Two timely articles published in this volume of Circulation by Scheinman et al1 and Kowey et al2 present data from recently completed trials confirming the efficacy of intravenous amiodarone in life-threatening ventricular tachyarrhythmias. Intravenous amiodarone has recently received Food and Drug Administration approval for the acute treatment and prevention of ventricular fibrillation (VF) and hemodynamically destabilizing ventricular tachycardia (VT) refractory to other therapy. The above-mentioned two trials were performed in severely ill patients who had life-threatening ventricular arrhythmias not controlled by several other intravenous antiarrhythmics.
The mean age of the patients in these studies was in the 60-year range, 75% of the patients were men, the mean ejection fraction was 31%, 81% had had a prior myocardial infarction, 19% were on ventilator support, and 23% were on balloon pump support. Therefore, these patients were elderly, had severe ischemic structural heart disease and left ventricular dysfunction, and all the patients had hemodynamically destabilizing VT, incessant VT, and/or VF. The poor prognosis of this population limited the study design: (1) it was unethical to consider a placebo control group; (2) supplemental bolus doses were permitted to prevent recurrence of ventricular tachyarrhythmias; (3) open-label therapy was permitted even after double-blind therapy in attempts to save patients from dying; and (4) given the limitations of the enrollment criteria, a large number of centers were required for enrollment.
A prior study3 using doses of 500, 1000, and 2000 mg every 24 hours demonstrated that all of these doses were about equally effective in treating ventricular tachyarrhythmias. A dose-related increase in hypotension was noted at higher doses. Therefore, although intravenous amiodarone at these doses appeared to have some efficacy, no effective dose range had been established to guide dosing in the clinical situation.
Scheinman et al1 conducted a double-blind, dose-ranging study comparing three different doses of intravenous amiodarone (125, 500, and 1000 mg/24 h). With increasing doses, the overall efficacy, defined by the total number of VT event rates during double-blind therapy, decreased at the higher doses. There was a statistical (P<.05) difference between the 125- and the 1000-mg doses. These data suggest that 1000 mg/24 h would be a reasonable starting dose for intravenous amiodarone. The trend toward a lower number of supplemental doses at the 1000-mg dose supported this dosing recommendation. Of note, there was no dose-related increase in drug-induced hypotension between the 125-, 500-, and 1000-mg doses.
The study by Kowey et al2 was a comparative trial comparing intravenous bretylium (2500 mg/24 h) with two doses of intravenous amiodarone (125 and 1000 mg/24 h). This study demonstrated that the 1000-mg dose was more efficacious than the 125-mg dose, as evidenced by the less frequent need for supplemental doses and significantly fewer arrhythmic events per hour with the higher dose of amiodarone. These data were consistent with the findings of Scheinman et al.1 Intravenous amiodarone appeared to have an efficacy at least equal to that of intravenous bretylium. The bretylium-treated patients had more drug-related hypotension and a higher patient dropout rate than the amiodarone-treated patients. Therefore, intravenous amiodarone had an improved safety profile compared with the acute use of intravenous bretylium in this patient setting.
These trials demonstrate the efficacy of intravenous amiodarone in the treatment of life-threatening ventricular tachyarrhythmia by (1) the dose-related decrease in VT event rates, (2) the dose-related increase in time to the first VT event, and (3) the dose-related decrease in the need for supplemental bolus amiodarone infusions. These comparative trials have established a clinical useful-dose range for intravenous amiodarone. At the 1000-mg/24-h dose, there is no evidence of a dose-related increase in treatment emergent adverse effects or mortality.
Intravenous amiodarone does have some negative inotropic effects that may be accentuated in critically ill patients.4 This effect is counterbalanced by the vasodilatory effects of the drug, and only a small overall decrease in cardiac output may be noted. Hypotension will occur if the drug is given either at too high a dose or too quickly. A small number of patients (about 3%) will require a dosage alteration or drug discontinuation because of hypotension. Part of the drug-induced hypotension may be secondary to the vasodilatation or the negative hemodynamics of the vehicle, polysorbate 80. Treatment of drug-induced hypotension includes decreasing the infusion rates, discontinuation of the infusion, intravenous volume expansion, and the use of vasopressor or positive inotropic agents.
