Non-invasive versus invasive respiratory support in preterm infants.

Respiratory insufficiency is almost ubiquitous in infants born preterm, with its incidence increasing with lower gestational age. A wide range of respiratory support management strategies are available for these infants, separable into non-invasive and invasive forms of respiratory support. Here we review the history and evolution of respiratory care for the preterm infant and then examine evidence that has emerged to support a non-invasive approach to respiratory management where able. Continuous positive airway pressure (CPAP) is the non-invasive respiratory support mode currently with the most evidence for benefit. CPAP can be delivered safely and effectively and can commence in the delivery room. Particularly in early life, time spent on non-invasive respiratory support, avoiding intubation and mechanical ventilation, affords benefit for the preterm infant by virtue of a lessening of lung injury and hence a reduction in incidence of bronchopulmonary dysplasia. In recent years, enthusiasm for application of non-invasive support has been further bolstered by new techniques for administration of exogenous surfactant. Methods of less invasive surfactant delivery, in particular with a thin catheter, have allowed neonatologists to administer surfactant without resort to endotracheal intubation. The benefits of this approach appear to be sustained, even in those infants subsequently requiring mechanical ventilation. This cements the notion that any reduction in exposure to mechanical ventilation leads to alleviation of injury to the vulnerable preterm lung, with a long-lasting effect. Despite the clear advantages of non-invasive respiratory support, there will continue to be a role for intubation and mechanical ventilation in some preterm infants, particularly for those born <25 weeks' gestation. It is currently unclear what role early non-invasive support has in this special population, with more studies required.

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.

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.

Nasal high flow therapy for primary respiratory support in preterm infants.

