FLUID THERAPY

in dogs and cats

Fabio Viganò
Deborah C. Silverstein
FLUID
THERAPY
in dogs and cats
second edition
Fluid Therapy in dogs and cats - Second Edition
Fabio Viganò, Deborah C. Silverstein
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Authors
Fabio Viganò, DVM, Cert. Emergency Medicine and Surgery,
Specialist in Small Animal Diseases, ECVECC AM
Clinica Veterinaria San Giorgio, San Giorgio su Legnano (Italy)
Deborah C. Silverstein, DVM, DACVECC
Department of Clinical Sciences and Advanced Medicine
University of Pennsylvania School of Veterinary Medicine
Philadelphia, Pennsylvania (USA)
Contributors
Brett Montague, DVM
Department of Clinical Sciences and Advanced Medicine
University of Pennsylvania School of Veterinary Medicine
Philadelphia, Pennsylvania (USA)
Corinna Uboldi, DVM
Clinica Veterinaria San Giorgio, San Giorgio su Legnano (Italy)
Introduction
Fluid therapy is one of the most widely used and necessary therapies for
critically ill patients and those who are not able to hydrate and feed
themselves spontaneously. This handbook, enriched by the contribution of
two specialists, Deborah Silverstein and Brett Montague, to whom I am
sincerely grateful, summarizes the fundamentals for understanding the
water and electrolyte requirements of critical patients, the types of fluids
that can be administered, and the consequences that a decision may entail.
From a scientific point of view, this volume is published at a particularly
relevant time, with the recent developments in orthogonal polarization
spectral imaging; the advancements in hemodynamics, which have made it
possible to assess the real efficacy of therapy and the side effects fluids can
produce if not provided correctly; and the evidence-based advances that
have changed the way fluid therapy in both human and veterinary medicine
is now provided, which is very different from how it had been performed
over the past 30 years.
Far from being an exact science, fluid therapy is based on constant
observation and continuous analysis in order to understand how it should be
provided, monitor its effects, assess its efficacy, and anticipate possible
collateral effects due to inappropriate administration.
Indeed, the history of fluid therapy provides many examples of events
that have resulted in serious injuries and even the death of critical and
noncritical patients; therefore, it has always been the subject of discussion
and reevaluation based on recent discoveries, with regulatory changes
implemented by international health authorities.
An attempt has been made in this book to address the topics
homogeneously, following a functional approach for readers.
Chapter 1 sets out the fundamental concepts of fluid therapy, such as the
principles of hemodynamics and the compartmentalization of fluids in the
body. Understanding the “movement” of water in the body makes it
possible to predict where the administered fluids will be distributed, in
which compartments the water and electrolyte balance will be restored, and,
consequently, what type of fluids should be administered. The fundamentals
of hemodynamics discussed in the chapter provide information on the
methods that can be used to assess the status of the cardiocirculatory
activity and monitor the effects of the fluid therapy provided to a specific
patient at a given moment, dose and frequency, and with a certain mode of
administration.
Chapter 2 discusses the acid–base balance and explains, in a clear way,
the principles of chemistry of organic and inorganic fluids, so that even
veterinarians new to this discipline can assess possible acid–base alterations
and choose the most appropriate treatments for each patient.
Chapter 3 shows all the different types of fluids available and when to
administer them to maintain the hydration status and provide fluid
resuscitation. Even today, an agreement on the volumes and types of fluids
to be administered in these two situations has not yet been reached by the
scientific community.
Chapter 4 examines the electrolyte disorders that very frequently follow
water imbalances: knowing which electrolytes are most commonly
involved, the consequences that an alteration in their concentration may
have, and how such imbalances can be corrected are the main objectives of
fluid therapy.
Chapter 5 addresses hemorrhagic shock and discusses the management
of critically ill patients in order to speed up triage times and find the most
appropriate therapy. This chapter sets out, in a very clear manner, the basic
information needed to recognize what the patient is suffering from, the
consequences, and possible treatment strategies.
Finally, Chapter 6 deals with the correlation between microcirculation
and fluid therapy: understanding the microcirculatory hemodynamic
alterations that may occur and being able to recognize them are two
fundamental steps in choosing the appropriate fluid therapy.
Every chapter ends with a clinical case, which is useful for putting into
practice what has been explained in the text.
This book is aimed at all the veterinarians who are new to fluid therapy,
as well as at experienced practitioners who are used to dealing with
emergency patients and who, after the latest findings in this field, are
interested in expanding their knowledge.
Fabio Viganò
Table of contents
1. Fundamentals of Fluid Therapy, Hemodynamics and
Compartmentalization of Fluids in the Body
Fabio Viganò
Introduction
Dynamics and hemodynamics of fluid compartments
Water
Blood volume and cardiac output
Parameters to evaluate the hemodynamic response
Blood volume
Evaluation of cardiac output and stroke volume
Central venous pressure and pulmonary artery occlusion pressure
Clinical hemodynamic monitoring
Water distribution in the body
Osmotic pressure
Colloid oncotic pressure
Glycocalyx
Clinical consequences of the glycocalyx model

■ Clinical Case.
Dehydrated dog with respiratory alkalosis

2. Acid–Base Disorders
Fabio Viganò
Introduction
Chemical species involved in the acid–base balance
Traditional approach
Blood gas analyzers
Interpretation of blood gas analysis
Primary disorder
 Compensatory responses
Base excess (BE)
Anion gap (AG)
Total oxygen content (CaO2)
Oxygen parameters to evaluate the effectiveness of oxygenation
Rule of 5
Rule of 120
Strong ion theory (Stewart’s approach)
Chemical species involved
Dependent and independent variables
Examples of pH variations according to the nontraditional approach
Fluid therapy and SID
Clinical case, example
Strong ion gap (SIG)
Correction of acid–base disorders
Metabolic acidosis
Metabolic alkalosis
Respiratory acidosis
Respiratory alkalosis
Mixed disorders

■ Clinical Case.
The cat who couldn’t urinate

3. Fluids: when and how to administer them

Fabio Viganò
Introduction
Daily intravenous fluid therapy
Daily water requirements
Hypotonic solutions
Antidiuretic hormone and fluid therapy
Fluid therapy under general anesthesia
Daily fluid therapy
Hydration
Calculation of daily fluid therapy
Hemodynamic monitoring
 Heart rate and cardiac output
Pulse quality
Capillary refill time (CRT)
Mucous membrane color
Body temperature
Jugular vein distension
Urine production
Parameters to evaluate the hemodynamic status
Invasive blood pressure (IBP) measurement
Measurement of lactatemia
Fluid resuscitation
Goal-directed therapy
ROSE model (Resuscitation, Optimization, Stabilization, Evacuation)
Crystalloids
Isotonic solutions
Hypertonic solutions
Colloids
Synthetic colloids
Natural colloids

■ Clinical Case.
Consequences of gastroenteritis

4. Electrolyte Disorders
Fabio Viganò, Corinna Uboldi
Introduction
Osmosis
Osmolarity and osmolality
Sodium
Hyponatremia
Hypernatremia
Potassium
Hypokalemia
Hyperkalemia
Calcium
Hypocalcemia
 Hypercalcemia
Phosphorus
Hyperphosphatemia
Hypophosphatemia
Chloride
Hyperchloremia
Hypochloremia
Magnesium
Hypomagnesemia
Hypermagnesemia

■ Clinical Case.
Electrolyte and acid–base imbalances during vomiting

5. Hemorrhagic Shock
Brett Montague, Deborah C. Silverstein
Introduction
Pathophysiology of hemorrhagic shock
Compensatory shock
Early decompensatory shock
Late decompensatory shock
Metabolic sequelae of hemorrhagic shock
Etiology of hemorrhagic shock
Diagnosis
Laboratory data
Monitoring
Shock index
Ultrasonography
Clinical management
Triage
Hypotensive resuscitation
Fluid therapy in hemorrhagic shock
Postresuscitation care
Reperfusion injury
Trauma-induced coagulopathy
■ Clinical Case.
Hemorrhagic shock following a ruptured hepatocellular carcinoma

6. The Microcirculation and Fluid Therapy

Deborah C. Silverstein
Introduction
Structure and function of the microcirculation
Microvascular perfusion – systemic control
Microvascular perfusion – local control
Microvascular changes with trauma and hemorrhagic shock
Microvascular changes with sepsis
Monitoring of the microcirculation vs. macrocirculation
Effects of fluid resuscitation on the microcirculation in trauma and
hemorrhagic shock
Effects of fluid resuscitation on the microcirculation in sepsis
Conclusion

■ Clinical Case.
Microcirculatory changes in a dog with sepsis secondary to bite wounds
Fundamentals of Fluid
Therapy,
Hemodynamics and
Compartmentalization
of Fluids in the Body
 CHAPTER
1

Fabio Viganò

Introduction
Fluid therapy has traditionally been used for various purposes and
administered by medical staff based on empirical knowledge and
mathematical formulas, without a full understanding or appreciation that
fluids can be considered drugs. The success or failure of the entire patient’s
treatment plan can depend on the adequate or ill-suited use of fluids, for
example, in terms of duration of administration, type and delivery method.
The aim of evidence-based medicine (EBM) should be to resolve such
issues and point to the most effective procedure. EBM in human medicine
does not provide clear guidance since results have been unclear and at times
conflicting. In veterinary medicine, the relatively low number of patients
and the absence of large-scale studies have not allowed EBM data to be
collected and analyzed. Fluid therapy in veterinary medicine was therefore
developed on guidelines based on human medicine. This type of approach
can be the cause of errors that prove difficult to identify since our patients’
hemodynamics are rarely accurately monitored and their water and
electrolyte balance is not recorded.
Another factor that hampers data collection in veterinary medicine is the
difficulty in defining clear guidelines. Many veterinary clinics may not be
able to follow them due to a lack of financial resources (clinic or patient’s
owner) or technological resources (necessary equipment). Moreover, the
conditions of many critical patients cannot be fully studied as all treatments
or analyses must be stopped once the owner asks for their animals to be
euthanized. These are the main reasons why there are so few veterinary
clinics capable of collecting EBM data that can be used to improve fluid
therapy and better understand the patients’ conditions (Box 1.1). The
scarcity of such data in small animals and the discrepancy between the
information, conclusions, and guidelines can be the cause of basic mistakes,
and the fluid therapy provided may therefore not be in line with the
patients’ needs. To reduce such mistakes and to correctly evaluate the
inefficacy and the strengths and weaknesses of fluid therapy, it is necessary
to carefully monitor the patient’s hemodynamics as well as osmotically and
oncotically active molecules.

Box 1.1 Fluid therapy indications

Maintenance of hydration
Restoration of lost fluids
Restoration of blood flow
Drug administration
Hemodynamic support

Dynamics and hemodynamics of fluid

compartments
The infusion of water-based solutions in the body can restore, expand or
contract one or more body fluid compartments. Knowing the structure of
the vascular wall and understanding how different types of fluids behave in
different compartments are the first and most fundamental steps to be able
to decide on which fluids should be administered and in what amounts.

Water
Some isotopes—both radioactive and nonradioactive, such as tritium and
deuterium—can be used to quantify the amount of water present in an
organism. It can take an expert operator up to 3 hours to complete the
procedure, which makes it impractical from a clinical point of view. The
process used to quantify the plasma volume is just as complex and difficult.
It entails the administration of iodinated albumin followed by the collection
of 3–4 blood samples (every 10 minutes for 40 minutes). This methodology
is not considered accurate, and the value is estimated at 0.91 that of humans
[1].
 To calculate the red blood cell mass, tracers such as chromium or
technetium can be used. Carbon monoxide, which is not a tracer but is
toxic, can also be used. The volume of water in the interstitial and
intracellular spaces cannot be measured using tracing molecules and is
therefore calculated by subtracting the plasma volume and the ECF
(extracellular fluid) from the total water measured.
These methods may be more accurate than static and dynamic clinical
evaluations but are more complex and difficult to perform in clinical
practice. For this reason, they tend to be preferred for research and are not
part of the standard practices of most veterinary clinics. In addition, to
correctly perform these procedures, the patient’s hemodynamics must be
stable, which is difficult to achieve when patients are in critical condition.
The redistribution of crystalloid fluids takes about 30 minutes, which makes
precise measurements very impractical.
For the above reasons, it is common practice to use a clinical estimation
of the amount of water in the body (hydration levels, see Chapter 3), which
is imprecise and subjective.

Blood volume and cardiac output

Blood volume (BV) and cardiac output (CO) can be measured with methods
that can be used in clinics and with critical patients. One such method is
PiCCO (pulse contour cardiac output), which requires correct
catheterization of a major artery (e.g., the femoral artery) and the placement
of a central venous line. The arterial catheter is inserted using the Seldinger
technique and is equipped with a thermistor and a light, which allows
continuous arterial pressure measurement. A standard central venous
catheter is used, but it is connected to a sensor that measures temperature.
The pulse contour in its systolic phase provides an estimation of the stroke
volume (SV), which, when multiplied by the heart rate, gives the CO. SV is
a very useful parameter to monitor increases in CO following fluid therapy
to restore the circulating volume in patients that are “fluid responders”.
Fluid responders are defined as such when a single bolus of fluids is enough
to improve the CO or any other parameter used to determine whether a
patient is in the ascending part of the Frank–Sterling curve (see Chapter 3,
Figure 3.8). The technique requires calibration to measure the patient’s
vascular compliance.
 Thanks to thermodilution, the instrument can measure the difference
between the temperature of the fluid when injected (typically, saline or 5%
glucose solution at 0–4 °C) and that when it comes out of the catheter. This
technique provides information on cardiac performance, global end-
diastolic volume (GEDV), intrathoracic total blood volume (ITBV), extra
vascular lung water (EVLW), and cardiac functionality index (CFI). The
instrument can also calculate stroke volume variation (SVV) and systemic
vascular resistance (SVR). This technique is difficult to perform in small-
sized animals and in those with arrhythmias or aortic insufficiency, but it
does not require a pulmonary arterial catheter, is quick to complete, and
provides sufficient information on the pulse.
Another method to obtain information on blood volume (BV) is lithium
dilution cardiac output (LiDCO), which includes two procedures: the
analysis of the pressure curve (Pulse CO System) and lithium
thermodilution (LiDCO System). The Pulse CO algorithm is based on the
correlation between the strength of the pulse and the net output and turns
the pressure/time curve into a volume/time curve. This method only
measures variations in the SV, not its magnitude. The LiDCO system uses
lithium thermodilution. The ion is administered in a bolus in either a
peripheral or central vein; a sensor is then inserted into a peripheral arterial
line to measure its dilution and thus the CO. This method can use both
peripheral venous and peripheral arterial blood vessels. LiDCO, as opposed
to PiCCO, can measure pulse pressure variation (PPV). Both methods
ensure the correct measurement of the patient’s CO and response to fluid
administration, and of the hemodynamic variations caused by the positive-
pressure ventilation.
LiDCO measures the invasive blood pressure (IBP), SV, CO, PPV, SVV
and SVR and has the advantage of being minimally invasive (peripheral
vascular lines) and provides continuous information on hemodynamics. The
major disadvantages of this technique are that the blood that comes into
contact with the lithium electrode is toxic, lithium interferes with some
drugs (e.g., muscle relaxants), instruments have to be correctly calibrated
from the beginning, results may be unreliable in patients with intracardiac
shunts, and the values can be altered by severe aortic regurgitation and
aortic counterpulsation.
Since both LiDCO and PiCCO are difficult procedures to perform, other
techniques have been developed to monitor the dynamic parameters that
depend on the blood volume and effectiveness of fluid therapy to correct
possible deficits (Box 1.2).
Another method that can be used to evaluate a patient’s blood volume is
the measurement of the LA/Ao (left atrium/aorta) ratio with an ultrasound
scanner. This is done by obtaining a parasternal view of the heart both
longitudinally and transversely. The standard values for both cats and dogs
in the transverse view are 1–1.5 (Figure 1.1). In cats, a ratio between the
aorta and left atrium greater than 2.5 is considered indicative an atrial
pathology.
In patients with clinical signs of hypovolemia, a decrease in the size of
the left atrium can confirm the disease. On the other hand, an increase in the
left atrial diameter with no retrograde congestive heart failure or
cardiomyopathy confirms hypervolemia.
An examination of the cardiac chambers in the long- and short-axis
views can be useful to diagnose hyper- or hypovolemia. A skilled operator
capable of performing ultrasound scans in emergency medicine can easily
notice an increase in the size of the cardiac chambers and therefore roughly
evaluate the total blood flow (Figures 1.2 and 1.3).

Methods to assess cardiac output with

Box 1.2
calibration

PiCCO (pulse contour cardiac output)

LiDCO (lithium dilution cardiac output)
Figure 1.1 LA/Ao ratio. Parasternal transverse transaortic view of the heart (aortic ratio: LA size
divided by Ao diameter). LA, left atrium; Ao, aorta.

Figure 1.2 Short-axis view. In the short-axis view, it is possible to measure the left ventricular
internal size when the papillary muscles are visualized at the end of diastole. RV, right ventricle; LV,
left ventricle.
Figure 1.3 Long-axis four-chamber view. The long-axis view is useful to evaluate the size of cardiac
chambers. RV, right ventricle; LV, left ventricle; RA, right atrium; LA, left atrium.

Parameters to evaluate the hemodynamic response

The parameters used to measure “fluid responsiveness” are divided into
dynamic and static parameters (Box 1.3). Dynamic parameters are useful to
assess whether a patient is in the ascending part of the Frank–Sterling curve
(see Chapter 3, Figure 3.8) and is therefore responsive to fluid therapy, or
whether it is in the flat part of the curve, which could suggest no response
to emergency fluid therapy and a possible circulatory overload. Static
parameters, if measured at regular intervals, can provide a trend of the
hemodynamic response.
Two typical examples of dynamic parameters are CO and SV measured
at regular intervals over time. Unfortunately, the measurement of both
parameters, in veterinary medicine, is only performed in research centers
and cannot be part of the clinical routine because of the invasive nature of
the procedure, the fact that only specialized clinicians can perform it, and
the cost of the whole process. In veterinary medicine, it is possible to use
methods that can repeatedly and accurately measure parameters correlated
with CO and SV; these must precisely measure variations caused by
emergency fluid therapy but should not be skewed by factors other than the
increase in preload. Point-of-care ultrasound (POCUS) scans can measure
the LA/Ao ratio, the diameter of the caudal vena cava (CVC), and the
collapsibility index of the caudal vena cava (CVCCI).
The patient’s heart rate (HR) can also be useful to identify fluid
responders. Unfortunately, the HR can be influenced by factors such as
pain, endogenous or exogenous catecholamines, or hyperexcitement. The
techniques that use POCUS can be quickly learned, depending on the
operators’ familiarity with the instrument.
The CVC diameter can be measured in three specific views: suprailiac,
right intercostal, and subxiphoid. The latter view is where the measurement
is most dependent on the operator’s skill. The subxiphoid view is the easiest
to obtain: the probe must be positioned longitudinally, below the xiphoid
cartilage and pointing towards the cranium, so as to show the diaphragm.
The probe is then oriented to show the CVC as it crosses the diaphragm
(Figure 1.4). This method is very quick and easy and can be performed
during the abdominal FAST (AFAST) without affecting the procedure.

Hemodynamic parameters: static and

Box 1.3
dynamic
Static Dynamic
Clinical history
Clinical examination Clinical evaluation, dynamic if repeated
Thoracic X-ray SVV
CVP PPV
PCWP Esophageal Doppler
Bioimpedance CVC
End expiratory occlusion
Figure 1.4. The subxiphoid view shows a normal CVC as it crosses the diaphragm. CVC, caudal
vena cava.

The right intercostal (also called hepatic) view is obtained by positioning

the probe parallel to the ribs, more precisely at the 10th–12th intercostal
space, and then by moving the probe from the hypaxial muscles towards the
ventral part of the thorax. If only the lung is visible, the probe should be
moved down one or more intercostal spaces. If only the right kidney is
visible, the probe should be moved up. The optimal position allows the
CVC, the portal vein, and the aorta to be seen at the same time (Figure 1.5)
just below the hypaxial muscles, close to the proximal part of the rib. When
air is present, the probe should be moved down in order to correctly see the
CVC. It is necessary that both the CVC and the aorta are visible at the same
time.
The suprailiac (also called paralumbar) view is achieved by positioning
the probe below the last right rib, guiding it towards the right kidney, and
then performing a medial rotation until the aorta and CVC are visible
(Figure 1.6). Once this is done, the probe should then be rotated to achieve
a longitudinal view of the vessels, which should be parallel to each other
(Figure 1.6). Variations in the CVC diameter are dictated by intra-aortic
pressure variations in the two phases of respiration. During the inhalation
phase, the negative pressure inside the thorax drives the blood from the
abdomen towards the right atrium, causing maximum CVC diameter
reduction. During the expiration phase, the opposite occurs, causing
maximum CVC relaxation.

Figure 1.5 Hepatic view (right 10th–12th intercostal space) showing the CVC, aorta and portal vein.
CVC, caudal vena cava; Ao, aorta; PV, portal vein.
Figure 1.6. Paralumbar view (suprailiac) view of the CVC and aorta. CVC, caudal vena cava; Ao,
aorta.

Hypovolemia causes the diameter of the CVC to be decreased; an

increase in the CVC diameter following fluid administration demonstrates a
positive response to emergency fluid therapy. This may also occur in cases
of mitral valve regurgitation. The sole monitoring of the CVC diameter is
not enough to measure the response to fluid therapy continuously and
precisely. The variation in the CV diameter between inhalation and
expiration is called CVCCI and can be calculated using the following
formula:

CVCCI, collapsibility index of the caudal vena cava; CVCd max, maximum diameter of the caudal
vena cava; CVCd min, minimum diameter of the caudal vena cava.

Values above 50% could indicate hypervolemia, hence the risk of an

increase of extravascular lung water (EVLW), congestive heart failure, or
cardiac tamponade. Values below 50% are usually recorded in hypovolemic
patients. The variation in the diameter of the CVC in hypovolemic patients
is very low and the CVC may appear as a collapsed vein that does not
expand during the respiratory cycle. In hypervolemic patients, the CVC
diameter does not change and will appear as a dilated blood vessel that has
lost its elasticity. A patient’s response to fluid therapy can be proved if,
following the administration of one or more boluses, there is relaxation of
the CVC. CVC diameter measurement can be invalidated by cardiac
performance, the intraabdominal and intrathoracic pressures, anxiety,
tachycardia, pregnancy, physical activity, stress, obesity, diabetes, and
kidney failure. This promising diagnostic tool remains to be validated
through publications involving a significant number of dogs and especially
cats.
A dedicated study [2] has successfully demonstrated the possibility of
evaluating whether patients are fluid responders by administering a small 4
mL bolus of Ringer’s lactate in 1 minute and measuring the left ventricular
end-diastolic internal diameter normalized to body weight (LVIDDn), the
left ventricular volume score (LVVS), the left ventricular end-diastolic
volume index (EDVI), and the aortic velocity time integral (VTI).
Unfortunately, this technique requires advanced skills since inaccurate
measurements can lead to errors in data interpretation. The measurement of
hemodynamic parameters has made the use of ultrasound in veterinary
emergency medicine and intensive care increasingly important. The
ultrasound scanner can be used to view the abdomen and respiratory system
but also to dynamically monitor the efficacy of fluid therapy.
A new method that has to be yet validated in veterinary medicine is
electrical velocimetry (EV). EV can detect CO and SVV [3] but should be
studied in a sufficient number of patients, both awake and under general
anesthesia. In human medicine, the dynamic parameters that can be used to
identify fluid responders are SVV (stroke volume variation), SPV (systolic
pressure variation) and PPV (pulse pressure variation). The correlation
between BV and SPV variations is well understood [2]. PPV is also
strongly correlated with SVV and is less affected by variations in SPV [3].
PPV is a more reliable parameter to measure the patient’s hemodynamic
response to fluid therapy than SVV, since it is measured directly and not
through specific instruments that use PCA (pulse contour analysis).
Another parameter commonly used in human medicine to determine the
response to fluid therapy, which is strongly correlated with PPV, is PVI
(pleth variability index). PVI is an automatic, noninvasive, and continuous
measurement performed by a specific instrument (Radical 7® Masimo),
which can detect plethysmographic variations and hence hemodynamic
variations during the respiratory cycle.
Increased variations during spontaneous respiration or positive pressure
ventilation (PPV) point to a reduced blood volume (i.e., preload) or
increased intrathoracic pressure. PVI is a variation of PI (perfusion index)
during the respiratory cycle; in human medicine, values greater than 10–
15% point to a reduced blood volume and to the fact that an increased blood
volume can lead to an increased CO and, therefore, to greater
responsiveness to fluid therapy. PVI is inversely proportional to the blood
volume, which means an increase in PVI indicates a reduction in blood
flow. The higher the PVI readings, the more severe the hypovolemia.
PI is a percentage of the light intensity emitted by the diode and the light
absorbed by the pulsatile arterial blood in circulation. It measures the
strength of the signal and the local vasomotor tone, and its values are
between 0.02% and 20%. In human medicine, values above 1% are
considered normal. PI can vary depending on the patient and on where the
measurement is performed. It is measured using the following formula:

AC, infrared light absorbed by the pulsatile arterial blood; DC, light emitted by the diode and
absorbed by the skin, the pulsatile arterial blood, and interposed tissues.

PVI is calculated by measuring PI over a sufficient period of time to

allow one or more respiratory cycles, using the following formula:

In human medicine, in 81% of cases, values above 14% indicate

responsiveness to fluid therapy. Values below 14% indicate
nonresponsiveness to fluid therapy in 100% of cases. It has also been
demonstrated that the administration of fluid therapy based on the careful
monitoring of PPV and PVI can improve the outcome [6] and optimize the
hemodynamic condition of patients undergoing abdominal surgery [7]. The
shortcomings of this monitoring method are that values may be altered in
case of an increase in abdominal pressure or right-heart failure, it is
necessary to have a sinus rhythm and the thorax must be closed, it has not
been validated in veterinary medicine, and PI and PVI may vary in animal
patients between spontaneous and controlled breathing (Box 1.4).

Box 1.4 Hemodynamic response monitoring

Parameters to evaluate the hemodynamic response

PPV (pulse pressure variation)
PVI (pleth variability index)
PI (perfusion index)
Hemodynamic support
Blood volume
The measurement of BV in animal patients requires an invasive procedure
that is difficult to perform. This explains why many studies are being
conducted on how to evaluate BV and the response to fluid therapy through
biodynamic parameters, such as the CVC diameter. The CVC has a very
thin wall sensitive to internal volume variations. During the respiratory
cycle, the CVC diameter varies. It should be highlighted that the venous
compartment holds around 2/3 of the blood volume and that the CVC is the
largest venous vessel in animals. During the inspiration phase, the negative
pressure inside the thorax reduces the blood flow inside the CVC, while
during the expiration phase the increase in the thoracic pressure causes a
greater flow of blood into the CVC, thereby increasing its diameter. Precise
measurement of the CVC during the two phases was performed in a recent
study [8]. Data have highlighted that the CVC/aorta diameter ratio,
measured in the lumbar region of the left kidney, can be used to evaluate
BV in dogs undergoing blood transfusion. This technique could become a
noninvasive method to evaluate the decrease in BV after a severe blood
loss. Its significance and accuracy in cases of circulatory overload or
following excessive fluid administration are not known. No similar study
has been performed in cats. Some limitations of this technique are the
impossibility to record data continuously, the probable unreliability when
intra-abdominal pressure increases (e.g., postsurgery or when fluids are
present in the abdomen cavity), and the patient’s morphology.

Evaluation of cardiac output and stroke volume

A noninvasive method to measure both SV and CO is esophageal Doppler.
This is done by inserting an ultrasound Doppler probe through the mouth
into the esophagus. By measuring the diameter of the aorta and the
distribution and velocity of the blood flow, the probe can evaluate the
cardiac preload [9]. The main drawbacks of this technique are the need to
perform general anesthesia and intubate the patient to protect the airways
from gastric contents in the event of vomiting, the need to recalibrate the
measurements every time, and the impossibility to monitor the parameters
continuously. Transesophageal echocardiography is similar to esophageal
doppler in terms of the parameters being measured, advantages and
disadvantages, but its reliability in animals has not been validated.
Bioimpedance, a technique used in human medicine to evaluate body
fluids, uses weak electrical currents that travel through tissues and are
hindered by the presence of water. In human medicine, this technique has
been used to evaluate both the intracellular fluid (ICF) and extracellular
fluid (ECF). In veterinary medicine there are no publications on this
technique in small animals. It is a static measurement of BV and, in
humans, it is strongly correlated with total water, which makes it useful in
treating congestive heart failure, during dialysis and terminal stage kidney
failure. It is not useful to determine the intravascular volume and the
response to fluid therapy [10] (Box 1.5).

Central venous pressure and pulmonary artery occlusion

pressure
Central venous pressure (CVP) and pulmonary artery occlusion pressure
(PAOP, or pulmonary capillary wedge pressure, PCWP) are static
parameters of preload and have been used evaluate the patient’s response to
fluid therapy, but recent studies in veterinary and human medicine have
questioned their reliability [11–13].
Their use is therefore not recommended to measure BV or as a tool to
assess the response to fluid therapy in critical patients or when excessive
amounts of fluids have been administered, since CVP increases over normal
values only when vessel compliance (elasticity of venous walls, especially
in large vessels) has been exceeded.

Parameters to evaluate blood volume,

Box 1.5
cardiac output and stroke volume

Assessment of blood volume

POCUS (point-of-care ultrasound)
CVC (caudal vena cava) diameter and CVCCI (CVC diameter
variations)
 Cardiac output and stroke volume
Esophageal Doppler
Transesophageal echocardiography
Bioimpedance
Electrical velocimetry

CVP is the pressure in the venous part of circulation, while mean arterial
pressure (MAP) is the pressure in the arterial part of circulation. CVP is
useful to detect decreases in CO in cardiogenic shock caused by insufficient
preload; in these cases, a reduction in CVP indicates the need to administer
fluids, while high values suggest tension pneumothorax or lung
thromboembolism. CVP is also useful to manage chronic heart failure since
high values cause a deterioration of kidney functions. CVP could be
considered as the interstitial compartment’s “exit” pressure.

Clinical hemodynamic monitoring

When it is not possible to assess hemodynamic parameters and the efficacy
of fluid therapy or vasoactive amines through dynamic monitoring with
POCUS or an invasive method, it is advisable to request the patient’s
history and to repeatedly perform clinical (Chapter 3) and lab monitoring in
order to determine at the very least the following parameters:
state of consciousness;
capillary refill time and mucous membrane color;
heart rate;
body temperature;
jugular vein relaxation;
mean arterial pressure and systolic arterial pressure;
pulse (characteristics and quality);
skin (elasticity, turgor, dryness, temperature at extremities);
shock index (HR/SAP, ≥0.9 unfavorable prognosis);
peripheral edema;
urine production and its specific weight;
lactatemia;
urea or creatinine.
Some of these parameters (pulse, state of consciousness, skin, CRT) are
subjective and not absolute points of reference. The values of such
parameters should be explained when choosing the therapy, in the medical
report, and at shift changes to reduce the possibility of mistakes and so
clinicians and the paramedical staff can make decisions based on the same
standards. Unfortunately, clinical monitoring is not reliable to evaluate BV
and it cannot identify fluid responders, even if an improvement in these
parameters would indicate a positive response to the treatment. The more
clinical parameters are recorded, the more accurate they will be in
monitoring the hemodynamic status.

Water distribution in the body

Water makes up around 60% of the total body weight. ECF is the water
present in the intravascular and interstitial compartments, while ICF (Figure
1.1) is intracellular water.
The fluid compartments and the water contained in them are:
intracellular (67%, about 0.4 L/kg);
interstitial (25%, about 0.13 L/kg);
intravascular (8%, about 0.06 L/kg).
Fluid therapy should not solely be based on the quantity of water present in
the body in normal conditions and on the water lost by the organism. It
should also take into consideration the patient’s hemodynamic parameters
and their water and electrolyte balance just before fluid administration. As a
matter of fact, any conditions prior to the body losing fluids and alterations
caused by the pathological process can change the patient’s needs, and the
composition and amount of fluids necessary and how they should be
administered. Two patients suffering from the same pathology causing
dehydration or compromising the efficacy of blood circulation may have
different needs. For example, a patient suffering from chronic congestive
heart failure caused by mitral regurgitation will have a limited tolerance to a
rapid infusion of large volumes of crystalloids compared to a patient whose
hemodynamic parameters are not affected by increases in pulmonary
arterial pressure. Water moves in the three compartments according to
osmotic and oncotic gradients. The walls dividing the three compartments
are the vascular and cellular walls (see Figure 1.7). The first is permeable to
water and small solutes such as sodium, chloride and potassium (the
diameter of sodium is 2–3 angstroms [Å], chlorine 2 Å and potassium about
2.2 Å). The smaller pores of the vascular membrane have a diameter of
about 40–45 Å. The cellular wall, on the other hand, is only permeable to
water (Box 1.6).

Osmotic pressure
Osmotic pressure is exerted by small particles such as sodium, urea, and
glucose, while oncotic pressure is exerted by large molecules, such as
proteins and hydroxyethyl starches.
The osmotic pressure can be calculated using the formula below (Box
1.7):

Normal osmotic values are about 310 mOsm/L in dogs and 320 mOsm/L
in cats. These can be measured with a specific tool, the osmometer. The
formula also shows that osmotic pressure is mostly exerted by chloride
(about 140 times 2) and, to a lesser extent, by glucose (about 100 divided
by 18) and nonprotein nitrogen (about 25 divided by 2.8).
Figure 1.7 Fluid compartments. ECF, extracellular fluid; ICF, intracellular fluid.

Box 1.6 Distribution of water in the organism

Water makes up around 60% of the total body weight, divided in:
intracellular: 67%, about 0.4 L/kg
interstitial: 25%, about 0.13 L/kg
intravascular: 8%, about 0.06 L/kg

Box 1.7 Osmotic and oncotic pressure formulas

 Osmotic pressure
Osm = 2 [Na+] + glucose (mg/dL)/18 + BUN (mg/dL)/2.8

Oncotic pressure
COP = (2.1 × PT) + (0.16 × PT) + (0.09 × PT)

BUN (blood urea nitrogen), azotemia; COP, osmotic colloid pressure;

[Na+], concentration of sodium in the blood; Osm, blood osmolality; PT,
total proteins.

Following the law of mass action, an increase in osmotic pressure in one

of the compartments separated by a semipermeable membrane causes the
movement of water from the compartment with a lower concentration
towards the compartment with a higher concentration, in an attempt to
balance the system in terms of particles present on both sides of the
membrane. Particles with an electric charge must be present in equal
amounts in compartments divided by a semipermeable membrane. The
osmotic pressure is therefore driven by the number of active particles
present in the solute inside the compartment.
For example, in cases of kidney failure with an increase in azotemia, or
in cases of hyperosmolar syndrome or illnesses such as diabetes mellitus
with an increase in blood glucose, the osmotic pressure inside in the
intravascular (IV) compartment will increase, causing water to move
towards this compartment and therefore dehydration of the extravascular
compartment. For the same reason, when the sodium concentration inside
the IV compartment increases (e.g., after the intravenous administration of a
hypertonic saline solution), water moves from the extravascular
compartment towards the IV compartment, causing an increase in blood
volume.
The same osmotic gradient can be exerted by a semipermeable
membrane, such as a cell wall, when the concentration of sodium or other
osmotically active molecules increases inside the cell. In these cases, the
amount of water increases and may cause cellular edema. When this
happens inside the brain, alterations of the state of consciousness may
occur, such as stupor, coma or death. Unlike cellular walls, vascular walls
allow the passage of some proteins, causing a continuous exchange of
proteins between the intravascular and extravascular compartments, with a
continuous flow of fluids through the capillary membranes between the
compartments. This flow is called transcapillary escape rate (TER), and
generally refers to albumin.

Colloid oncotic pressure

The oncotic gradient is created by the large molecules inside the IV
compartment. All molecules larger than 10 000 dalton can increase colloid
oncotic pressure (COP). The molecules naturally present in the IV
compartment and capable of generating this gradient are albumins,
globulins, and fibrinogen. Albumin is the smallest and its molecular mass is
69 000 dalton and diameter about 140 Å, but it is also the most abundant.
The oncotic gradient generated by large molecules is calculated with a
formula derived from Starling’s law, and published in 1896:

Jv, transvascular flow; Kf, filtration coefficient; Pc, capillary hydrostatic pressure; Pif, interstitial
hydrostatic pressure; πc, COP plasma; πif, interstitial COP; σ, reflection coefficient; Q lymph,
lymphatic drainage.

This formula suggested that the main driver of fluid movement (Jv) to
and from the IV compartment was hydrostatic pressure (intravascular and
interstitial). Hydrostatic pressure was therefore the main driver of an
increase in Jv, and for the same reason decreases in COP would increase Jv.
Conversely, increases in COP would lead to movement of fluids from the
extravascular space towards the intravascular space. This has led to
treatments that were not producing the expected results. For example, the
administration of solutions containing albumin did not lead to water
reabsorption from the interstitial sapce, while increases in hydrostatic
pressure were responsible for a short-term increase of Jv, which did not
occur in a state of hemodynamic equilibrium.
Thanks to studies on the vascular wall with the use of electronic
microscopy (e.g., using the orthonormalization method in ghost imaging)
and dilution techniques with dextran or indocyanine green, it was possible
to observe the internal surface of the vascular endothelium, where a viscous
substance called glycocalyx was found, the influence of which on Jv has
been evaluated.
Glycocalyx
The glycocalyx is a layer of glycoproteins and proteoglycans attached to the
endoluminal surface of blood vessels and negatively charged. The core is
made up of proteoglycans (syndecan, glypican, and versican) to which long
sulphate molecules (such as heparan, dermatan, hyaluronic acid, and
chondroitin sulfate) attach to create a surface resembling marine algae
(Figure 1.8).
Molecules positioned in this way dynamically interact with coagulation
factors and with the complement system/cascade that regulates the
permeability of blood vessels. The small space just below the glycocalyx is
called sub-glycocalyx. It has its own oncotic pressure (πsg), mostly exerted
by albumin, which creates a gradient between the endoluminal oncotic
pressure and the sub-glycocalyx. The sub-glycocalyx oncotic pressure
contributes to control Jv.

Figure 1.8 Representation of an electronic microscope scan of the glycocalyx. (A) Section of a
vessel with intact glycocalyx. (B) Detail of the glycocalyx.

The glycocalyx covers endothelial receptors as well as other molecules

attached to the endothelial membranes. Its average thickness is about 2 μm
and it stretches over a surface of about 350 m2. In humans, it has a volume
of about 1700 mL and the fluids it contains are not part of the total
circulating volume. It is thicker in large vessels (8 μm) and thinner in small
vessels (0.2 μm). The glycocalyx is semipermeable to albumin, to
molecules with a molecular weight below 70 kDa, and to dextran; it is
impermeable to red blood cells (RBCs).
The glycocalyx present in most capillaries acts like a plasma filter for
large molecules and is permeable to water. The glycocalyx divides the
intravascular space in three areas (Figure 1.9): the central area (plasma
volume), a noncirculating fluid component and the RBCs.
The vascular wall is different in the capillaries of the various tissues,
which is why crystalloids are useful in increasing blood volume: because of
their structure, they do not exit the capillaries of tissues (e.g., the brain,
muscles, lungs, connective tissues and capsules of parenchymatous organs)
and therefore increase the intravascular space. Conversely, when excessive
fluids are administered and there is damage to the vessel wall, crystalloids
can distribute to the ECF, causing interstitial edema and a possible
compartment syndrome [14].
In human anatomy, the blood vessels of the nervous system, muscles,
connective tissues, and lungs are terminal vessels, while endocrine blood
vessels and vessels of the choroid plexus and intestinal and glomerular
mucosa are fenestrated. However, the glycocalyx is not present in the blood
vessels of the liver, spleen, and bone marrow, and the fenestrations they
present thus allow the passage of macromolecules such as chylomicrons
and lipoproteins. For this very reason, COP does not influence the flow of
fluids through the vascular wall, but rather the flow depends predominantly
on the hydrostatic pressure in the lymphatic system (Figure 1.10) [14].
Figure 1.9 Vascular wall and glycocalyx. RBCs, red blood cells.

Figure 1.10 Capillary phenotypes with respective fenestration diameters.

According to the glycocalyx model, Jv is also influenced by the filtration

coefficient (Kf), which can affect vascular permeability, since an increase in
Kf helps the flow of water towards the extravascular space. Kf is the result
of the total capillary surface multiplied by the hydraulic conductivity and
the reflection coefficient (σ). The reflection coefficient influences the
permeability of plasma proteins and when their molecular weight exceeds
70 KDa, they become impermeable, thus generating oncotic pressure. A σ
equal to 1.0 indicates total impermeability of the membrane, while a σ equal
to 0.0 means molecules can freely pass through the membranes. In cats and
dogs, σ varies between 0.83 and 0.92. In humans, σ for albumin is
approximately 0.90–0.95 in the muscles, approximately 0.50–0.65 in the
lungs, and 0.8 in the intestine and subcutaneous tissue.
The Starling formula (Equation 4) was modified following the
knowledge provided by the study of the vascular walls and is now known as
the Michel–Weinbaum formula:

Jv, transvascular flow; Kf, filtration coefficient; Pc, capillary hydrostatic pressure; Pi, interstitial
hydrostatic pressure; σ, reflection coefficient; π p, plasma COP; πsg, sub-glycocalyx COP.

Clinical consequences of the glycocalyx model

The new formula considers the COP of the sub-glycocalyx (πsg) and that of
the IV compartment (πp) to be decisive, instead of the COP of the IV and
interstitial spaces.
This review [15] and the study of vascular walls suggest that Jv depends
predominantly on hydrostatic pressure; that an increase in COP at normal
capillary pressures (20 mmHg) does not cause the reabsorption of fluids
from the interstitial space; and that increases in the hydrostatic pressure (Pc)
above the oncotic pressure are responsible for a linear increase in Jv,
enough to drive a sudden rise in the filtration/hydrostatic pressure curve
(Figure 1.11). Experimental studies conducted on the mesenteric vessels of
frogs and rats have demonstrated that rapid increases in Pc cause a linear
rise in Jv, but when, under conditions of hemodynamic stability, Pc was
lower than πp, there was no reabsorption of fluids from the interstitial space.
When administering fluid therapy with crystalloids, even if pulmonary
capillaries have a very low Pc (between –5 mmHg and –10 mmHg), it is
important, to avoid pulmonary edema, to carefully monitor the blood COP
to ensure it is not excessively reduced, since this would increase the Jv and
cause interstitial edema.
 This new revision also demonstrates that, under normal conditions, the
plasma, interstitial fluid, and lymphatic system are placed in series, and
fluids continuously flow from one compartment to the other. Therefore,
reabsorption occurs through the lymphatic circulation and not through the
capillaries.

Figure 1.11 Relation between transvascular filtration (Jv) and hydrostatic pressure (Pc).

The administration of fluid therapy with colloids and crystalloids has

been reconsidered in light of the new model of Jv regulation. According to
Starling’s hypothesis, the administration of crystalloids limits the
physiological response to the simple reduction of total flow. The new
interpretation shows that when endocapillary pressure (Pc) decreases (e.g.,
during severe blood loss), the crystalloids administered remain in the blood.
This hypothesis has changed the fluids of choice (crystalloids over colloids)
to be administered to patients with low blood pressure [17].
In human medicine, the glycocalyx can perform a sort of
“autotransfusion” when the patient is suffering from hypotension following
severe blood loss (around 750 mL). In patients with a normal blood
pressure or hypertension, this phenomenon is reduced by a third to a half.
The effects of this phenomenon are highest when colloid solutions are
administered to patients with hypovolemia and an intact glycocalyx. The
expansion of the circulating volume following the administration of colloids
depends on the blood volume and the status of the glycocalyx.
When water and proteins accumulate in the interstitial space (e.g.,
during sepsis or as a consequence of an inflammatory disease such as
systemic inflammatory response syndrome [SIRS]), excess fluids are
transferred to the general circulation through the lymphatic system and only
in small part through capillary reabsorption. A deficient lymphatic
circulation and a rise in capillary permeability can therefore lead to an
excess of proteins and fluids in the interstitial space, causing interstitial
edema.
Lymphatic drainage increases with a rise in muscular activity and
decreases when the patient does not move. Hypovolemic patients with
reduced mobility who have developed an inflammatory illness such as SIRS
can more easily develop ECF edema following an increase in transvascular
flow and a decrease in lymphatic drainage. Physiotherapy and muscular
activity can reduce the need to administer colloid solutions since they
increase drainage in the ECF space. The brain, however, lacks lymphatic
drainage. In the brain, the capillary membrane is impermeable to most
molecules, with the exception of water. As a matter of fact, the blood–brain
barrier (BBB) is impermeable to large and small molecules (e.g., sodium
and proteins).
Within the brain, the Jv predominantly depends on the hydrostatic
pressure and on the blood’s oncotic and osmotic pressure. For this reason,
damage to the BBB, such as that caused by trauma, leads to an increase in
its permeability, thus allowing the passage of small solutes, which results in
an increase in Jv. This in turn leads to interstitial edema and, as a
consequence, to an increase in intracranial pressure.
A loss of glycocalyx integrity (known as shedding) causes an increase in
vascular permeability, especially with regard to proteins and negatively
charged molecules towards the extravascular space, which leads to
perivascular edema [18]. In humans, the rapid administration of crystalloids
causes an increase in hyaluronic acid, which indicates damage to the
glycocalyx [19,20]. Inflammatory states, sepsis, diabetes, surgery,
hypertension, and trauma are often associated with damage to the
glycocalyx.

Clinical consequences of the glycocalyx

Box 1.8
model

The COP of the glycocalyx and that of the IV compartment are very
important for Jv, but not the interstitial COP.
Jv mostly depends on hydrostatic pressure.
An increase in COP at a normal capillary pressure (20 mmHg) does not
cause the absorption of fluids from the interstitial space.
Increases in the hydrostatic pressure (Pc) greater than the oncotic
pressure lead to a linear increase in Jv.
When the total blood flow is reduced, the crystalloids administered
remain in the blood flow, just like colloids.
Water and proteins accumulated in the interstitial space are transferred
to the general blood circulation through the lymphatic system.
A loss of integrity of the glycocalyx causes and increase in vascular
permeability.

COP, osmatic colloid pressure; JV, transvascular flow.

Damage to the glycocalyx can be caused by inflammatory mediators

such as C-reactive protein, tissue necrosis factor, the stimulation of A3
adenosine receptors, bradykinin, and the activation of neutrophil
granulocytes and mast cells. The products of the fragmentation of the
glycocalyx in the blood circulation behave like proinflammatory
chemotactic molecules, which contributes to the worsening of inflammatory
states or inhibits counterregulation mechanisms.
Damage to the glycocalyx can be assessed in vivo with an electron
microscope or by measuring the glycocalyx degradation products (e.g.,
syndecan 1, hyaluronic acid, heparan sulphate, and chondroitin sulphate)
(Box 1.8).

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Clinical Case

Dehydrated dog with respiratory

alkalosis

History
The patient was brought to the clinic because he had not been eating
since the morning. He was able to drink, but occasionally regurgitated.
His feces were normal, but more solid than usual. These clinical signs
had been evident for at least 5 hours. The clinical parameters below were
recorded during the clinical examination:
Heart rate: 130 bpm;
Respiratory rate: 40 bpm;
Full pulse;
Rectal temperature: 37.9 °C;
 mucous membranes: pinkish; CRT: 2 seconds;
arterial pressure: 120/60 mmHg; MAP: 40 mmHg;
dehydration: 8%.

