Germán Soriano

EFFECT OF INTRAVENOUS ALBUMIN ON RENAL IMPAIRMENT AND MORTALITY IN PATIENTS WITH CIRRHOSIS AND SPONTANEOUS BACTERIAL PERITONITIS

BACKGROUND In patients with cirrhosis and spontaneous bacterial peritonitis, renal function frequently becomes impaired. This impairment is probably related to a reduction in effective arterial blood volume and is associated with a high mortality rate. We conducted a study to determine whether plasma volume expansion with intravenous albumin prevents renal impairment and reduces mortality in these patients. METHODS We randomly assigned 126 patients with cirrhosis and spontaneous bacterial peritonitis to treatment with intravenous cefotaxime (63 patients) or cefotaxime and intravenous albumin (63 patients). Cefotaxime was given daily in dosages that varied according to the serum creatinine level, and albumin was given at a dose of 1.5 g per kilogram of body weight at the time of diagnosis, followed by 1 g per kilogram on day 3. Renal impairment was defined as nonreversible deterioration of renal function during hospitalization. RESULTS The infection resolved in 59 patients in the cefotaxime group (94 percent) and 62 in the cefotaxime-plus-albumin group (98 percent) (P=0.36). Renal impairment developed in 21 patients in the cefotaxime group (33 percent) and 6 in the cefotaxime-plus-albumin group (10 percent) (P=0.002). Eighteen patients (29 percent) in the cefotaxime group died in the hospital, as compared with 6 (10 percent) in the cefotaxime-plus-albumin group (P=0.01); at three months, the mortality rates were 41 percent (a total of 26 deaths) and 22 percent (a total of 14 deaths), respectively (P=0.03). Patients treated with cefotaxime had higher levels of plasma renin activity than those treated with cefotaxime and albumin; patients with renal impairment had the highest values. CONCLUSIONS In patients with cirrhosis and spontaneous bacterial peritonitis, treatment with intravenous albumin in addition to an antibiotic reduces the incidence of renal impairment and death in comparison with treatment with an antibiotic alone.

Terlipressin and Albumin vs Albumin in Patients With Cirrhosis and Hepatorenal Syndrome : A Randomized Study

BACKGROUND & AIMS Hepatorenal syndrome is common in patients with advanced cirrhosis and constitutes a major problem in liver transplantation. There is no effective medical treatment for hepatorenal syndrome. METHODS Forty-six patients with cirrhosis and hepatorenal syndrome, hospitalized in a tertiary care center, were randomly assigned to receive either terlipressin (1-2 mg/4 hour, intravenously), a vasopressin analogue, and albumin (1 g/kg followed by 20-40 g/day) (n = 23) or albumin alone (n = 23) for a maximum of 15 days. Primary outcomes were improvement of renal function and survival at 3 months. RESULTS Improvement of renal function occurred in 10 patients (43.5%) treated with terlipressin and albumin compared with 2 patients (8.7%) treated with albumin alone (P = .017). Independent predictive factors of improvement of renal function were baseline urine volume, serum creatinine and leukocyte count, and treatment with terlipressin and albumin. Survival at 3 months was not significantly different between the 2 groups (terlipressin and albumin: 27% vs albumin 19%, P = .7). Independent predictive factors of 3-month survival were baseline model for end-stage liver disease score and improvement of renal function. Cardiovascular complications occurred in 4 patients treated with albumin alone and in 10 patients treated with terlipressin and albumin, yet permanent terlipressin withdrawal was required in only 3 cases. CONCLUSIONS As compared with albumin, treatment with terlipressin and albumin is effective in improving renal function in patients with cirrhosis and hepatorenal syndrome. Further studies with large sample sizes should be performed to test whether the improvement of renal function translates into a survival benefit.

