Efficacy of bretylium tosylate for ventricular tachycardia.

In 20 patients with inducible ventricular tachycardia (VT), intravenous bretylium tosylate infused as a 10-mg/kg bolus followed by 2 mg/min caused no change in refractory periods and did not suppress inducibility of VT. The use of bretylium for the treatment of VT should be reexamined.

Randomized, double-blind comparison of intravenous amiodarone and bretylium in the treatment of patients with recurrent, hemodynamically destabilizing ventricular tachycardia or fibrillation. The Intravenous Amiodarone Multicenter Investigators Group.

BACKGROUND: After several days of loading, oral amiodarone, a class III antiarrhythmic, is highly effective in controlling ventricular tachyarrhythmias; however, the delay in onset of activity is not acceptable in patients with immediately life-threatening arrhythmias. Therefore, an intravenous form of therapy is advantageous. This study was designed to compare the safety and efficacy of a high and a low dose of intravenous amiodarone with bretylium, the only approved class III antiarrhythmic agent. METHODS AND RESULTS: A total of 302 patients with refractory, hemodynamically destabilizing ventricular tachycardia or ventricular fibrillation were enrolled in this double-blind trial at 82 medical centers in the United States. They were randomly assigned to therapy with intravenous bretylium (4.7 g) or intravenous amiodarone administered in a high dose (1.8 g) or a low dose (0.2 g). The primary analysis, arrhythmia event rate during the first 48 hours of therapy, showed comparable efficacy between the bretylium group and the high-dose (1000 mg/24 h) amiodarone group that was greater than that of the low-dose (125 mg/24 h) amiodarone group. Similar results were obtained in the secondary analyses of time to first event and the proportion of patients requiring supplemental infusions. Overall mortality in the 48-hour double-blind period was 13.6% and was not significantly different among the three treatment groups. Significantly more patients treated with bretylium had hypotension compared with the two amiodarone groups. More patients remained on the 1000-mg amiodarone regimen than on the other regimens. CONCLUSIONS: Bretylium and amiodarone appear to have comparable efficacies for the treatment of highly malignant ventricular arrhythmias. Bretylium use, however, may be limited by a high incidence of hypotension.

Oral bretylium tosylate use during pregnancy and subsequent breastfeeding: a case report.

A 39-year-old woman with long QT interval syndrome received chronic oral bretylium tosylate during pregnancy and subsequent breastfeeding. The pregnancy and delivery were uncomplicated and no side effects have been observed in the infant.

Experimental and clinical pharmacology of bretylium tosylate in acute myocardial infarction: a 15-year journey.

Experimental and clinical studies demonstrate the antifibrillatory effectiveness of bretylium tosylate: Experimental ventricular fibrillation induced either by electrical stimulation or by ischemia is prevented by bretylium. In 2,000 acute myocardial infarction patients who received bretylium prophylactically primary ventricular fibrillation occurred in less than 1% of cases. In a randomized hemodynamic study in acute myocardial infarction patients bretylium induced a significant decrease in heart rate, systolic and mean left ventricular pressures, and in systolic and mean aortic pressures. In addition, a parallel and significant decrease in total pulmonary and systemic resistances was seen, accompanied by decreases in tension time and left ventricular (delta P/delta V) indexes. Bretylium tosylate induces stabilization of electrical systole duration (QTc) in acute myocardial infarction patients. The conclusions of the present review strongly support those of the United States Food and Drug Administration, approving bretylium for prophylaxis and treatment of ventricular fibrillation.

Deleterious effects of bretylium on hemodynamic recovery from ventricular fibrillation.

To study the effects of bretylium on the restoration of circulatory function after resuscitation from ventricular fibrillation, closed-chest anesthetized dogs were electrically fibrillated for 1 minute followed by defibrillation (direct-current shock). After one control episode of fibrillation and defibrillation, 16 dogs received a bolus of bretylium (10 mg/kg intravenously). A second episode of fibrillation and defibrillation was induced in eight dogs 3 minutes after bretylium and in eight dogs 4 hours after bretylium. Prior to bretylium, mean arterial blood pressure spontaneously recovered to exceed 200 mm Hg by 2 minutes after defibrillation in all 16 dogs. However, after bretylium, 13 of 16 dogs were in electromechanical dissociation 2 minutes after defibrillation (p less than 0.001). Despite external chest compression, epinephrine, and sodium bicarbonate, a stable blood pressure could not be restored in 6 of 16 dogs. Clofilium, a bretylium analogue lacking sympathetic influences, did not alter the pattern of hemodynamic recovery following defibrillation in five of five dogs. The results suggest that the effects of bretylium on the sympathetic nervous system may profoundly influence the outcome of cardiac resuscitation from fibrillation.

