Pulmonary Resilience: Moderating the Association between Oxygen Exposure and Pulmonary Outcomes in Extremely Preterm Newborns

Abstract

Bronchopulmonary dysplasia (BPD) is a chronic lung disease of infancy associated with high morbidity and mortality. Although most prevalent following extremely preterm birth, BPD is diagnosed at 36 weeks post-menstrual age, when the disease trajectory is underway, and long-term physiological implications may be irreversible. There is an urgent and unmet need to identify how early exposures can be modified to decrease the risk of developing BPD before disease progression becomes irreversible. Extremely preterm newborns encounter a paradox at birth: oxygen is a life-sustaining component of ex utero life yet is undeniably toxic. Attempts at minimizing supplemental oxygen exposure by targeting lower oxygen saturations appear to decrease BPD but may increase mortality. Given the potential association between lower oxygen saturations and increased mortality, practice guidelines favor targeting higher saturations. This uniformly increases oxygen exposure, prompting a cascade of pathogenic mechanisms implicated in BPD development. In this review, we introduce the concept of <i>pulmonary resilience</i>: a homeostatic process driven by the autonomic nervous system (ANS) as a moderator of physiologic stress that when functional, could inform successful environmental adaptation following extremely preterm birth. We hypothesize that infants with early-life ANS dysfunction require a higher oxygen dose for survival; conversely, oxygen exposure could be safely limited in infants with more robust early-life ANS function, an indicator of <i>pulmonary resilience</i>. Characterizing the <i>pulmonary resilience</i> continuum to guide individualized supplemental oxygen dosing may reduce morbidity and mortality in this growing population of extremely preterm infants at risk for BPD.