Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
THERAPY AND PREVENTION Treatment of torsade de pointes with magnesium sulfate DAN TzIvONI, M.D., SHMUEL BANAI, M.D., CLAUDIO SCHUGER, M.D., JESAIA BENHORIN, M.D., ANDRE KEREN, M.D., SHMUEL GOTTLIEB, M.D., AND SHLOMO STERN, M.D. Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017 ABSTRACT Twelve consecutive patients who developed torsade de pointes (polymorphous ventricular tachycardia with marked QT prolongation, TdP) over a 4 year period were treated with intravenous injections of magnesium sulfate. In nine of the patients a single bolus of 2 g completely abolished the TdP within 1 to 5 min, and in three others complete abolition of the TdP was achieved after a second bolus was given 5 to 15 min later. Nine of the patients also received continuous infusion of MgSO4 (3 to 20 mg/min) for 7 to 48 hr until the QT interval was below 0.50 sec. In nine of the 12 patients the TdP was induced by antiarrhythmic agents. The QT interval preceding TdP ranged from 0.54 to 0.72 sec. After the MgSO4 bolus, which prevented the recurrence of TdP, no significant changes were observed in the QT interval. There were no side effects of this treatment. In eight of the 12 patients potassium levels before the TdP were below 3.5 meq/liter; magnesium levels were available in eight patients before TdP, and were normal in all. Five additional patients with polymorphous ventricular tachycardia but normal QT intervals (non-TdP patients) received two to three boluses of MgSO4. This treatment was ineffective in all, but they responded to conventional antiarrhythmic therapy. Thus, MgSO4 is a very effective and safe treatment for TdP, and its application is rapid and simple. Its use is therefore recommended as the first line of therapy for TdP. Circulation 77, No. 2, 392-397, 1988. TORSADE DE POINTES (TdP) is a distinct form of ventricular tachycardia occurring in patients with marked QT prolongation. The conventional treatment is aimed at shortening the QT interval by accelerating the heart rate with isoproterenol infusion or by cardiac pacing. Three years ago we first reported our experience with magnesium sulfate as a treatment for TdP in three patients. Now with extended experience the role of magnesium sulfate seems to be well established in the treatment of patients with TdP. Patients and methods Twelve consecutive patients who developed TdP with QT prolongation between March 1982 and December 1986 were treated with magnesium sulfate. There were 10 women and two men. Their ages ranged from 46 to 87 years (mean, 69 years). Six patients had chronic ischemic heart disease, two had valvular rheumatic heart disease, two had atrial arrhythmia, and two had no signs of organic heart disease. Of the 12 patients nine were on antiarrhythmic therapy: six received type 1 antiarrhythmic drug only (quinidine, three patients; procainamide, three patients), one received amiodarone alone, and two received a From the Heiden Department of Cardiology, Bikur Cholim Hospital and The Hebrew University Hadassah Medical School, Jerusalem. Address for correspondence: Dan Tzivoni, M.D., Department of Cardiology, Bikur Cholim Hospital, P.O. Box 492, Jerusalem, Israel. Received Aug. 24, 1987; accepted Sept. 24, 1987. 392 combination of quinidine or procainamide with amiodarone. Of the remaining three patients, one tried to commit suicide with imipramine and thioridazine, one received furosemide alone, and one had psychogenic polydipsia. Eight of the 12 patients were on diuretic therapy. Five additional patients with chronic ischemic heart disease (two had acute myocardial infarction and three chronic congestive heart failure) developed polymorphous ventricular tachycardia with normal QT interval and received magnesium sulfate therapy, and their response was compared with that in the TdP group. TdP was diagnosed as a recurrent polymorphous ventricular tachycardia in which the peaks of the QRS complexes twisted around the isolectric line in a set up of marked QT interval prolongation (figure 1). The QT intervals were measured in the limb leads of the electrocardiogram when possible, from the sinus beat immediately preceding the TdP. The corrected QT interval (QTc) was calculated according to Bazett's formula. Solutions of 25% or 50% MgSO4 were used. The magnesium was given as an intravenous bolus of 2 g within 1 to 2 mn and in most patients this was followed by a continuous infusion (3 to 20 mg/min). Results Magnesium sulfate was given intravenously to all 12 patients. Four of the patients received other modes of therapy before the administration of magnesium sulfate. Two of them