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Ann Thorac Surg 2001;72:1256-1262
© 2001 The Society of Thoracic Surgeons
a Department of Cardiovascular Surgery, Acibadem Hospital, Istanbul, Turkey
b Department of Cardiology, Acibadem Hospital, Istanbul, Turkey
Address reprint requests to Dr Alhan, Acibadem, Sebboylu Sok. Mazharbey apt. No:2/8, Kadikoy, 81010, Istanbul, Turkey
e-mail: cemalhan{at}superonline.com
Presented at the Thirty-seventh Annual Meeting of The Society of Thoracic Surgeons, New Orleans, LA, Jan 29–31, 2001.
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Abstract |
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Methods. A total of 200 consecutive patients who had elective, isolated, first-time coronary artery bypass grafting were prospectively randomized to two groups. Patients in the magnesium group (n = 100) received 6 mmol MgSO4 infusion in 100 mL 0.9% NaCl solution (25 mL/h) the day before surgery, just after cardiopulmonary bypass, and once daily for 4 days after surgery. Patients in the control group (n = 100) received only 100 mL 0.9% NaCl solution (25 mL/h) at the same time points.
Results. Postoperative AF occurred in 2 (2%) patients in the magnesium group and in 21 (21%) patients in the control group (p < 0.001). Atrial fibrillation started, on average, 49.4 ± 16.8 hours postoperatively. The postoperative length of hospital stay was not significantly different in patients with AF (7.4 ± 8.0 days) compared with patients without AF (5.4 ± 1.1 days; p = 0.236).
Conclusions. The use of magnesium in the preoperative and early postoperative periods is highly effective in reducing the incidence of AF after coronary artery bypass grafting.
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Introduction |
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It has been shown that noradrenaline, through ß-adrenergic stimulation and increase of cyclic adenosine monophosphate (AMP), stimulates a large efflux of magnesium from cardiac cells. This transport is of major dimensions and can move up to 20% of total cellular magnesium within a few minutes [14]. Changes in magnesium levels have profound effects on cellular metabolism, structure, and bioenergetics. Key enzymes or metabolic pathways, mitocondrial ion transport, calcium channel activities in the plasma membrane and intracellular organelles, reactions requiring adenosine triphosphate (ATP), and structural properties of cells and nucleic acids are modified by changes in Mg2+ concentration [14]. Magnesium suppresses catecholamine-induced abnormal pacemaker activity and has the potential to prevent cardiac arrhythmias, the mechanisms of which are increased automaticity and reentry circuits [15, 16].
In a recent study, Zaman and colleagues [17] detected low serum magnesium levels on postoperative day 1 to be an independent predictor of AF occuring after elective coronary artery bypass surgery. Moreover, the magnesium concentration in the right atrial appendage was found to be inversely related to the age, which may explain the increased incidence of AF in these patients [18].
For these reasons, magnesium, like several other pharmacologic agents, has been used in the treatment and prophylaxis of postoperative AF with varying degrees of success [19–22], although conflicting evidence exists [23]. However, the dose and the timing of magnesium prophylaxis need to be clarified. The purpose of this study was to assess the effect of intermittent magnesium infusion on postoperative AF.
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Material and methods |
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Study protocol
The patients were randomly allocated to two groups. Patients in the magnesium group (n = 100) received 6 mmol MgSO4 infusion in 100 mL 0.9% NaCl solution (25 mL/h) the day before surgery, just after cardiopulmonary bypass, and once daily for 4 days after surgery. The control group (n = 100) received only 100 mL 0.9% NaCl solution (25 mL/h) at the same time points. Potassium (10 mEq potassium chloride in 100 mL normal saline solution) was administered as required to maintain the concentration of potassium at 4 mmol/L or greater.
Interventions were directed to maintain normal tissue perfusion as indicated by normal urine output, absence of metabolic acidosis, and normal lactate level. Inotropic agents were not used to raise perfusion pressure during cardiopulmonary bypass. However, pump flow was never allowed to fall to less than 2.2 L/m2. In addition to potassium and calcium measurements obtained during operation and in the intensive care unit, serum magnesium, calcium, and potassium concentrations were measured the day before surgery (before the magnesium or placebo infusion), 12 hours after termination of cardiopulmonary bypass, and each morning for the first 4 days postoperatively. A blood gas analysis was also performed at the latter time points and oxygen saturation obtained by pulse oximetry was recorded every 4 hours until discharge. The reference range for serum magnesium in our laboratory is 0.7 to 1.05 mmol/L.
