1Division of Surgical Intensive Care, Department of Anaesthesiology, Pharmacology and Surgical Intensive Care, 2Institute of Social and Preventive Medicine and 3Cardiology Centre, University Hospital of Geneva, Switzerland*Corresponding authors: Division of Surgical Intensive Care, University Hospital of Geneva, CH-1211 Geneva 14, Switzerland
Accepted for publication: June 27, 2000
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Abstract |
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Br J Anaesth 2000; 85: 6905
Keywords: surgery, cardiovascular; heart, arrhythmia, supraventricular; heart, arrhythmia, antiarrythmics
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Introduction |
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Methods |
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Preoperative and postoperative management
Before transfer to the operating room, all patients received premedication with diazepam and morphine, and chronic ß-blocker therapy was replaced with metoprolol by mouth. General anaesthesia was induced and maintained with midazolam, fentanyl and pancuronium bromide, adjusted to body weight and elimination half-time. Systemic hypothermic (28°C) cardiopulmonary bypass (CPB; aortic and right atrium cannulation) associated with repeated cold cardioplegic-induced cardiac arrest was used. At the end of the surgical procedure, the patients were transferred to the ICU.
Weaning from mechanical ventilation and tracheal extubation were done as early as possible. Weaning from catecholamine infusion was guided by standard haemodynamic criteria. The pulmonary artery catheter was removed when there was no evidence of cardiac dysfunction and no need for catecholamine infusion. Patients were discharged from the ICU to the ward as soon as their haemodynamic and respiratory condition was stable.
Study design
The randomization procedure was accomplished by the Pharmacy Department using colour-coded spheres extracted from an opaque container. Additional patients were allocated to compensate for technical drop-outs. Patients were allocated to one of three groups, to receive a 72-h continuous intravenous infusion of amiodarone 900 mg per 24 h (Cordarone; Sanofi-Winthrop, Basel, Switzerland) or magnesium sulphate 4 g (16 mmol, 32 mEq) per 24 h (Bichsel, Interlaken, Switzerland) or placebo (0.9% NaCl), starting within 1 h of arrival in the ICU. The study drugs were prepared daily in an opaque syringe and tubing (Perfusor; Braun, Melsungen, Germany) by an independent observer. Throughout the 72-h infusion period, a Holter ECG recording (Cardiocorder three-channel recorder, model 459; Delmar Avionics, Irvine, California, USA) was obtained. Additional 12-lead ECGs were recorded every 12 h.
The primary end-point of the study was the prevention of AF. If AF occurred, the prophylaxis was considered to have failed and the study was terminated; the drug code was opened and the patient was treated as appropriate. The Holter ECG recording was analysed on completion of the 72-h study period or earlier if the study was terminated because of arrhythmia. Supraventricular arrhythmia episodes were then detected visually and printed for accurate diagnosis by two of the investigators. Considering the potential adverse effect of acute amiodarone infusion,15 an intermediate safety analysis was planned after the inclusion of half of the patients.
Definitions of supraventricular arrhythmia
Supraventricular tachycardia was defined as an arrhythmia of more than three narrow QRS complexes at a rate greater than 100/b.p.m. and lasting more than 30 s. Atrial fibrillation was defined as totally irregular atrial rhythm leading to irregular ventricular rhythm.
Data collection
Relevant patient characteristics, associated medical conditions, concomitant treatment, pulmonary and renal function tests were recorded. Also recorded were perioperative variables, including aortic cross-clamping and CPB duration, the number and type of coronary bypasses performed, and treatment at weaning from CPB. After surgery, heart rate, mean arterial pressure, central venous pressure and, when available, mean pulmonary artery pressure, pulmonary capillary wedge pressure, cardiac index (triplicate normal saline injection at room temperature, thermodilution technique) and stroke volume index were recorded 6-hourly. Arterial blood gases and electrolytes (Na+, K+ and Ca2+) were also measured at the same intervals. Total plasma magnesium concentrations were measured 12-hourly. Additional recorded variables included postoperative complications and drug-related side-effects. Data obtained from the Holter ECG recording were the number of isolated or paired supraventricular ectopic beats and the number of supraventricular tachycardia runs, with their ventricular response rate and the respective count of QRS complexes. To adjust for the variability in the number of beats per hour of the ECG Holter recordings, the number of abnormalities was normalized to 1000 recorded beats.
