Impact of Prolonged Perioperative Sedation on Infant Brain

摘要 长期镇静治疗目前被认为是安全和同情护理的标准做法， 危重新生儿和婴儿，尽管导致阿片类药物耐受和高发生率（35-57%）的身体 依赖一个独特的队列婴儿先天性长间隙食管闭锁（EA）经历了复杂的 围手术期重症监护需要非常长时间的镇静（以周为单位）。虽然我们的 一个研究小组最近报道，在长期间隔后， EA修复并延长术后镇静时间，我们对（i）基础知识存在根本性差距 机制和（ii）长期神经发育结果。 在强有力的初步数据的指导下，这项建议将解决我们知识中的3个关键空白：（1）大脑活动的时间 结果（术前与围手术期修复期间）;（2）（mal）适应的区域特异性（灰质与白色物质）; 以及（3）婴儿大脑和临床与1岁时的早期神经发育结果相关。的 研究将采用结构MRI技术来实现这些目标。选定的足月和早产儿 将扫描短间隙（短暂疼痛/镇静治疗）和长间隙EA（长期镇静治疗） 两次（AIM 1）：之前（新生儿）和复杂围手术期重症监护之后（4（±1）个月）。早期 将使用标准方法（AIM 2）评估神经发育结果。 这些发现将为（I）与延迟与异常大脑相关的大脑（异常）适应机制提供信息 婴儿暴露于长期镇静的发展;（二）确定早期诊断和预后指标， 纵向神经认知相关性;和（III）告知新生儿/婴儿治疗的未来发展，以减轻 易受伤害的婴儿长时间处于镇静状态对神经系统的影响。我们的应用程序符合目标 国家儿童健康和人类发展研究所（NICHD）和国家药物滥用研究所 （NIDA），以改善儿童在各个发展阶段的生活。我们建立了可行性 服务于关键数据收集，我们组建了一个跨学科的专家团队， 建成这项研究是创新的，因为它包括一组选定的足月出生的婴儿暴露于 与镇静药物依赖相关的长期镇静;新颖之处在于它将研究潜在的 复杂胸部非心脏重症监护的机制和神经发育影响; 它有望通过开发针对年龄特异性疼痛的新型辅助疗法来发展儿科重症监护， 在美国和世界上的镇静治疗。

ABSTRACT Prolonged sedation treatment is currently considered standard practice in the safe and compassionate care of critically ill neonates and infants despite leading to opioid tolerance and a high incidence (35-57%) of physical dependence. A unique cohort of infants with congenital long-gap esophageal atresia (EA) undergoes complex perioperative critical care necessitating extraordinarily prolonged sedation (on the scale of weeks). Although our group recently reported decreased brain size and delayed brain growth in term-born infants following long-gap EA repair with prolonged postoperative sedation, there is a fundamental gap in our knowledge of (i) underlying mechanisms and (ii) long-term neurodevelopmental outcomes. Guided by strong preliminary data, this proposal will address 3 key gaps in our knowledge: (1) timing of brain findings (pre vs. during perioperative repair); (2) regional specificity (gray vs. white matter) of (mal)adaptations; as well as (3) infant brain and clinical correlates to early neurodevelopmental outcomes at 1-year of age. The study will employ structural MRI techniques to address these aims. Selected term-born and premature infants with short-gap (brief pain/sedation treatment) and long-gap EA (prolonged sedation treatment) will be scanned twice (AIM 1): before (as neonates), and after complex perioperative critical care (at 4(±1) months of age). Early neurodevelopmental outcomes will be evaluated using standard approaches (AIM 2). The findings will inform (I) mechanisms of brain (mal)adaptations associated with delayed vs. abnormal brain development in infants exposed to prolonged sedation; (II) identify early diagnostic and prognostic indicators for longitudinal neurocognitive correlates; and (III) inform future development of neonatal/infant therapies to mitigate the neurological effects in vulnerable infants exposed to prolonged sedation. Our application aligns with the goals of the National Institute of Child Health and Human Development (NICHD) and National Institute of Drug Abuse (NIDA) to improve the lives of children throughout all stages of development. We established the feasibility serving critical data collection, and we assembled an interdisciplinary team of experts for its successful completion. This research is innovative in that it encompasses a selected group of term-born infants exposed to prolonged sedation associated with dependence to drugs of sedation; novel in that it will investigate underlying mechanisms and neurodevelopmental impact of complex thoracic non-cardiac critical care; and significant in that it is expected to evolve pediatric critical care by developing novel adjunct therapies for age-specific pain and sedation treatment in the United States and the world.