Precision Medicine for Nutrition in EDEN

项目摘要 营养是护理急性呼吸窘迫综合征危重病人的重要组成部分 (ARDS)通常意志力摄入受限，继发于以下疾病的新的身体功能缺陷 他们的病。尽管营养不足和不良后果之间的关系有很好的特点， 特定营养策略的大型多中心试验未能始终如一地证明临床益处 使用任何特定的方法。具有里程碑意义的NHLBI资助的早期肠内营养与延迟肠内营养[伊甸园]试验 对1000名患者进行了低水平(营养性)与全肠道喂养的对比调查，结果显示 完全肠内喂养的胃肠道并发症，没有任何临床益处。随后，当前 指南建议对所有ARDS患者进行低水平喂养，然而，ARDS越来越被认为是一种 异质疾病和一刀切的方法可能并不合适。关键的第一步 ARDS的个体化营养是确定导致异质性的临床和生物学变量 个人或群体对治疗的反应不同的治疗效果。因此，这一计划的总体目标是 建议是通过利用数据和来自 伊甸园审判。在目标1中，这项建议将调查ARDS亚型是否因低-低反应而不同 伊甸园的肠内营养水平与完全肠内营养。最近的研究发现了两种不同的ARDS亚型 在预后、宿主反应以及潜在的治疗反应方面存在差异。ARDS亚型有 没有在营养方面进行调查。因此，目标1号将进行生物检测，以促进ARDS 亚表型鉴定，并将在肠道中测试不同亚型在临床结果中的差异 渗透性，以及胰岛素激素。当在生理水平上对肠道营养做出反应时， 胰岛素对胰岛素的释放和葡萄糖代谢有有益的影响，但在 超生理水平在对肠道炎症的反应中，胰岛素可能通过以下方式恶化营养耐受性 降低胃动力。胰岛素在急性呼吸窘迫综合征中的特征不是很好。在目标2中，该提案将使用 基于患者协变量允许的直接模拟个体治疗效果的计算方法 对于基线人口统计之间的复杂交互作用导致的治疗反应的调查， 疾病的严重程度、内分泌激素和单个患者水平的炎症。成功完成 将提供有关营养策略的生物反应的新知识，确定 在个体水平上促进治疗效果异质性的机制，并为 ARDS的下一代精确营养研究。

PROJECT ABSTRACT Nutrition is an essential component in the care of critically ill patients with acute respiratory distress syndrome (ARDS) who are often limited in volitional intake and who incur new deficits in physical function secondary to their illness. Despite well-characterized associations between inadequate nutrition and adverse outcomes, large multicenter trials of specific nutrition strategies have failed to consistently demonstrate clinical benefit with any particular approach. The landmark NHLBI-funded Early versus Delayed Enteral Nutrition [EDEN] trial investigated low-level (trophic) versus full enteral feeds in 1000 patients and demonstrated increased gastrointestinal complications with full enteral feeds without any clinical benefit. Subsequently, current guidelines recommend low-level feeds for all ARDS patients, however, ARDS is increasingly recognized as a heterogeneous disease and a one-size-fits-all approach may not be appropriate. An essential first step in individualizing nutrition in ARDS is identifying the clinical and biologic variables that contribute to heterogeneity of treatment effect whereby individuals or groups vary in response to treatment. Thus, the overall goal of this proposal is to characterize differential responses to nutrition by leveraging data and biospecimens from the EDEN trial. In Aim 1, this proposal will investigate whether ARDS subphenotypes differed in response to low- level versus full enteral nutrition in EDEN. Recent studies have identified two distinct ARDS subphenotypes that differ in prognosis, host response, and potentially in response to treatments. ARDS subphenotypes have not been investigated with regards to nutrition. Thus, Aim 1 will perform biologic assays to facilitate ARDS subphenotype identification and will test for differences by subphenotype in clinical outcomes, in intestinal permeability, and in incretin hormones. When released at physiologic levels in response to enteral nutrients, incretins have beneficial effects on insulin release and glucose metabolism, but when released at supraphysiologic levels in response to intestinal inflammation, incretins may worsen tolerance to nutrition by reducing gastric motility. Incretins are not well characterized in ARDS. In Aim 2, this proposal will use computational approaches that directly model individual treatment effects based on patient covariates allowing for investigations of treatment response that result from a complex interaction between baseline demographics, severity of illness, endocrine hormones, and inflammation at an individual patient level. Successful completion of the proposed Aims will provide new knowledge on biologic responses to nutrition strategies, identify mechanisms that contribute to heterogeneity of treatment effect at an individual level, and provide direction for the next generation of precision nutrition studies in ARDS.