Construction and analysis of early warning and prediction model for risk factors of sepsis-associated encephalopathy / 中华危重病急救医学

Objective:To investigate the epidemiological characteristics of sepsis-associated encephalopathy (SAE) in patients with sepsis, analyze its risk factors and build a prediction model, which provides evidence for early clinical identification of SAE patients and improvement of clinical outcomes.Methods:A retrospective observational study was conducted. Sepsis patients admitted to the critical care medical center of the First Affiliated Hospital of Xinjiang Medical University from February 2022 to February 2023 were enrolled. According to whether SAE occurred, the patients were divided into sepsis group and SAE group. The 24 patients without sepsis in the same period were used as controls (non-sepsis group). Demographic data, relevant scores and laboratory test indicators at admission to intensive care unit (ICU), and prognostic indicators were collected. Univariate and multivariate Logistic regression analysis was used to analyze the risk factors for sepsis and SAE. Receiver operator characteristic curve (ROC curve) was drawn. The predictive value of each risk factor for sepsis and SAE.Results:A total of 130 patients with sepsis were included, of which 52 had SAE, and the incidence of SAE was 40.00%. There were significant differences in the length of ICU stay and total length of stay among all groups, while there were no significant differences in hospitalization cost and mechanical ventilation time. Multivariate Logistic regression analysis showed that pulmonary infection [odds ratio ( OR) = 46.817, 95% confidence interval (95% CI) was 5.624-389.757, P = 0.000], acute physiology and chronic health evaluation Ⅱ (APACHEⅡ: OR = 1.184, 95% CI was 1.032-1.358, P = 0.016), sequential organ failure assessment (SOFA: OR = 9.717, 95% CI was 2.618-36.068, P = 0.001), Charson comorbidity index (CCI: OR = 4.836, 95% CI was 1.860-12.577, P = 0.001), hemoglobin (Hb: OR = 0.893, 95% CI was 0.826-0.966, P = 0.005), glutamyltranspeptidase ( OR = 1.026, 95% CI was 1.008-1.045, P = 0.006) were independent risk factors for sepsis in ICU patients. Pulmonary infection ( OR = 28.795, 95% CI was 3.296-251.553, P = 0.002), APACHEⅡ score ( OR = 1.273, 95% CI was 1.104-1.467, P = 0.001), SOFA score ( OR = 8.670, 95% CI was 2.330-32.261, P = 0.001), CCI ( OR = 5.141, 95% CI was 1.961-13.475, P = 0.001), Hb ( OR = 0.922, 95% CI was 0.857-0.993, P = 0.031), glutamyltranspeptidase ( OR = 1.020, 95% CI was 1.002-1.038, P = 0.030) were independent risk factors for SAE in sepsis patients. ROC curve analysis showed that the area under the curve (AUC) of pulmonary infection, APACHEⅡ score, SOFA score, CCI, Hb, and glutamyltranspeptidase for predicting sepsis were 0.792, 0.728, 0.987, 0.933, 0.720, and 0.699, respectively; the AUC of the combined prediction of the above 6 variables for sepsis was 1.000, with a sensitivity of 100% and a specificity of 100%. The AUC predicted by pulmonary infection, APACHEⅡ score, SOFA score, CCI, and Hb for SAE were 0.776, 0.810, 0.907, 0.917, and 0.758, respectively; the AUC of the combined prediction of the above 5 variables for SAE was 0.975, with a sensitivity of 97.3% and a specificity of 93.1%. Conclusions:Sepsis is more severe when accompanied by encephalopathy. Pulmonary infection, Hb, APACHEⅡ score, SOFA score and CCI were independent risk factors of SAE. The combination of the above five indicators has good predictive value for early screening and prevention of the disease.

Correlation between four limbs perfusion index and lactic acid in patients with severe neurological diseases / 中华危重病急救医学

OBJECTIVE@#To observe the correlation between the four limbs perfusion index (PI) and blood lactic acid in patients with neurosis, and evaluate the predictive value of PI on microcirculation perfusion metabolic disorder in patients with neurosis.@*METHODS@#A prospective observational study was conducted. Adult patients admitted to the department of neurological intensive care unit (NICU) of the First Affiliated Hospital of Xinjiang Medical University from July 1 to August 20 in 2020 were enrolled. Under the condition of indoor temperature controlled at 25 centigrade, all patients were placed in the supine position, and the blood pressure, heart rate, PI of both fingers and thumb toes and arterial blood lactic acid were measured within 24 hours and 24-48 hours after NICU. The difference of four limbs PI at different time periods and its correlation with lactic acid were compared. Receiver operator characteristic curve (ROC curve) was used to evaluate the predictive value of four limbs PI on patients with microcirculatory perfusion metabolic disorder.@*RESULTS@#A total of 44 patients with neurosis were enrolled, including 28 males and 16 females; average age (61.2±16.5) years old. There were no significant differences in PI of the left index finger and the right index finger [2.57 (1.44, 4.79) vs. 2.70 (1.25, 5.33)], PI of the left toe and the right toe [2.09 (0.85, 4.76) vs. 1.88 (0.74, 4.32)] within 24 hours after entering the NICU, and the PI of the left index finger and the right index finger [3.17 (1.49, 5.07) vs. 3.14 (1.33, 5.36)], PI of the left toe and the right toe [2.07 (0.75, 5.20) vs. 2.07 (0.68, 4.67)] at 24-48 hours after NICU admission (all P > 0.05). However, compared to the PI of the upper and lower limbs on the same side, except for the 24-48 hours after ICU of the PI difference between the left index finger and the left toe (P > 0.05), the PI of the toe was lower than that of the index finger at the other time periods (all P < 0.05). The correlation analysis showed that the PI value of four limbs of patients in both time periods were significantly negatively correlated with arterial blood lactic acid (the r values of the left index finger, the right index finger, the left toe and the right toe were -0.549, -0.482, -0.392 and -0.343 respectively within 24 hours after entering the NICU; the r values of the left index finger, the right index finger, the left toe and the right toe were -0.331, -0.292, -0.402 and -0.442 respectively after entering the NICU 24-48 hours, all P < 0.05). Taking lactic acid ≥ 2 mmol/L as the diagnostic standard for metabolic disorder of microcirculation perfusion (total 27 times, accounting for 30.7%). The efficacy of four limbs PI in predicting microcirculation perfusion metabolic disorder were compared. ROC curve analysis showed that the area under the curve (AUC) and 95% confidence interval (95%CI) of left index finger, right index finger, left toe and right toe predicting microcirculation perfusion metabolic disorder were 0.729 (0.609-0.850), 0.767 (0.662-0.871), 0.722 (0.609-0.835), 0.718 (0.593-0.842), respectively. There was no significant difference in AUC compare with each other (all P > 0.05). The cut-off value of PI of right index finger for predicting microcirculation perfusion metabolic disorder was 2.46, the sensitivity was 70.4%, the specificity was 75.4%, the positive likelihood ratio was 2.86, and the negative likelihood ratio was 0.30.@*CONCLUSIONS@#There are no significant differences in PI of bilateral index fingers, bilateral toes in patients with neurosis. However, unilateral upper and lower limbs showed lower PI in the toe than in the index finger. There is a significantly negatively correlation between PI and arterial blood lactic acid in all four limbs. PI can predict the metabolic disorder of microcirculation perfusion, and its cut-off value is 2.46.

