Objectives To identify variables associated with successful elective extubation, and to determine neonatal morbidities associated with extubation failure in extremely preterm neonates. Study design This study was a secondary analysis of the National Institute of Child Health and Human Development Neonatal Research Network’s Surfactant, Positive Pressure, and Oxygenation Randomized Trial that included extremely preterm infants born at 240/7 to 276/7 weeks’ gestation. Patients were randomized either to a permissive ventilatory strategy (continuous positive airway pressure group) or intubation followed by early surfactant (surfactant group). There were prespecified intubation and extubation criteria. Extubation failure was defined as reintubation within 5 days of extubation. Results Of 1316 infants in the trial, 1071 were eligible; 926 infants had data available on extubation status; 538 were successful and 388 failed extubation. The rate of successful extubation was 50% (188/374) in the continuous positive airway pressure group and 63% (350/552) in the surfactant group. Successful extubation was associated with higher 5-minute Apgar score, and pH prior to extubation, lower peak fraction of inspired oxygen within the first 24 hours of age and prior to extubation, lower partial pressure of carbon dioxide prior to extubation, and non-small for gestational age status after adjustment for the randomization group assignment. Infants who failed extubation had higher adjusted rates of mortality (OR 2.89), bronchopulmonary dysplasia (OR 3.06), and death/bronchopulmonary dysplasia (OR 3.27). Conclusions Higher 5-minute Apgar score, and pH prior to extubation, lower peak fraction of inspired oxygen within first 24 hours of age, lower partial pressure of carbon dioxide and fraction of inspired oxygen prior to extubation, and nonsmall for gestational age status were associated with successful extubation. Failed extubation was associated with significantly higher likelihood of mortality and morbidities. Trial registration ClinicalTrials.gov: NCT00233324.

IMPORTANCE Hypothermia at 33.5°C for 72 hours for neonatal hypoxic ischemic encephalopathy reduces death or disability to 44% to 55%; longer cooling and deeper cooling are neuroprotective in animal models. OBJECTIVE To determine if longer duration cooling (120 hours), deeper cooling (32.0°C), or both are superior to cooling at 33.5°C for 72 hours in neonates who are full-term with moderate or severe hypoxic ischemic encephalopathy. DESIGN, SETTING, AND PARTICIPANTS Arandomized, 2 × 2 factorial design clinical trial performed in 18 US centers in the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network between October 2010 and November 2013. INTERVENTIONS Neonates were assigned to 4 hypothermia groups; 33.5°C for 72 hours, 32.0°C for 72 hours, 33.5°C for 120 hours, and 32.0°C for 120 hours. MAIN OUTCOMES AND MEASURES The primary outcome of death or disability at 18 to 22 months is ongoing. The independent data and safety monitoring committee paused the trial to evaluate safety (cardiac arrhythmia, persistent acidosis, major vessel thrombosis and bleeding, and death in the neonatal intensive care unit [NICU]) after the first 50 neonates were enrolled, then after every subsequent 25 neonates. The trial was closed for emerging safety profile and futility analysis after the eighth review with 364 neonates enrolled (of 726 planned). This report focuses on safety and NICU deaths by marginal comparisons of 72 hours’ vs 120 hours’ duration and 33.5°C depth vs 32.0°C depth (predefined secondary outcomes). RESULTS The NICU death rates were 7 of 95 neonates (7%) for the 33.5°C for 72 hours group, 13 of 90 neonates (14%) for the 32.0°C for 72 hours group, 15 of 96 neonates (16%) for the 33.5°C for 120 hours group, and 14 of 83 neonates (17%) for the 32.0°C for 120 hours group. The adjusted risk ratio (RR) for NICU deaths for the 120 hours group vs 72 hours group was 1.37 (95% CI, 0.92–2.04) and for the 32.0°C group vs 33.5°C group was 1.24 (95% CI, 0.69–2.25). Safety outcomes were similar between the 120 hours group vs 72 hours group and the 32.0°C group vs 33.5°C group, except major bleeding occurred among 1% in the 120 hours group vs 3% in the 72 hours group (RR, 0.25 [95% CI, 0.07–0.91]). Futility analysis determined that the probability of detecting a statistically significant benefit for longer cooling, deeper cooling, or both for NICU death was less than 2%. CONCLUSIONS AND RELEVANCE Among neonates who were full-term with moderate or severe hypoxic ischemic encephalopathy, longer cooling, deeper cooling, or both compared with hypothermia at 33.5°C for 72 hours did not reduce NICU death. These results have implications for patient care and design of future trials.

