Long-term effects of therapeutic caffeine use for apnea of prematurity on sleep d

描述（由申请人提供）： 早产儿呼吸暂停是一种常见的疾病，通常用甲基黄嘌呤治疗。甲基黄嘌呤是腺苷受体阻滞剂，对中枢神经系统有强大的影响。然而，关于甲基黄嘌呤对发育中的大脑的长期影响知之甚少。特别是，目前还不知道甲基黄嘌呤是否对睡眠结构和睡眠控制有永久性的不良影响，导致睡眠障碍，如失眠和阻塞性睡眠呼吸暂停综合征（OSAS）的患病率增加。早产的孩子患神经行为异常的风险增加。这些神经系统合并症可能部分通过甲基黄嘌呤暴露导致的睡眠障碍介导。这项研究计划将利用一个独特的早产儿队列，5-6岁的儿童在出生时随机接受咖啡因或安慰剂，目前正在接受详细的神经认知和行为评估（咖啡因治疗早产儿呼吸暂停[CAP]试验）。由于CAP队列的随访正在进行中，需要在接近睡眠评估时进行神经行为评估，因此进行本研究具有时间紧迫性。总的假设是，甲基黄嘌呤在早产儿中的使用，虽然在短期内有益，但会导致睡眠调节和睡眠期间呼吸的长期异常。在目标1中，我们将确定甲基黄嘌呤给药对睡眠/觉醒模式的长期影响。具体来说，我们将使用活动记录仪，睡眠日记和问卷调查来测量在新生儿期接受咖啡因或安慰剂的5-6岁早产儿的睡眠。我们假设，与对照组相比，接受咖啡因的儿童睡眠时间减少，入睡困难和保持睡眠的患病率增加。在目标2中，我们将确定甲基黄嘌呤给药对儿童期OSAS患病率的长期影响。具体来说，我们将使用动态多导睡眠图来描述在新生儿期接受咖啡因或安慰剂的5-6岁早产儿在睡眠期间的呼吸特征。我们假设接受咖啡因的儿童会增加OSAS的患病率。在目标3中，我们将确定睡眠中断，阻塞性睡眠呼吸暂停综合征和甲基黄嘌呤管理的神经认知和行为异常的早产儿的贡献。具体来说，我们将确定在新生儿期接受咖啡因或安慰剂的5-6岁早产儿的睡眠时间、OSAS和神经行为指标（通过父母研究获得）之间的关系。我们假设睡眠中断和OSAS会导致神经认知和行为异常。这些研究将有助于确定新生儿甲基黄嘌呤治疗的长期后果，最终改善早产儿呼吸暂停的管理。公共卫生相关性：甲基黄嘌呤常用于新生儿重症监护室治疗早产儿呼吸暂停。然而，这些药物的长期后果尚不清楚。这项研究将确定新生儿甲基黄嘌呤治疗是否会导致睡眠长期扰动，睡眠期间的呼吸，从而导致神经认知和行为异常。

DESCRIPTION (provided by applicant): Apnea of prematurity is a common condition that is usually treated with methylxanthines. Methylxanthines are adenosine receptor blockers that have powerful influences on the central nervous system. However, little is known about the long-term effects of methylxanthines on the developing brain. In particular, it is not known whether methylxanthines have permanent adverse effects on sleep architecture and ventilatory control, resulting in an increased prevalence of sleep disorders such as insomnia and the obstructive sleep apnea syndrome (OSAS). Children who were born prematurely are at increased risk for neurobehavioral abnormalities. It is possible that these neurologic comorbidities are mediated, in part, through sleep disturbances that may result from methylxanthine exposure. This research proposal will take advantage of a unique cohort of ex-premature, 5-6 year old children who were randomized at birth to receive either caffeine or placebo, and are currently receiving detailed neurocognitive and behavioral assessments (the Caffeine for Apnea of Prematurity [CAP] trial). There is a time-based urgency to performing this study, as follow-up of the CAP cohort is in progress, and neurobehavioral assessments need to be performed in close proximity to the sleep assessments. The overall hypothesis is that methylxanthine use in preterm infants, while beneficial in the short term, results in longstanding abnormalities in the regulation of sleep, and breathing during sleep. In Aim 1, we will determine the long-term effects of methylxanthine administration on sleep/wake patterns. Specifically, we will use actigraphy, sleep diaries and questionnaires to measure sleep in ex-premature 5-6 year old children who received either caffeine or placebo during the neonatal period. We hypothesize that children who received caffeine will have decreased sleep time, and increased prevalence of difficulties falling asleep and staying asleep, compared to controls. In Aim 2, we will determine the long-term effects of methylxanthine administration on the prevalence of OSAS during childhood. Specifically, we will use ambulatory polysomnography to characterize breathing during sleep in ex-premature 5-6 year old children who received either caffeine or placebo during the neonatal period. We hypothesize that children who received caffeine will have an increased prevalence of OSAS. In Aim 3, we will determine the contribution of sleep disruption, OSAS and methylxanthine administration to neurocognitive and behavioral abnormalities in ex-premature children. Specifically, we will determine the relationship between sleep time, OSAS and neurobehavioral measures (being obtained through the parent study) in ex-premature 5-6 year old children who received either caffeine or placebo during the neonatal period. We hypothesize that sleep disruption and OSAS will contribute to neurocognitive and behavioral abnormalities. These studies will help determine the long-term consequences of neonatal methylxanthine therapy, ultimately resulting in improved management of apnea of prematurity. PUBLIC HEALTH RELEVANCE: Methylxanthines are used often in the neonatal intensive care unit to treat premature infants with apnea of prematurity. However, the long-term consequences of these drugs are unknown. This study will determine whether neonatal methylxanthine treatment results in long-term perturbations in sleep, breathing during sleep, and hence, neurocognitive and behavioral abnormalities.