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Long-term arrhythmic outcome in survivors of ventricular fibrillation with absence of inducible ventricular tachycardia
Long-Term Ventricular
Arrhythmic Oufcome in Survivors of Fibrillation with Absence of Inducible Ventricular Tachycardia
Terry A. Zheutlin, MD, Russell T. Steinman, MD, Thomas A. Mattioni, MD, and Richard F. Kehoe, MD
While programmed electrical stimulation of the heart is useful in directing therapy in cardiac arrest survivors who exhibit inducible ventricular tachycardia (VT), controversy exists as to the risk of recurrent ventricular fibrillation (VF) and need for antiarrhythmic therapy in patients without inducible VT during drug-free control programmed stimulation studies. In this study, the clinical features and arrhythmic outcome of 43 survivors of VF without inducible VT at control programmed stimulation were examined., In 38 patients, factors that may have played a potentiating role in the genesis of VF included ischemia in 15, proarrhythmia in IS, rapid rate response to atrial fibrillation in 3 and acute alcoholism in 2. Three patients required antiarrhythmic drugs for supraventricular tachyarrhythmia and 40 patients were discharged without antiarrhythmic therapy. At 32 -f 21 months (range 1 to 82), 37 (92%) have remained free of arrhythmic recurrence while 3 have had sustained subsequent major arrhythmic events (syncope 1 patient, VF 1, sudden cardiac death 1). Thus, survivors of VF without inducible VT at drug-free control programmed stimulation are characterized by (1) potentiating factors--often identifiable and correctable-that may be important to the genesis of VP; (2) generally low risk of arrhythmic recurrence; and (3) effective long-term management often achieved without the use of additional antiarrhythmic drugs or antitachycardial defibrillation devices. (Am J Cardiol 1988;62:1213-1217)
From the Clinical Cardiac Electrophysiology Laboratory, Section of Cardiology, Department of Medicine, Northwestern University School of Medicine, Chicago, Illinois. Manuscript received December 24, 1987; revised manuscript received July 26, 1988, and accepted August 22. Address for reprints: Terry A. Zheutlin, MD, Northwestern Memorial Hospital, 250 East Superior Street, 501 Wesley, Chicago, Illinois 60611.
P
atients surviving out-of-hospital ventricular fibrillation (VF) unrelated to acute myocardial infarction are known to be at increased risk for recurrent cardiac arrest.1-5 The ability of programmed electrical stimulation techniques to identify effective antiarrhythmic therapy in cardiac arrest survi,vors with inducible ventricular tachycardia (VT) has been demonstrated by multiple investigators.e-lo However, controversy exists as to the risk of arrhythmic recurrence and need for therapy in VF survivors who are free of inducible VT at control programmed electrical stimulation.“-I6 The effort to accurately characterize the natural history of noninducible VF survivors in many of the previously reported studies has been complicated by the empiric use of class I or class III antiarrhythmic drugs and the inclusion of patients presenting with arrhythmias other than VF at the time of cardiovascular collapse (e.g., sustained VT). To more clearly define the natural history of survivors of VF free of inducible VT at drug-free control programmed electrical stimulation, we examined the clinical features and arrhythmic outcome of 43 noninducible VF survivors who were discharged and followed without class I or class III antiarrhythmic drug therapy or automatically functioning antitachycardia/defibrillation devices. METHODS Patient selection: Between January 1979 and Janu-
ary 1986, 124 consecutive survivors of prehospital VF underwent programmed electrical stimulation studies: 79 patients (65%) had inducible VT whereas 43 patients (35%) were noninducible. The 43 patients free of inducible VT form the basis of this study. All 43 patients presented with at least 1 episode of VF documented during cardiopulmonary resuscitation. Patients with a prior history of recurrent sustained VT and those with arrhythmias other than VF at the time of the cardiac arrest were excluded from the study. None had electrocardiographic or enzymatic evidence of an acute myocardial infarction. Patients who exhibited signs of antiarrhythmic drug intoxication, marked electrolyte abnormalities or a prolonged QTc interval on 12-lead electrocardiogram after arrest were also excluded. The type and extent of underlying heart disease were documented by cardiac catheterization in 35 patients and by noninvasive methods in 8. Significant coronary artery disease was defined as a lumen diameter reduction >70% by coronary angiography.
THE AMERICAN
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NONlNDUClBll.lTY
TABLE
I Clinical
IN CARDIAC ARREST SURVIVORS
Features Pts (n = 43) 26/17 58f13 24-81
Male/female Age* Ws) Range (yrs) Type of heart disease Coronary artery disease (%) Cardiomyopathy (%) Valvular disease (%) No apparent heart disease (“70) LV function History of heart failure (%) Ejection fraction* (%) Range (%) LV ejection fraction by heart disease* Coronary artery disease (%) Cardiomyopathy (%) Valvular disease (%) No apparent OHD (%)
21 (49) 12 (28) 3 (7) 7 (16) 18 (42) 43f15 19-70 45zk 15 34f9 49f13 6Ok9
* Mean f standard deviation. LV = left ventricle; OHD = organic heart disease.
