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Oral administration of clonidine in patients with alcoholic cirrhosis
GASTROENTEROLOGY 1992;102:248-254
Oral Administration of Clonidine in Patients With Alcoholic Cirrhosis Hemodynamic
and Liver Function
Effects
AGUSTIN ALBILLOS, RAFAEL BAÑARES, CESAR BARRIOS, GERARD0 CLEMENTE, IRMA ROSSI, PEDRO ESCARTIN, and JAIME BOSCH Department of Gastroenterology, Clinica Puerta de Hierro, Madrid, Spain; Department of Gastroenterology, Hospita1 Gregorio Marañon, Madrid, Spain; and Liver Unit, Hospita1 Clinico y Provincial, Barcelona, Spain
The effects of long-term oral clonidine treatment on hepatic and systemic hemodynamics and on quantitative liver function tests were investigated in 15 patients with alcoholic cirrhosis. Clonidine was administered at a mean dose of 0.33 rt 0.1 mg/day (mean f SD) for a mean period of 84 f 10 days. Oral clonidine induced a significant reduction in the hepatic venous pressure gradient from 18.8 f 3.0 mm Hg to 15.9 f 3.4 mm Hg (P < O.OOl),which was the result of an increase in the free hepatic venous pressure from 5.1+ 4.2mm Hg to 8.7f 3.8mm Hg (P < 0.05). In 10 of the 15 patients (87%),the reduction in the hepatic venous pressure gradient was >lO% of baseline values. Hepatic blood flow did not change significantly after clonidine treatment. Additionally, treatment with clonidine decreased mean arterial pressure by 15.5% + 8% (P < O.OOl), heart rate by 17.7% + 7% (P < O.OOl), and cardiac output by 14.8% k 7% (P < 0.001). However, systemic vascular resistance did not change significantly. There were no adverse effects on liver function, as shown by the nonsignificant changes in galactose-elimination capacity (149 f 59 vs. 170 + 58 mg/min), hepatic clearance of indocyanine green (0.19 + 0.10 vs. 0.17f 0.07L/min), and hepatic intrinsic clearance of indocyanine green (0.23 f 0.14 vs. 0.21 -r 0.1 IJmin) before and after clonidine treatment, respectively. In none of the patients was the drug withdrawn because of side effects, although 12 subjects complained of dry mouths. This study suggests that in patients with alcoholic cirrhosis, long-term oral clonidine administration achieves a reduction in the hepatic venous pressure gradient without adverse effects on hepatic blood flow and liver function.
S
tudies in patients with cirrhosis and in experimental models of portal hypertension have shown that propranolol, a nonselective B-blocker, reduces cardiac output as wel1 as portocollateral blood flows and portal venous pressure.‘-3 However,
the reduction of portal pressure achieved by propranolol averages only l5%, and more than one third of the patients show no decrease in portal pressure despite proper B-blockade. Moreover, the reduction of portal venous and hepatic arterial blood flows induced by propranolol may result in a decrease in liver perfusion.4*5 This decreased Ever perfusion might be associated with changes in microvascular exchange, as suggested by a reduction in the hepatic intrinsic clearance of indocyanine green (ICG), a quantitative test of hepatic function that reflects the ability of the Ever to remove ICG in the absente of limitations of blood flo~.~ Clonidine, a centrally acting a,-agonist, diminishes the centra1 sympathetic nervous stem outflow.’ Previous studies have suggested that this reduction in adrenergic output after acute administration of clonidine in cirrhotic patients results in a decrease in portal venous pressure while maintaining liver perfusion.8sg Thus, clonidine may have the potential advantage over propranolol of not being associated with deleterious effects on liver function. The present study was aimed specifically at investigating (a) whether continuous oral administration of clonidine allows an effective and sustained reduction of portal pressure in patients with alcoholic cirrhosis, and (b) the impact of this therapy on liver function as evaluated by quantitative liver function tests. Patients and Methods Patients Fifteen patients with alcoholic cirrhosis were included in this study. There were 14 males and 1 female, and the mean age was 52 + 2 years. Al1 patients had clinical, biochemical, and liver scan signs compatible with cirrhosis. This diagnosis was confirmed by liver biopsy in 9 patients. Inclusion criteria for the study required presence of esophageal varices at endoscopy. Al1 patients had ab0 1992 by the American Gastroenterological 0016-5085/92/$3.00
Association
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January 1992
stained from alcohol for at least 4 weeks, and none of them had evidente of hepatic encephalopathy at the time of the study. Severity of liver disease was graded according to Pugh’s criteria l”.. 2 patients were grade A, 8 were grade B, and 5 were grade C. Five patients had a history of bleeding esophageal varices, and ascites were present in 4 patients at the time of inclusion. Patients had no evidente of cardiac disease by history, physical examination, or electrocardiogram. The study was approved by the Clinical Research Committees of the participating hospitals and consent to take part in the study was obtained from patients individually. Further details of the patients are given in Table 1. Methods Pressure measurements. After the patient fasted overnight and received local anesthesia, a Swan-Ganz catheter (Edwards Laboratories; Los Angeles, CA) was advanced into the pulmonary artery through the right jugular vein for the measurement of cardiopulmonary pressures and cardiac output (thermal dilution). A 7F balloon-tipped catheter (Medi Tech, Cooper Scientific Corp., Watertown, MA) was then placed into the main right hepatic vein to measure the gradient between wedged hepatic venous pressure (WHVP) and free hepatic venous pressure (FHVP) [hepatic venous pressure gradient (HVPG)]. The occluded position of the catheter was checked by the absente of reflux after the injection of 2 mL of contrast medium. Permanent tracings of al1 measurements were obtained with a multichannel recorder. Each pressure reading was recorded in triplicate, and for each an electronic mean was obtained. Five measurements of the cardiac output were taken in every patient; the highest and the lowest values were discarded, and the arithmetical mean of the other three was calculated. Arterial pressure was measured by sphygmomanometry. Mean arterial pressure (MAP) was calculated according to the formula MAP (mm Hg) = (Systolic + Diastolic x 2)/3. Heart rate was derived from continuous electro-
Table 1. Main Clinical
Patients 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Characteristics
