The keys to quickly identifying anaphylaxis

July 1, 2005
John F. O'brien, MD
John F. O'brien, MD

Volume 5, Issue 7

Abstract: The classic presentation of anaphylaxis includes urticaria, angioedema, dyspnea, and systemic hypoperfusion. However, anaphylaxis may be more difficult to recognize if syncope, bronchospasm, or cardiovascular collapse is the predominant feature. Essential components of the history include previous allergic reactions, medication use, recently ingested foods, and exposure to latex. Although angioedema is often obvious, it also can be subtle and may require asking patients about changes they have observed. Other findings include tachypnea; wheezing; inspiratory stridor; conjunctival injection; rhinorrhea; and hoarseness, which may suggest laryngeal edema. Oxygen with ventilatory support, epinephrine, and crystalloid volume resuscitation are the mainstays of therapy for anaphylactic shock. Additional therapy often includes H1 antagonists, H2 antagonists, and corticosteroids. (J Respir Dis. 2005;26(7):308-316)

Anaphylaxis can produce a form of distributive shock that is typically quite unexpected and can deteriorate rapidly to a life-threatening condition. It is a clinical syndrome that involves activation of an allergic mechanism, often after previous sensitization to an antigen that the patient may not have known could cause problems.

Patients with anaphylaxis may present with variable degrees of urticaria; angioedema, which may involve the upper airway; dyspnea; and systemic hypoperfusion. However, atypical presentations are common, and the clinician must consider the possibility of anaphylaxis in virtually any abruptly ill patient.1 Prompt recognition followed by aggressive management can be lifesaving.

In this article, I will discuss how to recognize anaphylaxis rapidly and how to manage this condition to ensure the best patient outcome.


Anaphylaxis is the most severe allergic reaction and is responsible for at least 1500 deaths in the United States annually, although it may contribute to many unexplained sudden deaths.2 Autopsy data demonstrate that even in cases of known fatal anaphylaxis, diagnostic postmortem findings are often absent.3

The allergic mechanism

There is a complex genetic predisposition to allergy. The allergic mechanism involves the development of hypersensitivity to an antigen that may be a protein or a hapten, which is a small molecule that must bind to something in the body to be antigenically recognized. True allergy is IgE-mediated and requires previous antigen exposure for sensitization. This involves both T and B lymphocytes, which control antigen-specific IgE antibody production.

The allergic mechanism initiates chemical changes through activation of the main effector cells of allergy--mast cells and basophils (Figure). The culprit antigen cross-links to specific immunoglobulins previously bound to effector cell membranes. This binding stimulates the release of preformed mediators that are stored in secretory granules and initiates production of secondary mediators of the allergic mechanism.

Many preformed mediators have been recognized; among the most important are histamine, eosinophilic chemotactic factor of anaphylaxis, and neutrophil chemotactic factor of anaphylaxis. Spontaneously generated mediators of immediate hypersensitivity are also produced, principally through metabolism of arachidonic acid by the enzymes lipoxygenase and cyclooxygenase, which compete for the same substrate. Lipoxygenase produces many leukotrienes, which are proinflammatory, while cyclooxygenase produces several prostaglandins, which are generally less inflammatory.

Many patients have sensitivities to aspirin and other NSAIDs, which block the cyclooxygenase pathway and lead to increased production of various leukotrienes through lipoxygenase. Knowledge of these inflammatory pathways has led to the development of many medications, including antihistamines, leukotriene receptor antagonists, and lipoxygenase inhibitors, which are effective in blunting the allergic response.

Although the mechanism responsible for anaphylaxis is usually initiated by antigen binding to sensitized IgE antibodies on mast cells and basophils, it can be triggered by a number of other factors. When the process is activated by a trigger that does not involve antigen-specific antibodies, it is termed an "anaphylactoid reaction."

Types of reactions

The most common manifestations of allergic reactions are respiratory and dermatologic. The classic allergic reaction--immediate hypersensitivity--occurs within minutes of activation of the allergic mechanism. The typical findings include flushing, pruritus, vascular leakage with angioedema and hypotension, smooth muscle contraction with bronchospasm and increased mucus secretion, and intestinal cramping with vomiting and diarrhea.

