Angelo Luca

Early Use of TIPS in Patients with Cirrhosis and Variceal Bleeding

BACKGROUND Patients with cirrhosis in Child-Pugh class C or those in class B who have persistent bleeding at endoscopy are at high risk for treatment failure and a poor prognosis, even if they have undergone rescue treatment with a transjugular intrahepatic portosystemic shunt (TIPS). This study evaluated the earlier use of TIPS in such patients. METHODS We randomly assigned, within 24 hours after admission, a total of 63 patients with cirrhosis and acute variceal bleeding who had been treated with vasoactive drugs plus endoscopic therapy to treatment with a polytetrafluoroethylene-covered stent within 72 hours after randomization (early-TIPS group, 32 patients) or continuation of vasoactive-drug therapy, followed after 3 to 5 days by treatment with propranolol or nadolol and long-term endoscopic band ligation (EBL), with insertion of a TIPS if needed as rescue therapy (pharmacotherapy-EBL group, 31 patients). RESULTS During a median follow-up of 16 months, rebleeding or failure to control bleeding occurred in 14 patients in the pharmacotherapy-EBL group as compared with 1 patient in the early-TIPS group (P=0.001). The 1-year actuarial probability of remaining free of this composite end point was 50% in the pharmacotherapy-EBL group versus 97% in the early-TIPS group (P<0.001). Sixteen patients died (12 in the pharmacotherapy-EBL group and 4 in the early-TIPS group, P=0.01). The 1-year actuarial survival was 61% in the pharmacotherapy-EBL group versus 86% in the early-TIPS group (P<0.001). Seven patients in the pharmacotherapy-EBL group received TIPS as rescue therapy, but four died. The number of days in the intensive care unit and the percentage of time in the hospital during follow-up were significantly higher in the pharmacotherapy-EBL group than in the early-TIPS group. No significant differences were observed between the two treatment groups with respect to serious adverse events. CONCLUSIONS In these patients with cirrhosis who were hospitalized for acute variceal bleeding and at high risk for treatment failure, the early use of TIPS was associated with significant reductions in treatment failure and in mortality. (Current Controlled Trials number, ISRCTN58150114.)

Relation between portal pressure response to pharmacotherapy and risk of recurrent variceal haemorrhage in patients with cirrhosis

In patients with variceal bleeding as a complication of hepatic cirrhosis, propranolol therapy reduces the risk of recurrent variceal haemorrhage. However, the relation between portal pressure response to pharmacological treatment and clinical events has not been well defined. This relation was prospectively investigated in 69 cirrhotic patients receiving continued propranolol therapy after an episode of variceal bleeding. Hepatic venous pressure gradient (HVPG) was measured before and at 3 months of continued drug therapy. At 3 months HVPG had fallen by 20% or more in 25 patients. During follow-up of 28 (SD 17) months rebleeding occurred in 2 of these 25 patients compared with 23 of 44 who had lesser reductions in HVPG. Cumulative probability of rebleeding at 1, 2, and 3 years was 4%, 9%, and 9% in patients with a decrease in HVPG > or = 20%, and 28%, 39%, and 66% in patients with a decrease in HVPG < 20% (p < 0.001, log-rank test). On multivariate analysis, a decrease in HVPG > or = 20% was the only independent predictor of rebleeding (relative risk 0.09, 95% CI 0.02-0.41. Of the 8 patients in whom the HVPG fell to 12 mm Hg or less, none rebled. This study suggests that measurement of the HVPG response to pharmacotherapy will provide useful prognostic information on the long-term risk of variceal rebleeding.

Use of early-TIPS for high-risk variceal bleeding: Results of a post-RCT surveillance study

BACKGROUND & AIMS In a recent randomized international clinical trial (RCT) in high-risk cirrhotic patients with acute variceal bleeding, the early use of transjugular intrahepatic portosystemic shunt (TIPS) was associated with marked and significant reductions in both treatment failure and mortality. The aim of this study was to confirm these results in clinical practice in the same centers of the RCT study. METHODS We retrospectively reviewed patients admitted for acute variceal bleeding and high risk of treatment failure (Child C <14 or Child B plus active bleeding), treated with early-TIPS (n=45) or drugs+endoscopic therapy (ET) (n=30). RESULTS Patients treated with early-TIPS had a much lower incidence of failure to control bleeding or rebleeding than patients receiving drug+ET (3 vs. 15; p <0.001). The 1-year actuarial probability of remaining free of this composite end point was 93% vs. 53% (p <0.001). The same was observed in mortality (1-year actuarial survival was 86% vs. 70% respectively; p=0.056). Actuarial curves of failure to control bleeding+rebleeding and of survival were well within the confidence intervals of those observed in the RCT. CONCLUSIONS This study supports the early use of TIPS in patients with cirrhosis and a high-risk variceal bleeding.

