Evidence-based Pharmacologic Therapy During Cardiac Arrest
Intravenous (IV) antiarrhythmic agents are commonly used as adjuncts to DC cardioversion during cardiopulmonary resuscitation. The agents most often used for this purpose, and those mentioned in the American Heart Association advanced cardiac life support (ACLS) guidelines, include lidocaine, bretylium, magnesium, and procainamide. IV amiodarone is an antiarrhythmic agent with a broad pharmacologic spectrum that includes beta receptor, alpha receptor, and sodium, calcium, and potassium channel antagonism. This agent has enjoyed world-wide use for the treatment of life-threatening ventricular arrhythmias since the early 1980's, and was approved by the United States Food and Drug Administration (F.D.A) on August 3, 1995 for treatment of ventricular arrhythmias "resistant to other therapy." Since its approval, IV amiodarone has increasingly been utilized to treat sustained ventricular tachycardia (VT) or ventricular fibrillation (VF) in hospitalized patients throughout the United States. The recent trial by Kudenchuk and colleagues1, reviewed in this SCA newsletter, may extend the spectrum of IV amiodarone use to out-of-hospital cardiac arrest. How compelling are these data, and how should the findings influence our treatment of sustained ventricular arrhythmias in perioperative settings?
Given that nearly 50% of cardiac-related deaths result from arrhythmias, there is a surprising paucity of prospective clinical data evaluating the efficacy of antiarrhythmic agents for sustained VT and VF. Of all the available IV agents (including lidocaine, procainamide, and bretylium), amiodarone is by far the most extensively studied in prospective, controlled clinical trials. F.D.A. approval of IV amiodarone was supported by trials in hospitalized patients.2-4 Scheinman et al.2 examined the efficiacy of IV amiodarone in 342 patients who had proven refractory or intolerant to IV lidocaine, procainamide, and bretylium. Eighty percent of the patients had a previous myocardial infarction, 30% percent of the patients had incessant VT at the start of amiodarone therapy, and 10% were receiving cardiopulmonary resuscitation. The 24-hour dose-response relationship was evaluated as a means of establishing efficacy of IV amiodarone. The incidence of hemodynamically destabilizing ventricular arrhythmias decreased from 0.07 events/ hour for patients receiving a low dose (125 mg/24 hour) to 0.02 events/ hour for patients receiving the highest (and now standard) dose (1000 mg/24 hour). After 48 hours, 26% of patients in the 1000 mg dose group remained arrhythmia free, versus only 16% of patients in the 125 mg/ 24 hours group. Overall, 78% of the patients survived 48 hours, and 60% survived to 30 day follow-up. Although the use of a placebo group was deemed unethical by the investigators, survival in similar patient groups has been estimated to be < 20% despite aggressive therapy.5
Another trial compared IV amiodarone and IV bretylium for 48 hours in 302 patients who were refractory to lidocaine and procainamide.3 At a dose of 1000 mg/24 hours, IV amiodarone was equivalent to the standard IV bretylium dose (2500 mg/24 hours) in arrhythmia event rate, the time to first arrhythmia recurrence, and the number of patients requiring supplemental infusions for recurrent arrhythmias. Survival rates over 48 hours were similar between groups (86% overall). However, when compared to the 1000 mg/24 hour amiodarone group, significantly more patients treated with bretylium experienced hypotension (33% versus 21%) or congestive heart failure (5% versus 0%), leading to substantial between-group crossover from bretylium to amiodarone. Despite their widespread use, it is noteworthy that no comparable prospective clinical trials are available for either IV lidocaine or IV procainamide.
