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Clinical, electrocardiographic and follow-up observations in patients having ventricular fibrillation during holter monitoring
Clinical, Electrocardiographic and Follow-Up Observations in Patients Having Ventricular Fibrillation During Holter Monitoring Role of Quinidine Therapy
PABLO DENES, MD, FACC ALAN GABSTER, MD SHOEI K. HUANG, MD Chicago, Illinois
From the Section of Cardiology, Department of Medicine, RushPresbyterian St. Luke’s Medical Center, Chicago, Illinois. Manuscript received November 10, 1980; revised manuscript received February 2, 1981, accepted February 11, 1981. Address for reprints: Pablo Denes, MD, Professor of Medicine, Department of Medicine, Rush-Presbyterian St. Luke’s Medical Center, Chicago, Illinois 60612.
Ventricular fibriiiation occurred during Hoiter electrocardiographic monitoring in 5 of 3,307 consecutive patients. Ail five patients had Hoiter studies for evaluation of antiarrhythmic drug therapy; their ages ranged from 51 to 65 years. No patient had acute myocardiai infarction; ail had congestive heart failure and severe left ventricular dysfunction. One patient had ischemic and four had nonischemic cardiomyopathy. Ail patients had recently begun treatment with oral quinidine and had plasma quinidine levels of 1.24 to 5.16 pg/mi. The Hoiter monitoring revealed that ail had a long O-T interval and that ventricular fibriiiation began during frequent ventricular premature beats and was immediateiy preceded by ventricular tachycardia of the torsade de pointes type. The coupling interval of the ventricular premature beats initiating torsade de pointes was late (440 to 720 ms) and followed long preceding cycles (640 to 1920 ms). Ventricular fibriiiation resolved spontaneously in two patients, but two of the remaining three patients died despite attempted cardiopulmonary resuscitation. it is concluded that (1) left ventricular dysfunction, chronic ventricular arrhythmias and initiation of quinidine therapy were the common findings in these patients; (2) a long Q-T interval, late coupled ventricular premature beats and long preceding cycles facilitate initiation of ventricular fibrillation in quinidine-treated patients; and (3) direct on-line monitoring should be utilized in the management of these patients.
Dynamic electrocardiographic (Holter) monitoring is frequently used to evaluate the significance of arrhythmias and conduction disturbances in symptomatic patients and to evaluate response to antiarrhythmic drug therapy.l In a review of published data on patients who died suddenly during Holter monitoring we found eight reported cases.2-6 Two of the eight patients died of bradyarrhythmias, whereas the remaining six had ventricular fibrillation. All six patients had coronary artery disease and none had a long Q-T interval. All episodes of ventricular fibrillation were initiated by early coupled premature ventricular beats resulting in the R on T phenomenon.24 Reviewing 3,307 consecutive Holter records from our laboratory we found five patients in whom ventricular fibrillation resulting in loss of consciousness developed during monitoring. In two patients the arrhythmia resolved spontaneously but two of the remaining three patients died despite attempted cardiopulmonary resuscitation. The clinical, electrocardiographic and Holter monitoring findings in these patients are described. Clinical
Features
of Cases
Clinica! characteristics
(Table I): The five patients included two men and three women ranging in age from 51 to 65 years. All five were
in-patients at the time of the Holter recordings. They were initially hospitalized because of decompensation of congestive heart failure. All
July 1981
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Volume 48
9
VENTFWJLAR
FIBRILLATION ON HOLTER MONlTOf?ING-DENES
ET AL.
patients were in New York Heart Association functional class III to IV7 because of dyspnea or fatigue. Heart disease had first been diagnosed 8 months to 9 years before admission. Two patients had primary myocardial disease, one had rheumatic heart disease and one had hypertensive heart disease. All patients had marked cardiomegaly and significantly depressed ventricular function. All patients were known to have ventricular arrhythmias detected on routine electrocardiography 10 days to 60 months before the Holter monitor test. Complex ventricular arrhythmias (bigeminy, multifocal ventricular premature beats, couplets and salvos) were documented on at least one Holter recording in four of the five patients before initiation of quinidine therapy. Ant&rhythmic drugs (Table II): Antiarrhythmic therapy was initiated to control supraventricular arrhythmias in one patient and ventricular arrhythmias in four patients. Three patients began treatment with quinidine while being monitored in the medical intensive care unit. At the time of Holter recording all patients were on a medical ward without on-line arrhythmia monitoring. Holter monitor recordings were obtained in order to evaluate the results of antiarrhythmic drug therapy. Four patients received quinidine sulfate (0.8 to 2.0 g/day) and one patient had
quinidine gluconate (2.6 g/day). The 1 hour post-dose serum drug levels ranged from 1.24 to 5.18 pg/ml. All patients received long-term digitalis therapy and four had stable plasma digoxin levels of 1.0 to 1.5 ng/ml. In four of the five patients plasma digoxin levels were obtained after the initiation of quinidine therapy. One patient (Case 2) had an elevated plasma digoxin level (3.1 ng/ml) obtained 3 days before the Holter recording; digoxin was withheld for 72 hours in this patient. One patient (Case 3), in addition to digoxin and quinidine also received procainamide and had a peak serum level of 16.4 pg/ml. No other antiarrhythmic drugs were utilized. All patients had normal serum electrolytes within 24 hours of the Holter recording. Electrocardiographic findings (Table III): The last 12 lead electrocardiogram before the Holter recording showed normal sinus rhythm in four patients and atria1 fibrillation in one. The Q-T interval in lead Vs ranged from 360 to 480 ms and the associated R-R intervals from 680 to 1,100ms. The longest Q-T interval in the electrocardiogram ranged from 440 to 500 ms. Two patients had a prolonged interval. Four electrocardiograms showed left ventricular hypertrophy (one showing an old anteroseptal infarct). Ventricular arrhythmias were present in only one electrocardiogram.
