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Background Lidocaine has been the initial antiarrhythmic drug treatment recommended for patients with ventricular fibrillation that is resistant to conversion by defibrillator shocks. We performed a randomized trial comparing intravenous lidocaine with intravenous amiodarone as an adjunct to defibrillation in victims of out-of-hospital cardiac arrest.
Methods Patients were enrolled if they had out-of-hospital ventricular fibrillation resistant to three shocks, intravenous epinephrine, and a further shock; or if they had recurrent ventricular fibrillation after initially successful defibrillation. They were randomly assigned in a double-blind manner to receive intravenous amiodarone plus lidocaine placebo or intravenous lidocaine plus amiodarone placebo. The primary end point was the proportion of patients who survived to be admitted to the hospital.
Results In total, 347 patients (mean [±SD] age, 67±14 years) were enrolled. The mean interval between the time at which paramedics were dispatched to the scene of the cardiac arrest and the time of their arrival was 7±3 minutes, and the mean interval from dispatch to drug administration was 25±8 minutes. After treatment with amiodarone, 22.8 percent of 180 patients survived to hospital admission, as compared with 12.0 percent of 167 patients treated with lidocaine (P=0.009; odds ratio, 2.17; 95 percent confidence interval, 1.21 to 3.83). Among patients for whom the time from dispatch to the administration of the drug was equal to or less than the median time (24 minutes), 27.7 percent of those given amiodarone and 15.3 percent of those given lidocaine survived to hospital admission (P=0.05).
Conclusions As compared with lidocaine, amiodarone leads to substantially higher rates of survival to hospital admission in patients with shock-resistant out-of-hospital ventricular fibrillation.
Antiarrhythmic therapy is often administered to patients with ventricular fibrillation; the "Guidelines 2000 for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care" of the American Heart Association and the International Liaison Committee on Resuscitation recommend antiarrhythmic drugs as "acceptable" and "probably helpful" in the treatment of ventricular fibrillation that persists after three or more external defibrillation shocks.2 Lidocaine has traditionally been used in such cases, as well as for the prevention of recurrent ventricular fibrillation.3 However, no randomized clinical trial has demonstrated the efficacy of lidocaine for these indications. The current guidelines recommend considering the use of either amiodarone or lidocaine for shock-resistant ventricular fibrillation.2
The Amiodarone versus Lidocaine in Prehospital Ventricular Fibrillation Evaluation (ALIVE) was a double-blind, controlled clinical trial comparing amiodarone with lidocaine in patients with out-of-hospital ventricular fibrillation in Toronto.
Methods
Patients
Patients were eligible if they were adults with electrocardiographically documented out-of-hospital ventricular fibrillation, not due to trauma, or with other cardiac rhythms that converted to ventricular fibrillation; if the ventricular fibrillation was resistant to three shocks from an external defibrillator, at least one dose of intravenous epinephrine, and a fourth defibrillator shock; and if they continued to have ventricular fibrillation or had recurrent ventricular fibrillation after successful initial defibrillation.
Protocol
The study was conducted under the auspices of the Toronto Emergency Medical Services system, a multitiered out-of-hospital emergency-response system that follows treatment protocols in accordance with the American Heart Association guidelines for advanced cardiac life support.2 The human-subjects review committee of the University of Toronto approved the study, including its provisions for waiver of informed consent. The investigator-initiated protocol was designed, drafted, and executed, and the results were analyzed, without any contribution from the study sponsors (WyethAyerst Laboratories). The manuscript was written entirely by the study authors and was not sent to the sponsors for review. All the authors contributed to the planning and execution of the trial, as well as to the analysis of the results and the drafting of the manuscript.
Drug-administration kits were distributed to ambulances, one at a time, in balanced, randomized order in blocks of four. Each kit contained either active amiodarone (Cordarone, WyethAyerst Laboratories, Philadelphia) and lidocaine placebo or active lidocaine (supplied by Sanofi-Synthelabo, Paris) and amiodarone placebo. Amiodarone (5 mg per kilogram of estimated body weight) or its matching placebo containing the same diluent (polysorbate 80), diluted to 30 ml with 5 percent dextrose in water, and lidocaine (1.5 mg per kilogram at a concentration of 10 mg per milliliter) or its matching placebo were infused rapidly into a peripheral vein, and further defibrillator shocks were administered as necessary, along with further advanced cardiac life support.2,3
If ventricular fibrillation persisted after a further shock, a second dose of the study drug was 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. Resuscitated patients were admitted to 1 of 17 community hospitals, without disclosure of their treatment assignment or any directives for further treatment.
