A medical treatment of esophageal varices by propranolol

The effect of a long-term propranolol administration on portal hemodynamics, liver function tests and endoscopic findings of esophageal varices were evaluated in 27 patients with established esophageal varices. And the following results were obtained. 1) After a long-term propranolol administration, the portal vein pressure fell in 8 of 12 cases (75%), portal blood flow volume reduced in 12 of 13 cases (92.3%) and the improvement of endoscopic findings of esophageal varices were observed in 17 of 27 cases (63%). 2) No significant correlation between dosage and serum concentration of propranolol was observed, and the effective serum concentrations of propranolol were found to be different on each individual. 3) It is considered that the periodical observation of the changes of portal hemodynamics and the endoscopic findings of esophageal varices must be performed under the therapy of a long-term propranolol administration, because that the effect is different on each individual, and when the treatment is not effective, the dosage of the drug should be changed.     

Effect of endoscopic sclerotherapy of esophageal varices on liver blood flow and liver function. An experimental study

In 10 G?ttingen mini-pigs esophageal varices developed after banding of the portal vein. In five pigs the varices were treated by paravariceal injection of polidocanol, and the rest served as controls. As judged from endoscopy and portography, the varices disappeared after four sclerotherapy sessions within 4 weeks, and at the same time portal venous pressure rose from 19 to 38 mm Hg. No changes were seen in the control group. After 24 weeks of observation the hepatic blood flow in the untreated group was 10 ml/kg/min, and portal angiography showed that nearly all the portal blood bypassed the liver. In the pigs treated with sclerotherapy the hepatic blood flow increased to 28 ml/kg/min, angiography showed a normal hepatogram, and no filling of the collaterals was seen. Sclerotherapy induced only a few changes in liver function, and these may be related to the concomitant increase in liver blood flow.     

Effects of Propranolol on Portal Hemodynamics in Patients with Chronic Liver Disease

To elucidate the mechanism by which propranolol reportedly affects portal hemodynamics, we investigated the effect of propranolol on systemic and splanchnic hemodynamics in 15 patients with portal hypertension and esophageal varices by simultaneous catheterization of the portal vein and the right hepatic vein and measurement of portal venous flow using an ultrasound doppler system. Infusion of 5 mg of propranolol significantly decreased pulse rate (-12.6%), cardiac output (-24.5%), portal venous flow (-22.3%), portal venous pressure (-13.3%), and gradient between portal venous pressure and free hepatic venous pressure (-24.8%). Thus, propranolol seems to decrease portal venous pressure by reducing portal venous flow, at least in part, as a result of reduction of cardiac output due to its beta 1 adrenergic receptor blocking action.     

Chronic Portal Venous Hypertension: The Effect on Liver Blood Flow and Liver Function and the Development of Esophageal Varices

Portal venous hypertension was induced in Göttingen minipigs by banding the portal vein. The pigs were checked repeatedly during the following 24 weeks. Portal pressure increased immediately on banding, from 8.4 ± 0.7 mm Hg to 19.4 ± 0.7 mm Hg, and remained constant throughout the observation period. Within 5 weeks all pigs developed esophageal varices, as demonstrated by portal angiography and endoscopy. The experimentally induced portal hypertension was accompanied by a 65% decrease in hepatic blood flow, most probably caused by almost complete shunting of portal venous blood. The hepatic arterial flow appeared to be within normal limits and sufficient to cover the oxygen demand of the liver; to judge from the splanchnic elimination rate of galactose, the hemodynamic changes did not affect the functional capacity of the liver.     