Laboratory tests
A blood gas analysis was performed since the patient had been suffering
from regurgitation and was likely to suffer from electrolytic and acid–
base imbalances.
Fluid therapy must be aimed at satisfying the patients’ needs, so a
complete blood count was performed to assess hematological parameters,
as well as a biochemistry profile to evaluate a potential dysfunction of
the organs related to the digestive system and check whether other
metabolic components were also involved.

Venous blood gas analysis

Since there were no issues with the respiratory system, blood samples
were taken from a vein given that these are reliable with regards to pH
and bicarbonate, carbon dioxide and electrolyte levels:
pH: 7.60;
pvCO2: 25;
HCO3–: 24;
BE: +5;
Na+: 135 mmol/L;
Cl–: 95 mmol/L;
K+: 3.2 mmol/L;
lactatemia: 2.2 mmol/L;
AG: 19.2;
FiO2: 0.21.

Biochemistry profile
BUN 15 mg/dL, creatinine 1.2 mg/dL, ALT 24 U/L, AST 31 U/L, total
proteins 8.4 g/dL, albumin 5.3 g/dL, total bilirubin 0.2 mg/dL, GGT 12
U/L, blood glucose 104 mg/100 mL, phosphate 4.1 mg/dL.
Complete blood count
RBC 8.5 × 1012/L, WBC 14.9 × 109/L, Hct 63%, Hb 16.3 g/dL, PLT 320
× 109/L, neutrophils 14 × 103/µL.

Interpretation of the results

The blood gas analysis showed evidence of respiratory alkalosis, since
pCO2 readings were low, while bicarbonate readings were normal. There
was no evidence of bicarbonate compensation since it was too early for
renal compensation to have kicked in in an attempt to withhold
bicarbonate. The patient was therefore suffering from respiratory
alkalosis, which had started a few hours earlier.
According to the nontraditional approach, a moderate alkalosis and SID
alkalosis (–5 nmol/L) were present. In addition, a weak acid acidosis
(increase in total proteins and albumin) was observed, which concealed
and compensated for the respiratory alkalosis. Mild hypokalemia was
also detected. The biochemistry profile highlighted an increase in total
proteins and albumin, probably due to dehydration. The complete blood
count showed an increased hematocrit, also probably due to dehydration.
Osmolarity is calculated as follows:

Osm = 2 × [Na+] + glucose (mg/dL)/18 + BUN (mg/dL)/2.8

Osm = (2 ×135) + (104/18) + (15/2.8)

Osm = 281 mOsm/L

Osmolarity was lower than average due to hyponatremia.

Diagnostic investigations
An X-ray of the abdomen highlighted the presence of foreign objects in
the patient’s stomach, most probably stones, as shown in the picture.
Daily fluid therapy
Maintenance fluid therapy was provided, to which the volume
corresponding to the percentage of dehydration (about 8%) was added, as
well as the losses since the patient’s arrival at the clinic (the dog had
regurgitated 4 times, 30 mL each time). Resuscitative fluid therapy was
not necessary since the patient was not showing signs of shock.
Ongoing: 2 mL/kg/hour IV, which corresponds to 44 mL/hour.
Rehydration: 8% of 22 kg corresponds to 1760 mL which, over 24
hours, corresponds to about 73 mL/hour EV.
This means that the total amount of solution to be administered for a least
24 hours was 117 mL/hour IV. In this case, 0.9% NaCl was chosen to
restore the water and sodium lost due to regurgitation. Moreover, since
normal saline is acid and it contains large amount of chloride, it is useful
to normalize the water and electrolyte balance. There is no potassium in
the solution, and it must therefore be added (see Chapter 4, Table 4.1). In
this case, 15 mEq/L in 500 mL of potassium chloride were added. To
correctly administer the solution an infusion pump is recommended. The
patient’s weight should be checked twice a day, while the electrolytes and
acid–base status should be checked at least once every 24 hours.
The patient was treated this way for 24 hours; then the 76 mL/hour of the
rehydration solution were subtracted from the total volume.
The patient was discharged the following day since regurgitation had
stopped and he was eating and drinking spontaneously. Since the foreign
objects were very small, they did not pose a threat to the transit of food
through the digestive tract. The at-home supportive treatment included a
mild proton pump inhibitor for 7 days (pantoprazole 1 mg/kg twice a day
PO) and an intestinal absorbent (diosmectite 1 g twice a day PO for 7
days) to promote recovery from the possible lesions the foreign objects
could have caused to the gastrointestinal mucosa.
Acid–Base Disorders
 CHAPTER
2

Fabio Viganò

Introduction
When fluid therapy is required, it is important to know, in addition to the
electrolyte status, the acid–base balance of the patient. In this chapter, acid–
base disturbances will first be evaluated based on the traditional approach,
before being analyzed according to a nontraditional approach (the Stewart
approach), for a better understanding of how some electrolytes and ions can
influence the acid–base balance.
One interpretation, however, does not exclude the other; indeed, both
complement each other to provide an overview that allows an evaluation of
the greatest number of components of the acid–base balance.

Chemical species involved in the acid–base

balance
Under normal conditions, the body produces more acidic chemical species
(about 15,000–20,000 mEq) than buffer systems (about 2500 mEq); it must
therefore be able to quickly eliminate or buffer excess acids.
The body has a better ability to correct acidosis than alkalosis, and thus
tolerates metabolic acidosis better than metabolic alkalosis.
A dog running in a field during a walk may have some degree of
metabolic acidosis, but this will be corrected promptly; however, if the
effort, because of its intensity and duration, were to exceed the normal
compensation capacity, acidosis could become incompatible with life or
create acid–base disorders with a negative impact on several of the animal’s
vital functions.
It is the clinician’s task to identify as early as possible severe
uncompensated acid–base alterations that could compromise the patient’s
vital functions.
Carbon dioxide (CO2) acts as an acid in the body because carbonic
anhydrase, a ubiquitous enzyme, catalyzes a reaction that converts CO2 and
water into carbonic acid (H2CO3). With an increase in partial pressure of
carbon dioxide (PaCO2), the carbonic acid equation (Equation 1) will shift
to the right and the hydrogen ion concentration will increase:

CO2, in addition to being transformed into H2CO3, is mainly eliminated

through alveolar ventilation. If alveolar ventilation is compromised (e.g.,
due to pneumothorax or positive pressure ventilation with high levels of
CO2), this mechanism becomes ineffective and the reaction will shift to the
right. Alveolar ventilation can change the CO2 concentration within 1–5
minutes; for example, if a patient has an increased respiratory rate as a
result of fear or pain during blood sampling, the blood gas analysis (ABG)
may indicate a false respiratory alkalosis (decreased CO2).
While the respiratory system can correct the pH through alveolar
ventilation within a few minutes, renal adaptation, which is characterized
by bicarbonate reabsorption (80–90% of which occurs in the proximal
tubule) and excretion of ammonium and phosphate ions and water, needs a
few hours to begin and is completed within 2–5 days.
According to the law of mass action, the elements of the chemical
species indicated in Equation 1 (Box 2.1) must remain in equilibrium on
both sides of the equation. For example, if HCO3− increases, as occurs when
sodium bicarbonate is administered, the reaction will tend to shift to the
left; but if the patient’s ventilation is impaired, the reaction will shift to the
right, thus inducing a paradoxical acidosis. That is why the patient’s
ventilation should be assessed before administering sodium bicarbonate.
Similarly, when the equilibrium shifts to the right with an increase in H+
ions, it must be compensated for by a greater production of HCO3− by the
kidneys since the HCO3− generated by the reaction is consumed by fixed
acids. As a result, when kidney function is compromised, metabolic
acidosis occurs.
 It may be more useful to use the Stewart approach for proper fluid
therapy; in patients with mixed or complex acid–base disorders, this
approach also provides a more comprehensive evaluation of the acid–base
status and a greater insight into its possible causes and the most appropriate
treatment. However, before describing the Stewart approach, the traditional
acid–base analysis will be discussed.

Chemical species involved in acid–base

Box 2.1
disorders, traditional approach

CO2
H+
HCO3−
H2O

Traditional approach
The traditional approach is based on the Henderson–Hasselbalch equation
(Equation 2) and considers bicarbonate concentration (HCO3−) and partial
pressure of carbonic dioxide (PCO2). The formula uses the common
logarithm of the molar concentration of hydrogen ions, which would
otherwise generate complex numbers: 0.0000001 gEq/L or 1 × 10−7 H+.

From this equation, it can easily be seen that an increase in HCO3−

concentration will be responsible for an increase in pH (alkalosis), while a
decrease will cause the opposite phenomenon. Conversely, an increased
CO2 concentration will be responsible for a decreased pH (acidosis),
whereas a drop in CO2 concentration will cause an increase in pH. Because
they are retained by the kidneys, HCO3− ions are defined as a metabolic
component of the acid–base balance, while CO2, which is primarily
removed by alveolar ventilation, is defined as a respiratory component. A
PaCO2 greater than 45 mmHg is termed respiratory acidosis, while a PaCO2
below 35 mmHg defines respiratory alkalosis. Metabolic acidosis, on the
other hand, occurs when HCO3− falls below 20 and metabolic alkalosis
when it is greater than 24.
An increase in H+ ions in blood results in acidemia, i.e., a decreased pH
(<7.35); conversely, a decrease in H+ ions in blood results in alkalemia, i.e.,
an increased pH (>7.45). The suffix “-emia” indicates the presence of a
certain kind of substance in the blood that causes an imbalance, while the
suffix “-osis” (acidosis or alkalosis) indicates the development of a
condition (Box 2.2).
If the fixed acids produced by the body are not eliminated or buffered,
metabolic acidosis occurs. Some of them are eliminated by alveolar
ventilation, such as CO2 and water; this process begins within a few
minutes and is completed within a few hours. An acid can be buffered or
excreted through metabolic pathways. It can be buffered by bicarbonate (in
the renal proximal tubules, 40% of the total buffering capacity), by
hemoglobin (35% of the buffer system and 80% of the nonbicarbonate
buffer system), by the formation of ammonium ions (NH4+, in the renal
collecting tubule), by proteins (which represent 7% of the buffer system and
of which albumin is the most abundant), by ATP (adenosine triphosphate),
by 2,3-diphosphoglycerate, and by organic (3% of buffer system) and
inorganic (2% of buffer system) phosphates.

Effects of chemical species on pH,

Box 2.2
traditional approach

An increase in H+ ions causes a reduction in pH.

A reduction in H+ ions causes an increase in pH.
An increase in CO2 causes a reduction in pH.
A reduction in CO2 causes an increase in pH.
An increase in HCO3− causes an increase in pH.
A reduction in HCO3− causes a reduction in pH.
Blood gas analyzers
Blood gas analyzers measure pH, PCO2 and PaO2 and calculate bicarbonate
and base excess (BE). The conversion factor from mmHg to kPa is 0.133
and 7.5006 from KPa to mmHg. Devices with a cooxymeter can also
measure the percentage of saturation of hemoglobin, the percentage of
carboxyhemoglobin, the percentage of methemoglobin and the amount of
hemoglobin. Most modern blood gas analyzers also measure electrolytes
such as sodium, potassium, chloride and calcium, and some of them
determine blood lactate and glucose concentrations, urea, creatinine, cardiac
troponin, activated coagulation time and total bilirubin.
The determination of electrolytes, along with the measurement of total
proteins, albumin, and phosphates (with other instruments), also allows an
interpretation of acid–base disorders using the Stewart approach. The
equipment should also measure electrolytes to help the clinician select the
appropriate fluid therapy, correct electrolyte imbalances, and monitor the
speed of correction of these imbalances. Not all devices use the same
algorithms to calculate values, so it is advisable to always ask the supplier
about the mathematical formulas used for the determination of BE and
bicarbonate, and whether the device distinguishes between the canine and
feline species (Table 2.1).
Table 2.1 Normal values of blood gas analysis in dogs and cats
Interpretation of blood gas analysis
Primary disorder
Once the arterial blood gas (ABG) has been performed, the clinician must
identify the primary disorder, that is, understand whether the metabolic or
respiratory component varies in the same direction as pH. For example, if
the pH value is acidic, it must be determined if it is the respiratory
component (CO2) that produces the acidosis (after an increase in CO2
concentration), or if it is the metabolic component that that lowers the pH
(with a reduction in HCO3−). The reading sequence of a blood gas analysis
should be as follows:
pH;
CO2;
HCO3−.

The identification of the primary disorder is fundamental to treat its origin

because the adaptive response depends on it, but not only for that reason: if
at least two separate primary acid–base disturbances are present
simultaneously, treating the main one will often correct the entire acid–base
imbalance. Some examples are given below.
The first parameter that should be assessed is therefore pH, which
should then be compared with normal values (acidosis or alkalosis, see
Table 2.1). This should be followed by evaluation of the PCO2 : if it is
altered in the same direction as pH, a respiratory disorder is in progress. For
example, if pH is <7.35 and the PCO2 is >45–50 mmHg, the primary
disorder is respiratory acidosis; conversely, if the pH is >7.35 and the PCO2
is <40 mmHg the primary disorder is respiratory alkalosis. The clinician
should then look at the HCO3− concentration: if the PCO2 is normal while
HCO3− goes in the same direction as the pH alteration, the disorder has a
metabolic origin. For example, if the pH is >7.45, the PCO2 is normal, and
HCO3− is >24, the primary disorder is a metabolic alkalosis; conversely, if
the pH is <7.4, the PCO2 is normal, and HCO3− is <20 mEq/L, the patient is
suffering from a metabolic acidosis. Once the primary disorder has been
identified, it is necessary to check whether the clinical findings are
concordant with the ABG values. For example, if a respiratory alkalosis is
diagnosed, the respiratory pattern and rate should be assessed and, if
necessary, additional tests performed (e.g., diagnostic imaging) (Box 2.3).

Compensatory responses
When an acid–base imbalance (acidosis or alkalosis) occurs, the body
responds with a compensatory mechanism. For example, in respiratory
acidosis, the opposite reaction to compensate for the alteration in pH will be
a metabolic alkalosis. The type of compensatory response depends on the
acid–base imbalance and on when it is established (Table 2.2).

Box 2.3 Primary disorder, traditional approach

If the pH decreases and CO2 increases, respiratory acidosis is the

primary disorder.
If the pH increases and CO2 decreases, respiratory alkalosis is the
primary disorder.
If the pH decreases and HCO3− decreases, metabolic acidosis is the
primary disorder.
If the pH increases and HCO3− increases, metabolic alkalosis is the
primary disorder.

It should be remembered that the body never overcompensates. This

means that the increase or reduction in the PaCO2 and HCO3− beyond the
compensation values indicated in Table 2.2 are suggestive of the presence
of another pathological condition; these are defined as mixed acid–base
disorders. There are no guidelines regarding compensatory responses in
cats, and the values for dogs generally serve as a reference, although their
accuracy in the feline species has not been established, especially with
regard to respiratory compensation.
Table 2.3 shows some characteristic examples of acid–base disturbances.
Table 2.2 Normal compensation
 Primary disorder Alteration Compensatory response

Metabolic acidosis HCO3− reduction of PaCO2 reduction of 0.7

1 mEq/L mmHg
Metabolic alkalosis HCO3− increase of 1 PaCO2 increase of 0.7
mEq/L mmHg
Respiratory acidosis PaCO2 increase of 1 HCO3− increase of 0.15
Acute mmHg mEq/L
Chronic PaCO2 increase of 1 HCO3− increase of 0.35
mmHg mEq/L
Respiratory alkalosis PaCO2 reduction of HCO3− reduction of 0.25
Acute 1 mmHg mEq/L
Chronic PaCO2 reduction of HCO3− reduction of 0.55
1 mmHg mEq/L
HCO3−, bicarbonate ion concentration; paCO2, partial pressure of carbon dioxide.

Table 2.3 Examples of diseases associated with acid–base disorders

 Imbalance Diseases

Respiratory acidosis Diseases of pleural space, anesthetic drugs, airway

obstruction, compensation of metabolic alkalosis,
parenteral feeding with excess carbohydrates,
central nervous system diseases, ineffective
positive pressure ventilation
Metabolic acidosis Normal anion gap: diarrhea, proximal tubular
acidosis (inability to tubular reabsorption),
compensation of respiratory alkalosis, dilution
acidosis (excessive administration of 0.9% saline
solution), hypoadrenocorticism, carbonic anhydrase
inhibitor, administration of ammonium chloride,
parenteral nutrition with cationic amino acids (e.g.,
lysine, arginine, histidine)
High anion gap: lactic acidosis, diabetic
ketoacidosis, hyperphosphatemia, phosphate and
sulfate acidosis (oliguric renal failure), salicylate
intoxication, ethylene glycol intoxication,
metaldehyde intoxication, paraldehyde
intoxication, methanol intoxication, severe
rhabdomyolysis
Respiratory alkalosis Hyperventilation (e.g., pain), restrictive respiratory
distress, hypotension, anxiety, exercise,
compensation for metabolic acidosis, congestive
heart failure
Metabolic alkalosis Vomiting, hypokalemia, refeeding after fasting,
loss of renal function due thiazides,
mineralocorticoids, high doses of β-lactam
antibiotics, hypovolemic alkalosis, compensation
of respiratory acidosis, posthypercapnia,
administration of bicarbonate, fluid therapy with
alkalizing solutions
 In many cases it is possible to find simultaneous metabolic and
respiratory alterations in opposite directions; the resulting pH can be normal
or almost normal, and such alterations are called mixed acid–base disorders.
Mixed acid–base disorders do not always go in the opposite direction; two
or more pathological conditions in the same patient can all induce acidosis
or alkalosis. These pathological alterations are the most difficult to diagnose
and manage because, if they are not readily recognized and treated, they can
quickly lead to a fatal outcome. To determine which of the disturbances
should be treated first, it is necessary to perform another evaluation of the
patient’s clinical condition; for example, if a patient has a metabolic
acidosis due to severe diarrhea and a respiratory acidosis resulting from a
severe central nervous system (CNS) depression (e.g., stupor or coma), we
must first treat the disease that most impairs the animal’s vital functions.
An ABG should be performed not only when acid–base imbalances exist
or are suspected, or when fluid therapy is to be performed, but also in all
patients with disturbances in the extracellular space (e.g., dehydration,
vomiting, diarrhea and hypovolemia) or electrolytes, in those with
respiratory or cardiorespiratory diseases requiring general anesthesia, and in
all critically ill patients suffering from any pathological processes that may
compromise their vital functions.

Base excess (BE)

BE is part of the buffer system, which includes not only the bicarbonate
system but also hemoglobin. The BE indicates the amount of strong base or
acid that must be added to 1 L of oxygenated whole blood to restore the pH
to 7.4 at 37 °C and at a PaCO2 of 40 mmHg. A normal value of BE is about
0 (±2). In cats it is slightly lower and influenced only by the amount of
fixed acids; it is therefore an indicator of the metabolic state. A reduced BE
indicates metabolic acidosis, while an increased BE indicates metabolic
alkalosis.
An altered BE value may be normal and may indicate the body’s
compensatory response. For example, a patient with chronic respiratory
acidosis (e.g., secondary to an obstructive pulmonary disease) may have a
BE above normal to buffer a chronic increase in CO2 and therefore in the
H+ ions present in the blood; in this case, a high BE is not a pathological
finding, but rather indicates an adaptive response to a chronic acid–base
disorder. An increased BE may be due to an increase in bases or a decrease
in fixed acids; a decreased BE may be due to a decrease in bases or an
increase in fixed acids. BE is especially useful during metabolic acidosis to
confirm and understand if the disorder is compensated for by bases or if it is
necessary to intervene with appropriate therapy. In the latter case, if the BE
is below normal, the clinician must decide whether the disorder should be
corrected by administering buffer systems (nonbicarbonate buffer or
bicarbonate) or by limiting the production of acid.

Anion gap (AG)

When reading an ABG and diagnosing metabolic acidosis, it is important to
read the AG value. In the body, electroneutrality between all ions must be
maintained, so there must be an equal number of cations and anions in the
blood; however, not all cations and anions are normally measured.
Measured cations are more than measured anions, so the difference will
be in favor of cations, which is why this is referred to as the AG (see
Equation 5). In other words, there are more unmeasured anions (UAs) than
unmeasured cations (UCs) and the AG has a positive value. The commonly
measured cations are sodium (Na+) and potassium (K+), while the
commonly measured anions are chloride (Cl−) and bicarbonate (HCO3−).
The most frequently unmeasured cations are calcium (Ca2+) and magnesium
(Mg2+), while unmeasured anions are proteins, of which albumin is the most
abundant, and lactate, phosphates and sulfates.
The balance between cations and anions is summarized by the following
equations:

The difference between cations and anions is calculated using the terms
from the previous equation:

Simplifying the formula, the AG is calculated by subtracting the

measured anions from the measured cations:
 The normal AG value is approximately 12 to 20 mmol/L. When UAs
increase, major anions (Cl− + HCO3−) must decrease to maintain an
electrolyte balance, which causes an increase in the AG. Some diseases
increase the presence of fixed acids with negative charges, which become
part of the UAs responsible for metabolic acidosis and an increased AG,
such as:
lactic acidosis;
diabetic ketoacidosis;
renal failure (uremia and increased phosphates and sulfates);
rhabdomyolysis;
sepsis;
convulsion;
poisonings: ethylene glycol, methylene glycol, alcohol, salicylates,
paraldehyde, iron.
These pathological processes, also referred to as normochloremic or
hypochloremic metabolic acidosis, are characterized by an increase in UAs
(e.g., lactate and ketones), and chloride ions must decrease accordingly or
remain normal to compensate for the increase in negative electrical charges
(UAs).
Metabolic acidosis with an increased AG is typical of renal failure and
diarrhea. In response to bicarbonate losses resulting from diarrhea, a
compensatory retention of chloride ions occurs to maintain
electroneutrality. This type of acidosis is therefore called hyperchloremic
metabolic acidosis.

Box 2.4 Metabolic acidosis and anion gap

 Increased anion gap Normal anion gap
Lactic acidosis Diarrhea, duodenal vomiting
Ketoacidosis Renal tubular acidosis
Renal failure: uremia and Administration of NaCl
increased phosphates and Compensation of respiratory
sulfates alkalosis
Sepsis Parenteral nutrition (increased
Seizures amino acids: arginine, lysine,
Poisonings: ethylene glycol, histidine, cystine, methionine)
methylene glycol, alcohol, Hypoadrenocorticism
salicylates, paraldehyde, iron Ammonium chloride or
Rhabdomyolysis acetazolamide therapy

Therefore, in the course of metabolic acidosis, chloride ions can increase

to compensate for a reduction in bicarbonate or decrease as UAs increase.
In conclusion, the AG is useful to better define the origin of metabolic
acidosis. When diagnosing metabolic acidosis, it is thus necessary to check
if the AG is normal or increased. When it is increased or normal, the list of
differential diagnoses should be examined to identify the possible cause
(Box 2.4).

Total oxygen content (CaO2)

CaO2 is the total amount of oxygen present in the blood. Part of the oxygen
is bound to hemoglobin (component in greater amount) and a small amount
is dissolved in blood. The amount of dissolved oxygen is proportional to the
partial pressure of oxygen and its solubility coefficient. Oxygen has a
plasma solubility of 0.003 and each gram of hemoglobin saturated with
100% of oxygen carries 1.34 mL of oxygen, so CaO2 is calculated using the
following formula:

As can be seen in the formula, most of the oxygen contained in the

blood is bound to hemoglobin, while the oxygen dissolved by the pressure
gradient (PaO2 × 0.003) represents only a small part of the total. For
example, if a patient has a hemoglobin saturation (SaO2) of 98%, a PaO2 of
95 mmHg, and 10 g/dL of hemoglobin, the CaO2 can be calculated as
follows:

Using this calculation, it is possible to assess the magnitude of the

decrease in blood oxygen content if a patient suffers an acute hemorrhage
causing the loss of half of their hemoglobin. The CaO2 would be reduced by
about half, thus decreasing drastically the patient’s chances of survival. This
is because CaO2 and cardiac output (CO) constitute the two fundamental
components of oxygen availability (DO2), according to the following
calculation: (95 × 0.003) + (1.34 × 5 × 0.98) = 6.851.
If oxygen is administered to this patient, for example through a nasal
cannula, the percentage of inhaled oxygen will become about 40%, which
will increase the PaO2 from about 95 to 200 mmHg. The CaO2, however,
will only increase slightly (comparing it with the normal value, Equation 7),
according to the following calculation: (200 × 0.003) + (1.34 × 5 × 0.98) =
7.166.
In anemic patients, hemoglobin should be administered (e.g., using
packed red blood cells) to significantly increase the CaO2 and consequently
the chances of survival. If only the fraction of inspired oxygen (FiO2) is
increased by administering oxygen, a significant increase in CaO2 will not
be achieved; despite this, in some patients, even a modest increase in CaO2
achieved through oxygen therapy can favor a positive outcome. As it is
impossible to know in advance which anemic patients can survive thanks to
oxygen therapy, it is a good idea to always administer oxygen in these
critically ill patients.

Oxygen parameters to evaluate the effectiveness of oxygenation

By measuring the alveolar–arterial gradient (A–a) or the PaO2/FiO2 ratio, it
is possible to determine the amount of oxygenated blood and quantify the
shunt fraction, that is, the amount of blood that travels through the lungs
without receiving oxygenation. The most common causes of pulmonary
shunts are post-traumatic pulmonary insufficiency, pulmonary edema, acute
respiratory distress syndrome (ARDS), pulmonary atelectasis (e.g., as a
result of prolonged decubitus), aspiration pneumonia, some lung neoplasms,
inhalation of toxic gases, some bronchospastic diseases (e.g., asthma,
alveolar lung diseases, and bronchospasm), and, finally, right-to-left
anatomic shunts (e.g., patent ductus arteriosus, tetralogy of Fallot and
atrioventricular fistula).

Alveolar–arterial gradient
The alveolar–arterial gradient (A–a gradient) is calculated by measuring
the difference between the oxygen present in the pulmonary alveoli (pAO2)
and the oxygen is present in the blood (PaO2). It is an index of the ability of
the cardiovascular and respiratory systems to transfer oxygen from room air
to the blood. The alveolar–arterial gradient is the difference between the
calculated alveolar partial pressure of oxygen and the measured arterial
partial pressure of oxygen:

In the first part of the Equation 10, the partial pressure of oxygen in
room air is measured by multiplying the FiO2 (fraction of inspired oxygen)
by the barometric pressure subtracted from the partial pressure of water
vapor (barometric pressure – 47); in the second part of the equation, the
ratio between the PaCO2 (partial pressure of carbon dioxide) and R
(respiratory quotient, 0.8) must be subtracted from the amount of oxygen
obtained from the first part of the equation.
In healthy patients, with an FiO2 of 0.21 because they breathe room air,
the A–a gradient should be less than or equal to 15 mmHg; higher values
indicate a deficit in the ventilation/perfusion ratio (V/Q). Over the course of
parenchymal lung diseases (e.g., pneumonia, ARDS, post-traumatic
pulmonary insufficiency), the V/Q ratio increases and is the cause of
hypoxemia. The higher the V/Q ratio, the greater the hypoxemia. The
difference between the oxygen present in the alveoli and that present in the
arterial blood is due to impaired oxygen diffusion through the lung
parenchyma and is not necessarily affected by the inhaled oxygen. The A–a
gradient also increases in cases of diffusion hypoxia and right-to-left
pulmonary shunts. Therefore, the A–a gradient is important to understand
the severity of some lung diseases, establish therapy (e.g., need for oxygen
therapy or positive pressure ventilation), assess the course of the disease
process, and monitor the effectiveness of therapy. When, despite oxygen
therapy, no improvement in the A–a gradient is achieved, the need for
positive pressure ventilation should be considered. The greater the
measured value, the more severe the oxygen deficit. Values between 10 and
20 indicate a slight deficit, values greater than 30 indicate severely impaired
oxygen diffusion.

PaO2/FiO2 ratio
Another method to assess the body’s ability to oxygenate the blood is to
measure the partial pressure of oxygen in arterial blood and divide it by the
fraction of inspired oxygen: PaO2/FiO2. This is the most frequently used
method to evaluate the oxygenation capacity because it is very simple and
the ratio can be calculated even when patients are undergoing oxygen
therapy, considering FiO2 is a value that can be set arbitrarily depending on
the therapy that the patient is receiving. Therefore, for patients breathing
room air it is possible to use the A–a gradient, while for patients on oxygen
therapy the PaO2/FiO2 ratio must be used and the FiO2 adjusted when
necessary. Under normal conditions, the PaO2/FiO2 ratio should be greater
than or equal to about 500 (105/0.21); values between 300 and 500 indicate
mild hypoxemia, while values between 200 and 300 reveal moderate to
severe hypoxemia (e.g., acute lung injury [ALI]), and values below 200
indicate severe hypoxemia (e.g., acute respiratory distress syndrome).
This method is used to differentiate, together with other clinical findings
(e.g., presence of a pathology able to cause ARDS, chest X-rays, presence
of high concentration of proteins in the surfactant, absence of heart disease),
ALI from ARDS (<200) (Box 2.5). When it is necessary to assess the lungs’
efficiency in oxygenating blood, especially during oxygen therapy, the
PaO2/ FiO2 ratio is the most frequently used method, because it is very
simple, quick, and effective in assessing the severity of hypoxemia and in
monitoring the effectiveness of treatment. This method can be used for
normal atmospheric pressures (comparable to that of sea level). FiO2 can be
given as a percentage or fraction, with conversion of FiO2 in L/min to a
percentage value using the following equation:

For example, the following values can be obtained: 1 L/min = 24%, 3

L/min = 30%, 5 L/min = 36%, 6 L/min = 39%.

Box 2.5 PaO2/FiO2 ratio, clinical interpretation

500 = normal value

300–500 = mild hypoxemia
200–300 = moderate/severe hypoxemia (e.g., ALI)
<200 = very serious hypoxemia (e.g., ARDS)

Rule of 5
A very practical and empirical method for assessing the ability to oxygenate
the blood is the rule of 5. In practice, the FiO2 is multiplied by 5, and the
value obtained is compared with the PaO2. For example, in a patient who
breathes room air, the PaO2 should be about 100 mmHg (21% × 5); if the
patient receives oxygen through a nasal cannula, their PaO2 should be about
200 mmHg (40% × 5). Values lower than expected indicate hypoxia. This
method can be used for normal atmospheric pressures (comparable to that
of sea level).

Rule of 120
The rule of 120, on the other hand, refers to the sum of the arterial partial
pressures of oxygen and carbon dioxide. This sum normally should
normally be between 120 and 160 mmHg; if it is less than 120 mmHg there
is insufficient oxygen exchange at the alveolar level and the cause of the
hypoxia must be investigated. This method can only be used if the patient
breathes room air at normal atmospheric pressures (comparable to that of
sea level).

Strong ion theory (Stewart’s approach)

The strong ion theory was elaborated by Peter Stewart in 1983 and draws its
foundations from the laws of mass action and electroneutrality. According
to these physical laws, the quantity of chemical species involved in the
acid–base balance remains constant until a certain amount is added,
generated, removed or destroyed, while electroneutrality must be
maintained (the sum of the positive charges must be equal to the sum of the
negative charges).
The interpretation of acid–base imbalances according to the strong ion
theory is very useful for fluid therapy, as it allows us to understand some of
these imbalances especially with regard to electrolytes and fluid
administration, but also when weak acids (Atot) and phosphates are
involved.

Chemical species involved

According to the laws of mass action and electroneutrality, if a positive or
negative charge increases, H+ or OH− concentrations must change to
balance the charge (e.g., if Cl– increases, H+ must increase to compensate
for the alteration in the electric charge), thereby changing the pH.
According to this approach, the only three independent variables—i.e.,
those that can vary in quantity independently from each other—are:
CO2;
Atot (total weak acids);
SID (strong ion difference).
CO2, as in the traditional approach, is conditioned by ventilation (an
increase in frequency causes a reduction in CO2 and vice versa).
Nonvolatile Atot (total weak acids) are proteins (under normal
conditions, these make up 90% of Atot), predominantly total proteins,
albumin and inorganic phosphate.
The SID corresponds to the difference between strong ions, which
depend on metabolism, imbalances in the extracellular space, and fluid
therapy. The balance of the SID can be obtained by subtracting anions from
cations, as shown in the following equation:

SID, strong ion difference; PO42−, phosphates; Alb–, albumin; KK, ketone bodies.

The SID is so called because, at pH 7.4, ions completely dissociate and

are found dissolved in the blood practically only as positive or negative
charges. The ions found in higher concentrations are Na+ and Cl− (Box 2.6).
In the traditional approach the independent variables depend on renal and
pulmonary function, perfusion and metabolism, while according to the
Stewart approach, the independent variables also depend on liver function
(Figure 2.1).

Chemical species involved in acid–base

Box 2.6
disturbances, nontraditional approach

CO2.
Atot (total weak acids): total proteins, albumin, phosphates.
Strong ions: Na+, Ca2+, Mg2+, Cl–, PO42–, lactate, ketone bodies.
With an increase in positive charge, H+ must be reduced; with an
increase in the negative charges, H+ must increase.
Reductions in SID cause metabolic acidosis.
Figure 2.1 Comparison between the components of the traditional approach and Stewart approach.

Tables 2.4 and 2.5 show the contribution to the acid–base equilibrium of
sodium, chloride, water and Atot. Alterations in concentrations of strong
cations or strong anions are responsible for acid–base alterations. If you
want evaluate pH using the Stewart approach by modifying the Henderson–
Hasselbalch equation, the components that influence pH are:
 Independent variables are indicated in blue, while dependent variables in
black.
Table 2.4 Biological behavior of various components of the acid–base disorders according to the
nontraditional approach

Component Consequence

↓ Water ⇒ ↑ [Na ] ⇒ ↓ [H ]+
+
Hypovolemic alkalosis

↑ Water ⇒ ↓ [Na ] ⇒ ↑ [H ] +
+
Hypervolemic acidosis

↑ [Cl ] ⇒ ↑ [H ] ⇒ ↓ pH
– + Hyperchloremic acidosis

↓ [Cl ] ⇒ ↓ [H ] ⇒ ↑ pH
– + Hypochloremic alkalosis

↑ [Pr ] ⇒ ↑ [H ] ⇒ ↓ pH
– + High-protein acidosis

↓ [Pr ] ⇒ ↓ [H ] ⇒ ↑ pH
– + Low-protein alkalosis

↓ [Albumin ] ⇒ ↓ [H ] ⇒ ↑ pH
– + Hypoalbuminemic alkalosis

↑ [Albumin ] ⇒ ↑ [H ] ⇒ ↓ pH
– + High-protein acidosis

↑ [Cations ] ⇒ ↓ [H ]
+ + Alkalizing effect

↑ [Lactate ] ⇒ ↑ [H ] ⇒ ↓ pH
– + Acidifying effect

↑ [UAs ] ⇒ ↑ [H ] ⇒ ↓ pH
– + Acidifying effect

Table 2.5 Calculation of the effect of strong ions on the base excess
 Na+ 0.25 × (Na+ patient – 145) dog
0.22 × (Na+ patient – 155) cat
Cl– 110 – (Cl– × 145/Na+) dog
120 – (Cl– × 155/Na+) cat
Contribution from proteins or 3 × (6.5 – TP) or
contribution from albumin 3.7 × (3.1 – albumin)
Phosphates 0.58 × (normal phosphate mg/dL –
patient phosphates mg/dL)
Lactate –1 × [lactate]
Effect of unmeasured anions UAs = BE – (Na+ + Cl– + Pr– o Alb–
+ lactate)
BE, base excess calculated with blood gas analysis; UAs, unmeasured anions.

Box 2.7 Features of the nontraditional approach

An increase in positive charges induces a reduction in H+ (alkalosis).

An increase in negative charges induces an increase in H+ (acidosis).
An increase in SID causes a reduction in H+ and thus induces alkalosis.
A reduction in SID causes an increase in H+ and thus induces acidosis.
The SID can change, in general, due to variations in the water volumes
(sodium), chloride, strong negative ions (albumin, lactate, phosphates,
ketone bodies, globulins).

Dependent and independent variables

According to the traditional approach (see Equation 2), the dependent
variable is H+, while the independent variables are PaCO2 and HCO3−;
according to the nontraditional approach, however, the dependent variables
are H+ and HCO3−, while the independent variables are PaCO2, SID and
Atot. In other words, it can be said that the pH is conditioned by variations
in CO2, SID and Atot; for this reason, when analyzing a clinical case, if
these last three elements are within the reference range, the traditional
approach is sufficient to understand the possible acid–base disturbance.
Each component of the nontraditional approach has a different influence,
which can be described as in Table 2.4. Looking at Table 2.5, it can easily
be inferred that the greatest influence on pH is produced by a reduction in
SID. A reduction in UAs, produced by the difference between the BE and
the contribution of all strong ions, indicates the presence of unmeasured
strong anions (UAs) or cations responsible for acid–base disturbances (Box
2.7).

Examples of pH variations according to the nontraditional

approach
Pure water losses cause an increase in Na+ concentration, which has an
alkalizing effect because the number of cations is increased and the number
of H+ ions must decrease in order to maintain electroneutrality, thus raising
the pH. A reduction in water is therefore also referred to as hypovolemic
alkalosis. Typical causes of increases in sodium concentration due to
hypovolemia are diabetes insipidus, vomiting, diarrhea and osmotic
diuresis. Conversely, an increase in pure water, which leads to dilution and
therefore to a lower Na+ concentration, induces, according to the law of
electroneutrality, an increase in H+. This is why an increase in water is also
called hypervolemic acidosis. Typical causes are hyperadrenocorticism,
administration of hypertonic saline fluid or sodium bicarbonate fluid, and
common salt poisoning.
Chloride, in the body, is in balance with bicarbonate, so that if chloride
is reduced bicarbonate is retained and vice versa. The relation between the
two ions, however, is not quantitative, because the buffer system is not only
made up of bicarbonate, but also of other bases that have negative charges.
The amount of chloride also depends on the amount of water available, so
its effect must be compensated for by the concentration of sodium (see
Tables 2.4 and 2.5). Reductions in chloride levels may be due to vomiting,
administration of fluids containing more sodium than chloride (0.9% NaCl
solution or sodium bicarbonate), administration of furosemide,
hyperadrenocorticism and hyperaldosteronism (which induce sodium
retention). Albumin, on the other hand, behaves like a weak acid because it
has a negative charge and induces a higher concentration of H+ ions; its
reduction has an alkalizing effect, while its increase has an acidifying effect.
In some patients, hypoalbuminemia may occur to compensate for chronic
respiratory acidosis; in these cases, the body, which is not able to
completely eliminate CO2, tries to compensate for respiratory acidosis with
hypoalbuminemic alkalosis (which reduces the concentration of albumin).
Lactate is derived from lactic acid, and for 1 mole of lactic acid 1 mole of
H+ is produced, so an increase in lactate should be interpreted as a sign of
increase in an acidic chemical species. Phosphates and sulfates are normally
excreted through the kidneys. Their increase is therefore an indicator of
impaired renal function; in addition, as they are acidic chemical species,
i.e., they have negative charges, their increase causes an increase in H+.
Because they have a negative charge, sulfates promote an acidifying effect,
but they are not usually measured in clinical practice. An increase in
sulfates is one of the causes of an elevated AG in metabolic acidosis due to
renal failure.
Reductions in SID cause acidosis and are the most frequent cause of
metabolic acidosis. Typical causes of a reduced SID are diarrhea, duodenal
vomiting, excessive water retention (hypervolemic acidosis) caused by
congestive heart failure, cavitary effusions, hyperadrenocorticism and the
administration of unbalanced electrolyte solutions. Hyperchloremic acidosis
can be the consequence of diarrhea (loss of bicarbonate from the intestine
with a compensatory increase in chloride), renal failure and, rarely,
excessive administration of potassium chloride.

Fluid therapy and SID

When administering fluids, it is important to consider the patient’s SID. For
example, administration of a large volume of fluid (e.g., liberal fluid
management) with a different SID to that of blood can cause an alteration of
the patient’s SID, and considering that a reduction in the SID is the main
factor responsible for changes in pH, its incorrect evaluation can be the
cause of a patient’s acid–base disturbances. The blood SID, under normal
conditions, is about 24. For this reason, when large volumes of fluids are to
be administered, it is preferable to choose fluids with an appropriate SID
instead of considering only the concentration of chloride and other
elements. When fluids are administered in large volumes or for a long
period, it is advisable to use balanced solutions with a SID of about 24,
which are usually obtained by adding molecules with a negative charge and
buffer capacity to sodium; instead of chloride alone (such as 0.9% NaCl),
acetate, lactate, malate, or gluconate are usually used as anions, so that,
instead of reducing the SID, these can behave as buffers (increasing the
SID). In fact, it should be remembered that some of these ions, in vivo,
have a different behavior: for example, solutions containing lactate should
theoretically be acidifying because lactate is negatively charged, but
because lactate is mainly transformed into a buffer by the liver, in vivo it
behaves as an alkalizing solution rather than as an acidifying solution.
Bicarbonate is not typically used as it requires glass bottles and can produce
vasodilation and calcium carbonate if calcium is present in the solution.
Sodium bicarbonate is incompatible with some drugs, such as epinephrine,
amoxicillin and clavulanic acid, dobutamine, ketamine, morphine,
midazolam, norepinephrine tartrate, ondasentron, and chloride verapamil.
Solutions that have an SID of about 24 should theoretically be neutral
from the acid–base point of view, but in reality, altering Atot, they should
have a greater SID, or rather a SID comparable to that of the patient, while
a solution with a SID of 40–50 should preferably be used when attempting
to correct a metabolic acidosis. Colloidal solutions can also affect the SID
because they contain Atot in different concentrations, such as gelatin and
albumin, while hydroxyethyl starches depend on the solution in which they
are dissolved (see Table 2.1 and Table 3.8 in Chapter 3). In general, for
maintenance fluid therapy and especially when dealing with
hyperchloremic acidosis, it is recommended to use solutions with a high
SID or one that is at least greater than that of the patient’s plasma, even in
the postoperative period, which is generally characterized by metabolic
acidosis. When there is no acid–base alteration and the SID is normal, it is
preferable to use solutions with an SID similar to that of the patient’s
plasma.

Clinical case, example

A clinical case interpreted with the traditional and nontraditional approach
is described below.
The patient is a male German Shepherd of 5 months of age suffering
from sepsis (suspected parvovirosis in its gastrointestinal form), with the
following laboratory values:
pH: 6.8;
PaCO2: 22 mmHg;
HCO3−: 3.4 mEq/L;
PaO2: 98 mmHg;
lactate: 7.0 mmol/L;
Na+: 150 mEq/L;
K+: 3.4 mEq/L;
Cl−: 98 mEq/L;
phosphates: 3.0 mEq/L;
AG: 28;
BE: –34.52;
albumin: 0.9 g/dL;
hemoglobin: 14.2 g/dL;
FiO2: 0.4.

According to the traditional approach, the patient has a mixed disorder,

because he has a severe metabolic acidosis: the pH is decreased, with a
reduction in HCO3− and a severe reduction in BE; in addition, respiratory
alkalosis is present. The expected respiratory compensation should bring
CO2 to about 36.6 mmHg, but its value is 22 mmHg.
This means the patient is suffering from hyperventilation and mixed
acid–base disorders, since the body never compensates in excess; another
morbid process (e.g., pain, anemia) causing hyperventilation and a
reduction in CO2 must therefore be present. The increased AG is likely the
consequence of the presence of lactate in the blood as a result of
hypovolemic shock.
According to the nontraditional approach, the patient has severe
metabolic acidosis (due to a likely increase in lactates) and
hypoproteinemic and hyperchloremic alkalosis. In addition, there is an
excess of UAs (–26,5). The SID, which should normally be about 29.1
mEq/L, is about 52.6 mEq/L in the patient. The Atot, which should be about
17.4 mEq/L, are about 5 mEq/L. It is therefore a case of severe metabolic
acidosis, confirmed by the high concentration of UAs. A metabolic
alkalosis is also present due to hypoalbuminemia and hypochloremia; the
patient’s acidosis is therefore more severe than the pH seems to indicate,
because it is “masked” by hypoalbuminemia and hypochloremia. This
patient has an H+ concentration of about 158 nmol/L (under normal
conditions, it should be about 34 nmol/L). Hypoalbuminemia reduce the H+
concentration by about 42 nmol/L, while respiratory alkalosis compensates
for acidosis to an extent of about 40 nmol/L.
Table 2.6 Calculation of the effect of strong ions on the base excess
Na+ 0.25 × (150 – 145) 1.25
Cl– 110 – (98 × 145/150) 10.78
Albumin 3.7 × (3.1 – 0.9) 8.14
Phosphates 0.58 × (5.0 – 3.0) 1.16
Lactate –1 × [7] –7
Effect of unmeasured UAs = –34.52 – (1.25 +
anions (UAs) 10.78 + 8.14 + 1.16 + [–7])
UAs = –20.19
As shown in this case, when dealing with metabolic acidosis it is
necessary to pay attention to the concentrations of albumin, Atot and
chloride (the latter because it could aggravate metabolic acidosis).
By calculating each component and subtracting it from the BE, the
values listed in Table 2.6 are obtained for each component.
From the calculation of the strong ions reported in Table 2.6, the severe
acidosis is evident, given the presence of a considerable amount of UAs,
and of an alkalosis from hypoalbuminemia and hypochloremia, although
there is also an alkalosis from SID that compensates for it.

Strong ion gap (SIG)

The SIG is another quantitative approach to determining the presence of
UAs in dogs and cats. According to this theory, the net sum of strong ions
(sodium, potassium, calcium, magnesium, from which chloride and lactate
are subtracted) must be balanced by the activity of anions (albumin, total
proteins and phosphorus). The simplified SIG is measured using the
following formulas:
[alb], measured albumin concentration; AG = (Na+ + K+) – (Cl− + HCO3−).
In the presence of hyperphosphatemia, the AG must be corrected: correct AG = AG + (2.52 – 0.58 ×
[phosphate])

Values below –5 or –6 suggest the presence of UAs; values above +5 or

+6 suggest the presence of UCs (unmeasured cations), an event that occurs
rarely. The cause for a reduction in the SIG below the normal range should
be promptly investigated and treated.

Correction of acid–base disorders

The possible acid–base disorders are as follows:
metabolic acidosis;
metabolic alkalosis;
respiratory acidosis;
respiratory alkalosis;
mixed, respiratory and metabolic disorders:
– respiratory acidosis and metabolic alkalosis;
– respiratory and metabolic acidosis;
– respiratory alkalosis and metabolic acidosis;
– respiratory and metabolic alkalosis;
– metabolic acidosis and metabolic alkalosis;
– respiratory acidosis and respiratory alkalosis;
– metabolic acidosis with normal or increased AG;
– metabolic acidosis with elevated AG;
– metabolic acidosis with normal AG;
– triple disorders.

Metabolic acidosis
Metabolic acidosis consists in a decreased pH (<7,4) and can be caused by a
decrease in bicarbonate or an increase in hydrogen ions; it is characterized
by a secondary compensatory respiratory alkalosis (decreased PaCO2). The
most common causes of metabolic acidosis are summarized in Table 2.3.