Objective To characterize actual achieved patterns of oxygenation in appropriate (AGA) versus small (SGA) for gestational age infants randomized to a lower (85–89%) versus higher (91–95%) oxygen saturation target in the Surfactant, Positive Pressure and Oxygen Trial (SUPPORT). To determine the association between achieved oxygen saturation levels and survival in AGA and SGA infants enrolled in SUPPORT. Study design Median oxygen saturation and intermittent hypoxemia events (<80%, 20sec–5min) were documented in 1054 infants of 24–27 6/7wks gestation while receiving supplemental oxygen during the first three days of life. Results Lower target SGA infants had the lowest oxygen saturation and highest incidence of IH during the first three days of life. The lowest quartile of oxygen saturation (≤92%) during the first three days of life was associated with lower 90 day survival for both AGA and SGA infants. An increased incidence of IH events during the first three days of life was associated with lower 90 day survival only in SGA infants. Conclusion Lower achieved oxygen saturation during the first three days of life was associated with lower 90 day survival in extremely preterm infants. SGA infants had enhanced vulnerability to lower oxygen saturation targets as evidenced by lower achieved oxygen saturation and an association between increased IH events and lower survival.

Objective To estimate risk of NEC for ELBW infants as a function of preterm formula and maternal milk (MM) intake and calculate the impact of suboptimal feeding on NEC incidence and costs. Design We used adjusted odds ratios (aORs) derived from the Glutamine Trial to perform Monte Carlo simulation of a cohort of ELBW infants under current suboptimal feeding practices, compared to a theoretical cohort in which 90% of infants received at least 98% MM. Results NEC incidence among infants receiving ≥98% MM was 1.3%; 11.1% among infants fed only preterm formula; and 8.2% among infants fed a mixed diet (p=0.002). In adjusted models, compared with infants fed predominantly MM, we found an increased risk of NEC associated with exclusive preterm formula (aOR=12.1, 95% CI 1.5, 94.2), or a mixed diet (aOR 8.7, 95% CI 1.2-65.2). In Monte Carlo simulation, current feeding of ELBW infants was associated with 928 excess NEC cases and 121 excess deaths annually, compared with a model in which 90% of infants received ≥ 98% MM. These models estimated an annual cost of suboptimal feeding of ELBW infants of $27.1 million (CI $24million, $30.4 million) in direct medical costs, $563,655 (CI $476,191, $599,069) in indirect nonmedical costs, and $1.5 billion (CI $1.3 billion, $1.6 billion) in cost attributable to premature death. Conclusions Among ELBW infants, not being fed predominantly MM is associated with an increased risk of NEC. Efforts to support milk production by mothers of ELBW infants may prevent infant deaths and reduce costs.

Objective To assess the association between prophylactic indomethacin and bronchopulmonary dysplasia (BPD) in a recent, large cohort of extremely preterm infants. Study design Retrospective cohort study using prospectively collected data for infants with gestational ages < 29 weeks or birth weights of 401–1000g born between 2008 and 2012 at participating hospitals of the National Institute of Child Health and Human Development Neonatal Research Network. Infants treated with indomethacin in the first 24 hours of life were compared with those who were not. Study outcomes were BPD, defined as use of supplemental oxygen at 36 weeks postmenstrual age among survivors to that time point, death, and the composite of death or BPD. Pre-specified subgroup analyses were performed. Results Prophylactic indomethacin use varied by hospital. Treatment of a patent ductus arteriosus (PDA) after the first day of life was less common among 2,587 infants who received prophylactic indomethacin compared with 5,244 who did not (21.0% vs. 36.1%, p<0.001). After adjustment for potential confounders, use of prophylactic indomethacin was not associated with higher or lower odds of BPD (OR 0.89, 95% CI 0.72–1.10), death (OR 0.80, 95% CI 0.64–1.01), or death or BPD (OR 0.87, 95% CI 0.72–1.05). The only evidence of subgroup effects associated with prophylactic indomethacin were lower odds of death among infants with birth weights above the 10th percentile and those who were not treated for a PDA after the first day of life. Conclusions Prophylactic indomethacin was not associated with either reduced or increased risk for BPD or death.