TABLE I Clinlcal Findings In Five Cases Congestive Heart Failure
Case
Age (yr) a Sex
Cause of Heart Disease
1
65M
Present
2
64M
3
51F
Coronary artery disease Rheumatic heart disease Primary myocardial disease
4
61F
Present
5
56F
Hypertensive heart disease Primary myocardial disease
Present Present
Present
Ventricular Function A;;izphic 00 Angiographic EF 33% LVEDP 35 mm Ha: cardiac index -’ 1.5 literslmin per m* Nuclear EF 20% Nuclear EF 18%
Documented Arrhythmias on ECG
Duration of Ventricular Arrhythmias
Bigeminy, paired VP0 Multiform VPB
8mo
Multiform and paired VPB Multiform and paired VP0 Multiform VPB
19d 6mo
10d 80 mo
d = days; ECG = electrocardiography: EF = ejection fraction: LVEDP = left ventricular end-diastolic pressure; VPB = ventricular premature beats.
TABLE II Antlarrhythmlc Therapy In Five Cases
l
10
Serum Quinidine Level (1 h/post dose
Digoxin Dose
Serum Digoxin Level
bdmll)
@WW
0W-N
Case
Ouinidine Dose (g/day)
1 :
2.0 0.8 1.2
2.96 5.18 1.24
0.25 0.25
;
2.6 1.6
3.6 1.96
0.125 0.25
l
Digoxin withheld for 72 hours before ventricular fibrillation.
July 1961
The American Journal of CARDIOLOGY
Volume 48
Duration of Quinidine Therapy
(days)
1.0 <3.1 1.3
8 8
1.5 1.1
12 :
VENTFWIJLAR FlSRLLATlON
ON HOLTER MONITOl?INQ-DENES
ET AL.
TABLE III Scalar Electrocardiographic
Flndlngs Before Ventricular Fibrillation
Case
P-R (s)
DBS Duration (s)
Arrhythmia
Time Before Hoher Monitoring (days)
1 3
0.18 0.20
0.09 0.10
840 1100 780
480 400 440
480 (V,) 500 (Ill)
LVH LVH
None None
1 1
4
0.24
0.10
880
360
tt:
g;)
0.28
0.12
900
420
480
W3)
Paired VPB PAB
z
5
Anteroseptal MI LVH, IVCD
(leZTVs) (m@
Longest G-T (ECG lead) (ms)
Diagnosis
3
ECG = electrocardiographic; IVCD = intraventricular conduction defect; LVH = left ventricular hypertrophy; MI = myocardial infarctlon; VPB = ventricular premature beat.
FIGURE 1. Onset of torsade de polntes in Patients 1 (upper) and 3 (lower). Modified leads Vs and VI are shown. Paper speed Is 25 mm/s in this and subsequent Illustrations.
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VENTRICULAR FIBRILLATION ON HOLTER MONITORINGOENES
ET AL.
Holter monitor findings (Table IV): Four patients had sinus rhythm and one had atria1 fibrillation. The Q-T interval, measured in modified lead Vs before the onset of torsade de pointes, ranged from 480 to 680 ms and the associated R-R interval from 640 to 1,080 ms. It is possible that this measurement of the Q-T interval also included the U wave, because separation of T and U waves in the chest bipolar lead recording is uncertain. The Q-T interval was prolonged in all patients. The Holter recordings showed that all five patients had frequent ventricular premature beats with couplets and periods of bigeminy. Most ventricular premature beats had long coupling intervals and there were frequent fusion beats. The onset of torsade de pointes in Case 1 was preceeded by ventricular bigeminy followed by a fusion beat (860 ms). The first beat of the tachycardia had a coupling interval of 640 ms (Fig. 1, top panel). In Case 2 the onset of torsade de pointes was also preceded by ventricular bigeminy followed by a ventricular escape beat (1,320 ms). The first beat of the tachycardia had a coupling interval of 720 ms (Fig. 2, top panel). In Case 3, there was ventricular bigeminy, a short run of ventricular tachycardia followed by a sinus beat (1,460 ms). The first beat of the torsade de pointes had a coupling interval of 440 ms (Fig. 2, bottom panel). In Case 4 both episodes of tachycardia were mixed with frequent ventricular ectopic beats. The first episode occurred during ventricular bigeminy followed by an accelerated ventricular escape beat (840 ms). The coupling interval of the first beat of the polymorphous ventricular tachycardia was 600 ms (Fig. 3, top panel). The second episode was preceded by six polymorphous ventricular ectopic beats at various rates. The onset of torsade de pointes was preceded by an R-R interval of 1,020 ms and the coupling interval of the first beat was 580 ms (Fig. 3, bottom panel). In Case 5, the onset of torsade de pointes was preceded by a run of ventricular tachycardia followed by a sinus beat (1,920 ms). The coupling interval of the first beat was 560 ms (Fig. 4, top panel). There was a long cycle terminated by a sinus beat in two patients (Cases 3 and 5) and by ventricular beats in the remaining three. The coupling interval of the initiating beat ranged from 440 to 720 ms (mean 590). All patients had a syncopal attack associated with the arrhythmia. In two patients reversion to the original
rhythm occurred (atria1 fibrillation in Case 2 and sinus rhythm in Case 5 (Fig. 2 and 4, bottom panels); in the other three patients resuscitative measures were nec-