Hemodynamic Effects of Acute Changes in Intra-abdominal Pressure in Patients With Cirrhosis

BACKGROUND Changes in intra-abdominal pressure (IAP) have significant circulatory effects. However, whether this may influence the gastroesophageal collateral blood flow in patients with cirrhosis has not been studied. METHODS In 14 portal hypertensive cirrhotics, serial hemodynamic measurements were obtained in baseline conditions 30 minutes after the mechanical increase of IAP by 10 mm Hg and 30 minutes after returning IAP to baseline levels. RESULTS Increasing IAP caused similar increases in free and wedged hepatic venous pressures (+10.3 mm Hg and +11.0 mm Hg, respectively; P < 0.005), without changing the hepatic venous pressure gradient (HVPG). However, there were significant decreases in cardiac output (-18%; P < 0.005) and hepatic blood flow (-20%; P < 0.05), whereas azygos blood flow, an index of gastroesophageal collateral blood flow, increased markedly (+23%; P < 0.005). The opposite occurred after releasing the high IAP. CONCLUSION In portal hypertensive cirrhotics, acute changes in IAP did not change HVPG but markedly modified splanchnic and systemic hemodynamics. Brief elevations of IAP may have deletereous effects, as shown by the increase in azygos blood flow and the decrease in cardiac output and hepatic blood flow, whereas reduction of a high IAP causes the opposite changes and may be beneficial.

Effects of Ethanol Consumption on Hepatic Hemodynamics in Patients With Alcoholic Cirrhosis

BACKGROUND & AIMS Increased portal blood flow represents a compensatory mechanism preventing hepatic hypoxia after ethanol consumption. In addition, alcohol increases hepatic vascular resistance. Thus, ethanol consumption, by increasing hepatic vascular resistance and portal flow, may worsen portal hypertension in patients with cirrhosis. The aim of this study was to investigate the effects of ethanol consumption on hepatic hemodynamics in patients with alcohol-induced cirrhosis. METHODS Measurements of hepatic venous pressure gradient (HVPG), azygos blood flow, hepatic blood flow, heart rate, and arterial pressure were obtained in 16 patients with alcohol-induced cirrhosis and portal hypertension before and after random administration of a noncaloric fruit drink (250 mL, n = 7) or of an identical beverage plus 0.5 g/kg of ethanol (n = 9). RESULTS Vehicle caused no effects. By contrast, ethanol increased HVPG (P < 0.0001). The increase in HVPG was maximum at 15 minutes and remained significant at 45 minutes (P < 0.05 vs. vehicle). Ethanol increased azygos blood flow (P < 0.05) without changes in hepatic blood flow. Heart rate and arterial pressure slightly increased. CONCLUSIONS Oral ethanol consumption increases portal pressure and portocollateral blood flow in patients with alcohol-induced cirrhosis. These findings suggest that even moderate alcohol consumption worsens the portal-hypertensive syndrome and, therefore, may increase the risk of variceal bleeding in patients with alcohol-induced cirrhosis.

Effects of isosorbide-5-mononitrate on variceal pressure and systemic and splanchnic haemodynamics in patients with cirrhosis

BACKGROUND Isosorbide-5-mononitrate is a long-acting nitrovasodilator which was introduced for the treatment of portal hypertension because of its capacity to reduce portal pressure. In contrast to vasoconstrictors, isosorbide-5-mononitrate acts primarily by decreasing portal-collateral resistance without deleterious effects on liver function, although at high doses, a reflex splanchnic vasoconstriction elicited by the fall in arterial pressure may further decrease portal pressure. However, there is no information on the effects of isosorbide-5-mononitrate on variceal pressure, which is thought to be a major determinant of variceal haemorrhage. METHODS We investigated the effects of isosorbide-5-mononitrate (40 mg, orally; n = 12) or placebo (n = 10) on variceal pressure (non-invasive endoscopic gauge) and hepatic haemodynamics in 22 patients with cirrhosis. RESULTS Placebo administration had no significant effects. In contrast, isosorbide-5-mononitrate significantly reduced variceal pressure (from 13.5 +/- 3.6 to 9.8 +/- 3.2 mmHg, p < 0.005). This was associated with a fall in wedged hepatic venous pressure (from 28 +/- 5.8 to 25.9 +/- 6.2 mmHg, p < 0.005), hepatic venous pressure gradient (from 20 +/- 4 to 18 +/- 4.7 mmHg, p < 0.005) and azygos blood flow (from 668 +/- 197 to 597 +/- 160 ml/min, p < 0.05), suggesting that the decrease in variceal pressure caused by isosorbide-5-mononitrate could be caused by both reductions in collateral resistance and collateral blood flow. Isosorbide-5-mononitrate moderately reduced mean arterial pressure (-13 +/- 16%; p < 0.005), its fall being directly related to the fall in hepatic venous pressure gradient (r = 0.6, p < 0.01). CONCLUSIONS The results of this study show that isosorbide-5-mononitrate markedly and significantly reduces variceal pressure in patients with cirrhosis and provide further support for its clinical use in the pharmacological treatment of portal hypertension.

