The treatment of quinidine-induced ventricular fibrillation by closed-chest resuscitation and external defibrillation

Clinic al communications

The tre&ment of quinidine-induced ventricular by closed-chest resuscita#ion external de#kiktion

fibriktion and

C. R. Rainier-Pope, M.B., M.Med. (Cupe Town), D. C.H. (Lond.) V. Schrire, M.Sc., Ph.D., M.B. (Cape Town), M.R.C.P. (Lond.), F.R.C.P.E. W. Beck, M.Sc., M.Med. (Cape Town), M.R.C.P. (Lond.) C. N. Barnard, M.D., M.Med. (Cape Town), M.S., Ph.D. (Minnesota) Cape Town, South Africa

V

entricular fibrillation is probably the cause of sudden death in at least half the patients who die of ischemic heart disease,l and may well be the most common termination in many other conditions. At one time, ventricular fibrillation was regarded as always being terminal, but it is now known, both from experimental work2 and clinical experience,3-6 that spontaneous recovery can occur, particularly in patients with complete heart block.7-s If recognized early, means can be taken to correct this otherwise fatal arrhythmia.*JO-l3 Ventricular fibrillation can be accidentally induced, as in electric shock or during cardiac catheterization. There are also a number of drugs, such as chloroform, cyclopropane, digitalis, adrenaline, acetylcholine, benzene, and veratrum alkaloids, which are fibrillatory agents. Potassium chloride and cooling can also produce ventricular fibrillation. Quinidine rarely causes accidentally induced ventricular fibrillation, although it has been implicated in several cases.r4J6 From

Quinidine is well recognized in the treatment of atria1 fibrillation, because of its ability to decrease myocardial excitability.16J7 Thus, it is paradoxical that occasionally it can produce a serious arrhythmia, whereas in therapeutic amounts it is used in the management of arrhythmias. Until recently, ventricular fibrillation has been treated by open thoracotomy, cardiac massage, and direct defibrillation,‘O with increasing success. The pathology has usually been ascribed to coronary vascular disease, although this need not be gross.18-20 Many patients who die suddenly because of coronary occlusion have intact myocardiums at necropsy.21 With the development of external cardiac massage,zz and external defibrillation,23 it is now possible to restore the rhythm and to resuscitate the patient by external means on1y.24-26 The purpose of this paper is to describe two patients who had very numerous attacks of ventricular flutter and ventricular fibrillation due to quinidine. Closed-

the Departments of Medicine and Surgery and the Council for Scientific monary Research Group, University of Cape Town, and the Cardiac Clinic, South Africa. The expenses of this work have been defrayed by grants received from the Council and the City Council of Cape Town. Received for publication Oct. 9, 1961.

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chest resuscitation and external defibrillation was completely successful in one patient. The other died some time after control of the arrhythmia. Case reports Case 1. V. L., a dl-year-old white woman, had developed valvular disease of the heart at the age of 6 years, after an attack of rheumatic fever. At school she did not take part in games, and when she was 17, she presented with subacute bacterial endocarditis and a soft, apical systolic murmur. She had three subsequent attacks of bacterial endocarditis; all were proved by positive blood cultures and responded to therapy. Cesarean section was performed when she was 21 years old, and she was sterilized because of severe mitral incompetence. In December, 19.57, after the recurrence of rheumatic fever, atria1 fibrillation developed; with this, her effort tolerance diminished progressively, so that admission for treatment of congestive cardiac failure was necessary. Surgical repair of gross mitral incompetence by means of an annuloplasty was performed as described elsewhere,*’ with an excellent immediate result. Within a fortnight of the operation, atria1 fibrillation was restored to sinus rhythm with moderate doses of quinidine (30 grains in 10 hours), and she was discharged on a maintenance dose of 18 grains daily; digitalis was continued. A month after the operation, 5 days after quinidine was stopped, atria1 fibrillation recurred, and correction with quinidine again was successful. The maintenance dose was increased to 6 grains four times a day, which was tolerated without symptoms. Sinus rhythm was maintained for 19 months after the operation, but during this period, signs of mitral incompetence gradually returned and increased. A gastrointestinal infection precipitated her into congestive cardiac failure with rapid atria1 fibrillation. Hospitalization for control of the heart failure with digitalis and diuretics was once more necessary. She was then given our usual course of quinidine (6 grains every 2 hours, for 5 doses), with electrocardiographic control before each dose; this course was without success and without toxicity. The following day she received 9 grains every 2 hours for 5 doses; the last dose was given at 9 P.M., and again there was no clinical or undue electrocardiographic effect, and no signs of cinchonism. Three and a half hours later she suddenly collapsed and became pulseless, but recovered spontaneously. The electrocardiographic tracing showed atria1 fibrillation, runs of paroxysmal ventricular ectopic beats, and ventricular flutter. Half an hour later she developed a second Stokes-Adams attack; ventricular fibrillation was recorded. This was treated by external cardiac massage with a return of pulse and spontaneous restoration to atria1 fibrillation. Thereafter, at frequent intervals, numerous paroxysms of ventricular flutter and ventricular fibrillation occurred (Fig. 1). Syncope was always associated with ventricular fibrillation. During the ventricular flutter, which generally preceded ventricular fibrillation, the patient was able to predict the onset of the Stokes-Adams attack. This gave sufficient time to prepare for cardiac massage. W’hen the arrhythmia