Chronic portal venous hypertension. The effect on liver blood flow and liver function and the development of esophageal varices

Portal venous hypertension was induced in G?ttingen minipigs by banding the portal vein. The pigs were checked repeatedly during the following 24 weeks. Portal pressure increased immediately on banding, from 8.4 +/- 0.7 mm Hg to 19.4 +/- 0.7 mm Hg, and remained constant throughout the observation period. Within 5 weeks all pigs developed esophageal varices, as demonstrated by portal angiography and endoscopy. The experimentally induced portal hypertension was accompanied by a 65% decrease in hepatic blood flow, most probably caused by almost complete shunting of portal venous blood. The hepatic arterial flow appeared to be within normal limits and sufficient to cover the oxygen demand of the liver; to judge from the splanchnic elimination rate of galactose, the hemodynamic changes did not affect the functional capacity of the liver.     

Hemodynamic effect of spironolactone in liver cirrhosis and propranolol-resistant portal hypertension.

OBJECTIVE: In a proportion of patients with liver cirrhosis, portal pressure does not decrease adequately with propranolol. These patients may benefit from another drug that may reduce portal pressure. We evaluated the role of spironolactone, alone or with propranolol, in such patients. METHODS: Patients with cirrhosis, with or without ascites, with esophageal varices and with hepatic venous pressure gradient exceeding 12 mmHg, which did not show a 20% reduction after an 80-mg oral dose of propranolol, were studied. They were allocated to receive spironolactone 100 mg orally once daily either alone (group 1, n=10) or with propranolol 40 mg orally twice daily (group 2, n=10), for 7 days, after which the hemodynamic study was repeated. RESULTS: Hepatic venous pressure gradient decreased in those receiving spironolactone and propranolol (p=0.007); 5 patients in group 1 and 7 in group 2 showed a reduction in hepatic venous pressure gradient by more than 20%. However, the reduction produced by spironolactone alone (20.5 [31.3]%) was not significantly different from that produced by combination therapy (30.3 [25.9]%; p=0.46). CONCLUSION: Spironolactone in combination with propranolol achieves adequate reduction (> or = 20%) in hepatic venous pressure gradient in propranolol-resistant portal hypertension in patients with liver cirrhosis. Spironolactone alone was also effective in some patients.     

Effects of metoclopramide and domperidone on azygos venous blood flow in patients with cirrhosis and portal hypertension

The effects of pharmacological manipulation of the lower esophageal sphincter pressure on the esophageal circulation in patients with cirrhosis and portal hypertension were investigated in 33 patients by measuring the azygos venous blood flow, which is an index of blood flow through esophageal varices and periesophageal collaterals draining into the azygos venous system. Measurements were performed in baseline conditions and after the blind administration of metoclopramide (20 mg i.v.) (12 patients), domperidone (10 mg i.v.) (12 patients) and placebo (9 patients). Both metoclopramide and domperidone caused a significant reduction of azygos blood flow, that decreased by 11.5% (p less than 0.01) and 15.6% (p less than 0.02) respectively, while no change was observed in patients receiving placebo (+1.4%, not statistically significant). Reduction of azygos blood flow represents a selective effect of metoclopramide and domperidone on the esophageal circulation, since portal pressure, hepatic blood flow, cardiac output, heart rate and arterial blood pressure were unchanged by the administration of metoclopramide, domperidone or placebo. These results indicate that the administration of drugs that increase the lower esophageal sphincter pressure may reduce the inflow of blood into the esophageal varices in cirrhotic patients with portal hypertension.     

Long term effects of propranolol on portal pressure in cirrhotic patients

Bleeding from varices is a very serious complication in cirrhotic patients, with a mean mortality rate around 30 %. If the portal vein pressure is decreased by pharmacological therapy the varices will not bleed and progressively decrease in size. The portal hypertension in cirrhotic patients develops as a consequence of two mechanisms: the increase of portal inflow and the increase of intrahepatic resistance. The aim of our study was to find out if propranolol can prevent the bleeding from esophageal varices and if it acts by reducing the portal inflow due to splanchnic vasodilatation. The study was initiated in 53 patients with portal hypertension, of whom 14 were withdrawn because of adverse effects of propranolol. Abdominal ultrasonography and Doppler of portal vein system were performed in all subjects. The ultrasonographic parameters were measured before and after a 3-year treatment with propranolol. The patients also underwent endoscopy for evaluation of esophageal varices; the endoscopy was repeated at the end-point of treatment. We noted that propranolol reduced the portal blood inflow and the size of esophageal varices, and that the incidence of hemorrhages by variceal rupture was very low in these patients.     

