Introduction: Inhaled nitric oxide (INO) has been shown in several clinical trials in term infants with respiratory failure to acutely increase oxygenation and significantly decrease the incidence of death and/or ECMO. However the potential pulmonary toxicity and long term effects of INO remain largely unknown. Both NO and its metabolites may react to form secondary cytotoxic species which may be linked to the development of chronic lung disease. The purpose of this study was to investigate whether INO causes increased oxidant stress in the serum of newborns when compared to normal controls and infants exposed to hyperoxia.

Methods: Serum samples were obtained from three groups of infants; term infants in room air, infants with severe respiratory failure requiring ≥80% oxygen for ≥8 hours, and infants on oxygen and INO for 1, 24 and 48 hours. The samples were assayed for lipid hyproperoxides (LPO) and serum glutathione (GSH) as well as serum nitrotyrosine residues, protein carbonyls and total antioxidant status.

Results: Mean birth weight, gestational age, and chronological age for the 27 infants by group were as follows: room air (3.2 kg, 37.3 weeks, 2 days), oxygen (3.5 kg, 40.1 weeks, 1.7 days) and oxygen + INO (3.2 kg, 39 weeks, 2 days). After 24 hours of INO, serum LPO increased 3 fold compared to oxygen alone (31.46 ± 8.4 vs 11.45 ± 2.7 nmol/L, p=0.0046, n=6-9 in each group). Furthermore, after 48 hours of INO, serum GSH levels showed a trend towards lower levels compared to oxygen alone (32.79 ± 10.7 vs. 58.42 ± 7.2 umol/L, p =0.06, n=7-9 in each group).

Conclusions: We conclude that longer INO exposures are associated with evidence of increased oxidative injury and depleted antioxidant defenses. Although INO appears to be an important therapy for severe respiratory failure, prolonged use may be be associated with adverse consequences resulting from oxygen radical injury such as chronic lung disease. (Funded by NIH M01 RR00070)