Advanced cardiac life support controversy: where do antiarrhythmic agents fit in?

Approximately half of all cardiovascular fatalities are attributable to sudden cardiac death, and the majority of sudden cardiac deaths result from ventricular fibrillation (VF). Antiarrhythmic agents are needed to manage refractory VF and ventricular tachycardia (VT); the primary reason for their administration is to prevent recurrence of VF and to abolish VT. The American Heart Association recommends lidocaine hydrochloride as a first-line antiarrhythmic agent in the advanced cardiac life support (ACLS) setting, followed by bretylium tosylate. Although the newly approved intravenous antiarrhythmic agent, amiodarone hydrochloride, may potentially be effective in ACLS, studies are needed to document its clinical benefit in this setting. Such studies are currently under way to document this potential use.

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.

Extreme pyrexia during bretylium administration.

Body temperatures exceeding 41.1 degrees C (106 degrees F) occur with relatively few conditions. In the unusual case reported here, the patient's temperature reached 42.3 degrees C (108.2 degrees F) during intravenous administration of bretylium for refractory ventricular fibrillation. The temperature started to drop as soon as the infusion was stopped and was close to normal within four hours. This appears to be the first report of extreme pyrexia resulting from use of this agent.

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.

Clinical pharmacokinetics of bretylium.

Bretylium is a class III antiarrhythmic agent which is used for the management of serious and refractory ventricular tachyarrhythmias. It exhibits a complex pharmacokinetic profile which is poorly understood. The drug is poorly absorbed following oral administration, and its oral bioavailability is in the region of 18 to 23%. Peak plasma concentrations occur at 1 to 9 hours after oral ingestion, and following oral doses of 5 mg/kg average 76 ng/ml, which is 28-fold lower than those achieved after equivalent intravenous doses. Approximately 75% of a bretylium dose is absorbed within 24 hours of intramuscular administration. Peak plasma concentrations occur at 30 to 90 minutes after intramuscular administration and range from 670 to 1500 ng/ml in subjects receiving 4 mg/kg. Bretylium is negligibly bound to plasma proteins (1-6%). Although drug tissue concentrations have not been reported in humans, high values for the apparent volume of distribution suggest extensive tissue binding. In animals, bretylium is progressively taken up by the myocardium over a period of 12 hours, and at 12 hours after bolus administration, myocardial concentrations exceed plasma concentrations 6 to 12 times. It is also avidly taken up by adrenergic nerves in animals. Bretylium is almost entirely cleared by the renal route and its total body clearance is closely correlated with renal clearance. Available data suggest that bretylium exhibits a complex pharmacokinetic profile which has been described by a 3-compartment model in subjects receiving intravenous dosing. The terminal elimination half-life ranges from 7 to 11 hours following oral, intramuscular and intravenous administration, and renal clearance is about 600 ml/min after intravenous administration.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

["Torsades de pointe" and reentry induced by anti-arrhythmia agents]. / Torsades de pointe et rentrées provoquées par les antiarythmiques.

Some anti-arrhythmic agents which have a stabilising effect on the membrane, particularly those belonging to Group I of Vaughan William's classification, are likely to cause rythmic disturbances by a re-entry phenomenon (atrial flutter 1/1, premature ventricular contractions, ventricular tachycardia, "torsades de pointe", even fatal ventricular fibrillation). The quinidines have been the most often condemned due to their effect on the action potential and on the speed of conduction. The fact that these re-entry phenomena are more frequent at therapeutic doses than at high or toxic doses suggests an individual susceptibility and the interaction of various predisposing factors: renal insufficiency, potassium depletion, pre-existing conduction disturbances, potentialsing drugs. In order to prevent these incidents it is advisable not to prescribe such anti-arrhythmic agents for susceptible patients, to control individual tolerance and to watch for the first ECG signs of conduction disturbances or of re-entry, such as premature contraction with fixed coupling. Treatment consists in an electrosystolic stimulus and the possible administration of potassium and bretylium.

Bretylium Tosylate; adverse effects in acute myocardial infarction.

The effects of bretylium tosylate in managing acute myocardial infarction were studied in 16 patients within 24 hours from the onset of symptoms and were compared to those of lidocaine in a comparable group of 15 patients. Both drugs were equally effective in preventing cardiac arrhythmias during the 48 hours of trial. No deleterious hemodynamic effects were associated with lidocaine treatment. However, marked supine hypotension developed in seven patients treated with bretylium. No changes occurred simultaneously in heart rate, left ventricular ejection time, or central venous pressure. The occurrence of hypotension correlated with a poor initial hemodynamic state. The substantial and unpredictable circulatory effects of bretylium in acute myocardial infarction contraindicates its routine use in the prevention of infarction arrhythmias.