HEMODYNAMIC ALTERATIONS IN HYPERTENSIVE PATIENTS DUE TO CHLOROTHIAZIDE* Epwarp D. Frouuicu, M.D.,f Harotp W. ScHNnarer, M.D.,f [tse M. Witson, M.D.,} ano Epwarp D. Freis, M.D.§ WASHINGTON, D. C. NLY two studies have been published that detail the changes in cardiac output after chloro- thiazide.*? Other reports** have alluded to the changes in cardiac output without tabulating any data. In the studies in which results were reported in detail, cardiac output was performed by the dye-dilution technic. Aleksandrow and his co-workers' reported variable results in 7 hypertensive patients whereas Dustan and her associates’ demonstrated a consistent decrease. This communication reports on a series of hypertensive patients in whom cardiac output was measured before and after administration of chloro- thiazide. In the majority of patients the direct Fick method was used, the dye-dilution technic being em- ployed in the others. MareriAL AND METHODS Seven male patients with moderately severe hyper- tension were selected for study. The average age was forty-eight years. None had a history of congestive heart failure. Before the control determinations were obtained, the patients were in the hospital, without antihypertensive medications, for three or more days depending on the time required for the blood pres- sure to reach a relatively constant level. All patients were given the usual hospital diet containing between 6 and 8 gm. of sodium chloride per day. Experiments were carried out, with the patient fast- ing, approximately one hour after the oral adminis- tration of 100 mg. of pentobarbital. In the first 5 patients (Table 1), three control determinations of cardiac output were performed at fifteen-minute in- tervals by means of the direct Fick method. The catheter tip was placed in the mid-position of the right atrium to avoid the unnecessary risk of ventricu- *From the Medical Service, Veterans Administration Hospital, and the Department of Medicine, Cardiovascular Research Laboratory, Genrectown University School of Medicine. pported in part by United States Public Health Service Grants H- 0 und H-1904 (National Heart Institute). +Fellow in cardiovascular research, Department of Medicine, George- town University School of Medicine. fAssistant professor of medicine, Georgetown University School of Medicine; assistant chief of medicine, Mount Alto Veterans Adminis- tration Hospital. §Associate professor of medicine, Georgetown University School of Medicine; Senior Medical Investigator, Mount Alto Veterans Administra- tion Hospital. lar catheterization. In the last 2 patients (Table 1), cardiac outputs were determined with the use of the dye-dilution technic (T-1824). The dye was injected through a polyethylene catheter threaded into the axillary vein, and collections were made at two- second intervals from the femoral artery. After the first determination of cardiac output each subject was given 1.5 gm. of chlorothiazide daily for three days. On the fourth day the cardiac output was repeated. Blood and plasma volumes and hematocrit were de- termined from dye samples at ten, fifteen and twenty minutes. Blood and plasma volumes were determined in the first 5 patients (Table 1) by means of I*** labeled albumin. Blood samples were obtained ten minutes after injection and were counted for gamma activity in a well counter. Body weights were determined with the use of a beam-balance scale just before each determination of cardiac output. Calculations of the hemodynamic data in the patients studied by the direct Fick and dye-dilution technics were carried out according to the methods previously described.