Pressure and tidal volume delivery in extremely preterm infants at birth using different t-piece resuscitation devices.

Infants <28 weeks' gestation in need of inflations at birth were recorded with Respiratory Function Monitor. Two devices were used for resuscitation. Peak Inspiratory Pressure spikes were visible in all inflations with GE Panda and in none with Neo-Puff. There was no significant difference in mean Vte/kg between GE Panda and Neo-Puff.

Longitudinal changes in lung function in very prematurely born young people receiving high-frequency oscillation or conventional ventilation from birth.

OBJECTIVE: To examine changes in lung function over time in extremely prematurely born adolescents. WORKING HYPOTHESIS: Changes in lung function during adolescence would vary by ventilation mode immediately after birth. STUDY DESIGN: Longitudinal follow-up study. PATIENT SUBJECT SELECTION: Participants from the United Kingdom Oscillation Study who were randomized at birth to high-frequency oscillation (HFO) or conventional ventilation (CV) were assessed at 11-14 years (n = 319) and at 16-19 years (n = 159). METHODOLOGY: Forced expiratory flow (FEF), forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and lung volumes including functional residual capacity (FRC) were reported as z-scores. The diffusion capacity of the lungs for carbon monoxide (DLCO) was measured. Lung function trajectories were compared by mode of ventilation using mixed models. Changes in z-scores were scaled to 5-year average follow-up. RESULTS: There were significant changes in the mean FEF75, FEF50, FEF25, FEV1, FVC, and DLCO z-scores within the CV and HFO cohorts, but no significant differences in the changes between the two groups. The mean FRC z-score increased in both groups, with an average change of greater than one z-score. The mean FEV1/FVC z-score increased significantly in the CV group, but not in the HFO group (difference in slopes: p = 0.02). Across the population, deterioration in lung function was associated with male sex, white ethnicity, lower gestational age at birth, postnatal corticosteroids, oxygen dependency at 36 weeks postmenstrual age, and lower birth weight, but not ventilation mode. CONCLUSIONS: There was little evidence that the mode of ventilation affected changes in lung function over time.

Respiratory management and bronchopulmonary dysplasia in extremely preterm infants: a comparison of practice between centres in Oxford and Melbourne.

OBJECTIVE: Considerable variation in the care of extremely low gestational age infants (ELGAN) contributes to the variation in incidence of bronchopulmonary dysplasia (BPD). We compared management and outcomes of two neonatal centres with different respiratory support strategies. STUDY DESIGN: Retrospective cohort study of infants <28 weeks gestational age treated at two units in Australia and the UK between 2015 and 2017. RESULT: Of 492 infants, the overall incidence of BPD for extremely preterm infants was 62.20% and was similar across both sites (64.84% at Monash vs. 60.65% at Oxford). Independent predictors for the development of BPD or mortality included the days on mechanical ventilation (MV, adjusted OR 1.13, 95% Cl 1.07-1.19) and use of inhaled nitric oxide (adjusted OR 13.42, 95% Cl 1.75-103.28). CONCLUSION: Primary choice of non-invasive respiratory support had no significant impact on BPD development. Duration of MV and using nitric oxide were independent predictors for death or BPD.

Enteral Feeding Strategies in Preterm Neonates ≤32 weeks Gestational Age: A Systematic Review and Network Meta-Analysis.

