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American Heart Journal
Volume 139 � Number 3 � March 2000
Copyright � 2000 Mosby, Inc.

Electrophysiology

Magnesium supplementation in the prevention of arrhythmias in pediatric patients undergoing surgery for congenital heart defects

B. Hugh Dorman PhD, MD
Robert M. Sade MD
Jeffrey S. Burnette BS
Henry B. Wiles MD
Mark L. Pinosky MD
Scott T. Reeves MD
Brian R. Bond PhD
Francis G. Spinale PhD, MD

From the Department of Anesthesia and Perioperative Medicine, the Department of Cardiothoracic Surgery, and the Department of Pediatric Cardiology, Medical University of South Carolina.
Submitted April 20, 1999.
Accepted July 15, 1999.
Reprint requests: Dr Dorman, Medical University of South Carolina, Department of Anesthesia and Perioperative Medicine, Children's Hospital, 165 Ashley Ave, Suite 525, PO Box 250912, Charleston, SC 29425.

Copyright � 2000 by Mosby, Inc.

Charleston, SC

Background The efficacy of magnesium in the prevention of arrhythmias in pediatric patients after heart surgery remains unknown. Therefore we prospectively examined the effect of magnesium treatment on the incidence of postoperative arrhythmias in pediatric patients undergoing surgical repair of congenital heart defects.
Methods and Results Twenty-eight pediatric patients undergoing heart surgery with cardiopulmonary bypass were prospectively, randomly assigned in a double-blind fashion to receive intravenous magnesium (magnesium group, n = 13; 30 mg/kg) or saline (placebo group, n = 15) immediately after cessation of cardiopulmonary bypass. Magnesium, potassium, and calcium levels were measured at defined intervals during surgery and 24 hours after surgery. Continuous electrocardiographic documentation by Holter monitor was performed for 24 hours after surgery. Magnesium levels were significantly decreased below the normal reference range for patients in the placebo group compared with the magnesium group on arrival in the intensive care unit and for 20 hours after surgery. Magnesium levels remained in the normal range for patients in the magnesium group after magnesium supplementation. In 4 patients in the placebo group (27%), junctional ectopic tachycardia developed within the initial 20 hours in the intensive care unit. No junctional ectopic tachycardia was observed in the magnesium group (P = .026).
Conclusions Although this study was originally targeted to include 100 patients, the protocol was terminated because of the unacceptable incidence of hemodynamically significant junctional ectopic tachycardia that was present in the placebo group. Thus low magnesium levels in pediatric patients undergoing heart surgery are associated with an increased incidence of junctional ectopic tachycardia in the immediate postoperative period. (Am Heart J 2000;139:522-8.)

Magnesium has been used successfully for several decades in the treatment of a variety of atrial and ventricular arrhythmias including torsade de pointes and sustained monomorphic ventricular tachycardia[1] [5] and appears efficacious in resolving ventricular arrhythmias caused by digoxin intoxication and in decreasing the incidence of ventricular fibrillation and supraventricular tachycardia in acute myocardial infarction.[6] [9] Recently, magnesium has been shown to reduce the frequency of ventricular dysrhythmias and atrial fibrillation in adults after heart surgery.[10] [12] Furthermore, the concentration of magnesium in right atrial tissue has been shown to be lower in adult patients with postoperative cardiac arrhythmias compared with adult patients without arrhythmias after heart surgery.[13] However, the efficacy of magnesium in the prevention of arrhythmias in pediatric patients after heart surgery remains unclear. Arrhythmias are common in the pediatric population after heart surgery, especially after procedures involving injury of conduction pathways. Therefore we prospectively examined the effect of magnesium treatment on the incidence of postoperative arrhythmias in pediatric patients undergoing cardiopulmonary bypass (CPB) for surgical repair of congenital cardiac defects to ascertain any protective effect on arrhythmia development.

