Quantitative evaluation of myocardial layer-specific strain using two-dimensional speckle tracking echocardiography in septic patients.

BACKGROUND: Although global longitudinal strain (GLS) is proven to be reduced and associated with adverse outcomes in septic patients, it has not been elucidated whether or not layer-specific strains are reduced. We aimed to explore the layer-specific strains of left ventricular (LV) for assessing myocardial dysfunction in septic patients. METHODS: A prospective observational study of patients with sepsis was conducted in a tertiary hospital in China. Routine two-dimensional speckle tracking echocardiography was performed within 24 h of enrollment. Demographic data, laboratory values, and clinical outcomes were collected. RESULTS: We recruited 79 septic patients finally. The mean age of septic patients was 59.4 years old and 45 (57.0%) were male. The median Acute Physiology Age and Chronic Health Evaluation (APACHE II) score, and mean sequential organ failure assessment (SOFA) score of all patients were 19.0 and 7.7, respectively. According to the left ventricular ejection fraction (LVEF) value of 50%, the patients were categorized into two groups: SICM (sepsis-induced cardiomyopathy, LVEF < 50%, n = 22) and non-SICM group ( LVEF ≥ 50%, n = 57). The median LVEF of SICM and non-SICM patients were 41.9% and 58.7%, and SICM patients had less negative layer-specific strain and global strain than that of non-SICM patients. The echocardiographic comparison of non-SICM and healthy controls was conducted to explore the myocardial injuries of non-SICM patients and the non-SICM had worse LS-epi than that of controls (-18.5% vs. -21.4%, p = 0.024). CONCLUSION: There were 72.2% (57) septic patients presented with non-SICM (LVEF ≥ 50%), and the strain value of epicardium of them was less negative than healthy controls.

Extracellular Histone-Induced Protein Kinase C Alpha Activation and Troponin Phosphorylation Is a Potential Mechanism of Cardiac Contractility Depression in Sepsis.

Reduction in cardiac contractility is common in severe sepsis. However, the pathological mechanism is still not fully understood. Recently it has been found that circulating histones released after extensive immune cell death play important roles in multiple organ injury and disfunction, particularly in cardiomyocyte injury and contractility reduction. How extracellular histones cause cardiac contractility depression is still not fully clear. In this work, using cultured cardiomyocytes and a histone infusion mouse model, we demonstrate that clinically relevant histone concentrations cause significant increases in intracellular calcium concentrations with subsequent activation and enriched localization of calcium-dependent protein kinase C (PKC) α and ßII into the myofilament fraction of cardiomyocytes in vitro and in vivo. Furthermore, histones induced dose-dependent phosphorylation of cardiac troponin I (cTnI) at the PKC-regulated phosphorylation residues (S43 and T144) in cultured cardiomyocytes, which was also confirmed in murine cardiomyocytes following intravenous histone injection. Specific inhibitors against PKCα and PKCßII revealed that histone-induced cTnI phosphorylation was mainly mediated by PKCα activation, but not PKCßII. Blocking PKCα also significantly abrogated histone-induced deterioration in peak shortening, duration and the velocity of shortening, and re-lengthening of cardiomyocyte contractility. These in vitro and in vivo findings collectively indicate a potential mechanism of histone-induced cardiomyocyte dysfunction driven by PKCα activation with subsequent enhanced phosphorylation of cTnI. These findings also indicate a potential mechanism of clinical cardiac dysfunction in sepsis and other critical illnesses with high levels of circulating histones, which holds the potential translational benefit to these patients by targeting circulating histones and downstream pathways.

Longitudinal phenotypes in patients with acute respiratory distress syndrome: a multi-database study.

BACKGROUND: Previously identified phenotypes of acute respiratory distress syndrome (ARDS) have been limited by a disregard for temporal dynamics. We aimed to identify longitudinal phenotypes in ARDS to test the prognostic and predictive enrichment of longitudinal phenotypes, and to develop simplified models for phenotype identification. METHODS: We conducted a multi-database study based on the Chinese Database in Intensive Care (CDIC) and four ARDS randomized clinical trials (RCTs). We employed latent class analysis (LCA) to identify longitudinal phenotypes using 24-hourly data from the first four days of invasive ventilation. We used the Cox regression model to explore the association between time-varying respiratory parameters and 28-day mortality across phenotypes. Phenotypes were validated in four RCTs, and the heterogeneity of treatment effect (HTE) was investigated. We also constructed two multinomial logistical regression analyses to develop the probabilistic models. FINDINGS: A total of 605 ARDS patients in CDIC were enrolled. The three-class LCA model was identified and had the optimal fit, as follows: Class 1 (n = 400, 66.1% of the cohort) was the largest phenotype over all study days, and had fewer abnormal values, less organ dysfunction and the lowest 28-day mortality rate (30.5%). Class 2 (n = 102, 16.9% of the cohort) was characterized by pulmonary mechanical dysfunction and had the highest proportion of poorly aerated lung volume, the 28-day mortality rate was 47.1%. Class 3 (n = 103, 17% of the cohort) was correlated with extra-pulmonary dysfunction and had the highest 28-day mortality rate (56.3%). Time-varying mechanical power was more significantly associated with 28-day mortality in Class 2 patients compared to other phenotypes. Similar phenotypes were identified in four RCTs. A significant HTE between phenotypes and treatment strategies was observed in the ALVEOLI (high PEEP vs. low PEEP) and the FACTT trials (conservative vs. liberal fluid management). Two parsimonious probabilistic models were constructed to identify longitudinal phenotypes. INTERPRETATION: We identified and validated three novel longitudinal phenotypes for ARDS patients, with both prognostic and predictive enrichment. The phenotypes of ARDS can be accurately identified with simple classifier models, except for Class 3.