*-* REsuLTS The cardiac output fell in 6 of the 7 patients after chlorothiazide. In Case 5 there was a 5 per cent increase in cardiac output. The average decrease in cardiac output for the entire group was 29 per cent. In the 6 subjects in whom the cardiac output fell, the decrease ranged from 8 to 50 per cent (average fall, 34 per cent). The systolic pressure fell in all 7 patients. The de- crease in systolic pressure ranged from 3 to 33 per cent, with a mean fall of 17 per cent. The diastolic pressure fell in only 5 of the 7 patients. In Case 5 there was a 5 per cent rise in diastolic pressure; there was no change in Case 7. The decreases in diastolic pressure ranged from 5 to 33 per cent. The average change for all patients was a decrease of 13 per cent. The mean arterial pressure fell in 6 of the 7 patients. In Case 5 there was a 2 per cent rise. The average fall was 15 per cent. In the 3 patients in whom pressures in the right atrium were recorded, the following results were ob- Reprinted from the New England fownal i Medicine 262:1261-1263 (June 23), tained after administration of chlorothiazide: a de- crease of 5.5 mm. of mercury in Case 1; a decrease of with those of Aleksandrow and his associates’ (Table 2). The increase in total peripheral resistance of 3% Taste 1. Hemodynamics of Chlorothiazide in Hypertensive Patients. SysTotic PressuRE Case AGE Carpiac OuTPuT No. CONTROL EXPERI- CONTROL MENTAL*™ yr. ml.fmin. ml.émin. mm. Hg. 1+ 52 6112 2825 194 a+ 52 5018 3649 314 3 36 6481 5974 180 4+ 45 4133 2085 223 3+ 52 5281 5535 181 6 50 6336 3429 170 7 51 6286 4600 190 Averages 48 5664 4014 207 Mean percentage 29 change Diastoiic PRESSURE MEAN ARTERIAL Press uRE EXPERI- CONTROL EXPERI- CONTROL EXPERI- MENTAL™ MENTAL* MENTAL* mm. He. mm. Hg, mm, He. mm. Hg. mm. Hg. 174 108 98 137 123 209 156 119 209 149 140 135 90 150 107 176 141 134 168 148 175 93 98 122 124 140 110 90 130 107 185 105 105 133 132 171 121 105 150 127 -17 —13 -15 *Results alter 3 days of chlorothiazide therapy. +Control value average of 3 separate determinations. 2.0 mm. in Case 2; and a decrease of 8.2 mm. in Case 4. The plasma and blood volumes were decreased in 6 of the 7 patients studied. In Case 4 there was a 7 per cent in the present series and 23 per cent in the report of Dustan et al. are at variance with the lack of average change (—10 per cent) found by Alek- sandrow and his co-workers. Similarly, the magnitude Taste 2. Comparison of Three Studies on Hemodynamic Effects of Chlorothiazide. Stupy Group No. oF CHANGE IN Car- CHANGE IN Sys- CHANGE IN Di- CHANGE IN CHANGE IN CHANGE IN CasEs DIAG OutPutT TOLIG BLoop ASTOLIC BLoop = MgzaN ArTERIAL ToTAL PERIPH- PLasMA PRESSURE PRESSURE PRESSURE ERAL RE- VoLuME SISTANCE % To % %o % % Present series 7 -29 -17 —13 -15 +33 -13 Dustan et al.? 9 —23* -ll -8 —6 +23 ~14 Aleksandrow et al.1 7 -5 + -19 -10 _ *Expressed as cardiac index. +Value not given. and 6 per cent increase in the plasma and blood volumes respectively. The mean decrease in the plas- ma volume for the entire group of 7 cases was 13 per cent. The hematocrit demonstrated a slight increase. The average weight loss was 3.2 kg. The total peripheral resistance increased in 5 of the 7 patients. The increase averaged 33 per cent. In 2 patients there was a decrease in the total periph- eral resistance of 2 and 23 per cent respectively. Discussion The present results are similar to those reported by Dustan et al.’ They are, however, at some variance of change in averaged cardiac output was in agree- ment —— — 29 per cent for the present results and — 23 per cent for those of Dustan and her associates (ex- pressed as cardiac index) — but differed from those of Aleksandrow, Wysznacka and Gajewski! (—5 per cent). All 9 of the patients of Dustan and her co- workers exhibited decreased cardiac output after chlorothiazide; 6 of 7 of the present series showed a similar decrease, whereas only 2 of the 7 subjects studied by Aleksandrow et al. showed a decrease. The reduction of the pressure in the right atrium suggests that the fall in cardiac output was a conse- quence of decreased filling pressures in the right side of the heart. The latter in turn may have been related nisms of the antihypertensive effect of chlorothiazide — namely, that contraction of plasma volume and Taste 1 (Concluded). Case TotaL PERIPHERAL PLasMA VoLUME No. RESISTANCE CONTROL EXPERI- CONTROL — EXPERI- MENTAL*® MENTAL*® dynes cm. -* dynes em. -§ ml, ml. Sec. See, + 1789 3486 2915 2760 at 3314 3254 2379 1390 3F 1850 1425 _ _ 4t 3243 5632 1951 1732 St 1766 1795 3188 2946 6 1634 2500 3175 2526 7 1687 2283 2770 2968 Averages 2183 2911 2730 2387 Mean percentage +33 ~13 change Bioop VoLuME Hematocrir WEIGHT CONTROL — EXPERI- CONTROL EXPERI- CONTROL EXPERI- MENTAL* MENTAL* MENTAL* ml. ml. mm. mm. kg, kg. 4826 4936 39.5 41.1 76.4 76.4 4102 2279 42.0 39.0 66.0 65.0 _ — 48.0 48.8 95.5 88.6 3101 2961 41.0 45.8 54.1 51.8 4951 4709 38.1 38.0 90.0 82.7 6712 5526 52.7 53.0 85.9 83.6 4328 4566 36.0 35.0 - 78.6 77 4670 4163 42.5 43.0 78.2 75.0 -1t +1 —4 *Results after 3 days of chlorothiazide therapy. +Control value average of 3 separate determinations. to a decreased plasma volume, as reported by Freis et al? and Tapia and his associates. Although in- creased, the total peripheral resistance was not suf- ficiently elevated to maintain the level of the pre- treatment basal blood pressure. SuMMARY AND CONCLUSIONS Cardiac output was determined in compensated hy- pertensive patients. Five were studied by the direct Fick method, and 2 by the dye-dilution technic before and after chlorothiazide therapy. There was a reduction of cardiac output, mean arterial pressure, plasma and blood volumes, body weight and pressures in the right atrium. The total peripheral resistance was increased. These data add support to the suggested mecha- possibly reduction of tissue pressure lead to a decrease in filling pressure in the right side of the heart and hence to a decreased cardiac output. REFERENCES 1. Aleksandrow, D., Wysznacka, W., and Gajewski, J. Studies on anism of hypotensive action of chlorothiazide. New Eng. J. me Med. 260:51-55, 1959. 2. Dustan, H. P., ‘Cumming, G. R., Corcoran, A. C., and Page, IL. H. Mechanism of chlorothiazide-enhanced effectiveness of antihyper- tensive ganglioplegic drugs. Circulation 19:360-365, 9. 3. Crosley, A. P., Jr., Castillo, C., Freeman, D. J., White, D. H., Jr., and Rowe, G. G. Acute effects of carbonic an ydrase inhibitors on systemic hemodynamics. J. Clin. Investigation 37:887, 4. Kirkendall, W. M. Clinical evaluation of chlorothiazide. tion 19:933-941, 1959. 5. Freis, E. D., Schnaper, H. W., Johnson, R. L., and Schreiner, G,. E. Hemodynamic alterations in acute myocardial infarction. I. Cardiac output, mean arterial pressure, total peripheral resist- ance, ‘‘central’’ and total blood volumes, venous pressure and aver- age circulation time. J. Clin. Investigation 31:131-140, 1952. 6. Freis, E. D., et al. Hemodynamic effects of hypotensive drugs in re Ill. Hexamethonium. Jj. Clin. Investigation 32:1285-1298, OD. 7. Freis, E, D., Wanko, A., Wilson, I. M., and Parrish, A. E. Chlorothiazide in hypertensive and normotensive subjects. Ann. New York Acad. Se. 71:450-455, 1958. 8. Tapia, F. A., Dustan, H. P. Schneckloth, R. A., Corcoran, A. C., and Page, I. ’H. Enhanced effectiveness of ganglion- blocking agents in hypertensive patients during administration of saluretic agent (chlorothiazide). Lancet 2:831-833, 1957. Circula- Copyright, 1960, by the Se Medical Society rinted in the U. S.