Torsade de pointes ventricular tachycardia a complication of disopyramide shared with quinidine

J. ELECTROCARDIOLOGY 14 (3), 1981, 301-308

Case Studies: A R Y L. GOLDBERGER, M . D . , EDITOR

Torsade de Pointes Ventricular Tachycardia A Complication of Disopyramide Shared with Quinidine BY ROBERT W. WALD, M.D., MENASHE B. WAXMAN, M.D. AND JACK M. COLMAN, M.D.

SUMMARY Two cases of documented torsade de pointes ventricular tachycardia in association with the use of disopyramide are described. One patient had previously experienced an episode suggestive of quinidine induced ventricular t a e h y c a r d i a while the other developed ventricular tachycardia during quinidine t r e a t m e n t which was later exacerbated and sustained by the administration of disopyramide. Both patients exhibited a prolonged QTc or QUc interval at the time of the a r r h y t h m i a . These cases suggest t h a t a propensity to ventricular a r r h y t h m i a s induced by quinidine may identify individuals who are likely to develop similar a r r h y t h m i a s during disopyramide t r e a t m e n t as well. tions. She had been on oral propranolol 10 mg four times daily for nine years and digoxin 0.125 mg once daily for three years. She had been hypertensive for six years, treated with diuretics. A goiter was surgically removed one year previously because of dysphagia and she was maintained on 1-thyroxine 0.10 mg daily. Recently her palpitations were accompanied by shortness of breath and increasing fatigue. On physical examination, she was normotensive and exhibited findings of mild mitral stenosis and regurgitation. The ECG showed atrial fibrillation with a m e a n ventricular response rate of 100/rain and left v e n t r i c u l a r hypertrophy. The QTc interval was normal at 0.32 sec and there was no U wave. An echocardiogram confirmed mitral stenosis with slight dilatation of the left a t r i u m at 42 mm. She was clinically and chemically euthyroid. One y e a r previously, she had been in sinus r h y t h m and because her palpitations had become symptomatic, it was decided to a t t e m p t conversion to sinus rhythm. She was anticoagulated, propranolol was increased to 20 mg four times daily and she was started on sustained release quinidine bisulfate 250 mg every eight hours. Three weeks later, she was still in atrial fibrillation. Her digoxin was increased to 0.25 mg daily (serum level was 0.7 mcg/1, therapeutic range 0.8 - 1.9 mcg/1) and the dose ofquinidine bisulfate increased to 500 mg every eight hours. Three days later, during the night, she developed stertorous breathing which aroused her husband who then noted t h a t she became apneic and limp. He shook her, administered mouth-to-mouth resuscitation and pounded her on the chest following which she began to breathe again. After a 30 m i n u t e period of unconsciousness, she woke up and was com-

Disopyramide is a relatively new antiarrhythmic agent effective in the t r e a t m e n t of sup r a v e n t r i c u l a r and ventricular r h y t h m disturbances.~2 Since it shares m a n y electrophysiologic effects with quinidine~3,4 without some of the side effects of the latter, 1 p a t i e n t s are f r e q u e n t l y placed on disopyramide after experiencing adverse side effects on quinidine. Torsade de pointes ventricular tachycardia with syncope is one of the most serious potential complications of quinidine t r e a t m e n t . ~,~ Recently s i m i l a r r h y t h m disturbances have been reported to occur as a result of disopyramide treatment. 7,s We describe two cases of torsade de pointes ventricular tachycardia during disopyramide administration. Both patients had been treated previously with quinidine which was replaced with disopyramide because of suspected or documented ventricular tachycardia resulting from quinidine treatment.

CASE REPORTS Case #1. A 50-year-old woman with known mitral stenosis was seen because of recurrent palpitaFrom the Department of Medicine, Faculty of Medicine, University of Torontoand the Divisionof Cardiology,Mount Sinai Hospital, Toronto, Ontario, Canada. This work was supported in part by the Canadian Heart Foundation, Ottawa, the Ontario Heart Foundation, and the Mount Sinai Institute, Toronto, Ontario, Canada. The cost of publication of this article were defrayedin part by the payment of page charges. This article must therefore be hereby marked "advertisemenf' in accordance with 18 U.S.C. w 1734 solelyto indicate this fact. Reprint requests to: Robert W. Wald, M.D., Mount Sinai Hospital, 600 University Ave., Suite 632; Toronto, Ontario, Canada. M5G 1X5. 301

