Parenteral Methionine Requirements in Septic Children

描述（由申请人提供）：全肠外营养（TPN）是无法耐受肠内喂养的儿童的救命药物。很大一部分重症儿科ICU患者是患有急性脓毒症的慢性疾病的儿童，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。含硫氨基酸甲硫氨酸和半胱氨酸在危重疾病中很重要，因为甲硫氨酸作为肌酸、胆碱和DNA甲基化的甲基供体，以及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。目前尚不清楚重症脓毒症儿童的胃肠外含硫氨基酸需求，但目前儿童接受的氨基酸配方中大量补充了蛋氨酸，没有或提供最少量的半胱氨酸。本申请将通过使用指示氨基酸氧化和平衡技术（IAAOB），确定在存在半胱氨酸的情况下，需要长期使用TPN的重症脓毒症患者（目标1）对蛋氨酸的胃肠外需求。这是一种剂量反应技术。终点为蛋氨酸需求量，由胃肠外蛋氨酸摄入分级水平与氧化速率和指示氨基酸平衡之间的断点确定。我们假设，目前的胃肠外氨基酸配方缺乏或提供最少量的半胱氨酸，但大量补充蛋氨酸，提供蛋氨酸大大超过需求，并应确定胃肠外蛋氨酸的需求。饮食摄入推动新陈代谢。因此，在目标#2中，我们将通过甲硫氨酸的转甲基化、转硫化和再甲基化速率来探索甲硫氨酸代谢，当前甲硫氨酸标准摄入量为120 mg.kg.d，半胱氨酸量可忽略不计，由商业氨基酸配方提供，与目标#1中定义的含硫氨基酸摄入量相比。终点是在两种不同水平的胃肠外含硫氨基酸摄入量下的转甲基化、再甲基化和转硫作用的速率、GSH合成速率和甲基可用性（由腺苷甲硫氨酸/腺苷高半胱氨酸比率定义）。我们假设在炎症条件下，需要平衡的含硫氨基酸摄入，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。仅提供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量营养政策的变化，并在未来测试我们既定要求对临床相关结局的影响。

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.