Conflict of Interest Declaration
The ILCOR Continuous Evidence Evaluation process is guided by a rigorous ILCOR Conflict of Interest policy. The following Task Force members and other authors were recused from the discussion as they declared a conflict of interest: none applicable
The following Task Force members and other authors declared an intellectual conflict of interest and this was acknowledged and managed by the Task Force Chairs and Conflict of Interest committees: none applicable.
Task Force Scoping Review Citation
Carlson JN, Djarv T, Woodin JA, Singletary EM, Zideman DA. On behalf of the International Liaison Committee on Resuscitation First Aid Task Force. Second Dose of Epinephrine for Anaphylaxis Scoping Review and Task Force Insights [Internet] Brussels, Belgium: International Liaison Committee on Resuscitation (ILCOR) First Aid Task Force, 2019 December 17. Available from: http://ilcor.org
Methodological Preamble and Link to Published Scoping Review
The continuous evidence evaluation process started with a scoping review of a second dose of epinephrine for anaphylaxis conducted by the ILCOR First Aid Task Force Scoping Review team. Evidence from published and grey literature was sought and considered by the First Aid Task Force. This topic was last reviewed in 2015 and a Consensus on Science with Treatment Recommendations was published (Singletary 2015 S269; Zideman 2015 e225). Critical outcomes for the 2015 review included resolution of symptoms, adverse effects and complications. For the current scoping review, all clinical outcomes were considered.
Webmaster to insert the Scoping Review citation and link to PubMed using this format when/if it is available.
Description (with recommended text)
Adults and children experiencing anaphylaxis requiring the use of epinephrine
administration of a second dose of epinephrine
administration of only one dose
Resolution of symptoms (critical)
Adverse effects (critical)
Randomized controlled trials (RCTs) and non-randomized studies (non-randomized controlled trials, interrupted time series, controlled before-and-after studies, cohort studies) were eligible for inclusion. Unpublished studies (e.g., conference abstracts, trial protocols) were included.
Scoping search strategy: All years and all languages were included as long as there was an English abstract
Re-running of existing search strategy: from 1st January 2014 to October 22, 2019 for the published literature (for the 2015 PICO) to ensure we captured all data published leading up to the 2015 PICO. There were no date restrictions for the grey literature search which was run on October 18, 2019.
Published Literature (See Appendix 1, PRISMA diagram)
Searches executed on October 22, 2019.
Embase 1163 22 oct (2014-2019 472 papers)
'adrenalin'/exp OR epinephrine:ab,ti OR adrenaline:ab,ti OR adrenalin:ab,ti AND (repeat:ti OR 'repeat epinephrine':ab,ti OR dose:ab,ti OR dosage:ab,ti OR doses:ab,ti OR 'second injection':ab,ti OR 'next injection':ab,ti OR '2 injections':ab,ti OR 'two injections':ab,ti OR twinject:ab,ti OR 'additional injection':ab,ti OR 'additional injections':ab,ti OR 'repeated injection':ab,ti OR 'repeated injections':ab,ti OR 'repeat injection':ab,ti OR 'repeat injections':ab,ti OR multiple:ab,ti) AND ('anaphylaxis'/exp OR 'anaphylactic shock'/exp OR anaphylaxis:ab,ti OR anaphylactic:ab,ti OR 'severe allergic reaction':ab,ti OR 'severe allergic reactions':ab,ti) NOT ('animal'/exp NOT 'human'/exp) NOT ([editorial]/lim OR [letter]/lim OR 'case report'/de) AND [embase]/lim
PubMed 1542 (all dates)
((((((("multiple dose"[TI] or "multiple doses"[TI] or repeat[TI] or second dose[TI] or second doses[TI]) AND epinephrine[TI])))) OR (((((((("Epinephrine"[Mesh] OR Epinephrine[TIAB] OR Adrenaline[TIAB] or adrenalin[TIAB]))) AND (("administration and dosage" [Subheading] OR "therapeutic use" [Subheading:NoExp] OR "repeat epinephrine"[TIAB] OR dose[TIAB] OR dosage[TIAB] or doses[TIAB] or "second injection"[TIAB] or "next injection"[TIAB] or "2 injections"[TIAB] or "two injections"[TIAB] or Twinject[TIAB] or "additional injection"[TIAB] or "additional injections"[TIAB] OR "repeated injection"[TIAB] or "repeated injections"[TIAB] or "repeat injection"[TIAB] or "repeat injections"[TIAB] or multiple[TIAB])))) AND ((("Anaphylaxis"[Mesh] OR Anaphylaxis[TIAB] or anaphylactic[TIAB] or "severe allergic reaction"[TIAB] or "severe allergic reactions"[TIAB]) AND ("therapy" [Subheading:NoExp] OR "drug therapy" [Subheading] OR "prevention and control" [Subheading])))))))) NOT ((animals[mh] NOT humans[mh]) NOT ("letter"[pt] OR "comment"[pt] OR "editorial"[pt] or Case Reports[ptyp] ))
Grey Literature (See Appendix 2)
Google search conducted on November 18, 2019
Inclusion and Exclusion criteria
Inclusion: Human studies, all languages, all ages.
Exclusion: Studies not reporting on outcomes
Grey Literature search
Date searched: 18-October-2019
Task Force Insights
1. Why this topic was reviewed.
The 2015 ILCOR Consensus on Science for this topic identified very low certainty evidence from 9 observational studies evaluating the critical outcomes of resolution of symptoms, adverse effects and complications. [Singletary 2015 S269; Zideman 2015 e225] Since that review, the ILCOR continuous evidence evaluation process has included automated regular database searches for new studies, without results that would trigger a new systematic review. The First Aid Task Force sought to conduct a scoping review to search for additional publications in the grey literature that would support past recommendations or lead to a systematic review.