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Fig. 1. Case 1. Top: Continuous strips of monitor lead showing torsade de pointes ventricular tachycardia in short self-terminating bursts. Bottom: Recording from the same lead a few minutes later during sinus rhythm with no ectopic beats. Note the prolongation in the QU interval. pletely back to her normal self, exhibiting no neurological abnormalities. She had never experienced syncope in the past. When she was admitted to hospital, the ECG showed continuing atrial fibrillation. The QUc interval was prolonged at 0.67 sec. Serum digoxin level was 1.9 mcg/1 and the serum quinidine level was 2.9 mg/1 (therapeutic range 3-7 mg/1). Although no ventricular arrhythmia was documented at the time, it was felt that quinidine-induced ventricular tachycardia was the most likely etiology of this sinister episode and quinidine bisulfate was stopped. Three weeks later in December, 1978, the patient was admitted to the Intensive Care Unit of our hospital for elective cardioversion. Because

the use of quinidine was felt to be contraindicated, she was given disopyramide 100 mg intravenously over 30 minutes, prior to cardioversion. Her rhythm converted to sinus after one DC shock of 50 joules but atrial fibrillation recurred within a few minutes. A further 50 mg of disopyramide was given intravenously over 15 minutes and a second shock of 100 joules converted her to sinus rhythm. She received disopyramide 150 mg by mouth six hours later and remained in sinus rhythm. Four hours after the last dose of disopyramide, she developed multiple short bursts of torsade de pointes ventricular tachycardia lasting up to 12 seconds (Fig. 1 top). All episodes were self-terminating, Her QUc interval was prolonged at 0.60 sec (Fig. 1 bottom). A d i a g n o s i s of J. ELECTROCARDIOLOGY, VOL. 14, NOI 3, 1981

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Fig. 2. Case 2. Discontinuous recordings from monitor lead showing torsade de pointes ventricular tachycardia. All episodes terminated spontaneously. The QT interval is prolonged to 0.60 sec. disopyramide-induced v e n t r i c u l a r t a c h y c a r d i a was made and the drug was discontinued. Serum potassium was 3.9 mcg/1 and serum digoxin level was 1.3 mcg/1. The patient was continuously monitored. She tolerated the arrhythmia quite well from a hemodynamic point of view and no further t r e a t m e n t was instituted. Six hours later, her ventricular arrhythmia subsided completely and 24 hours later her r h y t h m reverted to atrial fibrillation. No further attempts were made to revert her to normal sinus rhythm. Over the ensuing 14 months, she has remained in atrial fibrillation and has been m a i n t a i n e d on digoxin 0.25 mg daily and propranolol 20 mg by mouth four times daily. The QTc interval returned to control and the U wave disappeared. No recurrence of any ventricular r h y t h m disturbance was detected during the follow-up period and she has experienced no syncope. Case #2. A 71-year-old woman was admitted to another hospital in April, 1980, with cellulitis of the right leg. She had a two year history of atrial fibrillaJ. ELECTROCARDIOLOGY,

VOL. 14, NO. 3, 1981

tion and congestive heart failure which was well compensated with digoxin 0.25 mg daily. She had no past history of myocardial infarction. On admission, her ECG showed atrial fibrillation with a mean ventricular response rate of 80/min, frontal QRS axis deviated to the left at - 6 0 ~ QRS duration slightly prolonged at 0.10 seconds, small R-waves in leads V3 and V4 in keeping with a possible old anterior myocardial infarction and nonspecific repolarization abnormalities. Digoxin was not a d m i n i s t e r e d in hospital and on the fourth day of hospitalization, the p a t i e n t developed pulmonary edema: This was successfully treated with oxygen, digoxin and diuretics. Following this, she was noted to have frequent unifocal premature ventricular beats. Quinidine was started on the sixth hospital day in an attempt to control the premature ventricular beats and to convert the rhythm to sinus. At first, oral quinidine sulfate 200 mg was administered at six-hourly intervals. Because of increasing frequency of premature ventricular beats a n d continuing atrial fibrillation, the dose was increased

