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Right arrow Electrophysiology - arrhythmias

Ann Thorac Surg 2005;79:117-126
© 2005 The Society of Thoracic Surgeons

Original article: Cardiovascular

Three-Day Magnesium Administration Prevents Atrial Fibrillation After Coronary Artery Bypass Grafting

Hiroki Kohno, MDa,b,*, Toshiya Koyanagi, MDa, Hitoshi Kasegawa, MDa, Masaru Miyazaki, MDb

a Department of Cardiovascular Surgery, Sakakibara Heart Institute, Tokyo
b Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan

Accepted for publication June 16, 2004.

* Address reprint requests to Dr Kohno, Department of General Surgery, Graduate School of Medicine, Chiba University, 1–8–1 Inohana, Chuo-ku, 260–8670 Chiba, Japan (E-mail: hkcw{at}mac.com).


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Comment
 Acknowledgments
 References
 
BACKGROUND: The efficacy of magnesium administration in preventing the occurrence of atrial fibrillation after coronary artery bypass grafting surgery remains controversial. Optimal dose and timing of the administration also await clarification. The purpose of this study was to assess the effect of 3-day postoperative infusion of magnesium on postoperative atrial fibrillation and to find factors that can influence the efficacy of this treatment.

METHODS: After institutional review board approval, a retrospective study was conducted reviewing 200 consecutive patients who underwent isolated, initial coronary artery bypass grafting operation. The first 100 patients did not receive the prophylactic treatment, whereas the next 100 patients were treated with magnesium postoperatively. Patients in the magnesium-treated group received 10 mmol (2.47 g) of magnesium sulfate (MgSO4 · 7H2O) infused daily for 3 days after surgery.

RESULTS: The incidence of postoperative atrial fibrillation was 35% in the untreated group compared with 16% in the magnesium-treated group (p = 0.002). Multivariate logistic regression analysis revealed that advanced age, decreased left ventricular ejection fraction, and absence of magnesium therapy were independent predictors of postoperative atrial fibrillation. For patients receiving the magnesium therapy, advanced age and decreased ejection fraction were the independent factors that predicted the arrhythmia.

CONCLUSIONS: Postoperative 3-day magnesium infusion is effective in reducing the incidence of atrial fibrillation occurring after coronary artery bypass grafting surgery. However, in older patients or in patients with reduced left ventricular function, magnesium treatment alone is insufficient for prophylaxis of postoperative atrial fibrillation.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Comment
 Acknowledgments
 References
 
Despite substantial improvements in surgical techniques and perioperative managements, atrial fibrillation (AF) remains a common complication after coronary artery bypass grafting surgery (CABG). Its onset is usually between 24 and 96 hours after surgery, with a peak incidence on the second to third postoperative days [1, 2]. Atrial fibrillation potentially leads to prolonged hospitalization and significant morbidity, particularly hemodynamic deterioration and thromboembolism [1, 3–6], and its occurrence has long been a distress to most cardiac surgeons.

The etiology of AF after CABG is unclear. Many causal factors have been identified, but lack consistency. A general agreement exists, however, in that the cause of such a complication is most likely multifactorial. The factors included are advanced age, male sex, hypertension, hypothyroidism, withdrawal of ß-blockers, impaired cardiac function, chronic lung disease, chronic renal failure, diabetes, cardiopulmonary bypass and cardioplegia, myocardial ischemia and reperfusion, myocardial infarction, right coronary artery disease, local inflammatory reaction, metabolic disorder, excessive catecholamine, and electrolyte imbalance [1–6], particularly hypomagnesemia, which has also been identified as an independent predictor of postoperative AF [6, 7].

