Binding domain peptide ameliorates alveolar hypercoagulation and fibrinolytic inhibition in mice with lipopolysaccharide-induced acute respiratory distress syndrome Via NF-κB signaling pathway.

BACKGROUND: Alveolar hypercoagulation and fibrinolytic inhibition are shown to be associated with refractory hypoxemia in acute respiratory distress syndrome (ARDS), and the NF-κB pathway is involved in this process. The purpose of this study is to explore the role of NEMO-binding domain peptide (NBDP) in alleviating alveolar hypercoagulation and fibrinolytic inhibition induced by lipopolysaccharide (LPS) in ARDS mice and its related mechanisms. MATERIALS AND METHODS: ARDS was induced by inhalation of LPS (mg/L) in adult male BALB/c mice. Mice were treated with intratracheal inhalation of NBDP or saline aerosol at increased concentrations 30 minutes before LPS administration. Six hours after LPS treatment, bronchoalveolar lavage fluids (BALF) were collected and then all mice were euthanized. In addition, coagulation and fibrinolysis associated factors in lung tissues and BALF were detected, and the activation of NF-κB signaling pathway was observed. RESULTS: NBDP pretreatment dose-dependently inhibited the expression of tissue factor (TF) and plasminogen activator inhibitor (PAI) 1 in lung tissues, reduced the secretions of TF, PAI-1, thrombin-antithrombin (TAT) complex, and promoted activated protein C (APC) secretion in BALF induced by LPS. LPS-induced high expression of pulmonary procollagen peptide type lll (PIIIP) was also reduced in a dose-dependent manner under NBDP pretreatment. Western blotting showed that NBDP pretreatment significantly attenuated LPS-induced activation of IKKα/ß, Iκα and NF-κB p65. NBDP pretreatment also inhibited the DNA binding activity of p65 induced by LPS. We also noticed that NBDP protected mice against LPS-induced lung injury in a dose-dependent manner. CONCLUSIONS: The experimental findings demonstrate that through inhibiting the NF-κB signaling pathway, NBDP dose-dependently ameliorates LPS-induced alveolar hypercoagulation and fibrinolytic inhibition, which is expected to be a new therapeutic target to correct the abnormalities of alveolar coagulation and fibrinolytic pathways in ARDS.

Andrographolide sulfonate attenuates alveolar hypercoagulation and fibrinolytic inhibition partly via NF-κB pathway in LPS-induced acute respiratory distress syndrome in mice.

BACKGROUND: Alveolar hypercoagulation and fibrinolytic inhibition are important characteristics during acute respiratory distress syndrome (ARDS), and NF-κB p65 signaling pathway is involved to regulate these pathophysiologies. We hypothesize that targeting NF-κB signal pathway could ameliorate alveolar hypercoagulation and fibrinolyitc inhibition, thus attenuating lung injury in ARDS. PURPOSE: We explore the efficacy and the potential mechanism of andrographolide sulfonate (Andro-S) on alveolar hypercoagulation and fibrinolytic inhibition in LPS-induced ARDS in mice. METHODS: ARDS was made by lipopolysaccharide (LPS) inhalation in C57BLmice. Andrographolide sulfonate (2.5, 5 and 10 mg/kg) was intraperitoneally given to the mice (once a day for three consecutive days) before LPS administration. NEMO binding domain peptide (NBD), an inhibitor of NF-κB, was used as the positive control and it replaced Andro-S in mice of NBD group. Mice in normal control received saline instead of LPS. Lung tissues and bronchoalveolar lavage fluid (BALF) were collected for analysis of alveolar coagulation, fibrinolytic inhibition as well as of pulmonary inflammatory response after 8 h of LPS inhalation. NF-κB signal pathway in lung tissue was simultaneously determined. RESULTS: Andro-S dose-dependently inhibited tissue factor (TF) and plasminogen activator inhibitor (PAI)-1 expressions either in mRNA or in protein in lung tissue of ARDS mice, and it also decreased the concentrations of TF, PAI-1, thrombin-antithrombin complex (TAT), procollagen peptide type Ⅲ (PⅢP) while promoting the production of activated protein C (APC) in BALF. Meanwhile, Andro-S effectively inhibited inflammatory response (interleukin 1ß and myeloperoxidase) induced by LPS. LPS stimulation dramatically activated NF-κB signal pathway, indicated by increased expressions of phosphorylation of p65 (p-p65), p-IKKα/ß and p-IκBα and the higher p65-DNA binding activity, which were all dose-dependently reversed by Andro-S. Andro-S and NBD presented similar efficacies. CONCLUSIONS: Andro-S treatment improves alveolar hypercoagulation and fibrinolytic inhibition and attenuates pulmonary inflammation in LPS-induced ARDS in mice partly through NF-κB pathway inactivation. The drug is expected to be an effective choice for ARDS.

