Two-Year Outcomes After Minimally Invasive Surfactant Therapy in Preterm Infants: Follow-Up of the OPTIMIST-A Randomized Clinical Trial.

Importance: The long-term effects of surfactant administration via a thin catheter (minimally invasive surfactant therapy [MIST]) in preterm infants with respiratory distress syndrome remain to be definitively clarified. Objective: To examine the effect of MIST on death or neurodevelopmental disability (NDD) at 2 years' corrected age. Design, Setting, and Participants: Follow-up study of a randomized clinical trial with blinding of clinicians and outcome assessors conducted in 33 tertiary-level neonatal intensive care units in 11 countries. The trial included 486 infants with a gestational age of 25 to 28 weeks supported with continuous positive airway pressure (CPAP). Collection of follow-up data at 2 years' corrected age was completed on December 9, 2022. Interventions: Infants assigned to MIST (n = 242) received exogenous surfactant (200 mg/kg poractant alfa) via a thin catheter; those assigned to the control group (n = 244) received sham treatment. Main Outcomes and Measures: The key secondary outcome of death or moderate to severe NDD was assessed at 2 years' corrected age. Other secondary outcomes included components of this composite outcome, as well as hospitalizations for respiratory illness and parent-reported wheezing or breathing difficulty in the first 2 years. Results: Among the 486 infants randomized, 453 had follow-up data available (median gestation, 27.3 weeks; 228 females [50.3%]); data on the key secondary outcome were available in 434 infants. Death or NDD occurred in 78 infants (36.3%) in the MIST group and 79 (36.1%) in the control group (risk difference, 0% [95% CI, -7.6% to 7.7%]; relative risk [RR], 1.0 [95% CI, 0.81-1.24]); components of this outcome did not differ significantly between groups. Secondary respiratory outcomes favored the MIST group. Hospitalization with respiratory illness occurred in 49 infants (25.1%) in the MIST group vs 78 (38.2%) in the control group (RR, 0.66 [95% CI, 0.54-0.81]) and parent-reported wheezing or breathing difficulty in 73 (40.6%) vs 104 (53.6%), respectively (RR, 0.76 [95% CI, 0.63-0.90]). Conclusions and Relevance: In this follow-up study of a randomized clinical trial of preterm infants with respiratory distress syndrome supported with CPAP, MIST compared with sham treatment did not reduce the incidence of death or NDD by 2 years of age. However, infants who received MIST had lower rates of adverse respiratory outcomes during their first 2 years of life. Trial Registration: anzctr.org.au Identifier: ACTRN12611000916943.

Non-invasive respiratory support in preterm infants.

Survival of preterm infants has increased steadily over recent decades, primarily due to improved outcomes for those born before 28 weeks of gestation. However, this has not been matched by similar improvements in longer-term morbidity. One of the key long-term sequelae of preterm birth remains bronchopulmonary dysplasia (also called chronic lung disease of prematurity), contributed primarily by the effect of early pulmonary inflammation superimposed on immature lungs. Non-invasive modes of respiratory support have been rapidly introduced providing modest success in reducing the incidence of bronchopulmonary dysplasia when compared with invasive mechanical ventilation, and improved clinical practice has been reported from population-based studies. We present a comprehensive review of the key modes of non-invasive respiratory support currently used in preterm infants, including their mechanisms of action and evidence of benefit from clinical trials.

Effect of Minimally Invasive Surfactant Therapy vs Sham Treatment on Death or Bronchopulmonary Dysplasia in Preterm Infants With Respiratory Distress Syndrome: The OPTIMIST-A Randomized Clinical Trial.

