Octreotide decreased liver metabolic activity in patients with hepatitis B surface antigen positive cirrhosis The influence of octreotide and somatostatin on liver metabolic activity were studied in 16 patients with cirrhosis that was positive for hepatitis B surface antigen (HkAg). In patients receiving a 50 lig bolus and a 50 lig/lir infusion of octreotide, the hepatic blood flow, hepatic clearance, and the maximum velocity/metabolic elimination rate constant (V./Icn) were significantly reduced after octreotide infusion compared with basal values. Similarly, the hepatic blood flow, hepatic clearance, and Vms,,/k, were significantly decreased in patients receiving a 250 lig bolus and a 250 tig/hr infusion of somatostatin. The extraction ratio and the systemic hemodynamic values, including cardiac index, heart rate, mean arterial pressure, and systemic vascular resistance, showed no significant changes in patients receiving either octreotide or somatostatin. These findings suggest that, as with somatostatin, octreotide reduced hepatic blood flow and impaired liver metabolic activity in patients with HBsAg-positive cirrhosis. These effects may have important clinical implications in the management of bleeding esophageal varices in patients with cirrhosis. ( CLIN PHARMACOL THER 1992;52:134-8.)
Han-Chieh Lin, MD, Yang-Te Tsai, MD, Shou-Dong Lee, MD, Fa-Yauh Lee, MD, Hsiao-Chung Hsia, MD, Hong-Chiang Meng, MD, Sun-Sang Wang, MD, and Kwang-Juei Lo, MD Taipei and Taichung, Taiwan Somatostatin has been proposed as a treatment of acute variceal hemorrhage in patients with cirrhosis. 1-4 This drug has been noted to reduce liver blood flow in patients with cirrhosis," but there have been reports of conflicting effects on portal pressure""" and intravariceal pressure.12, 3 Moreover, previous studies reported a decrease in metabolic activity of the liver during somatostatin infusion, a side effect potentially harmful to patients with cirrhosis.6a In addition, the clinical use of somatostatin may be limited by its short half-life of only a few minutes. Octreotide is a synthetic octapeptide analog of somatostatin that has a much longer biologic half-life.14 It has been reported to reduce liver blood flow in pa1
From the Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, the Department of Medicine, Taichung Veterans General Hospital, Taichung, and the National Yang-Ming Medical College, Taipei. Supported by grant No. NSC 80-0412-B075-l17 from the National Science Council, Taiwan, Republic of China. Received for publication Feb. 4, 1992; accepted April 21, 1992. Reprint requests: Yang-Te Tsai, MD, Department of Medicine, Taichung Veterans General Hospital, 160, Sec. 3, Chung-Kang Road, Taichung 407, Taiwan. 13/1/38798
134
tients with cirrhosis,15.16 but its effect on portal pressure is uncertain.15-I8 Furthermore, the influence of octreotide on liver metabolic activity has not been established. Our study used current models of hepatic elimination, "intrinsic" hepatic clearance,19'20 which provide a quantitative index of hepatic metabolic activity in patients with cirrhosis,6'7'21 to investigate the influence of octreotide on liver metabolic activity in patients with cirrhosis that is positive for hepatitis B surface antigen (HBsAg).
MATERIAL AND METHODS Sixteen patients with histologically proved postnecrotic cirrhosis were included in the study. Liver biopsies were performed percutaneously by the needle technique. All the patients were positive for serum HB,Ag by radioimmunoassay (Ausria, Abbott Laboratories, Chicago, Ill.). Effects of octreotide were studied in eight patients, the others received somatostatin and served as control subjects. The clinical and laboratory data of the two groups of patients are summarized in Table I. The severity of liver cirrhosis was classified according to the Pugh's modification of Child's classification.22 All patients had endoscopically demonstrable esophageal varices, but only two
VOLUME 52 NUMBER 2
Octreotide in cirrhosis
135
Table I. Clinical and laboratory data in patients receiving octreotide and somatostatin Patients receiving octreotide No. of patients Age (yr) Sex (male/female) Body weight (kg) Pugh's classification (A/B/C) Biochemistry Serum albumin (gm/d1) Serum bilirubin (mg/dl) Serum alanine aminotransferase (U/L) Prothrombin time (%)
Patients receiving somatostatin
8
8
65 ± 2* 7/1 58 ± 2* 2/4/2
60 ± 3*
3.0 ± 0.1* 1.4 ± 0.2* 44 ± 6* 70 ± 3*
7/1
59 -± 2* 5/2/1
3.3
-±
0.2*
1.2 ± 0.1* 92 ± 45* 76 ± 2*
*Mean ± SEM.
