Review Of: Jacobs I, Finn J, Jelinek G, et al. Effect of adrenaline on survival in out-of-hospital cardiac arrest: A randomized double-blind placebo-controlled trial. Resuscitation. 2011;82(9):1138–1143.
The Science: This is a randomized double blind, placebo control trial out of western Australia that looks at the effects of adrenaline (epinephrine) in prehospital cardiac arrest. The primary outcome to be measured was survival to hospital discharge, but the study also included a secondary analysis of return of spontaneous circulation (ROSC). Over the course of the study period, more than 4,000 patients were screened for eligibility, with a total of 534 patients being enrolled in the study: 262 in the placebo group vs. 272 in the control group (adrenaline). Investigators found those receiving adrenaline had 3.4 times great odds of achieving ROSC, and 2.2 great odds of survival to discharge.
However, the primary outcome of the study failed to reach statistical significance The investigators conclude the administration of adrenaline during out of hospital cardiac arrest increases the likelihood of achieving ROSC, but fails to demonstrate improved survival to hospital discharge.
Dr. Wesley: There have been several studies recently that would indicate that few, if any of the ACLS drugs have any clinical effect. This randomized, double blind study showed a clear improvement in ROSC for these Australian cardiac arrest patients. So should we hold tightly to our amps of epinephrine? Not so fast. Let’s look more closely at this study.
First, the average EMS response time was 10 minutes. This probably falls in the metabolic phase of cardiac arrest resuscitation, where the benefit of CPR begins to diminish. Secondly, the increase in return of spontaneous circulation (ROSC) was only noted in non-shockable rhythms (asystole and PEA), which also correlates to what if found with longer response times.
Third, the study failed to show an effect on survival to discharge, which is not surprising since survival to discharge for non-shockable rhythms is dismal regardless of what we do. Fourth, there was no mention of the use of an impedance threshold device (ITD), which has clearly been shown to improve ROSC and survival by what some speculate is the ability to prolong the circulatory phase of cardiac arrest and perhaps obviate the need for vasopressors.
Finally, and the authors openly admit, their study failed to enroll 50% of the eligible patients because several institutions had ethical concerns to withholding the “standard of care,” which is outlined in the American Heart Association (AHA) guidelines. This failure could have affected the findings, most notably the survival to discharge rate.
However, I do applaud the authors. I wish that we could do such studies in the U.S., but the Institutional Review Boards for cardiac arrest research are simply not interested in performing such research. What I do take from this study is that perhaps we should have different treatment protocols for cardiac arrest with prolonged response. Epinephrine may play a role, but I suspect it requires a more complex recipe for success.
Medic Marshall: Although the Doc is quick to point out potential issues with the study, I’m going to say “bravo” to these investigators. Finally, someone was able to attempt a study of the highest caliber, looking at the use of epinephrine during cardiac arrest.
A key factor about this study was it compared the use of epinephrine only to a placebo—anti-arrythmics or any other “ACLS” drugs were not used, which makes this a remarkable study. Any time the standard of care is brought into question, it becomes difficult to actually study any potential changes to that standard, especially in the case of managing cardiac arrests. People’s lives are actually on the line.
Although Dr. Wesley points out some potential issues with the study, in my opinion, the glaring problem is the actual number of patients enrolled, though this is no fault of the investigators. The study was designed to be powered enough with a large sample size to determine a detectable difference in survival-to-hospital discharge. But because of politics, this multi-center study design became a single-center study, thus inhibiting the generalizability and decreasing the number of patients that could be enrolled.
It’s truly unfortunate this study was reduced in scope by so much; it had the potential to have a global effect on how cardiac arrest is treated pharmacologically, as well as set the stage for similar studies to occur.
But don’t get me wrong. I’m not advocating that epinephrine is the answer here. I agree with the Doc’s thoughts that cardiac arrest treatment “…requires a more complex recipe for success.” He’s right. Interventions such as good and early CPR, early defibrillation, use of an ITD, and the development of resuscitation centers that have cath labs and therapeutic hypothermia, are all necessary for improved outcomes for patients suffering from cardiac arrest. At least now we know that if we keep pushing epinephrine as it’s currently recommended, the odds of getting ROSC are better than they would be if the patient hadn’t received epinephrine at all.
Background: There is little evidence from clinical trials that the use of adrenaline (epinephrine) in treating cardiac arrest improves survival, despite adrenaline being considered standard of care for many decades. The aim of our study was to determine the effect of adrenaline on patient survival to hospital discharge in out of hospital cardiac arrest.
Methods: We conducted a double blind randomized placebo-controlled trial of adrenaline in out-of-hospital cardiac arrest. Identical study vials containing either adrenaline 1:1000 or placebo (sodium chloride 0.9%) were prepared. Patients were randomly allocated to receive 1 mL aliquots of the trial drug according to current advanced life support guidelines. Outcomes assessed included survival to hospital discharge (primary outcome), prehospital return of spontaneous circulation (ROSC) and neurological outcome (Cerebral Performance Category Score – CPC).
Results: A total of 4103 cardiac arrests were screened during the study period of which 601 underwent randomization. Documentation was available for a total of 534 patients: 262 in the placebo group and 272 in the adrenaline group. Groups were well matched for baseline characteristics including age, gender and receiving bystander CPR. ROSC occurred in 22 (8.4%) of patients receiving placebo and 64 (23.5%) who received adrenaline (OR = 3.4; 95% CI 2.0–5.6). Survival to hospital discharge occurred in 5 (1.9%) and 11 (4.0%) patients receiving placebo or adrenaline respectively (OR = 2.2; 95% CI 0.7–6.3). All but two patients (both in the adrenaline group) had a CPC score of 1–2.)
Conclusion: Patients receiving adrenaline during cardiac arrest had no statistically significant improvement in the primary outcome of survival to hospital discharge although there was a significantly improved likelihood of achieving ROSC.