Lung-Gut Microbiota and Tryptophan Metabolites Changes in Neonatal Acute Respiratory Distress Syndrome.

Purpose: Neonatal Acute Respiratory Distress Syndrome (NARDS) is a severe respiratory crisis threatening neonatal life. We aim to identify changes in the lung-gut microbiota and lung-plasma tryptophan metabolites in NARDS neonates to provide a differentiated tool and aid in finding potential therapeutic targets. Patients and Methods: Lower respiratory secretions, faeces and plasma were collected from 50 neonates including 25 NARDS patients (10 patients with mild NARDS in the NARDS_M group and 15 patients with moderate-to-severe NARDS in the NARDS_S group) and 25 control patients screened based on gestational age, postnatal age and birth weight. Lower airway secretions and feces underwent 16S rRNA gene sequencing to understand the microbial communities in the lung and gut, while lower airway secretions and plasma underwent LC-MS analysis to understand tryptophan metabolites in the lung and blood. Correlation analyses were performed by comparing differences in microbiota and tryptophan metabolites between NARDS and control, NARDS_S and NARDS_M groups. Results: Significant changes in lung and gut microbiota as well as lung and plasma tryptophan metabolites were observed in NARDS neonates compared to controls. Proteobacteria and Bacteroidota were increased in the lungs of NARDS neonates, whereas Firmicutes, Streptococcus, and Rothia were reduced. Lactobacillus in the lungs decreased in NARDS_S neonates. Indole-3-carboxaldehyde decreased in the lungs of NARDS neonates, whereas levels of 3-hydroxykynurenine, indoleacetic acid, indolelactic acid, 3-indole propionic acid, indoxyl sulfate, kynurenine, and tryptophan decreased in the lungs of the NARDS_S neonates. Altered microbiota was significantly related to tryptophan metabolites, with changes in lung microbiota and tryptophan metabolites having better differentiated ability for NARDS diagnosis and grading compared to gut and plasma. Conclusion: Significant changes occurred in the lung-gut microbiota and lung-plasma tryptophan metabolites of NARDS neonates. Alterations in lung microbiota and tryptophan metabolites were better discriminatory for the diagnosis and grading of NARDS.

Evolution and considerations of diagnostic criteria for neonatal acute respiratory distress syndrome / 解放军医学杂志

Since acute respiratory distress syndrome(ARDS)was firstly reported in 1967,the diagnostic criteria and classification standard have evolved continually.Neonatal ARDS has drawn increasing attention in recent years,while research on neonatal ARDS has proceeded slowly,partly because of ambiguity in the definitions and diagnostic criteria of neonatal ARDS.In this comment,we overview the application of the Berlin definition made in 2012,the Montreux definition made in 2017,and the definition of pediatric ARDS update by the Second Pediatric Acute Lung Injury Consensus Conference made in 2023(PALICC-2 definition)in neonatal ARDS,then compare the similarities and differences among the three definitions.Finally,the differences in classification standard,triggers,morbidity,mortality,poor prognosis,and treatment among the three definitions for neonatal ARDS were analyzed,and the research directions in the future of the definition for neonatal ARDS were proposed.

Establishment and evaluation of nomogram for predicting intraventricular hemorrhage in neonatal acute respiratory distress syndrome.

BACKGROUND: Intraventricular hemorrhage (IVH) is the most common type of brain injury in newborns, especially in newborns with Neonatal acute respiratory distress syndrome (ARDS). IVH can cause brain parenchyma damage and long-term neurological sequelae in children. Early identification and prevention of sequelae are essential. This study aims to establish a predictive nomogram for the early prediction of IVH in newborns with ARDS. METHODS: From 2019 to 2021, we collected data from 222 infants diagnosed with ARDS in the Department of Neonatology, First Affiliated Hospital of Xinjiang Medical University. Infants have been randomly assigned to the training set (n = 161) or the validation set (n = 61) at a ratio of 7:3. Variables were screened using the Least Absolute Contract and Selection Operator (LASSO) regression to create a risk model for IVH in infants with ARDS. The variables chosen in the LASSO regression model were used to establish the prediction model using multivariate logistic regression analysis. RESULTS: We recognized 4 variables as independent risk factors for IVH in newborns with ARDS via LASSO analysis, consisting of premature rupture of membranes (PROM), pulmonary surfactant (PS) dosage, PH1 and Arterial partial pressure of oxygen (PaO21). The C-Index for this dataset is 0.868 (95% CI: 0.837-0.940) and the C index in bootstrap verification is 0.852 respectively. The analysis of the decision curve shows that the model can significantly improve clinical efficiency in predicting IVH. We also provide a website based on the model and open it to users for free, so that the model can be better applied to clinical practice. CONCLUSION: In conclusion, the nomogram based on 4 factors shows good identification, calibration and clinical practicability. Our nomographs can help clinicians make clinical decisions, screen high-risk ARDS newborns, and facilitate early identification and management of IVH patients.

