Jennifer L. Lyons
Jennifer is a veterinary technician at BluePearl Veterinary Partners in Midvale, Utah. Before moving to Utah, she attended the University of California, Davis, for 6 years where she received a BS in animal biology and an MS in animal biology with a specialization in reproduction. Her interests include emergency triage, critical care, and endocrinology.Read Articles Written by Jennifer L. Lyons
Jordan R. Scherk
Dr. Scherk is a staff criticalist and the medical director of BluePearl Veterinary Partners in Midvale, Utah. He graduated from Western University of Health Sciences, completed an internship at VCA Veterinary Special Center of Seattle, and completed his residency training at the University of Georgia. His interests include trauma, acute kidney injury disease, cardiac critical care, cardiopulmonary resuscitation (CPR), and mechanical ventilation. He has lectured on CPR, congestive heart failure, and respiratory distress, as well as anaphylaxis.Read Articles Written by Jordan R. Scherk
Anaphylaxis is defined as the acute onset of a hypersensitivity reaction causing the release of mediators from mast cells and basophils. Anaphylaxis may be a life-threatening condition that can involve one or more organ systems. Often, a specific cause for anaphylaxis is not known. Anaphylaxis may be brought on by anaphylactic or anaphylactoid reactions; treatment is the same regardless of reaction type.1,2
Veterinarians are seeing an increasing number of anaphylaxis patients because of the range of substances patients are exposed to, such as vaccines, new medications, and those from outdoor physical exposures3 (see Specific Causes of Anaphylaxis). However, anaphylaxis is often misdiagnosed because definitive criteria to distinguish anaphylaxis from an allergic reaction are lacking.10 This article reviews anaphylaxis pathophysiology, diagnostic criteria, treatment, and clinical examples.
Hymenoptera is an order of insects that includes bees, wasps, and ants. The venom of each species has different effects in patients.
Bees pose an anaphylactic threat because the venom in their stings contains peptide 401, phospholipase A2, melittin, and hyaluronidase. Peptide 401 is also known as mast cell–degranulating peptide and causes histamine release. Phospholipase A2 works with melittin to cause intravascular hemolysis. Hyaluronidase changes vascular permeability by disrupting collagen and allowing other venom components to penetrate cells. Melittin hydrolyzes cell membranes, thus altering permeability. It also causes biogenic amines and potassium to leak from cells and induces catecholamine release. Melittin is the primary cause for localized pain.4,5 A bee can only sting once because of the barbs on its stinger.
Wasps and Hornets
Wasps, unlike bees, have smooth stingers and may sting multiple times. They are much more aggressive than bees. Hornets defend their nests aggressively and have much more painful stings than either wasps or bees due to the amount of acetylcholine in their venom. Wasp and hornet stings contain the same proteins associated with bee venom with the exception of melittin. Bites and stings may produce a toxic envenomation response. The estimated lethal dose is 20 stings/kg.5
Fire ants can be very aggressive. They attach to their prey with their mandibles and may sting with a nonbarbed stinger multiple times. Their venom contains hyaluronidase, phospholipase, and water-insoluble alkaloid compounds. Alkaloid venom causes cytotoxic, hemolytic pustules. Fire ants do not elicit an IgE-mediated anaphylactic response but an anaphylactoid one.6
Other common causes of anaphylactic reactions include ophthalmic antibiotic ointment (in cats), drugs (some chemotherapy agents, contrast material, and antibiotics), and blood transfusions.
