Effects of Propranolol on Patients with Complete Heart Block and Implanted Pacemakers

Transcription

1 Effects of Propranolol on Patients with Complete Heart Block and Implanted Pacemakers By EPHRAIM DONOSO, M.D., LAWRENCE J. COHN, M.D., BERTRAM J. NEWMAN, M.D., HENRY S. BLOOM, M.D., WILLIAm C. STFIN, M.D., AND CHARLES K. FRIEDBERG, M.D. SUMMARY The effects of beta-adrenergic blockade with propranolol were studied in 1 patients with complete heart block and fixed rate internal pacemakers. The patients were grouped according to the absence or presence of premature systoles before propranolol was given. In the patients with premature systoles propranolol was uniformly effective in abolishing the premature systoles. Propranolol was found to increase the systemic venous pressure, to decrease the cardiac output, and to lower myocardial contractility both at rest and during exercise in both groups. Since the heart rate was fixed, it was concluded that beta-adrenergic blockade has a significant negative inotropic effect, in addition to the chronotropic effect. Additional Indexing Words: Beta-adrenergic blockade Hemodynamics with pacemaker Premature systoles Venous pressure Cardiac output Downloaded from by on January 17, 219 PROPRANOLOL BLOCKS both the inotropic and chronotropic effects of betaadrenergic stimulators on the heart.' The availability of patients with complete heart block and fixed rate ventricular pacemakers provided an opportunity for studying the effect of propranolol on cardiac contractility independent of changes in the heart rate. Methods Ten elderly patients with complete heart block and fixed rate internal pacemakers were selected for this study. All of the patients were more than 65 years of age (range 66 to 84 years) and all were in complete heart block at From the Division of Cardiology, Department of Medicine, Mount Sinai Hospital, New York, New York 129. This investigation was supported in part by Grants HE , FR-55-4, and HE from the National Institutes of Health, U.S. Public Health Service. Work was done while Drs. Cohn, Newman, and Bloom held postdoctoral fellowships from the U.S. Ptublic Health Service. the time of study. There was complete ventricular capture by the pacemaker at rates of 66 to 85/min. The patients were grouped according to the absence or presence of premature systoles before propranolol was given. In four patients (group 1) there were no premature systoles while the remaining six patients (group 2) had premature systoles at either rest or exercise. In five of the group 2 patients, the premature systoles were ventricular in origin and in one patient they were due to pacemaker-induced reciprocal beats. Two patients in group 1 and five of the six patients in group 2 had been in clinical congestive heart failure prior to the insertion of a pacemaker, but heart failure was not evident in any of the subjects at the time of study. All studies were carried out in the basal, postabsorptive state without premedication while the patient was in the supine position. A constant level of exercise was performed on a bicycle ergometer with the rate and work load remaining the same during all exercise periods. Measurements of oxygen consumption were attempted but were uniformly unsuccessful because of the inability of the patients to tolerate the mouthpiece and nose clips. An 18T Cournand needle was employed in the brachial artery for measurement of systemic 534

