Multicentre, parallel, open-label, two-arm, randomised controlled trial on the prognosis of electrical impedance tomography-guided versus low PEEP/FiO2 table-guided PEEP setting: a trial protocol.

INTRODUCTION: Previous studies suggested that electrical impedance tomography (EIT) has the potential to guide positive end-expiratory pressure (PEEP) titration via quantifying the alveolar collapse and overdistension. The aim of this trial is to compare the effect of EIT-guided PEEP and acute respiratory distress syndrome (ARDS) network low PEEP/fraction of inspired oxygen (FiO2) table strategy on mortality and other clinical outcomes in patients with ARDS. METHODS: This is a parallel, two-arm, multicentre, randomised, controlled trial, conducted in China. All patients with ARDS under mechanical ventilation admitted to the intensive care unit will be screened for eligibility. The enrolled patients are stratified by the aetiology (pulmonary/extrapulmonary) and partial pressure of arterial oxygen/FiO2 (≥150 mm Hg or <150 mm Hg) and randomised into the intervention group or the control group. The intervention group will receive recruitment manoeuvre and EIT-guided PEEP titration. The EIT-guided PEEP will be set for at least 12 hours after titration. The control group will not receive recruitment manoeuvre routinely and the PEEP will be set according to the lower PEEP/FiO2 table proposed by the ARDS Network. The primary outcome is 28-day survival. ANALYSIS: Qualitative data will be analysed using the χ2 test or Fisher's exact test, quantitative data will be analysed using independent samples t-test or Mann-Whitney U test. Kaplan-Meier analysis with log-rank test will be used to evaluate the 28-day survival rate between two groups. All outcomes will be analysed based on the intention-to-treat principle. ETHICS AND DISSEMINATION: The trial is approved by the Institutional Research and Ethics Committee of the Peking Union Medical College Hospital. Data will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT05307913.

[The value of maximal rate of left ventricular pressure in evaluating cardiac function in patients with sepsis-induced cardiomyopathy].

OBJECTIVE: To investigate the value of maximal rate of left ventricular pressure (dp/dtmax) in evaluating the changes of cardiac function before and after heart rate reduction in patients with sepsis-induced cardiomyopathy (SIC). METHODS: A single-center, prospective randomized controlled study was conducted. Adult patients with sepsis/septic shock admitted to the department of intensive care unit (ICU) of Tianjin Third Central Hospital from April 1, 2020 to February 28, 2022 were enrolled. Speckle tracking echocardiography (STE) and pulse indication continuous cardiac output (PiCCO) monitoring were performed immediately after the completion of the 1 h-Bundle therapy. The patients with heart rate over 100 beats/minutes were selected and randomly divided into esmolol group and regular treatment group, 55 cases in each group. All patients underwent STE and PiCCO monitoring at 6, 24 and 48 hours after admission in ICU and calculated acute physiology and chronic health evaluation II (APACHE II) and sequential organ failure assessment (SOFA). Primary outcome measure: change in dp/dtmax after reducing heart rate by esmolol. Secondary outcome measures: correlation between dp/dtmax and global longitudinal strain (GLS); changes of vasoactive drug dosage, oxygen delivery (DO2), oxygen consumption (VO2) and stroke volume (SV) after the administration of esmolol; proportion of heart rate reaching the target after the administration of esmolol; 28-day and 90-day mortality in two groups. RESULTS: Baseline data on age, gender, body mass index, SOFA score, APACHE II score, heart rate, mean arterial pressure, lactic acid, 24-hour fluid balance, sepsis etiology and prior comorbidities were similar between esmolol group and regular treatment group, there were no significant differences between the two groups. All SIC patients achieved the target heart rate after 24 hours of esmolol treatment. Compared with regular treatment group, parameters reflecting myocardial contraction such as GLS, global ejection fraction (GEF) and dp/dtmax were significantly increased in esmolol group [GLS: (-12.55±4.61)% vs. (-10.73±4.82)%, GEF: (27.33±4.62)% vs. (24.18±5.35)%, dp/dtmax (mmHg/s): 1 312.1±312.4 vs. 1 140.9±301.0, all P < 0.05], and N-terminal pro-brain natriuretic peptide (NT-proBNP) significantly decreased [µg/L: 1 364.52 (754.18, 2 389.17) vs. 3 508.85 (1 433.21, 6 988.12), P < 0.05], DO2 and SV were significantly increased [DO2 (mL×min-1×m-2): 647.69±100.89 vs. 610.31±78.56, SV (mL): 49.97±14.71 vs. 42.79±15.77, both P < 0.05]. The system vascular resistance index (SVRI) in esmolol group was significantly higher than that in regular treatment group (kPa×s×L-1: 287.71±66.32 vs. 251.17±78.21, P < 0.05), even when the dosage of norepinephrine was similar between the two groups. Pearson correlation analysis showed that dp/dtmax was negatively correlated with GLS in SIC patients at 24 hours and 48 hours after ICU admission (r values were -0.916 and -0.935, respectively, both P < 0.05). Although there was no significant difference in 28-day mortality between esmolol group and regular treatment group [30.9% (17/55) vs. 49.1% (27/55), χ2 = 3.788, P = 0.052], the rate of esmolol use in patients who died within 28 days was lower than that in patients who survived [38.6% (17/44) vs. 57.6% (38/66), χ2 = 3.788, P = 0.040]. In addition, esmolol has no effect on the 90-day mortality of patients. Logistic regression analysis showed that after adjusting for SOFA score and DO2 factors, patients who used esmolol had a significantly lower risk of 28-day mortality compared with patients who did not use esmolol [odds ratio (OR) = 2.700, 95% confidence interval (95%CI) was 1.038-7.023, P = 0.042]. CONCLUSIONS: dp/dtmax in PiCCO parameter can be used as a bedside indicator to evaluate cardiac function in SIC patients due to its simplicity and ease of operation. Esmolol control of heart rate in SIC patients can improve cardiac function and reduce short-term mortality.