Ophthalmic Antibiotic Ointment in Cats
In a retrospective evaluation of observed cases of anaphylaxis in cats that were administered a topical ophthalmic antibiotic, 56% of evaluated cats had anaphylactic reactions within 10 minutes. All ointments used contained polymyxin B. Clinical signs manifested in at least 2 body systems. Most commonly reported signs included respiratory and gastrointestinal compromise. Other organ systems involved were cardiovascular and cutaneous. Standard, symptomatic treatment aided in recovery; however, 13% of patients in this study died.7
A case study of 3 canine patients recorded severity of anaphylactoid reactions to magnetic resonance imaging contrast media in anesthetized patients. Clinical signs ranged from very mild (cutaneous edema, which resolved during recovery) to severe (cardiovascular collapse, which necessitated swift emergency care).8
IgE-mediated anaphylactic reactions may occur in patients receiving blood transfusions because of the presence of IgE and mast cells. Reported mild clinical signs include edema, urticaria, vomiting, and dyspnea. At onset of mild signs, the transfusion should be stopped. If the signs resolve in a timely fashion, the transfusion may continue at a slower rate (25%–50%). If there is evidence of more severe clinical signs, the transfusion should be discontinued and emergency action taken.9
Anaphylactic reactions are classified into 4 separate categories: type I, or immunologic IgE mediated; types II and III, which are immunologic IgE independent; and type IV, or nonimmunologic. Most anaphylaxis patients are likely to have type I reactions, but it is unclear why.2
Anaphylactic Reaction: Immunologic IgE Mediated
In immunologic IgE-mediated reactions, patients do not show clinical signs at the initial allergen exposure. Upon reexposure, IgE antibodies are produced, and the allergen forms a “bridge” that cross-links these antibodies via a high-affinity receptor, FcεRI, located in the membrane of mast cells and basophils. After binding, antibodies cause mast cell and basophil activation and start the immediate hypersensitivity reaction. Cross-linking induces a membrane change, causing an influx of calcium ions into the cell that initiates degranulation and, thus, a release of mediators (eg, histamine). Interactions between mediators and host organs cause clinical signs to appear.2
Anaphylactoid Reaction: Immunologic IgE Independent
In contrast, immunologic IgE-independent reactions occur through IgG antibody production. Allergen exposure activates IgG antigen binding to low-affinity receptors on macrophages. IgE-independent reactions require more antigen exposure and do not result in the release of histamine as a mediator. Furthermore, IgE-independent reactions do not require initial allergen exposure.2,3
Anaphylactoid Reaction: Nonimmunologic Anaphylaxis
Nonimmunologic reactions may occur via degranulation of mast cells and basophils without immunoglobulins. They may be triggered by external influences, such as physical factors, drugs, and external toxins.2,3
Mediators stored in mast cells and basophils (ie, histamine, heparin, proteases such as tryptase and chymase, and cytokines) are released during degranulation (Figure 1), which causes an increased production of phospholipase A and thus arachidonic acid and its metabolites. Downstream activation of this cascade leads to an increase in newly synthesized mediators, such as prostaglandins, leukotrienes, and plasma activating factor. These newly synthesized mediators induce an inflammatory response. The release of inflammatory and vasoactive mediators leads to shock.10,12
Once an antigen has bound to the primed IgE receptors, histamine is released. Histamine is the principal mediator stored in granules of mast cells and basophils. It is released quickly during anaphylaxis and can be found in elevated concentrations in circulating plasma less than 1 minute after allergen interaction.3 Histamine acts through 3 receptors (H1R, H2R, H3R) to promote signs of shock. H1R increases smooth muscle contraction, causing vasodilation and increased vascular permeability. It also stimulates the conversion of l-arginine into nitric oxide, which leads to vasodilation and therefore decreases venous return. H2R increases gastric acids, increases heart rate and ventricular contractility, and further promotes vasodilation. H3R inhibits norepinephrine release, thus increasing the degree of systemic shock. Without norepinephrine, vasodilation can persist and lead to clinical hypotension. Clinical signs of histamine release include rhinitis, pruritus, dyspnea, hypotension, and tachycardia.13
Heparin is also released from mast cell granules. The release of heparin inhibits clot formation by decreasing clotting factors.13 This may lead to a hypocoagulable state and predispose a patient to clinical bleeding.
Cytokines, such as interleukin-4 and interleukin-13, are synthesized and released in response to the arachidonic acid cascade. The release of cytokines leads to an increase in cellular responsiveness to inflammatory mediators, up to 6 times normal.12
Prostaglandins released may cause bronchoconstriction, pulmonary and coronary vasoconstriction, and peripheral vasodilation.14 Clinically, airway obstruction, increased airway secretions, and decreased cardiac output may be noted (hypotension).
Platelet activating factor decreases coronary blood flow and myocardial contractility and increases pulmonary resistance, vasodilation, hypotension, and platelet aggregation.13,14 Decreases in myocardial contractility in conjunction with vasodilation can lead to profound hypotension.
