Protective mechanism of quercetin in alleviating sepsis-related acute respiratory distress syndrome based on network pharmacology and in vitro experiments

BACKGROUND:Sepsis-related acute respiratory distress syndrome(ARDS)has a high mortality rate,and no effective treatment is available currently.Quercetin is a natural plant product with many pharmacological activities,such as antioxidative,anti-apoptotic,and anti-inflammatory effects.This study aimed to elucidate the protective mechanism of quercetin against sepsis-related ARDS.METHODS:In this study,network pharmacology and in vitro experiments were used to investigate the underlying mechanisms of quercetin against sepsis-related ARDS.Core targets and signaling pathways of quercetin against sepsis-related ARDS were screened and were verified by in vitro experiments.RESULTS:A total of 4,230 targets of quercetin,360 disease targets of sepsis-related ARDS,and 211 intersection targets were obtained via database screening.Among the 211 intersection targets,interleukin-6(IL-6),tumor necrosis factor(TNF),albumin(ALB),AKT serine/threonine kinase 1(AKT1),and interleukin-1β(IL-1β)were identified as the core targets.A Gene Ontology(GO)enrichment analysis revealed 894 genes involved in the inflammatory response,apoptosis regulation,and response to hypoxia.Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analysis identified 106 pathways.After eliminating and generalizing,the hypoxia-inducible factor-1(HIF-1),TNF,nuclear factor-κB(NF-κB),and nucleotide-binding and oligomerization domain(NOD)-like receptor signaling pathways were identified.Molecular docking revealed that quercetin had good binding activity with the core targets.Moreover,quercetin blocked the HIF-1,TNF,NF-κB,and NODlike receptor signaling pathways in lipopolysaccharide(LPS)-induced murine alveolar macrophage(MH-S)cells.It also suppressed the inflammatory response,oxidative reactions,and cell apoptosis.CONCLUSION:Quercetin ameliorates sepsis-related ARDS by binding to its core targets and blocking the HIF-1,TNF,NF-κB,and NOD-like receptor signaling pathways to reduce inflammation,cell apoptosis,and oxidative stress.

Outcomes of combined mitochondria and mesenchymal stem cellsderived exosome therapy in rat acute respiratory distress syndrome and sepsis

BACKGROUND The treatment of acute respiratory distress syndrome(ARDS)complicated by sepsis syndrome(SS)remains challenging.AIM To investigate whether combined adipose-derived mesenchymal-stem-cells(ADMSCs)-derived exosome(EXAD)and exogenous mitochondria(mitoEx)protect the lung from ARDS complicated by SS.METHODS In vitro study,including L2 cells treated with lipopolysaccharide(LPS)and in vivo study including male-adult-SD rats categorized into groups 1(sham-operated-control),2(ARDS-SS),3(ARDS-SS+EXAD),4(ARDS-SS+mitoEx),and 5(ARDS-SS+EXAD+mitoEx),were included in the present study.RESULTS In vitro study showed an abundance of mitoEx found in recipient-L2 cells,resulting in significantly higher mitochondrial-cytochrome-C,adenosine triphosphate and relative mitochondrial DNA levels(P<0.001).The protein levels of inflammation[interleukin(IL)-1β/tumor necrosis factor(TNF)-α/nuclear factor-κB/toll-like receptor(TLR)-4/matrix-metalloproteinase(MMP)-9/oxidative-stress(NOX-1/NOX-2)/apoptosis(cleaved-caspase3/cleaved-poly(ADP-ribose)polymerase)]were significantly attenuated in lipopolysaccharide(LPS)-treated L2 cells with EXAD treatment than without EXAD treatment,whereas the protein expressions of cellular junctions[occluding/β-catenin/zonula occludens(ZO)-1/E-cadherin]exhibited an opposite pattern of inflam-mation(all P<0.001).Animals were euthanized by 72 h post-48 h-ARDS induction,and lung tissues were harvested.By 72 h,flow cytometric analysis of bronchoalveolar lavage fluid demonstrated that the levels of inflam-matory cells(Ly6G+/CD14+/CD68+/CD11b/c+/myeloperoxidase+)and albumin were lowest in group 1,highest in group 2,and significantly higher in groups 3 and 4 than in group 5(all P<0.0001),whereas arterial oxygen-saturation(SaO2%)displayed an opposite pattern of albumin among the groups.Histopathological findings of lung injury/fibrosis area and inflammatory/DNA-damaged markers(CD68+/γ-H2AX)displayed an identical pattern of SaO2%among the groups(all P<0.0001).The protein expressions of inflammatory(TLR-4/MMP-9/IL-1β/TNF-α)/oxidative stress(NOX-1/NOX-2/p22phox/oxidized protein)/mitochondrial-damaged(cytosolic-cytochrome-C/dynamin-related protein 1)/autophagic(beclin-1/Atg-5/ratio of LC3B-II/LC3B-I)biomarkers exhibited a similar manner,whereas antioxidants[nuclear respiratory factor(Nrf)-1/Nrf-2]/cellular junctions(ZO-1/E-cadherin)/mitochondrial electron transport chain(complex I-V)exhibited an opposite manner of albumin among the groups(all P<0.0001).CONCLUSION Combined EXAD-mitoEx therapy was better than merely one for protecting the lung against ARDS-SS induced injury.

