Beate Appenrodt

Early Use of TIPS in Patients with Cirrhosis and Variceal Bleeding

BACKGROUNDnPatients 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.nnnMETHODSnWe 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).nnnRESULTSnDuring 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.nnnCONCLUSIONSnIn 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.)

A Randomized, Prospective, Double-Blind, Placebo-Controlled Trial of Terlipressin for Type 1 Hepatorenal Syndrome

BACKGROUND & AIMSnHepatorenal syndrome (HRS) type 1 is a progressive functional renal failure in subjects with advanced liver disease. The aim of this study was to evaluate the efficacy and safety of terlipressin, a systemic arterial vasoconstrictor, for cirrhosis type 1 HRS.nnnMETHODSnA prospective, randomized, double-blind, placebo-controlled clinical trial of terlipressin was performed. Subjects with type 1 HRS were randomized to terlipressin (1 mg intravenously every 6 hours) or placebo plus albumin in both groups. The dose was doubled on day 4 if the serum creatinine (SCr) level did not decrease by 30% of baseline. Treatment was continued to day 14 unless treatment success, death, dialysis, or transplantation occurred. Treatment success was defined by a decrease in SCr level to </=1.5 mg/dL for at least 48 hours by day 14 without dialysis, death, or relapse of HRS type 1.nnnRESULTSnFifty-six subjects were randomized to each arm. Treatment success with terlipressin was double that with placebo (25% vs 12.5%, P = .093). SCr level improved from baseline to day 14 on terlipressin (-0.7 mg/dL) as compared with placebo (0 mg/dL), P < .009. Terlipressin was superior to placebo for HRS reversal (34% vs 13%, P = .008), defined by decrease in SCr level </=1.5 mg/dL. Overall and transplantation-free survival was similar between study groups; HRS reversal significantly improved survival at day 180. One nonfatal myocardial infarction occurred with terlipressin, but the total adverse event rate was similar to placebo.nnnCONCLUSIONSnTerlipressin is an effective treatment to improve renal function in HRS type 1.

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

BACKGROUND & AIMSnIn 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.nnnMETHODSnWe 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).nnnRESULTSnPatients 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.nnnCONCLUSIONSnThis study supports the early use of TIPS in patients with cirrhosis and a high-risk variceal bleeding.

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

BACKGROUND & AIMSnPatients 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.nnnMETHODSnWe 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.nnnRESULTSnA 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.nnnCONCLUSIONSnPlacement 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.

Prognostic factors for patients with cirrhosis and kidney dysfunction in the era of MELD: results of a prospective study

Abstract: Background/Aim: Hepatorenal syndrome (HRS) is associated with a poor prognosis. The incidence and prognostic impact of kidney dysfunction due to other causes in cirrhotic patients are less well known. The current study prospectively evaluated the incidence and the prognostic relevance of different etiologies of kidney failure in cirrhotic patients.

Impact of liver transplantation on the survival of patients treated for hepatorenal syndrome type 1.

The development of hepatorenal syndrome type 1 (HRS1) is associated with a poor prognosis. Liver transplantation improves this prognosis, but the degree of the improvement is unclear. Most patients receive vasoconstrictors such as terlipressin before transplantation, and this may affect the posttransplant outcomes. We examined a cohort of patients with access to liver transplantation from our previously published study of terlipressin plus albumin versus albumin alone in the treatment of HRS1. The purpose of this analysis was the quantification of the survival benefits of liver transplantation for patients with HRS1. Ninety‐nine patients were randomized to terlipressin or placebo. Thirty‐five patients (35%) received a liver transplant. Among those receiving terlipressin plus albumin, the 180‐day survival rates were 100% for transplant patients and 34% for nontransplant patients; among those receiving only albumin, the rates were 94% for transplant patients and 17% for nontransplant patients. The survival rate was significantly better for those achieving a reversal of hepatorenal syndrome (HRS) versus those not achieving a reversal (47% versus 4%, P < 0.001), but it was significantly lower for the responders versus those undergoing liver transplantation (97%). We conclude that the use of terlipressin plus albumin has no significant impact on posttransplant survival. Liver transplantation offers a clear survival benefit to HRS1 patients regardless of the therapy that they receive or the success or failure of HRS reversal. The most likely benefit of terlipressin in patients undergoing liver transplantation for HRS1 is improved pretransplant renal function, and this should make the posttransplant management of this difficult group of patients easier. For patients not undergoing transplantation, HRS reversal with terlipressin and/or albumin improves survival. Liver Transpl 17:1328–1332, 2011.

Prevention of paracentesis‐induced circulatory dysfunction: midodrine vs albumin. A randomized pilot study

Background/Aims: Large‐volume paracentesis in patients with cirrhosis and ascites induces arterial vasodilatation and decreases effective arterial blood volume, termed paracentesis‐induced circulatory dysfunction (PICD), which can be prevented by costly intravenous albumin. Vasoconstrictors, e.g. terlipressin, may also prevent PICD. The aim was to compare the less expensive vasoconstrictor midodrine, an α‐adrenoceptor agonist, with albumin in preventing PICD.

Endotoxin and tumor necrosis factor-receptor levels in portal and hepatic vein of patients with alcoholic liver cirrhosis receiving elective transjugular intrahepatic portosystemic shunt.

