6-Gingerol ameliorates alveolar hypercoagulation and fibrinolytic inhibition in LPS-provoked ARDS via RUNX1/NF-κB signaling pathway.

BACKGROUND: Alveolar hypercoagulation and fibrinolytic inhibition play a central role in refractory hypoxemia in acute respiratory distress syndrome (ARDS), but it lacks effective drugs for prevention and treatment of this pathophysiology. Our previous experiment confirmed that RUNX1 promoted alveolar hypercoagulation and fibrinolytic inhibition through NF-κB pathway. Other studies demonstrated that 6-gingerol regulated inflammation and metabolism by inhibiting the NF-κB signaling pathway. We assume that 6-gingerol would ameliorate alveolar hypercoagulation and fibrinolytic inhibition via RUNX1/ NF-κB pathway in LPS-induced ARDS. METHODS: Rat ARDS model was replicated through LPS inhalation. Before LPS inhalation, the rats were intraperitoneally treated with different doses of 6-gingerol or the same volume of normal saline (NS) for 12 h, and then intratracheal inhalation of LPS for 24 h. In cell experiment, alveolar epithelial cell type II (AECII) was treated with 6-gingerol for 6 h and then with LPS for another 24 h. RUNX1 gene was down-regulated both in pulmonary tissue and in cells. Tissue factor (TF), plasminogen Activator Inhibitor 1(PAI-1) and thrombin were determined by Wester-blot (WB), qPCR or by enzyme-linked immunosorbent (ELISA). Lung injury score, pulmonary edema and pulmonary collagen III in rat were assessed. NF-κB pathway were also observed in vivo and in vitro. The direct binding capability of 6-gingerol to RUNX1 was confirmed by using Drug Affinity Responsive Target Stability test (DARTS). RESULTS: 6-gingerol dose-dependently attenuated LPS-induced lung injury and pulmonary edema. LPS administration caused excessive TF and PAI-1 expression both in pulmonary tissue and in AECII cell and a large amount of TF, PAI-1 and thrombin in bronchial alveolar lavage fluid (BALF), which all were effectively decreased by 6-gingerol treatment in a dose-dependent manner. The high collagen Ⅲ level in lung tissue provoked by LPS was significantly abated by 6-gingerol. 6-gingerol was seen to dramatically inhibit the LPS-stimulated activation of NF-κB pathway, indicated by decreases of p-p65/total p65, p-IKKß/total IKKß, and also to suppress the RUNX1 expression. RUNX1 gene knock down or RUNX1 inhibitor Ro5-3335 significantly enhanced the efficacies of 6-gingerol in vivo and in vitro, but RUNX1 over expression remarkably impaired the effects of 6-gingerol on TF, PAI-1 and on NF-κB pathway. DARTS result showed that 6-gingerol directly bond to RUNX1 molecules. CONCLUSIONS: Our experimental data demonstrated that 6-gingerol ameliorates alveolar hypercoagulation and fibrinolytic inhibition via RUNX1/NF-κB pathway in LPS-induced ARDS. 6-gingerol is expected to be an effective drug in ARDS.

[Prognosis of patients planned and unplanned admission to the intensive care unit after surgery: a comparative study].