cardiographic monitoring. Systemic vascular resistance (SVR) was calculated according to the formula SVR (dyne - s - cm-“) = (MAP - RAP/CO) X 80, in which RAP is the mean right atria1 pressure (mm Hg) and CO is the cardiac output (L/min). Hepatic blood flow and indocyanine green clearance. The hepatic blood flow (HBF) was measured during a continuous infusion of ICG (Serb, Paris, France) through an antecubital vein at a constant rate of 0.20 mg/min after a priming injection of 10 mg. After an equilibration period of 40 minutes, four sets of blood samples were drawn from a peripheral vein and from the hepatic vein over a 10-minute period. Determination of ICG plasma concentration was performed immediately at the end of the investigation by spectrophotometry at 805 nm and 900 nm. A hepatic extraction above 10% and steady arterial ICG levels were required for the calculation of the HBF.” Hepatic plasma blood flow (HPF) was calculated as I/Cp - Ch, where I was the infusion rate of ICG and Cp and Ch were the mean plasma concentrations of ICG in the peripheral venous blood and in the hepatic vein, respectively. Hepatic blood flow was calculated as HPF/l - Hematocrit. The hepatic clearance of ICG was measured as I/Cp. The intrinsic hepatic clearance (CI int) of ICG was calculated according to the sinusoidal model as CI int = -HBF - ln(1 - E), where E was the extraction ratio of ICG calculated at steady state as Cp - Ch/Cp.= Galactose-elimination capacity. Galactose-elimination capacity (GEC) was measured after an overnight fast the day after obtaining the hemodynamic measurements. Galactose concentrations were determined in antecubital venous blood every 10 minutes over a 90-minute period after IV injection of 0.5 g/kg body wt of galactose in a 30% solution. The GEC was calculated according to Tygstrup,13 assuming a urinary loss of galactose equal to 10% of the injected dose.13 Galactose concentration was determined enzymatically (test: combination galactose, BoehringerMannheim, Barcelona, Spain). Clonidine administration. After obtaining baseline mea-
and Hepatic Venous Pressure Gradients
Previous gastrointestinal bleeding
Previous ascites
+ + + + + _ _ _ _ _ _ _ _ _
+ _ + _ + _ _ + + _ + _ _
Bilirubin (mg/dU 3.3 1.1 3.1 0.7 1.3 3.6 1.7 2.7 2.8 2.7 1.4 2.3 1.3 1.8 3.0
of the 15 Patients
Albumin (g/dLJ 3.2 3.7 3.1 3.6 3.7 3.3 3.1 2.7 3.2 3.0 3.8 3.2 2.8 3.4 2.0
Studied
Prothrombin time (%) 61 69 57 69 77 40 69 60 77 62 87 65 48 87 40
19.0 22.0 16.0 20.5 20.0 15.0 20.0 24.5 ia.0 19.0 13.0 17.5 la.5 16.0 23.0
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GASTROENTEROLOGY Vol. 102, No. 1
clonidine was administered orally two times each day at increasing doses up to 0.30 - 0.45 mg/day. The starting dose of clonidine was 0.075 mg/day and was increased by 0.075 mg every day 3 days up to a minimum dose of 0.30 mg/day and a maximum of 0.45 mg/day. The maximum dose was adjusted to avoid a reduction of systolic arterial pressure below 100 mm Hg. Once the maximum dose of the drug was reached, clinical tolerante and side effects were evaluated by weekly clinical examinations. Al1 the hemodynamic and analytical measurements were repeated 64 +- 10 days after reaching the maximum dose of the drug. Statistical analysis. The results are given as mean + SD. Paired and unpaired Student’s t tests and linear regression were used in the statistical analysis of the results. Results were considered significant at P < 0.05. surements,
Results As shown in Table 2, long-term clonidine administration induced a significant decrease in HVPG from 18.8 * 3.0 mm Hg to 15.9 + 3.4 mm Hg (P < 0.001) (a mean reduction of 15.4% f 9.0%). This reduction in HVPG was due to a significant increase in FHVP from 5.1 f 4.2 mm Hg to 8.7 & 3.8 mm Hg (P c 0.05), because WHVP did not change significantly (23.9 f 5.3 vs. 24.6 + 5.1 mm Hg). Individual values for HVPG before and after clonidine administration are shown in Figure 1. The reduction of HVPG was greater than 10% of baseline values in 10 of 15 subjects (67%). The mean HVPG reduction in these 10 “responders” was 22% f 8%, whereas in the other 5 “nonresponders” this value was 1.5% f 5%. On the other hand, the differences in the mean HVPG reduction between previous variceal bleeders and
TabJe 2. Splanchnic and Systemic Hemodynamics Before and After Clonidine Administration Basal HVPG (mm Hg] FHVP (mm Hg) WHVP (mm Hg) Hepatic blood flow (L/min) Heart rate (beats/min) Mean arterial pressure (mm Hg) Cardiac output (L/min) Systemic vascular resistance (dyne - s - cmm5)
Clonidine
P
18.8 + 3.0 5.1 + 4.2 23.9 f 5.3
15.9 f 3.4 8.7 + 3.8 24.6 + 5.1
1.2 + 0.4 87 + 8
1.1 + 0.5 71 f 9
10.001
93 f 11 7.8 + 2
78 f 8 6.7 f 1.8
982 + 259
948 + 250
NS NS
NS
Right atria1 pressure (mm Hg) Pulmonary artery pressure (mm Hg)
2.6 + 2
4.2 + 2
12.5 + 3.1
16.3 i 4.2
-zo.05
Pulmonary capillary pressure (mm Hg)
6.8 * 3
9.7 f 3.6
NOTE. Values are mean k SD.
nonbleeders were nonsignificant (14.1% f 10% vs. 14.8% i 9%). The mean value of HBF was not significantly modified by clonidine (1.2 i 0.4 vs. 1.1 + 0.5 L/min) (Table 2 and Figure 2). As expected, clonidine decreased arterial blood pressure (Table 2). Mean arterial pressure decreased by 15.5% f 6% (P < O.OOl), systolic blood pressure by 18% f 7% (P < O.OOl), and diastolic blood pressure by 12% + 9%) (P < 0.001). Clonidine also caused a significant decrease in heart rate (17.7% f 7%, P < 0.001; Figure 2) that was accompanied by a similar decrease in cardiac output (14.6% + 7%, P < 0.001; Table 2). However, systemic vascular resistance did not change significantly during treatment (982 & 259 vs. 948 f 250 dyne - s - cmm5). Clonidine induced an increase in cardiopulmonary pressures. Right atria1 pressure increased by 182% k 24% (P < 0.05), pulmonary artery pressure by 39% & 58% (P < O.Ol), and pulmonary capillary pressure by 64% + 83% (P < 0.01; Table 2). The absolute increase in FHVP was not significantly different from the increases in right atria1 pressure, pulmonary artery pressure, and pulmonary capillary pressure. The metabolic activity of the liver assessed by GEC and ICG clearance was not affected by clonidine administration (Figure 3). In fact, GEC showed a statistically insignificant increase from 149 + 59 mg/min to 170 f 58 mg/min. Neither the hepatic clearance of ICG (0.19 f 0.10 vs. 0.17 f 0.07 L/min) nor the hepatic intrinsic clearance of ICG (0.23 + 0.14 vs. 0.21 f 0.1 L/min) changed significantly during clonidine administration. NO significant correlations were observed between changes in cardiac output, arterial pressure, HVPG, and HBF during clonidine therapy. The adverse effects elicited were dry mouth in 12 patients, drowsiness in 1 patient, and impairment of sexual performance in 1 patient. These effects tended to decrease with time and were not severe enough to require withdrawal of the drug treatment. On the other hand, no patient developed ascites during treatment or required an increase in the dose of diuretics. In fact, diuretic requirements decreased in two patients while they were receiving clonidine. Discussion The results of the present study show that in patients with alcoholic cirrhosis, continuous oral clonidine administration achieves an effective reduction in HVPG. This effect of clonidine was not associated with significant changes in systemic hemodynamics or adverse effects on metabolic liver function capacity. The reduction in HVPG induced by clonidine in our patients was entirely due to an increase in the
CLONIDINE IN PORTAL
January 1992
HYPERTENSION
251
22 -
r”
E
16-
14 Figure 1. Individual data of changes in HVPG after longterm oral administration of clonidine. Note that HVPG decreased in al1 but 2 patients.
