cardiac and skeletal muscle of primarily young assayed for selenium content. Normal liver concentrations of
foals. selenium are 1.05 to 3.5 ppm on a dry matter (DM) basis (fresh
liver approximately 30% DM).
Pathogenesis
NMD is caused by a dietary deficiency of selenium and/or Pathology
vitamin E (α-tocopherol) in young, rapidly growing foals born Skeletal muscle degeneration is characterized by pale streaks
to dams that consumed selenium-deficient diets during gesta- of discoloration and a dry appearance of affected muscle, cal-
tion.112,113 Selenium and vitamin E appear to be synergistic in cification, and intramuscular edema in bilaterally symmetric
preventing NMD; however, selenium deficiency appears to be muscle groups.112 Affected muscle bundles are often adjacent
the most important contributor to oxidant damage of muscle to apparently normal or minimally affected muscle. Histo-
cell membranes. Selenium is a key component of glutathione logically, affected muscle fibers are often hypercontracted and
peroxidase (GSH-Px) that acts to destroy hydrogen peroxide fragmented, with some mineralization of muscle fibers, and in
and lipoperoxides that are generated during normal muscle later stages macrophage infiltration is notable.114
metabolism. Vitamin E acts within the cell membrane as an
antioxidant that scavenges free radicals that otherwise might Treatment and Prognosis
react with unsaturated fatty acids to form lipid hydroperoxides. The cardiorespiratory form of NMD carries a poor prognosis.
The precise interrelationships among selenium, vitamin E, In contrast, the skeletal form of NMD is more amenable to
other metabolic factors, and triggering mechanisms in NMD treatment if secondary complications such as pneumonia can
are not fully understood because many foals deficient in sele- be managed. Progressively decreasing CK activity and ability
nium and/or vitamin E have no evidence of muscle disease. In to stand are good prognostic indicators for NMD. The label
dose for selenium is 0.055 to 0.067 mg/kg (2.5–3 mg/45 kg)

body weight given intramuscularly. Injections can be irritat-
ing so dilution in sterile saline and administration in muscles
such as pectorals is recommended. Dosage should not be
greatly increased above the label dose to prevent an inad-
vertent selenium toxicosis. Absorption and distribution of
injectable selenium occurs rapidly and may account for the
rapid improvement in clinical signs seen in reversible cases.
Injectable selenium products contain a minimal amount of
α-tocopherol (50 mg/mL [68 IU]), and additional supplemen-
tation with water-dispersible RRR-α-tocopherol is recom-
mended (10 IU/kg).
Supportive therapy may include administration of antibiot-
ics to help combat secondary pneumonia and infected decu-
bital lesions that are common in recumbent patients. When
dysphagia is present feeding via nasogastric tube, provision of
adequate energy intake, and attention to the fluid and elec-
trolyte balance are of critical importance if recovery is to be
successful. Hyperkalemia may be life threatening in affected
foals. Mineralocorticoids, alkalinizing fluids, and dextrose
and insulin may be used to reduce circulating potassium
concentrations.8
Foals with primary muscular NMD often show improve-
ment after a few days of rest and treatment with selenium.
They can often stand and walk within 3 to 5 days. FIG. 10.12 Pronounced atrophy of the masseter muscle in a Quarter
Horse resulting in prominence of the facial crest.
Prevention and Control
In regions where selenium deficiency exists, diets of pregnant
mares need to be supplemented with selenium either in their damage should be suspected. Chronic clinical signs include
daily concentrate or through additional oral supplementa- masseter muscle atrophy, trismus, dysphagia, and weight loss.
tion to provide 1 mg of selenium per day.115,116 Only limited Horses usually have normal postural and locomotor muscles
selenium may cross the placenta; however, supplementation on clinical examination, although stiffness has been reported.
during lactation increases the levels of selenium in milk and Accompanying clinical pathologic findings include pigmen-
thus provides a potential means of selenium supplementation turia, elevated serum AST and CK activity, and potentially
in foals. In deficient areas, this increased level of selenium in elevated cardiac troponin concentrations. Ultrasonography is
milk may not meet a young animal’s nutrient requirements.117 useful to determine the extent of masseter muscle swelling or
In such cases injectable selenium products used every 30 to atrophy and to assess myocardial dysfunction.
45 days might be needed in areas where NMD is a particular
problem.118 Periodic blood sampling of foals in high-risk areas Diagnosis
is recommended. On the basis of these assessments, adjust- Elevated serum CK and AST activities accompanied by low
ments to the rate or extent of selenium supplementation can whole blood selenium concentrations (less than 1.1–2 ppm)
be made. Access to high-quality green forage should ensure support selenium deficiency as a cause of masseter muscle
adequate vitamin E intake. atrophy.
Treatment
Masseter Muscle Myodegeneration Analgesics, intramuscular selenium (0.055–0.067 mg/kg),
Pathogenesis oral α-tocopherol (2000–5000 IU/day RRR-α-tocopherol),
Masseter muscle swelling and degeneration occur in adult nutritional and fluid support if needed via stomach tube, and
horses and can be followed by masseter muscle atrophy and IV fluids are recommended. A fasciotomy to relieve pressure
trismus (Fig. 10.12). An inflammatory myopathy such as that in masseter muscles has been advocated, but results are not
seen in dogs with canine masseter muscle myositis has not reported. Progression to bilateral muscle atrophy can occur,
been identified (Valberg, unpublished data). An association and depending on the severity of myofiber and nerve damage
has been made between selenium deficiency and masseter this can resolve after a period of months. Prognosis is guarded,
muscle myodegeneration in some cases.119-121 Histopathologic but there are individual reports of successful treatment. With-
evidence of bilateral symmetric lesions in masseter muscles, out early treatment, permanent trismus can occur due to mus-
as well as muscles of the hind and thoracic limbs, has been cle atrophy and fibrosis.
observed in such cases.120
Clinical Signs Vitamin E–Deficient Myopathy

Unilateral or bilateral swelling of the masseter and temporal Pathogenesis
muscles is the predominant acute clinical sign accompanied by Vitamin E–deficient myopathy may be an entity unto itself or
pain or difficulty opening the jaw. Exophthalmos can be pres- a predecessor to development of equine motor neuron disease
ent. If tachycardia and dysrhythmias are present myocardial (EMND). Clinical signs of EMND occur in the absence of the
hallmark of EMND, neurogenic atrophy in sacrocaudalis dor- low or within the normal range. The distinction between vitamin
salis medialis muscle biopsies.13 Unlike EMND, horses with a E–deficient myopathy and EMND is the presence of myopathic
vitamin E–deficient myopathy have characteristic histochemi- rather than neuropathic features in sacrocaudalis dorsalis muscle
cal alterations in mitochondrial distribution that appears to biopsies and the remarkable response to treatment with vitamin
be a reversible manifestation of skeletal muscle mitochondrial E.13,122 The characteristic finding in muscle biopsy is the presence
oxidative stress.13 of a “moth-eaten” staining pattern in mitochondrial stains of fro-
zen sections of the sacrocaudalis dorsalis muscle. Mitochondrial
Clinical Signs stains of muscles such as the gluteus medius are normal.
Horses can present with a gradual onset of reduced perfor-
mance and muscle loss, but usually owners report a sudden Treatment
onset of muscle weakness. Horses show signs of symmetric Vitamin E–deficient myopathy is highly responsive to treat-
generalized muscle atrophy, trembling, muscle fasciculations, ment with natural liquid RRR-α-tocopherol (5000 IU/day for
inability to fix the stifles with weight shifting, and frequent a 500-kg horse) and a very gradual reintroduction to exercise
attempts to lie down (Fig. 10.13A). Differential diagnoses for once strength returns (Fig. 10.13B).13 Powdered formulations
horses with muscle atrophy are provided in Box 10.3. of α-tocopherol acetate are not recommended as an acute
treatment because they do not restore serum α-tocopherol
Diagnosis concentrations at the same rapid rate as liquid α-tocopherol.
Low muscle α-tocopherol concentrations have been identified in
affected horses, and serum α-tocopherol concentrations can be
Y INFLAMMATORY MYOPATHIES
Viral-Associated Myopathies
Infrequently, skeletal muscle degeneration and stiffness occur
in association with equine influenza A2 and equine herpesvirus
1 in association with typical clinical signs of viral disease.123,124
Sarcocystosis
Pathogenesis
Equine skeletal muscle, especially esophageal muscle, com-
monly contains a few dormant cysts of the sporozoan parasite
Sarcocystis fayeri, for which the dog is the definitive host. Cysts
usually pose no problem, but when ponies and horses were
experimentally infected with large doses of S. fayer dysphagia,
severe myositis and stiff gait occurred. There are also a few
clinical cases of S. fayeri myositis reported in horses.125
A
Clinical Signs
Clinical signs include fever, malaise, chronic muscle atrophy,
stiffness, weakness, and muscle fasciculations. Clinicopath-
ology is typified by normochromic normocytic anemia and
elevations in CK and AST activities.125,126
BOX 10.3
Atrophy
1. Myogenic
a. Disuse
b. Cachexia
c. Cushing’s disease
d. Immune-mediated myositis (rapid atrophy)
e. Vitamin E–deficient myopathy
f. Type 2 PSSM
B g. Severe rhabdomyolysis
2. Neurogenic atrophy
a. Focal nerve damage
FIG. 10.13 (A) Belgian Warmblood gelding with generalized symmet- • Trauma
ric muscle loss, decreased performance, and low serum and muscle vita-
• Tumor
min E concentrations. Muscle biopsy of the sacrocaudalis dorsalis muscle
• Infectious (equine protozoal myelitis)
revealed numerous moth-eaten mitochondria establishing a diagnosis of
• Idiopathic peripheral neuropathy
vitamin E–deficient myopathy. (B) The same horse after 8 weeks of vi-
b. Generalized nerve damage
tamin E treatment and an exercise program. In addition to weight gain,
• Equine motor neuron disease
increased muscle mass in the hindquarters is apparent.
Diagnosis Diagnosis. Hematology and serum biochemical analyses

Diagnosis of sarcocystosis requires history, clinical signs, lab- usually reflect a generalized state of toxemia with hemocon-
oratory and serologic evaluation, and the demonstration of centration and a stress/toxic leukogram. In severely affected
immature cysts in muscle biopsies, ideally in conjunction with horses with rapid disease progress, there is usually evidence
inflammatory infiltrates. of multiorgan failure and disseminated intravascular coagula-
tion. Moderate increases in the activities of serum CK and se-
Treatment and Control rum AST usually occur; however, they often do not reflect the
Successful treatment of sarcocystosis is reported using phen- clinical toxicity of clostridial myonecrosis. Characteristic hy-
ylbutazone, trimethoprim-sulfamethoxazole, and pyrimeth- perechoic gas accumulation and hypoechoic fluid are usually
amine.125 Current antiparasitic medications such as diclazuril observed with ultrasonography of the affected site. Fasciotomy
should also be effective. Control involves preventing gross or aspiration of the affected area usually reveals the presence of
contamination of equine feeds with carnivore feces. malodorous, serosanguineous fluid with an odor of rancid but-
ter. Aspirates of affected tissues examined via direct smears or
fluorescent antibody staining should show characteristic gram-
Bacterial-Associated Myositis positive, rod-shaped bacteria. Anaerobic bacterial culture of
Clostridial Myonecrosis freshly acquired samples may also be of value. At postmortem,
Clostridial myonecrosis is caused by infection with one of a swelling, crepitus, and autolysis are rapid, and bloodstained
variety of clostridial bacteria, most commonly Clostridium fluid is often observed discharging from body orifices.
perfringens. Sporadic cases have been attributed to C. septi- Treatment. Wound fenestration and aggressive surgical
cum, C. chauvoei, C. novyi, and other related species. Clostrid- debridement over the entire affected area are required for suc-
ial organisms are gram-positive, rod-shaped, spore-forming cessful treatment.129 Sufficient fenestrations should be made
obligate anaerobes with the potential to produce a variety of to establish drainage and aeration over the entire affected area.
exotoxins that can cause extensive tissue damage and necrosis The horse should be frequently reevaluated to assess spread
with secondary life-threatening toxemia, multiple-organ fail- of cellulitis and repeat fenestration procedures may be re-
ure, and death. quired. Fenestrations should be made in parallel to muscle
Pathogenesis. Clostridia gain access to the body through fiber bundles to prevent excessive scarring and future impair-
the alimentary tract and are present in liver and muscle in ment of muscle function. Additional treatment includes high
the dormant spore form.127 Most reports of clostridial myo- doses of IV potassium penicillin (up to 88,000 IU/kg) every
necrosis in horses implicate intramuscular injection sites or, 2 to 4 hours until the animal is stable (1–5 days) in combina-
less commonly, puncture wounds or other traumatic inju- tion with oral metronidazole. Aggressive fluid, electrolyte, and
ries in creating a suitable environment for the development cardiovascular support is often required. Severe hypotension,
of clostridial myonecrosis.128,129 Intramuscular injections of diminished cardiac output, impaired renal function, and high
irritating drugs such as NSAIDs, prostaglandins, anthelmin- levels of myoglobinemia place the patient at risk for pigment
tics, and antihistamines are commonly implicated as initiat- nephropathy and acute renal failure. Extensive skin slough-
ing factors for clostridial myonecrosis in horses. When local ing over the affected area is common in surviving horses. The
tissue is devitalized and the appropriate anaerobic condition prognosis for life in all horses with clostridial myonecrosis
is created, spores may vegetate and begin exponential growth, is guarded, and the owner should be aware from the start of
releasing powerful exotoxins that act locally and systemically treatment that extensive skin sloughing can occur and eutha-
to create widespread organ dysfunction. The specific toxins nasia could become a consideration at a later stage.
vary depending on the clostridial species involved. With C.
perfringens infection, the most important toxin implicated Anaplasma-Associated Rhabdomyolysis
in clinical disease is alpha toxin, a dermonecrotic toxin with There is a report of a Quarter Horse with clinical signs of stiff-
phospholipase C and sphingomyelinase activity. Theta toxin ness, pyrexia, tachycardia, and marked elevations of serum
(perfringolysin), kappa toxin (collagenase), and mu toxin (hy- CK activity in association with Anaplasma phagocytophilum
aluronidase) may also play important roles in the development infection.130
of clinical disease. Clostridium septicum, C. chauvoei, C. sporo-
genes, and mixed infections are associated with a high fatality
rate, whereas C. perfringens type A has a mortality rate of 20% Streptococcus equi Subsp. equi–Associated
in horses that receive early and aggressive treatment.129 Myopathy
Clinical Signs. Horses initially have clinical signs related to Acute Rhabdomyolysis
their wound or disease that required an intramuscular injec- Pathogenesis. Quarter Horses generally less than 7 years
tion. Depending on the injection site, lameness or a sore neck of age can develop severe, generalized rhabdomyolysis in asso-
may be the initial clinical sign. Within 48 hours of the incit- ciation with an active Streptococcus equi subsp. equi infection
ing event horses develop swelling and variable crepitus at the (referred to as S. equi for the remainder of this chapter).131,132
wound/injection site accompanied by depression, fever, tox- Two etiologies have been proposed: (1) a toxic shock–like re-
emia, and tachypnea. Clostridial infection can migrate along action arising from profound nonspecific T-cell stimulation
fascial planes to affect extensive areas of the body with resul- by streptococcal superantigens with the release of high levels
tant spread of crepitus (Fig. 10.14). Severe toxemia, multior- of inflammatory cytokines and (2) bacteremia with local mul-
gan failure, coma, and death can occur within the next 12 to 24 tiplication and production of exotoxins or proteases within
hours in severely affected horses. An intravascular hemolytic skeletal muscle. S. equi virulence factors that may account for
crisis may develop late in the disease process in some affected muscle necrosis include an unidentified cytotoxic protein, sev-
horses. It is unclear whether hemolysis is the result of a bacte- eral proteases, streptokinase, and streptolysin S.133 Although
rial exotoxin or another mechanism. S. equi has not been cultured in skeletal muscle from horses
A
C
D
B
FIG. 10.14 Clostridium perfringens myositis in the cervical muscles following an intramuscular injection.
The low head posture was due to pain and depression. (A) Malodorous fluid exudes from multiple fenestra-
tions made over areas of crepitus. (B) Granulation tissue and minor sloughing of skin is apparent at wound
edges. (C) Subsequent massive sloughing of skin. (D) Healing wound after many months of treatment.
with rhabdomyolysis, S. equi bacteria have been identified with a degree of macrophage infiltration. Sublumbar muscles
in affected muscle using immunofluorescent stains for both often show the most severe and chronic necrosis as indicated by
Lancefield group C carbohydrate and S. equi M protein.131 greater macrophage infiltration of myofibers.
There is currently no evidence that the S. equi involved is an Treatment. A high mortality rate has been reported in hors-
atypical genetic strain of S. equi.134 es receiving IV penicillin therapy once clinical signs of strangles
Clinical Signs. Affected horses have evidence of enlarged and myopathy were well established. It is possible that early rec-
submandibular lymph nodes and/or guttural pouch empyema. ognition of the signs of muscle stiffness in horses with S. equi
Horses develop a stiff gait that progresses rapidly to markedly infections and prompt aggressive treatment may be required for
firm, swollen, painful epaxial and gluteal muscles. The major- a successful outcome. Although streptococcal species are exqui-
ity of reported cases become recumbent, are unable to rise, sitely susceptible to β-lactam antibiotics, a mortality rate of 85%
and develop unrelenting pain necessitating euthanasia within has been reported in human group A streptococcal myositis de-
24 to 48 hours of hospitalization. spite penicillin treatment.135 An antimicrobial that inhibits pro-
Diagnosis. Hematologic abnormalities include mature neu- tein synthesis, such as rifampin, combined with IV penicillin,
trophilia, hyperfibrinogenemia, normal albumin, and marked might enhance survival rates in horses with S. equi rhabdomy-
increases in serum CK (115,000–587,000 U/L) and AST activi- olysis. In addition, flushing infected guttural pouches and drain-
ties (600–14,500 U/L). Titers to the M protein of S. equi are low ing abscessed lymph nodes will diminish the bacterial load.
in affected horses, unless horses have been recently vaccinated NSAIDs and possibly high doses of short-acting corticosteroids
for strangles. Titers to another protein called myosin binding may assist in diminishing the inflammatory response. Control of
protein have been high in a small number of horses that were unrelenting pain is a major challenge in horses with severe rhab-
tested.131 Endoscopy of the guttural pouches reveals pools of domyolysis. Constant rate infusion of lidocaine, detomidine, or
pus that are positive in culture and polymerase chain reaction ketamine may provide better anxiety and pain relief than pe-
(PCR) for S. equi. riodic injections of tranquilizers. Horses should be placed in a
At postmortem examination, large pale areas of necrotic deeply bedded stall and moved from side to side every 4 hours if
muscle are evident in hindlimb and lumbar muscles. The histo- they are unable to rise. Some horses may benefit from a sling if
pathologic lesions are characterized by severe acute myonecrosis they will bear weight on their hindlimbs when assisted to stand.
FIG. 10.15 Infarctive hemorrhagic purpura resulting in firm painful FIG. 10.16 Extensive infarction of the large colon in a horse with infarc-
swelling within the muscles of the antebrachium on the right forelimb. tive hemorrhagic purpura.
(Photo courtesy Dr. Raphaela Texeira.)
Postmortem findings of horses with IPH include infarction

Immune-Mediated Myopathies of the skeletal musculature, skin, gastrointestinal tract, pan-
Infarctive Purpura Hemorrhagica creas, and lungs and S. equi abscessation of a lymph node (Fig.
Pathogenesis. Infarctive purpura hemorrhagica (IPH) is a 10.16). Definitive histopathologic findings include leukocy-
severe form of purpura with a high fatality rate. Infarctions toclastic vasculitis and acute coagulative necrosis resembling
initially occur in skeletal muscles that are compressed during infarction in numerous tissues.139
recumbency and progress to involve multiple organs, includ- Treatment. Early recognition of signs and aggressive anti-
ing the gastrointestinal tract and the mucous membranes.136 biotic and corticosteroid treatment are essential to combat the
In one study prevalence of IPH was 3 of 53 cases of purpura.137 high fatality rate with IHP. Treatment of Henoch-Schönlein
Exposure to S. equi within 3 weeks of presentation, vaccination purpura in humans, including cases with intestinal infarctions,
for S. equi, or a concurrent Salmonella infantum infection are involves high-dose IV pulse therapy with methylpredniso-
reported inciting causes. IPH resembles Henoch-Schönlein lone followed by oral corticosteroids plus immunosuppressive
purpura in humans, which is characterized by infarctive vas- agents such as cyclophosphamide and azathioprine. One horse
culitis of the skin, kidneys, and gastrointestinal tract resulting with IPH was successfully treated with penicillin, NSAIDs,
from immunoglobulin A (IgA) immune complex deposition. and 3 weeks of dexamethasone (0.1–0.07 mg/kg) followed
Immune complexes present in the sera of horses with IPH by a 10-week tapering course of oral prednisolone (2 mg/kg
appear to be composed primarily of IgM or IgA and strepto- initially).139
coccal M protein.138 Deposition of complement near immune
complexes in vessel walls may result in cell membrane destruc-
Immune-Mediated Myositis in Quarter
tion, cell death, and vascular occlusion. Horse–Related Breeds
Clinical Signs. The primary presenting complaint is often Pathogenesis. Malaise, rapid onset of severe atrophy par-
painful lameness with limb swelling, muscle stiffness, and/or ticularly affecting epaxial and gluteal muscles, and high serum
colic (Fig. 10.15). Careful physical examination reveals classic CK and AST activities occur in equine immune-mediated
signs of IPH such as petechiae, oral infarctions resembling ul- myositis (IMM) as a result of lymphocytic destruction of myo-
cers, and well-demarcated moderate limb edema. Horses with fibers by CD4+ and to a lesser extent CD8+ cells.11 For yet
IPH will have focal firm intramuscular swellings in abdomi- unknown reasons a loss of self-tolerance to antigens expressed
nal, pectoral, adductor, and tarsocrural muscles. Horses with by muscle cells may occur after rhabdomyolysis, infection
evidence of colic may have markedly decreased borborygmi with S. equi, or vaccination. Myoblasts and myotubes do not
and hemorrhagic gastric reflux. normally express detectable human leukocyte antigen (HLA)
Diagnosis. Hematologic abnormalities include a leukocy- class II molecules and therefore do not display potentially
tosis characterized by neutrophilia with a left shift and toxic immunogenic peptides to cells of the immune system. Loss of
change, hyperproteinemia, hypoalbuminemia, and marked self-tolerance could occur with IMM as a result of activation of
elevations in CK (47,000–280,000 U/L) and AST (960–7000 otherwise inactivated autoreactive T cells by either (1) shared
U/L) activities.132,139 Serum titers for enzyme-linked immu- epitopes with an infectious agent causing antigenic mimicry;
nosorbent assay (ELISA) M protein are usually markedly el- (2) microbial superantigens produced by infectious agents; (3)
evated.139 Peritoneal fluid obtained by abdominocentesis may high concentrations of local cytokines such as interleukin-2
be normal or may have an increased total protein and nucle- (IL2) or IL4; or (4) expression of an abnormal protein on sar-
ated and red blood cell counts if gastrointestinal infarction is colemmal membranes. There is strong evidence of a genetic
present. Ultrasonographic examination of swollen muscle re- susceptibility to IMM in the Quarter Horse breed.11
veals focal hypoechoic lesions within muscle tissue. Biopsies History and Clinical Signs. Generalized IMM usually af-
of abnormal muscle show diffuse acute coagulative necrosis, fects horses of Quarter Horse–related breeds that are either
whereas samples from palpably normal muscle tissue show no younger than 8 years of age or older than 16 years of age
pathologic abnormalities. without gender predilection.11 A history of exposure to a
Corticosteroids are the mainstay of treatment, and, unlike

immune-mediated disorders in humans and dogs, antiinflam-
matory rather than immunosuppressive doses are effective.
Recommended dosages are dexamethasone (0.05 mg/kg intra-
venously) for 3 days, followed by prednisolone (1 mg/kg PO)
for 7 to 10 days tapered by 100 mg per week over 1 month.11
Prevention is challenging because only a small proportion of
affected horses have a history of a triggering factor. Suggested
strategies include preventing exposure to respiratory infec-
tions where possible; spacing out vaccines to prevent a surge
of inflammatory cytokines; avoiding immune stimulants; and
monitoring horses closely to institute treatment early if atro-
phy recurs. Malaise often resolves rapidly following treatment
with corticosteroids and muscle atrophy quickly ceases. Se-
rum CK activity often returns to normal after 7 to 10 days of
corticosteroid treatment. Recovery of the muscle mass is more
gradual and usually takes 2 to 3 months, and some focal resid-
ual muscle atrophy can remain.11 Horses that are not treated
with corticosteroids may develop extensive muscle atrophy,
but in many cases muscle mass will gradually recover. Atrophy
recurs in approximately 40% of susceptible horses, and these
horses may require repeated bouts of corticosteroid treatment.
Systemic Calcinosis
FIG. 10.17 Pronounced atrophy of the gluteal muscles of a young Pathogenesis. Systemic calcinosis occurs in humans, par-
Paint Horse with immune-mediated myositis. Atrophy is more severe on ticularly those on dialysis because of renal failure. In human
the right side, which creates shadowing over the area where a biopsy was medicine a product of Ca multipled by P of greater than 65
previously obtained. (Photo courtesy Dr. Carrie Finno.) to 70 is used as an indicator of a potential risk of dystrophic
calcification.142 A Ca × P product greater than 66 was pres-
ent in horses that developed systemic dystrophic calcification.
triggering factor exists in approximately one third of cases; The reason for the elevated Ca × P in horses with systemic
the known triggering factor is usually exposure to S. equi, calcinosis is not known, but there is a strong suspicion that a
another respiratory pathogen, or possibly vaccination. The predisposing inflammatory process could be a trigger. Hyper-
most prominent clinical sign is dramatic muscle atrophy, phosphatemia can induce dystrophic calcification through
particularly of the epaxial and gluteal muscles, accompanied (1) passive calcium phosphate deposition from phosphate
by stiffness and general malaise (Fig. 10.17). Muscle atro- supersaturation in the blood; (2) an active process promot-
phy is usually rapid and may progress to involve 40% of the ing the conversion of smooth muscle cells to osteogenic cell
horse’s muscle mass within a week. Horses can develop gen- types; (3) directly increasing parathyroid hormone secretion
eralized weakness leading to frequent periods of recumben- and transcription; or (4) interference with renal production of
cy. Muscle atrophy often persists for months before a gradual 1,25-(OH)2D levels, which has been associated with increased
increase in muscle mass occurs. coronary artery calcification in humans.143
Diagnosis. Hematologic abnormalities apart from eleva- A novel fatal syndrome of systemic dystrophic calcification
tions in CK and AST activities are uncommon with IMM un- called systemic calcinosis or calciphylaxis occurs in horses that
less there is a concurrent infectious process. During the acute share a similar initial presentation to generalized IMM that is
phase of muscle atrophy serum CK and AST activities are followed by diverse organ failure.140,141 Systemic calcification
moderately to markedly elevated, but during the later phase of appears to be triggered when the serum calcium concentra-
chronic atrophy serum CK and AST activities can be normal. tion multiplied by serum phosphorus concentration exceeds
The most useful diagnostic test during the acute phase of the 65.
disease is a muscle biopsy of the epaxial and/or gluteal mus- Clinical Signs. All horses reported with systemic calcinosis
cles.11 Several formalin-fixed Trucut samples from the epaxial have been of Quarter Horse–related breeds and under 9 years
or gluteal muscles are often sufficient to establish a clinical of age.140,141 Initial clinical signs include a mild fever, malaise,
diagnosis. Histologic abnormalities include infiltration of the stiffness, and loss of muscle mass, particularly over the lumbar
myofibers by lymphocytes, lymphocytic vasculitis, anguloid and gluteal area (Fig. 10.18). Many horses have evidence of
atrophy of the myofibers, fiber necrosis, and multinucleated cough, tachypnea, and mild ventral edema. As the disease pro-
giant cells. Biopsies taken several weeks after the onset of atro- gresses progressive weakness, inability to remain standing, re-
phy may reveal only nonspecific findings of myogenic atrophy spiratory distress, laminitis, or gastrointestinal inflammation
without evidence of the hallmark feature of lymphocytic infil- may become evident. Whether these signs are a direct result of
trates. Biopsies of the semitendinosus or semimembranosus systemic dystrophic calcification or an underlying precipitat-
muscles may not be helpful in establishing a diagnosis because ing inflammatory disorder is unclear.
they are often normal or have evidence of atrophy and mild Diagnosis. A wide range of hematologic abnormalities may be
inflammatory cell infiltration. observed depending on the underlying disease process that pre-
Treatment and Prevention. Appropriate antimicrobials cedes dystrophic calcification. The most consistent alterations in
should be selected if there is evidence of concurrent infection. the hemogram are hyperfibrinogenemia and mild leukocytosis.
suspicion of an inflammatory/immune process was based

on the presence of lymphocytic infiltrates in muscle biopsy
specimens.
Y TOXIC CAUSES OF RHABDOMYOLYSIS

Chemical
Horses can periodically gain access to ionophores when equine
grains are mixed in a feedmill that did not properly clean
machinery after producing cattle feeds containing ionophores.
The primary clinical signs of ionophore toxicity depend on
the type of ionophore but usually suggest cardiomyopathy or
neurologic disease rather than overt rhabdomyolysis. Experi-
mental studies have indicated that LD50 values for monensin
are 2 to 3 mg/kg body weight for horses versus 21 to 36 mg/
FIG. 10.18 Severe muscle wasting of the topline and hindquarter mus- kg for cattle.
cles in a horse with systemic calcinosis. Several miniature horses being fed a complete feed con-
taining tetrachlorovinphos, an oral fly control agent, were
In the biochemistry profile the product of calcium multiplied by reported to develop chronic myonecrosis involving masseter,
phosphorus is greater than 65, and serum CK activities are at least tongue, neck, respiratory, and postural muscles and occasion-
threefold higher than the normal range.140 ally cardiac muscle.145 Affected horses showed signs of leth-
Systemic calcinosis should be suspected if a horse presents argy, dysphagia, fasciculations, tachypnea, and tachycardia.
with muscle atrophy, malaise, respiratory distress, or renal Muscle tissue showed evidence of chronic myonecrosis and
insufficiency with evidence of hyperfibrinogenemia and an lipid accumulation. Myonecrosis was attributed to acetylcho-
elevated Ca × P product. The histopathologic findings in mus- line accumulation at muscarinic and nicotinic sites producing
cle biopsies resemble those of IMM; however, multinucleated oxidant stress. Low selenium concentrations may contribute
giant cells are consistently present, and dystrophic calcification to the toxicosis.
of muscle fibers is also evident.140 At postmortem, dystrophic Blister beetle toxicosis can cause elevations in serum CK in
calcification is also evident in one or all of the following tissues some horses.146
in addition to skeletal muscle, the alveoli in pulmonary tissue,
cardiac myofibers, renal tubules, and tunica intima of blood Plants
vessels.140 In one case, dramatic lesions of arterial medial cal- Cassia obtusifolia (sicklepod) is prevalent in the southeastern
cification of the aorta and coronary and pulmonary arteries United States, and ingestion of seeds can cause degenerative
were reported.141 myopathy and cardiomyopathy with evidence of myofiber
Treatment and Prognosis. This condition is often associat- atrophy, segmental necrosis, and mitochondrial disruption.147
ed with a fatal outcome. Horses are usually euthanized because Tremetone-containing plants can cause a fatal cardiomyopa-
of progressive weakness, inability to remain standing, respira- thy and severe skeletal muscle degeneration in horses when
tory distress, laminitis, or other underlying disease. Treatment ingested at 0.5% to 2% of body weight.148,149 Both white snake-
is largely directed toward the underlying inflammatory condi- root (Eupatorium rugosum), which grows in shaded areas of
tion. In human medicine, corticosteroid treatment has been the eastern and central United States, and rayless goldenrod
implicated as a triggering mechanism for systemic calcinosis. (Isocoma wrightii), which is common in the Southwest on
In horses, however, the clinical signs that precede systemic cal- open pastures, contain tremetone. Tremetone remains active
cinosis so closely resemble IMM, a corticosteroid-responsive in hay and in the stalks of the dead plants on pasture, so both
disease, that corticosteroid treatment is often instituted when the fresh and the dried forms of the plants should be kept from
signs of rapid muscle atrophy develop. horses.150 Microsomal activation of the toxin in the liver may
be necessary for toxic effects.148
Idiopathic Immune-Mediated/Inflammatory
Myopathies Hypoglycin a Myopathy
Individual cases of myositis occur outside the Quarter Pathogenesis. Seeds or young shoots of Acer species trees
Horse breed that likely have an inflammatory or immune- such as the box elder (Acer negundo) and the European syca-
mediated basis. Focal atrophy of neck muscles was reported more maple (Acer pseudoplatanus) contain highly variable
in a 16-year-old pony with normal serum CK and AST amounts of the toxic nonproteogenic amino acid hypoglycin A
activities and interstitial aggregates of lymphocytes, plasma (Fig. 10.19).151,152 Hypoglycin A is metabolized in the liver to
cells, histiocytes, and eosinophils.144 Muscle mass returned methylenecyclopropylacetic acid (MCPA), and MCPA CoA ir-
to normal following treatment with dexamethasone. Within reversibly binds to multiple acyl CoA dehydrogenases, enzymes
the Neuromuscular Diagnostic Laboratory database at that are essential for metabolism of short- and medium-chain
Michigan State University a small number of horses of fatty acids and branched chain amino acids.9,153 Accumulation
breeds other than Quarter Horses have also been diagnosed of fat esters damages muscle cell membranes, and an energy
with a suspected inflammatory or immune-mediated myo- deficiency arises from an inability to metabolize fat.
sitis. These included an Anglo-Arabian, a mixed breed pony, Prevalence. Cases of hypoglycin A myopathy have been re-
a Percheron, a Warmblood, and two Thoroughbreds. The ported in northern and central Europe, the United Kingdom,
common clinical presentation was muscle atrophy, and the New Zealand, and central and northeastern North America.
Treatment and Prognosis. The mortality rate for horses

with overt clinical signs is high at 75%; however, early recog-
nition may improve the prognosis.159 Early aggressive fluid
therapy with antioxidant and antiinflammatory treatment, in-
cluding dimethylsulfoxide (DMSO), vitamin E, vitamin C, and
NSAIDs, is indicated.14 Cograzing horses with elevated serum
CK activity and no clinical signs may be successfully treated if
removed from the source of seeds immediately.
Although many older horses are asymptomatic on pastures
with Acer species trees, young horses or new horses should
not be pastured with box elder or European sycamore maple
trees in the fall or early spring. Provision of additional feed or
reducing grazing time during these seasons may also decrease
the incidence of hypoglycin A myopathy.
A
Y POSTANESTHETIC MYOPATHY
Postanesthetic myopathies occur in several forms: focal myop-
athy-neuropathy, generalized postoperative rhabdomyolysis,
and fulminant malignant hyperthermia.
Focal Myopathy
B Pathogenesis
Focal myopathy and potentially neuropathy occurs in muscles
FIG. 10.19 (A) Seeds from box elder trees. (B) Sycamore maple seed. When that are in contact with a hard surface during anesthesia or in
either seeds are ingested by horses they can cause hypoglycin A myopathy.
muscles that have positional occlusion of arterial blood sup-
ply. If mean arterial pressure is allowed to fall below 70 mm
Hg for several hours during inhalation anesthesia the inci-
The distribution of cases overlaps with the distribution of syc- dence of postanesthetic myopathy increases substantially.162,163
amore maple trees (UK and Europe) or box elder trees (North Muscles with dense fascia are most susceptible to necrosis as
America).14,154-157 Before identification of the toxin, hypogly- arterial blood flow and oxygen supply decrease further with
cin A myopathy was termed atypical myopathy or seasonal pas- the increased pressure within a compartmentalized swollen
ture myopathy because it occurred in pastured horses in the muscle. Commonly affected muscles include triceps, deltoid,
fall and less often the spring and often preceded by wet, windy masseter, hindlimb extensors, or, if the horse has been in dorsal
weather. Affected horses are usually young or new to affected recumbency, the hindlimb adductor and gluteal muscles.164-166
pastures and kept on wooded pastures for more than 12 hours Injury can also occur to nerves in the compressed swollen
a day without additional feed provided.158,159 Selenium defi- muscles, resulting in temporary radial, peroneal, or femoral
ciency appears to enhance toxic effects.160 nerve paralysis.
Clinical Signs. Clinical signs develop acutely within 3 to 5
days of exposure to toxic doses and include muscular weak- Clinical Signs
ness, sweating, fasciculations, stiffness, tachycardia, tachypnea, Clinical signs become apparent on recovery or 30 to 60 min-
recumbency, and, when urine is observed, myoglobinuria. A utes after recovery from anesthesia. Affected muscles are
rapid rise in respiratory rate is usually followed by collapse and swollen, hot, and painful on deep palpation, and the horse is
death from respiratory or cardiac failure. Pasture-mates can be often reluctant to bear weight on the affected limb. Weakness
subclinically affected. of affected muscles is common, particularly with peripheral
Diagnosis. A high index of suspicion of hypoglycin A my- nerve involvement. In some horses this condition may limit
opathy occurs in horses with rhabdomyolysis and an acidic the animal’s ability to stand for some time following anesthe-
urine pH. The most notable change in serum biochemistry is a sia. The loss of muscle strength, particularly when involving
marked increase in serum CK and AST activity, which is often adductor muscles, can contribute to orthopedic injury during
accompanied by hyperglycemia, lactic acidemia, and in some repeated attempts to rise. Many horses with mild to moderate
cases elevated serum troponin I concentrations.161 A defini- muscle injury recover over a period of hours to days even if
tive diagnosis can be made by identifying a specific pattern of untreated.164
accumulation of serum acylcarnitines and urine organic acids
and glycine conjugates typical of a deficiency in multiple acyl Diagnosis
CoA dehydrogenases, as well as isolation of the conjugated Diagnosis is based on a history of anesthesia or prolonged
toxic metabolite methylenecyclopropyl acetic acid (MCPA) or recumbency, clinical signs, and marked elevations in serum
hypoglycin A in blood or urine.9,151,153,154 Postmortem find- CK activity (thousands to tens of thousands of IU/L) within 4
ings include extensive necrosis in deep postural and respira- to 6 hours after anesthesia.
tory muscles and the myocardium in 50% or more of cases.
Frozen sections of myocardium, intercostal, diaphragm, or Treatment
deep postural muscles show marked intracellular lipid accu- Antiinflammatory drugs, dimethylsulfoxide, and dan-
mulation in oxidative fibers (oil red O stain).14,156 trolene sodium 2 to 4 mg/kg PO often are sufficient in mild
to moderate cases.59 Significant muscle atrophy may develop Horses with HYPP should be premedicated with acetazol-
over the ensuing 3 to 4 weeks but usually will resolve within amide. Dantrolene sodium at 2 to 4 mg/kg PO 1 to 2 hours
2 to 3 months unless substantial nerve damage has occurred. before anesthesia may be beneficial in reducing the incidence
Treatment of more severe cases is outlined previously in this of postanesthetic myopathies in problematic horses; however,
chapter (see section on treatment of acute rhabdomyolysis). 6 mg/kg has caused decreased cardiac output and hypoten-
sion, as well as elevated serum potassium, which would be
Prevention detrimental to horses with HYPP.72,168
Correct positioning and judicious use of padding and water-
or air-filled mattresses can reduce dependent muscle pressure
up to 50%, thereby aiding in the reduction of this disorder. In Malignant Hyperthermia
addition, by elevating the upper limb during anesthesia, the Pathogenesis
pressure on the lower limbs is significantly reduced. Pulling Fulminant cases of malignant hyperthermia (MH) are docu-
the lower forelimb forward also markedly reduces pressure mented in horses of many breeds. In Quarter Horses a muta-
in the dependent triceps muscle. When the horse is in dorsal tion in the ryanodine receptor 1 (RYR1) gene, the same gene
recumbency, padding under the shoulders and hips is abso- involved in MH of swine, has been linked to fulminant anes-
lutely imperative. thetic reactions caused by excessive calcium release from the
Maintaining anesthesia at the lightest plane possible for a sarcoplasmic reticulum.67-72 In other breeds, a specific cause of
specific surgical procedure is beneficial in prophylaxis. Simi- MH reactions has not been identified. Excessive myoplasmic
larly, if possible, maintaining systemic mean arterial blood calcium concentrations result in muscle contractures, anaero-
pressure above 80 to 85 mm Hg during anesthesia is advis- bic metabolism of glycogen, hyperthermia, lactic acidosis, and
able. The use of ionotropic agents such as dobutamine dur- hypercapnia.
ing anesthesia has been useful in reducing the occurrence of
anesthetic myopathies. Administration of dantrolene sodium Clinical Signs
(2 to 4 mg/kg PO) 1 hour before induction of anesthesia may Marked muscle rigidity, hyperthermia, hyperkalemia, hypercap-
result in a reduction in the incidence of this myopathy; how- nia, and metabolic and respiratory acidosis develop during anes-
ever, decreased cardiac output can occur in conjunction with thesia.38,70,169,170 Horses usually die within a matter of hours. In
higher Dantrium doses.72 some cases, shock and pigmenturia may lead to renal failure.
Treatment and Prevention

Generalized Postanesthetic Myopathy Genetic screening for MH in Quarter Horses and Paints may
Pathogenesis be warranted before elective procedures, although the prev-
The development of generalized rhabdomyolysis and weak- alence of the MH mutation is less than 1% in these breeds.
ness in horses can occur during recovery from anesthesia or If hyperthermia and contracture develop during anesthesia,
hours after recovery. In some cases, systemic hypotension anesthesia should be immediately discontinued. Attempts to
and hypoxemia may create local ischemic lesions, with the cool the animal with alcohol or cold-water baths are indicated.
pathologic changes becoming more generalized as a result of IV administration of sodium bicarbonate at dosages calcu-
the stress of anesthesia and the sensitivity of muscle cells to lated from acid-base measurements is most appropriate. If not
anesthetic agents or muscle relaxants.162,164 In other cases, an possible, a dosage of 1 to 2 mEq/kg slowly is recommended.
underlying myopathy such as hyperkalemic periodic paralysis, Administration of a large amount of soluble, lyophilized dan-
recurrent exertional rhabdomyolysis, or PSSM may increase trolene sodium for IV administration may alleviate clinical
the risk of a generalized postanesthetic myopathy.34,38,95,167 signs in these horses. However, availability and expense of the
agent in this form highly restrict its use. A dosage rate of 1
Clinical Signs mg/kg intravenously may be appropriate, although more con-
Anxiety, hyperthermia, tachycardia, tachypnea, profuse sweat- trolled studies are required.164
ing, and myoglobinuria with firm painful swelling of multiple
muscle groups is an occasional serious complication of anes- Y MYOTONIC DISORDERS
thesia.165,166 Horses may not be able to rise and may struggle
violently, resulting in prolonged, traumatic recoveries. Differential diagnoses for muscle fasciculations in horses are
listed in Box 10.4.
Diagnosis
Diagnosis is based on clinical signs and assessment of serum
CK activity taken at least 4 hours after anesthesia to allow levels Myotonia
to peak. Pathogenesis
Myotonic muscle disorders are a heterogeneous group of
Treatment acquired or congenital diseases that share the feature of delayed
Aims of therapy include pain relief, correction of fluid and relaxation of muscle after mechanical stimulation or voluntary
electrolyte deficits, prevention of ongoing necrosis, and nurs- contraction caused by abnormal muscle membrane excitability.
ing care as outlined previously in this chapter (see section on Congenital or inherited causes include defects in the skeletal
treatment of acute rhabdomyolysis). muscle chloride channel (myotonia congenita) or sodium chan-
nel (hyperkalemic periodic paralysis). Acquired causes include
Prevention infestation with the spinous ear tick Otobius megnini. The cause
The principles described for localized myoneuropathies apply of many cases of myotonia in horses, especially dystrophic
to the prevention of generalized anesthetic-related myopathies. forms, remains unknown.
BOX 10.4
Muscle Fasciculations
1. Pain, anxiety
2. Weakness
a. Botulism
b. Vitamin E–deficient myopathy
c. Equine motor neuron disease
3. Increased motor neuron firing
a. Electrolyte abnormalities
b. Focal nerve irritation
c. Otobius megnini ear tick infestation
FIG. 10.21 Severe muscle cramping (arrow) associated with ear ticks
d. Stiff horse syndrome
that is so painful to horses it results in colic-like signs and recumbency.
e. Shivers
f. Neuromyotonia
4. Abnormal sarcolemmal conductivity have been documented.178 The basis for myotonia dystrophica
a. Hyperkalemic periodic paralysis is unknown.
b. Myotonia congenita
c. Myotonia dystrophica Diagnosis
A tentative diagnosis of myotonia can be made on the basis
of age, clinical signs of stiff gait, muscle bulging, and myo-
tonic dimpling following percussion. Definitive diagnosis
requires electromyographic (EMG) examination. Affected
muscles manifest pathognomonic high-frequency repeti-
tive discharges that wax and wane, creating the sound of
“dive bombers” resulting from abnormal repetitive firing
of affected muscle fibers.49 Muscle biopsies from foals with
myotonia congenita can have normal histopathology or may
demonstrate extremely variable muscle fiber diameters up to
twice those of normal age-matched controls.174 Type 1 fiber
hypertrophy or hypotrophy is reported. Muscle pathology is
more dramatic in myotonia dystrophica, including ringed
fibers, centrally displaced myonuclei, sarcoplasmic masses,
and an increase in endomysial and perimysial connective tis-
sue.175,177-179 Fiber type grouping and atrophy of both type 1
and type 2 muscle fibers are present.
Treatment and Prognosis

There is no efficacious treatment for myotonia in horses. Prog-
FIG. 10.20 Middle gluteal muscle hypertrophy and superficial gluteal nosis appears to be variable and dependent on the severity
muscle atrophy in a horse with myotonia dystrophica. of clinical signs. Mildly affected animals with myotonia con-
genita can show improvement in clinical signs with increasing
Clinical Signs age. The reason(s) for regression of signs is unknown. Other
Myotonia Congenita. Myotonia congenita is usually more severely affected horses, particularly those with myo-
detected in the first year of life.171-174 Affected foals have con- tonia dystrophica, have progression of signs, including atro-
spicuously well-developed musculature with mild to moder- phy and fibrosis or pseudohypertrophy to the point at which
ate pelvic limb stiffness that is most pronounced when exercise the animal is no longer able to move without great difficulty.
begins and diminishing as exercise continues. Bilateral bulg- Euthanasia of such animals is often warranted. Conclusive evi-
ing (dimpling) of the thigh and rump muscles is often obvi- dence regarding the genetic basis of myotonia dystrophia is
ous, and percussion dimpling occurs with tactile stimulation lacking.
over the muscle. Percussed muscles can remain contracted for
up to a minute or more with subsequent slow relaxation.174,175 Ear-Tick Associated Myotonia
Progression of clinical signs does not usually occur beyond 6 Otobius megnini is commonly found in the southwestern
to 12 months of age.175 An autosomal recessive mutation of United States. Intermittent painful nonexertional muscle con-
the CLCN1 gene was identified in one New Forest Pony with traction and mild to moderate rhabdomyolysis occur in some
myotonia congenita.176 horses in conjunction with O. megnini infestations.180 Intermit-
Myotonia Dystrophica. Myotonia dystrophica resembles tent contraction of pectoral, triceps, abdominal, or semitendi-
myotonia congenita in early phases; however, weanlings have nosus/semimembranosus muscles, lasting from minutes to a
progressive multifocal muscle atrophy, hypertrophy, and per- few hours, can be so painful that it results in recumbency often
sistent stiffness that worsen with exercise (Fig. 10.20). It has resembling colic (Fig. 10.21). Contraction with myotonic dim-
been described in a variety of breeds, including Quarter Hors- pling of a muscle can be induced by tactile stimulation of the
es, Appaloosa, and Italian-bred foals.175,177,178 In some foals muscle with a percussion hammer. Horses may fall over with
retinal dysplasia, lenticular opacities, and gonadal hypoplasia pain when stimulated. Between muscle cramps horses appear
to be normal. Horses have elevated serum CK activities rang-

ing from 4000 to 170,000 IU/L. Numerous ear ticks are present
in the external ear canal of affected horses. Without treatment
for ear ticks, the spasms continue; however, local treatment of
the ear ticks using pyrethrins and piperonal butoxide results in
recovery within 12 to 36 hours. Acepromazine may be helpful
to relieve painful cramping.
Y HYPERKALEMIC PERIODIC PARALYSIS

