Lisa J. Kobrynski, MD, MPH
Anaphylaxis is a clinical syndrome characterized by an abrupt, severe, life-threatening event with cutaneous, respiratory, cardiovascular, and gastrointestinal symptoms mediated by IgE and non-IgE immunologic reactions to a particular antigen. Several other syndromes have symptoms that may mimic those of anaphylaxis, and a rapid diagnostic laboratory test is not readily available in most emergency departments. Thus, it is important that physicians in the emergency department are familiar with the signs and symptoms of anaphylaxis and are able to distinguish this condition from disorders presenting with similar symptoms. Prompt recognition of anaphylaxis and initiation of treatment with epinephrine in a timely fashion is critical to prevent fatalities. This article will review the pathophysiology of anaphylaxis, the common triggers, the clinical findings, the treatment and prevention of this disorder. Clin Ped Emerg Med 8:110-116 ª 2007 Published by Elsevier Inc. KEYWORDS anaphylaxis, anaphylactoid, angioedema, epinephrine
he term anaphylaxis was originally used to refer to severe allergic reactions, mediated by immunoglobulin (Ig) E, necessitating exposure, sensitization, and reexposure to a particular agent. Later on, the term anaphylactoid reaction was used to refer to a similar clinical syndrome occurring due to other immunologic responses to a foreign antigen. In many ways, these 2 entities are clinically indistinguishable. In this article, anaphylaxis will be used as a descriptive term to denote a clinical syndrome characterized by an abrupt, severe, life-threatening event with cutaneous, respiratory, cardiovascular, and gastrointestinal symptoms mediated by IgE and non-IgE immunologic reactions to a particular antigen.
Anaphylaxis occurs when a foreign antigen elicits an immunologic response in an individual leading to the release of histamine and other chemokines causing systemic symptoms. This response can occur secondary to preformed IgE molecules because of the formation of antigen-antibody complexes or due to direct mast cell degranulation. The commonly associated symptoms of anaphylaxis are caused by the release of inflammatory mediators such as histamine, leukotrienes, anaphylatoxins 110
C3a and C5a (slow releasing substance of anaphylaxis), neuropeptides, platelet-activating factor, tryptase, chymase, and prostaglandins. These mediators are responsible for peripheral vasodilation, bronchoconstriction, urticaria, and angioedema because of increased vascular permeability, chemotaxis of eosinophils, activation of complement, and coronary vasoconstriction. Anaphylaxis can occur after reexposure to an antigen, frequently a foreign protein, which binds preformed antigen specific IgE bound to the high affinity IgE receptor on the surface of mast cells. Once antigen is bound, crosslinking of the IgE molecules on the cell surface occurs and the mast cell degranulates, releasing histamine, tryptase, and other enzymes. Histamine is a potent vasodilator and bronchoconstrictor and causes urticaria, angioedema, flushing, hypotension, vomiting, and diarrhea. Anaphylaxis can also occur when an antigen binds IgG and complement in the serum to form immune complexes. Activation of complement results in the release of C3a, C5a, and the slow releasing substances of anaphylaxis. These substances also cause contraction
Division of Allergy and Immunology, Emory University School of Medicine, Atlanta, GA. Reprint requests and correspondence: Lisa J. Kobrynski, MD, MPH, Division of Allergy and Immunology, Emory University School of Medicine, 2015 Uppergate Dr., Atlanta, GA 30322. 1522-8401/$ - see front matter ª 2007 Published by Elsevier Inc. doi:10.1016/j.cpem.2007.04.006
of bronchial smooth muscle, vasodilation, and induce the release of other mediators from mast cells and basophils. Still, other substances will cause abnormalities in the arachadonic acid pathway, leading to the release of metabolites such as leukotrienes. These substances mainly cause bronchoconstriction. Other agents have been shown to cause the release of histamine from mast cells without the presence of specific IgG or IgE antibody. These reactions have been called banaphylactoidQ reactions, but the symptoms are identical to anaphylactic reactions, differing only in the mechanism of the reaction such that sensitization and the formation of specific antibody is not required.
Table 1 Causes of anaphylaxis.
