Modulation of lung inflammation of preterm ventilated infants: role of IL-6 trans-signalling and IL-8 isoforms

Chronic lung disease (CLD) is a common respiratory sequalae of infants born extremely premature (< 32 weeks gestational age). A persistent and poorly-resolving neutrophilic lung inflammation has been strongly implicated in the development of CLD. Pathways of resolution of lung inflammation have been poorly characterised in preterm infants. Interleukin-8 (IL-8) is an key neutrophil chemokine implicated in the pathogenesis of CLD. Longer, and less functionally potent, isoforms of IL-8 predominate the preterm circulation but their expression and function in the preterm lungs is not known. The complex of interleukin-6 (IL-6), along with the soluble IL-6 receptor (sIL-6R), initiates IL-6 trans-signalling which experimentally has demonstrated downregulation of IL-8 during acute inflammation. Expression of IL-6 trans-signalling cytokines and their functional activity in the preterm lungs have not been studied. My work shows that the concentration of sgp130, a specific inhibitor of IL-6 trans-signalling, was significantly increased in the bronchoalveolar lavage fluid (BALF) of preterm ventilated baboons, and human infants developing CLD later, compared to infants who did not. Although total IL-6 activity was detected in a specific functional assay, IL-6 trans-signalling activity could not be detected from the BALF samples or by using a complex from recombinant cytokines. I have shown that the long isoform of IL-8, IL-877 was a minor proportion of total IL-8 in the preterm ventilated BALF, although significant expression of IL-877 was detected in vitro from lung cells. Preterm BALF efficiently converted exogenously added recombinant IL-877 to shorter isoforms, mainly by the activity of serine proteases from neutrophils and the clotting cascade. BALF from CLD infants converted significantly more IL-877, compared to BALF from No-CLD infants. Among the neutrophil serine proteases, proteinase-3 (Pr-3) converted IL-877 to functionally more potent isoforms; Pr-3 antigen and thrombin activity was also significantly increased in BALF from CLD infants, making them attractive targets for intervention

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

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

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

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

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

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

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