Role and mechanism of SIRT1 in regulating Nrf2/HO-1 signaling pathway in septic liver injury / 中华危重病急救医学

OBJECTIVE@#To investigate the role and mechanism of silent information regulator 1 (SIRT1) in regulating nuclear factor E2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway in oxidative stress and inflammatory response to sepsis-induced liver injury.@*METHODS@#A total of 24 male Sprague-Dawley (SD) rats were randomly divided into sham operation (Sham) group, cecal ligation and puncture (CLP) group, SIRT1 agonist SRT1720 pretreatment (CLP+SRT1720) group and SIRT1 inhibitor EX527 pretreatment (CLP+EX527) group, with 6 rats in each group. Two hours before operation, SRT1720 (10 mg/kg) or EX527 (10 mg/kg) were intraperitoneally injected into the CLP+SRT1720 group and CLP+EX527 group, respectively. Blood was collected from the abdominal aorta at 24 hours after modeling and the rats were sacrificed for liver tissue. The serum levels of interleukins (IL-6, IL-1β) and tumor necrosis factor-α (TNF-α) were detected by enzyme-linked immunosorbent assay (ELISA). The serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were detected by microplate method. Hematoxylin-eosin (HE) staining was used to observe the pathological injury of rats in each group. The levels of malondialdehyde (MDA), 8-hydroxydeoxyguanosine (8-OHdG), glutathione (GSH) and superoxide dismutase (SOD) in liver tissue were detected by corresponding kits. The mRNA and protein expressions of SIRT1, Nrf2 and HO-1 in liver tissues were detected by real-time quantitative polymerase chain reaction (RT-qPCR) and Western blotting.@*RESULTS@#Compared with the Sham group, the serum levels of IL-6, IL-1β, TNF-α, ALT and AST in the CLP group were significantly increased; histopathological results showed that liver cords were disordered, hepatocytes were swollen and necrotic, and a large number of inflammatory cells infiltrated; the contents of MDA and 8-OHdG in liver tissue increased, while the contents of GSH and SOD decreased; and the mRNA and protein expressions of SIRT1, Nrf2 and HO-1 in liver tissues were significantly decreased. These results suggest that sepsis rats have liver dysfunction, and the levels of SIRT1, Nrf2, HO-1 and antioxidant protein in liver tissues were decreased, while the levels of oxidative stress and inflammation were increased. Compared with the CLP group, the levels of inflammatory factors and oxidative stress were significantly decreased in the CLP+SRT1720 group, the mRNA and protein expressions of SIRT1, Nrf2 and HO-1 were significantly increased [IL-6 (ng/L): 34.59±4.21 vs. 61.84±3.78, IL-1β (ng/L): 41.37±2.70 vs. 72.06±3.14, TNF-α (ng/L): 76.43±5.23 vs. 130.85±5.30, ALT (U/L): 30.71±3.63 vs. 64.23±4.59, AST (U/L): 94.57±6.08 vs. 145.15±6.86, MDA (μmol/g): 6.11±0.28 vs. 9.23±0.29, 8-OHdG (ng/L): 117.43±10.38 vs. 242.37±11.71, GSH (μmol/g): 11.93±0.88 vs. 7.66±0.47, SOD (kU/g): 121.58±5.05 vs. 83.57±4.84, SIRT1 mRNA (2-ΔΔCt): 1.20±0.13 vs. 0.46±0.02, Nrf2 mRNA (2-ΔΔCt): 1.21±0.12 vs. 0.58±0.03, HO-1 mRNA (2-ΔΔCt): 1.71±0.06 vs. 0.48±0.07, SIRT1 protein (SIRT1/β-actin): 0.89±0.04 vs. 0.58±0.03, Nrf2 protein (Nrf2/β-actin): 0.87±0.08 vs. 0.51±0.09, HO-1 protein (HO-1/β-actin): 0.93±0.14 vs. 0.54±0.12, all P < 0.05], these results indicated that SIRT1 agonist SRT1720 pretreatment could improve liver injury in sepsis rats. However, pretreatment with SIRT1 inhibitor EX527 showed the opposite effect [IL-6 (ng/L): 81.05±6.47 vs. 61.84±3.78, IL-1β (ng/L): 93.89±5.83 vs. 72.06±3.14, TNF-α (ng/L): 177.67±5.12 vs. 130.85±5.30, ALT (U/L): 89.33±9.52 vs. 64.23±4.59, AST (U/L): 179.59±6.44 vs. 145.15±6.86, MDA (μmol/g): 11.39±0.51 vs. 9.23±0.29, 8-OHdG (ng/L): 328.83±11.26 vs. 242.37±11.71, GSH (μmol/g): 5.07±0.34 vs. 7.66±0.47, SOD (kU/g): 59.37±4.28 vs. 83.57±4.84, SIRT1 mRNA (2-ΔΔCt): 0.34±0.03 vs. 0.46±0.02, Nrf2 mRNA (2-ΔΔCt): 0.46±0.04 vs. 0.58±0.03, HO-1 mRNA (2-ΔΔCt): 0.21±0.03 vs. 0.48±0.07, SIRT1 protein (SIRT1/β-actin): 0.47±0.04 vs. 0.58±0.03, Nrf2 protein (Nrf2/β-actin): 0.32±0.07 vs. 0.51±0.09, HO-1 protein (HO-1/β-actin): 0.19±0.09 vs. 0.54±0.12, all P < 0.05].@*CONCLUSIONS@#SIRT1 can inhibit the release of proinflammatory factors and alleviate the oxidative damage of hepatocytes by activating Nrf2/HO-1 signaling pathway, thus playing a protective role against CLP-induced liver injury.

Effect of SIRT1 regulating Nrf2/HO-1 signaling pathway on sepsis-induced acute lung injury / 中华危重病急救医学

Objective:To investigate whether silence information regulator 1 (SIRT1) could regulate nuclear factor E2-related factor 2/heme oxygenase 1 (Nrf2/HO-1) signaling pathway and its role in acute lung injury (ALI) in sepsis rats.Methods:Twenty-four male Sprague-Dawley (SD) rats were randomly divided into sham operation group (Sham group), cecal ligation and puncture (CLP) induced sepsis group (CLP group), sepsis+SIRT1 specific agonist group (CLP+SRT1720 group,10 mg/kg SRT1720 was intraperitoneally injected 2 hours before CLP), sepsis+SIRT1 specific inhibitor group (CLP+EX527 group, 10 mg/kg EX527 was intraperitoneally injected 2 hours before CLP), with 6 rats in each group. The rats were killed 24 hours after modeling and their lung tissues were taken for pathological score (Smith score), superoxide dismutase (SOD), glutathione (GSH), malondialdehyde (MDA), 8-hydroxydeoxyguanosine (8-OHdG), tumor necrosis factor-α (TNF-α), interleukins (IL-6, IL-1β), and SIRT1, Nrf2 and HO-1 mRNA and protein expression were detected.Results:The lung tissue of the CLP group mice was severely damaged, the alveolar interval was widened and a large number of inflammatory cells infiltrated, and there was visible pulmonary capillary hyperemia. The Smith score, the levels of TNF-α, IL-6, IL-1β, MDA and 8-OHdG were significantly increased, the levels of SOD, GSH, SIRT1, Nrf2 and HO-1 were significantly decreased in CLP group. After using SIRT1 specific agonist, the lung injury in CLP+SRT1720 group was significantly alleviated compared with that in CLP group, Smith score and lung tissue TNF-α, IL-6, and IL-1β levels were significantly decreased [Smith score: 2.83±0.75 vs. 5.67±0.52, TNF-α (ng/L): 36.78±5.36 vs. 66.99±5.44, IL-6 (ng/L): 23.97±3.76 vs. 45.70±4.16, IL-1β (ng/L): 16.76±1.39 vs. 39.64±2.59, all P < 0.05], SOD activity and GSH content increased [SOD (kU/g): 115.88±3.31 vs. 101.65±1.09, GSH (μmol/g): 8.42±0.81 vs. 5.74±0.46, both P < 0.05], MDA and 8-OHdG contents decreased [MDA (μmol/g): 5.24±0.33 vs. 9.86±0.66, 8-OHdG (ng/L): 405.76±8.54 vs. 647.12±10.64, both P < 0.05], the mRNA and protein expressions of SIRT1, Nrf2 and HO-1 were increased [SIRT1 mRNA (2 -ΔΔCT): 1.49±0.15 vs. 0.64±0.03, Nrf2 mRNA (2 -ΔΔCT): 1.19±0.08 vs. 0.84±0.02, HO-1 mRNA (2 -ΔΔCT): 1.80±0.41 vs. 0.64±0.11, SIRT1 protein (SIRT1/β-actin): 1.03±0.06 vs. 0.52±0.05, Nrf2 protein (Nrf2/β-actin): 1.14±0.10 vs. 0.63±0.05, HO-1 protein (HO-1/β-actin): 1.01±0.11 vs. 0.73±0.03, all P < 0.05]. The lung injury in CLP+EX527 group was more severe than that in CLP group, Smith score and lung tissue TNF-α, IL-6, IL-1β levels were significantly increased [Smith score: 8.00±0.89 vs. 5.67±0.52, TNF-α (ng/L): 87.15±4.23 vs. 66.99±5.44, IL-6 (ng/L): 66.79±2.93 vs. 45.70±4.16, IL-1β (ng/L): 58.99±2.12 vs. 39.64±2.59, all P < 0.05], SOD activity and GSH content decreased [SOD (kU/g): 72.84±3.85 vs. 101.65±1.09, GSH (μmol/g): 3.30±0.67 vs. 5.74±0.46, both P < 0.05], the contents of MDA and 8-OHdG were increased [MDA (μmol/g): 14.14±0.70 vs. 9.86±0.66, 8-OHdG (ng/L): 927.66±11.47 vs. 647.12±10.64, both P < 0.05], the mRNA and protein expressions of SIRT1, Nrf2 and HO-1 were decreased [SIRT1 mRNA (2 -ΔΔCT): 0.40±0.07 vs. 0.64±0.03, Nrf2 mRNA (2 -ΔΔCT): 0.48±0.07 vs. 0.84±0.02, HO-1 mRNA (2 -ΔΔCT): 0.27±0.14 vs. 0.64±0.11, SIRT1 protein (SIRT1/β-actin): 0.20±0.05 vs. 0.52±0.05, Nrf2 protein (Nrf2/β-actin): 0.45±0.01 vs. 0.63±0.05, HO-1 protein (HO-1/β-actin): 0.36±0.08 vs. 0.73±0.03, all P < 0.05]. Conclusions:In the rat model of ALI induced by sepsis, SIRT1 can regulate the activation of Nrf2/HO-1 signaling pathway, upregulate the expression of downstream antioxidant enzymes, reduce oxidative stress injury, and then alleviate the ALI induced by sepsis in rats.