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ceased, there was immediate return of consciousness; Molar lactate, 240 c.c., was infused intravenously, with no appreciable effect. Continuous electrocardiographic monitoring recorded numerous attacks of ventricular flutter/fibrillation, which sometimes subsided spontaneously (Fig. 1) and sometimes required external cardiac massage before coordinated ventricular contraction was restored. After 8 hours a Morris internal defibrillator was attached and used externally. By this time the attacks of ventricular fibrillation had become more prolonged and were no longer reverted by external cardiac massage. Despite this the frequency of the attacks increased. Ventricular flutter became the dominant rhythm disturbance. As a desperate measure, procaine amide was administered; 100 milligrams was infused intravenously and repeated at lo-minute intervals for a total of 3 doses. Thereafter the attacks became much less frequent and were ultimately abolished. Hypotension developed and was initially controlled by an infusion of noradrenaline. The blood pressure, however, could not be maintained in spite of increased doses of noradrenaline, and consciousness was lost for the first time. Finally, respiration was assisted by an endotracheal tube and a Bennet respirator. Cardiac standstill developed 28 hours after the first attack of ventricular fibrillation. In all, she had 50 attacks of ventricular flutter, 25 of alternating flutter fibrillation, and 15 of ventricular fibrillation; thus, a total of 90 episodes was recorded. Many more short attacks were not recorded. At necropsy, mitral valve disease (incompetence), left ventricular hypertrophy, and signs of chronic venous congestion were present. Histology showed that there were no active rheumatic lesions. There was slight myocardial and subendocardial fibrosis in the region of the mitral valve. Case 2. H. M., a 28-year-old white woman, developed valvular disease of the heart at the age of 9 years, after an attack of rheumatic fever. At 21, a recurrence aggravated her condition and was followed by symptoms, although she was able to go through a normal pregnancy when she was 2.5. Atria1 fibrillation probably developed shortly after the pregnancy, and her symptoms slowly progressed thereafter. Despite full cardiac therapy she became completely disabled from chronic heart failure. The signs were those of gross mitral and tricuspid incompetence, atria1 fibrillation, and congestive heart failure. Surgical repair of. the mitral incompetence with a baffle was carried out on April 13, 1961, as described elsewhere.28 The initial response to the operation was excellent. The postoperative course was uneventful, and there was improvement in the mitral and tricuspid incompetence. Two weeks after the operation, after a test dose, 6 grains of quinidine was administered at 2-hour intervals for 5 doses in an attempt to correct the atria1 fibrillation. Conversion to sinus rhythm did not occur nor were there any signs of toxicity clinically or electrocardiographically. On the following day, 9 grains every 2 hours for 5 doses were given again without effect. Three hours after the last dose the patient complained of giddiness and nausea. She was found to be pale, shocked, and hypotensive. The electro-

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Fig. 1. The ventricular cessation of fifth tracing

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top tracing shows a paroxysm of ventricular flutter at 170 per minute. The second tracing shows flutter/fibrillation. The third shows ventricular fibrillation, and the fourth shows spontaneous an attack of flutter fibrillation, atria1 fibrillation with ventricular ectopic beats being restored. The was taken preterminally and shows atria1 standstill with slow ventricular rhythm.

cardiogram showed marked quinidine effect with many aberrantly conducted beats or ventricular ectopic beats. Molar lactate, 120 cc., was infused intravenously, with apparent improvement and return of the blood pressure. Three hours later, shock and hypotension recurred and the electrocardiogram showed atria1 fibrillation with numerous ectopic beats and small paroxysms of ventricular tachycardia, indicative of extremely irritable ventricles (Fig. 2). Shortly thereafter she developed a Stokes-Adams attack which was treated by external cardiac massage and mouth-to-mouth breathing. An intravenous drip of 240 C.C.of molar lactate was begun immediately. The patient was completely conscious, with no objective abnormality after the attack. Continuous electrocardiographic monitoring was instituted, and 3 hours later, ventricular hbrillation recurred, associated with a Stokes-Adams attack. External cardiac massage was again SUCCPSSful in terminating the arrhythmia.