Bretylium: relations between plasma concentrations and pharmacologic actions in high-frequency ventricular arrhythmias.

Although it is widely assumed that the early arrhythmogenic and pressor responses to bretylium are caused by catecholamine release from the adrenergic neuron, this assumption has not been systematically studied in humans. Pharmacologic responses to a placebo infusion and 3 separate bretylium infusions (2.5, 5.0, 10 mg/kg over 60 minutes) were assessed in 6 patients with recurrent, nonsustained ventricular tachycardia. Plasma bretylium concentration, blood pressure (BP), plasma norepinephrine (NE) concentration, arrhythmia frequency and adrenergic neuronal blockade (assessed by the presence or absence of reflex venoconstriction) were measured. Adrenergic blockade was seen with every bretylium infusion and at a time when relatively small amounts of bretylium had been administered (range 160 to 750 mg, median 252). Temporal relations (p less than 0.03) were noted among the time of onset of adrenergic neuronal blockade, onset of the pressor response, increase in NE plasma concentration and increase in ventricular arrhythmia frequency. BP responses during the infusions were linearly related to change in plasma NE at the time of development of adrenergic neuronal blockade. Bretylium plasma concentrations higher than 3 micrograms/ml were frequently associated with a short-lived pressor response. There was a significant relation (p less than 0.06) between the increase in plasma NE during the infusion and an increase in ventricular arrhythmia frequency. Reduction in arrhythmia frequency was seen in only 1 patient, beginning 6 hours after the development of adrenergic neuronal blockade.(ABSTRACT TRUNCATED AT 250 WORDS)

Bretylium tosylate: profile of the only available class III antiarrhythmic agent.

Bretylium tosylate, the only approved class III antiarrhythmic agent, is a unique quaternary ammonium compound with prominent experimental and clinical antifibrillatory effects. Intravenous bretylium causes a biphasic hemodynamic response; initial norepinephrine release is followed by sympathetic ganglionic blockade. Cardiac output is well maintained. Electrocardiographic intervals are unchanged, and global conduction unchanged or facilitated. With long-term experimental use, proportionate lengthening of ventricular action potential and refractory period occurs. Bretylium is largely eliminated unchanged in the urine, with a long terminal half-life of about 13 hours. Bretylium demonstrates substantial activity in several animal models and clinical circumstances of ventricular fibrillation, including those in which standard antiarrhythmic therapy is ineffective. Bretylium is thus currently approved as a first-line agent for prophylaxis and treatment of ventricular fibrillation, and as a second-line agent for ventricular tachycardia and other prefibrillatory ventricular arrhythmias. In contrast, bretylium's weak antiectopic activity and limited oral absorption make it a poor choice for management of simple ventricular ectopy. Side effects of bretylium are generally limited to its hemodynamic actions (eg, postural hypotension). Nausea may occur with rapid intravenous administration. Emerging clinical concepts emphasize the clinical importance of antifibrillatory action over antiectopic effects alone. Bretylium is thus likely to continue to find increasing usage in the acute management of malignant ventricular arrhythmia.

Therapy of ventricular tachycardia.

Therapeutic modalities for ventricular tachycardia include antiarrhythmic drugs, direct current cardioversion, electrical pacing and surgical intervention. Lidocaine, procainamide and bretylium are all capable of controlling recurrent ventricular tachycardia; bretylium has the advantage of also being antifibrillatory and of raising the threshold for ventricular fibrillation. Lidocaine and bretylium are available only in i.v. form. Procainamide is available in i.v. as well as oral form. Other oral antiarrhythmic agents include quinidine, disopyramide, beta-blockers such as propranolol and verapamil. The latter may be useful in ventricular arrhythmias induced by ischemia; of these, only beta-blockers appear to significantly raise the threshold for ventricular fibrillation. Control of ventricular ectopy does not always preclude ventricular tachycardia and ventricular fibrillation. In treating ventricular tachycardia, bretylium tosylate is generally given 5 to 10 mg/kg i.v. over 10 to 20 minutes. Given too rapidly, it may cause nausea and vomiting. Orthostatic hypotension, a common side effect, generally abates with continued use and may be ameliorated with tricyclic antidepressants such as protriptyline. Significant supine hypotension may be encountered in patients with acute myocardial infarction and may be managed with pressor agents or fluids, or both. The antiarrhythmic efficacy of bretylium was analyzed in 40 patients. Five etiologic groups were defined by cardiac catheterization: 19 patients had atherosclerotic heart disease, 6 had primary myocardial disease, 4 had mitral valve prolapse, 4 had rheumatic heart disease and 7 had miscellaneous or no heart disease. All patients had recurrent ventricular tachycardia (VT); 23 had ventricular fibrillation (VF) as well. Other antiarrhythmic agents had failed in 38 patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Endotracheal bretylium tosylate in a canine model.

