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 The study was initiated in 53 patients with portal hypertension, of whom 14 were withdrawn because of adverse effects of propranolol.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.     

丹参、心得安对门静脉高压症大鼠门静脉压力和胃肠激素的影响

目的:观察丹参、心得安对门脉高压症大鼠门静脉压力、胃肠激素的影响.方法:采用CCl4加酒精饮料制作大鼠门脉高压模型,造模4周后分别给大鼠服用丹参、心得安,造模结束后用Medlab-Ug4Cs生物信号采集处理系统检测正常组、模型组、丹参治疗组、心得安治疗组大鼠门静脉压力.处死大鼠后颈动脉取血,用放免法检测4组大鼠血浆胃肠激素(胃动素、胃泌素、胰高血糖素)的含量.结果:模型组大鼠门静脉压力较正常组明显升高(P＜0.01),丹参治疗组、心得安治疗组大鼠门脉压力较模型组明显下降(P＜0.01),丹参治疗组大鼠门脉压力与心得安治疗组比较差异无显著性意义(P＞0.05).心得安组大鼠与模型组比较胃动素含量无明显改善(P＞0.05),而胃泌素、胰高血糖素明显下降(P＜0.05).丹参治疗组大鼠胃泌素、胃动素、胰高血糖素含量与模型组比较明显下降(P＜0.01或P＜0.05),与心得安治疗组比较,胃动素、胰高血糖素指标下降明显(P＜0.05).结论:丹参能有效降低门脉高压症大鼠门静脉压力,调节胃肠激素,疗效优于心得安治疗组.其作用机制可能与其良好的抗肝纤维化、阻止肝硬化形成、调节胃肠激素水平、改善肝功能等作用有关.     

Discrepancy between wedged hepatic venous pressure and portal venous pressure after acute propranolol administration in patients with alcoholic cirrhosis

In patients with alcoholic cirrhosis, wedged hepatic venous pressure closely reflects portal venous pressure. This study was carried out to determine if propranolol-induced reductions in portal venous pressure are accurately evaluated by the measurement of wedged hepatic venous pressure. Hepatic venous cannulation and percutaneous transhepatic catheterization of the portal vein were simultaneously performed in 7 patients with alcoholic cirrhosis. One hour after oral administration of 40 mg of propranolol, wedged hepatic and portal venous pressures significantly decreased from 24.3 +/- 3.5 (mean +/- SD) to 19.0 +/- 3.0 mmHg, and from 24.7 +/- 3.9 to 22.4 +/- 3.6 mmHg, respectively. Although no significant difference was found between baseline wedged hepatic and portal venous pressures, a significant difference was found between these pressures after propranolol administration. We concluded that during acute administration of a drug acting on the splanchnic circulation, the measurement of wedged hepatic venous pressure may not provide a reliable estimation of the magnitude of the changes in portal venous pressure. There is, however, no evidence that the direction of the changes might not be adequately assessed by wedged hepatic venous pressure measurement.     

Hemodynamic effects of nifedipine on hepatic venous pressure gradient in patients with portal hypertension

The effect of Nifedipine on hepatic venous pressure gradient (HVPG) was determined in 10 patients with portal hypertension due to cirrhosis of the liver, and in 7 control subjects, by hepatic vein catheterization. Twenty min. after sublingual application of 10 mg Nifedipine, patients and controls showed significant hemodynamic changes in the systemic circulation. In contrast, HVPG after Nifedipine was not statistically different from the basal values--neither in patients with portal hypertension (p = 16.6 +/- 5.2 mmHg vs 17.9 +/- 5.3 mmHg) nor in the control subjects (p = 2.9 +/- 1.1 mmHg vs. 1.0 mmHg). We conclude that calcium entry blockade by Nifedipine is not effective in acutely reducing portal venous pressure.     

