Tranexamic acid in upper gastrointestinal bleed in patients with cirrhosis: A randomized controlled trial.

BACKGROUND AND AIMS: Patients with Child-Turcotte-Pugh class B and C cirrhosis with upper gastrointestinal bleeding (UGIB) have systemic as well as localized (in the mucosa of the esophagus and stomach) fibrinolysis. The aim of this study was to evaluate the efficacy and safety of tranexamic acid in the treatment of acute UGIB in patients with cirrhosis. APPROACH AND RESULTS: A total of 600 patients with advanced liver cirrhosis (Child-Turcotte-Pugh class B or C) presenting with UGIB were randomly allocated to either the tranexamic acid (n=300) or the placebo group (n=300). The primary outcome measure was the proportion of patients developing 5-day treatment failure. Failure to control bleeding by day 5 was seen in 19/300 (6.3%) patients in the tranexamic acid group and 40/300 (13.3%) patients in the placebo group ( p =0.006). Esophageal endoscopic variceal ligation (EVL) site as a source of failure to control bleeding by day 5 among patients undergoing first-time esophageal EVL (excluding patients with a previous post-EVL ulcer as a source of bleed) was seen in 11/222 (4.9%) patients in the tranexamic acid group and 27/225 (1212.0%) patients in the placebo group ( p =0.005). However, 5-day and 6-week mortality was similar in the tranexamic acid and placebo groups. CONCLUSIONS: Tranexamic acid significantly reduces the failure to control bleeding by day 5 and failure to prevent rebleeding after day 5 to 6 weeks in patients with advanced liver cirrhosis (Child-Turcotte-Pugh class B or C) presenting with UGIB, by preventing bleeding from the EVL site.

Combination of carvedilol with variceal band ligation in prevention of first variceal bleed in Child-Turcotte-Pugh B and C cirrhosis with high-risk oesophageal varices: the 'CAVARLY TRIAL'.

OBJECTIVES: Beta-blockers and endoscopic variceal band ligation (VBL) have been preferred therapies for primary prophylaxis of variceal bleeding. However, the choice of therapy in patients with advanced liver disease with high-risk varices is not clear. A comparison of these therapies alone or in combination to prevent the first variceal bleed in advanced cirrhosis patients was carried out. DESIGN: 330 Child-Turcotte-Pugh (CTP) B and C cirrhosis patients, with 'high-risk' varices were prospectively enrolled (n=110 per group) to receive carvedilol (group A), VBL (group B) or combination (group C). Primary endpoint was reduction in the incidence of first variceal bleed at 12 months. The secondary endpoints included overall mortality, bleed-related mortality, new-onset decompensation, change in hepatic vein pressure gradient (HVPG) and treatment-related adverse events. RESULTS: The patients were predominantly males (85.2%), aged 51.4±10.5 years with CTP score of 8.87±1.24, MELD score 15.17±3.35 and HVPG-16.96±3.57 mm Hg. The overall incidence of variceal bleed was 23.8% (n=78) at 1 year. Intention-to-treat analysis showed that the combination arm (group C) significantly reduced the incidence of first variceal bleed by 62.9% as compared with group B (HR 0.37, 95% CI 0.192 to 0.716, p<0.003) and by 69.3% as compared with group A (HR 0.31, 95% CI 0.163 to 0.578, <0.001). The overall mortality was 13.6% (45/330). The 1-year mortality in group C was lowest among the three groups (A, B, C=20%, 14.5%, 6.3%, p=0.012). Reduction in HVPG (20.8% vs 25.1%, p=0.54) and the rate of non-response to carvedilol (53.4% vs 41.25%, p=0.154) were not different between group A and C patients. The incidence of new-onset ascites, spontaneous bacterial peritonitis, shock, and acute kidney injury and postbleed organ failure was also comparable between the groups. CONCLUSION: In CTP B and C cirrhosis patients with high-risk varices, combination of carvedilol and VBL is more effective than either therapy alone, for primary prevention of variceal bleeding. TRIAL REGISTRATION NUMBER: NCT03069339.

Granulocyte Colony-Stimulating Factor Improves Prednisolone Responsiveness and 90-Day Survival in Steroid-Eligible Severe Alcohol-Associated Hepatitis: The GPreAH Study a Randomized Trial.