I
10 !
BASAL
FHVP. When considering the therapeutic potential of a drug in portal hypertension, it is a matter of controversy whether a decrease in the HVPG due to a reduction in the absolute portal pressure (or WHVP) has the same value as a similar reduction induced by an increase in FHVP.l4 However, al1 studies that have established the prognostic value of measurements of portal pressure, as wel1 as the beneficial effects of pharmacological agents on portal hypertension, have used the HVPG to express values of portal pressure. l5 The increased HVPG represents not only the increased portal perfusion gradient but also the pressure gradient promoting the formation
I CLONIME
and eventually leading to the rupture of the varices.‘“,” Therefore, it is likely that any decrease in HVPG represents a real beneficial effect in portal hypertension.” Several factors may explain the increase in FHVP after clonidine administration. Changes in either the external reference point or the intraabdominal pressure due to the presence of ascites are unlikely, because the WHVP would have also increased.lg A major contributing factor might have been the observed increase in cardiopulmonary pressures, because right atria1 pressure, pulmonary artery pressure, and pulmonary capillary pressure were found to be ele-
8
2 5 8
-25 -
HiPG
Figure 2. Hemodynamic effects of chronic oral administration of clonidine. Data are shown as percentage of change film baseline (mean -t SD). **Statistical eipilcance of the differente fkom baseline.
252
ALBILLOS ET AL.
GASTROENTEROLOGY Vol. 102. No.I
A NS
NS
1-
BASAL
CLONIDINE
C
B
SASAL
l-
NS
-
-
CLONIDINE
BASAL
CLONIDINE
Figure 3. Effects of long-term oral administration of clonidine on quantitative liver function tests. (A)Galactose-elimination (B) Hepatic clearance. (C) Intrinsic hepatic clearance.
vated after clonidine and their changes paralleled those of the FHVP. It should be noted that the absolute increase in FHVP was not significantly different from that of the cardiopulmonary pressures. Such an increase in cardiopulmonary pressures and FHVP has also been observed following vasopressin and propranolol administration.15 These changes may be the result of either an increase in the venous tone caused by clonidine, a decrease in cardiac output, or a combination of these factors. The fact that the increase in FHVP was not accompanied by an increase in WHVP led to the significant decrease in HVPG following clonidine administration. The mechanism by which portal pressure was reduced by clonidine is likely to be due to a reduction in the portal venous inflow. In analogy with clinical studies following one-time clonidine injections, the reduction in HVPG was not associated with a significant decrease in HBF.8*g The mechanism by which clonidine induces these hemodynamic effects is thought to be related to a decrease in adrenergic output.’ Acting as a centra1 a-adrenergic agonist, this drug is known to suppress systemic catecholamine spillover with a resultant reduction in a- and j.% adrenergic tones.’ It is not surprising, therefore, that some of the effects of clonidine are reminiscent of those of @blockers; this is wel1 represented by our findings of significant reduction in heart rate and cardiac output together with an increase in cardiopulmonary pressures after clonidine therapy. It is likely that these changes are accompanied by a reduction in the splanchnic inflow, which might in part account for the reduction in HVPG.” Although an estimation of the portal venous inflow cannot be made in the present study, Moreau et al. have observed a
capacity.
reduction in azygos venous blood flow after acute IV clonidine administration, reflecting a significant decrease in portocollateral blood flow.’ The fact that neither our study nor previous ones have documented any decrease in HBF suggests that hepatic arterial blood flow may increase following clonidine administration. This wil1 be an example of a buffer response of the hepatic artery aimed at preventing a decrease in liver perfusion when portal blood flow is decreased.” In addition, the reduced norepinephrine spillover induced by clonidine results in a decrease in aadrenergic activity and hence in vasodilatation.’ This was manifested in our patients by a decrease in arterial blood pressure. Although we did not observe a significant reduction in systemic vascular resistante, our patients did not show the increase in that parameter noticed after P-blocker therapy in cirrhotic patients. It is likely that the preserved liver perfusion observed during clonidine therapy may be related to such a reduction in a-adrenergic tone, because a-adrenergic stimulation markedly increases the hepatic vascular resistance.22 Therefore, it appears that the net hemodynamic effects following clonidine administration mimic the expected effects of the sum of an a- and a j3-adrenergic blockade. Our finding of a reduction in HVPG after 2 months clonidine administration contrasts with our recent observation in 17 patients with alcoholic cirrhosis in whom the administration of placebo over 3 months was not accompanied by significant changes in HVPG or in other splanchnic and systemic hemodynamic parameters. 23 A spontaneous and significant decrease in portal pressure had been reported to occur in some patients with alcoholic cirrhosis studied
CLONIDINE IN PORTAL HYPERTENSION
January 1992
over a l-year period.‘* Therefore, if longer-term studies with clonidine are contemplated, it would be necessary to include a simultaneous placebo group. An outstanding finding of the present study was that chronic clonidine administration was not associated with any deterioration in liver metabolic function. This was evaluated by means of measurements of GEC and of the hepatic clearance and intrinsic clearance of ICG. These parameters are wellknown quantitative markers of overall liver function and bear a good correlation with prognosis in patients with chronic liver disease.24,25 The lack of deleterious effects of clonidine on liver function contrasts with the observed effects of propranolol, which is associated with a decrease in hepatic and intrinsic clearance of ICG.” Although the significance of this finding in cirrhotic patients is unknown, it is conceivable that even a smal1 further impairment in hepatic function could be clinically relevant in subjects with advanced liver disease. These considerations suggest that clonidine may be a therapeutic alternative to propranolol for prevention of esophageal varices hemorrhage. It is worth remarking that the clinical tolerante of clonidine in our patients was excellent. The only observed side effects were mild and diminished gradually during the course of therapy. Although the observed reduction in arterial blood pressure might suggest that clonidine may negatively influence sodium retention in subjects with cirrhosis, this was not observed in our patients. In this regard, it should be noted that an improvement in renal function after one-time IV clonidine administration has been reported in cirrhotics with ascites.26 It is wel1 known that the sudden interruption of clonidine administration may be followed by rebound adrenergic activity, which may be associated with a severe hypertensive crisis.” However, none of this happened in our patients who were carefully instructed about the risk of abruptly interrupting clonidine therapy. When considering the clinical use of clonidine, it is important to emphasize that the magnitude of the decrease in the HVPG after clonidine administration (15%) was not greater than that reported using propranolol.‘8 This moderate decrease in the mean HVPG was due to the fact that HVPG in up to one third of our patients did not decrease by more than 10%. Hence, the prevalente of nonresponders to clonidine appears to be similar to that observed with propranolol. Moreover, in analogy with propranolol nonresponders, there was no clinical parameter that identified clonidine nonresponders.‘J* Therefore, repeated hemodynamic studies appear to be the only way of detecting the pattern of portal pressure response to clonidine. In summary, a reduction in the HVPG is achieved
