Response Guided Slow Infusion of Albumin, Vasoconstrictors and Furosemide Improves Ascites Mobilization and Survival in Acute on Chronic Liver Failure: A Proof-of-Concept Study.

Background and Aims: Acute-on-chronic liver failure (ACLF) with increasing organ failure is associated with poor outcomes. Severely deranged systemic hemodynamics and decreased effective arterial blood volume contribute to tissue damage and organ failure. Response-guided therapy with albumin, vasoconstrictors, and furosemide may help overcome effective hypovolemia, improve diuresis and impact survival. Methods: In the observation cohort, 230 patients with ACLF (CANONIC criteria) with ascites (≥Grade II) and ACLF ≥Grade I were enrolled. A total of 136 patients (GROUP I) received response-guided (urine sodium >80mmol/day) slow albumin-furosemide infusion ±â€…terlipressin (SAFI ± T), while 94 patients (GROUP II) received standard medical therapy. Twenty-eight-day survival, ascites mobilization (nil or grade 1), and adverse events were noted. In another mechanistic cohort (n = 40), laboratory evidences for improvement in various pathophysiological alterations; gut permeability, endotoxemia, cytokine storm, neutrophil dysfunction, and hemodynamic alterations following SAFI ± T/Noradrenaline (NAdr) were evaluated. Results: Age, gender, CLIF-C-ACLF, SOFA and MELD scores, ACLF grades and urine sodium were not different between the two groups in the observation cohort. Ascites was mobilized in 102/136 in GROUP I (SAFI ± T) and 23/94 in GROUP II (p < 0.05). Twenty-eight-day survival was significantly higher in GROUP I = 103/136 (75.7%) vs GROUP II = 50/94 (53.2%), (P = <0.001). All those who were unable to reach urine sodium >80 mmol/day died. Four patients in GROUP I developed scrotal gangrene. In the mechanistic cohort, 72% of patients survived with significant improvement in gut permeability, endotoxemia, serum cytokines, neutrophil dysfunction, and hemodynamic alterations. Conclusion: Ascitic fluid mobilization by response-guided SAFI ± T/NAdr therapy improves survival by improving splanchnic and systemic hemodynamics, decreasing gut congestion, gut permeability, and endotoxemia, improving neutrophil functions, and reducing pro-inflammatory cytokines in circulation.

Utility of neutrophil CD64 in distinguishing bacterial infection from inflammation in severe alcoholic hepatitis fulfilling SIRS criteria.

To assess utility of neutrophilCD64 (nCD64) expression in differentiating bacterial infection from inflammation in patients with severe alcoholic hepatitis (SAH) fulfilling systemic inflammatory response syndrome criteria. Patients with SAH and infection (n = 58), SAH without infection (n = 70), and healthy controls (n = 20) were included. Neutrophil CD64 expression by flowcytometry, serum Procalcitonin (ELISA) and C-reactive protein (Nephelometry) and neutrophil-lymphocyte ratio (NLR) were studied. Percentage of neutrophils with CD64 expression (nCD64%) was significantly higher in patients with SAH and infection than in those without infection and controls [76.2% (56.9-86.5) vs. 16% (12.6-23.1) vs. 7.05% (1.4-9.5), p < 0.05], as was their mean fluorescence intensity [MFI; 1431 (229-1828) vs. 853 (20-968) vs. 99.5 (54.7-140.7), p < 0.05]. Using a cut-off of 27%, the sensitivity and specificity of nCD64% to diagnose bacterial infection was 94% and 81%, respectively, with area under curve (AUC) of 0.95. At a cut-off value of 0.261 ng/ml, the sensitivity and specificity of serum procalcitonin was 83% and 72%, respectively, with AUC of 0.86. Serum CRP, total leukocyte count, NLR had AUCs of 0.78, 0.63 and 0.64, respectively. Quantitative measurement of nCD64 can better distinguish systemic bacterial infection and inflammation in SAH as compared to traditional biomarkers.