AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• References

Background

Anaphylaxis is an acute, potentially life-threatening syndrome, with multisystemic manifestations resulting from the rapid release of inflammatory mediators.

The term anaphylaxis, derived from Greek for "contrary to protection," was coined by Charles R. Richet and Paul Portier in 1902 after their experiments showed a small, nonlethal dose of toxin caused rapid death in sensitized dogs. While the clinical presentation and management are the same, some authors use the term anaphylaxis for immunoglobulin E (IgE)–mediated reactions and anaphylactoid for non–IgE-mediated reactions. The term anaphylaxis syndrome is best used to describe the clinical event.

In children, foods can be a very significant trigger for IgE-mediated anaphylaxis. Milk, eggs, wheat, and soy (MEWS) as a group are the most common food allergens; however, peanuts and fish are among the most potent. Children can develop anaphylaxis from the fumes of cooking fish or residual peanut in a candy bar.

Other common triggers include preservatives (in food and drugs), medications (antibiotics), insect venom (bee sting), and bioactive substances (eg, blood, blood products). Environmental allergens such as pollens, molds, and dust mites are a less common and infrequent cause of anaphylaxis.

Non-IgE triggers include infection, opiates, radiocontrast dye, and exercise.

Pathophysiology

Both IgE and non-IgE activation of mast cells and basophils ignites a cascade that results in the release and production of several inflammatory and vasoactive substances. These bioactive materials include histamine, tryptase, heparin, prostaglandins (PGD₂, PGF₂), leukotrienes (LTC₄, LTD₄, and LTE₄), cytokines (TNF‑α), and platelet-activating factor (PAF). In anaphylaxis, these substances most commonly involve the skin, respiratory, cardiovascular, and gastrointestinal systems. As a result, urticaria, angioedema, bronchospasm, bronchorrhea, laryngospasm, increased vascular permeability and decreased vascular tone, and bloody diarrhea can develop.
 
The most common cause of mediator release is due to an IgE-mediated reaction. A previously sensitized B lymphocyte produces IgE against a specific antigen. The IgE resides on the mast cells and basophils. When the specific antigen, or one similar to it, binds to the high affinity FcεRI-α receptor of the immunoglobulin, mast cell and basophil degranulation occurs.
 
Non-IgE mediator release can be triggered by several different mechanisms including stimulation of the complement cascade to produce C3a, C4a, and C5a anaphylatoxin, neuropeptide and cytokine activity, and direct contact (kallikrein-kinin system) stimulation by certain agents (eg, opiates, radiocontrast media).
 
Many of the clinical presentations seen in anaphylaxis are due to activation of multiple histamine receptors.¹ For example, acute bronchospasm (wheezing, dyspnea) is a result of the interaction between H₁ and H₂ receptor activity; bronchial smooth muscle constriction and increased mucus viscosity from H₁ receptor activity and H₂ activity causes increased mucus production. The combination of H₁ and H₂ receptor stimulation results in increased vascular permeability, flushing, hypotension, tachycardia, and headache. H₁ and H₃ activity results in cutaneous itch and nasal congestion.
 
However, histamine is not the only agent that causes the symptoms in anaphylaxis.² Prostaglandin, leukotrienes, and PAF all contribute to the bronchoconstriction, vascular changes, and changes in vascular capacitance (increased vascular permeability and vasodilatation).

Frequency

United States

Frequency estimates are difficult to determine. Part of the reason may be due to the methodology used by researchers (differing criteria and populations), part likely is due to underreporting, and part is likely due to lack of consistent diagnoses. In a review of the literature by Neugut et al, the overall occurrence of anaphylaxis in the US ranges from 1.24-16.8%.³ However, a working group on anaphylaxis from the American College of Allergy, Asthma, and Immunology estimated the lifetime prevalence at 0.5-2%.⁴

International

Prevalence is similar to that in the United States.⁴

Mortality/Morbidity

Risk of death due to respiratory and cardiovascular complications is significant. Mortality rate estimates vary from 100 to more than 500 cases per year in the United States. The estimated death rate is 0.002%.³

Race

While asthma is more prevalent and has a higher mortality rate in African American children, race does not appear to affect the frequency of having anaphylaxis.⁵

Sex

One retrospective study showed that males younger than 15 years were approximately twice as likely to have anaphylaxis compared with girls (odds ratio 1.917; 95% confidence interval, 1.294 –3.003; P>0.001).⁶ This balance appears to reverse in older patients.⁴

Age

Bohlke and colleagues estimated the rate of anaphylaxis in children at the rate of 10.5 per 100,000 person-years.⁷

