The relationship between intrahepatic portal systemic shunts and microsphere induced portal hypertension in the rat liver

Background—Portal hypertension is associated with gross haemodynamic disturbances characterised by high cardiac output, low peripheral vascular resistance, increased splanchnic blood flow, and portal systemic shunting.Aims—To study the relationship between intrahepatic portal systemic shunts and microsphere induced portal hypertension in the rat liver.Methods—Different sized microspheres were sequentially injected into the portal vein of male Wistar rats.Results—Steady state portal venous pressure was increased by 102.2 (35.6)% (14.9 (3.6) mm Hg) and 272.3 (78.0)% (24.0 (2.2) mm Hg) above the basal pressure following sequential injections of 15 and 80 μm diameter microspheres, respectively. Sequential injection of 15, 40, and 80 μm diameter microspheres in either ascending or descending order of size did not generate further increases in portal venous pressure. A single injection of 1.8 × 105 80 μm microspheres consistently produced a steady state portal venous pressure of 19.0 (1.3) mm Hg but did not approach the much higher value of 36.6 (43.2) mm Hg measured during clamping of the portal vein. These data indicate that the opening of patent intrahepatic shunts was responsible for the reduced pressures observed during microsphere injections and further evidence for this was provided by the location of microspheres in the pulmonary vascular bed. The elevation in portal venous pressure achieved by microsphere injections was not significantly different to that produced in rats subjected to partial portal vein ligation (20.7 (0.5) mm Hg, p>0.05). Wedged hepatic venous pressure decreased from 6.7 (0.7) to 3.0 (0.6) mm Hg following injection of 80 μm microspheres, suggesting a decrease in total hepatic blood flow. Conversely, injection of 15 μm microspheres induced an increase in wedged hepatic venous pressure from 7.0 (1.0) mm Hg to 12.4 (1.8) mm Hg, indicating a localised redistribution of blood flow at the presinusoidal level of the portal venous vascular network and increased intrahepatic shunt flow.Conclusion—It is suggested that there may be a protective pathophysiological role for these shunts when the liver is subjected to changes which induce acute portal hypertension.

Pharmacokinetics of Octreotide in Patients With Cirrhosis and Portal Hypertension; Relationship Between the Plasma Levels of the Analogue and the Magnitude and Duration of the Reduction in Corrected Wedged Hepatic Venous Pressure

In healthy subjects octreotide is largely metabolised by the liver suggesting that the plasma half-life of the somatostatin analogue may be prolonged in patients with hepatic dysfunction. The aim of this study was therefore (a) to determine the pharmacokinetics of octreotide following its subcutaneous injection in 6 patients with cirrhosis and portal hypertension and (b) compare the magnitude and duration of the effects of intravenous administration of 250 μg somatostatin and 50 μg octreotide on corrected wedged hepatic venous pressure (WHVP) and to relate the findings to the plasma levels of the analogue 1h after administration in 13 patients with cirrhosis and portal hypertension. Following subcutaneous administration of 50 μg octreotide the circulating half life (range 2.4 to 4.79 h) was prolonged whereas the clearance (range 2.101 to 4.775 L/h) was decreased compared to healthy controls. Intravenous bolus administration of 25 μg somatostatin or 50 μg octreotide resulted in a reduction in WHVP of approximately the same magnitude and duration despite appreciable quantities of the analogue in the blood lh after administration (1944 ± 226 pg/ml). These results indicate that the circulating half-life of octreotide is prolonged in cirrhotics suggesting that the dosage regimens should be modified in such patients to avoid accumulation of the analogue in the blood which may result in undesirable side-effects or toxicity. Furthermore, since the magnitude and duration of the reduction in WHVP elicited by IV octreotide is similar to that obseved with somatostatin, the analogue, like the native hormone, must be administered by continuous IV infusion to produce a sustained response and hence a therapeutic effect in the management of acute variceal bleeding.