Anaphylaxis

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Chapter 30 Anaphylaxis

Linda D. Arnold, MD

1 What is anaphylaxis?

Anaphylaxis is an acute, systemic allergic reaction with varied mechanisms and clinical presentations. Signs and symptoms develop rapidly as mast cells and basophils release potent biologically active mediators. The acute constellation of symptoms results from the effect of these mediators on multiple target organs, including the skin, the respiratory and gastrointestinal tracts, and the cardiovascular system. Severity can vary from mild to life-threatening or fatal; more severe reactions are characterized by respiratory insufficiency and hemodynamic compromise. “Classic” anaphylaxis refers to IgE-mediated hypersensitivity responses, though other immunopathogenic mechanisms exist.

2 How common is anaphylaxis?

Although frequency and causes vary with the population studied, most estimates of prevalence fall just below 1%. In the United States, food allergies are the most common cause of anaphylaxis, accounting for 30,000 emergency department (ED) visits, 2000 hospitalizations, and 150–200 deaths each year. Among children under age 4 years, 6–8% have documented food allergies, with the rates dropping to 2% after age 10. One percent of people in the United States are allergic to peanuts, tree nuts, or both. Hypersensitivity reactions account for one third of all adverse drug reactions. Serious systemic reactions to hymenoptera stings occur in 0.4–0.8% children and 3% of adults, resulting in approximately 50 deaths each year.

Sampson HA: Anaphylaxis and emergency treatment. Pediatrics 111:1601–1608, 2003.

Ellis AK, Day JH: Clinical reactivity to insect stings. Curr Opin Allergy Clin Immunol 5:349–354, 2005.

3 How dangerous is anaphylaxis?

Anaphylaxis often occurs outside of the hospital setting, with case fatality rates of 0.7%. The median time to respiratory or cardiac arrest in fatal cases of anaphylaxis is 5 minutes for reactions to medications or contrast material, 15 minutes for reactions to insect venom, and 30 minutes for reactions to food. Fatal reactions are frequently the first reactions for most sting, medication, and contrast deaths. Most ingestions are inadvertent, and reactions to aerosolized fish and shellfish in restaurants have been reported. The majority of allergic reactions for children take place in school or daycare. In the rare instances when written management plans exist, they are implemented only 75% of the time.

Sicherer SH, Furlong TJ, DeSimone J, et al: The US peanut and tree nut allergy registry: Characteristics of reactions in schools and day care. J Pediatr 138:560–565, 2001.

4 What are common causes of anaphylaxis?

Food allergies are the leading cause of anaphylaxis for children presenting to EDs in the United States, accounting for a third to a half of such visits. Allergies to peanuts, tree nuts, shellfish, cow’s milk, eggs, soy, and wheat are most common. Peanuts and tree nuts alone are responsible for 90% of all food anaphylactic events, with commercial catering implicated in the majority of nut-related reactions.

Among antibiotics, cephalosporins, sulfonamides, and penicillins are most frequently implicated. Insect stings and allergen immunotherapy are also important causes of anaphylaxis. Anaphylaxis to immunizations is rare.

5 What are some of the causes of anaphylaxis related to medical treatment?

Neuromuscular blockers (succinylcholine, vecuronium, atracurium) account for 60% of episodes of anaphylaxis related to medical treatment.

Latex, antibiotics, induction agents (barbiturates, etomidate, propofol) and narcotics (fentanyl, meperidine, morphine) are also important causes.

Colloids, opioids, radiocontrast media, and blood products are implicated less than 10% of the time.

The incidence of latex allergy has leveled off, probably because of increased awareness and the use of latex-free and low-powder gloves. Reactions are more common in atopic individuals, health care workers, and patients with a history of genitourinary surgeries or long-term bladder catheterizations.

Lieberman P: Anaphylactic reactions during surgical and medical procedures. J Allergy Clin Immunol 110:S64–S69, 2002.

6 Is there a way to predict who is at risk for more severe anaphylactic reactions?

Most deaths from anaphylaxis due to food occur in adolescents and young adults. Patients with poorly controlled asthma and those with a history of previous anaphylaxis are at greater risk. Reactions to peanuts, tree nuts, fish, and shellfish are the most severe, with peanuts and tree nuts responsible for 94% of deaths. The severity of previous episodes does not predict the severity of future reactions, as antigen doses may vary. Large local reactions to stings are not predictive of anaphylaxis to insect venom. Many fatal or near-fatal reactions to foods and insect venom occur in children who have not required previous urgent medical intervention.

Bock SA, Munoz-Furlong A, Sampson HA: Fatalities due to anaphylactic reactions to food. J Allergy Clin Immunol 108:861–866, 2001.

