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Ann Thorac Surg 2002;74:720-726
© 2002 The Society of Thoracic Surgeons
a Division of Cardiac Surgery, "Tor Vergata," University of Rome, Rome, Italy
* Address reprint requests to Dr Forlani, Cattedra di Cardiochirurgia, Università di Roma "Tor Vergata," European Hospital, Via Portuense 700, 00149 Rome, Italy
e-mail: hhstel{at}tiscali.it
Presented at the Thirty-eighth Annual Meeting of The Society of Thoracic Surgeons, Fort Lauderdale, FL, Jan 28–30, 2002.
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Abstract |
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Methods. Two hundred seven consecutive coronary artery bypass patients (mean age 62 ± 11 years) were randomized to receive sotalol alone (80 mg twice daily for 5 days starting from the morning of the first postoperative day) (group S), magnesium alone (1.5 g daily for 6 days starting in the operating room just before cardiopulmonary bypass) (group M), both pharmacologic agents at the same dosages (group S+M), or no antiarrhythmic agents (group CTR). All patients with an ejection fraction less than 0.40 were excluded.
Results. The incidence of postoperative AF was 11.8% (6/51) in the S group, 14.8% (8/54) in the M group, 1.9% (1/52) in the S+M group, and 38% (19/50) in the CTR group. The following differences were significant: group CTR versus groups S, M, and S+M with values of p = 0.002, p = 0.007 and p < 0.0001, respectively; and group S+M versus groups S and M with p = 0.04 and p = 0.01, respectively.
Conclusions. Incidence of AF after coronary operation was significantly reduced by the administration of sotalol alone and magnesium alone; more importantly, the incidence was further reduced by combining these agents.
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Introduction |
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Patients and methods |
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TopAbstractIntroductionPatients and methodsResultsCommentAcknowledgmentsDiscussionReferences |
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The study was approved by the Human Ethical Committee at our institution and all patients gave informed consent; pharmaceutical companies were not involved in the study.
Surgical procedure
All medications, including ß-blockers, were discontinued the day before the operation. After premedication with diazepam (0.1 mg/kg orally), morphine (0.14 mg/kg intramuscularly), and scopolamine (0.003 mg/kg intravenously), anesthesia was induced with intravenous fentanyl (5.0 µg/kg), diazepam (0.1 mg/kg), and pancuronium (0.1 mg/kg). Patients were ventilated with a mixture of air and oxygen; anesthesia was maintained with repeated doses of fentanyl and volatile anesthetic agents. The electrocardiogram (leads I and II) and hemodynamic measurements, which included arterial blood pressure, heart rate (HR), and central venous pressure, were monitored continuously throughout the surgical procedure and for the first 48 hours postoperatively (HP M 1166 model 66; Hewlett-Packard, Palo Alto, CA). An Edwards Laboratory Swan-Ganz catheter was used to measure pulmonary artery pressure, pulmonary capillary wedge pressure, and thermodilution cardiac output. The cardiac index (CI) was derived from standard equations.
Normothermic CPB was instituted between a right atrial cannula and an ascending aortic perfusion cannula. Cardiac arrest was obtained by antegrade normothermic hyperkalemic blood cardioplegia (10 mg/kg) as described previously [26]; distal anastomoses were performed during a single period of aortic cross-clamping; and 50 mL of blood cardioplegia was injected manually into each vein graft after completion of the corresponding distal anastomosis. The proximal anastomoses were performed after aortic declamping and heart reperfusion. All procedures were performed by the same surgical team.
Study design
Before CPB, according to a computer-generated random code, the patients were randomized into four groups: Controls (CTR): no drug were administered; sotalol (S): administration of sotalol 80 mg orally twice daily starting from the first postoperative day until the fifth postoperative day, then sotalol 40 mg orally twice daily for 4 weeks; magnesium (M): administration of magnesium sulfate 1.5 g (12 mEq) intravenous daily starting just before CPB until the fifth postoperative day; sotalol plus magnesium (S+M): a combination of both drugs in the same dosages as groups S and M.
The morning of the first postoperative day, hemodynamic calculations were recorded. We excluded patients with HRs < 60 bpm, systolic systemic arterial pressure < 100 mm Hg, wedge pulmonary pressure > 15 mm Hg, cardiac index < 2.5 L · min-1 · m-2 with inotropic support (dopamine dose > 3 µg · kg-1 · min-1). Cardiac rhythm was continuously monitored in the intensive care unit until the morning of the second postoperative day. For the remaining days until discharge, 12-lead electrocardiograms were recorded every 8 hours. Serum levels of creatinine, potassium, calcium, and magnesium were measured preoperatively and every day after the operation.