Methods

Patients

After approval was given by the Human Subjects Review Committee of the Medical University of South Carolina, 28 pediatric patients undergoing heart surgery with CPB for repair of congenital defects were enrolled in the study. Exclusion criteria for participation in the study included age >18 years, emergent surgery, or refusal to participate in the study. In addition, patients with any chronic arrhythmia other than sinus tachycardia or taking any medication prescribed for control of a chronic arrhythmia were excluded from the study. On the day before surgery, a standard coagulation screen, electrolyte panel, and complete blood count were performed, and parents or legal guardians provided informed consent for study participation. All chronic medications and concurrent diseases were recorded. Induction of anesthesia was accomplished with halothane; fentanyl and midazolam were administered once intravenous access was obtained. Systemic heparinization was achieved with a heparin dose of 400 units/kg. Additional heparin was administered during CPB as necessary to maintain an activated clotting time >400 seconds. The pump prime consisted of 0.45% NaCl, supplemented with 30 ml/L 50% dextrose, 15 mEq/L NaHCO3 , and a calculated dose of 25% albumin to ensure a colloid osmotic pressure of 15 to 17 mm Hg. Red blood cells were added to the prime solution as necessary to maintain the patient's hematocrit >30%, and fresh frozen plasma was included as needed to achieve a fibrinogen level >100 mg/dL during CPB. CPB was maintained at 2.0 to 2.5 cardiac index with a Stockert-Shiley roller pump with a Sarns membrane oxygenator (Sarns 3M, Ann Arbor, Mich). Cardioplegic solution consisted of Ringer's solution containing 20 mEq/L KCl and 5 mEq/L NaHCO3 . At the termination of CPB, heparin was neutralized in a 1:1 ratio with protamine.

Experimental design

Patients were prospectively, randomly assigned in a double-blind fashion to receive either intravenous magnesium (magnesium group; 30 mg/kg; n = 13) or saline (placebo group; n = 15) immediately after cessation of CPB. The magnesium sulfate was administered over a period of 10 minutes as a 5% solution in saline. Magnesium, calcium, and potassium levels were measured before surgery, just before CPB, immediately after CPB but before study drug administration, upon arrival in the intensive care unit (ICU), and after surgery every 4 hours for 24 hours. Calcium and potassium were supplemented to normal levels if deficient for any measurement after CPB. Intravenous potassium replacement to the normal reference range was accomplished with 0.3 mEq/kg KCl over a period of 1 hour for a potassium level <3.5 mmol/L. Calcium supplementation was achieved with 10 mg/kg CaCl over a period of 30 minutes for an ionized calcium level <0.8 mmol/L. After the initial magnesium bolus, patients in the magnesium group were designated to receive 10 mg/kg magnesium intravenously if the level was below the normal reference range of 1.6 to 2.3 mg/dL at any sample point in the ICU; patients in the placebo group were designated to receive saline. Upon arrival in the ICU, a 2-channel, 5-lead Holter monitor (Marquette Series 8500, Milwaukee, Wis) was attached to each patient in the study; continuous electrocardiographic documentation of arrhythmias was performed for 24 hours after surgery. An independent observer blinded to study group interpreted each Holter with regard to arrhythmia determination. Core body temperature was measured every hour while the patient was in the ICU and was maintained between 36� and 37�C with standardized temperature management protocols. Inotrope requirement, duration of ventilatory support, and pacing requirement also were documented for the first 24 hours in the ICU. In the setting of a hemodynamically compromising arrhythmia, the study code was unblinded and patient study group was identified to facilitate appropriate antiarrhythmic treatment.

Data analysis

Comparisons between the 2 treatment groups with respect to continuous variables such as hemodynamics, electrolytes, and operative times were compared with the use of analysis of variance for repeated measures. If the analysis of variance revealed significant differences, then pairwise comparisons at specific time intervals were performed with a t statistic corrected by Bonferroni bounds. Discrete variables were compared between the 2 groups with the use of chi-square analysis. Differences between the main effect (magnesium treatment) were examined by the likelihood ratio chi-square. The incidence of postoperative arrhythmias was classified into discrete frequency intervals, and comparisons between the 2 treatment groups were performed with chi-square analysis. All statistical procedures were performed with BMDP statistical software (UCLA Press, Los Angeles, Calif, 1992). Statistical significance was considered as a value of P .05. The means of the continuous variables are presented as mean � standard error of the mean.

Results

There was no difference in age or sex between patients in the placebo and magnesium groups (Table I).

Table I. Demographic characteristics and preoperative medications

Placebo group Magnesium group
Age (y) 4.3 � 4.1 4.9 � 4.2
Sex

   Male 8 8
   Female 7 5
Preoperative medications

   Digitalis 3 0*
   Diuretics 5 3
   Angiotensin converting enzyme inhibitor 5 4

*P < .05 vs placebo group.