Intravenous amiodarone has interesting and complex pharmacokinetics. Peak serum concentrations after 15-minute infusions in healthy volunteers range from 5 to 41 mg/L. Peak levels after 150 mg of supplemental infusions in patients with VT/VF range between 7 and 26 mg/L. Because of the rapid distribution of this drug, serum concentrations decline to 10% of peak values within 30 to 45 minutes after the end of the infusion. After 48 hours of continuous infusion plus supplemental infusions, serum amiodarone concentrations range from 0.7 to 1.4 mg/L. There appears to be little importance of desethyl amiodarone, since the concentrations of this active metabolite are unmeasurable in the acute setting. No dosage adjustment appears to be needed in patients with renal problems, hepatic disease, or left ventricular dysfunction.
Special precautions need to be followed in the use of intravenous amiodarone. To avoid phlebitis, administration through a central venous line is recommended. If the drug is administered through a peripheral line, concentrations should not exceed 2 mg/mL. The drug does not need to be protected from light and is stable in 5% dextrose in water (D5W) solution in polyolefin or glass containers. Amiodarone adsorbs to polyvinyl chloride tubing; however, current dosing recommendations appear to correct for this. Because of formation of precipitate, intravenous amiodarone should not be given concurrently with acetic acid, aminophylline, mezlocillin sodium, cefamandole nafate, cefazolin sodium, heparin sodium, sodium acetate, or quinidine gluconate.
The mechanism of action of intravenous amiodarone is unclear. Obviously, a drug with a long oral half-life that works within an hour when given intravenously has some mechanism of action different from that of its oral counterpart. Unlike oral amiodarone, short-term dosing with intravenous amiodarone is not associated with any significant prolongation of action potential duration (QT interval) or use-dependent sodium channel blockade. In the short term, antisympathetic and calcium channel blockade properties are noted. Although intravenous amiodarone prolongs AV nodal conduction and refractoriness, it differs from oral amiodarone in that short-term intravenous amiodarone has little or no effect on sinus cycle length, infranodal or intraventricular conduction, or atrial and ventricular refractory periods.5 Scheinman et al1 note that “the faster onset of action for the intravenous formulation compared with the oral formulation may be a result of faster delivery, increased blood levels, and increased bioavailability, resulting in the exposure of cardiac tissues to higher amiodarone concentrations.”
Intravenous amiodarone can be given parenterally in critically ill patients. The parenteral option is important to patients not controlled with intravenous lidocaine, procainamide, or bretylium. The rapid onset of action appears to be secondary to high serum concentrations when the drug is given by this route. The current dosing recommendation for intravenous amiodarone is to give ≈1000 mg over the first 24 hours. The initial infusion should contain 3 mL of amiodarone injection (150 mg) in 100 mL D5W (concentration of 1.5 mg/mL). One should infuse this 100 mL over 10 minutes (15 mg/min) for a total of 150 mg. Therapy is continued with a slow loading infusion containing 18 mL (900 mg) of amiodarone injection in 500 mL of D5W (concentration of 1.8 mg/mL). This infusion should be administered at a rate of 1 mg/min for 6 hours, which will provide about 360 mg over that time period. This is followed by a maintenance infusion at a rate of 0.5 mg/min, which over 18 hours will total about 540 mg. The above recommendations will give ≈1000 mg of amiodarone over the first 24 hours. For treatment after the first 24 hours, the maintenance infusion of 0.5 mg/min, or 30 mg/h, should be continued. In the event of breakthrough episodes of VT/VF, 150-mg supplemental infusions of drug mixed with 100 mL of D5W may be administered over 10 minutes to minimize the potential for hypotension.
Intravenous amiodarone will be an important adjunctive therapy for the management of life-threatening ventricular tachyarrhythmias in the critical-care setting. Once the patient is stabilized, a long-term decision concerning continuous oral dosing needs to be made. When this drug is used short-term, the long-term side-effect profile of oral amiodarone is of little concern. How this drug will fit into the armamentarium of clinicians is yet to be determined; however, the availability of another antiarrhythmic treatment option in the critical care setting is long overdue.
- Copyright © 1995 by American Heart Association
Scheinman MM, Levine JH, Cannom DS, Friehling T, Kopelman HA, Chilson DA, Platia EV, Wilber DJ, Kowey PR, for the Intravenous Amiodarone Multicenter Investigators Group. Dose-ranging study of intravenous amiodarone in patients with life-threatening ventricular tachyarrythmias. Circulation. 1995;92:3264-3272.
Kowey PR, Levine JH, Herre JM, Pacifico A, Lindsay BD, Plumb VJ, Janosik DL, Kopelman HA, Scheinman MM, for the Intravenous Amiodarone Multicenter Investigators Group. 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.
Levine J, Massumi A, Scheinman MM, Winkle RA. The intravenous amiodarone multicenter group: preliminary report. J Am Coll Cardiol. 1990;15:27A. Abstract.