Jennifer Jane Pillow

Aim: To describe the frequency, burden, and pathogen profile of acute respiratory illnesses (ARIs) in very preterm infants during the first year after neonatal intensive care unit (NICU) discharge. Methods: Very preterm infants were followed prospectively (August 2015–January 2017) with monthly assessments of symptoms, medication use, and healthcare utilisation. Parent‐reported ARIs triggered additional clinical follow‐up. Nasal swabs were collected monthly and during ARIs and tested for respiratory pathogens using real‐time PCR. Results: Of 125 eligible infants, 99 (79.2%) were enrolled, and 89 completed the 12‐month follow‐up. All infants experienced at least one ARI during the first year. Male sex was associated with increased risk of wheezy lower respiratory tract illness (LRTI) (RR 1.61), hospitalisation (RR 3.89), and asthma medication use (RR 5.89). NICU discharge during summer was associated with higher ARI rates (RR 1.33) and hospitalisation (RR 2.54). Rhinovirus was most frequently detected (13.5% of monthly swabs; 43.8% of ARI swabs), whereas respiratory syncytial predominated in emergency department presentations and hospital admissions (18.8% and 20.0%, respectively). Conclusions: Very preterm infants experienced substantial respiratory morbidity during the first year after NICU discharge. These findings highlight the need for improved preventive and post‐discharge strategies in this high‐risk population.

Introduction: Very preterm infants (<32 weeks gestation) have an undeveloped primary endogenous circadian rhythm and are deprived abruptly of vital maternal circadian inputs after delivery. Postnatal care in neonatal intensive care units is characterised by constant levels of lighting and noise. Stress arising from disrupted cues for circadian rhythmicity likely disrupts development of coordinated circadian rhythms critical for neurogenesis, organ growth and development. We hypothesise that cycled environmental light and noise commenced soon after birth and continued until discharge home will improve cognitive outcomes compared with infants whose postnatal care comprises constant light (bright or dim) and constant noise. Methods and analysis: Australasian multicentre, two-arm, parallel-group, prospective, randomised, open, blinded-endpoint superiority trial in 868 infants born less than 32 weeks’ gestation. Infants are randomised to cycled environmental light and noise or routine care in a non-cycled hospital environment from soon after birth until discharge home. The intervention comprises wearing eye-masks and ear plugs from 20:00 to 6:00, followed by removal of these devices and exposure to normal environmental noise and 300-600 lux light from 6:00 to 20:00. The primary outcome is composite cognitive score on Bayley-4 developmental assessment at 2 years corrected postnatal age. Ethics and dissemination: The trial is approved by the Child and Adolescent Health Service Human Research Ethics Committee under the National Mutual Acceptance Scheme in Australia. Infants are randomised to intervention or control group after informed parental consent is obtained. Results of the CIRCA DIEM Study will be disseminated widely via presentations at local, national and international conferences, publication in international peer-reviewed journals and inclusion on the study website. Information about trial findings will also be communicated directly to the parents/guardians of trial participants through the regular study newsletter. The trial investigators will seek opportunities to communicate study results to the lay public through media and social media avenues. Trial registration number: ANZCTRN12618000371291.

Objectives: Understand how bronchopulmonary dysplasia (BPD) and antenatal and postnatal factors influence diaphragmatic functional effectiveness in very preterm infants. Working Hypothesis: Diaphragmatic functional effectiveness during spontaneous breathing is impaired in infants with BPD. Moreover, diaphragmatic functional effectiveness is influenced by adverse antenatal and postnatal factors. Methodology: Diaphragmatic functional effectiveness was assessed in a single‐centre, prospective observational study in preterm infants. Transdiaphragmatic pressure (Pdi) and respiratory flow were measured during quiet sleep at 36 weeks' postmenstrual age (PMA). Pdi was normalized to tidal volume (Pdi/ V _T ). Diaphragmatic work of breathing per minute was calculated from the inspiratory pressure time integral (PTIdi) and respiratory rate. Factors predictive for each outcome were identified from multivariable linear regression. Results: Very preterm infants ( n = 182) were measured at a median (IQR) 35.6 (1.3) weeks' PMA. Infants with BPD had a lower Pdi/ V _T ( p = 0.007) and lower PTIdi·min ⁻¹ ( p = 0.022) but higher minute ventilation ( p = 0.032) and similar respiratory rates ( p = 0.419) compared to infants without BPD. Birthweight Z score ( R ² = 0.08, p < 0.001) and BPD ( R ² = 0.04, p = 0.022) were independent negative predictors for Pdi/ V _T while gestational age ( R ² = 0.04, p = 0.01) and average early postnatal energy intake ( R ² = 0.03, p = 0.026) were independent positive predictors for PTIdi·min ⁻¹ on multivariable analysis. Chorioamnionitis and duration of mechanical ventilation did not contribute to the final model. Conclusions: Contrary to our hypothesis, diaphragm functional effectiveness appears improved in infants with BPD. We speculate this finding may reflect an adaptive process, or alternatively indicate an increased recruitment of accessory muscles to achieve required ventilation in BPD infants. Adverse antenatal and postnatal factors only explain a small proportion of variance in diaphragm effectiveness.

