Role of the PPAR-α agonist fenofibrate in severe pediatric burn.

Fenofibrate is a peroxisome proliferator activated receptor alpha agonist that contains both pro and anti-inflammatory properties, and has been used in the treatment of dyslipidemia and diabetes for decades. Its receptors are expressed in the liver, skeletal muscle, cardiac, enteric, and renal cells, which allow it to provide systemic regulation of lipoprotein metabolism, fatty acid oxidation, and fatty acid transport. Hyperglycemia is a common complication found in the burn population because hepatic glucose production and catecholamine-mediated hepatic glycogenolysis are augmented. Insulin resistance occurs often in these patients and is associated with poor outcomes. In the pediatric burn population, fenofibrate has been found to ameliorate or decrease the number of hypoglycemic episodes when compared to management with insulin alone. Its mechanism of action is thought to involve an improvement in insulin signaling in skeletal muscle, as well as improvements in mitochondrial function, glucose oxidation, and insulin sensitivity. The long term use of fenofibrate in severely burned patients may improve hyperglycemia and insulin resistance, as well as improve wound healing, and reduce apoptosis, and oxidative stress.

The GH/IGF-1 system in critical illness.

The Growth Hormone and Insulin-like Growth Factor-1 (IGF-1) axis plays a pivotal role in critical illness, with a derangement leading to profound changes in metabolism. Protein wasting with skeletal muscle loss, delayed wound healing, and impaired recovery of organ systems are some of the most feared consequences. The use of human recombinant Growth Hormone (rhGH) and Insulin-like Growth Factor-1 (IGF-1) - alone and in combination - has been studied extensively in preclinical and clinical trials. This article reviews the current knowlegde and clinical practice of the use of rhGh and IGF-1 in critically ill patients, with a special focus on the trauma and burns patient population.

Adult patients are more catabolic than children during acute phase after burn injury: a retrospective analysis on muscle protein kinetics.

PURPOSE: This study was performed to determine if there is an age-related specificity in the response of muscle protein metabolism to severe burn injury during acute hospitalization. This is a retrospective analysis of previously published data. METHODS: Nineteen adult and 58 pediatric burn-injured patients (age 43.3 ± 14.3 vs. 7.2 ± 5.3 years, adult vs. children) participated in stable isotope [ring-(2)H(5)]phenylalanine (Phe) infusion studies. Femoral arterial and venous blood samples and muscle biopsy samples were collected throughout the study. Data are presented as means ± standard deviation (SD). A p value less than 0.05 was considered statistically significant. RESULTS: Muscle net protein balance (NB) was higher in children (adult vs. children, -43 ± 61 vs. 8 ± 68 nmol Phe/min/100 ml leg volume, p < 0.05). Muscle protein fractional synthesis rate (FSR) was higher in children (adult vs. children, 0.11 ± 0.05 vs. 0.16 ± 0.10 %/h, p < 0.05). Leg muscle protein breakdown was not different between the groups (adult vs. children, 179 ± 115 vs. 184 ± 124 nmol Phe/min/100 ml leg volume, p > 0.05); synthesis rate was 134 ± 96 and 192 ± 128 nmol Phe/min/100 ml leg volume in adults and children, respectively (p = 0.07). Age significantly correlated with muscle protein NB (p = 0.01) and FSR (p = 0.02); but not with breakdown (p = 0.67) and synthesis (p = 0.07) rates measured by using a three-pool model. CONCLUSION: In burn injury, the muscle protein breakdown may be affected to the same extent in adults and children, whereas synthesis may have age-related specificities, resulting in a better but still low NB in children.

Increased poly(ADP-ribosyl)ation in skeletal muscle tissue of pediatric patients with severe burn injury: prevention by propranolol treatment.

Activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) has been shown to promote cellular energetic collapse and cellular necrosis in various forms of critical illness. Most of the evidence implicating the PARP pathway in disease processes is derived from preclinical studies. With respect to PARP and burns, studies in rodent and large animal models of burn injury have demonstrated the activation of PARP in various tissues and the beneficial effect of its pharmacological inhibition. The aims of the current study were to measure the activation of PARP in human skeletal muscle biopsies at various stages of severe pediatric burn injury and to identify the cell types where this activation may occur. Another aim of the study was to test the effect of propranolol (an effective treatment of patients with burns) on the activation of PARP in skeletal muscle biopsies. Poly(ADP-ribose) polymerase activation was measured by Western blotting for its product, poly(ADP-ribose) (PAR). The localization of PARP activation was determined by PAR immunohistochemistry. The results showed that PARP becomes activated in the skeletal muscle tissue after burns, with the peak of the activation occurring in the middle stage of the disease (13-18 days after burns). Even at the late stage of the disease (69-369 days after burn), an elevated degree of PARP activation persisted in some of the patients. Immunohistochemical studies localized the staining of PAR primarily to vascular endothelial cells and occasionally to resident mononuclear cells. There was a marked suppression of PARP activation in the skeletal muscle biopsies of patients who received propranolol treatment. We conclude that human burn injury is associated with the activation of PARP. We hypothesize that this response may contribute to the inflammatory responses and cell dysfunction in burns. Some of the clinical benefit of propranolol in burns may be related to its inhibitory effect on PARP activation.

The social milieu of burn injury and recovery: using "social capital" as a framework for evaluating sex differences.

This retrospective review describes differences in social and demographic factors of women and men hospitalized for acute burns. These differences are examined using the framework of social capital to assess burn injury outcomes. Our TRACS-ABA registry was used to identify adult women admitted for the treatment of acute burns from 1998 to 2002. Each woman was matched by age (+/-5 years), %TBSA (+/-5%), and inhalation injury to a man hospitalized during the same period. Patient medical records were reviewed for sociodemographic data, burn etiology, hospital course, and discharge information. One hundred forty-five adult women hospitalized for burn injury during the study period were successfully matched by age, burn size, and inhalation injury to 145 men. The mean age of study patients was 46.4 +/- 18 years. The mean %TBSA burned was 13.0 +/- 18, and 15.5% had inhalation injury. There were no sex-related differences in any clinical outcomes evaluated. A surprising finding was that women were admitted to the hospital significantly later than men after injury (3.7 vs 1.2 days; P < .05). Days from admit to injury negatively correlated with %TBSA in women, but not in men. Women also differed from men in a number of sociodemographic factors. Social and demographic differences exist between men and women admitted for treatment of acute burn injury. These differences influence admission after burn injury. Additional efforts are needed to better measure and evaluate the role of social capital in burn injury epidemiology, management, and outcomes.

Influence of hippocampectomy on habituation, exploratory behavior, and spatial memory in rats.

Two frequently cited functions of the hippocampus are mediation of spatial memories and habituation. The present investigation employed head-shake response (HSR) as the habituated behavior in intact and bilaterally hippocampectomized rats. This HSR appears to be minimally influenced by spatial cues. These rats were further tested on two behavioral paradigms that make use of spatial cues, namely open field object exploration, and the Morris water maze. The results indicate that hippocampectomized rats revealed habituation of the HSR, but not to objects within the open field. In agreement with previous reports, hippocampectomized rats were severely impaired both in acquiring and recalling the location of the submerged platform in the Morris water maze task. In a separate experiment independent groups of rats were trained on one of these three paradigms, and tissues were collected from hippocampal, prefrontal, and piriform cortices for the measurement of matrix metalloproteinases (MMPs) as markers of neural plasticity. There were significant MMP-9 elevations in the prefrontal and piriform cortices of rats tested using the object exploration task, in the prefrontal and hippocampal cortices of rats that solved the Morris water maze task, but minimal MMP changes in any tissues taken from HSR habituated rats. These results question the hypothesis that habituation is solely mediated by the hippocampus in favor of a process that utilizes different brain structures and degrees of neural plasticity dependent upon task requirements.