Author and Editor Disclosure

Synonyms and related keywords: systemic allergic reaction, anaphylactic reaction, anaphylactoid reaction, allergic reaction, allergies, peanut allergy, latex allergy, shellfish allergy, hypersensitivity reaction, food allergy, insect sting, Hymenoptera venom, wasp sting, bee sting, yellow jacket sting, hornet sting, penicillin allergy, radiocontrast medium allergy, contrast allergy, RCM allergy, cardiovascular collapse, laryngeal edema, atopy, atopic disease, fire ant bite, fire ant sting, immunotherapy

Background

Portier and Richet first coined the term anaphylaxis in 1902 when a second vaccinating dose of sea anemone toxin caused a dog's death. The response was the opposite of prophylaxis and thus was referred to as anaphylaxis, meaning without protection.

Anaphylaxis is an acute systemic reaction caused by the release of mediators from mast cells and basophils. More than one organ system should be involved for the reaction to be considered anaphylaxis. The most common organ systems involved include the cutaneous, respiratory, cardiovascular, and gastrointestinal systems.

The phrase anaphylactic reaction usually refers to a type I hypersensitivity reaction with mast cell and basophil degranulation mediated by antigen binding of specific immunoglobulin E (IgE). The term anaphylactoid reaction refers instead to a non–IgE-mediated mechanism of mast cell/basophil activation. The term anaphylaxis refers to the physiologic events due to either mechanism.

Pathophysiology

When mast cells and basophils degranulate, whether by IgE- or non–IgE-mediated mechanisms, preformed histamine and newly generated leukotrienes and prostaglandins are released. The physiologic responses to these mediators include smooth muscle spasm in the respiratory and gastrointestinal tract, vasodilation, increased vascular permeability, and stimulation of sensory nerve endings. These physiologic events lead to the classic symptoms of anaphylaxis: flushing; urticaria; pruritus; bronchospasm; and abdominal cramping with nausea, vomiting, and diarrhea. Hypotension and shock can result from intravascular volume loss, vasodilation, and myocardial dysfunction. Increased vascular permeability can result in a shift of 50% of vascular volume to the extravascular space within 10 minutes.

Additional mediators activate other pathways of inflammation: the neutral proteases, tryptase and chymase; proteoglycans such as heparin and chondroitin sulfate; and chemokines and cytokines. These mediators can activate the kinin system, the complement cascade, and coagulation pathways. Working together, these inflammatory pathways recruit other inflammatory cells, including eosinophils and lymphocytes, resulting in prolonged, biphasic, and/or intensified reactions.

Despite the potential contribution of multiple mediators, histamine infusion alone is sufficient to produce most of the symptoms of anaphylaxis. Histamine mediates its effects through activation of histamine 1 (H1) and histamine 2 (H2) receptors. Vasodilation is mediated by both H1 receptors and H2 receptors. H2 receptors exert a direct effect on vascular smooth muscle, whereas H1 receptors stimulate endothelial cells to produce nitric oxide. Cardiac effects of histamine are largely mediated through H2 receptors. H1 receptors are primarily responsible for extravascular smooth muscle contraction (eg, bronchial tree, gastrointestinal tract). Both H1 receptors and H2 receptors mediate glandular hypersecretion.

Frequency

United States

The true incidence is unknown. Moneret-Vautrin et al recently reviewed the published literature and stated that severe anaphylaxis affects at least 1-3 persons per 10,000 population. Neugut et al estimated that 1-15% of the US population are at risk of experiencing an anaphylactic or anaphylactoid reaction. They estimated that the rate of actual anaphylaxis to food was 0.0004%, 0.7-10% for penicillin, 0.22-1% for radiocontrast media (RCM), and 0.5-5% after insect stings.

A population-based study from Olmsted County, Minnesota, detected an average annual incidence of anaphylaxis of 21 cases per 100,000 person-years. Ingestion of a suspect food was the cause in 36% of cases; a medication, allergy immunotherapy, or a diagnostic agent was the cause in 17% of cases; and an insect sting was the cause in 15% of cases. Thirty-two percent of cases were considered idiopathic. Episodes of anaphylaxis occurred more frequently in the summer months of July through September, which is attributable to insect stings.

In a study of patients referred to an allergy practice in Memphis, Tennessee, food was the cause of anaphylaxis in 34% of patients, medications in 20%, and exercise in 7% (insect sting anaphylaxis was excluded from the study). The cause of anaphylaxis was undetermined in 37% of patients. A separate study estimated the number of cases of idiopathic anaphylaxis in the United States to be 20,000-47,000 cases per year (approximately 8-19 episodes per 100,000 person-years).

International

Geographic location is not thought to exert a major effect on incidence. Two European studies detected a lower average annual incidence than found in the Olmsted County study (3.2 cases of anaphylactic shock per 100,000 person-years in Denmark; 9.8 cases of out-of-hospital anaphylaxis per 100,000 person-years in Munich, Germany). Rates in Europe range from 1-3 cases per 10,000. Simons and colleagues examined the rate of epinephrine prescriptions for a population of 1.15 million patients in Manitoba, Canada, and found that 0.95% of this population was prescribed epinephrine, an indicator of perceived risk that future anaphylaxis may occur.

Mortality/Morbidity

• Fatalities from anaphylaxis are infrequent but not rare. Estimates range from 0.65-2% of patients with anaphylaxis. The case-fatality rate from the Olmsted County study was 0.65%. Severe reactions to penicillin occur with a frequency of 1-5 cases per 10,000 patient courses, with fatalities in 1 case per 50,000-100,000 courses. Insect stings cause 25-50 deaths per year. Reactions to foods are thought to be the most common cause of anaphylaxis when it occurs outside of the hospital and are estimated to cause 125 deaths per year in the United States. Anaphylactoid reactions to RCM were estimated to have caused 500 deaths in 1982, although this number has likely decreased because of increased awareness and the use of pretreatment regimens and/or lower osmolar agents for patients with a history of RCM reaction.
• In the United Kingdom, one half of fatal anaphylaxis episodes have an iatrogenic cause (ie, anesthesia, antibiotics, or radiocontrast), while foods and insect stings each account for a quarter of the fatal episodes.
• The most common causes of death are cardiovascular collapse and laryngeal edema.

