Epinephrine has been a fundamental therapeutic agent for managing cardiac arrest since the inception of advanced life support. Despite its ubiquitous use, this practice has never been supported by high-quality evidence. The publication of the PARAMEDIC-2 trial, however, puts us far closer to understanding the true value of epinephrine for out-of-hospital cardiac arrest (OHCA). (New Engl J Med 2018 July 18. doi:10.1056/nejmoa1806842; http://bit.ly/2wbqW5Q.)
The authors performed a multicenter double-blind, randomized, controlled trial, enrolling adult patients who experienced sustained OHCA and in whom initial resuscitative attempts were ineffective (defined as no response to initial round of CPR and defibrillation). Patients were randomized to receive 1 mg epinephrine or a matching syringe of normal saline given IV or IO every three to five minutes. A total of 8,014 of the 10,623 patients screened were enrolled and included in the final analysis, 4,015 in the epinephrine group and 3,999 in the placebo group.
As one would expect with an 8,000-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 just shy of 70, 65 percent were male, a little less than 20 percent had an initial shockable rhythm, 50 percent were witnessed by a bystander, and 59 percent 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 percent in the epinephrine group and 2.4 percent in the placebo group (unadjusted odds ratio for survival, 1.39; 95% confidence interval, 1.06 to 1.82; p=0.02). This 0.8 percent absolute difference in survival remained consistent at three months (3% vs 2.2%), translated to a NNT of 112 patients to prevent one death at 30 days. The authors also reported an increase in the number of patients who were transported to the hospital (50.8% v. 30.7%) and survived to ICU admission (14.1% v. 6.8%).
Flawless Design, but...
Methodologically speaking, this trial was designed and conducted almost flawlessly, but their selection of a primary outcome is somewhat misleading. The resuscitative properties of epinephrine were well documented in the literature even before this trial. (N Engl J Med 2004;351:647; http://bit.ly/2w3UPFk; JAMA 2009;302:2222; http://bit.ly/2w7AQWg; JAMA 2012;307:1161; http://bit.ly/2Ml0SAg.)
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. Epinephrine has consistently demonstrated its ability to flog a dying heart into temporary cooperation, so the authors' primary endpoint was almost a foregone conclusion.
In fact, it is somewhat surprising that the difference in overall survival was so small (only 0.8%). The question we hoped to glean from PARAMEDIC-2 is what effect epinephrine has on neurologically intact survival. The authors reported no difference in the rate of neurologically intact survival in patients randomized to receive epinephrine v. 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 percent of the survivors in the epinephrine group had an mRS score of 4 or 5, with only 17 percent in the placebo group.
PARAMEDIC-2 does not entirely eliminate the potential benefits of epinephrine administered in drip form or titrated to a physiological endpoint, but 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 with no hope of neurological recovery. That's a heavy cost for such an ineffective therapeutic agent.