Anti&rhythmic drug therapy was withdrawn under continuous electrocardiographic monitoring. All patients underwent drug-free control 24-hour Holter monitoring before the programmed stimulation studies. Holter monitoring data analysis was completed using an Avionics cardiac arrhythmia analyzer with a tape playback system that allows 60 X 120 X real time analysis of 24-hour cassettes. Ventricular ectopic activity was classified according to the Lown system.16 Programmed
electrical
stimulation
techniques:
Drug-free, control programmed electrical stimulation studies were undertaken between 1 week and 2 months after the presenting episode of VF. Stimulation was performed with the patient in the postabsorptive, nonsedated state using a stimulus duration of 2 ms and a stimulus current at twice the diastolic threshold necessary for capture. Multiple surface and intracavitary electrograms were recorded. Two stimulation protocols were used. A standard stimulation protocol was employed in all 43 patients and consisted of single and paired ventricular extrastimulus testing coupled to multiple driven ventricular cycle lengths and rapid ventricular pacing consisting of 4 to 8 consecutive captures at rates of 150 to 250 beats/min. Stimulation was carried out at both the right ventricular apex and outflow tract. Inducible VT was defined as the reproducible initiation of 17 repetitive ventricular responses, excluding bundle branch reentry. For the 21 patients who presented after January 1983, a more aggressive stimulation protocol was undertaken. This included >-1 of the following: multiple control studies on separate days (20 patients), use of a third ventricular extrastimulus (14), pacing of the left ventricular apex (7), stimulation after pharmacologic autonomic manipulation with isoproterenol (3) or atropine (2) and stimulation after challenge with a potentially offending agent including intravenous procainamide (3) and ethanol (2).
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All patients also underwent additional electrophysiologic evaluation to exclude sinus or atrioventricular node dysfunction, conduction system disease, bypass tract physiology or inducible supraventricular tachyarrhythmia as possible explanations for the development of VF. Follow-up: Follow-up data were obtained on a prospective basis by outpatient visits to the Northwestern Memorial Hospital Arrhythmia Clinic, by telephone conversation with the patient and by communication with the patient’s private physician. Information was obtained regarding the development of subsequent major arrhythmic events defined as syncope, symptomatic or sustained VT, VF or sudden cardiac death. Additional information regarding the interim development of angina pectoris or congestive heart failure, medication compliance and nonarrhythmic death was also collected. Statistical analysis: The Kaplan-Meier method was used to construct the curves that describe the occurrence of subsequent major arrhythmic events and the occurrence of death from all causes.t7 Data are expressed as mean f standard deviation unless otherwise noted. RESULTS Clinical, electrocardiographic and angiographic features: The clinical features of the 43 survivors of pre-
hospital VF without inducible VT at drug-free programmed stimulation studies are listed in Table I. Thirty-six patients had underlying heart disease, including 21 with documented coronary artery disease, 12 with idiopathic dilated cardiomyopathy and 3 with mitral valve prolapse, 2 of whom had required prior valve replacement for mitral regurgitation. Seven patients had no apparent heart disease. Although 18 patients (42%) had a history of at least 1 prior episode of heart failure, left ventricular function as measured by ejection fraction was generally well preserved. The mean ejection fraction was 43 f 15% and exceeded 40% in 21 patients. The distribution of ejection fractions is shown in Figure 1. The extent of spontaneous ventricular ectopy during drug-free, continuous 24-hour Holter monitoring is shown in Figure 2. Most patients had evidence of repetitive ventricular firing, 9 with pairs and 19 with salvos of 3 or more consecutive premature ventricular beats. Therapeutic interventions: Efforts were made to identify factors that may have potentiated the development of VF. In 15 patients, ischemia was postulated as having contributed to the genesis of VF. All of them had severe proximal coronary arterial obstructions, generally well-preserved left ventricular function and multiple myocardial segments in ischemic jeopardy. Of these 15 patients, 9 had 3-vessel disease, 4 had 2-vessel disease and 2 had l-vessel disease with critical stenoses of the proximal left anterior descending coronary artery. Because 13 of these 15 patients had cardiac arrest in the setting of exertion or psychological stress, provocative
tests for ischemia such as exercise treadmill testing, ergonovine stimulation or dipyridamole thallium imaging studies were not performed. All 15 patients underwent antiischemic therapy that included coronary artery bypass grafting in 12 patients and pharmacologic therapy with fi-adrenergic blocking agents in 3. All 15 patients were discharged without class I or class III antiarrhythmic drug therapy. Eighteeen patients were receiving class I antiarrhythmic drugs at the time of the presenting episode of VF. Although neither QT prolongation nor episodes of polymorphous VT15 were documented in the immediate period after arrest, proarrhythmia was postulated as a possible mechanism for the development of VF because no other etiology for arrhythmogenesis could be identified. Ten patients had been receiving quinidine, 2 disopyramide, 3 procainamide and 1 imipramine. Two patients had sustained multiple cardiac arrests, each occurring during therapy with separate class I antiarrhythmic agents. These antiarrhythmic drugs were withdrawn in all 18 patients, 17 of whom were discharged without specific antiarrhythmic therapy. One patient required amiodarone to suppress repetitive episodes of symptomatic junctional tachycardia. Three other patients presented with poorly controlled atria1 fibrillation and prolonged rapid rate response. It was hypothesized that these rapid ventricular rates were contributing to the genesis of VF. Although digoxin and P-blockade therapy were sufficient to slow ventricular rate response in 1 patient, the second one required disopyramide and the other amiodarone to control ventricular rates. Of the remaining 7 patients, 2 presented with significantly elevated serum alcohol levels at the time of their cardiac arrest. In the other 5 no factor could be identitied which might have potentiated arrhythmogenesis. No specific interventions were undertaken in these 7 patients and they were discharged without antiarrhythmic drug therapy. Predischarge therapy and follow-up: Although 3 patients required class I or class III antiarrhythmic drugs for the treatment of supraventricular tachycardia,
O-10
11-20 LV
FIGURE patients.
