Intratracheal budesonide mixed with surfactant to increase survival free of bronchopulmonary dysplasia in extremely preterm infants: statistical analysis plan for the international, multicenter, randomized PLUSS trial.

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.

Two-Year Outcomes After Minimally Invasive Surfactant Therapy in Preterm Infants: Follow-Up of the OPTIMIST-A Randomized Clinical Trial.

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.

Intratracheal budesonide mixed with surfactant to increase survival free of bronchopulmonary dysplasia in extremely preterm infants: study protocol for the international, multicenter, randomized PLUSS trial.

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.

Trientine tetrahydrochloride versus penicillamine for maintenance therapy in Wilson disease (CHELATE): a randomised, open-label, non-inferiority, phase 3 trial.

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.

Nasal High-Flow Therapy during Neonatal Endotracheal Intubation.

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.).

Effects of tactile stimulation on spontaneous breathing during face mask ventilation.

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); padj<0.001) and VTe increased (0.5 mL/kg (-0.5 to 1.7), padj=0.028), whereas mask leak (0% (-20 to 1), padj=0.12) and percentage of obstructed inflations (0% (0-0), padj=0.14) did not change, compared with the period immediately prior to stimulation. Increased duration of stimulation (padj<0.001) and surface area of applied stimulus (padj=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).

Extubation generates lung volume inhomogeneity in preterm infants.

OBJECTIVE: To evaluate the feasibility of electrical impedance tomography (EIT) to describe the regional tidal ventilation (VT) 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 ΔVT, 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 H2O. SpO2/FiO2 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). VT was increased immediately after extubation, especially in the central and ventral regions of the lung, but the application of nCPAP returned VT 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.

Effect of Minimally Invasive Surfactant Therapy vs Sham Treatment on Death or Bronchopulmonary Dysplasia in Preterm Infants With Respiratory Distress Syndrome: The OPTIMIST-A Randomized Clinical Trial.

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.

A multi-centre randomised controlled trial of respiratory function monitoring during stabilisation of very preterm infants at birth.

AIM: To determine whether the use of a respiratory function monitor (RFM) during PPV of extremely preterm infants at birth, compared with no RFM, leads to an increase in percentage of inflations with an expiratory tidal volume (Vte) within a predefined target range. METHODS: Unmasked, randomised clinical trial conducted October 2013 - May 2019 in 7 neonatal intensive care units in 6 countries. Very preterm infants (24-27 weeks of gestation) receiving PPV at birth were randomised to have a RFM screen visible or not. The primary outcome was the median proportion of inflations during manual PPV (face mask or intubated) within the target range (Vte 4-8 mL/kg). There were 42 other prespecified monitor measurements and clinical outcomes. RESULTS: Among 288 infants randomised (median (IQR) gestational age 26+2 (25+3-27+1) weeks), a total number of 51,352 inflations were analysed. The median (IQR) percentage of inflations within the target range in the RFM visible group was 30.0 (18.0-42.2)% vs 30.2 (14.8-43.1)% in the RFM non-visible group (p = 0.721). There were no differences in other respiratory function measurements, oxygen saturation, heart rate or FiO2. There were no differences in clinical outcomes, except for the incidence of intraventricular haemorrhage (all grades) and/or cystic periventricular leukomalacia (visible RFM: 26.7% vs non-visible RFM: 39.0%; RR 0.71 (0.68-0.97); p = 0.028). CONCLUSION: In very preterm infants receiving PPV at birth, the use of a RFM, compared to no RFM as guidance for tidal volume delivery, did not increase the percentage of inflations in a predefined target range. TRIAL REGISTRATION: Dutch Trial Register NTR4104, clinicaltrials.gov NCT03256578.

The addition of fetal scalp blood lactate measurement as an adjunct to cardiotocography to reduce caesarean sections during labour: The Flamingo randomised controlled trial.

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.

Lung ultrasound during newborn resuscitation predicts the need for surfactant therapy in very- and extremely preterm infants.