patients had had an episode of variceal hemorrhage 3 months and 5 weeks before the present investigation, respectively, and were treated by sclerotherai5y. No patient had a history of alcohol consumption. All patients were screened by abdominal ultrasound or computerized tomography, and none of them was associated with hepatocellular carcinoma. Patients who had bleeding diathesis, hepatic encephalopathy, previous operation for portal hypertension, or heart or kidney diseases were not included in the study. Written informed consent was obtained from each patient before the study. The study protocol was reviewed and approved by the Hospital Ethics Committee of Taipei Veterans General Hospital. After an overnight fast, the patients were prepared for hepatic vein catheterization by use of a 7F balloontipped pulmonary artery thermodilution catheter (Gould Inc., Cupertino, Calif.) as in our previous study.23 The hepatic blood flow and liver metabolic activity were assessed by the indocyanine green continuous infusion method as described previously.21 In brief, 0.5 mg/kg indocyanine green (Cardiogreen, Hynson, Westcott & Dunning, Inc., Baltimore, Md.) was infused through an antecubital vein over 5 minutes and then at a constant rate of 0.48 mg/min. After waiting 30 minutes to obtain a steady state in indocyanine green plasma concentration, blood samples were drawn simultaneously from a peripheral vein and from the hepatic vein at 2-minute intervals for 10 minutes and collected in lithium heparin tubes. After collection of the blood samples, the catheter was advanced into the pulmonary artery where cardiac output was measured by thermodilution by use of 10 ml of 0° to 4° C 5% dextrose in water injected through the balloontipped pulmonary artery catheter into the pulmonary artery.24 The cardiac output determinations were made in triplicate. Systemic mean arterial pressure and heart
rate were measured and recorded with an external electronic vital sign monitor (Dinamap 8100, Critikon, Inc., Tampa, Fla.). After basal cardiac output determination and blood pressure measurement and after withdrawal of blood from both peripheral and hepatic vein, the patients were randomly assigned to receive a continuous infusion of 50 11,g/hr octreotide (Sandostatin; Sandoz Pharmaceutical Ltd., Berne, Switzerland) after an initial bolus of 50 lig or to receive a continuous infusion of 250 gig/hr somatostatin (Stilamin; Serono Laboratories, Inc., Randolph, Mass.) after an initial bolus of 250 pg. The cardiac output determinations and blood pressure measurements were performed again at 30 minutes after the beginning of the infusion of somatostatin and 60 minutes after the beginning of the infusion of octreotide. At the same time peripheral and hepatic blood samples were simultaneously drawn at 2-minute interval for a period of 10 minutes. In addition, blood samples for plasma glucose analysis were collected from the antecubital vein in the basal state and at 30 minutes after somatostatin infusion and 60 minutes after octreotide infusion. The hepatic clearance was calculated as follows: V/Cp, in which V is the rate of infusion of indocyanine green (0.48 mg/min), and Cp is the plasma concentration of ICG in peripheral venous blood. The hepatic extraction ratio (ER) was calculated as follows: (Cp Ch)/Cp, in which CI, is the plasma concentration of indocyanine green in the hepatic vein. The hepatic plasma flow (HPF) was calculated as follows: V/(Cp Ch). The hepatic blood flow was calculated as follows: HPF/(1 hematocrit). To estimate the metabolic activity of hepatocyte responsible for the removal of indocyanine green, the sinusoidal perfusion model of hepatic elimination was used. According to this model6,20,21 the intrinsic
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Table II. Influence of octreotide and somatostatin on hepatic blood flow and liver metabolic activity Patients receiving octreotide Basal After octreotide Hepatic blood flow (ml/min) Hepatic clearance (ml/min) Clearance Vn.,/k, (ml/min) Hepatic extraction ratio (%)
1301
± 159
282 ± 57 355 ±- 83 30.9 ± 5.2
Patients receiving somatostatin Basal After somatostatin
1000 ± 105* 233 ± 50* 298 ± 73*
1434 ± 115 372 ± 38 478 ± 54
32.3
38.9 ± 3.5
-±
5.5
1203 ± 111* 316 ± 35*
406 ± 48* 39.1 ± 3.1
Data are mean values -± SEM. Vmax/kn Maximum velocity/metabolite elimination rate constant. *p < 0.05 versus basal values.
