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. 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. 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

Dilated and dysfunctional gut lymphatic vessels (LVs) have been reported in experimental cirrhosis. Here, we studied LVs in duodenal (D2)-biopsies of liver cirrhosis patients and investigated the prognostic role of a LV marker, podoplanin (PDPN), in predicting the mortality of patients with cirrhosis. A prospective, single-center cohort study was performed in liver cirrhosis patients (n = 31) and matched healthy controls (n = 9). D2-biopsies were obtained during endoscopy procedure, immunostained with PDPN, and scored based on 1) intensity and 2) density of positively-stained LVs per high power field. Gut and systemic inflammation were estimated by quantifying duodenal CD3+ intraepithelial lymphocytes (IELs), CD68+ macrophages, and serum TNF-α and IL-6 levels, respectively. Gut permeability and inflammation as assessed by quantifying gene expression of TJP1, OCLN, TNF-α, and IL-6 in D2-biopsies. Gene expression of LV markers, PDPN (8-fold), and LYVE1 (3-fold) was enhanced in D2-biopsies of cirrhosis patients compared to control (p < 0.0001). The mean PDPN score in decompensated cirrhosis patients (6.91 ± 1.26, p < 0.0001) was significantly increased as compared to those with compensated (3.25 ± 1.60). PDPN score positively and significantly correlated with the number of IELs (r = 0.33), serum TNF-α (r = 0.35), and IL-6 (r = 0.48) levels, while inversely correlated with TJP1 expression (r = -0.46, p < 0.05 each). In Cox regression, the PDPN score was a significant and independent 3-month-mortality predictor in patients (HR: 5.61; 1.08-29.109; p = 0.04). The area under the curve for the PDPN score was 84.2, and cutoff value for predicting mortality was ≥6.5 with 100% sensitivity and 75% specificity. Collectively, dilated LVs with high PDPN expression in D2-biopsies is a characteristic feature of patients with decompensated cirrhosis. PDPN score correlates with enhanced gut and systemic inflammation and also associates with 3-month mortality in cirrhosis.

Background and Aim: Propranolol is effective in preventing first variceal bleed in cirrhosis patients, but can have adverse effects in patients with severe ascites. Midodrine, alpha-1 aenergic agonist, increases mean arterial pressure (MAP) by increasing splanchnic and systemic blood pressure. We studied the efficacy of addition of Midodrine with propranolol in these patients. Methods: In this open-label, randomized controlled trial, decompensated cirrhosis patients with severe ascites, were randomised to either propranolol plus Midodrine combination (Gr.A) or to propranolol monotherapy (Gr.B). Dose of propranolol was escalated in both the groups to achieve target heart rate (THR). Midodrine dose was adjusted to MAP >70 mmHg. The dose escalation was performed for two weeks and the patients were followed. Primary endpoints included proportion of patients who did not bled at 1 year. Secondary endpoints included proportion of patients achieving complete and partial resolution of ascites, development of complications including SBP, hepatic encephalopathy, paracentesis induced circulatory dysfunction (PICD), AKI, hyponatremia and survival at 1 year. Results: A total of 140 patients were randomized to the groups. Baseline parameters such as age, CTP, MELD, high risk esophageal varices, severe ascites, MAP, sarcopenia were comparable between the groups. The incidence of first variceal bleed was lower in Gr.A than B (8.5% vs 25.7%; p=0.043). Patients in gr.A achieved THR (84.2 % vs 55.7%), with maximum tolerable daily dose of propranolol (96.6 ±36.6 mg vs 76.5 ±24.4 mg), with paracentesis requirement (11.4% vs 24.2%, p-0.013), PICD (22.8% vs 51.4%, p=0.01), SBP (10 % vs 15.7%, p-0.03), diuretic introduction (80% vs 60%, p=0.047). The mean HVPG reduction was 4.3 mm Hg (23.5%) vs 2.6 mm Hg (14.5%) (p=0.045) over a period of 3 months. Conclusions: Addition of Midodrine to beta-blockers in decompensated cirrhosis with severe ascites improves systemic hemodynamics and helps in prevention of variceal bleed and better control of ascites.