Relationship between neonatal respiratory distress syndrome pulmonary ultrasonography and respiratory distress score,oxygenation index,and chest radiography grading

BACKGROUND Accurate condition assessment is critical for improving the prognosis of neonatal respiratory distress syndrome(RDS),but current assessment methods for RDS pose a cumulative risk of harm to neonates.Thus,a less harmful method for assessing the health of neonates with RDS is needed.AIM To analyze the relationships between pulmonary ultrasonography and respiratory distress scores,oxygenation index,and chest X-ray grade of neonatal RDS to identify predictors of neonatal RDS severity.METHODS This retrospective study analyzed the medical information of 73 neonates with RDS admitted to the neonatal intensive care unit of Liupanshui Maternal and Child Care Service Center between April and December 2022.The pulmonary ultrasonography score,respiratory distress score,oxygenation index,and chest Xray grade of each newborn before and after treatment were collected.Spearman correlation analysis was performed to determine the relationships among these values and neonatal RDS severity.RESULTS The pulmonary ultrasonography score,respiratory distress score,oxygenation index,and chest X-ray RDS grade of the neonates were significantly lower after treatment than before treatment(P<0.05).Spearman correlation analysis showed that before and after treatment,the pulmonary ultrasonography score of neonates with RDS was positively correlated with the respiratory distress score,oxygenation index,and chest X-ray grade(ρ=0.429–0.859,P<0.05).Receiver operating characteristic curve analysis indicated that pulmonary ultrasonography screening effectively predicted the severity of neonatal RDS(area under the curve=0.805–1.000,P<0.05).CONCLUSION The pulmonary ultrasonography score was significantly associated with the neonatal RDS score,oxygenation index,and chest X-ray grade.The pulmonary ultrasonography score was an effective predictor of neonatal RDS severity.

Clinical significance of platelet mononuclear cell aggregates in patients with sepsis and acute respiratory distress syndrome

BACKGROUND The diagnosis of sepsis combined with acute respiratory distress syndrome(ARDS)has increased owing to the enhanced awareness among medical profes-sionals and the continuous development of modern medical technologies,while early diagnosis of ARDS still lacks specific biomarkers.One of the main patho-genic mechanisms of sepsis-associated ARDS involves the actions of various pathological injuries and inflammatory factors,such as platelet and white blood cells activation,leading to an increase of surface adhesion molecules.These adhesion molecules further form platelet-white blood cell aggregates,including platelet-mononuclear cell aggregates(PMAs).PMAs has been identified as one of the markers of platelet activation,here we hypothesize that PMAs might play a potential biomarker for the early diagnosis of this complication.METHODS We selected 72 hospitalized patients diagnosed with sepsis as the study population between March 2019 and March 2022.Among them,30 patients with sepsis and ARDS formed the study group,while 42 sepsis patients without ARDS comprised the control group.After diagnosis,venous blood samples were imme-diately collected from all patients.Flow cytometry was employed to analyze the expression of PMAs,platelet neutrophil aggregates(PNAs),and platelet aggregates(PLyAs)in the serum.Additionally,the Acute Physiology and Chronic Health Evaluation(APACHE)II score was calculated for each patient,and receiver operating characteristic curves were generated to assess diagnostic value.RESULTS The study found that the levels of PNAs and PLyAs in the serum of the study group were higher than those in the control group,but the difference was not statistically significant(P>0.05).However,the expression of PMAs in the serum of the study group was significantly upregulated(P<0.05)and positively correlated with the APACHE II score(r=0.671,P<0.05).When using PMAs as a diagnostic indicator,the area under the curve value was 0.957,indicating a high diagnostic value(P<0.05).Furthermore,the optimal cutoff value was 8.418%,with a diagnostic sensitivity of 0.819 and specificity of 0.947.CONCLUSION In summary,the serum levels of PMAs significantly increase in patients with sepsis and ARDS.Therefore,serum PMAs have the potential to become a new biomarker for clinically diagnosing sepsis complicated by ARDS.

