Effects of early inhaled nitric oxide therapy and vitamin A supplementation on the risk for bronchopulmonary dysplasia in premature newborns with respiratory failure.

OBJECTIVE: To assess whether the combination of early inhaled nitric oxide (iNO) therapy and vitamin A supplementation lowers the incidence of bronchopulmonary dysplasia (BPD) in premature newborns with respiratory failure. STUDY DESIGN: A total of 793 mechanically ventilated infants (birth weight 500-1250 g) were randomized (after stratification by birth weight) to receive placebo or iNO (5 ppm) for 21 days or until extubation (500-749, 750-999, or 1000-1250 g). A total of 398 newborns received iNO, and of these, 118 (30%) received vitamin A according to their enrollment center. We compared patients who received iNO + vitamin A with those who received iNO alone. The primary outcome was a composite of death or BPD at 36 weeks postconceptual age. RESULTS: BPD was reduced in infants who received iNO + vitamin A for the 750-999 g birth weight group compared with iNO alone (P = .01). This group also showed a reduction in the combined outcome of BPD + death compared with iNO alone (P = .01). The use of vitamin A did not change the risk for BPD in the placebo group. Overall, the use of vitamin A was low (229 of 793 patients, or 29%). Combined therapy improved Bayley Scales of Infant Development II Mental and Psychomotor Developmental Index scores at 1 year compared with infants treated solely with iNO for the 500-749 g birth weight group. CONCLUSIONS: In this retrospective analysis of the nonrandomized use of vitamin A, combined iNO + vitamin A therapy in preterm infants with birth weight 750-999 g reduced the incidence of BPD and BPD + death and improved neurocognitive outcomes at 1 year in the 500-749 g birth weight group.

Prolonged infusion of amino acids increases leucine oxidation in fetal sheep.

Maternal high-protein supplements designed to increase birth weight have not been successful. We recently showed that maternal amino acid infusion into pregnant sheep resulted in competitive inhibition of amino acid transport across the placenta and did not increase fetal protein accretion rates. To bypass placental transport, singleton fetal sheep were intravenously infused with an amino acid mixture (AA, n = 8) or saline [control (Con), n = 10] for ∼12 days during late gestation. Fetal leucine oxidation rate increased in the AA group (3.1 ± 0.5 vs. 1.4 ± 0.6 µmol·min(-1)·kg(-1), P < 0.05). Fetal protein accretion (2.6 ± 0.5 and 2.2 ± 0.6 µmol·min(-1)·kg(-1) in AA and Con, respectively), synthesis (6.2 ± 0.8 and 7.0 ± 0.9 µmol·min(-1)·kg(-1) in AA and Con, respectively), and degradation (3.6 ± 0.6 and 4.5 ± 1.0 µmol·min(-1)·kg(-1) in AA and Con, respectively) rates were similar between groups. Net fetal glucose uptake decreased in the AA group (2.8 ± 0.4 vs. 3.9 ± 0.1 mg·kg(-1)·min(-1), P < 0.05). The glucose-O(2) quotient also decreased over time in the AA group (P < 0.05). Fetal insulin and IGF-I concentrations did not change. Fetal glucagon increased in the AA group (119 ± 24 vs. 59 ± 9 pg/ml, P < 0.05), and norepinephrine (NE) also tended to increase in the AA group (785 ± 181 vs. 419 ± 76 pg/ml, P = 0.06). Net fetal glucose uptake rates were inversely proportional to fetal glucagon (r(2) = 0.38, P < 0.05), cortisol (r(2) = 0.31, P < 0.05), and NE (r(2) = 0.59, P < 0.05) concentrations. Expressions of components in the mammalian target of rapamycin signaling pathway in fetal skeletal muscle were similar between groups. In summary, prolonged infusion of amino acids directly into normally growing fetal sheep increased leucine oxidation. Amino acid-stimulated increases in fetal glucagon, cortisol, and NE may contribute to a shift in substrate oxidation by the fetus from glucose to amino acids.