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Fig. 3. Case 2. Continuous recordings of lead 1. No arrhythmias are present during ventricular pacing at 100/min. The pacemaker is slowed then turned off (at the arrow) and several seconds later torsade de pointes ventricular tachycardia recurs. The arrhythmia is immediately suppressed when pacing is resumed. to 400 mg every six hours on the seventh hospital day. On the eighth hospital day, the patient continued to have frequent premature ventricular beats which were now multiform. Atrial fibrillation had converted to an AV junctional r h y t h m at 50/rain. An attempt to control the premature ventricular beats with lidocaine 50 mg i.v. administered as a bolus followed by lidocaine drip 2 mg/ min was unsuccessful. Five hours after the last dose of quinidine, the patient demonstrated short bursts of torsade de pointes ventricular tachycardia and she was started on oral disopyramide 150 mg every six hours. One hour later, she was given disopyramide 100 mg i n t r a v e n o u s l y b u t continued to exhibit short bursts of torsade de pointes ventricular tachycardia (Fig. 2). A right ventricular temporary pacemaker electrode was inserted and the ventricular p r e m a t u r e beats and ventricular tachycardia were well controlled by overdrive pacing at 100/min over the e n s u i n g 24 hours. Disopyramide 150 mg orally every six

hours was continued for three further doses. On the ninth hospital day, repeated episodes of ventricular t a c h y c a r d i a recurred coincident with intermittent failure of overdrive pacing due to displacement of the right ventricular electrode. The patient was transferred to this hospital. A diagnosis of atypical ventricular tachycardia resulting from quinidine and exacerbated and sustained by disopyramide was made and no further doses of these drugs were administered. The right ventricular electrode catheter was repositioned and successful right ventricular capture and pacing at 100/min resulted in complete elimination of all ventricular arrhythmias. However, when the pacemaker was turned off, ventricular tachycardia of similar morphology to that noted previously promptly recurred (Fig. 3). The patient's QTc interval was markedly prolonged at 0.63 seconds, significantly longer than one week earlier when it had been 0.38 seconds. Serum potassium on admission to this hospital was 5.5 mM/1. The followJ. ELECTROCARDIOLOGY, VOL. 14, NO. 3, 1981

VENTRICULAR TACHYCARDIA WITH DISOPYRAMIDE

ing day, serum digoxin level was 0.5 mcg/1, serum quinidine level was 1.2 rag/1 and serum disopyramide level was 3.3 rag/1 (therapeutic range 1.7 - 3.0 mg/1). The ventricular arrhythmia continued to be well controlled with right ventricular pacing. Two days after admission, the right ventricular pacemaker was turned off. The patient was back in atrial fibrillation and no further premature ventricular beats were present. The QTc interval shortened to control. She was discharged on digoxin, furosemide and potassium and remained stable over the ensuing eight weeks.

DISCUSSION Torsade de pointes ventricular tachycardia ~12 is a paroxysmal ventricular arrhythmia characterized morphologically by cyclic undulations in QRS axis resulting in a gradual cyclic change in the direction of the points and in the amplitude of the complexes. This results in a characteristic f u s i f o r m or t w i s t e d b a n d a p p e a r a n c e w i t h changes in the polarity of the points occurring at "nodes" of diminished amplitude. Also known as polymorphous 1~ or atypical 7 ventricular tachycardia, this arrhythmia has been noted to occur under many diverse circumstances2 -12 A variety of drugs including quinidine, lidocaine, procainamide, prenylamine, phenothiazines and tircyclic antidepressants have been implicated in its genesis2 Disopyramide is the latest addition to this list.Z8 The QT or QU interval of intervening sinus conducted beats is prolonged almost universally in each clinical setting where this ventricular arrhythmia arises, l~ Prolongation of the QTc interval is probably a reflection of nonuniform prolongation of ventricular repolarization time. m Since the U wave on the ECG may be a manifestation of repolarization of the ventricular Purkinje system, '4 prolongation of the QUc interval may have the same significance as QTc interval prolongation and may also reflect increased asynchrony of ventricular repolarization. As in our Case 1, disopyramide-induced ventricular arrhythmias occurred against a background of prolonged QUc interval in one of three patients described by Nicholson et al. 8 Although the exact mechanism of torsade de pointes ventricular tachycardia is not known, some authors have postulated that it may arise by ventricular re-entry ~~ favoured by temporal dispersion of refractory periods. ~5 In addition to providing the electrophysiologic substrate for reJ. ELECTROCARDIOLOGY, VOL. 14, NO. 3, 1981