essary. Cardiopulmonary resuscitation was successful in one patient (Case 1) and unsuccessful in the remaining two patients (Cases 3 and 4). Discussion Clinical and electrocardiographic features: In a retrospective review of all patients undergoing 24 hours of dynamic electrocardiographic monitoring, we found five patients who had syncopal attacks caused by ventricular tachyarrhythmias. Certain clinical and electrocardiographic findings were present in all five cases: (1) All patients had advanced organic heart disease with congestive heart failure, cardiomegaly and marked left ventricular dysfunction. (2) All patients had recently begun therapy with oral quinidine. (3) All patients had Q-T prolongation and frequent multiform ventricular premature beats recorded on Holter monitoring. Torsade de pointes was induced by ventricular premature beats with long coupling intervals and was followed by ventricular fibrillation. (4) A high mortality rate (40 percent) was associated with this syndrome. The previously reported cases of patients who died suddenly because of ventricular fibrillation during Holter monitoring also manifested certain common clinical and electrocardiographic findings2-‘? (1) All patients had coronary artery disease. (2) Frequent multiform ventricular premature beats were recorded on Holter monitoring. The Q-T interval was not prolonged and ventricular fibrillation was always induced by ventricular premature beats that had short coupling resulting in an R on T phenomenon.2-s The findings in these reports differ from our observations in the duration of the Q-T intervals and the coupling intervals of the initiating ventricular premature beats. Mechanism of ventricular fibrillation: Ventricular fibrillation is defined as chaotic asynchronous activation of the ventricles.8 The mechanism of ventricular fibrillation is related to an increased temporal dispersion of refractoriness and delayed activation of ventricular myocardium.g-ll Initiation of ventricular fibrillation may depend on the extent of delayed conduction and dispersion of refractoriness that exists during the predominant rhythm and to the degree that it is affected by premature ventricular beats.
TABLE IV Holter Monltor Flndings Predominant
Case
Rhythm
1
Sinus
2
Atrial fibrillation
3 4 5
Sinus Sinus Sinus
VPB Coupling Intervals (ms)
Q-T (ms)
720
520
520-860
RBBB
1080
560
540-780
RBBB
900 640 820
600 480 680
440-700 440-620 520-800
RBBB -I- LBBB RBBB + LBBB RBBB + LBBB
R-R
DC = direct current; LBBB = left bundle branch block: RBBB = right bundle branch block.
12
July 1981
VPB Configuration
(ms)
The American Journal of CARDIOLOGY
Volume 48
Outcome DC cardioversion Spontaneous termination Death Death Spontaneous termination
VENTRICULAR FIBRILLATION ON HOLTER MONlTORlNG-DENES
On the basis of observations in these Holter monitoring studies we propose that in delayed repolarization syndromes there may be sufficient dispersion of refractoriness and delayed ventricular activation (due to the effect of drugs, electrolyte disturbances, intrinsic heart disease or abnormalities of the central nervous system) that late coupled premature ventricular beats could result in ventricular fibrillation. In the patients who died suddenly from coronary artery disease, early ventricular premature beats were required to achieve a similar degree of inhomogeneity in conduction and refractoriness to initiate ventricular fibrillation. Quinidine syncope: Quinidine syncope and quinidine-related sudden death are manifestations of the same arrhythmia exhibited by our patients.12-21 Published tracings have been labeled as showing ventricular fibrillation, ventricular flutter, ventricular tachycardia,
ET AL.
polymorphous ventricular tachycardia and torsade de pointes.12-21 The incidence of quinidine syncope was reported15 to be 4.4 percent during attempted conversion of atria1 fibrillation or flutter with quinidine. A review20 of published cases of quinidine syncope found an overall mortality rate of 11.5percent. The association between quinidine syncope and concomitant use of a digitalis preparation was amply demonstrated in the past.l5slW2-24 H owever, a more recent reportlg shows occurrence of quinidine syncope in patients who received no digitalis therapy. Toxic manifestations such as cinchonism and widening of the QRS complex are noticeably absent in patients with quinidine syncope.20 However, most patients exhibited a prolonged Q-T interval or a large U wave, or both, in the electrocardiogram.” We noted similar changes in the Holter recordings that showed marked Q-T prolongation and the
FIGURE 2. Case 2. Onset (upper) and spontaneous termination (lower) of ventricular fibrillation.
