Bioinformatics analysis of ventilator-induced lung injury genome microarray based on gene expression omnibus database and key gene verification / 中华危重病急救医学

Objective:To investigate differential expression gene (DEG) in mice with ventilator-induced lung injury (VILI) by bioinformatics analysis, and to verify the key genes by reproducing the VILI mouse model.Methods:① Experiment 1 (bioinformatics analysis): the microarray dataset of GSE9368 and GSE11662 regarding VILI mice and those in the spontaneous breathing control group were downloaded from the gene expression omnibus (GEO) database. DEG obtained by R and Venn map was further used to obtain common DEG. DAVID online database was used to obtain gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Finally, the protein-protein interaction (PPI) analysis of common DEG was carried out by using Search Tool for the Retrieval of Interacting Genes Database (STRING) and the key genes were screened out by using CytoScape software, molecular complex detection (MCODE) analysis plug-in and CytoHubba plug-in with maximum cluster centrality (MCC), maximum neighbor connectivity (MNC) and degree. ② Experiment 2 (related protein verification): VILI mouse model was reproduced by high tidal volume (20 mL/kg) ventilator. Spontaneous breathing control group was set up. Hematoxylin-eosin (HE) staining was performed to assess lung injury and the key genes screened in experiment 1 were verified by immunohistochemical staining.Results:① Experiment 1 results: a total of 114 DEG were screened from GSE9368 dataset, including 99 up-regulated genes and 15 down-regulated genes. A total of 258 DEG were screened from GSE11662 dataset, including 188 up-regulated genes and 70 down-regulated genes. Furthermore, 66 common DEG were obtained, including 61 up-regulated genes and 5 down-regulated genes. GO analysis showed that the common DEG were mainly involved in inflammatory response, immune response, leukocyte and neutrophil chemotaxis. KEGG analysis showed that the common DEG were involved cell adhesion, cytokine receptor interaction and tumor necrosis factor (TNF) signaling pathway. STRING and CytoScape analysis were used to construct gene PPI network diagram and important sub modules. And the CytoHubba plug-in with MCC, MNC and degree algorithms was used to perform topology analysis and then taken an intersection to obtain eight genes including suppressor of cytokine signaling 3 (SOCS3), interleukin-1β (IL-1β), matrix metalloproteinase-9 (MMP-9), integrin Itgam, CXC chemokine ligand 2 (CXCL2), CXC chemokine receptor 2 (CXCR2), Sell and CC chemokine receptor 1 (CCR1). ② Experiment 2 results: a mouse model of high tidal volume VILI was reproduced. Compared with the spontaneous breathing control group, the lung tissue was injured slightly at 0 hour after the end of ventilation, and the lung tissue structure was significantly damaged at 6 hours after the end of ventilation, showing bleeding in alveolar cavity, significant increase and collapse of alveolar wall thickness, and infiltration of inflammatory cells. The top three genes from intersection and topological analysis including IL-1β, SOCS3 and MMP-9 were verified by immunohistochemical staining. The results showed that the expressions of IL-1β, SOCS3 and MMP-9 were gradually increased with time of ventilation, the differences were found at 6 hours as compared with those in the spontaneous breathing control group [IL-1β (integral A value): 8.40±2.67 vs. 5.10±0.94, SOCS3 (integral A value): 9.74±1.80 vs. 5.95±1.31, MMP-9 (integral A value): 11.45±6.20 vs. 5.36±1.28, all P < 0.05]. Conclusion:Bioinformatics analysis based on GSE9368 and GSE11662 data sets found that VILI is mainly related to inflammatory injury, cytokines and immune cell infiltration; IL-1β, SOCS3 and MMP-9 might be biomarkers of VILI.

Clinical factors associated with composition of lung microbiota and important taxa predicting clinical prognosis in patients with severe community-acquired pneumonia / 医学前沿

Few studies have described the key features and prognostic roles of lung microbiota in patients with severe community-acquired pneumonia (SCAP). We prospectively enrolled consecutive SCAP patients admitted to ICU. Bronchoscopy was performed at bedside within 48 h of ICU admission, and 16S rRNA gene sequencing was applied to the collected bronchoalveolar lavage fluid. The primary outcome was clinical improvements defined as a decrease of 2 categories and above on a 7-category ordinal scale within 14 days following bronchoscopy. Sixty-seven patients were included. Multivariable permutational multivariate analysis of variance found that positive bacteria lab test results had the strongest independent association with lung microbiota (R2 = 0.033; P = 0.018), followed by acute kidney injury (AKI; R2 = 0.032; P = 0.011) and plasma MIP-1β level (R2 = 0.027; P = 0.044). Random forest identified that the families Prevotellaceae, Moraxellaceae, and Staphylococcaceae were the biomarkers related to the positive bacteria lab test results. Multivariable Cox regression showed that the increase in α-diversity and the abundance of the families Prevotellaceae and Actinomycetaceae were associated with clinical improvements. The positive bacteria lab test results, AKI, and plasma MIP-1β level were associated with patients' lung microbiota composition on ICU admission. The families Prevotellaceae and Actinomycetaceae on admission predicted clinical improvements.