The exact incidence of anaphylactic reactions is not known. Estimates derived from retrospective reviews and analyses of published literature put the annual incidence rates for anaphylaxis between 3 and 21 per 100 000 person years [1-5]. This is likely an underestimation and the occurrence rates could be as high as 590 per 100,000 . The rate of fatality from anaphylaxis is also unknown, and estimates vary widely. Is has been estimated that between 1443 and 1503 deaths occur each year due to anaphylaxis for a fatality rate of 0.002% . Overall, there may be a slight increase in the frequency of anaphylactic reactions in females, especially in cases due to aspirin or latex [7,8]. Anaphylaxis occurs in all age groups, but children are more likely to experience anaphylaxis due to foods and antibiotics. In children with spina bifida and ventriculoperitoneal shunts, and in health care workers, the risk of anaphylaxis is linked to repetitive exposures to agents such as latex. A similar situation occurs in diabetic patients exposed to protamine. The most common identifiable causes are foods and drugs, particularly penicillin.
IgE-mediated Antibiotics (eg, penicillins, cephalosporins, vancomycin, neomycin, amphotericin B) Foreign proteins (eg, serum, insulins, asparaginase, chymopapain, venoms, penicillinase, blood, blood products, protamine, antithymocyte globulins, latex) Other medications (eg, allergen extracts, methylprednisolone, local anesthetics, vaccines, thiopental) Foods (eg, milk, eggs, wheat, soy, peanuts, tree nuts, shellfish, fish, corn, seeds, bananas) Immune complex–mediated Biologics (eg, blood, blood products, immunoglobulin) Medications (methotrexate) Radiocontrast media Arachadonic acid pathway Acetylsalicylic acid and nonsteroidal anti-inflammatory agents Tartrazine Direct histamine release Medications (eg, opiates, iron-dextran, thiamine, mannitol, pentamidine) Radiocontrast media Dextran
A large variety of agents can trigger anaphylactic reactions (Table 1). The risk of developing anaphylaxis after exposure to any of these agents is increased by decreasing the time interval between the first exposure and subsequent reexposures, by intravenous (IV) administration, and by a history of atopic disease. Food-induced anaphylaxis accounts for one third to one half of pediatric cases [5,6,9]. The cause of anaphylaxis may remain unidentified in up to two thirds of patients .
The symptoms and signs of anaphylaxis may vary in timing of onset, symptom progression, and severity. Table 2 shows the commonly seen symptoms of anaphy-
laxis. These symptoms may occur in any order, although cutaneous symptoms are generally one of the first manifestations of an anaphylactic reaction, followed by respiratory and cardiovascular symptoms. However, if there is rapid progression, cutaneous symptoms may be delayed or not apparent at the time of presentation. Cardiovascular collapse can be the presenting sign of anaphylaxis. Although signs and symptoms of anaphylaxis usually appear within 5 to 30 minutes after exposure, occasionally, symptoms will not develop for several hours. Rapid onset of symptoms after exposure is associated with a more severe and life-threatening course of anaphylaxis. Between 5% and 20% of patients may experience a recurrence of anaphylaxis 8 to 12 hours after the initial presentation [10-12]. Biphasic episodes are more likely to occur if administration of epinephrine was delayed or if multiple doses were required to treat the initial event. About 1% of patients will experience protracted anaphylaxis with symptoms lasting up to 32 hours. Fatal reactions are more common in the setting of protracted anaphylaxis . Cutaneous symptoms include urticaria, flushing, and angioedema. These symptoms occur in over 90% of cases . Less commonly (2%-5%), pruritus without rash will occur. Respiratory symptoms occur secondary to airway edema and bronchoconstriction and include dyspnea, wheezing (45%-59%), stridor, or dysphonia (20%-50%), and rhinorrhea (8%-20%). Signs of cardiovascular involvement include chest pain (6%), hypotension (15%-30%), and syncope/dizziness (30%-35%). Cardiac dysrhythmias can occur due to vagal effects or myocardial
Table 2 Signs and symptoms of anaphylaxis.
vasodilation and bradycardia. Generally, the only treatment required is to place the patient in the supine or Trendelenburg position.