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• References

History

Anaphylaxis is a range of signs and symptoms from hives and wheezing to cardiovascular collapse and death. At least 2 organ systems (most commonly skin, respiratory, cardiovascular, gastrointestinal systems) need to be involved to make the diagnosis.^{8, 9}

• Usually, cutaneous symptoms present first.
• Often, a history of exposure to a known trigger is given, (eg, bee sting, peanut ingestion, antibiotic administration). At times, the inciting agent may be unknown or unclear.
• Symptoms may develop slowly and insidiously over several hours or may rapidly progress over several minutes. Parenteral agents generally have a faster onset of symptoms than ingested ones.
• Children may not be able to express the initial symptoms of anaphylaxis. They may initially have apparent discomfort or a generalized irritability. Additionally, the child may not be able to identify the triggering agent (eg, food) even when known to the parent or caretaker.
• Between 5% and 20% of patients may experience a recurrence of anaphylaxis 8-12 hours after the initial presentation.¹⁰

Physical

Initial symptoms may include an awareness that "something isn't right"; a tingling sensation in the mouth; itchy, watery nose and eyes; and/or the feeling of being warm and flushed.

• Cutaneous (skin)
• • Urticaria (hives, welts, "whelps")
  • Pruritus (itching)
  • Angioedema (swelling) of the face, extremities, or both
• Ear, nose, mouth
• • Nasal congestion
  • Sneezing
  • Rhinorrhea (runny nose)
  • Metallic taste
  • Laryngeal edema (throat tightness)
• Respiratory
• • Cough
  • Wheezing
  • Hoarseness
  • Chest pain (respiratory symptom in children)
  • Shortness of breath
  • Stridor ("crowing" inspiratory sound)
• Gastrointestinal
• • Nausea/vomiting
  • Abdominal cramps
  • Diarrhea (at times bloody)
• Cardiovascular
• • Tachycardia (rapid heart rate)
  • Arrhythmias (irregular heart beat)
  • Decreased peripheral perfusion
  • Hypotension (low blood pressure - usually a late finding in children)
• Central nervous system
• • Dizziness
  • Syncope (fainting)
  • Altered mental status
  • Coma

Causes

The following is only meant to be illustrative of the more common triggers but should not be considered an exhaustive listing. These triggering agents may cause an IgE- or non–IgE-mediated anaphylaxis.

• Foods (most common cause in children) - Milk, eggs, wheat, soy, fish, shell fish, legumes (peanuts), nuts
• Medicinals - Antibiotics (penicillins, cephalosporins), local anesthetics (lidocaine), analgesics (aspirin, nonsteroidal anti-inflammatory drugs [ibuprofen], opiates [codeine, morphine]), dextran, radiocontrast media
• Biologicals - Venoms (bee sting, ant or snake bite), blood and blood products, vaccines, allergen extracts
• Preservatives and additives - Metabisulfite, monosodium glutamate
• Other - Latex, unknown/idiopathic

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• References

Other Problems to be Considered

Mastocytosis
Physical urticaria
Red man syndrome (vancomycin related)
Vocal cord dysfunction

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• References

Lab Studies

Anaphylaxis is essentially a clinical diagnosis. Laboratory tests generally are not useful for the acute diagnosis of this condition.

• Serum histamine level rises quickly with the onset of symptoms but does not remain elevated after 30-60 minutes.
• Serum tryptase level peaks 60-90 minutes after the onset of symptoms and remains elevated for up to 5 hours.
• • β-tryptase is released with degranulation of mast cells, while α-tryptase is secreted constitutively by them.
  • The ratio of total tryptase to β-tryptase can help distinguish systemic mastocytosis from anaphylaxis. A ratio £10 implies anaphylaxis, while ³20 is consistent with systemic mastocytosis.¹¹ Other tests that may be useful in distinguishing anaphylaxis from other conditions in the differential include C1 inhibitor functional assay (C1INH) (hereditary angioedema) and urine vanillylmandelic acid and serum serotonin levels (carcinoid syndrome).

Imaging Studies

No imaging studies assist in making this diagnosis.

Other Tests

Radioallergosorbent test (RAST) or cutaneous antigen testing (preferably by a specialist) can be used after recovery to try to identify the inciting antigen.

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• References

Prehospital Care

Prehospital care should be directed at stabilization of the airway, breathing, and circulation.