The end point of the study was considered any AF episode that required treatment for symptoms or hemodynamic deterioration from the first postoperative day until the 1-month control visit.
Statistical analysis
All analyses were performed according the intention-to-treat principle. Data are expressed as mean ± SD. Comparisons of the continuous or discrete variables between the four groups were performed using an unpaired Student’s t test or a 
2 test, respectively. Multi-way ANOVA with repeated measures on one factor was used to compare pre- and postoperative biochemical data in the four groups of patients. Post hoc comparisons were made using the Fisher PLSD test. To investigate the independent predictors of AF, a multivariate analysis was performed using a stepwise logistic regression for all variables that showed a value of p 
0.01 at univariate analysis. A value of p < 0.05 was considered statistically significant. All statistical analyses were performed with StatView (version 5.0) for Windows 8.0 (SAS Institute, Cary, NC).
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Results |
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Two patients, both in the M group, experienced AF the day of the operation and were excluded from the study. The total incidence of AF was 16.4% (34/207) and occurred most often in the second postoperative day (Fig 1). Atrial fibrillation occurred in 38% of patients (19/50) in the CTR group, 11.8% (6/51) in the S group, 14.8% (8/54) in the M group, and 1.9% (1/52) in the S+M group (Fig 2). No differences were noted among the groups for ventricular rate during AF or for time of onset of AF.
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All preoperative values of QTc were in normal ranges and did not differ among groups. At discharge a significant increase of QTc in the S and S+M groups versus preoperative values (419 ± 26 ms versus 389 ± 28 ms in group S, p = 0.03; 432 ± 128 ms versus 373 ± 39 ms in group S+M, p = 0.008) was observed. No difference in QTc was observed between the S group versus the S+M group at discharge.
Calcium and potassium serum levels were similar among groups. Conversely, magnesium serum levels were significantly lower in the two groups not receiving e.v. magnesium (Fig 3). Of note, the highest differences were observed on the second postoperative day when the highest the incidence of AF was also recorded.
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Comment |
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Fatigue, dizziness, dyspnea, headache, bronchospasm, and the more serious sinus bradycardia, hypotension, and exacerbation of heart failure are side effects related to sotalol. These adverse effects are similar to those of other ß-blockers even if the aggravation of heart failure due to sotalol is less frequent and usually occurs with dosages well above those used in our study and in patients with an ejection fraction of < 0.45 or cardiomegaly [27]. For these reasons sotalol was started the first postoperative day after hemodynamic evaluation of the patients; considering the low incidence of postoperative AF the day of the operations and the fact that sotalol serum level peaks between 2 to 4 hours with oral administration, this approach did not reduce the efficacy of the protocol.
The most dangerous effect of an antiarrhythmic drug is the aggravation of a preexisting arrhythmias or the provocation of a new one such as torsade de pointes for the sotalol. It has been demonstrated that the proarrhythmic effect of sotalol is dosage related and directly related to QTc interval elongation. In fact, by increasing the sotalol dosage from 160 to 640 mg/day, a QTc interval increase from 40 to 100 ms has been reported [27].
Many of the sotalol-induced torsade de pointes have been observed in patients with intentional overdose, bradycardia, hypokalemia, or concomitant use of drugs prolonging the QT interval. In our study, the dosage of 80 mg twice daily was decided based on the minimal effective dosage [27], already reported in other studies for the treatment of AF [28] and for the prevention of post-CABG AF [5, 6, 15]. This dosage was considered safe; in fact only 2 (1.9%) patients required a cautious discontinuation of sotalol, and none experienced torsade de pointes or significant ventricular arrhythmias. Only 1 patient had bradycardia, which could also be explained by the high adrenergic state in the postoperative period [9]. Usually wide oscillations of plasmatic potassium level are observed after cardiac operation with CPB, but with frequent controls, hourly in the intensive care unit and daily in the ward, we never observed serious episodes of hypokalemia. The use of other drugs that prolong the QTc value was avoided.
We considered in this pilot study several exclusion criteria so that the results would be valid for a selected low-risk CABG population; however, the absolute contraindications of sotalol are a QT interval of more than 450 ms, heart failure, and creatinine clearance below 30 mL/min. Therefore, the administration of sotalol at 80 mg twice daily associated with a strict control of QT interval, HR, potassium serum level, and renal function might be extended to a larger population, particularly in patients with reduced ejection fraction but without signs of heart failure, as already demonstrated in another setting [29].