OBJECTIVE: To compare and analyze the effect of unplanned versus planned admission to the intensive care unit (ICU) on the prognosis of high-risk patients after surgery, so as to provide a clinical evidence for clinical medical staff to evaluate whether the postoperative patients should be transferred to ICU or not after surgery. METHODS: The clinical data of patients who were transferred to ICU after surgery admitted to the Affiliated Hospital of Guizhou Medical University from January to December in 2021 were retrospectively analyzed, including gender, age, body mass index, past history (whether combined with hypertension, diabetes, pulmonary disease, cardiac disease, renal failure, liver failure, hematologic disorders, tumor, etc.), acute physiology and chronic health evaluation II (APACHE II), elective surgery, pre-operative hospital consultation, length of surgery, worst value of laboratory parameters within 24 hours of ICU admission, need for invasive mechanical ventilation (IMV), duration of IMV, length of ICU stay, total length of hospital stay, ICU mortality, in-hospital mortality, and survival status at 30th day postoperative. The unplanned patients were further divided into the immediate transfer group and delayed transfer group according to the timing of their ICU entrance after surgery, and the prognosis was compared between the two groups. Cox regression analysis was used to find the independent risk factors of 30-day mortality in patients transferred to ICU after surgery. RESULTS: Finally, 377 patients were included in the post-operative admission to the ICU, including 232 in the planned transfer group and 145 in the unplanned transfer group (42 immediate transfers and 103 delayed transfers). Compared to the planned transfer group, patients in the unplanned transfer group had higher peripheral blood white blood cell count (WBC) at the time of transfer to the ICU [×109/L: 10.86 (7.09, 16.68) vs. 10.11 (6.56, 13.27)], longer total length of hospital stay [days: 23.00 (14.00, 34.00) vs. 19.00 (12.00, 29.00)], and 30-day post-operative mortality was higher [29.66% (43/145) vs. 17.24% (40/232)], but haemoglobin (Hb), arterial partial pressure of carbon dioxide (PaCO2), oxygenation index (PaO2/FiO2), and IMV requirement rate were lower [Hb (g/L): 95.00 (78.00, 113.50) vs. 98.00 (85.00, 123.00), PaCO2 (mmHg, 1 mmHg ≈ 0.133 kPa): 36.00 (29.00, 41.50) vs. 39.00 (33.00, 43.00), PaO2/FiO2 (mmHg): 197.00 (137.50, 283.50) vs. 238.00 (178.00, 350.25), IMV requirement rate: 82.76% (120/145) vs. 93.97% (218/232)], all differences were statistically significant (all P < 0.05). Kaplan-Meier survival curve showed that the 30-day cumulative survival rate after surgery was significantly lower in the unplanned transfer group than in the planned transfer group (Log-Rank test: χ2 = 7.659, P = 0.006). Univariate Cox regression analysis showed that unplanned transfer, APACHE II score, whether deeded IMV at transfer, total length of hospital stay, WBC, blood K+, and blood lactic acid (Lac) were associated with 30-day mortality after operation (all P < 0.05). Multifactorial Cox analysis showed that unplanned transfer [hazard ratio (HR) = 2.45, 95% confidence interval (95%CI) was 1.54-3.89, P < 0.001], APACHE II score (HR = 1.03, 95%CI was 1.00-1.07, P = 0.031), the total length of hospital stay (HR = 0.86, 95%CI was 0.83-0.89, P < 0.001), the need for IMV on admission (HR = 4.31, 95%CI was 1.27-14.63, P = 0.019), highest Lac value within 24 hours of transfer to the ICU (HR = 1.17, 95%CI was 1.10-1.24, P < 0.001), and tumor history (HR = 3.12, 95%CI was 1.36-7.13, P = 0.007) were independent risk factors for patient death at 30 days post-operative, and the risk of death was 2.45 times higher in patients unplanned transferred than in those planned transferred. Subgroup analysis showed that patients in the delayed transfer group had significantly longer IMV times than those in the immediate transfer group [hours: 43.00 (11.00, 121.00) vs. 17.50 (2.75, 73.00), P < 0.05]. CONCLUSIONS: The 30-day mortality, WBC and total length of hospital stay were higher in patients who were transferred to ICU after surgery, and PaO2/FiO2 was lower. Unplanned transfer, oncology history, use of IMV, APACHE II score, total length of hospital stay, and Lac were independent risk factors for patient death at 30 days postoperatively, and patients with delayed transfer to ICU had longer IMV time.