Table III. Systemic hemodynamic values in patients receiving octreotide and somatostatin Patients receiving octreotide Basal After octreotide Heart rate (beats/min) Cardiac index (L/min m2) Mean arterial pressure (mm Hg) Systemic vascular resistance (dyne
71
sec/cm5)
± 5
4.1 ± 0.2 93 ± 7 1129 ± 103
69 ± 4 4.2 ± 0.2 91
±
7
1088 ± 97
Patients receiving somatostatin Basal After somatostatin 67
± 4
3.7 ± 0.2 92 ± 3 1214 ± 63
66 ± 4 3.8 ± 0.2 93 ± 5 1193 ± 72
Data are mean values ± SEM.
hepatic clearance, or the maximum velocity/metabolite elimination rate constant (Vmax/km) was calculated as follows: HPF X In (1 ER). The cardiac index was calculated according to the formula: Cardiac index (L/min m2) = cardiac output/body surface area. The systemic vascular resistance was calculated by the formula: Systemic vascular resistance (dyne sec/cm5) = (mean arterial pressure right atrial pressure) 80/cardiac output. The findings were expressed as mean values ± SEM. The Wilcoxon signed rank test and the MannWhitney U test were used for statistical analysis (a =
0.05).
RESULTS The clinical and laboratory data of these patients are summarized in Table I. There were no significant differences in all the clinical and laboratory parameters between patients receiving octreotide and somatostatin infusion. The hepatic vein catheterization is a rather safe procedure, and no complications were observed in our patients. Only one patient had had a hematoma over the puncture site, which resolved spontaneously after the procedure. The effects of octreotide and somatostatin on hepatic clearance, hepatic blood flow, clearance Vnia,,/k and hepatic extraction ratio are summarized in Table II. In patients receiving octreotide, the hepatic clearance, clearance Vmax/km, and hepatic blood
flow were significantly reduced at 60 minutes after octreotide infusion, whereas the hepatic extraction ratio was not significantly altered. Similarly, in patients receiving somatostatin, the hepatic clearance, clearance Vmax/km, and hepatic blood flow were significantly reduced at 30 minutes after somatostatin infusion, but the hepatic extraction ratio showed no significant changes. The systemic hemodynamic effects of octreotide and somatostatin are summarized in Table III. The cardiac index, heart rate, mean arterial pressure, and systemic vascular resistance were not significantly different in patients receiving either octreotide or somatostatin. In patients receiving octreotide, plasma glucose level was significantly decreased 60 minutes after octreotide infusion (75 ± 4 mg/di, p < 0.05) compared with basal values (111 ± 8 mg/di). In addition, in patients receiving somatostatin, plasma glucose level significantly decreased 30 minutes after somatostatin infusion (67 ± 3 mg/di, p < 0.05) compared with basal values (100 ± 7 mg/dl).
DISCUSSION In the present study, consistent with previous studies," somatostatin infusion significantly reduced hepatic blood flow in our patients with HB,Ag-positive cirrhosis. Moreover, the liver metabolic activity estimated by the intrinsic hepatic clearance (i.e., clearance Vmax/k,,,) was also decreased after somatostatin
VOLUME 52 NUMBER 2
infusion. Similar observations in reduced liver metabolic activity after somatostatin administration have been described previously in patients with alcoholic cirrhosis.67 As previously reported,25 estimates of the clearance V./km according to the sinusoidal perfusion model of hepatic elimination were used to express the metabolic activity of all hepatocyte in contact with functional blood flow and responsible for the removal of indocyanine green. In our patients with HB,Ag-positive cirrhosis, octreotide significantly reduced hepatic blood flow. These findings are consistent with previous observations. 