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.).

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

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

Combining activity and grimace scores reflects perinatal stability in infants <32 weeks gestational age.

BACKGROUND: Over 95% of infants less than 32 weeks gestational age-very preterm infants (VPTI)-require cardiorespiratory support at birth. Clinical condition at birth is assessed by the Apgar score, but the precision and accuracy of activity and grimace has not been evaluated. We hypothesised activity and grimace could predict the level of cardiorespiratory support required for stabilisation. METHODS: Two hundred twenty-nine videos of VPTI resuscitations at Monash Children's Hospital and The Royal Women's Hospital, Melbourne were evaluated, with 78 videos eligible for assessment. Activity and grimace were scored (0, 1, or 2) by seven consultant neonatologists, with inter-rater reliability assessed. Activity and grimace were correlated with the maximum level of cardiorespiratory support required for stabilisation. RESULTS: Kendall's Coefficient of Concordance (W) showed strong interobserver agreement for activity (W = 0.644, p < 0.001) and grimace (W = 0.722, p < 0.001). Neither activity nor grimace independently predicted the level of cardiorespiratory support required. Combining activity and grimace showed non-vigorous infants (combined score <2) received more cardiorespiratory support than vigorous (combined score ≥ 2). CONCLUSION: Scoring of activity and grimace was consistent between clinicians. Independently, activity and grimace did not correlate with perinatal stabilisation. Combined scoring showed non-vigorous infants had greater resuscitation requirements. IMPACT: Our study evaluates the precision and accuracy of activity and grimace to predict perinatal stability, which has not been validated in infants <32 weeks gestational age. We found strong score agreement between assessors, indicating video review is a practical and precise method for grading of activity and grimace. Combined scoring to allow a dichotomous evaluation of infants as non-vigorous or vigorous showed the former group required greater cardiorespiratory support at birth.

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.

Physiologically based cord clamping for infants ≥32+0 weeks gestation: A randomised clinical trial and reference percentiles for heart rate and oxygen saturation for infants ≥35+0 weeks gestation.

BACKGROUND: Globally, the majority of newborns requiring resuscitation at birth are full term or late-preterm infants. These infants typically have their umbilical cord clamped early (ECC) before moving to a resuscitation platform, losing the potential support of the placental circulation. Physiologically based cord clamping (PBCC) is clamping the umbilical cord after establishing lung aeration and holds promise as a readily available means of improving early newborn outcomes. In mechanically ventilated lambs, PBCC improved cardiovascular stability and reduced hypoxia. We hypothesised that PBCC compared to ECC would result in higher heart rate (HR) in infants needing resuscitation, without compromising safety. METHODS AND FINDINGS: Between 4 July 2018 and 18 May 2021, infants born at ≥32+0 weeks' gestation with a paediatrician called to attend were enrolled in a parallel-arm randomised trial at 2 Australian perinatal centres. Following initial stimulation, infants requiring further resuscitation were randomised within 60 seconds of birth using a smartphone-accessible web link. The intervention (PBCC) was to establish lung aeration, either via positive pressure ventilation (PPV) or effective spontaneous breathing, prior to cord clamping. The comparator was early cord clamping (ECC) prior to resuscitation. The primary outcome was mean HR between 60 to 120 seconds after birth, measured using 3-lead electrocardiogram, extracted from video recordings blinded to group allocation. Nonrandomised infants had deferred cord clamping (DCC) ≥120 seconds in the observational study arm. Among 508 at-risk infants enrolled, 123 were randomised (n = 63 to PBCC, n = 60 to ECC). Median (interquartile range, IQR) for gestational age was 39.9 (38.3 to 40.7) weeks in PBCC infants and 39.6 (38.4 to 40.4) weeks in ECC infants. Approximately 49% and 50% of the PBCC and ECC infants were female, respectively. Five infants (PBCC = 2, ECC = 3, 4% total) had missing primary outcome data. Cord clamping occurred at a median (IQR) of 136 (126 to 150) seconds in the PBCC arm and 37 (27 to 51) seconds in the ECC arm. Mean HR between 60 to 120 seconds after birth was 154 bpm (beats per minute) for PBCC versus 158 bpm for ECC (adjusted mean difference -6 bpm, 95% confidence interval (CI) -17 to 5 bpm, P = 0.39). Among 31 secondary outcomes, postpartum haemorrhage ≥500 ml occurred in 34% and 32% of mothers in the PBCC and ECC arms, respectively. Two hundred ninety-five nonrandomised infants (55% female) with median (IQR) gestational age of 39.6 (38.6 to 40.6) weeks received DCC. Data from these infants was used to create percentile charts of expected HR and oxygen saturation in vigorous infants receiving DCC. The trial was limited by the small number of infants requiring prolonged or advanced resuscitation. PBCC may provide other important benefits we did not measure, including improved maternal-infant bonding and higher iron stores. CONCLUSIONS: In this study, we observed that PBCC resulted in similar mean HR compared to infants receiving ECC. The findings suggest that for infants ≥32+0 weeks' gestation who receive brief, effective resuscitation at closely monitored births, PBCC does not provide additional benefit over ECC (performed after initial drying and stimulation) in terms of key physiological markers of transition. PBCC was feasible using a simple, low-cost strategy at both cesarean and vaginal births. The percentile charts of HR and oxygen saturation may guide clinicians monitoring the transition of at-risk infants who receive DCC. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12618000621213.

