The Answer to "When to Clip" After Colorectal Endoscopic Mucosal Resection Based on a Cost-Effectiveness Analysis.

INTRODUCTION: Delayed bleeding (DB) is the most common major complication of endoscopic mucosal resection (EMR). Two randomized clinical trials recently demonstrated that clip closure after EMR of large nonpedunculated colorectal polyps (LNPCPs) reduces the risk of DB. We analyzed the cost-effectiveness of this prophylactic measure. METHODS: EMRs of LNCPCPs were consecutively registered in the ongoing prospective multicenter database of the Spanish EMR Group from May 2013 until July 2017. Patients were classified according to the Spanish Endoscopy Society EMR group (GSEED-RE2) DB risk score. Cost-effectiveness analysis was performed for both Spanish and US economic contexts. The average incremental cost-effectiveness ratio (ICER) thresholds were set at 54,000 € or $100,000 per quality-adjusted life year, respectively. RESULTS: We registered 2,263 EMRs in 2,130 patients. Applying their respective DB relative risk reductions after clip closure (51% and 59%), the DB rate decreased from 4.5% to 2.2% in the total cohort and from 13.7% to 5.7% in the high risk of the DB GSEED-RE2 subgroup. The ICERs for the universal clipping strategy in Spain and the United States, 469,706 € and $1,258,641, respectively, were not cost effective. By contrast, selective clipping in the high-risk of DB GSEED-RE2 subgroup was cost saving, with a negative ICER of -2,194 € in the Spanish context and cost effective with an ICER of $87,796 in the United States. DISCUSSION: Clip closure after EMR of large colorectal lesions is cost effective in patients with a high risk of bleeding. The GSEED-RE2 DB risk score may be a useful tool to identify that high-risk population.

Frailty in outpatients with cirrhosis: A prospective observational study.

BACKGROUND AND AIM: Frailty is increasingly recognized as a major prognostic factor in cirrhosis in addition to conventional liver insufficiency scores. The aim was to compare the prevalence and characteristics of frailty between patients with cirrhosis and controls, and to analyse its prognostic value. METHODS: We included outpatients with cirrhosis and age- and gender-matched non-cirrhotic controls. Frailty was defined according to the Fried frailty criteria. In patients with cirrhosis, we analysed the ability of the degree of frailty to predict a composite endpoint, consisting of hospitalization, admission to a long-term care centre, falls or death. RESULTS: We included 135 patients with cirrhosis and 135 controls. The prevalence of frailty was higher among patients with cirrhosis: 35 (25.9%) frail, 74 (54.8%) pre-frail and 26 (19.2%) robust vs 14 (10.4%) frail, 67 (49.6%) pre-frail and 54 (40%) robust (P < .001) in controls. This difference was mainly as a result of decreased muscle strength in patients with cirrhosis. During follow-up, frail patients with cirrhosis showed a higher probability of composite endpoint, hospitalization and falls than pre-frail and robust cirrhotic patients but mortality was similar. MELD-Na score and frailty were independent predictive factors for hospitalization, frailty for falls, and MELD-Na score and albumin for survival. Vitamin D deficiency and increased cystatin C were associated with frailty. CONCLUSIONS: Frailty was more frequent in outpatients with cirrhosis than in controls, mainly because of a decrease in muscle strength, and it could be a predictive factor for hospitalization and falls in these patients.

Clip Closure After Resection of Large Colorectal Lesions With Substantial Risk of Bleeding.

BACKGROUND & AIMS: It is not clear whether closure of mucosal defects with clips after colonic endoscopic mucosal resection (EMR) prevents delayed bleeding, although it seems to have no protective effects when risk is low. We performed a randomized trial to evaluate the efficacy of complete clip closure of large (≥2 cm) nonpedunculated colorectal lesions after EMR in patients with an estimated average or high risk of delayed bleeding. METHODS: We performed a single-blind trial at 11 hospitals in Spain from May 2016 through June 2018, including 235 consecutive patients who underwent EMR for large nonpedunculated colorectal lesions with an average or high risk of delayed bleeding (based on Spanish Endoscopy Society Endoscopic Resection Group score). Participants were randomly assigned to groups that received closure of the scar with 11-mm through-the-scope clips (treated, n = 119) or no clip (control, n = 116). The primary outcome was proportion of patients in each group with delayed bleeding, defined as evident hematochezia that required medical intervention within 15 days after colonoscopy. RESULTS: In the clip group, complete closure was achieved in 68 (57%) cases, with partial closure in 33 (28%) cases and failure to close in 18 (15%) cases. Delayed bleeding occurred in 14 (12.1%) patients in the control group and in 6 (5%) patients in the clip group (absolute risk difference, reduction of 7% in the clip group; 95% confidence interval, -14.7% to 0.3%). After completion of the clip closure, there was only 1 (1.5%) case of delayed bleeding (absolute risk difference, reduction of 10.6%; 95% confidence interval, -4.3% to 17.9%). CONCLUSIONS: In a randomized trial of patients with large nonpedunculated colorectal lesions undergoing EMR, we found that clip closure of mucosal defects in patients with a risk of bleeding can be a challenge, but also reduces delayed bleeding. Prevention of delayed bleeding required complete clip closure. ClinicalTrials.gov ID: NCT02765022.