Shock is a state of low blood perfusion to tissues that causes inadequate delivery of oxygen and decreased cellular energy production. Shock is often brought on by hypovolemia, maldistribution of vascular volume, or failure of the cardiac pump (cardiogenic shock). Anaphylactic shock results from massive vasodilation secondary to mast cell degranulation, histamine release, and the rapid release of inflammatory and vasoactive mediators. Vasodilation in turn decreases the relative circulatory volume, decreasing perfusion and thus oxygen delivery to tissues. This leads to splenic contraction and tachycardia, and ultimately myocardial and cerebral hypoxemia, cardiovascular collapse, and death.12
Because of differences in immune response, smooth muscle anatomy, and antigen degradation rates, each species has different physiologic responses to anaphylaxis.12
Dog: Liver, Gastrointestinal System
In dogs, histamine is primarily released from the gastrointestinal tract into the portal vein, thus leading to hepatic arterial vasodilation and an increase in arterial hepatic blood flow. In addition, histamine release into the portal system creates a large venous outflow obstruction that results in a hepatic vascular resistance increase of up to 220% of normal within seconds.15,16 As a result, venous return to the heart is decreased. Reduced hepatic venous return to the heart decreases cardiac output and therefore contributes to hypovolemia and decreased oxygen delivery to the tissues. Because of decreased oxygen delivery and hypovolemic shock, common clinical signs include collapse and acute onset of gastroenteritis that is sometimes hemorrhagic.16
In cats, anaphylactic reactions are seen primarily in the lungs. Cats typically respond to allergens via profound bronchoconstriction. This leads to reduced blood oxygen levels, increased dissolved carbon dioxide levels, and decreased cardiac output. Acute hypoxemia can increase sympathetic tone, causing splenic contractions and eventually hemoconcentration.16
Signs of anaphylaxis may be categorized based on the affected organ system: cutaneous, respiratory, cardiovascular, or gastrointestinal.16
Cutaneous signs are the most common initial clinical sign of an allergic reaction but may be a precursor for more severe reactions, such as anaphylaxis. If severe anaphylaxis has a rapidly acute onset, cutaneous signs may be absent. The most common cutaneous clinical signs include erythema, urticaria, pruritus, wheals, and angioedema. These signs are often short in duration.
Respiratory signs often result from laryngeal and pharyngeal edema, bronchoconstriction, and increased mucus secretion. They include dyspnea, bronchospasm, stridor, tachypnea, and coughing.
Because of the intensity of vasodilation during anaphylaxis, hypotension is the primary cardiovascular sign. Hypotension is further exacerbated by fluid extravasation as vascular permeability increases; intravascular blood volume can decrease up to 35%, leading to both a hypovolemic and a distributive shock state.15 Tachycardia due to hypovolemia may also be present in anaphylaxis patients. Conversely, bradycardia may be caused by increased vagal reactivity. Careful auscultation may reveal cardiac arrhythmias.
Signs of decreased perfusion may exist, including pale mucous membranes, increased capillary refill time, decreased pulses, hypothermia, and depressed mentation. Because of vasodilation, injected or “brick red” mucous membranes may be noted on physical examination.
Gastrointestinal signs may include nausea, vomiting, and diarrhea. A recent study of 96 dogs revealed that during anaphylaxis, blood flow is altered throughout the liver (portal circulation) and gastrointestinal tract, and hepatocytes are directly affected,17 resulting in excessive leakage of alanine aminotransferase (ALT). The ALT levels in this study increased in the first 12 hours and peaked 24 to 48 hours later. This study also revealed that changes in the gallbladder wall may be detectable on ultrasound evaluation almost immediately following an episode of anaphylaxis. Striations in the gallbladder wall (“halo effect”) may be seen because of inflammation as well as impaired venous drainage.17
Primary Clinical Signs in Dogs
Cutaneous signs, such as urticaria, erythema, angioedema of the face and muzzle, hypersalivation, and pruritus, can be seen but may be subtle and short lived.2 Hemorrhagic enteritis caused by portal hypertension is one of the most commonly noted clinical antemortem signs as visceral pooling of blood in the intestines increases, leading to vomiting and diarrhea.12,16 As a result of the degree of liver involvement, dogs typically exhibit signs of cardiovascular impairment due to hepatic venous congestion. Other common clinical signs include hypotension and cardiovascular collapse; dyspnea, bronchospasm, and stridor may be noted as well.
Primary Clinical Signs in Cats
Cats typically exhibit respiratory and gastrointestinal signs. Respiratory distress is often the first sign exhibited. Cats’ clinical signs may also include hypersalivation, laryngeal swelling, edema, pruritus, and signs of hypovolemic shock.12,16 Cats are less likely than dogs to experience cutaneous effects.