Nadolol plus Isosorbide Mononitrate Compared with Sclerotherapy for the Prevention of Variceal Rebleeding

BACKGROUND Patients who have bleeding from esophageal varices are at high risk for rebleeding and death. We compared the efficacy and safety of endoscopic sclerotherapy with the efficacy and safety of nadolol plus isosorbide mononitrate for the prevention of variceal rebleeding. METHODS Eighty-six hospitalized patients with cirrhosis and bleeding from esophageal varices diagnosed by endoscopy were randomly assigned to treatment with repeated sclerotherapy (43 patients) or nadolol plus isosorbide-5-mononitrate (43 patients). The primary outcomes were rebleeding, death, and complications. The hepatic venous pressure gradient was measured at base line and after three months. RESULTS Base-line data were similar in the two groups, and the median follow-up was 18 months in both. Eleven patients in the medication group and 23 in the sclerotherapy group had rebleeding. The actuarial probability of remaining free of rebleeding was higher in the medication group for all episodes related to portal hypertension (P = 0.001) and variceal rebleeding (P = 0.002). Four patients in the medication group and nine in the sclerotherapy group died (P = 0.07 for the difference in the actuarial probability of survival). Seven patients in the medication group and 16 in the sclerotherapy group had treatment-related complications (P = 0.03). Thirty-one patients in the medication group underwent two hemodynamic studies; 1 of the 13 patients with more than a 20 percent decrease in the hepatic venous pressure gradient had rebleeding, as compared with 8 of the 18 with smaller decreases in the pressure gradient (P = 0.04) for the actuarial probability of rebleeding at two years). CONCLUSIONS As compared with sclerotherapy, nadolol plus isosorbide mononitrate significantly decreased the risk of rebleeding from esophageal varices.

Norfloxacin Prevents Bacterial Infection in Cirrhotics With Gastrointestinal Hemorrhage

To assess the efficacy of selective intestinal decontamination with norfloxacin in the prevention of bacterial infections in cirrhotic patients with gastrointestinal hemorrhage, 119 patients were included in a prospective randomized study. Group 1 (n = 60) received norfloxacin orally or through a nasogastric tube, 400 mg twice daily for 7 days beginning immediately after emergency gastroscopy; group 2 (n = 59) was the control group. We found a significantly lower incidence of infections (10% vs. 37.2%; P = 0.001), bacteremia and/or spontaneous bacterial peritonitis (3.3% vs. 16.9%; P less than 0.05), and urinary infections (0% vs. 18.6%; P = 0.001) in patients receiving norfloxacin, as a consequence of decrease in the incidence of infections caused by aerobic gram-negative bacilli. The decrease in mortality observed in the treated group (6.6% vs. 11.8%) did not reach statistical significance. The cost for antibiotic treatment showed a 62% reduction in the treated group compared with the control group. The results show that selective intestinal decontamination with norfloxacin is useful in preventing bacterial infections in cirrhotics with gastrointestinal hemorrhage.

Development and Validation of a Prognostic Score to Predict Mortality in Patients with Acute on Chronic Liver Failure.

BACKGROUND & AIMS Acute-on-chronic liver failure (ACLF) is a frequent syndrome (30% prevalence), characterized by acute decompensation of cirrhosis, organ failure(s) and high short-term mortality. This study develops and validates a specific prognostic score for ACLF patients. METHODS Data from 1349 patients included in the CANONIC study were used. First, a simplified organ function scoring system (CLIF Consortium Organ Failure score, CLIF-C OFs) was developed to diagnose ACLF using data from all patients. Subsequently, in 275 patients with ACLF, CLIF-C OFs and two other independent predictors of mortality (age and white blood cell count) were combined to develop a specific prognostic score for ACLF (CLIF Consortium ACLF score [CLIF-C ACLFs]). A concordance index (C-index) was used to compare the discrimination abilities of CLIF-C ACLF, MELD, MELD-sodium (MELD-Na), and Child-Pugh (CPs) scores. The CLIF-C ACLFs was validated in an external cohort and assessed for sequential use. RESULTS The CLIF-C ACLFs showed a significantly higher predictive accuracy than MELDs, MELD-Nas, and CPs, reducing (19-28%) the corresponding prediction error rates at all main time points after ACLF diagnosis (28, 90, 180, and 365 days) in both the CANONIC and the external validation cohort. CLIF-C ACLFs computed at 48 h, 3-7 days, and 8-15 days after ACLF diagnosis predicted the 28-day mortality significantly better than at diagnosis. CONCLUSIONS The CLIF-C ACLFs at ACLF diagnosis is superior to the MELDs and MELD-Nas in predicting mortality. The CLIF-C ACLFs is a clinically relevant, validated scoring system that can be used sequentially to stratify the risk of mortality in ACLF patients.

