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Ann Thorac Surg 2004;77:824-830
© 2004 The Society of Thoracic Surgeons

Original article: cardiovascular

The efficacy of supplemental magnesium in reducing atrial fibrillation after coronary artery bypass grafting

Stephen R. Hazelrigg, MDa*, Theresa M. Boley, MSNa, Ibrahim B. Cetindag, MDa, Kreigh P. Moulton, MDb, Gary L. Trammell, PhDc, Joan E. Polancic, PhDc, Tilitha S. Shawgo, MSNa, Jacquelyn A. Quin, MDa, Stephen Verhulst, PhDa

a Southern Illinois University School of Medicine, Springfield, IL, USA
b Prairie Cardiovascular Consultants, Springfield, IL, USA
c University of Illinois–Springfield, Springfield, Illinois, USA

Accepted for publication August 21, 2003.

* Address reprint requests to Dr Hazelrigg, Division of Cardiothoracic Surgery, SIU School of Medicine, 800 N. Rutledge, Room D319, PO Box 19638, Springfield, IL 62794-9638, USA.
e-mail: shazelrigg{at}siumed.edu


   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 
BACKGROUND: Atrial fibrillation after coronary artery bypass is reported from 17% to 53%. Hypomagnesemia after this surgery is considered a contributing factor.

METHODS: Two hundred-two coronary bypass patients were randomized to magnesium (n = 105) or placebo (n = 97). The experimental group received 80-mg magnesium sulfate per kilogram ideal weight in 100 mL dextrose 5% water 30 minutes preoperatively. Postoperatively, patients received 8-mg magnesium sulfate per kilogram ideal weight intravenous per hour more than 48 hours. The control group received dextrose 5% water at these intervals.

RESULTS: After the first bolus serum magnesium was experimental 4.75 mg/dL versus control 1.91 mg/dL, p less than 0.001, and remained different until postoperative day 4 (experimental 2.33 mg/dL vs control 2.26 mg/dL, p = 0.24). Atrial appendage and strap muscle were analyzed after the first bolus and after revascularization. There were no differences between groups in tissue magnesium or calcium. Urinary magnesium was elevated in the experimental (experimental 324.5 mg/24 hours, vs control 45.1 mg/24 hours, p = 0.01). Calcium excretion was higher (experimental 370 mg/24 hours vs control 186 mg/24 hours, p < 0.001) and was associated with lower serum calcium. Serum calcium was higher in the control through the fourth postoperative day. The incidence of atrial fibrillation was experimental 32 of 105 (30.5%) versus control 41 of 97 (42.3%) p = 0.08. Atrial fibrillation was different on the first postoperative day (experimental 3/105, 2.9% vs control 9/97, 9.3%), p = 0.05.

CONCLUSIONS: Overall prophylactic magnesium supplementation does not significantly reduce atrial and ventricular arrhythmias. The only significant benefit of magnesium supplementation was on the first postoperative day.


   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Magnesium (Mg) is an important cation in cardiovascular physiology. It is the second most abundant intracellular cation after potassium. It is a cofactor for the activation of many enzymatic processes of cellular homeostasis, including the turnover of adenosine triphosphate (ATP) the energy source for contractility, maintenance of membrane potentials, and the control of vascular tone [1–3]. It has been used extensively in cardiology after myocardial infarction (MI) for the prevention of supraventricular and ventricular arrhythmias, prevention of coronary spasms, and sudden death [4–6].

Hypomagnesemia is a common finding after open-heart surgery. This is the result of hemodilution, preoperative and perioperative use of diuretics, and catecholamine discharge. This acute loss of magnesium has been suggested as an etiology of many postoperative arrhythmias [7–11]. Prospective randomized studies have been conducted to examine the efficacy of prophylactic magnesium for the prevention of postoperative arrhythmias after open-heart surgery. Although most of these studies have reported favorable results with systemic prophylactic magnesium administration [7, 9, 11], others have failed to confirm these results [8, 10, 12, 13]. We believe only four of these studies were conducted in a double-blinded fashion with the largest population being 155 patients [7, 9, 10, 13].