15'16 The main findings of the present study are the decreases in hepatic clearance and liver metabolic activity by octreotide in patients with cirrhosis. The magnitudes of the reduction in hepatic blood flow, hepatic clearance, and liver metabolic activity after octreotide were similar to those observed after somatostatin administration. The decrease in hepatic clearance may theoretically be caused by a decreased hepatic blood flow or by reduced liver metabolic activity. For substances with low hepatic clearance, as is the case in cirrhosis, changes in hepatic clearance depend mainly on the changes in V./km and secondarily on hepatic blood flow. 19'25 Therefore the reduced hepatic clearance observed after octreotide in our patients with HB,Ag-positive cirrhosis was mainly caused by the reduction in the metabolic activity of the liver. The possible mechanisms by which the vasoactive agents decrease the liver metabolic activity include an increase in shunted blood or a decrease in the true metabolic activity of hepatocytes as a result of reduced functional blood flow or direct effect of the vasoactive drugs on the exposed hepatocytes.6 These findings may have important clinical implications. Because recent studies showed a potential benefit of octreotide in the control of acute variceal bleeding,26-28 it should be noticed that the reduced hepatic blood flow and impaired liver metabolic activity after octreotide may be hazardous to patients with cirrhosis during hemorrhage. In this study, the heart rate, mean arterial pressure, cardiac index, and systemic vascular resistance were not affected by octreotide or somatostatin infusion. Therefore the decrease in the hepatic blood flow is not a likely reflection of altered systemic hemodynamics. The mechanism of action of somatostatin or octreotide in the reduction of hepatic blood flow is still not established. Although Bosch et al.5 postulated that somatostatin had a selective vasoconstrictive effect on splanchnic vasculature, recent studies showed that somatostatin or octreotide had no direct effect on the
Octreotide in cirrhosis
137
blood vessels.29'30 Moreover, in portal hypertensive animals it has been shown that inhibition of glucagon release may represent the main mechanism of somatostatin or octreotide in reducing splanchnic blood flow,3I because hyperglucagonism may be responsible for the splanchnic hyperemia in chronic portal hypertension,32.33 and can contribute to vasodilation by reducing the vascular sensitivity to endogenous vasoconstrictors .34'35 In this study, we concluded that, similar to the effect of somatostatin, octreotide reduced hepatic blood flow and hepatic clearance in patients with HBsAgpositive cirrhosis. The reduced hepatic clearance after octreotide was mainly attributable to the reduction in the metabolic activity of the liver. We thank Miss Li-Fen Lin and Mr. Dong-Ming Liao for technical and editorial assistance.
References Kravetz D, Bosch J, Teres J, Rimola A, Rodes J. Comparison of intravenous somatostatin and vasopressin infusion in treatment of acute variceal hemorrhage. Hepatology 1984;4:442-6. Jenkins SA, Baxter JN, Corbett W, Devitt P, Ware J. Shields R. A prospective randomized controlled clinical trial comparing somatostatin and vasopressin in controlling acute variceal haemorrhage. Br Med J 1985; 290:275-8. Burroughs AK, McCormick PA, Hughes MD, Sprengers D, D'Heygere F, McIntyre N. Randomized, doubleblind, placebo-controlled trial of somatostatin for variceal bleeding. Gastroenterology 1990; 99:1388-95. Jaramillo JL, Mata M, Mino G, Gomez-Camacho F. Somatostatin versus Sengstaken balloon tamponade for primary haemostasia of bleeding esophageal varices. A randomized pilot study. J Hepatol 1991;12:100-5. Bosch J, Kravetz D, Rodes J. Effect of somatostatin on hepatic and systemic hemodynamics in patients with cirrhosis of the liver: comparison with vasopressin. Gastroenterology 1981;80:518-25. Barbare JC, Poupon R, Jaillon P, et al. The influence of vasoactive agents on metabolic activity of the liver in cirrhosis: a study of the effects of posterior pituitary extract, vasopressin, and somatostatin. Hepatology 1984;4:59-62. Merkel C, Gatta A, Caregaro L, Sacerdoti D, Rondana M, Ruol A. Effect of somatostatin on liver blood flow and liver metabolic activity in patients with cirrhosis. Scand J Clin Lab Invest 1987;47:667-72. Eriksson LS, Law DH, Sato Y, Wahren J. Influence of somatostatin in splanchnic haemodynamics in patients with liver cirrhosis. Clin Physiol 1984;4:5-11. Naeiji R, Hallemans R, Mils P, Melot C, Reding P. Effects of vasopressin and somatostatin on hemodynamics
