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 declared an intellectual conflict of interest and this was acknowledged and managed by the Task Force Chairs and Conflict of Interest committees:
Janice Tijssen – published previous studies on intramuscular epinephrine and is funded for a trial on IM Epinephrine.
CoSTR Citation
Tijssen JA, Acworth J, Bansal A, Bittencourt Couto T, de Caen A, del Castillo J, Katzenschlager S, Morgan R, Myburgh M, Nadkarni V, Tiwari L, Morrison LJ, Scholefield BR on behalf of the Pediatric Life Support Task Force. Intramuscular Epinephrine for Cardiac Arrest: Consensus on Science with Treatment Recommendations [Internet] Brussels, Belgium, International Liaison Committee on Resuscitation (ILCOR) Pediatric Life Support Task Force, 2026. Available from http://ilcor.org.
Methodological Preamble and Link to Published Systematic Review
This topic was chosen for review because it has never been systematically reviewed by ILCOR.
The continuous evidence evaluation process to produce this Consensus on Science with Treatment Recommendations started with an adolopment of a recently published SR. The adolopment process is designed to guide the adaptation of an existing published systematic review. The condition for proceeding with adolopment requires that the original SR is methodologically rigorous, assessed using the AMSTAR 2 checklist. The original SR by Alshaikh et al. (2025) “Intramuscular epinephrine in cardiac arrest: A systematic review” met all criterion.1 Thus, the Pediatric Task Force proceeded with the adolopment.
Systematic Review
Alshaikh et al. Intramuscular epinephrine in cardiac arrest: A systematic review. Resuscitation Plus. 2025;26:101133. doi: https://doi.org/10.1016/j.resplu.2025.1011331
PICOST
The PICOST (Population, Intervention, Control, Outcomes, Study design and Timeframe)
Population: In pediatric patient who suffer a cardiac arrest in any setting
Intervention: did the intramuscular (IM) route of epinephrine administration
Comparison: compared to IV/IO
Outcomes: result in improved patient and/or process outcomes? Patient outcomes included ROSC, survival, and neurologically favourable survival. Process outcomes included administration of epinephrine, time to epinephrine, and accuracy of dosing.
Study Design: Systematic reviews, randomized control trials (RCTs) and non-RCTs (interrupted time series, controlled before-and-after studies, cohort studies) were included. Because we hypothesized that human data would be limited, animal studies were also included but analyzed separately. Simulation studies were included for process outcomes. We included only those with an English abstract. Studies involving neonates and unpublished studies (such as conference abstracts and trial protocols) were excluded. Neonates were excluded due to significant differences in resuscitation steps and medication administration.
Timeframe: All years
Prospero ID: CRD42021259729
The risk of bias was assessed using the Robins-I Tool for non-randomized studies, while the OHAT Risk of Bias Tool was applied to animal studies. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess the certainty of the body of evidence (https://www.gradeworkinggroup.org/).
Consensus on Science
There were eight studies evaluating IM epinephrine for cardiac arrest2-8, including 1 in adult OHCA patients2 and 3 in pediatric animal models5,6,8. The remaining studies were not relevant- one in an overlapping adult OHCA population3, 1 topic review9, and 2 in adult animal models4,7.
The before-after interventional adult OHCA study involved 1,405 adults aged 18 years and over with non-traumatic cardiac arrest from a single EMS system in the USA between 2010 (pre-2019: before) and 2024.2 The patients received a single IM dose while IV or IO was secured, then IV or IO epinephrine every 3-5 minutes. IM epinephrine was associated with improved survival to discharge (11.0% vs 7.0%; aOR 1.73, 95% CI 1.10–2.71) and neurologically favourable survival (9.8% vs 6.2%; aOR, 1.72, 95% CI 1.07–2.76) compared to IV/IO alone. The per-protocol analyses were adjusted for age, sex, bystander CPR, witnessed arrest, interval from emergency call to EMS arrival, public location of the arrest, and initial cardiac rhythm. Two sensitivity analyses were performed to address the fifty-two (3.7%) patients who received IV/IO epinephrine instead of IM epinephrine in the ‘after’ period, first by intention-to-treat and then these patients were excluded. Both sensitivity analyses were consistent for survival and neurologically favourable survival (aOR 2.06 (1.33–3.20) and aOR 2.16 (1.36–3.43) for ITT and aOR 1.91 (1.20–3.03) and 1.95 (1.19–3.17), respectively).