miR-9 targeting RUNX1 improves LPS-induced alveolar hypercoagulation and fibrinolysis inhibition through NF-κB inactivation in ARDS.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a clinical and pathophysiological complex syndrome with high mortality. Alveolar hypercoagulation and fibrinolytic inhibition constitute the core part of the pathophysiology of ARDS. miR-9 (microRNA-9a-5p) plays an important role in the pathogenesis of ARDS, but whether it regulates alveolar pro-coagulation and fibrinolysis inhibition in ARDS remains to be elucidated. We aimed to determine the contributing role of miR-9 on alveolar hypercoagulation and fibrinolysis inhibition in ARDS. METHODS: In the ARDS animal model, we first observed the miR-9 and runt-related transcription factor 1 (RUNX1) expression in lung tissue, the effects of miR-9 on alveolar hypercoagulation and fibrinolytic inhibition in ARDS rats, and the efficacy of miR-9 on acute lung injury. In the cell, alveolar epithelial cells type II (AECII) were treated with LPS, and the levels of miR-9 and RUNX1 were detected. Then we observed the effects of miR-9 on procoagulant and fibrinolysis inhibitor factors in cells. Finally, we explored whether the efficacies of miR-9 were associated with RUNX1; we also preliminarily examined the miR-9 and RUNX1 levels in plasma in patients with ARDS. RESULTS: In ARDS rats, miR-9 expression decreased, but RUNX1 expression increased in the pulmonary tissue of ARDS rats. miR-9 displayed to attenuate lung injury and pulmonary wet/dry ratio. Study results in vivo demonstrated that miR-9 ameliorated alveolar hypercoagulation and fibrinolysis inhibition and attenuated the collagen III expressions in tissue. miR-9 also inhibited NF-κB signaling pathway activation in ARDS. In LPS-induced AECII, the expression changes of both miR-9 and RUNX1 were similar to those in pulmonary tissue in the animal ARDS model. miR-9 effectively inhabited tissue factor (TF), plasma activator inhibitor (PAI-1) expressions, and NF-κB activation in LPS-treated ACEII cells. Besides, miR-9 directly targeted RUNX1, inhibiting TF and PAI-1 expression and attenuating NF-κB activation in LPS-treated AECII cells. Clinically, we preliminarily found that the expression of miR-9 was significantly reduced in ARDS patients compared to non-ARDS patients. CONCLUSION: Our experimental data indicate that by directly targeting RUNX1, miR-9 improves alveolar hypercoagulation and fibrinolysis inhibition via suppressing NF-κB pathway activation in LPS-induced rat ARDS, implying that miR-9/RUNX1 is expected to be a new therapeutic target for ARDS treatment.

The Efficacy and Safety of Early Renal Replacement Therapy in Critically Ill Patients With Acute Kidney Injury: A Meta-Analysis With Trial Sequential Analysis of Randomized Controlled Trials.

The efficacy and safety of early renal replacement therapy (eRRT) for critically ill patients with acute kidney injury (AKI) remain controversial. Therefore, the purpose of our study was to perform an up-to-date meta-analysis with the trial sequential analysis (TSA) of randomized controlled trials (RCTs) to evaluate the therapeutic effect of eRRT on patients in an intensive care unit (ICU). We extensively searched MEDLINE, EMBASE, LILACS, the Cochrane Central Register of Controlled Trials and ClinicalTrials.gov, Gray Literature Report, and Bielefeld Academic Search Engine (BASE), and conducted an updated search on December 27, 2021. The included studies were RCTs, which compared the efficacy and safety of eRRT and delayed renal replacement therapy (dRRT) on critically ill patients with AKI. We adopted TSA and sensitivity analysis to strengthen the robustness of the results. About 12 RCTs with a total of 5,423 participants were included. Patients receiving eRRT and dRRT had the similar rate of all-cause mortality at day 28 (38.7% vs. 38.9%) [risk ratio (RR), 1.00; 95%CI, 0.93-1.07, p = 0.93, I 2 = 0%, p = 0.93]. A sensitivity and subgroup analysis produced similar results for the primary outcome. TSA showed that the required information size was 5,034, and the cumulative Z-curve crossed trial sequential monitoring boundaries for futility. Patients receiving eRRT had a higher rate of renal replacement therapy (RRT) (RR, 1.50, 95% CI: 1.28-1.76, p < 0.00001, I 2 = 96%), and experienced more adverse events comparing to those receiving dRRT (RR: 1.41, 95% CI: 1.22-1.63, p < 0.0001, heterogeneity not applied). The most remarkable and important experimental finding is that, to our knowledge, the current meta-analysis included the largest sample size from the RCTs, which were published in the past 10 years to date, show that eRRT had no significant survival benefit for ill patients with AKI compared with dRRT and TSA indicating that no more studies were needed to confirm it. Trial Registration: INPLASY, INPLASY2020120030. Registered 04 December 2020.