Although most allergic reactions have a rapid onset within seconds to minutes after exposure to a trigger, a delay of several hours may occur in some persons, particularly with oral ingestions. In general, the sooner a reaction occurs after antigen exposure, the more likely it is to be severe. A biphasic allergic reaction occurs in a small number of patients; the second phase occurs 1 to 24 hours after initiation of the allergic mechanism.4

The severity of systemic allergic reactions varies, depending on the degree of hypersensitivity to the initiating factor; the quantity, rate, and route of antigen exposure; the pattern and quantity of mediators released; and target organ sensitivity. The mildest reaction is simple urticaria, which presents as well-circumscribed, pruritic wheals. In a large retrospective study, cutaneous features (urticaria and angioedema) were present in 94% of patients with anaphylaxis and a precipitant was recognized in almost three fourths of the patients.5

Angioedema involves well-demarcated, localized edema involving the deeper layers of the skin, including the entire dermis and subcutaneous tissue. The skin and upper airway are commonly involved; respiratory distress, and even death, can occur as a result of severe airway obstruction. Angioedema of the GI tract can lead to severe crampy abdominal pain with vomiting and diarrhea.

Anaphylaxis is characterized by a severe reaction of multiple organ systems. Hypotension, bronchoconstriction, and upper airway obstruction are common.

Allergic triggers

About 30% of persons are allergic to something--most often, inhaled proteins, certain foods, stinging insects, or certain medications.6 Many triggers exist. Although any medication may cause a reaction, the penicillins, certain neuromuscular blocking agents, and NSAIDs are the most common initiators. Approximately 10% of patients with documented penicillin allergy also have positive results on skin testing for cephalosporins, which should, in general, be avoided in patients with known significant penicillin hypersensitivity.7

Hymenoptera stings from bees, hornets, and fire ants are common triggers of anaphylaxis. Systemic reactions occur in 1% to 3% of Hymenoptera stings.8 Latex sensitivity also is important to recognize, especially in patients who were previously sensitized or in those who present with perioperative cardiovascular collapse.9

Food allergy occurs in approximately 1% to 2% of adults. Common triggers include peanuts, tree nuts, seafood, eggs, wheat, soy, and fruits.10 Sulfites and other food additives may cause reactions in some patients. In children, the incidence of food allergy may be as high as 6%; eggs, cow's milk, and peanuts cause more than 50% of reactions.10 Immunologic tolerance may occur in some children.11

Radiocontrast media reactions usually manifest as simple urticaria, but they may be severe and lead to anaphylactoid reactions and death in as many as 1 per 50,000 persons. Options for prevention include alternative imaging techniques (noncontrast CT for suspected renal stones); use of low- osmolality, nonionic agents; and pretreatment with prednisone and antihistamines.

In one study that excluded patients with Hymenoptera and immunotherapy reactions, anaphylaxis was triggered by food and food additives in 34% (crustaceans and peanuts in half of these), by medications in 20% (NSAIDs in half), and by exercise in 7%.12 The anaphylaxis was idiopathic in 37%.12

Exercise-induced urticaria with anaphylaxis is a less well recognized clinical entity. It may present with postexercise cardiovascular collapse. As many as 50% of patients with this type of reaction have a subclinical food allergy that is triggered by exercise. The diagnosis of exercise-induced anaphylaxis is generally based on the patient's history.


Recognizing anaphylaxis and distinguishing it from other causes of sudden cardiorespiratory distress may be difficult. Initial symptoms and signs, such as dizziness, hypotension, syncope, laryngeal edema, and respiratory distress, may occur in isolation. A history of a precipitating event or exposure is important, particularly if it involves medications (including over-the-counter and herbal medications), certain foods (peanuts, tree nuts, shellfish, fish, or eggs), and environmental exposures.

Mistakenly attributing symptoms to vasovagal syncope, panic attacks, pulmonary embolism, septic or other forms of shock, severe bronchospasm, or foreign-body aspiration can delay the correct diagnosis (Table 1). Ask the patient about previous episodes, triggers, duration of illness, and effects of treatment.

