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Ann Thorac Surg 2000;69:1358-1362
© 2000 The Society of Thoracic Surgeons

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Original articles: Cardiovascular

Intraoperative amiodarone as prophylaxis against atrial fibrillation after coronary operations

^a Thoracic and Cardiovascular Surgery, Universitätsklinikum RWTH Aachen, Aachen, Germany
^b Medical Clinic I, Universitätsklinikum der RWTH Aachen, Aachen, Germany

Address reprint requests to Dr Dörge, Thoracic and Cardiovascular Surgery, Universitätsklinikum der RWTH Aachen, Pauwelsstrasse 30, D-52057 Aachen, Germany

	Abstract

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Background. New onset of atrial fibrillation is a frequent complication after coronary artery bypass grafting and is a major cause of postoperative morbidity. Preoperative oral treatment with amiodarone hydrochloride has been shown to be efficacious as prophylaxis. The present study investigated whether intraoperative use of intravenous amiodarone has a preventive effect on the incidence of atrial fibrillation after coronary revascularization.

Methods. In a prospective study, 150 consecutive patients (mean age, 63 ± 8 years; 132 men and 18 women) undergoing coronary artery bypass grafting were randomly assigned to one of three groups. Two groups received different doses of intravenous amiodarone (group I, 300-mg bolus and 20 mg · kg^-1 · day^-1 for 3 days; group II, 150-mg bolus and 10 mg · kg^-1 · day^-1 for 3 days) after aortic cross-clamping and one group, placebo (group III). Continuous electrocardiographic on-line monitoring was performed for 10 days. Arrhythmias were analyzed with respect to type, frequency, duration, and clinical relevance.

Results. New onset of atrial fibrillation occurred in 24% of patients in group I, 28% in group II, and 34% in group III (p = not significant). Atrial fibrillation with a rapid ventricular response (>120 beats per minute) was significantly more frequent in the control group (group I, 14%; group II, 24%; group III, 32%; p < 0.05, group I versus group III) and appeared significantly earlier (group I, day 4.3 ± 2.5; group II, day 4.8 ± 2.9; group III, day 2.6 ± 1.3; p < 0.05, group III versus groups I and II). Temporary atrial pacing because of bradycardia (<60 beats per minute) was necessary significantly more often in group I (group I, 48%; group II, 40%; group III, 28%; p < 0.05, group I versus group III). Early mortality rate (group I, 4%; group II, 2%; group III, 4%), rate of perioperative complications (group I, 14%; group II, 20%; group III, 14%), and duration of hospital stay (group I, 14.0 days; group II, 14.4 days; group III, 14.7 days) were not different between groups.

Conclusions. Intraoperative prophylactic use of amiodarone does not prevent new onset of atrial fibrillation in patients undergoing coronary artery bypass grafting and had no effect on outcome. Therefore, intraoperative prophylactic treatment with amiodarone at the tested doses does not appear to be justified.

	Introduction

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New onset of atrial flutter or atrial fibrillation (AF) is a frequent event after coronary artery bypass grafting (CABG), with an incidence of 15% to 40% [1–3]. It can cause nonfatal minor complications such as hemodynamic compromise during the immediate postoperative period as well as major complications including embolic cerebrovascular accidents and sustained AF [3], thus prolonging hospital stay and increasing costs. The efficacy of pharmacologic prophylaxis in reducing the incidence of AF has been investigated in several studies. Digoxin [4, 5] ß-blocking agents [5, 6], and calcium antagonists [7] have not proved efficacious in preventing arrhythmias without adverse effects.

Amiodarone hydrochloride has been reported to be effective in converting AF to sinus rhythm [8] and as prophylactic therapy for AF refractory to other drugs [9]. Cardioversion of AF was facilitated in patients pretreated with amiodarone after cardiac surgical procedures [10, 11]. Preoperative oral treatment with amiodarone starting 7 days before operation has been shown to be effective as prophylaxis against AF after surgical procedures on the heart [12]. The aim of the present study was to investigate whether intraoperative prophylactic use of intravenous amiodarone has the same preventive effect on the incidence of AF in patients undergoing CABG.

	Material and methods

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Patient population
One hundred fifty consecutive patients undergoing elective CABG were included in the study. Exclusion criteria were as follows: contraindications to amiodarone (sick sinus syndrome, atrioventricular conduction abnormalities, thyroid disease, interstitial lung disorders, renal or liver disease), need of concomitant cardiac surgical procedure, emergency operation, history of chronic or intermittent AF, and pretreatment with digoxin or amiodarone. Preoperative evaluation included a detailed medical history with documentation of preoperative medication, physical examination, 12-lead electrocardiogram, chest roentgenogram, pulmonary function test if lung disease was suspected, and thyroid function tests.

