Epinephrine for Out-of-Hospital Cardiac Arrest Questioned

March 20, 2012

March 20, 2012 (Fukuoka, Japan) — Another study, > 400 000 cases strong, disputes the longstanding practice of administering epinephrine during cardiopulmonary resuscitation (CPR) for out-of-hospital cardiac arrest, at least the way it's currently given [1].

In analyses of a massive national registry of out-of-hospital cardiac arrest in Japan, the approximately 15 000 subjects who received prehospital epinephrine were far more likely to return to spontaneous circulation before hospital arrival than the remaining majority who didn't get epinephrine. But they showed significantly poorer outcomes at one month: their survival fell by about half and survival with good or only mildly impaired cerebral function by more than two-thirds (p < 0.001 for all outcomes).

With the results pointing to a favorable short-term effect but much poorer longer-term outcomes from epinephrine in out-of-hospital arrest, the implication is that "epinephrine administration might save the heart but not the brain," write the authors, led by Dr Akihito Hagihara (Kyushu University Graduate School of Medicine, Fukuoka, Japan). Their research is published in the March 21, 2012 issue of the Journal of the American Medical Association.

Other studies have questioned whether epinephrine improves outcomes in this setting. However, the current analysis is "based on one of the largest observational databases of CPR ever assembled," notes an accompanying editorial [2], making it "the best comparison of outcomes likely to be achieved in an observational study."

Although a randomized controlled trial of epinephrine for out-of-hospital cardiac arrest "previously seemed unethical," such a trial "now seems necessary and timely," writes Dr Clifton W Callaway (University of Pittsburgh, PA) in his editorial. "While awaiting results of such a definitive trial, physicians and other practitioners involved in cardiac resuscitation must consider carefully whether continued use of epinephrine is justified."

Dr Michael Sayre (Ohio State University, Columbus), who wasn't involved in the current study, agreed that no recommendations can be made based on an observational study and said he "wonders a bit why they would find such a dramatic difference [in outcomes for those getting epinephrine] when randomized trials have found small differences."

Sayre agreed for heartwire that the study and others before it indeed question the use of epinephrine in out-of-hospital cardiac arrest, at least the way it's used now. "The tradition that everybody gets epinephrine is based on animal evidence, and the emerging human evidence would suggest that the drug at best is not very helpful and might be harmful."

But that doesn't mean the drug shouldn't have a role: maybe it would work better at very small dosages or in selected cases, according to Sayre. "My belief is that there are some people whom this drug is hurting, and there are other people whom it's probably helping, but we just don't have any strategy to tell the difference right now."

Of 417 188 adults with out-of-hospital cardiac arrest in the current study, covering the years 2005 to 2008, who were treated by emergency medical service (EMS) personnel in Japan and transported to a hospital, 15 030 had received prehospital epinephrine.

The favorable early findings and poorer one-month outcomes were observed in two controlled analyses: a multivariate analysis that covered demographic, geographic, and treatment-related variables; and one with the same covariates plus propensity matching.

Adjusted odds ratio (OR) for outcomes in out-of-hospital cardiac arrest by prehospital epinephrine use (yes vs no)

Analysis Multivariate analysis, OR (95% CI) Multivariate with propensity matching, OR (95% CI)
ROSC before hospital arrival 2.36 (2.22–2.50) 2.51 (2.24–2.80)
1-mo survival 0.46 (0.42–0.51) 0.54 (0.43–0.68)
1-mo survival with CPC 1–2a 0.31 (0.26–0.36) 0.21 (0.10–0.44)
1-mo survival with OPC 1–2b 0.32 (0.27–0.38) 0.23 (0.11–0.45)

ROSC=return of spontaneous circulation

CPC=Cerebral performance category

>OPC=Overall performance category

a good or moderate cerebral performance

b no, mild, or moderate neurological disability

Because their data base was so huge, the authors note, the analysis was able to adjust effectively for a number of factors seldom included in other studies, including whether the arrest was witnessed or bystander CPR was given (and whether it included chest compressions, rescue breathing, or a public-access defibrillator), time from call to EMS arrival and to hospital arrival, and use of advanced life-support measures.

Sayre wholeheartedly agreed that it's high time for a randomized, controlled trial to define the best role for epinephrine in out-of-hospital cardiac arrest. But it should be designed "in a way that offers different options instead of an all-or-nothing approach." So far, he said, "It's been pretty much a one-size-fits-all treatment. There's nothing personalized about it."

For example, animal studies suggest that current epinephrine doses may be too high. "It could be that with good CPR and a very tiny dose of epinephrine, they would come back and it wouldn't be at the same cost of brain function," he proposed. Or "maybe they need the epinephrine [to recover] but they could also get treatments that might ameliorate its effects on the brain, such as therapeutic hypothermia."

Neither Hagihara nor his coauthors had disclosures. Callaway reports being an investigator for the Resuscitation Outcomes Consortium, "which is commissioned to perform clinical trials in cardiac arrest"; receiving consulting fees or honoraria from Take Heart Austin, the Post-Cardiac Arrest Symposium, the Sudden Cardiac Arrest Association, and the Society for Critical Care Medicine and a stipend from the National Institutes of Health; and receiving an "equipment loan for laboratory studies" from Medivance and "royalties on patents related to defibrillation" from Medtronic. Sayre has previously reported that he has no relevant disclosures.

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