Nasal High-Flow Therapy for Newborn Infants in Special Care Nurseries.

BACKGROUND: Nasal high-flow therapy is an alternative to nasal continuous positive airway pressure (CPAP) as a means of respiratory support for newborn infants. The efficacy of high-flow therapy in nontertiary special care nurseries is unknown. METHODS: We performed a multicenter, randomized, noninferiority trial involving newborn infants (<24 hours of age; gestational age, ≥31 weeks) in special care nurseries in Australia. Newborn infants with respiratory distress and a birth weight of at least 1200 g were assigned to treatment with either high-flow therapy or CPAP. The primary outcome was treatment failure within 72 hours after randomization. Infants in whom high-flow therapy failed could receive CPAP. Noninferiority was determined by calculating the absolute difference in the risk of the primary outcome, with a noninferiority margin of 10 percentage points. RESULTS: A total of 754 infants (mean gestational age, 36.9 weeks, and mean birth weight, 2909 g) were included in the primary intention-to-treat analysis. Treatment failure occurred in 78 of 381 infants (20.5%) in the high-flow group and in 38 of 373 infants (10.2%) in the CPAP group (risk difference, 10.3 percentage points; 95% confidence interval [CI], 5.2 to 15.4). In a secondary per-protocol analysis, treatment failure occurred in 49 of 339 infants (14.5%) in the high-flow group and in 27 of 338 infants (8.0%) in the CPAP group (risk difference, 6.5 percentage points; 95% CI, 1.7 to 11.2). The incidences of mechanical ventilation, transfer to a tertiary neonatal intensive care unit, and adverse events did not differ significantly between the groups. CONCLUSIONS: Nasal high-flow therapy was not shown to be noninferior to CPAP and resulted in a significantly higher incidence of treatment failure than CPAP when used in nontertiary special care nurseries as early respiratory support for newborn infants with respiratory distress. (Funded by the Australian National Health and Medical Research Council and Monash University; HUNTER Australian and New Zealand Clinical Trials Registry number, ACTRN12614001203640.).

Oxygen saturation and heart rate in healthy term and late preterm infants with delayed cord clamping.

Blood oxygen in the fetus is substantially lower than in the newborn infant. In the minutes after birth, arterial oxygen saturation rises from around 50-60% to 90-95%. Initial respiratory efforts generate negative trans-thoracic pressures that drive liquid from the airways into the lung interstitium facilitating lung aeration, blood oxygenation, and pulmonary artery vasodilatation. Consequently, intra- (foramen ovale) and extra-cardiac (ductus arteriosus) shunting changes and the sequential circulation switches to a parallel pulmonary and systemic circulation. Delaying cord clamping preserves blood flow through the ascending vena cava, thus increasing right and left ventricular preload. Recently published reference ranges have suggested that delayed cord clamping positively influenced the fetal-to-neonatal transition. Oxygen saturation in babies with delayed cord clamping plateaus significantly earlier to values of 85-90% than in babies with immediate cord clamping. Delayed cord clamping may also contribute to fewer episodes of brady-or-tachycardia in the first minutes after birth, but data from randomized trials are awaited. IMPACT: Delaying cord clamping during fetal to neonatal transition contributes to a significantly earlier plateauing of oxygen saturation and fewer episodes of brady-and/or-tachycardia in the first minutes after birth. We provide updated information regarding the changes in SpO2 and HR during postnatal adaptation of term and late preterm infants receiving delayed compared with immediate cord clamping. Nomograms in newborn infants with delayed cord clamping will provide valuable reference ranges to establish target SpO2 and HR in the first minutes after birth.

Rapid centralised randomisation in emergency setting trials using a smartphone.

