Acute hemodynamic effects of octreotide and terlipressin in patients with cirrhosis: a randomized comparison

BACKGROUND: Octreotide and terlipressin are widely used in acute variceal hemorrhage to reduce the bleeding rate. They purportedly act by mesenteric arterial vasoconstriction, thus reducing portal venous flow (PVF) and portal pressure. Little is known about the immediate-early hemodynamic effects of these drugs. AIM: To compare the acute hemodynamic effects of octreotide and terlipressin in patients with cirrhosis. PATIENTS: Forty-two cirrhotic patients with a history of variceal bleeding were randomized to receive either octreotide 100 microg intravenous bolus followed by a continuous infusion at 250 microg/h (n = 21), or terlipressin 2 mg intravenous bolus (n = 21). METHODS: Mean arterial pressure (MAP), heart rate (HR), hepatic venous pressure gradient (HVPG), and PVF, assessed by duplex Doppler ultrasonography, were measured before and at 1, 5, 10, 15, 20, and 25 min after the start of drug administration. RESULTS: Octreotide markedly decreased HVPG (-44.5 +/- 17.8%) and PVF (-30.6 +/- 13.6%) compared to the baseline at 1 min (p < 0.05). Thereafter, both variables rapidly returned toward the baseline, and by 5 min, no significant differences in HVPG (-7.1 +/- 28.9%) and PVF (10.2 +/- 26.2%) were noted. A similar transient effect on MAP and HR was observed. Terlipressin significantly decreased HVPG (-18.3 +/- 11.9%) and PVF (-32.6 +/- 10.5%) at 1 min (p < 0.05) and sustained these effects at all time points. The effects on arterial pressure and HR were also sustained. CONCLUSIONS: Octreotide only transiently reduced portal pressure and flow, whereas the effects of terlipressin were sustained. These results suggest that terlipressin may have more sustained hemodynamic effects in patients with bleeding varices.     

Splanchnic haemodynamics after intravenous terlipressin in anaesthetised healthy pigs

BACKGROUND/AIMS: Terlipressin is used for the treatment of bleeding oesophageal varices. We evaluated the effects of terlipressin on hepatic haemodynamics, with special focus on the interactions between portal venous flow and hepatic arterial flow over time. Secondly, we evaluated the estimated hepatic blood flow by the ICG clearance method against direct measurements of hepatic blood flow. METHODS: Eight healthy anaesthetised pigs received terlipressin 1 mg or placebo intravenously in a randomised, blind, cross-over design. Hepatic arterial flow, portal venous flow, systemic haemodynamics, and portal vein diameter were recorded simultaneously. Portal venous flow and hepatic arterial flow were measured by transit time ultrasound flowmetry. Estimated hepatic blood flows at baseline and after terlipressin were compared with the sum of the portal venous flow and hepatic arterial flow. RESULTS: Portal venous flow decreased significantly 5 min after administration of terlipressin (p<0.05). At 30 min it had decreased by 34% (p<0.01) and the hepatic arterial flow had increased by 81% (p<0.01). The estimated hepatic blood flow and the hepatic blood flow decreased by 23% (p<0.015). At baseline the estimated hepatic blood flow and the hepatic blood flow correlated significantly (r=0.85, p<0.01), but this correlation disappeared after administration of terlipressin (r=0.06, p=ns). The hepatic blood flow was 12% higher than the estimated hepatic blood flow before and after terlipressin. CONCLUSIONS: Terlipressin decreased the portal venous flow, hepatic blood flow, and estimated hepatic blood flow significantly and was accompanied by a substantial increase in hepatic arterial flow. The estimated hepatic blood flow and hepatic blood flow were strongly correlated at baseline, but after terlipressin the correlation disappeared.     