Association Between Pathophysiology and Volume of Distribution Among Patients With Sepsis or Septic Shock Treated With Imipenem: A Prospective Cohort Study.

BACKGROUND: This study was performed to explore the apparent volume of distribution (Vd) of imipenem in patients with sepsis or septic shock. METHODS: A prospective, observational, single-center study was conducted in patients with sepsis or septic shock. The patients were treated with 1 g of imipenem mixed with 200 mL of normal saline infused intravenously over a 3-hour period at 8-hour intervals. The concentration of imipenem was 5 mg/mL, and the rate of infusion was 5.5 mg/min. Blood samples for measuring imipenem serum concentrations with high-performance liquid chromatography were obtained before and at 0, 1, 2, 3, and 5 hours after drug infusion on study days 1 and 3. Pharmacokinetic parameters were calculated according to a noncompartment model. RESULTS: A total of 25 adult patients were enrolled in this study, of whom 15 were diagnosed with sepsis and 10 with septic shock. The initial Vd (Vc) of imipenem was significantly lower in the sepsis than that in the septic shock group (mean [standard deviation], 26.5 [7.1] vs 40.7 [11.0] L; P = .001). The Vc of imipenem was significantly related to serum albumin levels (r = -0.517; P = .008) as well as Acute Physiology and Chronic Health Evaluation II (APACHE II) scores (r = 0.606; P = .001). Multivariate linear regression identified serum albumin levels and APACHE II scores on day 1 as independent factors influencing the Vc of imipenem (P < .05). The difference in Vd between the imipenem steady state and the initial state was significantly higher in nonsurvivors than in survivors (mean [standard deviation], 1.7 [21.5] vs -13.1 [11.4] L; P = .046). CONCLUSIONS: APACHE II scores and serum albumin levels were found in this study to be independent factors that may affect the Vc of imipenem in patients with sepsis or septic shock. CLINICAL TRIALS REGISTRATION: clinicaltrials.gov, NCT03308214.

Mesenchymal stem cells activate Notch signaling to induce regulatory dendritic cells in LPS-induced acute lung injury.

BACKGROUND: Mesenchymal stem cells (MSCs) have been shown to alleviate acute lung injury (ALI) and induce the production of regulatory dendritic cells (DCregs), but the potential link between these two cell types remains unclear. The goal of this study was to investigate the effect and mechanism of MSC-induced regulatory dendritic cells in ALI mice. MATERIAL/METHODS: In vivo experiments, C57BL/6 wild-type male mice were sacrificed at different times after intratracheal injection of LPS to observe changes in lung DC maturation and pathological damage. MSCs, DCregs or/and carboxyfluorescein diacetate succinimidyl ester (CFSE)-labeled DCs were administered to the mice by tail vein, and flow cytometry was performed to measure the phenotype of lung DCs and T cells. Lung injury was estimated by the lung wet weight/body weight ratio and histopathological analysis. In vitro, Western blotting or flow cytometry was used to detect the expression of Notch ligand or receptor in MSCs or DCs after coculture or LPS stimulation. Finally, in vivo and in vitro, we used the Notch signaling inhibitor DAPT to verify the effect of the Notch pathway on MSC-induced DCregs and their pulmonary protection. RESULTS: We showed significant accumulation and maturation of lung DCs 2 h after intratracheal injection of LPS, which were positively correlated with the lung pathological injury score. MSC treatment alleviated ALI lung injury, accompanied by a decrease in the number and maturity of classical DCs in the lungs. CFSE-labeled DCs migrated to the lungs of ALI mice more than those of the normal group, and the elimination of CFSE-labeled DCs in the blood was slower. MSCs inhibited the migration of CFSE-labeled DCs to the lung and promoted their elimination in the blood. DCregs, which are obtained by contact coculture of mDCs with MSCs, expressed reduced levels of MHCII, CD86, CD40 and increased levels of PD-L1, and had a reduced ability to stimulate lymphocyte proliferation and activation (expression of CD44 and CD69). mDCs expressing Notch2 significantly increased after coculture with MSCs or rhJagged1, and MSCs expressed more Jagged1 after LPS stimulation. After stimulation of mDCs with recombinant Jagged1, DCs with low expression of MHCII, CD86 and CD40 were also induced, and the effects of both rhJagged1 and MSCs on DCs were blocked by the Notch inhibitor DAPT. Intra-airway DAPT reversed the inhibitory effect of mesenchymal stem cells on DC recruitment to the lungs and its maturation. CONCLUSIONS: Our results suggested that the recruitment and maturation of lung DCs is an important process in early ALI, MSCs attenuate LPS-induced ALI by inducing the production of DCregs by activating Notch signaling.

