This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator. Inhaled nitric oxide (iNO) therapy is a safe and effective treatment for term newborns with persistent pulmonary hypertension of the newborn and hypoxemic respiratory failure. However, little is known about the potential role of iNO in premature newborns with respiratory failure. The premature newborn is particularly susceptible to the adverse effects of ventilator-induced lung injury, oxygen toxicity, and lung inflammation which contribute to the development of chronic lung disease (CLD). Despite treatment with exogenous surfactant and steroids, CLD remains a major cause of morbidity and mortality in premature newborns. Moreover, there is increasing evidence that steroid treatment causes long term adverse neurodevelopmental and cardiopulmonary sequelae. Early clinical observations suggest that low-dose iNO improves oxygenation and decreases the need for mechanical ventilator support in the premature infant. In addition to its effects on gas exchange, recent laboratory and clinical observations suggest that iNO may also act as a lung-specific anti-inflammatory treatment and reduce the contribution of lung inflammation to the evolution of acute and chronic lung injury in premature infants. To begin to address the potential role of low-dose iNO (5 ppm) in premature subjects, we first performed a series of animal experiments in extremely premature lambs (115 days gestation, 78% of term), then conducted a pilot study of low-dose iNO in premature newborns with severe hypoxemic respiratory failure. Our laboratory experiments demonstrated that: 1) endogenous NO modulates fetal pulmonary vascular tone early in gestation and the transitional premature pulmonary circulation dilates in response to iNO; 2) iNO improves gas exchange and causes sustained reductions in pulmonary vascular resistance in the premature lamb with severe respiratory distress syndrome (RDS), without increasing lung vascular leak; and 3) iNO decreases lung neutrophil accumulation in the mechanically ventilated premature lamb with RDS. These laboratory experiments and others provided the rationale for clinical trials of low-dose iNO in premature newborns. To test the hypothesis that iNO would improve oxygenation in premature newborns without increasing bleeding complications, we recently conducted a masked, randomized, controlled pilot study of low-dose iNO in premature newborns with severe hypoxemic respiratory failure. We felt that the initial trials of iNO in premature newborns must include only the most severely ill patients to generate data from which to judge safety and efficacy. This study was designed to determine the impact of iNO on survival to discharge (primary outcome measure) and adverse events (secondary outcome measures: ICH, periventricular leukomalacia, pulmonary hemorrhage, chronic lung disease). Eighty patients were randomized within two gestational age strata in 12 centers with 48 iNO patients and 32 control patients at the time the study was stopped. At the time the study was stopped (because we were unlikely with the proposed sample size to achieve the mortality differences hypothesized), we found no difference in survival to discharge between iNO treated and control groups (52% iNO vs. 47% control). However, in contrast to previous case reports of iNO treated babies, we found no difference in adverse outcomes between groups (ICH grade 2-4 = 28% iNO vs. 33% control), periventricular leukomalacia = 8% iNO vs. 13% control, chronic lung disease at 36 weeks gestation = 60% iNO vs. 80% control). Based on these laboratory and clinical observations, we hypothesize that early treatment with low-dose iNO may reduce the incidence of chronic lung disease in premature newborns with respiratory failure.
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