Sharon J. Spier
Pathogenesis
Hyperkalemic periodic paralysis (HYPP) is an autosomal
codominant form of myotonia in Quarter Horses, American
Paint Horses, and Appaloosas that are descendants of the
popular Quarter Horse stallion Impressive. HYPP is due to
a mutation in the gene encoding the voltage-dependent skel-
etal muscle sodium channel.181-185 Horses with HYPP have
resting sarcolemmal membrane potentials that are closer
to firing. When muscle cells begin to depolarize during an
episode of HYPP, a subpopulation of sodium channels fail
to inactivate, producing an excessive inward flux of sodium
and outward flux of potassium resulting in persistent depo-
larization of muscle cells, general muscle fasciculations, and
weakness.
Prevalence
Approximately 1.5% of the Quarter Horse breed and 4.5% of
the Paint Horse breed are affected.83 Notably, however, 58% of
halter horses of these breeds have the HYPP mutation likely FIG. 10.22 Heavily muscled phenotype and myotonic cramping in a
because the disorder is linked to large muscle mass and suc- Quarter Horse suffering from HYPP. (Photo courtesy Dr. Monica Aleman.)
cess in the halter horse industry.83 Horses homozygous for the
HYPP mutation can no longer be registered with the Ameri-
can Quarter Horse Association.
Clinical Signs
Clinical signs are intermittent and highly variable in nature
beginning by 2 to 3 years of age.182,183 Some heterozygous
horses are completely asymptomatic, whereas other hetero-
zygous horses have daily muscle fasciculations and weakness.
Episodes often begin with a brief period of facial myotonia and
potentially prolapse of the third eyelid. Sweating and muscle
fasciculations progress to involve the flanks, neck, and shoul-
ders. Attempts to move the horse can exacerbate muscle trem-
ors. Overt myotonic cramping of muscle groups can occur in
some horses (Fig. 10.22). Heart and respiratory rates can be
elevated. During mild attacks horses remain standing, but epi-
sodes can evolve within a few minutes to encompass severe
weakness, swaying, staggering, dog sitting, and recumbency.
Paralysis of upper respiratory muscles during episodes can
result in respiratory distress and sudden death if a tracheos-
tomy is not performed. Horses remain conscious even when
recumbent and often have an anxious alert eye responding
FIG. 10.23 Hypertrophy and closure of the vocal folds in a foal ho-
to noise and painful stimuli. Episodes usually last from 15 to
mozygous for HYPP that resulted in severe dyspnea.
60 minutes. After the episode subsides, horses regain their
feet and appear normal with no apparent or minimal gait
abnormalities. Risk Factors
Foals homozygous for the HYPP mutation can present The factor that precipitates an episode of HYPP in genetically
with dysphagia, respiratory stridor, and periodic obstruction susceptible horses is often not obvious. Diets high in potas-
of the upper respiratory tract (Fig. 10.23). Endoscopic findings sium (greater than 1.1%), such as those containing alfalfa
include pharyngeal collapse and edema, laryngopalatal dislo- hay, molasses, electrolyte supplements, and kelp-based sup-
cation, and laryngeal paralysis.186 plements, can precipitate an episode.187,188 Other potential
triggering factors include sudden dietary changes, fasting, potassium concentrations. Oats, corn, wheat, barley, and beet
anesthesia or heavy sedation, trailer rides, stress, cold, preg- pulp should be fed in small meals several times a day. Horses
nancy, and concurrent disease. HYPP is not triggered by will adapt to diets higher in potassium over a period of 2
exercise. weeks and will experience fewer fluctuations in serum potas-
sium with subsequent decreased frequency of clinical signs.188
Clinical Pathology Regular exercise and/or frequent access to a large paddock or
In most cases, hyperkalemia (6–9 mEq/L), hemoconcentra- yard are also beneficial. Supplementation with salt and bal-
tion, and mild hyponatremia occur during periods of muscle anced vitamins and minerals is indicated to meet nutritional
fasciculations with normal acid-base balance.183 Serum potas- requirements. Commercially available complete feeds with
sium concentration returns to normal following the abatement a guaranteed K+ content may be more convenient for some
of clinical signs. Some affected horses may have normal serum HYPP horses, especially for owners with few horses.
potassium concentrations during minor episodes of muscle For horses with recurrent episodes of muscle fasciculations
fasciculations.182 Serum CK activity shows no change or only even with dietary modification, acetazolamide (2–3 mg/kg
mild increases during episodic fasciculations and weakness. orally, every 8–12 hours) or hydrochlorothiazide (0.5–1 mg/
kg orally, every 12 hours) may be indicated. Although these
Diagnosis agents exert their effects through different mechanisms they
A definitive diagnosis of HYPP is made through genetic test- both increase renal potassium excretion. Acetazolamide also
ing for the F1416L mutation in the SCN4A gene encoding the stabilizes blood glucose and potassium by stimulating insu-
alpha subunit of the sodium channel.184 Submission of mane lin secretion. Breed registries and other associations may have
or tail hair with roots should be made to a licensed laboratory restrictions on the use of these drugs during competitions as
such as the Veterinary Genetics Laboratory at the University diuretics may mask prohibited substances.
of California, Davis, www.vgl.ucdavis.edu. Electromyographic
examination of affected horses has also been used for diagnostic Prognosis
purposes. Affected horses have abnormal fibrillation potentials, HYPP is usually a manageable disorder, although recurrent
complex repetitive discharges, occasional myotonic potentials, bouts may occur and severe episodes can be fatal. As this is a
and trains of doublets even between episodes of HYPP.183,189 dominant trait, breeding an affected horse to a normal horse
results in a 50% chance of producing a foal with HYPP. All
Treatment affected horses share the same mutation regardless of whether
Many horses experience spontaneous recovery from episodes or not owners have witnessed symptoms in their horses.191
of paralysis and appear normal by the time a veterinarian Owners of affected horses should advise veterinarians of
arrives. If horses are just beginning to exhibit clinical signs, HYPP status before anesthesia or procedures requiring heavy
owners may be advised to provide mild exercise or to feed sedation, as these circumstances could precipitate an episode
grain or corn syrup before the veterinarian’s arrival. Grain and of paralysis.192
high-fructose corn syrup (e.g., Karo syrup) lower serum potas-
sium by stimulating insulin-mediated movement of potassium
across cell membranes. Other options for treatment during an Y ELECTROLYTE IMBALANCES
acute episode of hyperkalemia include epinephrine (3 mL of
1:1000/500 kg administered intramuscularly), acetazolamide Muscle Cramping
(3 mg/kg PO every 8–12 hours), or calcium gluconate (0.2–0.4 Severe electrolyte imbalances cause muscle cramping. Muscle
mL/kg of a 23% IV solution, diluted in 1 L of 5% dextrose). cramps are a painful condition that arises from hyperactivity
An increase in extracellular calcium concentration raises the of motor units caused by repetitive firing of the peripheral and/
muscle membrane threshold potential, which decreases mem- or central nervous system. The origin of the cramp in most
brane hyperexcitability. Other options include IV dextrose cases is believed to be the intramuscular portion of the motor
(6 mL/kg of a 5% solution) alone or combined with sodium nerve terminals.193,194 Most muscle cramps are also accompa-
bicarbonate (1–2 mEq/kg) to enhance intracellular movement nied by fasciculations in the same muscle. Muscle cramps can
of potassium. With severe respiratory obstruction, a tracheos- be induced by forceful contraction of a shortened muscle, by
tomy may be necessary. changes in the electrolyte composition of extracellular fluid,
and by ear tick infestations in horses.180,193 In contrast, muscle
Control contractures are painful muscle spasms that represent a state
Ideally, horses with recurrent episodes of HYPP should be fed of muscle contracture unaccompanied by depolarization of
a balanced diet containing between 0.6% and 1.1% total potas- the muscle membrane.192 Muscle contractures occur with MH
sium by weight and meals containing less than 33 g of potas- and some forms of exertional myopathies and are invariably
sium.187,188,190 The principal source of potassium in the equine accompanied by markedly increased serum CK activity.
diet is forage. In general, early cuts of alfalfa, orchard grass,
and brome hay have higher potassium concentrations, and Hypocalcemic Tetany
later cuts of timothy or Bermuda grass hay have lower potas- Pathogenesis. Hypocalcemia is a rare occurrence in horses
sium concentrations, but this is not always the case. Horses and is usually associated with parturition, heavily lactating
having frequent episodes should have forages analyzed for mares, transportation, prolonged endurance rides, or grazing
potassium concentrations.190 Pasture works well for horses lush pastures.195 Idiopathic fatal hypocalcemia has also been
with HYPP because the high water content of pasture grass reported in foals.196
makes it unlikely that horses will consume large amounts of Clinical Signs. Clinical signs are similar to those seen
potassium in a short period of time. Feeds containing soy- with tetanus and include a stiff, stilted gait, muscle fascicu-
bean meal, sugar molasses, or beet molasses can have higher lations (especially temporal, masseter, and triceps muscles),
trismus, dysphagia, salivation, anxiety, profuse sweating, In some horses SDF may be a chronic, recurring problem,
tachycardia, elevated body temperature, cardiac arrhyth- particularly if they have received prolonged administration
mias, synchronous diaphragmatic flutter, convulsions, coma, of high-calcium supplements.199
and death.195 Subclinical evidence of abnormal neuromus- Treatment. In most cases SDF is a transient event, usually
cular conductivity has been documented by EMG in horses abating when the underlying cause resolves, either sponta-
with experimentally induced hypocalcemia.197 In lactating neously or in response to treatment.199 Most horses undergo
mares this disorder can be progressive over a 24- to 48-hour rapid remission of signs when given calcium solutions intra-
period and potentially fatal. Clinical signs are related to the venously as described earlier for treatment of hypocalcemic
magnitude of decline in serum calcium concentration. In- tetany. Although hypomagnesemia is often present with SDF,
creased excitability is usually the only sign when values are horses do not respond to magnesium supplementation unless
below normal but above 8 mg/dL total calcium. Values of 5 to calcium is administered concurrently. Response to therapy is
8 mg/dL usually produce tetanic spasms and incoordination. also reflected by improved mental status, return of appetite,
Concentrations below 5 mg/dL usually result in recumbency and gut motility.198
and stupor. Control. Electrolyte supplementation and some dietary
Diagnosis. Diagnosis is usually based on clinical signs, a manipulations may help reduce the incidence of SDF in some
history of lactation, previous prolonged exercise, or transport. endurance horses suffering recurrent bouts. Provision of chlo-
Along with hypocalcemia, metabolic alkalosis, hypomagnese- ride, potassium, and sodium during prolonged exercise may
mia/hypermagnesemia, and hyperphosphatemia/hypophos- help reduce fluid losses and the metabolic alkalosis that com-
phatemia are frequently present. These alterations may need monly accompanies this form of exercise and frequently oc-
correction before tetanus and fasciculation abate. curs in association with SDF. Metabolic alkalosis decreases the
Treatment. IV administration of calcium solutions such amount of free calcium available. Supplementation of calcium
as 20% calcium borogluconate or those recommended for and magnesium during endurance rides has been suggested to
the treatment of parturient paresis in cattle is required. These be helpful in horses prone to SDF.
preparations should be administered slowly in conjunction Alternative approaches involve reduction of dietary cal-
with close monitoring of the cardiovascular response. Dilution cium in horses prone to SDF for a few days before an endur-
at the rate of 250 to 500 mL/500 kg diluted 1:4 with saline or ance ride. It is postulated that this reduction in dietary
dextrose before infusion decreases the chance of cardiotoxic- calcium stimulates the endocrine homeostatic mechanisms
ity. Normally there is a positive inotropic effect in response to and increases osteoclastic activity. In the short term the
calcium administration; however, alterations in rate or rhythm horse depends less on dietary calcium and is able to mobilize
provide evidence to suspend the infusion. If no response to substantial amounts of calcium in response to the demands
an initial infusion occurs, a second dose may be given 15 to imposed by exercise; calcium losses in sweat are overcome
30 minutes later. Most cases respond to this form of therapy, by the release of calcium from endogenous storage pools
although in some cases in which signs persist, repeated treat- (bone).199 Horses routinely fed alfalfa hay, which has a rel-
ments may be necessary. atively high calcium concentration, may be more prone to
development of SDF. Limitation of this feedstuff may be indi-
Synchronous Diaphragmatic Flutter cated in chronically affected horses.
Pathogenesis. Synchronous diaphragmatic flutter (SDF),
or “thumps,” arises when fluid and electrolyte imbalances dis- Y CONFLICT OF INTEREST STATEMENT
rupt the membrane potential of the phrenic nerve. The phrenic
nerve begins to discharge in concert with atrial depolariza- Dr. Valberg is co-owner of the license for PSSM testing and
tion with subsequent contraction of the diaphragm.198 The receives sales income from its use. Her financial and busi-
most consistent metabolic derangement reported in horses ness interests are managed by Michigan State University in
with SDF is low serum ionized calcium concentrations usu- accordance with its conflict of interest policies. Dr. Valberg
ally associated with hypochloremic metabolic alkalosis.198,199 receives royalties from Kentucky Equine Research for the sale
Metabolic alkalosis may alter the ratio of free to bound cal- of Re-Leve.
cium (increasing calcium binding to protein and decreasing
ionized calcium), which possibly induces SDF. REFERENCES
Risk Factors. Inciting causes include hypocalcemia aris- 1. Firshman AM, Borgia LA, Valberg SJ. Effects of training at a
ing from lactation, transport, prolonged endurance exercise, walk on conventional and underwater treadmills on fiber prop-
primary hypoparathyroidism, digestive disturbances, admin- erties and metabolic responses of superficial digital flexor and
istration of furosemide, and possibly other medications.198-200 gluteal muscles to high-speed exercise in horses. Am J Vet Res.
Ingestion of blister beetles (cantharidin toxicosis) can also 2015;76:1058–1065.
cause hypocalcemia and SDF.146 2. Cheng AJ, Andersson DC, Lanner JT. Can’t live with or with-
Clinical Signs. A thumping or twitch in the flank region out it: calcium and its role in Duchenne muscular dystrophy-
(unilateral or bilateral) is seen when the diaphragm con- induced muscle weakness. Focus on SERCA1 overexpression
tracts synchronously with the heart. In severe cases this minimizes skeletal muscle damage in dystrophic mouse models.
Am J Physiol Cell Physiol. 2015;308:C697–C698.
twitch may produce an audible thumping sound. Signs 3. Cardinet GH, Littrell JF, Freedland RA. Comparative investiga-
of dehydration and volume depletion can be present de- tions of serum creatine phosphokinase and glutamic-oxaloacetic
pending on the etiology of the calcium imbalance. SDF is transaminase activities in equine paralytic myoglobinuria. Res
a component of the exhausted horse syndrome in endur- Vet Sci. 1967;8:219–226.
ance horses and often accompanies signs of dehydration, 4. Wilberger MS, McKenzie EC, Payton ME, et al. Prevalence of
inappropriate sweating responses, persistently elevated exertional rhabdomyolysis in endurance horses in the Pacific
body temperature, depression, anorexia, and aperistalsis.25 Northwestern United States. Equine Vet J. 2015;47:165–170.
5. Valberg SJ, Mickelson JR, Gallant EM, et al. Exertional rhabdo- 29. McKenzie EC, Valberg SJ, Godden SM, et al. Comparison of
myolysis in quarter horses and thoroughbreds: one syndrome, volumetric urine collection versus single-sample urine collec-
multiple aetiologies. Equine Vet J Suppl. 1999;30:533–538. tion in horses consuming diets varying in cation-anion balance.
6. Valberg S, Haggendal J, Lindholm A. Blood chemistry and skeletal Am J Vet Res. 2003;64:284–291.
muscle metabolic responses to exercise in horses with recurrent 30. Roneus B, Hakkarainen J. Vitamin E in serum and skeletal
exertional rhabdomyolysis. Equine Vet J. 1993;25:17–22. muscle tissue and blood glutathione peroxidase activity from
7. Valberg SJ, MacLeay JM, Billstrom JA, et al. Skeletal muscle horses with the azoturia-tying-up syndrome. Acta Vet Scand.
metabolic response to exercise in horses with “tying-up” due to 1985;26:425–427.
polysaccharide storage myopathy. Equine Vet J. 1999;31:43–47. 31. Beech J. Treating and preventing chronic intermittent rhabdo-
8. Perkins G, Valberg SJ, Madigan JM, et al. Electrolyte distur- myolysis. Vet Med May. 1994:458–461.
bances in foals with severe rhabdomyolysis. J Vet Intern Med. 32. Beech J, Lindborg S, Fletcher JE, et al. Caffeine contractures,
1998;12:173–177. twitch characteristics and the threshold for Ca2+-induced Ca2+
9. Westermann CM, Dorland L, Votion DM, et al. Acquired mul- release in skeletal muscle from horses with chronic intermittent
tiple Acyl-CoA dehydrogenase deficiency in 10 horses with rhabdomyolysis. Res Vet Sci. 1993;54:110–117.
atypical myopathy. Neuromuscul Disord. 2008;18:355–364. 33. Beech J. Chronic exertional rhabdomyolysis. Vet Clin North Am
10. McCue ME, Anderson SM, Valberg SJ, et al. Estimated preva- Equine Pract. 1997;13:145–168.
lence of the type 1 polysaccharide storage myopathy mutation 34. Lentz LR, Valberg SJ, Balog EM, et al. Abnormal regulation of
in selected North American and European breeds. Anim Genet. muscle contraction in horses with recurrent exertional rhabdo-
2010;41(Suppl 2):145–149. myolysis. Am J Vet Res. 1999;60:992–999.
11. Lewis SS, Valberg SJ, Nielsen IL. Suspected immune-mediated 35. MacLeay JM, Sorum SA, Valberg SJ, et al. Epidemiologic analy-
myositis in horses. J Vet Intern Med. 2007;21:495–503. sis of factors influencing exertional rhabdomyolysis in Thor-
12. Valentine BA, de Lahunta A, George C, et al. Acquired equine oughbreds. Am J Vet Res. 1999;60:1562–1566.
motor neuron disease. Vet Pathol. 1994;31:130–138. 36. Valberg S, Jonsson L, Lindholm A, et al. Muscle histopathol-
13. Bedford HE, Valberg SJ, Firshman AM, et al. Histopathologic ogy and plasma aspartate aminotransferase, creatine kinase and
findings in the sacrocaudalis dorsalis medialis muscle of horses myoglobin changes with exercise in horses with recurrent exer-
with vitamin E–responsive muscle atrophy and weakness. J Am tional rhabdomyolysis. Equine Vet J. 1993;25:11–16.
Vet Med Assoc. 2013;242:1127–1137. 37. Lindholm A, Johansson HE, Kjaersgaard P. Acute rhabdomyol-
14. Finno CJ, Valberg SJ, Wunschmann A, et al. Seasonal pasture ysis (“tying-up”) in standardbred horses. A morphological and
myopathy in horses in the midwestern United States: 14 cases biochemical study. Acta Vet Scand. 1974;15:325–339.
(1998-2005). J Am Vet Med Assoc. 2006;229:1134–1141. 38. Hildebrand SV, Arpin D, Cardinet III G. Contracture test and
15. Cardinet 3rd GH, Holliday TA. Neuromuscular diseases of do- histologic and histochemical analyses of muscle biopsy speci-
mestic animals: a summary of muscle biopsies from 159 cases. mens from horses with exertional rhabdomyolysis. J Am Vet
Ann N Y Acad Sci. 1979;317:290–313. Med Assoc. 1990;196:1077–1083.
16. Wijnberg ID, Franssen H. The potential and limitations of quan- 39. Hunt LM, Valberg SJ, Steffenhagen K, et al. An epidemiologi-
titative electromyography in equine medicine. Vet J. 2016;209: cal study of myopathies in Warmblood horses. Equine Vet J.
23–31. 2008;40:171–177.
17. Robinson JA, Naylor JM, Crichlow EC. Use of electromyogra- 40. McGowan CM, Fordham T, Christley RM. Incidence and risk
phy for the diagnosis of equine hyperkalemic periodic paresis. factors for exertional rhabdomyolysis in thoroughbred race-
Can J Vet Res. 1990;54:495–500. horses in the United Kingdom. Vet Rec. 2002;151:623–626.
18. Valberg SJ, Dyson S. Skeletal muscle and lameness. In: Ross M, 41. MacLeay JM, Valberg SJ, Pagan JD, et al. Effect of ration and
Dyson S, eds. Lameness in the horse. Philadelphia: Saunders; exercise on plasma creatine kinase activity and lactate concen-
2003:723–743. tration in Thoroughbred horses with recurrent exertional rhab-
19. Morris E, Seeherman HJ, O’Callaghan MW, et al. Scintigraphic domyolysis. Am J Vet Res. 2000;61:1390–1395.
identification of skeletal muscle damage in horses 24 hours after 42. McKenzie EC, Valberg SJ, Godden SM, et al. Effect of dietary
strenuous exercise. Equine Vet J. 1991;23:347–352. starch, fat, and bicarbonate content on exercise responses and
20. Cole FL, Mellor DJ, Hodgson DR, et al. Prevalence and demo- serum creatine kinase activity in equine recurrent exertional
graphic characteristics of exertional rhabdomyolysis in horses rhabdomyolysis. J Vet Intern Med. 2003;17:693–701.
in Australia. Vet Rec. 2004;155:625–630. 43. Upjohn MM, Archer RM, Christley RM, et al. Incidence and
21. Steckel RR. The role of scintigraphy in the lameness evaluation. risk factors associated with exertional rhabdomyolysis syn-
Vet Clin North Am Equine Pract. 1991;7:207–239. drome in National Hunt racehorses in Great Britain. Vet Rec.
22. McGowan CM, Posner RE, Christley RM. Incidence of exer- 2005;156:763–766.
tional rhabdomyolysis in polo horses in the USA and the United 44. MacLeay JM, Valberg SJ, Sorum SA, et al. Heritability of recur-
Kingdom in the 1999/2000 season. Vet Rec. 2002;150:535–537. rent exertional rhabdomyolysis in Thoroughbred racehorses.
23. Grobler LA, Collins M, Lambert MI, et al. Skeletal muscle pa- Am J Vet Res. 1999;60:250–256.
thology in endurance athletes with acquired training intoler- 45. Valberg SJ. Metabolic response to racing and fiber properties
ance. Br J Sports Med. 2004;38:697–703. of skeletal muscle in Standardbred and Thoroughbred horses. J
24. Carlson GP: Response to oral and intravenous fluid. In Pro- Equine Vet Sci. 1987;7:7.
ceedings of the Fifth Annual Scientific Meeting of the Associa- 46. Valberg S, Gustavsson BE, Lindholm A, et al. Blood chemistry
tion for Equine Sports Medicine, 1985, pp 82–90. and skeletal muscle metabolic responses during and after dif-
25. Foreman JH. The exhausted horse syndrome. Vet Clin North Am ferent speeds and durations of trotting. Equine Vet J. 1989;21:
Equine Pract. 1998;14:205–219. 91–95.
26. Valentine BA, Van Saun RJ, Thompson KN, et al. Role of dietary 47. Lentz LR, Valberg SJ, Herold LV, et al. Myoplasmic calcium
carbohydrate and fat in horses with equine polysaccharide stor- regulation in myotubes from horses with recurrent exertional
age myopathy. J Am Vet Med Assoc. 2001;219:1537–1544. rhabdomyolysis. Am J Vet Res. 2002;63:1724–1731.
27. Valentine BA, Hintz HF, Freels KM, et al. Dietary control of 48. Lopez JR, Linares N, Cordovez G, et al. Elevated myoplasmic
exertional rhabdomyolysis in horses. J Am Vet Med Assoc. calcium in exercise-induced equine rhabdomyolysis. Pflugers
1998;212:1588–1593. Arch. 1995;430:293–295.
28. Harris P, Colles C. The use of creatinine clearance ratios in the 49. Waldron-Mease E, Klein LV, Rosenberg H, et al. Malignant hy-
prevention of equine rhabdomyolysis: a report of four cases. perthermia in a halothane-anesthetized horse. J Am Vet Med
Equine Vet J. 1988;20:459–463. Assoc. 1981;179:896–898.
50. Lentz LR, Valberg SJ, Mickelson JR, et al. In vitro contrac- 71. McCue ME, Valberg SJ, Jackson M, et al. Polysaccharide storage
tile responses and contracture testing of skeletal muscle from myopathy phenotype in Quarter Horse–related breeds is modi-
Quarter Horses with exertional rhabdomyolysis. Am J Vet Res. fied by the presence of an RYR1 mutation. Neuromuscul Disord.
1999;60:684–688. 2009;19:37–43.
51. Ward TL, Valberg SJ, Gallant EM, et al. Calcium regulation by 72. McKenzie EC, Di Concetto S, Payton M, et al. Effect of dan
skeletal muscle membranes of horses with recurrent exertional trolene premedication on various cardiovascular and biochemi-
rhabdomyolysis. Am J Vet Res. 2000;61:242–247. cal variables and the recovery in healthy isoflurane-anesthetized
52. Isgren CM, Upjohn MM, Fernandez-Fuente M, et al. Epidemiol- horses. Am J Vet Res. 2015;76:293–301.
ogy of exertional rhabdomyolysis susceptibility in Standardbred 73. Valberg SJ, Cardinet III GH, Carlson GP, et al. Polysaccharide
horses reveals associated risk factors and underlying enhanced storage myopathy associated with recurrent exertional rhabdo-
performance. PLoS One. 2010;5:e11594. myolysis in horses. Neuromuscul Disord. 1992;2:351–359.
53. Fraunfelder HC, Rossdale PD, Rickets SW. Changes in serum 74. Valentine BA, Credille KM, Lavoie JP, et al. Severe polysac-
muscle enzyme levels in associated with training schedules and charide storage myopathy in Belgian and Percheron draught
stages of oestrus cycle in Thoroughbred racehorses. Equine Vet horses. Equine Vet J. 1997;29:220–225.
J. 1986;18:371–374. 75. Valentine BA, McDonough SP, Chang YF, et al. Polysaccharide
54. Dranchak PK, Valberg SJ, Onan GW, et al. Inheritance of re- storage myopathy in Morgan, Arabian, and Standardbred related
current exertional rhabdomyolysis in Thoroughbreds. J Am Vet horses and Welsh-cross ponies. Vet Pathol. 2000;37:193–196.
Med Assoc. 2005;227:762–767. 76. Valentine BA, Cooper BJ. Incidence of polysaccharide storage my-
55. MacLeay JM, Valberg SJ, Sorum SA, et al. Heritability of recur- opathy: necropsy study of 225 horses. Vet Pathol. 2005;42:823–827.
rent exertional rhabdomyolysis in Thoroughbred racehorses. 77. McCue ME, Valberg SJ, Miller MB, et al. Glycogen synthase
Am J Vet Res. 1999;60:250–256. (GYS1) mutation causes a novel skeletal muscle glycogenosis.
56. Harris PA, Snow DH, Greet TR, et al. Some factors influencing Genomics. 2008;91:458–466.
plasma AST/CK activities in Thoroughbred racehorses. Equine 78. McCue ME, Armien AG, Lucio M, et al. Comparative skeletal
Vet J Suppl. 1990:66–71. muscle histopathologic and ultrastructural features in two
57. Quiroz-Rothe E, Novales M, Guilera-Tejero E, et al. Polysac- forms of polysaccharide storage myopathy in horses. Vet Pathol.
charide storage myopathy in the m. longissimus lumborum of 2009;46:1281–1291.
showjumpers and dressage horses with back pain. Equine Vet J. 79. Baird JD, Valberg SJ, Anderson SM, et al. Presence of the gly-
2002;34:171–176. cogen synthase 1 (GYS1) mutation causing type 1 polysaccha-
58. Finno CJ, McKenzie E, Valberg SJ, et al. Effect of fitness on glu- ride storage myopathy in continental European draught horse
cose, insulin and cortisol responses to diets varying in starch breeds. Vet Rec. 2010;167:781–784.
and fat content in Thoroughbred horses with recurrent exer- 80. Stanley RL, McCue ME, Valberg SJ, et al. A glycogen synthase
tional rhabdomyolysis. Equine Vet J Suppl. 2010:323–328. 1 mutation associated with equine polysaccharide storage myo-
59. McKenzie EC, Valberg SJ, Godden SM, et al. Effect of oral ad- pathy and exertional rhabdomyolysis occurs in a variety of UK
ministration of dantrolene sodium on serum creatine kinase breeds. Equine Vet J. 2009;41:597–601.
activity after exercise in horses with recurrent exertional rhab- 81. McGowan CM, Menzies-Gow NJ, McDiarmid AM, et al. Four
domyolysis. Am J Vet Res. 2004;65:74–79. cases of equine polysaccharide storage myopathy in the United
60. Freestone JF, Wolfsheimer KJ, Kamerling SG, et al. Exercise Kingdom. Vet Rec. 2003;152:109–112.
induced hormonal and metabolic changes in Thoroughbred 82. McGowan CM, McGowan TW, Patterson-Kane JC. Prevalence
horses: effects of conditioning and acepromazine. Equine Vet J. of equine polysaccharide storage myopathy and other myopa-
1991;23:219–223. thies in two equine populations in the United Kingdom. Vet J.
61. Edwards JG, Newtont JR, Ramzan PH, et al. The efficacy of dan- 2009;180:330–336.
trolene sodium in controlling exertional rhabdomyolysis in the 83. Tryon RC, Penedo MC, McCue ME, et al. Evaluation of allele
Thoroughbred racehorse. Equine Vet J. 2003;35:707–711. frequencies of inherited disease genes in subgroups of American
62. Beech J, Fletcher JE, Lizzo F, et al. Effect of phenytoin on the Quarter Horses. J Am Vet Med Assoc. 2009;234:120–125.
clinical signs and in vitro muscle twitch characteristics in horses 84. McCue ME, Ribeiro WP, Valberg SJ. Prevalence of polysaccha-
with chronic intermittent rhabdomyolysis and myotonia. Am J ride storage myopathy in horses with neuromuscular disorders.
Vet Res. 1988;49:2130–2133. Equine Vet J Suppl. 2006:340–344.
63. Beech J. Treating and preventing chronic intermittent rhabdo- 85. Johlig L, Valberg SJ, Mickelson JR, et al. Epidemiological and
myolysis. Vet Med. 1994;May:458–461. 41. genetic study of exertional rhabdomyolysis in a Warmblood
64. Vischer CM, Foreman JH, Constable PD, et al. Hemodynamic horse family in Switzerland. Equine Vet J. 2011;43:240–245.
effects of thyroidectomy in sedentary horses. Am J Vet Res. 86. Firshman AM, Valberg SJ, Bender JB, et al. Epidemiologic char-
1999;60:14–21. acteristics and management of polysaccharide storage myopathy
65. Waldron-Mease E. Hypothyroidism and myopathy in racing in Quarter Horses. Am J Vet Res. 2003;64:1319–1327.
Thoroughbreds and Standardbreds. J Equine Vet Sci. 1979;3: 87. Firshman AM, Baird JD, Valberg SJ. Prevalences and clinical
124–128. signs of polysaccharide storage myopathy and shivers in Belgian
66. Tiidus PM. Manual massage and recovery of muscle function draft horses. J Am Vet Med Assoc. 2005;227:1958–1964.
following exercise: a literature review. J Orthop Sports Phys Ther. 88. Ribeiro WP, Valberg SJ, Pagan JD, et al. The effect of varying
1997;25:107–112. dietary starch and fat content on serum creatine kinase activ-
67. Aleman M, Riehl J, Aldridge BM, et al. Association of a mutation ity and substrate availability in equine polysaccharide storage
in the ryanodine receptor 1 gene with equine malignant hyper- myopathy. J Vet Intern Med. 2004;18:887–894.
thermia. Muscle Nerve. 2004;30:356–365. 89. Byrne E, Jones SL, Valberg SJ, et al. Rhabdomyolysis in two foals
68. Aleman M, Nieto JE, Magdesian KG. Malignant hyperthermia with polysaccharide storage myopathy and concurrent pneu-
associated with ryanodine receptor 1 (C7360G) mutation in monia. Comp Cont Educ Pract Vet. 2000;22:503–507.
Quarter Horses. J Vet Intern Med. 2009;23:329–334. 90. De La Corte FD, Valberg SJ, MacLeay JM, et al. Developmental
69. Mickelson JR, Louis CF. Malignant hyperthermia: excitation- onset of polysaccharide storage myopathy in 4 Quarter Horse
contraction coupling, Ca2+ release channel, and cell Ca2+ regula foals. J Vet Intern Med. 2002;16:581–587.
tion defects. Physiol Rev. 1996;76:537–592. 91. Sprayberry KA, Madigan J, Lecouteur RA, et al. Renal failure,
70. Aleman M, Brosnan RJ, Williams DC, et al. Malignant hyper- laminitis, and colitis following severe rhabdomyolysis in a draft
thermia in a horse anesthetized with halothane. J Vet Intern horse-cross with polysaccharide storage myopathy. Can Vet J.
Med. 2005;19:363–366. 1998;39:500–503.
92. Valberg SJ, MacLeay JM, Mickelson JR. Polysaccharide storage 113. Maylin GA, Rubin DS, Lein DH. Selenium and vitamin E in
myopathy associated with exertional rhabdomyolysis in horses. horses. Cornell Vet. 1980;70:272–289.
Comp Cont Educ Pract Vet. 1997;19(9):1077–1086. 114. Roneus B, Jonsson L. Muscular dystrophy in foals. Zentralbl
93. Valberg SJ. Milne Lecture: Muscling in on the cause of tying-up. Veterinarmed A. 1984;31:441–453.
Proceedings American Assoc Equine Pract. 2012;58:85–123. 115. Roneus B, Lindholm A. Glutathione peroxidase activity in the
94. Rosie J. Naylor, RJ, Livesey L, Schumacher J, et al., Allele copy blood of healthy horses given different selenium supplementa-
number and underlying pathology are associated with sub- tion. Nord Vet Med. 1983;35:337–345.
clinical severity in equine type 1 polysaccharide storage myo- 116. Roneus B. Glutathione peroxidase and selenium in the blood of
pathy (PSSM1) PLoS One. 2012; 7(7): e42317. healthy horses and foals affected by muscular dystrophy. Nord
95. Bloom BA, Valentine BA, Gleed RD, et al. Postanaesthetic re- Vet Med. 1982;34:350–353.
cumbency in a Belgian filly with polysaccharide storage myopa- 117. Koller LD, Whitbeck GA, South PJ. Transplacental transfer and
thy. Vet Rec. 1999;144:73–75. colostral concentrations of selenium in beef cattle. Am J Vet Res.
96. Naylor RJ, Luis-Fuentes V, Livesey L, et al. Evaluation of cardiac 1984;45:2507–2510.
phenotype in horses with type 1 polysaccharide storage myopa- 118. Maas J, Peauroi JR, Tonjes T, et al. Intramuscular selenium
thy. J Vet Intern Med. 2012;26:1464–1469. administration in selenium-deficient cattle. J Vet Intern Med.
97. Raben N, Danon M, Lu N, et al. Surprises of genetic engineer- 1993;7:342–348.
ing: a possible model of polyglucosan body disease. Neurology. 119. Aharonson-Raz K, Milgram J, Chai O, et al. Fibrosis of the
2001;56:1739–1745. masseter leading to trismus and dysphagia in a mare. Vet Rec.
98. Borgia LA, Valberg SJ, McCue ME, et al. Effect of dietary fats 2009;164:597–598.
with odd or even numbers of carbon atoms on metabolic re- 120. Pearson EG, Snyder SP, Saulez MN. Masseter myodegenera-
sponse and muscle damage with exercise in Quarter Horse– tion as a cause of trismus or dysphagia in adult horses. Vet Rec.
type horses with type 1 polysaccharide storage myopathy. Am J 2005;156:642–646.
Vet Res. 2010;71:326–336. 121. Step DL, Divers TJ, Cooper B, et al. Severe masseter myonecro-
99. Annandale EJ, Valberg SJ, Essen Gustavsson B. The effect of sis in a horse. J Am Vet Med Assoc. 1991;198:117–119.
submaximal exercise on adenine nucleotide concentrations in 122. Divers TJ, Mohammed HO, Cummings JF, et al. Equine mo-
skeletal muscle fibers of horses with polysaccharide storage. tor neuron disease: findings in 28 horses and proposal of a
Myopathy Am J Vet Res. 2005;66:839–845. pathophysiological mechanism for the disease. Equine Vet J.
100. Hardie DG, Schaffer BE, Brunet A. AMPK: an energy-sensing 1994;26:409–415.
pathway with multiple inputs and outputs. Trends Cell Biol. 123. Harris PA. An outbreak of the equine rhabdomyolysis syn-
2016;26:190–201. drome in a racing yard. Vet Rec. 1990;127:468–470.
101. Hardie DG. AMP-activated protein kinase: a key system me- 124. Freestone JF, Carlson GR. Muscle disorders in the horse: a ret-
diating metabolic responses to exercise. Med Sci Sports Exerc. rospective study. Equine Vet J. 1991;23:86–90.
2004;36:28–34. 125. Traub-Dargatz JL, Schlipf Jr JW, Granstrom DE, et al. Multifo-
102. Smith AC, Bruce CR, Dyck DJ. AMP kinase activation with AI- cal myositis associated with Sarcocystis sp in a horse. J Am Vet
CAR simultaneously increases fatty acid and glucose oxidation Med Assoc. 1994;205:1574–1576.
in resting rat soleus muscle. J Physiol. 2005;565:537–546. 126. Fayer R, Dubey JP. Development of Sarcocystis fayeri in the
103. Valberg SJ, McCue ME, Mickelson JR. The interplay of genet- equine. J Parasitol. 1982;68:856–860.
ics, exercise and nutrition in polysaccharide storage myopathy. 127. Vengust M, Arroyo LG, Weese JS, et al. Preliminary evidence
Equine Vet Sci. 2011;31:5. for dormant clostridial spores in equine skeletal muscle. Equine
104. Aleman M, Lecouteur RA, Nieto JE, et al. Sarcoplasmic masses in Vet J. 2003;35:514–516.
equine skeletal muscle. Neuromuscul Disord. 2005;15:147–153. 128. Rebhun WC, Shin SJ, King JM, et al. Malignant edema in
105. Firshman AM, Valberg SJ, Bender JB, et al. Comparison of his- horses. J Am Vet Med Assoc. 1985;187:732–736.
topathologic criteria and skeletal muscle fixation techniques for 129. Peek SF, Semrad SD, Perkins GA. Clostridial myonecrosis in
the diagnosis of polysaccharide storage myopathy in horses. Vet horses (37 cases 1985–2000). Equine Vet J. 2003;35:86–92.
Pathol. 2006;43:257–269. 130. Hilton H, Madigan JE, Aleman M. Rhabdomyolysis associated
106. Borgia L, Valberg S, McCue M, et al. Glycaemic and insuli- with Anaplasma phagocytophilum infection in a horse. J Vet In-
naemic responses to feeding hay with different non-structural tern Med. 2008;22:1061–1064.
carbohydrate content in control and polysaccharide storage 131. Sponseller BT, Valberg SJ, Tennent-Brown BS, et al. Severe
myopathy-affected horses. J Anim Physiol Anim Nutr (Berl). acute rhabdomyolysis associated with Streptococcus equi in-
2011;95:798–807. fection in four horses. J Am Vet Med Assoc. 2005;227:1800–
107. Valberg SJ, McKenzie EC, Eyrich LV, et al. Suspected myofi- 1804.
brillar myopathy in Arabian horses with a history of exertional 132. Valberg SJ, Bullock P, Hogetvedt W, et al. Myopathies associ-
rhabdomyolysis. Equine Vet J. 2016;48(5):548–56. ated with Streptococcus equi infections in horses. Proceedings
108. Valberg SJ, Carlson GP, Cardinet III GH, et al. Skeletal muscle Am Assoc Equine Pract. 1996;42:292–293.
mitochondrial myopathy as a cause of exercise intolerance in a 133. Sweeney CR, Timoney JF, Newton JR, et al. Streptococcus equi
horse. Muscle Nerve. 1994;17:305–312. infections in horses: guidelines for treatment, control, and pre-
109. Ward TL, Valberg SJ, Adelson DL, et al. Glycogen branching en- vention of strangles. J Vet Intern Med. 2005;19:123–134.
zyme (GBE1) mutation causing equine glycogen storage disease 134. Al-Ghamdi GM, Kapur V, Ames TR, et al. Use of repetitive
IV. Mamm Genome. 2004;15:570–577. sequence-based polymerase chain reaction for molecular epi-
110. Wagner ML, Valberg SJ, Ames EG, et al. Allele frequency and demiologic analysis of Streptococcus equi subspecies equi. Am J
likely impact of the glycogen branching enzyme deficiency gene Vet Res. 2000;61:699–705.
in Quarter Horse and Paint Horse populations. J Vet Intern Med. 135. Adams EM, Gudmundsson S, Yocum DE, et al. Streptococcal
2006;20:1207–1211. myositis. Arch Intern Med. 1985;145:1020–1023.
111. Valberg SJ, Ward TL, Rush B, et al. Glycogen branching en- 136. Kaese HJ, Valberg SJ, Hayden DW, et al. Infarctive pur-
zyme deficiency in Quarter Horse foals. J Vet Intern Med. pura hemorrhagica in five horses. J Am Vet Med Assoc.
2001;15:572–580. 2005;226(11):1893–8, 1845.
112. Dill SG, Rebhun WC. White muscle disease in foals. Comp Cont 137. Pusterla N, Watson JL, Affolter VK, et al. Purpura haemorrhag-
Educ Pract Vet. 1985;7:S627–S636. ica in 53 horses. Vet Rec. 2003;153:118–121.
138. Galan JE, Timoney JF. Immune complexes in purpura hemor- 160. Gomez DE, Valberg SJ, Magdesian KG, et al. Acquired multi-
rhagica of the horse contain IgA and M antigen of Streptococcus ple acyl-CoA dehydrogenase deficiency and marked selenium
equi. J Immunol. 1985;135:3134–3137. deficiency causing severe rhabdomyolysis in a horse. Can Vet J.
139. Kaese HJ, Valberg SJ, Hayden DW, et al: Infarctive purpura hem- 2015;56:1166–1171.
orrhagica in five horses. J Am Vet Med Assoc. 2005;226:1845, 161. van Galen G, Cerri S, Porter S, et al. Traditional and quantita-
1893–1898. tive assessment of acid-base and shock variables in horses with
140. Tan JY, Valberg SJ, Sebastian MM, et al. Suspected systemic cal- atypical myopathy. J Vet Intern Med. 2013;27(1):186–93.
cinosis and calciphylaxis in 5 horses. Can Vet J. 2010;51:993– 162. Grandy JL, Steffey EP, Hodgson DS, et al. Arterial hypotension
999. and the development of postanesthetic myopathy in halothane-
141. Fales-Williams A, Sponseller B, Flaherty H. Idiopathic arterial anesthetized horses. Am J Vet Res. 1987;48:192–197.
medial calcification of the thoracic arteries in an adult horse. J 163. Duke T, Filzek U, Read MR, et al. Clinical observations surround-
Vet Diagn Invest. 2008;20:692–697. ing an increased incidence of postanesthetic myopathy in halo-
142. Carter T, Ratnam S. Calciphylaxis: a devastating complication thane-anesthetized horses. Vet Anaesth Analg. 2006;33:122–127.
of derangements of calcium-phosphorus metabolism—a case 164. White NAI. Postanesthetic recumbency myopathy in horses.
report and review of the literature. Nephrol Nurs J. 2013;40:431– Compend Cont Educ. 1982;4:544–550.
435; quiz 436. 165. Hennig GE, Court MH. Equine postanesthetic myopathy: an
143. Llach F. Hyperphosphatemia in end-stage renal disease pa- update. Compend Cont Educ. 1991;13:1709–1715.
tients: pathophysiological consequences. Kidney Int Suppl. 166. Norman WM, Williams R, Dodman NH, et al. Postanesthet-
1999;73:S31–37. ic compartmental syndrome in a horse. J Am Vet Med Assoc.
144. Barrott MJB, H.W, McGowan C.M. Suspected immune-mediat- 1989;195:502–504.
ed myositis in a pony. Equine Vet Educ. 2004;16:4. 167. Klein L, Ailes N, Fackelman GE, et al. Postanesthetic equine
145. Myers CJ, Aleman M, Heidmann R, et al. Myopathy in Ameri- myopathy suggestive of malignant hyperthermia. A case report.
can miniature horses. Equine Vet J. 2006;38:272–276. Vet Surg. 1989;18:479–482.
146. Helman RG, Edwards WC. Clinical features of blister beetle 168. Valverde A, Boyd CJ, Dyson DH, et al. Prophylactic use of dan
poisoning in equids: 70 cases (1983–1996). J Am Vet Med Assoc. trolene associated with prolonged postanesthetic recumbency
1997;211:1018–1021. in a horse. J Am Vet Med Assoc. 1990;197:1051–1053.
147. Putnam MR, Boosinger T, Spano J, et al. Evaluation of Cassia 169. Hildebrand SV, Howitt GA. Succinylcholine infusion associ-
obtusifolia (sicklepod) seed consumption in Holstein calves. Vet ated with hyperthermia in ponies anesthetized with halothane.
Hum Toxicol. 1988;30:316–318. Am J Vet Res. 1983;44:2280–2284.
148. Beier RC, Norman JO, Irvin TR, et al. Microsomal activation of 170. Manley SV, Kelly AB, Hodgson D. Malignant hyperthermia-like
constituents of white snakeroot (Eupatorium rugosum Houtt) to reactions in three anesthetized horses. J Am Vet Med Assoc.
form toxic products. Am J Vet Res. 1987;48:583–585. 1983;183:85–89.
149. Beier RC, Norman JO. The toxic factor in white snakeroot: identity, 171. Lehmann-Horn F, Jurkat-Rott K, Rudel R. Periodic paralysis:
analysis and prevention. Vet Hum Toxicol. 1990;32(suppl):81–88. understanding channelopathies. Curr Neurol Neurosci Rep.
150. Thompson LJ. Depression and choke in a horse: probable white 2002;2:61–69.
snakeroot toxicosis. Vet Hum Toxicol. 1989;31:321–322. 172. Lehmann-Horn F, Jurkat-Rott K. Voltage-gated ion channels
151. Valberg SJ, Sponseller BT, Hegeman AD, et al. Seasonal pasture and hereditary disease. Physiol Rev. 1999;79:1317–1372.
myopathy/atypical myopathy in North America associated with 173. Bryant SH, Lipicky RJ, Herzog WH. Variability of myotonic
ingestion of hypoglycin A within seeds of the box elder tree. signs in myotonic goats. Am J Vet Res. 1968;29:2371–2381.
Equine Vet J. 2013;45:419–426. 174. Schooley EK, MacLeay JM, Cuddon P, et al. Myotonia congenita
152. Unger L, Nicholson A, Jewitt EM, et al. Hypoglycin A concen- in a foal. J Equine Vet Science. 2004;24:483–488.
trations in seeds of Acer pseudoplatanus trees growing on atypi- 175. Jamison JM, Baird JD, Smith-Maxie LL, et al. A congenital
cal myopathy-affected and control pastures. J Vet Intern Med. form of myotonia with dystrophic changes in a Quarter Horse.
2014;28:1289–1293. Equine Vet J. 1987;19:353–358.
153. Sponseller BT, Valberg SJ, Schultz NE, et al. Equine multiple 176. Wijnberg ID, Owczarek-Lipska M, Sacchetto R, et al. A mis-
acyl-CoA dehydrogenase deficiency (MADD) associated with sense mutation in the skeletal muscle chloride channel 1
seasonal pasture myopathy in the midwestern United States. J (CLCN1) as candidate causal mutation for congenital myotonia
Vet Intern Med. 2012;26:1012–1018. in a New Forest pony. Neuromuscul Disord. 2012;22:361–367.
154. Votion D-M, van Galen G, Sweetman L, et al. Identification of 177. Montagna P, Liguori R, Monari L, et al. Equine muscular dys-
methylenecyclopropyl acetic acid in serum of European horses trophy with myotonia. Clin Neurophysiol. 2001;112:294–299.
with atypical myopathy. Equine Vet J. 2014;46:146–149. 178. Reed SM, Hegreberg GA, Bayly WM, et al. Progressive myoto-
155. Whitwell KE, Harris P, Farrington PG. Atypical myoglobinuria: nia in foals resembling human dystrophia myotonica. Muscle
an acute myopathy in grazing horses. Equine Vet J. 1988;20:357– Nerve. 1988;11:291–296.
363. 179. Hegreberg GA, Reed SM. Skeletal muscle changes associ-
156. Cassart D, Baise E, Cherel Y, et al. Morphological alterations in ated with equine myotonic dystrophy. Acta Neuropathol (Berl).
oxidative muscles and mitochondrial structure associated with 1990;80:426–431.
equine atypical myopathy. Equine Vet J. 2007;39:26–32. 180. Madigan JE, Valberg SJ, Ragle C, et al. Muscle spasms associated
157. Gerber V, Straub R, Frey J. Equine botulism and acute pasture with ear tick (Otobius megnini) infestations in five horses. J Am
myodystrophy: new soil-borne emerging diseases in Switzer- Vet Med Assoc. 1995;207:74–76.
land? Schweiz Arch Tierheilkd. 2006;148:553–559. 181. Meyer TS, Fedde MR, Cox JH, et al. Hyperkalaemic periodic
158. van Galen G, Marcillaud PC, Saegerman C, et al. European paralysis in horses: a review. Equine Vet J. 1999;31:362–367.
outbreaks of atypical myopathy in grazing equids (2006–2009): 182. Naylor JM. Equine hyperkalemic periodic paralysis: review and
spatiotemporal distribution, history and clinical features. implications. Can Vet J. 1994;35:279–285.
Equine Vet J. 2012;44:614–620. 183. Spier SJ, Carlson GP, Holliday TA, et al. Hyperkalemic periodic
159. van Galen G, Saegerman C, Marcillaud PC, et al. European out- paralysis in horses. J Am Vet Med Assoc. 1990;197:1009–1017.
breaks of atypical myopathy in grazing horses (2006–2009): de- 184. Rudolph JA, Spier SJ, Byrns G, et al. Linkage of hyperkalaemic
termination of indicators for risk and prognostic factors. Equine periodic paralysis in quarter horses to the horse adult skeletal
Vet J. 2012;44:621–625. muscle sodium channel gene. Anim Genet. 1992;23:241–250.
185. Cox JH. An episodic weakness in four horses associated with 192. DS (1) Pang, Panizzi L, Paterson JM. Successful treatment of
intermittent serum hyperkalemia and the similarity of the dis- hyperkalaemic periodic paralysis in a horse during isoflurane
ease to hyperkalemic periodic paralysis in man. Proc Am Assoc anaesthesia. Vet Anaesth Analg. 2011;38(2):113–120.
Equine Practitioners. 1985;21:383–391. 193. Sieb JP, Penn AS. Myoglobinuria. In: Engel AG, Franzini-Arm-
186. Carr EA, Spier SJ, Kortz GD, et al. Laryngeal and pharyngeal strong C, eds. Myology. 3rd ed.Vol. New York: McGraw-Hill;
dysfunction in horses homozygous for hyperkalemic periodic 2004:1677–1692.
paralysis. J Am Vet Med Assoc. 1996;209:798–803. 194. Layzer RB. Muscle pain, cramps and fatigue. In: Engel AG,
187. Reynolds AJ. Equine hyperkalemic periodic paralysis (HYPP): Franzini-Armstrong C, eds. Myology. 2nd ed. Vol. New York:
overview and management strategies. http://www.admani.com McGraw-Hill; 1994:1754–1768.
/AllianceEquine/TechBulletins/HYPP.htm. Accessed February 195. Baird JD. Lactation tetany (eclampsia) in a Shetland pony mare.
2017. Aust Vet J. 1971;47:402–404.
188. Reynolds JA, Potter GD, Greene LW. Genetic-diet interactions 196. Beyer MJ, Freestone JF, Reimer JM, et al. Idiopathic hypocalcemia
in the hyperkalemic periodic paralysis syndrome in Quarter in foals. J Vet Intern Med. 1997;11:356–360.
Horses fed varying amounts of potassium: III. The relationship 197. Wijnberg ID, van der Kolk JH, Franssen H, et al. Electro-
between plasma potassium concentration and HYPP symp- myographic changes of motor unit activity in horses with in-
toms. J Equine Vet Sci. 1998;18:731–735. duced hypocalcemia and hypomagnesemia. Am J Vet Res.
189. Naylor JM. Hyperkalemic periodic paralysis. Vet Clin North Am 2002;63:849–856.
Equine Pract. 1997;13:129–144. 198. Mansmann RA, Carlson GP, White NA, et al. Synchronous dia-
190. Ott EA. National Research Council: Nutrient Requirements of phragmatic flutter in horses. J Am Vet Med Assoc. 1974;165:265–
Horses, 2007. Washington, DC: National Academies Press; 270.
1989. 199. Carlson GP. Synchronous diaphragmatic flutter. In: Robinson NE,
191. Zhou J, Spier SJ, Beech J, et al. Pathophysiology of sodium chan- ed. Current therapy in equine medicine. 2nd ed. Philadelphia: WB
nelopathies: correlation of normal/mutant mRNA ratios with Saunders; 1987:485–486.
clinical phenotype in dominantly inherited periodic paralysis. 200. Hudson NP, Church DB, Trevena J, et al. Primary hypoparathy-
Hum Mol Genet. 1994;3:1599–1603. roidism in two horses. Aust Vet J. 1999;77:504–508.
C HA P T E R 11
Disorders of the Neurologic System
Monica Aleman, Yvette S. Nout-Lomas, and Stephen M. Reed*
Y NEUROLOGIC EXAMINATION this is not possible, one should consider the possibility of mul-
tifocal disease or multiple diseases. In addition to anatomic
Assessment of the central nervous system (CNS) in horses localization of a lesion, it is important to record the findings of
may seem a difficult task; however, with careful examination the examination as a baseline for comparison of future evalua-
using a craniocaudal approach, assessment is not difficult. A tions. After anatomic localization, one must decide what addi-
craniocaudal approach is the most logical and efficient. The tional testing is necessary to determine the underlying cause
goal of the examination is to determine the neuroanatomic of the clinical signs. Ancillary imaging, cerebrospinal fluid
localization of the lesion or lesions and should be completed (CSF) analysis, and electrodiagnostic testing may be useful in
as part of the physical examination. Subtle neurologic defi- locating and determining the cause of the lesions.
cits may be hidden by musculoskeletal disease or missed The neurologic examination should be considered part
because of lack of knowledge or understanding of these dis- of the physical examination. The author prefers to begin the
orders. To accomplish a complete and accurate neurologic examination at the head and proceed caudally to the tail. The
examination, the veterinarian must feel comfortable with the examiner should proceed in a consistent fashion and should
format chosen for evaluating the nervous system and must record findings in an orderly manner to avoid any part of
have knowledge of which musculoskeletal disorders com- the examination being omitted. Fig. 11.1 shows a sample for-
monly are associated with neurologic disease. Problems such mat. One may use the craniocaudal approach for all animals,
as osteochondrosis of the stifle, hock, and shoulder joints whether ambulatory or recumbent.
often occur concurrently in horses with cervical vertebral The equine neurologic examination procedure has been
stenotic myelopathy. described in detail elsewhere.1-4 The author follows the for-
Examples of typical histories in horses presented for neuro- mat developed by Mayhew,4 which divides the examination
logic examination, especially for signs of spinal ataxia, include into five categories: (1) the head and mental status, (2) gait
previous medial patellar desmotomy, bilateral bog spavin in and posture, (3) neck and forelimbs, (4) trunk and hindlimbs,
early life, osteochondrosis of the distal tibia or femur, and con- and (5) tail and anus. The functional divisions of the nervous
tracted tendons. All of these problems associated with devel- system include the sensory, integration, and motor systems.
opmental orthopedic diseases are examples of conditions that Before starting the examination, the age, gender, breed, and
may occur simultaneously. Bilateral bog spavin often is asso- use of the horse should be determined, although these are not
ciated with osteochondrosis of the distal tibia or other sites essential. The owner should be questioned about any unusual
in the tibiotarsal joint. Patellar desmotomy to correct upward behavior the horse has exhibited and the date of onset of the
fixation of the patella may be necessary because of a confor- behavior. Age is helpful because problems such as cervical ver-
mational problem of the stifle joint or as a result of abnormal tebral stenotic myelopathy and cerebellar abiotrophy begin at
joint proprioception or quadriceps weakness after neurologic a young age, usually less than 1 year. These problems occur
disease. The foregoing problem is more commonly associated more often in certain breeds. For example, cervical vertebral
with neurologic disease than many veterinarians realize, and stenotic myelopathy is most common in Thoroughbreds, and
the gait deficits caused by these lamenesses often mimic neu- cerebellar abiotrophy most often is observed in Arabians.
rologic disease. Horses with bilateral osteochondritis disse-
cans (OCD) lesions of the stifle joints will often “bunny-hop” Examination
while running, which may be interpreted as a sign of neuro- The evaluation of the head should include observation of the
logic disease rather than as a result of an underlying musculo- horse at rest and during motion; palpation, postural reactions,
skeletal disease. cranial nerve function, and cervicofacial reflexes; and evalu-
The goals of a neurologic examination are to establish ation of sensation. At the start of the examination the horse
whether a neurologic problem is present and to determine the should be observed for alertness, mentation, attitude, and
anatomic localization of the problem. Being able to account behavior (remembering that the animal’s environment may
for all clinical signs with a single lesion is ideal; however, if influence its degree of excitement). Evaluation of the head
*The editors and authors acknowledge and appreciate the contributions of Frank M. Andrews, Veronique A. Lacombe, Bonnie R. Rush, Barbara A. Byrne, Caroline N.
Hahn, Martin Furr, W. David Wilson, Nicola Pusterla, William J. Saville, Joseph Bertone, Maureen T. Long, Cartla S. Sommerdahl, Peter R. Morresey, Ramiro E. Toribio,
Robert H. Mealey, and Eduard Jose-Cunillerasas previous contributors to this chapter. Some of their original work has been incorporated into this edition.
580
CHAPTER 11 Disorders of the Neurologic System 581 581
includes observation of the behavior and mental status of the alert and responds appropriately to external stimuli. While the
horse. This portion of the examination can be completed by horse is being caught, the examiner can look for unusual behav-
careful observation even before handling the horse. A close and iors such as yawning, abnormal or aimless wandering, seizures,
careful examination is necessary to evaluate the head and neck or circling or head tilt and can begin to assess the vision and
posture and coordination and to identify abnormalities of the hearing of the horse. This is also a good time to observe how
cranial nerves. Initial consideration includes the environmen- the horse is standing and whether it has the limbs positioned
tal awareness of the horse. A normal horse appears bright and appropriately under its body. The veterinarian should note any
FIG. 11.1 Example of a neurologic examination form. PLR, Pupillary light response.
Continued
FIG. 11.1, cont’d
behavioral abnormalities, such as head pressing (a clear sign large circles may have an asymmetric forebrain lesion. Horses
of cerebral disease) and aggressiveness (noted in animals that that have a serious systemic illness also may appear depressed
are not feeling well, as well as animals with CNS disease). If the or stuporous. The level of consciousness is recorded as alert,
examiner suspects rabies, precautions should be taken to avoid depressed, stuporous, or comatose. An animal that is depressed
unnecessary and potentially dangerous exposure. may react to its environment in an inappropriate or unrespon-
Lesions of the reticular activating system or the cerebral sive fashion. Stuporous horses may appear to be asleep unless
hemispheres could result in coma or obtundation of con- stimulated with pain, light, or noise and often demonstrate
sciousness. Horses demonstrating compulsive walking may impaired reactivity. Comatose animals are completely unre-
have a diffuse cerebral disease, whereas a horse walking in sponsive and cannot be aroused.
Head posture and coordination are controlled by the cerebel- elsewhere.6,7 If a horse has a lesion of the eye or optic nerve,
lar and vestibular regions of the brain and brainstem in response the lesion will result in complete or partial ipsilateral blind-
to sensory input from receptors in the head, neck, limbs, and ness. To develop contralateral blindness, the horse would have
trunk. Examining the head and neck posture with the horse at to have a lesion in the optic tract or the lateral geniculate
rest, while eating, and while moving is helpful. In horses with nucleus. Pupil size and symmetry are under control of the
normal head carriage, the head should be held straight and autonomic nervous system and are affected by environmental
upright when viewed from the front. Careful examination of light and level of fear or excitement. To test the pupillary
the vestibular region is important because many horses develop response, one should direct a light in each eye and note the
a head tilt resulting from head trauma, temporohyoid osteo- constriction of the pupil. Identifying a consensual response in
arthropathy (THO), or guttural pouch disease. A head tilt is the horse is often difficult when one works alone. A swinging
characterized by the poll deviated about the muzzle and must light test has been described. In the performance of this test,
be distinguished from abnormal or unusual turning of the head the light is shone alternately into each eye, and the more pow-
or lateral deviation of the head as may occur with damage to the erful direct pupillary light response is observed. A unilateral
forebrain or injury to the cervical vertebrae. Additional signs lesion affecting the afferent tracts in the eye, optic nerve, optic
that may accompany vestibular disease or injury include nystag- chiasm, or optic tract to the level of the midbrain will result in
mus, ipsilateral weakness, and facial nerve paralysis. ipsilateral dilation when the light reaches the affected eye.
Postural abnormalities of the head and neck sometimes can Moving the light from side to side takes advantage of the ipsi-
be difficult to distinguish from head tilt. Horses with torticollis lateral light response being stronger than the consensual
of the head and neck may have a congenital abnormality of the response. The examiner can perform this procedure alone.
vertebrae or may have injured the muscles of the neck region. These reflexes are in the brainstem and are not affected by
Damage to the dorsal gray columns can result in abnormal head lesions in the visual cortex.
and neck posture (acquired scoliosis) that has been described as One possible cause of asymmetric pupils in a horse is
a result of parasitic migration such as Paralaphostrongylus Horner syndrome. Horner syndrome is the collection of clini-
tenuis.5 Careful examination, including palpation, should help cal signs associated with dysfunction of the sympathetic nerve
identify fractures of the cervical vertebrae or painful muscles supply to the head and neck. The sympathetic nerve supply to
caused by trauma or an injection reaction. Neck pain may man- the head includes upper motor neurons in the caudal hypo-
ifest as a reluctance to move the head and neck through a full thalamus, parts of the midbrain and pons, and parts of the
range of motion. In the absence of pain or mechanical limita- medulla oblongata. Axons from these centers descend in the
tions to movement, normal horses should be able to turn their cervical spinal cord to the preganglionic neurons in the cra-
head to retrieve feed offered at the lateral thorax on each side, nial thoracic spinal cord. From here, preganglionic axons leave
elevated to a level above the withers, or lowered to a point the cord and join the paravertebral sympathetic trunk, where
between the front legs just beneath the pectoral muscles. In they ascend up the neck to synapse in the cranial cervical gan-
some horses, radiographs of the cervical vertebrae may be use- glion in the guttural pouch. This syndrome includes ptosis of
ful to confirm a fracture or osteomyelitis. Blindness sometimes the upper eyelid, miosis of the pupil, and protrusion of the
can lead to an abnormal head or neck posture. third eyelid (nictitating membrane). In addition, the horse has
The cerebellum helps regulate rate and range of motion. unilateral facial sweating, increased facial temperature, and
With damage to this area a horse often shows fine resting hyperemia of the nasal and conjunctival membranes. These
tremors of the head that worsen with intentional movements. signs should alert the examiner to the possibility of a previ-
One may normally observe this tremorous movement of the ous perivascular injection, guttural pouch disease, or dam-
head and neck in the newborn or young foal, but it is not nor- age to the sympathetic nerves in the vagosympathetic trunk,
mal in older foals and adult horses. In young Arabians and a which courses from the cranial thoracic spinal cord through
few other breeds, a condition of cerebellar abiotrophy has been the thoracic inlet and upward to the orbit. Loss of sympa-
reported. Horses with this condition show a hypermetric gait, thetic innervation to the head results in the triad of clinical
failure to blink when exposed to bright light, and absence of a signs described, with the most prominent initial sign being
menace response. increased sweating caused by disruption of sympathetic fibers
After evaluating the alertness, mental attitude, head and to the blood vessels and sweat glands of the head and neck.
neck posture, and coordination of the horse, the examiner This results in cutaneous vasodilation with subsequent more
should examine the face and cranial nerves closely. Systematic local circulating adrenaline.
examination of the first to twelfth cranial nerves helps to Loss of symmetric positioning of the eyes or the presence
ensure that a subtle lesion along the brainstem is less likely to of abnormal deviation (i.e., strabismus) occurs when a horse
be missed, although in fact the examiner assesses many of the has injured the third (oculomotor), fourth (trochlear), or
cranial nerves simultaneously on approach to the horse. The sixth (abducens) cranial nerve or the connections between the
examiner evaluates facial symmetry, facial sensation (includ- eighth (vestibulocochlear) cranial nerve and these nuclei in
ing sensation inside the nares), head posture, eyes, nose, the brainstem along the medial longitudinal fasciculus. Devia-
mouth, jaw tone, pharynx, and larynx. To determine whether tions of the eyes may occur with head trauma or midbrain
an animal can detect scent is usually not as important, but lesions or can be normal variations in newborn foals. When
determining whether it can see, hear, breathe, and swallow is the head is elevated dorsally, the eyes should move ventrally to
critical. maintain a normal horizontal gaze. When the head is moved
Examination of the eyes should include evaluation of the from side to side, the eyes should move slowly opposite to the
blink or menace response, the ability of the horse to negotiate direction of the head movement, move quickly in the direction
in a strange environment, pupillary light response, and in of the head movement; this is referred to as normal vestibu-
some cases a funduscopic examination. Excellent descriptions lar nystagmus. Spontaneous or positional nystagmus is always
of the equine neuroophthalmic examination are available abnormal.
The nuclei along the fifth (trigeminal) cranial nerve are sweating in a horse indicates involvement of the peripheral
among the largest nuclei along the brainstem of the horse. The preganglionic or postganglionic sympathetic neurons. Identi-
fifth cranial nerve contains motor and sensory branches that fication of this problem also can aid in the anatomic localiza-
supply innervation to the muscles of mastication and sensation of a neurologic lesion.
tion to the skin and mucous membranes of the head. Injury Intact innervation to the larynx and pharynx is important,
to this nerve leads to dropped jaw and ipsilateral loss of, or especially if the horse is to be used as an athlete. The easiest
decreased sensation to, the side of the face and the inside of means to evaluate this region is by endoscopic examination
the nares. of the pharyngeal and laryngeal regions. One can perform
Damage to the seventh (facial) and eighth cranial nerves is throat latch palpation and a laryngeal adductory slap test.
common in horses. Injury to the seventh cranial nerve results Endoscopic examination is helpful and important to a com-
in unilateral facial paralysis. This nerve contains branches plete evaluation. The innervation of the pharynx and larynx
that supply the ears, eyelids, and nares; therefore injury to is via the ninth, tenth (vagus), and eleventh (accessory) cra-
this nerve may affect all or only part of these structures. The nial nerves and the connections of these nerves in the caudal
most easily recognized sign is deviation of the nares toward medulla oblongata.
the unaffected side coupled with drooping of the eyelid and The twelfth cranial nerve, the hypoglossal nerve, has
ear on the affected side. Because this nerve also innervates the cell bodies in the hypoglossal nucleus of the caudal medulla
salivary and lacrimal glands, loss of or damage to this nerve oblongata and provides motor innervations to the muscle of
may cause dry eye and decreased salivation. the tongue. Normal horses provide a strong resistance to with-
Eighth cranial nerve deficits are easy to recognize, because drawing the tongue from the mouth; horses with unilateral cra-
unilateral injury to this nerve results in a head tilt toward the nial nerve XII dysfunction have unilateral atrophy with weak
affected side. The eighth cranial nerve is important to hear- retraction. Bilateral dysfunction interferes with prehension and
ing and control of balance. Projections from this nerve pass to swallowing, the tongue often protrudes from the mouth, and
the medulla and cerebellum. A horse that has damage to this the horse has difficulty or is unable to withdraw the tongue.
nerve often appears disoriented and has a head tilt toward the Severe cerebral lesions may also interfere with tongue retrac-
side of the lesion along with abnormal position of the limbs tion because of interference with voluntary control pathways.
and body and horizontal nystagmus. If the lesion involves the After careful examination of the mental status and behav-
peripheral portion of the vestibular system, the fast phase of ior of the horse and of the head, neck, and cranial nerves,
the nystagmus is directed away from the side of the lesion. If the examiner should look for asymmetry of the muscles of
the lesion involves the central portion of the vestibular system, the trunk, pelvic region, tail, and anus. Identification of focal
the nystagmus may appear vertical, rotary, or horizontal and sweating, focal muscle atrophy, or increased or decreased pain
may not always appear the same, depending on head position. responses is helpful in localizing signs. In addition, the horse
Horses that have peripheral damage to the vestibular sys- has two cervical reflexes. The cervicofacial reflexes result in a
tem usually compensate for the deficits in a short time by use of local twitch and drawing back of the lips (smile reflex) when
visual and proprioceptive input. Therefore avoiding the use of one pricks the skin along the side of the neck down to the
a blindfold in cases of suspected vestibular disease is judicious. region of the second cervical vertebra. Below the region of the
Using a blindfold hampers the ability of the horse to compensate, second cervical vertebra one should observe a local response.8
and the horse may become dangerous. However, blindfolding a To evaluate the tail and anus, the tail carriage is first
horse with a suspected vestibular disease but no longer showing observed at rest and with the horse in motion. The normal tail
an obvious head tilt may be helpful to localize the lesion. carriage is straight down but with free movement in all direc-
Within the medial compartment of the guttural pouch, tions. Some normal horses allow the tail to be lifted, giving
along the caudodorsal and lateral walls, are the ninth (glos- little resistance, whereas other horses strongly resist and clamp
sopharyngeal) cranial nerve and a branch of the vagus nerve. the tail. The usual response to anal stimulation is to clamp the
When a horse develops guttural pouch disease, these nerves tail and squat down, although with prolonged stimulation the
may be damaged, resulting in loss of innervation to the pha- horse may relax and eventually raise its tail.
ryngeal muscles. The clinical signs include dysphagia on Before evaluation of gait, evaluation of postural reactions
the same side as the damaged nerve. If the disease is severe and possibly evaluation of spinal reflexes should take place.
enough to involve the internal carotid nerve, which contains Spinal reflexes can be evaluated in foals or small horses, as
postganglionic sympathetic fibers to the structures of the head well as in recumbent horses. Evaluation of spinal reflexes can
and eye, Horner syndrome results. As mentioned, the signs be very helpful in lesion localization, although interpreta-
include ptosis of the upper eyelid, enophthalmos resulting in tion of responses is sometimes difficult in adult recumbent
prolapse of the third eyelid, miosis of the pupil, and sweating horses.9 The author nearly always places the feet and limbs
along the side of the face. in an unusual position to observe the response of the horse;
Other diseases one should consider when Horner syndrome however, because postural reactions are sometimes difficult
is evident during a neurologic examination include injury or to interpret in horses, it is essential to use gait evaluation to
infarction to the cranial thoracic spinal cord, avulsion of the help localize a lesion. Additional tests to assess propriocep-
brachial plexus, a hematoma, or tumor invading the sympa- tive function include a standing sway test in which one applies
thetic trunk in the region of the caudal, cervical, or cranial pressure to the shoulder. The horse initially should press into
thoracic sympathetic trunk. Mycosis of the guttural pouch can the examiner and then lean away, and finally it should step
cause damage to the internal carotid nerve or the cranial cervi- away with the offside limb. Also, the examiner might lift one
cal ganglion along the caudodorsal wall of the guttural pouch. thoracic limb and force the horse to hop on the opposite limb
Finally, an injury to or neoplasia of the structures within or in a modified postural reaction test. The important centers for
just behind the orbit also may cause Horner syndrome. Focal posture and coordination in the brainstem and spinal cord are
located in the regions of the sixth cervical to second thoracic alleviate pain and help one distinguish between lameness and
(T2) and fourth lumbar to second sacral (S2) vertebrae in the a neurologic gait deficit.
spinal cord, along with coordination centers in the brainstem. Following a neurologic examination, the examiner must
Horses that demonstrate a wide base stance at rest often have identify the presence of weakness, ataxia, and dysmetria in
a lesion of the cerebellum or vestibular system or may have each limb. One can evaluate the strength and ability of the
conscious proprioceptive abnormalities. horse to correct body positions by performing the sway test
at a walk, in addition to the standing sway test. One applies
Evaluation of Gait lateral pressure at the shoulder, hip, and tail while the horse
Foals are ambulatory within hours after birth, making it pos- is walking. One should apply pressure several times while the
sible to evaluate gait at a young age; however, newborns may horse is walking to catch the limb in various stages of weight
appear weak and ataxic. Gait abnormalities that are observed bearing. The examiner should observe the movements of each
commonly in horses with neurologic disease include ataxia, limb carefully to determine whether a deficit is present and
dysmetria, and weakness or paresis. Evaluation of gait is criti- should assign a grade to the deficit. The author uses a system
cal because subtle neurologic gait deficits often go unrecog- modified from the grades described by de Lahunta and col-
nized or sometimes may incorrectly be considered leagues1 and Mayhew.4 The severity is graded between 0 and
insignificant. 5. Grade 0 means no gait deficits. A grade 1 deficit requires
The horse should be observed at a walk and trot in a careful observation to be certain the gait abnormality is caused
straight line and while turning. At a walk the examiner can by a neurologic dysfunction. Grade 2 deficits are mild to
walk alongside, in step with first the pelvic limbs and then moderate but obvious to most observers as soon as the horse
the thoracic limbs. This allows the examiner to more easily begins to move. Grade 3 deficits are obvious and are exagger-
determine the stride length and foot placement. A weak limb ated during the negotiation of a slope or with head elevation.
often has a low arc and longer stride length. In some horses, Grade 4 gait deficits may cause a horse to fall or nearly fall.
observing the horse negotiate over small obstacles such as a When attempting to walk, an animal with these severe deficits
curb is helpful. It can also be helpful to evaluate the horse on often displays abnormal positioning while standing in its stall.
different surfaces (hard ground vs. arena) at different gaits. Grade 5 horses are recumbent. However, clinicians should be
Blindfolding the horse can also be helpful during a neuro- cautious making decisions about horses based on this sub-
logic evaluation. Observing a horse during the backing pro- jective assessment of gait, especially when signs are subtle.
cess is important. When a normal horse is backing, it should A recent investigation showed only poor to fair agreement
lift each leg and place it in a coordinated and appropriate between skilled and experienced observers of gait abnormali-
location. Horses with neurologic abnormalities often place ties in horses using this scale.10
the limbs in wide-based positions or lean back and are reluc- Weakness or paresis is a deficiency of voluntary move-
tant or refuse to move. The horse also may step on the feet of a ment as a result of loss of muscle power because of either
pelvic limb with the front feet. The horse should be observed damage to upper motor neurons, lower motor neurons, or
closely while being turned in a tight circle to identify abnor- the muscle. It can be described as knuckling, stumbling, or
mal wide outward excursions of the pelvic limb (circumduc- buckling and sometimes can be characterized by toe-drag-
tion). When possible, the examiner should observe the horse ging while walking. Weakness may be associated with an
turned free and walking up and down an incline. Elevation of upper motor neuron or lower motor neuron lesion. In the
the head and walking on a slope may exaggerate a subtle defi- case of a lower motor neuron or peripheral nerve injury or
cit and make it more noticeable. These procedures provide a illness, the horse shows muscle atrophy and sensory loss. A
degree of “challenge” to the horse and may help to demon- spastic movement of the limbs often accompanies the weak-
strate if the horse is showing persistent irregular movements ness that results from loss of upper motor neurons. Ataxia is
with its limbs. In some circumstances horses may need to typified by abnormal foot placement and wide swaying of the
be evaluated under saddle or in tack. Although observing foot and limb, especially while turning. Ataxia appears as a
the horse running free in a paddock or round pen and while lack of coordination of motor movements. It can arise from
being ridden can sometimes be helpful, this is not always damage to the vestibular, cerebellar, or sensory portions of
possible. One must consider safety for the horse and rider, as the nervous system. Ataxia in horses is most often a result
well as certain legal ramifications, before asking a person to of loss of sensory input through injury, damage, or disease
ride a horse during the examination. in the spinal cord blocking normal input to the cerebellum.
The examiner should pay attention to which limbs show Cerebellar ataxia is seen most often in young horses, typi-
abnormal posture or abnormal movements and must be able cally Arabians with a condition known as cerebellar abiotro-
to determine whether the horse has a painful or mechanical phy. Vestibular ataxia is often accompanied by a head tilt and
musculoskeletal problem or a neurologic gait deficit. Horses other cranial nerve deficits.
with a musculoskeletal problem have been described as hav- Horses may also demonstrate dysmetria, which is charac-
ing a regularly irregular gait, whereas a horse with neuro- terized as exaggerated hypermetric or hypometric movements
logic gait deficits shows less consistency placing its limbs of the limbs. Horses with hypometric gaits often appear to
(an irregularly irregular gait). Differentiating between subtle have a straight leg or “tin soldier” way of moving (sometimes
lameness and subtle neurologic disease can be very difficult. referred to as spasticity). A spastic gait is the result of increased
One should reexamine horses with an obscure or unusual muscle tone and is generally associated with upper motor
gait that might be the result of lameness after the use of local neuron disease resulting from reduced inhibition of extensor
anesthetics (to block selected peripheral nerves) or intraar- motor neurons.
ticular medications. The use of nonsteroidal antiinflammatory The gait abnormalities, along with the findings from other
drugs (NSAIDs) for a period of 1 to 2 days or longer also may parts of the neurologic examination, allow the examiner to
determine the neuroanatomic site of the disease. The severity this book (see Chapter 10). These conditions sometimes can
of the clinical signs also helps one evaluate the extent or sever- mimic a neurologic problem.
ity of the condition.
One must realize that many horses that have minimal Description of Normal and Abnormal Gaits
(grade 1 or mild grade 2) deficits often can race or perform A walk is a natural four-beat gait in the horse. At this gait
other athletic activities.11 The examining veterinarian has the the normal horse has three feet on the ground at all times.
responsibility of separating a neurologic from a musculoskele- Therefore the walk is a stable gait. The trot is a two-beat sym-
tal gait deficit and helping the owner determine the usefulness metric gait in which the diagonal limbs are in contact with
of the horse. For example, a horse with gait deficits up to grade the ground at the same time. If one examines the horse on
3 may be useful as a broodmare or breeding stallion if the con- hard pavement, the trot is the most helpful gait to distinguish
dition is not considered genetic and if the horse is handled by lameness from a neurologic gait deficit. The pace is a two-
careful, knowledgeable persons who understand the risks and beat symmetric gait in which the legs on the same side of
have the facilities to accommodate a horse in need of special the body strike the ground simultaneously, resulting in sig-
management. Stallions with this degree of impairment may nificant truncal sway. In horses that have neurologic disease,
require assistance when mounting and dismounting mares. If identifying ataxia with truncal sway, which is often accompa-
the breed association allows artificial insemination, the stal- nied by pacing, is common. In horses with subtle ataxia, one
lion may be easier to manage. observes pacing when horses walk with the head held in an
extended position. Whenever one observes a horse pacing,
Localization of the Lesion the pacing may indicate an underlying neurologic disorder;
At the conclusion of the examination, the veterinarian however, many normal horses will also pace when their head
needs to determine whether a neurologic abnormality exists is elevated.
and where it is located. If the horse shows no evidence of The gallop is a high-speed four-beat gait that often seems to
abnormal behavior, seizures, or abnormal mental status be easier to perform than walking in a tight circle or moving at
and shows no cranial nerve deficits, the lesion is most likely a slow trot. Therefore some horses with a neurologic gait defi-
caudal to the foramen magnum. The most difficult lesions cit may perform better at high speed. As the horse accelerates
to localize are in the brainstem, unless the signs include or slows down, one may detect abnormalities, and one must
cranial nerve deficits or depression. Horses with brainstem observe the horse carefully at this time when an ataxic horse
lesions often show signs of weakness and ataxia similar to is most unsafe.
horses with a lesion in the cervical spinal cord. Two of the Abnormal gaits associated with stringhalt, upward fixa-
most common brainstem lesions in horses involve the sev- tion of the patella, and fibrotic myopathy deserve careful
enth and eighth cranial nerves. Vestibular disease or injury attention. Horses that show these gait abnormalities have a
may be a sequela of head trauma or an inner ear infection. mechanical lameness, although the exact cause is unknown
Facial nerve paralysis may result from trauma to the nerve and may sometimes be associated with underlying neuro-
root origin in the brainstem or where the nerves course logic disease. Stringhalt often begins as an abrupt onset of
along the neck and face to the ears, eyelids, and nares. Spe- excessive flexion of one or both rear limbs. In some horses
cific cranial nerve involvement, such as head tilt, facial the condition may worsen and result in frequent episodes
nerve paralysis, or loss of facial sensation, can result from of the foot hitting the abdomen. The condition has been
trauma, guttural pouch infection, THO, or equine proto- reported for a long time and in some areas of the world may
zoal myeloencephalitis. In addition, cranial nerve deficits occur as an outbreak. The clinical syndrome is similar to the
may occur with polyneuritis equi and equine motor neuron movement of a horse with a tibial neurectomy with unop-
disease. Cerebellar lesions are characterized by a failure to posed flexion of the hock and extension of the digit. In the
blink to bright light, lack of a menace response, and a head case of Australian stringhalt, the forelimbs and neck muscles
tremor that worsens with intentional movements. The most may be involved. Stringhalt deserves mention in this chapter
common form of cerebellar disease in horses is abiotrophy, because when the examiner observes this gait, the examiner
which occurs most frequently in Arabian horses. should be certain no other signs of neurologic gait deficits
Cervical spinal cord disease includes gait and propriocep- exist. The primary condition usually can be corrected by a
tive deficits in all four limbs with no signs of brain, brainstem, tenectomy of the lateral digital extensor tendon, including a
or cranial nerve deficits. One should note that horses with portion of the muscle belly. The underlying cause of the dis-
cervical vertebral stenotic myelopathy might have mild pel- ease may be a sensory neuropathy, a myopathy, or primary
vic limb deficits with minimal or barely detectable signs in the spinal cord disease. The defect likely affects the neuromus-
thoracic limbs. Horses with signs of neurologic gait deficits cular spindle, as well as the efferent and afferent pathways
confined to the pelvic limbs have a neuroanatomic localization controlling muscle tone. Fibrotic myopathy results from
caudal to T2. When examining a horse with a lesion caudal scar tissue formation after injury to the semitendinosus and
to T2, carefully checking the tail and anus for involvement of semimembranosus muscles. One may confuse the charac-
the peripheral nerves or spinal cord segments in this region is teristic foot placement coupled with the abrupt rearward
important. movement of the affected limb with a spastic gait caused
Horses that have peripheral nerve injury (Table 11.1), by spinal cord injury or disease. With careful examination,
equine motor neuron disease, or polyneuritis equi show evi- a horse suffering from fibrotic myopathy likely will not go
dence of weakness, muscle atrophy, and in some cases selected undiagnosed. Upward fixation of the patella in horses with
areas of sensory loss. Primary muscle diseases such as exer- neurologic disease may result from weakness in the quad-
tional rhabdomyolysis, myotonia (congenita or dystrophica), riceps muscle group. This weakness is thought to occur
and hyperkalemic periodic paralysis are covered elsewhere in because of a lack of use of these muscles or may be caused
TABLE 11.1 Localization of Peripheral Nerve Injuries in Horses

Nerve Clinical Signs Common Causes of Injury
Suprascapular Injury is termed sweeney. Eventual atrophy of supraspinatus Collision of shoulder with objects.
and infraspinatus muscles. Lateral subluxation (popping) of the
shoulder on weight bearing. This may be caused by lack of lat-
eral collateral support (suprascapular muscles) or by additional
involvement of the pectoral nerve, subscapular nerve, caudal
cervical nerve roots, or other muscular and tendinous support-
ing structures of the shoulder.
Radial Unable to bear weight on affected limb because of a lack of Often damaged in conjunction with
elbow extension. The shoulder is rested in an extended posi- humeral fracture; occasionally ob-
tion, and the limb rests with the dorsum of the pastern on the served after recovery from general
ground. The limb may be moved forward by the action of the anesthesia.
pectoral girdle muscles while the horse walks.
Brachial plexus Signs of radial nerve paralysis often predominate. Evidence of Compression of the brachial plexus
suprascapular involvement not uncommon. Involvement of and radial nerve roots between the
other nerves and nerve roots may be confirmed with EMG. scapula and the ribs.
Possible long-term atrophy of triceps. May have diffuse hypal-
gesia of lower limb.
Musculocutaneous Paralysis not common. Gait not markedly altered. Elbow may be Uncommon.
overextended. Hypalgesia of medial forearm. Ultimately biceps
and brachial muscles atrophy.
Median and ulnar Stiff, goose-stepping gait with hyperextension of the carpal, Uncommon.
fetlock, and pastern joints.
Femoral Unable to support weight as a result of lack of stifle extension. At External blow to the limb; occasionally
a walk, the limb is advanced only with difficulty, and the stride is observed after recovery from general
markedly shortened. The limb buckles due to stifle, hock, and anesthesia.
fetlock flexion if the horse attempts to bear weight. Quadriceps
muscle will atrophy after 10–14 days. Patellar reflex is absent.
Sciatic Poor limb flexion with stifle and hock extended and fetlock Variety of injuries may be causal.
flexed when the horse is not bearing weight. Weight can be Occasionally occurs secondary to
supported if the foot is extended; otherwise weight is support- intramuscular injections, especially
ed on the dorsal surface of the foot. Limb hypalgesia from stifle in foals; occasionally observed after
downward with the exception of the medial surface between recovery from general anesthesia.
stifle and hock.
Tibial Hypermetric or stringhalt-like gait with flexion of the hock Uncommon.
(dropped hock) at rest. Hypalgesia of areas of caudal limb
distal to the hock including most of the caudal and medial
coronary band area.
Peroneal Frequently a component of sciatic nerve injury. Inability to flex Accessible to injury as it passes across
the hock and extend the digits. Acutely there is hyperextension the lateral surface of the tibia. Injury
of the hock and hyperflexion of the fetlock and interphalangeal seen in horses after recovery from
joints causing the horse to drag the fetlock along the ground. general anesthesia or secondary to a
Short protraction phase to the stride. If the foot is placed in a kick or blow to the lateral side of the
normal position, the limb may bear weight. Hypalgesia of the pelvic limb.
craniolateral portion of the limb from the level of the hock to
the fetlock.

by abnormal transmission of proprioceptive information to pelvic limbs, the neuroanatomic localization of the lesion is
and from the muscles and joint capsule because of damage between T2 and S2 or involves the nerves and muscles of the
to the spinal cord. pelvic limbs. However, horses with cervical spinal cord lesions
Horses with profound ataxia may pace when they walk, often demonstrate signs in the pelvic limbs that are one grade
which often is accompanied by circumduction of the outside worse than those observed in the thoracic limbs. Therefore a
rear limb while turning. These signs suggest general proprio- mild cervical spinal cord or brainstem lesion could show min-
ceptive deficits. If the horse has these deficits while walking, imal or no thoracic limb signs with grade 1 or subtle signs in
the examiner should observe the horse walking with its head the pelvic limbs.
elevated and on a slope (these maneuvers often exaggerate a Palpating the horse over its back, rump, and muscles of the rear
subtle problem). If the horse shows signs only in the trunk and limbs while being careful to detect any muscle atrophy is helpful.
The author routinely stimulates the horse over the side of its body neurologic disease, but this is not without limitations. CSF
and observes for any twitching of the cutaneous trunci muscles. values may be normal in an animal with severe neurologic
Such twitching usually is accompanied by a cerebral response and deficits because the lesion is extradural, collection occurred
requires a fairly severe lesion to detect areas of analgesia. early or late in the course of disease, collection occurred too
A sway reaction performed while the horse is standing and far from the lesion, or the ventral roots and peripheral nerve
walking is also necessary to assess the pelvic limb strength and have been affected by the disease. Even with its limitations,
proprioceptive functions. In addition, one may evaluate CSF provides valuable information about the CNS. However,
strength by slow but deliberate and forceful pressure along the one must emphasize that CSF evaluation is another piece of
back and sacral muscles. A normal horse should reflexively the diagnostic puzzle and together with the history, physical
arch its back upward, whereas a horse with rear limb weakness examination, neurologic examination, and other ancillary
may be unable to withstand this pressure, and its rear limbs procedures may help in the diagnosis and prognosis of neuro-
may even buckle. logic disease in horses.
To complete the neurologic examination, one must examine
the tail and anus to determine whether damage has occurred Formation, Flow, and Function of
to the sacrococcygeal nerve and muscle segments. A normal
perineal reflex results in contraction of the anus and clamping Cerebrospinal Fluid
of the tail in response to light stimulation of the skin in this CSF is produced as an ultrafiltrate of plasma and is actively
region. Cauda equina neuritis or polyneuritis equi, trauma, secreted by ependymal cells of the ventricles and choroid
and iatrogenic injury resulting from an alcohol tail block are plexus. The CSF is located in the ventricles of the brain and
some disorders that may affect this area. subarachnoid space of the spinal canal (Fig. 11.2) and bathes
The evaluation of the major peripheral nerves in the horse the CNS. CSF flows from the ventricular system up and over
is also an important part of the neurologic examination (see the cerebral hemispheres and through the subarachnoid
Table 11.1). The important points to remember are that dam- space surrounding the spinal cord. Pulsation of blood in
age to a peripheral nerve can result in sensory and motor the choroid plexuses forces the CSF in a caudal direction.
deficits in the area supplied by the nerve and that focal mus- The rate of CSF production is constant, varies among spe-
cle atrophy follows within a short time after damage to one of cies, and is independent of vascular hydrostatic pressure. The
these nerves. The examiner is referred to other portions of rate of CSF production for horses has not been determined
this book for a more detailed anatomic description of these but in humans is estimated to be approximately 0.34 mL/
nerves in the horse; however, a dropped elbow joint with min.12 Hypertonic solutions such as mannitol, when added
radial nerve paralysis, inability to fix the stifle with femoral to blood, decrease CSF production and decrease CSF pres-
nerve paralysis, and atrophy of the supraspinatus and infra- sure and edema.1
spinatus muscles (sweeney) with damage to the suprascapu- Collections of arachnoid villi (arachnoid granulations) are
lar nerve are classic examples of what to expect with located in the venous sinus or the cerebral vein and absorb
peripheral nerve injuries. CSF. CSF absorption is related directly to the pressure gradi-
ent between the CSF and venous sinus. When CSF pressure
exceeds venous pressure, these villi act as one-way ball valves,
Y CONCLUSION forcing CSF flow to the venous sinus.
CSF functions to protect the brain from trauma and to
For a horse to be a good athlete, it must gather information maintain a consistent extracellular environment for the CNS.
from muscles, tendons, and nerves; process this information
in the brain, brainstem, and spinal cord; and relay this infor- Collection of Cerebrospinal Fluid
mation to the musculoskeletal system. The horse must accom- Techniques for collecting CSF in horses have been described
plish all of this in a short time to perform complex maneuvers in detail elsewhere.1,3,4,13 CSF may be collected from the lum-
at a high rate of speed. When performing in a setting involving bosacral site in a standing sedated horse. Alternatively, it can
many other horses or when a rider or driver is involved, the be collected from the atlantooccipital site of an anesthetized
horse needs to be able to control these movements in a coordi- horse. In foals and recumbent adult horses, one can collect
nated fashion to protect itself, other horses, and especially CSF from the atlantooccipital site while the animal is recum-
those persons handling, riding, or driving the horse. bent, restrained, and heavily sedated. The lumbosacral col-
Beyond this, veterinarians must recognize which muscu- lection of CSF is traditionally performed based on anatomic
loskeletal and neurologic conditions occur together to assist landmarks, but one can also perform the procedure using
prospective buyers with horse-purchasing decisions. Recog- ultrasound guidance.14 Similarly, atlantooccipital collection
nizing and understanding these things helps the veterinarian of CSF is typically performed in the recumbent horse using
determine whether a particular horse with subtle neurologic anatomic landmarks. Two techniques have been described for
gait deficits caused by trauma, infection, or compression may upper cervical puncture in the standing sedated horse using
still be a safe and useful athlete. ultrasound guidance.15,16 Pease and colleagues16 describe fluid
collection between C1 and C2 using a lateral approach in
Y CEREBROSPINAL FLUID EVALUATION the standing sedated horse under ultrasound guidance, and
Depecker and colleagues15 describe fluid collection from the
Yvette S. Nout-Lomas spinal cistern at the atlantooccipital site using parasagittal
ultrasound guidance. If the lesion is localized to an area above
Cerebrospinal fluid evaluation has diagnostic importance the foramen magnum (at least cranial to the second cervical
regarding neurologic disease in horses. Collection and anal- vertebra), CSF collected from the atlantooccipital site may be
ysis of CSF is indicated to make or confirm a diagnosis of more diagnostic. If the lesion is localized to an area below the
Sublumbar
muscles
Dura mater
Subarachnoid
space
Spinal cord
Pia mater
FIG. 11.2 Lumbosacral spinal fluid collection from a horse showing the various tissue layers that the spi-
nal needle must pass through to obtain a sample. The spinal fluid is collected ventral to the spinal cord in the
subarachnoid space. Inset, Lateral view of spinal needle placement in the lumbosacral space for collection of
cerebrospinal fluid (CSF). (From deLahunta A, Glass EN: Veterinary neuroanatomy and clinical neurology, ed 3,
St. Louis, 2009, WB Saunders.)
foramen magnum (caudal to the second cervical vertebra), stopcock to a properly placed spinal needle, allowing the CSF
CSF collected from the lumbosacral site will be more diagnos- to rise within it.21 Because the cranial and vertebral cavities
tic. These differences result from the craniocaudal circulation are enclosed in a rigid bony compartment, changes in blood
of CSF. Collecting CSF from both sites at the same time and pressure or volume can cause a concomitant increase in CSF
comparing the findings may be helpful in cases in which neu- pressure. Thus increased CSF pressure may occur from venous
roanatomic localization of the lesion is difficult.4 compression or jugular occlusion. Venous compression causes
increased blood volume in the cranial cavity and compres-
Examination of Cerebrospinal Fluid sion of the CSF space, leading to increased CSF pressure. One
Reference values for CSF in foals, horses, and other equids can use jugular occlusion clinically to increase CSF pressure
have been reported,3,17-23 but each laboratory should deter- and facilitate collection of CSF fluid. The jugular compres-
mine its own reference ranges. CSF determinations that are sion maneuver, or Queckenstedt’s phenomenon, can help one
helpful in evaluating horses with neurologic diseases include diagnose compressive lesions, neoplastic lesions, or an abscess
pressure, appearance, cellular content, protein concentration along the spinal cord. With compression and obliteration of
(total protein, albumin, immunoglobulin G [IgG]), enzyme the subarachnoid space by a compressive lesion in the cervi-
activity (creatine kinase [CK], aspartate aminotransferase cal or thoracic spinal cord, jugular vein compression does not
[AST], lactate dehydrogenase), and lactic acid concentration. cause a CSF pressure increase in the lumbosacral site.1
Increased CSF pressure may occur after injury, after sys-
Pressure temic changes in blood pressure, and in the presence of an
One can measure opening CSF pressure before withdrawal intracranial space-occupying mass such as a tumor, abscess,
of CSF by attaching a manometer tube with a three-way hemorrhage, or edema. One must provide an adequate airway
after injury and during surgery to prevent hypoxia-mediated ethanol to preserve cellular characteristics.21 CSF from normal
cytotoxic cerebral edema and vasogenic cerebral edema. Cyto- horses and foals usually contains fewer than 7 white blood
toxic edema is caused by inadequate cerebral oxygenation and cells per microliter.3 Most studies show no differences in white
leads to neuronal, glial, and endothelial cell swelling. Such blood cell counts in normal CSF samples obtained from the
reactions are especially important during long surgical proce- atlantooccipital space compared with samples obtained from
dures or recumbency in which respiratory hypoxia and poor the lumbosacral space.
alveolar ventilation (hypercapnia) may occur. Hypercapnia Small mononuclear cells (70%–90%) and large mononuclear
increases cerebral blood flow in the cranial cavity, and CSF cells (10%–30%) predominate in equine CSF. Rarely, one may
pressure and may worsen existing cerebral edema. see neutrophils in horse CSF. Increased CSF large mononuclear
Increased CSF volume may occur in hydrocephalus, which phagocytes are visible in diseases of axonal degeneration.18 One
is defined as an increased volume of CSF and can be classified may see increased CSF neutrophil numbers in encephalomyeli-
as compensatory or obstructive. Compensatory hydrocephalus tis, bacterial meningitis, parasitism, and diseases with extensive
is an accumulation of CSF in areas in which brain tissue has inflammation. Occasionally, in severe inflammatory diseases of
been destroyed and may occur from brain injury or inflam- the neurologic system or parasitism, eosinophils may be vis-
mation. Hydranencephaly is destruction of brain tissue from ible.18,24 In some cases, cytologic evaluation of CSF may reveal
a viral or other infectious agent and results in severe accumu- specific agents causing neurologic disease such as fungal organ-
lation of CSF. CSF pressure in compensatory hydrocephalus isms, bacteria, or tumor cells. Although CSF cytologic examina-
usually does not increase. tion may support a diagnosis of neurologic disease, it may not
Obstructive hydrocephalus is an accumulation of CSF in yield a specific causative diagnosis. Analysis of cytokine gene
the ventricles from an obstruction to CSF outflow or absorp- expression in the nucleated cells of equine CSF suggests that
tion. Cerebral aqueduct malformation may lead to obstruction there are distinct gene signatures expressed by nucleated cells in
of ventricular CSF outflow. Inflammatory lesions, especially the CSF of horses without neurologic signs versus horses with
of the arachnoid villi, result in decreased absorption of CSF inflammatory or traumatic neurologic disorders.25
and increased CSF pressure. The white matter is affected more
severely than the gray matter in obstructive hydrocephalus, Protein Concentration and Composition
but the cerebral cortex usually is spared. CSF pressure in Normal total protein values range from 20 to 124 mg/dL,
obstructive hydrocephalus usually increases. The presence of depending on the measuring method used (Table 11.2). Total
an abnormally high opening pressure that drops by 25% to protein concentration is higher in lumbosacral CSF compared
50% after removing 1 to 2 mL of fluid suggests a space-occu- with atlantooccipital CSF.26 A difference of 25 mg/dL of pro-
pying intracranial mass or spinal cord compression cranial to tein between the atlantooccipital and lumbosacral spaces may
the site of collection. The removal of more fluid would risk suggest a lesion closer to the space with greater spinal fluid
causing tentorial herniation.21 protein.22 Proteins in the CSF are derived from the peripheral
blood and include albumin, IgG, and possibly other globulins.
Appearance Increased CSF albumin and IgG concentrations may occur
One can evaluate the appearance of CSF immediately after col- with damage to the blood-brain barrier or increased intra-
lection. Normal CSF is clear and colorless and does not clot, thecal production of IgG. One can determine CSF albumin
and newsprint is visible through it. CSF may be red tinged from and IgG concentrations by electrophoresis and radial immu-
blood contamination after a traumatic tap or from preexisting nodiffusion, respectively, and can compare these with serum
trauma to the CNS. In the case of a traumatic tap, the CSF usu- concentrations. One can calculate the albumin quotient (AQ)
ally will clear if allowed to flow for several seconds (about 0.5– ([Albc]/[Albs] × 100) and IgG index ([IgGc]/[IgGs] × [Albs]/
1.0 mL). With preexisting trauma and secondary hemorrhage, [Albc]) to determine blood-brain barrier permeability and
the supernatant of CSF after centrifugation is xanthochromic. intrathecal IgG production. Increased intrathecal IgG pro-
Other causes of CSF xanthochromia include increased production (increased IgG index) may occur in inflammatory
tein concentration (150 mg/dL) and direct bilirubin leakage spinal cord disease such as equine protozoal myeloencepha-
from serum in horses with high serum bilirubin concentra- litis (EPM), equine neuroborreliosis, bacterial meningitis,
tion. In addition, indirect bilirubin may leak across a damaged some tumors, and equine motor neuron disease. Determin-
blood-brain barrier. Clots in the CSF are abnormal and may ing blood-brain barrier integrity is also important in planning
be caused by increased amounts of fibrinogen resulting from therapy. If the blood-brain barrier is damaged, pharmacologic
inflammation. agents such as penicillin that do not normally penetrate the
Turbid CSF may indicate an increased number of white blood-brain barrier will penetrate a disrupted blood-brain
blood cells (greater than 200/μL), an increased number of red barrier and attain bactericidal CSF concentration.
blood cells (RBCs) (greater than 400/μL), epidural fat, bacte-
ria, fungal elements, or amebic organisms. Cytologic evalua- Enzyme Determination
tion and cultures can help differentiate causes of turbidity. CSF enzyme activity may be increased in neurologic disease.
CK and AST activity may be increased in diseases with myelin
Cytologic Evaluation degeneration and neuronal cell damage such as EPM, poly-
One can use a standard hemocytometer to obtain a complete neuritis equi, equine degenerative myelopathy, and equine
blood count (CBC). In addition, a sedimentation chamber motor neuron disease. Increased CK activity also may occur
requiring 0.5 to 1.0 mL of CSF is a rapid method for cytologic in conditions that alter blood-brain barrier permeability, such
evaluation. One must perform cell counts and cytologic evalu- as equine herpesvirus–1. In diseases in which the blood-brain
ation within 30 minutes to avoid degeneration. If cell counts barrier is damaged, serum CK can leak into the CSF and
or cytologic evaluation cannot be performed immediately, one increase CSF CK activity. This increased CK activity is not
can mix a portion of the sample with an equal volume of 50% associated with damaged myelin.
TABLE 11.2 Cerebrospinal Fluid Values from Atlantooccipital and Lumbosacral Spaces of Normal Healthy Adult Horses
Atlantooccipital Space (Mean ± SD [Range]) Lumbosacral Space (Mean ± SD [Range])
Red blood cell (RBC) count (per μL) 51.0 ± 160 (0–558) 36.8 ± 59.7 (0–167)
White blood cell count (per μL) 0.33 ± 0.49 (0–1) 0.83 ± 1.11 (0–3)
Total protein (mg/dL)a 87.0 ± 17.0 (53 ± 11.6) 93.0 ± 16.0 (58.0 ± 11.0)
(59–118) (35–74) (65–124) (39–78)
Albumin (mg/dL) 35.8 ± 9.7 (24–51) 37.8 ± 11.2 (24–56)
Albumin quotient (AQ) 1.4 ± 0.4 (1.0–2.0) 1.5 ± 0.4 (1.0–2.0)
Immunoglobulin G (IgG) (mg/dL) 5.6 ± 1.4 (3–8) 6.0 ± 2.1 (3–10)
IgG index 0.19 ± 0.046 (0.12–0.27) 0.19 ± 0.5 (0.12–0.26)
Creatine kinase (CK) (IU/L) 0–8 0–8
Lactate dehydrogenase (IU/L) 0–8 0–8
Aspartate aminotransferase (AST) (IU/L) 4–16 0–16
Glucose (mg/dL) 35%–70% of blood glucose
Lactate (mg/dL) 1.92 ± 0.12 2.30 ± 0.21
Sodium (mEq/L) 140–150 140–150
Potassium (mEq/L) 2.5–3.5 2.5–3.5

aTotal protein concentration next to the mean ± SD in parentheses is the value expected using a total protein standard.
Increased CK activity also may suggest other diseases of tissue. Fibrosis of nervous tissue may result in significant
the CNS. In one study, CK activity (greater than 1 IU/L) most neurologic gait deficits and normal CSF constituents. CSF
often was associated with EPM in horses and may be helpful taken away from the site of the lesion shows normal find-
in differentiating compressive spinal cord disease from EPM. ings despite significant neurologic gait deficits. For example,
Furthermore, persistently increased CSF CK activity may CSF in a horse with a cervical spinal cord abscess may show
be associated with a poor prognosis in horses with EPM.27 a suppurative inflammation in the lumbosacral CSF and a
Lactate dehydrogenase activity may be increased in spinal normal atlantooccipital CSF. This discrepancy is caused by
lymphosarcoma. the caudad flow of CSF.
CSF may be helpful in supporting the diagnosis of neurologic
Lactic Acid Concentration disease in horses and is part of the diagnostic workup. Because
CSF lactic acid concentration may be an indicator of neuro- CSF evaluation is an ancillary diagnostic test, one should use
logic disease (see Table 11.2). CSF lactic acid concentration it with, and not as a substitute for, a thorough history, physical
increases in eastern equine encephalomyelitis (4.10 ± 0.6 examination, neurologic examination, and other diagnostic
mg/dL), head trauma (5.40 ± 0.9 mg/dL), and brain abscess tests.
(4.53 mg/dL). Lactic acid concentration may be the only CSF
parameter increased in horses with brain abscess.28 Y NEUROELECTRODIAGNOSTICS
Caffeine M. Aleman
CSF concentrations of caffeine and its metabolites were evalu-
ated using a novel microdialysis system that allowed simulta- Neuroelectrodiagnostic testing is a useful modality that
neous monitoring of locomotor activity and collection of CSF comprises various diagnostic modalities to evaluate brain,
and blood samples for pharmacokinetic analysis.29 Investiga- brainstem, nerve, neuromuscular, and muscle electrical activ-
tors found that 3 mg/kg caffeine increased spontaneous loco- ity, among others. Neuroelectrodiagnostics should be used
motor activity, which was correlated to increased blood and as an extension of the neurologic examination that might
CSF caffeine concentrations. aid in further localization of lesions in certain challenging
cases. Depending on the specific diagnostic aid, horses might
Summary require sedation (i.e., electromyography, electroretinography,
Normal CSF findings do not always rule out the presence of brainstem auditory evoked potential, otoacoustic emissions,
neurologic disease. CSF values may be normal with lesions visual evoked potentials, electroencephalography) or general
outside the CNS that are not bathed in the CSF, such as extra- anesthesia (i.e., nerve conduction studies, repetitive nerve
dural, ventral root, and peripheral nerve lesions. Normal stimulation).30
CSF values also may occur early or late in the disease process
and in CSF samples obtained from a site distant from the Electromyography
lesion. Acute neurologic disease, especially if multifocal, may Electromyography (EMG) refers to the study of the electrical
not have sufficient time to cause significant damage to the activity of the muscle.31-34 The distribution of EMG abnor-
blood-brain barrier and alter CSF constituents, whereas in malities can assist in the localization of lesions to spinal cord
chronic CNS disease the blood-brain barrier may be repaired segments, nerves, and/or muscles.31-34 Quantitative EMG can
and functional but with nervous tissue replaced by fibrous further assist in the determination of disorders as myopathic,
TABLE 11.3 Muscles, Nerves, and Nerve Roots Evaluated during Routine Electromyographic Examination of Horses
Muscles Peripheral Nerve Spinal Nerve Root
REAR LIMB
Long digital extensor Peroneal nerve L6–S1
Gastrocnemius Tibial nerve S1–S2
Deep digital flexor Tibial nerve S1–S2
Semimembranosus Ischiatic nerve L5–S2
Vastus lateralis Femoral nerve L3–L5
Biceps femoris Caudal gluteal, ischiatic, and peroneal nerves L6–S2
Middle gluteal Cranial and caudal gluteal nerves L5–S2
PARAVERTEBRAL
Paravertebral muscles (segmentally) Dorsal branches of ventral spinal nerves (L6–C1) L6–C1
THORACIC LIMB
Subclavius Pectoral nerve C6–C7, T1
Supraspinatus Suprascapular nerve C6–C8
Infraspinatus
Deltoideus Axillary nerve C6–C8
Biceps brachii Musculocutaneous nerve C6–C8
Triceps Radial nerve C7–T1
Extensor carpi radials Radial nerve C7–T1
Superficial digital flexor Ulnar nerve C8–T2
Deep digital flexor Ulnar and median nerve C7–T1, T2

neurogenic, or both.31-35 EMG might not provide a definitive phasic configuration but could be monophasic, biphasic, or
diagnosis but will aid to support or refute a suspected clinical polyphasic (Fig. 11.3).32 A few polyphasic potentials (greater
diagnosis and further our understanding of disease processes. than four phases) might occur in normal muscle but usu-
EMG can be performed in the unsedated horse; however, for ally do not exceed 5% to 15% of the population of MUAPs
safety reasons and duration of the study, sedation is recom- observed.31-33 MUAPs have an amplitude ranging from 500
mended. Sedation can be achieved with xylazine hydrochlo- to 3000 μV and a duration ranging from 1 to 15 ms. Exami-
ride at 0.2 to 0.5 mg/kg IV or detomidine hydrochloride at nation of the conscious horse enhances the evaluation of the
0.005 to 0.01 mg/kg IV.30 Examination of the awake horse aids amplitude and number of phases of MUAPs in the muscle.
in evaluating motor unit action potentials (MUAPs).30 The MUAPs can be observed when the horse bears weight on or
waveforms of EMG are derived from the action potentials of retracts a limb, resulting in contraction of that explored mus-
the muscle fibers that are firing singly or in groups near the cle. As muscle contraction becomes more intense, more mo-
electrode.32 tor units are recruited and the greater frequency of MUAPs
In the needle EMG examination, one should thrust the is observed.
exploring electrode briskly into the muscle and hold it until Resting Activity. Resting activity (electrical silence ap-
the animal completely relaxes. To enable relaxation, pressure pears as a flat line) is observed in relaxed muscle.31-33 When
can be applied to the animal to bear weight on the opposite the needle comes to rest near a nerve twig or end plate, the
limb. Once relaxation has occurred, resting activity or any needle might irritate small intramuscular nerve terminals.
postinsertional activity of the muscle can be evaluated. EMG However, end plate noise and end plate spikes might be ob-
records insertional and spontaneous activities (normal and served. End plate noise produces a rippling of the baseline
pathologic). Evaluation of multiple areas (at least four to six) and a low-pitched continuous noise (Fig. 11.4).31,33 End plate
and depth within skeletal muscles under study should be spikes, on the other hand, are high-amplitude intermittent
performed. Table 11.3 provides examples of muscles, nerves, spikes and make a popping sound. End plate noise and spikes
and spinal cord segments that can be tested. A thorough and can occur alone or together. The origin of end plate noise is
systematic evaluation must be performed to avoid missing a due to extracellularly recorded miniature end plate poten-
lesion. tials,31,33 whereas end plate spikes are due to single muscle fi-
ber contractions after needle electrode irritation of the nerve
Normal Electromyographic Potentials terminals.31,33 In human beings, these potentials are associ-
Motor Unit Action Potentials. MUAPs result from volun- ated with dull pain; repositioning the needle often eliminates
tary or reflex muscle contractions observed after insertion their activity.
of the needle electrode. They represent the sum of a number Insertional Activity. Insertional activity is that EMG activ-
of muscle fiber potentials. MUAPs are characterized by its ity caused by mechanical stimulation of muscle fibers on needle
appearance, duration, amplitude, number of turns, number insertion and usually does not go beyond 1 to 2 seconds after
of phases, area, and rise time.32 MUAPs normally have a tri- insertion. Spontaneous activity might be found at the end plate
B
D
C
E G
F
FIG. 11.5 Normal insertional activity in the infraspinatus muscle. Gain:

0.500 mV/division; time: 10 ms/division.
Decreased Insertional Activity. Decreased insertional ac-

FIG. 11.3 Electromyograph of the middle gluteal muscle showing nor- tivity (decreased amplitude, duration, or both) is associated
mal resting activity (arrowheads), fasciculation potentials (A, E, G), fibril- with a decreased number of functioning muscle fibers and
lation potentials (C), positive sharp waves (B, F), and a small motor and can be seen with neuropathies and myopathies. Infiltration of
action potential (D). connective tissue and fat in the muscle leads to a decreased
number of muscle fibers, which decreases insertional activity.
Complete fibrosis of the muscle results in loss of insertional
activity. Insertional activity also might be absent when muscle
fibers are functionally inexcitable, as occurs during attacks of
familial periodic paralysis,31-34 or if a faulty needle electrode
is used.
Abnormal Electromyographic Potentials

Spontaneous activity in a relaxed muscle after cessation of nee-
dle movement is considered abnormal. Abnormal spontaneous
activities include fibrillation potentials, positive sharp waves,
complex repetitive discharges, myotonic discharges, pseudo-
myotonic discharges, and neuromyotonic discharges.31-34 In
acute neuropathic disorders, EMG abnormalities might not be
evident immediately.31-34 It might take about 2 weeks to detect
EMG alterations.31-34
FIG. 11.4 Electromyograph from triceps brachii muscle showing end Polyphasic Motor Unit Action Potentials. Polyphasic
plate spikes (large arrowheads) and end plate noise (small arrowheads). MUAPs (myopathic potentials) have increased frequency
Gain: 0.500 mV/stair step; time: 10 ms/division. (greater than four phases) and decreased amplitude and
duration (Fig. 11.6) observed during submaximal muscle
contraction and that result from an increased number of
or motor unit region.31-33 Alterations of insertional activity in- action potentials for a given strength of contraction. Myo-
clude absent, decreased, increased, or prolonged activities.31-33 pathic potentials result from a diffuse loss of muscle fibers
Insertional activity consists of short bursts of high-amplitude, and indicate the need for extra motor units to perform the
moderate- to high-frequency (less than 200 Hz) electrical activ- work normally done by fewer motor units.31-33 Myopathic
ity during and shortly after the insertion or movement of the potentials are polyphasic and most often occur in primary
exploring electrode in the muscle (Fig. 11.5). Prolonged ongo- myopathies such as myotonia-like syndromes, periodic
ing electrical activity after cessation of needle insertion is con- paralysis, myositis, botulism, and myasthenia gravis–like
sidered abnormal. syndromes. These potentials also have been reported in
Prolonged Insertional Activity. Prolonged electric activity steroid-induced myopathies, pars intermedia pituitary
continuing 1 to 10 ms after needle insertion and placement dysfunction, and membrane defect myopathies.36 MUAPs
in the muscle is considered abnormal and caused by hyperir- of neurogenic origin can have a decreased frequency and
ritability and instability of the muscle fiber membrane.31-34 longer duration than myopathic potentials and might oc-
Increased or prolonged insertional activity usually precedes cur during minimal and maximal muscle contraction (see
the onset of other denervation potentials (fibrillation po- Fig. 11.6). Thus one observes fewer MUAPs of increased
tentials and positive sharp waves) and might suggest early amplitude than expected for the strength of contraction,
denervation atrophy.31-34 However, prolonged insertional ac- which is more noticeable during maximal contraction
tivity can also be observed in myotonic disorders and myo- and produces a sputtering or motorboat sound. Abnormal
sitis.31-34 MUAPs of neurogenic origin can be caused by a decreased
EMG FINDINGS
Lesion Neurogenic lesion Myogenic lesion

EMG Normal
steps Lower motor Upper motor Myopathy Myotonia Polymyositis
Normal Increased Normal Normal Myotonic Increased

Insertional discharge
1
activity
Fibrillation Fibrillation
Spontaneous
2
activity Positive wave Positive wave
Large Normal Small unit Myotonic Small unit