Hemodynamic effects of a combination of octreotide and terlipressin in patients with viral hepatitis related cirrhosis

BACKGROUND: Terlipressin or octreotide given alone has been used as the first-line pharmacological treatment for acute variceal bleeding. In portal hypertensive animals, pre-infusion of octreotide followed by the addition of terlipressin has an additive or complementary effect on splanchnic hemodynamics. The current study was aimed at evaluating such a combination treatment in patients with cirrhosis and portal hypertension. METHODS: Patients were randomly assigned to receive either a placebo (n = 11) or an intravenous infusion of octreotide 100 microg/h after an initial bolus of 100 microg (n = 13). Thereafter, each patient received an intravenous injection of terlipressin 2 mg. Hemodynamic values were measured basally, 30 min after octreotide or placebo, and 60 min after terlipressin. RESULTS: Placebo administration did not affect any of the hemodynamic values. Terlipressin administration resulted in expected changes in hepatic venous pressure gradient, hepatic blood flow and systemic hemodynamics. In contrast, octreotide administration significantly decreased hepatic blood flow but did not affect other hemodynamic values. After terlipressin administration, significant hemodynamic changes were observed that were similar to the hemodynamic changes with terlipressin alone. The magnitude of changes in hepatic venous pressure gradient, cardiac index and systemic vascular resistance were no different between the two groups of patients. The heart rate was significantly lower in patients receiving octreotide plus terlipressin than those receiving terlipressin alone. CONCLUSION: The current study showed that a combination of octreotide and terlipressin did not exert an additive effect in reducing hepatic venous pressure gradient in patients with cirrhosis. In addition, the systemic hemodynamic changes were comparable between the two groups.     

Hemodynamic effects of a combination of prazosin and terlipressin in patients with viral cirrhosis

OBJECTIVES: Terlipressin reduces portal pressure in cirrhotic patients mainly through intense splanchnic vasoconstriction that decrease portal venous inflow. Hepatic blood flow may also be reduced by terlipressin. Prazosin (an alpha1-adrenoceptor antagonist) has also been proposed to decrease portal pressure in cirrhotic patients possibly through a decrease in the intrahepatic vascular resistance. The current study was aimed to evaluate whether a combination of prazosin and terlipressin exerts more beneficial effects than terlipressin alone. METHODS: Patients were randomly assigned to receive either a placebo (n = 12) or an oral administration of prazosin 2 mg (n = 12). Thereafter, each patient received an intravenous injection of terlipressin 2 mg. Hemodynamic values were measured basally, 30 min after prazosin or placebo, and 30 min after terlipressin. RESULTS: Placebo administration did not affect any hemodynamic values. Terlipressin administration, on the other hand, resulted in expected changes on the hepatic venous pressure gradient, hepatic blood flow, and systemic hemodynamics. In contrast, prazosin significantly decreased hepatic venous pressure gradient with an increased hepatic blood flow and intrinsic hepatic clearance. After terlipressin administration, a further decrease in hepatic venous pressure gradient was observed with preservation of hepatic blood flow and intrinsic hepatic clearance. The magnitude of decrease in hepatic venous pressure gradient was more profound in patients receiving prazosin plus terlipressin than in those receiving terlipressin alone. However, the magnitude of changes in systemic hemodynamics was no different between the two groups of patients. CONCLUSIONS: The current study showed that a combination of prazosin and terlipressin resulted in a more profound reduction of hepatic venous pressure gradient with a preservation of hepatic blood flow and intrinsic hepatic clearance than did terlipressin alone. However, the combined therapy did not modify the systemic hemodynamic effects exerted by terlipressin.     