Treatment of metabolic acidosis

The treatment of metabolic acidosis should primarily aim to treat the
morbid process that caused the acid–base disorders (see Table 2.3). To this
end, the primary disorder must be identified, so we must ensure that there is
no alteration caused or modified by strong ions that control the SID, Atot,
phosphates and sulfates. The etiology of metabolic acidosis is variable and
a specific therapy will be needed in each case, but all types of metabolic
acidosis will have to be treated with balanced isotonic solutions containing
bicarbonate precursors (e.g., lactate or acetate). The choice of the type of
solution will depend on the patient’s electrolytes and blood pH. Generally,
treating the cause of acidosis, restoring the lost volume, and continuing with
maintenance fluid therapy using isotonic crystalloids that contain
bicarbonate precursors (e.g., electrolyte replenishment solution with sodium
gluconate or acetated Ringer’s solution) will correct metabolic acidosis.
After restoring the lost volume and starting maintenance fluid therapy, it is
advised to repeat the ABG after at least 30 minutes. In some cases of severe
metabolic acidosis, such as those caused by chronic kidney failure, an
alkalizing treatment with sodium bicarbonate will be necessary.

Sodium bicarbonate therapy

An alkalizing treatment with sodium bicarbonate should be considered in
patients with a pH below 7.2, a BE below –10 mEq/L and bicarbonate
levels below 14 mEq/L. When the pH reaches values below 7.0, the acid–
base disorder can impair vital functions and must be treated urgently and
aggressively, not with sodium bicarbonate but with alkalizing solutions,
given that bicarbonate infusion can be fatal it is performed too quickly (<20
min).
The alkalizing effect of NaHCO3− is also obtained thanks to the large
amount of sodium present in the solution: as it is a strong cation, it induces
a reduction in H+. An 8.4% solution contains 1000 mEq/L of NaHCO3− and
thus has a SID of 1000. The dose of bicarbonate to be administered is
calculated using the following equation:
 Approximately 1/4 or 1/2 of the calculated dose should be administered
at a rate greater than that necessary to be redistributed from the
intravascular compartment to the interstitial compartment, i.e., in about 20–
30 minutes. Faster administration can cause cardiovascular collapse and
death of the patient. In the absence of an ABG, the empirical dose that is
sometimes used is 1–5 mEq/kg, and corresponds to the amount needed to
correct an approximate deficit of 5–15 mEq/L. This method is dangerous as
not knowing the required amount of sodium bicarbonate that should be
administered can be the cause of iatrogenic alkalosis.
Before administering sodium bicarbonate, it is necessary to check the
patient’s ability to ventilate, as it is important that the CO2 produced as a
result of this treatment can be eliminated through ventilation; CO2 is then
rapidly excreted, which generates an excess of intracellular H+ (paradoxical
acidosis), responsible for the depression of the CNS and myocardial
function. Patients with normal ventilation only require a few ventilatory
cycles to eliminate excess CO2.
Rapid administration of bicarbonate or excessive alkalinization can
cause nausea, vomiting, hypotension, collapse, and death. The cause of such
effects lies in the rapid alteration of the H+ concentration, with a reduction
in potassium and calcium ion levels. The administration of sodium
bicarbonate also causes hypernatremia, especially when repeated doses are
administered; it is therefore necessary to perform another ABG at least 30
minutes after its administration.
Sodium bicarbonate solution is hypertonic (2000 mOsm/kg) and it can
cause vascular irritation and pain when infused peripherally. To reduce its
osmolality, it is possible to dilute one part of sodium bicarbonate in 6.5
parts of 5% dextrose solution, which will reduce natremia (154 mEq/L) and
make the solution iso-osmolar (308 mOsm/L).

Metabolic alkalosis
Metabolic alkalosis consists of an increase in pH (>7.45) and bicarbonate
(>24 mEq/L) associated with a reduction in H+. It is characterized by a
compensatory increase in CO2. Metabolic alkalosis is less frequent than
metabolic acidosis and it is often associated with hypokalemia and
hypovolemia. The most common cause of alkalosis is the loss of hydrogen
ions due to vomiting, more rarely to urine excretion or the administration of
diuretics; it can also develop after hypercapnia.
After diagnosing alkalosis, it is necessary to ensure that no alteration has
been caused or modified by strong ions by checking sodium, chloride,
protein (especially albumin), phosphate and sulfate levels. In particular,
chloremia must be verified, because its reduction is the cause of alkalosis; it
is frequently produced by the loss of gastroenteric fluids (e.g., following
vomiting and diarrhea), which contain large quantities of chloride.
Iatrogenic alkalosis rarely occurs due to administration of alkalis as the
body can eliminate them. When this phenomenon occurs, kidney function
must be controlled.
Alkalosis is frequently associated with potassium losses (e.g., following
vomiting). In this case, intracellular potassium moves out of cells to
compensate for the losses and electroneutrality is maintained by the
movement of sodium and hydrogen ions into cells, which produces
extracellular alkalosis and intracellular acidosis. Compensatory
hypochloremia (to achieve electroneutrality) resulting from an increase in
extracellular negative charges aggravates alkalosis, thus reducing the
possibility of anion reabsorption in the renal proximal tubules. Sodium and
potassium are reabsorbed into cells, which causes hypokalemia.
Bicarbonate binds to the hydrogen ions moving out of the cell to form
carbonic acid; this generates CO2, which must be eliminated through
ventilation. Large losses of extravascular volume (e.g., due to incoercible
vomiting or duodenal diarrhea) favor sodium and bicarbonate ion
reabsorption by the renal proximal tubules, the movement of potassium into
the lumen of the tubules (which is then excreted with urine), and metabolic
alkalosis.
During therapy with furosemide, alkalosis may occur due to
extracellular fluid contraction, as the loss of chloride ions is compensated
for by an increase in bicarbonate. Under normal conditions this effect is
compensated for by the activity of the normal cell membrane and bones, but
in case of renal failure this phenomenon is more severe.
 Metabolic alkaloses can be classified into two types: with severe
extracellular fluid (ECF) depletion and with normal ECF. The former
alkaloses respond to chloride therapy (administration of NaCl 0.9%), while
the latter do not and are less frequent and caused by hyperaldosteronism or
hyperadrenocorticism.
The most common causes of metabolic alkalosis are the following:
gastric diseases;
vomiting;
aspiration of gastric contents;
hypochloremia (e.g., from diarrhea);
hypokalemia;
administration of mineralocorticoids;
administration of furosemide or thiazide diuretics;
hypomineralcorticism;
metabolism of citrate and ketone bodies;
administration of carbenicillin or penicillin derivatives;
administration of antacids;
contraction alkalosis;
alkalizing therapy;
compensation of respiratory acidosis.

Treatment of metabolic alkalosis

The treatment of metabolic alkalosis depends on the type of alkalosis
(chloride-responsive or non-chloride-responsive). With the first type it is
necessary to administer acidifying crystalloid solutions such as 0.9% NaCl;
with the second type (hyperaldosteronism or hyperadrenocorticism), the
morbid process must be treated. In patients with imbalances that respond to
chloride therapy, volemia should be restored with 0.9% NaCl solution; this
ensures losses (dehydration) are replenished and hypokalemia is treated.
After this initial phase of fluid therapy, an ABG should be performed to
check the effectiveness of the treatment. When the arterial pH is between
7.4 and 7.65, it is sufficient to treat the morbid process that caused the
disorder (e.g., by controlling vomiting) and initiate fluid therapy with
isotonic saline solution. A pH greater than 7.65 requires a more aggressive
treatment with acidifying fluid therapy (0.9% NaCl with added KCl) and
close monitoring of the patient. If the pH is above 7.8, immediate therapy is
required as this value is incompatible with life. Fluid therapy with 0.9%
NaCl solution should always be supplemented with potassium chloride (see
Chapter 3) in order to correct hypokalemia.

Respiratory acidosis
Respiratory acidosis is the consequence of insufficient ventilation,
responsible for an increase in CO2. It is characterized by a reduction in pH
and a compensatory increase in blood bicarbonate concentration. In chronic
forms, there may be a reduction in total protein or albumin, or both. This
disturbance is caused by an inability of the body to eliminate CO2 due to
airway stenosis (e.g., asthma, pleural effusion) or impaired ventilatory
function (e.g., CNS diseases). In the body, the CO2 produced can be
eliminated through ventilation or combine with the hemoglobin in red blood
cells to form carbaminohemoglobin.
The causes of respiratory acidosis are as follows:
alterations of CNS activity: head trauma, general anesthesia, opioids,
neoplasms;
diseases of the peripheral nervous system: tetanus, botulism,
organophosphates, hypokalemia, tick paralysis, polyradicoloneuritis,
polymyositis, phrenic nerve dysfunction, myasthenia gravis;
injuries of the chest wall: trauma, rib fractures, pleural effusions;
lung diseases: pneumonia, asthma, pulmonary thromboembolism, severe
pulmonary edema, smoke inhalation;
airway obstructions: diseases of the pleural space, diaphragmatic hernia,
pneumothorax, pleural effusions, laryngospasm, tracheal collapse,
laryngeal paralysis, brachycephalic syndrome, asthma;
ineffective mechanical ventilation;
increased CO2 production: heatstroke, malignant hyperthermia,
cardiopulmonary arrest.
Respiratory acidosis can be acute (e.g., pneumothorax) or chronic (e.g.,
feline asthma). Chronic acidosis can be compensated for by renal retention
of bicarbonate ions, while acute acidosis cannot benefit from this
compensatory mechanism because the kidneys need several hours to initiate
bicarbonate ion retention (which culminates within 2–5 days). Chronic
acidosis can be compensated for by a decrease in albumin, which, because
of its negative charge, can reduce the H+ concentration.
During respiratory acidosis, in addition to compensation with retention
of bicarbonate ions, the body buffers excess hydrogen ions with basic
phosphate to form phosphoric acid, and with blood proteins.
Excess hydrogen ions enter the cells by exchanging with potassium, thus
causing hypokalemia. Increased CO2 is often associated with hypoxia,
which is why some severe cases of respiratory acidosis, if not treated with
oxygen therapy, can be fatal. In these patients, oxygen therapy is provided
(when the partial pressure of oxygen is ≤80 mmHg or oxygenated
hemoglobin falls below 95%), although the administration of oxygen
cannot reduce CO2 because it does not improve ventilation if it is impaired;
in fact, it improves it only in case of hypoxia.
When hypercapnia is not corrected, patients show respiratory distress,
reduced cardiac output and blood pressure, depression of the CNS and loss
of consciousness.

Treatment of respiratory acidosis

Treatment begins with the diagnosis of acute hypercapnia, as this should be
treated as early as possible (e.g., with chest drainage or positive pressure
ventilation). In all cases it is advisable to also provide oxygen therapy, from
the moment the patient is admitted until the treatment is initiated to reduce
cerebral hypoxia. In acute and severe forms (e.g., laryngeal paralysis,
brachycephalic syndrome, severe tracheal collapse), it is necessary to
induce anesthesia and emergency orotracheal intubation or tracheostomy in
order to perform positive pressure ventilation; in chronic forms, appropriate
diagnostic investigations must be performed to identify the morbid process
and take the most appropriate therapeutic measures. Chronic respiratory
acidosis leads to compensatory metabolic alkalosis, but this latter can also
be of iatrogenic origin as a result of the administration of diuretics and
corticosteroids.
In hypercapnic patients, excessive oxygen administration can suppress
the hypoxic reflex, which is the natural ventilatory stimulus, so when
adequate oxygenation is achieved (PaO2 >80 mmHg or oxygenated
hemoglobin >95%) aggressive ventilation should be discontinued.
 Fluid therapy should consist of balanced isotonic solutions containing
bicarbonate precursors; when it is associated with correction of the main
problem, it is usually sufficient to correct acidosis. Bicarbonate
administration is not recommended as it can increase the SID and ultimately
reduce the pH, as well as reduce the ventilatory stimulus and aggravate
hypoxia with an increase in CO2, which will in turn aggravate acidosis
because the patient is not able to eliminate the increased fraction of CO2
resulting from bicarbonate administration.

Respiratory alkalosis
Respiratory alkalosis involves decreased CO2 and is characterized by an
increase in pH and a compensatory reduction in bicarbonate. It is the result
of an increase in ventilation that exceeds the production of CO2. The causes
of hyperventilation are hypoxemia (e.g., right-to-left shunts, congestive
heart failure), tissue hypoxia without hypoxemia (e.g., anemia, hypotension,
carboxyhemoglobin), shock, SIRS (systemic inflammatory response
syndrome), acute lung diseases (e.g., pneumonia, thromboembolism,
pulmonary edema, ARDS), and stimulation of receptors located in the CNS
(e.g., pain, trauma, infections, liver disease, resolution of metabolic
acidosis, pregnancy, salicylate poisoning and heatstroke).

Treatment of respiratory alkalosis

The treatment of respiratory alkalosis requires rapid diagnosis and treatment
of its cause. Generally, treatment of hypoxia (oxygen therapy) is sufficient
to correct hyperventilation. In cases refractory to oxygen therapy, i.e., when
the PaO2 is <60 mmHg or hemoglobin saturation remains ≤90%, positive
pressure ventilation is required. Respiratory alkalosis can also result from
pain: in these cases, the administration of analgesic drugs corrects the acid–
base imbalance.

Mixed disorders
Mixed acid–base disorders occur when two or more primary disorders (e.g.,
triple disorders) develop at the same time. A typical example is a patient
with chronic renal failure who may have a pH close to normal due to a
metabolic alkalosis from vomiting (e.g., due to gastric mucosal erosion) and
a simultaneous acidosis due to loss of bicarbonate ions resulting from renal
failure.
Mixed disorders should always be suspected when the pH is normal or
close to normal while the metabolic (bicarbonate) and respiratory (carbon
dioxide) components have opposite directions and values beyond normal
compensation. The definitive diagnosis is made by identifying the different
acid–base disturbances. In summary, the suggestive alterations of a mixed
disorder are:
a normal pH with changes in PaCO2 and HCO3− in the opposite direction;
a change in pH in the opposite direction from the primary disorder;
alterations of the metabolic and respiratory components beyond the
expected compensation;
changes in metabolic and respiratory components in the same direction.

Treatment of mixed disorders

The treatment of mixed disorders should be aimed at treating the primary
disorder. The first step is therefore to diagnose and correct the main
problem, before repeating the ABG. If secondary disorders have not
normalized, they must be corrected (e.g., by fluid therapy and correction of
electrolyte or respiratory disorders). For example, if, in a patient with
pneumothorax, diagnosed with a respiratory alkalosis and a circulatory
failure due to a reduction in cardiac output resulting from the increase in
intrathoracic pressure, a perfusion deficiency is still observed after the air
has been removed with a thoracic drainage, then it is advisable to
administer resuscitation fluids. If these fluids had been administered before
drainage, they could have been ineffective or have further impaired
ventilation due to pulmonary overload. In summary, the most severe disease
process should be treated first, as it can compromise the patient’s vital
functions, and only then should the other disturbances be corrected if they
are still present. Generally, correction of the main disorder and
administration of balanced isotonic solutions (chosen based on the results of
the assessment of the acid–base and electrolyte status) are sufficient to
correct mixed disorders.
Suggested readings
[1] Rose BD. Introduction to simple and mixed acid base disorder. In Rose BD, Post TW (eds.).
Clinical physiology of acid-base and electrolyte disorders, 5th ed. New York: McGraw Hill;
2001. pp. 535–550.
[2] Martin L. All you really need to know to interpret arterial blood gases. Philadelphia:
Lippincott Williams & Wilkins; 1999.
[3] DiBartola SP. Fluid, electrolyte, and acid-base disorders in small animal practice, 4th ed. St.
Louis: Elsevier Saunders; 2011.
[4] Hahn RG. Clinical fluid therapy in the perioperative setting. Cambridge: Cambridge
University Press; 2016.
Clinical Case

The cat who couldn’t urinate

Clinical history
The patient is presented to the clinic due to stranguria; he has not been
eating or drinking for 2 days and is continuously licking his foreskin,
where some blood loss can be observed. His last stool was normal. He is
restless and does not want to be held by his owner or anyone who
approaches.
At triage, the following vital parameters are assessed:
heart rate: 180 bpm;
respiratory rate: 52 bpm;
pulse: normal;
rectal temperature: 39.3 °C;
mucous membranes: pink, CRT <1.5 seconds;
 blood pressure: 180/120 mmHg, MAP: 140 mmHg;
dehydration: absent;
pain on abdominal palpation and presence of a distended bladder.

Laboratory tests
A blood gas analysis is performed as part of the laboratory tests, as a
urethral obstruction is suspected with possible electrolyte complications,
in particular a risk of hyperkalemia. In these cases, it is important to
know the acid–base and electrolyte status, because potential
hyperkalemia could compromise vital functions. A complete blood count
is also performed to assess hematological parameters and the likelihood
of an infection. A biochemical profile is used to evaluate the possible
presence of kidney or other organ dysfunction and to check whether,
using the nontraditional approach to acid–base disorders, other metabolic
components are involved.

Venous blood gas analysis

Given that there is no disease of the respiratory system, venous sampling
is performed, since venous blood gas analysis is a reliable way of
measuring pH, bicarbonate, carbon dioxide and electrolytes.
pH: 7.10;
pvCO2: 39;
HCO3−: 12;
BE: –17;
Na+: 150 mmol/L;
Cl–: 121 mmol/L;
K+: 7.3 mmol/L;
lactate: 1.4 mmol/L;
AG: 26.8;
FiO2: 0.21.

Biochemical profile
BUN >300 mg/dL, creatinine 9.3 mg/dL, ALT 32 U/L, AST 12 U/L, total
protein 4.2 g/dL, albumin 1.0 g/dL, total bilirubin 0.01 mg/dL, GGT 2
U/L, glucose 153 mg/100 mL, phosphorus 9.4 mg/dL.

Complete blood count

RBC 5.9 × 1012/L, WBC 8.5 × 109/L, Hct 34%, Hb 11.0 g/dL, PLT 245 ×
109/L, neutrophils 10 × 103/µL.

Interpretation of laboratory tests

The blood gas analysis shows a metabolic acidosis and a compensatory
respiratory alkalosis; CO2 reflects the expected value of compensation: it
had to be reduced by about 10 units. Bicarbonate is very low and
corresponds to the primary disturbance, as it goes in the same direction as
pH. The cause probably lies in postrenal acute kidney injury due to
urinary tract obstruction.
According to the nontraditional approach, a severe acidosis and mild SID
alkalosis (-6 nmol/L) are present. There is also an Atot alkalosis that
contributes in about –22 nmol/L acidity, given that the severe acidosis is
caused by unmeasured anions. Severe hyperkalemia is present and could
lead to fatal arrythmias. The biochemical profile reveals a very severely
increased BUN and serum creatinine probably of postrenal origin. The
complete blood count shows a mild anemia, which is probably due to
chronic hematuria.
Osmolarity is calculated as follows:

Osm = 2 × [Na+] + glucose (mg/dL)/18 + BUN (mg/dL)/2.8

Osm = (2 × 150) + (153/18) + (300/2.8)

Osm = 416 mOsm/L

Osmolarity is higher than normal due to the slight increase in natremia,
but especially as a result of severe azotemia. Control of osmolality will
be achieved, more than with fluid therapy, by treating the urethral
obstruction, which will reduce azotemia and therefore the osmotic
pressure of blood.
Diagnostic tests
An X-ray of the abdomen is taken and reveals a distended urinary
bladder and numerous bladder stones.

Daily fluid therapy

Maintenance fluid therapy with a high SID should be provided to try to
correct the severe metabolic acidosis. Since the patient is not dehydrated
and is not suffering from any other losses, administration of the
maintenance fluid volume only is sufficient.
Maintenance fluid therapy: 2 mL/kg/hour IV, which corresponds to 8
mL/hour.
The solution chosen for the patient is a balanced polyelectrolyte solution
with sodium gluconate, as it contains 50 bicarbonate precursors (SID
equal to 50). If the previous solution is not available, it is also possible to
administer lactated or acetated Ringer’s solution; although these solutions
contain potassium, this does not affect the outcome of the treatment of
the morbid process, because the most critical element is to resolve the
urethral obstruction as quickly as possible. Before treating the urethral
obstruction, an electrocardiogram is performed that does not show any
rhythm alterations, only a sinus tachycardia and a slight elevation of the
T wave, with the first abnormality probably being due to pain and
agitation caused by handling.

Treatment of urethral obstruction

To unblock the urethra, the patient is put under general anesthesia by gas
after induction by intramuscular administration of 10 mg/kg ketamine
and 0.4 mg/kg midazolam in the same syringe, followed by oxygen
therapy and mask induction with 2.5% isoflurane. Once the induction is
complete, the patient is intubated and the urethra is unblocked.
The urethra is easily unblocked by placing a bladder catheter. A high
amount of blood is present in the urine drained by the catheter, thus
prompting the decision to leave the catheter until this amount is reduced;
if this is not done, the presence of a considerable amount of blood could
cause a new urethral obstruction. The bladder catheter is then removed
on day 2.
In this case, only a slight elevation of the T wave was observed on the
electrocardiogram, but if more severe abnormalities had been detected, 2
mL of 10% calcium gluconate could have been administered to the
patient by slow intravenous infusion. The following day the patient starts
eating and drinking again spontaneously, so the blood gas analysis and
biochemical profile are repeated with the following results:
pH: 7.45;
pvCO2: 42;
HCO3−: 22;
BE: 4.2;
Na+: 143 mmol/L;
Cl–: 121 mmol/L;
K+: 3.5 mmol/L;
lactate: 0.4 mmol/L;
AG: 3.5;
FiO2: 0.21.

The biochemical profile shows the following results: BUN 54 mg/dL,

creatinine 3.8 mg/dL, ALT45 U/L, AST 23 U/L, total proteins 3.8 g /dL,
albumin 1.2 g/dL, total bilirubin 0.02 mg/dL, GGT 2 U/L, blood glucose
97 mg/100 mL, phosphate 6.5 mg /dL.
The patient is discharged on day 3 with a diet to dissolve stones and
supplements for restoring the integrity of the bladder mucosa.
Fluids: when and how
to administer them
 CHAPTER
3

Fabio Viganò

Introduction
The administration of fluids, like that of any other drug, has its indications
and contraindications; however, unlike with other drugs, fluid therapy
requires an evaluation of the water and electrolyte balance and of the
hemodynamic effects that it can produce. When administering fluid therapy,
the following priorities must be followed:
identifying the patient’s needs;
establishing the objectives to be achieved;
performing hemodynamic monitoring;
performing electrolytic and acid–base monitoring.
Fluid therapy is indicated to maintain hydration, restore an effective
circulating volume (resuscitative fluid therapy), and achieve correct
rehydration.

Daily intravenous fluid therapy

Under normal conditions, the patient’s water requirements are satisfied by
the ingestion of water and food. However, when, due to some pathological
processes, the patient cannot take anything by mouth, it is necessary to
replace the physiological intake of water and electrolytes by the
administration of fluids to maintain the hydration status and replace
ongoing losses. Normally, the body loses water through the feces and urine.
These losses are defined as sensitive and measurable. Other losses, which
occur through breathing and sweating, are defined as insensitive and are not
easily measurable; they typically do not cause significant electrolyte losses.
Like sensitive losses, insensitive losses can become clinically relevant and
aggravate dehydration, for example, when the respiratory rate increases due
to hyperthermia or in case of pulmonary hypertension. Since sweating in
dogs and cats is negligible, it cannot cause water and electrolyte imbalances
as is the case, for example, in horses.

Daily water requirements

The NRC (National Research Council of the United States) has established,
based on a review of the literature [1], that the water requirements of dogs,
expressed in mL, correspond to kcal (1 kcal = 1 mL), using a range of
values between 94 and 183 multiplied by the metabolic weight, as shown in
the following equation:

The NRC has also established water requirements for cats, which
correspond to about 0.6–0.7 mL per kcal, calculated based on energy
requirements ranging from 31 to 100 kcal/kg for a total of about 22–70
mL/kg/day. The needs calculated by the NRC are based on healthy patients,
so a sick animal that is unable to move is likely to have reduced water
requirements. In addition, it should be remembered that the oxidation of
100 g of fat generates about 100 mL of water, while that of 100 g of
carbohydrates generates 60 mL of water, and that of 100 g of protein
generates 40 mL of water. In a recent study in veterinary medicine [2], the
authors recommended using the following equation to calculate daily water
requirements:

Another method to determine daily water requirements in dogs and cats

is to apply the equation used to calculate calorie requirements, assuming
that the caloric and water needs in mL are equivalent:

In patients weighing less than 2 kg, the equation that considers the
metabolic weight can be used:
 Another method for a very quick calculation of water needs is to
estimate them based on kg of body weight and administer fluids at a rate of
1.2–2.0 mL/kg/hour intravenously. The lower values should be used in large
or giant dogs, while the higher values should be used in small or dehydrated
patients. This method, which is very quick and simple, can be used at first,
but it is always recommended, as with the other methods, to constantly
monitor the patient’s clinical, hemodynamic, and laboratory parameters to
evaluate the effectiveness or toxicity of the volume of fluids administered.

Figure 3.1 Fluid volume and complications.

Therefore, daily fluid therapy should avoid the risks and complications
resulting from hypovolemia, such as hypoperfusion, organ dysfunction, and
an unfavorable outcome of the ongoing pathological process; on the other
hand, an excess of fluids can cause edema, in addition to organ dysfunction
and unfavorable outcome (Figure 3.1).
Daily fluid therapy can be provided using balanced solutions, which
have a similar composition and osmolarity to those of plasma, or hypotonic
solutions, which have a lower electrolyte content than balanced solutions in
order to reduce the likelihood of causing water retention and electrolyte
imbalances (Table 3.1). Electrolyte and water requirements in dogs and cats
have been established by the NRC [1] and are summarized in Tables 3.2 and
3.3. For the calculation of daily maintenance water requirements, see Box
3.1.

Hypotonic solutions
For maintenance fluid therapy, in addition to establishing the amount of
fluids that should be administered daily (see above), it is necessary to
determine the tonicity the solution should have and, therefore, how much
sodium it should contain; its appropriate SID (strong ion difference), i.e.,
how many bicarbonate precursors and how many electrolytes such as
potassium and chloride it should contain; and whether glucose or other
electrolytes should be added.
Table 3.1 Composition of crystalloids in 500 mL

Table 3.2 Daily electrolyte and water requirements in dogs and cats
Table 3.3 Examples of daily water and electrolyte requirements in dogs and cats

Calculation examples for daily water

Box 3.1
maintenance in mL

Dogs: 94 / 183 × kg0.75

Dogs and cats: 97 × kg0.655
30 × kg + 70
70 × kg0.75
30–48 mL/kg/day

In human medicine, the following guidelines for daily fluid therapy were
established in 2015 [3] (NICE guidelines): 25–30 mL/kg/day of water; 1
mmol/kg/day of sodium, potassium, chloride; and 50–100 g/day of glucose
(100 mL of a 5% solution contains 5 g of glucose). In veterinary medicine,
guidelines for daily fluid therapy have not yet been established. The risk of
administering hypotonic fluids is that these can cause hyponatremia: a study
conducted in 690 pediatric human patients [4] who were given a 0.45%
solution of NaCl showed a three-fold increase in cases of hyponatremia. In
a study [5] in 12 healthy fasted human patients who were administered
either hypotonic (Na+ 50 mEq/L, K+ 26 mEq/L, Cl– 55 mEq/L, phosphate
6.2 mEq/L, glucose 50 g/L, lactate 25 mEq/L) or isotonic fluids (Na+ 154
mEq/L, K+ 40 mEq/L, Cl– 194 mEq/L, glucose 50 g/L) for 48 hours, a
reduction in urine production, lower production of antidiuretic hormone,
and expansion of the circulating volume was observed in the group
receiving the isotonic solution, while those patients who had been
administered an hypotonic solution developed hyperchloremia with no
reduction in the blood concentration of sodium or potassium.
The contradictory studies in human and veterinary medicine do not
allow a conclusion to be reached or the establishment of definitive
guidelines, and it is therefore recommended, when providing daily fluid
therapy and especially when large volumes are administered for several
days, to check the patient’s body weight (to identify any weight gain or loss
from water retention or dehydration) twice a day, the electrolyte
concentration and pH at least once a day, and the production of urine over
24 hours. Since balanced saline solutions contain an excess of sodium and
chloride, but little potassium, a possible maintenance solution could be as
follows: Na+ 34–51 mEq/L + 5% dextrose + K+ 40 mEq/L + Mg+ 8 mEq/L.
Hypotonic solutions low in sodium are available on the market, such as
Normosol M® Hospira, which contains Na+ 40 mEq/L, Cl– 40 mEq/L, K+ 13
mEq/L, Mg+ 3 mEq/L, acetate 16 mEq/L (Osm 363 and pH 4.0–6.5). When
looking at its composition, it can easily be seen that this solution is also
hyponatremic and hyperkalemic compared to the plasma of our patients, so
when it is administered at high rates and for long periods it is advisable to
closely monitor the electrolytes, pH and patient’s weight.

Antidiuretic hormone and fluid therapy

The effects of ADH (antidiuretic hormone) should also be considered in the
daily fluid therapy of critically ill patients, given that in the presence of
severe stress, hypovolemia or hypotension, ADH promotes water retention
by retaining sodium and thus limiting urine production in an attempt to
correct hemodynamic deficits. Therefore, the administration of hypotonic
fluids in patients in which ADH release is increased can more easily cause
hyponatremia due to the increased water retention induced by ADH.

Fluid therapy under general anesthesia

Even in patients under general anesthesia there is an excess of ADH release,
which is insensitive to the administration of fluids [6]. In these patients it is
therefore advisable to administer isotonic saline solutions at 2–3
mL/kg/hour IV. In the past, much larger volumes of up to 10 mL/kg/hour IV
were used, as it was assumed that this infusion rate was necessary to restore
water losses due to evaporation from the exposed viscera during abdominal
and thoracic surgery. In humans, water losses through perspiration have
been estimated and are proportional to those due to exposure of the viscera,
as occurs during abdominal surgery: a small incision with no exteriorization
of the viscera (e.g., appendectomy) produces a loss of water of about 2.1
mL/kg/hour, while losses through evaporation are about 8.0 mL/kg/hour
with an average incision with partial exteriorization of the viscera (e.g.,
cholecystectomy), and 32.2 mL/kg/hour with an extended incision with
exteriorization of all viscera. Such losses are reduced by 50% after 20
minutes; if the viscera are placed in a plastic bag, losses are reduced by
87%.
A recent study called RELIEF conducted in human patients [7,8] has
demonstrated the potential benefits of restrictive fluid therapy during
abdominal surgery when compared to liberal fluid therapy [9]. In this study,
restrictive fluid therapy involved administering 5 mL/kg of fluids at
induction and 5 mL/kg/hour during surgery (lasting at least 2 hours). After
surgery, 0.8 mL/kg/hour of fluids were administered and fluid
administration was discontinued as early as possible. The control group
receiving liberal fluid therapy were administered 10 mL/kg of fluids at
induction and 8 mL/kg/hour during surgery (lasting at least 2 hours). After
surgery, >1.5 mL/kg/hour of fluids were administered over a period of 24
hours or more (Box 3.2).
Daily fluid therapy
Before calculating the daily fluid therapy, it is essential to establish whether
a rapid replacement of the circulating volume is necessary or whether the
patient only needs replacement of the water (rehydration) and electrolytes
lost in addition to maintenance fluid therapy. Once the need for
resuscitative fluid therapy has been ruled out, the patient’s requirements
should be assessed before deciding whether a so-called “restrictive” fluid
therapy, with a water balance equal to zero, should be provided, or whether
fluid therapy should be performed in a liberal manner, that is, infusing
generous quantities of fluids. In the former case, restrictive administration
of fluids involves replacing those lost using solutions equal in composition
and amount to the patient’s deficit, while in the latter case, much larger
amounts of fluids are administered: for example, in humans, 3–7 L are
administered on the day of surgery and more than 3 L per day over the
following 3–4 days [9]. These doses correspond to approximately 1.7–4.2
mL/kg/hour on the day of surgery and 1.7 mL/kg/hour on the following
days.

Box 3.2 Fluid volumes under general anesthesia

Isotonic saline solution: 2–3 mL/kg/hour

Fluid bolus: 5 mL/kg/5 min (if not due to vasodilation)
Hemorrhage: isotonic saline solution 3:1 lost blood volume

Excessive administration of fluids can cause increased blood pressure

and hemodilution; it should be remembered that the reduction of hematocrit
and viscosity contributes to the collapse of the capillaries and the flow
within them [10]; causes tissue and pulmonary edema; reduces the ability to
transport oxygen and therefore leads to tissue hypoxia; causes coagulation
disorders; increases the blood flow rate, thereby inducing a reduction in the
opening in the microcapillaries; and leads to bacterial translocation,
increased concentration of atrial natriuretic peptide responsible for
glycocalyx damage, sepsis, and delay in wound healing, with an increased
risk of dehiscence of surgical sutures. Insufficient fluid administration, on
the other hand, can cause other complications, such as insufficient perfusion
pressure, reduced oxygen availability (oxygen delivery, DO2), anaerobic
metabolism, hypovolemia, collapse, and possible death of the patient. For
these reasons, the administration of fluids must be adapted to the patient’s
requirements (see Figure 3.1), which can also be estimated based on the
hydration and perfusion status.

Hydration
The hydration status is usually assessed through a clinical evaluation, as the
methods to calculate the amount of water present in the body require
techniques that are not usually accessible in clinical practice (see Chapter
1). Therefore, the interpretation based on clinical parameters is
unfortunately subjective and can be altered by factors not dependent on the
hydration status, such as obesity or severe slimming and cachexia.
The patient should be weighed during the physical examination, as
weight is a useful parameter to establish the volume of fluids to be
administered, and then, during fluid therapy, to determine if the patient
retains the fluids administered or if there is fluid depletion despite the
infusion. The amount of fluid loss is obtained by multiplying the percentage
of dehydration, obtained by assessing several physical parameters (Table
3.4), by the body weight expressed in kg; the value obtained corresponds to
the liters of fluid to be infused.
Table 3.4 Clinical signs of dehydration
 Percentage of
Clinical signs
dehydration

5 Undetectable clinical signs

5–6 Dry oral and ocular mucous membranes
6–8 Slight delay in repositioning of skin folds and
slight increase in capillary refill time (CRT)
9–12 Severe delay in skin fold repositioning, CRT >2
seconds or absent, dry and hyperemic oral and
ocular mucous membranes, sunken eyes, weak
pulse and hypotension
>12 Decompensated hypovolemic shock (tachycardia,
tachypnea, hypotension, weak pulse, pale mucous
membranes, CRT >2 seconds, cold extremities and
CNS depression)

For example, if a 15 kg patient shows signs of 10% dehydration, it

means that about 1.5 L of fluids should be administered. It is recommended
to distribute the volume of fluids to be infused over 24 hours, so as to
monitor the evolution of the hydration status and any electrolyte imbalances
that may be present. In some cases, for example of severe hypovolemia, the
volume of solution necessary to correct dehydration can be infused more
quickly (e.g., in 4–12 hours), but careful evaluation is needed of whether
fluid resuscitation might be more appropriate than routine fluid therapy.

Calculation of daily fluid therapy

To calculate daily fluid therapy in patients who are unable to drink or who
have continuous losses that cannot be replaced by oral administration, the
volume of fluids required to replace losses due to dehydration and any other
ongoing losses must be added to the maintenance fluids, as shown in the
following equation:
 “Ongoing losses” means the water and electrolytes lost through
vomiting, diarrhea and polyuria, more rarely through sialorrhea or
evaporation due to tachypnea that does respond to therapy. Quantification
of the ongoing losses is performed by monitoring the output of body fluids,
for example through urinary catheterization, or by measuring any fluids
collected in a recipient or weighing absorbent materials (e.g., hygienic
absorbent sleepers) before and after use. Urinary catheterization allows
accurate monitoring of the infused fluids and those excreted by the kidneys
(input and output) and urine production per hour.
For example, a dog weighing 20 kg with 9% dehydration (decrease in
skin turgor, CRT of 2.5 seconds and dry oral mucous membranes) and
continuous episodes of vomiting (8 episodes/day of about 35 mL each one)
will need the following daily fluid therapy:

mL/day = (30 × kg + 70) + (kg × % dehydration) + (ongoing losses)

mL/day = (30 × 20 + 70) + (20 × 9%) + (8 × 35)

mL/day = 670 + 1800 + 280

mL/day = 2750

mL/hour = 114

Once lost fluids, calculated on the basis of dehydration, have been

replaced (usually after 24 hours), the volume of fluids necessary for
rehydration (which in the example corresponds to 1800 mL/day) is
subtracted from the total daily fluid volume, and the fluids necessary for
maintenance and any ongoing losses are continued until the patient resumes
normal eating and the clinical signs disappear. In the example above, if the
patient, after 24 hours, is rehydrated and the episodes of vomiting are down
to 4 per day, the volume of fluids to be administered in the following 24
hours will be 670 mL + 140 mL, which corresponds to about 34 mL/ hour.
In order to monitor whether the volume of fluids administered meets the
patient’s needs, it is important to remember that the patient should always
be weighed twice a day, so as to reduce the risks of fluid overload or weight
loss resulting from insufficient fluid therapy.
To objectively assess whether perfusion and oxygenation are improved
thanks to fluid therapy, it is possible to measure ScvO2 (see Table 3.6).

Hemodynamic monitoring
The need to administer fluids to restore effective circulation (i.e., fluid
resuscitation) is established by assessing the patient’s hemodynamic status
using clinical and instrumental examinations. Some of these parameters are
static and detect a value at a particular time, while others are dynamic and
therefore allow continuous monitoring of the hemodynamic status.
The physical perfusion parameters (Box 3.3) are heart rate, pulse
quality, CRT (capillary refill time), mucous membrane color, body
temperature, jugular ectasia and urine output.

Heart rate and cardiac output

Heart rate is a parameter that is very simple but very important to measure
since it directly affects cardiac output, as expressed in the following
equation:

CO, cardiac output; VEF, ventricular ejection fraction; HR, heart rate.

Cardiac output (CO) measures the amount of blood pumped in 1 minute

from the left ventricle (see Equation 6); stroke volume (SV) is the volume
of blood ejected during each contraction from the left ventricle; heart rate
(HR), which is multiplied by the volume of blood ejected during each
contraction, can increase or decrease CO. When patients are hypovolemic,
the SV is reduced, which causes a reduction in the circulating volume and a
rapid response of the body with an increase in heart rate; conversely, a
reduction in heart rate can cause a reduction in CO. Therefore, in
hemodynamically unstable or hypovolemic patients, attention should be
paid to the heart rate, which is usually increased before the fluid bolus and
normalizes in patients responsive to fluid therapy. CO can also increase due
to increases in myocardial contractility as well as in preload (i.e., the
volume of blood that reaches the heart from the venous compartment).

Box 3.3 Clinical parameters of perfusion

Heart rate: dogs 80–160 bpm; cats and pediatric patients 160–240 bpm
Pulse: full, hyperdynamic, weak, absent
Capillary refill time (CRT): 1–2 seconds
Mucous membrane color: pink, red, pale, yellow, bluish
Central temperature: rectal or esophageal 38–39 °C
Peripheral temperature: interdigital 35–36 °C
Jugular ectasia: evidenced by hemostasis
Urine output: 1–2 mL/kg/hour

Pulse quality
The peripheral pulse represents the movement of blood on the vascular wall
(Figure 3.2). It is an easily detectable, repeatable and useful parameter
when evaluating the hemodynamic status, especially when the femoral
pulse is compared with the metatarsal pulse (Box 3.4). The pressure wave is
transmitted more quickly (about 10 m/s) through the vascular wall, while
blood moves at a much lower speed (about 0.5 m/s). Therefore, when the
pulse is palpated, more than the movement of blood, what is perceived is
the pressure wave moving through the vascular wall.
In critically ill patients, the assessment of pulse quality plays an
important role as their condition can change very quickly. In these cases, a
rapid and repeatable method that is easily applicable by all medical and
paramedical staff can make a difference in the evaluation of the
hemodynamic status and response to fluid therapy or inotropes and/or
vasopressor drugs, especially when no effective tools are available for this
hemodynamic assessment or when these tools fail to provide reliable
information and their ability to detect data when the circulation is
compromised by excessive vasoconstriction or vasodilation needs to be
checked.
 The metatarsal pulse is the first to disappear (systolic pressure <90
mmHg) during hypovolemia or hypotension; it can be palpated dorsal and
medial to the tibiotarsal joint. The femoral pulse becomes absent when
systolic pressure becomes severely reduced (<70 mmHg); severe
vasoconstriction or vasodilation can also hinder its detection. In addition, a
discrepancy between the cardiac auscultation and pulse is a sign of
arrhythmia.

Figure 3.2 Normal pulse, pressure curve.

Lower empirical pressures at which the

Box 3.4
pulse cannot be perceived

Metatarsal pulse: about 90 mmHg

Femoral pulse: 70 mmHg
Palpable apical impulse: <50-60 mmHg
 In thin patients and particularly in dolichocephalic dogs, the
disappearance of a palpable apical impulse on the left chest wall in the
cardiac projection area between the third and sixth intercostal spaces may
be related to severely impaired myocardial performance, severe
hypotension (<50–60 mmHg), and hypoperfusion. When the previously
detectable apical impulse disappears, it is necessary to reevaluate the
patient, since cardiopulmonary resuscitation or shock fluid therapy may be
indispensable.
The peripheral pulse intensity, depth, amplitude, rate, rhythm, length and
type should be identified. The peripheral pulse can then be classified as
bounding, increased, normal, weak or absent.
Increases in heart rate (>220 bpm) may be suggestive of hypovolemia
and tachyarrhythmias; pain can also increase the amplitude of the pulse and
reduce its duration, while during decompensated shock the pulse increases
in rate but is reduced in amplitude. A weak pulse can be symptomatic of
hypovolemia, anemia, or heart failure, while sepsis can generate a
hyperkinetic pulse with an increased amplitude, but that disappears easily
with digital pressure (i.e., that is very compressible) and with a shorter
duration (see Figure 3.2; Figure 3.3). A reduction in duration, amplitude
and intensity is typically related to hypovolemia.

Capillary refill time (CRT)

CRT is assessed by causing, with digital pressure, a displacement of the
blood from the vascular bed of an accessible mucous membrane (e.g., the
gingiva), and then measuring the time necessary for the blood to return to
the capillary bed from which it was removed, which is done based on the
return of the mucous membrane to its original color. Under normal
conditions, the time it takes for the mucous membrane to return to its
original color is about 1.5–2 seconds. An increased CRT can be caused by
contraction of the precapillary sphincters, capillary vasodilation, and a
decreased circulating volume (e.g., hypotension, hypovolemia).
To determine if the CRT is increased due to excessive vasoconstriction
or to vasodilation, the temperature of the distal limbs can be assessed by
palpation; when vasoconstriction occurs, the temperature of the extremities
is decreased and vice versa. It is also possible to measure the rectal and
interdigital temperatures with a common clinical thermometer. The
difference between the rectal and interdigital temperatures, under normal
conditions, is about 3–4 °C.

Figure 3.3 A. Hyperdynamic pulse. B. Hypodynamic pulse.

Mucous membrane color

Although it does not always have an unequivocal and pathognomonic
interpretation, the color of the mucous membranes is important to recognize
signs of pathological processes that are not always readily diagnosed. The
mucous membranes can be injected or bright red in case of sepsis and septic
shock; red, hyperemic, in case of hyperthermia, hypertension, vasodilation,
intoxication, hyperthyroidism; pale, in case of anemia, vasoconstriction,
hypotension, hypovolemic shock; bluish, in case of hypoxemia, cyanosis;
brown, in case of methemoglobinemia; yellow, in case of jaundice, severe
hepatic insufficiency, administration of hemoglobin glutamer; and grayish,
in case of severe oxygen deficiency, decompensated shock, imminent death.
Body temperature
Body temperature plays a very important role in critically ill patients, and a
decreased temperature can be a suggestive sign of reduced activity of the
central nervous system (CNS). Severe hypothermia can be a sign of
imminent cardiopulmonary arrest because the thermoregulatory center is
located near the cardiorespiratory center. A reduction in body temperature
can affect many vital functions, such as coagulation and the acid–base
balance. In critically ill human patients, a body temperature below 32 °C is
related to 100% mortality. For this reason, an attempt must always be made
in critically ill patients to correct hypothermia with active or passive
systems.
Active systems are devices capable of generating heat, such as hot air
devices, which are effective as they heat the patient evenly without placing
them in contact with hot surfaces that could cause exemia due to
vasodilation and therefore aggravate an already compromised circulation;
systems that use semiconductive fabrics (e.g., Hot Dog®), which provide
heating of the patient by direct contact; infrared lamps and electric mats,
which can however cause second- to third-degree burns in addition to
plasmatic exemia if they are not used appropriately.
Passive systems are suitable to avoid heat dispersion at the body surface;
for this purpose, thermal blankets (e.g., wool) or aluminum blankets may be
used. Passive systems are used when heat loss must be avoided in mild
hypothermia, while active systems are used in severe forms of hypothermia,
because they are able to generate heat.
Body temperature should be measured centrally, when possible, by
inserting a temperature probe in the esophagus at the level of the base of the
heart; a simpler technique is to measure it rectally with a clinical
thermometer. The interdigital temperature can be measured using a
common clinical thermometer or with the temperature probe of a
multiparameter monitor. The interdigital temperature is useful to for
comparison with the central temperature: a reduction >3–4 °C is suggestive
of peripheral vasoconstriction and therefore of a circulatory alteration
capable of hindering peripheral and organ perfusion.

Jugular vein distension

Jugular vein distension can be detected at the level of the jugular fossa on
the side of the neck. To identify it, an area of about 15 x 5 cm should be
clipped along an imaginary line that runs from the corner of the jaw to the
tip of the shoulder. To cause ectasia of the jugular vein, hemostasis is
achieved by exerting pressure with two fingers at the level of the entrance
of the jugular vein into the chest, at the medial surface of the shoulder tip.
Under normal conditions it is most evident after 3–4 seconds and disappears
within 1–2 seconds. The absence of ectasia despite exerting pressure on the
vein indicates hypovolemia of the venous compartment or severe heart
failure, while ectasia with no hemostasis indicates an excess of blood
volume in the venous compartment; a jugular pulse may be due to right
cardiac regurgitation, an increase in intrathoracic pressure (e.g., effusion or
pneumothorax), or a pericardial effusion.

Urine production
Urine production is a useful parameter to determine whether the body is
able to eliminate the catabolites of metabolism and some trace elements and
to maintain the water, electrolyte and acid–base balance. A reduction in
urine production in a normohydrated patient can be considered an
indication of impaired perfusion, as the kidneys receive about 25% of
cardiac output. Arterial pressures <70 mmHg may be responsible for
impaired renal perfusion, as the kidney is able to regulate perfusion when
the blood pressure is between 70 and 200 mmHg; hypotension therefore
causes a reduction in renal blood flow (RBF) and urine output.
Under normal conditions, urine output should be about 1–2 mL/kg/hour.
Small patients have a higher urine production than large ones.
If the composition of the urine does not reflect the ongoing pathological
process, then another unidentified pathological process may be present, or
the kidneys may be damaged. If renal function is normal and excess fluids
are administered, the compensation will be an increase in urine output;
conversely, in case of dehydration, the kidneys will concentrate urine.
This is why, in a dehydrated patient, the urine should be more
concentrated (increased specific gravity). If a dehydrated patient’s urine has
a low specific gravity or there is oliguria in the presence of systemic or
pulmonary edema, the renal function should be assessed as it is likely to be
compromised.

