What is the optimal timing of repeat epinephrine administration in patients with out-of-hospital cardiac arrest (OHCA)?
Date First Published:
July 17, 2026
Last Updated:
July 17, 2026
Report by:
Andy Trieu, Medical Student (Oregon Health & Science University)
Search checked by:
Joshua Lupton, MD and Andrew Lichtenheld, MD, Emergency Medicine Attending Physician
Three-Part Question:
In [adult patients with out-of-hospital cardiac arrest], what is the [optimal timing to deliver subsequent doses of epinephrine] for [mortality and/or neurological outcome benefit] and does this timing change for increased cumulative doses of epinephrine?
Clinical Scenario:
A 58-year-old male suffers a witnessed collapse at home and receives immediate bystander cardiopulmonary resuscitation (CPR). Paramedics arrive 7 minutes after arrest onset; he is found to be in pulseless electrical activity (PEA) at the initial rhythm check and is given epinephrine 1 mg intravenous (IV). He is transported to the emergency department (ED) where resuscitation is continued and on subsequent rhythm checks he remains in PEA. As you consider additional treatments, you wonder what the optimal time interval is for additional doses of epinephrine.
Search Strategy:
A PubMed‑only search was performed using free‑text terms relating to out-of-hospital cardiac arrest, epinephrine, and terms related to timing, dosing, or interval of given epinephrine. All studies were screened by title and abstract.
Search Details:
("cardiac arrest" [tiab]) AND (epinephrine [ti] OR adrenaline [ti]) AND (time [tiab] OR timing [tiab] OR interval [tiab]) AND (mortality OR surviv* OR "return of spontaneous circulation") OR ("epinephrine dosing interval" [tiab]) OR ("epinephrine administration interval" [tiab]).
Outcome:
From over 188 studies on PubMed, 6 high fidelity studies were identified which were all retrospective cohort studies/retrospective analyses.
Relevant Paper(s):
| Study Title | Patient Group | Study type (level of evidence) | Outcomes | Key results | Study Weaknesses |
|---|---|---|---|---|---|
| How Epinephrine Administration Interval Impacts the Outcomes of Resuscitation during Adult Cardiac Arrest: A Systematic Review and Meta-Analysis Wongtanasarasin, W., Srisurapanont, K., and Nishijima, D.K. January 6th, 2023. | Adults experiencing OHCA/IHCA who received both CPR and epinephrine. Enrolled a total of 47,783 participants throughout all three studies. | Favorable neurological status at hospital discharge. Rates of ROSC, survival to hospital admission, and survival to hospital discharge. | There was no statistically significant difference between current standard 3-5 minute interval and alternate proposed frequencies of 5 minutes for both (1) favorable neurological outcome and (2) survival to hospital discharge. | Review limited to retrospective studies. Heterogenous patient population with both in and out of hospital cardiac arrest. | |
| Epinephrine dosing interval and neurological outcome in out-of-hospital cardiac arrest Fukuda, T., Kaneshima, H., Matsudaira, A., et al. June 12th, 2021. | 10,965 adult patients experiencing OHCA who received at least two prehospital doses of epinephrine and achieved ROSC. | 1 month neurologically favorable survival and overall survival at 1 month. | Relative to standard 3-5 minute interval reference group, neither short interval (5 minute) showed statistically significant differences in neurologically favorable survival and 1-month overall survival. | Retrospective with significant proportion of missing data, exclusion of patients without ROSC is a significant potential source of bias. | |
| Adrenaline (epinephrine) dosing period and survival after in-hospital cardiac arrest: a retrospective review of prospectively collected data Warren, S.A., Huszti, E., Bradley, S.M., et al. November 16th, 2013. | 20,909 adult patients who experienced IHCA, received CPR, and received >= 2 doses of epinephrine. | Survival to hospital discharge and ROSC sustained for >=20 minutes, sub grouped by initial cardiac rhythm (shockable vs. non-shockable). | Patients who received less frequent epinephrine administrations had better survival in hospital discharge. Patients who received interval 6 to <7 min/dose had an odds ratio of 1.41 (95% CI: 1.12-1.78) which uptrended with those receiving epinephrine at an interval 9-10 min/dose had an odds ratio of 2.17 (95% CI: 1.62-2.92). | No logged timestamps for individual doses were seen, and intervals were calculated by dividing total CPR duration by number of administrated doses. Highly susceptible to unmeasured confounding bias. Unclear generalizability to OHCA. | |