138 Lin et al. and blood gases in patients with cirrhosis. Crit Care Med 1982;10:578-82. Sonnenberg GE, Keller U, Perruchoud A, Burckhardt D, Gyr K. Effect of somatostatin on splanchnic hemodynamics in patients with cirrhosis of the liver and in normal subjects. Gastroenterology 1981;80:526-32. Merkel C, Gatta A, Zuin R, Finucci GF, Nosadini R, Ruol A. Effect of somatostatin on splanchnic hemodynamics in patients with liver cirrhosis and portal hypertension. Digestion 1985;32:92-8. Clements D, Rhodes JM, Elias E. Effect of somatostatin on oesophageal variceal pressure assessed by direct measurement. J Hepatol 1986;2:262-6. Kleber G, Sauerbruch T, Fischer G, Paumgartner G. Somatostatin dose not reduce oesophageal variceal pressure in liver cirrhosis. Gut 1988;29:153-6. Bauer W, Briner U, Doepfner W, et al. SMS 201-995: a very potent and selective octapeptide analogue of somatostatin with prolonged action. Life Sci 1982;31:1133-40. Eriksson LS, Brundin T, Soderlund C, Wahren J. Haemodynamic effects of a long-acting somatostatin analogue in patients with liver cirrhosis. Scand J Gastroenterol 1987;22:919-25. Lin HC, Tsai YT, Lee FY, et al. Systemic and hepatic hemodynamic changes following octreotide administration in patients with hepatitis B-related cirrhosis [Abstract]. Hepatology 1991;14:84A. Pringle SD, McKee RF, Garden OJ, Lorimer AR, Carter DC. The effect of a long-acting somatostatin analogue on portal and systemic haemodynamics in cirrhosis. Aliment Pharmacol Ther 1988;2:451-9. McCormick PA, Dick R, Siring° S, et al. Octreotide reduces azygos blood flow in cirrhotic patients with portal hypertension. Eur J Gastroenterol Hepatol 1990; 2:489-92. Wilkinson GR, Shand DG. A physiological approach to hepatic drug clearance. CLIN PHARMACOL THER 1975;18: 377-90. Winkler K, Bass L, Keiding S, et al. The physiologic basis for clearance measurements in hepatology. Scand J Gastroenterol 1979;14:439-48. Lay CS, Tsai YT, Kong CW, et al. The influence of verapamil and nifedipine on hepatic indocyanine green clearance in patients with HB,Ag-positive cirrhosis and ascites. CLIN PHARMACOL THER 1988;44:453-7. Pugh RNH, Marray-Lyon M, Dawson JL, Pietroni MC, Williams R. Transaction of the oesophagus for bleeding oesophageal varices. Br J Surg 1973;60:646-9. Tsai YT, Lee FY, Lin HC, et al. Lack of effects of
CLIN PHARMACOL THER AUGUST 1992
isosorbide-5-mononitrate on hepatic hemodynamics in HBsAg-positive cirrhosis. Hepatology 1989;10:283-7. Forrester JS, Ganz W, Diamond G, McHugh T, Chonette DW, Swan HJC. Thermodilution cardiac output determination with a single flaw-directed catheter. Am Heart J 1972;83:306-11. Poupon RY, Poupon RE, Lebrec D, et al. Mechanism for reduced hepatic clearance and elevated plasma levels of bile acids in cirrhosis. A study in patients with an end-to-side portacaval shunt. Gastroenterology 1981; 80:1438-44. Silvain C, Carpentier S, Sautereau D, et al. A randomized trial of glypressin plus transdermal nitroglycerin versus octreotide in the control of acute variceal hemorrhage [Abstract]. Hepatology I991;14:133A. McKee R. A study of octreotide in oesophageal varices. Digestion 1990;45(suppl I):60-5. Hwang SJ, Lin HC, Chang CF, et al. A randomized controlled trial comparing octreotide and vasopressin in the control of acute esophageal variceal bleeding. .1 Hepatol [In press]. Maynard KI, Saville VL, Burnstock G. Somatostatin modulates vascular sympathetic neurotransmission in the rabbit ear artery. Eur J Pharmacol 1991;196:125-31. Sieber CC, Mosca PG, Groszmann RJ. Effect of somatostatin on mesenteric vascular resistance in normal and portal hypertensive rats. Am J Physiol 1992;262: G274-7. Pizcueta MP, Garcia-Pagan IC, Fernandez M, Casamitjana R, Bosch J, Rodes J. Glucagon hinders the effects of somatostatin on portal hypertension. A study in rats with partial portal vein ligation. Gastroenterology 1991;101:1710-5. Benoit JN, Zimmerman B, Premen AJ, Go W, Granger DN. Role of glucagon in the splanchnic hyperemia of chronic portal hypertension. Am J Physiol 1986;251: G674-7. Kravetz D, Bosch J, Arderiu MT, et al. Effects of somatostatin on splanchnic hemodynamics and plasma glucagon in portal hypertensive rats. Am J Physiol 1988;254:G322-8. Pizcueta MP, Casamitjana R, Bosch J, Rodes J. Decreased systemic vascular sensitivity to norepinephrine in portal hypertensive rats: role of hyperglucagonism. Am .1 Physiol 1990;258:G191-5. Mesh CL, Joh T, Korthuis RJ, Granger DN, Benoit JN. Intestinal vascular sensitivity to vasopressin in portal hypertensive rats. Gastroenterology 1991;100:916-21.
