Vec 12066
Vec 12066
Abstract
Objective – To review and summarize current information regarding the pathophysiology and clinical man-
ifestations associated with anaphylaxis in dogs and cats. The etiology, diagnosis, treatment, and prognosis is
discussed.
Etiology – Anaphylaxis is a systemic, type I hypersensitivity reaction that often has fatal consequences. Many
of the principal clinical manifestations involve organs where mast cell concentrations are highest: the skin, the
lungs, and the gastrointestinal tract. Histamine and other deleterious inflammatory mediators promote vascular
permeability and smooth muscle contraction; they are readily released from sensitized mast cells and basophils
challenged with antigen. Anaphylaxis may be triggered by a variety of antigens including insect and reptile
venom, a variety of drugs, vaccines, and food.
Diagnosis – Anaphylaxis is a clinical diagnosis made from a collection of signs and symptoms. It is most
commonly based on pattern recognition. Differential diagnoses include severe asthma, pheocromocytoma, and
mastocytosis.
Therapy – Epinephrine is considered the drug of choice for the treatment of anaphylaxis. It acts primarily as
a vasopressor in improving hemodynamic recovery. Adjunctive treatments include fluid therapy, H1 and H2
antihistamines, corticosteroids, and bronchodilators; however, these do not substitute for epinephrine.
Prognosis – Prognosis depends on the severity of the clinical signs. The clinical signs will vary among species
and route of exposure. The most severe clinical reactions are associated when the antigen is administered
parenterally.
Introduction
Abbreviations
Definitions for anaphylaxis in common use include ‘‘a
ALT Alanine transaminase
severe, potentially fatal, systemic allergic reaction that
AVP Arginine-vasopressin
occurs suddenly after contact with an allergy causing
CO Cardiac output
substance”1 and ‘‘a serious allergic reaction that is rapid
H1R H1 histamine receptor
in onset and might cause death.’’2 From the standpoint
H2R H2 histamine receptor
of the specialist in allergy-immunology, an anaphylactic
H3R H3 histamine receptor
reaction is mechanistically defined as “a systemic, imme-
H4R H4 histamine receptor
diate hypersensitivity reaction most commonly caused
IgE Immunoglobulin E
by IgE-mediated immunologic release of mediators from
IgG Immunoglobulin G
mast cells and basophils.”3 The term, anaphylaxis, is de-
IL Interleukin
rived from the Greek words a (against) and phylaxis (pro-
MAP Mean arterial pressure
tection). The phenomenon of anaphylaxis was first de-
NO Nitric oxide
scribed in 1902 by Portier and Richet when they were
NSAIDs Nonsteroidal anti-inflammatory agents
attempting to produce tolerance in dogs to sea anemone
PAF Platelet activating factor
SRS-A Slow-reacting substances of anaphylaxis
From the Oradell Animal Hospital, Emergency and Critical Care, 580 Winters VAAEs Vaccine-associated adverse events
Avenue, Paramus, NJ 07652. WAO World Allergy Organization
The authors declare no conflict of interests.
Address correspondence and reprint requests to
Dr. Daniella L. Shmuel, Oradell Animal Hospital, Emergency and Critical
Care, 580 Winters Avenue, Paramus, NJ 07652, USA.
Email: [email protected] venom. Rather than generating protection, it precipitated
Submitted October 31, 2011; Accepted May 27, 2013. the rapid onset of fatal or near-fatal symptoms. They
C Veterinary Emergency and Critical Care Society 2013 377
D. L. Shmuel and Y. Cortes
concluded that the immune system first becomes sen- epidemiologic evidence in human medicine estimated
sitized to the allergen over several weeks and upon re- that the frequency of anaphylaxis was approximately 50–
exposure to the same allergen may result in a severe 2,000 episodes per 100,000 persons or a lifetime preva-
reaction. They coined the term "aphylaxis" to differen- lence of 0.05–2.0%.2, 26, 29–31
tiate it from the expected "prophylaxis" they hoped to Although the prevalence of anaphylaxis in small ani-
achieve. The term aphylaxis was replaced with the term mals is unknown, anaphylactic reactions are being seen
anaphylaxis shortly thereafter.3, 4 with increasing frequency, as the number of antigenic
Although anaphylaxis was first described over 100 substances to which patients are exposed increases, both
years ago and is one of the most alarming disorders as diagnostic aids and therapeutic modalities.5 More-
encountered in humane medicine, the definition of this over, nearly any foreign substance by any route of expo-
term has been elusive since its discovery and there is still sure is a potential cause of these reactions.28 The sudden,
debate as to the proper definition for the term “anaphy- often unanticipated, onset and the catastrophic impact
laxis.” It seems anti-intuitive that a phenomenon with of anaphylaxis makes proper diagnosis and appropriate
such explosive manifestations and distinct symptoms treatment critical to favorable patient outcomes.