The physical examination findings in patients who have anaphylaxis are often obvious but may be subtle. Tachypnea is common and often associated with respiratory distress as a result of bronchospasm and upper airway edema. Hypotension may occur; usually, it is associated with tachycardia, but occasionally, it occurs with relative bradycardia.

Urticaria is usually present in patients who have anaphylaxis, although in persons with dark skin, it may be recognized only by palpation of the skin. Angioedema may be subtle and may require asking patients about changes they have observed. Look for conjunctival injection and rhinorrhea, and listen for hoarseness, which suggests laryngeal edema.

Severe wheezing with increased sputum production is common, and inspiratory stridor may be observed. Circulatory collapse with various dysrhythmias and cardiac arrest may occur in patients who have severe anaphylaxis. GI involvement may confuse the diagnosis, since crampy abdominal pain with vomiting and diarrhea is not usually attributed to allergy. CNS involvement is the result of hypoperfusion in severe allergic reactions and may include altered mental status and even coma.

Laboratory tests are rarely helpful in the evaluation of anaphylaxis. An elevated serum tryptase level confirms the diagnosis of an anaphylactic reaction, but testing is rarely necessary and results are not rapidly available.13

What diagnoses are most easily confused with anaphylaxis? The simple faint is a common mimic, and perhaps we too often interpret a sudden collapse as a vasovagal reaction. If bronchospasm is the predominant symptom, it may be confused with asthma or other bronchospastic diseases.

Cardiovascular collapse may be confused with acute coronary syndrome and various primary dysrhythmias. A careful history taking and physical examination, as well as the patient's failure to quickly respond to treatment for these suspected conditions, should bring anaphylaxis to the forefront of the differential diagnosis.

The differential diagnosis of anaphylaxis also includes hereditary angioedema, an autosomally dominant inheritance of C1 esterase inhibitor deficiency, which may present with angioedema of the extremities, upper airway, and GI tract. A family history of this defi- ciency and the absence of urticaria may suggest this diagnosis. Hereditary angioedema must be distinguished from allergic reactions, because it does not respond to standard therapy and requires the administration of fresh frozen plasma to replace the deficient factor.

The differential diagnosis also includes angioedema induced by an angiotensin-converting enzyme (ACE) inhibitor. The patient may present with upper airway and skin edema, which may occur months to even years after regular use of an ACE inhibitor. The angioedema is the result of sudden buildup of bradykinin and other mediators not metabolized after ACE inhibition. It does not resolve with standard allergy treatment.


Initial management

Prevention is paramount. If known antigen exposure occurs, absorption should be delayed or eliminated. For example, patients who orally ingest a known allergen should be treated with oral charcoal if they present soon after ingestion. Injected antigen absorption may be delayed with a loose tourniquet, locally injected epinephrine, and judicious use of ice to delay antigen delivery centrally. Do not forget to ask about allergies before prescribing any medication.

The most useful therapies for anaphylaxis include oxygen, epinephrine, and intravenous fluids. The main cause of death from immediate hypersensitivity reactions is respiratory failure. Oxygen supplementation should be standard in the management of anaphylaxis, with recognition that pulse oximetry is often unreliable if hypoperfusion exists.

Early endotracheal intubation with 100% oxygen supplementation is appropriate if significant airway angioedema or cardiovascular collapse is present, particularly if there is no rapid response to early therapeutic interventions. Nasotracheal intubation should generally be avoided in anaphylaxis because patients often have severe nasal mucosal swelling.

Epinephrine is the rescue medication of choice in severe anaphylaxis (Table 2). A potent a- and ß-receptor agonist, epinephrine is relatively contraindicated in older patients, especially those with known coronary artery disease or severe hypertension. However, there is no contraindication to judicious use of epinephrine in a true anaphylactic emergency.

