Highlights
– Multiple recent multicenter analyses show early epinephrine in pediatric in‑hospital cardiac arrest (IHCA) is common and associated with higher rates of return of spontaneous circulation (ROSC) and shorter CPR duration, but not consistently with improved survival to discharge or favorable neurologic outcome.
– Nearly half of children with initially shockable IHCA received epinephrine before or during the same minute as first defibrillation; after adjustment this timing was not statistically associated with survival.
– Epinephrine dosing intervals <3 minutes improved sustained ROSC and shortened CPR duration, but did not significantly change neurologic survival in adjusted analyses.
Background
Pediatric in‑hospital cardiac arrest (IHCA) remains a high‑risk event with substantial mortality and risk of new morbidity among survivors. The balance of interventions that improve immediate hemodynamics (for example, epinephrine to augment coronary and cerebral perfusion pressure) versus those that provide definitive correction of arrhythmia (defibrillation for ventricular fibrillation/pulseless ventricular tachycardia) is central to best practice. International and national resuscitation guidelines provide time‑based recommendations for drug administration and defibrillation, but pediatric data have historically been sparse. Several large registry‑based and multicenter secondary analyses published in 2024–2025 begin to clarify associations between epinephrine timing/dosing and outcomes in pediatric IHCA.
Study Designs and Populations
1) Epinephrine Before Defibrillation in Children With Initially Shockable IHCA (Swanson et al., Crit Care Med 2025)
Retrospective cohort analysis using American Heart Association Get With The Guidelines‑Resuscitation Registry (2000–2020). Included children (<18 years) with index IHCA and an initial shockable rhythm (ventricular fibrillation or pulseless VT) who received at least one defibrillation attempt. Primary exposure was epinephrine given before or during the same minute as first defibrillation. Outcomes: survival to hospital discharge (primary), ROSC ≥20 minutes, and survival with favorable neurologic outcome. Propensity‑score matching with exact matching on time to defibrillation categories was used to adjust for confounding.
2) Association of Early Epinephrine with Hemodynamics and Outcome (Siems et al., Ann Am Thorac Soc 2025; ICU‑RESUS secondary analysis)
Secondary analysis of the ICU‑RESUS trial database (multicenter, cluster‑randomized QI trial). Population: children with pulseless nonshockable IHCA. Exposure: early epinephrine (≤2 minutes) versus later (>2 minutes) bolus administration. Primary outcome: survival to discharge; secondary outcomes included ROSC, functional outcomes (Functional Status Scale, FSS), new morbidity, and invasively measured blood pressure during CPR.
3) Epinephrine Dosing Intervals Are Associated With Pediatric IHCA Outcomes (Kienzle et al., Crit Care Med 2024)
Secondary analysis from ICU‑RESUS across 18 PICUs/CICUs. Included patients receiving ≥2 doses of epinephrine and excluded ECPR and doses with intervals >8 minutes. Primary exposure: epinephrine dosing interval <3 minutes versus ≥3 minutes. Primary outcome: survival to discharge with favorable neurologic status (Pediatric Cerebral Performance Category). Secondary outcomes: ROSC and CPR duration.
4) Early Bolus Epinephrine for Bradycardia with Poor Perfusion (O’Halloran et al., Crit Care 2024)
ICU‑RESUS derived cohort focusing on bradycardia with poor perfusion events. Compared early epinephrine administration versus later. Outcomes included survival to discharge, favorable neurologic outcome, and invasive BP waveform characterization during CPR.
Key Findings
Epinephrine timing relative to defibrillation (Swanson et al.)
Among 492 pediatric IHCA events with initial shockable rhythm, median age 7 years, 71% occurred in the ICU. Overall, 47% received epinephrine before or during the same minute as first defibrillation (29% before; 18% same minute). Unadjusted outcomes favored the non‑epinephrine‑before‑defibrillation group: survival to discharge 51.2% vs 37.1%, ROSC 84.6% vs 74.6%, favorable neurologic outcome 40.4% vs 22.1%. However, after propensity‑score matching (with exact matching on time to defibrillation category), epinephrine before or same‑minute as defibrillation was not significantly associated with hospital survival (OR 0.84; 95% CI 0.46–1.56), ROSC (OR 0.97; 95% CI 0.48–1.96), or favorable neurologic outcome (OR 0.52; 95% CI 0.27–1.00). Interpretation: although numerically lower survival in the epinephrine first group, adjusted analyses did not confirm a statistically significant harmful effect.
