Anaphylaxis

Introduction
Background
Anaphylaxis is a severe allergic reaction that is rapid in onset and may cause death. There are usually prominent dermal and systemic signs and symptoms. The full-blown syndrome includes urticaria (hives) and/or angioedema with hypotension and bronchospasm. The classic form, described in 1902, involves prior sensitization to an allergen with later re-exposure, producing symptoms via an immunologic mechanism. An anaphylactoid reaction produces a very similar clinical syndrome but is not immune-mediated. Treatment for both conditions is similar, and this article uses the term anaphylaxis to refer to both conditions unless otherwise specified. A recent consensus report reviewed the definition and management of anaphylaxis.1 For a CME/CE activity, see Anaphylaxis. Also see Medscape's Allergy & Immunology Resource Center.

Pathophysiology
Rapid onset of increased secretion from mucous membranes, increased bronchial smooth muscle tone, decreased vascular smooth muscle tone, and increased capillary permeability occur after exposure to an inciting substance. These effects are produced by the release of mediators, which include histamine, leukotriene C4, prostaglandin D2, and tryptase. In the classic form, mediator release occurs when the antigen (allergen) binds to antigen-specific immunoglobulin E (IgE) attached to previously sensitized basophils and mast cells. The mediators are released almost immediately when the antigen binds. In an anaphylactoid reaction, exposure to an inciting substance causes direct release of mediators, a process that is not mediated by IgE. Increased mucous secretion and increased bronchial smooth muscle tone, as well as airway edema, contribute to the respiratory symptoms observed in anaphylaxis. Cardiovascular effects result from decreased vascular tone and capillary leakage. Histamine release in skin causes urticarial skin lesions. The most common inciting agents in anaphylaxis are parenteral antibiotics (especially penicillins), IV contrast materials, Hymenoptera stings, and certain foods (most notably, peanuts). Oral medications and many other types of exposures also have been implicated. Anaphylaxis also may be idiopathic.

Frequency
United States

The true incidence of anaphylaxis is unknown, partly because of the lack of a precise definition of the syndrome. Some clinicians reserve the term for the full-blown syndrome, while others use it to describe milder cases. Fatal anaphylaxis is relatively rare; milder forms occur much more frequently. The frequency of anaphylaxis is increasing, and this has been attributed to the increased number of potential allergens to which people are exposed. Up to 500-1,000 fatal cases of anaphylaxis per year are estimated to occur in the United States. A recent review concluded that the lifetime prevalence of anaphylaxis is 1-2% of the population as a whole.2
International

Reactions to insects and other venomous plants and animals are more prevalent in tropical areas because of the greater biodiversity in these areas.

Mortality/Morbidity
Approximately 1 in 5000 exposures to a parenteral dose of a penicillin or cephalosporin antibiotic causes anaphylaxis. More than 100 deaths per year are reported in the United States. Fewer than 100 fatal reactions to Hymenoptera stings are reported each year in the United States but this is considered to be an underestimate. One to 2% of people receiving IV radiocontrast experience some sort of reaction. The majority of these reactions are minor, and fatalities are rare. Low molecular weight contrast causes fewer and less severe reactions.

Race
Well-described racial differences in the incidence or severity of anaphylaxis do not exist. Cultural and socioeconomic differences may influence exposure rates.

Sex
Differences have been reported in the incidence and prevalence of anaphylactic reactions between men and women. Overall, women have a higher incidence of anaphylaxis than men, but, in some series of children, males predominate.2

Age
Anaphylaxis occurs in all age groups. Food allergies are more common in the young, whereas more drug reactions occur in adults, possibly due to greater exposure. Although prior exposure is essential for the development of true anaphylaxis, reactions occur even when no documented prior exposure exists. Thus, patients may react to a first exposure to an antibiotic or insect sting. Elderly persons have the greatest risk of mortality from anaphylaxis due to the presence of preexisting disease.

Clinical
History
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Anaphylactic reactions almost always involve the skin or mucous membranes. More than 90% of patients have some combination of urticaria, erythema, pruritus, or angioedema. The upper respiratory tract commonly is involved, with complaints of nasal congestion, sneezing, or coryza. Cough, hoarseness, or a sensation of tightness in the throat may presage significant airway obstruction. Eyes may itch and tearing may be noted. Conjunctival injection may occur. Dyspnea is present when patients have bronchospasm or upper airway edema. Hypoxia and hypotension may cause weakness, dizziness, or syncope. Chest pain may occur due to bronchospasm or myocardial ischemia (secondary to hypotension and hypoxia). GI symptoms of cramplike abdominal pain with nausea, vomiting, or diarrhea also occur but are less common, except in the case of food allergy. In a classic case of anaphylaxis, the patient or a bystander provides a history of possible exposures that may have caused the rapid onset of skin and other manifestations. This history often is partial; exposure may not be recalled, or it may not be considered significant by the patient or health care provider. For example, when queried about medications, a patient may not mention over-the-counter (OTC) products. The clinician may not realize that, while reactions are usually rapid in onset, they also may be delayed.