Recording of Data
All data were analyzed without knowledge of the patients' treatment assignments. Data on the patient's course before hospitalization were obtained from the ambulance call report, which included documentation of the initial and all subsequent cardiac rhythms during treatment of the arrest, all drugs administered, the state of circulation (the presence or absence of a spontaneous palpable pulse), and the time, recorded in Utstein reference format. The time of dispatch was recorded as the time when the emergency-response dispatch center ordered emergency personnel to go to the scene. Data on admission to and discharge from the hospital were obtained from hospital charts.
End Points
The primary study end point was survival to admission to the hospital intensive care unit; patients who died in the emergency department were not considered to have been admitted. Secondary end points included survival to discharge from the hospital and adverse events, defined as the need to administer atropine or dopamine after administration of the study drug.
Statistical Analysis
On the basis of an estimated improvement in survival to hospital admission from 25 percent among patients receiving lidocaine to 40 percent among those receiving amiodarone, an alpha error of 0.05, and a power of 80 percent, a required sample size of 160 patients in each treatment group, or a total of 320 patients, was calculated; this figure was increased to 350 to allow for missing data. The study results were reviewed by an independent data and safety monitoring board, whose members could recommend termination of the study.
Summary statistics for continuous variables were recorded as means and standard deviations, as well as medians; comparisons between the two treatment groups were performed with the Wilcoxon rank-sum test. All P values are two-tailed. Categorical data were summarized as frequencies and percentages, and comparisons between the two treatment groups were performed with the Pearson chi-square test or Fisher's exact test. Multiple logistic regression with backward selection of variables and calculation of odds ratios was used to identify variables that predicted the rate of survival to hospital admission.
Results
Between November 1995 and April 2001, 347 patients (mean [±SD] age, 67±14 years) were randomly assigned to receive amiodarone (180 patients) or lidocaine (167 patients). During this period, cardiac arrests occurred at the rate of approximately 1400 per year in the metropolitan Toronto Emergency Medical Services system; 78 percent of these arrests were treated by advanced life-support crews. Approximately 26 percent of the patients treated by the crews had ventricular fibrillation.
All patients in the study had ventricular fibrillation or pulseless ventricular tachycardia at some time during treatment of the cardiac arrest. The distribution of initial rhythms and rhythm at the time of administration of the study drug, intervals to procedures, and characteristics of patients is given in Table 1. The mean interval from the time at which 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. Except for the study drugs administered, there were no significant differences between the amiodarone and lidocaine groups in any treatment or procedure (Table 1). Eighty-seven patients in the amiodarone group and 86 patients in the lidocaine group received a second dose of the study drug.
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Shorter intervals from the dispatch of the crew to the administration of the study drug were associated with increased survival to hospital admission. The 50 percent of patients with such intervals at or below the median of 24 minutes had an overall survival to hospital admission of 21.4 percent, as compared with 12.7 percent for the patients with intervals above the median (P=0.04). Unadjusted analysis found no association between survival to hospital admission and whether or not the first shock was administered by a basic-life-support crew (which was not equipped for advanced cardiac life-support treatment or administration of the study drug), the interval from dispatch to the first attempt at defibrillation (for patients with ventricular fibrillation as the initial rhythm), or whether or not a bystander performed cardiopulmonary resuscitation (Table 2). However, among patients whose initial rhythm was ventricular fibrillation, the interval from the first shock to the administration of the drug was a significant predictor of survival (odds ratio for survival for each minute of delay, 0.87; 95 percent confidence interval, 0.80 to 0.96; P=0.003).
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0.001). The characteristics of resuscitation and treatment before and after the administration of amiodarone or lidocaine are listed in Table 3.
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Forty-one patients (22.8 percent) in the amiodarone group survived to hospital admission, as compared with 20 patients (12.0 percent) in the lidocaine group (P=0.009; unadjusted odds ratio for survival, 2.17; 95 percent confidence interval, 1.21 to 3.83) (Table 2). This change represents a relative improvement of 90 percent (Figure 1). After adjustment for other factors that may influence the likelihood of survival, the only factors that significantly influenced the primary outcome were the study-drug assignment, the length of time to the administration of the drug (odds ratio for survival for each minute of delay, 0.88; 95 percent confidence interval, 0.83 to 0.93; P<0.001), and the presence or absence of a transient return of spontaneous circulation before the administration of the study drug (odds ratio for survival with transient return, 5.93; 95 percent confidence interval, 2.46 to 14.26; P<0.001). The adjusted odds ratio for survival to hospital admission in recipients of amiodarone as compared with recipients of lidocaine was 2.49 (95 percent confidence interval, 1.28 to 4.85; P=0.007).