Hemodynamic Effects of a Combination of Octreotide and Terlipressin Patients with Viral Hepatitis Related Cirrhosis

Background: Terlipressin or octreotide given alone has been used as the first-line pharmacological treatment for acute variceal bleeding. In portal hypertensive animals, pre-infusion of octreotide followed by the addition of terlipressin has an additive or complementary effect on splanchnic hemodynamics. The current study was aimed at evaluating such a combination treatment in patients with cirrhosis and portal hypertension. Methods: Patients were randomly assigned to receive either a placebo ( n = 11) or an intravenous infusion of octreotide 100 μg/h after an initial bolus of 100 μg ( n = 13). Thereafter, each patient received an intravenous injection of terlipressin 2 mg. Hemodynamic values were measured basally, 30 min after octreotide or placebo, and 60 min after terlipressin. Results: Placebo administration did not affect any of the hemodynamic values. Terlipressin administration resulted in expected changes in hepatic venous pressure gradient, hepatic blood flow and systemic hemodynamics. In contrast, octreotide administration significantly decreased hepatic blood flow but did not affect other hemodynamic values. After terlipressin administration, significant hemodynamic changes were observed that were similar to the hemodynamic changes with terlipressin alone. The magnitude of changes in hepatic venous pressure gradient, cardiac index and systemic vascular resistance were no different between the two groups of patients. The heart rate was significantly lower in patients receiving octreotide plus terlipressin than those receiving terlipressin alone. Conclusion: The current study showed that a combination of octreotide and terlipressin did not exert an additive effect in reducing hepatic venous pressure gradient in patients with cirrhosis. In addition, the systemic hemodynamic changes were comparable between the two groups.     

Hemodynamic effects of the administration of terlipressin alone or combined with nitroglycerin in patients with cirrhosis]

Terlipressin (Glypressin), a synthetic analog of vasopressin, induces arteriolar vasoconstriction which causes both a portal hypotensive effect and certain side-effects on the systemic circulation (elevated arterial pressure and reduced cardiac output). The combination of nitroglycerin with terlipressin might accentuate the portal hypotensive effect and prevent the side-effects on the systemic circulation. The aim of this study was to examine the systemic and splanchnic hemodynamic responses to terlipressin administered alone or combined with nitroglycerin in patients with cirrhosis. Systemic and splanchnic hemodynamics were measured before and 1 h after a bolus of terlipressin (1 to 2 mg IV) given alone (n = 10) or in association with nitroglycerin infusion (25 micrograms/min, n = 9). Terlipressin alone significantly increased the arterial pressure by 21%, systemic vascular resistance by 60%, and significantly decreased cardiac output by 23%. The right atrial and pulmonary pressures significantly increased and the wedged hepatic venous pressure and hepatic venous pressure gradient significantly decreased by 8% and 16%, respectively. The combined therapy decreased the cardiac output by 20%, but did not significantly modify the other systemic and splanchnic hemodynamic values. No significant differences were found between terlipressin and the combined therapy concerning changes in wedged hepatic venous pressure or hepatic venous pressure gradient. We conclude that in patients with cirrhosis, nitroglycerin prevents the deleterious vasoconstrictor and vasopressor effects of terlipressin. However, the combined therapy, as terlipressin alone, decreases the cardiac output.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effects of chronic endoscopic variceal sclerotherapy on portal pressure in cirrhotics

The effect of obliterating esophageal varices by endoscopic sclerotherapy on portal pressure was prospectively studied in 11 cirrhotic patients with variceal hemorrhage. Portal venous pressure gradient, determined as the difference between transhepatic portal and hepatic vein pressure, increased by a mean of 31.1% +/- 14.5% in 8 (73%) and decreased by a mean of 30.1% +/- 11.7% in 3 (27%) patients, with no statistically significant change overall (P = 0.1). These changes in portal venous pressure gradient occurred despite an improvement in the laboratory and clinical parameters of hepatic function. Deep abdominal sonography with color flow imaging at variceal obliteration showed patent paraumbilical veins in 6 (55%) patients, 3 of whom had decreases in portal venous pressure gradient (29%, 19%, 42.5%) at variceal obliteration. In 5 (45%) patients without patent paraumbilical veins, a statistically significant increase in portal venous pressure gradient between initial endoscopic variceal sclerotherapy and variceal obliteration was noted (P = 0.008). Rebleeding (single episode in all 4 patients, before obliteration in 3 patients) occurred in those with an increase in portal venous pressure gradient; all patients with portal venous pressure gradient decreases were nonbleeders. No correlation between changes in portal venous pressure gradient and time to variceal obliteration, number of sclerotherapy treatments, or rebleeding episodes was observed. Thus, an increase in portal venous pressure gradient was noted in the majority of patients at variceal obliteration. Although the portal venous pressure gradient decrease may be explained by a patent paraumbilical vein, the mechanism of portal venous pressure gradient increase is not clear. It is speculated that this portal venous pressure gradient increase may be caused by an increase in collateral resistance or flow or a combination of both, resulting from obliteration of esophageal varices by endoscopic sclerotherapy.     

