Effects of Intravenous Magnesium Sulfate on the QT Interval in Patients Receiving Ibutilide

Michael F. Caron, Pharm.D., Jeffrey Kluger, M.D., James P. Tsikouris, Pharm.D., Arnold Ritvo, M.D., James S. Kalus, Pharm.D., C. Michael White, Pharm.D.

Disclosures

Pharmacotherapy. 2003;23(3) 

In This Article

Discussion

In this study, the QTc interval was increased by 75 msec over baseline levels 30 minutes after the last ibutilide infusion in the placebo group. In contrast, patients receiving magnesium sulfate prophylaxis had an attenuated QTc interval increase of only 19 msec over baseline levels 30 minutes after ibutilide therapy. This time point is important because a previous study in patients receiving ibutilide demonstrated a significant association between occurrence of polymorphic ventricular tachycardia and change from baseline in the QTc interval at 30 minutes (p=0.01).[14] Also in that study, the authors found a significant increase of 106 msec in the QTc interval at 30 minutes versus that at baseline.

In addition, our study showed trends in reducing the risk of having QTc interval increases of greater than 30 msec and greater than 60 msec and in having a posttreatment QTc interval value of more than 500 msec in the magnesium sulfate group at 30 minutes. This is notable from a clinical standpoint since the Committee for Proprietary Medicinal Products (London, England) identified these factors as being either a cause of concern (QTc increase > 60 msec or QTc value > 500 msec) or a potential concern (QTc increase > 30 msec) germane to the risk of torsades de pointes.[15] Further, in a review of 116 cases of torsades de pointes reported in the literature, 107 individuals (92.2%) had a measured QTc interval value that exceeded 500 msec, suggesting that torsades de pointes rarely occurs unless the QTc interval value exceeds 500 msec.[4]

No changes in QT interval dispersion were observed in our study. Although it is not the most reliable prognostic index, QT interval dispersion (40-60 msec is considered normal) is an additional indicator of the electrical stability of ventricular repolarization.[4]

No torsades de pointes occurred in either group in our study, but these electrocardiographic results support a potential anti-torsades de pointes effect from prophylactic magnesium sulfate therapy. This is similar to a rabbit trial that investigated the effects of intravenous magnesium sulfate on the arrhythmogenic potential of clofilium, an experimental class III antiarrhythmic agent.[9] Rabbits received either magnesium sulfate 60-mg/kg bolus and 0.6-mg/kg/minute continuous infusion or matching placebo concurrently with clofilium 5 mg/kg over 30 minutes. The magnesium sulfate group had significantly fewer occurrences of torsades de pointes and early afterdepolarizations than those of the placebo group (100% vs 20%, p=0.048 for both comparisons).

The effect of magnesium sulfate on the QTc interval is thought to be the result of two mechanisms. Magnesium sulfate blocks calcium entrance into the cell by inhibiting L-type calcium channels during phase 3 of the action potential, an effect that potentially would shorten the QTc interval.[16] Conversely, magnesium sulfate also blocks the outward movement of potassium by inhibiting the inward rectifier potassium channel, potentially leading to prolongation of the QTc interval. Because of these counteracting cellular mechanisms, magnesium sulfate may terminate torsades de pointes independently of the QT interval. Magnesium sulfate decreases early afterdepolar-izations, which are changes occurring in the cardiac action potential that can lead to depolarization of the cell membrane to threshold, causing induced triggered responses.[9] These triggered responses can cause electrical instability in cardiac muscle, leading to torsades de pointes.

Class III antiarrhythmic agents cause chemical cardioversion from atrial flutter and fibrillation by prolonging repolarization. Thus, magnesium sulfate could protect against torsades de pointes but also diminish effectiveness. Future study needs to be done to determine the implications of prophylactic magnesium sulfate on ibutilide's conversion rate in atrial tachyarrhythmias. Our conversion rates ( Table 1 ) are similar to those observed in previous studies; however, this study was not powered to detect any differences in cardioversion outcomes. If magnesium sulfate is found, after subsequent study, not to effect the efficacy of ibutilide, a large trial to prove a reduction in torsades de pointes rates would be warranted. Magnesium sulfate may be an inexpensive and safe adjunctive therapy for ibutilide and other class III agents.

The limitations of our study were the following. Theoretically, magnesium sulfate could quicken repolarization and lessen ibutilide's cardioversion success. Therefore, further studies should be adequately powered to assess the conversion rate of ibutilide with concomitant prophylactic magnesium sulfate. Also, because the QT and R-R intervals were read while some patients were in atrial fibrillation or atrial flutter, there was the potential for reduced accuracy of these electrocardiographic variable measurements. In an effort to resolve this, we measured all of the QT and R-R intervals in each lead and averaged them for a more precise evaluation.

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