Triptolide dose-dependently improves LPS-induced alveolar hypercoagulation and fibrinolysis inhibition through NF-κB inactivation in ARDS mice.

BACKGROUND: Alveolar hypercoagulation and fibrinolysis inhibition were associated with the refractory hypoxemia and the high mortality in patient with acute respiratory distress syndrome (ARDS), and NF-κB pathway was confirmed to contribute to the process. Triptolide (TP) significantly inhibited NF-κB pathway and thus depressed accessive inflammatory response in ARDS. We speculate that TP could improve alveolar hypercoagulation and fibrinolytic inhibition in LPS-induced ARDS via NF-κB inactivation. PURPOSE: The aim of this experiment was to explore the efficacy and potential mechanism of TP on alveolar hypercoagulation and fibrinolysis inhibition in LPS-induced ARDS in mice. METHODS: 50 µl of LPS (5 mg/ml) was inhalationally given to C57BL/6 mice to set up ARDS model. Male mice were randomly accepted with LPS, LPS + TP (1 µg/kg, 10 µg/kg, 50 µg/kg respectively), or with NEMO Binding domain peptide (NBD), an inhibitor of NF-κB. TP (1 µg/kg, 10 µg/kg, 50 µg/kg) were intraperitoneally injected or 10 µg/50 µl of NBD solution were inhaled 30 min before LPS inhalation. A same volume of normal saline (NS) substituted for TP in mice in control. The endpoint of experiment was at 8 hours after LPS stimulation. Pulmonary tissues were taken for hematoxylin-eosin (HE) staining, wet / dry ratio and for lung injury scores (LIS). Tissue factor (TF) and plasminogen activator inhibitor (PAI)-1 in lung tissue were detected by Western-blotting and by quantitative Real-time PCR(qPCR) respectively. Concentrations of TF, PAI-1, thrombin-antithrombin complex (TAT), procollagen peptide type Ⅲ (PⅢP) and activated protein C (APC) in bronchoalveolar lavage fluid (BALF) were measured by ELISA. NF-κB activation and p65-DNA binding activity in pulmonary tissue were simultaneously determined. RESULTS: LPS stimulation resulted in pulmonary edema, neutrophils infiltration, obvious alveolar collapse, interstitial congestion, with high LIS, which were all dose-dependently ameliorated by Triptolide. LPS also dramatically promoted the expressions of TF and PAI-1 either in mRNA or in protein in lung tissue, and significantly stimulated the secretions of TF, PAI-1, TAT, PⅢP but inhibited APC production in BALF, which were all reversed by triptolide treatment in dose-dependent manner. TP dose-dependently inhibited the activation of NF-κB pathway induced by LPS, indicated by the changes of phosphorylations of p65 (p-p65), p-IKKα/ß and p-IκBα, and weakened p65-DNA binding activity. TP and NBD had same efficacies either on alveolar hypercoagulation and fibrinolysis inhibition or on NF-κB signalling pathway in ARDS mice. CONCLUSIONS: TP dose-dependently improves alveolar hypercoagulation and fibrinolysis inhibition in ARDS mice through inhibiting NF-κB signaling pathway. Our data demonstrate that TP is expected to be an effective selection in ARDS.

[Effects of andrographolide on the expression of procoagulant and fibrinolytic inhibition factors in rat type II alveolar epithelial cells stimulated by lipopolysaccharide].

