- Email: [email protected]
Anabolic agents in trauma and sepsis: repleting body mass and function
SYMPOSIUM PROCEEDINGS
Nutrition Vol. 14, No. 6, 1998
Anabolic Agents in Trauma and Sepsis: Repleting Body Mass and Function HIDEAKI SAITO, MD From the Surgical Center, Department of Surgery, The University of Tokyo, Tokyo, Japan ABSTRACT
Both growth hormone (GH) and insulin-like growth factor 1 (IGF-1) are potent anabolic agents. Exogenous GH improves nitrogen metabolism in patients undergoing surgery; however, the anabolic effects of GH in cases of multiple injury, burn, and sepsis are equivocal. Moreover, few data are available concerning the effects of GH in organ failures. Exogenous IGF-1 attenuates catabolism in animal trauma models. A clinical trial, however, did not confirm the anabolic actions of IGF-1. Further knowledge of the interaction between the GH/IGF-1 axis in critical illness is essential for GH and IGF-1 therapy. 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 decreases the postoperative depression of hand grip strength. GH also stimulates wound healing. Both GH and IGF-1 exert their effects on immune system, suggesting that these anabolic agents are potentially beneficial for the prevention and treatment of sepsis. On the contrary, inhibition of polymorphonuclear neutrophil apoptosis and the potentiation of PMNs by GH may have harmful effects on the systemic responses. Further studies are required to determine the safety and clinical benefits of GH administration in critical illness. Nutrition 1998;14:554 –556. ©Elsevier Science Inc. 1998 Key words: growth hormone, insulin-like growth factor 1, anabolism, immunostimulation
INTRODUCTION
Characteristic metabolic responses to trauma and sepsis are catabolism of whole-body protein stores and negative nitrogen balance. Immunodepression is also associated with trauma and sepsis. Nutritional therapy is an important aspect of managing patients with trauma and sepsis. However, conventional nutritional support, especially total parenteral nutrition (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 those patients. One of the options investigated is exogenous anabolic hormones. Growth hormone (GH) is a potent anabolic agent. Insulin-like growth factor 1 (IGF-1) mediates the anabolic effect of GH. Moreover, both GH and IGF-1 have immunostimulatory effects. This review 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.1– 4 Our clinical investigation of postcolectomy patients showed that GH treatment decreases urinary nitrogen excretion, improves nitrogen balance, and enhances whole-body protein turnover. Several stud-
ies have demonstrated higher levels of IGF-1 and insulin, lower urea production, reduced 3-methylhistidine excretion, and enhanced fat oxidation with the administration of GH.1– 4 However, available data are not sufficient to define dose-response relationships for the anabolic effect of GH in catabolic patients. We found 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 z kg21 z d21 of GH was apparently more efficient than 0.2 IU z kg21 z d21 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, after 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 posttraumatic patients,5– 8 whereas negative effects have also been demonstrated in such critical illness.9 –11 The difference may be owing to the severity of catabolism, the mode and quantity of GH administration, and the intake of calories and nitrogen. The different GH/IGF-1 axis in various surgical stresses may also contribute to GH efficacy.12,13 Few data are available concerning the effects of GH in multiple
Correspondence to: Dr. Hideaki Saito, Surgical Center, Department of Surgery, The University of Tokyo, 7-3-1 Hongo, Bunkyoku, Tokyo, Japan 113.
Nutrition 14:554 –556, 1998 ©Elsevier Science Inc. 1998 Printed in the USA. All rights reserved.
