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Three Part Question

In [patients undergoing cardiac surgery, going into atrial fibrillation] is [the addition of magnesium] more effective than standard therapy alone in [cardioverting or controlling ventricular rate].

Clinical Scenario

You are seeing a patient on the ward who is a 65-year-old man 2 days after coronary arterial bypass surgery. He has just gone into atrial fibrillation with a fast ventricular response. He is haemodynamically stable. You prescribe him amiodarone. The SHO sent off blood tests 1 h ago that showed that his plasma potassium was 4.9 and his magnesium was 1.1. The nurse asks you if you want him to have magnesium in addition to the anti-arrhythmic you prescribed. You are not sure if additional magnesium will be of any benefit. Rather than prescribing blind treatment you decide to review the literature before making your decision.

Search Strategy

Medline 1966 to Oct 2004, Embase 1980 to Oct 2004 and CINAHL 1982 to Oct 2004 using the OVID interface.
[exp atrial fibrillation/ OR atrial fibrillation.mp OR AF.mp OR exp atrial flutter OR atrial flutter.mp OR exp supraventricular tachycardia/ OR SVT.mp] AND [exp magnesium/ OR magnesium.mp].
In addition, the 2001 American Heart Association (AHA) guidelines for patients in Atrial Fibrillation and the 2004 AHA guidelines for patients undergoing Coronary Artery Surgery were hand searched

Search Outcome

Two hundred and six papers were found in Medline. Two hundred and fifty-two papers in Embase, and 8 papers in CINAHL were also found using the appropriate MeSH terms. Cochrane reviews were searched using the term Magnesium. Seven papers were found which gave the best evidence to answer the question

