Predictors of the need for necrosectomy in patients with walled-off pancreatic necrosis treated with lumen apposition metal stents.

BACKGROUND AND AIMS: Endoscopic necrosectomy through lumen apposition metal stents (LAMS) is increasingly being used for complicated walled-off pancreatic necrosis (WOPN), but the need for necrosectomy after stent placement is not well understood. The aim of this study was to evaluate clinical, endoscopic, and radiologic predictors of the need for necrosectomy in patients treated with LAMS. METHODS: We retrospectively reviewed patients with WOPN treated with LAMS from 2014 to 2017. Necrosectomy was performed only in patients who had recurrent fever or hemodynamic instability during follow-up. Univariate and multivariate analyses were performed. RESULTS: We included 15 patients, 67% men and median age was 75 (54-76) years. Two (13%) presented adverse events, one immediate and one delayed. In the first case, the stent migrated to the gastric cavity during deployment but was relocated in the same procedure. In the second case, the patient presented bleeding on day 36 due to a pseudoaneurysm that was successfully treated with embolization. Clinical success was 100%, but five patients (33%) required endoscopic necrosectomy (4 mechanical and 1 irrigation) and one (7%) required surgical necrosectomy of distant collections. The percentage of necrosis in the collection detected in a previous CT scan (45 [35-66]% vs 10 [5-17]%) was the only factor to predict the need for necrosectomy in the multivariate analysis (OR 1.18 [1.01-1.39]). CONCLUSION: LAMS is efficient to treat WOPN but more than a third will need necrosectomy. The percentage of necrosis in the collection detected in the CT scan seems to predict the need for necrosectomy.

Chronic pancreatitis for the clinician. Part 1: Etiology and diagnosis. Interdisciplinary position paper of the Societat Catalana de Digestologia and the Societat Catalana de Pàncrees. / Pancreatitis crónica para el clínico. Parte 1: etiología y diagnóstico. Documento de posicionamiento interdisciplinar de la Societat Catalana de Digestologia y la Societat Catalana de Pàncrees.

Chronic pancreatitis is a chronic fibroinflammatory disease of the pancreas with prevalence around 50 cases per 100,000 inhabitants. It appears to originate from diverse and yet mixed etiological factors. It shows highly variable presenting features, complication types and disease progression rates. Treatment options are as wide as the multiple personalized scenarios the disease might exhibit at a given time point. Some medical societies have developed guidelines for diagnosis and treatment based on scientific evidence. Although these efforts are to be acknowledged, the gathered level of evidence for any topic is usually low and, therefore, recommendations tend to be vague or weak. In the present series of position papers on chronic pancreatitis from the Societat Catalana de Digestologia and the Societat Catalana de Pàncrees we aimed at providing defined position statements for the clinician based on updated review of published literature and on interdisciplinary expert agreement. The final goal is to propose the use of common terminology and rational diagnostic/therapeutic circuits based on current knowledge. To this end 51 sections related to chronic pancreatitis were reviewed by 21 specialists from 6 different fields to generate 88 statements altogether. Statements were designed to harmonize concepts or delineate recommendations. Part 1 of this paper series discusses topics on aetiology and diagnosis of chronic pancreatitis. Main clinical features are abdominal pain, exocrine and endocrine insufficiency and symptoms derived from complications. Some patients remain symptom-free. Diagnosis (definitive, probable or uncertain) should be based on objective data obtained from imaging, histology, or functional tests.

Chronic pancreatitis for the clinician. Part 2: Treatment and follow-up. Interdisciplinary Position Paper of the Societat Catalana de Digestologia and the Societat Catalana de Pàncrees. / Pancreatitis crónica para el clínico. Parte 2: Tratamiento y seguimiento. Documento de posicionamiento interdisciplinar de la Societat Catalana de Digestologia y la Societat Catalana de Pàncrees.