0899-9007/98/$19.00 PII S0899-9007(98)00049-5
SYMPOSIUM PROCEEDINGS
555
organ failure (MOF). A study revealed that GH may be ineffective in patients with MOF when the IGF-1 response to exogenous GH is blunted.14 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.15 Experiments in animal trauma models have shown that exogenous IGF-1 attenuates catabolism.15–17 However, a clinical trial from Germany did not confirm the anabolic actions of IGF-1.18 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 insulin growth factor binding protein-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.19 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.3 However, GH did not improve ventilator weaning in ICU patients.20 GH is potentially beneficial for patients with renal failure, based on reduced urea production and maintenance of intracellular potassium levels.14 It has been reported that GH may stimulate wound healing. Accelerated wound healing with exogenous GH in pediatric and adult burn patients has been demonstrated.21 Exogenous IGF-1 reduces gut mucosal atrophy in trauma.17 However, GH administration failed to prevent mucosal atrophy, despite the increased plasma IGF-1 level induced by GH, in our gastrectomized rats.17 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.22–24 Both GH and IGF-1 exert their effects on lymphoid cells. Exogenous GH and IGF-1 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.25 In addition, IGF-1 reportedly increased the CD4/CD8 ratio following severe head injury.26 Both GH and IGF-1 are powerful modulators of the effector function of phagocytic cells.22–24 These hormones augment granulocyte differentiation, chemotaxis, and phagocytosis. GH and IGF-1 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 Escherichia coli peritonitis model.27 Local production of cytokines was enhanced by GH. Moreover, in vitro investigation has revealed that both GH and IGF-1 directly enhance the E. coli-killing activity of peritoneal exudative cells.28 In human studies, we observed that GH and IGF-1 enhanced in vitro polymorphonuclear neutrophil phagocytosis in healthy human volunteers as well as patients undergoing surgery.29 Furthermore, IGF-1 increased monocyte human leukocyte antigen-DR expression after major surgery.29 It is noteworthy that GH pretreatment inhibited spontaneous apoptotic PMN cell death.30 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. In contrast, activated PMNs play an important role in the development of multiple organ failure. Inhibition of PMN apoptosis and the potentiation of PMNs by GH may have harmful effects on the systemic responses. Therefore, further studies are required to determine the safety and clinical benefits of GH administration in trauma and sepsis. CONCLUSION
GH and IGF-1 have anabolic as well as immunostimulatory effects. The benefits of GH and IGF-1 should be determined in randomized clinical trials involving critically ill patients in the near future.
REFERENCES 1. Ward HC, Halliday D, Sim AJW. Protein and energy metabolism with biosynthetic human growth hormone after gastrointestinal surgery. Ann Surg 1987;206:56 2. Ponting GA, Ward HC, Halliday D, Sim AJW. Protein and energy metabolism with biosynthetic human growth hormone in patients on full intravenous nutritional support. JPEN 1990;14:437 3. Jiang ZM, He GZ, Zhang SY, et al. Low dose growth hormone and hypocaloric nutrition attenuate the protein-catabolic response after major operation. Ann Surg 1989;210:513 4. Jeevanandam M, Ali MR, Holaday NJ, Petersen SR. Adjuvant recombinant human growth hormone normalizes plasma amino acids in parenterally fed trauma patients. JPEN 1995;19:137 5. Gottardis M, Benzer A, Koller W, Luger TJ, Puhringer F, Hackl J. Improvement of septic syndrome after administration of recombinant human growth hormone. J Trauma 1991;31:81 6. Voerman HJ, van Schijndel RJ, Groeneveld AB, et al. Effects of recombinant human growth hormone in patients with severe sepsis. Ann Surg 1992;216:648 7. Petersen SR, Holaday NJ, Jeevanandam M. Enhancement of protein synthesis efficiency in parenterally fed trauma victims by adjuvant recombinant human growth hormone. J Trauma 1994;36:726 8. Koea JB, Breier BH, Douglas RG, Gluckman PD, Shaw JH. Anabolic and cardiovascular effects of recombinant human growth hormone in surgical patients with sepsis. Br J Surg 1996;83:196 9. Dahn MS, Lange P, Jacobs LA. Insulin-like growth factor 1 production is inhibited in human sepsis. Arch Surg 1988;123:1409