The Effect of High-Flow Nasal Oxygen Therapy on Postoperative Pulmonary Complications and Hospital Length of Stay in Postoperative Patients: A Systematic Review and Meta-Analysis.

OBJECTIVE: To evaluate the effect of high-flow nasal cannula oxygen (HFNO) therapy on hospital length of stay (LOS) and postoperative pulmonary complications (PPCs) in adult postoperative patients. DATA SOURCES: PubMed, Embase, the Cochrane Library, Web of Science of Studies, China National Knowledge Index, and Wan Fang databases were searched until July 2018. STUDY SELECTION: Randomized controlled trials (RCTs) comparing HFNO with conventional oxygen therapy or noninvasive mechanical ventilation in adult postoperative patients were included. The primary outcomes were hospital LOS and PPCs; short-term mortality (defined as intensive care unit, hospital, or 28-day mortality) and intubation rate were the secondary outcomes. DATA EXTRACTION: Demographic variables, high-flow oxygen therapy application, effects, and side effects were retrieved. Data were analyzed by the methods recommended by the Cochrane Collaboration. The strength of evidence was assessed by the Grading of Recommendations Assessment, Development and Evaluation. Random errors were evaluated with trial sequential analysis. DATA SYNTHESIS: Fourteen studies (2568 patients) met the inclusion criteria and were included. Compared to the control group, the pooled effect showed that HFNO was significantly associated with a shorter hospital stay (mean difference: -0.81; 95% confidence interval [CI]: -1.34 to -0.29, P = .002), but not mortality (risk ratio [RR]: 1.0, 95% CI: 0.63 to 1.59, P = 1.0). Weak evidence of a reduction in reintubation rate (RR: 0.76, 95% CI: 0.57-1.01, P = .06) and PPC rate (RR: 0.89, 95% CI: 0.75-1.06, P = .18) with HFNO versus control group was recorded. CONCLUSIONS: The available RCTs suggest that, among the adult postoperative patients, HFNO therapy compared to the control group significantly reduces hospital LOS.

Physiological effects of different recruitment maneuvers in a pig model of ARDS.

BACKGROUND: In acute respiratory distress syndrome (ARDS), lung recruitment maneuvers can recruit collapsed alveoli in gravity-dependent lung regions, improving the homogeneity of ventilation distribution. This study used electrical impedance tomography to investigate the physiological effects of different recruitment maneuvers for alveolar recruitment in a pig model of ARDS. METHODS: ARDS was induced in ten healthy male pigs with repeated bronchoalveolar lavage until the ratio of arterial partial pressure of oxygen (PaO2) of fraction of inspired oxygen (P/F) was < 100 mmHg and remained stable for 30 min (TARDS). ARDS pigs underwent three sequential recruitment maneuvers, including sustained inflation, increments of positive end-expiratory pressure (PEEP), and pressure-controlled ventilation (PCV) applied in random order, with 30 mins at a PEEP of 5 cmH2O between maneuvers. Respiratory mechanics, hemodynamics, arterial blood gas, and electrical impedance tomography were recorded at baseline, TARDS, and before and after each recruitment maneuver. RESULTS: In all ten pigs, ARDS was successfully induced with a mean 2.8 ± 1.03 L bronchoalveolar lavages. PaO2, P/F, and compliance were significantly improved after recruitment with sustained inflation, increments of PEEP or PCV (all p < 0.05), and there were no significant differences between maneuvers. Global inhomogeneity index significantly decreased after recruitment with sustained inflation, increments of PEEP, or PCV. There were no significant differences in global inhomogeneity before or after recruitment with the different maneuvers. The decrease in global inhomogeneity index (ΔGI) was significantly greater after recruitment with increments of PEEP compared to sustained inflation (p = 0.023), but there was no significant difference in ΔGI between increments of PEEP and PCV or between sustained inflation and PCV. CONCLUSION: Sustained inflation, increments of PEEP, and PCV increased oxygenation, and regional and global compliance of the respiratory system, and decreased inhomogeneous gas distribution in ARDS pigs. Increments of PEEP significantly improved inhomogeneity of the lung compared to sustained inflation, while there was no difference between increments of PEEP and PCV or between sustained inflation and PCV.

Circulating Th1 and Th2 Subset Accumulation Kinetics in Septic Patients with Distinct Infection Sites: Pulmonary versus Nonpulmonary.