Sivelestat protects acute kidney injury by inhibiting the PI3K/AKT pathway in septic rats / 中华危重病急救医学

Objective:To explore the protective effect of sivelestat (SV) against sepsis-induced acute kidney injury (AKI) and its molecular mechanism.Methods:According to the random number table method, 64 male Wistar rats were divided into sham operation group (Sham group), sepsis due to cecal ligation and puncture group (CLP group), low dose of SV treatment group (SL group, 50 mg/kg SV was injected into the tail vein at 12 hours and 24 hours after CLP), and high dose of SV treatment group (SH group, 100 mg/kg SV was injected into the tail vein at 12 hours and 24 hours after CLP), with 16 rats in each group. 48 hours after CLP, the 48-hour survival of rats were recorded, all rats were sacrificed and samples were harvested. Enzyme-linked immunosorbent assay (ELISA) was used to detect the serum levels of kidney injury molecule-1 (KIM-1), interleukins (IL-1β, IL-6), tumor necrosis factor-α (TNF-α) and neutrophil elastase (NE). Hematoxylin-eosin (HE) staining was used to observe histopathological changes and assess renal tubule injury score. Masson staining was used to detect the collagen volume fraction (CVF) of kidney tissue. Western blotting was used to detect the protein expressions of phosphatidylinositol 3-kinase (PI3K), phosphorylation PI3K (p-PI3K), protein kinase B (AKT), phosphorylation AKT (p-AKT), nuclear factor-κB p65 (NF-κB p65) and NE. The protein expressions of p-PI3K, p-AKT, NF-κB p65 were detected by immunohistochemistry.Results:Compared with Sham group, the 48-hour survival rate of CLP group was significantly reduced. Histopathological results showed that large tubular epithelial cells and brush margins were shed, tubular casts were formed, some tubular atrophy, glomerular hyperemia, renal interstitial inflammatory cell infiltration and increased renal tubular injury score. Renal interstitial fibrosis was obvious and CVF increased. The levels of KIM-1, IL-1β, IL-6, TNF-α and NE in serum were significantly elevated in the CLP group. The proteins expression of inflammatory pathway-related p-PI3K/PI3K, p-AKT/AKT, NF-κB p65 and NE were significantly increased in kidney tissue. It suggested that septic rats had renal injury and the PI3K/AKT inflammatory pathway was activated. Compared with CLP group, there was no significant difference in 48-hour survival in SL group and SH group (68.75%, 75.00% vs. 56.25%, both P > 0.05), but kidney injury was significantly relieved. Specifically: renal tubular injury score and CVF significantly decreased [tubular injury score: 2 (1, 2), 1 (1, 1) vs. 2 (2, 3); CVF: (22.36±0.86)%, (18.74±1.05)% vs. (58.38±0.79)%, all P < 0.05]; the serum levels of KIM-1, IL-1β, IL-6, TNF-α and NE also decreased significantly [KIM-1 (ng/L): 145.03±8.88, 117.58±7.02 vs. 158.22±12.00; IL-1β (ng/L): 108.32±9.00, 92.98±8.06 vs. 133.78±8.48; IL-6 (ng/L): 124.33±10.11, 115.42±8.17 vs. 165.19±5.70; TNF-α (ng/L): 321.56±19.29, 289.68±21.57 vs. 424.88±22.76, NE (mol/L): 93.84±9.14, 75.01±10.56 vs. 113.45±6.39, all P < 0.05]; the proteins expression of inflammatory pathway-related p-PI3K/PI3K, p-AKT/AKT, NF-κB p65 and NE were significantly decreased (p-PI3K/PI3K: 0.93±0.06, 0.67±0.04 vs. 1.27±0.08; p-AKT/AKT: 0.78±0.09, 0.47±0.05 vs. 0.96±0.12; NF-κB p65/GAPDH: 1.43±0.13, 0.85±0.08 vs. 1.88±0.17; NE/GAPDH: 1.45±0.06, 0.91±0.04 vs. 1.71±0.08, all P < 0.05), the positive expressions of p-PI3K, p-AKT and NF-κB p65 in kidney tissue were decreased [p-PI3K positive expression area: (13.36±1.84)%, (8.03±1.12)% vs. (21.56±1.20)%; p-AKT positive expression area: (21.57±0.91)%, (15.21±2.76)% vs. (30.81±2.12)%; NF-κB p65 positive expression area: (25.17±1.38)%, (17.07±2.11)% vs. (37.85±2.50)%, all P < 0.05]. Serum inflammatory factor level, and PI3K/AKT pathway related protein, NF-κB p65, NE protein expression level and p-PI3K, p-AKT, NF-κB p65 positive area and other indicators in renal tissue in SH group were further lower than those in SL group (all P < 0.05). Conclusions:SV can ameliorate sepsis-induced AKI. The mechanism may be related to the inhibition of PI3K/AKT pathway, and high dose of SV has better efficacy.

Research progress of sepsis-associated acute kidney injury based on Gut-Kidney axis / 中华危重病急救医学

Sepsis-associated acute kidney injury (SA-AKI), as a common renal dysfunction in sepsis, has become one of the major diseases threatening human health with increasing morbidity and mortality. Based on the theory of "gut-kidney axis", the intestine and kidney have a two-way synergistic relationship in sepsis. Intestinal flora imbalance, endogenous metabolite imbalance, and impaired endothelial barrier integrity are involved in renal injury, and the increase of renal inflammatory mediators interferes with the composition of intestinal microorganisms. Therefore, understanding the intestinal-renal crosstalk mechanism of SA-AKI will help to provide a potential basis for new treatment strategies for SA-AKI.