KEY POINTS: RISK FACTORS FOR SEVERE ANAPHYLAXIS

1 Adolescent or young adult

2 History of previous severe reaction

3 Peanuts, tree nuts, fish, or shellfish as inciting agent

4 Asthma, especially if poorly controlled

5 Taking β-blockers

7 What are anaphylactoid reactions? How do they differ from anaphylaxis?

Anaphylactoid reactions result from non–IgE-mediated degranulation of mast cells or basophils. They are clinically indistinguishable from anaphylaxis, and the treatment is identical. Examples include reactions to nonsteroidal anti-inflammatory drugs (NSAIDs), radiocontrast media, blood products, and exercise.

8 What are the clinical manifestations of anaphylaxis?

Anaphylaxis is characterized by the abrupt onset of symptoms minutes to hours after an ingestion or exposure (Table 30-1). The timing, sequence, and severity of symptoms vary. The shorter the interval between the exposure and the symptoms, the more likely the reaction is to be severe.

The oral cavity and throat are affected first, with a tingling or pruritic sensation and edema of the lips or mucosa. Laryngeal and epiglottic edema may develop.

Gastrointestinal signs follow and include nausea, vomiting, and colicky pain.

Skin symptoms and signs, which may be absent in up to 30% of severe reactions, include flushing, pruritus, and urticaria. The urticaria may be localized or diffuse.

Respiratory symptoms, such as stridor or wheezing, may develop in more severe reactions.

Dizziness and altered mental status are associated with hypotension, resulting from effects on the cardiovascular system.

Table 30-1 Clinical Signs and Symptoms of Anaphylaxis

Oropharyngeal: metallic taste, pruritus, and/or edema of lips, tongue, palate or uvula

Otorhinolaryngologic: congestion, rhinorrhea, pruritus, sneezing, throat tightness, hoarseness, dysphagia

Dermatologic: erythema, pruritus, urticaria, angioedema, morbilliform rash

Gastrointestinal: nausea, colicky abdominal pain, vomiting, diarrhea

Respiratory: cough, shortness of breath, dyspnea, chest tightness, stridor, wheezing

Cardiovascular: faintness, tachycardia, syncope, chest pain, hypotension

Neurologic: headache, mental status changes

General: anxiety, sense of impending doom

9 What is the differential diagnosis of anaphylaxis?

Anaphylaxis must be ruled out first since failure to identify it can have serious consequences for the patient. The differential diagnosis includes:

Scombroid poisoning: Develops within a half hour of eating spoiled fish; urticaria, nausea, headache, and dizziness occur.

Physical urticaria: Examples include cold urticaria and cholinergic urticaria.

Near-fatal asthma exacerbations: Can present with bronchospasm and stridor but usually without a rash.

Angioedema: The hereditary form is difficult to distinguish from early anaphylaxis.

Panic disorder: Can present with functional stridor but none of the other symptoms.

2005 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Part 10.6: Anaphylaxis.

10 How should anaphylaxis be managed?

See Table 30-2. The extent and severity of symptoms should be rapidly assessed, with a focus on airway, oxygenation, cardiac output, circulation, and tissue perfusion. A history of any confounding medications should be obtained.

Table 30-2 Acute Management of Anaphylaxis

Rapid assessment of ABCs

Place patient in supine position, with legs elevated

Supplemental oxygen and airway management

Epinephrine IM or IV, as indicated

IV fluids for hypotension

Albuterol for bronchospasm

Consider H₁ and H₂ antagonists

Consider IV or PO steroids

Monitor for a minimum of 4 hours for signs of a biphasic reaction

Administer epinephrine promptly and repeat as necessary. Place patients in a supine position, with legs elevated, to improve venous return and help maintain adequate blood pressure. When hypotension is present, aggressively support the circulation with intravenous crystalloids. Supportive care should include oxygen and bronchodilators for wheezing. Steroids and antihistamines are often administered but have no effect on acute symptoms.

11 What are the most common errors in the management of anaphylaxis?

Studies suggest that anaphylaxis is under-recognized and undertreated in both prehospital and ED settings. Delays in initial treatment of anaphylaxis are associated with worse outcomes and higher fatality rates. The more advanced the reaction, the less likely it is to reverse with epinephrine. Failure to administer epinephrine, delayed administration, and errors in dosing and route of administration are all common. Notably, multiple studies have shown that few physicians can demonstrate proper use of an EpiPen, and even fewer have a placebo to demonstrate use to patients and families.

Sampson HA, Munoz-Furlong BA, Bock A, et al: Symposium on the definition and management of anaphylaxis: Summary report. J Allergy Clin Immunol 115:584–591, 2005.

12 How can severity be determined?

As a general rule, the rapid onset of symptoms following allergen exposure suggests a more severe or life-threatening reaction. Many different grading systems exist, ranking severity on the basis of the organ systems involved and the presence of respiratory symptoms and hypotension. Reactions that are confined to the skin are classified as mild. Urticaria and angioedema alone are not correlated with hypoxia or hypotension. Moderate reactions are characterized by diaphoresis, throat tightness or respiratory features, and abdominal pain or vomiting. Neurologic changes signify a severe reaction. The presence of airway obstruction in conjunction with cardiovascular symptoms is an ominous sign.