Background: Surfactant is a well-established therapy for preterm neonates affected by respiratory distress syndrome (RDS). The goals of different methods of surfactant administration are to reduce the duration of mechanical ventilation and the severity of bronchopulmonary dysplasia (BPD); however, the optimal administration method remains unknown. This study compares the effectiveness of the INtubate-RECruit-SURfactant-Extubate (IN-REC-SUR-E) technique with the less-invasive surfactant administration (LISA) technique, in increasing BPD-free survival of preterm infants. This is an international unblinded multicenter randomized controlled study in which preterm infants will be randomized into two groups to receive IN-REC-SUR-E or LISA surfactant administration. Methods: In this study, 382 infants born at 24⁺⁰–27⁺⁶ weeks’ gestation, not intubated in the delivery room and failing nasal continuous positive airway pressure (nCPAP) or nasal intermittent positive pressure ventilation (NIPPV) during the first 24 h of life, will be randomized 1:1 to receive IN-REC-SUR-E or LISA surfactant administration. The primary outcome is a composite outcome of death or BPD at 36 weeks’ postmenstrual age. The secondary outcomes are BPD at 36 weeks’ postmenstrual age; death; pulse oximetry/fraction of inspired oxygen; severe intraventricular hemorrhage; pneumothorax; duration of respiratory support and oxygen therapy; pulmonary hemorrhage; patent ductus arteriosus undergoing treatment; percentage of infants receiving more doses of surfactant; periventricular leukomalacia, severe retinopathy of prematurity, necrotizing enterocolitis, sepsis; total in-hospital stay; systemic postnatal steroids; neurodevelopmental outcomes; and respiratory function testing at 24 months of age. Randomization will be centrally provided using both stratification and permuted blocks with random block sizes and block order. Stratification factors will include center and gestational age (24⁺⁰ to 25⁺⁶ weeks or 26⁺⁰ to 27⁺⁶ weeks). Analyses will be conducted in both intention-to-treat and per-protocol populations, utilizing a log-binomial regression model that corrects for stratification factors to estimate the adjusted relative risk (RR). Discussion: This trial is designed to provide robust data on the best method of surfactant administration in spontaneously breathing preterm infants born at 24⁺⁰–27⁺⁶ weeks’ gestation affected by RDS and failing nCPAP or NIPPV during the first 24 h of life, comparing IN-REC-SUR-E to LISA technique, in increasing BPD-free survival at 36 weeks’ postmenstrual age of life. Trial registration: ClinicalTrials.gov NCT05711966. Registered on February 3, 2023.

We evaluated the effect of antenatal creatine supplementation to reduce pulmonary inflammation and oxidative stress in the fetal lamb lungs arising from lipopolysaccharide (LPS)-induced chorioamnionitis. Fetal creatine supplementation increased lung creatine content and had no adverse effects on systemic fetal physiology and overall lung architecture. Importantly, fetuses that received creatine had significantly lower levels of inflammation and oxidative stress in the lungs, suggesting an anti-inflammatory and antioxidant benefit of creatine.