Effects of pulmonary surfactant combined with noninvasive positive pressure ventilation in neonates with respiratory distress syndrome

BACKGROUND Neonatal respiratory distress syndrome(NRDS)is one of the most common diseases in neonatal intensive care units,with an incidence rate of about 7%among infants.Additionally,it is a leading cause of neonatal death in hospitals in China.The main mechanism of the disease is hypoxemia and hypercapnia caused by lack of surfactant AIM To explore the effect of pulmonary surfactant(PS)combined with noninvasive positive pressure ventilation on keratin-14(KRT-14)and endothelin-1(ET-1)levels in peripheral blood and the effectiveness in treating NRDS.METHODS Altogether 137 neonates with respiratory distress syndrome treated in our hospital from April 2019 to July 2021 were included.Of these,64 control cases were treated with noninvasive positive pressure ventilation and 73 observation cases were treated with PS combined with noninvasive positive pressure ventilation.The expression of KRT-14 and ET-1 in the two groups was compared.The deaths,complications,and PaO_(2),PaCO_(2),and PaO_(2)/FiO_(2)blood gas indexes in the two groups were compared.Receiver operating characteristic curve(ROC)analysis was used to determine the diagnostic value of KRT-14 and ET-1 in the treatment of NRDS.RESULTS The observation group had a significantly higher effectiveness rate than the control group.There was no significant difference between the two groups in terms of neonatal mortality and adverse reactions,such as bronchial dysplasia,cyanosis,and shortness of breath.After treatment,the levels of PaO_(2)and PaO_(2)/FiO_(2)in both groups were significantly higher than before treatment,while the level of PaCO_(2)was significantly lower.After treatment,the observation group had significantly higher levels of PaO_(2)and PaO_(2)/FiO_(2)than the control group,while PaCO_(2)was notably lower in the observation group.After treatment,the KRT-14 and ET-1 levels in both groups were significantly decreased compared with the pre-treatment levels.The observation group had a reduction of KRT-14 and ET-1 levels than the control group.ROC curve analysis showed that the area under the curve(AUC)of KRT-14 was 0.791,and the AUC of ET-1 was 0.816.CONCLUSION Combining PS with noninvasive positive pressure ventilation significantly improved the effectiveness of NRDS therapy.KRT-14 and ET-1 levels may have potential as therapeutic and diagnostic indicators.

Microvesicles derived from mesenchymal stem cells inhibit acute respiratory distress syndrome-related pulmonary fibrosis in mouse partly through hepatocyte growth factor

BACKGROUND Pulmonary fibrosis is one of the main reasons for the high mortality rate among acute respiratory distress syndrome(ARDS)patients.Mesenchymal stromal cell-derived microvesicles(MSC-MVs)have been shown to exert antifibrotic effects in lung diseases.AIM To investigate the effects and mechanisms of MSC-MVs on pulmonary fibrosis in ARDS mouse models.METHODS MSC-MVs with low hepatocyte growth factor(HGF)expression(siHGF-MSC-MVs)were obtained via lentivirus transfection and used to establish the ARDS pulmonary fibrosis mouse model.Following intubation,respiratory mechanics-related indicators were measured via an experimental small animal lung function tester.Homing of MSC-MVs in lung tissues was investigated by near-infrared live imaging.Immunohistochemical,western blotting,ELISA and other methods were used to detect expression of pulmonary fibrosis-related proteins and to compare effects on pulmonary fibrosis and fibrosis-related indicators.RESULTS The MSC-MVs gradually migrated and homed to damaged lung tissues in the ARDS model mice.Treatment with MSC-MVs significantly reduced lung injury and pulmonary fibrosis scores.However,low expression of HGF(siHGF-MSC-MVs)significantly inhibited the effects of MSC-MVs(P<0.05).Compared with the ARDS pulmonary fibrosis group,the MSC-MVs group exhibited suppressed expression of type I collagen antigen,type III collagen antigen,and the proteins transforming growth factor-βandα-smooth muscle actin,whereas the siHGF-MVs group exhibited significantly increased expression of these proteins.In addition,pulmonary compliance and the pressure of oxygen/oxygen inhalation ratio were significantly lower in the MSC-MVs group,and the effects of the MSC-MVs were significantly inhibited by low HGF expression(all P<0.05).CONCLUSION MSC-MVs improved lung ventilation functions and inhibited pulmonary fibrosis in ARDS mice partly via HGF mRNA transfer.

