Efficacy of enteral glutamine in reducing bloodstream infections in SBS infants

描述(申请人提供)：短肠综合征(SBS)后大规模肠切除后的各种情况，特别是坏死性肠结肠炎(NEC)，是一种毁灭性的并发症，影响新生儿，特别是那些交付和36周孕周。这些儿童特别容易患上反复的血流感染(BSI)、反复住院以及随后的生长不良。所有这些都给初级照顾者和卫生保健系统造成了非常沉重的负担。在这些儿童中，与复发的BSI相关的微生物主要与肠道有关。然而，对于这些儿童的肠道微生物生态，以及它是否在BSI、肠道喂养和最终生长中起作用，仍然缺乏了解。在成人SBS患者中，补充谷氨酰胺(Gln)可以减少粘膜损伤，降低BSI和相关脓毒症的发生率，并改善正氮平衡。在儿童中，目前没有足够的数据来确定肠内补充谷氨酰胺是否改善了胃肠道切除导致SBS的婴幼儿的临床结果。这项先导性临床研究的总体目的是在一项严格的双盲探索性临床试验的背景下，获得所需的初步数据，以了解肠内补充Gln对NEC引起的SBS患儿的疗效：具体目标1：对NEC所致的肠内依赖SBS儿童进行为期6个月的双盲、随机、安慰剂对照的GLN(0.6g/kg)与等热量、等氮丙氨酸(安慰剂)治疗的初步研究，以评估GLN降低BSI(主要终点)和血清中肿瘤坏死因子、白介素1-2的系列浓度的效果。IL-6和IL-8(次要终点)。具体目的2：评价应用谷氨酰胺治疗6个月对目标1受试者体长、体重、头围等生长参数的影响，以及BSI对这些生长参数的影响。具体目标3：全面评估目标1 SBS患者与年龄匹配的非SBS对照受试者(主要终点)的肠腔微生物群(使用最先进的分子方法)，将肠腔内存在的主要细菌动态与特定微生物引起的BSI相关联，并探索肠道内Gln治疗是否改变了肠腔微生物群。这项建议将促进来自埃默里大学、密歇根大学和科罗拉多大学博尔德分校的多中心、多学科团队的发展，以评估减少BSI和改善生长的新方法，并深入了解SBS儿童的肠道微生物生态。 与公共卫生相关：短肠综合征(SBS)是一种破坏性的临床问题，影响着大约30,000名美国人，他们受到其并发症和高昂的护理费用的困扰。目前的治疗策略在预防SBS并发症或改善预后方面效果不佳。这项拟议的试验将评估谷氨酰胺补充作为一种新的营养策略来改善儿童SBS的临床结果，并为SBS患者的肠道微生物生态提供洞察力。

DESCRIPTION (provided by applicant): Short bowel syndrome (SBS) following massive bowel resection for various conditions, especially necrotizing entercolitis (NEC), is a devastating complication that affects neonates especially those delivered < 36 weeks gestational age. These children are especially susceptible to recurrent blood stream infections (BSI), repeated hospital admissions and subsequent poor growth. All of these contribute to a very high burden on the primary caretakers and the health care system. Organisms associated with recurrent BSI in these children are predominantly gut related. However, there is still a lack of understanding of the intestinal microbial ecology of these children and whether it has a role in BSI, enteral feeds and ultimately growth. Glutamine (GLN) supplementation has been shown in adults with SBS to decrease mucosal damage, lower rates of BSI and associated sepsis and improve positive nitrogen balance. In children, there is currently insufficient data to determine whether enteral GLN supplementation improves clinical outcomes in young infants with significant gastrointestinal resection leading to SBS. The overall purpose of this pilot clinical study is to obtain needed preliminary data on the efficacy of enteral GLN supplementation in children with SBS as a result of significant intestinal resection due to NEC in the context of a rigorous, double-blind exploratory clinical trial with the following specific aims: Specific Aim 1: To perform a double-blind, randomized, placebo controlled, 6-months pilot study of enteral GLN (0.6g/kg) vs. isocaloric, isonitrogenous alanine (placebo) treatment in PN-dependent SBS children due to NEC to evaluate the efficacy of GLN to decrease BSI (primary endpoint) and serial serum concentrations of TNF- , IL1- 2, IL-6 and IL-8 (secondary endpoint). Specific Aim 2: To assess the efficacy of 6 months of therapy with enteral GLN on somatic growth parameters [length velocity (primary endpoint), weight velocity and head circumference] in Aim 1 subjects and the impact of BSI on these growth parameters. Specific Aim 3: To comprehensively assess the gut lumenal microbiome (using state-of-the art molecular methods) in Aim 1 SBS patients versus non-SBS, age-matched control subjects (primary endpoint), to correlate major bacterial dynamics present in the lumen with BSI due to specific microbes and to explore whether the gut lumenal microbiome is altered by enteral GLN treatment. This proposal will facilitate the development of a multicenter, multidisciplinary team from Emory University, University of Michigan and University of Colorado at Boulder to assess new methods for decreasing BSI and improving growth as well as to gain insights into the intestinal microbial ecology of SBS children. PUBLIC HEALTH RELEVANCE: Short bowel syndrome (SBS) is a devastating clinical problem affecting approximately 30,000 Americans who suffer from its complications and high cost of care. Current management strategies are not effective in preventing the complications or improving outcomes in SBS. This proposed trial will assess glutamine supplementation as a novel nutrient strategy to improve clinical outcomes in pediatric SBS and provide insight into the intestinal microbial ecology of SBS patients.