0.5-3.0 unit discharge
Motor unit mV
3
potential Limited Early Early
5-10 ms recruitment recruitment recruitment
Full Reduced Reduced Full Full Full
Interference
4 pattern
Fast firing rate Slow firing rate Low amplitude Low amplitude Low amplitude
FIG. 11.6 Differential electromyographic findings in neurogenic and myogenic conditions. (Modified from
Kimura J: Electrodiagnosis in diseases of nerve and muscle: principles and practice, Philadelphia, 1984, FA
Davis.)
number of functioning axons firing during maximal mus-

cle contraction. These potentials are most often present in
primary neuropathies in which collateral reinnervation has
occurred.31-33
Fibrillation Potentials. These spontaneous discharges (see
Fig. 11.3) sound like frying eggs, crinkling cellophane, or
frying bacon and have an initial positive deflection of 100
to 300 μV in amplitude and 2 to 4 ms in duration.31-33 They FIG. 11.7 Electromyograph showing trains of positive sharp waves.
are diphasic or triphasic in waveform. Fibrillation poten- Gain: 500 V/stair step.
tials strongly suggest denervation but have been observed
in polymyositis, muscular dystrophy, and botulism.37 Fibril-
lation potentials could result from spontaneous discharges potentials followed by the recording of MUAPs might indicate
from acetylcholine-hypersensitive denervated muscle fibers reinnervation and might suggest a favorable prognosis.31-33
or muscle inflammation and focal muscle degeneration.31-33 Positive Sharp Waves. Positive sharp waves are potentials
A few fibrillation potentials have been observed in normal in which the primary deflection is downward, followed by a
healthy muscle, but they are usually not reproducible in oth- lower amplitude, longer duration negative deflection (see Fig.
er areas of the muscle. 11.3). This waveform has been described as resembling a saw-
The onset of fibrillation potentials after denervation tooth.31-33 Positive sharp waves occur with muscle denervation
depends on the size of the animal. The larger the animal, and muscular diseases such as myositis, exertional rhabdomy-
the later the onset of fibrillation potentials; they have been olysis (tying-up syndrome), and spinal shock. Positive sharp
reported between days 5 and 16 after denervation in dogs and waves might occur in denervated muscle after chronic exer-
human beings.31-33,37,38 The authors have observed fibrillation tional rhabdomyolysis, myotonia, EPM, laryngeal hemiplegia,
potentials 7 to 10 days after nerve injury in horses. Fibrilla- suprascapular nerve injury (sweeney), and compressive my-
tion potentials often occurred along with positive sharp waves; elopathies.39-42 Positive sharp waves often precede or appear
they increase and then decrease in amplitude as the muscle along with fibrillation potentials in denervated muscle. These
atrophies, with activity ceasing on complete muscle atrophy. potentials can be observed singly or in trains (Fig. 11.7) and
Fibrillation potentials occurring alone denote a more severe sound like a machine gun.31-33
disease process than the presence of positive sharp wave poten- Fasciculation Potentials. Fasciculation potentials are spon-
tials alone. Fibrillation potentials are helpful in evaluating the taneous discharges from a group of muscle fibers representing
length of time muscle denervation has been present and are the whole or part of a motor unit (see Fig. 11.3).32 Fascicula-
important in diagnosing denervation before clinical muscle tion potentials occur in diseases of anterior horn cells and
atrophy. Fibrillation potentials can be used to monitor progres- irritative-type lesions of root or peripheral nerve, such as ra-
sion of disease over time. In addition, a decrease in fibrillation diculopathies and nerve entrapments in human beings.31-33
Median nerve
1
Medial epicondylar
crest
Ulnar head
DDF
FIG. 11.8 Electromyograph showing waxing and waning myotonic po- Humeral head
tentials. Gain: 500 V/stair step. DDF
2
Fasciculation potentials in the presence of fibrillation potentials

or positive sharp waves might indicate lower motor neuron Branch to radial
disease43 and might occur in suprascapular nerve entrapment head DDF
(sweeney) in horses.
Complex Repetitive Discharges and Myotonic Poten- Radial head DDF
tials. These potentials are repetitive MUAPs induced by in-
sertion of the needle electrode or percussion of muscle.31-33
Bizarre high-frequency potentials tend to be shorter in du-
ration and end abruptly compared with myotonic discharg-
es. Bizarre high-frequency potentials sound like a machine
gun. However, myotonic potentials wax and wane in am-
plitude, last 4 to 5 seconds, and sound like a dive-bomber, Median nerve
hence the nickname dive-bomber potential (Fig. 11.8).31-33 (medial view, deep)
Myotonic and bizarre high-frequency potentials are as-
sociated with hyperexcitability of the muscle cell mem-
brane.31-33 Bizarre high-frequency potentials might occur
in diseases of the lower motor unit such as muscular dys-
trophy, steroid-induced myopathy, polymyositis, chronic FIG. 11.9 Illustration of anatomy and electrode placement used in me-
denervation, and hyperkalemic periodic paralysis.31-33,44,45 dian nerve conduction velocities. DDF, Deep digital flexor. (From Henry
Myotonic potentials occur in myotonia congenita and myo- RW, Diesem CD, Wiechers MD: Evaluation of equine radial and median
tonia dystrophica and might occur in hyperkalemic peri- nerve conduction velocities, Am J Vet Res. 40:1406-1410, 1979.)
odic paralysis in human beings, which reflects abnormal
muscle chloride or potassium conductance.31-33 Complex
repetitive discharges are seen in horses with hyperkalemic be used as a control. In horses, radial nerve recordings can be
periodic paralysis.45 obtained from the extensor carpi radialis and abductor digi-
torum longus muscles (Fig. 11.10) and for the median nerve
Nerve Conduction Studies from the humeral and radial heads of the deep digital flexor
Nerve conduction velocity (NCV) studies assess the motor muscle50,51 (Fig. 11.9). Facial nerve recordings can be obtained
and sensory evoked responses to stimulation of nerves.33 The from the levator nasolabialis muscle by stimulating the buccal
evaluation of nerve conduction velocities requires knowl- branch of the facial nerve just ventral to the facial crest.47 Sen-
edge of the topographic anatomy of nerves and muscles. In sory nerve action potentials (SNAPs) can also be evaluated in
horses, this diagnostic modality could be technically chal- the anesthetized horse.
lenging, is time consuming, and requires general anesthe-
sia because electrical stimulation is applied.30 NCV studies
aid in the localization of nerve, neuromuscular junction, Diseases Affecting the Motor Unit and Nerves
and muscle disease. Furthermore, it aids in the distinction Focal and Multifocal Myelopathies
between axonal degeneration and demyelination.33 Nerve Compressive cervical myelopathies, cervical stenotic myelop-
conduction velocity studies of the maxillary, facial, radial, athy, and EPM are common causes of neurologic disease in the
median, ulnar, lateral and medial palmar and plantar, sural, horse. These conditions can affect sensory and motor path-
superficial, and deep peroneal nerves have been reported in ways. Physical examination might reveal muscle atrophy and
horses and ponies.46-56 sweating over affected muscles. Needle EMG of the cervical
Stimulation of a specific motor nerve consists of insert- axial musculature in horses with truncal, thoracic, and pelvic
ing a needle near the nerve that records a compound motor limb ataxia might reveal increased insertional activity, fibrilla-
action potential from an innervated muscle (Figs. 11.9 and tion potentials, and positive sharp waves supporting the con-
11.10). The examiner might see or palpate the contraction of clusion that there is a lesion of the ventral horn cells or ventral
appropriate muscles on stimulation. The unaffected limb can roots. Abnormal postinsertional activity at the level of the
Radial nerve
Lateral head
TRICEPS
Lateral
epicondylar
ECR crest
CDE
LDE
Branch
to ECO
Radial nerve
FIG. 11.11 Horse with gluteal muscle atrophy due to EPM showing
(lateral view) distribution of abnormal electromyographic potentials.
ECO
the extent of damage to these and other nerves and might be

able to differentiate lost or reduced limb function caused by
nerve damage from painful conditions. Muscle groups that
have atrophied because of disuse (disuse atrophy) caused by
a painful condition show no postinsertional activity on needle
EMG examination.
Positive sharp waves and fibrillation potentials in the
FIG. 11.10 Illustration of anatomy and electrode placement used triceps brachii and extensor carpi radialis muscles might
in radial nerve conduction velocities. ECR, Extensor carpi radialis; CDE, suggest radial nerve injury. Positive sharp waves and fibril-
common digital extensor; LDE, long digital extensor; ECO, extensor lation potentials in the supraspinatus and infraspinatus
carpi obliquus. (From Henry RW, Diesem CD, Wiechers MD: Evaluation muscles suggest injury to those muscles or suprascapular
of equine radial and median nerve conduction velocities, Am J Vet Res. nerve injury (Fig. 11.12). Postinsertional activity in these
40:1406-1410, 1979.) muscle groups and the lateral head of the triceps suggests
damage to the brachial plexus (Fig. 11.13). Thus needle
EMG might be helpful in differentiating suprascapular
spinal cord compression might allow the clinician to focus the nerve injury from brachial plexus injury. Visible evidence
radiographic examination. of muscle atrophy might not be present until several days
In cases of EPM, needle EMG might reveal fibrillation to weeks after injury. To confirm a radial nerve injury,
potentials, positive sharp waves, and abnormal insertional nerve conduction velocity studies are recommended (Fig.
activity in affected limb muscles in horses presented for 11.14). Nerve conduction velocity less than 60 m/sec or sig-
obscure lameness. One also can examine horses with muscle nificantly less than the opposite limb supports radial nerve
asymmetry (Fig. 11.11) via needle EMG to determine the dysfunction. In addition to reduced nerve conduction
extent of muscle involvement. Serial needle EMG examination velocity, alterations in amplitude and duration of the action
also might be helpful in monitoring the response to treatment potential support abnormalities. Needle EMG and nerve
and prognosis. For more in-depth information on electrodiag- conduction studies might be helpful in determining success
nostics in the horse, the reader is referred to multiple publica- of nerve decompression surgery and evaluating whether
tions by Wijnberg.34 permanent nerve damage has occurred and the extent of
return of nerve function.
Radial and Suprascapular Nerve Injury
Damage to nerves leads to muscle atrophy of the innervated Laryngeal Hemiplegia
muscle. Damage to the radial and suprascapular nerves can Laryngeal hemiplegia has been described extensively in the
occur with trauma to the cranial aspect of the shoulder. Needle literature as denervation of the intrinsic laryngeal muscula-
EMG and nerve conduction studies are helpful in evaluating ture, specifically the recurrent laryngeal nerve.57 Recognizing
Radial nerve conduction velocities
mV
DL PL
msec
0.100 mV
10 msec
FIG. 11.14 Evoked muscle action potential from the extensor carpi
radialis muscle showing decreased amplitude and decreased nerve con-
duction velocity, suggesting radial nerve injury. DL, Distal latency; PL,
FIG. 11.12 Horse with suprascapular nerve injury with characteristic proximal latency.
electromyographic distribution of fibrillation potentials and positive sharp
waves in supraspinatus and infraspinatus muscles. Brainstem Auditory Evoked Response
Brainstem auditory evoked response (BAER) testing evaluates
the integrity of the auditory pathway from its peripheral part
(cochlear nerve) to the brainstem.59 It is useful in the detec-
tion of unilateral and bilateral deafness, as well as differen-
tiation between conductive and sensorineural hearing loss.
Reference values for BAERs in adult horses and ponies60-73
and neonatal foals are available in the literature.61,72 Head-
phones or earphones are used to transmit sound through the
external ear canal to the middle ear to the inner ear to evoke a
response. The BAERs are evoked potentials, or waves, arising
within the first 10 ms after delivery of an acoustic stimulus
(clicks; Fig. 11.15). In human beings, BAERs are recognized
as consisting of from five to seven waves, generally designated
I through VII. Of these, waves I through V are the most com-
mon. In dogs, cats, and horses waves I to V are easily identified
if normal (Fig. 11.16).60 In human beings and animals, a cor-
respondence exists between these waves and certain anatomic
generator sites.59,60 Wave I corresponds to cochlear nerve, II
to cochlear nucleus, III to olivary nucleus, IV to lateral lem-
FIG. 11.13 Horse with brachial plexus injury showing characteristic niscus, and V to caudal colliculus. Two derivations (vertex to
distribution of electromyographic charges, including fibrillations and pos-
mastoid and vertex to C2), depending on recording electrode
itive sharp waves. The involvement of the supraspinatus, infraspinatus,
placement, have been used in the horse to better identify the
triceps brachii, extensor carpi radialis, and pectoral muscles is notable.
waves.
BAERs vary with age, gender, breed, head size, and tem-
the disorder before the onset of clinical signs could be chal- perature in other species. No differences in BAER latencies
lenging. However, fibrillation potentials and positive sharp are apparent between neonatal foals and adult horses.60,61
waves in the dorsal cricoarytenoid muscle on needle EMG However, older horses might suffer from partial hearing loss
examination might appear before clinical signs.58 Thus nee- as they age. Auditory brainstem response (ABR) testing is a
dle EMG might be useful in the early detection of laryngeal method of assessing not only auditory function but also a
hemiplegia in horses. Spontaneous EMG activity, includ- variety of neurologic disorders involving the brainstem. ABR
ing fibrillation potentials, positive sharp waves, or bizarre testing is unaffected by the state of arousal of the test sub-
high-frequency discharges, have been reported in the dor- ject, and responses are not degraded by sedation or general
sal cricoarytenoid muscle of horses affected with laryngeal anesthesia.61 Examination can be done in the awake horse,
hemiplegia. Fibrillation potentials and positive sharp waves with or without mild sedation, or anesthetized. If a conscious
are the most common abnormalities observed in horses with awake horse is tested, one stimulates each ear and records the
laryngeal hemiplegia. Decreased insertional activity and resultant waveforms independently. If the patient is anesthe-
bizarre high-frequency discharges were reported at a lesser tized, one examines the uppermost ear first, turns the horse,
frequency.58 and examines the lower ear.
Exploring
(pickup)
Reference
Ground
Preamplifier
Click
generator
FIG. 11.15 System used for auditory brainstem response (ABR) testing in the horse. (From Rolf SL, Reed SM,
Melnick W, et al.: Auditory brainstem response testing in anesthetized horses, Am J Vet Res. 48:910-914, 1987.)
The most common causes of BAER abnormalities in adult

90 horses include temporohyoid osteoarthropathy, congenital
sensorineural deafness in Paint Horses, multifocal brain dis-
ease, and otitis media/interna. BAER can be used in horses
with vestibular disease (Fig. 11.17) to investigate if hearing
80
is also affected as is the case in horses with temporohyoid
osteoarthropathy. BAER testing might be helpful in the diag-
nosis and prognosis of traumatic, infectious, or inflamma-
tory brainstem lesions such as vascular infarcts or anomalies,
ischemic fibrocartilaginous emboli, basisphenoid bone frac-
Stimulus intensity (dB hearing level)
70 ture, and protozoal encephalomyelitis. Reported causes of

hearing loss in neonatal foals include congenital sensorineu-
ral hearing loss, congenital anomalies (skull deformation),
sepsis, neonatal encephalopathy, neonatal isoerythrolysis,
60 and prematurity.61,72
Electroencephalography
Electroencephalography (EEG) is the graphic representation
of the difference in voltage in microvolts between two dif-
ferent locations within the cerebral cortex plotted over time.
50 EEG recordings represent spontaneous electrical activity
primarily synaptic, excitatory postsynaptic potentials, and
inhibitory postsynaptic potentials from cortical neurons.
Pyramidal cells are the most important neuronal source for
the EEG. It is estimated that a minimum of 108 neurons or
40 an area of 6 cm2 is required to produce a detectable change
in voltage. Thalamic oscillations are transmitted to the cortex
via projection neurons and are thought to be responsible for
the slow waves and spindles associated with slow wave sleep
30 (SWS). This electrical activity might be modified by deeper
structures such as the brainstem, reticular activating system,
and thalamus. EEG is a valuable tool for the investigation
Latency (ms) of brain disease, particularly seizures and sleep disorders,
localization of abnormal activity, and extent (focal or dif-
FIG. 11.16 Mean latency waves at 136 dB, sound pressure level (SPL) fuse). EEG has been used extensively in other species and
through 87 dB SPL. Five waves are present, except at 40 of 80 dB SPL. more limited in horses.74-88 In horses, EEG has been used to
(From Rolf SL, Reed SM, Melnick W, et al.: Auditory brainstem response study sleep, seizures, nociception, effects of drugs on cerebral
testing in anesthetized horses, Am J Vet Res. 48:910-914, 1987.) activity, and euthanasia.74-88
FIG. 11.18 Photograph of horse illustrating bipolar montage for elec-

troencephalography (EEG). RO, Right occipital; LO, left occipital; RF, right
frontal; LF, left frontal; V, vertex; G, ground; ECG, electrocardiogram posi-
tion.
is as follows: delta 0 to 3 Hz, theta 4 to 7 Hz, alpha 8 to 12 Hz,

beta 13 to 29 Hz, gamma ≥30 Hz.
A Whenever possible EEG should be done in the nonanes-
thetized horse because the effects of drugs on EEG recordings
such as suppression of EEG activity, transient paroxysmal dis-
Right ear charges, and the lack of observation of all states of vigilance.
The major disadvantage of performing EEGs in the sedated
horse is movement artifacts. However, interpretable record-
ings are possible. Further, the states of vigilance can be evalu-
ated. States of vigilance in the horse as determined through
EEG consist of wakefulness, drowsiness, slow wave sleep, and
rapid eye movement (REM) sleep.86
Transcranial magnetic stimulation testing: Although not
entirely new to equine neurology, transcranial magnetic stim-
Left ear
ulation testing has not be used a lot in evaluation of neurologi-
cal disease in horses. In human medicine, evoked potentials
are widely used to quantify the function of both descend-
ing and ascending spinal cord tracts. The descending tracts,
which carry motor information from the brain to spinal cord
neurons, can be evaluated using transcranial magnetic motor
evoked potentials (TMMEPs). These evoked potentials are
non-painful and produced by electromagnetic stimulation of
the brain in the conscious human or animal with simultaneous
B electrical recordings made from needle electrodes in relevant
muscle groups.265
FIG. 11.17 A, Photograph of foal with a right head tilt and drooping of
the right ear. B, Auditory brainstem response (ABR) (see Fig. 11.18) shows a
hearing loss in the left ear, the presumed cause of the head tilt. The right Y MAGNETIC RESONANCE IMAGING
ear was normal. Katherine S. Garrett
Two EEG montages have been described: bipolar and refer- Although magnetic resonance imaging (MRI) has been
ential. Electrode placement could be rostral to caudal or trans- used for diagnosis of neurologic disease in human beings
verse in a bipolar montage (Fig. 11.18). EEG recordings are for decades, it has only come into clinical use for horses
evaluated for symmetry, waveform, morphology, frequency, within the past 15 years.89-102 Imaging of the brain and spi-
and amplitude. There is a wide range of frequencies but con- nal cord is essentially impossible without MRI or computed
fined to a relatively low range (0.5–50 Hz) with most below 30 tomography (CT), so this represents an exciting new imag-
Hz. Amplitude varies from a few to several hundred microvolts ing modality to aid in the diagnosis of neurologic disease
but usually remaining below 100 μV. Waveform nomenclature in horses.
Principles to be reviewed, and it usually takes between 1 and 2 hours to

Magnetic field strength is measured in Tesla (T). The strength complete the acquisition of images. Some series are acquired
of the magnetic field varies among types of magnets but is typ- in a way that permits reconstruction in multiple planes or in
ically between 0.25 T and 1.5 T for most magnets currently in three dimensions.
routine equine clinical use, although 3.0-T magnets will likely
become more widely available in the near future. Equipment
Most MRI applications use hydrogen nuclei (protons) The main magnetic field can be generated in a variety of
as the molecule of interest, but other nuclei can be used. ways. Permanent magnets are used in lower field systems
Application of the strong magnetic field causes the magnetic (less than 0.4 T). These magnetic fields are generated by
moments of the protons within tissues to orient themselves using ferromagnetic materials of the same type as in every-
parallel to the main magnetic field. A radiofrequency pulse day magnets. Stronger magnetic fields are produced using
at a specific frequency is then applied, which causes a change superconducting electromagnets. These magnets use liquid
in the cumulative magnetic moment of the protons and syn- helium to cool the electromagnetic coils and reduce the
chronizes the phase of the protons’ precessions (rotation resistance, allowing much stronger magnetic fields to be
about an axis). After the radiofrequency pulse is discontin- generated. Liquid helium is expensive and requires periodic
ued, the protons will return to the resting state governed by replenishment, but it is necessary to efficiently generate the
the main magnetic field alone, and the precessional phase stronger magnetic fields in clinical use. Regardless of the
synchrony will degrade. Different tissues return to the rest- type of magnet, the room must be shielded to prevent any
ing state at different times and in different ways. In a basic external radiofrequency pulses (e.g., radio signals, cellular
sense, the time for the magnetic moment of a tissue to return phone transmission) from entering the room and introduc-
to the direction of the main magnetic field is a description of ing artifacts.
the T1 time of the tissue, and the time for the phase coher- Two types of MRI systems are used for horses. One
ence to degrade is a description of the T2 time of the tissue. type consists of systems designed for use in human beings.
These are inherent properties, and the differences between These tend to be high field magnets with strengths ≥1.0
tissues form the basis of MRI. T of closed bore construction and require the horse to be
Different pulse sequences produce different types of con- under general anesthesia. The horse is positioned either in
trast, based on each tissue’s hydrogen content and its response. lateral or dorsal recumbency on a nonferromagnetic pad-
Proton density sequences have contrast determined by the pro- ded table with the body part of interest positioned into the
ton content of each tissue. Cortical bone, tendons, ligaments, bore. Foals can be imaged using the human patient table in
and air have low proton density, so they appear hypointense any recumbency.
(dark) on all sequences, as well as on proton density–weighted The other group consists of magnets that have been specifi-
sequences. T1-weighted sequences have contrast dominated cally designed for veterinary use. These magnets are generally
by the T1 relaxation times of the tissues. Fat is hyperintense low field magnets with a strength in the 0.25-T range. Many
(bright) and fluid is hypointense. T2-weighted sequences have have an open bore design and can be positioned about a body
contrast dominated by the T2 relaxation time of the tissues. part; some require general anesthesia and some only sedation.
Fat is hypointense and fluid is hyperintense. Fluid attenuation The images produced with these weaker magnets require lon-
inversion recovery (FLAIR) sequences have the signal from ger scan times to obtain and are of lower resolution. Motion
CSF specifically nulled using an inversion pulse. This allows artifact in studies obtained on standing horses can signifi-
abnormal fluid within the brain or spinal cord parenchyma to cantly reduce image quality.
be more apparent. Intravenous contrast can also be used in Examinations are limited to regions that can fit into the bore
MRI. Gadolinium compounds are typically used, which allow of the magnet to be positioned at or near the isocenter (cen-
assessment of abnormal patterns of blood flow or delineation ter of the magnetic field). Depending on the type of magnet,
of anatomic structures, similar to the use of contrast in CT this requires that either the horse be pushed into the center of
imaging. the magnet bore or that the magnet be positioned around the
Two major families of pulse sequences exist. Spin echo region of interest. These limits will vary among magnets based
sequences use multiple radiofrequency pulses to generate on their construction.
a signal. Turbo or fast spin echo sequences are a subset of
spin echo sequences that are faster than traditional spin echo Safety
sequences. Image contrast can be altered slightly; for example, Most safety hazards associated with MRI are related to the
fat on T2-weighted turbo spin echo sequences is hyperin- introduction of ferromagnetic objects into a strong mag-
tense instead of hypointense. Gradient echo sequences use a netic field, as opposed to the existence of the magnetic field
changing magnetic field gradient to generate a signal. Gradi- itself. No known adverse effects have been reported for MRI
ent echo sequences can be acquired more quickly than spin at field strengths currently used in equine clinical imaging.
echo sequences but are more susceptible to magnetic field Any object that is magnetic (scissors, oxygen tanks, scalpel
inhomogeneities. blades) will be attracted to the magnet; thus all the equipment
For each series of slices, the operator must choose the ori- in the room must be nonmagnetic or MRI compatible, includ-
entation of the slices, as well as the type of pulse sequence ing the anesthesia equipment. The strength of the magnetic
used. A typical MRI examination will consist of many series, field increases exponentially as the distance to the magnet
each with a different combination of orientation and pulse decreases. In practical terms, this means that the pull of the
sequence. Unlike CT imaging, the orientation of the images magnet on any ferromagnetic object becomes quickly stronger
obtained during each pulse sequence can be selected by the as the object approaches the magnet (to prevent injury this is
operator. These are typically 1- to 5-mm-thick slices. A com- especially important to bear in mind when considering stron-
plete examination produces hundreds of individual images ger magnets).
The strong magnetic field can also affect internal implants a tail pull test. An anatomic diagnosis of a CNS lesion rostral
and is especially dangerous for people with cardiac pace- to the foramen magnum was made. Endogenous adrenocorti-
makers, who should not enter an MRI room under any cir- cotropic hormone, triiodothyronine (T3), and thyroxine (T4)
cumstances because of the potential for serious cardiac levels were normal. An MRI examination was undertaken in
arrhythmias resulting from the effect of the magnetic field on an attempt to find the cause of the neurologic signs and to fur-
the pacemaker. Metal shards in the cornea can also be affected ther investigate a possible pituitary lesion.
by the magnet and can move within the cornea, causing ocular A mass was found on the median plane ventral to the dien-
damage. The changing of the magnetic gradients can be quite cephalon, with the ventral aspect of the mass within the sella
loud. Any personnel who remain in the scan room during the turcica (Fig. 11.19). A portion of the pituitary distinct from
examination should wear protective equipment to prevent the mass can be identified in part of the sella turcica. The
hearing damage. mass compresses the thalamus, hypothalamus, and optic chi-
asm. Portions of the mass appear hemorrhagic, and regions
Patient Preparation of the thalamus and hypothalamus surrounding the mass are
Horseshoes should be removed before the examination to edematous.
eliminate the risk of potential magnetic attraction. Appro- This horse was treated with pergolide and cyproheptadine
priate preparations should be carried out for images requir- in an attempt to ameliorate the signs of pituitary pars inter-
ing general anesthesia. After induction to anesthesia but media dysfunction, and improvement was seen for a brief
before entering the scan room, any metal objects (e.g., period of time. Its condition then deteriorated after 6 weeks
halters) should be removed from the horse. A specialized, with progressive anorexia, weight loss, and depression despite
nonferromagnetic table must be used to support the horse aggressive supportive care. The mare was euthanized, and
during the examination. After the horse is positioned in the necropsy results showed a large pituitary mass with histologic
bore of the magnet, it must remain completely motionless features consistent with a pituitary macroadenoma of the pars
during image acquisition to prevent blurring of the image. intermedia.
Because MRI examinations typically take between 1 and
2 hours, urinary catheterization or some other means of Equine Protozoal Myeloencephalitis
urine collection is recommended to protect the equipment An 18-year-old Thoroughbred gelding became ataxic 9
from contamination with fluid. Because an MRI exami- months before presentation. Two months before presen-
nation can be lengthy, it is extremely important that the tation, the horse started to exhibit weight loss, dysphagia,
primary region of interest be localized as specifically as and facial muscle wasting. The animal had been treated
possible. MRI has proven particularly useful in areas that for equine protozoal myelitis twice before presentation
are not amenable to examination using other diagnostic and exhibited grade 3/4 ataxia in all limbs. In addition, the
imaging modalities. horse had atrophy of the left facial muscles, as well as the
Use of Magnetic Resonance Imaging in Equine

Neurologic Disease
In adult horses, examination is limited to the brain and cra-
nial cervical spine because of limitations of current magnet
design. However, the trunk of foals up to approximately 500
lb may fit inside the bore of some magnets, enabling imag-
ing of any part of the spinal column. Few reports exist of
clinical use of MRI in neurologic disease.89-102 Some exam-
ples of neurologic disease include nigropallidal encepha-
lomalacia, head trauma, brain abscess, pituitary mass, *
cholesterol granuloma, congenital hydrocephalus, trigemi-
nal neuritis, stylohyoid bone fracture, EPM, and cervical
vertebral compressive myelopathy.89-91,93,95,97,98,101,102 Diag-
noses of equine protozoal myelitis, neoplasia, inflamma-
tory disease, encephalomyelitis, meningitis, otitis media,
hydrocephalus, and ischemic injury have been made at the
author’s clinic. In addition, substantial information has
been gained regarding the extent of damage after traumatic
injury. Although this clinic’s experience with MRI of the
nervous system is limited, the possibilities of this technique
are exciting.
Pituitary Adenoma
A 13-year-old Thoroughbred mare had decreased mentation, FIG. 11.19 Transverse T2-weighted fast spin echo image of the brain
poor appetite, weight loss, and absence of normal estrous at the level of the sella turcica. The asterisk indicates a large mass of het-
cycles. The decreased mentation had progressed to prolonged erogeneous signal intensity displacing the diencephalon laterally. The ar-
periods of somnolence, slow circling behavior, and an appar- rowhead indicates normal pituitary tissue compressed by the mass. The
ent decrease in vision. The mare had decreased menace and arrow indicates high T2 signal (edema) within the diencephalon adjacent
pupillary light responses and demonstrated slight weakness on to the mass.
FIG. 11.21 Transverse T2-weighted turbo spin echo image of the brain
at the level of the thalamus. The lateral (A) and third (C) ventricles are
FIG. 11.20 Transverse T2-weighted fast spin echo image of the brain massively dilated with cerebrospinal fluid (CSF) present outside of the
at the level of the pons. The arrow indicates an area of T2 hyperintensity brain (B). The arrow indicates the cerebral cortex, and the arrowhead in-
in the region of the nuclei of the seventh and eighth cranial nerves. The dicates the thalamus.
arrowhead indicates temporalis muscle atrophy.
CSF. The parenchyma of the cerebral hemispheres was

left temporalis and masseter muscles, muzzle deviation to thinned, and the cerebellum was compressed and herniated
the right side, and difficulty moving food to the pharynx through the foramen magnum. A meningocele and an open
with normal tongue tone, prehension, and ability to swal- fontanelle were noted at the junction of the left and right
low. These neurologic signs suggested multifocal disease frontal and parietal bones.
with involvement of cranial nerves V, VII, IX, and X, as well Treatment was not pursued, although the possibility of place-
as the cervical spinal cord and brainstem. Equine protozoal ment of a ventriculoperitoneal shunt was discussed with the
myelitis Western blot was weakly positive on the CSF and owners. The foal remained alive and was weaned successfully.
positive on serum.
MRI findings consistent with inflammation and edema Spinal Cord Compression
were seen throughout the right side of the medulla and cau- A 4-month-old Thoroughbred colt had a 2-day history of
dal pons in areas including the nuclei of cranial nerves V, VII, pyrexia and “knuckling over” of the left hind fetlock. Ultra-
VIII, and XII (Fig. 11.20). These findings are consistent with sound examination of the lumbar, sacral, and gluteal regions
those seen in a previously reported case of EPM.95 showed an abscess within the musculature. The extent of the
Nitazoxanide, vitamin E, and flunixin meglumine were abscess could not be determined but was suspected to involve
administered. Supportive care, including intravenous fluid the pelvis, so MRI examination was undertaken.
therapy and enteral feeding via nasogastric tube, was also per- Severe compression and inflammation of the spinal cord in
formed. The horse became progressively more depressed and the sacral region was seen on MRI (Fig. 11.22). The left side of
developed pleuropneumonia 1 week after admission, likely the sacrum had heterogeneous signal intensity suggestive of
secondary to aspiration because of dysphagia. The next day, osteomyelitis.
the horse became acutely more ataxic, was unable to rise, and The foal was treated with antiinflammatory and anti-
died. On postmortem examination, neuronal degeneration, microbial medication and establishment of drainage of the
inflammation, and protozoal organisms consistent with Sar- intramuscular portion of the abscess. The foal’s condition
cocystis neurona were identified in the nuclei and nerves of improved, and it was discharged on long-term antimicrobial
cranial nerves V, VII, and VIII. therapy. During follow-up MRI examination 2 months later,
the compression of the spinal cord had been relieved, and the
Hydrocephalus intramuscular abscess had decreased in size. The heteroge-
A 1-month-old Quarter Horse filly was noticed by the owners neous signal intensity within the sacrum had improved but
to have a dome-shaped head, blindness, and obtundation. A not resolved completely.
congenital brain lesion was suspected.
MRI images showed severe communicating hydroceph- Conclusion
alus with a specific location of obstruction not identified Although MRI of equine neurologic disease remains in
(Fig. 11.21). The ventricles were enlarged and filled with its infancy, veterinarians are increasingly able to use this
occurrence of at least one epileptic seizure.” Status epilepticus

(SE) is defined as “a condition resulting either from the fail-
ure of the mechanisms responsible for seizure termination or
from the initiation of mechanisms, which lead to abnormally
prolonged seizures (after time point t1). It is a condition
[that] can have long-term consequences (after time point t2),
including neuronal death, neuronal injury, and alteration of
neuronal networks, depending on the type and duration of
seizures.” In the case of tonic-clonic convulsions, the time
points are 5 minutes for t1 and 30 minutes for t2. Emergency
treatment of SE in human medicine is instituted if epileptic
seizure is greater than 5 minutes.
Epileptic seizure has a specific neural origin and can
occur as a single event or be recurrent. Epileptic seizures
can be further classified as primary (i.e., idiopathic), sec-
ondary (as the result of structural cerebral abnormalities),
or reactive (reaction of the healthy brain to transient sys-
temic insult). Epilepsy specifically refers to reoccurring
epileptic seizures from a chronic brain disorder, which may
be genetic (primary) or acquired (secondary). Epilepsy has
been rarely documented in horses, except for juvenile idio-
pathic epilepsy in Arabian foals.75 Finally, convulsions refer
to seizures accompanied by tonic-clonic muscle activity and
FIG. 11.22 Transverse T2-weighted turbo spin echo image of the spi- loss of consciousness. Classification of epilepsy has been
nal canal at the level of the sacroiliac joint. The arrowhead indicates the done by the ILAE in human medicine. Previously, epilepsy
laterally compressed spinal cord, and the arrow indicates a region of ede- was classified as idiopathic (primary) and symptomatic or
ma and proteinaceous fluid accumulation within and around the sacrum cryptogenic (secondary). Idiopathic epilepsies included dis-
(osteomyelitis). orders with suspected genetic etiology with no brain abnor-
malities. Symptomatic epilepsies have a known cause that
involves brain pathology, whereas cryptogenic epilepsies
technology to make more specific and timely diagnoses. As were those with unknown etiology. Classification of epilepsy
the knowledge base regarding MRI progresses, practitioners has evolved to genetic, structural, and unknown. In small
will be able to advance their care and treatment of equine animal medicine, the International Veterinary Epilepsy Task
patients to new levels. Force reported a consensus on epilepsy definition, classifica-
tion, and terminology.103,105
Similar to standardized classifications described in small
Y SEIZURES AND SLEEP DISORDERS animals and humans, seizures in horses can be classified as
being partial (simple and complex), generalized (primary or
Seizures secondary), or status epilepticus.106,107 Seizures that involve
Monica Aleman a discrete area of the cerebral cortex are classified as simple
partial seizures when consciousness is not impaired and
Terminology complex partial seizures when consciousness is impaired.
Seizures (from the Latin sacire, “to take possession of ”) have Partial seizures result in localized clinical signs, such as
been referred as fits, attacks, strokes, convulsions, or epilepsy facial or limb twitching, compulsive running in a circle,
and were first described around 500 to 700 B.C. Seizures are or self-mutilation. A partial seizure might be observed
a common problem in both human and veterinary medicine following a procedure such as collection of CSF, cervi-
but are less common in horses compared with other species. cal myelography, anesthesia, or cranial trauma that might
Seizures are clinical manifestations of rapid excessive and/or spread throughout the cerebral cortex and produce a sec-
hypersynchronous abnormal neuronal activity from the ondary generalized seizure. A generalized seizure involves
cerebral cortex that result in involuntary alterations of motor the entire cerebral cortex and results in generalized tonic-
activity, consciousness, autonomic functions, or sensa- clonic muscle activity over the whole body, with loss of con-
tion.103-105 Seizures can occur as single or recurrent events. sciousness. Seizures generalized from the onset are defined
Recurrent seizures are termed epilepsy. There has been a as primary generalized seizures. Secondary generalized sei-
great deal of confusion about the definition and classification zures could originate from both types of partial seizures.
of seizures and epilepsy, terms that have been used mistakenly The most common types of seizures observed in an equine
as the same. The International League Against Epilepsy referral center were partial seizures (simple or complex,
(ILAE) has defined epileptic seizure as “a transient occur- 30%) and secondary generalized seizures (30%).106 This is
rence of signs and/or symptoms due to abnormal excessive in agreement with data in dogs, for which partial seizures
or synchronous neuronal activity in the brain” and epilepsy as with or without secondary generalization appear to be the
“a disorder of the brain characterized by an enduring predis- most common types of seizures observed. Complex par-
position to generate epileptic seizures and by the neurobio- tial seizures are commonly observed in neonatal foals and
logic, congnitive, psychological, and social consequences of are referred as “chewing-gum fits,” jaw chomping, and lip
this condition. The definition of epilepsy requires the smacking.4
TABLE 11.4 Known and Suspected Causes of Seizures in Horses Less Than 1 Year of Age
Differential Diagnosis
Classification Extracranial Intracranial Diagnostic Aidsa

Anomalies (congenital) Hydrocephalus
Hydranencephaly 1–6, 8
Benign epilepsy 1, 10
Metabolic Hypoxia, hyponatremia, 2–6
hypoglycemia, hyperkalemia
Toxic Organophosphates Moldy corn 2–6
Strychnine Locoweed 9–11
Metaldehyde
Traumatic Brain trauma 2–6, 8
Lightning 2–5
Vascular Neonatal maladjustment syndrome 2–6
(vascular accidents)
Infectious Septicemia Bacterial meningitis 2–6
Hyperthermia Cerebral abscesses 5, 6, 8
Rabies 2, 3, 11
Viral encephalitis 6, 7

aKey: 1, Breed; 2, onset; 3, clinical course; 4, physical examination; 5, neurologic examination; 6, clinical pathology (e.g., cerebrospinal fluid analysis);
7, serologic testing; 8, radiology (computed tomography scan, ultrasound, radiographs); 9, toxicologic testing; 10, electrodiagnostics (electroencephalography,
electromyelography); 11, pathologic examination.
Etiology/Pathogenesis during perinatal asphyxia), intracellular calcium overload

Etiologies of seizures in horses include intracranial and extra- causes neuronal necrosis by activation of lytic enzyme systems
cranial diseases (for which the healthy brain is reactive to and nitric oxide synthase with generation of free radicals.113,114
an insult) (Tables 11.4 and 11.5). The most common causes Conditions leading to the summation of excitatory postsyn-
of seizures in foals under 2 weeks of age are neonatal malad- aptic potentials include excessive excitations and also loss of
justment syndrome (both hypoxic-ischemic and nonhypoxic inhibitions without normal regulatory feedbacks. In response
encephalopathy), trauma, and bacterial meningitis.108-111 The to the sudden depolarization shift of a neuronal aggregate,
most common causes of seizures in foals less than 1 year of local surround inhibitory zones are established to try to pre-
age are shown in Table 11.4. The most common causes of sei- vent the spread of the epileptogenic activity. γ-Aminobutyric
zures in adult horses older than 1 year of age are brain trauma, acid (GABA) is the major inhibitory neurotransmitter of the
hepatoencephalopathy, and toxicity.105 Masses such as mela- CNS. GABAergic inhibition can be presynaptic (release of
noma, pituitary adenoma, cholesteatoma, and rarely glioma GABA from the GABAergic nerve terminal into presynap-
can cause seizures in mature to older horses. tic nerve terminals causing a reduction of neural transmitter
Irrespective of the etiology, the pathogenesis of epileptic release) or postsynaptic (caused by the interaction of GABA
seizure is caused by an abnormal hypersynchronous electrical with specific postsynaptic receptors).115 In GABA-system dys-
activity of neurons, caused by an imbalance between excita- function, an abnormal neuronal hypersynchronous activity
tion and inhibition in the brain.104,112-116 If the balance shifts will spread, resulting in depolarization of more neurons.115
toward excessive excitation (theory of excitatory postsynaptic Once a “critical mass” of neurons has fired, uncontrolled
potentials), a prolonged depolarization of neuronal aggregate spread of electric activity may occur over the cerebral cortex,
will occur, a phenomenon known as “paroxysmal depolariza- which may precipitate an epileptic seizure. Thus these seizures
tion shift,” which might generate an epileptic seizure. Several can be blocked by use of agents that potentiate inhibitory neu-
mechanisms are thought to cause paroxysmal depolarization ral transmitters, such as phenobarbital. In brief, seizures may
shifts and include increased excitatory neural transmitters develop because of a summation of synchronous excitatory
(e.g., glutamate), decreased inhibitory neural transmitters (e.g., postsynaptic potentials in large groups of neurons that may be
γ-aminobutyric acid), alteration in neural transmitter receptor precipitated by an increase in excitatory neurons, a decrease
sites, or a derangement in the internal cellular metabolism of in inhibitory neurons, a decrease in inhibitory neurotransmit-
the neuron. Notably, much research has focused on glutamate, ters, or any combination of these mechanisms.
the principal excitatory neurotransmitter in the brain, and its Alterations in the neuronal cell microenvironment might
receptor complex, the N-methyl-d-aspartate (NMDA) recep- also lead to seizure generation. Systemic and local neuronal
tor. Glutamate binds to NMDA receptors, which open sodium electrolyte abnormalities might disturb excitatory neuron
and calcium channels, leading to entry of these ions in the homeostasis and lead to spontaneous and excessive action
neuron and to postsynaptic depolarizations.112-116 In addition, potentials.115 Intracellular potassium released during neu-
NMDA receptors have been implicated in the pathogenesis ronal activity may reach sufficient concentration to move
of seizures in infants and foals because if exacerbated (e.g., the resting membrane potential toward the threshold and
TABLE 11.5 Known and Suspected Causes of Seizures in Horses More Than 1 Year of Age
Classification Extracranial Intracranial Diagnostic Aidsa

Metabolic Hepatoencephalopathy, 2–6, 8
hypocalcemia, uremia, hyperlipidemia
Toxic Organophosphates Moldy corn 2–6
Strychnine Locoweed 9, 11
Metaldehyde Bracken fern
Lead, arsenic, mercury
Rye grass
Traumatic Brain trauma 2–6, 8
Vascular Strongylus vulgaris 2–5
Cerebral thromboembolism 5, 6, 11
Intracarotid injection 2, 3
Tumor Neoplasia 2–5, 8, 10, 11
Hemarthroma 6, 8, 10, 11
Cholesterol granuloma 8, 11
Infectious Cerebral abscess 5, 6, 8
Rabies 2, 3, 11
Arbovirus encephalitides 6, 7
Mycotic cryptococcosis 5, 6
Equine protozoal myeloencephalitis 6, 7

aKey: 1, Breed; 2, onset; 3, clinical course; 4, physical examination; 5, neurologic examination; 6, clinical pathology (e.g., cerebrospinal fluid analysis);
7, serologic testing; 8, radiology (computed tomography scan, ultrasound, radiographs); 9, toxicologic testing; 10, electrodiagnostics (electroencephalography,
electromyelography); 11, pathologic examination.
generate a seizure focus. Spontaneous action potentials gen- Horses also might show deviation of eyeballs, dilated pupils,
erated by alteration in intracellular potassium concentration ptyalism, trismus or jaw clamping, opisthotonos, lordosis or
may spread to other parts of the cerebral cortex, causing a kyphosis, violent paddling movements of the limbs, uncon-
generalized seizure. Alterations in one intracellular neuronal trolled urination and defecation, and excessive sweating. After
electrolyte may alter the homeostasis of other intracellular the seizure (postictus), horses might appear obtunded, disori-
electrolytes. Increased intracellular potassium concentration ented, and blind for a few minutes, hours, or days.4,75,106,107
and decreased intracellular calcium, magnesium, and chloride Diagnosis of seizure is based on history, clinical signs, and
concentrations are observed during interictal epileptogenesis ancillary diagnostic tests to determine an underlying cause,
and the transition from interictal to ictal activities. whenever possible (see Tables 11.4 and 11.5). Diagnosing sei-
Alterations in sodium conductance have also been impli- zures in horses can be challenging. Because many horses are
cated in the onset of seizures. Rapid influxes of sodium into unobserved for long periods of the day, the presence of a sei-
the neuron may lead to hyperexcitability of the neuron and zure might be suspected after recognition of unexplained
rapid firing. Phenytoin, a hydantoin derivative, blocks these trauma to the head or limbs and disruption of the stall or out-
rapid influxes of sodium into neurons and suppresses repeti- side paddock. At other times, the caretaker might identify a
tive firing by hyperexcitable neurons.116 Thus a complex inter- change in attitude or behavior of the horse such as restlessness
action may occur between these electrolytes and the internal or a “far-off ” appearance, which might be a prodromal sign
cell homeostasis that precipitates seizure formation. (aura) of an impending seizure. Careful and thorough ques-
tioning of the caretaker should be performed to determine the
Clinical Signs and Diagnosis duration and frequency of the episodes, date(s), the time of
Seizure activity is manifested clinically in a variety of ways day, the relationship to feeding, any event(s) associated with
depending on the area and the extent of the cerebral cortex the episode (e.g., injection in the carotid and traumatic event),
involved. In partial seizures, asymmetric twitching of a limb, any unusual environmental circumstances (stimuli such as
facial twitching, excessive chewing, compulsive behavior, or thunderstorms, fireworks, changes in housing), recent trauma,
self-mutilation might occur. A localized seizure might develop febrile episodes, exposure to drugs or toxins, recent behavioral
into a generalized seizure. Three distinct clinical periods might changes, and the seizure history of the dam, sire, and other
be observed in a generalized seizure. Just before the seizure siblings. The veterinarian should always consider rabies in the
(aura), horses might exhibit signs of anxiety and uneasiness. list of differential diagnoses, even if the horse has been vacci-
During the seizure (ictus), horses might become recumbent, nated and especially in endemic areas.
unconscious, and have symmetric clonic muscle contractions A complete physical examination should be performed to
(contractions and relaxations of muscles occurring in rapid rule out noncerebral clinical conditions that might mimic sei-
succession), followed by symmetric tonic muscle contrac- zures, including painful conditions (acute severe pain, trem-
tions (continuous unremitting muscle contractions).4,75,106,107 ors and fasciculations, episodes of hyperkalemic periodic
paralysis, sleep disorders). In these conditions, horses do not considered if recurrent seizures occur. However, long-term
lose consciousness but remain bright and alert. Horses with therapy can be expensive, and expectations must be discussed
HYPP might show prolapse of the nictitating membranes of with the owner because antiseizure medication is not a cura-
the eye and muscle fasciculations but remain anxious, alert, tive measurement and the horse might still have seizures while
and have normal pain perception. Cardiac disorders might on medication. For short-term management, drugs such as
precipitate syncopal episodes, which could be confused with benzodiazepines (diazepam, midazolam) or intravenous bar-
seizures. Auscultation of the heart might help identify the biturates (phenobarbital) can be used.114
presence of murmurs, and electrocardiography may help Benzodiazepines hyperpolarize neuronal cells by binding
determine the presence of arrhythmias. to GABA receptors, resulting in change of the chloride con-
A complete blood cell count (CBC) and serum biochemistry ductance pathways and making cells resistant to depolariza-
analysis should elucidate the presence of systemic extracranial tion. The overall result is a decrease in the electrical activity
disease, which may predispose to seizures. CBC and fibrinogen of the seizure focus and an increase in the seizure threshold.114
may suggest inflammation (leukocytosis and hyperfibrinogen- Although quite effective, the half-life of diazepam is short, 10
emia) or viral infection. A complete serum biochemistry pro- to 15 minutes, making repeated doses sometimes necessary.
file should be performed to rule out metabolic abnormalities Caution is warranted as prolonged usage might cause respira-
that might trigger seizures. Hypoglycemia could be a cause of tory depression/arrest and drug accumulation in foals as its
seizures in both adults and foals. An arterial blood gas evalua- clearance is slower in this age group.120 In patients that do not
tion is indicated to rule out hypoxia. Liver function tests, liver respond to the initial bolus doses of diazepam, a constant-rate
biopsy, and determination of serum ammonia concentration infusion of diazepam can be implemented at an initial rate of
should be performed if hepatic encephalopathy is suspected. 0.1 mg/kg/hr.75,122 Midazolam is a potent short-acting benzo-
CSF evaluation might be helpful in approaching a diagno- diazepine that can be used in foals at 0.05 to 0.1 mg/kg intrave-
sis but commonly does not provide a definitive diagnosis. A nously or intramuscularly or as a continuous-rate infusion.122
normal cytology and biochemistry profile does not rule out Intravenous phenobarbital rapidly (within 20 minutes)
disease. The site of choice is the atlantooccipital cistern, but provides a high serum concentration and will reduce cere-
this may be contraindicated if the horse is showing signs of bral metabolic rate. The mechanisms of action of phenobar-
increased CSF pressure (such as mydriasis or papilledema) bital include (1) facilitation of inhibitory neurotransmission
or if general anesthesia is not appropriate. Alternatively, CSF via GABA receptors; (2) inhibition of postsynaptic potentials
fluid collection from the lumbosacral space could be per- produced by glutamate; and (3) inhibition of voltage-gated
formed, providing that it can be safely done in the standing calcium channels at excitatory nerve terminals. Caution must
and sedated animal. Interpretation of equine CSF abnormali- be practiced in neonatal foals, and lower loading dosages com-
ties is described previously in this chapter. pared with adult horses can be used such as 3 to 6 mg/kg IV
EEG, the graphic recording of the rhythmic bioelectrical diluted in saline and infused over 30 minutes (unpublished
activity arising predominantly from the cerebral cortex, is the data, Aleman). Start with the lowest dosage and increase
most important clinical test in humans suffering from epi- if needed. Older foals and adults can be loaded with 6 mg/
lepsy. Similarly, this diagnostic test has been useful in horses kg IV diluted in saline (500 mL) and given over 30 minutes.
with seizures.80,85-88,117 Paroxysmal activity includes spikes, Maintenance dosage is 3 to 4 mg/kg PO q 12 h. If necessary,
sharp waves, spike-and-wave discharges, and other transient higher dosages or frequency of administration can be used
events.80,85-88,117 Focal, multifocal, or generalized epilepti- (q 8 h instead of q 12 h). Other authors have reported higher
form activity can be recorded on EEGs of epileptic patients, loading dosages for foals of 20 m/kg IV followed by mainte-
depending on the localization of the discharges and the extent nance dosages of 9 mg/kg IV q 8 h.118 In adult horses, a par-
of the cerebral cortex involved.80,85-88,117 The lack of recording enteral loading dosage of 12 mg/kg IV followed by 6 mg/kg
of epileptical activity does not rule out seizures.88 The proxim- IV (20-minute infusion) q 12 h has been recommended.119
ity of a seizure to the EEG examination might influence the The therapeutic dosage for horses is unknown. Maintenance
amount of epileptiform activity present in the EEG. Therefore therapy is administered by the oral route at dosages of 3 to
consideration of performing more than one EEG examination 6 mg/kg.
is recommended.80,85-88,117 Horses suffering from extracranial Sodium pentobarbital could be used for the short-term
diseases might also have an abnormal EEG recording such as management (1–3 days) of seizures in neonatal foals because
during metabolic diseases.80,85-88,117 of its anesthetic effects. Although this anesthetic agent has lit-
The best imaging modality specifically for the brain is MRI. tle use in the management of seizures in adult horses, general
Other modalities might aid in identifying abnormalities of anesthesia with continuous infusion of pentobarbital (for up
the skull, including trauma that might be associated with or to 24 hours) might be required for horses suffering from sta-
causing seizures. Those modalities include skull radiographs tus epilepticus, which might not be controlled effectively with
and CT. regular anticonvulsant therapy. Other agents such as propofol
and ketamine might be considered for the management of sta-
Treatment tus epilepticus.123
The goals of treatment are to stop ongoing seizures, address Primidone and phenytoin might be considered as an alter-
underlying diseases, and prevent future seizure activity. native therapy if previous drugs are ineffective. Primidone is
Initial Therapy: Controlling Seizures. Prompt control of sei metabolized to phenobarbital (main active metabolite) and to
zures is a priority as prolonged or recurring seizures might a smaller extent to phenylethylmalonamide (a metabolite that
result in neuronal injury, self-trauma, and trauma to caregivers. might potentiate the anticonvulsant effects of phenobarbital).
Short- and long-term anticonvulsants have been used in hors- Primidone has been reported anecdotally for treating foals
es.75,118-121 Short-term treatment implies controlling seizures with seizures.124 Phenytoin inactivates voltage-dependent
at the time they are occurring. Long-term therapy should be neuronal sodium channels, preventing depolarization of the
presynaptic neuronal membrane at the excitatory nerve ter- seizures are not controlled with one anticonvulsant therapy,
minal, and thus reducing release of glutamate. Adverse effects one could consider reducing the dose by 20% or to nontoxic
of phenytoin include prolonged depression in foals, as well as level and beginning a second anticonvulsant therapy, such as
mild atrioventricular block and decrease in blood pressure in potassium bromide.124
adults.114 Bromide (sodium or potassium) appears to compete with
Drugs such as acetylpromazine, xylazine, and ketamine chloride to hyperpolarize neuronal membranes, as well as
should be used with caution for emergency seizure manage- enhancing GABA-activated chloride conductance. Because
ment if emergency antiseizure medication is not available. the elimination half-life of this drug in horses is 3 to 5 days, it
There have been reports of acetylpromazine lowering seizure often takes a few weeks to reach a steady-state level in horses.
threshold; however, the editor has used acepromazine safely Because of the long elimination half-life, potassium bromide
in the past in small and large animals with seizure disorders should not be used alone to treat ongoing seizures but in com-
without triggering seizures. Ketamine might exacerbate sei- bination with phenobarbital, with an initial dose of 25 to 40
zures because it increases cerebral blood flow, oxygen con- mg/kg/day PO.126,127 When used as monotherapy, a loading
sumption, and intracranial pressure. However, ketamine dose of 120 mg/kg daily for 5 days followed by a daily oral dose
also antagonizes NMDA receptors and thus appears helpful of 40 mg/kg achieved a serum level of 1 mg/mL. The therapeu-
in a rodent model of status epilepticus, as well as in some tic level for horses is not known. Adverse effects appear to be
neonatal foals with seizures, although further studies are rare in horses.
required.122 Newer antiepileptic drugs have been introduced in vet-
Maintenance Therapy: Preventing Seizures. The goal of erinary medicine, with improved therapeutic indices (i.e.,
long-term anticonvulsant therapy is to reduce the frequency, effective dose compared with toxic dose) with a reduction of
duration, and severity of seizures with no or minimal adverse the sedative and organ-toxic adverse reactions. These drugs
effects associated with such therapy. Therefore the initiation include felbamate, gabapentin, clorozepate, toparimate, leve-
of long-acting anticonvulsant therapy depends on consider- tiracetam, and zonisamide and can be used as monotherapy
ation of the underlying cause, frequency, and severity of the or in combination.128,129 Gabapentin, a structural analog of
episodes. Client factors such as owner preference and compli- GABA, has been used as adjunctive therapy in humans and
ance and the long-term expense of medication should also be dogs for the treatment of partial seizures refractory to pheno-
considered. The owners should be aware that therapy for the barbital and bromide therapy. Gabapentin128 at 5 to 10 mg/kg
control of seizures, particularly in adult horses, might contin- orally 2 to 3 times a day has been used anecdotally to aid in sei-
ue for months or years. In addition, the initiation of treatment zure management. However, the clinical efficacy of gabapentin
does not guarantee elimination of seizures. It is paramount to and other new anticonvulsant drugs is currently unknown in
recommend against riding a horse with seizures or on antisei- horses. Based on pharmacokinetic studies on levetiracetam in
zure medication. horses using 20 mg/kg IV or 30 mg/kg intragastric immedi-
With identified intracranial diseases, the therapy should be ate and extended release, an intravenous or oral dosage of 32
initiated at the onset of seizures. When no etiology has been mg/kg q 12 h was proposed.129 Bioavailability in this study was
determined, the decision to place the horse on long-term determined to be excellent, and the mean terminal half-life
maintenance therapy is based on recognition of either a cluster was 6 to 7 hours.129
of seizures (greater than 3–4 times per year or 2 seizures per It is difficult to provide recommendation for when to ter-
month) or severe generalized seizures that result in injury to minate anticonvulsant therapy. If no adverse effects are seen,
the horse and danger to those in the environment regardless of the dose should not be altered for most horses until the patient
frequency. Foals with idiopathic epilepsy that have several sei- has been seizure free for at least 6 months in the author’s opin-
zures over 1 to 3 days also might require long-term (months) ion (Aleman). If one needs to discontinue anticonvulsant ther-
anticonvulsant therapy.105,108 apy, this should be done slowly because sudden withdrawal of
One should select a single anticonvulsant medication drugs might precipitate seizures. In neonates, the dose can be
for maintenance; the choices include phenobarbital, bro- decreased by one-fourth to one-half each day for a minimum
mide, phenytoin, and primidone. Phenobarbital is the drug of 3 days and then discontinued. In an adult that has been
of choice for long-term maintenance in horses. Phenobar- on long-term anticonvulsant maintenance therapy, a longer
bital is well absorbed following oral administration and is weaning period is suggested. Anecdotal reports of decreasing
metabolized in the liver. It induces hepatic cytochrome P450 dosages by 20% every other day for 1 week before stopping the
enzyme complex with resultant increase in its own rate of anticonvulsant have been proposed. The editor prefers a more
metabolism, often resulting in the need to adjust the dose gradual decrease of the dosage by 20% every 2 to 4 weeks.
over time.125 Therapy must be tailored to fit the individual Serial EEGs might provide valuable information on the pro-
needs, using the lowest concentration effective at control- gression or resolution of the disease in horses and might help
ling seizures, in conjunction with monitoring of serum drug the clinician in determining whether continued maintenance
concentration. Once the seizure activity is under control, anticonvulsant therapy is necessary.
phenobarbital monitoring approximately every 60 days is
usually adequate. Although phenobarbital is well tolerated in
horses, potential adverse effects include excessive sedation,
respiratory depression, bradycardia, hypotension, and hypo-
Sleep
thermia in neonatal foals. Veterinarians should avoid using Monica Aleman
other drugs with known interactions, such as ivermectin, a
GABA agonist. Tetracyclines and chloramphenicol inhibit Sleep in the horse is essential for its overall health.130 Lack of
hepatic microsomal enzymes, thereby prolonging the effects sleep and sleep disorders can compromise the horse’s health,
of phenobarbital. If the adverse effects are unacceptable and performance, and quality of life. Limited information and lack
of understanding of normal sleep in the horse can result in primed (ready to kick predators?) during drowsiness. Occa-
erroneous interpretation of normal and abnormal sleep, inac- sional vertex sharp waves (V waves) and transient benign
curate diagnosis of presumed sleep disorders, and manage- variants that may appear epileptiform have been observed
ment failure. Studies of sleep in the horse have mainly relied in healthy horses. These transient discharges are similar
on behavioral observations, which is the first essential step in to those observed in healthy humans during this stage of
the evaluation of sleep. In addition to observation, the use of sleep. These benign variants have been observed in sleep-
simultaneous EEG has redefined sleep medicine in humans deprived horses. During slow wave sleep, horses can sleep
through the determination of EEG characteristics of sleep and standing with the head held low or in sternal recumbency
its various stages. This is important because the definition of if safe and comfortable. Many horses in this stage display
various sleep disorders in people depends on identifying alter- a second atrioventricular block (not present during other
ations in the sequence, duration, and pattern of stages of sleep. states of vigilance).
Sleep staging is based on specific features recorded in the EEG, REM sleep is similar among species in which low voltage
electrooculogram (EOG), EMG, electrocardiogram (ECG), and mixed frequencies with episodic fast eye movements
and respiratory patterns. Collectively, these studies and their and loss of EMG activity are noted. Horses appear to devote
interpretation are known as polysomnography. Polysomnog- about 15% of their total sleep time to this state. Horses can
raphy is emerging in veterinary medicine. have REM sleep while in sternal recumbency while sup-
Horses sleep an average of 3 to 4 hours per day with multi- porting their head on the ground or on an object, or more
ple phases of rest and sleep (polyphasic sleepers) throughout a commonly in lateral recumbency if safe and comfortable.
24-hour period.130 Most of their sleep occurs at night. Approx- During REM sleep there is loss of muscle tone. In addition
imately 6 phases of rest and sleep during nighttime have been to rapid eye movements, twitching, blinking, flaring nos-
seen in horses based on observational studies. Duration of trils, and even limb stretching might be observed. These
lateral recumbency during nighttime has been reported to be movements have been wrongly interpreted as seizures.
2% to 9% and 5% to 15% in wild and stabled horses, respec- Brief standing REM sleep has been documented, but the
tively. In the wild, horses take turns for rest and sleep, where accompanying loss of muscle tone precludes extended peri-
a few horses remain on alert while others rest or sleep. Horses ods because of resulting collapse. Lack of REM sleep can
on alert stand on higher areas where visualization of possible result in sleep deprivation.
predators is better. Foals and especially neonatal foals sleep
more time per day than adults. Their periods of rest and sleep Sleep Deprivation
are more in number and frequency and of longer duration Sleep deprivation is the result of lack of adequate sleep.130,131
than those of adults. The need for rest and sleep in the foal What is considered adequate or enough sleep in the horse?
declines as the foal matures. From observational studies in This should be considered on an individual basis, and varia-
wild horses and horses housed in pastures, it has been noted tions among healthy individuals can be expected. Sleep depri-
that a shift in the amount of sleep substantially declines in vation can be manifested in the horse as excessive daytime
foals by 3 months of age. Differences in breed and gender have sleepiness and collapsing episodes. Horses commonly present
been reported, with draft breeds resting more than light breeds with abrasions in their dorsal carpi and fetlocks that suggest
and fillies resting more than colts. There are many factors that collapsing episodes. Sleep deprivation must be considered as
can influence sleep in horses such as the environment, safety, a possible cause of collapse, but other causes of collapse must
companions, hierarchy, physiologic state and age, exercise, be ruled out. Complete history, presence of concurrent medi-
diet, and disease (see causes of sleep deprivation). Naturally, cal problems, and information about the environment where
horses are herd animals, and through domestication we have the horse sleeps are essential in the investigation of alterations
altered sleep in horses. of sleep. Horses could be subjected to a variety of factors that
can interfere with normal sleep. These factors are listed in
Stages of Sleep Table 11.6.
Sleep staging in horses is not nearly as sophisticated as it is
in humans because of the unease of performing EEG in the Y OTHER SLEEP DISORDERS
natural setting.86 However, the recent introduction of tele-
metric EEG units in veterinary medicine has opened a major Sleep disorders in horses are poorly understood. A few dis-
opportunity to study sleep in the horse. Challenges presented orders have been reported or suspected in equine medi-
in performing EEG include distance of recording, maintain- cine. These include hypersomnia, narcolepsy with cataplexy,
ing EEG electrodes, and movement artifacts. In horses, four altered arousal, and REM disorders. Before considering a
states of vigilance can be determined through observation sleep disorder, first rule out sleep deprivation.132,133 Hyper-
and simultaneous video and EEG recording. The electrophysi- somnia means excessive sleepiness. However, these horses
ologic evaluation includes EEG, EMG, EOG, ECG, and respi- appear to have “apparently normal” cycles of sleep but may
ratory monitoring for the definition of the stages of sleep. The lack periods of REM sleep despite being observed lying
stages include wakefulness, drowsiness, slow wave sleep, and down for considerable time. A common complaint in these
REM sleep. horses besides excessive sleep is decreased performance.
In wakefulness, the horse is bright and alert, standing This disorder might be secondary to other diseases such as
with all limbs unless moving. Movement artifacts (eyes, endocrinopathies (suspected hypothalamic dysfunction,
ears, jaw, head) and EMG activity are common. Heart and pituitary pars intermedia dysfunction),134 neurologic disease
respiratory rates are within reference values. Horses can (encephalitis, brain trauma, EPM, West Nile virus observed
adopt a stance characterized by weight bearing of both tho- by author), and others yet to be identified. Specific mecha-
racic limbs and one pelvic limb with the other pelvic limb nism of disease is unknown.
TABLE 11.6 Causes of Sleep Deprivation

Environmental Nonneurologic Medical Problems Neurologic Problems
Wild horses Pain (specially chronic) Inability or unsafe to lie down
• Predators • Orthopedic, musculoskeletal Recumbency
• Rank in the herd disease Neuropathic pain
• Dominant horses (on constant alert) • Gastrointestinal (e.g., enteroliths)
• Bottom of herd (constant harassment by others) • Pleuropneumonia
• Establishing ranking order in the pack
• Constant search for food
• Extreme temperatures, natural disasters (e.g., fire)
• Physiologic state
• Pregnant mares not lying down enough
• Lactating mares on constant alert to protect
their foal
• Domesticated horses
• Housing (indoors: stall vs. outdoors: pasture)
• Predators in the area
• Rank in the herd
• Lack of companion(s)
• Bedding (lack of or uncomfortable)
• Traveling and shows
• Quarantine areas
• Hospitalization (more common in intensive
care units)

A history of collapse or presence of abrasions or fibrosis in rare and is breed specific. Both familial and sporadic cases
the dorsal carpi and fetlocks should alert the clinician of a pos- of narcolepsy have been presumed observed in horses.136-140
sible sleep disorder. Other causes of collapse must be ruled out The disease has been reported in Suffolk and Shetland foals
(cardiovascular, respiratory, neurologic conditions, electrolyte (the fainting disease),137 Welsh ponies, Miniature Horses,
derangements). Video surveillance for 24 hours for a mini- Thoroughbreds, Quarter Horses, Morgans, Appaloosas,
mum of 7 days will provide useful information about the sleep Standardbreds, and Lippizaners.136-140 A familial occurrence
behavior of the affected horse. Ideally, this video should be is thought to exist in affected Suffolk and Shetland pony
recorded in the environment where the horse usually sleeps. foals, American Miniature Horses, and Lippizaners. In gen-
Hospital video monitoring is useful but can greatly alter sleep eral, narcolepsy is identified in two distinct groups: in foals
patterns (stress, noise, unfamiliar territory). However, it is rec- (for which the onset occurs within a few months of life) and
ommended. A questionnaire with specific questions regard- in adult horses.
ing the environment, presence of wildlife, companions, diet, A condition of excessive daytime sleepiness with episodes
traveling, shows, medical or painful conditions, and medica- of collapse or near-collapse is described in horses that have
tion should be included. Ask if other horses suffer from similar been deprived of REM sleep or not enough slow wave sleep
problems. Before considering a sleep disorder, rule out sleep for a period of time.130,131 This might be the result of medical
deprivation as the cause of abnormal sleep behavior because conditions inhibiting recumbency (pain, altered neurologic
this might be corrected if the primary cause is corrected. status), housing and environmental factors (weather, wild-
Without simultaneous video and electrodiagnostic testing, it life), or social and behavioral factors. This apparently exces-
is not possible to determine whether all stages of sleep occur sive sleepiness has been commonly confused as narcolepsy,
or if paroxysmal activity may be occurring. but this clinical manifestation in many instances is due to
lack of adequate sleep as defined for the particular individ-
Narcolepsy ual. However, this lack of sleep can have serious conse-
Narcolepsy is a nonprogressive sleep disorder of the central quences in the overall health and performance of the horse.
nervous system characterized by excessive daytime sleepi- Therefore every effort to determine and address the primary
ness with manifestations of REM sleep. These manifestations cause must be made.130
also include uncontrolled episodes of loss of muscle tone Pathophysiology. Four components of narcolepsy are ap-
(cataplexy), although narcolepsy might also occur without parent in human beings: excessive daytime sleepiness associ-
cataplexy.132 ated with short periods of REM sleep, cataplexy, hypnagogic
Narcolepsy has been recognized in humans and suspected hallucinations, and sleep paralysis.133 Cataplexy or sudden
in a variety of domestic animals, affecting 0.02% of adults collapse with complete inhibition of skeletal muscle tone oc-
worldwide and over 17 breeds of dogs.132,133,135 Although its curs in horses with narcolepsy.137-140 Respiratory and cardiac
prevalence is not known in horses, narcolepsy appears to be muscles are spared.
With narcolepsy and cataplexy, a biochemical abnormal- Response to atropine sulfate supports a possible cholinergic
ity of the brainstem or sleep-wake center might be present. mechanism for causing cataplexy. One must monitor horses
In people, evidence suggests that narcolepsy with cataplexy given atropine sulfate for ileus and colic.
is related to an underlying deficiency in the hypothalamic Differential Diagnosis. Cataplexy, which is commonly
orexin/hypocretin system.132,133,135 Although their physi- seen with narcolepsy, is the best diagnostic marker of this
ologic roles are not fully understood, hypocretins are hypo- disease and should be distinguished from other causes of
thalamic-specific neuropeptides, which are involved in episodic weakness or collapse. Ruling out collapse second-
various functions such as sleep, feeding, energy homeosta- ary to prolonged sleep deprivation is important as it might
sis, and neuroendocrine and autonomic nerve functions. A be common in horses. This disorder might be caused by
mutation in the hypocretin receptor 2 gene has been identi- chronic pain, environmental factors, or social/behavioral
fied in Dobermans and Labrador Retrievers, with secondary factors. In these cases, administrating NSAIDs to animals
impairment in postsynaptic hypocretin neurotransmission. with chronic pain and/or providing the horse with a com-
In acquired canine narcolepsy, the concentration of hypocre- fortable environment (to encourage the horse to lie down)
tin-1 in the brain and CSF was undetectably low, suggest- might resolve the clinical signs.130 Acute collapse without
ing a loss of production of hypocretin peptides, similar to premonitory signs is characteristic of cardiovascular col-
the pathophysiologic mechanisms reported in humans.132,133 lapse or syncope, and unlike narcolepsy is not preceded by
Although the role of hypocretins in equine narcolepsy is gradual lowering of the head and drowsiness. Atrial fibril-
unknown, horses with pituitary pars intermedia dysfunction lation, ruptured chordae tendinae, myocardial infarction,
and narcolepsy-like episodes had low concentration of hypo- myocardial fibrosis, aortic endocarditis, and pericarditis
cretin-1 in the CSF.134 have been associated with syncope in horses. Cerebral hy-
Clinical Signs. Cataplectic episodes are triggered by poxia might occur in these conditions and might lead to
strong emotions (usually positive), such as laughing or coma, with or without signs of cardiac failure. One should
anger in humans and excitement associated with play or differentiate seizures from narcolepsy/cataplexy, botulism,
the presentation of food in dogs. In horses, the initiation myasthenia-like syndrome, hypocalcemia, and hyperkale-
of eating or drinking, petting or stroking of the head and mic periodic paralysis, among others.
neck, hosing with cold water after exercise, and leading out Treatment and Prognosis. In general, drugs that stimu-
of a stall might precipitate a cataplectic episode. The epi- late monoamine systems (e.g., dopamine) in the brain are
sodes have also been reported during riding. Adult horses effective suppressors of narcolepsy, whereas drugs that
might drop their heads, buckle at the knees, and stumble. If stimulate cholinergic activity in the brain exacerbate nar-
forced to walk, the horse might appear ataxic. Pony breeds colepsy. Imipramine, a tricyclic antidepressant drug, has
are more likely to become recumbent. Affected horses are been recommended to control narcolepsy and cataplexy.138
neurologically normal between attacks. The drug blocks the uptake of serotonin and norepineph-
Diagnosis. Diagnosis of narcolepsy is based on his- rine and decreases REM sleep. Oral administration (250–
tory, clinical signs, pharmacologic testing (not always reli- 750 mg) produces inconsistent results.138 Potentially serious
able), and the absence of other diseases. Careful question- adverse effects including muscle fasciculations, tachycar-
ing of the caretaker should be performed to determine any dia, hyperresponsiveness to sound, and hemolysis may be
event(s) associated with the episode, and video documenta- seen in horses receiving intravenous dosages of imipramine
tion of the episode(s) is optimal. Physical examination may that exceed 2 mg/kg.138 Adverse effects are not seen when
reveal the presence of superficial trauma, particularly over the drug is administered orally, but that is likely because
the dorsal aspect of the fetlocks and carpi in most, but not of very poor bioavailability. The disorder might persist
all, cases. A CBC and serum biochemical profile are nor- for life.
mal in affected horses and may help to exclude underlying
systemic and metabolic abnormalities. CSF cytology is usu- Y CENTRAL NERVOUS SYSTEM TRAUMA
ally normal, and EEG might reveal REM sleep during an
episode. Yvette S. Nout-Lomas
A presumed provocative test with variable results to
diagnose narcolepsy or cataplexy in horses is the use of Trauma to the CNS is the most common cause of neuro-
physostigmine salicylate. Physostigmine is an anticholines- logic disease in horses, accounting for 22% to 24% of neuro-
terase drug given at 0.05 to 0.1 mg/kg slowly intravenously logic disorders.141,142 Both of these studies reported trauma
that might precipitate a cataplectic attack within 3 to 10 to the spinal cord to be more prevalent than brain injury.
minutes after administration in affected horses. This com- Traumatic brain injury (TBI) was reported in 23% to 44%
pound crosses the blood-brain barrier. Careful monitoring of cases, and spinal cord injury (SCI) was reported in 56%
of the horse after physostigmine administration is neces- to 77% of cases. A more recent investigation into exercise-
sary because of untoward effects such as colic and cholin- associated sudden deaths in previously apparently healthy
ergic stimulation. In addition, lack of positive response to Thoroughbred racehorses from six racing jurisdictions
physostigmine does not rule out a diagnosis of narcolepsy around the world showed that 13% (18 of 143) of deaths
because individual response to the drug is quite variable were attributed to CNS trauma.143 Of these, 60% (11 of 18)
and some affected horses failed to respond to this provoca- had SCI associated with cervical vertebral fracture, 17% (3
tive testing. of 18) had CNS hemorrhage, 11% (2 of 18) had TBI associ-
Atropine sulfate, a muscarinic blocker, given at 0.04 to ated with skull fracture, 6% (1 of 18) had CNS injury associ-
0.08 mg/kg intravenously, reduces the severity of cataplectic ated with both skull and cervical vertebral fractures, and 6%
attacks minutes after administration and can prevent their (1 of 18) of cases had SCI associated with cervical vertebral
reoccurrence for 12 to 30 hours following administration. instability.
Although mechanisms of CNS cell damage, to a certain occipital cortical injury may occur and, as described for poll
degree, are similar after TBI and SCI, a few different processes impact injuries, with frontal injuries the optic nerves may be
exist with regard to cause and pathophysiology. Clinical syn- stretched.
dromes as a result of traumatic injury to the CNS can vary Pneumocephalus was diagnosed by radiographs or CT
tremendously, but the most common are coma, vestibular disin horses after trauma to the head with suspected or con-
ease, tetraparesis, paraparesis, tetraplegia, and cauda equina firmed fractures to the sinuses152 and after sinus surgery.153
syndrome. Treatment regimens for CNS injury are aimed Pneumocephalus, also known as intracerebral airocele or
toward reducing inflammation and swelling, halting second- pneumatocele, is defined as the presence of gas within any
ary injury mechanisms, and promoting regeneration and intracranial compartment (intraventricular, intraparen-
recovery of function. Prognosis depends primarily on severity chymal, subarachnoid, subdural, and epidural). In the six
of primary injury and on the extent and neuroanatomic loca- horses described in these reports, there were no neurologic
tion of CNS damage. sequelae noticed that could be attributable specifically to
the pneumocephalus. However, in humans clinical signs
include headache, nausea and vomiting, seizures, dizziness,
Traumatic Brain Injury and depressed neurologic status. Although pneumocepha-
Pathophysiology lus can be an incidental finding, it is a possible life-threat-
Head trauma is typically caused by incidents such as col- ening complication that can occur after head trauma in
lision with an immovable object such as a fencepost or horses.
another horse, falling down, flipping over backward, being After trauma, the most severe damage generally takes place
kicked by another horse, and, although rare, impact by a at the place of impact (coup), opposite to the side of impact
projectile (e.g., gunshot). A retrospective study involving 34 (contrecoup), or in both locations. Additionally, the brain is
horses with TBI showed that the most common cause (44%) subjected to other forces after trauma, such as rotational and
of injury was rearing and falling backward, resulting in poll shock wave forces. TBI is a result of both direct, immediate
injury.144 Another type of head injury that may lead to CNS mechanical disruption of brain tissue (primary injury) and
damage is fracture of the petrous temporal bone associated indirect, delayed (secondary) injury mechanisms. The pri-
with THO.145 mary damage is a result of the biomechanical effects of the
Although traumatic injury to the head is reported to be injury and is characterized by immediate and often irrevers-
common in horses, subsequent TBI occurs only in 25% to ible damage to neuronal cell bodies, dendritic arborizations,
50% of cases.146,147 The remaining horses typically present axons, glial cells, and brain vasculature. This initial brain
for fractures of the orbit, periorbital rim, and zygomatic, injury may be focal, multifocal, or diffuse. Secondary injury
mandibular, or maxillary bones. TBI may occur with or is a complex cascade of molecular, cellular, and biochemical
without fracture of the calvarium; however, some of the events that can occur for days to months after the initial insult,
most severe injuries to the brain occur when the injury is resulting in delayed tissue damage. In addition, systemic
contained within the closed calvarium (i.e., no skull frac- alterations further contribute to the tissue damage. Hypoxia,
tures).148 Within the closed calvarium, the sum of the intra- ischemia, brain swelling, alterations in intracranial pressure,
cranial volumes of the brain, blood, and CSF are constant; hydrocephalus, infection, breakdown of blood-brain bar-
volume or pressure changes within one of these compart- rier, impaired energy metabolism, altered ionic homeostasis,
ments will affect volume (anatomy) or pressure of the other changes in gene expression, inflammation, and activation and
compartments. release of autodestructive molecules occur and exacerbate the
Consequences of impact sustained to the poll in horses initial injury. Recently the pathology of TBI after blunt non-
that flip over backward include fracture of the bones on the missile and penetrating missile head injuries in veterinary
side and base of the calvarium such as the petrous temporal, species was reviewed.154
squamous temporal, and parietal bones. However, more com- Principles of raised intracranial pressure are described in
monly these bones remain intact, and more serious injury the Monro-Kellie doctrine, which states that once the fonta-
occurs to the basilar bones as a result of strong traction forces nelles and sutures of the skull are closed, the brain is enclosed
from the rectus capitis ventralis muscles (Fig. 11.23).149,150 In in a nonexpandable case of bone, the brain parenchyma is
addition, adjacent large vessels are lacerated, and hemorrhage nearly incompressible, the blood volume in the cranial cav-
into the retropharyngeal spaces or guttural pouches can occur. ity is therefore nearly constant, and a continuous outflow of
In severe cases, transverse fracture of the basilar bones at the venous blood from the cranial cavity is required to make room
level of the basioccipital-basisphenoidal suture can occur. for continuous incoming arterial blood.155 Blood flow to the
Young horses may be more susceptible to this type of injury brain is controlled by changes in diameter of resistance blood
because the joint between the basilar bones fuses by 5 years vessels, and cerebral blood flow is controlled by autoregulation
of age.150 In most cases the fracture site is stable, and minimal whereby the perfusion pressure is maintained within a range
displacement occurs. The cerebellum is seldom severely dam- of approximately 50 to 150 mm Hg. Beyond these limits, cere-
aged after poll impact,145 but the cerebral parenchyma is more bral blood flow decreases at pressures below the lower limit
commonly injured after being subjected to rapid acceleration- and increases at pressures above the higher limit. Cerebral
deceleration forces. Moreover, optic nerves and other attach- perfusion pressure (mean arterial blood pressure minus intra-
ments may be torn from the cerebral hemispheres.151 Impact cranial pressure) is the stimulus to which the autoregulatory
to the dorsal surface of the head may result in damage to the response of the vasculature occurs. Cerebral autoregulation is
frontal or parietal bones, with subsequent cerebral cortical altered unpredictably after TBI, and it appears that the mini-
injury or, more commonly, damage to the cervical vertebrae mum acceptable cerebral perfusion pressure is higher than
with subsequent SCI. In addition, cranial nerve XII may be normal after trauma. Increased intracranial pressure leads
injured as it exits the hypoglossal foramen. Furthermore, to a decreased cerebral perfusion pressure and subsequently
A
A B
C D
FIG. 11.23 A, Radiograph from a 3-year-old Thoroughbred colt that flipped while playing on the end of the lead shank. The horse hit its head on a
small board along the side of the walkway and was unconscious for 3 to 5 minutes. The horse had blood coming from the nostrils, paralysis of the right
eyelid, a corneal ulcer on the right eye, and weakness in all four limbs. The radiograph shows a fluid line in the guttural pouch (small white arrows) and a
basisphenoid fracture (large black arrows) with a large fragment (arrowheads) visible in the guttural pouch area. B, This is a radiograph taken from a horse
after head injury and subsequent rupture of the longus capitis muscle and an avulsion fracture from the basisphenoid bone. This is a radiograph image C
taken from a horse that flipped while playing on the end of the lead shank. This is a radiograph image D taken from a horse with head injury that resulted
in rupture of the longus capitus. The arrow is pointed at the avulsed bone located behind the guttural pouch. Image from The Ohio State University.
(A, Courtesy Stephen Reed, DVM, Rood and Riddle Equine Hospital. B, Courtesy The Ohio State University.)
reduces cerebral blood flow. Reduced cerebral blood flow bright red and then usually originates from larger vessels in
results in areas of ischemia and subsequent restriction of the guttural pouches. Respiratory distress can occur associ-
delivery of substrates such as oxygen and glucose to the brain. ated with significant throat swelling after profuse hemorrhage
Brain swelling after TBI because of edema formation and into the guttural pouches. Furthermore, neurogenic pulmo-
hematoma formation within the skull are the most common nary edema has been reported to occur. Acute elevation of
causes of increased intracranial pressure. Vascular damage intracranial pressure may result in Cushing’s reflex, which is
that occurs after head injury can be epidural (between dura a hypothalamic response to brain ischemia and is character-
mater and the skull), subdural (between the dura mater and ized by hypertension and secondary baroreceptor-mediated
arachnoid mater), subarachnoid (between arachnoid mater bradycardia. Continued elevation of intracranial pressure and
and pia mater), superficial (vessels immediately under the pia reduction of cerebral blood flow results in increased sympa-
mater), intraparenchymal, and intraventricular. thetic discharge (catecholamines), with subsequent myocar-
The cascade of secondary injury that results in necrotic and dial ischemia and development of cardiac arrhythmias. This is
apoptotic cell death is described in more detail in the section referred to as the brain-heart syndrome.
on pathophysiology of SCI. Uncontrolled glutamate release Life-threatening injuries should be attended to first, and
and failure of energy systems in neuronal and supporting tis- then a complete neurologic examination should be performed.
sues lead to elevated intracellular calcium concentrations and Horses may be recumbent, intractable, or both after a trau-
subsequent cell death. Hemorrhage, ischemia, and the primary matic incident; examination and management of these horses
tissue damage lead to sequestration of vasoactive and inflam- can be difficult and dangerous.9 Signs of focal brain injury are
matory mediators at the injury site and are thus involved in listed in Table 11.7. Sedation may be necessary for examina-
the secondary injury cascade. Inflammation and endothelial tion. Although α2-agonists may transiently cause hyperten-
damage cause derangements in normal cerebrovascular reac- sion, which may potentiate intracranial hemorrhage, xylazine
tivity and contribute to a mismatch of oxygen delivery to tis- has been found to cause a minor decrease in cerebrospinal
sue demand, resulting in local or diffuse ischemia. pressure in normal, conscious horses158 and is considered a
A major consequence of ischemia is reduced delivery of safe sedative to use in horses with head trauma if the head is
oxygen and glucose. Blood flow interruption is responsible not allowed to drop too low that it could affect physiologic
for disruption in ion homeostasis (especially calcium, sodium, changes in intracranial pressure.
and potassium) and a switch to anaerobic glycolysis resulting The complete neurologic examination should include an
in lactic acid production and acidosis. Cell membrane lipid assessment of the horse’s mentation, cranial nerve function,
peroxidation with subsequent prostaglandin and thrombox- posture, and ability to coordinate movements, as well as its
ane synthesis, formation of reactive oxygen species (ROS), ability to regulate rate and range of motion. In addition, reflex
nitric oxide, and energy failure also ensue. Because of the and nociceptive testing should be performed to investigate any
high metabolic rate and oxygen demand of the brain, disrup- concurrent SCI. Serial neurologic examinations, particularly
tion of blood flow rapidly compromises the energy-supply- during the first hours, are important for diagnostic purposes
ing processes and leads to impaired nerve cell function and and to allow prediction of a more accurate prognosis. Further-
even cell death. Impaired mitochondrial function with sub- more, serial examinations are important to assess response to
sequent energy depletion leads to a loss in maintenance of therapy. Pupil size, symmetry, and response to light should be
membrane potentials resulting in depolarization of neurons assessed in all horses and followed carefully, particularly in
and glia.156 Cytotoxic edema develops through the failure of recumbent horses. A change from bilateral pupillary constric-
the sodium-potassium ATPase-dependent pump in the pres- tion to bilateral dilation with no response to light is a poor
ence of hypoxia and the subsequent influx of water that pas- prognostic indicator.
sively follows sodium and chloride. In addition to cytotoxic The most common neurologic syndromes after head
edema, vasogenic edema develops as a result of disruption of trauma are a result of hemorrhage into the middle and inner
the blood-brain barrier, which includes damage of endothe- ear cavities. Signs are those of central or peripheral vestibu-
lial cells, degeneration of pericytes, and loss of astrocytes.157 lar disease and facial nerve damage and include recumbency,
Extravasation of blood components and water occurs result- head tilt, neck turn, body lean, and circling, all toward the
ing in increased extracellular fluid accumulation. Understand- side of the lesion. The ipsilateral eye may be rotated ventrally
ing the complex pathophysiologic events that take place after and laterally, and there may be horizontal or rotary nystag-
TBI is important for the development of effective monitoring mus with the fast phase away from the lesion. Facial paralysis
and treatment strategies. on the same side as the lesion is seen with cranial nerve VII
damage. Central vestibular disease is suspected when signs of
Neurologic Evaluation brainstem disease or other cranial nerve deficits are present.
Clinical signs associated with TBI range from inapparent Central vestibular lesions can result in a paradoxic vestibular
to recumbency with unconsciousness or death (Fig. 11.24). syndrome, in which the lesion is located on the side opposite
A complete physical examination is very important in head to that which is expected from the clinical signs. More serious
trauma cases, because fractures and other concurrent injuries trauma can lead to alterations of mentation, behavior, or both.
are not uncommon and require identification and treatment. The level of consciousness is affected by the degree of
Physical examination findings as a result of head trauma can damage to the cerebrum and reticular activating system in
include fractures; hemorrhage from the nostrils, mouth, and the brainstem. Immediately after cerebral injury, a period of
ears; CSF draining from the ear (Fig. 11.25); respiratory dis- concussion occurs, with unconsciousness for various peri-
tress; cardiac arrhythmias; and hypotension or hypertension. ods of time, or even coma. Usually a horse recovers from this
Hemorrhage from the nose typically presents as dark-colin minutes to hours. Comatose horses may have an irregu-
ored (venous) blood and originates from a paranasal sinus, lar breathing pattern with periods of either Cheyne-Stokes
ethmoid turbinates, or nasal cavity. Occasionally, blood is breathing or hyperventilation. In some horses, seizures can
occur after initial concussion; these are typically generalized pupil size, and loss of pupillary light response can be present
seizures. Level of mentation and responsiveness to reflexes because of damage to cranial nerve III. Apneustic or erratic
should be assessed and recorded. Injury to the occipital cortex breathing reflects a poor prognosis, and bilaterally dilated and
can result in impairment of vision and menace response of the unresponsive pupils indicate an irreversible brainstem lesion.
eye contralateral to the lesion. Pupillary light reflex, however, These lesions can occur immediately after injury, secondary
should remain intact. Injury to the parietal cortex can result in to herniation of components of the cerebrum or cerebellum,
decreased facial sensation on the contralateral side. Another or after hemorrhage. Severe brainstem injuries may result
sign of cerebral damage is dementia, or altered behavior, such in a decorticate posture, characterized by rigid extension of
as walking in circles (toward the side of the lesion), head press- neck, back, and limbs. Injury to caudal parts of the brainstem
ing, hyperexcitability, or aggression. (pons and medulla) result in dysfunction of multiple cranial
Severe rostral brainstem injuries (mesencephalon) can nerves in addition to depression and limb ataxia and weak-
be associated with coma and depression because of damage ness. To make a distinction between a cranial cervical spinal
to the reticular activating system. Strabismus, asymmetric cord and caudal brainstem lesion, careful assessment of the
No
Is dementia, ataxia,
weakness, spasticity, or The horse is normal
hypermetria present?
Yes
No The lesion is below