BACKGROUND: Nasal high flow (nHF) therapy provides heated, humidified air and oxygen via two small nasal prongs, at gas flows of more than 1 litre/minute (L/min), typically 2 L/min to 8 L/min. nHF is commonly used for non-invasive respiratory support in preterm neonates. It may be used in this population for primary respiratory support (avoiding, or prior to the use of mechanical ventilation via an endotracheal tube) for prophylaxis or treatment of respiratory distress syndrome (RDS). This is an update of a review first published in 2011 and updated in 2016. OBJECTIVES: To evaluate the benefits and harms of nHF for primary respiratory support in preterm infants compared to other forms of non-invasive respiratory support. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date March 2022. SELECTION CRITERIA: We included randomised or quasi-randomised trials comparing nHF with other forms of non-invasive respiratory support for preterm infants born less than 37 weeks' gestation with respiratory distress soon after birth. DATA COLLECTION AND ANALYSIS: We used standard Cochrane Neonatal methods. Our primary outcomes were 1. death (before hospital discharge) or bronchopulmonary dysplasia (BPD), 2. death (before hospital discharge), 3. BPD, 4. treatment failure within 72 hours of trial entry and 5. mechanical ventilation via an endotracheal tube within 72 hours of trial entry. Our secondary outcomes were 6. respiratory support, 7. complications and 8. neurosensory outcomes. We used GRADE to assess the certainty of evidence. MAIN RESULTS: We included 13 studies (2540 infants) in this updated review. There are nine studies awaiting classification and 13 ongoing studies. The included studies differed in the comparator treatment (continuous positive airway pressure (CPAP) or nasal intermittent positive pressure ventilation (NIPPV)), the devices for delivering nHF and the gas flows used. Some studies allowed the use of 'rescue' CPAP in the event of nHF treatment failure, prior to any mechanical ventilation, and some allowed surfactant administration via the INSURE (INtubation, SURfactant, Extubation) technique without this being deemed treatment failure. The studies included very few extremely preterm infants less than 28 weeks' gestation. Several studies had unclear or high risk of bias in one or more domains. Nasal high flow compared with continuous positive airway pressure for primary respiratory support in preterm infants Eleven studies compared nHF with CPAP for primary respiratory support in preterm infants. When compared with CPAP, nHF may result in little to no difference in the combined outcome of death or BPD (risk ratio (RR) 1.09, 95% confidence interval (CI) 0.74 to 1.60; risk difference (RD) 0, 95% CI -0.02 to 0.02; 7 studies, 1830 infants; low-certainty evidence). Compared with CPAP, nHF may result in little to no difference in the risk of death (RR 0.78, 95% CI 0.44 to 1.39; 9 studies, 2009 infants; low-certainty evidence), or BPD (RR 1.14, 95% CI 0.74 to 1.76; 8 studies, 1917 infants; low-certainty evidence). nHF likely results in an increase in treatment failure within 72 hours of trial entry (RR 1.70, 95% CI 1.41 to 2.06; RD 0.09, 95% CI 0.06 to 0.12; number needed to treat for an additional harmful outcome (NNTH) 11, 95% CI 8 to 17; 9 studies, 2042 infants; moderate-certainty evidence). However, nHF likely does not increase the rate of mechanical ventilation (RR 1.04, 95% CI 0.82 to 1.31; 9 studies, 2042 infants; moderate-certainty evidence). nHF likely results in a reduction in pneumothorax (RR 0.66, 95% CI 0.40 to 1.08; 10 studies, 2094 infants; moderate-certainty evidence) and nasal trauma (RR 0.49, 95% CI 0.36 to 0.68; RD -0.06, 95% CI -0.09 to -0.04; 7 studies, 1595 infants; moderate-certainty evidence). Nasal high flow compared with nasal intermittent positive pressure ventilation for primary respiratory support in preterm infants Four studies compared nHF with NIPPV for primary respiratory support in preterm infants. When compared with NIPPV, nHF may result in little to no difference in the combined outcome of death or BPD, but the evidence is very uncertain (RR 0.64, 95% CI 0.30 to 1.37; RD -0.05, 95% CI -0.14 to 0.04; 2 studies, 182 infants; very low-certainty evidence). nHF may result in little to no difference in the risk of death (RR 0.78, 95% CI 0.36 to 1.69; RD -0.02, 95% CI -0.10 to 0.05; 3 studies, 254 infants; low-certainty evidence). nHF likely results in little to no difference in the incidence of treatment failure within 72 hours of trial entry compared with NIPPV (RR 1.27, 95% CI 0.90 to 1.79; 4 studies, 343 infants; moderate-certainty evidence), or mechanical ventilation within 72 hours of trial entry (RR 0.91, 95% CI 0.62 to 1.33; 4 studies, 343 infants; moderate-certainty evidence). nHF likely results in a reduction in nasal trauma, compared with NIPPV (RR 0.21, 95% CI 0.09 to 0.47; RD -0.17, 95% CI -0.24 to -0.10; 3 studies, 272 infants; moderate-certainty evidence). nHF likely results in little to no difference in the rate of pneumothorax (RR 0.78, 95% CI 0.40 to 1.53; 4 studies, 344 infants; moderate-certainty evidence). Nasal high flow compared with ambient oxygen We found no studies examining this comparison. Nasal high flow compared with low flow nasal cannulae We found no studies examining this comparison. AUTHORS' CONCLUSIONS: The use of nHF for primary respiratory support in preterm infants of 28 weeks' gestation or greater may result in little to no difference in death or BPD, compared with CPAP or NIPPV. nHF likely results in an increase in treatment failure within 72 hours of trial entry compared with CPAP; however, it likely does not increase the rate of mechanical ventilation. Compared with CPAP, nHF use likely results in less nasal trauma and likely a reduction in pneumothorax. As few extremely preterm infants less than 28 weeks' gestation were enrolled in the included trials, evidence is lacking for the use of nHF for primary respiratory support in this population.

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.

Late (≥ 7 days) systemic postnatal corticosteroids for prevention of bronchopulmonary dysplasia in preterm infants.

