Amiodarone vs. Lidocaine for Shock-Resistant Ventricular Fibrillation

Abstract & Commentary

Synopsis: The use of amiodarone results in a better outcome than use of lidocaine in patients with shock resistant out-of-hospital cardiac arrest.

Source: Dorian P, et al. N Engl J Med. 2002;346: 884-890.

Dorian and colleagues performed a double-blind, clinical trial comparing amiodarone with lidocaine in patients with out-of-hospital ventricular fibrillation. Adults with out-of-hospital cardiac arrest in whom ventricular fibrillation was documented were potential candidates. If ventricular fibrillation was resistant to 3 shocks from an external defibrillator followed by 1 dose of intravenous epinephrine and a fourth defibrillator shock, they were then eligible for entry into the trial. Drug administration kits were distributed to ambulances in a balanced randomized order in blocks of four. A double-blind, double-dummy technique was used. Each kit contained either active amiodarone and a lidocaine placebo or active lidocaine and an amiodarone placebo. Amiodarone was administered at a dose of 5 mg/kg of estimated body weight. Lidocaine was given at a dose of 1.5 mg/kg estimated body weight. Both drugs were infused rapidly into a peripheral vein and then further defibrillator shocks were delivered as necessary. If ventricular fibrillation persisted after the next shock, a second dose of the study drug could be administered (1.5 mg of lidocaine per kilogram or 2.5 mg of amiodarone per kilogram) together with placebo, and attempts at resuscitation were continued. The primary study end point was survival to admission to the hospital intensive care unit. Patients who died in the field or in the emergency department were not considered to have been admitted. Secondary end points included survival to discharge from hospital and adverse events.

Between November 1995 and April 2001, 347 patients were enrolled in the trial. The mean interval from the time at which the paramedics were dispatched to the scene and their arrival at the patient’s side was 7 ± 3 minutes and the mean interval from dispatch to the time of drug administration was 25 ± 8 minutes. The group was approximately 80% male with a mean age of 67 years. Sixty percent of the patients had a history of prior cardiac disease. The cardiac arrest had been witnessed in 77% of the patients. Twenty-seven percent of the patients had received bystander cardiopulmonary resuscitation. Before receiving the study drug, patients had received 5 ± 2 shocks. Twenty-four patients in the amiodarone group (13%) and 11 (7%) in the lidocaine group had manifested a transient return of spontaneous circulation before receiving study drug. Eighty seven patients in the amiodarone group and 86 patients in the lidocaine group received a second dose of the study drug.

In the amiodarone group, 41 of 180 patients (22.8%) survived to hospital admission as compared with 20 of 167 patients (12%) in the lidocaine group (P = 0.009). In addition to treatment with amiodarone, other factors that significantly influenced survival to hospital admission were the length of time to the administration of the drug and the presence or absence of a transient return of spontaneous circulation before the administration of the study drug. The adjusted odds ratio for survival to hospital admissions in recipients of amiodarone as compared with recipients of lidocaine was 2.49 (P = 0.007). There were no differences between the treatment groups in the proportion of the patients who needed treatment of bradycardia or hypotension. Asystole was more common in the lidocaine group (40 of 142 patients, 28.9%) than in the amiodarone group (28 of 152, 18.4%). Among the 41 patients who received a hospital admission in the amiodarone group, 9 (5%) survived to hospital discharge as compared with 5 of the 20 initial survivors in the lidocaine group (3% of the entire group).

Dorian et al conclude that the use of amiodarone results in a better outcome than use of lidocaine in patients with shock resistant out of hospital cardiac arrest.

Comment by John P. DiMarco, MD, PhD

Although lidocaine has traditionally been the intravenous antiarrhythmic drug of choice in the treatment of shock-resistant ventricular fibrillation, there are few data supporting a role for lidocaine in this setting. It has remained in resuscitation algorithms mostly by default since no other agent had been shown to be superior. Several years ago the amiodarone in out-of-hospital resuscitation of refractory sustained ventricular tachycardia (ARREST) study (N Engl J Med. 1999;341:871-878) showed improved survival to hospital admission when amiodarone was compared to placebo in patients with shock-resistant ventricular fibrillation. The current study confirms the benefit of amiodarone over lidocaine in this setting.

The mechanism by which amiodarone produces its effect is uncertain. Amiodarone has complex electrophysiologic properties including: noncompetitive beta-adrenergic blockade, calcium channel blockade, sodium channel blockade, and prolongation of the action potential. However, in studies looking at the onset of these effects after IV administration, beta-adrenergic blockade has been the effect seen first. It is possible that what we are seeing here is an early effect due to noncompetitive beta-adrenergic blockade on either the tendency to re-fibrillate after an initial defibrillation or an effect on defibrillation threshold itself. However, it should be remembered that chronic amiodarone therapy does not lower defibrillation thresholds.

Intravenous amiodarone is relatively costly and has a short shelf life. In its current formulation, which requires a solubilizing agent, it may cause hypotension and phlebitis after peripheral injection. These factors argue against its inclusion early in a resuscitation algorithm. An effective alternative to amiodarone would be of value. If the results seen in this trial and in the ARREST study are really due to beta-adrenergic blockade, then use of other less toxic and more readily available intravenous beta-adrenergic blockers might produce similar results.

It is also important to note that amiodarone did not improve survival to hospital discharge. This is not an unexpected finding since the mean time for administration was 25 minutes after collapse. The patients who received the drugs earlier after arrest seemed to do better. Further trial in out-of-hospital resuscitation should seek to improve survival to discharge, the most meaningful clinical measurement of drug efficacy.

Dr. DiMarco is Professor of Medicine, Division of Cardiology, University of Virginia, Charlottesville.