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Fl9+WATlDN ON HOLTER MONITORINGDENES ET AL.
presence of complex ventricular arrhythmias before the onset of torsade de pointes. The electrocardiograms taken 1 to 5 days before the syncopal episodes did not reveal significant ventricular arrhythmias but demonstrated Q-T prolongation. Further prolongation of the Q-T interval was observed to precede the episode of quinidine syncope in the Holter recording. Clinical implications: We have modified our clinical use of quinidine on the basis of this experience and are now more reluctant to initiate quinidine therapy in patients with severe left ventricular dysfunction. We begin therapy with quinidine in such patients in the hospital and with continuous, on-line electrocardiographic monitoring. We continue such monitoring for at least 48 hours after each change in dosage in order to
assess the Q-T interval. We terminate quinidine therapy immediately if the patient has an episode of torsade de pointes, even if the episode is brief and self-terminating. If the Q-T interval exceeds 500 ms we administer another antiarrhythmic drug unless the number of ventricular premature beats is markedly reduced. Although procainamide probably sensitizes the susceptible patients to quinidine, and although it is ineffective in the treatment of torsade de pointes, it may be effective and well tolerated in patients who have this adverse reaction to quinidine. Our study also raises the question whether antiarrhythmic drugs should be used to treat premature ventricular beats in certain patients in whom the risk of such therapy may outweigh its potential benefits.
FIGURE 3. Case 4. Onset of polymorphous ventricular tachycardia
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(top panel) and torsade de pointes (bottom panel).
VENTRlCULAR
FIWWLATION
ON HOLTER MDNtTDRING-DENES ET AL.
FIGURE 4. Case 5. Onset of torsade de pointes (top) and spontaneous termination (bottom) of polymorphous ventricular tachycardia.
References 1. Winkle R. Ambulatory electrocardiography. Mod Concepts Cardiovasc Dis 1980;49:7-12. 2. Bklfer SB, Flelfer DJ, Hansmann DR. Diagnosis of occult arrhythmias by Halter electrocardiography. Prog Cardiovas Dis 1974;16:569-99. 3. Gradman AH, Bell PA, De Bush FF. Sudden death during ambulatdry monltoring: clinical and electrocardiographic correlations. Report of a case. Circulation 1977;55:210-1. 4. Pool J, Kunel K, Van Wermeskerken JL. Two monitored cases of sudden death out&de hospital. Br Heart J 1978;40:627-9. 5. Hlnkle LE, Argyroe DC, RobInson 1, Alonse DR, Shlpmann SC, Edwards ME. Pathogensis of an unexpected sudden death: role of early cycle ventricular premature contractions. Am J Cardiol 1977;39:873-9. 8. Lahlrl A, Balaaubramanlan V, Raftery EB. Sudden death during ambulatory monitoring. Br Mad J 1979;1:1676-8. 7. Criteria Committee of the New York Heart Association. Diseases of the Heart and Great Vessels. Nomenclature and Criteria for Diagnosis. 6th ed. Boston: Little, Brown 1979:112-3. 8. W@ers DJ. The mechanism and nature of ventricular fibrillation. Am Heart J 1940:20:399-412.
9. Han J, Moe GK. Nonuniform recovery of excitability in ventricular muscle. Circ Res 1964; 1444-60. 10. Wllllams Do, Scherlag BJ, Hope RR, El-Sherll N, Lauara RP. The pathophysiology of malignant ventricular arrhythmias during acute myocardial ischemia. Circulation 1975,50: 1163-72. 11. Josephson ME, Splelman SR, Greenspan AM, Horowitz LN. Mechanism of ventricular fibrillation in man. Am J Cardiol 1979; 44:623-3 I. 12. Kerr WJ, Bender WL. Paroxysmal ventricular fibrillation with cardiac recovery in a case of auricutar fibrillation and complete heart block while under quinidine sulphate therapy. Heart 1922; 9:269-81. 13. Davls 0, Sprague HB. Ventricular fibrillation; Its relation to heart block: report of a case in which syncopal attacks and death occurred in the course of quinidine therapy. Am Heart J 1929;4: 559-72. 14. Binder MJ, Rosove L. Paroxysmal ventricular tachycardia and fibrillation due to quinidine. Am J Med 1952;12:491-7. 15. Rokeeth R, Slereteln 0. QuinMine therapy of chronic auricular filXiltatfkm:occurrence and mechanism of syncope. Arch kltenl Med 1963;111:102-7.
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FIBRILLATION ON HOLTER MONITORING-DENES
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16. Seizer A, Wray HW. Quinidine syncope: paroxysmal ventricular fibrillation occurring during treatment of chronic atrial arrhythmias. Circulation 1964;30: 17-26. 17. Dravetz J, Sfedki SJ. Recurrent ventricular fibrillation precipitated by quinidine. Arch Intern Med 1966;122:63-5. 16. Motie G, Ceumel PH, Abllbel G, Deseerferre F, Slama R. Le synckoma QT long et syncopes par “torsade da pointes.” Arch Mal Coeur 1970;63:631-53. 19. Kosher RW, Wellens HJJ. Quinidine-induced ventricular flutter and fibrillation without digitalis therapy. Am J Cardiol 1976;36:51923. 20. Reynolds EW, Vander Ark CR. Quinidine syncope and the delayed
16
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2 1.
22. 23. 24.
repolarization syndromes. Mod Concepts Cardiovasc Dis 1976; 45: 117-22. Sclarovsky S, Sfraeeberg 6, Levln RF, Agmon J. Polymorphous ventricular tachycardia clinical features and treatment. Am J Cardiol 1979;44:339-44. Gold H, Modell W, Price L. Combined action of quinidine and digitalis on the heart. Arch Intern Med 1932;50:766-96. Brandfonbrener M, KJobech C, Cooper E. The effect of digitalization on qulnidine toxicity. Am Heart J 1966;76:249-51. Leahy EB, Relffel JR, Drusin RE, Heieenbuttel RM, Lovejoy WP, Bigger JT Jr. A drug interaction between quinidine and digoxin. JAMA 1976;240:533-4.