should be difficult to define. The lack of specific crite-
ria for diagnosing anaphylaxis has greatly hampered
research into the epidemiology, pathophysiology, and Pathophysiology
management of this disorder, subsequently resulting in
a failure to diagnose and treat anaphylaxis in a consis- Anaphylaxis is a systemic, immediate type hypersen-
tent manner.1 In the last decade, great effort has been sitivity reaction.28, 31 The traditional nomenclature for
made to determine the criteria necessary to make a di- anaphylaxis reserves the term anaphylactic for reactions
agnosis and to establish appropriate terminology suit- mediated by immunoglobulin E (IgE) and the term ana-
able for all episodes.3 Published reports of anaphylac- phylactoid for IgE-independent events. Clinically, these
tic reactions in veterinary patients are unusually rare.5 are indistinguishable; therefore, diagnosis and treat-
To the authors’ knowledge, there are less than 25 clin- ment are identical. In 2003, the World Allergy Organiza-
ical reports published since 1950, most of which de- tion (WAO) suggested that the term “anaphylactoid” be
scribed reactions to antimicrobials, vaccines, and Hy- abandoned and all such events, regardless of the mecha-
menoptera stings.6–25 This makes determining the risks nism of production, be called “anaphylactic episodes.”2
of anaphylaxis difficult to assess in veterinary patients, The WAO further suggested that these anaphylactic
as it is likely that many more reactions have been ob- episodes be divided into immunologic and nonimmuno-
served, but go unreported for a variety of reasons. This logic events.2 The nonimmunologic anaphylactic events
review relies on both the human and veterinary litera- could be considered synonymous with the term “ana-
ture to summarize the pathophysiology, clinical presen- phylactoid,” and the immunologic events were further
tation, therapeutic recommendations, and prognosis of subcategorized as IgE- and non-IgE-mediated.2 The de-
anaphylaxis. bate as to whether all clinically similar events, not medi-
ated by IgE, should also be referred to as anaphylactic as
suggested by the WAO or called anaphylactoid reactions
Epidemiology still rages on.
Only 1% of human emergency department visits for Anaphylactic reactions are currently classified as
acute systemic allergic reactions receive the diagnosis follows:2, 31
of anaphylaxis; many visits are coded as "acute allergic
reactions," or "acute hypersensitivity reactions."26 There
is consistent failure to appreciate the variable presen- 1. Immunologic IgE-mediated: Causes include, but are
tations and disagreement among physicians in what is not limited to, insect stings/bites, reptile venom, food,
severe enough to be considered anaphylaxis rather than and medications (eg, -lactam antimicrobials).
an allergic reaction.1, 27 Underreporting and miscoding of 2. Immunologic non-IgE-mediated: Caused, for exam-
anaphylaxis remain current important issues in human ple, by immune aggregates (eg, IV immunoglobulin,
as well as in veterinary medicine. In prospective human such as IgG- or IgM-related, transfusion), comple-
medicine studies, underreporting likely occurs because ment system activation, coagulation system activa-
anaphylaxis may be underdiagnosed in individuals who tion, and autoimmune mechanisms.
present with mild or partially treated episodes.26 Also, 3. Non-immunologic: Causes include, but are not lim-
underdiagnosing is more likely to occur if it is a patient’s ited to, physical factors (eg, cold, water exposure,
first episode or if there is a hidden or previously un- heat, and exercise), certain medications (eg, opioids),
recognized trigger.26, 28 A recent review of the available and some chemotherapeutic agents.
378
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protracted reactions.43 Of the newly formed mediators, ficient return of blood to the heart.78 Hepatic changes,
PAF, a potent bronchoconstrictor, has been suggested to as a result of anaphylaxis, have been demonstrated in
play a major role in anaphylaxis. PAF decreases coro- multiple veterinary clinical reports. In one study, one
nary blood flow and myocardial contractility, causes a dog progressed to severe hepatic compromise follow-
prolonged increase in pulmonary resistance, and induces ing an insect sting.20 Another case report revealed sig-
local and systemic platelet aggregation as well as periph- nificant postmortem changes in the hepatic system, in-
eral vasodilatation and severe hypotension.32, 46, 49, 67, 68 cluding portal vein, central vein, and sinusoidal con-
Tumor necrosis factor-␣ activates neutrophils, recruits gestion following dexamethasone administration in a
other effector cells, and increases chemokine synthesis.32 dog.15 And a recent study revealed expected antemortem
Tryptase, a serine protease activates complement, coagu- changes in the liver and gallbladder in dogs with ana-
lation pathways, and the kallikrein-kinin contact system phylaxis. This study showed that an increase in activity
with the potential clinical consequences of hypotension, of the hepatic enzyme, alanine transaminase (ALT), and
angioedema, clot formation, and disseminated intravas- an abnormal gallbladder wall (eg, thickened wall with
cular coagulation.33, 46 a distinctive striated pattern) proved to be significant
markers of anaphylaxis in dogs with hypersensitivity
reactions.73
Shock Organs There is little published information on the effects of
There are well-recognized species differences for acute acute systemic anaphylaxis in cats and the few that exist
systemic anaphylaxis in the major organ systems affected report almost entirely subjective assessments and clinical
and the associated clinical signs. The different physio- signs rather than objective physiological variables.74–76 It
logical response to a similar antigen challenge is influ- was originally thought that cats could not be sensitized
enced by variations in immune response, location and to foreign antigens, since no reliable method was devel-
distribution of smooth muscle, rate of antigen degrada- oped until the late 1960s.74 A recent in vivo study was
tion, and responsiveness to inflammatory mediators.33 conducted and aimed to understand the pathophysiol-