hatched
1. Distribution
21-30
31-40
Ejection
Fractions
‘II-50
51-M)
40 patients were discharged without antiarrhythmic drug therapy or antitachycardia/defibrillation devices but were followed prospectively for the occurrence of subsequent major arrhythmic events. At 32 f 21 months, 37 patients (92%) have remained free of arrhythmic recurrence while 3 patients (8%) recurred: 1 died suddenly, 1 was successfully resuscitated from an episode of documented VF and 1 experienced a prolonged syncopal episode. Six patients died of noncardiac causes: 4 from cerebrovascular disease and 2 from metastatic carcinoma. The cumulative occurrence over time for both major arrhythmic episodes and estimated overall survival is shown in Figure 3. At 18 and 36 months of follow-up, the estimated probabilities of arrhythmia-free survival were 94 and 88%, respectively. The cumulative occurrence over time of death from all causes at 30 and 60 months was 84 and 54%, respectively. There was only 1 arrhythmic death in the entire patient population. Characteristics of patients with arrhythmic rence: Two of the 3 patients with arrhythmic
recur-
recurrence had cardiomyopathy and minimally depressed ejection fractions of 42 and 40% at the time of their initial evaluation. The first patient, treated with procainamide during the index episode of VF, died suddenly at 29 months of follow-up. The second patient was self-administering multiple over-the-counter dietary drugs and had hypokalemia (3.0 mEq/ml) at the time of her initial cardiac arrest. She had syncope 19 months later, at which time her serum potassium was normal and no interim decrease in ejection fraction was documented. She was noninducible at repeat programmed stimulation despite the use of an aggressive stimulation protocol. She was treated with amiodarone and has had no arrhythmic recurrence during the subsequent 20 months of follow-up.
61-70 LOWN
(% )
of LV ejection fractions in our 43 The mean LV ejection fraction is 44 f 15%. The areas represent patients with arrhythmic recurrence.
GRADE
FIGURE 2. Extent of spontaneous ventricular ectopy as classified according to the Lown grading system. The hatched areas represent patients with arrhythmic recurrence.
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NONINDUCIBILITY
IN CARDIAC
ARREST
SURVIVORS
The third patient was a 24-year-old lactating female whose initial cardiac arrest occurred 1 month postpartum and was associated with hypomagnesemia of 1.4 mg/dl and hypokalemia of 3.2 mEq/liter. Noninvasive and invasive cardiac evaluation revealed no evidence of underlying organic heart disease. The patient was discharged with potassium and magnesium supplementation but without antiarrhythmic drug therapy. At 8 months of follow-up, she was resuscitated from recurrent VF at which time her serum electrolytes were documented to be normal. Treatment with amiodarone was initiated and she has remained free of subsequent arrhythmic episodes during the last 33 months. The 3 patients given antiarrhythmic drugs after discharge to treat supraventricular tachyarrhythmias are also alive and free of arrhythmic recurrence at 12, 25 and 53 months. It is noteworthy that amiodarone was discontinued early during follow-up (<7 months) in the 2 patients who were receiving the drug after discharge. Both have remained arrhythmia-free despite the absence of chronic antiarrhythmic drug therapy.
remaining 40 patients were discharged without class I or class III antiarrhythmic drugs or automatically functioning antitachycardia/defibrillation devices. At 32 f 21 months, 37 patients (92%) have remained free of subsequent major arrhythmic events. The relatively low recurrence rate of 8% supports the premise that survivors of VF with absence of inducible VT during drugfree programmed electrical stimulation studies are generally at low risk for arrhythmic recurrence and can usually be safely managed without antiarrhythmic therapy. Thus, the potential toxicity and expense of empiric antiarrhythmic drugs-and even cardioversion/defibrillation devices-can often be avoided in these patients. The long-term survival for this group of patients was also excellent. Actuarial estimates of survival were 84 and 54% at 30 and 60 months, respectively. This finding lends support to the use of an aggressive arrhythmia evaluation in survivors of cardiac arrest because these noninducible patients do not exhibit an extremely high incidence of death from nonarrhythmic causes. In contrast to our findings which support an excellent outcome in VF survivors without inducible VT, other investigators report a higher incidence of arrhythmic recurrence.12-l4 For example, Roy et all2 reported a 32% incidence of subsequent sudden cardiac death in noninducible survivors of cardiac arrest at 20 months of follow-up. They included, however, patients in whom the arrhythmia documented during cardiovascular collapse was sustained VT. Because the pathophysiology of sustained VT is likely to be different from that of VF or VT degenerating to VF, the arrhythmic outcome and predictive value of programmed stimulation may also vary as a function of the type of presenting arrhythmia. Another factor that may account for these differences in arrhythmic outcome was the empiric use of antiarrhythmic drugs in 29 of 47 noninducible patients report-
DISCUSSION
The majority of patients who survive prehospital VF exhibit inducible VT in response to drug-free programmed electrical stimulation studies. When antiarrhythmic therapy renders these patients free of inducible VT, they appear to be at low risk for arrhythmic recurrence.5-8 However, 12 to 37% of VF survivors are noninducible at control programmed stimulation and the value of this technique in predicting their subsequent arrhythmic course is not yet well defined.lO-l3 In an effort to more clearly define the natural history of noninducible VF survivors, we examined the arrhythmic outcome of 43 such patients (only 3 of whom received long-term antiarrhythmic drug therapy). The
-9L--.,
MAE ‘1.--------------, DEATH 1
FIGURE 3. Kaplan-Meier analysis of the cumulative occurrence over time of subsequent major arrhythmic events (MAE) for patients without inducible ventricular tachycardia (so/id line) and cumulative occurrence of death from all causes (dashed line). There was 1 arrhythmic death in this group.