Chronic pancreatitis is associated with impaired quality of life, high incidence of comorbidities, serious complications and mortality. Healthcare costs are exorbitant. Some medical societies have developed guidelines for treatment based on scientific evidence, but the gathered level of evidence for any individual topic is usually low and, therefore, recommendations tend to be vague or weak. In the present position papers on chronic pancreatitis from the Societat Catalana de Digestologia and the Societat Catalana de Pàncrees we aimed at providing defined position statements for the clinician based on updated review of published literature and on multidisciplinary expert agreement. The final goal is to propose the use of common terminology and rational diagnostic/therapeutic circuits based on current knowledge. To this end 51 sections related to chronic pancreatitis were reviewed by 21 specialists from 6 different fields to generate 88 statements altogether. Statements were designed to harmonize concepts or delineate recommendations. Part 2 of these paper series discuss topics on treatment and follow-up. The therapeutic approach should include assessment of etiological factors, clinical manifestations and complications. The complexity of these patients advocates for detailed evaluation in multidisciplinary committees where conservative, endoscopic, interventional radiology or surgical options are weighed. Specialized multidisciplinary units of Pancreatology should be constituted. Indications for surgery are refractory pain, local complications, and suspicion of malignancy. Enzyme replacement therapy is indicated if evidence of exocrine insufficiency or after pancreatic surgery. Response should be evaluated by nutritional parameters and assessment of symptoms. A follow-up program should be planned for every patient with chronic pancreatitis.

Antibiotic Prophylaxis Is Not Required for Endoscopic Ultrasonography-Guided Fine-Needle Aspiration of Pancreatic Cystic Lesions, Based on a Randomized Trial.

BACKGROUND & AIMS: Guidelines recommend routine antibiotic prophylaxis for patients undergoing endoscopic ultrasonography-guided fine needle aspiration (EUS-FNA) of pancreatic cysts, but there is conflicting evidence for its necessity. We investigated whether performing the procedure without antimicrobial prophylaxis increases the incidence of infection. METHODS: We performed a multicenter, randomized, noninferiority trial to compare prophylaxis with ciprofloxacin vs placebo in patients with a pancreatic cyst requiring EUS-FNA at multiple centers in Spain. From September 2014 to June 2018, patients were randomly assigned to groups that received the prophylaxis with ciprofloxacin (n = 112) or saline solution (n = 114, placebo). We recorded patients' demographic data, lesion characteristics, and procedure data and followed patients for 21 days. A total of 205 patients completed the trial (90.7%), receiving ciprofloxacin or the control, with no statistically significant differences in demographics, baseline data, or procedure characteristics between groups. The primary outcome was FNA-related infection. Secondary outcomes were incidence of fever, procedure complications, and medication-related adverse events. RESULTS: The only case of FNA-related infection (0.44%) occurred in a patient in the placebo group (0.87%); this patient developed acute pancreatitis and bacteremia after the procedure. Prevention of infection was not inferior in the control group; the difference between proportions was 0.87% (95% confidence interval, -0.84% to 2.59%). There were no differences between groups in fever (2 patients in each group: 1.78% vs 1.76%; P = 1.00) or other adverse events. CONCLUSIONS: In a randomized trial of patients undergoing EUS-FNA for pancreatic cyst evaluation, we found the risk of infection to be low. The incidence of infections did not differ significantly with vs without ciprofloxacin prophylaxis. (ClinicalTrials.gov, Number: NCT02261896).

Short-term hemodynamic effects of ß-blockers influence survival of patients with decompensated cirrhosis.