Cutaneous: flushing, pruritus, urticaria, angioedema Oral: pruritus, edema of lips and tongue, metallic taste Nasal: pruritus, rhinorrhea, sneezing, congestion Respiratory: laryngeal edema, dysphagia, dysphonia, chest tightness, shortness of breath, wheezing, cough Cardiovascular: faintness, syncope, chest pain, hypotension, dysrhythmia Gastrointestinal: nausea, abdominal pain/cramping, vomiting, diarrhea Other: feeling of impending doom, sweating, uterine contractions, incontinence
A 15-year-old cheerleader complains of the sudden onset of difficulty breathing during the homecoming football game. She tells a teammate that her throat feels tight, and she can’t take a breath. She uses her albuterol inhaler without relief then collapses on the field. Emergency medical services are called, and on arrival, they find a pale, thin girl in moderate respiratory distress. Her heart rate is 120, respirations are 30 and shallow, and she has audible inspiratory and expiratory wheezing. Her blood pressure is normal. She receives oxygen and albuterol and begins to improve slightly after her second nebulizer treatment. According to her parents, who arrived in the emergency department (ED) a short while later, she has experienced several of these sudden battacksQ since their divorce 6 months ago. Acute episodes of dyspnea with wheezing and dizziness not responsive to albuterol can be seen in patients with vocal cord dysfunction (VCD). Typically, this entity is seen in adolescent girls, who are high achievers, with multiple stressors at home and at school. The symptoms are brought on by involuntary adduction of the vocal cords, causing upper airway obstruction with wheezing heard during both inspiration and expiration. Approximately half of the patients with VCD will have asthma as well; however, wheezing episodes due to VCD do not respond to bronchodilators or corticosteroids. The lack of cutaneous symptoms and hypotension can help distinguish VCD from anaphylaxis. The diagnosis of VCD can be confirmed by direct visualization of the vocal cords during an episode. During inspiration and phonation of certain vowel sounds, there is inappropriate adduction of the
Table 3 Differential diagnosis. Differential Vasovagal reaction Hypovolemic/septic shock Carcinoid syndrome Red man syndrome Scromboid fish poisoning Monosodium glutamate ingestion Urticaria pigmentosa/mastocytosis Scromboid fish poisoning Asthma exacerbation Vocal cord dysfunction Airway foreign body Hereditary angioedema Serum sickness Vasovagal reaction Pseudoanaphylaxis (procaine penicillin)
ischemia. The most frequent gastrointestinal symptoms are diarrhea and abdominal cramps (25%-30%), most likely secondary to contraction of smooth muscle in the gastrointestinal tract and increased mucus secretion. Nausea and vomiting occur in 20% of cases. Less common manifestations of anaphylaxis include headache (3%-5%), blurry vision (1%), and seizures (1%) [8,13]. Many patients report experiencing a feeling of impending doom at the onset of anaphylaxis.
Numerous clinical conditions may mimic anaphylaxis, and it can be difficult to distinguish these entities from anaphylaxis, especially when a patient is seen after the episode (Table 3). The diagnosis of anaphylaxis requires a careful medical history with particular attention to the circumstances preceding the onset of symptoms, the order and time course of symptoms, and the response to treatment. The following cases illustrate some of the clinical situations commonly mistaken for anaphylaxis.
A 16-year-old male adolescent presents to his pediatrician for his yearly sports physical. While in the office, he receives his tetanus booster immunization. Five minutes later, he appears diaphoretic, pale, and complains of feeling dizzy. He has a syncopal episode in the office. His vital signs are the following: heart rate, 50; blood pressure, 85/40 mm Hg; and respiratory rate, 22. He regains consciousness after being placed in the Trendelenburg position but complains of nausea and vomits a short time later. The occurrence of a syncopal episode, associated with a traumatic or painful event accompanied by bradycardia and hypotension, is characteristic of a vasovagal reaction. Although diaphoresis, dizziness, hypotension, and syncope can be symptoms of anaphylaxis, the absence of cutaneous symptoms such as urticaria, flushing or angioedema, and the presence of bradycardia can distinguish a vasovagal reaction from anaphylaxis. Typically, vasovagal reactions result from venous pooling causing a paradoxical stimulation of the vagal nerve, leading to
Sign/symptom Hypotension Flushing
Urticaria Respiratory distress (wheezing) Angioedema Syncope
Adapted with permission from Ref. .
vocal cords anteriorly with a characteristic diamondshaped posterior glottic chink . Spirometry performed during a symptomatic episode frequently shows flattening of the inspiratory loop of the flow-volume curve. Therapy for this disorder must include evaluation and counseling regarding stressors, as well as the recognition of the cause of the wheezing and dyspnea. Speech therapy may be helpful in teaching patients breathing techniques for relaxing the vocal cords during an episode.
