Abraham Koshy

Circulatory effects of somatostatin analogue in two conscious rat models of portal hypertension.

A somatostatin analogue, a long-acting octapeptide (SMS 201-995), has been reported to decrease portal pressure, but the mechanism is unclear. To elucidate the effects of this drug on both systemic and splanchnic hemodynamics, it was administered in two conscious rat models of portal hypertension. The dose-response curves showed that the somatostatin analogue significantly decreased portal pressure at a lower dose in rats with cirrhosis than in portal vein-stenosed rats. Calculated ED50 values were significantly different among all groups. Intravenous infusion of 8 micrograms/kg body wt.h of somatostatin analogue significantly decreased cardiac output by approximately 20% in both groups of portal hypertensive rats and increased mean arterial pressure by 7%. Accordingly, systemic vascular resistance markedly increased, indicating vasoconstrictor effects of this drug. The somatostatin analogue also significantly decreased portal tributary blood flow by 18% in portal vein-stenosed rats and 27% in cirrhotic rats. In sham-operated rats, somatostatin analogue had no effect on the systemic or splanchnic circulation. This study shows that somatostatin analogue decreases portal pressure principally by reducing portal tributary blood flow. This reduction may be due to either a direct vasoconstrictive effect or diminution in vasoactive hormone release.

Study of an epidemic of jaundice, presumably due to toxic hepatitis, in Northwest India.

An epidemic of jaundice probably due to toxic hepatitis occurred in three adjoining districts of Northwest India during the period November and December, 1974. The dogs of the villages were affected first, then the human beings. Detailed clinical features, appropriate laboratory tests, and liver biopsies were studied. A retrospective epidemiological survey was carried out. The disease had a subacute onset starting with high fever, followed by rapidly progressive jaundice. Ascites appeared simultaneously and soon became quite massive. Hepatomegaly was recorded when ascites decreased. Liver function tests suggested cholestatic jaundice. The mortality rate in the hospital was 10%. Clinical features in dogs were similar, but mortality was almost 100%. Liver histology was characterized by (1) edema and collagenization of the central veins, never with thrombosis, (2) cholangiolar proliferation, (3) moderate to severe ballooning of the hepatocytes, (4) perisinusoidal fibrosis, (5) cholestasis, and finally, (6) cirrhosis with reverse lobulation. Etiology of this epidemic of hepatitis could not be unequivocally established. Critical analysis of the data suggests that some food toxin may have been a factor in the outbreak of this unusual epidemic of toxic hepatitis.

Treatment of hepatitis C virus genotype 4-related cirrhosis: Ribavirin and interferon combination compared with interferon alone

Background Response to treatment with interferon alfa, with or without concomitant ribavirin, varies with the viral genotype and the degree of fibrosis in patients with chronic hepatitis C virus (HCV). Goals To determine the response of HCV type 4–related cirrhosis to interferon and ribavirin combination treatment compared with interferon alone. Study Patients living in Kuwait were assigned to take either interferon alone at a dosage of 5 million units thrice weekly (26 patients) or interferon 5 million units thrice weekly combined with ribavirin 1,000 mg/d (21 patients) for 24 weeks. Biochemical response was defined as normal alanine aminotransferase (ALT) at end of therapy. Sustained biochemical response was defined as normal ALT 6 months after the end of therapy. Sustained virologic response was defined as negative serum HCV RNA 6 months after the end of therapy. Results Only 2 (8%) of 26 patients showed biochemical response after interferon alone, whereas 11 (52%) of 21 showed biochemical response after interferon combined with ribavirin (p < 0.01). Only 2 (8%) of 26 patients showed sustained biochemical response after interferon alone, whereas 5 (23%) of 21 showed sustained biochemical response after interferon combined with ribavirin (not significant, p > 0.1). None of the 26 patients showed virologic response after interferon alone, whereas 3 (14%) of 21 showed sustained virologic response after interferon combined with ribavirin (not significant, p > 0.1). Conclusion These results suggest that patients with cirrhosis caused by HCV type 4 show no response to interferon alone and only slightly better response to 24 weeks of interferon combined with ribavirin.