Anaphylaxis may be difficult to diagnose and is often overlooked. Diagnostic differentials include severe asthma, a vasovagal event, and neoplasia, such as a pheochromocytoma or mast cell tumor degranulation.10 Rate of onset of clinical signs is an important diagnostic criterion. Anaphylaxis usually occurs within the first 30 minutes after allergen exposure and progressively worsens. However, a general rule of thumb is that the more quickly the signs manifest, the more severe the anaphylaxis will be. Box 1 presents criteria that can be used to assess the likelihood of anaphylaxis in a presenting patient.
Clinical signs sometimes subside and acutely reappear after several hours. These are known as biphasic reactions and can increase mortality if they are not recognized and treated appropriately.18 Obtaining a detailed history about past allergic reactions, vaccinations, outside exposure, and previous medical ailments can be an important tool in diagnosing anaphylaxis.
- Acute onset of an illness with involvement of the skin, mucosal tissue, or both (ie, pruritus, edema, facial swelling), plus at least 1 of the following:
a. Respiratory compromise (ie, dyspnea, bronchospasm, stridor, hypoxemia)
b. Symptoms of end-organ dysfunction (ie, hypotension, syncope, incontinence
2. Two or more of the following that occur rapidly after exposure to a likely allergen:
a. Involvement of the skin-mucosal tissue
b. Respiratory compromise
c. Reduced blood pressure or associated symptoms
d. Persistent gastrointestinal symptoms (ie, vomiting, diarrhea)
3. Reduced blood pressure after exposure to known allergen for that patient
Treatment of anaphylaxis is entirely based on clinical signs but should follow the guidelines for fundamental life support. Treatment should be initiated quickly and take priority over diagnostics because of the likelihood of rapid progression of clinical signs and increasing possibility of death.14,16 As with all life support treatment, rapid triage assessment, including airway, breathing, circulation, and mental status, is paramount. Delays in treatment can lead to worsening outcomes.2 Immunologic and nonimmunologic hypersensitivity responses produce identical clinical signs and are thus treated the same.1,2
If the patient presents in respiratory distress, it may be necessary to secure an airway. An endotracheal tube may be placed for patients with laryngeal swelling. If an endotracheal tube is not feasible because of swelling, a temporary tracheostomy tube may be placed surgically. Albuterol (a β-agonist) may help cause bronchodilation and decrease bronchospasm.
Doses for all drugs discussed below are listed in Box 2.
- 0.02–0.04 mg/kg via endotracheal tube
- 0.2–0.5 mg (total dose) SC or IM
- 0.01–0.1 mg/kg IV
- 0.05 mcg/kg/min CRI
- Famotidine: 0.5–1 mg/kg IV
- Ranitidine: 0.5–2.5 mg/kg IV
- Diphenhydramine: 1–4 mg/kg IM (dogs); 0.5 to 2 mg/kg IM (cats)
- Dexamethasone-SP: 0.1–0.5 mg/kg IV
- Prednisone: 0.5–1.0 mg/kg PO
- Albuterol: 1 to 2 puffs via inhaler; can be administered up to every 15 minutes as a 90-g/puff inhaler, up to 3 doses10
- Aminophylline: 5–10 mg/kg IM or slow IV
- Norepinephrine: 0.01–1 mcg/kg/min IV CRI
- Dopamine: 5–10 mcg/kg/min IV CRI
- Vasopressin: 0.5–1.25 mU/kg/min IV CRI
- Atropine: 0.02–0.04 mg/kg IV
As an α- and β-agonist, epinephrine is essential in the treatment of anaphylaxis. It has the following effects:
- α-adrenergic effects. Vasoconstriction, which increases vascular resistance and thus blood pressure and coronary perfusion, and decreased edema, which leads to relief of upper airway obstruction
- β1-adrenergic effects. Positive inotropic and chronotropic activity, leading to increased cardiac output
- β2-adrenergic effects. Bronchodilation, leading to increased tissue oxygenation; also, the rate of adenosine triphosphate hydrolysis into adenosine monophosphate increases, which results in inhibition of histamine and cytokine release from mast cells and basophils, truncating the type 1 hypersensitivity reaction
In total, epinephrine works to accelerate heart rate, increase cardiac contractions, decrease mast cell degranulation, and improve oxygenation through bronchodilation.19 Potential adverse reactions include ventricular arrhythmias; hypertension; tachycardia; and transient, mild effects, including pallor, tremors, and dizziness (in humans).2
Epinephrine may be administered via the endotracheal tube; via SC, IM, or IV routes; or as a continuous-rate infusion (CRI). Current recommendations state that an initial dose of epinephrine may be administered IM. This can be repeated every 5 to 15 minutes.19 For the fastest and most profound effect, IV administration is recommended. If shock has developed, IV administration of epinephrine (bolus dose) followed by a CRI that can be titrated to effect is recommended.2,19 If IV epinephrine boluses appear to have little to no effect, a CRI may be started.20 Studies have shown that SC administration may provide a very delayed effect and is not recommended.