Although serum and tissue levels have been reported to be somewhat related to the incidence of arrhythmias after acute MI [4], this has not been extensively studied in patients following coronary artery bypass surgery. Our research is designed to determine the effects of acute magnesium (Mg) supplementation on myocardial Mg levels, incidence and postoperative timing of arrhythmias.


   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Comment
 Acknowledgments
 References
 
After local institutional review board approval, patients undergoing elective isolated coronary artery bypass grafting (CABG) were approached for consent. The study was conducted over a 5-year period in a midwestern university medical center, which includes a 562-bed and a 606-bed hospital. After consent, 202 patients were randomly assigned to receive either placebo or prophylactic supplemental magnesium. The pharmacy staff assigned patients to study and control groups using a randomization table created by a statistician. The patients and those caring for the patients were blinded to the randomization arm.

Patients
In addition to elective isolated CABG, inclusion criteria included age 18 years and older, lack of chronic arrhythmia history, ejection fraction more than 25%, and normal renal function (creatinine less than 1.5 mg/dL). Patients were excluded if they had elevated liver functions, hypotension (systolic blood pressure less than 90 mm Hg), postoperative creatinine more than 1.8, or required cardiac assist.

Study Design
A pilot study was conducted with increasing doses of magnesium sulfate to determine a dosage that prevented hypomagnesemia in the study postoperative period (unpublished data). The dosage chosen prevented any hypomagnesemia in the early postoperative period of the experimental group. In the experimental group, 80 mg/kg (ideal body weight) of magnesium sulfate (MgSO4) was administered in 100 mL of 5% dextrose water solution (D5W) over a 30-minute period before cardiopulmonary bypass (CPB). After this, 8 mg/kg (ideal body weight) per hour MgSO4 intravenous (IV) infusion continued for 48 hours (Table 1). Ideal body weight for females was considered 100 pounds for the first 5 feet, and 5 more pounds for each additional inch. Male ideal weight was considered 106 pounds for the first 5 feet, and 6 more pounds for each additional inch.


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  		Table 1. Experimental and Control Group Profiles

 
Both groups received the same potassium (K) replacement protocol. Eighty milliliters per hour D5W with 80 mEq/L of potassium chloride (KCl) was used as maintenance fluid. The serum potassium level was also checked throughout the intensive care period with every 8-hour blood gas draw. Potassium was replaced at 20 mEq/hour over 2-hour KCl infusion if the serum level was less than 3.5 mEq/L. Replacement was 20 mEq/hour over 1 hour with a KCl infusion if the serum potassium level was between 3.5 and 3.9 mEq/L and the patient was having any persistent arrhythmia. After transfer to the general floor all patients received 20 mEq oral KCl twice daily. All patients received the same intensive care and floor protocols in terms of other treatments such as wound care, analgesics, antibiotics, etc. All preoperative medications were restarted if there were no contraindications on the first postoperative day.

Operative technique
The same CPB protocol was used in all patients. Cold blood cardioplegia free of Mg was used in antegrade fashion in all patients and given after each distal graft or every 20 minutes. Ice slush and cold water was used for topical cooling. Body temperature was dropped to 28°C to 32°C depending on the anticipated length of CPB time. All operative variables (cross-clamp time, CPB time, number of grafts, etc.) were recorded for comparison. All proximal anastomoses were done under partial clamping of the aorta.

Tissue sample analysis
Strap and right atrial appendage muscle samples were taken in a subset of 80 patients for tissue level Mg analysis immediately after pericardiotomy before CPB and before the sternal wiring. Simultaneous blood samples were drawn for biochemistry during each muscle sampling.

These tissue samples were frozen in a -70°C freezer until analyzed. The tubes were placed on the VerTis Freezemobile (VerTis, Gardiner, NY) to lyophilize the samples. The dry weight was calculated for each sample. Concentrated 1-mL HNO3 was added to each sample tube. Samples were allowed to digest at room temperature. After digestion, distilled water was added to the samples to bring the total volume to 5 mL. The phosphorus level was determined by using the Sigma Procedure No. 670C (Sigma-Aldrich, St. Louis, MO) and the Beckman DCL Spectrophotometer Model 7400 (Beckman Coulter, Fullerton, CA). The concentration of magnesium and calcium levels was determined using the Perkin-Elmer Atomic Absorption Spectrometer Model 2100 (Perkin-Elmer, Shelton, CT) and using an air/acetylene flame.

