Alexander Zipprich

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)

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.

Prognostic indicators of survival in patients with compensated and decompensated cirrhosis

Patients with cirrhosis are classified in a compensated and a decompensated stage. Portal hypertension is responsible for most of the complications of cirrhosis that mark the transition from compensated to decompensated cirrhosis. The objectives of this study were (a) to analyse survival of the different stages and substages of cirrhosis and (b) to examine the prognostic value of the hepatic venous pressure gradient (HVPG) at each of the stages.

Hepatic arterial flow volume and reserve in patients with cirrhosis: use of intra-arterial Doppler and adenosine infusion.

BACKGROUND & AIMS In cirrhosis, liver blood flow becomes increasingly dependent on the hepatic artery. The aim of this study was to investigate hepatic arterial blood flow volume and resistance and hepatic arterial flow reserve in relation to liver function and systemic hemodynamic alterations in patients with cirrhosis. METHODS In 38 patients with cirrhosis, liver function, cardiac output, and systemic vascular resistance were studied, and hepatic arterial blood flow velocity, flow volume, and pulsatility index at baseline and during intra-arterial administration of adenosine (2-40 microg. min-1. kg body wt-1) were assessed by angiography combined with intravascular Doppler flowmetry. RESULTS Hepatic arterial flow velocity was 21 +/- 11, 31 +/- 17, and 41 +/- 27 cm/s; flow volume was 266 +/- 246, 342 +/- 289, and 417 +/- 220 mL/min; and pulsatility index was 2.2 +/- 0.7, 1.7 +/- 0.6, and 1.5 +/- 0.5 in Child-Pugh classes A, B, and C, respectively (differences not statistically significant). Adenosine-induced changes in these parameters were more marked in Child-Pugh class A (68 +/- 15 cm/s, 1246 +/- 486 mL/min, and -1.14 +/- 0.5) than in class C (45 +/- 23, P < 0.05; 704 +/- 492, P = 0.02; and -0.58 +/- 0.38, P < 0.05). Using analysis of variance, cardiac index, systemic vascular resistance, and ascites, but not Child-Pugh class, were related to baseline values and adenosine-induced changes. CONCLUSIONS Adenosine is a potent dilator of the hepatic artery in humans. The data suggest that hepatic arterial blood flow and adenosine-dependent flow reserve in patients with cirrhosis are under systemic hemodynamic or neurohormonal control.

Prevention of Rebleeding From Esophageal Varices in Patients With Cirrhosis Receiving Small-Diameter Stents Versus Hemodynamically Controlled Medical Therapy

BACKGROUND & AIMS Patients with cirrhosis and variceal hemorrhage have a high risk of rebleeding. We performed a prospective randomized trial to compare the prevention of rebleeding in patients given a small-diameter covered stent vs those given hepatic venous pressure gradient (HVPG)-based medical therapy prophylaxis. METHODS We performed an open-label study of patients with cirrhosis (92% Child class A or B, 70% alcoholic) treated at 10 medical centers in Germany. Patients were assigned randomly more than 5 days after variceal hemorrhage to groups given a small covered transjugular intrahepatic portosystemic stent-shunt (TIPS) (8 mm; n = 90), or medical reduction of portal pressure (propranolol and isosorbide-5-mononitrate; n = 95). HVPG was determined at the time patients were assigned to groups (baseline) and 2 weeks later. In the medical group, patients with an adequate reduction in HVPG (responders) remained on the drugs whereas nonresponders underwent only variceal band ligation. The study was closed 10 months after the last patient was assigned to a group. The primary end point was variceal rebleeding. Survival, safety (adverse events), and quality of life (based on the Short Form-36 health survey) were secondary outcome measures. RESULTS A significantly smaller proportion of patients in the TIPS group had rebleeding within 2 years (7%) than in the medical group (26%) (P = .002). A slightly higher proportion of patients in the TIPS group experienced adverse events, including encephalopathy (18% vs 8% for medical treatment; P = .05). Rebleeding occurred in 6 of 23 patients (26%) receiving medical treatment before hemodynamic control was possible. Per-protocol analysis showed that rebleeding occurred in a smaller proportion of the 32 responders (18%) than in nonresponders who received variceal band ligation (31%) (P = .06). Fifteen patients from the medical group (16%) underwent TIPS placement during follow-up evaluation, mainly for refractory ascites. Survival time and quality of life did not differ between both randomized groups. CONCLUSIONS Placement of a small-diameter, covered TIPS was straightforward and prevented variceal rebleeding in patients with Child A or B cirrhosis more effectively than drugs, which often required step-by-step therapy. However, TIPS did not increase survival time or quality of life and produced slightly more adverse events. Clinical Trial no: ISRCTN 16334693.

