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Aim It takes several minutes for infants to become pink after birth. Preductal oxygen saturation (SpO2) measurements are used to guide the delivery of supplemental oxygen to newly born infants, but pulse oximetry is not available in many parts of the world. We explored whether the pinkness of an infant's tongue provided a useful indication that supplemental oxygen was required. Methods This was a prospective observational study of infants delivered by Caesarean section. Simultaneous recording of SpO2 and visual assessment of whether the tongue was pink or not was made at 1-7 and 10 min after birth. Results The 38 midwives and seven paediatric trainees carried out 271 paired assessments on 68 infants with a mean ( SD) birthweight of 3214 (545) grams and gestational age of 38 (2) weeks. When the infant did not have a pink tongue, this predicted SpO2 of <70% with a sensitivity of 26% and a specificity of 96%. Conclusion Tongue colour was a specific but insensitive sign that indicated when SpO2 was <70%. When the tongue is pink, it is likely that an infant has an SpO2 of more than 70% and does not require supplemental oxygen. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To determine the accuracy of three tests used to predict successful extubation of preterm infants. STUDY DESIGN: Mechanically ventilated infants with birth weight <1250 g and considered ready for extubation were changed to endotracheal continuous positive airway pressure (ET CPAP) for three minutes. Tidal volumes, minute ventilation (V e), heart rate, and oxygen saturation were recorded before and during ET CPAP. Three tests of extubation success were evaluated: (a) expired V e during ET CPAP; (b) ratio of V e during ET CPAP to V e during mechanical ventilation (V e ratio); (c) the spontaneous breathing test (SBT)-the infant passed this test if there was no hypoxia or bradycardia during ET CPAP. The clinical team were blinded to the results, and all infants were extubated. Extubation failure was defined as reintubation within 72 hours of extubation. RESULTS: Fifty infants were studied and extubated. Eleven (22%) were reintubated. The SBT was the most accurate of the three tests, with a sensitivity of 97% and specificity of 73% and a positive and negative predictive value for extubation success of 93% and 89% respectively. CONCLUSION: The SBT used just before extubation of infants <1250 g may reduce the number of extubation failures. Further studies are required to establish whether the SBT can be used as the primary determinant of an infant's readiness for extubation. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Endotracheal intubation of newborn infants is a mandatory competence for many pediatric trainees. The Neonatal Resuscitation Program recommends a 20-second limit for intubation attempts. Intubation attempts by junior doctors are frequently unsuccessful, and many infants are intubated between 20 and 30 seconds without apparent adverse effect. Little is known about the proficiency of more senior medical staff, the time taken to determine endotracheal tube (ETT) position, or the effects of attempted intubation on infants' heart rate (HR) and oxygen saturation (Spo2) in the delivery room (DR). The objectives of this study were to determine (1) the success rates and duration of intubation attempts during DR resuscitation, (2) whether experience is associated with greater success rates and shorter time taken to intubate, (3) the time taken to identify ETT position after intubation, and (4) the frequency with which infants deteriorated during intubation attempts and the time at which this occurred. METHODS: We reviewed videos of DR resuscitations; identified whether intubation was attempted; and, when attempted, whether intubation was attempted by a resident, a fellow, or a consultant. We defined the duration of an intubation attempt as the time from the introduction of the laryngoscope blade to the mouth to its removal, regardless of whether an ETT was introduced. We determined the time from removal of the laryngoscope to the clinicians' decision as to whether the intubation was successful and noted the basis on which this decision was made (clinical assessment, flow signals, or exhaled carbon dioxide [ETCO2] detection). We determined success according to clinical signs in all cases and used flow signals that were obtained during ventilation via the ETT or ETCO2 when available. When neither was available, the chest radiograph on admission to the NICU was reviewed. For infants who were monitored with pulse oximetry, we determined their HR and Spo2 before the intubation attempt. We then determined whether either or both fell by > or =10% during the attempt and, if so, at what time it occurred. RESULTS: We reviewed 122 video recordings in which orotracheal intubation was attempted 60 times in 31 infants. We secondarily verified ETT position using flow signals, ETCO2, or chest radiographs after 94% of attempts in which an ETT was introduced. Thirty-seven (62%) attempts were successful. Success rates and mean (SD) time to intubate successfully by group were as follows: residents: 24%, 49 seconds (13 seconds); fellows: 78%, 32 seconds (13 seconds); and consultants: 86%, 25 seconds (17 seconds). Of the 23 unsuccessful attempts, 13 were abandoned without an attempt to pass an ETT and 10 were placed incorrectly. The time to determine ETT position in the DR was longer when clinical assessment alone was used. Infants who were monitored with oximetry deteriorated during nearly half of the intubation attempts. Deterioration seemed more likely when HR and Spo2 were low before the attempt. CONCLUSIONS: Intubation attempts often are unsuccessful, and successful attempts frequently take >30 seconds. Greater experience is associated with greater success rates and shorter duration of successful attempts. Flow signals and ETCO2 may be useful in determining ETT position more quickly than clinical assessment alone. Infants frequently deteriorate during intubation attempts. Improved monitoring of infants who are resuscitated in the DR is desirable. [ABSTRACT FROM AUTHOR]

