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Acute Hemodynamic Effects of Hexamethonium in Normotensive Man By Louis RAKITA, M.D., AND SALVATORE M. ASSISTANCE OF GLADYS HECKMAN, R.N., SANCETTA, M.D., WITH THE TECHNICAL AND HANNA JANOUSKOVEC, R.X. The effect of intravenous hexamethonium bromide was studied in 10 normotensive human subjects in the steady state. In the absence of over-all change in cardiac output, the variable decrease in arterial pressure is accounted for by decrease in calculated total peripheral resistance. in Douglas bags (four minutes), and the oxygen content obtained by passage through the Pauling oxygen analyzer. All volumes were corrected to standard temperature and pressure. The maximal difference allowed between two successive oxygen consumption and cardiac output check determinations was 10 per cent (steady state). Following basal determinations, hexamethonium was administered intravenously at a rate of 1 mg. per minute for 10 minutes; dosage and rate of administration were grossly doubled thereafter until a noticeable decrease in brachial arterial pressure was observed. In three patients receiving a total of 120 nig., the last 50 mg. were injected at a rate of 10 mg. per minute. The total dosage varied from 15 to 120 mg. Basal studies were repeated 30 minutes following termination of injection. The following changes from the basal during the experimental period were considered significant: (a) 20 per cent for mean brachial artery pressure, (b) more than 10 per cent for cardiac index, (c) more than 15 beats per minute for heart rate, (d) 5 mm. Hg for pulmonary artery pressure, and (e) 20 per cent for calculated resistances and left ventricular work. Complete data are presented in 10 of 12 patients; the other six were eliminated from the documentation because of failure to maintain a steady state or poor blood analysis checks. T Downloaded from http://circres.ahajournals.org/ by guest on June 15, 2017 HE INCREASING clinical use of hexamethonium, a ganglion blocking agent, makes desirable a detailed knowledge of its acute hemodynamic effects in normotensive man. Recent work on dogs 1 ' 2 indicates that the hexamethonium-induced fall in arterial pressure is accompanied by significant decrease in cardiac output with increase in the calculated total peripheral resistance. Accordingly, the authors concluded that the decrease in arterial pressure was due to the reduction in the cardiac output. Such findings require confirmation in humans. The present investigation was designed to serve this purpose. MATERIAL AND METHODS Eighteen normal subjects free of cardiac or pulmonary disease, infection or fever were selected from the medical wards. Following light sedation, routine dextrocardiao catheterization was performed in an ambient temperature of 24 C. Central venous pressures transduced via Statham strain gages, and brachial arterial pressures, measured through an indwelling arterial needle, were simultaneously inscribed with an electrocardiogram on a Brush sixchannel oscillograph. Mean pressures were derived by planimetries integration of two consecutive respiratory cycles. Left ventricular work as well as total peripheral and pulmonary resistance was calculated by conventional formulas. All blood specimens were withdrawn in duplicate and oxygen contents were determined spectrophotometrically.3 The maximal variation allowed between checks was ±0.2 volumes per cent. Expired air, measured through a dry gas test meter, was collected RESULTS AND DISCUSSION Pertinent data are presented in table 1. 1. Brachial artery pressure tended to decrease in all patients except D. B. In the latter, a larger dose might have been effective, since there was great variation in dosage-response. 2. Pulmonary artery pressure tended to decrease in nine subjects; there was an insignificant rise in three subjects. 3. The cardiac index increased in three, decreased in three, and was unaltered in four individuals. The average change for the entire group was +0.8 per cent. From the Department of Medicine, Western Reserve University at City Hospital, Cleveland, Ohio. This investigation was supported by a grant (No. H-13S2) from the National Heart Institute of the U. S. Public Health Service. Received for publication June 4, 1953. 