Race

• Race has no known effect on the risk of anaphylaxis.

Sex

• In the Olmsted County study, men and women were equally affected.
• The Memphis study showed a slight female predominance.
• Earlier studies have suggested that episodes of anaphylaxis to intravenous muscle relaxants, aspirin, and latex are more common in women, while insect sting anaphylaxis is more common in men. These sex discrepancies are likely a function of exposure frequency.

Age

• Anaphylaxis can occur at any age. In the Olmsted County study, the age range was 6 months to 89 years. The mean age was 29 ±19 years. The Memphis study had an age range of 12-75 years, with a mean of 38 years.
• Simons and colleagues noted the highest frequency of prescriptions for epinephrine in boys aged 12-17 months (5.3%). The rate was 1.4% for those younger than 17 years, 0.9% for those aged 17-64 years, and 0.3% for those aged 65 years or older.
• Severe food allergy is more common in children than in adults. However, since severe food allergy often persists into adulthood, the frequency in adults may be rising.

• Anaphylaxis to RCM, insect stings, and anesthetics has been reported to be more common in adults than in children. Whether this is a function of exposure frequency or increased sensitivity is unclear.

Other risk factors:

• Atopy is risk factor. In the Olmsted County study, 53% of the patients with anaphylaxis had a history of atopic diseases (eg, allergic rhinitis, asthma, atopic dermatitis). The Memphis study detected atopy in 37% of the patients. Other studies have shown atopy to be a risk factor for anaphylaxis from foods, exercise-induced anaphylaxis, idiopathic anaphylaxis, radiocontrast reactions, and latex reactions. Underlying atopy does not appear to be a risk factor for reactions to penicillin or insect stings.

• Route and timing of administration affect anaphylactic potential. The oral route of administration is less likely to cause a reaction, and the reaction is usually less severe, although fatal reactions occur following ingestions of foods by someone who is allergic. The longer the interval between exposures, the less likely an anaphylactic (IgE-mediated) reaction will recur. This is thought to be due to catabolism and decreased synthesis of specific IgE over time. This does not appear to be the case for anaphylactoid reactions.

• Asthma is a risk factor for fatal outcomes.

• Delay in administration of epinephrine is also a risk factor for fatal outcomes.

History

In most studies, the frequency of symptoms and signs of anaphylaxis are grouped together by organ system. For example, in the Olmsted County study, 100% of patients with anaphylaxis had cutaneous manifestations. This resulted from the study's definition of anaphylaxis, which required one symptom of generalized mediator release, which was defined mostly by skin manifestations. Nevertheless, other studies have reported that 90% of patients have skin involvement. In the Olmsted County study, 69% had respiratory manifestations, 41% had cardiovascular involvement, and 24% had oral or gastrointestinal manifestations. Other studies have reported similar findings.

• Patients often initially describe a sense of impending doom, accompanied by pruritus and flushing. This can evolve rapidly into the following symptoms, broken down by organ system:
• • Cutaneous/ocular - Flushing, urticaria, angioedema, cutaneous and/or conjunctival pruritus, warmth, and swelling

  • Respiratory - Nasal congestion, rhinorrhea, throat tightness, wheezing, shortness of breath, cough, hoarseness

  • Cardiovascular - Dizziness, weakness, syncope, chest pain, palpitations

  • Gastrointestinal - Nausea, vomiting, diarrhea, bloating, cramps

  • Neurologic - Headache (rare except in exercise-induced anaphylaxis) and seizure (very rare)

• Symptoms usually begin within 5-30 minutes from the time the antigen is injected but can occur within seconds. If the antigen is ingested, symptoms usually occur within 2 hours, although symptoms often occur much faster, as with severe food allergy. In rare cases, symptoms can be delayed in onset for several hours.

Physical

The first priority should be to assess the patient's respiratory and cardiac status.

• Respiratory
• • Severe angioedema of the tongue and lips may obstruct airflow.

  • Laryngeal edema may manifest as stridor or severe air hunger.

  • Loss of voice, hoarseness, and/or dysphagia may occur.

  • Bronchospasm, airway edema, and mucus hypersecretion may manifest as wheezing. In the surgical setting, increased pressure of ventilation can be the only manifestation of bronchospasm.

  • Hypoxia can cause altered mental status.

• Cardiovascular
• • Tachycardia is present in one fourth of patients, usually as a compensatory measure for intravascular volume loss.

  • Bradycardia is more suggestive of a vasovagal reaction, although it has been observed in true anaphylaxis.

  • Hypotension (and resultant loss of consciousness) may be observed secondary to capillary leak, vasodilation, and hypoxic myocardial depression.

  • Cardiovascular collapse with shock can occur immediately, without any other findings. This is an important consideration in the surgical setting.

• Cutaneous
• • The first sign of anaphylaxis is flushing, noted especially in the cheeks. Urticaria (hives) can occur anywhere on the body, often localizing to the palms, soles, and inner thighs. The lesions are erythematous, raised, highly pruritic, and of variable size.

  • Angioedema is also commonly observed. These lesions involve the deeper dermal layers of skin and are usually nonpruritic and nonpitting. Common areas of involvement are the larynx, lips, eyelids, hands, feet, and genitals.

  • Isolated, whole-body erythematous flushing is also occasionally observed.

• Gastrointestinal: Vomiting, diarrhea, and abdominal distention are frequently observed.

Causes

• IgE-mediated anaphylaxis: This is the classic form of anaphylaxis, whereby a sensitizing antigen elicits an IgE antibody response in a susceptible individual. The antigen-specific IgE antibodies then bind to mast cells and basophils. Subsequent exposure to the sensitizing antigen causes cross-linking of cell-bound IgE, resulting in mast cell (and/or basophil) degranulation. Typical examples of IgE-mediated anaphylaxis include the reactions to many drugs, insect stings, and foods.
• • Certain drugs cause IgE-mediated anaphylaxis. Most cases of IgE-mediated drug anaphylaxis in the United States are due to penicillin antibiotics.
    • Penicillin is metabolized to a major determinant, benzylpenicilloyl, and multiple minor determinants. Penicillin and its metabolites are haptens, small molecules that only elicit an immune response when conjugated with proteins.

