Impact of Prolonged Perioperative Sedation on Infant Brain

摘要 延长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病率(35-57%) 依赖。先天性长间隙食道闭锁(EA)婴儿中一个独特的队列经历复杂 围手术期需要非常长时间的镇静(数周)的危重护理。虽然我们的 该研究小组最近报道，在长时间间隔后，足月出生的婴儿大脑体积变小，大脑发育迟缓 EA修复术后长时间镇静，我们对(I)潜在的知识有一个根本的差距 机制和(Ii)长期神经发育结果。 在强大的初步数据的指导下，这项建议将解决我们知识中的三个关键差距：(1)大脑的时间 结果(术前与围手术期修复)；(2)(不良)适应的区域特异性(灰质与白质)； 以及(3)婴儿的大脑和临床与1岁时的早期神经发育结果相关。这个 这项研究将使用结构磁共振技术来解决这些目标。精选足月儿和早产儿 短间隙(短暂疼痛/镇静治疗)和长间隙EA(长期镇静治疗)将被扫描 两次(目标1)：出生前(作为新生儿)和复杂的围术期危重护理后(4(±1)个月)。早些时候 将使用标准方法评估神经发育结果(目标2)。 这些发现将揭示(I)大脑(不良)适应与延迟和异常大脑有关的机制。 长期镇静的婴儿的发育；(Ii)确定早期诊断和预后指标 纵向神经认知相关；和(Iii)为新生儿/婴儿治疗的未来发展提供信息，以减轻 长期镇静对易受伤害婴儿的神经影响。我们的应用程序与目标保持一致 国家儿童健康与人类发展研究所(NICHD)和国家药物滥用研究所 (NIDA)在发展的所有阶段改善儿童的生活。我们确定了可行性 服务于关键数据收集，我们组建了一个跨学科的专家团队，为其成功 完成了。这项研究是创新的，因为它包括了一组精选的足月出生的婴儿 与对镇静药物的依赖有关的长时间镇静；新奇的是它将调查潜在的 复杂的胸腔非心脏重症监护的机制和神经发育影响 它有望通过为特定年龄的疼痛和疾病开发新的辅助疗法来发展儿科重症护理 镇静治疗在美国和世界。

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.