INTRODUCTION: Severe alcohol-associated hepatitis (SAH) carries high 1-month mortality. Corticosteroids provide a modest 28-day but not 90-day survival benefit, due to development of infections and organ failures. Granulocyte colony-stimulating factor (GCSF) has shown promise in patients with SAH by its immunomodulatory and regenerative capabilities. We studied the safety and efficacy of combination (GCSF + prednisolone, GPred) therapy in management of steroid-eligible patients with SAH. METHODS: Steroid eligible patients with SAH (discriminant function scores 32-90) were randomized to receive prednisolone (GrA, n = 42), GPred (GrB, n = 42), or GCSF alone (GrC, n = 42). GCSF was given as 150-300 mcg/d for 7 days followed by every third day for a maximum of 12 doses in 1 month. Prednisolone 40 mg/d was given for 7 days and continued for 28 days in responders (Lille score <0.45). RESULTS: Baseline characteristics of patient groups were comparable. On intention-to-treat analysis, the primary endpoint of 90-day survival was achieved in 64.3% (27/42) in prednisolone, 88.1% (37/42) in GPred, and 78.6%(33/42) in GCSF groups, respectively ( P = 0.03, prednisolone vs GPred). The 28-day survival was not different between the groups (85.7%, 95.2%, and 85.7%, respectively [ P = 0.27]). The GPred group had more responders by day 7 (71.4% vs 92.9% vs 76.2%, P = 0.037) and had greater reduction in discriminant function (-7.33 ± 4.78, -24.59 ± 3.7, -14.59 ± 3.41, P = 0.011) and MELDNa (-1.69 ± 1.26, -7.02 ± 1.24, -3.05 ± 0.83, P = 0.002) by day 90. The prednisolone-only group had higher incidence of new infections (35.7%, 19%, 7.1%, respectively, P < 0.002). Acute kidney injury (33.3%, 7.1%, 11.9%, P = 0.002), hepatic encephalopathy (35.7%, 9.5%, 26.2%, P = <0.001), and rehospitalizations (59.5%, 14.3%, 30.9%, P =<0.01) were lower in the GPred group. CONCLUSION: Addition of GCSF to prednisolone improves steroid responsiveness and 90-day survival with fewer infections and new onset complications in patients with SAH.

Severity of Acute Portal Hypertension Determines the Clinical Outcomes in Severe Alcoholic Hepatitis.

BACKGROUND: Severe alcohol-associated hepatitis (SAH) presenting as acute-on-chronic liver failure (ACLF) has high mortality. Severe hepatic inflammation and ongoing hepatocellular cell death lead to rapid rise in portal pressure, a hyperdynamic circulation that might precipitate infections and organ failures. METHODS: Consecutive SAH patients were classified based on baseline HVPG measurement as 6to < 12 mmHg, 12to < 20 mmHg, and ≥ 20 mmHg. We analyzed portal hypertension severity in relation to fibrosis stage, ACLF at presentation, response to prednisolone, severity scores(MELD and Maddrey's Discriminant Function, mDF), and 90-day mortality. RESULTS: Of 819 SAH patients (94.6% ACLF, 85.4% histological cirrhosis, median MELD and mDF scores 25 and 66, respectively), 250(30.5%) had HVPG ≥ 20 mmHg. Patients with HVPG ≥ 20 mmHg more often had large esophageal varices (25.2%vs.13.2%; p-0.001), higher baseline MELD (27.1 ± 5.6vs.25.3 ± 5.2; p-0.001), and mDF(76.1 ± 16vs.68.4 ± 15.1; p-0.01) scores. No patient without ACLF had HVPG ≥ 20 mmHg. Moreover, during hospital course these patients had higher incidence of variceal bleed (17.2%vs.8.8%; p-0.001), acute kidney injury (36.4%vs.25.3%; p-0.001), and spontaneous bacterial peritonitis (6.4%vs.3.5%; p-0.05). Of 412(50.3%) eligible patients treated with prednisolone, 69.2% showed response at day 7(Lille's score < 0.45). 90-day mortality was 27.6%; and baseline MELD > 25.5[HR 1.78], HVPG ≥ 20 mmHg [HR 1.86], the presence of HE[HR 1.63], and prednisolone ineligibility due to sepsis[HR 1.27] were independent predictors. Mortality was unrelated to varices grade, variceal bleed, and histological cirrhosis. Repeat HVPG performed in 114(19.2%) patients after a median of 5.2 months showed significant decrease (3.6 mmHg; p-0.001) which correlated with improvement in MELD score(13points; p-0.05). CONCLUSION: Development of ACLF and complications in SAH are likely a result of acute rise in HVPG. "High-risk" SAH are SAH patients with HVPG ≥ 20 mmHg in the presence of ascites. Understanding the drivers for acute rise in portal pressure in SAH ACLF might help introduction of newer therapies.

Derivation of Splenic Stiffness in Subjects with Normal Liver Stiffness and No Vascular Liver Disease Using Transient Elastography with a Spleen-Dedicated Module: A Large Cross Sectional Study.

BACKGROUND: Liver and splenic stiffness measurements (LSM and SSM) are useful to predict varices and clinical decompensation in cirrhosis. SSM values are highly variable and overlapping and no guidelines exists on what constitutes normal SSM, that might limit interpretation of results. METHODS: Consecutive subjects with LSM < 6 kPa and reliable SSM (FibroScan630 Expert device with spleen-dedicated module) and no vascular liver disease were analysed for significant correlations of SSM values with age, sex, BMI, portal and splenic vein diameter, splenic diameter, liver fat and diabetes. Based on timeline of SSM, subjects were randomly assigned in 70:30 ratio into derivation [n = 502] and validation subset [n = 214]. RESULTS: Of 7200 subjects with simultaneous reliable LSM and SSM, 715 fulfilled the selection criteria (mean age: 43.8 ± 12.8 years, 67.2% male, mean BMI-26.4 ± 4.5 kg/m2). The mean SSM was 22.6 ± 5.8 kPa (c10-c90 percentile range: 15.2-31.3 kPa) and followed the normal distribution curve. In the derivation subset, mean SSM for males was higher than female (23.06 ± 6.2 vs. 21.78 ± 5.93 kPa; p = 0.028). SSM value correlated with LSM (r = 0.454, p = 0.001). Mean SSM in subjects with LSM 3-4, 4.1-5 and 5.1-6 kPa were 21.7 ± 5.8, 22.27 ± 5.67 and 23.76 ± 5.88 kPa (p value = 0.001). There was no difference in SSM based on age, BMI, diabetes and liver fat on ultrasound. Above results hold true for subjects in validation subset. CONCLUSION: SSM range in subjects with normal LSM and no vascular liver disease using spleen-dedicated module varies from 15.2 to 31.3 kPa, values being higher in male and not affected by Age, BMI, spleen size, liver fat and diabetes. Our results may serve as reference point in evaluation of SSM in compensated advanced liver disease patients.