Effects of propranolol on venous compliance in conscious rats with pre-hepatic portal hypertension

BACKGROUND/AIMS: The venous system is the primary capacitance region in the body. However, the influence of active changes in the venous system on the hemodynamic alterations of portal hypertension is poorly understood. To investigate venous compliance (VC) in conscious partial portal vein ligated rats (PPVL) and the effect of propranolol on VC. METHODS: Venous compliance was derived from the relationship between changes in mean circulatory filling pressure (MCFP) and changes in blood volume (BV). Measurements were performed before and after i.v. propranolol (7.5 mg/Kg) or placebo in rats with portal hypertension due to PPVL and sham operated controls. RESULTS: PPVL rats had an increased VC when compared to Sham (4.9+/-1.4 vs. 3.7+/-0.9 ml kg-1 mm Hg-1; P<0.02). VC did not change after placebo but was significantly reduced by Propranolol in PPVL (-32.9+/-15.7%; P<0,007). Propranolol did not modify venous compliance in sham operated rats (+10.9+/-13.4%; P=ns). CONCLUSIONS: Venous compliance is increased in portal hypertensive rats, suggesting that the venous system contributes to the profound circulatory changes encountered in portal hypertension. The increased venous compliance is markedly attenuated by propranolol, suggesting that this abnormality is related to increased adrenergic activity.     

卡维地洛与普萘洛尔降低肝硬化门静脉高压患者肝静脉压力梯度效果的对比分析

目的探讨卡维地洛和普萘洛尔降低肝硬化门静脉高压患者肝静脉压力梯度(HVPG)的幅度、应答率以及用药后不良反应的差异,对卡维地洛降低门静脉压力的有效性和安全性进行评价。方法收集2010年10月-2012年1月在山东大学附属省立医院确诊的64名肝硬化门静脉高压患者,随机分为2组:普萘洛尔组(n=33)和卡维地洛组(n=31),根据血压和心率调整剂量,疗程7 d,均于治疗前后行HVPG测定及肝肾功能指标检测,比较2组患者HVPG降低的幅度及应答率,并观察患者低血压、腹水、肾损伤等不良反应的发生情况。计量资料组间比较采用t检验,计数资料组间比较采用χ2检验或Fisher精确概率法。结果卡维地洛组和普萘洛尔组的HVPG均明显降低,降低幅度分别为(28.30±22.19)%和(12.38±24.09)%,其中卡维地洛组降低更明显,差异有统计学意义(t=0.223 4,P=0.032)。2组应答率分别为:卡维地洛组56.7%(17/30),普萘洛尔组41.9%(13/31),2组差异无统计学意义(χ2=1.324,P=0.250)。卡维地洛组平均动脉压的降低较普萘洛尔组明显,差异有统计学意义(t=2.338,P=0.024),但患者未出现明显低血压的不良反应;2组患者胆红素、血肌酐和尿素氮在治疗前后无明显升高,亦无腹水生成或加重的趋势。结论本研究提示在短期内卡维地洛降低HVPG的作用较普萘洛尔显著,且无明显不良反应;其用于肝硬化门静脉高压的治疗是安全有效的。     

Comparison of portal vein velocity and the hepatic venous pressure gradient in assessing the acute portal hemodynamic response to propranolol in patients with cirrhosis

OBJECTIVE: The aim of this prospective study was to compare noninvasive Doppler sonography and invasive measurement of the hepatic venous pressure gradient (HVPG) to determine the acute portal hemodynamic response to propranolol in patients with liver cirrhosis. METHODS: In a blinded study design, portal vein velocity (PVV) and HVPG were simultaneously assessed in 11 cirrhotic patients for 4 h after oral ingestion of 40 mg propranolol. RESULTS: Both HVPG (17.2% +/- 4.3%, p < 0.0001) and PVV (15.6% +/- 2.1%, p < 0.0002) showed a highly significant reduction during the study period versus baseline. Based on HVPG measurements, four patients (36%) were classified as nonresponders. These patients had a significantly lower PVV reduction compared to the responders (responders: 18.8% +/- 2.0% vs nonresponders: 10.0% +/- 2.1%, p < 0.05). Nonresponders were identified by Doppler sonography with a sensitivity of 1.0, specificity of 0.86, and positive predictive value of 0.9 when a threshold of 20% PVV reduction 120 min after drug intake was applied. CONCLUSIONS: Doppler sonography is a useful tool for assessment of the acute portal hemodynamic effect of propranolol. To distinguish portal hemodynamic nonresponders from responders to propranolol, PVV measurements should be carried out 2 h after drug administration, and PVV reduction should be not <20% in propranolol responders.     