Effects of active inter-hospital transfer on the clinical outcomes of neonatal acute respiratory distress syndrome / 中国新生儿科杂志

Objective:To study the effects of active inter-hospital transfer on the clinical outcomes of neonatal acute respiratory distress syndrome (nARDS).Methods:From September 2018 to December 2020, neonates with nARDS transferred by ground ambulance to NICU of our hospital were retrospectively analyzed. The neonates were assigned into active transfer group and passive transfer group. Their general status, severity of nARDS, incidences of complications, duration of oxygen therapy, mechanical ventilation and hospital stay were analyzed.Results:A total of 78 neonates were enrolled in the study, including 45 cases in active transfer group and 33 cases in passive transfer group. No significant differences existed in gestational age, body weight, severity of nARDS, transfer distance and transfer duration between the two groups ( P>0.05). Active transfer group had significantly lower incidence of pneumothorax (3/45, 6.7%) than passive transfer group (6/33, 18.2%) ( P<0.05). No significant differences existed in the incidences of pulmonary hemorrhage, persistent pulmonary hypertension of newborn, intraventricular hemorrhage, hypoxic ischemic encephalopathy and length of hospital stay between the two groups ( P>0.05). Active transfer group had significantly shorter duration of oxygen therapy [(9.7±2.9) d vs. (11.3±4.0) d], non-invasive[(2.7±1.0) d vs. (3.7±1.4) d] and invasive ventilation [(5.0±1.9) d vs. (6.2±2.3) d] than passive transfer group ( P<0.05). Conclusions:Active inter-hospital transfer may reduce the incidence of pneumothorax in neonates with nARDS, shorten the duration of oxygen therapy, non-invasive and invasive ventilation during hospitalization without affecting the length of hospital stay.

A prediction nomogram for neonatal acute respiratory distress syndrome in late-preterm infants and full-term infants: A retrospective study.

Background: Neonatal acute respiratory distress syndrome (ARDS) is a critical clinical disease with high disability and mortality rates. Early identification and treatment of neonatal ARDS is critical. This study aimed to build a perinatal prediction nomogram for early prediction of neonatal ARDS. Methods: A prediction model was built including 243 late-preterm and full-term infants from Daping Hospital in Chongqing, China, hospitalised between Jan 1, 2018 and Dec 31, 2019. 80 patients from the Children's Hospital in Chongqing, China, hospitalised between Jan 1, 2018 and June 30, 2018 were considered for external validation. Multivariate logistic regression was performed to identify independent predictors and establish a nomogram to predict the occurrence of neonatal ARDS. Both discrimination and calibration were assessed by bootstrapping with 1000 resamples. Findings: Multivariate logistic regression demonstrated that mother's education level (odds ratio [OR] 0·478, 95% confidence interval [CI] 0·324-0·704), premature rupture of membrane (OR 0·296, 95% CI 0·133-0·655), infectious disease within 7 days before delivery (OR 0·275, 95% CI 0·083-0·909), hospital level (OR 2·479, 95% CI 1·260-4·877), and Apgar 5-min score (OR 0·717, 95% CI 0·563-0·913) were independent predictors for neonatal ARDS in late-preterm and full-term infants, who experienced dyspnoea within 24 h after birth and required mechanical ventilation. The area under the curve and concordance index of the nomogram constructed from the above five factors were 0·760 and 0·757, respectively. The Hosmer-Lemeshow test showed that the model was a good fit (P = 0.320). The calibration curve of the nomogram was close to the ideal diagonal line. Furthermore, the decision curve analysis demonstrated significantly better net benefit in the model. The external validation proved the reliability of the prediction nomogram. Interpretation: A nomogram based on perinatal factors was developed to predict the occurrence of neonatal ARDS in late-preterm and full-term infants who experienced dyspnoea within 24 h after birth and required mechanical ventilation. It provided clinicians with an accurate and effective tool for the early prediction and timely management of neonatal ARDS. Funding: No funding was associated with this study.