had received lidocaine because the ventricular tachycardia was not diagnosed initially as TdP, and the drug was ineffective in both. Three CIRCULATION THERAPY AND PREVENTION-ARRHYTHMIA Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017 FIGURE 1. A rhythm strip of TdP induced by quinidine. Note the marked QT prolongation before the ventricular arrhythmia, the twisting of the QRS axis, and the spontaneous termination. patients were treated with intravenous isoproterenol (1 to 5 g.g/min), which was effective in only one, and because of intolerable palpitations had to be stopped. Cardiac pacing was tried in one patient and was not effective. In the other eight patients magnesium sulfate was the only treatment given. A bolus of 2 g of MgSO4 was given intravenously to all 12 patients (table 1). In nine of the patients the TdP was completely abolished after this initial treatment. Three other patients who did TABLE 1 Magnesium therapy for TdP MgSo administration Patient No. Bolus 1 (g) 1 2 3 4 5 6 7 8 9 10 11 12 2 2 2 2 2 2 2 2 2 2 2 2 Vol. 77, No. 2, February 1988 Bolus 2 Infusion (g) (mg/ml) 4 2 2 5 7.5 3 15 5 15 20 5 5 not respond completely to the first MgSO4 bolus received a second bolus within 5 to 15 min. In nine patients MgSO4 infusion was given at rates of 3 to 20 mg/min. In three of these patients the infusion was given after a second bolus of MgSO4 was required, while in the other six, it was given preventively. In two patients the TdP recurred 1 to 6 hr after the intravenous infusion of magnesium was begun; therefore another bolus was given that was effective in both. Intravenous infusion of MgSO4 was continued in nine of the patients until the QT interval was shortened below 0.50 sec (7 to 48 hr). Table 2 details the QT, QTc, potassium, and mag- nesium levels in all patients before and after administration of magnesium. The QT intervals ranged from 0. 54 to 0.72 sec (mean, 0.61 sec) and the QTc intervals ranged from 0.53 to 0.80 sec (mean, 0.64 sec). No significant changes in the QT or QTc intervals were observed in most patients immediately after magnesium therapy (table 2, figure 2). Serum potassium levels before the development of TdP were below 3.5 meq/ liter in eight of 12 patients. These patients received oral and intravenous potassium supplements after magnesium therapy was given. Magnesium levels were within normal limits (1.6 to 2.5 meq/liter) at the time of the arrhythmia in all eight patients in whom magnesium levels were available. 393 TZIVONI et al. TABLE 2 QT, QTc, potassium, and magnesium levels before and after magnesium therapy of TdP After MgSO4 therapy Before MgSO, therapy Patient No. QT (sec) QTc (see) K+ (meq/1) Mg+ + (meq/1) l 2 3 4 5 6 7 8 9 10 11 12 Mean 0U60 0.69 0.80 0.63 0.62 0.55 0.56 0.53 0.73 0.69 0.63 0.57 0.66 0.64 3.4 4.2 3.6 3.1 2.9 3.2 1.7 2.1 2.0 1.6 0.68 0.72 0.56 0.60 0.54 0.64 0.60 0.60 0.60 0.56 0.60 0.61 2.9 2.9 1.7 3.4 3.5 3.3 4.2 3.8 1.8 2.0 2.1 1.9 Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017 patients suffering from ischemic heart disease developed recurrent polymorphous ventricular tachycardia with normal QT intervals (figure 3). Four patients had recurrent nonsustained polymorphous ventricular .24 - - --- 4 QTc (sec) K+ (meq/1) 0.56 0.50 0.66 0.52 0.58 0.52 0.64 0.60 0.56 0.58 0.54 0.64 0.57 0.64 0.52 0.62 0.57 0.51 0.56 0.54 0.68 0.64 0.62 0.63 0.61 0.59 4.0 4.2 3.6 3.5 3.3 3.7 4.7 3.9 3.6 4.5 4.0 4.5 4.06 Mg+ + (meq/1) 2.5 5 2.3 2.3 3.5 3.1 tachycardia and one had sustained polymorphous ventricular tachycardia (more than 30 sec) requiring several direct-current shocks. Three of the patients were on antiarrhythmic therapy; one received ajmaline, one disopyramide, and one lidocaine. The QT intervals ranged from 0.38 to 0.49 sec (mean, 0.46). The potas- Magnesium sulfate in patients with polymorphous ventricular tachycardia and normal QT interval. Five other Vl QT (see) V4 1 4 K W4 Ww Alttr-K> 4 - 4 o.lr4>X4 4- ';i; ~ ~ --~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~..... V 4 1. FIGURE 2. Rhythm strip 5 min after 2 g of intravenous magnesium sulfate, which suppressed the TdP. Note the marked QT prolongation. 