Plasma Proteome Profiles Associated with Early Development of Lung Injury in Extremely Preterm Infants.

The biological mediators which initiate lung injury in extremely preterm infants during early postnatal life remain largely unidentified, limiting opportunities for early treatment and diagnosis. This exploratory study used SWATH-mass spectrometry to identify bronchopulmonary dysplasia (BPD)-specific changes in protein abundance in plasma samples obtained in the first 72 hours of life from extremely preterm infants and bioinformatic analysis to identify BPD-related biological categories and pathways. Lasty, binary logistic regression analysis was used to test the BPD predictive potential of a base model alone (gestational age, birth weight, sex) and with the protein biomarker added, with bootstrap resampling used to internally validate protein predictors and adjust for overoptimism. We observed disturbance of key processes including coagulation, complement activation, development and extracellular matrix organisation in the first days of life in extremely preterm infants who were later diagnosed with BPD. In the BPD prediction analysis, 49 plasma proteins were identified which when each singularly was combined with birth characteristics had a C-index of 0.65-0.84 (optimism-adjusted C-index) suggesting predictive potential for BPD outcomes. Taken together, this study demonstrates that alterations in plasma proteins can be detected from 4 hours of age in extremely preterm infants who later develop BPD and that protein biomarkers when combined with three birth characteristics have the potential to predict BPD development within the first 72 hours of life.

Early Hyperoxemia and 2-year Outcomes in Infants with Hypoxic-ischemic Encephalopathy: A Secondary Analysis of the Infant Cooling Evaluation Trial.

OBJECTIVE: To determine the causal relationship between exposure to early hyperoxemia and death or major disability in infants with hypoxic-ischemic encephalopathy (HIE). STUDY DESIGN: We analyzed data from the Infant Cooling Evaluation (ICE) trial that enrolled newborns ≥35 weeks' gestation with moderate-severe HIE, randomly allocated to hypothermia or normothermia. The primary outcome was death or major sensorineural disability at 2 years. We included infants with arterial pO2 measured within 2 hours of birth. Using a directed acyclic graph, we established that markers of severity of perinatal hypoxia-ischemia and pCO2 were a minimally sufficient set of variables for adjustment in a regression model to estimate the causal relationship between arterial pO2 and death/disability. RESULTS: Among 221 infants, 116 (56%) had arterial pO2 and primary outcome data. The unadjusted analysis revealed a U-shaped relationship between arterial pO2 and death or major disability. Among hyperoxemic infants (pO2 100-500 mmHg) the proportion with death or major disability was 40/58 (0.69), while the proportion in normoxemic infants (pO2 40-99 mmHg) was 20/48 (0.42). In the adjusted model, hyperoxemia increased the risk of death or major disability (adjusted risk ratio 1.61, 95% CI 1.07-2.00, P = .03) in relation to normoxemia. CONCLUSION: Early hyperoxemia increased the risk of death or major disability among infants who had an early arterial pO2 in the ICE trial. Limitations include the possibility of residual confounding and other causal biases. Further work is warranted to confirm this relationship in the era of routine therapeutic hypothermia.

Blood pressure and cerebral oxygenation with physiologically-based cord clamping: sub-study of the BabyDUCC trial.

BACKGROUND: Cord-clamping strategies may modify blood pressure (BP) and cerebral tissue oxygen saturation (rStO2) immediately after birth. METHODS: We conducted a sub-study nested within the Baby-Directed Umbilical Cord-Clamping trial. Infants ≥32+0 weeks' gestation assessed as requiring resuscitation were randomly allocated to either physiologically-based cord clamping (PBCC), where resuscitation commenced prior to umbilical cord clamping, or standard care where cord clamping occurred early (ECC). In this single-site sub-study, we obtained additional measurements of pre-ductal BP and rStO2. In a separate observational arm, non-randomised vigorous infants received 2 min of deferred cord clamping (DCC) and contributed data for reference percentiles. RESULTS: Among 161 included infants, n = 55 were randomly allocated to PBCC (n = 30) or ECC (n = 25). The mean (SD) BP at 3-4 min after birth (primary outcome) in the PBCC group was 64 (10) mmHg compared to 62 (10) mmHg in the ECC group, mean difference 2 mmHg (95% confidence interval -3-8 mmHg, p = 0.42). BP and rStO2 were similar across both randomised arms and the observational arm (n = 106). CONCLUSION: We found no difference in BP or rStO2 with the different cord clamping strategies. We report reference ranges for BP and rStO2 for late-preterm and full-term infants receiving DCC. IMPACT: Among late-preterm and full-term infants receiving varying levels of resuscitation, blood pressure (BP, at 3-4 minutes and 6 min) and cerebral tissue oxygen saturation (rStO2) are not influenced by timing of cord clamping in relation to establishment of ventilation. Infants in this study did not require advanced resuscitation, where cord clamping strategies may yet influence BP and rStO2. The reference ranges for BP and rStO2 represent the first, to our knowledge, for vigorous late-preterm and full-term infants receiving deferred cord clamping. rStO2 > 90% (~90th percentile) may be used to define cerebral hyperoxia, for instance when studying oxygen supplementation after birth.

