Jeffrey D. Merrill

BACKGROUND: Bronchopulmonary dysplasia in premature infants is associated with prolonged hospitalization, as well as abnormal pulmonary and neurodevelopmental outcome. In animal models, inhaled nitric oxide improves both gas exchange and lung structural development, but the use of this therapy in infants at risk for bronchopulmonary dysplasia is controversial. METHODS: We conducted a randomized, stratified, double-blind, placebo-controlled trial of inhaled nitric oxide at 21 centers involving infants with a birth weight of 1250 g or less who required ventilatory support between 7 and 21 days of age. Treated infants received decreasing concentrations of nitric oxide, beginning at 20 ppm, for a minimum of 24 days. The primary outcome was survival without bronchopulmonary dysplasia at 36 weeks of postmenstrual age. RESULTS: Among 294 infants receiving nitric oxide and 288 receiving placebo birth weight (766 g and 759 g, respectively), gestational age (26 weeks in both groups), and other characteristics were similar. The rate of survival without bronchopulmonary dysplasia at 36 weeks of postmenstrual age was 43.9 percent in the group receiving nitric oxide and 36.8 percent in the placebo group (P=0.042). The infants who received inhaled nitric oxide were discharged sooner (P=0.04) and received supplemental oxygen therapy for a shorter time (P=0.006). There were no short-term safety concerns. CONCLUSIONS: Inhaled nitric oxide therapy improves the pulmonary outcome for premature infants who are at risk for bronchopulmonary dysplasia when it is started between 7 and 21 days of age and has no apparent short-term adverse effects. (ClinicalTrials.gov number, NCT00000548 [ClinicalTrials.gov] .).

BACKGROUND: The use of indomethacin as a tocolytic agent in pregnant women appears to be accompanied by a low incidence of neonatal complications. However, the neonatal effects of indomethacin have been studied primarily in infants born after 32 weeks' gestation. This study was designed to examine the incidence of neonatal complications in very premature infants. METHODS: We identified 57 infants delivered at or before 30 weeks' gestation whose mothers had been treated with indomethacin for preterm labor and matched them with 57 infants whose mothers had not received indomethacin. The infants in the two groups were matched for sex, gestational age at delivery (mean [+/- SD], 27.6 +/- 2.0 weeks), exposure to betamethasone for 24 hours or more before delivery, and rupture of membranes 24 hours or more before delivery. RESULTS: There were no significant differences between the two groups in birth weight, Apgar scores, cord-blood gas values, frequency of multiple gestation, or incidence of respiratory distress syndrome. The proportion of infants who required exogenous surfactant was similar, as were ventilator settings at 24 hours, the incidence of chronic lung disease, and the incidence of sepsis. The infants exposed to indomethacin had a lower urine output and higher serum creatinine concentrations during the first three days after delivery. More indomethacin-exposed infants had necrotizing enterocolitis (29 percent vs. 8 percent, P = 0.005), intracranial hemorrhage grade II to IV (28 percent vs. 9 percent, P = 0.02), and patent ductus arteriosus (62 percent, vs. 44 percent, P = 0.05). More indomethacin-exposed infants with a patent ductus arteriosus required surgical ligation because of either a lack of initial response or a reopening of the duct after postnatal indomethacin therapy (50 percent vs. 20 percent of the unexposed infants, P = 0.05). CONCLUSIONS: Antenatal indomethacin therapy for preterm labor appears to increase the risk of serious neonatal complications in infants born at or before 30 weeks' gestation.

OBJECTIVES: We sought to examine outcome for premature neonates after multiple courses of antenatal corticosteroids compared with a single course. STUDY DESIGN: We performed a post hoc nonrandomized analysis on 710 neonates of 25-32 weeks' gestation who were born to mothers enrolled in the North American Thyrotropin-Releasing Hormone Trial and who received 1, 2, or >/=3 courses of antenatal corticosteroids. RESULTS: There was no detectable clinical difference in incidence of respiratory distress syndrome, chronic lung disease, and intraventricular hemorrhage related to courses of antenatal corticosteroids, and outcome was similar for infants delivered at 7-13 days compared with those delivered at 1-6 days after receiving antenatal corticosteroids. Compared with those who received a single course, neonates who received >/=2 courses had lower birth weights (-39 g, P =.02), and those receiving >/=3 courses had increased risk of death (adjusted odds ratio, 2.8; 95% confidence interval, 1.3-5.9; P =.01) and lower levels of plasma cortisol at age 2 hours. CONCLUSION: In this retrospective analysis multiple courses of antenatal corticosteroids did not improve outcome and were associated with increased mortality, decreased fetal growth, and prolonged adrenal suppression.

BACKGROUND: Severe bronchopulmonary dysplasia (BPD), which is associated with high mortality and morbidity, is thought to be the result of mechanical, inflammatory, and oxidant injury to the immature lung, and includes the development of pulmonary hypertension with vascular remodeling. METHODS: A phase II pilot study was conducted to determine the effect of inhaled nitric oxide (iNO) on oxygenation in severe BPD. This was an open-labeled, noncontrolled trial to evaluate safety and determine appropriate dosing for a future randomized controlled trial. Infants were eligible for enrollment if they were >/=4 weeks of age and ventilator dependent with a mean airway pressure of >/=10 cm H2O and an FIO2 of >/=0.45. Study infants received iNO (20 ppm) for 72 hours, and FIO2 was adjusted to maintain oxygen saturations of >92%. Infants who had a >/=15% reduction in FIO2 after 72 hours received prolonged treatment with low-dose iNO, weaning by 20% every 3 days as tolerated. FINDINGS: Sixteen preterm infants (23-29 weeks of gestation), age 1 to 7 months, were enrolled. Eleven of 16 infants had a significant increase in PaO2 after 1 hour of iNO (median change, 24 mm Hg; range, -15 to 59 mm Hg; P <.01), but there was no significant change in PaCO2. After 72 hours of iNO, 11 infants had >/=15% reduction in FIO2, and 7 of the 11 had >/=35% reduction (P <. 01). Among the 11 infants who responded to iNO after 72 hours, 10 had a sustained improvement in oxygenation throughout their course of treatment (duration, 8-90 days), and ventilator support could also be decreased. No adverse effects from iNO (increased methemoglobin, bleeding, or increased plasma 3-nitrotyrosine) were observed. Four of the 11 infants (36%) who responded to iNO ultimately weaned off mechanical ventilation and 4 died, whereas all the infants who failed to respond to iNO either died or continue to require mechanical ventilation. INTERPRETATION: We conclude that the use of low-dose iNO may improve oxygenation in some infants with severe BPD, allowing decreased FIO2 and ventilator support without evidence of adverse effects. Randomized clinical trials of low-dose iNO for BPD are warranted.