Randomised trials in emergency settings must quickly confirm eligibility and allocate participants to an intervention group without delaying treatment. We report rapid randomisation during two neonatal resuscitation trials using the non-commercial REDCap platform accessed via smartphone. This simple, reliable method has wide applicability for trials in emergency settings. What is Known: • Randomised trials in emergency settings need to rapidly allocate participants to an intervention group. • This process should not delay treatment. What is New: • This non-commercial, smartphone-accessible application enabled rapid, accurate randomisation at the bedside. • This has broad applicability for emergency setting trials.

Nucleated Red Blood Cells as Markers of Perinatal Adaptation in Preterm Neonates Receiving Minimally Invasive Surfactant Therapy.

OBJECTIVE: The study aimed to assess the association of nucleated red blood cells (NRBC), a surrogate of intrauterine hypoxia, and elevated pulmonic vascular resistance (E-PVR) and oxygen requirement after minimally invasive surfactant therapy (MIST). STUDY DESIGN: Retrospective study of a cohort of preterm neonates that received MIST in a single unit. RESULTS: NRBC were measured in 65 of 75 (87%) neonates administered MIST during the period. In total, 22 of 65 (34%) infants had pre-MIST echocardiography (ECHO).Neonates with elevated NRBC (predefined as >5 × 109/L, n = 16) required higher post-MIST fraction of inspired oxygen (FiO2) than neonates with normal NRBC (<1 × 109/L, n = 17; FiO2 = 0.31 ± 0.10 and 0.24 ± 0.04, respectively, p = 0.02).NRBC correlated positively with % of time in right to left ductal shunt (r = 0.51, p = 0.052) and inversely with right ventricular stroke volume (r = -0.55, p = 0.031) and time to peak velocity to right ventricular ejection time ratio (r = -0.62, p < 0.001). CONCLUSION: Elevated NRBC are associated with elevated FiO2 after MIST and elevated E-PVR. Intrauterine hypoxia may impact postnatal circulatory adaptations and oxygen requirement. KEY POINTS: · Post-MIST FiO2 requirements are significantly higher in infants with elevated NRBC.. · NRBC correlates positively with elevated PVR in neonates requiring.. · Intrauterine hypoxia may play a role in postnatal circulatory adaptations in neonates with RDS..

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.

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.

Predicting Nasal High-Flow Treatment Success in Newborn Infants with Respiratory Distress Cared for in Nontertiary Hospitals.

OBJECTIVE: To evaluate demographic and clinical variables as predictors of nasal high-flow treatment success in newborn infants with respiratory distress cared for in Australian nontertiary special care nurseries. STUDY DESIGN: A secondary analysis of the HUNTER trial, a multicenter, randomized controlled trial evaluating nasal high-flow as primary respiratory support for newborn infants with respiratory distress who were born ≥31 weeks of gestation and with birth weight ≥1200 g, and cared for in Australian nontertiary special care nurseries. Treatment success within 72 hours after randomization to nasal high-flow was determined using objective criteria. Univariable screening and multivariable analysis was used to determine predictors of nasal high-flow treatment success. RESULTS: Infants (n = 363) randomized to nasal high-flow in HUNTER were included in the analysis; the mean gestational age was 36.9 ± 2.7 weeks and birth weight 2928 ± 782 g. Of these infants, 290 (80%) experienced nasal high-flow treatment success. On multivariable analysis, nasal high-flow treatment success was predicted by higher gestational age and lower fraction of inspired oxygen immediately before randomization, but not strongly. The final model was found to have an area under the curve of 0.65, which after adjustment for optimism was found to be 0.63 (95% CI, 0.57-0.70). CONCLUSIONS: Gestational age and supplemental oxygen requirement may be used to guide decisions regarding the most appropriate initial respiratory support for newborn infants in nontertiary special care nurseries. Further prospective research is required to better identify which infants are most likely to be successfully treated with nasal high-flow. TRIAL REGISTRATION: ACTRN12614001203640.

Nasal High-Flow Therapy for Primary Respiratory Support in Preterm Infants.

