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

项目摘要 拟议研究的广泛长期目标是使用全面的最先进的高保真度 监测以研究自主神经呼吸成熟的生理生物标志物， 分析早产儿的自主神经系统（ANS）反应，并评估其在早产儿中的作用。 呼吸不稳、支气管肺发育不良（BPD）和合并症（包括神经运动功能受损） 生命第一年的发展。具体目标1将建立频谱和发展轨迹 ANS成熟/功能使用20小时高分辨率记录的排尿，心血管， 典型内源性日常活动期间（32和36周; 3个月）的脑血管生理学和短暂 诱发外周和中枢化学感受器的低氧、高氧和高碳酸挑战， 潜伏性自主神经和呼吸不稳定（36周; 3和12个月）。目标1检验假设， ANS功能的个体和综合指标将展示赋予弹性的成熟模式 或对生理挑战的脆弱性。具体目标2将决定呼吸和神经发育 使用复合呼吸道疾病严重程度评分评估整个生命第1年的发病率，包括 需要呼吸支持、药物治疗或住院治疗（3、6、9、12个月），以及神经系统， 感觉、运动、发育评估（3、6、12个月）作为临床适用的结局指标，以及 将这些措施与ANS的发展和功能。目标2检验婴儿 证明ANS成熟延迟或对生理扰动的脆弱性将需要更多的 呼吸干预，并将在生命的第一年表现出神经运动延迟。具体目标3将 通过轨迹分析确定自主神经呼吸稳定性和成熟的内在型， 综合生理建模目标3测试假设，轨迹分析将揭示3自主 成熟模式（1）预期成熟，能够承受生理扰动; 2）预期 成熟没有能力承受生理扰动;和3）延迟或无序的成熟， 即使在没有环境扰动的情况下也不能保持生理稳定性），这将预测 1年时不同程度的呼吸系统发病率和神经运动损伤。这种新方法将 建立自主神经呼吸成熟在整个第一年的氧合稳定性中的作用 生活，提供洞察BPD发病机制，允许前瞻性识别高危婴儿，并允许 制定有可能影响成千上万个家庭的针对具体机制的干预措施， 在美国，每年有数十亿美元的医疗费用，一个人

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.