Are there cranial
nerve signs and/or the foramen magnum
dementia?
Yes
Are the rear limbs more

Does the horse exhibit
Yes severely affected than
mild depression, aimless the front limbs? Yes
Cerebral
wandering, seizures,
disease
delirium, blindness with Cervical (C1-C5)
normal pupillary light No spinal cord disease
response, and mild
weakness?
Are the front limbs more
severely affected than
No the rear limbs? Yes
Disease of the cranial

Yes Does the horse exhibit No intumescence (C6-T2)
Cerebellar hypermetria, intention
disease tremors, muscle hyper-
tonicity, and a deficit in Are the front limbs
its menace response? normal and the rear
limbs mildly affected? Yes
No
Thoracolumbar (T3-L4)
No spinal cord disease
Does the horse exhibit
Yes spasticity, tetraparesis,
Brainstem ataxia, narrow circling, Are rear limbs
disease cranial nerve signs, or severely affected?
severe depression? Is Yes
it in a semicoma?
No
Disease of the caudal
intumescence (L4-S2)
No Does the horse have tail
weakness, bladder atony,
No and perineal hypalgesia?
Diffuse
or Yes Does the horse exhibit
multifocal some or all of the above Yes
neurologic signs?
disease Sacral (>S2) spinal cord disease
FIG. 11.24 Flow chart for localizing a lesion in the nervous system in a recumbent horse.
horse’s mentation and function of cranial nerves X and XII is areas of the brain are damaged, this will be reflected in the dif-
important. ferent clinical signs. Multifocal damage or progression of dis-
Signs of cerebellar injury occur infrequently and include ease through hemorrhage, secondary injury mechanisms, or
intention tremor, broad-based stance, spastic limb movements, both is suggested when clinical signs become more widespread.
and absent menace response with normal vision. If multiple Diagnostic tools that are helpful in further defining cranial
trauma include radiography, CT, MRI, endoscopy, electrodi-
agnostics, transcranial magnetic stimulation, and CSF analy-
sis. Although radiographs typically are the first-line diagnostic
tool to use for determination of the presence and severity of
fractures, hemorrhage in cavities, or thickening of stylohyoid
bone or bulla (or both), one study showed that only 50% of
bony fractures of the calvarium were confirmed radiographi-
cally.144 CT has been shown to be an excellent neurodiagnostic
tool in identifying skull fractures, intracranial space-occupy-
ing lesions (e.g., neoplasia), and acute hemorrhage and allows
one to rule in intracranial disorders.159 However, this same
report showed that CT has limited sensitivity in identifying
inflammatory disorders and small parenchymal lesions in the
equine brain. Soft tissue changes that can be seen on CT after
TBI include change in the size, shape, and position of the ven-
tricles, deviation of the falx cerebri, and focal changes in brain
opacity. Enhancement of areas of injury or hemorrhage is
sometimes possible with iodinated contrast agents. MRI offers
a higher sensitivity for examination of soft tissue structures
and has the ability to acquire images in all planes. However, the
use of MRI is not yet possible for all equine clinicians. Upper
respiratory endoscopy is an important diagnostic procedure
for evaluation of cranial nerve function, stylohyoid bones,
retropharyngeal area, and appearance of guttural pouches.
Transcranial magnetic stimulation and measurement of the
magnetic motor-evoked potentials in the thoracic and pelvic
limbs has been shown to be helpful to assess the integrity of the
descending motor pathways, to confirm or exclude a descend-
ing motor tract lesion as the cause of the recumbency.160 Elec-
FIG. 11.25 Blood and cerebrospinal fluid (CSF) draining from the ear troencephalograms are used for assessment of seizure activity,
after a basilar skull fracture. BAER is used for examination of vestibular function, and
TABLE 11.7 Signs Characteristic of Focal Brain Injury

Levels Consciousness Motor Function Pupils Other Sign
Cerebrum Behavior change, Circling Normal Blindness
depression, coma
Cerebellum Ataxia and hypermetria, Menace response deficit
intention tremor without blindness
Diencephalon Depression to stupor Normal to mild tetraparesis, Bilateral, nonreactive None
(thalamus) “aversive syndrome”a pupils with visual
deficit
Midbrain Stupor to coma Hemiparesis, tetraparesis Nonreactive pupils, Ventrolateral strabis-
or tetraplegia mydriasis, anisocoria mus
Pons Depression Ataxia and tetraparesis, Normal Head tilt, abnormal
tetraplegia nystagmus, facial
paralysis, medial
strabismus
Rostral medulla Depression Ataxia or hemiparesis to Normal Same
oblongata (including tetraplegia
inner ear)
Caudal medulla Depression Ataxia, hemiparesis to Normal Dysphagia, flaccid
oblongata tetraparesis, abnormal tongue
respiratory patterns

From Robinson NE, editor: Current therapy in equine medicine, ed 6, St. Louis, 2009, WB Saunders.
aDeviation of the head and eyes with circling toward the side of a unilateral lesion.
visual function is examined with visual-evoked potential in and substrates to brain tissue to salvage brain tissue that is
combination with electroretinography. CSF analysis may not undamaged or reversibly damaged. This requires optimiz-
always be indicated after acute trauma, but it may be useful for ing cerebral blood flow (i.e., optimizing mean arterial blood
excluding other diseases. Cisternal CSF collection is contrain- pressure and hemoglobin concentration; ensuring intracra-
dicated if increased intracranial pressure is suspected because nial pressure is not elevated). Emergency surgical treatment
of the possibility of brain herniation through the foramen (although not commonly performed) is warranted in open
magnum. Lumbosacral collection is a safer alternative but can cranial fractures and in the face of deterioration despite medi-
be normal despite a traumatic episode, especially in the acute cal therapy. In Fig. 11.26 a flow chart is shown that can serve as
phase, and because if the sample is not obtained closest to the a guide to the management of cranial trauma in horses.
lesion it may not reflect the changes that have occurred. Methods to reduce intracranial pressure include hyperven-
In human medicine, development of advanced bedside tilation, CSF drainage, treatment with hyperosmolar agents
neuromonitoring devices has been an important focus in or barbiturates, head elevation, and decompressive surgery.
neurocritical care. The four most important parameters to be Hyperventilation reduces the partial pressure of carbon diox-
determined are (1) intracranial pressure, (2) cerebral blood ide in blood and subsequently leads to cerebral vasoconstric-
flow, (3) information on brain metabolism, and (4) functional tion. Reduced cerebral blood volume reduces intracranial
outcome. For example, catheters can be placed into the brain pressure. However, cerebral vasoconstriction may lead to
tissue to determine glucose, glycerol, and glutamate concen- reduction of cerebral blood flow to ischemic levels. Hyperven-
trations, indicators of secondary ischemia, by microdialysis, tilation could be considered in cases of increased intracranial
and probes can be placed to determine brain tissue oxygen pressure in horses. Proper hyperventilation requires moni-
tension. Methods to measure and monitor intracranial and toring of arterial blood gases and may require use of neuro-
cerebral perfusion pressures have been described for use in muscular blockers if the horse is not comatose and is resisting
foals161 and adult horses162; however, these techniques have the ventilator. CSF drainage is commonly used in people to
thus far not been scientifically evaluated in clinical cases. One reduce intracranial pressure; however, it is therapeutic only if
study demonstrated the use of near-infrared spectroscopy to CSF outflow obstruction is noted. If these methods are ineffec-
measure regional cerebral oxygen saturation in horses.163 tive, repeat imaging is pursued to investigate the presence of
mass lesions before medical treatments are commenced such
Treatment and Prognosis as administration of hyperosmolar substances and induction
Based on the pathophysiology of events that occur after TBI, of barbiturate coma. Hyperosmolar treatment is commonly
it is likely that single-drug intervention would not be effective. used in horses with neurologic signs attributable to TBI. This
Treatment of TBI is aimed at optimizing delivery of oxygen is discussed later in this section.
Level of
consciousness Alert Lethargic Stupor Coma
Depressed
Pupils Normal Small, reactive Bilateral nonresponsive, Bilateral nonresponsive,

or miotic mydriatic
unilaterally dilated
Motor
function Normal Hemiparetic Hemiparetic Decerebrate Flaccid
or or rigidity paralysis
tetraparetic tetraparetic
Static Progressive
Time course
(hours to Static Static Progressive Static Progressive
( )
days) from
time of
accident
Prognosis Good Guarded Guarded Poor Grave
Specific
management Observe Corticosteroids Corticosteroids, Corticosteroids, Corticosteroids, dimethyl
mannitol, mannitol, sulfoxide, mannitol,
dimethyl sulfoxide dimethyl sulfoxide assisted ventilation
Surgery Not indicated Not indicated Progressive Progressive
Exploratory craniotomy Craniotomy
FIG. 11.26 Flow chart for management of cranial trauma. (From Robinson NE, editor: Current therapy
in equine medicine, ed 6, St. Louis, 2009, WB Saunders; modified from Kirk KW, editor: Current veterinary
therapy VII, Philadelphia, 1980, WB Saunders.)
Mean arterial blood pressure should be maintained within However, the actual benefits of barbiturate use on the neuro-
normal limits. Blood transfusion may be indicated in cases logic outcome remain controversial. The effects of barbiturates
of severe hemorrhage. Crystalloid fluids are recommended on lowering intracranial pressure are enhanced by concur-
as fluid therapy of choice, particularly in light of findings of rent hyperventilation. An exact dosage regimen for barbitu-
the serum versus albumin fluid evaluation (SAFE) study164 rate treatment in horses has not been investigated, but 5 to 10
that determined no difference in outcomes between admin- mg/kg IV to effect is reported to be useful. The major adverse
istering albumin versus normal saline in the intensive care effect of barbiturates is hypotension, especially if mannitol
unit. Furthermore a post hoc follow-up study demonstrated and furosemide have been administered, so they must be used
a higher mortality rate in TBI patients that were treated with with caution and adequate blood pressure monitoring. Barbi-
albumin compared with those treated with saline.165 There turates should be reserved for those cases in which elevated
remain questions concerning optimal composition and vol- intracranial pressure is refractory to other treatments. Other
ume of fluid therapy for TBI. There is a physiologic rationale methods to lower intracranial pressure include elevation of
why excessive fluid administration and positive fluid balance the head by 30 degrees if no cervical fractures are present and
may increase brain swelling and intracranial pressure, and decompressive craniectomy.
current recommendations include refined usage of intrave- Hyperosmolar therapy, which includes mannitol or hyper-
nous fluids.166 tonic saline, is frequently used in human patients to reduce
It has been well established that maintaining blood glucose intracranial pressure. Both of these treatments appear effective
concentrations at 80 to 110 mg/dL through intensive insulin at reducing intracranial pressure, and there does not appear to
therapy reduces morbidity and mortality in human critical be a clinically significant difference between the two with regard
care patients.167 However, neurointensivists have shown that to mortality or neurologic outcomes.172 Hypertonic saline has
intensive insulin therapy increases markers of cellular distress a number of beneficial effects in TBI. The permeability of the
in the brain and suggest that systemic glucose concentrations blood-brain barrier to sodium is low. Hypertonic saline pro-
of 80 to 110 mg/dL are too low in TBI and may lead to cerebral duces an osmotic gradient between the intravascular and the
hypoglycemia. Recommendations now are to maintain blood interstitial-intracellular compartments, leading to shrinkage
glucose concentrations at 120 to 140 mg/dL in TBI. of brain tissue and subsequent reduction of intracranial pres-
Treatment with antiinflammatories is likely the most com- sure. It augments volume resuscitation and increases circulat-
monly used treatment in equine TBI. Indications for use of ing blood volume, mean arterial blood pressure, and cerebral
antiinflammatory treatment are to combat the inflammatory perfusion pressure. Other beneficial effects include restora-
pathways of secondary injury mechanisms (cytokine release, tion of neuronal membrane potential, maintenance of blood-
free radicals), improve comfort level, and reduce fever. Fever brain barrier integrity, and modulation of the inflammatory
is extremely common after TBI, and it has been well docu- response by reducing adhesion of leukocytes to endothelium.
mented in animal models and in human beings to negatively In horses, hypertonic saline can be administered intravenously
affect outcome after TBI (e.g., by augmenting secondary injury to head trauma patients in shock as 5% or 7% sodium chloride
mechanisms).168,169 Researchers have proposed that a proactive (NaCl) solutions (4–6 mL/kg) over 15 minutes. Isotonic fluids
approach should be taken toward reducing fever. In fact, hypo- can then be used for maintenance if needed. Contraindications
thermia has been shown to be neuroprotective. Hypothermia to the use of hypertonic saline include dehydration, ongo-
results in decreased cellular metabolism, and in humans ther- ing intracerebral hemorrhage, hypernatremia, renal failure,
apeutic hypothermia and targeted temperature management hyperkalemic periodic paralysis, and hypothermia. Systemic
have been proven efficacious as a treatment for TBI in experi- side effects include coagulopathies, excessive intravascular
mental and clinical settings; however, large multicenter trials volume, and electrolyte abnormalities. Monitoring central
have so far failed to demonstrate clinical benefits.170 Thera- venous pressure and maintaining it within normal limits (5–7
peutics with antiinflammatory properties that are common cm H2O) is therefore important, as well as monitoring serum
to equine practice include corticosteroids, NSAIDs, dimethyl sodium and potassium concentrations if hypertonic saline is
sulfoxide (DMSO), and vitamin E. These drugs are discussed used frequently. Mannitol induces changes in blood rheology
in more detail in the section pertaining to SCI. Corticosteroids and increases cardiac output, leading to improved cerebral
are no longer recommended for use in TBI following results perfusion pressure and cerebral oxygenation. Improved cere-
of studies showing no benefit of these drugs and results of the bral oxygenation induces cerebral artery vasoconstriction and
CRASH trial that showed increased mortality in adults who subsequent reduction in cerebral blood volume and intracra-
received methylprednisolone after TBI.171 nial pressure. Mild dehydration after osmotherapy is desirable
Controlling seizure activity is very important after TBI, and may improve cerebral edema; however, severe dehydra-
because seizure activity increases cerebral metabolic rate and tion can lead to hyperosmolality and renal failure. In horses,
is detrimental to secondary injury. It is not unusual for horses 20% mannitol can be administered at 0.25 to 2.0 mg/kg IV
sustaining cranial trauma to develop seizures. Diazepam, mid- over 20 minutes. Horses receiving osmotic diuretics should
azolam, phenobarbital, and pentobarbital are drugs that can be adequately hydrated. The use of osmotic substances is war-
be used to control seizures. Intractable seizures may necessi- ranted in any horse with worsening mental status, abnormal
tate general anesthesia. Agents useful for general anesthesia pupillary size or inequality indicating transtentorial hernia-
include guaifenesin, chloral hydrate, barbiturates, and gas tion, or development of paresis. Although mannitol admin-
anesthesia. Ketamine is not recommended as part of a bal- istration is very effective in reducing intracranial pressure,
anced anesthesia regimen because it increases cerebral blood several limitations to its use exist. Hyperosmolality can be
flow and intracranial pressure. associated with renal and CNS effects. Furthermore, adminis-
Barbiturate treatment or coma may decrease cerebral tration of multiple doses of mannitol may lead to intravascu-
metabolism, thereby providing a protective effect against cere- lar dehydration, hypotension, and reduction of cerebral blood
bral ischemia. Barbiturates may also limit lipid peroxidation. flow. Furosemide has experimentally been found effective in
decreasing intracranial pressure. Normal hydration status is basilar fractures and severe brainstem injuries carry a grave
required before furosemide is administered. Furosemide may prognosis.144 Time, good nursing care, and adequate nutri-
also be used concurrently with mannitol to increase the dura- tional support, especially in the recumbent horse, are vital
tion of intracranial pressure reduction provided by mannitol for a positive outcome.
and to diminish the potential for rebound intracranial pres-
sure elevation. Antibiotic treatment is usually warranted in Spinal Cord and Vertebral Injury
cases of head trauma, especially when fractures are involved.
The presence of hemorrhage increases the possibility of septic Pathophysiology
meningitis. Antibiotic choice should be based on culture and Trauma to the vertebral column is typically caused by inci-
sensitivity testing. Good empiric choices for broad-spectrum dents such as collision with an immovable object or falling
coverage include trimethoprim-sulfamethoxazole and penicil- down. Recently there have been a number of reports on
lin in combination with gentamicin. Appropriate monitoring exercise-associated vertebral trauma with or without sec-
for aminoglycoside toxicity should be undertaken with their ondary SCI as a cause of sudden death in Thoroughbred and
use. Owing to disruption of the blood-brain barrier, other Quarter Horse racehorses.143,175,176 Injury to the vertebral col-
antimicrobials probably penetrate into the CNS, and therefore umn can occur at all sites, but trauma to or fractures of the
their use may also be efficacious. cervical vertebrae are the most common.141,142 Foals appear
Nutritional support plays a role in the outcome after neu- to be more susceptible to vertebral trauma than adults and
rologic injury. In human beings, neurologic recovery from frequently suffer injury to the cranial cervical (C1–C3) and
head injury occurs faster in patients receiving early adequate caudal thoracic (T15–T18) regions.148 In fact, fracture of the
nutritional support.173 If the horse is able to eat and the gas- axial dens with atlantoaxial subluxation is most commonly
trointestinal tract is functioning normally, water and good- seen in foals less than 6 months of age and involves disrup-
quality hay should be available at all times. Small amounts tion of the physis of the dens and separation of the odontoid
of grain should be fed three to four times a day to boost process.177 Vertebral fracture with subsequent SCI, not as a
caloric intake. The amount of grain fed should be based on result of trauma but secondary to osteomyelitis, has been
the horse’s condition and ability to tolerate grain feeding. reported in a foal.178 Predilection sites for vertebral trauma
Horses in which enteral feeding is not possible are candidates in adult horses are the occipital-atlantoaxial region, the cau-
for total parenteral nutrition. Thiamine may be of benefit in dal cervical region (C5–T1), and the caudal thoracic region.
treating head injuries because thiamine aids in metabolism Reports also exist of injuries at the lumbosacral143,175,176 and
of lactic acid and is a necessary coenzyme in brain energy coccygeal179 regions.
pathways. Typically, the more severe the insult is, the more damage
The prognosis for cranial trauma is dependent on occurs to the vertebral column (and the more severe clinical
severity of insult and early treatment, and it is gauged by signs are due to soft tissue damage and osseous fragments
response to treatment. An early prognosis based on initial compressing the spinal cord; Table 11.8). With very severe
findings is important to establish for owners and thus can injury, soft tissue structures supporting the vertebral column
influence clinical decisions. However, in a study performed may be disrupted, resulting in dislocation of vertebrae. Both
in human TBI patients, even with sophisticated clinical subluxation and luxation of vertebrae have been reported in
and radiologic technologies, it was not possible to predict horses.180 An increased incidence of luxations, subluxations,
outcome on the first day after the accident with sufficient and epiphyseal separations is seen in young horses, which is
accuracy to guide early management.174 In general, recum- likely because cervical vertebral growth plate closure does
bency of more than 4 hours’ duration and the presence of not occur until 4 to 5 years of age. Compression injuries are
TABLE 11.8 Common Types of Vertebral Trauma

Level of Injury Age Type of Vertebral Trauma Common Traumatic Injury Syndrome
Cervical Foal to yearling Fracture of dens, Hyperflexion (e.g., Tetraparesis, respiratory
luxation C1–C2 somersault) depression, death
Cervical Young adult Epiphyseal fracture Hyperextension Tetraparesis to tetraplegia
Cervical Adult Compression fracture Head-on collision Tetraparesis to tetraplegia
Cranial thoracic Usually young Fracture of dorsal spinous Flipping over backward Often none
process
T2–S1 Any Transverse fracture of vertebral Somersaulting or falls Paraparesis
arch, with dislocation
Sacroiliac subluxation Adult Subluxation Falls or slipping on ice None
Sacral fracture Any Compression Fall over backward Urinary and fecal incon-
or dog sitting when tinence with or without
backed posterior paresis,
paralysis of the tail and
anus

From Robinson NE, editor: Current therapy in equine medicine, ed 6, St. Louis, 2009, WB Saunders.
associated with shortening of the vertebral body and result and the inhibition of neurotransmitter release. In addition, in
from a head-on collision with an immovable object. hypoxic states, the sodium-potassium ATPase-dependent cell
SCI secondary to trauma is a dynamic process of which the pump is inhibited or damaged, resulting in the cell’s inability to
severity is related to the velocity, degree, and duration of the maintain its electric polarity. Damage to this pump allows for
impact. Cord concussion with transient neurologic deficits is accumulation of potassium extracellularly and sodium intra-
a result of local axonal depolarization and transient dysfunc- cellularly, which contributes to the development of edema.183
tion, whereas permanent paralysis is a result of primary tis- Free radicals can cause progressive oxidation of fatty acids
sue injury followed by spreading of secondary damage that in cellular membranes (lipid peroxidation) through reactions
expands from the injury epicenter. with their unpaired electrons. Furthermore, oxidative stress
Primary injury is the initial mechanical damage to the can disable key mitochondrial respiratory chain enzymes,
components of the spinal cord that follows acute insult. Blood alter DNA/RNA and their associated proteins, and inhibit
vessels are broken, axons are disrupted, and neuron and glial sodium-potassium ATPase. These changes can induce meta-
cell membranes are damaged. Ensuing pathophysiologic pro- bolic collapse and necrotic or apoptotic cell death and are con-
cesses involving ischemia, release of chemicals from injured sidered important during the initial period of hypoperfusion
cells, and electrolyte shifts alter the metabolic milieu at the (and perhaps even more important during the period of reper-
level of the lesion and trigger a secondary injury cascade that fusion). In addition to oxidative stress and membrane damage,
substantially compounds initial mechanical damage. These nitric oxide production and excitatory amino acid–induced
secondary injury processes do not necessarily coincide with calcium entry are considered important mediators of necrotic
the clinical picture, because pathologic changes may progress and apoptotic cell death.184 Apoptosis, or programmed cell
in severity for weeks to months, even in the face of clinical death, is a slowly spreading form of cell death induced by the
improvement. injury. It is characterized by apoptotic neurons at the lesion
Secondary injury involves both necrotic and programmed margins and, even later, apoptosis of oligodendrocytes in
cell death, and although mechanisms involved in this are areas with degenerating axons that were injured at the origi-
not fully understood, some aspects of this process are well nal lesion site.184,185 Apoptosis can thus occur at quite remote
described. Disruption of cellular and subcellular membranes distances from the point of impact. Oligodendrocytes appear
of glia, neurons, and vascular endothelial cells is believed to be vulnerable to apoptosis, and death of these cells can result in
the initiator of this autodestructive cascade of events, and it is demyelination of otherwise spared axons, thus contributing to
likely that multiple mechanisms are involved such as ischemia, the loss of distal neurologic function.
inflammation, free radical–induced cell death, excitotoxicity, Excitotoxicity refers to the deleterious cellular effects of
cytoskeletal degradation, and induction of apoptotic path- excess glutamate and aspartate stimulation of ionotropic
ways. The consequence of secondary injury is enlargement and metabotropic receptors. Extracellular concentrations of
of the area of cell death. The phase of secondary injury is both of these excitatory amino acids are increased after acute
widely studied because this process progresses from minutes SCI, which occurs through release from damaged neurons,
to months after injury and is thus considered to be a target decreased uptake by damaged astrocytes, and through depo-
for therapeutic interventions. Minimizing secondary injury larization-induced release. Ionotropic receptors include the
through protection of neural elements that initially survived NMDA and α-amino-3-hydroxy-5-methyl-4-isoxazole propi-
the mechanical injury would increase the quantity of spared onic acid (AMPA)/kainite receptors through which extracellu-
tissue and could lead to reduced functional impairment. lar calcium and sodium can pass down a massive concentration
Acute injury results in immediate hemorrhage and cell gradient into the cell or, when activated, can result in release
destruction within the central gray matter. Loss of microcir- of calcium from intracellular stores. Metabotropic glutamate
culation and cord swelling within minutes of injury occur receptors are coupled to G proteins that act as secondary
mainly because of hemorrhage and development of edema. intracellular messengers to mediate a wide spectrum of cellu-
The initial hemorrhage, edema, and hypoperfusion of the lar functions. Furthermore, elevation of intracellular calcium
gray matter extend centripetally within minutes to hours of concentration can occur through direct membrane damage
injury and result in central necrosis, white matter edema, and, and voltage-gated calcium channels triggered by membrane
eventually, demyelination of axons through secondary injury depolarization. Elevated intracellular calcium concentra-
processes. Spinal cord ischemia develops over several hours tions can trigger a multitude of calcium-dependent processes
after injury and is considered one of the most important con- that can lethally alter cellular metabolism, such as activation
tributors to secondary injury.181,182 Mechanical disruption of of lytic enzymes (calpains, phospholipase A2, proteases, and
the microvasculature, vasospasm of intact vessels, and edema lipoxygenase), generation of free radicals, impairment of
together lead to profound local hypoperfusion and ischemia. mitochondrial function, spasm of vascular smooth muscle,
Cord swelling that exceeds venous blood pressure results in and binding of phosphates with subsequent depletion of cell
secondary ischemia, and ischemia is further exacerbated by energy sources. Sodium dysregulation is thought to be impor-
cessation of autoregulation of spinal cord blood flow and sys- tant in the pathophysiology of damage to axonal and glial
temic hypotension. components in the white matter through similar mechanisms
During the ischemic hypoxic state, cell metabolism is altered that lead to elevated intracellular calcium concentrations.
such that a shift occurs from aerobic to anaerobic metabolism, Controversy exists surrounding the role of inflammation
which is a less efficient method of energy production. Anaero- in acute SCI, mainly because the effects of inflammatory cells
bic metabolism results in lactic acid accumulation, causing can be both cytotoxic and protective. After SCI, the injury site
acidosis in nervous tissue, thus decreasing glucose and oxygen is rapidly infiltrated by blood-borne neutrophils, which can
consumption. Furthermore, lactic acid stimulates prostaglan- secrete lytic enzymes and cytokines. Later, blood-borne mac-
din production, adenosine diphosphate release, platelet aggre- rophages and monocytes are recruited, as well as locally acti-
gation, thromboxane A2 release, vasospasm, vasoconstriction, vated resident microglia, both of which subsequently invade to
phagocytize the injured tissue. These and other reactive cells In horses, lesions in the C1 to T2 region are most common
produce cytokines, such as tumor necrosis factor–α (TNF-α), and result in varying degrees of dysfunction ranging from
interleukins (ILs), and interferons, that mediate the inflamma- tetraparesis to recumbency. Thoracolumbar SCI can result
tory response and can further damage local tissue and recruit in paraparesis to recumbency, and horses may dog sit. Sacral
other inflammatory cells. Among the cytokines involved in cord damage can result in fecal and urinary incontinence, loss
secondary SCI, TNF-α is perhaps the most extensively stud- of use of tail and anus, muscle atrophy, and mild deficits of
ied. It is produced by a range of different cell populations, pelvic limb function. Sacrococcygeal cord injury can produce
including neutrophils, macrophages and microglia, astrocytes, hypalgesia; hypotonia and hyporeflexia of the perineum, tail,
and T cells and has been shown to accumulate quickly at the and anus; or total analgesia and paralysis of those structures.
site of SCI. It has been suggested that the early inflammatory In addition to these clinical signs, loss of sensation can occur
phases are deleterious in nature, whereas the later inflamma- distal to the level of SCI. Furthermore, diffuse sweating can
tory events appear to be protective.182 be seen as a result of loss of supraspinal input to the pregan-
glionic cell bodies of the sympathetic system in the thoraco-
Neurologic Evaluation lumbar intermediate gray matter. Patchy sweating can be seen
Clinical signs seen as a result of SCI reflect the extent and with damage to specific preganglionic or postganglionic nerve
location of the injury. Neurologic signs are usually observed fibers.
immediately after the accident but may occur weeks to months Ancillary diagnostics that may aid in diagnosing or local-
after the initial insult because of delayed damage to the spinal izing SCI include radiography, myelography, CT, MRI, nuclear
cord caused by instability, arthritis, or bony callus formation at scintigraphy, CSF analysis, nerve conduction velocities, EMG,
the site of impact. Clinical signs depend on the neuroanatomic and transcranial magnetic stimulation. Radiography may
location of injury and range between inapparent to severe inca- demonstrate fractures, luxations, subluxations, and vertebral
pacitating tetraparesis or tetraplegia (see Fig. 11.24). Lesions compression. As presented previously, CT and radiography
causing recumbency are mostly found in the caudal cervical or are the diagnostic aids of choice to evaluate skeletal injury,
thoracic spinal cord, whereas lesions of nonrecumbent horses whereas MRI is more sensitive for evaluation of soft tissue
are mostly found farther cranial in the cervical spinal cord or structures such as the spinal cord and ligaments. With respect
in the lumbosacral cord.142 to imaging the vertebral column with computed tomography
Initial evaluation of the patient should be directed toward and MRI devices, however, the size of the horse, the size of
stabilization and correction of any life-threatening problems the equipment aperture, and the cost of the equipment aper-
such as airway obstruction, hemorrhage, cardiovascular col- ture limit its use to investigations of the cervical and cranial
lapse, and pneumothorax. In addition, major long-bone frac- thoracic spinal cord. Myelography may be required to con-
tures must be identified, because these may be the limiting firm spinal cord compression and can be used at the level
factor for survival of the horse. All affected horses may be ner- of the cervical, cranial thoracic, and sacral-coccygeal spinal
vous or agitated as a result of pain and the inability to stand. cord. Nuclear scintigraphy can be useful in diagnosing non-
A systematic neurologic evaluation should then be performed displaced or occult fractures and soft tissue lesions. Common
to localize the site of injury.3 In recumbent horses the use of CSF abnormalities after SCI include xanthochromia and mild
a sling to assist standing may be a valuable diagnostic tool for to moderate increased total protein concentrations. CSF anal-
localizing the site of injury and for assessing progression of ysis may be normal, especially in very acute or chronic cases.
disease and prognosis.9 NCV and EMG studies evaluate the lower motor neuron and
In animals, SCI usually occurs as a solitary lesion and the aid in lesion localization. Electromyographic changes, how-
level of the lesion can be diagnosed by neurologic examina- ever, may not develop until 1 to 4 weeks after nerve damage.
tion.186 Depression or loss of a segmental spinal reflex implies Transcranial magnetic stimulation allows detection of func-
damage to either the afferent, efferent, or connecting pathways tional lesions in descending motor tracts through recording
of the reflex arc. However, after acute SCI a phase of spinal of magnetic motor-evoked potentials. This method has been
shock can occur in which profound depression is noted in seg- validated and used to distinguish motor tract disorders from
mental spinal reflexes caudal to the level of the lesion, even other causes of recumbency in clinical cases.160
though reflex arcs are physically intact. Spinal shock occurs
in all species; however, it appears to be of much shorter dura- Treatment and Prognosis
tion in dogs, cats, and rabbits compared with primates.1,186 Spinal cord injury is currently incurable, and treatment is
Another syndrome that occurs infrequently and is short-lived limited to minimizing secondary complications and maximiz-
in the horse is Schiff-Sherrington syndrome, in which exten- ing residual function by rehabilitation. It is the assortment
sor hypertonus is present in otherwise normal thoracic limbs of pathophysiologic processes that occur during the period
in patients with severe cranial thoracic lesions.1 of secondary injury that are considered the target for phar-
Cord injury typically results in damage that is worse in the maceutical intervention. The first 48 hours after acute SCI
large myelinated motor and proprioceptive fibers compared are dominated by the vascular and biochemical changes that
with the smaller or nonmyelinated nociceptive fibers. There- occur within the spinal cord. Then follows a period charac-
fore ataxia and loss of proprioception and motor function terized by the effects of inflammatory cells that occurs within
will occur before the loss of deep pain. Flaccid paralysis with hours of injury, peaking around 4 days after injury. Last there
hyporeflexia or areflexia, muscular hypotonia, and neurogenic is a period that starts approximately 1 week after injury and
muscle atrophy are characteristic of a lower motor neuron is characterized by axonal regeneration and lesion repair. The
lesion. Signs resulting from an upper motor neuron spinal goals of treatment are to stop the cascade of cellular events
cord lesion include loss of voluntary motor function, whereas initiated by the traumatic insult, to protect spared neural tis-
muscle tone may be increased and spinal reflexes may be nor- sue, and to promote regeneration. Studies of spinal cord repair
mal to hyperactive. can be categorized by clinical target and have been reviewed
elsewhere.183,187 Rescue therapies encompass early interven- on corticosteroid therapy should be monitored closely for the
tions that prevent the spread of damage beyond the initial site development of laminitis or Aspergillus spp. pneumonia. If
of injury. Examples include surgical decompression, cooling improvement in clinical signs is observed, the horse may be
or hypothermia, and interventions targeting a specific biologic placed on oral prednisolone therapy (0.5–1.0 mg/kg tapered
event such as inflammation. Reactivate therapies refer to how over 3–5 days) to decrease the chance of laminitis. The neu-
spared systems, which are nearly always present in clinical roprotective effect of corticosteroids is thought primarily
SCI, can be exploited through rehabilitation, pharmacologic to be mediated by free radical scavenging but may include
or electrical stimulation of spinal networks, or remyelination decreased catecholamines and glutamate, as well as decreased
of denuded axons. Rewiring interventions encompass treat- apoptosis-related cell death.190 Other potential beneficial
ments aimed at regrowth of injured axons or repurposing of effects of corticosteroids include reduction in the spread of
spared ones, with strategies aimed at increasing the intrinsic morphologic damage, prevention of the loss of axonal con-
growth capacity of injured neurons or reducing inhibitors of duction and reflex activity, preservation of vascular mem-
axon growth. brane integrity, and stabilization of white matter neuronal cell
Surgical intervention is warranted when the need exists for membranes in the presence of central hemorrhagic lesions.183
stabilization or fracture repair, as well as when a compressive Furthermore, their antiinflammatory properties may be use-
lesion is evident; however, this is uncommonly done in equine ful in reducing edema and fibrin deposition, as well as their
medicine.177 Conservative management is often effective, but ability to reverse sodium and potassium imbalance because
there may be advantages of performing stabilization surgery of edema and necrosis. Another beneficial effect of corticoste-
before clinical signs deteriorate.188 Furthermore, it is possible roids is maintenance of normal blood glucose concentrations
that future neurologic disease progression occurs as a result of while maintaining electrolyte balance.183
a “domino effect” involving the vertebral bodies cranial and/ Promising studies that target rescue investigate (1) the
or caudal to an (incomplete) fused articulation.189 This process macrophage response after SCI; (2) peroxisome proliferator-
may take months to years to occur. The use of medical treat- activated receptors, which are a family of ligand-activated
ment to stabilize the patient should always be instituted before transcription factors that regulate many aspects of neuroin-
surgery is performed. flammation; (3) GM6001, a broad-spectrum matrix metallo-
Acute SCI often results in impaired cardiopulmonary func- protease inhibitor; and (4) riluzole, a sodium channel blocker
tion such as impaired ventilation, bradycardia, and hypo- and glutamate antagonist. As mentioned for TBI, the use of
tension. This is particularly the case in lesions cranial to NSAIDs such as flunixin meglumine and phenylbutazone may
C5 (respiratory center affected) and cranial to T2 (origin of decrease the inflammation in horses associated with a trau-
sympathetic outflow = thoracolumbar spinal cord). Systemic matic episode. In addition, there is likely a benefit to main-
hypotension may exacerbate spinal cord hypoperfusion and taining a normal rectal temperature. These compounds work
ischemia, and maintaining systemic blood pressure has been by inhibiting cyclooxygenase, which converts arachidonic acid
shown to improve spinal cord perfusion. Volume resuscitation to inflammatory mediators (endoperoxides). In addition, the
is clearly indicated in shock and for restitution of tissue perfu- potential beneficial properties of DMSO, 1 g/kg intravenously
sion. The current recommendation is to maintain euvolemic as a 10% solution for 3 consecutive days followed by three treat-
normotension; because of sympathetic outflow disruption ments every other day, likely warrant inclusion of this drug in
after cranial SCI, pressor therapy is commonly indicated in the the treatment of CNS trauma.147 Reported benefits of DMSO
treatment regimen. Maintaining normal mean arterial blood include increased brain and spinal cord blood flow, decreased
pressure is also important to consider during stabilization brain and spinal cord edema, increased vasodilating prosta-
of the acutely injured horse, and it is particularly important glandin E1 (PGE1), decreased platelet aggregation, decreased
when horses are placed under general anesthesia for various prostaglandin E2 (PGE2) and prostaglandin F2 (PGF2), protec-
diagnostic and therapeutic procedures. tion of cell membranes, and trapping of hydroxyl radicals.183
Similar to TBI, SCI has a complex multifactorial patho- The exact mechanism of DMSO remains unknown, and this
physiology and likely requires a combinational treatment treatment remains controversial because some researchers
intervention for successful outcome. Many agents, which have found no positive effects on neurologic outcome from the
could target different aspects of the secondary injury mecha- use of DMSO. Although the free radical scavengers vitamin E
nisms, have been investigated for use in SCI and have been and selenium have been shown to be beneficial in SCI, these
reviewed.187 After the initial trauma of SCI, cell death and antioxidants do not appear useful in the acute management
tissue loss continue for several weeks, a period during which because of the length of time required to achieve therapeutic
one could intervene with neuroprotective strategies. Histori- concentrations in the CNS.
cally, three approaches have been taken to restrict secondary Similar as is stated for TBI, antibiotics are not always nec-
damage: surgical decompression, therapeutic hypothermia, essary in the treatment of vertebral or spinal cord trauma;
and drugs targeting inflammation or excitotoxicity.187 Meth- however, they are indicated in treating open fractures and
ylprednisolone sodium succinate (MPSS) offers little benefit secondary complications associated with a recumbent horse,
and might actually have detrimental effects, but although it such as pneumonia and decubital sores.
has been formally denounced as a standard of care for human Physical therapy is important in the rehabilitative process
SCI in most countries, the drug is still used in some clinical in spine-injured horses. The field of equine rehabilitation is
practices. In horses, corticosteroids, alone or in combination growing rapidly, and novel techniques and ideas have recently
with other drugs, are likely the most commonly used drugs been reviewed.191-194 Controlled exercise allows the unaffected
for acute CNS trauma. Reported dosages of dexametha- parts of the nervous system to compensate for the affected
sone for horses range from 0.1 to 0.25 mg/kg intravenously parts by increasing strength and conscious proprioception.
every 6 to 24 hours for 24 to 48 hours. A favorable response Exercise is especially helpful in improving weakness, ataxia,
is expected within 4 to 8 hours after administration. Horses spasticity, and hypermetria. In recumbent horses, massage,
therapeutic ultrasound, and hydrotherapy of affected muscle 4. Spinal cord:

groups for 10 to 15 minutes at least twice a day are impor- a. Lateral vestibulospinal tract
tant. These measures help combat necrosis and muscle atro- b. Medial vestibulospinal tract
phy of the horse’s dependent muscle groups. Passive flexion A more detailed explanation follows. Axons from the
and extension of all limbs are helpful in maintaining full range medial vestibular nucleus project through the medial longi-
of motion in recumbent horses. Furthermore, experimental tudinal fasciculus. Vestibular signals travel through to the
studies have shown that exercise enhances functional recovery contralateral medial geniculate nuclei of the thalamus to the
after SCI.195 cerebral cortex. In addition to proprioceptive information
Prognosis is based on response to therapy and is directly from other parts of the body, the cerebral cortex facilitates
related to the time from injury to the institution of treatment. conscious perception of orientation.1
Horses that show rapid neurologic improvement have a fair The ascending portions of the medial longitudinal fascic-
to good prognosis. Recumbent horses or horses suffering ulus course to the motor nuclei of the third, fourth, and sixth
from fractures or luxations have a guarded to poor prognosis. cranial nerves (oculomotor, trochlear, and abducens).1,4,196
Horses that have lost deep pain sensation have a functional or These fibers coordinate conjugate eye movement with
anatomic spinal cord transection and have a grave prognosis. changes in head position. This pathway, along with cerebellar
The longer the time from loss of deep pain to treatment, the input, controls physiologic (vestibular) nystagmus.1,196 Nys-
poorer the prognosis. Partial or complete recovery of horses tagmus is characterized by involuntary, conjugate, rhythmic
with spinal cord trauma may take weeks to months, so time eyeball oscillations with a fast and slow phase. The direction
and nursing care are required. of nystagmus is defined by the direction of the fast phase and
is induced by movements of the head. Rapid dorsiflexion of
the neck results in vertical nystagmus, whereas side-to-side
Y VESTIBULAR DISEASE movement of the head induces horizontal nystagmus. Turn-
Monica Aleman ing the head to the left results in a horizontal nystagmus with
the fast phase to the left. The accompanying slow phase is in
The vestibular system is a special proprioceptive system a direction opposite to body motion and allows the eyes to
responsible for maintenance of balance and reflex orienta- fix on a stationary image. The fast phase is initiated when
tion to gravitational forces. This system functions to maintain the eyeball reaches the lateral limit of ocular movement
appropriate eye, head, trunk, and limb position during rest and allows the eyeballs to jump forward and focus on a new
and movement.1,4,196 image.1 The slow phase is controlled by vestibular input, and
the fast phase is a function of the brainstem.1 Physiologic nys-
Vestibular System tagmus induced by rapid manipulation of the head is called
The vestibular pathway, from neural receptor to cerebral the oculocephalic reflex. This reflex occurs independent of
cortex and tracts in the spinal cord, is comprised of periph- vision.1,196 Descending portions of the medial longitudinal
eral and central components.196 The peripheral part of the fasciculus travel in the ventral funiculus of the cervical and
vestibular system is housed in the petrous part of the tem- cranial thoracic spinal cord segments and control the posi-
poral bone. Neuron 1 (first-order neuron) is located in the tion and activity of the limbs and trunk in coordination with
vestibular ganglion, which receives impulses from five sites: head position.1,196
the crista of the ampulla of each of three semicircular canals, Fibers from the vestibular nuclei that project to the retic-
and the macula of the utricle and macula of the saccule. The ular formation provide afferent nerves to the vomit center,
cristae record movement of the head, and the maculae record which is the pathway for the development of motion sickness.
position of the head. Movement and gravity act on neuro- Reticulospinal tracts also aid in the maintenance of extensor
epithelial cells that transform physical forces into electrical tone to support the body against gravity.1,196
impulses. The axon of neuron 1 projects into the vestibular Vestibular impulses enter the cerebellum via the caudal
nuclei of the same side. Neuron 2 is located in the vestibu- cerebellar peduncles. Fibers of the vestibulocerebellar tracts
lar nuclei, which lie near the cochlear nuclei in the medulla terminate primarily in the flocculonodular lobe and fastigial
oblongata. Some of the axons from these neurons ascend on nucleus.1,196 The cerebellum functions to coordinate protago-
the same side, and others decussate. Their axons project to nistic, antagonistic, and synergistic muscle groups for con-
one of multiple areas196: trolled responses to gravity. The vestibular apparatus provides
1. Cerebral cortex: information to the cerebellum, dictating the relative degree of
a. Axons of the medial geniculate nucleus (neuron 3) with- contraction necessary to maintain equilibrium.1,196
in the medial geniculate body project to the cerebral The vestibulospinal tract courses in the ipsilateral ventral
cortex. funiculus and terminates in interneurons of the ventral gray
2. Brainstem: column. Stimulation of the vestibulospinal tract is facilitatory
a. Motor nuclei of cranial nerves III, IV, and VI—influenc- to α- and γ-motor neurons of the ipsilateral extensor muscles,
ing eye movement (nystagmus) when the head moves. inhibitory to the α-motor neurons of the ipsilateral flexor
This normal movement is called physiologic nystagmus muscles, and inhibitory to contralateral extensor muscles.1,196
or vestibular-ocular nystagmus. The net result is ipsilateral extensor tonus and contralateral
b. Ascending and descending reticular formation (in- flexor tonus that act as an adaptive mechanism against gravity
volved in cardiovascular and vomiting reactions [peo- by catching the body and preventing a fall in the direction of
ple] with vestibular disturbances) vestibular stimulation.196
3. Cerebellum: The vestibular system is capable only of detecting move-
a. Flocculonodular lobe of cerebellum (when altered: par- ment and orientation of the head in relationship to the rest
adoxic vestibular disease) of the body. Afferent pathways from the neck allow the head
to be cognizant of the orientation of the rest of the body.1,196

Exteroceptor receptors of the skin and proprioceptive recep-
tors in other joints also are integrated in the cerebellum and
reticular formation to aid in the maintenance of equilib-
rium. These signals allow the vestibular system to know if
the body remains in an appropriate position with respect
to gravity while the head is bent. Visual images can help to
maintain balance by visual detection of the upright stance.
In addition, slight linear or angular movement of the head
shifts the image on the retina, which relays directional infor-
mation to equilibrium centers. Visual compensation might
be capable of maintaining balance in the face of vestibular
dysfunction, if the eyes are open and motions are performed
slowly.196
The seventh cranial nerve (the facial nerve) emerges from
the lateral medulla ventral to the vestibulocochlear nerve at
the level of the trapezoid body. The two nerves are associated
closely with the petrous temporal bone and enter the internal
auditory meatus together.1,196-198 Within the internal auditory
meatus, the facial nerve separates from the vestibular nerve
and courses through the facial canal of the petrosal bone.1,196-198
The facial nerve exits the cranium from the stylomastoid
foramen located immediately caudal to the external auditory
meatus. Because of the proximity of the facial and vestibu-
lar nerves, a single disease process commonly affects both
nerves simultaneously.197,199 FIG. 11.27 Horse with peripheral vestibular disease. Note head tilt and
Sympathetic innervation to the eye also is associated ana- turn to the left; horse is bright and alert.
tomically with the petrous temporal bone. Damage to this
nerve (Horner syndrome), along with vestibular and facial
nerve deficits, frequently occurs with petrous temporal bone
trauma and otitis media in small animals.4 The association of
Horner syndrome, facial nerve paralysis, and vestibular dis-
ease rarely is documented in the horse.1
Clinical Signs of Vestibular Dysfunction
Knowledge of the anatomy and function of structures related
to the peripheral and central vestibular system aids in neuro-
anatomic localization of the lesion.1 Differentiation of central
versus peripheral vestibular disease is important for estab-
lishing a list of differential diagnoses, initiating therapy, and
formulating a prognosis. A thorough physical and neurologic
examination is essential. Historical information, including
duration of condition, rate of onset, and disease progression,
also may aid in differentiation of central from peripheral ves-
tibular disease.
Signs of acute peripheral vestibular system dysfunction
include head tilt (Fig. 11.27), nystagmus, falling, circling,
reluctance to move, and asymmetric ataxia with preserva-
tion of strength. Horses affected with peracute vestibular
disease are often violent because of disorientation.4 Head
tilt is a consistent sign of vestibular disease and is character-
ized by ventral deviation of the poll of the head toward the
affected side (Fig. 11.28).1,4,197,199,200 The horse prefers to lie
on the side of the lesion and might lean on the wall toward
the affected side when standing. When forced to move, the
horse takes short, uncoordinated steps in a circle toward the
direction of the lesion. The body may be flexed laterally with
a concavity toward the lesion.198,201 Extensor hypotonia ipsi-
lateral to the lesion and mild hypertonia and hyperreflexia
of the extensor muscles of the contralateral side result in FIG. 11.28 Thoroughbred with right-sided peripheral vestibular dis-
asymmetric ataxia.200 Extensor hypotonia occurs from loss ease caused by a temporohyoid osteoarthropathy (THO) and acute frac-
of facilitatory neurons of the vestibulospinal tract to ipsilat- ture. The head tilt, dropped pinna, and eyelid droop occur on the affected
eral extensor muscles. side, whereas the muzzle is pulled toward the contralateral side.
Contralateral extensor hypertonia occurs from loss of

inhibitory neurons and unopposed extensor tone of the con-
tralateral vestibulospinal tract.1 Central vestibular disease has
similar clinical signs, but proprioceptive deficits are a distin-
guishing sign from peripheral vestibular disease. Other signs
of central vestibular disease include involvement of other cra-
nial nerves, alterations in mentation, cerebellar disease, and
dysconjugate and/or positional nystagmus.1,202 The presence
of vertical nystagmus is only observed with central vestibular
disease.1
Pathologic nystagmus, rhythmic oscillations of the eyes
occurring while the head is in a normal position, is involun-
tary and indicates a lesion in the vestibular system or cerebel-
lum.202 As in physiologic nystagmus, one can identify a fast
and a slow phase. The direction of nystagmus is defined by
the direction of the fast phase.1,198,203 Pathologic nystagmus
might be spontaneous, occurring with the head in the resting
position, or positional, which is induced by elevation or lateral
flexion of the head.1 Nystagmus usually appears with the onset FIG. 11.29 Horse with central vestibular disease. Note mild head tilt
and turn to the right; horse is obtunded.
of other peripheral vestibular signs but might last only 2 to 3
days because of central compensation.200 Concomitant blink-
ing of the eyelid might hinder detection of nystagmus.1 by ataxia, head tilt contralateral to the side, and postural reac-
Peripheral vestibular dysfunction might result in horizontal tion deficits.1,4,202
or rotary nystagmus. The fast phase of nystagmus is directed Central or peripheral vestibular disease might produce
away from the lesion and does not change with changing head strabismus. One observes ventrolateral strabismus ipsilateral
position.1,201 The direction of rotary nystagmus is defined by to the vestibular lesion with elevation of the head and exten-
the direction the limbus moves from the 12 o’clock position sion of the neck.1,4,202 One observes mild ventral deviation of
during the fast phase.1 Horizontal, rotary, or vertical nystag- the eyes in normal horses when the head is elevated, but the
mus can result from a central vestibular lesion. In addition, finding is symmetric. Ventrolateral strabismus of vestibular
the type of nystagmus observed might change with changing disease is not a sign of a cranial nerve deficit of the extraocular
head position in a patient with central vestibular disease.4,198 muscles1 but is a reflection of abnormal upper motor neuron
In central vestibular disease, the fast phase is away from the influences on the oculomotor nucleus from the ipsilateral ves-
lesion except in cerebellar-vestibular disease (paradoxic vestibular nucleus via the medial longitudinal fasciculus. If the
tibular disease).4,204 strabismus is purely vestibular in origin, normal ocular mobil-
In the healthy animal a constant stream of electric stimula- ity is visible with manipulation of the head.197
tion arises in each vestibular end organ and transmits signals Signs of vestibular disease might improve rapidly 2 to 3
that control ocular position via the medial longitudinal fascic- weeks after onset because of visual and central accommoda-
ulus. These signals normally drive the eyes toward the oppo- tion.1,197 Central vestibular lesions are slower to compensate
site direction. The eyes are maintained centrally, however, than peripheral vestibular lesions; signs might even progress
because vestibuloocular pathways are opposed in an equal if the central lesion is an expanding space-occupying mass.
and opposite manner. Unilateral vestibular disease upsets this Blindfolding a horse with compensated disease results in
balance, resulting in slow deviation of both eyes toward the ataxia and a head tilt (Romberg’s test). Blindfolding elimi-
lesion. Individuals that are blind at birth or have been blind nates visual and limb proprioceptive orientation; the body is
for an extended time might exhibit irregular eyeball oscillation forced to rely on the impaired vestibular system for equilib-
with no slow or fast component.1 Loss of hearing is a common rium.1,197,199 This test is unreliable for localizing the side of the
finding with peripheral vestibular disease because of the prox- lesion.196 Horses might decompensate dramatically when the
imity of the cochlea to the vestibular receptor organs.60-62,205 blindfold is placed over the eyes, resulting in anxiety, disorien-
Signs of vestibular disease along with obtundation and pro- tation, and falling.1 One should perform the test with caution
prioceptive deficits are signs of central vestibular disease (Fig. on a padded surface with good footing.
11.29).1 With a central lesion, abnormal proprioception occurs Horses affected with bilateral peripheral disease demon-
because of damage within the brainstem of the descending strate no head tilt, circling, or pathologic nystagmus, and one
upper motor neuron tracts to the limbs.4 Damage to the spi- cannot induce physiologic nystagmus by rapid manipulation
nocerebellar tracts or caudal cerebellar peduncles results in of the head (the oculocephalic reflex) or by caloric testing. The
abnormal unconscious proprioception and hypermetria.4 The head might sway with wide excursions from side to side.203 As
nuclei of the trigeminal (fifth cranial nerve) and the abducens with all peripheral vestibular disease, strength is preserved.1
nerves (sixth cranial nerve) are in anatomic proximity to the Clinically, horses affected with bilateral vestibular disease
vestibular nuclei and are damaged readily in a common dis- exhibit more symmetric ataxia similar to generalized cerebel-
ease process. Trigeminal nerve paralysis creates a loss of sen- lar disease.4
sation to the head and atrophy of the muscles of mastication. Facial nerve (seventh cranial nerve) paralysis frequently
Trochlear nerve damage results in medial strabismus.197 occurs concurrently with peripheral vestibular disease because
Destructive space-occupying lesions in the cerebellopon- of its proximity to the vestibular nerve within the petrous tem-
tine angle or flocculonodular lobe may result in paradoxic poral bone. Facial nerve paralysis worsens the long-term prog-
central vestibular disease.1,4,202 This syndrome is manifested nosis and complicates the management of vestibular disease
patients. The facial nerve innervates the muscles of facial infection at the time of diagnosis or historically. Some or all
expression, and damage to this nerve results in muzzle devia- cases of THO are quite likely the result of primary degenera-
tion away from the affected side, lack of menace and palpe- tive joint disease rather than an extension of a bacterial ear
bral response, ear droop, decreased nostril flare impeding air or guttural pouch infection.
flow, and buccal impaction of feed.197,198 Keratitis and corneal Regardless of initial cause, inflammation induces bony
ulceration are common because of the inability to blink and proliferation at the articulation of the stylohyoid bone with
decreased tear production.62,198 Decreased tear production the petrous temporal bone, resulting in loss of the joint space
results from damage to parasympathetic fibers to the lacrimal and fusion of the temporohyoid joint. The hyoid apparatus
gland. Preganglionic fibers travel with the facial nerve through is attached to the tongue and larynx; fusion of the temporo-
the internal auditory meatus and separate in the facial canal hyoid joint results in impaired flexibility of the unit. A stress
proximal to the geniculate nucleus.198 The fibers split from fracture of the petrous temporal bone, the stylohyoid bone,
the facial nerve to join the superior petrosal nerve, which or both might result from eating, vocalization, or any activity
carries fibers to the sphenopalatine ganglion. Postganglionic associated with normal tongue movement.201,202 Occasionally,
fibers join the sympathetic fibers to the eye and travel with fracture and acute onset of severe neurologic signs (collapse
the vasculature to the lacrimal gland.1,198 Corneal ulcerations and seizure) may be associated with passage of a nasogastric
occur in the inferior portion of the cornea and are slow to tube or other veterinary procedure.207 The fracture line may
heal because of ongoing exposure.62,197 Lack of tear produc- extend into the cranial vault at the level of the internal audi-
tion aids in localization of the lesion, indicating the damage is tory meatus, resulting in direct neural tissue trauma and hem-
within the petrous temporal bone, proximal to the geniculate orrhage into the middle and inner ear.4,206
nucleus.1,62,198 Clinical signs of facial nerve paralysis might not Neurologic signs are rarely apparent during the formation
appear for several days after the onset of vestibular disease, of proliferative osteitis and temporohyoid joint fusion. The
because damage to the nerve might result from hematoma, cal- onset of neurologic signs corresponds with the occurrence of
lus, or an extension of inflammation and secondary neuritis.203 the stress fracture. Early signs, before fracture, might include
Because of the proximity of the nuclei of the facial and ves- headshaking, resistance to the bit, ear rubbing, resentment
tibular nerves, extensive lesions of the medulla might involve of manipulation of the head or ears, or pain on pressure at
both nerves. If no improvement of facial nerve deficits occurs the base of the ear. Occasionally more overt signs of otitis
within 3 to 4 months after the onset of disease, the prognosis is externa or otitis media-interna might be present, including
poor for recovery. If one notes even mild improvement in the evidence of exudate from the external ear canal. Most horses
first 4 months, facial nerve function might return.203 Horses exhibit acute onset of cranial nerve VII or VIII abnormalities
might learn to retract the globe, allowing the eyelid and nic- (or both) at the time of fracture. Fractures can tear or stretch
titating membrane to slide across the surface of the cornea, the facial or vestibulocochlear nerves as they exit the skull or
distributing lubrication and protecting the eye from trauma.197 within the skull, respectively. Some fractures extend into the
Careful observation is necessary to differentiate this adapta- cranial vault with resultant seizures, bacterial meningitis, or
tion from improvement of lid function. death.206,207 Vestibular signs can vary between mild head tilt to
circling with severe loss of balance and horizontal nystagmus
Peripheral Vestibular Disease or recumbency. Auditory abnormalities are evident in most
Acute onset of peripheral vestibular disease and facial nerve affected horses when assessed by brainstem auditory-evoked
paralysis is not a rare occurrence in the horse. Damage to the responses.60,62,205 If the facial nerve is damaged, ptosis, muzzle
temporal bone is the most likely anatomic location when these deviation away from the side of the lesion, a drooping lower
nerves are affected concurrently. THO and traumatic skull lip and ear on the side of the lesion, and accumulation of feed
fractures are the most common causes of these signs in large within the cheek occur. Preganglionic parasympathetic fibers
animals.1 THO is the most common cause of peripheral ves- in the facial nerve that innervate the lacrimal gland may also
tibular disease in horses and should be the number one rule be damaged with resultant keratoconjunctivitis sicca. Many
out for horses with acute onset of vestibular dysfunction, espe- affected horses have corneal ulceration varying from mild to
cially if accompanied by facial nerve palsy.62,205-207 severe. Corneal disease is secondary to decreased tear produc-
tion and facial nerve dysfunction that diminishes the horse’s
Temporohyoid Osteoarthropathy ability to effectively close the eyelids and spread the tear film
Temporohyoid osteoarthropathy is one of the most common across the eye. Rarely, horses may have intermittent acute epi-
causes of acute-onset peripheral vestibular disease, facial sodes of vestibular disease with intervening periods of appar-
nerve paralysis, or both in horses.60,62,205-207 Varying causes ent normal neurologic function. Occasionally, the fracture
for the disorder have been suggested, including extension of extends to the foramen lacerum, caudal to the petrous tem-
inflammation and infection from otitis media-interna208 or poral bone, where the glossopharyngeal and vagus nerves exit
guttural pouch infection, repetitive trauma, and nonseptic the skull. Trauma to these nerves might result in dysphagia.197
osteoarthritis. Much of the older veterinary literature refers A diagnosis of THO may be confirmed by imaging of the
to this disorder as otitis media-interna, whereas newer refer- stylohyoid bone or petrous temporal bone by endoscopy, radi-
ences use the designation THO because of the uncertaintly ography, nuclear scintigraphy, CT, or MRI.207,209 Although
concerning underlying cause in most horses. The earlier most affected horses have acute onset of unilateral neurologic
presumption of underlying otitis media-interna hypoth- signs, it is not uncommon for imaging to identify bilateral
esized that rather than rupturing the tympanic membrane, THO and bony proliferation.
the inflammatory process might extend ventrally to involve CT of the skull followed by endoscopy of the pharynx and
the bones of the tympanic bulla and temporohyoid joint. guttural pouch are the most sensitive diagnostic tests for THO
However, this theory remains speculative, and relatively few in horses.207,209 One should perform this noninvasive proce-
horses with THO have evidence of otitis or guttural pouch dure on every horse suspected of having proliferative osteitis,
FIG. 11.30 Endoscopic view of the right guttural pouch of a horse with
acute onset of right-sided vestibular disease and facial nerve paralysis.
Bony proliferation of the proximal stylohyoid bone is consistent with
chronic THO.
because one often can identify bony proliferation of the proxi-

mal stylohyoid bone within the guttural pouch (Fig. 11.30).
Many horses also have evidence of hyperemia, bruising, or FIG. 11.31 Ventrodorsal skull radiograph demonstrating bony prolif-
hematoma formation in the dorsal mucosa of the guttural eration of the proximal left stylohyoid and petrous temporal bones (ar-
pouch, near the head of the stylohyoid bone. rows) associated with THO.
Dorsoventral radiographs of the caudal skull should reveal
the characteristic periosteal proliferation and sclerosis of the be used to direct the selection of an appropriate antimicrobial
stylohyoid bone and petrous temporal bone (Fig. 11.31). The treatment plan.200
fracture line is often difficult to identify because of minimal Treatment of horses with acute onset of neurologic dys-
displacement of the fracture fragments. Lateral oblique radio- function secondary to THO should focus on four areas:
graphs obtained at varying angles might aid in localization of 1. Stabilization of the horse and decreasing inflammation
a fracture of the basisphenoid, occipital, or petrous tempo- near the fracture site
ral bones. Moderate bony proliferation might not occur for 2. Treatment with broad-spectrum antimicrobials for either
several weeks and must be present to diagnose the condition extension of a possible otitis interna-media or secondary
radiographically.205 infection in the hemorrhage that follows the fracture
Bone scintigraphy is a noninvasive technique that may allow 3. Treatment of exposure keratitis and keratoconjunctivitis
for an immediate identification of early lesions of the petrous sicca
temporal bone. Radiography can identify only structural 4. Surgical procedures to remove pressure on the temporohy-
abnormalities of bone. Bone scintigraphy is capable of detecting oid articulation to decrease pain and to decrease the likeli-
dynamic characteristics of bone. Increased metabolic activity hood of repeated petrous temporal bone fracture
and blood supply to the bone, caused by infection or fracture, Medical therapy usually includes antiinflammatory medi-
results in increased uptake of the radiolabeled compound cations as described elsewhere in this text for treatment of
(technetium-99m–labeled phosphate) before radiographic evi- acute head trauma. Trimethoprim-sulfonamide antimicro-
dence of bony proliferation.210,211 bials for 30 days are often recommended to treat potential
When available, CT and MRI are extremely sensitive diag- bacterial infection. If culture and sensitivity of CSF or other
nostic tests for identification of inflammation, bony prolifera- diagnostic sample are available, those results may direct alter-
tion, and fracture.212-214 However, CT and MRI of the skull of native antimicrobial choices. Treatment of corneal ulceration
horses require general anesthesia. The risks associated with and keratoconjunctivitis sicca is described elsewhere in this
recovery from general anesthesia, when a horse has compro- text.
mised neurologic function and possible skull fracture, should Surgical treatment of THO might take the form of
be considered seriously before recommendation of these either a partial stylohyoid ostectomy or a ceratohyoidec-
procedures. tomy.205-207,215-217 Surgical removal of a 2- to 3-cm segment of
One might consider analysis of CSF in affected horses. the midbody of the stylohyoid bone results in a fibrous non-
Cytologic evaluation, culture, and sensitivity may help to union of the stylohyoid bone that should interrupt the trans-
reveal the presence of secondary bacterial meningitis and can mission of hyoid forces to the temporohyoid joint. Reported
complications include transection of the lingual artery, injury early as 20 days after trauma and obscures the fracture line.203
to the hypoglossal or facial nerve, and regrowth of the stylohy- One often can identify basioccipital fractures easily but can
oid ostectomy site.215,216 The goal of ceratohyoidectomy is also confuse them with the suture lines in the base of the skull.218
to remove mechanical stress on the fused temporohyoid joint, Treatment of vestibular signs after head trauma is similar to
but the surgery is technically easier to accomplish without the that of any acute head trauma as described previously in this
risk of many of the more serious complications that may be chapter.
seen with partial stylohyoidectomy.216,217
Diagnosis of THO before the acute onset of neurologic Drug Toxicities
signs is difficult because most horses exhibit few, if any, clini- Drug toxicities can result in unilateral or bilateral periph-
cal signs before fracture. Some horses may demonstrate ear eral vestibular disease and deafness. Degeneration of the hair
rubbing, head tossing or shaking, chomping movements, and cells within the peripheral receptor organs of the auditory
sensitivity or pain on palpation at the base of the ear. and vestibular system occurs with prolonged administration
Prognosis for life in horses with THO is fair to good if the of aminoglycoside antibiotics. Severely affected animals also
horse survives the immediate fracture episode.205,207 However, develop neural degeneration. A more common manifestation
it might take up to 2 years for maximum neurologic improve- of aminoglycoside toxicity is renal failure. As renal clear-
ment after fracture, and the majority of affected horses have ance of the aminoglycoside decreases, the ototoxic effects
long-term, probably permanent, deficits. Some degree of facial of the antibiotics are potentiated.4,199 Clinical signs of ves-
nerve paralysis is common, and persistent or recurrent corneal tibular disease appear before deafness. Early vestibular dis-
ulceration may result. However, many horses eventually learn ease may be reversible or centrally compensated, but loss of
to retract the globe to assist in eyelid closure to spread the tear auditory function is permanent.1,199 Streptomycin preferen-
film across the eye, lessening the severity and frequency of cor- tially affects the vestibular system, whereas dihydrostrepto-
neal ulceration. Many horses return to some level of athletic mycin, kanamycin, gentamicin, neomycin, and vancomycin
function after THO.207 However, owners of horses with THO are more toxic to the auditory system.1,202 Vincristine, a
should be cautioned regarding the potential for acute onset of vinca alkaloid, can cause bilateral cochlear nerve damage in
severe neurologic signs with no warning as a result of refrac- human beings. Auditory function improves several months
ture. Therefore affected horses pose a risk to human beings after discontinuation of the drug. This antimitotic drug is a
in the environment, and recognition of this risk is important. common component of multiagent chemotherapy protocols
Surgical treatment may possibly diminish the risk for subse- in the treatment of lymphoma in the horse. Vincristine also
quent fracture217; however, currently no long-term follow-up is used for immunosuppression and stimulation of platelet
studies of large numbers of affected horses exist to quantify or function in refractory cases of immune-mediated thrombo-
compare risk with or without surgery. cytopenia. One should carefully monitor auditory function
when using this drug.
Head Trauma Sudden loud noises can result in degeneration and necrosis
Traumatic fractures of the petrous temporal bone result in of the sensory hair cells of the inner ear. A lightning strike,
damage to the vestibular and facial nerves. Profuse aural although usually fatal, is reported to cause acute onset of uni-
hemorrhage or loss of CSF from the external ear canal fre- lateral vestibular disease in the horse. Facial nerve paralysis
quently is observed. Bleeding from the nose occurs if the may or may not accompany the vestibular signs. Documenta-
fracture extends to the cribriform plate.203 Clinical signs usu- tion of histopathologic findings in one case revealed hemor-
ally appear immediately after trauma and include vestibular rhage and necrosis of the temporal bone, vestibular nerve, and
disease, facial nerve paralysis, recumbency, or coma. Dam- adjacent tissue. Whether the mechanism of damage is electro-
age to nervous tissue might be caused by hematoma, callus cution or noise trauma is unknown.4
formation, or displacement of fracture fragments resulting
in delayed onset of clinical signs. Signs from brainstem con- Central Vestibular Disease
tusion or concussion might be more severe than vestibular Any inflammatory disease or space-occupying mass of the
dysfunction. If blindness is present, the prognosis worsens CNS may damage the vestibular nuclei and related tracts. Clin-
because of the loss of visual compensation of vestibular dis- ical signs vary with the type and extent of the disease process.
ease in the future. If one cannot elicit the oculocephalic reflex One should suspect a CNS disease if abnormal mentation, sei-
(physiologic nystagmus), the examiner should suspect dam- zures, blindness, or multiple cranial nerve abnormalities are
age to the medial longitudinal fasciculus, indicating exten- seen with general proprioceptive deficits. One should perform
sive brainstem damage; a poor prognosis is indicated.1 One an EEG to detect the location and extent of the CNS lesion.
might recall that bilateral peripheral vestibular disease also The EEG can detect only cerebral damage and cannot identify
results in loss of the oculocephalic reflex; however, this is an lesions of the brainstem. Inflammatory, parasitic, and neoplas-
unlikely scenario for trauma. tic diseases have been implicated in central vestibular disease
Fractures of the basioccipital and basisphenoid bones occur of the horse.
most frequently in horses that rear over backward and strike Inflammatory disease affecting the CNS includes bacte-
the poll of the head. This fracture does not result from referred rial abscess, equine protozoal myelitis, and viral enceph-
impact from the poll but is thought to be an avulsion fracture alitis. One should perform CSF analysis to identify the
from the pull of the powerful ventral straight muscle of the inflammatory process. In the case of brain abscessation,
neck (rectus capitis ventralis) on its insertion on the basioccip- a culture of the CSF might identify the causative organ-
ital bone.218 Basioccipital fractures result in neurologic signs ism; Streptococcus equi subsp. equi is a common causative
associated with damage to the brainstem; signs of vestibular agent.210,211 EPM is a common neurologic disease in Amer-
disease are common. Petrous temporal bone fractures are dif- ica and should be suspected if multifocal disease is present.4
ficult to identify radiographically; tympanosclerosis appears as For polyneuritis equi to occur with vestibular dysfunction
is common, but the signs of cauda equina neuritis predomi- noninvasive, electrodiagnostic test stimulates the auditory
nate.1 Rabies might present as an encephalitis or spinal cord system with a series of clicks. Far-field potentials of the
disease and should be considered in the differential diag- brainstem auditory components are recorded via cutane-
nosis of any horse with neurologic disease. Spinal ataxia is ous electrodes and a signal-averaging system.60-62,67,71,205
the primary neurologic deficit observed in horses affected The response is a series of evoked potentials occurring
with equine herpesvirus (EHV) myelitis, but the presence within 10 ms after the stimulus. In the horse the evoked
of concurrent vestibular disease is reported.219 The major potentials appear on the oscilloscope as a series of five
clinical signs observed with a togavirus (eastern, western, waveforms.33 Abnormalities of the specific waveforms can
and Venezuelan encephalitis) infection are depression and identify a lesion of the corresponding neurologic structure.
seizure, although cranial nerve deficits are observed.4,211 In the horse, functional loss of the cochlea or eighth cranial
Horses with West Nile virus (WNV) infection may display nerve results in the loss of the entire waveform on the side
cranial nerve signs, including vestibular disease. Concur- of injury, and the presence or absence of the waveform can
rent behavioral and mentation changes, ataxia, fever, and differentiate a central from a peripheral vestibular lesion.
muscle fasciculations are common General anesthesia is not necessary to perform the test, but
Aberrant parasite migration of the CNS in horses results in sedation is recommended.60-62,71,205
acute onset of neurologic signs. Clinical signs vary, but pro-
gression of clinical signs occurs in most instances. Neurologic Y DISEASES OF THE CEREBELLUM
signs are generally asymmetric because of the random nature
of migration. Neurologic disease secondary to parasite migra- Cerebellar abnormalities reported in horses consist primar-
tion is discussed in detail later in this chapter. Fungal granulo- ily of neurodegenerative disorders confined primarily to a
mata caused by Aspergillus spp. and Cryptococcus neoformans small number of breeds, including Arabians and Gotland
have been reported as space-occupying masses within the cra- pony foals. The cerebellum is essential for the coordination
nium of a horse.4,220 Cholesteatoma (cholesterol granuloma) of movement. Afferent information arises from the general
could involve the vestibular system by extending from the and special (vestibular) proprioceptive systems and the spe-
choroid plexus of the fourth ventricle of the brain.4 Neoplastic cial somatic (auditory and visual) systems. The cerebellum
diseases of the CNS are rare in the horse. Any tumor affecting is responsible for regulation of the rate, range, and strength
the cerebellomedullary angle could result in vestibular signs.1 of movement, as well as integration and coordination for
Lymphoma, ependymoma, meningeal melanoma, and mela- balance and posture. Cerebellar abnormalities in horses are
notic hamartoma have been reported to affect the CNS of the unusual; however, when present, they can have a profound
horse.1,221 effect on gait and posture.
Structure and Function
Ancillary Diagnostic Tests Knowledge of the structure and development of the cerebel-
Caloric Testing lum is important for understanding cerebellar function in
The caloric test is a diagnostic aid that might be helpful in health and disease. The cerebellum is located in the meten-
differentiating central from peripheral vestibular disease. cephalon dorsal to the pons and is attached to the pons via
The test is able to assess each peripheral vestibular sensory three cerebellar peduncles (Fig. 11.32). The caudal peduncle is
organ separately. In the normal animal, irrigation of ice-cold composed primarily of afferent fibers arising from the medulla,
water (12°C) into the external auditory canal for 3 to 5 min- the vestibular nuclei via the vestibulocerebellar tracts, and the
utes induces a horizontal nystagmus with the fast phase away spinal cord via the spinocerebellar tracts. The middle cerebel-
from the tested labyrinth.1,201 The water cools endolymph lar peduncle contains only afferent fibers to the cerebellum
closest to the tympanic membrane, increasing its density. that arise from the transverse fibers of the pons. The rostral
A density gradient is created within the semicircular canal, cerebellar peduncle is the primary connection to the mesen-
and the cooled endolymph sinks, causing displacement of cephalon and carries the majority of cerebellar efferent fibers,
the hair cells. Warm water (45°C) irrigation of the exter- although a few afferent fibers arise from the spinocerebellar
nal auditory canal results in horizontal nystagmus with a tracts. The cerebellum consists of two hemispheres and a cen-
fast phase toward the tested labyrinth. The warm-water test tral region known as the vermis.1 The extensive convolutions
is less reliable.199 The test does not induce nystagmus in a of the cerebellar cortex are termed folia. The cortex covers
nonfunctional labyrinth. Animals may resist the procedure, the surface of the cerebellum. On cut section, the cerebellar
making the test difficult to interpret, and in some animals, medulla is a central region of white matter with multiple pro-
one cannot induce nystagmus. If an asymmetric response jections called arbor vitae. These branches extend to the cer-
is obtained, the depressed reaction indicates the abnormal ebellar cortex and form the white matter portion adjacent to
labyrinth.1 The test is difficult to perform and not entirely the cerebellar cortex.
reliable, although it might be a helpful diagnostic aid in the The cerebellar medulla has three nuclei: (1) the fastigial, (2)
anesthetized or comatose horse.201 the interpositus, and (3) the lateral nuclei from medial to lat-
eral on each side of the cerebellum. The cerebellum also can
Brainstem Auditory Evoked Response be divided into three bilateral longitudinal regions in asso-
The cochlea is damaged by trauma or inflammation of the ciation with these nuclei.1,222 The medial zone, containing the
peripheral vestibular receptor organs, and detection of vermis and the fastigial nucleus, primarily regulates the tone,
hearing loss may help to differentiate central from periph- posture, and equilibrium of the body in general. The inter-
eral vestibular disease. Unilateral hearing loss is difficult mediate zones contain the interpositus nucleus and cortex
to assess subjectively in the horse. BAER is a method of adjacent to the vermis and adjust the orientation of limbs in
objective assessment of auditory function in the horse. This space, maintaining balance, posture, and muscle tone during
Cerebellum
Cerebrum
Cerebellar
peduncles
Spinal cord
Midbrain Pons Medulla
FIG. 11.32 Schematic diagram of cerebellar efferent and afferent information pathways via the cerebellar
peduncles. The arrow size reflects the relative contribution of each pathway (see text for details).
complex movements. The lateral zones, consisting of the lat-

eral nuclei and lateral portions of the cerebral hemispheres,
have a similar function but do not influence posture or muscle
tone directly.222
The cerebellum arises from the alar plate region of the met-
encephalon and originates initially as a proliferation of cells in
the rhombic lip that extend dorsally and medially to form the
dorsal portion of the metencephalon. Germinal cells prolifer-
ating in the rhombic lip eventually migrate into the cerebel-
lum and differentiate to form the specialized neurons of the
cerebellar cortex. The cerebellar cortex has three layers: (1) the
outer molecular layer, (2) the middle Purkinje layer, and (3)
the inner granular layer (Fig. 11.33). The molecular layer is
acellular and consists primarily of the dendritic zones of the
Purkinje cells and axons of the granular cells.1 The Purkinje
layer is only one cell thick and consists of Purkinje neurons.
The granular layer is densely cellular with granular neurons.
All layers must be present and aligned in proper orientation
for normal function.
Organization of the specialized structure of the cerebel-
lar cortex allows integration and coordination of movement.
The cerebellum primarily provides regulation of skeletal
movement, allowing coordinated movement; it does not
initiate muscular activity. Afferent information regarding
movement and balance arising from the mesencephalon, the
brainstem, and the spinal cord enters the cerebellum via the
cerebellar peduncles, and regulation of movement is coor-
dinated by the inhibitory influence of Purkinje neurons on
the cerebellar nuclei. Information enters the cerebellum via
the cerebellar peduncles and is carried on two major afferent
nerves termed Mossy fibers and climbing fibers.1 Mossy fibers
originate from the brainstem and spinal cord. Mossy fibers
send collateral fibers to synapse with the cerebellar nuclei;
FIG. 11.33 Photomicrograph of a normal cerebellum. M, Molecular lay-
they terminate by synapsing with granular neurons in the
er; P, Purkinje layer; G, granular layer; Md, medulla; arrowhead, a Purkinje
cerebellar cortex. These fibers are facilitatory at these syn-
neuron. (Hematoxylin-eosin stain; ×55.) (Courtesy the Washington Animal
apses. The axons that granular neurons send to the molecular
Disease Diagnostic Laboratory, Pullman, WA.)
layer course transversely through this layer to synapse with
the dendritic zone of multiple Purkinje cells and also provide
facilitatory influence at these synapses. Climbing fibers origi- Purkinje neurons provide the sole efferent fibers from the
nate in the olivary nucleus, which provides most of the extra- cerebellar cortex. The majority of Purkinje cell axons termi-
pyramidal projections to the cerebellum. Similar to mossy nate on neurons in the cerebellar nuclei, although direct pro-
fibers, climbing fibers send collaterals to synapse on neurons jections from these neurons to the vestibular nuclei occur via
in the cerebellar nuclei; however, the axon continues through the caudal cerebellar peduncle. Purkinje neurons are inhibi-
the cerebellar cortex to synapse with the dendritic zone of tory and use the neurotransmitter GABA.1 Efferent nerves
the Purkinje neurons in the molecular layer. As with mossy from the cerebellum are primarily from the cerebellar nuclei
fibers, climbing fibers provide a facilitative influence at the that facilitate activity of upper motor neurons originating in
synapses. the brainstem.
Thus much of the influence of the cerebellum on skeletal more frequently than fillies, although subsequent reports have
muscle activity is to modulate the upper motor neuron. Infor- not substantiated this finding.225 The cerebellar abiotrophy
mation regarding movement and balance enters the cerebel- that occurs in Oldenburg horses is progressive and fatal, with
lar cortex via the cerebellar peduncles. This afferent activity atypical histologic lesions compared with the syndrome that
stimulates inhibitory Purkinje neurons by climbing or mossy occurs in Arabian foals, in which the degeneration is charac-
fibers. Purkinje neurons in turn modulate the activity of the terized by apoptosis of Purkinje cells.233 Cerebellar abiotrophy
cerebellar nuclei to regulate movement and muscular tone. generally affects foals less than 1 year of age and occurs most
Purkinje neurons also provide direct inhibitory input to the frequently in 1- to 6-month-old foals. Adult-onset cerebellar
vestibular nuclei. abiotrophy has been reported in other species such as the dog
and has been observed in two horses.1 Many foals are born
Clinical Signs with no abnormalities and later develop disease; however,
Clinical signs associated with cerebellar disease generally occasionally they are affected at or shortly after birth.202,225,228
reflect the loss of coordination. Mentation is normal in horses Clinical signs associated with cerebellar abiotrophy include
with cerebellar disease, provided that other regions of the intention tremors of the head, ataxia, wide-based stance and
brain are unaffected and metabolic disturbances such as septi- gait, dysmetria, and spasticity.202,223-229 The most frequently
cemia or endotoxemia are not present. Cerebellar distur- reported initial signs noted by owners are an intention tremor
bances result in ataxia and inability to regulate the rate, range, of the head, vertical or horizontal, or a hypermetric forelimb
and force of movement.1 Dysmetria refers to alterations in the gait.223,228 The neurologic examination reveals no change in
range of gait. Hypermetria is an exaggerated range of move- mentation. One almost never observes nystagmus, which
ment. When moving, the limb has a higher or longer flight has been reported in only one case of abiotrophy in a Got-
compared with normal. Initiation of movement might be land pony.226 A menace reflex frequently is absent or dimin-
jerky and awkward, and the trunk may sway from side to side ished.202,228 One must interpret this finding with caution
when the horse moves. Spasticity is caused by hypertonia and because normal foals may lack or have a depressed menace
results in a jerky stiff gait. Diffuse cerebellar disease results in reflex until at least 2 weeks of age.234
bilateral signs. In general, unilateral lesions result in signs Stance and gait abnormalities seen with cerebellar abi-
ipsilateral to the lesion. Intention tremor is another promi- otrophy generally consist of a wide-based stance or gait and
nent sign of diffuse severe cerebellar disease. Tremor is most ataxia.202,227,228 The foal may move stiffly and have a high
obvious as vertical or horizontal head motions and can be goose-stepping gait. The horse may protract the limb when
observed readily as a horse approaches feed or attempts to walking, resulting in slamming of the foot to the ground.
nurse. The tremor is present only when a movement is initi- Movement may be spastic with circumduction. Walking on
ated and tends to become more exaggerated as the horse an incline, asking the foal to step over obstacles, and blind-
approaches an object. folding the foal exacerbate gait abnormalities. Generally, gait
Cerebellar disease also might cause loss of menace response abnormalities are symmetric, although in a Welsh Cob and
and vestibular abnormalities. Disruption of the flocculonodu- Arabian cross foal the initial signs were characterized by a stiff
lar lobe, located in the ventral cerebellum, or the fastigial motion in the left front limb. Signs in this foal progressed to
nucleus might result in vestibular signs characterized by dis- severe ataxia.224 Foals affected at birth may have difficulty ris-
equilibrium; a variable nystagmus, which may be positional; ing.202,225,226 Segmental reflexes are normal. Some affected ani-
and positioning difficulties.1 Unilateral lesions might result in mals fall when startled or when raising their heads. Signs are
a head and body tilt toward the side of the lesion and nys- generally progressive for several months after diagnosis. Once
tagmus with the fast phase away from the lesion. Paradoxic the animal has reached maturity, the condition becomes static,
vestibular syndrome, characterized by a head tilt away from although mild improvement has been observed.229
the lesion and nystagmus with the fast phase toward the lesion, Ancillary testing is of limited value in diagnosing cerebel-
is apparent with unilateral lesions involving the cerebellar lar abiotrophy but can be helpful to rule out other causes of
peduncle.1,222 ataxia. The CBC and serum biochemistry profile are normal in
affected foals. Usually, there are no abnormalities in CSF and,
if present, are not specific. In one study, three of four foals had
Diseases of the Cerebellum an elevated CSF CK activity. Values in affected foals ranged
Cerebellar Abiotrophy and Degeneration from 6.6 to 62 IU/μL (normal range, 0–8 IU/μL).228 CSF CK
Cerebellar abiotrophy is the most commonly reported cer- elevations generally are associated with neural necrosis or
ebellar disease in horses.202,223-229 Abiotrophy in the nervous degeneration, although they are not associated specifically
system refers to premature degeneration of neurons caused by with a particular disease.27,235,236
some intrinsic abnormality in their structure or metabolism.230 In addition, CSF total protein might be elevated. In the study
Cerebellar abiotrophy has been reported in Arabian, Gotland cited previously, three foals had elevated total protein with an
pony, and Oldenburg horse breeds. Degenerative cerebellar average of 226 mg/dL (normal, 0–100 mg/dL) in all foals with
lesions have been observed in one Thoroughbred and two cerebellar abiotrophy. As with CK, total protein elevations are
Paso Fino newborn foals.231 The disorder has been commonly not specific for abiotrophy and might occur with disruption of
reported in Arabian and Arabian-related breeds.202,223-225,227,229 the blood-brain barrier or with CNS inflammation or degen-
The disorder is inherited as an autosomal recessive trait and is eration. Many foals with cerebellar abiotrophy have normal
associated with a single-nucleotide polymorphism (SNP) on CSF analysis. EEG abnormalities, including increased syn-
equine chromosome 2 (13074277G>A), located in the fourth chrony and increased number of abrupt frequency changes,
exon of TOE1 and in proximity to MUTYH on the antisense also may be detectable in affected foals.228 In this study, these
strand.232 The incidence in some Arabian horse herds has been abnormalities were not observed in normal foals anesthetized
reported to be as high as 8%. In one report, colts were affected under similar conditions. Skull and cervical radiographs are
No virus has been isolated from the CSF or brain of affected