Outpatient insulin use in type 2 diabetes mellitus and acute respiratory distress syndrome outcomes:A retrospective cohort study

BACKGROUND The impact of type 2 diabetes mellitus(T2DM)on acute respiratory distress syndrome(ARDS)is debatable.T2DM was suspected to reduce the risk and complications of ARDS.However,during coronavirus disease 2019(COVID-19),T2DM predisposed patients to ARDS,especially those who were on insulin at home.AIMTo evaluate the impact of outpatient insulin use in T2DM patients on non-COVID-19 ARDS outcomes.METHODS We conducted a retrospective cohort analysis using the Nationwide Inpatient Sample database.Adult patients diagnosed with ARDS were stratified into insulin-dependent diabetes mellitus(DM)(IDDM)and non-insulindependent DM(NIDDM)groups.After applying exclusion criteria and matching over 20 variables,we compared cohorts for mortality,duration of mechanical ventilation,incidence of acute kidney injury(AKI),length of stay(LOS),hospitalization costs,and other clinical outcomes.RESULTS Following 1:1 propensity score matching,the analysis included 274 patients in each group.Notably,no statistically significant differences emerged between the IDDM and NIDDM groups in terms of mortality rates(32.8%vs 31.0%,P=0.520),median hospital LOS(10 d,P=0.537),requirement for mechanical ventilation,incidence rates of sepsis,pneumonia or AKI,median total hospitalization costs,or patient disposition upon discharge.CONCLUSION Compared to alternative anti-diabetic medications,outpatient insulin treatment does not appear to exert an independent influence on in-hospital morbidity or mortality in diabetic patients with non-COVID-19 ARDS.

A Comparison between Late Preterm and Term Infants with Respiratory Distress Syndrome, Early-Onset Sepsis, and Neonatal Jaundice in Ecuadorian Newborns

Background: To examine the differences in prevalence of respiratory distress syndrome, early-onset sepsis and jaundice, between late preterm infants versus term infants in Ecuadorian newborns. Methods: Study design: Epidemiological, observational, and cross-sectional, with two cohorts of patients. Settings: IESS Quito Sur Hospital at Quito, Ecuador, from February to April of 2020. Participants: This study included 204 newborns, 102 preterm infants, 102 term infants. Results: There are significant differences between late preterm infants and term infants, with a p-value of 0.000 in the prevalence of early sepsis, 70.59% vs. 35.29%. In respiratory distress syndrome between late and term premature infants, significant differences were observed with a p-value of 0.000, the proportion being 55.58% vs. 24.51% respectively. The prevalence of jaundice is higher in term infants with a p value of 0.002, 72.55%, versus 51.96% in late preterm infants, and the mean value of bilirubins in mg/dL was higher in term infants 14.32 versus 12.33 in late preterm infants;this difference is statistically significant with a p value of 0.004. Admission to the NICU is more frequent in late preterm infants with a p-value of 0.000, being 42.16% for late preterm infants vs. 7.84% in term infants;the mean of the hospital days with p-value 0.005, was higher in late preterm infants 4.97 days vs. 3.55 days for term newborns. Conclusion: Due to the conditions of their immaturity, late preterm infants are 2.86 times more likely to present early sepsis than full-term newborns. It is shown that late preterm infants are 2.69 times more likely to have respiratory distress syndrome compared to term infants, therefore, late preterm infants have a longer hospital stay of 4.97 days versus 3.55 days in term infants. Jaundice and mean bilirubin levels are higher in term infants due to blood group incompatibility and insufficient breastfeeding.