Early Versus Standard Initiation of Terlipressin for Acute Kidney Injury in ACLF: A Randomized Controlled Trial (eTerli Study).

BACKGROUND AND AIMS: Terlipressin infusion is effective in hepatorenal syndrome (HRS-AKI). However, its efficacy for HRS-AKI resolution in acute-on-chronic liver failure (ACLF) patients has been suboptimal. Progression of AKI is rapid in ACLF. We investigated whether early initiation of terlipressin(eTerli) can improve response rates. METHODS: Consecutive ACLF patients with stage II/III AKI despite albumin resuscitation (40 g) were randomized to receive terlipressin at 2 mg/24 h plus albumin at 12 h (ET, n = 35) or at 48 h as standard therapy (ST, n = 35). (June 22, 2020 to June 10, 2022). The primary end-point was AKI reversal by day7. RESULTS: Baseline parameters including AKI stage and ACLF-AARC scores in two arms were comparable. Full AKI response at day 7 was higher in ET [24/35 (68.6%)] than ST arm [11/35 (31.4%; P 0.03]. Day3 AKI response was also higher in ET arm [11/35 (31.4%) vs. 4/35 (11.4%), P 0.04]. Using ST compared to ET [HR 4.3; P 0.026] and day 3 serum creatinine > 1.6 mg/dl [HR 9.1; AUROC-0.866; P < 0.001] predicted HRS-AKI non-response at day 7. ET patients showed greater improvement in ACLF grade, mean arterial pressure, and urine output at day 3, and required lower albumin within 7 days than ET arm (149.1 ± 41.8 g vs. 177.5 ± 40.3 g, P 0.006) and had lower 28-day mortality: 40% vs. 65.7%, P 0.031]. Early use of terlipressin than ST [HR 2.079; P 0.038], baseline HE [HR 2.929; P 0.018], and AKI persistence at day 3 [HR 1.369; P 0.011] predicted 28-day mortality. Fifteen (21.4%) patients had treatment related adverse effects, none was life threatening. CONCLUSION: In ACLF patients, early initiation of terlipressin for AKI persisting after 12 h of volume expansion with albumin helps in reduced short-term mortality and early AKI reversal with regression of ACLF stage. These results indicate need for change in current practice for terlipressin usage in HRS-AKI.

Ethanol with thioacetamide murine model of alcoholic liver disease identifies hepatic pathways as targets for the human disease.

INTRODUCTION AND OBJECTIVES: Hepatic proteome and gut microbiota alterations are known in alcohol-associated hepatitis (AAH). Current animal models sparsely mimic human AAH. We aimed to develop an murine model that closely resembled human AAH. MATERIALS AND METHODS: Male C57BL/6N mice were pair-fed control/incremental ethanol Lieber-DeCarli diets and thioacetamide (TAA) for 12-weeks to induce AAH. Hepatic proteome was analyzed using LC-MS/MS. Gut-bacteria was determined using 16s-rRNA sequencing. RESULTS: Mice exposed to EtOH+TAA displayed higher expression of liver triglycerides (1.5-fold, p = 0.001), pro-inflammatory (IL6, 1.5-fold, p = 0.002 and TNFα, 1.7-fold, p = 0.01), fibrotic (TGF-ß, 2.7-fold, p = 0.01 and Col1α1, 2-fold, p = 0.01) and oxidative markers (GSH and SOD (-1.5 fold, p = 0.004 & 0.005 respectively)) as compared to EtOH alone. Histology of EtOH+TAA liver displayed pericellular liver fibrosis, increased steatosis, and neutrophil infiltration, which resembled human AAH. In the 12wk EtOH+TAA group, Desulfobacteria, Campylobacteria, and Patescibacteria increased by 2-fold (p = 0.02). Pathway combined score (CS, log10) in EtOH+TAA treatment showed upregulated hepatic ethanol oxidation (CS=1.93), fatty acid biosynthesis (CS=2.48), necrosis (CS=1.59), collagen formation (CS=1.28) and hypoxia (CS=0.68) and downregulated fatty acid beta-oxidation (CS=2.37), PPAR signaling (CS=1.35) fatty acid degradation (CS=2.35), bile acid metabolism (CS=1.87), and oxidative phosphorylation (CS=1.50), as observed in human disease. CONCLUSIONS: Using an ethanol-thioacetamide combination in mice results in a faster establishment of AAH with fibrosis than previously known models. Differential protein expression strongly correlates with pathways found altered in human AAH, thus making the model mimic human disease better than other known models., respectively. Thioacetamide (TAA) was administered to enhance liver fibrosis and mimic human AAH.

Clinical and Genomic Perspective of SARS CoV-2 Infection in Liver Disease Patients: A Single-Centre Retrospective Study.