Background and Aim: Cirrhosis is a state of immune dysfunction and exhaustion which leads to worse outcomes. Previous studies have shown prevention of sepsis with immune modulation in patients with ACLF and decompensated cirrhosis. Spontaneous bacterial peritonitis (SBP) lead to septic shock and multi-organ failure. We studied the efficacy of adding GM-CSF to imipenem and tigecycline in these patients. Methods: Consecutive patients of cirrhosis with SBP and septic shock were enrolled and randomized into imipenem and tigecycline (Gr.A) and imipenem, tigecycline and GM-CSF (Gr.B). Standard dose of Imipenem and tigecycline were administered in both groups and intravenous GM-CSF 500mcg administered as infusion over 24 hours for 5 days and followed up till day-28. Primary objective included resolution of SBP at day 5. Secondary objective included response at day 2, reversal of shock, development of complications (HE, AKI, pneumonia, coagulopathy) and survival at 7-day and 28-day. Results: Overall, 90 patients were enrolled and randomized into the two groups. Baseline characteristics were comparable between groups age, organ failures, serum creatinine, serum bilirubin, ascitic fluid analysis, serum lactate, procalcitonin, CTP, MELD and APACHE score. In Gr A compared to Gr. B, the resolution of SBP at day 5 was seen in 51.1% vs 71.1% (p=0.035), complete response at day 2 was seen in 40% vs 64.4% (p<0.001), reversal of shock in 66.7% vs 80% (p=0.04), AKI resolution in 20% vs 42.2% (p=0.001), pneumonia resolution in 28.8% vs 51.1% (p=0.03), lactate clearance 1.8±0.4 vs 2.9±0.8 units (p=0.005), survival at day 7 in 64.4% versus 84.4% (p=0.014) was seen. Conclusions: Our results clearly show that a combination of imipenem, tigecycline with GM-CSF gives higher resolution of SBP, AKI, pneumonia along with reversal of shock, and improved survival in patients with decompensated cirrhosis having SBP and septic shock.

Background: Bowel colonization with anti-microbial resistant bacteria is associated with worse outcomes in post-transplant setting, and among immunocompromised. Aims: To study the faecal carriage of anti-microbial resistant, potentially pathogenic bacterial species among hospitalized patients with ACLF, and correlate it with extra- intestinal infections and clinical outcome. Methods: 130 inpatients with ACLF (APASL criteria), admitted to ILBS were screened for inclusion between Jun2020-Feb2021, and 95 were included. Stool cultures were carried out at baseline, and every five days thereafter till discharge or death. All surviving patients were followed up till 60 days after discharge. Primary objective was fecal isolation rates of carbapenem resistant gram-negative bacterial species(CR+GNB). The trial was registered online(NCT04383106 and CTRI/2020/05/025096). Results: Mean age was 44.9(8.7) years, with 88.4% males, and alcohol aetiology in 64.2%. At admission, extended-spectrum beta-lactamase resistant (ESBL+) and CR+GNB were isolated from stool in 46.3% and 40%, respectively, most commonly Klebsiella pneumonia. Fecal carriage of resistant bacteria was associated with higher CTP, MELD and DF scores, but not with recent antibiotic, PPI, or lactulose use. Extra-intestinal infections developed in 58(61.1%). Infection rates were higher with more severe disease, and with ESBL+GNB and/or CR+GNB fecal carriage at admission (77.3% vs. 47.1%; P=0.0032, and 86.8% vs. 43.9%; P<0.001, respectively). Peripheral cultures were positive in 33/58 with extra-intestinal infections, with species and antibiotic resistance concordance with fecal isolates in 30/33. 82(86.3%) survived to discharge, and 72(76.6%) were alive at day60. In-hospital mortality was correlated with renal, cerebral, circulatory, and respiratory organ failures (P<0.001), and with ESBL+GNB(22.7% vs.5.8%; P=0.033), and CR+GNB fecal carriage(31.6% vs.1.8%; P<0.001). Conclusions: Isolation of resistant bacterial species in stool is simple and widely applicable way to stratify ACLF patients for mortality risk. ACLF patients with ESBL+ or CR+GNB isolates in stool have higher extra-intestinal infections, in-hospital mortality, and mortality after initial discharge upto 3 months. Study limitations: Concordance between bowel colonising resistant species and peripheral isolates not be established by molecular typing.

