Arthur P. Sanford

American Burn Association consensus conference to define sepsis and infection in burns.

Because of their extensive wounds, burn patients are chronically exposed to inflammatory mediators. Thus, burn patients, by definition, already have “systemic inflammatory response syndrome.” Current definitions for sepsis and infection have many criteria (fever, tachycardia, tachypnea, leukocytosis) that are routinely found in patients with extensive burns, making these current definitions less applicable to the burn population. Experts in burn care and research, all members of the American Burn Association, were asked to review the literature and prepare a potential definition on one topic related to sepsis or infection in burn patients. On January 20, 2007, the participants met in Tucson, Arizona to develop consensus for these definitions. After review of the definitions, a summary of the proceedings was prepared. The goal of the consensus conference was to develop and publish standardized definitions for sepsis and infection-related diagnoses in the burn population. Standardized definitions will improve the capability of performing more meaningful multicenter trials among burn centers.

Ingestion of Casein and Whey Proteins Result in Muscle Anabolism after Resistance Exercise

PURPOSE Determination of the anabolic response to exercise and nutrition is important for individuals who may benefit from increased muscle mass. Intake of free amino acids after resistance exercise stimulates net muscle protein synthesis. The response of muscle protein balance to intact protein ingestion after exercise has not been studied. This study was designed to examine the acute response of muscle protein balance to ingestion of two different intact proteins after resistance exercise. METHODS Healthy volunteers were randomly assigned to one of three groups. Each group consumed one of three drinks: placebo (PL; N = 7), 20 g of casein (CS; N = 7), or whey proteins (WH; N = 9). Volunteers consumed the drink 1 h after the conclusion of a leg extension exercise bout. Leucine and phenylalanine concentrations were measured in femoral arteriovenous samples to determine balance across the leg. RESULTS Arterial amino acid concentrations were elevated by protein ingestion, but the pattern of appearance was different for CS and WH. Net amino acid balance switched from negative to positive after ingestion of both proteins. Peak leucine net balance over time was greater for WH (347 +/- 50 nmol.min(-1).100 mL(-1) leg) than CS (133 +/- 45 nmol.min(-1).100 mL(-1) leg), but peak phenylalanine balance was similar for CS and WH. Ingestion of both CS and WH stimulated a significantly larger net phenylalanine uptake after resistance exercise, compared with the PL (PL -5 +/- 15 mg, CS 84 +/- 10 mg, WH 62 +/- 18 mg). Amino acid uptake relative to amount ingested was similar for both CS and WH (approximately 10-15%). CONCLUSIONS Acute ingestion of both WH and CS after exercise resulted in similar increases in muscle protein net balance, resulting in net muscle protein synthesis despite different patterns of blood amino acid responses.

Amino acid supplementation increases lean body mass, basal muscle protein synthesis, and insulin-like growth factor-I expression in older women.

CONTEXT Inadequate dietary protein intake has been implicated in sarcopenia. OBJECTIVE AND DESIGN The objectives of this study were to determine whether: 1) chronic essential amino acid (EAA) supplementation improves postabsorptive muscle protein fractional synthesis rate (FSR), lean body mass (LBM), and one-repetition maximum muscle strength, and androgen receptor and IGF-I muscle protein expression; and 2) the acute anabolic response to EAA ingestion is preserved after a 3-month supplementation period. Using a randomized, double-blinded, placebo-controlled design, older women (68 +/- 2 yr) were assigned to receive either placebo (n = 7), or 15 g EAA/d [supplemented treatment group (SUP)] (n = 7) for 3 months. Metabolic outcomes were assessed in association with stable isotope studies conducted at 0 and 3 months. SETTING The study was performed at The University of Texas Medical Branch General Clinical Research Center. RESULTS Ingestion of 7.5 g EAA acutely stimulated FSR in both groups at 0 months (P < 0.05). Basal FSR at 3 months was increased in SUP only. The magnitude of the acute response to EAA was unaltered after 3 months in SUP. LBM increased in SUP only (P < 0.05). One-repetition maximum strength remained unchanged in both groups. Basal IGF-I protein expression increased in SUP after 3 months (P = 0.05), with no changes in androgen receptor or total and phosphorylated Akt, mammalian target of rapamycin, S6 kinase, and 4E-binding protein. CONCLUSIONS EAA improved LBM and basal muscle protein synthesis in older individuals. The acute anabolic response to EAA supplementation is maintained over time and can improve LBM, possibly offsetting the debilitating effects of sarcopenia.

