Agustín Albillos

Bacterial infections in cirrhosis: A position statement based on the EASL Special Conference 2013

Bacterial infections are very common and represent one of the most important reasons of progression of liver failure, development of liver-related complications, and mortality in patients with cirrhosis. In fact, bacterial infections may be a triggering factor for the occurrence of gastrointestinal bleeding, hypervolemic hyponatremia, hepatic encephalopathy, kidney failure, and development of acute-on-chronic liver failure. Moreover, infections are a very common cause of repeated hospitalizations, impaired health-related quality of life, and increased healthcare costs in cirrhosis. Bacterial infections develop as a consequence of immune dysfunction that occurs progressively during the course of cirrhosis. In a significant proportion of patients, infections are caused by gram-negative bacteria from intestinal origin, yet gram-positive bacteria are a frequent cause of infection, particularly in hospitalized patients. In recent years, infections caused by multidrug-resistant bacteria are becoming an important clinical problem in many countries. The reduction of the negative clinical impact of infections in patients with cirrhosis may be achieved by a combination of prophylactic measures, such as administration of antibiotics, to reduce the occurrence of infections in high-risk groups together with early identification and management of infection once it has developed. Investigation on the mechanisms of altered gut microflora, translocation of bacteria, and immune dysfunction may help develop more effective and safe methods of prevention compared to those that are currently available. Moreover, research on biomarkers of early infection may be useful in early diagnosis and treatment of infections. The current manuscript reports an in-depth review and a position statement on bacterial infections in cirrhosis.

Extracorporeal albumin dialysis with the molecular adsorbent recirculating system in acute‐on‐chronic liver failure: The RELIEF trial

Acute‐on‐chronic liver failure (ACLF) is a frequent cause of death in cirrhosis. Albumin dialysis with the molecular adsorbent recirculating system (MARS) decreases retained substances and improves hemodynamics and hepatic encephalopathy (HE). However, its survival impact is unknown. In all, 189 patients with ACLF were randomized either to MARS (n = 95) or to standard therapy (SMT) (n = 94). Ten patients (five per group) were excluded due to protocol violations. In addition, 23 patients (MARS: 19; SMT: 4) were excluded from per‐protocol (PP) analysis (PP population n = 156). Up to 10 6‐8‐hour MARS sessions were scheduled. The main endpoint was 28‐day ITT and PP survival. There were no significant differences at inclusion, although the proportion of patients with Model for Endstage Liver Disease (MELD) score over 20 points and with spontaneous bacterial peritonitis (SBP) as a precipitating event was almost significantly greater in the MARS group. The 28‐day survival was similar in the two groups in the ITT and PP populations (60.7% versus 58.9%; 60% versus 59.2% respectively). After adjusting for confounders, a significant beneficial effect of MARS on survival was not observed (odds ratio [OR]: 0.87, 95% confidence interval [CI] 0.44‐1.72). MELD score and HE at admission and the increase in serum bilirubin at day 4 were independent predictors of death. At day 4, a greater decrease in serum creatinine (P = 0.02) and bilirubin (P = 0.001) and a more frequent improvement in HE (from grade II‐IV to grade 0‐I; 62.5% versus 38.2%; P = 0.07) was observed in the MARS group. Severe adverse events were similar. Conclusion: At scheduled doses, a beneficial effect on survival of MARS therapy in patients with ACLF could not be demonstrated. However, MARS has an acceptable safety profile, has significant dialysis effect, and nonsignificantly improves severe HE. (HEPATOLOGY 2013)

Recombinant factor VIIa for variceal bleeding in patients with advanced cirrhosis: A randomized, controlled trial