Role of Nrf2/GPX4 mediated ferroptosis in intestinal injury in sepsis / 中华危重病急救医学

OBJECTIVE@#To investigate whether ferroptosis exists in sepsis induced intestinal injury, and to verify the association between ferroptosis in sepsis induced intestinal injury and intestinal inflammation and barrier function by stimulating and inhibiting the nuclear factor E2-related factor 2/glutathione peroxidase 4 (Nrf2/GPX4) pathway.@*METHODS@#Forty-eight SPF grade male Sprague-Darvley (SD) rats with a body weight of 220-250 g were divided into sham operation group (Sham group), sepsis group (CLP group), sepsis+iron chelating agent deferoxamine (DFO) group (CLP+DFO group) and sepsis+ferroptosis inducer Erastin group (CLP+Erastin group) using a random number table method, with 12 rats in each group. The sepsis model was established by cecal ligation and puncture (CLP). The Sham group was only performed with abdominal opening and closing operations. After modeling, the CLP+DFO group received subcutaneous injection of 20 mg/kg of DFO, the CLP+Erastin group was intraperitoneally injected with 20 mg/kg of Erastin. Each group received subcutaneous injection of 50 mg/kg physiological saline for fluid resuscitation after surgery, and the survival status of the rats was observed 24 hours after surgery. At 24 hours after model establishment, 6 rats in each group were selected. First, live small intestine tissue was taken for observation of mitochondrial morphology in smooth muscle cells under transmission electron microscopy and determination of reactive oxygen species (ROS). Then, blood was collected from the abdominal aorta and euthanized. The remaining 6 rats were sacrificed after completing blood collection from the abdominal aorta, and then small intestine tissue was taken. Western blotting was used to detect the expression of intestinal injury markers such as Claudin-1 and ferroptosis related proteins GPX4 and Nrf2. Observe the pathological changes of small intestine tissue using hematoxylin-eosin (HE) staining and complete Chiu score; Detection of tumor necrosis factor-α (TNF-α), interleukins (IL-1β, IL-6) levels in serum using enzyme-linked immunosorbent assay (ELISA). The levels of serum iron ions (Fe3+), malondialdehyde (MDA), and D-lactate dehydrogenase (D-LDH) were measured.@*RESULTS@#(1) Compared with the Sham group, the 24-hour survival rate of rats in the CLP group and CLP+Erastin group significantly decreased (66.7%, 50.0% vs. 100%, both P < 0.05), while there was no significant difference in the CLP+DFO group (83.3% vs. 100%, P = 0.25). (2) Western blotting results showed that compared with the Sham group, the expressions of GPX4 and Claudin-1 in the small intestine tissue of the CLP group, CLP+DFO group, and CLP+Erastin group decreased significantly, while the expression of Nrf2 increased significantly (GPX4/β-actin: 0.56±0.02, 1.03±0.01, 0.32±0.01 vs. 1.57±0.01, Claudin-1/β-actin: 0.60±0.04, 0.96±0.07, 0.41±0.01 vs. 1.40±0.01, Nrf2/β-actin: 0.88±0.02, 0.72±0.01, 1.14±0.01 vs. 0.43±0.02, all P < 0.05). Compared with the CLP group, the expressions of GPX4 and Claudin-1 were significantly increased in the CLP+DFO group, while the expression of Nrf2 was significantly reduced. In the CLP+Erastin group, the expressions of GPX4 and Claudin-1 further decreased, while the expression of Nrf2 further increased (all P < 0.05). (3) Under the light microscope, compared with the Sham group, the CLP group, CLP+DFO group, and CLP+Erastin group showed structural disorder in the small intestinal mucosa and submucosal tissue, significant infiltration of inflammatory cells, and destruction of glandular and villous structures. The Chui score was significantly higher (3.25±0.46, 2.00±0.82, 4.50±0.55 vs. 1.25±0.45, all P < 0.05). (4) Under transmission electron microscopy, compared with the Sham group, the mitochondria in the other three groups of small intestinal smooth muscle cells showed varying degrees of volume reduction, increased membrane density, and reduced or disappeared cristae. The CLP+Erastin group showed the most significant changes, while the CLP+DFO group showed only slight changes in mitochondrial morphology. (5) Compared to the Sham group, the CLP group, CLP+DFO group, and CLP+Erastin group had serum levels of TNF-α, IL-1β, IL-6, MDA, D-LDH, and ROS in small intestine tissue were significantly increased, while the serum Fe3+ content was significantly reduced [TNF-α (ng/L): 21.49±1.41, 17.24±1.00, 28.66±2.72 vs. 14.17±1.24; IL-1β (ng/L): 108.40±3.09, 43.19±8.75, 145.70±11.00 vs. 24.50±5.55; IL-6 (ng/L): 112.50±9.76, 45.90±6.52, 151.80±9.38 vs. 12.89±6.11; MDA (μmol/L): 5.61±0.49, 3.89±0.28, 8.56±1.17 vs. 1.86±0.41; D-LDH (kU/L): 39.39±3.22, 25.38±2.34, 53.29±10.53 vs. 10.79±0.52; ROS (fluorescence intensity): 90 712±6 436, 73 278±4 775, 110 913±9 287 vs. 54 318±2 226; Fe3+ (μmol/L): 22.19±1.34, 34.05±1.94, 12.99±1.08 vs. 51.74±11.07; all P < 0.05]. Compared with CLP group, the levels of TNF-α, IL-1β, IL-6, MDA, D-LDH and ROS in CLP+Erastin group were further increased, and the content of Fe3+ was further decreased, the CLP+DFO group was the opposite (all P < 0.05).@*CONCLUSIONS@#Ferroptosis exists in the intestinal injury of septic rats, and stimulating or inhibiting ferroptosis through the Nrf2/GPX4 pathway can effectively intervene in the inflammatory state and intestinal mechanical barrier of the body.

Predictive value of albumin/fibrinogen ratio for 28-day mortality risk in patients with sepsis / 中华急诊医学杂志

Objective:To investigate the predictive value of albumin/fibrinogen ratio (AFR) for 28-d mortality in patients with sepsis.Methods:A total of 186 patients with sepsis admitted to the Intensive Care Unit of the First Affiliated Hospital of Xinjiang Medical University from January 2019 to December 2021 were studied retrospectively. They were divided into the survival group ( n=124) and death group ( n=62) according to the 28-d survival conditions. Clinical data of each group within 24 h after admission were recorded, including age, sex, underlying diseases, white blood cell count, albumin, fibrinogen (FIB), PCT, CRP and other laboratory examination indexes. APACHEⅡ scores and SOFA scores were recorded at the time of admission. Cox regression was used to analyze the influence of each index on the prognosis of patients. Receiver operating characteristic (ROC) curve was used to analyze the predictive value of AFR for 28-d mortality in patients with sepsis. Kaplan-Meier method was used to draw survival curves under different AFR levels for survival analysis. Pearson correlation was used to analyze the relationship between AFR and APACHEⅡ score. Rseults:Age, number of patients with septic shock, mechanical ventilation, APACHEⅡ score, SOFA score, blood lactic acid and fibrinogen increased significantly in the death group ( P<0.05), while albumin and AFR were significantly decreased ( P<0.001). ROC curve analysis showed that the area under the curve of AFR in predicting 28-d mortality risk of patients with sepsis was 0.900. When the cut-off value of AFR was 7.64, the sensitivity was 80.0% and the specificity was 85.5%. Kaplan-Meier survival analysis showed that patients with AFR >7.64 had better prognosis. Cox regression analysis showed that AFR, APACHEⅡ score and the presence of septic shock were independent risk factors affecting the prognosis of patients with sepsis. AFR was strongly correlated with APACHEⅡ score ( r=-0.462, P<0.001). Conclusions:As a simple, effective and safe biomarker, AFR has a certain predictive value for 28-d mortality risk in patients with sepsis.

Inhibition of toll-like receptor 4 inflammatory pathway by β-blocker attenuates myocardial injury in sepsis / 中华急诊医学杂志