Decreased Heart Rate Variability in COVID-19.

Purpose: Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which primarily infects the lower airways and binds to angiotensin-converting enzyme 2 (ACE2) on alveolar epithelial cells. ACE2 is widely expressed not only in the lungs but also in the cardiovascular system. Therefore, SARS-CoV-2 can also damage the myocardium. This report aimed to highlight decreased heart rate variability (HRV) and cardiac injury caused by SARS-CoV-2. Materials and Methods: We evaluated three COVID-19 patients who died. Patients' data were collected from electronic medical records. We collected patient's information, including baseline information, lab results, body temperature, heart rate (HR), clinical outcome and other related data. We calculated the HRV and the difference between the expected and actual heart rate changes as the body temperature increased. Results: As of March 14, 2020, 3 (2.2%) of 136 patients with COVID-19 in Tianjin died in the early stage of the COVID-19 epidemic. The immediate cause of death for Case 1, Case 2, and Case 3 was cardiogenic shock, cardiac arrest and cardiac arrest, respectively. The HRV were substantially decreased in the whole course of all three cases. The actual increases in heart rate were 5 beats/min, 13 beats/min, and 4 beats/min, respectively, less than expected as their temperature increased. Troponin I and Creatine Kinase MB isoenzyme (CK-MB) were substantially increased only in Case 3, for whom the diagnosis of virus-related cardiac injury could not be made until day 7. In all three cases, decreased in HRV and HR changes occurred earlier than increases in cardiac biomarkers (e.g., troponin I and CK-MB). Conclusions: In conclusion, COVID-19 could affect HRV and counteract tachycardia in response to increases in body temperature. The decreases of HRV and HR changes happened earlier than the increases of myocardial markers (troponin I and CK-MB). It suggested the decreases of HRV and HR changes might help predict cardiac injury earlier than myocardial markers in COVID-19, thus its early identification might help improve patient prognosis. Supplementary Information: The online version contains supplementary material available at 10.1007/s44231-022-00024-1.

[A clinical study on the wean effect of setting parameters of proportional pressure support on acute exacerbation of chronic obstructive pulmonary disease patients with difficult weaning].