BACKGROUND: Persistent peripheral CD4+T cell differentiation towards T helper (Th)2 rather than Th1 has been proved to be related to immunosuppression and poor prognosis in sepsis. However, it is unclear whether these circulating Th1 and Th2 subtype accumulations differed in septic populations of distinct infection sites and presented different associations with outcomes among patients with pulmonary versus nonpulmonary sepsis. METHODS: From a secondary analysis of a prospective observational study, seventy-four previously immunocompetent patients with community-acquired severe sepsis within 24 hours upon onset were enrolled. Whole blood was collected on the admission day (D0), 3rd day (D3), and 7th day (D7). The patients were classified as pulmonary (n = 52) and nonpulmonary sepsis (n = 22). Circulating Th1 and Th2 populations were evaluated by flow cytometry, and clinical data related to disease severity and inflammatory response were collected. The associations of circulating Th1 and Th2 subset accumulations with distinct infection sites or outcomes within subgroups were explored. RESULTS: Patients with pulmonary sepsis held similar disease severity and 28-day mortality with those of nonpulmonary sepsis. Of note is the finding that circulating Th2 levels on D7 (P = 0.04) as well as Th2/Th1 on D3 (P = 0.01) and D7 (P = 0.04) were higher in the pulmonary sepsis compared with nonpulmonary sepsis while Th1 levels were lower on D0, D3, and D7 (P = 0.01, <0.01, and =0.05, respectively). Compared to 28-day survivors, higher Th2/Th1 driven by increased Th2 were observed among 28-day nonsurvivors on D3 and D7 in both groups. The association between circulatory Th2 populations or Th2/Th1 and 28-day death was detected in pulmonary sepsis (P < 0.05, HR > 1), rather than nonpulmonary sepsis. CONCLUSIONS: Circulating Th2 accumulation was more apparent among pulmonary sepsis while nonpulmonary sepsis was characterized with the hyperactive circulating Th1 subset among previously immunocompetent patients. This finding suggested that circulating Th1 and Th2 subset accumulations vary in septic subgroups with different infection sites.

mTOR/STAT-3 pathway mediates mesenchymal stem cell-secreted hepatocyte growth factor protective effects against lipopolysaccharide-induced vascular endothelial barrier dysfunction and apoptosis.

Mesenchymal stem cells (MSCs) protect the endothelial barrier complex and survival, implicated in the pathogenesis of acute lung injury (ALI) via paracrine hepatocyte growth factor (HGF). However, the mechanism of HGF in endothelial regulation remains unclear. Here, we introduced a coculture protocol of pulmonary microvascular endothelial cells (PMVECs) and overexpression of the HGF gene of MSCs (MSC-HGF). Immunofluorescence and endothelial permeability analysis revealed that MSC-HGF protected endothelial tight junction protein occludin expression and attenuated cellular permeability as well as endothelial apoptosis. To investigate the novel mechanism mammalian TOR (mTOR)/ signal transducer and activator of transcription 3 (STAT-3) signaling in HGF protective effects against endothelial barrier and apoptosis, we used recombinant mouse HGF in endothelial cells. In addition, we used mTOR inhibitor rapamycin to inhibit the mTOR pathway. Our study demonstrated that rapamycin decreased the protective effects of HGF on the endothelium by decreasing tight junction protein occludin expression and cell proliferation, and raising lipopolysaccharide (LPS)-induced endothelial permeability, endothelial cell injury factors ET-1 and vWF. Similarly, the protective effects of HGF on reducing endothelial barrier and apoptosis were weakened when PMVECs were treated with the STAT-3 inhibitor S3I-201. Moreover, mTOR/STAT-3 were activated by HGF demonstrated as raising mTOR (Ser2448) and STAT3 (Ser727) phosphorylation proteins, leading to endothelial barrier improvement and survival. Reversely, rapamycin or S3I-201 inhibited mTOR/STAT-3 activation. Taken together, our findings highlight that the activation of the mTOR/STAT-3 pathway provides novel mechanistic insights into MSC-secreted HGF protection against LPS-induced vascular endothelial permeability dysfunction and apoptosis, which contributes to decreasing microvascular loss and lung injury.

Early and dynamic alterations of Th2/Th1 in previously immunocompetent patients with community-acquired severe sepsis: a prospective observational study.