The role of prostacyclin in patients with portal hypertension

The serum levels of prostacyclin in portal venous blood samples from patients with portal hypertension were measured by radioimmunoassay to assess the role of prostacyclin in this clinical entity. Portal venous prostacyclin activity exceeded peripheral venous activity 2-3 fold in both cirrhotics and non-cirrhotics. The size of esophageal varices showed an inverse relation to the concentration of portal venous prostacyclin in the cirrhotics. There was no significant difference between the portal vein pressure and the size of varices, and the portal vein pressure did not correlate with the concentration of 6 keto-PGF1 alpha. Thus, serum levels of portal venous prostacyclin may depend on the development of collateral circulation in cirrhotics and increased splanchnic blood flow probably accelerates the washout effect.     

Propranolol compared with propranolol plus isosorbide-5-mononitrate for portal hypertension in cirrhosis. A randomized controlled study

OBJECTIVE: To investigate whether isosorbide-5-mononitrate (Is-5-Mn) given with propranolol reduces hepatic portal pressure more than does propranolol alone in patients with cirrhosis. DESIGN: A randomized controlled trial. PATIENTS: Fifty patients with cirrhosis and esophageal varices entered and 42 completed the study. INTERVENTION: Twenty-one patients received oral propranolol at increasing doses until their resting heart rate was reduced by 25%, and 21 patients received oral propranolol (on the same schedule) plus oral Is-5-Mn, 40 mg twice a day. MEASUREMENTS: Hepatic vein pressure gradient, liver function, and splanchnic and systemic hemodynamics before and after 3 months of continuous therapy. MAIN RESULTS: At 3 months, the hepatic venous pressure gradient decreased more (P less than 0.01) in patients given propranolol plus Is-5-Mn (19%, from 18.4 +/- 3.9 to 14.9 +/- 3.8 mm Hg; 95% CI, -2.4 to -4.5 mm Hg) than in those given propranolol alone (10%, from 18.2 +/- 3.5 to 16.3 +/- 3.1 mm Hg; CI, -1.1 to -2.7 mm Hg). The hepatic venous pressure gradient decreased by more than 20% of the baseline value in 10% of patients receiving propranolol, but in 50% of patients receiving combined therapy (P less than 0.02). There were statistically significant decreases in hepatic blood flow and the intrinsic clearance of indocyanine green after propranolol therapy, but not after combined therapy. The treatments caused similar reductions in azygos blood flow and cardiac output. CONCLUSIONS: The long-term combined administration of propranolol plus Is-5-Mn reduces portal pressure more than propranolol alone without adverse effects on hepatic perfusion and liver function. Whether this greater hemodynamic effect translates into better clinical efficacy should be determined in randomized controlled trials.     

Influence of long-term injection sclerotherapy on portal venous component of total liver perfusion measured by hepatosplenic radionuclide angiography

In an attempt to establish whether repeated injection sclerotherapy (ST) has any influence on the portal venous fraction of hepatic blood flow, we investigated 8 patients with liver cirrhosis and esophageal varices immediately prior to and six months after ST, using computerized hepatosplenic radionuclide angiography. The mean values of the portal venous fraction of the hepatic blood flow before and after treatment did not differ (20 +/- SD 9% vs. 20 +/- 11%). Eight cirrhotics with esophageal varices who had received no ST served as controls. Also in these patients, the mean values did not change over a period of six months (17 +/- 10% vs. 17 +/- 14%). The mean portal venous fraction of hepatic blood flow was significantly higher (56 +/- 9%, p less than 0.001) in 10 subjects without hepatobiliary disease. The results show that while the portal venous fraction of hepatic blood flow is significantly reduced in patients with liver cirrhosis and esophageal varices, it is not influenced by ST.     