BACKGROUND: Treatment with nasal high-flow therapy has efficacy similar to that of nasal continuous positive airway pressure (CPAP) when used as postextubation support in neonates. The efficacy of high-flow therapy as the primary means of respiratory support for preterm infants with respiratory distress has not been proved. METHODS: In this international, multicenter, randomized, noninferiority trial, we assigned 564 preterm infants (gestational age, ≥28 weeks 0 days) with early respiratory distress who had not received surfactant replacement to treatment with either nasal high-flow therapy or nasal CPAP. The primary outcome was treatment failure within 72 hours after randomization. Noninferiority was determined by calculating the absolute difference in the risk of the primary outcome; the chosen margin of noninferiority was 10 percentage points. Infants in whom high-flow therapy failed could receive rescue CPAP; infants in whom CPAP failed were intubated and mechanically ventilated. RESULTS: Trial recruitment stopped early at the recommendation of the independent data and safety monitoring committee because of a significant difference in the primary outcome between treatment groups. Treatment failure occurred in 71 of 278 infants (25.5%) in the high-flow group and in 38 of 286 infants (13.3%) in the CPAP group (risk difference, 12.3 percentage points; 95% confidence interval [CI], 5.8 to 18.7; P<0.001). The rate of intubation within 72 hours did not differ significantly between the high-flow and CPAP groups (15.5% and 11.5%, respectively; risk difference, 3.9 percentage points; 95% CI, -1.7 to 9.6; P=0.17), nor did the rate of adverse events. CONCLUSIONS: When used as primary support for preterm infants with respiratory distress, high-flow therapy resulted in a significantly higher rate of treatment failure than did CPAP. (Funded by the National Health and Medical Research Council and others; Australian New Zealand Clinical Trials Registry number, ACTRN12613000303741 .).

Cost-Effectiveness Analysis of Nasal Continuous Positive Airway Pressure Versus Nasal High Flow Therapy as Primary Support for Infants Born Preterm.

OBJECTIVE: To compare the cost-effectiveness of 2 common "noninvasive" modes of respiratory support for infants born preterm. STUDY DESIGN: An economic evaluation was conducted as a component of a multicenter, randomized control trial from 2013 to 2015 enrolling infants born preterm at ≥28 weeks of gestation with respiratory distress, <24 hours old, who had not previously received endotracheal intubation and mechanical ventilation or surfactant. The economic evaluation was conducted from a healthcare sector perspective and the time horizon was from birth until death or first discharge. The cost-effectiveness of continuous positive airway pressure (CPAP) vs high-flow with "rescue" CPAP backup and high-flow without rescue CPAP backup (as sole primary support) were analyzed by using the hospital cost of inpatient stay in a tertiary center and the rates of endotracheal intubation and mechanical ventilation during admission. RESULTS: Hospital inpatient cost records for 435 infants enrolled in all Australian centers were obtained. With "rescue" CPAP backup, an incremental cost-effectiveness ratio was estimated of A$179 000 (US$123 000) per ventilation avoided if CPAP was used compared with high flow. Without rescue CPAP backup, cost per ventilation avoided was A$7000 (US$4800) if CPAP was used compared with high flow. CONCLUSIONS: As sole primary support, CPAP is highly likely to be cost-effective compared with high flow. Neonatal units choosing to use only one device should apply CPAP as primary respiratory support. Compared with high-flow with rescue CPAP backup, CPAP is unlikely to be cost-effective if willingness to pay per ventilation avoided is less than A$179 000 (US$123 000).

Refining the Use of Nasal High-Flow Therapy as Primary Respiratory Support for Preterm Infants.

OBJECTIVE: To identify clinical and demographic variables that predict nasal high-flow (nHF) treatment failure when used as a primary respiratory support for preterm infants. STUDY DESIGN: This secondary analysis used data from a multicenter, randomized, controlled trial comparing nHF with continuous positive airway pressure as primary respiratory support in preterm infants 28-36 completed weeks of gestation. Treatment success or failure with nHF was determined using treatment failure criteria within the first 72 hours after randomization. Infants in whom nHF treatment failed received continuous positive airway pressure, and were then intubated if failure criteria were again met. RESULTS: There were 278 preterm infants included, with a mean gestational age (GA) of 32.0 ± 2.1 weeks and a birth weight of 1737 ± 580 g; of these, nHF treatment failed in 71 infants (25.5%). Treatment failure was moderately predicted by a lower GA and higher prerandomization fraction of inspired oxygen (FiO2): area under a receiver operating characteristic curve of 0.76 (95% CI, 0.70-0.83). Nasal HF treatment success was more likely in infants born at ≥30 weeks GA and with prerandomization FiO2 <0.30. CONCLUSIONS: In preterm infants ≥28 weeks' GA enrolled in a randomized, controlled trial, lower GA and higher FiO2 before randomization predicted early nHF treatment failure. Infants were more likely to be successfully treated with nHF from soon after birth if they were born at ≥30 weeks GA and had a prerandomization FiO2 <0.30. However, even in this select population, continuous positive airway pressure remains superior to nHF as early respiratory support in preventing treatment failure. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12613000303741.

Nursing perceptions of high-flow nasal cannulae treatment for very preterm infants.

