Endotracheal epinephrine at standard versus high dose for resuscitation of asystolic newborn lambs.

INTRODUCTION: Endotracheal (ET) epinephrine administration is an option during neonatal resuscitation, if the preferred intravenous (IV) route is unavailable. OBJECTIVES: We assessed whether endotracheal epinephrine achieved return of spontaneous circulation (ROSC), and maintained physiological stability after ROSC, at standard and higher dose, in severely asphyxiated newborn lambs. METHODS: Near-term fetal lambs were asphyxiated until asystole. Resuscitation was commenced with ventilation and chest compressions. Lambs were randomly allocated to: IV Saline placebo (5 ml/kg), IV Epinephrine (20 micrograms/kg), Standard-dose ET Epinephrine (100 micrograms/kg), and High-dose ET Epinephrine (1 mg/kg). After three allocated treatment doses, rescue IV Epinephrine was administered if ROSC had not occurred. Lambs achieving ROSC were monitored for 60 minutes. Brain histology was assessed for microbleeds. RESULTS: ROSC in response to allocated treatment (without rescue IV Epinephrine) occurred in 1/6 Saline, 9/9 IV Epinephrine, 0/9 Standard-dose ET Epinephrine, and 7/9 High-dose ET Epinephrine lambs respectively. Blood pressure during CPR increased after treatment with IV Epinephrine and High-dose ET Epinephrine, but not Saline or Standard-dose ET Epinephrine. After ROSC, both ET Epinephrine groups had lower pH, higher lactate, and higher blood pressure than the IV Epinephrine group. Cortex microbleeds were more frequent in High-dose ET Epinephrine lambs (8/8 lambs examined, versus 3/8 in IV Epinephrine lambs). CONCLUSIONS: The currently recommended dose of ET Epinephrine was ineffective in achieving ROSC. Without convincing clinical or preclinical evidence of efficacy, use of ET Epinephrine at this dose may not be appropriate. High-dose ET Epinephrine requires further evaluation before clinical translation.

Postnatal corticosteroids and developmental outcomes in extremely preterm or extremely low birth weight infants: The Victorian Infant Collaborative Study 2016-17 cohort.

AIM: Systemic postnatal corticosteroids are used to treat or prevent bronchopulmonary dysplasia (BPD) in extremely preterm (EP) or extremely low birth weight (ELBW) infants but are associated with long-term harm. We aimed to assess the relationship between cumulative postnatal corticosteroid dose and neurodevelopmental outcomes. METHODS: Longitudinal cohort study of all EP/ELBW livebirths in Victoria, Australia 2016-2017. Perinatal data were collected prospectively. Neurodevelopmental assessment was performed at 2 years' corrected age. Linear and logistic regression were used to determine relationships between cumulative corticosteroid dose and neurodevelopment, adjusted for gestational age, birth weight, sex and major intraventricular haemorrhage. RESULTS: Seventy-six EP/ELBW infants received postnatal corticosteroids to treat or prevent BPD, 62/65 survivors were seen at 2 years. Median (IQR) cumulative postnatal corticosteroid dose was 1.36 (0.92-3.45) mg/kg dexamethasone equivalent. Higher cumulative corticosteroid dose was associated with increased odds of cerebral palsy, adjusted OR (95% CI) 1.47 (1.04, 2.07). Higher cumulative corticosteroid dose was also associated with lower cognitive and motor developmental scores, however, this weakened after adjustment for confounding variables: cognitive composite score adjusted coefficient (95% CI) -1.3 (-2.7, 0.1) and motor composite score adjusted coefficient (95% CI) -1.3 (-2.8, 0.2). CONCLUSION: Higher cumulative postnatal corticosteroid dose in EP/ELBW infants is associated with increased odds of cerebral palsy at 2 years' corrected age. Adequately powered studies are needed to assess the independent effects of cumulative steroid dose on neurodevelopmental outcomes.

Cardiorespiratory adaptation to low-dose dexamethasone for lung disease in extremely preterm infants: A prospective echocardiographic study.