2 Downloaded from by on January 17, 219 EFFECTS OF PROPRANOLOL arterial pressure and for the withdrawal of blood for the dye-dilution curves. A vinyl catheter was inserted percutaneously into a peripheral vein and advanced to the right atrium or superior vena cava for venous pressure measurements and dye injections. Cardiac outputs were determined in duplicate by the dye-dilution method utilizing indocyanine green, a cuvette densitometer, and a constant speed withdrawal pump. Pressures were measured with ultra-low displacement unbonded strain gauges, and an RC differentiating circuit was employed to determine the first derivative of the brachial artery pressure. Data were recorded on an oscilloscopic photographic recorder. Arterial ph was measured in five subjects with a calomel electrode ph meter. At the time of study, patients first completed a 1-minute practice exercise period during which the maximum exercise tolerance was determined and the patient was familiarized with the ergometer. After a suitable delay to re-establish a basal state, base-line resting studies followed by base-line exercise studies were carried out. Five minutes of exercise were allowed for achieving a steady state prior to measurements; then cardiac outputs were measured approximately 3 minutes apart, at 5 and 8 minutes of exercise. At the completion of the exercise studies,.1 mg/kg of propranolol (AY-6443)* was infused intravenously over a 2-minute period, but one patient in group 2 (M.K.) required a total dose of 1 mg (.16 mg/kg) to abolish the premature systoles. On the basis of previous studies 2 minutes were allowed to attain a steady state after which time resting and exercise studies were repeated. In assessing the significance of changes in cardiac index, the inherent error of the dyedilution method (±+ 1%) was employed, any variation greater than 1% being considered significant.2 In all subjects the time constant of the logarithmic extrapolation of the dye-dilution curves increased after propranolol. In one subject (D.S.) the time constant after propranolol was too prolonged to allow accurate calculation of the cardiac output, and the cardiac index data on this patient were excluded from the averages in table 1. However, the prepropranolol values were included for reference. In one subject (J.Z.) technical difficulties prevented an accurate dp/ dt from being calculated. *The propranolol used in this study was kindly supplied by Dr. Alex Shahaygian-Edwards of Ayerst Laboratories. 535 Results Rhythm. All four patients had complete ventricular capture by the pacemaker without premature systoles and this rhythm was unchanged after propranolol.. Two patients had premature systoles at rest and all six had premature systoles with exercise. In the two patients with premature systoles at rest, the rate was 5/min or more in one and less than 5/min in the other. In both of these two patients the frequency of premature systoles increased with exercise. In the four patients who had premature systoles on exercise only, the incidence was 5/min or more in two and less than 5/min in two., premature systoles were completely suppressed in all six patients, both at rest and exercise. This effect was observed within 5 minutes of propranolol administration and persisted for more than 2 hours. Cardiac Index (Table 1). The basal cardiac index in all four patients was less than 2.5 L/min/m2 and averaged 2.8 L/min/m2. With exercise all four subjects showed significant (>1%) increments in their cardiac index., the basal cardiac index fell in all by an average of 28 ml/min/m2 and with exercise the average cardiac index was 51 ml/min/m2 less than with exercise before propranolol.. The basal cardiac index in all six subjects was 2.2 L/min/m2 or less and averaged 1.76 L/min/m2. Five of the six were able to increase their cardiac index with exercise., the resting cardiac index fell significantly in four of five subjects in whom it could be measured by an average of 34 ml/min/m2. The fifth subject (M.K.) showed no change in cardiac index at rest. With exercise after propranolol the cardiac index fell in all five subjects in whom it could be measured by an average of 64 ml/min/m2 compared to the exercise values before propranolol.

3 536 DONOSO ET AL. Cardiac Index (L/min/m2) Table 1 Pacemaker Electrode Rate site per min J.F LV 66 R.B LV 72 A.Z LV 74 G.L LV I.M LV 67 R.V LV 73 D.R LV 68 M.K RV 85 J.Z LV 66 D.S. 1.15* 1.62* - LV *Not included in group 2 average. Abbreviations: LV left ventricular epicardial electrodes; RV = permanent right ventricular endocardial catheter electrode. Downloaded from by on January 17, 219 Brachial Artery Pressure (mm Hg) J.F. 186/78,14 R.B. 247/19,133 A.Z. 129/65,85 G.L. 162/78,1 181/83,16 I.M. 171/83,16 R.V. 186/75,124 D.R. 16/74,99 M.K. 141/68,94 J.Z. 118/65,86 D.S. 121/67,9 15/72,1 Table 2 229/75, /17, /69,95 182/75,18 27/82,121 18/85, /82,122 2/83,114 14/65,9 148/65,93 141/67,92 173/75,16 187/85, /15, /74,96 153/77,14 172/85, /86, /8, /69,89 122/69,79 127/62,86 113/69,84 139/73,95 21/77,12 219/95, /71,89 162/73,18 18/79, /95, /8, /82,16 125/69,82 126/67,88 115/68,85 15/77,11 Arterial Pressures (Table 2) Brachial artery pressures in both groups were similar. Except for one hypertensive patient in group 1 all patients had normal basal diastolic pressures, while six had systolic hypertension (>15 mm Hg), the average basal pressures being 162/76, m = 12. With exercise before propranolol systolic pressures tended to rise with little change in diastolic pressures (average pressures, 186/ 77, m 112)., systolic pressures fell slightly in six patients and were the same in four patients, while diastolic pressures were unchanged (average pressures, 152/78, m= 12). With exercise after propranolol systolic pressures fell in all 1 patients, while diastolic pressures showed little change (average pressures, 162/78, m = 17). Arterial Pressure-Maximum dp/dt (Table 3). Basal maximum dp/dt was greater than 1, mm Hg/sec in all four subjects