Brown SG: Clinical features and severity grading of anaphylaxis. J Allergy Clin Immunol 114:371–376, 2004.

13 What are the most common causes of death?

Most deaths are caused by respiratory arrest or cardiovascular collapse. Severe bronchospasm and upper airway swelling can both lead to asphyxia. Increased vascular permeability can result in transfer of up to 50% of the intravascular fluid into the extravascular space within 10 minutes. Concomitant vasodilation leads to mixed distributive/hypovolemic shock, which may be refractory to aggressive fluid resuscitation and pressor support, particularly in patients taking β-blockers. Direct mediator effects on the myocardium are associated clinically with myocardial ischemia, conduction defects, atrial and ventricular arrhythmias, and T-wave abnormalities.

14 How does epinephrine work in anaphylactic reactions?

Epinephrine is a direct-acting sympathomimetic with complex pharmacologic effects on many target organs. Vasoconstriction, with subsequent reversal of peripheral vasodilation and increases in peripheral vascular resistance, is the primary α effect. β effects include prevention of further mediator release, bronchodilation via smooth muscle relaxation, and increases in heart rate and contractility via direct effects on the myocardium. Clinically, these effects decrease the cutaneous signs of angioedema and urticaria. More importantly, they lead to improvements in cardiovascular function by increasing blood pressure and enhancing coronary blood flow.

KEY POINTS: EPINEPHRINE

1 Most important medication in the treatment of anaphylaxis

2 Reverses bronchospasm by relaxing bronchial smooth muscle

3 Increases blood pressure via peripheral vasoconstriction

4 Increases heart rate and contractility

5 Delays in administration are associated with higher fatality rates

15 How should epinephrine be administered?

Epinephrine should be administered by intramuscular injection at a dose of 0.01 mL/kg body weight of the 1:1000 solution (maximum dose, 0.5 mL). The anterolateral thigh is the preferred injection site because of superior vascularity compared with the deltoid muscle. Doses can be repeated every 5 minutes, as needed. Epinephrine should not be given subcutaneously, as slow absorption by this route leads to extreme delays in peak plasma concentration. IV epinephrine may be required for refractory anaphylaxis; it should be diluted and administered slowly, to minimize the risk of adverse cardiac effects.

16 When should bronchodilators be used in anaphylaxis?

Use intermittent or continuous aerosolized β-adrenergic agents (e.g., albuterol) when wheezing is present.

17 Are H₁ and H₂ blockers effective in relieving symptoms of anaphylaxis?

Histamine is an important mediator in anaphylaxis, producing symptoms of pruritis, rhinorrhea, tachycardia, bronchospasm, headache, flushing, and hypotension. Histamine levels peak early and transiently during anaphylaxis, while the onset of activity for oral diphenhydramine occurs up to an hour after administration. IV diphenhydramine has a faster onset of action, but, it too, is likely of little benefit for all but limited cutaneous reactions. H1 antihistamines may work better in combination with H2 blockers, such as ranitidine or cimetidine, although they have not been shown to reduce the release of mediators, fail to relieve upper airway edema or hypotension, and have little to no role in relieving respiratory or gastrointestinal symptoms.

Simons FE: First-aid treatment of anaphylaxis to food: focus on epinephrine. J Allergy Clin Immunol 113(5):837–844, 2004.

18 Do steroids have a role in treatment?

Steroids have no immediate effect in the acute management of anaphylaxis but may help to modulate late-phase responses. Many experts recommend giving prednisone (1–2 mg/kg orally) for mild to moderate reactions, and methylprednisolone (2 mg/kg via IV route) for severe allergic reactions. Despite the lack of supporting evidence, oral steroids are often prescribed for 48–72 hours after the initial episode. Table 30-3 summarizes the drugs used to treat anaphylaxis.

Table 30-3 Medications Used to Treat Anaphylaxis

Epinephrine:	0.01 mg/kg (1:1000) IM in the anterolateral thigh (max 0.5 mg); repeat q 5 min as needed; 0.01–1.0 μg/kg/min (1:10,000) IV infusion for refractory hypotension
Albuterol:	Intermittent or continuous nebulized solution for bronchospasm
Diphenhydramine:	1 mg/kg PO, IM, or IV (max 75 mg)
Ranitidine:	1–2 mg/kg PO or IV (max 75 mg)
Cimetidine:	5–10 mg/kg PO, IM, or IV (max 300 mg)
Prednisone:	1–2 mg/kg PO (max 75 mg)
Methylprednisolone:	1–2 mg/kg IV (max 125 mg)
Glucagon:	5–15 μg/min IV infusion for refractory hypotension
Dopamine:	2–20 μg/kg/min IV infusion for refractory hypotension

19 Are laboratory tests ever helpful?

In a word: no. Though histamine levels rise dramatically in the setting of acute anaphylaxis, it is only for a few minutes, and special collection techniques are required for measurement. During reactions due to drugs and bee stings, plasma tryptase levels become elevated within an hour, and stay elevated for up to 12 hours. Tryptase is stable at room temperature and post mortem (i.e., levels may be helpful retrospectively in establishing a cause of sudden death). Notably, tryptase levels are not elevated in food-related anaphylaxis.