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For reasons that are not well understood, a lack of dermal findings is more common in children than in adults.

Physical
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General

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Physical examination of patients with anaphylaxis depends on affected organ systems and severity of attack. Vital signs may be normal or significantly disordered with tachypnea, tachycardia, and/or hypotension. Place emphasis on determining the patient's respiratory and cardiovascular status. Frank cardiovascular collapse or respiratory arrest may occur in severe cases. Anxiety is common unless hypotension or hypoxia causes obtundation. Shock may occur without prominent skin manifestations or history of exposure; therefore, anaphylaxis is part of the differential diagnosis for patients who present with shock and no obvious cause. General appearance and vital signs vary according to severity of attack and affected organ system(s). Patients commonly are restless due to severe pruritus from urticaria. Anxiety, tremor, and a sensation of cold may result from compensatory endogenous catecholamine release. Severe air hunger may occur when the respiratory tract is involved. If hypoperfusion or hypoxia occurs, the patient may exhibit a depressed level of consciousness or may be agitated and/or combative. Tachycardia usually is present, but bradycardia may occur in very severe reactions.

Skin The classic skin manifestation is urticaria (ie, hives). Lesions are red and raised, and they sometimes have central blanching. Intense pruritus occurs with the lesions. Lesion borders usually are irregular and sizes vary markedly. Only a few small or large lesions may become confluent, forming giant urticaria. At times, the entire dermis is involved with diffuse erythema and edema. Hives can occur anywhere on the skin. o In a local reaction, lesions occur near the site of a cutaneous exposure (eg, insect bite). The involved area is erythematous, edematous, and pruritic. If only local skin reaction (as opposed to generalized urticaria) is present, systemic manifestations (eg, respiratory distress) are less likely. Local reactions, even if severe, are not predictive of systemic anaphylaxis on reexposure. o Lesions typical of angioedema also may manifest in anaphylaxis. The lesions involve mucosal surfaces and deeper skin layers. Angioedema usually is nonpruritic and associated lesions are nonpitting. Lesions most often appear on the lips, palms, soles, and genitalia. Pulmonary o Upper airway compromise may occur when the tongue or oropharynx is involved. When the upper airway is involved, stridor may be noted. The patient may have a hoarse or quiet voice and may lose speaking ability as the edema progresses. Complete airway obstruction is the most common cause of death in anaphylaxis. o Wheezing is common when patients have lower airway compromise due to bronchospasm or mucosal edema. o In angioedema, due to ACE inhibitors, marked edema of the tongue and lips may obstruct the airway. Cardiovascular o Cardiovascular examination is normal in mild cases. In more severe cases, compensatory tachycardia occurs due to loss of vascular tone.

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Intravascular volume depletion may take place as a consequence of capillary leakage. These mechanisms also lead to development of hypotension. Relative bradycardia has been reported.

Causes
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A wide variety of substances can cause anaphylaxis. Drugs and foods are the most common causes. Peanuts, tree nuts, and shellfish are the most commonly implicated foods, while antibiotics (especially penicillins) and nonsteroidal anti-inflammatory drugs (NSAIDs) are the most common drugs. Anaphylaxis also may be idiopathic. In the classic form of anaphylaxis, a foreign protein is the inciting agent (eg, antigen). On initial exposure, the antigen elicits generation of an IgE antibody. The antibody residue binds to mast cells and basophils. On reexposure, the antigen binds to the antibody, and the receptors are activated. Clinical manifestations result from release of immune response mediators such as histamine, leukotrienes, tryptase, and prostaglandins. The same mechanism occurs when a nonimmunogenic foreign substance binds as a so-called hapten to a native carrier protein, creating an immunogenic molecule. Factors influencing severity of a reaction include degree of host sensitivity and dose, route, and rate of administration of the offending agent. Parenteral exposures tend to result in faster and more severe reactions. Most severe reactions occur soon after exposure. The faster a reaction develops, the more severe it is likely to be. While most reactions occur within hours, symptoms may not occur for as long as 3-4 days after exposure.

Drugs

Penicillin and cephalosporin antibiotics are the most commonly reported medical agents in anaphylaxis. This prevalence is a function of the immunogenicity and frequent use of these agents. Because of their molecular and immunologic similarity, cross-sensitivity may exist. o Reports based on skin testing indicate that about 10% of patients allergic to a penicillin antibiotic are allergic to cephalosporins.  One report suggested that the actual incidence of clinical cross-reactivity is lower (perhaps 1%), with most reactions considered mild.3 Another paper indicated that patients with a history of allergy to penicillin seem to have a higher risk (by a factor of about 3) of subsequent reaction to any drug and that the risk of an allergic reaction to cephalosporins in patients with a history of penicillin allergy may be up to 8 times as high as the risk in those with no history of penicillin allergy (ie, at least part of the observed "cross reactivity" may represent a general state of immune hyperresponsiveness, rather than true "cross-reactivity").4  One retrospective study evaluated 606 hospitalized patients with a history of penicillin allergy who were given a cephalosporin. Only one patient (0.17%) had a reaction, and it was minor.5 o Patients with a history of positive skin tests for penicillin allergy are at high risk of subsequent reactions. However, approximately 85% of patients with a history of penicillin allergy have negative skin tests and a low risk of reactions.  When a drug in either class is the drug of choice for a patient with a life-threatening emergency, a number of options exist. When the history is indefinite, the drug may be administered under close observation; however, when possible, obtain the patient's informed consent. Immediate treatment measures for anaphylaxis should be