OBJECTIVE: To investigate the clinical effect of setting proportional pressure support (PPS) parameters by target tidal volume (VT) method. METHODS: The study was conducted retrospectively on acute exacerbation of chronic obstructive pulmonary disease (AECOPD) patients admitted to Tianjin Third Central Hospital from January 2016 to December 2020. According to the PPS parameter setting method, the patients were divided into the airway blocking group and target VT group. The baseline characteristics, initial setting values of flow assist (FA) and volume assist (VA), respiratory system parameters, and clinical outcomes were collected and compared between the two groups. RESULTS: Fifty-nine patients were enrolled, 29 patients in the airway blocking group, and 30 in the target VT group. There was no statistically significant difference in baseline characteristics, compliance, resistance, and initial settings of FA and VA between the two groups. Compared with the target VT group, the respiratory rate (RR), mean arterial pressure (MAP), VT, and arterial partial pressure of oxygen (PaO2) recorded 1 hour after the initial setting of the PPS parameters in the airway block method group were significantly reduced [RR (times/minute): 21.0 (18.5, 22.5) vs. 23.0 (21.0, 25.0), MAP (mmHg, 1 mmHg = 0.133 kPa): 84.0 (79.0, 90.5) vs. 90.0 (87.0, 96.2), VT (mL): 305.24±41.07 vs. 330.87±46.84, PaO2 (mmHg): 68.0 (66.0, 73.5) vs. 74.0 (69.8, 82.5), all P < 0.05], while arterial partial pressure of carbon dioxide (PaCO2) and oral closure pressure (P0.1) were both increased significantly [PaCO2 (mmHg): 41.0 (39.0, 46.0) vs. 37.5 (35.0, 42.2), P0.1 (cmH2O, 1 cmH2O = 0.098 kPa): 1.42±0.78 vs. 0.90±0.67, both P < 0.05]. Compared with airway blocking group, the duration of weaning, ICU stay, and hospital stay in the target VT group were significantly shorter [duration of weaning (hours): 42.0 (24.0, 70.5) vs. 64.0 (30.5, 97.5), ICU stay: 10.00±3.38 to 13.28±5.41, hospital stay (days): 12.07±3.40 vs. 15.41±5.60, all P < 0.05]. There was no statistically significant difference in the invasive mechanical ventilation time, weaning failure rate, ICU mortality and in-hospital mortality between the two groups. CONCLUSIONS: This study suggested that the target TV method has the advantages of practicality, safety, convenience, and rapid to set PPS parameters than the airway block method, which shortens the duration of weaning and ICU stay, and has a good clinical prospect.

Individualized positive end-expiratory pressure setting in patients with severe acute respiratory distress syndrome supported with veno-venous extracorporeal membrane oxygenation.

BACKGROUND: Patients with acute respiratory distress syndrome supported with veno-venous extracorporeal membrane oxygenation benefit from higher positive end-expiratory pressure combined with conventional ventilation during the early extracorporeal membrane oxygenation period. The role of incremental positive end-expiratory pressure titration in patients with severe acute respiratory distress syndrome supported with veno-venous extracorporeal membrane oxygenation remains unclear. This study aimed to determine the preferred method for setting positive end-expiratory pressure in patients with severe acute respiratory distress syndrome on veno-venous extracorporeal membrane oxygenation support. METHODS: We retrospectively reviewed all subjects supported with veno-venous extracorporeal membrane oxygenation for severe acute respiratory distress syndrome from 2009 to 2019 in the intensive care units in Tianjin Third Central Hospital. Subjects were divided into two groups according to the positive end-expiratory pressure titration method used: P-V curve (quasi-static pressure-volume curve-guided positive end-expiratory pressure setting) group or Crs (respiratory system compliance-guided positive end-expiratory pressure setting) group. RESULTS: Forty-three subjects were included in the clinical outcome analysis: 20 in the P-V curve group and 23 in the Crs group. Initial positive end-expiratory pressure levels during veno-venous extracorporeal membrane oxygenation were similar in both groups. Incidence rates of barotrauma and hemodynamic events were significantly lower in the Crs group (all p < 0.05). Mechanical ventilation duration, intensive care unit length of stay, and hospital length of stay were significantly shorter in the Crs group than the P-V curve group (all p < 0.05). Subjects in the Crs group showed non-significant improvements in the duration of extracorporeal membrane oxygenation support and 28-day mortality (p > 0.05). CONCLUSION: Respiratory system compliance-guided positive end-expiratory pressure setting may lead to more optimal clinical outcomes for patients with severe acute respiratory distress syndrome supported by veno-venous extracorporeal membrane oxygenation. Moreover, the operation is simple, safe, and convenient in clinical practice.