113 trolled activation of the complement cascade. This may be triggered by physical stressors such as an injury, dental and abdominal surgery, or infection and may also be triggered by certain medications. Angioedema occurs without the presence of pruritus or urticaria and can involve the face, larynx, gastrointestinal tract, and extremities . Epinephrine has little effect on the angioedema during an acute attack, and antihistamines and corticosteroids are also ineffective. Hereditary angioedema is diagnosed by demonstrating a qualitative or quantitative deficiency of C1INH. Frequently, C4 is decreased during an acute episode . Androgenic steroids such as danazol and stanazolol are of limited usefulness during acute attacks but are effective in preventing a recurrence. The most promising therapy for HAE is C1INH concentrates , and clinical trials are underway in this country. Fresh frozen plasma and antifibrinolytics may also have a role in the acute management of HAE [16,18]. Airway management is critical in patients with laryngeal edema, and intubation should be considered early in the course of the attack.
A 7-year-old boy presents to the ED with the sudden onset of flushing of the face and chest and hives over the torso, headache, and diarrhea. His family had just returned home after eating dinner at their favorite sushi restaurant when his symptoms began. According to the parents, they have eaten at this restaurant before, and he has eaten fish and shellfish previously without any problems. During the meal tonight, he ate several pieces of tuna sashimi and some rice. On exam, he is irritable and complains of headache and some abdominal pain. His face and chest are flushed and warm to the touch. He has some large confluent hives over his trunk and neck. Respiratory rate is mildly elevated, heart rate is elevated, and blood pressure is decreased. He has normal breath sounds. He receives diphenhydramine and a fluid bolus and begins to feel better within 15 to 20 minutes. Scromboid poisoning occurs after ingestion of histamine in spoiled fish. The histamine is produced by the conversion of histidine to histamine by bacteria in the fish. This occurs after the fish have been caught, primarily if they are not kept at a cold-enough temperature before consumption. The fish have a normal smell and taste, and the histamine is not destroyed by cooking. Scromboid poisoning is seen mainly after consumption of fish such as tuna, mackerel, mahi-mahi, or herring . The severity of symptoms is related to the amount of histamine ingested, thus, smaller persons are more likely to experience symptoms. The onset of symptoms occurs minutes to several hours after the meal, and symptoms last for several hours. The presence of elevated plasma histamine without elevated tryptase is consistent with scromboid poisoning. Treatment with antihistamines and fluid boluses (if hypotension is present) are helpful in alleviating the symptoms, although the course is generally self-limited. Other flushing syndromes that can mimic anaphylaxis include bred-man syndrome,Q cutaneous flushing after administration of vancomycin; carcinoid syndrome, with release of histamine and other mediators from the carcinoid tumor; and monosodium glutamate ingestion. One other condition that can mimic anaphylaxis, with potentially fatal complications is hereditary angioedema (HAE). Hereditary angioedema is an autosomal dominant condition where there is an absence of a functional C1 esterase inhibitor protein (C1INH), leading to the uncon-
The diagnosis of anaphylaxis rests on the pattern of the clinical signs and symptoms, along with a history of exposure to a known trigger. Careful attention must be paid to possible exposures (foods, medications, latex, insect stings, radiographic contrast media, and blood products) during the 2 to 4 hours before the onset of symptoms. Laboratory testing may be helpful in diagnosing some of the other disorders listed in the differential. An abnormal C1INH or functional assay, along with a decrease in C4, is seen in patients with symptoms due to HAE. Patients with scromboid poisoning may have elevated plasma histamine levels with normal serum tryptase levels. Blood serotonin and urinary vanillylmandelic acid will be elevated in patients with carcinoid syndrome. A rise in total serum tryptase levels has been reported to occur in anaphylaxis . Plasma histamine levels rise within minutes of the onset of symptoms and only remain elevated for 30 to 60 minutes . Thus, its usefulness as a diagnostic test is limited. The rise in serum tryptase occurs within 60 minutes, and levels can remain elevated for up to 6 hours after the onset of symptoms . However, serum tryptase may not be elevated in food induced anaphylaxis . Serum tryptase may also be useful in distinguishing anaphylaxis from systemic mastocyctosis. There are two forms of tryptase in the serum. Alpha-tryptase is produced and secreted constitutively by mast cells, whereas beta-tryptase is released during mast cell degranulation. Therefore, levels of beta-tryptase are elevated during anaphylaxis and levels of alpha-tryptase remain elevated in systemic mastocytosis . Following an episode of anaphylaxis, identification of specific IgE against a suspected trigger, such as a food, an
114 insect venom, or a medication, either by skin prick testing or radioallergosorbent testing (RAST) can help to confirm allergic sensitivity to this agent. The absence of a positive test does not rule out the possibility of an IgG or immune complex mediated reaction and is not helpful for agents known to cause direct degranulation of mast cells, such as radiocontrast media.