Background: Steroids are mainstay of treatment in severe alcoholic hepatitis and steroid ineligibility is major cause of mortality, specially in the absence of transplant option. There is paucity of data on the proportion and causes of steroid ineligibility, and the natural history and outcome in such patients.This data would help in planning alternative therapeutic strategies.We aimed to study the factors responsible for steroid ineligibility and clinical course of these patients. Methods: Consecutive patients of SAH admitted to the Institute of Liver and Biliary Sciences, between April 2017 to February 2021 were screened for steroid eligibility. All patients who left against medical advice or had likelihood of death within 24 hours of admission, were excluded. The criteria for ineligibility were MDF >90,Acute kidney injury, sepsis, extrahepatic organ failures or severe comorbidities. The patients who developed an event in the hospital or were discharged were followed for 90days survival. Results: Altogether,522 patients were admitted with SAH,138(26.4%) were steroid eligible and 384(73.6%) were ineligible(figure 1).The main reasons for steroid ineligibility were: one or more organ failures in 179(46.7%) patient, with 37(9.6%), 71(18.4%), 28(7.2%) and 43(11.1%) patients having 4,3,2 and 1 organ failures respectively. Specifically, 28.3%(109) patients had AKI, 31.8% (122) had respiratory failure, 33.5% (129) had circulatory failure, 39.3%(159) had grade 3 or more encephalopathy. In addition, 32(8.3%) patients had a DF of >90, 27(7.0%) patients had recent upper GI bleed,25/384(6.5%) had superadded acute viral hepatitis ,20(5.2%) patients had severe alcohol withdrawal and 7(1.8%) had SBP. 15(4%) patients were not given steroid due to spontaneous reduction in mDF to <32 after admission. Further, 42(10.9%) patients were either found to spontaneously improve during the period of evaluation and hence were not taken up for steroid therapy. 37(9.6%) patients were not given steroids due urinary infection, continuous fever, cellulitis, mild COVID and active tuberculosis. The overall survival in the steroid ineligible cohort at day 90 was 54.4%, while the 28 day survival was 58.5%. On multivariate Analysis the presence of any organ failure, Age, albumin, AARC score, Presence of variceal bleed increase the risk of mortality (table1). 42 patients had spontaneously resolving jaundice were not given steroids, out of them 6 patients were readmitted and required the therapy. None of them died on follow up at day 90. Twenty patients had alcohol withdrawal at presentation;6 of them subsequently received steroids. Conclusion: Almost two-third patients with SAH are not eligible to receive steroids and carry a high 90 days mortality. The age, albumin, AARC score, variceal bleed and presence of organ failure predict mortality in steroid non exposed SAH patients. RCT's are needed for comparing various therapies used in such patients. .