4 Downloaded from by on January 17, 219 EFFECTS OF PROPRANOLOL Table 3 Brachial Artery (Maximum dpldt) J.F. R.B. A.Z. G.L. I.M. R.V. D.R. M.K. J.Z. D.S and increased with exercise in all., the resting value fell in all by an average of 3 mm Hg/sec while the exercise value fell by an average of 4 mm Hg/sec.. Basal maximum dp/dt was greater than 1, mm Hg/sec in all five subjects in whom it was measured and increased with exercise in all. the resting value fell in all by an average of 4 mm Hg/ sec. With exercise after propranolol, maximum dp/dt failed to increase in two subjects, increased by only 7 mm Hg/sec in one, and the average value fell by 9 mm Hg/sec. Venous Pressure (Table 4). The basal central venous pressure was normal (< 6 mm Hg) in all four subjects and rose to abnormal levels (6 mm Hg or more) in two subjects with exercise. After propranolol the resting venous pressure remained normal in all but with exercise rose to abnormal levels in three subjects.. The basal venous pressure was normal in all five in which it was measured, but it became abnormal with exercise in four subjects. the venous pressure was abnormal in one subject at rest and in four subjects with exercise. Discussion In patients with heart disease most investigators have reported falls in the cardiac out- Table 4 Central Venous Pressure (mm Hg) J.F. R.B. A.Z. G.L. I.M. R.V. D.R. M.K. D.S put after beta-adrenergic blockade.3-5 However, the cardiac output is unchanged in some patients,3' 6'7and an increased cardiac output has been found in other patients, unrelated to the control of arrhythmia.8 Wolfson and associates7 reported the case of one patient in sinus rhythm in whom the resting rate was held constant by atrial pacing. In this subject, cardiac output and mean myocardial fiber shortening rate (measured indirectly) were unaltered after propranolol. They suggested that the effects of propranolol were due solely to the change in rate. However, Sonnenblick and associates9 also employed atrial pacing at a constant rate in one patient in sinus rhythm and found a reduction in the cardiac output without any change in myocardial shortening velocity (measured directly). In a preliminary report, Whalen and coworkers' reported that propranolol lowered the resting cardiac output in dogs with surgically induced complete heart block and internal pacemakers when the rate of pacing was slow (68/min). Sowton and Hamer5 have reported hemodynamic data on one patient with complete heart block and an internal pacemaker in whom the cardiac output at both rest and exercise fell after propranolol. The present study confirns this individual case report and

5 538 clarifies the role of the positive inotropic effect of the beta-adrenergic system. Acknowledgment The cardiac pacemakers were implanted by Drs. Robert Litwak and Howard Gadboys. Mr. Dimitris Karabelas gave us invaluable tecbnical assistance. References 1. BRAUNWALD, E.: Editorial: Symposium on betaadrenergic blockage. Amer J Cardiol 18: 33, SLEEPER, J. C., THOMPSON, H. K., JR., MCIN- TOSH, H. D., AND ELSTON, R. C.: Reproducibility of results obtained with indicatordilution techniques for estimating cardiac output in man. Circulation Research 11: 712, SCHRODER, G., AND WERK6, L.: Hemodynamic studies and clinical experiences with Nethalide, a beta-adrenergic blocking agent. Amer J Cardiol 15: 58, HAMER, J., AND SOWTON, E.: Cardiac output after beta-adrenergic blockage in ischemic heart disease. Brit Heart J 27: 892, DONOSO ET AL. 5. SOWTON, E., AND HAMER, J.: Hemodynamic changes after beta-adrenergic blockade. Amer J Cardiol 18: 317, HOWITT, G., TINKER, J., AND WADE, E. G.: Effect of pronethalol in mitral stenosis. Clin Sci 28: 417, WOLFSON, S., HEINLE, R. A., HERMAN, M. V., KEMP, H. G., SULLIVAN, J. M., AND GORLIN, R.: Propranolol and angina pectoris. Amer J Cardiol 18: 345, TSOLAKAS, T. C., DAVIES, J. P. H., AND OCRAM, S.: Effect of a beta-adrenergic-blocking agent on the pulmonary circulation in mitral stenosis. Lancet 2: 416, SONNENBLICK, E. H., BRAUNWALD, E., WILLIAMS, J. F., JR., AND GLICK, G.: Effects of exercise on myocardial force velocity relations in intact unanesthetized man: Relative roles of changes in heart rate, sympathetic activity, and ventricular dimensions. J Clin Invest 44: 251, WHALEN, R. E., MORRIS, J. J., JR., BEHAR, V. S., THOMPSON, H. K., JR., AND MCINTOSH, H. D.: Hemodynamic effects of beta-adrenergic blockade at controlled heart rates. Clin Res 14: 265, Downloaded from by on January 17, 219 Circulation, VoluMe XXXVI. October 1967