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Supplemental Digital Content is available in the text., Objectives: To investigate whether XueBiJing injection improves clinical outcomes in critically ill patients with severe community-acquired pneumonia. Design: Prospective, randomized, controlled study. Setting: Thirty-three hospitals in China. Patients: A total of 710 adults 18–75 years old with severe community-acquired pneumonia. Interventions: Participants in the XueBiJing group received XueBiJing, 100 mL, q12 hours, and the control group received a visually indistinguishable placebo. Measurements and Main Results: The primary outcome was 8-day improvement in the pneumonia severity index risk rating. Secondary outcomes were 28-day mortality rate, duration of mechanical ventilation and total duration of ICU stay. Improvement in the pneumonia severity index risk rating, from a previously defined endpoint, occurred in 203 (60.78%) participants receiving XueBiJing and in 158 (46.33%) participants receiving placebo (between-group difference [95% CI], 14.4% [6.9–21.8%]; p < 0.001). Fifty-three (15.87%) XueBiJing recipients and 84 (24.63%) placebo recipients (8.8% [2.4–15.2%]; p = 0.006) died within 28 days. XueBiJing administration also decreased the mechanical ventilation time and the total ICU stay duration. The median mechanical ventilation time was 11.0 versus 16.5 days for the XueBiJing and placebo groups, respectively (p = 0.012). The total duration of ICU stay was 12 days for XueBiJing recipients versus 16 days for placebo recipients (p = 0.004). A total of 256 patients experienced adverse events (119 [35.63%] vs 137 [40.18%] in the XueBiJing and placebo groups, respectively [p = 0.235]). Conclusions: In critically ill patients with severe community-acquired pneumonia, XueBiJing injection led to a statistically significant improvement in the primary endpoint of the pneumonia severity index as well a significant improvement in the secondary clinical outcomes of mortality, duration of mechanical ventilation and duration of ICU stay.

This study was undertaken to examine the regulatory role of multidrug resistance-associated protein 4 (MRP4) in an experimental model of sepsis-induced acute lung injury in rats. Sepsis was induced by cecal ligation and puncture in anesthetized rats. Animals were then randomly assigned to receive intravenous injection of vehicle or MRP4 inhibitor (MK571, 20 mg/kg). The pathological changes were observed by hematoxylin and eosin staining. Lung water content, lung vascular permeability and inflammatory cell count in bronchoalveolar lavage fluid (BALF) were quantified. Serum tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) levels were measured. In addition, lung tissue cyclic adenosine monophosphate (cAMP) levels were examined by enzyme-linked immunosorbent assay. Furthermore, the effects of MRP4 knockdown on lipopolysaccharide (LPS)-induced endothelial permeability and the cytoskeleton of rat pulmonary microvascular endothelial cells (PMVECs) were detected. The protein expression levels of MRP4, Rac1, VE-cadherin, β-catenin and ZO-1 were measured by Western blot analysis. MK571 significantly reduced lung tissue damage, lung water content and lung vascular permeability. Lung tissue cAMP levels were attenuated in MK571-treated animals compared with vehicle controls. MK571 also decreased sepsis-induced inflammatory cell accumulation in BALF. In addition, the MK571 group had significantly lower serum TNF-α and IL-6 levels compared with vehicle controls. Consistently, knockdown of MRP4 protected against LPS-induced increase in the endothelial permeability and the destruction of cytoskeleton in vitro. Furthermore, silencing MRP4 gene significantly reduced MRP4 protein expression and restored the protein expression of Rac1, VE-cadherin, β-catenin and ZO-1 in rat PMVECs in response to LPS stimulation. These data suggest that inhibition of MRP4 significantly alleviates sepsis-induced acute lung injury in rats.