BACKGROUND & AIMS: Whether the effect of ß-blockers on arterial pressure and/or cardiac function may offset the benefit of reducing portal pressure in advanced cirrhosis is controversial. Herein, we aimed to evaluate the systemic and splanchnic hemodynamic effects of ß-blockers in decompensated vs. compensated cirrhosis and to investigate the influence of systemic hemodynamic changes on survival times in decompensated cirrhosis. METHODS: Patients with cirrhosis and high-risk esophageal varices, without previous bleeding, were consecutively included and grouped according to the presence or absence of decompensation (ascites with or without overt encephalopathy). Systemic and hepatic hemodynamic measurements were performed before starting ß-blockers and again after 1 to 3 months of treatment (short-term). RESULTS: Four hundred and three patients were included (190 decompensated and 213 compensated). At baseline, decompensated patients had higher portal pressure than compensated patients and were more hyperdynamic, with higher cardiac output (CO) and lower arterial pressure. Under ß-blockers, decompensated patients had lower portal pressure decrease (10 ± 18% vs. 15 ± 12%; p <0.05) and had greater reductions in heart rate (p <0.001) and CO (17 ± 15% vs. 10 ± 21%; p <0.01). Among patients with decompensated cirrhosis, those who died had a greater decrease in CO with ß-blockers than survivors (21 ± 14% vs. 15 ± 16%; p <0.05) and CO under ß-blockers independently predicted death by competing-risk regression analysis, with good diagnostic accuracy (C-index 0.74; 95% CI 0.66-0.83). Death risk was higher in decompensated patients with CO <5 L/min vs. CO ≥5 L/min (subdistribution hazard ratio 0.44; 95% CI 0.25-0.77; p = 0.004). CONCLUSIONS: In patients with high-risk varices treated to prevent first bleeding, the systemic hemodynamic response to ß-blockers is greater and the portal pressure decrease is smaller in those with decompensated cirrhosis. The short-term effect of ß-blockers on CO might adversely influence survival in decompensated cirrhosis. LAY SUMMARY: ß-blockers are often used to reduce the risk of variceal bleeding in patients with cirrhosis. However, it is not known whether the effect of ß-blockers on arterial pressure and/or cardiac function may offset the benefit of reducing portal pressure. Herein, we show that in patients with decompensated cirrhosis the potentially detrimental systemic effects of ß-blockers are greater than in compensated patients, while the beneficial pressure lowering effects are reduced. The short-term effect of ß-blockers on cardiac output may adversely influence survival in patients with decompensated cirrhosis.

A randomized trial to assess whether portal pressure guided therapy to prevent variceal rebleeding improves survival in cirrhosis.

Monitoring the hemodynamic response of portal pressure (PP) to drug therapy accurately stratifies the risk of variceal rebleeding (VRB). We assessed whether guiding therapy with hepatic venous pressure gradient (HVPG) monitoring may improve survival by preventing VRB. Patients with cirrhosis with controlled variceal bleeding were randomized to an HVPG-guided therapy group (N = 84) or to a control group (N = 86). In both groups, HVPG and acute ß-blocker response were evaluated at baseline and HVPG measurements were repeated at 2-4 weeks to determine chronic response. In the HVPG-guided group, acute responders were treated with nadolol and acute nonresponders with nadolol+nitrates. Chronic nonresponders received nadolol+prazosin and had a third HVPG study. Ligation sessions were repeated until response was achieved. The control group was treated with nadolol+nitrates+ligation. Between-group baseline characteristics were similar. During long-term follow-up (median of 24 months), mortality was lower in the HVPG-guided therapy group than in the control group (29% vs. 43%; hazard ratio [HR] = 0.59; 95% confidence interval [CI] = 0.35-0.99). Rebleeding occurred in 19% versus 31% of patients, respectively (HR = 0.53; 95% CI = 0.29-0.98), and further decompensation of cirrhosis occurred in 52% versus 72% (HR = 0.68; 95% CI = 0.46-0.99). The survival probability was higher with HVPG-guided therapy than in controls, both in acute (HR = 0.59; 95% CI = 0.32-1.08) and chronic nonresponders (HR = 0.48; 95% CI = 0.23-0.99). HVPG-guided patients had a greater reduction of HVPG and a lower final value than controls (P < 0.05). CONCLUSION: HVPG monitoring, by stratifying risk and targeting therapy, improves the survival achieved with currently recommended treatment to prevent VRB using ß-blockers and ligation. HVPG-guided therapy achieved a greater reduction in PP, which may have contributed to reduce the risk of rebleeding and of further decompensation of cirrhosis, thus contributing to a better survival. (Hepatology 2017;65:1693-1707).

