1.1.1
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1.1.1 · Allergy and Immunology · Anaphylaxis

Anaphylaxis: recognize it, give IM epinephrine first

<2% of the exam 7 min

What the exam asks

Whether a vignette is anaphylaxis (often without hives), the first drug with its dose, route and site, what to add when epinephrine is not working (the patient on a beta-blocker), how long to observe, and what to give at discharge. ABIM's tasks here: making the diagnosis, recommending treatment, assessing risk.

The one-minute version

  • Anaphylaxis is a clinical diagnosis: acute skin or mucosal signs with breathing, circulation or severe gut involvement, or hypotension, bronchospasm or laryngeal involvement after a likely allergen even with no skin signs1.
  • IM epinephrine into the anterolateral thigh is first line: 0.01 mg/kg of 1 mg/mL, at most 0.5 mg, repeated every 5 to 15 minutes12.
  • Antihistamines and glucocorticoids do not treat airway obstruction or shock and do not prevent a biphasic reaction; they never replace or delay epinephrine34.
  • Observe until symptoms have fully resolved, longer after a severe reaction or more than one epinephrine dose45.
  • At discharge: epinephrine auto-injector and training, a written action plan, allergist referral41.

Recognize it

The WAO 2020 criteria need one of two patterns: acute skin or mucosal involvement plus respiratory compromise, low blood pressure or end-organ dysfunction, or severe gastrointestinal symptoms; or acute hypotension, bronchospasm or laryngeal involvement after exposure to a known or highly probable allergen, even without skin signs1.

Skin signs are missing in 10 to 20% of reactions, so "no urticaria" does not exclude anaphylaxis1.

The older NIAID/FAAN criteria (2006) are sensitive but less specific: about 97% sensitivity and 82% specificity against allergists' diagnoses in the emergency department6.

Do not wait for a criteria set to be met before treating a severe reaction, and do not use the response to epinephrine as proof of the diagnosis5.

Evidence: the sources' own words
  • 1 Anaphylaxis is highly likely when any one of the following 2 criteria are fulfilled
  • 1 Skin signs are absent in 10–20% of anaphylaxis reactions
  • 6 sensitivity, 96.7% (95% CI, 88.8% to 99.1%); specificity, 82.4%
  • 5 nor response to epinephrine, should be used as a surrogate marker for anaphylaxis diagnosis

Treat: epinephrine first

  • Dose: 0.01 mg/kg of 1 mg/mL (1:1000) epinephrine, maximum 0.5 mg in an adult, intramuscular, repeated every 5 to 15 minutes if symptoms persist1.
  • Site: the mid-anterolateral thigh. Peak plasma levels are higher after IM injection into the thigh than after IM or subcutaneous injection into the arm2, and in children IM reached its peak in about 8 minutes against 34 minutes subcutaneously7.
  • Position and support: lie the patient flat (sitting if breathless), give oxygen and IV fluids; upright posture is a feature of fatal food and venom anaphylaxis18.
  • No IV bolus outside cardiac arrest: outside imminent arrest the IV bolus route is avoided, because of arrhythmia and dosing errors3.
  • Age and heart disease are no reason to withhold it: epinephrine is not contraindicated in known or suspected cardiovascular disease or in older patients3.
Evidence: the sources' own words
  • 1 0.01 mg/kg of body weight, to a maximum total dose of 0.5 mg
  • 1 Dosing should be repeated every 5–15 min if symptoms are refractory to treatment.
  • 1 Most patients should be placed in a supine position during anaphylaxis unless there is respiratory distress
  • 2 Peak plasma epinephrine concentrations were significantly higher (P < .01) after epinephrine was injected intramuscularly into the thigh
  • 7 achieved at a mean time of 8 +/- 2 minutes, which was significantly faster
  • 8 Upright posture is a feature of fatal anaphylaxis to both food and venom.
  • 3 in other anaphylaxis scenarios, this route of administration should be avoided
  • 3 epinephrine is not contraindicated in the treatment of anaphylaxis in patients with known or suspected cardiovascular disease

When it does not respond

Refractory anaphylaxis continues despite three or more doses of epinephrine plus symptom-directed treatment; it is rare but carries a mortality of about 26%5.

