Epinephrine in Resuscitation: Curse or Cure?

Robert R Attaran; Gordon A Ewy

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

Historical Considerations

In 1874, Pellacani became perhaps the first to administer adrenal extract to animals.^[9] The extract was found to increase arterial tone, ventricular contractions and blood pressure. In 1896, after inducing profound hypotension, Gottlieb restored circulation by administering adrenal extract.^[10]

As early as 1906, Crile and Dolley noted the importance of an adequate aortic diastolic pressure during attempted cardiac resuscitation.^[11] They stated that it often was not possible to achieve an adequate aortic diastolic pressure without the addition of epinephrine.

Since epinephrine has both inotropic and chronotropic effects on the beating heart and also produces peripheral vasoconstriction, there was confusion regarding which of these effects was the most important. Epinephrine increases the peripheral vascular resistance, transiently decreasing perfusion to most of the body, but in the process increases the aortic diastolic pressure and perfusion to the heart.

The classic studies of Pearson and Redding performed in the 1960s merit emphasis.^[12–14] After induction of asphyxial cardiac arrest, chest compressions and ventilations resulted in survival of none of the ten animals that received isoproterenol, all of the animals that received epinephrine and nine of the ten animals that received the α-agonist methoxamine. In a similar study following VF induction, survival was one out of ten without drugs, nine out of ten with epinephrine and ten out of ten with the α-agonist phenylephrine. In the 1970s, a re-examination of this phenomenon found that α-adrenergic blockade administered with epinephrine prevented resuscitation in animals with cardiac arrest. However, resuscitation of animals with β-adrenergic blockade administered with epinephrine, however, was uniformly successful.^[15] Early on it was concluded that drugs that have their principal effect by cardiac stimulation, such as isoproterenol or dobutamine, did not help during cardiac arrest. Drugs that were potent peripheral vasoconstrictors, such as phenylephrine, methoxamine or dopamine, were as effective as epinephrine during cardiopulmonary resuscitation (CPR).

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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?

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