394 CIRCULATION THERAPY AND PREVENTION-ARRHYTHMIA 1A^ft ;j I t N4V~ 'A ,M: .1 V v\''), ,' ..1e a. '4E # ( iti1 X# t .3 $1 2$ v '/ f' , ` .11 I V Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017 QT=0.44sec ,,,iJ n /S _ ... moo. T X FIGURE 3. Polymorphous ventricular tachycardia with normal QT induced by disopyramide. Three boluses of magnesium sulfate were given intravenously but were ineffective. sium levels at the time of the ventricular tachycardia ranged from 3.1 to 4.3 meq/liter (mean, 3.7). Serum magnesium levels before the ventricular tachycardia were available in two of the patients, and were normal in both. MgSO4 was given as a 2 g bolus to all patients and was inelfective in all. A second bolus was therefore given and two of the patients received a third bolus that was also ineffective; another antiarrhythmic drug was therefore administered. Three patients responded to intravenous lidocaine and two to procainamide. Discussion Since the first description of TdP by Dessertenne,2 controversy has existed as to whether polymorphous ventricular tachyarrhythmias associated with a normal QT interval should also be called TdP. Our group3 and others4-7 have expressed their opinion that the term Torsade de pointes should be reserved only for a ventricular tachycardia with a polymorphous appearance that is associated with marked prolongation of the QT interval, since the presence of the QT prolongation mandates completely different therapy. The treatment of TdP was the subject of many reports. The aim of the treatment has been to shorten the delayed repolarization by increasing the heart rate Vol. 77, No. 2, February 1988 with the infusion of isoproterenol j atrial or ventricular pacing,9'10 or atropine. Isoproterenol is an effective mode for accelerating the heart rate and thereby shortening the QT interval. However, this drug is contraindicated in patients with acute myocardial infarction, angina pectoris, or hypertension. In some patients it may cause intolerable side effects, such as severe palpitations, and in others it may be ineffective. " 8 Furthermore, use of isoproterenol may be fatal if it is given to patients with a ventricular tachycardia that is not TdP (without QT prolongation). Cardiac pacing is an effective and safe method for treating TdP,8 9 but its application requires certain skills and equipment and therefore it can not be applied in an ambulance or in every emergency room, and even if skilled personnel and equipment are available there is a considerable delay between the time of diagnosis of TdP and the initiation of cardiac pacing. The role of magnesium in ventricular tachyarrhythmias has been the subject of several clinical investigations. 1t113 Magnesium sulfate was used empirically for many years as a treatment for atrial and ventricular arrhythmias in patients with normal or low magnesium levels,14-17 in patients with digitalis toxicity, and in alcoholics. 395 TZIVONI et al. Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017 In 1984 we reported the first three patients with TdP who were successfully treated with MgSO4.1 In the present report we describe our extended experience in 12 patients with TdP, all of whom responded to intravenous magnesium sulfate. In eight of the patients magnesium was the only therapy given, while in four others initial therapy failed and therefore magnesium sulfate was given. The treatment with magnesium sulfate consisted of an initial bolus of 2 g, given within 1 to 2 min. In nine of the 12 patients this was associated with complete eradication of TdP and most ventricular premature beats. In three patients, only a partial response was observed and therefore a second bolus was given 5 to 15 min later. Infusion of magnesium sulfate (3 to 20 mg/min) was given to nine of the patients after the initial bolus. In three of them it was given because of partial response to the initial bolus, while in the others it was given preventively. It seems to us that if a complete response is observed after the first bolus of 2 g no further therapy is required, while in patients with no or a partial response a second bolus is indicated together with continuous infusion of 3 to 10 mg/min. In two of our patients TdP recurred after few hours of continuous infusion of magnesium and another bolus abolished it. In the nine patients in whom a continuous infusion of magnesium was given, the indication for cessation of infusion was shortening of QT below 0.50 sec, which occurred within 7 to 48 hr. Except for flushing sensations during the bolus injection no side effects were noted. As in many previously reported cases of TdP, eight of our 12 patients suffered from hypokalemia (K level below 3.5 meq/liter). Therefore, in addition to the administration of MgSO4, these patients received intravenous and oral potassium supplements. Serum magnesium levels were available in eight of the 12 patients and in all it was within normal range. Thus, the TdP could not be attributed to serum hypomagnesemia. Intracellular magnesium levels were not available in our study. The effect of magnesium sulfate was assessed in five additional patients with polymorphous