Clinical manifestations of anaphylactic reactions are ogy of anaphylaxis in Dirofilaria immitis-sensitized cats.74
therefore species dependent and directly related to the This was achieved by investigating objective physiologi-
location of the largest population of mast cells.73 In cal and hematological measurements after an IV antigen
people, the predominant “shock organs” are the lungs challenge and by describing the major clinical signs as-
and the heart.33, 43, 69 In the dog, the gastrointestinal sociated with it.74 The main physiological effects found
tract and the liver57, 70–73 are the primary affected or- in this experimental model included severe dyspnea
gans, whereas in the cat the respiratory tract pre- and reduced blood oxygen saturation, expired carbon
dominates.57, 69–71, 73–75 dioxide, and systolic blood pressure. The most common
In dogs, it appears that the severity of shock is directly and reliable hematological change associated with se-
proportional to the degree of congestion to the liver and vere clinical effects of D. immitis antigen challenge was
gallbladder.77 Histamine is released from the gastroin- increased HCT. The loss of intravascular fluid during
testinal tract into the portal vein during anaphylaxis; this acute systemic anaphylaxis could explain the rise in
causes hepatic arterial vasodilation and a concurrent in- HCT seen in this study. Also, increased sympathetic tone
crease in arterial hepatic blood flow within seconds.73, 78 due to acute hypoxemia in acute systemic anaphylaxis
The intraportal infusion of histamine also causes a con- could result in splenic contraction. Since the feline spleen
siderable increase in hepatic venous outflow obstruc- has a large capacity to store both red blood cells and
tion (attributed to the hepatic venous sphincter at the platelets, splenic contraction results in the addition of
junction of the inferior vena cava and the hepatic veins large numbers of these cells to the circulating pool.74 Sus-
in the dog) which, in turn, increases the hepatic portal tained dyspnea and gastrointestinal signs were the most
vascular resistance significantly (up to 220% in approxi- common clinical manifestations of anaphylaxis in the
mately 12 seconds).73, 78, 79 Consequently, the portal blood antigen-challenged cats. This in vivo study concluded
supply and the venous return from the liver to the sys- that IV challenge with D. immitis antigen in sensitized
temic circulation are severely compromised.73, 78–80 Since cats resulted in dyspnea, hypoxemia, and systemic hy-
the cardiac output (CO) is generally equal to that of ve- potension accompanied by hemoconcentration.74 The
nous return, it is the reduced venous return rather than a rationale for this work was to provide a feline model
failing heart that accounts for the markedly suppressed of acute systemic anaphylaxis, presenting an objective
CO observed.81 This said, histamine acts primarily on framework for comparison with other species in which
hepatic veins to raise intrahepatic pressure and produce the lung is the main shock organ and the possible devel-
massive infiltration of fluid, which results in an insuf- opment of therapies for anaphylaxis.74
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D. L. Shmuel and Y. Cortes
Etiology and Clinical Manifestations cular signs include arrhythmias, myocardial ischemia,
and cardiac arrest.57, 84 Gastrointestinal symptoms are
Virtually any agent capable of activating mast cells or ba-
common but nonspecific, and include nausea, vomit-
sophils might potentially cause anaphylaxis.43 The most
ing, and diarrhea, which may be hemorrhagic.4, 28, 56, 57
common antigens identified in the veterinary literature
Other manifestations of anaphylaxis include neurologic
include insect and reptile venom, antimicrobial agents,
and ocular signs, such as weakness, syncope, seizures,
NSAIDs, opiates, vaccines, blood-based products, radio-
conjunctival injection, and lacrimation.57, 70, 71
contrast agents, food, and physical factors (ie, cold and
Dogs usually exhibit signs related to the general sys-
exercise).15, 57, 70, 82
temic circulatory system. Hypotension and cardiovascu-
Signs and symptoms can be divided into 4 major cat-
lar collapse are often clinically observed, while signs of
egories: cutaneous, respiratory, cardiovascular, and gas-
respiratory compromise are less common.41, 57, 73 In addi-
trointestinal. In people, the most frequent manifestations
tion, hepatic signs are also predominant.57, 73, 80, 88 Hep-
of anaphylaxis are cutaneous, occurring in 80–90% of re-
atic venous congestion is manifested which results in
ported series.56 Cutaneous signs are considered as poten-
portal hypertension and visceral pooling of blood lead-
tial precursors to more severe anaphylactic reactions.4, 56
ing to vomiting and diarrhea.57, 59, 73, 88 Immediate and
However, they may be delayed or absent in rapidly
fulminating hemorrhagic enteritis is one of the main
progressive anaphylaxis.1, 27, 56, 73 Severe episodes char-
antemortem clinical manifestations in dogs, while se-
acterized by rapid cardiovascular collapse and shock
vere congestion of the liver and intestines is observed
can occur without cutaneous manifestations.1, 4, 27, 56
at necropsy.88–90 Cats often exhibit pulmonary and gas-
Cutaneous symptoms seen in dogs and cats commonly
trointestinal signs, with respiratory distress being typi-
consist of generalized erythema, urticaria, pruritis, and
cally the first sign observed.57, 74–76 Other manifestations
facial angioedema.57, 70 Although cutaneous signs are
observed in cats include hypersalivation, facial swelling,
commonly reported in anaphylaxis, these symptoms are
severe pruritis, incoordination, vomiting, and hemor-
often subtle and short-lived.2, 57, 83 A recent study in
rhagic diarrhea, which may eventually lead to hypo-
canine hypersensitivity patients found that cutaneous
volemic shock.24, 41, 57, 91
manifestations were milder and more challenging to
There appears to be a lack of reported anaphylac-
identify in patients with anaphylaxis, most likely be-
tic reactions described in cats in the veterinary litera-
cause of their fur and pigmentation, with only 57%