[Risk factors for death in elderly patients admitted to intensive care unit after elective abdominal surgery: a consecutive 5-year retrospective study].

OBJECTIVE: To investigate the risk factors that were associated with the death of elderly patients who were admitted to the intensive care unit (ICU) after elective abdominal surgery, and to find reliable and sensitive predictive indicators for early interventions and reducing the mortality. METHODS: A retrospective case-control study was conducted. The clinical data of elderly (age ≥ 65 years old) patients after elective abdominal surgery admitted to the ICU of the Affiliated Hospital of Guizhou Medical University from January 1st 2016 to December 31st 2020 were collected, including the patient's gender, age, body mass index (BMI), medical history, American Society of Anesthesiologists (ASA) grades, surgical classification, intraoperative blood loss, duration of operation, interval time between end of operation and admission to the ICU, acute physiology and chronic health evaluation II (APACHE II) score and the worst laboratory examination results within 24 hours of ICU admission, the first blood gas analysis in ICU, the duration of invasive mechanical ventilation, and the length of ICU stay. Postoperative abdominal infection was evaluated by the pathogenic culture of peritoneal drainage fluid and clinical symptoms and signs. The patients were divided into death group and survival group based on clinical outcomes, and clinical data were compared between the two groups. Binary multivariate Logistic regression analysis was used to screen the risk factors of death, and the receiver operator characteristic curve (ROC curve) was plotted to analyze the predictive values of these risk factors. RESULTS: A total of 226 elderly patients with elective abdominal surgery were admitted to the ICU of our hospital during the past 5 years, of whom, two patients who did not undergo laboratory examinations within 24 hours of admission to the ICU were excluded. Finally, 224 patients met the criteria, with 158 survivors and 66 deaths. Univariate analysis showed that: compared with survival group, APACHE II score, blood lactate acid (Lac) and the proportion of postoperative abdominal infection were higher in death group [APACHE II score: 27.5 (25.0, 31.3) vs. 23.0 (18.0, 27.0), Lac (mmol/L): 2.9 (1.8, 6.6) vs. 1.8 (1.1, 2.8), the proportion of postoperative abdominal infection: 65.2% (43/66) vs. 35.4% (56/158), all P < 0.01], prothrombin time (PT), activated partial thromboplastin time (APTT) and interval time between end of surgery and admission to ICU were longer [PT (s): 17.20 (14.50, 18.63) vs. 14.65 (13.90, 16.23), APTT (s): 45.15 (38.68, 55.15) vs. 39.45 (36.40, 45.70), interval time between end of surgery and admission to ICU (hours): 39.2 (0.7, 128.9) vs. 0.7 (0.3, 2.0), all P < 0.01], postoperative hemoglobin (Hb), platelet count (PLT), prealbumin (PA), mean arterial pressure (MAP) and oxygenation index (PaO2/FiO2) were lower in death group [Hb (g/L): 95.79±23.64 vs. 105.58±19.82, PLT (×109/L): 138.5 (101.0, 177.5) vs. 160.5 (118.5, 232.3), PA (g/L): 80.88±43.63 vs. 116.54±50.80, MAP (mmHg, 1 mmHg = 0.133 kPa): 76.8±19.1 vs. 91.6±19.8, PaO2/FiO2 (mmHg): 180.0 (123.5, 242.5) vs. 223.5 (174.8, 310.0), all P < 0.05]. Binary multivariate Logistic regression analysis showed that APACHE II score [odds ratio (OR) = 1.187, 95% confidence interval (95%CI) = 1.008-1.294, P < 0.001], interval time between end of operation and admission to ICU (OR = 1.005, 95%CI = 1.001-1.009, P = 0.016) and postoperative abdominal infection (OR = 2.630, 95%CI = 1.148-6.024, P = 0.022) were independent risk factors for prognosis in these patients. MAP (OR = 0.978, 95%CI = 0.957-0.999, P = 0.041) and PaO2/FiO2 (OR = 0.994, 95%CI = 0.990-0.998, P = 0.003) were protective factors for the patients' prognosis. Lac, Hb, PLT, PA, PT and APTT had no predictive value for the prognosis of elderly patients admitted to ICU after elective abdominal surgery [OR value and 95%CI were 1.075 (0.945-1.223), 1.011 (0.99-1.032), 1.000 (0.995-1.005), 0.998 (0.989-1.007), 1.051 (0.927-1.192) and 1.003 (0.991-1.016), respectively, all P > 0.05. ROC curve analysis showed that APACHE II score, interval time between end of operation and admission to the ICU and the postoperative abdominal infection had certain predictive values for the prognosis of elderly patients, the area under ROC curve (AUC) were 0.755, 0.732 and 0.649 respectively, all P < 0.001; When the cut-off of APACHE II score and interval time between end of operation and admission to the ICU were 24.5 scores and 2.15 hours, the sensitivity were 78.8% and 66.7%, respectively, and the specificity were 62.0% and 76.6%, respectively. The combined predictive value of the three variables was the highest, which AUC was 0.846, the joint prediction probability was 0.27, the sensitivity was 83.3%, and the specificity was 75.3%. CONCLUSIONS: APACHE II score, interval time between end of surgery and admission to ICU, and postoperative abdominal infection may be independent risk factors for the death of elderly patients who were admitted to the ICU after elective abdominal surgery, there would be far greater predictive values when the three variables were combined.