499 Circulation Research, Volume I, November 1953 500 EFFECTS OF HEXAMETHONIUM IN MAN 4. Tlcart rate rose in all subjects except one (L. B.) in whom an insignificant fall was noted. 5. Total peripheral resistance decreased in noted in II. G., and was dissociated from the changes in T.P.R. and cardiac index. 7. Left ventricular work was reduced in nine TABLE 1.—Hemodynamic Effects of Hexamethonium Bromide in Normotensive Humans Pt. Hex. mg. OJCM' us C.I. H.R. P A .P. T.P.R. Pu.AR. L.V.W. 71 88 + 17 17/5 (10.8) 16/5 ( 9.5) - 1 2 % •- ( 1.3) 1750 11S5 -32.3% ISO 144 -22.0% 6.42 5.55 -12.0% 14/8 (10.7) 8/3 ( 5.0) —17.0% - ( 5.1) 1572 1372 -12.7% 226 147 -35.0% 3.79 2.06 —15.6% (102) 138/81 (78) 107/71 -23.5% - ( 3 4 ) +6.7% 2.73 3.10 + 13.5% B. Ex. 96/59 ( 74) 62/45 ( 52) —30.6% - ( 22) 102 93 -8.8% 2.21 1.75 —20. S% 73 88 + 15 L. A. M-48 1.65 M" 50 B. Ex. 105/53 ( 76) 80/44 (59) -22.0% - (17) 130 136 +4-6% 3.51 3.19 -9.1% 73 79 +0 F. P. M—30 1.68 M1 70 90/60 ( 73) 77/4S ( 59) -19.0% - ( 14) 128 13S 3.60 4.27 + 18.6% J. 11. M—29 1.78 M« 70 A. C. M-25 1.87 M« 120 E. II. F-26 1.71 M' 70 8. II. G. M—49 1.87 M> 58 9. L. B. F— 53 1.80 M1 15 B. Ex. D. B. F-34 1.62 M ! 65 B. Ex. 11.* C. T. M—28 1.81 M' 120 12.' D . V. M—23 1.79 M 1 120 W. J. M-37 1.69 M» 70 2. A. R. M—39 1.69 MJ 20 1. 3. Downloaded from http://circres.ahajournals.org/ by guest on June 15, 2017 4. 5. 0. 7. 10. Average percentile change B. Ex. B.A.P. B. Ex. B. Ex. B. Ex. B. Ex. B. Ex. B. Ex. B. Ex. 126 +7.8% +2.0% + ( 0.3) 106S 920 -13.1% + 12.1% 5.84 4.14 -29.0% 73 109 +36 18/5 (11.0) 15/5 ( 9.0) —18.1% - ( 2.0) 960 654 -31.8% 148 99 -32.4% 6.15 5.69 -7-4% 3.51 4.22 +20.2% 55 94 + 39 22/14 (17.0) 14/8 (11.0) - 3 5 . 3 % - ( 6.0) 9S0 690 -29.6% 3.12 3.42 S3 97 + 14 18/10 (14.0) 14/7 (10.0) -28.5% -(4.0) 975 7S6 -19.3% 83 103 12/5 ( 7.8) 11/6 ( 7.3) -6.4% -(0.5) 950 879 -7.4% +2.5% 5.04 3.80 —22.6% 993 825 —16.8% 173 203 + 17.3% 5.65 3.55 -37.3% 24/8 23/7 (14.9) (15.2) 209 234 ( 74) 1OS/51 90/51 ( 65) -12.9% - ( 9) +2.2% 91/63 ( 71) S9/57 ( 64) -10.9% - ( 7) 126 130 +3.1% 87/51 ( 67) 66/45 ( 56) -16.2% - ( 11) 114 118 +3.5% 3.27 2.96 -9.4% 89/59 ( 72) 66/48 ( 52) -28.4% - ( 20) 139 133 -4.3% 3.10 2.70 -12.9% +9 (12.6) (12.8) + 1.5% + ( 0.2) 120/63 ( 92) 72/46 ( 58) -37.0% - ( 34) 126 119 -5.5% 3.21 3.07 -4.3% 79 74 —5 23/12 (15.6) 19/12 (13.1) —16.0% —( 2.5) 1232 812 -34.0% 208 181 —12.8% 7.44 4.47 -38.4% 1.77 1.60 -10.0% 63 88 +25 20/10 (13.2) 12/7 ( 7.7) - 4 1 . 6 % - ( 5.5) 2038 2264 + 11.0% 368 240 -34.7% 2.80 2.50 -10.7% 75 83 (11.4) (11.7) +2.6% + ( 0.3) -17.0% —20.9% -20.5% 92/59 90/62 0% ( 73) ( 74) +( 0 135 138 81 85 +7.8% +9.6% 106/60 ( 76) Sl/51 ( 58) - 2 3 . 6 % - ( 18) 91 100 17/8 21/S 73 90 -46.3% 6.50 +3.1% 186 130 -30.0% 5.63 5.50 -24.0% 112 115 19/7 (11.4) 13/8 (10.0) - 1 2 . 3 % - ( 1.4) + 17 +0.8% 6.30 us 17/8 16/9 +8 111/66 ( 79) 90/5S ( 71) - 9 . 8 % - ( 8) —20 3 % +20 220 + 19.1% —17. 3 % ! Key: B.: basal, Ex.: experimental, B.A.P.: mean brachial arterial pressure, O2CM : oxygen consumption in cc./sq. meter/min.. C.I.: cardiac index in liters/niin., H . R . : heart rate, P.A.P.: pulmonary arterial pressure (mean pressures in parentheses), T.P.R.: total peripheral resistance, Pu.A.R.: pulmonary artery resistance (dynes/sec./cm." 6 ), L.V.W.: left ventricular work (Kg. meters/min.) * Not included in averages. all patients except one (D. B.) in whom a negligible increase occurred. 