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
CoSTR Citation
Granfeldt A., Soar J., Grunau B., Couper K. on behalf of the Advanced Life Support Task Force. Intramuscular Epinephrine for Cardiac Arrest: Consensus on Science with Treatment Recommendations 5. 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. It was prioritized by the ALS Task Force as there is great interest in the topic after a recent publication.
The continuous evidence evaluation process to produce this Consensus on Science with Treatment Recommendations started with an adolopment of a recently published SR.1 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 criteria. Thus, the Advanced Life Support Task Force proceeded with the adolopment.1
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.2025.101133
PICOST
The PICOST (Population, Intervention, Control, Outcomes, Study design and Timeframe)
Population: Adult patients who suffer a cardiac arrest in any setting
Intervention: Intramuscular (IM) route of epinephrine administration
Comparison: IV/IO epinephrine administration
Outcomes: Clinical outcomes including survival/survival with a favorable neurological outcome at hospital discharge/28 days/30 days/1 month, survival/survival with a favorable neurological outcome after hospital discharge/28 days/30 days/1 month (e.g., 90 days, 180 days, and 1 year), health-related quality of life were considered critical outcomes. Return of spontaneous circulation and exploratory outcomes including administration of epinephrine, time to epinephrine, accuracy of dosing, and cost-effectiveness were all considered important outcomes.
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 expected human data would be limited, animal studies were also included but analyzed separately. Simulation studies were included for process outcomes. Only those with an English abstract were included. Unpublished studies (such as conference abstracts and trial protocols) were excluded.
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 arrest. Of these, two were human observational studies.13,14 Five included studies were in animal models of cardiac arrest.9-12,15 The final included study was a systematic review.18
Clinical data
Two human studies were conducted in adults with OHCA. Both of these studies were conducted within a single EMS system, with the larger study covering all years included in the smaller study plus additional years.13,14 According to the study authors, the larger study included all patients from the smaller study. Therefore, the systematic review by Alshaikh et al. utilized in this adolopment only reported on the larger study.1
The clinical study was a single-center study comparing patient outcomes before and after implementation of an early, first-dose IM epinephrine EMS protocol for adult OHCA patients. In both groups epinephrine 1 mg IV or IO was provided every 3–5 min once vascular access was established. The pre-intervention period took place between January 2010 and October 2019. The post-intervention period was between November 2019 and May 2024. The study included 1405 patients with OHCA.
The risk of bias was assessed as serious by the ALS Task Force due to the before-and-after study design which introduced serious risk of confounding.16
For the explanatory outcome of time from EMS arrival to the first epinephrine dose one study including 1405 adults found that time was 4.3 min (IQR 3.0–6.0) with IM-first epinephrine protocol (IM 5 mg followed by standard IV/IO dosing) compared to 7.8 min (IQR 5.8–10.4) in the standard IV/IO-only group.
For the critical outcome of survival to hospital admission, one study including 1405 adults provided very low-certainty evidence (downgraded for risk of bias and imprecision) for benefit with a IM-first epinephrine protocol (IM 5 mg followed by standard IV/IO dosing) compared to standard IV/IO-only (Adjusted odds Ratio [OR] 1.37, 95% CI [1.06–1.77]).
For the critical outcome of survival to discharge, one study of 1405 adults provided very low-certainty evidence (downgraded for risk of bias and imprecision) for benefit with a IM-first epinephrine protocol (IM 5 mg followed by standard IV/IO dosing) compared to standard IV/IO-only (Adjusted odds Ratio [OR] 1.73, 95% CI [1.10–2.71]).
For the critical outcome of favorable neurologic outcome at discharge, one study of 1405 patients provided very low-certainty evidence (downgraded for risk of bias and imprecision) for benefit with a IM-first epinephrine protocol (IM 5 mg followed by standard IV/IO dosing) compared to standard IV/IO-only (Adjusted odds Ratio [OR] 1.72, 95% CI [1.07–2.76]).
Animal Data
The animal studies were heterogenous in methodology and interventions, precluding meaningful synthesis.9-12,15 The studies primarily compared the IM and IV routes directly and did not address the clinically relevant question of whether early IM epinephrine is beneficial when added to the standard protocol of IV epinephrine. Due to these concerns, the animal data included in the systematic review were not considered when devising treatment recommendations.
Grade Table: ALS 3212 Table GRADE
Treatment Recommendations
There is insufficient evidence to recommend adding intra-arrest intramuscular epinephrine to standard resuscitation care for cardiac arrest. (weak recommendation, very-low certainty of evidence)
Justification and Evidence to Decision Framework Highlights
The TF recognized that intramuscular epinephrine is an interesting area of research and has gained increased attention. It is a relatively inexpensive intervention that can be delivered by a variety of first responders and enable earlier administration of epinephrine.5,17 In the management of cardiac arrest, earlier epinephrine is associated with improved clinical outcomes7, however these studies are confounded by resuscitation time bias.2 Additionally, in a secondary analysis of the PARAMEDIC2 study, shorter time to treatment, whether treatment was adrenaline or placebo, was also associated with improved outcome.
The key historical concern regarding IM epinephrine has been uncertainty regarding its absorption in cardiac arrest.4,8 The limited available data suggest that IM epinephrine may be associated with earlier administration, but the clinical effect on outcomes remains uncertain. However, the Task Force felt that it would be premature to recommend the use of IM epinephrine at this stage given that evidence is limited to a single observational study and extrapolation of potential benefit from studies exploring the association between time to drug administration and clinical outcome. The task force highlighted the need for randomized controlled trials to evaluate IM epinephrine in cardiac arrest, with a focus on shortening the time to first dose by administering epinephrine IM compared with IV/IO. The ALS TF considered that some patients receiving CPR may have been in a low flow state and they may be a group that potentially would benefit from early IM epinephrine.
