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Does Bretylium Have a Place in Cardiac Arrest?

Hockstein, Max MD; Velez, Larissa MD

doi: 10.1097/01.EEM.0000731712.30017.b9
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    bretylium, cardiac arrest
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    The mortality of ventricular arrhythmias, especially in hemodynamic compromise or cardiac arrest, remains significant despite years of research and advancements. (Heart Rhythm. 2019;16[3]:358.) Antiarrhythmics, in addition to defibrillation, have been included in the Advanced Cardiovascular Life Support guidelines since their inception in 1974. (JAMA. 1974;227[7]:833.) Various antiarrhythmics, including lidocaine, procainamide, bretylium, and amiodarone, have been featured medications in the ventricular fibrillation (VF) and pulseless ventricular tachycardia (VT) algorithm over the past 45 years.

    Bretylium tosylate (Bretylol) was discovered in the late 1950s, and was first used as an antiarrhythmic in 1968. (Ann Intern Med. 1979;91[2]:229; Am J Cardiol. 1968;21[4]:530.) Bretylium was included in the ACLS algorithms for refractory ventricular arrhythmias as a second-line agent after lidocaine from 1986 to 2000. (JAMA. 1992;268[16]:2199.) The 2000 ACLS update, however, removed bretylium from the VF/pulseless VT algorithm because of a lack of evidence of utility and a raw materials shortage that began in 1988. (Circulation. 2000;102[8 Suppl]:I86.)

    Hospira withdrew its new drug application with the Food and Drug Administration approximately three months after the ACLS guideline change, and bretylium became unavailable to clinicians. (Federal Register. Dec. 19, 2011; https://bit.ly/34mUBvY.) Now, almost two decades later, ANI Pharmaceuticals announced that its partner Pharmaceutics International, Inc., had received FDA approval to manufacture bretylium once again. (PR Newswire. Oct. 31, 2019; https://prn.to/2YpDx4C.) The reintroduction came on the heels of a perceived market need for an alternative antiarrhythmic. Given the two-decade gap between its removal and reintroduction, little recent evidence on bretylium's role in treating ventricular arrhythmias has been published.

    Bretylium's mechanism of action is multifaceted. It is primarily a Singh-Vaughan-Williams Class III antiarrhythmic (potassium channel blocker) and prolongs action potential duration and reduces the heterogeneity in action potential duration between ischemic and nonischemic areas of the myocardium. (Ann Intern Med. 1979;91[2]:229.) Bretylium also displays a biphasic adrenergic action. (Ann Intern Med. 1979;91[2]:229.)

    After a brief initial increase in the release of norepinephrine from the sympathetic nerve terminals, bretylium causes an abrupt decrease in norepinephrine release from those same terminals. (Br J Pharmacol Chemother. 1959;14[4]:536; https://bit.ly/3l5QBFX.) This sympathetic blockade is responsible for bretylium's most notorious adverse effect, hypotension. (Am J Ther. 2009;16[6]:480.)

    Early study of bretylium also showed that it produced a chemical defibrillation, a termination of ventricular fibrillation without the use of electricity. (Int J Cardiol. 1983;4[2]:133.) Given the significant time interval this clinical effect requires and the clear benefit of early defibrillation, this effect will be difficult to observe in present-day practice. Bretylium also inhibits sodium-potassium ATPase, so there is a theoretical possibility of an exacerbation of digoxin-induced arrhythmias. (Br J Pharmacol. 1991;104[4]:895; https://bit.ly/32cyq8T.) The manufacturer recommends that bretylium be avoided in cases of confirmed and suspected digoxin toxicity.

    Refractory VF/VT

    The primary FDA-approved indication for bretylium is refractory VF/VT. There is scant good quality evidence that the administration of any antiarrhythmics in out-of-hospital cardiac arrests contributes to improved patient outcomes. (Heart Lung Circ. 2018;27[3]:280; Circulation. 2017;136[22]:2119; https://bit.ly/3l4ri7d.) It has been suggested that bretylium and lidocaine have synergistic effects, but this has not been explicitly studied. (Ann Emerg Med. 1993;22[2 Pt 2]:307.) Beta-blockers may confer improved outcomes on patients with refractory VF/VT, so the antiadrenergic effects of bretylium might confer a benefit. (Resuscitation. 2020;146:118.)

    Bretylium is also FDA-approved for arrhythmia prophylaxis. This practice, however, has been largely abandoned because it increases mortality in acute coronary syndrome. (N Engl J Med. 1991;324[12]:781; https://bit.ly/2CLB3pq; N Engl J Med. 1992;327[4]:227; https://bit.ly/3hhY2HV.)

    The existing evidence surrounding the role of bretylium is not robust, but potential uses can be projected if its mechanism of action is understood. (Table 1.) The majority of trials examining bretylium also looked at refractory VT/VF, which already has a high mortality rate. The current dosing recommendations are shown in Table 2.