Effect of a Multistrain Probiotic on Cognitive Function and Risk of Falls in Patients With Cirrhosis: A Randomized Trial.

Probiotics can modulate gut microbiota, intestinal permeability, and immune response and could therefore improve cognitive dysfunction and help avoid potential consequences, such as falls, in patients with cirrhosis. The aim of this study was to evaluate the effect of a multistrain probiotic on cognitive function, risk of falls, and inflammatory response in patients with cirrhosis. Consecutive outpatients with cirrhosis and cognitive dysfunction (defined by a Psychometric Hepatic Encephalopathy Score [PHES] < -4) and/or falls in the previous year were randomized to receive either a sachet of a high-concentration multistrain probiotic containing 450 billion bacteria twice daily for 12 weeks or placebo. We evaluated the changes in cognitive function (PHES); risk of falls (Timed Up and Go [TUG] test, gait speed, and incidence of falls); systemic inflammatory response; neutrophil oxidative burst; intestinal barrier integrity (serum fatty acid-binding protein 6 [FABP-6] and 2 [FABP-2] and zonulin and urinary claudin-3); bacterial translocation (lipopolysaccharide-binding protein [LBP]); and fecal microbiota. Thirty-six patients were included. Patients treated with the probiotic (n = 18) showed an improvement in the PHES (P = 0.006), TUG time (P = 0.015) and gait speed (P = 0.02), and a trend toward a lower incidence of falls during follow-up (0% compared with 22.2% in the placebo group [n = 18]; P = 0.10). In the probiotic group, we observed a decrease in C-reactive protein (P = 0.01), tumor necrosis factor alpha (P = 0.01), FABP-6 (P = 0.009), and claudin-3 (P = 0.002), and an increase in poststimulation neutrophil oxidative burst (P = 0.002). Conclusion: The multistrain probiotic improved cognitive function, risk of falls, and inflammatory response in patients with cirrhosis and cognitive dysfunction and/or previous falls.

Ascitic fluid regulates the local innate immune response of patients with cirrhosis.

Ascitic neutrophils from cirrhotic patients with spontaneous bacterial peritonitis (SBP) exhibit an impaired oxidative burst that could facilitate bacterial infection. However, the influence of the cell-free ascitic fluid of these patients on neutrophil function has not been investigated. To analyze this influence, we determined the ascitic levels of cytokines, resistin, and lactoferrin and their association with neutrophil function, disease severity score, and SBP resolution. We analyzed NETosis induction by microscopy and oxidative burst by the flow cytometry of healthy neutrophils cultured in ascitic fluid from cirrhotic patients with sterile ascites (SA) and with SBP before and after antibiotic treatment. Resistin, IL-6, IL-1 receptor antagonist, IL-1ß, and lactoferrin levels were measured in ascitic fluids and supernatants of cultured neutrophils and PBMCs by ELISA. Upon stimulation, healthy neutrophils cultured in SBP ascitic fluid produced lower NETosis and oxidative burst than those cultured in SA. Ascitic resistin levels were negatively correlated with NETosis, oxidative burst, and ascitic glucose levels; and positively correlated with the model for end-stage liver disease score. After an E. coli or TNF-α stimulus, neutrophils were the major resistin producers. Resistin indirectly reduced the oxidative burst of neutrophils and directly reduced the inflammatory phenotype of monocytes and TNF-α production. Bacterial-induced resistin production can down-regulate the inflammatory response of macrophages and neutrophil function in ascitic fluid. Consequently, this down-regulation may jeopardize the elimination of bacteria that translocate to ascitic fluid in patients with cirrhosis.

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.

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.

