Parenteral Methionine Requirements in Septic Children

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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.