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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM056687-14
Application #
8629361
Study Section
Special Emphasis Panel (ZRG1-SBIB-V (82))
Program Officer
Somers, Scott D
Project Start
1998-01-01
Project End
2018-04-30
Budget Start
2014-08-05
Budget End
2015-04-30
Support Year
14
Fiscal Year
2014
Total Cost
$1,102,701
Indirect Cost
$382,701
Name
University of Texas Medical Br Galveston
Department
Surgery
Type
Schools of Medicine
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555
Sousse, Linda E; Herndon, David N; Andersen, Clark R et al. (2015) Pulmonary histopathologic abnormalities and predictor variables in autopsies of burned pediatric patients. Burns 41:519-27
Kraft, Robert; Herndon, David N; Finnerty, Celeste C et al. (2015) Predictive Value of IL-8 for Sepsis and Severe Infections After Burn Injury: A Clinical Study. Shock 43:222-7
Diaz, Eva C; Herndon, David N; Porter, Craig et al. (2015) Effects of pharmacological interventions on muscle protein synthesis and breakdown in recovery from burns. Burns 41:649-57
Jeschke, Marc G; Pinto, Ruxandra; Herndon, David N et al. (2014) Hypoglycemia is associated with increased postburn morbidity and mortality in pediatric patients. Crit Care Med 42:1221-31
Peterson, Jonathan R; De La Rosa, Sara; Eboda, Oluwatobi et al. (2014) Treatment of heterotopic ossification through remote ATP hydrolysis. Sci Transl Med 6:255ra132
Jeschke, Marc G; Gauglitz, Gerd G; Finnerty, Celeste C et al. (2014) Survivors versus nonsurvivors postburn: differences in inflammatory and hypermetabolic trajectories. Ann Surg 259:814-23
Porter, Craig; Herndon, David N; Børsheim, Elisabet et al. (2014) Uncoupled skeletal muscle mitochondria contribute to hypermetabolism in severely burned adults. Am J Physiol Endocrinol Metab 307:E462-7
Kraft, Robert; Herndon, David N; Mlcak, Ronald P et al. (2014) Bacterial respiratory tract infections are promoted by systemic hyperglycemia after severe burn injury in pediatric patients. Burns 40:428-35
Gerö, Domokos; Szoleczky, Petra; Chatzianastasiou, Athanasia et al. (2014) Modulation of poly(ADP-ribose) polymerase-1 (PARP-1)-mediated oxidative cell injury by ring finger protein 146 (RNF146) in cardiac myocytes. Mol Med 20:313-28
Chondronikola, Maria; Meyer, Walter J; Sidossis, Labros S et al. (2014) Predictors of insulin resistance in pediatric burn injury survivors 24 to 36 months postburn. J Burn Care Res 35:409-15

Showing the most recent 10 out of 101 publications