Inhaled Nitric Oxide Therapy in Premature Infants Plasma Biomarkers of Oxidative Stress: Relationship to Lung Disease

OBJECTIVES. Inhaled nitric oxide treatment for ventilated premature infants improves survival without bronchopulmonary dysplasia. However, there has been no information regarding possible effects of this therapy on oxidative stress. We hypothesized that inhaled nitric oxide therapy would not influence concentrations of plasma biomarkers of oxidative stress. PATIENTS AND METHODS.As part of the Nitric Oxide Chronic Lung Disease Trial, we collected blood samples at specified intervals from a subpopulation of 100 infants of 1250 g birth weight who received inhaled nitric oxide (20 ppm, weaned to 2 ppm) or placebo gas for 24 days. Plasma was assayed for total protein and for 3-nitrotyrosine and carbonylation by using immunoassays. RESULTS. The demographic characteristics and primary outcome for the infants were representative of the entire group of infants who were in the Nitric Oxide Chronic Lung Disease Trial. For all infants at baseline, before receiving study gas, the concentration of total protein was inversely correlated with the respiratory severity score, and plasma carbonyl was positively correlated with severity score, supporting an association between oxidative stress and severity of lung disease. Infants who survived without bronchopulmonary dysplasia had 30% lower protein carbonylation concentrations at study entry than those who had an adverse outcome. At each of 3 time points (1–10 days) during exposure to study gas, there were no significant differences between control and treated infants for concentrations of plasma protein, 3-nitrotyrosine, and carbonylation. CONCLUSIONS. Inhaled nitric oxide treatment for premature infants who are at risk for bronchopulmonary dysplasia does not alter plasma biomarkers of oxidative stress, which supports the safety of this therapy. A THE BENEFIT and safety of inhaled nitric oxide (iNO) therapy for persistent pulmonary hypertension in term and near-term infants is well established, the use of iNO treatment in premature infants with respiratory failure or chronic lung disease is still under investigation. Controlled clinical trials of iNO in moderately ill, ventilated premature infants have reported benefit in prevention of bronchopulmonary dysplasia (BPD) without apparent adverse effects, particularly in infants between 1000 g and 1250 g birth weight.1–6 In addition, there is evidence of neurologic protection in treated infants.1,5 Premature infants experience oxidative stress as a result of lung disease and exposure to oxygen and ventilator therapy (reviewed in ref 7). Reactive oxygen and nitrogen species increase formation of relatively stable carbonyl adducts of proteins by both direct and indirect oxidation reactions.8 Protein carbonylation can modify protein www.pediatrics.org/cgi/doi/10.1542/ peds.2007-2479 doi:10.1542/peds.2007-2479