The limited literature on the clinical course of COVID-19 among patients with underlying liver disease (LD) is available from India. The present study aimed to evaluate the clinical and mutational profile of SARS-CoV-2 among LD cases. This was a retrospective study including admitted LD cases in whom SARS-CoV-2 RT-PCR testing was performed. Complete demographic and clinical details were retrieved from Hospital Information System. Detailed mutational analysis was performed by comparing LD COVID-19 positive study group, i.e. LD-CoV(+) with COVID-19 positive outpatients without any underlying LD as control, i.e. NLD-CoV(+). Out of 232 enrolled LD cases, 137 (59.1%) were LD-CoV(+). LD cases with existing co-morbidities were affected more (P = 0.002) and had 2.29 times (OR 2.29, CI 95%, 1.25-4.29) higher odds of succumbing to COVID-19 (P = 0.006). On multivariate regression analysis, ascites (P = 0.05), severe COVID-19 pneumonia (P = 0.046), and an increased levels of bilirubin (P = 0.005) and alkaline phosphatase (P = 0.003) were found to be associated with adverse outcome in LD-CoV(+).On mutational analysis, we found certain differences between LD- and NLD-CoV(+) infected with Delta [LD- and NLD-CoV (+ /D)] and Omicron [LD- and NLD-CoV(+/O)]. More mutations were shared between LD- and NLD-CoV(+/O) compared to LD- and NLD-CoV(+/D). There were differences in prevalence of indel mutations specific to LD-CoV ( +) for both Delta and Omicron. Moreover, we also reported an interesting genic bias between LD- and NLD-CoV( +) in harbouring deleterious/tolerated mutations. To conclude, LD cases with comorbidities were affected more and had higher odds of mortality due to COVID-19. The definite difference between LD- and NLD-CoV(+) groups with respect to frequency of harboured mutations and an inherent genic bias between them is of noteworthy importance.

Therapeutic plasma exchange provides native liver survival benefit in children with acute liver failure: A propensity score-matched analysis.

OBJECTIVES: This study aimed to evaluate the safety and efficacy of therapeutic plasma exchange (TPE) in pediatric acute liver failure (PALF). METHODS: All children aged 2-18 years with PALF were included. The intervention cohort included a subset of PALF patients undergoing complete three sessions of TPE, whereas the matching controls were derived by propensity score matching from the patient cohort who did not receive any TPE. Propensity matching was performed based on the international normalized ratio (INR), grade of hepatic encephalopathy (HE), age, bilirubin, and ammonia levels. The primary outcome measure was native liver survival (NLS) in the two arms on day 28. RESULTS: Of the total cohort of 403 patients with PALF, 65 patients who received TPE and 65 propensity-matched controls were included in analysis. The 2 groups were well balanced with comparable baseline parameters. On day 4, patients in the TPE group had significantly lower INR (P = 0.001), lower bilirubin (P = 0.008), and higher mean arterial pressure (MAP) (P = 0.033) than controls. The NLS was 46.15% in the TPE arm and 26.15% in the control arm. The overall survival (OS) was 50.8% in the TPE arm and 35.4% in the control arm. Kaplan-Meier survival analysis showed a significantly higher NLS in patients receiving TPE than controls (P = 0.001). On subgroup analysis, NLS benefit was predominantly seen in hepatitis A-related and indeterminate PALF. CONCLUSION: TPE improved NLS and OS in a propensity-matched cohort of patients with PALF. Patients receiving TPE had lower INR and bilirubin levels and higher MAP on day 4.

Impact of educational interventions on hepatitis B and C awareness among school students of Delhi NCR, India.

BACKGROUND: Viral hepatitis, particularly B and C, is a major cause of liver cirrhosis and cancer, leading to about 1.4 million deaths annually. Alarmingly, less than 20% of those with hepatitis are aware of their status, with only 6.3% receiving treatment. School children can play a pivotal role in raising awareness and preventing the spread of infections. This intervention study focuses on understanding and enhancing the knowledge, attitudes, and practices related to Hepatitis B and C, among school children in Delhi NCR to foster dialogue and awareness. METHODS: An intervention study was conducted in selected schools across Delhi NCR between September and October 2022 to assess baseline knowledge, attitudes, and practices related to Hepatitis B and C. Three of seven schools were randomly selected by probability sampling, representing 9-12 grade students, and 901 students participated. Following this, an educational interventional program was conducted using educational material, interactive sessions, and audiovisual aids. Post-intervention assessments were done to measure the impact on knowledge improvement. RESULTS: The study is expected to provide insights into the current level of awareness regarding Hepatitis B and C. Furthermore, the intervention's effectiveness was analysed using the pre-formed questionnaire. The average pre-test knowledge score was 8.9 ± 3.2, while the post-test average was 15.6 ± 4.4, indicating a substantial increase of 6.7 ± 4.7 points (+ 75.2%). There was a positive correlation of 0.240 between pre and post-test scores. Attitude change before and after the session showed a positive percentage change of + 38.0% with a correlation of 0.351. The study indicated substantial improvements in knowledge about hepatitis B and C, notably regarding awareness about transmission methods and risk factors. CONCLUSION: This interventional study seeks to bridge the knowledge gap among school children regarding Hepatitis B and C in Delhi NCR, fostering a proactive approach towards prevention, detection, and treatment. The considerable rise in awareness and favourable changes in perspectives post-intervention say that specific health education initiatives are pivotal in raising awareness and comprehension of infectious diseases, ultimately contributing to improving community health.