    • Other beta-lactam antibiotics may cross-react with penicillins or may have unique structures that also act as haptens. The incidence rate of anaphylaxis to cephalosporins in penicillin-anaphylactic patients appears to be much less than the 10% frequently quoted. Pichichero recently reviewed this complicated literature and offers specific guidance for the use of cephalosporins in patients who have a history of IgE-mediated reactions to penicillin.

    • Patients with less well-defined reactions to penicillin have a very low risk (1-2%) of developing anaphylaxis to cephalosporins. The rate of skin-test reactivity to imipenem in patients with a known penicillin allergy is almost 50%. In contrast, no known in vitro or clinical cross-reactivity exists between penicillins and aztreonam.

    • Many other drugs have been implicated less frequently in IgE-mediated anaphylaxis.

  • In the surgical setting, anaphylactic reactions are most often due to muscle relaxants and latex but can also be due to hypnotics, antibiotics, opioids, colloids, and other agents. Volatile anesthetic agents can cause immune-mediated hepatic toxicity but have not been implicated in anaphylactic reactions.

  • Insect stings, that is, venoms from Hymenoptera insects (ie, bees, yellow jackets, hornets, wasps, fire ants), can elicit an IgE antibody response. From 0.5-3% of the population experience a systemic reaction after being stung.

  • Hypersensitivity to foods is now recognized as a worldwide problem in the industrialized world. In the United States, an estimated 4 million Americans have well-substantiated food allergies. In Montreal, 1.5% of early elementary school students were found to be sensitized to peanuts. Reactions to foods are thought to be the most common cause of anaphylaxis when it occurs outside of the hospital and are estimated to cause 125 deaths per year in the United States.
    • Certain foods are more likely than others to elicit an IgE antibody response and lead to anaphylaxis. Foods likely to elicit an IgE antibody response in all age groups include peanuts, tree nuts, fish, and shellfish. Foods likely to elicit an IgE antibody response in children include egg, soy, and milk.

    • An analysis of 32 fatalities thought to be due to food-induced anaphylaxis revealed that peanut was the likely responsible food in 62% of the cases. In placebo-controlled food challenges, peanut-sensitive patients can react to as little as 100 µg of peanut protein. The Olmsted County study, in agreement with earlier studies, found that food ingestion was the leading cause of anaphylaxis, accounting for as many as one third of all cases. Scombroid fish poisoning can occasionally mimic food-induced anaphylaxis. Bacteria in spoiled fish can decarboxylate histidine, producing a chemical with histaminelike activity.

  • Latex hypersensitivity is a phenomenon that has been recognized in the last 20 years, corresponding with the increased use of latex gloves because of the AIDS epidemic and the institution of universal precautions. In 1995, an estimated 8-17% of healthcare professionals were at risk for latex reactions. The incidence rate is already decreasing, at least in part, because of increased awareness, improved manufacturing practices, and a change to unpowdered latex and nonlatex gloves.

  • Allergen-specific immunotherapy can cause IgE-mediated anaphylaxis. Allergy injections are a common trigger for anaphylaxis. This is not unexpected because the treatment is based on injecting an allergen to which the patient is sensitive. However, life-threatening reactions are rare. A total of 46 deaths due to allergen immunotherapy and skin testing were reported from 1945-1987. Risk factors for severe anaphylaxis due to immunotherapy include poorly controlled asthma, concurrent use of beta-blockers, high allergen dose, errors in administration, and lack of a sufficient observation period following the injection.

• Anaphylactoid reactions
• • Complement-mediated reactions are described. Anaphylaxis resulting from administration of blood products, including intravenous immunoglobulin, or animal antiserum is due, at least in part, to activation of complement. Immune complexes formed either in vivo or in vitro can activate the complement cascade. Certain byproducts of the cascade, namely plasma-activated complement 3 (C3a), plasma-activated complement 4 (C4a), and plasma-activated complement 5 (C5a), are called anaphylatoxins and are capable of causing mast cell/basophil degranulation.

  • Certain agents (ie, direct mast cell activators) are thought to cause direct, nonimmunologic release of mediators from mast cells. These include opiates, RCM, dextrans, protamine, and vancomycin. Mechanisms underlying these reactions are poorly understood but may involve specific receptors (eg, opioids) or non–receptor-mediated mast cell activation (eg, hyperosmolarity). Evidence also exists that RCM, dextrans, and protamine can activate several inflammatory pathways, including complement, coagulation, and vasoactive (kallikrein-kinin) systems.

• Aspirin and nonsteroidal anti-inflammatory drugs
• • Aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) have been placed in the anaphylactoid category in the past because reactions were thought to occur through the aberrant metabolism of arachidonic acid. Isolated cutaneous reactions to aspirin/NSAIDs and aspirin-sensitive asthma (often in association with nasal polyposis) are indeed mediated through non-IgE mechanisms. Blockade of cyclooxygenase by these drugs causes the 5-lipoxygenase pathway to shut down, resulting in an overproduction of leukotrienes. These patients have marked cross-reactivity between aspirin and most NSAIDs.

  • True anaphylaxis after taking these drugs appears to have a different mechanism that is more consistent with IgE-mediated anaphylaxis. With true anaphylaxis, the different cyclooxygenase inhibitors do not appear to cross-react. Anaphylaxis only occurs after 2 or more exposures to the implicated drug, suggesting a need for prior sensitization. Finally, patients with true anaphylaxis do not usually have underlying asthma, nasal polyposis, or urticaria. In one study of nearly 52,000 people taking NSAIDs, 35 developed anaphylactic shock.

• Exercise-induced anaphylaxis
• • This is a rare syndrome that can take one of two forms. The first form is food-dependent, requiring both exercise and the recent ingestion of particular foods to cause an episode of anaphylaxis. In these patients, exercise alone does not result in an episode, and eating the culprit food alone does not result in an episode.