IL-6, IL-10 and TNFα do not improve early detection of post-endoscopic retrograde cholangiopancreatography acute pancreatitis: a prospective cohort study.

The most reliable indicators for post-ERCP acute pancreatitis are elevated amylase levels and abdominal pain 24 hours after ERCP. As ERCP is often performed on an outpatient basis, earlier diagnosis is important. We aimed to identify early predictors of post-ERCP pancreatitis. We prospectively analyzed IL-6, IL-10, TNFα, CRP, amylase and lipase before and 4 hours after ERCP, and studied their association with abdominal pain. We included 510 patients. Post-ERCP pancreatitis occurred in 36 patients (7.1%). IL-6, IL-10, TNFα and CRP were not associated with post-ERCP pancreatitis. Levels of amylase and lipase were higher in patients with pancreatitis (522 U/L and 1808 U/L vs. 78 U/L and 61 U/L, respectively; p < 0.001). A cut-off of 218 U/L for amylase (x2.2 ULN) and 355 U/L for lipase (x6 ULN) had a negative predictive value of 99.2% and 99.5%, respectively. Amylase and lipase present a good correlation (Pearson coefficient 0.912). Among 342 (67.1%) patients without abdominal pain at 4 hours, post-ERCP pancreatitis was diagnosed in 8 (2.3%). Only 4 of these patients presented amylase or lipase > 3 ULN. Amylase and lipase were the only markers of post-ERCP pancreatitis 4 hours after the procedure.

Impaired innate immune response of leukocytes from ascitic fluid of patients with spontaneous bacterial peritonitis.

An ascitic microenvironment can condition the immune response of cells from cirrhotic patients with spontaneous bacterial peritonitis. To characterize this response, we determined the cytokine concentrations in ascitic fluid and analyzed the phenotype and function of ascitic leukocytes at diagnosis and after antibiotic-induced resolution in sterile ascites and ascitic fluid of 2 spontaneous bacterial peritonitis variants: positive and negative bacteriological culture. At diagnosis, a high concentration was found of IL-6 and IL-10 in the ascitic fluid from negative and positive bacteriological culture. The IL-6 concentration correlated with the percentage of neutrophils (R = 0.686, P < 0.001). In this context, positive and negative culture neutrophils had an impaired oxidative burst, and, after the antibiotic, the negative culture spontaneous bacterial peritonitis burst was fully recovered. Higher concentrations of IL-6 and IL-10 correlated with the presence of low granular CD 14(low) macrophages (R = -0.436, P = 0.005 and R = 0.414, P = 0.007, respectively). Positive culture spontaneous bacterial peritonitis macrophages expressed the lowest levels of CD16, CD86, CD11b and CD206, and HLA-DR, suggesting an impaired global function. Treatment increased all markers on the positive culture macrophages and CD11b and CD86 on negative culture macrophages. In negative culture spontaneous bacterial peritonitis, this increase was accompanied by phagocytic function recovery. The antibiotics then reverted the marker levels on positive and negative culture macrophages to the levels on sterile ascitis macrophages and restored ascitic negative culture cell function.

Effect of long-term acid gastric inhibition on bacterial translocation in cirrhotic rats.

BACKGROUND: Bacterial translocation (BT) related to intestinal bacterial overgrowth (IBO) plays an important role in the pathogenesis of bacterial infections in cirrhosis. Inhibition of acid gastric secretion promotes IBO and might favor BT. We evaluated the effect of long-term inhibition of acid gastric secretion on BT in cirrhotic rats. METHODS: Cirrhotic rats with and without ascites induced by oral CCl4 and controls were randomized to treatment with a daily subcutaneous injection of placebo, ranitidine (50 mg/kg), or pantoprazole (8 mg/kg) during 2 weeks. Continuous pH-metry was performed for 2 h before and at the end of treatment; thereafter, a laparotomy to obtain samples of blood, mesenteric lymph nodes, ascites, spleen, liver, and cecal stools was performed. RESULTS: Ranitidine and pantoprazole increased gastric pH as compared with placebo (P<0.001). However, antisecretory drugs increased the incidence of BT only in ascitic rats treated with ranitidine (P<0.05) or pantoprazole (P=0.07) when compared with placebo-treated ascitic rats or cirrhotic rats without ascites treated with the same drug. Cirrhotic ascitic rats treated with pantoprazole showed a trend toward an increased incidence of IBO (P=0.08), a higher ileal malondialdehyde level (P<0.01), and an increased production of tumor necrosis factor-α (P<0.05). CONCLUSION: Although inhibition of acid gastric secretion increased gastric pH in all animals, the incidence of BT increased only in ascitic rats, and it was associated with a trend toward an increase in IBO incidence, a higher ileal malondialdehyde level, and an increased production of serum tumor necrosis factor-α. Therefore, antisecretory drugs should be carefully administered to cirrhotic ascitic patients.