foals, and no viral inclusions have been observed on histologic
examination. No toxin has been associated consistently with
cerebellar abiotrophy of Arabian foals. Experimental breed-
ings of Arabian horses indicate an autosomal recessive mode of
inheritance, but an exact genetic basis for disease has not been
determined. A pedigree analysis of Gotland ponies similarly
suggests an autosomal recessive mode of inheritance226; how-
ever, a high degree of inbreeding was noted, making definitive
conclusions difficult. Attempts to breed affected individuals in
this study were unsuccessful.
No treatment exists for cerebellar abiotrophy. As noted pre-
viously, signs may be progressive until the foal reaches matu-
rity. Signs may stabilize or improve slightly with time.
Gomen Disease
FIG. 11.34 Photomicrograph of the cerebellum from a 9-month-old Gomen disease is a degenerative cerebellar condition rec-
foal with cerebellar abiotrophy. The decreased number of Purkinje neu-
ognized in the northwest part of New Caledonia.237 Gomen
rons is notable. (Hematoxylin-eosin stain; ×139.) (Courtesy the Washing-
disease is a progressive cerebellar disease that causes mild to
ton Animal Disease Diagnostic Laboratory, Pullman, WA.)
severe ataxia. Horses that are indigenous or are introduced
to the region may be affected. The disease occurs only in
horses that are allowed to roam free, and signs may take
unremarkable. However, because mentation is normal in foals 1 to 2 years to develop once a horse is introduced into an
with cerebellar abiotrophy, EEG examination is not necessary endemic area. Horses that are confined generally are unaf-
to make a diagnosis and is primarily useful to exclude seizure fected. Clinical signs consist of ataxia, which is most promi-
disorders as a cause of the tremors observed. nent in the pelvic limbs; toe dragging; and a wide-based
Antemortem diagnosis of cerebellar abiotrophy is based stance. As the disease progresses, horses might have dif-
on a typical history and the clinical signs of intention tremor, ficulty rising. The signs are primarily referable to involve-
lack of menace, failure to blink to bright light, and ataxia in ment of the cerebellum; however, weakness likely is caused
Arabian, part-Arabian, or Gotland pony foals. The differential by brainstem or spinal cord involvement. Nystagmus is not
diagnoses for cerebellar abiotrophy include cranial malfor- observed. Ataxia is progressive over 3 to 4 years until the
mations; congenital spinal malformations, including atlanto- horse dies or is euthanized.
axial malformations and stenotic myelopathy; inflammation Mild cerebellar atrophy might be apparent on gross
or infection of the cerebellum; and trauma. One can rule out examination of the brain. Histologically, severe depletion of
these conditions based on the neurologic examination, CSF Purkinje neurons is evident throughout the cerebellum.238
analysis, and radiography. The signs of characteristic ataxia Purkinje neurons might contain lipofuscin pigment and
and head tremor without weakness in the appropriate breed vacuoles. Moderate to severe lipofuscin pigmentation of neu-
are nearly pathognomonic. ron cell bodies occurs throughout the brain and spinal cord.
Postmortem examination provides a definitive diagnosis Although lipofuscin accumulation might be considered a nor-
of this disorder. Generally, no gross abnormalities are notable; mal variation of aging, the degree of pigment accumulation is
however, careful examination of the cerebellum might reveal far more severe than that in horses of similar age. The patho-
an increased lobular pattern with prominent folia. In the Got- genesis of this disease is unknown. Pedigree analysis has not
land pony, the weight ratio of the cerebellum to the cerebrum revealed any genetic component for susceptibility to develop-
is reduced significantly in foals with cerebellar abiotrophy.226 ment of disease.237 A condition of neuronal lipofuscinosis in
Normal foals had a 13% ratio, and affected foals had a 10% dogs has some similarities to this disease.238 The accumula-
ratio. In the degenerative cerebellar condition in the Paso Fino tion of lipofuscin pigment and association with free-ranging
and Thoroughbred foals, a decrease in the cerebellar-to-whole horses suggest a metabolic disorder, perhaps resulting from
brain weight ratio was evident.231 This ratio in normal foals toxicity.237,238
was 8% and in affected foals was 6%.
Histologic abnormalities are consistent in cases of cerebel- Developmental Abnormalities
lar abiotrophy. The most prominent finding is the widespread Dandy-Walker syndrome is characterized by a midline defect
loss of Purkinje neurons202,223-229 (Fig. 11.34). Degenerative of the cerebellum and cystic dilation of the fourth ventricle,
changes, such as shrunken and angular neurons with hyper- which separates the cerebral hemispheres.239 Frequently, all
chromasia and dispersion of Nissl’s substance, are apparent. or portions of the cerebellar vermis fail to form, and the cor-
One may observe occasional “baskets” or clear spaces where pus callosum may be absent. The condition is rare in horses
the Purkinje neuron is lost. Thinning of the molecular layer and has been observed in Thoroughbred and Arabian foals.240
occurs with gliosis. The granular layer is also thin with a loss Foals with this syndrome might be abnormal neurologically
of cellularity. Similar histologic findings were found in Thor- from birth, with difficulty rising, seizures, and absence of the
oughbred and Paso Fino foals with vacuolation and prolifera- suckle reflex.240 The forehead might be domed excessively.
tion of Bergmann’s glia in the Purkinje cell layer.231 Ataxia, nystagmus, aggression, and difficulty in training might
The pathogenesis of cerebellar abiotrophy is unknown. Viral, persist as the foal ages.240 Diagnosis generally is made at post-
toxic, and genetic causes have been investigated.202,223,225,228 To mortem examination; however, one case was diagnosed ante-
date no evidence has been found to support an infectious cause. mortem using CT.240
Several individual cases of equine developmental cerebel- birth and developed signs of severe incoordination, a wide-
lar abnormalities have been described. Cerebellar hypoplasia based stance, and recumbency at 2 to 5 days of age. The con-
has been described in a Thoroughbred foal that had difficulty dition appeared more severe when the foals became excited
rising and developed seizures shortly after birth.241 Bilateral or struggled; consequently, they were treated symptomatically
focal cerebellar cortical hypoplasia has been reported in a with diazepam. The signs would improve with this treatment
6-year-old Thoroughbred gelding.242 No gait abnormalities and return as the sedation diminished. These foals improved
were detected in this horse, although it had fallen over repeat- with stall rest over 7 to 10 days. The cause of the clinical signs
edly before euthanasia. The relationship between falling and in these foals is unknown; however, the authors suggested pos-
the cerebellar abnormality is unclear. Possibly the abnormality sible viral or toxic causes.
in this adult horse resulted from a secondary problem, such as Cerebellar ataxia in two Thoroughbred fillies has been
vascular injury, rather than a developmental defect.233 associated with hematoma in the fourth ventricle.250 These
A single case of cerebellar dysplasia has been described in a two horses demonstrated fever, dysmetria, spasticity, and
4-year-old Thoroughbred horse.243 This horse had a 7-month weakness. Clinical signs most likely resulted from compres-
history of circling and collapsing to the left side. In this case sion of the adjacent cerebellum. CSF analyses in these cases
the horse had hyperplasia of the right side of the cerebellum revealed xanthochromia, elevated RBC and white blood cell
with no associated central white matter. Histologically, the counts, and elevated total protein concentrations. The cause of
granule layer was thinning, with increased thickness of the the hematomas was not identified; damage to regional small
molecular layer and cavitation of the white matter. vessels and a vascular anomaly were suspected.
Additional reported developmental disorders include cer- Chronic methylmercurial poisoning in horses can cause a
ebellar hypoplasia with internal hydrocephalus and cerebellar number of clinical abnormalities, including cerebellar ataxia.251
aplasia with hydranencephaly in two fetuses from Haflinger Severe poisoning can result in incoordination, dysmetria, and
mares with hydrops allantois.244 Mild cerebellar degenerative gross head nodding in the experimental setting. Associated
changes consisting of Purkinje neuron granularity have been clinical signs include lethargy, anorexia, exudative dermati-
noted in a Standardbred filly with a chromosomal abnormal- tis, and laminitis. Lesions in the cerebellum consisted of focal
ity.245 This abnormality was accompanied by mild spongiotic atrophy and cellular depletion in the granular layer with little
degeneration of the cerebrum. Abnormal neurologic signs in to no involvement of Purkinje cells. Additional abnormalities
this filly included difficulty standing at birth, mental dullness, included neuronal necrosis and gliosis in the cerebrum, lym-
and a head tilt. Growth retardation, small inactive ovaries, and phocytic perivascular cuffing, and swollen axons in the spinal
a consistently wrinkled muzzle accompanied these signs. cord. Preferential accumulation of inorganic mercury in the
brain and resulting cell injury most likely led to the neurologic
Infectious Conditions signs observed. Diagnosis of methylmercurial poisoning can
Unlike in many other large animals, no infectious agents have be based on clinical signs and measurement of mercury in the
the cerebellum as their primary target; however, a number of liver and kidney.
agents might affect the cerebellum. Any agent that targets the
CNS, especially those that have a multifocal distribution, also
may involve the cerebellum. Occasionally, disseminated Strep-
Y SHIVERS
tococcus equi subsp. equi infection (bastard strangles) may Monica Aleman
result in a cerebellar abscess.246 Neurologic abnormalities in one
reported case included proprioceptive deficits in the right tho- Shivers is a chronic progressive equine movement disorder of
racic limb, nystagmus, and a head tilt. Meningitis contributed unknown etiology. Affected horses display difficulty walking
to other CNS signs such as depression, blindness, and recum- backward, assume hyperflexed pelvic limb posture, and have
bency. Diagnosis of this condition can be based on a history of tremors during backward movement.252,253 The condition
previous S. equi subsp. equi infection, evidence of severe suppu- might progress to involve thoracic limb movement. The condi-
rative inflammation in the CSF, and culture of S. equi subsp. equi tion has been reported in draft breeds, Thoroughbreds, Warm-
from the CSF. Treatment consists of penicillin. The prognosis is bloods, and others with less frequency such as Connemara,
guarded; however, successful surgical drainage of a cerebral S. Welsh, Quarter Horses, Standardbreds, Saddlebreds, Tennes-
equi subsp. equi abscess has been reported.247 see Walking horses, Missouri Fox Trotters, Paint, Morgan, and
Focal involvement of the cerebellum has been associated with mixed breeds.252 Gait patterns of shivering were characterized
aberrant parasite migration in the horse.224,248 In a 6-year-old in one study as (1) hyperextension when backing and lifting
pony, infection with Halicephalobus gingivalis resulted in severe the limb, (2) hyperflexion and abduction during backward
ataxia.248 Histologic study showed lesions scattered through- walking, (3) shivering hyperflexion with abduction during
out the cerebellum, brainstem, thalamus, and pituitary gland, backward walking, and (4) shivering-forward hyperflexion
and nematodes were observed throughout the lesions. A sec- including intermittent hyperflexion and abduction with for-
ond case involving a 1-year-old Thoroughbred colt had a sud- ward walking.253 Horses with shivering-hyperflexion, shiv-
den onset of severe ataxia.224 Multifocal malacia with numerous ering-forward hyperflexion, and stringhalt had a prolonged
eosinophils was observed throughout the cerebellar white mat- swing phase duration compared with control horses and oth-
ter. No nematode was detected, although parasitic involvement ers with other types of shivers. Initially forward movements
was suspected based on the eosinophilic inflammation. are normal.253 Other signs might include muscle atrophy,
reduced muscle strength, exercise intolerance, facial twitch-
Miscellaneous Conditions ing, elevated tail head, and problems picking up feet for farrier
A familial neurologic condition in newborn Thoroughbred (common complaint).252 Shivering signs usually begin at less
foals has been reported.249 This syndrome affected three of than 5 years of age and progress in the majority of cases (74%
five foals of a Thoroughbred mare. The foals were normal at reported in one study).252 Horses with shivers are significantly
taller (mean 173 ± 6.2 cm) with a higher male-to-female reatio

(3:1) than a control population.252
There are no histologic lesions in the thoracic and pelvic
limb skeletal muscle. In a study, eosinophilic segmented axo-
nal spheroid and calretinin-positive axonal spheroids were
found to be common lesions in the CNS, particularly in the
nucleus cuneatus lateralis.254 Calretinin-negative, calbindin-
positive, and glutamic acid decarboxylase-positive spheroids
were found increased 80-fold in Purkinje cell axons within the
deep cerebellar nuclei in affected horses.254 Unusual lamel-
lar structures resembling marked myelin decompaction were
observed between myelin sheaths of presumed Purkinje cell
axons in the deep cerebellar nuclei of shivers but not control
horses.254 The authors concluded that shivers is characterized
by end-terminal neuroaxonal degeneration in the deep cer-
ebellar nuclei, which results in context-specific hypermetria A
and myoclonus.254
Y CERVICAL VERTEBRAL COMPRESSIVE

MYELOPATHY
Yvette S. Nout-Lomas
Cervical vertebral compressive myelopathy (CVCM) is a com-

mon cause of ataxia and weakness in horses. It is the most
common cause of ataxia in horses in Europe and Australia and
is an important differential diagnosis in regions affected by
inflammatory diseases such as EPM and WNV. Differentiating
CVCM from other conditions that cause ataxia is important
for prognostic and therapeutic considerations. The disease
is also referred to as cervical vertebral malformation, cervi-
cal vertebral stenotic myelopathy, cervical stenotic myelopa-
thy, cervical spondylotic myelopathy, equine sensory ataxia,
equine incoordination, spinal ataxia, and wobbler syndrome.
Compression of the spinal cord occurs secondary to steno-
sis, or narrowing, of the vertebral canal anywhere from C1 to
T1. Stenosis of the cervical vertebral canal is a result of bone B
and joint malformations, the pathogenesis of which remains
unclear but is likely multifactorial.
CVCM is most frequently seen in young, well-fed, rapidly FIG. 11.35 A shows a lateral cervical radiograph taken from an
8-month-old Quarter Horse colt with grade 4 out of 5 ataxia. Cervical
growing horses. Analysis of over 800 horses with CVCM
vertebrae 3–7 are indicated with evidence of malformation at C3–4 and
confirmed what previous studies have shown: males (stal-
C5–6 (arrows). Collapsing of the dorsal aspect of the disk space is seen
lions and geldings) and Thoroughbreds, Tennessee Walking
at C3–4 with surrounding bony proliferation. Caudal extension of the
Horses, and Warmbloods have a significantly higher likeli-
dorsal aspect of the vertebral arch of C5 (arrow) and obvious malalign-
hood of having CVCM compared with mares and other
ment and stenosis of the vertebral canal at C5–6 are shown. B shows a
breeds. CVCM has been shown to affect 1.3% to 2% of Thor-
lateral cervical radiograph taken from a 17-year-old Thoroughbred geld-
oughbred horses.255,256 Furthermore, horses that ranged
ing with a chronic bilateral front limb lameness and a 1-month history
from less than 6 months to less than 7 years of age had sig-
of progressive ataxia. Shown are the C5–C7 vertebrae with extensive
nificantly higher odds of having CVCM compared with
bony proliferation at the articular processes (arrows) of both C5–C6
horses 10 years of age or older.257 Developmental bone dis-
and C6–C7.
ease in younger horses can lead to deformation and malar-
ticulation or malalignment of vertebral bodies (Fig. 11.35A).
In older horses, spinal cord compression more commonly (more cranial vertebral) or extended (more caudal verte-
occurs secondary to vertebral malformation because of brae), and (2) static compressions, in which spinal cord com-
osteoarthritis of caudal cervical articular process joints, pression is continuous regardless of cervical position.259
although there may be some overlap in this distinction. Male Both syndromes are likely to occur in individual cases or can
horses and horses of Warmblood or Tennessee Walking occur simultaneously. The clinical significance of distin-
Horse breeds may be predisposed to development of CVCM guishing between the two types of CVCM is unknown, but it
at an older age.258 Spinal cord compression has traditionally is important for imaging studies because significant flexion
been separated into two categories: (1) dynamic vertebral or extension may be necessary to demonstrate dynamic com-
compressions, whereby the spinal cord compression is inter- pressions. Proposed etiologic factors that result in develop-
mittent and occurs when the cervical vertebrae are flexed mental bone disease include high planes of nutrition,
accelerated growth rates, altered ratios of copper and zinc, detailed MRI and histopathologic analyses have also identi-
and inherited genetic determinants. None of these has so far fied bone cysts within the articular processes of horses with
been shown to be a direct cause of CVCM. CVCM.94 The abnormalities found in the necks of horses
with CVCM are generalized and not limited to the site(s) of
Clinical Signs spinal cord compression. Histopathologic examination of the
Most horses are diagnosed with CVCM when they are spinal cord reveals wallerian-like degeneration, loss of axons
between 12 and 23 months of age.257 Cervical vertebral and fibrosis at the sites of spinal cord compression, and axon
compressive myelopathy is characterized by symmetric loss in the ascending and descending white matter tracts
ataxia, upper motor neuron paresis, and dysmetria, which within adjacent segments of the spinal cord cranial and cau-
are usually worse in the pelvic limbs than thoracic limbs.40 dal to the site of spinal cord compression.40
Physical examination sometimes reveals palpable cranial A high dietary energy intake is almost certainly necessary
cervical vertebral flexion-fixation, and affected horses tend for expression of the disease, and trauma to the neck probably
to be large for their age and breed. Male animals appear to plays a role as young, large, fast-growing animals (often male
be more frequently affected. Often a history of increased animals) are most commonly affected. CVCM resulting from
clumsiness occurs, and mild to moderately affected horses developmental bone disease almost certainly has a genetic
show symmetric ataxia with circumduction of the pelvic basis; however, a breeding trial using horses with CVCM that
limbs, especially when the animal is made to walk in small had had corrective surgery resulted in offspring that did not
circles. Proprioceptive deficits, toe dragging (flexor paresis), have CVCM but did have a higher frequency of developmental
and varying degrees of upper motor neuron extensor paresis orthopedic diseases than expected.261
(assessed by pulling on the horse’s tail at a walk) are also pres- CVCM in older horses is frequently associated with
ent. Thoracic limbs often have a hypometric, stiff (spastic) arthritis of the articular processes of the caudal (C5–T1)
component to the strides, especially while walking the horse cervical vertebrae, and articular process osteophytes are the
down a slope and with the head elevated. Thoracic limb defi- most commonly seen radiographic lesions.258 Biomechani-
cits are usually less severe than pelvic limb deficits because of cal forces are likely to play a part in the onset of the disease.
the more superficial location of pelvic limb spinocerebellar Compression of the spinal cord is due to vertebral malforma-
proprioceptive tracts in the spinal cord. Horses with chronic tion at C5, C6, and C7, resulting in cone-shaped caudal cer-
disease tend to show less paresis than those with recent-onset vical vertebrae with a reduction in a cross-sectional area of
clinical signs.4 Neck pain or stiffness may be present in some the vertebral canal and resultant impingement on the spinal
older horses. An accident or injury to the neck is sometimes cord by proliferating articular and periarticular soft tissues.
in the history, and clinical signs may have an abrupt onset There may be concurrent formation of epidural and periar-
or indeed the horse may be tetraplegic, especially if external ticular cysts, which can result in sudden onset of symmetric
trauma plays a major role. The ataxia, however, was likely or asymmetric signs without a contemporaneous episode
present before the traumatic incident. of external injury. Bleeding into one of these cysts has been
Clinical signs of concurrent developmental orthope- observed and adds to the compression. Occasionally these
dic disease of the appendicular skeleton, such as physeal cause acute-onset severe clinical signs that can abate within a
enlargement of the long bones, joint effusion after osteo- few hours only to reappear later.
chondrosis, and flexural limb deformities, are often present
in young horses with CVCM.40 It is worth remembering that Diagnosis
sometimes horses affected with CVCM may have another Fortuitously, the narrowing of the cervical vertebral canal
concurrent neurologic disease such as equine protozoal and associated spinal cord compressive lesions in horses
encephalomyelitis. occur most commonly in a dorsoventral orientation, allow-
ing the diagnosis to be made using (lateral) cervical myelog-
Pathogenesis raphy (Fig. 11.36). Good-quality, standing plain lateral
Compression of the spinal cord is a result of stenosis, or nar- radiographs of C1 to T1 vertebrae provide information on
rowing, of the vertebral canal anywhere from C1 to T1. Ste- anatomy of the vertebral bodies and width of the vertebral
nosis of the cervical vertebral canal is a result of bone and canal but do not show the spinal cord. It should be remem-
joint malformations, the pathogenesis of which remains bered that the lack of dorsoventral radiographic projections
unclear. Currently it is thought that in some horses there effectively makes traditional lateral imaging an incomplete
is an underlying developmental disorder of bone and car- diagnostic series. The assessment of qualitative features of
tilage morphogenesis and maturation that leads to cervical vertebral malformation, including physitis of the caudal
vertebral malformations, whereas in other horses malforma- vertebral body, caudal extension of the dorsal arch of the
tions are thought to be the result of abnormal biomechanical vertebral body, intervertebral malalignment, and arthropa-
stresses and forces on the cervical column.94 Neurologic signs thy of the articular processes, is useful; however, alone these
result from progressive spinal cord compression secondary findings offer poor positive and negative predictive values.
to structural changes to vertebral and surrounding tissues. The most important factor in the diagnosis of CVCM
Pathologic changes of the cervical vertebrae leading to spinal in adult horses and foals is the identification of a decrease
cord compression consist of malformation including angular in the diameter of the vertebral canal, be it within a verte-
deformity of the vertebrae, malalignment between adjacent bra or, more commonly, between two vertebrae. Corrected
vertebrae, stenosis of the vertebral canal, flare or epiphysitis intravertebral and particularly intervertebral sagittal ratios
of the caudal vertebral epiphysis of the vertebral body, exten- (SRs) from C2 to C7 calculated from lateral standing cervi-
sion of the dorsal aspect of the vertebral arch, abnormal cal radiographs can be used to accurately diagnose CVCM
ossification of the articular processes, and degenerative joint in horses.262,263 The intravertebral and intervertebral sagittal
disease of the articular processes (Fig. 11.35B).40,260 Recently, diameter of the vertebral canal is measured at the narrowest
b c
a
A B
FIG. 11.37 Two cervical vertebra showing sites for measuring the in-
travertebral and intervertebral sagittal diameter and the width of the ver-
tebral body (A) (B). For a particular vertebra, the minimum intravertebral
diameter could be anywhere along the vertebral canal (a), and the mini-
mum intervertebral sagittal diameter is the smallest of the two measure-
ments (b) or (c) compared with the diameter of the more caudal vertebral
FIG. 11.36 A lateral cervical myelogram showing compression of the diameter (B).
cervical cord at C3–C4 (arrow). At C3–C4 there is complete attenuation
of the ventral contrast column with significant narrowing (>50%) of the
dorsal contrast column. spinal cord compression.4 Cervical scintigraphic examina-
tions similarly cannot determine whether active arthritis is
actually causing spinal cord compression. Spinal magnetic
points and corrected for radiographic magnification and size motor evoked responses265 may be used more in the future
of horse by being expressed as a ratio of the maximal height to objectively grade the degree of electric conductivity across
of the cranial vertebral physis (Fig. 11.37). The minimum a spinal lesion site.
intravertebral diameter is measured at the point along the Before deciding on surgical decompression or vertebral
vertebral canal where the diameter is at a minimum, whereas fusion, positive contrast myelographic evidence of spinal cord
the minimum intervertebral sagittal diameter ratio is made compression is mandatory. It should be remembered, however,
from the caudal aspect of the dorsal lamina of the vertebral that myelography under general anesthesia is not an innocu-
arch of the more cranial vertebra to the dorsocranial aspect ous procedure in the horse. Adverse reactions have been
of the body of the more caudal vertebra, or from the cau- shown to occur in one third of horses undergoing myelogra-
dal vertebral body of the more cranial vertebra to the cranial phy, with the procedure having a mortality rate of 2%, which
dorsal lamina of the vertebral arch of the more caudal verte- is similar to any type of surgery under general anesthesia.266
bra, whichever was smaller. For vertebrae C2–C3 to C5–C6, Neurologic complications including worsening of neurologic
the minimum diameter is invariably found to be the former grade and seizures are the most common adverse reaction
measurement (see Fig. 11.37). seen.266 Myelography has traditionally been considered the
Reference figures for intravertebral and intervertebral SR in gold standard antemortem diagnostic test; however, sagittal
a limited number of horses are shown in Tables 11.9 and 11.10. diameter ratio analysis may be more sensitive and specific
A specific site can be considered very likely to be compressed than myelography, at least if the 50% or 2-mm reduction of
if it is more than 2 standard deviations smaller than the refer- the dorsal contrast medium myelographic rules are used.267,268
ence values. As a general rule of thumb, horses with signs of Myelography can result in acceptable sensitivity and specific-
cervical spinal cord disease that have SR values at any interver- ity for detecting sites of compression by using a 20% reduction
tebral or intravertebral site that are less than 50% of reference of the total dural diameter on a neutral myelographic view for
values have a greatly increased risk of having cervical vertebral the midcervical sites, and a 20% reduction of the same mea-
canal stenosis. One must consider, however, that there is poor surement at C6–C7 with the neck in either neutral or flexed
agreement among observers when performing these measure- position.267 In some horses with CVCM, particularly those
ments, which is likely influenced by experience. This may limit with caudal cervical arthropathy, spinal cord compression
the accuracy of this method and could result in discrepancies may occasionally occur in a lateral or transverse plane with
of diagnosis.264 no dorsoventral compression. In these cases, more subjective
In older horses with CVCM, spinal cord compression is assessments, such as observing a blanching of the contrast col-
most often the result of coning of affected caudal cervical umn or split dorsal margins, may be the only myelographic
vertebrae. The measurements can be difficult to perform on abnormalities.
caudal cervical vertebrae, particularly if the radiographs in More recently a technique has been described for cervical
large horses are underexposed. In addition, these horses have vertebral canal endoscopy during which a flexible videoen-
enlarged and remodeled intervertebral joints of the caudal doscope with an external diameter of 4.9 mm is introduced
cervical vertebrae. Many horses without neurologic signs into the subarachnoid space dorsal to the spinal cord.269 This
have degrees of cervical vertebral osteoarthritis and consid- technique allows for direct visualization of the structures in
erable arthritic enlargement of articular processes that can the vertebral canal and may allow for recognition of more
occur well lateral and dorsal to the vertebral canal with no subtle abnormalities in the epidural space. In the future this
TABLE 11.9 Summary Data for Sagittal Diameter Ratio by Vertebral Site in Eighteen Horses without Cervical Vertebral Malformation
Intravertebral Intervertebral
Site
C2 C3 C4 C5 C6 C7 C2–C3 C3–C4 C4–C5 C5–C6 C6–C7
Mean 7.2 6.1 5.9 6.1 6.0 6.2 9.1 7.1 7.4 8.0 7.1
Standard deviation 0.79 0.56 0.54 0.54 0.62 0.52 1.17 0.93 1.11 0.95 0.88

TABLE 11.10 Summary Data for Sagittal Diameter Ratio by Vertebral Site in Eight Horses with Cervical Vertebral Malformation
Intravertebral Intervertebral
Site
C2 C3 C4 C5 C6 C7 C2–C3 C3–C4 C4–C5 C5–C6 C6–C7
Mean 6.3 4.8 4.8 4.9 4.8 4.8 7.0 5.5 5.7 5.8 5.9
Standard deviation 1.19 0.33 0.37 0.26 0.44 0.17 1.93 1.28 0.59 1.14 0.68

technique may prove to be reliable for localization of vertebral Y EQUINE NEUROAXONAL DYSTROPHY/
canal stenosis and diagnosis of CVCM.270 EQUINE DEGENERATIVE
Treatment MYELOENCEPHALOPATHY
Stall rest, glucocorticoids, DMSO, and other antiinflamma- Yvette S. Nout-Lomas
tory drugs may provide transient improvement in clinical
signs in horses with CVCM, especially if acute exacerbation Neuroaxonal dystrophies (NADs) are a group of neurodegen-
of disease secondary to trauma is seen. However, continued erative diseases described in human beings and animals that
compression of the spinal cord is inevitable, and clinical signs are characterized by dystrophic alterations of neurons and
will persist. For most horses for which surgical treatment is axons and development of spheroid bodies. In the horse, equine
not an option or with multiple intervertebral site involve- degenerative myeloencephalopathy (EDM) is considered a
ment and severe, chronic clinical signs, the prognosis is poor more severe form of equine neuroaxonal dystrophy (ENAD)
to grave and humane destruction is advised. A recent review where CNS lesions are thought to be on a continuum, with
of 103 horses with presumptive CVCM showed that 33 were EDM lesions being more widely distributed than those seen in
euthanized after diagnosis, and of the remaining horses 30% ENAD.3,275,276 Clinically, ENAD and EDM are indistinguish-
had at least one racing start. Horses were more likely to race if able, and both have the same basic underlying neuropatho-
they had a neurologic grade less than 1 in the thoracic limbs logic lesions.277-279 ENAD/EDM is a noncompressive, diffuse,
and less than 2 in the pelvic limbs.11 In a controlled field study, symmetric, degenerative neurologic disease characterized by
in which growing foals with CVCM were fed a diet restricted symmetric ataxia, weakness, and dysmetria in young horses of
in protein and energy (65%–75% of National Research Coun- many breeds and both genders. Mayhew and colleagues first
cil recommendations), clinical signs and radiographic lesions described the disease in 1976,280 and it has been subsequently
resolved in some foals and significantly improved in others.271 diagnosed in many other breeds of horses. In addition, identi-
A positive effect of dietary modification and changing the rate cal syndromes have been observed in Mongolian wild horses
of growth is likely to be seen only in young horses less than 1 (Equus przewalskii)281 and Grant’s zebras.282 Earlier work sug-
to 2 years of age.11 gested that the pathogenesis of the disease involved a familial
Young patients with mild clinical signs of short dura- vitamin E deficiency,283,284 and a series of recent studies sup-
tion and with only one site of cervical spinal cord compres- ports the theory that ENAD/EDM is inherited as a complex
sion have a good prognosis for return to athletic function trait and affects genetically predisposed horses that undergo a
with surgery. No controlled trials have been performed; period of α-tocopherol deficiency.279,285 ENAD/EDM was one
however, it is estimated that more than 60% of such horses of the most prevalent causes of spinal cord disease in horses in
return to athletic function.272-274 Ventral intervertebral the United States during an approximate 15-year span after it
fusion using a stainless steel fenestrated basket or threaded was first recognized. Although no recent epidemiologic sur-
cylinder can allow expansion of the vertebral canal, atro- veys exist, the prevalence of EDM appears to have declined
phy of articular enlargements, and resolution of some or all since about 1990.3 In Europe the disease has been reported
the clinical signs in selected cases. This procedure has been only sporadically. However, it should be noted that clinical
most successful in horses with acute clinical signs result- signs of ENAD/EDM are similar to those seen in CVCM, and
ing from spinal cord compression at only one intervertebral the diagnosis can only be made after careful histologic evalu-
site between C2 and C7 and in horses with absolute steno- ation of the CNS.
sis and enlarged articular processes of the caudal cervical
vertebrae. Horses with persistent neck pain associated with Clinical Signs
cervical osteoarthritis but no evidence of fractures to the The onset of clinical signs may be abrupt but is usually insidi-
bodies of the vertebrae are also well suited to cervical inter- ous, and the age at which signs are noticed varies from less
vertebral fusion surgery. than 1 month to several years, with most horses manifesting
signs within the first year of life. One older study of 128 horses migration disorder, although this could not be proven to
with EDM showed the age of onset ranged between 1 month have occurred in conjunction with ENAD. Migration disor-
to 20 years, with 16% of the horses showing signs at older than ders are another complex group of diseases resulting from
28 months of age.286 A more recent evaluation of a group of 88 failure of embryologic neuronal cells to migrate properly to
horses with neurologic deficits suspected to be secondary to their final location.
ENAD/EDM showed that 42% of the horses were older than
3 years at the time of examination; however, no specific infor- Pathology
mation on age of onset of clinical signs was provided.279 There Gross necropsy findings in EDM are unremarkable. Classic
is no sex predilection. histologic lesions are evident in the brainstem and spinal
Signs are referable to upper motor neuron and general cord.40,279,287,290 In ENAD, lesions are restricted to certain
proprioceptive deficits and include symmetric ataxia, weak- nuclei in the brainstem and spinal cord gray matter, whereas
ness, and dysmetria, most notably hypometria (spasticity), of in EDM, lesions also occur in white matter tracts of the spinal
all four limbs, often worse in the pelvic limbs.3,287 Signs may cord.3,279,290 Specific brainstem nuclei in which lesions have
begin in the pelvic limbs and progress to the thoracic limbs. been found are the lateral and medial cuneate nuclei, grac-
Postural placing reactions may show conscious propriocep- ile nucleus, nucleus of the solitary tract, trigeminal nucleus,
tive deficits. The gait is characterized by dysmetria and stab- vestibular nuclei, olivary nuclei, and reticular formation.
bing of the ground with the limbs. Horses may walk with Lesions have also been identified in the medial lemniscus
a two-beat lateral gait, referred to as pacing, as also some- of the medulla oblongata and cerebellar vermis. Spinal cord
times seen in horses with any spinal cord disease.3 Often, gray matter lesions have been found in the lateral cervical
hindlimb interference and dragging or scuffing of the toes and thoracic nuclei, and lumbosacral and cervical inter-
are present. When walking backward, the horse may resist mediate gray columns.279,287 Ascending spinal cord white
or rock back on the pelvic limbs and dog sit. When circling, matter tracts involved in horses with EDM are the spino-
affected horses often pivot on the inside hindlimb and cir- cuneocerebellar tract (unconscious proprioception; thoracic
cumduct the outside limb. Affected horses may have trouble limbs), the spinocerebellar tract (unconscious propriocep-
stopping, and it is not unusual for them to fall while running tion; trunk and pelvic limbs), and the dorsal column-medial
in the pasture or being worked. Cranial nerve involvement, lemniscal tract (conscious proprioception).287,290 Lesions
muscle atrophy, or changes in skin sensation or tail tone are in the ventromedial funiculi of the spinal cord contain-
absent in ENAD/EDM280; however, a recent evaluation of ing descending tracts have also been described.287,291 With
88 horses with suspected ENAD/EDM found 60% of those chronicity, the dorsal and ventral spinocerebellar tracts
horses to have an abnormal mentation ranging from quiet to and the medial part of the ventral funiculi of the thoracic
obtunded, and 38% had a decreased or inconsistent to absent segments are more severely affected.40,287 Astrocytosis,
menace without loss of vision.279 In addition, the presence astrogliosis, vacuolization, myelin loss, spheroid formation
of a pigment retinopathy in 4 out of 10 related Warmblood (axonal swelling), and lipofuscin-like pigment accumulation
horses that had clinical signs of ENAD/EDM was recently are present in these areas.287,290 Recently, histopathologic
demonstrated.288 Because previous work from this same changes characteristic of EMND were identified in horses
group had not found evidence of ocular disease in a group with clinical signs of ENAD/EDM.292 EMND is also attribut-
of Quarter Horses with ENAD/EDM it is suspected that the able to α-tocopherol deficiency but is characterized by clini-
development of ocular lesions is associated with genetic dif- cal signs of lower motor neuron disease and seen in older
ferences and/or severity of α-tocopherol deficiency. It should horses. Although clinical signs of EMND and ENAD/EDM
be noted that none of the horses in which ocular lesions are very different, this report shows that there is overlap pos-
were identified had clinical signs of visual deficits; however, sible in the histopathologic lesions identified in horses with
given these findings it is highly recommended to perform these diseases.
a careful ophthalmologic examination on cases in which
ENAD/EDM is suspected. Lower motor neuron signs such Pathophysiology
as hyporeflexia over the neck and trunk with diminished to For years it has been proposed that there is a familial tendency
absent cervical, cervicofacial, cutaneous trunci, and laryn- to develop EDM and that there was an association between
geal adductor reflexes may be found, especially in severe disease development and vitamin E deficiency. Breeds in
and long-standing cases.283 The disease is considered not or which a familial tendency to develop EDM has been sug-
very slowly progressive, and most horses stabilize at around gested include the Arabian,287 Thoroughbred,283 and wild
3 years of age. Horses do not recover from this neurodegen- horses,281 and breeds in which this has been demonstrated
erative condition. include Morgans,293 Appaloosas,278 Standardbreds and Paso
ENAD/EDM should also be included in the differential Finos,283 Lusitanos,276 American Quarter Horses,285 and
diagnosis of young horses presenting with different neu- Warmbloods.288 Pedigree analyses support a genetic cause
rologic deficits, because it is possible for ENAD/EDM to for increased susceptibility to α-tocopherol deficiency with
occur in conjunction with other developmental brain dis- subsequent development of NAD/EDM; however, the mode
eases. For example, a 2009 report described a foal with con- of inheritance of NAD/EDM has been difficult to ascertain.
firmed ENAD that had clinical signs of cerebellar disease, From previous studies the mode of inheritance was most
most noticeably a head tilt and head tremor and pendular likely considered to be an autosomal dominant one with vari-
nystagmus, in addition to signs consistent with ENAD.289 able expression or a polygenic one, based on a breeding trial in
A detailed postmortem examination showed a prominent Morgan horses and pedigree analysis in Lusitano horses.276,286
external granular layer of the cerebellum, in addition to Most recent work indeed suggests the disease is being inher-
the histopathologic features of ENAD. The authors sug- ited as a complex trait,285 whereby effects of more than one
gested that the cerebellar lesion might have been a type of gene along with environmental influences determine the
phenotype. Currently, it is hypothesized that the genetic vari- O2 Oxygen

ant of ENAD/EDM is a susceptibility locus, and the amount of e –
α-tocopherol received by a foal during the first year of life may
play a role in determining the final phenotype.285 O2• Superoxide radical
In humans a condition referred to as ataxia with vitamin + –
2H e
E deficiency occurs that is caused by various mutations in the
α-tocopherol transfer protein gene (TTPA). Clinical signs and H2O2 Hydrogen peroxide
neuropathologic findings in people are similar to those seen in Fe(II)
horses with ENAD/EDM. In a group of 88 American Quarter –
e
Horses pedigree analysis demonstrated inheritance as a poly-
genic trait with high heritability; however, this study excluded Fe(III)
Hydroxyl radical
TTPA as a candidate gene for ENAD in this group of horses.285 OH• + OH–
+ hydroxyl ion
Degenerative myelopathy in other species, which bears 2H
+
e–
clinical and histopathologic similarities to EDM, has been
linked to vitamin E and copper deficiencies, hereditary fac- A 2 H2O Water
tors, and toxic insults.294 An older study involving 56 affected
and 179 control horses identified three risk factors associated
with the development of EDM: (1) use of insecticides, (2) O2
exposure to wood preservatives, and (3) spending frequent
time on a dirt lot.295 This same study showed that spending Fe, Cu, Zn
time on green pastures was found to be a protective factor, and O2 • superoxide
H2O2
a foal was 25 times more likely to develop EDM if its dam had dismutase
any other foals diagnosed with EDM. More recently an epi- superoxide
demiologic study involving 3 index case horses with ENAD dismutase
Se
and 145 randomly selected horses from a single farm showed glutathione
2 H2O
that most affected and unaffected horses had low serum vita- peroxidase
H2O2
min E concentrations, hepatic vitamin E concentrations were H 2 O2
low, and the pastures on the farm were deficient in vitamin catalase 2 H2O + O2
E and selenium.279 Further, serum concentrations of other
trace minerals were within normal limits, and environmental OH• + OH
–
samples were negative for insecticides and ionophores. Heavy
metal concentrations in samples were within normal limits. scavengers
Studies over the years support the hypothesis that exposure of
genetically predisposed young foals to environmental oxidants B 2 H2O
and lack of antioxidants, including vitamin E, are important
factors in the pathophysiology of ENAD/EDM. FIG. 11.38 A, Physiologic metabolism of molecular oxygen to water.
Oxidative stress is caused by the imbalance between pro- B, The mechanisms of action of four antioxidant systems. Superoxide dis-
duction of prooxidants and the antioxidant defenses. ROS mutase may act as a prooxidant by increasing the formation of hydrogen
(e.g., superoxide anion, hydrogen peroxide, hydroxyl radical) peroxide and as an antioxidant by decreasing the superoxide radical con-
are formed during the reduction of oxygen to water in normal centration. Cofactors for superoxide dismutase are iron, zinc, and copper.
cellular metabolism (Fig. 11.38A). Aerobic cells have antioxi- The cofactor for glutathione peroxidase is selenium.
dant defense mechanisms that protect them from oxidative
stress (Fig. 11.38B). The brain’s high consumption of oxygen,
high metabolic activity, and high concentration of polyunsatu- The main endogenous antioxidants are superoxide dis-
rated fatty acids, which can easily be oxidized to ROS, make mutase, catalase, glutathione peroxidase (that contains sele-
the CNS extremely vulnerable to oxidative attack by ROS. nium), α-tocopherol (vitamin E), and ascorbic acid (vitamin C)
Another source of ROS is through the metabolism of excit- (see Fig. 11.38B and Fig. 11.39B). Another protective mecha-
atory amino acids and neurotransmitters such as glutamate nism is the existence of iron-binding proteins that keep iron in
and aspartate. When present in excess, excitatory amino acids a less reactive form and prevent iron from catalyzing free radi-
can trigger a series of events including an increase in intracel- cal reactions. Vitamin E reacts directly with OH− and prevents
lular calcium, which can lead to the production of free radicals oxidant injury to polyunsaturated fatty acids and thiol-rich
and subsequent neuronal damage and death. Other sources of proteins in cellular membranes (see Fig. 11.39B). Insufficient
free radicals that arise from brain metabolism include cyto- vitamin E may result in oxidative damage and lipid peroxida-
chrome P-450 electron transport, monoamine oxidase activity, tion of cell membranes and may therefore cause the accumula-
and endogenous guanidine compounds. Lipid peroxidation of tion of lipopigment. Accumulation of lipofuscin-like pigment
cellular membranes and the direct oxidation of amino acids is a common feature of experimentally induced vitamin E
leading to inactivation of enzymes, receptors, and structural deficiency in rats and monkeys297 and in human and equine
proteins are the main consequences of oxidative injury (Fig. motor neuron disease.298 Lipofuscin accumulation in the CNS
11.39A). Increased evidence exists for a role of redox signal- of ENAD/EDM-affected horses has been reported,283,290,299
ing by oxygen radicals that targets mitochondrial cytochrome and the amount exceeds the amount found in age-matched
c release, DNA repair enzymes, and transcriptional factor controls.299 Further evidence for oxidative injury within the
nuclear factor–κβ. Neuronal damage occurs once these physi- spinal cord of horses with EDM has been provided by positive
ologic systems are disrupted.296 immunoreactivity for peroxynitrite (3-NT) and unsaturated
Initiation proteins and abnormal accumulation of neurofilaments in dys-

PUFA Lipid radical Peroxyl radical trophic axons has been described in two Arabian horses with
EDM.301 Presynaptic proteins such as synaptophysin, synapto-
R R R
• OH H2O O2 somal-associated protein 25 kDa (SNAP-25), syntaxin-1, and
CH2 HC• HCOO • α-synuclein participate in trafficking, docking, and fusion of
the synaptic vesicle to the plasma membrane, facilitating synap-
CH3 CH3 CH3 tic transmission and exocytosis of neurotransmitter. Findings
in this study are similar to what has been reported in dogs with
NAD and suggest a loss of synapse and accumulation of synap-
tic proteins in dystrophic neurons.
Propagation R
Peroxyl radical
Diagnosis
Lipid HCOOH
peroxide Definitive diagnosis of ENAD/EDM can be made only with
CH3 histopathologic examination of the spinal cord and brainstem.
Lipid
radical Antemortem diagnosis is based on clinical signs and ruling
A PUFA
out other neurologic diseases (especially CVM and EPM). In
ENAD/EDM, CSF analysis and cervical spinal radiographs are
usually within normal limits, although increased CSF creatine
Vitamin C
Vitamin C • kinase (CK) levels have been found in horses affected with
–
EDM.40
+e Measuring serum/plasma α-tocopherol concentrations
Vitamin E Vitamin E • may be unreliable when the animal is examined after the criti-
cal deficient period. Moreover, it should be noted that a single
Peroxyl radical Lipid peroxide
serum α-tocopherol sample may not adequately reflect the
B PUFA Lipid radical true vitamin E status of the horse, because up to 12% varia-
tion in concentrations can occur normally.302 However, a low
serum/plasma α-tocopherol concentration (less than 1.5 mg/
FIG. 11.39 A, Mechanism of peroxidation of polyunsaturated fatty
mL) in a horse with clinical signs is supportive of the diag-
acids in cell membranes. B, Antioxidant mechanisms of α-tocopherol
nosis. One can also measure the α-tocopherol concentration
(vitamin E) and ascorbic acid (vitamin C). Polyunsaturated fatty acids are
in the CSF, which is significantly correlated to the serum303
spared from oxidation because vitamin E is oxidized to a free radical in-
and brain tissue concentration.304 Reference ranges for serum/
stead. This prevents the propagation of lipid peroxidation in cell mem-
plasma and CSF α-tocopherol concentrations are available.305
branes and is referred to as the chain-breaking action of vitamin E. Vitamin
C is a reducing agent that donates electrons to free radicals. Treatment and Prevention
Oral supplementation with vitamin E to genetically suscep-
aldehyde (4-NHE).291 These substrates markedly increase in tible foals in the first year of life may reduce the incidence and
neurons in conditions involving oxidative stress and mediate severity of disease279,283,295,299; however, one of these studies
neuronal apoptosis. showed that new cases did still occur despite vitamin E sup-
The association between vitamin E deficiency and ENAD/ plementation.279 Typically animals are supplemented at 1000–
EDM is based on epidemiologic studies, the similarities 2000 IU/450 kg/day of vitamin E. There are mixed reports on
between ENAD/EDM and vitamin E deficiency in human efficacy of supplementation with vitamin E in affected horses,
beings and other animals, the reduced incidence of ENAD/ where some reports suggest improvement of clinical signs after
EDM seen after prophylactic treatment with vitamin E, and treatment with vitamin E at 6000 IU/day,306 and others report
the response to treatment with vitamin E in affected horses. no effect.279 Additionally, one study reports improvement of
However, vitamin E deficiency has not been a consistent find- clinical signs after gaining access to fresh grass.307 The NRC
ing in horses with ENAD/EDM.300 Two studies have shown a requirements for dietary vitamin E concentrations are 500 to
high incidence of ENAD/EDM on farms in which low serum 1000 IU/kg dry weight for a 500-kg horse. Additional supple-
vitamin E concentrations were found, and in both studies mentation for healthy adult horses appears not necessary.305
affected and unaffected horses were vitamin E deficient.279,283 Heat-treated pellets, stored oats, and sun-baked forages have
Furthermore, vitamin E supplementation decreased the inci- marginal vitamin E concentrations, and horses fed a diet of
dence and severity of disease seen in both studies. Another these or horses kept on dry lots should have frequent access
study documented significantly lower vitamin E concentra- to fresh green forage or vitamin E supplementation to meet
tions and clinical signs compatible with EDM in eight of nine their reported needs. Horses with clinical signs of ENAD/
foals sired by an EDM-affected stallion. Age-matched control EDM may benefit from large doses of vitamin E (6000–10,000
foals raised in the same environment had normal serum vita- IU/day) for an extended period of time; however, more recent
min E concentrations and no signs of EDM. Oral vitamin E work suggests that this does not lead to resolution of clinical
absorption tests were performed on both groups, and no sig- signs.279 The current recommendation is that a natural RRR-
nificant differences were found between the groups.284 Thus α-tocopherol (nonacetate) form of vitamin E is used to supple-
an inability to absorb vitamin E from the gastrointestinal tract ment deficient horses with ENAD/EDM because this form is
does not appear to be a factor in the low serum vitamin E con- the most biologically available, is the most readily absorbed,
centrations in EDM-affected horses. and has the most potent antioxidant activity.305 Vitamin E
In horses with EDM evidence has been found for severe toxicity associated with supplementation in horses has not
axonal transport impairment. Abnormal expression of synaptic been reported, and the risk is considered minimal in horses;
however, adverse effects have been reported with doses greater Numerous seroprevalence studies have been performed,
than 10 times NRC requirements.305 casting light on the distribution of the infection and life cycle
of the organism. Horses in the United States have a variable
Prognosis but generally high seropositive incidence to S. neurona, rang-
Although clinical signs of ENAD/EDM typically appear to ing from 15% to 89%, depending on geographic location.312,313
stabilize by 2 to 3 years of age, affected horses are neurologi- Seroprevalence increases with increasing age, and an associa-
cally abnormal and often unfit for any performance activity. tion with temperature whereby the lowest seroprevalence was
Generally, horses with ENAD/EDM do not progress to a state found in regions with a higher number of days of freezing
of recumbency. Severely affected horses usually have an ear- temperature or during the colder months.312,315,317,318 Seroprev-
lier age of onset and rapid disease progression, whereas mildly alence against N. hughesi is low and has been reported to vary
affected horses usually have a later age of onset and the disease from less than 3% to 10%.312,313 A large seroprevalence study
has a less rapid course. recently demonstrated that some horses are seropositive for
both S. neurona and N. hughesi.312
All horses are susceptible to the development of EPM, but
Y EQUINE PROTOZOAL epidemiologic surveys have suggested that the average age of
affected horses is approximately 4 years.319,320 More than 60%
MYELOENCEPHALITIS of cases were less than 4 years old, and less than 20% were 8
Yvette S. Nout-Lomas years or older.320 Another study found that young horses (1–5
years) and older horses (greater than 13 years) had a higher
Equine protozoal myeloencephalitis is a commonly diagnosed risk of developing EPM.317 The age range of reported cases is
condition of the horse, which J. Rooney originally described in from 2 months321 to 24 years.322 Data from 364 horses with
1964 and termed segmental myelitis. Later descriptions used the histologically confirmed EPM taken from across the United
terminology focal myelitis encephalitis, recognizing that lesions States and Canada revealed that Thoroughbreds, Standard-
within the brain occurred.308 Eventually, an organism that breds, and Quarter Horses were most commonly affected,
resembled toxoplasma was seen in histologic sections, and in although many other breeds were represented; no gender pre-
1976, Dubey first suggested that EPM was caused by a member dilection exists.320
of the genus Sarcocystis.309 A Sarcocystis organism was eventu- Most cases appear to be individual cases, and “outbreaks”
ally cultured from the spinal cord of an affected horse and named of EPM appear to be very rare, although one author has
Sarcocystis neurona because it often develops within neurons.310 described an epizootic of EPM on a single farm.323 A report
Since that time, S. neurona or S. neurona–like organisms have from Ohio, however, did find that previous diagnosis of the
been cultured from several ataxic horses, as well as numerous disease on the farm increased a horse’s risk of subsequently
other animals including the zebra, domestic cat, Canadian lynx, developing EPM (greater than 2.5 times higher).317 This find-
sea otter, straw-necked ibis, mink, raccoon, and skunk. Another ing suggests clustering of cases may occur when all the risk
protozoan parasite (Neospora hughesi) has also been shown to factors for EPM are present. Analysis from data collected
be a cause of EPM in the horse; however, the majority of cases during the USDA/APHIS NAHMS Equine '98 study324 and
are because of infection with S. neurona.311-313 The S. neurona another epidemiologic study317 demonstrated the following
genome has now been sequenced and annotated, potentially risk factors for EPM:
leading to discovery of better diagnostic methods and thera- 1. Environmental and management factors that affect expo-
pies.314 Recently a panel of experts has provided a comprehen- sure to opossums. A higher risk for disease occurs in the
sive review of this disease315 and up-to-date information on fall of the year.
the pathophysiology, diagnosis, and treatment of this clinically 2. Type of housing for horses (decreased risk with pasture
important disease in the form of a consensus statement.313 housing), stocking density (increased risk with increased
numbers of horses), the choice of bedding material (wood
Epidemiology products lower odds than straw or corn stalks), or safe
EPM is one of the most commonly diagnosed neurologic storage of concentrate feeds (lower odds at operations that
diseases of the horse in the Western Hemisphere. Given the stored feeds in rodent-proof containers).
complexity of clinical diagnosis, and the difficulty of finding 3. Horses that were used primarily for racing had a greater
conclusive lesions in the CNS, the true incidence of EPM is dif- risk compared with horses used primarily for pleasure.
ficult to state conclusively. Two older studies reported that 25% Thoroughbreds, Standardbreds, and Warmblood horses
of equine neurologic cases were diagnosed with EPM,40,316 and had markedly greater odds of disease compared with Quar-
a national study conducted by the United States Department of ter Horses. Young horses had a higher risk of developing
Agriculture (USDA/APHIS NAHMS Equine '98 study) in 1998 EPM than older ones, and recent transportation increased
found an average incidence of 14 + 6 cases per 10,000 horses per odds of disease.
year. The overall prevalence was estimated at 0.5% to 1% of the 4. Larger number of resident horses and finding evidence of
horse population. The lowest incidence was in farm and ranch wildlife on premises increased the risk of EPM. Premises
horses (1 + 1 case/10,000 horses), with 6 + 5 cases/10,000 horses near a marsh/creek/river decreased the risk for EPM.
for pleasure horses. A much higher incidence of 51 + 39 and 38 5. Horses were more than twice as likely to have EPM if they
+ 16 cases/10,000 horses was seen for competition and racing resided in Kentucky, Michigan, Missouri, New Jersey, New
horses, respectively. An intermediate incidence of 17 + 12 cases York, Ohio, Pennsylvania, and Tennessee.
was reported for breeding animals. This is similar to the find- EPM is a disease of the Western Hemisphere, with cases
ings of other studies showing racing and showing animals to reported from many states within the United States, as well
have a higher risk than breeding and pleasure horses.317 as Canada, Mexico, Panama, Argentina, and Brazil. Most
horses with a diagnosis of EPM outside this region appear hosts.330 The life cycle of S. neurona has been completed in
to have spent some time in the endemic area. EPM has a laboratory setting.331 The horse has traditionally been con-
been reported in England among horses imported from sidered an aberrant, dead-end host, in that sarcocysts have
the eastern United States and in an 8-month-old Arabian never been reported. One report, however, describes mature
horse in South Africa that had been imported from the sarcocysts that were well characterized as S. neurona and
United States approximately 5 months before the onset of found on the tongue of a horse suffering from EPM.332 This
signs.325 Another report concerned a horse from Califor- suggests that horses can be intermediate hosts but requires
nia that developed clinical signs of EPM after 10 months further confirmation.
in Hong Kong.326 These cases demonstrate the probability Horses are infected with S. neurona by ingesting food or
of persistent, subclinical, latent infections. However, a few water that has been contaminated with feces from an infected
reports exist of neurologic horses with consistent clinical opossum. Some evidence suggests that the organism may be
signs, positive immunoblot test results, and no history of transmitted by methods other than direct contact with opos-
travel in the American continent.327,328 The nature of the sum feces. It has been suggested that birds may mechanically
infection in these horses is unclear and may be because of disseminate sporocysts and that secondary transmission via
cross-reacting antigens. “pass-through” of infective sporocysts in the feces of bud-
Immune suppression because of stress or advanced age gerigars, canaries, mice, and chickens fed opossum feces has
might predispose a horse to development of EPM. Stressful occurred. At least some organisms appeared to retain viability
events such as heavy exercise, transport, injury, surgery, or and infectivity after transit through the digestive tract.333 This
parturition have all been found to increase the risk of EPM.317 is most likely to be a laboratory phenomenon; its importance
Racehorses and show horses had a higher risk of develop- in nature is unknown but likely to be small. Importantly, S.
ing EPM compared with breeding and pleasure horses. Not neurona is not transmitted horizontally among horses, nor
surprisingly, horses with EPM that were treated with an anti- can it be transmitted to horses from nonequine intermediate
coccidial drug were 10 times more likely to improve than hosts. Antibodies against S. neurona in foals before suckling
untreated horses. have been reported,334,335 but current evidence indicates that
transplacental or lactogenic transmission of S. neurona is very
Life Cycle uncommon or absent.313,315
Sarcocystis spp. belongs to the phylum Apicomplexa, which The life cycle of Neospora hughesi in horses is understood
includes several genera of coccidia that use an obligatory poorly. The definitive host of N. caninum has been demon-
predator-prey or scavenger-carrion life cycle.329 Sarcocystis strated to be the dog,336 but whether the dog is the definitive
spp. produce sporulated oocysts by sexual reproduction (gam- host of N. hughesi is not known. Tachyzoites, as well as tis-
etogony) in the gut wall of the appropriate predator or defini- sue cysts, have been found in other horse tissues in two of the
tive host. Infective sporocysts are introduced into the food and horses reported to have EPM caused by Neospora spp.337 Verti-
water supply of the prey animal or intermediate host by fecal cal transmission of N. caninum is very efficient in cattle, and
contamination from the predator. In the S. neurona life cycle, several recent studies indicate that N. hughesi can be transmit-
the definitive host is the opossum, whereas the intermediate ted transplacentally in horses.335,338
hosts are skunks, raccoons, and armadillos, among others.
Once ingested by the intermediate host, sporocysts excyst, Pathogenesis
releasing four sporozoites that penetrate the gut and enter arte- Despite the often-high rate of exposure to the organism, only
rial endothelial cells in various organs. Meronts develop rap- a small percentage of horses develop clinical illness. This sug-
idly and eventually rupture the host cell, releasing merozoites gests that immune clearance of the parasite is very effective
into the bloodstream, which usually is followed by a second but that unknown factors must exist in certain cases to allow
round of merogony in capillary endothelial cells throughout clinical disease to be expressed. Parasite dose is likely to be
the body. Second-generation merozoites are released into the a factor, and in fact this has been experimentally demon-
bloodstream and usually enter skeletal muscle cells, where they strated.339 Other factors that have been considered to have a
develop into specialized meronts known as sarcocysts. Mature role in the induction of EPM include physiologic stress associ-
sarcocysts contain bradyzoites, which are able to complete the ated with shipping, training, showing, and pregnancy that may
life cycle only when ingested by the appropriate predator or make animals more susceptible to EPM.317 Indeed, one reliable
scavenger. model of inducing EPM incorporates long-range shipping as
S. neurona may infect a large number of intermediate a stressor, performed immediately before infection.340 Other
hosts aberrantly, unlike most Sarcocystis spp. Several spe- attempts to induce EPM using the oral infection route that do
cies of animals and birds have been reported to exhibit signs not incorporate stressors such as shipping have led to incon-
similar to those in horses with EPM. This feature made the sistent and only mild illness.341 The assumption is that these
experimental elucidation of the S. neurona life cycle quite stressors lead to some degree of immune suppression, which
challenging. At the present time, domestic cats (Felis domes- is a commonly implicated factor in protozoan parasite infec-
ticus), nine-banded armadillos (Dasypus novemcinctus), tions. However, treatment of horses with immunosuppressive
striped skunks (Mephitis mephitis), raccoons (Procyon lotor), doses of steroids associated with oral infection with S. neurona
and sea otters (Enhydra lutris nereis) are considered to be did not result in significantly worse histopathologic changes
viable intermediate hosts. Feeding studies, as well as epide- in the CNS, although clinical signs were slightly more severe
miologic and seroprevalence data, have determined this. Ini- than in non–steroid-treated horses.341 Additional evidence for
tially the domestic cat was thought to be only a laboratory the role of physiologic stress is found in the observation that
intermediate host; however, several epidemiologic studies stressed horses develop more severe clinical signs than natu-
have now incriminated domestic cats as natural intermediate rally infected (nonstressed) horses.342 It thus appears likely
that stress has a role in the development of EPM; however, the the process between antigen-presenting cells (monocyte/
interaction is complex and not fully understood at this time. dendritic cells) and/or T-cell antigen recognition may be
Further, genetic variation has been observed among the strains impaired in S. neurona–infected horses.350
of S. neurona that have been analyzed,343,344 and although
there is evidence that specific parasite genotypes may be par- Pathology
ticularly virulent in marine mammals,345 such an association Confirmation of disease is through demonstration of pro-
has not been found in isolates from horses clinically affected tozoa in CNS lesions. However, the diagnosis is frequently
by EPM. Recent studies have demonstrated differences among made presumptively when organisms are not detected if the
isolates in the expression of surface receptors, which may have characteristic inflammatory lesions are found.313 Gross lesions
substantial implications for immunodiagnosis.346 consist of multifocal areas of hemorrhage in the acute setting
After infective sporocysts of S. neurona are passed from the and foci of malacia and areas of discoloration ranging from
definitive host and subsequently ingested by a horse, infection pale to dark tan in the subacute to chronic phase.315 Lesions
proceeds. Clinical disease results from the inflammation and are most commonly seen in the spinal cord. The brainstem is
neuronal necrosis associated with infection of the CNS with more often involved than other parts of the brain, and, in rare
live organisms. The mechanisms by which S. neurona enters cases, lesions are found in both spinal cord and brain. Micro-
the CNS are unclear but are thought to involve either infec- scopically, lesions are characterized by focal to diffuse areas
tion of endothelial cells or leukocytes.347-350 One hypothesis of nonsuppurative inflammation and necrosis with perivascu-
is that S. neurona organisms that have been phagocytosed by lar infiltration of mononuclear cells, including lymphocytes,
leukocytes in the periphery are transported across the blood- macrophages, and plasma cells. Giant cells, eosinophils, and
brain barrier in the process of normal immune surveillance. gitter cells also are present in inflammatory infiltrates. Gray or
Once within the CNS, the organisms proliferate. This “Tro- white matter (or both) is affected. Organisms have been found
jan horse” hypothesis of CNS infection is attractive and has in neurons, leukocytes, and vascular endothelium, although
support from experimental work in which clinical disease they tend to develop most often in neurons.
can be induced by administering horses autologous lympho-
cytes, which have been infected with S. neurona.348 There Clinical Signs
does not appear to be “targeting” of the CNS by the organism; The clinical signs associated with S. neurona infection vary from
rather the organism is not cleared from the CNS tissue while acute to chronic with insidious onset or focal or multifocal signs
it is cleared elsewhere. Once organisms enter the CNS, it is of neurologic disease involving the brain, brainstem, or spinal
likely that the immunosuppressive environment of the CNS cord. Clinical signs are variable, which reflects the random distri-
plays a role by diminishing clearance of the organism in this bution of the lesions that may occur within the CNS. Signs of gray
immune-privileged tissue. The parasite itself may also induce matter involvement include focal muscle atrophy and severe
some immunosuppression. muscle weakness, whereas damage to white matter frequently
Resistance to Sarcocystis neurona is presumed to be the results in ataxia and weakness in limbs caudal to the lesion.
result of the combined effects of humoral and cellular immu- Usually the physical examination is within normal lim-
nity. After infection, a relatively rapid production of antibod- its, and the horse appears bright and alert, although one
ies occurs. In horses challenged with live S. neurona organisms may observe focal muscle atrophy. Neurologic examination
orally, all horses seroconverted within 32 days,341 whereas in typically reveals asymmetric ataxia, weakness, and spasticity
another study, horses challenged with a larger number of involving all four limbs. The most common signs of brain/
organisms seroconverted by day 13 after infection (if stressed brainstem involvement are obtundation, head tilt, facial nerve
by transport) and by day 30 if unstressed.340 It has been dem- paralysis, and difficulty swallowing. Abnormal airway func-
onstrated with various apicomplexan parasites that antibody is tion, unusual lameness, and seizures are also sometimes seen,
at least partially protective. and visual deficits and behavioral abnormalities have also
Although the effects of circulating antibody are likely to been reported. A typical history is a slowly progressive ataxia,
be very important, cell-mediated immunity is necessary for which may initially have been identified as a musculoskeletal
the elimination of intracellular forms of most organisms. disorder, since early signs may include stumbling and frequent
Mouse studies have confirmed the importance of CD8+ T interference between limbs. Commonly horses exhibit a grad-
cells in protection against S. neurona encephalopathy in that ual progression in severity and range of clinical signs. Some-
species; it is presumed to be similar in horses. Endothelitis times clinical signs stabilize and then relapse days or weeks
and meningoencephalitis developed in CD8 knockout mice later, and sometimes a gradual onset of clinical signs suddenly
after challenge with S. neurona, highlighting the importance worsens, resulting in recumbency. Occasional acute and rap-
of this cell subset in protection against S. neurona,351 at least idly progressive disease is seen; empirically this presentation
in the mouse. The CD8+ T cell is one important source of seems more commonly associated with brainstem disease,
interferon-gamma (IFN-γ), which is critical for protection although this has not been formally evaluated.
against S. neurona–induced neurologic disease in mice.315,352 The presence of ataxia, asymmetry, and atrophy (the “three
Infection of IFN-γ knockout mice leads to fulminant neuro- A’s of EPM”) suggests multifocal or diffuse disease, which is
logic disease. These findings support the critical importance characteristic of, although not pathognomonic for, EPM. Less
of IFN-γ in protection against S. neurona. Recent research commonly observed are diseases of the cerebrum, cerebellum, or
demonstrated that S. neurona–infected horses have altered brainstem resulting in a variety of cranial nerve deficits including
immune cell subset expression and immune cell function dysphagia, head tilt, tongue or master paralysis, or masseter atro-
that changes during disease progression. S. neurona infec- phy. The clinician needs to recognize that all of the clinical signs
tion alters the ability of antigen-presenting cells to stimulate listed previously may be caused by conditions other than EPM,
CD4+ and CD8+ proliferation, and the data suggest that all of which should be considered in the differential diagnosis.
Diagnosis misdiagnose affected horses. Some horses simply may fail

An important point to remember is that EPM is an easy diag- to respond to the S. neurona–specific proteins identified by
nosis to make but difficult to substantiate and confirm in a live the immunoblot. Horses that initially tested positive have
patient. Experts recommend the following steps to be taken become negative after several weeks of treatment and appar-
before a diagnosis of EPM is rendered.313 ently have recovered. A chronically affected horse may test
1. A thorough neurologic examination must reveal clinical negative and still be infected, or the horse still may exhibit
signs arising from disease of the nervous system that are neurologic signs. Persistent neurologic damage (i.e., scar-
consistent with EPM as described previously. ring) may be present in some cases, resulting in permanent
2. Other conditions that could give rise to the clinical signs neurologic damage in the absence of active infection. One
observed should be ruled out to the degree possible. This should retest acute cases that initially test negative in 2 to
may require radiographs of the cervical spine or head, nu- 3 weeks. However, the incubation period appears to be suf-
clear scintigraphy, CSF evaluation, or testing for EHV, for ficiently long to allow production of detectable amounts of
example. These tests will be determined based on a careful IgG before the onset of clinical signs in most cases.
physical and neurologic examination, as well as a consid- A whole organism IFAT was developed and is currently
eration of the horse’s history and progression, risk factors, available from the University of California Diagnostic Labo-
and related information. ratory.357 Serum titers of greater than 1:100 and CSF titers
3. Immunodiagnostic testing of serum and CSF should be of greater than 1:5 are considered positive and diagnostic of
conducted to confirm intrathecal antibody production active infection. This test is considered to be robust in the
against S. neurona or N. hughesi. presence of blood contamination of the CSF sample. How-
At the present time there are several immunodiagnostic ever, the superiority of the IFAT as a diagnostic for EPM is not
tests in use for EPM diagnosis. These tests are all based on clearly established and it has been demonstrated that the test
detection of antiprotozoal antibodies in serum, CSF, or both. was unable to differentiate between S. neurona and S. fayeri (a
EPM only occurs in a small portion of horses infected with nonpathogenic Sarcocystis) infection.358
S. neurona so serologic testing has minimal diagnostic value Most recently the SnSAG ELISAs, quantitative (end-point
unless test results are negative (low positive predictive value, titer) tests based on S. neurona surface antigens, have been
high negative predictive value). A negative serum test usu- evaluated as a diagnostic tool.354,359,360 These surface antigen
ally indicates that the horse has not been infected; however, a molecules have proven to be good serologic targets in the
recently infected horse may display clinical signs before sero- assays because of their high level of expression in the parasite
conversion, and retesting in 10 to 14 days is recommended. and their immunogenicity in infected horses. The SnSAG2
Detection of antibodies in the CSF alone is not a definitive ELISA and the SnSAG4/3 ELISA accurately detect antibodies
indicator of EPM because there is passive transfer of antibody against S. neurona in equine serum and CSF samples,361,362
across a healthy blood-brain barrier and blood contamination and although none of the tests described here is considered
of CSF samples can cause false-positive results.353,354 Intrathe- a gold standard,313 most recent studies suggest the SAG2,
cal antibody production, indicative of active parasite infection 4/3 ELISA serum:CSF titer ratio, should be utilized for ante-
in the CNS, can be determined by tests of proportionality that mortem testing for EPM.359,360 A study that used 59 sets of
assess whether the amount of pathogen-specific antibody in samples from 57 horses compared the SnSAG ELISAs to the
the CSF is greater than should be present from normal passive IFAT and showed that using serum alone was least accurate,
transfer across the blood-brain barrier. The Goldman-Witmer and that the overall accuracy was highest for the SnSAG2,
coefficient (C-value) and the antigen-specific antibody index 4/3 ELISA with a titer ratio set at 0.97. The sensitivity was
(AI) are such tests.313,354 0.88 and the specificity was 1. The IFAT CSF and titer ratio
The immunodiagnostics that have been developed over results also showed high accuracy at 0.88 but lower sensitiv-
the years include a Western blot, a direct agglutination test, ity at 0.65.359 Another study confirmed the value of detect-
an indirect fluorescent antibody test (IFAT), and enzyme- ing intrathecal antibody production, and the authors showed
linked immunosorbent assays (ELISAs) based on single or excellent diagnostic sensitivity and specificity obtained from
multiple S. neurona surface antigens (SnSAGs). The first test the SnSAG2, 4/3 serum:CSF titer ratio with sensitivity and
developed to aid in the diagnosis of EPM was immunoblot specificity of 93.2 and 81.1%, respectively, using a ratio cutoff
analysis (Western blot) of serum and CSF to provide ante- of ≤100. If a more rigorous cutoff of ≤50 was used sensitiv-
mortem information regarding exposure to S. neurona.355 The ity and specificity were 86.4% and 95.9%, respectively.313 Two
test uses cultured merozoites to detect antibodies directed studies have also shown that modest blood contamination of
against proteins considered unique to S. neurona. Antibodies the CSF, up to 10,000 RBCs/L, will have minimal effect on
produced to proteins shared with S. fayeri or other organ- SnSAG2 test results.353,354
isms found in North America can be differentiated with this There is an NhSAG1 ELISA and an IFAT available for
test. False-positive results are obtained through hemorrhage immunodiagnostic testing for Neospora hughesi. Neither
occurring in the brain or through blood contamination of one of these tests has been fully validated for EPM diagno-
CSF samples. In an effort to differentiate false-positive CSF sis because of inadequate number of samples from EPM cases
antibody tests, a number of techniques have been described, caused by this parasite.313
including determination of the albumin quotient (AQ) and As previously noted, most horses with EPM do not show
the IgG index; however, the sensitivity of these tests appeared constitutional signs of illness, such as fever, depression, or
to be too low, and their use is no longer recommended as a anorexia. Changes in the CBC are not recognized, and changes
diagnostic aid for EPM.356 False-negative results have been in serum biochemistry analysis are not noted, unless the
rare but may occur. The possible causes of false-negative severity of the neurologic signs is such that the horse falls or is
responses are important to consider so that one does not recumbent, or it is dysphagic and cannot drink or eat. In these
horses, secondary changes in the serum biochemistry panel grade) is 60% to 70%.313,363 The duration of treatment varied
may be seen. between 90 to 270 days, and complications of this drug regi-
A key part of the diagnosis of EPM is ruling out other con- men were reported as anemia (22%), leukopenia (19%), and
ditions that may be present; evaluation of CSF is necessary for neutropenia (5%).363 These signs are usually self-limiting and
this process. Conditions such as intrathecal hemorrhage, neo- resolve with cessation of treatment. Folic acid supplementa-
plasia, meningitis, neuroborreliosis, and verminous encepha- tion has been advised by some authors to limit the degree
litis can be ruled out when evaluating EPM suspects using CSF of anemia; however, no support for this practice exists, and
analysis. CSF analysis should be considered a key part of the research has demonstrated increased toxicity when folic acid
full diagnostic evaluation of horses with CNS disease. Most supplementation is provided. Hence its use is discouraged.
horses with EPM have normal CSF cytology. Early work iden- Use of sulfadiazine in breeding animals is controversial,
tified the occasional increase in RBC count; however, in more although one study has shown no effect on pregnancy rates
recent times this finding has been considered to be spurious or early embryonic death.
and a result of unrecognized blood contamination from the The first FDA-approved drug for the treatment of EPM was
collection. The severe and fulminant case may have a mildly ponazuril (Marquis, Bayer Animal Health) to be administered
increased total protein or white blood cell count, but these as an oral paste. Ponazuril is a member of the benzeneacetoni-
situations are rare. trile compounds, which have demonstrated broad-spectrum
anticoccidial activity in many avian and mammalian spe-
Differential Diagnosis cies. These drugs are related to the herbicide atrazine and are
Given the variety of clinical abnormalities that may be thought to target the parasite’s apicoplast organelle. Ponazuril
expressed in horses with EPM, the differential diagnosis is well absorbed orally and within 3 days achieves a therapeu-
includes virtually all diseases of the equine CNS. However, tic steady-state concentration in the CSF of horses treated with
the results of a careful history, physical examination, and 5-mg/kg body weight.364 A field efficacy study of 101 horses
neuroanatomic localization help to limit the number of rule with well-characterized EPM and treated with ponazuril dem-
outs and guide further diagnostic efforts. The most com- onstrated successful treatment in 60% of treated animals, suc-
mon and likely rule out is probably cervical vertebral com- cess defined as improvement by at least one neurologic grade.
pressive myelopathy (CVCM). In contrast to EPM, CVCM A 90-day relapse rate of 8% after the termination of treatment
usually results in symmetric gait deficits, which are worse was found.365 Animals typically responded within 10 days and
in the pelvic limbs and are characterized by spasticity and often continued to improve even after treatment stopped at
hypermetria, with good retention of strength and no mus- 28 days.
cle wasting. Diclazuril is chemically similar to ponazuril and is also a
Infectious diseases such as WNV encephalitis, equine member of the benzeneacetonitrile compounds. Diclazuril
encephalitis (eastern equine encephalitis [EEE] and west- is FDA approved as Protazil, antiprotozoal oral pellets to be
ern equine encephalitis [WEE]), and equine herpesvirus–1 administered as a top dressing. In one study, treatment of
(EHV-1) may all cause neurologic disease that could resem- EPM-affected horses with diclazuril resulted in improve-
ble EPM. Horses affected with these conditions are typically ment in 58% of the treated animals, when given for 28 days.363
systemically ill, demonstrating fevers and alterations in the Because ponazuril and diclazuril are highly selective against
leukogram. The neurologic deficits of EHV-1 are fairly char- apicomplexan parasites, little to no toxicity is to be expected
acteristic in that dysuria is a common component that is not at therapeutic doses.
often seen in horses with EPM. CSF cytology is abnormal in Regardless of the drug used, the duration of treatment
most such cases (e.g., WNV, EEE, EHV-1), in contrast to EPM, necessary and when to stop treatment are considerations in
and a variety of specific diagnostic tests exist for each of these all EPM cases. Duration of treatment depends on response
conditions, such as IgM capture ELISA for WNV and PCR to antiprotozoal administration, and although the FDA-
testing for EHV-1. approved products are labeled for a treatment course of
Polyneuritis equi and ENAD/EDM may also be confused 28 days, the majority of horses with EPM are treated for a
with EPM and can have signs of multifocal disease, ataxia, and longer period of time, generally 6 to 8 weeks or longer if
muscle atrophy. Less common conditions, such as verminous clinical improvement is still apparent.313 Attempting to treat
encephalitis, bacterial meningitis, or CNS abscessation, can be until the horse is negative on immunodiagnostic testing is
seen, but alterations in the leukogram and the CSF are usually currently not recommended.313 Other treatments that have
present, distinguishing these cases from EPM. been investigated or used in the past have been reviewed
elsewhere.315,366
Treatment Administration of nonsteroidal antiinflammatory drugs,
The cornerstone of treatment for horses with EPM is antipro- corticosteroids, and dimethyl sulfoxide is justified in certain
tozoal medication. At the present time the Food and Drug conditions—for example, to prevent worsening of neurologic
Administration (FDA) has approved a number of compounds signs during the early antiprotozoal treatment or in horses that
for the treatment of EPM. The first compounds used for the are in danger of falling down or exhibit signs of brain disease.
treatment of EPM were the sulfonamide drugs combined Similarly, vitamin E is sometimes used; however, some infor-
with pyrimethamine to achieve a synergistic effect. Clini- mation suggests that this may not be efficacious if the horse is
cal efficacy studies have been performed using sulfadiazine not vitamin E deficient.305 Furthermore, some people include
(20 mg/kg) and pyrimethamine (1 mg/kg) orally once per immunomodulators in the treatment of this disease based on
day, marketed and FDA approved as Re-Balance (PRN Phar- the thought that horses with EPM may be immune compro-
macal). Using this dose in well-characterized cases of EPM, mised; however, there are no studies to evaluate efficacy of this
the overall success rate (e.g., improvement by one clinical practice.313
Relapses are a concern and are probably dependent on a Y EQUINE HERPESVIRUS–1

