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Postgraduate Medical Journal (November 1979) 55, 832-835 Postgrad Med J: first published as 10.1136/pgmj.55.649.832 on 1 November 1979. Downloaded from

Iatrogenic 'torsade de pointes' ventricular NICHOLAS G. KOUNIS M.D. Chest Branch, East Birmingham Hospital, Birmingham, England

Summary (Krikler and Curry, 1976) myocardial ischaemia Three patients who developed a distinctive form of (Prinzmetal's variant , ), with oscillating QRS axis, electrolytic deficits (hypokalaemia, hypomagnes- while they were receiving drugs known to prolong aemia), acquired disease (, coron- the time are described. In one of the ary arteriosclerosis), slow basic rhythm (sino-atrial patients suffering from psychiatric illness and receiving disease, high degree AV block), electrical ventricular psychotropic drugs the was fatal. It is stimulation and congenital disorders with deafness postulated that the tendency to this arrhythmia was (Jervell-Lange-Nielsen syndrome, Romano-Ward- augmented by repeated electric counter shocks and Barlow syndrome) with apparent (or only after negative bathmotropic drugs. Functional factors may exercise as a forme fruste) QT prolongation (Bernuth contribute to the pathogenesis ofthis arrhythmia which et al., 1973). seems to constitute an entity. The following report emphasizes the iatrogenicProtected by copyright. nature of the arrhythmia which can have a fatal Introduction outcome. Paroxysmal ventricular tachycardia in which the QRS axis oscillates over runs of 3 to 20 beats with Case reports definite changes in the direction has been recently Patient I recognized as the result of pharmacological overdose A 68-year-old man was admitted for investigation or side effects of certain drugs (Fazzini, Marchi of his fainting attacks. He had suffered from chronic and Pucci, 1973, 1975; Krikler and Curry, 1976a, bronchitis for 10 years and had had a myocardial b). This arrhythmia constitutes a distinctive type of infarction 2 years before. His fainting attacks started ventricular tachycardia with the accepted term from 2 months before admission when the only medication the French literature of torsade de pointes ventricular was prenylamine lactate tablets 60 mg thrice daily tachycardia (Krikler and Curry, 1976a, b). It is for his angina. A general practitioner who examined caused by prolonged myocardial repolarization time him during one of these episodes, prescribed slow manifested by prolongation of QT or QU interval release isoprenaline tablets 30mg thrice daily http://pmj.bmj.com/ (Bens et al., 1973; Fazzini et al., 1975), which favours because of his slow following the episode. a state of asynchronous depolarization (Han et al., Although prenylamine had been discontinued, the 1966) and encourages re-entry processes (Raynaud patient continued to have fainting attacks (more et al., 1969; Evans et al., 1976). often now, 3 to 4 times daily) while he was taking The drugs which, so far, have been implicated to isoprenaline for the next 7 days. On admission and induce torsade de pointes ventricular tachycardia during a routine electrocardiogram he fainted owing are cardioactive agents such as (Rainier- to runs of torsade de pointes ventricular tachycardia Pope et al., 1962; Seizer and Wray, 1964), procain- (Fig. 1). The ECG revealed prolonged Q-T interval on September 26, 2021 by guest. amide (McCord and Taguchi, 1951; Castellanos and (QTc 0.75 s), increased ventricular ectopic activity Salhanick, 1967), and lignocaine (Krikler and and prominent U waves. Successive treatment with Curry, 1976a), antianginal drugs such as prenyl- bolus lignocaine, followed by intravenous infusion, amine (Puritz et al., 1977) and (Bens quinidine sulphate tablets 200 mg 4 times daily, et al., 1973), psychotropic agents (Fowler et al., and repeated (18) DC countershocks, although 1976), such as phenothiazines (, initially successful, seemed to worsen the condition , trifluoperazine, ) and