| Pharmacokinetics of Epinephrine During Cardiac Arrest: A Pilot Study Heradstveit, B.E., Sunde, G., Asbjornsen, H., et al. October 27th, 2023. | 9 patients with out-of-hospital cardiac arrest | Plasma elimination half time of epinephrine following measurement of peak concentration during active CPR | Modeled epinephrine half-life when administered through IV was 2.6 minutes (95% CI: 1.9 to 4.4 minutes. Persistently elevated levels in all subjects at the 5-minute mark. | Limited study with small sample size and missing data. | |
| The Association of the Average Epinephrine Dosing Interval and Survival With Favorable Neurologic Status at Hospital Discharge in Out-of-Hospital Cardiac Arrest Grunau, B., Kawano, T., Scheuermeyer, F.X., et al. December 2019. | 15,909 patients who experienced a non-traumatic OHCA and received 2 or more doses of epinephrine during pre-hospital resuscitation | Survival with favorable neurologic status at hospital discharge | A dose interval of < 3 minutes was associated with survival and survival with favorable neurological function as compared to longer dose intervals. This association was maintained across subgroups. | Retrospective study with susceptibility to unmeasured confounding. Epinephrine dosing intervals were averaged over the course of the resuscitation rather than directly measured. |
|
| The influences of adrenaline dosing frequency and dosage on outcomes of adult in-hospital cardiac arrest: A retrospective cohort study Wang, C., Huang, C., Chang, W., et al. June 2016. | 896 adult patients who experienced an IHCA with chest compressions lasting >=2 minutes. | Survival to hospital discharge, sustained ROSC, survival >24 hours, and favorable neurological outcome at hospital discharge. | Higher average adrenaline dosing frequency was associated with significantly worse outcomes with survival to discharge (OR: 0.05 (95% CI: 0.01–0.23) and favorable neurological outcome (OR: 0.02 (95% CI: 0.002–0.16). | Retrospective study with susceptibility to unmeasured confounding. Epinephrine dosing intervals were averaged over the course of the resuscitation rather than directly measured. |
Author Commentary:
Our results are summarized in Table 1. We identified several large retrospective observational studies and meta-analyses investigating this question. Overall, the available evidence is mixed with some studies identifying an association between improved outcomes and administration intervals shorter than the standard 3-5 minute interval, some finding an association between improved outcomes with longer than standard dose interval, and others finding no difference. One large retrospective cohort did demonstrate a significant association between shorter epinephrine and improved outcomes while in contrast, studies limited to patients with in-hospital cardiac arrest (IHCA) also demonstrated mixed results with longer dosing intervals. This apparent contradiction may reflect meaningful differences in the physiology of OHCA vs IHCA, differences in systems of care, or may simply be due to unmeasured confounding.
These findings should be interpreted cautiously because many studies contain important methodological limitations that reduce both interpretability and generalizability. Specifically, all of the available evidence is retrospective and at high risk of confounding and bias. Several studies lacked precise timing data for epinephrine administration and instead relied on averaged dosing intervals, introducing the potential for resuscitation time bias.
These findings should be interpreted cautiously because many studies contain important methodological limitations that reduce both interpretability and generalizability. Specifically, all of the available evidence is retrospective and at high risk of confounding and bias. Several studies lacked precise timing data for epinephrine administration and instead relied on averaged dosing intervals, introducing the potential for resuscitation time bias.
Bottom Line:
In patients with OHCA, there is insufficient evidence to recommend epinephrine administration intervals shorter or longer than the standard recommendation of 3-5 minutes. Future research should include prospective and randomized trial data to limit the effects of confounding and resuscitation time bias and to further investigate the impact of subsequent doses of epinephrine on OHCA patient outcomes.
References:
1. Wongtanasarasin, W., Srisurapanont, K., & Nishijima, D. K. (2023). How Epinephrine Administration Interval Impacts the Outcomes of Resuscitation during Adult Cardiac Arrest: A Systematic Review and Meta-Analysis. Journal of clinical medicine, 12(2), 481. https://doi.org/10.3390/jcm12020481
2. Fukuda, T., Kaneshima, H., Matsudaira, A., Chinen, T., Sekiguchi, H., Ohashi-Fukuda, N., Inokuchi, R., & Kukita, I. (2022). Epinephrine dosing interval and neurological outcome in out-of-hospital cardiac arrest. Perfusion, 37(8), 835–846. https://doi.org/10.1177/02676591211025163
