IMPORTANCE Experimental data suggest that intravenous vitamin C may attenuate inflammation and vascular injury associated with sepsis and acute respiratory distress syndrome (ARDS).OBJECTIVE To determine the effect of intravenous vitamin C infusion on organ failure scores and biological markers of inflammation and vascular injury in patients with sepsis and ARDS. DESIGN, SETTING, AND PARTICIPANTSThe CITRIS-ALI trial was a randomized, double-blind, placebo-controlled, multicenter trial conducted in 7 medical intensive care units in the United States, enrolling patients (N = 167) with sepsis and ARDS present for less than 24 hours. The study was conducted from September 2014 to November 2017, and final follow-up was January 2018.INTERVENTIONS Patients were randomly assigned to receive intravenous infusion of vitamin C (50 mg/kg in dextrose 5% in water, n = 84) or placebo (dextrose 5% in water only, n = 83) every 6 hours for 96 hours. MAIN OUTCOMES AND MEASURESThe primary outcomes were change in organ failure as assessed by a modified Sequential Organ Failure Assessment score (range, 0-20, with higher scores indicating more dysfunction) from baseline to 96 hours, and plasma biomarkers of inflammation (C-reactive protein levels) and vascular injury (thrombomodulin levels) measured at 0, 48, 96, and 168 hours. RESULTS Among 167 randomized patients (mean [SD] age, 54.8 years [16.7]; 90 men [54%]), 103 (62%) completed the study to day 60. There were no significant differences between the vitamin C and placebo groups in the primary end points of change in mean modified Sequential Organ Failure Assessment score from baseline to 96 hours (from 9.8 to 6.8 in the vitamin C group [3 points] and from 10.3 to 6.8 in the placebo group [3.5 points]; difference, −0.10; 95% CI, −1.23 to 1.03; P = .86) or in C-reactive protein levels (54.1 vs 46.1 μg/mL; difference, 7.94 μg/mL; 95% CI, −8.2 to 24.11; P = .33) and thrombomodulin levels (14.5 vs 13.8 ng/mL; difference, 0.69 ng/mL; 95% CI, −2.8 to 4.2; P = .70) at 168 hours. CONCLUSIONS AND RELEVANCEIn this preliminary study of patients with sepsis and ARDS, a 96-hour infusion of vitamin C compared with placebo did not significantly improve organ dysfunction scores or alter markers of inflammation and vascular injury. Further research is needed to evaluate the potential role of vitamin C for other outcomes in sepsis and ARDS.

Background and Aims The 7α-dehydroxylation of primary bile acids (BAs), chenodeoxycholic (CDCA) and cholic acid (CA) into the secondary BAs, lithocholic (LCA) and deoxycholic acid (DCA) is a key function of the gut microbiota. We aimed to study the linkage between fecal BAs and gut microbiota in cirrhosis since this could help understand cirrhosis progression. Methods Fecal microbiota were analyzed by culture-independent multitagged-pyrosequencing, fecal BAs using HPLC and serum BAs using LC-MS in controls, early (Child A), and advanced cirrhotics(Child B/C). A subgroup of early cirrhotics underwent BA and microbiota analysis before/after eight weeks of rifaximin. Results Cross-sectional: 47 cirrhotics(24 advanced) and 14 controls were included. In feces, advanced cirrhotics had the lowest total, secondary, secondary/primary BA ratios, and highest primary BAs compared to early cirrhotics and controls. Secondary fecal BAs were detectable in all controls but in a significantly lower proportion of cirrhotics (p<0.002). Serum primary BAs were higher in advanced cirrhotics compared to the rest. Cirrhotics, compared to controls, had a higher Enterobacteriaceae (potentially pathogenic) but lower Lachonospiraceae, Ruminococcaceae and Blautia (7α-dehydroxylating bacteria) abundance. CDCA was positively correlated with Enterobacteriaceae(r=0.57, p<0.008) while Ruminococcaceae were positively correlated with DCA(r=0.4, p<0.05). A positive correlation between Ruminococcaceae and DCA/CA (r=0.82, p<0.012) and Blautia with LCA/CDCA (r=0.61, p<0.03) was also seen. Prospective study: Post-rifaximin, six early cirrhotics had reduction in Veillonellaceae and in the secondary/primary BA ratios. Conclusions Cirrhosis, especially advanced disease, is associated with a decreased conversion of primary to secondary fecal BAs which is linked with abundance of key gut microbiome taxa.