Preoperative medications were similar with the exception of digitalis; 3 patients in the placebo group were receiving digitalis before surgery compared with none in the magnesium group (P = .04). In each case, digitalis was prescribed for congestive heart failure symptoms. A digitalis level was obtained before surgery for each patient and was not abnormally elevated. Moreover, no digitalis was administered during the study period. Electrolytes and laboratory indexes of coagulation were similar between the study groups, and preoperative magnesium levels were within the normal reference range for all patients enrolled in the study. The type of surgical procedure performed and the volume of magnesium-free pump prime did not differ between groups. There were also no significant differences in the duration of surgery (258.6 � 56.8 vs 308.3 � 116.2 minutes), duration of CPB (79.2 � 31.5 vs 117.2 � 69.4 minutes), or duration of aortic cross-clamp (54.3 � 24.2 vs 84.7 � 55.6 minutes) between the placebo and magnesium groups, respectively. In the first 24 hours after surgery, inotrope requirements, duration of mechanical ventilation, and pacing requirements were similar when comparing the placebo and magnesium groups.

Magnesium levels were similar between patients in the placebo and magnesium groups before surgery, just before CPB, and immediately after CPB before administration of study medication.

Magnesium levels were significantly decreased for patients in the placebo group compared with the magnesium group upon arrival in the ICU and for 20 hours after surgery. Magnesium levels were consistently within the normal reference range (1.6 to 2.3 mg/dL) for patients in the magnesium group after study drug administration (magnesium 30 mg/kg); thus no patients required additional supplementation. However, magnesium levels were consistently below the normal range for all patients in the placebo group from cessation of CPB through 20 hours after surgery. Potassium and ionized calcium levels were within the normal reference range for patients in both the placebo and magnesium groups throughout the entire study, from the preoperative sample through 24 hours after surgery. There was no difference between study groups in the level of calcium and potassium or the amount of calcium and potassium supplementation required.

 

The incidence of arrhythmias for the first 24 hours after surgery was documented by Holter monitor and then compared between patients in the placebo and magnesium groups. The incidence of supraventricular tachycardia (P = .27), premature atrial contractions (P = .88), premature ventricular contractions (P = .80), ventricular tachycardia (P = .53), and multifocal premature ventricular contractions (P = .29) was similar between patients in the placebo and magnesium groups. However, in 4 patients, junctional ectopic tachycardia accompanied by hypotension developed within the initial 20 hours in the ICU. In each case the study code was unblinded, revealing that all 4 patients were in the placebo group (27%; Figure 2).

Fig 2:  Not shown

All the patients with junctional ectopic tachycardia had magnesium levels below the normal reference range and had undergone a variety of procedures that included an atrial-septal defect repair, ventricular-septal defect repair, Fontan, and Hemi-Fontan. In each case, the arrhythmia slowly resolved over hours after magnesium supplementation (25 to 50 mg/kg). Two of the patients also received 0.3 mEq/kg potassium and a third patient received esmolol infusion with hypothermia for arrhythmia resolution. No junctional ectopic tachycardia was observed in patients in the magnesium group (Figure 2). Chi-square analysis revealed that this incidence of junctional ectopic tachycardia in the placebo group was greater than chance (P = .026).

 

Discussion

Magnesium appears to be important in arrhythmia prophylaxis after heart surgery in adults and may contribute to improved cardiac contractile indexes after CPB.[10] [12] However, the role of magnesium in arrhythmia prevention and optimal magnesium dosage protocols in pediatric patients undergoing heart surgery remained unclear. Therefore we examined the efficacy of magnesium administration in postoperative arrhythmia prophylaxis in pediatric patients undergoing surgery for congenital heart defects. The unique results of the current study revealed that maintenance of magnesium levels within the normal reference range in the immediate postoperative period of heart surgery decreased junctional ectopic tachycardia. Thus this study represents the first prospective, randomized trial that demonstrates that magnesium supplementation is safe in pediatric patients undergoing heart surgery and may reduce the incidence of junctional ectopic tachycardia.