INTRODUCTION: Early identification of infants requiring surfactant therapy improves outcomes. We evaluated the accuracy of delivery room lung ultrasound (LUS) to predict surfactant therapy in very- and extremely preterm infants. METHODS: Infants born at <320/7 weeks were prospectively enrolled at 2 centres. LUS videos of both sides of the chest were obtained 5-10 min, 11-20 min, and 1-3 h after birth. Clinicians were masked to the results of the LUS assessment and surfactant therapy was provided according to local guidelines. LUS videos were graded blinded to clinical data. Presence of unilateral type 1 ('whiteout') LUS or worse was considered test positive. Receiver Operating Characteristic (ROC) analysis compared the accuracy of LUS and an FiO2 threshold of 0.3 to predict subsequent surfactant therapy. RESULTS: Fifty-two infants with a median age of 276/7 weeks (IQR 260/7-286/7) were studied. Thirty infants (58%) received surfactant. Area under the ROC curve (AUC) for LUS at 5-10 min, 11-20 min and 1-3 h was 0.78 (95% CI, 0.66-0.90), 0.76 (95% CI, 0.65-0.88) and 0.86 (95% CI, 0.75-0.97) respectively, outperforming FiO2 at the 5-10 min timepoint (AUC 0.45, 95% CI 0.29-0.62, p = 0.001). At 11-20 min, LUS had a specificity of 95% (95% CI 77-100%) and sensitivity of 59% (95% CI, 39-77%) to predict surfactant therapy. All infants born at 23-276/7 weeks with LUS test positive received surfactant. Twenty-six infants (50%) had worsening of LUS grades on serial assessment. CONCLUSIONS: LUS in the delivery room and accurately predicts surfactant therapy in infants <320/7 weeks.

Outcomes after Introduction of Minimally Invasive Surfactant Therapy in Two Australian Tertiary Neonatal Units.

OBJECTIVE: To assess the procedural and clinical outcomes associated with the introduction of minimally invasive surfactant therapy (MIST) into standard care at 2 tertiary Australian neonatal intensive care units. STUDY DESIGN: A prospective audit was designed before the introduction of MIST in 2018, with data collected over a period of 18 months. Procedural data were completed by the clinical team performing MIST, including clinical observations, medication use, and adverse events. The audit team collected demographic data and subsequent clinical outcomes from medical records. RESULTS: There were 135 MIST procedures recorded in 122 infants. For the included infants, the median gestation was 302/7 weeks (IQR, 276/7 to 322/7 weeks) and birth weight was 1439 g (IQR, 982-1958 g). During the MIST procedure, desaturation to a peripheral oxygen saturation of <80% was common, occurring in 75.2% of procedures. Other adverse events included need for positive pressure ventilation (10.6%) and bradycardia <100 beats per minute (13.3%). The use of atropine premedication was associated with a significantly lower incidence of bradycardia: 8.6% vs 52.9% (P < .01). Senior clinicians demonstrated higher rates of procedural success. The majority of infants (63.9%) treated with MIST did not require subsequent intubation and mechanical ventilation. CONCLUSIONS: MIST can be successfully introduced in neonatal units with limited experience of this technique. The use of atropine premedication decreases the incidence of bradycardia during the procedure. Success rates can be optimized by limiting MIST to clinicians with greater competence in endotracheal intubation.

Neonatal videolaryngoscopy as a teaching aid: the trainees' perspective.

INTRODUCTION: Neonatal intubation is a challenging skill to acquire. A randomised controlled trial (RCT) found junior trainees had higher intubation success rates if their supervisor shared their airway view on a videolaryngoscope screen compared with intubations where the supervisor could not see the videolaryngoscope screen. The intubations in the trial were supervised by a group of experienced neonatologists who developed an intubation teaching package that aimed to be informative, consistent and supportive. We surveyed the trainees to assess their experiences of the intubation attempts. METHODS: Trainees participating in the RCT completed questionnaires anonymously after each intubation attempt. Questionnaires used 5-point Likert scales and free comment sections. Quantitative analysis was performed using descriptive statistics. In a qualitative analysis, free comments were coded to identify central recurring themes. RESULTS: Two hundred and six questionnaires were completed by 36 trainees. The majority reported that the guidance received during intubation was helpful, the postprocedure feedback was educational and their confidence levels were increased. Trainees appreciated a controlled environment and calm, consistent guidance. They found intubations in the delivery room, those involving unstable infants, large audiences and parental presence more stressful. Responses were positive whether the videolaryngoscope screen was visible or covered, emphasising the importance of consistent guidance. Overall, 16% of intubations were reported as intimidating. CONCLUSION: The shared airway view offered by videolaryngoscopy was well received. In addition, taking measures to control the setting, with standardised guidance and feedback, improved confidence and created a more positive learning experience.

Physiological responses to facemask application in newborns immediately after birth.