ture. It may be because these systemic reactions do not
having detectable cutaneous manifestations.73 Common
occur as frequently or simply go unrecognized com-
respiratory manifestations consist of dyspnea, bron-
pared to dogs. Three recent publications further sup-
chospasm, stridor, tachypnea, and cough.57 Dyspnea
port this. A retrospective study, evaluating the incidence
results from laryngeal and pharyngeal edema, bron-
of vaccine-associated adverse events (VAAEs), showed
choconstriction, and excessive mucus production. The
that the overall VAAE rate within 3 days of vaccine ad-
cardinal clinical feature of cardiovascular compromise
ministration in cats was approximately 25% greater than
during anaphylaxis is hypotension.84 This may be as-
in dogs.91, 92 Nonspecific systemic reactions with clini-
sociated with clinically obvious vasodilation (ie, gen-
cal signs of anorexia, lethargy, fever, or soreness were
eralized erythema) or a rapid onset of shock with pe-
the most common VAAEs observed. However, clinical
ripheral circulatory failure. Clinical signs in dogs may
signs attributable to anaphylaxis (eg, vomiting, facial
include pale mucous membranes with a prolonged cap-
edema, and pruritus) were less common in this cat pop-
illary refill time, poor pulse quality, hypothermia, and a
ulation than reported in dogs. Specific causes of vaccine-
depressed to dull mentation.70 The main cardiovascular
induced immediate-type hypersensitivity reactions have
changes are fluid extravasation and vasodilation, caus-
not been investigated in cats, but heterologous proteins
ing a mixed distributive-hypovolemic shock pattern.84, 85
(eg, bovine serum albumin) found in vaccines have been
Increased vascular permeability, a key characteristic fea-
implicated as a cause in dogs.93 Also, a published re-
ture of anaphylaxis, allows massive fluid shifts of as
port describing an anaphylactic event due to ophthalmic
much as 35% of the intravascular volume into the ex-
medication in a cat might have helped increase pub-
travascular space within 10 minutes.1, 2, 27, 33, 56, 84, 85 The
lic awareness. Two additional cases were reported to
redistribution of blood volume can result in rapid hemo-
the pharmaceutical company shortly thereafter.18 There
dynamic collapse, with little or no cutaneous or respi-
is rising concern that many more cases of anaphylaxis
ratory manifestations. Additionally, anaphylaxis is often
due to ophthalmic medications have gone unrecognized
associated with a compensatory tachycardia occurring in
and potentially attributing the cause of death related to
response to the decreased effective vascular volume.84, 86
the anesthesia rather than anaphylaxis during routine
However, bradycardia, presumably caused by increased
surgeries. Another recent publication showed similar
vagal reactivity, can also occur.3, 42, 84, 87 Other cardiovas-
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Anaphylaxis in dogs and cats
findings, where only half of the cases were reported to type III hypersensitivity. All dogs developed signs of a
a regulatory agency or pharmaceutical company follow- type III hypersensitivity reaction 5–13 days after admin-
ing anaphylactic reactions to ophthalmic antibiotics in istration of 25% human albumin solution. Clinical signs
cats.24 included lethargy, lameness, edema, and cutaneous le-
Anaphylaxis usually occurs rapidly, eliciting clinical sions indicative of vasculitis, vomiting, and inappetence.
signs within minutes of antigenic exposure (5–30 min- All dogs included in the study were found to have anti-
utes), followed by rapid progression over minutes to human albumin antibodies.102
hours.2, 3, 33, 34, 43, 56, 57 Occasionally, some reactions may Anaphylactic reactions after parenteral antigenic ex-
not develop for several hours. As a general rule, the on- posure are usually more immediate at onset, more
set of clinical signs is directly proportional to the sever- rapidly progressive, and more severe in quality com-
ity of the systemic reaction; the sooner the syndrome pared with those occurring after topical or cutaneous
manifests after antigenic exposure, the more severe the exposure.15, 49, 57 It can be difficult to predict the rate of
reaction will be.1, 4, 15, 33, 46, 49, 56, 57, 94 An episode can abate progression or the ultimate severity of the reaction since
and then exhibit a recurrence several hours after the dis- anaphylactic episodes can manifest in unusual ways.
appearance of the original manifestations. Such events Anaphylaxis can also resolve spontaneously within min-
are termed “biphasic” anaphylactic episodes. The oc- utes to hours if there is sufficient endogenous produc-
currence of biphasic reactions in the human literature tion of compensatory mediators, such as epinephrine,
appears to occur in as low as 1% to as high as 20% of angiotensin II, and endothelin.30, 42, 53 One study evalu-
anaphylactic reactions.1–3, 42, 43, 87, 95 The reported time in- ating insect sting hypersensitivity reactions in humans
terval between the initial reaction and the onset of the showed gradual hemodynamic recovery over a period
second phase ranges from 1 to 72 hours (most within of 60–90 minutes postchallenge, and did not seem di-
8–10 hours).1–4, 26, 43, 57, 95 Biphasic reactions, also referred rectly related to any specific therapeutic intervention.53
to as late phase reactions, are thought to increase the However, in fatal cases of anaphylaxis, cardiovascular
risk of fatal anaphylaxis.1, 43, 56, 95 Persistent anaphylaxis, and respiratory disturbances predominate and usually
defined as an anaphylactic reaction that continues for a occur early.15, 33, 43, 56 Death as a result of anaphylaxis
protracted period of time, has also been described in the can occur within minutes1, 2, 56, 103, 104 and is frequently
human literature.2, 4, 43, 55, 96 Although uncommon, some reported to occur in less than 1 hour.70, 71, 73, 105–108 Ana-
protracted reactions can last up to 32 hours, despite ag- phylaxis occurs as part of a dynamic continuum; symp-
gressive treatment.96 Similar to biphasic anaphylaxis, it toms not appearing immediately life-threatening may
is impossible to anticipate these reactions based on ini- progress quickly unless treated aggressively.