Risk factors and diagnostic methods of intensive care unit-acquired weakness / 中华危重病急救医学

Objective:To explore the risk factors of intensive care unit-acquired weakness (ICU-AW) and the characteristics of Medical Research Council (MRC) score and electromyogram.Methods:A case control study was conducted. Patients with mechanical ventilation ≥ 7 days and MRC score admitted to department of respiratory and critical care medicine of China-Japan Friendship Hospital from September 2018 to January 2020 were enrolled, and they were divided into ICU-AW group (MRC score < 48) and non-ICU-AW group (MRC score ≥ 48) according to MRC score. The general situation, past medical history, related risk factors, MRC score, respiratory support mode, laboratory examination results, electromyogram examination results, ICU-AW related treatment, outcome and length of ICU stay were collected, and the differences between the two groups were compared. The risk factors of ICU-AW were analyzed by binary multivariate Logistic regression, and the characteristics of MRC score and electromyogram were analyzed.Results:A total of 60 patients were enrolled in the analysis, including 17 patients in ICU-AW group and 43 patients in non-ICU-AW group. Univariate analysis showed that there were significant differences in acute physiology and chronic health evaluation Ⅱ (APACHEⅡ) score, sequential organ failure assessment (SOFA) score, brain natriuretic peptide (BNP), blood urea nitrogen (BUN) on the first day of ICU admission and the ratio of invasive mechanical ventilation between ICU-AW group and non-ICU-AW group [APACHEⅡ score: 21 (18, 25) vs. 18 (15, 22), SOFA score: 7 (5, 12) vs. 5 (3, 8), BNP (ng/L): 364.3 (210.1, 551.2) vs. 160.1 (66.8, 357.8), BUN (mmol/L): 9.9 (6.2, 17.0) vs. 6.0 (4.8, 9.8), invasive mechanical ventilation ratio: 88.2% vs. 46.5%, all P < 0.05]. Binary multivariate Logistic regression analysis showed no independent risk factor for ICU-AW. The average MRC score of 17 ICU-AW patients was 33±11. The limb weakness was symmetrical, and the proximal limb weakness was the main manifestation. Electromyography examination showed that the results of nerve conduction examination in ICU-AW patients mainly revealed that the amplitude of compound muscle action potential (CMAP) and sensory nerve action potentials (SNAP) were decreased, and the conduction velocity was slowed down; needle electromyography showed increased area of motor unit potential (MUP), prolonged time limit and a large number of spontaneous potentials. Prognosis evaluation showed that compared with non-ICU-AW group, patients in ICU-AW group underwent more tracheotomy (70.6% vs. 11.6%), longer length of ICU stay (days: 57±52 vs. 16±8), and more rehabilitation treatment (58.8% vs. 14.0%), and the differences were statistically significant (all P < 0.01). Conclusions:The occurrence of ICU-AW may be related to high APACHEⅡ score and SOFA score, high levels of BNP and BUN on the first day of ICU admission and the proportion of invasive mechanical ventilation, but the above factors are not independent risk factors for ICU-AW. The MRC score of ICU-AW patients was characterized by symmetrical limb weakness, mainly proximal limb weakness; in electromyography examination, the nerve conduction examination results mainly showed that CMAP and SNAP amplitude were decreased, and conduction velocity was slowed down; needle electromyography examination showed increased MUP area, prolonged duration and a large number of spontaneous potentials.