253
after long-term oral clonidine administration in alcoholic cirrhotic patients. This effect is not accompanied by deleterious changes in liver function test results or significant systemic side effects. Future clinical trials wil1 be required to assess the clinical significante of these findings in the pharmacological treatment of portal hypertension. References Bosch J, Mastai R, Kravetz D, Bruix J, Gaya J, Rigau J, Rodés J. Effects of propranolol on azygos venous flow and hepatic hemodynamics in cirrhosis. Hepatology 1984;4:1200-1205. 2. Lebrec D, Hillon P, Muííoz C, Goldfarb G, Novel 0, Benhamou JP. The effect of propranolol on portal hypertension in patients with cirrhosis. A hemodynamic study. Hepatology 1982;2:523-527. 3. Kroeger RJ, Groszmann RJ. Increased portal venous resistance hinders portal pressure reduction during the administration of beta-adrenergic blocking agents in a portal hypertensive model. Hepatology 1985;5:97-101. 4. Mastai R, Bosch J, Bruix J, Navasa M, Kravetz D, Rodes J. Betablockade with propranolol and hepatic artery flow in patients with cirrhosis. Hepatology 1989;10:269-272. 5. Garcia-Pagan PC, Navasa M, Bosch J, Bru C, Pizcueta P, Rodes J. Enhancement of portal pressure reduction by the association of isosorbide-5-monitrate to propranolol administration in patients with cirrhosis. Hepatology 1990;11:230-238. 6. Vinel JP, Caucanas JP, Cales P, Suduca JM, Voigt JJ, Pascal JP. Effect of propranolol on metabolic activity of the liver in patients with alcoholic cirrhosis. J Hepatol 1988;7:186-192. 7. Van Zwieten PA. Pharmacology of centrally acting hypotensive drugs. Br J Pharmacol 1980;10:135-205. 8. Willet IR, Esler M, Jennings G, Dudley FJ. Sympathetic tone modulates portal venous pressure in alcoholic cirrhosis. Lancet 1986;2:939-943. 9. Moreau R, Lee S, Hadengue A, Braillon A, Lebrec D. Hemodynamic effects of a clonidine-induced decrease in sympathetic tone in patients with cirrhosis. Hepatology 1987;7:149-154. 10. Pugh RNH, Murray-Lyon M, Dawson JL, Pietroni MC, Williams R. Transection of the esophagus for bleeding esophageal varices. Br J Surg 1973;60:646-690. ll. Navasa M, Chesta J, Bosch J, Rodes J. Reduction of portal pressure by isosorbide+mononitrate in patients with cirrhosis. Gastroenterology 1989;96:1110-1118. 12. Winkler K, Bass L, Keiding S, et al. The physiological basis for clearance measurements in hepatology. Stand J Gastroenterol 1979;14:439-448. 13. Tygstrup N. Determination of the hepatic elimination capacity (Lm) of galactose by single injection. Stand J Clin Invest 1966;18(Suppl):118-125. 14. Bosch J, Bordas JM, Mastai R, Karetz D, Narasa M, Chesta J, Pizcueta P, García-Pagán JC, Rodés J. Effects of vasopressin on the intravariceal pressure in patients with cirrhosis: Comparison with the effects on portal pressure. Hepatology 1988; 8:861-865. 15. Bosch J. Effect of pharmacological agents on portal hypertension: A haemodynamic appraisal. Clin Gastroenterol 1985; 14:169-184. 16. Garcia-Tsao G, Groszmann RJ, Fisher JL, Conn HO, Atterbury CE, Glickman M. Portal pressure, presence of gastroesophageal varices, and variceal bleeding. Hepatology 1985;5:419424. 17. Rigau J, Bosch J, Bordas JM, et al. Endoscopic measurement of variceal pressure in cirrhosis: Correlation with portal pres1.
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18.
19. 20.
21.
22.
23.
24.
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sure and variceal hemorrhage. Gastroenterology 1989;96:873880. Groszmann RJ, Bosch J, Grace ND, Conn HO, Garcia-Tsao G, Navesa M, Alberts J, Rodés J, Fisher R, Bermann M, Rofe S, Patrick M, Lerner E. Hemodynamic events in a prospective randomized trial of propranolol versus placebo in the prevention of a first variceal hemorrhage. Gastroenterology 1990;99:1401-1407, Reynolds TB, ho S, Iwatsuki S. Measurements of portal pressure and its clinical application. Am J Med 1970;49:649-657. Roulot D, Braillon A, Gaudin C, Ozier Y, Lebrec D. Mechanisms of a clonidine-induced decrease in portal pressure in normal and cirrhotic conscious rats. Hepatology 1989;10:477481. Lautt WW. Mechanism and role of intrinsic regulation of hepatic arterial blood flow: the hepatic artery buffer response. Am J Physiol 1985;249:549-556. Lautt WW, Greenway CV, Legare DJ. Effect of hepatic nerves, norepinephrine, angiotensin, elevated centra1 venous pressure on postsinusoidal resistance sites and intrahepatic pressures. Microcirculation 1987;33:50-61. Garcia-Pagan JC, Feu F, Navasa M, Bru G, Ruit del Arbol L, Bosch J, Rodés J. Long-term hemodynamic effects of isosorbide 5-mononitrate in patients with cirrhosis and portal hypertension. J Hepatol 1990;11:189-195. Barbare JC, Poupon RE, Jaillon P, Prod’homme S, Darnis F, Poupon RY. Intrinsic hepatic clearance and Child-Turcotte
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classification for assessment of liver function in cirrhosis. J Hepatol 1985;1:253-259. 25. Merkel C, Bolognesi M, Finuci GF, Angeli P, Caregaro L, Rondana M, Gatta A. Indocyanine green intrinsic hepatic clearante as a prognostic index of survival in patients with cirrhosis. J Hepatol 1989;9:16-22. 26. Debinski H, Colman J, Wood M, Esler M, Massie D, Jones P, Dudley FJ. The acute effects of inhibition of SNS activity on renal function in cirrhosis (abstr). Hepatology 1989;10:588. 27. Rudd P, Blaschke TF. Antihypertensive agents and the drug therapy of hypertension. In: Goodman and Gilman, eds. The pharmacological basis of therapeutics. 7th ed. New York: Macmillan, 1985:784-805. 28. Garcia-Tsao G, Grace ND, Groszmann RJ, Conn HO, Bermann MM, Patrick MJC, Morse SS, Alberts JL. Short-term effects of propranolol on portal venous pressure. Hepatology 1986;6: 101-106.
Received July 16,1990.Accepted April 19, 1991. Address requests for reprints to: Jaime Bosch, M.D., Liver Unit, Hospita1 Clinico y Provincial, Villarroel 170, 0836 Barcelona, Spain. Supported in part by a grant from the Fondo de Investigación de la Seguridad Social (no. 89/114). Presented in part at the meeting of the American Association for the Study of Liver Diseases held in Chicago, IL (October 1989) and published in abstract form (Hepatology 1989;10:578).