PABLO DENES, MD, FACC ALAN GABSTER, MD SHOEI K. HUANG, MD Chicago, Illinois
From the Section of Cardiology, Department of Medicine, RushPresbyterian St. Luke’s Medical Center, Chicago, Illinois. Manuscript received November 10, 1980; revised manuscript received February 2, 1981, accepted February 11, 1981. Address for reprints: Pablo Denes, MD, Professor of Medicine, Department of Medicine, Rush-Presbyterian St. Luke’s Medical Center, Chicago, Illinois 60612.
Ventricular fibriiiation occurred during Hoiter electrocardiographic monitoring in 5 of 3,307 consecutive patients. Ail five patients had Hoiter studies for evaluation of antiarrhythmic drug therapy; their ages ranged from 51 to 65 years. No patient had acute myocardiai infarction; ail had congestive heart failure and severe left ventricular dysfunction. One patient had ischemic and four had nonischemic cardiomyopathy. Ail patients had recently begun treatment with oral quinidine and had plasma quinidine levels of 1.24 to 5.16 pg/mi. The Hoiter monitoring revealed that ail had a long O-T interval and that ventricular fibriiiation began during frequent ventricular premature beats and was immediateiy preceded by ventricular tachycardia of the torsade de pointes type. The coupling interval of the ventricular premature beats initiating torsade de pointes was late (440 to 720 ms) and followed long preceding cycles (640 to 1920 ms). Ventricular fibriiiation resolved spontaneously in two patients, but two of the remaining three patients died despite attempted cardiopulmonary resuscitation. it is concluded that (1) left ventricular dysfunction, chronic ventricular arrhythmias and initiation of quinidine therapy were the common findings in these patients; (2) a long Q-T interval, late coupled ventricular premature beats and long preceding cycles facilitate initiation of ventricular fibrillation in quinidine-treated patients; and (3) direct on-line monitoring should be utilized in the management of these patients.
Dynamic electrocardiographic (Holter) monitoring is frequently used to evaluate the significance of arrhythmias and conduction disturbances in symptomatic patients and to evaluate response to antiarrhythmic drug therapy.l In a review of published data on patients who died suddenly during Holter monitoring we found eight reported cases.2-6 Two of the eight patients died of bradyarrhythmias, whereas the remaining six had ventricular fibrillation. All six patients had coronary artery disease and none had a long Q-T interval. All episodes of ventricular fibrillation were initiated by early coupled premature ventricular beats resulting in the R on T phenomenon.24 Reviewing 3,307 consecutive Holter records from our laboratory we found five patients in whom ventricular fibrillation resulting in loss of consciousness developed during monitoring. In two patients the arrhythmia resolved spontaneously but two of the remaining three patients died despite attempted cardiopulmonary resuscitation. The clinical, electrocardiographic and Holter monitoring findings in these patients are described. Clinical
Features
of Cases
Clinica! characteristics
(Table I): The five patients included two men and three women ranging in age from 51 to 65 years. All five were
in-patients at the time of the Holter recordings. They were initially hospitalized because of decompensation of congestive heart failure. All
July 1981
The American Journal of CARDIOLOGY
Volume 48
9
VENTFWJLAR
FIBRILLATION ON HOLTER MONlTOf?ING-DENES
ET AL.
patients were in New York Heart Association functional class III to IV7 because of dyspnea or fatigue. Heart disease had first been diagnosed 8 months to 9 years before admission. Two patients had primary myocardial disease, one had rheumatic heart disease and one had hypertensive heart disease. All patients had marked cardiomegaly and significantly depressed ventricular function. All patients were known to have ventricular arrhythmias detected on routine electrocardiography 10 days to 60 months before the Holter monitor test. Complex ventricular arrhythmias (bigeminy, multifocal ventricular premature beats, couplets and salvos) were documented on at least one Holter recording in four of the five patients before initiation of quinidine therapy. Ant&rhythmic drugs (Table II): Antiarrhythmic therapy was initiated to control supraventricular arrhythmias in one patient and ventricular arrhythmias in four patients. Three patients began treatment with quinidine while being monitored in the medical intensive care unit. At the time of Holter recording all patients were on a medical ward without on-line arrhythmia monitoring. Holter monitor recordings were obtained in order to evaluate the results of antiarrhythmic drug therapy. Four patients received quinidine sulfate (0.8 to 2.0 g/day) and one patient had
quinidine gluconate (2.6 g/day). The 1 hour post-dose serum drug levels ranged from 1.24 to 5.18 pg/ml. All patients received long-term digitalis therapy and four had stable plasma digoxin levels of 1.0 to 1.5 ng/ml. In four of the five patients plasma digoxin levels were obtained after the initiation of quinidine therapy. One patient (Case 2) had an elevated plasma digoxin level (3.1 ng/ml) obtained 3 days before the Holter recording; digoxin was withheld for 72 hours in this patient. One patient (Case 3), in addition to digoxin and quinidine also received procainamide and had a peak serum level of 16.4 pg/ml. No other antiarrhythmic drugs were utilized. All patients had normal serum electrolytes within 24 hours of the Holter recording. Electrocardiographic findings (Table III): The last 12 lead electrocardiogram before the Holter recording showed normal sinus rhythm in four patients and atria1 fibrillation in one. The Q-T interval in lead Vs ranged from 360 to 480 ms and the associated R-R intervals from 680 to 1,100ms. The longest Q-T interval in the electrocardiogram ranged from 440 to 500 ms. Two patients had a prolonged interval. Four electrocardiograms showed left ventricular hypertrophy (one showing an old anteroseptal infarct). Ventricular arrhythmias were present in only one electrocardiogram.