PATHOPHYSIOLOGY OF PORTAL HYPERTENSION AND IMPLICATIONS FOR ITS PHARMACOLOGICAL CONTROL

Bleeding from esophageal varices complicating portal hypertension is a major cause of morbidity and mortality in patients with chronic liver disease. Therapy has been directed towards obliteration of esophageal varices (endoscopic sclerotherapy, transhepatic sclerosis, or esophageal transection) or decompression of the portal vascular bed by the creation of surgical portasystemic shunts. The use of pharmacological agents to lower portal venous pressure (PVP) was for many years limited to intravenous or intraarterial vasopressin in the setting of acute variceal hemorrhage. However, since Lebrec et al.,¹ reported the favourable effect of propranolol on PVP and on the incidence of rebleeding from the upper gastrointestinal tract in patients with portal hypertension,² there has been an increasing interest in the potential use of a number of pharmacological agents in the short and long term management of patients with portal hypertension. The purpose of such therapy would be to reduce the incidence of complications of portal hypertension. These may include upper gastrointestinal bleeding, ascites via reduced ascitic fluid formation, and even portasystemic encephalopathy via improvement of hepatic perfusion and reduction of collateral shunting of blood.     

卡维地洛治疗老年乙肝肝硬化门静脉高压症疗效分析

目的探讨卡维地洛对老年乙肝肝硬化门静脉高压症患者的治疗效果。 方法选取2014年8月至2018年1月山东省泰安市中心医院收治的60例老年乙肝肝硬化门静脉高压症患者,其中采用常规治疗30例（对照组）,在常规治疗基础上加用卡维地洛治疗30例（观察组）。对照组进行常规保肝、抗病毒、抗肝纤维化治疗,治疗组在对照组的基础上给予卡维地洛口服治疗（12.5 mg,1次/d）。6个月后观察门静脉血流动力学、食管胃底静脉曲张程度、肝纤维化指标、凝血指标的变化。 结果观察组患者治疗后门静脉主干内径（DPV）、脾静脉内径（DSV）、静脉主干血流量（QPV）、脾静脉血流量（QSV）、透明质酸（HA)、Ⅲ型前胶原N端肽（PCⅢ）、层粘连蛋白（LN）、Ⅳ型胶原（CⅣ）、凝血酶原时间（PT）、活化部分PT（APTT）、PT活动度（PTA）均较治疗前均明显改善（P<0.05或0.01）,而对照组治疗后各指标并无明显改善（均P>0.05）。治疗前,两组患者DPV、DSV、QPV、QSV、HA、PCⅢ、LN、CⅣ、PT、APTT、PTA的差异均无统计学意义（均P>0.05）;治疗后,观察组DPV、DSV、QPV、QSV、HA、PCⅢ、LN、CⅣ、PT、APTT、PTA均较对照组明显改善（P<0.05或0.01）。治疗前,两组患者食管-胃底静脉曲张程度的差异无统计学意义（z=-0.319,P>0.05）;治疗后,观察组轻度曲张患者明显增多、重度曲张患者明显减少,明显优于对照组（z=-2.277,P<0.05）。 结论在常规治疗基础上口服卡维地洛治疗,能显著提高老年乙肝肝硬化门静脉高压症患者的治疗效果。     

Systemic and Hepatic Hemodynamics in Hepatosplenic Manson's Schistosomiasis with and Without Propranolol

Systemic and hepatic hemodynamics wereprospectively studied in 11 patients with Manson'sschistosomiasis and portal hypertension, as well asalterations resulting from the use of propranolol. Itwas decided that patients whose portal pressure was reducedby 30% with the use of the drug would not undergosurgery and that treatment would consist of the chronicuse of propranolol, associated with sclerosis of esophageal varices. This objective was not metby any of the patients whose portal pressure wasmeasured and the study was interrupted. Results showthat patients with Manson's schistosomiasis and portal hypertension have hyperdynamic circulation,mild pulmonary hypertension, greatly increased splenicblood flow, and preservation of total hepatic bloodflow. Administration of propranolol correctshyperdynamic circulation, aggravates pulmonary hypertension,does not alter portal pressure and reduces the sectorialportal blood flows, especially of the azygos vein, withmaintenance of total hepatic blood flow. These data favor the hypothesis of portaloverflow in the physiopathology of portal hypertensionof schistosomiasis.     