It soon became evident that the appearance of fairly regular ventricular ectopic beats heralded the onset of an attack. After the first few StokesAdams attacks, external cardiac massage could no longer terminate the arrhythmia, so that external defibrillation with a Morris external defibrillator became necessary. The appearance of ventricular ectopic beats accurately predicted an impending attack of ventricular flutter or fibrillation, so that the resuscitation team could control each attack at its onset. Consciousness was lost shortly after the onset of flutter or fibrillation (Fig. 2). The patient herself was often able to anticipate an attack when she became aware of the ventricular ectopic beats. As soon as ventricular flutter or fibrillation began, external cardiac massage was instituted and oxygen was administered by an anesthetist. If the attack did not subside immediately, external defibrillation was employed. During the succeeding 6 hours, three intramuscular injections of 10 cc. of 20 per cent

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magnesium sulfate, 120 C.C.of molar lactate, 100 mg. of intravenous hydrocortisone, and 1 Gm. of potassium chloride by slow intravenous drip were given without any apparent effect. It was found that small shocks merely controlled the individual attacks of ventricular fibrillation, but the attacks would then come on at more frequent intervals. With the application of shocks larger than necessary to control the immediate attack, the intervals between episodes of ventricular fibrillation became more prolonged. In all, 10 attacks of ventricular flutter, 2 of flutter fibrillation, and 2 of fibrillation, totalling 14 attacks, were recorded, all associated with syncope. During each attack, coronary and cerebral circulation was adequately maintained by closed-chest massage, and the arrhythmia was terminated by electrical defibrillation. A pacemaker was never required. Fourteen hours after the onset, the paroxysmal arrhythmia disappeared and sinus rhythm was restored. Over the ensuing 18 hours, atria1 fibrillation returned. No further attempts at correction were made. Postoperative recovery was satisfactory. Six months later she was remarkably well and was asymptomatic, living a full, normal life. There appeared to be no permanent damage produced by the recurrent episodes of ventricular fibrillation or by the defibrillation. Discussion

These two patients are extraordinary because of the number of attacks of ventricular flutter and ventricular fibrillation that they had. There were at least 90 episodes in the first subject, and at least 14

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in the second. In both the arrhythmia was ultimately controlled. Spontaneous defibrillation can occur in small animals and dogs,2 but ventricular fibrillation is generally fatal in the higher mammals. Although rare, spontaneous defibrillation has been encountered in man,3-6,2g and occurred in both our patients on several occasions. As a rule, however, ventricular flutter and fibrillation are cardiac disturbances from which the heart seldom recovers on its own. Until recently, the accepted method of restoring the heart after cardiac standstill or fibrillation was to open the chest and massage the heart directly, and then later defibrillate electrically if spontaneous recovery did not occur .l” Thoracotomy, however, has been a most serious drawback, since few physicians can embark on this procedure in a consulting room, and most would think twice before doing it in the medical ward, even though the practicality of this procedure has been reported.18J0JiJ2 The introduction of external defibrillation, first by ZolP and later by Kouwenhovenn in 19.57, is obviously far more satisfactory than thoracotomy and cardiac massage, if the apparatus is at hand. The problem,

Fig. 2. The top tracing was taken just prior to the first Stokes-Adams attack and shows atria1 fibrillation, right bundle branch block, and small paroxysms of ventricular tachycardia (flutter). The second tracing is extracted from a paroxysm of ventricular fibrillation. The third shows a paroxysm of ventricular flutter just after the onset. Two shocks were required to restore the basic rhythm (atria1 fibrillation).