The incidence of hypomagnesemia during heart surgery and after surgery has been well characterized in the adult population. Significant deficiencies of magnesium have been demonstrated in up to 100% of adults after heart surgery requiring CPB, with a duration ranging from 4 to 14 days after surgery.[14] [15] Alterations in magnesium in pediatric patients during and after heart surgery have not been as well characterized. Plasma depletion and total body magnesium depletion also occur in pediatric patients after heart surgery and may be more pronounced than in adults because the volume of prime for CPB is large compared with blood volume, and preoperative magnesium levels may be below normal, especially in critically ill neonates.[16] [17] A recent study examining magnesium flux in pediatric patients undergoing open heart surgery demonstrated that depletion of total body magnesium occurs during and after surgery despite the inclusion of magnesium in cardioplegic solutions.[16] Depletion of ionized magnesium was also reported in a study limited to the surgical procedure in pediatric patients undergoing repair of congenital heart lesions, with changes in magnesium levels dependent on both patient weight and the inclusion of magnesium in cardioplegia.[17] The current study builds on prior studies by further characterizing the dynamics of magnesium flux after CPB and after surgery in pediatric patients undergoing heart surgery who did not receive supplemental magnesium in cardioplegia or priming solutions for CPB.

The mechanism for hypomagnesemia in pediatric patients undergoing heart surgery is not completely understood but is probably multifactorial. Increased perioperative urinary magnesium losses can occur after administration of loop or thiazide diuretics, and hemoglobinuria from red cell destruction during CPB can potentiate urinary excretion of magnesium.[18] [19] The administration of digoxin or calcium gluconate or the development of a metabolic alkalosis also can cause excessive renal loss of magnesium.[20] [22] Moreover, lipolysis with increases in free fatty acids occurs during myocardial ischemia or with elevated catecholamine levels and is associated with significant decreases in serum magnesium levels caused by chelation of magnesium ions that can persist for several days.[23] Finally, hemodilution during CPB with magnesium-depleted solutions can contribute to the reduction in serum magnesium levels.[14] The role of hemodilution as a causative factor in hypomagnesemia may be particularly significant in the current study because the volume of magnesium-free prime for CPB was large relative to circulating blood volume.

Magnesium has a major influence on myocardial tissues. It plays an essential role in the maintenance of resting membrane potential and attenuates electrophysiologic effects of hyperkalemia.[24] [25] Magnesium deficiency can impair cardiac conduction, increase the risk for arrhythmias, predispose to coronary artery spasm, and contribute to neurologic irritability.[26] [30] Magnesium also has been shown to reduce platelet aggregation,[31] inhibit catecholamine release associated with stressful events such as tracheal intubation, [32] and reduce systemic and coronary vascular resistance.[32] [34] There is also evidence that inclusion of magnesium ions in cardioplegic solutions and maintenance of normal magnesium levels during and after heart surgery in adults can improve ventricular recovery and postoperative cardiac indexes.[11] [35] This improved ventricular recovery after hypothermic cardioplegic arrest may be related to the calcium antagonist properties of magnesium, including inhibition of voltage-dependent calcium channels and increased mitochondrial and sarcoplasmic reticulum calcium uptake, which attenuates calcium overload after reperfusion.[35] [36] Appropriate magnesium supplementation in heart surgery in adults has been well documented and can be administered by an intravenous bolus dose after CPB or a continuous infusion into the postoperative period.[10] [12] However, prior studies have not defined optimal magnesium supplementation after CPB and heart surgery in the pediatric population. Therefore we examined the postoperative magnesium requirement to better understand appropriate magnesium supplementation in pediatric patients undergoing heart surgery. The initial 30 mg/kg dose of magnesium administered to patients after CPB resulted in resolution of low magnesium levels to the normal reference range that persisted for the 24-hour period of observation. Additional magnesium supplementation was not required at any of the electrolyte measurement points in the ICU. This dose of magnesium (30 mg/kg) administered intravenously over a period of 10 minutes after CPB does not appear to result in toxic sequelae, and there were similar pacing requirements between patients who received magnesium or saline.