  • The second form is characterized by intermittent episodes of anaphylaxis during exercise, independent of any food ingestion. Anaphylaxis will not necessarily occur during every episode of physical exertion.

• Anaphylaxis associated with systemic mastocytosis
• • Anaphylaxis can be a manifestation of systemic mastocytosis, a disease characterized by excessive mast cell numbers.

  • Such patients appear to be at increased risk for food and venom reactions.

• Idiopathic anaphylaxis
• • A syndrome of recurrent anaphylaxis without any consistent triggers (despite an exhaustive search for such) exists. This recurrent syndrome should be distinguished from a single episode of anaphylaxis in which the etiology may be unclear.

  • Most patients treated with antihistamines and steroids have complete remission following tapering of steroids.

  • Most of these patients are female, and atopy appears to be an underlying risk factor.

  • Two thirds of patients have 5 or fewer episodes per year, while one third have more than 5 episodes per year.

Angioedema
Malignant Carcinoid Syndrome
Mastocytosis, Systemic
Pheochromocytoma
Thyroid, Medullary Carcinoma

Other Problems to be Considered

Red man syndrome (vancomycin)
Vasovagal reaction
Monosodium glutamate poisoning
Scombroid fish poisoning
Panic attack
Somatoform anaphylaxis

Lab Studies

• Anaphylaxis is a clinical diagnosis based on a history of acute exposure to a causative agent followed by the typical systemic manifestations. Laboratory studies are not usually required and are rarely helpful.
• If the diagnosis is unclear, especially with a recurrent syndrome, or if other diseases need to be excluded, some limited laboratory studies are indicated.
• • For example, if carcinoid syndrome is considered, urinary 5-hydroxyindoleacetic acid levels should be measured.

  • If a patient is seen shortly after an episode, plasma histamine, urinary histamine metabolites, or serum tryptase measurements may be helpful in confirming the diagnosis.
    • Plasma histamine levels rise within 10 minutes but fall again within 60 minutes.

    • Urinary histamine metabolites remain elevated for longer periods, but generally, this test is not available.

    • Serum mature tryptase (previously called beta-tryptase) levels peak 1 hour after the start of an episode and may persist for as long as 5 hours.

    • Detecting the rise of histamine or tryptase can be difficult, and some patients might have a rise in one but not the other. Therefore, a negative histamine and tryptase test result does not exclude the diagnosis of anaphylaxis.

    • Basal levels of total and mature tryptase between episodes of anaphylaxis can be helpful to rule out systemic mastocytosis.

Imaging Studies

• No role exists for imaging studies in the diagnosis or management of anaphylaxis.

Other Tests

• Once an acute episode of anaphylaxis has occurred, additional testing may be helpful to identify an etiologic agent.
• • Patient diary: A thorough history remains the best test to determine a causative agent. For recurrent idiopathic episodes, a patient diary may be helpful to implicate specific foods or drugs.

  • Food reactions: If the patient's history suggests a possible association with eating, percutaneous food-skin tests and/or in vitro IgE tests (eg, radioallergosorbent assay test [RAST] or Immuno Cap tests) can be performed, with an understanding that false-positive results may occur. Intradermal skin testing and IgG RAST tests have no role in food-skin testing. A double-blind, placebo-controlled food challenge may need to be performed to confirm clinical reactivity. However, when a particular food is clearly temporally related to the reaction, a food-skin test should not be performed with standard concentrations of food extracts because deaths have occurred secondary to food-skin testing, particularly with peanuts).

  • Insect stings: If the patient's history suggests an insect sting, skin testing and in vitro IgE tests to Hymenoptera venoms should be performed. The in vitro IgE tests should be included because cases have occurred in patients with negative skin test results and with severe clinical reactivity and positive in vitro IgE results. Patients' abilities to identify the type of flying insect are unreliable, mandating testing of all flying Hymenoptera. For example, many patients confuse yellow jackets and bees. Skin testing and in vitro IgE testing should be performed 4-6 weeks following the episode of anaphylaxis to improve sensitivity.

  • Suspected medication etiology
    • If the patient's history suggests a penicillin etiology and the reagents are available, skin testing for penicillin should be performed with the appropriate positive and negative controls. Penicillin G and major determinant (Pre-Pen) are usually commercially available for skin testing, although at the time this was last updated, Pre-Pen was unavailable in the United States. Minor determinant mix (MDM) is available primarily at research centers. The minor determinants comprise only 5% of penicillin metabolites but are implicated in anaphylaxis risk. Therefore, if MDM is not available for skin testing for patients with a good history, a desensitization protocol may be the safest path regardless of skin test results.

    • If MDM is not available for skin testing for patients with a history that is not suggestive of an immediate hypersensitivity reaction who have negative results to penicillin G and Pre-Pen, penicillin should only be administered as an incremental challenge under close medical observation. If possible, give oral penicillin before administering it intravenously or intramuscularly.

    • Skin testing for reactivity to other beta-lactam antibiotics, or any other medicine for that matter, should be considered experimental because the haptenic determinants are unknown. Skin testing with the parent drug may be beneficial if the results are positive, but a negative result does not exclude the potential for severe clinical reactivity.

  • Testing for anaphylactoid etiologies: Because these reactions are not mediated through IgE, skin testing has no role in diagnosis. No other diagnostic tests help assess the risk of recurrent anaphylactoid reactions.

Medical Care

Anaphylaxis is a medical emergency that requires immediate recognition and intervention. Basic equipment and medication should be readily available in the physician's office. Lieberman et al have recently described this in great detail.

• For the initial assessment, check the airway closely and secure as needed. Assess the level of consciousness and obtain blood pressure, pulse, and oximetry values.

• Place the patient in the supine position, and begin supplemental oxygen.

• Remove the source of the antigen if possible (eg, stinger after bee sting).

• A tourniquet applied to the extremity with the antigen source can retard antigen exposure to the systemic circulation. Release the tourniquet every 5 minutes, and do not leave it in place for longer than 30 minutes.