BACKGROUND: Neonatal resuscitation is a common and important intervention, and adequate ventilation is the key to success. In the delivery room, positive pressure ventilation is given with manual ventilation devices using face masks. Mannequins are widely used to teach and practise this technique. During both simulated and real neonatal resuscitation, chest excursion is used to assess tidal volume delivery, and leakage from the mask is not measured. OBJECTIVE: To describe a system that allows measurement of mask leakage and estimation of tidal volume delivery. METHODS: Respiratory function monitors, a modified resuscitation mannequin, and a computer were used to measure leakage from the mask and to assess tidal volume delivery in a model of neonatal resuscitation. RESULTS: The volume of gas passing through a flow sensor was measured at the face mask. This was a good estimate of the tidal volume entering and leaving the lung in this model. Gas leakage between the mask and mannequin was also measured. This occurred principally during inflation, although gas leakage during deflation was seen when the total leakage was large. A volume of gas that distended the mask but did not enter the lung was also measured. CONCLUSION: This system can be used to assess the effectiveness of positive pressure ventilation given using a face mask during simulated neonatal resuscitation. It could be useful for teaching neonatal resuscitation and assessing ventilation through a face mask. [ABSTRACT FROM AUTHOR]

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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2025. No commercial re-use. See rights and permissions. Published by BMJ Group.)

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.

The biological mediators that initiate lung injury in extremely preterm infants during early postnatal life remain largely unidentified, limiting opportunities for early treatment and diagnosis. In this exploratory study, we used sequential window acquisition of all theoretical mass spectra 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. Last, 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 organization, in the first days of life in extremely preterm infants who later received diagnoses of BPD. In the BPD prediction analysis, 49 plasma proteins were identified; when each singularly was combined with birth characteristics the optimism-adjusted C index was 0.65-0.84, suggesting predictive potential for BPD outcomes. Taken together, the results of this study demonstrate 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.

Trientine tetrahydrochloride (TETA-4HCl, Cuvrior ® ) is a copper chelating agent with the active moiety triethylenetetramine (trientine), developed by Orphalan, Inc. to address the unmet needs in the treatment of Wilson disease. The journey from bench to bedside builds upon the documented safety profile of trientine hydrochloride capsules developed initially to meet the needs of individuals intolerant to D-penicillamine (DPA). Trientine hydrochloride capsules are inherently unstable requiring strict cold chain storage conditions from production, transportation, and use at home by the patient. Trientine tetrahydrochloride has a distinctive, patent-protected unique polymorphic form, which permits the production at scale of film-coated scored tablets deemed room temperature stable for 36 months. Trientine tetrahydrochloride is supported by a well-characterized pharmacodynamic, pharmacokinetic, and metabolic profile demonstrating reliable and predictable dose linearity and dose proportionality kinetics. Trientine tetrahydrochloride is the only trientine formulation that has been compared with DPA in a prospective randomized clinical trial, demonstrating non-inferiority to DPA in adults with stable Wilson disease. On 28 April, 2022, the US Food and Drug Administration approved TETA-4HCl for use in adult patients with Wilson disease who are de-coppered and tolerant to DPA. Health authorities in multiple countries worldwide have approved TETA-4HCl for the treatment of adults and children aged 5 years or more who are intolerant to DPA including the European Union, UK, Saudi Arabia, Switzerland, Colombia, Australia, New Zealand, and China. This article aims to provide a comprehensive narrative review of the key milestones in the development of TETA-4HCl., Competing Interests: Declarations. Funding: No external funding was used for the preparation of this article. Conflicts of Interest: C. Omar F. Kamlin, Timothy M. Jenkins, Jamie L. Heise, and Naseem S. Amin are all employees of Orphalan Inc. Ethics Approval: Not applicable. Consent to Participate: Not applicable. Consent for Publication: Not applicable. Availability of Data and Material: Not applicable. Code Availability: Not applicable. Authors’ Contributions: All authors contributed to the study conception and design. The first draft of the manuscript was written by Carol Ogg, BS Pharm. Critical review and revisions of the manuscript: JH, TJ, COFK, NA. All authors commented on previous versions of the manuscript. All authors read and approved the final version., (© 2024. The Author(s).)