number of factors, including the exact drug and dose used and MYELOENCEPHALOPATHY
the duration of treatment. Extended dosing may reduce the
occurrence of relapse.363 The relapse rate for horses treated for EHV-1 is an economically important pathogen of horses and
28 days with ponazuril was 8%, when examined 90 days after exerts its major effect by inducing abortion storms or sporadic
cessation of therapy.365 Relapse rates for the other drugs are abortions in pregnant mares, early neonatal death in foals,
not reported. Relapse implies that the horse responded well and respiratory disease in young horses.374-381 Myeloencepha-
to the initial drug treatment; hence horses that relapse can be lopathy is an uncommon manifestation of EHV-1 infection
treated with the same drug that was initially used but for a but can cause devastating losses during outbreaks on indi-
longer period. vidual farms, racetracks, veterinary hospitals, or boarding
No studies have been conducted to determine the effec- stables.382-384 Although EHV-4 rarely causes clinical manifes-
tiveness of the currently approved antiprotozoal medications tations of disease in organs other than the respiratory tract,
against N. hughesi. Ponazuril has demonstrated in vitro effec- isolated cases of myeloencephalopathy and sporadic abortions
tiveness against N. caninum.367,368 Ponazuril (5 mg/kg body have been reported in EHV-4 infections.374-376,385,386 Clinical
weight, once per day for 28 days) was used in three horses with signs of neurologic disease reflect a diffuse multifocal myelo-
N. hughesi EPM. All three horses showed clinical improve- encephalopathy after vasculitis, hemorrhage, thrombosis, and
ment, and one showed complete resolution.369 ischemic neuronal injury. Sudden onset and early stabilization
The prognosis for horses diagnosed with EPM appears of signs including ataxia, paresis, and urinary incontinence;
to be similar regardless of the treatment used, because most involvement of multiple horses on the premises; and a recent
reports suggest an approximate improvement rate of 60% to history of fever, abortion, or viral respiratory disease in the
75% with the standard therapy. affected horse or herdmates are typical features, although
considerable variation exists between outbreaks concern-
Prevention ing epidemiologic and clinical findings.387 Prevention is dif-
The widespread distribution of the parasite and the variety of ficult because many horses are latently infected with EHV-1,
intermediate hosts make control of EPM complicated. A vac- allowing the virus to circulate silently in horse populations,
cine was available, but it has been removed from the market and current vaccines do not confer protection against neu-
because of failure to demonstrate efficacy. Decreasing stress rologic manifestations of infection.381,388 The distribution of
and preventing contamination of feed and water with opos- lesions that can result after infection with neurotropic EHV-1
sum feces is essential to prevent EPM in the horse. Opossums results in the need to include many conditions on the differ-
can produce millions of sporocysts that can be excreted in ential diagnosis list, including EPM, cervical vertebral insta-
feces for months. Sporocysts are resistant to environmental bility, cervical stenotic myelopathy, vertebral or CNS trauma,
influences, and most commonly used disinfectants do not kill polyneuritis equi, fibrocartilaginous emboli, aberrant parasite
S. neurona sporocysts.315 Practical approaches including not migration, degenerative myelopathy, togaviral encephalitis,
feeding off the ground, providing separate sources of fresh rabies, botulism, toxins, and other disorders.
water for horses and preventing wildlife access to horse pas-
tures, paddocks, and stalls may also help reduce the incidence Virologic Findings
of protozoal infections in horses.313 Of the five distinct herpesviruses that are known to infect
Monitoring high-risk age groups such as young and old horses, three are typical α-herpesviruses with a double-
horses closely for evidence of neurologic disease may help stranded DNA genome and are designated EHV-1 (equine
detect EPM early. That EPM may be the cause of the clinical abortion virus, formerly known as EHV-1, subtype 1), EHV-4
signs when horses are presented for treatment of neurologic (equine rhinopneumonitis virus, formerly known as EHV-1,
disease in the warmer months should raise the index of sus- subtype 2), and EHV-3 (equine coital exanthema virus), and
picion. Because many major horse competitions take place two are γ-herpesviruses, designated EHV-2 (formerly called
in the fall of the year, monitoring of horses before transport equine cytomegalovirus) and EHV-5 (which has recently been
and competition may be helpful. Close monitoring of brood- associated with interstitial pulmonary disease).375,376,389-391 In
mares close to foaling and horses that develop a major illness addition, three asinine α-herpesviruses (AHV1, AHV2, and
or injury is important, because it may help early diagnosis of AHV3) have been isolated from donkeys. Of these, AHV3 has
EPM cases. been shown by many criteria to be related closely to EHV-1.
Intermittent use of coccidiostatic and coccidiocidal drugs Indeed, EHV-1 and AHV3 are related more closely to each
is another approach used to prevent EPM. Two studies that other than either is to EHV-4.375,391-393 Phylogenetic analy-
evaluated prophylactic use of ponazuril showed that daily sis and epidemiologic evidence suggest that EHV-1 recently
or intermittent treatment minimized but did not eliminate has been derived from AHV3 and that donkeys may remain
infection in horses experimentally infected with S. neu- an alternate host for EHV-1, serving as a reservoir to infect
rona.370,371 Recently it was shown that the daily administra- horses.389,391
tion of a low-dose diclazuril pellet top dressing to healthy EHV-1 and EHV-4 are distinguishable from EHV-2, EHV-
foals from a farm with a high exposure rate to S. neurona sig- 3, and EHV-5 by biologic properties and virus neutralization
nificantly reduced the monthly seroprevalence to S. neurona tests (and distinguishable from each other by restriction endo-
compared with untreated foals.372,373 This preventive strategy nuclease fingerprinting of DNA, DNA sequences, and several
has the potential to be used in high-risk horses in an attempt immunologic tests based on monoclonal antibodies to each
to reduce the incidence of EPM, although future longitudi- virus).374-376,389,390,394 EHV-1 and EHV-4 produce eosinophilic
nal studies will be required before establishing a standard intranuclear inclusion bodies in infected cells in vivo and
protocol.313 in vitro. Several strains have been identified within EHV-4 and
EHV-1, although the epidemiologic, immunologic, and patho- in Denmark, The Netherlands, Germany, Sweden, Austria,
genic significance of this finding is not known. The 1-p and 1-b Britain, Ireland, Australia, India, the United States, and Can-
subtypes of EHV-1 likely are capable of inducing neurologic ada.382,383,387,398,412,413 In view of the ubiquitous occurrence of
disease. Apart from differences in endotheliotropism, genetic EHV-1 infection in horse populations, outbreaks of EHV-1
and antigenic fingerprinting and experiments in baby mice myeloencephalopathy are rare. In many instances, cases of
have not yielded clear markers distinguishing EHV-1 strains neurologic EHV-1 infection occur in association with out-
that induce neurologic disease or abortion (or both).389,395-399 breaks of abortion or respiratory disease, although some out-
However, a recent analysis of EHV-1 isolates from neurologic breaks occur in the absence of other manifestations of EHV-1
and nonneurologic disease outbreaks revealed a point muta- infection and without the introduction of new horses into the
tion within the DNA polymerase gene that was strongly asso- group.394,407,414,415
ciated with neuropathogenic disease.400,401 A hamster model The myeloencephalopathic form of EHV-1 infection may
has been described showing some potential for discrimination occur as sporadic individual cases or, more often, as outbreaks
between abortigenic and neuropathogenic EHV-1 strains.402 involving multiple individuals over a period of several weeks
on one or more premises within a limited geographic region.
Epidemiology and Immunity Secondary or tertiary waves of clinical disease may occur as
EHV-1 and EHV-4 are enzootic in most horse populations, previously unexposed horses become infected from a com-
and the majority of horses show serologic evidence of expo- mon source over a short period.383,394,416,417 There has been an
sure to these viruses. Most horses become infected via the increased reporting of occurrences of EHV-1 myeloencepha-
respiratory tract with EHV-1 or EHV-4 (or both) during the lopathy418 in congregations of horses around the United States.
first year of life. After an incubation period of 2 to 10 days, Most of these outbreaks have been associated with a mutant
clinical signs of respiratory disease of variable severity develop strain of herpesvirus, which appears to replicate rapidly, lead-
and resolve within 1 to 2 weeks in uncomplicated cases.374-376 ing to a very high level of viremia and an apparent increased
Resolution of clinical signs is coincident with development incidence of neurologic manifestations of this disease.400,401,419
of virus-specific neutralizing antibody directed primarily Morbidity rates ranging from less than 1% to almost 90% of
against surface viral glycoproteins. The development of cell- exposed individuals and mortality rates ranging from 0.5%
mediated responses is probably critical for recovery.403 Resis- to 40% of in-contact horses have been reported. Neurologic
tance to reinfection with homologous virus is demonstrable EHV-1 infection can occur at any time of year, but the highest
after recovery but generally persists for only 3 to 4 months. incidence is in the late winter, spring, and early summer, per-
Subsequent infections typically induce milder clinical signs or haps reflecting the seasonal occurrence of abortigenic EHV-1
subclinical infection, although virus shedding from the naso- infections during the same months.219
pharynx occurs.374,375 The immune response frequently is not The neurologic form of EHV-1 infection has been observed
successful in clearing herpesviral infection, and the majority of in pregnant mares, barren mares, geldings, stallions, and foals,
clinically recovered horses remain latently (asymptomatically) although foals frequently do not show neurologic manifesta-
infected with EHV-1 or EHV-4 (or both) for life.374,375,404,405 tions of infection during outbreaks that involve severe neuro-
EHV-1 has been shown to evade the host immune system in logic disease in adult horses.382,416 The disease also appears to
part by downregulating major histocompatibility complex less commonly affect pony breeds. Pregnant mares and mares
class I expression at the cell surface. This process may be a pre- nursing foals appear be at increased risk for developing neu-
requisite to the establishment of latency.406 rologic manifestations of EHV-1 infection, and the stage of
Recrudescence of latent infection is important in the epi- gestation may be important in determining the outcome of
demiology of EHV-1 and EHV-4 and explains why these infection in pregnant mares.377,382,416,420,421 Mares infected dur-
diseases can occur in closed populations without the intro- ing the first 2 trimesters of gestation appear to be more likely
duction of new horses.374,375,405,407 Signs of EHV-1 infection to develop neurologic signs without abortion, whereas mares
may occur in the horse in which stress-associated recrudes- infected during the last trimester are more likely to abort with-
cence of infection has occurred, or the horse may remain out showing neurologic signs.377,394,420,422,423
asymptomatic but shed infectious virus in nasal secretions All breeds of horses are susceptible to the neurologic form
to infect other horses. Natural infection with EHV-1 occurs of EHV-1 infection, and other Equidae also may be affected.
by inhalation or ingestion of aerosolized infective virus or by EHV-1 was the suspected cause of myeloencephalopathy
direct contact with virus shed in the products of abortion or in that developed in a zebra 1 week after an in-contact onager
the nasal and ocular discharges and saliva of horses with overt (Equus hemionus onager) aborted an EHV-1 infected fetus.424
clinical disease, subclinically infected horses, or shedding car- The authors are unaware of reports of neurologic EHV-1
rier horses.374,375,394 Infectious EHV-1 virus was detected in affecting donkeys and mules, although donkeys and mules
the feces of experimentally infected foals that developed diar- have shown seroconversion indicating infection with EHV-1
rhea, suggesting that fecal spread is a possibility.408 Virus may while in contact with affected horses during outbreaks.425-427
be shed by clinically affected and inapparently infected horses Indeed, donkeys and mules returning from a show were
for 3 weeks or more, and EHV-1 may remain infective in the thought to be responsible for dissemination of EHV-1 and
environment for up to 14 days and on horse hair for 35 to 42 propagation of multiple outbreaks of neurologic EHV-1
days.375,409,410 infection in Southern California in 1984 (and in several sub-
The first definitive association between EHV-1 and myelo- sequent years), suggesting that a donkey-adapted variant of
encephalopathy was made in 1966 in Norway with the isola- EHV-1 with an increased neuropathogenicity for horses may
tion of the virus from the brain and spinal cord of a horse that have been involved.427
showed signs of severe neurologic dysfunction.411 The myelo- A modified live EHV-1 vaccine of monkey cell line ori-
encephalopathic form of EHV-1 infection now is considered gin was associated with neurologic disease in 486 of 60,000
to have a worldwide distribution, having been recognized recipients, prompting its withdrawal from the U.S. market
in 1977.406 No reports of EHV-1 myeloencephalopathy have frame 30, causing a mutation in the DNA polymerase, is asso-
been associated with use of the modified live vaccine currently ciated with replicative aggressiveness and a greater potential
approved for use in horses in the United States. for causing neurologic disease.419 The nature and extent of
lesions resulting from EHV-1 infection appear to be influ-
Pathogenicity and Pathogenesis enced by the age, gender, reproductive status (including stage
Natural infection with EHV-1 occurs by inhalation or inges- of pregnancy), and immune status of the horse; the magnitude
tion, after which the virus attaches to and rapidly replicates of challenge; strain variations; and perhaps the route of infec-
in cells of the nasopharyngeal epithelium and associated lym- tion.382,436,437 In one carefully monitored outbreak of EHV-1
phoreticular tissues, causing necrosis, exudation, and infil- infection on a stud farm in England, less than 17% of infected
tration of phagocytic cells. Bronchial and pulmonary tissues horses developed neurologic manifestations of infection,
also become infected, particularly in foals, thus predispos- even though almost 60% of the horses on the farm were con-
ing them to secondary bacterial pneumonia.374,375,394,403,428 firmed to have been infected.382 Endothelial cell infection and
Migration of virus-infected phagocytes into the circulation perivascular cuffing within the CNS appeared to be at least
results in viremia associated with mononuclear cells (pri- as pronounced in foals that died during this outbreak with-
marily T lymphocytes) of the buffy coat.374,375,394,429 The out showing neurologic signs as in profoundly paretic mares
immunologically privileged intracellular location of the virus with severe CNS lesions; however, parenchymal neural lesions
appears to protect it from inactivation by circulating anti- were minimal in the foals.382,436 A notable finding during this
body and permits dissemination to other tissues, including outbreak was that mares and stallions that developed neuro-
the CNS, even in the presence of high levels of antibody.430 logic signs had considerable antibody responses, whereas the
EHV-1 is capable of spreading directly from one infected majority of foals did not, despite experiencing a prolonged
cell to contiguous cells without an extracellular phase.394 period of viremia.382
Vascular endothelium is the initial site of infection in the The majority of EHV-1 infections that cause neurologic
CNS and appears to be the predilection site for replication signs probably represent reinfection rather than a new infec-
of EHV-1 after transfer of the virus from circulating leuko- tion.412,438,439 Infection occurs in horses with significant
cytes.377,431,432 Viremia, which may be of prolonged duration, preexisting serum EHV-1 antibody titers. Affected horses fre-
can occur during primary and all successive infections with quently have high titers at the onset of neurologic signs, and
EHV-1, even when no clinical signs are apparent; thus all those horses that develop the most severe clinical signs are
EHV-1 infections pose a threat of inducing neurologic dis- frequently the ones that show the most rapid increase in anti-
ease or abortion.374,382 body titer after infection.77,382,421 In addition, the characteristic
The acute onset of clinical signs of EHV-1 myeloencepha- vascular lesions in neural tissues of affected horses are typical
lopathy appears to result from vasculitis and thrombosis of of type III (Arthus) hypersensitivity reactions, and circulat-
arterioles in the brain and especially the spinal cord. This ing immune complexes have been demonstrated at the onset
causes functional impairment of blood flow and metabolic of neurologic signs, suggesting that they may result from an
exchange and, in severe cases, hypoxic degeneration and immune-complex vasculitis. An immune-mediated mecha-
necrosis (malacia) with hemorrhage into adjacent neural tis- nism is supported further by the difficulty experienced in iso-
sues of the white and, to a lesser extent, gray matter. This pro- lating the virus from neural tissues of affected horses.413,414,436
posed pathogenesis, based primarily on interpretation of the In addition, assessment of risk factors during outbreaks of
prominent vasculitis seen histopathologically in infected neurologic EHV-1 infection in Southern California in 1984
horses and the lack of definitive evidence of viral multiplica- revealed that horses vaccinated with killed or modified live
tion in neural tissues, contrasts greatly with the well-estab- EHV-1 vaccine within the previous year were significantly
lished pathogenesis of encephalitis caused by herpesviruses (9–14 times) more likely to develop neurologic manifestations
in other species.389 The propensity of certain EHV-1 isolates of infection than were nonvaccinated horses.427
to induce myeloencephalopathy does not appear to reflect The finding of circulating antibodies to the myelin protein
specific neurotropism but rather a significant endotheliotro- P2 in the serum of horses that died from EHV-1 myeloenceph-
pism. The finding of chorioretinopathy and neural lesions in alopathy (but not in horses that recovered) has led to the sug-
experimentally infected specific pathogen-free ponies, how- gestion that an alternate immune-mediated mechanism may
ever, suggests that at least some strains of EHV-1 may exhibit play a role in the pathogenesis of neurologic EHV-1.440 The
neurotropism.433 Furthermore, strong evidence indicates that presence of this antibody, however, may represent a response
in addition to circulating T lymphocytes, epithelial cells of to leakage of the protein after damage induced by another
the respiratory tract, and lymphoid tissues draining the respi- mechanism.
ratory tract, trigeminal ganglia are important sites for estab- Despite the foregoing observations, evidence for an
lishing and maintaining the lifelong state of latency that immune-mediated pathogenesis for EHV-1 myeloencepha-
occurs in most, if not all, horses during primary infection lopathy is by no means conclusive. In experimental EHV-1
with EHV-1 and EHV-4.388,433-435 The ubiquitous EHV-2 has infections in which the onset of neurologic signs 8 to 9 days
been proposed to play an important role in promoting reacti- after infection correlated with a peak in the level of circulat-
vation of EHV-1 and EHV-4 from these sites in latently ing immune complexes, vasculitis was not present in vessels in
infected horses.404 which endothelial cells did not support viral replication or in
No satisfactory explanation exists as to why some outbreaks organs such as the kidney that one would expect to trap circu-
of EHV-1 infection are associated with a high incidence of lating immune complexes.431 The finding of greatly depressed
neurologic disease, whereas others are not, or why different platelet counts several days before the onset of clinical signs,
horses show different clinical manifestations of EHV-1 infec- presumably the result of consumption in thrombi after endo-
tion during outbreaks.382,383,417,436 A genetic strain of EHV-1 thelial damage, suggests that the neuropathologic changes
with an adenine-to-guanine mutation at the open reading are initiated before circulating immune complexes peak and
that the action of immune complexes may be secondary and horse.219,412,420,446 Consistent with predominant involvement
localized. Failure to isolate the virus from the CNS may be of the white matter of the spinal cord, flexor reflexes are nor-
attributable to high levels of circulating antibody and to the mal and perineal reflexes are preserved. In recumbent horses,
endotheliotropism of the virus.431 spinal tendon reflexes can be tested and may be increased.
Atrophy is rarely seen, even in the later stages of the disease.219
Clinical Signs Affected horses usually remain alert and have good appetites,
In natural and experimental infections, neurologic signs even when recumbent, although some show modest depres-
appear 6 to 10 days after infection by the intranasal route. sion and inappetence.416,447 Severe depression, when it occurs,
The onset of neurologic signs may be preceded or accompa- is more often caused by secondary complications than by brain
nied by signs of upper respiratory disease, fever, inappetence, involvement.447 Unequivocal signs of brain disease are rare,
or hindlimb edema within the previous 2 weeks, although in although infarction of the brainstem may cause depressed sen-
many instances no antecedent signs are notable unless one sorium, altered behavior, and cranial nerve damage leading to
routinely monitors rectal temperature. However, frequently vestibular signs and to lingual, mandibular, and pharyngeal
one finds a herd or stable history of current or recent cases paresis, which may manifest as dysphagia.422,445,447-449 Strabis-
of respiratory tract infection, fever, inappetence, distal limb mus, nystagmus, circling, and head tilt have been observed on
edema, abortion, neonatal death, foal diarrhea, or neurologic occasion.219,387,422,446
disease, and for one to encounter different signs of EHV-1 Affected horses show variable progression of clinical signs.
infection in different groups of horses on a particular farm is Those horses that are affected mildly frequently stabilize rap-
not unusual.382 idly over a period of hours to a few days as edema and hemor-
Affected horses are occasionally febrile at the onset of rhage resolve; generally they recover completely over a period
neurologic disease, although most are normothermic and of days to several weeks.382,383,412,416,417 If recumbency occurs,
some are hypothermic. Neurologic signs are generally of it generally does so during the first 24 hours, with some horses
acute or peracute onset, after which they tend to stabilize showing such complete motor paralysis that they are unable
rapidly and generally do not progress after the first 1 or 2 to lift their heads.442 Severely affected horses may show pro-
days.219,412,416,420,441 Clinical signs vary depending on the loca- gression of signs during the first few days and may die in
tion and severity of lesions, but in most horses, signs reflect coma or convulsion or be euthanized because of secondary
predominant involvement of the spinal white matter.219 complications.382
Ataxia and paresis of the limbs are the most common signs,
with hypotonia of the tail and anus, tail elevation, and uri- Laboratory Findings
nary incontinence being common but not invariable findings. CSF analysis typically, although by no means always, reveals
Clinical signs are usually bilaterally symmetric or only mildly xanthochromia, an increased protein concentration (100–500
asymmetric, although hemiparesis or sudden onset of unilat- mg/dL), and increased AQ (ratio of CSF to serum albumin
eral hind- or forelimb lameness progressing to unilateral or concentration), reflecting vasculitis and protein leakage into
more generalized ataxia, paresis, and recumbency have been CSF. The white blood cell count in CSF is usually normal (0–5
reported.219,442-445 Lesions in peripheral nerves and spinal cells/μL) but occasionally is increased. Abnormalities in CSF
cord were observed in some of these cases.442 The hindlimbs are not present at the onset of clinical signs in some horses,
generally are affected more severely and earlier in the disease and changes resolve rather quickly; thus the CSF may be nor-
course than the forelimbs. In mildly affected horses, transient mal within 2 weeks of onset of clinical signs.219,377,441
ataxia and stiffness of the pelvic limbs or dribbling of urine The presence of antibodies to EHV-1 in the CSF of
after overflow from a distended atonic bladder may be the affected horses strongly suggests a diagnosis of EHV-1
only signs noted.219,420 One may note conscious propriocep- myeloencephalopathy, although such antibodies are absent
tive deficits in these cases as reluctance to move, clumsiness, in many cases.219,377,387,422,450 One should take into account
toe dragging, knuckling, stumbling, pivoting, and circumduc- the albumin concentration, IgG concentration, and EHV-1
tion in one or more limbs on circling, with spasticity evident antibody titer in serum and CSF when interpreting positive
in some cases.44,52,85 These signs are often subtle and may go antibody titers in CSF.451 Because the AQ usually is elevated
unnoticed. More severely affected horses show profound limb in affected horses and the IgG index is normal, the presence
weakness and swaying of the hindquarters, and a small proof EHV-1 antibodies in CSF reflects leakage of protein across
portion show complete paralysis of affected limbs, manifested a damaged blood-brain or blood-CSF barrier after vasculi-
as paraplegia and sitting like a dog, complete recumbency, or tis rather than intrathecal antibody production.440,450,451
tetraplegia.219,382,394,446 Antibodies therefore are more likely to be present in the
Distention of the urinary bladder is common and may cause CSF of affected horses with concomitantly high serum
signs of colic or dribbling of urine, which frequently results in titers.219,377,440,450,451 Blood contamination during collec-
scalding of the perineum, legs, and other areas.426 Cystitis is tion of CSF and other diseases that cause an increase in the
a frequent complication, particularly when repeated catheter- permeability of the blood-brain barrier or bleeding into the
ization is necessary to relieve bladder distention.441 Affected subarachnoid space may elevate CSF antibody titers falsely if
stallions and geldings may develop penile flaccidity and para- serum titers are also high. Isolation of EHV-1 from the CSF
phimosis or repeated erections, whereas mares may develop of affected horses would confirm a diagnosis but is rarely
vulvar flaccidity. In addition, stallions may experience reduced successful.219,426
libido and swelling of the testes.382,436 Scrotal edema may Virus isolation and identification of EHV-1 from naso-
accompany hindlimb edema at the onset of neurologic signs pharyngeal swabs or buffy coat samples strongly support a
in some cases.382,416,420,423,436 Sensory deficits are uncommon, diagnosis of EHV-1 myeloencephalopathy in a horse with
but perineal hypalgia or analgesia has been noted, and analge- compatible clinical signs and should be attempted by sub-
sia of the caudal half of the body was observed in one affected mission of nasopharyngeal swabs in viral transport medium
and an uncoagulated blood sample (citrated or heparinized). fibrocartilaginous infarction, aberrant parasite migration,
Diagnosis may be achieved more rapidly using real-time PCR degenerative myelopathy, other viral encephalitides (flavivi-
for identification of EHV DNA from nasopharyngeal swabs ruses and alphaviruses), rabies, botulism, CNS abscess, and a
or buffy coat samples. The likelihood of isolating EHV-1 dur- variety of plant and chemical intoxications.219,387 Sudden onset
ing outbreaks of neurologic disease increases by monitoring and early stabilization of neurologic signs including ataxia,
in-contact horses and collecting nasal swab and buffy coat paresis, and urinary incontinence; involvement of multiple
samples during the prodromal febrile phase before neu- horses on the premises; and a recent history of fever (most
rologic signs develop.416 Even so, interpretation of positive consistently reported clinical sign before onset of ataxia),
results can be confusing because EHV-1 and EHV-4 have abortion, or viral respiratory disease in the affected horse
been isolated from the respiratory tract of normal horses.409 or herdmates are sufficient to make a tentative diagnosis of
Application of new diagnostic methods such as polymerase EHV-1 myeloencephalopathy.387 Antemortem diagnosis is
chain reaction (PCR), in situ hybridization, antigen-capture supported by ruling out other conditions; demonstrating xan-
ELISA, and dot immunobinding to nasal swabs or scrapings, thochromia and elevated protein concentration in CSF; identi-
buffy coat samples, or pathologic specimens have improved fying EHV-1 in or isolating EHV-1 from the respiratory tract,
the speed and specificity greatly with which one can diag- buffy coat, or CSF; and demonstrating a fourfold increase in
nose EHV-1 infection.452-460 Many conventional PCR proto- antibodies using serum-neutralizing, complement fixation,
cols targeting specific genes of EHV-1 have been published or ELISA tests performed on acute and convalescent serum
in recent years for molecular detection of EHV-1 in naso- samples collected from affected or in-contact horses 7 to 21
pharyngeal swabs or buffy coat samples.405,455-459 Although days apart.383,417,465 Antemortem confirmation of a diagnosis
considerable progress has been made in developing PCR proof EHV-1 myeloencephalopathy is frequently not possible,
tocols for clinical use, quality control of nucleic acid ampli- however, particularly when an individual horse is affected,
fication techniques remains an ongoing challenge because because the foregoing tests do not yield consistent results in all
of lack of protocol standardization among laboratories.461 cases. Hematologic abnormalities with EHM are inconsistent
Furthermore, the majority of PCR assays targeting genomic but may include mild anemia and lymphopenia, followed by
EHV-1 DNA are unable to differentiate between a lytic and increased plasma concentration of fibrinogen.
a latent infection. Novel technologies such as real-time
PCR that allow quantitation of viral DNA and detection at Treatment and Prognosis
the level of gene expression likely will feature prominently Because EHV-1 is a contagious and potentially devastating
as molecular diagnostic approaches to EHV-1 infection are infection, horses suspected of being affected should be isolated
refined further in the future. promptly and strictly until EHV-1 is ruled out by confirmation
Serologic testing that demonstrates a fourfold or greater of an alternate diagnosis.447 No specific treatment is available;
increase in serum antibody titer using serum-neutralizing or thus management of horses with EHV-1 myeloencephalopa-
complement fixation tests on acute and convalescent samples thy aims toward supportive nursing and nutritional care and
collected 7 to 21 days apart provides presumptive evidence reduction of CNS inflammation.387 One should encourage
of infection. Many horses with EHV-1 myeloencephalopa- horses that are not recumbent to remain standing and should
thy, however, do not show a fourfold rise in serum-neutral- protect them from self-inflicted trauma by the provision of
izing titer, and some actually show a decline.426 This may be good footing, such as a grass paddock, by placement of food
explained by the finding that when antibody titers rise, they and water in an accessible location at a convenient height
do so rapidly within 6 to 10 days of infection and already may above ground level, and by other measures, including the use
have peaked by the time neurologic signs appear. Although of padded hoods and elimination of obstacles. Patients that
serologic testing has limitations in confirming a diagnosis of become recumbent should be maintained in a sternal position
EHV-1 myeloencephalopathy in an individual horse, testing on a thick cushion of dry absorbent bedding and should be
of paired serum samples from in-contact horses is recom- rolled frequently (at least every 2–4 hours) to reduce the risk
mended because a significant proportion of affected and of myonecrosis and decubital ulcers. Whenever possible, one
unaffected in-contact horses seroconvert, providing indirect should lift and support the horse in the standing position using
evidence that EHV-1 is the causative agent. Interpretation of an appropriately fitting sling.383 Slings are most beneficial for
the results of serologic tests is complicated by the fact that moderately affected horses that are too weak to rise but are
the serum-neutralizing, complement-fixation, and ELISA able to maintain a standing position with minimal assistance.
tests in use at most diagnostic laboratories do not distin- Affected horses usually maintain a good appetite, even
guish between antibodies to EHV-1 and EHV-4 because of when recumbent, although hand feeding may be necessary
cross-reaction between these viruses. A specific ELISA test to encourage some horses to eat. Maintenance of hydration is
based on the C-terminal portion of glycoprotein G of both important, and provision of a laxative diet or the administra-
viruses has been developed and should prove valuable in the tion of laxatives such as bran mashes, mineral oil, or psyllium
investigation and management of disease outbreaks in the may be necessary to reduce intestinal impaction. One usually
future.462-464 can meet the caloric and water needs of anorectic patients
by feeding gruels of alfalfa-based or similar pelleted feeds in
Diagnosis water or balanced electrolyte solution via nasogastric tube.
The multifocal distribution of lesions results in variability of If oral intake is insufficient to meet the daily water needs
clinical presentation, which necessitates inclusion of a num- of 60 to 80 mL/kg of body mass per day, one can maintain
ber of conditions in the differential diagnosis. These condi- hydration by intravenous administration of balanced electro-
tions include EPM, cervical stenotic myelopathy, and cervical lyte solutions.219 Partial or total parenteral nutrition can also
vertebral instability (wobbler syndrome), cervical vertebral be used to meet the caloric needs of anorectic, recumbent
fracture or other CNS trauma, neuritis of the cauda equina, horses.
If affected horses are unable to stand and posture to uri- Affected horses that remain standing have a good prog-
nate or if bladder function is impaired significantly, manual nosis for recovery, and improvement generally is apparent
evacuation of the bladder by application of pressure per the within a few days, although a period of several weeks to more
rectum may be necessary. If these measures are unsuccessful, than a year may be required before horses with severe defi-
judicious urinary catheterization is indicated and should be cits show complete recovery. In these instances, control of
performed aseptically with the collection tubing attached to urination frequently returns before gait abnormalities resolve
a sterile closed bag to minimize the risk of inducing urinary completely.447 Some horses may be left with permanent resid-
tract infection.387,446,447 Cystitis is, however, a frequent com- ual neurologic deficits, including urinary incontinence and
plication, particularly in recumbent horses, and can lead to ataxia, that may necessitate euthanasia many months beyond
bladder wall necrosis, bladder rupture, and systemic sepsis. onset of neurologic signs.219,383,425,426 Horses that become
Urine scalding can become a major problem, particularly in recumbent have a greatly increased likelihood of developing
mares that dribble urine. Prevention involves regular washing complications such as myonecrosis, urinary tract infection,
of the perineum, tail, and hind legs with water, application of decubital ulcers, respiratory tract infection, gastrointestinal
water-repellent ointments, and braiding or wrapping the tail obstruction and ulceration, injuries, and complications of
to simplify cleaning.387 Administration of enemas or manual dehydration and malnutrition. Their prognosis for recovery
emptying of the rectum also may be necessary to promote def- is therefore poor, particularly if they remain recumbent for
ecation and improve patient comfort.387 more than 24 hours and they are unable to stand after being
Because vasculitis, hemorrhage, and edema are promi- lifted with a sling.382,383 One should not elect euthanasia pre-
nent early lesions and may have an immune basis, treatment maturely in valuable horses, however, because reports docu-
with corticosteroids early in the disease course is recom- ment horses standing again and recovering completely to
mended by some clinicians, although no objective data are race successfully after being recumbent for several days to 3
available to document the efficacy of these or other antiin- weeks.416,423,442 Most mildly affected mares return to breeding
flammatory drugs.219,416,447 A short course of treatment with soundness in the same season, whereas fertility is likely to be
prednisolone acetate (1–2 mg/kg/day) or dexamethasone compromised in more severely affected mares that experience
(0.05–0.25 mg/kg parenterally twice daily) for 2 to 3 days urinary retention.382 Recurrence or exacerbation of neuro-
with decreasing doses over another 1 to 3 days may be ben- logic signs in horses that have recovered completely has not
eficial.219,387,446 Flunixin meglumine (1.1 mg/kg body mass been documented, even though the majority likely remain
every 12 hours) is indicated to treat CNS vasculitis. DMSO latently infected.219,394,407,447
at a dose of 0.5 to 1.0 g/kg administered intravenously as a
10% to 20% solution in normal saline or 5% dextrose once Pathologic Findings
daily for up to 3 days commonly is used to treat horses with When horses with suspected EHV-1 myeloencephalopathy die
suspected CNS trauma or inflammatory disease, such as or are euthanized, one should submit the whole carcass or at
EHV-1.384,387 Although the efficacy of DMSO for treating least the head, spine, spleen, thyroid, and lung for postmor-
herpesvirus myeloencephalopathy has not been evaluated, its tem examination because lesions frequently are not confined
reported ability to inhibit platelet aggregation and scavenge to the CNS of horses with EHV-1 myeloencephalopathy.471
free radicals supports its continued use. Because of the high Gross pathologic lesions in the CNS frequently are not found,
risk of development of cystitis and other secondary bacterial but small (2–6 mm) focal areas of hemorrhage distributed
infections, administering broad-spectrum antibiotics such as randomly throughout the meninges and parenchyma of the
potentiated sulfonamides (trimethoprim-sulfamethoxazole brain and spinal cord may be observed. More diffuse dural
30 mg/kg body mass orally every 12 hours) or ceftiofur (2.2 hemorrhage is notable in some cases and may extend to spi-
mg/kg body mass intramuscularly or intravenously every 12 nal nerve roots and the cauda equina.377,421,414 Small plum-
hours) is advisable, particularly when corticosteroid treat- colored areas of degeneration and hemorrhage are sometimes
ment is used.19,383,387 One should base the choice of antibi- grossly visible in fresh tissue at various levels of the spinal cord
otics for treating established secondary bacterial infections (white matter), and malacic foci may be visible macroscopi-
of the urinary tract, respiratory tract, or other areas on the cally in the gray and white matter in sliced fixed sections of
results of culture and susceptibility testing. brain.377,414,421,423,428
Acyclovir, a synthetic purine nucleoside analog with inhib- The gross and histologic lesions in the CNS reflect vas-
itory activity against several human herpesviruses, has been culitis, congestion, and secondary ischemic degeneration
shown to exert an inhibitory effect on EHV-1 in vitro.466 of nervous tissue. Although vasculitis is a consistent find-
Apparent efficacy of acyclovir was suggested by a successful ing, degeneration of nervous tissue is evident chiefly in
treatment outcome in occasional outbreak situations.417,467 those horses with clinical signs of severe neurologic dis-
Although these anecdotal reports seemed promising, data ease.377,421,436 The vasculitis is often severe and has a wide-
describing the pharmacokinetics, bioavailability, and safety spread, random, multifocal distribution, with the most
of acyclovir in horses do not support claims of efficacy, espe- severe lesions usually in the brainstem and spinal cord. In the
cially after oral administration. Bioavailability of acyclovir brain the meningeal and penetrating or radiating vessels in
after oral administration to horses is extremely low; in con- gray matter are the major sites of vascular involvement. Thus
trast, bioavailability of valacyclovir, a prodrug for acyclovir, foci of axonal swelling and malacia develop in the gray and
is much higher.468,469 Clearly, additional studies are needed white matter, particularly adjacent to the meningeal surface
to define the appropriate dose for valacyclovir in horses and and in the deep cortex adjacent to the white matter.377,421,414
to document its efficacy for the treatment of EHV-1 myelo- In the spinal cord a similar orientation to meningeal vessels
encephalopathy. Another nucleoside analog, penciclovir, has results in degeneration of white matter within ovoid, linear,
been shown to have excellent activity against EHV-1 in tissue or wedge-shaped foci, affecting predominantly the lateral
culture and in a mouse model of EHV-1 infection.470 and the ventral white columns.377 In some instances, sheaths
of nerve roots and nerves and capsules of ganglia also are out, or transport affected horses also should be cleaned and
involved.219,377,421,436 Trigeminal ganglionitis might be pres- disinfected or disposed of properly. Thereafter separate equip-
ent but usually is not manifest clinically.442 ment and personnel should be used for affected and unaffected
Ocular lesions, including uveal vasculitis with perivascular horses, or at least caretakers should handle affected horses last
mononuclear cell cuffing in the ciliary body and optic nerve and wear disposable gloves, surgical masks, and protective
or extensive retinal degeneration, have been observed in foals clothing that can be changed or disinfected between groups.394
showing signs of bilateral hypopyon and iritis or severe visual Although control measures are frequently successful in stop-
impairment and chorioretinopathy without anterior segment ping further spread of infection during outbreaks, one should
involvement during field and experimental EHV-1 infec- note that transmission of infection before control measures
tions.377,382,414,433,436 In some foals, EHV-1 appears to induce are implemented may result in a secondary wave of disease 1
ocular and neural damage in the absence of gross signs of neu- to 2 weeks later.382,394,416
rologic or visual impairment.433 During paralytic infections, Traffic of horses and human beings on the premises
secondary viral replication occurs in blood vessels of the testis should be minimized, and movement of horses onto and off
and epididymis in addition to CNS and may be responsible for of the infected premises should be suspended until at least
reported signs of scrotal edema and loss of libido in affected 3 weeks after resolution of acute signs in the last clinical
stallions.382,472 case or until tests show that virus transmission is no longer
EHV-1 infrequently is isolated from the CNS of affected occurring.374-376,387,394 Collection of nasal swabs and unco-
horses that show typical lesions. Thus one should attempt to agulated blood (buffy coat) samples from clinically affected
isolate the virus from other sites to support the diagnosis. and exposed horses within each group and demonstration of
Those sites most likely to yield virus or to contain viral anti- stable or declining antibody titers in serum samples proved
gen include the turbinates and nasal passages, as well as lymph to be helpful in determining patterns of exposure and spread
nodes draining the upper respiratory tract, lung, thyroid, and in establishing when virus transmission had ceased in one
spleen, and endometrium, in addition to the brain.219,436,473 reported outbreak. Protracted viremia lasting several weeks or
Immunofluorescent antibody testing of brain and spinal cord months occurs in some horses and extends the period during
sections is considered to be more sensitive than virus isola- which movement of horses should be restricted.382
tion, but false-negative results have been observed.219,413,436 If horses must enter the farm, they should be current on
An indirect immunoperoxidase method using orthodox light EHV-1 vaccination and should be isolated away from the
microscopy was highly sensitive for identifying individual resident population. Although giving booster vaccinations
antigen-containing cells in the CNS and other areas of the to exposed pregnant mares during outbreaks of abortigenic
body, even at sites containing few or no lesions or inclusion EHV-1 infection is common practice,374,375,394 vaccination of
bodies and in which virus could not be detected by immu- exposed horses during outbreaks of EHV-1 myeloencephalop-
nofluorescent antibody testing or virus isolation.436 Similarly, athy has not been investigated and cannot be recommended
the PCR technique is more sensitive than virus isolation for at this time because of the possibility of an immune-mediated
detecting viral antigen in nasopharyngeal swabs collected pathogenesis. Administering booster doses of inactivated
from horses with respiratory tract disease caused by EHV-1 EHV-1 vaccine to all unexposed horses that have not been
or EHV-4.455 Both of these techniques—as well as antigen- vaccinated within the previous month is common practice,
capture ELISA tests, dot immunobinding, and in situ DNA however.
hybridization, which are sensitive and readily differentiate Preventive measures should include routine management
between EHV-1 and EHV-4—show great promise for routine practices aimed at reducing the chances of introducing and
application to samples collected antemortem or at necropsy disseminating infection.376,394,444,474 New arrivals should be
from affected horses.432,436,453,456,460 isolated for at least 3 weeks before joining the herd, distinct
herd groups should be maintained based on the age and use
Control and Prevention of horses, and care should be taken to minimize or eliminate
Control measures during outbreaks of EHV-1 infection aim commingling of resident horses with visiting or transient
at reducing spread by infectious aerosols, direct contact, and horses. In particular, pregnant broodmares should be main-
fomites, as well as at reducing stress-induced recrudescence tained in groups separate from the remaining farm population.
of latent EHV-1 infection.374,375,394 If neurologic signs or other In addition, minimizing stress associated with overcrowding
clinical signs suggestive of EHV-1 infection occur, one should and handling procedures is prudent in an attempt to reduce
isolate affected animals promptly and completely in a well- recrudescence of latent EHV-1 infection.394,407,444,474
ventilated airspace separate from the remainder of the herd. No method is known that reliably prevents the neurologic
In-contact horses should be isolated in their current location form of EHV-1 infection. None of the EHV-1 or EHV-4 vac-
in small groups for at least 1 month; pregnant mares should be cines currently available carries a claim that they prevent EHV-1
isolated preferably until they foal.374-376,382,394,416,449 On breed- myeloencephalopathy, and the disease has been observed in
ing farms, one should suspend covering.382 Aborted fetuses horses vaccinated regularly at 3- to 5-month intervals with
and fetal membranes are rich sources of infectious virus; inactivated or modified live vaccines.219,387,417,426,448 Repeti-
therefore they should be collected and placed in leak-proof tive administration of currently available EHV-1 and EHV-4
containers (e.g., heavy-gauge plastic bags) for submission for vaccines appears to induce some immunity to respiratory dis-
diagnostic evaluation or disposal by burning.374,375 Similarly, ease and reduce the incidence of abortion but does not block
bedding and dirt contaminated with fetal fluids should be infection and induction of viremia or eliminate the pos-
disposed of or burned, and stalls or other areas occupied by sibility of clinical disease and establishment of the carrier
infected horses should be cleaned thoroughly, disinfected with state.374,375,394,448,474-479 Although the protection induced by
an iodophor or a phenolic product, and left empty for several inactivated EHV-1 vaccines is incomplete and of short dura-
weeks.394 Equipment used to handle, groom, feed, water, muck tion, the vaccine reduces virus excretion in horses that do
become infected.476,479 To maintain appropriate vaccination II, III, IV, VI, IX, X, and XII also may be involved.4,484,486,487
procedures in an attempt to reduce the incidence of other As a result of damage to the cranial nerves, horses might have
manifestations of EHV-1 infection and reduce the magnitude trouble with mastication and swallowing.493 A head tilt, ear
of challenge experienced by in-contact horses is logical. This droop, lip droop, and ptosis are common signs.4,493 One report
indirectly may help prevent EHV-1 myeloencephalopathy.219 describes a horse with brachial neuritis along with involve-
An attenuated live virus vaccine based on the temperature- ment of cranial nerves V, VII, and XII. The horse in that report
sensitive and host range mutant clone 147 of EHV-1 has been also exhibited mild ataxia and weakness in all limbs. The horse
evaluated recently. The novelty of this vaccine lies in the fact performed the hopping test poorly on the right thoracic limb,
that a low dose administered intranasally replicated in con- and the horse resented palpation in the right caudal cervical
ventional target species and conferred exceptional efficacy and prescapular region.484
against respiratory disease, virus shedding, viremia, and abor- Colic caused by fecal retention may be the primary sign
tion caused by a severe EHV-1 challenge.480-482 Intranasal vac- when one initially examines horses with polyneuritis equi.
cine also claims to protect against less common manifestations Fecal retention leads to an impaction caused by the flaccid
of EHV-1 infection such as paresis and jaundice.381 anal sphincter, often accompanied by an atonic, distended
bladder.483 If the clinician sees these signs in the acute or
Y POLYNEURITIS EQUI hyperesthetic form, they usually progress to hypalgesia or
anesthesia. An area of hyperesthesia might surround the area
Polyneuritis equi is an uncommon neurologic disease of all of anesthesia.4,483,484
equine species that is characterized by tail and anal sphincter
paralysis, often accompanied by cranial and peripheral nerve Diagnosis
damage.4,483-493 Previous reports referred to the disease as neu- The definitive diagnostic test is a postmortem examination.
ritis of the cauda equina because of the susceptibility of this Blood work might be normal or reveal a mature neutrophilia
region, but frequent involvement of the cranial and peripheral with hyperfibrinogenemia, mild to moderate anemia, and an
nerves led to the term polyneuritis equi.375 Although the disease increased total protein—all indications of a chronic inflamma-
has been recognized more readily in Europe, where Dexler first tory process.485,487 Results of CSF are variable and nonspecific,
reported it in 1897, cases have now been reported in Great Brit- ranging from mild mixed mononuclear to primarily neutro-
ain, Canada, and the United States.485,486,488,494 The disease does philic pleocytosis, with normal to increased protein concen-
not appear to have a breed, gender, or age predilection, but the trations (70–300 mg/dL). There could be a mixed pleocytosis
youngest horse affected was 17 months of age.484,487,488,494,495 with predominance of lymphocytes and marked lymphoid
The cause of this disease is unknown. Primary immune reactivity supportive of humoral response to inflammation.495
reaction and viral inflammatory disease have been suggested, Cytologic examination of CSF might be normal in the acute
although possibly one may be a consequence of the other.484 stage of disease.4,484,485,487,488,492
Several infectious agents have been suggested, such as EHV- Radiography might be helpful to rule out trauma to the tail-
1, equine adenovirus, and streptococcal and Campylobacter head or cranial nerve involvement, such as a fractured petrous
spp. bacteria.491,493,496 The pathologic lesions resemble those temporal or other bones of the skull.4,484
of Guillain-Barré syndrome in human beings, and the dis- Some horses with clinical signs exhibit circulating serum
ease is similar to experimental allergic neuritis in rats.491 Evi- antibodies to P2 myelin.491,497 However, the presence of this
dence suggests that the immune system is involved because antibody is only weakly supportive of the diagnosis because
horses with polyneuritis equi have circulating antibodies to the same antibody has been detected in horses with EHV-1
P2 myelin protein, which is present in rats with experimen- and equine adenovirus infections.440,483,491,496
tal allergic neuritis.491,497 Inflammatory lesions contain both T Classically, the primary pathologic lesions involve the
and B lymphocytes, suggesting the possibility of an immune- extradural nerve roots but also might involve the intradural
mediated reaction to myelin.495,498 nerve roots.484,485,487,493 The lesions are granulomatous with
various degrees of inflammation and infiltration of lympho-
Clinical Signs cytes, eosinophils, macrophages, giant cells, and plasma cells.
Although the disease manifests itself in two forms, signs are This inflammation leads to myelin degeneration, subsequent
generally slow and progressive: (1) the acute or early signs axonal degeneration, and thickening of the epineurium, endo-
include hyperesthesia of the perineal or head regions (or neurium, and perineurium with proliferation, which causes
both), and (2) in the chronic form, horses show paralysis of the obliteration of the neural architecture by the fibrous tis-
tail, anus, rectum, and bladder. Paralysis often is accompanied sue.483,484,490 The most severe lesions are in the cauda equina,
by fecal and urinary retention, urinary scalding of the pelvic but swelling, edema, and hemorrhage of cranial nerves may
limbs, and penile paralysis in male horses.4,483-485,488,490,493 occur. The fibrous tissue formation might lead to adhesions
The pelvic limb signs are often symmetric, whereas the between the meninges and the periosteum of the verte-
signs involving the head and cranial nerves are often asym- bral bodies. Reports describe involvement of the autonomic
metric.488 Muscle atrophy in the gluteal region is sometimes nervous system, but no changes in clinical signs have been
present along with mild degrees of ataxia.484,485,487,488,490 Mus- reported (postmortem only).484,486
cle atrophy associated with cranial nerve involvement may The polyneuritis lesions are similar to those observed
occur in the head region. Damage to peripheral motor nerves with Guillain-Barré syndrome in human beings, experi-
might result in gait deficits and abnormal use of thoracic or mental allergic neuritis in rats, and coonhound paralysis in
pelvic limbs.483,493 dogs.484,487,492,493 This similarity might indicate a combination
Although cranial nerve involvement is reported primarily of inflammatory and immune-mediated mechanisms in the
to affect cranial nerves V, VII, and VIII, any of cranial nerves pathogenesis of polyneuritis equi.
onset of bilateral pelvic limb digital extensor dysfunction

Differential Diagnosis and knuckling.503,504 Ataxia is not a feature of this polyneu-
The most important differential diagnosis is trauma to the ropathy. The disease has been described in horses of vari-
sacrococcygeal area of the spinal canal, which can be differ- ous breeds during the months from December to April in
entiated by radiography of the area looking for fractures or Sweden, Norway, and Finland. The estimated prevalence of
displacements.4,484,488 EPM is the second most common dis- disease on farms in Norway and Sweden is 27% with a case
ease in the differential diagnosis of polyneuritis equi. The fatality rate of 29%. Duration of clinical signs in survivors
usual signs of EPM include asymmetric multifocal signs of varies from 1 to 17 months (median 4.4 months). Survi-
brain and spinal cord injury causing cranial nerve deficits with vors can return to full work within 19 months (median 6.6
alterations in mentation, whereas the cranial nerve deficits of months). Younger horses have a greater chance of survival
polyneuritis equi are peripheral, with no change in mentation than older horses. However, the disease was less prevalent
or behavior.313,488 in horses over 12 years old according to an epidemiologic
EHV-1 myeloencephalitis should be another rule out of study.503 The exact etiology of disease is unknown but sus-
polyneuritis equi. However, signs of fever in the acute stage pected to be forage-related toxicity. Histologic lesions consist
of EHV-1 infection does not develop in horses with poly- of inflammatory demyelinating polyneuropathy and intracis-
neuritis equi. This condition frequently affects more than ternal Schwann cell inclusions.505
one horse on a farm. Herpesvirus has a rapid onset with
ataxia as a predominant or common sign, which is usu- Y NEUROMUSCULAR DISORDERS
ally not the case in horses with polyneuritis equi. Urinary
incontinence can commonly develop in horses with EHV-1 The neuromuscular system is an important part of the ner-
infection along with ataxia and pelvic limb neurologic defi- vous system. This system has central and peripheral com-
cits. The ataxia and weakness are usually symmetric and ponents. The central components include motor neurons
might result in recumbency. Occasionally, affected horses located in the central nervous system (brain [nuclei of cra-
sit like a dog because of profound pelvic limb weakness. nial nerves III–VII, IX–XII] and spinal cord). Its peripheral
Cranial nerve involvement is not common but might occur part includes all structures located outside the brain and
in between 10% and 15% of affected horses.375,421,471,499 spinal cord. The peripheral nervous system can be classi-
One should consider verminous myeloencephalitis as a dif- fied into two major functional systems: afferent or sensory
ferential diagnosis for polyneuritis equi. The signs vary and and efferent or motor systems. The neuromuscular system is
depend on the migratory pathway of the parasite. Diffuse or composed of motor units. A motor unit consists of a single
multifocal brain and spinal cord lesions have been reported. lower motor neuron, its axon and supportive cells (Schwann
The onset is usually sudden, with rapid deterioration and cells), neuromuscular junction, and all the muscle fibers
death. The incidence of this disease is low, perhaps because of innervated by the motor neuron. The neuromuscular junc-
more intense parasite control.248,500,501 tion can be further divided in presynaptic (axonal terminal),
One should consider EMND in the differential diagnosis. synaptic (synaptic space), and postsynaptic (muscle mem-
Horses with motor neuron disease have symmetric muscle brane) regions.
wasting or atrophy and weight loss with significant weakness, A single lower motor neuron innervates muscle fibers
sweating, and muscle fasciculations. However, these horses contained within one muscle and not of different muscle
are usually not ataxic, and their unique clinical feature is that groups. One muscle fiber is innervated by one motor neu-
they walk better than they stand. This disease is a denerva- ron. Large muscles (postural and locomotion muscles) on
tion atrophy of both muscle fiber types (1 and 2) with a pre- which fine movements are not required generally have a
dominance of type 1 muscle fibers. The diagnosis is through a few hundred to thousands of muscle fibers per motor unit.
spinal accessory nerve biopsy or sacrodorsalis caudalis muscle Whereas muscles required for more dexterous movement
biopsy.502 However, any muscle containing both fiber types is such as those for ocular movement have fewer muscle fibers
useful for diagnosis. per motor unit. A single discharge of a motor neuron will
result in the contraction of all muscle fibers innervated by
Treatment its axon. All motor neurons innervating skeletal muscle are
The primary therapy is palliative. No treatment for the disease exclusively excitatory. However, interneurons located within
is known. Removing feces from the rectum and evacuating the spinal cord can have either excitatory or inhibitory effects
the bladder are usually necessary. If cystitis caused by bladon the motor neurons.
der distention occurs, systemic antibiotics might be indicated. Neuromuscular disorders are those affecting any compo-
Some attempts have been made at treating the inflammation nent of the neuromuscular system and their supporting cells.
with corticosteroids, but the effects have been short lived. The Signs of dysfunction can be variable depending on the spe-
prognosis is poor. Some animals might be maintained for a cific area affected. Lower motor neuron dysfunction results
few months. in muscle weakness, paresis to paralysis, decreased muscle
tone, decreased to absent reflexes, and neurogenic muscle
Y ACQUIRED EQUINE POLYNEUROPATHY atrophy. Definition of a few terms will be provided for clari-
fication. Neuronopathy is the abnormality of the neuron cell
IN SCANDINAVIA body, whereas neuropathy is the abnormality of the nerve. A
Monica Aleman nerve might be motor or sensory or both. Neuropathies can
be characterized by degeneration of its axons (axonopathy),
Acquired equine polyneuropathy (AEP), also known as demyelination (e.g., Schwannopathy), or both. Junctionopa-
Scandinavian knuckling syndrome, is characterized by acute thies are disorders involving any of the presynaptic, synaptic,
and postsynaptic regions of the motor end plate. Examples of TABLE 11.11 Neuromuscular Disorders Reported or Suspected
neuromuscular disorders are shown in Table 11.11.30 in Horses30
Diagnostic Approach CENTRAL
Complete signalment and history are the essential first step Interneuron (Inhibitory: Renshaw cells)
in the investigation of any disorder. A history of a few or sev- Tetanus (C. tetani toxins)
eral horses affected in the same premises should raise suspi- Motor Neuron Cell Body
cion of nutritional, toxic, or infectious causes. A thorough Equine motor neuron disease
physical and neurologic examination must be performed PERIPHERAL
for the evaluation of patients with suspected neuromuscu- Neuropathy: Mononeuropathy/Multiple Mononeuropathy/
lar dysfunction. Neuroanatomic localization is essential, Polyneuropathy
and disorders that may present with clinical signs similar to Anesthesia associated (compression, ischemia, hypoxia)
those of neuromuscular dysfunction must be ruled out, par- Drugs (cisplatin, colchicine, metronidazole, vincristine)
ticularly in the sick neonatal foal on which weakness, inabil- Endocrinopathies/metabolic
ity to rise, apparent decreased muscle tone, among others, Guttural pouch infection associated
might be a common presentation for various disorders. Full Iatrogenic (drugs, alcohol blocks, neurolytics, postsurgical)
blood work (CBC, chemistry panel, blood gases and pH), Immune-mediated/inflammatory
and urinalysis should be part of a minimum database col- Polyneuritis equi
lection. Neuromuscular disorders on which muscle enzymes Infection of adjacent tissues
may be elevated include ionophores and OP toxicity and Neoplasia (primary: peripheral nerve sheath tumor,
those associated with tick infestation. Electrolyte analysis secondary: lymphoma)
must also include ionized calcium (Ca++) and magnesium Neuroma (postsurgical)
(Mg++) because these are physiologically active ions essential Neuropathic pain
for neuromuscular homeostasis and function. Cerebrospinal Recurrent laryngeal neuropathy
fluid (CSF) cytology is usually normal in neuromuscular dis- Toxic
orders. Toxicologic screening of the diet, water, plants, soil, Arsenic
blood, stomach contents, feces, and body fluids including Lead
CSF might add useful information. Consider imaging modal- Ionophores (monensin, salynomycin, narasin)
ities such as radiographs, ultrasound, scintigraphy, com- Mercury
puted tomography, and magnetic resonance if indicated by a Organophosphates (delayed motor polyneuropathy)
problem-oriented diagnostic approach. A full body necropsy Polyneuropathy of Scandinavian horses (presumed toxic)
and thorough evaluation of the nervous system by a trained “Stringhalt” (distal axonopathy)
neuropathologist are essential. Neuroelectrodiagnostics are Idiopathic, toxic, traumatic
essential in the evaluation and diagnosis of neuromuscular
dysfunction. Examples of electrodiagnostics include elec- Presynaptic
tromyography (EMG), nerve conduction studies (NC), sin- Reduced Acetylcholine (ACh) Release
gle fiber EMG (SF-EMG), and repetitive nerve stimulation Botulism (C. botulinum toxins A, B, C, D)
(RNS—more specific for neuromuscular disorders). Drugs (e.g., aminoglycosides, tetracyclines, antiarrhythmics,
anticholinesterases)
Hypermagnesemia
Y VIRAL ENCEPHALITIS Hypocalcemia
Tick paralysis (females of Ixodes holocyclus [Australia],
Monica Aleman Dermacentor sp. [USA])
Increased ACh Release
A wide variety of viruses can affect the CNS of horses, result- Envenomations (e.g., black widow spider [Latrodectus
ing in encephalitis, meningoencephalitis, encephalomyeli- matans, alpha-latrotoxin])
tis, or myeloencephalitis. Table 11.12 depicts reported viral Hypomagnesemia
diseases that affect the CNS in equids. Viruses can spread to Hyperkalemic periodic paralysis
the CNS from distal sites through adjacent tissues, nerves Myasthenia gravis–like
or via blood. To spread from blood, viruses must cross the Myotonic disorders
blood-brain barrier, which can occur via infected leuko- Tick myotonia (Otobius megnini),
cytes or by active or passive transport through the vascular myotonia congenital/dystrophica
wall. Viruses can infect neurons and glial cells (astrocytes, Snake envenomation (rare: coral snake, rattlesnake)
microglia, oligodendrocytes). Lytic infections to neurons Myopathy
are caused by togaviruses, flaviviruses, herpesviruses, and Non-Inflammatory
others leading to encephalitis or encephalomyelitis. Lytic Multiple subcategories
infections are characterized by neuronal necrosis, neuro- Drugs (long-term steroids)
nophagia, perivascular inflammation. In contrast to noncy-
tocidal infection of neurons as in the case of rabies virus on Inflammatory
Immune-mediated
which little to no inflammation is observed. EHV-1 can pro-
Infectious
duce infection of the respiratory system; reproductive tract;
Paraneoplastic
fetus or embryo causing abortion or fetal or early neonatal
death; and the CNS. The type of nucleic acid and genomic and CNS infections caused by viruses from miscellaneous
structure are used to classify viruses into RNA or DNA viral families.506
viruses (Table 11.13). This section describes disease result-
ing from infections with members of the Togaviridae family Togaviral Encephalitis
of viruses (eastern, western, and Venezuelan encephalitis) Togaviruses are small lipid- and protein-enveloped RNA
viruses. Viruses in the family Togaviridae include the genera
TABLE 11.12 Viruses That Affect the Central Nervous System Alphavirus and Rubivirus. Rubivirus exclusively affects humans
in Equids (rubella virus). The alphavirus equine encephalitides are mos-
quito-borne infections that cause neurologic disease and death
BORNAVIRIDAE in humans and horses (Table 11.14). Togaviral encephalitis
Borna disease virusa can cause severe encephalitis and has been commonly referred
BUNYAVIRIDAE to as sleeping sickness due to the degree of obtundation that
Shuni virus affected horses develop. The incubation period is variable and
California serogroup virusesa depends on virus type but usually ranges from 5 to 14 days.
Bunyamwera virusa EEE, WEE, and Venezuelan (VEE) equine encephalitis
FLAVIVIRIDAE viruses are the most frequently isolated alphaviruses from
Mosquito-bornea epidemics of encephalitis in horses and human beings in the
Japanese encephalitis virus Western Hemisphere (see Table 11.14). The first recorded epi-
St. Louis encephalitis virus demic of EEE in North America likely occurred in Massachu-
Murray Valley encephalitis virus setts in 1831.507 The viruses have been isolated from infected
West Nile virus mosquitoes, horses, humans, birds, and rodents and are trans-
Kunjin virus mitted by hematophagous arthropods.508
Tick-bornea Epizootiology
Louping ill virus The alphaviruses EEE and WEE are specific and discrete toga-
Powassan virus viral species; North and South American antigenic variants
Tick-borne encephalitis virus of EEE exist.509 WEE is a recombinant between an EEE-like
HERPESVIRIDAE virus and a Sindbis-like virus.510 Two antigenic subtypes of
Equine herpesvirus 1 (D752 and N752) WEE virus exist: (1) WEE and (2) Highlands J viruses. The
PARAMYXOVIRIDAE Highlands J virus causes most infections that occur east of the
Nipah virusa Mississippi River. Although these alphaviruses have different
REOVIRIDAE
antigenic properties, there is extensive overlap in geographic
Equine encephalosis virus
distribution.506,511 VEE virus has six distinct subtypes desig-
Peruvian horse sickness virus
nated by Roman numerals I through VI. Subtypes IAB, IC, and
Elsey virus
IE have been responsible for large outbreaks of encephalitis in
Yunnan orbivirus
horses in the Western Hemisphere in the past 20 years. Sub-
types ID and IF have been reported in Central America and
RETROVIRIDAE Brazil, respectively; type II (Everglades) virus in Florida; and
Equine infectious anemia virus types II, IV, V, and VI viruses.512-515 Encephalitis has had a high
RHABDOVIRIDAE morbidity and mortality in the United States.516-519 Horses
Rabies virusa immunized with strains of virus isolated from infected horses
Bat lyssavirusesa from the East or West were protected when vaccinated with
TOGAVIRIDAE attenuated virus.519-522 Table 11.15 summarizes the most com-
Equine alphavirusesa mon types of alphaviruses associated with encephalitic disease
Eastern equine encephalomyelitis (EEE) virus in horses and their geographic distribution.
Western equine encephalomyelitis (WEE) virus
Venezuelan equine encephalomyelitis (VEE) virus
Distribution
Ross River virus Disease associated with EEE, WEE, and VEE is restricted to
Getah virus the Western Hemisphere and ranges from temperate to des-
ert climates. Many seropositive horses do not have recog-
aMay also affect humans. nizable clinical disease.522-549 The presence of EEE virus has
TABLE 11.13 Properties of Viral Families

Family Genome Configuration Size (kb) Envelope Morphology Virion size (nM)
Herpesviridae dsDNA 1 linear 125–240 + Isometric 150
Reoviridae dsRNA 10–12 segments 19–32 − Isometric 60–80
Rhabdoviridae NssRNA 1 − segment 11–15 + Bullet-shaped 100–430 × 45–100
Bornaviridae NssRNA 1 − segment 9 + Spherical 80–100
Bunyaviridae NssRNA 3 − or +/− segments 11–19 + Spherical 80–120
Togaviridae ssRNA 1 + segment 10–12 + Spherical 70
Flaviviridae ssRNA 1 − circular 3–4 + Spherical 40–60

TABLE 11.14 A Summary of the Major Togaviral Equine Encephalitidesa

Amplification from
Virus Major Disease Vector Zoonotic Potential Horses Disease Spread Viremia Equine Mortality
EEE Aedes spp. Unlikely Unlikely Vector Low 75%−100%
WEE Culex tarsalis Unlikely Unlikely Vector ± secretions Low 20%−50%
VEE Culex melanconium, Occurs Occurs Vector ± secretions High 40%−80%
Aedes spp.
Phosphora spp.

EEE, Eastern equine encephalitis virus; WEE, western equine encephalitis virus; VEE, Venezuelan equine encephalitis virus.
aThe statements made are generalizations, and some degree of variation occurs.
been reported from Canada to Central and South America. In TABLE 11.15 Alphavirus Types and Geographic Distributions
the United States disease has been reported primarily in the
southeastern states, some western states, and east of the Mis- Eastern Equine Encephalomyelitis Virus
sissippi River. Other parts of the world include the Philippines • Multiple lineages
and some areas in Europe.550,551 Historically large outbreaks of ○ Lineage 1, subtype I in North America
WEE have been described in horses in California and other ○ Lineage 2, subtypes II to IV in South America
western states, and uncommonly in eastern states.552 Venezu- • Horse is a dead-end host
elan equine encephalitis is a very important human and veteri- Western Equine Encephalomyelitis Virus
nary pathogen in the Western Hemisphere that can cause large • North American and South American lineages with
outbreaks of disease in human beings and horses over large multiple variants
geographic areas. Disease due to VEE virus has been reported • Primarily found in western United States
in Mexico, Venezuela, Colombia, Trinidad, French Guiana, • Highlands J variant in eastern North America
Peru, and Brazil. • Horse is a dead-end host
Venezuelan Equine Encephalomyelitis Virus
Epidemic • Genetically diverse with six primary subtypes (I–VI)
For outbreaks to occur several factors play a role such as pres- • Epidemic or “epizootic” subtypes (IAB, IC, IE) in Central
ence of reservoir animals, intermediate hosts, insect vectors, America and South America
and susceptible horse and human populations.450,553 Prediction • Endemic subtype II (Everglades) in Florida has low
of outbreaks has been attempted but without success,507,524,546 pathogenicity
which indicates that other unknown factors may exist. In the • Horse is amplifying host
environment, Togaviridae persist by asymptomatically infect-
ing wild animals (sylvatic hosts) such as birds, small mammals,

and reptiles.554 The viruses may survive during the winter or
nonvector season in sylvatic populations.524,555 milder than disease in horses for the respective viruses. Burros
and mules may contract all three diseases, and the disease is
Vectors as severe as that identified in horses.568 Experimental models
Specificity of the viruses for particular vectors occurs. The vec- of infection have included mice, hamsters, guinea pigs, and
tors for EEE include Culiseta melanura, Aedes spp., and C. mel- rhesus monkeys.507
anura.522,539,556,557 Aedes spp. appear to be more important in
epizootics and epidemics. Culex tarsalis is the primary vector Pathogenesis
that maintains WEE virus. Dermacentor andersoni ticks,558,559 Alphaviruses can replicate to very high titers and cause severe
Triatoma sanguisuga (assassin bug),560,561 and the cliff swallow cytopathic changes in many cells of vertebrates.506 In mam-
bug (Oeciacus vicarius)558,562 may also be involved as vectors malians and birds, infection causes complete shutdown of
or overwintering reservoirs for WEE. Several species of mos- host-cell protein and nucleic acid synthesis. In mosquitoes,
quitoes from at least 11 genera have been determined to be cell division can continue, with cells becoming persistently
naturally infected with epidemic strains of VEE virus, includ- infected and continuously shedding virus.506 After viruses are
ing Culex melanconium, and Mansonia, Aedes, and Psorophora inoculated, they multiply in muscle, enter the lymphatic circu-
spp.526,527,534,535 Ticks may also be capable of virus transmis- lation, and localize in lymph nodes. Viruses replicate in mac-
sion. Although less likely, EEE and VEE may spread by nasal rophages and neutrophils and subsequently are shed in small
secretions.526,527,561,563 Vectors transmit viral particles between numbers. Many of the viral particles are cleared at this time.
sylvatic hosts when taking a blood meal. Mosquitoes remain If clearance mechanisms are successful, no further clinical
infected for life.557,564 Seasonal incidence depends on peak of signs develop. Neutralizing antibodies still will be produced.
seasonal vectors. The highest number of cases occurs between Several mechanisms of viral immunologic avoidance exist and
June and November in temperate climates. If vector season include erythrocyte and leukocyte absorption. If viral elimina-
is longer such as in warmer climates, disease outbreaks last tion is not complete, the remaining viruses infect endothelial
longer.565 cells and concentrate in highly vascular organs such as the
Outbreaks of disease because of EEE have been described in liver and spleen. Viral replication in these tissues subsequently
emus, ostriches, and swine, with isolated cases in cattle, sheep, is associated with circulating virus. The second viremic period
and nondomestic ungulates.566,567 Pigs may also be affected by often is associated with early clinical signs of disease. Infection
VEE.567 The signs of disease in these species are similar but are of the CNS occurs within 3 to 5 days.514,527,569,570
Clinical Signs infections are reportable diseases to state health officials.507,579

Alphavirus clinical infection in humans is associated with EEE virus has poor ability to replicate in lymphoid tissues,
insect vector contact and usually involves old or young per- whereas VEE does so efficiently. Therefore EEE virus can
sons.507 Morbidity and mortality rates are virus specific.571 avoid IFN-α and IFN-β induction in vivo, which may allow
Clinical signs in human beings include acute fulminant EEE to evade the host’s innate immune responses and thereby
encephalitis, headache, altered consciousness, and seizures. enhance neurovirulence. Inhibition of genome translation
The mortality rate in human patients varies depending on spe- restricts EEE infectivity for myeloid but not mesenchymal
cific virus.571 Human beings and horses are terminal hosts for cells. This factor likely contributes to the observed differences
WEE. A transient viremia occurs in horses in the acute stages in disease cause and presentation.580
of disease.
EEE virus is probably the most virulent of the alphaviruses Diagnosis
with a case fatality in humans of 50% to 70%.508,571 In humans, The diagnosis of equine encephalitides can be made by
the virus causes fever, muscle pain, headache, disorientation, viral isolation or detection through virus-specific antibody
stupor, vomiting, respiratory signs, leukocytosis, hematuria, response, viral nucleic acid, and presence of viral antigen in
seizures, and coma.508,571 MRI has shown lesions in the basal tissue samples. Clinically, a presumptive diagnosis is based
ganglia and thalamus.508 Horses could be a natural amplifier on clinical findings of acute onset of altered behavior, obtun-
of EEE, and infection in equines precedes human cases by 2 dation, preceded by fever; season of the year, presence of
to 5 weeks.572,573 Thus horses are sentinels for human beings in vectors and hosts. IgM antibody-capture enzyme-linked
a given area. In animals, acute clinical signs of EEE and WEE immunosorbent assay can detect recently infected horses and
include mild fever to severe pyrexia, anorexia, and stiffness. humans.508 These antibodies are not produced in response to
Viremia occurs during this period. The incubation period vaccine.581 The antibodies disappear by 21 days after infec-
(1–3 weeks) is often shorter with EEE than WEE. Early signs tion.582 The assay for confirming acute VEE infection should
of the disease include fever and mild obtundation. With EEE, be used when one cannot collect convalescent serum sam-
progression is more common. Once nervous signs develop, ples. Detection of IgG antibodies is not predictive of recent
the viremia is past, and animals are unlikely to be able to infection and may be confused with vaccine-induced anti-
amplify the disease. Cerebrothalamic signs such as compul- bodies.506 Viral antibodies are commonly present within 24
sive walking, altered behavior, hyperesthesia, excitability, and hours after the initial viremia, and their presence often pre-
obtundation occur. Cranial nerve dysfunction can also occur, cedes clinical encephalitis.551 The concentration of antibod-
with signs such as vestibular, facial, pharyngeal, laryngeal, and ies increases rapidly and then decreases over 6 months.582
tongue dysfunction. Death often is preceded by recumbency An initial sample often is taken when encephalitic signs are
for 1 to 7 days. Comatose animals rarely survive. If animals present, which may be after titers have peaked. Therefore a
survive, slow gradual improvement is observed over weeks second sample possibly may have a decreased titer compared
to months.574-577 Clinical signs are more profound in unvac- with the initial sample. Hemagglutination-inhibition and
cinated animals.573,576 neutralization assay can also detect within a few days after
VEE virus circulates in enzootic cycles between rodent host onset of infection.578 Fourfold antibody rise in IgG antibody
and mosquito vector.578 Clinical signs with VEE vary depend- 10 days to 2 weeks apart supports infection. Complement fix-
ing on virus subtype from mild to severe to fatal. In general, ation has also been used for the diagnosis of alphaviruses.583
severe encephalitis in humans infected with VEE virus is less The virus can also be isolated from vertebrates and mosqui-
common than with EEE and WEE virus infection. Neurologic tos. Immunohistochemistry of brain tissue can be done for
disease in humans can be detected in up to 14% of cases, mainly the detection of virus. More recently, RT-PCR has been used
children, and fatality rate is about 1%.508,571 VEE viral infec- for the diagnosis.584 Viral cultures are unlikely to be fruitful,
tions in human epidemics and equine epizootics have been except in the case of acute VEE. One may isolate the virus
associated with subtypes ID and IE, which are less virulent for from CSF of horses with acute infections.527 The usefulness
horses. In contrast, subtypes IAB and IC are highly pathogenic of CSF viral titers in light of a negative viral isolation is ques-
to horses with case fatality of 20% to 80%. Epidemic strains tionable. Fluorescent antibody, ELISA, and viral isolation are
are associated with severe pyrexia and leukopenia.514,570 Neu- useful in identifying virus in brain tissue.585,586
rologic signs occur at approximately 4 days after infection Colostral antibodies may interfere with diagnosis in foals. The
and include severe obtundation and recumbency. Diarrhea antibody titers to VEE, WEE, and EEE viruses in the sera of 2- to
can occur before neurologic deficits. Other associated signs 8-day-old foals are similar to those of dams. The serum half-life
include abortion, oral ulceration, pulmonary hemorrhage, of maternal antibodies in foals is approximately 20 days.587
and epistaxis.526,527 Horses with VEE have sufficient circulat-
ing viral concentrations that act as amplifiers of disease.534,579 Clinical Pathology
Ocular and nasal secretions from infected horses contain high The CSF changes associated with togaviral infections are simi-
concentrations of VEE virus.526,527 Infection via entry through lar to those of other viral encephalitides and include most
the respiratory tract may occur by direct contact with infected commonly lymphocytic pleocytosis (50–400 mononuclear
animals. Equine and human survivors of VEE infection and cells/μL) and protein concentration (100–200 mg/dL).
clinical disease may develop chronic relapsing viremias and
serve as chronic disease amplifiers.566 Clinical signs in human Necropsy Findings
beings include fever, headache, myalgia, and pharyngitis. With any of the alphaviral equine encephalitides, sufficient
Accidental cases in humans have occurred in laboratory viral particles for infection may be present in CNS and other
conditions.508 Viral load in infected tissue could be high, tissues, and one should take precautions when performing a
therefore, precautions must be taken when performing nec- necropsy examination on suspect cases. The brain and spinal
ropsies or handling tissue from diseased animals. Alphavirus cord often have a normal gross appearance. In some cases
TABLE 11.16 Vaccination Protocol for EEE/WEE Recommended by the American Association of Equine Practitioners Guidelines 2015
Horse Group Unvaccinated or Unknown (EEE/WEE) Seasonal Exposure Year-Round Exposure
Adults 2 doses 4−6 weeks apart Annual before vector season Every 6 months
Pregnant mares 2 doses 4−6 weeks apart 4−6 weeks before foaling or
before vector season
Foals (vaccinated mare) 3 doses at 4−6 months of age with a Third dose at 10−12 months
4−6-week interval between 1st and of age or before vector season
2nd vaccination; if high risk start at
2−3 months of age
Foals (unvaccinated mare) 3 doses with a 4-week interval 4th dose at 10−12 months
of age or before vector season