Newborn resuscitation timelines: Accurately capturing treatment in the delivery room.

OBJECTIVES: To evaluate the use of newborn resuscitation timelines to assess the incidence, sequence, timing, duration of and response to resuscitative interventions. METHODS: A population-based observational study conducted June 2019-November 2021 at Stavanger University Hospital, Norway. Parents consented to participation antenatally. Newborns ≥28 weeks' gestation receiving positive pressure ventilation (PPV) at birth were enrolled. Time of birth was registered. Dry-electrode electrocardiogram was applied as soon as possible after birth and used to measure heart rate continuously during resuscitation. Newborn resuscitation timelines were generated from analysis of video recordings. RESULTS: Of 7466 newborns ≥28 weeks' gestation, 289 (3.9%) received PPV. Of these, 182 had the resuscitation captured on video, and were included. Two-thirds were apnoeic, and one-third were breathing ineffectively at the commencement of PPV. PPV was started at median (quartiles) 72 (44, 141) seconds after birth and continued for 135 (68, 236) seconds. The ventilation fraction, defined as the proportion of time from first to last inflation during which PPV was provided, was 85%. Interruption in ventilation was most frequently caused by mask repositioning and auscultation. Suctioning was performed in 35% of newborns, in 95% of cases after the initiation of PPV. PPV was commenced within 60 s of birth in 49% of apnoeic and 12% of ineffectively breathing newborns, respectively. CONCLUSIONS: Newborn resuscitation timelines can graphically present accurate, time-sensitive and complex data from resuscitations synchronised in time. Timelines can be used to enhance understanding of resuscitation events in data-guided quality improvement initiatives.

Predicting extubation failure in preterm infants using lung ultrasound: a diagnostic accuracy study.

OBJECTIVE: To determine the accuracy of pre-extubation lung ultrasound (LUS) to predict reintubation in preterm infants born <32 weeks' gestation. DESIGN: Prospective diagnostic accuracy study. SETTING: Two neonatal intensive care units. METHODS: Anterior and lateral LUS was performed pre-extubation. The primary outcome was the accuracy of LUS scores (range 0-24) to predict reintubation within 72 hours. Secondary outcomes were accuracy in predicting (1) reintubation within 7 days, (2) reintubation stratified by postnatal age and (3) accuracy of lateral imaging only (range 0-12). Pre-specified subgroup analyses were performed in extremely preterm infants born <28 weeks' gestation. Cut-off scores, sensitivities and specificities were calculated using receiver operating characteristic analysis and reported as area under the curves (AUCs). RESULTS: One hundred preterm infants with a mean (SD) gestational age of 27.4 (2.2) weeks and birth weight of 1059 (354) g were studied. Thirteen were subsequently reintubated. The AUC (95% CI) of the pre-extubation LUS score for predicting reintubation was 0.63 (0.45-0.80). Accuracy was greater in extremely preterm infants: AUC 0.70 (0.52-0.87) and excellent in infants who were <72 hours of age at the time of extubation: AUC 0.90 (0.77-1.00). Accuracy was poor in infants who were >7 days of age. Lateral imaging alone demonstrated similar accuracy to scanning anterior and lateral regions. CONCLUSIONS: In contrast to previous studies, LUS was not a strong predictor of reintubation in preterm infants. Accuracy is increased in extremely preterm infants. Future research should focus on infants at highest risk of extubation failure and consider simpler imaging protocols. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry: ACTRN12621001356853.

Predictors of successful neonatal intubation in inexperienced operators: a secondary, non-randomised analysis of the SHINE trial.