Importance: The benefits of surfactant administration via a thin catheter (minimally invasive surfactant therapy [MIST]) in preterm infants with respiratory distress syndrome are uncertain. Objective: To examine the effect of selective application of MIST at a low fraction of inspired oxygen threshold on survival without bronchopulmonary dysplasia (BPD). Design, Setting, and Participants: Randomized clinical trial including 485 preterm infants with a gestational age of 25 to 28 weeks who were supported with continuous positive airway pressure (CPAP) and required a fraction of inspired oxygen of 0.30 or greater within 6 hours of birth. The trial was conducted at 33 tertiary-level neonatal intensive care units around the world, with blinding of the clinicians and outcome assessors. Enrollment took place between December 16, 2011, and March 26, 2020; follow-up was completed on December 2, 2020. Interventions: Infants were randomized to the MIST group (n = 241) and received exogenous surfactant (200 mg/kg of poractant alfa) via a thin catheter or to the control group (n = 244) and received a sham (control) treatment; CPAP was continued thereafter in both groups unless specified intubation criteria were met. Main Outcomes and Measures: The primary outcome was the composite of death or physiological BPD assessed at 36 weeks' postmenstrual age. The components of the primary outcome (death prior to 36 weeks' postmenstrual age and BPD at 36 weeks' postmenstrual age) also were considered separately. Results: Among the 485 infants randomized (median gestational age, 27.3 weeks; 241 [49.7%] female), all completed follow-up. Death or BPD occurred in 105 infants (43.6%) in the MIST group and 121 (49.6%) in the control group (risk difference [RD], -6.3% [95% CI, -14.2% to 1.6%]; relative risk [RR], 0.87 [95% CI, 0.74 to 1.03]; P = .10). Incidence of death before 36 weeks' postmenstrual age did not differ significantly between groups (24 [10.0%] in MIST vs 19 [7.8%] in control; RD, 2.1% [95% CI, -3.6% to 7.8%]; RR, 1.27 [95% CI, 0.63 to 2.57]; P = .51), but incidence of BPD in survivors to 36 weeks' postmenstrual age was lower in the MIST group (81/217 [37.3%] vs 102/225 [45.3%] in the control group; RD, -7.8% [95% CI, -14.9% to -0.7%]; RR, 0.83 [95% CI, 0.70 to 0.98]; P = .03). Serious adverse events occurred in 10.3% of infants in the MIST group and 11.1% in the control group. Conclusions and Relevance: Among preterm infants with respiratory distress syndrome supported with CPAP, minimally invasive surfactant therapy compared with sham (control) treatment did not significantly reduce the incidence of the composite outcome of death or bronchopulmonary dysplasia at 36 weeks' postmenstrual age. However, given the statistical uncertainty reflected in the 95% CI, a clinically important effect cannot be excluded. Trial Registration: anzctr.org.au Identifier: ACTRN12611000916943.

Predicting extubation outcomes using the Heart Rate Characteristics index in preterm infants: a cohort study.

A strategy of early extubation to noninvasive respiratory support in preterm infants could be boosted by the availability of a decision support tool for clinicians. Using the Heart Rate Characteristics index (HRCi) with clinical parameters, we derived and validated predictive models for extubation readiness and success.Peri-extubation demographic, clinical and HRCi data for up to 96 h were collected from mechanically ventilated infants in the control arm of a randomised trial involving eight neonatal centres, where clinicians were blinded to the HRCi scores. The data were used to produce a multivariable regression model for the probability of subsequent re-intubation. Additionally, a survival model was produced to estimate the probability of re-intubation in the period after extubation.Of the 577 eligible infants, data from 397 infants (69%) were used to derive the pre-extubation model and 180 infants (31%) for validation. The model was also fitted and validated using all combinations of training (five centres) and test (three centres) centres. The estimated probability for the validation episodes showed discrimination with high statistical significance, with an area under the curve of 0.72 (95% CI 0.71-0.74; p<0.001). Data from all infants were used to derive models of the predictive instantaneous hazard of re-intubation adjusted for clinical parameters.Predictive models of extubation readiness and success in real-time can be derived using physiological and clinical variables. The models from our analyses can be accessed using an online tool available at www.heroscore.com/extubation, and have the potential to inform and supplement the confidence of the clinician considering extubation in preterm infants.

Efficacy and safety of systemic hydrocortisone for the prevention of bronchopulmonary dysplasia in preterm infants: a systematic review and meta-analysis.

