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1.  Pilot Randomized Trial of Hydrocortisone in Ventilator-Dependent Extremely Preterm Infants: Effects on Regional Brain Volumes 
The Journal of pediatrics  2012;162(4):685-690.e1.
Objective
To test the hypothesis that high-risk ventilator-dependent extremely low birth weight (ELBW; BW ≤1000g) infants treated with seven days of hydrocortisone will have larger total brain tissue volumes than placebo treated infants.
Study design
A predetermined sample size of 64 ELBW infants, between 10 to 21 days old and ventilator-dependent with a respiratory index score ≥2, were randomized to systemic hydrocortisone (17 mg/kg cumulative dose) or saline placebo. Primary outcome was total brain tissue volume. Volumetric MRI was performed at 38 weeks postmenstrual age; brain tissue regions were segmented and quantified automatically with a high degree of accuracy and nine structures were segmented manually. All analyses of regional brain volumes were adjusted by postmenstrual age at MRI scan.
Results
The study groups were similar at baseline and eight infants died in each arm. Unadjusted total brain tissue volume (mean±SD) in the hydrocortisone (N=23) and placebo treated infants (N=21) was 272±40.3 cm3 and 277.8±59.1 cm3, respectively (adjusted mean difference: 6.35 cm3 (95% CI: (−20.8, 32.5); P=0.64). Three of the 31 hydrocortisone treated infants and five of the 33 placebo treated infants survived without severe BPD (RR 0.62, 95% CI: 0.13, 2.66; P=0.49). No significant differences were noted in pre-specified secondary outcomes of regional structural volumes or days on respiratory support. No adverse effects of hydrocortisone were observed.
Conclusions
Low dose hydrocortisone in high-risk ventilator-dependent infants after a week of age had no discernible effect on regional brain volumes or pulmonary outcomes prior to NICU discharge.
doi:10.1016/j.jpeds.2012.09.054
PMCID: PMC3609889  PMID: 23140612
Bronchopulmonary dysplasia; corticosteroids; extremely low birth weight; magnetic resonance imaging; brain injury; mechanical ventilation
2.  Does Aggressive Phototherapy Increase Mortality while Decreasing Profound Impairment among the Smallest and Sickest Newborns? 
Objective
Aggressive phototherapy (AgPT) is widely used and assumed to be safe and effective for even the most immature infants. We assessed whether the benefits and hazards for the smallest and sickest infants differed from those for other extremely low birth weight (ELBW; (≤1000 g) infants in our Neonatal Research Network trial, the only large trial of AgPT.
Study Design
ELBW infants (n=1974) were randomized to AgPT or conservative phototherapy at age 12–36 hours. The effect of AgPT on outcomes (death; impairment; profound impairment; death or impairment [primary outcome], and death or profound impairment) at 18–22 months corrected age was related to BW stratum (501–750 g; 751–1000 g) and baseline severity of illness using multilevel regression equations. The probability of benefit and of harm was directly assessed with Bayesian analyses.
Results
Baseline illness severity was well characterized using mechanical ventilation and FiO2 at 24 hours age. Among mechanically ventilated infants ≤750 g BW (n =684), a reduction in impairment and in profound impairment was offset by higher mortality (p for interaction <0.05) with no significant effect on composite outcomes. Conservative Bayesian analyses of this subgroup identified a 99% (posterior) probability that AgPT increased mortality, a 97% probability that AgPT reduced impairment, and a 99% probability that AgPT reduced profound impairment.
Conclusions
Findings from the only large trial of AgPT suggest that AgPT may increase mortality while reducing impairment and profound impairment among the smallest and sickest infants. New approaches to reduce their serum bilirubin need development and rigorous testing.
doi:10.1038/jp.2012.64
PMCID: PMC3558278  PMID: 22652561
Phototherapy; bilirubin; severity of illness; ELBW infant; impairment; randomized clinical trial; statistical interaction; Bayesian analysis
3.  Is phototherapy exposure associated with better or worse outcomes in 501–1000 gram birth weight infants? 
Aim
To compare risk-adjusted outcomes at 18–22 months corrected age for extremely low birth weight (ELBW) infants who never received phototherapy (NoPTx) to those who received any phototherapy (PTx) in the NICHD Neonatal Research Network randomized trial of Aggressive vs. Conservative Phototherapy.
Methods
Outcomes at 18–22 months corrected age included death, neurodevelopmental impairment (NDI), and Bayley Scales Mental Developmental Index (MDI). Regression models evaluated the independent association of PTx with adverse outcomes controlling for center and other potentially confounding variables.