Risk factors for intracranial hemorrhage and mortality in adult patients with severe respiratory failure managed using veno-venous extracorporeal membrane oxygenation / 中华医学杂志(英文版)

BACKGROUND@#Intracerebral hemorrhage (ICH) is one of the most severe complications during veno-venous extracorporeal membrane oxygenation (VV-ECMO). This study aimed to determine the risk factors for ICH and mortality in such patients.@*METHODS@#We analyzed the clinical data of 77 patients who received VV-ECMO due to severe respiratory failure from July 2013 to May 2019 at China-Japan Friendship Hospital. Demographical data, laboratory indices, imaging characteristics, and other clinical information were collected. Multivariable logistic regression analyses were performed to identify risk factors for ICH and mortality.@*RESULTS@#Of 77 patients, 11 (14.3%) suffered from ICH, and 36 (46.8%) survived. The survival rate was significantly lower (18.2% [2/11] vs. 51.5% [34/66], P = 0.040) in patients with ICH than in those without ICH. Multivariable analysis revealed that factors independently associated with ICH were diabetes mellitus (adjusted odds ratio [aOR]: 12.848, 95% confidence interval [CI]: 1.129-146.188, P = 0.040) and minimum fibrinogen during ECMO (aOR: 2.557, 95% CI: 1.244-5.252, P = 0.011). Multivariable analysis showed that factors independently associated with mortality were acute hepatic failure during ECMO (aOR: 9.205, 95% CI: 1.375-61.604, P = 0.022), CO2 retention before ECMO (aOR: 7.602, 95% CI: 1.514-38.188, P = 0.014), and minimum platelet concentration during ECMO (aOR: 0.130, 95% CI: 0.029-0.577, P = 0.007).@*CONCLUSIONS@#Diabetes mellitus and minimum fibrinogen concentration during ECMO are risk factors for ICH in patients with severe respiratory failure managed using VV-ECMO. This indicated that anticoagulants use and nervous system monitoring should be performed more carefully in patients with diabetes when treated with VV-ECMO due to severe respiratory failure.

Incidence of acute kidney injury within 3 days after lung transplantation, related risk factors and its influences on short-term prognosis / 中华器官移植杂志

Objective:To explore the incidence and relevant risk factors of acute kidney injury (AKI)after lung transplantation(LT).Methods:Retrospective analysis was performed for clinical data of 70 recipients of LT at China-Japan Friendship Hospital.Results:Among them, 61.4 % developed AKI within 3 days post-LT. As compared with non-AKI and AKI 1 groups, AKI 2~3 group had more plasma transfusion(median 0, 0, 200 ml, P=0.027) and more cardiovascular events during operation(0, 0, 14.3 %, P=0.023). As compared with non-AKI group, AKI 1 and 2~3 groups had lower postoperative hemoglobin in the first day(median 119, 106, 104 g/L, P=0.032). The duration of invasive mechanical ventilation was longer in AKI 2~3 group(median 56 h)than non-AKI group (median 49 h, P=0.034). The 3-month all-cause mortality post-LT was higher in AKI 2~3 (24.1 %)and AKI 1 recipients(21.4 %)than that in non-AKI counterparts(0)( P=0.034, P=0.007). Conclusions:Recipients with more blood transfusion and cardiovascular events during operation and those with more severe anemia in the first day post-LT might be at higher risks for postoperative AKI. Postoperative AKI prolongs the duration of invasive mechanical ventilation and increases 3-month all-cause mortality post-LT.

Pharmacokinetics changes of antimicrobial agents in adult patients receiving extracorporeal membrane oxygenation: an updated literature review / 中华危重病急救医学

Extracorporeal membrane oxygenation (ECMO) is a viable ultimate support therapy for patients with severe cardiorespiratory failure. Antimicrobial agents are commonly prescribed in critically ill patients with ECMO. However, an increasing number of studies have shown that ECMO circuit is associated with significant pharmacokinetic (PK) alterations, including the increased volume of distribution and reduced the clearance. In addition, the critical illness pathophysiology can also influence PK of antimicrobial, such as systemic inflammation, excessive fluid resuscitation, hypo-albuminemia, worsening hepatic or renal function. These PK alterations may increase the possibility of therapeutic failure or toxicity. Therefore, this study reviews published studies of the effects of ECMO on PK of antimicrobial agents in adults and makes preliminary recommendations on possible dosing regimen.