Early lung inflammation has been implicated in the pathogenesis of bronchopulmonary dysplasia (BPD). We aimed to establish the efficacy and safety of systemic hydrocortisone for the prevention of BPD. A systematic review and meta-analysis were undertaken, with a detailed electronic literature search. Trials involving preterm infants were included if they were randomised to receive systemic hydrocortisone or a placebo. The primary outcome was the composite of survival without BPD at 36-week postmenstrual age (PMA). Results are presented as relative risk (RR) or risk difference (RD) with 95% confidence intervals (CIs), along with numbers needed to treat (NNT) or harm (NNH). After filtering, 12 studies using early (within 1 week of birth) and two using late hydrocortisone were identified. Early systemic hydrocortisone significantly increased the chances of survival without BPD (RR 1.13, 95% CI [1.01, 1.26], NNT 18), and survival without moderate-to-severe neurodevelopmental impairment (1.13 [1.02, 1.26], NNT 14). Infants who received hydrocortisone had a higher risk of intestinal perforation (1.69 [1.07, 2.68], NNH 30), primarily with concurrent treatment for patent ductus arteriosus.Conclusion: Early systemic hydrocortisone is a modestly effective therapy for the prevention of BPD in preterm infants, although some safety concerns remain. No conclusions could be drawn for late hydrocortisone due to the paucity of studies. What is Known: • Preterm infants are at high risk of developing bronchopulmonary dysplasia (BPD) and early lung inflammation plays a significant role in its pathogenesis. • Both early and late systemic dexamethasone seems to reduce the incidence of BPD, but its use is associated with serious neurodevelopmental impairment at follow-up. What is New: • Early systemic hydrocortisone significantly improved survival without BPD at 36 weeks and survival without moderate to severe neurodevelopmental impairment on follow up. • Incidence of gastrointestinal perforation associated with concurrent treatment for PDA was significantly higher, although early systemic hydrocortisone reduced the need for treatment of PDAs.

Predicting Extubation Outcomes-A Model Incorporating Heart Rate Characteristics Index.

OBJECTIVE: To test the hypothesis that in neonates on mechanical ventilation, heart rate characteristics index (HRCi) can be combined with a clinical model for predicting extubation outcomes in neonates. STUDY DESIGN: HRCi and clinical data for all intended intubation-extubation events (episodes) were retrospectively analyzed between June 2014 and January 2015. Each episode started 6 hours pre-extubation or at the time of primary intubation if ventilation duration was shorter than 6 hours (baseline). The episodes ended at 72 hours postextubation for successful extubations or at reintubation for failed extubations. Mean of 6 hourly epoch HRCi-scores (baseline) or fold-changes (postextubation) were analyzed. Results are expressed as medians (IQR) for continuous data and proportions for categorical data. Multivariable logistic regression mixed model was used for statistical analysis. RESULTS: Sixty-six infants contributed to 96 episodes (18 failed extubations, 78 successful extubations) in the study. Failed extubations had significantly longer duration of ventilation (65.3 hours, 19.94-158.2 vs 38.4, 16.5-71.3) and more culture positive sepsis (33.3% vs 3.8%) than successful extubations. Baseline HRCi scores (1.68, 1.29-2.45 vs 0.95, 0.54-1.86) and postextubation epoch-1 fold changes (1.25, 0.94-1.55 vs 0.94, 0.82-1.11) were higher in failed extubations compared with successful extubations. Multivariable linear mixed-effects regression was used to create prediction models for success of extubation, using relevant variables. CONCLUSIONS: The baseline and postextubation HRCi were significantly higher in neonates with extubation failure compared with those who succeeded. Models using HRCi and clinical variables to predict extubation success may add to the confidence of clinicians considering extubation.

Prophylactic Acid-suppression Medication to Prevent Anastomotic Strictures After Oesophageal Atresia Surgery: A Systematic Review and Meta-analysis.