tial clinical presentation.1, 2, 4, 43 Other types of hypersen-
sitivity reactions can also occur days to weeks postanti-
Diagnosis
genic exposure. These immune responses are known as
type III or immune complex-mediated hypersensitivity Due to the lack of accepted standard working defini-
reactions. Serum sickness is an example of this type of tion and wide variability of clinical manifestations, ana-
reaction.97–99 The pathogenesis involves synthesis of an- phylaxis can be difficult to diagnose.1 The diagnosis
tibodies (IgG) that bind to the antigens, forming solu- is based primarily on a detailed history and clinical
ble immune complexes in the presence of antigen ex- findings.1, 2, 26, 27, 33 Information regarding a previous his-
cess. An inflammatory cascade ensues as complement tory of hypersensitivity reactions, recent vaccinations,
is bound and anaphylatoxin is generated, leading to previous transfusions, exposure to new foods, medica-
mast cell degranulaton.100, 101 Histamine released from tions, and insect bites or stings should be included in the
mast cell granules causes increased vascular permeabil- history.26, 56 Diagnosis also depends on pattern recogni-
ity, local platelet aggregation, and vasoactive amine re- tion. It involves the sudden onset of characteristic signs
lease from activated platelets.100 The cascade of events and symptoms after exposure to a known or potential
leads to basement membrane damage with resultant stimulus, the time elapsed between exposure and symp-
vasculitic skin lesions, immune-mediated polyarthritis, tom onset, and the evolution of these manifestations over
proteinuria, and myocardial lesions, with potentially, minutes to hours.1, 2, 51
secondary arrhythmias.102 In people, signs can begin be- The vast majority of patients presenting with a his-
tween 3 and 21 days postexposure with most occurring tory consistent with anaphylaxis will have experienced
at 7–10 days.97, 99 A recent publication described the first an anaphylactic event. Nonetheless, it is important not
reported case of antivenin-associated serum sickness in to immediately assume this diagnosis. Several systemic
a dog.97 Another report suggested that administration conditions may present themselves with similar clini-
of human albumin solution in healthy dogs with normal cal signs. Severe asthma, pheochromocytoma, vasode-
serum albumin concentrations may result in signs of a pressor events (vasovagal), and systemic mastocytosis
C Veterinary Emergency and Critical Care Society 2013, doi: 10.1111/vec.12066 383
D. L. Shmuel and Y. Cortes
should be considered in the differential diagnoses of Table 1: Clinical criteria for diagnosing anaphylaxis1–3, 27, 56
anaphylaxis.4, 56, 57 In addition, other causes of shock,
Anaphylaxis is highly likely when any 1 of the following 3 criteria is
cardiovascular and respiratory events of unknown etiol-
fulfilled:
ogy have the ability to mimic the clinical presentation of 1. Acute onset of an illness (minutes to several hours) with involvement
anaphylaxis.56 IV lipid emulsion has also been reported of the skin, mucosal tissue, or both (eg, generalized hives; pruritus
to cause clinical “anaphylactoid-like signs,” which can or flushing; swollen lips, tongue, vulva)
occur within 20 minutes of administration.109 These reac- And at least 1 of the following:
a. Respiratory compromise (eg, dyspnea, wheeze/bronchospasm,
tions are rare and have been reported to occur in less than
stridor, reduced peak expiratory flow [PEF], hypoxemia)
1% of human cases. Clinical signs include fever, nausea, b. Reduced blood pressure (BP) or associated symptoms of
vomiting, dyspnea, tachypnea, cyanosis, arrhythmias, end-organ dysfunction (eg, collapse, syncope, incontinence)
hypotension, and cardiovascular collapse.110, 111 Adverse 2. Two or more of the following that occur rapidly after exposure to a
effects of IV lipid emulsion are due to direct reaction to likely allergen (minutes to several hours):
a. Involvement of the skin/mucosal tissue (eg, generalized hives,
the emulsion, which results in an acute adverse pyro-
pruritis, flushing)
genic reaction or “colloid reaction.”111 b. Respiratory compromise (eg, dyspnea, wheeze/bronchospasm,
stridor, reduced PEF, hypoxemia)
c. Reduced BP or associated symptoms of end-organ dysfunction
Clinical criteria (eg, collapse, syncope, incontinence)
Universal clinical criteria for classifying anaphylaxis d. Persistent gastrointestinal symptoms (eg, abdominal pain,
have recently been defined in people.1–3, 27, 56 However, vomiting)
complete universal criteria have not been established for 3. Reduced BP after exposure to a known allergen (minutes to several
hours):
any other species. In 2005, an international panel, re-
a. Infants and children: low systolic BP or > 30% decrease in systolic
cruited by the National Institutes of Health (NIH) and BP
the Food Allergy and Asthma Network (FAAN), delin- b. Adults: systolic BP < 90 mm Hg or > 30% decrease from their
eated the clinical characteristics that would establish a baseline
diagnosis of anaphylaxis. This classification highlights a
two-system involvement that makes anaphylaxis highly
likely even though a known allergen had not been en-
rently available to support the diagnosis of anaphy-
countered, and a one-system event (eg, shock) if a known
laxis in people include histamine and total tryptase
allergen had been encountered.1–3, 27, 56 Anaphylaxis is
concentrations.1–4, 31, 33, 46, 47, 51, 87 Their usefulness is lim-
highly likely when any 1 of the following 3 criteria is
ited by several factors. These biomarkers have sub-
fulfilled: (1) the acute onset of a reaction (minutes to
optimal sensitivities and specificities, assays are not
hours) with involvement of the skin, mucosal tissue, or
universally available and generally are unable to be
both, and at least 1 of the following: (a) respiratory com-
performed on an emergency basis.1, 47, 56, 108 Also, sam-
promise; (b) or reduced blood pressure or symptoms
ples must be obtained in fairly close proximity to the
of end-organ dysfunction; (2) 2 or more of the follow-
reaction to be valuable.2–4, 87 Total tryptase measure-
ing that occur rapidly after exposure to a likely aller-
ment is currently the most widely used laboratory test
gen for that patient—involvement of the skin/mucosal
to confirm a diagnosis of anaphylaxis in people.3, 87
tissue, respiratory compromise, reduced blood pres-
The optimal time to obtain a serum tryptase is within
sure, or associated symptoms of end-organ dysfunction
3 hours of the onset of symptoms.2, 46, 51, 56 Tryptase con-
and/or persistent gastrointestinal symptoms; or (3) re-
centrations generally correlate with the clinical severity
duced blood pressure after exposure to a known allergen
of anaphylaxis.31, 33, 47 However, the route of allergen ex-
(Table 1).1–3, 27, 56
posure appears to influence tryptase concentrations.33, 47
Although no criteria will provide 100% sensitivity and
As a result, serum tryptase levels may correlate poorly
specificity, it is believed that the criteria proposed should
to food triggered anaphylaxis.2, 3, 31, 33, 47, 51 Also, tryptase
accurately identify anaphylactic reactions in more than
concentrations are rarely increased when hypotension
95% of cases.1, 2 Nevertheless, although these criteria pro-
or shock is absent.2, 49, 51 Nonetheless, postmortem mea-
claim to be useful, their utility and value in the human
surements of serum tryptase might be useful in establish-
and small animal population require further investiga-
ing anaphylaxis as the cause of death in subjects experi-
tion. Since their development, no further attempts have
encing sudden death of uncertain cause.2 Generally, se-
been made to establish diagnostic criteria.