Oral Administration of Clonidine in Patients With Alcoholic Cirrhosis Hemodynamic
and Liver Function
Effects
AGUSTIN ALBILLOS, RAFAEL BAÑARES, CESAR BARRIOS, GERARD0 CLEMENTE, IRMA ROSSI, PEDRO ESCARTIN, and JAIME BOSCH Department of Gastroenterology, Clinica Puerta de Hierro, Madrid, Spain; Department of Gastroenterology, Hospita1 Gregorio Marañon, Madrid, Spain; and Liver Unit, Hospita1 Clinico y Provincial, Barcelona, Spain
The effects of long-term oral clonidine treatment on hepatic and systemic hemodynamics and on quantitative liver function tests were investigated in 15 patients with alcoholic cirrhosis. Clonidine was administered at a mean dose of 0.33 rt 0.1 mg/day (mean f SD) for a mean period of 84 f 10 days. Oral clonidine induced a significant reduction in the hepatic venous pressure gradient from 18.8 f 3.0 mm Hg to 15.9 f 3.4 mm Hg (P < O.OOl),which was the result of an increase in the free hepatic venous pressure from 5.1+ 4.2mm Hg to 8.7f 3.8mm Hg (P < 0.05). In 10 of the 15 patients (87%),the reduction in the hepatic venous pressure gradient was >lO% of baseline values. Hepatic blood flow did not change significantly after clonidine treatment. Additionally, treatment with clonidine decreased mean arterial pressure by 15.5% + 8% (P < O.OOl), heart rate by 17.7% + 7% (P < O.OOl), and cardiac output by 14.8% k 7% (P < 0.001). However, systemic vascular resistance did not change significantly. There were no adverse effects on liver function, as shown by the nonsignificant changes in galactose-elimination capacity (149 f 59 vs. 170 + 58 mg/min), hepatic clearance of indocyanine green (0.19 + 0.10 vs. 0.17f 0.07L/min), and hepatic intrinsic clearance of indocyanine green (0.23 f 0.14 vs. 0.21 -r 0.1 IJmin) before and after clonidine treatment, respectively. In none of the patients was the drug withdrawn because of side effects, although 12 subjects complained of dry mouths. This study suggests that in patients with alcoholic cirrhosis, long-term oral clonidine administration achieves a reduction in the hepatic venous pressure gradient without adverse effects on hepatic blood flow and liver function.
S
tudies in patients with cirrhosis and in experimental models of portal hypertension have shown that propranolol, a nonselective B-blocker, reduces cardiac output as wel1 as portocollateral blood flows and portal venous pressure.‘-3 However,
the reduction of portal pressure achieved by propranolol averages only l5%, and more than one third of the patients show no decrease in portal pressure despite proper B-blockade. Moreover, the reduction of portal venous and hepatic arterial blood flows induced by propranolol may result in a decrease in liver perfusion.4*5 This decreased Ever perfusion might be associated with changes in microvascular exchange, as suggested by a reduction in the hepatic intrinsic clearance of indocyanine green (ICG), a quantitative test of hepatic function that reflects the ability of the Ever to remove ICG in the absente of limitations of blood flo~.~ Clonidine, a centrally acting a,-agonist, diminishes the centra1 sympathetic nervous stem outflow.’ Previous studies have suggested that this reduction in adrenergic output after acute administration of clonidine in cirrhotic patients results in a decrease in portal venous pressure while maintaining liver perfusion.8sg Thus, clonidine may have the potential advantage over propranolol of not being associated with deleterious effects on liver function. The present study was aimed specifically at investigating (a) whether continuous oral administration of clonidine allows an effective and sustained reduction of portal pressure in patients with alcoholic cirrhosis, and (b) the impact of this therapy on liver function as evaluated by quantitative liver function tests. Patients and Methods Patients Fifteen patients with alcoholic cirrhosis were included in this study. There were 14 males and 1 female, and the mean age was 52 + 2 years. Al1 patients had clinical, biochemical, and liver scan signs compatible with cirrhosis. This diagnosis was confirmed by liver biopsy in 9 patients. Inclusion criteria for the study required presence of esophageal varices at endoscopy. Al1 patients had ab0 1992 by the American Gastroenterological 0016-5085/92/$3.00
Association
CLONIDINE IN PORTAL HYPERTENSION 249
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stained from alcohol for at least 4 weeks, and none of them had evidente of hepatic encephalopathy at the time of the study. Severity of liver disease was graded according to Pugh’s criteria l”.. 2 patients were grade A, 8 were grade B, and 5 were grade C. Five patients had a history of bleeding esophageal varices, and ascites were present in 4 patients at the time of inclusion. Patients had no evidente of cardiac disease by history, physical examination, or electrocardiogram. The study was approved by the Clinical Research Committees of the participating hospitals and consent to take part in the study was obtained from patients individually. Further details of the patients are given in Table 1. Methods Pressure measurements. After the patient fasted overnight and received local anesthesia, a Swan-Ganz catheter (Edwards Laboratories; Los Angeles, CA) was advanced into the pulmonary artery through the right jugular vein for the measurement of cardiopulmonary pressures and cardiac output (thermal dilution). A 7F balloon-tipped catheter (Medi Tech, Cooper Scientific Corp., Watertown, MA) was then placed into the main right hepatic vein to measure the gradient between wedged hepatic venous pressure (WHVP) and free hepatic venous pressure (FHVP) [hepatic venous pressure gradient (HVPG)]. The occluded position of the catheter was checked by the absente of reflux after the injection of 2 mL of contrast medium. Permanent tracings of al1 measurements were obtained with a multichannel recorder. Each pressure reading was recorded in triplicate, and for each an electronic mean was obtained. Five measurements of the cardiac output were taken in every patient; the highest and the lowest values were discarded, and the arithmetical mean of the other three was calculated. Arterial pressure was measured by sphygmomanometry. Mean arterial pressure (MAP) was calculated according to the formula MAP (mm Hg) = (Systolic + Diastolic x 2)/3. Heart rate was derived from continuous electro-
Table 1. Main Clinical
Patients 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Characteristics