BACKGROUND: Anastomotic stricture is a common postoperative complication of oesophageal atresia ± tracheoesophageal fistula (OA/TOF) repair. Acid gastro-oesophageal reflux disease (GORD) is considered to be a factor in stricture formation and acid suppression medication is recommended post-operatively in consensus guidance. We aimed to investigate whether patients who were treated prophylactically with acid suppression medication had a reduced incidence of strictures compared to those who did not receive it. METHODS: A systematic review of studies was performed, searching multiple databases without language or date restrictions. Multiple reviewers independently assessed study eligibility and literature quality. The primary outcome was anastomotic stricture formation, with secondary outcomes of GORD, anastomotic leak, and oesophagitis. Meta-analysis was performed using a random effects model, and the results were expressed as an odds ratio (OR) with 95% confidence intervals (CI). RESULTS: No randomised studies on the topic were identified. Twelve observational studies were included in the analysis with ten reporting the primary outcome. The quality assessment showed a high risk of bias in several papers, predominantly due to non-objective methods of assessment of oesophageal stricture and the non-prospective, non-randomised nature of the studies. Overall, 1395 patients were evaluated, of which 753 received acid suppression medication. Meta-analysis revealed a trend towards increased odds of anastomotic strictures in infants receiving prophylactic medication, but this was not statistically significant (OR 1.33; 95% CI 0.92, 1.92). No significant differences were found in secondary outcomes. CONCLUSIONS: This meta-analysis found no evidence of a statistically significant link between the prophylactic prescribing of acid suppression medication and the risk of developing anastomotic stricture after OA repair. The literature in this area is limited to observational studies and a randomised controlled trial is recommended to explore this question. LEVEL OF EVIDENCE: Level III.

Early childhood parent-reported speech problems in small and large for gestational age term-born and preterm-born infants: a cohort study.

OBJECTIVE: (1) To assess if preterm and term small for gestational age (SGA) or large for gestational age (LGA) infants have more parent-reported speech problems in early childhood compared with infants with birth weights appropriate for gestational age (AGA). (2) To assess if preterm and term SGA and LGA infants have more parent-reported learning, behavioural, hearing, movement and hand problems in early childhood compared with AGA infants. DESIGN: Cohort study. SETTING: Wales, UK. PARTICIPANTS: 7004 children with neurodevelopmental outcomes from the Respiratory and Neurological Outcomes of Children Born Preterm Study which enrolled 7129 children, born from 23 weeks of gestation onwards, to mothers aged 18-50 years of age were included in the analysis. OUTCOME MEASURES: Parent-reported single-answer questionnaires were completed in 2013 to assess early childhood neurodevelopmental outcomes. The primary outcome was parent-reported speech problems in early childhood adjusted for clinical and demographic confounders in SGA and LGA infants compared with AGA infants. Secondary outcomes measured were parent-reported early childhood learning, behavioural, hearing, movement and hand problems. RESULTS: Median age at the time of study was 5 years, range 2-10 years. Although the adjusted OR was 1.19 (0.92 to 1.55) for SGA infants and OR 1.11 (0.88 to 1.41) for LGA infants, this failed to reach statistical significance that these subgroups were more likely to have parent-reported speech problems in early childhood compared with AGA infants. This study also found parent-reported evidence suggestive of potential learning difficulties in early childhood (OR 1.51 (1.13 to 2.02)) and behavioural problems (OR 1.35 (1.01 to 1.79)) in SGA infants. CONCLUSION: This study of 7004 infants in Wales suggests that infants born SGA or LGA likely do not have higher risks of parent-reported speech problems in early childhood compared with infants born AGA. To further ascertain this finding, studies with wider population coverage and longer-term follow-up would be needed.

Measuring the impact of deprivation on learning difficulties and behaviour among infants born preterm: A cohort study.

BACKGROUND: Preterm birth and social deprivation are known risk factors for learning difficulties. However there has been little work looking into the interaction between these two risks. We aimed to identify if children born preterm to families with higher levels of social deprivation are disproportionately more likely to have learning difficulties than those with lower levels of social deprivation. METHODS: Data from the RANOPS (Respiratory And Neurological Outcomes in children born Preterm Study) was used to assess prevalence of learning difficulties. The effects of preterm birth and deprivation were reviewed. Multi-level logistic regression models were used to examine if gestational age and deprivation impacts interacted after adjustment for possible confounders. Primary outcome measure was parent-reported learning difficulties. Secondary outcome measures were parent-reported behavioural problems and a statement of special educational need. RESULTS: We investigated the developmental outcomes of 6,691 infants with a median age of 5 years at time of survey (IQR 5). Deprivation decile (OR 1.08 (1.03,1.12)) and preterm birth (OR 2.67 (2.02,3.53)) were both associated with increased risk of learning difficulties. There was little evidence for any interaction between preterm birth and deprivation (p = 0.298) and the risk of learning difficulties. CONCLUSIONS: Deprivation and preterm birth have significant associations with learning difficulties. While deprivation does not appear to have potentiated the impact of preterm birth, preterm infants in the most deprived areas have the highest risk of learning difficulties with almost 1 in 3 extremely premature infants with a learning difficulty in the most deprived areas.