Mechanisms and Research Progress of Traditional Chinese Medicine Regulating NF-κB in the Treatment of Acute Lung Injury/Acute Respiratory Distress Syndrome

Acute lung injury(ALI)has multiple causes and can easily progress to acute respiratory distress syndrome(ARDS)if not properly treated.Nuclear factorκB(NF-κB)is a key pathway in the treatment of ALI/ARDS.By exploring the relevance of NF-κB and the pathogenesis of this disease,it was found that this disease was mainly associated with inflammation,dysfunction of the endothelial barrier,oxidative stress,impaired clearance of alveolar fluid,and coagulation disorders.Traditional Chinese medicine(TCM)has the characteristics of multitargeting,multipathway effects,and high safety,which can directly or indirectly affect the treatment of ALI/ARDS.This article summarizes the mechanism and treatment strategies of TCM in recent years through intervention in the NF-κB-related signaling pathways for treating ALI/ARDS.It provides an overview from the perspectives of Chinese herbal monomers,TCM couplet medicines,TCM injections,Chinese herbal compounds,and Chinese herbal preparations,offering insights into the prevention and treatment of ALI/ARDS with TCM.

Steroids in acute respiratory distress syndrome:A panacea or still a puzzle?

Acute respiratory distress syndrome(ARDS)is a unique entity marked by various etiologies and heterogenous pathophysiologies.There remain concerns regarding the efficacy of particular medications for each severity level apart from respiratory support.Among several pharmacotherapies which have been examined in the treatment of ARDS,corticosteroids,in particular,have demonstrated potential for improving the resolution of ARDS.Nevertheless,it is imperative to consider the potential adverse effects of hyperglycemia,susceptibility to hospital-acquired infections,and the development of intensive care unit acquired weakness when administering corticosteroids.Thus far,a multitude of trials spanning several decades have investigated the role of corticosteroids in ARDS.Further stringent trials are necessary to identify particular subgroups before implementing corticosteroids more widely in the treatment of ARDS.This review article provides a concise overview of the most recent evidence regarding the role and impact of corticosteroids in the management of ARDS.

Studies on monitoring hemodynamics and oxygen dynamics of adult respiratory distress syndrome secondary to high altitude pulmonary edema

To study monitoring hemodynamics and oxygen dynamics of adult respiratory distress syndrome (ARDS) secondary to high altitude pulmonary edema (HAPE),we performed clinic and laboratory studies in 8 patients who preliminarily developed high altitude cerebral edema (HACE) and then ARDS occurred at an altitude of 4 500 m. After an initial emergency treatment on high mountains,all the patients were rapidly transported to a hospital at a lower altitude of 2 808 m. The right cardiac catheterizations were carried out within 5 h after hospitalized. The monitoring hemodynamics and oxygen dynamics were studied via a thermodilution Swan-Gaze catheter. The results showed that before treatments at the beginning of monitoring,there presented a significant pulmonary artery hypertension with a decreased cardiac function,and a lower oxygen metabolism in all the 8 patients. However,after some effective treatments,including mechanical ventilation and using dexamethasone,furosemide,etc,four days later the result of a repeated monitoring showed that their pulmonary artery pressure had been decreased with an improved cardiac function with all the oxygen metabolic indexes increased significantly. Our studies suggested that performing monitoring hemodynamics in patients with ARDS secondary to HAPE will define the clinical therapeutic measures which will benefit the outcome.

Study on acid-base disorders in patients with adult respiratory distress syndrome

Arterial blood gases and electrolytes were determined in 159 cases of adult respirato-ry distress syndrome(ARDS).It was found that disordered acid-base balance was a commonfinding in various kinds of ARDS.In mild ARDS,respiratory alkalosis and the combination ofrespiratory alkalosis plus metabolic alkalosis or metabolic acidosis were usually encounted,whilein moderate and severe cases of ARDS,triple acid-base disorders,respiratory acidosis,and thecombination of respiratory acidosis plus metabolic acidosis were commonly seen.Severe alkalosiswas one of the factors to result in death.