The cardiovascular impact of dexamethasone (Dex) is not well understood. Most data are obtained from a 6 week, high-dose regimen, and are limited to findings of hypertension and cardiac hypertrophy. The present study ascertained the impact of low-dose Dex on cardiac indices when administered to extremely preterm infants for lung disease. A pre-post intervention prospective echocardiographic (Echo) study was undertaken, with cardiac assessments performed before and within 24 h after completion of first course of therapy (10 day regimen, cumulative 0.89 mg kg-1 ). Thirty infants with a gestational age of 24.6 ± 1.1 weeks and birthweight of 612 ± 125 g, respectively, were studied. The age at Dex administration was 20 ± 9 days. Fractional inspired oxygen decreased from 0.7 ± 0.23 to 0.35 ± 0.14 (P < 0.001). Patent ductus arteriosus was noted in 20 infants at Echo1. At Echo2, the ductal diameter decreased from 2.16 ± 0.8 to 1.1 ± 0.8 mm (P = 0.0003), with complete closure in 7/20 (35%). A reduction in left pulmonary artery end-diastolic velocity was noted (17 ± 12 to 9 ± 10 cm s-1 , P < 0.001). Pulmonary vascular resistance decreased (increased time to peak velocity/right ventricular ejection time, 0.2 ± 0.03 to 0.23  ± 0.03, P = 0.0001) and right ventricular systolic performance improved (tricuspid annular plane systolic excursion, 4.9 ± 0.8 to 5.5 ± 0.9 mm, P = 0.02). No significant changes in fractional shortening and left ventricular mass were noted. A significant increase in blood pressure was noted. As a percentage of pre-treatment baseline, the mean increase for systolic blood pressure was 20.3% (95% confidence interval = 14-26) on day 2 (P = 0.008). Low-dose Dex influenced cardiovascular parameters related to pulmonary circulation. KEY POINTS: Corticosteroid therapy is frequently used in preterm infants who are dependent on ventilator support. Echocardiographic studies in infants administered a 6 week course of steroids have noted left ventricular hypertrophy, outlet obstruction and hypertension, but no information is available on right heart indices. The cardiopulmonary effects of the current, significantly lesser cumulative dose (10 day regimen, commonly described as 'DART') have not been evaluated. The present study noted a significant influence on ductal and pulmonary circulation indices. Left heart architecture and function was maintained, whereas a significant but transient increase in blood pressure was noted.

Introduction of a Quality Improvement Bundle Is Associated with Reduced Exposure to Mechanical Ventilation in Very Preterm Infants.

INTRODUCTION: Exposure to mechanical ventilation (MV) is a risk factor for bronchopulmonary dysplasia (BPD) in very preterm infants (VPTIs). We assessed the impact of a quality improvement (QI) bundle in VPTIs (<32 week gestation) on exposure to MV. METHODS: We introduced a QI bundle consisting of deferred cord clamping (DCC), nasal bubble continuous positive airway pressure (bCPAP) in the delivery room (DR), and minimally invasive surfactant therapy (MIST). We compared respiratory outcomes and neonatal morbidity in historical pre-QI (July-December 2017) and prospective post-QI (February-July 2019) cohorts (QICs) of VPTIs. We pre-specified an adjusted analysis to account for the effects of gestational age, sex, antenatal steroids, and any demographic data that significantly differed between cohorts. RESULTS: The pre-QI and post-QICs included 87 and 98 VPTIs, respectively. The post-QIC had decreased rates of MV in the DR (adjusted odds ratio [aOR] 0.26, 95% confidence interval [CI] 0.09-0.71), in the first 72 h of life (aOR 0.27, 95% CI 0.11-0.62) and during admission (aOR 0.28, 95% CI 0.12-0.66). Rates of BPD, combined BPD/death, and BPD severity were similar. The post-QIC was less likely to be discharged with home oxygen (aOR 0.27, 95% CI 0.08-0.91). Necrotising enterocolitis grade ≥2 increased (aOR 19.01, 95% CI 1.93-188.6) in the post-QIC. CONCLUSION: In this rapid-cycle QI study, implementation of a QI bundle consisting of DCC, early nasal bCPAP, and MIST in VPTIs was associated with reduced rates of MV in the DR, in the first 72 h of life and during admission, and reduced need for home oxygen.

Impact of early respiratory care for extremely preterm infants.

Despite advances in neonatal intensive care, more than half of surviving infants born extremely preterm (EP; < 28 weeks' gestation) develop bronchopulmonary dysplasia (BPD). Prevention of BPD is critical because of its associated mortality and morbidity, including adverse neurodevelopmental outcomes and respiratory health in later childhood and beyond. The respiratory care of EP infants begins before birth, then continues in the delivery room and throughout the primary hospitalization. This chapter will review the evidence for interventions after birth that might improve outcomes for infants born EP, including the timing of umbilical cord clamping, strategies to avoid or minimize exposure to mechanical ventilation, modes of mechanical ventilation and non-invasive respiratory support, oxygen saturation targets, postnatal corticosteroids and other adjunct therapies.

Assessing pulmonary circulation in severe bronchopulmonary dysplasia using functional echocardiography.

