This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Bronchopulmonary dysplasia (BPD) of prematurity has emerged as the most common, lethal and expensive neonatal pulmonary disorder in the United States. The pathogenesis of BPD is multi-factorial, has a genetic contribution, and involves injury and inflammation associated with oxygen toxicity and mechanical ventilation in an underdeveloped, immature lung. The estimated prevalence is 30,000 cases/year. Current therapeutic approaches to the prevention and treatment of lung disease in premature infants, including antenatal corticosteroid treatment, replacement surfactant at birth, postnatal administration of corticosteroids, vitamin A, diuretics, caffeine, and bronchodilators have not significantly impacted the overall occurrence of BPD. Recent clinical trials of inhaled nitric oxide (iNO) indicate a beneficial impact on the incidence and severity of BPD as well as short- and long-term safety including 2-year neurodevelopmental outcome. Extremely low birth weight infants (ELBW, defined as <1000 g and <30 wk gestation for the purposes of this study) who continue to require mechanical ventilation at 7 d of age have the highest incidence and severity of BPD, which is associated with chronic pulmonary disease and abnormal neurodevelopmental outcome. In recent studies we found that this group of infants has frequent respiratory deteriorations that are associated with dysfunctional pulmonary surfactant and decreased content of surfactant proteins (SP) B and C, which are critical for normal surfactant function to maintain patency of alveoli and terminal airways. Based on these observations, we have performed pilot studies of late administration of SP-B-containing commercial surfactant (Infasurf?). Our preliminary data confirm that the majority of infants still requiring ventilation after 7 d of age have abnormal surface tension measurements and that late doses of surfactant are well tolerated and transiently improve respiratory status. Episodes of surfactant dysfunction also occur among infants receiving iNO. Moreover, surfactant dysfunction in iNO-treated infants is associated with adverse outcome. In this pilot study, we plan to study the addition of late surfactant administration to infants at high risk for BPD who are receiving iNO therapy. We hypothesize that late booster doses of surfactant, in addition to iNO, administered to ELBW infants who continue to require mechanical ventilation between 7 and 14 days of age will significantly decrease the frequency of episodes of surfactant dysfunction in these infants. We further hypothesize that there will be no adverse effects of surfactant treatment on short-term outcomes including death or BPD at 36 weeks postmenstrual age.
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