and made the episodes more frequent. Chest X-ray, tricyclic antidepressants (amitriptyline, imipramine, ECG electrolytes and urinary catecholamines were protriptiline, nortriptyline,) diuretics, corticosteroids normal. Cardiac screening revealed systolic expan- and glycyrrhizin (Bens et al., 1973), which induce sion at cardiac apex consistent with a ventricular hypokalaemia. Torsade de pointes can complicate aneurysm. Electrophysiological studies showed 0032-5473/79/1100-0832 $02.00 ( 1979 The Fellowship of Postgraduate Medicine Case reports 833 Postgrad Med J: first published as 10.1136/pgmj.55.649.832 on 1 November 1979. Downloaded from

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FIG. 1. Routine electrocardiogram showing torsade de pointes in leads III and V2. Protected by copyright. prolonged repolarization time, increased ventricular countershocks aggravated the situation. Transvenous ectopic activity to stimuli during the refractory ventricular pacing was introduced but it provoked period and normal SA and AV nodal studies. The ventricular tachycardia culminating in ventricular arrhythmia finally was suppressed with mexiletine which did not respond to DC counter- without any sequelae. shocks and the patient died. Post-mortem examina- tion revealed no gross or microscopic cardiac Patient 2 abnormality and histology of the conducting A 63-year-old woman with a 10-year history of system showed normal SA and AV nodes with depression was admitted to hospital after an normal common and bifurcated bundle of His. episode of . The patient was receiving thioridazine hydrochloride tablets 50 mg 4 times Patient 3 daily and amitriptyline hydrochloride tablets 25 A 51-year-old man was admitted to hospital with mg thrice daily at the time of syncope. She gave a severe retrosternal pain and a diagnosis of antero- 2-year history of syncopal attacks but these were septal myocardial infarction was made. The patient http://pmj.bmj.com/ thought to be due to vertebro-basilar insufficiency. was taking, at the time of admission, prednisolone There was no past history of cardiac disease. On tablets 5 mg daily for his bronchial asthma and admission, a routine ECG (Fig. 2) revealed markedly frusemide 40 mg daily for congestive cardiac failure. prolonged Q-T interval (QTc 0'80 s). Clinical exam- The prednisolone tablets had been taken contin- ination revealed no abnormality. Chest X-ray, uously for the last 5 years and the frusemide tablets electrolytes, cardiac enzymes, echocardiogram, for the last one year. Two hours after admission he plasma cortisol and peripheral blood counts were developed acute left ventricular failure and he was on September 26, 2021 by guest. normal. Two days after admission she experienced treated with frusemide 80 mg i.v. and venesection. 2 syncopal attacks accompanied by weakness, He improved thereafter but the following day he dizziness, nausea and vomiting. Electrocardiographic developed 18 episodes of ventricular tachycardia monitoring revealed runs of ventricular tachycardia resembling the torsade de pointes. The plasma resembling the torsade de pointes form. A bolus potassium was 3 mmol/l on admission and 2-8 injection of 100 mg of lignocaine abolished the mmol/l the following day during the attacks of , but while she was on lignocaine infusion arrhythmia. Careful examination of his ECG the arrhythmia reappeared. Treatment with procain- showed accentuation and QT and QU amide hydrochloride 500 mg 4 times daily did not prolongation (QTc 0.78 s). Chest X-ray, echocardio- affect the runs of torsade de pointes and it looked gram, plasma cortisol, urinary potassium excretion likely that quinidine and repeated direct current and peripheral blood counts were normal. His Postgrad Med J: first published as 10.1136/pgmj.55.649.832 on 1 November 1979. Downloaded from Case reports