Immune and metabolic markers for identifying and investigating severe Coronavirus disease and Sepsis in children and young people (pSeP/COVID ChYP study): protocol for a prospective cohort study.

INTRODUCTION: Early recognition and appropriate management of paediatric sepsis are known to improve outcomes. A previous system's biology investigation of the systemic immune response in neonates to sepsis identified immune and metabolic markers that showed high accuracy for detecting bacterial infection. Further gene expression markers have also been reported previously in the paediatric age group for discriminating sepsis from control cases. More recently, specific gene signatures were identified to discriminate between COVID-19 and its associated inflammatory sequelae. Through the current prospective cohort study, we aim to evaluate immune and metabolic blood markers which discriminate between sepses (including COVID-19) from other acute illnesses in critically unwell children and young persons, up to 18 years of age. METHODS AND ANALYSIS: We describe a prospective cohort study for comparing the immune and metabolic whole-blood markers in patients with sepsis, COVID-19 and other illnesses. Clinical phenotyping and blood culture test results will provide a reference standard to evaluate the performance of blood markers from the research sample analysis. Serial sampling of whole blood (50 µL each) will be collected from children admitted to intensive care and with an acute illness to follow time dependent changes in biomarkers. An integrated lipidomics and RNASeq transcriptomics analyses will be conducted to evaluate immune-metabolic networks that discriminate sepsis and COVID-19 from other acute illnesses. This study received approval for deferred consent. ETHICS AND DISSEMINATION: The study has received research ethics committee approval from the Yorkshire and Humber Leeds West Research Ethics Committee 2 (reference 20/YH/0214; IRAS reference 250612). Submission of study results for publication will involve making available all anonymised primary and processed data on public repository sites. TRIAL REGISTRATION NUMBER: NCT04904523.

Challenging molecular dogmas in human sepsis using mathematical reasoning.

Sepsis is defined as a dysregulated host-response to infection, across all ages and pathogens. What defines a dysregulated state remains intensively researched but incompletely understood. Here, we dissect the meaning of this definition and its importance for the diagnosis and management of sepsis. We deliberate on pathophysiological features and dogmas that range from cytokine storms and immune paralysis to dormancy and altered homeostasis setpoints. Mathematical reasoning, used to test for plausibility, reveals three interlinked cardinal rules governing host-response trajectories in sepsis. Rule one highlights that the amplitude of the immune response while important is not sufficient and is strictly dependent on rule two, specifying bioenergetic capacity and are together dynamically driven by rule three, delineating stability and alterations in setpoints. We consider these rules and associated pathophysiological parameters for guiding data-science and artificial intelligence mining of multi-omics and big-data for improving the precision of diagnostic and therapeutic approaches to sepsis. FUNDING: PG funded by the European Regional Development Fund and Welsh Government (Ser Cymru programme - Project Sepsis).

Estimating insertion length of umbilical arterial and venous catheters in newborn infants: time for change.

BACKGROUND: Umbilical catheters are inserted through the umbilical artery or vein at birth and are crucial in neonatal care. There are several different methods of estimating adequate insertion length of umbilical catheters based on one of two hypotheses; that the insertion length of the UC is correlated to either the infant's birth weight or an external length measurement. AIM: To review the published literature on methods of estimating insertion lengths of umbilical arterial catheters (UACs) and umbilical venous catheters (UVCs) in newborn infants. METHODS: Systematic search on Medline was undertaken using keywords for relevant papers up to March 2019. Papers were selected by manual search of titles and abstracts. RESULTS: Formulae for predicting umbilical catheter insertion length are unreliable, particularly for UVCs. There is also conflicting evidence around whether birth weight-based formulae are more reliable than external length-based formulae. Studies comparing various methods to determine their efficacy to show that current formulae have a low accuracy for determining both UVC and UAC positioning. CONCLUSIONS: Current formulae for estimating insertion length of umbilical catheters are not fit for purpose. We propose a new observational study which uses a new external length measurement, the sternal notch to umbilicus length, to develop a more reliable formula for the insertion of UVC and UAC to an adequate length.