Selective intestinal decontamination prevents spontaneous bacterial peritonitis

In a prospective randomized study, selective intestinal decontamination with norfloxacin was performed during hospitalization in 32 cirrhotic patients with low ascitic fluid total protein levels. The incidence of infections was compared with that in a control group of 31 nontreated cirrhotic patients of similar characteristics. We found a significantly lower incidence of infections [1/32 (3.1%) vs. 13/31 (41.9%); P less than 0.005] and spontaneous bacterial peritonitis [0/32 (0%) vs. 7/31 (22.5%); P less than 0.05] in patients receiving norfloxacin. The lower incidence of extraperitoneal infections [1/32 (3.1%) vs. 7/31 (22.5%); P = 0.052] in the treated group did not reach statistical significance. The incidence of infections [1/28 (3.6%) vs. 9/22 (40.9%); P less than 0.01] and spontaneous bacterial peritonitis [0/28 (0%) vs. 5/22 (22.7%); P less than 0.05] in cirrhotic patients admitted because of ascites was also significantly lower in the treated group. The decrease in the rate of mortality observed in the group undergoing selective intestinal decontamination did not reach statistical significance. These data show that selective intestinal decontamination is useful to prevent spontaneous bacterial peritonitis and extraperitoneal infections in hospitalized cirrhotic patients with low ascitic fluid total protein levels.

Amoxicillin-clavulanic acid versus cefotaxime in the therapy of bacterial infections in cirrhotic patients.

BACKGROUND/AIM Cefotaxime is considered the first-choice antibiotic for empirical treatment in cirrhotic patients developing bacterial infections. It has been suggested that amoxicillin-clavulanic acid could be an alternative to cefotaxime, particularly in patients developing bacterial infections while on prophylactic norfloxacin. The aim of the present study was to compare amoxicillin-clavulanic acid with cefotaxime in the treatment of bacterial infections in cirrhosis. METHODS Ninety-six hospitalized cirrhotic patients with suspicion of bacterial infection were prospectively included and randomized into two groups: one group (n=48) received amoxicillin-clavulanic acid, first intravenously 1 g-0.2 g every 8 h, and then orally 500 mg-125 mg every 8 h, and the other group (n=48) received intravenous cefotaxime 1 g every 6 h. Patients were stratified for previous prophylaxis with norfloxacin and ascitic fluid infection. RESULTS Sixteen patients were excluded from the analysis because bacterial infection was not demonstrated or because of secondary peritonitis. Therefore, 38 patients from the amoxicillin-clavulanic acid group and 42 from the cefotaxime group were finally analyzed. There were 24 ascitic fluid infections in each group. Infection resolution (86.8% vs 88%, 95% CI: -0.15 to 0.13, p NS), spontaneous bacterial peritonitis resolution (87.5% vs 83.3%, 95% CI: -0.15 to 0.24, p NS), duration of treatment, incidence of complications, time of hospitalization and hospital mortality were similar in both groups. Considering patients on prophylactic norfloxacin, infection resolution was also similar (100% vs 83.3%, 95% CI: -0.04 to 0.37, p NS). No adverse events were observed in either of the two groups. The cost of antibiotics was statistically lower in the amoxicillin-clavulanic acid group (p<0.001). CONCLUSIONS Amoxicillin-clavulanic acid is as effective as cefotaxime in the treatment of bacterial infections in cirrhotic patients, but is less expensive and can be administered orally. These results suggest that amoxicillin-clavulanic acid is an effective alternative to cefotaxime for the empirical treatment of bacterial infections in cirrhosis.

Bacterial translocation and its consequences in patients with cirrhosis.