Review:Acute lung injury/acute respiratory distress syndrome (ALI/ARDS): the mechanism,present strategies and future perspectives of therapies

Acute lung injury/acute respiratory distress syndrome （ALI/ARDS）, which manifests as non-cardiogcnic pulmonary edema, respiratory distress and hypoxemia, could be resulted from various processes that directly or indirectly injure the lung. Extensive investigations in experimental models and humans with ALI/ARDS have revealed many molecular mechanisms that offer therapeutic opportunities for cell or gene therapy. Herein the present strategies and future perspectives of the treatment for ALI/ARDS, include the ventilatory, pharmacological, as well as cell therapies.

Early Intratracheal Administration of Corticosteroid and Pulmonary Surfactant for Preventing Bronchopulmonary Dysplasia in Preterm Infants with Neonatal Respiratory Distress Syndrome: A Meta-analysis

There is uncertain result with regard to the use of inhalation or instillation steroids to prevent bronchopulmonary dysplasia in preterm infants. This meta-analysis was designed to evaluate the efficacy and safety of early airway administration (within 2 days after birth) of corticosteroids and pulmonary surfactant (PS) for preventing bronchopulmonary dysplasia (BPD) in premature infants with neonatal respiratory distress syndrome (NRDS). The related studies were retrieved in PubMed, EMBASE, the Cochrane Library, Clinical Trial, CNKI, Wanfang and VIP Database from inception to August 2018. Two reviewers independently screened the studies to ensure that all patients with diagnosis of NRDS were enrolled to studies within 1 day after birth, assessed the quality of included studies by GRADEpro system and extracted the data for review. The meta-analysis was performed by RevMan 5.2 software. A subgroup analysis about inhaled corticosteroid (ICS) delivery method was made between ICS inhalation subgroup [inhalation of ICS by nebulizer or metered dose inhaler (MDI)] and ICS intratracheal instillation subgroup (PS used as a vehicle). Eight randomized controlled trials were enrolled in the meta-analysis, 5 trials of which stated the randomized method, grouping and blinded method, and the follow-up procedures were reported. GRADEpro system showed high quality of 4 trials (5 articles), and the rest 4 trials had moderate quality. Meta-analysis showed that the incidence of BPD was decreased in ICS group, the relative risk (RR) was 0.56 (95% CI: 0.42-0.76), and similar trends were found in ICS inhalation subgroup and ICS intratracheal instillation subgroup, with the corresponding RR being 0.58 (95% CI: 0.41-0.82) and 0.47 (95% CI: 0.24-0.95) respectively. ICS could also significantly reduce the mortality risk as compared with placebo control group (RR: 0.67;95% CI: 0.45-0.99), with RR of ICS inhalation subgroup and ICS intratracheal instillation subgroup being 0.81 (95% CI: 0.34-1.94) and 0.64 (95% CI: 0.41-0.99) respectively. Moreover, the percentage of infants using PS more than one time was lower in ICS group than in the placebo control group, with the RR and 95% CI being 0.55 (95% CI: 0.45-0.67), and that in ICS intratracheal instillation subgroup lower than in ICS inhalation subgroup (RR: 0.56;95% CI: 0.45-0.69, and RR: 0.35;95% CI:0.08-1.52 respectively). There was no significant difference in the incidence of infection or retinopathy of prematurity and neuro-motor system impairment between ICS group and placebo control group, with the corresponding RR being 0.95 (95% CI:0.59-1.52), 0.92 (95% CI: 0.62-1.38) and 1.13 (95% CI: 0.92-1.39), respectively. It was concluded that early administration of ICS and PS is an effective and safe option for preterm infants with NRDS in preventing BPD and reducing mortality, decreasing the additional PS usage, especially for the ICS intratracheal instillation subgroup. Furthermore, the appropriate dose and duration of ICS, combined use of inhalation or instillation of ICS with PS and the long-term safety of airway administration of corticosteroids need to be assessed in large trials.