Definition of arrhythmias
Atrial fibrillation (AF), ventricular tachycardia (VT), and ventricular fibrillation (VF) episodes were recorded daily until the fifth postoperative day. The definition of ventricular early beats was more than 6 per minute or multifocal.

Statistical analysis was performed for each day and for the total number of arrhythmias to determine the most susceptible period after surgery for arrhythmias.

Statistical analysis
Based on the reported incidence of arrhythmias after CABG, it was determine that a sample size of 200 patients (100/group) would assure detecting an effect of supplemental Mg that reduced arrhythmias by half, with a power of 0.80 and a two-sided significance level of 0.05. A 2x2 {chi}-squared test was used to compare the incidence of arrhythmias between the groups. Other comparisons of groups used {chi}-squared tests, a Fischer's exact test for categorized variables, and independent groups t test for continuous variables. Statistical significance was determined with a p value of 0.05 or lower.


   Results
Top
 Abstract
 Introduction
 Material and methods
 Results
Comment
 Acknowledgments
 References
 
A total of 202 patients were enrolled in the study. One hundred-five patients were in the Mg group and 97 were assigned as controls. There were no significant differences in preoperative and operative variables except the mean cross-clamp time was about 5 minutes longer in the experimental group (E), 61.11 ± 21.1, versus control group (C) 55 ± 21.89 minutes (p = 0.04). Age, sex, preoperative albumin, preoperative and postoperative renal function, preoperative and postoperative use of medications, CPB times, use and types of arterial grafts, number of grafts, postoperative ICU, and hospital stay were similar between the two groups (Table 2). Packed red blood cells were administered in 59% of the E group and 54% of the C group. The amount of packed red blood cells transfused per patient was not significantly different between the two groups (Table 2). Two patients died in the C group versus one death in the E group.


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  		Table 2. Patient Variables

 
Hemodynamic values were followed with a Swan-Ganz catheter (Baxter Healthcare Corp., Deerfield, IL) in a subset of patients in both groups. There were no significant differences in hemodynamic values noted between the two groups before and early after surgery (Table 3). Mean arterial pressure was statistically lower in the E group immediately after surgery, on the operative day evening, and on the first postoperative day morning. However, the actual millimeters of mercury difference was not at a clinically significant level. Blood pressures were carefully recorded as a routine to assure that hypotension did not result from the Mg supplementation (Fig 1).


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  		Table 3. Hemodynamic Parameters

 


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  		Fig 1. Mean arterial pressure in millimeters mercury. (c = control; mg = magnesium; OP = operation; PO = postoperative; POD = postoperative day; PRE-OP = preoperative.)

 
After the first Mg bolus, the serum Mg levels were significantly higher in the E group until the fourth postoperative day (Table 4). With the exception of Calcium (Ca) levels the electrolyte levels were similar between the two groups. Calcium levels were significantly higher in the C group from the operative day evening until the fourth postoperative day (Table 4). There were no differences between the two groups with regard to tissue levels of Mg or inorganic phosphate levels either before, or following, Mg infusion in the operating room. This was true for both skeletal and heart muscle tissues (Table 5). The 24-hour urine analysis demonstrated elevated excretion of Mg and Ca (p < 0.001) in the E group (Table 6). Concomitant serum Ca analyses on the operative evening and first postoperative morning were also significantly lower in the E group. Potassium excretion was slightly increased in the C group, but this did not reach a significant level.