Background & Aims: Wilson disease (WD) is caused by accumulation of copper primarily in the liver and brain. During maintenance therapy of WD with D-penicillamine, current guidelines recommend on-treatment ranges of urinary copper excretion (UCE) of 200-500 μg/24 h and serum non-ceruloplasmin-bound copper (NCC) of 50-150 μg/L. We compared NCC (measured by two novel assays) and UCE from patients with clinically stable WD on D-penicillamine therapy with these recommendations., Methods: This is a secondary analysis of data from the Chelate trial (NCT03539952) that enrolled physician-selected patients with clinically stable WD on D-penicillamine maintenance therapy (at an unaltered dose for at least 4 months). We analyzed laboratory samples from the first screening visit, prior to interventions. NCC was measured by either protein speciation (NCC-Sp) using anion exchange high-performance liquid chromatography protein speciation followed by copper determination with inductively coupled plasma mass spectroscopy or as exchangeable copper (NCC-Ex). NCC-Sp was also analyzed in healthy controls (n = 75)., Results: In 76 patients with WD with 21.3±14.3 average treatment-years, NCC-Sp (mean±SD: 56.6±26.2 μg/L) and NCC-Ex (mean±SD: 57.9±24.7 μg/L) were within the 50-150 μg/L target in 61% and 54% of patients, respectively. In addition, 36% and 31%, respectively, were even below the normal ranges (NCC-Sp: 46-213 μg/L, NCC-Ex: 41-71 μg/L). NCC-Ex positively correlated with NCC-Sp (r 2  = 0.66, p < 0.001) but with systematic deviation. UCE was outside the 200-500 μg/24 h target range in 58%. Only 14/69 (20%) fulfilled both the NCC-Sp and UCE targets. Clinical or biochemical signs of copper deficiency were not detected., Conclusion: Clinically stable patients with WD on maintenance D-penicillamine therapy frequently have lower NCC-Sp or higher UCE than current recommendations without signs of overtreatment. Further studies are warranted to identify appropriate target ranges of NCC-Sp, NCC-Ex and UCE in treated WD., Impact and Implications: Chelator treatment of patients with Wilson disease (WD) is currently guided by measurements of non-ceruloplasmin-bound copper (NCC) and 24 h urinary copper excretion (UCE) but validation is limited. In 76 adults with ≈21 years history of treated WD and clinically stable disease on D-penicillamine therapy, NCC was commonly found to be below normal values and recommended target ranges whether measured by protein speciation (NCC-Sp) or as exchangeable copper (NCC-Ex), while UCE values were above the recommended target range in 49%. Common wisdom would suggest overtreatment in these cases, but no clinical or biochemical signs of copper deficiency were observed. Exploratory analysis of liver enzymes suggested that NCC below levels seen in controls may be beneficial, while the relation to UCE was less clear. The data calls for critical re-evaluation of target ranges for treatment of WD, specific for drug and laboratory methodology., Clinical Trial Number: (NCT03539952)., (© 2024 The Authors.)

Background: Bronchopulmonary dysplasia (BPD), an inflammatory-mediated chronic lung disease, is common in extremely preterm infants born before 28 weeks' gestation and is associated with an increased risk of adverse neurodevelopmental and respiratory outcomes in childhood. Effective and safe prophylactic therapies for BPD are urgently required. Systemic corticosteroids reduce rates of BPD in the short term but are associated with poorer neurodevelopmental outcomes if given to ventilated infants in the first week after birth. Intratracheal administration of corticosteroid admixed with exogenous surfactant could overcome these concerns by minimizing systemic sequelae. Several small, randomized trials have found intratracheal budesonide in a surfactant vehicle to be a promising therapy to increase survival free of BPD. The primary objective of the PLUSS trial is to determine whether intratracheal budesonide mixed with surfactant increases survival free of bronchopulmonary dysplasia (BPD) at 36 weeks' postmenstrual age (PMA) in extremely preterm infants born before 28 weeks' gestation., Methods: An international, multicenter, double-blinded, randomized trial of intratracheal budesonide (a corticosteroid) mixed with surfactant for extremely preterm infants to increase survival free of BPD at 36 weeks' postmenstrual age (PMA; primary outcome). Extremely preterm infants aged < 48 h after birth are eligible if (1) they are mechanically ventilated, or (2) they are receiving non-invasive respiratory support and there is a clinical decision to treat with surfactant. The intervention is budesonide (0.25 mg/kg) mixed with poractant alfa (200 mg/kg first intervention, 100 mg/kg if second intervention), administered intratracheally via an endotracheal tube or thin catheter. The comparator is poractant alfa alone (at the same doses). Secondary outcomes include the components of the primary outcome (death, BPD prior to or at 36 weeks' PMA), and potential systemic side effects of corticosteroids. Longer-term outcomes will be published separately, and include cost-effectiveness, early childhood health until 2 years of age, and neurodevelopmental outcomes at 2 years of age (corrected for prematurity)., Statistical Analysis Plan: A sample size of 1038 infants (519 in each group) is required to provide 90% power to detect a relative increase in survival free of BPD of 20% (an absolute increase of 10%), from the anticipated event rate of 50% in the control arm to 60% in the intervention (budesonide) arm, alpha error 0.05. To allow for up to 2% of study withdrawals or losses to follow-up, PLUSS aimed to enroll a total of 1060 infants (530 in each arm). The binary primary outcome will be reported as the number and percentage of infants who were alive without BPD at 36 weeks' PMA for each randomization group. To estimate the difference in risk (with 95% CI), between the treatment and control arms, binary regression (a generalized linear multivariable model with an identity link function and binomial distribution) will be used. Along with the primary outcome, the individual components of the primary outcome (death, and physiological BPD at 36 weeks' PMA), will be reported by randomization group and, again, binary regression will be used to estimate the risk difference between the two treatment groups for survival and physiological BPD at 36 weeks' PMA., (© 2023. The Author(s).)