Early epinephrine (≤2 minutes) in pulseless, nonshockable rhythms (Siems et al.)
Among 352 CPR events, early epinephrine was common (78% received ≤2 minutes), median time 1.0 minute. Survival to discharge was similar between early and later epinephrine groups. However, early epinephrine was associated with higher ROSC, better functional outcomes (improved FSS change from baseline, lower total FSS at discharge), and lower rates of new morbidity. The probability of ROSC and survival with favorable neurologic outcome decreased progressively for each minute of delay in epinephrine administration. Importantly, invasively measured systolic and diastolic blood pressure targets during the first 10 minutes of CPR did not differ by timing group, suggesting benefit was not captured by simple BP metrics recorded early in CPR.
Epinephrine dosing interval and outcomes (Kienzle et al.)
Among 382 patients receiving ≥2 epinephrine doses, dosing intervals <3 minutes (vs ≥3 minutes) were not associated with improved survival with favorable neurologic outcome after adjustment (adjusted RR 1.10; 95% CI 0.84–1.46). However, dosing <3 minutes was associated with higher sustained ROSC (aRR 1.21; 95% CI 1.07–1.37) and significantly shorter CPR duration (adjusted reduction ~9.5 minutes). This suggests more frequent dosing promotes earlier ROSC and shorter resuscitation, but translation into improved survival/neurologic outcome remains uncertain.
Bradycardia with poor perfusion subgroup (O’Halloran et al.)
Of 452 subjects, 71% received early epinephrine. The early group had higher pre‑arrest severity and inotrope scores. Early epinephrine was not associated with survival to discharge (aRR 0.97; 95% CI 0.82–1.14) or survival with favorable neurologic outcome (aRR 0.99; 95% CI 0.82–1.18). Analysis of invasive waveforms showed many events had brief pulselessness early in CPR: 46% by 2 minutes and 54% by 3 minutes, and ROSC varied by physiologic trajectory (highest when bradycardic poor perfusion never progressed to pulselessness). These data highlight heterogeneity and the dynamic nature of pediatric CPR physiology.
Comparative Interpretation and Mechanistic Considerations
Across these large pediatric cohorts, two consistent signals emerge: earlier epinephrine administration and shorter dosing intervals are associated with higher rates of ROSC and shorter CPR duration. However, associations with survival to discharge and favorable neurologic outcome are inconsistent and, when adjusted for confounders, generally not statistically significant.
Biologic plausibility supports epinephrine for improving coronary and cerebral perfusion pressure during low‑flow states, thereby increasing the chance of ROSC. Earlier administration could avert progression to prolonged ischemia and limit organ injury, potentially translating into better function among survivors — a signal observed in improved FSS in the ICU‑RESUS secondary analysis. At the same time, epinephrine’s alpha‑adrenergic vasoconstriction may reduce microcirculatory flow or exacerbate post‑resuscitation myocardial dysfunction, possibly offsetting survival benefits. The absence of clear survival improvement may reflect competing physiologic effects, differences in underlying etiologies, timing and quality of CPR, and residual confounding in observational analyses.
Clinical and Guideline Implications
Current resuscitation guidance (AHA pediatric BLS/ALS) prioritizes rapid identification and treatment of reversible causes, early chest compressions, timely defibrillation for shockable rhythms, and early administration of epinephrine for nonshockable pulseless arrests. These new data support clinical emphasis on rapid epinephrine for pulseless nonshockable arrests and suggest that relatively short dosing intervals (<3 minutes) may improve ROSC and shorten CPR duration. For initially shockable arrests, the practice of administering epinephrine before defibrillation remains common despite guideline-recommended immediate defibrillation; adjusted analyses do not demonstrate a clear survival harm but the data do not support routine delay of defibrillation in favor of drug delivery.