BACKGROUND: T helper (Th) cells regulate sepsis processes, including primary pathogen clear and secondary pathogen defence. The objectives of this study were to determine the early and dynamic alterations of Th1 and Th2 populations to community-acquired severe sepsis upon onset among previously immunocompetent patients and whether it was related to clinical outcomes. METHODS: This prospective observational cohort study was conducted at a general intensive care unit (ICU) of a tertiary teaching hospital in China. Immunocompetent patients with community-acquired severe sepsis within 24 h upon onset were included as septic group. Healthy volunteers and critically ill patients without severe sepsis were recruited as controls. Whole blood was collected on D0, 3rd day (D3) and 7th day (D7) for septic group and once upon enrollment for controls. Th1 and Th2 populations were measured by flow cytometry and assessed for associations with 28-day mortality using cox proportional hazard models. Associations of dynamic alterations of Th cell subpopulations with clinical outcomes were investigated. RESULTS: This study demonstrated that community-acquired severe sepsis patients (n = 71) had increased Th2/Th1 and Th2 populations, compared to healthy controls (n = 7) and critically ill patients without severe sepsis (n = 7) at admission. Among the septic cohort, values of Th2/Th1 were significantly higher in non-survivors than survivors on D0 (p = 0.04), D3 (p < 0.001) and D7 (p < 0.001). Patients with persistently increasing Th2/Th1 demonstrated the highest mortality (47.1%) and incidence of ICU-acquired infections (64.7%). CONCLUSIONS: Th2/Th1 was markedly up-regulated with Th2 dominance upon community-acquired severe sepsis onset among previously immunocompetent patients and its persistently dynamic increase was associated with ICU-acquired infections and 28-day death. Trial registration Institutional Ethics Committee of Zhongda Hospital, 2014ZDSYLL086, registered in June 2014-prospectively registered; ClinicalTrials.gov, NCT02883218, registered on 25 Aug 2016-retrospectively registered, https://www.clinicaltrials.gov/ct2/show/NCT02883218?cond=NCT02883218&rank=1.

A prospective observation on nutrition support in adult patients with severe burns.

Nutrition therapy is considered an important treatment of burn patients. The aim of the study was to delineate the nutritional support in severe burn patients and to investigate association between nutritional practice and clinical outcomes. Severe burn patients were enrolled (n 100). In 90 % of the cases, the burn injury covered above 70 % of the total body surface area. Mean interval from injury to nutrition start was 2·4 (sd 1·1) d. Sixty-seven patients were initiated with enteral nutrition (EN) with a median time of 1 d from injury to first feed. Twenty-two patients began with parenteral nutrition (PN). During the study, thirty-two patients developed EN intolerance. Patients received an average of about 70 % of prescribed energy and protein. Patients with EN providing <30 % energy had significantly higher 28- d and in-hospital mortality than patients with EN providing more than 30 % of energy. Mortality at 28 d was 11 % and in-hospital mortality was 45 %. Multiple regression analysis demonstrated that EN providing <30 % energy and septic shock were independent risk factors for 28- d prognosis. EN could be initiated early in severe burn patients. Majority patients needed PN supplementation for energy requirement and EN feeding intolerance. Post-pyloric feeding is more efficient than gastric feeding in EN tolerance and energy supplement. It is difficult for severe burn patients to obtain enough feeding, especially in the early stage of the disease. More than 2 weeks of underfeeding is harmful to recovery.

Effect of surfactant administration on outcomes of adult patients in acute respiratory distress syndrome: a meta-analysis of randomized controlled trials.

INTRODUCTION: Surfactant is usually deficiency in adult acute respiratory distress syndrome(ARDS) patients and surfactant administration may be a useful therapy. The aim of this study was to perform a meta-analysis of the effect of surfactant administration on outcomes of adult patients with acute respiratory distress syndrome. METHODS: PubMed, EMBASE, Medline, Cochrane database, Elsevier, Web of Science and http://clinicaltrials.gov were searched and investigated until December 2017. Randomized controlled trials(RCTs) comparing surfactant administration with general therapy in adult patients with ARDS were enrolled. The primary outcome was mortality (7-10-day, 28-30-day and 90-180-day). Secondary outcome included oxygenation (PaO2/FiO2 ratio). Demographic variables, surfactant administration, and outcomes were retrieved. Sensitivity analyses were used to evaluate the impact of study quality issues on the overall effect. Funnel plot inspection, Egger's and Begger's test were applied to investigate the publication bias. Internal validity was assessed with the risk of bias tool. Random errors were evaluated with trial sequential analysis(TSA). Quality levels were assessed by Grading of Recommendations Assessment, Development, and Evaluation methodology(GRADE). RESULTS: Eleven RCTs with 3038 patients were identified. Surfactant administration could not improve mortality of adult patients [Risk ratio (RR) (95%CI)) = 1.02(0.93-1.12), p = 0.65]. Subgroup analysis revealed no difference of 7-10-day mortality [RR(95%CI)) = 0.89(0.54-1.49), p = 0.66], 28-30-day mortality[RR(95%CI) = 1.00(0.89-1.12), p = 0.98] and 90-180-day mortality [RR(95%CI) = 1.11(0.94-1.32), p = 0.22] between surfactant group and control group. The change of the PaO2/FiO2 ratio in adult ARDS patients had no difference [MD(95%CI) = 0.06(- 0.12-0.24), p = 0.5] after surfactant administration. Finally, TSA and GRADE indicated lack of firm evidence for a beneficial effect. CONCLUSIONS: Surfactant administration has not been shown to improve mortality and improve oxygenation for adult ARDS patients. Large rigorous randomized trials are needed to explore the effect of surfactant to adult ARDS patients.