INTRODUCTION: Critical aspects of time of feed initiation, advancement, and volume of feed increment in preterm neonates remain largely unanswered. METHODS: Medline , Embase, CENTRAL and CINAHL were searched from inception until 25th September 2020. Network meta-analysis with the Bayesian approach was used. Randomized controlled trials (RCTs) evaluating preterm neonates ≤32 weeks were included. Feeding regimens were divided based on the following categories: initiation day: early (<72 h), moderately early (72 h-7 days), and late (>7 days); advancement day: early (<72 h), moderately early (72 h-7 days), and late (>7 days); increment volume: small volume (SV) (<20 mL/kg/day), moderate volume (MoV) (20-< 30 mL/kg/day), and large volume (≥30 mL/kg/day); and full enteral feeding from the first day. Sixteen regimens were evaluated. Combined outcome of necrotizing enterocolitis (NEC) stage ≥ II or mortality before discharge was the primary outcome. RESULTS: A total of 39 studies enrolled around 6,982 neonates. Early initiation (EI) with moderately early or late advancement using MoV increment enteral feeding regimens appeared to be most efficacious in decreasing the risk of NEC or mortality when compared to EI and early advancement with SV increment (risk ratio [95% credible interval]: 0.39 [0.12, 0.95]; 0.34 [0.10, 0.86]) (GRADE-very low). CONCLUSIONS: Early initiated, moderately early, or late advanced with MoV increment feeding regimens might be most appropriate in decreasing the risk of NEC stage ≥II or mortality. In view of the certainty of evidence being very low, adequately powered RCTs evaluating these 2 strategies are warranted.

Postnatal dexamethasone exposure and lung function in adolescents born very prematurely.

We previously demonstrated corticosteroid administration on the neonatal intensive care unit was associated with reduced lung function at 11 to 14 years of age in children born very prematurely. The objective of this observational study was to assess if lung function remained impaired at 16 to 19 years of age in those who had received postnatal corticosteroids and whether the trajectory of lung function with increasing age differed between those who had and had not received corticosteroids. One hundred and fifty-nine children born prior to 29 weeks of gestational age had comprehensive lung function measurements; 49 had received postnatal dexamethasone. Lung function outcomes were compared between those who had and had not received postnatal dexamethasone after adjustment for neonatal factors. Forced expiratory flow at 75%, 50%, 25% and 25-75% of the expired vital capacity, forced expiratory volume in one second, peak expiratory flow and forced vital capacity and lung volumes (total lung capacity and residual volume) were assessed. The majority of results were significantly lower in those who received dexamethasone (between 0.61 to 0.78 standard deviations). Lung function reduced as the number of courses of dexamethasone increased. Between 11 and 14 years and 16 to 19 years, lung function improved in the unexposed group, but forced expiratory flow at 75% of the expired vital capacity and forced expiratory volume in one second deteriorated in those who had received postnatal corticosteroids (p = 0.0006). These results suggest that prematurely born young people who received postnatal corticosteroids may be at risk of premature onset of chronic obstructive pulmonary disease.

Exploring the Conformational Landscape of Bioactive Small Molecules.

By using a combination of classical Hamiltonian replica exchange with high-level quantum mechanical calculations on more than one hundred drug-like molecules, we explored here the energy cost associated with binding of drug-like molecules to target macromolecules. We found that, in general, the drug-like molecules present bound to proteins in the Protein Data Bank (PDB) can access easily the bioactive conformation and in fact for 73% of the studied molecules the "bioactive" conformation is within 3kBT from the most-stable conformation in solution as determined by DFT/SCRF calculations. Cases with large differences between the most-stable and the bioactive conformations appear in ligands recognized by ionic contacts, or very large structures establishing many favorable interactions with the protein. There are also a few cases where we observed a non-negligible uncertainty related to the experimental structure deposited in PDB. Remarkably, the rough automatic force field used here provides reasonable estimates of the conformational ensemble of drugs in solution. The outlined protocol can be used to better estimate the cost of adopting the bioactive conformation.

Bioactive Conformational Ensemble Server and Database. A Public Framework to Speed Up In Silico Drug Discovery.

