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Ann Thorac Surg 2000;69:126-129
© 2000 The Society of Thoracic Surgeons

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Original Articles

The combination of propranolol and magnesium does not prevent postoperative atrial fibrillation

^a Division of Cardiology, Department of Medicine, Georgetown University Medical Center, Washington, DC, USA
^b Division of Cardiothoracic Surgery, Department of Surgery, Georgetown University Medical Center, Washington, DC, USA

Address reprint requests to Dr Solomon, Division of Cardiology, Georgetown University Medical Center, Rm M4222, 3800 Reservoir Rd NW, Washington, DC 20007
e-mail: solomona{at}gunet.georgetown.edu

	Abstract

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Background. Atrial fibrillation is a common complication of cardiovascular surgery. ß-Blockers have been shown to decrease the incidence of postoperative atrial fibrillation. However, the use of magnesium is more controversial. It was our hypothesis that adjunctive magnesium sulfate would improve the efficacy of ß-blockers alone in the prevention of postoperative atrial fibrillation.

Methods. We prospectively randomized 167 coronary artery bypass patients (mean age 61 ± 10 years, 115 men) to receive propranolol alone (20 mg four times daily) or propranolol and magnesium (18 g over 24 hours). Magnesium was begun intraoperatively, and propranolol was started on admission to the intensive care unit.

Results. Using an intention-to-treat analysis, the incidence of postoperative atrial fibrillation was 19.5% in the propranolol-treated patients and 22.4% in propranolol + magnesium-treated patients (p = 0.65). Because combination therapy resulted in an excess of postoperative hypotension, which required withholding doses of propranolol, an on-treatment analysis was also performed. In this analysis, the incidence of atrial fibrillation was still not significantly different (18.5% in propranolol-treated patients and 10.0% in propranolol + magnesium-treated patients, p = 0.20).

Conclusions. Adjunctive magnesium sulfate, in combination with propranolol, does not decrease the incidence of postoperative atrial fibrillation.

	Introduction

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Atrial fibrillation is a common complication of cardiovascular surgery, occurring in up to 50% of patients [1–6]. Its incidence clearly increases with advancing age [1–3, 7]. It usually occurs 24 to 96 hours after surgery, with a peak incidence on the second postoperative day [1, 2]. Although postoperative atrial fibrillation usually does not result in long-term sequelae, potential complications include thromboembolic events, hemodynamic compromise, and an increased length and cost of hospitalization [1, 2].

Several pharmacologic agents have been used to prevent postoperative atrial fibrillation with varying degrees of success. Only ß-blockers and amiodarone have convincingly been shown to decrease its incidence [4, 5]. The preoperative administration of digoxin, calcium channel antagonists, and procainamide has been disappointing [4, 8]. The effectiveness of magnesium has been more controversial.

Hypomagnesemia is common after cardiovascular surgery [9]. This may be the result of hemodilution, increased urinary loss, elevated epinephrine levels, or the preoperative use of diuretics. This reduction in magnesium levels has been shown to enhance excitability of atrial myocardium [10, 11]. In addition, the administration of high-dose preoperative magnesium may provide cellular protection during ischemia and decrease reperfusion injury [12–14]. Moreover, several studies have shown that the administration of magnesium decreases supraventricular arrhythmias after acute myocardial infarction or cardiovascular surgery [15–17]. As a result, we tested the hypothesis that adjunctive magnesium sulfate would improve the efficacy of ß-blockers in the prevention of postoperative atrial fibrillation.

	Material and methods

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Patient population
This prospective, randomized trial evaluated 167 patients undergoing elective initial coronary artery bypass graft surgery. All patients were in sinus rhythm at the time of surgery. Patients were excluded for concurrent valvular surgery, repeat coronary artery bypass surgery, an initial systolic blood pressure of less than 100 mm Hg, a resting heart rate of less than 50 beats per minute, renal insufficiency (serum creatinine greater than 2.0 mg/dL), asthma, chronic obstructive pulmonary disease, or a prior history of atrial fibrillation. This protocol was approved by the Institutional Review Board of Georgetown University Medical Center (July 18, 1996), and all patients gave written informed consent for participation in the study.