Objective:To investigate the protective effect of β- blocker (esmolol) on myocardia and toll-like receptor 4 (TLR4) inflammatory pathway in septic rats.Methods:Sixty male Wistar rats were randomly (random number) divided into the shame group, sepsis group (CLP group), esmolol group (CLP+ES group) and TLR4 inhibitor group (CLP+TAK-242 group) with 15 rats in each group. Cecal exploration was performed in the shame group, and cecal ligation and perforation (CLP) was performed in the CLP group, CLP+ES group and CLP+TAK-242 group. The CLP+ES group received intraperitoneal injection of esmolol diluent 20 mg/kg 12 h after CLP. The CLP+TAK-242 group was given intraperitoneal injection of TAK-242 3 mg/kg at the same time point as above. The shame group and CLP group were given the same amount of normal saline. Rats in all groups were sacrificed 24 h after operation, and the samples were collected and processed. The pathological changes of myocardium were observed by hematoxylin - eosin staining. The expression of TLR4, myeloid differentiation protein 88 (MyD88) and nuclear factor -κB (NF-κB) in myocardial tissue were observed by immunohistochemistry. Masson staining was used to observe the expression of fibers and inflammatory factors in myocardial tissue. The protein expressions of TLR4, MyD88, NF-κB and aspartic acid specific cysteine protease 1 (caspase-1) were detected by Western blot. Serum levels of cardiac troponin I (cTn-I), tumor necrosis factor α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β) were detected by enzyme-linked immunosorbent assay (ELISA).Results:Compared with the shame group, myocardial injury, fibrosis and inflammatory cell infiltration were significantly aggravated in the CLP group, and the levels of myocardial injury index cTn-I and inflammatory mediators TNF-α, IL-6 and IL-1β were significantly increased [(8.70±0.22) vs. (4.41±0.31), (445.57±9.13) vs. (219.60±5.52), (165.55±2.18) vs. (93.47±3.37), (124.12±2.59) vs. (67.63±6.04),all P<0.05]. Compared with the CLP group, myocardial injury was significantly reduced in the CLP+ES group and CLP+TAK-242 group, and the levels of inflammatory transmitters were significantly reduced [(5.38±0.18) and (5.37±0.13) vs. (8.70±0.22), (322.73±7.63) and (300.58±17.47) vs. (445.57±9.13), (121.28±5.44) and (120.30±4.95) vs. (165.55±2.18), (102.60±4.09) and (105.08±7.21) vs. (124.12±2.59), all P<0.05]. Western blot analysis showed that the protein expression levels of TLR4, MyD88, NF-κB and caspase-1 in the CLP group were significantly higher than those in the shame group [(1.79±0.15) vs. (1.15±0.04), (4.70±0.30) vs. (3.87±0.10), (0.35±0.04) vs. (0.18±0.02), (2.27±0.29) vs. (1.15±0.07), all P<0.05], while the protein expression levels in the CLP+ES group and CLP+TAK-242 group were significantly lower than those in the CLP group [(1.31±0.16) and (1.18±0.14) vs. (1.79±0.15), (1.50±0.16) and (1.46±0.19) vs. (2.27±0.29), (0.27±0.02) and (0.24±0.01) vs. (0.35±0.04), (1.50±0.16) and (1.46±0.19) vs. (2.27±0.29), all P<0.05]. Conclusions:β-blocker can reduce myocardial injury and inhibit the expression of inflammatory mediators in septic rats by blocking the inflammatory response mediated by TLR4 signaling pathway.

Predictive value of six critical illness scores for 28-day death risk in comprehensive and specialized intensive care unit patients based on MIMIC-Ⅳ database / 中华危重病急救医学

Objective:To explore the basic characteristics of various types of intensive care unit (ICU) patients and the predictive value of six common disease severity scores in critically ill patients on the first day on the 28-day death risk.Methods:The general information, disease severity scores [acute physiology score Ⅲ (APSⅢ), Oxford acute disease severity (OASIS) score, Logistic organ dysfunction score (LODS), simplified acute physiology score Ⅱ (SAPSⅡ), systemic inflammatory response syndrome (SIRS) score and sequential organ failure assessment (SOFA) score], prognosis and other indicators of critically ill patients admitted from 2008 to 2019 were extracted from Medical Information Mart for Intensive Care-Ⅳ 2.0 (MIMIC-Ⅳ 2.0). The receiver operator characteristic curve (ROC curve) of six critical illness scores for 28-day death risk of patients in various ICU, and the area under the ROC curve (AUC) was calculated, the optimal Youden index was used to determine the cut-off value, and the AUC of various ICU was verified by Delong method.Results:A total of 53 150 critically ill patients were enrolled, with medical ICU (MICU) accounted for the most (19.25%, n = 10 233), followed by cardiac vascular ICU (CVICU) with 17.78% ( n = 9 450), and neurological ICU (NICU) accounted for the least (6.25%, n = 3 320). The patients in coronary care unit (CCU) were the oldest [years old: 71.79 (60.27, 82.33)]. The length of ICU stay in NICU was the longest [days: 2.84 (1.51, 5.49)] and accounted for the highest proportion of total length of hospital stay [63.51% (34.61%, 97.07%)]. The patients in comprehensive ICU had the shortest length of ICU stay [days: 1.75 (0.99, 3.05)]. The patients in CVICU had the lowest proportion of length of ICU stay to total length of hospital stay [27.69% (18.68%, 45.18%)]. The six scores within the first day of ICU admission in NICU patients were lower than those in the other ICU, while APSⅢ, LODS, OASIS, and SOFA scores in MICU patients were higher than those in the other ICU. SAPⅡ and SIRS scores were both the highest in CVICU, respectively. In terms of prognosis, MICU patients had the highest 28-day mortality (14.14%, 1 447/10 233), while CVICU patients had the lowest (2.88%, 272/9 450). ROC curve analysis of the predictive value of each score on the 28-day death risk of various ICU patients showed that, the predictive value of APSⅢ, LODS, and SAPSⅡ in comprehensive ICU were higher [AUC and 95% confidence interval (95% CI) were 0.84 (0.83-0.85), 0.82 (0.81-0.84), and 0.83 (0.82-0.84), respectively]. The predictive value of OASIS, LODS, and SAPSⅡ in surgical ICU (SICU) were higher [AUC and 95% CI were 0.80 (0.79-0.82), 0.79 (0.78-0.81), and 0.79 (0.77-0.80), respectively]. The predictive value of APSⅢ and SAPSⅡ in MICU were higher [AUC and 95% CI were 0.84 (0.82-0.85) and 0.82 (0.81-0.83), respectively]. The predictive value of APSⅢ and SAPSⅡ in CCU were higher [AUC and 95% CI were 0.86 (0.85-0.88) and 0.85 (0.83-0.86), respectively]. The predictive value of LODS and SAPSⅡ in trauma ICU (TICU) were higher [AUC and 95% CI were 0.83 (0.82-0.83) and 0.83 (0.82-0.84), respectively]. The predictive value of OASIS and SAPSⅡ in NICU were higher [AUC and 95% CI were 0.83 (0.80-0.85) and 0.81 (0.78-0.83), respectively]. The predictive value of APSⅢ, LODS, and SAPSⅡ in CVICU were higher [AUC and 95% CI were 0.84 (0.83-0.85), 0.81 (0.80-0.82), and 0.78 (0.77-0.78), respectively]. Conclusions:For the patients in comprehensive ICU, MICU, CCU, and CVICU, APSⅢ or SAPSⅡ can be applied for predicting 28-day death risk. For the patients in SICU and NICU, OASIS or SAPSⅡ can be applied to predict 28-day death risk. For the patients in TICU, SAPSⅡ or LODS can be applied for predicting 28-day death risk. For CVICU patients, APSⅢ or LODS can be applied to predict 28-day death risk.

Research progress of ferroptosis related pathways in sepsis / 中华危重病急救医学

Sepsis is a disease caused by pathogenic microorganisms such as bacteria, which is characterized by host response disorder, organ dysfunction and high mortality. In early stage, it is mainly inflammatory reaction, howeverin late stage, it is mainly immunosuppression. It is a little pale to explain the poorprognosis caused by sepsis only by severe infection and immunosuppression. From the perspective of the absolute mortality of sepsis over the world, the battle against sepsis has not won a comprehensive victory. It has been 10 years since "ferroptosis" was formally proposed by Dixionet al. in 2012. The research areahas never decreased from the initial tumor related diseases to nervous system diseases and cardiovascular system diseases, and has made some progress. At present, in the context of sepsis, it is found that ferroptosis plays an increasingly important role in organ dysfunction, and also has an important impact on the treatment and prognosis of the disease. This article summarizes the related pathways and interventions of several major ferroptosis at present, in order to have a more comprehensive understanding of the pathogenesis of sepsis, seek new treatment targets, optimize diagnosis and treatment strategies, and improve survival rate, quality of life and clinical prognosis.

Research advance of the mechanism and treatment of septic cardiomyopathy / 中华危重病急救医学

Sepsis is a life-threatening organ dysfunction caused by dysregulation of the body's response to infection. It is one of the common and serious complications in clinically critical patients with trauma, burn, shock, infection, etc., with high morbidity and mortality. Although the treatment of sepsis has made great achievements in clinical practice, the mortality of patients with sepsis is still increasing due to its secondary complications. Septic cardiomyopathy (SCM) is one of the major complications that threaten septic patient's life. SCM refers to myocardial dysfunction with the aggravation of the primary disease, which is manifested by biventricular dilatation accompanied by a decrease in left ventricular ejection fraction (LVEF). It is one of the major complications that threaten the life of patients with sepsis. The existing research shows that the mechanism of SCM includes myocardial mitochondrial dysfunction, myocardial cell apoptosis, calcium circulation disorder and its treatment including conventional treatment, β 1 receptor blocker treatment and traditional Chinese medicine treatment, etc. This paper reviewed the pathogenesis of SCM and its related, in order to provide references for the rational diagnosis and treatment of SCM.