Global health systems' data science approach for precision diagnosis of sepsis in early life.

Neonates and children in low-income and middle-income countries (LMICs) contribute to the highest number of sepsis-associated deaths globally. Interventions to prevent sepsis mortality are hampered by a lack of comprehensive epidemiological data and pathophysiological understanding of biological pathways. In this review, we discuss the challenges faced by LMICs in diagnosing sepsis in these age groups. We highlight a role for multi-omics and health care data to improve diagnostic accuracy of clinical algorithms, arguing that health-care systems urgently need precision medicine to avoid the pitfalls of missed diagnoses, misdiagnoses, and overdiagnoses, and associated antimicrobial resistance. We discuss ethical, regulatory, and systemic barriers related to the collection and use of big data in LMICs. Technologies such as cloud computing, artificial intelligence, and medical tricorders might help, but they require collaboration with local communities. Co-partnering (joint equal development of technology between producer and end-users) could facilitate integration of these technologies as part of future care-delivery systems, offering a chance to transform the global management and prevention of sepsis for neonates and children.

mSep: investigating physiological and immune-metabolic biomarkers in septic and healthy pregnant women to predict feto-maternal immune health - a prospective observational cohort study protocol.

INTRODUCTION: Maternal sepsis remains a leading cause of death in pregnancy. Physiological adaptations to pregnancy obscure early signs of sepsis and can result in delays in recognition and treatment. Identifying biomarkers that can reliably diagnose sepsis will reduce morbidity and mortality and antibiotic overuse. We have previously identified an immune-metabolic biomarker network comprising three pathways with a >99% accuracy for detecting bacterial neonatal sepsis. In this prospective study, we will describe physiological parameters and novel biomarkers in two cohorts-healthy pregnant women and pregnant women with suspected sepsis-with the aim of mapping pathophysiological drivers and evaluating predictive biomarkers for diagnosing maternal sepsis. METHODS AND ANALYSIS: Women aged over 18 with an ultrasound-confirmed pregnancy will be recruited to a pilot and two main study cohorts. The pilot will involve blood sample collection from 30 pregnant women undergoing an elective caesarean section. Cohort A will follow 100 healthy pregnant women throughout their pregnancy journey, with collection of blood samples from participants at routine time points in their pregnancy: week 12 'booking', week 28 and during labour. Cohort B will follow 100 pregnant women who present with suspected sepsis in pregnancy or labour and will have at least two blood samples taken during their care pathway. Study blood samples will be collected during routine clinical blood sampling. Detailed medical history and physiological parameters at the time of blood sampling will be recorded, along with the results of routine biochemical tests, including C reactive protein, lactate and white blood cell count. In addition, study blood samples will be processed and analysed for transcriptomic, lipidomic and metabolomic analyses and both qualitative and functional immunophenotyping. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Wales Research Ethics Committee 2 (SPON1752-19, 30 October 2019). TRIAL REGISTRATION NUMBER: NCT05023954.

Volatile organic compounds as disease predictors in newborn infants: a systematic review.

Volatile organic compounds (VOCs) detected in human breath, urine, stool, sweat, saliva, and blood result from metabolic processes in the body during health or disease. Using sophisticated measurement systems, small amounts of these compounds can be detected in the above bodily fluids. Multiple studies in adults and children have shown the potential of these compounds to differentiate between healthy individuals and patients by detecting profiles of compounds in non-invasively collected samples. However, the detection of biomarkers in VOCs from neonates is particularly attractive due to the non-invasive nature of its approach, and its ability to track disease progress by longitudinal sampling. In this work we have reviewed the literature on the use of VOCs in neonates and identified areas for future work. Overview of VOCs and their usefulness as metabolic signatures. Detailed review of studies on VOCs in neonates Learn about potential uses of VOCs as derived from adult and paediatric studies. Examine current limitations and identify future work. Detailed studies on VOCs involving neonatal patients including sick preterm infants and term infants with specific morbidities are needed. These studies should collect longitudinal samples using non-invasive methods for the detection of potential biomarkers. Underlying metabolic processes need to be identified so that any therapeutic options can be clarified.

nSeP: immune and metabolic biomarkers for early detection of neonatal sepsis-protocol for a prospective multicohort study.