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available. Alternatively, when the history is more convincing, a desensitization or prophylactic pretreatment protocol may be instituted or another agent selected. Reactions to medications tend to be more severe and rapid in onset when the antibiotic is administered parenterally. A drug reaction may occur in a patient with no prior history of drug exposure. Aspirin and NSAIDs commonly are implicated in allergic reactions and anaphylaxis. Bronchospasm is common in patients with reactive airway disease and nasal polyps. Cross-reactivity often occurs between the various NSAIDs. ACE inhibitors, widely used in the treatment of hypertension, are associated with angioedema in 0.51.0% of patients who take them. Systemic anaphylaxis is rarely associated with these agents. The reaction is thought to be medicated by bradykinin and is more common in African Americans.

Intravenous radiocontrast media

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IV administered radiocontrast media causes an anaphylactoid reaction that is clinically similar to true anaphylaxis and is treated in the same way. The reaction is not related to prior exposure. Shellfish or "iodine allergy" is not a contraindication to use of IV contrast and does not mandate a pretreatment regimen. As with any "allergic" patient, give consideration to use of low molecular weight (LMW) contrast. The term iodine allergy is a misnomer. Iodine is an essential trace element present throughout the body. No one is allergic to iodine. Patients who report iodine allergy usually have had either a prior contrast reaction, a shellfish allergy, or a contact reaction to povidone-iodine (Betadine). Manage these patients as indicated earlier. Approximately 1-3% of patients who receive hyperosmolar IV contrast experience a reaction. Use of LMW contrast decreases incidence of reactions to approximately 0.5%. Personnel, medications, and equipment needed for treatment of allergic reactions always should be available when these agents are administered. Obtain consent before administration. Reactions to radiocontrast usually are mild (most commonly urticarial), with only rare fatalities reported. Risk of a fatal reaction has been estimated at 0.9 cases per 100,000 exposures. Mucosal exposure (eg, GI, genitourinary [GU]) to radiocontrast agents has not been reported to cause anaphylaxis; therefore, a history of prior reaction is not a contraindication to GI or GU use of these agents. Pretreatment with antihistamines or corticosteroids and use of LMW agents lead to lower rates of anaphylactoid reactions to IV contrast. Consider these measures for patients who have prior history of reaction, since rate of recurrence is estimated at 17-60%. Some institutions use only LMW agents. Patients who are atopic and/or asthmatic also are at increased risk of reaction. In addition, allergic reaction is more difficult to treat in those taking beta-blockers.

Hymenoptera stings

Hymenoptera stings are a common cause of allergic reaction and anaphylaxis. An uncertain but enormous number of exposures occur; accurate reaction rates are therefore difficult to estimate. In the United States, Hymenoptera envenomations result in fewer than 100 reported deaths per year. Local reaction and urticaria without other manifestations of anaphylaxis are much more common than full-blown anaphylaxis. Generalized urticaria is a risk factor for subsequent anaphylaxis; but a local reaction, even if severe, is not a risk factor for anaphylaxis.

Caution patients treated and released from the ED after an episode of anaphylaxis or generalized urticaria from Hymenoptera envenomation to avoid future exposure when possible. Consider referral to an allergist for desensitization, particularly when further exposure is likely. Additionally, consider prescribing a treatment kit with an epinephrine auto-injector and oral antihistamine. Both are effective measures in preventing or ameliorating future reactions.

Food and environmental allergies

Food allergy is common. Symptoms usually are mild and limited to the GI tract, but full-blown anaphylaxis can occur. Fatalities are rare compared to number of exposures; however, the number of exposures is so high that foods may be the commonest cause of anaphylaxis. Anaphylaxis due to foods may be an underrecognized cause of sudden death and an unappreciated cause of diagnosed anaphylaxis. Commonly implicated foods include peanuts, tree nuts, legumes, fish and shellfish, milk, and eggs. Reports of severe allergic reactions to peanuts are increasing. Latex allergy is an increasingly recognized problem in medical settings, where use of gloves and other latex products is ubiquitous. Most reactions are cutaneous or involve the mucous membranes. Anaphylactic reactions occur and have been reported with seemingly benign procedures (eg, Foley catheter insertion, intraperitoneal exposure to gloves during surgery).

