Glutamine supplementation and GH/IGF-I treatment in critically ill patients: effects on glutamine metabolism and protein balance

Abstract

Critical illness resulting from trauma, burns, major surgery, or sepsis is characterized by an increased catabolic rate, loss of lean body mass, immunosuppression, and compromised wound healing. Increased protein catabolism mobilizes amino acids for use by organs in the splanchnic area for gluconeogenesis, oxidation, and protein synthesis and for use as substrates for wound healing and the immune system.1 The wasting of lean body mass often persists despite nutrition support. Because maintenance of body protein stores may have an impact on morbidity and mortality, several strategies are currently being investigated to prevent the loss of lean tissue. These include the uses of specialized nutrition and anabolic hormones such as growth hormone (GH) and insulin-like growth factor-I (IGF-I). Glutamine is a major vehicle for nitrogen exchange between tissues and is the most abundant amino acid in plasma and the free intracellular amino acid pool in skeletal muscle.2 Most tissues can synthesize glutamine; thus it is defined as a non-essential amino acid and including glutamine was considered unnecessary in nutritional formulas. However, some tissues in the body have very high rates of glutamine uptake and metabolism, in particular rapidly dividing cells such as enterocytes and immunocytes.3 Free glutamine concentrations appear to be extremely labile and, despite the increased nutrient supply resulting from protein catabolism, marked decreases in glutamine have been reported in critical illness.4 Glutamine may now be considered a conditionally essential amino acid.5 Griffiths et al. found that glutamine supplementation of total parenteral nutrition (TPN) in critically ill patients can improve nitrogen balance and decrease the number of bacterial infections, length of hospital stay, and 6-mo mortality.6 The availability of recombinant human GH and IGF-I has led to considerable interest in their use, alone or in combination, to reduce protein catabolism in a variety of catabolic states. Treatment with GH has been shown to increase whole-body protein synthesis in GH-deficient adults in the fasted and postprandial states.7,8 GH treatment also has been shown to improve nitrogen balance, increase protein synthesis, and reduce leucine oxidation in parenterally fed catabolic patients.9,10 The demonstration that GH had protein anabolic effects led to two European multicenter trials being conducted in patients in intensive care units (ICUs). However, rather than improving mortality, as was expected, exogenous GH significantly increased mortality (42% versus 18%).11 In those trials, the patients did not receive routine glutamine supplementation. Because glutamine is mobilized from protein stores during periods of illness, an increase in protein anabolism may exacerbate the glutamine depletion seen in these patients and might have contributed to the increased mortality in these trials. IGF-I also has protein anabolic effects, and there is interest in the use of this hormone in the treatment of catabolic patients. In normal subjects, combined GH/IGF-I has been shown to have a synergistic effect on protein synthesis.12 Thus combined GH/IGF-I may have a greater effect on improving protein balance in critically ill patients. Combining GH treatment with IGF-I also may be a more appropriate treatment than GH alone because IGF-I can counteract the insulin resistance caused by GH. We used stable isotope tracer dilution techniques to gain a better understanding of the effects of glutamine supplementation on glutamine and protein metabolism. Because GH/IGF-I treatment may have adverse effects on glutamine metabolism, the effects of this treatment on glutamine and protein metabolism also were investigated.