VSL#3 probiotic treatment decreases bacterial translocation in rats with carbon tetrachloride-induced cirrhosis.

BACKGROUND & AIMS: Probiotics can prevent pathological bacterial translocation in cirrhosis by modulating intestinal microbiota and improving gut barrier and immune disturbances. To evaluate the effect of probiotic VSL#3 on bacterial translocation, intestinal microbiota, gut barrier and inflammatory response in rats with experimental cirrhosis. METHODS: Forty-six Sprague-Dawley rats with CCl4 -induced cirrhosis were randomized into two groups: VSL#3 group (n = 22) that received VSL#3 in drinking water, and water group (n = 24) that received water only. Treatment began at week 6 of cirrhosis induction and continued until laparotomy, performed 1 week after development of ascites or at week 20. A control group included 11 healthy rats. At this study end, we evaluated bacterial translocation, intestinal flora, intestinal barrier (ileal claudin-2 and 4, ß-defensin-1, occludin and malondialdehyde as index of oxidative damage) and serum cytokines. RESULTS: Mortality during this study was similar in the VSL#3 group (10/22, 45%) and the water group (10/24, 42%) (P = 1). The incidence of bacterial translocation was 1/12 (8%) in the VSL#3 group, 7/14 (50%) in the water group (P = 0.03 vs. VSL#3 group) and 0/11 in the control group (P = 0.008 vs. water group). The concentration of ileal and caecal enterobacteria and enterococci was similar in the two groups of cirrhotic rats. The ileal occludin concentration was higher and ileal malondialdehyde and serum levels of TNF-α were lower in the VSL#3 group than in the water group (P < 0.05). CONCLUSIONS: VSL#3 decreases bacterial translocation, the pro-inflammatory state and ileal oxidative damage and increases ileal occludin expression in rats with experimental cirrhosis.

Cytokine production in patients with cirrhosis and TLR4 polymorphisms.

AIM: To analyze the cytokine production by peripheral blood cells from cirrhotic patients with and without TLR4 D299G and/or T399I polymorphisms. METHODS: The study included nine patients with cirrhosis and TLR4 D299G and/or T399I polymorphisms, and 10 wild-type patients matched for age, sex and degree of liver failure. TLR4 polymorphisms were determined by sequence-based genotyping. Cytokine production by peripheral blood cells was assessed spontaneously and also after lipopolysaccharide (LPS) and lipoteichoic acid (LTA) stimulation. RESULTS: Patients with TLR4 polymorphisms had a higher incidence of previous hepatic encephalopathy than wild-type patients (78% vs 20%, P = 0.02). Spontaneous production of interleukin (IL)-6 and IL-10 was lower in patients with TLR4 polymorphisms than in wild-type patients [IL-6: 888.7 (172.0-2119.3) pg/mL vs 5540.4 (1159.2-26053.9) pg/mL, P < 0.001; IL-10: 28.7 (6.5-177.1) pg/mL vs 117.8 (6.5-318.1) pg/mL, P = 0.02]. However, the production of tumor necrosis factor-α, IL-6 and IL-10 after LPS and LTA stimulation was similar in the two groups. CONCLUSION: TLR4 polymorphisms were associated with a distinctive pattern of cytokine production in cirrhotic patients, suggesting that they play a role in the development of cirrhosis complications.

Somatostatin for prevention of post-ERCP pancreatitis: a randomized, double-blind trial.

