Peter A. Dargaville

Description:This study aimed to characterize how peak inspiratory pressure (PIP) and positive end-expiratory pressure (PEEP) influence regional lung volume heterogeneity as a result of mechanical ventilation and the influence of this heterogeneity on markers of inflammation within the lungs. Four groups of BALB/C mice (n = 7 or 8 per group) were mechanically ventilated for 2 h using low or high (12 cmH2O or 20 cmH2O) peak inspiratory pressure (PIP) with or without 2 cmH2O positive end-expiratory pressure (PEEP). Four-dimensional computed tomography (4-DCT) images were acquired using synchrotron-based radiation source at baseline and after 2 h. Regional tidal volumes were obtained by 4-D cross-correlational X-ray velocimetry, whereas end-expiratory volume was quantified by Hounsfield units. Tissue was harvested from 10 lung regions, and expression of IL-6 and monocyte chemo-attractant protein 1 (MCP-1) was quantified using qPCR. We found a significant reduction in specific end-expiratory volume (sEEV) in mice ventilated with low PIP and no PEEP and a reduction in tidal volume in groups without PEEP. End-expiratory volume heterogeneity decreased in the low PIP and no PEEP group, whereas tidal volume heterogeneity decreased in the equivalent high PIP group, potentially due to regional redistribution of lung volumes. We found associations between IL-6 expression and tidal volume heterogeneity. In this study, we have demonstrated that changes in PIP and PEEP impact atelectasis, overdistension, and heterogeneity, and that increases in tidal volume heterogeneity may be driving IL-6-mediated biotrauma. These findings highlight the importance of considering the spatial distribution of tidal volumes as a driver of lung injury during mechanical ventilation.NEW & NOTEWORTHY The combination of low inspiratory and expiratory pressure promotes atelectasis but is not associated with markers of injury in the healthy lung during short-term ventilation. High inspiratory pressures promote tidal volume heterogeneity, which is correlated with the expression of genetic markers of lung injury. These data suggest that heterogeneity in tidal volume may be a key driver of biotrauma in the healthy, mechanically ventilated lung.

Description:Non-invasive ventilation (NIV) commenced soon after birth is highly effective in providing mechanical respiratory support for preterm infants with respiratory distress syndrome (RDS). However, NIV alone frequently fails to provide adequate respiratory support for infants with more significant respiratory compromise due to RDS. Without an endotracheal tube as the conduit to administer exogenous surfactant in such cases, less invasive approaches to surfactant delivery have emerged, with those involving the use of a thin catheter (termed minimally invasive surfactant therapy, MIST) now in the ascendancy. The application of MIST with NIV support continuing allows spontaneous breathing to be harnessed for optimal surfactant dispersal to the distal airspaces. Here we examine the importance of this pairing of NIV with MIST and review the evidence for optimization of NIV before, during and after delivery of surfactant. All evidence points to NIV and MIST being an elegant and synergistic pairing of two therapies for optimal respiratory support of preterm infants in early life. Whilst much of the clinical trial data regarding the pairing of NIV and MIST relates to application of standard continuous positive airway pressure, non-invasive positive pressure ventilation in its various forms may offer additional advantage, and further studies are warranted.

Description:Background: Antimicrobials are frequently prescribed to neonates who require hospital care, but the influences on clinical decision-making and practice variation in this process are ill-understood. We performed a cross-sectional survey of practitioners who prescribe antimicrobials in 3 Australian neonatal units. Methods: During two 5-day data capture periods per center, 56 practitioners reported their general confidence in antimicrobial decision-making for neonates. Then, 4 questionnaires evaluated diagnostic certainty and influences on antimicrobial decision-making for 68 antimicrobial courses and 11 infection evaluations where antimicrobials were not prescribed. Results: Self-reported guideline use at antimicrobial commencement was high (26/31, 84%). Clinical risk factors, clinical signs and laboratory tests contributed variably to decisions to start and cease antimicrobials. Consultation with a colleague contributed to 14/31 (45%) decisions to commence antimicrobials and 13/34 (38%) decisions to cease them. The most frequent responses to questions regarding the likelihood of infection and the possibility of an alternative diagnosis were "some possibility" and "some likelihood." Team concordance in responses ranged from 14% to 50%. While practitioners in roles that denoted more clinical experience had greater general confidence in antimicrobial decision-making, this difference was not observed in real-world clinical situations where infection was not microbiologically confirmed. Conclusions: Clinical, laboratory, practitioner, team and center-based factors each influence antimicrobial prescribing decisions. Clinical uncertainty and differing guidelines likely contribute to practice variation. Future work to inform stewardship efforts should include improved guideline consistency, roles of diagnostic aids and a better understanding of the medicocultural contributors to neonatal antimicrobial prescribing.

Description:Importance: Bronchopulmonary dysplasia (BPD) is a common adverse outcome in extremely preterm infants born at less than 28 weeks' gestation. Systemic corticosteroids are effective against BPD but may be associated with adverse outcomes. Corticosteroids given directly into the lungs may be effective and safer. Objective: To investigate the effectiveness of early intratracheal corticosteroid administration on survival free of BPD in extremely preterm infants. Design, setting, and participants: Double-blind randomized clinical trial conducted in 21 neonatal units in 4 countries (Australia, New Zealand, Canada, and Singapore), enrolling infants born at less than 28 weeks' gestation and less than 48 hours old who were mechanically ventilated (regardless of ventilator settings or oxygen requirements) or who were receiving noninvasive respiratory support and had a clinical decision to treat with surfactant. Recruitment occurred from January 2018 to March 2023. The last participant was discharged from the hospital in August 2023. Interventions: Infants were randomly allocated (1:1) to receive budesonide, 0.25 mg/kg, mixed with surfactant (poractant alfa), administered via an endotracheal tube or thin catheter, or surfactant only. Main outcomes and measures: The primary outcome was survival free of BPD at 36 weeks' postmenstrual age. There were 15 secondary outcomes, including the 2 components of the primary outcome (survival at 36 weeks and BPD among survivors), and 9 predefined safety outcomes (adverse events). Results: The primary analysis included 1059 infants, 524 in the budesonide and surfactant group and 535 in the surfactant-only group. Overall, infants had a mean gestational age of 25.6 weeks (SD, 1.3 weeks) and a mean birth weight of 775 g (SD, 197 g); 586 (55.3%) were male. Survival free of BPD occurred in 134 infants (25.6%) in the budesonide and surfactant group and 121 infants (22.6%) in the surfactant-only group (adjusted risk difference, 2.7% [95% CI, -2.1% to 7.4%]). At 36 weeks' postmenstrual age, 83.2% of infants were alive in the budesonide and surfactant group and 80.6% in the surfactant-only group. Of these, 69.3% and 71.9% were diagnosed with BPD, respectively. Conclusions and relevance: In extremely preterm infants receiving surfactant for respiratory distress syndrome, early intratracheal budesonide may have little to no effect on survival free of BPD. Trial registration: anzctr.org.au Identifier: ACTRN12617000322336.