The influence of endoscopic variceal ligation on the portal pressure gradient in cirrhotics

BACKGROUND/AIMS: After variceal eradication by endoscopic ligation, fundal varices and worsening of portal hypertensive gastropathy can occur. The aim of this study is to verify the impact of the eradication of esophageal varices by endoscopic ligation on the portal pressure gradient, worsening of portal hypertensive gastropathy and development of fundal varices. METHODOLOGY: Twenty-two (15M/7F, mean age: 54.5 years) cirrhotics with previous variceal bleeding were submitted to measurement of hepatic venous pressure gradient before and after variceal eradication by endoscopic ligation. RESULTS: The mean hepatic venous pressure gradient in the first measurement was 14.1 mmHg and after eradication, 13.5 mmHg (p = 0.403). After eradication, 12 patients experienced a reduction in portal pressure and 10, an elevation. Three patients developed fundal varices. Their mean gradient before treatment was 22 mmHg and 18.8 mmHg after therapy (p = 0.368). The gastropathy worsened in 9 patients (mean gradient before therapy of 15.2 mmHg; and 16.1 mmHg after treatment) (p = 0.303). The initial pressure gradient of these patients was not different from the other 13 cases (p = 0.463). CONCLUSIONS: The esophageal variceal eradication by endoscopic band ligation does not alter the hepatic venous pressure gradient. There is no significant variation in the portal pressure of patients in whom there was a worsening of portal hypertensive gastropathy or fundal varices development.     

Endoscopic measurement of variceal pressure in cirrhosis: correlation with portal pressure and variceal hemorrhage

This study evaluated the clinical application of a pressure-sensitive gauge that allows the noninvasive measurement of the pressure of esophageal varices at endoscopy. The study was performed in 70 patients with cirrhosis and portal hypertension. Among them, 47 had bled from the varices and 23 had varices but had not bled. In addition to measurements of variceal pressure, the size of the varices was estimated semiquantitatively at endoscopy. This allowed an estimate of the tension on the wall of the varices as the product of the transmural pressure and the estimated radius of the varices. Most patients had a standard hemodynamic evaluation of portal hypertension, with measurements of wedged and free hepatic venous pressures, and of azygos blood flow. These were performed within 24 h of the variceal pressure measurements. Variceal pressure was significantly higher in bleeders than in nonbleeders (15.7 +/- 2.8 vs. 12.1 +/- 2.6 mmHg, p less than 0.001) in spite of a similar portal pressure in both groups (20.1 +/- 5.1 vs. 20.4 +/- 7.6 mmHg, NS). More than 60% of the bleeders, but only 22% of the nonbleeders had a variceal pressure greater than or equal to 15 mmHg (p less than 0.005). Among nonbleeders, variceal pressure was higher in patients with large varices (13.9 +/- 2 mmHg, n = 9) than in those with small varices (10.9 +/- 2.4 mmHg, n = 14) (p less than 0.01). Estimates of variceal wall tension further exaggerated the differences between bleeders and nonbleeders (66.1 +/- 22.6 vs. 32.0 +/- 19.8 mmHg.mm, p less than 0.001). More than 50% of bleeders, but just 9% of nonbleeders had an estimated variceal tension greater than 50 mmHg.mm (p less than 0.001). Our findings support the role of an increased variceal pressure in the pathogenesis of variceal hemorrhage, and suggest that this noninvasive technique can be valuable in assessing the risk of variceal hemorrhage in patients with portal hypertension.     