In piglets, Mauch et al. found similar ROSC rates across the IV (8/8), IM (7/8), and control (4/8) groups, where p=0.077 for IV vs control groups.6 In another piglet study of arrest induced by asphyxia, 10/28 piglets had ROSC from CPR alone, prior to the planned epinephrine. The remaining groups became unbalanced following the dropouts. The authors reported the median increases in plasma epinephrine concentration 3 minutes after epinephrine was administered (IV and IM, only) was 138, 134, and 29nM in group IV, IM, and control, respectively.5 O’Reilly et al. reported comparable rates of ROSC and time to ROSC between IM and IV epinephrine in a juvenile piglet model equivalent to a 1-month old human infant.8 Risk of bias for these studies was moderate4 to moderately high5,6. The certainty of evidence for animal studies was low, because even though they were randomized, they were downgraded for important indirectness and risk of bias.
Treatment Recommendations
There is no pediatric evidence to recommend adding intra-arrest intramuscular (IM) epinephrine to standard resuscitation care for cardiac arrest in children.
Justification and Evidence to Decision Framework Highlights
The TF recognized that intramuscular epinephrine is an interesting area of research. In the management of cardiac arrest, earlier epinephrine is associated with improved clinical outcomes.10,11 Meanwhile, administration of epinephrine by IV and IO routes has its challenges.12 IM epinephrine may be a more efficient route of administration of epinephrine but it may also lead to suboptimal effects.13 Adult and animal studies were included in the SR for comprehensiveness but the results of these should be interpreted with caution. The task force explicitly refrained from using adult-derived indirect evidence for many paediatric recommendations because of fundamental differences in arrest aetiology.14 Animal studies often fail to integrate standard of care post-arrest therapies and do not report neurological outcomes.15 In addition, time to drug administration in animals does not reflect the human clinical experience, where epinephrine administration is often delayed compared to animal studies.16
Knowledge Gaps
There are no pediatric studies evaluating intramuscular epinephrine in cardiac arrest. The TF suggests that there is sufficient biological plausibility and equipoise for this therapy to warrant human pediatric trials. Future studies should evaluate IM epinephrine compared to no epinephrine (e.g., in low resourced settings), in addition to IM epinephrine compared to IV/IO epinephrine, in children with cardiac arrest.
There are no dosing studies of IM epinephrine in cardiac arrest. Future studies should evaluate the pharmacokinetic profile of IM epinephrine in cardiac arrest to inform dosing.
There are no safety studies of IM epinephrine in cardiac arrest. There is a potential for harm by detracting from standard of care, and by having 2 different concentrations of epinephrine for one clinical condition (1:1000 for IM epinephrine and 1:10,000 for IV/IO epinephrine).