High frequency oscillatory ventilation for acute respiratory distress syndrome / 中国小儿急救医学

High frequency oscillatory ventilation(HFOV) in the treatment of acute respiratory distress syndrome(ARDS), there are significant differences in clinical research status and evidence level among different participants.HFOV for adult ARDS: current clinical evidence suggests that HFOV is not recommended for routine mechanical ventilation in adults with ARDS.HFOV for pediatric ARDS: there is no sufficient evidence to show that HFOV is superior to conventional mechanical ventilation.Nor does it prove that HFOV is harmful.The current recommendation is: HFOV could be considered as an alternative ventilatory mode in patients with moderate-to-severe pediatric ARDS, whom with conventional mechanical ventilation plateau airway pressures exceed 28 cmH 2O(1 cmH 2O=0.098 kPa) in the absence of clinical evidence of reduced chest wall compliance.HFOV for neonatal ARDS: the existing research evidence shows that HFOV can moderately reduce the incidence of chronic lung disease in the premature infants with neonatal ARDS.It has certain advantages in improving oxygenation and alleviating ventilator induced lung injury in acute phase.It also has certain advantages for improving pulmonary function and neurodevelopmental in the long term.

Expression of miR-155 and IFN-γ in lung injury model of neonatal rats with acute respiratory distress syndrome / 国际儿科学杂志

Objective:To study the expression of micro RNA-155(miR-155) and IFN-γ in lung tissue in a neonatal rat model of acute respiratory distress syndrome(ARDS)lung injury by intraperitoneal injection of lipopolysaccharide(LPS).Methods:Eighty neonatal SD rats on the 7th day after birth were assigned to the experimental group(LPS group)and control group(isotonic NaCl group), with 40 rats in each group.LPS solution(4 mg/kg)was injected into the abdominal cavity of neonatal SD rats in the experimental group to establish an animal model of neonatal acute respiratory distress syndrome(NARDS). The control group was established by isotonic NaCl solution(4 ml/kg)in the same way.The lung tissue samples were taken at 3 h, 6 h, 12 h and 24 h after drug administration to observe the surface changes.Then the lung sections were stained with HE to observe the pathological changes and score the lung tissue injury.Finally, the expression levels of miR-155 and IFN-γ in the lung tissue were tested by RT-PCR and ELISA techniques, respectively.Results:(1)At the beginning of the experiment, the neonatal rats in the experimental group gradually showed the clinical manifestations of ARDS, and the macroscopic observation, pathological changes and lung tissue injury scores of the lung tissues suggested the appearance of NARDS lung injury, indicating that the model was successful.(2)The expression levels of miR-155(1.33±0.12 vs 0.95±0.02、1.77±0.17 vs 0.96±0.01、2.18±0.09 vs 0.96±0.02 and 2.43±0.06 vs 0.96±0.02)and IFN-γ(370.79±13.89 vs 273.03±11.44、424.24±10.11vs270.70±13.05、466.63±6.57 vs 268.11±7.88 and 519.13±7.09 vs 272.97±12.54)ng/L in the lung tissue of rats between the experimental group and the control group were significantly different( P<0.01), and the difference was statistically significant among the groups in the experimental group( F values were 165.983 and 408.574, P<0.01). The expression levels of miR-155 and IFN-γ in the lung tissue of the experimental group increased gradually over time and showed an increasing trend. Conclusion:After the successful establishment of NARDS animal model, the expression levels of miR-155 and IFN-γ in the lung tissue of NARDS rats have significantly increased and showed a sequential pattern.MiR-155 is expected to become an early biomarker for the diagnosis of NARDS.