[Preliminary establishment of weaning prediction model].

OBJECTIVE: To establish a model that can predict weaning failure from ventilation through hemodynamic and fluid balance parameters. METHODS: A retrospective analysis was conducted. The patients who underwent invasive mechanical ventilation for more than 24 hours and having spontaneous breathing test admitted to intensive care unit (ICU) of Tianjin Third Central Hospital from January 1st, 2017 to December 31st, 2018 were enrolled. The information was collected, which included the baseline data, hemodynamic parameters by pulse indicator continuous cardiac output (PiCCO) monitoring, B-type natriuretic peptide (BNP), urinary output, fluid balance in first 24 hours when patients admitted to ICU, and hemodynamic parameters by PiCCO monitoring, BNP, urinary output, fluid balance, diuretic usage, noradrenalin usage within 24 hours before weaning as well as usage of continuous renal replacement therapy (CRRT) during mechanical ventilation. According to weaning success or failure, the patients were divided into weaning success group and weaning failure group, and the statistical differences between the two groups were calculated. Variables with statistical significance within 24 hours before weaning were included in the multivariate Logistic regression analysis to establish weaning failure prediction model and find out the possible risk factors of weaning failure. RESULTS: A total of 159 patients were included in this study, which included 138 patients in the weaning success group and 21 patients in the weaning failure group. There were no statistical differences in all hemodynamic parameters by PiCCO monitoring, BNP, urinary output, fluid balance within 24 hours into ICU between two groups. There were statistical differences in BNP (χ2 = 9.262, P = 0.026), central venous pressure (CVP; χ2 = 7.948, P = 0.047), maximum rate of the increase in pressure (dPmx; χ2 = 10.486, P = 0.015), urinary output (χ2 = 8.921, P = 0.030), fluid balance (χ2 = 9.172, P = 0.027) within 24 hours before weaning between two groups. In addition, variable about cardiac index (CI; χ2 = 7.789, P = 0.051) was included into multivariate Logistic regression model to improve the prediction model and enhance the accuracy of model. Finally, variables included in the multivariate Logistic regression model were BNP, CVP, CI, dPmx, urinary output, fluid balance volume, and the accuracy of the weaning failure prediction model was 92.9%, the sensitivity was 100%, and the specificity was 76.8%. When the model was adjusted by variables of age and noradrenalin usage, the accuracy of model to predict failure of weaning was 94.2%, the sensitivity was 100%, the specificity was 81.2%. CONCLUSIONS: Weaning failure prediction model based on hemodynamic parameters by PiCCO monitoring and variables about liquid balance has high accuracy and can guide clinical weaning.

[Clinical study on the factors associated with long-term cognitive function in patients with sepsis].

OBJECTIVE: To investigate the occurrence and influencing factors of long-term cognitive impairment in patients with sepsis. METHODS: The septic patients admitted to intensive care unit (ICU) of Tianjin Third Central Hospital from July 2014 to September 2017 were enrolled. Montreal cognitive assessment scale (MoCA) was used to assess the cognitive function of patients at 3, 12 and 24 months after discharge from hospital. The patients were divided into cognitive impairment group (MoCA score < 26) and normal cognitive function group (MoCA score ≥ 26) according to the MoCA scores at 12 months after discharge from hospital. The basic characteristics and clinical data were recorded in both groups, the variables with statistical significance in univariate analysis were enrolled in bivariate Logistic regression analysis, and the influencing factors of cognitive impairment in patients with sepsis were screened. RESULTS: During the study period, 1 748 patients with sepsis were admitted, 210 survived and discharged, and 125 patients participated in the follow-up. Cognitive impairment occurred in 61.6% (77/125), 54.4% (56/103) and 54.2% (39/72) of the septic patients at 3, 12 and 24 months after discharge, respectively. The MoCA score of 103 patients who completed 12-month follow-up was significantly higher than that of 3-month follow-up (23.4±5.7 vs. 23.0±6.0, P < 0.01); the MoCA score of 72 patients who completed 24-month follow-up was only slightly lower than that of 12-month follow-up (23.6±5.4 vs. 23.7±5.0, P > 0.05). Following up for 12 months, 47 patients were enrolled in the normal cognitive function group and 56 in the cognitive impairment group. Compared with the normal cognitive function group, the cognitive dysfunction group had more female [51.8% (29/56) vs. 31.9% (15/47)] and older patients (years old: 66.1±15.9 vs. 52.4±18.9), also had shorter time to receive education (years: 7.6±4.0 vs. 11.2±3.1), longer duration of delirium [days: 2 (0, 3) vs. 0 (0, 1)], with significant differences (all P < 0.05). There was no significant difference in the marital status, severity of infection, underlying diseases, routes of transfer, total length of hospital stay, the length of ICU stay, acute physiology and chronic health evaluation II (APACHE II) score, sequential organ failure assessment (SOFA) score, Charlson comorbidity index (CCI) score within 24 hours of admission to ICU, hypoxemia, hypotension, mechanical ventilation, hemofiltration, or drug use between the two groups. Bivariate Logistic regression analysis showed that the duration of education was a protective factor for cognitive impairment in patients with sepsis who were followed up for 12 months [odds ratio (OR) = 0.791, 95% confidence interval (95%CI) = 0.678-0.923, P = 0.003], and age and duration of delirium were risk factors (age: OR = 1.038, 95%CI = 1.009-1.068, P = 0.010; duration of delirium: OR = 1.314, 95%CI = 1.002-1.724, P = 0.048). CONCLUSIONS: Long-term cognitive impairment occurs in many septic patients after discharge and improves over time. Duration of education is a protective factor for cognitive impairment in patients with sepsis, while age and delirium duration are risk factors.