Anesthetic technique
Midazolam was used for premedication, and the anesthetic agent consisted of a combination of fentanyl, midazolam, and pancuronium. After tracheal intubation, mechanical ventilation was started with oxygen and nitrogen, and anesthesia was maintained with midazolam and vecuronium infusion and with inhaled sevoflurane.
Operative technique
The amount of the priming solution was kept to less than 1500 mL, and 0.5 mg/kg furosemide was used after the induction to avoid excessive hemodilution. Cardiopulmonary bypass was established by cannulation of the ascending aorta and the right atrium (double-stage, single cannula), moderate hemodilution (hematocrit, 22% to 25%), and moderate systemic hypothermia (32°C). Myocardial viability was preserved with topical hypothermia and cold hyperkalemic crystalloid cardioplegia (Plegisol, Abbott Laboratories, Abbott Park, IL) containing 16 mmol magnesium administered intermittently into the aortic root and through saphenous grafts after each distal anastomosis. The distal anastomoses were constructed during a single period of total aortic occlusion, and the proximal anastomoses were constructed with partial clamping of the aorta. Repeated doses of diclofenac sodium was used for postoperative analgesia. If there were no contraindications the patients were extubated within 6 hours after surgery. In patients with radial artery grafts nitroglycerine infusion was started routinely after termination of cardiopulmonary bypass and continued in the intensive care unit; this was then changed to oral therapy that lasted for 6 months postoperatively. Metoprolol and nifedipine were used for hypertension and sinusal tachycardia.
Electrocardiograms were obtained preoperatively and postoperatively on days 0 to 5. The day of the operation was defined as day 0. The patients were continuously monitored during their stay in the intensive care unit, using bedside monitors (Siemens, Munich, Germany) that are alarm triggered. After discharge from the intensive care unit, trained nurses performed clinical observations every 4 hours, and all patients were monitored routinely with an alarm-triggered seven-lead telemetry system (Siemens infinity telemetry system) until the morning of postoperative day 5 under the close attention of a monitor technician. The lower and the upper alarm limits for the heart rate were 50 and 90 beats per minute, respectively. When there was a question of AF either on clinical grounds or by telemetry, a 12-lead electrocardiogram was obtained. All electrocardiograms were analyzed by a cardiologist who was blinded to the study. Atrial fibrillation was defined as the absence of consistent P waves before each QRS complex and an irregular rate lasting more than 10 minutes or requiring therapy as a result of hemodynamic compromise. Left ventricular ejection fraction was digitized from a preoperative single-plane left ventriculogram in the right anterior oblique projection. Postoperative low cardiac output was defined as hemodynamic instability requiring inotropic support other than dopamine infusion less than 5 µg · kg-1 · min-1 or intraaortic balloon counterpulsation. The European System for Cardiac Operative Risk Evaluation (EuroSCORE) was used for risk stratification.
Statistical analysis
Demographic and clinical variables as well as the incidence of atrial fibrillation were analyzed using the 
2 test or Fisher’s exact test for categorical variables and t tests for continuous variables. Kruskal-Wallis one-way analysis of variance was used to perform rank analysis. Statistical analysis was performed using SPSS statistical software (SPSS Inc, Chicago, IL). Variables were considered significant if p values were less than 0.05. Patient and perioperative characteristics are reported as means ± standard deviations unless otherwise stated.
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Results |
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Comment |
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TopAbstractIntroductionMaterial and methodsResultsCommentDiscussionReferences |
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It must be recognized that the correlation between serum magnesium levels and clinical signs and symptoms is poor, and that normal serum magnesium level may coexist with tissue magnesium deficiency. Plasma magnesium level may be normal in the presence of magnesium depletion. By measuring the retention of administered magnesium, Manners and Nielsen [24] showed that 17% of patients undergoing cardiac surgery were magnesium depleted and that there was significant positive balance in every patient despite normal serum magnesium levels.
