Association Between Epinephrine Administration Timing and Outcomes in Adult Out-of-Hospital Cardiac Arrest: A Systematic Review and Dose–Response Meta-Analysis

Background and Objectives: The optimal timing of epinephrine in out-of-hospital cardiac arrest (OHCA), and whether it differs by initial rhythm, is uncertain and rests almost entirely on confounded observational data. We synthesized this evidence, noting each study’s time origin. Materials and Methods: PubMed, Embase, and the Cochrane Central Register of Controlled Trials were searched from inception to 15 March 2026 for studies relating epinephrine timing to outcome in adult non-traumatic OHCA. Per-minute, categorical and dose–response random-effects meta-analyses were performed by rhythm, with ROBINS-I and GRADE appraisal. Results: Twenty-five studies were included. For non-shockable rhythm, each 1 min delay was associated with 4.2% lower survival odds (OR 0.958, 95% CI 0.949–0.968; k = 4, I2 = 0%), unchanged when restricted to studies sharing one time origin. Early epinephrine was associated with favorable neurological outcome (k = 9, OR 2.76, 95% CI 2.06–3.71; I2 = 88%), though the prediction interval crossed the null (0.98–7.79), and the shockable-versus-non-shockable difference did not persist under a common time origin (p = 0.46). Several estimates were biologically implausible (adjusted OR 5.92), indicating substantial residual confounding; GRADE certainty was very low. Conclusions: The per-minute survival gradient in non-shockable rhythm was the most internally consistent estimate—internally consistent rather than reliable, since studies sharing one structural bias can agree without being valid. Every estimate is almost certainly inflated by resuscitation time bias. The evidence supports minimizing avoidable delay but cannot define a timing threshold; trials randomizing timing and individual patient data meta-analyses with harmonized time definitions are needed.