OBJECTIVE: To determine the effect of andrographolide (AD) on the expression of procoagulant and fibrinolytic inhibitory factors in rat type II alveolar epithelial cells (AEC II) stimulated by lipopolysaccharide (LPS). METHODS: The AEC II cells RLE-6TN in the logarithmic growth phase were divided into 5 groups: the normal control (NC) group, the LPS group, and the 6.25, 12.5, and 25 mg/L AD groups (AD 6.25 group, AD 12.5 group, AD 25 group). The NC group was cultured with RPMI 1640 conventional medium. In the LPS group, 5 mg/L LPS was added to the RPMI 1640 conventional medium for stimulation. Cells in the AD groups were treated with 6.25, 12.5, and 25 mg/L AD in advance for 1 hour and then given LPS to stimulate the culture. The cells and cell culture supernatant were collected 24 hours after LPS stimulation. The protein and mRNA expressions of tissue factor (TF), tissue factor pathway inhibitor (TFPI), and plasminogen activator inhibition-1 (PAI-1) in cells were detected by Western blotting and real-time fluorescent quantitative polymerase chain reaction (RT-qPCR). The levels of procollagen III peptide (PIIIP), thrombin-antithrombin complex (TAT), antithrombin III (AT-III) and activated protein C (APC) in the cell supernatant were detected by enzyme linked immunosorbent assay (ELISA). RESULTS: Compared with the NC group, the protein and mRNA expressions of TF and PAI-1 in the LPS group were significantly increased, and the protein and mRNA expressions of TFPI were significantly reduced. At the same time, the levels of PIIIP and TAT in the cell supernatant were significantly increased, the levels of AT-III, APC were significantly reduced. Compared with the LPS group, the protein and mRNA expressions of TF and PAI-1 in AD 6.25 group, AD 12.5 group, AD 25 group were significantly reduced [TF/GAPDH: 0.86±0.08, 0.45±0.04, 0.44±0.04 vs. 1.32±0.10, TF mRNA (2-ΔΔCt): 2.59±0.25, 2.27±0.05, 1.95±0.04 vs. 4.60±0.26, PAI-1/GAPDH: 2.11±0.07, 1.45±0.04, 0.86±0.09 vs. 2.56±0.09, PAI-1 mRNA (2-ΔΔCt): 3.50±0.22, 2.23±0.29, 1.84±0.09 vs. 6.60±0.27, all P < 0.05], while the protein and mRNA expressions of TFPI were significantly increased [TFPI/GAPDH: 0.78±0.05, 0.81±0.03, 0.84±0.07 vs. 0.36±0.02, TFPI mRNA (2-ΔΔCt): 0.46±0.09, 0.69±0.07, 0.91±0.08 vs. 0.44±0.06, all P < 0.05]. Also the levels of PIIIP and TAT in the cell supernatant were significantly reduced, and the levels of AT-III and APC were significantly increased [PIIIP (µg/L): 13.59±0.23, 12.66±0.23, 10.59±0.30 vs. 15.82±0.29, TAT (ng/L): 211.57±6.41, 205.69±4.04, 200.56±9.85 vs. 288.67±9.84, AT-III (µg/L): 102.95±3.86, 123.92±2.63, 128.67±1.67 vs. 92.93±3.36, APC (µg/L): 1 188.95±14.99, 1 366.12±39.93, 1 451.15±29.69 vs. 1 145.55±21.07, all P < 0.05]. With the increase of the dose of AD, the above-mentioned promotion and inhibition effects became more obvious. In the AD 25 group, TF, PAI-1 protein and mRNA expressions decreased, TFPI mRNA expression increased, PIIIP level in the supernatant decreased and AT-III, APC levels increased compared with AD 6.25 group, the difference was statistically significant, and the decrease of PAI-1 protein expression and PIIIP level in the supernatant were also statistically significant compared with AD 12.5 group. CONCLUSIONS: Andrographolide in the dose range of 6.25-25 mg/L can dose-dependently inhibit the expression and secretion of procoagulant and fibrinolytic inhibitor-related factors in AEC II cells RLE-6TN stimulated by LPS, and promote the secretion of anticoagulant factors. 25 mg/L has the most obvious effect.

[Berberine dose-dependently inhibits the expression of procoagulant and fibrinolytic inhibitory factors in lipopolysaccharide-induced rat type II alveolar epithelial cells].

