Delay in administering epinephrine is associated with significantly poorer outcomes among pediatric patients who have in-hospital cardiac arrest with an nonshockable rhythm, according to a report published online Aug. 25 in JAMA.

For the approximately 16,000 U.S. children and adolescents in this patient population each year, epinephrine is the recommended first-line pharmacologic therapy, even though no randomized placebo-controlled trials have ever been performed to support this practice.

It is highly unlikely that any such study will ever be done, given the ethical considerations, so to examine the effect of the timing of epinephrine therapy, investigators analyzed data from the Get With the Guidelines-Resuscitation registry concerning 1,558 patients aged 0-18 years who were treated during a 15-year period, said Dr. Lars W. Andersen of the department of emergency medicine at Beth Israel Deaconess Medical Center, Boston, and the department of anesthesiology at Aarhus (Denmark) University and his associates.

All the patients received chest compressions and at least one epinephrine bolus while pulseless with a documented nonshockable initial rhythm. The median age was 9 months, and the median time to first epinephrine dose was 1 minute (range, 0-20 minutes). A total of 37% of these patients received their first dose of epinephrine within 1 minute after loss of pulse was noted, and 15% received their first dose more than 5 minutes afterward.

Delay in epinephrine treatment was significantly associated with a lower chance of survival to hospital discharge (relative risk, 0.95 per minute of delay), the primary outcome measure of the study. In addition, longer time to epinephrine delivery was significantly associated with a decreased chance of return to spontaneous circulation (RR, 0.97 per minute of delay), for survival at 24 hours (RR, 0.97 per minute of delay), and for survival with favorable neurologic outcome (RR, 0.95 per minute of delay).

In a further analysis of the data, patients were divided into two groups according to the length of time before epinephrine administration. The 1,325 patients who received epinephrine within 5 minutes had a 33.1% rate of survival to hospital discharge, while the 233 who received epinephrine after 5 minutes had elapsed had a significantly lower 21.0% rate of survival to hospital discharge, Dr. Andersen and his associates said (JAMA. 2015 Aug 25. doi: 10.1001/jama.2015.9678).

These findings suggest, but cannot establish, that treatment delay causes poorer outcomes because an observational study cannot determine causality. Even though the data were adjusted to account for numerous patient and hospital characteristics, and even though the results remained robust through multiple sensitivity analyses, it remains possible that time to epinephrine administration is not a causal mediator but a marker of other aspects of the resuscitation process, the researchers added.