rial measurement of tryptase concentrations are reported
to be more useful than measurement at only one point in
Biomarkers time.2, 47, 51 Plasma and urinary histamine are also com-
There are more than 100 biomarkers for mast cell monly used as biomarkers. Plasma histamine concen-
and basophil activation.51 Clinical laboratory tests cur- trations typically peak within 5–10 minutes of onset of
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the inciting trigger, and decline to baseline within 60 to the gallbladder wall (significant thickening and a dis-
minutes.2, 31, 47, 56 Concentrations must, therefore, be mea- tinctive striated pattern) in this study were almost imme-
sured within 1 hour of the onset of symptoms to obtain diate following an episode and were associated with im-
optimal results.2, 3 Increased plasma histamine concen- paired venous drainage as previously reported in canine
trations correlate with anaphylaxis symptoms and are anaphylaxis.71, 73, 78 The reported sensitivities and speci-
more likely to be increased than serum total tryptase ficities were 85% and 98%, respectively, for increased
concentrations.3, 47 However, due to its very short half- ALT, and 93% and 98%, respectively, for gallbladder
life in plasma (15–20 minutes), this test appears impracti- wall abnormalities. This study concluded that the in-
cal in many clinical circumstances. Measurement of his- crease in ALT concentration and a thickened, striated
tamine or the histamine metabolite N-methylhistamine gallbladder wall correlated significantly with anaphylac-
in a 24-hour urine collection may be more helpful.56 tic reactions and were valuable biomarkers in support-
Serum tryptase and histamine concentrations as ing the diagnosis of canine anaphylaxis.73 Although this
biomarkers have reasonably good specificity, but less study showed promising results, further investigations
than desirable sensitivity. Normal concentrations of are needed in a larger population size to determine their
either total tryptase or histamine do not rule out the practicality.
clinical diagnosis of anaphylaxis.2, 31, 47 Unfortunately,
histamine and tryptase measurements are not readily Skin allergy testing
available to veterinarians, their function has yet to be Various allergy testing, either by serological or via intra-
established in animals, and further studies are needed dermal skin injections are available. Unfortunately, the
to determine their usefulness. Additional mast cell acti- association between the results of such tests and the risk
vation products have been recently investigated as po- of a reaction is poor. Various tests have either a low speci-
tential confirmatory biomarkers of anaphylaxis in peo- ficity or low sensitivity for the diagnosis or prediction of
ple. These include measurement of plasma or serum reactions.1 Such testing is most accurate when performed
concentrations of mature  tryptase,108 mast cell car- after an anaphylactic event; it must be carried out within
boxypeptidase A3,2, 47 chymase,47 PAF,112 cytokines,112 4–6 weeks due to possible depletion of IgE, mast cell, or
as well as urinary levels of LTE4.51 Despite their promis- basophil levels, and may be of some use in document-
ing results, they currently remain experimental. Given ing hypersensitivity to a particular trigger following a
that different biomarkers are released at different times reaction.1 However, even a positive result may not nec-
from activated mast cells and basophils during ana- essarily predict a future adverse reaction, since such re-
phylaxis, and patients present at different times after sults may be indicative merely of previous exposure and
symptom onset; measurement of a panel of biomark- not necessarily hypersensitivity.47, 51 Therefore, skin tests
ers may be more helpful than measurement of a single and measurements of allergen-specific IgE may be use-
biomarker.47, 51 ful in determining sensitization; however, they are not
Identification of biomarkers in veterinary patients performed without risk and do not necessarily predict
would be particularly valuable since obtaining a per- the severity of, or risk of fatality in a future anaphylaxis
tinent history from pet owners can often be challeng- episode.1, 31, 42, 83
ing. A recent study investigated hepatobiliary parame- Despite scientific efforts, the goal of developing
ters (ie, ALT and gallbladder wall abnormalities as seen rapid, sensitive, and specific laboratory tests to diagnose
on ultrasound evaluation) in the canine hypersensitiv- anaphylaxis remains elusive. Consequently, anaphylaxis
ity patient.73 During anaphylaxis, alterations in blood remains a clinical diagnosis based on probability and
flow and possible direct effects of inflammatory medi- pattern recognition, with laboratory tests being of little
ators causes injury to the hepatocyte.73, 78, 79 ALT, a cy- assistance in the immediate direction of patient treat-
tosolic hepatocellular enzyme, is found in abundance in ment.