Ulinastatin for acute lung injury and acute respiratory distress syndrome: A systematic review and meta-analysis

AIM: To investigate the efficacy and safety of ulinastatin for patients with acute lung injury(ALI) and those with acute respiratory distress syndrome(ARDS).METHODS: A systematic review of randomized controlled trials(RCTs) of ulinastatin for ALI/ARDS was conducted. Oxygenation index, mortality rate [intensive care unit(ICU) mortality rate, 28-d mortality rate] and length of ICU stay were compared between ulinastatin group and conventional therapy group. Meta-analysis was performed by using Rev Man 5.1.RESULTS: Twenty-nine RCTs with 1726 participants were totally included, the basic conditions of which were similar. No studies discussed adverse effect. Oxygenation index was reported in twenty-six studies(1552 patients). Ulinastatin had a significant effect in improving oxygenation [standard mean difference(SMD) = 1.85, 95%CI: 1.42-2.29, P < 0.00001, I2 = 92%]. ICUmortality and 28-d mortality were respectively reported in eighteen studies(987 patients) and three studies(196 patients). We found that ulinastatin significantly decreased the ICU mortality [I2 = 0%, RR = 0.48, 95%CI: 0.38-0.59, number needed to treat(NNT) = 5.06, P < 0.00001], while the 28-d mortality was not significantly affected(I2 = 0%, RR = 0.78, 95%CI: 0.51-1.19, NNT = 12.66, P = 0.24). The length of ICU stay(six studies, 364 patients) in the ulinastatin group was significantly lower than that in the control group(SMD =-0.97, 95%CI:-1.20--0.75, P < 0.00001, I2 = 86%). CONCLUSION: Ulinastatin seems to be effective for ALI and ARDS though most trials included were of poor quality and no information on safety was provided.

Efficacy of prone position in acute respiratory distress syndrome patients: A pathophysiology-based review

Acute respiratory distress syndrome(ARDS) is a syndrome with heterogeneous underlying pathological processes. It represents a common clinical problem in intensive care unit patients and it is characterized by high mortality. The mainstay of treatment for ARDS is lung protective ventilation with low tidal volumes and positive end-expiratory pressure sufficient for alveolar recruitment. Prone positioning is a supplementary strategy available in managing patients with ARDS. It was first described 40 years ago and it proves to be in alignment with two major ARDS pathophysiological lung models; the "sponge lung"- and the "shape matching"-model. Current evidence strongly supports that prone positioning has beneficial effects on gas exchange, respiratory mechanics, lung protection and hemodynamics as it redistributes transpulmonary pressure, stress and strain throughout the lung and unloads the right ventricle. The factors that individually influence the time course of alveolar recruitment and the improvement in oxygenation during prone positioning have not been well characterized. Although patients' response to prone positioning is quite variable and hard to predict, large randomized trials and recent meta-analyses show that prone position in conjunction with a lung-protective strategy, when performed early and in sufficient duration, may improve survival in patients with ARDS. This pathophysiology-based review and recent clinical evidence strongly support the use of prone positioning in the early management of severe ARDS systematically and not as a rescue maneuver or a last-ditch effort.

Effects of Different Surfactant Administrations on Cerebral Autoregulation in Preterm Infants with Respiratory Distress Syndrome

To treat respiratory distress syndrome,surfactant is currently delivered via less invasive surfactant administration（LISA） or INtubation SURfactant Extubation（INSURE）.The aim of this study was to compare the effect of the two delivery methods of surfactant on cerebral autoregulation.Near infrared spectroscopy monitoring was carried out to detect cerebral oxygen saturation（Sc O2）,and the mean arterial blood pressure（MABP） was simultaneously recorded.Of 44 preterm infants included,the surfactant was administrated to 22 via LISA and 22 via INSURE.The clinical characteristics,treatments and outcomes of the infants showed no significant differences between the two groups.The correlation coefficient of Sc O2 and MABP（rSc O2-MABP） 5 min before administration was similar in the two groups.During surfactant administration,rSc O2-MABP increased in both groups（0.44±0.10 to 0.54±0.12 in LISA,0.45±0.11 to 0.69±0.09 in INSURE）.In the first and second 5 min after instillation,rSc O2-MABP was not significantly different from baseline in the LISA group,but increased in the first 5 min after instillation（0.59±0.13,P=0.000 compared with the baseline in the same group） and recovered in the second 5 min after instillation（0.48±0.10,P=0.321） in the INSURE group.There were significant differences in the change rates of rSc O2-MABP between the two groups during and after surfactant administration.Our results suggest that cerebral autoregulation may be affected transiently by surfactant administration.The effect duration of LISA is shorter than that of INSURE（〈5 min in LISA vs.5–10 min in INSURE）.