OBJECTIVE: To observe the effects of berberine on procoagulant and fibrinolytic inhibitory factors produced by rat type II alveolar epithelial cell (AEC II) induced by lipopolysaccharide (LPS). METHODS: AEC II cells (RLE-6TN cells) were cultured in vitro, and the cells in logarithmic growth phase were collected. The cytotoxicity text of berberine was detected by cell counting kit-8 (CCK-8) to determine the drug concentration range according to inhibition concentration of half cells (IC50). The RLE-6TN cells were divided into five groups, the cells in blank control group were cultured in DMEM; the cells in LPS group were stimulated with 5 mg/L LPS; and the cells in berberine pretreatment groups were pretreated with 20, 50 and 80 µmol/L berberine for 1 hour, and then were co-cultured with 5 mg/L LPS. The cells were collected after LPS induced for 24 hours. The protein and mRNA expression levels of tissue factor (TF), tissue factor pathway inhibitor (TFPI) and plasminogen activator inhibitor-1 (PAI-1) in the cells were detected by Western blotting and real-time fluorescence quantification reverse transcription-polymerase chain reaction (RT-qPCR). The levels of activated protein C (APC), precollagen III peptide (PIIIP), thrombin-antithrombin complex (TAT) and antithrombin III (AT III) in the cell supernatant were measured by enzyme linked immunosorbent assay (ELISA). RESULTS: According to the inhibition rate curve, the IC50 of berberine on RLE-6TN cells was 81.16 µmol/L. Therefore, 20, 50 and 80 µmol/L were selected as the intervention concentration of berberine. Compared with the blank control group, the expression and secretion of procoagulant and fibrinolytic inhibitory factors were abnormal in RLE-6TN cells after LPS induced for 24 hours. The protein and mRNA expression levels of TF and PAI-1 in the LPS group were significantly increased, but the protein and mRNA expression levels of TFPI were significantly decreased. Meanwhile, the levels of APC and AT III in the cell supernatant were significantly decreased, while the levels of PIIIP and TAT were significantly increased. After pretreatment with berberine, the abnormal expression and secretion of procoagulant and fibrinolytic inhibitory factors induced by LPS were corrected in a dose-dependent manner, especially in 80 µmol/L. Compared with the LPS group, the protein and mRNA expression levels of TF and PAI-1 in the berberine 80 µmol/L group were significantly decreased [TF protein (TF/GAPDH): 0.45±0.02 vs. 0.55±0.03, TF mRNA (2-ΔΔCt): 0.39±0.08 vs. 1.48±0.11, PAI-1 protein (PAI-1/GAPDH): 0.37±0.02 vs. 0.64±0.04, PAI-1 mRNA (2-ΔΔCt): 1.14±0.29 vs. 4.18±0.44, all P < 0.01] and those of TFPI were significantly increased [TFPI protein (TFPI/GAPDH): 0.53±0.02 vs. 0.45±0.02, TFPI mRNA (2-ΔΔCt): 0.94±0.08 vs. 0.40±0.05, both P < 0.01]. Meanwhile, the levels of APC and AT III in the cell supernatant were significantly increased [APC (µg/L): 1 358.5±26.0 vs. 994.2±23.1, AT III (µg/L): 118.0±7.4 vs. 84.4±2.7, both P < 0.01], while those of PIIIP and TAT were significantly decreased [PIIIP (µg/L): 11.2±0.4 vs. 18.6±0.9, TAT (ng/L): 222.1±2.8 vs. 287.6±7.0, both P < 0.01]. CONCLUSIONS: Berberine could inhibit the LPS-induced expressions of procoagulant and fibrinolytic inhibitory factors in rat AEC II cells and promote the expressions of anticoagulant factors in a dose-dependent manner. Berberine may be a new therapeutic target for alveolar hypercoagulability and fibrinolysis inhibition in acute respiratory distress syndrome (ARDS).

Emodin improves alveolar hypercoagulation and inhibits pulmonary inflammation in LPS-provoked ARDS in mice via NF-κB inactivation.

BACKGROUND: Alveolar hypercoagulation and pulmonary inflammation are important characteristics and they regulate each other in acute respiratory distress syndrome (ARDS). NF-κB pathway has been confirmed to be involved in regulation of this crosstalk. Emodin, a traditional Chinese herb, shows potent inhibitory effect on NF-κB pathway, but whether it is effective in alveolar hypercoagulation and pulmonary inflammation in ARDS remains to be elucidated. PURPOSE: The aim of this experiment was to evaluate the efficacy of emodin on LPS-provoked alveolar hypercoagulation and excessive pulmonary inflammation in ARDS, and its potential mechanism. METHODS: Mice ARDS was set up through LPS (40 µl, 4 mg/ml) inhalation. Male mice were randomly received with BPS, LPS only, LPS+ emodin (5 mg/kg, 10 mg/kg, 20 mg/kg, respectively) and BAY65-1942, an inhibitor of IKKß. After 48 h of LPS stimulation, pulmonary pathological injury, expressions of Tissue factor (TF), plasminogen activator inhibitor (PAI)-1, activated protein C (APC), collagen Ⅰ, collagen III, interleukin (IL) 8, IL-1ß and tumor necrosis factor (TNF)-α in lung tissues, as well as concentrations of antithrombin III (AT III), procollagen peptide type III (PIIIP), soluble thrombomodulin (sTM), thrombin antithrombin complex (TAT), myeloperoxidase (MPO) and the percentage of inflammatory cells in bronchoalveolar lavage fluid (BALF) were all determined. NF-κB pathway activation as well as NF-κB DNA binding activity in pulmonary tissue were simultaneously checked. RESULTS: LPS stimulation resulted in obvious lung injury, excessive inflammatory cells infiltration, which all were dose-dependently ameliorated by emodin. Expressions of TF, PAI-1, collagen Ⅰ and collagen III as well as IL-8, IL-1ß and TNF-α in pulmonary tissue were all elevated while APC decreased under LPS provocation, which were all reversed by emodin treatment in dose-dependent manner. LPS promoted the secretions of PIIIP, sTM, TAT and inhibited AT III production in BALF, and resulted in high levels of MPO and the percentage of inflammatory cells in BALF, all of which were significantly and dose-dependently attenuated while AT III production was increased by emodin. Meanwhile, emodin effectively inhibited NF-κB pathway activation and attenuated p65 DNA binding activity induced by LPS inhalation. Emodin and BAY-65-1942 had similar impacts in this experiment. CONCLUSIONS: Emodin improves alveolar hypercoagulation and fibrinolytic inhibition and depresses excessive pulmonary inflammation in ARDS mice in dose-dependent manner via NF-κB inactivation. Our data demonstrate that emodin is expected to be an effective drug in alveolar hypercoagulation and pulmonary inflammation in ARDS.