The next step is a titrated low-dose IV epinephrine infusion with aggressive fluid resuscitation; an infusion works better than repeated IV boluses9.

On a beta-blocker, add IV glucagon: it raises cardiac output through adenylyl cyclase, bypassing the blocked receptor, and guidelines advise it when epinephrine fails, on case-level evidence91.

For persistent wheeze an inhaled short-acting beta-agonist can be added, but it does not relieve laryngeal edema or shock and never replaces repeat epinephrine13.

Evidence: the sources' own words
  • 5 refractory (characterized by continued anaphylaxis despite three or more doses of epinephrine and symptom-directed therapy)
  • 5 it has an outsized impact on mortality (26.2% versus 0.35%)
  • 9 Low-dose intravenous adrenaline infusion is more effective than IV bolus dosing
  • 9 Glucagon exerts positive inotropic and chronotropic effects by directly activating adenylyl cyclase and bypassing β-adrenergic receptor blockade.
  • 1 inhaled short-acting beta-2 agonists can be given
  • 3 do not prevent or relieve laryngeal edema and upper airway obstruction, hypotension, or shock

After the reaction

  • Biphasic anaphylaxis is a recurrence within 48 hours after symptoms had resolved for at least an hour, with no new exposure5. Its risk factors are a severe first reaction and the need for more than one dose of epinephrine4.
  • Observation: every patient stays until symptoms have fully resolved4; in a meta-analysis, 6 hours or more of observation excluded a biphasic reaction in 97%10.
  • Tryptase: draw it during the reaction (it peaks 1 to 2 hours after onset) and again at baseline at least 24 hours after recovery; a normal value does not exclude anaphylaxis1.
  • Discharge: self-injectable epinephrine with training, a written action plan, trigger avoidance and referral to an allergist41.
Evidence: the sources' own words
  • 5 recurrent anaphylaxis within 48 hours after initial symptom resolution for at least 1 hour and no subsequent allergen exposures
  • 4 Severe anaphylaxis and/or the need for repeated doses of epinephrine to treat anaphylaxis are risk factors for biphasic anaphylaxis.
  • 4 all patients should be kept under observation until symptoms have fully resolved
  • 10 ≥6 h of observation provided a 97.3% negative predictive value
  • 1 levels peak between 1 and 2 h after the onset
  • 1 It is recommended to evaluate baseline serum tryptase at least 24 h after resolution of anaphylaxis symptoms
  • 1 normal levels do not exclude anaphylaxis having occurred
  • 1 have a written personalized anaphylaxis emergency action plan

Board traps

  • "Give IV diphenhydramine and methylprednisolone, then observe." Wrong first step: H1-antihistamines are not life-saving, and Cochrane reviews found no randomized trials for either drug31112.
  • "Steroids prevent the biphasic reaction." They do not: in matched patients given adrenaline, biphasic rates were 10.7% with glucocorticoids and 10.5% without134.
  • "No hives, so it is not anaphylaxis." Skin signs are absent in 10 to 20%1.
  • "Subcutaneous epinephrine in the arm." Absorption is slower and peaks are lower than IM in the thigh2.
Evidence: the sources' own words
  • 3 they should not be substituted for epinephrine because they are not life-saving
  • 11 We found no studies that satisfied the inclusion criteria.
  • 12 We found no studies that satisfied the inclusion criteria.
  • 13 10.7% in the glucocorticoids group vs. 10.5% in the control group
  • 4 Antihistamines and/or glucocorticoids are not reliable interventions to prevent biphasic anaphylaxis
  • 1 Skin signs are absent in 10–20% of anaphylaxis reactions
  • 2 after epinephrine was injected intramuscularly into the thigh than after epinephrine was injected intramuscularly or subcutaneously into the upper arm

Europe differs

EAACI 2021 agrees on the essentials: clinical criteria with blood kept for tryptase, and prompt IM adrenaline as first-line treatment14.

The German S2k guideline (2021) differs on two points: it gives an H1-antihistamine in every reaction once vital functions are stable, and keeps severe reactions in hospital for 24 hours15. The US position is that antihistamines and glucocorticoids have no role in acute management, with observation until resolution164.