Almost 80% of patients undergoing CABG have reduced total and ionized serum magnesium levels postoperatively [8, 9]. This reduction is attributable to a number of factors, mainly hemodilution, elevated catecholamine levels, and increased urinary loss [10]. The correlation between magnesium deficiency and postoperative AF is still unknown; however, most postulated mechanisms to explain their relationship have consistently referred to the role of magnesium in stabilizing the cellular transmembrane potential, suppressing excessive cellular calcium influx and energy demands, preserving myocardial metabolites, and reducing the severity of reperfusion injuries [11–13]. Furthermore, magnesium plays a key role in other important aspects of cellular function, including enzyme regulation, energy metabolism, and aerobic respiration [13, 14]. Magnesium depletion seen after CABG may adversely affect the various cellular processes that depend on magnesium, thus predisposing to unstable cellular activity.

For these reasons, perioperative magnesium supplementation has been suggested to play a role in the prophylaxis of AF after CABG. Although not all investigations have corroborated this, a number of them have demonstrated that magnesium infusion significantly reduced the incidence of AF [15–19]. Recently, we have begun administering magnesium to all patients undergoing CABG as a preventive measure for AF development. However, a paucity of material available on the optimization of magnesium administration has led us to investigate the efficacy of our treatment to provide additional insights into the clarification of this issue. This paper presents the results of a retrospective study designed to evaluate the effectiveness of postoperative 3-day magnesium sulfate administration and discusses, in the light of published data, possible dosing strategies for which the magnesium treatment can be beneficial. Analytical study to identify which patients do not respond to this treatment was also conducted.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Comment
 Acknowledgments
 References
 
Study Population
A retrospective study was conducted reviewing all patients who had undergone isolated, initial CABG at Sakakibara Heart Institute, Tokyo, Japan, before and after the time point when the magnesium supplementation protocol was initiated (April 1, 2002). Exclusion criteria included history of AF or other supraventricular arrhythmias (including paroxysmal supraventricular arrhythmias), implanted permanent pacemaker, postoperative myocardial infarction, and severe hemodynamic disorder requiring postoperative cardiopulmonary support or left ventricular assist devices. Also excluded from evaluation were patients assigned to the postoperative magnesium treatment but who did not receive the full intended dose. Qualified candidates were continuously enrolled until 100 consecutive patients not treated with magnesium (January 2001 to March 2002) and 100 consecutive patients receiving the treatment (April 2002 to March 2003) were obtained. All patients had sinus rhythm preoperatively. Perioperative clinical details of these patients were compared between groups with and without magnesium treatment and between patients who did and did not experience AF postoperatively. This study was approved by the institutional review board of Sakakibara Heart Institute, and informed consent was waived because of the retrospective nature of the study.

Preoperative Patient Demographics
Preoperative clinical information was obtained from all patients by reviewing medical records and included the variables listed in Table 1. Left ventricular ejection fraction (LVEF) was calculated by cineangiography or transthoracic echocardiography. Coronary artery stenosis was considered significant when the stenosis ratio exceeded 75% on angiographic findings. As shown in Table 1, the demographics of the patients in the magnesium-treated group did not differ significantly from the patients in the untreated group, except for the number of male patients, which was significantly greater in the magnesium-treated group than the untreated group.


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  		Table 1. Preoperative Patient Demographicsa
 
Intraoperative and Postoperative Details
Table 2 summarizes the intraoperative and postoperative information of the patients studied. Only blood transfusion was more frequent in the untreated group; otherwise, no statistical difference was found for other variables between the two groups.


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  		Table 2. Intraoperative and Postoperative Detailsa
 
Magnesium Administration
Patients in the treated group received 10 mmol of magnesium sulfate (2.47 g of MgSO4 · 7H2O solution [1 ampule]) in 100 mL of saline solution infused intravenously in 4 hours once daily for 3 days starting immediately after surgery. In addition, our standard practice for on-pump surgery requires a terminal infusion of warm cardioplegia that contains 4 mmol/L of magnesium sulfate, and because this was also a routine during the study period, all on-pump cases included in this study were subjected to the additional intraoperative magnesium infusion.