Aim: To evaluate delivery room (DR) interventions to prevent hypothermia and improve outcomes in preterm newborn infants <34 weeks' gestation., Methods: Medline, Embase, CINAHL and CENTRAL were searched till 22nd July 2022. Randomized controlled trials (RCTs), non-RCTs and quality improvement studies were considered. A random effects meta-analysis was performed, and the certainty of evidence was evaluated using GRADE guidelines., Results: DR temperature of ≥23 °C compared to standard care improved temperature outcomes without an increased risk of hyperthermia (low certainty), whereas radiant warmer in servo mode compared to manual mode decreased mean body temperature (MBT) (moderate certainty). Use of a plastic bag or wrap (PBW) improved normothermia (low certainty), but with an increased risk of hyperthermia (moderate certainty). Plastic cap improved normothermia (moderate certainty) and when combined with PBW improved MBT (low certainty). Use of a cloth cap decreased moderate hypothermia (low certainty). Though thermal mattress (TM) improved MBT, it increased risk of hyperthermia (low certainty). Heated-humidified gases (HHG) for resuscitation decreased the risk of moderate hypothermia and severe intraventricular hemorrhage (very low to low certainty). None of the interventions was shown to improve survival, but sample sizes were insufficient., Conclusions: DR temperature of ≥23 °C, radiant warmer in manual mode, use of a PBW and a head covering is suggested for preterm newborn infants <34 weeks' gestation. HHG and TM could be considered in addition to PBW provided resources allow, in settings where hypothermia incidence is high. Careful monitoring to avoid hyperthermia is needed., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Importance: The long-term effects of surfactant administration via a thin catheter (minimally invasive surfactant therapy [MIST]) in preterm infants with respiratory distress syndrome remain to be definitively clarified., Objective: To examine the effect of MIST on death or neurodevelopmental disability (NDD) at 2 years' corrected age., Design, Setting, and Participants: Follow-up study of a randomized clinical trial with blinding of clinicians and outcome assessors conducted in 33 tertiary-level neonatal intensive care units in 11 countries. The trial included 486 infants with a gestational age of 25 to 28 weeks supported with continuous positive airway pressure (CPAP). Collection of follow-up data at 2 years' corrected age was completed on December 9, 2022., Interventions: Infants assigned to MIST (n = 242) received exogenous surfactant (200 mg/kg poractant alfa) via a thin catheter; those assigned to the control group (n = 244) received sham treatment., Main Outcomes and Measures: The key secondary outcome of death or moderate to severe NDD was assessed at 2 years' corrected age. Other secondary outcomes included components of this composite outcome, as well as hospitalizations for respiratory illness and parent-reported wheezing or breathing difficulty in the first 2 years., Results: Among the 486 infants randomized, 453 had follow-up data available (median gestation, 27.3 weeks; 228 females [50.3%]); data on the key secondary outcome were available in 434 infants. Death or NDD occurred in 78 infants (36.3%) in the MIST group and 79 (36.1%) in the control group (risk difference, 0% [95% CI, -7.6% to 7.7%]; relative risk [RR], 1.0 [95% CI, 0.81-1.24]); components of this outcome did not differ significantly between groups. Secondary respiratory outcomes favored the MIST group. Hospitalization with respiratory illness occurred in 49 infants (25.1%) in the MIST group vs 78 (38.2%) in the control group (RR, 0.66 [95% CI, 0.54-0.81]) and parent-reported wheezing or breathing difficulty in 73 (40.6%) vs 104 (53.6%), respectively (RR, 0.76 [95% CI, 0.63-0.90])., Conclusions and Relevance: In this follow-up study of a randomized clinical trial of preterm infants with respiratory distress syndrome supported with CPAP, MIST compared with sham treatment did not reduce the incidence of death or NDD by 2 years of age. However, infants who received MIST had lower rates of adverse respiratory outcomes during their first 2 years of life., Trial Registration: anzctr.org.au Identifier: ACTRN12611000916943.