A beneficial effect of recombinant activated factor VII (rFVIIa) in Child‐Pugh class B and C patients with cirrhosis who have variceal bleeding has been suggested. This randomized controlled trial assessed the efficacy and safety of rFVIIa in patients with advanced cirrhosis and active variceal bleeding. At 31 hospitals in an emergency setting, 256 patients (Child‐Pugh > 8; Child‐Pugh B = 26%, C = 74%) were randomized equally to: placebo; 600 μg/kg rFVIIa (200 + 4× 100 μg/kg); or 300 μg/kg rFVIIa (200 + 100 μg/kg). Dosing was intravenous at 0, 2, 8, 14, and 20 hours after endoscopy, in addition to standard vasoactive, prophylactic antibiotic, and endoscopic treatment. The primary composite endpoint consisted of failure to control 24‐hour bleeding, or failure to prevent rebleeding or death at day 5. Secondary endpoints included adverse events and 42‐day mortality. Baseline characteristics were comparable between groups. Administration of rFVIIa had no significant effect on the composite endpoint compared with placebo (P = 0.37). There was no significant difference in 5‐day mortality between groups; however, 42‐day mortality was significantly lower with 600 μg/kg rFVIIa compared with placebo (odds ratio 0.31, 95% confidence interval = 0.13–0.74), and bleeding‐related deaths were reduced from 12% (placebo) to 2% (600 μg/kg). A marked heterogeneity in the failure rate in all treatment groups was observed across participating centers. Adverse events, including overall thromboembolic events, were comparable between groups. Conclusion: Treatment with rFVIIa had no significant effect on the primary composite endpoint compared with placebo. Therefore, decision on the use of this hemostatic agent in acute variceal bleeding should be carefully considered, because results of this study do not support the routine use of rFVIIa in this setting. Adverse events were comparable across groups. (HEPATOLOGY 2008.)

Efficacy and Safety of Anticoagulation on Patients With Cirrhosis and Portal Vein Thrombosis

BACKGROUND & AIMS Portal vein thrombosis (PVT) is a frequent event in patients with cirrhosis; it can be treated with anticoagulants, but there are limited data regarding safety and efficacy of this approach. We evaluated this therapy in a large series of patients with cirrhosis and non-neoplastic PVT. METHODS We analyzed data from 55 patients with cirrhosis and PVT, diagnosed from June 2003 to September 2010, who received anticoagulant therapy for acute or subacute thrombosis (n = 31) or progression of previously known PVT (n = 24). Patients with cavernomatous transformation were excluded. Thrombosis was diagnosed, and recanalization was evaluated by using Doppler ultrasound, angio-computed tomography, and/or angio-magnetic resonance imaging analyses. RESULTS Partial or complete recanalization was achieved in 33 patients (60%; complete in 25). Early initiation of anticoagulation was the only factor significantly associated with recanalization. Rethrombosis after complete recanalization occurred in 38.5% of patients after anticoagulation therapy was stopped. Despite similar baseline characteristics, patients who achieved recanalization developed less frequent liver-related events (portal hypertension-related bleeding, ascites, or hepatic encephalopathy) during the follow-up period, but this difference was not statistically significant (P = .1). Five patients developed bleeding complications that were probably related to anticoagulation. A platelet count <50 × 109/L was the only factor significantly associated with higher risk for experiencing a bleeding complication. There were no deaths related to anticoagulation therapy. CONCLUSIONS Anticoagulation is a relatively safe treatment that leads to partial or complete recanalization of the portal venous axis in 60% of patients with cirrhosis and PVT; it should be maintained indefinitely to prevent rethrombosis.

Administration of Nω-nitro-l-arginine ameliorates portal-systemic shunting in portal-hypertensive rats

Abstract Background: Nitric oxide, a vasodilator synthesized from l-arglnine by vascular endothelial cells, may play a role in the development of portal-systemic collaterals. This study investigated the effect of long-term inhibition of NO secretion on portal systemic shunting. Methods: Systemic and splanchnic hemodynamics and the degree of portal-systemic shunting were evaluated in partial portal vein-ligated rats after administration of placebo (0.9% saline) or N ω -nitro-l-arginine (NNA) (~2 μg · kg −1 · min −1 ) intravenously for 6 days. Results: NNA treatment induced increases in splanchnic arterial resistance ( P P P P 2 O · mL −1 · min −1 ; P Conclusions: The results show that in portal hypertensive rats, NNA reduces portal-systemic shunting without reducing portal pressure, suggesting that NO plays a role in the collaterallzation of the portal system. In addition, high flow through the portal-collateral bed is probably an important driving force that is independent of portal hypertension for the development of portal-systemic shunting in portal-hypertensive rats.