BACKGROUND: Many infants born preterm develop bronchopulmonary dysplasia (BPD), with lung inflammation playing a role. Corticosteroids have powerful anti-inflammatory effects and have been used to treat individuals with established BPD. However, it is unclear whether any beneficial effects outweigh the adverse effects of these drugs. OBJECTIVES: To examine the relative benefits and adverse effects of late (starting at seven or more days after birth) systemic postnatal corticosteroid treatment for preterm infants with evolving or established BPD. SEARCH METHODS: We ran an updated search on 25 September 2020 of the following databases: CENTRAL via CRS Web and MEDLINE via OVID. We also searched clinical trials databases and reference lists of retrieved articles for randomised controlled trials (RCTs). We did not include quasi-RCTs. SELECTION CRITERIA: We selected for inclusion in this review RCTs comparing systemic (intravenous or oral) postnatal corticosteroid treatment versus placebo or no treatment started at seven or more days after birth for preterm infants with evolving or established BPD. We did not include trials of inhaled corticosteroids. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. We extracted and analysed data regarding clinical outcomes that included mortality, BPD, and cerebral palsy. We used the GRADE approach to assess the certainty of evidence. MAIN RESULTS: Use of the GRADE approach revealed that the certainty of evidence was high for most of the major outcomes considered, except for BPD at 36 weeks for all studies combined and for the dexamethasone subgroup, which were downgraded one level to moderate because of evidence of publication bias, and for the combined outcome of mortality or BPD at 36 weeks for all studies combined and for the dexamethasone subgroup, which were downgraded one level to moderate because of evidence of substantial heterogeneity. We included 23 RCTs (1817 infants); 21 RCTS (1382 infants) involved dexamethasone (one also included hydrocortisone) and two RCTs (435 infants) involved hydrocortisone only. The overall risk of bias of included studies was low; all were RCTs and most trials used rigorous methods. Late systemic corticosteroids overall reduce mortality to the latest reported age (risk ratio (RR) 0.81, 95% confidence interval (CI) 0.66 to 0.99; 21 studies, 1428 infants; high-certainty evidence). Within the subgroups by drug, neither dexamethasone (RR 0.85, 95% CI 0.66 to 1.11; 19 studies, 993 infants; high-certainty evidence) nor hydrocortisone (RR 0.74, 95% CI 0.54 to 1.02; 2 studies, 435 infants; high-certainty evidence) alone clearly reduce mortality to the latest reported age. We found little evidence for statistical heterogeneity between the dexamethasone and hydrocortisone subgroups (P = 0.51 for subgroup interaction). Late systemic corticosteroids overall probably reduce BPD at 36 weeks' postmenstrual age (PMA) (RR 0.89, 95% CI 0.80 to 0.99; 14 studies, 988 infants; moderate-certainty evidence). Dexamethasone probably reduces BPD at 36 weeks' PMA (RR 0.76, 95% CI 0.66 to 0.87; 12 studies, 553 infants; moderate-certainty evidence), but hydrocortisone does not (RR 1.10, 95% CI 0.92 to 1.31; 2 studies, 435 infants; high-certainty evidence) (P < 0.001 for subgroup interaction). Late systemic corticosteroids overall probably reduce the combined outcome of mortality or BPD at 36 weeks' PMA (RR 0.85, 95% CI 0.79 to 0.92; 14 studies, 988 infants; moderate-certainty evidence). Dexamethasone probably reduces the combined outcome of mortality or BPD at 36 weeks' PMA (RR 0.75, 95% CI 0.67 to 0.84; 12 studies, 553 infants; moderate-certainty evidence), but hydrocortisone does not (RR 0.98, 95% CI 0.88 to 1.09; 2 studies, 435 infants; high-certainty evidence) (P < 0.001 for subgroup interaction). Late systemic corticosteroids overall have little to no effect on cerebral palsy (RR 1.17, 95% CI 0.84 to 1.61; 17 studies, 1290 infants; high-certainty evidence). We found little evidence for statistical heterogeneity between the dexamethasone and hydrocortisone subgroups (P = 0.63 for subgroup interaction). Late systemic corticosteroids overall have little to no effect on the combined outcome of mortality or cerebral palsy (RR 0.90, 95% CI 0.76 to 1.06; 17 studies, 1290 infants; high-certainty evidence). We found little evidence for statistical heterogeneity between the dexamethasone and hydrocortisone subgroups (P = 0.42 for subgroup interaction). Studies had few participants who were not intubated at enrolment; hence, it is not possible to make any meaningful comments on the effectiveness of late corticosteroids in preventing BPD in non-intubated infants, including those who might in the present day be supported by non-invasive techniques such as nasal continuous positive airway pressure or high-flow nasal cannula oxygen/air mixture, but who might still be at high risk of later BPD. Results of two ongoing studies are awaited. AUTHORS' CONCLUSIONS: Late systemic postnatal corticosteroid treatment (started at seven days or more after birth) reduces the risks of mortality and BPD, and the combined outcome of mortality or BPD, without evidence of increased cerebral palsy. However, the methodological quality of studies determining long-term outcomes is limited, and no studies were powered to detect increased rates of important adverse long-term neurodevelopmental outcomes. This review supports the use of late systemic corticosteroids for infants who cannot be weaned from mechanical ventilation. The role of late systemic corticosteroids for infants who are not intubated is unclear and needs further investigation. Longer-term follow-up into late childhood is vital for assessment of important outcomes that cannot be assessed in early childhood, such as effects of late systemic corticosteroid treatment on higher-order neurological functions, including cognitive function, executive function, academic performance, behaviour, mental health, motor function, and lung function. Further RCTs of late systemic corticosteroids should include longer-term survival free of neurodevelopmental disability as the primary outcome.