Background: Equipoise exists regarding the implementation of evidence-based guidelines for nutritional therapy in critical illness because some previous cluster-randomised controlled trials (cRCTs) demonstrate patient benefits whilst others do not. We aimed to resolve this issue by initiating an appropriately powered cRCT to assess whether active implementation of an evidence-based guideline for nutrition therapy in critical illness could reduce mortality. Methods: We did a multicentre, cluster-randomised, parallel-controlled trial in 97 intensive care units (ICUs) throughout China. We developed an up-to-date, evidence-based nutrition guideline. ICUs randomly allocated to implement the guideline formed a local "intervention team", which actively implemented the guideline using standardized educational materials. ICUs assigned to the control group remained unaware of the guideline. All ICUs enroled critically ill patients who were expected to stay longer than seven days. The primary outcome was all-cause mortality within 28 days of enrolment . Findings Between March, 2018 and July, 2019, we enrolled 1,373 patients at 48 guideline ICUs and 1,399 patients at 49 control ICUs. Implementation of the nutrition guideline resulted in significantly earlier enteral nutrition (EN) initiation (1.20 vs. 1.55 mean days to initiation of EN; difference -0.40 [95% CI, -0.71 to -0.09]; P=0.01) and delayed parenteral nutrition (PN) initiation (1.29 vs. 0.80 mean days to start of PN; difference 1.06 [95% CI, 0.44 to 1.67]; P=0.001). There was no significant difference in 28-day mortality (14.2% vs. 15.2%; difference -1.6% [95% CI -4.3% to 1.2%]; p=0.42) between study groups. Interpretation: Active implementation of an evidence-based guideline can change practice. Our active implementation strategy improved the provision of nutrition therapy to critically ill patients. However, in our cRCT, this improvement in care did not translate to a reduction in mortality. We did not identify any safety concerns associated with the active implementation of our evidence-based guideline for nutrition therapy. Trial Registration: The study was registered in the ISRCTN registry before enrolment commenced (No. ISRCTN12233792). Funding Statement: The study was funded by the Key Research and Development Program Foundation of Jiangsu Province of China (no. BE2015685) and Nutricia, Wuxi, China. Declaration of Interests: Dr. GSD reported receiving academic research grants related to nutrition in critical illness from the Australian National Health and Medical Research Council, Fresenius Kabi Deutschland GmbH and Baxter Healthcare Pty Ltd and speakers honoraria from Fresenius Kabi Deutschland GmbH, Baxter Healthcare Australia, Pty Ltd, Nestle Healthcare, Vevy, Switzerland and Nutricia Pharmaceutical (Wuxi) Co., Ltd. China. Dr. AvZ reports personal fees from Baxter, personal fees from Nestle, personal fees from Fresenius Kabi, grants and personal fees from Nutricia, grants from Cardinal Health grants from Mermaid grants from Lyric, outside the submitted work. Dr. WqL reported receiving speakers honoraria from Nutricia Pharmaceutical (Wuxi) Co., Ltd. China. No other disclosures were reported. Ethics Approval Statement: The study was approved by the local hospital ethics committees of all the participating ICUs. At each site, informed consent was obtained from the patients or their next of kin before enrolment.

Inflammation and oxidative stress are critical pathologies that contribute to sepsis-induced acute lung injury (ALI). This study investigated the regulatory role of estrogen-related receptor alpha (ERRα) in an experimental model of sepsis-induced ALI. In vivo, a cecal ligation and puncture- (CLP-) induced ALI model was established in anesthetized rats. Animals were then randomly assigned to receive an intraperitoneal injection of vehicle or ERRα inverse agonist (XCT-790, 2.5 mg/kg). Administration of XCT-790 significantly aggravated a sepsis-induced increase in pathological damage of lung tissues, lung endothelial permeability, myeloperoxidase (MPO) activity in lung tissues, production of serum inflammatory factors, and inflammatory cell accumulation in bronchoalveolar lavage fluid. In addition, XCT-790 treatment exacerbated a CLP-induced decrease in lung superoxide dismutase and an increase in lung malondialdehyde levels. In vitro, the exposure of rat pulmonary microvascular endothelial cells (PMVECs) to lipopolysaccharide (LPS) resulted in increased endothelial permeability and reduced expression of tight junction protein ZO-1, Occludin, JAM-A, and adherens junction protein VE-cadherin, which were further deteriorated by knockdown of ERRα. In addition, LPS-triggered inflammatory factor production and increase in the expression of phosphorylated IκBα and NF-κB p65 were also exacerbated by silencing ERRα gene. Meanwhile, knockdown of ERRα dramatically promoted LPS-activated mitochondrial reactive oxygen species production and LPS-induced downregulation of Sirt3 protein levels in rat PMVECs. Taken together, our present study provides evidences that ERRα functions as a novel negative modulator of sepsis-induced ALI in rats. The underlying mechanisms responsible for ERRα-elicited effects are largely dependent on the regulation of inflammatory response and oxidative stress.