Regarding the magnesium, the dosage of 1.5 g/day, starting just before the end of CPB, was sufficient to correct the reduced serum levels up to the fourth postoperative day observed in the CTR and S groups. After CPB, the presence of hypomagnesemia [21, 22] as well as the depletion of magnesium despite normal serum levels [24] have been described. This results in higher atrial myocardium excitability and higher incidence of postoperative AF [21, 31]. Magnesium sulfate has been widely used at different dosages and timing for the prevention of postoperative AF: some studies [19, 21, 22] have reported the efficacy even with a residual incidence of AF ranging from 7% to 14%. In a recent study [24], the addition of 30 mEq to the cardioplegia followed by 6 mmol/day intravenously, reduced the incidence of AF to 2%; of note, in the studies that reported no benefit from magnesium, the groups of patients were not comparable for age and other factors [20, 23]. Finally, although the necessity of replacing magnesium during the postoperative period is well established and should ordinarily occur, we noted that, in the published studies designed to prevent postoperative AF with ß-blockers or amiodarone, this either did not occur or at least was rarely indicated [4–8, 10–12, 14, 15].
The efficacy of the combination of a ß-blocker with magnesium to prevent postoperative AF was evaluated in only one other study [25]; the authors investigated the possible benefit of the systematic combination of a pure ß-blocker (propranolol) and magnesium sulfate. They did not report any benefit in the reduction of postoperative AF; however, in an intention-to-treat analysis including 94 patients, they observed a reduction of AF, although not significant, from 18.5% in the propranolol group to 10% in the propranolol plus magnesium group. More importantly, they did not report any adjunctive side effect in the group of patients treated with the combination of the two drugs with the exception of mild hypotension (43.5% versus 24.4%); of note, all patients with a systolic blood pressure less than 120 mm Hg had been arbitrarily considered to be hypotensive.
The mechanism underlying the benefit of the combination of sotalol and magnesium compared with other combinations could be only speculative. Sotalol has antiarrhythmic class II properties, but its main action is due to an adjunctive class III effect prolonging the duration of both action potentials and the refractory period, as demonstrated by the increase of the QTc interval. This effect is related to its interaction with the potassium current at the cardiac cellular membrane [27]. The known close relation between the homeostasis of potassium and magnesium [30] might explain the synergism with sotalol that is not observed with other ß-blockers. Of note, we did not observe any adjunctive prolongation of the QTc interval in the patients of the S+M group compared with those of the S group, thus excluding, for the magnesium, the same mechanism of action of sotalol in the prevention of postoperative AF.
Other authors have already demonstrated the efficacy of sotalol in the prevention of AF after CABG [4–7, 10, 11, 14]. However, all these studies except one [8] reported a residual incidence of AF ranging between 10% and 26% with doses of sotalol varying between 120 and 320 mg divided into two to three doses per day. In addition, the incidence of side effects requiring the discontinuation of sotalol ranged from 1.0% to 10.7% and was correlated in all but one study [8] with the increasing dosage.
Many studies tried to identify patients at risk for postoperative AF and numerous predictive factors have been identified. However, a general agreement exists only for age where well-known structural changes in atrial myocardium are present [10, 11]. Our multivariate analysis confirmed the age and the absence of prevention as the only predictors of AF. No other previously reported factors, including ß-blocker withdrawal, preoperative use of digoxin, chronic obstructive pulmonary disease, and ischemic time at the operation, were found.
Despite the improvement of surgical techniques and methods of myocardial protection, the incidence of AF has not been reduced over the years, but has, in fact, increased [1]. Atrial fibrillation is the most expensive complication after coronary operation; any reduction in the incidence would result in enormous savings in hospital resources [3, 12, 16]. Our results showed a significant reduction of postoperative length of stay between patients with or without postoperative AF and, more importantly, between patients treated with sotalol plus magnesium and controls. Our results indicated that the combination of sotalol and magnesium in the early postoperative period is highly effective in preventing AF after coronary operation in a selected population of patients at low risk, with trivial incidence of side effects and low cost.
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Discussion |
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TopAbstractIntroductionPatients and methodsResultsCommentAcknowledgmentsDiscussionReferences |
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Doctor Forlani was very prompt in sending me this study several weeks ago by e-mail, and I appreciate his giving me ample time to review it in some detail. I would first like to congratulate Dr Forlani and his associates on the meticulous manner in which they designed and implemented this study and for the complete review of the background literature that was provided with the manuscript.