Early (< 7 days) systemic postnatal corticosteroids for prevention of bronchopulmonary dysplasia in preterm infants.

BACKGROUND: Bronchopulmonary dysplasia (BPD) remains a major problem for infants born extremely preterm. Persistent inflammation in the lungs is important in its pathogenesis. Systemic corticosteroids have been used to prevent or treat BPD because of their potent anti-inflammatory effects. OBJECTIVES: To examine the relative benefits and adverse effects of systemic postnatal corticosteroids commenced within the first six days after birth for preterm infants at risk of developing BPD. SEARCH METHODS: We ran an updated search of the following databases on 25 September 2020: CENTRAL via CRS Web and MEDLINE via OVID. We also searched clinical trials databases and reference lists of retrieved articles for randomised controlled trials (RCTs). We did not include cluster randomised trials, cross-over trials, or quasi-RCTs. SELECTION CRITERIA: For this review, we selected RCTs examining systemic (intravenous or oral) postnatal corticosteroid treatment started within the first six days after birth (early) in high-risk preterm infants. We included studies that evaluated the use of dexamethasone, as well as studies that assessed hydrocortisone, even when the latter was used primarily for management of hypotension, rather than for treatment of lung problems. We did not include trials of inhaled corticosteroids. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. We extracted and analysed data regarding clinical outcomes that included mortality, BPD, mortality or BPD, failure to extubate, complications during the primary hospitalisation, and long-term health and neurodevelopmental outcomes. We used the GRADE approach to assess the certainty of evidence. MAIN RESULTS: Use of the GRADE approach revealed that the certainty of evidence was high for the major outcomes considered, except for BPD at 36 weeks for all studies combined, which was downgraded one level to moderate because of evidence of publication bias. We included 32 RCTs (4395 infants). The overall risk of bias of included studies was low; all were RCTs, and most trials used rigorous methods. Early systemic corticosteroids overall have little or no effect on mortality to the latest reported age (risk ratio (RR) 0.95, 95% confidence interval (CI) 0.85 to 1.06; 31 studies, 4373 infants; high-certainty evidence), but hydrocortisone alone reduces mortality (RR 0.80, 95% CI 0.65 to 0.99; 11 studies, 1433 infants; high-certainty evidence). Early systemic corticosteroids overall probably reduce BPD at 36 weeks' postmenstrual age (PMA) (RR 0.80, 95% CI 0.73 to 0.88; 26 studies, 4167 infants; moderate-certainty evidence), as does dexamethasone (RR 0.72, 95% CI 0.63 to 0.82; 17 studies, 2791 infants; high-certainty evidence), but hydrocortisone has little to no effect (RR 0.92, 95% CI 0.81 to 1.06; 9 studies, 1376 infants; high-certainty evidence). Early systemic corticosteroids overall reduce the combined outcome of mortality or BPD at 36 weeks' PMA (RR 0.89, 95% CI 0.84 to 0.94; 26 studies, 4167 infants; high-certainty evidence), as do both dexamethasone (RR 0.88, 95% CI 0.81 to 0.95; 17 studies, 2791 infants; high-certainty evidence) and hydrocortisone (RR 0.90, 95% CI 0.82 to 0.99; 9 studies, 1376 infants; high-certainty evidence). Early systemic corticosteroids overall increase gastrointestinal perforation (RR 1.84, 95% CI 1.36 to 2.49; 16 studies, 3040 infants; high-certainty evidence), as do both dexamethasone (RR 1.73, 95% CI 1.20 to 2.51; 9 studies, 1936 infants; high-certainty evidence) and hydrocortisone (RR 2.05, 95% CI 1.21 to 3.47; 7 studies, 1104 infants; high-certainty evidence). Early systemic corticosteroids overall increase cerebral palsy (RR 1.43, 95% CI 1.07 to 1.92; 13 studies, 1973 infants; high-certainty evidence), as does dexamethasone (RR 1.77, 95% CI 1.21 to 2.58; 7 studies, 921 infants; high-certainty evidence) but not hydrocortisone (RR 1.05, 95% CI 0.66 to 1.66; 6 studies, 1052 infants; high-certainty evidence). Early systemic corticosteroids overall have little to no effect on the combined outcome of mortality or cerebral palsy (RR 1.03, 95% CI 0.91 to 1.16; 13 studies, 1973 infants; high-certainty evidence), nor does hydrocortisone (RR 0.86, 95% CI 0.71 to 1.05; 6 studies, 1052 infants; high-certainty evidence). However, early dexamethasone probably increases the combined outcome of mortality or cerebral palsy (RR 1.18, 95% CI 1.01 to 1.37; 7 studies, 921 infants; high-certainty evidence), In sensitivity analyses by primary intention for treatment with hydrocortisone (lung problems versus hypotension), there was little evidence of differences in effects on major outcomes of mortality, BPD, or combined mortality or BPD, by indication for the drug. AUTHORS' CONCLUSIONS: Early systemic postnatal corticosteroid treatment (started during the first six days after birth) prevents BPD and the combined outcome of mortality or BPD. However, it increases risks of gastrointestinal perforation, cerebral palsy, and the combined outcome of mortality or cerebral palsy. Most beneficial and harmful effects are related to early treatment with dexamethasone, rather than to early treatment with hydrocortisone, but early hydrocortisone may prevent mortality, whereas early dexamethasone does not. Longer-term follow-up into late childhood is vital for assessment of important outcomes that cannot be assessed in early childhood, such as effects of early corticosteroid treatment on higher-order neurological functions, including cognitive function, executive function, academic performance, behaviour, mental health, motor function, and lung function. Further RCTs of early corticosteroids, particularly of hydrocortisone, should include longer-term survival free of neurodevelopmental disability as the primary outcome.