• Administer intramuscular epinephrine into a different extremity immediately (the thigh muscle is preferable; see Medication). Epinephrine maintains the blood pressure, antagonizes the effects of the released mediators, and inhibits further release of mediators from mast cells and basophils. Physicians are sometimes reluctant to administer epinephrine for fear of adverse effects. However, epinephrine is usually well tolerated and is lifesaving. Anaphylactic deaths correlate with a delay in the administration of epinephrine. The initial dose can be repeated as necessary, depending on the response.

• Intramuscular administration of epinephrine results in higher and more rapid maximum plasma concentrations of epinephrine compared with the subcutaneous route in both rabbit animal models and a small number of children.

• Antihistamine therapy is considered adjunctive to epinephrine. Administer both an H1 blocker and an H2 blocker because studies have shown the combination to be superior to an H1 blocker alone in relieving the histamine-mediated symptoms. Diphenhydramine and ranitidine are an appropriate combination.

• Establish intravenous access for (1) the administration of adjunctive medications and (2) the administration of intravenous fluids to maintain blood pressure, if needed.

• Racemic epinephrine via a nebulizer can be used to reduce laryngeal swelling but does not replace intramuscular administration of epinephrine.

• Treat bronchospasm that has not responded to subcutaneous epinephrine with inhaled beta2-adrenergic agonists such as albuterol.

• Corticosteroids do not have an immediate effect on anaphylaxis; however, administer them early to prevent a potential late-phase reaction (biphasic anaphylaxis).

• Maintaining proper blood pressure is important in the treatment of anaphylactic reactions.
• • Hypotension is often the most difficult manifestation of anaphylaxis to treat.

  • Persons with protracted hypotension must be monitored in an intensive care unit setting.

  • Because hypotension in anaphylaxis is due to a dramatic shift of intravascular volume, the fundamental treatment intervention (after epinephrine) is aggressive intravenous fluid administration. Large volumes of crystalloid may be required, potentially exceeding 5 L. The exact amount should be individualized, based on blood pressure recovery and urine output. In severe cases, invasive monitoring of central venous pressure and cardiac output may be required.

  • Pressors may also be needed to support blood pressure. Intravenous epinephrine (1:10,000 preparation) can be administered as a continuous infusion, especially when the response to intramuscular or subcutaneous epinephrine (1:1000) is poor. Dopamine infusion can also be used.

  • Military antishock trousers have also been used successfully to maintain blood pressure in persons with anaphylaxis.

  • Patients with anaphylaxis who are taking a beta-adrenergic blocking agent (eg, for hypertension, migraine prophylaxis) can have refractory anaphylaxis that is poorly responsive to standard measures. Glucagon is the drug of choice in this situation. It has both inotropic effects and chronotropic effects on the heart by increasing intracellular levels of cyclic adenosine 3,'5'-monophosphate, independent of the beta-adrenergic receptors.

• Respiratory compromise in the acute setting (ie, respiratory failure) mandates endotracheal intubation. If the endotracheal tube cannot be passed because of severe laryngeal edema, tracheotomy is required.

• For vascular collapse, depending on severity, refractory hypotension may require placement of an invasive cardiovascular monitor (Swan-Ganz catheter) and arterial line.

• Treatment of cardiopulmonary arrest is discussed elsewhere.
• Anti-IgE (omalizumab) complexes circulating (but not receptor-bound) IgE and keeps it from binding to its receptors. It does not remove IgE bound to receptors and takes several months to have a substantial effect. It is not to be used in an acute setting.

Surgical Care

This is limited to the possible need for surgical airway intervention.

Consultations

• Most patients with an episode of anaphylaxis should be referred to an allergist/immunologist for further evaluation and treatment. Despite the logic of this recommendation, the Olmsted County study demonstrated that only 52% of patients were referred for such a consultation.

• In the case of severe anaphylaxis requiring admission to the intensive care unit, an intensivist should be consulted.
• Prophylaxis for intravenous RCM involves prednisone (or hydrocortisone), diphenhydramine, ranitidine (or another type 2 antihistamine), with or without ephedrine, and/or the use of a different contrast agent.
• • Administer prednisone (50 mg PO) or hydrocortisone (200 mg IV) at 12, 6, and 1 hour before the radiocontrast procedure.

  • Administer diphenhydramine (50 mg PO/IV) and ranitidine (150 mg PO or 50 mg IV) with or without ephedrine (25 mg PO) 1 hour before the procedure. Ephedrine should not be used in patients with hypertension, CAD, older patients with a strong family history of CAD, arrhythmia, thyrotoxicosis, monoamine oxidase inhibitor use, or porphyria.

  • Consider using a contrast agent with lower osmolarity.

• Desensitization procedures can be used for a medication allergy.
• • Published protocols exist for desensitization to various medications. Consult an allergist/immunologist skilled in desensitization procedures to perform these protocols. The patient should usually be in an intensive care unit setting with intravenous access and epinephrine and parenteral diphenhydramine at the bedside. Obtain informed consent prior to the procedure. Anaphylactic reactions that may result in death is a potential complication of this procedure.

  • A typical desensitization protocol for beta-lactam antibiotics involves starting at a dose that is 6-7 logs below the usual therapeutic dose and increasing the dose by 1 log every 20-30 minutes.

• Pretreatment protocols do not work for IgE-mediated anaphylaxis.

• Patients should be given epinephrine autoinjectors and should be instructed in the use of the device. Good evidence suggests that physicians underprescribe epinephrine and that patients (or their parents) fail to use epinephrine as quickly as possible.

Diet

The only dietary consideration is the future avoidance of a suspect or culprit food.

Activity

Once the acute episode of anaphylaxis has resolved, no activity limitations are necessary, with the rare exception of exercise-induced anaphylaxis.

The primary medication for acute anaphylaxis is epinephrine. All other therapies are adjunctive, including antihistamines, corticosteroids, and albuterol. Dopamine may be required to maintain blood pressure, and glucagon can be used in patients taking beta-blockers who have refractory anaphylaxis.

Drug Category: Adrenergic agonists

These agents help maintain blood pressure, antagonize effects of released mediators, and prevent further release of mediators.