Anesthetic Management
All patients received premedication with oral diazepam (or calcium pentobarbital) and an intramuscular injection of scopolamine (or atropine) and pethidine before entering the operation room. Anesthesia was induced with intravenous fentanyl, diazepam, and a muscle relaxant (pancuronium or vecuronium) and maintained with additional doses of these drugs or with inhaled sevoflurane.

Surgical Procedures
Ascending aortic and right atrial double-staged cannulation with mild systemic hypothermia (34°C) was implemented for patients in whom cardiopulmonary bypass was used. Cardiac arrest was obtained and maintained by intermittent antegrade hyperkalemic blood cardioplegia. Additional infusion of cardioplegic solution was performed manually with a 20-mL syringe into each harvested graft after completion of the corresponding distal anastomosis. Both proximal and distal anastomoses were constructed during a single period of aortic occlusion. During cardiopulmonary bypass, blood flow rate and systemic perfusion pressure were kept at greater than 2.2 L · m–2 · min–1 and 50 mm Hg, respectively. Terminal warm blood cardioplegia (400 to 500 mL) was given after completion of the coronary anastomoses just before aortic declamping.

In patients who underwent off-pump surgery, the procedures were performed through a median sternotomy approach. The type of stabilization device used was determined by the discretion of the individual surgeon. Proximal anastomoses were performed either directly to the internal mammary artery as composite grafts or to the aorta with an aortic connecting device or with a partial occlusion clamp.

The same medical staff performed all operations and anesthetic management throughout the study period.

Perioperative Measurements
Electrocardiograms and hemodynamic variables, including arterial blood pressure, heart rate, and central venous pressure, were monitored continuously throughout the operation and during the period in the intensive care unit. After discharge from the intensive care unit, all patients were monitored with an alarm-triggered telemetry system and double-checked for unnoticed events every morning for at least 6 postoperative days. In addition, a 12-lead electrocardiogram was obtained if clinical observation or telemetric monitoring detected a tachycardia attack or the development of an arrhythmia.

Serum magnesium concentration was measured before surgery, immediately after surgery, and every morning for 4 days postoperatively. Serum potassium and calcium concentrations were also measured perioperatively and adjusted to maintain the potassium levels at greater than 4 mmol/L and calcium levels within the normal physiologic range.

The end point of the study was postoperative development of AF. Atrial fibrillation was considered significant if it persisted for greater than 15 minutes or required treatment because of intolerable symptoms and hemodynamic deterioration.

Statistical Analysis
Values are presented as mean ± standard deviation or percent of patients. Proportions were compared with the Pearson {chi}2 test. If any of the cells from a 2 x 2 table had an expected count below 5, then the Fisher's exact test was applied. Quantitative variables were normally distributed and compared with the Student's t test. The independent contribution of the potential factors involved in the development of AF was determined by using stepwise logistic regression analysis. In the multivariate analysis, the dependent variable was the occurrence of postoperative AF, and the initial independent variables were those that showed on univariate analysis a significant correlation with the occurrence of AF (p < 0.05), as well as those that showed a marked trend (p < 0.1) and those with well-known clinical relevance. Differences were considered to be statistically significant when p was less than 0.05. The JMP statistical software (version 5.0.1.2, SAS Institute Inc, Cary, NC) was used for all calculations.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Comment
 Acknowledgments
 References
 
The incidence of postoperative AF was 16% (16 patients) in the magnesium-treated group and 35% (35 patients) in the untreated group (p = 0.002). Regarding time of AF onset and duration of postoperative hospital stay, no statistically significant difference was found between the two groups (Table 2).

Mean serum magnesium concentration decreased to subnormal value (reference range, 1.8 to 2.6 mg/dL) immediately after surgery in both magnesium-treated and untreated groups (Fig 1). The two groups differed significantly in their serum magnesium levels at postoperative days 1 and 2, showing a marked increase for patients treated with magnesium, whereas for patients in the untreated group, it remained decreased (day 1) or only slightly greater than the lower normal limit (day 2). The two mean magnesium concentrations were comparable by the third postoperative day.