Captopril reduces portal pressure effectively in portal hypertensive patients with low portal venous velocity

Background The effect of an angiotensin II blockade in lowering the portal pressure in patients with liver cirrhosis and portal hypertension is controversial. This prospective study was undertaken to evaluate the portal hypotensive effect of captopril compared to that of propranolol, and to determine the factors that contribute to a successful reduction in the portal pressure after longterm captopril administration in patients with liver cirrhosis.Methods The hepatic venous pressure gradient (HVPG) and portal venous velocity (PVV) were measured both before and 3 months after initiation of the administration of captopril (n = 29) or propranolol (n = 29) in cirrhotic patients with a variceal bleeding episode. Patients who showed a reduction in the HVPG of more than 20% of the baseline were defined as being responders.Results At 3 months, the mean reduction in the HVPG after captopril was less than that after propranolol (–3.0 ± 9.3% vs –28.5% ± 4.1%; P 0.05). However, of the 29 patients receiving captopril, 9 were classified as being responders. On multivariate analysis with parameters including age, cause, Child-Pugh score, HVPG, and PVV, only low PVV was found to be a significant independent factor for responders (PVV 12cm/s; odds ratio [OR], 12.2; 95% confidence interval [CI], 1.47–102.40) in the captopril group.Conclusions Longterm captopril administration reduces the portal pressure effectively in cirrhotic patients with a low PVV. This suggests that the reduction in portal pressure after captopril administration is a result of improved portal venous outflow brought about by a decrease in the intrahepatic vascular resistance. When the PVV is below 12cm/s, a captopril trial might be useful in preventing variceal bleeding in portal hypertensive patients.Part of this work has appeared in abstract form, in J Hepatol 2002;36 (Suppl 1):64     

Double-blind investigation of the effects of propranolol and placebo on the pressure of esophageal varices in patients with portal hypertension

This study was aimed at investigating the effects of propranolol on esophageal variceal pressure in patients with portal hypertension. Variceal pressure was measured at endoscopy using a miniature pressure-sensitive gauge in 20 patients with portal hypertension. Measurements were obtained under baseline conditions and 20 min after double-blind administration of propranolol (0.15 mg/kg; n = 10) or an identical amount of placebo (normal saline, 0.3 ml/kg; n = 10). Under baseline conditions, variceal pressure was similar in propranolol and placebo groups (14.1 +/- 5 mm Hg vs. 14.9 +/- 6.6 mm Hg, respectively; not significant). Placebo had no significant effect on variceal pressure (baseline = 14.9 +/- 6.6 mm Hg; placebo = 15.5 +/- 6.6 mm Hg; not significant), and values after placebo administration were closely correlated with baseline values (r = 0.98; y = 1.1 + 0.97 x; p less than 0.0001). In contrast, propranolol caused a significant decrease in the pressure of esophageal varices (from 14.1 +/- 5 mm Hg to 11.3 +/- 4.4 mm Hg; p less than 0.0002). No significant changes in the size of esophageal varices were observed after propranolol or placebo administration. This study shows (a) the endoscopic pressure-gauge technique has a low variability and may be used to assess acute drug-induced changes in variceal pressure; and (b) propranolol causes significant decreases in variceal pressure in patients with portal hypertension and esophageal varices.     

Wedged hepatic venous pressure reflects portal venous pressure during vasoactive drug administration in nonalcoholic cirrhosis

Hepatic venous catheterization is widely used to assess portal pressure. However, it remains unclear whether wedged hepatic venous pressure is a close indicator of portal venous pressure during vasoactive drug administration in nonalcoholic cirrhosis. To address this issue, we analyzed the data from our previous published studies. Forty patients with nonalcoholic cirrhosis (HBV infection in five, HCV infection in 28, and cryptogenic in seven) were available in this analysis. A vasoconstrictor (N=14), vasodilator (N=10), or combination (N=16) was administered. The agreement of the changes between portal and wedged hepatic venous pressures during pharmacological manipulation was assessed by an intraclass correlation coefficient. The intraclass correlation coefficient in each subgroup was more than 0.60 (0.62 in vasoconstrictor group, 0.87 in vasodilator group, and 0.73 in combination group). When the analysis was performed according to the cause of liver disease, the values were 0.67 in HBV infection, 0.73 in HCV infection, and 0.74 in cryptogenic cirrhosis. These results suggest that wedged hepatic venous pressure reflects portal venous pressure during vasoactive drug administration in patients with nonalcoholic cirrhosis.     