these cells. The subsequent alterations to the hepatocytic
membrane permeability result in excessive leakage of
Treatment
cytosolic enzymes. ALT is known to be a sensitive indi-
cator of hepatic damage with a half-life of approximately Anaphylaxis is a true medical emergency. There is
60 hours in the dog.73 The results of the study showed considerable controversy about the choice of treat-
that at the onset of an episode, ALT rapidly increases ment for anaphylactic reactions with therapy appear-
(<12 hours), peaks in 24–48 hours, and returns to normal ing to be mostly symptom-based. Most recommenda-
over a period of 2–3 weeks.73, 78, 80 Multiple striations in tions are based solely on subjective clinical experience
the gallbladder wall (eg, halo or double rim effect) are in- and opinion.2 Prompt assessment and management are
dicative of inflammation that can be related to causes in- critically important. The fundamentals of basic life sup-
dependent of gallbladder disease. The reported changes port form the mainstay of the initial management of
C Veterinary Emergency and Critical Care Society 2013, doi: 10.1111/vec.12066 385
D. L. Shmuel and Y. Cortes
anaphylaxis; treatment begins with a rapid assessment mation from mast cells and basophils, and relief of
of airway, breathing, circulation, and mental status. urticaria.2, 115, 117 Regardless of the route of administra-
Aggressive treatment should be initiated before diagnos- tion, epinephrine has a short duration of action and a
tics are performed since rapid and progressive deteriora- narrow therapeutic index.94, 115 It also has biphasic phar-
tion and mortality can occur frequently. In Hymenoptera macologic effects. A low dose of epinephrine might have
stings in dogs, severe systemic anaphylactic signs usu- the opposite effect of which it is intended and might
ally are apparent within 15 minutes of the bee or wasp lead to vasodilation and increased release of mediators
sting and can rapidly lead to death if left untreated.106 of inflammation.115
A recent retrospective study reported that the major- Despite epinephrine’s multiple beneficial pharmaco-
ity of anaphylactic reactions occurred within 5 minutes logic properties, serious adverse effects, such as ven-
of ophthalmic antibiotic application in cats, with some tricular arrhythmias, hypertensive crisis, myocardial in-
reactions being observed within the first 60 seconds of farction, and pulmonary edema, have been reported,
allergen exposure.24 Consequently, delay in treatment especially after an overdose of epinephrine by any route
leads to an increased likelihood of poor outcome with of administration (most commonly following an IV bo-
potential life-threatening consequences.2, 73, 113 No ran- lus injection).115 Usually mild and transient pharmaco-
domized controlled trials that meet optimal standards logic effects, such as pallor, tremor, anxiety, palpitations,
have been published for any medication used in the and dizziness, are expected and occur within minutes
treatment of acute anaphylaxis; however, strong evi- after epinephrine injection.2, 115, 118, 119 However, concerns
dence base for epinephrine supports its use as a first about the potential serious adverse effects of epinephrine
line drug.1, 2, 4, 26, 51, 56, 94, 114, 115 need to be weighed against concerns about the cardiac
manifestations of untreated anaphylaxis.2, 114, 115, 118, 119
Epinephrine
Epinephrine is a natural body constituent, comprising
approximately 80% of the catecholamines in the adrenal Clinical relevance of epinephrine
medulla.115 During life-threatening situations, endoge- Epinephrine’s efficacy has been evaluated through in
nous epinephrine is released and impacts innervated vitro and vivo studies. Conflicting conclusions have
structures throughout the body. This, in turn, accelerates been deducted from these studies. In vitro studies con-
the heart rate and consequently increases the force of car- cluded that epinephrine is beneficial when administered
diac contractions. While blood pressure rises, blood flow prior to allergen challenge. The -adrenergic effects of
is redistributed from the skin and SC tissue to the skeletal epinephrine cause an increase in intracellular 3 5 cAMP,
muscles, splanchnic circulation, and brain. Oxygenation which, in turn, inhibits mediator release during im-
tends to increase, blood glucose rises, and the body is munologic challenge.57, 120, 121 This finding supports the
prepared for a state of “fight or flight.”115, 116 Currently, rationale for its use. Although, in vivo studies, con-
the World Health Organization (WHO) and the WAO ducted to date, showed that epinephrine was of little
consider epinephrine to be an essential medication for or no benefit when administered during fully developed
treatment of anaphylaxis.2 shock.120–122 A canine ragweed model was used to ex-
amine the effect of IV bolus epinephrine on improving
systemic hemodynamics in anaphylactic shock.120 When
Pharmacology effects of epinephrine
epinephrine (at 2 different doses: 0.01 mg/kg and 0.025
Relative to anaphylaxis, its most important effects occur mg/kg IV) was given during maximal hypotension, only
in the cardiovascular system and the vascular smooth transient increases in mean arterial pressure (MAP), CO
muscle.117 Epinephrine stimulates both ␣ and  adren- and pulmonary wedge pressure (Pwp) were observed.
ergic receptors. Epinephrine’s ␣1 -adrenergic effects re- By 20 minutes postshock, these values were not different
sult in vasoconstriction, leading to increases in periph- from control values. This study concluded that no pos-
eral vascular resistance, blood pressure, and coronary itive effects were observed on reversing cardiovascular
artery perfusion, as well as decreases in mucosal edema collapse when an IV bolus of epinephrine was adminis-
within the airways.115, 117 Through its vasoconstrictor tered during maximal hypotension. In fact, deleterious
properties, it prevents and relieves upper airway ob- effects on cardiac mechanics and mediator release were
struction and helps to prevent and relieve shock.94, 115 found when a higher bolus dose of epinephrine was
Its 1 -adrenergic effects include positive inotropic and used.120 Another study showed similar findings, where
chronotropic activity leading to an increase in CO.2, 94, 115 no beneficial effect of epinephrine was observed after
The 2 -adrenergic effects of epinephrine result in bron- fully developed shock to Hymenoptera venom allergen
chodilation, suppressed release of mediators of inflam- in people.53
386
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C Veterinary Emergency and Critical Care Society 2013, doi: 10.1111/vec.12066 387
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388
C Veterinary Emergency and Critical Care Society 2013, doi: 10.1111/vec.12066
Anaphylaxis in dogs and cats
signs and symptoms (especially urticaria and pruritis) as not prevent a reaction, but simply may blunt the physi-
well as decrease gastric acid secretion.1, 2, 4, 27, 29, 56, 57, 129, 131 ologic response.