1 20 MAE-FREE DEATH-FREE
1216
N ~40 N ~40
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80 3 3
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ed by Roy et a1.12Thus, proarrhythmia may have contributed to the less favorable outcome observed in their patients. Finally, because the extent and nature of underlying heart disease were not clearly specified in the 18 patients discharged without antiarrhythmic therapy in the study by Roy et al, it is conceivable that more advanced coronary disease or poorer left ventricular function may have contributed to the higher incidence of arrhythmic recurrence observed by these investigators. In contrast, our study was limited exclusively to patients with VF, empiric antiarrhythmic drug therapy was not used and patients with significant coronary artery disease underwent aggressive antiischemic therapy. Accordingly, differences in patient population and type of therapy undertaken could account for the more favorable outcome of our noninducible VF survivors. It is important to note that possible potentiating factors for the development of VF were identified and corrected in 38 of the 43 patients in our study. The role these factors played in the genesis of VF is hypothetical, although supported by the clinical presentation and subsequent benign course of these patients. Thus, the favorable long-term arrhythmic outcome of the majority of the patients in the present study may in part be related to a modification of conditions critical to arrhythmogenesis. Of note are the 15 patients in whom critical coronary artery disease was identified and aggressively treated, and who remain free of arrhythmic recurrence despite discharge without specific antiarrhythmic drugs or devices, The favorable arrhythmic outcome of this group of patients lends support to the hypothesis that acute ischemia may have been critical to the development of VF. The role of acute ischemia in mediating VF has also been proposed by other investigators. Morady et allo reported no recurrent episodes of VF at 26 months of follow-up in 11 noninducible survivors of VF in whom therapy was directed solely at treatment of their underlying ischemic heart disease. Similarly, Swerdlow et all3 found no arrhythmic recurrence in 9 noninducible cardiac arrest survivors in whom a potential ischemic mechanism for arrhythmogenesis was identified and who were given antiischemic therapy alone after discharge. Despite the fact that the majority of our noninducible VF survivors has remained free of arrhythmic recurrence, 3 patients did sustain subsequent major arrhythmic events. If one excludes from the study population the 15 patients in whom critical coronary artery disease was identified and in whom aggressive antiischemic measures were used, 3 of the remaining 25 patients sustained arrhythmic recurrence and increased the recurrence rate to 12%. Thus, invoking nonischemic factors as potentiators of VF development should be undertaken only with caution. Among these 25 patients, no com-
mon feature could be identified that would allow for the prospective identification of these higher-risk patients. Accordingly, in noninducible VF survivors without critical coronary artery disease, the use of automatically functioning antitachycardia/defibrillation devices is not unreasonable, particularly because their use has been clearly demonstrated to improve arrhythmic outcome in certain subsets of cardiac arrest survivors. Further studies to more accurately characterize the natural history of the noninducible VF survivor are obviously required, an effort that may actually be facilitated by the use of these devices. Acknowledgment: The authors wish to thank Mary Mays, Michele Parker, RN, MS, and Catherine Summers Dunnington, RN, MS, for their invaluable help in the preparation of this manuscript.
REFERENCES 1. Liberthson RR, Nagel EL, Hirschman JC, Nussenfeld SR. Prehospital ventricular defibrillation: prognosis and follow-up course. N Engl J ked 1975; 291:317-321. 2. Baum RS, Alvarez H III, Cobb LA. Survival after resuscitation from out-ofhospital ventricular fibrillation. Circuhtion 1974;50:1231-1235. 3. Schaffer WA, Cobb LA. Recurrent ventricular fibrillation and mode of death in survivors of out-of-hospital ventricular fibrillation. N Engl J Med 1975; 293:259-262. 4. Cobb LA, Baum RS, Alvarez H III, Schaffer WA. Resuscitation from out-ofhospital ventricular fibrillation: 4 years follow-up. Circulation 197.5:51/ 52:111223-111228. 5. Myerburg RJ, Kessler KM, Estes D, Conde CA, Luceri RM, Zaman L, Kozlovskis PL, Castellanos A. Long-term survival after prehospital cardiac arrest: analysis of outcome during an 8 year study. Circulation 1984;70:538-546. 6. Josephson ME, Horowitz LN, Spielman SR, Greenspan AM. Electrophysiologic and hemodynamic studies in patients resuscitated from cardiac arrest. Am J Cardiol 1980;46:948-955. 7. Ruskin JN, DiMarco JP, Garan H. Out-of-hospital ventricular fibrillation: electrophysiologic observations and selection of long-term ant&rhythmic therapy. N Engl J Med 1980;303:607-613. 8. Morady F, Scheinman MM, Hess DS, Sung RJ, Shapiro W. Electrophysiologic testing in the management of survivors of out-of-hospital cardiac arrest. Am J Cardiol 1983;51:85m89. 9. Myerburg RJ, Conde CA, Sung RJ, Mayorga-Cartes A, Mallon SM, Sheps DS, Appel RA, Castellanos A. Clinical, electrophysiologic and hemodynamic profile of patients resuscitated from prehospital cardiac arrest. Am J Med 1980;68:568-576. 10. Morady F, DiCarlo L, Winston S, Davis JL, Scheinman MM. Clinical features and prognosis of patients with out-of-hospital cardiac arrest and a normal electrophysiologic study. JACC 1984;4:39-44. 11. Ruskin JN, McGovern B. Garan H, DiMarco JP, Kelly E. Antiarrhythmic drugs: a possible cause of out-of-hospital cardiac arrests. N Engl J Med 1983;309:1302~1306. 12. Roy D, Waxman HL, Kienzle MG, Buxton AE, Marchlinski FE, Josephson ME. Clinical characteristics and long-term follow-up in 119 survivors of cardiac arrest: relation to inducibility at electrophysiologic testing. Am J Cardiol 1983:52:969-974. 13. Swerdlow CD, Freedman RA. Peterson J, Clay D. Determinants of prognosis in ventricular tachyarrhythmia patients without induced sustained arrhythmias. Am Heart J 1986;111:433-437. 14. Benditt DG, Benson DW, Klein GJ, Pritzker MR, Kriett JM, Anderson RW. Prevention of recurrent sudden cardiac arrest: role of provocative electropharmacologic testing. JACC 1983;2:418-425. 15. Smith WM, Gallagher JL. Les Torsades de Pointes: an unusual ventricular arrhythmia. Ann Intern Med 1980;93:578-584. 16. Lown B, Wolf M. Approaches to sudden death from coronary disease. Circulation 1977;44:130m142. 17. Kaplan EL, Meier P. Non-parametric estimations from incomplete observations. J Am Stat Assoc 1958:53:457-581.