Effects of nifedipine on hepatic venous pressure gradient and portal vein blood flow in patients with cirrhosis

Abstract We investigated the effects of nifedipine on splanchnic haemodynamics in 13 patients with cirrhosis and portal hypertension, and in 10 control subjects using hepatic venous catheterization and pulsed Doppler ultrasound. There were no significant changes in systemic or splanchnic haemodynamics in control patients. In contrast, systemic vascodilatation, evidenced by significant decreases in mean arterial pressure and systemic vascular resistance, was observed in patients 20 min after sublingual application of 10 mg nifedipine. Moreover, hepatic venous pressure gradient and portal vein blood flow significantly increased after nifedipine administration. There was a significant correlation between the percentage increases in portal vein blood flow and in hepatic venous pressure gradient. However, no correlation was found between the percentage change in cardiac output and that in portal vein blood flow. Thus the increase in portal vein blood flow appears to be related to splanchnic arterial vasodilatation by nifedipine. Consequently, nifedipine has deleterious effects on portal haemodynamics in patients with cirrhosis. As nifedipine may potentially increase the risk of variceal haemorrhage in patients with less advanced varices, this drug should be used with caution in patients with chronic liver disease.     

Influence of the sclerosing of esophageal varices on portal pressure and azygos venous blood flow

Endoscopic sclerotherapy is widely employed for esophageal variceal hemorrhage. However it has side effects and can aggravate portal hypertension by suppression of portosystemic shunt. The purpose of the present investigation was to study the effect of variceal thrombosis on hepatic venous pressure gradient and azygos blood flow. Eight alcoholic cirrhotic patients with a first variceal hemorrhage were included. According to Child Pugh's classification, 4 patients were group A, 2 group B and 2 group C. At each session 40 to 60 ml of 1 p. 100 polidocanol were injected into the varices. A hemodynamic study was performed in each patient before and about one week after variceal obliteration (mean 3.3 procedures). Mean value of hepatic venous pressure gradient was 16.6 +/- 5.5 mm Hg and 17.0 +/- 3.8, respectively, before sclerotherapy and after eradication of varices; azygos blood flow 663 +/- 506 ml/mn before and 682 +/- 522 after; cardiac, output was 6.5 +/- 0.7 ml/min before and 6.5 +/- 0.8 after. None of these differences were significant. These results suggest that endoscopic sclerotherapy using polidocanol does not change hepatic venous pressure gradient and azygos blood flow, and does not lower blood flow through the gastroesophageal collaterals draining into the azygos vein. This is consistent with the hypothesis that thrombosis remains localized.     

Hemodynamic effects of terlipressin and high somatostatin dose during acute variceal bleeding in nonresponders to the usual somatostatin dose

OBJECTIVES: High dose of somatostatin infusion achieves a greater reduction of hepatic venous pressure gradient (HVPG) than the usual dose, and terlipressin decreases HVPG through mechanisms other than somatostatin. Our aim was to assess the hemodynamic effects of terlipressin and high somatostatin dose during acute variceal bleeding in nonresponders to the usual somatostatin dose. METHODS: Hemodynamic studies were performed in 80 patients with cirrhosis and variceal bleeding during the first 3 days of admission. After baseline measurements, somatostatin was administered (250 microg/h with an initial bolus of 250 microg). Patients were considered responders when the HVPG decreased by >10% from baseline (n = 31). Nonresponders were randomized under double-blind conditions to a control group (n = 7), or to receive terlipressin (2 mg IV bolus, n = 22), or high dose of somatostatin (500 microg/h, n = 20). Final measurements were obtained 30 min later. RESULTS: Terlipressin caused a decrease in HVPG (from 22.2 +/- 5 to 19.1 +/- 5.2, p < 0.01) and heart rate (p < 0.01), while mean arterial pressure increased (p < 0.01). High somatostatin dose also reduced HVPG (from 21.8 +/- 3.4 to 19.6 +/- 3.1, p < 0.01), although this decrease was more pronounced with terlipressin (15%+/- 9%vs 10%+/- 6% from baseline, p= 0.05). Both terlipressin and high somatostatin dose achieved a significantly higher rate of response than that in the control group. A decrease in HVPG >20% was observed in 36% of cases with terlipressin versus 5% with high somatostatin dose (p= 0.02). CONCLUSIONS: In nonresponders to usual somatostatin dose, both terlipressin and high-dose of somatostatin infusion significantly decreased HVPG and increased the rate of hemodynamic responders. Such effects were greater with terlipressin. Both treatments may be an alternative when standard somatostatin fails.     