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  		Fig 1. Graphic analysis of perioperative serum magnesium concentrations with average administered dose of magnesium sulfate in magnesium-treated group (squares) and untreated group (triangles). Dotted line represents physiologic limit (reference range, 1.8 to 2.6 mg/dL). * Intraoperative dose (note that no significant difference exists between groups; p = 0.62). (C = untreated [control] group; Mg = magnesium-treated group; POD = postoperative day; POD 0 = day of operation; Preop = preoperative.)

 
Comparison between those who experienced and those who did not experience postoperative AF revealed that age, preoperative LVEF (including LVEF < 0.30), and magnesium administration were the variables that showed statistical significance (Table 3). Significantly more patients experiencing AF were older, had reduced LVEF, and did not receive the magnesium therapy. A similar comparison but limited to those treated with magnesium showed that significantly more patients experiencing AF were older, had reduced LVEF, and received blood transfusion, whereas significantly fewer patients in that group received calcium antagonist medication (Table 4).


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  		Table 3. Comparison of All Patients With and Without Atrial Fibrillation
 

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  		Table 4. Comparison of Patients With and Without Atrial Fibrillation for Only Those Treated With Magnesiuma
 
Variables included in the multivariate analysis were age, preoperative LVEF, magnesium administration, sex, right coronary artery disease, New York Heart Association classification, previous congestive heart failure and myocardial infarction, hypertension, hyperlipidemia, cardiopulmonary bypass time, perioperative blood transfusion, postoperative calcium antagonist, and ß-blocker withdrawal. Variables that emerged as independent predictors of postoperative AF were advanced age (p = 0.002), low preoperative LVEF (p = 0.001), and absence of magnesium treatment (p = 0.04). When only the group that received the magnesium treatment was analyzed, the independent predictors of postoperative AF were advanced age (p = 0.008) and low preoperative LVEF (p = 0.001).

No adverse effect of magnesium infusion (eg, bradycardia, hypotension, respiratory depression) was detected in any of the patients receiving the treatment.


   Comment
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
Acknowledgments
 References
 
The reported incidences of AF after CABG range from 10% to 50% [1, 5, 6]. Despite recent improvements in perioperative management, its occurrence has not decreased during the years and is associated with significant morbidity. Given this consequence, a wide variety of prophylactic strategies have been evaluated, including perioperative magnesium administration; at present, the efficacy of this treatment is still controversial. In the 100 consecutive patients we reviewed who did not receive the prophylactic treatment, 35% developed new-onset AF, which is comparable to that reported in the literature. A significant reduction in its incidence was found, however, for the next consecutive 100 patients treated with the 3-day magnesium administration (16%; p = 0.002). Although conflicting data exist, our findings suggest a possibility for a beneficial role of magnesium in preventing AF after CABG.

A review of the literature shows diversity in the dosing and timing of magnesium administration. This diversity accounts for the inconsistency in the reported outcomes of the magnesium trials as listed in Table 5. However, certain discernible strategic affinities exist among each method of administration that may explain why some methods are effective while others are not. In five [15–19] of the prospectively controlled clinical trials [7, 15–26], magnesium administration significantly reduced the frequency of AF after CABG. In most of these trials, magnesium was dosed for at least 3 consecutive days after surgery [15–17, 19]. Considering that the onset of AF after CABG usually occurs between postoperative day 1 and 4 [1, 2], and that it is often associated with hypomagnesemia [8, 9], magnesium administration throughout this period may have a significant role in the suppression of this arrhythmia. Another reason for the discrepancy in results may ascribe to the daily dose of magnesium. Parikka and associates [21] have shown that high serum magnesium levels caused by the magnesium dosing provoke higher incidences of AF. In most clinical trials that have demonstrated effective prophylaxis with magnesium, the amount of magnesium per day given was no greater than 15 mmol, and the reported mean serum magnesium levels after each dose were within normal physiologic range [15–18]. On the contrary, most ineffective methods have incorporated high-dose magnesium sulfate infusion in their administration protocols [20–22, 24, 25]. The protocol used in the present study consisted of 10 mmol of magnesium sulfate infused daily for 3 days, and we found none of the mean serum total magnesium concentrations measured during this period exceeded the physiologic range. It must be noted, however, that several works have confirmed serum magnesium concentration, total or ionized, as an unreliable indicator of total body stores of magnesium [10, 14, 27]. Normal or high concentrations of serum magnesium can coexist with suboptimal magnesium supply, and correcting only the values of serum magnesium may not appropriately eliminate the clinical consequences of tissue magnesium abnormality. Low myocardial magnesium content is known to be associated with postoperative arrhythmia [27]; however, controversies persist concerning the efficacy of prophylactic magnesium infusion, and the current literature offers only conflicting statements regarding the cellular regulation of exogenous magnesium. Whether serum magnesium concentrations represent the true state of magnesium metabolism remains questionable, and given these ambiguities, the clinical relevancy of serum magnesium monitoring with AF treatment requires further investigation.