OBJECTIVE: Application of a face mask may induce apnoea and bradycardia, possibly via the trigeminocardiac reflex (TCR). We aimed to describe rates of apnoea and bradycardia in term and late-preterm infants following facemask application during neonatal stabilisation and compare the effects of first facemask application with subsequent applications. DESIGN: Subgroup analysis of a prospective, randomised trial comparing two face masks. SETTING: Single-centre study in the delivery room PATIENTS: Infants>34 weeks gestational age at birth METHODS: Resuscitations were video recorded. Airway flow and pressure were measured using a flow sensor. The effect of first and subsequent facemask applications on spontaneously breathing infants were noted. When available, flow waveforms as well as heart rate (HR) were assessed 20 s before and 30 s after each facemask application. RESULTS: In total, 128 facemask applications were evaluated. In eleven percent of facemask applications infants stopped breathing. The first application was associated with a higher rate of apnoea than subsequent applications (29% vs 8%, OR (95% CI)=4.76 (1.41-16.67), p=0.012). On aggregate, there was no change in median HR over time. In the interventions associated with apnoea, HR dropped by 38bpm [median (IQR) at time of facemask application: 134bpm (134-150) vs 96bpm (94-102) 20 s after application; p=0.25] and recovered within 30 s. CONCLUSIONS: Facemask applications in term and late-preterm infants during neonatal stabilisation are associated with apnoea and this effect is more pronounced after the first compared with subsequent applications. Healthcare providers should be aware of the TCR and vigilant when applying a face mask to newborn infants. TRIAL REGISTRATION NUMBER: ACTRN12616000768493.

Characterization of the pathoimmunology of necrotizing enterocolitis reveals novel therapeutic opportunities.

Necrotizing enterocolitis (NEC) is a severe, currently untreatable intestinal disease that predominantly affects preterm infants and is driven by poorly characterized inflammatory pathways. Here, human and murine NEC intestines exhibit an unexpected predominance of type 3/TH17 polarization. In murine NEC, pro-inflammatory type 3 NKp46-RORγt+Tbet+ innate lymphoid cells (ILC3) are 5-fold increased, whereas ILC1 and protective NKp46+RORγt+ ILC3 are obliterated. Both species exhibit dysregulation of intestinal TLR repertoires, with TLR4 and TLR8 increased, but TLR5-7 and TLR9-12 reduced. Transgenic IL-37 effectively protects mice from intestinal injury and mortality, whilst exogenous IL-37 is only modestly efficacious. Mechanistically, IL-37 favorably modulates immune homeostasis, TLR repertoires and microbial diversity. Moreover, IL-37 and its receptor IL-1R8 are reduced in human NEC epithelia, and IL-37 is lower in blood monocytes from infants with NEC and/or lower birthweight. Our results on NEC pathomechanisms thus implicate type 3 cytokines, TLRs and IL-37 as potential targets for novel NEC therapies.

A randomized trial of oropharyngeal airways to assist stabilization of preterm infants in the delivery room.

OBJECTIVE: Positive pressure ventilation (PPV) using a ventilation device and a face mask is recommended for compromised newborn infants in the delivery room (DR). Airway obstruction and face mask leak during PPV may contribute to failure of resuscitation. Using an oropharyngeal airway (OPA) may improve efficacy of mask PPV. To determine whether the use of an OPA with mask PPV in the DR during stabilization of infants <34 weeks' gestational age, reduces the incidence of airway obstruction. INTERVENTION AND MEASUREMENTS: An international two center unblinded randomized trial. Infants assessed by the clinical team to require PPV, were randomly assigned to receive PPV using a T Piece device with either a soft round face mask alone or in combination with an appropriately sized OPA. Resuscitation protocols were standardized. A hot-wire anemometer flow sensor measured respiratory function during the first five minutes of stabilization. The primary outcome was the incidence of airway obstruction, either complete (no gas flow) or partial (minimal gas flows resulting in expired tidal volumes <2 mL/kg). MAIN RESULTS: A total of 137 infants were enrolled. Obstructed inflations were more frequently observed in infants stabilized with an OPA (81% vs. 64%; p = 0.03). Partial obstruction was more common in infants stabilized with an OPA (70% vs 54%; p = 0.04). There were no differences in mortality or respiratory outcomes for the whole cohort or in gestational age subgroups. CONCLUSIONS: Airway obstruction is common in preterm infants receiving mask ventilation in the DR. Using an oropharyngeal airway significantly increases the incidence of airway obstruction. REGISTERED CLINICAL TRIAL: Australian and New Zealand Clinical Trials Register; ACTRN 12612000392864.

Outcomes following antenatal identification of hydrops fetalis: a single-centre experience from 2001 to 2012.

