[[ International Symposium�F07 ]]

Anabolic Agents: Repleting Body Mass and Function Hideaki Saito, MD. Surgical Center, Department of Surgery, The University of Tokyo

Introduction Characteristic metabolic responses to trauma and sepsis are catabolism of whole body protein stores and negative nitrogen balance. Immuno-depression is also associated with trauma and sepsis. Nutritional therapy is an important aspect of managing patents with trauma and sepsis. However, conventional nutritional support, especially TPN, has not been particularly successful in reducing morbidity and mortality. This has prompted the search for new nutritional support strategies aimed at enhancing protein metabolism and immunity in critical illness. One of the options investigated is exogenous anabolic hormones. Growth hormone (GH) is a potent anabolic agent. Insulin-like growth factor I (IGF-1) mediates the anabolic effect of GH. Moreover, both GH and IGF-1 have immuno-stimulatory effects. This presentation focuses on the effects of these anabolic agents in repleting body mass and function in trauma and sepsis. Effects of anabolic agents on the repletion of body mass Several studies have demonstrated that the administration of GH improves nitrogen metabolism in traumatic states. Our clinical investigation of postcolectomy patients showed that GH treatment decreases urinary nitrogen excretion, improves nitrogen balance, and enhances wholebody protein turnover. Several studies, including ours, have demonstrated increased levels of IGF-1 and insulin, decreased urea production, reduced 3-methylhistidine excretion and enhanced fat oxidation with the administration of GH. However, available data are not sufficient to define dose-response relationships for the anabolic effect of GH in catabolic patients. We revealed postoperative GH treatment to be more efficacious in patients with greater surgical stress. In addition, at higher stress levels, a dose of 0.4 IU (0.132 mg)/kg/day of GH was apparently more efficient than 0.2 IU (0.066 mg)/kg/day in promoting nitrogen retention. Moreover, the effect of caloric intake on protein metabolism in trauma patients receiving GH is not well known. We observed that GH administration produced a better nitrogen balance, regardless of the caloric intake level, following surgery. However, a daily caloric intake of around 20 kcal achieved an optimally positive nitrogen balance. Thus, adequate caloric intake appears to be necessary for the anticatabolic effect of GH in trauma. The anabolic effects of GH in multiple injury, burn and sepsis are equivocal. Positive anabolic effects of GH have been reported in septic, burned and post-traumatic patients, while negative effects have also been demonstrated in such critical illness. The difference may be due to the severity of catabolism, the mode and quantity of GH administrations, and the intakes of calories and nitrogen. The different GH/IGF-1 axis in various surgical stresses may also contribute to GH efficacy. Few data are available concerning the effects of GH in MOF. A study revealed that GH may be ineffective in patients with MOF when the IGF-1 response to exogenous GH is blunted. IGF-1, mainly produced in the liver, mediates the anabolic effect of GH. Thus, liver dysfunction may lead to an attenuated response to exogenous GH. We demonstrated that exogenous GH failed to express IGF-1 mRNA in the cirrhotic rat liver. We observed that the preoperative plasma IGF-1 level correlated inversely with the ICG retention rate in patients with cirrhosis. Moreover, postoperative plasma IGF-1 and IGFBP-3 levels were severely depressed despite increased GH in cirrhosis. In addition, our study showed that only exogenous IGF-1, not GH, improved whole-body protein turnover after gastrectomy in rats with chronic mild liver injury. Experiments in animal trauma models have shown that exogenous IGF-1 attenuates catabolism. However, a clinical trial from Germany did not confirm the anabolic actions of IGF-1. The mechanism(s) of failure to improve nitrogen metabolism by postoperative IGF-1 treatment in this study appear to be complex, and may include suppression of GH and endogenous IGF-1 secretion, accelerated IGF-1 metabolism, direct antagonism of free IGF-1 by IGFBP-1, and administration of an inadequate IGF-1 dosage. Combined GH and IGF-1 treatment is a potential option for overcoming the weak anabolic effects of IGF-1 in critical illness. Further knowledge of the interaction between the GH/IGF-1 axis in critical illness is essential for GH and IGF-1 therapy. Effects of anabolic agents on body function Theoretically, the improved nitrogen metabolism achieved with exogenous anabolic agents may provide functional benefits. However, only a few studies have confirmed the beneficial effects of GH on body function in trauma and sepsis. GH treatment reportedly decreases the postoperative depression of hand grip strength. Use of GH in a critical care unit also improved respiratory muscle strength. By contrast, GH did not improved ventilator weaning in ICU patients. GH is potentially beneficial for patients with renal failure, based on reduced urea production and maintenance of intracellular potassium levels. It has been reported that GH may stimulate wound healing in rats. Accelerated wound healing with exogenous GH in pediatric and adult burn patients has also been demonstrated. Exogenous IGF-1 reduces gut mucosal atrophy in trauma. However, GH administration failed to prevent mucosal atrophy, despite the increased plasma IGF-I level induced by GH, in our gastrectomized rats. Prevention of gut atrophy by IGF-1 is important because mucosal atrophy is a serious disadvantage of TPN that may result in bacterial translocation. Several recent studies have revealed the roles of these anabolic hormones in regulating the immune system. Both GH and IGF-1 exert their effects on lymphoid cells. Exogenous GH and IGF-I increased spleen weight. Our investigation demonstrated that the delayed hypersensitivity response in gastrectomized rats was enhanced by GH. Furthermore, we observed that GH augmented T-cell proliferation and natural killer cell activity in patients undergoing surgery. In addition, IGF-1 reportedly increased the CD4/CD8 ratio following severe head injury. Both GH and IGF-1 are powerful modulators of the effector function of phagocytic cells. These hormones augment granulocyte differentiation, chemotaxis, and phagocytosis. GH and IGF-I also prime phagocytes and macrophages for the production of cytokines and superoxide. We demonstrated that pretreatment with GH or IGF-1 increased the survival rate in a murine E. coli peritonitis model. Local production of cytokines was enhanced by GH. Moreover, in vitro investigation has revealed that both GH and IGF-I directly enhance the E. coli killing activity of peritoneal exudative cells. In human studies, we observed that GH and IGF-I enhanced PMN phagocytosis in healthy human volunteers as well as patients undergoing surgery. Furthermore, IGF-I increased monocyte HLA-DR expression after major surgery. It is noteworthy that GH pretreatment inhibited spontaneous apoptotic PMN cell death. GH also inhibited both necrotic and apoptotic cell death after E. coli coculture. Thus, these anabolic agents are potentially beneficial for the prevention, as well as treatment, of severe sepsis. Conclusion GH and IGF-1 have anabolic as well as immuno-stimulatory effects. The benefits of GH and IGF-1 should be determined in randomized clinical trials involving critically ill patients in the near future.