Reduction of portal pressure by acute administration of furosemide in patients with alcoholic cirrhosis

In patients with cirrhosis, it has been demonstrated that blood volume and degree of portal hypertension are correlated. Hence, a reduction of blood volume by furosemide could decrease portal pressure and could thereby be useful in the treatment of portal hypertension. Splanchnic and systemic haemodynamics were evaluated before and 1 h after intravenous administration of furosemide (0.75 mg/kg) in 10 patients with cirrhosis. Furosemide significantly increased haemoglobin from 12.4 to 13.0 g/dl and patients passed more than 1 l of urine within the 3 h following furosemide administration. These findings confirm that blood volume decreased after diuretic administration. Cardiac output significantly decreased from 6.6 +/- 2.3 to 5.5 +/- 2.2 l/min, while arterial pressure and heart rate did not change significantly. Furosemide significantly decreased wedged hepatic venous pressure from 31.1 +/- 6.2 to 27.7 +/- 5.2 mmHg, but not free hepatic venous pressure. Accordingly, the hepatic venous pressure gradient significantly decreased from 22.1 +/- 5.4 to 19.5 +/- 4.0 mmHg. Azygos blood flow and hepatic blood flow also significantly decreased from 0.40 +/- 0.17 to 0.31 +/- 0.13 l/min and from 1.49 +/- 0.50 to 0.82 +/- 0.30 l/min, respectively. These results show that diuretic therapy markedly influences splanchnic haemodynamics.

Effects of oxygen inhalation on tissue oxygenation in patients with cirrhosis: Evidence for an impaired arterial baroreflex control

In patients with cirrhosis, O2 uptake, i.e., O2 consumption, is abnormally decreased. We administered 50% O2 for 30 min in eight patients with alcoholic cirrhosis to determine whether the subsequent increase in arterial O2 content may correct the low O2 consumption. In addition, we studied in these patients the reflex control of cardiac output and blood pressure by arterial baroreceptors, as O2 inhalation induces a systemic vasoconstriction. Arterial O2 tension, oxyhaemoglobin saturation and arterial O2 content significantly increased as well as systemic vascular resistance and arterial pressure. In contrast, O2 consumption (which was below normal values) under basal conditions, O2 transport, O2 extraction ratio, heart rate, right atrial and pulmonary wedged pressures, cardiac output, hepatic venous pressures, hepatic and azygos blood flows were unaffected by O2 administration. In three patients receiving air, no significant change was observed. Our results show that, in patients with cirrhosis, inhalation of 50% O2 does not correct O2 consumption. We may conclude that reflex control of cardiac output and arterial pressure by arterial baroreceptors is impaired in these patients.

Possible deleterious hemodynamic effect of nifedipine on portal hypertension in patients with cirrhosis

The acute effects of nifedipine, 10 mg administered sublingually, were studied in 10 patients with alcoholic cirrhosis. Nifedipine significantly increased cardiac output and reduced systemic vascular resistance. Nifedipine also increased the hepatic venous pressure gradient by 15% (P < 0.01). Hepatic blood flow and azygos blood flow did not change significantly. It is suggested that nifedipine increases portal pressure and thus may be deleterious to patients with portal hypertension.

Regional Blood Flows by the Microsphere Method: Reproducibility in Portal Hypertensive Rats and Influence of a Portal Vein Catheter

Abstract To determine the reproducibility of splanchnic blood flow measurements by the microsphere method in rats with portal hypertension and the effects of laparotomy with portal vein cannulation, eight groups of 10 rats were studied. Cardiac output and regional blood flows were measured twice, 10 min apart, in pentobarbital anesthetized or awake, sham-operated or portal vein-ligated rats, with or without portal cannulation. Variability between the two successive measurements was not affected by portal hypertension or portal cannulation, and was not different in the splanchnic territory and in other organs. Laparotomy with portal cannulation had no significant effect in sham-operated rats. In awake portal hypertensive rats, cardiac output (53.9 ± 3.0 vs 45.8 ±2.9 ml · min-1 · 100 g body wt-l, P < 0.01) and splanchnic blood flow (12.31 ± 0.72 vs 9.34 ± 0.85 ml · min-1 · 100 g body wt-1, P < 0.01) were lower in portal vein cannulated rats compared with those of non-cannulated animals. In anesthetized portal hypertensive rats blood flows were unaffected by portal cannulation, but arterial pressure (100.2 ± 4.3 vs 119.9 ± 3.4 mm Hg, P < 0.01) and heart rate (366.5 ± 10.0 vs 405.5 ± 7.4 beats · min-1, P < 0.01) were elevated. Anesthesia also decreased portal pressure (14.8 ± 0.5 vs 12.0 ± 0.4 mm Hg, P < 0.05) in portal hypertensive rats. We conclude that the microsphere method remains reproducible in portal hypertensive rat models. Laparotomy with portal cannulation can alter systemic and splanchnic hemodynamics in portal hypertensive rats; these effects can also be changed during pentobarbital anesthesia. Regional blood flow measurements in portal hypertensive rats should be performed in animals without portal cannulation and preferably in the awake state.

