Epinephrine in Resuscitation: Curse or Cure?

Robert R Attaran; Gordon A Ewy

Future Cardiol. 2010;6(4):473-482.

Abstract and Introduction

Abstract

The use of epinephrine during cardiac arrest has been advocated for decades and forms an integral part of the published guidelines. Its efficacy is supported by animal data, but human trial evidence is lacking. This is partly attributable to disparities in trial methodology. Epinephrine's pharmacologic and physiologic effects include an increase in coronary perfusion pressure that is key to successful resuscitation. One possible explanation for the lack of epinephrine's demonstrated efficacy in human trials of out-of-hospital cardiac arrest is the delay in its administration. A potential solution may be intraosseus epinephrine, which can be administered quicker. More importantly, it is the quality of the basic life support, early and uninterrupted chest compressions, early defibrillation and postresuscitation care that will provide the best chance of neurologically intact survival.

Introduction

Epinephrine administration has been advocated during resuscitation of cardiac arrest for decades.^[1–5] The 2005 guidelines by both the American Heart Association and the European Resuscitation Council recommend its use.^[6–8] Surprisingly, definitive evidence for epinephrine's efficacy in humans is lacking. As with many components of the Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiac Care, its recommendation is largely based on tradition and its success in animal models. Conflicting results between animal and human research are due to the disparate methodology and populations studied, as well as the duration of untreated and treated cardiac arrest prior to epinephrine administration. The purpose of this article is to review the pertinent literature and to provide our perspective on the present role of epinephrine in resuscitation of out-of-hospital cardiac arrest (OHCA), with emphasis on primary cardiac arrests owing to ventricular fibrillation (VF). This perspective is influenced by the senior author's extensive experience with epinephrine use during experimental and clinical resuscitation studies of subjects with primary cardiac arrest.

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Executive Summary

Introduction

Epinephrine administration has been advocated in resuscitation for decades and forms a key component of published guidelines. Its usage is based chiefly on animal studies, and human trial evidence is scant.

Pharmacologic & physiologic considerations: the importance of coronary perfusion pressure

There are subtypes of both the α- and β-adrenergic receptors, and that epinephrine's effects are mediated through α ₁ -, α ₂ -, β ₁ - and β ₂ -receptors.
The key to successful resuscitation is to achieve a high aortic diastolic pressure and, by extension, coronary perfusion pressure.
High coronary perfusion pressures have been associated with improved return of spontaneous circulation (ROSC) in human and animal studies and with improved survival in animal studies.
Epinephrine can also have adverse effects including increased myocardial oxygen consumption and necrosis, postresuscitation myocardial dysfunction and ventricular arrhythmias.

Epinephrine dosing

Higher-dose epinephrine has been found to be harmful in animal studies.
Limited human trial data show no benefit to higher-dose epinephrine over standard dosing.

Human studies of epinephrine in cardiac arrest

To date, no randomized controlled human trial has specifically evaluated early epinephrine administration in cardiac arrest.
One recent randomized controlled trial (RCT) from Norway evaluated early administration of epinephrine and other intravenous drugs (atropine and amiodarone) in out-of-hospital cardiac arrest (OHCA). The group treated with early intravenous drugs had higher ROSC and survival to hospital admission, but there was no difference in survival to discharge, survival with good neurological function or longer-term survival. This RCT did not find epinephrine use to be an independent predictor of poor outcome.

Intraosseous administration of epinephrine

Animal studies support early administration of vasopressors for improving neurologically intact survival.
Vasopressor administration times in animal studies are often less than 10 min.
By contrast, in human studies, the first drugs are administered at 10–25 min (mean: 17.7 min) post-emergency medical services dispatch. This can explain the lack of observed benefit of epinephrine usage in human OHCA.
One way to administer epinephrine quicker is with intraosseus access.

Deleterious effects of multiple-dose epinephrine

Epinephrine is not always the ideal vasopressor and this may be attributable to its β-adrenergic effects.
Epinephrine usage may result in increased recurrent VF and in electrical storm, β-blockade is the preferred treatment.
Future human RCTs should evaluate epinephrine combined with β-blockers and pure α-adrenergic drugs.
Epinephrine usage is so engrained in the current guidelines that it would take compelling evidence to remove it, evidence that to this day does not exist.

Quality of resuscitation is critically important

The message regarding optimal care in cardiac arrest, in particular OHCA, should not be lost in the debate over the use of epinephrine. It is the quality of the basic and advanced resuscitation efforts that determines survival.
During early cardiac arrest, interventions that have been shown to improve survival must be emphasized: early and continuous chest compressions, early defibrillation and delaying endotracheal intubation.
Interruptions to chest compressions to obtain intravenous access may be counterproductive. Intraosseus administration of epinephrine can minimize the interruption and allow for quicker drug delivery.
Cardiocerebral resuscitation, a system that prohibits early endotracheal intubation, advocates 200 chest compressions before and immediately after a single shock and advocates the early administration of epinephrine, significantly improves survival of patients with OHCA who have a witnessed arrest and a shockable rhythm on arrival of the paramedics.

Conclusion

Epinephrine can be either a curse or a cure in cardiac arrest.
Its value depends on the dosage given, the timing of administration, and the initiating factor of the cardiac arrest.
Epinephrine can be a curse in excessive doses or if used too late in resuscitation efforts, resulting in ROSC without improved (and neurologically intact) survival.
Despite the demonstrated benefit of epinephrine in animal studies, human trials have failed to show a benefit. The two major explanations for this disparity are: epinephrine in animal trials is given approximately 10 min sooner; and the initiating factor of the VF arrest in animal studies is often different.
Nevertheless, earlier administration of epinephrine (e.g., via the intraosseus route) is not the cure by itself. Its usage should be integrated into a series of essential steps including cardiocerebral resuscitation and postresuscitation care.

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Epinephrine in Resuscitation: Curse or Cure?

Abstract and Introduction

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