• Epinephrine is the first drug of choice.
• • The 1:1000 strength should preferentially be administered intramuscularly (IM) as opposed to subcutaneously.¹²
  • Intravenous administration (1:10,000 strength) should be reserved for patients with marked hypotension.
• High-flow oxygen by nonrebreather mask
• • In the awake child who is having some difficulty maintaining their airway, a nasopharyngeal (NP) airway is better tolerated than an oropharyngeal (OP) airway.
  • Continuous positive airway pressure (CPAP) may be considered prior to using an advanced airway (eg, noninvasive pharyngeal airway, endotracheal intubation) if the child is unable to maintain his or her airway, has decreased oxygen saturation, and/or has decreasing level of consciousness.
  • Nebulized albuterol should be administered for cough and wheezing unresponsive to epinephrine.
• Intravenous (IV) access should be obtained. Intraosseous (IO) access should be considered when intravenous access cannot be quickly obtained in unstable patients.
• Crystalloid fluids should be given rapidly if the patient is hypotensive or has other signs of shock.
• Diphenhydramine may be given orally (for mild symptoms) via intramuscular or intravenous administration.

Emergency Department Care

Not all patients will present in shock. Most patients present with skin complaints (eg, urticaria, angioedema) along with respiratory or cardiovascular symptoms. Primary attention is directed at the ABCs. If not already given, epinephrine (which acts as a physiologic antagonist) should be administered as soon as the diagnosis is suspected.

• Epinephrine, 1:1000 intramuscularly, is the initial drug of choice. It may be repeated every 20 minutes, not to exceed 3 doses. Administration in the anterolateral thigh appears to provide superior absorption compared with deltoid and subcutaneous injections.^{12, 13}

• Because of the risk of potentially lethal dysrhythmias, intravenous/intraosseous epinephrine (1:10,000) is reserved for the patient with uncompensated shock.

• If the patient is hypoxic or with respiratory complaints, high-flow oxygen (warm, humidified preferred) by nonrebreather mask should be given.
• • An advanced airway (eg, endotracheal intubation) should be placed if the patient cannot maintain adequate oxygen saturation, if the level of consciousness is decreasing, or both. The airway should be secured with an endotracheal tube early in cases of upper airway obstruction. Advanced airway techniques may be required.
  • Nebulized albuterol (2.5-5 mg/dose) may be used for bronchospasm not responding to epinephrine.
  • • While the addition of ipratropium to albuterol has been shown to be beneficial in severe asthma exacerbations in children, this combination in anaphylaxis has not been studied.
    • Nebulized epinephrine has been used for stridor secondary to laryngeal edema but has not been studied in anaphylaxis.
• An intravenous line should be started in all but the mildest cases. Intraosseous access should be considered when intravenous access cannot be quickly obtained in unstable patients.
• Placing the patient in the Trendelenburg position should be used for initial vascular support. Unresponsive patients should receive a rapid crystalloid fluid bolus of (lactated Ringer or isotonic sodium chloride) of 20 mL/kg. Repeat boluses up to 60-80 mL/kg may be necessary for correcting the hypovolemia.
• • Recall that children are more likely to have compensated shock where tachycardia and signs of hypoperfusion (eg, decreased peripheral pulses, cool extremities) are present but the blood pressure is normal.¹⁴ A systolic pressure of less than the 5^th percentile for age would indicate uncompensated shock:
  • • <70 mm Hg in children aged 1-12 months
    • <70 mm Hg + (2X age in years) in children aged 1-10 years
    • <90 mm Hg in children ≥10 years of age
• Patients unresponsive to fluid resuscitation should receive vasopressors.
• • Epinephrine (0.1-1 mcg/kg/min IV) should be considered as the initial vasopressor in children. Doses at <0.3 mcg/kg/min will tend to have more β-activity, whereas α-action becomes more pronounced at higher doses.
  • Dopamine (2-20 mcg/kg/min IV) may be used in addition to epinephrine. Greater α-activity is seen at higher doses.
  • Norepinephrine (0.1-2 mcg/kg/min IV) is a potent vasopressor. It is usually considered in children unresponsive to epinephrine.
• The combination of H₁ and H₂ antihistamines appears to be more effective, especially for cutaneous symptoms.¹⁵ Their onset of activity is slower than epinephrine and are considered next-in-line treatment.
• • Diphenhydramine 1 mg/kg (not to exceed 50 mg/dose) may be given IV/IM/PO; oral use should be restricted to mild cases.
  • Second-generation H₁ antihistamines (eg, cetirizine, loratadine) have not been studied in anaphylaxis.
  • Ranitidine 1 mg/kg (not to exceed 50 mg/dose IV or 150 mg/dose PO) has a low side effect profile in children. Oral treatment may be used in mild cases.
• Corticosteroids do not have an immediate effect on the symptoms but may help reduce or prevent a biphasic "late phase" reaction.
• • The choice between of methylprednisolone (IV), prednisone, or prednisolone (PO) 1-2 mg/kg should be based on the patient's presentation and condition. The effect and time of onset are similar. Dose may be repeated at 6-hour intervals as indicated.
  • No published studies compare dexamethasone with other corticosteroids in the treatment of anaphylaxis. However, based on its use in other allergic conditions, a dose of 0.15-0.6 mg/kg IV would be appropriate.
• Glucagon may help with refractory symptoms in the patient taking a beta-blocker. In children, administer 20-30 mcg/kg (not to exceed a cumulative dose of 1 mg) IV over 5 minutes followed by an IV maintenance infusion and titrated to clinical effect at 5-15 mcg/min.
• Observation and hospitalization
• • A delayed or biphasic response may occur in 1-20% of patients.¹⁶ The literature is unclear as to which patients are at greatest risk from having this condition. The secondary response may be milder, the same, or more severe than the initial presentation.
  • Even patients with mild symptoms should be observed for a minimum period of time. While the time of observation should be individualized to the patient, a minimum of 4-8 hours appears appropriate.
  • Patients with greater risk of biphasic response should be observed a minimum of 12-24 hours. Severity of symptoms, delay in receiving epinephrine, and ingested antigen have been implicated as risk factors.
  • Children who require fluid resuscitation, multiple doses of epinephrine, or repeated doses of a bronchodilator should be hospitalized.
  • At a minimum, children who require vasopressors or glucagon should be admitted to a tertiary pediatric intensive care center.