    Table 1: - Relevant Clinical Studies of Bretylium in Refractory Ventricular Arrhythmias
    Year Design n Population Comparator Outcome Result
    1968 Observational 30 In-hospital, acute MI, heart failure, cardiotomy, digitalis intoxication N/A N/A 27/30 patients demonstrated arrhythmia suppression within minutes
    1972 Observational 30 In-hospital, refractory VT (MI/CAD, PE, AVR) N/A N/A 18/30 patients achieved arrhythmia suppression
    1981 Prospective, randomized, double-blind 59 Out-of-hospital VF or asystole, initial drug Normal saline ED survival Bretylium increased chances of successful resuscitation
    1981 Prospective, randomized, double-blind 146 Out-of- hospital VF, initial drug Lidocaine Admitted to hospital, 12 hours: complex ventricular arrhythmias, defibrillation, vasopressors, pulmonary edema, discharge from hospital, death Performed similarly to lidocaine
    1984 Prospective, randomized 91 Out-of-hospital, refractory VF Lidocaine Organized, rhythm ROSC, ED admission alive at discharge Lidocaine had conversion to organized rhythm more often, no significant change in other outcomes
    1984 Observational 218 Out-of- hospital, refractory VF Lidocaine N/A Bretylium increased chances of successful resuscitation and discharge
    1995 Randomized, double-blind 302 In-hospital, refractory VF/VT Amiodarone Number of VF/VT events per hour Equal efficacy, more hypotension in bretylium group
    Sources: Am J Cardiol. 1968;21(4):530; Circulation. 1972;45(5):1024; https://bit.ly/3iVHkOK; Ann Emerg Med. 1981;10(8):404; Am J Cardiol. 1981;48(2):353; Ann Emerg Med. 1984;13(9 Pt 2):807; Ann Emerg Med. 1984;13(4):234; Circulation. 1995;92(11):3255; https://bit.ly/3aWEtCF.

    Table 2: - Bretylium Dosing Information
    Administration Information
    • Ventricular fibrillation or hemodynamically unstable ventricular tachycardia

      • 5-10 mg/kg rapid IV bolus

      • Repeat 10 mg/kg every 15-30 minutes to a maximum of 30 mg/kg

    • Refractory stable ventricular tachycardia

      • 5-10 mg/kg in 50-100 mL over eight or more minutes, may repeat every one to two hours if needed

      • Infusion rate is 1-2 mg/min

      • Maximum of 30 mg/kg

    • No dose adjustment required for renal failure

    • May be given intramuscularly

    Source: ANI Pharmaceuticals; https://bit.ly/2YnBpdx.

    Percutaneous coronary intervention was less commonplace during the decades when bretylium was studied. (J Am Heart Assoc. 2013;2[6]:e000370; https://bit.ly/3aJF0aM.) The most common etiologies for malignant ventricular arrhythmias are ischemic, and the incidence of refractory VT/VF if studied today may be lower than that in the existing studies on bretylium. In bretylium's absence, many changes have been made to the way cardiac arrest is treated. The most significant change to cardiac arrest management over the past decades has been the widespread availability of automated external defibrillators and emphasis on early defibrillation and high-quality chest compressions.

    Hypothermic arrest is an area in which bretylium has received specific consideration. (Resuscitation. 2008;78[1]:21.) Bretylium was able to raise the fibrillatory threshold in animal models, but the effects of the drug were likely isolated to fibrillatory prevention rather than fibrillatory treatment. (Cardiovasc Res. 2019;115[3]:501; Arch Intern Med. 1969;124[1]:95.) The only clinical study examining the utility of bretylium in hypothermic patients is an intraoperative study in patients after cardiopulmonary bypass, which reported a trend that bretylium lowered the number of shocks required to restore a supraventricular rhythm compared with lidocaine. These findings, however, did not achieve statistical significance. (J Cardiothorac Anesth. 1990;4[5]:582.)

    The evolution in managing cardiac arrest over the past 20 years means bretylium is being reintroduced into a different clinical environment, making the existing evidence difficult to interpret and apply. The new availability of bretylium tosylate, however, may generate renewed interest in its effectiveness in treating refractory VT/VF, hypothermic cardiac arrest, and perhaps in nonischemic arrhythmia prevention.

    No clinical trials involving bretylium are planned, and it is unknown if the American Heart Association will reincorporate bretylium into its resuscitation guidelines, though, ANI Pharmaceuticals has approached it and the International Liaison Committee on Resuscitation with product information.

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    Dr. Hocksteinis an emergency medicine and critical care medicine physician in Washington, DC. Follow him on Twitter@maxhockstein. Dr. Velezis a professor of emergency medicine and the associate dean for graduate medical education at UT Southwestern Medical School in Dallas, TX. Follow her@lvelezEM.

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