Phase 2 Trial to Examine the Metabolic Effects of Fenofibrate in Burned Patients

We will study patients with severe burns, defined as 2nd or 3rd degree burn covering >40% of total body surface area (TBSA). We propose to study burned children from Shriners Burns Hospital. The Shriners census is such that approximately 50 children with severe burns are treated every year. We will study patients immediately prior to their third surgical procedure, approximately 12-15 days after injury. One half of the patients will be given fenofibrate (5 mg/kg/day) daily delivered through feeding tube from the time of consent following admission until 12-14 days post-burn. This length of time after injury will ensure that untreated patients will have a large accumulation of hepatic TG. Because the "control" group of patients will have elevated liver TGs, the "experimental" group will have their hepatic TGs lowered by fenofibrate. By studying the patients the day before the operations, it will be possible to remove the staples used in skin grafting without risk of loss of adhesion of the graph, thereby ensuring safety in the MRS. Femoral line inserted for the surgery can also be utilized, and all patient generally receive a full transfusion during surgeries, minimizing any study related blood loss. In addition to the liver, we will study the muscle in burn patients. Patients will be studied during brief fasted state. The will be fasted four hours prior to the study and then through out the study. Their TPN will be immediately reconnected following the study. The surgical team at the Shrine places 3Fr, 8 cm polyethylene catheters (Cook, Inc., Bloomington, IN) into the femoral vein and femoral artery under local anesthesia the day before surgery. Both femoral catheters will be used for blood sampling, while the femoral arterial catheter will also used for indocyanine green infusion for the determination of leg blood flow. Systemic concentration of indocyanine green will be measured from a central vein, as standard procedure has a multi-lumen subclavian line in all patients. Patency of all catheters is maintained by saline infusion.

Patients will be infused with stable (non-radioactive) isotope tracers of glucose, phenylalanine and palmitate for up to 8 hours. After 4 hours, without interruption of the tracer infusion, an infusion of insulin will be started and maintained at the rate of 1.5 mU/kg•min for the final 4 h. Blood glucose concentrations will be measured throughout the insulin infusion and glucose infused as necessary to maintain the basal plasma glucose concentration.

A biopsy of the quadriceps will be obtained with a Bergstrom needle at the beginning of the study, 4 h (immediately before the insulin infusion) and at the end of the 4 h insulin infusion. We will use the A-V balance technique to address the relation between tissue fatty acid and TG metabolism and the insulin responsiveness of glucose uptake and myofibrillar and mitochondrial protein synthesis and net protein balance.

b. Subjects Patients are admitted to the burn unit within 48 h of injury. Fluid resuscitation is provided as previously described (94). Within 48 h of admission, the burn wound is excised and subsequently grafted by autograft or cadaveric allograft. Patients typically return to the operating room for reharvesting of donor sites every five to seven days. The experiments proposed here will be performed the day prior to the third surgery at day 12-15, as femoral catheters are normally inserted at the time for access during surgery. Enteral feeding with Vivonex TEN (Sandoz Nutrition Corp, Minneapolis, MN) is started within 24h of admission and continued until the patient is capable of food by mouth. All patients will be eligible for the study unless one of the exclusion criterion listed below apply.

c. Procedures From day 1 to day 22 patients will be maintained on enteral feeding of a high carbohydrate/amino acid mixture (Vivonex, Novartis, Minneapolis, MN). Vivonex contains 300 kcal/serving in the following caloric breakdown: 82.3% carbohydrate, 15% protein, 2.7% fat (linoleic acid). Patients will be given 25 kcal/kg of Vivonex plus an additional 45 kcal/kg for each percentage point of total body surface area burned. One half of the patients will be given fenofibrate (5 mg/kg/day - maximum daily dose) from the time of the first tracer study until the time of the second tracer study.