Mixed endothelin receptor antagonist, SB209670, decreases portal pressure in biliary cirrhotic rats in vivo by reducing portal venous system resistance

BACKGROUND/AIMS: This study aimed to evaluate the hemodynamic effects of endothelin-1 or mixed endothelin receptor antagonist, SB209670 in cirrhotic rats, and to elucidate the role of endothelin in cirrhotic portal hypertension. METHODS: Secondary biliary cirrhosis was induced by bile duct ligation. Hemodynamics were studied using the radioactive microsphere technique. RESULTS: Plasma and hepatic endothelin levels in cirrhotic rats were significantly higher than those in normal rats (plasma, 9.0+/-1.3 vs. 2.6+/-0.5 pg/ml, p<0.001; liver, 74.8+/-13.3 vs. 12.6+/-2.5 pg/g wet tissue, p<0.001). Intraportal administration of endothelin-1 (3 nmol/kg) progressively raised portal pressure without an initial transient reduction, which was observed in systemic arterial pressure, in both cirrhotic and normal rats. SB209670 (5.4 micromol/kg) reduced portal pressure in cirrhotic rats (-19+/-5%, p<0.01) without modifying systemic arterial pressure and renal blood flow, but not in normal rats. This reduction was associated with reduced portal venous system resistance (vehicle, 2.5+/-0.2 vs. SB209670, 1.7+/-0.1 mmHg x min x 100 g bw/ml, p<0.01), but not with change in portal venous inflow and collateral blood flow. CONCLUSIONS: Mixed endothelin antagonist, SB209670, decreased portal pressure by reducing portal venous system resistance without modifying systemic arterial pressure and renal blood flow in cirrhotic rats. This result, together with the findings that plasma and hepatic endothelin levels were elevated in cirrhotic rats and that exogenous endothelin-1 increased portal pressure, provides further support for a role of endothelin in portal hypertension and suggests a potential use of mixed endothelin antagonist in the pharmacological treatment of portal hypertension.     

Pharmacology,clinical efficacy and safety of terlipressin in esophageal varices bleeding,septic shock and hepatorenal syndrome

Terlipressin, a vasopressin agonist, is a commonly used drug with different indications, particularly in patients with end-stage liver disease. As a V₁ receptor agonist, it increases systemic vascular resistance, particularly in the splanchnic area, resulting in a decrease of portal pressure. Besides the approved use for variceal bleeding, terlipressin also has beneficial effects in the treatment of hepatorenal syndrome and norepinephrine-resistant septic shock. In patients with cirrhosis and variceal bleeding, the use of terlipressin reduces the portal vein pressure and decreases the pressure in esophageal varices. This can save lives when skilled endoscopists are not immediately available. Hepatorenal syndrome is associated with vasodilation in the mesenteric circulation with arterial underfilling and consecutive renal vasoconstriction. Restoration of an effective arterial blood volume can be achieved by the combination of terlipressin and volume expansion. In some cases, a success rate of up to 75% is reported. The early use of terlipressin in catecholamine-resistant shock can improve organ perfusion.     

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.     