305

entry, asynchronous repolarization may also be responsible for the cyclic alterations in the QRS axis during the tachycardia by continuously displacing the re-entrant pathway in a direction in which refractory periods are shorter. Quinidine therapy was initially instituted in both cases described here, at least in part in an attempt to pharmacologically convert atrial f i b r i l l a t i o n to sinus r h y t h m . A l t h o u g h not documented, a quinidine-induced ventricular arrhythmia was very likely responsible for the unusual episode of apnea and unconsciousness experienced by the first patient. The propensity to spontaneous termination is a well known feature oftorsade de pointes ventricular tachycardia. The role of the chest thump in the restoration of signs of life in this patient cannot be determined but this procedure is known to terminate some cases of ventricular flutter or ventricular tachycardia if applied soon after its onset. 16 In the wake of this event, disopyramide was administered to this patient with some trepidation and under carefully controlled conditions. Although w e were not aware at that time of any published reports of disopyramide-induced ventricular arrhythmias, extreme caution was dictated by the high index of suspicion about the etiology of the previous episode on quinidine and the known similarities in electrophysiologic properties between the two drugs. Documentation of torsade de pointes ventricular tachycardia in association with QT int e r v a l p r o l o n g a t i o n following d i s o p y r a m i d e administration supports the idea that a similar mechanism was responsible for the quinidinerelated event as well. As might be expected, withdrawal of the offending agent led to a satisfactory and relatively uneventful resolution of the arrhythmia without the need for any interventions. Quinidine treatment resulted in an exacerbation of ventricular arrhythmia in the second patient. Although this fact is easily recognized in retrospect it would have been considerably more difficult to recognize it early because ventricular premature beats were initially present in association with myocardial disease. Since the causative agent was unclear, exacerbations in the degree of ventricular irritability could be reasonably assumed to be within the limits of variability of the underlying condition. Following the appearance of torsade de pointes ventricular tachycardia the patient was switched to disopyramide. Although it is not certain to what extent this may have exacerbated the arrhythmia, it was very likely responsible for its continued presence over 24

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hours later. The s a l u t a r y effect of overdrive pacing illustrates the successful use of this t r e a t m e n t modality which, along with isoproterenol is well known for its specific value in the t r e a t m e n t of this a r r h y t h m i a , l~ It should be noted t h a t isop r o t e r e n o l and pacing s h o r t e n v e n t r i c u l a r repolarization time 17-19 and t e n d to c ount e r the u n d er ly in g disturbance. Metabolic factors which tend to exacerbate the a r r h y t h m i a ~1 were not identified. In particular, the serum potassium was normal in both cases. Bradycardia, a n o t h e r predisposing factor ~ was only present in the second pa t i e nt after termination of atrial fibrillation, although the h e a r t r at e was significantly slower after cardioversion in the first p atien t as well. Storstein reported t h a t pat i e n t s with q u i n i d i n e syncope i n v a r i a b l y h ad toxic serum concentrations of quinidine. 2~ This appeared not to have been the case in the first patient but m a y have been t r ue in the second patient. The serum disopyramide level in the second p a t i en t was high even the day after the last dose. It is quite possible t h a t the r h y t h m disorder in this instance was a manifestation of an additive effect to t h a t of q u i n i d i n e and/or t oxi ci t y associated with an excessive s e r um concentration of disopyramide. 7 However, as in t he case of quinidine, we have no reason to believe t h a t toxic s e r u m c o n c e n t r a t i o n s of d i s o p y r a m i d e a r e a n e c e s s a r y p r e r e q u i s i t e for t he d e v e l o p m e n t of v e n t ricu lar a r r h y t h m i a s . Both patients were also on digoxin at the time of development of t he i r v e n t r i c u l a r a r r h y t h m i a s . K o s t e r and Wellens ~ have described similar r h y t h m disturbances as a r e s u l t of quinidine t r e a t m e n t w i t hout digoxin. Since t h e m e c h a n i s m of di s opyr a m i de r e l a t e d v e n t r i c u l a r a r r h y t h m i a s is probably similar to those induced by quinidine, we have no reason to believe t h a t the concommitant use of digoxin in our patients played a significant role in the development of these a r r h y t h m i a s . These cases illustrate several i m p o r t a n t points. First, t h e y provide f u r t h e r documentation of this p o t e n t i a l l y l e t h a l side-effect of d i s o p y r a m i d e t r e a t m e n t . Second, patients who experienced vent ri c u lar a r r h y t h m i a s or syncope as a result of quinidine t r e a t m e n t m a y be likely to develop the same complication during disopyramide t h e r a p y and possibly the reverse also applies. Third, vent ri c u lar a r r h y t h m i a s exacerbated by quinidine should not be t r e a t e d with disopyramide. Finally, the occurrence of torsade de pointes vent r i c ular tachycardia against a background of long QT or QU interval and a n t i a r r h y t h m i c or other drug

t h e r a p y should alert the clinician to the possibility t h a t the a r r h y t h m i a m a y be drug-induced, irrespective of w h e t h e r the phenomenon has been reported previously with any particular drug.

