Parenteral Methionine Requirements in Septic Children

描述（由申请人提供）：对于无法耐受肠内喂养的儿童，全肠外营养（TPN）可以挽救生命。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，其中许多患者需要延长TPN的使用。这些患者的发病率和死亡率较高。硫氨基酸蛋氨酸和半胱氨酸在危重疾病中很重要，因为蛋氨酸是肌酸、胆碱和DNA甲基化的甲基供体，也是半胱氨酸的前体，半胱氨酸是谷胱甘肽（GSH）合成中的限速氨基酸，是一种主要的抗氧化剂。重症脓毒症儿童的肠外硫氨基酸需求尚不清楚，但目前儿童服用的氨基酸配方中大量补充了蛋氨酸，缺乏或只提供少量的半胱氨酸。本应用将通过使用指示氨基酸氧化和平衡技术（IAAOB），确定在半胱氨酸存在的情况下，需要长期使用TPN的危重脓毒症患者蛋氨酸的肠外需氧量（目的1）。这是一种剂量反应技术。终点是蛋氨酸需要量，由肠外蛋氨酸摄入量与氧化率和指示氨基酸平衡之间的断点确定。我们假设，目前的肠外氨基酸配方缺乏或提供极少量的半胱氨酸，但大量补充蛋氨酸，提供的蛋氨酸大大超过了需求，肠外蛋氨酸的需求应该明确。饮食摄入推动新陈代谢。因此，在目标# 2中，我们将通过转甲基化、转硫化和再甲基化的速率来探索蛋氨酸的代谢，在目前的标准蛋氨酸摄入量为120 mg.kg.d，半胱氨酸可忽略不计，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肠外硫氨基酸摄入量下的转甲基化、再甲基化和转硫化率，GSH合成率和甲基可利用性（由腺苷-蛋氨酸/腺苷-同型半胱氨酸比率定义）。我们假设，在炎症条件下，需要平衡的硫氨基酸摄入，包括肠外蛋氨酸和半胱氨酸，以维持最佳的硫氨基酸代谢和功能。只供应蛋氨酸或有限数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。

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.