Statistical analysis
Continuous variables were expressed as mean (SD) unless otherwise specified. The two intervention groups were compared with placebo using the unpaired t-test when dealing with approximately normally distributed variables and the MannWhitney test otherwise. The 2 test was used for categorical variables. KaplanMeier analysis was used to analyse the delay in the onset and the duration of arrhythmia in the three groups. Potential predictors of the development of AF included patient characteristics, perioperative myocardial infarction and plasma magnesium concentration. Logistic regression was used to assess univariate associations between predictor variables and the onset of AF. All predictor variables that exhibited significant univariate associations with AF (P<0.05) were tested in multivariate models; the final model included only statistically significant predictors (at the P<0.05 level).
Sample size and power
The frequency of AF detected by Holter ECG monitoring after CABG surgery is about 40%.16 From previous studies on AF prophylaxis after CABG surgery,8 17 18 we expected a reduction of 50% in the occurrence of AF. Ninety-one patients per group would have been needed to detect such a difference with a power of 80% and =5%. An interim analysis was planned after inclusion of 50 patients in each group.
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Results |
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The mean age of evaluable patients was 65 yr (range 3788). The three groups were similar in baseline characteristics and surgical procedure (Table 1). Variables recorded on arrival at the ICU, including haemodynamics, laboratory and electrocardiograph findings, were similar among the three groups (data not shown).
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Postoperative course
Haemodynamics, blood gas and electrolytes
No differences in haemodynamic values were found compared with placebo, except that patients receiving intravenous amiodarone had slower heart rates from 18 h after starting the infusion (Fig. 2). No differences were observed in pH, PaCO2 and PaO2, or in blood concentrations of potassium and ionized calcium. In the magnesium group, higher plasma magnesium levels compared with baseline and the placebo group (P<0.01) were detected 12 h after starting the infusion and thereafter.
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Compared with the placebo group, patients in the amiodarone group required a longer period of catecholamine infusion [placebo 19 (13), amiodarone 32 (18) h; P<0.01] and concomitant invasive monitoring with an indwelling pulmonary artery catheter [placebo 31 (14) h, amiodarone 42 (16) h; P<0.01]. In the magnesium group, neither the duration of catecholamine infusion [10 (11) h, not significant] nor the duration of invasive monitoring [31 (10) h, not significant] was different from the values for the placebo group.
The length of stay in the ICU was significantly longer in patients receiving amiodarone (median 4 days, range 29 days) than in the placebo group (3, 27 days; P<0.05). The median length of stay in the ICU in the magnesium group was 3 days (221). In the placebo group, patients with sustained AF stayed longer in the ICU (5, 47 days) than patients maintaining a sinus rhythm (3, 26 days; P<0.05).
One patient in the amiodarone group died 3 days after surgery from acute myocardial infarction and cardiogenic shock and a patient in the placebo group died 5 days after surgery.
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Discussion |
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Prophylaxis against AF in cardiac surgery may still be indicated in selected populations such as patients presenting with valvular disease, which is complicated by a higher incidence of AF. Furthermore, as shown in our study, older patients are at higher risk of developing AF and may also benefit from prophylaxis.
The relevance of the delayed onset of AF with amiodarone remains questionable.
In our study, as shown by England and colleagues,20 although magnesium sulphate prophylaxis was ineffective in preventing AF, patients presenting with plasma magnesium levels higher than 0.95 mmol litre1 were protected from the development of AF. Variables predictive of postoperative AF onset were older age, and plasma magnesium concentrations in the low normal range (<0.95 mmol litre1) regardless of replacement therapy. Previous retrospective and observational studies emphasized the importance of age as an important independent predictor of AF after CABG.2124 Other predictors were chronic obstructive pulmonary disease, right coronary artery stenosis, preoperative ß-adrenergic blockers and digoxin and chronic renal failure.2124 Among the variables we studied, our results confirm the increased risk associated with older age, with a 2-fold increase for each 10-yr interval.
In conclusion, perioperative administration of amiodarone intravenously required prolonged vasoactive and inotropic support, longer invasive monitoring and a longer stay in the ICU. The decision to administer amiodarone prophylaxis should be made cautiously, taking account of the increased risks of arrhythmia associated with, for example, age and mitral valve surgery, and the side-effects associated with this drug. Postoperative magnesium supplementation was ineffective in reducing the occurrence of AF.
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Acknowledgements |
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References |
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