Incorporating indocyanin green clearance into the Model for End Stage Liver Disease (MELD-ICG) improves prognostic accuracy in intermediate to advanced cirrhosis

Background The Model for End Stage Liver Disease (MELD) predicts mortality in end stage liver disease. Incorporation of serum sodium into the MELD may improve diagnostic accuracy in decompensated patients with ascites. However, other complications of cirrhosis are not reflected. This study investigates whether quantitative liver function tests predict survival and increase prognostic accuracy of the MELD. Methods 604 patients with suspected cirrhosis were staged clinically and haemodynamically. Galactose-elimination-capacity, sorbitol clearance, lidocaine metabolism and indocyanin green (ICG) half life were determined. Survival was the primary end point of the study. Prognostic effects of individual parameters were calculated using Cox regression models and ROC curves. Results 321 patients on standard pharmacological and endoscopic treatment (PET) and 74 patients undergoing transjugular portosystemic shunting (TIPS) were studied. Of all quantitative liver function tests, ICG half life was the most accurate in predicting survival. Upon incorporation into the MELD, it modified the score in patients with PET up to 35 points. Clinically relevant changes to the score, however, occurred in patients with a MELD score between 10 and 30, allowing an objective prognostic discrimination of individual survival based on laboratory liver function and blood flow. The MELD-ICG was validated in the second cohort of patients undergoing TIPS implantation. Conclusion ICG had the highest predictive value of the examined tests. Its incorporation into the MELD adds an estimation of liver blood flow and renders the new score MELD-ICG more accurate in predicting survival in intermediate to advanced cirrhosis than the MELD and MELD-Na.

Comparison of balloon vs. straight catheter for the measurement of portal hypertension

Aliment Pharmacol Ther 2010; 32: 1351–1356

13C-Methacetin metabolism in patients with cirrhosis: relation to disease severity, haemoglobin content and oxygen supply

Background:  Hypoxia may contribute to impairment of liver function and thus interfere with results of liver tests. In patients with cirrhosis, cytochrome P‐450 mediated metabolism of substrates is facilitated in the presence of supplemental oxygen. It has not been studied how this relates to liver function and haemoglobin content.

Comparison of balloon versus straight catheter for measurement of portal hypertension

Aliment Pharmacol Ther 2010; 32: 1351–1356

The phosphodiesterase-5-inhibitor udenafil lowers portal pressure in compensated preascitic liver cirrhosis. A dose-finding phase-II-study

BACKGROUND Phosphodiesterase-5-inhibitors may lower portal pressure. AIMS To investigate the effect of the phosphodiesterase-5-inhibitor udenafil on hepatic and systemic haemodynamics in liver cirrhosis. METHODS In an open-label phase-II-study, patients with liver cirrhosis Child A/B and hepatic venous pressure-gradient ≥ 12 mmHg received 12.5mg/day, 25mg/day, 50mg/day, 75 mg/day (n = 5, each), or 100mg/day (n = 10) udenafil p.o. for one week. On days 0 and 6, hepatic venous pressure-gradient was measured prior to and one hour after drug ingestion. Endpoints were reduction of hepatic venous pressure-gradient from day 0 pre to day 6 post intake and reduction in the acute setting. Pharmacokinetics were measured in the two lowest dosage groups. RESULTS Combining the 75 and 100mg/day groups hepatic venous pressure-gradient reduction after drug intake was 19.9% (p = 0.0006) on day 0. From day 0 pre-dose to day 6 post-dose hepatic venous pressure-gradient decreased by 15.7% (p = 0.040) and in 5/15 patients by ≥ 20% or to <12 mmHg. In the 100mg/day group, mean arterial pressure decreased from 98.9 mmHg by 6.2 mmHg (p = 0.037) from day 0 pre-dose to day 6 post-dose. Heart rates or electrocardiograms were unchanged. Udenafil was eliminated with t1/2 = 25 h. CONCLUSIONS Oral application of 75-100mg of the phosphodiesterase-5-inhibitor udenafil lowers portal pressure in the acute setting by about 20% without relevant systemic cardiovascular side effects.