Effects of resveratrol-mediated inhibition of NOD-like receptor protein 3 inflammasomevia activating silent information regulator 1 on the injury of intestinal mucosal barrier function after sepsis / 中华危重病急救医学

Objective:To explore whether resveratrol (RSV) could activate silent information regulator 1 (SIRT1) to regulate the activation of NOD-like receptor protein 3 (NLRP3) inflammasome in sepsis induced intestinal injury model, and then reduce intestinal inflammation and cell apoptosis, so as to play a protective role in intestinal barrier function.Methods:① In vitro experiment: human Colorectal adenocarcinoma cells (Caco-2) were cultured, which were divided into normal group (normal culture on complete medium for 48 hours), lipopolysaccharide (LPS) group (normal culture on complete medium for 24 hours, then LPS containing 2 mg/L complete medium intervention for 6 hours), RSV low, medium and high concentration groups and SIRT1 inhibitor (EX-527) group (complete medium normal culture for 24 hours, LPS containing 2 mg/L complete medium intervention for 6 hours, followed by RSV 10, 20, 40 μmol/L or EX-527 10 μmol/L intervention for 6 hours, respectively). The levels of tumor necrosis factor-α (TNF-α) and interleukins (IL-6, IL-18, IL-1β) in the cell supernatant were determined by enzyme linked immunosorbent assay (ELISA). The apoptosis level of the cells was detected by flow cytometry. Western blotting was used to detect the protein levels of NLRP3, SIRT1, caspase-1 and apoptosis-associated speck-like protein containing a CARD (ASC). ② In vivo experiment: according to random number table method, 24 male Wistar rats were divided into sham operation group (Sham group), cecal ligation and perforation (CLP) 6 hours group (CLP 6 h group), CLP 24 h group and RSV intervention group [RSV (20 mg/kg) was intraperitoneally injected 6 hours and 12 hours after CLP], with 6 rats in each group. The levels of NLRP3, caspase-1 and ASC in the intestine of rats were detected by immunohistochemistry. Results:① Compared with the normal group, the levels of inflammatory factors in the cell supernatant of the LPS group were increased and the expression of SIRT1 protein was decreased, while the protein expressions of NLRP3, caspase-1 and ASC were increased. Compared with LPS group, different concentrations of RSV reduced the level of inflammatory factors, increased the activity of SIRT1, inhibited the expression of NLRP3 inflammasome and its downstream products caspase-1 and ASC, and the effect of high concentration of RSV (40 μmol/L) was the most significant [TNF-α (ng/L): 8.77±0.43 vs. 12.66±0.81, IL-6 (ng/L): 1.35±0.20 vs. 1.93±0.09, IL-1β (ng/L): 1.05±0.04 vs. 1.31±0.07, IL-18 (ng/L): 519.50±11.16 vs. 622.70±30.69, SIRT1/β-actin: 0.80±0.05 vs. 0.58±0.02, caspase-1/β-actin: 0.55±0.06 vs. 0.78±0.06, ASC/β-actin: 0.78±0.08 vs. 1.04±0.15, all P < 0.05], while SIRT1 inhibitor EX-527 had the opposite effects. There was no significant difference in the apoptosis rate among normal group, LPS group, and low, medium and high concentration RSV groups, as well as EX-527 group [(7.03±0.57)%, (9.67±0.55)%, (9.57±0.70)%, (9.30±2.15)%, (9.87±0.97)%, (9.07±0.93)%, F = 2.590, P = 0.082]. ② Immunohistochemical results showed that compared with the Sham group, the expressions of NLRP3 inflammasomes and downstream products caspase-1 and ASC in the intestinal epithelial cells in CLP 6 h group, CLP 24 h group and RSV intervention group were significantly increased. The percentage of ASC-positive area in intestinal epithelium of RSV intervention group was significantly lower than that of CLP 6 h group [(15.22±2.73)% vs. (19.88±2.67)%, P < 0.05], and the expressions of NLRP3 and caspase-1 were significantly lower than those of CLP 24 h group [(9.31±1.37)% vs. (13.19±1.92)%, (19.57±3.92)% vs. (27.28±6.33)%, both P < 0.05]. Conclusion:After sepsis, high concentration of RSV could inhibit the activation of NLRP3 inflammasome by activating SIRT1, thereby reduce the expression of caspase-1 and ASC, and inhibit the secretion of inflammatory factors to reduce the inflammatory response.

Activation of NOD-like receptor protein 3 inflammasome mediates inflammatory response and apoptosis in septic intestinal injury model / 中华危重病急救医学

Objective:To investigate the expression of NOD-like receptor protein 3 (NLRP3) inflammasome in intestinal injury models with different severity of sepsis and the inflammatory response and apoptosis mediated by NLRP3 inflammasome.Methods:Human colorectal adenocarcinoma cells (Caco-2) were cultured in vitro. The logarithmic growth phase cells were divided into blank control group (normal culture in complete medium) and lipopolysaccharide (LPS) 1, 2 and 4 mg/L groups (complete medium containing 1, 2 and 4 mg/L LPS, respectively). The supernatant were collected at 6, 12 and 24 hours, and the levels of tumor necrosis factor-α (TNF-α), interleukins (IL-6, IL-1β, IL-18) were detected by enzyme linked immunosorbent assay (ELISA). The apoptotic level of cells was detected by flow cytometry. The cells were harvested, and the real-time fluorescence quantitative reverse transcription-polymerase chain reaction (RT-qPCR) was used to detect the mRNA expressions of NLRP3 and silent information regulator 1 (SIRT1). Western blotting was used to detect the protein expressions of NLRP3, SIRT1, caspase-1 and apoptosis-associated speck-like protein (ASC). Results:ELISA results showed that the levels of IL-6, TNF-α, IL-1β, and IL-18 in cell supernatant of LPS groups increased in a dose-dependent and time-dependent manner as compared with the blank control group during the same intervention period. The increase was most significant in LPS 4 mg/L group at 24 hours [IL-6 (ng/L): 3.55±0.06 vs. 0.67±0.09, TNF-α (ng/L): 15.37±0.19 vs. 5.04±0.14, IL-1β (ng/L): 2.26±0.10 vs. 0.56±0.09, IL-18 (ng/L): 433.92±22.55 vs. 93.55±21.13, all P < 0.05]. The results of the apoptotic test showed that, compared with the blank control group, the apoptotic rate of LPS groups increased in a dose-dependent and time-dependent manner, and the apoptotic rate of LPS 4 mg/L group increased most significantly at 24 hours [(14.83±3.73)% vs. (5.87±1.17)%, P < 0.05]. RT-qPCR results showed that the expression level of NLRP3 mRNA was increased, while the expression level of SIRT1 mRNA was decreased with the increase of LPS intervention dose and the prolonging of intervention time. At 24 hours, there were significant differences between LPS 4 mg/L group and blank control group [NLRP3 mRNA (2 -ΔΔCt): 8.20±2.82 vs. 1.00±0.36, SIRT1 mRNA (2 -ΔΔCt): 0.58±0.01 vs. 1.03±0.06, both P < 0.05]. Western blotting showed that compared with the blank control group, the protein expression levels of NLRP3, caspase-1 and ASC in LPS groups were significantly increased, while the protein expression levels of SIRT1 were significantly decreased. During each intervention period, with the increase of LPS dose, the expressions of NLRP3, caspase-1 and ASC protein increased gradually, while the expression of SIRT1 protein decreased gradually. At 24 hours, the difference between the LPS 4 mg/L group and the blank control group was significant [NLRP3 protein (NLRP3/β-actin): 1.48±0.03 vs. 0.90±0.12, caspase-1 protein (caspase-1/β-actin): 1.18±0.11 vs. 0.72±0.09, ASC protein (ASC/β-actin) : 1.09±0.01 vs. 0.82±0.03, SIRT1 protein (SIRT1/β-actin): 0.48±0.03 vs. 0.76±0.05, all P < 0.05]. Conclusion:In vitro, in the sepsis induced intestinal inflammation model, with the increase of LPS intervention dose and the prolongation of intervention time, intestinal inflammatory response and cell apoptosis showed an increasing trend, which may be related to the up-regulation of NLRP3 inflammasome and its downstream products ASC and caspase-1, and to the down-regulation of SIRT1 expression.

