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 evaluate the temperature distribution among moderately preterm (MPT, 29–33 weeks) and extremely preterm (EPT, <29 weeks) infants upon neonatal intensive care unit (NICU) admission in 2012–2013, the change in admission temperature distribution for EPT infants between 2002–2003 and 2012–2013, and associations between admission temperature and mortality and morbidity for both MPT and EPT infants. Study design Prospectively collected data from 18 centers in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network were used to examine NICU admission temperature of inborn MPT and EPT infants. Associations between admission temperature and mortality and morbidity were determined by multivariable logistic regression. EPT infants from 2002–2003 and 2012–2013 were compared. Results MPT and EPT cohorts consisted of 5818 and 3213 infants, respectively. The distribution of admission temperatures differed between the MPT vs EPT (P < .01), including the percentage <36.5°C (38.6% vs 40.9%), 36.5°C–37.5°C (57.3% vs 52.9%), and >37.5°C (4.2% vs 6.2%). For EPT infants in 2012–2013 compared with 2002–2003, the percentage of temperatures between 36.5°C and 37.5°C more than doubled and the percentage of temperatures >37.5°C more than tripled. Admission temperature was inversely associated with in-hospital mortality. Conclusions Low and high admission temperatures are more frequent among EPT than MPT infants. Compared with a decade earlier, fewer EPT infants experience low admission temperatures but more have elevated temperatures. In spite of a change in distribution of NICU admission temperature, an inverse association between temperature and mortality risk persists.
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.
Our objective was to determine if nebulized racemic epinephrine is more efficacious than nebulized albuterol or saline placebo in the treatment of bronchiolitis in the outpatient setting when dosing is equivalent in terms of beta-2 agonist potency. Sixty-five patients between ages 6 weeks and 24 months with a diagnosis of bronchiolitis, defined as first-time wheezing, upper respiratory symptoms and/or fever, and a Respiratory Distress Assessment Instrument score of at least 4, were randomized to receive 5 mg nebulized albuterol, 5 mg nebulized racemic epinephrine, or an equivalent volume of placebo at 0, 30, and 60 min. The primary outcome measure was need for hospital admission or home oxygen. Secondary outcome measures were changes in clinical scores and oxygen saturations. There were no significant statistical differences between groups in terms of need for hospital admission or outpatient management with home oxygen therapy. There were no differences between groups in terms of changes in clinical scores or oxygen saturations. Racemic epinephrine and albuterol at equivalent doses had no effect on the need for hospitalization or supplemental oxygen in bronchiolitis in the outpatient setting compared to nebulized saline placebo, though this study may have missed less dramatic clinical effects due to small sample size.
The majority of MPT infants receive some level of delivery room resuscitation. Increased intensity of delivery room interventions was associated with prolonged respiratory and nutritional support, increased mortality, and a longer length of stay.
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