Background: Bronchopulmonary dysplasia (BPD), an inflammatory-mediated chronic lung disease, is common in extremely preterm infants born before 28 weeks' gestation and is associated with an increased risk of adverse neurodevelopmental and respiratory outcomes in childhood. Effective and safe prophylactic therapies for BPD are urgently required. Systemic corticosteroids reduce rates of BPD in the short-term but are associated with poorer neurodevelopmental outcomes if given to ventilated infants in the first week after birth. Intratracheal administration of corticosteroid admixed with exogenous surfactant could overcome these concerns by minimizing systemic sequelae. Several small, randomized trials have found intratracheal budesonide in a surfactant vehicle to be a promising therapy to increase survival free of BPD., Methods: An international, multicenter, double-blinded, randomized trial of intratracheal budesonide (a corticosteroid) mixed with surfactant for extremely preterm infants to increase survival free of BPD at 36 weeks' postmenstrual age (PMA; primary outcome). Extremely preterm infants aged < 48 h after birth are eligible if: (1) they are mechanically ventilated, or (2) they are receiving non-invasive respiratory support and there is a clinical decision to treat with surfactant. The intervention is budesonide (0.25 mg/kg) mixed with poractant alfa (200 mg/kg first intervention, 100 mg/kg if second intervention), administered intratracheally via an endotracheal tube or thin catheter. The comparator is poractant alfa alone (at the same doses). Secondary outcomes include the components of the primary outcome (death, BPD prior to or at 36 weeks' PMA), potential systemic side effects of corticosteroids, cost-effectiveness, early childhood health until 2 years of age, and neurodevelopmental outcomes at 2 years of age (corrected for prematurity)., Discussion: Combining budesonide with surfactant for intratracheal administration is a simple intervention that may reduce BPD in extremely preterm infants and translate into health benefits in later childhood. The PLUSS trial is powered for the primary outcome and will address gaps in the evidence due to its pragmatic and inclusive design, targeting all extremely preterm infants regardless of their initial mode of respiratory support. Should intratracheal budesonide mixed with surfactant increase survival free of BPD, without severe adverse effects, this readily available intervention could be introduced immediately into clinical practice., Trial Registration: Australian New Zealand Clinical Trials Registry ( https://www.anzctr.org.au ), ACTRN12617000322336. First registered on 28th February 2017., (© 2023. The Author(s).)

Background: Wilson disease is an inherited disorder of copper transport. Whereas penicillamine is used therapeutically to re-establish copper balance, trientine is indicated for patients with penicillamine intolerance. We aimed to compare penicillamine with trientine tetrahydrochloride (TETA4) for maintenance therapy in patients with Wilson disease., Methods: We conducted a randomised, open-label, non-inferiority, phase 3 trial at 15 health-care centres across nine countries (patients were recruited from 13 of these health-care centres across Brazil, Europe, and the USA). We enrolled patients aged 18-75 years with stable Wilson disease who were treated for at least 1 year with penicillamine. Patients entered a 12-week period to determine stability through clinical assessment by site investigators and predefined thresholds for serum non-caeruloplasmin-bound copper (NCC; by an exchangeable copper assay; 25-150 μg/L), 24 h urinary copper excretion (100-900 μg/24 h), and alanine aminotransferase (ALT; <2 × upper limit of normal). Stable patients were randomly assigned (1:1) to continue receiving the maintenance twice daily dose of oral penicillamine or switched mg-for-mg to oral TETA4 centrally with a web-based system using minimisation. The primary endpoint, assessed 24 weeks after randomisation, was NCC by speciation assay. The non-inferiority margin of mean difference in NCC by speciation assay was -50 μg/L, as estimated by a general linear model for repeated visits, adjusted for baseline values. Further data on safety and efficacy were collected during a 24-week extension period. Data were analysed using an intention-to-treat approach. Safety was assessed in all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03539952 (active, not recruiting)., Findings: Between June 4, 2018, and March 10, 2020, 77 patients were screened. 