SN50 attenuates alveolar hypercoagulation and fibrinolysis inhibition in acute respiratory distress syndrome mice through inhibiting NF-κB p65 translocation.

BACKGROUND: It has been confirmed that NF-κB p65 signaling pathway is involved in the regulation of alveolar hypercoagulation and fibrinolysis inhibition in acute respiratory distress syndrome (ARDS). Whether SN50, a NF-κB cell permeable inhibitor, could attenuate alveolar hypercoagulation and fibrinolysis inhibition in ARDS remains to be elucidated. PURPOSE: We explored the efficacy and potential mechanism of SN50 on alveolar hypercoagulation and fibrinolysis inhibition in ARDS in mice. MATERIALS AND METHODS: Mouse ARDS was made by 50 µl of lipopolysaccharide (LPS) (4 mg/ml) inhalation. Male BALB/c mice were intraperitoneally injected with different does of SN50 1 h before LPS inhalation. Lung tissues were collected for hematoxylin-eosin (HE) staining, wet/dry ratio. Pulmonary expressions of tissue factor (TF), plasminogen activator inhibitor-1 (PAI-1), collagen III, as well as phosphorylated p65 (p-p65), p65 in nucleus (p'-p65), IκBα and IKKα/ß were measured. Bronchoalveolar lavage fluid (BALF) was gathered to test the concentrations of TF, PAI-1, activated protein C (APC) and thrombinantithrombin complex (TAT). DNA binding activity of NF-κB p65 was also determined. RESULTS: After LPS stimulation, pulmonary edema and exudation and alveolar collapse occured. LPS also stimulated higher expressions of TF and PAI-1 in lung tissues, and higher secretions of TF, PAI-1, TAT and low level of APC in BALF. Pulmonary collagen III expression was obviously enhanced after LPS inhalation. At same time, NF-κB signaling pathway was activated with LPS injury, shown by higher expressions of p-p65, p'-p65, p-IKKα/ß, p-Iκα in pulmonary tissue and higher level p65 DNA binding activity. SN50 dose-dependently inhibited TF, PAI-1 and collagen IIIexpressions, and decreased TF, PAI-1, TAT but increased APC in BALF. SN50 treatment attenuated pulmonary edema, exudation and reduced lung tissue damage as well. SN50 application significantly reduced p'-p65 expression and weakened p65 DNA binding activity, but expressions of p-p65, p-IKKα/ß, p-Iκα in cytoplasm of pulmonary tissue were not affected. CONCLUSIONS: SN 50 attenuates alveolar hypercoagulation and fibrinolysis inhibition in ARDS via inhibition of NF-κB p65 translocation. Our data demonstrates that NF-κB p65 pathway is a viable new therapeutic target for ARDS treatment.

[Small dose of low molecular weight heparin improves the prognosis of elderly patients with severe pneumonia: a Meta-analysis of 1 173 patients].

OBJECTIVE: To explore the effect of small dose of low molecular weight heparin on the prognosis of elderly patients with severe pneumonia using systematic evaluation method. METHODS: Databases including Wanfang data, VIP, CNKI, SinoMed, PubMed, Embase and Cochrane Library were searched for randomized controlled trial (RCT) studies about the comparison of conventional therapy and low molecular weight heparin on prognosis of elderly patients with severe pneumonia from the time of database establishment to August 2019. The patients in conventional treatment group were treated by improving ventilation, anti-infection, eliminating phlegm, relieving asthma and maintaining homeostasis while those in low molecular weight heparin group were subcutaneously injected with low molecular weight heparin of 4 000 U, once a day for 7 days. The patients' main outcomes included the oxygenation index (PaO2/FiO2) after 7 days of treatment, duration of mechanical ventilation, mortality in hospital, and secondary outcomes included acute physiology and chronic health evaluation II (APACHE II) score and coagulation function after 7 days of treatment, the length of intensive care unit (ICU) stay, and incidence of bleeding. Data extraction and quality evaluation were conducted. The Meta-analysis of included studies that met the quality standards was performed using RevMan 5.3 software. Funnel diagram analysis was used to analyze the parameters with no less than 10 studies enrolled. RESULTS: A total of 14 RCT studies were enrolled involving 1 173 elderly patients with severe pneumonia, among whom 590 received low molecular weight heparin while the other 583 received conventional therapy. All the included studies were well designed and of high quality. The results of Meta-analysis showed that compared with conventional therapy, small dose of low molecular weight heparin significantly elevated PaO2/FiO2 after 7 days of treatment [mean difference (MD) = 19.25, 95% confidence interval (95%CI) was 16.88 to 21.61, P < 0.000 01], shortened the duration of mechanical ventilation (MD = -48.88, 95%CI was -67.42 to -30.33, P < 0.000 01), and decreased mortality in hospital [odds ratio (OR) = 0.40, 95%CI was 0.22 to 0.73, P = 0.003] and APACHE II score after 7 days of treatment (MD = -3.38, 95%CI was -3.94 to -2.83, P < 0.000 01), and shortened the length of ICU stay (MD = -4.51, 95%CI was -5.75 to -3.27, P < 0.000 01). There was no significant difference in the changes of coagulation parameters after 7 days of treatment or the incidence of bleeding between low molecular weight heparin group and conventional therapy group [7-day thrombin time (TT): MD = 0.57, 95%CI was -0.15 to 1.28, P = 0.12; 7-day prothrombin time (PT): MD = 0.32, 95%CI was -0.35 to 0.98, P = 0.35; 7-day fibrinogen (FIB): MD = -0.17, 95%CI was -0.45 to 0.10, P = 0.22; incidence of bleeding: OR = 0.86, 95%CI was 0.36 to 2.07, P = 0.74]. The funnel diagram showed that there was publication bias of included 10 studies about APACHE II score after 7 days of treatment. CONCLUSIONS: Small dose of low molecular weight heparin can improve the prognosis of elderly patients with severe pneumonia and it has no obvious side-effect on coagulation function.