Consultations

• ED consultation with a pediatric critical care specialist should be obtained in unstable patients and those unresponsive to treatment.
• Outpatient consultation with an allergist is appropriate for most patients with anaphylaxis, especially those with the following:
• • Significant clinical presentation or those requiring prolonged treatment
  • History of atopic disease
  • Unclear trigger or inciting agent
  • Recurrent episodes of anaphylaxis

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• References

Epinephrine is the most important medication in managing anaphylaxis. Antihistamines (H₁ and H₂ blockers), corticosteroids, crystalloid fluids, and other adrenergic agonists can also be beneficial in the management of this condition.

Drug Category: Adrenergic Agonist Agents

These agents stimulate different adrenergic receptors. Effectiveness in treating anaphylaxis depends on which receptor types are stimulated and on the concentration of receptors in the target tissues.

Drug Category: Antihistamines

Antihistamines decrease histamine activity by reversible competitive blockade of the histamine receptor. H₁-receptor stimulation can lead to bronchial smooth muscle constriction and capillary leakage. H₂-receptor activity increases gastric acid secretion and pacemaker rate. Stimulation of histamine H₁ and H₂ receptors may produce vasodilation and dysrhythmias. Therefore, use of H₁ and H₂ blockers should be considered.

Drug Category: Bronchodilators

Bronchodilators provide relief of bronchial smooth muscle contraction.

Drug Category: Corticosteroids

Anti-inflammatory activity counters actions caused by histamine and other inflammatory mediators. Also potentiates the effect of beta-agonists.

Drug Category: Adenyl Cyclase Activator

Glucagon has been used to reverse bradycardia and hypotension associated with beta-adrenergic blocker overdose. Proposed mechanism of action is increased cyclic adenosine monophosphate production resulting in positive ionotropic and chronotropic effects.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• References

Further Inpatient Care

• Patients with symptoms that require admission should continue to receive supportive care (eg, intravenous fluids, vasopressors, antihistamines, steroids) as indicated.

Further Outpatient Care

• Patients with anaphylaxis should follow up with their pediatrician and be given a referral for allergy evaluation and counseling.

In/Out Patient Meds

• All patients who had more than mild symptoms and/or required more than 4 hours of observation should be given a prescription for an auto-injector of epinephrine. Patients and families should be advised to call 911 or seek immediate medical attention after epinephrine self-administration.
• Patients should be continued on H₁ and H₂ blockers for 24-48 hours after resolution of symptoms.
• A short course of oral steroids may be warranted.

Transfer

• Patients who require aggressive or extensive stabilization should be admitted to an intensive care unit at a tertiary pediatric center.

Deterrence/Prevention

• Exposure to inciting agent, if known, should be avoided.
• When avoidance is impossible, the patient should receive prophylaxis with H₁ and H₂ antihistamines and steroids after exposure. Also, the patient should have an auto-injector of epinephrine readily available for use if severe symptoms develop.

Complications

• Respiratory failure
• Shock
• Multiorgan system failure
• Disseminated intravascular coagulation

Prognosis

• Prognosis is good if treated early.
• Development of shock is a poor prognostic indicator.