Protocol
At the termination of cardiopulmonary bypass, patients were randomized to magnesium (n = 85) or no magnesium (n = 82). Patients in the magnesium arm received a 2-g intravenous bolus of magnesium sulfate over 10 minutes, followed by a continuous infusion of 16 g over the next 24 hours. Our dosing schedule was based on the safety profile from the second Leicester Intravenous Magnesium Intervention Trial (LIMIT-II) [18]. All 167 patients received propranolol within 24 hours of surgery. This was begun at 20 mg every 6 hours (orally or via nasogastric tube). Doses were held if the heart rate was less than 60 beats per minute or the systolic blood pressure was less than 120 mm Hg. A control group (no ß-blocker or magnesium) was not included in this study because our Institutional Review Board felt that ß-blocker therapy represented the current standard of care.

After surgery, all patients were admitted to the cardiovascular surgical intensive care unit and electrocardiographic monitoring was begun. Patients were continuously monitored in the unit with a Solar 7000 cardiac telemetry system (Marquette Medical Systems, Inc, Milwaukee, WI), which was alarm-triggered, and data were stored for 24 hours. Arrhythmias were reviewed at the end of each nursing shift by a physician and confirmed by a second blinded physician. The primary end point of the trial was the development of postoperative atrial fibrillation, which was defined as atrial fibrillation or flutter lasting longer than 1 hour or requiring therapy as a result of hemodynamic compromise. Secondary end points included the ventricular rate at the onset of atrial fibrillation, the day of onset of atrial fibrillation, and the length of hospital stay. The management of postoperative atrial fibrillation was directed by the cardiac surgery team.

Statistical analysis
All continuous variables are presented as the mean ± 1 standard deviation. Continuous variables were compared using a Student’s t test, and categorical variables were compared by Fisher’s exact test. Data were initially analyzed using an intention-to-treat analysis. Data were also evaluated utilizing an on-treatment analysis, in which patients were included only if they had received at least 75% of the study medications. A p value of less than 0.05 was considered to indicate statistical significance.

	Results

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Baseline characteristics
This study evaluated 167 patients undergoing coronary artery surgery, with 82 receiving propranolol alone and 85 receiving propranolol and magnesium sulfate. The mean age of the study population was 61 ± 10 years, and 77% were men. The characteristics of the patients are summarized in Table 1. There were no significant differences between the two groups.

On-treatment analysis
We performed a pill count on all patients, and identified those who received at least 75% of their propranolol, and an on-treatment analysis was then performed on this subgroup (n = 94). Patients included in the on-treatment analysis did not differ significantly from patients included in the intention-to-treat analysis (Table 1). In this analysis, the incidence of postoperative atrial fibrillation was 10.0% in propranolol plus magnesium-treated patients and 18.5% in patients treated with propranolol alone (p = 0.20). Of note, all patients in the magnesium group received their full 18 g of magnesium sulfate.

Adverse events
There were no important differences between propranolol-treated patients and patients receiving combination therapy with respect to survival or bradyarrhythmias. Patients receiving combination therapy did demonstrate an increased incidence of hypotension (Table 3).

	Comment

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Atrial fibrillation is a common complication of coronary artery bypass graft surgery, especially in the elderly [1–6]. Although long-term sequelae of postoperative atrial fibrillation are unusual, it frequently results in an increased length and cost of hospitalization. In a single patient, atrial fibrillation is not the most expensive complication of cardiovascular surgery, but its high incidence results in a cumulative cost that exceeds all other complications. Aranki and colleagues found that the length of hospitalization directly attributable to atrial fibrillation was 4.9 days [2]. This translated into more than $10,000 in hospital charges per patient. Therefore, any intervention that would reduce the incidence of postoperative atrial fibrillation would result in a tremendous economic benefit.

Several pharmacologic agents have been used in the prophylaxis of postoperative atrial fibrillation with varying degrees of success. Of these, ß-blockers have been the most effective agents. A meta-analysis by Andrews and associates demonstrated a dramatic reduction in postoperative atrial fibrillation when ß-blockers were compared with controls (OR = 0.28, 95% CI = 0.21 to 0.36) [4]. However, this benefit was not observed with digoxin (OR = 0.97, 95% CI = 0.62 to 1.49) or verapamil (OR = 0.91, 95% CI = 0.57 to 1.46). Recently, two studies of amiodarone have yielded promising results. Daoud and associates began amiodarone 1 week before elective cardiac surgery and continued it until the day of discharge [5]. Amiodarone-treated patients had a significant reduction in the incidence of postoperative atrial fibrillation, as well as length of hospitalization compared with controls. In the ARCH trial [6], postoperative intravenous amiodarone reduced the incidence of atrial fibrillation.