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  		Table 5. Prospectively Controlled Studies on Efficacy of Magnesium Infusion for Prevention of Atrial Fibrillation After Coronary Artery Bypass Grafting
 
The incongruous results of the magnesium studies reported in the literature may also be attributed to the period of AF monitoring. Some authors have attempted to demonstrate the prophylactic effect of magnesium on AFs occurring within 48 hours after surgery [18, 23]. In their investigations, however, the data acquired during the first 48 hours postoperatively may have been insufficient for accurate efficacy assessment, as AF can occur even after 48 hours, particularly during the first 4 days after surgery [1, 2]. The effect of their magnesium administrations, if they had been observed for a longer period, might not have resulted likewise.

Of note, the criteria that defined AF in some studies included arrhythmias with remarkably short duration, for instance 30 seconds, which might have included clinically harmless episodes that may not benefit from the prophylaxis. Provided with no absolute guideline based on a risk stratification to identify AF duration at risk for complications, we have empirically established the concept of significant AF, defined as AF at high risk of engendering clinical inconveniences, and which persisted for greater than 15 minutes or necessitating therapeutic procedures. As we believe that the underlying principle in this prophylactic therapy aims at treating significant AFs, we have excluded AF incidences that did not meet with our concept. Jensen and coworkers [24] have documented that magnesium decreases the duration of AF after CABG, which validates the speculation that if all investigators had adopted a criterion similar to ours, the result of some magnesium trials might have shown a greater reduction in AF incidence after magnesium administration.

Demographic bias owing to an inadequately randomized patient cohort may be another reason for the discordance in the reported results of magnesium prophylaxis. The biased variable, if it happens to be a powerful predictor of AF, would apparently have a strong influence on the outcome of the study. For example, in one investigation that showed no benefit from magnesium, patients in the magnesium group had more preoperative episodes of AF and were significantly older [21]. Those characteristics, advanced age and prior AF episodes, have been consistently related to the development of postoperative AF [1–3, 5, 6].

Risk analysis for post-CABG AF performed in the present study revealed that advanced age and reduced LVEF were predictors of AF. Advanced age is a well-known predictor; decreased LVEF is less frequently presented but has been indicated by some [7, 28]. An explanation for their influences on AF occurrence may involve the degenerative changes in atrial anatomy, usually causing dilation or fibrosis, and consequently electrophysiologic alterations. Furthermore, advanced age and decreased LVEF both represented the cause of ineffectuality in our magnesium therapy, and this may likewise be explained by their degenerative nature associated with reduced cellular functioning and tolerability, which cannot be improved by magnesium supplementation alone.

