Epinephrine has been a fundamental therapeutic agent in the management of cardiac arrest since the inception of advanced life support. Despite its ubiquitous use, this practice has never been supported by high quality evidence. With the publication of the PARAMEDIC-2 trial by Perkins et al1, we are now far closer to understanding the true value of epinephrine for out of hospital cardiac arrest (OHCA).
The authors performed a multicenter double-blind RCT, enrolling adult patients who experienced sustained OHCA, in which initial resuscitative attempts were ineffective (defined as no response to initial round of CPR and defibrillation). Patients were randomized to receive 1 mg of epinephrine or a matching syringe of normal saline given IV or IO every 3-5 minutes. Of the 10623 patients screened, 8014 patients were enrolled and included in the final analysis. (4015 patients in the epinephrine group and 3999 patients in the placebo group). As one would expect with an 8000 patient study, the two groups were fairly well balanced. The population study was typical for a cohort of patients experiencing OHCA. The mean age was 69, 65% were male, about 20% of the patients had an initial shockable rhythm, 50% were witnessed by a bystander and 59% received bystander CPR prior to the arrival of EMS.
The authors noted a statistically significant difference in their primary outcome, 30-day survival, which was 3.2% in the epinephrine group and 2.4% in the placebo group (unadjusted odds ratio for survival, 1.39; 95% confidence interval [CI], 1.06 to 1.82; P=0.02). This 0.8% absolute difference in survival remained consistent at 3-months (3% vs 2.2%), translated to a NNT of 112 patients to prevent 1 death at 30-days. The authors also reported an increase in the number of patients who were transported to the hospital (50.8% vs 30.7%) and survived to ICU admission (14.1% vs 6.8%).
Although methodologically speaking Perkins et al designed and conducted an almost flawless trial, their selection of a primary outcome is somewhat misleading. Even before this trial the resuscitative properties of epinephrine have been well documented in the literature 2,3,4 (2-4). Study after study has demonstrated that patients who receive epinephrine during cardiac arrest experience ROSC more frequently, are transported to the hospital more often, and are more likely to be admitted to the ICU. Since epinephrine has consistently demonstrated its ability to flog a dying heart into temporary cooperation, the authors primary endpoint was almost a foregone conclusion. In fact, it is somewhat surprising the difference in overall survival was so small (only 0.8%). The question we hoped to glean from PARAMEDIC-2 is what effect does epinephrine have on neurologically intact survival The authors reported no difference in the rate of neurologically intact survival in patients randomized to receive epinephrine vs placebo (2.2% vs 1.9). In fact, the increased survival reported in their primary outcome consisted entirely of patients with severe neurological disability, 31% of the survivors in the epinephrine group had a mRS score of 4 or 5, with only 17% in the placebo group.
While PARAMEDIC-2 does not entirely eliminate the potential benefits of epinephrine administered in drip form, or titrated to a physiological endpoint, these results do not support the continued use of bolus dose epinephrine in patients experiencing OHCA. Not only did the authors fail to demonstrate improvement in neurologically intact survival, epinephrine’s use was associated with a significant increase in critically ill patients without hope of neurological recovery. A heavy cost for such an ineffective therapeutic agent.