Parenteral Methionine Requirements in Septic Children

脓毒症儿童的肠外蛋氨酸需求

• 批准号: 8274581
• 负责人: Leticia Castillo
• 金额: $ 34.56万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8274581
• 关键词: Acute; Age; Amino Acids; Antioxidants; Betaine; Cerebral Edema; Child; Childhood; Cholestasis; Choline; Chronic; Clinical; Clinical Research; Creatine; Critical Illness; Cysteine; DNA Methylation; Data; Dietary Intervention; Dietary intake; Dose; Enteral; Enteral Feeding; Equilibrium; Essential Amino Acids; Event; Figs - dietary; Folate; Future; Glutathione; Hepatic; Homocysteine; Homocystine; Human; Inflammation; Inflammatory; Intake; Life; Metabolism; Methionine; Methionine Metabolism Pathway; Morbidity - disease rate; Non-Essential Amino Acid; Nutritional; Nutritional Requirements; Nutritional Support; Outcome; Oxidation-Reduction; Parenteral Nutrition; Pathway interactions; Patients; Pediatric Intensive Care Units; Policies; Polyamines; Process; Production; Protein Biosynthesis; Proteins; Publishing; Reaction; Recommendation; Role; Seizures; Sepsis; Signal Transduction; Skeletal Muscle; Sulfur; Sulfur Amino Acids; Techniques; Testing; Total Parenteral Nutrition; Toxic effect; Transduction Gene; base; clinically relevant; cysteinylglycine; evidence base; functional outcomes; high risk; methyl group; mortality; oxidation; response; septic; sound; transmethylation

DESCRIPTION (provided by applicant): Total Parenteral nutrition (TPN) is life-saving for children unable to tolerate enteral feedings. A large proportion of critically ill pediatric ICU patients are children with chronic conditions suffering from an acute episode of sepsis, many of these patients require extended use of TPN. Morbidity and mortality is higher in these patients. The sulfur amino acids methionine and cysteine are important in critical illness due to methionine role as a methyl group donor for creatine, choline and DNA methylation, and as the precursor of cysteine, the rate limiting amino acid in glutathione (GSH) synthesis, which is a major antioxidant. Parenteral sulfur amino acid requirements in critically ill septic children are not known, but currently children receive amino acid formulas greatly supplemented with methionine and devoid or supplying minimal amount of cysteine. This application will determine the parenteral requirements of methionine, in the presence of cysteine, in critically ill septic patients requiring extended use of TPN (aim # 1), by using the indicator amino acid oxidation and balance technique (IAAOB). This is a dose-response technique. The endpoint is methionine requirement as determined by the breakpoint between graded levels of parenteral methionine intake and the rates of oxidation and balance of an indicator amino acid. We hypothesize that the current parenteral amino acid formulas devoid or providing minimal amounts of cysteine, but largely supplemented with methionine, provide methionine largely in excess of requirements, and that parenteral methionine requirements should be defined. Dietary intake drives metabolism. Hence in aim # 2 we will explore methionine metabolism through the rates of transmethylation, transsulfuration and remethylation at the current standard intakes of methionine of 120 mg.kg.d with negligible amounts of cysteine, provided by commercial amino acid formulas, versus the sulfur amino acid intake defined in aim # 1. The endpoint is the rates of transmethylation, remethylation and transsulfuration at the two different levels of parenteral sulfur amino acid intakes, GSH synthesis rates and methyl group availability defined by the adenosyl- methionine/adenosyl-homocysteine ratio. We hypothesize that under conditions of inflammation a balanced sulfur amino acid intake, involving parenteral methionine and cysteine, is required to maintain optimal sulfur amino acid metabolism and function. Exclusive supply of methionine or a limited amount of cysteine will fail to support sulfur amino acid function. In summary, our overall objective is to generate data to support changes on nutritional policy on parenteral sulfur amino acid intakes, and in the future test the impact of our established requirements on clinically relevant outcomes.

描述（由申请人提供）：全肠外营养 (TPN) 对于无法耐受肠内喂养的儿童来说可以挽救生命。 ICU 重症儿科患者中很大一部分是患有脓毒症急性发作的慢性病儿童，其中许多患者需要长期使用 TPN。这些患者的发病率和死亡率较高。含硫氨基酸蛋氨酸和半胱氨酸在危重疾病中非常重要，因为蛋氨酸作为肌酸、胆碱和 DNA 甲基化的甲基供体，并且作为半胱氨酸的前体，半胱氨酸是谷胱甘肽 (GSH) 合成中的限速氨基酸，谷胱甘肽是一种主要的抗氧化剂。危重脓毒症儿童的胃肠外含硫氨基酸需求量尚不清楚，但目前儿童接受的氨基酸配方奶粉大量补充了蛋氨酸，但不含或仅提供极少量的半胱氨酸。该应用将通过使用指示剂氨基酸氧化和平衡技术 (IAAOB) 来确定需要延长使用 TPN 的危重脓毒症患者（目标 #1）在存在半胱氨酸的情况下对蛋氨酸的胃肠外需求。这是一种剂量反应技术。终点是蛋氨酸需求，由胃肠外蛋氨酸摄入分级水平与指示氨基酸的氧化和平衡速率之间的断点确定。我们假设当前的肠胃外氨基酸配方缺乏或提供极少量的半胱氨酸，但大量补充了蛋氨酸，提供的蛋氨酸大大超过了需要量，并且应该确定肠外蛋氨酸的需要量。饮食摄入促进新陈代谢。因此，在目标 # 2 中，我们将通过商业氨基酸配方提供的 120 mg.kg.d 蛋氨酸（含可忽略量的半胱氨酸）的当前标准摄入量与目标 # 1 中定义的含硫氨基酸摄入量相比，通过转甲基、转硫和再甲基化的速率来探索蛋氨酸代谢。终点是转甲基、再甲基化和再甲基化的速率。 两种不同水平的肠外含硫氨基酸摄入量、GSH 合成率和甲基可用性（由腺苷甲硫氨酸/腺苷高半胱氨酸比率定义）的转硫作用。我们假设在炎症条件下，需要平衡的含硫氨基酸摄入量，包括肠外蛋氨酸和半胱氨酸，以维持最佳的含硫氨基酸代谢和功能。单独供应蛋氨酸或有限量的半胱氨酸将无法支持含硫氨基酸的功能。总之，我们的总体目标是生成数据以支持肠外含硫氨基酸摄入营养政策的变化，并在未来测试我们既定要求对临床相关结果的影响。