Modern high-throughput structure-based drug discovery algorithms consider ligand flexibility, but typically with low accuracy, which results in a loss of performance in the derived models. Here we present the bioactive conformational ensemble (BCE) server and its associated database. The server creates conformational ensembles of drug-like ligands and stores them in the BCE database, where a variety of analyses are offered to the user. The workflow implemented in the BCE server combines enhanced sampling molecular dynamics with self-consistent reaction field quantum mechanics (SCRF/QM) calculations. The server automatizes all of the steps to transform one-dimensional (1D) or 2D representation of drugs into 3D molecules, which are then titrated, parametrized, hydrated, and optimized before being subjected to Hamiltonian replica-exchange (HREX) molecular dynamics simulations. Ensembles are collected and subjected to a clustering procedure to derive representative conformers, which are then analyzed at the SCRF/QM level of theory. All structural data are organized in a noSQL database accessible through a graphical interface and in a programmatic manner through a REST API. The server allows the user to define a private workspace and offers a deposition protocol as well as input files for "in house" calculations in those cases where confidentiality is a must. The database and the associated server are available at https://mmb.irbbarcelona.org/BCE.

DFFR: A New Method for High-Throughput Recalibration of Automatic Force-Fields for Drugs.

We present drug force-field recalibration (DFFR), a new method for refining of automatic force-fields used to represent small drugs in docking and molecular dynamics simulations. The method is based on fine-tuning of torsional terms to obtain ensembles that reproduce observables derived from reference data. DFFR is fast and flexible and can be easily automatized for a high-throughput regime, making it useful in drug-design projects. We tested the performance of the method in a few model systems and also in a variety of druglike molecules using reference data derived from: (i) density functional theory coupled to a self-consistent reaction field (DFT/SCRF) calculations on highly populated conformers and (ii) enhanced sampling quantum mechanical/molecular mechanics (QM/MM) where the drug is reproduced at the QM level, while the solvent is represented by classical force-fields. Extension of the method to include other sources of reference data is discussed.

A Comparison of UK Preterm Anthropometric Charts and INTERGROWTH-21st: Is It Time to Change Growth Charts?

BACKGROUND: Current practice in the UK is to plot premature infant anthropometric measurements on Neonatal and Infant Close Monitoring (NICM) reference charts. These charts have several known limitations. The INTERGROWTH-21st Project has recently produced international ante- and postnatal growth standards. Exact knowledge of growth centiles allows clinicians to accurately assess infant nutritional requirements. OBJECTIVE: To compare target centile measurements between INTERGROWTH-21st and UK NICM growth charts for premature infants. METHOD: Anthropometric measurements (weight and head circumference) of a convenience sample of neonates born between 24 and 32 weeks of gestation were analysed retrospectively. Measurements were collected across three time points and plotted on both the NICM and INTERGROWTH-21st growth charts. The respective centiles were compared and analysed by paired-sample t test, Wilcoxon rank test analysis, and multilevel mixed-effect linear regression models. RESULTS: Centiles for weight and head circumference measurements of 96 infants plotted on INTERGROWTH-21st charts were significantly greater than their corresponding UK charts at all three time points. For weight, the average difference between the two charts varied from 9.1 to 16.4 centiles. The difference between the two charts was greater for female than male infants by up to 6.9 centiles (95% CI 10.1-3.8). CONCLUSION: Existing UK NICM reference charts are significantly different to the growth standards of INTERGROWTH-21st. The choice of which growth chart to adopt in the UK could have important consequences on premature infants' future adult health and therefore requires further prospective observational studies with larger data sets including length measurements and more comprehensive population characteristics.

Caffeine in preterm infants: where are we in 2020?