Portal hemodynamics in patients with gastric varices. A study in 230 patients with esophageal and/or gastric varices using portal vein catheterization

The hemodynamic features of gastric varices are not well documented. The purpose of this study was to investigate the nature of hepatofugal collateral veins, their origins, the direction of blood flow in the major veins and collateral veins, and portal venous pressure. To this end, 230 patients, mostly cirrhotic, who had esophageal or gastric varices, or both, demonstrated by endoscopy were investigated by portal vein catheterization. The findings were correlated with endoscopically assessed degrees of varices. Gastric varices were seen in 57% of the patients with varices due to portal hypertension. In most of the patients with advanced gastric varices, esophageal varices were minimal or absent. When patients with gastric varices were compared with those having predominantly esophageal varices, it was found that advanced gastric varices were more frequently supplied by the short and posterior gastric veins, they were almost always associated with large gastrorenal shunts, and portal venous pressure in patients with large gastric varices was lower. Chronic portal systemic encephalopathy was more common in patients with large gastric varices due to hepatofugal flow of superior mesenteric venous blood in the splenic vein than in patients with predominantly esophageal varices. Thus, the hemodynamics in patients with large gastric varices are distinctly different from those in patients with mainly esophageal varices, and such differences seem to account for the differing incidence of chronic encephalopathy and variceal bleeding.     

Effect of enalapril treatment and sclerotherapy of esophageal varices on hepatic hemodynamics in portal hypertension.

The hemodynamic effects of long-term (3 months) treatment with enalapril, a potent angiotensin converting enzyme inhibitor, were studied in 12 randomly selected patients with portal hypertension and a previous episode of hemorrhage from esophageal varices. All these patients underwent injection sclerotherapy of varices at 1-week intervals. As a control group 13 patients treated only with injection sclerotherapy and placebo were used. After 3 months the wedged hepatic venous pressure (25.5 +/- 4.8 vs. 21.3 +/- 4.8 mmHg) and the non-wedged hepatic venous pressure gradient (17.0 +/- 6.0 vs. 12.6 +/- 3.4 mmHg) were significantly lower than the basal values (p < 0.01) in the group treated with enalapril. A large decrease (> 3 mmHg) in these pressures was observed only in 50% of the patients. In the group treated with sclerotherapy+placebo this pressure reduction was not observed. Systemic hemodynamics and liver function tests did not change during the treatment. None of our patients died during the study or the next 6 months. We conclude that enalapril lowers portal pressure in patients with portal hypertension, although not in all of them, and may be used to good effect to manage patients with esophageal varices in combination with sclerotherapy.     

Hepatic radionuclide angiography and Doppler ultrasonography in the detection and assessment of vascular disturbances in the portal system

BACKGROUND/AIMS: The aim of the study was evaluation of the morphology of the blood vessels, blood flow velocity and direction with Doppler ultrasound (D-US) and correlation with the relative liver parenchymal perfusion assessed by hepatic radionuclide angiography (HRA). METHODOLOGY: Real-time, D-US and HRA were performed in 108 patients. RESULTS: In patients with portal venous aneurysm, hepatopetal blood flow was increased, while portal perfusion did not differ from controls. In portal hypertensive patients, D-US detected dilatation of the portal system veins, with decreased blood flow. In comparison to the portal perfusion in controls and portal venous aneurysm, values were significantly (p < 0.01) lower in chronic active hepatitis and liver cirrhosis and differed between themselves (p < 0.01). In the groups of cirrhotic patients with esophageal varices, sclerosed esophageal varices, recanalized umbilical vein, partial portal thrombosis and cavernous portal vein with hepatofugal, hyperkinetic or slow blood flow, and very low velocities beside the thrombi, portal perfusion was lower (p < 0.01) than in controls, portal venous aneurysm, chronic active hepatitis and liver cirrhosis without collaterals. In complete thrombosis, minimal collateral flow was found with D-US, while HRA proved no portal supply. CONCLUSIONS: D-US and HRA are complementary for the estimation of various liver vascular disorders.     