[Meta-analysis of the impact of continuous anticoagulation therapy with low-dose heparin or low molecular weight heparin on the prognosis of patients with acute respiratory distress syndrome].

OBJECTIVE: The effects of low-dose heparin and low molecular weight heparin on the efficacy and prognosis of patients with acute respiratory distress syndrome (ARDS) were systematically evaluated. METHODS: Chinese and English databases such as Wanfang data, VIP database, China National Knowledge Infrastructure (CNKI), China Biomedical Literature Service system (SinoMed), American National Medical Library database (PubMed), Netherlands Medical Abstracts database (Embase) and Cochrane library database were searched for the randomized controlled trials (RCTs) of heparin or low molecular weight heparin in the treatment of ARDS. The search time is from July 1999 to June 2020. The control group was given routine treatment, while the experimental group was given heparin 5-10 U×kg-1×h-1, or low molecular heparin subcutaneous injected 2 500-5 000 U once every 12 hours for 7 days on the basis of the routine treatment. The main outcome were 28-day mortality, arterial oxygen saturation (SaO2), acute physiology and chronic health evaluation II (APACHE II), length of stay in (intensive care unit) ICU and mechanical ventilation time, and the secondary outcome indexes were C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), lung injury score, respiratory frequency, activated partial thromboplastin time (APTT) and prothrombin time (PT) after 7 days' treatment. The two researchers collected data and evaluated the quality of the literature according to the Cochrane 5.1. The stability of the Meta-analysis results was tested by sensitivity analysis, and the publication bias was included in the funnel chart analysis. RESULTS: Fourteen Chinese literatures were included, with a total of 894 cases, including 454 cases in the experimental group and 440 cases in the control group. The results of Meta-analysis showed that the 28-day fatality rate in the experimental group was significantly lower than that in the control group [relative risk (RR) = 0.54, 95% confidence interval (95%CI) was 0.38-0.76, P = 0.000 4], and 7-day SaO2 significantly increased [heparin: mean difference (MD) = 48.27, 95%CI was 29.95-66.59, P < 0.000 01]. Low molecular weight heparin: MD = 56.67, 95%CI was 41.22-71.13, P < 0.000 01]. Compared with the control group, the APACHE II score (MD = -4.28, 95%CI was -5.15 to -3.42, P < 0.000 01), the lung injury score (MD = -1.19, 95%CI was -1.35 to -1.03, P < 0.000 01) and the respiratory rate (MD = -4.76, 95%CI was -6.26 to -3.26, P < 0.000 01) in the experimental group were significantly lower than those in the control group after 7 days' treatment. The time of staying in ICU (MD = -4.85, 95%CI was -6.94 to -2.76, P < 0.000 01) and the time of mechanical ventilation (MD = -2.93, 95%CI was -3.34 to -2.52, P < 0.000 01) in the experimental group were lower than those in the control group. After 7 days' treatment, the levels of IL-6 (MD = -38.50, 95%CI was -59.01 to -17.99, P < 0.000 01), TNF-α (MD = -16.24, 95%CI was -31.11 to -1.38, P < 0.000 01) and CRP (MD = -5.5, 95%CI was -6.47 to -4.27, P < 0.000 01) were significantly lower in the experimental group than those in the control group. However, after 7 days' treatment, there were no significant differences in APTT (MD = -0.55, 95%CI was -1.61 to 0.51, P = 0.27) or PT (MD = -0.41, 95%CI was -1.48 to 0.66, P = 0.45). For the indicators with high heterogeneity, Meta-analysis was carried out again by excluding any study, and the overall effect value did not change significantly, suggesting that the results were relatively robust. Funnel chart analysis was carried out on the indexes with more than 10 articles included in the literature. The results showed that the literature had publication bias, but the bias was small. CONCLUSIONS: Continuous anticoagulation therapy with low dose heparin and low molecular weight heparin can improve the prognosis and reduce the mortality of patients with ARDS.