TABLE I Clinlcal Findings In Five Cases Congestive Heart Failure
Case
Age (yr) a Sex
Cause of Heart Disease
1
65M
Present
2
64M
3
51F
Coronary artery disease Rheumatic heart disease Primary myocardial disease
4
61F
Present
5
56F
Hypertensive heart disease Primary myocardial disease
Present Present
Present
Ventricular Function A;;izphic 00 Angiographic EF 33% LVEDP 35 mm Ha: cardiac index -’ 1.5 literslmin per m* Nuclear EF 20% Nuclear EF 18%
Documented Arrhythmias on ECG
Duration of Ventricular Arrhythmias
Bigeminy, paired VP0 Multiform VPB
8mo
Multiform and paired VPB Multiform and paired VP0 Multiform VPB
19d 6mo
10d 80 mo
d = days; ECG = electrocardiography: EF = ejection fraction: LVEDP = left ventricular end-diastolic pressure; VPB = ventricular premature beats.
TABLE II Antlarrhythmlc Therapy In Five Cases
l
10
Serum Quinidine Level (1 h/post dose
Digoxin Dose
Serum Digoxin Level
bdmll)
@WW
0W-N
Case
Ouinidine Dose (g/day)
1 :
2.0 0.8 1.2
2.96 5.18 1.24
0.25 0.25
;
2.6 1.6
3.6 1.96
0.125 0.25
l
Digoxin withheld for 72 hours before ventricular fibrillation.
July 1961
The American Journal of CARDIOLOGY
Volume 48
Duration of Quinidine Therapy
(days)
1.0 <3.1 1.3
8 8
1.5 1.1
12 :
VENTFWIJLAR FlSRLLATlON
ON HOLTER MONITOl?INQ-DENES
ET AL.
TABLE III Scalar Electrocardiographic
Flndlngs Before Ventricular Fibrillation
Case
P-R (s)
DBS Duration (s)
Arrhythmia
Time Before Hoher Monitoring (days)
1 3
0.18 0.20
0.09 0.10
840 1100 780
480 400 440
480 (V,) 500 (Ill)
LVH LVH
None None
1 1
4
0.24
0.10
880
360
tt:
g;)
0.28
0.12
900
420
480
W3)
Paired VPB PAB
z
5
Anteroseptal MI LVH, IVCD
(leZTVs) (m@
Longest G-T (ECG lead) (ms)
Diagnosis
3
ECG = electrocardiographic; IVCD = intraventricular conduction defect; LVH = left ventricular hypertrophy; MI = myocardial infarctlon; VPB = ventricular premature beat.
FIGURE 1. Onset of torsade de polntes in Patients 1 (upper) and 3 (lower). Modified leads Vs and VI are shown. Paper speed Is 25 mm/s in this and subsequent Illustrations.
July 1981
The American Journal of CARDIOLOGY
Volume 48
11
VENTRICULAR FIBRILLATION ON HOLTER MONITORINGOENES
ET AL.
Holter monitor findings (Table IV): Four patients had sinus rhythm and one had atria1 fibrillation. The Q-T interval, measured in modified lead Vs before the onset of torsade de pointes, ranged from 480 to 680 ms and the associated R-R interval from 640 to 1,080 ms. It is possible that this measurement of the Q-T interval also included the U wave, because separation of T and U waves in the chest bipolar lead recording is uncertain. The Q-T interval was prolonged in all patients. The Holter recordings showed that all five patients had frequent ventricular premature beats with couplets and periods of bigeminy. Most ventricular premature beats had long coupling intervals and there were frequent fusion beats. The onset of torsade de pointes in Case 1 was preceeded by ventricular bigeminy followed by a fusion beat (860 ms). The first beat of the tachycardia had a coupling interval of 640 ms (Fig. 1, top panel). In Case 2 the onset of torsade de pointes was also preceded by ventricular bigeminy followed by a ventricular escape beat (1,320 ms). The first beat of the tachycardia had a coupling interval of 720 ms (Fig. 2, top panel). In Case 3, there was ventricular bigeminy, a short run of ventricular tachycardia followed by a sinus beat (1,460 ms). The first beat of the torsade de pointes had a coupling interval of 440 ms (Fig. 2, bottom panel). In Case 4 both episodes of tachycardia were mixed with frequent ventricular ectopic beats. The first episode occurred during ventricular bigeminy followed by an accelerated ventricular escape beat (840 ms). The coupling interval of the first beat of the polymorphous ventricular tachycardia was 600 ms (Fig. 3, top panel). The second episode was preceded by six polymorphous ventricular ectopic beats at various rates. The onset of torsade de pointes was preceded by an R-R interval of 1,020 ms and the coupling interval of the first beat was 580 ms (Fig. 3, bottom panel). In Case 5, the onset of torsade de pointes was preceded by a run of ventricular tachycardia followed by a sinus beat (1,920 ms). The coupling interval of the first beat was 560 ms (Fig. 4, top panel). There was a long cycle terminated by a sinus beat in two patients (Cases 3 and 5) and by ventricular beats in the remaining three. The coupling interval of the initiating beat ranged from 440 to 720 ms (mean 590). All patients had a syncopal attack associated with the arrhythmia. In two patients reversion to the original
rhythm occurred (atria1 fibrillation in Case 2 and sinus rhythm in Case 5 (Fig. 2 and 4, bottom panels); in the other three patients resuscitative measures were nec-