Han-Chieh Lin, MD, Yang-Te Tsai, MD, Shou-Dong Lee, MD, Fa-Yauh Lee, MD, Hsiao-Chung Hsia, MD, Hong-Chiang Meng, MD, Sun-Sang Wang, MD, and Kwang-Juei Lo, MD Taipei and Taichung, Taiwan Somatostatin has been proposed as a treatment of acute variceal hemorrhage in patients with cirrhosis. 1-4 This drug has been noted to reduce liver blood flow in patients with cirrhosis," but there have been reports of conflicting effects on portal pressure""" and intravariceal pressure.12, 3 Moreover, previous studies reported a decrease in metabolic activity of the liver during somatostatin infusion, a side effect potentially harmful to patients with cirrhosis.6a In addition, the clinical use of somatostatin may be limited by its short half-life of only a few minutes. Octreotide is a synthetic octapeptide analog of somatostatin that has a much longer biologic half-life.14 It has been reported to reduce liver blood flow in pa1
From the Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, the Department of Medicine, Taichung Veterans General Hospital, Taichung, and the National Yang-Ming Medical College, Taipei. Supported by grant No. NSC 80-0412-B075-l17 from the National Science Council, Taiwan, Republic of China. Received for publication Feb. 4, 1992; accepted April 21, 1992. Reprint requests: Yang-Te Tsai, MD, Department of Medicine, Taichung Veterans General Hospital, 160, Sec. 3, Chung-Kang Road, Taichung 407, Taiwan. 13/1/38798
134
tients with cirrhosis,15.16 but its effect on portal pressure is uncertain.15-I8 Furthermore, the influence of octreotide on liver metabolic activity has not been established. Our study used current models of hepatic elimination, "intrinsic" hepatic clearance,19'20 which provide a quantitative index of hepatic metabolic activity in patients with cirrhosis,6'7'21 to investigate the influence of octreotide on liver metabolic activity in patients with cirrhosis that is positive for hepatitis B surface antigen (HBsAg).
MATERIAL AND METHODS Sixteen patients with histologically proved postnecrotic cirrhosis were included in the study. Liver biopsies were performed percutaneously by the needle technique. All the patients were positive for serum HB,Ag by radioimmunoassay (Ausria, Abbott Laboratories, Chicago, Ill.). Effects of octreotide were studied in eight patients, the others received somatostatin and served as control subjects. The clinical and laboratory data of the two groups of patients are summarized in Table I. The severity of liver cirrhosis was classified according to the Pugh's modification of Child's classification.22 All patients had endoscopically demonstrable esophageal varices, but only two
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135
Table I. Clinical and laboratory data in patients receiving octreotide and somatostatin Patients receiving octreotide No. of patients Age (yr) Sex (male/female) Body weight (kg) Pugh's classification (A/B/C) Biochemistry Serum albumin (gm/d1) Serum bilirubin (mg/dl) Serum alanine aminotransferase (U/L) Prothrombin time (%)
Patients receiving somatostatin
8
8
65 ± 2* 7/1 58 ± 2* 2/4/2
60 ± 3*
3.0 ± 0.1* 1.4 ± 0.2* 44 ± 6* 70 ± 3*
7/1
59 -± 2* 5/2/1
3.3
-±
0.2*
1.2 ± 0.1* 92 ± 45* 76 ± 2*
*Mean ± SEM.
patients had had an episode of variceal hemorrhage 3 months and 5 weeks before the present investigation, respectively, and were treated by sclerotherai5y. No patient had a history of alcohol consumption. All patients were screened by abdominal ultrasound or computerized tomography, and none of them was associated with hepatocellular carcinoma. Patients who had bleeding diathesis, hepatic encephalopathy, previous operation for portal hypertension, or heart or kidney diseases were not included in the study. Written informed consent was obtained from each patient before the study. The study protocol was reviewed and approved by the Hospital Ethics Committee of Taipei Veterans General Hospital. After an overnight fast, the patients were prepared for hepatic vein catheterization by use of a 7F balloontipped pulmonary artery thermodilution catheter (Gould Inc., Cupertino, Calif.) as in our previous study.23 The hepatic blood flow and liver metabolic activity were assessed by the indocyanine green continuous infusion method as described previously.21 In brief, 0.5 mg/kg indocyanine green (Cardiogreen, Hynson, Westcott & Dunning, Inc., Baltimore, Md.) was infused through an antecubital vein over 5 minutes and then at a constant rate of 0.48 mg/min. After waiting 30 minutes to obtain a steady state in indocyanine green plasma concentration, blood samples were drawn simultaneously from a peripheral vein and from the hepatic vein at 2-minute intervals for 10 minutes and collected in lithium heparin tubes. After collection of the blood samples, the catheter was advanced into the pulmonary artery where cardiac output was measured by thermodilution by use of 10 ml of 0° to 4° C 5% dextrose in water injected through the balloontipped pulmonary artery catheter into the pulmonary artery.24 The cardiac output determinations were made in triplicate. Systemic mean arterial pressure and heart
rate were measured and recorded with an external electronic vital sign monitor (Dinamap 8100, Critikon, Inc., Tampa, Fla.). After basal cardiac output determination and blood pressure measurement and after withdrawal of blood from both peripheral and hepatic vein, the patients were randomly assigned to receive a continuous infusion of 50 11,g/hr octreotide (Sandostatin; Sandoz Pharmaceutical Ltd., Berne, Switzerland) after an initial bolus of 50 lig or to receive a continuous infusion of 250 gig/hr somatostatin (Stilamin; Serono Laboratories, Inc., Randolph, Mass.) after an initial bolus of 250 pg. The cardiac output determinations and blood pressure measurements were performed again at 30 minutes after the beginning of the infusion of somatostatin and 60 minutes after the beginning of the infusion of octreotide. At the same time peripheral and hepatic blood samples were simultaneously drawn at 2-minute interval for a period of 10 minutes. In addition, blood samples for plasma glucose analysis were collected from the antecubital vein in the basal state and at 30 minutes after somatostatin infusion and 60 minutes after octreotide infusion. The hepatic clearance was calculated as follows: V/Cp, in which V is the rate of infusion of indocyanine green (0.48 mg/min), and Cp is the plasma concentration of ICG in peripheral venous blood. The hepatic extraction ratio (ER) was calculated as follows: (Cp Ch)/Cp, in which CI, is the plasma concentration of indocyanine green in the hepatic vein. The hepatic plasma flow (HPF) was calculated as follows: V/(Cp Ch). The hepatic blood flow was calculated as follows: HPF/(1 hematocrit). To estimate the metabolic activity of hepatocyte responsible for the removal of indocyanine green, the sinusoidal perfusion model of hepatic elimination was used. According to this model6,20,21 the intrinsic
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Table II. Influence of octreotide and somatostatin on hepatic blood flow and liver metabolic activity Patients receiving octreotide Basal After octreotide Hepatic blood flow (ml/min) Hepatic clearance (ml/min) Clearance Vn.,/k, (ml/min) Hepatic extraction ratio (%)
1301
± 159
282 ± 57 355 ±- 83 30.9 ± 5.2
Patients receiving somatostatin Basal After somatostatin
1000 ± 105* 233 ± 50* 298 ± 73*
1434 ± 115 372 ± 38 478 ± 54
32.3
38.9 ± 3.5
-±
5.5
1203 ± 111* 316 ± 35*
406 ± 48* 39.1 ± 3.1
Data are mean values -± SEM. Vmax/kn Maximum velocity/metabolite elimination rate constant. *p < 0.05 versus basal values.
Table III. Systemic hemodynamic values in patients receiving octreotide and somatostatin Patients receiving octreotide Basal After octreotide Heart rate (beats/min) Cardiac index (L/min m2) Mean arterial pressure (mm Hg) Systemic vascular resistance (dyne
71
sec/cm5)
± 5
4.1 ± 0.2 93 ± 7 1129 ± 103
69 ± 4 4.2 ± 0.2 91
±
7
1088 ± 97
Patients receiving somatostatin Basal After somatostatin 67
± 4
3.7 ± 0.2 92 ± 3 1214 ± 63
66 ± 4 3.8 ± 0.2 93 ± 5 1193 ± 72
Data are mean values ± SEM.
hepatic clearance, or the maximum velocity/metabolite elimination rate constant (Vmax/km) was calculated as follows: HPF X In (1 ER). The cardiac index was calculated according to the formula: Cardiac index (L/min m2) = cardiac output/body surface area. The systemic vascular resistance was calculated by the formula: Systemic vascular resistance (dyne sec/cm5) = (mean arterial pressure right atrial pressure) 80/cardiac output. The findings were expressed as mean values ± SEM. The Wilcoxon signed rank test and the MannWhitney U test were used for statistical analysis (a =
0.05).