Stable overexpression of p130/E2F4 affects the multipotential abilities of bone-marrow-derived mesenchymal stem cells.

Bone-marrow-derived mesenchymal stem cells (MSCs) have great potential in transplantation medicine due to their multiple advantages. However, the controlled differentiation of MSCs is one of the key aspects of effective clinical transplantation. Growing evidence suggests that the cell cycle plays an important role in regulating differentiation, while p130 and E2F4 are key to cell cycle checkpoints. The aim of the study is to evaluate the effects and mechanism of p130/E2F4 on the multidifferentiation of MSCs. Our data showed that the transduction efficiencies of p130 or E2F4 mediated by lentiviral vectors were 80.3%-84.4%. p130 and E2F4 mRNA expression was significantly higher in MSC-p130 and MSC-E2F4 cells than in MSC normal control (NC) cells. Similar results were also observed for p130 and E2F4 protein expression. After osteogenic or adipogenic differentiation, the G1 phase was significantly delayed in the MSC-p130 and MSC-E2F4 groups compared with that in the MSC-NC group. However, the G1 phase in the MSC-p130 and MSC-E2F4 groups did the opposite after chondrogenic differentiation. Moreover, overexpressing p130 or E2F4 significantly improved osteogenic differentiation while inhibiting adipogenic and chondrogenic differentiation of mouse MSCs (mMSCs). Moreover, overexpressing p130 or E2F4 significantly improved migration but not proliferation of mMSCs. Our data suggest that cell cycle regulation may be involved in p130/E2F4-mediated changes in the multipotential abilities of bone-marrow-derived mMSCs.

Noninvasive Ventilation in Acute Hypoxemic Nonhypercapnic Respiratory Failure: A Systematic Review and Meta-Analysis.

OBJECTIVE: To evaluate the effectiveness of noninvasive ventilation in patients with acute hypoxemic nonhypercapnic respiratory failure unrelated to exacerbation of chronic obstructive pulmonary disease and cardiogenic pulmonary edema. DATA SOURCES: PubMed, EMBASE, Cochrane library, Web of Science, and bibliographies of articles were retrieved inception until June 2016. STUDY SELECTION: Randomized controlled trials comparing application of noninvasive ventilation with standard oxygen therapy in adults with acute hypoxemic nonhypercapnic respiratory failure were included. Chronic obstructive pulmonary disease exacerbation and cardiogenic pulmonary edema patients were excluded. The primary outcome was intubation rate; ICU mortality and hospital mortality were secondary outcomes. DATA EXTRACTION: Demographic variables, noninvasive ventilation application, and outcomes were retrieved. Internal validity was assessed using the risk of bias tool. The strength of evidence was assessed using Grading of Recommendations Assessment, Development, and Evaluation methodology. DATA SYNTHESIS: Eleven studies (1,480 patients) met the inclusion criteria and were analyzed by using a random effects model. Compared with standard oxygen therapy, the pooled effect showed that noninvasive ventilation significantly reduced intubation rate with a summary risk ratio of 0.59 (95% CI, 0.44-0.79; p = 0.0004). Furthermore, hospital mortality was also significantly reduced (risk ratio, 0.46; 95% CI, 0.24-0.87; p = 0.02). Subgroup meta-analysis showed that the application of bilevel positive support ventilation (bilevel positive airway pressure) was associated with a reduction in ICU mortality (p = 0.007). Helmet noninvasive ventilation could reduce hospital mortality (p = 0.0004), whereas face/nasal mask noninvasive ventilation could not. CONCLUSIONS: Noninvasive ventilation decreased endotracheal intubation rates and hospital mortality in acute hypoxemia nonhypercapnic respiratory failure excluding chronic obstructive pulmonary disease exacerbation and cardiogenic pulmonary edema patients. There is no sufficient scientific evidence to recommend bilevel positive airway pressure or helmet due to the limited number of trials available. Large rigorous randomized trials are needed to answer these questions definitely.

Endotoxemia accelerates diaphragm dysfunction in ventilated rabbits.