Bacterial translocation is the passage of viable bacteria from the intestinal lumen to mesenteric lymph nodes and other extraintestinal sites. Spontaneous bacterial peritonitis is the main clinical consequence of bacterial translocation in cirrhosis. Translocation of bacterial products of viable or non-viable bacteria, such as endotoxin and/or bacterial DNA, through the intestinal wall could stimulate the immune system and the hyperdynamic circulatory state in cirrhosis with clinical consequences that are under evaluation. Bacterial translocation is currently considered the passage of viable gut flora across the intestinal barrier to extraluminal sites. Aerobic Gram-negative bacilli are the most common translocating bacteria. Intestinal bacterial overgrowth, impairment in permeability of the intestinal mucosal barrier, and deficiencies in local host immune defences are the major mechanisms postulated to favour bacterial translocation in cirrhosis. Bacterial translocation is a key step in the pathogenesis of spontaneous bacteraemia and spontaneous bacterial peritonitis in cirrhosis. Translocation of intestinal bacterial products from viable or non-viable bacteria, such as endotoxin and bacterial DNA, has recently been associated with pathophysiological events, such as activation of the immune system and derangement of the hyperdynamic circulatory status in cirrhosis. Clinical consequences of these effects of bacterial products are presently under investigation.

Embolization of large spontaneous portosystemic shunts for refractory hepatic encephalopathy: A multicenter survey on safety and efficacy

Refractory hepatic encephalopathy (HE) remains a major cause of morbidity in cirrhosis patients. Large spontaneous portosystemic shunts (SPSSs) have been previously suggested to sustain HE in these patients. We aimed to retrospectively assess the efficacy and safety of patients treated with embolization of large SPSSs for the treatment of chronic therapy‐refractory HE in a European multicentric working group and to identify patients who may benefit from this procedure. Between July 1998 and January 2012, 37 patients (Child A6‐C13, MELD [Model of Endstage Liver Disease] 5‐28) with refractory HE were diagnosed with single large SPSSs that were considered eligible for embolization. On a short‐term basis (i.e., within 100 days after embolization), 22 out of 37 patients (59.4%) were free of HE (P < 0.001 versus before embolization) of which 18 (48.6% of patients overall) remained HE‐free over a mean follow‐up period of 697 ± 157 days (P < 0.001 versus before embolization). Overall, we noted improved autonomy, decreased number of hospitalizations, and severity of the worst HE episode after embolization in three‐quarters of the patients. Logistic regression identified the MELD score as strongest positive predictive factor of HE recurrence with a cutoff of 11 for patient selection. As to safety, we noted one major nonlethal procedure‐related complication. There was no significant increase in de novo development or aggravation of preexisting varices, portal hypertensive gastropathy, or ascites. Conclusion: This multicenter European cohort study demonstrated a role for large SPSSs in chronic protracted or recurrent HE and substantiated the effectiveness and safety of embolization of these shunts, provided there is sufficient functional liver reserve. (HEPATOLOGY 2013;57:2448–2457)

Effect of Lactobacillus johnsonii La1 and antioxidants on intestinal flora and bacterial translocation in rats with experimental cirrhosis

BACKGROUND/AIMS Probiotics and antioxidants could be alternatives to antibiotics in the prevention of bacterial infections in cirrhosis. The aim of the present study was to determine the effect of Lactobacillus johnsonii La1 and antioxidants on intestinal flora, endotoxemia, and bacterial translocation in cirrhotic rats. METHODS Twenty-nine Sprague-Dawley rats with cirrhosis induced by CCl(4) and ascites received Lactobacillus johnsonii La1 10(9)cfu/day in vehicle (antioxidants: vitamin C+glutamate) (n=10), vehicle alone (n=11), or water (n=8) by gavage. Another eight non-cirrhotic rats formed the control group. After 10 days of treatment, a laparotomy was performed to determine microbiological study of ileal and cecal feces, bacterial translocation, endotoxemia, and intestinal malondialdehyde (MDA) levels as index of intestinal oxidative damage. RESULTS Intestinal enterobacteria and enterococci, bacterial translocation (0/11 and 0/10 vs. 5/8, P<0.01), and ileal MDA levels (P<0.01) were lower in cirrhotic rats treated with antioxidants alone or in combination with Lactobacillus johnsonii La1 compared to cirrhotic rats receiving water. Only rats treated with antioxidants and Lactobacillus johnsonii La1 showed a decrease in endotoxemia with respect to cirrhotic rats receiving water (P<0.05). CONCLUSIONS Antioxidants alone or in combination with Lactobacillus johnsonii La1 can be useful in preventing bacterial translocation in cirrhosis.