Muscle Protein Catabolism After Severe Burn: Effects of IGF-1/IGFBP-3 Treatment

Abstract

ObjectiveTo determine the effects of recombinant human insulin-like growth factor-1 (IGF-1) complexed with its principal binding protein, IGFBP-3, on skeletal muscle metabolism in severely burned children. Summary Background DataSevere burns are associated with a persistent hypermetabolic response characterized by hyperdynamic circulation and severe muscle catabolism and wasting. Previous studies showed that nutritional support and pharmacologic intervention with anabolic agents such as growth hormone and insulin abrogated muscle wasting and improved net protein synthesis in the severely burned. The use of these agents, however, has several adverse side effects. A new combination of IGF-1 and IGFBP-3 is now available for clinical study. MethodsTwenty-nine severely burned children were prospectively studied before and after treatment with 0.5, 1, 2, or 4 mg/kg/ day IGF-1/IGFBP-3 to determine net balance of protein across the leg, muscle protein fractional synthetic rates, and glucose metabolism. Another group was studied in a similar fashion without IGF-1/IGFBP-3 treatment as time controls. ResultsSeventeen of 29 children were catabolic before starting treatment. The infusion of 1.0 mg/kg/day IGF-1/IGFBP-3 increased serum IGF-1, which did not further increase with 2.0 and 4.0 mg/kg/day. IGF-1/IGFBP-3 treatment at 1 to 4 mg/ kg/day improved net protein balance and increased muscle protein fractional synthetic rates. This effect was more pronounced in catabolic children. IGF-1/IGFBP-3 did not affect glucose uptake across the leg or change substrate utilization. ConclusionsIGF-1/IGFBP-3 at doses of 1 to 4 mg/kg/day attenuates catabolism in catabolic burned children with negligible clinical side effects.Severe burns are associated with a persistent hypermetabolic response characterized by hyperdynamic circulation and increased circulating levels of catabolic hormones such as catecholamines, glucagon, and cortisol.

The Hepatic Response to Thermal Injury: Is the Liver Important for Postburn Outcomes?

“…The IGF-I system is synthesized in the liver and its production is stimulated by GH (131)(132)(133). IGF-I has been shown to improve cell recovery, muscle protein synthesis, gut and immune function, and exert promitogenic functions not only after burn, but also in various other pathological states (7,(134)(135)(136)(137). Recent evidence suggests that IGF-I is instrumental in the early phases of liver regeneration after trauma and modulates the hepatic acute phase response in burned rats restoring hepatic homeostasis and improving hepatic morphology (136,137).…”

Liposomal IGF-1 gene transfer modulates pro- and anti-inflammatory cytokine mRNA expression in the burn wound

“…1,2 The prolonged post-traumatic hypermetabolic state has been attenuated by aggressive nutritional and pharmacologic interventions. [3][4][5] The release of pro-inflammatory cytokines after severe trauma occurs not only at a systemic level but also in the burn wound itself and to a lesser extent in the surrounding uninjured tissue. 6,7 The skin constitutes the body's largest immune organ, thus a thermal injury clearly influences immune competence and resistance against infection and inflammation.…”

The Pathophysiologic Response to Severe Burn Injury.

“…Agents known to affect postburn hypermetabolism and catabolism are insulin, IGF-I, oxandrolone, GH, and propranolol. 4,18,[30][31][32][33] As GH increases mortality in critically ill adults 34 and IGF-I is at the moment limited in its availability, we recommend the use of insulin, oxandrolone, or propranolol to attenuate hypermetabolism and catabolism.…”

“…In fact, we conducted an animal and a clinical study in which we showed that IGF-I, in combination with its principle binding protein, improved muscle protein synthesis, hepatic acute phase and inflammatory response, and immune system. 30,32,50 However, we suggest that it would be necessary to test IGF-I in a large multicenter trial to determine whether IGF-I would be a beneficial treatment option in severely burned patients.…”