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Among patients who had ventricular fibrillation or pulseless ventricular tachycardia as their initial rhythm, 35 of 141 given amiodarone (24.8 percent) survived to hospital admission, as compared with 19 of 134 given lidocaine (14.2 percent, P=0.03). Among 69 patients with an initial rhythm other than ventricular fibrillation or pulseless ventricular tachycardia, 6 of 38 given amiodarone (15.8 percent) survived to hospital admission, as compared with 1 of 31 given lidocaine (3.2 percent, P=0.08) (Figure 1).
Figure 2 illustrates the effect of length of time between the dispatch of the crew and the administration of the study drug on the proportion of amiodarone-treated and lidocaine-treated patients who survived to hospital admission. Among both patients treated at or before the median interval (24 minutes) and those treated after the median interval, the proportion surviving until admission was significantly higher after treatment with amiodarone than after treatment with lidocaine (time effect, P<0.001; drug effect, P=0.005; interaction between time and drug, P=0.26).
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The proportion of patients in whom asystole occurred following defibrillation shock after administration of the initial study drug was significantly higher in the lidocaine group (41 of 142 patients, 28.9 percent) than in the amiodarone group (28 of 152, 18.4 percent; P=0.04).
Survival after Hospital Admission
Among the 41 patients who survived to hospital admission after receiving amiodarone, 9 (5 percent of the entire group) survived to hospital discharge, as compared with 5 of the 20 initial survivors in the lidocaine group (3 percent of the entire group, P=0.34). The initial rhythm was ventricular fibrillation in all the long-term survivors; among those in whom the initial rhythm was ventricular fibrillation, 9 of 140 treated with amiodarone (6.4 percent) and 5 of 132 treated with lidocaine (3.8 percent) were discharged from the hospital alive (P=0.32).
Discussion
Although antiarrhythmic drug therapy is often administered during the course of cardiac arrest due to ventricular fibrillation or pulseless ventricular tachycardia, there has been no agreement on the preferred drug in such situations.1 According to the "Guidelines 2000 for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care," amiodarone and lidocaine should be considered for patients with persistent or recurrent ventricular fibrillation or pulseless ventricular tachycardia after three unsuccessful defibrillator shocks, administration of epinephrine or vasopressin, and one or more subsequent attempts at defibrillation.2 The evidence in favor of amiodarone is classified as 2b (i.e., its use is based on "fair to good evidence," and it is "acceptable, safe, and useful") and the evidence in favor of lidocaine as "indeterminate" (i.e., it is "recommended for use, but where the research quantity/quality falls short of supporting a final class decision").
Lidocaine has traditionally been the antiarrhythmic drug of choice for the treatment of shock-resistant ventricular fibrillation, as well as for the prevention of recurrence of ventricular fibrillation after out-of-hospital cardiac arrest.1,2,4 Despite its long history of use, ease and simplicity of administration, and well-understood pharmacologic and adverse-effect profiles, there is no evidence from randomized, clinical trials in the out-of-hospital setting that lidocaine is superior to other drugs or to placebo in terms of any end point related to out-of-hospital resuscitation, including the rates of survival to hospital admission and survival to hospital discharge.2 In small randomized trials comparing lidocaine with bretylium, there were no significant differences between the treatment groups in the proportion surviving until admission to the hospital.5,6 A small randomized comparison of amiodarone with lidocaine (involving 20 patients) found that more patients treated with amiodarone were successfully resuscitated.7 A randomized study comparing lidocaine with epinephrine found that more patients treated with lidocaine had asystole and that there was no difference between the groups in the proportion with return of spontaneous circulation.8 In a retrospective study of in-hospital cardiac arrest, there were more deaths among patients given lidocaine than among patients not given lidocaine,9 and in an animal model of cardiac arrest, amiodarone was associated with significantly better resuscitation rates than lidocaine.10 In animal models of myocardial ischemia, lidocaine, like other sodium-channel blockers, may be proarrhythmic.11 However, lidocaine continues to be used in many emergency-medical-services systems as an adjunctive treatment for shock-resistant ventricular fibrillation and for the prevention of recurrent ventricular fibrillation after successful defibrillation.12
Intravenous amiodarone has been used in the treatment of frequent recurrences of destabilizing ventricular tachycardia or ventricular fibrillation in the hospital.13,14,15 Intravenous amiodarone appears effective in the prevention of recurrent ventricular fibrillation and unstable ventricular tachycardia that is resistant to lidocaine and procainamide.13,14 The Amiodarone in Out-of-Hospital Resuscitation of Refractory Sustained Ventricular Tachycardia (ARREST) study compared amiodarone with placebo in a blinded, randomized trial in patients with shock-refractory out-of-hospital ventricular fibrillation or pulseless ventricular tachycardia; 44 percent of amiodarone-treated patients and 34 percent of placebo-treated patients survived to hospital admission (P=0.03).16 This was the first large, randomized study to show a benefit of any antiarrhythmic drug over placebo in patients with out-of-hospital cardiac arrest.