After written informed consent, 150 patients were randomly assigned to three groups. Patients in group I received a 300-mg bolus of amiodarone intravenously after removal of the aortic cross-clamp followed by continuous infusion of 20 mg · kg^-1 · day^-1 for the next 3 days. Patients in group II received a 150-mg amiodarone bolus after cross-clamping followed by continuous infusion of 10 mg · kg^-1 · day^-1 for the next 3 days. Group III received a placebo and served as the control. There were no significant differences regarding age, sex, Canadian Cardiology Society classification [13], preoperative myocardial infarction, severity of coronary artery disease, ventricular function, and number of redo procedures (Table 1).

Surgical procedure
All operations were performed with cardiopulmonary bypass, cardioplegic arrest (HTK solution, 4°C, 15 mL/kg), and moderate hypothermia (28°C). Venous cannulation was done separately with two cannulas through the right atrium; the arterial cannula was placed into the ascending aorta. The left ventricle was vented with a left ventricular cannula through the right pulmonary veins. All patients received atrial and ventricular temporary bipolar pacing wires intraoperatively. There were no significant differences regarding cross-clamp time, bypass time, number of grafts, use of the internal mammary artery, and coronary thromboendarterectomy (Table 2).

Data analysis
Statistical analysis was performed with the Statistical Package for Social Sciences (SPSS Inc, Chicago, IL). Where appropriate, data are expressed as the mean ± the standard deviation. Significant differences between nominally scaled and ordinally scaled variables were determined with a ² test. Fisher’s exact test was used when the number of observations was small (less than 50% of the cells with less than five observations). Student’s t test for independent samples was used for interval scaled variables. A p value of less than 0.05 was considered significant.

	Results

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Mortality, complications, and hospitalization
The hospital mortality rate was 3.3% (5/150 patients) and was not different between groups (Table 3). Causes of death were perioperative infarction with subsequent pump failure in 4 patients and sepsis with multiple-organ failure in 1 patient. Severe but nonfatal complications occurred in 16% (24 of 150) of the patients, and again there was not a significant difference between groups (see Table 3). Complications included low cardiac output syndrome with implantation of an intraaortic balloon pump, perioperative infarction, pneumonia, and repeat thoracotomy because of perioperative bleeding. A 77-year-old patient in group I sustained an embolic cerebrovascular accident resulting in right-sided hemiparesis despite oral anticoagulation when spontaneously converting to sinus rhythm after 5 days of AF. The mean postoperative hospital stay was 14.4 ± 3.6 days; it was not different between groups (see Table 3).

Atrial fibrillation
New onset of AF occurred in 24% of patients in group I, 28% in group II, and 34% in group III (p = not significant) (Fig 1). The incidence of AF with a ventricular response rate higher than 120 beats per minute, which is considered hemodynamically compromising in the immediate postoperative period, was lower in group I (14%) than in group III (32%) (see Fig 1).

View larger version (18K): [in this window] [in a new window]   Fig 1. Incidence of atrial fibrillation (AF) was not different between groups (n.s.). With the maximal dosage of intravenous amiodarone (group I), significantly fewer patients had tachycardia (p < 0.05) and more patients had bradycardia (p < 0.05) versus the placebo-treated patients (group III).

Time of new onset of AF
New onset of AF was significantly earlier in group III compared with groups I and II (Fig 2). In contrast to both the amiodarone-treated groups, patients in group III had no new onset of AF after the fifth postoperative day.

View larger version (8K): [in this window] [in a new window]   Fig 2. Time of new onset of AF during the postoperative period was significantly delayed in the amiodarone-treated groups (groups I and II) compared with the placebo-treated group (group III).

	Comment

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Although the risks of cardiac surgical procedures have been reduced significantly [14], arrhythmias continue to be a major cause of postoperative morbidity. Postoperative arrhythmias can delay recovery and prolong hospitalization [3], and AF is by far the most common rhythm disturbance [3]. The incidence of new onset of AF in patients with CABG ranges between 15% and 40% [1–5], which compares well with the incidence of 34% in the placebo-treated group in this study.

Little consensus exists regarding predisposing and etiologic factors. It has been suggested that increasing age, hypertension, greater number of grafts, myocardial infarction, previous cardiac surgical procedures, poor left ventricular function, prolonged duration of the operative ischemic period, and poor myocardial preservation of the atria will increase the incidence of postoperative AF [1, 3, 15, 16], but a single causal factor can rarely be identified. It is likely that interaction between these factors is important in the pathogenesis of AF after a cardiac operation. The study population showed a homogeneous distribution regarding potential predisposing and etiologic factors.