Management of portal hypertension based on portal hemodynamics

Portal hypertension is most commonly caused by chronic liver disease. As liver damage progresses, portal pressure gradually elevates and hemodynamics of the portal system gradually change. In normal liver, venous returns from visceral organs join the portal trunk and flow into the liver (hepatopetal blood flow). As portal pressure increases due to liver damage, congestion of some veins of the visceral organ occurs (blood flow to and from). Finally, the direction of some veins (the left gastric vein in particular) of the visceral organ change (hepatofugal blood flow) and develop as collateral veins (portosystemic shunt) to reduce portal pressure. Therefore, esophagogastric varices serve as drainage veins for the portal venous system to reduce the portal pressure. In chronic liver disease, as intrahepatic vascular resistance is increased (backward flow theory) and collateral veins develop, adequate portal hypertension is required to maintain portal flow into the liver through an increase of blood flow into the portal venous system (forward flow theory). Splanchnic and systemic arterial vasodilatations increase the blood flow into the portal venous system (hyperdynamic state) and lead to portal hypertension and collateral formation. Hyperdynamic state, especially around the spleen, is detected in patients with portal hypertension. The spleen is a regulatory organ that maintains portal flow into the liver. In this review, surgical treatment, interventional radiology, endoscopic treatment, and pharmacotherapy for portal hypertension (esophagogastric varices in particular) are described based on the portal hemodynamics using schema.     

Effect of Phenoxybenzamine (POB) on Portal Venous Pressure in Patients with Portal Hypertension

In order to assess an effect of phenoxybenzamine (POB) on portal circulation, POB (0.5-1.0 mg./kg.) was administered intravenously to six patients with portal hypertension and two patients without portal hypertension. In patients with portal hypertension, POB reduced portal venous pressure (PVP) from 362.5 +/- 53.8 mm. H2O to 282.5 +/- 50.4 mm. H2O (P less than 0.001) where central venous pressure (CVP) was maintained constant. In patients without portal hypertension, change in PVP was in parallel with that in CVP where the decrease in PVP was regarded as not specific. This preferential reduction of PVP in portal hypertension seemed to implicate functional vasoconstriction of the portal venous system. In the treatment of bleeding esophageal varices, use of POB with blood transfusion after decompression of the Sengstaken-Blakemore tube should be beneficial because of its prolonged effect of lowering PVP and preventing ischemic liver damage.     

Endoscopic measurement of gastric mucosal blood flow with special reference to the effect of sclerotherapy in patients with liver cirrhosis

Gastric mucosal blood flow plays an important role as a background factor in the pathogenesis of acute gastric mucosal lesion. In this study, endoscopic measurement of regional gastric mucosal blood flow was performed on 41 patients with esophageal varices due to liver cirrhosis to ascertain the possible relations of this parameter to liver function, portal pressure, and acute gastric mucosal lesion. The effect of sclerotherapy and of esophageal transection on gastric mucosal blood flow were also investigated. Regional gastric mucosal blood flow in either the antrum or the corpus was significantly decreased in these patients, compared with normal controls. There was also a significant difference in gastric mucosal blood flow between two subgroups of patients, one with gastric mucosal lesions and the other without these lesions. Sclerosing therapy for esophageal varices tended to affect this parameter. Gastric mucosal blood flow had no significant correlation with portal pressure.