[Performance of clinical pulmonary infection score induces the duration and defined daily doses of antibiotics in patients with bacterial severe pneumonia in intensive care unit].

OBJECTIVE: To explore the impacts of clinical pulmonary infection score (CPIS) on duration and defined daily doses (DDDs) of antibiotics in patients with bacterial severe pneumonia in intensive care unit (ICU). METHODS: Patients with severe pneumonia, whose antibiotic usage was prescribed with the guide of CPIS, and admitted to ICU severe respiratory and infectious disease ward of Guizhou Medical University Affiliated Hospital from May 2017 to October 2017 were enrolled as CPIS group. Patients with the first CPIS score > 5 were given antimicrobial therapy, and the score was dynamically evaluated every 2-3 days. If the CPIS score < 5, the score was evaluated again after 2 days. If the score was still < 5, the antimicrobial drugs were discontinued. Patients admitted to the same ward from November 2016 to April 2017 were regarded as controls, of whom the antibiotic usage was completely conducted by the clinical experience of the chief physician. The duration and DDDs of antibiotics were compared between patients in two groups. At the same time, the usage of ventilator and prognostic indicators (the length of ICU stay, ICU mortality) were recorded. Kaplan-Meier survival curve was drawn, and the cumulative survival rates of 28 days, 90 days and 12 months were analyzed and compared between the two groups. RESULTS: In our department, 177 and 182 patients were admitted to ICU from November 2016 to April 2017 and from May 2017 to October 2017, respectively, of whom 101 and 65 patients with severe pneumonia were collected respectively during the two stages. There was no significant difference in gender composition, age, underlying diseases, vital signs, acute physiology and chronic health evaluation II (APACHE II) score, or peripheral blood routine at admission between the two groups, indicating that the baseline data of the two groups were equally comparable. During the treatment process, there was no significant difference in the duration of mechanical ventilation [hours: 126.0 (69.0, 228.8) vs. 120.0 (72.0, 192.0)], the length of ICU stay [days: 7.0 (5.0, 11.0) vs. 8.0 (5.0, 14.0)], or ICU mortality [18.8% (19/101) vs. 26.2% (17/65)] between the control group and CPIS group (all P > 0.05). Kaplan-Meier survival curve analysis showed that there was no significant difference in the cumulative survival rate of 28 days (log-rank test: χ2 = 0.540, P = 0.462), 90 days (log-rank test: χ2 = 0.332, P = 0.564) or 12 months (log-rank test: χ2 = 0.833, P = 0.362). Patients from CPIS guided group, however, had a shorter duration of antibiotics usage (days: 7.54±4.81 vs. 9.88±4.96, P < 0.01), and had a lower DDDs of antibiotics (17.58±13.09 vs. 22.73±18.31, P < 0.05) as compared with those in the control group. CONCLUSIONS: CPIS-guided therapeutic regimen shortens antibiotic duration and decreases antibiotic DDDs in patients with severe pneumonia in ICU, indicating the values of CPIS in guiding antibiotics usage in these patients.

[Sevoflurane inhalation sedation could shorten the duration of endotracheal intubation and the total length of hospital stay of critical patients after surgery as compared with propofol intravenous sedation: a Meta-analysis of 537 patients].