FIG. 2. Electrocardiogram showing marked prolongation of Q-T interval in patient 2. Protected by copyright. arrhythmia was successfully treated with lignocaine with meperidine, hydroxyzine, atropine, morphine and the hypokalaemia with potassium chloride in- and curare and during treatment with trifluoperazine fusion (64 mmol in 24 hr) and spironolactone (Reynolds and Vander Ark, 1976), ventricular tablets 25 mg 4 times daily. No further sequelae arrhythmias have appeared during the transient were noticed during his stay in hospital and after prolongation of QT interval, but they did not his discharge. recur when the QT interval became normal. The long QT interval and the arrhythmias disappeared when Discussion the drug was discontinued. The cases described developed repeated attacks Electrolytic disturbance and especially hypo- of ventricular tachycardia while receiving anti- kalaemia increases the ectopic activity and decreases anginal, psychotropic, inducing hypokalaemia and the conduction velocity in AV node (Curry et al., negative bathomotropic agents. Two of these 1976). This presumably induced the torsade de patients had suffered from ischaemic heart disease pointes in the third patient. The presence of U http://pmj.bmj.com/ also. In all patients the arrhythmia seemed to be waves in the described patients was due to hypo- aggravated by the repeated direct current counter- kalaemia, phenothiazines and negative batho- shocks. In one of the patients histological examina- motropic drug administration. However, in hypo- tion of the conducting system failed to reveal any calcaemia, which is not associated with ventricular pathological changes. In this patient functional arrhythmias, U waves cannot be identified. In rather than anatomical factors may be implicated. hypocalcaemia the ST segment is flat with delayed This fact underlines the complexity in the patho- onset and end of which occupies a modestly genesis of this arrhythmia. Ventricular arrhythmias increased time interval, if at all (Reynolds and on September 26, 2021 by guest. known as quinidine syncope have long been recog- Vander Ark, 1976). nized (Vico, Marvin and White, 1923; Parkinson The first of the above patients continued to have and Campbell, 1929) in patients suffering, not only torsade de pointes attacks while he was taking slow from coronary heart disease but also from pul- release tablets of isoprenaline hydrochloride. Iso- monary embolism and aortic and mitral valve disease. prenaline shortens the ventricular repolarization Considerable evidence suggests that prolongation of time and thus prevents the state of asynchronous QT interval or the presence of giant U waves is depolarization. While isoprenaline infusion shortens directly related to this type of tachycardia and in the the QT interval (Abildskov, 1976) rapid intravenous presence of normal QT such arrhythmias do not infusion of isoprenaline may prolong it (Yanowitz, occur (Reynolds and Vander Ark, 1976). In patients Preston and Abildskov, 1966). In this patient, with transient hemiparesis following anaesthesia isoprenaline either aggravated the situation (Kounis, Postgrad Med J: first published as 10.1136/pgmj.55.649.832 on 1 November 1979. Downloaded from Case reports 835 1976), or its effect in accelerating the heart rate and tachycardia: a new iatrogenic possibility (annotation). American Heart Journal, 90, 805. shortening the QT interval had been inadequate FOWLER, N.O., MCCALL, D., CHOU, T.C., HOLMES, J.C. (Krikler and Curry, 1976). Isoprenaline and atrial & HAMENSON, I.B. (1976) Electrocardiographic changes pacing have been shown to be of value in the and cardiac arrythmias in patients receiving psychotropic treatment of torsade de pointes (Slama et al., 1973). drugs. American Journal of Cardiology, 37, 223. HAN, J., MILLET, D., CHIZZONITrI, B. & MOE, G.K. (1966) However, a cautious trial is necessary to determine Temporal dispersion of recovery of excitability in atrium whether the rhythm disturbance is improved or and as a function of heart rate. American Heart worsened by isoprenaline (Puritz et al., 1977). Journal, 71, 481. It looks likely that the arrhythmogenicity of the KouNs, N.G. (1976) Torsade de pointes (Letter). British Heart Journal, 39, 338. above drug is due to facilitation of re-entrant excita- KRIKLER, D.M. & CURRY, P.V.L. (1976a) Torsade de pointes, tion as a result of decreased conduction velocity an atypical ventricular tachycardia (Editorial). British and temporal dispersion of the action potentials in Heart Journal, 38, 117. different types of cardiac fibres (Arita and Surawicz, KRIKLER, D. & CURRY, P.V.L. (1976b) Torsade de pointes (Letter). British Heart Journal, 39, 338. 1973). MCCORD, M.C. & TAGUCHI, J.T. (1951) A study of the Although the above described iatrogenic arrhyth- effect of procainamide hydrochloride in supraventricular mia is not frequently encountered, knowledge of arrhythmias. Circulation, 4, 387 its existence should be kept in mind by physicians PARKINSON, J. & CAMPBELL, M. (1929) Quinidine treatment of auricular fibrillation. Quarterly Journal of Medicine, 22, and precautions should always be taken. 281. PURITZ, R., HENDERSON, M.A., BAKER, S.N. & CHAMBERLAIN, D.A. (1977) Ventricular arrythmias caused by prenylamine. British Medical Journal, 4, 608. References RAINIER-POPE, C.R., SCHRITE, V., BECH, W. & BARNARD, C. ABILDSKOV, J.A. (1976) Adrenergic effects on Q-T interval (1962) The treatment of quinidine-induced ventricular of the electrocardiogram. American Heart Journal, 22, 210. fibrillation by closed-chest resuscitation and external ARITA, M. & SURAWICZ, B. (1973) Electrophysiologic aspects defibrillation. American Heart Journal, 63, 582. Protected by copyright. of phenothiazines on canine cardiac fibers. Journal of RAYNAUD, R., BROCHIER, M., NEEL, J.L., FAUCHIER, J.P. Pharmacology and Experimental Therapeutics, 184, 619. & RAYNAUD, P. (1969) Tachycardie ventriculaire a foyer BENS, J.L., BUBOISSET, M., QUIRET, J.C., LESBRE, J.P. & variable et dyskali6mie. Archives des maladies du coeur, BERNASCONI, T. (1973) Syncopes par torsade de pointes des vaisseaux et du sang, 62, 1578. induites ou favoris6es par la prenylamine. Archives des REYNOLDS, E.W. & VANDER ARK, C.R. (1976) Quinidine maladies du roeur, des vaisseaux et du sang, 66, 1427. syncope and the delayed repolarization syndromes. BERNUTH, G. VON, BELZ, G.G., EVERTZ, W. & STANCH, M. Modern Concepts in , 45, 117. (1973) QTU abnormalities, sinus and Adams- SELZER, A. & WRAY, H.W. (1964) Quinidine syncope. Stokes attacks due to ventricular tachyarrhythmia. Paroxysmal occurring during Acta paediatrica scandinavica, 62, 675. treatment of chronic atrial arrhythmias. Circulation, 30, 17. CASTELLANOS, A. & SALHANICK, L. (1967) Electrocardio- SLAMA, R., COUMEL, P., MOTTE, G., GOURGON, R., WAYN- graphic patterns of procaine amide toxicity. American BERGER, M. & TOUCHE, S. (1973) Tachycardies ventricu- Journal of Medical Science, 253, 52. laires et torsade de pointes: frontieres morphologiques entre CURRY, P., FITCHETT, D., STUBBS, W. & KRIKLER, D. (1976) les dysrhythmies ventriculaires. Archives des maladies Ventricular arrhythmias and hypokalaemia. Lancet, ii, 231. du coeur, des vaisseaux et du sang, 66, 1401. EVANS, T.R., CURRY, P.V.L., FITCHETT, D.H. & KRIKLER, VIco, L.E., MARVIN, A.M. & WHITE, P.D. (1925) Clinical D.M. (1976) "Torsade de pointes" initiated by electrical report of the use of quinidine sulfate. Archives of Internal ventricular stimulation. Journal of Electrocardiology, 9, Medicine, 31, 345. http://pmj.bmj.com/ 255. YANOWITZ, F., PRESTON, J.B. & ABILDSKOV, J.A. (1966) FAZZINI, P.F., MARCHI, F. & Pucci, P. (1973) Q-T lungo, Functional distribution ofright and left stellate innervation syncope e prenilamina. Giornale italiano di cardiologia, 3, of the ventricles: production of neurogenic electrocardio- 233. graphic changes by unilateral alteration of sympathetic FAZZINI, P.F., MARCHI, F. & Pucci, P. (1975) Ventricular tone. Circulation Research, 18, 416. on September 26, 2021 by guest.