cardiographic monitoring. Systemic vascular resistance (SVR) was calculated according to the formula SVR (dyne - s - cm-“) = (MAP - RAP/CO) X 80, in which RAP is the mean right atria1 pressure (mm Hg) and CO is the cardiac output (L/min). Hepatic blood flow and indocyanine green clearance. The hepatic blood flow (HBF) was measured during a continuous infusion of ICG (Serb, Paris, France) through an antecubital vein at a constant rate of 0.20 mg/min after a priming injection of 10 mg. After an equilibration period of 40 minutes, four sets of blood samples were drawn from a peripheral vein and from the hepatic vein over a 10-minute period. Determination of ICG plasma concentration was performed immediately at the end of the investigation by spectrophotometry at 805 nm and 900 nm. A hepatic extraction above 10% and steady arterial ICG levels were required for the calculation of the HBF.” Hepatic plasma blood flow (HPF) was calculated as I/Cp - Ch, where I was the infusion rate of ICG and Cp and Ch were the mean plasma concentrations of ICG in the peripheral venous blood and in the hepatic vein, respectively. Hepatic blood flow was calculated as HPF/l - Hematocrit. The hepatic clearance of ICG was measured as I/Cp. The intrinsic hepatic clearance (CI int) of ICG was calculated according to the sinusoidal model as CI int = -HBF - ln(1 - E), where E was the extraction ratio of ICG calculated at steady state as Cp - Ch/Cp.= Galactose-elimination capacity. Galactose-elimination capacity (GEC) was measured after an overnight fast the day after obtaining the hemodynamic measurements. Galactose concentrations were determined in antecubital venous blood every 10 minutes over a 90-minute period after IV injection of 0.5 g/kg body wt of galactose in a 30% solution. The GEC was calculated according to Tygstrup,13 assuming a urinary loss of galactose equal to 10% of the injected dose.13 Galactose concentration was determined enzymatically (test: combination galactose, BoehringerMannheim, Barcelona, Spain). Clonidine administration. After obtaining baseline mea-
and Hepatic Venous Pressure Gradients
Previous gastrointestinal bleeding
Previous ascites
+ + + + + _ _ _ _ _ _ _ _ _
+ _ + _ + _ _ + + _ + _ _
Bilirubin (mg/dU 3.3 1.1 3.1 0.7 1.3 3.6 1.7 2.7 2.8 2.7 1.4 2.3 1.3 1.8 3.0
of the 15 Patients
Albumin (g/dLJ 3.2 3.7 3.1 3.6 3.7 3.3 3.1 2.7 3.2 3.0 3.8 3.2 2.8 3.4 2.0
Studied
Prothrombin time (%) 61 69 57 69 77 40 69 60 77 62 87 65 48 87 40
19.0 22.0 16.0 20.5 20.0 15.0 20.0 24.5 ia.0 19.0 13.0 17.5 la.5 16.0 23.0
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clonidine was administered orally two times each day at increasing doses up to 0.30 - 0.45 mg/day. The starting dose of clonidine was 0.075 mg/day and was increased by 0.075 mg every day 3 days up to a minimum dose of 0.30 mg/day and a maximum of 0.45 mg/day. The maximum dose was adjusted to avoid a reduction of systolic arterial pressure below 100 mm Hg. Once the maximum dose of the drug was reached, clinical tolerante and side effects were evaluated by weekly clinical examinations. Al1 the hemodynamic and analytical measurements were repeated 64 +- 10 days after reaching the maximum dose of the drug. Statistical analysis. The results are given as mean + SD. Paired and unpaired Student’s t tests and linear regression were used in the statistical analysis of the results. Results were considered significant at P < 0.05. surements,
Results As shown in Table 2, long-term clonidine administration induced a significant decrease in HVPG from 18.8 * 3.0 mm Hg to 15.9 + 3.4 mm Hg (P < 0.001) (a mean reduction of 15.4% f 9.0%). This reduction in HVPG was due to a significant increase in FHVP from 5.1 f 4.2 mm Hg to 8.7 & 3.8 mm Hg (P c 0.05), because WHVP did not change significantly (23.9 f 5.3 vs. 24.6 + 5.1 mm Hg). Individual values for HVPG before and after clonidine administration are shown in Figure 1. The reduction of HVPG was greater than 10% of baseline values in 10 of 15 subjects (67%). The mean HVPG reduction in these 10 “responders” was 22% f 8%, whereas in the other 5 “nonresponders” this value was 1.5% f 5%. On the other hand, the differences in the mean HVPG reduction between previous variceal bleeders and
TabJe 2. Splanchnic and Systemic Hemodynamics Before and After Clonidine Administration Basal HVPG (mm Hg] FHVP (mm Hg) WHVP (mm Hg) Hepatic blood flow (L/min) Heart rate (beats/min) Mean arterial pressure (mm Hg) Cardiac output (L/min) Systemic vascular resistance (dyne - s - cmm5)
Clonidine
P
18.8 + 3.0 5.1 + 4.2 23.9 f 5.3
15.9 f 3.4 8.7 + 3.8 24.6 + 5.1
1.2 + 0.4 87 + 8
1.1 + 0.5 71 f 9
10.001
93 f 11 7.8 + 2
78 f 8 6.7 f 1.8
982 + 259
948 + 250
NS NS
NS
Right atria1 pressure (mm Hg) Pulmonary artery pressure (mm Hg)
2.6 + 2
4.2 + 2
12.5 + 3.1
16.3 i 4.2
-zo.05
Pulmonary capillary pressure (mm Hg)
6.8 * 3
9.7 f 3.6
NOTE. Values are mean k SD.
nonbleeders were nonsignificant (14.1% f 10% vs. 14.8% i 9%). The mean value of HBF was not significantly modified by clonidine (1.2 i 0.4 vs. 1.1 + 0.5 L/min) (Table 2 and Figure 2). As expected, clonidine decreased arterial blood pressure (Table 2). Mean arterial pressure decreased by 15.5% f 6% (P < O.OOl), systolic blood pressure by 18% f 7% (P < O.OOl), and diastolic blood pressure by 12% + 9%) (P < 0.001). Clonidine also caused a significant decrease in heart rate (17.7% f 7%, P < 0.001; Figure 2) that was accompanied by a similar decrease in cardiac output (14.6% + 7%, P < 0.001; Table 2). However, systemic vascular resistance did not change significantly during treatment (982 & 259 vs. 948 f 250 dyne - s - cmm5). Clonidine induced an increase in cardiopulmonary pressures. Right atria1 pressure increased by 182% k 24% (P < 0.05), pulmonary artery pressure by 39% & 58% (P < O.Ol), and pulmonary capillary pressure by 64% + 83% (P < 0.01; Table 2). The absolute increase in FHVP was not significantly different from the increases in right atria1 pressure, pulmonary artery pressure, and pulmonary capillary pressure. The metabolic activity of the liver assessed by GEC and ICG clearance was not affected by clonidine administration (Figure 3). In fact, GEC showed a statistically insignificant increase from 149 + 59 mg/min to 170 f 58 mg/min. Neither the hepatic clearance of ICG (0.19 f 0.10 vs. 0.17 f 0.07 L/min) nor the hepatic intrinsic clearance of ICG (0.23 + 0.14 vs. 0.21 f 0.1 L/min) changed significantly during clonidine administration. NO significant correlations were observed between changes in cardiac output, arterial pressure, HVPG, and HBF during clonidine therapy. The adverse effects elicited were dry mouth in 12 patients, drowsiness in 1 patient, and impairment of sexual performance in 1 patient. These effects tended to decrease with time and were not severe enough to require withdrawal of the drug treatment. On the other hand, no patient developed ascites during treatment or required an increase in the dose of diuretics. In fact, diuretic requirements decreased in two patients while they were receiving clonidine. Discussion The results of the present study show that in patients with alcoholic cirrhosis, continuous oral clonidine administration achieves an effective reduction in HVPG. This effect of clonidine was not associated with significant changes in systemic hemodynamics or adverse effects on metabolic liver function capacity. The reduction in HVPG induced by clonidine in our patients was entirely due to an increase in the
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HYPERTENSION
251
22 -
r”
E
16-
14 Figure 1. Individual data of changes in HVPG after longterm oral administration of clonidine. Note that HVPG decreased in al1 but 2 patients.