Massive cellular necrosis in acute liver failure (ALF) is dominantly immune mediated and innate immune cells are major pathophysiological determinants in liver damage. In fifty ALF and fifteen healthy, immune cells phenotyping by flow-cytometry, DAMPs using ELISA were analysed and correlated with clinical and biochemical parameters. ALF patients (aged 27 +/- 9 yr, 56% males, 78% viral aetiology) showed no difference in neutrophils and classical monocytes, but significantly increased intermediate monocytes (CD14(+)CD16(+)) (p < 0.01), decreased non-classical monocytes (CD1(-)CD16(+)) and CD3(-ve)CD16(+)CD56(+) NK cells compared to HC. ALF patients who survived, showed higher NK cells (9.28 vs. 5.1%, p < 0.001) among lymphocytes and lower serum lactate levels (6.1 vs. 28, Odds ratio 2.23, CI 1.27-3.94) than non-survivors had higher. Logistic regression model predicted the combination of lactate levels with NK cell percentage at admission for survival. In conclusion, Combination of NK cell frequency among lymphocytes and lactate levels at admission can reliably predict survival of ALF patients.

Objective: Gut lymphatic vessels are crucial in maintaining abdominal fluid homeostasis. We studied these vessels in clinical cirrhosis and explored effects of vascular endothelial growth factor-C (VEGF-C), a pro-lymphangiogenic factor, in experimental portal hypertension. Design: Vascular endothelial growth factor receptor 3 (vegfr3)-positive lymphatic channels were enumerated in duodenal (D2) biopsies from cirrhotic patients. Vegfr3 antibody-tagged lipid nanocarriers were used to formulate novel nano-engineered (E-VEGF-C) molecule for targeted lymphangiogenesis of gut lymphatic vessels. The uptake of E-VEGF-C was evaluated in lymphatic endothelial cells (LyECs) in vitro and in vivo. The effects of E-VEGF-C were tested in cirrhotic and non-cirrhotic animal models of portal hypertension. Animals given nanocarriers alone served as vehicle. Mesenteric lymphatic vessel numbers/proliferation and drainage were analyzed. Abdominal ascites, hepatic and systemic hemodynamics was measured. Liver, duodenum, mesentery and plasma were examined. Results: In D2 biopsies, number of dilated vegfr3+ lymphatic vessels was significantly increased in decompensated as compared to compensated cirrhosis and correlated with presence of ascites. E-VEGF-C was efficiently taken up by the mesenteric LyECs. E-VEGF-C treated rats displayed a marked increase in the proliferation of mesenteric lymphatic vessels and drainage as compared to CCl4-vehicle. Ascites and mesenteric inflammation were markedly reduced in E-VEGF-C treated cirrhotic rats. Portal pressures were attenuated in both cirrhotic and non-cirrhotic portal hypertensive rats treated with E-VEGF-C as compared to respective vehicle groups. Conclusion: E-VEGF-C molecule enhances mesenteric lymphangiogenesis and improves lymphatic vessel drainage, attenuating abdominal ascites and portal pressures. Targeted gut lymphangiogenesis may serve as an emerging therapy for portal hypertension.

INTRODUCTION:Critically ill patients with liver disease commonly present to the intensive care unit (ICU) with need for prolonged ventilation, difficult weaning, and refractory coagulopathy. These patients experience both bleeding and thrombotic complications with a precariously balanced state of coagulopathy. The purpose of this study was to assess the bleeding complications of tracheostomy in critically ill patients with liver disease.METHODS:A retrospective study was conducted in liver ICU of a tertiary teaching institute. Medical records were analyzed to assess postprocedure complication rate among 73 critically ill liver disease patients who had undergone tracheostomy during the period of October 2017 to September 2018.RESULTS:Ten out of 73 patients (13%) required transfusion of blood products after 12 h of procedure, despite thromboelastography (TEG)-based correction prior to procedure. Of these, 7 patients (9%) underwent surgical tracheostomy (ST) and three patients (4%) underwent percutaneous tracheostomy. Statistically no significant difference in bleeding was seen among the two groups, but a rising trend was seen with the ST group (P = 0.52). None of the patients experienced procedure-related pneumothorax and subcutaneous emphysema, as observed in the chest X-ray.CONCLUSION:We conclude that coagulopathy should not be deterrence for the performance of tracheostomy in critically ill patients with liver disease. Adequate clotting support guided by the global tests of coagulation, such as TEG, ensures lesser incidence of bleeding.