BACKGROUND: Ventilators may induce diaphragm dysfunction, and most of the septic population who are admitted to the intensive care unit require mechanical ventilation. However, there is no evidence that sepsis accelerates the onset of ventilator-induced diaphragm dysfunction or affects the microcirculation. Our study investigated whether lipopolysaccharide (LPS)-induced endotoxemia accelerated diaphragm dysfunction in ventilated rabbits by evaluating microcirculation, lipid accumulation, and diaphragm contractility. METHODS: After anesthesia and tracheostomy, 25 invasively monitored and mechanically ventilated New Zealand white rabbits were randomized to control (n = 5), controlled mechanical ventilation (CMV) (n = 5), pressure support ventilation (PSV; n = 5), CMV or PSV with LPS-induced endotoxemia (CMV-LPS and PSV-LPS, respectively; n = 5 for each). Rabbits were anesthetized and ventilated for 24 h, except the control rabbits (30 min). Diaphragmatic contractility was evaluated using neuromechanical and neuroventilatory efficiency. We evaluated the following at the end of the protocol: (1) diaphragm microcirculation; (2) lipid accumulation; and (3) diaphragm muscular fibers structure. RESULTS: Diaphragm contractility, microcirculation, lipid accumulation, and fiber structures were severely compromised in endotoxemic animals after 24 h compared to nonendotoxemic rabbits. Moreover, a slight but significant increase in lipid accumulation was observed in CMV and PSV groups compared with controls (P < 0.05). CONCLUSIONS: Endotoxemia accelerates the diaphragm dysfunction process in ventilated rabbits, affects the microcirculation, and results in diaphragmatic lipid accumulation and contractility impairment.

Antimicrobial stewardship of Chinese ministry of health reduces multidrug-resistant organism isolates in critically ill patients: a pre-post study from a single center.

BACKGROUND: China's Ministry of Health (MOH) has established a policy about the antimicrobial stewardship. To date, the effects of this policy on multidrug-resistant organism (MDRO) in critically ill patients are unknown. METHODS: A pre-post study was conducted on intensive care unit (ICU) patients from June 2010 to May 2011 and from June 2012 to May 2013. Bacterial cultures were conducted at ICU admission and discharge. In June 2011, our hospital started to administer the antimicrobial stewardship program of Chinese MOH. We collected the data on antimicrobial consumption during the 3-year period in all hospital and individual department every month, and analyzed the correlation between the proportion of critically patients colonized or infected with MDRO and antimicrobial consumption. RESULTS: A total of 978 patients were involved in the present study. With the intervention, the monthly mean Defined Daily Dose (DDD) per 100 occupied bed-days throughout the hospital decreased from 96 ± 7 to 65 ± 6 (p < 0.001), and the proportion of patients colonized or infected with MDRO decreased from 36 to 13% at the time of ICU admission and declined from 48 to 29% at the time of ICU discharge (both p < 0.001). There was a significant positive relationship between the proportion of all critically ill patients colonized or infected with MDRO at ICU admission and the DDD of the entire hospital (R2 = 0.7858, p < 0.001). CONCLUSION: The antimicrobial stewardship program of Chinese MOH reduced the consumption of antibiotics. Moreover, the proportion of patients colonized or infected with MDRO decreased along with reduced consumption of antibiotics. TRIAL REGISTRATION: Retrospectively registered: NCT02128399; Date of registration: 22 APR 2014; Detail information web link: https://clinicaltrials.gov/ct2/show/NCT02128399?term=NCT02128399&rank=1.

Identification of regional overdistension, recruitment and cyclic alveolar collapse with electrical impedance tomography in an experimental ARDS model.

BACKGROUND: Information on regional ventilation distribution in mechanically ventilated patients is important to develop lung protective ventilation strategies. In the present prospective animal study, we introduce an electrical impedance tomography (EIT)-based method to classify lungs into normally ventilated, overinflated, tidally recruited/derecruited and recruited regions. METHODS: Acute respiratory distress syndrome (ARDS) was introduced with repeated bronchoalveolar lavage in ten healthy male pigs until the ratio of arterial partial pressure of oxygen and fraction of inspired oxygen (PaO2/FiO2) decreased to less than 100 mmHg and remained stable for 30 minutes. Stepwise positive end-expiratory pressure (PEEP) increments were performed from 0 cmH2O to 30 cmH2O with 3 cmH2O increase every 5 minutes. Respiratory system compliance (Crs), blood gases and hemodynamics were measured at the same time. Lung regions at end-expiration and during tidal breathing were identified in EIT images. RESULTS: Overinflated regions contain air at end-expiration but they are not or are only minimally ventilated. Recruited regions compared to reference PEEP level contain air at end-expiration of arbitrary PEEP level but not at that of reference PEEP level. Tidally recruited/derecruited regions are not represented in lung regions at end-expiration but are ventilated during tidal breathing. The results coincided with measurements of blood gases. The coefficient for correlation between the number of recruited pixels and PaO2/FiO2 was 0.89 ± 0.12 (p = 0.02). CONCLUSION: The proposed novel EIT-based method provides information on overinflation, recruitment and cyclic alveolar collapse at the bedside, which may improve the ventilation strategies used.

The Effect of Early Goal-Directed Therapy on Outcome in Adult Severe Sepsis and Septic Shock Patients: A Meta-Analysis of Randomized Clinical Trials.