Drug Name	Epinephrine (Adrenalin, EpiPen, EpiPen Jr)
Description	DOC for treating anaphylaxis. Has alpha-agonist effects that include increased peripheral vascular resistance, reversed peripheral vasodilatation, systemic hypotension, and vascular permeability. Beta-agonist effects include bronchodilatation, chronotropic cardiac activity, and positive inotropic effects.
Adult Dose	0.3-0.5 mL (0.3-0.5 mg) of 1:1000 solution IM; administer fraction of total dose (0.1-0.2 mL) at site of antigenic exposure, if accessible, and 0.3 mL into different extremity (thigh muscle is preferable); repeat prn, depending on response 1-2 mL (0.1-0.2 mg) of 1:10,000 preparation (0.1 mg/mL) IV q5-20min prn or continuous IV infusion of 2-10 mcg/min for more critical situations
Pediatric Dose	0.01 mg/kg IM prn 2 mcg/min IV infusion
Contraindications	No absolute contraindications in life-threatening anaphylaxis; documented hypersensitivity; cardiac arrhythmias; angle-closure glaucoma; during labor (may delay second stage of labor)
Interactions	Beta-blockers antagonize physiologic effects; increases toxicity of alpha-blocking agents and halogenated inhalational anesthetics; TCAs and MAOIs potentiate effects; digoxin potentiates arrhythmogenic effects
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in elderly persons and those with prostatic hypertrophy, hypertension, cardiovascular disease, diabetes mellitus, hyperthyroidism, or cerebrovascular insufficiency; rapid IV infusions may cause death from cerebrovascular hemorrhage or cardiac arrhythmias; adverse effects include anxiety, headache, palpitations, and hypertension

Drug Category: Antihistamines

These agents block effects of released histamine at H1 receptor, thereby treating flushing, urticarial lesions, vasodilation, and smooth muscle contraction in bronchial tree and GI tract.

Drug Name	Diphenhydramine (Benadryl)
Description	Widely available with a long history of efficacy and relative safety. FDA indication for anaphylaxis. IV administration provides faster onset of action.
Adult Dose	10-50 mg IV/IM q4h prn; IV rate not to exceed 25 mg/min; not to exceed 400 mg/d 25-50 mg PO q6-8h prn; not to exceed 400 mg/d
Pediatric Dose	12.5-25 mg PO tid/qid or 5 mg/kg/d or 150 mg/m2/d divided tid/qid; not to exceed 300 mg/d 5 mg/kg/d IV/IM or 150 mg/m2/d divided qid; IV rate not to exceed 25 mg/min; daily dose not to exceed 300 mg/d
Contraindications	Documented hypersensitivity; concurrent use of MAOIs
Interactions	Potentiates effect of alcohol and other CNS depressants (eg, hypnotics, sedatives, tranquilizers); MAOIs prolong and intensify anticholinergic effects of antihistamines
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Caution in breastfeeding and newborns secondary to risk of convulsions and death in the baby; may exacerbate angle-closure glaucoma, hyperthyroidism, peptic ulcer, or urinary tract obstruction; adverse effects include drowsiness, reduced mental alertness, and xerostomia

Drug Category: Histamine2-receptor antagonists

These agents block effects of released histamine at H2 receptors, thereby treating vasodilation, possibly some cardiac effects, and glandular hypersecretion. H2 blockers with H1 blockers have additive benefit over H1 blockers alone in treating anaphylaxis. Ranitidine (Zantac) probably preferred over cimetidine (Tagamet) in anaphylaxis in light of the risk for hypotension with rapidly infused cimetidine and the multiple, complex drug interactions with cimetidine. Famotidine (Pepcid) IV is another good alternative.

Drug Name	Ranitidine (Zantac)
Description	H2 antagonist, which, when combined with an H1 type, may be useful in treating allergic reactions that do not respond to H1 antagonists alone.
Adult Dose	50 mg/dose IV/IM q6-8h IV bolus administration: Dilute 50 mg in 20 mL NS (concentration of 2.5 mg/mL), inject at rate not >4 mL/min (5 min) Alternatively, 150 mg PO bid; not to exceed 600 mg/d
Pediatric Dose	<12 years: Not established >12 years: 1.25-2.5 mg/kg/dose PO q12h; not to exceed 300 mg/d 0.75-1.5 mg/kg/dose IV/IM q6-8h; not to exceed 400 mg/d
Contraindications	Documented hypersensitivity
Interactions	May decrease effects of ketoconazole and itraconazole; may alter serum levels of ferrous sulfate, diazepam, nondepolarizing muscle relaxants, and oxaprozin
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Caution in renal or liver impairment; if changes in renal function occur during therapy, consider adjusting dose or discontinuing treatment; if CrCl is <50 mL/min, maintain 50-mg dose and increase administration interval to 18-24 h; IV administration for >5 d may cause ALT elevations; case reports suggest ranitidine may precipitate acute porphyria

Drug Category: Bronchodilators

These agents stimulate beta2-adrenergic receptors in bronchial smooth muscle, causing bronchodilation.

Drug Name	Albuterol (Proventil, Ventolin)
Description	Beta-agonist for bronchospasm refractory to epinephrine. Relaxes bronchial smooth muscle by action on beta2-receptors, with little effect on cardiac muscle contractility.
Adult Dose	Nebulizer: 2.5-5 mg q4-6h in 2-5 mL sterile NS or water; to make solution, dilute 0.5 mL (2.5 mg) of 0.5% inhalation solution in 1-2.5 mL of NS (more frequent administration can be used for severe bronchospasm) MDI: 1-2 puffs q4-6h; more frequent administration can be used for severe bronchospasm
Pediatric Dose	Nebulizer <5 years: 1.25-2.5 mg in 1-2.5 mL q4-6h; to make solution, dilute 0.25-0.5 mL (1.25-2.5 mg) of 0.5% inhalation solution in 1-2.5 mL of NS >5 years: Administer as in adults MDI <12 years: 1-2 puffs qid with tube spacer >12 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Beta-adrenergic blockers antagonize effects; inhaled ipratropium may increase duration of bronchodilatation by albuterol; cardiovascular effects may increase with MAOIs, inhaled anesthetics, TCAs, and sympathomimetic agents; may exacerbate diuretic-induced hypokalemia; may decrease digoxin levels
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in cardiovascular disorders (eg, coronary artery disease, cardiac arrhythmias, severe hypertension), hyperthyroidism, diabetes mellitus, and seizure disorder; adverse effects include tremor and mild tachycardia

Drug Category: Corticosteroids

Bind to the intracellular glucocorticoid receptors in inflammatory cells with multiple downstream immunomodulating effects. Glucocorticoids ameliorate delayed effects of anaphylaxis.