EtD table: PLS 4090 05 Et D IM Epi
References
References listed alphabetically by first author last name in this citation format (Circulation)
1. Alshaikh R, Sheikh A, Fleming C, Garcia-Bournissen F, Tijssen JA. Intramuscular epinephrine in cardiac arrest: A systematic review. Resusc Plus. 2025;26:101133. doi: 10.1016/j.resplu.2025.101133
2. Palatinus HN, Johnson MA, Wang HE, Hoareau GL, Youngquist ST. Early intramuscular adrenaline administration is associated with improved survival from out-of-hospital cardiac arrest. Resuscitation. 2024;201:110266. doi: 10.1016/j.resuscitation.2024.110266
3. Pugh AE, Stoecklein HH, Tonna JE, Hoareau GL, Johnson MA, Youngquist ST. Intramuscular adrenaline for out-of-hospital cardiac arrest is associated with faster drug delivery: A feasibility study. Resusc Plus. 2021;7:100142. doi: 10.1016/j.resplu.2021.100142
4. Lim D, Lee SH, Kim DH, Kang C, Jeong JH, Lee SB. The effect of high-dose intramuscular epinephrine on the recovery of spontaneous circulation in an asphyxia-induced cardiac arrest rat model. BMC Cardiovasc Disord. 2021;21:113. doi: 10.1186/s12872-021-01917-7
5. Mauch J, Ringer S, Spielmann N, Weiss M. Impact of catecholamines in cardiac arrest due to acute asphyxia--a study in piglets. Paediatr Anaesth. 2014;24:933–939. doi: 10.1111/pan.12457
6. Mauch J, Ringer SK, Spielmann N, Weiss M. Intravenous versus intramuscular epinephrine administration during cardiopulmonary resuscitation - a pilot study in piglets. Paediatr Anaesth. 2013;23:906–912. doi: 10.1111/pan.12149
7. Redding JS, Asuncion JS, Pearson JW. Effective routes of drug administration during cardiac arrest. Anesth Analg. 1967;46:253–258.
8. O'Reilly M, Tijssen JA, Lee TF, Ramsie M, Cheung PY, Schmolzer GM. Intramuscular versus intravenous epinephrine administration in a pediatric porcine model of cardiopulmonary resuscitation. Resusc Plus. 2024;20:100769. doi: 10.1016/j.resplu.2024.100769
9. Williams CA, Fairley HE, Tran QK, Pourmand A. Use of Epinephrine in Cardiac Arrest: Advances and Future Challenges. Medicina (Kaunas). 2024;60. doi: 10.3390/medicina60111904
10. Hansen M, Schmicker RH, Newgard CD, Grunau B, Scheuermeyer F, Cheskes S, Vithalani V, Alnaji F, Rea T, Idris AH, et al. Time to Epinephrine Administration and Survival From Nonshockable Out-of-Hospital Cardiac Arrest Among Children and Adults. Circulation. 2018;137:2032–2040. doi: 10.1161/CIRCULATIONAHA.117.033067
11. Fukuda T, Kondo Y, Hayashida K, Sekiguchi H, Kukita I. Time to epinephrine and survival after paediatric out-of-hospital cardiac arrest. Eur Heart J Cardiovasc Pharmacother. 2018;4:144–151. doi: 10.1093/ehjcvp/pvx023
12. Besserer F, Kawano T, Dirk J, Meckler G, Tijssen JA, DeCaen A, Scheuermeyer F, Beno S, Christenson J, Grunau B, et al. The association of intraosseous vascular access and survival among pediatric patients with out-of-hospital cardiac arrest. Resuscitation. 2021;167:49–57. doi: 10.1016/j.resuscitation.2021.08.005
13. Berkelhamer SK, Vali P, Nair J, Gugino S, Helman J, Koenigsknecht C, Nielsen L, Lakshminrusimha S. Inadequate Bioavailability of Intramuscular Epinephrine in a Neonatal Asphyxia Model. Front Pediatr. 2022;10:828130. doi: 10.3389/fped.2022.828130
14. Scholefield BR, Acworth J, Ng KC, Tiwari LK, Raymond TT, Christoff A, Katzenschlager S, Escalante-Kanashiro R, Bansal A, Topjian A, et al. Pediatric Life Support: 2025 International Liaison Committee on Resuscitation Consensus on Science With Treatment Recommendations. Circulation. 2025;152:S116–S164. doi: 10.1161/CIR.0000000000001362
15. Lind PC, Johannsen CM, Vammen L, Magnussen A, Andersen LW, Granfeldt A. Translation from animal studies of novel pharmacological therapies to clinical trials in cardiac arrest: A systematic review. Resuscitation. 2021;158:258–269. doi: 10.1016/j.resuscitation.2020.10.028
16. Reynolds JC, Rittenberger JC, Menegazzi JJ. Drug administration in animal studies of cardiac arrest does not reflect human clinical experience. Resuscitation. 2007;74:13–26. doi: 10.1016/j.resuscitation.2006.10.032