Effects of α1 and β-adrenergic antagonists and 5-hydroxytryptamine receptor antagonist on portal-systemic collateral vascular resistance in conscious rats with portal hypertension

In order to study the acute effects of pharmacological agents on the vascular resistance of portal‐systemic collaterals, a model of total portal vein occlusion with 100% portal‐systemic shunts was developed in the conscious rat. The haemodynamic effects of several vaso‐active substances were evaluated in this model and compared with those obtained after saline administration. Prazosin (0.5 mg), an α1‐adrenergic antagonist, significantly reduced mean arterial pressure by 29%, portal pressure from 13.8 ± 1.0 (mean ± s.e.m.) to 10.1 ± 0.4 mmHg and portal tributary blood flow (radioactive microspheres) from 13.6 ± 2.1 to 11.7 ± 1.2 mL/min. It also decreased portal‐systemic vascular resistance from 95 ± 16 to 73 ± 9 dyn s/cm5 x 103. Propranolol (4 mg), a β‐adrenergic antagonist, significantly reduced mean arterial pressure by 12% and portal pressure from 15.5 ± 1.2 to 13.3 ± 0.9 mmHg while reducing portal tributary blood flow from 14.6 ± 1.5 to 11.0 ± 1.7 mL/min and increasing portal systemic collateral vascular resistance from 88 ± 7 to 103 ± 8 dyn s/cm5 x 103. Ketanserin (0.25 mg/kg), a 5‐hydroxytryptamine receptor antagonist, reduced portal pressure from 15.8 ± 1.0 to 13.3 ± 0.7 mmHg at a dose that did not alter mean arterial pressure or portal tributary blood flow. It achieved this by reducing portal‐systemic collateral vascular resistance from 90 ± 14 to 74 ± 13 dyn s/cm5 x 103. Saline had no significant effect on systemic and splanchnic haemodynamics. This study shows that ketanserin decreases vascular resistance of portal‐systemic collaterals while propranolol increases it. Thus, it is suggested that collateral vascular resistance is accessible to pharmacological manipulation.

Heterogeneous hepatic venous pressures in patients with liver cancer

We carried out hepatic vein catheterization in 73 patients with liver cancer, 52 with primary and 21 with metastatic cancer. A heterogeneous hepatic venous pressure gradient, defined as a difference of >4 mmHg between the highest and lowest values of the pressure gradient in any patient, was found in 46% of the hepatocellular carcinoma cases and 43% of the metastatic cancers. Comparing the diagnostic efficacy of this phenomenon with an elevated a-fetoprotein, based on 500 randomly selected catheterizations, showed that the heterogeneous gradient was 46% sensitive and 99% specific for the diagnosis of hepatocellular carcinoma, while the α-fetoprotein was 67% sensitive and 99% specific. Positive and negative predictive values were 86 and 95%, respectively, for the heterogeneous gradient, and 83 and 97% for the a-fetoprotein. Its expense and relative invasiveness make hepatic vein catheterization an unacceptable routine in patients suspected of having hepatic malignancy. However, we suggest that the unexpected finding of a heterogeneous pressure gradient should trigger a search for hepatic cancer.

Effects of glucagon on systemic and splanchnic circulation in conscious rats with biliary cirrhosis

To elucidate the relationship between the haemodynamic changes and glucagon in cirrhosis, we infused physiologic and supraphysiologic doses of this hormone in conscious rats with portal hypertension due to biliary cirrhosis. Cardiac output and splanchnic organ blood flows were measured by the radioactive microsphere method before and 30 min after glucagon infusion at doses of 2, 5 and 10 ng/min. Serum glucagon increased from a basal level of 92 +/- 17 pg/ml (mean +/- S.E.) to 399 +/- 89, 1151 +/- 136 and 2064 +/- 328 pg/ml, respectively, in sham-operated rats, and from 743 +/- 75 pg/ml to 1497 +/- 197, 1583 +/- 356 and 2957 +/- 649 pg/ml, respectively, in cirrhotic animals at 2, 5 and 10 ng/min doses. In both groups, cardiac output did not change after glucagon infusion at 2 and 5 ng/min doses, suggesting that factors other than glucagon are primarily responsible for the systemic hyperdynamic circulation in cirrhosis. Portal tributary blood flow increased significantly after glucagon infusion in sham-operated rats by 34 and 65% at doses of 5 ng/ml and 10 ng/ml, respectively, and in cirrhotic rats by 29% at a dose of 10 ng/ml. However, portal tributary blood flow did not change after glucagon infusion at the physiologic dose of 2 ng/min. This study shows that glucagon infused at a physiologic dose does not increase splanchnic blood flow, although it increases portal tributary blood flow at supraphysiologic doses. The discrepancy between blood glucagon levels and splanchnic haemodynamic responses suggests that glucagon plays only a minor role and that other factors are primarily responsible for the hyperdynamic state of the splanchnic circulation in rats with biliary cirrhosis.