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Shiga et al, 2004, Japan	17 Trials (n=2069 patients) studying prophylaxis of AF with Magnesium in patients undergoing Cardiac Surgery.	Meta-analysis (level 1a)	Relative Risk reduction of supra-ventricular arrhythmias.	SVTs in Mg group 234/1014 (23%) Control group 312//1015 (31%) Risk reduction is 0.77 95% CI: 0.63 to 0.93 P=0.002	Well conducted meta-analysis Significant heterogeneity and publication bias found across studies Range of Mg doses were from 5 mmol to 40 mmol in first 24 h.
			Relative risk reduction of ventricular arrhythmias.	VTs in Mg group 36/596 (6%) Control group 79/599 (13%) Risk reduction is 0.52 95% CI: 0.31 to 0.87 P=0.0001
			Clinical outcomes	No differences found for hospital stay, MI or death
Kalus et al, 2003, USA	321 patients with atrial fibrillation or flutter were eligible (over five years) 107 received IV Mg (2.2±1 g up to 2 h before or during treatment) and ibutilide administration 214 received ibutilide only	Retrospective multi-centre cohort study (level 2b)	Chemical Cardioversion	Mg group 67.2% No Mg group 58.2%	Mg dose wasn't controlled Retrospective study therefore lack of data in some notes e.g. duration of arrhythmia before cardioversion, reason for Mg administration and EF% Low rates of ibutilide usage in full cohort
			Occurrence of VT	Mg group 78.3% No Mg Group 64.4%
			Need for electrical cardioversion	The need for DC cardioversion was decreased by 34% in the Mg group P=0.045. Higher conversion rate when 2 g or more was given (Compared with 0 or 1 g) 74% vs. 61% P=0.043
Brodsky et al, 1994, USA	18 medical outpatients presenting with AF <7days duration Rate >100 and <200 Randomised to:- 10 received Mg (10 g) and Digoxin (0.375 to 0.625 mg tds) 8 received Placebo and Digoxin	Double blind PRCT (level 2b)	Mean Vent. Rate of <90 for 1 h (AF or SR)	End point reached in 10 (100%) of Mg and Digoxin group. End point reached in 4/8 (50%) patients in digoxin alone group. P<0.05. Mean time to endpoint 4 in Mg group, 15 h in Control group. Conversion to SR in 6/10 (60%) in Mg + Digoxin group compared with 3/8 (38%) in the digoxin + placebo group P=NS	Small sample size
Hays et al, 1994, USA	15 Patients with AF (Vent rate>99) Mg group (n=7) 2 g Mg over 1 min followed by 4 g Mg over 4 h and 0.5 mg digoxin after 30 min. Control group (n=8) Received placebo then 0.5 mg digoxin after 30 min	Double blind PRCT (level 2b)	Ventricular rate changes (at 5 min intervals for 30 min then 30 min intervals for 3.5 h)	Ventricular rate: placebo Initial 135±27 5 min 132±28 30 min 131±31 240 min 110±16. Ventricular rate Mg Group;Initial 140±43 5 min 120±25 30 min 120±25 240 min 101±15	Small sample size
			Conversion to normal sinus rhythm	Cardioversion 3 in placebo group, 1 in Mg group P=NS
Frick et al, 1999, Sweden	30 medical patients who have been in AF for over 2 months. Low dose group received 10 mmol Mg over 1 h, or placebo High dose group received 16 mmol Mg over 1 h, or placebo	Double blind PRCT (level 2b)	Heart rate at 1 h	Mg heart rate 81.5±11.2 bpm Control heart rate 81.5±10.1 bpm P=NS	Good blinding protocol, but small study, and no sample size estimates performed.
			Heart rate variability, RR interval heart rate at 1 week	No significant differences found
Chiladakis et al, 2001, Greece	46 symptomatic patients presenting with paroxysmal atrial fibrillation of less than 12 h duration. Mg Group (N=23) 2.5 g over 15 min and then 7.5 g over 6 h Diltiazem group (N=23) 25 mg over 15 min and then 12.5 mg/h over 6 h	Single blind PRCT (level 2b)	Conversion to SR at 6 h	Magnesium group 13/23 pts (57%) Control group 5/23 pts, (22%), P=0.03	No sample size calculations performed. Serum Magnesium levels not taken.
			Side effects	No episodes of hypotension, 2 episodes of bradycardia in diltiazem groups.
Moran et al, 1995, Australia	42 patients on a mixed intensive care unit going into fast AF for more than 1 hr Magnesium group (N=21) 0.15 mmol/kg for 15 min then 0.1 mmol/kg/h. Amiodarone group (N=21) 5-mg/kg over 15 min then 10 mg/kg/24 h.	PRCT (level 2b)	Conversion to sinus rhythm	Mg group (n=21)11 pts at 4 h and 14 at 24 h Amiodarone group 7 pts at 4 h and 7 pts at 24 h	Non consecutive patient recruitment
			Reduction in ventricular response	Significant decrease in heart rate in Mg group up to 30 min, thereafter no significant difference
Gullestad et al, 1993, Norway	57 medical patients with atrial fibrillation, flutter or SVT, all over 100 bpm, of less than 1 week duration. Magnesium group (n=26), 5 mmol bolus of Mg over 5 min then 5 mmol over 10 min, then 0.04 mmol/min if no response. Verapamil group (n=31). 5 mg over 5 min, then 5 mmol over 10 mins then 0.1 mg/min if no response.	Single blind PRCT (level 2b)	Conversion to sinus rhythm by 4 h	Magnesium group 15/26 (58%). Verapamil group 7/31 (23%) P<0.01.	No sample size calculation performed 6 verapamil patients withdrawn due to hypotension or worsening heart failure. No withdrawals in magnesium group
			Time to conversion	Magnesium group 2.4±4.3 h. Verapamil group 8.7±7.8 h P<0.05
			Rate control to under 100 bpm by 4 h	Magnesium group 6/26 (28%). Verapamil group 15/31 (48%) P<0.01

Comment(s)