10. Belcher HJCR, Mercer D, Judkins KC, et al. Biosynthetic human growth hormone in burned patients: a pilot study. Burns 1989;15:99 11. Roth E, Valentini L, Semsroth M, et al. Resistance of nitrogen metabolism to growth hormone treatment in the early phase after injury of patients with multiple injuries. J Trauma 1995;38:136 12. Jenkins RC, Ross RJ. Acquired growth hormone resistance in catabolic states. Baillieres Clin Endocrinol Metab 1996;10:411 13. Donaghy AJ, Baxter RC. Insulin-like growth factor bioactivity and its modification in growth hormone resistant states. Baillieres Clin Endocrinol Metab 1996;10:421 14. Young L, Byrne T, Wilmore D. Organ specific nutrients and associated therapy: growth factors-growth hormone. In: Wilmore D, Carpentier Y, eds. Metabolic support of the critically ill patients. Update in intensive care and emergency medicine, Series 17. Vincent JL, ed. Berlin: Springer-Verlag, 1993:254 15. Inaba T, Saito H, Fukushima R, et al. The effects of growth hormone and insulin-like growth factor 1 (IGF-1) on hepatic IGF-1-mRNA, plasma IGF-1 and nitrogen excretion in gastrectomized rats with liver cirrhosis. Clin Nutr 1996;15:321 16. Inaba T, Saito H, Fukushima R, et al. Effects of growth hormone and insulin-like growth factor 1 (IGF-1) treatments on the nitrogen metabolism and hepatic IGF-1-messenger RNA expression in postoperative parenterally fed rats. JPEN 1996;20:325 17. Inaba T, Saito H, Fukushima R, et al. Insulin-like growth factor 1 has beneficial effects, whereas growth hormone has limited effects on
556
18.
19. 20.
21. 22. 23.
SYMPOSIUM PROCEEDINGS postoperative protein metabolism, gut integrity, and splenic weight in rats with chronic mild liver injury. JPEN 1997;21:55 Goeters C, Mertes N, Tacke J, et al. Repeated administration of recombinant human insulin-like growth factor-I in patients after gastric surgery. Effect on metabolic and hormonal patterns. Ann Surg 1995;222:646 Wolf SE, Barrow RE, Herndon DN. Growth hormone and IGF-1 therapy in the hypercatabolic patient. Baillieres Clin Endocrinol Metab 1996;10:447 Pichard C, Kyle U, Chevrolet JC, et al. Lack of effects of recombinant growth hormone on muscle function in patients requiring prolonged mechanical ventilation: a prospective, randomized, controlled study. Crit Care Med 1996;24:403 Gilpin DA, Barrow RE, Rutan RL, Broemeling L, Herndon DN. Recombinant human growth hormone accelerates wound healing in children with large cutaneous burns. Ann Surg 1994;220:19 Kelley KW. The role of growth hormone in modulation of the immune response. Ann N Y Acad Sci 1990;594:95 Wiedermann CJ, Reinisch N, Kahler C, Braunsteiner H. Regulation of myeloid phagocyte development and function by growth hormone: a review. J Pediatr Endocrinol 1993;6:85
24. Saito H, Inoue T, Fukatsu K, et al. Growth hormone and the immune response to bacterial infection. Horm Res 1996;45:50 25. Saito H, Taniwaka K, Fukushima R, et al. Growth hormone treatment stimulates immune responsiveness after abdominal surgery. Clin Nutr 1990;9(suppl):16 26. Kudsk KA, Mowatt-Larssen C, Bukar J, et al. Effect of recombinant human insulin-like growth factor 1 and early total parenteral nutrition on immune depression following severe head injury. Arch Surg 1994; 129:66 27. Inoue T, Saito H, Fukushima R, et al. Growth hormone and insulinlike growth factor 1 enhance host defense in a murine sepsis model. Arch Surg 1995;130:1115 28. Inoue T, Saito H, Hashiguchi Y, et al. Growth hormone and insulinlike growth factor 1 augment Escherichia coli-killing activity of murine peritoneal exudative cells. Shock 1996;6:345 29. Inoue T, Saito H, Matsuda T, et al. Effects of growth hormone and insulin-like growth factor 1 on PMN phagocytosis and monocyte HLA-DR expression in postoperative patients. Clin Nutr 1997; 16(suppl 2):13 30. Matsuda T, Saito H, Tsuno N. Growth hormone (GH) inhibits human neutrophil cell death in vitro. JPEN 1997;15(suppl):21