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  		Table 4. Serum Electrolyte Levels

 

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  		Table 5. Tissue Levels

 

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  		Table 6. Twenty-Four Hour Urine Analysis

 
The incidence of arrhythmias was evaluated on a daily and cumulative basis (Table 7). AF was significantly higher in the C group on the first postoperative day. Those in the E and C groups having AF were similar in age (71.3 years old [E group] vs 68.7 years old [C group]). There was no significant difference in the cumulative amount of supraventricular (AF and atrial flutter) and ventricular arrhythmias (premature ventricular contractions, VT, VF). AF was 32 of 97 (30.5%) in the E group and 41 of 97 (42.3%) in the C group. However, this was not enough to reach statistical significance (p = 0.08). The incidence of VT was significantly higher in the C group on the fifth postoperative day.


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  		Table 7. Evaluation of Arrhythmias

 

   Comment
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
Acknowledgments
 References
 
Magnesium is an important cation in cardiovascular physiology. Supplemental Mg creates a ß-adrenergic blocking effect on the myocardial cell by affecting the G proteins; those play a role in the signaling path of the ß-adrenergic stimuli in myocytes [14, 15]. Mg is also an important cofactor in maintaining the intracellular electrolyte balance and membrane potentials by altering the activity of Na-K-ATP channels and it also acts like a natural Ca antagonist [1, 3, 14, 15].

Low Mg levels are a frequent finding after CPB. Diuretics, stress-related catecholamine-induced increase in Mg excretion, and hemodilution are the contributing factors. Postoperative hypomagnesaemia was thought to be partially responsible for cardiac arrhythmias after coronary artery bypass [7–11]. Many studies have been conducted to demonstrate the efficacy of prophylactic Mg supplementation on postoperative arrhythmias after coronary artery bypass [7–13]. Based on different designs of these studies the results are varied. [7–13] We evaluated our results with other double-blinded placebo controlled trials in the literature. Treggeiari-Venzi and colleagues [13] investigated the effects of amiodarone versus prophylactic Mg and placebo in a 155-patient study. They gave a total of 4 g of Mg every 24 hours for 72 hours. In their results, although they found low Mg levels as a risk factor for AF, Mg prophylaxis was not effective for the prevention of AF. However, hypomagnesemia was found to be associated with a higher incidence of AF. In our study, the incidence of AF was significantly higher on the first day when the mean serum Mg level was the lowest [13]. Overall, our results support the conclusion of this study.

England and associates [7] conducted a study on 100 patients who underwent not only coronary artery bypass surgery but also other open-heart surgery. They gave 2 g of prophylactic Mg intraoperatively in the study group. Ventricular arrhythmias were found to be significantly lower in the Mg supplemented group. The prophylactic Mg group exhibited a similar amount of supraventricular arrhythmias. Although this study strongly suggests that Mg supplementation may reduce ventricular arrhythmias, the patient population is different than a pure coronary artery bypass population. Hypomagnesemia was also associated with a higher incidence of AF, in this study. Fanning and associates [9], in their prospective, double-blinded, placebo controlled trial, and Toraman and colleagues [11], in their controlled, prospective, randomized trial, have found results that strongly favor the use of prophylactic Mg. In both studies, they strictly avoided preoperative ß-blockers and Ca channel blockers or excluded the patients who received these regimens from the study. However, Toraman and colleagues [11] found no difference in the subset of patients who received ß-blockers and Ca channel blockers in the postoperative period. It is revealed that the incidence of postoperative AF is increased in patients who use preoperative ß-blockers if they are not restarted on ß-blockers after CABG.

Cardiac surgery induces sympathetic nervous system activity, further exaggerated by withdrawal of ß-blockers [16–18]. The ß-blockers prevent the loss of intracellular Mg. It has been reported that using Mg and ß-blockers has no superior effect in prevention of postoperative arrhythmias than their use alone [19]. Based on these findings, it can be postulated that prophylactic Mg may be more effective in patients who are not offered preoperative ß-blockers.