Until now, various therapeutic methods have been proposed to prevent postoperative AF. Most of these methods have incorporated pharmacologic contrivances that may be contraindicated for patients who are especially susceptible to pharmacologic side effects. Older patients and patients with impaired cardiac function are undoubtedly among those in whom initiating a pharmacologic therapy should be well deliberated. Alternatively, nonpharmacologic therapy, particularly that using atrial overdrive pacing [28] or biatrial simultaneous pacing [29], has been proposed with encouraging data while avoiding the potential life-threatening side effects of antiarrhythmic drugs. However, uncertainties relating to the feasibility and cost-effectiveness of the electrical treatment have precluded its routine postoperative use, and the most effective method and mode of pacing have not been determined yet. If further studies should warrant its efficacy, the adjunction of pacing technique to magnesium therapy may be one attractive strategy for patients who are especially resistant to the magnesium treatment alone.

Several limitations exist in the present study. The first is the absence of continuous Holter electrocardiogram monitoring. However, during the immediate postoperative period when AF occurrence is most frequent, an alarm-triggered telemetry system detected and recorded all suspicious events, and it is unlikely that significant AF episodes (>15 minutes or requiring therapy) were missed. This limitation occurs after the telemetry is discontinued, as the arrhythmia can only be detected after occasional electrocardiogram checkup or by clinical observations. Given that this limitation should be equal for both groups, however, the incidence of clinically detected AF after cessation of the telemetric monitoring, usually after day 7, was still lower in the magnesium group (1 patient) than the untreated group (5 patients).

The second limitation is the definition of significant AF itself, which may still be inadequate to denote clinically detrimental AF. However, as mentioned earlier, the relation of AF duration to complications has not been extensively studied, and therefore, any duration implying significant AF is arbitrary. It seems likely, though, that the longer the AF duration selected the more prominent the benefit of the magnesium treatment will be.

The third limitation is the unequal amount of magnesium used on the day of surgery; on-pump patients received additional doses during surgery. Our data indicated no significant differences between off-pump and on-pump groups regarding serum magnesium concentration immediately after surgery (1.7 ± 0.3 mg/dL versus 1.7 ± 0.2 mg/dL, respectively; p = 0.61) and AF incidence with and without the magnesium intervention (20.0% versus 15.3%, respectively, p = 0.70; and 37.5% versus 34.5%, respectively, p = 0.82). Thus, it can be speculated that the 4 mmol/L magnesium sulfate contained in the terminal cardioplegia does not affect the outcome of the postoperative treatment.

Finally and most important, lack of randomization and the nature of the retrospective analysis have weakened the cogency of the study. Although the patients selected were consecutive and similar in respect to their demographic and intraoperative and postoperative details, time bias and other related limitations, including those mentioned previously, cannot be controlled and avoided with this retrospective design. Our findings, however, complement other previously reported data, and we believe that they can further serve as landmarks for future investigations seeking optimization and efficacy in the magnesium treatment, as this was the aim of the study.

In conclusion, postoperative 3-day supplementation of magnesium sulfate is effective in reducing the incidence of AF after CABG. Although much has yet to be clarified regarding optimization of the magnesium regimen, our results support the possibility that constant low-dose administration of magnesium has a role in the success. However, in older patients as well as those with poor LVEF, magnesium supplementation alone is insufficient for the prophylaxis of postoperative AF. Adjunctive therapy, preferably nonpharmacologic, is required to enhance the quality of this safe and efficacious treatment.


   Acknowledgments
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 Acknowledgments
References
 
This study could not have been performed without the support and cooperation of the medical and nursing staff of the intensive care and cardiovascular surgical units of Sakakibara Heart Institute. Deep appreciation is extended to Ryo Hoshino, MD, Ikuko Shibazaki, MD, Keima Nagamachi, MD, Hiroki Hayashi, MD, Naoki Wada, MD, Tomoki Shimokawa, MD, and Takao Ida, MD, for their contributions and technical assistance in the preparation of the study. We also thank the cardiovascular staff of Chiba University, Department of General Surgery, for the constant backup during the writing of the manuscript.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 Acknowledgments
 References
 

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Hitoshi Kasegawa
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