Novel drug and exercise therapies to restore metabolic function in children with severe burns

Abstract

Severe burns encompassing over 30% of the total body surface area result in a pathophysiological stress response characterized by increased cardiac workload, elevated energy expenditure, altered muscle metabolism, a severe loss in lean body mass, and impaired physical function. This stress response can extend well beyond wound healing, which can negatively impact an individual’s quality of life and their ability to reintegrate into society. Clinical and translational research in the past few decades has vastly improved the outcomes of patients who have suffered severe burns. However, continued research is needed to answer more questions to help us further understand severe burn trauma and how to improve medical care and rehabilitation. In the studies described within this dissertation, novel methods to measure the perturbations in skeletal muscle metabolism were employed, including stable isotope approached to quantify muscle protein turnover and high-resolution respirometry (HRR) to assay muscle mitochondrial function. Additionally, we were able to use these methods to test the efficacy of a combined pharmacological treatment of a testosterone analog and -blockade in severely burned pediatric patients during their acute hospitalization period. Following their discharge, we were able to test the effectiveness of this new pharmacological approach combined with a hospital-based exercise program in restoring metabolic and physical function. Our results shows for the first time, that -blockade and testosterone therapy can significantly reduce cardiac workload, decrease resting energy expenditure, and restore skeletal muscle mass and function in children recovering from severe burns. Our study is limited to a small sample size, but our results have tremendous implications in clinical treatment of patients with severe burns. Future multi-center clinical trials involving men and women of all ages are now needed to validate the utility of the combined drug therapy in restoring physiological function in burn survivors.