ventricular tachycardia and a normal QT interval. Two to three boluses of magnesium sulfate were given (4 to 6 g) to these patients without any response. Subsequent conventional therapy for ventricular tachycardia with lidocaine or procainamide was given with satisfactory results. Thus, MgSO4 is not effective in the treatment of patients with polymorphous ventricular tachycardia without QT prolongation. The mechanism of action of MgSO4 is not understood. Unlike isoproterenol infusion and cardiac pac396 ing, MgSO4 prevented the recurrence of TdP without shortening the QT interval. The fact that the QT interval remained unchanged despite the suppression of the ventricular arrhythmia suggests that the salutary effect of magnesium is not related to shortening of repolarization. Since magnesium is a cofactor in the sodiumpotassium ATPase activity, it may have prevented the TdP by facilitating influx of potassium into the cells, thereby stabilizing membrane potential, correcting the dispersed repolarization process without shortening it. It is well known that various drugs that cause QT interval prolongation are capable of inducing TdP.4 7, 18, 19 It has been suggested that asynchronous recovery of excitability is a predisposing factor for reentrant ventricular arrhythmias.20 Dispersion of refractoriness has been demonstrated in a number of conditions, such as left stellate ganglion stimulations, myocardial ischemia, hypothermia,21 and also after premature stimulation or pacing at a long cycle length. The recently described observation that the last supraventricular beat (before the initiation of TdP) is almost always preceded by a long cycle length (either postextrasystolic pause or bradycardia) favors this hypothesis. On the other hand, the inability to induce TdP in the laboratory by premature electrical stimulation22 is a serious argument against a reentrant mechanism for TdP. Dessertenne,2 in his original description of TdP, suggested that this arrhythmia may be a result of the activity of two automatic foci. Naumann et al.,23 who succeeded in building a model of TdP-like arrhythmia in isolated pig hearts by simultaneous pacing from both ventricles, also suggested that the tachycardia is a result of the interference of two separate foci acting at two different rates. On the other hand, Bhargava et al.24 presented evidence against the multiple focal cause for TdP, based on their results of spectral-analysis data of the electrocardiograms of three patients with TdP; they suggested that the origin of the tachycardia is in a single ectopic center, migrating around the ventricles in a periodic way. Triggered activity and afterdepolarization may play a role in the initiation and/or perpetuation of TdP.22 Jackman et al.25 succeeded in inducing TdP in dogs with cessium cloride, which in vitro prolongs repolarization and induces bradycardia-dependent early afterdepolarization and triggered activity. The ionic mechanism responsible for afterdepolarization is not clear. Intracellular calcium may play a role as an oscillatory modulator of inward currents that are not specific and are probably responsible for the afterdepolarization.26 Kass et al.27 suggested that the phasic movement of calcium in and out the sarcoplasmic reticulum as a CIRCULATION THERAPY AND PREVENTION-ARRHYTHMIA Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017 result of intracellular gain of sodium and loss of potassium might cause transient inward currents and transient depolarization and that high magnesium levels block, and low magnesium levels potentiate, the phasic movement. It is possible also that magnesium deficiency may lead to influx of calcium and may be the primary cause of intracellular potassium loss.28' 29 Because of the properties of magnesium as a modulator of calcium ions it has been called "nature's physiologic calcium blocker."30 In the light of the above discussion it seems to us that the effectiveness of intravenous magnesium therapy in patients with TdP might be related to suppression of oscillatory currents responsible for afterdepolarization. From our experience with the above-described 12 patients with TdP who were effectively treated with MgSO4, it is our recommendation that this treatment should be used as the first line of therapy for patients suffering from this disorder. This treatment is not only very effective, but is also safe and easily applied, and the response is very rapid. References 1. Tzivoni D, Keren A, Cohen AM, Stern S: Magnesium therapy for Torsade de Pointes. Am J Cardiol 53: 528, 1984 2. Dessertenne F: La tachycardie ventriculaire a deux foyes oposes variables. Arch