Vascular endothelial functional dysregulation and barrier disruption are involved the initiation and development of sepsis. Growth arrest-specific protein 6 (Gas6), one of the endogenous ligands of TAM receptors (Tyro3, Axl, and Mertk), is confirmed to have beneficial functions in hemostasis, inflammation, and cancer growth. Here, we demonstrated the protective effects of Gas6 on multi-organ dysfunction syndrome (MODS) in sepsis and the underlying mechanisms. We investigated Gas6-ameliorated MODS by inhibiting vascular endothelial hyperpermeability in a mouse model of sepsis. Additionally, in vitro , under lipopolysaccharide (LPS) stimulation in vascular endothelial cells, Gas6 attenuated vascular endothelial hyperpermeability by reinforcing the tight junction proteins occludin, zonula occludens-1 (ZO-1), and claudin5. Furthermore, Gas6 substantially suppressed NF-κB p65 activation. In addition, blocking the Gas6 receptor, Axl, partially reduced the protective effect of Gas6 on the vascular endothelial barrier and diminished the inhibitive effect of Gas6 on NF-κB p65 activation. Taken together, this study suggests that Gas6 has a protective effect on MODS in sepsis by inhibiting the vascular endothelial hyperpermeability and alteration of tight junction and that the Axl/NF-κB signaling pathway underlies these effects.

Lactate clearance (Δ24Lac) was reported to be inversely associated with mortality in critically ill patients. The aim of our study was to assess the value of Δ24Lac for the prognosis of critically ill patients with cirrhosis and acute-on-chronic liver failure (ACLF). We analysed 954 cirrhotic patients with hyperlactatemia admitted to intensive care units (ICUs) in the United States and eastern China. The patients were followed up for at least 1 year. In the unadjusted model, we observed a 15% decrease in hospital mortality with each 10% increase in Δ24Lac. In the fully adjusted model, the relationship between the risk of death and Δ24Lac remained statistically significant (hospital mortality: odds ratio [OR] 0.84, 95% confidence interval [CI]: 0.78- 0.90, p < 0.001; 90-day mortality: hazard ratio [HR] 0.94, 95%CI 0.92- 0.97, p < 0.001; for Δ24Lac per 10% increase). Similar results were found in patients with ACLF. We developed a Δ24Lac-adjusted score (LiFe-Δ24Lac), which performed significantly better in the area under the receiver operating characteristic curves (AUROCs) than the original LiFe score for predicting mortality. Lactate clearance is an independent predictor of death, and the LiFe-Δ24Lac score is a practical tool for stratifying the risk of death.

Background and aim Critically ill patients with cirrhosis are at an increased risk of mortality. Our study aimed to externally validate the ability of the prothrombin time–international normalized ratio to albumin ratio (PTAR), an objective and simple scoring system, to predict 90-day mortality in critically ill patients with cirrhosis. Patients and methods A total of 865 patients were entered into the study, and all the participants were followed up for at least 90 days. Clinical parameters on the first day of intensive care unit admission were included to compare survivors with nonsurvivors. Results After multivariable adjustment, the association between the risk of 90-day mortality and PTAR remained statistically significant with a hazard ratio of 2.71 (95% confidence interval: 1.99–3.68). The PTAR score showed good discrimination ability for predicting 90-day mortality with an area under receiver operating characteristic curve of 0.72 (95% confidence interval: 0.68–0.75). To improve its feasibility, we regrouped the PTAR scores into three levels of risk (low risk: <0.55, intermediate risk: 0.55–1.00, and high risk: ≥1.00); the 90-day mortality rates were 20.1% (74/368), 41.7% (168/403), and 73.4% (69/94), respectively. Conclusion The PTAR score system is a convenient and practical tool for predicting the prognosis of critically ill patients with cirrhosis.

Background/Aims: Metabolic acidosis is a common complication in patients with cirrhosis at the intensive care units (ICUs) and associated with increased mortality. The aim of our research was to explore the epidemiology and risk factors of metabolic acidosis in critically ill patients with cirrhosis. Materials and Methods: A total of 975 patients with cirrhosis were selected into our study, and all participants were followed up for at least 28 days. Cox regression model and machine-learning algorithm were used to identify the importance of different risk factors, respectively. Finally, an improved prognostic model as Model for End-stage Liver Disease and metabolic acidosis (MELD-MA) was developed. Results: Among the 975 patients with liver cirrhosis, 506 had metabolic acidosis, including 257 patients who had decompensated metabolic acidosis at ICU admission. The 28-day mortality was 41% (206/506) in patients with metabolic acidosis.

Background/Aims: Critically ill patients with cirrhosis with pneumonia are at an increased risk for mortality. Only a few accurate predictive models are existing specific to these patients. The aim of the present study was to compare the existing prognostic models and to develop an improved mortality risk model for patients with cirrhosis and pneumonia. Materials and Methods: A total of 231 patients were enrolled in our study (70% training and 30% validation cohorts). All participants were followed up for at least 21 days. Model for End-stage Liver Disease and Pneumonia (MELD-P) was derived by the Cox proportional hazards model. The performances of prognostic scoring systems were compared by calculation of the area under the receiver operating characteristic (AUROC) curve. Results: MELD-P showed better discriminative capabilities than existing scoring systems. Four clinical variables, including loge bilirubin (hazard ratio (HR) 1.29, 95% confidence interval (CI) 1.01-1.73), loge international normalized ratio (HR 3.57, 95% CI 1.30-9.78), loge pulse oxygen saturation/fraction of inspired oxygen (HR 0.38, 95% CI 0.14-0.99), and vasopressors used (HR 3.72, 95% CI 1.85-7.49), were considered as independent prognostic values associated with 21-day mortality. MELD-P had AUROC curve values of 0.78 (95% CI 0.71-0.84) in predicting in-hospital mortality, 0.78 (95% CI 0.70-0.84) at 21-day, 0.88 (95% CI 0.82-0.93) at 14-day, and 0.87 (95% CI 0.81-0.92) at 7-day. A similar result was obtained in validation cohort. Conclusion: MELD-P, as the first model specifically designed to evaluate the risk of mortality in critically ill patients with cirrhosis and pneumonia, performs well on the mortality assessment of short-term mortality.