Integrated analysis of autonomic biomarkers in prematurity-related ventilatory control: Determination of neurorespiratory maturation and predictors of co-morbidity risk

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Project Summary The broad long-term objective of the proposed study is to use comprehensive state-of-the-art high-fidelity monitoring to investigate physiological biomarkers of autonomic neurorespiratory maturation with integrated analysis of autonomic nervous system (ANS) responses in preterm infants, and to evaluate their role in ventilatory instability, bronchopulmonary dysplasia (BPD), and co-morbidities including impaired neuromotor development in the 1st year of life. SPECIFIC AIM 1 will establish the spectrum and developmental trajectory of ANS maturation/function using 20-hour high-resolution recordings of ventilatory, cardiovascular, and cerebrovascular physiology during typical endogenous daily activity (32 and 36 weeks; 3 months) and brief evoked hypoxic, hyperoxic, and hypercarbic challenges of peripheral and central chemoreceptors to unmask latent autonomic and respiratory instability (36 weeks; 3 and 12 months). Aim 1 tests the hypothesis that individual and integrated metrics of ANS function will demonstrate maturational patterns that impart resilience or vulnerability to physiologic challenges. SPECIFIC AIM 2 will determine respiratory and neurodevelopmental morbidity throughout the 1st year of life using a composite Respiratory Morbidity Severity Score that includes need for respiratory support, medications, or hospitalization (3, 6, 9, 12 months), and the Neurological, Sensory, Motor, Developmental Assessment (3, 6, 12 months) as clinically applicable outcome measures, and will associate these measures with ANS development and function. Aim 2 tests the hypothesis that infants demonstrating delayed ANS maturation or vulnerability to physiologic perturbations will require more respiratory interventions and will demonstrate neuromotor delays in the 1st year of life. SPECIFIC AIM 3 will determine endotypes of autonomic neurorespiratory stability and maturation through trajectory analysis and integrated physiological modeling. Aim 3 tests the hypothesis that trajectory analysis will reveal 3 autonomic maturation patterns (1)anticipated maturation with ability to withstand physiologic perturbations; 2)anticipated maturation without ability to withstand physiologic perturbations; and 3)delayed or disordered maturation with an inability to maintain physiologic stability even in the absence of environmental perturbations) that will predict varying degrees of respiratory morbidity and neuromotor impairment at 1 year. This novel approach will establish the role of autonomic neurorespiratory maturation in stability of oxygenation throughout the 1st year of life, provide insight into BPD pathogenesis, allow prospective identification of at-risk infants, and permit development of mechanism-specific interventions that have potential to impact thousands of families and billions of dollars in healthcare costs each year in the U.S., alone.