Mal Coeur 59: 263, 1966 3. Tzivoni D, Keren A, Stern S: Torsade de pointes versus polymorphous ventricular tachycardia. Am J Cardiol 52: 639, 1983 (edi- torial) 4. Kay GN, Plumb VJ, Arciniegas JG, Henthorn RW, Waldo AL: Torsades de pointes: the long-short initiating sequence and other clinical features. Observations in 32 patients. J Am Coll Cardiol 2: 806, 1983 5. Mazhar MK, Kathleen RL, Janet MM, Jennifer A: Management of recurrent ventricular tachyarrhythmias associated with QT prolongation. Am J Cardiol 47: 1301, 1981 6. Smith WM, Gallagher JJ: "Les torsade de pointes." An unusual ventricular arrhythmia. Ann Intern Med 93: 578, 1980 7. Soffer J, Dreifus L, Michelson E: Polymorphous ventricular tachycardia associated with normal and long QT intervals. Am J Cardiol 49: 2021, 1982 8. Keren A, Tzivoni D, Benhorin J, Gottlieb S, Stern S: Etiology, warning signs and therapy of torsade de pointes. A study of 10 patients. Circulation 64: 1167, 1981 Vol. 77, No. 2, February 1988 9. Keren A, Tzivoni D, Golhman J, Benhorin J, Stern S: Ventricular pacing in atypical ventricular tachycardia. J Electrocardiol 14: 201, 1981 10. Ewy GA: Therapy for cardiovascular emergencies. Circulation 74: 111, 1986 11. Loeb HS, Petras RJ, Gunnar RM, Tobin JR: Paroxysmal ventricular fibrillation in two patients with hypermagnesemia. Circulation 37: 210, 1968 12. Chadda KD, Gupta PK, Lichsten E: Magnesium in cardiac arrhythmia. N Engl J Med 287: 1102, 1972 13. Iseri LT, Freed J, Bures AR: Magnesium deficiency and cardiac disorders. Am J Med 58: 837, 1975 14. Boyd LJ: Magnesium sulfate in paroxysmal tachycardia. Am J Med Sci 206: 43, 1943 15. Szekely P: The action of magnesium on the heart. Br Heart J 8: 115, 1946 16. Enselberg CD, Sinmons HG, Mintz AA: The effects of magnesium upon cardiac arrhythmias. Am Heart J 39: 703, 1950 17. Iseri LT, Chung P, Tobis J: Magnesium therapy for intractable ventricular tachyarrhythmias in normomagnesemic patients. West J Med 138: 823, 1983 18. Keren A, Tzivoni D, Gottlieb S, Benhorin J, Stern S: Atypical ventricular tachycardia induced by amiodarone: arrhythmia previously induced by quinidine and disopyramid. Chest 81: 384, 1982 19. Tzivoni D, Keren A, Gottlieb S, Stern S: Atypical ventricular tachycardia induced by disopiramide. Arch Intern Med 141: 946, 1981 20. Kossmann CE: Torsade de pointes: an addition to the nosography of ventricular tachycardia. Am J Cardiol 42: 1054, 1978 21. Somberg J, Tepper D, Wynn J: Prolonged repolarization a historical prospective. Proceedings of the symposium on QT prolongation: Antiarrhythmic and arrhythmogenic effects. Am Heart J 109: 395, 1985 22. Schechter E, Freedman CC, Lazzara R: After depolarizations as a mechanism for long QT syndrome: electrophysiologic studies of a case. J Am Coll Cardiol 3: 1556, 1984 23. Naumann D, Zierhut W, Luderitz B: "Torsade de pointes" tachycardia re-entry or focal activity? Br Heart J 48: 213, 1982 24. Bhargava V, Goldberger AL, Ward D, Ahnve S: Torsade de pointes: a characteristic spectral pattern in sudden cardiac death. IEEE BME-33. No. 9,894, 1986 25. Jackman WM, Friday KJ, Scherlag BJ, Harrison LA: Torsade de pointes: clinical experimental observations bearing on mechanism. Clin Res 31: 193A, 1983 (abst) 26. Tsien RW, Carpenter OD: Ionic mechanism of pacemaker activity in cardiac purkinje fibers. Fed Proc 37: 2127, 1978 27. Kass RS, Lederer WJ, Tsien RW, Weingart R: Rate of calcium ions in transient inward currents and aftercontractions induced by stroptianthidine in-cardiac purkinje fibers. J Physiol 281: 187, 1978 28. Whang R, Welt LG: Observation in experimental magnesium depletion. J Clin Invest 42: 305, 1963 29. Wutzen J: Effect of low magnesium diet on the histology and the activity of certain enzymes of rat myocardium. Pol Med Sci Hist Bull 15: 531, 1975 30. Iseri LT, French JH: Magnesium: nature's physiologic calcium blocker Am Heart J 108: 188, 1984 397 Treatment of torsade de pointes with magnesium sulfate. D Tzivoni, S Banai, C Schuger, J Benhorin, A Keren, S Gottlieb and S Stern Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017 Circulation. 1988;77:392-397 doi: 10.1161/01.CIR.77.2.392 Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 1988 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7322. Online ISSN: 1524-4539 The online version of this article, along with updated information and services, is located on the World Wide Web at: http://circ.ahajournals.org/content/77/2/392 Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: http://www.lww.com/reprints Subscriptions: Information about subscribing to Circulation is online at: http://circ.ahajournals.org//subscriptions/