Patient Education

• Patients and their caregivers should be educated about exposure risk, early management, and access to medical care.
• 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 Allergy: Insect Sting.
• For more information, see Medscape’s Allergy Resource Center.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• References

Medical/Legal Pitfalls

• Using medications other than epinephrine for initial care
• Failure to identify and treat appropriately
• Failure to prescribe an auto-injector of epinephrine
• Nonreferral to an allergy-immunology specialist

FURTHER READING

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• References

AAAAI Board of Directors. Position Statement: Anaphylaxis in schools and other child-care settings. American Academy of Allergy Asthma & Immunology. Available at http://www.aaaai.org/media/resources/academy_statements/position_statements/ps34.asp. Accessed August 19, 2007.

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Further Reading
• References

1. Simons EFR. Advances in H1-antihistamines. N Engl J Med. Nov 2004;351 (21):2203-17. [Medline].
2. Ogawa Y, Grant JA. Mediators of anaphylaxis. Immunol Allergy Clin North Am. May 2007;27(2):249-60, vii. [Medline].
3. Neugut AI, Ghatak AT, Miller RL. Anaphylaxis in the United States: an investigation into its epidemiology. Arch Intern Med. Jan 8 2001;161(1):15-21. [Medline]. [Full Text].
4. Lieberman P, Camargo CA Jr, Bohlke K, et al. Epidemiology of anaphylaxis: findings of the American College of Allergy, Asthma and Immunology Epidemiology of Anaphylaxis Working Group. Ann Allergy Asthma Immunol. Nov 2006;97(5):596-602. [Medline].
5. Sheikh A, Alves B. Age, sex, geographical and socio-economic variations in admissions for anaphylaxis: analysis of four years of English hospital data. Clin Exp Allergy. Oct 2001;31(10):1571-6. [Medline].
6. Jirapongsananuruk O, Bunsawansong W, Piyaphanee N, Visitsunthorn N, Thongngarm T, Vichyanond P. Features of patients with anaphylaxis admitted to a university hospital. Ann Allergy Asthma Immunol. Feb 2007;98(2):157-62. [Medline].
7. Bohlke K, Davis RL, DeStefano F, Marcy SM, Braun MM, Thompson RS. Epidemiology of anaphylaxis among children and adolescents enrolled in a health maintenance organization. J Allergy Clin Immunol. Mar 2004;113(3):536-42. [Medline].
8. Sampson HA, Muñoz-Furlong A, Campbell RL, et al. Second symposium on the definition and management of anaphylaxis: summary report--Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin Immunol. Feb 2006;117(2):391-7. [Medline].
9. Joint Task Force on Practice Parameters, American Academy of Allergy, Asthma and Immunology; American College of Allergy,Asthma and Immunology and Joint Council of Allergy, Asthma and Immunology. The diagnosis and management of anaphylaxis: an updated practice parameter. J Allergy Clin Immunol. Mar 2005;115(3 Suppl 2):S483-523. [Medline].
10. Kobrynski LJ. Anaphylaxis. Clin Ped Emerg Med. 2007;8:110-16. [Full Text].
11. Schwartz LB, Irani AM. Serum tryptase and the laboratory diagnosis of systemic mastocytosis. Hematol Oncol Clin North Am. Jun 2000;14(3):641-57. [Medline].
12. Simons FE, Roberts JR, Gu X, Simons KJ. Epinephrine absorption in children with a history of anaphylaxis. J Allergy Clin Immunol. Jan 1998;101(1 Pt 1):33-7. [Medline].
13. Simons FE, Gu X, Simons KJ. Epinephrine absorption in adults: intramuscular versus subcutaneous injection. J Allergy Clin Immunol. Nov 2001;108(5):871-3. [Medline].
14. American Heart Association. Part 12: Pediatric Advanced Life Support. Circulation. 2005;112(Suppl 1):IV-167-87. [Full Text].
15. Lin RY, Curry A, Pesola GR, Knight RJ, Lee HS, Bakalchuk L. Improved outcomes in patients with acute allergic syndromes who are treated with combined H1 and H2 antagonists. Ann Emerg Med. Nov 2000;36(5):462-8. [Medline].
16. Lieberman P. Biphasic anaphylactic reactions. Ann Allergy Asthma Immunol. Sep 2005;95(3):217-26. [Medline].
17. Lieberman P. Anaphylaxis and anaphylactoid reactions. In: Adkinson NF, Yunginger JW, Busse MW, et al, eds. Middleton's Allergy Principles and Practice. Vol 2. 6^th ed. Philadelphia, PA: Mosby; 2003:1497-522.

Article Last Updated: Jan 10, 2008