Predictive Factors for Failure of Noninvasive Ventilation in Adult Intensive Care Unit: A Retrospective Clinical Study.

Background: Noninvasive ventilation (NIV) has been reported to be beneficial for patients with acute respiratory failure in intensive care unit (ICU); however, factors that influence the clinical outcome of NIV were unclarified. We aim to determine the factors that predict the failure of NIV in critically ill patients with acute respiratory failure (ARF). Setting. Adult mixed ICU in a medical university affiliated hospital. Patients and Methods. A retrospective clinical study using data from critical adult patients with initial NIV admitted to ICU in the period August 2016 to November 2017. Failure of NIV was regarded as patients needing invasive ventilation. Logistic regression was employed to determine the risk factor(s) for NIV, and a predictive model for NIV outcome was set up using risk factors. Results: Of 101 included patients, 50 were unsuccessful. Although more than 20 variables were associated with NIV failure, multivariate logistic regression demonstrated that only ideal body weight (IBW) (OR 1.110 (95%1.027-1.201), P=0.009), the maximal heart rate during NIV period (HR-MAX) (OR 1.024 (1.004-1.046), P=0.021), the minimal respiratory rate during NIV period (RR-MIN) (OR 1.198(1.051-1.365), P=0.007), and the highest body temperature during NIV period (T-MAX) (OR 1.838(1.038-3.252), P=0.037) were independent risk factors for NIV failure. We set up a predictive model based on these independent risk factors, whose area under the receiver operating characteristic curve (AUROC) was 0.783 (95% CI: 0.676-0.899, P < 0.001), and the sensitivity and specificity of model were 68.75% and 71.43%, respectively, with the optimal cut-off value of 0.4863. Conclusion: IBW, HR-MAX, RR-MIN, and T-MAX were associated with NIV failure in patients with ARF. A predictive model based on the risk factors could help to discriminate patients who are vulnerable to NIV failure.

[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.