The incidence of preterm birth is increasing, leading to a growing population with potential long-term pulmonary complications. Apnoea of prematurity (AOP) is one of the major challenges when treating preterm infants; it can lead to respiratory failure and the need for mechanical ventilation. Ventilating preterm infants can be associated with severe negative pulmonary and extrapulmonary outcomes, such as bronchopulmonary dysplasia (BPD), severe neurological impairment and death. Therefore, international guidelines favour non-invasive respiratory support. Strategies to improve the success rate of non-invasive ventilation in preterm infants include pharmacological treatment of AOP. Among the different pharmacological options, caffeine citrate is the current drug of choice. Caffeine is effective in reducing AOP and mechanical ventilation and enhances extubation success; it decreases the risk of BPD; and is associated with improved cognitive outcome at 2 years of age, and pulmonary function up to 11 years of age. The commonly prescribed dose (20 mg·kg-1 loading dose, 5-10 mg·kg-1 per day maintenance dose) is considered safe and effective. However, to date there is no commonly agreed standardised protocol on the optimal dosing and timing of caffeine therapy. Furthermore, despite the wide pharmacological safety profile of caffeine, the role of therapeutic drug monitoring in caffeine-treated preterm infants is still debated. This state-of-the-art review summarises the current knowledge of caff-eine therapy in preterm infants and highlights some of the unresolved questions of AOP. We speculate that with increased understanding of caffeine and its metabolism, a more refined respiratory management of preterm infants is feasible, leading to an overall improvement in patient outcome.

Lung function and respiratory outcomes in teenage boys and girls born very prematurely.

OBJECTIVES: Male sex in prematurely born infants has been associated with worse respiratory outcomes in early childhood. WORKING HYPOTHESIS: Respiratory outcomes at 11 to 14 years of age in children born very prematurely and routinely exposed to antenatal corticosteroids and postnatal surfactant would differ according to sex. STUDY DESIGN: Analysis of follow-up data. PATIENT-SUBJECT SELECTION: Three hundred and nineteen children born before 29 weeks of gestational age from the United Kingdom Oscillation Study. METHODOLOGY: Spirometry was used to assess forced expiratory flow at 75%, 50%, and 25% of expired vital capacity (FEF75 , FEF50 , and FEF25 ), forced expiratory volume in 1 second (FEV1 ), peak expiratory flow (PEF), and forced vital capacity (FVC). Lung volumes were measured using a helium dilution technique (FRCHe ) and by plethysmography (FRCpleth ). Total lung capacity (TLC) and residual volume (RV) were calculated. Mean lung function measurements were compared using linear mixed models and reported as unadjusted and adjusted for neonatal and age 11 to 14 years factors. The participants also completed health questionnaires and provided a urine sample for assessment of passive or active smoking. RESULTS: Three (FEF25 , FEF25-75 , FEV1 ) lung function measures showed significant differences in favor of females after adjustment. The percentage of children with abnormal lung function (below 5th centile for normal) had adjusted differences between 10 and 30 percentage points, for example, for FEF25 15% females compared with 26% males. CONCLUSIONS: Among extremely prematurely born school children airway function was significantly worse in males.

Variations in preterm stabilisation practices and caffeine therapy between two European tertiary level neonatal units.

AIM: To investigate interinstitutional differences in preterm infant stabilisation between two European tertiary neonatal centres with particular focus on intubation timing, surfactant administration, caffeine therapy and neonatal morbidity and mortality. METHODS: Retrospective (2012-2014) study of very low birth weight (VLBW) preterm infants admitted to John Radcliffe Hospital (UK centre) and Charité Medical Centre (German centre). Timing of intubation, surfactant and caffeine administration and respiratory outcomes were examined. RESULTS: Gestational age, birth weight and five-minute Apgar scores of VLBW infants from the UK centre (n = 86) were comparable to those from the German centre (n = 96). Significant differences in antenatal steroid therapy, intubation timing and surfactant therapy were noted. Timing of caffeine initiation differed significantly between centres (median 0 [0-2.5] UK vs. 2 [1.5-4] days German centre); however, caffeine was discontinued at a similar corrected gestational age of 34.7 weeks. Mechanical ventilation was significantly longer at the UK centre, but there was no difference in bronchopulmonary dysplasia (BPD) (44% UK vs. 36% German centre) or mortality (15% UK vs. 13% German centre). CONCLUSION: Timing of primary intubation and caffeine therapy differed significantly between centres. However, earlier intubation and caffeine administration in the UK centre were not associated with a changed incidence of BPD.

