Critical Appraisal on “Single Dose Epinephrine Protocol Is Associated With Improved Survival of Older Adults With Out‐of‐Hospital Cardiac Arrest”

We read with great interest the study by Ashburn and colleagues [1], examining the effect of a single-dose epinephrine protocol (SDEP) on survival after out-of-hospital cardiac arrest (OHCA) across distinct age groups. The authors should be commended for addressing a clinically urgent question, given the persistently poor survival of older adults with OHCA and the ongoing uncertainty regarding epinephrine dosing strategies. The finding that SDEP was associated with improved survival among older adults is clinically meaningful, particularly in light of the longstanding concern about the adverse cardiovascular effects of repeated epinephrine dosing in this population. By conducting a multicounty implementation study with adjustments for key resuscitation covariates, the authors provide evidence that directly informs protocol design for emergency medical services (EMS) systems. However, certain aspects of the statistical framework raise questions about its clinical interpretation. The analysis treated all patients in the pre-implementation period as having received multidose epinephrine (MDEP) and all patients in the post-implementation period as having received SDEP, without confirmation of actual dosing. While this design reflects pragmatic registry limitations, it introduces potential misclassification that is not random; protocol deviations, incomplete administration, or omitted epinephrine doses could differ systematically across age groups. In clinical terms, such a nondifferential assignment may dilute or exaggerate the survival benefit [2]. For instance, if older patients were more likely to receive fewer doses under MDEP due to rapid termination of resuscitation, then the observed relative advantage of SDEP may partially reflect differences in treatment intensity rather than the effect of a single, standardized dose. Additionally, while the generalized estimating equation (GEE) models accounted for clustering and covariates, the primary outcome survival to hospital discharge was analyzed without concurrent modeling of neurological status. This separation risks overstating clinical benefits. A 5.6% absolute survival gain in older adults is compelling, but the simultaneous reduction in return of spontaneous circulation (ROSC) across all age groups indicates a potential mechanistic trade-off. If survival gains are concentrated among patients discharged with unfavorable neurological function, the clinical significance of long-term quality of life is diminished [3]. Coupling survival and neurologic outcomes in a joint model would better delineate whether SDEP confers genuine functional benefit rather than prolongation of hospitalization. Finally, interaction terms identifying differential benefit in older versus younger cohorts (p = 0.001 and p = 0.05) must be interpreted within a clinical framework. Statistical evidence of heterogeneity is valuable only if it informs EMS decision-making. For providers, the critical question is not whether effect modification exists, but whether protocol adoption leads to meaningful improvements in neurologically intact survival for older adults with limited physiological reserve [4]. In summary, this study advances discussion by suggesting that a simplified epinephrine strategy may improve outcomes in older adults. Attention to treatment fidelity and neurological outcomes will be essential in future investigations. R.M.M. contributed to correspondence, literature review, and writing – original draft preparation. M.M.U.H. contributed to conceptualization, validation, supervision, and writing – review and editing of the manuscript. Both authors reviewed and approved the final version of the manuscript. Generative AI tools, including Paperpal and ChatGPT-5, were utilized solely for language refinement, grammar enhancement, and stylistic polishing. These tools had no role in conceptualization, data analysis, interpretation of results, or substantive content development. All intellectual contributions, data interpretation, and scientific insights remain solely those of the authors. The final version was critically reviewed to ensure originality and accuracy. The authors have nothing to report. The authors have nothing to report. The authors have nothing to report. The authors have nothing to report.