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.

Predictors and outcomes of extubation failure in extremely preterm infants.

AIM: To determine predictors and outcomes of extubation failure in extremely preterm (EP) infants born <28 weeks' gestational age (GA). METHODS: Retrospective clinical audit across two tertiary-level neonatal intensive care units in Melbourne, Australia. Two-hundred and four EP infants who survived to their first extubation from mechanical ventilation. Extubation failure (re-intubation) within 7 days after the first extubation. RESULTS: Lower GA (odds ratio [OR] 0.71, 95% confidence interval (CI), 0.61-0.89, P < 0.001) and higher pre-extubation measured mean airway pressure (MAP) on the mechanical ventilator (OR 1.9 [95% CI 1.41-2.51], P < 0.001) predicted extubation failure. The area under a receiver operating characteristic curve for GA and MAP was 0.77 (95% CI 0.70-0.82). After adjustment for GA, infants who experienced extubation failure had higher rates of bronchopulmonary dysplasia (P < 0.001), post-natal systemic corticosteroid treatment (P < 0.001), airway trauma (P < 0.003), longer durations of treatment with mechanical ventilation (P < 0.001), non-invasive respiratory support (P < 0.001), supplemental oxygen therapy (P = 0.05) and longer hospitalisation (P = 0.025). CONCLUSIONS: Lower GA and higher pre-extubation measured MAP were predictive of extubation failure within 7 days in extremely preterm infants. Extubation failure was associated with increased morbidity and extended periods of respiratory support and hospitalisation.

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.

The evolution of modern respiratory care for preterm infants.

Preterm birth rates are rising, and many preterm infants have breathing difficulty after birth. Treatments for infants with prolonged breathing difficulty include oxygen therapy, exogenous surfactant, various modes of respiratory support, and postnatal corticosteroids. In this Series paper, we review the history of neonatal respiratory care and its effect on long-term outcomes, and we outline the future direction of the research field. The delivery and monitoring of oxygen therapy remains controversial, despite being in use for more than 50 years. Exogenous surfactant replacement has been used for 25 years and has dramatically reduced mortality and morbidity, but more research on when and how it is administered is needed. Methods and techniques of neonatal respiratory support are evolving. Clinicians are moving away from routine intubation and ventilation, and new modes of non-invasive support are being investigated. Postnatal corticosteroids have a limited role in infants with evolving bronchopulmonary dysplasia, but more research is needed to identify the best timing, type, dose, and method of administration. Despite advances in neonatal care in the past 50 years, bronchopulmonary dysplasia, with all its adverse short-term and long-term consequences, is still a serious problem in neonatal care. The challenge remains to support breathing in preterm infants, with special attention to risk factors in the subpopulation of infants that are at highest risk of bronchopulmonary dysplasia, without damaging their lungs or adversely affecting their long-term health.