Pigtail catheters versus traditional chest drains for pneumothorax treatment in two NICUs.

Pneumothorax in newborns can be life-threatening. The traditional treatment of pneumothorax is chest drain placement. Recently, modified pigtail catheter has been proposed as a less traumatic approach despite limited experience in infants. To compare the effectiveness and safety of pigtail catheters versus traditional straight chest drains in term and preterm infants with pneumothorax, in two tertiary neonatal units: Policlinico Hospital in Bari, IT and John Radcliffe Hospital in Oxford, UK. We retrospectively reviewed medical records of 47 newborns with pneumothorax admitted to the two units between October 2009 and June 2017, and treated with either pigtail catheters or straight chest drains. Three newborns (6.7%) were excluded from the study because they were treated with both types of drains. The remaining 44 neonates were included in the analysis. Overall, 56.8% (n = 25/44) of pneumothoraces were drained with pigtail catheters and 43.2% (n = 19/44) with straight drains. No differences in gestational age and birth weight were found. The success rate, defined as complete radiological resolution of the pneumothorax after drainage, was significantly higher in the pigtail group (96.0% versus 73.7%; p < 0.05). Days of drainage, length of hospital stay and duration of respiratory support were not significantly different. Subcutaneous emphysema and drain dislodgement/malfunction occurred only in the straight drain group (0.0% versus 11.1%; p = 0.181). No significant differences in mortality between the two groups were found (28.0% pigtail group versus 26.3% straight drain group; p > 0.05).Conclusion: Pigtail catheters are a safe and effective alternative to traditional chest drains for infants with pneumothorax. What is Known:• Air leaks in newborns can represent an emergency, especially among preterms;• The first treatment in a life-threatening pneumothorax is thoracentesis with needle aspiration or placement of a chest drain.What is New:• Pigtail catheter have been described as an alternative to traditional chest drains;• Pigtail catheters are a safe and effective alternative to traditional chest drains for infants with pneumothorax.

Participant retention in follow-up studies of prematurely born children.

BACKGROUND: Follow-up studies of infants born prematurely are essential to understand the long-term consequences of preterm birth and the efficacy of interventions delivered in the neonatal period. Retention of participants for follow-up studies, however, is challenging, with attrition rates of up to 70%. Our aim was to examine retention rates in two follow-up studies of prematurely born children and identify participant or study characteristics that were associated with higher attrition, and to discuss retention strategies with regard to the literature. METHODS: Data from children recruited at birth to one of two studies of prematurely born infants were assessed. The two studies were the United Kingdom Oscillation Study (UKOS, a randomised study comparing two modes of neonatal ventilation in infants born less than 29 weeks of gestational age (GA)), and an observational study examining the impact of viral lower respiratory tract infections in infancy in those born less than 36 weeks of GA (virus study). The UKOS participants, but not those in the virus study, had regularly been contacted throughout the follow-up period. UKOS subjects were followed up at 11 to 14 years of age and subjects in the virus study at 5-7 years of age. At follow up in both studies, pulmonary function and respiratory morbidity were assessed. Retention rates to follow-up in the two studies and baseline characteristics of those who were and were not retained were assessed. RESULTS: Retention was significantly higher in UKOS than the virus study (61% versus 35%, p < 0.0001). Subjects lost to UKOS follow up had greater deprivation scores (p < 0.001), a greater likelihood of intrauterine tobacco exposure (p = 0.001) and were more likely to be of non-white ethnicity (p < 0.001). In the virus study, those lost to follow-up had higher birth weights (p = 0.036) and were less likely to be oxygen dependent at hospital discharge (p = 0.003) or be part of a multiple birth (p = 0.048). CONCLUSIONS: Higher retention was demonstrated when there was regular contact in the follow-up period. Both social factors and initial illness severity affected the retention into follow-up studies of prematurely born infants, though these factors were not consistent across the two studies.