Microarray and Bioinformatics Analysis of Circular RNA Differential Expression in Newborns With Acute Respiratory Distress Syndrome.

Previous studies pointed out that a variety of microRNAs (miRNAs) are involved in the pathogenesis of neonatal acute respiratory distress syndrome (NARDS) and play different roles in the pathological process. However, there have been few studies reporting the connection between circular RNA (circRNA) and NARDS, so the expression profile of circRNAs in newborns with acute respiratory distress syndrome remains largely unknown. In the present study, 10 samples obtained from remaining clinical blood samples of newborns hospitalized in a neonatal ward of the First Affiliated Hospital of Nanjing Medical University from January 2020 to October 2020 were divided into the "NARDS" group and "non-NARDS" group according to the Montelux standard and then were analyzed in microarray, and 10 other samples collected from the same place and from January 1, 2021 to August 31, 2021, were used to do RT-qPCR experiment. circRNA expression profiles, in which 741 circRNAs were downregulated and 588 were upregulated, were screened with circRNA high-throughput sequencing. Subsequently, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis of parent genes of the differentially expressed circRNAs revealed that these circRNAs may be related to the process of protein synthesis and metabolism in NARDS. Moreover, five circRNAs-hsa_circ_0058495, hsa_circ_0000367, hsa_circ_0005389, hsa_circ_0059571, and hsa_circ_0006608-were selected randomly among the top 10 circRNAs of the downregulated or upregulated expression profiles. Then, bioinformatics tools were used to predict correlative miRNA and its target genes, which were also subjected to the same bioinformatics analysis for further study. The top 30 enriched KEGG pathway analyses of the 125 target genes suggested that these target genes are widely involved in the synthesis and secretion of endocrine hormones, and the top 30 enriched GO terms based on the 125 target genes are also focused on the protein and DNA processing. Thus, the present results show that circRNAs could promote the inflammation of NARDS which may provide a new therapeutic direction and it can be used as molecular markers for early diagnosis of NARDS, but further molecular biology verification is needed to define the specific role of differentially expressed circRNAs in NARDS.

Venoarterial Extracorporeal Membrane Oxygenation for Severe Neonatal Acute Respiratory Distress Syndrome in a Developing Country.

Objective: Extracorporeal membrane oxygenation (ECMO) has supported oxygen delivery and carbon dioxide removal in neonatal severe respiratory failure for more than 4 decades. The definition and diagnosis of neonatal acute respiratory distress syndrome (ARDS) was made according to the criteria first established by a Montreux Conference in 2017. By far, there has been no ECMO efficiency studies in neonatal ARDS. We aimed to compare the outcomes of neonates with severe ARDS supported with and without ECMO. Design: Retrospective pair-matched study. Setting: In the present retrospective pair-matched study, the outcomes of severe ARDS with ECMO support and without ECMO support were analyzed and compared. Propensity score matching was conducted. The study subjects were selected from a China Neonatal ECMO (CNECMO) study. In total, five hospitals were included in the CNECMO study. The patients were matched with demographic and clinical data. The primary endpoint was in-hospital mortality. Secondary outcomes included ventilator-time, ICU stay, hospitalization costs and cranial MRI results. Patients: 145 neonates with severe ARDS (Oxygenation Index, OI ≥16) from 5 hospitals. Interventions: No interventions. Measurements and Main Results: We collected the data of 145 neonates with severe ARDS (Oxygenation Index, OI≥16) from 5 hospitals. Among them, 42 neonates received venoarterial (VA) ECMO support, and the remaining 103 neonates were treated with conventional mechanical ventilation. The mortality of ECMO-supported neonates was not significantly different compared with the ESLO neonatal respiratory-supported from 2012 to 2018 (23.8 vs. 32.5%, p = 0.230). After matching with the propensity score we got 31 pairs. The ECMO-supported neonates had a lower in-hospital mortality (6 of 31, 19.4%) vs. non ECMO-supported patients (18 of 31, 58.1%) (p = 0.002). Hospitalization costs of survivors in ECMO-supported neonates were significantly higher than that of non-ECMO-supported neonates (p < 0.001). There was no difference of ventilator-times (p = 0.206), ICU stay (p = 0.879) and cranial MRI (p = 0.899) between the survivors of ECMO-supported and non-ECMO-supported neonates with ARDS. Conclusions: By far, there has been no ECMO efficiency studies in neonatal ARDS. This study found that ECMO-support have superior outcomes compared with non-ECMO-support in neonates with severe ARDS.