While pretreatment with antihistamines is widely practiced to prevent the onset of anaphylaxis, studies show that their use during anaphylaxis may not relieve serious clinical signs. However, they may be administered in an effort to downregulate the release of more mediators during treatment.20
Both H1 and H2 antihistamines act as inverse agonists, not competitive antagonists. Inverse agonists differ from competitive antagonists in that when they bind to the receptor, they induce an opposite response instead of simply not causing receptor activation. H1 antihistamines have a higher affinity for H1R and may act to stabilize the receptors. H1 antihistamines are most effective in treating localized allergic reactions and include diphenhydramine, chlorpheniramine, and cyproheptadine. H1 antihistamines cross the blood–brain barrier; therefore, they may cause central nervous system depression.
H2 antihistamines include famotidine, ranitidine, and cimetidine. Studies have shown that use of H1 and H2 antihistamines together relieved cutaneous symptoms of anaphylaxis more effectively.20 However, these drugs should never be substituted for epinephrine during anaphylaxis. They should be used as ancillary treatments to help reduce some of the cutaneous and gastrointestinal signs.
Glucocorticoids do not relieve initial clinical signs but may be used in long-term management of anaphylaxis. Clinical improvement is typically seen up to 4 to 6 hours after administration. Glucocorticoids act to inhibit the inflammatory responses of the late-phase eosinophil response and inhibit the arachidonic cascade.4
Albuterol, an inhaled β-adrenergic agonist, may be used to treat respiratory signs and to relieve bronchospasm. However, it does not replace the need for epinephrine because it has minimal α-adrenergic effect. Aminophylline, a phosphodiesterase inhibitor, may be useful for increasing amounts of cyclic adenosine monophosphate, which in turn increases the release of endogenous epinephrine and thus furthers the inhibition of mediator release.16 Aminophylline also directly relaxes smooth muscles in the bronchi and pulmonary vasculature.
Fluid therapy is useful in treating patients with hypotension. Severe decrease in blood volume secondary to permeability changes and vasodilation secondary to histamine and cytokine release make aggressive fluid therapy necessary. Fluid therapy helps prevent cardiovascular collapse by increasing vascular volume.14,16 Basic guidelines for fluid therapy are as follows:16
- Crystalloids: 10- to 20-mL/kg boluses over 5 to 15 minutes; this can be repeated up to 90 mL/kg (dogs) or 60 mL/kg (cats)
- Colloids: 5-mL/kg bolus; this can be repeated up to 20 mL/kg
Volume resuscitation should be tailored to the patient’s clinical response. Improvement in perfusion parameters (mentation, mucous membrane color, capillary refill time), rectal temperature, heart rate, blood pressure, and lactate measurements can help determine whether resuscitation is adequate.
When patients with respiratory or hemodynamic compromise are treated, high-flow oxygen should be administered via facemask, nasal cannula, or endotracheal tube.14,16
Treatment of Severe Anaphylaxis
In some cases, a more aggressive approach may be needed for treatment of anaphylaxis. Patients with severe hypotension and/or bradycardia that is unresponsive to epinephrine and fluid resuscitation should be treated symptomatically with vasopressors and/or anticholinergics.
Use of vasopressors should be considered when epinephrine and fluid resuscitation fail to improve blood pressure. Vasopressors act to increase myocardial contractility and cause vasoconstriction.2,16 These effects may help to counteract the vasodilation and myocardial dysfunction that occur during an anaphylactic reaction.