This study was conducted to determine whether bretylium tosylate (BT) is effectively and safely absorbed through the endotracheal route in the canine model. Eleven adult mongrel dogs were anesthetized with pentobarbital, were orally intubated, and had continuous blood pressure and electrocardiographic monitoring. Four dogs received 5 mg/kg BT, three dogs received 10 mg/kg BT, two dogs received 20 mg/kg BT, and two control dogs were given volumes of normal saline equal to those given the 5- and 10-mg/kg groups. Each dog received the same dose of BT both endotracheally and intravenously, but in a random order and on different dates. Following each drug administration arterial blood was drawn at various intervals over two hours and sent for immediate gas analysis; serum samples were frozen for future determination of BT levels. Regardless of the amounts delivered, the peak levels of BT in the arterial blood following administration by the endotracheal route were consistently low (4.13 micrograms/mL to 14.00 micrograms/mL) when compared to those levels following intravenously administered BT (120 micrograms/mL to 268 micrograms/mL) (all P less than .002 for the 5- and 10-mg/kg groups). No depot effect was observed during a two-hour period. The arterial blood gases did not change significantly following the administration of BT by the endotracheal route in the 5- and 10-mg/kg groups, and sections of these autopsied dog lungs showed no apparent pathologic changes.

Life threatening ventricular dysrhythmias: intervention with bretylium tosylate.

The impact of psychogenic and physical stressors has been shown to have a negative effect on cardiovascular homeostasis (Figure 2). As CRNAs, we have a responsibility to maintain the patient's equilibrium under the stress-provoking conditions of surgery. Experience in coronary care units over the last 16 years has shown that the majority of patients who develop primary ventricular fibrillation during AMI can be rapidly resuscitated by prompt defibrillation. Only in a small number of patients does ventricular tachycardia or ventricular fibrillation become recurrent or resistant to treatment. It is in this small number that bretylium has proven itself to be a life-saving treatment.

Severe hypotension due to the use of bretylium for postcardiotomy ventricular arrhythmias.

We describe three patients who developed refractory hypotension after the administration of bretylium tosylate for postoperative ventricular ectopy. In one patient, the administration of vasopressors and fluid restored the blood pressure, but in the other two patients these measures failed, necessitating open-heart cardiac massage. The hemodynamic effects of bretylium are unpredictable; therefore, this drug should be used cautiously in the treatment of postcardiotomy ventricular arrhythmias.

Paradoxical ventricular tachycardia and fibrillation after intravenous bretylium therapy. Report of two cases.

Two patients were treated with bretylium tosylate for malignant ventricular arrhythmias after inadequate response to conventional agents. In the first patient, two episodes of ventricular tachycardia requiring cardioversion occurred in close temporal sequence with administering bretylium. With drug rechallenge two days later, ventricular tachycardia recurred within minutes. In the second case, five cardiac arrests due to ventricular tachycardia and fibrillation occurred during several hours after beginning a trial of bretylium maintenance therapy for complex ventricular ectopy. Although transient increases in ectopy after bretylium therapy have been described, presumably due to catecholamine release, the occurrence of life-threatening ventricular arrhythmia leading to cardiac arrest has not previously been emphasized. There is potential for this side effect, and additional caution in the use of this drug should be followed.

Massive intravenous bolus bretylium tosylate.

A 30 mg/kg (2-gm) intravenous bolus of bretylium tosylate was administered to a patient with recurrent ventricular tachycardia and fibrillation. After successful defibrillation the patient exhibited marked hypertension followed by protracted refractory hypotension. There was no further ventricular ectopy in spite of a very low cardiac index. A bretylium level of 8,800 ng/ml is the highest reported in man from a single bolus injection. This case demonstrates the exaggerated hemodynamic response to massive intravenous bolus bretylium tosylate.

Pharmacokinetics of bretylium in man after intravenous administration.

The pharmacokinetic profile of bretylium was studied in four normal male volunteers using a new sensitive EC-GC procedure for its quantitative in biological fluids. The plasma concentrations and urinary excretion rates following the constant i.v. infusion of a single 4 mg/kg dose of bretylium tosylate declined biexponentially and the data were fitted to a two-compartment model with a renal and a nonrenal route of elimination. The drug had a mean half-life (t1/2 beta) of 7.8 hr and apparent volume of distribution (Vd, beta) of 8.18 liters/kg. The renal clearance, which was 6 times that of the glomerular filtration rate, accounted for almost 84% of the total body clearance and correlated linearly with the subjects' creatinine clearance. The observed side effects of bretylium were mild and similar to those of other adrenergic blocking agents.