Inhaled Nitric Oxide Increases Urinary Nitric Oxide Metabolites and Cyclic Guanosine Monophosphate in Premature Infants: Relationship to Pulmonary Outcome

Abstract

Objective Inhaled nitric oxide (iNO) has been tested to prevent bronchopulmonary dysplasia (BPD) in premature infants, however, the role of cyclic guanosine monophosphate (cGMP) is not known. We hypothesized that levels of NO metabolites (NOx) and cGMP in urine, as a noninvasive source for biospecimen collection, would reflect the dose of iNO and relate to pulmonary outcome.

Study Design Studies were performed on 125 infants who required mechanical ventilation at 7 to 14 days and received 24 days of iNO at 20–2 ppm. A control group of 19 infants did not receive iNO.

Results In NO-treated infants there was a dose-dependent increase of both NOx and cGMP per creatinine (maximal 3.1- and 2-fold, respectively, at 10–20 ppm iNO) compared with off iNO. NOx and cGMP concentrations at both 2 ppm and off iNO were inversely related to severity of lung disease during the 1st month, and the NOx levels were lower in infants who died or developed BPD at term. NOx was higher in Caucasian compared with other infants at all iNO doses.

Conclusion Urinary NOx and cGMP are biomarkers of endogenous NO production and lung uptake of iNO, and some levels reflect the severity of lung disease. These results support a role of the NO–cGMP pathway in lung development.

Keywords

nitric oxide - cyclic GMP - bronchopulmonary dysplasia - premature - urine

Note

Other contributing TOLSURF Pilot and TOLSURF investigators: Elizabeth Rogers, MD (University of California San Francisco, San Francisco CA); Anne Marie Reynolds, MD (Women and Children's Hospital of Buffalo, Buffalo, NY); Aruna Parekh, MD (Stonybrook University Hospital, Stonybrook, NY); Dennis Mayock, MD (University of Washington, Seattle, WA); Mark Hudak, MD (University of Florida College of Medicine at Jacksonville, UF Health and Wolfson Children's Hospital, Jacksonville, FL); Beatrice Stefanescu, MD, Jennifer B. Helderman, MD, T. Michael O'Shea, MD (Wake Forest School of Medicine and Forsyth Medical Center, Winston Salem, NC); Michael Georgieff, MD, Catherine M. Bendel, MD (University of Minnesota Amplatz Children's Hospital, Minneapolis, MN); Andrea Lampland, MD (Department of Pediatrics, Children's Hospital and Clinics of Minnesota, St. Paul, MN); Ellen Bendel-Stenzel, MD, Neil Mulrooney (Children's Hospitals and Clinics of Minnesota, Minneapolis, MN); Frances Koch, MD (Medical University of South Carolina, Charleston, SC); Reddy Dhanireddy, MD (University of Tennessee-Memphis, Memphis TN); Victor McKay, MD (All Children's Hospital, St Petersburg, FL); Rajan Wadhawan, MD (Florida Hospital for Children, Orlando FL); Nicolas Porta, MD (Northwestern Memorial Hospital, Chicago, IL)

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