AIM: This study aims to assess nursing perceptions of high-flow nasal cannulae (HFNC) in comparison with nasal continuous positive airway pressure (NCPAP) as post-extubation respiratory support for very preterm infants. METHODS: A standardised questionnaire form was distributed in person to nursing staff in The Royal Women's Hospital neonatal unit, where HFNC had been recently introduced in the context of a clinical trial. Nursing staff were eligible to participate if they routinely cared for infants receiving respiratory support. RESULTS: The survey was completed by 99/144 eligible nurses. The majority of the 99 nurses surveyed felt that HFNC was less likely than NCPAP to prevent re-intubation of infants 24-26 weeks' gestation but equally likely to prevent re-intubation of infants 28-30 weeks' gestation. Nurses preferred NCPAP for post-extubation support of 24- and 26-week infants, and HFNC for 28- and 30-week infants, despite being less experienced with HFNC. Perceptions of HFNC compared with NCPAP included increased ease-of-use, improved infant comfort and reduced nasal trauma. CONCLUSIONS: Neonatal nurses preferred NCPAP for post-extubation support of infants <28 weeks' gestation and HFNC for infants of 28 or 30 weeks' gestation. Nurses accurately predicted varying efficacy of HFNC across different gestational ages, consistent with the findings of a contemporaneous randomised trial. In the context of clinical non-inferiority, as shown in the randomised trial, nursing preference for HFNC over NCPAP in preterm infants ≥28 weeks' gestation supports the use of HFNC as post-extubation support in this population.

Cardiac Agents during Neonatal Cardiopulmonary Resuscitation.

BACKGROUND: Epinephrine (adrenaline) is currently the only cardiac agent recommended during neonatal resuscitation. The inability to predict which newborns are at risk of requiring resuscitative efforts at birth has prevented the collection of large, high-quality human data. SUMMARY: Information on the optimal dosage and route of epinephrine administration is extrapolated from neonatal animal studies and human adult and pediatric studies. Adult resuscitation guidelines have previously recommended vasopressin use; however, neonatal studies needed to create guidelines are lacking. A review of the literature demonstrates conflicting results regarding epinephrine efficacy through various routes of access as well as vasopressin during asystolic cardiac arrest in animal models. Vasopressin appears to improve hemodynamic and post-resuscitation outcomes compared to epinephrine in asystolic cardiac arrest animal models. KEY MESSAGES: The current neonatal resuscitation guidelines recommend epinephrine be primarily given via the intravenous or intraosseous route, with the endotracheal route as an alternative if these routes are not feasible or unsuccessful. The intravenous or intraosseous dose ranges between 0.01 and 0.03 mg/kg, which should be repeated every 3-5 min during chest compressions. However, the optimal dosing and route of administration of epinephrine remain unknown. There is evidence from adult and pediatric studies that vasopressin might be an alternative to epinephrine; however, the neonatal data are scarce.

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

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

Assessing the influence of abdominal compression on time to return of circulation during resuscitation of asphyxiated newborn lambs: a randomised preclinical study.

OBJECTIVE: During neonatal resuscitation, the return of spontaneous circulation (ROSC) can be achieved using epinephrine which optimises coronary perfusion by increasing diastolic pressure. Abdominal compression (AC) applied during resuscitation could potentially increase diastolic pressure and therefore help achieve ROSC. We assessed the use of AC during resuscitation of asystolic newborn lambs, with and without epinephrine. METHODS: Near-term fetal lambs were instrumented for physiological monitoring and after delivery, asphyxiated until asystole. Resuscitation was commenced with ventilation followed by chest compressions. Lambs were randomly allocated to: intravenous epinephrine (20 µg/kg, n=9), intravenous epinephrine+continuous AC (n=8), intravenous saline placebo (5 mL/kg, n=6) and intravenous saline+AC (n=9). After three allocated treatment doses, rescue intravenous epinephrine was administered if ROSC had not occurred. Time to achieve ROSC was the primary outcome. Lambs achieving ROSC were ventilated and monitored for 60 min before euthanasia. Brain histology was assessed for micro-haemorrhage. RESULTS: Use of AC did not influence mean time to achieve ROSC (epinephrine lambs 177 s vs epinephrine+AC lambs 179 s, saline lambs 602 s vs saline+AC lambs 585 s) or rate of ROSC (nine of nine lambs, eight of eight lambs, one of six lambs and two of eight lambs, respectively). Application of AC was associated with higher diastolic blood pressure (mean value >10 mm Hg), mean and systolic blood pressure and carotid blood flow during resuscitation. Cortex and deep grey matter micro-haemorrhage was more frequent in AC lambs. CONCLUSION: Use of AC during resuscitation increased diastolic blood pressure, but did not impact time to ROSC.