THE AMERICAN
JOURNAL
OF CARDIOLOGY
DECEMBER
1, 1988
1217
Arrhythmic Oufcome in Survivors of Fibrillation with Absence of Inducible Ventricular Tachycardia
Terry A. Zheutlin, MD, Russell T. Steinman, MD, Thomas A. Mattioni, MD, and Richard F. Kehoe, MD
While programmed electrical stimulation of the heart is useful in directing therapy in cardiac arrest survivors who exhibit inducible ventricular tachycardia (VT), controversy exists as to the risk of recurrent ventricular fibrillation (VF) and need for antiarrhythmic therapy in patients without inducible VT during drug-free control programmed stimulation studies. In this study, the clinical features and arrhythmic outcome of 43 survivors of VF without inducible VT at control programmed stimulation were examined., In 38 patients, factors that may have played a potentiating role in the genesis of VF included ischemia in 15, proarrhythmia in IS, rapid rate response to atrial fibrillation in 3 and acute alcoholism in 2. Three patients required antiarrhythmic drugs for supraventricular tachyarrhythmia and 40 patients were discharged without antiarrhythmic therapy. At 32 -f 21 months (range 1 to 82), 37 (92%) have remained free of arrhythmic recurrence while 3 have had sustained subsequent major arrhythmic events (syncope 1 patient, VF 1, sudden cardiac death 1). Thus, survivors of VF without inducible VT at drug-free control programmed stimulation are characterized by (1) potentiating factors--often identifiable and correctable-that may be important to the genesis of VP; (2) generally low risk of arrhythmic recurrence; and (3) effective long-term management often achieved without the use of additional antiarrhythmic drugs or antitachycardial defibrillation devices. (Am J Cardiol 1988;62:1213-1217)
From the Clinical Cardiac Electrophysiology Laboratory, Section of Cardiology, Department of Medicine, Northwestern University School of Medicine, Chicago, Illinois. Manuscript received December 24, 1987; revised manuscript received July 26, 1988, and accepted August 22. Address for reprints: Terry A. Zheutlin, MD, Northwestern Memorial Hospital, 250 East Superior Street, 501 Wesley, Chicago, Illinois 60611.
P
atients surviving out-of-hospital ventricular fibrillation (VF) unrelated to acute myocardial infarction are known to be at increased risk for recurrent cardiac arrest.1-5 The ability of programmed electrical stimulation techniques to identify effective antiarrhythmic therapy in cardiac arrest survi,vors with inducible ventricular tachycardia (VT) has been demonstrated by multiple investigators.e-lo However, controversy exists as to the risk of arrhythmic recurrence and need for therapy in VF survivors who are free of inducible VT at control programmed electrical stimulation.“-I6 The effort to accurately characterize the natural history of noninducible VF survivors in many of the previously reported studies has been complicated by the empiric use of class I or class III antiarrhythmic drugs and the inclusion of patients presenting with arrhythmias other than VF at the time of cardiovascular collapse (e.g., sustained VT). To more clearly define the natural history of survivors of VF free of inducible VT at drug-free control programmed electrical stimulation, we examined the clinical features and arrhythmic outcome of 43 noninducible VF survivors who were discharged and followed without class I or class III antiarrhythmic drug therapy or automatically functioning antitachycardia/defibrillation devices. METHODS Patient selection: Between January 1979 and Janu-
ary 1986, 124 consecutive survivors of prehospital VF underwent programmed electrical stimulation studies: 79 patients (65%) had inducible VT whereas 43 patients (35%) were noninducible. The 43 patients free of inducible VT form the basis of this study. All 43 patients presented with at least 1 episode of VF documented during cardiopulmonary resuscitation. Patients with a prior history of recurrent sustained VT and those with arrhythmias other than VF at the time of the cardiac arrest were excluded from the study. None had electrocardiographic or enzymatic evidence of an acute myocardial infarction. Patients who exhibited signs of antiarrhythmic drug intoxication, marked electrolyte abnormalities or a prolonged QTc interval on 12-lead electrocardiogram after arrest were also excluded. The type and extent of underlying heart disease were documented by cardiac catheterization in 35 patients and by noninvasive methods in 8. Significant coronary artery disease was defined as a lumen diameter reduction >70% by coronary angiography.
THE AMERICAN
JOURNAL
OF CARDIOLOGY
DECEMBER
1, 1988
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NONlNDUClBll.lTY
TABLE
I Clinical
IN CARDIAC ARREST SURVIVORS
Features Pts (n = 43) 26/17 58f13 24-81
Male/female Age* Ws) Range (yrs) Type of heart disease Coronary artery disease (%) Cardiomyopathy (%) Valvular disease (%) No apparent heart disease (“70) LV function History of heart failure (%) Ejection fraction* (%) Range (%) LV ejection fraction by heart disease* Coronary artery disease (%) Cardiomyopathy (%) Valvular disease (%) No apparent OHD (%)
21 (49) 12 (28) 3 (7) 7 (16) 18 (42) 43f15 19-70 45zk 15 34f9 49f13 6Ok9
* Mean f standard deviation. LV = left ventricle; OHD = organic heart disease.