Optimal timing for a second ERCP after failure of initial biliary cannulation following precut sphincterotomy: an analysis of experience at two tertiary centers.

BACKGROUND AND STUDY AIMS: Precut sphincterotomy increases the success of deep biliary cannulation, but the method fails at the initial ERCP in 5-12% of cases. Although other invasive strategies are often used to access the bile duct, a second ERCP may be effective and safe. We evaluated the efficacy, safety, and factors related to a second ERCP after failed cannulation using a precut sphincterotomy. PATIENTS AND METHODS: We reviewed all patients that underwent an ERCP with native papilla from 2006 to 2014 at two tertiary institutions. Efficacy was based on the cannulation rate of the second ERCP, and safety was assessed in terms of adverse events. RESULTS: We identified 112 patients with failed cannulation after precut, and a second ERCP was performed in 72 (64.3%). Median time between procedures was 7 days (IQR 5-11). Deep cannulation was achieved in 54 cases (75%). The only factor associated with cannulation failure was an ERCP within 4 days after the initial precut (cannulation success 44.4 vs. 79.4% after 4 days, p = 0.026). Adverse events were recorded after the first ERCP in 13 of 112 patients (11.8%): delayed bleeding in four, pancreatitis in five, and perforation in four. After the second ERCP, three of 72 patients (4.2%) presented adverse events: two delayed bleeding and one pancreatitis. CONCLUSIONS: A second ERCP after failure of initial biliary cannulation following precut appears to be safe and effective. A second ERCP should be delayed at least 4 days if feasible.

Transfusion strategies for acute upper gastrointestinal bleeding.

BACKGROUND: The hemoglobin threshold for transfusion of red cells in patients with acute gastrointestinal bleeding is controversial. We compared the efficacy and safety of a restrictive transfusion strategy with those of a liberal transfusion strategy. METHODS: We enrolled 921 patients with severe acute upper gastrointestinal bleeding and randomly assigned 461 of them to a restrictive strategy (transfusion when the hemoglobin level fell below 7 g per deciliter) and 460 to a liberal strategy (transfusion when the hemoglobin fell below 9 g per deciliter). Randomization was stratified according to the presence or absence of liver cirrhosis. RESULTS: A total of 225 patients assigned to the restrictive strategy (51%), as compared with 61 assigned to the liberal strategy (14%), did not receive transfusions (P<0.001) [corrected].The probability of survival at 6 weeks was higher in the restrictive-strategy group than in the liberal-strategy group (95% vs. 91%; hazard ratio for death with restrictive strategy, 0.55; 95% confidence interval [CI], 0.33 to 0.92; P=0.02). Further bleeding occurred in 10% of the patients in the restrictive-strategy group as compared with 16% of the patients in the liberal-strategy group (P=0.01), and adverse events occurred in 40% as compared with 48% (P=0.02). The probability of survival was slightly higher with the restrictive strategy than with the liberal strategy in the subgroup of patients who had bleeding associated with a peptic ulcer (hazard ratio, 0.70; 95% CI, 0.26 to 1.25) and was significantly higher in the subgroup of patients with cirrhosis and Child-Pugh class A or B disease (hazard ratio, 0.30; 95% CI, 0.11 to 0.85), but not in those with cirrhosis and Child-Pugh class C disease (hazard ratio, 1.04; 95% CI, 0.45 to 2.37). Within the first 5 days, the portal-pressure gradient increased significantly in patients assigned to the liberal strategy (P=0.03) but not in those assigned to the restrictive strategy. CONCLUSIONS: As compared with a liberal transfusion strategy, a restrictive strategy significantly improved outcomes in patients with acute upper gastrointestinal bleeding. (Funded by Fundació Investigació Sant Pau; ClinicalTrials.gov number, NCT00414713.).