Parameters to evaluate the hemodynamic status

The instrumental parameters to assess a patient’s hemodynamic status can
be static or dynamic. Dynamic parameters are most effective in assessing a
patient’s response to fluid therapy. The use of dynamic parameters allows
the implementation of the so-called goal-directed therapy (GDT). It is not
possible to determine if the objectives of fluid therapy have been achieved
and if the patient is responsive to fluid resuscitation with static parameters
(Box 3.5). Not all hemodynamic instrumental parameters can assess
whether the patient will respond to the fluid bolus (fluid responder), and
unfortunately most of these parameters have only been evaluated in human
patients, so their reliability and the normal values in our patients have not
yet been determined. The parameters that can identify fluid responders are:
clinical parameters detected at regular intervals, SVV, PPV, SPV, PVI,
cardiac ouput with esophageal Doppler, inferior vena cava diameter (IVCD)
variation, CVCCI and end-expiratory occlusion (see Chapter 1).

Blood pressure (BP)

BP is the measurement of the pulsatile pressure wave that moves from the
aortic valve to the arteries. During systole, BP increases and is called
systolic blood pressure, while during diastole it decreases and is called
diastolic blood pressure. The arterial pressure waveform has two distinct
parts, an ascending anacrotic limb and a descending dicrotic limb. The
steepness of the wave is related to myocardial contractility; closure of the
aortic valve is responsible for a short deceleration of the blood flow that
corresponds to the dicrotic notch (see Figure 3.2).

Static and dynamic parameters for

Box 3.5
hemodynamic assessment
 Static parameters Dynamic parameters
Invasive or non-invasive blood CVC (caudal vena cava):
pressure: MAP >70 mmHg or diameter variation during
systolic ≥90 mmHg. breathing.
ScvO2: 70%. Echocardiography.
CVP (central venous pressure), Clinical evaluation: of limited
normal values: 0–5 cmH2O; value, but can detect
circulatory overload: >10 inadequate organ perfusion if
cmH2O. repeated frequently.
Esophageal Doppler: requires
PCWP (pulmonary capillary
general anesthesia and specific
wedge pressure): pulmonary
instrument.
artery catheter needed (Swan–
SVV (stroke volume
Ganz catheter).
variation): requires controlled
Chest X-ray, e.g., pulmonary
positive pressure ventilation
edema, hypovolemic condition
and veterinary validation.
with microcardia,
End-expiratory occlusion test:
hypervolemia.
requires controlled positive
pressure ventilation and
veterinary validation.
PPV (pulse pressure variation)
>10%: requires controlled
positive pressure ventilation
and veterinary validation.
PVI (pulse variation index)
>14%: requires controlled
positive pressure ventilation
and veterinary validation.

BP measures the hydrostatic pressure of arterial blood; it is therefore an

important parameter to evaluate whether the blood can reach peripheral
circulation and thus ensure effective peripheral perfusion. Peripheral
vasoconstriction, which causes an increase in systemic vascular resistance
(SVR), hinders organ and peripheral perfusion, but it can compensate for
the reduced circulating volume and keep BP within normal or close to
normal values. For these reasons, BP alone cannot be considered as a
parameter of organ or peripheral perfusion, even if it may be impaired by
severe hypotension. Peripheral vasodilation can also occur as a
compensatory mechanism for the increase in CO, as occurs for example
during a physical activity that increases heart rate. Both a persistent
reduction and an increase in BP can cause organ failure, in particular of the
kidneys, CNS, eyeballs and heart.
The most common causes of hypertension are hypervolemia, the use of
vasoconstrictor drugs (e.g., sympathomimetic amines) or drugs responsible
for water retention (e.g., corticosteroids, nonsteroidal anti-inflammatory
drugs, salt, estrogens, antidepressant drugs, progestins, and finasteride). The
pathological processes that may be responsible for water retention are renal
failure, liver failure, diabetes mellitus, hypothyroidism,
hypoadrenocorticism, congestive heart failure, and hyperadrenocorticism.
The pathological processes that can cause hypotension are hypovolemia,
dehydration, sepsis, septic shock, distributive shock, cardiogenic shock, and
vasodilation.
The mean arterial pressure (MAP) must be between 50 and 150 mmHg
to ensure adequate cerebral blood flow (CBF), so in patients with head
trauma, monitoring of systemic BP is a fundamental parameter to control
secondary damage to the brain and spinal tissue (Figure 3.4, Table 3.5). BP
can be measured both noninvasively (NIBP, noninvasive blood pressure) or
invasively (IBP, invasive blood pressure). The first method, which is the
most widely used, can be performed more easily and quickly than IBP
measurement.

Noninvasive blood pressure (NIBP)

Unfortunately, NIBP can provide unreliable data because it is obtained
through an inflatable cuff (Figure 3.5) placed around the extremity of a limb
or at the base of the tail, and so is affected by tremors of the skeletal
muscles of the limbs, peripheral vasoconstriction, tachycardia, and
arrhythmias. NIBP generally overestimates low pressures and
underestimates high pressures.
Cuffs not appropriate to the patient’s size can alter the measurement:
cuffs that are too wide can give falsely reduced measurements, while cuffs
that are too narrow can produce falsely increased measurements. Therefore,
when taking measurements, it is recommended to record the size of the cuff
used, so as to always use the same for that patient. The inflatable cuff must
be adapted to the diameter of the limb or tail; its length must be about 80%
of that of the limb and its width 40% of the circumference of the limb.
To reduce artifacts produced by tremors, it is recommended to place the
cuff around the base of the tail. This site is better tolerated in awake patients
than the limbs, especially in trauma cases in which the limbs may not be a
suitable site for measurement and constriction by the inflatable cuff could
cause intolerance reactions, in particular if the patient is suffering from
acute pain. The limbs, at the level of the humerus or, worse, the femur, have
a conical longitudinal section that hinders the correct positioning of the
inflatable cuff, which thus affects measurements. For this reason, it is
advisable to wrap the cuff around the second distal third of the forelimb,
with the cuff tube in a position corresponding to that of the artery.
When the cuff is wrapped around the base of the tail, the hair on its
ventral aspect should be clipped in the case of patients with long hair (e.g.,
Persian cat or Maltese dog) so that the variation in the arterial wall diameter
is more easily picked up by the instrument performing the oscillometric
measurement. The position of the cuff tube for measurements at the base of
the tail should also correspond to that of the caudal artery (ventral and
medial).

Figure 3.4 Components of DO2 and blood pressure. BP, blood pressure; CaO2, total oxygen content;
CO, cardiac output; DO2, availability of oxygen; Hb, hemoglobin; HR, heart rate; paO2, partial
oxygen pressure; pre, preload; post, afterload; SV, stroke volume; SVR, systemic vascular resistance.
Table 3.5 Normal blood pressure values

Parameter Dog Cat

SAP 90–150 85–160

DAP 60–90 60–90
MAP 70–100 70–110

DAP, diastolic blood pressure; MAP, mean blood pressure; SAP, systolic blood pressure.

Figure 3.5 Inflatable cuff for measuring blood pressure.

Mean arterial pressure (MAP)

Once NIBP has been measured, it is possible, using a mathematical
calculation, to obtain the MAP. The systolic phase constitutes about 1/3 of
the entire cardiac cycle, while the diastolic phase constitutes about 2/3 of
the cardiac cycle; this is why, when calculating the MAP, the SAP is
divided by three, as in the following formula:

MAP, mean arterial pressure; DAP, diastolic blood pressure; SAP, systolic blood pressure.
 In the presence of tachycardia this time interval is altered and the MAP
is affected, while under normal conditions the MAP is closer to organ
perfusion pressure. For these reasons, peripheral perfusion is not only
influenced by DAP, but also by the difference between SAP and DAP. To
obtain a peripheral perfusion pressure capable of supporting the vital
functions of tissues and therefore of the organ, the MAP should be at least
70 mmHg. Normal values in dogs and cats are given in Tables 3.6 and 3.7.
Thanks to SVR self-regulation mechanisms, the brain can maintain organ
perfusion for MAP values between 50–150 mmHg, while the kidneys need
a slightly higher ideal pressure of 70–200 mmHg.

Doppler ultrasonic method

The Doppler ultrasonic method to measure NIBP requires an instrument
capable of generating 10 MHz ultrasound waves, which detect the passage
of blood through the peripheral arteries and, in exotic patients, also through
the heart chambers or large vessels.
To take the measurement, the probe of the instrument is applied at the
level of the common palmar digital artery of the hindlimb or frontlimb, after
placing ultrasound gel between the patient’s skin and the surface of the
probe to prevent the presence of air bubbles from hindering the passage of
ultrasound. The area above the artery must therefore be clipped, as would
be done in preparation for surgery. The chosen area does not require
surgical preparation. The probe is attached to the limb with the help of an
adhesive plaster.
The flow of red blood cells inside the vessel is responsible for the
variations detected by the probe. These are then conducted to the
instrument, which generates the typical sound. The intensity of the sound
produced depends on the blood flow in the vessel: the greater the blood
flow, the greater the intensity of the sound.
Table 3.6 Objectives of fluid therapy
 Parameter Normal goals Minimum goals

Heart rate 80–160 bpm 80–140 bpm

Dog >160 <240 bpm 200–240 bpm
Cat
Pulse Full Palpable
CRT <2 seconds <2 seconds
Color of mucous pink pink
membranes
Rectal temperature 37.5–38.0 °C 36.0 °C
Extremity 34.5 °C 33.0 °C
temperature
Mean blood pressure ≥70 mmHg ≥60 mmHg
Urine output 1–2 mL/kg/hour 0.5 mL/kg/hour
Lactate <2.5 mmol/L 2.5–3.5 mmol/L
ScvO2 >70% >70%
Normal goals: hypovolemia, severe dehydration; minimum goals: ongoing active hemorrhage,
pulmonary and cerebral edema, coagulopathies.

Table 3.7 Shock: consequences and therapy

 Once the probe has been placed, an inflatable cuff with the
characteristics (length and width) described above must be placed upstream
of the probe. The cuff is inflated until the sound generated by the instrument
disappears; it is then slowly deflated. Systolic pressure is the value obtained
when the first audible sound appears. About 15 mmHg are added to this
value since this method slightly underestimates the peak pressure.
Unfortunately, it is not possible to determine the DAP with a sufficient
objective approximation, as it would correspond to the variation in intensity
of the sound emitted during the continuous deflation of the cuff after the
appearance of the first audible sound.
This method is very useful when wanting to know the peripheral
perfusion of a particular region (intensity of the sound produced by the
Doppler device); for example, the common palmar digital arteries can be
used to assess peripheral perfusion, or the probe can be applied to the
corneal surface (where ultrasound gel was previously placed) during
cardiocirculatory resuscitation to check if resuscitation maneuvers are able
to restore cerebral blood flow. Continuous and intense sounds indicate good
perfusion, while weak or absent sounds are suggestive of poor perfusion.
The Doppler ultrasound method offers the following advantages: it assesses
local perfusion, it can measure SAP even in very small and hypotensive
patients, it detects the pulse when this cannot be done by digital pressure,
and it enables assessment of the presence of peripheral vasoconstriction or
vasodilation as well as its duration based on the intensity of the sound
emitted (e.g., during general anesthesia, hypotension produced by
vasodilation by drugs is responsible for a reduction in sound intensity).
Reduction of the pulse quality may be useful when checking for an increase
in intrathoracic pressure (e.g., pneumothorax).
The main disadvantages of the method are that it can only measure the
SAP; an operator is needed to perform the procedure; BP measurements
cannot be obtained at predetermined intervals; the method is poorly
tolerated by awake patients, especially in the feline species and in patients
in pain; the procedure is difficult to perform in hypotensive and
vasoconstricted patients; and detection is operator-dependent, since the first
sound corresponding to the SAP may be detected differently by different
operators.

Invasive blood pressure (IBP) measurement

Invasive blood pressure (IBP) measurement is the best technique for
assessing blood pressure, because it directly determines the blood pressure
in a peripheral or central arterial vessel. The change in blood pressure inside
the vessel is transformed into an electric signal thanks to a transducer,
which sends the signal to a monitor that amplifies it and generates a
graphical representation of the pressure waves. It is not affected by the
artifacts that affect NIBP, such as vasoconstriction, hypotension,
hypertension, and arrhythmias, but requires catheterization of an artery. The
same arterial access used for IBP can also be used to collect serial arterial
samples for performing a blood gas analysis to monitor cardiorespiratory
function. Typically, this catheter is placed in the dorsal metatarsal artery
(Figure 3.6), but the coccygeal and radial arteries can also be used. In very
small patients, it is necessary to use arteries of a larger diameter, such as the
femoral artery.
Changes in blood pressure are comparable in most arteries because
blood is a noncompressible liquid and spreads the sphygmic wave in the
various arterial districts to a comparable degree. The pressure will remain
undetected or be unreliable only in the case of local circulatory impairment
or in the presence of clots or a bent catheter. The chosen artery should be
identified with the index finger; the area is then surgically prepared and a
21–23 gauge IV catheter is flushed with heparinized saline (e.g., normal
saline containing 1 IU of heparin sodium/mL), before inserting the IV
catheter through the skin at an angle of about 15–30°, in the opposite
direction to blood flow. The catheter can remain in situ for 5–7 days. If
inflammation or swelling appears near the IV catheter insertion site, it
should be removed and the site of insertion changed. To avoid tissue
ischemia from obstruction of the vessel, the IV catheter patency and local
peripheral perfusion should be monitored at least every 8 hours, along with
the interdigital temperature (which must be about 3–4 °C lower than the
rectal temperature) and, when possible, the skin color.

Figure 3.6 Metatarsal artery.

Technique
Once the IV catheter has been inserted into the vessel and as soon as blood
appears, the needle is withdrawn while at the same time continuing to fully
insert the catheter into the artery. The IV catheter should be secured in place
with adhesive tape and connected to an extension tube equipped with a
three-way stopcock, previously filled with heparinized saline; the three-way
stopcock is connected to the pressure transducer, which must be placed at
the height of the patient’s right atrium.
The transducer is equipped with a diaphragm: when the blood, thanks to
the thrust received from the heart and mostly to the elasticity of the large
vessels, hits the diaphragm, it causes its distension. This displacement is
then converted into an electrical impulse, which the monitor amplifies
(through an amplifier) and shows on the device’s screen.
An IV line connected to a bag of heparinized saline is connected to the
perpendicular port of the three-way stopcock (in a vertical position with
respect to the IV catheter). Then (using an electric cable provided in the kit)
the transducer is connected to the monitor, the bag containing saline
solution is compressed using a pressure bag (300 mmHg), and any air
bubbles that might be present in the circuit is removed, thus creating a
pressure greater than the patient’s systolic pressure.
Subsequently, the monitor is zeroed by opening the transducer to the
environment to neutralize the effect of atmospheric pressure (760 mmHg at
sea level) and setting this pressure value as zero. At this point, the patient is
connected to the monitor through the three-way stopcock to start arterial
blood pressure measurements. The device should be zeroed every 8 hours,
or whenever the patient is mobilized or their decubitus changed, or when
measurements are doubtful. The infusion rate should be approximately
3mL/hour; the resonance frequency (distance between two systolic peaks
divided by the velocity) should be greater than 30 Hz when the patient has
an HR ≥180 bpm and >20 Hz for an HR of up to 120 bpm.

Indications and interpretation

IBP measurement is particularly indicated if continuous monitoring of BP
over an entire cardiac cycle needs to be performed, in the presence of
vasoconstriction, or in patients with or at risk of severe hypotension that
could compromise vital functions and cause death. Some typical cases of
hypotension that benefit from continuous monitoring of IBP are sepsis,
septic shock, general anesthesia (especially with gaseous anesthetic agents)
in high-risk patients, when vasoactive amines are administered to evaluate
their effectiveness, during a fluid challenge test to evaluate the efficacy and
duration of effect of the bolus, and when deciding whether vasoactive
amines need to be administered because fluid boluses are not effective.
In addition to providing numerical data concerning arterial pressures,
IBP measurement makes it possible, through the study of the sphygmic
wave, to evaluate myocardial contractility, the transmission of the pressure
wave through the vascular wall, and blood flow dynamics. The first phase
of the waveform, called anacrotic limb, shows a rapid increase that reaches
a peak called systolic or anacrotic peak (under normal conditions, in dogs it
is about 90–150 mmHg). The beginning of the first phase coincides with the
contraction of the left ventricle, the opening of the aortic valve, and the
outflow of blood from the ventricle, which generates a pressure wave on the
wall of the aortic root that is then transmitted to all the arteries. The
inclination, or rather the steepness, of the anacrotic limb and its height
depend on the speed of the blood, and they are an expression of the
contractility and function of the left ventricle. The steepness increases in
hypervolemic patients or when cardiac inotropy increases, while it is
reduced in hypovolemic patients, when cardiac contractility is reduced (e.g.,
due to dilated cardiomyopathy), or when both situations occur. The peak of
the waveform becomes more acute in hypovolemic patients or when a
reduction in CO occurs.
The dicrotic notch corresponds to the closure of the aortic valve, when
the wave starts to rapidly decrease to reach zero at the end of systole. The
effect of the wall of vessels with a lower diameter than that of the aorta can
sometimes cause undulations that can be detected along the dicrotic limb. In
elderly patients, as ventricular contractility becomes less effective and
arterial stiffening increases, the waveform may decrease in height, and the
anacrotic and dicrotic limbs may become less steep (the curve flattens and
widens).
Vasodilation causes a reduction in the peak as well as rounding of the
waveform, hypovolemia leads to a reduction in the peak and amplitude of
the waveform, and hypotension causes the disappearance of the peak (tip
shape) and dicrotic notch. Conversely, vasoconstriction can cause an
increase in the peak, while arrhythmias typically reduce the ventricular
filling volume, which increases the steepness of the anacrotic limb and a
reduction in the peak.
 Pressure waveforms are a complex set of oscillatory waves that have a
particular frequency and amplitude. Together they constitute the classic
sphygmic wave that is observed on the monitor and is called harmonic
frequency. The monitor detects harmonic frequencies at each pulse and
shows them on the screen with the typical shape (see Figure 3.4).
Underdamping refers to an exaggerated response due to the alteration of the
harmonic frequency that occurs when the tube is too soft and too long or
during tachydysrhytmias. This phenomenon shows an increase of the
systolic pressure characterized by a narrow systolic peak and oscillation of
the dicrotic limb causing an overestimation of the systolic pressure and an
understimation of the diastolic pressure. Conversely, overdamping refers to
an attenuated response due to the alteration of the harmonic frequency that
occurs if the tube is too long (>1 m), if it is too soft, if the arterial catheter is
too small, or if air bubbles are present. In case of overdamping the wave is
flatter with a reduced or absent dicrotic wave.

Measurement of lactatemia
The measurement of lactatemia has gained a lot of attention in recent years
following the development of guidelines for the management of severe
sepsis and septic shock by the Surviving Sepsis Campaign in 2016; these
suggest, among other objectives of resuscitation, normalizing lactate levels
in patients with hyperlactatemia (grade 2C recommendation).
Lactate is a molecule that consists of three carbon atoms and a carboxyl
group capable of accepting a hydrogen ion and producing lactic acid.
Lactate is synthesized in the cytoplasm of cells due to the presence of
lactate dehydrogenase (LDH), which allows the conversion of pyruvate and
the regeneration of NAD+ (nicotinamide adenine dinucleotide), as shown in
the following equation:

NADH and ATP are produced in sufficient amounts only under aerobic
conditions. NADH is needed to convert pyruvate into lactate. The greater
the availability of NADH, the greater the production of pyruvate, which
enters the Krebs cycle as acetyl-coenzyme A to produce energy, CO2 and
water. Under anaerobic conditions, lactate cannot be oxidized to pyruvate,
so its concentration increases (the equilibrium shifts to the right, see
Equation 8). If lactate is not oxidized it will also produce an increase in the
hydrogen ion concentration (the equilibrium shifts to the right, see Equation
8). Lactate metabolism therefore requires mitochondrial aerobic
metabolism; when this cannot happen, an increase in lactatemia occurs.
Lactatemia can also increase due to an enzyme deficit responsible for a lack
of pyruvate dehydrogenase, which converts pyruvate into acetyl-coenzyme
A, or due to causes other than anaerobiosis, which induce the so-called type
B lactatemia, such as diabetes mellitus, hypoglycemia, liver disease,
systemic neoplasms, sepsis, renal failure, salicylate intoxication, carbon
monoxide inhalation, ethylene glycol poisoning, administration of albuterol,
or hereditary diseases (mitochondrial myopathy, gluconeogenesis
deficiency).
After ruling out the presence of type B hyperlactatemia, it is necessary
to check whether the patient’s increase in lactate results from a pathology
able to cause a release of catecholamines and alter the perfusion and
oxygenation of tissues, or if there is an increased demand for oxygen that is
not satisfied by oxygenation and tissue perfusion. This condition is called
type A hyperlactatemia. Some examples are sepsis, shock, septic shock,
congestive heart failure, systolic heart failure, cardiopulmonary arrest,
pulmonary edema, seizure, and exercise.
The production of lactate ensures the synthesis of two molecules of ATP
instead of the 36 produced by 1 mole of glucose during aerobic metabolism;
in addition, two protons are consumed for the synthesis of lactate, so the
production of lactate does not cause metabolic acidosis, but actually delays
it. Except for type B hyperlactatemia, hyperlactatemia is not a disease in
itself but a marker of perfusion. An ineffective tissue perfusion is one of the
causes of increased lactatemia [11]. Hypoxia alone is not responsible for an
increase in lactatemia, as demonstrated in a study conducted in healthy men
who were climbing Mount Everest, in which a median lactatemia of 2.2
mmol/L was found, even with a paO2 of 25 mmHg [12]. The major organs
producing lactate are the skeletal muscles, intestines, brain, erythrocytes,
and skin. Lactate is used for gluconeogenesis mainly by the liver and
kidneys, and as fuel mostly by the brain and myocardium, which rely on its
oxidation for energy production, especially under conditions of stress.
During sepsis, hyperlactatemia derives, rather than from a deficit of
tissue perfusion and oxygenation, from an increase in production due to
stress, which generates an adrenergic stimulation that produces energy by
oxidizing lactate [13]. During hyperlactatemia, the myocardium uses lactate
as an energy source for more than half of its energy needs. For these
reasons, an increased lactatemia should not be considered as a negative fact,
but as the marker of a type of metabolic activity that allows the body to
survive stress.
Ringer’s lactate solution does not cause lactic acidosis, because it is
transformed into a buffer in the liver, but it can alter the measurement of
lactate concentration if the blood sample is collected shortly after its
administration. Normal lactate values are approximately 2.5 mmol/L. A
description of the methods for measuring the other hemodynamic
parameters and of how to interpret them is given in Chapter 1.

Fluid resuscitation
So-called fluid responders who require fluid resuscitation are typically
patients suffering from hypovolemic or traumatic shock. In the first case,
these patients have ineffective tissue perfusion due to a reduction in the
circulating blood volume caused by fluid losses from the extracellular
and/or intracellular space (e.g., vomiting, diarrhea, and polyuria). These
patients are those who respond best to fluid therapy.
Patients with an insufficient circulating blood volume and ineffective
organ perfusion due to traumatic shock may be hypovolemic as a result of a
rapid blood loss of more than 20–30% of the total circulating volume, or
because the site of trauma has caused the release of vasoactive and
myocardial depressing agents, which may be responsible for a circulatory
failure resulting from an increase in blood vessel capacitance of both the
venous and arterial compartments.
In the latter case, fluid resuscitation cannot restore an adequate systemic
circulation and can in fact aggravate the patient’s condition, because the
administration of large volumes of fluids over a short period of time can
cause tissue edema, especially in the presence of prerenal failure caused by
prolonged hypotension.
Before administering several fluid boluses, it is necessary to check that
the patient does not have an increased venous or arterial capacitance or
both. This manifests as vasodilation (e.g., hot extremities) and reduced
SVR. The clinical history helps to identify these patients.
The pathological processes that can cause vasodilation are sepsis, septic
shock, pancreatitis, trauma, systemic inflammation, systemic neoplasms,
heat stroke, burns, autoimmune diseases, ischemic diseases, some snake
poisons, and inflammatory gastroenteric diseases. Hypovolemic patients
who need fluid resuscitation may show the following signs: tachycardia,
prolonged CTR, hypotension, hypothermia, cold extremities, and dry
mucous membranes.
Patients responsive to fluid therapy can be identified by monitoring
hemodynamic parameters after the administration of a fluid bolus. The
evaluation of hemodynamic parameters can be clinical (see above) or
instrumental (see Chapter 1) [14].
The instrumentally measured hemodynamic parameters used in humans
to identify patients who respond to fluid therapy are still a subject of
controversy; some of these are SVV, PPV, end-expiratory occlusion
maneuver, and CO measured with esophageal Doppler and other methods
(see Chapter 1).

Goal-directed therapy
Fluid therapy aimed at optimizing the hemodynamic status, also known as
GDT (goal-directed therapy), began to be used in the 1980s when, with the
use of the thermodilution pulmonary artery catheter (Swan–Ganz catheter),
it became possible to measure the PAOP (pulmonary artery occlusion
pressure). With the Swan–Ganz catheter, CO measurement also became
possible and, in 1988, W. Shoemaker [15] published the first study that
showed how an increase in DO2 (measured by placing a Swan–Ganz
catheter and determining the CO) led to a reduction in mortality in high-risk
surgical patients. To do so, a therapeutic protocol was used that increased
DO2 through the administration of fluids, inotropic drugs (mainly
dobutamine) and vasoactive amines; this laid the foundations for other
protocols for the management of critically ill patients still in use today. The
goal of GDT is to treat hypovolemia, hypoxia, and decreased blood flow.
The Swan-Ganz catheter was then abandoned due to the side effects of such
invasive monitoring and the introduction of other less invasive monitoring
methods that measured CO, such as SVV, PPV, esophageal Doppler, LiDCO
and plethysmographic variability index (see Chapter 1). The scientific
literature, however, reports contradictory data. For example, a systematic
review by the Cochrane Library, which evaluated 31 studies involving 5292
human patients [16], found that GDT—through the administration of fluids,
associated when necessary with inotropic and vasoactive drugs, and the
consequent increase in DO2 and improvement of systemic blood flow—
does not reduce mortality, but decreases morbidity (hospital stay 1 day
shorter, but no reduction in the length of stay in the intensive care unit) of
renal and respiratory complications and wound healing time. However, for
nine other causes of morbidity (arrhythmias, pneumonia, sepsis, abdominal
or urinary infections, myocardial infarction, congestive heart failure,
pulmonary edema, and deep thrombosis), no improvements were achieved.
The parameters used to perform GDT were the cardiac index (CI, which is
obtained by dividing the CO by the body surface area), DO2, oxygen
consumption (VO2), SV and the parameters derived from it (e.g., SVV),
central venous oxygen saturation (ScvO2), oxygen extraction ratio (O2ER),
and lactatemia.
Another randomized multicenter study conducted in 734 patients [17]
concluded that GDT does not reduce mortality at 30 days postsurgery but
reduces complications in patients undergoing gastrointestinal surgery.
The analysis of these studies shows that critical human patients at higher
risk of mortality could benefit from invasive monitoring of hemodynamic
parameters, such as CO and SVV; in veterinary medicine, the same benefits
could be obtained by noninvasive monitoring of parameters such as PPV,
lactatemia and the variation in the diameter of the vena cava.
Nonhypovolemic patients with a reduced risk of mortality could benefit
from a more restrictive daily fluid therapy with a zero balance.
Hypovolemic dogs and cats showing alterations of perfusion parameters,
such as hypotension, increased CTR, reduced CO, reduced urine output, or
increased azotemia and lactatemia, or those with impaired blood flow and
oxygenation detected by the methods described above, require rapid
normalization of these parameters (see Tables 3.6 and 3.7). In patients
receiving fluid resuscitation, instrumental monitoring of the following
parameters should be performed: MAP, CVP, CO or SVV, SpO2, lactatemia
or ScvO2, and urine output.

Crystalloids or colloids?
The fluids used to restore an effective circulating blood volume are
crystalloids and colloids (Figure 3.7). Which are most effective has not yet
been demonstrated, although a recent multicenter and randomized study
[18] conducted in human patients concluded that colloid fluid resuscitation
of critically ill patients at risk of death from trauma, burns, or surgery does
not reduce the risk of death, which is even increased if hydroxyethyl starch
is used. Finally, given the higher cost of colloids compared to crystalloids,
no reason has emerged to prefer the former to the latter. Another recent
randomized study [19] conducted in 2305 human patients, which evaluated
fluid resuscitation with colloids vs. with crystalloids in critically ill patients
admitted to intensive care and in a state of hypovolemic shock, found
mortality to be similar at 28 days, but reduced with crystalloids at 90 days.
The authors considered this conclusion as tentative and pointed out that
further confirmation is needed regarding the efficacy described.
Figure 3.7 Fluid resuscitation. HES, hydroxyethyl starch; Plasma-Lyte, electrolyte replacement
solution with sodium gluconate.

In veterinary medicine there is no evidence of such an effect [20].

According to two studies [21,22] it seems that damage to renal function is
more present when hydroxyethyl starch (HES) is used at high
concentrations (10% HES is more harmful than tetrastarch at 6%).
According to the revision of Starling’s law (see Chapter 1), when capillary
pressure is low, infused crystalloids should remain in the circulation as
much as colloidal solutions. This is supported by a human study [23] that
showed that crystalloids seem to be more effective in restoring blood
plasma volume when infused during anesthesia after trauma than when
administered in healthy patients in experimental studies, because renal
clearance in these conditions is only 10–20%. Therefore, considering the
evidence gathered in human medicine, the lack of randomized multicenter
studies in veterinary medicine and the absence of evidence, in dogs and
cats, of a greater effectiveness of colloid solutions compared to crystalloids,
fluid resuscitation usually consists in the administration of crystalloid
boluses until the targeted objectives are achieved.
 The type of crystalloid to be used in resuscitation depends on the
patient’s needs (acid–base balance [SID] and electrolytes [at least sodium,
potassium, and chloride]). In the absence of these data, the use of balanced
crystalloid solutions is recommended. If invasive parameters cannot be used
to monitor the effectiveness of fluid administration in hypovolemic patients
(fluid responsiveness), as is done, for example, during GDT in human
patients, the objectives of fluid resuscitation must be established based on
the patient’s needs. The objectives (endpoints) are different and depend on
the patient’s condition before hypovolemia set in (e.g., presence of renal or
heart failure) and the ongoing pathological process (e.g., sepsis or severe
dehydration), as indicated in Tables 3.6 and 3.7. Generally, the minimum
effective fluid volume to achieve the targeted goal should be used, to avoid
fluid accumulation in the various compartments in the postresuscitation
phase.
Patients at highest risk of developing edema from aggressive fluid
therapy are those with congestive heart failure, renal failure, pulmonary
edema, and cerebral edema. In cats, hypothermia and peripheral
vasoconstriction can promote the onset of edema, so it is important in this
species to restore body temperature with active systems, such as devices
that use hot air. The use of warm surfaces in contact with the patient’s skin
can cause plasmatic exemia, responsible for compartmentalized
hypovolemia due to vasodilation in the contact area, which compromises an
already impaired circulation.
Until the body temperature is restored to about 37 °C, small volume
fluid resuscitation with minimum objectives is preferable, using balanced
crystalloids in boluses of 5–15 mL over 20 minutes. Particular attention
should also be paid to patients with a primary or secondary coagulopathy.
The coagulation disorder of such patients may indeed be aggravated as a
result of hemodilution or due to the interference of colloids with
coagulation (see below); in addition, in patients with unstable clots (e.g.,
with traumatic bleeding), a sudden increase in systemic and capillary blood
pressure can break down clots and aggravate bleeding.
In the absence of lesions that may alter the state of consciousness (e.g.,
head trauma), it should not be forgotten that the level of consciousness is a
very useful parameter to evaluate the effectiveness of fluid therapy in
restoring perfusion and brain oxygenation. Indeed, the recovery of
consciousness or of a normal posture (e.g., patient standing up or lying in
sternal recumbency) becomes clinically observable when a patient responds
to fluid therapy, oxygenation, and the use of positive inotropic agents or
vasoactive amines. Therefore, the state of consciousness can also be
considered a monitoring parameter to evaluate the effectiveness of fluid
resuscitation.

Fluid resuscitation with crystalloids

Fluid resuscitation with crystalloids is performed by administering IV
boluses of 20–30 mL/kg over 15–20 minutes. Perfusion parameters are
checked every 15–20 minutes; once they have been restored, fluid
resuscitation is interrupted and daily fluid therapy is initiated. Generally, up
to 3 IV 20 mL/kg boluses are administered in cats, and up to 4 IV 20 mL/kg
boluses in dogs. When administering the penultimate bolus (the third in
dogs and the second in cats), it is recommended to check for the presence of
any vasodilation that might affect fluid therapy. It should be remembered
that rapid administration of large volumes of crystalloids can cause
glycocalyx damage (shedding) [24,25]. In addition, large volumes of
crystalloids, especially when administered very quickly, can worsen the
condition of patients with vasodilation (especially if renal failure is also
present) and cause, for example, pulmonary and cerebral edema as well as
generalized edema.

Fluid resuscitation with colloids

Colloids (Table 3.8) for fluid resuscitation should be administered IV; the
usual shock dose in dogs is 10–20 mL/kg over 15–20 minutes. In cats they
should be administered much more slowly, 5 mL/kg IV over 15–20
minutes: larger volumes and a faster administration may be responsible for
neurological signs such as skeletal muscle tremor or CNS excitation. In a
recent experimental study [26] conducted in pigs in which blood was
collected until their baseline stroke volume index (SVI) dropped by 50%
(about 500 mL of blood), 15 animals were administered a crystalloid
solution (Ringer’s lactate), while another 15 were administered a colloid
solution (tetrastarch). All the animals underwent invasive and noninvasive
monitoring of the following parameters: PPV, SVV, CI, MAP, ScvO2,
lactate, pH, and bicarbonate; laser Doppler flowmetry was used to assess
blood flow in the microvascular system. To assess glycocalyx integrity,
blood concentrations of syndecan-1 and glypican were quantified and
showed that the glycocalyx was not damaged by the bleeding. The pigs
were then provided fluid resuscitation with two types of fluids: for
crystalloids it was necessary to administer about three times the lost volume
(average of 1390 mL of Ringer’s lactate solution, with a ratio of 3.03),
while for colloids it was necessary to administer approximately the lost
volume (average of 425 mL, with a ratio of 0.92). The study showed that,
during acute bleeding (e.g., during surgery and trauma), the volume needed
to restore the lost blood follows the Starling principle (crystalloids 3:1 and
colloids 1:1), the glycocalyx remains intact, and colloids achieve
hemodynamic stability more quickly. However, it should be remembered
that in severely traumatized patients or those undergoing surgery with tissue
damage, and in all cases in which glycocalyx damage may occur (sepsis,
septic shock, hyperglycemia, systemic inflammation, and circulatory
overload), the dynamics of the two types of fluids may change and the
Starling principle of fluid exchange in the three compartments may no
longer be valid (see Chapter 1).
Table 3.8 Composition of colloids

The adverse effects of fluid resuscitation with colloids are allergic

reactions (25% especially with human albumin solution [25–30]) and
coagulopathies, not due to hemodilution, which can also be caused by
crystalloids, but to a specific antithrombotic action that hinders the
polymerization of fibrin. The magnitude of this effect in the different
colloids is, in descending order: dextran > hetastarch > pentastarch >
tetrastarch > gelatin > albumin. In humans, the main reactions are related to,
in descending order of frequency, gelatin (0.35%), dextran (0.27%),
albumin (0.10%), and hydroxyethyl starches (0.06%). Severe reactions
were recorded in sensitive patients in 20% of cases [31].

ROSE model (Resuscitation, Optimization,

Stabilization, Evacuation)
Fluid therapy is usually used as a first treatment in critically and
traumatized or hypovolemic patients. In the patients who respond to fluid
therapy, i.e., those in the ascending part of the Starling curve (Figure 3.8),
the increase in the venous compartment promotes an increase in the cardiac
output and therefore in the hemodynamic parameters related to it (e.g.,
cardiac output and variation in ventricular ejection fraction). In practice, in
human medicine it has been observed that only 50% of hemodynamically
unstable patients are fluid responsive [30]. Aggressive fluid therapy without
close hemodynamic monitoring (see Chapter 1) may be responsible for
tissue edema and an obstacle to healing.
To optimize fluid therapy in critically ill or septic patients, the following
subcategories have been proposed:
Fluid resuscitation: aims to restore fluid losses with crystalloids or
colloids; balanced crystalloid solutions are usually used.
Daily fluid therapy with balanced isotonic solutions (see the Isotonic
solutions section) that are in accordance with the patient’s needs, in terms
of volume of fluids and solution composition. In humans, a 10% increase
in body weight is associated with a more unfavorable prognosis.
Replacement fluid therapy: this corresponds to the fluids prepared based
on the electrolytes and volume lost by the patient, and administered to
replace losses (dehydration).
Generalized increase in vascular permeability: it usually develops about 3
days after shock, during which vascular damage occurs due to cytokines
and other proinflammatory molecules. At this stage, it is dangerous to
perform aggressive fluid therapy as the risk of tissue edema is very high.
At this stage it is advisable to switch to maintenance fluid therapy or, even
better, to stop fluid therapy or maintain a zero fluid balance. The
 administration of fluids, at this stage, could fill the venous compartment
only and increase its pressure without increasing the cardiac output-

Figure 3.8 Variation of cardiac output by preload (Frank–Starling law).

Fluid bolus: in humans, fluid boluses of 3–4 mL/ kg over 10–15 minutes
have been used. In veterinary medicine, before administering a fluid bolus
of 20 mL/kg, a mini-fluid bolus of isotonic crystalloid solution may be
administered at a dose of 3–5 mL/kg over 1 minute to check if the patient
is fluid responsive. If the patient does not respond to both boluses (mini-
fluid bolus and fluid bolus) it is likely non-fluid-responsive, due to
damage to the vascular wall and glycocalyx, severe vasodilatation (e.g.,
sepsis), or heart failure;
Evacuation: it is the phase during which the patient must eliminate excess
fluids. This can be achieved through normal renal function, with the
administration of drugs (e.g., furosemide) and, in very severe cases, with
renal replacement therapy (RRT).

The acronym ROSE in reference to fluid therapy can be summarized as

follows.
 Resuscitation (fluid resuscitation): it lasts a few minutes and corresponds
to the phase during which fluids are administered quickly to restore the
effective circulating volume in a hypovolemic patient (for example, with
severe dehydration). Close hemodynamic monitoring is necessary at this
stage.
Optimization: in this phase, which lasts a few hours, the patient is always
critical and hemodynamic monitoring must be performed, but the fluids
are no longer administered through boluses and may be interrupted or
infused at the maintenance rate. Tissue perfusion should be maintained.
Stabilization: it follows the optimization phase, with an evolution over the
next few days; in this phase a zero-fluid balance must be targeted and no
accumulation of fluids must occur. During this phase, fluids are
administered for maintenance and possibly to replace ongoing losses. In
dogs and cats, an empirical but effective method to check for any fluid
accumulation is to weigh the patient twice a day; better monitoring is
achieved if this is combined with daily control of electrolytes, total
proteins and hematocrit.
Evacuation: this phase lasts from days to weeks. Typically, in our patients,
it lasts only a few days (2–3 days) but it depends on the circulatory
overload that may have occurred in the three previous phases. At this
stage, fluid leakage from the vascular wall may occur. This means that the
pathological process is still ongoing, and the patient may experience
peripheral edema (pitting edema) or pulmonary edema (which manifests
with tachypnea, hypoxia, and pulmonary congestion or edema, which can
also be seen with a simple chest X-ray or TFAST). The patient may need
supportive therapy to avoid fluid accumulation. In this phase, spontaneous
fluid intake by the patient is encouraged (Box 3.6).

Crystalloids
Crystalloids are aqueous solutions containing small solutes that can
crystallize and freely cross the vascular wall and interstitial compartment.
As they move from the intravascular to the extravascular space (see Chapter
1), these solutes can cause a movement of water due to the concentration
gradient. For this reason, most of these solutions contain large amounts of
sodium, which not only contribute to ensure a similar osmolality to that of
blood but also allow a larger volume of the water administered to remain
inside the body and for a longer period than with water only. In fact, the
administration of water only would cause the blood’s osmotic pressure to
drop and red blood cells to swell and eventually burst; in addition, such a
solution administered in large amounts would cause tissue edema. In
crystalloid solutions, one or more solutes are dissolved until an osmolality
of about 300 mOsm/L is reached. Solutes are not metabolized by the
patient, so their plasma concentration depends on their absorption and
elimination. The chloride content of some solutions (e.g., balanced
solutions) is significantly lower (about 40 mEq/L) than that of sodium;
because chloride has a negative charge, negative charges are replaced by
other molecules such as lactate, acetate, bicarbonate, or gluconate.

Box 3.6 Fluid therapy: ROSE acronym

Resuscitation: fluid resuscitation and hemodynamic monitoring; lasts a

few minutes.
Optimization: maintenance of effective circulation, hemodynamic
monitoring; lasts a few hours.
Stabilization: maintenance fluid therapy; lasts a few days. Weigh twice
a day, check at least the hematocrit, total proteins, acid–base and
electrolyte balance daily.
Evacuation: it is done through the kidneys, but in the presence of
vascular damage, leakage of fluids from the vascular wall may occur
with subsequent edema (pulmonary, cerebral or peripheral); lasts a few
days.

The famous pediatrician Alexis Hartmann added lactate (1930) to the

balanced solution made by Sydney Ringer (1880) to treat metabolic
acidosis in children, which is why the solution takes its name from him. In
human medicine there is still some debate over whether it is appropriate to
avoid infusing solutions with a high chloride concentration (e.g., saline
solution) in critically ill patients during fluid resuscitation or when large
volumes of fluids are infused to reduce mortality or hospitalization. The
solutes, as they are not able to cross the cell membrane, remain in the
extracellular fluid (ECF), where they normalize the osmolality of the
intravascular and interstitial compartments. If the intracellular fluid (ICF)
were to undergo an increase in osmolality, as occurs in severe forms of ICF
dehydration (so-called cellular dehydration), water from the ECF would
follow the concentration gradient and enter the cell and restore its
osmolality and hydration.
Crystalloids are mainly used to restore the ECF, but thanks to their
redistribution they can also be used to restore the ICF. The movement of
water by osmotic gradient takes seconds, while the redistribution of
electrolytes between the ICF and ECF spaces—which depends on the
activity of the sodium–potassium pump and thus requires energy (produced
in the mitochondria in the form of ATP) and oxygen—takes minutes to
hours. The distribution of fluids can be represented using the two-volume
model [23,24], which states that when the vc (the expanded central body
fluid space) is close to the Vc (same body fluid space at baseline), the
increase in volume is close to zero; when this happens, the total clearance
of water is close to Clo (sum of all fluid losses) (Figure 3.9). This means
that the distribution between the Vc and the Vt (interstitial fluid volume), or
Jv, depends on the osmotic gradients multiplied by clearance, while
elimination takes place from the Vc and is proportional to plasma dilution
multiplied by the Cl (losses caused by fluid therapy). When the elimination
of the administered fluid is complete, redistribution occurs, that is, fluid
passes from Vt to Vc [23]. In humans, the distribution of crystalloids stops
during episodes of acute hypotension (e.g, during anesthesia), and their
redistribution is also hindered by rapid infusions and probably by large
volumes; their elimination is reduced by hypotension [23].
Figure 3.9 Fluid kinetics, two-volume model: when fluid administration causes an expansion of
vascular volume (Vc), an increase in Cl occurs; when vc is close to Vc, Cl is close to Clo (see text).
Cl, losses resulting from fluid therapy; Clo, insensitive leaks; Jv, transvascular flow; Vc,
intravascular space; vc, expanded intravascular space; Vt, interstitial fluid volume; vt, Vt expanded
with fluids.

Intravenously infused crystalloids have a short half-life; in humans,

when the vascular wall is intact (healthy patients), it is about 60 minutes for
Ringer’s lactate and 130 minutes for saline solution. Their distribution from
plasma to the interstitial space occurs over about 20–30 minutes (Box 3.7).
Of course, in patients with vascular and glycocalyx damage, their
distribution will be altered and they may remain in the vascular
compartment for a shorter period of time, as occurs for example in patients
with sepsis or systemic inflammation.
Crystalloids are considered the first choice of fluids to restore the ECF
volume and are also used for fluid resuscitation, given that the revision of
Starling’s principle has shown that, at low capillary pressures (<20 mmHg),
crystalloids remain in the circulation like colloids.
Crystalloids can be administered intravenously or subcutaneously. The
latter route of administration is only used when crystalloids cannot be
administered intravenously due to the impossibility of hospitalizing the
patient for 24 hours. In such special cases, the largest possible volume is
administered intravenously, and the remainder (usually the night dose) is
administered subcutaneously. When using this route, it is essential not to
administer hypertonic solutions, because they have a tissue-damaging
action; up to 600–700 mOsm/L can be administered intravenously.
Subcutaneous administration is not effective in quickly correcting
electrolyte imbalances because fluids must be reabsorbed from the
interstitial space, where electrolytes can be retained and, if they are present
in high concentrations, cause inflammation. The addition of electrolytes to
balanced crystalloid solutions (e.g., potassium chloride) administered
subcutaneously may be responsible for cutaneous and subcutaneous
inflammation, ulcers, and necrosis with loss of skin barrier integrity. The
maximum recommended dose to be administered subcutaneously is
approximately 1–1.5% of the body weight.

Box 3.7 Crystalloids

Crystalloids: aqueous solutions that contain small solutes, e.g., 0.9%

NaCl, Ringer, 5% glucose
Isotonic saline solution: crystalloid solution with a plasma-like osmotic
pressure
“Balanced” isotonic solutions: solutions with a concentration of
electrolytes similar to that of plasma (e.g., Ringer’s lactate); used in
maintenance fluid therapy but also in fluid resuscitation
“Unbalanced” solutions: solutions with a concentration of electrolytes
different to that to plasma (e.g., 0.9% NaCl, 5% glucose); mainly used
in maintenance fluid therapy
Crystalloids are distributed in the three compartments (intravascular,
interstitial and intracellular) in about 30 minutes
Daily fluid dose: 1–2 mL/kg/day. Fluid resuscitation dose: maximum of
4 boluses 20 mL/kg over 15–20 min IV in dogs; in cats, maximum of 3
boluses

Crystalloids are also classified as isotonic, hypotonic, or hypertonic,

based on their osmolality with respect to that of plasma (see Table 3.1).
Isotonic crystalloids are mainly used as maintenance fluids, while
hypotonic crystalloids are used when it is necessary to administer fluids that
are retained within the circulatory system for the shortest possible time
(e.g., half strength in congestive heart failure). Another example of a
hypotonic solution is 5% glucose. The osmolality of this solution is about
50 mEq/L lower than that of plasma and it is mainly used to administer
water, glucose, and a modest caloric intake (0.17 kcal/mL). It does not
contain any electrolytes; therefore, it is not used as a maintenance fluid and
has an acidic pH (about 5.0). It is often used to maintain blood sugar levels
and is added to other crystalloids to reduce their osmolality. When the
objective is to administer water only, the glucose contained in the solution
is transformed very quickly into CO2 and water.