Surfactant Injury in the Early Phase of Severe Meconium Aspiration Syndrome.

No in vivo data are available regarding the effect of meconium on human surfactant in the early stages of severe meconium aspiration syndrome (MAS). In the present study, we sought to characterize the changes in surfactant composition, function, and structure during the early phase of meconium injury. We designed a translational prospective cohort study of nonbronchoscopic BAL of neonates with severe MAS (n = 14) or no lung disease (n = 18). Surfactant lipids were analyzed by liquid chromatography-high-resolution mass spectrometry. Secretory phospholipase A2 subtypes IB, V, and X and SP-A (surfactant protein A) were assayed by ELISA. SP-B and SP-C were analyzed by Western blotting under both nonreducing and reducing conditions. Surfactant function was assessed by adsorption test and captive bubble surfactometry, and lung aeration was evaluated by semiquantitative lung ultrasound. Surfactant nanostructure was studied using cryo-EM and atomic force microscopy. Several changes in phospholipid subclasses were detected during MAS. Lysophosphatidylcholine species released by phospholipase A2 hydrolysis were increased. SP-B and SP-C were significantly increased together with some shorter immature forms of SP-B. Surfactant function was impaired and correlated with poor lung aeration. Surfactant nanostructure was significantly damaged in terms of vesicle size, tridimensional complexity, and compactness. Various alterations of surfactant phospholipids and proteins were detected in the early phase of severe meconium aspiration and were due to hydrolysis and inflammation and a defensive response. This impairs both surfactant structure and function, finally resulting in reduced lung aeration. These findings support the development of new surfactant protection and antiinflammatory strategies for severe MAS.

18:1/18:1-Dioleoyl-phosphatidylglycerol prevents alveolar epithelial apoptosis and profibrotic stimulus in a neonatal piglet model of acute respiratory distress syndrome.

BACKGROUND: 18:1/18:1-Dioleoyl-phosphatidylgycerol (DOPG) is a surfactant phospholipid that is nearly non-detectable in neonatal surfactant films. When alveolar macrophages are exposed to DOPG in vitro, secretory phospholipase A2 (sPLA2) production is blocked, resulting in suppressed macrophage activity and improved surfactant function. We investigated whether the addition of DOPG to a commercially available surfactant preparation would improve lung function in a neonatal piglet model of acute respiratory distress syndrome. MATERIALS AND METHODS: Respiratory failure was achieved by triple-hit lung injury (repeated broncho-alveolar lavage, injurious ventilation, tracheal lipopolysaccharide instillation, each intervention 24 h apart) in twenty-four domestic piglets aged 2-6 days and subject to mechanical ventilation. Following each lung injury protocol the piglets were treated with surfactant alone or with surfactant + DOPG. RESULTS: Within 72 h of mechanical ventilation, we observed significantly improved gas exchange (oxygenation and ventilation), lung mechanics (compliance and resistance of the respiratory system), and pulmonary oedema (extra-vascular lung water index) in the surfactant + DOPG group. This favourable clinical effect could be attributed to improved surfactant function, reduced sPLA2 secretion, inhibition of macrophage migration, reduced alveolar epithelial apoptosis, and suppression of amphiregulin and TGF-ß1 expression in pulmonary tissues as a prerequisite for fibrous lung repair. CONCLUSIONS: We conclude that surfactant fortified by DOPG preserves lung function, and prevents alveolar epithelial injury and fibrous stimulus by reduction of sPLA2 in a neonatal model of acute respiratory distress syndrome without any relevant discernable side effects. Hence, DOPG supplementation in a neonatal lung exerts important function protecting effects and seems to be justified in cases of overwhelming pulmonary inflammation.