Emerging Infections in Burns

BACKGROUND Patients who suffer severe burns are at higher risk for local and systemic infections. In recent years, emerging resistant pathogens have forced burn care providers world wide to search for alternative forms of treatment. Multidrug-resistant Staphylococcus aureus, Pseudomonas aeruginosa, Acinetobacter spp., and various fungal strains have been the major contributors to the increase in morbidity and mortality rates. Multi-drug-resistant S. aureus remains the major cause of gram-positive burn wound infections world wide. Treatment strategies include rigorous isolation protocols and new types of antibiotics where necessary. METHODS We reviewed 398 severely burned patients (burns >40% total body surface area [TBSA]) admitted to our hospital between 2000 and 2006. Patients who did not contract multi-drug-resistant gram-negative organisms during their hospital course and received our standard antibiotic regimen-vancomycin and piperacillin/tazobactam-served as controls (piperacillin/tazobactam; n = 280). The treatment group consisted of patients who, during their acute hospital stay, developed infections with multi-drug-resistant gram-negative pathogens and were treated with vancomycin and colistin for at least three days (colistin; n = 118). RESULTS Gram-negative organisms continue to cause the most severe infections in burn patients. Colistin has re-emerged as a highly effective antibiotic against multiresistant Pseudomonas and Acinetobacter infections of burns. Patients who required colistin therapy had a significantly larger average total and full-thickness burn than patients treated with piperacillin/tazobactam and vancomycin, and the mortality rate was significantly higher in the colistin group (p < 0.05). However, there was no significant difference between the colistin and piperacillin/tazobactam groups in the incidence of neurotoxicity, hepatic toxicity, or nephrotoxicity. The main fungal pathogens in burn patients are Candida spp., Aspergillus spp., and Fusarium spp. A definitive diagnosis is more difficult to obtain than in bacterial infections. Amphotericin B and voriconazole remain the two most important anti-fungal substances in our practice. CONCLUSIONS Innovations in fluid management, ventilatory support, surgical care, and antimicrobial therapy have contributed to a significant reduction in morbidity and mortality rates in burn patients. Vancomycin and clindamycin are the two most important reserve antibiotics for methicillin-resistant Staphylococcus aureus infection. Oxazolidinones and streptogramins have showed high effectiveness against gram-positive infections. Colistin has re-emerged as a highly effective antibiotic against multiresistant Pseudomonas and Acinetobacter infections. Current challenges include Candida, Aspergillus, and molds. The development of new agents, prudent and appropriate use of antibiotics, and better infection control protocols are paramount in the ongoing battle against multi-resistant organisms.

Effects of oxandrolone on outcome measures in the severely burned: a multicenter prospective randomized double-blind trial.

Severe burns induce pathophysiologic problems, among them catabolism of lean mass, leading to protracted hospitalization and prolonged recovery. Oxandrolone is an anabolic agent shown to decrease lean mass catabolism and improve wound healing in the severely burned patients. We enrolled 81 adult subjects with burns 20% to 60% TBSA in a multicenter trial testing the effects of oxandrolone on length of hospital stay. Subjects were randomized between oxandrolone 10 mg every 12 hours or placebo. The study was stopped halfway through projected enrollment because of a significant difference between groups found on planned interim analysis. We found that length of stay was shorter in the oxandrolone group (31.6 ± 3.1 days) than placebo (43.3 ± 5.3 days; P < .05). This difference strengthened when deaths were excluded and hospital stay was indexed to burn size (1.24 ± 0.15 days/% TBSA burned vs 0.87 ± 0.05 days/% TBSA burned, P < .05). We conclude that treatment using oxandrolone should be considered for use in the severely burned while hepatic transaminases are monitored.

Longitudinal assessment of Integra in primary burn management: a randomized pediatric clinical trial.

Background:Early excision with autograft-allograft closure is standard in severe burn management. Cadaver skin is associated with risks such as antigenicity, infection, and limited availability and shelf life. Previous studies have shown that Integra is safe to use in burns of <20% total body surface area. However, the suitability of its use in large burns (>50% total body surface area), its effects on postburn hypermetabolism, and the long-term cosmetic and functional results have not yet been evaluated. Materials and Methods:Twenty children with an average burn size of 73 ± 15% total body surface area (71 ± 15% full-thickness burn) were randomized to be treated with either Integra or with autograft-allograft technique. Outcome measures such as length of hospital stay, mortality, incidence of infection and sepsis, acute phase protein levels, and muscle fractional synthetic rate were compared between and within groups during the acute stay (admission to discharge). Outcome measures such as resting energy expenditure, body composition data (measured by dual-energy radiograph absorptiometry), cardiac function indexes, and number of reconstructive procedures were compared during acute hospital stay and at long-term follow-up (up to 2 yrs postinjury). Scar evaluation was performed at long-term follow-up. Results:There were no significant differences between Integra and controls in burn size (70 ± 5% vs. 74 ± 4% total body surface area), mortality (40% vs. 30%), and length of stay (41 ± 4 vs. 39 ± 4 days). In the short term, resting energy expenditure significantly decreased (p < .01), and serum levels of constitutive proteins significantly increased (p < .03) in the Integra group compared with controls. Long-term follow-up revealed a significant increase in bone mineral content and density (24 months postburn, p < .05), as well as improved scarring in terms of height, thickness, vascularity, and pigmentation (12 months and 18–24 months, p < .01) in the Integra group. Conclusion:Integra can be used for immediate wound coverage in children with severe burns without the associated risks of cadaver skin.