Evidence: the sources' own words
  • 14 The prompt use of intramuscular adrenaline as first-line management is recommended
  • 15 antihistamines should be given in all anaphylactic reactions in order to antagonize the effect of histamine as early on as at the initial stage, once vital functions have been stabilized
  • 15 should be hospitalized and supervised for 24 h due to the risk of a biphasic (bimodal) reaction
  • 16 Antihistamines and glucocorticoids have no role in the acute management of anaphylaxis
  • 4 all patients should be kept under observation until symptoms have fully resolved

Think it through

A 58-year-old man with hypertension, on metoprolol, is stung while gardening. Twenty minutes later he has generalized urticaria and wheeze; blood pressure is 78/40 mm Hg and heart rate 62/min. He has had two 0.5 mg IM doses of epinephrine into the thigh, 5 minutes apart, oxygen and 2 L of crystalloid. Blood pressure is now 80/45 mm Hg.

What is the most appropriate next step?

Show the answer

IV glucagon, while epinephrine continues. A beta-blocker blunts the response to epinephrine; glucagon acts through adenylyl cyclase and bypasses the blocked receptor, and it is advised when the response to epinephrine is poor in patients taking beta-blockers91. If shock persists, the next step is a titrated IV epinephrine infusion with fluids, not IV boluses9. IV methylprednisolone or diphenhydramine would not reverse the shock3. Later he needs venom testing (lesson 1.1.3).

Evidence: the sources' own words
  • 9 bypassing β-adrenergic receptor blockade
  • 9 Low-dose intravenous adrenaline infusion is more effective than IV bolus dosing
  • 1 in particular, in patients taking beta-blockers
  • 3 they do not prevent or relieve upper airway obstruction, hypotension, or shock

References

Every claim above carries its number. Records come from PubMed; the evidence lines quote each source's own words.

  1. 1.

    Cardona V, Ansotegui IJ, Ebisawa M, et al. World allergy organization anaphylaxis guidance 2020. World Allergy Organ J 2020.

    study PMID 33204386 DOI 10.1016/j.waojou.2020.100472 PMC7607509 Read: full text

    Open access, CC BY-NC-ND

  2. 2.

    Simons FE, Gu X, Simons KJ Epinephrine absorption in adults: intramuscular versus subcutaneous injection. J Allergy Clin Immunol 2001.

    trial PMID 11692118 DOI 10.1067/mai.2001.119409 Read: abstract

    Not open access: cited and paraphrased, abstract read; no text reproduced beyond short evidence quotes.

  3. 3.

    Simons FE, Ardusso LR, Bilò MB, et al. World allergy organization guidelines for the assessment and management of anaphylaxis. World Allergy Organ J 2011.

    guideline PMID 23268454 DOI 10.1097/WOX.0b013e318211496c PMC3500036 Read: full text

    Not open access: cited and paraphrased, abstract read; no text reproduced beyond short evidence quotes.

  4. 4.

    Shaker MS, Wallace DV, Golden DBK, et al. Anaphylaxis-a 2020 practice parameter update, systematic review, and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) analysis. J Allergy Clin Immunol 2020.

    guideline PMID 32001253 DOI 10.1016/j.jaci.2020.01.017 Read: abstract

    Not open access: cited and paraphrased, abstract read; no text reproduced beyond short evidence quotes.

  5. 5.

    Shaker MS Anaphylaxis: Definition and criteria. J Food Allergy 2024.

    study PMID 39257603 DOI 10.2500/jfa.2024.6.240002 PMC11382771 Read: full text

    Open access, CC BY-NC-ND

  6. 6.

    Campbell RL, Hagan JB, Manivannan V, et al. Evaluation of national institute of allergy and infectious diseases/food allergy and anaphylaxis network criteria for the diagnosis of anaphylaxis in emergency department patients. J Allergy Clin Immunol 2012.

    study PMID 22051698 DOI 10.1016/j.jaci.2011.09.030 Read: abstract

    Not open access: cited and paraphrased, abstract read; no text reproduced beyond short evidence quotes.

  7. 7.

    Simons FE, Roberts JR, Gu X, et al. Epinephrine absorption in children with a history of anaphylaxis. J Allergy Clin Immunol 1998.

    trial PMID 9449498 DOI 10.1016/S0091-6749(98)70190-3 Read: abstract

    Not open access: cited and paraphrased, abstract read; no text reproduced beyond short evidence quotes.