2. Narrative summary of evidence identified
Two studies were identified from our PubMed search that compared outcomes in the healthcare setting between patients who received a single dose of epinephrine and those that received a second dose of epinephrine.
Campbell et al. (Campbell 2015 576) performed a combined retrospective chart review and prospective, observational study of 582 emergency department (ED) patients (n=532 retrospective and 50 prospective) with anaphylaxis of which 45 had multiple doses of epinephrine administered. Receiving more than 1 dose of epinephrine was associated with higher rates of admission to a general medical floor (odds ratio [OR] 2.8; 95% confidence interval [CI] 1.1-7.2) or the intensive care unit (OR 7.6; 95% CI 3.7-15.6). In addition, a lower proportion of patients who received at least two doses of epinephrine were discharged home (9/45 [20%] vs 244/537 [45%]; p=0.002]. No data were reported on the critical outcomes of resolution of symptoms, adverse effects or complications.
Akari et al (Araki 2018 751] performed an oral food challenge in 42 patients; 18 required epinephrine with 5 requiring multiple doses. The authors report that patients with multiple doses had higher rates of cardiovascular, neurologic and gastrointestinal symptoms (unable to estimate from the published data). During the course of the study, all 5 patients where a second dose of epinephrine was administered had resolution of symptoms although the exact duration and how this compared to those patients not receiving a second dose of epinephrine was unable to be estimated from the published data. No data were reported on the critical outcome of survival or the important outcomes of time to resolution of symptoms or hospital admission.
Our grey literature search did not identify any additional sources of information that addressed the outcomes of our PICOST.
3. Narrative Reporting of the task force discussions
We discussed many issues relating to evaluation of this PICOST. We utilized the outcomes from the 2015 PICOST. Alternative outcomes were identified through this scoping review (e.g. hospital admission, time to resolution of symptoms, etc.) that may need to be considered in future reviews. In reviewing manuscripts for this PICOST, we identified several studies that sought to determine predictors of repeated doses of epinephrine. While this was outside the scope of this review, this topic is relevant to the field of anaphylaxis management and epinephrine administration and may benefit from a dedicated scoping or systematic review in the future. We did not identify any prospective, randomized trials comparing the efficacy of a second dose of epinephrine.
The studies identified in this review and in the 2015 PICOST were predominantly retrospective in nature and suffered from confounding by indication whereby it is unclear why patients received a second dose of epinephrine. As such, interpreting outcomes such as survival and hospital admission may be complicated by the fact that individuals with more severe cases of anaphylaxis may receive additional doses of epinephrine. In these cases, the outcome (e.g. hospital admission) may not be related to the medication administration but instead be a marker of illness severity alone as also evidenced by the second dose of epinephrine. Neither of the two included studies were performed in the first aid setting. As such, how these findings generalize to the first aid setting is unclear.
In addition to the limited data on use of a second dose epinephrine, it is also unclear how accurately first aid providers can correctly identify anaphylaxis. Finally, we discussed that there remains uncertainty around epinephrine dosing and the need for a second dose. Concern was expressed that in some countries, the initial dose of epinephrine administered may be less than recommended in other countries, potentially leading to a greater chance of requiring a second dose. The task force also discussed the potential impact, if any, from a change in the recommended technique for administration of epinephrine via autoinjector, with a decreased ‘hold time’ during injection.
The 2015 ILCOR Treatment Recommendation for this PICOST states:
“We suggest a second dose of epinephrine be administered by autoinjector to individuals with severe anaphylaxis whose symptoms are not relieved by an initial dose (weak recommendation, very-low-quality evidence).” [Singletary 2015 S269]
Given these discussion points, combined with the limited additional information identified in this review, the task force did not feel there was sufficient information to alter the existing ILCOR treatment recommendations or to pursue a systematic review.
Although this scoping review has not identified sufficient new evidence to prompt a systematic review or reconsideration of current resuscitation guidelines, it highlights significant gaps in the research evidence.
- The identified studies suffer from confounding by indication, limiting the understanding of the benefits of second (or multi-dose) epinephrine in the setting of anaphylaxis
- Research is needed to evaluate this question in the first aid setting
- Only short term/surrogate outcomes were evaluated. Future studies should document survival, resolution of symptoms, time to resolution of symptoms and need for hospital admission
- The correct dose of epinephrine for anaphylaxis is unclear. There is no known maximum dose. The dosing of epinephrine autoinjectors varies by region (e.g. 0.3mg in the United States and 0.5mg in the UK) and therefore the need for additional doses of epinephrine may vary based on the initial dose delivered.
Second Epi Grey Search Websites
PRISMA flow diagram second adrenaline
Araki M, Hamahata Y, Usui M, Akashi M. [Use of Multiple Doses of Adrenaline for Food-Induced Anaphylaxis]. Arerugi = [Allergy]. 2018;67(6):751-758.
Campbell RL, Bashore CJ, Lee S, et al. Predictors of Repeat Epinephrine Administration for Emergency Department Patients with Anaphylaxis. The journal of allergy and clinical immunology. In practice. Jul-Aug 2015;3(4):576-584.
Singletary EM, Zideman DA, De Buck ED, et al. Part 9: First Aid: 2015 International Consensus on First Aid Science With Treatment Recommendations. Circulation. Oct 20 2015;132(16 Suppl 1):S269-311.
Zideman DA, Singletary EM, De Buck EDJ, Chang WT, Jensen JL, Swain JM, Woodin JA, Blanchard IE,
Herrington RA, Pellegrino JL, Hood NA, Lojero-Wheatley LF, Markenson DS, Yang HJ; on behalf of the First Aid Chapter Collaborators. Part 9: First aid: 2015 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations. Resuscitation. 2015; 95:e225-e261.