For more than 40 years, epinephrine has been regarded as a standard of care in advanced cardiac life support. In the March 21 issue of The Journal of the American Medical Association, Hagihara et al performed the largest prospective, nonrandomized observational study to date to determine how epinephrine use in cardiopulmonary resuscitation before hospital arrival was associated with immediate and one-month survival. 

The investigators used a national registry of out-of-hospital cardiac arrests that occurred between 2005 and 2008 inJapan. Patients were at least 18 years of age and were followed one month after the event. Outcomes of interest included return of spontaneous circulation, survival with good or moderate cerebral outcome (as measured by the Glasgow-Pittsburgh Cerebral Performance Category scale), and survival at one month post-arrest. A propensity score was developed for epinephrine use to control for selection bias, and the score was used to create a matched sample of patients sharing the same distributions of known confounders. 

Among cardiac arrest patients, 15,030 received epinephrine versus 402,158 patients who did not. In the adjusted propensity-matched analysis, epinephrine use was associated with better return of spontaneous circulation (hazard ratio [HR], 2.5; 95% confidence interval [CI], 2.03 to 2.48), but worse one-month survival (HR, 0.54; 95% CI, 0.43 to 0.68) and worse functional outcomes (HR, 0.21; 95% CI, 0.10-0.44). In all other adjusted analyses, including various sensitivity analyses, epinephrine was found to have a negative association with survival at one month and with functional outcomes, despite an improvement in immediate return of spontaneous circulation. 

The authors performed a rigorous analysis using state-of-the-art statistical techniques to adjust for known confounders, but because epinephrine was not assigned in a random fashion, it is possible that selection bias due to unmeasured confounders was not accounted for.  Should clinicians consider rejecting the current standard of care that strongly endorses epinephrine as a frontline medication in cardiac arrest? Although this is the largest observational study on this topic to date, these results are only applicable for cardiac arrest patients outside the hospital. The study’s findings must be confirmed by additional efforts that include in-hospital resuscitation data. The authors’ data create equipoise for potential future randomized studies that would have previously been considered unethical.

Concise Critical Appraisal is a regular feature authored by SCCM member Samuel M. Galvagno Jr., DO. Each installment highlights journal articles most relevant to the critical care practitioner.