INTRODUCTION: Diagnosing neonatal sepsis is heavily dependent on clinical phenotyping as culture-positive body fluid has poor sensitivity, and existing blood biomarkers have poor specificity.A combination of machine learning, statistical and deep pathway biology analyses led to the identification of a tripartite panel of biologically connected immune and metabolic markers that showed greater than 99% accuracy for detecting bacterial infection with 100% sensitivity. The cohort study described here is designed as a large-scale clinical validation of this previous work. METHODS AND ANALYSIS: This multicentre observational study will prospectively recruit a total of 1445 newborn infants (all gestations)-1084 with suspected early-or late-onset sepsis, and 361 controls-over 4 years. A small volume of whole blood will be collected from infants with suspected sepsis at the time of presentation. This sample will be used for integrated transcriptomic, lipidomic and targeted proteomics profiling. In addition, a subset of samples will be subjected to cellular phenotype and proteomic analyses. A second sample from the same patient will be collected at 24 hours, with an opportunistic sampling for stool culture. For control infants, only one set of blood and stool sample will be collected to coincide with clinical blood sampling. Along with detailed clinical information, blood and stool samples will be analysed and the information will be used to identify and validate the efficacy of immune-metabolic networks in the diagnosis of bacterial neonatal sepsis and to identify new host biomarkers for viral sepsis. ETHICS AND DISSEMINATION: The study has received research ethics committee approval from the Wales Research Ethics Committee 2 (reference 19/WA/0008) and operational approval from Health and Care Research Wales. Submission of study results for publication will involve making available all anonymised primary and processed data on public repository sites. TRIAL REGISTRATION NUMBER: NCT03777670.

Acute lung injury in preterm newborn infants: mechanisms and management.

Respiratory morbidity and mortality remain common in preterm infants. The immature preterm lung is especially prone to injury. This process often starts in-utero due to maternal chorioamnionitis, priming the lung for further injury in response to post-natal ventilation, oxygen and nosocomial infection. Pulmonary inflammation has been strongly implicated in the pathway leading to lung injury in this population of infants. Several therapeutic approaches have been attempted to prevent acute lung injury or to limit its progress. The mechanisms of acute lung injury in preterm infants; their clinical correlates and available therapeutic approaches are reviewed here.

Management of Respiratory Distress Syndrome in Preterm Infants In Wales: A Full Audit Cycle of a Quality Improvement Project.

Respiratory Distress Syndrome (RDS) is the commonest diagnosis after premature birth. We aimed to audit clinical practices before and after introduction of a national guideline in Wales on RDS management. Anonymised, prospective data on all infants born at <34 weeks of gestation and cared for at one of the participating neonatal units in Wales were collected in two six-month time periods in 2015 and 2018. A national guideline was introduced in 2016 by the Wales Neonatal Network. Data collection included areas of antenatal management, delivery room stabilisation, invasive and non-invasive respiratory support, surfactant treatment and elements of supportive care. Univariate and multivariate methods were used to compare data between the two epochs. Comparing care before and after introduction of the national guideline, areas of significant improvement include use of targeted tidal volume ventilation, use of caffeine therapy, oxygen therapy post-surfactant and increasing early use of parenteral nutrition. Areas of poorer management included levels of positive end expiratory pressures and timing of introduction of enteral feeds. Little variation was seen between level two and three units, although gestational age was a significant independent variable for several practices, including delayed cord clamping, stabilisation with intubation, early enteral feeding and caffeine administration. A national guideline for management of RDS in Wales has significantly improved practice in several areas. However, despite a large volume of high-quality evidence and robust guidance, there remains a significant variation in some elements of best practice for RDS management. Further work should focus on education and training, especially for elements requiring cross-departmental work.