Drug Name	Methylprednisolone (Solu-Medrol)
Description	May help prevent late-phase allergic reactions (biphasic anaphylaxis). No immediate effects.
Adult Dose	Loading: 125-250 mg IV over several min Maintenance: 0.25-1 mg/kg/dose IV q6h for up to 5 d
Pediatric Dose	Loading: 2 mg/kg IV Maintenance: Administer as in adults
Contraindications	Documented hypersensitivity; viral, fungal, or tubercular skin infections
Interactions	Coadministration with digoxin may increase digitalis toxicity secondary to hypokalemia; estrogens may increase levels; phenobarbital, phenytoin, and rifampin may decrease levels (adjust dose); monitor patients for hypokalemia when taking medication concurrently with diuretics; concomitant use with NSAIDs increases risk of peptic ulcer
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Hyperglycemia, edema, osteonecrosis, hypokalemia, osteoporosis, euphoria, psychosis, growth suppression, myopathy, and infections are possible complications of glucocorticoid use (most are unlikely with short-term use for acute anaphylaxis)

Drug Category: Positive inotropic agents

These agents help maintain blood pressure independent of adrenergic receptors by increasing intracellular levels of cyclic AMP. In addition, stimulate release of endogenous catecholamines.

Drug Name	Glucagon (GlucaGen)
Description	DOC for severe anaphylaxis in patients taking beta-blockers (should be used in addition to epinephrine, not as a substitute). Pancreatic alpha cells of the islets of Langerhans produce glucagon, a polypeptide hormone. Exerts opposite effects of insulin on blood glucose. Elevates blood glucose levels by inhibiting glycogen synthesis and enhancing formation of glucose from noncarbohydrate sources, such as proteins and fats (gluconeogenesis). Increases hydrolysis of glycogen to glucose (glycogenolysis) in liver in addition to accelerating hepatic glycogenolysis and lipolysis in adipose tissue. Also increases force of contraction in heart and has a relaxant effect on GI tract. Dose used for anaphylaxis is higher than usual dose of 1 mg (1 U) IV/IM/SC used to treat hypoglycemia.
Adult Dose	1-5 mg IV bolus, followed by infusion of 5-15 mcg/min titrated against blood pressure
Pediatric Dose	Hypoglycemia <20 kg: 0.5 mg (0.5 U) IV/IM/SC or a dose equivalent to 20-30 mcg/kg >20 kg: 1 mg (1 U) IV/IM/SC Anaphylaxis: May need higher doses
Contraindications	Documented hypersensitivity; pheochromocytoma
Interactions	Effects of anticoagulants may be enhanced (although onset may be delayed); monitor prothrombin activity for signs of bleeding in patients receiving anticoagulants and adjust dose accordingly
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Adverse effects include nausea, vomiting, sudden and marked increase in blood pressure in patients with pheochromocytoma, and severe rebound hypoglycemia in patients with insulinoma

Drug Category: Vasopressors

These agents are useful as adjunctive therapy to IV fluids to treat refractory hypotension from anaphylaxis.

Drug Name	Dopamine (Intropin)
Description	Considered DOC for anaphylaxis-induced refractory hypotension. Stimulates both adrenergic and dopaminergic receptors. Hemodynamic effect is dependent on dose. Lower doses predominantly stimulate dopaminergic receptors, which, in turn, produce renal and mesenteric vasodilation. Cardiac stimulation and peripheral vasoconstriction produced by higher doses. More than 50% of patients are satisfactorily maintained on doses <20 mcg/kg/min.
Adult Dose	2-5 mcg/kg/min IV; after initiating therapy, increase dose by 1-4 mcg/kg/min q10-30min until optimal response obtained; not to exceed 50 mcg/kg/min
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; pheochromocytoma; ventricular fibrillation
Interactions	Phenytoin, alpha- and beta-adrenergic blockers, general anesthesia, and MAOIs increase and prolong effects
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Monitor urine flow, cardiac output, pulmonary wedge pressure, and blood pressure closely during infusion; prior to infusion, correct hypovolemia; monitoring central venous pressure or left ventricular filling pressure may be helpful for detecting and treating hypovolemia; extravasation can cause necrosis of surrounding tissue, which is treated with phentolamine injected at the site

Further Inpatient Care

• Because of the potential for biphasic reactions, the patient should be observed for as long as 24 hours in severe episodes of anaphylaxis.
• In milder episodes, a 2-hour observation period after the symptoms have subsided is usually adequate.
• Indications for hospital admission include refractory hypotension, persistent severe bronchospasm, a biphasic reaction, the need for intubation, and secondary complications such as arrhythmias or myocardial ischemia.
• Hypotension should be treated with aggressive intravenous fluids and vasopressors (epinephrine and dopamine) in an intensive care unit setting with invasive monitoring as required.
• Persistent bronchospasm should be treated by continuing albuterol and intravenous steroid administration.
• Biphasic reactions should be treated by continuing steroids and directing therapy at the specific manifestations of the late-phase response (eg, repeat doses of antihistamine for recurrent skin manifestations).

Further Outpatient Care

• Once a patient has been treated successfully and sent home, therapy with antihistamines and oral glucocorticoids should probably continue for another 2-3 days to prevent recurrence.
• The most important aspect of outpatient follow-up is evaluation by an allergist/immunologist.
• • Skin testing and/or in vitro IgE tests for foods, stinging insects, medications, or latex should be performed as directed by the patient's history. Documented hypersensitivity to latex is an indication for evaluation of possible allergy cross-reacting foods (eg, banana, kiwi, avocado).

  • If the patient's history and skin test or in vitro IgE tests results confirm Hymenoptera sensitivity as the probable cause of anaphylaxis, immunotherapy should be initiated to prevent future episodes.