Attenuation of Sepsis-Induced Cardiomyopathy by Regulation of MicroRNA-23b Is Mediated Through Targeting of MyD88-Mediated NF-κB Activation.

Myocardial cell injury or cardiomyopathy is associated with excessive inflammatory response and apoptosis of cardiac myocytes during sepsis. MicroRNA-23b (miR-23b) is a multifunctional miRNA that is considered to regulate immunosuppression in sepsis. The aim of this study was to examine the effect of miR-23b on cardiomyopathy induced by sepsis and to explore the potential mechanism involved. Sprague-Dawley rats were subjected to cecal ligation and puncture (CLP), and the level of miR-23b at different time points was measured by quantitative real-time polymerase chain reaction (qPCR). Then, we overexpressed miR-23b in vivo and in vitro. The rats were subjected to CLP 7 days after transfection. Cardiac function, inflammatory response, and heart tissues were examined 3 days thereafter. In an in vitro experiment, H9C2 cardiomyoblasts were stimulated with lipopolysaccharide (LPS) after transfection of miR-23b, following which apoptosis and the level of NF-κB were analyzed. The expression of miR-23b was upregulated during polymicrobial sepsis, and transfection of miR-23b lentivirus improved the outcome of sepsis-induced cardiomyopathy by attenuating inflammatory responses and protecting against histopathological damage. In in vitro experiments, elevated miR-23b inhibited excessive apoptosis of cardiomyocytes, which may be because activation of the NF-κB signaling pathway was inhibited by the decreased levels of TRAF6 and IKKß. Therefore, miR-23b improved sepsis-induced cardiomyopathy by attenuating the inflammatory response, suppressing apoptosis, and preventing NF-κB activation via targeted inhibition of TRAF6 and IκκB. These results indicated that miR-23b may represent a novel therapeutic approach for clinical treatment of sepsis-induced cardiomyopathy.

[Comparison of the effect of CPAP+PPS mode and CPAP+ASB mode in weaning on acute exacerbation of chronic obstructive pulmonary disease patients].

