Respiratory morbidity, particularly chronic lung disease (CLD), remains a major cause of long-term morbidity and mortality for preterm infants. Although surfactant replacement has decreased acute respiratory morbidity and mortality, it has not reduced the incidence of CLD. A number of other approaches, including antenatal thyrotropin releasing hormone in conjunction with corticosteroids, postnatal steroid administration, as well as administration of Vitamin E, diuretics, and bronchodilators, have not resulted in clinically important decreases in CLD. Infants with the most severe CLD go on to develop findings suggestive of pulmonary hypertension with cor pulmonale. There is preliminary evidence in the preterm infant with severe chronic lung disease that low-dose inhaled nitric oxide may significantly attenuate the disease and decrease mortality. We propose a multi-center, controlled and blinded trial to investigate the hypothesis that low-dose inhaled nitric oxide administered to preterm infants between 500 and 1250 grams birth weight who continue to require mechanical ventilation at 10 days of age will increase survival without CLD at 36 weeks post menstrual age. Demonstrating an increase from 50 percent to 60 percent survival without CLD requires 726 randomized infants to have 80 percent power to detect this difference while controlling for a one-sided alpha of 0.05 and allowing for one interim analysis at one-third of outcome data available. Secondary outcomes are duration of ventilation, oxygen requirement and duration of hospitalization. We expect, in addition, that there will be improvement in infant respiratory status (ventilatory support, airway resistance and compliance) associated with inhaled nitric oxide treatment. Indicators of inflammation and oxidant stress will be assessed by measurements of specific cytokines and protein modifications in tracheal aspirate and plasma samples, respectively. We also will evaluate safety of this therapy by assessing toxicity as measured by clinical bleeding, including intraventricular hemorrhage as well as the incidence of other morbidities of the preterm infant (necrotizing enterocolitis, retinopathy of prematurity and infection) and assess neurodevelopmental outcome through two years of age. In summary, this clinical trial will assess the efficacy and safety of inhaled nitric oxide for amelioration of a major disease of premature infants.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project--Cooperative Agreements (U01)
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Clinical Trials Review Committee (CLTR)
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Berberich, Mary Anne
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Children's Hospital of Philadelphia
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Hibbs, Anna Maria; Black, Dennis; Palermo, Lisa et al. (2010) Accounting for multiple births in neonatal and perinatal trials: systematic review and case study. J Pediatr 156:202-8
Walsh, Michele C; Hibbs, Anna Maria; Martin, Camilia R et al. (2010) Two-year neurodevelopmental outcomes of ventilated preterm infants treated with inhaled nitric oxide. J Pediatr 156:556-61.e1
Posencheg, M A; Gow, A J; Truog, W E et al. (2010) Inhaled nitric oxide in premature infants: effect on tracheal aspirate and plasma nitric oxide metabolites. J Perinatol 30:275-80
Zupancic, John A F; Hibbs, Anna Maria; Palermo, Lisa et al. (2009) Economic evaluation of inhaled nitric oxide in preterm infants undergoing mechanical ventilation. Pediatrics 124:1325-32
Hibbs, Anna Maria; Walsh, Michele C; Martin, Richard J et al. (2008) One-year respiratory outcomes of preterm infants enrolled in the Nitric Oxide (to prevent) Chronic Lung Disease trial. J Pediatr 153:525-9
Ballard, Philip L; Truog, William E; Merrill, Jeffrey D et al. (2008) Plasma biomarkers of oxidative stress: relationship to lung disease and inhaled nitric oxide therapy in premature infants. Pediatrics 121:555-61
Truog, William E; Ballard, Philip L; Norberg, Michael et al. (2007) Inflammatory markers and mediators in tracheal fluid of premature infants treated with inhaled nitric oxide. Pediatrics 119:670-8
Di Fiore, J M; Hibbs, A M; Zadell, A E et al. (2007) The effect of inhaled nitric oxide on pulmonary function in preterm infants. J Perinatol 27:766-71
Ballard, Philip L; Merrill, Jeffrey D; Truog, William E et al. (2007) Surfactant function and composition in premature infants treated with inhaled nitric oxide. Pediatrics 120:346-53
Farkouh, Christiana R; Merrill, Jeffrey D; Ballard, Phillip L et al. (2006) Urinary metabolites of oxidative stress and nitric oxide in preterm and term infants. Biol Neonate 90:233-42

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