A randomised-controlled trial (TARGET-C) of high vs. low target mean arterial pressure in patients with cirrhosis and septic shock.

BACKGROUND & AIMS: A high mean arterial pressure (MAP) target has been associated with improved renal outcomes in patients with cirrhosis, though it has not been studied in critically ill patients with cirrhosis and septic shock (CICs). We compared the efficacy of a high (80-85 mmHg; H-MAP) vs. low (60-65; L-MAP) target MAP strategy in improving 28-day mortality in CICs. METHODS: We performed open-label 1:1 randomisation of 150 CICs (H-MAP 75; L-MAP 75). The primary endpoint was 28-day mortality and secondary endpoints included reversal of shock, acute kidney injury (AKI) at day 5, the incidence of intradialytic hypotension (IDH), and adverse events. Endothelial markers were analysed in a subset of patients. RESULTS: The baseline characteristics were comparable. On intention-to-treat analysis, 28-day mortality (65% vs. 56%; p = 0.54), reversal of shock (47% vs. 53%; p = 0.41) and AKI development (45% vs. 31%;p = 0.06) were not different between the H-MAP and L-MAP groups, respectively. A lower incidence of IDH (12% vs. 48%; p <0.001) and higher adverse events necessitating protocol discontinuation (24% vs. 11%; p = 0.031) were noted in the H-MAP group. On per-protocol analysis (L-MAP 67; H-MAP 57), a significantly higher reversal of AKI (53% vs. 31%; p = 0.02) and a lower incidence of IDH (4% vs. 53%; p <0.001) were observed in the H-MAP group. Endothelial repair markers such as ADAMTS (2.11 ± 1.13 vs. 1.15 ± 0.48; p = 0.002) and angiopoietin-2 (74.08 ± 53.00 vs. 41.80 ± 15.95; p = 0.016) were higher in the H-MAP group. CONCLUSIONS: A higher MAP strategy does not confer a survival benefit in CICs, but improves tolerance to dialysis, lactate clearance and renal recovery. Higher adverse events indicate the need for better tools to evaluate target microcirculation pressures in CICs. IMPACT AND IMPLICATIONS: Maintaining an appropriate organ perfusion pressure during sepsis is the ultimate goal of haemodynamic management. A higher mean arterial pressure (MAP) improves renal outcomes in patients with hepatorenal syndrome. Patients with cirrhosis and septic shock have severe circulatory disturbances, low MAP, and poor tissue perfusion. In these patients, targeting higher MAP vs. lower MAP does not confer any survival benefit but is associated with more adverse events. A higher target strategy was associated with better tolerance and lesser episodes of hypotension on dialysis. Patients who could achieve the higher target MAP, without the development of adverse events, had improved renal outcomes and better lactate clearance. Higher MAP was also associated with improvements in markers of endothelial function. A higher target MAP strategy, with close monitoring of adverse events, may be recommended for patients with cirrhosis and septic shock. CLINICAL TRIAL NUMBER: NCT03145168.

Hepatopulmonary syndrome is associated with low sphingosine-1-phosphate levels and can be ameliorated by the functional agonist fingolimod.

BACKGROUND & AIMS: Hepatopulmonary syndrome (HPS) is characterised by a defect in arterial oxygenation induced by pulmonary vascular dilatation in patients with liver disease. Fingolimod, a sphingosine-1-phosphate (S1P) receptor modulator, suppresses vasodilation by reducing nitric oxide (NO) production. We investigated the role of S1P in patients with HPS and the role of fingolimod as a therapeutic option in an experimental model of HPS. METHODS: Patients with cirrhosis with HPS (n = 44) and without HPS (n = 89) and 25 healthy controls were studied. Plasma levels of S1P, NO, and markers of systemic inflammation were studied. In a murine model of common bile duct ligation (CBDL), variations in pulmonary vasculature, arterial oxygenation, liver fibrosis, and inflammation were estimated before and after administration of S1P and fingolimod. RESULTS: Log of plasma S1P levels was significantly lower in patients with HPS than in those without HPS (3.1 ± 1.4 vs. 4.6 ± 0.2; p <0.001) and more so in severe intrapulmonary shunting than in mild and moderate intrapulmonary shunting (p <0.001). Plasma tumour necrosis factor-α (76.5 [30.3-91.6] vs. 52.9 [25.2-82.8]; p = 0.02) and NO (152.9 ± 41.2 vs. 79.2 ± 29.2; p = 0.001) levels were higher in patients with HPS than in those without HPS. An increase in Th17 (p <0.001) and T regulatory cells (p <0.001) was observed; the latter inversely correlated with plasma S1P levels. In the CBDL HPS model, fingolimod restored pulmonary vascular injury by increasing the arterial blood gas exchange and reducing systemic and pulmonary inflammation, resulting in improved survival (p = 0.02). Compared with vehicle treatment, fingolimod reduced portal pressure (p <0.05) and hepatic fibrosis and improved hepatocyte proliferation. It also induced apoptotic death in hepatic stellate cells and reduced collagen formation. CONCLUSIONS: Plasma S1P levels are low in patients with HPS and even more so in severe cases. Fingolimod, by improving pulmonary vascular tone and oxygenation, improves survival in a murine CBDL HPS model. IMPACT AND IMPLICATIONS: A low level of plasma sphingosine-1-phosphate (S1P) is associated with severe pulmonary vascular shunting, and hence, it can serve as a marker of disease severity in patients with hepatopulmonary syndrome (HPS). Fingolimod, a functional agonist of S1P, reduces hepatic inflammation, improves vascular tone, and thus retards the progression of fibrosis in a preclinical animal model of HPS. Fingolimod is being proposed as a potential novel therapy for management of patients with HPS.