Isotonic solutions
Isotonic saline solutions are the most commonly used solutions. Saline,
when prepared with 0.9% NaCl, has a plasma-like osmolality, but a higher
concentration of sodium and especially of chloride than plasma (about 50
mEq/L more than plasma). The administration of saline can cause metabolic
acidosis, because chloride is negatively charged and therefore causes an
increase in protons (H+), as saline does not contain bicarbonate or other
buffer molecules of acidic chemical species.
Saline solution is used to correct hypochloremic metabolic alkalosis, as
a maintenance fluid, to correct hyponatremia (caused, for example, by
vomiting and polyuria), and for fluid resuscitation. It is the most commonly
used solution in human medicine and is also used in hospitalized patients as
a vehicle for the administration of drugs; it can be responsible for
hypernatremia or hyperchloremia. There is no data available on its
frequency of administration in veterinary medicine. Due to its high sodium
concentration, it remains longer in the circulation (about 10%) than other
balanced solutions (e.g., Ringer’s lactate). Because it does not contain
calcium, it is also used to administer drugs that are not compatible with
other solutions, such as bicarbonate, whole blood, or blood products that
contain anticoagulants that chelate calcium.
Ringer’s solutions are named after the physiologist who first prepared
them after observing, in his studies on animal models, that the
administration of a solution containing more electrolytes, such as sodium,
potassium, calcium, and chloride, was able to preserve protoplasmic
activities, unlike simple water. Ringer’s solutions contain about 30 mEq/L
of buffer, in the form of acetate or lactate. Both types provide a very low
caloric intake (about 5 kcal/L). Acetate is metabolized more quickly than
lactate and in more tissues (e.g., liver and muscles). In addition, this process
requires half the oxygen needed to metabolize lactate.
During hepatic failure, acetate is transformed in the kidney into ketone
bodies, which are useful as a source of energy [31]. Rapid administration of
Ringer’s acetate may be responsible for a reduction in SVR. During shock
in dogs, the metabolism of acetate is preserved while that of lactate is
reduced [32]. In humans, acetate increases the bicarbonate concentration
after only 15 minutes and has a greater alkalizing activity than lactate [33].
Because acetate is not converted into glucose like lactate, it does not cause
hyperglycemia. This phenomenon becomes especially important when
administering fluids in diabetic patients. Ringer’s solutions cannot be used
when administering substances that are incompatible with calcium, such as
certain drugs, blood products, or whole blood (incompatible with the
sodium citrate contained in the anticoagulant). Their elimination is very
rapid and is slowed down during hypotension and general anesthesia (in
humans, under normal conditions, about 70% is eliminated in 2 hours).
Ringer’s solutions are used in fluid resuscitation and in daily fluid therapy
when the patient’s electrolyte and acid–base status is unknown, so as to
reduce the risk of electrolyte and acid–base imbalances, given that the
composition of these solutions is close to that of plasma.
Plasma-Lyte is another isotonic solution of balanced electrolytes used
predominantly to correct metabolic acidosis, as it contains about 50
bicarbonate precursors. Its concentration in sodium and chloride is close to
that of plasma and it does not contain calcium but magnesium, which can
be useful to correct refractory hypokalemia. Hypokalemia is very frequent
in critically ill patients, especially those with ECF imbalances (e.g., with
vomiting and diarrhea). Gluconate has a lower alkalizing effect than acetate.
Since it does not contain calcium, this solution can also be used when
administering substances that are incompatible with calcium, such as
certain drugs, blood products or whole blood. This isotonic solution is
preferred in the therapy of renal failure, as it contains more buffers to treat
metabolic acidosis and a number of ions more similar to that of plasma than
other isotonic solutions. It is also used to treat patients in shock and when
the patient’s electrolyte and acid–base status is unknown.
Hypertonic solutions
Hypertonic solutions are used when the objective is to expand the
circulating volume. A sudden increase (a few seconds or minutes) in blood
osmolality thanks to the created osmotic gradient can lead to an expansion
of the circulating volume proportional to its concentration. A typical
hypertonic solution is 7.5% NaCl, because it can draw water into the
intravascular compartment by osmotic gradient in a few seconds and
therefore expands the plasma volume very quickly. It is also used in patients
with cerebral edema, to reduce its extent, and is administered at a dose of
2–5 mL/kg IV. Due to its high osmolality, 7.5% NaCl should only be
administered intravenously. Before administration it should be checked that
the patient is not severely hyponatremic, because too rapid an increase in
serum sodium can cause severe neurological lesions (e.g., pontine
myelinolysis), even 2–3 days after administration. To check if the
administration of this fluid has caused an electrolyte disorder it is necessary
to wait at least 30 minutes, so that the solution can be redistributed. Its use
is also advised against in cases of hypernatremia and severe dehydration: its
rapid administration can cause hypertension and bradycardia.
Another frequently used hypertonic solution is 18% mannitol. It draws
water from the extravascular space through the osmotic gradient produced
by its high osmolality (about 988 mOsm/L). It is therefore administered
exclusively intravenously and is irritant to the vascular walls. Mannitol
should only be administered in hemodynamically stable patients and is used
in cases of head trauma as it can reduce cerebral edema. In such cases, it is
administered at a dose of 500 mg/kg IV over 15–20 minutes. Typically, 3–4
boluses are administered at an interval of 2–6 hours, depending on the
severity of the edema and the response to therapy. The diuretic effect after
administration in boluses occurs over approximately 20 minutes. In patients
at risk of hypervolemia, such as those with congestive heart failure or
kidney failure, hemodynamic parameters should be closely monitored. In
these patients, the administration of mannitol may cause an increase in the
respiratory rate due to pulmonary congestion or pulmonary edema.
Mannitol, thanks to its hypertonicity, causes osmotic diuresis by drawing
water into the nephron, reduces blood viscosity, improves blood flow in the
kidneys and capillaries, and reduces edema of the epithelial tubular cells
and obstruction of the tubular lumen caused by casts and cell debris; in
addition, it eliminates free radicals.

Colloids
Colloids are aqueous solutions that contain macromolecules of such size
that they are not able to cross the vascular wall under normal conditions
(intact vascular wall) and therefore increase the oncotic pressure in the
intravascular compartment. The degradation of these macromolecules
affects the permanence of the colloid in the intravascular compartment. The
size, molecular weight, and chemical structure of these molecules affect the
oncotic pressure and dynamics of the fluids. The shorter the degradation
time of the macromolecules, the shorter the duration of their effect. Because
they do not generate a sufficient osmotic pressure, they must be combined
with some electrolytes to maintain an osmotic pressure that will not cause
intravascular hemolysis. For this reason, colloid solutions are prepared with
normal saline, Ringer’s lactate or other isotonic saline solutions. Their
kinetics are one-compartment, that is, the administered fluid does not
distribute through the various compartments but is used to expand the
intravascular volume. In this sense, colloids are more effective and rapid
than crystalloids.
They are also used to restore the circulating volume in case of
hemorrhage with a blood loss equal to or greater than 10–15% of the
circulating volume. Recently, their use has been questioned in human
medicine, as it has been reported that hydroxyethyl starches can increase
the risk of renal failure and mortality. Therefore, their use is not
recommended in patients with sepsis, septic shock, kidney failure, or head
trauma, or in case of organ donation [34,35]. Colloids can be divided into
synthetic and natural colloids (Box 3.8).

Box 3.8 Colloids

Colloids: aqueous solutions that contain large solutes, from 30 kDa to

450 kDa
Synthetic colloids: dextran, hydroxyethyl starches
 Natural colloids: plasma, canine albumin, human albumin, gelatin,
HBOC (hemoglobin-based oxygen-carrying solution)
Daily dose: 10–20 mL/kg/day. Resuscitation dose: in dogs, they can be
administered in a single bolus; in cats, in boluses of 5 mL/kg IV over
15–20 min. In both species the doses can be administered as a CRI of 2
mL/kg/hour.

Synthetic colloids
The most commonly used synthetic colloids are dextran-70 and
hydroxyethyl starches, while natural colloids are gelatin, species-specific
plasma, and canine and human albumin. The major limitations to their use
are allergic reactions and their high cost compared to crystalloids. The
maximum recommended dose is 20 mL/kg/day IV; colloids cannot be
administered subcutaneously. Higher doses may be responsible for
coagulopathies and circulatory overload, as well as for an increased risk of
hypersensitivity reactions [37]. The recommended maintenance rate is 2
mL/kg/hour IV. This type of administration is preferred when there is
chronic or continuous plasma protein leakage (e.g., protein-losing
enteropathy, gastrointestinal form of parvovirus disease).
Dextran solutions are aqueous solutions containing long-chain glucose
molecules (polysaccharides) with a high molecular weight, derived from the
fermentation of glucose by specific bacteria (Leuconostoc mesenteroides or
lactobacilli). Like other colloids, polysaccharides also have a low
osmolality and need to be dissolved in crystalloids such as normal saline,
Ringer’s solution or hypertonic saline (rescue solution). Dextran solutions
can contain polysaccharides with a high average molecular weight, such as
dextran-70 (70 kDa), or with a lower molecular weight, such as dextran-40
(40 kDa). The most commonly used dextran solution is 6% dextran-70,
since it expands the circulating volume by a volume equal to that infused,
while dextran-40 can cause tubular obstruction or renal failure, especially in
dehydrated patients. The effect of dextran-70 is long-lasting (about 24
hours) and it has a positive rheological activity that makes the surface of
cells (blood cells, platelets and white blood cells) less adhesive, thus
reducing blood viscosity and improving capillary blood flow; however, it
can prolong clotting times. For these reasons, dextran solutions should be
used with caution and under close monitoring during surgery, in patients
with bleeding, or in those with a coagulation disorder (e.g., disseminated
intravascular coagulation). Thanks to the above mentioned properties,
dextran can be used to expand the circulating volume and prevent the
formation of thrombi. Dextran solutions are administered at a dose of 10–20
mL/kg/day. The rescue solution should be administered as a bolus at a dose
of 2–4 mL/kg IV (in dogs). Like other colloids, in the cat they should be
administered much more slowly: 5 mL/ kg IV over 15–20 minutes.
Hydroxyethyl starches (HES) are amylopectins derived from corn or
wheat, dissolved in isotonic crystalloids (e.g., saline or Ringer’s solution).
HES are also dissolved in hypertonic solutions such as dextran-70 and
hypertonic saline solution. HES are used in fluid resuscitation to expand the
circulating volume by a greater volume than that infused. Amylopectins are
hydroxylated because they would otherwise be degraded very quickly by
plasma amylases. HES are a mixture of smaller molecules (50–70 kDa),
which are quickly excreted through the kidneys, and larger molecules than
average, which are degraded by amylases and partly phagocytosed by the
reticuloendothelial system, so that it is possible in humans to detect them in
the liver and spleen for years [35,36]. The number and position of
hydroxylations (OH groups) present in amylopectin molecules modify their
biological behavior. Molecular weight and concentration (6–10%) are also
responsible for the activity of the solution; therefore, to know the blood
volume expansion capacity and duration of effect of a HES, its molecular
weight, the C2/C6 ratio, and the degree of substitution should be identified.
The degree of substitution varies from 0.4 to 0.8: the higher the degree of
substitution, the greater the resistance of the HES to degradation by
amylases, and therefore the longer its persistence in the vascular bed.
Solutions with a low degree of substitution (0.4) are generally preferred.
The C2/C6 ratio, which indicates the position of the OH groups, affects the
half-life and thus the persistence of the HES in blood. Values ≥8 are
considered high, while values of 4–5 are preferred. The molecular weight
can be high, as in hetastarch, which has a molecular weight of about 450
kDa and thus is the HES with the greatest duration of effect (about 24
hours). Pentastarch has an intermediate molecular weight of 260 kDa, while
tetrastarch has the lowest molecular weight (130 kDa) and consequently a
shorter duration of effect, about 2–4 hours. Sixty percent of tetrastarch
molecules can be found in the urine for 72 hours.
The duration of effect of HES may be prolonged in states of
hypotension, and it is greater after a hemorrhage. The higher the molecular
weight, the greater the risk of hypersensitivity reactions and coagulopathies.
In humans, the perception of subcutaneous tingling has been described; it
can last for months and, in severe cases, even up to 2 years. This has not
been reported in animals.
Solutions containing molecules weighing 50 kDa or less have a very
short shelf-life of about 2–4 hours. Tetrastarch is preferred over the other
two types of HES, because its duration usually allows stabilization of
critical patients. The most commonly used solutions have a molecular
weight of 130 kDa, a degree of substitution of 0.4, and a C2/C6 ratio of 9:1
(Voluven®), or a molecular weight of 130 kDa, a degree of substitution of
0.62, and a C2/C6 ratio of 6:1 (Venofundin®).
In humans, the main indication for the administration of HES is the
expansion of the circulating volume in patients suffering from bleeding,
while its use in intensive care is not recommended. The dose used in dogs
and cats is 10–20 mL/kg/day IV; in cats they should be administered much
more slowly (5 mL/kg IV over 15–20 minutes).

Natural colloids
Albumin is the plasma protein with the highest concentration; it has a
molecular weight of about 70 kDa and can generate 3/4 of the oncotic blood
pressure. Its particular symmetrical quaternary structure and its negative
charge (-19) allow it to bind to ions, lipids, metals, hormones and drugs. It
transports and binds to various biologically active molecules, it is anti-
inflammatory and antioxidant, it stabilizes the endothelium, it is present in
the glycocalyx, it has antiplatelet activity, and it contributes to the acid–base
balance. The synthesis of albumin occurs mainly in the liver and is induced
by osmoreceptors located in the interstitial space of the liver. Its reduction is
a marker of hepatic function deficiency. Its production is reduced if its
concentration is high; the hepatic capillaries, as they are fenestrated, allow
osmoreceptors to perceive increased levels of albumin. For this reason, the
intravenous administration of albumin at high concentrations (e.g., 20%)
can cause an inhibition of its synthesis. Decreased blood albumin levels can
be caused by peritonitis, pleurisy, liver disease, kidney failure, protein-
losing enteropathy, pericardiectomy, and neoplasms. The biological activity
of some drugs and calcium (see Chapter 4) depends on its concentration;
the patient’s plasma albumin concentration should therefore be evaluated
before administering it. The drugs most affected by serum albumin
concentration are many antibiotics, diazepam, midazolam, thiopental,
nonsteroidal anti-inflammatory drugs, digoxin, and warfarin.
In addition to expanding the circulating volume, albumin helps to reduce
transvascular flow when the capillary hydrostatic pressure increases,
improves the microcirculation by modifying the laminar blood flow, and
contributes to increasing blood pressure by expanding the circulating
volume and to the removal of many reactive chemical species, such as
superoxides, some cations, anions, and many inflammatory molecules,
especially those with a positive charge. The polynitroxylated albumin that
forms in the circulation, thereby increasing the redox potential, protects
cells from reperfusion injury and inhibits xanthine oxidase, which is
responsible for cell death.
For the reasons mentioned above, the administration of human albumin
(HSA, human serum albumin) constitutes a therapeutic option to be
considered during septic shock (not for fluid resuscitation, see below). Its
higher concentration in the intravascular compartment (4 g/dL) than in the
extravascular compartment (1.4 g/dL) creates an essential osmotic gradient
for the passage of fluids from the intravascular to the extravascular space
(see Chapter 1). The passage of albumin from the intravascular to the
extravascular compartment is called TER (transcapillary escape rate). TER
is conditioned by the integrity of the vascular wall, the glycocalyx, the
serum albumin concentration and subglycocalyx space, the volume of water
in plasma and the electrical charges present on the two sides of the vessel
wall. The pathological processes that most frequently alter the TER are
sepsis, septic shock, systemic inflammation, severe trauma, pneumonia,
hyperosmolar syndrome, heat stroke, ischemic diseases, burns, animal
poisons, autoimmune diseases, and systemic neoplasms.
The leakage of albumin from the vascular bed, which under normal
conditions is about 5%, can reach 20% during sepsis due to glycocalyx
damage. To normalize the TER rapidly, albumin can be administered slowly
by an intravenous constant rate infusion (CRI). On the market there are
HSA preparations at 3.5%, 5%, 20%, 25%. Canine albumin is also available
in some countries. HSA at 5% is iso-oncotic compared to blood (308
mOsm/L), while 25% HSA is hyperoncotic (1500 mOsm/L). Five percent
HSA can expand the circulating volume in 30–60 minutes, by a volume
close to the infused one. Its effect lasts about 24 hours and it is used when
albumin is less than 2 g/dL or in cases of severe and continuous losses.
It should be remembered that hypoalbuminemia is the sign of a disease
and not a disease in itself, so it is recommended to first treat the
pathological process that caused it, and only when losses are continuous
and may cause complications should albumin be administered. The volume
to be administered is 10–20 mL/kg/day IV. It should be diluted until a 5%
solution is obtained and administered as a CRI at a rate of 2 mL/kg/hour IV,
which corresponds to a 5- to 10-hour infusion, during which the serum
albumin concentration is normalized and clinical hemodynamic benefits can
be observed. The above dose can be repeated daily and for several days, as
needed by the patient. In the author’s experience, 5% HSA has been
administered daily for up to 11 consecutive days in dogs. At these doses and
rate, and even with repeated daily administrations in the same patient (dog
or cat), the author has never observed any hypersensitivity reactions over
the course of 30 years of administration in dogs and cats [38]. The author
administers 20% HSA by diluting it to 5% in saline or Ringer’s solution
depending on the patient’s needs (acid–base and electrolyte status),
according to the protocol indicated above [36]. HSA should not be
administered at high concentrations and during fluid resuscitation due to the
high risk of type I hypersensitivity reactions (e.g., anaphylactic shock),
especially when administered at 25%.
Adverse effects, in addition to possible hypersensitivity reactions, are
comparable to those of other colloids: hemodilution, reduction in the
concentration of coagulation factors, and circulatory overload. When
administered, patients should be closely monitored for type I
hypersensitivity reactions, such as tremors, hyperthermia, facial and
laryngeal edema, bronchospasm, hypotension, and anaphylactic shock.
Rapid administration of albumin may impair its peripheral lymphatic
reabsorption, so it is recommended to administer it slowly (2 mL/kg/hour).
Studies in human medicine [39,40] have demonstrated a survival benefit in
septic shock patients.
 Albumin administration is therefore recommended in acute
hypoalbuminemia, since in chronic forms (e.g., in cases of leishmaniasis),
the presence of circulating globulins generally compensates for the deficient
colloid osmotic pressure (COP). It is not recommended to administer
human albumin during cardiopulmonary resuscitation and over 1 g/kg/day
(20 mL/kg/day of 5% HAS), due to the increased risk of type I
hypersensitivity reactions.
Species-specific plasma must belong to the same blood type as the
receiving patient. For this reason, before administering it, it is good to test
the recipient’s blood type. Due to its high cost and scarce availability, it is
mainly used to treat secondary coagulopathies (coagulation factor
deficiency) and, to a lesser extent, to treat hypoproteinemia. Plasma, which
contains numerous proteins, may be responsible for type I and type III
hypersensitivity reactions. The first are the typical reactions that occur
shortly after plasma administration (minutes or hours), causing tremors,
hyperthermia, facial and laryngeal edema, bronchospasm, hypotension, and
anaphylactic shock. Type III hypersensitivity reactions are characterized by
the formation of antigen–antibody immunocomplexes that may result in
vasculitis, glomerulonephritis, arthritis, vesicular or ulcerative dermatitis,
and hemolytic anemia. These last reactions can occur after several days and
for up to 3–4 weeks.
Fresh plasma, in order to preserve coagulation factors, must be separated
from whole blood within 8 hours of its collection and stored at a
temperature of 1–6 °C. Fresh plasma can be kept refrigerated for up to 6
weeks, after which it must be frozen at –18 °C. In addition to coagulation
factors, plasma, whether fresh or fresh frozen, contains albumin,
fibronectin, antitrypsin, and antithrombin III. Plasma frozen for more than 1
year and up to 5 years no longer contains effective coagulation factors, so it
can only be used, after slow thawing, for the administration of plasma
proteins. The dose for administration of coagulation factors or plasma
proteins is 10–20 mL/kg/day IV.
Gelatin is a product obtained from the thermal chemical hydrolysis of
bovine bone collagen. This was one of the first colloids to be made for
medical purposes; in fact, its use dates to the First World War, when Bayliss
made a solution containing 5% gelatin to treat patients in shock. Gelatin can
have a reticular structure with urea bridges (e.g., Emagel® 3.5%), or be
composed of succinyl-gelatin (Eufusin® 4%) or modified fluid gelatin
(Gelplex® 3%). Succinyl-gelatin has higher negative charges, which give it
a greater oncotic activity, and in humans it has a lower risk of anaphylaxis.
In humans, gelatin interferes less with coagulation [41]. Because it has a
very low molecular weight (30 kDa), it is eliminated mainly through the
kidneys and has a short duration of action of about 2 hours. This short
duration of action can be a downside but also an advantage, since, if gelatin
is used to quickly restore the circulating volume (fluid resuscitation), it will
expand it to an extent comparable to HES, but for a shorter period of time
and without interfering with the continuation of therapy. Gelatin is easily
available and costs less than other colloids. It also interferes less with
coagulation than HES. In humans, hypersensitivity reactions are greater
with gelatin than with HES and dextran; no data about this is available in
veterinary medicine. The daily dose is 10–20 mL/kg IV.

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Clinical Case

Consequences of gastroenteritis

History
The patient was taken for a medical examination because he had been
showing anorexia for 3 days, with about five episodes of vomiting per
day (described as gastric juice) and four episodes of diarrhea with blood.
The owner explained that the dog refused to take food, even when
offered by hand, and that he kept vomiting shortly after drinking.
Abdominal pain and intestinal loop enlargement were detected on
physical examination.
The initial examination revealed the following vital parameters:
heart rate: 170 bpm;
respiratory rate: 55;
full pulse;
 rectal temperature: 39.8 °C;
mucous membranes: pink, CRT <1.5 seconds;
blood pressure: 85/57 mmHg, MAP: 65 mmHg;
dehydration: about 12%;
pain on abdominal palpation and intestinal loop enlargement;
hot extremities.

Laboratory tests
A blood gas analysis was performed because a disease affecting the
extracellular compartment (ECF) was suspected, although it could also
involve the intracellular compartment. It is important perform this test, as
it guides us in the choice of fluid therapy and of a treatment for the acid–
base imbalances that are most likely present.
A blood count was also performed to evaluate the hematocrit and white
blood cell levels, which are useful for therapeutic and prognostic
purposes.
The measurement of biochemical parameters is also useful to assess
whether the organs related to the gastrointestinal system are
compromised or if there is multiple organ failure. In this case, given the
presence of diarrhea with blood, coagulation tests were also performed to
exclude any poisoning, and a blood smear was made to evaluate platelets.
A blood smear is recommended in all critically ill patients, however,
since it can provide a lot of information at a very low cost (e.g.,
erythrocyte morphology, leukocyte count, presence of parasites). An
ELISA test was also performed for the rapid diagnosis of canine
parvovirus infection.

Arterial blood gas analysis

Since there was an increase in the respiratory rate and severe prostration,
the effectiveness of the cardiorespiratory system in oxygenating the
blood was also evaluated, for which an arterial sample from the
metatarsal artery was collected. The blood gas analysis also allows
oxygen parameters to be calculated and the pH, bicarbonate, carbon
dioxide and electrolytes levels to be determined.
pH: 7.38;
 paCO2: 25;
paO2: 85;
HCO3–: 15;
BE: –9,7;
Na+: 134 mmol/L;
Cl–: 127 mmol/L;
K+: 3,1 mmol/L;
lactate: 5.4 mmol/L;
AG: 4,9;
FiO2: 0.21.

Biochemical profile
BUN 30 mg/dL, creatinine 1.2 mg/dL, ALT 41 U/L, AST 35 U/L, total
proteins 3.7 g/dL, albumin 0.9 g/dL, total bilirubin 0.5 mg/dL, GGT 14
U/L, blood glucose 78 mg/100 mL, phosphorus 5.4 mg/dL.

Complete blood count

RBC 4.9 × 1012/L, WBC 7.3 × 109/L, Hct 29%, Hb 9.5 g/dL, PLT 104 ×
109/L, neutrophils 12 × 103/μL, normal platelet count.

Coagulation test
In this case the PT test was performed: 8.5 seconds; the aPTT was about
27 seconds and the fibrinogen was approximately 180 mg/dL.

Interpretation of laboratory tests

The blood gas analysis showed an almost normal pH but an altered
paCO2, which suggested the presence of respiratory alkalosis, while
bicarbonate levels indicated the presence of metabolic acidosis.
Therefore, according to the traditional approach, this was a case of mixed
acid–base imbalance. It was therefore necessary to decide which acid–
base imbalance should be treated first so it could be done as quickly as
possible. In general, the imbalance that compromises more vital functions
must be treated first. Many times, treating the main problem also treats
mixed acid–base imbalances. In this case, by treating circulatory failure
(i.e., hypotension and peripheral vasodilation), vomiting and diarrhea, the
main problems are treated.
Hypoxia was also present due to the decreased paO2. The paO2/FiO2
ratio was about 405, which was indicative of an effective although
suboptimal oxygenation. However, oxygen therapy was recommended
given the dog’s critical condition.
According to the nontraditional approach, the pH revealed mild acidemia,
while severe SID acidemia (94 nmol/L) was present. At the same time
there was a very high concentration of unmeasured cations; the Atot
helped to correct acidosis as they were reduced, and respiratory alkalosis
contributed to raising the pH. The greatest contribution was given by the
increase in SID (presence of unmeasured cations).
Biochemical tests showed a reduction in proteins and albumin probably
due to protein-losing enteropathy caused by a lesion of the gastroenteric
mucosa.
Multiple organ failure was not present, as the other biochemical
parameters were normal. At that moment there was no leukopenia and
lymphopenia but monitoring was required over the following days.
The coagulation tests ruled out anticoagulant rodenticide poisoning since
the PT was normal while the aPTT was prolonged.
The osmolarity is calculated as follows:

Osm = 2 × [Na+] + glucose (mg/dL) /18 + BUN (mg/dL)/2.8

Osm = (2 × 134) + (78/18) + (30/2.8)

Osm = 283 mOsm/L

Osmolarity was slightly reduced compared to normal values as a result of
reduced natremia. In this case, the administration of an isotonic saline
solution containing large amounts of sodium (e.g., Ringer’s acetate or
Normosol-R with sodium gluconate) can be useful to correct the
problem.

Diagnostic tests
An X-ray (shown below) of the abdomen was taken and did not reveal
the presence of foreign bodies, but intestinal loop enlargement was
present.
Other lesions of the gastrointestinal tract cannot be detected with this
diagnostic test. As the dog was a puppy, it was chosen to use this imaging
technique to assess the presence of foreign bodies (e.g., stones, bones or
fragments of wood), which is frequent in young dogs.

Daily fluid therapy

As the patient was hypotensive, with perfusion parameters that suggested
a circulatory deficit, it was decided to administer a fluid bolus of Plasma-
Lyte with sodium gluconate. A dose of 240 mL was delivered over 20
minutes, but this did not improve the hemodynamic condition. A second
bolus was therefore administered, which was able to normalize the
patient’s perfusion parameters. At this point it was decided to switch to
daily maintenance fluid therapy plus fluids to treat dehydration.
If the patient had not responded to fluid resuscitation, the administration
of vasoactive drugs (e.g., CRI of norepinephrine) should have been
considered. In this case the risk of requiring vasoactive support was high,
as the hot extremities could lead to the suspicion of the presence of
peripheral vasodilation and sepsis.
The recommended fluid therapy was a maintenance fluid therapy with a
high SID, to attempt to correct the metabolic acidosis. In this case, daily
fluid therapy consisted in the administration of Plasma-Lyte with sodium
gluconate. The volume of fluids lost (12% dehydration) must also be
added to the maintenance fluids.
Maintenance fluids: 2 mL/kg/hour IV, which corresponds to 24 mL/hour
IV.
Dehydration: 12% of 12 kg corresponds to 1440 mL/ day, which once
divided by 24 hours corresponds to 60 mL/ hour IV.
Due to the severely decreased serum albumin concentration, it was
decided to simultaneously administer 5% human albumin at a dose of 20
mL/kg/day and at a rate of 2 mL/kg/hour IV. Albumin was administered
for 3 consecutive days, because the serum albumin concentration
remained low.
Additional therapy
The patient, in addition to 5% human albumin, was given broad-spectrum
antibiotics: amoxicillin and clavulanic acid 20 mg/kg every 12 hours IV,
and metronidazole 20 mg/kg every 12 hours IV. For emesis,
metoclopramide was administered as a CRI at a dose of 0.02 mg/kg/hour
IV; 1 gram of diosmectite every 8 hours was also administered. A nasal
cannula was placed on the patient to bring the FiO2 to 0.40. The patient
was discharged on the fifth day, when he resumed eating and drink ing
spontaneously.
Electrolyte Disorders
 CHAPTER
4

Fabio Viganò, Corinna Uboldi

Introduction
Body fluids consist of water, the solvent, and the particles dissolved in it,
the solutes.
Water is the major component of body fluids and in dogs and cats it
accounts for about 60% of the total body weight. It is distributed in distinct
compartments, namely the intracellular compartment (intracellular fluid,
ICF), which contains most of the body fluids (about 2/3) and the
extracellular compartment (extracellular fluid, ECF), which contains a
much smaller amount (about 1/3) (see Chapter 1). In addition to water, body
fluids contain various solutes distributed differently in the two
compartments (Figure 4.1). Solutes are molecules that can be dissociated
into electrically charged atoms, called ions. Ions can have a positive charge
(cations) or a negative charge (anions). Because of this they can conduct
electrochemical energy and are called electrolytes. Each electrolyte is
characterized by a valence, which is the ability to create chemical bonds
based on the magnitude of its charges. For example, sodium has one
positive charge and is thus defined as monovalent, i.e., it can bind to an
atom with a monovalent negative charge, such as chloride; calcium, on the
other hand, has a double positive charge, can bind to two chloride atoms
and for this reason it is defined as bivalent.
Figure 4.1 Concentration of electrolytes in the extra- and intracellular compartments. ICF,
intracellular compartment; ECF, extracellular compartment.

Electrolytes are therefore particles that dissociate into ions with a

negative or positive charge as they dissolve in water. This phenomenon is
called ionization. A typical example of this reaction is the dissociation of
⇋
hydrochloric acid: HCl + H2O H3O+ + Cl–.
The aqueous solution containing the electrolytes thus dissociated is able
to conduct the electric current. If dissociation is complete (called
quantitative) or almost complete (equilibrium to the right), the electrolytes
that are free are defined as strong. If dissociation is partial, i.e., the
electrolytes only have a slight tendency to dissociate and a part or most of
them remain linked to the molecule from which they originated, they are
defined as weak and remain largely in solution in a non-dissociated form.
An example of complete dissociation of an acid, which is therefore defined
as strong, is that of hydrochloric acid (HCl); an example of a strong base is
sodium hydroxide (NaOH), while the chemical species that partially
dissociate and are thus considered weak are carbonic acid (H2CO3) and
ammonia (NH3).
Electrolytes, in clinical practice, are measured in equivalents (Eq). One
Eq is defined as a mole of any anion that combines with hydrogen, or a
mole of any monovalent cation that can replace hydrogen in the following
chemical reaction: 1 mole of H+ + 1 mole of Cl– = 1 mole of HCl
(monovalent cation); or 1 mole of Ca2+ + 2 moles of Cl– = 1 mole of CaCl2
(bivalent cation).
In biological fluids, electrolyte concentrations are very diluted and for
this reason milliequivalents (mEq) are generally used as a unit of
measurement.

Osmosis
The different concentration of solutes between the intracellular
compartment (ICF) and the extracellular compartment (ECF) is regulated
by the presence of semipermeable membranes, which allow the passage of
water and some solutes. The movement of water through semipermeable
membranes (e.g., the cell wall membrane) creates a pressure gradient that is
called osmosis. Water moves from the less concentrated to the more
concentrated compartment.
If a solute is in higher concentration in a compartment, it generates a
movement of water to that compartment. The measurement of the volume
of displaced water is called the osmotic pressure of the solute. According to
the Gibbs–Donnan effect, large molecules (e.g., proteins) with a negative
charge attract positive charges to their compartment and drive negatively
charged molecules away. These phenomena occur with no expenditure of
energy and only by osmotic gradient.
The solutes that freely cross the semipermeable membranes reach
balanced concentrations on both sides of the membrane without resulting in
solvent movement.
Osmotic pressure is defined as the hydrostatic pressure necessary to
prevent the phenomenon of osmosis and is expressed in mmHg. It depends
on the number of particles, so an increase in positive charges close to the
negative charges of proteins will increase their osmotic effect. This osmotic
effect of a nondiffusible colloid is called oncotic pressure and is the reason
for the difference in osmotic pressure between the protein-rich plasma and
the interstitial fluid.
Osmolarity and osmolality
Osmolarity is defined as the concentration of osmotically active particles in
1 liter of solution (Osm/L), while osmolality indicates the concentration of
osmotically active particles in 1 kilogram of water (Osm/kg).
The osmotic activity of a solution is related to the number of particles
present in it, regardless of their mass or charge. Molecules that do not
dissociate, such as glucose and urea, will have a number of osmotically
active particles (osmoles and milliosmoles) equal to the number of
molecules in the solution, i.e., 1 millimole equals 1 milliosmole. Molecules
that dissociate will produce more milliosmoles when the solutes are
dissociated. For example, sodium chloride is dissociated into sodium ions
and chloride ions, so 1 millimole of NaCl generates 2 milliosmoles. To have
an osmotic effect, the solute must be on only one side of the semipermeable
membrane. Small molecules, such as urea, are diffused freely through some
membranes (e.g., the vascular membrane) and therefore do not generate an
effective osmolality; conversely, if the solute is too large to cross the
semipermeable membrane (e.g., proteins and vascular wall), the molecules
will exert an osmotic effect.
Effective osmolality is called tonicity and refers to the ability of solutes
to create an osmotic force by moving water between compartments
separated by semipermeable membranes. Sodium, for example, cannot
cross a semipermeable membrane such as that of the cell, and its movement
is regulated by the sodium–potassium pump. This pump requires energy
(ATP, adenosine triphosphate), which is obtained through oxidative
phosphorylation in the mitochondria and thus requires oxygen. Because it
remains outside the cell wall, sodium exerts an osmotic effect that attracts
water to this compartment. Conversely, although it represents part of the
dissolved solutes, urea is freely diffusible and does not produce the
movement of solvent. Sodium is responsible for the tonicity of extracellular
fluids, while potassium maintains the tonicity of intracellular fluids.
Isotonic solutions are defined as those that have the same tonicity as the
body’s fluids (very close to 300 mOsm), such as 0.9% NaCl. Hypotonic
solutions have a lower osmolality than biological fluids, while hypertonic
solutions have a higher tonicity. Sometimes the hypertonicity of a solution
is incompatible with its administration through the peripheral veins, and
solutions with an osmolality >600 mOsm should be administered in the
central vessels (e.g., jugular vein).
The osmolality of blood can be calculated using the following formula:

With this formula, the osmotic pressure is calculated based mainly on

the blood sodium concentration; it is not measured (see Chapter 1). In the
presence of osmotically active molecules, as in hyperlipemia, the osmotic
pressure calculated using the formula above may not correspond to the
patient’s actual osmotic pressure. However, it can detect alterations in
osmotic pressure caused by hyperglycemia or azotemia, which are common
in critically ill patients.

Sodium
Seventy percent of the body’s sodium is found in the extracellular and
intracellular fluids; it can be exchanged between these different
compartments. Of this share, about 81% is found in the interstitial and
transcellular fluids, 16% in plasma and 3% in the intracellular
compartment. The remaining sodium is contained in the bones and is
therefore difficult to use.
The need for water is detected through changes in blood tonicity, which
depends on natremia. Central osmoreceptors are located in the lamina
terminalis of the hypothalamus, adjacent to the third ventricular wall.
Sensory cells are activated by changes in plasma osmolarity that promote
water movement between the ICF and the ECF. They are also activated
when an expansion in blood volume is required and during hypotension.
Osmoreceptors can activate the thirst center and the neurons of the
supraoptic nucleus, which contains vasopressin that is transported to the
posterior pituitary. If ECF tonicity increases, thirst and the release of ADH
are stimulated; conversely, if tonicity decreases, an inhibitory effect is
produced. In addition, ADH release is influenced by afferents from the
brainstem, which respond to blood volume variations. The so-called “high
pressure” receptors, which are located in the carotid sinus and aortic arch,
are sensitive to changes in arterial blood volume, and modulate sympathetic
and parasympathetic activity as well as ADH release. In the presence of
hypovolemia, these receptors elicit an increase in sympathetic activity and a
decrease in parasympathetic activity, which results in an increased heart rate
and peripheral vasoconstriction. Increased ADH enhances vasoconstriction
by acting on the smooth muscle cells and reduces diuresis, thereby
promoting sodium retention. High pressure receptors are also present in the
afferent arterioles of the renal glomeruli. As they detect changes in
perfusion, these receptors modulate the production of renin. For example,
when perfusion of the renal afferent arterioles is reduced due to
hypovolemia, juxtaglomerular cells increase renin secretion. Renin converts
angiotensinogen into angiotensin I, which is in turn converted into
angiotensin II; subsequently, by enzymatic cascade, angiotensin III and IV
are produced. Angiotensin II causes arteriolar vasoconstriction and
stimulates thirst and ADH release at the central nervous system level. At the
kidney level, preferential vasoconstriction of the efferent arteriole occurs,
which aims to hinder the outflow of blood from the glomerulus in order to
increase the pressure and maintain the filtration pressure. Finally,
angiotensin II and III stimulates the secretion of aldosterone from the
adrenal cortex, which promotes sodium reabsorption in the distal tubule
(Figure 4.2).
Figure 4.2 Renin–angiotensin–aldosterone system in sodium and water reabsorption.

The ADH released enters the circulation and reaches the renal
peritubular capillaries, where it diffuses towards the tubules and acts by
binding to the V2 receptors of the collecting tubule cells, which are found at
their basal surface, facing the interstitium. This binding induces important
cellular events, including the synthesis and expression of new channels for
water reabsorption (aquaporins) on the cell surface facing the tubular
lumen. This results in water retention and a decrease in ECF tonicity.
The amount of sodium excreted in urine depends on glomerular filtration
(amount of filtered sodium that reaches the kidney) and its tubular
reabsorption (sodium saved). Glomerular filtration depends on hydrostatic
pressure (difference between blood pressure and Bowman’s capsule), which
induces filtration, and the oncotic pressure of albumin, which hinders it.
Fifty percent of the tubular reabsorption of sodium occurs at the proximal
tubule, where there are Na–H exchangers between the cells and tubule.
Protons are eliminated in exchange for sodium, which passes from the
lumen into the tubular cell. This exchange is favored, indirectly, by the
sodium–potassium pump, which is found on the basolateral side of the cell
and pumps 3Na+ into the interstitium and only 2K+ into the cell. Due to the
net loss of positive charges, the intracellular potential is more negative than
the tubular fluid and favors the entry of sodium.
During hypovolemia, a reduction in glomerular perfusion and in
pressure in the capillaries of the afferent arteriole surrounding the proximal
tubule favors oncotic reabsorption and hydrostatic absorption. The opposite
effect occurs in case of hypervolemia.
The loop of Henle reabsorbs about 45% of the filtered sodium. At the
level of its ascending branch, the tubular wall becomes impermeable to
water but maintains its permeability to solutes. A Na–K–2Cl cotransporter
acts at this level to transport chloride inside the cell together with sodium.
Sodium is also passively reabsorbed by the thin ascending branch of the
loop. Reabsorption by the loop of Henle is stimulated by sympathetic
activity, ADH release, and reduced blood flow in the medullary capillaries.
The distal tubule, on the other hand, reabsorbs 3% of the filtered
sodium. Sodium enters together with chloride from the luminal side and is
actively transferred into the interstitium by the Na–K pump located on the
basal side.
About 2% of sodium is reabsorbed in the collecting tubule. The main
cells absorb sodium from the tubular lumen and release it into the
interstitium at their basal side, where it is exchanged for potassium thanks
to an ionic pump that is activated by aldosterone and keeps the intracellular
concentration of sodium low.
Sodium is then eliminated mainly by the kidney, which regulates its
excretion according to the needs of the body and thus controls the amount
of sodium in the extracellular fluid and, consequently, the blood volume.
Another route of excretion, but of lesser magnitude, is elimination through
feces.

Hyponatremia
Hyponatrema is a condition characterized by a low sodium concentration
(dog <145 mEq/L, cat <150 mEq/L) that frequently, but not always, causes
hyposmolality. In hyponatremic patients it is necessary to first determine
the osmolality of the ECF by calculating, or rather measuring, the
osmolality of plasma. The following three conditions can be associated with
hyponatremia:
Hyponatremia with normal osmolality (290–310 mOsm/kg): it is also
called pseudohyponatremia, as the presence of a high amount of lipids and
proteins artificially alters tonicity. In these patients, it is not necessary to
correct hyponatremia but the pathological process that causes
hyperproteinemia and hyperlipidemia.
Hyponatremia with increased plasma osmolality (>310 mOsm/kg): this
situation occurs, for example, when there are other molecules in addition
to sodium capable of increasing blood tonicity, as in hyperosmolar
syndromes (e.g., uncontrolled diabetes mellitus, administration of
mannitol). Because glucose is an effective osmole, i.e., it can draw water
from the intracellular into the extracellular compartment, it causes a
reduction in sodium concentration due to dilution. It is therefore not a true
hyponatremia, but the consequence of sodium dilution. As in the previous
case, it is not necessary to correct hyponatremia but the pathological
process that causes it (e.g., treatment of diabetes).
Hyponatremia with reduced plasma osmolality (<290 mOsm/kg): it
requires determination of whether the patient is normovolemic,
hypovolemic, or hypervolemic. In order to identify which condition is
associated with hyponatremia, the clinical history should be taken
(presence of vomiting, diarrhea, tachypnea, administration of diuretics, or
drugs that promote diuresis), the clinical parameters used to assess the
hydration status should be evaluated (skin turgor through the skin fold
test, skin edema, presence of skin fovea, dryness of the mucous
membranes—especially the oral mucous membranes—, CRT, pulse,
ectasia of the jugular vein, presence of a jugular pulse, ascites, blood
pressure, disappeared heart sounds, and dulling of breathing sounds), and
the hematocrit and total plasma proteins should be measured (Figure 4.3);
– Hyponatremia with normovolemia: it is caused by inappropriate ADH
secretion due to abnormal vasopressin production. The causes can be:
– Psychogenic polydipsia, a condition seen especially in large dogs
after a stressful event, or in hyperactive dogs kept in a very small
place. It has not been demonstrated in cats [1].
– Syndrome of inappropriate antidiuretic hormone secretion
(SIADH): it is rare in dogs and is reported in association with
 heartworm disease, carcinoma, neoplasms of the hypothalamus,
granulomatous meningoencephalitis, hydrocephalus, and idiopathic
causes [2].
– Administration of barbiturates, nitrous oxide, narcotics,
isoproterenol.
– Use of hypotonic fluids [3].
– Lung diseases (ARDS, bacterial pneumonia).
– Hypothyroidism.
– Hyponatremia with hypovolemia: a typical example is
hypoadrenocorticism [4], which causes a loss of NaCl in urine and a
reduction in the ECF volume, which in turn stimulates vasopressin
release and impairs water excretion. Other causes are the
administration of diuretics and fluid losses secondary to vomiting and
diarrhea. Three events leading to hyponatremia can occur:
– Hypovolemia causes a reduction in glomerular filtration resulting in
reduced water excretion.
– Hypovolemia stimulates the release of vasopressin, which leads to
an increase in its concentration in plasma and impairs water
excretion.
– There is not enough water available to meet the patient’s needs.
Other causes are fluid leakage during pancreatitis, peritonitis,
uroperitoneum, pleural effusion.
– Hyponatremia with hypervolemia: a condition found in patients with
edema or ascites resulting from heart failure, severe chronic liver
disease and nephrotic syndrome. It can be due to three alterations:
– Activation of the renin–angiotensin–aldosterone system, which
leads to reduced renal perfusion and thus to increased sodium
retention by the kidney and reduced water excretion.
– Vasopressin release with reduced water excretion.
– Activation of the kidney’s intrinsic mechanism of sodium retention
in nephrotic syndrome.
Figure 4.3 Causes and therapy of hyponatremia with reduced blood osmolality.

Clinical signs
They appear especially during acute hyponatremia. The most common are
lethargy, nausea, weight gain, and vomiting. More severe signs may also
occur, such as cerebral and pulmonary edema, weakness, incoordination,
convulsions, stupor, and coma. Chronic hyponatremia is generally not
responsible for pathognomonic signs.

Treatment
Symptomatic acute hyponatremia requires administration of 0.9% NaCl or
of another solution with a high sodium concentration. The volume of
solution to be administered can be calculated by measuring the patient’s
blood sodium concentration and subtracting it from the normal sodium
concentration. The value obtained is multiplied by the body weight, as
shown in the formula below (Box 4.1):
 The sodium deficiency thus obtained must be divided by the sodium
concentration of the chosen solution, as shown in the following formula:

The formula below can be used to calculate the duration of

administration of the solution:

In chronic hyponatremia, to avoiding correcting the blood sodium too

quickly when using solutions other than 0.9% NaCl, the sodium deficiency
can be calculated as follows:

Box 4.1 Treatment of acute hyponatremia

Acute hyponatremia: dog <145 mEq/L, cat <150 mEq/L

(140 – [Na+]p) × kg × 0.3 = Na+ deficit
Na+ deficit/[Na+] of the solution = volume in liters of solution to be
administered
(140 – [Na+]p)/ 0.5 = number of hours of infusion
Maximum correction speed: 0.5 mEq/hour, better over 48–72 hours
Chronic hyponatremia: [Na+]p – Na+ in the fluid = Na+ to be added to 1
L of solution
Pure water losses: patient weight (kg) × 0.6 × [([Na+]p /[Na+]n) – 1] =
water deficit in liters

[Na+]p, natremia of the patient; [Na+]n, normal natremia.

 When the patient has lost pure water, such a deficit can be calculated as
follows:

Correction should be progressive, as cells produce other osmotically

active molecules to control the imbalance, which are slowly eliminated.
This mechanism allows cells to adapt to the transport of sodium, potassium,
and other solutes from inside to outside the cell. The presence of these
solutes lowers intracellular osmolality and slows down the entry of water
into the intracellular environment, thus reducing the extent of edema.
The maximum rate of correction of hyponatremia should be 0.5
mEq/L/hour (10–12 mEq/L/hour) to reduce the risk of central pontine
myelinolysis, an irreversible brain condition that may appear approximately
3–4 days after treatment. As an indication, 10 mEq/L should be corrected in
the first 24 hours, and a maximum of 18 mEq/L in the first 48 hours.
Hyponatremia should ideally be corrected over 48–72 hours.
In overhydrated patients with cerebral edema, solutions containing large
amounts of sodium can be combined with the administration of natriuretic
diuretics such as furosemide in order to achieve faster correction.
Symptomatic chronic hyponatremia requires the same treatment.
During the correction of hyponatremia, especially if it is rapid and
hyponatremia is severe, sodium and, if possible, chloride and potassium
levels should be monitored every 2–4 hours until these values normalize.
The patient’s vital parameters and neurological status should be assessed
every 8 hours, while the acid–base balance should be evaluated every 12–
24 hours.
In patients with chronic and asymptomatic hyponatremia, correction
should occur slowly since rapid correction is more dangerous than the
disorder itself. In these cases, the administration of saline solutions that are
hypernatremic relative to plasma must therefore be avoided.
Rapid correction (in 38 hours) of chronic hyponatremia, such as that
caused by trichuriasis, can lead to neurological signs such as lethargy,
nausea, ataxia, hypermetria, and tetraparesis [5].
 Patients with chronic hyponatremia (normovolemic or hypervolemic)
and with heart failure can be treated with diuretics and ACE inhibitors,
which, by improving cardiac output, reducing preload and afterload, and
decreasing vasopressin secretion, increase water excretion and can improve
and correct hyponatremia.
Hypovolemic patients need correction with solutions containing high
sodium concentrations, such as 0.9% NaCl.
Research is underway to establish the efficacy of antagonists of the
arginine-vasopressin receptors (vaptans), V2 receptors (lixivaptan,
tolvaptan, satavaptan) and V2 and V1 receptors (conivaptan), which
increase water excretion, thereby normalizing natremia in patients with
normovolemia or hypervolemia. Conivaptan is added to a 5% dextrose
solution and administered intravenously as a constant rate infusion, while
tolvaptan, lixivaptan and satavaptan are administered orally.
In human patients these drugs have minimal side effects (thirst and dry
mouth) and minimize the risk of developing neurological symptoms in the
days following the correction of hyponatremia. They correct natremia in 24
hours.