Systemic and portal haemodynamic changes following triglycyllysine vasopressin plus nitroglycerin administration in patients with hepatitis B-related cirrhosis

We measured the haemodynamic changes following triglycyllysine vasopressin administration and after addition of nitroglycerin in twelve patients with portal hypertension due to hepatitis B-related cirrhosis. A bolus i.v. injection of triglycyllysine vasopressin at a dose of 2 mg reduced the hepatic venous pressure gradient from 18.5 +/- 3.7 (mean +/- S.D.) to 15.6 +/- 4.0 mmHg, p less than 0.001. However, the cardiac index decreased from 4.8 +/- 1.0 to 3.7 +/- 0.8 l/min m2, p less than 0.001; the heart rate decreased from 79 +/- 15 to 71 +/- 13, p less than 0.01; the right atrial pressure increased from 3.2 +/- 1.9 to 5.3 +/- 2.3 mmHg, p less than 0.001; the mean arterial pressure increased from 92 +/- 13 to 103 +/- 13 mmHg, p less than 0.05; and the systemic vascular resistance rose from 939 +/- 182 to 1367 +/- 310 dyn/s cm-5, p less than 0.001. Furthermore, both mean pulmonary arterial pressure and pulmonary capillary wedge pressure showed a significant increase following triglycyllysine vasopressin administration as compared with baseline values (p less than 0.005). The addition of sublingual nitroglycerin at a dose of 0.6 mg returned all the systemic haemodynamic parameters to baseline levels. On the other hand, nitroglycerin administration caused no further change in the hepatic venous pressure gradient. We concluded that although triglycyllysine vasopressin significantly reduced portal pressure in patients with hepatitis B-related cirrhosis, it produced untoward systemic haemodynamic changes similar to those seen with vasopressin. The addition of nitroglycerin improved the detrimental systemic haemodynamic effects produced by triglycyllysine vasopressin without further reducing the hepatic venous pressure gradient.     

Chronic administration of losartan, an angiotensin II receptor antagonist, is not effective in reducing portal pressure in patients with preascitic cirrhosis

OBJECTIVES: Plasma angiotensin II (ANG II) concentrations are elevated in cirrhosis and have been implicated as a cause of portal hypertension. We aimed to study both the systemic and portal hemodynamics, and tolerability after chronic administration of losartan, an ANG II receptor antagonist. METHODS: Twelve patients with preascitic cirrhosis were studied: mean age of 53.8 +/- 3.3 yr; average Child-Pugh score of 5.8 +/- 0.3; alcohol etiology (5), hepatitis B/C (1/3), primary biliary cirrhosis (3). No patients were on diuretics or vasoactive medication. Hemodynamic measurements were performed at baseline and 4 weeks after daily administration of 25 mg losartan. RESULTS: There was no significant change in the hepatic venous pressure gradient (15.4 +/- 1.5 to 13.6 +/- 1.6 mmHg, -11.7%, p = NS), despite a significant reduction in the wedge hepatic venous pressure (20.3 +/- 1.8 to 17.3 +/- 1.8 mmHg, -14.8%, p < 0.05). Cardiac output, hepatic blood flow, systemic vascular resistance, creatinine clearance, and natriuresis were unaffected. The plasma renin activity increased significantly from 2.7 +/- 0.4 to 5.2 +/- 1.1 ng/ml/h (p < 0.05). There was a significant reduction in the mean arterial pressure from 96.9 +/- 3.3 to 89.3 +/- 3.5 mmHg, -7.8 +/- 3.0% (p = 0.02), with 1 patient experiencing symptomatic hypotension. CONCLUSIONS: Chronic administration of low-dose losartan does not lead to a significant reduction in the portal pressure gradient. Losartan is unlikely to be useful in the management of patients with early cirrhosis, who are at risk of variceal bleeding.     