BACKGROUND AND STUDY AIMS: Meta-analyses suggest that an intravenous bolus or a high dose continuous infusion of somatostatin reduces the incidence of acute pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP). Clinical guidelines, however, do not recommend this prophylaxis. The aim of this randomized, double-blind clinical trial was to evaluate the effect of somatostatin on the incidence of post-ERCP pancreatitis. PATIENTS AND METHODS: Patients undergoing ERCP at a single center were randomized to either intravenous bolus of somatostatin followed by a short (4-hour) continuous infusion, or to a similar placebo regimen. The primary outcome was post-ERCP pancreatitis, defined as abdominal pain with an amylase level at least three times higher than the upper limit of normality 24 hours after the ERCP and requiring admission for at least 2 days. RESULTS: A total of 510 patients were enrolled (255 patients per group) and all completed follow-up. The main indications for ERCP were choledocholithiasis (62 %), and biliary malignant stricture (31 %). Post-ERCP pancreatitis occurred in 19 patients (7.5 %) in the somatostatin group and 17 patients (6.7 %) in the placebo group (relative risk [RR] 1.12, 95 % confidence interval [95 %CI] 0.59 - 2.1; P = 0.73). The number of cases of moderate or severe acute pancreatitis was similar in the somatostatin (2.4 %) and the placebo (3.5 %) groups (RR 0.67, 95 %CI 0.24 - 1.85, P = 0.43). No side effects were observed related to the use of somatostatin. CONCLUSIONS: Administration of an intravenous bolus of somatostatin followed by a short continuous infusion does not reduce the incidence of post-ERCP pancreatitis. Clinical Trials.gov number: NCT01060826.

Drugs plus ligation to prevent rebleeding in cirrhosis: an updated systematic review.

BACKGROUND & AIMS: Combined therapy with endoscopic variceal ligation (EVL) and ß-blockers ± isosorbide mononitrate (ISMN) is currently recommended to prevent variceal rebleeding. However, the role of this combined therapy has been challenged by some studies. We performed a systematic review to assess the value of combined therapy with EVL and ß-blockers ± ISMN as compared with each treatment alone to prevent rebleeding. METHODS: Databases, references and meeting abstracts were searched to retrieve randomized trials comparing combined therapy with EVL and ß-blockers ± ISMN vs either treatment alone, to prevent variceal rebleeding in cirrhosis. Random-effects model was used for meta-analysis. RESULTS: We identified five studies comparing EVL alone or combined with drugs, including a total of 476 patients. Combination therapy reduced overall rebleeding [risk ratios (RR) = 0.44, 95% confidence interval (CI) = 0.28-0.69], and showed a trend towards lower mortality (RR = 0.58, 95% CI = 0.33-1.03), without increasing complications. We identified four trials comparing drugs alone or associated with EVL, including 409 patients. All used ß-blockers plus ISMN. Variceal rebleeding decreased with combined therapy (P < 0.01) but rebleeding from oesophageal ulcers increased (P = 0.01). Overall, there was a trend towards lower rebleeding (RR = 0.76, 95% CI = 0.58-1.00) without effect on mortality (RR = 1.24, 95% CI = 0.90-1.70). CONCLUSIONS: The addition of drug therapy to EVL improves the efficacy of EVL alone. However, the addition of EVL to ß-blockers and ISMN achieves a non-significant decrease of rebleeding with no effect on mortality. Although combination therapy with EVL plus ß-blockers ± ISMN is adequate to prevent rebleeding, ß-blockers + ISMN alone may be a valid alternative.

Modulation of inflammatory response in a cirrhotic rat model with induced bacterial peritonitis.

Bacterial peritonitis is a severe complication in patients with cirrhosis and ascites and despite antibiotic treatment, the inflammatory response to infection may induce renal dysfunction leading to death. This investigation evaluated the effect of TNF-α blockade on the inflammatory response and mortality in cirrhotic rats with induced bacterial peritonitis treated or not with antibiotics. Sprague-Dawley rats with carbon-tetrachloride-induced cirrhosis were treated with an intraperitoneal injection of 10(9) CFU of Escherichia coli diluted in 20 mL of sterile water to induce bacterial peritonitis and randomized to receive subcutaneously-administered placebo, ceftriaxone, anti-TNF-α mAb and ceftriaxone, or anti-TNF-α mAb alone. No differences were observed between groups at baseline in respect to renal function, liver hepatic tests, serum levels of nitrite/nitrate and TNF-α. Treatment with ceftriaxone reduced mortality (73.3%) but differences did not reach statistical significance as compared to placebo. Mortality in rats treated with ceftriaxone and anti-TNF-α mAb was significantly lower than in animals receiving placebo (53% vs. 100%, p<0.01). Serum TNF-α decreased significantly in surviving rats treated with ceftriaxone plus anti-TNF-α mAb but not in treated with antibiotics alone. Additional studies including more animals are required to assess if the association of antibiotic therapy and TNF-α blockade might be a possible approach to reduce mortality in cirrhotic patients with bacterial peritonitis.

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.).

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.