A butyl-3-(3,5,diiodo-4-/3-diethylaminoethoxybenzoy1)-benzofuran

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1 Amiodarone-Induced Complications After Cardiac Operation for Obstructive Hypertrophic Cardiomyopathy John P. Kupferschmid, MD, Todd K. Rosengart, MD, Charles L. McIntosh, MD, PhD, Martin B. Leon, MD, and Richard E. Clark, MD Surgery and Cardiology Branches, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland The occurrence of unanticipated and seemingly unexplicable major complications of hepatic, pulmonary, and cardiac dysfunction after palliative operation for obstructive hypertrophic cardiomyopathy prompted a review of 7 sequential patients. Fifty-five patients had been treated preoperatively with Pblockers, calcium-channel inhibitors, or both, and 6 had received amiodarone for six to 566 days (mean time, 2 days) at total doses ranging from 8 to 75 g (mean dose, 82 g) and had drug-free intervals prior to operation of zero to 457 days (mean time, 9 days). Comparisons were made between the two treatment groups and between those with and without major complications within the amiodaronetreated group. Preoperative cardiac studies, sex, age, functional class, and type of operation were not related to outcome for the entire patient cohort. In amiodaronetreated patients, the major findings were as follows: a 5% incidence of hepatic dysfunction with a tenfold increase in concentrations of serum glutamic-oxaloacetic transaminase and serum glutamic-pyruvic transaminase; a 25% incidence of pulmonary dysfunction necessitating a fourfold increase in the number of days of ventilator support; and a 9% incidence of low cardiac output syndrome with two deaths. Only 44% of the amiodarone- treated group had no serious complications. The incidence of major complications of the liver, lungs, and heart was 2%, %, and 2%, respectively, in patients not treated with amiodarone. Abnormal preoperative pulmonary function studies were predictive of prolonged postoperative ventilatory support. Discontinuation of amiodarone for several months prior to operation appeared to reduce the incidence of major complications. The necessary drug-free interval required preoperatively could not be determined from this retrospective experience. The recommendations resulting from this analysis are as follows: amiodarone should be discontinued and the operation delayed for as long an interval as possible; any abnormality in liver or pulmonary function studies should delay the procedure; and patients and referring physicians should be informed of the probability of increased complications, especially if the treatment regimen included more than g of amiodarone for 3 days or more. It is concluded that caution must be used when patients who have been treated with amiodarone are being considered for surgical palliation of obstructive hypertrophic cardiomyopathy. (Ann Thorac Surg 989;48:35944) miodarone, an iodinated benzofuran derivative [2- A butyl-3-(3,5,diiodo-4-/3-diethylaminoethoxybenzoy)-benzofuran hydrochloride] was introduced in Europe in 967 as an antianginal agent [l]. Structurally similar to thyroxin, it has since found widespread use in Europe, South America, and eventually in the United States as an antiarrhythmic agent effective against both ventricular and supraventricular arrhythmias [2-7. In 986, it was approved for use in the United States by the Food and Drug Administration for treatment of documented life-threatening recurrent arrhythmias, recurrent ventricular fibrillation, and recurrent hemodynamically unstable ventricular tachycardia [8]. Although amiodarone was originally thought to have very low toxicity [2, 3, numerous reports have listed an alarming number of serious side effects including pulmo- Accepted for publication Feb 29, 989. Address reprint requests to Dr Clark, Surgery Branch, NHLBI, National Institutes of Health, 9 Rockville Pike, Bldg, Room 2N244, Bethesda, MD nary fibrosis [P7, 9-3], hepatic dysfunction [4-7,, proarrhythmic effects [2, 4, and worsening of cardiac failure [3, 5, 7. Despite these reports of its toxicity, little is known about the effects of amiodarone on patients