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however, is the maintenance of cerebral and coronary circulation until defibrillation can be carried out. The heart will remain viable up to an hour, but in order to function as a hydrostatic pump it must be adequately oxygenated.11v33 Defibrillation will be successful up to 3 to 4 minutes,” but, if successful thereafter, restoration of an adequate circulation with a normal blood pressure seldom occurs. Intracardiac injection of adrenaline or intra-arterial infusion of 5 per cent glucose and 1 to 2 milligrams of adrenaIine” have been tried to restore the circulation. In June, 1960, Kouwenhoven and associates,22 from the Johns Hopkins Hospital, published a method of closed-chest massage in man, though apparently this method had been known experimentally to the Russians since 1945.33 This method will maintain an adequate circulation until electrical defibrillation can be instituted and adequate cardiac function restored. The method is now frequently used with success24,26m34and has even been reviewed in the lay press.36 In regard to the patients reported on here, the one died ultimately of cardiac standstill after prolonged hypotension but not of ventricular fibrillation, and the other recovered completely. External cardiac massage was easy to perform on both patients and immediately restored the pulse and circulation. When the coronary blood supply is improved, the heart stands a better chance of reverting spontaneously to normal rhythm. Moreover, the procedure allowed sufficient time for the necessary resuscitation equipment and staff to be assembled to deal with the situation. The external defibrillator was very effective in ending the arrhythmia, and cardiac standstill was only momentary, so that spontaneous ventricular function was soon restored. The resuscitative procedures were so effective that, even though our first patient had over 90 attacks, and the second had more than 14, no cerebral or cardiac damage developed during the period of the arrhythmias. Quinine was first used in cardiology by Wenckebach.36 This was later replaced by quinidine as a more effective drug.37 Quinidine is used to prevent or abolish cardiac arrhythmias, because of its ability

Am. Heart I. May, 1962

to depress myocardial excitability.16,17 In spite of its wide range of usefulness, however, it can be very toxic. Its toxicity is unpredictable, and even though a careful watch is kept on plasma quinidine concentrations and regular electrocardiograms, toxicity may still occur. Quinidine is used primarily in the treatment of patients with organic cardiac disease, often severe, and these patients are prone to unpredictable accidents even when quinidine is not given.” Severe myocardial toxicity is manifested by frequent extrasystoles (or aberration), prolongation of the QRS, and sinoatrial or complete A-V block, ventricular tachycardia, and ventricular fibrillation. Marked hypotension and cardiac standstill may also occur. Routine electrocardiographic monitoring before each dose is generally advised but, as is well demonstrated in our two patients, may be of no value at all in preventing toxic manifestations. In one of our patients the StokesAdams attack was the first manifestation of toxicity, whereas in the other, numerous ventricular ectopic beats appeared just before the first Stokes-Adams attack. Once the arrhythmia was established, however, continuous electrocardiographic monitoring was invaluable in treatment and control. The onset of a fresh paroxysm of fibrillation could be accurately predicted by the appearance of ventricular ectopic beats, and appropriate measures applied. Ventricular tachycardia has been frequently reported as a manifestation of quinidine toxicity,14,i6,2g,38-42 although, at the same time, quinidine is often the treatment of choice for this arrhythmia. The diagnosis of paroxysmal ventricular tachycardia must be made with great care,43 however, and cannot be substantiated unless evidence of atria1 activity can be demonstrated either on the electrocardiogram or the phonocardiogram.44 Quinidine is known to increase the conductivity of the A-V node, and, for this reason, digitalization is always recommended prior to treatment of atria1 fibrillation with quinidine. The atria1 rate is slowed, conduction across the A-V node increased, and, as a result, one-to-one conduction may occur. At fast rates, aberration is frequently present, so that a one-to-one rhythm with bundle branch block appears (Fig. 3). Nonethe-

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less, authentic cases of paroxysmal ventricular tachycardia undoubtedly occur, although probably far less frequently than the reports would indicate. Sudden death as a result of quinidine therapy was reviewed by Thomson46 in 1956. He noted that in the vast majority of cases in which necropsy was performed no cause for the sudden death could be found, and, thus, quinidine was implicated. Ventricular fibrillation due to quinidine may have been the cause of death, but this has been reported in the literature with extreme rarity. Kalmansohn and Sampson,46 in a footnote, reported two cases of ventricular fibrillation which occurred during quinidine therapy in 1950. These cases occurred with low doses of the drug. A case each of ventricular fibrillation which occurred after quinidine was reported by Davis and Sprague4* and by Acierno and Grubner.15 In several other patients, ventricular fibrillation has been noted after quinidine, but the drug could not be implicated solely, since these patients had coronary heart disease4’ or heart block.7~48~4g The infrequent reports of ventricular fibrillation due to quinidine therapy is surprising in that, experimentally, quinidine readily produces ventricular fibrillation in animals.50-5z Ventricular fibrillation occurred in both our patients, and there are probably many more instances, but unless electrocardiograms are recorded at the time of death, the arrhythmia will be missed. Ventricular fibrillation is probably the common cause of sudden death during quinidine therapy. Treatment of quinidine toxicity” is primarily the cessation of the drug. The peak concentration of serum quinidine occurs 2 to 4 hours after a single oral dose. The disappearance from the serum follows an exponential decay curve and less than 10 per cent remains after 24 hours.53 After repetitive doses, approximately 40 per cent remains 12 hours after the last dose. Thus, it is apparent that simply tiding the patient over the first acute toxicity should be all that is necessary. With the metabolic detoxification of the drug, recovery occurs rapidly. It is, however, the short period of severe toxicity that is the major problem. Marked toxic symptoms, such as tinnitus and nausea, can be treated with sedatives