OBJECTIVE: Neonatal endotracheal intubation is a lifesaving but technically difficult procedure, particularly for inexperienced operators. This secondary analysis in a subgroup of inexperienced operators of the Stabilization with nasal High flow during Intubation of NEonates randomised trial aimed to identify the factors associated with successful intubation on the first attempt without physiological stability of the infant. METHODS: In this secondary analysis, demographic factors were compared between infants intubated by inexperienced operators and those intubated by experienced operators. Following this, for inexperienced operators only, predictors of successful intubation without physiological instability were analysed. RESULTS: A total of 251 intubations in 202 infants were included in the primary intention-to-treat analysis of the main trial. Inexperienced operators were more likely to perform intubations in larger and more mature infants in the neonatal intensive care unit where premedications were used. When intubations were performed by inexperienced operators, the use of nasal high flow therapy (nHF) and a higher starting fraction of inspired oxygen were associated with a higher rate of safe, successful intubation on the first attempt. There was a weaker association between premedication use and first attempt success. CONCLUSIONS: In inexperienced operators, this secondary, non-randomised analysis suggests that the use of nHF and premedications, and matching the operator to the infant and setting, may be important to optimise neonatal intubation success. TRIAL REGISTRATION NUMBER: ACTRN12618001498280.

Higher versus lower nasal continuous positive airway pressure for extubation of extremely preterm infants in Australia (ÉCLAT): a multicentre, randomised, superiority trial.

BACKGROUND: Extremely preterm infants often require invasive mechanical ventilation, and clinicians aim to extubate these infants as soon as possible. However, extubation failure occurs in up to 60% of extremely preterm infants and is associated with increased mortality and morbidity. Nasal continuous positive airway pressure (nCPAP) is the most common post-extubation respiratory support, but there is no consensus on the optimal nCPAP level to safely avoid extubation failure in extremely preterm infants. We aimed to determine if higher nCPAP levels compared with standard nCPAP levels would decrease rates of extubation failure in extremely preterm infants within 7 days of their first extubation. METHODS: In this multicentre, randomised, open-label controlled trial done at three tertiary perinatal centres in Australia, we assigned extremely preterm infants to extubation to either higher nCPAP (10 cmH2O) or standard nCPAP (7 cmH2O). Infants were eligible if they were born at less than 28 weeks' gestation, were receiving mechanical ventilation via an endotracheal tube, and were being extubated for the first time to nCPAP. Eligible infants must have received previous treatment with exogenous surfactant and caffeine. Infants were ineligible if they were planned to be extubated to a mode of respiratory support other than nCPAP, if they had a known major congenital anomaly that might affect breathing, or if ongoing intensive care was not being provided. Parents or guardians provided prospective, written, informed consent. Infants were maintained within an assigned nCPAP range for a minimum of 24 h after extubation (higher nCPAP group 9-11 cmH2O and standard nCPAP group 6-8 cmH2O). Randomisation was stratified by both gestation (22-25 completed weeks or 26-27 completed weeks) and recruiting centre. The primary outcome was extubation failure within 7 days and analysis was by intention to treat. This trial was prospectively registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12618001638224. FINDINGS: Between March 3, 2019, and July 31, 2022, 483 infants were born at less than 28 weeks and admitted to the recruiting centres. 92 infants were not eligible, 172 were not approached, 65 families declined to participate, and 15 consented but were not randomly assigned. 139 infants were enrolled and randomly assigned, 70 to the higher nCPAP group and 69 to the standard nCPAP group. One infant in the higher nCPAP group was excluded from the analysis because consent was withdrawn after randomisation. 104 (75%) of 138 mothers were White. The mean gestation was 25·7 weeks (SD 1·3) and the mean birthweight was 777 grams (201). 70 (51%) of 138 infants were female. Extubation failure occurred in 24 (35%) of 69 infants in the higher nCPAP group and in 39 (57%) of 69 infants in the standard nCPAP group (risk difference -21·7%, 95% CI -38·5% to -3·7%). There were no significant differences in rates of adverse events between groups during the primary outcome period. Three patients died (two in the higher nCPAP group and one in the standard nCPAP group), pneumothorax occurred in one patient from each group, spontaneous intestinal perforation in three patients (two in the higher nCPAP group and one in the standard nCPAP group) and there were no events of pulmonary interstitial emphysema. INTERPRETATION: Extubation of extremely preterm infants to higher nCPAP significantly reduced extubation failure compared with extubation to standard nCPAP, without increasing rates of adverse effects. Future larger trials are essential to confirm these findings in terms of both efficacy and safety. FUNDING: National Health and Medical Research Council Centre for Research Excellence in Newborn Medicine, number 1153176.