Author + information
- Gordon A. Ewy, MD∗ ()
- ↵∗Reprint requests and correspondence:
Dr. Gordon A. Ewy, Sarver Heart Center, University of Arizona College of Medicine, 932 West San Martin Drive, Tucson, Arizona 85704.
For nearly a half-century, guidelines have recommended epinephrine (adrenaline) as an essential adjunct to resuscitation of patients with cardiac arrest. However, the report by Dumas et al. (1) in this issue of the Journal is one of a growing number of papers questioning the role of this vasopressor in the management of patients with out-of-hospital cardiac arrest (OHCA) (1).
Time-Sensitive Role of Vasopressors During Resuscitation
Vasopressors have an essential but time-sensitive role in improving return of spontaneous circulation (ROSC) and neurologically intact survival in studies of ventricular fibrillation (VF) arrest. Insight into their role is perhaps best appreciated in the context of Weisfeldt and Becker’s (2) “3-phase time-sensitive model” of VF. In this model, during the first few minutes, called the “electrical” phase, all that is needed is prompt defibrillation. This is why implantable cardioverter-defibrillators and automated external defibrillators are effective. The initial phase of VF arrest may be prolonged by early and near continuous chest compressions, as first reported a half-century ago by Kouwenhoven et al. (3).
Patients defibrillated during this preliminary phase are more likely to respond with a perfusing rhythm and therefore less likely to need vasopressors. Thus, any comparison of survival between patients with OHCA treated by emergency medical service personnel who do or do not receive epinephrine during the electrical phase will most likely favor those who do not receive epinephrine.
In contrast, during the second or “circulatory” phase of VF, vasopressors are often necessary to augment the coronary perfusion pressure (CPP) generated by chest compressions to increase the chance of obtaining ROSC (4–6). It should not need emphasis, but without ROSC there is no survival.
During the third or “metabolic” phase of VF arrest, survival is rare. Even restoration of optimal CPP is unlikely to result in survival (7). Very late in cardiac arrest, those who attain ROSC without epinephrine obviously have a better pathophysiological condition than those who require epinephrine for ROSC; therefore, in the absence of a randomized trial, comparing survival of those who did and did not receive epinephrine after 20 min of cardiac arrest is not helpful. This fact, long known from animal research, is becoming of concern in humans, perhaps accounting for the increasing number of reports questioning the role of epinephrine in managing OHCA.
Dumas et al. (1) also found the effects of epinephrine during resuscitation efforts of OHCA to be time sensitive. When epinephrine was given within the first 9 min after cardiac arrest, patients had a better outcome (adjusted odds ratio [aOR]: 0.54; 95% confidence interval [CI]: 0.32 to 0.91) compared with those who received treatment between 10 and 15 min (aOR: 0.33; 95% CI: 0.20 to 0.56), between 16 and 22 min (aOR: 0.23; 95% CI: 0.12 to 0.43), and >22 min after cardiac arrest (aOR: 0.17; 95% CI: 0.09 to 0.34).
Randomized Controlled Trial in Humans
The first and, to date, only reported randomized, double-blind, placebo-controlled trial of adrenaline (epinephrine) in patients with OHCA by Jacobs et al. (8) showed that ROSC occurred in 8.4% of patients receiving placebo versus 23.5% receiving adrenaline (odds ratio: 3.4; 95% CI: 2.0 to 5.6) (8). Survival to hospital discharge was 1.9% and 4.0% for those who received placebo or adrenaline, respectively (odds ratio: 2.2; 95% CI: 0.7 to 6.3). All but 2 patients (both in the adrenaline group) had a Cerebral Performance Category score of 1 to 2. However, in this study, patients receiving adrenaline had no statistically significant improvement in survival to hospital discharge. Unfortunately, in this important study, time to administration of adrenaline was not reported. However, the overwhelmingly negative effect of epinephrine reported by Dumas et al. (1) is not supported by this randomized control trial of epinephrine in humans.
Thus, a key question is whether any vasopressor agent administered in the circulatory phase of resuscitation will result in improved survival. Future human investigation of vasopressor agents for OHCA, whether prospective or retrospective, must separate time courses for vasopressor administration.
Epinephrine Is Not the Ideal Vasopressor
The key question is whether epinephrine is the optimal vasopressor. Over the past half-century, resuscitation research in animals found that during the circulatory phase (after 10 min) of untreated VF arrest, survival was better when the CPP produced by chest compressions was enhanced by a variety of vasopressors (pure alpha-adrenergic drugs such as phenylephrine or methoxamine, alpha- and beta-adrenergic agonists such as epinephrine, and epinephrine given with a beta-adrenergic blocker) (9–11). It has been shown that during the circulatory phase of VF arrest, resuscitation was effective with epinephrine plus a beta-adrenergic blocker but not with epinephrine plus an alpha-adrenergic blocker (10).
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.
Limitations and Contributions
There are 3 limitations to the study by Dumas et al. (1) that readily come to mind. The first is that it is not known why about one-fourth of the patients were not given epinephrine. The second is that those receiving epinephrine had less favorable prognostic characteristics; 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). Third, the survival rates of emergency medical services that followed guideline recommendations for early treatment with epinephrine and had short response times reported excellent survival rates of patients with OHCA secondary to VF arrest (12).
Nevertheless, Dumas et al. (1) have made a major contribution to resuscitation science for at least 2 reasons. First, their work adds to the concern that epinephrine is not the ideal vasopressor during resuscitation of patients with OHCA. Second, they found that the adverse effects associated with late and repeated doses of epinephrine were not modified by post-resuscitation care such as hypothermia. This finding is disappointing but requires further investigation, for example, to determine if longer durations of hypothermia might be necessary in this or other subgroup of patients with ROSC after OHCA.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Dr. Ewy has reported that he has no relationships relevant to the contents of this paper to disclose.
- American College of Cardiology Foundation