vascular congestion and discoloration of the CNS is evident. Prognosis

Histologic findings include nonseptic mononuclear cell and Complete recoveries from the neurologic deficits associated
neutrophilic inflammation of the entire brain.526,588-590 Severe with these viruses are reported, but they are rare.591 Ani-
lesions are evident in the cerebral cortex, thalamus, and hypo- mals that have recovered from EEE often have residual neu-
thalamus. Specific lesions include significant perivascular rologic deficits that commonly include ataxia, obtundation,
cuffing with mononuclear and neutrophil cell infiltration, gli- and abnormal behavior. Neurologic sequelae are similar but
osis, neuronal degeneration, and mononuclear cell meningeal less common in horses that recover from WEE. For horses
inflammation. With VEE, liquefactive necrosis and hemor- that develop neurologic disease, the mortality rate for EEE
rhage of the cerebral cortex, atrophy of the pancreatic acinar is between 75% and 100%; for WEE, 20% and 50%; and for
cells, and hyperplasia of the pancreatic duct cells commonly VEE, 40% and 80%.526,551 If horses recover from any of the dis-
occur.589 Immunohistochemistry can be diagnostic on nec- eases, they seem to be protected variably for up to 2 years after
ropsy samples.591,592 infection. One would wisely assume that infection affords no
protection.
The differential diagnosis for EEE, WEE, and VEE should Prevention
include other acute conditions associated with diffuse or mul- Prevention of alphavirus encephalitis should aim at reduc-
tifocal neurologic deficits such as other viral diseases including ing the concentration of insect vectors and implement-
other togaviral encephalitides, trauma, hepatoencephalopathy, ing vaccination programs.543-545,568,593-596 EEE, WEE, VEE
rabies, WNV, and leukoencephalomalacia. Others such as bac- are included as core vaccines in endemic areas as defined
terial meningoencephalitis, EPM, and verminous encephalitis by the American Veterinary Medical Association. Cur-
should also be considered. rent commercial vaccines are formalin inactivated viruses
(Table 11.16). Significant increases in antibody titer occur
Treatment at 3 days after vaccination.526,527,595-598 One should vaccinate
There is no specific treatment for alphavirus infection. How- susceptible horse populations with monovalent, divalent, or
ever, appropriate management includes supportive therapy, trivalent vaccines containing EEE, WEE, or VEE. Adminis-
treatment of other concurrent disease, and prevention of tration of trivalent vaccines increases specific antibody pro-
complications. Supportive therapy includes meeting needs duction to all viruses. Some cross-protection exists between
of hydration, nutrition, urination, defecation, and bed- EEE and WEE and between EEE and VEE, but none exists
ding. NSAIDs (phenylbutazone, 2–4 mg/kg every 12 hours; between WEE and VEE.587,599,600 If one is to give VEE vac-
flunixin meglumine, 1 mg/kg every 12–24 hours) control cine, simultaneous administration of all three vaccines is
pyrexia, inflammation, and discomfort. DMSO given at 1 g/ recommended.601-603 The response to VEE vaccination alone
kg intravenously in a 20% solution may be useful in control- is poorer in horses previously vaccinated against WEE and
ling inflammation. The use of corticosteroids is controversial EEE.597,598,602,603 VEE vaccination does not seem to inter-
because beneficial effects are short term, and the risk of devel- fere with responses to EEE or WEE vaccination.604 One
oping secondary bacterial infections increases. One might should complete annual vaccinations in late spring or several
control seizures as described in this chapter previously. One months before the beginning of the encephalitis season. Ade-
should monitor hydration and administer balanced isotonic quate titers appear to last for 6 to 8 months. In areas in which
fluid solutions orally or intravenously as needed. Other sup- the mosquito problem is prolonged or continuous, biannual
portive care should include dietary supplementation and or triannual vaccination is suggested. Vaccination of sus-
administration of laxatives to minimize the risk of gastroin- ceptible horses in the face of an outbreak is recommended.
testinal impaction. If anorexia persists for more than 48 hours, If vaccinated horses develop disease, the affected individu-
enteral or parenteral supplementation should be used. For the als are often young or old. Vaccination of mares 1 month
short term, pelleted feeds may be put into suspension for oral before foaling enhances colostral antibody concentrations.
administration. Protection from self-induced trauma may Antibody concentrations in foals born to immunized mares
require protective limb wraps and head protection. If the horse appear by 3 hours after colostrum is fed and persist for 6 to 7
is recumbent, one should attempt to provide support in a sling, months.592 Vaccination may begin at any age, but if they are
and all animals should be bedded heavily. vaccinated early, one should revaccinate foals at 6 months
and 1 year to ensure adequate protection. Foals respond to to ascertain; however, reports exist of Japanese encephalitis
vaccination with VEE in utero.605 A prospective study to isolation from horses in Taiwan, China, Pakistan, and Austra-
determine the serologic response of previously vaccinated lia in the literature since the 1980s. Outbreaks in horses have
horses to revaccination against EEE and WEE identified that also been reported in India, Nepal, the Philippines, Sri Lanka,
horses responded variably to each antigen, and some horses and northern Thailand. Seroconversion of young horses over
had low or undetectable antibodies 6 months after vaccina- their first year of exposure in Hong Kong is as high as 63% in
tion. Some horses did not develop increasing titers to EEE some locales. The disease has a high mortality rate of 10% to
or WEE despite recent vaccination. Geometric mean titers 40%, with 40% to 70% of survivors having permanent neuro-
peaked 2 weeks after revaccination and were significantly logic deficits.621 Japanese encephalitis should be suspected in
increased from before revaccination.606,607 horses with compatible clinical signs that reside in an area of
Novel vaccines have been developed experimentally, such as virus activity. Diagnostic confirmatory tests include serologic
modified live, chimeric gene-deleted live mutants, DNA, and assays such as neutralizing, complement fixation, hemagglu-
adenovirus-vectored alphavirus vaccines.581 The results have tination inhibition, and ELISA tests.621 All single sera test-
appeared promising. The development in new vaccines has ing, including IgM assays, must be interpreted with caution
been the result of concerns involved in the production of inac- in horses from areas with other endemic flaviviruses. In fatal
tivated vaccines. These concerns mainly involve the manipula- Japanese encephalitis cases, viral isolation, PCR assays, and
tion of large quantities of viral particles under biosafety level 3 immunohistochemistry for detection of virus in CNS tissues
containment laboratories, which poses a possible risk of infec- are confirmatory.
tion for operators producing vaccines. Further, these vaccines St. Louis encephalitis virus is associated most commonly
have not been able to induce long-lasting immunity. with encephalitis in human beings and may rarely be involved
Owners should use insecticides and repellents when possible in equine disease. Experimental inoculation in horses pro-
and practical, should eliminate standing water, and in endemic duces viremia but no clinical signs. Neutralizing antibody is
areas or during an outbreak should implement environmental often present. Culex pipiens and C. tarsalis are the major vec-
insecticide application and should screen stalls. Horses with tors. Wild birds seem to be the primary reservoir.608,613
VEE can be persistently viremic and should be quarantined Experimental infection with Murray Valley virus results
for 3 weeks after complete recovery. Cases of VEE must be in transient pyrexia, myalgia, and ataxia. Horses are unlikely
reported to regulatory authorities in the United States. Public to be efficient amplifiers of this virus.610-612 In Australia, the
health officials may institute other measures of disease control. virus is more commonly a disease of human beings. An
epidemic in human beings was associated with significant
Flavivirus Encephalitis titers in horses. Some horses with clinical signs, significant
Monica Aleman titers, and histologic evidence of viral encephalitis were
identified.611,612
The family Flaviviridae comprises three genera: Flavivirus, Powassan virus has been associated with nonsuppurative,
Pestivirus, and Hepacivirus.608-620 Although these viruses have focal necrotizing meningoencephalitis in horses.609 Antibod-
similar genomic organization, they are genetically and bio- ies for Powassan virus commonly are identified in Ontario
logically different. At least half of the members of Flaviviri- and the eastern United States. Ixodes cookei, I. marxi, and
dae are zoonotic. The genus Flavivirus has at least 70 viruses. Dermacentor andersoni appear to be important vectors, with
Of importance in equine species are Japanese encephalitis, snowshoe hares and striped skunks as major reservoirs. Zoo-
St. Louis encephalitis, West Nile, Powassan, and louping ill noses occur after bites by infected ticks. Approximately 13% of
viruses. Arthropod-borne (e.g., Culex spp.) diseases include horses sampled across Ontario in 1983 were serologically pos-
Japanese encephalitis, St. Louis encephalitis, and West Nile itive for the virus.609 Experimental infection with Powassan
virus infection. Powassan and louping ill viruses are trans- virus strain M794 in horses was associated with neurologic
mitted as tick-borne (Ixodes spp.) diseases.608-614 The mos- deficits within 8 days. A nonsuppurative encephalomyelitis,
quito- and tick-borne flaviviruses are maintained in nature in neuronal necrosis, and focal parenchymal necrosis occur.
arthropod-vertebrate-arthropod cycles, whereas the nonar- Signs include tremors of the head and neck, ptyalism, myalgia,
thropod-borne viruses are transmitted directly among bats or ataxia, and recumbency. No clinical signs were identified in
rodents.608 inoculated rabbits, but widespread encephalitis characterized
Serocomplex Japanese encephalitis viruses include Japanese by lymphoid perivascular cuffing, lymphocytic meningitis,
encephalitis, St. Louis encephalitis, Murray Valley encephali- and lymphocytic choroiditis occurred.609
tis, Kunjin virus, and West Nile virus. These group of viruses The other two genera have viruses of veterinary and human
are vector borne, with transmission occurring to avian and importance, with the genus Pestivirus containing the ubiqui-
mammalian hosts from blood meal–seeking mosquitoes.621 tous bovine diarrhea virus (BVD) and Hepacivirus containing
Virus is either maintained or cycled between vectors, and bio- the human pathogen hepatitis C virus (HCV). There was no
logic amplification occurs within the vector species. Vertical known Pestivirus affecting the nervous system in horses until
transmission within vectors must occur for maintenance of recently when a Hepacivirus was implicated as causing central
virus within a geographic area.621 The distribution of Japanese nervous system disease in horses as previously mentioned in
encephalitis occurs in most countries of southeast Asia and this chapter.622
has extended to India, Pacific islands, and northern Australia.
Japanese encephalitis virus causes between 30,000 and 50,000 West Nile Virus
human encephalitis cases annually worldwide, with endemic Monica Aleman
areas including China, the southeast region of the Russian Fed- West Nile virus (WNV) is an important cause of neurologic
eration, South and Southeast Asia, and Australia. Exact num- disease in humans and horses worldwide.506,620,623 The
bers of horses with clinical Japanese encephalitis are difficult virus is neurotropic, and access to the brain is proposed to
be hematogenous and transneural through the disruption has been confirmed as WNV in gray squirrels and fox squir-
of the blood-brain barrier and retrograde axonal trans- rels. Alligators can have an extremely high titer of viremia and
port. Historically, WNV was first recognized in humans may be an important reservoir for WNV in the Southeast.
in Uganda in 1937 and the Middle East as a febrile ill- Reports exist of both farmed and free-ranging alligators with
ness. Since then, the infection has spread globally to other neurologic signs from which WNV has been isolated. In farm-
parts of Africa, the Middle East, Asia, Australia, Eastern raised alligators, cloacal shedding of virus has been demon-
Europe, and North, Central, and South America.506,623 strated with oral infection likely.
The first reports of encephalitis in humans from North The virus may also be transmitted through contaminated
America occurred in August 1999 in Queens, New York.506 blood transfusion or organ transplantation if donors are vire-
These patients developed fever, altered mental status, flac- mic. Vertical transmission through placenta and milk has
cid paralysis causing respiratory failure, and weakness. All been demonstrated in people.628-630
patients were over 50 years old, spent time outdoors, and The outbreaks are seasonal and reflect mosquito activity. In
lived close to mosquito-breeding sites. These patients were the northeastern United States, more than half of the WNV-
positive for IgM on ELISA testing on CSF. There are two positive mosquito pools are C. pipiens.506 In the West, popula-
major genetic lineages (1 and 2) of West Nile virus. Kun- tions of the highly efficient C. tarsalis constitute the majority
jin virus is a variant of lineage 1 WNV. WNV lineage in of positive pools, with C. pipiens the next most commonly
North America is 1. Before 1999 veterinarians, trainers, and found Culex spp.506,624,626 In the Southeast, C. quinquefasciatus
horse owners on the American continent had little familiar- and C. nigripalpus have the highest WNV infection rates. In
ity with flaviviruses. Since that time, several thousands of the Southwest, epidemics are most commonly associated with
equine cases have been reported to have disease, with an positive mosquito pools of C. quinquefasciatus, C. tarsalis, and
estimated 30% to 40% case fatality rate in the United States. C. pipiens.
Horses represent 96.9% of all reported nonhuman mam- A reservoir host (mostly birds) is one in which a pathogen
malian cases of WNV. is amplified in vivo so that it can be transmitted to a vector
Etiology. All flaviviridae are positive-sense single-stranded species.631 Horses and human beings are considered dead-end
RNA viruses measuring approximately 50 nm.506 The viri- (nonreservoir) hosts for WNV.631 To date, more than 300 spe-
ons are spherical and enveloped with the C protein, mak- cies of birds have been reported WNV-positive in the United
ing up a nucleocapsid of about 25 nm. Electron microscopy States. High levels of viral amplification occur in many bird
reveals an icosahedral symmetry of the envelope and capsid species.
of these viruses. An approximately 11-kb genome contains Because transmission is via vectors, transmission could be
a single open reading frame that is translated in its entirety seasonal in temperate regions and year-round in subtropical
and cleaved into 10 viral proteins by both cell and viral pro- regions. Intense virus activity in the United States begins in
teases.506 Three structural and seven nonstructural proteins July, with a peak incidence in September and October.506,620 A
exist; the structural proteins include the capsid (C), premem- drop in ambient temperature with soft frost usually results in a
brane (prM) and membrane (M), and envelop (E) proteins. rapid decrease in reporting activity.
The nonstructural (NS) proteins, numbered 1 through 5, are Older people appear more susceptible to neuroinvasive
cleaved after translation and are required for viral replication disease from WNV. Similarly, older horses appeared to be
and assembly. more susceptible.632 Although men are more frequently
The final M protein and the E protein are important for affected with neuroinvasive disease, there appears to be
virulence.506,620,623 The M protein is formed from a precursor no breed or gender predilection in horses. In one study of
protein (prM protein) that is modified as immature virions are horses with WNV encephalomyelitis, female horses were
secreted through the Golgi network of the cell. The E protein 2.9 times more likely to die than male horses with neuro-
is only secreted in its native conformation through association logic signs.633
with the prM protein. The E protein is the immunodominant Clinical Signs. Neurologic disease has been reported in
viral protein and is important in receptor ligand binding and horses naturally and experimentally infected.634-639 Most horses
fusion to host cells. seroconvert without clinical disease after infection with WNV.
Epidemiology. WNV is generally transmitted via bite from However, approximately 8% to 10% of infected naïve horses de-
infected mosquitoes. There are several species of mosquito ca- velop clinical disease with neurologic signs.623 Neurologic signs
pable of acquiring the virus after feeding in infected vertebrate usually develop 5 to 22 days post infection. The most common
amplifying hosts (most common birds), but the most impor- clinical signs are weakness (94–100%), ataxia (72%), altered
tant in the United States include Culex genus (C. pipiens, C. re- mentation (67%), fever early in disease (65%), fasciculations
stuans, C. salinarius, C. tarsalis).506,620,624-626 WNV penetrates (61%), cranial nerve deficits (44%), and recumbency (30%).
the mosquito gut and replicates in multiple tissues including Other common signs include anorexia (47%) and bruxism
nervous system and salivary glands, infecting the mosquito (20%).634,636,637
for life. The virus is transmitted from females transovarially Alterations in behavior such as hyperexcitability, appre-
to offspring, continuing its persistence in the environment. hension, aggression, and compliance occur mainly due to
Mosquitoes transmit WNV to over 300 species of birds and thalamic involvement. Interspersed during periods of hyper-
at least 30 vertebrates.627 Birds include crows, magpies, jays, excitability, some horses appear to have abnormalities of
house sparrows, finches, and grackles. Vertebrates include hu- sudden sleeplike activity resembling narcolepsy. This can
mans, horses, mules, donkeys, camelids, pigs, dogs, cats, birds, occur to the point of cataplexy, and horses may partially or
and harbor seal, among others.506,620 Seropositive free-ranging completely collapse for a short period of time. Because WNV
mammals include the big brown bat, little brown bat, eastern affects predominantly the brainstem, signs such as abnormal
chipmunk, eastern gray squirrel, eastern striped skunk, white- state of consciousness, mainly obtundation due to injury to
tailed deer, and the brown bear.506,620,627 Neurologic disease the reticular formation, is common. In some horses a change
of mentation is persistent, and a state of nonresponsiveness Diagnosis. CBC and serum biochemistry profiles are usu-
resembling coma results. Both gray and white matter can be ally within reference values. Occasionally, creatine kinase
infected. In the brain, gray matter of the midbrain and hind- might be elevated due to trauma and/or recumbency. A fre-
brain is affected, resulting in cranial nerve deficits (mainly quent finding is hyponatremia, which has also been described
VII, IX, and XII) along with altered mentation.4,639 Injury in human beings with encephalitis, potentially caused by in-
to these cranial nerves results for short periods of time in appropriate release of antidiuretic hormone.645,646 CSF analy-
weakness of the tongue, muzzle deviation, and head tilt. Dys- sis could be normal or reflect lymphocytic pleocytosis with
phagia has been reported with choke as a sequela. A cauda elevated protein. In contrast, the most numerous cells in the
equina syndrome consisting of stranguria and rectal impac- CSF of horses with EEE are neutrophils, especially during the
tion is infrequently reported. Involvement of lower motor initial stages of disease.647
neurons in the spinal cord results in weakness, gait abnor- Differential diagnosis should include alphavirus encephali-
malities, and proprioceptive deficits. tis, rabies, EPM, EHV-1, botulism, and verminous meningo-
WNV can affect sensory and motor tracts within the spinal encephalomyelitis (e.g., Halicephalobus gingivalis, Setaria spp.,
cord, and the signs could be diffuse or multifocal symmetric or Strongylus vulgaris). Noninfectious causes to consider include
asymmetric. However, motor and sensory deficits could also hypocalcemia, tremorgenic toxicities, hepatoencephalopathy,
be caused by involvement of relay tracts and centers within and leukoencephalomalacia.
the brain (thalamus and basal nuclei).635-637,639-642 These two Confirmation of WNV infection with encephalitis in
clinical signs are likely a reflection of brain and spinal cord dis- horses begins with assessment of whether or not a horse meets
ease through direct infection of the spinal cord, interruption the case definition based on clinical signs, as well as whether
of motor tracts in the hindbrain, and loss of fine motor control or not the horse resides in an area in which WNV has been
through infection of the large nuclei of the thalamus and the confirmed in the current calendar year in mosquitoes, birds,
basal nuclei. General proprioceptive ataxia, paresis, weakness, human beings, or horses.641 Serologic testing developed by the
and proprioceptive deficits result from lesions in the spinal National Veterinary Services Laboratory (NVSL) is based on
cord. Many horses might have difficulty standing primarily detection of the IgM antibody response that uniformly occurs
because of profound weakness. in acutely infected horses. The preferred test is an IgM cap-
Involuntary skin and muscle fasciculations, tremors, and ture ELISA (MAC-ELISA).648 Horses develop a very intense
hyperesthesia, extremely common in this disease, likely result IgM response on exposure to WNV that lasts approximately 6
from loss of fine motor control, which is regulated mainly by weeks. This immunologic reaction is much more reliable than
the basal nuclei.643,644 Movement disorders are detected with in human infection in which a more persistent IgM response
flavivirus infection in a long-term Parkinson-like syndrome is common. Most diagnostic laboratories use the WNV IgM
in rats and experimental infection in monkeys.644 Fine and capture ELISA (MAC) for actual confirmation of disease
coarse fasciculations of the muscles of the face and neck are (increases in IgM rarely occur after vaccination). The sensitiv-
very common. Fasciculations can be quite severe and involve ity and specificity of this test are 81% and 100%, respectively.
all four limbs and trunk, affecting normal activities such as In nonvaccinated horses, a fourfold increase in neutral-
walking, eating, and interactions with handlers and other izing antibody titers is confirmatory of a diagnosis of WNV
horses. The fasciculations are most notable at the muzzle and infection. The most common neutralizing antibody test for-
eyelids. Eyelid activity during this period is enhanced with mats are the classic plaque reduction neutralizing antibody
light, and at times it appears that horses are quite photophobic. response (PRNT) and a more recently developed microwell
Horses develop clinical signs when infected with the neu- format.648,649 Vaccination induces formation of neutralizing
rally invasive lineage type I WNV, whereas infection with antibody that likely confounds interpretation of the PRNT.
the African lineage type II viruses is universally subclinical Other methods for confirmation of a diagnosis of WNV
in nature. A mild to moderate increase in rectal tempera- include postmortem detection of WNV by PCR, culture, and
ture (38.6°C–39.4°C), anorexia, and depression are the most immunohistochemistry in tissues of the CNS. Nested PCR tar-
common initial systemic signs.634 Abdominal pain is not an geting the E protein has demonstrated sensitivity for relatively
uncommon initial presenting complaint.631,633,634,636 Gait low viral load in equine tissues.650,651 Real-time PCR method-
abnormalities, including overt lameness or dragging of a limb ology has been used to detect WNV in equine tissues.651 The
before development of an obvious neurologic syndrome, have E-protein target appears less sensitive; however, the NS5 target
also been reported. has detected WNV nucleic acids in CNS tissues, heart, and
Overall, the combination, severity, and duration of clini- intestine of clinically affected horses.
cal signs can be highly variable. After initial signs abate, about Pathologic Findings. Flaviviruses cause polioencephalo-
30% of horses experience a recrudescence in clinical signs myelitis (inflammation of the gray matter) with lesions that
within the first 7 to 10 days of apparent recovery. Irrespec- increase in number from the diencephalon through the hind-
tive of recrudescence, about 30% of affected horses progress brain and frequently increase in severity caudally through the
to complete paralysis of one or more limbs overall. Most spinal cord. The basal nuclei, thalamus, pons, and medulla
of these horses are euthanized for humane reasons or die have the highest numbers of lesions with two to several cell
spontaneously. layers of mononuclear perivascular cuffing. Neuronal dam-
Many horses will improve within 3 to 7 days of displaying age includes chromatolytic neurons and neuronophagia. In
clinical signs. If the horse demonstrates significant improve- long-standing disease, areas of neuronal dropout may exist.
ment, full recovery within 1 to 6 months can be expected in By contrast, lesions are limited in the cortex and cerebellum.
90% of patients. Residual weakness and ataxia appear to be In the spinal cord, perivascular cuffing, gliosis, and damaged
common, with long-term loss of the use of one or more limbs neurons may be seen.
infrequently described. Mild to moderate persistent fatigue on Therapy. The goals of therapy are supportive and pre-
exercise has been observed. ventive. Treatment is mainly supportive care as there are no
known antiviral medications.634,636,652-654 Survival of horses rate), progressive meningopolioencephalitis that affects
with WNV is higher compared with other viral encephalitis. horses and sheep most commonly.664 Less often the virus
Horses might start recovering between 3 to 5 days post onset affects other equids, cattle, goats, camelids, fox, dogs, cats,
of clinical signs. Most cases that have been euthanized have rabbits, rodents, birds, primates, and humans. The disease is
been the result of progressive disease resulting in recumben- recognized to date in Germany, Switzerland, Liechtenstein,
cy. Therapy of recumbent horses is generally more aggressive and Austria. Antibody-positive horses are present in the
and might include dexamethasone sodium (0.05–0.1 mg/kg Middle East, Asia, Australia, and the United States. Reser-
IV every 24 hours) and mannitol (0.25–2.0 g/kg IV every 24 voirs include rodents, rabbits, and deer. The route of trans-
hours). Controversy remains as to whether corticosteroids mission includes nasal secretions and saliva, and vectors are
enhance peripheral and CNS viral load.655-658 Detomidine hy- believed to be rodents. Virus is shed in body secretions, gain-
drochloride (0.02–0.04 mg/kg IV or IM) is effective for pro- ing entrance to a new host through exposed nerve endings in
longed tranquilization. Low doses of acepromazine (0.02 mg/ the nasal and pharyngeal mucosa.665,666
kg IV or 0.05 mg/kg IM) provide excellent relief from anxiety Borna disease is caused by a virus-induced immuno-
in both recumbent and standing horses. In addition, treat- pathologic reaction.665-667 The virus is a noncytolytic, neuro-
ment of concurrent disease is recommended. IFN-α has been tropic, single-stranded RNA virus. The glycoproteins GP43
used in humans and veterinary medicine. However, studies on and GP84 are important in pathogenesis of disease. GP84
its efficacy are limited.653,654,659-661 Plasma containing WNV- serves for attachment to cells and GP43 for the internaliza-
specific immunoglobulins for intravenous administration has tion to cells via endocytosis. The virus gets access to nasal
been used, but plasma treatment did not change outcome and mucosa and migrates to olfactory bulbs via axonal transport
severity of WNV disease. mechanisms. The virus has tropism for the limbic system,
Prevention. Experimental models of disease have shown particularly the hippocampus. Once in the central nervous
that 70% to 100% of nonvaccinated healthy horses become vi- system, the virus migrates centrifugal to the peripheral
remic upon viral challenge through mosquitoes, needle, or in- nervous system. Main histologic lesions occur in Ammon’s
trathecal injection. Epidemiologic and experimental evidence horn, olfactory bulb, caudate nuclei, thalamus, and less com-
exists regarding the effectiveness of vaccination.648,662 Several monly the cerebellar nuclei. The virus causes progressive
commercially available vaccines are licensed by the USDA as severe immune-mediated nonsuppurative meningoencepha-
an aid in prevention of viremia, encephalitis, and mortality litis. Natural infection in horses results in peracute, acute,
and reduction of viremia, encephalitis, and mortality. Avail- or subacute meningoencephalitis leading to death in 1 to 4
able vaccines are inactivated whole WNV or a nonreplicating weeks of affected animals. In endemic areas (Germany), the
live canary pox recombinant vector vaccine. An inactivated prevalence of disease is estimated to be 12%.664,665 There can
flavivirus chimera vaccine is no longer commercially available. be subclinical carriers. Specific neurologic signs are variable
Vaccination before the mosquito season is critical. Manufac- but may include slow-motion eating, chewing motions of the
turer’s labeling instructions must be followed for induction of mouth, head pressing, somnolence and stupor, hyperexcit-
immunity with initial immunization. All available vaccines are ability, fearfulness, aggressiveness, hypokinesia, abnormal
labeled for administration every 12 months after the initial se- posture, hyporeflexia, head tilt, neurogenic torticollis, and
ries; however, only the modified live chimera vaccine has pub- inability to swallow. Diagnosis is made through serology
lished 12-month efficacy data.663 More frequent vaccination in such as Western blot, ELISA, IFAT; virus isolation; IMHC;
areas with year-round mosquito seasons is recommended for and RT-PCR.
most vaccines because it is not expected that the initial vaccine
series will provide long-term protection, especially with killed Miscellaneous Viral Encephalitides
virus vaccines with which antibody levels rapidly decrease af- Other mosquito-borne encephalitides reported in Califor-
ter 4 to 6 months. Where these viruses are endemic, vaccina- nia have been caused by a group of closely related viruses
tion schedules should be maintained even when a decrease in belonging to the Orthobunyavirus genus of the Bunyaviri-
the incidence of overt disease exists. dae family.506,668 Snowshoe hare and Jamestown Canyon
Public Health Considerations. WNV is a zoonotic disease. viruses have been isolated in Canada and California.669-672
Bird reservoirs maintain the virus in an endemic life cycle, Snowshoe hare virus is the most widely occurring arbovi-
allowing for transmission by mosquitoes to human beings. rus in Canada and is maintained in an amplification cycle
Therefore control of the mosquito population is important. involving small mammals and mosquitoes primarily of the
Little risk exists of disease by direct contact with an infected Aedes genus.669,671 Seroconversion without clinical dis-
horse, except during postmortem examination with inappro- ease is widespread. One report exists of acute encephali-
priate handling of infected tissues. Blood-borne transmission tis with complete recovery in a horse that seroconverted
can occur between viremic hosts. In addition, occupational to the snowshoe hare serotype of California encephalitis
infection has occurred through necropsy of avian hosts. viruses.669 Jamestown Canyon virus has been isolated from
vesicular lesions in a horse.670,672
Bornavirus Main drain virus, a member of the Orthobunyavirus genus
Borna disease was first described in the town of Borna in of the Bunyaviridae family that is not part of the California
Saxony, Germany, in 1766 as “sad horse disease” due to encephalitis serogroup, was isolated from the brain of a horse
the obtunded appearance of diseased horses. However, the with encephalitis in Sacramento County, California.673 Signs
virus was not identified until 1926. The virus is a member included incoordination, ataxia, stiffness of the neck, head
of the Bornavirus genus of the Bornaviridae family, a group pressing, dysphagia, fever, and tachycardia. The major vec-
of enveloped viruses with a nonsegmented, negative-sense, tor is Culicoides variipennis, which transmits the virus from
single-stranded RNA genome. It is the cause of a naturally infected rabbits and rodents.673 The Cache Valley virus, a
occurring infectious, usually fatal (80%–100% mortality member of the Bunyamweravirus genus of the Bunyaviridae
family, has been isolated from a clinically normal horse; a high equids due to its zoonotic potential, it should be considered as
seroprevalence exists for this virus among horses in some geo- a differential diagnosis in horses with acute progressive neuro-
graphic areas.674 logic signs. Rabies is estimated to cause 35,000 to 70,000
Nipah virus, a member of the Henipavirus genus of the human deaths worldwide annually.506 Rabies surveillance in
Paramyxoviridae family, causes encephalitis in human 2009 showed that 49 states and Puerto Rico reported 6690
beings and pigs in Southeast Asia. It is transmitted from rabid animals and 4 human rabies.684
bats to pigs and then spreads horizontally to other pigs The most common route of transmission of the virus is via
and human beings. One anecdotal report exists of dilated saliva-contaminated wounds or bites from a wild carnivorous
meningeal vessels in a horse from which Nipah virus was or insectivorous bat carrying the virus. In Africa and Asia
isolated.675 most of the human cases result from bites from rabid dogs,
Equine encephalosis virus, a member of the Orbivirus whereas in North America they result more commonly from
genus of the Reoviridae family, is an insect-borne virus wildlife.506 The most common reservoir hosts in the United
transmitted by a variety of Culicoides spp.676 Horses, don- States are skunks, raccoons, and the red fox.683 However,
keys, and zebra in Southern Africa are frequently seroposi- domestic dogs, cats, and other horses may transmit rabies to
tive. The clinical importance of equine encephalosis virus as horses by bite wounds. An important reservoir of rabies in
a cause of neurologic disease in equids appears to be limited the Caribbean islands is the gray mongoose. Furthermore,
despite the fact that it was originally isolated from a horse rabies virus can be transmitted by droplet inhalation, orally,
with clinical neurologic disease. Clinical signs that have been or transplacentally. Droplet transmission has been reported to
attributed to equine encephalosis virus include fever, depres- have occurred in foxes, coyotes, opossums, and raccoons in
sion, edema of the lips, acute neurologic signs, enteritis, and a bat cave in Texas. In that report the virus was isolated from
abortion. the air in the cave.685 Aerosolization of the virus also caused
Other viruses, identified in areas around the world, that an outbreak of rabies in a laboratory. Transmission via aero-
have been implicated in equine encephalitis or that are associ- sol has also been reported in a few humans working in bat
ated with encephalitis in other species and for which signifi- caves.506 Transplacental transmission of the virus has occurred
cant titers have been identified in horses include the louping in naturally infected cattle and experimentally infected mice
ill,677,678 Maguari,679,680 Aura,680 Una,680 Highlands J,681 Sem- and bats.683
liki forest,682 and Getah619 viruses. Virus entry into host cells occurs by receptor-mediated
Three recently identified viruses (anellovirus, hepacivi- endocytosis via coated pits, pH-dependent fusion of the viral
rus, and parvovirus) were found through PCR in CSF from envelope with the endosomal membrane releasing the viral
horses with neurologic signs predominantly involving brain- nucleocapsid into the cytoplasm where replication occurs.506
stem and spinal cord (personal observation, Aleman).622 Rabies virus infects and replicates in myocytes at the inoc-
Cytologic analysis of CSF showed lymphocytic pleocytosis in ulation site and might remain undetectable for weeks or
these horses. months before moving centrally. The virus infects peripheral
nerves by traversing neuromuscular and neurotendinous
spindles. Progression along the nerve is thought to occur in
Y RABIES
the tissue spaces of the nerve fasciculus.685 After progressing
Monica Aleman centripetally up the peripheral nerve by axoplasmic flow, the
virus replicates in spinal and dorsal root ganglia of the corre-
The family Rhabdoviridae includes six genera of viruses sponding peripheral nerve. Once the virus reaches the CNS,
that infect a variety of species such as mammals, birds, fish, spread occurs rapidly through multiplication in neurons of
insects, and plants. The genera consist of Lyssavirus, Vesicu- the brain, spinal cord, sympathetic trunk, and glial cells.
lovirus, Ephemerovirus, Novirhabdovirus, Cytorhabdovirus, Spread of rabies virus also can occur through passive trans-
and Nucleorhabdovirus. There are other unclassified rhabdo- port within CSF or blood.683 Finally, the virus reaches tissues
viruses. Rhabdoviruses are enveloped with single-stranded outside the CNS via centrifugal movement of the virus along
RNA.506,683 The family Rhabdoviridae includes viruses of nerve axons.683
importance to animal and human disease such as rabies, The incubation period is usually between 14 and 90 days,
vesicular stomatitis, and bovine ephemeral fever viruses. but it could be longer, up to a year. The incubation period can
Rabies virus belongs to the genus Lyssavirus.506 Other related be affected by the virus strain, host species, inoculum size,
viruses such as Mokola, Lagos bat, European bat lyssaviruses and proximity of the inoculation site to the CNS.683 Reten-
1 and 2, and Australian bat lyssavirus also belong to the tion of virus in myocytes at the inoculation site may be a
genus Lyssavirus and cause rabies-like disease in animals and mechanism for variation in the incubation period. A shorter
humans. The rabies virus is a large, cylindric, bullet-shaped incubation period also might be explained by the virus
neurotropic rhabdovirus.683 Rhabdoviruses are relatively entering peripheral nerves soon after exposure and rapidly
stable in the environment. However, rabies virus is inacti- migrating centripetally to the CNS without replication in
vated by detergent-based disinfectants, iodine-containing non-neural tissue.683
solutions, radiation, strong acids, alkalis, lipid solvents, and
anionic solvents.506,683 Clinical Signs
Rabies was first recognized as a fatal disease in Egypt before No signs are pathognomonic for rabies infection in horses.
2300 bc and in ancient Greece. The virus has a worldwide dis- There is usually a prodromal phase on which signs are often
tribution except for Australia, New Zealand, Japan, Antarc- overlooked or not appearing as neurologic in origin. This
tica, and certain islands. The virus was recently eradicated also occurs in horses. Clinical signs on presentation vary and
from portions of Europe (e.g., Switzerland, France) and Scan- range from lameness to sudden death.686-689 Hyperesthesia,
dinavia.506 Although rabies is uncommonly diagnosed in ataxia, behavior change, anorexia, paralysis or paresis, and
colic have been reported as initial clinical signs.686-691 One for rabies.683 However, in 15% to 30% of confirmed rabies
rarely finds a bite wound, and the horse might or might not cases, Negri bodies are not present in histopathologic sec-
be febrile. The site of inoculation and its proximity to the tions, especially if the animal died or was euthanized early
CNS influence what clinical signs one observes.683,687,688 in the disease process.683 The most commonly used and fast-
The neurologic signs exhibited in rabies-infected horses can est diagnostic test for rabies is the direct fluorescent anti-
be classified into three forms, depending on the neuroana- body test. This technique may identify 98% of infected brain
tomic location in the CNS infected by the virus. First, in the specimens.
cerebral or furious form, one might see aggressive behavior, A recent histologic study characterized the lesions caused
photophobia, hydrophobia, hyperesthesia, self-mutilation, by rabies virus in cattle and horses.693 Inflammatory lesions in
straining, muscular tremors, convulsions, and blindness.4 horses were moderate at the thoracic, lumbar, and sacral levels,
Second, in the brainstem or dumb form, one commonly sees and marked at the lumbar enlargement level. Gitter cells were
obtundation, anorexia, head tilt, circling, excess salivation, present in large numbers in the lumbar enlargement region.
facial and pharyngeal paralysis (giving the name of “hydro- Immunohistochemistry staining intensity ranged from mod-
phobia”).4,690 Finally, in the paralytic or spinal form, one sees erate to strong in the spinal cord. Only two horses exhibited
progressing ascending paralysis, ataxia, shifting lameness lesions in the brain, which were located mainly in the obex
with hyperesthesia, self-mutilation of an extremity, flaccid and cerebellum. The study concluded that the odds of detect-
tail and anus, and urinary incontinence.4,691,692 Most affected ing lesions in horses with rabies are 3.5 times higher in spinal
animals with the paralytic form become recumbent in 3 to cord compared with brain alone.693
5 days. The neurologic signs may vary as the virus spreads The mouse inoculation test is the most accurate method for
to other portions of the CNS. Thus horses may have clini- diagnosing rabies virus infection but requires 5 to 6 days to
cal signs of two or all forms of rabies. Regardless of form complete. The mouse inoculation test involves the injection
presented, progression occurs to severe altered behavior of suspect brain or salivary gland tissue homogenates intra-
and mentation and paralysis leading to recumbence. Antiin- cerebrally in mice and observation of clinical and neurologic
flammatory therapy can delay virus progression,4 but death signs or death.683 The monoclonal antibody test has been used
usually occurs within 5 to 10 days after onset of clinical most recently for rabies diagnosis in horses. The test can dif-
signs.506,689 ferentiate specific street, fixed, or vaccinal strains of rabies
virus by their glycoprotein or nucleocapsid antigens.683 This is
Diagnosis important in postexposure vaccination of human beings and
Antemortem diagnosis of rabies is difficult, but one should animals when using the specific strain of virus.
consider the disease in horses showing rapidly progressing Rapid and accurate laboratory diagnosis of rabies is essen-
or diffuse neurologic signs. Other diseases that one should tial for timely administration of postexposure prophylaxis in
consider include other viral encephalitis such as togaviral humans and control of the disease in animals. RT-qPCR assays
encephalitis, hepatoencephalopathy, protozoal encepha- have been developed and proved to be a fast and useful diag-
lomyelitis, nigropallidal encephalomalacia, botulism, lead nostic method. One study evaluated 211 biologic samples from
poisoning, polyneuritis, meningitis, space-occupying mass, humans including saliva, skin, and brain biopsies. RT-qPCR
trauma to the brain or spinal cord, and esophageal obstruc- had a sensitivity of 91.5% for skin biopsies and 54% for saliva.
tion.685 Clinical laboratory data of body fluids are nonspe- This methodology has been implemented in a few countries as
cific. CSF might be within normal reference range or might an antemortem diagnostic aid.694
show a moderate increase in total protein concentration This method was also evaluated for the diagnosis of human
(60–200 mg/dL) and lymphocytic pleocytosis (5–200 mg/ rabies on 211 biologic samples (positive n = 76 and negative
dL).685 Fluorescent antibody testing of tactile hair follicles of n = 135) including saliva, skin, and brain biopsies. It detected
facial skin taken on biopsy or from corneal epithelium might all 41 human cases of rabies tested and confirmed the sensitiv-
help diagnose rabies antemortem. The fluorescent antibody ity and the interest of skin biopsy (91.5%) and saliva (54%)
technique detects the rabies virus antigen in these tissues. samples for intra vitam diagnosis of human rabies. Finally, this
However, a negative test does not exclude rabies as a differ- method was successfully implemented in two rabies reference
ential diagnosis.689 One can achieve definitive postmortem laboratories in enzootic countries (Cambodia and Morocco).
diagnosis by submitting half the brain in 10% formaldehyde This combined RT-qPCR method constitutes a relevant, use-
for histologic examination and the other half frozen to a ful, validated tool for the diagnosis of rabies in both humans
public health diagnostic laboratory for direct immunofluo- and animals and represents a promising tool for lyssavirus
rescent antibody tests, mouse inoculation, and monoclonal surveillance.
antibody techniques. The whole brain might be shipped Recently a pan-lyssavirus (multiplex) Taqman RT-PCR
unfrozen on ice for further rabies evaluation and testing. assay named LN34 for the detection of highly variable rabies
One should examine the rest of the carcass only with care- virus and other lyssaviruses was developed. LN34 assay uses
ful precautions against transmission of the virus, if present, a combination of degenerate primers and probes along with
by wearing gloves, caps, and masks until a negative rabies probe modifications to achieve identification of the Lyssa-
diagnosis is made. virus genus. The LN34 assay was successfully used for both
Common histopathologic changes are a mild, nonsuppura- antemortem and postmortem diagnosis of over 200 clinical
tive encephalomyelitis; perivascular cuffing by mononuclear samples.695
cells; gliosis; glial nodules; and neuronal degeneration. These
lesions occur most commonly in the hippocampus, brain- Treatment and Prevention
stem, cerebellum, and gray matter of the spinal cord. Large As for most viral encephalitis, there is no specific treatment
intracytoplasmic eosinophilic inclusions within neurons and for rabies. Aggressive supportive therapy might prolong the
ganglion cells, known as Negri bodies, are pathognomonic disease course. However, this increases the risk of exposure
to those involved with the horse’s care. Rabies should always The disease affects primarily the motor neurons in the spi-
be considered as a differential diagnosis for acute progres- nal cord ventral horn cells and brainstem and leads to char-
sive neurologic disease, and all measures to minimize expo- acteristic clinical signs, including generalized neuromuscular
sure to personnel must be taken. These measures include weakness and neurogenic muscle atrophy.697,699,703 EMND
isolation of the animal and minimal handling of the animal. closely resembles progressive spinal muscular atrophy, a
Horses that are known to have been exposed to rabies should variant of amyotrophic lateral sclerosis (ALS) or Lou Gehrig’s
have all wounds cleaned and lavaged with iodine or quater- disease.697,704 However, EMND only affects lower motor neu-
nary ammonium disinfectant (and rabies antiserum, if avail- rons, which is not the case in ALS. A chronic lack of antioxi-
able, infiltrated around the bite wound). No postexposure dants is implicated in the pathogenesis of EMND, but
protocol exists for unvaccinated or vaccinated horses. How- experimental and clinical studies also suggest that there is an
ever, exposed horses should be quarantined for 6 months and individual predisposition to this neurodegenerative
observed for the occurrence of neurologic signs. Unvaccinated disease.705
horses should not receive postexposure prophylaxis until after
the 6 months of quarantine. Clinical Signs
Currently, there are three inactivated (tissue culture– EMND occurs in adult horses 2 years and older with a mean
derived products with an adjuvant) vaccines licensed for rabies age of onset of clinical signs of 9 years.704 The risk for EMND
to be administered intramuscularly. The American Associa- increases with age, peaking at around 15 years.706 No gender
tion of Equine Practitioners recommends that all horses in the predilection is apparent, and although initial studies showed
United States be vaccinated against rabies. Foals from vacci- the Quarter Horse to be at increased risk for disease, this likely
nated mares should be vaccinated no earlier than 6 months of was a reflection of management factors.706
age. The second dose of vaccine should be given 4 to 6 weeks Clinical signs reflect motor denervation of skeletal muscles.
after the first. A third dose should be given at 10 to 12 months Muscle wasting despite a normal or ravenous appetite, trem-
of age. The first dose of vaccine should be given to foals from bling or muscle fasciculations, and excessive recumbency are
unvaccinated mares at 3 to 4 months of age. A second dose the predominant signs of EMND, and each of these was shown
should be given at 10 to 12 months of age. Adult horses should to be present in greater than 90% of 77 cases.705 Muscle wasting
receive annual revaccination. Pregnant mares might be vac- is most noticeable in the quadriceps, triceps, and gluteal areas.
cinated annually before breeding or 4 to 6 weeks before foal- Onset of muscle wasting usually occurs before the other clini-
ing. Testing for rabies antibodies using the rapid fluorescence cal signs do, but sometimes signs of muscle weakness are seen
focus inhibition test (RFFIT) is available through the Kansas in normally muscled horses. Generally onset is acute, and, in
State Veterinary Diagnostic Laboratory. addition to the aforementioned signs, gait abnormalities such
Recently a study investigating the serologic response to vac- as short-stridedness and weight shifting in the pelvic limbs
cination in 48 horses with undocumented vaccination history are frequently seen. Ataxia is not a clinical sign of EMND. A
was conducted.696 These horses were vaccinated and blood horse with EMND is said to move better than it stands. Other
collected before, 3 to 7 weeks, and at 6-month intervals for 2 abnormalities that are seen in horses with EMND include a
to 3 years post vaccination. Serum rabies virus–neutralizing base-narrow stance and abnormal sweating. Also, in more than
antibody (RVNA) values were measured. A protective RVNA 50% of cases, horses may display a lower than normal head car-
value (≥0.5 U/mL) as defined by the World Health Organi- riage with muscle wasting of the cervical musculature (hangdog
zation for humans was maintained for 2 to 3 years in horses appearance) and an elevated tail head carriage (Fig. 11.40).697,699
inferred to have been previously vaccinated on the basis of Elevated tail head carriage is likely secondary to denervation
prevaccination RVNA values. The authors found significant atrophy and fibrotic contracture of the sacrococcygeus dor-
differences between horses inferred to have been previously salis medialis muscle. Occasionally horses are presented for
vaccinated and horses inferred to be naïve before the study. poor performance or development of noncharacteristic gait
Based on these results, the conclusion was that a rabies vac-
cination interval greater than 1 year may be appropriate for
previously vaccinated horses but not for horses vaccinated
only once.696
Y EQUINE MOTOR NEURON DISEASE

Equine motor neuron disease (EMND) is an acquired neu-

rodegenerative disease of adult horses that has been reported
in North and South America, Japan, and Europe.697-700 Lower
motor neuron disease was first recognized in 1988 based on
histologic changes in skeletal muscle,701 and EMND was first
described in 1990.697 In the 1990s, EMND was recognized
worldwide in an apparently increasing frequency that was esti-
mated to have peaked in 1997.3 A study conducted between
1997 and 2007 suggested incidence was still decreasing,702 and
currently the disease is seen only sporadically. The decrease FIG. 11.40 Characteristic appearance of a horse with equine motor
may be the result of preventive management measures taken neuron disease (EMND), including muscle wasting, sweating, base-narrow
for horses at risk of developing the disease. stance, low head carriage (hangdog appearance), and tailhead elevation.
abnormalities (stringhalt-like movement). Despite the frequent concentrations,715 and in five horses that were on pasture
occurrence of cranial nerve nuclei pathology clinical signs of at the onset of the disease.716 The latter studies suggest that,
cranial nerve dysfunction are very uncommon; in 2013 a case besides inadequate intake of vitamin E, abnormal bioavail-
of acute-onset EMND was discussed that had marked reduction ability or excessive utilization of vitamin E may play a role
of tongue tone.707 In nearly 40% of EMND cases ocular fundu- in the pathogenesis of EMND. Evidence of chronic oxida-
scopic examination reveals a yellow-brown-black pigment that tive stress in horses with EMND includes the pronounced
has a reticulated appearance and is located in a horizontal band type I muscle fiber atrophy and the lipopigment deposition
above the optic disc at the tapetal-nontapetel junction.705,708 in the capillaries of the spinal cord and the epithelium of the
Loss of vision has not been reported. retina. In addition, there is overwhelming epidemiologic and
experimental evidence that a diet low in vitamin E is a strong
Pathologic Findings risk factor for EMND.705,713,717
Gross necropsy findings in EMND include diffuse muscle Although EMND is the only naturally occurring model for
atrophy and pallor (especially of the intermediate vastus and ALS and oxidative injury is implicated in the cause of both dis-
medial head of the triceps muscles). Despite the obvious eases, some important differences exist between the two.703 In
weight loss seen in horses with EMND, fat deposits are usually contrast to EMND, in which the disease process is limited to
within normal limits.697,703 The CNS and peripheral nerves are the lower motor neurons, ALS affects upper and lower motor
grossly normal. neurons. Only mild degeneration of the pyramidal tracts is
Histologically, one may detect noninflammatory neuronal present in horses with EMND, but the pyramidal tracts in
degeneration and neuronal loss at all levels of the spinal cord, horses are less extensive and poorly developed compared with
but such loss is most obvious in the cervical and lumbar intu- human beings. Why both these diseases affect motor neurons
mescence. In addition, degenerative axonal changes can be so selectively is unclear. Motor neurons are particularly sus-
found in the ventral roots and peripheral nerves. Degenera- ceptible to oxidative injury by having high energy require-
tive lesions and neuronal loss are found in the ventral horn ments associated with the maintenance of long axons. The
cells (lower motor neurons) of the spinal cord gray matter; the high concentration of polyunsaturated fatty acids in neuronal
nucleus ambiguous, and all brainstem cranial nerve somatic cell membranes make these cells particularly susceptible to
motor nuclei, except III, IV, and VI. Most affected neurons are lipid peroxidation.718 About 10% of human ALS cases are con-
swollen, markedly chromatolytic, and diffusely argyrophilic, sidered familial, of which about 20% are associated with muta-
and severely affected neurons are shrunken or vacuolated. In tions in the Cu/Zn superoxide dismutase gene. Mutations of
chronic cases there are glial scars consisting of astrocytes and this gene were not found in horses with EMND.711 Pathologic
lipofuscin-laden microglia. In the retinal epithelium, liver, and protein aggregates that are found in neural tissues of humans
intestine additional deposits of ceroid-lipofuscin can be found. with ALS or other neurodegenerative diseases may reflect a
Skeletal muscle changes include nonspecific myopathic common pathway for a variety of destructive processes, includ-
changes such as excessive fiber size variation, internal nuclei, ing oxidative injury. In 2012, one of those proteins, transactive
and cytoarchitectural alterations. Scattered fiber degenera- response DNA binding protein of 43 kDa, was shown to be
tion and necrosis are consistent findings in EMND. Atrophy present in neural tissues of EMND-affected horses but not in
of type I and type II muscle fibers occurs in severely affected those of control horses.719 In addition to gene mutations, other
muscles in EMND and is pathognomonic of denervation atro- causal factors for ALS include excess iron and copper intake
phy.697,703 EMND predominantly affects type I fibers, in con- and exposure to lead, solvents, and chemicals. For some of
trast to denervating diseases in other species, and has not been these there is evidence these may play a role in the patho-
reported in ALS. Motor neurons supplying the type I fibers genesis of EMND as well. For example, a case report and an
have a higher oxidative activity and thus may be more suscep- experimental feeding trial have shown that excessive copper
tible to oxidative injury. Similar to ALS, in which at least 30% and iron may increase the risk of development of EMND.715,717
of motor axons must be destroyed before clinical evidence Moreover, elevated copper concentrations were found in the
of atrophy occurs, in horses with muscle wasting caused by spinal cords of EMND-affected horses compared with con-
EMND, a mean motor neuron loss of 31% was recorded.709 trols.720 Further, similarities in the clinicopathologic features
There have been some reports of horses with EMND having of EMND and lead toxicosis suggest a trace element toxicosis
small intestinal lesions including evidence of lymphocytic or is possible.721 Another recent hypothesis involved a neurotoxin
eosinophilic-lymphocytic infiltration, edema, and catarrhal called β-N-methylamino-l-alanine, which can be found in the
enteritis.699,710 brains of human patients with ALS or other neurodegenerative
conditions such as Alzheimer disease and Parkinson dementia
Pathogenesis complex. This toxin is produced by cyanobacteria that can be
The clinical signs of neuromuscular weakness result from the present in the intestinal tract of humans and horses. Altered
generalized denervation muscle atrophy found in horses with intestinal conditions may lead to overgrowth of cyanobacteria
EMND. Oxidative stress is believed to be the underlying mech- and resultant toxin production.722
anism for development of EMND, either through a deficiency A temporal vitamin E deficiency is also implicated in the
in antioxidant elements, such as vitamin E, and/or an excess of pathophysiology of NAD/EDM. NAD/EDM develops in
prooxidant elements such as copper and iron.706,711-714 However, genetically susceptible animals if vitamin E deficiency occurs
besides oxidative stress it appears there must be other factors during the first year of life,279,723 whereas EMND occurs
involved in the pathogenesis of this disease. in adult horses after an extended period of vitamin E defi-
A chronic vitamin E deficiency is thought to be the ciency.713 Clinical signs and histopathologic findings are very
most important contributor to the state of oxidative stress different in these two diseases, and they are therefore consid-
in horses with EMND, although recently it has been shown ered distinct entities. However, recently evidence was pro-
that EMND occurred in a horse with high tissue iron vided for the concurrent presence of NAD/EDM and EMND
in three young horses.292 Although the authors did not find Examination of a biopsy of the ventral branch of the spinal
evidence of mutations in the superoxide dismutase gene, they accessory nerve may be more sensitive in chronic cases. Nerve
did suggest that there could be overlap in genetic susceptibility biopsies must be placed on a tongue depressor and in 10% for-
to developing both NAD/EDM and EMND in certain families malin or another fixative suitable for electron microscopy. An
when a nutritional vitamin E deficiency is present. experienced neuropathologist should examine nerve biopsies
carefully; wallerian degeneration, Schwann cell proliferation,
Diagnosis and sometimes only evidence of smaller Bungner’s bands
Clinical signs and a history of other EMND cases in the stable (columns of proliferated Schwann cells) can be detected.703,729
and absence of pasture or green hay may lead to a tentative This nerve biopsy technique is described postmortem and
diagnosis of EMND. One must be aware of the fact that a recent in horses under general anesthesia, but it is also possible in
European study showed EMND to occur in horses that did standing sedated horses.730
have access to pasture.716 Ophthalmoscopic examination may A definitive diagnosis is based on postmortem examination
reveal fundic lesions in approximately 30% of cases. Serum of spinal cord, brainstem, nucleus ambiguus, and skeletal mus-
enzyme activities of AST and CK are generally mildly to mod- cle. The most important differential diagnoses that one should
erately increased. The plasma vitamin E concentration is con- consider are laminitis, rhabdomyolysis, and colic. Other dis-
sistently low (less than 1 μg/mL); however, a 2006 case report eases that may cause similar signs are botulism, EPM, poly-
described a horse with EMND that had normal serum vitamin saccharide storage myopathy, iliac thrombosis, equine grass
E concentrations and was hypothesized to have developed the sickness, and lead toxicosis.502,721
disease secondary to high tissue iron concentrations.715 CSF
analysis has been performed in horses with EMND and dem- Treatment, Prognosis, and Prevention
onstrated elevated IgG concentrations in approximately 50% The only recommended treatment is based on the idea that
of cases. Intrathecal production of IgG also occurs in ALS; this disorder is caused by oxidative injury and on the fact
however, in both diseases this is considered a secondary effect that horses with EMND consistently have low plasma vita-
of the disease process rather than a cause. The AQ was normal min E concentrations. Supplementation with vitamin E
in most horses examined, indicative of normal blood-brain (5000–7000 IU/horse/day) results in an increase of plasma
barrier function.699 EMG of cervical, facial, triceps, rear limb, vitamin E concentrations to 2.0 μg/mL or greater after 4 to 6
and tailhead muscles may be useful in acute cases. However, weeks.502 Treatment with vitamin E has been associated with
the electromyographic changes, which include positive sharp improvement of clinical signs in about 40% of cases within
waves and fibrillation potentials, may be difficult to evaluate 6 weeks of treatment, of which many horses can make a near
because they are expected in any peripheral nerve disease, full recovery in 3 months502; however, no published studies
myopathy, or myositis.697,724 In approximately 50% of horses examining the effect of treatment exist at this time. Response
with EMND, the plasma glucose curve is decreased after oral to treatment is thought to depend on the number of neu-
glucose tolerance testing, whereas results of xylose absorption rons that are damaged versus those that are dead; in the case
tests are normal or only slightly abnormal.699,725 Research sug- of neuronal death, full recovery is unlikely because this is
gests that increased glucose metabolism, rather than reduced irreversible.
intestinal absorption, is the cause of abnormal glucose toler- The prognosis is poor for return to performance and
ance in horses with EMND.726 The clinical significance of this guarded for life. Although no published investigations exist
finding is unknown. regarding the survival rate and follow-up of horses with
An antemortem diagnosis of EMND can be reached through EMND, horses with EMND generally have been shown to fol-
examination of muscle and/or nerve biopsies. A biopsy of the low one of three possible clinical courses.502 Approximately
sacrocaudalis dorsalis muscle is easy to obtain in a standing 20% of horses continue to deteriorate, and the severe weak-
horse, and histopathologic examination of this muscle reveals ness and excessive recumbency necessitate humane eutha-
changes consistent with denervation muscle atrophy and scat- nasia. In approximately 40% of horses, clinical signs appear
tered muscle necrosis.703 This test has a sensitivity of approxi- to stabilize; however, these horses do not regain muscle mass
mately 90%, and it has recently been hypothesized that horses and may develop severe gait abnormalities. Continued clini-
with a syndrome of vitamin E–responsive muscle atrophy and cal abnormalities frequently lead to euthanasia within 1 year
weakness may account for the less than 10% of false negatives. of onset of clinical signs. The third group of horses (approxi-
This is because vitamin E–related pathology is only detectable mately 40%) show dramatic improvement after treatment with
using mitochondrial stainings in fresh frozen sections, and not vitamin E, and many may regain a normal muscle mass. These
in formalin-fixed tissue, whereas evidence of denervation can horses may remain stabilized, that is, appear normal, for 1 to 6
be seen in formalin-fixed tissue. Horses with this syndrome years or more; however, many relapse, resulting in euthanasia.
have clinical signs of EMND but do not have evidence of lower This relapse appears associated with return to exercise, train-
motor neuron involvement in biopsies.727 Advanced quanti- ing, and competition. The group of horses that recover and
tative analytical techniques have shown that muscle biopsy appear normal may be affected by a more recently discovered
samples from EMND-affected horses have a lower percent- syndrome of vitamin E–responsive muscle atrophy and weak-
age of type I fibers and higher percentages of type II fibers, ness that may be a separate disease entity or a predecessor to
reduced oxidative capacity, increased glycolytic capacity, development of EMND.727 Horses affected by this syndrome
diminished intramuscular glycogen, lower capillary-to-fiber have clinical signs of EMND but they lack evidence of neuro-
ratio, a higher ratio of myofibers expressing sarcoendoplasmic genic atrophy in the sacrocaudalis dorsalis medialis muscle. It
Ca2+-ATPase 1a to the 2a isoform, and a lower percentage of is suggested that such undiagnosed cases may be the result of
fibers expressing phospholamban. The extent of the changes a specific myogenic presentation of vitamin E deficiency that
observed in this study appeared to be related to the duration can only be identified in mitochondrial stains of frozen sacro-
of the disease.728 caudalis dorsalis medialis muscle.727
In healthy young and middle-aged horses receiving ade- filamentous chains. Organisms are highly motile by means of
quate dietary vitamin E intake, there is no research-based flagellae uniformly distributed over the entire bacterial sur-
evidence for the need for additional vitamin E supplementa- face, allowing them to swarm over a culture plate. Optimal
tion above 500 IU/day.305 The goal of vitamin E supplemen- growth occurs at 37°C. Colonies have irregular margins and
tation in horses at risk of developing EMND (horses at risk are flat, translucent, and gray with a matte surface on blood
for oxidative stress) is to increase α-tocopherol concentrations agar. Colonies are 4 to 6 mm in diameter with a narrow zone
in the CNS. A dose of 10,000 IU RRR-α-tocopherol/500-kg of clear (β-type) hemolysis.
horse/day was shown to do this303; however, it is important
to consider that this dose equals the NRC upper limit safety Toxins
recommendation.305 Periodic monitoring of blood antioxidant Under anaerobic conditions, C. tetani spores germinate and
status is recommended in horses that are at risk for developing produce three exotoxins: tetanolysin, tetanospasmin, and
EMND.713,731 nonspasmogenic toxin. Tetanospasmin is the most powerful
and most important clinically.
Y TETANUS Tetanospasmin
Tetanospasmin is produced in the bacterial cell as a single
Yvette S. Nout-Lomas polypeptide chain of 1315 amino acids733 with a molecular
mass of approximately 150 kd.735 The amino acid sequence
Tetanus is an infectious disease of all domestic animals and of tetanus toxin shares marked similarities to the amino acid
human beings. Tetanus has been recognized since ancient sequences of botulinum toxins A, B, and E, suggesting that,
times, including mention in the writings of Hippocrates. Tet- although neurotoxins from C. tetani and C. botulinum have
anus (from the Greek tetanos, to contract) was first identified different clinical effects, they are derived from a common
as a neurologic disease more than 20 centuries ago by Greek ancestral gene.733 After release from the cell, the molecule
physicians. A causative infectious agent was first hypothe- is cleaved into two polypeptide fragments by proteases pro-
sized in the 1860s. In 1884 Nicolaire produced tetanus with duced by the organism—a heavy chain of about 100 kd and
injections of garden soil into mice and transfer of tetanus a light chain of about 50 kd that remain joined by a disulfide
by injection of infected material from a human wound into bond.736 Toxin spreads from the infected site by diffusing into
a rabbit was demonstrated. Reinforcing the transmissible the adjacent tissues and is subsequently transported by the
nature of an infectious agent, smears of wounds from infected lymphatic system, allowing entrance to the bloodstream.732
patients showed a bacillus-like organism under microscopy. Toxin also travels up (centripetal transport) peripheral nerve
Pure culture of the toxigenic organism was obtained by endings, sensory and autonomic fibers, into the central ner-
Kitasato in 1889, and it was subsequently shown that animals vous system through retrograde axonal transport.732 Tetano-
immunized with modified tetanus toxin generated neutral- spasmin localizes in the ventral horn of the gray matter of
izing serum antibodies.732 Passive immunization of horses the spinal cord and binds to inhibitory interneurons, called
against tetanus using horse serum antitoxin was practiced by Renshaw cells. There are three steps that result in action of
Nocard as early as 1892. In 1986 the amino acid sequence of this toxin: (1) binding to the neuronal cell membrane; (2)
tetanus toxin was revealed,733 with the mechanism of action internalization by endocytosis; and (3) the intracellular
elucidated in 1992.734 blockade of neurotransmitter release.737 Binding of the toxin
Although equine tetanus is an increasingly rare disease, to receptors on the nerve endings is the initial step in the
tetanus occurs worldwide and is considered enzootic in many paralytic process. Membrane receptors for these toxins con-
warmer countries in the developing world where vaccination sist of membrane gangliosides GT and GD1b and a receptor
programs for both man and equids are not established. Teta- protein. This binding is almost irreversible and thus accounts
nus is a distressing and often-fatal disease caused by 3 protein for the prolonged nature of the signs. Once toxin is bound,
exotoxins liberated by the bacterium Clostridium tetani of the it is internalized by endocytosis. The light chain, where it
family Bacillaceae. Equids are particularly susceptible to the displays its zinc-endopeptidase activity specific for protein
tetanus exotoxin. components of the neuroexocytosis apparatus, is translo-
cated into the cytosol where it can exert its effect.738,739 This
Biology of Clostridium Tetani process of internalization makes toxin unavailable to be
C. tetani is a large gram-positive bacillus and is an obligate bound and neutralized by circulating antibodies. Finally,
anaerobic spore former. It is part of the normal flora of the tetanospasmin blocks the postsynaptic inhibitory signal of
intestinal tract of humans and animals and can be readily iso- the spinal cord motor neurons by preventing release of the
lated from the intestinal tract and feces of a wide range of ani- inhibitory neurotransmitters glycine and GABA. This disin-
mals, with fecal surveys in North America, Brazil, and Canada hibition leads to continued stimulation of motor and reflex
revealing between 30% and 42% positive samples.732 C. tetani is arcs, which results in the characteristic muscular spasms
found ubiquitously and in adverse environmental conditions, and contractions, hyperesthesia, and eventually convulsions,
C. tetani produces round terminal spores able to survive in the respiratory arrest, and death seen in patients with tetanus.
environment for a prolonged period (years) in the absence of The specific target of tetanus toxin is synaptobrevin, also
direct sunlight. Spores are highly resistant to environmental known as vesicle-associated membrane protein (VAMP).740
changes, acid, alkali, boiling water, and many standard disin- This is one of three proteins that comprise the soluble N-
fection techniques. The vegetative form is susceptible to heat ethylmaleimide-sensitive factor attachment receptor (SNARE),
and numerous disinfectants. C. tetani spores are terminal and an integral membrane protein of the synaptic vesicles of nerve
oval, giving the bacillus a characteristic drumstick or tennis cell terminals crucial for normal vesicle physiology.737,741
racket appearance.732 The organisms may occur singly or in SNAREs are essential for a variety of vesicle docking and
fusion events,739 and mutant studies have shown that any Clinical Signs and Course of Disease
alteration in synaptobrevin leads to disturbed vesicle func- Tetanus is manifest as hypertonia of the striated muscles, with
tion.741 Two copies of a nine-residue motif situated in tandem, clonic paroxysmal muscular spasms superimposed. Muscular
each with three negatively charged residues, appear to be activity may be increased to the point that rectal temperature
responsible for toxin specificity.741 Cleavage of synaptobrevin becomes markedly elevated. Clinical signs may be generalized
by proteolytic action of the zinc-dependent endopeptidase of or localized. Localized tetanus involves muscular rigidity and
tetanospasmin light chain is the mechanism of toxicity, inca- spasms in the vicinity of the infected wound. With time, this
pacitating cellular exocytotic machinery and blocking neu- usually progresses to a more generalized tetanus affecting the
rotransmitter release.742 Both binding and internalization are entire body; however, the initial manifestation of tetanus is
mediated only by the heavy chain of the toxin, whereas the most often generalized rather than localized.732 With general-
intracellular blockade of neurotransmitter release involves the ized tetanus, a characteristic “sawhorse” stance, with an
light chain alone.737 extended, rigid tail, may be present, and the gait is stiff if the
Tetanospasmin is poorly absorbed across mucous mem- horse remains ambulatory (Fig. 11.41). Difficulty in standing
branes, is destroyed by gastric juices, and is unable to cross the or lying down is due to extensor muscle rigidity that is exacer-
placenta as result of its high molecular weight. bated by external stimuli. As a result of hyperesthesia, painful
Tetanolysin and Nonspasmogenic Toxin reflex muscle spasms progressing to generalized tonic contrac-
tions with opisthotonus may be the result of even mild stimu-
The effect of tetanospasmin is amplified by tetanolysin and lation. Progression of the disease makes voluntary movement
nonspasmogenic toxin. Tetanolysin facilitates the spread of impossible because of marked extensor rigidity of all four
infection by increasing the amount of local tissue necrosis. limbs, often leading to recumbency.
The mechanism of action is to cause permeability changes in Tetanospasmin affects both the sympathetic and para-
liposomes and biologic membranes resulting in cell lysis.743 sympathetic nervous systems. Sympathetic hyperactivity
Tetanolysin is an oxygen-sensitive hemolysin similar to strep-
tolysin and can affect a variety of cells including erythrocytes,
neutrophils, macrophages, fibroblasts, and platelets. Teta-
nolysin has an affinity for cholesterol and related sterols that
inhibit its lytic and lethal actions. The amount of tetanolysin
produced by the organism in vivo is unknown.732 The role of
nonspasmogenic toxin in the pathogenesis of tetanus is not
fully known but may involve blocking transmission in periph-
eral neuromuscular junctions.
Risk Factors for Disease
A 2007 report on tetanus in equids in a group of clinics in
Morocco showed that tetanus cases represented 0.07% of the
total patient load and 2% of all hospitalized patients.744
Animal species vary in their susceptibility to tetanus
toxin. The horse is the most susceptible animal, and the cow
is among the least. Neither age nor sex influences suscep-
tibility. Incidence of disease depends on susceptibility and
opportunity for exposure to the organism. Entry of organ-
isms into the animal is usually by inoculation into a con-
taminated deep-penetrating wound. From two retrospective
studies it appears that tetanus in equids is mostly associated
with wounds to the distal limbs and hooves, which were
found in 32 out of a combined 74 cases.744,745 Other sites
of wounds that were found in these studies were the head,
proximal limbs, tail, hobble wounds, fistulous withers, rec-
tal prolapse, and castration wounds. Other potential sites of
entry include lacerations, surgical sites, the umbilicus of the
neonatal foal, and the postfoaling reproductive tract. What
may complicate or delay the diagnosis of tetanus is that the
wound that served as the initial site of introduction of C.
tetani may involve unbroken skin or be healed by the time
clinical signs are observed. In fact, one study showed this had
occurred in 2 out of 18 cases,745 and another series showed
that 18 out of 56 equids with tetanus had no visible wound
at presentation.744 Devitalized tissue is essential for develop-
ment of tetanus. Once traumatized or devitalized tissue has
become contaminated with spores, the spores can remain
dormant until necrosis of the tissue provides the strict anaer-
obic environment necessary for germination to the vegeta- FIG. 11.41 The extended, rigid tail seen in this horse is characteristic
tive, toxin-producing form. of generalized tetanus.
associated with adrenergic stimulation may lead to tachycar- dysuria because of a hypertonic urethral sphincter, and con-
dia, cardiac arrhythmias, and peripheral vasoconstriction. stipation with gaseous distention because of a hypertonic anal
Parasympathetic hyperactivity increases vagal tone that may sphincter and lack of exercise. Death may result from respira-
result in bradyarrhythmias, atrioventricular block, and sinus tory failure secondary to the spasm of respiratory muscles or
arrest. Furthermore, tetanospasmin can act upon cranial central respiratory arrest from medullary intoxication. Aspira-
motor nuclei, resulting in spasms of cranial muscles. Trismus tion pneumonia secondary to dysphagia or increased airway
is due to contraction of the masticatory muscles, with sus- secretions may also be fatal. No characteristic necropsy lesions
tained facial muscle contracture and lip retraction resulting in can be ascribed to the tetanus toxins themselves.
risus sardonicus (a sardonic grin). Dorsomedial retraction of The prognosis for survival from this disease is reported to
the ears and excessive wrinkling of the skin of the forehead can depend on several factors, including the immune and vaccina-
be seen. Prolapse of the nictitating membrane and enophthal- tion status of the host, the dose of clostridial organism inocu-
mos is due to retraction of the globe by the hypertonic extra- lated, and the availability and duration of aggressive treatment
ocular muscles (Fig. 11.42). Miosis, dysphagia, ptyalism, and and supportive care.745 From the three reports available on
laryngeal spasm may also occur. survival of equine tetanus, the oldest describes a case fatal-
A series of 20 cases showed that hyperesthesia (17 of 20, ity rate of 75%, with previous vaccination strongly associated
85%) and prolapse of the third eyelid (17 of 20, 85%) were the with survival.745 Two other reports describe a mortality rate
most consistently observed clinical signs. A stiff gait, fever, of 68%746 and 59%.744 Severity of clinical signs is clearly asso-
tachycardia, tachypnea, erect ears and tail, elevated head, tris- ciated with survival across these three studies.744-746 In par-
mus, extensor spasms, sweating, and convulsions were seen in ticular, the presence of dyspnea, dysphagia, and recumbency
50% (10 of 20) of the horses.745 In an attempt to correlate clini- were significantly more common in nonsurvivors than survi-
cal signs to survival a disease severity scoring system has been vors and can be considered indicators of a poor prognosis.746
proposed using a clinical score from 1 indicating mild disease When using the clinical scoring system (see Table 11.17), ani-
to 4 indicating terminal disease (Table 11.17).744 mals categorized as grade 1 or 2 had a survival rate of over
Complications from tetanus include decubital ulcers after 60%, whereas this was less than 10% for animals categorized
periods of recumbency, regurgitation because of dysphagia, in grade 3.744 One report showed that younger horses were
significantly less likely to survive than older horses746; how-
ever, this was not the case in the other study that looked at
this.744 A study involving 56 cases showed that factors such as
sex, age, and chronicity at presentation had little relationship
with prognosis.744 Heart rate at presentation had little value as
a prognostic indicator, except where elevated above 80 beats/
min. Furthermore, survival was not different among donkeys,
horses, and mules.
Diagnosis
There is no definitive antemortem test for tetanus. There are
also no postmortem findings pathognomonic for the disease.
Finding microscopic evidence of the bacteria or its toxin at the
site of a wound is an unreliable diagnostic indicator. A bio-
logic assay for antemortem diagnosis is possible in some cases
by injecting infected material into the tail base of mice and
observing for onset of clinical signs. A presumptive diagnosis
of tetanus is based on history, clinical signs, and response to
treatment. Confirmation is difficult. On physical examination,
FIG. 11.42 This horse exhibits enophthalmus, prolapsed nictitans, and a recent or healed wound may be found; however, absence
rigidity of facial muscles, typical of generalized tetanus. of a detectable wound at the time of clinical onset is not
TABLE 11.17 Clinical Scoring System for Equids with Tetanus, According to Kay and Knottenbelt
Clinical Score Disease Severity Clinical Signs
1 Mild Nictitans membrane flashing, ears pulled caudally, slightly stiff gait but still
walking and eating without difficulty
2 Moderate Nictitans membrane flashing, ears pulled caudally, limbs stiff and walking
with difficulty, trismus and generalized muscle spasm, animal still capable
of eating and drinking voluntarily albeit slowly
3 Severe Capable of standing but incapable of walking, severe trismus, difficulty
with prehension, mastication and swallowing of food, and drinking voluntarily
4 Terminal Animal recumbent, incapable of standing, incapable of eating; animals presenting
in this situation are considered candidates for immediate euthanasia

From Kay G, Knottenbelt DC. Tetanus in equids: a report of 56 cases. Equine Vet Educ. 2007;19:107-112.
uncommon. Devitalization of deep tissue undetectable exter- in the blood and present in the wound. Injection of TAT, both
nally may be the site of toxin production. around and proximal to the wound site, has been suggested to
Gram staining of samples from the wound is of limited be beneficial in neutralizing unbound toxin. It is important to
diagnostic value. Sporulated and vegetative forms of C. tet- realize that once the toxin is bound and then internalized into
ani appear similar to other anaerobic bacteria. Furthermore, the neurons it can no longer be neutralized by antitoxin. There-
C. tetani may be present as a wound contaminant, with some fore the disease will likely continue to progress after the admin-
strains of C. tetani nontoxigenic because they lack the 75-kilo- istration of TAT. Although the use of TAT for neutralization of
base plasmid containing the toxin gene.733,741 Bacteriologic unbound toxin has been reported to be an effective adjunct to
confirmation of tetanus is not often attempted but would therapy, dosages and routes of administration vary and there are
be obtained by isolating C. tetani from the infected wound. few data for evidence-based therapy. Currently, recommended
However, isolation of C. tetani can be difficult and often fails doses range from a single administration of 5000 to 2.5 × 106
because of low concentration of organisms present in the IU/animal followed by lower doses over 5 days.744 The use of
wound and strict anaerobic conditions required for culture. TAT administered into the subarachnoid space (intrathecally)
Hematology, serum chemistry, and CSF analysis are usually has also been advocated. One of the first reports to use this
unremarkable. If a wound or aspiration pneumonia is present, method showed a recovery rate of 77.5% in horses treated with
neutrophilic leukocytosis with a left shift may be observed. Mus- 30,000 to 50,000 IU TAT intrathecally.751 Such success has not
cle enzymes may be elevated (CK and AST) because of muscle been repeated in more recent reports.744,745,752 The advantages
trauma from sustained contracture and prolonged recumbency. of the intrathecal route seem to be questionable, and it appears
that early diagnosis, nursing care, high doses of parenteral peni-
Treatment cillin, and establishing aerobic conditions at the infected site
The binding of tetanospasmin to the Renshaw cells via gan- may be the most important aspects of treatment.744
glioside receptors is almost irreversible. Recovery is slow and
does not occur until new interneuronal synapses develop to
replace those that were inactivated by toxin. Therapeutic man- Relief of Pain and Control of
agement of clinical cases of tetanus is centered around the fol- Neuromuscular Derangements
lowing five goals. Generalized muscle contractions can be painful and result in
hyperthermia that must be managed. Typically a combination
Elimination of the Source of the Toxin of sedatives and muscle relaxants is used to achieve the goals of
Local and parenteral antibiotic therapy is initiated to prevent pain relief and control of muscle spasms. Phenothiazine drugs
further production of tetanospasmin by eradication of the are commonly used for sedation and relieve of muscle spasms.
vegetative form of C. tetani at the site of infection. Penicillin The relaxing effects appear to allow some affected animals to eat
is the drug of choice for eliminating the vegetative form and and drink again, which are considered good prognostic indi-
is recommended to be administered at high dosages. Other cators. Phenothiazine drugs work at the level of the brainstem,
antimicrobials that may be effective include the tetracyclines, depressing descending excitatory input on the lower motor
macrolides (to be avoided in adults), and metronidazole. Met- neurons within the spinal cord. Although these medications
ronidazole is indicated for deep and contaminated wounds have been reported to lower the seizure threshold, their effec-
because it is able to penetrate necrotic tissues without losing tiveness in the management of clinical cases strongly supports
efficacy. Any visible wounds should be systematically cleaned, the use of these drugs. Phenothiazines potentiate barbiturates,
meticulously debrided, and lavaged thoroughly. If possible, which are also useful in the management of tetanus cases
aerobic conditions should be established at the infection site. because of their ability to depress the motor areas of the brain
and abolish spontaneous spinal cord activity. Muscle relaxants
Neutralizing Unbound Toxin such as the benzodiazepines indirectly antagonize the effects
Neutralizing any toxin that is not already bound to the gan- of tetanospasmin. Diazepam has glycine mimetic effects and
glioside receptors is of primary importance. Tetanus antitoxin potentiates release of GABA, an inhibitory neurotransmitter.
(TAT) is produced by hyperimmunization of horses with teta- The combination of benzodiazepines and α2-agonists such
nus toxoid. Administration of 1500 U of antitoxin to unvac- as xylazine may also be very effective in controlling muscle
cinated horses provides immediate passive protection lasting spasms. Methocarbamol or other central-acting muscle relax-
approximately 3 weeks.747 Higher doses result in longer dura- ants, such as guaifenesin or baclofen, would also be considered
tion of protection. In one study monitoring antitoxin levels as rational and useful therapeutic agents. Magnesium sulfate may
a measure of protection, combined active-passive immuni- also have beneficial effects in the treatment of tetanus.
zation (tetanus toxoid concurrently with TAT) was effective
at providing rapid and prolonged protection for previously Supportive Care
unvaccinated horses.748 Administration in separate, remotely Supportive care is of utmost importance in the successful
located sites on the horse was recommended. Subclinical and treatment of tetanus. Patients should be placed in a dark,
clinical hepatic disease after TAT administration has been quiet environment, with minimal stimulation and handling.
reported.749,750 Known as idiopathic acute hepatic disease, this Ear plugs can be placed to reduce auditory stimulation. If
condition has also been called Theiler’s disease, serum hepa- recumbent, supportive care for down horses needs to be
titis, serum sickness, and postvaccinal hepatitis. Signs vary provided.9 Maintaining adequate hydration and nutritional
from hepatic enzyme elevation to hepatic encephalopathy in status is of critical importance for care in these horses. In
severe cases. Occurrence of this disease is rare and sporadic, addition, providing deep soft bedding and regular turning
but prognosis is poor in most affected horses. (every 4 hours) to minimize decubital ulcers and pulmo-
Once TAT is administered to the affected horse, the passively nary congestion are essential. Urinary catheterization, ene-
acquired antibodies neutralize unbound toxin both circulating mas, and manual rectal evacuation of feces may be required
because of hypertonic urethral and anal sphincters and lack 4–6 weeks after primary vaccination and a second booster
of an effective abdominal press. If dysphagic, an esopha- 15–17 months after the second vaccination).754 The authors
gostomy or gastrostomy tube may be required for feeding. suggested our vaccination guidelines may need to be revisited
Tracheostomy may be required should laryngeal spasm and and annual revaccination may not be necessary. In clinical
respiratory obstruction occur. cases of tetanus, experts recommend that tetanus toxoid be
administered to horses with susceptible wounds if longer than
6 months since vaccination.
Generation of Active Immunity to In foals, tetanus-specific IgG antibodies inhibiting the
Tetanus Toxins foal’s response to tetanus toxoid are passively transferred via
Unfortunately, the concentration of tetanus toxin required to colostrum. High titers of IgGa, IgGb, and IgG(T) subisotypes
cause overt neurologic disease is insufficient to generate a pro- were detected in postsuckling serum samples collected from
tective immunologic response. Therefore at the initiation of foals born to mares that had received booster doses of mul-
treatment for tetanus, all horses should be immunized with ticomponent vaccines during the past 2 months of gestation.
tetanus toxoid to initiate a protective antibody response. An In addition, antibody response to vaccination of younger foals
antibody response may take 2 to 4 weeks to develop. has been shown to be poor, necessitating multiple doses of tox-
oid. Current recommendations are to vaccinate foals born to
Prognosis vaccinated mares at 4 to 6 months of age with boosters 4 to 6
Mortality rates of 54% to 75% have been reported for horses weeks later and a third vaccine at 10 to 12 months of age. Vac-
with tetanus.744-746 The prognosis for survival depends on sev- cination for foals born to unvaccinated mares should begin at
eral factors such as the immune and vaccination status of the a younger age: the current recommendations are to start at 1 to
horse, the dose of clostridial organisms, and the availability and 4 months of age with a booster 4 weeks after the first dose and
duration of treatment and supportive care. A short incubation a third vaccine 4 weeks after the second dose.
period, short duration of onset, and rapid progression of signs
is often associated with a poor prognosis. When attempting to
treat clinical cases, it must be realized that the required sup- Y BOTULISM
portive care is prolonged, labor intensive, and costly. One study
reported an association between survival and previous prophy- Yvette S. Nout-Lomas, (Stephen M. Reed)
lactic vaccination with tetanus toxoid; in that study none of the
nonvaccinated horses survived.745 One study showed that there Botulism is a severe neuroparalytic disease caused by bot-
was no association between sex, age, and duration of disease at ulinum neurotoxins (BoNTs) that are produced by BoNT-
presentation. However, what did affect prognosis was severity producing clostridia. The neurospecificity and toxic potency
of clinical signs: animals with severe clinical signs (grade 3) had of BoNTs make them the most powerful known toxins, and
the lowest survival rate (less than 10%).744 they are potential bioterrorism weapons.755,756 Horses are
more susceptible to botulism than other species such as
Prevention cattle, dogs, and humans, which are relatively resistant.757
Where possible, management of contaminated or necrotic In horses, botulism has been most commonly associated
wounds should include thorough debridement, large volume with BoNT serotype B (BoNT/B) and BoNT/C, followed by
flushing, aeration, and comprehensive cleansing. After this, BoNT/A and less commonly by BoNT/D.755,758-760 The dis-
rational antibiotic therapy should be instituted. Together these ease course is related to total toxin exposure and most com-
procedures, in conjunction with the following, should greatly monly results in death unless the horse is treated promptly
minimize the occurrence of tetanus. with specific antitoxin. A fast and accurate diagnosis is cru-
Low concentrations of tetanospasmin are capable of cial because of the necessity of rapid treatment and the large
inducing clinical signs. As a result, neither exposure to teta- potential of botulism outbreaks linked to a common feed
nospasmin nor recovery from clinical disease induces the source. Unfortunately, laboratory diagnosis has proven dif-
development of immunity. Prophylactic antibody formation ficult in horses, and botulism is generally considered to be a
and generation of immunity is stimulated by vaccination with clinical diagnosis.758,759
tetanus toxoid, derived from inactivation of tetanospasmin
with formaldehyde. Tetanus is a preventable disease, and vac- Biology of Bont-Producing Clostridia
cination with tetanus toxoid markedly reduces the occurrence
of clinical disease. However, no vaccination is absolute,745 with and their Toxins
protection being dependent on proper administration and There are six phylogenetically distinct groups of BoNT-
subject to breakdown in the face of overwhelming challenge. producing clostridia (Clostridium botulinum groups I–III,
The adjuvanted tetanus toxoid vaccine is highly immunogenic, Clostridium argentinense group IV, and some strains of Clos-
but efficacy of the vaccine relies heavily on the vaccination tridium baratii and Clostridium butyricum) that produce
program. Current recommendations for adult horses are an seven serotypically distinct BoNTs (serotypes A–G).755,756 The
initial vaccination followed by a booster 4 to 6 weeks later with number of subtypes has grown in recent years, owing to the
annual revaccination. Significant differences have been found increased use of whole-genome sequencing and mass spec-
in antibody response (IgG titers) between commercially avail- trometry, as well as the availability of high-affinity monoclo-
able multivalent vaccines,753 and it was suggested that these nal antibodies. This has revealed the striking variety of distinct
differences were the result of variations in antigenic mass. BoNT subtypes that are produced by clostridial species.756
Recently a prospective seroconversion study demonstrated Notably, C. botulinum strains from groups I and II produce
that protective titers against tetanus were present up to 3 years the widest range of neurotoxins; group I proteolytic C. botu-
after a series of vaccinations were administered (initial booster linum produces BoNT/A, BoNT/B, and BoNT/F; and group
II nonproteolytic C. botulinum produces BoNT/B, BoNT/E, demonstrated a predominance of BoNT/B-producing clos-