The Fanning study found the incidence of preoperative use of digoxin was much higher in the C group versus the study group, which also may be associated with increased incidence of arrhythmias [9]. The preoperative use of diuretics was also significantly higher in the C group of this study, and may contribute to perioperative electrolyte imbalance and lead to an increase in the incidence of arrhythmias. However, Forlani and associates [20], studied 207 consecutive patients who were randomized to sotalol alone, Mg alone, a combination of sotalol and Mg, or no antiarrhythmiac agents. They found significant differences in the incidence of AF with each individual therapy surpassing no antiarrhythmiac agents and combination therapy being most effective [20]. In our study we did not modify or change our protocols in terms of restarting the preoperative medications. This should better represent the routine practice and allow us to see the real impact of prophylactic Mg on patient care.

Magnesium is the second most abundant cation in the cell and is responsible for the activation of many enzymatic processes in the cell. Tissue levels of Mg, which may be a representation of intracellular Mg, were not found to be different after the first infusion. Concomitant Mg levels were highest in the experimental group (Tables 4 and 5). The increase in extracellular Mg is not always associated with a similar increase in intracellular Mg immediately after systemic infusion. This may be another explanation for the lack of significant difference on postoperative arrhythmias on the operative day (Table 7) even though the operative day serum Mg levels are below normal in the C group (Table 4).

Speziale and colleagues [10], blindly randomized a total of 200 patients into four groups. The placebo group received nonmagnesium cardioplegia and systemic saline infusion, the second group received systemic Mg in the pump prime and Mg containing cardioplegia, the third group received only Mg containing cardioplegia, and the last group received only Mg containing pump prime [10]. Serum Mg levels were found to be similar in the latter three groups. Atrial and ventricular arrhythmias were significantly lower in the groups that received Mg containing cardioplegia. There was no significant difference between the systemic Mg group and placebo group in the incidence of arrhythmias even though the serum Mg levels were significantly higher in the systemic Mg group. Even though the tissue levels were not studied it may be speculated that higher tissue levels may be achieved with local cardioplegic administration.

We did not have a protocol for the replacement of Ca in this study and lower serum total Ca levels were seen in the E group. We reviewed literature about the postoperative incidence of arrhythmias and lower total serum Ca levels and we could not find any that supports any kind of arrhythmogenic effects of mild hypocalcaemia in CPB patients. It is known, however, that hypocalcaemia is associated with decreased contractility and hypotension. Mg infusion is also expected to create some myocardial depression through its beta blocking and Ca channel blocker effects [15]. But the hemodynamic values and blood pressure levels were similar in both groups. Based on our findings, we believe that unless there are other systemic signs, hypocalcaemia as a result of Mg infusion is well tolerated in adult CPB patients.

We found that VT was higher in the C group on the fifth postoperative day. The serum Mg levels were not significantly different after the fourth postoperative day. Four of these five patients had atrial fibrillation treated with digoxin before the VT. Digoxin was used for AF episodes in 12 patients in the C group versus six patients in the Mg group. The fifth patient was given digoxin because digoxin was a preoperative medication. All but this one patient was from the earlier part of the study when we preferred digoxin and diltiazem infusion for treatment of AF. Increased incidence of VT may be due to digoxin's arrhythmogenic effects.

The overall incidence of postoperative arrhythmias with Mg supplementation does not reach statistical differences as in other studies, even though this study's population is one of the largest in the literature among prospective, randomized, double-blind trials. It is important to note that in our study we did not hold any cardiac medication (ie, ß-blockers, Ca blockers) after surgery, and all patients were offered their preoperative cardiac medications on the first postoperative day unless there was a contraindication. Additional medications were started based on the clinical expertise and judgment of the blinded cardiologist or the cardiac surgeon just as in our daily practice, to study the real impact of Mg prophylaxis on our clinical outcome. However, the most significant benefit of supplemental magnesium is the reduction of the incidence of atrial fibrillation during the first postoperative day.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
References
 
This work was funded, in part, by Southern Illinois University School of Medicine, Central Research Committee Grant: Efficacy of Magnesium in Reducing Cardiac Dysrhythmias.