OBJECTIVE: To investigate the effect of different appropriate modes of weaning from mechanical ventilation (MV) in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). METHODS: Patients with AECOPD and mechanically ventilated by orotracheal intubation, suitable for continuous positive airway pressure+proportional pressure support (CPAP+PPS) and CPAP+assisted spontaneous breath (ASB) ventilation mode for weaning from MV, admitted to intensive care unit (ICU) of Tianjin Third Central Hospital form January 1st, 2016 to December 31st, 2017 were enrolled. When the patients recovered to spontaneous respiration and down regulation of ventilator support frequency to 10 bpm, they were taken ventilator weaning in CPAP+PPS and CPAP+ASB mode according to the random number table method, respectively. Basic characteristics, ventilator parameters, the incidence of high man-machine confrontation (man-machine confrontation index > 10%) and clinical outcomes (ventilator weaning time, which was defined as the time from randomization to successful weaning from MV, ventilator weaning failure times, the duration of MV, the length of ICU stay and the length of hospital stay) were compared between the two groups. RESULTS: Eighty-seven AECOPD patients were selected, 44 in CPAP+ASB group and 43 in CPAP+PPS group. There was no significant difference in gender, age, acute physiology and chronic health evaluation II (APACHE II), sequential organ failure score (SOFA), Glasgow coma score (GCS), Charsen index and the highest arterial blood carbon dioxide partial pressure (PaCO2), the lowest arterial oxygen partial pressure (PaO2) and tidal volume (VT) at the time of onset between the two groups. Compared with CPAP+ASB group, incidence of high man-machine confrontation was significantly decreased in CPAP+PPS group [9.30% (4/43) vs. 27.27% (12/44), P = 0.027], and the airway occlusion pressure (P0.1) was significantly decreased [cmH2O (1 cmH2O = 0.098 kPa): 2.21±0.83 vs. 2.63±0.94, P = 0.032], and the failure rate of the first spontaneous breathing trial (SBT) was significantly decreased [6.98% (3/43) vs. 22.73% (10/44), P = 0.039], ventilator weaning time, the length of ICU stay and the length of hospital stay were significantly shortened [ventilator weaning time (hours): 12.73±14.23 vs. 50.64±38.11, the length of ICU stay (hours): 254.53±108.06 vs. 344.93±124.95, the length of hospital stay (days): 18.53±7.59 vs. 26.64±11.22, all P < 0.05]. However, there was no significant difference in PaCO2, duration of MV, ICU mortality and hospital mortality between the two groups. CONCLUSIONS: Compared with CPAP+ASB ventilation mode, CPAP+PPS ventilation mode can reduce respiratory muscle load, promote respiratory function recovery, and reduce the occurrence of man-machine confrontation, which is beneficial to AECOPD patients taking ventilator weaning, and can significantly shorten the ventilator weaning time of patients and further shorten the hospitalization time.

Ulinastatin mediates suppression of regulatory T cells through TLR4/NF-κB signaling pathway in murine sepsis.

CD4+CD25+ regulatory T cells (Tregs) play an essential role in the suppression of the immune response and prevention of autoimmune reactions. The activation of TLR4, which provides a critical link between the innate and adaptive immune systems, has been implicated in regulating the function of Tregs. Ulinastatin (UTI) is a broad-spectrum protease inhibitor that has been shown to modulate innate immunity and pro-inflammatory signaling in sepsis. In addition, there are reports that UTI may modulate the functional activity of Tregs to influence the inflammatory response in infectious disease. In the present study, we investigated the effect of UTI on the activity of Tregs, which was assessed by measuring the survival and inflammatory responses of mice with cecal ligation and puncture (CLP)-induced sepsis. In addition, we further explored the cellular and molecular mechanisms involved in these effects. The results showed that UTI could enhance survival and attenuate inflammatory responses during CLP-induced sepsis. Moreover, sepsis-induced increases in the quantity and activity of Tregs were attenuated under UTI treatment, but not in TLR4-/- mice. We also found that the functional changes in Tregs could be attributed to the TLR4/NF-κB signaling pathway. Collectively, our results indicated that UTI could ameliorate inflammatory damage by modulating the quantity and function of Tregs via the TLR4/NF-κB signaling pathway. Our study provides theoretical and experimental evidence for the administration of UTI in the treatment of sepsis and other acute critical illnesses.

Long-term quality of life after sepsis and predictors of quality of life in survivors with sepsis.