  • Future avoidance of culprit foods, medications, latex, or radiocontrast must be emphasized.

  • If a culprit medication is required in the future and no other alternatives are available, a desensitization procedure should be performed by the allergist/immunologist, usually in an intensive care unit setting.

  • If radiocontrast is required in the future, a pretreatment protocol may be used (see Prophylaxis for intravenous RCM).

  • The patient must be provided a prescription for an epinephrine automatic injector (EpiPen or EpiPen Jr) and instructed in its proper use.

In/Out Patient Meds

• Inpatient medications are those listed in Medication.
• Outpatient medications are the oral forms of antihistamines and corticosteroids that should be continued for a short time following an episode (a few days). The benefit of these drugs is more theoretical because no studies exist that prove their benefit in this setting.
• • See Medication for the oral doses of diphenhydramine and ranitidine.

  • A convenient oral corticosteroid is prednisone. No proven best dose exists. In adults, a dose of 1 mg/kg/day in divided doses is probably adequate; in children, a dose of 0.5-1 mg/kg bid is appropriate. Tapering is not necessary unless the patient has been taking steroids chronically.

• Patients with frequent idiopathic anaphylaxis may benefit from daily antihistamine therapy (both H1 antagonists and H2 antagonists) or, in rare circumstances, daily corticosteroid therapy. For daily therapy, diphenhydramine or hydroxyzine is often used first. Second-generation nonsedating antihistamines may be preferable because of decreased adverse effects, but they may be less effective. These include fexofenadine (Allegra) at 180 mg/d, loratadine (Claritin) at 10 mg/d, and cetirizine (Zyrtec) at 10 mg/d. Some specialists prescribe extra doses of antihistamines if tolerated as needed to control symptoms.
• The most important medicine following an episode of anaphylaxis is an epinephrine automatic injector, which the patient should always have immediately available in case of recurrence.
• • The EpiPen automatic injector for adults delivers 0.3 mL of 1:1000 epinephrine (0.3 mg), and the EpiPen Jr for children delivers 0.3 mL of 1:2000 epinephrine (0.15 mg). The adult injector is better for children who weigh more than 30 kg. For more information, see EpiPen.com.

  • The automatic injector is administered by taking off the cap and pushing the opposite end firmly into the upper lateral part of the thigh. The needle is delivered into the thigh automatically. The patient should count to 10 before removing the pen to ensure complete delivery of the medication.

  • The patient should be instructed to obtain emergent medical care immediately after injecting the EpiPen because the effect is short lived (<15 min) and additional doses of epinephrine and other therapy may be required.

Transfer

• The physician's office should be prepared to initiate therapy for anaphylaxis, but transfer to a hospital is necessary for further therapy and observation in all but the mildest cases.

Deterrence/Prevention

• As with most medical conditions, prevention is the most effective therapy against anaphylaxis. This can occur only if the inciting agent is identified, which mandates comprehensive evaluation by an allergist/immunologist. Prophylactic treatment with antihistamines may give sufficient protection, but this is variable among patients.



• Avoidance is the only form of prevention for most inciting agents. Insect sting anaphylaxis can be prevented with allergen immunotherapy, which is highly effective. Anaphylactoid reactions to radiocontrast can be prevented with pretreatment. Anti-IgE may be a good prophylactic agent for severe food allergy, but the one study published to date was with TNX-901, which is not being marketed. A study with omalizumab (Xolair) is currently (2005) recruiting subjects.



• Patients at risk for recurrent anaphylaxis should wear a MedicAlert bracelet (see MedicAlert Foundation). They should also avoid the use of beta-blockers, tricyclic antidepressants, and monoamine oxidase inhibitors because of potential drug interactions with necessary therapies.



• Patients at risk for recurrent anaphylaxis should be given a written Action Plan. A template can be downloaded from Food and Allergy Action Plan. An earlier version was published by the AAAAI Board of Directors in 1998 (see Bibliography).

Complications

• Death from anaphylaxis occurs but is uncommon (see Mortality/Morbidity).
• Complications are also unusual, with most patients recovering completely.
• Respiratory failure from severe bronchospasm or laryngeal edema can cause hypoxia, which could lead to brain injury if prolonged.
• Hypotension and hypoxia may lead to cardiac ischemia or arrhythmias.

Prognosis

• The Olmsted County study detected a total of 154 episodes involving 133 people in a 5-year period. Most patients (116) had only 1 episode in those 5 years. Thirteen people had 2 episodes, and 4 people had 3 episodes. In contrast, in the Memphis study, 61% of patients had 3 or more anaphylactic episodes, 15% had 2 episodes, and 24% had only 1 episode. The difference in these 2 studies likely reflects referral bias because the Memphis study was a referral population. That is, those patients with recurrent episodes are much more likely to be referred to the allergist/immunologist.

Patient Education

• Avoidance education is crucial, especially in younger patients with food anaphylaxis. Important issues include cross-contamination and inadequate labeling of foods. The Food Allergy & Anaphylaxis Network is an excellent resource for families.
• Patients must be educated regarding the indications for and proper technique of EpiPen administration and the need to seek further medical assistance following administration.
• Patients with sensitivity to multiple antibiotics should be provided a list of alternative antibiotics. They can present this list to their primary care physicians when antibiotic therapy is required.
• For excellent patient education resources, visit eMedicine's Allergy Center and Allergic Reaction and Anaphylactic Shock Center. Also, see eMedicine's patient education articles Severe Allergic Reaction (Anaphylactic Shock), Food Allergy, and Drug Allergy.

Medical/Legal Pitfalls

• Failure to consider anaphylaxis in a patient presenting with syncope or hypotension
• Failure to prescribe an epinephrine automatic injector and to document patient education regarding storage and use
• Failure to diagnose the cause of anaphylaxis
• Failure to avoid prescribing a drug to which the patient is known to be sensitive or a similar, cross-reacting drug
• Failure to expediently administer epinephrine in favor of less-effective medications
• Desensitizing a patient to a specific drug without documenting the need for the drug, failure to obtain informed consent, and a lack of adequate training