C Veterinary Emergency and Critical Care Society 2013, doi: 10.1111/vec.12066 389
D. L. Shmuel and Y. Cortes
effective circulating blood volume leads to distributive successfully treated with arginine-vasopressin (AVP).138
shock.1, 85 Thus, IV fluids are critical to prevent cardio- An experimental study, simulating the consequences
vascular collapse. Resuscitative volumes of crystalloids of systemic anaphylaxis, investigated the effects of
(90 mL/kg dog and 60 mL/kg cat)57, 70 should be given epinephrine, vasopressin, and inhibitors of NO and
rapidly at the onset of an anaphylactic reaction. Col- prostanoid pathways on histamine-induced relaxation in
loid support (eg, dextrans or hetarstarch) may be bene- the human internal mammary artery.139 They concluded
ficial, as it provides a more rapid and prolonged hemo- that epinephrine was only partially effective in reversing
dynamic response. Hetastarch can be administered at a histamine-induced vascular relaxation, whereas both va-
dose of 5 mL/kg as an IV bolus over 15 minutes and sopressin and methylene blue were able to completely
can be repeated as needed up to a total daily dosage of reverse histamine-induced vasodilation.139 Blockade of
20 mL/kg.70 The fluid volume replaced should be the target enzyme of NO pathway, guanylate cyclase,
titrated to the clinical response. Suggested parameters with vasopressin or use of methylene blue, may rep-
for optimal small animal fluid resuscitation are a central resent hopeful therapeutic options in the treatment of
venous pressure of 5–10 mm Hg, systolic BP of 100– anaphylactic shock in animals in the near future.
120 mm Hg, urine production of 0.5–1.5 mL/kg/h, PCV The mechanism of action for AVP in vasodilatory
> 25%, lactate concentration < 2.5 mmol/L, improved shock is most likely secondary to its ability to block ATP-
mentation, and normothermia.136 In a small percentage sensitive potassium channels (KATP ) in vascular smooth
of cases, bradycardia may be the first clinical sign ob- muscle and interfere with NO signaling.137 A recent case
served; this is a result of the Bezold-Jarisch cardiac re- series of dopamine resistant hypotension and vasodila-
flex and is a response to sudden, dramatic hypovolemia tory shock in dogs revealed an increase in MAP within
caused by fluid extravasation. The slowing of the heart is the first 15 minutes of exogenous AVP constant rate in-
likely a protective response to allow the ventricles to fill fusion therapy (0.5–1.25 mU/kg/min).140 AVP acts as a
during severe volume deficit, and rapid volume expan- potent vasoconstrictor by stimulation of V1 receptors in
sion, rather than anticholinergic administration is there- vascular smooth muscle, and should therefore be consid-
fore the most appropriate management.3, 5, 42, 84 ered in small animal veterinary patients with vasodila-
tory shock that is unresponsive to fluid resuscitation and
catecholamine administration.137, 140
Oxygen
High-flow oxygen (via a face mask, nasal cannulas, oxy-
gen cage, or endotracheal tube) should be administered
to all patients experiencing respiratory symptoms or hy- Glucagon and anticholinergic agents
poxemia. Those who are hemodynamically unstable may Glucagon is a polpypeptide with inotropic and
benefit from oxygen supplementation as well.57 chronotropic cardiac effects, independent of cate-
cholamine. It may be useful in anaphylactic patients
receiving a -adrenergic blocker who fail to respond
Treatment of Refractory Anaphylaxis
to epinephrine administration.1, 2, 56 -blockers may in-
Vasopressors terfere with epinephrine treatment by antagonizing its
Potent vasopressors, such as dopamine, norepinephrine, effects at the -adrenergic receptor.4, 43 Glucagon may
or vasopressin, may be required to overcome vasodilata- reverse refractory bronchospasm and hypotension dur-
tion if epinephrine and fluid resuscitation fail to main- ing anaphylaxis by activating adenyl cyclase directly and
tain adequate systolic blood pressure. Dopamine (2.5– bypassing the -adrenergic receptor.141 However, the oc-
10 mg/kg/min) is a precursor of norepinephrine and currence and importance of this mechanism of action in
exerts its effect in a dose-dependent manner: higher anaphylaxis is unproven. The recommended dosage in
doses (5–10 mg/kg/min) result in increased myocar- people is 1–2 mg administered IV followed by an IV
dial contractility and vasoconstriction via stimulation constant rate infusion of 5–15 mg/min titrated to clini-
of 1 - and ␣1 -adrenoreceptors. Norepinephrine (0.01– cal response.1, 4, 57 Protection of the airway is important
1 mg/kg/min) causes vasoconstriction and a resul- since glucagon may cause emesis and risk aspiration in
tant increase in peripheral vascular resistance via po- severely sedated or obtunded patients.
tent ␣1 - and ␣2 -adrenoreceptor effects.137 The effect of Anticholinergic agents are also sometimes needed
vasopressin on systemic anaphylaxis has not been in- for patients on -blockers. Atropine (0.02–0.04 mg/kg
vestigated in animal models, although it has been de- IV) may be indicated in those with persistent brady-
scribed in human clinical case reports and experimen- cardia and ipratropium (via inhalation; 18 g/
tal studies.138, 139 Two recent cases were reported in actuation) in those with epinephrine-resistant
the human literature where anaphylactic shock was bronchospasm.1, 2, 26, 56, 57
390
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C Veterinary Emergency and Critical Care Society 2013, doi: 10.1111/vec.12066 391
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