Differential Diagnoses
Angioedema Anxiety Asthma Conversion Disorder Epiglottitis, Adult Foreign Bodies, Trachea Myocardial Infarction Pulmonary Embolism Toxicity, Scombroid Urticaria

Other Problems to Be Considered

Globus hystericus Hereditary angioedema Monosodium glutamate poisoning (ie, Chinese restaurant syndrome)

Workup
Laboratory Studies
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The diagnosis of anaphylaxis is clinical and does not rely on laboratory testing. When typical symptoms are noted in association with a likely exposure, diagnosis is virtually certain. Ancillary testing may help assess severity of reaction, although this is primarily a clinical judgment. When unclear, ancillary testing may help establish the diagnosis. The only potentially useful test at the time of reaction is measurement of serum mast cell tryptase. Tryptase is released from mast cells in both anaphylactic and anaphylactoid reactions. Levels are usually raised in severe reactions. Mast cell tryptase is raised transiently with blood levels reaching a peak approximately an hour after reaction onset. o Tryptase levels may aid in later diagnosis and treatment. o Consider the test in cases for which diagnosis of anaphylaxis is uncertain.

o The utility of this test awaits full evaluation. Cardiac monitoring in patients with severe reactions and in those with underlying cardiovascular disease is important, particularly when adrenergic agonists are used in treatment. Pulse oximetry also is useful.

Imaging Studies
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Imaging studies are not generally useful in the diagnosis and management of anaphylaxis, although they may be used as diagnostic aids when diagnosis is unclear.

Other Tests
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Sensitivity testing o Testing for sensitivity to penicillin antibiotics may be useful when a penicillin or cephalosporin antibiotic is the drug of choice for a serious infection in a patient who has a history of severe allergic reaction. Obtain informed consent, and ensure that resuscitative equipment is immediately available. Protocols for acute testing for allergy to penicillin or cephalosporin antibiotics involve administration of increasing IV doses of the chosen antibiotic, while observing the patient for pruritus, flushing, urticaria, dyspnea, hypotension, or other manifestations of anaphylaxis. If no manifestations are observed, a full dose of the antibiotic may be administered safely. o A suggested protocol for IV testing begins with 0.001 mg of the chosen drug. At 10-min intervals, incrementally increase the dose (eg, 0.001 mg, 0.005 mg, 0.01 mg, 0.05 mg, 0.1 g, 0.5 mg, 1 mg, 10 mg, 50 mg, 100 mg, full dose), while observing the patient. Many other protocols exist. In most circumstances, perform desensitization on an inpatient basis. If the necessary resources are available, desensitization may be performed in the ED.

Procedures
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Intravenous contrast reaction prevention o Patients with a history of severe reactions to IV contrast material may require use of contrast in an urgent or emergency situation. Alternatives (eg, noncontrast spiral CT scan for ureteral stone, Doppler ultrasonography for deep venous thrombosis [DVT], nuclear scans for pulmonary embolism) should be considered but are not always feasible. In these circumstances, a prophylactic regimen of corticosteroids and antihistamines may be used. The precise efficacy of these regimens is difficult to evaluate, but they generally are considered effective. One author states that the recurrence rate for patients with a previous reaction was reduced from 17-60% to 9% when conventional contrast material was used; the rate was reduced to less than 1% when low osmolality material was employed after a pretreatment regimen. o The use of H2 blockers has not been shown to decrease the risk of reaction to IV contrast. One study suggests H2 blockers actually appear to increase the risk. o A widely quoted protocol for prevention of reactions to IV contrast suggests the following:  Use low osmolality contrast.  Administer hydrocortisone (200 mg IV); wait 2 hours if clinically appropriate.  Administer diphenhydramine (50 mg IM) immediately before the procedure. Desensitization regimens

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Desensitization regimens for penicillin and cephalosporin antibiotic allergy have been shown effective. Because these regimens are lengthy (approximately 6 h), they have limited applicability to the ED. When patients wait for long periods in the ED or in an observation unit, consider desensitization regimens. A typical desensitization regimen involves administering the antibiotic of choice in an initial dose of 0.01 mg. While observing the patient, double the dose every 10-15 minutes until a full dose has been administered. Desensitization regimens do not protect against non-IgE-mediated reactions that may be severe or even life threatening (eg, Stevens-Johnson syndrome). While theoretically attractive, premedication regimens have not been clinically shown to decrease incidence or severity of IgE-mediated allergic reactions to antibiotics.