53 patients were randomly assigned (27 to the penicillamine group and 26 to the TETA4 group). After 24 weeks, the mean difference in serum NCC by speciation assay between the penicillamine group and TETA4 group was -9·1 μg/L (95% CI -24·2 to 6·1), with the lower limit of the 95% CI within the defined non-inferiority margin. At 24 weeks, urinary copper excretion was lower with TETA4 than with penicillamine (mean difference 237·5 μg/24 h (99% CI 115·6 to 359·4). At 48 weeks, TETA4 remained non-inferior to penicillamine in terms of NCC by speciation assay (mean difference NCC -15·5 μg/L [95% CI -34·5 to 3·6]). Urinary copper excretion at 48 weeks remained in the expected range for well treated patients in both study groups, and the mean difference (124·8 μg/24 h [99% CI -37·6 to 287·1]) was not significantly different. At 24 weeks and 48 weeks, masked clinical adjudication of stability assessed by three independent clinicians confirmed clinical stability (100%) of all participants, in agreement with the stability seen with the NCC by speciation assay. There were no notable changes in either the Clinical Global Impression of Change or Unified Wilson Disease Rating Scale (neurological assessment) from baseline (pre-randomisation) at weeks 24 and 48. The mean change in serum total copper from baseline to 24 weeks was 17·6 μg/L (99% CI -9·5 to 44·7) with penicillamine and -6·3 μg/L (-34·7 to 22·1) with TETA4, and the mean change in serum total caeruloplasmin from baseline to 24 weeks was 1·8 mg/L (-19·2 to 22·8) with penicillamine and -2·2 mg/L (-6·1 to 1·7) with TETA4. All liver enzymes were similar at 24 weeks and 48 weeks, with the exception of elevated ALT concentration at 48 weeks for patients in the TETA4 group. Penicillamine was associated with three post-randomisation serious adverse events (leukopenia, cholangiocarcinoma, and hepatocellular cancer); none were reported for TETA4. The most common treatment-emergent adverse events were headache for penicillamine (five [19%] of 27 patients vs two [8%] of 26) and abdominal pain for TETA4 (one [4%] vs four [15%]); all treatment-emergent adverse events resolved and were mild to moderate. One patient developed a rash with TETA4 that resolved on discontinuation of therapy., Interpretation: The efficacy of TETA4 as oral maintenance therapy was non-inferior to penicillamine and well tolerated in adults with Wilson disease., Funding: Orphalan., Competing Interests: Declaration of interests MLS has received research (institutional) grants from Orphalan, Alexion, and Vivet Therapeutics and is the Chair (unpaid) of the Medical Advisory Committee of the Wilson Disease Association. DC has received research (institutional) grants, consulting fees, and speaker's fees from Orphalan. AA has received research (institutional) grants from Orphalan, Alexion, Univar, and the Wilson Disease Association; consulting fees from Alexion and Orphalan; speaker's fee from Orphalan; travel assistance to meetings from Orphalan and Univar; and advisory board payments from Alexion, Univar, and Orphalan. GD has received consulting fees from Orphalan, Alexion, and Univar, and speaker's fees from Orphalan. EC-B has received speaker's fees from Orphalan and travel assistance to meetings from Orphalan, and advisory board payments from Alexion and Orphalan. AP has received research (institutional) grants from Orphalan; consulting fees from Alexion, Orphalan, and Vivet Therapeutics; speaker's fees from Orphalan, Alexion, and Univar; and advisory board payments from Alexion, Orphalan, Univar, and Vivet Therapeutics. AC has received research (institutional) grants from Orphalan, Alexion, Public Heath Research Institute in Canada; consulting fees from Wilson Therapeutics, Alexion, Vivet Therapeutics, and Orphalan; speaker's fees from Ever Pharma; and travel assistance to meetings from Orphalan. KD'H and ND are IDDI (biostatistical CRO for the trial) employees. COFK is an Orphalan employee. PO has received research (institutional) grants from Orphalan, Alexion, Univar, and Vivex, and speaker's fees and travel assistance to meetings from Orphalan, and is convenor of the Aarhus Wilson Disease Symposium. JM has received consulting fees from Orphalan and Alexion, and speaker's fees from Shire. KHW has received research (institutional) grants from Orphalan; consulting fees from Orphalan, Univar, Pfizer, Alexion, and Vivet Therapeutics; speaker's fees from Falk, AbbVie, Alexion, and Orphalan; travel assistance to meetings from Alexion and Univar; and advisory board payments from Ultragenyx. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objective: We sought to determine the effect of stimulation during positive pressure ventilation (PPV) on the number of spontaneous breaths, exhaled tidal volume (VTe), mask leak and obstruction., Design: Secondary analysis of a prospective, randomised trial comparing two face masks., Setting: Single-centre delivery room study., Patients: Newborn infants ≥34 weeks' gestation at birth., Methods: Resuscitations were video recorded. Tactile stimulations during PPV were noted and the timing, duration and surface area of applied stimulus were recorded. Respiratory flow waveforms were evaluated to determine the number of spontaneous breaths, VTe, leak and obstruction. Variables were recorded throughout each tactile stimulation episode and compared with those recorded in the same time period immediately before stimulation., Results: Twenty of 40 infants received tactile stimulation during PPV and we recorded 57 stimulations during PPV. During stimulation, the number of spontaneous breaths increased (median difference (IQR): 1 breath (0-3); p adj <0.001) and VTe increased (0.5 mL/kg (-0.5 to 1.7), p adj =0.028), whereas mask leak (0% (-20 to 1), p adj =0.12) and percentage of obstructed inflations (0% (0-0), p adj =0.14) did not change, compared with the period immediately prior to stimulation. Increased duration of stimulation (p adj <0.001) and surface area of applied stimulus (p adj =0.026) were associated with a larger increase in spontaneous breaths in response to tactile stimulation., Conclusions: Tactile stimulation during PPV was associated with an increase in the number of spontaneous breaths compared with immediately before stimulation without a change in mask leak and obstruction. These data inform the discussion on continuing stimulation during PPV in term infants., Trial Registration Number: Australian and New Zealand Clinical Trial Registry (ACTRN12616000768493)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Neonatal endotracheal intubation often involves more than one attempt, and oxygen desaturation is common. It is unclear whether nasal high-flow therapy, which extends the time to desaturation during elective intubation in children and adults receiving general anesthesia, can improve the likelihood of successful neonatal intubation on the first attempt., Methods: We performed a randomized, controlled trial to compare nasal high-flow therapy with standard care (no nasal high-flow therapy or supplemental oxygen) in neonates undergoing oral endotracheal intubation at two Australian tertiary neonatal intensive care units. Randomization of intubations to the high-flow group or the standard-care group was stratified according to trial center, the use of premedication for intubation (yes or no), and postmenstrual age of the infant (≤28 or >28 weeks). The primary outcome was successful intubation on the first attempt without physiological instability (defined as an absolute decrease in the peripheral oxygen saturation of >20% from the preintubation baseline level or bradycardia with a heart rate of <100 beats per minute) in the infant., Results: The primary intention-to-treat analysis included the outcomes of 251 intubations in 202 infants; 124 intubations were assigned to the high-flow group and 127 to the standard-care group. The infants had a median postmenstrual age of 27.9 weeks and a median weight of 920 g at the time of intubation. A successful intubation on the first attempt without physiological instability was achieved in 62 of 124 intubations (50.0%) in the high-flow group and in 40 of 127 intubations (31.5%) in the standard-care group (adjusted risk difference, 17.6 percentage points; 95% confidence interval [CI], 6.0 to 29.2), for a number needed to treat of 6 (95% CI, 4 to 17) for 1 infant to benefit. Successful intubation on the first attempt regardless of physiological stability was accomplished in 68.5% of the intubations in the high-flow group and in 54.3% of the intubations in the standard-care group (adjusted risk difference, 15.8 percentage points; 95% CI, 4.3 to 27.3)., Conclusions: Among infants undergoing endotracheal intubation at two Australian tertiary neonatal intensive care units, nasal high-flow therapy during the procedure improved the likelihood of successful intubation on the first attempt without physiological instability in the infant. (Funded by the National Health and Medical Research Council; Australian New Zealand Clinical Trials Registry number, ACTRN12618001498280.)., (Copyright © 2022 Massachusetts Medical Society.)