The prophylactic administration of magnesium has been more controversial. Magnesium has several pharmacologic properties that may contribute to a therapeutic benefit after cardiovascular surgery. Magnesium results in afterload reduction and coronary vasodilation, decreases platelet aggregation, and provides cellular protection against ischemia and reperfusion [12]. This cellular protection appears to result from a combination of factors, including inhibition of calcium influx across the sarcolemma, reduction in mitochondrial calcium overload, and conservation of intracellular adenosine triphosphate [12].

As a result of these properties, magnesium has been studied in the prevention of atrial fibrillation after cardiovascular surgery. England and associates demonstrated that normomagnesemic patients had less postoperative supraventricular arrhythmias compared with hypomagnesemic patients [16]. In addition, Katholi and colleagues demonstrated a reduction in the incidence of atrial fibrillation after coronary artery surgery in patients "responding" to treatment with magnesium chloride (serum magnesium level > 2.0 mEq/L) [17]. In contrast, Parikka and associates were unable to find a benefit of magnesium sulfate on postoperative atrial fibrillation. In fact, patients with the highest postoperative serum magnesium levels had the highest incidence of atrial fibrillation [19]. Fanning and associates found no significant difference in the incidence of postoperative atrial fibrillation in magnesium-treated patients; however, the total number of episodes of atrial fibrillation were reduced [20]. Finally, Karmy-Jones and associates found no difference between magnesium sulfate and placebo in the incidence of postoperative atrial fibrillation [9].

As a result of the overwhelming data supporting the benefit of ß-blockers and some encouraging studies on the use of magnesium sulfate, we sought to determine whether adjunctive magnesium sulfate would be superior to propranolol alone in the prevention of atrial fibrillation after coronary artery bypass surgery. However, the combination of propranolol and magnesium did not reduce the incidence of postoperative atrial fibrillation compared with propranolol alone. We may have seen less initial hypotension with a lower dose of magnesium sulfate or giving the same dose over 48 to 72 hours. However, our dosing schedule was based on the safety and efficacy of LIMIT-II [18].

Limitations
Several limitations exist in this study. The first limitation is the lack of a placebo group. Our Institutional Review Board felt strongly that ß-blockers represented the current standard of care and should be included in any treatment strategy. However, it was our hope to demonstrate an incremental benefit of adjunctive magnesium sulfate compared with propranolol alone.

The second limitation is that Holter monitoring was not performed during the postoperative period. However, because the telemetry data on each patient were reviewed at the end of each nursing shift, and atrial fibrillation was defined as lasting longer than 1 hour or requiring therapy, it seems unlikely that episodes of atrial fibrillation were missed. In addition, because this limitation was the same in each treatment group, it is unlikely that this effected the results of our study.

The most important limitation of this study is the arbitrary definition of hypotension as a systolic blood pressure less than 120 mm Hg. As a result of this definition, mandated by the cardiac surgery team, many patients were considered to be hypotensive and therefore did not receive some of their scheduled doses of propranolol. Therefore, the true effect of combination therapy was difficult to fully evaluate. As a result, an on-treatment analysis was performed to assess the effect of this combination. Patients included in this analysis were not different from the initial 167 patients. However, even in the subgroup of patients who received at least 75% of their propranolol, no benefit was observed with combination therapy. Of note, this on-treatment analysis included only 94 patients. A larger cohort may have resulted in a significant difference.

Clinical implications
The combination of propranolol and magnesium sulfate does not appear to offer incremental benefit over propranolol alone in the prevention of atrial fibrillation after coronary artery bypass surgery. Furthermore, a higher incidence of postoperative hypotension was observed in patients receiving combination therapy. As a result, ß-blockers or amiodarone should be used for the prevention of postoperative atrial fibrillation.

	References

Top Abstract Introduction Material and methods Results Comment References

 

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