Treatment
Prehospital Care
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Prehospital patients with symptoms of severe anaphylaxis should first receive standard interventions. Interventions include high-flow oxygen, cardiac monitoring, and IV access. These measures are appropriate for an asymptomatic patient who has a history of serious reaction and has been reexposed to the inciting agent. Additional treatment depends upon the condition of the patient and the severity of the reaction. Measures beyond basic life support (BLS) are not necessary for patients with purely local reactions. Immediately assess airway patency due to the potential for compromise secondary to edema or bronchospasm. Active airway intervention may be difficult due to laryngeal or oropharyngeal edema. In this circumstance, it may be preferable to defer intubation attempts, and instead ventilate with a bag/valve/mask apparatus while awaiting medications to take effect. In extreme circumstances, cricothyrotomy or catheter jet ventilation may be lifesaving. Inhaled beta-agonists are used to counteract bronchospasm and should be administered to patients who are wheezing. The IV line should be of large caliber due to the potential requirement for large-volume IV fluid resuscitation. Isotonic crystalloid solutions (ie, normal saline, Ringer lactate) are preferred. A keep vein open (KVO) rate is appropriate for patients with stable vital signs and only cutaneous manifestations. If hypotension or tachycardia is present, administer a fluid bolus of 20 mg/kg for children and 1 L for adults. Further fluid therapy depends on patient response. Large volumes may be required in the profoundly hypotensive patient. Administer epinephrine to patients with systemic manifestations of anaphylaxis. With mild cutaneous reactions, an antihistamine alone may be sufficient, thus the potential adverse effects of epinephrine can be avoided. Patients on beta-blocker medications may not respond to epinephrine. In these cases, glucagon may be useful. The Medication section describes dosage, routes of administration, and contraindications for medications discussed in this section. Antihistamines (eg, H1 blockers), such as diphenhydramine (Benadryl) are important and should be administered for all patients with anaphylaxis or generalized urticaria. Corticosteroids are used in anaphylaxis primarily to decrease the incidence and severity of delayed or biphasic reactions. Corticosteroids may not influence the acute course of the disease; therefore, they have a lower priority than epinephrine and antihistamines.

Emergency Department Care

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ED care begins with standard monitoring and treatment, including oxygen, cardiac monitoring, and a large-bore IV with isotonic crystalloid solution. Further intervention depends on severity of reaction and affected organ system(s). Rapidly assess airway patency in patients with systemic signs or symptoms. If required, intubation may be difficult to achieve because of upper airway or facial edema. Standard rapid sequence induction (RSI) techniques can be used but may cause loss of the airway in a patient whose airway anatomy is altered by edema. Epinephrine may rapidly reverse airway compromise, and bag/valve/mask ventilation may be effective in the interim when intubation is not possible. Surgical airway intervention using standard cricothyrotomy is an option when orotracheal intubation or bag/valve/mask ventilation is not effective. o Wheezing or stridor indicates bronchospasm or mucosal edema. Treatment with epinephrine and inhaled beta-agonists is effective for these indications. o Recommendations to treat refractory bronchospasm with corticosteroids have been made because of their effectiveness in reactive airway disease. As in asthma therapy, onset of action is delayed for several hours. Aminophylline also has been recommended for bronchospasm in anaphylaxis and may be more rapidly effective than corticosteroids. Hypotension in anaphylaxis usually is due to vasodilatation and capillary fluid leakage. Epinephrine is the primary pharmacologic treatment for these findings. H1-blocking antihistamines also may have a role in reversing hypotension. Some authors also recommend H2-blocking agents. Large volume fluid resuscitation with isotonic crystalloid often is needed to support the circulation in patients with cardiovascular manifestations of anaphylaxis. o Refractory hypotension first should be treated with large volumes of crystalloid and repeated doses of epinephrine or a continuous epinephrine infusion. If this is not effective, other pressors with alpha-adrenergic activity, such as levarterenol (Levophed) or dopamine, may be considered. Cases of effective use of military antishock trousers (MAST) for refractory hypotension have been reported. o Mediators of anaphylaxis are not considered to have direct myocardial toxicity. In patients with preexisting heart disease, ischemic myocardial dysfunction may occur due to hypotension and hypoxia. Epinephrine still may be necessary in patients with severe anaphylaxis, but remember the potential for exacerbating ischemia. If pulmonary congestion or evidence of cardiac ischemia is present, fluid resuscitation should be approached more cautiously. o Patients taking beta-blockers may be resistant to the effects of epinephrine. Larger than usual doses may be needed. Glucagon may be effective in this circumstance, because it increases intracellular cyclic adenosine monophosphate (cAMP) levels by a mechanism that does not depend upon beta-receptors. Cutaneous effects of anaphylaxis are uncomfortable but not life threatening. Patients often respond promptly to epinephrine and H1 antihistamines. Some authors state that corticosteroids help prevent recurrence of symptoms (both cutaneous and systemic) that may occur 6-8 hours after successful treatment (so-called biphasic reaction). H2 blockers may have an added effect. GI symptoms in anaphylaxis respond to H1 antihistamines and epinephrine. Disposition: Disposition of patients with anaphylaxis depends upon the severity of the initial reaction and the response to treatment. Patients with non life-threatening symptoms may be observed for 4-6 hours after successful treatment and then discharged. Patients who have refractory or very severe anaphylaxis (with cardiovascular and/or severe respiratory symptoms) should be admitted or treated and observed for a longer period in the ED or an observation area. After discharge care: Patients with cardiovascular and/or respiratory symptoms who have an environmental trigger likely to be encountered after discharge should carry self-injectable epinephrine after discharge. Referral to an allergist should be considered.