A randomized-controlled trial comparing 20% albumin to plasmalyte in patients with cirrhosis and sepsis-induced hypotension [ALPS trial].

BACKGROUND & AIMS: The choice of resuscitation fluid in patients with cirrhosis and sepsis-induced hypotension is unclear. 5% albumin was superior to normal saline in the FRISC study. We compared the efficacy and safety of 20% albumin, which has greater oncotic properties, to plasmalyte in reversing sepsis-induced hypotension. METHODS: Critically ill patients with cirrhosis underwent open-label randomization to receive either 20% albumin (0.5-1.0 g/kg over 3 hours; n = 50) or plasmalyte (30 ml/kg over 3 hours, n = 50). The primary endpoint of the study was the attainment of mean arterial pressure (MAP) above 65 mmHg at 3 hours. RESULTS: Baseline characteristics were comparable in albumin and plasmalyte groups; arterial lactate (6.16±3.18 mmol/L vs. 6.38±4.77 mmol/L; p = 0.78), MAP (51.4±6.52 mmHg vs. 49.9±4.45 mmHg; p = 0.17) and SOFA score (10.8±2.96 vs. 11.1±4.2; p = 0.68), respectively. Most patients were alcoholics (39%) and had pneumonia (40%). In the intention-to-treat analysis, albumin was superior to plasmalyte in achieving the primary endpoint (62% vs. 22%; p <0.001). A faster decline in arterial lactate (p = 0.03), a reduced need for dialysis (48% vs. 62%; p = 0.16), and a longer time to initiation of dialysis (in hours) (68.13±47.79 vs. 99.7± 63.4; p = 0.06) were seen with albumin. However, the 28-day mortality rate was not different (58% vs. 62%, p = 0.57) and treatment had to be discontinued in 11 (22%) patients in the albumin group due to adverse effects compared to no discontinuations in the plasmalyte group. CONCLUSION: In patients with cirrhosis and sepsis-induced hypotension, 20% albumin leads to a faster improvement in hemodynamics and lactate clearance than plasmalyte, while 28-day survival was similar. However, patients on 20% albumin need to be closely monitored as it was more often associated with pulmonary complications. CLINICAL TRIAL REGISTRATION: NCT02721238. LAY SUMMARY: The current randomized-controlled trial performed in critically ill patients with cirrhosis and sepsis-induced hypotension highlights that 20% albumin restores arterial pressure more quickly but causes more pulmonary complications than plasmalyte. The impact on renal functions was also modest. These effects did not result in improvement in survival at 28 days. Plasmalyte is safer and well-tolerated and can be considered for volume resuscitation in patients with cirrhosis and sepsis-induced hypotension.

Standard-Volume Plasma Exchange Improves Outcomes in Patients With Acute Liver Failure: A Randomized Controlled Trial.

BACKGROUND: High volume plasma-exchange (HVPE) improves survival in patients with acute liver failure (ALF), but apprehension regarding volume overload and worsening of cerebral edema remain. METHODS: In an open-label randomized controlled trial, 40 consecutive patients of ALF were randomized 1:1 to either standard medical treatment (SMT) or SMT with standard-volume plasma-exchange (SVPE). SVPE was performed using centrifugal apheresis [target volume of 1.5 to 2.0 plasma volumes per session] until desired response was achieved. Cerebral edema was assessed by brain imaging. Results were analyzed in an intention-to-treat analysis. Primary outcome was 21-day transplant-free survival. The levels of cytokines, damage-associated molecular patterns (DAMPs) and endotoxins were analyzed at baseline and day 5. RESULTS: ALF patients [aged 31.5 ± 12.2 years, 60% male, 78% viral, 83% hyperacute, 70% with SIRS were included. At day 5, SVPE [mean sessions 2.15 ± 1.42, median plasma volume replaced 5.049 L] compared to SMT alone, resulted in higher lactate clearance (p = .02), amelioration of SIRS (84% vs. 26%; P = .02), reduction in ammonia levels [(221.5 ± 96.9) vs.(439 ± 385.6) µg/dl, P = .02) and SOFA scores [9.9(±3.3) vs. 14.6(±4.8); P = .001]. There were no treatment related deaths. SVPE was associated with a higher 21-day transplant free-survival [75% vs. 45%; P = .04, HR 0.30, 95%CI 0.01-0.88]. A significant decrease in levels of pro-inflammatory cytokines and an increase in anti-inflammatory cytokines along with a decrease in endotoxin and DAMPs was seen with SVPE. CONCLUSION: In ALF patients with cerebral edema, SVPE is safe and effective and improves survival possibly by a reduction in cytokine storm and ammonia. CLINICALTRIAL: gov (identifier: NCT02718079).

Natural history, spectrum and outcome of stage 3 AKI in patients with acute-on-chronic liver failure.