Multicenter randomized controlled trial comparing different schedules of somatostatin in the treatment of acute variceal bleeding

BACKGROUND/AIMS The dose of somatostatin used for variceal bleeding (250 microg/h) is lower than that proven to effectively decrease portal pressure and azygos blood flow (500 microg/h). Moreover, i.v. somatostatin boluses have greater effects than continuous infusions. The aim of this study was to investigate whether higher doses of somatostatin and repeated boluses may increase its efficacy in controlling variceal bleeding. METHODS A total of 174 patients with acute variceal bleeding were randomized to receive for 48 h: (A) one 250 microg bolus +250 microg/h infusion; (B) three 250 microg boluses +250 microg/h infusion; (C) three 250 microg boluses +500 microg/h infusion. RESULTS The three schedules of somatostatin were equally effective in controlling variceal bleeding (73, 75 and 81%, respectively, NS). Multivariate analysis showed active bleeding at endoscopy (n=75) as the only predictor of failure to control bleeding. In these patients, the 500 microg/h infusion dose achieved a higher rate of control of bleeding (82 vs. 60%, P<0.05), less transfusions (3.7 +/- 2.7 vs. 2.5 +/- 2.3 UU, P=0.07) and better survival (93 vs. 70%, P<0.05) than schedules A/B. CONCLUSIONS Somatostatin is highly effective in controlling variceal bleeding. Patients with active bleeding at emergency endoscopy may benefit from higher doses of somatostatin infusion.

Continuous prazosin administration in cirrhotic patients: Effects on portal hemodynamics and on liver and renal function☆☆☆

BACKGROUND & AIMS Hepatic vascular resistance is influenced by alpha-adrenergic tone. The aim of this study was to investigate the effects of continuous blockade of alpha-adrenoceptors with prazosin on hemodynamics, liver function, and renal function and whether the association of propranolol or furosemide enhances the portal pressure lowering effect of prazosin. METHODS Cirrhotic patients with portal hypertension were studied at baseline and after a 3-month course of prazosin (n = 18) or placebo (n = 10). RESULTS No changes were observed in the placebo group. Prazosin decreased the hepatic venous pressure gradient (HVPG) while increasing hepatic blood flow. Liver function improved as shown by an increase in hepatic and intrinsic hepatic clearances of indocyanine green and galactose elimination capacity. A significant reduction in mean arterial pressure and systemic vascular resistance was associated with increases in plasma renin activity and aldosterone concentration and a decrease in glomerular filtration rate. The plasma volume increased significantly, and 6 patients developed edema. The association of propranolol (n = 8) but not furosemide (n = 7) to prazosin increased the reduction in HVPG and attenuated the increase in plasma renin activity. CONCLUSIONS In cirrhotic patients, continuous prazosin administration reduces portal pressure and improves liver perfusion and function but favors sodium and water retention. The association of propranolol enhances the decrease in portal pressure, suggesting a potential benefit from this combined therapy.

Vasodilatation and sodium retention in prehepatic portal hypertension

Sodium retention and peripheral vasodilatation are common consequences of portal hypertension secondary to cirrhosis. Although peripheral vasodilatation has been extensively documented in prehepatic portal hypertension, it is not known whether sodium retention is also a feature of this entity. The aim of this study in portal vein-constricted rats was to evaluate (a) whether sodium retention is a feature of prehepatic portal hypertension and (b) if sodium retention is present in this model, what its temporal relationship with peripheral vasodilatation might be. It was proposed that an understanding of the temporal interplay between peripheral vasodilatation and sodium retention could shed light on the current theories of sodium retention in portal hypertension. Rats were studied 1, 2, 3, and 4 days after partial portal vein ligation (n = 80) or sham operation (n = 63). Sodium retention was evaluated by changes in the size of the sodium space measured by the volume of distribution of 22Na. Systemic vascular resistance was calculated from mean arterial pressure (measured by arterial catheterization) and cardiac index (measured by thermodilution). A decrease in systemic vascular resistance was already observed on day 1 after constriction of the portal vein (4.2 +/- 0.2 vs. 5.2 +/- 6.1 mm Hg.min.mL-1.100 g; P less than 0.01). However, an expansion of the sodium space, which indicates sodium retention, was not observed until day 2 after induction of portal hypertension (37.1 +/- 0.8 vs. 32.6 +/- 0.7 mL.100 g-1; P less than 0.01). Therefore, sodium retention should be considered along with peripheral vasodilatation among the characteristic features of prehepatic portal hypertension. Because the reduction in systemic vascular resistance preceded the expansion of the sodium space by at least 24 hours, the finding of this study indicates that sodium retention follows peripheral vasodilatation.