0 Total pulmonary artery resistance decreased in seven subjects; two showed a negligible rise. A slight and unexplained rise was patients; a negligible increase due to a significant rise in cardiac index was noted in J. H. Basal peripheral arterial oxygen saturation values (range: 94 to 96.5 per cent) were unchanged. The form of the electrocardiograms^ LOUIS RAKITA AND SALVATORE M. SANCETTA Downloaded from http://circres.ahajournals.org/ by guest on June 15, 2017 was unaltered except for changes produced by variations in heart rate. The data demonstrate that there is no direct relationship between the changes in cardiac index and those that occur in the arterial blood pressure. Rather, there is a tendency for pulmonary and peripheral arterial pressures, pulmonary and total peripheral resistances, and the mechanical work of the left ventricle to decrease. The differences between these findings and those in anesthetized normotensive and renal hypertensive dogs 1 ' 2 is emphasized by subjects W. J., F. P., J. H. in which definite decreases in arterial pressure were attended by increases in the cardiac index and reductions in calculated resistance. In other cases (A. R., E. H., L. B.), despite a decrease in the cardiac index, calculated resistance still was lowered. On the average, the cardiac index underwent no change, whereas the other modalities measured showed borderline significant percentile alterations. The action of hexamethonium in man appears to differ from that reported in dogs. The conclusion germane to the dog data, that decrease in cardiac output is responsible for fall in arterial pressure does not apply to man. With dosage at times greater than that administered to dogs, hexamethonium in man produced a fall in peripheral arterial pressure purely as a result of ganglion blockade, with variable changes in the cardiac output. The varying degree of tachycardia usually encountered altered the total output changes. Our findings corroborate the undocumented report of Freis and associates.4 There is much Individual variability in dose-response. Had our object been to produce a standard fall in blood pressure, greater reductions might have resulted. From the standpoint of caution, we ceased administration of 501 the drug pursuant to a noticeable decrease in peripheral arterial pressure, and did not feel justified in continued administration in the face of a definite tachycardia. SUMMARY AND CONCLUSIONS 1. Hexamethonium bromide was administered intravenously to 12 normotensive individuals in a steady state. Complete data are presented for 10 of these subjects. 2. Changes in cardiac output are variable, and the heart rate is generally increased. Brachial and pulmonary artery pressure, and calculated total peripheral and pulmonary resistances, and left ventricular work undergo an over-all decrease. There is marked individual variation in dose-response. 3. These data indicate that hexamethonium lowers arterial pressure in normotensive man primarily by diminishing total peripheral resistance, rather than by diminishing cardiac output. REFERENCES 1 MURPHY, Q. R., O'BRIEN, G. S., RENNIE, D. W., CAPPS, R. T., ROWE, G. G., ANTD CRUMPTON, C. W.: Effect of hexamethonium bromide (C-6) on cardiovascular system in normotensive and hypertensive dogs. Fed. Proc. 12: 101, (March), 1953. 2 CRUMPTON, C. W., ROWE, G. G., CAPPS, R. T., O'BRIEN, G. S., AND MURPHY, Q. R.: Effect of hexamethonium bromide on coronary flow, cardiac work and cardiac efficiency. Proc, Nat. Meet. Am. Fed. Clin. Res. No. 25, (May 3), 1953. 3 HICKAM, J. B., AND FRAYSEH, R.: Spectrophotometric determination of blood oxygen. J. Biol. Chem. 180: 457, 1949. * FREIS, E. D., ROSE, J. C, HIGGINS, T. F., KELLEY, R. T., SCHNAPER, H . W., AND JOHNSON, R. L.: The hemodynamic effects of hexamethonium in man. J. Clin. Investigation 31: 029, 1952 (Abstract) . Acute Hemodynamic Effects of Hexamethonium in Normotensive Man LOUIS RAKITA, SALVATORE M. SANCETTA, HECKMAN R.N. GLADYS and JANOUSKOVEC, R.Y. HANNA Downloaded from http://circres.ahajournals.org/ by guest on June 15, 2017 Circ Res. 1953;1:499-501 doi: 10.1161/01.RES.1.6.499 Circulation Research is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 1953 American Heart Association, Inc. All rights reserved. Print ISSN: 0009-7330. Online ISSN: 1524-4571 The online version of this article, along with updated information and services, is located on the World Wide Web at: http://circres.ahajournals.org/content/1/6/499 Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation Research can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. 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