  8. 8.

    Turner PJ, Jerschow E, Umasunthar T, et al. Fatal Anaphylaxis: Mortality Rate and Risk Factors. J Allergy Clin Immunol Pract 2017.

    review PMID 28888247 DOI 10.1016/j.jaip.2017.06.031 PMC5589409 Read: full text

    Open access, CC BY-NC-ND

  9. 9.

    Pouessel G, Dribin TE, Tacquard C, et al. Management of Refractory Anaphylaxis: An Overview of Current Guidelines. Clin Exp Allergy 2024.

    guideline PMID 38866583 DOI 10.1111/cea.14514 PMC11439156 Read: full text

    Open access, CC BY-NC-ND

  10. 10.

    Kim TH, Yoon SH, Hong H, et al. Duration of Observation for Detecting a Biphasic Reaction in Anaphylaxis: A Meta-Analysis. Int Arch Allergy Immunol 2019.

    meta-analysis PMID 30763927 DOI 10.1159/000496092 Read: abstract

    Not open access: cited and paraphrased, abstract read; no text reproduced beyond short evidence quotes.

  11. 11.

    Choo KJ, Simons FE, Sheikh A Glucocorticoids for the treatment of anaphylaxis. Cochrane Database Syst Rev 2012.

    systematic review PMID 22513951 DOI 10.1002/14651858.CD007596.pub3 PMC6517117 Read: abstract

    Not open access: cited and paraphrased, abstract read; no text reproduced beyond short evidence quotes.

  12. 12.

    Sheikh A, ten Broek Vm, Brown SG, et al. H1-antihistamines for the treatment of anaphylaxis with and without shock. Cochrane Database Syst Rev 2007.

    systematic review PMID 17253584 DOI 10.1002/14651858.CD006160.pub2 PMC6517288 Read: abstract

    Not open access: cited and paraphrased, abstract read; no text reproduced beyond short evidence quotes.

  13. 13.

    Nagata S, Ohbe H, Jo T, et al. Glucocorticoids and Rates of Biphasic Reactions in Patients with Adrenaline-Treated Anaphylaxis: A Propensity Score Matching Analysis. Int Arch Allergy Immunol 2022.

    study PMID 35526528 DOI 10.1159/000524612 PMC9533429 Read: full text

    Open access, CC BY-NC

  14. 14.

    Muraro A, Worm M, Alviani C, et al. EAACI guidelines: Anaphylaxis (2021 update). Allergy 2022.

    guideline PMID 34343358 DOI 10.1111/all.15032 Read: abstract

    Not open access: cited and paraphrased, abstract read; no text reproduced beyond short evidence quotes.

  15. 15.

    Ring J, Beyer K, Biedermann T, et al. Guideline (S2k) on acute therapy and management of anaphylaxis: 2021 update: S2k-Guideline of the German Society for Allergology and Clinical Immunology (DGAKI), the Medical Association of German Allergologists (AeDA), the Society of Pediatric Allergology and Environmental Medicine (GPA), the German Academy of Allergology and Environmental Medicine (DAAU), the German Professional Association of Pediatricians (BVKJ), the Society for Neonatology and Pediatric Intensive Care (GNPI), the German Society of Dermatology (DDG), the Austrian Society for Allergology and Immunology (ÖGAI), the Swiss Society for Allergy and Immunology (SGAI), the German Society of Anaesthesiology and Intensive Care Medicine (DGAI), the German Society of Pharmacology (DGP), the German Respiratory Society (DGP), the patient organization German Allergy and Asthma Association (DAAB), the German Working Group of Anaphylaxis Training and Education (AGATE). Allergo J Int 2021.

    guideline PMID 33527068 DOI 10.1007/s40629-020-00158-y PMC7841027 Read: full text

    Open access, CC BY 4.0

  16. 16.

    Wang J Epinephrine autoinjectors for individuals with food allergy: Who, how many, and when to use. J Food Allergy 2024.

    study PMID 39257596 DOI 10.2500/jfa.2024.6.240004 PMC11382762 Read: full text

    Open access, CC BY-NC-ND

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