Table 4 Drug Epinephrine
Dosing of medications for treatment of anaphylaxis Dose/route 1:1000 0.1 mg/kg IM (max, 0.5 mL) 1:10 000 0.01mg/kg IV over 1-2 minutes Continuous infusion: 0.1Mg/kg/minute 1-1.25 mg/kg (max, 50 mg) PO/IM/IV 1 mg/kg IV (max, 50 mg) 4 mg/kg IV (max, 300 mg) given slowly 1-2 mg/kg IV 1-2 mg/kg PO (max 80 mg) mild episodes 1-2 mg/kg IV (max 125 mg) 0.25-0.5 ml in 2 ml saline 20 mL/kg rapid bolus 5-20 M g/kg/min 1-5 mg IV
Rapid initiation of treatment, particularly administration of epinephrine, is essential in the treatment of anaphylaxis. Fatalities may be prevented by the early use of epinephrine. The treatment of anaphylaxis and the drugs and doses employed are presented in Figure 1 and Table 4. The immediate interventions should occur nearly simultaneously. Epinephrine should be administered intramuscularly (IM), preferably in the lateral aspect of the thigh. Absorption occurs more rapidly with IM injection, compared to the subcutaneous route. In addition, injection into the lateral thigh results in more rapid and higher plasma concentrations than injection into the deltoid muscle . The initial IM dose can be repeated at 10- to 15-minute intervals. Intravenous epinephrine is recommended if there is persistent hypotension and no
Diphenhydramine (H1 blocker) Ranitidine (H2 blockers) Cimetidine Hydrocortisone (corticosteroids) Prednisone Methylprednisolone
B -Agonists (bronchodilatorsalbuterol) Volume expanders (normal saline, Ringer’s lactate) Dopamine (vasopressor) Glucagon (B -blockade)
Figure 1 Treatment algorithm for anaphylaxis.
response to IM administration. Careful monitoring for arrhythmias is important with use of the IV route. Epinephrine can also be administered intraosseously or via the endotracheal tube, or injected sublingually, if IV access cannot be obtained. In the case of an anaphylactic reaction after an insect sting or injection of allergen extract or vaccine, a venous tourniquet should be placed above the injection site, and epinephrine should be injected locally to slow the absorption (the tourniquet should be released every 5 minutes for 2 to 3 minutes and not used for more than 30 minutes total). Antihistamines, both H1 and H2 blockers, are useful adjunctive treatment to epinephrine. They are especially effective in relieving pruritus and urticaria. The combination of H1 and H2 agents is superior to the use of an H1 antagonist alone . These agents have a slower onset of action than epinephrine and should be considered as an adjunct to epinephrine administration. The main role of corticosteroids in the management of anaphylaxis is to prevent recurrence of symptoms or protracted anaphylaxis. Administration of corticosteroids is advisable in moderate to severe cases of anaphylaxis. Hypotension due to anaphylaxis should be treated by placing the patient in the Trendelenburg position, unless respiratory symptoms are prohibitive, and by giving fluid replacement with a crystalloid solution. Some sources prefer normal saline over lactated Ringers because it may potentially contribute towards metabolic acidosis . Up to 30 mL/kg during the first hour may be required for children. If volume replacement does not correct hypotension, IV epinephrine should be administered either as
a bolus of 0.1 to 0.3 mL of 1:10 000 dilution given over several minutes or as a continuous infusion of 0.1 lg/kg per minute with a maximum dose of 10 lg/min. Alternately, a dopamine infusion of 5 to 20 lg/kg/min can be used for refractory hypotension. Patients taking a b-adrenergic blocking medication can have protracted anaphylaxis, often refractory to epinephrine treatment. In this case, glucagon has been shown to be effective in the treatment of hypotension through its inotropic effects. An IV bolus of 1 to 5 mg can be followed by an infusion of 5 to 15 lg/min . Any patient presenting to the ED for treatment of anaphylaxis should be observed for a period of time depending on the severity of the reaction. For mild cases, 2 hours may be sufficient. Patients with severe anaphylaxis, with respiratory compromise and hypotension, should be observed in the hospital overnight. This is essential because of the risk of a biphasic reaction, which occurs in 6% of cases . Medications needed for the resolution of the symptoms (antihistamines, H2 blockers, corticosteroids) should be continued for 24 to 48 hours after discharge.