20 What are some unusual causes of anaphylaxis in children?

Exercise-induced anaphylaxis develops when exercise follows the ingestion of a specific food to which an individual is sensitive. Symptoms may appear up to 4 hours after exercise stops. Generalized itching and flushing herald the onset of upper respiratory tract obstruction and hypotension. Management includes prompt cessation of exercise and administration of epinephrine. Vascular and airway support should be provided, if indicated. Antihistamines are partially effective at preventing exercise-induced anaphylaxis. Other measures include avoiding exercise 4–6 hours after eating and avoidance of aspirin and NSAIDs prior to exercise, as they may potentiate the reaction.

Cold urticaria is an acute reaction to cold temperatures. When generalized such as in an immersion in a cold body of water, an anaphylactic reaction can be precipitated.

Hosey RG, Carek PJ, Goo A: Exercise-induced anaphylaxis and urticaria. Am Fam Phys 64:1367–1372, 2001.

Stevenson M, Ruddy R: Asthma and allergic emergencies. In Fleisher G, Ludwig S, Henretig F (eds): The Textbook of Pediatric Emergency Medicine, 5th ed. Lippincott Williams & Wilkins, Philadelphia, 2006, pp 1077–1081.

21 What are biphasic anaphylactic reactions?

Classically, anaphylaxis is monophasic, with complete resolution within 2 hours of treatment. Biphasic reactions occur in 6–20% of patients, with recurrence of symptoms 2–72 hours after initial complete resolution, without a new exposure. Management may be complicated by a poor response to epinephrine and by severe bronchospasm, which is refractory to β-agonists. The likelihood of a biphasic reaction cannot be predicted on the basis of the severity of the initial episode, though more epinephrine may have been required to alleviate the initial symptoms. Prompt administration of epinephrine during the initial episode is associated with decreased occurrence of biphasic reactions, while steroids have no effect.

Shimamoto SR, Bock SA: Update on the clinical features of food-induced anaphylaxis. Curr Opin Allergy Clin Immunol 2:211–216, 2002.

22 How long should therapy for anaphylaxis be continued?

Duration of therapy depends on the severity of the anaphylactic reaction. Therapy with antihistamines or steroids, if initiated, is commonly continued for 48–72 hours after the exposure.

23 Which patients with an anaphylactic reaction should be admitted?

Children presenting with allergic reactions should be observed at least 4 hours for progression of symptoms or biphasic response. Those who have had a mild reaction, responded quickly to therapy, and can be closely monitored at home can then be discharged with detailed instructions about signs and symptoms of recurrence. Children who present with severe reactions, have a history of severe reactions, or are judged to be unable to return if symptoms recur should be admitted to the hospital or an extended-stay unit for observation.

24 Will children “outgrow” their sensitivities?

Conventional wisdom is that food allergies associated with milder symptoms, such as egg, milk, and soybean, are often outgrown. Persistent sensitivity is more common in allergies to peanuts, tree nuts, fish and shellfish, though recent studies suggest that up to a third of children may “outgrow” their peanut allergies. Tolerance to peanuts is more likely to develop in those whose initial presentations were milder. Despite this, parents should remain vigilant. Half of children with peanut allergy may experience life-threatening symptoms with repeat exposures—even when symptoms with the initial exposure were mild.

Kemp SF, Lockey RF: Anaphylaxis: A review of causes and mechanisms. J Allergy Clin Immunol 110:341–348, 2002.

25 Who should be discharged with EpiPens? What instructions should be given for their use?

Prescribe autoinjectable epinephrine (Fig. 30-1) for children who have had an anaphylactic reaction and who have a history of wheezing, a personal or family history of a severe reaction, or an allergy to peanuts, tree nuts, fish or shellfish. Train parents to administer intramuscular epinephrine during an acute event when a child experiences worrisome symptoms or has a history of severe anaphylaxis to that agent. The threshold should be lower if nonmedical people are with the child; the reaction is from peanuts, nuts, or seafood; or when the reaction occurs in a location that is more than 15 minutes from a medical facility. After epinephrine administration, the child should be taken to the hospital immediately. Doses may be repeated every 15–20 minutes as needed.