Results
Of 1972 infants, 216 were NoPTx and 1756 were PTx. For the entire 501–1000 g BW cohort, PTx was not independently associated with death or NDI (OR 0.85, 95% CI 0.60 –1.20), death, or adverse neurodevelopmental endpoints. However, among infants 501–750 g BW, the rate of significant developmental impairment with MDI<50 was significantly higher for NoPTx (29%) than PTx (12%) (p=0.004).
Conclusions
Phototherapy did not appear to be independently associated with death or NDI for the overall ELBW group. Whether PTx increases mortality could not be excluded due to bias from deaths before reaching conservative treatment threshold. The higher rate of MDI<50 in the 501–750g BW NoPTx group is concerning, and consistent with NRN Trial results.
doi:10.1111/j.1651-2227.2011.02175.x
PMCID: PMC3505994  PMID: 21272067
4.  The effects of aggressive vs. conservative phototherapy on the brainstem auditory evoked responses of extremely-low-birth-weight infants 
Pediatric Research  2012;71(1):77-84.
INTRODUCTION
This study was a two-center, stratified, parallel-group randomized trial comparing the effects of aggressive vs. conservative phototherapy on brainstem auditory evoked response (BAER) latencies in infants with extremely low birth weight (ELBW, ≤ 1,000 g).
RESULTS
BAER latencies of 751–1,000 g birth-weight infants were shorter by 0.37 ms (95% confidence interval (CI) = 0.02, 0.73) for wave V, 0.39 ms (0.08, 0.70) for wave III, and 0.33 ms (0.01, 0.65) for wave I after aggressive phototherapy at one center. Interwave intervals did not differ significantly. Similar nonsignificant trends were recorded for 501–750 g birth-weight infants. At the other participating center, no significant differences were recorded, cautioning against overgeneralizing these results.
DISCUSSION
The effects of bilirubin on the auditory pathway in ELBW infants depend on a complex interaction of bilirubin exposure, newborn characteristics, and clinical management.
METHODS
Aggressive phototherapy was initiated sooner and continued at lower bilirubin levels than conservative phototherapy. A total of 174 ELBW infants were enrolled in the study; 111 infants were successfully tested at 35 weeks postmenstrual age (PMA); 57 died; and 6 were not successfully tested.
doi:10.1038/pr.2011.17
PMCID: PMC3326602  PMID: 22289854
5.  Aggressive vs. Conservative Phototherapy for Infants with Extremely Low Birth Weight 
Background
It is unclear whether aggressive phototherapy to prevent neurotoxic effects of bilirubin benefits or harms infants with extremely low birth weight (1000 g or less).
Methods
We randomly assigned 1974 infants with extremely low birth weight at 12 to 36 hours of age to undergo either aggressive or conservative phototherapy. The primary outcome was a composite of death or neurodevelopmental impairment determined for 91% of the infants by investigators who were unaware of the treatment assignments.
Results
Aggressive phototherapy, as compared with conservative phototherapy, significantly reduced the mean peak serum bilirubin level (7.0 vs. 9.8 mg per deciliter [120 vs. 168 μmol per liter], P<0.01) but not the rate of the primary outcome (52% vs. 55%; relative risk, 0.94; 95% confidence interval [CI], 0.87 to 1.02; P = 0.15). Aggressive phototherapy did reduce rates of neurodevelopmental impairment (26%, vs. 30% for conservative phototherapy; relative risk, 0.86; 95% CI, 0.74 to 0.99). Rates of death in the aggressive-phototherapy and conservative-phototherapy groups were 24% and 23%, respectively (relative risk, 1.05; 95% CI, 0.90 to 1.22). In preplanned subgroup analyses, the rates of death were 13% with aggressive phototherapy and 14% with conservative phototherapy for infants with a birth weight of 751 to 1000 g and 39% and 34%, respectively (relative risk, 1.13; 95% CI, 0.96 to 1.34), for infants with a birth weight of 501 to 750 g.
Conclusions
Aggressive phototherapy did not significantly reduce the rate of death or neurodevelopmental impairment. The rate of neurodevelopmental impairment alone was significantly reduced with aggressive phototherapy. This reduction may be offset by an increase in mortality among infants weighing 501 to 750 g at birth. (ClinicalTrials. gov number, NCT00114543.)
doi:10.1056/NEJMoa0803024
PMCID: PMC2821221  PMID: 18971491

Results 1-5 (5)