Hypernatremia
Hypernatremia is defined as a sodium concentration >160 mEq/L.
Hypernatremia can be due to water deficiencies such as:
Central diabetes insipidus, due to no or insufficient release of
vasopressin, responsible for the formation of urine with a low specific
gravity (decreased urinary concentration). The causes can be of
neurological origin—such as primary pituitary neoplasia, meningioma,
head trauma, pituitary surgery, and metastatic-parasitic-inflammatory
lesions—or of idiopathic origin in young dogs. The clinical signs are
polyuria and polydipsia, with the animal constantly seeking water; weight
loss; and neurological signs.
Hypernatremia of renal origin responsible for water loss. It can be due to
insensitivity of the renal tubules to vasopressin, which has been reported
in Huskies in which it has a genetic origin, or result from diabetes
mellitus, pyometra, hyper- or hypoadrenocorticism, hyperthyroidism in
the cat, and congenital or acquired nephropathies.
The diagnosis of both forms can be achieved through urine examination,
water deprivation tests, and plasma vasopressin dosage. Treatment involves
the administration of vasopressin/desmopressin for the central form, and
thiazide diuretics as well as a low-sodium diet for the nephrogenic form.
Other causes of hypernatremia are:
severely increased ambient temperature;
high fever;
inadequate access to water;
postobstructive diuresis;
excessive fluid loss due to extrarenal causes (vomiting, diarrhea, small
bowel obstruction, peritonitis, pancreatitis, and burns) and renal causes
(administration of diuretics, mannitol, chronic kidney disease, acute renal
failure, and diabetes mellitus);
primary adipsia, congenital in the Miniature Schnauzer;
administration of hypertonic fluids, e.g., sodium bicarbonate, hypertonic
saline;
administration of drugs that can cause diuresis such as gentamicin and
amphotericin B, furosemide, corticosteroids, mannitol;
glycosuria;
ketonuria;
hyperadrenocorticism;
hyperaldosteronism.

Clinical signs
The clinical signs are numerous and not always pathognomonic: anorexia,
depression, vomiting and diarrhea, muscle weakness, behavioral alterations
and disorientation, pulmonary edema, tachycardia, polyuria, hyperthermia.
When the sodium concentration exceeds 170 mEq/L, neurological signs
appear such as epileptic seizures, coma, stupor, and ataxia. The more severe
the signs and with neurological manifestations, the more the imbalance has
arisen quickly; this is due to dehydration of the brain cells, which alters
their function.

Treatment
Acute hypernatremia should be promptly corrected with infusion of a 0.9%
saline solution. In some cases, fluid resuscitation with 0.9% NaCl is
necessary and involves the administration of 20 ml/kg IV over 15–20
minutes; 2–3 boluses can be repeated if necessary.
In severe forms of chronic hypernatremia, or when the duration of
hypernatriemia is unknown (it must be considered chronic until proven
otherwise), the correction of blood sodium should be gradual and achieved
with 0,9% NaCl to avoid excessively rapid changes in blood osmolarity, as
they carry a risk of neurological damage. In these cases, the following
formula may be used:

The solution to be infused can be prepared with water for injection and
hypertonic saline solution, or 5% dextrose solution and hypertonic saline
solution.
In acute forms of hypernatremia, rapid correction is generally well
tolerated. However, the correction rate should be less than 0.5 mEq/L/hour.
Monitoring of natremia should be performed every 4–6 hours. Complete
correction should be achieved in 48–72 hours. In these cases, the following
formula can be used:

The maximum correction rate can be 1 mEq/L/hour if the blood sodium

concentration is less than 180 mEq/L. When blood sodium is greater than
180 mEq/L, the correction rate should be 0.5 mEq/L/hour to reduce the risk
of cerebral edema and neurological damage. When fluid overload occurs,
furosemide may be used to reduce blood volume and natremia.
Monitoring can be performed by assessing the following parameters:
natremia, every 4 hours in severe forms and every 6–12 hours otherwise;
physical examination: temperature, heart and respiratory rates, pulse,
color and hydration of the mucous membranes, water retention (weigh the
patient twice a day), blood pressure and urine output every 8 hours;
 neurological status (Glasgow coma scale) every 8 hours;
hydration status every 12 hours (e.g., by measuring hematocrit, total
proteins and physical signs); acid–base status every 12–24 hours.

Potassium
Potassium is an essential element for most living organisms, and it is
present in organic fluids in its ionized form (K+) or bound to nondiffusible
anions such as proteins. Muscle tissue is particularly rich in potassium (it
contains about 2200 mEq). Ninety-seven percent of potassium is found in
the ICF at a concentration of about 160 mEq/L, compared to 3.5–5 mEq/L
in the ECF. These concentrations are maintained predominantly by the
sodium–potassium (Na–K) pump, which is powered by ATP and can be
found in the outer plasma membrane of the cell. The Na–K pump keeps
potassium inside the cell and expels sodium. The factors that regulate
potassium movements between the ECF and ICF are:
Acid–base balance: during metabolic acidosis, excess hydrogen ions are
buffered by entering the intracellular environment, which breaks
electroneutrality. To restore electroneutrality, potassium is drawn into the
extracellular compartment. For each 0.1 pH reduction, potassium
increases by 0.7 mmol/L. The situation is slightly different in respiratory
acidosis, where the increase in potassium is about 0.1 mmol/L lower for
each decimal reduction in pH. During metabolic or respiratory alkalosis,
on the other hand, there is a reduction in hydrogen ions in the intracellular
environment, so potassium enters the cell to compensate for the loss of
positive charges. For each decimal increase in pH there is a reduction in
potassium of 0.3 mmol/L.
Pancreatic hormones: insulin activates the Na–K pump and causes cellular
uptake of potassium in exchange for sodium, which exits the cell; this
therefore decreases the blood potassium concentration. Glucagon, by
opposite mechanisms, increases the blood potassium concentration.
Catecholamines: they act by stimulating ß receptors which, like insulin,
activate the Na–K pump by promoting the entry of K+ into the cell.
Thanks to this mechanism, ß-agonists, such as salbutamol, can be useful
in the treatment of hyperkalemia.
 Aldosterone: it acts by directly activating the Na–K pump or by
promoting the entry of sodium into the cell.
Osmolality: hyperosmolality causes an extracellular flow of water, which
carries with it potassium in the amount of 0.6 mmol/L for each increase of
10 mOsm/kg.
Cellular necrosis: it may be produced by many causes (e.g.,
rhabdomyolysis, hemolysis, burns and tumor lysis) and induces potassium
leakage.
Exercise: physical effort promotes the release of potassium, but
progressive training enhances the activity of the Na–K pump by
increasing the ability of the myocytes to retain the cation.
The potassium contained in the ICF is essential for maintaining the osmotic
balance and electric potential of the cell membrane. In addition, it is
essential for protein synthesis and cell growth.
Ninety percent of potassium is excreted by the kidneys. It is freely
filtered by the glomerulus and reabsorbed in the ascending loop of the
proximal tubule. Only 25% of the filtered potassium reaches the distal
tubule, where it is excreted or reabsorbed. The main regulators of renal
excretion of potassium are aldosterone, vasopressin, hyperkalemia,
increased anions in the tubular fluid, metabolic alkalosis, and increased
tubular flow. Conversely, factors that inhibit renal excretion of potassium
are hypokalemia, metabolic acidosis, and reduced tubular flow. The
remaining 10% of potassium is excreted in the proximal and distal colon,
where, under hormonal influence, sodium reabsorption and potassium
excretion take place. The intestinal loss of potassium is limited under
normal conditions, but it becomes constant during diarrhea and is an
important route of excretion in case of chronic kidney disease.

Hypokalemia
When hypokalemia is diagnosed (dog <3.4 mEq/L, cat <2.9 mEq/L), it is
important to establish whether it is due to pseudohypokalemia, hypokalemia
from redistribution, extrarenal potassium losses or renal potassium losses:
Pseudohypokalemia: blood samples with marked leukocytosis stored for
hours at room temperature can produce a false hypokalemia, because
leukocytes incorporate plasma potassium. The administration of insulin,
 hypokalemic fluids or albuterol, which induce an increase in the entry of
potassium into the cell, may also be responsible for false hypokalemia.
Redistributive hypokalemia: it can be due to the movement of potassium
into the cells during metabolic alkalosis; to increased ß2-adrenergic
activity in head trauma; or to intoxication by barium, which blocks
potassium channels and thus inhibits the exit of potassium from the cell.
Extrarenal losses: severe diarrhea, protobstructive diuresis, polyuria with
polydipsia, refeeding syndrome (caused by increased insulin secretion).
Renal losses: associated with states of acidosis (e.g, during diabetic
ketoacidosis), states of alkalosis (e.g., hyperaldosteronism),
administration of loop diuretics (furosemide and thiazide diuretics), and
severe emesis with chloride depletion.

Clinical signs
The appearance of clinical signs depends on the concentration of potassium:
If K <3 mmol/L, the clinical signs will be muscle weakness, lethargy,
atony, ileum, urinary retention, inability to concentrate urine, myocardial
depression, polyuria and polydipsia, and muscle cramps.
If K <1.5 mmol/L, very severe signs will develop such as cardiac and
respiratory arrest; in the cat, ventroflexion of the head is frequently seen.
Hypokalemia, regardless of its severity, may be responsible for
supraventricular and ventricular arrhythmias.

Treatment
Patients in a state of hypovolemic shock require fluid resuscitation with
balanced crystalloids (e.g., Ringer’s lactate or Plasma-Lyte with sodium
gluconate).
Potassium replacement therapy can be provided following the
indications obtained empirically (Table 4.1). In humans, supplementation
may not take into account the concentration of potassium in the balanced
crystalloid used.
The maximum rate of infusion of KCl is 0.5 mEq/kg/hour when
administered intravenously; the oral dose may be doubled.
In these patients, monitoring is very important and involves the
determination of potassium every 12–24 hours. During the correction of
severe hypokalemia, it is advisable to perform continuous
electrocardiographic monitoring. The patient’s vital signs (at least the heart
rate, pulse, CRT, mucous membrane color and respiratory rate) should be
assessed every 8–12 hours (values must be written down) and a blood gas
analysis should be performed every 12–24 hours (Box 4.2).

Hyperkalemia
Hyperkalemia (>5 mEq/L) may be caused by potassium redistribution or it
may be secondary to impaired potassium excretion.
In the first case, it may result from metabolic acidosis, respiratory
acidosis, treatment with betablockers or aldosterone inhibitor drugs (e.g.,
ACE inhibitors), KCl administration, parenteral nutrition, snakebite
poisoning, hypertonic states, and malignant hyperthermia. Reduced
potassium excretion may be due to urethral obstruction, severe tissue
trauma, bladder rupture, thoracoabdominal effusions, reperfusion injury,
infections, decreased aldosterone levels or lack of tubular response to
aldosterone in adrenocortical insufficiency, hypoinsulinemia (metabolic
ketoacidosis), tumor lysis, heat stroke, drugs (e.g., spironolactone,
trimethoprim, heparin, triamterene, NSAIDs, cyclosporine, tacrolimus,
amiloride, ACE inhibitors), or primary and secondary kidney disease with
CKD. Trichuriasis, duodenal perforations and salmonellosis can also cause
hyperkalemia.
False hyperkalemia, called pseudohyperkalemia, may also be seen, and
can be caused by the use of hemolytic samples, marked thrombocytosis, and
severe leukocytosis.
Table 4.1 Potassium supplementation per liter of solution

KCl per liter of Maximum infusion rate

[K+] mEq/L
solution (mL/kg/hour)

3.6–5.0 20 24
3.1–3.5 30 16
2.6–3.0 40 11
2.1–2.5 60 8
 <2.0 80 6

Box 4.2 Treatment of potassium imbalances

Hypokalemia correction: dog <3.4 mEq/L, cat <2.9 mEq/L

Maximum speed
[K ] mEq/L
+
KCl per liter of solution infusion
(mL/kg/hour)
3.6–5.0 20 24
3.1–3.5 30 16
2.6–3.0 40 11
2.1–2.5 60 8
<2.0 80 6
Maximum correction rate: 0.5 mL/kg/hour

Correction of hyperkalemia: >7.5 mEq/L

Onset of effect
1) 10% calcium gluconate: 50–100 mg/kg IV over Onset 2–5 min
10 minutes Offset 20–30
2) Regular insulin, 0.55–1.1 IU/kg IV, followed min
by 1–2 g of 25% glucose for each IU of insulin; Onset <30 min
then administer 5% glucose solution Onset <1 hour
3) 25% glucose, 0.7–1 g/kg IV over 3–5 min Onset 30 min
4) NaHCO3 1–2 mEq/kg IV in slow infusion Onset 20–40
5) Terbutaline 0.01 mg/kg IV in slow infusion min

Monitor potassium every 8 hours. If treatments are ineffective:

hemodialysis

In the presence of hyperkalemia, other emergency diagnostic

investigations should be performed, such as measurement of the hematocrit,
total proteins, blood sugar, azotemia, and serum creatinine concentration;
assessment of the acid–base status; and continuous electrocardiographic
monitoring.

Clinical signs
When hyperkalemia is >7.5 mEq/L, very severe clinical signs may appear,
such as abnormal mentation (depressed), muscle weakness, loss of appetite,
bradycardia, and possible cardiac arrest. Continuous electrocardiographic
monitoring should be performed in patients diagnosed with hyperkalemia,
because potassium values between 5.5 and 7.5 mEq/L cause the appearance
of narrow and peaked T waves, prolonged QRS complexes, reduced R
waves, and ST depression. The severity of electrocardiographic alterations
is subjective, and these alterations may appear even with modest variations
in potassium. When potassium is >7.5 mEq/L, it is possible to see the
disappearance of P waves, atrial standstill, sine-wave rhythm, biphasic QRS
complexes, ventricular flutter, ventricular fibrillation, and ventricular
asystole (Figure 4.4).

Treatment
Patients in a state of shock are given fluid resuscitation with 0.9% NaCl.
Hyperkalemia can be treated with the administration of 10% calcium
gluconate at a dose of 50–100 mg/kg IV over 10 minutes (onset 2–5 min,
offset 20–30 min). This should be done under close continuous
electrocardiographic monitoring because calcium gluconate can cause
severe bradycardia and, if administered too quickly, cardiac arrest.
Hyperkalemia can also be treated with regular insulin administration at a
dose of 0.55–1.1 IU/kg IV, followed by 1–2 g of 25% dextrose for each IU
of insulin; a 5% dextrose solution is therefore administered and blood sugar
monitored (every 2–4 hours). Onset is less than 30 minutes. If hyperkalemia
is associated with metabolic acidosis and renal failure, sodium bicarbonate
at a dose of 1–2 mEq/kg IV may be administered as a slow infusion over
approximately 15 minutes. This last procedure is to be avoided in
hypocalcemic patients. Other treatments involve the use of 25% dextrose at
a dose of 0.7–1 g/kg IV over 3–5 min (onset <1 hour), or terbutaline at a
dose of 0.01 mg/kg IV as a slow infusion (onset 20–40 min).
Figure 4.4 Alterations in potassium and electrocardiographic tracing

After correcting hyperkalemia, it is necessary to treat the cause, and then

to control metabolic acidosis and promote diuresis. If the above treatments
are not effective, it will be necessary to resort to hemodialysis. Patients
should be monitored as follows: measurement of potassium after 30
minutes from the end of the chosen protocol, to allow it to be redistributed,
and then every 8–24 hours, and a blood gas analysis every 12–24 hours (see
Box 4.2).

Calcium
Ninety-eight percent of body calcium is found in the bones in form of
hydroxyapatite; 1% is found in plasma and the remaining 1% in the
extracellular and intracellular fluids. In the extracellular fluid, calcium plays
a crucial role in neuromuscular excitation processes, while in the
intracellular fluid it is essential in some enzymatic reactions and during cell
division. It also conditions the activity of certain hormones (e.g., calcitonin
and parathyroid hormone).
 Plasma calcium can be found in free (ionized) form, bound to albumin
(about 40%) or bound to anions (in a small percentage, 5–10%) such as
citrate, phosphate, and bicarbonate (Figure 4.5). The binding with albumin
is pH-dependent: during metabolic alkalosis, proteins release hydrogen ions
to compensate for metabolic alkalosis and instead fix calcium, thereby
reducing its presence in ionized form. The opposite phenomenon occurs
during metabolic acidosis.
The absorption of calcium takes place partly in the small intestine, with
active transport thanks to the stimulation induced by vitamin D, and partly
at the renal level, thanks to the activity of the parathyroid hormone (PTH).
At the renal level, 50–60% of calcium is reabsorbed by the proximal tubular
cells, down the electrochemical gradient, while the remaining 40% is
reabsorbed in the distal tubule and collecting ducts through active sodium-
dependent reabsorption. This mechanism of calcium reabsorption plays a
crucial role in states of hypercalcemia induced by severe dehydration.
Indeed, severe dehydration stimulates the tubular reabsorption of calcium
together with sodium, leading to a state of hypercalcemia. This is why
appropriate fluid therapy is essential in states of hypercalcemia. Calcium
from the diet is absorbed by the intestine and transported by blood to all the
tissues, but more especially the bones, where the amount absorbed must be
comparable to the amount released by the bones in the blood, so as to keep
the circulating pool of calcium stable. This mechanism and renal tubular
reabsorption constitute the actual homeostatic regulation systems of serum
calcium concentration, the proper functioning of which depends on PTH,
vitamin D and calcitonin.
Figure 4.5 Distribution of calcium in plasma.

The most powerful stimulus of PTH secretion is the reduction of ionized

calcium, detected by specific membrane receptors on parathyroid cells.
PTH counteracts hypocalcemia by stimulating bone resorption through
osteoclast activation, tubular calcium reabsorption, and the production of
renal 1-α hydroxylase, which activates vitamin D.
Calcitonin is produced by the thyroid, thymus, adrenal glands and
pituitary gland. Its synthesis is stimulated by hypercalcemia, and its main
function is to inhibit bone resorption. Vitamin D is formed by the action of
UV sunlight and must undergo two hydroxylations to be activated, one in
the liver and the other in the kidney. Its production is increased in the
presence of calcium, phosphorus or vitamin D deficiency. Its main function
is to increase the intestinal absorption of calcium and stimulate the
reabsorption of phosphorus. In the bone, vitamin D promotes the
mineralization of the organic matrix and stimulates the differentiation of
monocytes into osteoclasts, thus favoring the mobilization of calcium and
phosphorus from the bone.
Hypocalcemia
Hypocalcemia (dog <5.0 mg/dL, cat <4.5 mg/dL) is defined as a reduction
in the blood calcium level in the presence of a normal concentration of
serum albumin.
The main causes of hypocalcemia are:
Renal failure with impaired activation of vitamin D and a consequent
reduction in the intestinal absorption of calcium. Chronic kidney disease
also causes a state of hyperphosphatemia due to reduced glomerular
filtration. Excess phosphorus binds to calcium and forms complexes that
are subsequently removed from the cells of the reticuloendothelial system,
causing hypocalcemia.
Insufficient PTH production due to hypoparathyroidism (insufficient
production by the parathyroid glands), caused by neoplasms,
inflammation, or amyloid infiltration.
Acute pancreatitis: calcium is sequestered in the necrotic tissue.
Paraneoplastic hypocalcemia from osteoblastic metastases of some
carcinomas (e.g., prostate and mammary carcinomas), due to the chelation
of calcium by phosphates and lactates released in tissue necrosis.
Anticonvulsant drugs.
Intoxication by ethylene glycol, the metabolites of which chelate calcium.
Sepsis and ARDS: the combination of a high concentration of
proinflammatory cytokines and a high amount of lactate may cause
hypocalcemia [6].
Puerperal eclampsia, which occurs in the postpartum period (1–4 days
postpartum) and during lactation.

Clinical signs
The most common signs of hypocalcemia are fasciculations, muscle
tremors, facial rubbing, muscle cramping, stiff gait, and behavioral changes
such as disorientation, hypersensitivity to stimuli, aggression, excitability,
or restlessness. Lethargy, anorexia, pyrexia, and prolapse of the third eyelid
may occasionally appear in cats, as well as, in dogs and cats, posterior and
anterior cataracts, tachycardia and electrocardiographic alterations
(prolongated QT interval), polyuria and polydipsia, and, in severe forms,
even cardiorespiratory arrest.
 Canine eclampsia manifests with neurological signs such as ataxia,
tremors, myoclonus, tachypnea and tachycardia, breathlessness, pyrexia,
and seizures without loss of consciousness. In severe forms, death from
cerebral edema and respiratory depression may occur.

Treatment
Once hypocalcemia has been diagnosed, it is important to determine if it is
associated with hypoalbuminemia or hypoproteinemia, as in these cases
calcium should not be administered but hypoalbuminemia corrected. The
concentration of PTH should then be measured to determine if the
imbalance is PTH-dependent (if PTH is present in a normal concentration,
hypocalcemia does not have a hormonal origin; see above).
Once the cause of hypocalcemia has been identified, it should be treated
as early as possible. Blood calcium levels are corrected by administering
10% calcium gluconate as a slow infusion (over 15–20 minutes) at a dose of
0.5–1.5 mL/kg IV, or as a continuous infusion at a dose of 5–15 mg/kg/hour
(Box 4.3). Another therapeutic option is the administration a continuous
infusion of 10% calcium hydrochloride at a dose of 5–15 mg/kg/hour. This
salt should only be administered intravenously because it is irritant and its
extravasation causes perivasculitis.
Administration should be discontinued if bradycardia, QT-interval
shortening, skin necrosis, or mineralization appears. To avoid the side
effects of therapy, it is necessary to perform continuous
electrocardiographic monitoring throughout the treatment and assess the
acid–base and electrolyte balance every 12–24 hours, as well as vital signs
every 8–12 hours.
Oral therapy is preferred in chronic hypocalcemia and consists in the
administration of:
calcium bicarbonate, 25–50 mg/kg/day;
calcium lactate, 25–50 mg/kg/day;
calcium chloride 27.2%, 25–50 mg/kg/day (may cause gastritis);
10% calcium gluconate, 25–50 mg/kg/day (may cause gastritis).

Box 4.3 Treatment of calcium imbalances

Acute hypocalcemia: dog <5.0 mg/dL, cat <4.5 mg/dL

 1) Calcium gluconate 10%: 0.5–1.5 mL/kg IV in slow infusion (over
15–20 min)
2) CRI: calcium gluconate 5–15 mg/kg/hour IV
3) CRI: calcium hydrochloride 10%: 5–15 mg/kg/hour IV
During administration, monitor with ECG.

Acute hypercalcemia: dog ≥6.0 mg/dL, cat ≥5.5 mg/dL

1) Fluid therapy with 0.9% NaCl or Plasma-Lyte with sodium gluconate
2) Furosemide 2 mg/kg IV, SC, orally, every 8–12 hours
3) Dexamethasone 0.1–0.22 mg/kg/12 hours IV, SC
4) Prednisone 1–2.2 mg/kg/12 hours IV, SC, orally
5) Calcitonin 4–6 IU/kg/8–12 hours SC for 24–48 hours
6) Biphosphonate 15 mg/kg/12–24 hours IV, orally

Treatment involves the simultaneous administration of vitamin D in the

form of ergocalciferol (vitamin D2), initially at a dose of 4000–6000 IU/
kg/day for 5–21 days depending on the severity. In the maintenance phase,
1000–2000 IU/kg are administered once a day once a week for 1–18 weeks.
Another option is the administration of calcitriol, initially at a dose of 0.2–
0.3 µg/kg/day for 3–4 days, and then at 0.005–0.015 µg/kg/day for 2–14
days.
The correction is aimed at resolving the clinical signs, without
necessarily achieving a normal calcium concentration so as to avoid a state
of hypercalcemia and hypercalciuria, especially in patients with
hypoparathyroidism.

Hypercalcemia
Hypercalcemia (dog ≥6.0 mg/dL, cat ≥5.5 mg/dL) occurs when the dynamic
balance between osteosynthesis (calcium uptake) and osteolysis (calcium
release) is altered, which causes excessive inhibition of sodium channels by
excess calcium ions. Hypercalcemia also leads to reduced neuromuscular
excitability, tissue irritation with deposition of calcium crystals, and
stimulation of gastric secretory activity and contractile activity of the
vascular muscle cells.
The causes of hypercalcemia are numerous:
 Pseudohypercalcemia due to increased calcium levels secondary to
hyperproteinemia or hyperalbuminemia.
Nonsignificant hypercalcemia, when hypercalcemia is considered normal
in growing subjects or severely dehydrated patients.
Increased PTH production due to primary hyperparathyroidism
(parathyroid neoplasms) or secondary renal hyperparathyroidism.
Malignant neoplasms such as T-cell lymphoma and various types of
carcinomas (e.g., adenocarcinomas of the anal sacs) that stimulate
excessive PTH production, monoclonal gammopathies responsible for an
increase in calcium bound to paraproteins (such as multiple myeloma and
some leukemias), and extensive bone metastases that cause bone lysis.
Increased absorption of intestinal calcium due to an excessive intake
(iatrogenic) or production of vitamin D, intoxications by some
rodenticides and toxic plants, granulomatous diseases, and some
neoplasms.
Reduced renal excretion caused by acute or chronic kidney disease or by
taking thiazide diuretics.
Corticosteroid deficiency due to primary or secondary
hypoadrenocorticism.
Reduction of the proportion of calcium bound to proteins in metabolic
acidosis.
Feline idiopathic hypercalcemia, often associated with calcium oxalate
urolithiasis, is diagnosed when no other cause is identified in this species.
The origin is unknown, and affected cats have a low PTH value or at the
lower limits of the norm [7–10].

Clinical signs
The most common signs of hypercalcemia are polyuria, polydipsia,
anorexia, dehydration, lethargy, nausea, vomiting, and chronic kidney
disease. Less common signs are constipation, arrhythmias, acute renal
failure, calcium oxalate urolithiasis, muscle spasms, and convulsive states
that, in the most severe forms, can lead to death. The rate at which
hypercalcemia develops and its duration determine the severity of the
clinical signs. In dogs, calcium values >15 mg/dL determine the onset of
the first signs and values >20 mg/dL can be lethal.

Treatment
Patients are treated when calcium values are >16 mg/dL, or when values are
lower but neurological or cardiac signs or alterations in renal function
appear.
Once hypercalcemia has been diagnosed, it is necessary to first exclude
all causes of artifacts before proceeding with one of the following
treatments:
Fluid therapy with 0.9% NaCl or another saline isotonic solution that does
not contain calcium, especially if the patient is in metabolic acidosis.
Fluid therapy must correct dehydration, if it is present, and produce a
slight expansion of the circulating volume, so as to facilitate calciuresis. If
fluid therapy is performed with saline, it should be supplemented with
potassium chloride. The infusion rate of the solution should be about
twice that used for maintenance fluids, taking special care not to cause
tissue edema, especially in patients suffering from heart or kidney failure.
In case of metabolic acidosis, sodium bicarbonate may be administered at
a dose of 1 mEq/kg in a slow intravenous infusion.
Administration of diuretics, such as furosemide at a dose of 2 mg/kg IV,
SC, or orally every 8–12 hours, to promote calciuresis. Thiazide diuretics
should not be used, as they involve hypocalciuria and aggravate
hypercalcemia. When administering diuretics, it is essential to avoid
dehydration and hypokalemia.
Administration of glucocorticoids such as dexamethasone at a dose of
0.1–0.22 mg/kg/12 hours IV or SC, or prednisone at a dose of 1–2.2
mg/kg/12 hours IV, SC, or orally. These steroids have a dual action: they
reduce bone resorption and calcium absorption in the intestine and
increase its renal excretion. In addition, they help to treat the primary
cause, such as lymphoma in cats, feline idiopathic hypercalcemia, anal sac
adenocarcinoma, multiple myeloma, hypoadrenocorticism,
hypervitaminosis D, and granulomatous pathologies.
Administration of calcitonin at a dose of 4–6 IU/kg/8–12 hours SC for
24–48 hours. Hypervitaminosis D reduces the activity and formation of
osteoclasts and the level of total calcium. Note that calcitonin can cause
anorexia and vomiting and is very expensive.
Administration of bisphosphonates (e.g., etidronate, pamidronate,
clodronate) at a dose of 15 mg/kg/12–24 hours to reduce the activity of
osteoclasts, by inducing their apoptosis. They are also used to inhibit bone
 calcium resorption in the management of feline idiopathic hypercalcemia
(see Box 4.3).

Phosphorus
Phosphorus is an essential mineral for bones, in which it is present in the
form of hydroxyapatite. It is also contained in cells as a constituent of
cAMP (cyclic adenosine monophosphate), ATP (adenosine triphosphate),
NADP (nicotinamide adenine dinucleotide phosphate), phospholipids, and
phosphoproteins (e.g., muscle phosphocreatine). A proportion of
phosphorus is found in plasma as inorganic phosphate, as lipid phosphorus,
and as an organic ester. Circulating phosphorus is measured by determining
its inorganic form.
Most phosphorus (about 65–70%) is absorbed in the intestines, more
particularly in the small intestine (duodenum and ileum) and to a lesser
extent in the colon. The intestinal absorption process can be active, through
a sodium-dependent cotransporter, or passive, by electrochemical gradient.
The factors regulating the intestinal absorption of phosphorus are vitamin
D, which enhances cotransporter function in the duodenum, and food
deficiency, which activates renal hydroxylation of vitamin D to increase
phosphorus absorption. Excessive oral doses of calcium cause a
precipitation of phosphorus in the intestine. The remaining part is
reabsorbed by the convoluted renal tubule, mainly the proximal convoluted
tubule, thanks to the presence of a sodium-dependent active transport
system. Factors that reduce tubular phosphorus absorption are the secretion
of excessive amounts of PTH; a high amount of calcitonin, which increases
renal excretion by increasing the filtered load; glucocorticoid intake, which
hinders the sodium-dependent transport system by activating
phosphorylation processes; and respiratory acidosis. The causes of an
increase in the tubular absorption of phosphorus are the administration of
insulin, which increases cellular phosphorus uptake for energy purposes and
thus leads to a reduction in its urinary excretion; the administration of
thyroid hormones, which are responsible for phosphorus retention; and
respiratory alkalosis, which stimulates cellular phosphorus uptake due to
hyperactivity of the respiratory muscles.
Hyperphosphatemia
Hyperphosphatemia (dog >7.4 mg/dL, cat >7.6 mg/dL) can be distinguished
into significant and nonsignificant hyperphosphatemia. Insignificant
increases in phosphorus can be due to analytical errors, i.e., the use of
hyperlipidemic or hemolytic samples, and is a common finding in growing
patients, in whom it is linked to the physiological processes of bone
remodeling.
Significant increases in phosphorus, on the other hand, are due to several
causes, which can be divided into the following categories:
Maldistribution of phosphorus: lysis of cancer cells, rhabdomyolysis,
tissue trauma, hemolysis and metabolic acidosis.
Increased intestinal absorption: diets rich in phosphorus (in dogs), intake
of laxatives containing phosphates, and hypervitaminosis D. The latter
condition can be caused by excessive iatrogenic supplementation of
vitamin D, intoxication with plants containing vitamin D, and poisoning
with certain rodenticides.
Reduced renal excretion of phosphorus: acute and chronic kidney disease,
urethral obstruction, uroabdomen, hypoparathyroidism, and
hyperthyroidism.

Clinical signs
Hyperphosphatemia causes hypocalcemia, which is responsible for the
typical signs of reduced calcium concentration (e.g., muscle weakness,
tetany, nausea, vomiting, arrhythmias; for more details see Hypocalcemia).

Treatment
Once hyperphosphatemia has been diagnosed, it is necessary to determine
whether it is an increase due to analytical errors or a consequence of the
conditions mentioned above. The patient’s hydration status should then be
assessed. In dehydrated patients, simple rehydration with an isotonic saline
solution (e.g., 0.9% NaCl or Ringer’s lactate) may be sufficient to reduce
phosphorus through increased renal excretion. Therapy should also control
intestinal absorption; the amount of phosphorus in the diet should be
reduced by administering low-protein diets (low-protein foods are also low
in phosphorus). In patients with acute or chronic kidney disease,
phosphorus-chelating substances, such as aluminum hydroxide or
aluminum carbonate, are administered to reduce intestinal absorption. The
most widely used is aluminum hydroxide at a dose of 30 mg/kg/8 hours
orally with meals, until phosphoremia is normalized. To correct
hyperphosphatemia, it should not be forgotten that the most effective
treatment is always to treat the cause (Box 4.4).

Hypophosphatemia
Hypophosphatemia is a pathological condition associated with reduced
intestinal absorption of phosphorus due to anorexia, diets low in meat,
intake of phosphorus binders such as aluminum hydroxide, malabsorption,
or hypovitaminosis D, and with reduced renal reabsorption of phosphorus
due to primary hyperparathyroidism, eclampsia, hyperadrenocorticism, or
disorders of the proximal renal tubule (e.g., Fanconi syndrome).

Box 4.4 Treatment of phosphorus imbalances

Hyperphosphatemia: dog >7.4 mg/dL, cat >7.6 mg/dL

Rehydration with 0.9% NaCl or Ringer’s lactate solution.
Low-protein diet.
Aluminum hydroxide, 30 mg/kg/8 hours orally.

Hypophosphatemia: 1.0-2.0 mg/dL

Potassium phosphate: 0.01–0.03 mmol/kg/hour IV in 0.9% NaCl or 5%
glucose solution for 6 hours. Severe hypophosphatemia (<1 mg/dL):
phosphate 0.03–0.12 mmol/kg/hour IV in 0.9% NaCl or 5% glucose
solution.
Typically, 2 hours of infusion every 6 hours is sufficient. Infuse up to 2
mg/dL blood. Usually, 2–4 treatments are enough.
Dilute phosphate in calcium-free solutions.

Clinical signs
Hypophosphatemia leads to several alterations of blood cells, in particular
erythrocytes, which may become more fragile due to a reduction in the
concentration of ATP. This phenomenon may be responsible for
intravascular hemolysis, especially when phosphorus is equal to or less than
1 mg/dL. Hypophosphatemia, in erythrocytes, is responsible for a reduction
in the concentration of the enzyme 2,3-DPG, which decreases the ability of
these cells to transport oxygen, resulting in poorer tissue oxygenation.
Other consequences are thrombocytopenia and a reduction in chemotaxis
and phagocytosis by leukocytes, with a greater predisposition to sepsis in
patients at risk. Patients may show muscle weakness and pain associated
with rhabdomyolysis, anorexia and vomiting secondary to paralytic ileus,
and central nervous system disorders (e.g., irritability, confusional states
and, in severe forms, coma).

Treatment
Only symptomatic patients are treated; treatment consists in the oral or
parenteral administration of phosphorus. The oral route, using multivitamin
and mineral preparations, is to be preferred over the parenteral route, as the
intravenous administration of sodium phosphate or potassium phosphate
(KH2PO4) can produce hyperphosphatemia with consequent hypocalcemia,
renal failure, tetany, and mineralization phenomena. Potassium and sodium
phosphate solutions contain 3 mmol of phosphate per milliliter and 4.4 mEq
of potassium or 4 mEq of sodium per milliliter. The initial dose of
phosphate is 0.01–0.03 mmol/kg/hour IV for 6 hours diluted in calcium-free
solutions (e.g., NaCl 0.9% or 5% glucose). In dogs and cats with severe
hypophosphatemia, it may be necessary to increase the dosage from 0.03 to
0.12 mmol/kg/hour. Initially, it is important to monitor the serum phosphate
concentration every 8–12 hours to correct supplementation. If the typical
clinical signs of hypocalcemia appear during treatment, the rate of
phosphate infusion should be decreased and ionized calcium, in addition to
phosphorus, should also be monitored.

Chloride
Chloride is the main anion in the extracellular fluid and is essential in
maintaining osmolarity and the acid–base balance. The normal serum
chloride concentration is about 110–115 mEq/L in dogs and about 120–125
mEq/L in cats. The mechanisms of regulation of chloremia are closely
linked to those of sodium, since much of the circulating chloride
contributes, with bicarbonates, to maintaining electrolyte neutrality. It is
therefore necessary to determine not only the patient’s natremia but also
their acid–base status to correctly interpret alterations in chloremia.
Alterations in chloremia accompanied by alterations in natremia in the
same direction are caused by water balance problems (e.g., severe
dehydration).
Alterations in chloremia that are not associated with equivalent changes
in natremia are usually caused by acid–base imbalances. Chloride ions are
constantly excreted in large amounts with gastric juices, and most of them
are reabsorbed by the intestine. Chloride ions are filtered by concentration
gradient across the glomeruli and reabsorbed by an active transport system
in the ascending limb of the loop of Henle and in the distal portion of the
proximal tubule of the nephron.

Hyperchloremia
Hyperchloremia may be due to preanalytical errors, such as dehydrated
samples or samples from patients receiving potassium bromide.
Hyperchloremia is significant when associated with hypernatremia. In
these cases, it can be produced by ECF imbalances, such as dehydration, or
result from an increased intake or iatrogenic retention of chloride due to the
administration of solutions containing high concentrations of NaCl, salt
poisoning, hyperadrenocorticism, chronic respiratory alkalosis, renal
failure, or diuretics (acetazolamide).
Iatrogenic hyperchloremia may be due to parenteral nutrition or to the
administration of 0.9% NaCl and hypertonic solutions, potassium, or
magnesium chloride. When associated with normo- or hyponatremia, it can
be caused by acid–base imbalances (e.g., metabolic acidosis).
Hypochloremia can be caused by diarrhea, vomiting, renal loss of
bicarbonate at the level of the proximal tubule, reduced renal excretion of
H+ and chloride through the distal tubule, and chronic respiratory alkalosis.
In the latter case, the kidney adapts to this chronic condition by increasing
bicarbonate excretion and consequently reducing chloride excretion.

Clinical signs
Clinical signs of hyperchloremia are not pathognomonic. Some of them are
attributable to the causes of metabolic acidosis.

Treatment
In cases of hyperchloremia it is necessary to determine the sodium-
corrected chloride concentration, as shown in the following formula:

[Cl–]p, patient’s blood chloride concentration; [Na+]n, normal blood sodium concentration; [Na+]p,
patient’s blood sodium concentration.
The normal value of [Na+] in dogs is 145 mEq/L, in cats it is 155 mEq/L.

If the corrected chloride value is normal, the patient should be

rehydrated with intravenous fluids. If, however, the corrected chloride
concentration is altered, metabolic acidosis must first be corrected by
administering fluids (e.g., replenishment solution with sodium gluconate or
Ringer’s acetate) and, if necessary, sodium bicarbonate. The underlying
cause that produced the acid–base disorder should also be treated for this
electrolyte imbalance.

Hypochloremia
Hypochloremia is called pseudohypochloremia when the sample is severely
lipemic or hyperproteinemic. True hypochloremia, on the other hand, can
be associated with hyponatremia (the corrected chloride value is normal)
and due to:
loss of Cl– and Na+ of renal, gastroenteric (e.g., vomiting) or cutaneous
origin;
sequestration of chloride and sodium in uroperitoneum and ascites;
water retention in the course of congestive heart disease, cirrhotic liver
disease, nephrotic syndrome and syndrome of inappropriate secretion of
ADH (false hypochloremia);
diuretics;
transfer of water from ICF to ECF (e.g., in diabetes mellitus)
chronic respiratory acidosis;
hyperadrenocorticism.
 Box 4.5 Treatment of chloride imbalances

Hyperchloremia
Corrected Cl– = [Cl–]p × [Na+]n/[Na+]p
If the corrected chloride concentration is normal, rehydrate the patient
Correct acidosis with solutions with a high SID (e.g., Plasma-Lyte with
sodium gluconate)

Hypochloremia
Rehydratation with chloride-containing solutions (e.g., 0.9% NaCl or
0.45% solution)
If the patient should not be administered more sodium, then potassium
chloride, ammonium chloride, calcium chloride, or magnesium chloride
can be used.

True hypochloremia may also be associated with normo- or hypernatremia

(the corrected chloride value is decreased). This condition can be caused by
metabolic alkalosis, since a reduction in chloride ions is associated with an
increase in bicarbonate; by gastric torsion (gastric sequestration of HCl);
and by administration of loop diuretics. True hypochloremia also occurs
during metabolic acidosis (e.g., ketoacidosis, lactic acidosis, and ethylene
glycol poisoning), since a reduction in chloremia is associated with a
reduction in the concentration of bicarbonate. Chronic respiratory acidosis,
which is responsible for a chronic increase in carbon dioxide, can induce
hypochloremia by renal compensation of the respiratory acid–base
imbalance (increased HCl secretion and HCO3– recovery).

Treatment
Treatment of hypochloremia involves correcting dehydration and the acid–
base imbalance by providing fluid therapy appropriate to the patient’s
needs; it is therefore recommended to assess the patient’s acid–base and
electrolyte status prior to administering fluids. The underlying cause of
hypochloremia must also be treated at the same time (Box 4.5).
Magnesium
Magnesium has received little attention in veterinary medicine and only
several studies conducted in dogs and cats since 1970 have shown the
importance of this electrolyte in maintaining homeostasis and for cardiac
and neuromuscular activity. The normal serum magnesium concentration in
dogs is about 1.9–2.5 mg/dL. The exact distribution of magnesium in the
body of animals is not yet fully understood; in humans, 99% of magnesium
is found inside the cells and only 1% in the extracellular fluid.
Approximately 67% is distributed in the bones, along with calcium and
phosphorus, 20% in muscle tissue and 11% in other tissues. The remaining
1% in the extracellular fluid can be found in free form (55%), bound to
proteins (20 to 30%), and in complex form (15 to 25%). The percentage of
magnesium bound to proteins (especially albumins) is lower than that of
calcium bound to proteins, so the concentration of magnesium is not very
conditioned by changes in serum protein concentration. Most of the
magnesium from the diet is absorbed by the ileum and a small part by the
jejunum and colon. Magnesium is transported across the intestine by two
mechanisms: a passive paracellular route and an active transcellular route.
These different types of transport are also present in the kidney and their
regulation depends on the concentration of calcium and some hormones,
such as the parathyroid hormone. The kidney therefore plays a fundamental
role in controlling and regulating the concentration of magnesium.
Approximately about 10–15% of magnesium is filtered in the proximal
tubule through passive transport, but this mechanism is not yet fully known;
most magnesium (60–70%) is reabsorbed in the loop of Henle.
Reabsorption is influenced by several factors: the positively charged
luminal environment, which depends on the movements of sodium and
chloride from the lumen to the interstitial space; sodium and water
movements; the presence of special cation detection receptors (CASR,
calcium-sensing receptors); and some hormones such as the parathyroid
hormone, calcitonin, glucagon, antidiuretic hormone, aldosterone and
insulin. These hormones promote the absorption of magnesium. Conversely,
conditions of hypokalemia, hypophosphatemia, and metabolic acidosis
reduce its absorption. As for the excretion of magnesium through urine, a
fundamental role is played by the distal convoluted tubule, although the
mechanisms by which it occurs are not fully understood. It seems that
several hormones (see above), in certain conditions such as those mentioned
above, and the presence of CASR and proteins such as TRMP6 and TRMP7
are responsible for the regulation of magnesium at the level of the distal
convoluted tubule.

Hypomagnesemia

Etiology
The causes of hypomagnesemia are numerous and can be classified into
three categories:
gastrointestinal pathologies: chronic diarrhea, malnutrition, malabsorption
syndrome, short bowel syndrome, intestinal neoplasm;
renal pathologies: acute or chronic kidney disease, urethral obstruction,
hyperaldosteronism and hyperthyroidism (which cause an increase in
diuresis), renal tubular acidosis, and treatment with diuretics;
various disorders: hyperglycemia, electrolytes disorders (hypokalemia,
hypercalcemia, hyperparathyroidism, hypophosphatemia), diabetes
mellitus, medications (e.g., gentamicin, cyclosporine, cisplatin),
myocardial infarction, acute pancreatitis, excess catecholamines,
excessive loss with lactation (especially in farm animals).

Diagnosis
The diagnosis of hypomagnesemia is complex since most of the magnesium
is contained within the cells (99%). Its measurement may therefore not be
reliable, as the measurement of its ion (Mg2+) does not evaluate the total
amount of magnesium present in the body. Its deficiency is often
hypothesized based on the clinical presentation and the appearance of
specific signs.

Clinical signs
Magnesium is fundamental in neuromuscular transmission and its
deficiency leads to the appearance of muscle tetany and mental confusion
(these clinical signs are rare in small animals, but more frequent in farm
animals). It plays an important role in the contraction and excitability of
striated muscles and in the contraction and conduction of the heart muscle.
 This electrolyte is also fundamental in regulating the calcium
concentration in muscle cells and the displacement of sodium and calcium
within myocytes, as well as in regulating the concentration of potassium
outside these cells. A magnesium deficiency can cause atrial fibrillation,
supraventricular tachycardia, ventricular tachycardia, ventricular ectopic
beats, and arrhythmias. Magnesium is also important for calcium regulation
in the smooth muscles of the peripheral vascular system and its deficiency
leads to vasoconstriction and, therefore, hypertension. Recent studies have
shown the importance of magnesium in the production of inflammatory
cytokines, such as tissue necrosis factor and interleukin 1. Typically,
hypomagnesemia is associated with other electrolyte imbalances. The most
frequent are hypokalemia and hypophosphatemia, with the characteristic
clinical signs (see Hypokalemia and Hypophosphatemia). Refractory
hypokalemia may be associated with hypomagnesemia; for this reason, in
severe or non-treatment-responsive hypokalemia, magnesium measurement
or supplementation during therapy is recommended.

Treatment
An adequate diet with specific dog or cat food is enough to prevent and
treat states of hypomagnesemia. If magnesium deficiency is caused by
gastrointestinal or kidney disease or the other conditions mentioned above,
the causes should be treated. The administration of magnesium in the form
of magnesium sulfate or chloride, in dogs and cats, is empirical and no
reliable data about this treatment are available. A possible therapy is the
intravenous administration of magnesium sulfate or chloride at a dose of
0.2–0.3 mEq/kg and a rate of 0.12 mEq/kg/min, in 5% glucose solution for
24–48 hours. In severe forms of hypomagnesemia, 0.2–1.0 mEq/kg/day
may be administered. During magnesium administration, the patient may
experience vomiting, diarrhea, respiratory depression, weakness,
hypotension, and cardiovascular collapse. Some electrolyte solutions
contain magnesium; for example, Plasma-Lyte contains 3 mEq in 500 mL
(see Table 3.1 in Chapter 3). Oral supplementation can be done with 1–2
mEq/kg/day (Box 4.6).