I
10 !
BASAL
FHVP. When considering the therapeutic potential of a drug in portal hypertension, it is a matter of controversy whether a decrease in the HVPG due to a reduction in the absolute portal pressure (or WHVP) has the same value as a similar reduction induced by an increase in FHVP.l4 However, al1 studies that have established the prognostic value of measurements of portal pressure, as wel1 as the beneficial effects of pharmacological agents on portal hypertension, have used the HVPG to express values of portal pressure. l5 The increased HVPG represents not only the increased portal perfusion gradient but also the pressure gradient promoting the formation
I CLONIME
and eventually leading to the rupture of the varices.‘“,” Therefore, it is likely that any decrease in HVPG represents a real beneficial effect in portal hypertension.” Several factors may explain the increase in FHVP after clonidine administration. Changes in either the external reference point or the intraabdominal pressure due to the presence of ascites are unlikely, because the WHVP would have also increased.lg A major contributing factor might have been the observed increase in cardiopulmonary pressures, because right atria1 pressure, pulmonary artery pressure, and pulmonary capillary pressure were found to be ele-
8
2 5 8
-25 -
HiPG
Figure 2. Hemodynamic effects of chronic oral administration of clonidine. Data are shown as percentage of change film baseline (mean -t SD). **Statistical eipilcance of the differente fkom baseline.
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GASTROENTEROLOGY Vol. 102. No.I
A NS
NS
1-
BASAL
CLONIDINE
C
B
SASAL
l-
NS
-
-
CLONIDINE
BASAL
CLONIDINE
Figure 3. Effects of long-term oral administration of clonidine on quantitative liver function tests. (A)Galactose-elimination (B) Hepatic clearance. (C) Intrinsic hepatic clearance.
vated after clonidine and their changes paralleled those of the FHVP. It should be noted that the absolute increase in FHVP was not significantly different from that of the cardiopulmonary pressures. Such an increase in cardiopulmonary pressures and FHVP has also been observed following vasopressin and propranolol administration.15 These changes may be the result of either an increase in the venous tone caused by clonidine, a decrease in cardiac output, or a combination of these factors. The fact that the increase in FHVP was not accompanied by an increase in WHVP led to the significant decrease in HVPG following clonidine administration. The mechanism by which portal pressure was reduced by clonidine is likely to be due to a reduction in the portal venous inflow. In analogy with clinical studies following one-time clonidine injections, the reduction in HVPG was not associated with a significant decrease in HBF.8*g The mechanism by which clonidine induces these hemodynamic effects is thought to be related to a decrease in adrenergic output.’ Acting as a centra1 a-adrenergic agonist, this drug is known to suppress systemic catecholamine spillover with a resultant reduction in a- and j.% adrenergic tones.’ It is not surprising, therefore, that some of the effects of clonidine are reminiscent of those of @blockers; this is wel1 represented by our findings of significant reduction in heart rate and cardiac output together with an increase in cardiopulmonary pressures after clonidine therapy. It is likely that these changes are accompanied by a reduction in the splanchnic inflow, which might in part account for the reduction in HVPG.” Although an estimation of the portal venous inflow cannot be made in the present study, Moreau et al. have observed a
capacity.
reduction in azygos venous blood flow after acute IV clonidine administration, reflecting a significant decrease in portocollateral blood flow.’ The fact that neither our study nor previous ones have documented any decrease in HBF suggests that hepatic arterial blood flow may increase following clonidine administration. This wil1 be an example of a buffer response of the hepatic artery aimed at preventing a decrease in liver perfusion when portal blood flow is decreased.” In addition, the reduced norepinephrine spillover induced by clonidine results in a decrease in aadrenergic activity and hence in vasodilatation.’ This was manifested in our patients by a decrease in arterial blood pressure. Although we did not observe a significant reduction in systemic vascular resistante, our patients did not show the increase in that parameter noticed after P-blocker therapy in cirrhotic patients. It is likely that the preserved liver perfusion observed during clonidine therapy may be related to such a reduction in a-adrenergic tone, because a-adrenergic stimulation markedly increases the hepatic vascular resistance.22 Therefore, it appears that the net hemodynamic effects following clonidine administration mimic the expected effects of the sum of an a- and a j3-adrenergic blockade. Our finding of a reduction in HVPG after 2 months clonidine administration contrasts with our recent observation in 17 patients with alcoholic cirrhosis in whom the administration of placebo over 3 months was not accompanied by significant changes in HVPG or in other splanchnic and systemic hemodynamic parameters. 23 A spontaneous and significant decrease in portal pressure had been reported to occur in some patients with alcoholic cirrhosis studied
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January 1992
over a l-year period.‘* Therefore, if longer-term studies with clonidine are contemplated, it would be necessary to include a simultaneous placebo group. An outstanding finding of the present study was that chronic clonidine administration was not associated with any deterioration in liver metabolic function. This was evaluated by means of measurements of GEC and of the hepatic clearance and intrinsic clearance of ICG. These parameters are wellknown quantitative markers of overall liver function and bear a good correlation with prognosis in patients with chronic liver disease.24,25 The lack of deleterious effects of clonidine on liver function contrasts with the observed effects of propranolol, which is associated with a decrease in hepatic and intrinsic clearance of ICG.” Although the significance of this finding in cirrhotic patients is unknown, it is conceivable that even a smal1 further impairment in hepatic function could be clinically relevant in subjects with advanced liver disease. These considerations suggest that clonidine may be a therapeutic alternative to propranolol for prevention of esophageal varices hemorrhage. It is worth remarking that the clinical tolerante of clonidine in our patients was excellent. The only observed side effects were mild and diminished gradually during the course of therapy. Although the observed reduction in arterial blood pressure might suggest that clonidine may negatively influence sodium retention in subjects with cirrhosis, this was not observed in our patients. In this regard, it should be noted that an improvement in renal function after one-time IV clonidine administration has been reported in cirrhotics with ascites.26 It is wel1 known that the sudden interruption of clonidine administration may be followed by rebound adrenergic activity, which may be associated with a severe hypertensive crisis.” However, none of this happened in our patients who were carefully instructed about the risk of abruptly interrupting clonidine therapy. When considering the clinical use of clonidine, it is important to emphasize that the magnitude of the decrease in the HVPG after clonidine administration (15%) was not greater than that reported using propranolol.‘8 This moderate decrease in the mean HVPG was due to the fact that HVPG in up to one third of our patients did not decrease by more than 10%. Hence, the prevalente of nonresponders to clonidine appears to be similar to that observed with propranolol. Moreover, in analogy with propranolol nonresponders, there was no clinical parameter that identified clonidine nonresponders.‘J* Therefore, repeated hemodynamic studies appear to be the only way of detecting the pattern of portal pressure response to clonidine. In summary, a reduction in the HVPG is achieved