Ulinastatin protects intestinal mucosal barrier by inhibiting the activation of intestinal NLRP3 inflammasomes in septic rats / 中华危重病急救医学

Objective:To explore the damage of the intestinal mucosal barrier of septic rats by the activation of NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasomes and the role of Ulinastatin (UTI) on the expression of intestinal nuclear factor-κB (NF-κB)/NLRP3 inflammasome signaling pathway in septic rats.Methods:According to the random number table method, 64 male Wistar rats were divided into sham operation group (Sham group), cecal ligation and puncture (CLP) group, UTI treatment group (100 kU/kg UTI was intraperitoneally injected 1, 6, 12 and 18 hours after CLP), and UTI pretreatment group (100 kU/kg UTI was given 1 hour before CLP), with 16 rats in each group. The survival of rats was observed after 24 hours, and the blood was collected from abdominal aorta at 24 hours after modeling, then rats were killed and their ileum tissues were taken. Hematoxylin-eosin (HE) staining was used to observe histopathological changes and Chiu score. The levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and intestinal fatty acid binding protein (I-FABP) in serum were detected by enzyme linked immunosorbent assay (ELISA). The protein expression of NF-κB p65 in intestinal tissue was detected by Western blotting. The expression of intestinal tight junction proteins Claudin-1, Occludin and the inflammasome NLRP3, apoptosis-associated speck-like protein containing CARD (ASC) and caspase-1 were detected by immunohistochemistry.Results:Compared with Sham group, the 24-hour survival rate of CLP group was significantly reduced. Histopathological results showed that the CLP group had severe edema of mucosa and submucosal stroma with obvious infiltration of inflammatory cells and disordered villi arrangement. Some glands were incomplete, and the villus structure was severely damaged. The Chiu score was significantly increased. The levels of TNF-α, IL-1β, I-FABP in serum and the protein expression of NF-κB p65 in intestinal tissue were significantly increased. The positive expressions of NLRP3, caspase-1 and ASC were also significantly increased. However, the positive expression of tight junction protein in small intestine tissue such as Occludin and Claudin-1 were significantly reduced. It suggested that when sepsis occurs, small intestinal mucosal barrier dysfunction happens, and mucosal permeability increases, while tight junction protein expression decreases, NLRP3 inflammasome and its upstream molecule NF-κB p65 were activated. After UTI treatment and UTI pretreatment intervention, although there was no significant difference in 24-hour survival compared with CLP group (62.5%, 68.8% vs. 43.8%, both P > 0.05), the intestinal tissue damage of septic rats was significantly improved. Specifically: Chiu score and the levels of TNF-α, IL-1β, I-FABP in serum were significantly decreased [Chiu score: 3.37±0.25, 3.23±0.16 vs. 4.08±0.13, TNF-α (ng/L): 147.62±20.74, 140.71±24.81 vs. 222.82±16.84, IL-1β (ng/L): 80.64±5.68, 78.11±4.75 vs. 133.73±3.92, I-FABP (μg/L): 38.29±3.60, 35.88±4.52 vs. 59.81±4.66, all P < 0.05]; the protein expression of NF-κB p65 was significantly decreased (NF-κB p65/β-actin: 0.65±0.10, 0.69±0.11 vs. 0.99±0.10, both P < 0.05), the positive expressions of Claudin-1 and Occludin in the small intestine tissue were increased [Claudin-1 positive expression area: (19.43±3.08)%, (23.99±6.27)% vs. (7.77±2.03)%; Occludin positive expression area: (19.58±4.75)%, (23.28±3.68)% vs. (11.69±4.30)%, all P < 0.05], while the positive expressions of NLRP3, caspase-1, ASC were decreased [NLRP3 positive expression area: (7.80±3.14)%, (6.86±2.63)% vs. (14.44±3.68)%; caspase-1 positive expression area: (10.62±3.52)%, (9.49±3.09)% vs. (26.69±8.05)%; ASC positive expression area: (9.95±2.81)%, (10.53±3.61)% vs. (24.16±5.48)%, all P < 0.05]. However, there was no significant difference in the improvement effect between UTI treatment group and UTI pretreatment group.Conclusions:Intestinal barrier dysfunction in sepsis may be related to the activation of NLRP3 inflammasomes in the intestinal mucosa. The protective effect of UTI in the intestinal mucosa may be related to inhibiting the activation of NLRP3 inflammasomes in the intestinal mucosa, but UTI pretreatment has no obvious advantage compared with UTI treatment.

Effect of terlipressin on prognosis of adult septic shock patients: a Meta-analysis / 中华危重病急救医学

Objective:To investigate the effect of terlipressin on prognosis of adult septic shock patients.Methods:All randomized controlled clinical trials (RCT) of terlipressin in the treatment of adult septic shock patients from January 1980 to December 2019 were retrieved from CNKI, Wanfang, SinoMed, PubMed, Embase, Springer Link, Cochrane Library, Google Scholar, and etc. Patients in the treatment group received terlipressin while patients in the control group received norepinephrine or other vasopressors. Main outcome indicator was mortality. Secondary outcome indicators included the incidence of severe adverse events, limb peripheral ischemic events and renal complications. Literature screening, data extraction and quality evaluation were conducted by two researchers respectively. Meta-analysis was performed with RevMan 5.3 software. Funnel plot was used to analyze the publication bias.Results:A total of 507 related literatures were retrieved. According to the inclusion and exclusion criteria, 8 RCT studies were finally included, with a total of 811 patients. One study was considered to have a lower risk of bias, 6 studies had uncertain risk of bias, and 1 study had a higher risk of bias. The Meta-analysis showed that terlipressin did not significantly improve the mortality of septic shock patients compared with the control group [odds ratio ( OR) = 0.89, 95% confidence interval (95% CI) was 0.67-1.19, P = 0.45]; increased the incidence of severe adverse events ( OR = 2.98, 95% CI was 1.99-4.45, P < 0.000 01); there was a tendency to increase the incidence of limb peripheral ischemic events, but without statistical difference ( OR = 10.81, 95% CI was 0.88-133.19, P = 0.06); and reduced the incidence of renal complications ( OR = 0.30, 95% CI was 0.09-0.96, P = 0.04). Funnel plot analysis indicated that there might be publication bias in a study on case fatality and incidence of serious adverse events in the included literature. No significant publication bias was found in studies on the incidence of limb peripheral ischemic events and the incidence of kidney-related complications. Conclusions:The available evidence suggests that terlipressin could not significantly improve mortality in adult's septic shock patients, but it may reduce the incidence of renal complications. A tendency to increase the incidence of limb peripheral ischemic events in the terlipressin-treated group needs to be emphasized.