Clinical Course of acute-on-chronic liver failure syndrome and effects on prognosis.

UNLABELLED: Acute-on-chronic liver failure (ACLF) is characterized by acute decompensation (AD) of cirrhosis, organ failure(s), and high 28-day mortality. We investigated whether assessments of patients at specific time points predicted their need for liver transplantation (LT) or the potential futility of their care. We assessed clinical courses of 388 patients who had ACLF at enrollment, from February through September 2011, or during early (28-day) follow-up of the prospective multicenter European Chronic Liver Failure (CLIF) ACLF in Cirrhosis study. We assessed ACLF grades at different time points to define disease resolution, improvement, worsening, or steady or fluctuating course. ACLF resolved or improved in 49.2%, had a steady or fluctuating course in 30.4%, and worsened in 20.4%. The 28-day transplant-free mortality was low-to-moderate (6%-18%) in patients with nonsevere early course (final no ACLF or ACLF-1) and high-to-very high (42%-92%) in those with severe early course (final ACLF-2 or -3) independently of initial grades. Independent predictors of course severity were CLIF Consortium ACLF score (CLIF-C ACLFs) and presence of liver failure (total bilirubin ≥12 mg/dL) at ACLF diagnosis. Eighty-one percent had their final ACLF grade at 1 week, resulting in accurate prediction of short- (28-day) and mid-term (90-day) mortality by ACLF grade at 3-7 days. Among patients that underwent early LT, 75% survived for at least 1 year. Among patients with ≥4 organ failures, or CLIF-C ACLFs >64 at days 3-7 days, and did not undergo LT, mortality was 100% by 28 days. CONCLUSIONS: Assessment of ACLF patients at 3-7 days of the syndrome provides a tool to define the emergency of LT and a rational basis for intensive care discontinuation owing to futility.

Relative adrenal insufficiency in severe acute variceal and non-variceal bleeding: influence on outcomes.

BACKGROUND & AIMS: Relative adrenal insufficiency (RAI) is common in critical illness and in cirrhosis, and is related with worse outcomes. The prevalence of RAI may be different in variceal and non-variceal bleeding and whether it may influence outcomes in these settings is unclear. This study assesses RAI and its prognostic implications in cirrhosis with variceal bleeding and in peptic ulcer bleeding. METHODS: Patients with severe bleeding (systolic pressure <100 mmHg and/or haemoglobin <8 g/L) from oesophageal varices or from a peptic ulcer were included. Adrenal function was evaluated within the first 24 h and RAI was diagnosed as delta cortisol <250 nmol/L after 250 µg of i.v. corticotropin. RESULTS: Sixty-two patients were included, 36 had cirrhosis and variceal bleeding and 26 without cirrhosis had ulcer bleeding. Overall, 15 patients (24%) had RAI, 8 (22%) with variceal and 7 (24%) with ulcer bleeding. Patients with RAI had higher rate of bacterial infections. Baseline serum and salivary cortisol were higher in patients with RAI (P < 0.001) while delta cortisol was lower (P < 0.001). There was a good correlation between plasma and salivary cortisol (P < 0.001). The probability of 45-days survival without further bleeding was lower in cirrhotic patients with variceal bleeding and RAI than in those without RAI (25% vs 68%, P = 0.02), but not in non-cirrhotic patients with peptic ulcer bleeding with or without RAI (P = 0.75). CONCLUSION: The prevalence of RAI is similar in ulcer bleeding and in cirrhosis with variceal bleeding. Cirrhotic patients with RAI, but not those with bleeding ulcers, have worse prognosis.

Role of albumin treatment in patients with spontaneous bacterial peritonitis.