Anti&rhythmic drug therapy was withdrawn under continuous electrocardiographic monitoring. All patients underwent drug-free control 24-hour Holter monitoring before the programmed stimulation studies. Holter monitoring data analysis was completed using an Avionics cardiac arrhythmia analyzer with a tape playback system that allows 60 X 120 X real time analysis of 24-hour cassettes. Ventricular ectopic activity was classified according to the Lown system.16 Programmed
electrical
stimulation
techniques:
Drug-free, control programmed electrical stimulation studies were undertaken between 1 week and 2 months after the presenting episode of VF. Stimulation was performed with the patient in the postabsorptive, nonsedated state using a stimulus duration of 2 ms and a stimulus current at twice the diastolic threshold necessary for capture. Multiple surface and intracavitary electrograms were recorded. Two stimulation protocols were used. A standard stimulation protocol was employed in all 43 patients and consisted of single and paired ventricular extrastimulus testing coupled to multiple driven ventricular cycle lengths and rapid ventricular pacing consisting of 4 to 8 consecutive captures at rates of 150 to 250 beats/min. Stimulation was carried out at both the right ventricular apex and outflow tract. Inducible VT was defined as the reproducible initiation of 17 repetitive ventricular responses, excluding bundle branch reentry. For the 21 patients who presented after January 1983, a more aggressive stimulation protocol was undertaken. This included >-1 of the following: multiple control studies on separate days (20 patients), use of a third ventricular extrastimulus (14), pacing of the left ventricular apex (7), stimulation after pharmacologic autonomic manipulation with isoproterenol (3) or atropine (2) and stimulation after challenge with a potentially offending agent including intravenous procainamide (3) and ethanol (2).
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All patients also underwent additional electrophysiologic evaluation to exclude sinus or atrioventricular node dysfunction, conduction system disease, bypass tract physiology or inducible supraventricular tachyarrhythmia as possible explanations for the development of VF. Follow-up: Follow-up data were obtained on a prospective basis by outpatient visits to the Northwestern Memorial Hospital Arrhythmia Clinic, by telephone conversation with the patient and by communication with the patient’s private physician. Information was obtained regarding the development of subsequent major arrhythmic events defined as syncope, symptomatic or sustained VT, VF or sudden cardiac death. Additional information regarding the interim development of angina pectoris or congestive heart failure, medication compliance and nonarrhythmic death was also collected. Statistical analysis: The Kaplan-Meier method was used to construct the curves that describe the occurrence of subsequent major arrhythmic events and the occurrence of death from all causes.t7 Data are expressed as mean f standard deviation unless otherwise noted. RESULTS Clinical, electrocardiographic and angiographic features: The clinical features of the 43 survivors of pre-
hospital VF without inducible VT at drug-free programmed stimulation studies are listed in Table I. Thirty-six patients had underlying heart disease, including 21 with documented coronary artery disease, 12 with idiopathic dilated cardiomyopathy and 3 with mitral valve prolapse, 2 of whom had required prior valve replacement for mitral regurgitation. Seven patients had no apparent heart disease. Although 18 patients (42%) had a history of at least 1 prior episode of heart failure, left ventricular function as measured by ejection fraction was generally well preserved. The mean ejection fraction was 43 f 15% and exceeded 40% in 21 patients. The distribution of ejection fractions is shown in Figure 1. The extent of spontaneous ventricular ectopy during drug-free, continuous 24-hour Holter monitoring is shown in Figure 2. Most patients had evidence of repetitive ventricular firing, 9 with pairs and 19 with salvos of 3 or more consecutive premature ventricular beats. Therapeutic interventions: Efforts were made to identify factors that may have potentiated the development of VF. In 15 patients, ischemia was postulated as having contributed to the genesis of VF. All of them had severe proximal coronary arterial obstructions, generally well-preserved left ventricular function and multiple myocardial segments in ischemic jeopardy. Of these 15 patients, 9 had 3-vessel disease, 4 had 2-vessel disease and 2 had l-vessel disease with critical stenoses of the proximal left anterior descending coronary artery. Because 13 of these 15 patients had cardiac arrest in the setting of exertion or psychological stress, provocative
tests for ischemia such as exercise treadmill testing, ergonovine stimulation or dipyridamole thallium imaging studies were not performed. All 15 patients underwent antiischemic therapy that included coronary artery bypass grafting in 12 patients and pharmacologic therapy with fi-adrenergic blocking agents in 3. All 15 patients were discharged without class I or class III antiarrhythmic drug therapy. Eighteeen patients were receiving class I antiarrhythmic drugs at the time of the presenting episode of VF. Although neither QT prolongation nor episodes of polymorphous VT15 were documented in the immediate period after arrest, proarrhythmia was postulated as a possible mechanism for the development of VF because no other etiology for arrhythmogenesis could be identified. Ten patients had been receiving quinidine, 2 disopyramide, 3 procainamide and 1 imipramine. Two patients had sustained multiple cardiac arrests, each occurring during therapy with separate class I antiarrhythmic agents. These antiarrhythmic drugs were withdrawn in all 18 patients, 17 of whom were discharged without specific antiarrhythmic therapy. One patient required amiodarone to suppress repetitive episodes of symptomatic junctional tachycardia. Three other patients presented with poorly controlled atria1 fibrillation and prolonged rapid rate response. It was hypothesized that these rapid ventricular rates were contributing to the genesis of VF. Although digoxin and P-blockade therapy were sufficient to slow ventricular rate response in 1 patient, the second one required disopyramide and the other amiodarone to control ventricular rates. Of the remaining 7 patients, 2 presented with significantly elevated serum alcohol levels at the time of their cardiac arrest. In the other 5 no factor could be identitied which might have potentiated arrhythmogenesis. No specific interventions were undertaken in these 7 patients and they were discharged without antiarrhythmic drug therapy. Predischarge therapy and follow-up: Although 3 patients required class I or class III antiarrhythmic drugs for the treatment of supraventricular tachycardia,
O-10
11-20 LV
FIGURE patients.
