Precision Medicine for Nutrition in EDEN

项目摘要 营养是急性呼吸窘迫综合征危重患者护理的重要组成部分 （ARDS），他们经常限制自愿摄入，并继发于 他们的病尽管营养不足和不良结果之间存在明显的关联， 特定营养策略的大型多中心试验未能一致地证明临床益处 任何特定的方法。具有里程碑意义的NHLBI资助的早期与延迟肠内营养[EDEN]试验 在1000名患者中研究了低水平（营养）与全肠道喂养， 胃肠道并发症，全肠内喂养，没有任何临床益处。随后，目前 指南建议所有ARDS患者低水平喂养，然而，ARDS越来越被认为是一种 异质性疾病和一刀切方法可能并不合适。必不可少的第一步 ARDS患者的个体化营养是确定导致异质性的临床和生物学变量 指个体或群体对治疗的反应不同的治疗效果。因此，这一总体目标 一项建议是通过利用数据和生物标本来描述对营养的不同反应， 伊甸园审判。在目标1中，该提案将调查低浓度的ARDS亚表型是否存在差异。 EDEN中的水平与完全肠内营养。最近的研究已经确定了两种不同的ARDS亚型 在预后、宿主反应和对治疗的潜在反应方面不同。ARDS亚型有 在营养方面还没有研究过。因此，目标1将进行生物测定以促进ARDS 亚表型鉴定，并将测试临床结果中亚表型的差异，在肠 渗透性和肠促胰岛素激素。当响应肠内营养素以生理水平释放时， 肠促胰岛素对胰岛素释放和葡萄糖代谢具有有益的作用，但是当在 肠促胰岛素在肠道炎症反应中的超生理水平，可能通过以下方式恶化对营养的耐受性： 降低胃蠕动。肠促胰岛素在ARDS中没有很好的特征。在目标2中，本提案将使用 基于患者协变量直接对个体治疗效果建模的计算方法， 对于由基线人口统计学之间的复杂相互作用引起的治疗反应的研究， 疾病的严重程度、内分泌激素和炎症。成功完成 提出的目标将提供关于营养战略的生物反应的新知识， 在个体水平上导致治疗效果异质性的机制，并为 下一代的ARDS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.