Efficacy and Mechanisms of GLN Dipeptide in the SICU

相对谷氨酰胺(Gln)缺乏可能导致外科重症监护中的发病率和死亡率 病房(SICU)的病人。在危重疾病期间，免疫系统、肠道粘膜和其他组织对谷氨酰胺的利用 ：问题超过内源性生产，血浆谷氨酰胺浓度下降，这可能有助于 细胞功能障碍，增加医院感染风险和死亡率。常规不含谷氨酰胺的肠外营养 营养(PN)对SICU预后的影响有限，并且不能修复谷氨酰胺缺乏。我们最新的试飞 数据显示，添加谷氨酰胺二肽的PN减少了医院感染，改善了临床 SICU患者的预后。受益的过程人们知之甚少，但动物和人类的数据 提示谷氨酰胺治疗与血液和组织中细胞保护分子的上调有关。 [例如，谷胱甘肽、特异性热休克蛋白(HSPs)和谷氨酰胺]；以及b)改善上皮屏障防御和 免疫细胞的数量和功能。L-谷氨酰胺的性质限制了溶液中的供应，但谷氨酰胺二肽 丙氨酰-谷氨酰胺(AG)在PN(AG-PN)中具有稳定性和溶解性。我们提出了一个多中心、双盲、 根据我们的飞行员数据进行的随机对照第三阶段试验，以检验AG-PN改善的假设 心脏、血管或结肠手术后需要肠外营养的SICU患者的临床结果。研究对象将 接受标准的不含谷氨酰胺的PN或等热量、等氮的AG-PN，直到建立肠内饲料。 具体目标1是确定AG-PN是否可以降低住院死亡率、医院感染和其他 重要的发病率指标。具体目标2是获得新的、机械上相关的观测数据 目的1)研究AG-PNa)是否升高血中GSH、HSP-70、-27和Gln的水平； B)减少血清中细菌产物鞭毛蛋白和脂多糖的存在以及适应性免疫 对这些介质的反应；以及c)改善先天/获得性免疫的关键指标。这项研究是 旨在描述一种主要的新营养支持策略在高危SICU患者中的临床益处。

Relative glutamine (GLN) deficiency may contribute to morbidity and mortality in surgical intensive care unit (SICU) patients. During critical illness, GLN utilization by the immune system, gut mucosa and other :issues exceeds endogenous production and plasma GLN concentrations decrease, which may contribute to cellular dysfunction and increase nosocomial infection risk and mortality. Conventional GLN-free parenteral nutrition (PN)has a limited impact on SICU outcomes and does not repair the GLN deficit. Our recent pilot data show that GLN dipeptide-supplemented PN decreases nosocomial infections and improves clinical outcomes in SICU patients. The process of benefit is poorly understood, but animal and human data suggest that GLN treatment correlates with a) up-regulation of cytoprotective molecules in blood and tissues [e.g, GSH, specific heat shock proteins (HSPs) and GLN]; and b) improved epithelial barrier defenses and immune cell number and function. Properties of L-GLN limit provision in solution, but the GLN dipeptide alanyl-GLN (AG) confers stability and solubility in PN (AG-PN). We propose a multicenter, double-blind, randomized, controlled phase III trial based on our pilot data to test the hypothesis that AG-PN improves clinical outcomes in SICU patients requiring PN after cardiac, vascular or colonic operations. Subjects will receive either standard GLN-free PN or isocaloric, isonitrogenous, AG-PN until enteral feeds are established. Specific Aim 1 is to determine whether AG-PN decreases hospital mortality, nosocomial infection and other important indices of morbidity. Specific Aim 2 is to obtain novel, mechanistically relevant observational data in the Aim 1 subjects on whether AG-PN a) increases serial blood levels of GSH, HSP-70 and -27, and GLN; b) decreases the presence in serum of the bacterial products flagellin and LPS and the adaptive immune response to these mediators; and c) improves key indices of innate/adaptive immunity. This study is designed to delineate the clinical benefit of a major new nutrition support strategy in high-risk SICU patients.