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after long-term oral clonidine administration in alcoholic cirrhotic patients. This effect is not accompanied by deleterious changes in liver function test results or significant systemic side effects. Future clinical trials wil1 be required to assess the clinical significante of these findings in the pharmacological treatment of portal hypertension. References Bosch J, Mastai R, Kravetz D, Bruix J, Gaya J, Rigau J, Rodés J. Effects of propranolol on azygos venous flow and hepatic hemodynamics in cirrhosis. Hepatology 1984;4:1200-1205. 2. Lebrec D, Hillon P, Muííoz C, Goldfarb G, Novel 0, Benhamou JP. The effect of propranolol on portal hypertension in patients with cirrhosis. A hemodynamic study. Hepatology 1982;2:523-527. 3. Kroeger RJ, Groszmann RJ. Increased portal venous resistance hinders portal pressure reduction during the administration of beta-adrenergic blocking agents in a portal hypertensive model. Hepatology 1985;5:97-101. 4. Mastai R, Bosch J, Bruix J, Navasa M, Kravetz D, Rodes J. Betablockade with propranolol and hepatic artery flow in patients with cirrhosis. Hepatology 1989;10:269-272. 5. Garcia-Pagan PC, Navasa M, Bosch J, Bru C, Pizcueta P, Rodes J. Enhancement of portal pressure reduction by the association of isosorbide-5-monitrate to propranolol administration in patients with cirrhosis. Hepatology 1990;11:230-238. 6. Vinel JP, Caucanas JP, Cales P, Suduca JM, Voigt JJ, Pascal JP. Effect of propranolol on metabolic activity of the liver in patients with alcoholic cirrhosis. J Hepatol 1988;7:186-192. 7. Van Zwieten PA. Pharmacology of centrally acting hypotensive drugs. Br J Pharmacol 1980;10:135-205. 8. Willet IR, Esler M, Jennings G, Dudley FJ. Sympathetic tone modulates portal venous pressure in alcoholic cirrhosis. Lancet 1986;2:939-943. 9. Moreau R, Lee S, Hadengue A, Braillon A, Lebrec D. Hemodynamic effects of a clonidine-induced decrease in sympathetic tone in patients with cirrhosis. Hepatology 1987;7:149-154. 10. Pugh RNH, Murray-Lyon M, Dawson JL, Pietroni MC, Williams R. Transection of the esophagus for bleeding esophageal varices. Br J Surg 1973;60:646-690. ll. Navasa M, Chesta J, Bosch J, Rodes J. Reduction of portal pressure by isosorbide+mononitrate in patients with cirrhosis. Gastroenterology 1989;96:1110-1118. 12. Winkler K, Bass L, Keiding S, et al. The physiological basis for clearance measurements in hepatology. Stand J Gastroenterol 1979;14:439-448. 13. Tygstrup N. Determination of the hepatic elimination capacity (Lm) of galactose by single injection. Stand J Clin Invest 1966;18(Suppl):118-125. 14. Bosch J, Bordas JM, Mastai R, Karetz D, Narasa M, Chesta J, Pizcueta P, García-Pagán JC, Rodés J. Effects of vasopressin on the intravariceal pressure in patients with cirrhosis: Comparison with the effects on portal pressure. Hepatology 1988; 8:861-865. 15. Bosch J. Effect of pharmacological agents on portal hypertension: A haemodynamic appraisal. Clin Gastroenterol 1985; 14:169-184. 16. Garcia-Tsao G, Groszmann RJ, Fisher JL, Conn HO, Atterbury CE, Glickman M. Portal pressure, presence of gastroesophageal varices, and variceal bleeding. Hepatology 1985;5:419424. 17. Rigau J, Bosch J, Bordas JM, et al. Endoscopic measurement of variceal pressure in cirrhosis: Correlation with portal pres1.
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sure and variceal hemorrhage. Gastroenterology 1989;96:873880. Groszmann RJ, Bosch J, Grace ND, Conn HO, Garcia-Tsao G, Navesa M, Alberts J, Rodés J, Fisher R, Bermann M, Rofe S, Patrick M, Lerner E. Hemodynamic events in a prospective randomized trial of propranolol versus placebo in the prevention of a first variceal hemorrhage. Gastroenterology 1990;99:1401-1407, Reynolds TB, ho S, Iwatsuki S. Measurements of portal pressure and its clinical application. Am J Med 1970;49:649-657. Roulot D, Braillon A, Gaudin C, Ozier Y, Lebrec D. Mechanisms of a clonidine-induced decrease in portal pressure in normal and cirrhotic conscious rats. Hepatology 1989;10:477481. Lautt WW. Mechanism and role of intrinsic regulation of hepatic arterial blood flow: the hepatic artery buffer response. Am J Physiol 1985;249:549-556. Lautt WW, Greenway CV, Legare DJ. Effect of hepatic nerves, norepinephrine, angiotensin, elevated centra1 venous pressure on postsinusoidal resistance sites and intrahepatic pressures. Microcirculation 1987;33:50-61. Garcia-Pagan JC, Feu F, Navasa M, Bru G, Ruit del Arbol L, Bosch J, Rodés J. Long-term hemodynamic effects of isosorbide 5-mononitrate in patients with cirrhosis and portal hypertension. J Hepatol 1990;11:189-195. Barbare JC, Poupon RE, Jaillon P, Prod’homme S, Darnis F, Poupon RY. Intrinsic hepatic clearance and Child-Turcotte
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classification for assessment of liver function in cirrhosis. J Hepatol 1985;1:253-259. 25. Merkel C, Bolognesi M, Finuci GF, Angeli P, Caregaro L, Rondana M, Gatta A. Indocyanine green intrinsic hepatic clearante as a prognostic index of survival in patients with cirrhosis. J Hepatol 1989;9:16-22. 26. Debinski H, Colman J, Wood M, Esler M, Massie D, Jones P, Dudley FJ. The acute effects of inhibition of SNS activity on renal function in cirrhosis (abstr). Hepatology 1989;10:588. 27. Rudd P, Blaschke TF. Antihypertensive agents and the drug therapy of hypertension. In: Goodman and Gilman, eds. The pharmacological basis of therapeutics. 7th ed. New York: Macmillan, 1985:784-805. 28. Garcia-Tsao G, Grace ND, Groszmann RJ, Conn HO, Bermann MM, Patrick MJC, Morse SS, Alberts JL. Short-term effects of propranolol on portal venous pressure. Hepatology 1986;6: 101-106.
Received July 16,1990.Accepted April 19, 1991. Address requests for reprints to: Jaime Bosch, M.D., Liver Unit, Hospita1 Clinico y Provincial, Villarroel 170, 0836 Barcelona, Spain. Supported in part by a grant from the Fondo de Investigación de la Seguridad Social (no. 89/114). Presented in part at the meeting of the American Association for the Study of Liver Diseases held in Chicago, IL (October 1989) and published in abstract form (Hepatology 1989;10:578).