Value of the hepatic venous pressure gradient to monitor drug therapy for portal hypertension: a meta-analysis.

OBJECTIVES:The use of the hepatic venous pressure gradient (HVPG) to assess the efficacy of the pharmacological treatment of portal hypertension in cirrhosis is controversial. Our aim was to establish whether target HVPG reduction predicts variceal bleeding in cirrhotic patients receiving variceal bleeding prophylaxis.METHODS:Data sources were MEDLINE, EMBASE, Cochrane Controlled Trials Register, citation lists, and abstracts (most recent search March 2006). Cohorts of patients on drug therapy from randomized and nonrandomized studies correlating variceal bleeding and HVPG change were used. Heterogeneity was explored by metaregression analysis.RESULTS:Ten studies totaling 595 patients undergoing two HVPG measurements were identified. The RR of bleeding was lower in patients achieving an overall (HVPG ≤12 mmHg or decrease ≥20%) (0.27, 95% CI 0.14–0.52), complete (HVPG ≤12 mmHg) (0.48, CI 0.28–0.81), or partial (HVPG decrease ≥20%) (0.41, CI 0.20–0.81) response, with significant heterogeneity. Regression analysis identified the interval between the HVPG measurements significantly associated with the RR of bleeding. Heterogeneity was no longer significant after exclusion of an outlier trial, which showed the longest interval to HVPG remeasurement and the lowest quality score. Even considering nonevaluable patients because of bleeding as HVPG responders, the RR of bleeding was lower in overall responders than in nonresponders (0.66, CI 0.51–0.86). Overall response was associated with lower liver-related mortality (RR 0.58, CI 0.37–0.91).CONCLUSIONS:Current evidence supports the validity of HVPG end points to monitor drug therapy efficacy for variceal bleeding prophylaxis. HVPG monitoring also provides valuable prognostic information.

Propranolol plus prazosin compared with propranolol plus isosorbide-5-mononitrate in the treatment of portal hypertension

BACKGROUND & AIMS The association of prazosin to propranolol enhances the decrease in portal pressure but may cause hypotension and sodium retention. The aim of this study was to compare the portal pressure reduction and safety of the combination of propranolol plus prazosin with that of propranolol plus isosorbide-5-mononitrate (ISMN). METHODS Fifty-six portal-hypertensive cirrhotics received randomly propranolol plus prazosin (n = 28) or propranolol plus ISMN (n = 28) orally for 3 months. Hemodynamics and liver and renal function were assessed at baseline and after 3 months. RESULTS Propranolol plus prazosin caused a greater reduction in hepatic venous pressure gradient (HVPG) than propranolol plus ISMN (-24.2% +/- 11% vs. -16.1% +/- 11%; P < 0.01). A reduction in HVPG of > 20% was significantly more frequent in the propranolol plus prazosin group than in the propranolol plus ISMN group (85% vs. 53%; P < 0.05). Neither treatment modified hepatic blood flow, quantitative liver function test results, glomerular filtration rate, plasma renin activity, or plasma aldosterone level. Side effects occurred in 13 patients receiving propranolol plus prazosin compared with 7 receiving propranolol plus ISMN (P = 0.16). CONCLUSIONS Propranolol plus prazosin has a greater portal pressure-lowering effect than propranolol plus ISMN. Both therapies were safe for liver and renal function. However, the combination of propranolol plus prazosin caused a greater decrease in arterial pressure and was less well tolerated than propranolol plus ISMN.