Anaphylaxis in Dogs and Cats

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Anaphylaxis in Dogs and Cats

Anaphylaxis, an acute and severe systemic allergic reaction that can be life-threatening, is
due to a massive release of inflammatory mediators by mast cells and basophils. It is triggered
by a wide variety of antigens, but most commonly by vaccines, drugs, insect and reptile venoms,
antimicrobials, non-steroidal anti-inflammatory medication, glucocorticoids, opiates, foods and
physical factors like cold and exercise. This hypersensitivity reaction can affect multiple organs,
including dermal, gastrointestinal, respiratory, cardiovascular, neurological and ocular
systems. Due to the wide variability in clinical manifestation and lack of accepted standard
working definitions, anaphylasixs can be difficult to diagnose. Its diagnosis is based primarily
on pattern recognition when there is a sudden onset of characteristic signs after exposure to a
known or potential stimulus.

Figure 1: Prior sensitization to an allergen results in an immune response initially mediated by


Th2 lymphocytes that promote mast cell proliferation and plasma cell production of IgE.
Pathophysiology:
Mast cells are the most important effector cells of immediate hypersensitivity reactions
and normally are present in high numbers in skin and mucosal surfaces. Anaphylaxis, as a Type
I hypersensitivity reaction, is mediated by IgE and basophil and mast cell activation and
degranulation. Prior sensitization to an allergen results in an immune response initially mediated
by Th2 lymphocytes that promote mast cell proliferation and plasma cell production of IgE (See
Figure 1). IgE will then bind to mast cells and basophils by high affinity receptors (for the Fc
portion of the immunoglobulin). With repeated exposure to the antigen, there is cross linkage of
the IgE molecules and this leads to degranulation of primary mediators (histamine, tryptase,
heparin, serotonin, cytokines, etc) within seconds to minutes. Histamine is the main mediator
and causes vasodilation, increased vascular permeability, bronchoconstriction, coronary artery
smooth muscle constriction, urticaria, and fever. Activation of the arachidonic acid cascade
occurs within minutes and results in release of secondary mediators (i.e. leukotrienes,
prostaglandins, etc.) which induce vasodilation, increase vascular permeability, potentiate
generation of histamine, cardiodepression, and increased airway mucus production.

Clinical signs and diagnosis:


A high index of suspicion for anaphylaxis is essential for a rapid diagnosis and initiation
of treatment. In human medicine, there are universal clinical criteria and biomarkers (histamine
and tryptase) for diagnosing anaphylaxis. Unfortunately, this may not be translatable to
veterinary medicine due to different target shock organs in humans and animals. Acute systemic
anaphylaxis manifests differently between species in terms of the major organ systems affected
and the clinical signs. The different physiological response is related to variations in the immune
system reponse, location and distribution of smooth muscle, rate of antigen degradation and
responsiveness to inflammatory mediators. It is directly related to the location of the largest
population of mast cells found in different species. The primary affected organs in humans are
the lungs and heart, in dogs the gastro-intestinal tract and liver and in cats the respiratory and
gastro-intestinal tract.
Figure 2: “Halo sign” or gallbladder wall edema noted on abdominal

Nearly any antigen that stimulates mast cells and basophils can cause anaphylaxis. Clinical signs
typically manifest soon after antigenic exposure (5-30 minutes) and progress rapidly over
minutes to hours. Sometimes, anaphylactic reactions may take hours to manifest or even be
biphasic in nature. Biphasic reactions will occur then abate with a time interval range of 1-72
hours (on average within 8-10 hours). In the human literature, persistent anaphylaxis has been
described lasting up to 32 hours despite aggressive treatment. In general, the sooner the
manifestion of anaphylaxis, the more severe the reaction will be. However, it is impossible to
anticipate the severity of anphylaxis and whether there will be a biphasic or persistent
component.

