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 综合监测研究自主神经呼吸成熟的生理生物标志物 早产儿自主神经系统(ANS)反应分析及其在早产儿发病中的作用 呼吸机不稳定、支气管肺发育不良(BPD)以及包括神经运动受损在内的共病 在生命的第一年发展。特定的目标1将建立光谱和发展轨迹 ANS成熟/功能使用20小时高分辨率记录的呼吸、心血管和 典型内源性日常活动(32周和36周；3个月)和短暂的脑血管生理学 外周和中枢化学感受器引起的低氧、高氧和高碳酸挑战以揭开面纱 潜在的自主神经和呼吸不稳定(36周；3个月和12个月)。AIM 1检验了假设 ANS功能的单独和综合衡量标准将展示提供弹性的成熟模式 或对生理挑战的脆弱性。特异性AIM 2将决定呼吸和神经发育 使用包括以下内容的综合呼吸道发病率严重程度评分，在生命的第一年期间的发病率 需要呼吸支持、药物或住院(3、6、9、12个月)，以及神经科、 感觉、运动、发育评估(3、6、12个月)作为临床适用的结果衡量标准； 将把这些措施与ANS的发展和功能联系起来。《目标2》验证了婴儿 要证明ANS成熟延迟或易受生理干扰影响，需要更多 呼吸干预，并将在生命的第一年表现出神经运动延迟。特定的AIM 3将 通过轨迹分析确定自主神经呼吸稳定性和成熟度的内型 综合生理学建模。AIM 3测试了轨迹分析将揭示3个自主神经的假设 成熟模式(1)预期成熟，具有抵抗生理扰动的能力；2)预期成熟 成熟而不能抵抗生理干扰；以及3)成熟延迟或无序成熟 即使在没有环境扰动的情况下也无法保持生理稳定性)，这将预测 1年后出现不同程度的呼吸道并发症和神经运动功能障碍。这一新颖的方法将 建立自主神经呼吸成熟在1岁时氧合稳定性中的作用 LIFE，提供对BPD发病机制的洞察，允许前瞻性识别高危婴儿，并允许 制定有可能影响千家万户的具体机制干预措施 仅在美国，每年的医疗成本就高达数十亿美元。

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.