Effects of fluid balance on prognosis of acute respiratory distress syndrome patients secondary to sepsis

BACKGROUND:Fluid management is crucial to acute respiratory distress syndrome(ARDS)secondary to sepsis.However,choices of fluid resuscitation strategies and fluid input volumes remain a thorny problem.Our study aimed to elucidate the relationship between fluid balance and prognosis of ARDS patients secondary to sepsis.METHODS:Our study included 322 sepsis patients from Ruijin Hospital between 2014 and 2018,and 84 patients were diagnosed as ARDS within 72 hours after onset of sepsis according to Berlin ARDS Defi nition.RESULTS:Among the 322 sepsis patients,84(26.1%)were complicated with ARDS within 72 hours.ARDS patients had a lower oxygenation index(PaO2/FiO2166.4±71.0 vs.255.0±91.2,P<0.05),longer duration of mechanical ventilation(11[6-24]days vs.0[0-0]days,P<0.05)than those without ARDS.Sepsis patients with ARDS showed daily positive net fl uid balance during seven days compared with those without ARDS who showed daily negative net fluid balance since the second day with signifi cant statistical differences.Among the 84 sepsis patients with ARDS,58(69.0%)died.Mean daily fl uid input volumes were much lower in survivors than in non-survivors(43.2±16.7 mL/kg vs.51.0±25.2 mL/kg,P<0.05)while output volumes were much higher in survivors(45.2±19.8 mL/kg vs.40.2±22.7 mL/kg,P<0.05).Using binary logistic regression analysis,we found that the mean daily fl uid balance was independently associated with mortality of sepsis patients complicating with ARDS(P<0.05).CONCLUSIONS:Early negative fluid balance is independently associated with a better prognosis of sepsis patients complicated with ARDS.

Biomarkers for patients with trauma associated acute respiratory distress syndrome

Trauma is a major factor that contributes to the risk for acute respiratory distress syndrome(ARDS).Biomarkers that predict the risk,diagnosis,treatment response and prognosis of ARDS after trauma have been widely investigated.In addition to their applications in clinical diagnosis and treatment,these biomarkers provide important insights into our understanding of the pathogenesis of ARDS.This review begins with a brief introduction regarding the incidence and pathogenesis of trauma-associated ARDS.Then,we focus on reviewing the clinical trials that have been designed to investigate the value of biomarkers in ARDS after trauma.Biomarkers with a confirmed value in ARDS have been organized on the basis of key pathogenic processes that are central to ARDS and are described in detail.Among these,angiopoietin 2(Ang-2),L-selectin,Clara cell protein 16(CC16),soluable receptor for advanced glycation end products(s RAGE),Surfactant protein D(SP-D),histones,mt DNAs and some biomarker panels had a certain association with the diagnosis and prognosis of trauma-related ARDS.Further investigations are needed regarding the design of trials,the best sampling approaches and the optimal combinations of the biomarker panels.

Ventilator management for acute respiratory distress syndrome associated with avian infl uenza A(H7N9) virus infection: A case series

BACKGROUND: Data on the mechanical ventilation(MV) characteristics and radiologic features for the cases with H7 N9-induced ARDS were still lacking.METHODS: We describe the MV characteristics and radiologic features of adult patients with ARDS due to microbiologically confirmed H7 N9 admitted to our ICU over a 3-month period.RESULTS: Eight patients(mean age 57.38±16.75; 5 male) were diagnosed with H7 N9 in the first quarter of 2014. All developed respiratory failure complicated by acute respiratory distress syndrome(ARDS), which required MV in ICU. The baseline APACHE II and SOFA score was 11.77±6.32 and 7.71±3.12. The overall CT scores of the patients was 247.68±34.28 and the range of CT scores was 196.3–294.7. The average MV days was 14.63±6.14, and 4 patients required additional rescue therapies for refractory hypoxemia. Despite these measures, 3 patients died.CONCLUSION: In H7 N9-infected patients with ARDS, low tidal volume strategy was the conventional mode. RM as one of rescue therapies to refractory hypoxemia in these patients with serious architectural distortion and high CT scores, which could cause further lung damage, may induce bad outcomes and requires serious consideration. Prone ventilation may improve mortality, and should be performed at the early stage of the disease, not as a rescue therapy.