Nutrition Vol. 14, No. 6, 1998
Anabolic Agents in Trauma and Sepsis: Repleting Body Mass and Function HIDEAKI SAITO, MD From the Surgical Center, Department of Surgery, The University of Tokyo, Tokyo, Japan ABSTRACT
Both growth hormone (GH) and insulin-like growth factor 1 (IGF-1) are potent anabolic agents. Exogenous GH improves nitrogen metabolism in patients undergoing surgery; however, the anabolic effects of GH in cases of multiple injury, burn, and sepsis are equivocal. Moreover, few data are available concerning the effects of GH in organ failures. Exogenous IGF-1 attenuates catabolism in animal trauma models. A clinical trial, however, did not confirm the anabolic actions of IGF-1. Further knowledge of the interaction between the GH/IGF-1 axis in critical illness is essential for GH and IGF-1 therapy. 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 decreases the postoperative depression of hand grip strength. GH also stimulates wound healing. Both GH and IGF-1 exert their effects on immune system, suggesting that these anabolic agents are potentially beneficial for the prevention and treatment of sepsis. On the contrary, inhibition of polymorphonuclear neutrophil apoptosis and the potentiation of PMNs by GH may have harmful effects on the systemic responses. Further studies are required to determine the safety and clinical benefits of GH administration in critical illness. Nutrition 1998;14:554 –556. ©Elsevier Science Inc. 1998 Key words: growth hormone, insulin-like growth factor 1, anabolism, immunostimulation
INTRODUCTION
Characteristic metabolic responses to trauma and sepsis are catabolism of whole-body protein stores and negative nitrogen balance. Immunodepression is also associated with trauma and sepsis. Nutritional therapy is an important aspect of managing patients with trauma and sepsis. However, conventional nutritional support, especially total parenteral nutrition (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 those patients. One of the options investigated is exogenous anabolic hormones. Growth hormone (GH) is a potent anabolic agent. Insulin-like growth factor 1 (IGF-1) mediates the anabolic effect of GH. Moreover, both GH and IGF-1 have immunostimulatory effects. This review 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.1– 4 Our clinical investigation of postcolectomy patients showed that GH treatment decreases urinary nitrogen excretion, improves nitrogen balance, and enhances whole-body protein turnover. Several stud-
ies have demonstrated higher levels of IGF-1 and insulin, lower urea production, reduced 3-methylhistidine excretion, and enhanced fat oxidation with the administration of GH.1– 4 However, available data are not sufficient to define dose-response relationships for the anabolic effect of GH in catabolic patients. We found 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 z kg21 z d21 of GH was apparently more efficient than 0.2 IU z kg21 z d21 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, after 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 posttraumatic patients,5– 8 whereas negative effects have also been demonstrated in such critical illness.9 –11 The difference may be owing to the severity of catabolism, the mode and quantity of GH administration, and the intake of calories and nitrogen. The different GH/IGF-1 axis in various surgical stresses may also contribute to GH efficacy.12,13 Few data are available concerning the effects of GH in multiple
Correspondence to: Dr. Hideaki Saito, Surgical Center, Department of Surgery, The University of Tokyo, 7-3-1 Hongo, Bunkyoku, Tokyo, Japan 113.
Nutrition 14:554 –556, 1998 ©Elsevier Science Inc. 1998 Printed in the USA. All rights reserved.