It has also been demonstrated that the serum magnesium concentration does not correlate with myocardial magnesium. Moreover, myocardial magnesium concentration was found to be lower in patients with postoperative arrhythmia compared with those without arrhythmia, even after adjustment for age [18].
Recent studies have demonstrated that prophylactic administration of magnesium sulfate decreased the incidence [19, 20, 22] and severity [25] of AF after coronary artery bypass grafting, although conflicting evidence exists [23, 26]. However, these conflicting reports were based on studies that were not well randomized. Parikka and associates [23] showed that administration of 70 mmol of magnesium sulfate in the first 48 hours after cardiac surgery did not decrease the incidence of postoperative AF. They also reported that high plasma magnesium concentrations perioperatively led to a higher incidence of postoperative AF. However, in that study, patients in the magnesium group were significantly older (p = 0.032), had more prior AF episodes (p = 0.061), and were using digoxin more frequently before the operation (p = 0.054). Karmy-Jones and associates [26] demonstrated that administration of 14.4 g of magnesium sulfate in the first 24 hours after the cardiac operation resulted in a decrease in the severity and the incidence of ventricular tachyarrythmias, but did not reduce the incidence of supraventricular tachyarrythmias. In that study the patients in the magnesium group were also significantly older (p = 0.036), and had more preoperative palpitations and supraventricular dysryhthmia.
In a study testing the hypothesis that adjunctive magnesium sulfate would improve the efficacy of ß-blockers in the prevention of postoperative AF [27], the incidence of postoperative AF was found to be 10% in patients treated with propranolol plus magnesium and was 18.5% in patients treated with propranolol alone (p = 0.20).
In accordance with other published studies [8, 19, 20, 22], we observed in our study a significant reduction in the incidence of postoperative AF with magnesium infusion. The electrophysiologic mechanism of postoperative AF is believed to be reentry resulting from dispersion of atrial refractoriness. When adjacent atrial areas have dissimilar or nonuniform refractoriness, a depolarizing wavefront becomes fragmanted as it encounters both refractory and excitable myocardium. This allows the wavefront to return and to stimulate previously refractory (but now repolarized) myocardium, leading to incessant propagation of the wavefront or to reentry. Currently, there is no adequate explanation for how magnesium infusion decreases the incidence of postoperative AF. The mechanism by which magnesium reduces myocardial irritability and tachyarrhythmias is unknown. The results of some in vitro experiments appear to be at variance with in vivo data. Thus it still remains unclear whether magnesium exerts its antiarrhythmic effect by stimulating the Na+-K+ ATPase, by directly inhibiting the efflux of potassium from the cell, by altering cellular calcium metabolism, or whether it works through some other mechanism.
Watanabe and Dreifus [28] studied the electrophysiologic effects of magnesium in an in vitro preperation of rabbit heart. In the presence of a normal potassium concentration, they demonstrated that a high magnesium concentration perfusate caused a prolongation of the atrioventricular conduction time, duration of the action potential, and duration of the effective refractory period. The effective refractory period was relatively more prolonged than the action potential, thus causing the membrane potential to be hyperpolarized. On the other hand, it has been shown that magnesium suppresses catecholamine-induced abnormal pacemaker activity and has the potential to prevent cardiac arrhythmias, the mechanisms of which are increased automaticity and reentry circuits [15, 16].
A faster normalization of intracellular potassium within 1 to 2 days after operation in the patients receiving magnesium sulfate may be another possible explanation for the observed antiarrhythmic effect of this treatment. This is because active transport of potassium into the cell is maintained by the membranous sodium-potassium pump, the activity of which depends on magnesium, among other factors [25].
The limitation of the present study is the absence of continuous Holter ECG monitoring. However, because telemetry system was alarm triggered, the patients were continuously monitored by a monitor technician, and AF was defined as lasting more than 10 minutes or requiring therapy; it seems unlikely that episodes of AF were missed. In addition, because this limitation was the same in each treatment group, it is unlikely that this affected the results of our study. In this study, the highly selected patient cohort that was randomized may not be very representative of the patients encountered in a typical adult cardiac surgical practice. However, the incidence of new-onset AF was only 6.48% in 494 consecutive patients who underwent isolated coronary artery bypass grafting by receiving the protocol outlined in this study within the last 2 years, which is still very impressive.