hatched
1. Distribution
21-30
31-40
Ejection
Fractions
‘II-50
51-M)
40 patients were discharged without antiarrhythmic drug therapy or antitachycardia/defibrillation devices but were followed prospectively for the occurrence of subsequent major arrhythmic events. At 32 f 21 months, 37 patients (92%) have remained free of arrhythmic recurrence while 3 patients (8%) recurred: 1 died suddenly, 1 was successfully resuscitated from an episode of documented VF and 1 experienced a prolonged syncopal episode. Six patients died of noncardiac causes: 4 from cerebrovascular disease and 2 from metastatic carcinoma. The cumulative occurrence over time for both major arrhythmic episodes and estimated overall survival is shown in Figure 3. At 18 and 36 months of follow-up, the estimated probabilities of arrhythmia-free survival were 94 and 88%, respectively. The cumulative occurrence over time of death from all causes at 30 and 60 months was 84 and 54%, respectively. There was only 1 arrhythmic death in the entire patient population. Characteristics of patients with arrhythmic rence: Two of the 3 patients with arrhythmic
recur-
recurrence had cardiomyopathy and minimally depressed ejection fractions of 42 and 40% at the time of their initial evaluation. The first patient, treated with procainamide during the index episode of VF, died suddenly at 29 months of follow-up. The second patient was self-administering multiple over-the-counter dietary drugs and had hypokalemia (3.0 mEq/ml) at the time of her initial cardiac arrest. She had syncope 19 months later, at which time her serum potassium was normal and no interim decrease in ejection fraction was documented. She was noninducible at repeat programmed stimulation despite the use of an aggressive stimulation protocol. She was treated with amiodarone and has had no arrhythmic recurrence during the subsequent 20 months of follow-up.
61-70 LOWN
(% )
of LV ejection fractions in our 43 The mean LV ejection fraction is 44 f 15%. The areas represent patients with arrhythmic recurrence.
GRADE
FIGURE 2. Extent of spontaneous ventricular ectopy as classified according to the Lown grading system. The hatched areas represent patients with arrhythmic recurrence.
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NONINDUCIBILITY
IN CARDIAC
ARREST
SURVIVORS
The third patient was a 24-year-old lactating female whose initial cardiac arrest occurred 1 month postpartum and was associated with hypomagnesemia of 1.4 mg/dl and hypokalemia of 3.2 mEq/liter. Noninvasive and invasive cardiac evaluation revealed no evidence of underlying organic heart disease. The patient was discharged with potassium and magnesium supplementation but without antiarrhythmic drug therapy. At 8 months of follow-up, she was resuscitated from recurrent VF at which time her serum electrolytes were documented to be normal. Treatment with amiodarone was initiated and she has remained free of subsequent arrhythmic episodes during the last 33 months. The 3 patients given antiarrhythmic drugs after discharge to treat supraventricular tachyarrhythmias are also alive and free of arrhythmic recurrence at 12, 25 and 53 months. It is noteworthy that amiodarone was discontinued early during follow-up (<7 months) in the 2 patients who were receiving the drug after discharge. Both have remained arrhythmia-free despite the absence of chronic antiarrhythmic drug therapy.
remaining 40 patients were discharged without class I or class III antiarrhythmic drugs or automatically functioning antitachycardia/defibrillation devices. At 32 f 21 months, 37 patients (92%) have remained free of subsequent major arrhythmic events. The relatively low recurrence rate of 8% supports the premise that survivors of VF with absence of inducible VT during drugfree programmed electrical stimulation studies are generally at low risk for arrhythmic recurrence and can usually be safely managed without antiarrhythmic therapy. Thus, the potential toxicity and expense of empiric antiarrhythmic drugs-and even cardioversion/defibrillation devices-can often be avoided in these patients. The long-term survival for this group of patients was also excellent. Actuarial estimates of survival were 84 and 54% at 30 and 60 months, respectively. This finding lends support to the use of an aggressive arrhythmia evaluation in survivors of cardiac arrest because these noninducible patients do not exhibit an extremely high incidence of death from nonarrhythmic causes. In contrast to our findings which support an excellent outcome in VF survivors without inducible VT, other investigators report a higher incidence of arrhythmic recurrence.12-l4 For example, Roy et all2 reported a 32% incidence of subsequent sudden cardiac death in noninducible survivors of cardiac arrest at 20 months of follow-up. They included, however, patients in whom the arrhythmia documented during cardiovascular collapse was sustained VT. Because the pathophysiology of sustained VT is likely to be different from that of VF or VT degenerating to VF, the arrhythmic outcome and predictive value of programmed stimulation may also vary as a function of the type of presenting arrhythmia. Another factor that may account for these differences in arrhythmic outcome was the empiric use of antiarrhythmic drugs in 29 of 47 noninducible patients report-
DISCUSSION
The majority of patients who survive prehospital VF exhibit inducible VT in response to drug-free programmed electrical stimulation studies. When antiarrhythmic therapy renders these patients free of inducible VT, they appear to be at low risk for arrhythmic recurrence.5-8 However, 12 to 37% of VF survivors are noninducible at control programmed stimulation and the value of this technique in predicting their subsequent arrhythmic course is not yet well defined.lO-l3 In an effort to more clearly define the natural history of noninducible VF survivors, we examined the arrhythmic outcome of 43 such patients (only 3 of whom received long-term antiarrhythmic drug therapy). The
-9L--.,
MAE ‘1.--------------, DEATH 1
FIGURE 3. Kaplan-Meier analysis of the cumulative occurrence over time of subsequent major arrhythmic events (MAE) for patients without inducible ventricular tachycardia (so/id line) and cumulative occurrence of death from all causes (dashed line). There was 1 arrhythmic death in this group.