0899-9007/98/$19.00 PII S0899-9007(98)00049-5
SYMPOSIUM PROCEEDINGS
555
organ failure (MOF). A study revealed that GH may be ineffective in patients with MOF when the IGF-1 response to exogenous GH is blunted.14 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.15 Experiments in animal trauma models have shown that exogenous IGF-1 attenuates catabolism.15–17 However, a clinical trial from Germany did not confirm the anabolic actions of IGF-1.18 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 insulin growth factor binding protein-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.19 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.3 However, GH did not improve ventilator weaning in ICU patients.20 GH is potentially beneficial for patients with renal failure, based on reduced urea production and maintenance of intracellular potassium levels.14 It has been reported that GH may stimulate wound healing. Accelerated wound healing with exogenous GH in pediatric and adult burn patients has been demonstrated.21 Exogenous IGF-1 reduces gut mucosal atrophy in trauma.17 However, GH administration failed to prevent mucosal atrophy, despite the increased plasma IGF-1 level induced by GH, in our gastrectomized rats.17 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.22–24 Both GH and IGF-1 exert their effects on lymphoid cells. Exogenous GH and IGF-1 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.25 In addition, IGF-1 reportedly increased the CD4/CD8 ratio following severe head injury.26 Both GH and IGF-1 are powerful modulators of the effector function of phagocytic cells.22–24 These hormones augment granulocyte differentiation, chemotaxis, and phagocytosis. GH and IGF-1 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 Escherichia coli peritonitis model.27 Local production of cytokines was enhanced by GH. Moreover, in vitro investigation has revealed that both GH and IGF-1 directly enhance the E. coli-killing activity of peritoneal exudative cells.28 In human studies, we observed that GH and IGF-1 enhanced in vitro polymorphonuclear neutrophil phagocytosis in healthy human volunteers as well as patients undergoing surgery.29 Furthermore, IGF-1 increased monocyte human leukocyte antigen-DR expression after major surgery.29 It is noteworthy that GH pretreatment inhibited spontaneous apoptotic PMN cell death.30 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. In contrast, activated PMNs play an important role in the development of multiple organ failure. Inhibition of PMN apoptosis and the potentiation of PMNs by GH may have harmful effects on the systemic responses. Therefore, further studies are required to determine the safety and clinical benefits of GH administration in trauma and sepsis. CONCLUSION
GH and IGF-1 have anabolic as well as immunostimulatory effects. The benefits of GH and IGF-1 should be determined in randomized clinical trials involving critically ill patients in the near future.
REFERENCES 1. Ward HC, Halliday D, Sim AJW. Protein and energy metabolism with biosynthetic human growth hormone after gastrointestinal surgery. Ann Surg 1987;206:56 2. Ponting GA, Ward HC, Halliday D, Sim AJW. Protein and energy metabolism with biosynthetic human growth hormone in patients on full intravenous nutritional support. JPEN 1990;14:437 3. Jiang ZM, He GZ, Zhang SY, et al. Low dose growth hormone and hypocaloric nutrition attenuate the protein-catabolic response after major operation. Ann Surg 1989;210:513 4. Jeevanandam M, Ali MR, Holaday NJ, Petersen SR. Adjuvant recombinant human growth hormone normalizes plasma amino acids in parenterally fed trauma patients. JPEN 1995;19:137 5. Gottardis M, Benzer A, Koller W, Luger TJ, Puhringer F, Hackl J. Improvement of septic syndrome after administration of recombinant human growth hormone. J Trauma 1991;31:81 6. Voerman HJ, van Schijndel RJ, Groeneveld AB, et al. Effects of recombinant human growth hormone in patients with severe sepsis. Ann Surg 1992;216:648 7. Petersen SR, Holaday NJ, Jeevanandam M. Enhancement of protein synthesis efficiency in parenterally fed trauma victims by adjuvant recombinant human growth hormone. J Trauma 1994;36:726 8. Koea JB, Breier BH, Douglas RG, Gluckman PD, Shaw JH. Anabolic and cardiovascular effects of recombinant human growth hormone in surgical patients with sepsis. Br J Surg 1996;83:196 9. Dahn MS, Lange P, Jacobs LA. Insulin-like growth factor 1 production is inhibited in human sepsis. Arch Surg 1988;123:1409