Data on chest wall compliance in very preterm infants in the postsurfactant era are scarce. To our knowledge, we are the first group to report data on static respiratory system compliance ( C_rs), lung compliance ( C_L), and chest wall compliance ( C_cw) in preterm infants with and without bronchopulmonary dysplasia (BPD) in the postsurfactant era.

Background: Surfactant is a well-established therapy for preterm neonates affected by respiratory distress syndrome (RDS). Goals of different methods of surfactant administration are to reduce duration of mechanical ventilation and the severity of bronchopulmonary dysplasia (BPD), however the optimal administration method remains unknown. This study compares the effectiveness of the INtubate-RECruit-SURfactant-Extubate (IN-REC-SUR-E) technique with the less invasive surfactant administration (LISA) technique, in increasing BPD-free survival of preterm infants. This is an international unblinded multicenter randomized controlled study in which preterm infants will be randomized into two groups to receive IN-REC-SUR-E or LISA surfactant administration. Methods: In this study 382 infants born at 24⁺⁰-27⁺⁶ weeks’ gestation, not intubated in the delivery room and failing nasal continuous positive airway pressure (nCPAP) or nasal intermittent positive pressure ventilation (NIPPV) during the first 24 h of life, will be randomized 1:1 to receive IN-REC-SUR-E or LISA surfactant administration. The primary outcome is a composite outcome of death or BPD at 36 weeks’ postmenstrual age. Secondary outcomes are: BPD at 36 weeks’ postmenstrual age; death; pulse oximetry/fraction of inspired oxygen; severe intraventricular haemorrhage; pneumothorax; duration of respiratory support and oxygen therapy; pulmonary hemorrhage; patent ductus arteriosus undergoing treatment; percentage of infants receiving more doses of surfactant; periventricular leukomalacia, severe retinopathy of prematurity, necrotizing enterocolitis, sepsis; total in-hospital stay; systemic postnatal steroids; neurodevelopmental outcomes and respiratory function testing at 24 months of age. Randomization will be centrally provided using both stratification and permuted blocks with random block sizes and block order. Stratification factors will include centre and gestational age (24⁺⁰ to 25⁺⁶ weeks or 26⁺⁰ to 27⁺⁶ weeks). Analyses will be conducted in both intention-to-treat and per-protocol populations, utilizing a log-binomial regression model that corrects for stratification factors to estimate the adjusted relative risk (RR). Discussion: This trial is designed to provide robust data on the best method of surfactant administration in spontaneously breathing preterm infants born at 24⁺⁰-27⁺⁶ weeks' gestation affected by RDS and failing nCPAP or NIPPV during the first 24 hours of life, comparing IN-REC-SUR-E to LISA technique, in increasing BPD-free survival at 36 weeks' postmenstrual age of life. Trial registration: ClinicalTrials.gov identifier NCT05711966

Creatine plays a fundamental role in cellular energy homeostasis. The current protocol describes an alternative method for creatine quantification in biological tissue samples using capillary electrophoresis, with high separation efficiency that enables rapid analysis with low sample volumes. The protocol involves homogenization of snap-frozen tissue in phosphate buffer, followed by electrophoresis through a bare-fused capillary (75 µm internal diameter) and measurement at 200 nm on the Agilent 7100 CE system. Under the optimised conditions, there was excellent linearity in creatine standards between 6.3 – 100 µM. The overall intra-assay variability for concentrations between 6.3 – 100 µM was 1.5 %, and the inter-assay variability was 6.4 %, with a limit of detection at 6 nmol/mg protein. The protocol was further benchmarked against a commercially available enzyme assay kit using lung samples from lambs that received continuous creatine or saline supplementation. There was good agreement between the two methods (mean difference = 0.42 [-0.26-1.1] nmol/mg protein). Importantly, capillary electrophoresis enables reliable detection of creatine in biological samples from just ∼1.5 mg of wet-weight lung tissue. Capillary electrophoresis enables rapid (<10 minutes) and highly efficient analysis of tissue samples and avoids challenges faced with traditional enzymatic assays. The current protocol was developed and optimised with ovine lung tissue, but it can be easily adapted to analyse various tissue types. For tissues with higher baseline creatine content, such as the skeletal muscles or brain, <1 mg wet weight tissue would be sufficient to detect creatine using capillary electrophoresis.