with hypertrophic cardiomyopathy who undergo a cardiac operation after preoperative treatment with this agent. This study was undertaken because several major unexplainable complications occurred in patients who underwent operative intervention to relieve obstruction of hypertrophic cardiomyopathy after they had been treated with amiodarone. Material and Methods This report is the result of a retrospective review of 7 patients operated on at the Surgery Branch, National Heart, Lung, and Blood Institute, during the interval April, 984, to September, 986, for symptoms of obstructive hypertrophic cardiomyopathy. Each patient was referred for operation by the Cardiology Branch after having failed maximal medical therapy and remaining in

2 36 KUI'FERSCHMID ET AL Ann Thorac Surg 989;48: Table. Summa y of Data for Amiodarone-Treated Group Treatment Total Average Drug- Cross- Patient Time Dose Dose Free Time Clamp Time No. Protocol (days) (9) (g/day) (days) (min) Operation Complica tion LCOS arrhythmia Hepatic + pulmonary + Hepatic Hepatic + severe photosensitivity Pulmonary Hepatic + pulmonary Hepatic + LCOS; died Hepatic Photosensitivity + alopecia Hepatic + pulmonary + + RVOT resection severe alopecia Hepatic + LCOS; died LCOS = low cardiac output syndrome; right ventricular outflow tract. = left ventricular septa myotomy-myomectomy; = mitral valve replacement; RVOT = New York Heart Association functional class I or IV. Sixteen patients had been treated preoperatively with amiodarone in varying doses and for varying intervals. Data were collected from reviews of the hospital chart, interviews with the patient or the referring physician or both, and review of the drug trial data. The 6 amiodarone-treated patients were compared with 55 patients with obstructive hypertrophic cardiomyopathy who were operated on during the same interval but did not receive amiodarone. Patient Group Characteristics The amiodarone-treated patients and the nonamiodaronetreated patients were similar in regard to age (43 k 4 years versus 49 k 2 years, respectively) and sex (44% male versus 45% male, respectively). They did not differ significantly in terms of the following: preoperative liver function tests (serum glutamic-oxaloacetic transaminase [SGOT], miu versus 9 f 2 miu, and serum glutamic-pyruvic transaminase [SGPT], 28 -C 3 miu versus 24 * 3 miu), pulmonary function tests (forced expiratory volume in second, 83% k 5% of predicted versus 88% f 2% of predicted; forced vital capacity, 82% k 5% of predicted versus 8% k 2% of predicted; forced expiratory volume in second to forced vital capacity ratio, % k 2% of predicted versus % +- 2% of predicted; and pulmonary diffusing capacity of carbon monoxide, 74% k 6% of predicted versus 75% f 5% of predicted), or pulmonary artery pressures (systolic, mm Hg versus 32 k mm Hg; diastolic, 5 k 8 mm Hg versus 4 * 6 mm Hg; wedge, 3 k 4 mm Hg versus 8 f 6 mm Hg; and left ventricular end-diastolic, 6 * 6 mm Hg versus 2 k mm Hg). In addition, there was no significant difference in preoperative ejection fraction (75% f % versus 76% k 2%). All patients in the amiodarone-treated group had a diagnosis of obstructive hypertrophic cardioniyopathy with hemodynamically significant left ventricular outflow tract obstruction (rest or provoked gradients > 5 mm Hg). Eight patients were prescribed amiodarone because of preoperative arrhythmias refractory to standard medical therapy: supraventricular tachycardia (3), atrial fibrillation (3), and ventricular tachycardia (2) (Table ). The 8 other patients were participants in a clinical trial evaluating the efficacy of amiodarone in relieving symptoms of obstructive hypertrophic cardiomyopathy. The total number of days of amiodarone treatment ranged from six to 566 with a mean of 2 days (see Table ). The total dose ingested ranged from 8 to 75 g with a mean of 82 g. The length of time from discontinuation of the drug to operation ranged from zero to 457 days with a mean of 9 days. The average dose ranged from 9 to,333 mg with a mean of 55 mg. Operations performed were similar in the amiodaronetreated and nonamiodarone-treated groups: mitral valve replacement, 5% versus 45%, respectively, and left ven-

