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Abstract & commentary
Synopsis: Amiodarone improves the probability of admission to the hospital after failure of initial resuscitation in victims of out-of-hospital cardiac arrest.
Source: Kudenchuk PJ, et al. N Engl J Med 1999; 341:871-878.
It has not been conclusively shown that antiarrhythmic drugs during cardiopulmonary resuscitation improve outcome. Kudenchuk and colleagues conducted a randomized, double-blind, placebo-controlled trial using intravenous amiodarone in patients with out-of-hospital cardiac arrest. Victims of cardiac arrest were initially treated by first responders who initiated basic life support measures including the delivery of shocks using an automatic external defibrillator. Adults with nontraumatic out-of-hospital cardiac arrest could be included in the study if ventricular fibrillation or pulseless ventricular tachycardia was still present after three or more precordial shocks had been delivered, if intravenous access had been established, and if a paramedic team with study drug arrived on the scene. At this point, patients underwent endotracheal intubation and received 1 mg of epinephrine intravenously according to the standard advanced cardiac life support protocol. Eligible patients then were randomly assigned to receive either 300 mg of intravenous amiodarone or its diluent, polysorbate 80, as placebo. The primary end point for the study was admission to the hospital with a spontaneously perfusing rhythm. This was defined as a rhythm and blood pressure sufficiently stable to allow assignment to an inpatient hospital bed. Deaths in the emergency room were not considered to have been admissions to the hospital. Secondary end points were adverse effects, number of shocks required after the administration of amiodarone or placebo, duration of resuscitation, survival to discharge, and functional neurologic status at discharge.
Fifteen hospitals participated in the study. During the study period (November 1994-February 1997), 3954 consecutive patients without a possible cardiac arrest were considered for enrollment in the trial. A total of 504 patients were appropriately randomized and received either amiodarone or placebo. The group was predominantly male, with a mean age of 66 years. Slightly more than 70% of the arrests were witnessed and approximately 60% of the patients received bystander cardiopulmonary resuscitations. The initial cardiac arrest rhythm was ventricular fibrillation in 83% of the study patients. The remaining patients either had asystole or pulseless electrical activity converting to ventricular fibrillation or had pulseless ventricular tachycardia. Arrival time for first responders was similar between the two groups (4.4 minutes), as was arrival time for paramedics (8.6 minutes). However, time to administration of study drug was approximately 21 minutes because of the previous resuscitation efforts.
An average of five shocks were delivered before the administration of amiodarone or placebo. Twenty-one percent of the patients had transient return of spontaneous circulation before administration of study drug. Bradycardia requiring treatment occurred in about one-fifth of the patients before study drug administration.
Of the 544 patients in the study, 197 (39%) survived to be admitted to the hospital. Admission to the hospital was more likely among recipients of amiodarone (44% vs 34%; P = 0.03). After adjustment for relevant clinical factors, the risk ratio for survival to admission to the hospital favored amiodarone by a factor of 1.6 (95% confidence interval, 1.1 to 2.24; P = 0.02). Patients whose cardiac arrest was due to ventricular fibrillation were more likely to survive to be admitted to the hospital than were those whose initial rhythm was asystole or pulseless electrical activity (44% vs 14%). Early transient return of spontaneous circulation was also a predictor of survival. After admission to the hospital, patients were managed by their physicians with conventional methods. A total of 67 patients (13%) were discharged alive from the hospital. One hundred seventeen of the patients admitted to the hospital never regained consciousness. There was no difference in survival to hospital discharge between the amiodarone and placebo groups (13.4% vs 13.2%). However, 35 of the 67 patients discharged after treatment resumed independent living or returned to their former employment after discharge.
Kudenchuk et al conclude that amiodarone improved the probability of admission to the hospital after failure of initial resuscitation in victims of out-of-hospital cardiac arrest. They also propose that further studies with amiodarone in this setting are indicated.
Comment by John P. DiMarco, MD, PhD
Although antiarrhythmic drugs are frequently used in the setting of cardiac arrest, no study has shown benefit with such therapy. In part, this is due to the difficulty in performing randomized clinical trials in out-of-hospital cardiac arrest. However, the limited data available have not shown benefit with lidocaine, bretylium, or other antiarrhythmic drugs. The present study that used amiodarone can be interpreted in several ways. An optimistic interpretation would be to say that a single dose of amiodarone in the setting of refractory cardiac arrest demonstrated an improvement in the survival rate to hospital admission. A conservative interpretation would say that survival to hospital discharge was not affected by drug therapy. In the later interpretation, the use of amiodarone only increased hospital admissions and costs without producing significant patient benefit. The real value of this paper probably lies somewhere in between. Amiodarone did produce a change in the primary end point of the study. However, amiodarone was administered relatively late during the resuscitation. The data suggest that earlier, more aggressive administration is worthy of study since this is the time in which real effects on long-term survival would be most likely.
The mechanism by which amiodarone produced its effect is unknown. A single dose of intravenous amiodarone probably results in relatively little change in the repolarization properties of the ventricle. In other studies, one of the first effects seen with intravenous amiodarone has been noncompetitive beta adrenergic blockade. Some authorities have recommended use of intravenous beta blockers to prevent early recurrence of ventricular fibrillation after an initial defibrillation. Thus, it is possible that some of the effects seen with amiodarone in this study are due to just beta blockade. In that case, use of intravenous beta adrenergic blockers would be easier and less expensive than adding amiodarone to the resuscitation algorithm.
Studies in out-of-hospital cardiac arrest victims are difficult both from a logistical and an ethical standpoint. However, it is clear that further studies need to be done. This paper by Kudenchuk et al should encourage further clinical trials in this important field.
a. increased survival to hospital discharge.
b. increased survival to hospital admission.
c. improved neurologic outcomes.
d. increased one-year survival.