The response to a severe burn is characterized by persistent hypermetabolic and catabolic state that result in the massive loss of muscle tissue, even in the fed state. In patients with >30% of total body surface area burned, protein breakdown persists for approximately one year after the burn wound is 95% healed. Endogenous catecholamines have been implicated as primary mediators of the hypermetabolic response to trauma or burn. Chronic elevation of plasma catecholamine levels results in the development of hyperdynamic circulation, increased basal energy expenditure, peripheral insulin resistance with hyperglycemia, increased peripheral lipolysis, depressed immune function, skeletal muscle protein catabolism and hypertrophic scarring. The hypermetabolic response to burns is also characterized by a profound tachycardia and increased cardiac work that are detrimental to the heart. The persistence of tachycardia and muscle catabolism significantly compromises rehabilitation and results in an excessive delay before resuming normal physical and functional activities. Recent studies from our institution have shown the negative impact of hyperglycemia and insulin resistance on survival, wound healing, and skeletal muscle catabolism. Insulin resistance can last for at least 3 years in severely burned patients, further delaying a patient's return to normal and reducing their quality of life. In the previous funding period, we demonstrated that administration of intensive insulin alone or in combination with propranolol improves outcomes for severely burned patients. However, the use of insulin was associated with high levels of hypoglycemia. Therefore, we now will utilize an anti-hyperglycemic therapy that does not have the risk of hypoglycemia. We have shown that acute administration of fenofibrate, a fibrate, reduces blood glucose levels in severely burned patients. We will now administer fenofibrate alone or in combination with propranolol to determine the clinical efficacy and underlying mechanisms of action on insulin resistance, wound healing, sepsis, and cardiac function. We hypothesize that reduction of blood glucose levels, along with blockade of catecholamines, will result in attenuation of the long-term post-burn catabolic and hypermetabolic responses, and that these responses will be ameliorated by the therapeutic use of fenofibrate alone or in combination with propranolol, administered for one year post burn. A total of 300 patients will be randomized to receive daily administration of Fenofibrate alone or in combination with propranolol. Comparison of the data from these patients to an equal number of placebo- or propranolol-treated patients will be accomplished using data from our already funded P50 burn center trial which will be completed by January 2015.
Severely burned patients experience long-term insulin resistance and increased cardiac work that can last for year's post- injury, increasing long-term morbidity. This will be the first trial of year-long administration of fenofibrate alone or in combination with propranolol. This long-term clinical trial will advance the understanding of burn-induced tissue-specific signaling pathways, alterations in clinical indices such as insulin resistance, body composition, and scarring, and may improve clinical outcomes of burn patients, and by extension also improve these in other hypermetabolic and hypercatabolic states.
|Bohanon, Fredrick J; Nunez Lopez, Omar; Herndon, David N et al. (2018) Burn Trauma Acutely Increases the Respiratory Capacity and Function of Liver Mitochondria. Shock 49:466-473|
|Cambiaso-Daniel, Janos; Boukovalas, Stafanos; Bitz, Genevieve H et al. (2018) Topical Antimicrobials in Burn Care: Part 1-Topical Antiseptics. Ann Plast Surg :|
|Rivas, Eric; Herndon, David N; Chapa, Martha L et al. (2018) Children with severe burns display no sex differences in exercise capacity at hospital discharge or adaptation after exercise rehabilitation training. Burns 44:1187-1194|
|Voigt, Charles D; Hundeshagen, Gabriel; Malagaris, Ioannis et al. (2018) Effects of a restrictive blood transfusion protocol on acute pediatric burn care: Transfusion threshold in pediatric burns. J Trauma Acute Care Surg 85:1048-1054|
|Cambiaso-Daniel, Janos; Parry, Ingrid; Rivas, Eric et al. (2018) Strength and Cardiorespiratory Exercise Rehabilitation for Severely Burned Patients During Intensive Care Units: A Survey of Practice. J Burn Care Res 39:897-901|
|Chao, Tony; Porter, Craig; Herndon, David N et al. (2018) Propranolol and Oxandrolone Therapy Accelerated Muscle Recovery in Burned Children. Med Sci Sports Exerc 50:427-435|
|Rivas, Eric; McEntire, Serina J; Herndon, David N et al. (2018) Resting ?-Adrenergic Blockade Does Not Alter Exercise Thermoregulation in Children With Burn Injury: A Randomized Control Trial. J Burn Care Res 39:402-412|
|Murton, Andrew; Bohanon, Fredrick J; Ogunbileje, John O et al. (2018) Sepsis Increases Muscle Proteolysis in Severely Burned Adults, But Does Not Impact Whole-Body Lipid or Carbohydrate Kinetics. Shock :|
|Malagaris, Ioannis; Herndon, David N; Polychronopoulou, Efstathia et al. (2018) Determinants of skeletal muscle protein turnover following severe burn trauma in children. Clin Nutr :|
|El Ayadi, Amina; Prasai, Anesh; Wang, Ye et al. (2018) ?-Adrenergic Receptor Trafficking, Degradation, and Cell Surface Expression Are Altered in Dermal Fibroblasts from Hypertrophic Scars. J Invest Dermatol 138:1645-1655|
Showing the most recent 10 out of 186 publications