3 Ann Thorac Surg 989;48: KUPFERSCHMID ET AL 36 tricular septa myotomy-myomectomy, 5% versus 55%, respectively. Average cross-clamp time was similar in both groups, 74 * minutes versus 73 rt 5 minutes, as was bypass time, 23 f 4 minutes versus 8 If- 6 minutes. Two (3%) of the 6 amiodarone-treated patients and (2%) of the 55 nonamiodarone-treated patients required an intraaortic balloon pump to be weaned from cardiopulmonary bypass. Myocardial protection methods, anesthesia techniques, preinduction and induction medications, and maintenance drugs were similar in both groups. Statistical Analysis Comparisons were made between the amiodarone-treated and nonamiodarone-treated groups and between those patients in the amiodarone-treated group who did not have complications versus those who did. The comparisons were performed using contingency table analyses and the Wilcoxon test. Results Complications A summary of the complications encountered in both groups is shown in Table 2. Six (38%) of the patients treated with amiodarone had no complications. One had mild skin problems of photosensitivity and alopecia. Nine patients (56%) had major complications involving substantial hepatic, pulmonary, and cardiac dysfunction. Two of these patients died. The incidence of complications was significantly higher in the amiodarone-treated group compared with the nontreated group (p <.5). Complete liver function tests were performed daily in all patients, though Table 3 provides the maximal values for only SGOT and SGPT. The incidence of hepatic Table 2. Postoperative Complications in Both Groupsa Complication Photosensitivity, alopecia (mild) Hepatic Hepatic + pulmonary Pulmonary LCOS LCOS + hepatic LCOS + hepatic + pulmonary Total Death No Amiodarone Amiodarone Treatment Treatment (n = 6) (n = 55) (62.5)b 6 (37.5) 2 (2.5) 2 (4) 53 (96) () a Numbers in parentheses are percentages. Nine patients had one or more major hepatic, pulmonary, or cardiac complications; only patient sustained just one major complication, a pulmonary complication. LCOS = low cardiac output syndrome. Table 3. Postoperative Data for Both Groupsn No Am i o d a r o n e Amiodarone Treatment Treatment Variable (n = 55) (n = 6) Hepatic dysfunction SGOT (miu/dl)b SGPT (miu/dl)b Patients with severe dysfunction Pulmonary dysfunction Ventilator (days) Moderate Adult respiratory distress syndrome Total Low cardiac output syndrome Moderate (no IABP; drug responsive) Severe (IABP; not responsive to inotropic drugs) Total Deaths 95 * ; > ; 37-,7 75 * 2; ; 44,2 /55 (2) 8/6 (5).8 4.3; * Numbers in parentheses are percentages. Data are shown as the mean k the standard error of the mean; the range follows. IABP = intraaortic balloon pump; SGOT = serum glutamic-oxaloacetic transaminase; SGPT = serum glutamic-pyruvic transaminase. dysfunction was 5% in the amiodarone-treated group and 2% in the other group. For all 6 patients in the former group, the mean maximal values of SGOT and SGPT were about ten times those in the latter group. Within the amiodarone-treated group, the mean values for patients who did not exhibit hepatic dysfunction versus those of patients who did were 53 and,939 miu/dl, respectively, for SGOT and 34 and,325 miu/dl, respectively, for SGPT. Pulmonary dysfunction occurred in 25% of the amiodarone-treated group and necessitated 3, 7, 4, and 35 days of ventilatory support. No patient in the nonamiodarone-treated group required more than 24 hours of support. Low cardiac output syndrome (LCOS), defined as a cardiac index of less than 2. L/minlm2 and evidence of poor organ perfusion, occurred in 3 patients in the amiodarone-treated group. One of these patients also had hepatic and pulmonary dysfunction, which abated concomitantly in response to inotropic agents. The 2 patients with severe LCOS had gross hepatic dysfunction as well, and were unresponsive to inotropic drugs and intraaortic balloon treatment. These 2 patients died. Only patient in the nonamiodarone-treated group sustained LCOS, and required substantial quantities of inotropic agents for a short time (less than 48 hours).

