Epinephrine (adrenaline) given before hospital arrival for cardiac arrest was associated with poorer chances of survival without substantial mental disability, an observational study showed.

Among those who initially recovered spontaneous circulation, survival to hospital discharge with a Cerebral Performance Category 1 or 2 occurred in 17% of those given prehospital epinephrine compared with 60% not given the drug (P<0.001), Florence Dumas, MD, PhD, of the Parisian Cardiovascular Research Center, and colleagues found.

In a propensity score-matched subanalysis, survival with good neurologic outcome remained substantially less common in the epinephrine group (30% versus 61%,P<0.001), the researchers reported in the Dec. 9 issue of the Journal of the American College of Cardiology.

That association in the large, single-center registry persisted regardless of length of resuscitation or in-hospital interventions performed.

The adjusted odds ratio also showed a dose-dependent risk compared with no epinephrine:

• 0.48 for 1 mg of epinephrine (95% confidence interval 0.27-0.84)
• 0.30 for 2 to 5 mg of epinephrine (95% CI 0.20-0.47)
• 0.23 for more than 5 mg of epinephrine (95% CI 0.14-0.37)

These findings come amid growing evidence questioning the role of this guideline-recommended vasopressor for out-of-hospital cardiac arrest, Gordon A. Ewy, MD, of the University of Arizona’s Sarver Heart Center in Tucson, noted in an accompanying editorial.

The reason might have to do with timing, or it could be that adrenaline isn’t the best vasopressor for the job, he suggested.

Animal research has shown that during the circulatory phase of ventricular fibrillation arrest (after the first 10 minutes), adding a beta-adrenergic blocker helped, although adding a pure alpha-adrenergic drug, such as phenylephrine or methoxamine, didn’t.

“Further research, first in animal models and later in humans, can continue to assess whether a pure alpha agent or combination of agents may be superior to epinephrine during the circulatory phase of resuscitation,” Ewy noted.

Timing of Epinephrine

Delayed administration of epinephrine was associated with worse outcome in Dumas’ study of patients admitted to a single large cardiac arrest-receiving hospital in Paris after out-of-hospital cardiac arrest and who achieved successful return of spontaneous circulation from January 2000 through August 2012.

Among the 1,556 such patients in the study, 73% had received epinephrine.

Outcomes weren’t as bad versus no epinephrine when the drug was given sooner after arrest, as reflected in adjusted odds ratios of

• 0.54 when given within the first 9 min after cardiac arrest (95% CI 0.32-0.91)
• 0.23 when given between 10 and 15 min after onset of arrest (95% CI 0.20-0.56)
• 0.23 when given between 16 and 22 min after onset of arrest (95% CI 0.12-0.43)
• 0.17 when given more than 22 min after cardiac arrest (95% CI 0.09-0.34)

The reason could be double-edged effects, Dumas’ group suggested.

“The alpha-adrenergic effects of epinephrine can increase coronary and cerebral perfusion pressure during the resuscitation period and subsequently help achieve return of spontaneous circulation,” they wrote. “However, epinephrine may exert adverse effects during the post-resuscitation phase and contribute to myocardial dysfunction, increased oxygen requirements, and microcirculatory abnormalities.”

The only randomized trial of epinephrine versus placebo in out-of-hospital cardiac arrest showed better rates of spontaneous circulatory recovery but no difference in survival to hospital discharge with the vasopressor, which did not support the overwhelmingly negative effect of epinephrine reported by Dumas’ group, Ewy noted.

“Unfortunately, in this important study, time to administration of adrenaline was not reported,” he wrote. “Future human investigation of vasopressor agents for out-of-hospital cardiac arrest, whether prospective or retrospective, must separate time courses for vasopressor administration.”

Limitations

One limitation was the lack of information about why one-quarter of patients didn’t receive epinephrine, Ewy said.

Another was the less favorable prognostic characteristics of those who did get epinephrine, he noted, writing that “they were older, less likely to have a witnessed event, and less likely to present with a shockable rhythm, and they had a longer duration of resuscitation (P<0.001).”

Those differences could be at the core of the findings, commented Karl B. Kern, MD, also of the Sarver Heart Center, where he is co-director.”It may really be as simple as these were a sicker group of people,” he told MedPage Today. “Even though the whole paper is really based on a number of statistical efforts to equalize those groups, it still leaves you wondering, Is it just a population study?”

“Really, all these studies have been cohorts, before and after, and the drug has been given really quite late, usually 20 to 25 minutes after onset of cardiac arrest,” he cautioned. “We need a randomized trial to really get that bias out of the way and understand does this drug really make a difference in the long-term outcome?”

Altogether, the message may be “if you’re going to use epinephrine, use it early,” Kern suggested, though he predicted that the level of evidence to date likely wouldn’t be enough to change the resuscitation guidelines that are being revised for 2015.