essary. Cardiopulmonary resuscitation was successful in one patient (Case 1) and unsuccessful in the remaining two patients (Cases 3 and 4). Discussion Clinical and electrocardiographic features: In a retrospective review of all patients undergoing 24 hours of dynamic electrocardiographic monitoring, we found five patients who had syncopal attacks caused by ventricular tachyarrhythmias. Certain clinical and electrocardiographic findings were present in all five cases: (1) All patients had advanced organic heart disease with congestive heart failure, cardiomegaly and marked left ventricular dysfunction. (2) All patients had recently begun therapy with oral quinidine. (3) All patients had Q-T prolongation and frequent multiform ventricular premature beats recorded on Holter monitoring. Torsade de pointes was induced by ventricular premature beats with long coupling intervals and was followed by ventricular fibrillation. (4) A high mortality rate (40 percent) was associated with this syndrome. The previously reported cases of patients who died suddenly because of ventricular fibrillation during Holter monitoring also manifested certain common clinical and electrocardiographic findings2-‘? (1) All patients had coronary artery disease. (2) Frequent multiform ventricular premature beats were recorded on Holter monitoring. The Q-T interval was not prolonged and ventricular fibrillation was always induced by ventricular premature beats that had short coupling resulting in an R on T phenomenon.2-s The findings in these reports differ from our observations in the duration of the Q-T intervals and the coupling intervals of the initiating ventricular premature beats. Mechanism of ventricular fibrillation: Ventricular fibrillation is defined as chaotic asynchronous activation of the ventricles.8 The mechanism of ventricular fibrillation is related to an increased temporal dispersion of refractoriness and delayed activation of ventricular myocardium.g-ll Initiation of ventricular fibrillation may depend on the extent of delayed conduction and dispersion of refractoriness that exists during the predominant rhythm and to the degree that it is affected by premature ventricular beats.
TABLE IV Holter Monltor Flndings Predominant
Case
Rhythm
1
Sinus
2
Atrial fibrillation
3 4 5
Sinus Sinus Sinus
VPB Coupling Intervals (ms)
Q-T (ms)
720
520
520-860
RBBB
1080
560
540-780
RBBB
900 640 820
600 480 680
440-700 440-620 520-800
RBBB -I- LBBB RBBB + LBBB RBBB + LBBB
R-R
DC = direct current; LBBB = left bundle branch block: RBBB = right bundle branch block.
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VPB Configuration
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Outcome DC cardioversion Spontaneous termination Death Death Spontaneous termination
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On the basis of observations in these Holter monitoring studies we propose that in delayed repolarization syndromes there may be sufficient dispersion of refractoriness and delayed ventricular activation (due to the effect of drugs, electrolyte disturbances, intrinsic heart disease or abnormalities of the central nervous system) that late coupled premature ventricular beats could result in ventricular fibrillation. In the patients who died suddenly from coronary artery disease, early ventricular premature beats were required to achieve a similar degree of inhomogeneity in conduction and refractoriness to initiate ventricular fibrillation. Quinidine syncope: Quinidine syncope and quinidine-related sudden death are manifestations of the same arrhythmia exhibited by our patients.12-21 Published tracings have been labeled as showing ventricular fibrillation, ventricular flutter, ventricular tachycardia,
ET AL.
polymorphous ventricular tachycardia and torsade de pointes.12-21 The incidence of quinidine syncope was reported15 to be 4.4 percent during attempted conversion of atria1 fibrillation or flutter with quinidine. A review20 of published cases of quinidine syncope found an overall mortality rate of 11.5percent. The association between quinidine syncope and concomitant use of a digitalis preparation was amply demonstrated in the past.l5slW2-24 H owever, a more recent reportlg shows occurrence of quinidine syncope in patients who received no digitalis therapy. Toxic manifestations such as cinchonism and widening of the QRS complex are noticeably absent in patients with quinidine syncope.20 However, most patients exhibited a prolonged Q-T interval or a large U wave, or both, in the electrocardiogram.” We noted similar changes in the Holter recordings that showed marked Q-T prolongation and the
FIGURE 2. Case 2. Onset (upper) and spontaneous termination (lower) of ventricular fibrillation.
