From the Journals

Epinephrine for cardiac arrest: Better survival, more brain damage

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Is epinephrine best for patients with shockable rhythms?

Epinephrine has been used in resuscitation efforts since the 1960s, yet no reliable evidence on the practice has been collected. Now, PARAMEDIC2 provides the most rigorous data on patient-centered outcomes with respect to epinephrine to date.

Epinephrine increased 30-day survival in patients with nonshockable rhythms by more than 100%, but the benefit was less clear in those with shockable rhythms. Shockable rhythms are more likely to occur in patients with cardiac or cardiovascular causes of arrest, which epinephrine may exacerbate. The results underscore the principle that drug administration should not compete with or delay defibrillation, and that epinephrine may have different effects in patients with different ECG rhythms.

The PARAMEDIC2 results leave us with several questions: Could other, additional treatments after a return of spontaneous circulation improve functional recovery, should drug use differ on the basis of cardiac rhythm, and would lower doses of epinephrine be superior to higher doses among patients with out-of-hospital cardiac arrest?

Clifton W. Callaway, MD, PhD, of the University of Pittsburgh, and Michael W. Donnino, MD, of Beth Israel Deaconess Medical Center, Boston, made these comments in an accompanying editorial (N Engl J Med. 2018 Jul 18. doi: 10.1056/NEJMe1808255). They had no relevant disclosures.



Using epinephrine for cardiac arrest improves 30-day survival by less than 1%, and nearly doubles the risk of severe brain damage among survivors, according to PARAMEDIC2, a randomized, double-blind trial in more than 8,000 patients in Great Britain.

It’s clear what patients want. “Our own work with patients and the public before starting the trial identified survival without brain damage [as] more important to patients than survival alone. The findings of this trial will require careful consideration by the wider community and those responsible for clinical practice guidelines for cardiac arrest,” lead investigator Gavin D. Perkins, MD, professor of critical care medicine at the University of Warwick, Coventry, England, and lead author of the study published in the New England Journal of Medicine, wrote in a statement.

In PARAMEDIC2, after initial attempts with CPR and defibrillation failed, 4,012 patients were given epinephrine 1 mg by intravenous or intraosseous infusion every 3-5 minutes for a maximum of 10 doses, and 3,995 were given a saline placebo in the same fashion. The median time from emergency call to ambulance arrival was just over 6 minutes in both groups, with a further 14 minutes until drug administration.

The heart restarted in a higher proportion of epinephrine patients (36.3% vs. 11.7%), and 3.2% of epinephrine patients were alive at 30 days, versus 2.4% in the placebo arm, a 39% increase.

However, that slight benefit came at a significant cost. Of the 126 epinephrine patients who survived to hospital discharge, 39 (31%) had severe brain damage, compared with 16 (17.8%) among the 90 placebo survivors. Severe brain damage meant inability to walk and tend to bodily functions, or a persistent vegetative state (modified Rankin scale grade 4 or 5).

The trial addresses a long-standing question in resuscitation medicine, the role of epinephrine in cardiac arrest. It’s a devil’s bargain: Epinephrine increases blood flow to the heart, so helps with resuscitation, but it also reduces blood flow in the brain’s microvasculature, increasing the risk of brain damage.

“The benefit of epinephrine on survival demonstrated in this trial should be considered in comparison with other treatments in the chain of survival.” Early cardiac arrest recognition saves 1 in every 11 patients, bystander CPR saves 1 in every 15, and early defibrillation saves 1 in 5, the investigators noted.

The trial did not collect data on prearrest neurologic status, but the number of subjects with impaired function was probably very small and balanced between the groups, according to the report.

On average, patients were aged just under 70 years, 65% were men, and bystander CPR was performed in about 60% in both groups. They were enrolled by five ambulance services in England and Wales. Informed consent was obtained, when possible, after resuscitation.

The trial was funded by the U.K. National Institute for Health Research. The researchers had no relevant disclosures to report.

SOURCE: Perkins GD et al. N Engl J Med. 2018 Jul 18. doi:10.1056/NEJMoa1806842.

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