Inhaled nitric oxide in premature infants: effect on tracheal aspirate and plasma nitric oxide metabolites
M A Posencheg, A J Gow, W E Truog, R A Ballard, A Cnaan, S G Golombek, P L Ballard, NO CLD Investigators, M A Posencheg, A J Gow, W E Truog, R A Ballard, A Cnaan, S G Golombek, P L Ballard, NO CLD Investigators
Abstract
Objective: Inhaled nitric oxide (iNO) is a potential new therapy for prevention of bronchopulmonary dysplasia and brain injury in premature infants. This study examined dose-related effects of iNO on NO metabolites as evidence of NO delivery.
Study design: A subset of 102 premature infants in the NO CLD trial, receiving 24 days of iNO (20 p.p.m. decreasing to 2 p.p.m.) or placebo, were analyzed. Tracheal aspirate (TA) and plasma samples collected at enrollment and at intervals during study gas were analyzed for NO metabolites.
Result: iNO treatment increased NO metabolites in TA at 20 and 10 p.p.m. (1.7- to 2.3-fold vs control) and in plasma at 20, 10, and 5 p.p.m. (1.6- to 2.3-fold). In post hoc analysis, treated infants with lower metabolite levels at entry had an improved clinical outcome.
Conclusion: iNO causes dose-related increases in NO metabolites in the circulation as well as lung fluid, as evidenced by TA analysis, showing NO delivery to these compartments.
Figures
References
- Wilson-Costello D, Friedman H, Minich N, Fanaroff AA, Hack M. Improved survival rates with increased neurodevelopmental disability for extremely low birth weight infants in the 1990s. Pedatrics. 2005;115:997–1003.
- Bland RD. Neonatal chronic lung disease in the post-surfactant era—lessons learned from authentic animal models. Biol Neonate. 2005;88:181–191.
- McCurnin DC, Pierce RA, Chang LY, Gibson LL, Osborne-Lawrence S, Yoder BA, et al. Inhaled NO improves early pulmonary function and modifies lung growth and elastin deposition in a baboon model of neonatal chronic lung disease. Am J Physiol Lung Cell Mol Physiol. 2005;288 3:L450–L459.
- Schreiber MD, Gin-Mestan K, Marks JD, Huo D, Lee G, Srisuparp P. Inhaled nitric oxide in premature infants with the respiratory distress syndrome. N Engl J Med. 2003;349 22:2099–2107.
- Kinsella JP, Cutter GR, Walsh WF, Gerstmann DR, Bose CL, Hart C, et al. Early inhaled nitric oxide therapy in premature newborns with respiratory failure. N Engl J Med. 2006;355 4:354–364.
- Ballard RA, Truog WE, Cnaan A, Martin RJ, Ballard PL, Merrill JD, et al. Inhaled nitric oxide in preterm infants undergoing mechanical ventilation. N Engl J Med. 2006;355 4:343–353.
- Ballard RA. Inhaled nitric oxide in preterm infants—correction. New Engl J Med. 2007;357 14:1444–1445.
- Hibbs AM, Walsh MC, Martin RJ, Truog WE, Lorch SA, Alessandrini E, et al. One year respiratory outcomes of preterm infants enrolled in the nitiric oxide (to prevent) chronic lung disease trial J Pediatr 20081534525–529.Epub ahead of print.
- Dezfulian C, Raat N, Shiva S, Gladwin MT. Role of the anion nitrite in ischemia-reperfusion cytoprotection and therapeutics. Cardiovasc Res. 2007;75:317–338.
- Ballard PL, Merrill JD, Godinez RI, Godinez MH, Truog WE, Ballard RA. Surfactant protein profile of pulmonary surfactant in premature infants. Am J Respir Crit Care Med. 2003;168 9:1123–1128.
- Ballard PL, Merrill JD, Truog WE, Godinez RI, Godinez MH, McDevitt TM, et al. Surfactant function and composition in premature infants treated with inhaled nitric oxide. Pediatrics. 2007;120 2:346–353.
- Truog WE, Ballard PL, Norberg M, Golombek S, Savani RC, Merrill JD, et al. Inflammatory markers and mediators in tracheal fluid of premature infants treated with inhaled nitric oxide. Pediatrics. 2007;19 4:670–678.
- Ballard PL, Truog WE, Merrill JD, Gow A, Posencheg M, Golombek SG, et al. Plasma biomarkers of oxidative stress: relationship to lung disease and inhaled nitric oxide therapy in premature infants. Pedatrics. 2008;121:555–561.
- Gow AJ, Thom SR, Brass C, Ischiropoulos H. Electrochemical detection of nitric oxide in biological systems. Microchem J. 1997;56:146–154.
- Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976;72:248–254.
- Van Meurs KP, Wright LL, Ehrenkranz RA, Lemons JA, Ball MB, Poole WK, et al. Inhaled nitric oxide for preterm infants with severe respiratory failure. New Engl J Med. 2005;353:13–22.
- Shaul PW, Afshar S, Gibson LL, Sherman TS, Kerecman JD, Grubb PH, et al. Developmental changes in nitric oxide synthase isoform expression and nitric oxide production in fetal baboon lung. Am J Physiol Lung Cell Mol Physiol. 2002;283:L1192–L1199.
- Munson DA, Grubb PH, Kerecman JD, McCurnin DC, Yoder BA, Hazen SL, et al. Pulmonary and systemic nitric oxide metabolites in a baboon model of neonatal chronic lung disease. Am J Respir Cell Mol Biol. 2005;33 6:582–588.
- Parks NJ, Krohn KA, Mathis CA, Chasko JH, Geiger KR, Gregor ME, et al. N-13-labeled nitrite and nitrate—distribution and metabolism after intra-tracheal administration. Science. 1981;212:58–61.
- Mestan KK, Marks JD, Hecok K, Huo D, Schreiber MD. Neurodevelopmental outcomes of premature infants treated with inhaled nitric oxide. New Engl J Med. 2005;353:13–22.
- Endo A, Izumi H, Ayusawa M, Minato M, Takahashi S, Harada K. Spontaneous labor increases nitirc oxide synthesis during the early neonatal period. Pediatr Int. 2001;43:340–342.
- Banks BA, Ischiropoulos H, McClelland M, Ballard PL, Ballard RA. Plasma 3-nitrotyrosine is elevated in premature infants who develop bronchopulmonary dysplasia. Pediatrics. 1998;101 5:870–874.
- Lorch SA, Banks BA, Christie J, Merrill JD, Althaus J, Schmidt K, et al. Plasma 3-nitrotyrosine and outcome in neonates with severe bronchopulmonary dysplasia after inhaled nitric oxide. Free Radic Biol Med. 2003;34 9:1146–1152.
Source: PubMed