Magnesium has been used successfully in the treatment of and/or prophylaxis for a variety of arrhythmias.[1] [9] The use of magnesium in arrhythmia management recently has been extended into the heart surgery arena. Magnesium administration was shown to be efficacious in decreasing the frequency of postoperative ventricular dysrhythmias and atrial fibrillation in adult patients undergoing heart surgery requiring CPB.[10] [11] In the current study, examining pediatric patients undergoing heart surgery, magnesium administration with normalization of serum magnesium levels appeared to reduce the incidence of junctional ectopic tachycardia in the immediate postoperative period. Postoperative junctional ectopic tachycardia in pediatric patients is difficult to diagnose and manage. The criteria for diagnosis of junctional ectopic tachycardia in the current report included a rapid tachycardia with unchanged QRS configuration associated with atrioventricular dissociation; the sinus P waves wander through the electrocardiogram at a rate slower than the junctional rate. Junctional ectopic tachycardia also was not affected by overdose pacing or DC cardioversion. Only 2 prior reports have examined magnesium flux and arrhythmias in pediatric patients undergoing repair of congenital cardiac lesions.[16] [17] Although neither study found an association between magnesium levels and arrhythmias, the incidence of hypomagnesemia was low, and the arrhythmias were documented by continuous monitoring and not Holter recorder. Moreover, in one of the studies the incidence of arrhythmia was documented during surgery, a time when mechanical irritation and electrical interference is prevalent. Thus this is the first study to document a significant protective effect by magnesium against the development of arrhythmias in pediatric patients after heart surgery.

The mechanism by which magnesium exerts its antiarrhythmic effect is not completely understood but may be attributed to several electrophysiologic properties. Magnesium has been shown to reduce the spontaneous sinus node rate and abnormal ventricular pacemaker activity from catecholamine stimulation and reduce atrial and ventricular conduction, which should prove efficacious on arrhythmias whose mechanism includes increased automaticity or reentry circuits.[37] [41] At the cellular level, magnesium is a cofactor for sodium-potassium ATPase, which is responsible for potassium flux across the myocyte membrane and maintenance of resting membrane potential.[42] Thus an increase in magnesium increases negative membrane resting potential, which reduces myocardial excitability. Magnesium infusion also increases the absolute refractory period and decreases the relative refractory period and thereby decreases the vulnerable period.[43] Finally, magnesium appears to interfere with the slow inward calcium current in cardiac myocytes and atrioventricular node and thereby reduce the tendency for transient depolarization or calcium-induced injury caused by calcium overload, especially with reperfusion of ischemic myocardium. [44] [45] While remaining speculative, several of these electrophysiologic properties of magnesium may play a role in resolution or prevention of junctional ectopic tachycardia observed in the current study. Causative factors involved in the development of junctional ectopic tachycardia are not completely understood but appear to involve enhanced automaticity in the bundle of His.[46] [48] Catecholamines, hypotension, and vagolysis appear to worsen the tachycardia, whereas increased vagal tone and cardiac output, decreased adrenergic tone, and normalization of metabolic parameters appear to improve the arrhythmia.[46] Thus the stabilization of membrane potential and reduction in catecholamine-induced pacemaker activity by magnesium may contribute to a reduction in automaticity and development of junctional ectopic tachycardia. The magnesium-induced increase in the functional and effective refractory periods of the atrioventricular node also may assist in prophylaxis against junctional tachycardias that have a pathogenesis of automaticity.[49] Finally, patients treated with magnesium after heart surgery appear to have increased cardiac index, which should contribute to a reduction in adrenergic tone.[11] [35] Thus magnesium may be a useful modality in the prevention of junctional ectopic tachycardia in pediatric patients after heart surgery and may be helpful in treating the arrhythmia in conjunction with other more conventional methods.[46]

There are several limitations to this study that require comment. First, the sample size of the current study is small. The original study design was to include 50 patients in each study group. However, the increased incidence of junctional ectopic tachycardia observed in the placebo group early in the project resulted in an ethical decision to prematurely terminate the study, especially because this arrhythmia was frequently accompanied by hypotension and was difficult to terminate. Thus the statistical power of the current study is low and may have failed to detect significant differences where one may exist (type II error). For example, it is possible that the incidence of more common arrhythmias, such as supraventricular tachycardia or ventricular ectopy, may have been significantly different between the magnesium and placebo groups if larger patient numbers were used. Moreover, the study was too small to develop a statistical model to identify magnesium level as an independent risk factor for perioperative junctional ectopic tachycardia. Nevertheless, low magnesium levels in pediatric patients undergoing heart surgery are associated with an increased incidence of junctional ectopic tachycardia in the postoperative period. We therefore recommend routine measurement of magnesium levels after CPB in pediatric patients undergoing heart surgery, with timely magnesium supplementation in the postoperative period.

References


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