Outcomes Worse in Cardiac Arrest Treated With Epinephrine

Pam Harrison

December 02, 2014

PARIS, FRANCE — An association between giving epinephrine during out-of-hospital cardiac arrest and poor neurological outcomes, with the risk going up with the dosage, was observed in a large cohort study that also saw the risk increase with the interval between the arrest itself and epinephrine administration[1].

The study was published in the December 9, 2014 issue of the Journal of the American College of Cardiology with Dr Florence Dumas (Paris Descartes University, France) as lead author.

Researchers analyzed all patients who had experienced an out-of-hospital cardiac arrest between January 2000 and August 2013 who had been resuscitated and admitted to a major Paris hospital.

During that period, 1646 patients were successfully returned to spontaneous circulation and were admitted to the hospital. Ninety patients were excluded from the analysis because their epinephrine status was unknown.

Nearly three-quarters of them had received epinephrine as part of their out-of-hospital resuscitation protocol. International guidelines recommend the administration of 1 mg of epinephrine every 3 to 5 minutes during cardiac resuscitation.

Of the 1556 patients included in the analysis, 31% survived to hospital discharge and 29% of them survived with good neurological outcomes.

However, as Dumas and multicenter colleagues reported, only 17% of patients who received epinephrine as part of the resuscitation protocol had a good neurological outcome compared with 63% of those who did not (P<0.001).

Moreover, compared with patients who did not receive epinephrine, the likelihood of patients surviving neurologically intact was less than half (adjusted odds ratio [OR] 0.48) in those who received 1 mg of epinephrine; 70% less for those who received 2 to 5 mg of epinephrine (OR 0.30); and 77% less for those who received greater than 5 mg of epinephrine (OR 0.23).

The adverse association of epinephrine was observed regardless of the length of resuscitation patients required or in-hospital interventions performed.

"Delayed administration of epinephrine was also associated with worse outcome," investigators add, those in whom epinephrine was given within the first nine minutes after cardiac arrest having a better outcome than those who received epinephrine later.

Association of Time of Administration of Epinephrine and Likelihood of Good Outcome

Interval between epinephrine and cardiac arrest (min) Likelihood of a good outcome (OR)
< 9 0.54
10–15 0.33
16–22 0.23
>22 0.17
Postresuscitation Intervention

Investigators also evaluated whether the use of evidence-based postresuscitation intervention, including coronary reperfusion with PCI and hypothermia, influenced outcome in patients who received epinephrine.

After adjustment for different confounders, use of epinephrine was negatively associated with favorable neurological outcomes (OR 0.32), even after adjustment for hospital interventions, the authors observe.

The adverse association between the use of epinephrine and survival was also apparent across different subgroups as defined by the initial rhythm, length of resuscitation, and postresuscitation care and the presence or absence of postresuscitation shock.

As the authors point out, patients who received epinephrine had less favorable prognostic characteristics than those who did not. For example, they were more likely to be older (P=0.02), less likely to have a witnessed event (P=0.006), and less likely to present with a shockable rhythm ( P<0.001). They also had had a longer duration of resuscitation (P<0.001).

Senior author Dr Alain Cariou (Paris Descartes University) told heartwire that while the negative association seen between epinephrine use and out-of-hospital cardiac arrest was seen across all subgroups, it was still an association, and the association should not be construed as causal.

"Probably in some patients, epinephrine could be associated with more risk than benefit, but it does not mean that we need to stop the use of epinephrine in resuscitation. Its use is still recommended," Cariou said.

Nevertheless, the fact that there appeared to be a dose-response relationship between worsening outcomes and increasing doses of epinephrine underscores the likelihood that the negative association seen in this study is "something we can trust."

"The problem is, if we do not use epinephrine in out-of-hospital cardiac arrest, we do not have many alternatives to use in this situation, and that is probably why the guidelines still recommend its use," Cariou said.

"So it's important to try to identify whether there are better alternatives, but in the meantime, an important question to answer for me now is whether a lower dose of epinephrine could be associated with a more beneficial risk/benefit ratio."

All Depends on Timing

Asked to comment on the study, Dr Gordon Ewy (University of Arizona College of Medicine, Tucson), who wrote an accompanying editorial[2], told heartwire that any potential benefit from the use of epinephrine in the out-of-hospital cardiac-arrest setting depends entirely on the timing of its administration.

"Epinephrine is not necessary early on, and that is why [automated external defibrillators] AEDs and [implantable cardioverter defibrillators] ICDs work," he said. "But when it's too late, nothing works, including epinephrine."

He also cautioned that this study was not a randomized controlled trial, and as such, there is no information about why patients did and did not receive epinephrine at the time of the arrest.

"All of the changes that we've made in resuscitation practices are based on our studies in the animal laboratory, and as researchers showed 50 years ago, after 10 minutes of untreated ventricular fibrillation, it is very hard to resuscitate an animal or a person if you don't give something," Ewy said.

"So if you give patients epinephrine at the right time, it increases the [coronary perfusion] pressure and perfuses the heart and the brain; it can work, but as time goes on, it's less effective, and finally it's not effective at all."

A large registry study by Hagihara et al also found that prehospital use of epinephrine was significantly associated with an increased chance of return of spontaneous circulation prior to hospital arrival in patients with out-of-hospital cardiac arrest in Japan but that chances of survival and good functional outcomes were decreased 1 month after the event[3].

The authors and Ewy have reported they have no relevant financial relationships.

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