The portal pressure response to beta-blockade is greater in cirrhotic patients without varices than in those with varices

BACKGROUND & AIMS: Nonselective beta-blockers are effective in reducing portal pressure in cirrhotic patients. However, this beneficial effect is highly variable and may depend on the extent of portal system collateralization. The aim of this study was to compare portal pressure response with timolol, a nonselective beta-blocker, in cirrhotic patients with and without varices. METHODS: Portal and systemic hemodynamics were measured before and after a single oral dose of 10 mg of timolol in 50 patients with cirrhosis and portal hypertension, 15 with and 35 without esophageal varices. RESULTS: Timolol significantly decreased portal pressure in all patients (mean reduction, 20% +/- 13%; P < 0.0001). The reduction in hepatic venous pressure gradient was greater in patients without varices (-24% +/- 14%) than in those with varices (-12% +/- 8%) (P < 0.01). A decrease in the hepatic venous pressure gradient of <12 mm Hg was achieved in 7 of 12 (58%) patients without varices and a baseline pressure gradient of <12 mm Hg, but only in 3 of 15 patients with varices (20%) (P < 0.01). CONCLUSIONS: Timolol is effective in reducing portal pressure in cirrhotic patients, more so in patients without varices, suggesting that nonselective beta-blockers will be more effective in the treatment of portal hypertension when administered at early stages, before the development of varices. (Gastroenterology 1997 Jun;112(6):2012-6)     

Portal hypertension: Pre-primary and primary prophylaxis of variceal bleeding

In liver cirrhosis, variceal bleeding is the last in a chain of events initiated by the increase in portal pressure (estimated in clinical practice by the hepatic venous pressure gradient). When hepatic venous pressure gradient goes above 10 mmHg the patient is at risk of developing varices, and when hepatic venous pressure gradient reaches 12 mmHg variceal bleeding might develop. Currently, there is not any effective therapy for the prevention of the development of varices. When varices are small, beta-adrenergic blockers might prevent the enlargement of the varices, and may reduce the risk of variceal bleeding. In patients with medium to large varices, beta-blockers are clearly effective in reducing the risk of variceal bleeding. Endoscopic band ligation might be more effective than beta-blockers, but available evidence is still very weak.     

Systemic, portal and renal effects of terlipressin in patients with cirrhotic ascites: pilot study

BACKGROUND AND AIM: Terlipressin is a vasopressin analog that may improve renal function in hepatorenal syndrome by mechanisms as yet unknown. The authors investigated the effect of the drug on systemic, hepatic and renal hemodynamics in cirrhosis. METHODS: Six patients with cirrhosis and ascites were studied (five Child's B and one Child's C). Heart rate (HR), mean arterial pressure (MAP), cardiac output (CO), systemic vascular resistance (SVR), hepatic venous pressure gradient (HVPG), reverse thermodilution unilateral real-time renal blood flow (RBF), urinary flow, and sodium concentrations were measured before and 1 h after an intravenous bolus of 2 mg of terlipressin. RESULTS: Following terlipressin administration, HR fell significantly (84.2 +/- 6 to 70.8 +/- 4.9, P = 0.013), MAP increased (72.7 +/- 3.6 to 87 +/- 5.3 mmHg, P = 0.027), CO fell (7.4 +/- 0.8 to 6.4 +/- 0.8 L/min, P = 0.02) and SVR increased (1368.5 +/- 236 to 2079.7 +/- 458, P = 0.04). There were no significant differences in HVPG (12.3 +/- 1.6 to 14 +/- 0.9 mmHg, P-value not significant [NS]), RBF (255 +/- 0.02 compared with 249 +/- 0.02 mL/min, P-value NS), urinary volume (49.1 +/- 8.9 compared with 49.6 +/- 16.7 mL/ h, P-value NS) and urinary sodium excretion (4 +/- 1.1 compared with 5.9 +/- 3.5 mmol/ h). CONCLUSION: In the present small study, the authors were able to demonstrate that a bolus injection of terlipressin produced an increase in MAP and SVR, along with a reduction in cardiac output without a reduction in renal blood flow. Further studies are necessary to define the effects of terlipressin on renal hemodynamics and sodium excretion.