Background There is a lack of large-scale epidemiological data on the clinical practice of enteral nutrition (EN) feeding in China. This study aimed to provide such data on Chinese hospitals and to investigate factors associated with EN delivery. Methods This cross-sectional study was launched in 118 intensive care units (ICUs) of 116 mainland hospitals and conducted on April 26, 2017. At 00:00 on April 26, all patients in these ICUs were included. Demographic and clinical variables of patients on April 25 were obtained. The dates of hospitalization, ICU admission and nutrition initiation were reviewed. The outcome status 28 days after the day of investigation was obtained. Results A total of 1953 patients were included for analysis, including 1483 survivors and 312 nonsurvivors. The median study day was day 7 (IQR 2–19 days) after ICU entry. The proportions of subjects starting EN within 24, 48 and 72 h after ICU entry was 24.8% (84/352), 32.7% (150/459) and 40.0% (200/541), respectively. The proportion of subjects receiving > 80% estimated energy target within 24, 48, 72 h and 7 days after ICU entry was 10.5% (37/352), 10.9% (50/459), 11.8% (64/541) and 17.8% (162/910), respectively. Using acute gastrointestinal injury (AGI) 1 as the reference in a Cox model, patients with AGI 2–3 were associated with reduced likelihood of EN initiation (HR 0.46, 95% CI 0.353–0.599; p

Purpose: To investigate the role of vagus nerve activation in the protective effects of hypercapnia in ventilator-induced lung injury (VILI) rats. Methods: Male Sprague-Dawley rats were randomized to either high-tidal volume or low-tidal volume ventilation (control) and monitored for 4h. The high-tidal volume group was further divided into either a vagotomy or sham-operated group and each surgery group was further divided into two subgroups: normocapnia and hypercapnia. Injuries were assessed hourly through hemodynamics, respiratory mechanics and gas exchange. Protein concentration, cell count and cytokines (TNF-α and IL-8) in bronchoalveolar lavage fluid (BALF), lung wet-to-dry weight and pathological changes were examined. Vagus nerve activity was recorded for 1h. Results: Compared to the control group, injurious ventilation resulted in a decrease in PaO2/FiO2 and greater lung static compliance, MPO activity, enhanced BALF cytokines, protein concentration, cell count, and histology injury score. Conversely, hypercapnia significantly improved VILI by decreasing the above injury parameters. However, vagotomy abolished the protective effect of hypercapnia on VILI. In addition, hypercapnia enhanced efferent vagus nerve activity compared to normocapnia. Conclusion: These results indicate that the vagus nerve plays an important role in mediating the anti-inflammatory effect of hypercapnia on VILI.

We conducted a randomized controlled study on the neuroprotective effect of a commonly used anesthetic, etomidate, in an ischemia-reperfusion (IR) injury rabbit model.We studied 24 white adult Japanese rabbits at the animal facility at the Medical College of Wuhan University. Rabbits were randomly assigned into a sham-operation group (group I), an IR group (group II), and an etomidate-treated IR group (group III). Rabbits in groups II and III were subjected to 45 min of infrarenal aortic cross-clamping to induce spinal cord ischemia, while group I rabbits received the sham operation as a control. Following an initial single-dose intravenous injection at 0.6 mg/kg 10 min before aortic clamping, etomidate was infused intravenously at 3mg/(kg . hr) in group III rabbits until unclamping, while 0.9% saline was given as the control in group II.Changes in neurological function scores, histopathology, electromyography, malondialdehyde levels, superoxide dismutase activities, and the concentrations of Ca(2+), Mg(2+), Cu(2+), and Zn(2+) ions were measured. Compared with the sham-operation group, group II showed significant IR injury-associated changes in all parameters evaluated (p0.01), whereas these unfavorable changes were significantly reversed in etomidate-treated animals (p0.05 or p0.01). No significant differences were observed between group I and group III animals in all parameters.Etomidate displayed a potent neuroprotective effect against IR-induced spinal cord injuries. We propose that this effect may be associated with the ability of etomidate to enhance the activities of endogenous antioxidants and maintain the ion balance in IR-affected tissues.