PURPOSE: To evaluate the quality of life among survivors after sepsis in 2 years, comparing with critical patients without sepsis and the general people, analyze the changes and the predictors of quality of life among septic survivors. METHODS: This prospective case-control study screened the intensive care unit (ICU) patients in Tianjin Third Central Hospital from January 2014 to October 2017, and the Chinese general population in the previous studies was also included. According to inclusion criteria and exclusion criteria, 306 patients with sepsis were enrolled as the observation group, and another 306 patients without sepsis in ICU during the same period, whose ages, gender and Charlson Comorbidity Index matched with observation group, were enrolled as the control group. At 3 mo, 12 mo, and 24 mo after discharge, the Mos 36-item Short Form Health Survey (SF-36), the Euroqol-5 dimension (EQ-5D), and the activities of daily living (ADL) were evaluated in face-to-face for the quality of life among survivors. RESULTS: There were 210 (68.6%) septic patients and 236 (77.1%) non-septic critically ill patients surviving. At 3 months after discharge, the observation and control groups had the similar demographic characteristics (age: 58.8 ± 18.1years vs. 57.5 ± 17.6 years, p = 0.542; male: 52.0% vs. 51.4%, p = 0.926). However, the observation group had higher acute physiology and chronic health evaluation II (APACHEII) scores, higher sequential organ failure assessment (SOFA) scores, longer hospital stay, and longer ICU stay than the control group did (p < 0.05). There were no significant differences in the eight dimensions of the SF36 scale, the EQ-5D health utility scores, and the activities of daily life scores between septic survivors and non-septic survivors (p > 0.05). In addition, compared with the quality of life of the Chinese general population (aged 55-64 years), the quality of life of septic patients were significantly lower at 3 months after discharge (p < 0.05). Comparing the quality of life of the ill patients who had been discharged at 3 mo and 24 mo, the general health improved statistically (p = 0.000) and clinically (score improvement > 5 points). Older age (OR, 1.050; 95% CI, 1.022-1.078, p = 0.000), female (OR, 3.375; 95% CI, 1.434-7.941, p = 0.005) and longer mechanical ventilation time (OR, 3.412; 95% CI, 1.413, 8.244, p = 0.006) were the risk factors for the quality of life of septic survivors. CONCLUSION: The long-term quality of life of septic survivors was similar to that of non-sepsis critically ill survivors. After discharge, the general health of sepsis improved overtime. Age, female and mechanical ventilation time (>5 days) were the predictors of the quality of life after sepsis.

Ulinastatin Protects Against LPS-Induced Acute Lung Injury By Attenuating TLR4/NF-κB Pathway Activation and Reducing Inflammatory Mediators.

Acute lung injury (ALI) and its severe form, acute respiratory distress syndrome, remain the leading causes of morbidity and mortality in intensive care units. Ulinastatin (UTI), a serine protease inhibitor, possesses anti-inflammatory properties and has been suggested to modulate lipopolysaccharide (LPS)-induced sepsis; thus, it is now widely used in the treatment of pancreatitis, sepsis, and septic shock. Toll-like receptor 4 (TLR4), an essential LPS signaling receptor, plays a critical role in the activation of innate immunity. The aim of this study was to investigate whether UTI alleviates ALI by attenuating TLR4 expression and to explore the underlying molecular mechanisms involved. Male C56BL/6 mice were administered UTI intravenously 1 h before and 6 h after exposure to LPS by intratracheal instillation. Human lung epithelial (BEAS-2B) cells were incubated with LPS in the presence or absence of UTI. An enzyme-linked immunosorbent assay was used to detect levels of inflammatory cytokines. Western blot analysis was performed to detect changes in TLR4 expression and nuclear factor-κB (NF-κB) activation. UTI significantly protected animals from LPS-induced ALI, decreasing the lung wet/dry weight ratio, ALI score, total cells, neutrophils, macrophages, myeloperoxidase activity, and malondialdehyde content, factors associated with lung histological damage. UTI treatment also markedly attenuated levels of TLR4 and other proinflammatory cytokines. Furthermore, UTI significantly attenuated LPS-induced increases in TLR4 protein expression and NF-κB activation in lung tissues. Similarly, UTI markedly attenuated TLR4 expression and NF-κB activation in LPS-stimulated BEAS-2B cells. These findings indicate that UTI ameliorates LPS-induced ALI by attenuating the TLR4/NF-κB pathway activation.

Comparison of the pulmonary dead-space fraction derived from ventilator volumetric capnography and a validated equation in the survival prediction of patients with acute respiratory distress syndrome.