3. Warren, S. A., Huszti, E., Bradley, S. M., Chan, P. S., Bryson, C. L., Fitzpatrick, A. L., Nichol, G., & American Heart Association's Get With the Guidelines-Resuscitation (National Registry of CPR) Investigators (2014). Adrenaline (epinephrine) dosing period and survival after in-hospital cardiac arrest: a retrospective review of prospectively collected data. Resuscitation, 85(3), 350–358. https://doi.org/10.1016/j.resuscitation.2013.10.004
4. Heradstveit, B. E., Sunde, G. A., Asbjørnsen, H., Aalvik, R., Wentzel-Larsen, T., & Heltne, J. K. (2023). Pharmacokinetics of Epinephrine During Cardiac Arrest: A Pilot Study. Resuscitation, 110025. Advance online publication. https://doi.org/10.1016/j.resuscitation.2023.110025
5. Grunau, B., Kawano, T., Scheuermeyer, F. X., Drennan, I., Fordyce, C. B., van Diepen, S., Reynolds, J., Lin, S., & Christenson, J. (2019). The Association of the Average Epinephrine Dosing Interval and Survival With Favorable Neurologic Status at Hospital Discharge in Out-of-Hospital Cardiac Arrest. Annals of emergency medicine, 74(6), 797–806. https://doi.org/10.1016/j.annemergmed.2019.04.031
6. Wang, C. H., Huang, C. H., Chang, W. T., Tsai, M. S., Yu, P. H., Wu, Y. W., Hung, K. Y., & Chen, W. J. (2016). The influences of adrenaline dosing frequency and dosage on outcomes of adult in-hospital cardiac arrest: A retrospective cohort study. Resuscitation, 103, 125–130. https://doi.org/10.1016/j.resuscitation.2015.12.008
References:
1. Wongtanasarasin, W., Srisurapanont, K., & Nishijima, D. K. (2023). How Epinephrine Administration Interval Impacts the Outcomes of Resuscitation during Adult Cardiac Arrest: A Systematic Review and Meta-Analysis. Journal of clinical medicine, 12(2), 481. https://doi.org/10.3390/jcm12020481
2. Fukuda, T., Kaneshima, H., Matsudaira, A., Chinen, T., Sekiguchi, H., Ohashi-Fukuda, N., Inokuchi, R., & Kukita, I. (2022). Epinephrine dosing interval and neurological outcome in out-of-hospital cardiac arrest. Perfusion, 37(8), 835–846. https://doi.org/10.1177/02676591211025163
3. Warren, S. A., Huszti, E., Bradley, S. M., Chan, P. S., Bryson, C. L., Fitzpatrick, A. L., Nichol, G., & American Heart Association's Get With the Guidelines-Resuscitation (National Registry of CPR) Investigators (2014). Adrenaline (epinephrine) dosing period and survival after in-hospital cardiac arrest: a retrospective review of prospectively collected data. Resuscitation, 85(3), 350–358. https://doi.org/10.1016/j.resuscitation.2013.10.004
4. Heradstveit, B. E., Sunde, G. A., Asbjørnsen, H., Aalvik, R., Wentzel-Larsen, T., & Heltne, J. K. (2023). Pharmacokinetics of Epinephrine During Cardiac Arrest: A Pilot Study. Resuscitation, 110025. Advance online publication. https://doi.org/10.1016/j.resuscitation.2023.110025
5. Grunau, B., Kawano, T., Scheuermeyer, F. X., Drennan, I., Fordyce, C. B., van Diepen, S., Reynolds, J., Lin, S., & Christenson, J. (2019). The Association of the Average Epinephrine Dosing Interval and Survival With Favorable Neurologic Status at Hospital Discharge in Out-of-Hospital Cardiac Arrest. Annals of emergency medicine, 74(6), 797–806. https://doi.org/10.1016/j.annemergmed.2019.04.031
6. Wang, C. H., Huang, C. H., Chang, W. T., Tsai, M. S., Yu, P. H., Wu, Y. W., Hung, K. Y., & Chen, W. J. (2016). The influences of adrenaline dosing frequency and dosage on outcomes of adult in-hospital cardiac arrest: A retrospective cohort study. Resuscitation, 103, 125–130. https://doi.org/10.1016/j.resuscitation.2015.12.008
Level of Evidence:
Level 2: Studies considered were neither 1 or 3
References:
- Wongtanasarasin, W., Srisurapanont, K., and Nishijima, D.K.. How Epinephrine Administration Interval Impacts the Outcomes of Resuscitation during Adult Cardiac Arrest: A Systematic Review and Meta-Analysis
- Fukuda, T., Kaneshima, H., Matsudaira, A., et al.. Epinephrine dosing interval and neurological outcome in out-of-hospital cardiac arrest
- Warren, S.A., Huszti, E., Bradley, S.M., et al.. Adrenaline (epinephrine) dosing period and survival after in-hospital cardiac arrest: a retrospective review of prospectively collected data
- Heradstveit, B.E., Sunde, G., Asbjornsen, H., et al.. Pharmacokinetics of Epinephrine During Cardiac Arrest: A Pilot Study
- Grunau, B., Kawano, T., Scheuermeyer, F.X., et al.. The Association of the Average Epinephrine Dosing Interval and Survival With Favorable Neurologic Status at Hospital Discharge in Out-of-Hospital Cardiac Arrest
- Wang, C., Huang, C., Chang, W., et al.. The influences of adrenaline dosing frequency and dosage on outcomes of adult in-hospital cardiac arrest: A retrospective cohort study