Pulmonary hypertension (PH) is common in infants with severe bronchopulmonary dysplasia (BPD) and increases the risk of death. The objectives of this preliminary study were to compare responses of pulmonary circulation parameters to 100% oxygen (O2 ) and inhaled nitric oxide (iNO) in infants with BPD and PH using echocardiography. Responses between fetal growth restriction (FGR) and appropriate for gestational age infants were compared. Ten infants <28 weeks GA at birth were assessed at ≥36 weeks corrected gestation. Baseline echocardiography1 was performed which was repeated (echocardiography2) after 30 minutes of O2 . After a gap of 2-3 hours, iNO was administered for 15 minutes and echocardiography3 was performed, followed by iNO weaning. The gestation and birthweight of the cohort were 25.9 ± 1.6 weeks and 612 ± 175 g. Assessments were performed at 38.7 ± 1.4 weeks corrected gestational age. Baseline time to peak velocity: right ventricular ejection time (TPV/RVETc) increased from 0.24 ± 0.02 to 0.27 ± 0.02 (O2 , p = .01) and 0.31 ± 0.03 (iNO, p < .001), indicating a decrease in pulmonary vascular resistance [PVR]. Baseline tricuspid annular plane systolic excursion (TAPSE) increased from 8.1 ± 0.6 mm to 9.3 ± 0.7 mm (O2 , p = .01) and 10.5 ± 1.1 mm (iNO, p = .0004), indicating improved ventricular systolic performance. Percentage change for all parameters was greater with iNO. Significant correlations between cardiac performance and PVR were noted. FGR infants noted higher baseline PVR (TPV/RVETc, 0.21 ± 0.02 vs. 0.25 ± 0.01, p = .002), lower ventricular performance (TAPSE, 7 ± 1.2 mm vs. 8.6 ± 6 mm, p = .003), and lower percentage change with O2 and iNO. A reactive component of pulmonary circulation provides real-time physiological information, which could rationalize treatment decisions.

A multicentre, randomised trial of stabilisation with nasal high flow during neonatal endotracheal intubation (the SHINE trial): a study protocol.

INTRODUCTION: Neonatal endotracheal intubation is an essential but potentially destabilising procedure. With an increased focus on avoiding mechanical ventilation, particularly in preterm infants, there are fewer opportunities for clinicians to gain proficiency in this important emergency skill. Rates of successful intubation at the first attempt are relatively low, and adverse event rates are high, when compared with intubations in paediatric and adult populations. Interventions to improve operator success and patient stability during neonatal endotracheal intubations are needed. Using nasal high flow therapy extends the safe apnoea time of adults undergoing upper airway surgery and during endotracheal intubation. This technique is untested in neonates. METHODS AND ANALYSIS: The Stabilisation with nasal High flow during Intubation of NEonates (SHINE) trial is a multicentre, randomised controlled trial comparing the use of nasal high flow during neonatal intubation with standard care (no nasal high flow). Intubations are randomised individually, and stratified by site, use of premedications, and postmenstrual age (<28 weeks' gestation; ≥28 weeks' gestation). The primary outcome is the incidence of successful intubation on the first attempt without physiological instability of the infant. Physiological instability is defined as an absolute decrease in peripheral oxygen saturation >20% from preintubation baseline and/or bradycardia (<100 beats per minute). ETHICS AND DISSEMINATION: The SHINE trial received ethical approval from the Human Research Ethics Committees of The Royal Women's Hospital, Melbourne, Australia and Monash Health, Melbourne, Australia. The trial is currently recruiting in these two sites. The findings of this study will be disseminated via peer-reviewed journals and presented at national and international conferences. TRIAL REGISTRATION NUMBER: ACTRN12618001498280.

Predictors and Outcomes of Early Intubation in Infants Born at 28-36 Weeks of Gestation Receiving Noninvasive Respiratory Support.

OBJECTIVE: To identify predictors and outcomes of early intubation in preterm infants with respiratory distress, and predictors of need for brief respiratory support (≤1 day). STUDY DESIGN: Secondary analysis of data from a randomized trial comparing nasal high-flow with continuous positive airway pressure as primary respiratory support in preterm infants born at 28-36 weeks of gestation. Intubation was assessed within 72 hours of randomization. RESULTS: There were 564 included infants with a mean (SD) gestational age of 32.0 (2.2) weeks and birth weight 1744 (589) g; 76 infants (13.5%) received early intubation. On multivariable analysis, lower gestational age and higher pre-randomization fraction of inspired oxygen (FiO2) predicted intubation. A test based on gestational age of <30 weeks and an FiO2 of ≥0.30 produced a likelihood ratio of 9.1. Intubation was associated with prolonged duration of respiratory support and supplemental oxygen, with pneumothorax and nasal trauma, and in infants born at <32 weeks of gestational, with bronchopulmonary dysplasia and patent ductus arteriosus requiring treatment. Greater gestational age and lower FiO2 predicted the need for ≤1 day of respiratory support. A test based on a gestational age of ≥34 weeks and an FiO2 of 0.21 produced a likelihood ratio of 4.7. CONCLUSIONS: In preterm infants 28-36 week of gestation receiving primary noninvasive respiratory support, lower gestational age, and higher FiO2 predicted need for intubation within 72 hours. Intubation was associated with adverse respiratory outcomes. Greater gestational age and lower FiO2 predicted need for ≤1 day of respiratory support. It may be reasonable to defer the use of respiratory support in more mature infants with low FiO2 requirements. TRIAL REGISTRATION AUSTRALIAN NEW ZEALAND CLINICAL TRIALS REGISTRY: ACTRN12613000303741.