Only one observational study was identified that evaluated a first-dose intramuscular (IM) epinephrine protocol for adult out-of-hospital cardiac arrest (OHCA) patients, followed by advanced life support and intravenous/intraosseous (IV/IO) epinephrine administration. Consequently, the treatment recommendation does not extend to settings where subsequent advanced life support and IV/IO epinephrine administration are not available. The task force discussed the possibility that IM epinephrine could be useful in such settings, but the evidence is too sparse (no human data comparing IM with IV/IO) to support a recommendation and the question was not directly assessed by the PICO in the review utilized in this adolopment. In addition, the task force discussed whether focus on IM epinephrine could result in delay of standard CPR.
Finally, the taskforce discussed whether the slower absorption of IM epinephrine compared to IV could be beneficial in the early post-resuscitation phase where hypotension is common and associated with poor outcomes, however this remains unknown.
The relevance of the current topic is unknown for patients with in-hospital cardiac arrest where time to drug administration is shorter due to the high prevalence of pre-existing vascular access and earlier initiation of advanced life support.3
Animal studies were included in the systematic review but the results should be interpreted with caution due to risk of bias and generalizability to humans. 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.
EtD Table: ALS 3212 Table Et D
Knowledge Gaps
There are no dose-response studies or pharmacokinetic studies on the use of IM epinephrine in cardiac arrest in humans. The pharmacokinetic profile could be markedly different from studies in healthy volunteers where only small doses of epinephrine have been tested.6 Future studies should try to evaluate the pharmacokinetic profile of IM epinephrine in cardiac arrest to inform dosing for clinical studies, even though pharmacokinetic studies in this context are likely to be challenging and may not be feasible.
There are no human randomized controlled trials evaluating the use of a first-dose intramuscular (IM) epinephrine protocol for adult out-of-hospital cardiac arrest (OHCA) patients, followed by advanced life support and intravenous/intraosseous (IV/IO) epinephrine administration.
Furthermore, no studies evaluated whether IM epinephrine is superior to no epinephrine in systems where access to IV/IO epinephrine is unavailable or will be substantially delayed.
Furthermore whether alternative ways of administration (intranasal, or sublingual) provides any benefit is unknown.
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. Resuscitation Plus. 2025;26:101133. doi: https://doi.org/10.1016/j.resplu.2025.101133
2. Andersen LW, Grossestreuer AV, Donnino MW. "Resuscitation time bias"-A unique challenge for observational cardiac arrest research. Resuscitation. 2018;125:79-82. doi: 10.1016/j.resuscitation.2018.02.006
3. Andersen LW, Isbye D, Kjærgaard J, Kristensen CM, Darling S, Zwisler ST, Fisker S, Schmidt JC, Kirkegaard H, Grejs AM, et al. Effect of Vasopressin and Methylprednisolone vs Placebo on Return of Spontaneous Circulation in Patients With In-Hospital Cardiac Arrest: A Randomized Clinical Trial. Jama. 2021;326:1586-1594. doi: 10.1001/jama.2021.16628
4. 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. Frontiers in pediatrics. 2022;10:828130. doi: 10.3389/fped.2022.828130
5. Couper K, Ji C, Deakin CD, Fothergill RT, Nolan JP, Long JB, Mason JM, Michelet F, Norman C, Nwankwo H, et al. A Randomized Trial of Drug Route in Out-of-Hospital Cardiac Arrest. N Engl J Med. 2024. doi: 10.1056/NEJMoa2407780
6. Greenhawt M, Lieberman J, Blaiss M, Bernstein DI, Oppenheimer J, DuBuske L, Fleischer D, Dworaczyk DA. Pharmacokinetic and Pharmacodynamic Profile of Epinephrine Nasal Spray Versus Intramuscular Epinephrine Autoinjector in Healthy Adults. J Allergy Clin Immunol Pract. 2024;12:3274-3282 e3272. doi: 10.1016/j.jaip.2024.10.006
7. 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
8. Kjaersgaard L, Norholt C, Moller KF, Nyengaard MR, Lund MH, Vilain S, Bojsen DB, Vammen L, Andersen LW, Granfeldt A. Intramuscular adrenaline to improve outcomes following cardiac arrest - An experimental porcine study. Resuscitation. 2025;215:110754. doi: 10.1016/j.resuscitation.2025.110754
9. 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
10. 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
11. 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
12. 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
13. 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
14. 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. Resuscitation Plus. 2021;7:100142. doi: https://doi.org/10.1016/j.resplu.2021.100142
15. Redding JS, Asuncion JS, Pearson JW. Effective routes of drug administration during cardiac arrest. Anesth Analg. 1967;46:253-258.
16. Sterne JA, Hernan MA, Reeves BC, Savovic J, Berkman ND, Viswanathan M, Henry D, Altman DG, Ansari MT, Boutron I, et al. ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ. 2016;355:i4919. doi: 10.1136/bmj.i4919
17. Vallentin MF, Granfeldt A, Klitgaard TL, Mikkelsen S, Folke F, Christensen HC, Povlsen AL, Petersen AH, Winther S, Frilund LW, et al. Intraosseous or Intravenous Vascular Access for Out-of-Hospital Cardiac Arrest. N Engl J Med. 2024. doi: 10.1056/NEJMoa2407616
18. 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