Epinephrine after OHCA: Is the survival benefit worth the neurological risk?

Epinephrine doses administered by paramedics significantly improved the odds of 30-day survival for patients following out-of-hospital cardiac arrest (OHCA), according to a randomized,  placebo-controlled trial published in the New England Journal of Medicine. The survivors who received epinephrine, however, had worse neurological outcomes, making the odds of living with favorable brain function similar between the two groups.

The researchers pointed out surviving with a favorable neurologic outcome might be even more important to patients than simply surviving. A favorable outcome was defined as a score of 3 or lower on the modified Rankin scale, which ranges from 0 (no symptoms) to 6 (death).

“Patients may be less willing to accept burdensome treatments if the chances of recovery are small or the risk of survival with an impaired neurologic outcome is high,” wrote lead author Gavin D. Perkins, MD, and colleagues.

More than 8,000 patients with OHCA in the U.K. were randomized 1:1 to receive epinephrine or a saline placebo if initial attempts of cardiopulmonary resuscitation (CPR) and defibrillation were unsuccessful. At 30 days, 3.2 percent of patients in the epinephrine group and 2.4 percent in the control group were alive, a relative difference of 39 percent.

But among survivors, 31 percent who received adrenaline doses had severe neurological impairment (a 4 or 5 on the modified Rankin scale), compared to 17.8 percent of patients in the control group. Overall, 2.2 percent of patients given epinephrine and 1.9 percent of patients injected with placebo survived with favorable brain outcomes—a nonsignificant difference.

The authors ventured guesses as to why brain functioning was more likely to be impaired with adrenaline treatment, but said the specific reasons are still unclear.

“One explanation is that although epinephrine increases macroscopic cerebral blood flow, it paradoxically impairs cerebral microvascular blood flow and thus has the potential to worsen brain injury after a return of spontaneous circulation,” Perkins et al. wrote.

“An alternative explanation is that the brain is more sensitive to ischemia and reperfusion injury and less able to functionally recover after restoration of circulation than are the heart and other organs. No specific therapies other than targeted temperature management have been shown to reduce the severity of brain injury after cardiac arrest.”

The results were largely consistent with previous observational studies, which reported greater odds of a return in spontaneous circulation with epinephrine but also worse neurological outcomes. The authors concluded the number of patients who would need to be treated with epinephrine to prevent one death after OHCA was 112, much higher than previously reported estimates for early recognition of cardiac arrest (number needed to treat, 11), bystander CPR (15) and early defibrillation (5).

“The small magnitude of the higher rate of survival and absence of functional recovery will prompt debate about whether epinephrine is truly beneficial for improving meaningful clinical outcomes,” Clifton W. Callaway, MD, PhD, and Michael W. Donnino, MD, wrote in an accompanying editorial.

“We now must ponder whether additional treatments after a return of spontaneous circulation could improve functional recovery, whether drug use should differ on the basis of cardiac rhythm, and whether lower doses of epinephrine would be superior to higher doses among patients with out-of-hospital cardiac arrest.”