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.

Nasal High-Flow Therapy for Preterm Infants: Review of Neonatal Trial Data.

Heated, humidified, nasal high-flow (HF) therapy is a promising treatment for preterm infants, and almost certainly has a place in the clinical care of this population. It is only in the last few years that data have become available from randomized trials comparing HF with other noninvasive respiratory support modes, particularly nasal continuous positive airway pressure. This article discusses the evidence for HF use from randomized clinical trials in preterm infants and proposes recommendations for evidence-based practice.

Extubating Extremely Preterm Infants: Predictors of Success and Outcomes following Failure.

OBJECTIVES: To identify variables that predict extubation success in extremely preterm infants born <28 weeks gestational age (GA), and to compare outcomes between those who had successful or failed extubation. STUDY DESIGN: A secondary analysis of data from a randomized trial of postextubation respiratory support that included 174 extremely preterm infants. "Extubation success" was defined as not requiring reintubation within 7 days, and "extubation failure" the converse. Predictive variables that were different between groups were included in a multivariable logistic regression model. RESULTS: Sixty-eight percent of infants were successfully extubated. Compared with those infants who had extubation failure, they had a higher GA and birth weight, were extubated earlier, were more often exposed to prolonged ruptured membranes, more often avoided intubation in the delivery room, had a higher pre-extubation pH, and had lower mean pre-extubation fraction of inspired oxygen and partial pressure of carbon dioxide (PCO2). Only GA and PCO2 remained significant in the multivariable analysis (area under a receiver operating characteristic curve = 0.81). Extubation failure was associated with death, bronchopulmonary dysplasia, severe retinopathy of prematurity, patent ductus arteriosus ligation, and longer durations of respiratory support, oxygen supplementation, and hospitalization. When adjusted for allocated treatment in the randomized trial, GA, and birth weight z-score, extubation failure remained associated with death before discharge and prolonged respiratory support and hospitalization. CONCLUSIONS: In extremely preterm infants, higher GA and lower pre-extubation PCO2 predicted extubation success. Infants in whom extubation failed were more likely to die and have prolonged respiratory support and hospitalization. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Network: ACTRN12610000166077.

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.

High-dose docosahexaenoic acid supplementation of preterm infants: respiratory and allergy outcomes.

BACKGROUND: Docosahexaenoic acid (DHA) has been associated with downregulation of inflammatory responses. OBJECTIVE: To report the effect of DHA supplementation on long-term atopic and respiratory outcomes in preterm infants. METHODS: This study is a multicenter, randomized controlled trial comparing the outcomes for preterm infants <33 weeks' gestation who consumed expressed breast milk from mothers taking either tuna oil (high-DHA diet) or soy oil (standard-DHA) capsules. Data collected included incidence of bronchopulmonary dysplasia (BPD) and parental reporting of atopic conditions over the first 18 months of life. RESULTS: Six hundred fifty-seven infants were enrolled (322 to high-DHA diet, 335 to standard), and 93.5% completed the 18-month follow-up. There was a reduction in BPD in boys (relative risk [RR]: 0.67 [95% confidence interval (CI): 0.47-0.96]; P=.03) and in all infants with a birth weight of <1250 g (RR: 0.75 [95% CI: 0.57-0.98]; P=.04). There was no effect on duration of respiratory support, admission length, or home oxygen requirement. There was a reduction in reported hay fever in all infants in the high-DHA group at either 12 or 18 months (RR: 0.41 [95% CI: 0.18-0.91]; P=.03) and at either 12 or 18 months in boys (RR: 0.15 [0.03-0.64]; P=.01). There was no effect on asthma, eczema, or food allergy. CONCLUSIONS: DHA supplementation for infants of <33 weeks' gestation reduced the incidence of BPD in boys and in all infants with a birth weight of <1250 g and reduced the incidence of reported hay fever in boys at either 12 or 18 months.