Limitations and Caveats
All reported studies are observational or secondary analyses of pragmatic trials and therefore subject to residual confounding, confounding by indication, and documentation timing granularity. Key limitations include potential misclassification of exact timing (clock synchronization, minute-level recording), selection bias, heterogeneity in prearrest conditions, variable CPR quality, and differences in post‑resuscitation care. Some subgroups (e.g., surgical cardiac vs medical patients) may respond differently. Finally, improved ROSC is an important outcome, but survival with good neurologic function remains the ultimate patient‑centered goal; available studies are underpowered or confounded to definitively show improved neurologic survival with earlier epinephrine or shorter dosing intervals.
Research and Practice Gaps
Key gaps include the need for prospective, ideally randomized or cluster-randomized, evaluations of epinephrine timing and dosing interval strategies with standardized CPR quality metrics and granular physiologic monitoring. Studies should stratify by arrest etiology, location, and patient age/weight, and prioritize functional neurologic outcomes. Investigations into the microcirculatory and myocardial effects of epinephrine during pediatric CPR and into adjuncts (vasopressin, ECMO‑CPR timing) could clarify mechanistic tradeoffs.
Conclusions
Recent high‑quality registry and multicenter analyses show that early epinephrine administration in pediatric IHCA is common and associated with higher ROSC rates and shorter CPR duration; dosing intervals <3 minutes similarly favor ROSC. However, consistent and independent improvement in survival to discharge and favorable neurologic outcome has not been demonstrated after adjustment. These data support adherence to rapid epinephrine for nonshockable pulseless arrests and reinforce that defibrillation should not be deferred in initial shockable rhythms. Clinicians should continue to emphasize high‑quality CPR, timely defibrillation for shockable rhythms, and rapid vascular access/drug delivery when indicated, while the field pursues prospective studies to define optimal epinephrine strategies that maximize meaningful survival.
Funding and ClinicalTrials.gov
Primary cited studies include secondary analyses of ICU‑RESUS (clinicaltrials.gov NCT02837497). Funding sources are reported within the cited papers; readers should consult original publications for full funding disclosures.
References
1. Swanson MB, Lasa JJ, Chan PS, et al. Epinephrine Before Defibrillation in Children With Initially Shockable In-Hospital Cardiac Arrest. Crit Care Med. 2025 Oct 1;53(10):e2005-e2015. doi:10.1097/CCM.0000000000006804. PMID: 40736349.
2. Siems A, Naim MY, Berg RA, et al. Association of Early Epinephrine with Hemodynamics and Outcome in Pediatric In-Hospital Cardiac Arrest: A Secondary Analysis of ICU-RESUS. Ann Am Thorac Soc. 2025 Sep;22(9):1361-1371. doi:10.1513/AnnalsATS.202408-825OC. PMID: 40466056; PMCID: PMC12416153.
3. Kienzle MF, Morgan RW, Reeder RW, et al.; Oxy‑PICU Investigators. Epinephrine Dosing Intervals Are Associated With Pediatric In-Hospital Cardiac Arrest Outcomes: A Multicenter Study. Crit Care Med. 2024 Sep 1;52(9):1344-1355. doi:10.1097/CCM.0000000000006334. PMID: 38833560; PMCID: PMC11326980.
4. O’Halloran AJ, Reeder RW, Berg RA, et al. Early bolus epinephrine administration during pediatric cardiopulmonary resuscitation for bradycardia with poor perfusion: an ICU‑resuscitation study. Crit Care. 2024 Jul 16;28(1):242. doi:10.1186/s13054-024-05018-7. PMID: 39010134; PMCID: PMC11251231.
5. American Heart Association. Highlights of the 2020 AHA Guidelines for CPR and Emergency Cardiovascular Care. Pediatrics and Advanced Life Support sections. (For guideline context on pediatric resuscitation recommendations.)