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Fig. 3. At first glance, the rhythm disturbance appears to be paroxysmal ventricular tachycardia. However, P waves can be detected in some of the leads at 190 per minute preceding each QRS complex. Quinidine has slowed the atria1 rate, but when one-to-one conduction occurs, aberration with right bundle branch block develops. In the tracing second from the bottom, one-to-one conduction has spontaneously changed to two-to-one conduction; the ventricular rate is halved to 95 per minute. The third beat is one-to-one conducted, hence the aberration. The bottom tracing shows normal venricular conduction with two-to-one block.

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or antihistaminics and there is seldom any cause for alarm. The severe cardiotoxic effects of quinidine are much more serious, and there is no specific antidotal agent that hastens the metabolic breakdown of the drug. A number of drugs have been tried in the treatment of quinidine toxicity. Adrenaline, noradrenaline, caffeine, acetylcholine, ephedrine, and phenylephrine have all been tested experimentally.64*66 Adrenaline and phenylephrine appear to be the most satisfactory, especially as pressor agents. However, Bellet and associates@ ‘have shown that molar lactate can reverse the cardiotoxic and hypotensive effects of quinidine in dogs. This was observed repeatedly in their experiments. Apparently, molar lactate decreases the concentration of quinidine, decreases serum potassium, and shifts the pH to the alkaline side. Bailey6’ used molar lactate very successfully in two patients. In regard to the patients reported on here, each was given full doses of molar lactate with no appreciable decrease in the frequency of the attacks of ventricular fibrillation. Apart from the cardiotoxic effects of quinidine, the hypotension is also reported to be relieved by molar lactate66; a rise in blood pressure follows very closely an improvement in the electrocardiogram. However, this is less likely to occur when the toxicity is severe, with prolonged and severe hypotension. In such cases, the response to adrenergic drugs is also poor. In our first patient, hypotension developed after procaine amide. The hypotensive effects of this drug are well recognized.68 These effects are most pronounced in patients with diseased hearts. Molar lactate, which acts in the same way as it does in quinidine toxicity, is advocated in the treatment of the hypotension produced by procaine amide. 6g It would seem that the progressive and subsequently irreversible hypotension this patient developed was due to a summation of effects due to procaine amide, quinidine, and a certain degree of cardiac and cerebral anoxia, which must have developed after so many attacks of ventricular fibrillation. It must be noted, however, that after procaine amide no additional attacks of ventricular fibrillation occurred.

In complete heart block, transient ventricular fibrillation or flutter is not an uncommon cause of syncope (Stokes-Adams attack), as has been well known for many years.8*g*44 These attacks are self limited and usually tend to end spontaneously. They do not carry quite the same ominous prognosis as does ventricular fibrilIation due to other causes. Quinidine and Pronestyl therapy is contraindicated in this condition,g*as60 but external defibrillation may be necessary. Ventricular fibrillation induced by quinidine has been reported in complete heart block, but, in view of the frequent association without this drug, care must be taken in attributing this arrhythmia to quinidine. Summary 1. Two patients who had numerous repetitive attacks of paroxysmal ventricular flutter and fibrillation due to quinidine are reported upon. 2. The arrhythmia was controlled by external cardiac massage and external electrical defibrillation. 3. One patient survived after at least 14 paroxysms: the other died of cardiac standstill after over 90 paroxysms. 4. The treatment of ventricular fibrillation by external cardiac massage and defibrillation is discussed and reviewed. 5. The incidence of quinidine-induced ventricular tachycardia and fibrillation is reviewed and the treatment discussed. Addendum Since this was written, tered a third patient! Stokes-Adams attacks fibrillation induced by minated by external chest. We wish

to

thank

the

we have encounwho developed two due to ventricular quinidine and terpummeling of the Anesthetic

Department

for their assistance in the treatment, and the hospital superintendent, Dr. J. Burger, for permission to publish. REFERENCES

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4. Beck, C. S., Pritchard, W. H., and Kiel, H.: Ventricular fibrillation of long duration abolished by electric shock, J.A.M.A. 135:985, 1947. 5. Schwartz, S. P., Arloff, J., and Fox, C.: Transient ventricular fibrillation, AM. HEART J. 37:21,

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