Modulation of types I and II acute phase reactants with insulin-like growth factor-1/binding protein-3 complex in severely burned children Marcus Spies, MD; Steven E. Wolf, MD; Robert E. Barrow, PhD; Marc G. Jeschke, MD; David N. Herndon, MD T he acute phase response to se- vere trauma causes an in- crease in the hepatic produc- tion of acute phase proteins (type I and type II) with a concomitant decrease in the production of constitutive hepatic proteins such as albumin, preal- bumin, and transferrin (1–5). The hepatic response to trauma is triggered and me- diated by the release of proinflammatory cytokines to restore tissue and systemic homeostasis (1–7). Clinical experiences and studies have shown that a sustained acute phase response and systemic in- flammatory response, which is triggered by action of proinflammatory cytokines, is associated with multiple organ dys- function, hypermetabolism, and catabo- lism, and thus may cause, in part, an increase in morbidity or mortality (8 – 10). An increased production of acute phase reactants, at the expense of consti- tutive hepatic serum protein production, may increase these detrimental effects (8 –10). Albumin and transferrin serve as transport proteins and maintain a normal plasma oncotic pressure and pH (2). Their down-regulation, after trauma, has been shown to be potentially harmful. The rate of synthesis or serum levels of these proteins has been shown predictive for mortality, nutritional status, and se- verity of stress (2, 6, 7). In an effort to control the acute phase response, several clinical trials to attenuate the overexpres- sion of proinflammatory cytokines and acute phase proteins have met with min- imal success (8, 11, 12). Recombinant human growth hor- mone given after severe burn was shown to decrease the levels of serum tumor necrosis factor (TNF)- with a conse- quent increase in serum albumin (13, 14). These effects are thought to be me- diated through the release of insulin-like growth factor (IGF)-1 (15, 16). The GH- IGF-1 axis has been a significant factor in post-traumatic metabolism and influ- ences recovery and outcome (15–18). IGF-1 is a 7.7 kDa single-chain polypep- tide consisting of 70 amino acids with sequence homology to proinsulin (19) and is 95% to 99% bound to one of six binding proteins for transportation in the systemic circulation (20). Studies have shown the beneficial effects of IGF-1 on cell recovery, wound healing, muscle pro- tein synthesis, gut barrier, and immune function after severe burn (16, 21–23). Physiologically effective doses of IGF-1, however, have resulted in adverse side effects such as hypoglycemia, electrolyte imbalances, edema, neuropathies, and cardiac arrest (16, 24). To diminish these risks, IGF-1 has been administered in a complex with its principle binding pro- tein, insulin-like growth factor binding protein (IGFBP)-3. This complex (IGF-1/ BP-3) has been shown to be effective in From the Shriners Hospital for Children and De- partment of Surgery, The University Texas Medical Branch, Galveston, TX. Supported, in part, by the Shriners Hospitals for Children, Grants 8660 and 8490, National Institutes of Health Grant 1 RO1-GM56687-01, and the Celtrix Pharmaceutical Company. Presented, in part, at the 30th International Sym- posium of the Society of Critical Care Medicine in San Francisco, CA, February 10 –14, 2001. Address requests for reprints to: Steven E. Wolf, MD, Department of Surgery, Shriners Hospitals for Children, 815 Market Street, Galveston, TX 77550. E-mail: swolf@utmb.edu Copyright © 2002 by Lippincott Williams & Wilkins Objective: To determine whether 0.5 mg/kg insulin-like growth factor (IGF)-1/binding protein (IGFBP)-3, given intravenously, ef- fectively alters the acute phase response in severely burned children. Design: Longitudinal trial with each patient serving as their own control. Setting: University-affiliated pediatric burn center. Patients: Nine children, 15 yrs of age or less, with burns covering >40% of the total body surface area. Interventions: Standard burn care with early burn wound ex- cision and grafting. Blood sampled at defined time points before and after operative procedures. Measurements and Results: Determination of types I and II acute phase reactant proteins, constitutive serum proteins, serum cytokines, serum IGF-1, IGFBP-3, and growth hormone levels. Treatment with IGF-1/BP-3 attenuated increases in type I (com- plement 3, 1-acidglycoprotein) and type II (haptoglobin, 1- antitrypsin) acute phase proteins. Further, IGF-1/BP-3 increased constitutive serum protein levels (prealbumin, retinol binding protein, transferrin) and decreased serum IL-6 levels. Conclusions: Low-dose IGF-1/BP-3 effectively attenuated the type I and type II hepatic acute phase response, increased serum levels of constitutive proteins, and modulated the hypermetabolic response. (Crit Care Med 2002; 30:83–88) KEY WORDS: insulin-like growth factor-1; insulin-like growth factor binding protein-3; acute phase response; acute phase proteins; constitutive serum proteins; inflammatory cytokines; low-dose insulin-like growth factor-1/binding protein-3; pharma- cological modulation; severe burns; pediatric burns 83 Crit Care Med 2002 Vol. 30, No. 1