OBJECTIVE: To compare the influence of sevoflurane inhalation sedation and propofol intravenous sedation on duration of endotracheal intubation as well as the length of intensive care unit (ICU) stay and total length of hospital stay in postoperative critical patients. METHODS: Six databases including CNKI, Wanfang data, PubMed, Embase, Cochrane Library and Web of Science were searched for randomized controlled trials (RCTs) about the influence of sevoflurane inhalation sedation or propofol intravenous sedation on the sedation time, the duration of endotracheal intubation, the length of ICU stay, the total length of hospital stay and the adverse effects rate in postoperative critical patients from the time of database establishment to July 2018. At the same time, the reference materials of included literature were retrieved manually. All literatures were screened by three independent reviewers, and the data extraction and quality evaluation of the included studies were conducted. Meta-analysis was used for RCT that met the quality standards. RESULTS: A total of 7 RCT studies were enrolled involving 537 patients who were all transferred into ICU after surgery with trachea cannula. Among the patients, 272 received sevoflurane sedation while the other 265 received propofol sedation. All the included studies were well designed and of high quality. The results of Meta-analysis showed that compared with propofol sedation, sevoflurane sedation could significantly shorten the duration of endotracheal intubation [standardized mean difference (SMD) = -0.60, 95% confidence interval (95%CI) = -0.88 to -0.31, P < 0.000 1] and the total length of hospital stay (SMD = -0.36, 95%CI = -0.61 to -0.12, P = 0.003), and lower the cardiac troponin T (cTnT) within 12-24 hours after ICU admission (SMD = -0.61, 95%CI = -0.85 to -0.36, P < 0.000 01). There was no significant difference in the sedation time (SMD = -0.07, 95%CI = -0.29 to 0.15, P = 0.52), the length of ICU stay (SMD = -0.19, 95%CI = -0.39 to 0.01, P = 0.06), the incidence of nausea and vomiting [odds ratio (OR) = 1.19, 95%CI = 0.61 to 2.32, P = 0.61] or incidence of delirium (OR = 0.80, 95%CI = 0.34 to 1.90, P = 0.62) between sevoflurane group and propofol group. CONCLUSIONS: Sevoflurane inhalation sedation may lead to shorter duration of endotracheal intubation and total length of hospital stay, and had better protection for myocardium as compared with propofol intravenous sedation. The above conclusions needed further study to confirm, due to the lack of literature enrolled in this Meta-analysis.

[Xuebijing improves clinical prognosis and reduces mortality in patients with acute paraquat poisoning: a Meta-analysis included 1 429 patients].

OBJECTIVE: To explore the therapeutic effect of Xuebijing on patients with acute paraquat poisoning (APP) by using systematic evaluation method. METHODS: PubMed, Cochrane Library, Embase, Wanfang database, China National Knowledge Infrastructure (CNKI), VIP database (VIP) and China Biology Medicine (CBM) were searched using the computers to find the literatures published about the Xuebijing injection for the treatment of APP. Randomized controlled trials (RCT) were retrieved from the establishment of the database to August 2019. Patients in experimental group were treated with Xuebijing injection combined with conventional treatment, while the patients in control group were only given conventional treatment. The patients' outcome included the 14-day mortality, arterial oxygen saturation (SaO2) and incidence of pulmonary fibrosis. In addition, the 6-month survival rate, alanine aminotransferase (ALT), serum creatinine (SCr), C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), malondialdehyde (MDA) and superoxide dismutase (SOD) between the two groups were compared. The literature data were extracted by two researchers independently, and the quality of the literatures was evaluated according to the Cochrane 5.1 handbook. The Meta-analysis was performed by using RevMan 5.3 software. The results stability of Meta-analysis was tested by sensitivity analysis. The publication bias was analyzed through drawing of funnel diagram. RESULTS: Twenty-seven RCT studies in total were enrolled, of which 26 were in Chinese and 1 was in English. A total of 1 429 patients were enrolled, among whom 726 were in experimental group and another 703 were in control group. Meta-analysis showed that compared with the control group, the 14-day mortality [relative risk (RR) = 0.62, 95% confidence interval (95%CI) was 0.54 to 0.72, P < 0.000 01] and incidence of pulmonary fibrosis (RR = 0.67, 95%CI was 0.53 to 0.85, P = 0.000 9) of patients in the experimental group were significantly lowered, while SaO2 at 7 days and 14 days were significantly increased [7 days: mean difference (MD) = 16.86, 95%CI was 9.89 to 23.83, P < 0.000 01; 14 days: MD = 16.51, 95%CI was 10.22 to 22.80, P < 0.000 01]. Compared with the control group, the survival rate within 6 months (RR = 1.55, 95%CI was 1.41 to 1.71, P < 0.000 01) and SOD (MD = 13.88, 95%CI was 7.43 to 20.33, P < 0.000 1) of patients in the experimental group were significantly increased, ALT at 14 days (MD = -78.35, 95%CI was -127.35 to -29.34, P = 0.000 5), SCr at 7 days and 14 days (7 days: MD = -135.13, 95%CI was -219.09 to -51.17, P = 0.002; 14 days: MD = -206.05, 95%CI = -290.13 to -121.96, P < 0.000 01), CRP (MD = -11.55, 95%CI was -17.77 to -5.33, P = 0.000 3), TNF-α (MD = -9.27, 95%CI was -15.48 to -3.96, P = 0.000 9) and MDA (MD = -1.27, 95%CI was -1.57 to -0.96, P < 0.000 01) were significantly lowered. The overall effect value of the parameters with high heterogeneity was not significantly changed after further Meta-analysis excluding any one of the studies, suggesting that the result was relatively stable. Funnel chart analysis was used to analyze the parameters from more than 10 articles enrolled, and it showed that there was publication bias. CONCLUSIONS: Xuebijing injection can reduce the mortality of patients with APP, which may because that it can improve liver and kidney function, reduce inflammation and oxidative stress damage, inhibit pulmonary fibrosis and increase oxygenation level.