   References
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 

  1. Iseri L.T., Allen B.J., Ginkel M.L., Brodsky M.A. Ionic biology and ionic medicine in cardiac arrhythmias with particular reference to magnesium. Am Heart J 1992;123:1404-1409.[Medline]
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  3. Agus M.S., Agus Z.S. Cardiovascular actions of magnesium. Crit Care Clin 2001;17:175-186.[Medline]
  4. Kafka H., Langevin L., Armstrong P.W. Serum magnesium and potassium in acute myocardial infarction. Influence on ventricular arrhythmias. Arch Intern Med 1987;147:465-469.[Abstract/Free Full Text]
  5. Orlov M.V., Brodsky M.A., Douban S. A review of magnesium, acute myocardial infarction and arrhythmia. J Am Coll Nutr 1994;13:127-132.[Abstract]
  6. Dyckner T., Wester P.O. Potassium/magnesium depletion in patients with cardiovascular disease. Am J Med 1987;82:11-17.
  7. England M.R., Gordon G., Salem M., Chernow B. Magnesium administration and dysrhythmias after cardiac surgery. A placebo-controlled, double blind, randomized trial. JAMA 1992;268:2395-2402.[Abstract/Free Full Text]
  8. Karmy-Jones R., Hamilton A., Dzavik V., Allegreto M., Finegan B.A., Koshal A. Magnesium sulfate prophylaxis after cardiac operations. Ann Thorac Surg 1995;59:502-507.[Abstract/Free Full Text]
  9. Fanning W.J., Thomas C.S., Jr, Roach A., Tomichek R., Alford W.C., Stoney W.S., Jr Prophylaxis of atrial fibrillation with magnesium sulfate after coronary artery bypass grafting. Ann Thorac Surg 1991;52:529-533.[Abstract/Free Full Text]
  10. Speziale G., Ruvolo G., Fattouch K., et al. Arrhythmia prophylaxis after coronary artery bypass grafting: regimens of magnesium sulfate administration. Thorac Cardiovasc Surg 2000;48:22-26.[Medline]
  11. Toraman F., Karabulute H., Alhan H.C., Dagdelen S., Tarcan S. Magnesium infusion dramatically decreases the incidence of atrial fibrillation after coronary artery bypass grafting. Ann Thorac Surg 2001;72:1256-1262.[Abstract/Free Full Text]
  12. Parikka H., Toivonen L., Pellinen T., Verkkala K., Jarvinen A., Nieminen M.S. The influence of intravenous magnesium sulfate on the occurrence of atrial fibrillation after coronary artery by-pass operation. Eur Heart J 1993;14:251-258.[Abstract/Free Full Text]
  13. Treggiari-Venzi M.M., Waeber J.L., Perneger T.V., Suter P.M., Adamec R., Romand J.A. Intravenous amiodarone or magnesium sulphate is not cost-beneficial prophylaxis for atrial fibrillation after coronary artery bypass surgery. Br J Anaesth 2000;85:690-695.[Abstract/Free Full Text]
  14. Chakraborti S., Chakraborti T., Mandal M., Mandal A., Das S., Ghosh S. Protective role of magnesium in cardiovascular diseases: a review. Mol Cell Biochem 2002;238:163-179.[Medline]
  15. Altura B.M., Altura B.T. New perspectives on the role of magnesium in the pathophysiology of the cardiovascular system. Magnesium 1985;4:226-244.[Medline]
  16. Parikka H., Toivonen L., Heikkila L., Virtanen K., Jarvinen A. Comparison of sotalol and metoprolol in the prevention of atrial fibrillation after coronary artery bypass surgery. J Cardiovasc Pharmacol 1998;31:67-73.[Medline]
  17. Reed H.L., Chernow B., Lake C.R., et al. Alterations in sympathetic nervous system activity with intraoperative hypothermia during coronary artery bypass surgery. Chest 1989;95:616-622.[Abstract/Free Full Text]
  18. Salazar C., Frishman W., Friedman S., et al. Beta-blockade therapy for supraventricular tachyarrhythmias after coronary surgery: a propranolol withdrawal syndrome?. Angiology 1979;30:816-819.[Medline]
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  20. Forlani S., De Paulis R., de Notaris S., et al. Combination of sotalol and magnesium prevents atrial fibrillation after coronary artery bypass grafting. Ann Thorac Surg 2002;74:720-726.[Abstract/Free Full Text]



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