115 reactions involving cutaneous symptoms without respiratory difficulty. If symptoms progress, or if there is a history of rapidly progressing symptoms, epinephrine should be administered as well. Other important preventative measures include the following: – Wearing a medical alert bracelet – Providing the family, daycare, and school with an emergency plan (Fig. 2)  – Administering drugs by the oral route, rather than IV – Providing schools and daycare centers with detailed instructions regarding food avoidance – Avoid the use of b-blockers and angiotensinconverting enzyme inhibitors – Desensitization for specific medications if no alternatives are available – Immunotherapy for insect venom – Pretreatment with antihistamines and corticosteroids before the use of radiocontrast media. Referral to an allergist is recommended to (1) assist in counseling the patient regarding avoidance measures, particularly for foods and insects; (2) assist in the
It is very important that patients are instructed in measures to prevent a recurrence and to provide the patient and family with the tools (education and a preloaded epinephrine autoinjector syringe) necessary to treat future episodes, should they occur. In cases where the trigger is fairly certain, such as a food, medication, or insect sting, complete avoidance is an absolute necessity. Confirmation of IgE-mediated hypersensitivity can be made through skin prick testing or RAST testing. In cases where the trigger is unknown, allergy testing may be useful in identifying possible allergic triggers. Although a blood sample for RAST testing can be obtained in the ED during the acute event, skin prick testing should not be done for at least 2 weeks after the anaphylactic reaction due to a refractory period that can occur resulting in anergy to the triggering agent. Because 30% to 35% of patients will have a recurrence [27,28], all patients should be instructed in the proper use of a preloaded epinephrine syringe and provided with a prescription for this medication before discharge from the ED or hospital. Epinephrine autoinjectors should be kept readily available at home, school, daycare, camp, and sporting events. The family should be instructed to use epinephrine in cases of anaphylaxis involving any respiratory difficulty or angioedema of the airway, which is demonstrated by hoarseness, stridor, drooling, or swelling of the tongue. Once epinephrine is administered, the patient should be immediately transported to the nearest ED. The family should also have diphenhydramine (liquid) available in case of a milder reaction and should be instructed to give this as the first line medication for
Figure 2 Emergency action plan. Adapted with permission from Ref. .
116 identification of possible triggers; (3) provide further education regarding management of anaphylaxis; and (4) determine if desensitization (eg, penicillin) or immunotherapy (eg, insect venom) is indicated and to begin therapy .
 Lee JM, Greene DS. Biphasic anaphylactic reactions in pediatrics. Pediatrics 2000;106:762276.  Stark BJ, Sullivan TJ. Biphasic and protracted anaphylaxis. J Allergy Asthma Clin Immunol 1986;78:76283.  Lieberman P. Anaphylaxis and anaphylactoid reactions. In: Adkinson NF, Yunginger JW, Busse MW, et al, editors. Middleton’s allergy principles and practice. 6th ed. vol 2. Philadelphia, PA: Mosby; 2003. p.14972522.  Wood RP, Milgrom H. Vocal cord dysfunction. J Allergy Clin Immunol 1996;98:48125.  Bork K, Hardt J, Schicketanz KH, et al. Clinical studies of sudden upper airway obstruction in patients with hereditary angioedema due to C1 esterase inhibitor deficiency. Arch Intern Med 2003;163:1229235.  Bowen T, Cicardi M, Farkas H, et al. Canadian 2003 international consensus algorithm for the diagnosis, therapy, and management of hereditary angioedema. J Allergy Clin Immunol 2004; 114:629237.  Waytes AT, Rosen FS, Frank MM. Treatment of hereditary angioedema with a vapor-heated C1 inhibitor concentrate. N Engl J Med 1996;334:163024.  Hill BJ, Thomas SH, McCabe C. Fresh frozen plasma for acute exacerbations of hereditary angioedema. Am J Emerg Med 2004;22:633.  