Despite searching Medline, Embase, CINAHL, Cochrane, and American Heart Association databases and guidelines, we could find no studies that looked into the effect of using magnesium to treat patients going into atrial fibrillation (AF) after cardiac surgery. We thus extended the search to papers that might aid in a decision as to whether magnesium may potentially aid rate control or cardioversion in cardiac surgical patients. Shiga et al, performed a comprehensive meta-analysis in 2004 looking at the benefit of prophylactic magnesium in the prevention of atrial fibrillation post cardiac surgery. Seventeen randomized controlled trials were identified, comprising of 2069 patients. In the pooled magnesium groups the incidence of SVT was 23%, but in the control group it was 31% (P=0.002). In addition the incidence of ventricular tachycardia was also significantly lower, and the mean serum magnesium was significantly higher than those in the control groups. Magnesium reduced the incidence of atrial fibrillation by 29% across the 17 trials performed. Kalus et al, considered the efficacy of magnesium as an adjunct to ibutilide in medical patients in atrial fibrillation. This was a retrospective multicenter cohort study where the authors reviewed the case notes of patients in atrial flutter/fibrillation in whom cardioversion with ibutilide had been attempted. The rate of conversion was 67.2% vs 58.2% for patients in atrial fibrillation and 78.3% vs 64.4% for those in atrial flutter (ibutilide and magnesium vs ibutilide only) resulting in a 34% reduction in the need for elective DC cardioversion. Brodsky et al, looked at 18 medical outpatients with recent onset fast atrial fibrillation. In all patients, digoxin was given and administered every 6 h up to 3 doses or until the study ended. Patients were then randomised to magnesium or placebo groups. Rate control was achieved in all patients receiving magnesium, in a mean time of 4 h, compared to only 50% of the control patients, who achieved rate control in a mean time of 15 h. Hayes et al, looked at a small number of patients that presented to A&E with fast AF. Patients were randomised to receive MgSO4 or placebo, then at 30 min 500 mcg of digoxin was given and the patients were monitored for the next 3.5 h. Three patients in the placebo group and one in the magnesium group were cardioverted back into SR (P=NS). In the remaining patients at 2.5 h ventricular rates were reduced by 18±10% for the placebo group and 26±7% for the MGSO4 group (P=0.08). Frick et al, performed a small study in patients in chronic AF. They gave 2 doses of Magnesium over 1 h, both with double blinded placebo groups, but could find no differenced in terms of heart rate, heart rate variability or RR interval changes, either in the first few hours after magnesium or at 1 week. Chiladakis et al, performed a trial in 46 medical patients presenting with a new episode of paroxysmal AF less than 12 h in duration. Magnesium cardioverted 57% of the patients within 6 h compared to only 22% of those treated with diltiazem. There was, however, no demonstrated difference in heart rate or time to return to sinus rhythm, due to the small size of the sample. Moran et al, performed a trial in a mixed practice intensive care unit. They compared amiodarone and magnesium treatment in 42 patients going into AF. At 24 h 14 of 21 patients receiving magnesium converted compared to only 7 of 21 patients in the amiodarone group. They concluded that addition of magnesium was superior to Amiodarone alone in conversion of AF in their ICU. Gullestad et a, compared magnesium infusion to verapamil infusion in 57 medical patients who had been in atrial fibrillation for less than one week. Magnesium converted 57% of patients compared to 23% within 4 h, but verapamil reduced the rate to under 100 bpm in 48% compared to 28%. There were no side effects with Magnesium but 6 patients were withdrawn from verapamil treatment due to hypotension or exacerbation of heart failure. Thus in summary, in the cardiac surgical literature, prophylactic magnesium has been well established in the prevention of atrial fibrillation with a reduction of up to 30% in the incidence of atrial fibrillation across 17 trials. However, there have been no studies looking at magnesium therapy in cardiac surgical patients going into AF. In the general medical literature we found 7 papers that looked at either addition of magnesium or magnesium alone in the therapy of AF. Four of these 7 papers demonstrated a significant benefit.

Clinical Bottom Line

While the literature on magnesium prophylaxis and non-cardiac surgical literature on magnesium therapy for atrial fibrillation suggests that magnesium may be of benefit, there are currently no studies in post-cardiac surgery atrial fibrillation to support the use of magnesium therapy.

References

1. Shiga T, Wajima Z, Inoue T, Ogawa R. Magnesium prophylaxis for arrhythmias after cardiac surgery: a meta-analysis of randomized controlled trials. Am J Med 2004;117:325–333.
2. Kalus JS, Spencer AP, Tsikouris JP. Impact of prophylactic i.v. magnesium on the efficacy of ibutilide for conversion of atrial fibrillation or flutter. Am J Health-Syst Pharm 2003;60:2308–2312.
3. Brodsky MA, Orlov MV, Capparelli EV, Allen BJ, Iseri LT, Ginkel M, Orlov YSK. Magnesium therapy in new onset atrial fibrillation. Am J Cardiol 1994;73:1227–1229.
4. Hays JV, Gilman JK, Rubal BJ. Effect of magnesium sulfate on ventricular rate control in atrial fibrillation. Ann Emerg Med 1994;24:61–64.
5. Frick M, Ostergren J, Rosenqvist M. Effect of intravenous magnesium on heart rate and heart rate variability in patients with chronic atrial fibrillation. Am J Cardiol 1999;84:104–108.
6. Chiladakis JA, Stathopoulos C, Davlouros P, Manolis AS. Intravenous magnesium sulfate versus diltiazem in paroxysmal atrial fibrillation. Int J Cardiol 2001;79:287–291.
7. Moran JL, Gallagher J, Peak SL, Cunningham DN, Salagaras M, Leppard P. Parenteral magnesium sulfate versus amiodarone in the therapy of atrial tachyarrhythmias: a prospective, randomized study. Crit Care Med 1995;23:1816–1824.
8. Gullestad L, Birkeland K, Molstad P, Hoyer MM, Vanberg P. The Effect of Magnesium Versus Verapamil on Supraventricular Arrhythmias. Clin Cardiol. 1993 May;16(5):429-34.