Remember that the pharmacologic stress of carefully titrated epinephrine is less than the physiologic stress of a severe allergic reaction. The route of administration and dosing depend on the severity of anaphylaxis. For mild to moderate reactions, epinephrine can be given subcutaneously or intramuscularly at 0.01 mL/kg of 1:1000 (1 mg/mL) every 10 to 20 minutes. If the reaction is severe, particularly with hypoperfusion, epinephrine should be administered intravenously; the regimen is 1 mL of 1:10,000 (1 mg/10 mL) every 5 to 10 minutes. The maintenance intravenous drip is 10 mL of 1:10,000 in 500 mL of normal saline (2 µg/mL), started at 1 mL/min and titrated to the patient's symptoms and signs.

Alternatively, an epinephrine drip (1 mg of epinephrine in 250 mL of normal saline = 4 µg/mL) can be used to carefully titrate control of anaphylaxis.14 Cardiac monitoring is always indicated in this setting. Inhalational epinephrine is also useful in patients with severe laryngeal edema.

Volume expanders are important in the management of anaphylaxis. Crystalloid solution is preferred over colloid solution.15 Several liters of isotonic saline or lactated Ringer solution may be required to replenish intravascular volume in patients with severe allergic reactions. Hypo-osmolar and dextrose-containing solutions should be avoided. Invasive hemodynamic and urine production monitoring may be important in patients who have severe reactions, particularly those with concomitant medical problems that may make them susceptible to volume overload.

Although an H1-antagonist antihistamine may be all that is required in mild allergic reactions, it is inadequate as sole therapy for severe anaphylaxis.16,17 A reasonable starting dosage for diphenhydramine (orally, intramuscularly, or intravenously) or hydroxyzine (orally or intramuscularly) is 1 mg/kg. Nonsedating antihistamines, such as cetirizine and loratadine, may be substituted but are not well studied in this setting.

A study comparing the H2 antagonist cimetidine (300 mg) with diphenhydramine showed it to be equally effective for managing simple urticaria.18 The combination of H1 antagonists and H2 antagonists is frequently used in the management of allergic reactions.

Corticosteroids are indicated in most significant allergic reactions and in all cases of anaphylaxis. Although the therapeutic effect may be delayed, studies show that corticosteroids shorten the duration of urticaria in patients with allergic reactions and shorten the duration of severe anaphylaxis.19

Aggressive dosing of methylprednisolone (1 mg/kg up to 125 mg intravenously) is warranted in severe anaphylaxis. Prednisone, 1 mg/kg/d, or its equivalent is probably indicated for 3 to 4 days after a significant allergic reaction. Corticosteroids may be continued longer if ongoing antigen exposure exists.

Other interventions deserve mention in severe anaphylaxis. Heliox may improve the ability to ventilate in severe respiratory distress, and inhalational therapy with ß- agonists and anticholinergics is effective in severe bronchospasm. Glucagon (1 mg) should be considered early in patients who are using ß-antagonists if they fail to respond rapidly to epinephrine, because it attenuates mediator release by alternative pathways.20 Glucagon has seemed to be effective in some case reports of patients who were unresponsive to other treatments for severe anaphylaxis.20

Referral for immunotherapy is appropriate and should be the standard of care for anaphylaxis caused by recognized antigens, particularly Hymenoptera stings.7 Immunotherapy has been demonstrated to reduce the recurrence rate of Hymenoptera-induced anaphylaxis from 35% to 60% to about 5%.21


All patients with anaphylactic reactions not promptly resolved by therapy should be hospitalized, particularly if they have significant airway angioedema or bronchospasm, have hypoperfusion or cardiac problems, are using ß-blockers, or have inadequate support systems. When in doubt, it is wise to hospitalize patients who have anaphylaxis.

If patients with significant immediate hypersensitivity reactions respond rapidly, they should be observed for 4 to 6 hours before they are discharged, and they should be discharged with H1 antagonists and/or H2 antagonists and corticosteroids, to be taken for at least 3 to 4 days. Prescription of self-administered epinephrine, with clear instructions for use, is appropriate for patients who have had severe reactions.

Medic alert bracelets may be recommended. Patient education about antigen avoidance should be completed, along with appropriate referral to a private physician or an allergist.



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