Consultations
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Acute manifestations of anaphylaxis usually respond to ED treatment. In refractory cases, consult with an allergist, cardiologist, pulmonologist, or other intensivist. Consultation with an allergist (when available) is appropriate when desensitization to an antibiotic is contemplated. When a patient at high risk for contrast reaction is under consideration for a contrast study, consultation with the radiologist regarding pretreatment and choice of contrast agent is appropriate. Refer patients who are treated and released from the ED after an episode of anaphylaxis or generalized urticaria to their primary care provider or to an allergist for follow-up. At that time, consideration can be given to skin testing and possible desensitization.

Medication
The primary drug treatments for acute anaphylactic reactions are epinephrine and H1 antihistamines. Epinephrine is the drug of choice for life-threatening reactions. When the intravenous route is not indicated, the intramuscular route is preferable to the subcutaneous route due to more rapid and reliable absorption. The anterolateral thigh is the preferred site, especially in children. Epinephrine is clearly effective for the most serious effects and H1-blockers are also effective; do not delay or defer their use in favor of other treatments. Inhaled beta-agonists lack some of the adverse effects of epinephrine and are useful for cases of bronchospasm, but they may not have additional effects when optimal doses of epinephrine are used. Corticosteroids are potentially effective in preventing biphasic (ie, recurrent) reactions. Due to their delayed effect, corticosteroids are not first-line treatments. H2-blocking antihistamines theoretically are attractive agents for dermal and GI manifestations, but evidence supporting their clinical effectiveness is less than that for H1-blocking agents. Some evidence suggests that combining H1 and H2 blockers may be more effective than H1 blockers alone. Glucagon may be useful in treating refractory cardiovascular effects in patients taking beta-blockers.

Parenteral adrenergic agents

Reverse cardiovascular, cutaneous, GI, and pulmonary manifestations of anaphylaxis.

Epinephrine (EpiPen, Adrenalin)

DOC for shock, angioedema, airway obstruction, bronchospasm, and urticaria in severe anaphylactic reactions. Administer IM (preferred) or SC, except for patients in extremis for whom it is administered IV. May be administered SL or via ET when no IV access available. Continuous infusion may be administered in cases of refractory shock.

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Dosing Interactions Contraindications Precautions

Adult

0.3-0.5 mL 1:1000 soln SC or IM q15min 0.5-1 mL 1:10,000 soln IV; slow administration; repeat prn

0.3-0.5 mL 1:1000 soln SL q15min 1 mL 1:1000 soln ET in approximately 10 mL NS IV infusion: 0.1-1 mcg/kg/min
Pediatric

0.01 mL/kg (minimum 0.1 mL) 1:1000 soln IM (preferred) or SC q15min 0.1 mL/kg 1:10,000 soln IV prn slow administration; repeat prn 0.01 mL/kg (minimum 0.1 mL) 1:1000 soln SL q15min 0.01 mL/kg (minimum 0.1 mL) 1:1000 soln ET in approximately 1-3 mL NS IV infusion: 0.1-1 mcg/kg/min

DosingInteractionsContraindicationsPrecautionsDosingInteractionsContraindicationsPrecautionsDosingInteractionsContraindicati onsPrecautionsInhaled

beta-agonists

Used to treat bronchospasm. Doses are identical to those used in the treatment of asthma.

Albuterol (Proventil, Ventolin)

Numerous inhaled beta-agonists are used for treatment of bronchospasm; albuterol is the most commonly used preparation.

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Dosing Interactions Contraindications Precautions

Adult

0.5 mL 0.5% soln in 2.5 cc NS nebulized q15min

Pediatric

0.03-0.05 mL/kg 0.5% soln in 2.5 cc of NS via nebulizer q15min

DosingInteractionsContraindicationsPrecautionsDosingInteractionsContraindicationsPrecautionsDosingInteractionsContraindicati onsPrecautionsH1-receptor

blockers (Antihistamines)

Primarily effective against cutaneous effects of anaphylaxis. Also may help antagonize cardiac and respiratory effects; should be used routinely in most cases of anaphylaxis. IV administration is preferable when a rapid effect is desired. IM dosing also is effective but has a slower onset than IV and may cause local tissue irritation. PO doses must be larger than parenteral doses because of 50% first-pass metabolism in the liver. Most recommendations for use of antihistamines state that they should be continued for 2-3 days after treatment of the acute anaphylactic event.

Diphenhydramine (Benadryl)

Many effective H1 blockers exist; diphenhydramine is effective and widely available.

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Dosing Interactions

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Contraindications Precautions

Adult

25-50 mg IV/IM q4-6h 50 mg PO q4-6h

Pediatric

1-2 mg/kg IV/IM q4-6h 2 mg/kg PO q4-6h

DosingInteractionsContraindicationsPrecautionsDosingInteractionsContraindicationsPrecautionsDosingInteractionsContraindicati onsPrecautionsH2-receptor

blockers (Antihistamines)

H2 blockers are used commonly by clinicians in treatment of allergic reactions and urticaria. Evidence of additive effect with H1-blocker anaphylaxis exists, but they should not be considered first-line therapy.