Predicting the Limit of Intramolecular Hydrogen Bonding with Classical Molecular Dynamics.

The energetics of intramolecular recognition processes are governed by the balance of pre-organization and flexibility, which is often difficult to measure and hard to predict. Using classical MD simulations, we predict and quantify the effective strength of intramolecular hydrogen bonds between donor and acceptor sites separated by a variable alkyl linker in several solvents and crowded solutions. The balance of entropic and enthalpic contributions poses a solvent-dependent limit to the occurrence of intramolecular H-bonding. Still, free energies show a constant offset among different solvents with, for example, a 13 kJ mol-1 difference between water and chloroform. Molecular crowding shows little effect on the thermodynamic equilibrium, but induces variations on the H-bond kinetics. The results are in quantitative agreement with experiments in chloroform and showcase a general strategy to investigate molecular interactions in different environments, extending the limits of current experiments towards the prospective prediction of H-bond interactions in a variety of contexts.

National surveys of UK and Italian neonatal units highlighted significant differences in the use of non-invasive respiratory support.

AIM: This study compared how non-invasive respiratory support (NRS) was provided in neonatal units in Italy and the UK. METHODS: An NRS questionnaire was sent to tertiary neonatal centres, identified by national societies, from November 2015 to May 2016. RESULTS: Responses were received from 49/57 (86%) UK units and 103/115 (90%) Italian units. NRS was started in the delivery room by 61% of UK units and 85% of Italian units. In neonatal intensive care units, 33% of UK units used nasal high-flow therapy (HFT) as primary support, compared to 3% in Italy. Nasal continuous positive airway pressure (CPAP) was used in 57% of UK units and 90% of Italian units. The commonest starting flow rate on nasal HFT for term and preterm infants was 6 L/min in the UK, while Italian units mainly used this flow for term infants. In the UK, 67% of units decreased nasal HFT by 1 L/min per day. In Italy, infants on nasal CPAP were weaned by 1 cm H2 O per day in 39% of units. CONCLUSION: The way that NRS was managed for very preterm infants differed between the UK and Italy, reflecting a lack of evidence on optimal NRS and the use of local protocols.

Nasal High-Flow Therapy as Primary Respiratory Support for Preterm Infants without the Need for Rescue with Nasal Continuous Positive Airway Pressure.

AIM: To evaluate the effectiveness of nasal high-flow therapy (nHFT) as primary respiratory support for preterm infants with respiratory distress syndrome (RDS) in two tertiary neonatal units. METHODS: A retrospective outcome analysis of initial respiratory support strategies was performed in two tertiary neonatal units in the UK: John Radcliffe Hospital (JRH), Oxford and St Peter's Hospital (SPH), Chertsey. Infants born between 28+0 and 36+6 weeks gestational age (GA) between May 2013 and June 2015 were included. RESULTS: A total of 381 infants, 191 from JRH and 190 from SPH, were analysed. Infants were stabilised in the delivery room using mask continuous positive airway pressure followed by nHFT. Endotracheal intubation was performed according to local protocols, depending on the severity of RDS. There were significant differences in initial intubation rates according to GA (26% JRH vs. 16.9% SPH, p < 0.001 for babies < 32 weeks GA, and 8.2% JRH vs. 6.5% SPH, p < 0.001 for babies > 32 weeks GA); however, most infants were successfully transitioned to nHFT. Intubation rates during the first 72 h were comparable between centres (14.7% JRH vs. 11.1% SPH, p = 0.29). There were no differences in neonatal morbidities, including air leak, duration of oxygen supplementation, bronchopulmonary dysplasia, sepsis, retinopathy of prematurity, intraventricular haemorrhage, necrotising enterocolitis, or median time to full-suck feeds. CONCLUSION: Use of nHFT for primary respiratory support, without use of nasal continuous positive airway pressure as "rescue" treatment, resulted in intubation rates lower or comparable to published data from randomised controlled trials.