The hypotensive effect of oral nitroglycerin on portal venous pressure in patients with cirrhotic portal hypertension

Abstract Nitroglycerin was administered orally to seven patients with cirrhosis and portal hypertension, to determine whether portal venous pressure (PVP) may be lowered without the systemic effects associated with its intravenous or sublingual use. PVP was measured via direct cannulation of the portal vein transhepatically using a Chiba needle. PVP decreased from 29 (s.d. = 4) to 22.7 (s.d. = 3.7) mmHg (22% mean fall) following 1.2 mg nitroglycerin with onset 7–15 min following ingestion, and the response persisted for up to 150 min. This was not associated with headache in any patient. Although a decrease in blood pressure was seen in most patients, this temporally followed the fall in PVP suggesting that it was a secondary response. Sublingual nitroglycerin was given to two patients without change in PVP yet both experienced severe headache. These findings support the hypothesis that oral nitroglycerin is delivered differentially to the portal venous bed with differential effects on PVP. Further studies are needed to evaluate this agent and this strategy for their potential role in long-term control of portal pressure.     

Randomized comparison of long-term losartan versus propranolol in lowering portal pressure in cirrhosis

BACKGROUND & AIMS: It has been suggested that losartan, an angiotensin II (A-II) type 1 receptor blocker, may have a pronounced portal pressure reducing effect, far greater than that of propranolol. This randomized controlled trial compared the hemodynamic and renal effects of continued 6-week administration of losartan (n = 25) vs. propranolol (n = 15) in portal hypertensive patients with cirrhosis treated endoscopically after a variceal bleeding episode. METHODS: Hepatic venous pressure gradient (HVPG), systemic hemodynamics, renal function, and vasoactive factors were measured before and at 6 weeks of treatment. RESULTS: Losartan did not reduce HVPG (-2% +/- 12%, NS) but significantly decreased mean arterial pressure (MAP, -8% +/- 10%, P = 0.001). On the contrary, propranolol significantly reduced HVPG (-10% +/- 11%, P = 0.003) and cardiac output (-16% +/- 12%, P = 0.001) but did not modify MAP (2.5% +/- 10%, NS). Losartan increased A-II levels, reduced aldosterone, and decreased glomerular filtration rate (GFR) in Child B patients. Propranolol did not modify renal function. Adverse events related to therapy were mild and similar in both groups. CONCLUSIONS: Unlike propranolol, long-term losartan administration does not significantly reduce HVPG in patients with cirrhosis treated after a variceal bleeding episode, and it caused hypotension and reduced GFR in patients with moderate liver failure. Therefore, losartan is not an alternative to propranolol in preventing variceal rebleeding.     

Short-term portal hemodynamic effects of partial splenic embolization for hypersplenism

BACKGROUND/AIMS: The purpose of this study was to investigate the short-term effects of partial splenic embolization (PSE) for hypersplenism on portal hemodynamics and liver function. METHODOLOGY: Thirty-seven patients with hypersplenism were included in this study. RESULTS: The wedged hepatic venous pressure before and after PSE were 39 +/- 10 and 33 +/- 8 cmH2O, respectively, showing significant change (p < 0.01). The flow volumes of the splenic vein before and after PSE were 477 +/- 200 and 319 +/-187 mL/min, respectively, also showing significant change (p < 0.05). However, the flow volumes of the portal vein before and after PSE were 713 +/- 284 and 684 +/- 152 mL/min, respectively, showing no significant change. The blood laboratory parameters showed no significant change after PSE. PSE damaged neither the portal blood flow volume nor the liver function, although it improved the local hyperdynamic state in the splenic area and thrombocytopenia. CONCLUSIONS: In conclusion, PSE is a safe and effective treatment for hypersplenism from the portal hemodynamic point of view.