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Background Infections worsen survival in cirrhosis; however, simple predictors of survival in infection-related acute-on-chronic liver failure (I-ACLF) derived from multi-center studies are required in order to improve prognostication and resource allocation. Methods Using the NACSELD database, data from 18 centers were collected for survival analysis of prospectively enrolled cirrhotic patients hospitalized with an infection. We defined organ failures as (i) shock, (ii) grade III/IV hepatic encephalopathy(HE), (iii) need for dialysis (iv) mechanical ventilation. Determinants of survival with these organ failures were analyzed. Results 507 patients were included (55 yrs, 52% HCV, 15.8% nosocomial infection, 96% Child score≥7) and 30-day evaluations were available in 453 patients. Urinary tract infection (UTI) (28.5%), and spontaneous bacterial peritonitis (SBP) (22.5%) were most prevalent. During hospitalization, 55.7% developed HE, 17.6% shock, 15.1% required renal replacement, and 15.8% needed ventilation; 23% died within 30-days and 21.6% developed second infections. Admitted patients developed none (38.4%), one (37.3%), two (10.4%), three (10%) or four (4%) organ failures. 30-day survival worsened with higher number of extra-hepatic organ failures, none (92%), one (72.6%), two (51.3%), three (36%) and all four (23%). I-ACLF was defined as ≥2 organ failures given the significant change in survival probability associated at this cutoff. Baseline independent predictors for development of ACLF were nosocomial infections, MELD score, low mean arterial pressure (MAP), and non-SBP infections. Independent predictors of poor 30-day survival were I-ACLF, second infections, and admission values of high MELD, low MAP, high white blood count and low albumin. In conclusion, using multi-center study data in hospitalized decompensated infected cirrhotic patients, I-ACLF defined by the presence of two or more organ failures using simple definitions is predictive of poor survival.

Hepatic encephalopathy (HE) has been related to gut bacteria and inflammation in the setting of intestinal barrier dysfunction. We aimed to link the gut microbiome with cognition and inflammation in HE using a systems biology approach. Multitag pyrosequencing (MTPS) was performed on stool of cirrhotics and age-matched controls. Cirrhotics with/without HE underwent cognitive testing, inflammatory cytokines, and endotoxin analysis. Patients with HE were compared with those without HE using a correlation-network analysis. A select group of patients with HE (n = 7) on lactulose underwent stool MTPS before and after lactulose withdrawal over 14 days. Twenty-five patients [17 HE (all on lactulose, 6 also on rifaximin) and 8 without HE, age 56 ± 6 yr, model for end-stage liver disease score 16 ± 6] and ten controls were included. Fecal microbiota in cirrhotics were significantly different (higher Enterobacteriaceae, Alcaligeneceae, and Fusobacteriaceae and lower Ruminococcaceae and Lachnospiraceae) compared with controls. We found altered flora (higher Veillonellaceae), poor cognition, endotoxemia, and inflammation (IL-6, TNF-α, IL-2, and IL-13) in HE compared with cirrhotics without HE. In the cirrhosis group, Alcaligeneceae and Porphyromonadaceae were positively correlated with cognitive impairment. Fusobacteriaceae, Veillonellaceae, and Enterobacteriaceae were positively and Ruminococcaceae negatively related to inflammation. Network-analysis comparison showed robust correlations (all P < 1E-5) only in the HE group between the microbiome, cognition, and IL-23, IL-2, and IL-13. Lactulose withdrawal did not change the microbiome significantly beyond Fecalibacterium reduction. We concluded that cirrhosis, especially when complicated with HE, is associated with significant alterations in the stool microbiome compared with healthy individuals. Specific bacterial families (Alcaligeneceae, Porphyromonadaceae, Enterobacteriaceae) are strongly associated with cognition and inflammation in HE.