Stratified outcomes of "Kidney Disease: Improving Global Outcomes" serum creatinine criteria in critical ill patients: a secondary analysis of a multicenter prospective study / 中华危重病急救医学

Objective:To investigate the different outcomes of two types of acute kidney injury (AKI) according to standard of Kidney Disease: Improving Global Outcomes-AKI (KDIGO-AKI), and to analyze the risk factors that affect the prognosis of intensive care unit (ICU) patients in China.Methods:A secondary analysis was performed on the database of a previous study conducted by China Critical Care Clinical Trial Group (CCCCTG), which was a multicenter prospective study involving 3 063 patients in 22 tertiary ICUs in 19 provinces and autonomous regions of China. The demographic data, scores reflecting severity of illness, laboratory findings, intervention during ICU stay were extracted. All patients were divided into pure AKI (PAKI) and acute on chronic kidney disease (AoCKD). PAKI was defined as meeting the serum creatinine (SCr) standard of KDIGO-AKI (KDIGO-AKI SCr) and the estimated glomerular filtration rate (eGFR) at baseline was ≥ 60 mL·min -1·1.73 m -2, and AoCKD was defined as meeting the KDIGO-AKI SCr standard and baseline eGFR was 15-59 mL·min -1·1.73 m -2. All-cause mortality in ICU within 28 days was the primary outcome, while the length of ICU stay and renal replacement therapy (RRT) were the secondary outcome. The differences in baseline data and outcomes between the two groups were compared. The cumulative survival rate of ICU within 28 days was analyzed by Kaplan-Meier survival curve, and the risk factors of ICU death within 28 days were screened by Cox multivariate analysis. Results:Of the 3 063 patients, 1 042 were enrolled, 345 with AKI, 697 without AKI. The AKI incidence was 33.11%, while ICU mortality within 28 days of AKI patients was 13.91% (48/345). Compared with PAKI patients ( n = 322), AoCKD patients ( n = 23) were older [years old: 74 (59, 77) vs. 58 (41, 72)] and more critical when entering ICU [acute physiology and chronic health evaluation Ⅱ (APACHEⅡ) score: 23 (19, 27) vs. 15 (11, 22)], had worse basic renal function [eGFR (mL·min -1·1.73 m -2): 49 (38, 54) vs. 115 (94, 136)], more basic complications [Charlson comorbidity index (CCI): 3 (2, 4) vs. 0 (0, 1)] and higher SCr during ICU stay [peak SCr for diagnosis of AKI (μmol/L): 412 (280, 515) vs. 176 (124, 340), all P < 0.01]. The mortality and RRT incidence within 28 days in ICU of AoCKD patients were significantly higher than those of PAKI patients [39.13% (9/23) vs. 12.11% (39/322), 26.09% (6/23) vs. 4.04% (13/322), both P < 0.01], while no significant difference was found in the length of ICU stay. Kaplan-Meier survival curve analysis showed that the 28-day cumulative survival rate in ICU in AoCKD patients was significantly lower than PAKI patients (Log-Rank: χ2 = 5.939, P = 0.015). Multivariate Cox regression analysis showed that admission to ICU due to respiratory failure [hazard ratio ( HR) = 4.458, 95% confidence interval (95% CI) was 1.141-17.413, P = 0.032], vasoactive agents treatment in ICU ( HR = 5.181, 95% CI was 2.033-13.199, P = 0.001), and AoCKD ( HR = 5.377, 95% CI was 1.303-22.186, P = 0.020) were independent risk factors for ICU death within 28 days. Conclusion:Further detailed classification (PAKI, AoCKD) based on KDIGO-AKI SCr standard combined with eGFR is related to ICU mortality in critical patients within 28 days.

Investigation and analysis of the development status of critical care medicine in Xinjiang Uygur Autonomous Region in 2019 / 中华危重病急救医学

Objective:To comprehensively understand the basic construction of intensive care unit (ICU) in the secondary and tertiary hospitals in Xinjiang Uygur Autonomous Region, and to provide a theoretical basis for the development direction of critical care medicine and the rational allocation of medical resources in our region.Methods:On the March 14th, 2020, a cross-sectional survey of 147 ICU in 122 hospitals in Xinjiang Uygur Autonomous Region was conducted using an online questionnaire. The survey included 6 modules: the basic conditions of the hospital, ICU profile, ICU human resources status, equipment allocation, technology development, and ICU quality control.Results:Among the 147 ICUs, there were 69 ICUs in tertiary hospital and 78 ICUs in secondary hospital. 75.51% (111/147) were comprehensive ICU and 24.49% (36/147) were specialized ICU. The total number of ICU beds was 1 818, accounted about 2.43% (1 818/74 912) of the total number of hospital beds. In ICU terms of human resourse, physicians/beds ratio was 0.54∶1, and nurses/beds ratio was 1.55∶1. Physicians/beds ratio in the secondary hospitals was 0.52∶1, and nurses/beds was 1.45∶1; physicians/beds ratio in the tertiary hospital was 0.56∶1, and nurses/beds ratio was 1.79∶1. The ICU management model was mainly closed management (82.99%, 122/147), and the proportion of closed management in tertiary hospitals was 88.41% (61/69), which was higher than that in secondary hospitals (78.21%, 61/78). In aspect of ICU equipment, the invasive ventilator/bed ratio, enteral nutrition infusion pump/bed ratio, and blood purifier/bed ratio in the tertiary hospitals were significantly higher than those in the secondary hospitals [0.70 (0.46, 1.00) vs. 0.45 (0.33, 0.67), 0.18 (0.00, 0.56) vs. 0.00 (0.00, 0.13), 0.08 (0.00, 0.13) vs. 0.00 (0.00, 0.10), respectively, all P < 0.01]. In the tertiary hospital, the chest sputum excretion device, blood gas analyzer, blood purification instrument, transport ventilator, fiber bronchoscope, enteral nutrition infusion pump, bedside ultrasound machine, continuous hemodynamics and oxygen metabolism monitor, electroencephalogram bispectral index monitor, bedside electroencephalography machine and extracorporeal membrane oxygenation (ECMO) were also superior to the secondary hospitals. ICU technologies, such as deep venipuncture, jejunal nutrition tube placement, percutaneous tracheotomy, invasive blood pressure monitoring, invasive hemodynamic monitoring, bedside ultrasound examination, continuous blood purification, fiber bronchoscopy, high frequency ventilation, intra-aortic balloon counterpulsation (IABP), and ECMO had also performed better than secondary hospitals. In the management of ICU medical quality control, in tertiary hospitals, the proportions of single or isolated room for patients with drug-resistant bacteria, 1-hour bundle and hemodynamic monitoring for patients with septic shock, routine prone position ventilation and lung recruitment for patients with acute respiratory distress syndrome (ARDS), common analgesic, and use of personal digital assistant (PDA) for pre-operation scan code by nurses and electronic medical record for routine rounds were significantly higher than those in secondary hospitals (91.30% vs. 85.90%, 68.12% vs. 48.72%, 85.51% vs. 70.51%, 28.99% vs. 12.82%, 85.51% vs. 61.54%, 76.81% vs. 61.54%, 71.01% vs. 29.49, 49.28% vs. 28.21%, respectively), and the differences were statistically significant (all P < 0.05). 89.74% (70/78) ICU in secondary hospitals and 89.86% (62/69) of tertiary hospitals used acute physiology and chronic health evaluation Ⅱ (APACHE Ⅱ) to evaluate the severity of critically ill patients; in terms of sequential organ failure assessment (SOFA), the difference between the secondary hospitals and the tertiary hospitals was not statistically significant (51.28% vs. 62.32%, χ2 = 1.814, P = 0.178). Conclusions:Although the ICU construction of the tertiary hospitals in Xinjiang Uygur Autonomous Region is more complete than secondary hospitals, there is a big gap between the requirements of the national guidelines and the developed regions in the east. The ICU's investment in human resource, equipment and supporting facilities allocation, promotion of suitable technology, and medical quality control management should be increased to promote the development of critical care medicine in Xinjiang Uygur Autonomous Region.

Sepsis: advancements in controversy / 中华危重病急救医学

Sepsis is one of the leading causes of inpatient deaths worldwide and is a major challenge in clinical work. The diagnosis and treatment of sepsis has been a research hotspot in critical care medicine. Through the efforts during the past decades, deeper understanding of the pathophysiology of sepsis and progress in the treatment have been made. But the latest sepsis guidelines and bundle strategies remain controversial, and clinical researches on sepsis are mixed. So far, there is no specific therapy for sepsis, and the mortality is still very high. Important researches and viewpoints in the field of sepsis in recent years are summarized and analyzed, so as to provide reference for the treatment of sepsis patients.

Sepsis: advancements in controversy / 中华危重病急救医学

Sepsis is one of the leading causes of inpatient deaths worldwide and is a major challenge in clinical work. The diagnosis and treatment of sepsis has been a research hotspot in critical care medicine. Through the efforts during the past decades, deeper understanding of the pathophysiology of sepsis and progress in the treatment have been made. But the latest sepsis guidelines and bundle strategies remain controversial, and clinical researches on sepsis are mixed. So far, there is no specific therapy for sepsis, and the mortality is still very high. Important researches and viewpoints in the field of sepsis in recent years are summarized and analyzed, so as to provide reference for the treatment of sepsis patients.