10. Belcher HJCR, Mercer D, Judkins KC, et al. Biosynthetic human growth hormone in burned patients: a pilot study. Burns 1989;15:99 11. Roth E, Valentini L, Semsroth M, et al. Resistance of nitrogen metabolism to growth hormone treatment in the early phase after injury of patients with multiple injuries. J Trauma 1995;38:136 12. Jenkins RC, Ross RJ. Acquired growth hormone resistance in catabolic states. Baillieres Clin Endocrinol Metab 1996;10:411 13. Donaghy AJ, Baxter RC. Insulin-like growth factor bioactivity and its modification in growth hormone resistant states. Baillieres Clin Endocrinol Metab 1996;10:421 14. Young L, Byrne T, Wilmore D. Organ specific nutrients and associated therapy: growth factors-growth hormone. In: Wilmore D, Carpentier Y, eds. Metabolic support of the critically ill patients. Update in intensive care and emergency medicine, Series 17. Vincent JL, ed. Berlin: Springer-Verlag, 1993:254 15. Inaba T, Saito H, Fukushima R, et al. The effects of growth hormone and insulin-like growth factor 1 (IGF-1) on hepatic IGF-1-mRNA, plasma IGF-1 and nitrogen excretion in gastrectomized rats with liver cirrhosis. Clin Nutr 1996;15:321 16. Inaba T, Saito H, Fukushima R, et al. Effects of growth hormone and insulin-like growth factor 1 (IGF-1) treatments on the nitrogen metabolism and hepatic IGF-1-messenger RNA expression in postoperative parenterally fed rats. JPEN 1996;20:325 17. Inaba T, Saito H, Fukushima R, et al. Insulin-like growth factor 1 has beneficial effects, whereas growth hormone has limited effects on
556
18.
19. 20.
21. 22. 23.
SYMPOSIUM PROCEEDINGS postoperative protein metabolism, gut integrity, and splenic weight in rats with chronic mild liver injury. JPEN 1997;21:55 Goeters C, Mertes N, Tacke J, et al. Repeated administration of recombinant human insulin-like growth factor-I in patients after gastric surgery. Effect on metabolic and hormonal patterns. Ann Surg 1995;222:646 Wolf SE, Barrow RE, Herndon DN. Growth hormone and IGF-1 therapy in the hypercatabolic patient. Baillieres Clin Endocrinol Metab 1996;10:447 Pichard C, Kyle U, Chevrolet JC, et al. Lack of effects of recombinant growth hormone on muscle function in patients requiring prolonged mechanical ventilation: a prospective, randomized, controlled study. Crit Care Med 1996;24:403 Gilpin DA, Barrow RE, Rutan RL, Broemeling L, Herndon DN. Recombinant human growth hormone accelerates wound healing in children with large cutaneous burns. Ann Surg 1994;220:19 Kelley KW. The role of growth hormone in modulation of the immune response. Ann N Y Acad Sci 1990;594:95 Wiedermann CJ, Reinisch N, Kahler C, Braunsteiner H. Regulation of myeloid phagocyte development and function by growth hormone: a review. J Pediatr Endocrinol 1993;6:85
24. Saito H, Inoue T, Fukatsu K, et al. Growth hormone and the immune response to bacterial infection. Horm Res 1996;45:50 25. Saito H, Taniwaka K, Fukushima R, et al. Growth hormone treatment stimulates immune responsiveness after abdominal surgery. Clin Nutr 1990;9(suppl):16 26. Kudsk KA, Mowatt-Larssen C, Bukar J, et al. Effect of recombinant human insulin-like growth factor 1 and early total parenteral nutrition on immune depression following severe head injury. Arch Surg 1994; 129:66 27. Inoue T, Saito H, Fukushima R, et al. Growth hormone and insulinlike growth factor 1 enhance host defense in a murine sepsis model. Arch Surg 1995;130:1115 28. Inoue T, Saito H, Hashiguchi Y, et al. Growth hormone and insulinlike growth factor 1 augment Escherichia coli-killing activity of murine peritoneal exudative cells. Shock 1996;6:345 29. Inoue T, Saito H, Matsuda T, et al. Effects of growth hormone and insulin-like growth factor 1 on PMN phagocytosis and monocyte HLA-DR expression in postoperative patients. Clin Nutr 1997; 16(suppl 2):13 30. Matsuda T, Saito H, Tsuno N. Growth hormone (GH) inhibits human neutrophil cell death in vitro. JPEN 1997;15(suppl):21