Moreover, until recently no prospective trial had shown a measurable benefit to the use of any pharmacologic agent during out-of-hospital cardiopulmonary resuscitation. Kudenchuk and colleagues1 conducted a randomized trial in Seattle, Washington between Nov, 1994 and Feb, 1997 to determine the efficacy of IV amiodarone in patients experiencing out-of-hospital cardiac arrest due to pulseless ventricular tachycardia or fibrillation refractory to direct current cardioversion. Following 3 defibrillation attempts, intubation, and 1 mg of epinephrine IV, adult victims of cardiac arrest were treated by emergency personnel in a randomized and blinded fashion with either 300 mg of IV amiodarone or placebo (the amiodarone diluent polysorbate 80) while CPR continued. Of the 504 patients enrolled, recipients of amiodarone were more likely to be resuscitated and admitted to the hospital than recipients of placebo (44% vs. 34%, p = 0.03). It is notable that the difference was more significant among the 221 patients who experienced witnessed arrests, likely due to the reduced interval from event to drug therapy (p = 0.008).
Should these findings influence the management of patients experiencing cardiac arrest? Several issues must be recognized. First, in the Seattle trial, only a small percentage of patients were discharged alive from the hospital, and the study did not detect survival-to-discharge differences between the amiodarone and placebo groups (13.4 and 13.2% respectively). Notably, the management of patients beyond initial admission to the hospital was not standardized, and the study was not powered to detect differences in survival. However, in the absence of longer-term survival data, we cannot dismiss the possibility (and the investigators acknowledge) that amiodarone caused side effects that balanced (or even overshadowed) the benefit derived from its probable antiarrhythmic effects. Although the metabolic derangement associated with chronic oral amiodarone therapy (hypothyroidism, skin discoloration, etc ) are not relevant to short-duration IV usage, hypotension and bradycardia are expected adverse effects of both IV amiodarone and its diluent, polysorbate 80.2 These hemodynamic issues are of particular relevance as we contemplate using IV amiodarone in the perioperative period. Although generally well-tolerated, some post-cardiac surgery patients who have very poor left ventricular function may experience worsening cardiogenic shock with IV amiodarone loading, requiring increased hemodynamic support with catecholamine infusions or, occasionally, intraaortic balloon counterpulsation.6 Balancing these hemodynamic concerns with IV amiodarone are the known detrimental hemodynamic effects of both IV procainamide and IV bretylium.
The literature describing the use of IV amiodarone as an acute therapy for life-threatening ventricular arrhythmias in the perioperative period remains sparse. In a retrospective analysis,6 recurrent postoperative ventricular tachycardia was suppressed in one of two patients, and IV amiodarone bolus injections controlled the ventricular arrhythmias of three patients near the end of cardiac surgery, thereby facilitating use of an intra-aortic balloon pump and separation from cardiopulmonary bypass. A number of anecdotal and retrospective studies have suggested a linkage between chronic oral amiodarone therapy and postoperative adult respiratory distress syndrome (ARDS),7 but prospective studies have not evaluated this possibility. Although IV amiodarone use was linked to postoperative adult respiratory distress syndrome (ARDS) in one trial examining atrial fibrillation prophylaxis in pneumonectomy patients,8 the risk of ARDS in pneumonectomy patients is generally elevated, and this may be a special high-risk subgroup. Two recent prospective trials have examined perioperative amiodarone prophylaxis for atrial fibrillation (oral and IV), and ARDS has not been detected in this potentially high-risk population.9,10 Admittedly, studies have not directly assessed whether immediate pre-operative, or even intraoperative, IV amiodarone administration poses any special risks for cardiac or general surgery patients. Unfortunately, the same limitation applies to most non-anesthetic drugs used routinely in the perioperative period.
Given these caveats, what is the role of IV amiodarone in the management of patients experiencing life-threatening VT or VF during, or immediately after, surgery? A strict adherence to evidence-based medicine would suggest that no IV antiarrhythmic drug has a role in the perioperative setting, since no drug has been evaluated prospectively for efficacy or toxicity during perioperative cardiac arrest. Moreover, there are no compelling survival-to-hospital discharge data for any of the IV antiarrhythmic agents. The difficulty with this extreme view is that, for many practitioners, antiarrhythmic drugs are a measure of last resort when a patient remains pulseless following repeated external cardioversion attempts and CPR. The motivation to use IV amiodarone in this setting is perhaps strengthened by this new evidence1 that IV amiodarone does produce at least a short-term survival benefit over placebo when administered during out-of-hospital cardiac arrest. Certainly, given the unique concerns of the perioperative period, extrapolating the results of this study to support the use of IV amiodarone during cardiac arrest in the perioperative setting requires a degree of optimism. However, one could argue, in the absence of prospective clinical data in any setting for the other IV antiarrhythmic agents, that our liberal use of IV lidocaine in perioperative cardiac arrest is a far more serious leap of faith.
