Effect of Route of Nutritional Support on Metabolic and Inflammatory Outcomes in Sepsis

营养支持途径对脓毒症代谢和炎症结果的影响

• 批准号: 8983231
• 负责人: Faraaz Ali Shah
• 金额: $ 6.66万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8983231
• 关键词: Affect; Animal Model; Attenuated; Basic Science; Cannulas; Cessation of life; Clinical Research; Clinical Trials; Critical Care; Critical Illness; Dedications; Development; Diabetes Mellitus; Dietary Intervention; Endotoxemia; Enteral; Enteral Feeding; Enteral Nutrition; Functional disorder; Future; Gastric Inhibitory Polypeptide; Glucose; Human; Hyperglycemia; Hypersensitivity; Implant; Infection; Inflammation; Inflammatory; Inflammatory Response; Infusion procedures; Interleukin-6; Investigation; Kinetics; Knowledge; Laboratories; Life; Ligation; Lipopolysaccharides; Liquid substance; Lung; Maintenance; Master' s Degree; Mediating; Medicine; Mentors; Metabolic; Metabolism; Modeling; Morbidity - disease rate; Mus; Nutrition Therapy; Nutritional Support; Organ; Outcome; Parenteral Nutrition; Pathway interactions; Patients; Pharmaceutical Preparations; Physicians; Play; Population Heterogeneity; Process; Puncture procedure; Recovery; Relative Risks; Research; Research Personnel; Resources; Risk; Role; Route; Sampling; Scientist; Sepsis; Signal Transduction; Stomach; Supplementation; Testing; Time; Total Parenteral Nutrition; Training; Translational Research; Tumor Necrosis Factor-alpha; Work; analog; base; career; cytokine; experience; glucagon-like peptide; glucagon-like peptide 1; glucose metabolism; glycemic control; improved; in vivo; incretin hormone; insulin secretion; insulin sensitivity; intravenous glucose tolerance test; meetings; mortality; mouse model; nutrition; nutritional supplementation; parenteral administration; prevent; public health relevance; septic; targeted treatment; translational study

 DESCRIPTION (provided by applicant): Project Summary Sepsis is a life threatening illness characterized by an overwhelming inflammatory response to infection, and the development of hyperglycemia during sepsis is associated with increased organ dysfunction and mortality. The factors contributing to the development of hyperglycemia are not completely understood but recently our laboratory demonstrated that nutritional support, in the form of parenteral infusions of dextrose, can have important effects on metabolic outcomes in sepsis. We found that both septic insult and dextrose infusions were necessary for the development of metabolic dysfunction and hyperglycemia in mouse models of sepsis and that development of hyperglycemia was associated with increased inflammation and increased mortality. Our objective for this proposal is to understand how the route of delivery of nutritional support (enteral or parenteral) influences the development of metabolic dysfunction in sepsis. Critically ill patients receive enteral nutrition in the form of tube feeds, and although the use of total parenteral nutrition has declined, parenteral dextrose infusions remain common in maintenance fluids and as medication carriers. We hypothesize that enteral administration of dextrose during sepsis will be associated with improved metabolic and inflammatory outcomes compared to parenteral infusion. We will test this hypothesis with the following aims: (1) We will determine the effect of route of nutritional support on development of metabolic dysfunction and inflammation in murine endotoxemia with the use of the frequently sampled intravenous glucose tolerance test, and (2) We will determine the roles of the incretin hormones gastric inhibitory peptide and glucagon like peptide 1 in improving glycemic control during sepsis and how they differ based on route of nutritional support. Together these studies will provide the platform for future development of translational investigations targeting improvement in outcomes of critically ill patients. This proposal will allow the candidate, a physician scientist in-training, the opportunity to develop further as a translational scientist and bridge between animal models and human studies. The candidate has a recent background in clinical research and through lab experience and meetings with his mentors will be gaining experience in developing animal models to answer questions that are otherwise difficult to answer solely in human studies. Additionally, he will undertake Master's degree training in Clinical Research with a focus in Translational Science which will strengthen his background in both basic science and clinical research. His mentors, Drs. O'Donnell and McVerry have extensive resources and knowledge to allow him to develop as a translational scientist and he will be well-supported by the Division of Pulmonary, Allergy, and Critical Care Medicine, which has demonstrated strong commitment to his development as an independent clinician investigator.

 描述（由申请人提供）： 项目摘要 脓毒症是一种危及生命的疾病，其特征是对感染的强烈炎症反应，脓毒症期间高血糖的发生与器官功能障碍和死亡率增加有关。导致高血糖发生的因素尚不完全清楚，但最近我们的实验室证明，以肠外输注葡萄糖的形式提供营养支持，可以对脓毒症的代谢结果产生重要影响。我们发现，脓毒症小鼠模型中，脓毒症损伤和葡萄糖输注对于代谢功能障碍和高血糖的发生都是必要的，并且高血糖的发生与炎症增加和死亡率增加相关。我们此提案的目标是了解营养支持的输送途径（肠内或肠外）如何影响脓毒症代谢功能障碍的发展。危重患者以管饲的形式接受肠内营养，尽管全肠外营养的使用已经减少，但肠外葡萄糖输注在维持液和药物载体中仍然很常见。我们假设，与肠胃外输注相比，败血症期间肠内给予葡萄糖与改善代谢和炎症结果相关。我们将通过以下目标检验这一假设：（1）我们将使用频繁采样的静脉内葡萄糖耐量试验确定营养支持途径对小鼠内毒素血症代谢功能障碍和炎症发展的影响，以及（2）我们将确定肠促胰岛素激素抑胃肽和胰高血糖素样肽1在改善小鼠内毒素血症期间血糖控制中的作用 脓毒症以及它们如何根据营养支持途径而有所不同。这些研究将为未来发展旨在改善危重患者预后的转化研究提供平台。该提案将使候选人（一名正在接受培训的医师科学家）有机会进一步发展为转化科学家，并在动物模型和人类研究之间架起桥梁。候选人最近具有临床研究背景，通过实验室经验以及与导师的会面，将获得开发动物模型的经验，以回答仅在人类研究中难以回答的问题。此外，他还将接受临床研究硕士学位培训，重点是转化科学，这将加强他在基础科学和临床研究方面的背景。他的导师，博士。奥唐纳和麦克维里拥有丰富的资源和知识，使他能够发展成为一名转化科学家，他将得到肺科、过敏科和重症监护医学科的大力支持，该科对他作为一名独立临床研究者的发展表现出了坚定的承诺。