BACKGROUND AND AIM: There is limited data on natural course and interventions in stage-3 acute kidney injury (AKI-3) in patients with acute-on-chronic liver failure (ACLF). We studied the factors of AKI-3 reversal and outcomes of dialysis in ACLF patients. METHODS: Consecutive patients with ACLF were prospectively enrolled (n = 1022) and variables determining AKI and its outcomes were analysed. RESULTS: At 1 month, 337 (33%) patients had AKI-3, of which, 131 had AKI-3 at enrolment and 206 developed AKI-3 during hospital stay. Of patients with AKI-3 at enrolment, 18% showed terlipressin response, 21% had AKI resolution and 59% required dialysis. High MELD (≥35) (model 1), serum bilirubin (≥23 mg/dL) (model 2) and AARC score (≥11) (model 3) were independent risk factors for dialysis. Dialysis was associated with worse survival in all AKI patients but improved outcomes in patients with AKI-3 (p = .022, HR 0.69 [0.50-0.95]). Post-mortem kidney biopsies (n = 61) revealed cholemic nephropathy (CN) in 54%, acute tubular necrosis (ATN) in 31%, and a combination (CN and ATN) in 15%. Serum bilirubin was significantly higher in patients with CN, CN and ATN compared with ATN respectively ([30.8 ± 12.2] vs. [26.7 ± 12.0] vs. [18.5 ± 9.8]; p = .002). CONCLUSION: AKI-3 rapidly increases from 13% to 33% within 30 days in ACLF patients. Histopathological data suggested cholemic nephropathy as the predominant cause which correlated with high bilirubin levels. AKI-3 resolves in only one in five patients. Patients with AARC grade 3 and MELD >35 demand need for early dialysis in AKI-3 for improved outcomes.

Subjective global nutritional assessment as a nutritional tool in childhood chronic liver disease.

Objective of the study was to assess subjective global nutritional assessment (SGNA) in children with chronic liver diseases (CLD). Children aged 3 months to 18 years with CLD were prospectively enrolled (January 2016 to October 2018). SGNA was performed as per validated pro forma for children. Nutritional categories were categorised into three groups: A (well-nourished), B (moderately malnourished) and C (severely malnourished). Agreement between SGNA and anthropometric measures, prediction of morbidity and death or liver transplantation (LT) at 1-year post-enrolment by SGNA and inter-observer reliability of SGNA were assessed. Ninety-two subjects were enrolled, median age 23·5 (3-216) months. SGNA classified 47 patients (51·1 %) in group A, 26 (28·3 %) in group B and 19 (20·6 %) in group C. Kendall coefficients disclosed significant association of SGNA with all anthropometric measurements, greatest with weight for age (r = -0·637), height for age (r = -0·581) and mid-arm fat area (r = -0·449). At 12 months follow-up, twenty children died and four received LT. A significantly higher number of children with malnutrition (groups B and C) had poor outcome (OR 6·74 (95 % CI 2·21, 20·55), P = 0·001), increased risk of hospital readmission (OR 12·2 (95 % CI 4·60, 35·88), P = 0·001), higher rate of infectious complications (OR 22·68 (95 % CI 7·29, 70·53), P < 0·0001) and lower median survival with native liver (Log Rank < 0·001) as compared with group A. Inter-observer agreement in assessment of SGNA was good (90·2 %). SGNA, in contrast to anthropometric measures, is a better nutritional assessment tool. It is reliable, comprehensive and predicts poor outcome in childhood CLD.

Mannitol Is Comparable to Hypertonic Saline for Raised Intracranial Pressure in Acute Liver Failure (MAHAL Study): A Randomized Controlled Trial.

BACKGROUND: Raised intracranial pressure (ICP) due to cerebral edema (CE) is central to development of hepatic encephalopathy in acute liver failure (ALF). Mannitol (MT) and hypertonic saline (HS) have been shown to improve CE. We compared the efficacy and safety of the 2 modalities. METHODS: ALF with CE was prospectively randomized in an open study to receive either 5 mL/kg of either 3% HS, as continuous infusion; titrated every 6 hourly to achieve serum sodium of <160 (Group A; n = 26) or 1 g/kg of 20% MN as a IV bolus, repeated every 6 hourly (Group B; n = 25) in addition to standard ALF care. Primary end-point was reduction of ICP defined as optic nerve sheath diameter <5 mm and middle cerebral arterial pulsatility index <1.2 at 12 h. RESULTS: Fifty-one patients with ALF, hepatitis E being commonest (33.3%), median jaundice to HE interval of 8 (1-16) days, were randomized to HS (n = 26) or MN (n = 25). Baseline characteristics were comparable including King's college criteria (>2: 38.4% vs.40%). Overall, 61.5% patients in the HS and 56% in the MN group showed reduction in ICP at 12 h (p = 0.25). Rebound increase in ICP indices was noted in 5 (20%) patients in MT and none in HS (p < 0.05) group. New onset acute kidney injury was common in the MT group than in the HS group. The ICU stay and 28-day transplant-free survival were not different between the groups. CONCLUSIONS: While both agents had comparable efficacy in reducing ICP and mortality in ALF patients was comparable, HS was significantly better in preventing reducing rebound CE with lower renal dysfunction.

Clinical Outcomes in Patients with Advanced Chronic Liver Disease and Hepatic Venous Pressure Gradient ≤ 10 mm Hg.