Hypermagnesemia
States of hypermagnesemia are rare in veterinary medicine and very few
studies are available about this imbalance. Two significant studies have
been conducted so far. In the first one, 11 cats treated with
methylprednisolone acetate following dermatitis experienced an increase in
magnesium after 3–6 days, but it was not considered clinically significant
[11]. In the other study, 50 small dogs with mitral valve insufficiency were
treated with spironolactone and an angiotensin inhibitor, and an increase in
magnesium levels was observed after 20 days, but again this was not
considered clinically significant [12]. Forms with severe clinical signs, such
as arrhythmias, unconsciousness, respiratory depression, and risk of death,
can be treated with 10% calcium gluconate at a dose of 0.5–1.5 mg/kg IV in
a slow infusion (over 10–15 minutes), as calcium gluconate acts as an
antagonist at the neuromuscular junction, or with physostigmine at a dose
of 0.02 mg/kg/12 hours IV (see Box 4.6).

Box 4.6 Treatment of magnesium imbalances

Hypomagnesemia: <1.5 mg/dL

Magnesium sulfate or chloride 0.2–0.3 mEq/kg, at 0.12 mEq/kg/min,
diluted up to <20% in 0.9% NaCl or 5%glucose.
Do not use solutions containing lactate and calcium bicarbonate.
Severe hypomagnesemia: 0.2–1.0 mEq/kg/day.
Oral supplementation: 1–2 mEq/kg/day.

Hypermagnesemia
Symptomatic therapy.
Severe: 10% calcium gluconate 0.5–1.5 mg/kg IV in slow infusion or
physostigmine 0.02 mg/kg/12 hours IV.

References
[1] DiBartola SP. Fluid, Electrolyte, and Acid-Base Disorders in Small Animal Practice, 4th ed. St.
Louis: Elsevier Saunders; 2012.
[2] Brofman PJ, Knostman KA, DiBartola SP. Granulomatous amebic meningoencephalitis
causing the syndrome of inappropriate secretion of antidiuretic hormone in a dog. J Vet Intern
Med. 2003;17(2):230–234.
[3] Moritz ML, Ayus JC. Hospital-acquired hyponatremia: why are hypotonic parenteral fluids still
being used? Nat Clin Pract Nephrol. 2007;3(7):374–382.
[4] Peterson ME, Kintzer PP, Kass PH. Pretreatment clinical and laboratory findings in dogs with
hypoadrenocorticism: 225 cases (1979-1993). J Am Vet Med Assoc. 1996;208(1):85–91.
[5] O’Brien DP, Kroll RA, Johnson GC et al. Myelinolysis after correction of hyponatremia in two
dogs. J Vet Intern Med. 1994;8(1):40–48.
[6] Lind L, Carlstedt F, Rastad J et al. Hypocalcemia and parathyroid hormone secretion in
critically ill patients. Crit Care Med. 2000;28(1):93–99.
[7] [Paltrinieri S, Bertazzolo W, Giordano A. Clinical Pathology of Dogs and Cats: Practical
Approach to Laboratory Diagnostics. Milan: Elsevier; 2010.
[8] Harvey A, Tasker S. BSAVA. Manuale di Medicina Felina. Milan: Edra; 2014.
[9] Viganò F. Manuale di pronto soccorso nel cane e nel gatto. Milan: Edra; 2013.
[10] Thompson MS. Small Animal Medical Differential Diagnosis, 2nd ed. St. Louis: Elsevier
Saunders; 2014.
[11] Sharkey LC, Ployngam T, Tobias AH et al. Effects of a single injection of methylprednisolone
acetate on serum biochemical parameters in 11 cats. Vet Clin Pathol. 2007;36:184.
[12] Thomason JD, Rockwell JE, Fallaw TK et al. Influence of combined angiotensin-converting
enzyme inhibitors and spironolactone on serum K+, Mg2+, and Na+ concentration in small dog
with degenerative mitral valve disease. J Vet Cardiol. 2007;9(2):103–108.
Clinical Case

Electrolyte and acid–base

imbalances during vomiting

History
The patient was brought to the clinic because he had not been eating
since the previous day and had experienced about 10 episodes of
vomiting per day for the previous 2 days. His last stools (the previous
day) were normal in consistency, but mucus was present on their surface.
At triage, the patient’s following vital parameters were as follows:
heart rate: 150 bpm;
respiratory rate: 23 bpm;
full pulse;
rectal temperature: 38.1 °C;
 mucous membranes: pink, CRT 1.5 seconds;
blood pressure: 145/113 mmHg; MAP: 124 mmHg;
10% dehydration.

Laboratory tests
A blood gas analysis was performed because the patient had vomited
numerous times and, given its young age, he was at risk of severe
electrolyte and acid–base imbalances. In these cases, a blood gas analysis
is useful to provide fluids that meet the patient’s requirements and can
correct any electrolyte and acid–base or disorders. A blood count was
performed to check for any hematological alterations, especially in the
hematocrit and leukocytes. A biochemistry profile was also used to detect
possible dysfunctions in the organs related to the digestive system and to
identify, with the nontraditional approach to acid–base balance, any other
potential metabolic components.

Venous blood gas analysis

Given that there was no problem with the respiratory system, a venous
blood sample was taken, since the values obtained with this type of blood
sample are reliable with regard to pH, bicarbonate and carbon dioxide
levels, and, more especially in this case, electrolytes. The first blood gas
analysis yielded the following results:
pH 7.65;
pvCO2 55;
HCO3– 45;
BE +35;
Na+ 125 mmol/L;
Cl– 84 mmol/L;
K+ 2.4 mmol/L;
lactate 4.8 mmol/L;
AG 2.4;
FiO2 0.21.

Biochemistry profile
BUN 45 mg/dL, creatinine 0.8 mg/dL, ALT 12 U/L, AST 27 U/L, total
proteins 8.1 g/dL, albumin 3.5 g/dL, Bilirubin Tot 0.1 mg/dL, GGT 9
U/L, blood glucose 112 mg/100 mL, phosphorus 3.1 mg/dL.

Blood count
RBC 4.5 × 1012/L, WBC 12.1 × 109/L, Hct 65%, Hb 22 g/dL, PLT 439 ×
109/L, neutrophils 10 × 103/µL.

Interpretation of laboratory tests

The traditional approach to blood gas analysis highlighted a severe
metabolic alkalosis because bicarbonate was significantly increased (45)
and carbon dioxide was increased (respiratory acidosis) as a result of
compensation. It was therefore a case of simple metabolic alkalosis with
respiratory compensation, but with severe sodium, chloride and
potassium imbalances. Lactic acidosis was also present, which was
unlikely to be of circulatory origin, as the hemodynamic parameters
detected did not point to a circulatory failure, but rather to a gastric wall
lesion. According to the nontraditional approach, severe metabolic
alkalosis and SID reduction alkalosis (-8 nmol/L) were present. There
was a noticeable increase in unmeasured cations. In this case, there was
no reason to suspect an increase in sulfates, so increases in calcium and
magnesium or the presence of paraproteinemia were suspected. The Atot
did not compensate for alkalosis like respiratory acidosis.
Severe hyponatremia and hypochloremia were present and needed to be
treated. The biochemistry profile highlighted an increase in proteinemia
due to dehydration.
The blood count showed an increased hematocrit, probably due to
dehydration.
The calculation of blood osmolarity was therefore carried out as follows:

Osm = 2 × [Na+] + glucose (mg/dL)/18 + BUN (mg/dL)/2.8

Osm = (2 × 125) + (112/18) + (45/2.8)

Osm = 272 mOsm/L

Osmolarity was lower than normal as a result of severe hyponatremia.

Diagnostic investigations
An X-ray of the abdomen was taken and revealed the presence of gastric
foreign bodies of an unidentified nature.

Daily fluid therapy

Since the hemodynamic parameters were normal and there were no signs
of hypovolemic shock, it was decided to provide maintenance fluid
therapy, to which a volume of fluids corresponding to the percentage of
dehydration (10%) was added.
Maintenance fluid therapy: 2 mL/kg/hour IV, which corresponds to 10
mL/hour.
Rehydration: 10% of 5 kg corresponds to 500 mL which, divided by 24
hours, corresponds to about 21 mL/hour IV.
So, the total amount of fluids to be infused per hour for at least 24 hours
was 31 mL/hour IV.
In this case, since there was dehydration with severe hyponatremia, the
volume of solution to be infused was calculated based on the measured
sodium concentration. It was decided to infuse 0.9% NaCl to quickly
restore both sodium and chloride losses. The calculation was made using
the following equation:

(140 – [Na+]p) × kg × 0.3 = Na+ deficit

 (140 – 125) × 5 × 0.3 = 22.5 mEq/L (patient’s sodium deficit)
The sodium deficit was then divided by the sodium concentration of the
solution used. In this case, 0.9% NaCl solution contains 154 mEq/L of
sodium, so the volume in liters to be administered was calculated with
the following formula:

Na+ deficit/[Na+] of the solution = volume in liters of solution to be

administered

22.5/154 = 0.15 L
To calculate the duration of administration, the following formula can be
used:

(140 – [Na+]p)/0.5 = number of hours of fluid therapy

(140 – 125)/0.5 = 30 hours

The initial administration rate calculated for the first 24 hours (31
mL/hour) meant that 744 mL of fluids would be administered in 24
hours, so it was decided to slow down the rate of administration to about
half (15 mL/hour) of what had initially been calculated and then to repeat
the blood gas analysis to monitor the correction obtained. The calculated
volume of fluids was enough to restore sodium losses. It was decided not
to further reduce the infusion rate due to the patient’s severe dehydration.
NaCl 0.9% solution is preferable to restore sodium and, because it has a
zero SID and contains large amounts of chloride, it is also useful for
correcting metabolic alkalosis. Potassium must be added to the solution
using the table for its replenishment (see Table 4.1), which indicates 30
mEq/L of potassium chloride in 500 mL of isotonic saline solution. To
correctly infuse the solution, it is necessary to use an infusion pump; the
acid–base status should be monitored at least after 24 hours and the
patient’s weight should be monitored twice a day.
After 24 hours, the venous blood gas analysis was repeated and revealed
the following results:
pH 7.42;
pvCO2 42;
 HCO3– 28;
BE +2;
Na+ 135 mmol/L;
Cl– 110 mmol/L;
K+ 3.5 mmol/L;
lactate 2.0 mmol/L;
AG 0.5;
FiO2 0.21.

The patient underwent a gastroscopy, which enabled the removal of three

ingested plastic foreign bodies (see figure below). On the second day,
dehydration was reduced to about 8%, so the rate of fluid therapy was
reduced according to the following calculation:
Maintenance fluid therapy: 2 mL/kg/hour IV, which corresponds to 10
mL/hour.
Rehydration: 8% of 5 kg corresponds to 400 mL which, divided by 24
hours, corresponds to about 17 mL/hour IV. The administration rate was
therefore kept at 15 mL/hour on day 2. On day 3, the patient received
only maintenance fluid therapy at 10 mL/hour IV.
The dog was discharged on day 3, once hydration had been restored and
he had resumed feeding and drinking spontaneously.
Home supportive care involved a proton pump inhibitor for about 7 days
(pantoprazole 1 mg/kg every 12 hours orally) and an intestinal adsorbent
(diosmectite 1 g every 8 hours orally for 7 days) to facilitate healing of
the necrotic ulcerative lesions found during the gastroscopy.
Hemorrhagic Shock
 CHAPTER
5

Brett Montague, Deborah C. Silverstein

Introduction
Shock is the pathophysiologic state caused by inadequate energy production
at the cellular level. Cardiovascular compromise can lead to shock by
interrupting delivery of oxygen and nutrients to tissues. Major etiologies of
cardiovascular compromise include failure to effectively pump blood into
the arterial circuit (cardiogenic shock, e.g., dilated cardiomyopathy);
maldistribution of blood, as seen in vasodilatory states such as sepsis or
anaphylaxis (distributive shock) or with excessive vasoconstriction (e.g.,
due to endogenous or exogenous epinephrine); and a loss of intravascular
circulating volume (hypovolemic shock). Other metabolic causes for
inadequate energy production and shock include hypoglycemia, defects of
hemoglobin, mitochondrial dysfunction (cytopathic shock), and hypoxemia
(hypoxic shock).
Hemorrhagic shock is a form of hypovolemic shock characterized by
acute external or internal blood loss that rapidly leads to hemodynamic
instability, decreased tissue perfusion, cellular hypoxia, coagulopathy, end-
organ damage, and potentially to death [1]. Regardless of whether these
patients present in early compensatory stages or in a life-threatening state,
an understanding of the pathophysiology involved in hemorrhagic shock is
critical to their rapid triage, diagnosis, treatment, and survival.

Pathophysiology of hemorrhagic shock

Acute blood loss leads to a rapid decline in effective circulating volume
(ECV) and arterial blood pressure, which triggers a series of compensatory
cardiovascular responses to maintain blood pressure and cardiac output.
Understanding these compensatory mechanisms can help the clinician
assess a patient’s clinical presentation and guide appropriate therapies in
patients with suspected or confirmed hemorrhage. The phases of
compensatory mechanisms can be broken down into compensatory shock,
early decompensatory shock, and late decompensatory shock.

Compensatory shock
Immediately following a loss in blood volume, venous return to the heart
decreases, leading to a decrease in right atrial pressure. According to the
Frank–Starling mechanism, the force generated by contraction of the
ventricular myocardium is directly related to the stretch of the sarcomeres
induced by the volume of venous return. Therefore, when venous return
decreases, there is a decrease in cardiac output, which leads to a decrease in
mean arterial pressure (MAP) [3]. This decrease in MAP is sensed by
baroreceptors located in the carotid bodies and the aortic arch. In health,
these baroreceptors respond to a normal or high blood pressure by
maintaining physiologic levels of sympathetic and parasympathetic tone
(Figure 5.1). A decrease in blood pressure following hemorrhage leads to a
disinhibition of afferent signaling to the vasomotor center of the medulla,
which triggers an increase in sympathetic tone (via endogenous
catecholamine release), a decrease in parasympathetic tone, and an increase
in vasopressin release. These autonomic changes result in an increase in
heart rate, ventricular contractility, and systemic vascular resistance (SVR).
The physiologic goals of these changes are to increase MAP, venous return,
and cardiac output despite volume loss to maintain perfusion to the vital
organs.
The decrease in cardiac output also stimulates the renin–angiotensin–
aldosterone system (RAAS) in order to increase the intravascular volume.
Initial renin release is triggered by an increase in sympathetic tone elicited
by the baroreceptor reflex in response to low MAP in the carotid bodies and
the afferent arterioles of the renal vasculature. Renin is released from the
renal juxtaglomerular cells, leading to an increased production of
angiotensin I, which is rapidly converted into angiotensin II by the
angiotensin-converting enzyme found mostly in the pulmonary
endothelium. Angiotensin II causes arteriolar vasoconstriction, which
further increases SVR. It also stimulates the release of aldosterone, thus
leading to increased sodium reabsorption in the distal convoluted tubules of
the nephron. Water follows this reabsorption of sodium into the kidney,
which results in an increase in intravascular volume and a more
concentrated urine.
Vasopressin, released from the hypothalamus via the baroreceptor reflex,
leads to peripheral arteriolar constriction by stimulation of V1 receptors,
which increases SVR. Stimulation of V2 receptors in the collecting ducts of
the nephron causes increased water reabsorption, thereby increasing the
intravascular volume.
During hemorrhage, chemoreceptors in the carotid bodies sense
hypoxemia, hypercarbia, and a low pH; this also stimulates sympathetic
outflow and vasopressin release, augmenting the baroreceptor reflex. These
chemoreceptors stimulate the central respiratory center to increase
ventilation in an attempt to increase oxygenation, eliminate carbon dioxide,
and maintain an electroneutral acid–base status.
Following acute blood loss, intravascular hydrostatic pressure decreases.
This change in Starling’s forces leads to reabsorption of fluid from the
interstitial and intracellular spaces. Alterations in oncotic pressure further
lead to autodilution by shifting of fluid from the subglycocalyx
compartment into circulation (see Chapter 1). The shifting caused by
Starling’s forces can restore plasma volume to 50% of the original volume
and MAP to 75% of its original level [4].
These initial reflexes occur within minutes following acute loss of
intravascular volume and can result in a normalization of MAP and
maintenance of celullar metabolic homeostasis with mild or moderate blood
loss. These compensatory mechanisms also explain the initial physical
examination findings seen in patients with hemorrhagic shock: tachycardia
(from increased sympathetic tone), pale mucous membranes, prolonged
capillary refill time, poor pulse quality, cool extremities (due to
vasoconstriction), and tachypnea (due to hypoxemia and compensation of
metabolic acidosis).
Cats in hypovolemic shock may present with bradycardia, likely
secondary to marked hypothermia that may improve as the patient is
warmed and resuscitated. The complete mechanism behind bradycardia in
cats with hemorrhagic shock is not fully understood but does not carry as
poor a prognosis as it does in dogs [5].

Early decompensatory shock

Decompensatory shock occurs when tissue perfusion and oxygen delivery
are not normalized, or hemorrhage is too great for compensatory
mechanisms to maintain MAP and adequate tissue perfusion. Moderate
normotensive hemorrhage has been documented in experimental dogs with
an acute loss of 30% of blood volume. Following removal of more than
30% of blood volume, sympathetic outflow is inhibited and MAP decreases
[4]. In the early stages of decompensatory shock, the patient can be
successfully resuscitated if this is done quickly, thus minimizing end-organ
damage. Bradycardia in dogs with hemorrhage-induced hypotension is
characteristic of decompensatory shock. These two variables are
independent of each other in these patients as treatment of the bradycardia
with anticholinergic stimulation does not lead to an improvement of blood
pressure or cardiac output. Peripheral pulses may also no longer be
palpable, mentation often worsens, and the patient may hyperventilate.

Late decompensatory shock

Late decompensatory shock occurs when a patient in decompensatory shock
continues to progress or the hemorrhage is uncontrolled. During this phase,
there is evidence of systemic vasodilation, decreased right atrial pressure,
poor myocardial contractility, and widespread cellular dysfunction. Once
late decompensatory shock is reached, cardiac output may not improve even
with complete volume resuscitation. Loss of >35—45% of total blood
volume will lead to a complete lack of cardiac output and is rapidly fatal
[4].
Figure 5.1 Algorithm of the compensatory mechanisms in patients with hemorrhagic shock. ECV,
effective circulating volume; MAP, mean arterial pressure; PaO2, partial pressure of oxygen in
arterial blood; HR, heart rate; SVR, systemic vascular resistance; PaCO2, partial pressure of carbon
dioxide in arterial blood; CO, cardiac output.

Metabolic sequelae of hemorrhagic shock

Hypovolemia and decreased cardiac output will eventually lead to a
decrease in oxygen delivery to tissues with resultant end-organ damage.
The brain, heart, and gastrointestinal tract, in particular, are prone to
hypoxic damage [6,7]. Cellular hypoxia leads to a transition from aerobic to
anaerobic metabolism within the mitochondria (Figure 5.2). Through this
process, glycolysis is the only source of cellular energy production, but it is
an inefficient process that forms only two molecules of adenosine
triphosphate (ATP) per molecule of glucose, compared to the 38 ATP
molecules produced per molecule of glucose in aerobic conditions. The
end-product of glycolysis, pyruvate, cannot enter the cell in the absence of
oxygen, and begins to accumulate before conversion to lactate via lactate
dehydrogenase. Hydrogen ions are also produced through this process,
forming lactic acid that contributes to the metabolic acidosis seen in
patients with hemorrhage. Due to the inefficiencies of this process, cellular
ATP is quickly depleted, and the cell can no longer meet the significant
energy requirements necessary to complete the active transport processes
involved in maintaining an electrical gradient across their cell membrane.
Sodium, calcium, and water then flow intracellularly, leading to cell
swelling, lysis, and death [2].

Figure 5.2 Glycolysis occurs in the cytoplasm, producing two molecules of pyruvate and adenosine
triphosphate (ATP). In the absence of oxygen, pyruvate cannot enter the mitochondria to complete
oxidative phosphorylation. Pyruvate is converted to lactate, recycling nicotinamide adenine
dinucleotide (NAD+) for further use in glycolysis. ATP is hydrolyzed into adenosine diphosphate
(ADP), producing hydrogen ions (H+), which combine with lactate to form lactic acid.

An influx of intracellular calcium can trigger calcium-dependent

phospholipases and proteases leading to cellular injury. Cellular acidosis
progresses, oxygen free radicals are generated, and adenine nucleotides are
lost from the cell [1]. Following treatment and control of hemorrhage, these
cellular changes can contribute to the permanent organ damage seen in the
postresuscitation state. If oxygen delivery is not restored, particularly to the
heart and brain, hemorrhagic shock can be rapidly fatal.
Shock will lead to inflammation, endothelial activation, and altered
coagulation. Inflammatory cytokines released following cell damage can
stimulate expression of procoagulant proteins (e.g., tissue factor), impair
platelet function, and alter coagulation factor synthesis. Tissue
hypoperfusion can lead to inhibition in the activation of protein C, inducing
a hyperfibrinolytic state and inhibition of coagulation factors. These
alterations in coagulation and hyperfibrinolysis are components of
traumatic coagulopathy; they are associated with massive transfusion
requirements and poor clinical outcomes [8].

Etiology of hemorrhagic shock

Though commonly thought of in the setting of trauma, there are many
causes of hemorrhagic shock in animals. Coagulopathy can lead to
spontaneous bleeding in patients with diseases such as anticoagulant
rodenticide toxicity, severe thrombocytopenia, thrombocytopathia, hepatic
failure, or breed-related factor deficiencies. Doberman Pinschers, Shetland
Sheepdogs, and Old English Shepherds are predisposed to platelet
dysfunctions. Factor VIII deficiency is common in German Shepherd dogs
and Golden Retrievers. Factor VII deficiency has been recognized most
commonly in Beagles, Airedales, and Giant Schnauzers. The
gastrointestinal tract can be a source of significant hemorrhage that is often
difficult to document in the early stages; some patients will have evidence
of melena or vomiting secondary to severe ulceration caused by NSAID
toxicity, neoplasia, or chronic gastrointestinal disease. Torsion of the
stomach, lung, spleen, or mesentery can rupture blood vessels and lead to
hemorrhage. Nontraumatic hemoabdomen is commonly seen with neoplasia
of the spleen or liver in dogs and cats [9].
Sources of traumatic or surgical hemorrhage can be compressible or
noncompressible. Compressible hemorrhage sources should be obvious and
controlled rapidly. If hemorrhage is suspected but not identified,
noncompressible hemorrhage should be assumed. Sources of
noncompressible hemorrhage include the pleural space, mediastinum,
lungs, peritoneal cavity, gastrointestinal tract, retroperitoneal space, or sites
of fracture such as the pelvis, humerus, or femur.

Diagnosis
Shock is a clinical disease syndrome that consists of a constellation of
clinical signs. No one sign or laboratory finding will confirm or deny the
presence of shock. Initial diagnosis should be suspected based on physical
examination findings such as tachycardia (or bradycardia in decompensated
shock), hypothermia, cool extremities, weak femoral or dorsal pedal pulses,
tachypnea, prolonged capillary refill times, pale mucous membranes, and an
altered mentation. Hypotension is common but the patient may have a
normal blood pressure due to compensatory mechanisms, pain, or anxiety.
Diagnosis is supported by further laboratory values and assessment.

Laboratory data
Clinicopathologic data can be helpful in the diagnosis and monitoring of
hemorrhagic shock. Packed cell volume (PCV) can correlate with the
hemoglobin level and oxygen-carrying capacity of blood. In the early stages
of hemorrhage, the PCV may be falsely elevated if blood is collected prior
to transcapillary shifting of extravascular fluid into the intravascular space
and/or by splenic contraction. A decline in total plasma protein (TP) levels,
measured by refractometry, and can indicate a loss of protein or decrease in
production if measured prior to fluid therapy. TP can also serve as an
estimate of colloid osmotic pressure (COP) in patients who have not
received treatment with a synthetic colloid. An elevated blood lactate level
can help quantify the degree of anaerobic metabolism and can serve as a
marker of poor tissue perfusion (type A hyperlactatemia), although this is
not the only cause of elevated lactate. Metabolic causes of an elevated
lactate level (type B hyperlactatemia) such as seizures, hepatic disease,
neoplasia, and certain drugs should be ruled out before using lactate as an
assessment of hypoperfusion. Elevations in lactate caused by poor perfusion
should quickly improve following resuscitation if adequate hepatic function
is present [4].
Monitoring
Other measures of perfusion and volume status include urine output and
central venous pressure (CVP). Inadequate renal perfusion or decreases in
glomerular filtration rate can lead to a decrease in urine output during
hemorrhage. Monitoring urine output can be helpful during
postresuscitative care to assess renal function.
Central venous pressure monitoring can be used to estimate ventricular
preload and can serve as an indirect marker of intravascular volume but
comes with significant limitations. Decreased lung compliance, increased
intrathoracic pressures from pleural space disease or abdominal distension,
and altered ventricular compliance can affect CVP readings. Measurement
of CVP also requires utilization of a jugular catheter, which may be
contraindicated in coagulopathic animals. Normal CVP values in animals
can vary greatly in disease states, but trending changes during volume
resuscitation and response to fluid challenges can be relevant in monitoring
goal-directed therapies (see Chapter 1). Due to the major imitations and
technical challenge of obtaining CVP values, this parameter is not routinely
used in the monitoring of veterinary patients [10].

Shock index
The shock index, defined as the ratio between heart rate and systolic blood
pressure, was developed to quantify the severity of shock upon presentation
to the emergency room and has been validated in humans and animals. The
shock index is inversely correlated with the cardiac index, stroke volume,
MAP, oxygen delivery, and mixed venous oxygen saturation. In people, a
shock index >0.9 is indicative of serious illness. In dogs, a shock index >1.0
is highly sensitive and specific to distinguish dogs in shock from healthy
dogs upon presentation [11]. A shock index >0.9 in dogs also correlates
with volume status in canine hemorrhagic shock models better than CVP,
heart rate, MAP, and pulmonary capillary pressures alone. It also aids in the
diagnosis of hemorrhage before changes in PCV develop [12]. Evaluation
of the shock index in cats has been limited and may be complicated by their
bradycardic presentation during compensated shock, but one report
identified a shock index of >1.6 as an indicator of hypoperfusion [13].
Ultrasonography
Point-of-care ultrasound in the emergency room is another method of
assessment for hemorrhagic shock. Focused assessment of sonography for
trauma of the abdomen and thorax (AFAST and TFAST, respectively) can
be used serially and noninvasively to detect pleural and peritoneal cavitary
effusion. Left atrial size and left ventricular ejection fraction can be used to
assess for evidence of cardiogenic shock upon presentation prior to
administration of potentially deleterious intravenous fluids. In a
hypovolemic patient, cavitary effusion may not initially be present. As
perfusion is restored and MAP improves, cavitary effusion can develop and
worsen rapidly. Progressive cavitary effusion may indicate ongoing
hemorrhage and the necessity for surgical intervention to control bleeding.
Ultrasound can also be used to assess fluid responsiveness during
resuscitation by measuring caudal vena cava diameter changes with
respiration. The caudal vena cava collapsibility index (obtained using M
mode ultrasound measurement of the difference in diameter of the caudal
vena cava near the insertion of the right hepatic vein between expiration
and inspiration) assesses variations in the diameter of the vena cava that
depend on blood volume. An index greater than 27% can identify a patient
whose cardiac function may be along the steep portion of the Frank–
Starling curve and who would benefit from additional fluid administration.
Measurement of the caudal vena cava collapsibility index is validated in
conscious, spontaneously ventilated dogs, is noninvasive, and
inexpensive.14 It does require a degree of technical competence and a
patient that tolerates the procedure since pressure in the upper abdomen is
often necessary.

Clinical management
Triage
Primary survey of a patient suffering from suspected hemorrhagic shock
should involve an assessment of the “ABCs” of triage: airway, breathing,
and circulation. Significant hypoxemia may be evident on presentation and
require varying degrees of oxygen supplementation. Intubation and positive
pressure ventilation may be indicated in patients with severe hypoxemia,
hypercapnia, or altered mentation with an inability to protect the airway.
If cardiovascular shock is suspected based on the presenting clinical
signs and additional diagnostics, venous access should be obtained as soon
as possible. Ideally, a peripheral venous catheter should be placed in either
the cephalic, medial saphenous, or lateral saphenous vein. The intravenous
catheter should be as large a gauge and as short as possible to achieve
maximal flow rates during resuscitation. Jugular venipuncture should be
avoided or performed with caution until bleeding caused by coagulopathy is
ruled out. If venous access is not obtainable due to severe hypovolemia, an
intraosseous catheter or venous cutdown may be necessary.
Once hemorrhagic shock is diagnosed, resuscitation should begin
immediately. A secondary survey should be performed as soon as possible,
and every effort should be made to identify a source of hemorrhage.
External, compressible sources of hemorrhage should be localized and
controlled with application of pressure, if possible. Ultimately, fluid therapy
is the cornerstone of treatment in hemorrhagic shock [15].

Hypotensive resuscitation
Hypotensive resuscitation, also known as permissive hypotension or limited
volume fluid resuscitation, is a goal-directed therapy for patients with active
hemorrhage. A blood pressure below normal is targeted to prevent the
disruption of blood clots forming in actively bleeding vessels. Avoiding
overzealous fluid resuscitation may also prevent the development of edema
and dilutional coagulopathy. Current guidelines recommend maintenance of
a MAP of 60 mmHg or a systolic blood pressure of 90 mmHg to maintain
perfusion to vital organs. Hypotensive resuscitation should only be used
until definitive hemorrhage control is initiated, typically with surgical
stabilization.
In animal models of hemorrhage, patients managed with hypotensive
resuscitation had decreased mortality compared to those with normotensive
resuscitation. In human clinical trials and meta-analysis, outcomes have
been less conclusive. Current clinical research in veterinary patients is
limited [16].
Hypotensive resuscitation is contraindicated in patients showing signs of
traumatic brain injury. The central nervous system relies on aerobic
metabolism for energy production; maintenance of adequate perfusion with
a systolic blood pressure >100 mmHg is essential to provide adequate
oxygenation and prevent secondary injury [17].

Fluid therapy in hemorrhagic shock

The goal of initial fluid therapy is to maintain an adequate perfusion
pressure and to support the delivery of oxygen to vital organs; in turn, this
will limit hypoxic damage, inflammation, and subsequent organ
dysfunction. Overzealous fluid therapy can have deleterious effects, the
most significant being the development of pulmonary edema or acute lung
injury. Throughout resuscitation, patients should be frequently reassessed
for continued fluid responsiveness and goal-directed therapy end points (see
Chapter 3). There is no “one size fits all” treatment strategy for shock. Fluid
therapy choices need to be made based on the history, clinical signs,
physical examination findings, and laboratory data along with constant
reassessment. Major fluid category choices for the treatment of shock
include isotonic crystalloids, hypertonic solutions, and synthetic colloids. A
full discussion of fluid products can be found in Chapter 3, but an overview
of their utilization in hemorrhagic shock is described below.

Isotonic crystalloids
Isotonic crystalloids have an osmolarity similar to that of plasma and an
electrolyte composition similar to that of extracellular fluid. In all isotonic
crystalloids, sodium serves as the primary source of osmotic pressure and is
distributed uniformly within the extracellular fluid. Since 75% of
extracellular fluid is in the interstitium, 75% of the volume from isotonic
crystalloids will rapidly equilibrate into the extravascular space, giving a
short-lived intravascular volume expansion effect. Shock doses are typically
defined as 60–90 mL/kg in the dog and 45–60 mL/kg in the cat and are
based on the total blood volume of these species. Rarely is an entire shock
dose indicated at once; instead, portions of the shock dose (typically one
half to one third) are given and the patient is reassessed before
administering further fluid resuscitation.
Aggressive administration of isotonic crystalloids can lead to interstitial
edema, pulmonary edema, acute lung injury, and/or cerebral edema.
Particular caution should be used in patients with a low colloid osmotic
pressure, pulmonary contusions, cardiac disease, or end-stage renal disease.
Administration of large volumes of isotonic crystalloids can also lead to
hemodilution, contributing to anemia, hypocoagulability, and
hypoproteinemia in addition to that already seen in patients with
hemorrhagic shock. Despite this, isotonic crystalloids are one of the most
common initial fluid choices for patients in shock due to their easy
accessibility and cheap cost. Isotonic crystalloids may be appropriate for
resuscitation of mild to moderate hemorrhage, but alternative therapy may
be necessary in more severe forms of shock [18].

Hypertonic solutions
A hypertonic solution is any solution with an effective osmolarity
exceeding normal plasma. This increased osmolarity allows this solution to
pull fluid from the extravascular space, leading to an increase in
intravascular volume greater than the volume of solution infused.
Hypertonic solutions are particularly attractive in patients with traumatic
brain injuries as they can reduce cerebral edema while also providing
intravascular fluid resuscitation. Hypertonic saline has also been shown to
have immunomodulatory effects, including decreased neutrophil activation
and endothelial adherence, stimulation of lymphocyte proliferation, and
inhibition of proinflammatory cytokine production. It has been shown to
improve rheologic properties of circulating blood, cause coronary
vasodilation and improve overall cardiac function [18]. Common initial
dosing for a 7.5% hypertonic saline solution is 4–5 mL/kg in dogs and 2–4
mL/kg in cats [19]. As with isotonic crystalloids, sodium will equilibrate
into the interstitium, thus limiting the duration of volume expansion.
Rapid administration of hypertonic saline (greater than 1 mL/kg/min)
can lead to vagally mediated hypotension, bradycardia, and
bronchoconstriction. An increase in sodium, chloride, and osmolarity and
decreases in potassium and bicarbonate are expected following hypertonic
saline administration, especially with repeated dosing. These changes are
typically corrected by the kidneys but may be of concern in patients with
preexisting electrolyte derangements. Hypertonic saline is contraindicated
in patients who are interstitially dehydrated since this prevents movement
of fluid into the intravascular space and will worsen dehydration [4].
Hypertonic solutions can also contribute to fluid overload and pulmonary
edema if the intravascular volume and hydrostatic pressure are increased
excessively prior to or following therapy, especially in patients with
endothelial damage/hyperpermeability or cardiac disease.

Synthetic colloids
Synthetic colloid solutions consist of large molecules that do not readily
cross the vascular endothelium; they therefore remain in the intravascular
space to continue exerting their oncotic effects longer than isotonic or
hypertonic crystalloid solutions. These solutions increase the colloid
osmotic pressure (COP) in the vasculature, thus pulling fluid from the
interstitium into the intravascular space and leading to volume expansion
greater than the infused volume of solution.
Adverse effects of synthetic colloids are well established, which makes
them a controversial fluid choice in certain situations. Synthetic colloid use
in patients with pulmonary contusions may lead to extravasation of high
molecular weight molecules into the interstitium and alveoli and worsen
pulmonary edema and hypoxemia. Use of synthetic colloids has also been
associated with coagulation impairment (beyond that expected from
hemodilution, renal impairment, and allergic reactions). Coagulation
impairments documented with synthetic colloid administration include the
dysfunction of platelets, factor VIII, and von Willebrand’s factor (vWF),
and increased fibrinolysis. Acute kidney injury has been extensively
documented in humans with severe sepsis that receive high molecular
weight synthetic colloid solutions but is less common when used in patients
with trauma or hemorrhage. Allergic reactions reported in dogs range from
pruritus to anaphylaxis.
Animals with a COP below 16 mmHg may benefit from administration
of a synthetic colloid. Doses of 2–5 mL/kg (cats) or 5–10 mL/kg (dogs) are
commonly used. Maximum daily volumes should not exceed 20 mL/kg/day
for most available synthetic colloids, although newer solutions have been
proven safe in doses up to 50 mL/kg/day [18].

Blood products
While fluid therapy may stabilize a patient with mild to moderate
hemorrhage, those with severe hemorrhage or ongoing bleeding will require
blood transfusion therapy to provide adequate oxygen-carrying capacity,
coagulation factors, and platelets while preparing for definitive therapy.
Patients with hemorrhage requiring surgical stabilization will not only need
an adequate intravascular volume, but also sufficient oxygen-carrying
capacity; a PCV greater than 20–25% is important for patients undergoing
general anesthesia. The transfusion trigger ultimately depends on the
individual patient, rapidity of the decline in PCV, and clinical judgement.
Close monitoring of the heart rate, respiratory rate, mentation, and
perfusion parameters are important.
Whole, anticoagulated blood collected from a donor animal is typically
separated into component parts. Appropriate blood product selection can
conserve resources and maximize the benefit of each blood donation as it is
a limited biologic resource. As with fluid therapy, there is no “one size fits
all” dose for blood product administration; dosing depends on the patient’s
needs and the supply of the hospital blood bank. The rate of transfusion
depends on the acuity of the need for the blood product, but the maximum
duration of a single transfused unit should be less than 4 hours to prevent
blood product contamination following puncture. Transfusion of blood
products comes with risks of volume overload, infection,
thromboembolism, acute lung injury, and hypersensitivity reactions.
To prevent potentially fatal transfusion reactions, ideally, both dogs and
cats should receive type-specific blood and cats should be cross matched
prior to their first transfusion of red blood cell–containing products. Dogs
should be cross-matched following an initial red blood cell transfusion if
additional blood products are indicated 48–72 hours after the first
transfusion. Clinical judgement and a discussion of the risks of transfusion
with the client may be necessary if a patient who needs cross-matched
blood is too unstable to wait for crossmatch results prior to red blood cell
administration.

Whole blood transfusion

A whole blood transfusion involves the administration of blood from a
donor animal without additional separation or processing other than
anticoagulation during collection. Whole blood contains red blood cells,
clotting factors, and platelets. Fresh whole blood should be collected and
used within 8 hours to maximize platelet numbers and function.
Fresh whole blood transfusion is ideal for patients with acute, ongoing
blood loss and hemorrhagic shock. Due to the timing of blood collection to
administration, this can be impractical for many hospitals unless a colony of
blood donor animals is available on site. Common dosing for fresh whole
blood is 20–30 mL/kg.

Packed red blood cell transfusion

Packed red blood cells (pRBCs) consist of the red blood cells that remain
following centrifugation of whole blood and removal of plasma. A
transfusion with pRBCs will treat anemia by providing oxygen-carrying
capacity in the form of hemoglobin but will not supply platelets or
coagulation factors.
Dosing ultimately depends on the donor’s and the patient’s PCV, but a
recent study has showed 1.5 mL/kg of pRBCs can increase the PCV by 1%
[20]. A typical pRBC transfusion (15 mL/kg) will increase the PCV by
10%. Red blood cells should be administered using an appropriate filter to
prevent infusion of emboli and should be carefully handled to prevent red
blood cell lysis.

Fresh frozen plasma transfusion

Plasma products are used to treat coagulopathies, clotting factor
deficiencies, and hypoalbuminemia. Fresh frozen plasma (FFP) contains all
coagulation factors and is collected following centrifugation of whole blood
and removal of the red blood cells, and frozen within 8 hours of collection.
A coagulopathy may be the strongest indication for FFP administration in
acute hemorrhage, but in all patients with hemorrhagic shock there is an
expected loss of coagulation factors, plasma proteins, and hemodilution that
may benefit from FFP administration. FFP may provide a small amount of
colloidal support but requires large transfusion volumes to clinically treat
hypoproteinemia (typically 45 mL/kg of plasma is needed to increase serum
albumin concentration by 1 g/dL). It might be useful in animals that need
intravascular volume that is not deplete of oncotic support to prevent a
further decline in total protein levels.
The typical dose of FFP is 10–15 mL/kg, but repeated dosing may be
needed in coagulopathic patients due to the short half-life of clotting
factors.
Other plasma-containing products used to provide coagulation factors
include frozen plasma, cryoprecipitate, and cryopoor plasma. Frozen
plasma is plasma that has been frozen for more than 8 hours following
collection from a donor, plasma that has been stored for longer than one
year, or plasma that has been thawed for longer than one hour and refrozen.
These storage changes lead to destruction of the more labile components of
plasma, including factor V, factor VIII, and vWF, making frozen plasma an
appropriate product choice for vitamin-K deficient coagulopathies and
hemophilia B but a poor product choice for a bleeding patient with
hemophilia A or von Willebrand’s disease.
Cryoprecipitate is created by partially thawing fresh frozen plasma,
centrifuging the plasma, and removing the precipitate. This precipitate is a
concentrated source of vWF, fibrinogen, factor XIII, and factor VIII, which
makes it an ideal targeted blood product for treatment of von Willebrand’s
disease, hemophilia A, congenital factor XIII deficiencies, and
dysfibrinogenemia. Cryopoor plasma is the remaining plasma after removal
of cryoprecipitate and contains the remaining coagulation factors, including
the vitamin-K dependent factors (factors II, VII, IX, and X) and albumin.

Albumin
Albumin is a critically important plasma protein, which provides most of
the oncotic pressure in the intravascular space. It also plays a role in wound
healing, free-radical scavenging and acid–base balance, and serves as an
important carrier molecule for many medications. Albumin can be
decreased in many disease states and is directly lost during hemorrhage.
Patients with low oncotic pressure (e.g., acute decrease in albumin
concentration to <1.5 gm/dL) are at an increased risk of interstitial and
pulmonary edema, especially when high volume fluid resuscitation is
administered. Concentrated albumin products are available in the form of
human or canine albumin. Albumin infusion is administered for acute
albumin loss until 2 g/dL is reached. When human serum albumin (HSA) is
chosen, to reduce the risk of type I and III hypersensitivity reactions, it is
suggested to administer HSA at 5% (diluting 20% or 25% in the preferred
isotonic crystalloid) at 2 mL/kg/hour for a total dose of 10–20 mL/kg/day
(see Chapter 3 for further details) [21].
Canine albumin is 79.3% structurally homologous to human albumin
and these mild differences in structure may contribute to antigenicity and
the potential to develop hypersensitivity reactions when administered to
dogs. Adverse effects can include both type I and type III hypersensitivity
reactions but may be less common in critically ill animals. Both canine and
human albumin products have been shown to successfully improve COP,
serum albumin, and TP. Both are made from lyophilized pooled plasma
samples from healthy donors. Large dogs, or severely hypoproteinemic
dogs may require large quantities of albumin transfusions to reach targeted
serum albumin levels and there is a significant cost disparity between
human and canine albumin products. Species-specific albumin products are
considered the product of choice in hypoalbuminemic patients, but human
albumin products can be considered to provide more cost-conscious
albumin support, though clients should be informed of the possible adverse
effects prior to administration.

Platelet transfusion
Severe thrombocytopenia and thrombocytopathia may lead to clinically
significant bleeding. Patients in hemorrhagic shock may directly lose or
utilize platelets and may therefore require platelet support prior to surgical
stabilization. In humans, it is recommended to transfuse platelets to patients
with a platelet count <50,000/μL who are about undergo general surgery, or
those with a platelet count below 30,000/μL and active bleeding. Similar
guidelines have not been established in veterinary patients. Platelets have
historically been difficult to preserve and have a short half-life (~3.5 days),
limiting platelet supplementation to fresh whole blood transfusions.
Emerging technologies are making canine platelet-specific products more
readily available, including platelet-rich plasma, canine cryopreserved
platelet concentrates, and lyophilized canine platelets.
Platelet-rich plasma is prepared from fresh whole blood that is slowly
centrifuged. With continuous agitation and careful temperature control,
platelets may remain viable for 24 hours before transfusion and provide a
more targeted blood component therapy if red blood cells and coagulation
factors are not needed, though this is unlikely in patients with hemorrhagic
shock. Canine cryopreserved platelets are apheresed and stabilized with 6%
dimethyl sulfoxide, allowing for significantly longer storage. These
platelets have been shown to retain procoagulant activity in vitro but have
significantly less aggregatory activity than fresh platelets.
A canine lyophilized platelet product has recently been developed in
which platelets are stabilized using aldehyde crosslinking of membrane
proteins and lipids, allowing for reconstitution with preservation of platelet
structure and hemostatic function. Early studies have showed that
lyophilized platelets may be as effective as fresh platelet-rich plasma with a
24-month shelf-life prior to reconstitution [22].
All transfused platelet products are short-lived and rapidly consumed or
destroyed, or they lose their function. Supplementation with any of these
products may raise platelet counts by only 10,000–30,000/μL, but this may
be sufficient to provide adequate hemostasis and could aid in survival
during surgical intervention in patients with hemorrhagic shock.

Hemoglobin-based oxygen carriers

Hemoglobin-based oxygen carriers, such as Oxyglobin®, are not true blood
products but are biological products that can improve the delivery of
oxygen to tissues by increasing hemoglobin levels and preload. Oxyglobin®
is a sterile, purified, nonantigenic bovine hemoglobin solution.
Administration of this product will lead to a rightward shift in the oxygen
dissociation curve, thus allowing oxygen to offload from red blood cells and
into tissues more easily. This product has safety concerns, including marked
vasoconstriction after administration. Oxyglobin® is also more expensive
and less effective than natural blood products. Oxyglobin® is currently not
commercially available [4].

Massive transfusion
Severe, exsanguinating hemorrhagic shock may require massive volume
replacement in the form of blood products to successfully stabilize the
patient. A massive transfusion is typically described as a transfusion of one
or more of a patient’s entire blood volume in a 24-hour period. Other
definitions include replacement of half of a patient’s blood volume in 3 to 4
hours or administration of 1.5 mL/kg/min of blood products over 20
minutes. Such rapid resuscitation can lead to life-threatening metabolic
changes in addition to the patient’s presenting severe injuries.
Electrolyte disturbances, including hypocalcemia and hypomagnesemia
can be seen during massive transfusion due to citrate toxicity. Citrate is
used as an anticoagulant in blood product storage to prevent clot formation
by binding calcium but also has an equal affinity for magnesium. Severe
hypocalcemia can lead to clinical signs of hypotension, muscle tremors, and
arrhythmias. Calcium supplementation should be considered in patients
receiving massive transfusion who are persistently hypotensive or severely
hypocalcemic. In humans, hyperkalemia is described during massive
transfusion due to inactivation of the sodium–potassium ATPase pump by
cold storage of blood products, but this has not been documented in dogs,
likely because most dogs (other than Akitas and Shiba Inus) lack significant
quantities of intracellular potassium. Hypothermia is common following
rapidly administered cold blood products, which can affect clotting factor
activation, decrease platelet activity, and enhance fibrinolysis. Stored blood
contains lactic and pyruvic acid produced from anaerobic glucose
metabolism by stored red blood cells and leads to a metabolic acidosis
following rapid transfusion. Typical immunologic and nonimmunologic
transfusion reactions are also possible when rapidly transfusing blood
products, especially if blood typing and crossmatching is not performed due
to the acute need for product administration.
In human trauma medicine, during a massive transfusion protocol
activation, blood products transfused in a 1:1:1 ratio of pRBC:FFP:platelet
products have shown improved outcomes. In veterinary medicine, studies
examining transfusion ratio protocols and platelet products are limited. For
this reason, during massive blood loss, for each pRBC transfusion, an FFP
transfusion of equal volume should be given. Blood products should be
given as fast as necessary to stabilize the patient. Aggressive heat support
should be utilized while attempting to normalize electrolyte values and
preparing for surgical stabilization.
Massive transfusion administration can quickly exhaust a hospital’s
blood bank supplies and will come at significant client cost. Injuries leading
to exsanguination likely carry a poor prognosis simply due to their inherent
severity; a staged damage control surgical approach may be necessary to
treat patients with such a magnitude of hemorrhage [23].