For patients with persistent bradycardia in which epinephrine does not aid in the treatment of bronchospasm, anticholinergics may be administered.2,16
Patients experiencing anaphylactic shock should be hospitalized for an observational period of 48 to 72 hours.16 Organs involved in the initial reaction may quickly deteriorate and should be monitored closely. These organ systems can experience a secondary or biphasic response.
Anaphylaxis is a severe condition that requires rapid emergency treatment. Because of the lack of definitive diagnostic criteria, it may be difficult to diagnose and is often overlooked. Rapid patient history and assessment are key in diagnosing and treating anaphylaxis.
- Kemp SF. Anaphylaxis: current concepts in pathophysiology, diagnosis, and management. J Allergy Clin Immunol 2001;22(4):611-634.
- Simons FE. Anaphylaxis. J Allergy Clin Immunol 2008;121(2 Suppl):S402-S407.
- Kemp SF, Lockey RF. Anaphylaxis: a review of causes and mechanisms. J Allergy Clin Immunol 2002;110(3):341-348.
- Golden DB, Moffitt J, Nicklas RA, et al. Stinging insect hypersensitivity: a practice parameter update 2011. J Allergy Clin Immunol 2011;127(4):852-854.e1-23.
- Cowell AK, Cowell RL, Tyler RD, Nieves MA. Severe systemic reactions to Hymenoptera stings in three dogs. JAVMA 1991;198(6):1014-1016.
- Mueller RS, Janda J, Jensen-Jarolim E, Rhyner C, Marti E. Allergens in veterinary medicine. Allergy 2016;71(1):27-35.
- Hume-Smith KM, Groth AD, Rishniw M, Walter-Grimm LA, Plunkett SJ, Maggs DJ. Anaphylactic events observed within 4 h of ocular application of an antibiotic-containing ophthalmic preparation: 61 cats (1993–2010). J Feline Med Surg 2011;13(10):744-751.
- Pollard RE, Pascoe PJ. Severe reaction to intravenous administration of an ionic iodinated contrast agent in two anesthetized dogs. JAVMA 2008;233(2):274-278.
- Gibson G. Transfusion medicine. In King LG, Boag A (eds): BSAVA Manual of Canine and Feline Critical Care. 2nd ed. Wiley; 2007:226.
- Johnson RF, Peebles RS. Anaphylactic shock: pathophysiology, recognition, and treatment. Semin Respir Crit Care Med 2004;25(6):695-703.
- Janeway CA, Travers P, Walport M, Shlomchik MJ. Immunobiology: The Immune System in Health and Disease. 6th ed. New York: Garland Science; 2004.
- Sampson HA, Muñoz-Furlong A, Campbell RL, et al. Second symposium on the definition and management of anaphylaxis: summary report—Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin Immunol 2006;117(2):391-397.
- Tucker A, Weir EK, Reeves TJ, Grover RF. Histamine H1 and H2 receptors in pulmonary and systemic vasculature of the dog. Am J Physiol 1975;229(4):1008-1013.
- Finkelman FD. Anaphylaxis: lessons from mouse models. J Allergy Clin Immunol 2007;120(3):506-515.
- Schadt JC, Ludbrook J. Hemodynamic and neurohumoral responses to acute hypovolemia in conscious mammals. Am J Physiol 1991;260(2 Pt 2):305-318.
- Lee JK, Vadas P. Anaphylaxis: mechanisms and management. Clin Exp Allergy 2011;41(7):923-938.
- Quantz JE, Miles MS, Reed AL, White GA. Evaluation of alanine transaminase and gallbladder wall abnormalities as biomarkers of anaphylaxis in canine hypersensitivity patients. J Vet Emerg Crit Care 2009;19(6):536-544.
- Stark BJ, Sullivan TJ. Biphasic and protracted anaphylaxis. J Allergy Clin Immunol 1986;78(1 Pt 1):76-83.
- Lieberman P. Use of epinephrine in the treatment of anaphylaxis. Curr Opin Allergy Clin Immunol 2003;3(4):313-318.
- Sheikh A, Ten Broek V, Brown SG, Simons FE. H1-antihistamines for the treatment of anaphylaxis: Cochrane systematic review. Allergy 2007;62(8):830-837.
- Choo KJ, Simons E, Sheikh A. Glucocorticoids for the treatment of anaphylaxis: Cochrane systematic review. Allergy 2010;65(10):1205-1211.