It is important to recognize that Kudenchuk and colleagues1 indicate that amiodarone did not exert "pharmacologic defibrillation." It is therefore likely that the drug primarily prevented recurrent episodes of VF after initial external defibrillation. The trial results do not suggest that IV amiodarone is a substitute for expeditious external defibrillation, but rather that the drug may be a useful adjunct to standard CPR measures. Future efforts to examine the benefit of amiodarone relative to other agents (i.e. lidocaine) and the optimal dose of amiodarone (the authors speculate higher doses may have been more beneficial) in both perioperative and general settings are badly needed. Given the preeminent importance of this public health issue, the influence of early pharmacologic intervention upon survival to hospital discharge during in- or out-of-hospital cardiac arrest merits further study.
1. Kudenchuk PJ, Cobb LA, Copass MK, Cummins RO, Doherty AM, Fahrenbruch CE, Hallstrom AP, Murray WA, Olsufka M, Walsh T. Amiodarone for resuscitation after out-of-hospital cardiac arrest due to ventricular fibrillation. N Engl J Med. 1999;341:871-8.
2. Scheinman MM, Levine JH, Cannom DS, Friehling T, Kopelman HA, Chilson DA, Platia EV, Wilber DJ, Kowey PR. Dose-ranging study of intravenous amiodarone in patients with life-threatening ventricular tachyarrhythmias. Circulation. 1995;92:3264-3272.
3. Kowey PR, Levine JH, Herre JM, Pacifico A, Lindsay BD, Plumb VJ, Janosik DL, Kopelman HA, Scheinman MM. Randomized, double-blind comparison of intravenous amiodarone and bretylium in the treatment of patients with recurrent hemodynamically destabilizing ventricular tachycardia or fibrillation. Circulation. 1995;92:3255-3263.
4. Levine JH, Massumi A, Scheinman MM, Winkle RA, Platia EV, Chilson DA, Gomes JA, Woosley RL. Intravenous amiodarone for recurrent sustained hypotensive ventricular tachyarrhythmias. Journal of the American College of Cardiology. 1996;27:67-75.
5. Bedell SE, Delbanco TL, Cook EF, Epstein FH. Survival after cardiopulmonary resuscitation in the hospital. The New England Journal of Medicine. 1983;309:569-576.
6. Installe E, Schoevaerdts JC, Gadisseux P, Charles S, Tremouroux J. Intravenous amiodarone in the treatment of various arrhythmias following cardiac operations. The Journal of Thoracic and Cardiovascular Surgery. 1981;81:302-308.
7. Balser JR. The rational use of intravenous amiodarone in the perioperative period. Anesthesiology. 1997;86:974-987.
8. Van Mieghem W, Coolen L, Malysse I, Lacquet LM, Deneffe GJD, Demedts MGP. Amiodarone and the development of ARDS after lung surgery. Chest. 1994;105:1642-1645.
9. Daoud EG, Strickberger SA, Man KC, Goyal R, Deeb GM, Bolling SF, Pagani FD, Bitar C, Meissner MD, Morady F. Preoperative amiodarone as prophylaxis against atrial fibrillation after heart surgery. The New England Journal of Medicine. 1997;337:1785-1791.
10. Guarnieri T, Nolan S, Gottlieb SO, Dudek A, Lowry DR. Intravenous amiodarone for the prevention of atrial fibrillation after open heart surgery: the Amiodarone Reduction in Coronary Heart (ARCH) trial [see comments]. J Am Coll Cardiol. 1999;34:343-7.
Jeffrey R. Balser, M.D., Ph.D.
Anesthesiology and Pharmacology
Physician Scientist Development
Vanderbilt University School of Medicine
See also Dr. Cheung's article: Amiodarone for resuscitation after out-of-hospital cardiac arrest due to ventricular fibrillation.