Use of multiple epinephrine doses in anaphylaxis: A systematic review and meta-analysis

J Allergy Clin Immunol. 2021 Nov;148(5):1307-1315. doi: 10.1016/j.jaci.2021.03.042. Epub 2021 Apr 20.


Background: Regulatory bodies recommend that all patients at risk of anaphylaxis be prescribed 2 epinephrine autoinjectors, which they should carry at all times. This is in contrast to some guidelines. The proportion of anaphylaxis reactions that are treated with multiple doses of epinephrine has not been systematically evaluated.

Objective: Our aim was to undertake a systematic review and meta-analysis of published studies reporting epinephrine treatment for anaphylaxis in which data relating to the number of doses administered were available.

Methods: We searched the Medline, Embase, and Cochrane databases for relevant studies reporting at least 10 anaphylaxis events (due to food or venom) from 1946 until January 2020. Data were extracted in duplicate for the meta-analysis, and the risk of bias was assessed. The study was registered under the PROSPERO identifier CRD42017069109.

Results: A total of 86 studies (36,557 anaphylaxis events) met the inclusion criteria (20 of the studies [23%] were prospective studies; 64 [74%] reported reactions in the community, and 22 [26%] included food challenge data). Risk of bias was assessed as low in 50 studies. Overall, 7.7% of anaphylaxis events from any cause (95% CI = 6.4-9.1) were treated with multiple doses of epinephrine. When only epinephrine-treated reactions for which subsequent doses were administered by a health care professional were considered, 11.1% of food-induced reactions (95% CI = 9.4-13.2) and 17.1% of venom-induced reactions (95% CI = 11.3-25.0) were treated with more than 1 epinephrine dose. Heterogeneity was moderate to high in the meta-analyses, but at sensitivity analysis this estimate was not affected by study design or anaphylaxis definition.

Conclusion: Around 1 in 10 anaphylaxis reactions are treated with more than 1 dose of epinephrine.

Keywords: Epinephrine; allergic reaction; anaphylaxis; autoinjector device; refractory anaphylaxis.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't
  • Systematic Review

MeSH terms

  • Anaphylaxis / drug therapy*
  • Animals
  • Bronchodilator Agents / therapeutic use*
  • Clinical Protocols
  • Drug Dosage Calculations
  • Epinephrine / therapeutic use*
  • Humans
  • Hypersensitivity / drug therapy*


  • Bronchodilator Agents
  • Epinephrine