New approaches in the pharmacologic treatment of portal hypertension

To alleviate the risk of variceal bleeding, the portal pressure gradient--usually evaluated as the hepatic venous pressure gradient (HVPG)--must be reduced to < or = 12 mmHg. Although beta-blocking agents are accepted therapy for preventing first or subsequent bleeding episodes, propranolol therapy decreases final HVPG to < or = 12 mmHg in only 12% of patients, while only 24% of patients have a > or = 20% reduction in HVPG and nearly 40% show no reduction in HVPG. This has stimulated research on alternative or additional treatments. Nitrates such as isosorbide dinitrate reduce portal pressure by decreasing resistance to portal and collateral blood flow and by promoting reflex splanchnic vasoconstriction. However, while nitrates are effective in the acute situation, tolerance leading to refractoriness develops over the long term unless they are combined with diuretics or other agents in the treatment of portal hypertension. Propranolol and isosorbide-5-mononitrate combined cause a substantially greater reduction in HVPG than monotherapy with either drug in both acute and long-term use. Presumably concomitant isosorbide-5-mononitrate administration opposes the increase in portal resistance induced by propranolol. Spironolactone, which has been shown to lower HVPG in patients with cirrhosis, produces a reduction in plasma volume that attenuates the increased cardiac output associated with cirrhosis and triggers vasoactive mechanisms that decrease splanchnic blood flow. Potentially, spironolactone may maintain and enhance the decrease in portal pressure achieved by nitrates or propranolol. Triple therapy with a beta-blocker, a nitrate and spironolactone may be feasible.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of balloon versus straight catheter for measurement of portal hypertension

Aliment Pharmacol Ther 2010; 32: 1351–1356

Nicardipine increases hepatic blood flow and the hepatic clearance of indocyanine green in patients with cirrhosis

The present study investigated the hemodynamic effects of nicardipine, a new calcium channel blocker, and placebo in 14 patients with cirrhosis. Sixty minutes after nicardipine administration (20 mg orally; n = 8), there was a significant increase in hepatic blood flow (25 +/- 21%; p < 0.05) and azygos blood flow (33 +/- 40%; p < 0.05) but no significant change in the hepatic venous pressure gradient. As a result of the increase in hepatic blood flow and the lack of change in the hepatic venous pressure gradient, nicardipine significantly reduced hepatic sinusoidal resistance (-14 +/- 15%; p < 0.05). Enhanced liver perfusion was associated with a significant increase in the hepatic clearance of indocyanine green (from 241 +/- 81 to 265 +/- 92 ml/min, p < 0.05). A mild, well-tolerated decrease in mean arterial pressure (-10 +/- 6%, p < 0.05), without significant changes in cardiac output, systemic vascular resistance and heart rate, was also observed. Placebo administration (n = 6) did not cause significant changes in systemic or hepatic hemodynamics. The results of the present study show that nicardipine, unlike other calcium channel blockers, effectively increases hepatic blood flow and the hepatic clearance of indocyanine green in patients with cirrhosis. The acute beneficial effects of nicardipine should be confirmed in chronic studies.

Effects of end-to-side portacaval shunt and distal splenorenal shunt on systemic and pulmonary haemodynamics in patients with cirrhosis

Background : Patients with cirrhosis exhibit splanchnic, peripheral and pulmonary vasodilation, which are thought to play a role in increasing portal pressure, promoting sodium retention and determining arterial hypoxaemia. The present study investigated whether these abnormalities are influenced by portal hypertension or by portal systemic shunting.