4 362 KUPFERSCHMID ET AL Ann Thorac Surg 989;48:359%64 Relationship of Complications to Four Variables in Amiodarone-Treated Group PREOPERATIVE DATA. Preoperative liver function test results did not predict which patients would or would not have major increases in serum enzyme concentrations in the immediate postoperative interval. The 7 patients without major dysfunction had mean values of 8.4 and 27.4 miu/dl for SGOT and SGPT, respectively. The 5 patients with hepatic dysfunction, with or without pulmonary complications, had values of 9.2 and 28.4 miu/dl for SGOT and SGPT, respectively. The one exception was the single patient in whom amiodarone-induced hepatitis developed preoperatively. She was operated on 39 days after discontinuation of amiodarone. At the time of operation, the liver function test results had returned to normal. Substantial hepatic dysfunction with maximal values of,225 and,835 miu/dl for SGOT and SGPT, respectively, developed postoperatively. Preoperative pulmonary function studies, on the other hand, were predictive of the development of complications. The mean values for forced expiratory volume in second, forced vital capacity, and diffusing capacity of carbon monoxide for the 4 patients with postoperative pulmonary dysfunction versus the 9 without this complication who were tested were 7% versus 89%, 68% versus 87%, and 55% versus 83%, respectively. The presence of pulmonary hypertension preoperatively was not related, as 2 of the 3 patients with pulmonary hypertension had no pulmonary complications. The occurrence of amiodarone-induced pulmonary fibrosis preoperatively also seemed to predispose to severe pulmonary dysfunction postoperatively, as was seen in patient despite normal pulmonary function test results. The development of LCOS was not related to pulmonary hypertension or preoperative cardiac function. of the 3 patients with this complication had elevated pulmonary artery pressures. All 3 had ejection fractions greater than 76% as measured by radionuclide angiography. The left ventricular end-diastolic pressures were not different from those in patients without the complication or those in the nonamiodarone-treated group. Two patients with LCOS who subsequently died had cross-clamp intervals of 48 and 7 minutes, and the patient with LCOS who survived had a cross-clamp interval of 8 minutes. TOTAL DOSE. The 7 patients without major complications had a mean dose of 49.6 g. The 4 patients with hepatic dysfunction only or pulmonary dysfunction only had injected 62 g. The 5 patients with two or more complications had a mean total dose of 43.8 g with a range of 7 to 75 g. There was no significant difference between the mean dose of patients with a single major complication and that of patients without complications. However, patients who received more than g were at high risk for two or more complications or death. AVERAGE DAILY DOSE. The average daily dose ranged from 9 to,333 mg. The mean value for those without complications was 685 mg and for those with complica- tions, 445 mg. No relationship was found with respect to the incidence of complications or any other variable. DRUG-FREE PREOPERATIVE INTERVAL. The 7 patients without major complications had preoperative drug-free intervals ranging from zero to 234 days with a mean interval of 8 days. In 4 of these patients, the drug-free interval was 42 days or less. The 9 patients with complications had intervals ranging from zero to 457 days. However, for 8 of the 9, the interval was zero to 96 days with a mean of 3 days. Three patients had no drug-free interval prior to operation; 2 of them had major complications and died. For the patients without complications, the mean drugfree interval was.4 days longer than the mean treatment duration. In contrast, the 9 patients with complications had a mean treatment duration 6.5 days longer than the mean drug-free interval. Comment Amiodarone has a wide variety of pharmacological effects. They include decreasing coronary vascular resistance and increasing coronary blood flow [4, 5, decreasing peripheral vascular resistance [ 4-6], causing an atropine-resistant sinus bradycardia [ 4, 6-8], causing a noncompetitive blockade of both a- and P-adrenergic receptors [4, 6, 7, 9, and a noncompetitive inhibition of both the inotropic and the chronotropic response to glucagon [7]. DeBoer and colleagues [2] showed that amiodarone favorably influenced hemodynamic values and decreased infarct size in experimental myocardial infarction. Charlier and associates [ 4 demonstrated in dogs that amiodarone had major negative inotropic effects, work later confirmed by others [5, 2. In addition, amiodarone possesses numerous electrophysiological effects, which make it attractive as an antiarrhythmic agent. It results in a marked prolongation of both atrial and ventricular action potentials [8] and a substantial increase in the effective refractory period of the atrium, ventricle, atrioventricular node, His-Purkinje system, and accessory pathways [2]. The pharmacokinetics and pharmacodynamics of amiodarone are not highly predictable [5-7. The drug has a low bioavailability after oral ingestion [22] and has an extremely variable half-life ranging from 2 to 8 days [3, 6. There is evidence to suggest that amiodarone possesses tissue-specific uptake and concentration [22] in addition to tissue-specific activity [9]. Amiodarone has been proven in numerous clinical series to be highly efficacious as an antiarrhythmic agent effective against both supraventricular and ventricular arrhythmias [2-7. Although its safety record during a decade of use in Europe and South America was impressive [2, 3, it has not found a similarly low riskhenefit ratio in the United States [2-7, 9-3]. Many reasons have been postulated to explain the higher incidence and severity of complications seen in the United States, the most convincing of which is that higher doses were used [4, 5, 7,, particularly for patients with drug-refractory arrhythmias [4]. Amiodarone is now prescribed for patients who will