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presence of complex ventricular arrhythmias before the onset of torsade de pointes. The electrocardiograms taken 1 to 5 days before the syncopal episodes did not reveal significant ventricular arrhythmias but demonstrated Q-T prolongation. Further prolongation of the Q-T interval was observed to precede the episode of quinidine syncope in the Holter recording. Clinical implications: We have modified our clinical use of quinidine on the basis of this experience and are now more reluctant to initiate quinidine therapy in patients with severe left ventricular dysfunction. We begin therapy with quinidine in such patients in the hospital and with continuous, on-line electrocardiographic monitoring. We continue such monitoring for at least 48 hours after each change in dosage in order to
assess the Q-T interval. We terminate quinidine therapy immediately if the patient has an episode of torsade de pointes, even if the episode is brief and self-terminating. If the Q-T interval exceeds 500 ms we administer another antiarrhythmic drug unless the number of ventricular premature beats is markedly reduced. Although procainamide probably sensitizes the susceptible patients to quinidine, and although it is ineffective in the treatment of torsade de pointes, it may be effective and well tolerated in patients who have this adverse reaction to quinidine. Our study also raises the question whether antiarrhythmic drugs should be used to treat premature ventricular beats in certain patients in whom the risk of such therapy may outweigh its potential benefits.
FIGURE 3. Case 4. Onset of polymorphous ventricular tachycardia
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(top panel) and torsade de pointes (bottom panel).
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FIGURE 4. Case 5. Onset of torsade de pointes (top) and spontaneous termination (bottom) of polymorphous ventricular tachycardia.
References 1. Winkle R. Ambulatory electrocardiography. Mod Concepts Cardiovasc Dis 1980;49:7-12. 2. Bklfer SB, Flelfer DJ, Hansmann DR. Diagnosis of occult arrhythmias by Halter electrocardiography. Prog Cardiovas Dis 1974;16:569-99. 3. Gradman AH, Bell PA, De Bush FF. Sudden death during ambulatdry monltoring: clinical and electrocardiographic correlations. Report of a case. Circulation 1977;55:210-1. 4. Pool J, Kunel K, Van Wermeskerken JL. Two monitored cases of sudden death out&de hospital. Br Heart J 1978;40:627-9. 5. Hlnkle LE, Argyroe DC, RobInson 1, Alonse DR, Shlpmann SC, Edwards ME. Pathogensis of an unexpected sudden death: role of early cycle ventricular premature contractions. Am J Cardiol 1977;39:873-9. 8. Lahlrl A, Balaaubramanlan V, Raftery EB. Sudden death during ambulatory monitoring. Br Mad J 1979;1:1676-8. 7. Criteria Committee of the New York Heart Association. Diseases of the Heart and Great Vessels. Nomenclature and Criteria for Diagnosis. 6th ed. Boston: Little, Brown 1979:112-3. 8. W@ers DJ. The mechanism and nature of ventricular fibrillation. Am Heart J 1940:20:399-412.
9. Han J, Moe GK. Nonuniform recovery of excitability in ventricular muscle. Circ Res 1964; 1444-60. 10. Wllllams Do, Scherlag BJ, Hope RR, El-Sherll N, Lauara RP. The pathophysiology of malignant ventricular arrhythmias during acute myocardial ischemia. Circulation 1975,50: 1163-72. 11. Josephson ME, Splelman SR, Greenspan AM, Horowitz LN. Mechanism of ventricular fibrillation in man. Am J Cardiol 1979; 44:623-3 I. 12. Kerr WJ, Bender WL. Paroxysmal ventricular fibrillation with cardiac recovery in a case of auricutar fibrillation and complete heart block while under quinidine sulphate therapy. Heart 1922; 9:269-81. 13. Davls 0, Sprague HB. Ventricular fibrillation; Its relation to heart block: report of a case in which syncopal attacks and death occurred in the course of quinidine therapy. Am Heart J 1929;4: 559-72. 14. Binder MJ, Rosove L. Paroxysmal ventricular tachycardia and fibrillation due to quinidine. Am J Med 1952;12:491-7. 15. Rokeeth R, Slereteln 0. QuinMine therapy of chronic auricular filXiltatfkm:occurrence and mechanism of syncope. Arch kltenl Med 1963;111:102-7.
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16. Seizer A, Wray HW. Quinidine syncope: paroxysmal ventricular fibrillation occurring during treatment of chronic atrial arrhythmias. Circulation 1964;30: 17-26. 17. Dravetz J, Sfedki SJ. Recurrent ventricular fibrillation precipitated by quinidine. Arch Intern Med 1966;122:63-5. 16. Motie G, Ceumel PH, Abllbel G, Deseerferre F, Slama R. Le synckoma QT long et syncopes par “torsade da pointes.” Arch Mal Coeur 1970;63:631-53. 19. Kosher RW, Wellens HJJ. Quinidine-induced ventricular flutter and fibrillation without digitalis therapy. Am J Cardiol 1976;36:51923. 20. Reynolds EW, Vander Ark CR. Quinidine syncope and the delayed
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2 1.
22. 23. 24.
repolarization syndromes. Mod Concepts Cardiovasc Dis 1976; 45: 117-22. Sclarovsky S, Sfraeeberg 6, Levln RF, Agmon J. Polymorphous ventricular tachycardia clinical features and treatment. Am J Cardiol 1979;44:339-44. Gold H, Modell W, Price L. Combined action of quinidine and digitalis on the heart. Arch Intern Med 1932;50:766-96. Brandfonbrener M, KJobech C, Cooper E. The effect of digitalization on qulnidine toxicity. Am Heart J 1966;76:249-51. Leahy EB, Relffel JR, Drusin RE, Heieenbuttel RM, Lovejoy WP, Bigger JT Jr. A drug interaction between quinidine and digoxin. JAMA 1976;240:533-4.