Depletion of Plasma Antioxidants in Surgical Intensive Care Unit Patients Requiring Parenteral Feeding: Effects of Parenteral Nutrition With or Without Alanyl-Glutamine Dipeptide Supplementation

Critically ill surgical patients requiring prolonged stays in surgical intensive care units (SICU) are at high risk for the development of nosocomial infection, sepsis syndrome, multiple organ failure, and related systemic inflammatory responses [1–2]. These individuals are typically extremely catabolic and exhibit compromised immune function, factors which are intimately linked to complex interactions of antioxidants, thiol-disulfide redox regulation and zinc homeostasis. Oxidative stress is common in critical illness as a result of the generation of oxygen- and nitrogen-derived free radicals and disruption of redox signaling and antioxidant control systems, including the decline in key antioxidant compounds [1–5]. The consequences of oxidative stress include protein oxidation, lipid peroxidation and DNA damage, which may contribute to cellular and organ dysfunction in SICU patients [2]. Enteral tube feedings and parenteral nutrition (PN) support is routinely provided to prevent micronutrient depletion, attenuate body protein catabolism and improve immune responses in this clinical setting. Vitamin C, vitamin E (α-tocopherol) and glutathione (GSH) the major low-molecular weight intracellular thiol antioxidant, are major mediators of host defense as direct free radical scavengers [3, 6]. GSH is inter-related with the major antioxidant nutrients vitamin C and α-tocopherol as it maintains these nutrients in their reduced (functional) state [7]. Low plasma concentrations of vitamin C and α-tocopherol and whole blood GSH have been variously reported in catabolic and critically ill patients [1–2, 6] and supplementation of these have been suggested to maintain redox homeostasis in critical illness [6]. We previously reported low plasma GSH in catabolic patients following high dose chemo-radiotherapy for bone marrow transplantation [7]. Low circulating antioxidant levels during severe illness likely reflects increased utilization coupled with inadequate exogenous provision (via diet or nutritional support) relative to needs. In the case of the GSH, a possible decline in precursor amino acids (cysteine, glycine and glutamate) for synthesis of this tripeptide may occur. Plasma GSH is largely derived from the liver and skeletal muscle which releases GSH in proportion to tissue concentrations [4, 8]. Thus, plasma GSH levels may reflect systemic oxidative stress [9]. Zinc is also important in the antioxidant defense system as a component in enzymes involved in free radical detoxification [10, 11] and in stabilization of thiol pools [12]. Previous studies have shown that zinc depletion is associated with increased oxidative stress in trauma patients [13]. In some studies, supplementation of zinc attenuated indices of oxidative stress, improved immune function and/or attenuated cytokine production [9, 14]. Thus, maintenance of optimal redox status and host defenses in catabolic conditions is interrelated with vitamin C, α-tocopherol and zinc nutriture and the levels of GSH and other antioxidants [1,4,6]. Unfortunately, the effects of conventional PN as a method to improve antioxidant nutrient levels in critically ill patients unable to be adequately fed by the enteral route have been little studied. Limited available data suggests that conventional PN does not maintain vitamin E and GSH redox status in catabolic patients undergoing bone marrow transplantation or after operation [7, 15], but it is unknown whether current levels of supplementation are adequate to maintain GSH and other antioxidants in the SICU setting [15]. Gln may be a conditionally essential amino acid during critical illness when its utilization exceeds endogenous production [16]. Gln is a precursor for GSH synthesis (possibly via glutamate), and parenteral Gln supplementation restores plasma and tissue GSH status in catabolic animal models, where it is also associated with increased resistance to infection [16–18]. The current study was designed to test the hypothesis that Gln-supplemented PN would improve plasma GSH concentrations and concomitantly increase key plasma antioxidant nutrient concentrations in critically ill SICU patients. We also sought to determine the effects of PN providing conventional doses of vitamins and minerals on these indices. Our specific aims were to determine: 1) whether key plasma antioxidant levels are low in PN-requiring SICU patients; 2) whether conventional PN improves these values from baseline over a 7-day period; and 3) whether alanyl-Gln dipeptide supplementation further upregulates plasma GSH, vitamin C, α-tocopherol and zinc levels in this clinical setting.