5 Ann Thorac Surg 989;48: KUPFERSCHMID ET AL 363 eventually require a cardiac operation, although there have been few reports of its use in the surgical setting [6, 2, 23. We are aware of two case reports of patients in whom LCOS developed [6, 2, two cases of atropineresistant sinus bradycardia [6, 23, and one case of complete heart block [23], all thought to be secondary to amiodarone. The most consistent finding in these reports is the development of LCOS, reported by Gallagher and associates [6] in 98 and by MacKinnon and colleagues [2] in 983. Both of these studies, however, dealt with patients who had severe coronary artery disease and underwent coronary artery bypass grafting and resection of a left ventricular aneurysm. This group of patients can be expected to have an increased incidence of LCOS postoperatively, which is related to the underlying cardiac disease, thus making it difficult to implicate the drug as a cause of LCOS. In the patient reported by Gallagher and co-workers [6], an inappropriately low systemic vascular resistance (6 dyne-sec/cm5), which was refractory to a-adrenergic agonists, developed. In addition, Liberman and Teasdale (23, in 985, reported that 6 of 2 patients who had a variety of cardiac operations and were treated preoperatively with amiodarone required an intraaortic balloon pump to be weaned from cardiopulmonary bypass. They also noted that in 2 patients, a state of alpha-adrenergic blockage leading to a low systemic vascular resistance developed, despite a-agonist therapy. The findings in this report support the previous citations of LCOS and clinically significant a-adrenergic blockade associated with the use of amiodarone. Although no test was found that would seem to indicate which patient was going to experience either LCOS or a-adrenergic blockade postoperatively, the development of pulmonary dysfunction postoperatively might be predicted on the basis of preoperative data. First, the development of pulmonary fibrosis preoperatively may place the patient at a higher risk of pulmonary dysfunction postoperatively, regardless of the pulmonary function variables at the time of operation. Second, a fall in pulmonary function test results (particularly the pulmonary diffusing capacity of carbon monoxide) to a level less than 8% of predicted that does not rise higher than 8% on withdrawal of amiodarone may place the patient at increased risk of pulmonary dysfunction postoperatively. Third, the development of drug-induced hepatitis while on a regimen of amiodarone may place a patient at risk for hepatic dysfunction even if the pulmonary function test results have returned to normal preoperatively. Two or more major complications in the same patient appeared to be dose related because those patients receiving more than g of amiodarone preoperatively had the highest incidence and seventy of complications. The development of pulmonary or hepatic dysfunction or LCOS does not appear to be related to the length of time from discontinuation of the drug to the time of operation except in a general way. However, the duration of the drug-free interval was related to the incidence of complications when it was shorter than the duration of drug administration. The 7 patients without major complications had longer drug-free intervals (mean interval, 8 days) than those with complications (mean interval, 3 days). In view of the extremely long and variable half-life of amiodarone, the appropriate drug-free interval required is unknown. Low cardiac output syndrome developed in 3 of the 6 amiodarone-treated patients, 2 of whom died, and in only of the 55 nonamiodarone-treated patients without any clear predictor to indicate this outcome. One of the patients who died had the longest cross-clamp time (7 minutes), but this did not differ significantly from the longest cross-clamp time in the nonamiodarone-treated group (54 minutes). In addition, the other patient who died had a cross-clamp time of 48 minutes. Thus, time of ischemia by itself was not a predictor of either LCOS or death. The possibility remains, however, that the combination of a long period of ischemia and a substantial intake of amiodarone preoperatively (>lo g) places the patient at a higher risk of LCOS, death, or both. A number of factors may be responsible for the variability in the drug-free interval. It is known that amiodarone uptake is, in part, tissue specific [22]. It is highly lipophilic, and penetrates and binds to tissues with high lipid content. It has been proposed that amiodarone binds to intracellular phospholipids and prevents the breakdown of these phospholipids [2]. The accumulation of phospholipids may then be responsible for some of the findings of dose-related toxicity, particularly in organs such as the lung (9, 2. We urge cardiac surgeons to exercise increased caution in considering operative palliation for patients treated with amiodarone, particularly if one or more of the following factors are present: there is clinical evidence of pulmonary or hepatic dysfunction preoperatively; there is a decline in pulmonary function studies (particularly the pulmonary diffusing capacity of carbon monoxide) to values less than 8% of predicted; after withdrawal of the drug, the pulmonary function test results fail to reach normal levels (greater than 8% of predicted); or the patient has taken more than g of amiodarone (total preoperatively), has taken the drug for 3 days or more, or has not had a drug-free interval equal to or greater than the drug treatment interval. References. Vastesaeger M, Gillot P, Rasson G. 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