The signs and symptoms can be divided into four major target organs – cutaneous,
respiratory, cardiovascular and gastrointestinal, however neurological and ocular systems can be
impacted as well. The essential clinical feature of cardiovascular compromise is hypotension
due to a distributive-hypovolemic state. Due to increased vascular permeability, there is a rapid
and major shift of intravascular fluid to extravascular space in as little as 10 minutes. The
cutaneous signs (erythema, urticaria, pruritis, and facial angiodema) are usually subtle and a
recent study found that only 57% of dogs have detecable cutaneous signs. This is likely due to
their fur and pigmentation making it difficult to detect. Respiratory signs include cough,
tachypnea, stridor, dypsnea, and tachypnea. Pharyngeal and laryngeal edema, increased mucus
production, and bronchoconstriction all contribute to cause dyspnea. The gastro-intestinal signs
are mainly nausea, vomiting, and diarrhea with or without blood. A 2009 study by Quantz et al.
showed that an increase in ALT and multiple striations in the gallbladder wall (i.e. halo or double
rim effect) are supportive of anaphylactic reactions. ALT was shown to rapidly increase (<12
hours) with a peak at 24-48 hours due to alterations in blood flow to the liver and likely direct
cytokine injury. The gall bladder wall “halo sign” (See Figure 2) occurred secondary to impaired
venous drainage (although it is not pathognomic for anaphylaxis). The reported sensitivities and
specificities for ALT elevation were 85% and 98%, and for the “halo sign” were 93% and 98%,
respectively.

Anaphylactic shock is the terminal phase of anaphylaxis involving multiple organ systems, with
the most severe changes involving the cardiovascular and pulmonary systems. Clincial signs of
anaphylactic shock can resemble signs from any cause of severe cardiopulmonary collapse. It is
important to rule out other conditions as they can present similarly (i.e. severe asthma, syncope,
pheochromocytoma, systemic mastocytosis, septic and cardiogenic shock, etc.).

Treatment:
Anaphylaxis is a true medical emergency and requires immediate intervention. Goals of
treatment are aimed at stabilization and include establishment of a patent airway, vascular
access, fluid therapy and administration of epinephrine. Depending on severity, airway
management may require supplemental oxygen or may require tracheal intubation or
tracheostomy. Mechanical ventilation may be required in severely affected patients with
edematous airways, pulmonary edema and bronchoconstriction.

Vascular access is critical for administration of fluid therapy and drugs. Aggressive fluid
therapy should be guided based on the patient’s cardiovascular parameters. Epinephrine is the
drug of choice and mainstay of therapy for anaphylaxis because it relieves bronchoconstriction,
supports arterial blood pressure, inhibits further mast cell degranulation, improves cardiac
contractility and heart rate and improves coronary artery blood flow. The recommended dose is
0.01-0.02mg/kg intramuscularly for less severe cases. Subcutaneous administration should be
avoided due to slow onset of pharmacological effect. The epinephrine dose can also be doubled
and given intra-trachea if vascular access is not available. In severe cases where shock has
already developed or there is refractory hypotension, a continuous rate infusion can be started at
0.05mcg/kg/min and titrated to effect.

Adjunctive therapy for anaphylaxis includes use of antihistamines, glucocorticoids and


additional supportive measures, as needed for hypotension, pulmonary edema,
bronchoconstriction, and arrhythmias. Although antihistamines and glucocorticoids are too slow
to be helpful in the initial management, they play an important role in preventing late phase
reactions and complications caused by secondary mediators. Diphenhydramine 2mg/kg IM is
the most commonly used H1-antihistamine and is expected to relieve cutaneous and nasal
symptoms in anaphylaxis. H2-antihistamines (i.e. famotidine 1mg/kg IV) used in combination
with H1-antihistamines have been reported to be more effective at improving the cutaneous signs
seen with anaphylaxis as well as decreasing gastric acid secretion. Dexamethasone 0.1-0.5mg/kg
IV is the most commonly used glucocorticoid, but benefits are not seen for at least 4-6
hours. Glucocorticoids block the arachidonic acid cascade and may reduce the severity of the
late phase reaction. Bronchodilators such as aminophylline (5-10mg/kg IM dogs and 5mg/kg
cats) or inhaled albuterol, should be employed if bronchospasms persists despite epinephrine
administration.

While there is no consensus on the time for monitoring needed for anaphylaxis, patients
that respond to therapy would benefit from 24 hours of careful monitoring and observation. The
prognosis for anaphylaxis is dependent on the severity and progression of the reaction and
preventive measures of avoiding potential triggers is highly recommended.

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