Background/aims In cirrhosis portal hypertension can promote bacterial translocation and increase serum endotoxin levels. Vice versa, endotoxin aggravates portal hypertension by induction of systemic and splanchnic vasodilation, and by triggering hepatic inflammatory response via tumor necrosis factor &agr; (TNF&agr;). However, the hepatic elimination of endotoxin in cirrhotic patients with severe portal hypertension, in the absence of acute complications, has not been investigated so far. Methods Twenty patients with alcoholic liver cirrhosis received transjugular intrahepatic portosystemic shunt at an event-free interval for either refractory ascites or recurrent bleeding. During the transjugular intrahepatic portosystemic shunt procedure portal and hepatic venous blood samples were obtained and endotoxin levels were measured by a chromogenic limulus-assay. In 16 of these patients an enzyme-linked immunosorbent assay was used to measure levels of the soluble TNF&agr;-receptors sTNF-R55 and sTNF-R75. Results Portal venous endotoxin levels correlated with portal vein velocity (P=0.03) and arterial systolic blood pressure (P=0.007). Portal endotoxin levels correlated with portal venous sTNF-R75-levels (P=0.039; r=0.521) and hepatic venous sTNF-R55-levels (P=0.009; r=0.669). Hepatic venous levels of both sTNF-R55 and sTNF-R75 correlated directly with the model for end-stage liver disease-score, and inversely with cholinesterase. However, we did not find significant differences in endotoxin levels nor in sTNF-R55-levels and sTNF-R75-levels between portal and hepatic venous blood. Conclusion Endotoxin levels correlated with hemodynamic derangement in cirrhotic severe portal hypertension, and with levels of soluble TNF&agr;-receptors. Soluble TNF&agr;-receptor levels correlated with the severity of liver dysfunction. However, in this study an endotoxin concentration gradient across the liver was absent, suggesting negligible primary hepatic endotoxin elimination in the absence of complications.

Severe respiratory failure due to diffuse alveolar hemorrhage: Clinical characteristics and outcome of intensive care

BACKGROUNDnThe aim of this study was to characterize patients and report outcome of diffuse alveolar hemorrhage (DAH) requiring intensive care unit support.nnnPATIENTS AND METHODSnThirty-seven patients were identified. Clinical characteristics and outcome were determined by chart review.nnnRESULTSnEighty-nine percent of patients presented with shortness of breath, 23% with cough, and 3% with hemoptysis. In 9% of patients, a diagnosis of DAH was suspected on admission. Diagnosis was confirmed by finding a progressively hemorrhagic bronchoalveolar lavage fluid in 89% and by a positive iron stain in 11% of patients. Vasculitis was causative in 19%, drug toxicity in 11%, thrombocytopenia in 27%, stem-cell transplantation in 5%, sepsis-associated lung injury in 22%, and unknown mechanisms in 16%. Thirty-two patients were mechanically ventilated, 4 received noninvasive ventilation, and 1 received supplemental oxygen therapy. Overall, 18 (49%) of 37 patients survived the intensive care unit stay. Survival was markedly different between patients with an immunologic/unknown etiology (82%) and patients with thrombocytopenia and/or sepsis (22%).nnnDISCUSSIONnDiffuse alveolar hemorrhage should be considered in all patients with persistent pulmonary infiltrates. Both bronchoalveolar lavage fluid and iron stain are mandatory diagnostic means. Patients with an immunologic/idiopathic pathogenetic mechanism have a relatively good prognosis, whereas the outcome in individuals with DAH secondary to cancer therapy or sepsis is poor.

Is detection of bacterial DNA in ascitic fluid of clinical relevance

Background In patients with cirrhosis, bacterial DNA has been found in ascites reflecting bacterial translocation. However, the clinical relevance of this finding is ill-defined especially compared with the standard diagnostics for detection of spontaneous bacterial peritonitis (SBP). Furthermore, other DNA tests have not been sufficiently evaluated. Patients and methods We prospectively included 151 patients with cirrhosis and ascites admitted to our department. The patients were evaluated for diagnosis of SBP (polymorphonuclear count>250 cells/mm3) or finding of bacterascites, defined by positive bacterial culture from ascites. To detect bacterial species of bacterial DNA fragments in ascites, broad-range polymerase chain reaction and nucleotide sequencing analysis with the LightCycler SeptiFast Kit Mgrade were performed. Routine parameters were correlated with these findings. Results Eighteen of 151 patients (12%) had SBP according to the classic definition. Bacterial DNA was detected in five of these 18 patients (3%), whereas in 13 patients (9%), bacterial DNA was detected without standard SBP. Seven patients (5%) had culture-positive SBP, only in two of them bacterial DNA was detected. In multivariate analysis, C-reactive protein (P=0.000), white blood cell count (P=0.019), and lactic acid dehydrogenase in ascites (P=0.000) were independently associated with SBP. In the DNA-positive ascites group, none of the assessed parameters was significantly associated with the bacterial DNA positivity. Conclusion We found no correlation between detection of bacterial DNA in ascites and SBP (polymorphonuclear count>250/mm3). In contrast to the patients with bacterial DNA in ascites, patients with SBP showed clinical signs of infection. This study provides no evidence that detection of bacterial DNA in ascites of patients with liver cirrhosis is of clinical or diagnostic relevance when using the panel of LightCycler SeptiFast Kit Mgrade.