and BoNT/F. Group III C. botulinum produces BoNT/C, tridial spores in the northeast and central states, from Ken-
BoNT/D, and their mosaic BoNT/CD and BoNT/DC. Group tucky to Pennsylvania, whereas BoNT/A-producing clostridial
IV C. argentinense produces BoNT/G, C. butyricum produces spores were found in samples from western states.764 BoNT/A
BoNT/E, and C. baratti produces BoNT/F. Each toxin sero- and B botulism are associated with forage, whereas BoNT/C
type is categorized into various subtypes on the basis of their botulism is associated with decomposing carcasses. Ravens
amino acid sequences, and, although most strains of C. botu- have been shown to serve as transport vectors by feeding off a
linum express a single toxin serotype, some isolates produce decomposing animal carcass and then transporting the toxin
more than one serotype; for example, some proteolytic C. bot- to the feed buckets or feed troughs of horses up to 1.5 miles
ulinum group I isolates produce a mixture of Ab, Af, Ba, and Bf distant from the decomposing carcass.765
subtypes.756 Investigators have shown that there are now more
than 40 different BoNTs.756 Mechanisms of Intoxication
Clostridia are sporulating and anaerobic gram-positive, Three routes of BoNT intoxication have been described in the
rod-shaped bacteria that are widely distributed in the envi- horse: (1) food-borne botulism, (2) toxicoinfectious botulism,
ronment and in anaerobic regions of the intestines of several and (3) wound botulism. Food-borne botulism is caused by
animals, where they are typically found as spores. Spores are ingestion of the preformed toxin present in feed materials,
resistant to physical and chemical stresses and can persist for most commonly roughage (hay, haylage, silage) but occa-
long periods of time until favorable conditions enable germi- sionally grain by adult horses. Typically, BoNT/B-producing
nation. Under appropriate environmental conditions (such as clostridia directly proliferate and produce toxins in decaying
humidity, nutrients, and the absence of oxygen), spores ger- vegetable matter. In contrast, BoNT/C-producing clostridial
minate into vegetative cells; conversely, exposure to oxygen, as spores that can be present in the intestinal tract of animals
well as water and nutrient deprivation, trigger sporulation.756 or birds can undergo germination and toxin production in a
Botulism outbreaks typically occur in environments that decomposing carcass, which provides an excellent anaerobic
contain C. botulinum spores, which can germinate in decom- environment. Toxins produced in the carcass over time leach
posing organic material under anaerobic conditions. Envi- out and contaminate the hay or other feed material.757
ronmental conditions that favor botulism outbreaks include Toxicoinfectious botulism, or “shaker foal syndrome,” is
warm temperatures, shallow alkaline waters that contain usually associated with BoNT/B and occurs in foals between
abundant invertebrate populations, and decomposing verte- 2 weeks and 8 months of age.757 The syndrome is similar to
brate carcasses.755,756 what is seen in human infants whereby spores are ingested,
Human botulism is much rarer than animal botulism and germinate, and produce toxin once in the gastrointestinal
is mostly caused by BoNT/A, BoNT/B, BoNT/E, and rarely tract. Under normal circumstances, the intestinal flora of
by BoNT/F. Botulism mostly affects wild and domesticated adult animals and humans inhibits the intestinal proliferation
animals, and outbreaks of animal botulism can spread rap- of BoNT-producing clostridia, thereby limiting the occur-
idly, leading to the intoxication of hundreds of thousands of rence of toxicoinfectious botulism to neonates.766 Endemic
animals in just a few days. The primary contamination route foal botulism is thus considered to occur from ingestion of
for both humans and animals is the ingestion of preformed spores present in contaminated soil. Toxin can be detected in
toxins in foods or feeds. Raw material, such as grass, hay, rot- the feces of approximately 30% to 40% of foals with botulism
ting vegetation, and slaughterhouse waste, as well as decay of but only during the acute clinical phase.757,767
vertebrate carcasses, invertebrates, and sewage may support Wound botulism occurs in horses when BoNT/B-producing
BoNT-producing clostridial growth and toxin production. clostridia infect a wound, germinate, proliferate, and release
Animals may directly ingest decaying organic matter contain- toxin under anaerobic conditions. In adult horses, wound bot-
ing toxin, or they may ingest toxins through the consumption ulism has been associated with an injection abscess and castra-
of zooplankton or invertebrates, such as larvae, that have con- tion, and in foals, it has been diagnosed in conjunction with
sumed toxic material. Fly larvae and other invertebrates are infected umbilical remnants and an infected limb wound.757
unaffected by the toxin, but feeding on toxigenic carcasses
may concentrate toxin. Ingestion of a single toxigenic maggot Mechanism of BoNT-Induced Neuroparalysis
could be lethal. This is described as the carcass-maggot cycle BoNT-producing clostridia secrete toxins during their vegeta-
of botulism.755 Typically carrion-associated (birds, small ani- tive growth as progenitor, inactive, single-chain polypeptide
mals) botulism is associated with contaminated water, feed, or toxins of approximately 150 kDa. Toxins are produced as het-
the environment involving BoNT/C and BoNT/D. Non–car- erodimers with proteins that effectively decrease the exposure
rion-associated botulism is caused by BoNT/A and BoNT/B. of BoNT to external damaging agents. These proteins may
In North America, over 85% of equine botulism cases are also facilitate crossing epithelial cells.755,756 BoNTs cross the
caused by BoNT/B.757 BoNT/A and BoNT/C have been asso- intestinal epithelial barrier, disperse in extracellular fluid, and
ciated with fewer cases, although studies suggest that BoNT/A enter the lymphatic system and the blood circulation where
botulism may be more common in horses than previously they can remain for many days. They are unable to cross the
assumed.761 BoNT/D botulism has been suspected in horses blood-brain barrier. BoNTs are very specific and only bind to
and cattle in the United States757 but has only been confirmed peripheral nerve terminals, particularly those of skeletal and
in equine botulism in Senegal.762 Equine botulism in Europe autonomic cholinergic nerves.768
appears to be mostly associated with BoNT/B and BoNT/C.763 BoNT mature toxins consist of a light chain and a heavy
In North America, BoNT/B botulism is endemic in the mid- chain. Internalization of the BoNT into nerve terminals
Atlantic states and Kentucky, and BoNT/A botulism is more occurs through binding of the carboxy-terminal end of the
common in the western states. This geographic distribution HC domain of the light chain to a polysialoganglioside (PSG)
is consistent with outcomes from soil surveys, which have receptor that is present on the presynaptic membrane, followed
by binding to a protein receptor (either synaptotagmin or SV2) Similar to adult horses, foals regain strength after lying down
that is located either inside the exocytosed synaptic vesicle or until they are too weak and unable to rise anymore.
on the presynaptic membrane. The light chain encodes the Clinical evaluation should include careful examination
toxic moiety, which is a metalloprotease domain that specifi- of cranial nerve and spinal cord function. Special attention
cally cleaves the SNARE (soluble N-ethylmaleimide-sensitive should be paid to the palpebral and pupillary light responses,
factor attachment protein receptor) proteins that are necessary tongue tone, ability to prehend, and evidence of dysphagia, tail
for neurotransmitter exocytosis. Some BoNTs cleave VAMP, tone, gait and posture, and assessment of vital parameters and
some cleave SNAP25, and some cleave both SNAP25 and syn- respiratory pattern. Vital signs are typically normal in the early
taxin. BoNTs thus act presynaptically at the peripheral cho- stages, but heart rate and respiratory rate increase once the
linergic neuromuscular junction and result in the inhibition horse is recumbent, depending on the amount of struggling
of neurotransmitter (acetylcholine) release and consequent that occurs. Affected horses appear to maintain coordination
neuroparalysis.756 and therefore appear weak but not ataxic. A low head and neck
The action of BoNTs is reversible likely because BoNTs carriage and inability to lift the head can be seen and initially
do not cause neuronal death. The duration of BoNT-induced were thought to be more prevalent in BoNT/C botulism770 but
neuroparalysis is quite variable, depending in part on the life- recently have been shown to occur in cases with BoNT/A bot-
time of the metalloprotease within the nerve terminal cytosol, ulism as well.771,772 Occasionally these horses develop severe
which is different for the different BoNTs (BoNT/A > BoNT/C edema of the head and airways and then inspiratory stridor.
> BoNT/B > BoNT/D). Also, the activity of the affected muscle Mydriasis and ptosis are observed early in the disease pro-
and toxin dose determine duration of BoNT action. Duration cess, as well as a sluggish pupillary light response. Reduced
of action determines the severity of disease, and in humans tongue tone and slow tongue retraction are characteristic
and horses there are data to suggest that BoNT/A causes more early signs of botulism that typically occur before the onset of
severe disease than BoNT/B.756,761 Once the toxin is bound, obvious muscle weakness. However, there are some cases of
improvement in clinical signs is achieved after sprouting of the botulism that do not demonstrate clear dysphagia. Tail tone
presynaptic axon terminal and subsequent formation of a new is frequently decreased in horses with botulism, but this can
synapse.769 be difficult to assess given the wide variation in normal tail
tone among horses. Profound tail tone reduction is frequently
Clinical Signs reported in advanced botulism.
BoNT intoxication results in diffuse, symmetric, flaccid The time to ingest a small quantity (usually a cup) of grain
paralysis and loss of muscle strength. Although there are can be useful as a predictor of whether the horse has botulism.
some suggestions that there may be subtle differences in clini- A botulism grain test has been described in which the suspect
cal signs depending on the BoNT involved, this remains horse is offered 8 ounces of sweet feed in a large flat feeding
unconfirmed in the horse, and the clinical signs of botulism in tub on the floor, and the horse’s ability to consume the feed is
horses are similar, regardless of the type or source of timed.757 Most normal horses will consume an 8-ounce cup
BoNT.758,761 The speed of progression of disease is variable, of sweet feed in less than 2 minutes and many horses faster
resulting in peracute, acute, and chronic forms of botulism. than that. As the ability to retract the tongue diminishes, the
Some cases may present as sudden deaths. Depending on the time for the horse to eat the grain becomes longer. Also, grain
amount of ingested toxin, initial signs may be subtle or overt. mixed with saliva often falls out of the mouth through the
Generally, the clinical signs appear from 24 hours up to 17 horse’s lips while eating. This is highly characteristic of botu-
days after exposure.755 The incubation period may be associ- lism and is one of the earliest clinical signs.
ated with inoculum size, which suggests that the shorter the
incubation, the more severe the disease. The disease usually Differential Diagnosis
affects motor nerves with high efferent traffic, resulting in The differential diagnosis for horses affected with botulism can
weakness, dysphagia, and poor muscle tone. Usually general- be any cause of weakness and dysphagia in horses and should
ized weakness, dysphagia, or both are the first clinical signs include EPM; EMND; EHV-1 myeloencephalopathy; WNV;
detected by observant horse owners. Early in some cases the rabies; several toxins such as lead, ionophore drugs, yew, and
owners will note prolongation of the time the horse takes to yellow star thistle; low blood calcium; and hyperkalemic peri-
eat its grain, or they will note abdominal discomfort and colic. odic paralysis.757 One also should consider less common clini-
Some horses may have decreased salivation and occasionally cal diseases such as tick paralysis, vascular accident, or even
urinary retention resulting from involvement of the choliner- unusual examples of exercise intolerance.
gic autonomic nervous system. Over time affected horses
demonstrate muscle fasciculations, often first in the triceps Diagnosis
region, that eventually progress to the entire body and result in The diagnosis of botulism is difficult and frequently is based
recumbency. At first the horse appears to gain strength after on compatible clinical signs of acute onset of flaccid paraly-
lying down for a short time and may return to standing spon- sis, weak or poor eyelid tone, poor tail tone, slow or diffi-
taneously or with coaxing. Eventually the horse is unable to cult eating, and dysphagia, as well as a compatible history
rise. Death often results from respiratory failure. In foals, clini- of possible exposure to toxin. Clinical pathology results are
cal signs are similar, although frequently foals are presented mostly within normal limits. Some of the abnormalities
for excessive recumbency ad muscle fasciculations. Foals are seen may be reflective of dehydration, there may be elevated
typically bright and alert when they are lying down, but when muscle enzymes detected in recumbent horses, and in the
they stand will develop fine muscle fasciculations that p
rogress case of wound botulism there may be results consistent with
to severe muscle trembling, hence the term “shaker foal syn- infection. CSF evaluation is normal. Electrodiagnostic test-
drome,” before the foal stumbles and falls down. Foals are too ing, specifically performing repetitive nerve stimulation,
weak to lie down in a normal fashion, yet they fall down. can demonstrate facilitation characterized by incremental
responses in both amplitude and area under the curve at a botulism or specific secondary complications. However, anti-
high stimulus rate.37 microbials can potentiate neuromuscular blockage (amino-
Laboratory support for a diagnosis of botulism requires at glycosides, tetracyclines, and procaine penicillin) and should
least one of the following: (1) detection of BoNT in serum, be avoided. Mineral oil or other cathartics may be indicated
gastrointestinal contents, or from a wound; (2) detection of to reduce impaction colic. Additional therapy includes appro-
BoNT and/or BoNT-producing clostridial spores in the feed priate nursing and supportive care. Of particular importance
and/or gastrointestinal contents in addition to compatible are maintaining the horse’s hydration status and providing
clinical signs; or (3) detection of an antibody response in a nutrient support through tube feeding in dysphagic animals.
convalescent patient.757 BoNT is stable in frozen tissues or In severely affected foals or adults with respiratory failure,
plasma and can be stored at −20°C for several weeks. The cur- mechanical ventilation is indicated.
rent gold standard test for botulism is the mouse bioassay.755,759 Prognosis for horses with untreated botulism is poor. In
This test involves the inoculation of mice with a sample from outbreak situations survival is typically reported at only 10%
the suspect horse and subsequent observation of the mice for to 30%.760,761,765,770 A recent review of 92 cases of botulism
development of clinical signs of botulism. Because the horse is in adult horses showed that overall survival was 48%. Sur-
extremely susceptible to BoNT the circulating concentration vival was significantly better for horses that arrived standing
in an affected horse is often below the threshold for detection (67%) and even higher (95%) for horses that remained able
by the mouse bioassay.757 The mouse bioassay was recently to stand throughout hospitalization.760 Treatment with anti-
reviewed and shown to have low sensitivity in adult horses toxin increased the odds of survival significantly, with treated
(32%) and foals (53%) but high specificity (97% in adults and patients being four times more likely to survive. Horses with
100% in foals).759 These results indicate that a positive result is abnormal respiratory effort or inability to stand had decreased
highly suggestive of botulism but that negative results do not odds of survival. Horses that lose the ability to stand have a
exclude the diagnosis. A higher sensitivity can be obtained by poor chance of survival. Unfortunately there are horses that
culture enrichment of the sample, which takes advantage of despite receiving antitoxin deteriorate over up to 5 days, likely
the presence of BoNT-producing clostridial spores that are not due to the fact that the antitoxin binds only unbound BoNT
present in unaffected humans or animals.758,759 The low sensi- and not the toxins already bound to the motor end plates.
tivity of the mouse bioassay is consistent with previous reports Horses in which treatment is initiated after they are recum-
in horses that show that preformed BoNT is only found in bent only have a 13% chance of survival. Early diagnosis and
approximately 20% of cases using this test.757,760 treatment are critical for horses with botulism. Development
Quantitative real-time PCR assays for BoNT genes have of complications such as decubital ulcers, corneal ulcerations,
been developed and validated and shown to have higher sen- muscle disease, pneumonia, and gastrointestinal disease dur-
sitivity with similar specificity as the mouse bioassay.773,774 ing hospitalization for botulism is common but does not
Other advantages of the qPCR test are that results are avail- affect overall survival.760 In horses that do survive, recovery
able much quicker (4 days vs. 2–3 weeks for culture-enriched is complete, but it can take months for the horse to regain full
mouse bioassay) and reduction of the live-animal use. The strength.
mouse bioassay would still be required to confirm gene In foals, survival can be high with appropriate treatment. A
expression by detection of BoNT in qPCR-positive sam- review of 30 foals that were less than 6 months of age showed
ples.773,774 Although ELISA tests have been developed these a survival of treated cases of greater than 96%. All foals,
have not been shown to be superior to the mouse bioassay except one mildly affected one, received botulism antitoxin.
and have not been validated in the horse.757 It is also pos- Approximately 50% of the cases required oxygen therapy,
sible to determine antibody titers in unvaccinated horses and 30% required mechanical ventilation. Mean duration of
that have survived botulism. Despite the relatively low prob- hospitalization was 14 days.767 It is possible that foals affected
ability of confirming botulism through laboratory tests, test- with BoNT/A may require longer term care and have slower
ing remains an important component in managing botulism recoveries than foals affected with other BoNTs.772 Mechanical
cases, first to identify the BoNT type, which may have impor- ventilation is an important aspect of treatment of botulism in
tant implications for treatment and prevention strategies and human infants and, although this is not commonly performed
will provide information on epidemiologic characteristics, in adult horses with botulism, it is a strategy that can be suc-
and second, if new botulism syndromes or toxin types were cessfully used to reduce death from respiratory failure in foals.
discovered, their full description would require as much test- A study of nine foals with toxicoinfectious botulism employed
ing data as we can provide. mechanical ventilation early on in the course of hospitalization
in foals that were progressively acidemic and had increased
Treatment and Prevention Paco2 tensions. Arterial blood gas abnormalities were amelio-
Treatment of horses with botulism is expensive, time consum- rated with mechanical ventilation, and survival in treated foals
ing, and often unrewarding. The first therapeutic objective was 87.5%.775
is prompt administration of specific or multivalent antitoxin Type B botulism is preventable by vaccination using type
to bind circulating BoNT. A single dose of antitoxin is con- B toxoid, which was initially developed to prevent disease in
sidered to be sufficient (30,000 IU for a foal and 70,000 IU newborn foals. The current USDA-approved available product
for an adult horse) because that should provide passive pro- is a killed (toxoid) vaccine directed against C. botulinum type
tection for more than 60 days.757,758 Antitoxin is not effec- B. The AAEP recommends a vaccination schedule that includes
tive after BoNT has translocated into the cells; the earlier in an initial three-dose series at 1-month intervals followed by an
the course of the disease the antitoxin is administered, the annual booster. For brood mares they recommend administer-
better. The horse should be confined to a stall, and physical ing the annual booster 4 to 6 weeks before foaling. Interestingly,
activity should be kept to a minimum, if necessary with the a recent large study evaluating 92 cases of botulism showed that
use of sedatives. Antimicrobial therapy may be used to treat two horses with botulism were reportedly fully vaccinated. Both
of these horses had mild clinical signs and both survived. These There is a strong association between EGS and grazing.
were the first two horses reported in the literature to develop Numerous epidemiologic studies have been performed over
botulism despite an adequate vaccination history, of which one the years, and besides grazing, other consistently reported risk
was confirmed positive for BoNT/B spores on mouse bioassay, factors for development of the disease are age, recent move-
representing a true vaccine failure.760 ment to new pasture or premises, and time of year, with most
Additional preventive measures involve (1) providing safe cases occurring in spring and early summer.780,782,783 Other
and high-quality feed; (2) properly storing animal feed; (3) factors that appear to increase the risk for disease, or recur-
inspecting water sources for dying of dead small animals and rence thereof, include previous occurrence of cases on the
birds; (4) avoiding spreading poultry litter that contains birds premises, recent prior movement to a new premises (within
or dead animals on pastures; and (5) avoiding use of poultry the previous 2 weeks), increased stock density, and cooler drier
litter as bedding material. Whenever more than one horse on weather and irregular ground frosts. Also, loam and sandy
a premise demonstrates clinical signs compatible with botu- soils are associated with an increased risk of EGS, and abun-
lism, quick analysis of the entire ration and the feeding meth- dance of Ranunculus species and higher herbage iron, lead,
odology to determine whether contamination has occurred is arsenic, and chromium concentrations, as well as increased
recommended. This aggressive approach may prevent addi- soil nitrogen and high titatium/low zinc and high titanium/
tional horses or other animals on the farm from becoming low chromium concentrations have been found in EGS pas-
infected. Beginning the investigation with the feed is always tures.780,784 Although a previous occurrence of EGS on the
best, because this is the most common source of toxin. Condi- premises is associated with an increased risk of diagnosing
tions may be optimal for proliferation of botulism spores and EGS on that premises again, previous contact and/or cograz-
toxin production in improperly prepared hay or hay stored in ing with a previous case of EGS appears to decrease the risk
plastic bags. of EGS in horses. Also, chalk soil reduced recurrence of EGS.
Interestingly, an increased risk of EGS is seen in horses with
low serum antibody titers to BoNT/C and to surface antigens
Y EQUINE GRASS SICKNESS (EQUINE of BoNT/C-producing clostridia and C. novyi Type A,785 and
horses with higher titers to BoNT/C and BoNT/C-producing
DYSAUTONOMIA) clostridia had reduced risk of developing EGS.786
Clinical Signs
Equine grass sickness (EGS) is an acquired degenerative poly- Acute, subacute, and chronic forms of EGS are recognized,
neuropathy that predominantly affects the neurons of the of which clinical signs are correlated with extent of neuro-
autonomic and enteric nervous system. As the name implies nal damage and overlap from one form to the other.780,787,788
there is a strong association between EGS and grazing. The Clinical signs are reflective of dysfunction of the autonomic
disease was recognized first in Scotland in 1909.776 Since then nervous system, including the enteric nervous system,
it has been reported in other parts of England, continental together with somatic dysfunction. Most horses are depressed,
Europe, the Falkland Islands, and Australia. Although there anorexic, dysphagic, and tachycardic. The dysphagia is likely
had been an earlier credible, but unpublished, report of EGS caused by cranial nerve dysfunction and possibly esopha-
from the United States (Missouri),777 the disease was not con- geal dysfunction and is recognized by drooling of saliva, feed
firmed until 2010, when it was diagnosed based on clinical material in the nares, impacted feed material in the buccal
and pathologic findings in a mule in Kansas.778 A clinically pouches, and difficulty drinking. The drooling of saliva seen
and histopathologically similar disease, mal seco, has been in EGS may also be caused by excessive salivation, which has
described in South America, predominantly in Chile. Britain been reported in some forms of human dysautonomia. Con-
has remained the country most affected by EGS, and a nation- tributors to the tachycardia include increased adrenaline and
wide surveillance scheme has been instituted.779 noradrenaline and removal of vagal inhibitory input. Ptosis,
The disease predominantly affects the prevertebral and sweating, and muscle fasciculations can also be present in all
paravertebral ganglia of the autonomic nervous system and forms of EGS.
enteric neurons (myenteric and submucosal plexuses) and is
therefore characterized as a dysautonomia; however, given the Acute Form
fact that neuronal degeneration has also been identified in the Clinical signs are related to acute onset of gastrointestinal
brain and spinal cord of horses with EGS, the disease is likely ileus. The course of disease is generally less than 48 hours.
better termed a multisystem neuropathy.780 Clinical signs vary, Signs of abdominal pain are mild to moderate and are caused
and the severity is likely related to the extent of degenerative by gastric and small intestinal distention. Typically these cases
neuronal damage. The disease occurs sporadically and is often produce large quantities of nasogastric reflux. Affected horses
fatal. Although EGS has been studied extensively, the cause of are hypovolemic, and the reduced circulating volume may
the disease remains unknown. cause death from cardiac failure. Considering the degree of
gastrointestinal distention, the severity of abdominal pain is
Epidemiology usually less than would be expected. Examination per rectum
EGS has been reported in other equids such as the Przewalski’s reveals small intestinal distention and often a mild secondary
Horse, zebra, donkey, mule, and pony, but it occurs primarily impaction of the large colon.
in young, mature horses that have access to pasture. Horses
with EGS are generally young adults between 2 and 7 years Subacute Form
of age.780 No gender predilection is apparent, but a study in The course of disease is 3 to 7 days, and clinical signs are simi-
Scotland found that there may be an increased susceptibility lar but less severe than in acute EGS. Horses with subacute
to EGS in native Scottish breeds.781 EGS do not develop gastric or small intestinal distention, and
nasogastric reflux is usually absent. Horses with subacute EGS gastrointestinal tract and reduction of interstitial cells of Cajal
often have large colon or cecal impactions. in the myenteric plexus regions of the gastrointestinal tract.
Neuropathologic lesions within the autonomic nervous system
Chronic Form have been reported at the ciliary ganglion, cranial cervical gan-
The course of the disease is weeks to months. Cachexia, with glion, caudal cervical ganglion, stellate ganglion, thoracic and
the development of a “tucked up” appearance, is the most abdominal sympathetic trunk, celiac/cranial mesenteric gan-
prominent clinical abnormality in horses with chronic EGS. glion, caudal mesenteric ganglion, and parasympathetic ter-
In addition, horses will develop evidence of progressive minal cardiac ganglion. Furthermore, CNS lesions have been
myasthenia, demonstrated by a base-narrow stance, leaning identified in brainstem nuclei, spinal cord lower motor neu-
back against walls and weight shifting of the limbs. Unlike rons, and spinal cord intermediolateral horn neurons.780 The
in botulism and equine lower motor neuron disease where association between central neuronal pathologic findings and
horses spend more time recumbent, this is not the case in severity of clinical disease is unclear. In one study, increased
horses with EGS. Furthermore, in EGS muscle fasciculations neuronal pathologic findings were observed in milder clini-
are also present when animals are lying down, which is typical cases (chronic EGS), which contrasts to another study that
cally not the case in botulism or equine lower motor neu- demonstrated increased neuronal pathologic findings in acute
ron disease. Development of rhinitis sicca is characteristic cases of EGS.790
of chronic EGS and is thought to be caused by loss of inner-
vation of the nasal mucosa. The entire gastrointestinal tract Pathogenesis
is empty in these horses, and they usually have dry mucus- Clinical signs are related predominantly to dysfunction of
covered feces in the rectum; the latter is a finding commonly the autonomic nervous system. The most severe lesions
seen in all three forms of EGS. Other clinical signs in ani- are found in the myenteric and submucosal plexuses of the
mals with chronic EGS are gait abnormalities (short strided), ileum, and less severe changes occur in the celiacomesen-
snoring, pica, and penile prolapse. In a later stage, one may teric ganglion. The altered autonomic activity results in ces-
observe coat abnormalities such as areas of piloerection, sation or decrease of intestinal peristalsis and subsequently
growth of a long coat, and pallor of the coat. leads to the development of ileus and colonic impaction.
The dysphagia in most cases of EGS is caused by cranial
Pathologic Findings nerve or brainstem involvement. Based on epidemiologic
Gross necropsy findings are usually reflective of gastroin- and pathologic findings in horses with EGS, an unidenti-
testinal dysfunction that was present antemortem.789 Gross fied neurotoxin is implicated as the causative agent of the
necropsy findings in acute EGS are consistent with gastroin- disease. Epidemiology supports the role of an ingested soil-
testinal ileus. A large fluid-filled stomach and distended small borne agent capable, under certain conditions, of producing
intestine are present. Secondary impacted ingesta is often pres- or liberating a putative neurotoxin. Some of the pathologic
ent in the large colon and cecum. Splenomegaly and erosions findings support retrograde axonal transport of the toxin
of the esophageal mucosa are other findings in acute EGS. from the gastrointestinal tract to the ganglia, whereas there
Gross necropsy findings in subacute EGS are less severe and are other studies that suggest that the widespread nature
include colonic impaction. One may find inspissated mucus of the neuropathology in EGS is also consistent with more
in the lumen of the small colon and rectum and evidence of extensive distribution of the toxin, for example, via hema-
intraluminal hemorrhage such as inspissated blood or black togenous dissemination.780
feces. In horses with subacute and chronic EGS, one may find Multiple experimental studies over the past decades have
rhinitis sicca. failed to identify the causative agent or agents of EGS. Agents
Neuronal lesions are most severe in the autonomic gan- studied include alsike clover, C. perfringens enterotoxicity,
glia (cranial cervical, stellate, celiacomesenteric) and enteric insect vectors, and fungi. Toxicoinfection with BoNT/C-
nerves. Lesions are also found in brainstem nuclei and the producing clostridia was proposed as an etiology for EGS
somatic efferent lower motor neurons of the spinal cord.787- in the 1920s,776 and it has dominated recent research efforts
789 Specific histopathologic findings characteristic of neuronal as well.780,786,791-795 The hypothesis is that a dietary trigger
degeneration include chromatolysis, loss of Nissl’s substance, induces intestinal bacterial overgrowth and in vivo produc-
eccentricity or pyknosis of the nuclei, neuronal swelling and tion of BoNT/C and/or BoNT/D. Despite the overwhelming
vacuolization, accumulation of intracytoplasmic eosinophilic evidence to support an association between BoNT-producing
spheroids, and axonal dystrophy. Although the locations clostridia and EGS, there are a number of significant differ-
of neuropathologic lesions found in EGS are very similar to ences between the clinical and pathologic findings of botulism
those found in dysautonomias of other species, including find- and EGS. Vaccine trials are under way in Britain and perhaps
ing lesions in brainstem nuclei and spinal cord, this latter fact the results of those will provide answers about the involve-
gives rise to the question of whether EGS is a true dysauto- ment of BoNTs in the pathogenesis of EGS.795,796 Given the
nomia or a multifocal neurologic disease.780 This similarity differences between EGS and botulism, investigators are cur-
in anatomic distribution of neuropathologic changes in EGS rently focusing investigative efforts on potential roles of other
supports the hypothesis of a common factor sensitizing the etiologic agents, for example, Fusarium spp. that are known to
neurons to specific insults. The insult in EGS appears to be produce mycotoxins.792,795
specific and repeatable, consistent with findings in primary
dysautonomias in other species. Diagnosis
The extent of lesions of the enteric nervous system largely No noninvasive definitive test exists to obtain an antemortem
determines the severity of disease, with most severe lesions diagnosis of EGS. A presumptive diagnosis is made based
seen in acute EGS. Specific lesions include neuronal loss in on the history, epidemiologic information, nature and pro-
both the submucosal and myenteric plexuses throughout the gression of clinical signs, and elimination of other possible
diagnoses. Serum biochemical and hematologic examina- a clear benefit of using ancillary treatments such as appetite
tions do not reveal specific changes in horses with EGS. Acute stimulants and prokinetics in the management of horses with
phase proteins and fibrinogen concentrations are significantly chronic EGS.780
higher in horses with EGS compared to those with intestinal
tract obstructions.797 Other ancillary diagnostic tests that may
be helpful include evaluation of esophageal motility by endos- Y LYME DISEASE IN HORSES
copy or contrast imaging, electrodiagnostic testing, and the
use of 0.5% phenylephrine applied to the cornea to confirm Stephen M. Reed
the presence of smooth muscle paralysis underlying the ptosis
(ptosis should temporarily disappear).798-800 A definite ante- Lyme disease is the most common vector-borne infectious dis-
mortem diagnosis can only be made following histopathologic ease in human beings in the United States. Initially recognized
examination of enteric ganglia.787,801 in the mid-1970s in Lyme, Connecticut, as the cause of unex-
Because antemortem diagnosis requires collection of biop- plained rheumatoid arthritis in children, the causative agent
sies via exploratory laparotomy, often taken at the ileum, of Lyme disease was discovered to be a spirochete, Borrelia
investigators have been evaluating alternative biopsy sites. His- burgdorferi (sensu lato). In addition to human beings, Lyme
topathologic examination of rectal biopsies was investigated as disease affects domestic animals such as dogs, cats, cattle, and
a less invasive and cost-prohibitive diagnostic tool; however, horses.808-814
the sensitivity of this approach was disappointing.802 Recently Human beings and animals acquire Lyme disease by trans-
histopathologic examination of gustatory papillae via a lingual mission of B. burgdorferi through the bite of infected hard
biopsy technique was evaluated in postmortem specimens of ticks (Ixodes spp.). In the Eastern and Midwestern United
horses with EGS and was shown to have a sensitivity of 100% States the vector is the blacklegged tick or deer tick, Ixodes
and a specificity of 98.2%.803 This approach has the potential scapularis (formerly I. dammini), whereas in the Western
to offer a valuable and cost-effective means of antemortem dis- United States the vector is the western blacklegged tick, I. paci-
ease confirmation but requires further prospective validation. ficus. In Europe the sheep tick, I. ricinus, is the vector of Lyme
The most important differential diagnoses for acute EGS borreliosis.
are a small intestinal strangulating lesion and duodenitis- Not all ticks are infected with the spirochete, and infec-
proximal jejunitis. Clinical signs and neuronal lesions in tion varies by tick species and geographic region. These ticks
chronic EMND and chronic EGS may be similar, and these have a 2-year, three-stage life cycle and feed once during each
similarities have led to the speculation that these two diseases stage.815,816 The larvae hatch in the spring and summer and
are related. Further examination, however, reveals important are usually noninfective because transovarial transmission is
differences such as the fact that EMND occurs in older horses rare.817 The tick may become infected at any stage of the life
that have not had access to pasture, and EGS occurs in young cycle by feeding on small mammalian hosts, typically the
horses with access to pasture. EGS sometimes occurs along white-footed mouse (Peromyscus leucopus), which is a natu-
with EMND.804 ral host for the spirochete. The nymphal stage emerges the
next spring and is most likely to transmit the disease because
Prognosis, Treatment, and Prevention it is small, difficult to see, and engorges faster; engorgement
The case fatality rates for acute and subacute EGS are 100%. is necessary to transmit B. burgdorferi. The white-tailed deer
No effective cure exists. Horses with acute EGS may respond (Odocoileus virginianus) is the host for adult ticks. The life
initially to gastric decompression, analgesic administration, cycle of I. ricinus in Europe involves birds and mammals
and intravenous fluid therapy, and this supportive treatment because immature stages feed on birds and reptiles. Nymphal
can be provided until a more definitive diagnosis is achieved, I. scapularis are the main vectors of B. burgdorferi in human
at which point euthanasia should be recommended. The clini- beings. These ticks are more active from May to July. Once the
cal signs that are generally associated with a grave prognosis tick has engorged, B. burgdorferi is transmitted to the host via
include persistent gastric reflux or the presence of firm colonic lymphatics or blood. Although larval and nymph stages are
impactions, both reflective of severe intestinal dysmotility responsible for B. burgdorferi transmission to other mammals,
resulting from extensive neuronal degeneration within the the stage responsible for transmitting Lyme disease in horses
ENS and generally accepted as supporting a diagnosis of acute is unknown.
and subacute EGS, respectively.
Horses with chronic EGS often are euthanized because of Epidemiology
weakness, inability to stand, and emaciation; however, when In endemic areas of the northeastern and midwestern United
given appropriate care at a referral hospital, approximately States, approximately 20% of nymphal stages and 30% to 40%
40% to 50% of horses may survive long term.787,805 Nonsur- of adult stages of Ixodes scapularis are infected with Borrelia
vival is associated with severe rhinitis sicca and high subjective burgdorferi. In contrast, I. pacificus often feeds on lizards that
clinical scores based on the severity of dysphagia, anorexia, are poor reservoirs for B. burgdorferi, and only 1% to 3% of
colic, and reduction in intestinal sounds.806 More recently it these ticks, including the nymphal stages, are infected with the
was shown that rapidity and magnitude of body-weight loss spirochete.817 This difference in the number of infected ticks
were predictive of outcome, with nonsurvivors losing more might explain the difference in the prevalence of Lyme bor-
weight than survivors.807 The greatest obstacle for treatment reliosis between the eastern and western United States. Equine
of horses with chronic EGS is the profound anorexia that is seroprevalence is high in the northeastern United States, but
often present. Providing palatable high-quality food is the limited information is available for other parts of the coun-
cornerstone for treatment of chronic EGS. In addition, use of try.809,813 In Europe, clinical cases and equine serorologic sur-
analgesics, antimicrobials, and providing light exercise may be veys have documented Lyme borreliosis as a cause of equine
indicated for selected cases. Unfortunately there has not been disease in Poland, Germany, Scandinavia, and England.812,818,819
The apparent increasing incidence of disease in human obvious. Blood tests are of limited value; however, ELISA,
beings and animals might result from an increased deer popu- kinetic ELISA, Western blot testing, and PCR on blood sam-
lation, increased number of ixodid ticks, expansion of human ples and synovial fluid from suspect animals have been evalu-
and horse populations into previously rural woodland areas, ated.809,812-814,822,823 One may test samples of joint fluid, CSF,
or increased recognition of the disease manifestations. and tissues from affected patients for the presence of organ-
The disease has a seasonal prevalence and is most common isms. Several pathologic conditions should be considered in
in spring, summer, and fall, with a peak incidence in June and the differential diagnosis of equine borreliosis, including Ana-
July. In some climates such as California, ticks might be active plasma phagocytophila infection, chronic diseases, vasculitis,
throughout the year. The organism is maintained in a complex and immune-mediated arthritis if limb or periarticular swell-
life cycle of small wild mammals and immature stages of the ing is present, as well as causes of neurologic disease.
blacklegged tick. Larval and nymphal stages of the tick acquire Neuroborreliosis is rarely diagnosed. CSF reveals neutro-
the infection when they feed on infected mice. The white- philic or lymphocytic pleocytosis and increased total protein.
tailed deer (Odocoileus virginianus) is not a reservoir for Lyme Other tests include culture of the organism, immunohisto-
disease but rather the host for the adult stages of the tick. This chemistry, PCR of tissue samples and CSF, and others pre-
is relevant to tick and Lyme disease control programs, because viously described. More recently a fluorescent bead–based
regional reductions in the number of I. scapularis has only multiplex assay (Multiplex) in serum and CSF has been devel-
been possible when the deer population has been decreased.815 oped for the diagnosis of borreliosis and neuroborreliosis.824
Multiplex assay tests serum at a dilution of 1:400 whereas CSF
Clinical Signs is generally run undiluted. In serologic assays, a positive result
Clinical signs associated with Borrelia burgdorferi in horses, indicates past or present infection (exposure) and not neces-
as in human beings, are often nonspecific and involve mul- sarily cause of clinical disease, and vaccination can also cause
tiple body systems. In human beings, clinical signs frequently a positive result. Horses living in endemic areas are often sero-
include annular rash, erythema migrans, myalgia, aseptic positive. Development of an antibody ratio test to compare
meningitis, arthritis, and seventh cranial nerve palsy.817 The antibody concentration in blood to the concentration in CSF
disease usually begins as a skin rash and often progresses to is being evaluated and may prove to be useful in the future
involve joints and the nervous and cardiac systems but may (Amy Johnson, personal communication).
involve other body systems as well. In human beings the skin
rash may be slowly progressive and sometimes may take up to Pathogenesis
1 month before becoming apparent. Borrelia burgdorferi organisms are capable of nonspecifically
In horses, reported clinical signs of Lyme borreliosis activating monocytes, macrophages, and synovial lining cells,
include chronic weight loss, sporadic lameness, laminitis, low- as well as natural killer cells, B cells, and complement, leading
grade fever, swollen joints, muscle tenderness, anterior uveitis, to production of host proinflammatory mediators. These pro-
encephalitis, and abortion.810,811,820 Some horses might dem- inflammatory mediators seem to localize in joints, leading to
onstrate clinical illness and obtundation and might go off feed chronic arthritis and lameness. B. burgdorferi has developed
in a short time. The bacteria might enter the CNS within a strategies to interact with the mammalian host, including adhe-
short time after exposure. Chronic arthritis might develop as sion to host cells and components of the extracellular matrix
a result of autoimmune mechanisms, although this is not fully such as fibronectin, β3 integrins, and glycosaminoglycans. The
understood. Ixodid spp. ticks are often coinfected with Bor- current thinking in the development of arthritis is that outer-
relia burgdorferi and Anaplasma phagocytophila; however, dual surface proteins (Osps) of B. burgdorferi trigger an autoimmune
infections remain to be documented in the horse. An impor- reaction because antibodies to OspA and OspB have been
tant consideration is that limb swelling and response to tet- detected in 50% to 80% of human patients with arthritis.825,826
racycline treatment, indicating Lyme borreliosis could be the Natural killer cells also play a central role in joint inflammation
result of A. phagocytophila infection. Infection with Borrelia by producing excessive amounts of TNF-α and IL-8.825
burgdorferi is common but rarely results in neuroborreliosis.
Neurologic signs could be variable. These signs might include Treatment and Prevention
behavioral changes, hyperesthesia, hyperreactivity, gait abnor- Recommended treatment includes oxytetracycline (6.6 mg/
malities, cranial nerve deficits, neck stiffness, muscle atrophy kg IV every 24 hours) or doxycycline (10 mg/kg PO every
and muscle tremors or fasciculations.821 12 hours).827 Treatment can be started with tetracycline for
1 week followed with doxycycline for 3 to 4 weeks. Ceftio-
Diagnosis fur (2.2–4.4 mg/kg IV every 12 hours) has also been evalu-
The diagnosis of Lyme disease is often difficult. History of tick ated.827 In animals infected with B. burgdorferi, a rapid clinical
exposure or living in a Lyme disease–endemic area is helpful; response (2–4 days) is expected with tetracyclines. In some
when combined with the identification of clinical signs and horses the clinical signs might show an initial worsening as a
the elimination of other diseases, this information allows the response to toxins released after death of the organisms. Cur-
clinician to make a presumptive diagnosis. Examination of rently, no licensed vaccine is available to prevent Lyme disease
blood work for other diseases is important. In human beings in horses, although vaccines are available for dogs and human
an early increase in serum IgM often occurs. Response to ther- beings. A recombinant OspA vaccine was evaluated in horses
apy might help to support a presumptive diagnosis of Lyme with promising results.828
disease, but it is not definitive. Diagnosis of Lyme disease in Aids to prevention include daily grooming with removal
horses is difficult,822 and in many cases one bases a presump- of ticks, along with the use of tick repellents that contain per-
tive diagnosis on history, clinical signs, and response to anti- methrin. One should apply tick repellents to the head, neck,
biotic therapy in an animal with probable cause to be infected legs, abdomen, and under the tail. Keeping pastures mowed
(i.e., possible exposure). In human beings the skin lesions are and removing brush and woodpiles makes the environment
less hospitable for rodents, which in turn decreases the tick of 100 headshaking horses revealed a potential specific cause
population. Regional programs to control Lyme disease are in only 11 horses, and elimination of the abnormality resulted
based on reducing the deer population. in resolution of the headshaking in only 2 of them.833 Idio-
pathic headshaking has been used to describe the majority
of cases in which no specific underlying cause is found, and
Y TRIGEMINAL-MEDIATED necropsy results in these horses reveal no lesions.845 Further,
HEADSHAKING a study evaluated the possibility of herpesvirus infection as a
potential cause of this disorder but found no association.845
Monica Aleman However, immune-mediated reaction or inflammation of the
trigeminal ganglia can cause headshaking.
Idiopathic headshaking has been recognized for over 100 The clinical signs exhibited by most headshaking horses now
years.829 The disorder is characterized by spontaneously occur- generally are thought to result from sharp, electric-like, burning
ring uncontrolled violent head shakes. One study showed that pain involving the trigeminal nerve.831,832 Trigeminal nerve
the maxillary branch of the trigeminal nerve, has a low thresh- involvement is supported by the observations that some horses
old for firing, therefore even innocuous stimuli could trigger
sensory activation and firing of this nerve, causing facial pain.46 TABLE 11.18 Potential Causes of Headshaking in Horses
Therefore the authors of the study proposed calling this con-
dition trigeminal-mediated headshaking to reflect more accu- Disorders of the Oral Cavity
rately the source of pain despite an uncertain etiology.830 It is Dental disorders
important to rule out other causes of headshaking (Table 11.18). Pharyngeal lesions
Headshaking is a widely recognized disorder characterized by Tongue or gingival lesions
persistent or intermittent, spontaneous, and frequently repeti- Buccal ulceration
tive vertical (most common), horizontal, or rotary movements Disorders of the Eyes
of the head and neck.831 The affected horse shakes, jerks, or flicks Abnormalities affecting vision
its head uncontrollably in the absence of obvious physical stim- Cysts, masses, foreign bodies, cataracts
uli or apparently innocuous stimuli (i.e., light, wind, exercise), Nasolacrimal duct disorders
and the condition can be severe enough to render the horse
Disorders of the Ear
unusable and dangerous.832-836 Headshaking often is accom-
Otitis
panied by snorting and sneezing, and many horses rub their
Ear ticks (Otobius megnini)
noses on stationary objects or on the ground while moving.
Mites
In addition to shaking the head up and down, flipping the upper
Mass lesion–neoplasia, abscess, granuloma
lip, or shaking the head side to side, horses also might act as if a
Foreign body
bee has flown up the nostril or might strike at the face with the
thoracic limbs.832,836,837 Headshaking horses also might exhibit Upper Airway Disorders
avoidance behavior, with low head carriage, corner seeking, and Nasal passages–e.g., masses
nostril clamping.831,838 To characterize the severity of clinical Rhinitis (allergic, vasomotor)
signs, a grading system of 1 to 5 has been described, with grade Sinuses–masses, exudate, sinusitis
1 being a rideable horse with intermittent and mild signs (facial Guttural pouch disease
muscle twitching) and grade 5 being an unrideable, uncontrol- Laryngeal disorders
lable, dangerous horse with bizarre behavior patterns.831 Clinical Disorders of the Skull
signs are usually worse during exercise; however, headshaking Fractures
can affect horses at rest.831-835,837 Severely affected horses might Neoplastic lesions
inflict self-trauma and compromise welfare.830 Mean age of onset Temporomandibular joint disorders
is typically 7 to 9 years, and Thoroughbreds and geldings appear Temporohyoid osteoarthropathy
to be overrepresented in some studies.832,833,836 Headshaking Other disorders of the hyoid apparatus
can be seasonal or nonseasonal. Early literature suggested an Neurologic Abnormalities
increased incidence of headshaking during the warmer months Trigeminal neuralgia
of the year,834 and a later study indicated that the peak periods of Equine protozoal myeloencephalitis
onset were spring and early summer.833 Studies have found that Photic headshaking
64%833 and 59%832 of headshaking horses are affected season-
ally, with the majority developing signs in the spring or early Cervical Pain
summer. Osteoarthritis
Neuropathy
Pathogenesis Myositis
It is important to rule out other causes of headshaking before Behavior
considering trigeminal-mediated headshaking (see Table Stereotypical behavior
11.18).839 Reported and suggested causes include behavioral Classical conditioning response
resentment to rider-induced head and neck flexion, exercise- Avoidance behavior
induced hypoxia, ear mites, cranial nerve dysfunction, otitis Objections to Rider or Tack
media or otitis interna, cervical injury, ocular disease, guttural Bridle, bit, browband fit and comfort
pouch mycosis, dental periapical osteitis, vasomotor rhinitis, Rider actions or interference
allergic rhinitis, Trombicula autumnalis (harvest mite) larval Excessive head and neck flexion
infestation, maxillary osteoma, and EPM.833,835,839-844 A study
improve after blocking the infraorbital nerve (part of the maxil- with anticholinergic effects, has been used (0.3 mg/kg PO
lary branch)846,847 and that most horses improve after blocking twice daily) to treat headshaking horses, resulting in improve-
the caudal nasal nerve, a branch of the maxillary nerve comment in 5 of 7 horses in one study838 and 43 of 61 horses in
monly referred to as the posterior ethmoidal nerve (branch of another.832 Horses that respond do so within 1 week, and some
ophthalmic nerve). Horses that headshake in response to light might respond within 24 hours. Cyproheptadine also works as
stimulation have been described as photic headshakers.838 Most a calcium channel blocker in addition to blocking serotonin-
of these horses are affected seasonally (spring and summer), mediated pain as a proposed mechanism of action.838 Cypro-
improve at night or when brought indoors, and improve when heptadine has also been used with carbamazepine (4–8 mg/kg
blindfolded or when gray lenses are placed over their eyes. Pho- PO q 6–8 h), resulting in 80% to 100% improvement in seven of
tic headshaking is hypothesized to be caused by optic-trigemi- nine cases, with horses responding within 3 to 4 days.831 Carba-
nal summation (stimulation of the optic nerve that results in mazepine is a sodium channel–blocking antiepileptic drug and
referred sensation to parts of the nose innervated by the trigem- is the drug of choice for treating trigeminal neuralgia in human
inal nerve), a mechanism similar to that proposed for photic beings.850 Carbamazepine alone was reported to be effective
sneezing in human beings.832,838 Many features of headshaking in headshaking horses, but results were unpredictable.831 The
in the horse are similar to trigeminal neuralgia in human elimination half-life of carbamazepine in the horse is less than
beings—a severe chronic pain syndrome characterized by dra- 2 hours, making sustaining therapeutic concentrations difficult;
matic, brief stabbing or electric shock–like pain paroxysms felt the drug is therefore of more benefit diagnostically than thera-
in one or more divisions of the trigeminal distribution, sponta- peutically in headshaking horses (D. C. Knottenbelt, personal
neously or on gentle tactile stimulation of a trigger point on the communication). Other medications and therapies, including
face or oral cavity. The disease is associated with microvascular NSAIDs, corticosteroids, antihistamines, acupuncture, chiro-
compression and pathologic changes in the trigeminal root and practic manipulation, homeopathy, and feed supplements, are
trigeminal ganglion.848 The trigeminal nerve was postulated to generally ineffective in most horses.832,851 Pulse therapy with
be hypersensitive and to fire in response to a variety of trigger corticosteroids has not been effective to manage trigeminal-
factors, including wind, airway turbulence, increased blood mediated headshaking.852
flow, pollen, dust, warmth, cold, insects, allergies, or other irri- Because the disorder affects more geldings than females
tations. These trigger factors appear to act intranasally in many and intact males, a study investigated the role of follicle-stimu-
horses but could act in any trigeminal sensory region.831 As pre- lating hormone (FSH) and luteinizing hormone (LH) by using
viously mentioned, there is evidence that the trigeminal nerve a gonadotropin-releasing hormone vaccine.853 This vaccine
has a low threshold for firing.849 significantly decreased FSH and LH levels but did not affect
headshaking in horses.
Diagnosis and Treatment Diagnostic blockade of trigeminal nerve branches can
One should perform a complete physical examination, includ- be useful for identifying trigger points in headshaking
ing neurologic, dental, ophthalmic, and otoscopic examina- horses. Blockade of the infraorbital nerve might improve
tions, to rule out potential underlying causes (see Table 11.18). some horses and might identify candidates for infraorbital
Other diagnostics could include endoscopy of the nasal pas- neurectomy.846,847 However, results of infraorbital blockade
sages, pharynx, and guttural pouches; radiography of the skull and infraorbital neurectomy do not correlate, and infraor-
and cervical spine; CBC; and serum biochemistry profile. For bital neurectomy is not a recommended procedure because
photic headshaking horses, clinical signs should improve after of neuroma formation, self-trauma, risk of infection, low
blindfolding or after placement of a mask shielding the eyes success rate, and recurrence of pain that might require a
from the sun. second surgery.846 A high percentage of horses improve
Treatment of trigeminal-mediated headshaking could be after blockade of branches of the maxillary nerve, and
challenging as shown in a recent owner survey (Table 11.19).830 sclerosis of this nerve results in temporary improvement
Because the etiology of headshaking is unknown, current treat- in some horses.831 More recently, a study investigated the
ments are neither specific nor curative; therefore the majority neuromodulation of the trigeminal nerve by using percuta-
of horses with headshaking are managed, rather than cured. neous electrical nerve stimulation under sedation. Horses
Cyproheptadine, an antihistamine and serotonin antagonist tolerated well the procedure, which proved to be safe and
TABLE 11.19 Drugs Used for the Treatment of Trigeminal-Mediated Headshaking

Drug Dosage (mg/kg) Route Frequency
Carbamazepine 2–8 PO q 6–12 hours
Clonidine 0.0025 PO q 12 hours
Cyproheptadine 0.3 PO q 12 hours
Fluphenazine 0.1 IM q 1–4 months
Gabapentin 5 PO q 8–12 hours
Hydroxyzine 0.6–0.8 PO q 12 hours
Magnesium 20–40 PO q 24 hours
Melatonin 0.03–0.04 PO q 24 hours at 5 pm
Phenobarbital 3 PO q 12 hours
Sodium chromoglycolate 1 drop Ophthalmic q 6 hours

minimally invasive and provided pain relief in the short to Most of the cases of Halicephalobus encephalomyelitis
medium term (months).854 in adult horses reported in the literature during the past 40
Therapies aimed at decreasing the response to trigger factors years describe simultaneous renal granulomatous lesions
can be effective and include tinted contact lenses; face masks or encapsulating the nematodes.248,859,861-874 Granulomata
hoods that block sunlight, wind, insects, and dust, with mesh within or adjacent to the renal parenchyma were observed
or dark eye cups; and nose nets.831,832,838,851,855,856 An owner on postmortem examination in 13 of 16 horses with neuro-
survey found that nose nets that cover the nostrils with mesh logic disease; of the other 3 horses, in one case lesions were
and include a drawstring or elastic band that applies pressure confined to the sacral spinal cord and cauda equine, and in
to the upper lip resulted in some improvement in 70% of head- another case only the skull and brain were examined at post-
shaking horses and that 70% or more improvement occurred mortem examination. In contrast, all three cases reported to
in about 30% of the horses.855 date in foals showed no renal involvement but did show pul-
monary granulomata.859,862
Y VERMINOUS ENCEPHALOMYELITIS
Strongylus vulgaris, Strongylus equinus,
Aberrant migration of helminth and fly larvae through the CNS and Angiostrongylus cantonensis
of horses and donkeys is a rare but important cause of severe Aberrant strongyle larval migration is a much less common
neurologic disease. Parasites that have been reported to affect cause of neurologic signs because of routine broad-spectrum
the brain and spinal cord of equids include rhabditid nematodes antiparasitic treatment with ivermectin and moxidectin. The
(Halicephalobus gingivalis), strongyloid nematodes (Strongylus pathogenic mechanisms described for strongyle encephalo-
vulgaris, S. equinus, and Angiostrongylus cantonensis), protostron- myelitis include aberrantly migrating fourth- and fifth-stage
gyloid nematodes (Parelaphostrongylus tenuis), spiruroid nema- larvae in the intima of the aorta or left ventricle, which causes
todes (Draschia megastoma), filarid nematodes (Setaria digitata endothelial damage, stimulates the clotting cascade, and
and other Setaria spp.), and warble fly larvae (Hypoderma spp.). results in formation of a thrombus that often contains the
Antemortem diagnosis is often impossible; however, a high parasitic larva.875 Lesions are generally asymmetric because of
index of suspicion might be warranted for certain clinical signs random migration in the brain, although migration along the
(acute onset or rapidly progressive asymmetric, focal, or mul- spinal cord has been reported in a donkey.500,875
tifocal brain or spinal cord signs) and changes in CSF analysis, Adult parasites of Angiostrongylus cantonensis are found in
in which case the treatment regimen should include specific the right ventricle and pulmonary artery of rats. The pulmo-
antiparasitic drugs (e.g., fenbendazole) in addition to the more nary circulation carries eggs released by adult worms to the
routinely used symptomatic and antiinflammatory treatments alveoli, where the first larval stage develops and migrates up
(e.g., NSAIDs, DMSO, corticosteroids, antiprotozoal drugs). the trachea, is swallowed, and passes in feces. Snails and slugs
are intermediate hosts, and ingestion of the snail results in
ingestion of the infective larvae that migrate through the CNS,
Causes and finally the larvae reach the heart via the circulation. Aber-
Halicephalobus gingivalis rant CNS migration of A. cantonensis larvae has been reported
Halicephalobus gingivalis was previously known as Micronema in two foals with tetraparesis in Australia,876 and aberrant
deletrix, then Halicephalobus deletrix.857 The parasite was migration is a recognized cause of eosinophilic meningoen-
referred to as Micronema deletrix until the 1970s and 1980s, cephalitis in human beings and dogs.877
with use of the new nomenclature beginning in 1990.857 The
life cycle of Halicephalobus spp. nematodes is unknown. This Parelaphostrongylus tenuis
small roundworm generally is considered a saprophytic organ- The meningeal worm Parelaphostrongylus tenuis causes neu-
ism that occasionally acts as a facultative parasite in horses rologic disease in cervids, ovids, bovids, and camelids. There
and human beings. The likely route of entry is through nasal have been multiple reports of similar disease in horses ranging
and oral mucosa, followed by possible hematogenous spread in age from 6 months to 9 years.5,878,879 Affected horses have
to organs with high vascularization such as the brain, spinal a history of sudden onset of scoliosis with no history or evi-
cord, and kidneys.858 H. gingivalis recently has been shown to dence of trauma.
be transmitted from a mare to her foal because of mammary
infestation.859 CSF is abnormal, showing mixed pleocytosis Draschia megastoma
with elevated protein concentration. In one study, H. gingivalis Adult Draschia megastoma worms are found in the stomach
was observed on cytologic examination of CSF.860 of equids where they cause mucosal granulomatous masses
Organs affected by migration of Halicephalobus spp. include and mild chronic gastritis. The life cycle of Draschia is indirect
the brain, spinal cord, nasal and oral cavities, pituitary gland, because the organism uses flies as the intermediate host. Eggs
and kidneys and less commonly the lymph nodes, heart, lungs, and larvae are released into the gastric lumen, and the first
stomach, liver, and bones.248,861 Organisms affecting the CNS larval stage passes in the feces and is ingested by fly larvae of
have been reported to have a predilection for the basilar, pitu- the genus Musca in which Draschia spp. organisms develop
itary region of the brainstem.862 Characteristic histopatho- to infective larvae. Finally, horses become infected when the
logic lesions in the CNS include malacia, granulomatous, third larval stage is deposited on the host by adult flies. Infec-
and lymphohistiocytic inflammatory infiltration, meningitis, tive larvae that are ingested and reach the stomach develop
and vasculitis in addition to identification of the nematodes. into adults and complete the life cycle. Larvae deposited in
Other clinical signs include oral and nasal granulomata, renal damaged skin result in local inflammation and development
involvement (H. gingivalis is visible in the urine), granuloma- of extensive granulation tissue, which is the typical lesion of
tous osteomyelitis,863 and granulomatous chorioretinitis.864 cutaneous habronemiasis.
Stray D. megastoma larvae may be found anywhere of cauda equine neuritis was reported to be caused by H. gin-
throughout the body, and a case has been reported of D. mega- givalis migration in the sacral spinal cord and cauda equina
stoma migration in the brainstem of a horse in the southern nerves.871
United States, resulting in asymmetric brainstem disease.880 Clinical signs of Parelaphostrongylus tenuis infection
are quite characteristic and include acute onset of scoliosis
Setaria Species (observed in 90% of reported cases), with progressive gait defi-
Infestation with the filarial nematode Setaria is common in cits. Scoliosis is most common in the cervical area.5,878,879 The
the abdominal cavity of ungulates where the organism does affected area of the vertebral column is usually C shaped, with
not cause significant clinical effects. S. labiatopapillosa is found flaccid muscles and decreased cutaneous sensation on the con-
in cattle, and S. equina is found in horses. Microfilariae gain vex side of the curve. Tetraparesis and ataxia is mild to mod-
access to peripheral circulation and then are transmitted to erate and predominantly ipsilateral to the convex side of the
other potential hosts via mosquitoes. In a postmortem exami- curve. If bilateral gait deficits are observed, they are worse on
nation study of 305 horses in Japan, S. equina was recovered the convex side. The proposed pathogenesis for clinical signs
from 66 of those horses (approximately 22%).881 involves unilateral weakness of the paraspinal epaxial muscles
The cattle parasite S. digitata occurs only in Asia, and infes- on the convex side of the curve.879 A linear lesion that extends
tation in unnatural hosts (horses, sheep, goats, camels, and for several segments, most likely in the dorsal gray column, is
human beings) has been associated with cerebrospinal nema- most likely to cause the observed signs.
todiasis. This condition can be enzootic in India, Burma, and
Sri Lanka, is called Kumri (weak back), and has a seasonal Differential Diagnosis
occurrence, usually during the fly season (late summer and One should consider verminous encephalomyelitis in all
fall).882 cases of acute or progressive asymmetric disease of the
Two cases of aberrant S. digitata CNS migration have been spinal cord, cerebrum, cerebellum, or brainstem. If brain
reported in Japanese racehorses, and one case of Setaria spp. involvement is evident without other localizing signs, the
larval migration in the brainstem and cervical spinal cord has differential diagnosis list might include equine togaviral
been reported in a 12-year-old Quarter Horse mare in the encephalomyelitis, rabies, equine protozoal myelitis (EPM),
midwestern United States.881,883 trauma, cerebral abscess or basilar epidural empyema, bacte-
rial meningitis, hepatic encephalopathy, neoplasia, and leu-
Hypoderma Species koencephalomalacia. If the neurologic signs are limited to
Cattle are normal hosts of Hypoderma spp., but horses are spinal cord involvement, other diseases to include in the dif-
accidental hosts of warble fly larvae. In cattle, Hypoderma ferential diagnosis list might be cervical stenotic myelopathy,
larvae penetrate the skin after hatching from eggs attached to EPM, EHV-1 myeloencephalopathy, trauma, WNV menin-
hair in the rump and lower legs. These larvae migrate through goencephalitis, EDM, trauma, spinal osteomyelitis or dis-
connective tissues to reach the esophagus, in the case of H. lin- cospondylitis, vertebral fracture, and neoplasia. If the only
eatum, or to the vertebral canal around epidural fat, in the case signs present are related to cauda equina syndrome, other
of H. bovis. Finally, the larvae migrate back to the skin over conditions to consider are polyneuritis equi, sacral or coccy-
the back where they create a breathing hole. Cutaneous myia- geal fracture, EPM, EHV-1 myeloencephalopathy, sorghum
sis is uncommon in horses, and warble fly larvae occasionally or Sudan grass toxicity, epidural abscess from tail blocking,
might migrate aberrantly into the brain. Tissue damage caus- and neoplasia.
ing necrosis and hemorrhage is extensive because of the big Initial diagnostics should include CBC, serum chemistry
size of the instars.884-886 Instars can enter through large natural profile, urinalysis, and CSF collection for cytologic evaluation.
foramina such as the foramen magnum, optic foramen, and Radiographs of the cervical or lumbosacral spine and myelog-
occasionally intervertebral foramina. raphy might be required to rule out more common causes
of spinal cord disease (cervical stenotic myelopathy, trauma,
Clinical Signs fractures). Although only routinely available at referral hos-
Severity and duration of clinical signs vary from mild, tran- pitals, advanced imaging techniques (e.g., CT, MRI) might be
sient, and insidious to severe and fatal. In some cases, clinical useful in diagnosing parasitic encephalomyelitis or other con-
signs progress over 2 to 4 months, with periods of improve- ditions with similar clinical signs.
ment or stabilization.861,865,880 Variability of clinical signs CSF analysis in cases of parasitic encephalomyelitis can be
depends on the number of parasites (thromboembolic shower normal; however, CSF changes are common and include xan-
of S. vulgaris), on the size of the migrating organism (Hypo- thochromia, increased protein, and neutrophilic and mono-
derma spp. larvae are large and cause severe necrosis and nuclear pleocytosis, but eosinophils rarely occur (Table 11.20).
hemorrhage as they migrate in the CNS parenchyma), and Only in a case of Angiostrongylus cantonensis were eosinophils
neuroanatomic localization of the lesions. Horses suffering the predominant cell type on CSF cytologic examination.
from larval migrations in the brain (S. vulgaris, Halicephalo- In addition, Halicephalobus gingivalis might be observed in
bus deletrix, Draschia megastoma, and Hypoderma spp.) might CSF subjected to cytocentrifugation.860,862 Similarly, H. gin-
display head tilt, circling, recumbency, blindness, hyperesthe- givalis larvae might be visible on microscopic examination
sia, stiff neck, ataxia, head pressing, recumbency, seizures, and of urine sediment or semen in cases of renal and testicular
coma. In those cases in which larvae cause lesions in the spinal involvement.861 Analysis of CSF obtained from horses with
cord (S. vulgaris, H. gingivalis, Setaria spp., Angiostrongylus Parelaphostrongylus tenuis neurologic disease has been within
cantonensis), clinical signs might include focal or multifocal normal limits.879 PCR is a highly sensitive diagnostic modality
asymmetric ataxia, weakness, dog-sitting posture caused by that can aid in the definitive diagnosis of disease as reported
paraparesis, increased patellar reflexes, atonic bladder, poor in one case of a horse with verminous encephalitis due to
tail tone, and poor rectal tone with impaction of feces. A case P. tenuis.878
TABLE 11.20 Cerebrospinal Fluid Analysis in Verminous Encephalomyelitis

Organism White Blood Cells in CSF Protein in CSF Cells in CSF Larvae Present in Urine Reference
Halicephalobus 2030 cells/μL 89 mg/dL Mostly PMNs — 865
Halicephalobus 25 cells/μL 69 mg/dL 15% N, 56% L, 22% M, — 868
5% E, 2% B
Halicephalobus 81 cells/μL 114 mg/dL 9% N, 41% L, 50% M — 868
Halicephalobus 60 cells/μL 710 mg/dL — — 869
Halicephalobus 495 cells/μL 112 mg/dL 34% N, 37% L, 29% M No 24
Halicephalobus — — — Yes 860
Halicephalobus — — — No 873
Halicephalobus 179 cells/μL 71 mg/dL Predominantly N; few L, No 861
M, and E
Halicephalobus 35 cells/μL 100 mg/dL 25% N, 58% M, 17% E, No 248
2% L
Halicephalobus 16 cells/μL 76 mg/dL 31% N, 22% L, 47% M — 858
Setaria Increased Increased — — 874
Strongylus Two of eight ponies One of eight — — 874
had increased white ponies had high
blood cell counts: 42 protein at 175
cells/μL and 1080 mg/dL
cells/μL
Strongylus 9988 cells/μL 550 mg/dL 72% N, 14% L, 12% M, — 500
2% E
Draschia Normal Normal — — 876
Angiostrongylus 1560 cells/μL — 1% N, 8% L, 14% M, No 877
77% E

B, Basophils; CSF, cerebrospinal fluid; E, eosinophils; L, small lymphocytes; M, large mononuclear cells; N, neutrophils; PMN, polymorphonuclear neutrophil
leukocytes.
Antemortem diagnosis might be possible in those cases other tissues for evidence of S. vulgaris thrombi or presence
in which renal or bony involvement is detected and nema- of Halicephalobus gingivalis granulomatous lesions might help
todes are identified in biopsies of the affected tissues.863 As establish a postmortem diagnosis.
described previously, renal involvement with granuloma- On histopathologic examination, one generally sees exten-
tous lesions encapsulating Halicephalobus gingivalis worms sive tissue necrosis with mixed inflammatory response.
is observed in most cases of H. gingivalis encephalomyelitis. H. gingivalis migration in the CNS typically results in histio-
Therefore transabdominal renal ultrasound examination and lymphocytic infiltrates, malacia, glial proliferation, and peri-
ultrasound-guided biopsy (in those cases with renal lesions vascular lymphocytic cuffing. Migrations of warble fly and
present), as well as microscopic examination of urine sedi- S. vulgaris larvae result in severe hemorrhage, large malacic
ment, might prove useful in cases of acute-onset progressive tracts, and edema caused by their relatively larger size.
asymmetric neurologic disease, especially if one suspects cere-
brospinal nematodiasis caused by H. gingivalis. Treatment
Additionally, a PCR-based diagnostic test has been devel- Treatment of verminous encephalomyelitis in horses is often
oped for confirmation of Setaria encephalomyelitis in goats, unrewarding. None of the cases reported in the literature has
sheep, and horses.887 This test is based on specific amplifica- responded favorably to antiinflammatory drugs and anthel-
tion of Setaria spp. filarial DNA from a blood sample from mintics. In one horse with a Halicephalobus gingivalis gran-
the host. uloma limited to the prepuce, therapy with ivermectin and
diethylcarbamazine was successful.888
Pathologic Findings Therapeutic recommendations depend on the severity,
The gross and histopathologic lesions depend on the parasite progression, and localization of neurologic signs, as well as
involved. Thorough postmortem examination with sectioning on consideration of possible contraindications (e.g., if one
and histopathologic examination of all areas of the CNS rele- suspects a bacterial or viral cause, one should avoid using
vant to the antemortem clinical signs are important to identify corticosteroids). In cases of acute neurologic disease use of
migrating parasites. Strongylus vulgaris and Hypoderma spp. the following antiinflammatory drugs might be warranted:
larvae are easy to see, but other nematodes are only visible on NSAIDs such as phenylbutazone (2.2 mg/kg twice a day), flu-
microscopic examination. Some reports describe how one may nixin meglumine (1 mg/kg twice a day), or ketoprofen (2 mg/
recover and examine whole, fixed nematodes for distinctive kg twice a day); intravenously administered DMSO (1 g/kg as
morphologic features by centrifugation of formalin solution a 10% solution once daily for 3–5 days); and corticosteroids
in which the brain had been fixed.866,873 Gross examination of (dexamethasone at 0.1–0.25 mg/kg once daily or prednisolone
at 0.2–4.4 mg/kg once daily). If cerebral and/or brainstem retinoblastoma, and microglioma.900,906-908 Neoplasms of
signs are observed, one might administer mannitol (0.25–2 g/ nerves and nerve sheaths appear to be more common than
kg as a 20% solution once daily), or hypertonic saline might be CNS neoplasia and include neurofibromas and neurofibro-
warranted in an attempt to minimize cerebral edema. In coun- sarcomas.909-914 The most common sites for neurofibromas
tries in which EPM is known to occur, antiprotozoal treatment are in the cutaneous tissues, of the pectoral region, abdomen,
is recommended. neck, and face, but gastrointestinal tract lesions have also been
Specific antiparasitics suggested for treating verminous described.909 There are also reports of intracranial and medi-
encephalomyelitis include benzimidazole compounds (oxfen- astinal schwannomas in horses.915,916
dazole, thiabendazole, fenbendazole, and mebendazole), The most common mesodermal neoplasm in horses appears
diethylcarbamazine and ivermectin for the treatment of nem- to be meningioma.892,905,917 Neoplastic reticulosis, lipoma in
atodes, and organophosphates with caution (trichlorfon and the mesencephalic aqueduct, angioma in the cervical spinal
dichlorvos) for the treatment of warble fly larvae. Although cord, primary meningeal lymphoma, and melanoblastoma of
ivermectin is effective against most equine parasites, it might the cerebellar meninges have also been described.918-920
not be the best choice because of its delayed method of kill- Older texts may refer to pituitary pars intermedia dysfunc-
ing, which might take as long as 10 to 14 days. Some authors tion (PPID) of older horses as a neoplastic lesion. This dis-
have suggested administration of fenbendazole at 50 mg/kg by order is most likely a manifestation of oxidative damage to
mouth once daily for 3 days4,501; however, specific data on the dopamine-producing neurons in the CNS with subsequent
efficacy of anthelmintics in treating nematode or warble fly dysregulation of hormone production within the pars inter-
larvae migration through the CNS are not available. media of the pituitary gland. PPID is discussed in detail in the
Endocrinology chapter (Chapter 16).
Cholesterol granulomas (cholesteatomas, cholesterinic
Y MISCELLANEOUS NEUROLOGIC granulomas) are likewise not neoplastic lesions.921-929 These
DISORDERS lesions are found in the choroid plexus of up to 20% of older
horses.930 Although more common in the choroid plexus of
Debra C. Sellon the fourth ventricle, lesions in the lateral ventricles may be
more likely to result in clinical signs. Lesions might represent
In addition to the numerous neurologic problems discussed a chronic granulomatous reaction to deposition of choles-
in detail earlier in this chapter, horses can develop a wide vari- terol crystals associated with chronic choroid plexus leakage.
ety of acute or chronic neurologic disorders with clinical signs Grossly the granulomas are circumscribed, firm, granular,
related to brain, spinal cord, or nerve dysfunction. Clinical and yellow-brown with a glistening cut surface. They are most
signs can occur because of primary disease or dysfunction of often recognized as incidental findings at necropsy of horses
the CNS or secondary to a variety of metabolic disorders or without noticeable clinical signs. If they are large enough, how-
disorders of other body systems. This section will mention the ever, they might cause CNS signs as a result of direct pressure
most important of the miscellaneous CNS disorders and refer on cerebral tissues or obstructive hydrocephalus. In affected
the reader to relevant chapters for more detailed information. horses, reported clinical signs have included altered behav-
ior, obtundation, somnolence, seizures, ataxia, weakness, and
Neurologic Neoplasia coma. CSF from affected horses might have an elevated pro-
Many types of neoplastic lesions have been identified in the tein and appear xanthochromic.921-923
brain and spinal cord of horses. A comprehensive review of Secondary neoplastic conditions affecting the CNS might
the clinical and pathologic aspects of equine CNS neoplasia, penetrate the cranial vault or vertebrae, extend through osse-
however, is lacking in the peer-reviewed veterinary literature. ous foramina, or metastasize via the vascular system. Clini-
Available case reports and summaries of pathologic studies cal signs vary depending on the type, site, and extent of the
suggest that CNS neoplasia is quite uncommon in horses. In lesion. Lymphoma is probably the most common secondary
one Australian survey of 450 horses, with neurologic disease, neoplasm of the CNS in horses.920,931-936 Lesions might cause
the prevalence of neurologic disease secondary to neoplasia forebrain signs if present in the cranial vault or ataxia and
was less than 2%.141 This percentage is likely to be much lower paresis if causing compression of the spinal cord.
in horses in the United States because of the much higher inci- Melanoma of the spinal cord, meninges, and brain may
dence of encephalitic disorders and EPM. occur with metastasis of primary cutaneous lesions.937-939
Tumors of the nervous system can be classified on the basis Alternatively, clinical signs may represent spread from affected
of their cellular origin as tumors of nerve cells, neuroepithe- sublumbar lymph nodes.920,940 Melanoma of the CNS is most
lium, glia, nerves and nerve sheaths, mesodermal structures, common in gray horses.
and endocrine organs. Neoplasms of nerve cell origin appear Hemangiosarcoma and undifferentiated sarcoma have
to be extremely uncommon in horses, with only a few reports been reported to affect the CNS of horses.920,941-943 There are
of ganglioneuromas, complex tumors arising in peripheral numerous descriptions of adenocarcinomas and carcinomas
ganglia and composed of well-differentiated neurons, nerve (including squamous cell carcinoma) affecting the CNS of
processes, Schwann cells, and glial cells.889,890 These tumors horses by direct spread from a primary site in the head or by
might cause intestinal obstruction and signs of colic in affected metastasis from a distant site.920,944-950 Tumors of the bone or
horses. bone marrow might involve the skull or vertebrae, resulting in
Tumors of neuroepithelial origin in horses include ependy- compression of the brain or spinal cord, respectively.920,951-953
moma, choroid plexus papilloma, neuroepithelial tumor of the Malformation tumors, including epidermoids, dermoids,
optic nerve, malignant medulloepithelioma, ocular medullo- teratomas, and teratoids, might also affect the CNS.920 They
epithelioma, and pineoblastoma.891-906 Glial cell tumors are often incidental findings at necropsy but might occasion-
include glioblastoma multiforme, optic disc astrocytoma, ally be clinically significant.
Supportive evidence for the presence of CNS neoplasia water in an apparent attempt to force water into the posterior
can be obtained with advanced imaging (i.e., CT, MRI) of the pharynx. Hypertonicity of facial muscles is common, with the
brain or spinal cord in select equine patients. Definitive diag- horse often holding the mouth partially open with the lips
nosis of primary CNS neoplasia in horses requires cytologic retracted. The tongue may protrude from the mouth, and many
or histopathologic identification of neoplastic cells or tissues. horses display constant chewing movements.
This diagnosis necessitates biopsy, cytologic evaluation of an
aspirate from a suspect lesion, or identification of neoplastic Fluphenazine Toxicity
cells in CSF. Analysis of CSF is rarely diagnostic of neoplasia in Fluphenazine administration to horses may result in charac-
horses because of the rarity of the presence of neoplastic cells teristic clinical signs of toxicity.987-991 Fluphenazine is a highly
in the fluid. Given the practical difficulties inherent in obtain- potent phenothiazine neuroleptic that is widely used in human
ing biopsy samples from the brain or spinal cord, definitive medicine for a variety of psychological disturbances. In horses,
diagnosis of primary CNS neoplasia in horses rarely occurs fluphenazine decanoate has been used to provide a persistent
antemortem. Definitive diagnosis is more likely in horses sedative effect. It binds avidly to dopamine D2 receptors in the
with secondary CNS neoplasia in which a diagnosis is made brain. The very slow dissociation of fluphenazine from these
by biopsy or cytologic evaluation of primary lesions identified receptors is associated with a greater risk of adverse extrapyra-
external to the CNS. midal signs than is observed with newer atypical antipsychotic
medications.987 Its administration to some horses can result in
Toxic Disorders severe extrapyramidal effects and parkinsonism with clinical
A wide variety of toxic substances can affect the CNS of horses. signs including agitation, profuse sweating, hypermetria, aim-
Most of these are discussed in detail in the Toxicology chapter less circling, intense pawing and striking with the thoracic
(Chapter 21). Three toxic neurologic conditions merit men- limbs, and rhythmic swinging of the head and neck alternating
tion in this chapter because of their common occurrence in with periods of severe stupor. A study using liquid chromatog-
some geographic areas and their distinctive clinical appear- raphy showed that fluphenazine decanoate administered
ance as demonstrated in the referenced video segments on the intramuscularly can be detected in serum up to 14 days after
DVD accompanying this text. administration, with the highest concentration detected in
serum at 1.4 ng/mL.992 The lower limit of detection was deter-
Leukoencephalomalacia mined to be 0.05 ng/mL.992 A long-acting depot formulation
Equine leukoencephalomalacia is a seasonal disorder of for intramuscular administration is available and appears to be
horses, ponies, donkeys, and mules, occurring most com- most commonly used. One published report suggests a dosage
monly in late fall through early spring. Most outbreaks are of 0.05 to 0.08 mg/kg IM every 2 weeks with a warning to
associated with a dry growing period followed by a wet period. beware of idiosyncratic reactions.993 Horses have exhibited
The disorder is caused by ingestion of the mycotoxin fumoni- signs of extrapyramidal effects of fluphenazine decanoate after
sin B1, a metabolite of Fusarium moniliforme.954-976 Two clini- receiving doses as low as 40 mg IM.987 Given that recom-
cal syndromes are associated with fumonisin B1 intoxication. mended doses for adult humans range from 25 to 50 mg, it is
The more common is a neurologic syndrome characterized reasonable to assume that at least some horses are much more
initially by incoordination, aimless walking, intermittent susceptible than humans to the adverse effects of fluphenazine
anorexia, lethargy, obtundation, blindness, and head pressing. decanoate. The severity of clinical signs observed in some
These signs might be followed by hyperexcitablity, belliger- affected horses is sufficient to pose considerable safety risks for
ence, extreme agitation, profuse sweating, and delirium. veterinarians and handlers treating these horses. This author is
Recumbency and clonic-tetanic seizures might occur before aware of at least one horse that was euthanized because of the
death. Less commonly, horses develop a hepatotoxic syndrome extreme danger of clinical signs after administration of flu-
with swelling of the lips and nose, somnolence, severe icterus phenazine; other authors have indicated similar adverse out-
and petechiation of mucous membranes, abdominal breath- comes.987 Treatment consists of discontinuation of drug
ing, and cyanosis. Gross lesions include liquefactive necrosis administration and enhancing cholinergic function by admin-
and degeneration of the cerebral hemispheres; changes might istering anticholinergic medications. Diphenhydramine chlo-
also occur in the brainstem, cerebellum, and spinal cord. ride results in significant improvement in some, but not all,
affected horses.987,989 Benztropine mesylate (0.018 mg/kg IV
Nigropallidal Encephalomalacia every 8 hours) has also been helpful for treatment of some
Yellow star thistle and Russian knapweed grow over much of affected horses.987 Other horses apparently benefited from
the western United States in nonirrigated pastures during dry sodium pentobarbital (2 mg/kg IV followed by a constant rate
seasons of summer and fall. Ingestion of these plants can result infusion at 2.5 mg/kg/h) in an attempt to control maniacal
in unilateral or more commonly bilateral softening and necrosis behavior without inducing recumbency or anesthesia.987
in areas of the globus pallidus and substantia nigra.977-986
Lesions are often sharply defined and may be cavitary. Although Metabolic Disorders
the plants are generally considered unpalatable by most horses, A wide variety of metabolic disorders can cause clinical signs
some horses may develop a craving for the plants and selectively indicative of central nervous system dysfunction. These signs
seek them out. The exact toxic principle in these plants has not include hepatic dysfunction, hypoglycemia, hypoxemia and
been determined. Affected horses demonstrate variable degrees ischemia, and severe abnormalities in plasma electrolyte
of impairment of eating and drinking with lack of coordination concentrations.
of movements of prehension, mastication, and deglutition.
Most horses appear to be able to swallow if food or water is Hepatoencephalopathy
placed in the posterior pharynx. Severely affected horses might An excellent review of the etiology, pathogenesis, clinical
attempt to drink by immersing their muzzle deeply into the signs, diagnosis, and treatment of liver disease is included
elsewhere in this text. A normally functioning liver is neces- 110 mEq/L. Profound hypernatremia might result in clinical
sary to maintain normal brain neuron and astrocyte function. signs of spasticity, myoclonus, and obtundation. Severe hypo-
With acute liver disease hepatoencephalopathy is most often a natremia was identified in 4% of foals (69 of 1718) presented to
result of astrocyte swelling, acute cytotoxic cerebral edema, an intensive care unit.994 Of those affected foals, 16% displayed
and intracranial hypertension. In chronic hepatic disease neurologic signs attributed to hyponatremic encephalopathy.994
astrocytes are swollen but also show evidence of Alzheimer Signs included seizures, obtundation, ataxia, and blindness.
type II changes. Horses with hepatoencephalopathy show Severe hyponatremia was associated with renal disease, entero-
signs of cerebral cortex dysfunction. The earliest recognizable colitis, and uroperitoneum. Survival rate to discharge was 72.5%
clinical signs in horses are often obtundation, lethargy, mild (50 of 69 foals).994 Long-term survival in a 12-month follow-
ataxia, and various forms of inappropriate behavior. These up was 76%.994 A different study in 4 foals with hyponatremic
signs can progress to head pressing, circling, somnolence, and encephalopathy reported resolution of neurologic signs in 3 of
diminished responsiveness to external stimuli. Eventually 4 foals.995 Signs were attributed to increased intracranial pres-
affected horses become recumbent and comatose. Seizures sure as the result of severe hyponatremia. Azotemia due to acute
might occasionally be observed, but they are not common renal failure in these foals was slow to resolve with intensive
(not clinically manifested). The type and severity of clinical therapy. Therapy of foals affected with profound hyponatremia
signs do not correlate with type or reversibility of the underly- or hypernatremia is discussed in Chapter 20.
ing hepatic disease.
REFERENCES
Hypoglycemia, Hypoxemia, and Ischemia 1. de Lahunta A, Glass E, Kent M. Veterinary Neuroanatomy and
Severe hypoglycemia is not common in adult horses but is Clinical Neurology. 4th ed. St. Louis: Saunders; 2014.
common in neonates, often as a complication of sepsis, pre- 2. Divers TJ, Johnson AL. Clinical neurology. Vet Clin North Am
maturity, hypoxic ischemic encephalopathy, or hypothermia. Equine Pract. 2011;27:ix–x.
When hypoglycemia does occur it might result in weakness, 3. Furr M, Reed S. Equine Neurology. 2nd ed. Philadelphia: Wiley-
obtundation, ataxia, and eventually loss of consciousness. Sei- Blackwell; 2015.
zure activity is not common in adult horses but might occa- 4. Mayhew J. Large Animal Neurology. 2nd ed. Philadelphia:
sionally be observed in affected foals. Iatrogenic hypoglycemia Wiley-Blackwell; 2008.
can occur in horses treated with insulin or with abrupt cessa- 5. Van Biervliet J, de Lahunta A, Ennulat D, et al. Acquired cervi-
cal scoliosis in six horses associated with dorsal grey column
tion of intravenous glucose therapy. Clinical signs are rapidly chronic myelitis. Equine Vet J. 2004;36:86–92.
reversed with intravenous administration of glucose-contain- 6. Irby NL. Neuro-ophthalmology in Horses. Vet Clin North Am
ing solutions. Guidelines for intravenous glucose therapy are Equine Pract. 2011;27:455.
included in Chapter 20. 7. Mayhew IG. Neuro-ophthalmology: a review. Equine Vet J Sup-
Because of the brain’s high and continuous demand for oxy- pl. 2010:80–88.
gen, the CNS is extremely susceptible to hypoxic or ischemic 8. Rooney JR. Two cervical reflexes in the horse. J Am Vet Med As-
damage. This is most apparent in the neonate with hypoxic soc. 1973;162:117–118.
ischemic encephalopathy, as discussed in detail in Chapter 20. 9. Nout YS, Reed SM. Management and treatment of the recum-
As nervous tissue switches to anaerobic glycolysis to meet its bent horse. Equine Vet Educ. 2005;7:416–432.
energy needs, brain glucose is depleted, and localized lactic 10. Olsen E, Dunkel B, Barker WH, et al. Rater agreement on gait
assessment during neurologic examination of horses. J Vet In-
acidosis occurs. Neurons swell, and cytotoxic edema exacer- tern Med. 2014;28:630–638.
bates ischemia. The end result is irreversible cell damage and 11. Hoffman CJ, Clark CK. Prognosis for racing with conservative
neuronal death. Clinical signs depend on what areas of the management of cervical vertebral malformation in thorough-
brain are affected. Localized hypoxia may occur with throm- breds: 103 cases (2002-2010). J Vet Intern Med. 2013;27:317–
boembolic disorders or intracarotid injections. Deprivation 323.
of oxygen to the entire CNS results in more dramatic clinical 12. Edsbagge M, Tisell M, Jacobsson L, et al. Spinal CSF absorption
signs of impaired cerebral function ultimately leading to sei- in healthy individuals. Am J Physiol Regul Integr Comp Physiol.
zures, coma, and death. This type of generalized severe tissue 2004;287:R1450–R1455.
hypoxia may result from decreased inspired oxygen, ventila- 13. MacKay RJ. Developments in ultrasound-guided thecal punc-
tion/perfusion abnormalities, right-to-left shunting of blood, ture in horses. Vet Rec. 2014;174:43–44.
14. Aleman M, Borchers A, Kass PH, et al. Ultrasound-assisted
impairment of gas diffusion within the lungs, hypoventilation, collection of cerebrospinal fluid from the lumbosacral space in
severe anemia, impaired oxygen utilization by tissues, or pro- equids. J Am Vet Med Assoc. 2007;230:378–384.
found hypotension secondary to sepsis, hemorrhage, anaphy- 15. Depecker M, Bizon-Mercier C, Courouce-Malblanc A. Ultra-
laxis, or cardiac failure. These disorders are discussed in detail sound-guided atlanto-occipital puncture for cerebrospinal fluid
in the appropriate chapters elsewhere in this text. analysis on the standing horse. Vet Rec. 2014;174:45.
16. Pease A, Behan A, Bohart G. Ultrasound-guided cervical cen-
Electrolyte Abnormalities tesis to obtain cerebrospinal fluid in the standing horse. Vet Ra-
Severe hyponatremia or hypernatremia can result in CNS diol Ultrasound. 2012;53:92–95.
dysfunction. Hyponatremia most often results from water 17. Andrews FM, Geiser DR, Sommardahl CS, et al. Albumin
intoxication because of excessive IV or oral administration or quotient, IgG concentration, and IgG index determina-
tions in cerebrospinal fluid of neonatal foals. Am J Vet Res.
consumption of hypotonic solutions. A common clinical sce- 1994;55:741–745.
nario resulting in hyponatremia is oral consumption of large 18. Beech J. Cytology of equine cerebrospinal fluid. Vet Pathol.
quantities of water by a patient with a disorder that results in 1983;20:553–562.
significant concurrent electrolyte loss (e.g., diarrhea, excessive 19. Furr M, Chickering WR, Robertson J. High resolution protein
sweating, polyuric renal failure). Clinical signs are most com- electrophoresis of equine cerebrospinal fluid. Am J Vet Res.
mon in horses with a serum sodium concentration of less than 1997;58:939–941.
20. Furr MO, Bender H. Cerebrospinal fluid variables in clini- 44. Kornegay JN, Gorgacz EJ, Dawe DL, et al. Polymyositis in dogs.
cally normal foals from birth to 42 days of age. Am J Vet Res. J Am Vet Med Assoc. 1980;176:431–438.
1994;55:781–784. 45. Spier SJ, Carlson GP, Holliday TA, et al. Hyperkalemic periodic
21. Hayes TE. Examination of cerebrospinal fluid in the horse. Vet paralysis in horses. J Am Vet Med Assoc. 1990;197:1009–1017.
Clin North Am Equine Pract. 1987;3:283–291. 46. Aleman M, Williams DC, Brosnan RJ, et al. Sensory nerve con-
22. Mayhew IG, Whitlock RH, Tasker JB. Equine cerebrospi- duction and somatosensory evoked potentials of the trigeminal
nal fluid: reference values of normal horses. Am J Vet Res. nerve in horses with idiopathic headshaking. J Vet Intern Med.
1977;38:1271–1274. 2013;27:1571–1580.
23. Mozaffari AA, Samadieh H. Analysis of serum and cerebrospi- 47. Anor S, Espadaler JM, Monreal L, et al. Electrically elicited
nal fluid in clinically normal adult miniature donkeys. N Z Vet blink reflex in horses with trigeminal and facial nerve blocks.
J. 2013;61:297–299. Am J Vet Res. 1999;60:1287–1291.
24. Darien BJ, Belknap J, Nietfeld J. Cerebrospinal fluid changes 48. Blythe LL, Engel Jr HN, Rowe KE. Comparison of sensory nerve
in two horses with central nervous system nematodiasis (Mi- conduction velocities in horses versus ponies. Am J Vet Res.
cronema deletrix). J Vet Intern Med. 1988;2:201–205. 1988;49:2138–2142.
25. Pusterla N, Wilson WD, Conrad PA, et al. Comparative analy- 49. Blythe LL, Kitchell RL, Holliday TA, et al. Sensory nerve
sis of cytokine gene expression in cerebrospinal fluid of horses conduction velocities in forelimb of ponies. Am J Vet Res.
without neurologic signs or with selected neurologic disorders. 1983;44:1419–1426.
Am J Vet Res. 2006;67:1433–1437. 50. Henry RW, Diesem CD. Proximal equine radial and median
26. Andrews FM, Maddux JM, Faulk D. Total protein, albumin motor nerve conduction velocity. Am J Vet Res. 1981;42:1819–
quotient, IgA and IgG index determinations for horse cerebro- 1822.
spinal fluid. Prog Vet Neurol. 1990;1:197–204. 51. Henry RW, Diesem CD, Wiechers DO. Evaluation of equine
27. Furr MO, Tyler RD. Cerebrospinal fluid creatine kinase activity radial and median nerve conduction velocities. Am J Vet Res.
in horses with central nervous system disease: 69 cases (1984- 1979;40:1406–1410.
1989). J Am Vet Med Assoc. 1990;197:245–248. 52. Huntington PJ, Jeffcott LB, Friend SC, et al. Australian String-
28. Green EM, Green S. Cerebrospinal fluid lactic acid concentration: halt—epidemiological, clinical and neurological investigations.
reference values and diagnostic implications of abnormal concen- Equine Vet J. 1989;21:266–273.
trations in adult horses. Ann Forum Am Coll Vet Int Med. 1990. 53. Whalen LR, Wheeler DW, LeCouteur RA, et al. Sensory nerve
29. Vickroy TW, Chang SK, Chou CC. Caffeine-in

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EQUINE

Stephen M. Reed, DVM, Dipl ACVIM

Warwick M. Bayly, BVSc, MS, PhD, Dipl ACVIM

Debra C. Sellon, DVM, PhD, Dipl ACVIM

EQUINE INTERNAL MEDICINE ISBN: 978-0-323-44329-6

Copyright © 2018, Elsevier Inc. All rights reserved.

Library of Congress Cataloging-in-Publication Data

Senior Content Strategist: Jennifer Flynn-Briggs

Printed in United States of America

Last digit is the print number: 9 8 7 6 5 4 3 2 1

nondisrupted skin surfaces. Even though horses inhabit an

TABLE 1.2 Major Types of Bacterial Adhesins

in a guinea pig model.93 Both of these mutants can proliferate

Coronaviridae Paramyxoviridae Bunyaviridae Toroviridae

RNA Orthomyxoviridae Arenaviridae Togaviridae Flaviridae ssRNA

Protein Synthetic Replicative New Viral

dsDNA Retroviridae dsDNA

1 (Fig. 1.5). Localized viral replication first occurs at the site of

1 Regional lymph node:

Skin: Focal infection

immunology.206 Work in the horse continues in many of Proinflammatory Cytokines,

Lectin Pathway Classical Pathway Alternate Pathway

Chemotaxis Opsonization Microbial Lysis

(NADPH)-oxidase–dependent respiratory burst. During Adaptive Immunity

CD4 TH1 IFN-γ

Distinguished by cell surface molecules Functional distinctions

Variable region Constant regions Fc region Fab region

TABLE 1.4 Immunoglobulin Isotypes

Ig gene rearrangement Antigen driven

cytoplasmic µ surface surface surface

Variable region genes Constant region genes

IgGa ? IgG(T) IgGb IgGc IgG(T)

V1 2 3 4 5 D1 J2 Cµ Cδ Cγ1 Cγ2 Cγ3 Cγ4 Cγ5 Cγ6 Cγ6 Cε Cα

V5 D1 J2 Cµ Cδ Cγ1 Cγ2 Cγ3 Cγ4 Cγ5 Cγ6 Cγ6 Cε Cα

Complete IgGb heavy chain polypeptide chain

Variable region Constant regions

Immature CD4-/CD8- double negative

Cortex Immature CD4+/CD8+ thymocytes interact

FIG. 1.11 T-cell maturation and selection in the thymus.

MHC I molecule plus peptide

b MHC II molecule plus

cascade that eventually leads to the production of various Costimulatory Signals

Antigen presenting cell

TABLE 1.5 Selected Cytokines

Ontogeny of the Equine Immune System Innate Immune Responses in Foals

TABLE 1.6 Hypersensitivity

Immune Mediator IgE IgG IgG, IgA TH1 TH2 CTL

1) Wash patient RBCs

equine IgE. Although equine IgE has long been known to

2a) Add anti-equine immunoglobulin Ab

Endpoint: agglutination no agglutination

2b) Add complement

Endpoint: lysis no lysis

Prepared SNAPTM unit

1) Add foal serum

Signals are typically displayed as either histograms or dual-

Normal Foal SCID Foal

Side Scatter (granularity)

A Forward Scatter (size)

Normal Foal SCID Foal

EQUINE INTERNAL MEDICINE ISBN: 978-0-323-44329-6

Drug concentration (g/mL)

Conc 10 mg/L Conc 5 mg/L

10 T2 6 hr 300 molecular weight) of free (unbound) drug. Large molecules

Drug concentration (g/mL)

BOX 2.4 Interpreting the Results of Therapeutic Drug Y DOSAGE ADJUSTMENTS IN

Y CONCURRENT USE OF ADDITIONAL 4. Antimicrobial prophylaxis in adult horses with diarrhea