Epinephrine for Cardiac Arrest: Guidance Inflated?

The use of epinephrine (EPI) in cardiac arrest has been a source of significant controversy for many years. Early studies of EPI, including the use of high-dose EPI, consistently showed improvements in rates of return of spontaneous circulation (ROSC) but failed to show improvements in subsequent survival or neurologic recovery. In fact, slight worsening of neurologic recovery was found in patients who received high-dose EPI or large cumulative doses of EPI.

The use of high-dose EPI was subsequently abandoned, but the use of regular-dose EPI in 1-mg IV boluses every 3-5 minutes was continually endorsed by the American Heart Association (AHA) with a Class IIb recommendation ("possibly helpful") since 2015, despite many authors who argued that there was insufficient evidence to continue to endorse the use of EPI.

On November 14, 2019, the AHA published a "Focused Update on Advanced Cardiac Life Support," addressing, among other topics, the use of EPI in cardiac arrest. This new update has elevated EPI to a Class I recommendation for use in patients with cardiac arrest. The AHA once again reiterated its prior statements recommending against the use of high-dose EPI.

In regard to the timing of the EPI, the AHA recommended the administration of epinephrine "as soon as feasible" to patients with nonshockable rhythms. For patients with shockable rhythms, however, AHA reminds providers that defibrillation should be attempted first, after which "it may be reasonable to administer epinephrine after initial defibrillation attempts have failed."

Epinephrine – The Debate Continues

The increase in EPI's rating from a Class IIb recommendation to Class I was largely the result of a randomized study by Perkins and colleagues, in which EPI was compared with placebo in prehospital victims of cardiac arrest. In that study, ROSC was better in the EPI group (36.3% vs 11.7%), as was the rate of survival to hospital admission (23.8% vs 8.0%). The primary outcome showed more modest benefits of EPI: At 30 days, 3.2% of patients in the EPI group were alive vs 2.4% of patients in the placebo group (P = .02; odds ratio for survival, 1.39; number needed to treat, 112).

There was no evidence, however, of a significant benefit between the EPI group and placebo group in terms of favorable neurologic outcome at discharge (2.2% for EPI, 1.9% for placebo), and survival with severe neurologic impairment (Modified Rankin Scale score of 4 or 5) was significantly higher in the EPI group (31.0%) than in the placebo group (17.8%). Panchal and colleagues point out that "the difference in survival with favorable neurological outcome approached significance in the epinephrine group (RR, 1.30 [95% CI, 0.94-1.80]." However, if we are to be scientific, "approached significance" is not the same thing as being significant.

Detractors of EPI in cardiac arrest will point out that, to date, we still don't have good evidence that EPI saves brains and that neurologic recovery is the most important outcome that we should seek. In fact, a prestudy survey by the Perkins research group revealed that neurologic recovery was felt to be a more important outcome than survival for the lay public as well, and nonrandomized data suggest that cumulative doses of EPI are associated with worsened neurologic function. One must question how the AHA decided to elevate the use of EPI from Class IIb (the therapy "may be reasonable/considered," "weak" recommendation) all the way to Class I (the therapy "is recommended/should be administered," "strong" recommendation) on the basis of results of the Perkins trial.

Supporters of EPI in cardiac arrest, on the other hand, will point out that before we can save the brain, we must first simply keep the patient alive (ROSC), and EPI has proven to do just that. The median time to administration of EPI in the Perkins trial was 21 minutes—a fairly long period to be without spontaneous circulation. EPI was associated with improved survival even in patients with long downtimes. These lengthy downtimes clearly compromise the brain, but we really don't have convincing data to show that EPI contributes to worsening neurologic recovery. Should we blame EPI for the worse neurologic recovery in survivors?

The debate will continue, but here is my take on the data and on the new AHA Focused Update:

The Update reminds us that EPI in cardiac arrest probably has the best evidence for patients with nonshockable rhythms; further studies are warranted.
The Update reminds us that the use of EPI in cardiac arrest in the presence of shockable rhythms should always be a lower priority than prompt defibrillations.
I still believe in the three-phase model of cardiac arrest (see my previous post on Medscape). EPI is probably helpful for survival and neurologic recovery when given in the first 15 minutes post-arrest, whereas EPI is probably detrimental with accumulating dosages after 20 minutes. Further studies are definitely warranted.
On the basis of the current literature, I do not believe that a Class I rating for the use of EPI in cardiac arrest was justified.

Please share your thoughts on use of EPI in cardiac arrest.

Amal Mattu, MD, is a professor, vice chair of education, and co-director of the emergency cardiology fellowship in the department of emergency medicine at the University of Maryland School of Medicine in Baltimore, Maryland. In 2017, he was rated one of the most influential emergency physicians on Twitter.

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