BACKGROUND & AIMS: Intravenous administration of albumin decreases the incidence of renal failure and mortality among patients with spontaneous bacterial peritonitis (SBP). However, it is unclear whether it should be given to all patients with SBP; we evaluated its efficacy. METHODS: We analyzed data from all episodes of SBP (n = 216) during a 7-year period that occurred in a nonselected series of 167 patients with cirrhosis. Low-risk episodes (urea <11 mmol/L and bilirubin <68 µmol/L) were not treated with albumin, whereas high-risk episodes (urea >11 mmol/L and/or bilirubin >68 µmol/L) were or were not given albumin at the discretion of the attending physician. RESULTS: Sixty-four episodes of SBP (29.6%) were low risk and not treated with albumin, whereas 152 (70.4%) were high risk; 73 of these (48%) were treated with albumin and 79 (52%) were not. Renal failure before SBP resolution was less frequent after low-risk episodes than high-risk episodes (4.7% versus 25.6%; P = .001), in-hospital mortality was lower (3.1% versus 38.2%; P < .001), and the 3-month probability of survival was higher (93% versus 53%; P < .001). In an analysis of only the high-risk group, patients who received albumin had lower in-hospital mortality than those not treated with albumin (28.8% versus 46.8%; P = .02) and a greater 3-month probability of survival (62% versus 45%; P = .01). CONCLUSIONS: Albumin therapy increases survival of patients who have high-risk episodes of SBP, although it does not seem to be necessary for patients with low risk of death.

Partially covered self-expanding metal stent for unresectable malignant extrahepatic biliary obstruction: results of a large prospective series.

BACKGROUND: Endoscopic biliary stenting is a well-established palliative treatment in patients with unresectable malignant biliary strictures. Obstruction of uncovered self-expanding metal stent (SEMS) due to tumor ingrowth is the most frequent complication. Partially covered SEMS might increase stent patency but could favor complications related to stent covering, such as pancreatitis, cholecystitis, and migration. The aim of this study was to evaluate the efficacy and safety of partially covered SEMS in patients with an unresectable malignant biliary stricture. METHODS: Patients with malignant extrahepatic biliary obstruction treated endoscopically with partially covered SEMS were included in this multicenter, prospective, nonrandomized study. RESULTS: One hundred ninety-nine patients were endoscopically treated with partially covered SEMS in 32 Spanish hospitals. Clinical success after deep cannulation was 96%. Early complications occurred in 4% (3 pancreatitis, 2 cholangitis, 1 hemorrhage, 1 perforation, and 1 cholecystitis). Late complications occurred in 19.5% (18 obstructions, 10 migrations, 6 cholangitis without obstruction, 3 acute cholecystitis, and 2 pancreatitis), with no tumor ingrowth in any case. Median stent patency was 138.9 ± 112.6 days. One-year actuarial probability of stent patency was 70% and that of nonmigration was 86%. Multivariate analysis showed adjuvant radio- or chemotherapy as the only independent predictive factor of stent patency and previous insertion of a biliary stent was the only predictive factor of migration. CONCLUSIONS: The partially covered SEMS was easily inserted, had a high clinical success rate, and prevented tumor ingrowth. The incidence of possible complications related to stent coverage, namely, migration, pancreatitis, and cholecystitis, was lower than in previously published series.

Chronic pancreatitis for the clinician. Complications and special forms of the disease. Interdisciplinary position paper of the Catalan Society of Digestology (SCD) and the Catalan Pancreatic Society (SCPanc).