Prognostic value of serum galactomannan index in critically ill patients with chronic obstructive pulmonary disease at risk of invasive pulmonary aspergillosis / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Critically ill chronic obstructive pulmonary disease (COPD) patients admitted to an intensive care unit (ICU) due to respiratory failure are at particularly high risk of Aspergillus infection. The serum galactomannan index (GMI) has proven to be one of the prognostic criteria for invasive pulmonary aspergillosis (IPA) in classical immunocompromised patients. However, the prognostic value of serum GMI in critically ill COPD patients needs evaluation. The purpose of this study is to investigate the prognostic value of serum GMI in patients with severe COPD.</p><p><b>METHODS</b>In this single-center prospective cohort study, serum samples for GMI assay were collected twice a week from the first day of ICU admission to the day of the patients' discharge or death. Patients were divided into two groups according to their clinical outcome on the 28th day of their ICU admission. Univariate analysis and survival analysis were tested in these two groups.</p><p><b>RESULTS</b>One hundred and fifty-three critically ill COPD patients were included and were divided into survival group (106 cases) and non-survival group (47 cases) according to their outcome. Univariate analysis showed that the highest GMI level during the first week after admission (GMI-high 1st week) was statistically different between the two groups. Independent prognostic factors for poor outcome in severe COPD patients were: GMI-high 1st week >0.5 (RR: 4.04, 95% CI: 2.17-7.51) combined with accumulative dosage of corticosteroids >216 mg before the RICU admission (RR: 2.25, 95% CI: 1.11-4.56) and clearance of creatinine (Ccr) ≤ 64.31 ml/min (RR: 2.48, 95% CI: 1.22 ± 5.07).</p><p><b>CONCLUSIONS</b>The positive GMI-high 1st week (>0.5) combined with an accumulative dosage of corticosteroids >216 mg before the ICU admission and a low Ccr may predicate a poor outcome of critically ill COPD patients.</p>

Clinical features of invasive bronchial-pulmonary aspergillosis in critically ill patients with chronic obstructive pulmonary diseases / 中华临床感染病杂志

Objective To investigate the clinical features of invasive bronchial-pulmonary aspergillosis (IBPA) in critically ill patients with chronic obstructive pulmonary diseases (COPD).Methods Clinical data of 7 COPD patients complicated with IBPA from respiratory intensive care unit (RICU) in Beijing Chaoyang Hospital during April 2006 and August 2012 were retrospectively analyzed.Results All patients were treated with several kinds of broad-spectrum antibiotics and 6 patients were also treated with large dose of corticosteroids before their admission to RICU.The most frequent clinical manifestations were fever,persistent bronchospasm induced dyspnea and bilateral wheezing which were unresponsive to large doses of corticosteroids and broad-spectrum antibiotics.In 5 patients with both aspergillus tracheobronchitis (ATB) and invasive pulmonary aspergillosis (IPA),bronchoscopy showed tracheobronchial inflammation,bronchospasm,phlegm and bronchial pseudomembrane formation.All these 5 patients had a rapid progression from normal to infiltrates or consolidation in chest X-ray,and died of respiratory failure or multiple organ failure.The other 2 cases were diagnosed with ATB and received prophylactic antifungal treatments before infiltrates were shown on their chest X-ray.Both of them survived.Conclusions In COPD patients combined with IBPA,ATB may progress rapidly to IPA which affect lung parenchyma and lead a high mortality.Bronchoscopy and bronchial mucous biopsy may be helpful in early diagnosis and treatment.

The second grade national prize for science and technology progress study on pathogenesis and treatment of respiratory failure / 中国实用内科杂志

To improve the status of management in respiratory failure in China,the project of Study on Pathogenesis and Treatment of Respiratory Failure was designed and conducted by three medical centers(Beijing Institute of Respiratory Medicine-Beijing Chaoyang Hospital,Affiliated to Capital Medical University,Zhongshang Hospital-Fudan University,Guangzhou Institute of Respiratory Medicine-First Guangzhou Medical College)for more than ten years.This project was focused on pathogenesis and treatment strategies of respiratory failure and achieved the following important innovations:(1)Pulmonary Infection Control Window(PIC Window)was firstly proposed and used to determine the time switching point of sequential invasive-noninvasive ventilation;(2)The largest sample size of early use of noninvasive positive pressure ventilation(NPPV)for acute exacerbated COPD(AECOPD)on general ward provided the evidence-based data for expanding the indication of NPPV from treating respiratory failure to alleviating respiratory muscle fatigue;(3)Three new types of masks with intellectual property for NPPV were developed;(4)Designing of intrinsic expiratory end positive pressure(PEEPi)lung model with property of expiratory flow limitation confirmed that PEEPi was the most important factor that increased inspiratory difficulty;(5)The systematic measurement was established for diaphragm strength and endurance;(6)Aquaporin 1(AQP1)was firstly proved the key channel of fluid transportation in the lung;(7)A multicenter prospective cohort study provided objective data that depression had causal effect on COPD exacerbation and hospitalization;(8)Two guidelines for NPPV and mechanical ventilation of AECOPD were initiated by this group.This project has been widely used in clinical practice and promoted the research and treatment of respiratory failure in China.