Objective: To evaluate the feasibility of electrical impedance tomography (EIT) to describe the regional tidal ventilation (V T ) and change in end-expiratory lung volume (EELV) patterns in preterm infants during the process of extubation from invasive to non-invasive respiratory support., Design: Prospective observational study., Setting: Single-centre tertiary neonatal intensive care unit., Patients: Preterm infants born <32 weeks' gestation who were being extubated to nasal continuous positive airway pressure as per clinician discretion., Interventions: EIT measurements were taken in supine infants during elective extubation from synchronised positive pressure ventilation (SIPPV) before extubation, during and then at 2 and 20 min after commencing nasal continuous positive applied pressure (nCPAP). Extubation and pressure settings were determined by clinicians., Main Outcome Measures: Global and regional ΔEELV and ΔV T , heart rate, respiratory rate and oxygen saturation were measured throughout., Results: Thirty infants of median (range) 2 (1, 21) days were extubated to a median (range) CPAP 7 (6, 8) cm H 2 O. SpO 2 /FiO 2 ratio was a mean (95% CI) 50 (35, 65) lower 20 min after nCPAP compared with SIPPV. EELV was lower at all points after extubation compared with SIPPV, and EELV loss was primarily in the ventral lung (p=0.04). V T was increased immediately after extubation, especially in the central and ventral regions of the lung, but the application of nCPAP returned V T to pre-extubation patterns., Conclusions: EIT was able to describe the complex lung conditions occurring during extubation to nCPAP, specifically lung volume loss and greater use of the dorsal lung. EIT may have a role in guiding peri-extubation respiratory support., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Importance: The benefits of surfactant administration via a thin catheter (minimally invasive surfactant therapy [MIST]) in preterm infants with respiratory distress syndrome are uncertain., Objective: To examine the effect of selective application of MIST at a low fraction of inspired oxygen threshold on survival without bronchopulmonary dysplasia (BPD)., Design, Setting, and Participants: Randomized clinical trial including 485 preterm infants with a gestational age of 25 to 28 weeks who were supported with continuous positive airway pressure (CPAP) and required a fraction of inspired oxygen of 0.30 or greater within 6 hours of birth. The trial was conducted at 33 tertiary-level neonatal intensive care units around the world, with blinding of the clinicians and outcome assessors. Enrollment took place between December 16, 2011, and March 26, 2020; follow-up was completed on December 2, 2020., Interventions: Infants were randomized to the MIST group (n = 241) and received exogenous surfactant (200 mg/kg of poractant alfa) via a thin catheter or to the control group (n = 244) and received a sham (control) treatment; CPAP was continued thereafter in both groups unless specified intubation criteria were met., Main Outcomes and Measures: The primary outcome was the composite of death or physiological BPD assessed at 36 weeks' postmenstrual age. The components of the primary outcome (death prior to 36 weeks' postmenstrual age and BPD at 36 weeks' postmenstrual age) also were considered separately., Results: Among the 485 infants randomized (median gestational age, 27.3 weeks; 241 [49.7%] female), all completed follow-up. Death or BPD occurred in 105 infants (43.6%) in the MIST group and 121 (49.6%) in the control group (risk difference [RD], -6.3% [95% CI, -14.2% to 1.6%]; relative risk [RR], 0.87 [95% CI, 0.74 to 1.03]; P = .10). Incidence of death before 36 weeks' postmenstrual age did not differ significantly between groups (24 [10.0%] in MIST vs 19 [7.8%] in control; RD, 2.1% [95% CI, -3.6% to 7.8%]; RR, 1.27 [95% CI, 0.63 to 2.57]; P = .51), but incidence of BPD in survivors to 36 weeks' postmenstrual age was lower in the MIST group (81/217 [37.3%] vs 102/225 [45.3%] in the control group; RD, -7.8% [95% CI, -14.9% to -0.7%]; RR, 0.83 [95% CI, 0.70 to 0.98]; P = .03). Serious adverse events occurred in 10.3% of infants in the MIST group and 11.1% in the control group., Conclusions and Relevance: Among preterm infants with respiratory distress syndrome supported with CPAP, minimally invasive surfactant therapy compared with sham (control) treatment did not significantly reduce the incidence of the composite outcome of death or bronchopulmonary dysplasia at 36 weeks' postmenstrual age. However, given the statistical uncertainty reflected in the 95% CI, a clinically important effect cannot be excluded., Trial Registration: anzctr.org.au Identifier: ACTRN12611000916943.

Background: Fetal scalp blood sampling for lactate measurement (FBSLM) is sometimes used to assist in identification of the need for expedited birth in the presence of an abnormal cardiotocograph (CTG). However, there is no randomised controlled trial evidence to support this., Aim: To determine whether adding FBSLM reduces the risk of birth by emergency caesarean section in labours complicated by an abnormal CTG, compared with CTG without FBS., Material and Methods: Labouring women at a tertiary maternity hospital in Melbourne, Australia with a singleton, cephalic presentation, at ≥37 weeks gestation with an abnormal CTG pattern were randomised to the intervention (n = 61), with intermittent FBSLM in addition to CTG monitoring, or control (CTG without FBS, n = 62). The primary outcome was rate of birth by caesarean section. Secondary outcomes included overall operative birth and fetal and neonatal safety endpoints., Trial Registration: ACTRN12611000172909., Results: The smaller than anticipated sample was unable to demonstrate an effect from adding FBSLM to CTG monitoring on birth by caesarean section vs monitoring by CTG without FBS (25/61 and 28/62 respectively, P = 0.64, risk ratio 0.91, 95% confidence intervals 0.60-1.36). One newborn infant in the CTG group met the criteria for the composite neonatal outcome of death or serious outcome, neonatal encephalopathy, five-minute Apgar score < 4, neonatal resuscitation, admission to neonatal intensive care unit for 96 h or more., Conclusion: We were unable to provide robust evidence of the effectiveness of FBSLM to improve the specificity of the CTG in the assessment of fetal wellbeing., (© 2021 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.)