As Dr Forlani noted, the incidence of postoperative atrial fibrillation (AF) has not been reduced significantly over the years despite the improvement of surgical techniques and methods of myocardial preservation, and, in fact, AF has now become the most expensive complication after coronary artery bypass grafting. This study indicates that by administering the combination of sotalol and magnesium starting on the morning of the operation, the incidence of postoperative AF after coronary artery bypass grafting (CABG) can be reduced 2%. Unfortunately, that finding is true only for the highly selected group of patients in this study. I have a concern that the multitude of exclusion criteria in this study design means that the findings may have only limited applicability.
For example, any patient with the following characteristics were excluded from the study: an ejection fraction less than 0.40; a sick sinus syndrome; A-V node reentry; a corrected QT interval of longer than 440 ms; the preoperative use of any antiarrhythmic drug with the exception of beta-blockers; any history of supraventricular arrhythmias; any history of severe chronic obstructive lung disease; serum creatinine levels above 2; a heart rate less than 60 beats per minute the morning of the operation; a heart rate less than 60 beats per minute during drug therapy, and so on. Atrial fibrillation, if it occurred on the day of the operation, also excluded the patients.
Since we know that postoperative AF is more common in sicker patients, these criteria might well exclude most CABG patients seen in the actual practice of most cardiac surgeons, especially in this age of coronary artery stents and aggressive cardiologists. Therefore, my perception of this study is that as a pure clinical evaluation of drug therapy protocol, the study is well designed, the variables are well controlled, and the conclusions are valid for this particular group of patients, but that as a practical guide to the treatment of postoperative AF in a standard clinical practice, its findings are of somewhat limited value.
I have two questions for Dr Forlani. First, during the course of this prospective randomized trial, what percentage of your patients initially presenting to you for possible inclusion in this study were eventually excluded from the study because of one of these 14 exclusion criteria?
And, number two, if I administer sotalol and magnesium in the next 100 CABG patients that I have, regardless of their criteria, how many of them do you think will develop postoperative AF?
Again, I congratulate Dr Forlani and his colleagues on an excellent, though somewhat confining, clinical experimental study, and I thank the Society for the privilege of discussing this report.
DR MICHAEL MAXWELL (Charlotte, NC): I had some questions about the exact protocol you used for the magnesium and the sotalol, just simply trying to follow it in your presentation. One, was the magnesium given only preoperatively or was it given every day postoperatively empirically or did you check levels? And number two, was the sotalol started on the day of the operation or the day after the operation, and how long was it continued? In other words, were the patients sent home on sotalol or was it stopped before they left the hospital?
DR FORLANI: I thank Dr Cox for his comments. I did not completely agree with you about your observations. This was a pilot study. It was the first time, to the best of my knowledge, that this type of combined treatment was used to prevent postoperative AF and, obviously, we were concerned about maintaining the study within the safety limits. However, despite all the limitations you mentioned, we observed an AF incidence of 38% in the control group. This is because none of our exclusion criteria (with the exception of COPD and history of supraventricular arrhythmias that has been occasionally observed) has been reported to be associated with postoperative AF.
The number of patients excluded has not been calculated; however, in our coronary patient population 15% to 20% have an EF of less than 0.40%, 3% have serum creatinine levels higher than 2.0 mg/dL, and approximately 5% have one of all the other exclusion criteria from the study. Therefore about 75% of all patients submitted to CABG should be considered suitable for the combined sotalol and magnesium treatment. The excluded 25% of patients can be obviously treated with magnesium alone, which also has been demonstrated to be effective.
So, in the next 100 patients, regardless of their criteria we could expect 4% to 5% of incidence of postoperative AF with our protocol.
In addition, in this study we observed very few side effects of sotalol. For example, ejection fraction, evaluated in a subgroup of patients before the operation and 5 days postoperatively, remained unchanged; in another subgroup of patients who underwent Holter monitoring, we did not note any proarrhythmic effects.
We are using this protocol now in a larger population including patients with valve disease, with or without coronary disease, and also in patients with aortic pathology. Preliminary results appear promising.
I also thank Dr Maxwell for his question. Our exact protocol was: 1.5 mg magnesium sulfate daily intravenously, starting just before cardiopulmonary bypass and continuing for 5 days postoperatively in all patients (the serum levels of magnesium were controlled every day); 80 mg/12 hours sotalol orally starting the first postoperative day and continuing for 5 days and, at discharge, reduced to 40 mg/12 hours for 4 weeks.
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