Bacterial infections are an important cause of mortality in cirrhosis but there is a paucity of multi-center studies. The aim was to define factors predisposing to infection-related mortality in hospitalized cirrhotic patients. Methods A prospective, cohort study of cirrhotic patients with infections was performed at eight North American tertiary-care hepatology centers. Data were collected on admission vitals, disease severity [MELD and sequential organ failure (SOFA)] scores], first infection site, type [community-acquired, health care-associated (HCA) or nosocomial], and second infection occurrence during hospitalization. The outcome was mortality within 30 days. A multi-variable logistic regression model predicting mortality was created. Results 207 patients (55 years, 60% men, MELD 20) were included. Most first infections were HCA (71%), then nosocomial (15%) and community-acquired (14%). Urinary tract infections (52%), spontaneous bacterial peritonitis (SBP, 23%) and spontaneous bacteremia (21%) formed the majority of the first infections. Second infections were seen in 50 (24%) patients and were largely preventable: respiratory, including aspiration (28%), urinary, including catheter-related (26%), fungal (14%) and C. difficile (12%) infections. Forty-nine patients (23.6%) who died within 30 days had higher admission MELD (25 vs 18, p<0.0001), lower serum albumin (2.4g.dL vs. 2.8g/dL, p=0.002), and second infections (49% vs. 16%, p<0.0001) but equivalent SOFA scores (9.2 vs. 9.9, p=0.86). Case fatality rate was highest for C. difficile (40%), respiratory (37.5%) and spontaneous bacteremia (37%), and lowest for SBP (17%) and urinary infections (15%). The model for mortality included admission MELD (OR: 1.12), heart rate (OR:1.03) albumin (OR:0.5) and second infection (OR:4.42) as significant variables. Conclusions Potentially preventable second infections are predictors of mortality independent of liver disease severity in this multi-center cirrhosis cohort.

Recurrent hepatic encephalopathy (HE) is a leading cause of readmission despite standard of care (SOC) associated with microbial dysbiosis. Fecal microbiota transplantation (FMT) may improve dysbiosis; however, it has not been studied in HE. We aimed to define whether FMT using a rationally-derived stool donor is safe in recurrent HE compared to SOC alone. An open-label, randomized clinical trial with a 5 month follow-up in outpatient cirrhotic men with recurrent HE on SOC was conducted with 1:1 randomization. FMT-randomized patients received 5-days of broad-spectrum antibiotic pre-treatment then a single FMT enema from the same donor with the optimal microbiota deficient in HE. Follow-up occurred on days 5, 6, 12, 35 and 150 post-randomization. The primary outcome was safety of FMT compared to SOC using FMT-related serious adverse events (SAE). Secondary outcomes were AEs, cognition, microbiota and metabolomic changes. Participants in both arms were similar on all baseline criteria and were followed till study-end. FMT with antibiotic pre-treatment was well-tolerated. Eight (80%) SOC participants had a total of 11 SAE compared to two (20%) FMT participants with SAEs (both FMT-unrelated, p=0.02). Five SOC and no FMT participants developed further HE (p=0.03). Cognition improved in FMT, but not SOC group. MELD score transiently worsened post-antibiotics, but reverted to baseline post-FMT. Post-antibiotics, beneficial taxa and microbial diversity reduction occurred with Proteobacteria expansion. However, FMT increased diversity and beneficial taxa. SOC microbiota and MELD score remained similar throughout. Conclusions: FMT from a rationally selected donor reduced hospitalizations, improved cognition and dysbiosis in cirrhosis with recurrent HE.

Objectives Cirrhosis and hepatic encephalopathy (HE) can adversely affect survival, but their effect on socioeconomic and emotional burden on the family is not clear. The aim was to study the emotional and socioeconomic burden of cirrhosis and HE on patients and informal caregivers. Methods A cross-sectional study in two transplant centers (Veterans and University) of cirrhotic patients and their informal caregivers was performed. Demographics for patient/caregivers, model-for-end-stage liver disease (MELD) score, and cirrhosis complications were recorded. Patients underwent a cognitive battery, sociodemographic, and financial questionnaires. Caregivers were given the perceived caregiver burden (PCB; maximum = 155) and Zarit Burden Interview (ZBI)-Short Form (maximum = 48) and questionnaires for depression, anxiety, and social support. Results A total of 104 cirrhotics (70% men, 44% previous HE, median MELD 12, 49% veterans) and their caregivers (66% women, 77% married, relationship duration 32 ± 14 years) were included. Cirrhosis severely impacted the family unit with respect to work (only 56% employed), finances, and adherence. Those with previous HE had worse unemployment (87.5 vs. 19%, P = 0.0001) and financial status (85 vs. 61%, P = 0.019) and posed a higher caregiver burden; PCB (75 vs. 65, P = 0.019) and ZBI (16 vs. 11, P = 0.015) compared with others. Cognitive performance and MELD score were significantly correlated with employment and caregiver burden. Veterans and non-veterans were equally affected. On regression, depression score, MELD, and cognitive tests predicted both PCB and ZBI score. Conclusions Previous HE and cognitive dysfunction are associated with worse employment, financial status, and caregiver burden. Cirrhosis-related expenses impact the family unit's daily functioning and medical adherence. A multidisciplinary approach to address this burden is required.