Chronic pancreatitis tends to develop a number of complications that may constitute the form of presentation of the disease. Some societies have issued guidelines for diagnosis and treatment of chronic pancreatitis complications, but the level of evidence for any topic is usually low and recommendations tend to be weak. We aimed at providing defined position statements for the clinician based on updated review of published literature and on multidisciplinary expert agreement. The goal was to propose defined terminology and rational diagnostic/therapeutic circuits based on current knowledge. To this end 14 sections related to complications and special forms of chronic pancreatitis (early chronic, groove and autoimmune pancreatitis) were reviewed by 21 specialists from 6 different fields to generate 32 statements. Featured statements assert common bile duct stenosis does not require invasive treatment (endoscopic or surgical) unless cholestasis, cholangitis, lithiasis or other symptoms develop. Pancreatic duct strictures and calculi should be approached (after ruling out malignancy) if causing pain, pancreatitis, pseudocysts or other complications. Treatment of symptomatic pseudocysts must be individualized, considering associated main duct stenosis, vascular and pericystic complications. Higher risk conditions for pancreatic cancer are advance age, smoking, genetic background, recent diagnosis of chronic pancreatitis or diabetes, and appearance of new symptoms. Groove pancreatitis can initially be treated with conservative measures. Both prednisolone or rituximab can induce remission and maintenance of autoimmune pancreatitis. Internal fistula, vascular complications, bacterial overgrowth, osteoporosis and renal lithiasis require specific therapeutic approaches.

Early rebleeding increases mortality of variecal bleeders on secondary prophylaxis with ß-blockers and ligation.

BACKGROUND/AIMS: Despite secondary-prophylaxis with ß-blockers and endoscopic-variceal-ligation rebleeding is frequent, particularly within the first-6-weeks. Early-rebleeding may have greater impact on death-risk than late rebleeding, which may affect therapy. We assessed whether the influence of rebleeding on long-term survival of patients on secondary-prophylaxis is greater in patients with early-rebleeding. METHODS: 369 patients with cirrhosis were consecutively included once recovered from first variceal-bleeding. The impact of rebleeding on survival was investigated according to whether it occurred within 6-weeks (early-rebleeding) or later (late-rebleeding). RESULTS: During 46-months of follow-up (IQR: 14-61), 45 patients (12%) had early-rebleeding, 74(20%) had late-rebleeding and 250(68%) had not rebleeding. Mortality risk was higher in early-rebleeding group vs. late-rebleeding (HR = 0.476, 95%CI = 0.318-0.712, p < 0.001) and was similar in late-rebleeding group vs. no-rebleeding (HR = 0.902, 95%CI = 0.749-1.086, p = 0.271). Adjusting for baseline risk-factors, early-rebleeding was independently associated with mortality-risk (HR = 1.58, 95%CI = 1.02-2.45; p = 0.04). Child-Pugh&MELD scores improved at 3rd-4th-week only in patients without early-rebleeding (p < 0.05). Presence of ascites or encephalopathy, MELD-score>12 and HVPG>20 mmHg identified patients at risk of early-rebleeding. CONCLUSIONS: Patients with early-rebleeding have higher risk of death than patients without rebleeding and even than those rebleeding later. Our results suggest that patients at risk of early rebleeding might benefit from preemptive therapies such as early-TIPS.

Toll-like receptor 4 polymorphisms and bacterial infections in patients with cirrhosis and ascites.

AIM: To assess the relationship between the presence of toll-like receptor 4 (TLR4) polymorphisms and bacterial infections in cirrhotic patients with ascites. METHODS: We prospectively included consecutive patients with cirrhosis and ascites hospitalized during a 6-year period. Patients with human immunodeficiency virus (HIV) infection or any other immunodeficiency, patients with advanced hepatocellular carcinoma (beyond Milan's criteria) or any other condition determining poor short-term prognosis, and patients with a permanent urinary catheter were excluded. The presence of D299G and/or T399I TLR4 polymorphisms was determined by sequencing and related to the incidence and probability of bacterial infections, other complications of cirrhosis, hepatocellular carcinoma, and mortality during follow-up. A multivariate analysis to identify predictive variables of mortality in the whole series was performed. RESULTS: We included 258 patients: 28 (10.8%) were carriers of D299G and/or T399I TLR4 polymorphisms (polymorphism group) and 230 patients were not (wild-type group). The probability of developing any bacterial infection at one-year follow-up was 78% in the polymorphism group and 69% in the wild-type group (P = 0.54). The one-year probability of presenting infections caused by gram-negative bacilli (51% vs 44%, P = 0.68), infections caused by gram-positive cocci (49% vs 40%, P = 0.53), and spontaneous bacterial peritonitis (29% vs 34%, respectively, P = 0.99) did not differ between the two groups. The one-year probability of transplant-free survival was 55% in the polymorphism group and 66% in the wild-type group (P = 0.15). Multivariate analysis confirmed that age, Child-Pugh score, active alcohol intake, previous hepatic encephalopathy, hepatocellular carcinoma and serum creatinine were associated with a higher risk of death during follow-up. CONCLUSION: Genetic polymorphisms D299G and/or T399I of TLR4 do not seem to play a relevant role in the predisposition of cirrhotic patients with ascites to bacterial infections.

