Epinephrine in Cardiac Arrest: Answers at Last or Just More Questions?

Epinephrine (EPI) has long been considered the cornerstone of care in cardiac arrest. The use of EPI was first introduced in the 1960s based on studies of asphyxiated dogs^[1] in which EPI was used in a standard dose of 1 mg without any weight adjustments or consideration of interspecies variation.^[2] The presumed benefits of EPI are mediated by its alpha-adrenergic effects, which include increases in aortic diastolic pressure and coronary blood flow.^[3]

Nonrandomized and poorly controlled studies in the 1980s and 1990s did in fact confirm increases in return of spontaneous circulation (ROSC).^{[3,4,5,6,7,8]} Unfortunately, those studies also demonstrated beta-adrenergic-mediated adverse effects associated with cumulative doses including dysrhythmias, increased myocardial oxygen demand, worsened neurologic outcome in survivors, and increased risk for recurrent cardiac arrest.

In spite of these concerns, the use of EPI every 3 to 5 minutes during cardiac arrest has remained in the national and international resuscitation guidelines^[9] despite much argument and controversy regarding whether EPI is beneficial or harmful.

A great deal of anticipation and excitement centered on a randomized, prehospital trial of EPI in out-of-hospital cardiac arrest,^[3] which would presumably finally, once and for all, answer the question regarding whether the use of EPI in cardiac arrest had an overall beneficial or harmful influence. Do we finally have the answer?

A Closer Look Into the Study Results

Perkins and colleagues^[3] performed a prospective, randomized, double-blind, placebo-controlled trial comparing the use of EPI vs saline placebo, given every 3 to 5 minutes, in patients with out-of-hospital cardiac arrest in the United Kingdom. A total of 8014 patients were randomized in the study: 4015 patients were in the EPI group and 3999 patients were in the saline placebo group.

The primary outcome was the rate of survival at 30 days. Secondary outcomes evaluated the rate of ROSC, survival to hospital discharge, and neurological outcome (modified Rankin scale of ≥ 3). What were the results?

Not surprisingly, ROSC was far better in the EPI group (36.3% vs 11.7%), as was the rate of survival to hospital discharge (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 [OR] for survival, 1.39; number needed to treat, 112).

The main criticism of EPI has always focused on neurologic effects in survivors, and this concern surfaced again in the study. There was no evidence 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 of 4 or 5) was significantly higher in the EPI group (31.0%) than in the placebo group (17.8%).

As with prior studies, this study demonstrated that EPI is associated with a very slight increase in survival but with greater overall neurological impairment. Interestingly, in the discussion, the authors pointed out that their work with the public prior to initiation of the trial indicated that survival with a favorable neurological outcome was a higher priority than survival alone.

So Where Does This Trial Leave Us?

The limitations of the trial should be pointed out. First and foremost, in this trial, the median time to administration of the first dose of EPI was 21 minutes after the emergency call. Previous authors^[10,11] have discussed the concept of time-sensitive phases of cardiac arrest, in which the maximal benefit of EPI appears to be within the first 10 to 15 minutes of cardiac arrest and subsequent dosing of EPI beyond this period is associated with detrimental effects. This theory certainly explains why EPI produced such unsatisfactory results in this study.

A second possible limitation was the lack of a distinction in treatment between shockable vs nonshockable rhythms. Recent studies have suggested that EPI may actually be more beneficial in nonshockable rhythms, and conversely may actually be detrimental in shockable rhythms.^[12,13] In the Perkins study, EPI did increase 30-day survival in patients with nonshockable rhythms (OR, 2.15; confidence interval [CI], 1.13-4.09), but it had uncertain benefit in patients with shockable rhythms (OR, 1.33; CI, 0.95-1.86).

In summary, the study we have all been waiting for did not, in fact, answer the general question of whether or not to use EPI in cardiac arrest. As I see it, however, it did do three things:

• The study confirmed that late use of EPI (beyond 10 to 15 minutes postarrest) is associated with adverse neurologic sequelae

• The study should make us start evaluating whether the use of EPI should be based on the presenting rhythm—shockable vs nonshockable

• The study forces us to consider whether survival or neurological outcome is more important

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