Introduction Nous avons mene une etude randomisee controlee sur l’effet neuroprotecteur d’un anesthesique communement utilise, l’etomidate, sur un modele d’ischemie-reperfusion (IR) chez le lapin. Methodes Nous avons etudie 24 lapins japonais adultes a l’animalerie de la faculte de medecine de l’universite de Wuhan. Les lapins etaient assignes de maniere aleatoire entre un groupe intervention factice (groupe I), un groupe IR (groupe II), et un groupe IR traite par etomidate (groupe III). Les lapins des groupes II et III etaient soumis a un clampage aortique sous-renal de 45 minutes afin d’induire une ischemie medullaire, alors que les lapins du groupe I avaient une operation factice et constituaient le groupe controle. Apres une injection intraveineuse initiale de 0,6mg/kg 10 minutes avant le clampage aortique, de l’etomidate etait infuse en intraveineux a la dose de 3mg/(kg·hr) chez les lapins du groupe III jusqu’au declampage, alors qu’une solution salee a 0,9% etait administree en tant que controle dans le groupe II. Resultats Les modifications des scores fonctionnels neurologiques, de l’histopathologie, de l’electromyographie, des niveaux de malondialdehyde, de l’activite superoxyde dismutase, ainsi que les concentrations en ions Ca 2+ , Mg 2+ , Cu 2+ , et Zn 2+ etaient mesurees. En comparaison au groupe intervention factice, le groupe II presentait des modifications significatives associees a des lesions d’IR au niveau de l’ensemble des parametres mesures ( p p p Conclusion L’etomidate fournissait un effet neuroprotecteur puissant face aux lesions medullaires d’IR. Nous suggerons que cet effet pourrait etre associe a la capacite de l’etomidate a favoriser les activites des anti-oxydants endogenes et a maintenir la balance ionique des tissus affectes par l’IR.

Background High mortality rate of critically-ill patients could be induced by sepsis and septic shock, which is the extremely life threatening. The purpose of this work is to identify and evaluate the potential regulatory mechanism of LPS-induced inflammation associated with miR-6835 and lipid rafts in HUVECs. Methods The 3’ UTR luciferase activity of AdipoR1 was detected, which was predicted the potential target gene of miR-6835. Moreover, the treated HUVECs with or without inhibitors or mimics of miR-6835 were used. Furthermore, the bio-functions of HUVECs were explored. The protein expression levels of SIRT-1, AMPK, and AdipoR1 were assessed, which were involved in the AdipoR1 signaling pathway. Then, the interaction between TLR-4 and AdipoR1 in lipid rafts and its mediation role on LPS-induced inflammation was investigated in HUVECs. Results MiR-6835 targeted directly on AdipoR1, and suppressed its expression in mRNA (mimics of miR-6835: 0.731±0.016 vs control: 1.527±0.015, P

Sepsis is a major cause of acute kidney injury (AKI) with high rates of morbidity and mortality. Surfactant proteins A and D (SP-A, SP-D) play a critical role in host defense and regulate inflammation during infection. Recent studies indicate SP-A and SP-D are expressed in the kidney. The current study examines the role of SP-A and SP-D in the pathogenesis of sepsis-induced AKI. Wild-type (WT) and SP-A/SP-D double-knockout (KO) C57BL/6 mice were treated by cecal ligation and puncture (CLP) or sham surgery. Histological, cellular, and molecular indices of kidney injury were investigated in septic mice 6 and 24 h after CLP. Twenty-four hours after CLP, kidney injury was more severe, renal function was decreased, and blood creatinine and blood urea nitrogen were higher in septic SP-A/SP-D KO mice (P < 0.05, versus septic WT mice). Kidney edema and vascular permeability were increased in septic SP-A/SP-D KO mice (P < 0.01, versus septic WT mice). Apoptotic cells increased significantly (P < 0.01) in the kidney of septic SP-A/SP-D KO mice compared with septic WT mice. Molecular analysis revealed levels of Bcl-2 (an inhibitor of apoptosis) were lower and levels of caspase 3 (a biomarker of apoptosis) were higher in the kidney of septic SP-A/SP-D KO mice (P < 0.01, versus septic WT mice). Furthermore, levels of nuclear factor κB and phosphorylated IκB-α increased significantly in the kidney of septic SP-A/SP-D KO mice compared with septic WT mice, suggesting SP-A/SP-D KO mice have a more pronounced inflammatory response to sepsis. We conclude SP-A and SP-D attenuate kidney injury by modulating inflammation and apoptosis in sepsis-induced AKI.

The aim of this study was to investigate the effect of propofol and its relation to postoperation recovery in children undergoing cardiac surgery with cardiopulmonary bypass (CPB). Twenty ASA class I–II children with congenital heart disease undergoing cardiac surgery were randomly allocated to a propofol group (n = 10) or a control group (n = 10). Blood samples were collected at five time points: before operation (T 0), before the start of CPB (T 1), 25 min after the aorta was cross-clamped (T 2), 30 min after release of the aortic cross-clamp (T 3), and 2 h after the cessation of CPB (T 4). The myocardial samples were collected at the time of incubation into the right atrium before CPB and at 30 min after reperfusion. After CPB, propofol significantly suppressed the increase of the serum lactate dehydrogenase (LDH), creatine phosphokinase (CK), and interleukin-6 (IL-6) levels and the decrease of the serum superoxide dismutase (SOD) level. In addition, propofol inhibited the increase of myocardial nuclear factor-κB (NF-κB) expression and inflammatory cells infiltration after CPB. Furthermore, propofol significantly shortened the tracheal extubation time. In conclusion, propofol exerts a protective effect and improves postoperation recovery through its antioxidant and anti-inflammatory actions in children undergoing cardiac surgery with CPB.