1 20 MAE-FREE DEATH-FREE
1216
N ~40 N ~40
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ed by Roy et a1.12Thus, proarrhythmia may have contributed to the less favorable outcome observed in their patients. Finally, because the extent and nature of underlying heart disease were not clearly specified in the 18 patients discharged without antiarrhythmic therapy in the study by Roy et al, it is conceivable that more advanced coronary disease or poorer left ventricular function may have contributed to the higher incidence of arrhythmic recurrence observed by these investigators. In contrast, our study was limited exclusively to patients with VF, empiric antiarrhythmic drug therapy was not used and patients with significant coronary artery disease underwent aggressive antiischemic therapy. Accordingly, differences in patient population and type of therapy undertaken could account for the more favorable outcome of our noninducible VF survivors. It is important to note that possible potentiating factors for the development of VF were identified and corrected in 38 of the 43 patients in our study. The role these factors played in the genesis of VF is hypothetical, although supported by the clinical presentation and subsequent benign course of these patients. Thus, the favorable long-term arrhythmic outcome of the majority of the patients in the present study may in part be related to a modification of conditions critical to arrhythmogenesis. Of note are the 15 patients in whom critical coronary artery disease was identified and aggressively treated, and who remain free of arrhythmic recurrence despite discharge without specific antiarrhythmic drugs or devices, The favorable arrhythmic outcome of this group of patients lends support to the hypothesis that acute ischemia may have been critical to the development of VF. The role of acute ischemia in mediating VF has also been proposed by other investigators. Morady et allo reported no recurrent episodes of VF at 26 months of follow-up in 11 noninducible survivors of VF in whom therapy was directed solely at treatment of their underlying ischemic heart disease. Similarly, Swerdlow et all3 found no arrhythmic recurrence in 9 noninducible cardiac arrest survivors in whom a potential ischemic mechanism for arrhythmogenesis was identified and who were given antiischemic therapy alone after discharge. Despite the fact that the majority of our noninducible VF survivors has remained free of arrhythmic recurrence, 3 patients did sustain subsequent major arrhythmic events. If one excludes from the study population the 15 patients in whom critical coronary artery disease was identified and in whom aggressive antiischemic measures were used, 3 of the remaining 25 patients sustained arrhythmic recurrence and increased the recurrence rate to 12%. Thus, invoking nonischemic factors as potentiators of VF development should be undertaken only with caution. Among these 25 patients, no com-
mon feature could be identified that would allow for the prospective identification of these higher-risk patients. Accordingly, in noninducible VF survivors without critical coronary artery disease, the use of automatically functioning antitachycardia/defibrillation devices is not unreasonable, particularly because their use has been clearly demonstrated to improve arrhythmic outcome in certain subsets of cardiac arrest survivors. Further studies to more accurately characterize the natural history of the noninducible VF survivor are obviously required, an effort that may actually be facilitated by the use of these devices. Acknowledgment: The authors wish to thank Mary Mays, Michele Parker, RN, MS, and Catherine Summers Dunnington, RN, MS, for their invaluable help in the preparation of this manuscript.
REFERENCES 1. Liberthson RR, Nagel EL, Hirschman JC, Nussenfeld SR. Prehospital ventricular defibrillation: prognosis and follow-up course. N Engl J ked 1975; 291:317-321. 2. Baum RS, Alvarez H III, Cobb LA. Survival after resuscitation from out-ofhospital ventricular fibrillation. Circuhtion 1974;50:1231-1235. 3. Schaffer WA, Cobb LA. Recurrent ventricular fibrillation and mode of death in survivors of out-of-hospital ventricular fibrillation. N Engl J Med 1975; 293:259-262. 4. Cobb LA, Baum RS, Alvarez H III, Schaffer WA. Resuscitation from out-ofhospital ventricular fibrillation: 4 years follow-up. Circulation 197.5:51/ 52:111223-111228. 5. Myerburg RJ, Kessler KM, Estes D, Conde CA, Luceri RM, Zaman L, Kozlovskis PL, Castellanos A. Long-term survival after prehospital cardiac arrest: analysis of outcome during an 8 year study. Circulation 1984;70:538-546. 6. Josephson ME, Horowitz LN, Spielman SR, Greenspan AM. Electrophysiologic and hemodynamic studies in patients resuscitated from cardiac arrest. Am J Cardiol 1980;46:948-955. 7. Ruskin JN, DiMarco JP, Garan H. Out-of-hospital ventricular fibrillation: electrophysiologic observations and selection of long-term ant&rhythmic therapy. N Engl J Med 1980;303:607-613. 8. Morady F, Scheinman MM, Hess DS, Sung RJ, Shapiro W. Electrophysiologic testing in the management of survivors of out-of-hospital cardiac arrest. Am J Cardiol 1983;51:85m89. 9. Myerburg RJ, Conde CA, Sung RJ, Mayorga-Cartes A, Mallon SM, Sheps DS, Appel RA, Castellanos A. Clinical, electrophysiologic and hemodynamic profile of patients resuscitated from prehospital cardiac arrest. Am J Med 1980;68:568-576. 10. Morady F, DiCarlo L, Winston S, Davis JL, Scheinman MM. Clinical features and prognosis of patients with out-of-hospital cardiac arrest and a normal electrophysiologic study. JACC 1984;4:39-44. 11. Ruskin JN, McGovern B. Garan H, DiMarco JP, Kelly E. Antiarrhythmic drugs: a possible cause of out-of-hospital cardiac arrests. N Engl J Med 1983;309:1302~1306. 12. Roy D, Waxman HL, Kienzle MG, Buxton AE, Marchlinski FE, Josephson ME. Clinical characteristics and long-term follow-up in 119 survivors of cardiac arrest: relation to inducibility at electrophysiologic testing. Am J Cardiol 1983:52:969-974. 13. Swerdlow CD, Freedman RA. Peterson J, Clay D. Determinants of prognosis in ventricular tachyarrhythmia patients without induced sustained arrhythmias. Am Heart J 1986;111:433-437. 14. Benditt DG, Benson DW, Klein GJ, Pritzker MR, Kriett JM, Anderson RW. Prevention of recurrent sudden cardiac arrest: role of provocative electropharmacologic testing. JACC 1983;2:418-425. 15. Smith WM, Gallagher JL. Les Torsades de Pointes: an unusual ventricular arrhythmia. Ann Intern Med 1980;93:578-584. 16. Lown B, Wolf M. Approaches to sudden death from coronary disease. Circulation 1977;44:130m142. 17. Kaplan EL, Meier P. Non-parametric estimations from incomplete observations. J Am Stat Assoc 1958:53:457-581.
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