REFERENCES 1. A seminar on Norpace (disopyramide phosphate)--a new antiarrhythmic agent. Angiology 26:65, 1975 2. KOCH-WESER,J: Disopyramide. New Engl J Med 300:957, 1979 3. DANILO,P, HURDOF,A J AND ROSEN,M R: Effects of disopyramide on electrophysiologic properties of canine Purkinje fibers. J Pharmacol Exp Ther 201:701, 1977 4. Kus, T AND SASYNIUK,B I: Electrophysiological actions of disopyramide phosphate on canine ventricular muscle and Purkinje fibers. Circ Res 37:844, 1975 5. SELTZER,A AND WRAY,H W: Quinidine syncope. Paroxysmal ventricular fibrillation occurring during treatment of chronic atrial arrhythmias. Circulation 30:17, 1964 6. KOSTER, R W AND WELLENS, H J J: Quinidineinduced ventricular flutter and fibrillation without digitalis therapy. Am J Cardiol 38:519, 1976 7. MELTZER,R S, ROBERT, E W, MCMORROW, M AND MARTIN, P P: Atypical ventricular tachycardia as a manifestation of disopyramide toxicity. Am J Cardiol 42:1049, 1978 8. NICHOLSON,W J, MARTIN, C E, GRACEY,J G AND KNOCH, H R: Disopyramide-induced ventricular fibrillation. Am J Cardiol 43:1053, 1979 9. DESSERTENNE, F: La tachycardie ventriculaire a deux foyers opposes variables. Arch Mal Coeur 59:263, 1966 10. SCLAROVKSY,S, STRASBERG, B, LEWIN, R F AND AGMON, J: Polymorphous ventricular tachycardia: Clinical features and treatment. Am J Cardiol 44:339, 1979 11. KRIKLER, D M AND CURRY, P V L: Torsade de pointes, an atypical ventricular tachycardia. Brit Heart J 38:117, 1976 12. KOSSMANN,C E: Torsade de pointes: an addition to the nosography of ventricular tachycardia. Am J Cardiol 42:1054, 1978 13. HAN, J AND GOEL, B S: Electrophysiologic precursors of ventricular tachyarrhythmias. Arch Int Med 129:749, 1972 14. WATANABE,Y AND TODA,H: The U wave and aberrant intraventricular conduction. Further evidence of the Purkinje repolarization theory on the genesis of the U wave. Am J Cardiol 41:23, 1978 15. HAN, J, MILLET, D, CHIZZONITTI,B AND MOE, G K: Temporal dispersion of excitability in the atrium and ventricle as a function of heart rate. Am Heart J 71:481, 1966 J. ELECTROCARDIOLOGY, VOL. 14, NO. 3, 1981

VENTRICULAR TACHYCARDIA WITH DISOPYRAMIDE

16. PENNINGTON,J E, TAYLOR, J AND LOWN, B: Chest thump for reverting ventricular tachycardia. N Engl J Med 283:1192, 1970 17. AUTENRIETH, G, SURAWICZ, B, KUO, C S AND ARITA, M: Primary T-wave abnormalities caused by uniform and regional shortening of ventricular monophasic action potential in dog. Circulation 51:668, 1975 18. HOFFMAN, B F AND CRANEFIELD, P F: Electrophysiology of the Heart. Futura, Mount Kosco,

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New York, 1976, p 180 19. MIRRO, M J, WATANABE, A M AND BAILEY, J C: Electrophysiological effects of disopyramide and quinidine on guinea pig atria and canine cardiac Purkinje fibers. Circ Res 46:5, 1980 20. STORSTEIN,O: Syncope and sudden death as a side effect of treatment with antiarrhythmic drugs. In Symposium on Cardiac Arrhythmias, E SANDOE, E FLENSTED-JENSEN and K H OLESEN, eds. A B Astra, Sodertalje, Sweden, 1970, p 505