Potential complications of AF include hemodynamic compromise during the immediate postoperative period, sustained AF, and embolic cerebrovascular accidents [3]. In the present study, 5 patients had sustained AF at hospital discharge but were in sinus rhythm at follow-up 1 month postoperatively. Because of our policy of oral anticoagulation for 4 months postoperatively in all patients after CABG, no additional therapy was necessary in these 5 patients. Nevertheless, another patient sustained an embolic cerebrovascular accident during the hospital stay despite oral anticoagulation while converting to sinus rhythm spontaneously after previous AF.

The efficacy of pharmacologic prophylaxis in reducing the incidence of AF has been investigated in several studies. Digoxin has not always been effective and has the potential to increase the incidence of ventricular arrhythmias [4, 5]. A variety of ß-blocking agents have been studied with different results [1, 5, 6], and prophylactic use of verapamil has not been shown to be effective and does have substantial negative inotropic effects [7]. Amiodarone was effective in converting AF to sinus rhythm and also as long-term prophylaxis of AF refractory to other drugs [8, 9]. Ventricular arrhythmias after CABG were suppressed with intravenous amiodarone [10], and cardioversion of AF after cardiac operation was facilitated in patients pretreated with amiodarone [11]. Conversion to sinus rhythm occurred in 61% of patients with postoperative AF during the 12 hours of an intravenous amiodarone infusion, and amiodarone led to a reduction in ventricular rate in all patients [18]. Oral treatment with amiodarone started 7 days prior to operation until the day of hospital discharge was effective as prophylaxis against AF after operations on the heart [12], but the requirement of 7 days’ pretreatment probably limits such prophylactic therapy for routine clinical use. As oral amiodarone does not reach its maximal antiarrhythmic effects before 7 to 20 days [17, 18] and as the onset of the antiarrhythmic effect of intravenous amiodarone is probably rapid, an intravenous infusion was started intraoperatively after removal of the aortic cross-clamp in our study. Two different doses were tested versus placebo. Plasma concentrations of amiodarone or its metabolite desmethylamiodarone were not measured, as they correlate poorly with clinical effects [10, 18].

Intraoperative intravenous use of amiodarone did not prevent new onset of AF in the present study, even when given at high dosage. However, the incidence of AF higher than 120 beats per minute was significantly reduced in the group with the maximal dosage because of a reduction in the ventricular response rate. The ability of amiodarone to lower the ventricular response rate in the presence of AF has been demonstrated previously [10, 19]. The main antiarrhythmic effects of intravenous amiodarone were attributed to prolongation of the refractory period of the atrioventricular node, effects of calcium-channel blocking, and noncompetitive adrenergic antagonism [18]. Consequently, a significantly higher incidence of bradycardias was documented in the amiodarone-treated groups, a finding suggesting a noncompetitive adrenergic antagonism of amiodarone with slowing of sinus rhythm. Heart rates lower than 60 beats per minute were considered inadequate in the immediate postoperative situation because of potential hemodynamic compromise. Therefore, temporary atrial pacing was instituted in these patients.

Unlike the control group in whom new onset of AF appeared significantly earlier, the amiodarone-treated groups, showed a distinct shift toward later onset of AF. This represents another unsatisfactory effect, because in routine clinical practice, patients have been transferred from the intensive care unit or intermediate-care station and are no longer receiving on-line monitoring at this time. Finally, the prophylactic administration of intravenous amiodarone had no effect on duration of hospitalization. This was mainly due to a higher incidence of bradycardias requiring temporary pacing and to later onset of AF.

In conclusion, prophylactic intraoperative amiodarone treatment does not prevent new onset of AF after CABG. However, the incidence of hemodynamically relevant AF is significantly reduced at the maximal dosage. Simultaneously, the incidence of bradycardia is increased with the higher dosage of amiodarone, and the time of occurrence of AF is delayed. Therefore, the results of the present study do not favor routine use of prophylactic intravenous amiodarone treatment in patients undergoing CABG. Whether specific subgroups of patients can benefit from amiodarone treatment remains to be seen.

	References

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Hilmar Dörge Friedrich A. Schoendube Bruno J. Messmer Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Dörge, H. Articles by Messmer, B. J. Search for Related Content PubMed PubMed Citation Articles by Dörge, H. Articles by Messmer, B. J.