RESULTS The clinical and laboratory data of these patients are summarized in Table I. There were no significant differences in all the clinical and laboratory parameters between patients receiving octreotide and somatostatin infusion. The hepatic vein catheterization is a rather safe procedure, and no complications were observed in our patients. Only one patient had had a hematoma over the puncture site, which resolved spontaneously after the procedure. The effects of octreotide and somatostatin on hepatic clearance, hepatic blood flow, clearance Vnia,,/k and hepatic extraction ratio are summarized in Table II. In patients receiving octreotide, the hepatic clearance, clearance Vmax/km, and hepatic blood
flow were significantly reduced at 60 minutes after octreotide infusion, whereas the hepatic extraction ratio was not significantly altered. Similarly, in patients receiving somatostatin, the hepatic clearance, clearance Vmax/km, and hepatic blood flow were significantly reduced at 30 minutes after somatostatin infusion, but the hepatic extraction ratio showed no significant changes. The systemic hemodynamic effects of octreotide and somatostatin are summarized in Table III. The cardiac index, heart rate, mean arterial pressure, and systemic vascular resistance were not significantly different in patients receiving either octreotide or somatostatin. In patients receiving octreotide, plasma glucose level was significantly decreased 60 minutes after octreotide infusion (75 ± 4 mg/di, p < 0.05) compared with basal values (111 ± 8 mg/di). In addition, in patients receiving somatostatin, plasma glucose level significantly decreased 30 minutes after somatostatin infusion (67 ± 3 mg/di, p < 0.05) compared with basal values (100 ± 7 mg/dl).
DISCUSSION In the present study, consistent with previous studies," somatostatin infusion significantly reduced hepatic blood flow in our patients with HB,Ag-positive cirrhosis. Moreover, the liver metabolic activity estimated by the intrinsic hepatic clearance (i.e., clearance Vmax/k,,,) was also decreased after somatostatin
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infusion. Similar observations in reduced liver metabolic activity after somatostatin administration have been described previously in patients with alcoholic cirrhosis.67 As previously reported,25 estimates of the clearance V./km according to the sinusoidal perfusion model of hepatic elimination were used to express the metabolic activity of all hepatocyte in contact with functional blood flow and responsible for the removal of indocyanine green. In our patients with HB,Ag-positive cirrhosis, octreotide significantly reduced hepatic blood flow. These findings are consistent with previous observations. 15'16 The main findings of the present study are the decreases in hepatic clearance and liver metabolic activity by octreotide in patients with cirrhosis. The magnitudes of the reduction in hepatic blood flow, hepatic clearance, and liver metabolic activity after octreotide were similar to those observed after somatostatin administration. The decrease in hepatic clearance may theoretically be caused by a decreased hepatic blood flow or by reduced liver metabolic activity. For substances with low hepatic clearance, as is the case in cirrhosis, changes in hepatic clearance depend mainly on the changes in V./km and secondarily on hepatic blood flow. 19'25 Therefore the reduced hepatic clearance observed after octreotide in our patients with HB,Ag-positive cirrhosis was mainly caused by the reduction in the metabolic activity of the liver. The possible mechanisms by which the vasoactive agents decrease the liver metabolic activity include an increase in shunted blood or a decrease in the true metabolic activity of hepatocytes as a result of reduced functional blood flow or direct effect of the vasoactive drugs on the exposed hepatocytes.6 These findings may have important clinical implications. Because recent studies showed a potential benefit of octreotide in the control of acute variceal bleeding,26-28 it should be noticed that the reduced hepatic blood flow and impaired liver metabolic activity after octreotide may be hazardous to patients with cirrhosis during hemorrhage. In this study, the heart rate, mean arterial pressure, cardiac index, and systemic vascular resistance were not affected by octreotide or somatostatin infusion. Therefore the decrease in the hepatic blood flow is not a likely reflection of altered systemic hemodynamics. The mechanism of action of somatostatin or octreotide in the reduction of hepatic blood flow is still not established. Although Bosch et al.5 postulated that somatostatin had a selective vasoconstrictive effect on splanchnic vasculature, recent studies showed that somatostatin or octreotide had no direct effect on the
Octreotide in cirrhosis
137
blood vessels.29'30 Moreover, in portal hypertensive animals it has been shown that inhibition of glucagon release may represent the main mechanism of somatostatin or octreotide in reducing splanchnic blood flow,3I because hyperglucagonism may be responsible for the splanchnic hyperemia in chronic portal hypertension,32.33 and can contribute to vasodilation by reducing the vascular sensitivity to endogenous vasoconstrictors .34'35 In this study, we concluded that, similar to the effect of somatostatin, octreotide reduced hepatic blood flow and hepatic clearance in patients with HBsAgpositive cirrhosis. The reduced hepatic clearance after octreotide was mainly attributable to the reduction in the metabolic activity of the liver. We thank Miss Li-Fen Lin and Mr. Dong-Ming Liao for technical and editorial assistance.
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