Cimetidine (Tagamet)

Many H2 blockers are available. Cimetidine is the prototype drug; other agents have much less evidence of effectiveness in anaphylaxis.

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Dosing Interactions Contraindications Precautions

Adult

300 mg PO/IV/IM q6h

Pediatric

5-10 mg/kg PO/IV/IM q6h

DosingInteractionsContraindicationsPrecautionsDosingInteractionsContraindicationsPrecautionsDosingInteractionsContraindicati onsPrecautionsCorticosteroids

These agents have a role in reversing bronchospasm and cutaneous effects of anaphylaxis. Corticosteroids have a delayed onset of action and do not reverse the cardiovascular effects of anaphylaxis. These agents should be used in severe reactions, but the use of epinephrine and H1 antihistamines has a higher priority. Some authors state that corticosteroids help prevent or ameliorate recurrent (biphasic) anaphylaxis, but the true incidence of this condition has not been determined, and recurrences are usually less severe than the initial attack. While corticosteroids usually are administered IV in patients with anaphylaxis for presumed rapidity of effect, PO and IV corticosteroids are equally efficacious in asthma therapy. When administered acutely, corticosteroids commonly are continued for 2-3 days. In asthma treatment, large parenteral doses customarily are administered acutely, followed by lower PO dosing for varying periods. Long-acting parenteral preparations may be administered as an alternative and have been shown effective in asthma therapy. Optimal dosage range for corticosteroids has not been established; thus, a range of dosages is provided based on published recommendations.

Methylprednisolone (Solu-Medrol, Adlone, Medrol, Depo-Medrol)

A multitude of corticosteroid preparations are available. Methylprednisolone is widely available in the ED because of other uses (ie, acute asthma, spinal cord injury). Supplied in both parenteral and oral formulations. Discussed here as typical drug of this class.

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Dosing Interactions Contraindications Precautions

Adult

40-250 mg IV/IM q6h 2-60 mg PO qd

Pediatric

1-2 mg/kg IV/IM q6h 1 mg/kg PO qd

DosingInteractionsContraindicationsPrecautionsDosingInteractionsContraindicationsPrecautionsDosingInteractionsContraindicati onsPrecautionsAntidote,

Hypoglycemia

Glucagon appears to benefit by stimulating the release of endogenous catecholamines.

Glucagon

Has inotropic, chronotropic, and vasoactive effects that are independent of beta-receptors. Glucagon also causes endogenous catecholamine release. Patients taking beta-blocking agents may be resistant to effects of epinephrine or other adrenergic agents used to treat the cardiovascular effects of anaphylaxis. Glucagon may be effective in these patients. Should be used in addition to epinephrine, not as a substitute. Reports of effectiveness of glucagon in anaphylaxis are anecdotal; therefore, it is difficult to specify a dose. Smaller doses are effective in elevating blood sugar in patients with hypoglycemia, but larger doses have been recommended in beta-blocker overdose. Given parenterally. IV route is preferable.

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Dosing Interactions Contraindications Precautions

Adult

1-10 mg IV/IM/SC; typically 1-2 mg q5min to effect

Pediatric

Not established; adult dose is approximately equivalent to 0.02 mg/kg

Follow-up
Further Inpatient Care

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Most patients with anaphylaxis may be treated successfully in the ED and then discharged. Treatment success operationally may be defined as complete resolution of symptoms followed by a short period of observation. The purpose of observation is to monitor for recurrence of symptoms (ie, biphasic anaphylaxis). Hospital admission is required for patients who (1) fail to respond fully, (2) have a recurrent reaction or a secondary complication (eg, myocardial ischemia), (3) experience a significant injury from syncope, or (4) need intubation. As with many other conditions, consider a lower admission threshold when patients are at age extremes or when they have significant comorbid illness. The presenting manifestation(s) of anaphylaxis dictate inpatient care. Essentially, this care consists of continuing the care initiated in the ED. Consider ICU admission for patients with persistent hypotension. The primary means of support are adrenergic agents (eg, epinephrine, dopamine) and fluid resuscitation. Persistent hypotension in the face of pressors and fluid resuscitation is an indication for invasive hemodynamic monitoring with evaluation of cardiac function and peripheral vascular resistance. Use of these parameters provides the basis for objective decisions regarding the use of fluids and pressors. Inpatient management of airway compromise consists of continuation of parenteral and inhaled adrenergic agents and corticosteroids that were initiated in the ED. Cutaneous manifestations of anaphylaxis are treated with repeated doses of antihistamines.

Further Outpatient Care

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Discharged patients who have been successfully treated for anaphylaxis usually should continue antihistamines for 2-5 days to prevent recurrence. When corticosteroids have been used as part of the initial treatment, common practice continues that treatment for a short period.