Interventions to Improve Rates of Successful Extubation in Preterm Infants: A Systematic Review and Meta-analysis.

Importance: Clinicians aim to extubate preterm infants as early as possible, to minimize the risks of mechanical ventilation. Extubation is often unsuccessful owing to lung disease or inadequate respiratory drive. Objective: To conduct a systematic review and meta-analysis of interventions to improve rates of successful extubation in preterm infants. Data Sources: Searches were undertaken in PubMed and The Cochrane Library. Study Selection: The review was conducted using the methods of the Cochrane Collaboration and Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Studies were included if they were randomized clinical trials published in English, enrolled intubated preterm infants (born <37 weeks' gestation), and reported 1 or both of the primary outcomes. Data Extraction and Synthesis: One thousand three hundred seventy-nine titles were screened independently by 2 investigators to assess need for full-text review. Disagreements were resolved via consensus of all authors. Where no Cochrane Review existed for an intervention, or not all identified studies were included, a new pooled analysis was performed. Main Outcomes and Measures: Primary outcomes were treatment failure or reintubation within 7 days of extubation. Results: Fifty studies were eligible for inclusion. Continuous positive airway pressure reduced extubation failure in comparison with head-box oxygen (risk ratio [RR], 0.59; 95% CI, 0.48-0.72; number needed to treat [NNT], 6; 95% CI, 3-9). Nasal intermittent positive pressure ventilation was superior to continuous positive airway pressure in preventing extubation failure (RR, 0.70; 95% CI, 0.60-0.81; NNT, 8; 95% CI, 5-13). High-flow nasal cannula therapy and continuous positive airway pressure had similar efficacy (RR, 1.11; 95% CI, 0.84-1.47). Methylxanthines reduced extubation failure (RR, 0.48; 95% CI, 0.32-0.71; NNT, 4; 95% CI, 2-7) compared with placebo or no treatment. Corticosteroids (RR, 0.18; 95% CI, 0.04-0.97; NNT, 12; 95% CI, 6-100) and chest physiotherapy (RR, 0.32; 95% CI, 0.13-0.82; NNT, 15; 95% CI, 7-50) both reduced extubation failure rates but were associated with significant adverse effects. Doxapram did not aid successful extubation (RR, 0.80; 95% CI, 0.22-2.97). Conclusions and Relevance: Preterm infants should be extubated to noninvasive respiratory support. Caffeine should be used routinely, while corticosteroids should be used judiciously, weighing up the competing risks of bronchopulmonary dysplasia and neurodevelopmental harm.

A multicentre, randomised controlled, non-inferiority trial, comparing high flow therapy with nasal continuous positive airway pressure as primary support for preterm infants with respiratory distress (the HIPSTER trial): study protocol.

INTRODUCTION: High flow (HF) therapy is an increasingly popular mode of non-invasive respiratory support for preterm infants. While there is now evidence to support the use of HF to reduce extubation failure, there have been no appropriately designed and powered studies to assess the use of HF as primary respiratory support soon after birth. Our hypothesis is that HF is non-inferior to the standard treatment--nasal continuous positive airway pressure (NCPAP)--as primary respiratory support for preterm infants. METHODS AND ANALYSIS: The HIPSTER trial is an unblinded, international, multicentre, randomised, non-inferiority trial. Eligible infants are preterm infants of 28-36(+6) weeks' gestational age (GA) who require primary non-invasive respiratory support for respiratory distress in the first 24 h of life. Infants are randomised to treatment with either HF or NCPAP. The primary outcome is treatment failure within 72 h after randomisation, as determined by objective oxygenation, blood gas, and apnoea criteria, or the need for urgent intubation and mechanical ventilation. Secondary outcomes include the incidence of intubation, pneumothorax, bronchopulmonary dysplasia, nasal trauma, costs associated with hospital care and parental stress. With a specified non-inferiority margin of 10%, using a two-sided 95% CI and 90% power, the study requires 375 infants per group (total 750 infants). ETHICS AND DISSEMINATION: Ethical approval has been granted by the relevant human research ethics committees at The Royal Women's Hospital (13/12), The Royal Children's Hospital (33144A), The Mercy Hospital for Women (R13/34), and the South-Eastern Norway Regional Health Authority (2013/1657). The trial is currently recruiting at 9 centres in Australia and Norway. The trial results will be published in peer-reviewed international journals, and presented at national and international conferences. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry ID: ACTRN12613000303741.