PURPOSE: This prospective observational study aims to evaluate the accuracy of dead-space fraction derived from the ventilator volumetric capnography (volumetric CO2) or a prediction equation to predict the survival of mechanically ventilated patients with acute respiratory distress syndrome (ARDS). METHODS: Consecutive VD/VT measurements were obtained based upon a prediction equation validated by Frankenfield et al for dead-space ventilation fraction: VD/VT = 0.320 + 0.0106 (PaCO2-ETCO2)⁺ 0.003 (RR)⁺0.0015 (age) in adult patients who had infection-related severe pneumonia and were confirmed as having ARDS. Here PaCO2 is the arterial partial pressure of carbon dioxide in mmHg; ETCO2, the end- tidal carbon dioxide measurement in mmHg; RR, respiratory rate per minute; and age in years. Once the patient had intubation, positive end expiratory pressure was adjusted and after Phigh reached a steady state, VD/VT was measured and recorded as the data for the first day. VD/VT measurement was repeated on days 2, 3, 4, 5 and 6. Meanwhile we collected dead-space fraction directly from the ventilator volu- metric CO2 and recorded it as Vd/Vt. We analyzed the changes in VD/VT and Vd/Vt over the 6-day period to determine their accuracy in predicting the survival of ARDS patients. RESULTS: Overall, 46 patients with ARDS met the inclusion criteria and 24 of them died. During the first 6 days of intubation, VD/VT was significantly higher in nonsurvivors on day 4 (0.70 ± 0.01 vs 0.57 ± 0.01), day 5 (0.73 ± 0.01 vs. 0.54 ± 0.01), and day 6 (0.73 ± 0.02 vs. 0.54 ± 0.01) (all p =0.000). Vd/Vt showed no significant difference on days 1e4 but it was much higher in nonsurvivors on day 5 (0.45 ± 0.04 vs. 0.41 ± 0.06) and day 6 (0.47 ± 0.05 vs. 0.40 ± 0.03) (both p=0.008). VD/VT on the fourth day was more accurate to predict survival than Vd/Vt. The area under the receiver-operating characteristic curve for VD/VT and Vd/Vt in evaluating ARDS patients survival was day 4 (0.974 ± 0.093 vs. 0.701 ± 0.023, p = 0.0024) with the 95% confidence interval being 0.857-0.999 vs. 0.525-0.841. CONCLUSION: Compared with Vd/Vt derived from ventilator volumetric CO2, VD/VT on day 4 calculated by Frankenfield et al's equation can more accurately predict the survival of ARDS patients.

Effect of Regulatory T Cells on Promoting Apoptosis of T Lymphocyte and Its Regulatory Mechanism in Sepsis.

With both in vivo and in vitro experiments, the present study was conducted to investigate the effect of regulatory T cell (Treg) on promoting T-lymphocyte apoptosis and its regulatory mechanism through transforming growth factor-beta (TGF-ß1) signaling in mice. A murine model of polymicrobial sepsis was reproduced by cecal ligation and puncture (CLP); PC61 and anti-TGF-ß antibodies were used to decrease counts of CD4(+)CD25(+) Tregs and inhibit TGF-ß activity, respectively. Splenic CD4(+)CD25(+) Tregs and CD4(+)CD25(-) T cells were isolated. Phenotypes, including cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), forkhead/winged helix transcription factor p3 (Foxp3), and TGFß1(m+), as well as the apoptotic rate of CD4(+)CD25(-) T cell, were analyzed by flow cytometry. Real-time reverse transcription-polymerase chain reaction was performed to determine mRNA expression of TGF-ß1, and the expressions of Smad2/Smad3, Bcl-2 superfamily members of Bcl-2/Bim, cytochrome C, the mitochondrial membrane potential, and caspases in CD4(+)CD25(-) T cells were simultaneously determined. After treatment with PC61 or anti-TGF-ß antibody, CTLA-4, Foxp3, and TGFß1(m+) expressions of CD4(+)CD25(+) Tregs were markedly decreased in comparison to that of the CLP group and the apoptosis rate of CD4(+)CD25(-) T cells was significantly positively correlated with the expression of TGF-ß1. Meanwhile, levels of P-Smad2/P-Smad3, proapoptotic protein Bim, cytochrome C, and activity of caspase-3, -8, -9 were downregulated, whereas the mitochondrial membrane potential and antiapoptotic protein Bcl-2 expression were restored. Taken together, our data indicated that the TGF-ß1 signal could be partly involved in the apoptosis of CD4(+)CD25(-) T cells promoted by CD4(+)CD25(+) Tregs, therefore inhibition of TGF-ß1 expression may provide a novel strategy for the improvement of host immunosuppression following sepsis.