BACKGROUND AND AIMS: Clinically significant portal hypertension (CSPH), defined as hepatic venous pressure gradient (HVPG) ≥ 10 mmHg predicts clinical decompensation (CD) in cirrhosis. A proportion of cirrhosis patients have HVPG 6-10 mmHg. Their natural history is largely unknown. DESIGN: Consecutive patients with advanced chronic liver disease (aCLD) [histological cirrhosis(n = 196) or liver stiffness measurement (LSM) > 15 kPa(n = 65)] and HVPG 6-10 mmHg were included. Primary objective was to study their natural course and patterns of CD. We also analyzed the predictors of CD at presentation and on follow-up and response to carvedilol. RESULTS: Of 261 patients with HVPG 6-10 mmHg, 129(49.4%) had CD at first presentation; 78(29.9%) had single and 51(19.5%) had ≥ 2 CD. The most common CDs were ascites(n = 77) and jaundice(n = 65). A baseline HVPG ≥ 8 mmHg was independently associated with greater risk of CD [HR:1.7; p-0.002, AUROC:0.85(95%CI-0.81-0.91)]. New CD developed in 14.4% patients with compensated aCLD (median duration-23.1 months). Despite comparable baseline HVPG, patients developing new CD had higher HVPG on follow-up(15.3 ± 3.7 vs. 8 ± 2.1 mmHg; p < 0.001). Baseline LSM > 26.6 kPa, portosystemic shunt and serum albumin independently predicted new CD. Overall HVPG response to carvedilol(n = 60) was 23.3%, independent of baseline CD and HVPG. Five-year mortality was higher with ≥ 2 CD compared to single or no CD (23.5, 10 and 3%, respectively; p < 0.001). CONCLUSION: Nearly one-half of aCLD patients with HVPG 6-10 mmHg had CD, justifying the need to redefine CSPH. Interventions to reduce portal pressure in patients with HVPG ≥ 8 mmHg might improve long-term outcomes.

Reversal of Feed Intolerance by Prokinetics Improves Survival in Critically Ill Cirrhosis Patients.

BACKGROUND AND AIMS: Feed intolerance (FI) is common in cirrhosis patients in intensive care units (ICU). Prokinetics are the first line treatment for FI but their efficacy and safety in critically ill patient with cirrhosis is unknown. We evaluated the role of prokinetics in reversal of FI and clinical outcomes. METHODS: Consecutive patients admitted in ICU developing new-onset FI, were randomized to receive either intravenous metoclopramide (Gr.A, n = 28), erythromycin (Gr.B, n = 27) or placebo (Gr.C, n = 28). FI was defined with the presence of 3 of 5 variables- absence of bowel sounds, gastric residual volume ≥ 500 ml, vomiting, diarrhoea and bowel distension. Primary end-point was complete resolution of FI (≥ 3 variables resolved) within 24-h and secondary end-points included resolution within 72-h and survival at 7-days. RESULTS: Of the 1030 ICU patients, 201 (19.5%) developed FI and 83 patients were randomized. Baseline parameters between the groups were comparable. Complete resolution at 24-h was higher in Gr.A (7.14%) and B (22.2%) than C (0%, p = 0.017). Overall, 58 (69.9%) patients achieved resolution within 72 h, more with metoclopramide (n = 24, 85.7%) and erythromycin (n = 25, 92.6%) than with placebo (n = 9, 32.1%, p < 0.001). The 7-day survival was better in patients who achieved resolution within 72-h (65.5 vs. 36%, p = 0.011) than non-responders. High lactate (OR-3.32, CI-1.45-7.70, p = 0.005), shock at baseline (OR-6.34, CI-1.67-24.1, p = 0.007) and resolution of FI within 72 h (OR-0.11, CI, 0.03-0.51, p = 0.04) predicted 7-day mortality. CONCLUSIONS: FI is common in critically-ill cirrhosis patients and non-resolution carries high mortality. Early recognition and treatment with prokinetics is recommended to improve short-term survival.

Gastrointestinal dysmotility is common in cirrhosis and higher incidence in critically ill patients. Promotility drugs are the first line of medication especially in ICU patients. In our study, we found that feed intolerance is present in nearly one in five critically ill cirrhosis and is associated with higher mortality. Patients who achieve resolution had an improved short-term survival. Prokinetic medications are safe in critically ill cirrhosis and help in early resolution of feed intolerance. Feed intolerance in critically ill cirrhosis should be recognized as an organ dysfunction and approaches for prevention and early diagnosis of feed intolerance could help in improving the outcomes in critical illness.

Comparison of safety and efficacy of convalescent plasma with fresh frozen plasma in severe covid-19 patients.

BACKGROUND: Role of Convalescent plasma (COPLA) to treat severe COVID-19 is under investigation. We compared efficacy and safety of COPLA with fresh frozen plasma (FFP) in severe COVID-19 patients. METHODS: One group received COPLA with standard medical care (n = 14), and another group received random donor FFP, as control with standard medical care (n = 15) in severe COVID-19 disease. RESULTS: The proportion of patients free of ventilation at day seven were 78.5% in COPLA group, and 93.3 % in control group were not significant (p= 0.258). However, improved respiratory rate, O2 saturation, SOFA score, and Ct value were observed in the COPLA group. No serious adverse events were noticed by plasma transfusion in both groups.