Impact of ornithine phenylacetate (OCR-002) in lowering plasma ammonia after upper gastrointestinal bleeding in cirrhotic patients.

BACKGROUND: Ornithine phenylacetate (OP) has been proven effective in lowering ammonia plasma levels in animals, and to be well tolerated in cirrhotic patients. A trial to assess OP efficacy in lowering plasma ammonia levels versus placebo in cirrhotic patients after an upper gastrointestinal bleeding was performed. The primary outcome was a decrease in venous plasma ammonia at 24 hours. METHODS: A total of 38 consecutive cirrhotic patients were enrolled within 24 hours of an upper gastrointestinal bleed. Patients were randomized (1:1) to receive OP (10 g/day) or glucosaline for 5 days. RESULTS: The primary outcome was not achieved. A progressive decrease in ammonia was observed in both groups, being slightly greater in the OP group, with significant differences only at 120 hours. The subanalysis according to Child-Pugh score showed a statistically significant ammonia decrease in Child-Pugh C-treated patients at 36 hours, as well as in the time-normalized area under the curve (TN-AUC) 0-120 hours in the OP group [40.16 µmol/l (37.7-42.6); median (interquartile range) (IQR)] versus placebo group [65.5 µmol/l (54-126);p = 0.036]. A decrease in plasma glutamine levels was observed in the treated group compared with the placebo group, and was associated with the appearance of phenylacetylglutamine in urine. Adverse-event frequency was similar in both groups. No differences in hepatic encephalopathy incidence were observed. CONCLUSIONS: OP failed to significantly decrease plasma ammonia at the given doses (10 g/day). Higher doses of OP might be required in Child-Pugh A and B patients. OP appeared well tolerated.

Smoking status and response to thiopurines in steroid-dependent inflammatory bowel disease.

BACKGROUND: The influence of smoking on inflammatory bowel disease (IBD) susceptibility and on its clinical course is well known, but not its impact on drug efficacy. The aim of this study was to evaluate the response to thiopurines in patients with steroid-dependent IBD according to their smoking habits. METHODS: The medical records of 163 IBD patients (103 Crohn's disease [CD], 60 ulcerative colitis [UC]) in whom thiopurines were started because of steroid-dependency were reviewed. Therapeutic response was defined by steroid-free clinical remission for at least 6 months after 12 months of starting thiopurines. Clinical data and smoking status at diagnosis, at the time thiopurines were started, and during the follow-up were registered. RESULTS: A therapeutic response was obtained in 72% of CD and 61% of UC patients. Smoking habits did not influence the rate of response to thiopurines, the need for rescue therapies, or the development of penetrating/stricturing complications (CD) or proximal progression (UC). However, CD responders who continued smoking required new courses of steroids more often during follow-up. No influence of smoking was found when these outcomes were analyzed depending on gender or disease location. In the multivariate analysis, smoking status was the only predictive factor of drug tolerance. CONCLUSIONS: Active smoking does not influence the response to thiopurines in steroid-dependent IBD, but may decrease the likelihood of drug tolerance.