Inpatient & Outpatient Medications

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Inpatient medications are identical to those listed for ED care (see Medication). Outpatient medications o Outpatient medications primarily consist of oral forms of the medications used in ED treatment. Adrenergic medications are not listed in this chapter, as it is assumed that patients who require these on an on-going basis will be admitted. o Consider patients who experience severe reactions to bites, stings, food, or other possibly unavoidable causes, as candidates for an epinephrine auto-injector prescription. These injectors may be packaged as kits that also contain an oral antihistamine. o The following regimens are used commonly by clinicians, though very little hard data concerning the natural history of anaphylaxis treated in the ED exists. In light of this, do not construe the following as an unqualified recommendation or as a standard of care. Evidence for efficacy of H2-blocker antihistamines is particularly sparse. The newer nonsedating antihistamines have not been studied in the context of treatment for anaphylaxis. o H1-blocker antihistamines  Diphenhydramine (Benadryl) - Adults: 25 mg PO q6h for 2-5 d; Children: 1 mg/kg PO q6h for 2-5 d  Hydroxyzine (Atarax) - Adults: 25 mg PO q8h for 2-5 d; Children: 1 mg/kg PO q8h for 2-5 d o Corticosteroids  Prednisone - Adults: 20-80 mg PO qd for 2-5 d; Children: 1-2 mg/kg PO qd for 2-5 d

 Many other glucocorticoid preparations may be used. H2-blocker antihistamines  Cimetidine - 300 mg PO qid for 2-5 d; Children: Not recommended  Epinephrine auto-injectors prefilled syringes: A number of forms are available. Instructions for self-administration are included.  Ana-Kit (Bayer): This product is a syringe with 0.3 mL 1:1000 epinephrine solution packaged with four 2-mg chewable chlorpheniramine tablets. The syringe has 0.1 mL gradations, allowing the injection of smaller doses for pediatric patients.  EpiPen and EpiPen Jr. Auto-Injector (Center): This product is an auto-injecting syringe containing 0.3 mL 1:1000 epinephrine solution (EpiPen) or 0.3 mL 1:2000 solution (EpiPen Jr).

Transfer
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Requirements for treating a patient with anaphylaxis are likely to exist in most hospitals within the United States and Canada; therefore, transfer of patients with anaphylaxis would be a very unusual occurrence in these locations.

Deterrence/Prevention
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Preventive therapy for anaphylaxis depends on identification of the inciting agent. When the agent has been identified, the key to prevention is avoidance. Certain prophylactic or preventative therapies may be employed when re-exposure cannot be avoided. When the inciting agent is not obviously known from the history, allergy testing may help identify it. When the allergen is a therapeutic agent for which subsequent usage is medically necessary, desensitization or pretreatment protocols may be employed. o Desensitization therapy for reactions to Hymenoptera venom is partially effective in preventing or ameliorating subsequent severe reactions. o At minimum, patients discharged from the ED after a severe reaction to Hymenoptera venom should be informed of the availability of this treatment. Referral to the patient's primary care source or directly to an allergist also may be appropriate.

Complications
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Complications from anaphylaxis are rare, and most patients completely recover. Myocardial ischemia may result from hypotension and hypoxia, particularly when underlying coronary artery disease exists. Ischemia or arrhythmias may result from treatment with pressors. Prolonged hypoxia also may cause brain injury. At times, a fall or other injury may occur when anaphylaxis leads to syncope.

Prognosis
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Anaphylaxis may occur following re-exposure to the inciting agent. Rates of recurrence vary with the nature of the inciting agent and host factors. Other than the possibility of recurrence or the occurrence of complications, anaphylaxis carries no long-term effects.

Patient Education

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As described above, caution patients who are discharged after an episode of anaphylaxis to avoid exposure to an inciting agent. When no inciting agent has been identified, consider referral to an allergist to identify the cause of anaphylaxis. Inform patients who react to Hymenoptera venom of the availability of desensitization therapy, and consider a self-administered epinephrine prescription. Sting avoidance is important for hypersensitive persons. Patients must be educated concerning steps they can take to reduce the risk of insect stings. o Caution patients to avoid use of perfumes or hygiene products that include perfumes, particularly floral scents, as these attract flying Hymenoptera. o Brightly colored clothing attracts bees and other pollinating insects. o Avoid locations of known hives or nests, and avoid using equipment that disturbs the hive. o Persons who are sensitive to Hymenoptera and who must be outdoors should carry a sting kit. On discharge, warn patients of the possibility of recurrent symptoms, and instruct them to seek further care if this occurs. For excellent patient education resources, visit eMedicine's Allergy Center and Allergic Reaction and Anaphylactic Shock Center. Also, see eMedicine's patient education article Severe Allergic Reaction (Anaphylactic Shock).

Miscellaneous
Medicolegal Pitfalls
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Claims of medical negligence related to the emergency treatment of anaphylaxis are not common. Potential pitfalls are as follows: o Failure to consider the diagnosis in patients with unexplained syncope or shock o Failure to warn the patient of avoidance or preventive measures o Prescription or administration of a drug to which the patient is known allergic o Failure to appreciate the potentially serious nature of symptoms, such as syncope or throat tightness, in a patient with an allergic reaction o Complications of epinephrine administration in patients without clear indication