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的发病率和死亡率 单位（SICU）患者。在危重病期间，免疫系统、肠粘膜和其他组织对GLN的利用， ：问题超过内源性生产和血浆GLN浓度下降，这可能有助于 细胞功能障碍并增加医院感染风险和死亡率。传统不含GLN的胃肠外 营养（PN）对SICU结果的影响有限，不能修复GLN缺陷。我们最近的飞行员 数据显示，补充GLN二肽的PN减少了医院感染并改善了临床症状。 SICU患者的结局。受益的过程知之甚少，但动物和人类数据 表明GLN治疗与a）血液和组织中细胞保护分子上调相关 [e.g GSH、特异性热休克蛋白（HSP）和GLN];和B）改善上皮屏障防御， 免疫细胞数量和功能。L-GLN的性质限制了在溶液中的提供，但GLN二肽 丙氨酰-GLN（AG）赋予PN（AG-PN）中的稳定性和溶解性。我们提出了一个多中心，双盲， 基于我们的初步数据的随机对照III期试验，以检验AG-PN改善 心脏、血管或结肠手术后需要PN的SICU患者的临床结局。受试者将 接受标准的不含GLN的PN或等热量、等氮的AG-PN，直至建立肠内营养。 具体目标1是确定AG-PN是否降低医院死亡率、医院感染和其他并发症。 发病率的重要指标。具体目标2是获得新的、机制相关的观察数据 在目标1受试者中，AG-PN是否a）增加GSH、HSP-70和HSP-27以及GLN的系列血液水平; B）减少血清中细菌产物鞭毛蛋白和LPS的存在， 对这些介质的反应;和c）改善先天/适应性免疫的关键指标。本研究 旨在描述一种主要的新营养支持策略在高危SICU患者中的临床获益。

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.