Uncertainties remain about the use of amiodarone outside the hospital. Intravenous amiodarone has adverse effects, including a tendency to cause hypotension and bradycardia; it also has complex electrophysiological properties, including adrenergic blockade, calcium-channel blockade, sodium-channel blockade, and at least some degree of prolongation of the action potential.13 In its current formulation, amiodarone is not available in prefilled syringes and must be drawn up into a syringe for dilution and administration a potentially time-consuming process, since the drug readily foams when the solution is agitated. The complexity of administration of amiodarone in its current formulation and its cost have been considered limitations to its out-of-hospital use.
Despite these potential limitations, amiodarone led to a statistically significant and relatively large improvement in the proportion of patients who survived to hospital admission in our study. Moreover, amiodarone led to a significant improvement in survival to admission in all patient subgroups a finding consistent with the results in the whole study. The study did not have adequate statistical power, and was not expected, to show a significant improvement in survival to hospital discharge, and none was seen.
One cannot conclude from this study that intravenous amiodarone will necessarily increase the proportion of patients surviving to hospital discharge if it is administered to patients with shock-resistant ventricular fibrillation in the community. However, our findings are consistent with those of the ARREST trial in strongly suggesting that amiodarone has clinical effectiveness in the initial stages of resuscitation, and they indicate that amiodarone is superior to lidocaine for shock-resistant out-of-hospital ventricular fibrillation. Our findings also suggest that the earlier amiodarone can be administered in the course of a complicated cardiac arrest, the greater is the likelihood of at least short-term benefit. On the basis of these results and the accumulated evidence from previous clinical trials, there appears to be no indication for the administration of lidocaine to patients with shock-resistant ventricular fibrillation in the out-of-hospital setting. We believe that if an antiarrhythmic drug is to be considered in this situation, intravenous amiodarone should be the drug of choice. The potential use of amiodarone earlier in the course of resuscitation from life-threatening out-of-hospital arrhythmias and its potential effect on survival to discharge from the hospital await clarification in future clinical trials.
Supported by an unrestricted research grant from WyethAyerst Laboratories.
Drs. Dorian and Cass have given lectures and participated in educational programs sponsored by WyethAyerst Laboratories.
We are indebted to Kim Dawdy, Marta Boszko, and James Noble for their assistance and to Graham Munro and Andy McCabe, paramedic representatives on the study steering committee, and all the paramedics of the Toronto Emergency Medical Services System, without whose efforts this study would not have been possible; to Stuart Connolly, M.D., and Robin Roberts, M.Tech., who were members of the Data and Safety Monitoring Board; and to Dr. Chris Rubes (deceased), former medical director, Sunnybrook Base Hospital Program, for his support and efforts during the planning and initiation of the trial.
Source Information
From the Departments of Medicine and Emergency Medicine, St. Michael's Hospital (P.D., D.C., R.G., A.B.); the Division of Prehospital Care, Sunnybrook and Women's College Health Sciences Centre (B.S.); and the Department of Anesthesia, University Health Network (R.C.) all in Toronto.
Address reprint requests to Dr. Dorian at St. Michael's Hospital, 30 Bond St., Toronto, ON M5B 1W8, Canada, or at dorianp{at}smh.toronto.on.ca.
References
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Related Letters:
Amiodarone versus Lidocaine for Shock-Resistant Ventricular Fibrillation
Silfvast T., Pettilä V., Ballew K. A., Philbrick J. T., Tomkiewicz W., Meininghaus D. G., Langes K., Spehn J., Dorian P., Schwartz B., Cooper R.
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N Engl J Med 2002;
347:368-370, Aug 1, 2002.
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