Purpose To investigate and compare the effects of propofol and midazolam on inflammation and oxidase stress in children with congenital heart disease undergoing cardiac surgery. Materials and Methods Thirty-two ASA class I-II children with congenital heart disease undergoing cardiac surgery were randomly divided into two groups: propofol combined with low dose fentanyl (PF group, n = 16) and midazolam combined with low dose fentanyl (MF group, n = 16). Tracheal extubation time and length of Intensive Care Unit (ICU) stay were recorded. Blood samples were taken before operation (T0), at 2 h after release of the aorta cross-clamp (T3) and at 24 h after operation (T4) to measure interleukin 6 (IL-6), IL-8, superoxide dismutase (SOD) and malondialdehyde (MDA) levels. Myocardium samples were collected at 10-20 min after aorta cross-clamp (T1) and at 10-20 min after the release of the aorta cross-clamp (T2) to detect heme oxygenase-1 (HO-1) expression. Results Tracheal extubation time and length of ICU stay in PF group were significantly shorter than those of the MF group (p < 0.05, respectively). After cardiopulmonary bypass, IL-6, IL-8 and MDA levels were significantly increased, and the SOD level was significantly reduced in both two groups, but PF group exhibited lower IL-6, IL-8 and MDA levels and higher SOD levels than the MF group (p < 0.05, respectively). The HO-1 expression in the PF group was significantly higher than that in MF group at the corresponding time points (p < 0.05, respectively). Conclusion Propofol is superior to midazolam in reducing inflammation and oxidase stress and in improving post-operation recovery in children with congenital heart disease undergoing cardiac surgery.

Background Injury to the kidney epithelial barrier is a characteristic feature of acute kidney injury (AKI). Serum surfactant protein-D (SP-D), a known biomarker of damaged alveolar epithelium, is also secreted by renal tubular epithelial cells. Therefore, the aim of this study was to examine the possible association of SP-D with AKI susceptibility and prognosis. Methods In this study, 159 AKI patients and 120 healthy individuals were included. SP-D polymorphisms Thr11Met and Thr160Ala, AKI patient serum SP-D levels at days 1, 3 and 7 and urine KIM-1 levels in both AKI patients and controls were examined. The obtained results were correlated with the AKI stage, duration of renal replacement therapy (RRT) and prognosis. Results Serum SP-D level in AKI patients was higher than controls (p

Background Surfactant protein A (SP-A), encoded by two functional genes, SP-A1 and SP-A2, is essential for the inflammatory process and host defence in the lungs. Recent studies have demonstrated the extrapulmonary expression of SP-A. Similar to the lungs, the kidneys are organs exposed to external pathogens. The present study evaluated the expression and location of SP-A in the kidneys. The effect of lipopolysaccharide (LPS) on the expression of SP-A subtypes was also studied in renal tubular epithelial (HK-2) cells. Methods Immunohistochemical staining was performed using polyclonal antibody against SP-A. RT-PCR was also performed using mRNA from normal human renal tissues and HK-2 cells. The expressions of the SP-A1 and SP-A2 genes were determined by PCR-based RFLP analysis, gene-specific amplification, and direct sequencing of RT-PCR products. Western blot was conducted to analyse the SP-A protein. HK-2 cells were treated with LPS at various concentrations (0, 0.1, 1, 2, 5, and 10 μg/mL) for 8 h and at 5 μg/mL at various time points (0, 2, 4, 8, 16, and 24 h). The LPS-induced expressions of SP-A1 and SP-A2 mRNA and protein were analysed by RT-PCR and Western blot. Results SP-A was localised in the renal tubular epithelial cells in the proximal and distal convoluted tubules. SP-A1 and SP-A2 mRNA and protein were expressed in HK-2 cells and human renal tissues, which were significantly increased in time- and dose-dependent manners after LPS treatment (P Conclusions Human renal tubular epithelial cells can express both SP-A1 and SP-A2 genes, which may play important roles in the inflammatory modulation of the kidney.