The results of this study lead us to conclude the following: (1) the use of magnesium in the preoperative and early postoperative periods is highly effective in reducing the incidence of AF after coronary artery bypass grafting; and (2) supplemental magnesium infusion, rather than efforts to correct hypomagnesemia, has the potential to lessen the incidence of AF even in normomagnesemic patients. At the study dosages, adverse effects due to hypermagnesemia are almost impossible in patients with normal renal function, and the cost of the treatment is very low.
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Discussion |
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Thank you.
DR ROBERT D. MOSES (Boston, MA): We conducted a prospective, randomized, double-blind, placebo-controlled study at St. Elizabeth’s Medical Center in Boston that was remarkably similar to yours, with very different results. We randomized 100 patients undergoing coronary bypass surgery to receive 2 g magnesium sulfate in the operating room, followed in the treatment group by 1.5 g intravenously twice daily for 3 days. We found no significant difference between groups, either in the incidence, the time to onset, the total duration, or the number of episodes of atrial fibrillation. The only major difference I can see between our protocols is that we did give a single dose of magnesium to all patients in the operating room before randomization, and all our patients were ß-blocked. I would appreciate any comments you might have regarding the discrepancy in results.
DR ELIAHU GOLOMB (Tel-Aviv, Israel): I would like to ask if there was any stratification of the age in these patients. And I want to ask also about the reason for the exclusion of the chronic obstructive pulmonary disease, because if there is a group that is more susceptible to developing atrial fibrillation, I would certainly want to have any idea whether the magnesium helps them more specifically.
DR JOHN D. PUSKAS (Atlanta, GA): Let me add a question regarding exclusion as well. You excluded patients who were taking ß-blockers preoperatively. Did you use any ß-blocker prophylaxis postoperatively? It has been demonstrated in numerous publications that a tapering dose of ß-blocker postoperatively may attenuate the incidence of atrial fibrillation. Perhaps you could comment on that exclusion criterion. And do you think that magnesium would offer an additive benefit to the rather less expensive and easier to administer oral doses of ß-blocker that are commonly used?
DR ALHAN: I thank all the discussants for their kind comments. The first question was about the preoperative infusion of the magnesium. After this study, this protocol became our routine for the prophylaxis of atrial fibrillation in patients undergoing all kinds of cardiac surgery, and we also do not have the possibility to use preoperative magnesium infusion in more than 20% of our patients upon whom we operate on an emergent basis. However, the analysis of the data so far shows that magnesium infusion started in the operation theater is as effective as preoperative infusion in decreasing the rate of new onset atrial fibrillation. So I am not quite sure if it is necessary to give the magnesium before the operation. However, the magnesium given with the cardioplegia is quite high (30 mEq) and it serves as a loading dose, which we think is an important step of this protocol. Patients with COPD were excluded from the study because the severity of the COPD is also a major determinant in postoperative hypoxemia that may be a factor in triggering atrial fibrillation. Thus, it would be difficult to randomize the patients with COPD.
For the new-onset atrial fibrillation after discharge, the hospital readmission rate for the magnesium group was 3%, and in none of them was the reason atrial fibrillation.
It is known that preoperative use of ß-blockers decreases the incidence of postoperative atrial fibrillation, and as this may affect the results, the patients using ß-blockers were excluded from the study. However, 19 patients in the magnesium group and 23 patients in the control group received metoprolol, and 8 patients in the magnesium group and 6 patients in the control group received nifedipine for hypertension and tachycardia in the postoperative period. ß-Blockers are less expensive and easier to administer compared with magnesium; however a further randomized study may be needed to test the efficacy of these drugs.
Thank you.
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References |
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TopAbstractIntroductionMaterial and methodsResultsCommentDiscussionReferences |
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., Böke E., Ersoy Ü., Bozer Y. Atrial fibrillation after coronary artery bypass surgery: predictors and the role of MgSO4 replacement. J Card Surg 1996;11:421-427.[Medline]
rd N.A. Magnesium substitution and postoperative arrhythmias in patients undergoing coronary artery bypass grafting. Scand Cardiovasc J 1997;31:265-269.[Medline]
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