OBJECTIVE: To describe the aetiologies and outcomes of pregnancies complicated by hydrops fetalis (HF). STUDY DESIGN: Case series of all pregnancies complicated by HF managed at The Royal Women's Hospital (RWH), Melbourne, Australia, between 2001 and 2012. Multiple pregnancies, and cases where antenatal care was not provided at RWH were excluded. Cases were identified from neonatal and obstetric databases. Data were extracted from maternal and neonatal case files, electronic pathology and radiology reports, and obstetric and neonatal databases. RESULTS: Over 12 years, 131 fetuses with HF with a median (IQR) gestational age (GA) at diagnosis of 24 (20-30) weeks were included in the analysis. There were 65 liveborn infants with a median (IQR) GA at birth of 33 (31-37) weeks and a median (IQR) birthweight Z-score of 1.4 (0.4-2.2). Overall survival from diagnosis was 27% (36/131) increasing to 55% (36/65) if born alive. CONCLUSIONS: The perinatal mortality risk for fetuses and newborn infants with HF is high with important differences dependent on underlying diagnosis and the time at which counselling is provided. Clinicians need to be aware of the outcomes of both fetuses and neonates with this condition.

Pulseless electrical activity: a misdiagnosed entity during asphyxia in newborn infants?

BACKGROUND: The 2015 neonatal resuscitation guidelines added ECG as a recommended method of assessment of an infant's heart rate (HR) when determining the need for resuscitation at birth. However, a recent case report raised concerns about this technique in the delivery room. OBJECTIVES: To compare accuracy of ECG with auscultation to assess asystole in asphyxiated piglets. METHODS: Neonatal piglets had the right common carotid artery exposed and enclosed with a real-time ultrasonic flow probe and HR was continuously measured and recorded using ECG. This set-up allowed simultaneous monitoring of HR via ECG and carotid blood flow (CBF). The piglets were exposed to 30 min normocapnic alveolar hypoxia followed by asphyxia until asystole, achieved by disconnecting the ventilator and clamping the endotracheal tube. Asystole was defined as zero carotid blood flow and was compared with ECG traces and auscultation for heart sounds using a neonatal/infant stethoscope. RESULTS: Overall, 54 piglets were studied with a median (IQR) duration of asphyxia of 325 (200-491) s. In 14 (26%) piglets, CBF, ECG and auscultation identified asystole. In 23 (43%) piglets, we observed no CBF and no audible heart sounds, while ECG displayed an HR ranging from 15 to 80/min. Sixteen (30%) piglets remained bradycardic (defined as HR of <100/min) after 10 min of asphyxia, identified by CBF, ECG and auscultation. CONCLUSION: Clinicians should be aware of the potential inaccuracy of ECG assessment during asphyxia in newborn infants and should rather rely on assessment using a combination of auscultation, palpation, pulse oximetry and ECG.

Respiratory changes in term infants immediately after birth.

INTRODUCTION: Over 5% of infants worldwide receive breathing support immediately after birth. Our goal was to define references ranges for exhaled carbon dioxide (ECO2), exhaled tidal volume (VTe), and respiratory rate (RR) immediately after birth in spontaneously breathing, healthy infants born at 36 weeks' gestational age or older. METHODS: This was a single-centre, observational study at the Royal Women's Hospital in Melbourne, Australia, a busy perinatal referral centre. Immediately after the infant's head was delivered, we used a face mask to measure ECO2, VTe, and RR through the first ten minutes after birth. Respiratory measurements were repeated at one hour. RESULTS: We analysed 14,731 breaths in 101 spontaneously breathing infants, 51 born via planned caesarean section and 50 born vaginally with a median (IQR) gestational age of 391/7 weeks (383/7-395/7). It took a median of 7 (4-10) breaths until ECO2 was detected. ECO2 quickly increased to peak value of 48 mmHg (43-53) at 143 s (76-258) after birth, and decreased to post-transitional values, 31 mmHg (28-24), by 7 min. VTe increased after birth, reaching a plateau of 5.3 ml/kg (2.5-8.4) by 130 s for the remainder of the study period. Maximum VTe was 19 ml/kg (16-22) at 257 s (82-360). RR values increased slightly over time, being higher from minute five to ten as compared to the first two minutes after birth. CONCLUSIONS: This study provides reference ranges of exhaled carbon dioxide, exhaled tidal volumes, and respiratory rate for the first ten minutes after birth in term infants who transition without resuscitation.

The Effect of Noninvasive High-Frequency Oscillatory Ventilation on Desaturations and Bradycardia in Very Preterm Infants: A Randomized Crossover Trial.

Noninvasive high-frequency oscillatory ventilation compared with nasal continuous positive airway pressure significantly reduced the number of desaturations and bradycardia in preterm infants. However, noninvasive high-frequency oscillatory ventilation was associated with increased oxygen requirements and higher heart rates. TRIAL REGISTRATION: Australian and New Zealand Clinical Trial Registry: ACTRN12616001516471.