Autotransfusion
Autotransfusion, or autologous blood transfusion, involves the collection of
cavitary hemorrhage and reinfusion intravenously to quickly provide blood
components and intravascular volume. Compared to allogenic blood
products, autotransfusions are nonantigenic, immediately available,
normothermic and lower in cost.
Blood becomes defibrinated after contact with serosal surfaces for more
than 1 hour and may not need to be anticoagulated prior to reinfusion.
When acute, active hemorrhage is suspected, anticoagulation may be
necessary following collection. Anticoagulation can be performed by
mixing 0.14 mL of citrate phosphate dextrose adenine per milliliter of blood
(or 63 mL of anticoagulant per 450 mL of red blood cells) during
collection. It is important to minimize mixing of collected blood with air
before administration to minimize lysis. Collected blood should be filtered
using a 20–270 μm filter to remove particles while avoiding further trauma
to red blood cells.
Complications of autotransfusion include hemolysis, coagulation
disorders, microembolism, and air embolism. Citrate toxicity and
hypocalcemia can develop with rapid or large volume administration of
anticoagulated blood or if blood and anticoagulant have been
inappropriately mixed. Concerns for sepsis following autotransfusion after
trauma may be unfounded if blood is collected in as clean a manner as
possible. Studies evaluating infusion of autologous blood with bile or fecal
contamination showed no increase in mortality when broad-spectrum
antibiotics were administered. In patients with cavitary bleeding due to a
ruptured neoplasm, metastasis through reinfusion of neoplastic cells may be
possible, but investigations in humans have failed to demonstrate a worse
outcome or an increased metastatic rate associated with autotransfusions in
patients undergoing oncological surgery [24].

Postresuscitation care
Following successful resuscitation from hemorrhagic shock and overall
control of bleeding, whether by compression, damage control surgery, or
definitive treatment, it is important to remember that sequelae related to the
initial hemorrhage event may be ongoing. Common complications seen in
the postresuscitative phase may include reperfusion injuries, organ damage
and/or dysfunction, and coagulation disturbances.

Reperfusion injury
When oxygen is reintroduced to cells, it is immediately used by xanthine
oxidase (which accumulates during ischemia) and then converts
hypoxanthine into reactive oxygen species [4]. Reactive oxygen species
lead to direct cell damage. High levels of intracellular calcium also
accumulate during ischemia, which can activate phospholipase A2 and lead
to arachidonic acid formation. Plasma membrane damage from cell
swelling and lysis can also stimulate the arachidonic acid cascade, leading
to production of prostaglandins, leukotrienes, and thromboxane and their
associated proinflammatory, procoagulant, and vasoactive effects.
As circulation returns, these proinflammatory mediators, cytokines, and
damage-associated membrane proteins will lead to further mitochondrial
damage and a postresuscitative cytopathic hypoxia. This damage can affect
organs throughout the body. In the lungs, inflammation and direct
endothelial damage can lead to acute lung injury and the development of
acute respiratory distress syndrome. In the kidneys, acute tubular necrosis
may occur and lead to acute kidney injury or failure. In the heart,
arrhythmias are common following resuscitation due to continued
sympathetic activation and circulating toxins during reperfusion.25 In the
gastrointestinal tract, endothelial damage and mucosal damage can lead to
bacterial translocation and endotoxemia.

Trauma-induced coagulopathy
In human trauma patients, coagulation abnormalities are reported in 25–
34% of cases, with 29% of these patients going on to develop multiorgan
dysfunction syndrome compared to 12% in trauma patients without
coagulation abnormalities. Coagulopathy prior to resuscitation has been
documented, indicating that it may be incited directly by trauma rather than
by resuscitative efforts, and has been termed acute traumatic coagulopathy.
Acute traumatic coagulopathy has been demonstrated in veterinary
populations and is associated with trauma severity [26]. Resuscitation-
associated coagulopathy can occur following large volume fluid
resuscitation, leading to hypothermia, acidosis, and hemodilution. These
factors can lead to failure of clotting factor activation and platelet
dysfunction.
The combination of acute traumatic coagulopathy and resuscitation-
associated coagulopathy has been termed trauma-induced coagulopathy.
Efforts to treat this include appropriate volume resuscitation, improvement
of acidosis and electrolyte derangements, treatment of hypoxemia and
hypoventilation, and correction of anemia and coagulopathy with necessary
blood component therapy.

References
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Antonio). 2022;32(S1):22–31.
[3] Costanzo LS. Costanzo Physiology E-Book. Elsevier Health Sciences; 2021. p. 181.
[4] Hopper K, Silverstein D, Bateman S. Chapter 23 - Shock Syndromes. In: DiBartola SP (ed.).
Fluid, Electrolyte, and Acid-Base Disorders in Small Animal Practice, 4th ed. Saint Louis:
W.B. Saunders; 2012.
[5] Polderman KH. Mechanisms of action, physiological effects, and complications of
hypothermia. Crit Care Med. 2009 Jul;37(7 Suppl):S186–202.
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[8] Maegele M, Gu Z-T, Huang Q-B, Yang H. Updated concepts on the pathophysiology and the
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[10] Hutchinson KM, Shaw SP. A Review of Central Venous Pressure and Its Reliability as a
Hemodynamic Monitoring Tool in Veterinary Medicine. Top Companion Anim Med. 2016 Sep
1;31(3):109–121.
[11] Porter AE, Rozanski EA, Sharp CR et al. Evaluation of the shock index in dogs presenting as
emergencies J Vet Emerg Crit Care (San Antonio). 2013;23(5):538–44.
[12] McGowan EE, Marryott K, Drobatz KJ, Reineke EL. Evaluation of the use of shock index in
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[13] Kenton R, Adamantos S. An evaluation of the shock index in cats with hypoperfusion; a novel,
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[14] Donati PA, Guevara JM, Ardiles V et al. Caudal vena cava collapsibility index as a tool to
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[15] Holmes CL, Walley KR. The evaluation and management of shock. Clin Chest Med. 2003 Dec
1;24(4):775–789.
[16] Hall K, Drobatz K. Volume Resuscitation in the Acutely Hemorrhaging Patient: Historic Use
to Current Applications. Front Vet Sci. 2021;8:638104.
[17] Kudo D, Yoshida Y, Kushimoto S. Permissive hypotension/hypotensive resuscitation and
restricted/controlled resuscitation in patients with severe trauma. J Intensive Care. 2017 Jan
20;5(1):11.
[18] Balakrishnan A, Silverstein DC. Chapter 60 - Shock Fluids and Fluid Challenge. In: Silverstein
DC, Hopper K (eds.). Small Animal Critical Care Medicine, 2nd ed. St. Louis: W.B. Saunders;
2015.
[19] Cavanaugh MT. 2013 AAHA/AAFP Fluid Therapy Guidelines for Dogs and Cats. J Am Anim
Hosp Assoc. 2013 May-Jun;49(3):149–159.
[20] Short JL, Diehl S, Seshadri R, Serrano S. Accuracy of formulas used to predict post-
transfusion packed cell volume rise in anemic dogs. J Vet Emerg Crit Care (San Antonio).
2012;22(4):428–434.
[21] Viganó F, Perissinotto L, Bosco VRF. Administration of 5% human serum albumin in critically
ill small animal patients with hypoalbuminemia: 418 dogs and 170 cats (1994-2008). J Vet
Emerg Crit Care (San Antonio). 2010 Apr 1;20(2):237–243.
[22] Davidow EB, Brainard B, Martin LG et al. Use of fresh platelet concentrate or lyophilized
platelets in thrombocytopenic dogs with clinical signs of hemorrhage: a preliminary trial in 37
dogs. J Vet Emerg Crit Care (San Antonio). 2012;22(1):116–125.
[23] Beer KS, Thomer A. Massive Transfusion. In: Textbook of Small Animal Emergency Medicine.
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[25] Basso C, Thiene G. The pathophysiology of myocardial reperfusion: a pathologist’s
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Clinical Case

Hemorrhagic shock following a

ruptured hepatocellular
carcinoma

An 8-year-old spayed female Portuguese Water Dog weighing 25 kg was

presented to the emergency room after collapsing during a walk. She had
a 3-day history of waxing and waning lethargy and a decreased appetite.
There was no history of trauma, toxin ingestion, or relevant previous
medical history.
On presentation, she was mentally obtunded with pale mucous
membranes, weak femoral pulses, absent dorsal pedal pulses, a capillary
refill time of 3 seconds, and cool extremities. Her rectal temperature was
35.3 °C, her heart rate 180 bpm, and her respiratory rate 60 bpm. She had
no external evidence of wounds. Cardiothoracic auscultation revealed no
murmurs or irregular rhythms and no crackles or wheezes, but she was
taking short, shallow breaths. Her abdomen was distended with a
palpable fluid wave and apparent pain on cranial abdominal palpation.
Her Doppler blood pressure was 50 mmHg.
This patient was in the early stages of decompensatory shock with a
concern for hemorrhagic shock due to a suspected fluid-filled abdomen.
There were classic signs of shock and baroreceptor-mediated reflexes
(vasoconstriction and tachycardia), but the Doppler blood pressure
remained dangerously low. The compensatory mechanisms were not
enough to improve perfusion to vital organs. Late decompensatory shock
is characterized by vasodilation and bradycardia due to
sympathoinhibition; urgent intervention is needed to prevent progression
to this irreversible state.
An 18 gauge, 0.75” intravenous catheter was placed in her right cephalic
vein. The patient was given a 500 mL (20 mL/kg) bolus of PlasmaLyte.
An AFAST examination showed a large volume of free fluid in all four
quadrants. A peripheral venous blood gas showed the following results:
pH: 6.942;
pCO2: 53.6 mmHg;
pO2: 25.8 mmHg;
Na: 139.5 mmol/L;
K: 3.76 mmol/L;
Cl: 110.2 mmol/L;
Glu: 26 mmol/L;
Lactate: 9.6 mmol/L;
BE: -20.8 mmol/L;
HCO3-: 11.7 mmol/L;
PCV; 34%;
TP; 4.2 g/dL.
These results indicate a marked lactic acidosis consistent with the poor
perfusion and anaerobic metabolism seen in shock. The patient’s
hypercapnia without compensation could be due to her abnormal
mentation caused by cerebral ischemia. Her hyperglycemia was likely
due to increased sympathetic tone. Her PCV was likely higher than
expected secondary to splenic contraction, with a low TP due to fluid
shifting from the interstitial and subendothelial glycocalyx
compartments.
An abdominocentesis was performed, and the effusion appeared bloody
with a PCV of 36% and TP of 6.2 g/dL. This similarity between the
peritoneal effusion PCV and peripheral PCV raised concern for active
bleeding into the peritoneal cavity.
After the initial PlasmaLyte bolus, the patient remained dull; her Doppler
blood pressure was 60 mmHg and her heart rate was 170 bpm. She was
given another 500 mL bolus of PlasmaLyte; her Doppler blood pressure
remained at 60 mmHg and her heart rate improved to 160 bpm. Her PCV
had decreased to 25% with a TP of 3.9 g/dL. A DEA 1.2(-) blood type
was obtained, and she was given 300 mL (12 mL/kg) of pRBCs over 30
minutes. Her heart rate remained at 160 bpm, but her blood pressure
improved to 80 mmHg. She appeared clinically brighter and had a better
pulse quality. A repeat venous blood gas showed the following results:
pH: 7.077;
pCO2: 47.6 mmHg;
pO2: 38.7 mmHg;
Na: 140.4 mmol/L;
K: 3.33 mmol/L;
Cl: 115.6 mmol/L;
Glu:10.6 mmol/L;
Lactate: 6.7 mmol/L;
BE: -14.1 mmol/L;
HCO3-: 14.1 mmol/L;
PCV: 35%;
TP: 3.8 g/dL.
Following pRBC transfusion, the patient’s PCV had appropriately
increased, but her TP remained low. Her lactate level had slightly
improved, along with her blood glucose and pCO2. Her pO2, although it
was collected from a peripheral vein and was therefore not indicative of
arterial or mixed venous oxygenation, had also improved, indicating
improved tissue oxygenation following pRBC administration.
PT/PTT were normal. She was given 250 mL (10 mL/kg) FFP over 30
minutes. Her blood pressure rose to 90 mmHg and her pulse quality
continued to improve. An abdominal ultrasound was performed and
showed a large, cavitated mass associated with the left medial liver lobe
and a large amount of free fluid. Thoracic radiographs showed no
evidence of metastasis. A full chemistry showed her albumin was 1.2
g/dL. She was then administered a transfusion of 6 grams of canine
albumin targeting a desired albumin of 2.0 g/dL (albumin dose = [desired
albumin – patient albumin] × 25 kg × 0.3).
Following albumin transfusion, the patient’s Doppler blood pressure was
140 mmHg and her heart rate improved to 107 beats per minute. Now
hemodynamically stable, she was prepared for general anesthesia and
surgery. Just prior to general anesthesia, a final venous blood gas
showed:
pH: 7.301;
pCO2: 40.2 mmHg;
pO2: 35.2 mmHg;
Na: 145.8 mmol/L;
K: 3.51 mmol/L;
Cl: 114.2 mmol/L;
Glu: 5.1 mg/dL;
Lactate: 2.3 mmol/L;
BE: - 4.6 mmol/L;
HCO3-: 20.0 mmol/L;
PCV: 30%;
TP: 4.4 g/dL.
Following FFP and albumin administration, her TS improved, but her
PCV worsened following initial improvement after pRBC transfusion.
Since she was likely continuing to bleed into her abdomen, damage
control surgery was recommended to control the hemorrhage as quickly
as possible. Despite this ongoing bleeding, adequate resuscitation led to
an improved metabolic acidosis, lactate, pCO2 and pO2, thus optimizing
her chances of successful surgery.
A laparotomy was performed, and a large volume of hemorrhagic
effusion was present within the peritoneal cavity. A total of 400 mL of
blood was collected from the abdomen into a sterile fluid bag.
Anticoagulant (56 mL of citrate phosphate dextrose adenine) was added
to the collected blood (0.14 mL anticoagulant per mL of blood) before IV
administration as an autotransfusion.
During surgery, the left medial liver lobe, which contained a large,
actively bleeding mass was isolated and removed. The dog recovered
well from surgery and histopathology was consistent with a
hepatocellular carcinoma.
While the most common cause for a neoplastic hemoabdomen is a
malignant hemangiosarcoma, a massive ruptured hepatocellular
carcinoma can carry a good prognosis. Proper stabilization and
resuscitation are key to a successful outcome, particularly when the
patient is presented in hemorrhagic shock.
The Microcirculation
and Fluid Therapy
 CHAPTER
6

Deborah C. Silverstein

Introduction
When assessing and monitoring unstable animals, both objective and
subjective indicators of tissue perfusion are often used to determine the
amount and rate of fluid to be administered, if indicated. These indicators
include parameters such as mentation, mucous membrane color, capillary
refill time, pulse quality, extremity temperature, heart rate, and blood
pressure (see Chapter 3). Although these are valid markers of
macrovascular blood flow, they are unable to assess the smaller vessels and
capillary beds, where gas and nutrient exchange occurs, also known as the
microcirculation. Unfortunately, clinical evaluation of the microcirculation
is not easily performed, and clinicians must therefore rely on global
markers of macrocirculatory perfusion when evaluating sick animals.
However, there are many diseases in which microcirculatory hypoperfusion
is present despite normal macrocirculatory parameters (also known as
cryptic shock or hemodynamic incoherence). This chapter will review the
structure, function, and regulation of the microcirculation, changes that
occur with disease states, and current methods for assessment. A clinical
case illustrating the importance of microcirculatory perfusion is also
presented.

Structure and function of the microcirculation

The microcirculatory unit is comprised of arterioles that feed into a
capillary bed and are drained by venules (Figure 6.1). Precapillary arterioles
have smooth muscle throughout, but terminal metarterioles have interrupted
bands of smooth muscle. The walls of true capillaries contain no muscle
and consist of one layer of endothelial cells attached to a basement
membrane. Arterioles and venules are less than 100 µm in diameter, while
capillaries are less than 10 µm in diameter [1]. Specialized shunt vessels
allow arterial blood to bypass the associated microcirculatory unit, as
dictated by arteriolar and precapillary sphincter tone [1]. The vascular
endothelial surface layer (ESL) is present on the intimal surface of blood
vessels and contains the endothelial glycocalyx and associated components
from the endothelial cells and plasma [2–3]. The ESL is between 200 nm
and 2 µm thick and makes up about 25% of the vascular space [4]. The
glycocalyx is comprised of a negatively charged carbohydrate rich gel-like
layer that creates a barrier between the vessel wall and the blood [5–7]. It
contains membrane-bound proteoglycans, secreted glycosaminoglycans,
sialic acid–containing glycoproteins, and glycolipids that are associated
with the vascular endothelial surface [8]. Proteins such as albumin and
antithrombin are also contained within the glycocalyx [8–10]. The ESL
functions to maintain the vascular permeability barrier; modulate nitric
oxide (NO) production in response to shear stress; retain protective
enzymes such as superoxide dismutase; inhibit coagulation via factors such
as antithrombin, tissue factor pathway inhibitor, and protein C; assist with
mechanotransduction; and prevent leukocyte adhesion and binding of
ligands to control local inflammation [3,11]. Based on recent research
examining the ESL, the Starling principle of transvascular fluid flux has
been revised to include the oncotic pressure gradient between the plasma
and glycocalyx rather than between the plasma and interstitial space (see
Chapter 1) [12].
The microcirculation is the largest vascular surface area in the body and
is vital for effective delivery of oxygen and nutrients to the cells and
removal of waste products from tissue beds [1]. Both systemic and local
regulation of blood flow through these units and maintenance of the ESL
are essential to maintain adequate perfusion and match metabolic demand
to oxygen/nutrient delivery.

Microvascular perfusion – systemic control

Vascular tone depends on many endogenous chemical mediators, such as
catecholamines, endothelin and thromboxane (Box 6.1). Catecholamines
are released in response to baro- or chemoreceptor activation of the
sympathetic nervous system [13]. Baroreceptors respond to changes in
blood pressure (stretching of the vessel wall) and chemoreceptors respond
to chemical changes in the blood such as hypoxia, hypercapnia, or
acidemia. Their effects are most critical when the systemic arterial pressure
falls below 80 mmHg and catecholamines help to maintain perfusion in
individual capillary beds despite a decreased systemic blood pressure [13].
However, true capillaries do not have sympathetic innervation or smooth
muscle like the arteries and most of the venous vessels. Therefore, blood
flow through each capillary bed is regulated by the hemodynamic pressures
generated between the precapillary sphincter and the postcapillary venules.
Since each capillary bed may be supplied by multiple arterioles, flow
through the capillary bed can increase by 200–500% without any significant
change in the arteriolar pressure [14]. This mechanism helps to preserve
microcirculatory flow to specific tissue beds during periods of transient
systemic hypotension in healthy animals.

Figure 6.1 Schematic of the microcirculation. Boxes on the left represent ranges of vessel diameters
at varying levels of the microcirculation. Boxes throughout the diagram represent the average
interstitial (tissue) oxygen tension (PtO2). The arrows represent the direction of blood flow across the
microcirculatory unit. From: Cooper ES, Silverstein DC. Fluid Therapy and the Microcirculation in
Health and Critical Illness. Front Vet Sci. 2021;8:625708. doi: 10.3389/fvets.2021.625708
 Endogenous mediators of vascular smooth
Box 6.1
muscle tone

Vasoconstrictors: Vasodilators:
Angiotensin II Acidosis
Alkalosis Carbon dioxide
Endothelin Endothelium-derived
Endothelium-derived hyperpolarizing factor
constricting factor Histamine
Epinephrine/norepinephrine Hyperthermia
Hypothermia Hypoxia
Hyperoxia Increased tissue potassium,
Thromboxane A2 ADP, or adenosine
Vasopressin Kinins
NO
Prostacyclin

In addition to vascular tone, intravascular volume is also important for

the maintenance of systemic blood pressure and tissue perfusion. The
renin–angiotensin–aldosterone system plays a major role in the
maintenance of adequate blood volume via sodium and water retention in
the kidneys, and in increasing vascular smooth muscle tone via angiotensin
II–mediated vasoconstriction [4,15]. Stimulation of vasopressin release
causes further retention of free water and can influence vasomotor tone in
certain situations [15].
Endogenous vasodilators are also important for increasing flow to
capillary beds; these include kinins (bradykinin and l-lysl-bradykinin),
adrenomedullin and atrial natriuretic peptide (ANP). They frequently work
to regulate local blood flow but may also enter the systemic circulation.
Bradykinin also increases capillary permeability, thereby augmenting
nutrient delivery to the tissue bed [16]. Similarly, histamine acts to cause
vasodilation and increased capillary permeability when released in response
to tissue damage or allergic reactions. Adrenomedullin exerts its
vasodilatory action by increasing the production of NO while ANP
antagonizes various vasoconstrictor agents [16].
 These chemical regulators are responsible for controlling the delivery of
blood to precapillary sphincters across the different tissue beds throughout
the cardiovascular system. Once blood arrives at a capillary bed, local
regulatory mechanisms act to maintain flow through this capillary bed. This
may function independent of systemic changes to perfusion [16].

Microvascular perfusion – local control

Each capillary bed has local regulators of microcirculatory flow that adjust
perfusion based on local tissue metabolic rate, nutrient availability, and
accumulation of waste products (Box 6.1). This causes precapillary
sphincters to open or close (microcirculatory shunting) according to an
increase or decrease in blood flow requirements, respectively. Adjustments
in capillary perfusion are vital for modulating cardiac workload based on
individual tissue bed demands [16].
Rapid mechanisms for the control of microcirculatory flow are mediated
at a local level via autoregulation. For example, flow autoregulation using
vascular stretch receptors maintains consistent capillary blood flow over a
wide range of arterial pressures. An increase in systemic vascular pressure
leads to increased tone of the precapillary sphincter, which mutes
transmission of the pressure through the capillary circuit [17]. The opposite
occurs when there is a decrease in peripheral pressure. This mechanism is
independent of any neurohormonal input and can maintain consistent blood
flow when the mean arterial pressure is 60–160 mmHg.
Variations in the metabolic demand of local tissues can greatly impact
the control of blood flow to associated capillary beds. An increase in
metabolic activity produces carbon dioxide, lactate, and hydrogen ions,
which stimulate vasodilation to enhance local blood flow and increase
oxygen/nutrient delivery. Even though these metabolites flow downstream,
the countercurrent flow between arterioles and venules allows them to be
“sensed” at the level of the precapillary sphincter, with a subsequent
increase in blood flow [17]. Additionally, intercell and local neural
pathways respond by enabling conduction of signals from the capillary
endothelium and venular smooth muscle [17].
Microcirculatory regulation also depends on the local oxygen tension
(PO2). Normally, capillary blood has a significantly lower PO2 (5–12
mmHg) than arteriolar blood (~60 mmHg) due to three mechanisms: early
off-loading of oxygen in precapillary tissues, endothelial oxygen
consumption, and countercurrent exchange with venous blood [17]. An
increase in precapillary tissue PO2 stimulates vasoconstriction, whereas a
decrease results in vasodilation, largely through the release of NO. The role
of NO in the regulation of microvascular tone is important in health and
disease [17]. In healthy animals, the constitutive form of NO synthetase
(cNOS) is responsible for maintaining a basal level of NO to modulate
vascular tone and meet tissue demands. In disease states that cause blood
hyperviscosity, such as polycythemia vera or severe hemoconcentration, the
increase in vascular endothelial shear stress leads to an increase in cNOS,
an increase in NO, and subsequent vasodilation. In contrast, patients with
severe anemia/hemodilution and a marked reduction in red cell mass have
decreased blood viscosity and less of a stimulus for vasodilation [18]. The
inducible form of NO synthetase (iNOS) can be produced by the endothelial
cells when triggered by inflammation and cytokines. Prostacyclin-induced
vasodilation may be important for producing a normal response to hypoxia,
especially when NO is inhibited [19].

Microvascular changes with trauma and

hemorrhagic shock
Patients suffering from trauma, acute pain, or hemorrhage experience rapid
stimulation of the sympathetic nervous system and subsequent release of
epinephrine and norepinephrine; this leads to vasoconstriction, particularly
in the large arterioles (70–150 μm) that supply skeletal muscles [20]. The
response is variable in the smaller arterioles (10–25 μm) with constriction
in some capillary beds and dilation in others, mostly dictated by metabolic
demand and the relative hierarchy of vital organs (e.g., the brain and heart
are a priority).
The tone of the small arterioles will decrease (i.e., small arterioles will
dilate) following trauma and hemorrhage resulting in decreased tissue
oxygen delivery. However, this change is counteracted by inhibition of
endothelial NO synthase (eNOS) in the early stages following trauma and
hemorrhage. As iNOS is upregulated secondary to tissue damage and
cytokine release, there is an increase in vasodilation [21]. An assortment of
vasoactive mediators with mixed effects will also be released and a
progressive acidosis and accumulation of cellular metabolites (particularly
in the terminal stages of shock) will then further promote vasodilation and
reverse systemic vasoconstrictive efforts. This can result in a decrease in
driving pressure in the face of hypotension that ultimately leads to
stagnation of blood flow.
The venous circulation also plays a role in the maintenance of
microvascular perfusion. Immediately following trauma and hemorrhage,
catecholamine-induced venoconstriction acts to decrease venous
capacitance and increase the return of blood to the heart. As shock
progresses, however, a more diffuse relaxation (through mechanisms
similar to those described above) causes pooling of blood in the venous
circulation, which may lead to downstream stagnation of blood flow with
negative implications on capillary perfusion and oxygen delivery.
Several additional factors may contribute to abnormal microcirculatory
flow. Patients with systemic inflammation, shock, or trauma may have
vascular endothelial cell swelling due to increased membrane permeability,
acidosis, and impaired electrolyte transport from failure of ATP-dependent
channels [22]. A decrease in the capillary lumen from endothelial swelling
can adversely affect capillary blood flow and patency. In addition,
endothelial cell edema may also impair the release of prostacyclin and NO
while increasing that of endothelin and thromboxane; the net effect is
upstream vasoconstriction, which further compromises capillary flow.
Oxidative injury, ATP deficiencies, cell membrane injury, and cellular
dehydration may also decrease red blood cell (RBC) deformability through
the narrow capillaries [22]. In normal patients, RBCs are slightly larger than
the capillary lumen; therefore, their folding is necessary to flow through the
microcirculation. The inability to fold, along with aggregation, may result
in capillary plugging and/or shearing injury/premature destruction of RBCs.
Additionally, increased rigidity and endothelial adherence of leukocytes
may lead to arteriolar and capillary plugging. Finally, the microthrombi that
form because of tissue/endothelial injury, the inflammatory response, and
hypercoagulability may become lodged at various levels of the
microcirculation and impede downstream flow.
The deleterious upstream and downstream effects have the potential to
greatly impact capillary flow and delivery of oxygen and nutrients to
tissues. Vasoconstriction leads to shunting of blood away from the capillary
bed (decreased vessel numbers), while hypotension, vasodilation, and
obstruction leads to stagnation of blood (decreased flow). These
derangements may persist for a prolonged time following resuscitation,
despite normalization of macrovascular parameters [22–23].
Shedding of the endothelial glycocalyx has been seen in experimental
rodent models of nontraumatic hemorrhagic shock, although the changes
are independent of increased vascular endothelial permeability [24–26].

Microvascular changes with sepsis

The progression of untreated sepsis leads to systemic deterioration and
culminates in septic shock, a condition originally defined as the presence of
refractory hypotension, hyperlactatemia, and organ dysfunction that persists
despite aggressive fluid resuscitation [27,28]. Marked changes in both the
macro- and microcirculation are believed to be responsible for the
deterioration from sepsis to septic shock and the consequent organ
dysfunction, organ failure, and death [29–32]. Changes in the
microcirculation include a decreased microvascular density and perfusion,
as well as increased capillary flow heterogeneity [29,30,33]. Studies have
found that microcirculatory changes often precede macrocirculatory
changes in humans with sepsis; improvement in microcirculatory
derangements is associated with improved survival [29,30,33,34]. Early
changes in microcirculatory indices were a stronger predictor of outcome
than any macrocirculatory variable monitored in humans with sepsis [35].
Microcirculatory derangements in septic patients are likely
multifactorial in origin. These factors include hypovolemia, endothelial cell
dysfunction secondary to adhesion molecule expression, increased adhesion
of white blood cells, endothelial glycocalyx degradation, uncoupling of
connexin, increased permeability of the vascular barrier, formation and
lodging of microthrombi, decreased vasomotor autoregulation and
reactivity, alterations in local perfusion pressure and flow, and shunting of
oxygen to hyperperfused capillary beds [36].
Based on both experimental and clinical studies, sublingual
microcirculatory derangements correlate with microcirculatory changes in
other organs such as the intestines and kidneys [37–39]. Changes in the
microcirculation in healthy, anesthetized dogs correlate with
macrocirculatory measurements of perfusion, although dogs with
hemorrhagic shock do not maintain this hemodynamic coherence [40–42].
The correlation in septic dogs has not yet been studied.
Sepsis-induced degradation of the glycocalyx allows plasma proteins
and fluid to move across the vascular wall and into the interstitium [43–44].
Damage to the glycocalyx is the result of inflammation and increased
circulating “sheddases” (e.g., metalloproteinases, heparinase, and
hyaluronidase), which are activated by reactive oxygen species and
proinflammatory cytokines [46]. Rodent sepsis studies have elucidated how
the endothelial glycocalyx peels away from the endothelial surface and
forms spherical bodies that are visible at the injured site [46]. Clinical
studies in humans with sepsis have found a decrease in the thickness of the
endothelial surface layer that correlated with the severity of critical illness.
However, an association between this thickness and microcirculatory
imaging parameters such as flow index and the proportion of perfused
vessels has not been demonstrated [47].

Monitoring of the microcirculation vs.

macrocirculation
There is evidence in the human literature that goal-directed therapy
targeting normalization of macrocirculatory parameters may not lead to
better outcomes [48–50]. This is likely because the heterogeneity of
microcirculatory flow can lead to hypoxic areas, even when treatment
successfully normalizes blood flow to organs [30,51]. In an attempt to
assess the microcirculation, numerous techniques have been developed and
used for diagnostic, prognostic and monitoring purposes. These include
laser Doppler, near-infrared spectroscopy, and videomicroscopy [52]. As
previously mentioned, macrocirculatory hypoperfusion is linked to
microcirculatory derangements; however, microcirculatory dysfunction can
occur despite normal macrocirculatory indices. This loss of hemodynamic
coherence may result in cryptic shock with hyperlactatemia and acidemia
despite adequate perfusion parameters [53]. Both clinical and experimental
research has found that normalization of cardiovascular parameters in shock
patients may not indicate similar improvements in microcirculatory
perfusion [30,33,35,54, 55]. Four possible mechanisms that might explain
this discrepancy include:
1. Heterogenous effects of inflammatory cytokines on the microcirculation
2. Intravenous fluid administration and subsequent hemodilution
3. Vasoconstriction of the microcirculation or tamponade from
endogenous/exogenous vasopressors and/or increased venous pressure
4. Edematous interstitium from damaged endothelium and glycocalyx [56]
Direct assessment of microcirculatory flow might therefore be a superior
monitoring tool for determining the presence of microcirculatory
derangements, as well as response to fluid resuscitation.
The use of videomicroscopy techniques such as sidestream dark field
(SDF) and incident dark field (IDF) microscopy enable direct imaging of
the microcirculation and subsequent determination of vessel density and
flow quality [57]. These two technologies require the use of a handheld
device that emits green light (530 nm) onto the mucosa of interest; the light
is absorbed by the hemoglobin of RBCs in the capillary bed of the tissue.
The illuminated RBCs show up as a dark density flowing through the
microcirculation, resulting in a real-time magnified video with resolution to
allow detection of true capillaries (Figure 6.2). Subsequent analysis of the
videos created then generates parameters that reflect the quality and
quantity of microcirculatory flow, including total vessel density (TVD),
proportion of perfused vessels (PPV), perfused vessel density (PVD), and
microvascular flow index (MFI). A standardized approach to microvascular
analysis has been published in the human field and provides consensus
criteria for the acquisition and analysis of microcirculatory images [58].
Figure 6.2 Image of microcirculation in a healthy dog using a sidestream dark-field microscopy. Not
the plethora of capillaries where only a single cell is able to move through at a time (arrows).

Direct microvascular imaging has been explored for two decades in

human medicine and within the past decade in clinical veterinary medicine
[40–41]. However, this technique has not become a standard monitoring
tool for the assessment of response to fluid therapy, likely due to the
limitations of these technologies. The videomicroscope is expensive, not
widely available, and requires the use of thin, mucosal surfaces that are free
of pigmentation due to interference with the light technology used for
imaging. Generation of quality diagnostic videos for analysis requires
training and practice to avoid insufficient or excessive pressure to maximize
focus and flow of blood within the microvasculature [58]. Recent advances
in the automation of vascular analysis (thereby avoiding time-consuming
manual analysis) have proven beneficial; however, the challenges of
accuracy remain in the automated vessel assignment used for these
calculations, which may lead to inconsistencies in the results. As a result,
despite the potential for microvascular imaging to help clinicians evaluating
a patient’s response to fluid therapy, further improvements in automated
vascular analysis and increased availability of the technology are needed
before its use can become routine.
In addition to direct imaging of the microcirculation, compromised
endothelial glycocalyx integrity can be assessed by measuring shed
glycocalyx components in the plasma or serum (e.g., glycosaminoglycans
such as hyaluronan, and proteoglycan ectodomains such as syndecan-1). A
variety of diseases can lead to damage of the ESL and shedding of the
glycocalyx; increased shedding is associated with poor outcomes [59].
There is ongoing research evaluating potential therapeutic strategies that
might stimulate repair of a damaged ESL, including specific fluid therapy
prescriptions.
The assessment of circulating biomarkers to determine the presence of
glycocalyx damage does have limitations. These include the variable
methodology used, potential for other causes of biomarker elevations, since
most are not unique to the glycocalyx, and upregulation of certain markers
with inflammatory or neoplastic diseases. Further details on glycocalyx
biomarkers can be found in Chapter 1.
Evaluation of the ESL has been extensively studied in vivo, ex vivo, and
in vitro using various techniques that include transmission electron
microscopy [60–62], intravital microscopy [63–64], microparticle image
velocimetry [65], confocal laser scanning microscopy or atomic force
microscopy [66], two-photon laser scanning microscopy [67], and
videomicroscopy using handheld devices and different imaging
technologies (i.e., orthogonal polarization spectroscopy, sidestream dark
field imaging and incident dark field imaging) [68]. Recently, indirect
assessment of the glycocalyx has been developed and studied in humans
and small animals using the sidestream dark field microscopic technique in
conjunction with specialized, proprietary software that measures the vessel
lumen width based on RBC movement within as an indirect assessment of
glycocalyx thickness (also known as the perfused boundary region or PBR)
[69–72]. If there is damage to the ESL, RBCs are able to penetrate further
towards the endothelium and the PBR increases [73].

Effects of fluid resuscitation on the

microcirculation in trauma and hemorrhagic
shock
Optimizing fluid therapy in the patient suffering from trauma or
hemorrhage is often challenging, especially when there is ongoing
hemorrhage, as well as progressive anemia, hypoproteinemia and
coagulopathy (see Chapter 5). The preferential use of blood products over
crystalloids or colloids is commonly recommended in human medicine
[74], but the limited natural resources in veterinary medicine frequently
result in more frequent use of crystalloids or possibly synthetic colloids.
Rodent experimental hemorrhagic shock studies have found that the use of
balanced crystalloids, fresh frozen plasma, or concentrated albumin to
restore the ESL to be better than normal saline [75–76]. However, results
are not consistent, and the use of albumin or fresh frozen plasma has been
shown to be more protective than synthetic colloids in a majority of
research studies [77]. Additional factors to consider include the rate and
volume of administration, but definitive guidelines are lacking. Aggressive
fluid administration may exacerbate ongoing hemorrhage, worsen
coagulopathy, and injure the endothelial glycocalyx [78–79].
Microcirculatory changes in response to the various fluid types and rates of
administration are an area of continued research. As stated above, it is
important to recall that improvement of macrovascular parameters does not
always correlate with normalization of microvascular perfusion.
How fluid therapy affects the microvasculature in patients with
hemorrhagic shock has been the subject of many experimental and
preclinical studies. One of the largest systematic reviews of this topic
examined 71 articles between 1990 and 2015 and included the use of blood
products, hemoglobin-based oxygen carriers, crystalloids and colloids for
the management of hemorrhagic shock [80]. The review found that
improvements in the microcirculation occurred more commonly with
solutions containing hemoglobin vs. those without, fluids that were
hyperoncotic vs. those that were not, and fluids that were hyperviscous vs.
those that were not [80]. A comparison of hydroxyethyl starch (HES) and
saline in an experimental sheep model revealed that saline only improved
macrovascular parameters, while HES resulted in better hemodynamic
coherence [81]. Despite this, continued concerns about the adverse effects
of synthetic colloids on kidney function significantly limit their clinical use
in both human and veterinary medicine. It remains unclear whether the use
of a dose-restricted, acute volume expansion with synthetic colloids carries
a similar risk. In humans suffering from hemorrhagic shock, persistent
microcirculatory derangements following resuscitative fluid therapy were
more predictive of the development of multiple organ dysfunction
syndrome than more commonly studied parameters, such as blood pressure
and blood lactate, regardless of the fluid type administered [82].
Whether or not blood transfusion administration restores microvascular
perfusion in patients with hemorrhagic shock is an area of great interest.
Packed RBCs were shown to improve microvascular parameters in trauma
patients that presented with abnormal values, but there was no change, or
even a reduction, in patients that had normal values prior to treatment [83].
A separate pilot study found that although there were no changes in
macrovascular parameters or hemoglobin concentrations following an RBC
transfusion in human patients with hemorrhagic shock, microvascular
perfusion indices did improve significantly [84]. It may be important to take
into consideration the duration of blood product storage prior to
administration; aged RBC units may have more free hemoglobin, which has
been found to scavenge NO and subsequently worsen microvascular blood
flow [85]. The use of plasma as a resuscitation fluid in trauma patients is
under investigation. Preliminary data suggests that plasma therapy may play
an important role in ameliorating immunomodulatory dysfunction and
trauma-induced endotheliopathy [86].

Effects of fluid resuscitation on the

microcirculation in sepsis
For decades, fluid therapy has been a cornerstone of sepsis treatment.
However, the effects of intravenous fluids on microvascular perfusion
depend on multiple factors, including the timing and amount of
administration, as well as the constituents of the fluids. If fluids are given
early to septic patients, microcirculatory parameters improve, but this effect
is not seen with fluid administration in the later stages of sepsis [87]. There
is some evidence suggesting that bolus fluid therapy worsened survival in
people with sepsis [88,89]. Although there was an increase in mean arterial
blood pressure, cardiac index, and sublingual microcirculatory RBC
velocity following a fluid challenge in humans with abdominal sepsis,
intestinal microcirculatory indices were unchanged following
administration [90]. Fluids may even contribute to septic endothelial
dysfunction and glycocalyx damage, although further research is required
[91]. Overall fluid balance in septic patients appears to be of utmost
importance; a positive fluid balance is commonly associated with a worse
outcome [92–97]. The administration of intravenous crystalloid and colloid
fluids was shown to promote endothelial glycocalyx degradation in
endotoxemic sheep [98] and humans with sepsis [91,99]. Potential reasons
for these findings include:
1. Acute stretching of the vessel wall in the presence of inflammatory
mediators could stimulate endothelial expression of glycocalyx-shedding
matrix metalloproteinase [100].
2. An increase in cathepsin L activation (an enzyme that may be involved
in post-translational activation of endothelial heparinase) following
oscillatory shear stress [101].
3. Triggering of neutrophil-elastase glycocalyx destruction secondary to
direct activation of circulating leukocytes [102–104].
4. Increased atrial natriuretic peptide release, which may induce glycocalyx
damage [27,105–106].
The type of fluid administered also affects the glycocalyx in septic patients.
Both laboratory and clinical data have shown that balanced crystalloids,
albumin, fresh frozen plasma, and synthetic colloids may be less injurious
than isotonic saline [107–109]. Albumin administration may preserve the
glycocalyx along with other benefits when compared to isotonic crystalloids
in experimental studies [110–111]; however, research evaluating the
glycocalyx following albumin therapy in septic patients is not yet available.
Concentrated albumin products enhance the delivery of erythrocyte-derived
sphingosine-1-phosphate to the endothelium, which supports glycocalyx
recovery by suppressing metalloproteinase activity [112–114]. The use of
individualized medicine whereby fluid therapy is determined based on
admission markers of endothelial glycocalyx damage might prevent the
negative consequences of fluid administration in patients that are prone to
vascular endothelial leak syndromes and subsequent organ dysfunction
[114].
Conclusion
Coherence between the macro- and microcirculation is often lacking in
humans and animals in shock states due to hemorrhage or sepsis.
Traditional monitoring strategies may not readily detect microvascular
changes in critically ill patients. Intravenous fluid resuscitation plans should
consider macrocirculatory upstream parameters (such as systemic arterial
blood pressure) as well as downstream measures (such as blood lactate
and/or microcirculatory assessments) when monitoring response to
treatment. An exciting path for future research might focus on the use of
different fluid therapy prescription types, rates, amounts, and goals and
their effects on the macro- and microcirculation/endothelial surface layer in
various disease states. How these findings affect patient outcome could
greatly affect the way clinicians administer fluid resuscitation in the future.

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Clinical Case

Microcirculatory changes in a dog

with sepsis secondary to bite
wounds

History
A 5-year-old male castrated Pomeranian (8 kg) was presented to the
emergency clinic 2 days after a fight with the neighbor’s Rottweiler. The
Pomeranian appeared fine, although shaken, to the owners following the
altercation, but had been displaying progressive lethargy and inappetence
over the last 48 hours. On the morning of the day of presentation, the dog
had vomited bile several times and had been sleeping a lot, which was
unusual for him. He also had not eaten breakfast and had passed some
soft, tan stool.

Physical examination and initial diagnostics

The dog was mentally dull, estimated 8% dehydrated, and his mucous
membranes were bright red with a capillary refill time (CRT) of <1
second. The feet were warm to the touch, femoral pulses were bounding
and synchronous with the heartbeat, his heart rate was 178 bpm with no
murmurs or arrhythmias, his respiratory rate was 36 bpm, breath sounds
were clear in all lungs fields, and his rectal temperature was 39.7 °C.
Penetrating bite wounds were discovered over the tail base after clipping
the area; purulent material was easily expressed. The skin appeared
discolored (purple/black) surrounding the puncture wounds and the area
measured approximately 8 cm × 5 cm.
Doppler blood pressure: 100 mmHg
SpO2: 96%
Electrocardiogram: sinus tachycardia
An intravenous catheter was placed in the right cephalic vein and a
venous blood gas was obtained, with the following results:
pH: 7.04;
pCO2: 29.3 mmHg;
pO2: 27 mmHg;
Na: 149.1 mmol/L;
K: 3.23 mmol/L;
Cl: 113.8 mmol/L;
Glu: 8.3 mmol/L;
Lactate: 4.7 mmol/L;
BE: -18.0 mmol/L;
HCO3-:12.2 mmol/L;
PCV: 46%;
TP: 78 g/L.
The patient appeared adequately perfused based on the physical
examination and blood pressure, but the tachycardia suggested either
pain, compensated shock, or systemic inflammation, or a combination of
these etiologies (other possibilities do exist as well). The venous blood
gas showed a primary metabolic acidosis with respiratory compensation.
The increased lactate, decreased base excess, and decreased bicarbonate
support a lactic acidosis.
Focused assesment with sonography for trauma of the thorax and
abdomen (TFAST and AFAST) were negative (no free fluid or other
abnormalities). The left atrium to aorta ratio was 1:1. Chest radiographs
were performed and interpreted as unremarkable.

Treatment
Treatment was initiated and included three 10 mL/kg boluses of
PlasmaLyte, each over 15–20 minutes. Methadone (0.1 mg/kg IV) and
maropitant (1 mg/kg IV) were also administered, and the patient’s heart
rate following these treatments was 130 bpm, his respiratory rate 28 bpm,
his rectal temperature 39.1 °C, and his Doppler blood pressure 120
mmHg. Antimicrobial therapy was initiated using ampicillin (22 mg/kg
IV) and enrofloxacin (15 mg/kg IV).
The dog was anesthetized for exploration of the wound. An arterial
catheter was placed for direct blood pressure monitoring. A large abscess
(8 cm ×12 cm) was identified and drained, flushed, and debrided to
remove necrotic skin/subcutaneous tissues. The wound was left open
with a wet to dry bandage, which was changed 1–2 times per day as
needed. While under general anesthesia, the dog’s heart rate was 128
bpm, his respiratory rate 14 bpm and his esophageal temperature 37.8 °C.
His mucous membranes were still bright pink with a rapid CRT, and his
direct arterial blood pressure was 110/30 with a mean of 58 mmHg. A
videomicroscope was used to evaluate the microcirculatory parameters
using the vessels in the buccal mucosa. Interpretation was consistent with
a decrease in the number of capillaries (see picture below), a decrease in
perfusion indices, and a decrease in the microcirculatory flow index.
Presumably, cytokines such as NO were causing heterogenous
redistribution of blood flow with vasodilation of some capillary beds, but
vasoconstriction of others. This created the bright mucous membranes
with brisk CRT as well as the bounding pulses (due to a decrease in the
diastolic blood pressure while systolic pressure was borderline normal).
Although there is no known treatment for microcirculatory
derangements, treatment of the underlying inflammatory stimulus and
restoration of adequate intravascular volume and albumin are necessary.
In this case, removal of the inflammatory stimulus included surgery,
debridement, and frequent bandage changes to continue gentle
debridement and encourage granulation tissue. Intravenous, broad-
spectrum, bactericidal antimicrobial therapy was continued pending
aerobic and anaerobic cultures and susceptibility results.
The wound was severely effusive with exudative secretions for 4 hours
following surgery and required bandage changes every 8–12 hours due to
strike-through of the bandage. The PCV/TP was 33/34 g/L on day 1
postoperatively. The albumin concentration at that time was 14 g/L and
the coagulation times were normal. Due to the increased fluid losses from
the wound, requirement for high rates of intravenous crystalloids to
maintain hydration and intravascular volume, and continued inappetence
of the dog, a continuous infusion of cryopoor plasma was initiated at 1.5
mL/kg/hour and continued for 36 hours. This fluid was chosen to
decrease the isotonic crystalloid rate to 1 mL/kg/hour while providing a
natural source of albumin to prevent a further decrease in the serum
albumin concentration and help maintain endothelial integrity.

The dog’s clinical signs of sepsis improved, the mucous membranes

appeared more normal on day 3 after wound exploration, and the blood
pressure and temperature normalized. The dog started eating voluntarily
on day 4 post-surgery. Organisms identified from the wound included
Pasteurella canis and Neisseria weaveri. Both were susceptible to
amoxicillin–clavulanic acid, so the dog was switched to oral therapy as
indicated.

Discharge and follow-up

On day 5 after the initial surgery and debridement, the dog was
anesthetized for wound closure. Repeat microcirculatory analysis was
performed while the dog was under general anesthesia. There was
marked improvement in the microcirculatory capillary numbers,
perfusion indices, and microcirculatory flow index, as would be expected
based on the clinical improvement in the dog’s disease process. The dog
was discharged on day 6 and continued his recovery at home. He was
prescribed gabapentin for pain and 5 additional days of ampicillin–
clavulanic acid. He was doing well at his follow-up examination 2 weeks
after discharge.