Lin RY, Schwartz LB, Curry A, et al. Histamine and tryptase levels in patients with acute allergic reactions: an emergency department based study. J Allergy Clin Immunol 2000;106:65271.  Schwartz LB, Yunginger JW, Miller J, et al. Time course of appearance and disappearance of human mast cell tryptase in the circulation after anaphylaxis. J Clin Invest 1989;83:155125.  Sampson HA, Mendelson LM, Rosen JP. Fatal and near-fatal anaphylactic reactions to food in children and adolescents. N Engl J Med 1992;327:38024.  Schwartz LB, Irani AM. Serum tryptase and the laboratory diagnosis of systemic mastocytosis. Hematol Oncol Clin North Am 2000;14:641257.  Simons FE, Roberts JR, Gu X. Epinephrine absorption in children with a history of anaphylaxis. J Allergy Clin Immunol 1998;101:3327.  Lin RY, Curry A, Pesola G. Improved outcomes in patients with acute allergic syndromes who are treated with combined H1 and H2 antagonists. Ann Emerg Med 2000;36:46227.  Joint Task Force on Practice Parameters, American Academy of Allergy, Asthma and Immunology; American College of Allergy, Asthma and Immunology and Joint Council of Allergy, Asthma and Immunology. The diagnosis and management of anaphylaxis: an updated practice parameter. J Allergy Clin Immunol 2005;115:S4832523.  Zaloga GP, Delacey W, Holmboe E, et al. Glucagon reversal of hypotension in a case of anaphylactoid shock. Ann Intern Med 1986;105:6526.  Kemp SF, Lockey RF, Wolf BL, et al. Anaphylaxis. A review of 266 cases. Arch Intern Med 1995;155:1749265.  Cianferoni A, Novembre E, Pucci N, et al. Anaphylaxis: a 7-year follow-up survey of 46 children. Ann Allergy Asthma Immunol 2004;92:46428.  American Academy of Allergy, Asthma and Immunology Position statement, anaphylaxis in schools and other child care settings. J Allergy Clin Immunol 1998;102:17326.
Anaphylaxis remains a serious, frequently underrecognized problem, which is eminently treatable given prompt recognition. Fortunately, fatalities due to anaphylaxis are uncommon. The risk of fatality is increased in patients with asthma, in cases where the triggering agent was injected intravenously and when the administration of epinephrine is delayed. Physicians should be familiar with the signs and symptoms of anaphylaxis and the conditions which mimic anaphylaxis in order to initiate prompt lifesaving treatment. However, the role of the ED physician does not stop after the symptoms have subsided. It is imperative that patients receive education before discharge to help prevent and treat recurrence of anaphylaxis. Early treatment of symptoms with epinephrine is life-saving, and all patients who have experienced an episode of anaphylaxis should carry an epinephrine autoinjector syringe.
 Bohlke K, Davis RL, DeStefano F, et al. Epidemiology of anaphylaxis among children and adolescents enrolled in a health maintenance organization. J Allergy Clin Immunol 2004; 113:536242.  Neugut AI, Ghatak AT, Miller RL Anaphylaxis in the United States. Arch Intern Med 2001;161:15221.  Sorenson HT, Nielsen-Ostergaard J. Anaphylactic shock occurring outside hospitals. Allergy 1989;44:288290.  Stewart AG, Ewan PW. The incidence, aetiology and management of anaphylaxis presenting to an accident and emergency department. Q J Med 1996;89:859286.  Yocum MW, Butterfield JH, Klein JS, et al. Epidemiology of anaphylaxis in Olmsted County: a population-based study. J Allergy Clin Immunol 1999;104:445226.  Boros CA, Kay D, Gold MS. Parent reported allergy and anaphylaxis in 4173 South Australian children. J Paediatr Child Health 2000;36:36240.  Hamman CP. Natural rubber latex protein sensitivity. Rev Am J Contact Dermatitis 1993;4:4.  Webb LM, Lieberman P. Anaphylaxis: a review of 601 cases. Ann Allergy Asthma Immunol 2006;97:39243.  Novembre E, Cianferoni A, Bernardini R, et al. Anaphylaxis in children: clinical and allergologic features. Pediatrics 1998; 101:E8.  Douglas DM, Sukenick E, Andrade WP, et al. Biphasic systemic anaphylaxis: an inpatient and outpatient study. J Allergy Clin Immunol 1994;93:977285.