BACKGROUND: Whether early goal-directed therapy (EGDT) improves outcome in severe sepsis and septic shock remains unclear. We performed a meta-analysis of existing clinical trials to examine whether EGDT improved outcome in the resuscitation of adult sepsis patients compared with control care. METHODS: We searched for eligible studies using MEDLINE, Elsevier, Cochrane Central Register of Controlled Trials, and Web of Science databases. Studies were eligible if they compared the effects of EGDT versus control care on mortality in adult patients with severe sepsis and septic shock. Two reviewers extracted data independently. Data including mortality, sample size of the patients with severe sepsis and septic shock, and resuscitation end points were extracted. Data were analyzed using methods recommended by the Cochrane Collaboration Review Manager 4.2 software. Random errors were evaluated by trial sequential analysis (TSA). RESULTS: Nine studies compared EGDT with control care, and 5202 severe sepsis and septic shock patients were included. A nonsignificant trend toward reduction in the longest all-cause mortality was observed in the EGDT group compared with control care (relative risk, 0.89; 99% confidence interval, 0.74-1.07; P = 0.10). However, EGDT significantly reduced intensive care unit mortality in severe sepsis and septic shock patients (relative risk, 0.72; 99% confidence interval, 0.57-0.90; P = 0.0002). TSA indicated lack of firm evidence for a beneficial effect. CONCLUSIONS: In this meta-analysis, a nonsignificant trend toward reduction in the longest all-cause mortality in patients resuscitated with EGDT was noted. However, EGDT significantly reduced intensive care unit mortality in severe sepsis and septic shock patients. TSA indicated a lack of firm evidence for the results. More powered, randomized controlled trials are needed to determine the effects.

MSCs modified with ACE2 restore endothelial function following LPS challenge by inhibiting the activation of RAS.

Angiotensin (Ang) II plays an important role in the process of endothelial dysfunction in acute lung injury (ALI) and is degraded by angiotensin-converting enzyme2 (ACE2). However, treatments that target ACE2 to injured endothelium and promote endothelial repair of ALI are lacking. Mesenchymal stem cells (MSCs) are capable of homing to the injured site and delivering a protective gene. Our study aimed to evaluate the effects of genetically modified MSCs, which overexpress the ACE2 protein in a sustained manner via a lentiviral vector, on Ang II production in endothelium and in vitro repair of lipopolysaccharide (LPS)-induced endothelial injury. We found that the efficiency of lentiviral vector transduction of MSCs was as high as 97.8% and was well maintained over 30 passages. MSCs modified with ACE2 showed a sustained high expression of ACE2 mRNA and protein. The modified MSCs secreted soluble ACE2 protein into the culture medium, which reduced the concentration of Ang II and increased the production of Ang 1-7. MSCs modified with ACE2 were more effective at restoring endothelial function than were unmodified MSCs, as shown by the enhanced survival of endothelial cells; the downregulated production of inflammatory mediators, including ICAM-1, VCAM-1, TNF-α, and IL-6; reduced paracellular permeability; and increased expression of VE-cadherin. These data demonstrate that MSCs modified to overexpress the ACE2 gene can produce biologically active ACE2 protein over a sustained period of time and have an enhanced ability to promote endothelial repair after LPS challenge. These results encourage further testing of the beneficial effects of ACE2-modified MSCs in an ALI animal model.

Novel avian-origin influenza A (H7N9) in critically ill patients in China*.

OBJECTIVES: In March 2013, human infection with a novel avian-origin reassortment influenza A (H7N9) virus was identified in China. A total of 26 cases were confirmed and treated in Jiangsu. All the patients had findings consistent with pneumonia and were admitted to an ICU, which pose a threat to human health. We aimed to provide the clinical features, treatment, and prognosis of the critically ill patients with H7N9 viral infection. DESIGN: A retrospective cohort study. SETTING: Eight closed ICUs in general hospitals distributed throughout the Jiangsu Provincial, China. PATIENTS: Patients infected with influenza A (H7N9) virus from March 20, 2013, through May 1, 2013, in Jiangsu Province were included. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Twenty-seven patients infected with H7N9 virus were identified in Jiangsu. Of these, 26 were hospitalized. The median age was 54.5 years, and 18 patients (69.2%) were men. The most common symptoms at the onset of illness were high fever and cough. White cell counts were normal or decreased. All the patients had findings consistent with pneumonia. Twenty-four patients (92.3%) developed acute respiratory distress syndrome, and 10 (38.5%) developed septic shock quickly after the onset of illness. Treatment with antiviral drugs was initiated in all the patients at a median of 8 days after the onset of illness. Mortality was 19.2% at 28 days and 30.8% at 90 days. Based on multiple logistic regression analysis, septic shock associated with severe hypoxemia was the only independent risk factor for mortality. CONCLUSIONS: Infection with novel avian-origin reassortment influenza A (H7N9) virus is characterized by high fever, cough, and severe respiratory failure and is associated with a high mortality. These data provide some general understandings for the early identification, ICU treatment, and short-term prognosis of hospitalized critical patients with H7N9.