Insulin sensitivity and mitochondrial function are improved in children with burn injury during a randomized controlled trial of fenofibrate.

Objective:To determine some of the mechanisms involved in insulin resistance immediately following burn trauma, and to determine the efficacy of PPAR-α agonism for alleviating insulin resistance in this population. Summary Background Data:Hyperglycemia following trauma, especially burns, is well documented. However, the underlying insulin resistance is not well understood, and there are limited treatment options. Methods:Twenty-one children 4 to 16 years of age with >40% total body surface area burns were enrolled in a double-blind, prospective, placebo-controlled randomized trial. Whole body and liver insulin sensitivity were assessed with a hyperinsulinemic-euglycemic clamp, and insulin signaling and mitochondrial function were measured in muscle biopsies taken before and after ∼2 weeks of either placebo (PLA) or 5 mg/kg of PPAR-α agonist fenofibrate (FEN) treatment, within 3 weeks of injury. Results:The change in average daily glucose concentrations was significant between groups after treatment (146 ± 9 vs. 161 ± 9 mg/dL PLA and 158 ± 7 vs. 145 ± 4 FEN; pretreatment vs. posttreatment; P = 0.004). Insulin-stimulated glucose uptake increased significantly in FEN (4.3 ± 0.6 vs. 4.5 ± 0.7 PLA and 5.2 ± 0.5 vs. 7.6 ± 0.6 mg/kg per minute FEN; pretreatment vs. posttreatment; P = 0.003). Insulin trended to suppress hepatic glucose release following fenofibrate treatment (P = 0.06). Maximal mitochondrial ATP production from pyruvate increased significantly after fenofibrate (P = 0.001) and was accompanied by maintained levels of cytochrome C oxidase and citrate synthase activity levels. Tyrosine phosphorylation of the insulin receptor and insulin receptor substrate-1 in response to insulin increased significantly following fenofibrate treatment (P = 0.04 for both). Conclusions:Fenofibrate treatment started within 1 week postburn and continued for 2 weeks significantly decreased plasma glucose concentrations by improving insulin sensitivity, insulin signaling, and mitochondrial glucose oxidation. Fenofibrate may be a potential new therapeutic option for treating insulin resistance following severe burn injury.

Metabolic and Hormonal Changes of Severely Burned Children Receiving Long-Term Oxandrolone Treatment

Objective:When given to children for 1 year after a severe burn, oxandrolone significantly improves lean body mass, bone mineral content, and muscle strength. The beneficial effects of oxandrolone on height and weight were observed 1 year after treatment was discontinued. To study the efficacy of oxandrolone in severely burned children for 12 months after burn and 12 months after the drug was discontinued. Summary Background Data:Oxandrolone attenuates body catabolism during the acute phase after burn. It is unclear whether oxandrolone would have any beneficial effects during long-term treatment or if there were any effects after the drug was stopped. Methods:Sixty-one children with 40% total body surface area burns were enrolled in this study. Patients were randomized into those to receive oxandrolone (n = 30) or placebo (n = 31) for the first 12 months. Treatment was discontinued after 12 months, and the patients were studied without the drug for the following 12 months. At discharge and 6, 12, 18, and 24 months after burn, height, weight, body composition, resting energy expenditure, muscle strength, and serum human growth hormone, insulin-like growth factor-I (IGF-1), IGF binding protein-3, insulin, cortisol, parathyroid hormone, tri-iodothyronine uptake (T3 uptake), and free thyroxine index (FTI) were measured. Statistical analysis used Tukey multiple comparison test. Significance was accepted at P < 0.05. Results:Oxandrolone improved lean body mass, bone mineral content and muscle strength compared with controls during treatment, P < 0.05. Serum IGF-1, T3 uptake, and FTI were significantly higher during drug treatment compared with controls, P < 0.05. Significant increases in height and weight with oxandrolone were observed after the end of treatment. Conclusions:Oxandrolone improved body composition and strength in severely burned children during the 12 months of treatment. Its effect on height and weight continued after treatment was discontinued.

Prediction of mortality from catastrophic burns in children

BACKGROUND We previously developed a model to predict survival in massive paediatric burns (>80% total body surface area [TBSA]). This model included not only demographic variables, but also variables obtained throughout the hospital course. We aimed to prospectively validate our model for accuracy of outcome prediction. METHODS We admitted 33 paediatric burn patients with burns greater than 80% TBSA. We recorded age, burn size, inhalation injury, resuscitation, packed-cell volume at admission, base deficit, serum osmolarity, sepsis, inotropic support, platelet count, creatinine, and ventilator dependency. We entered these data into our previous models. RESULTS 20 male and 13 female children with mean age 7.6 (SD 1) years with TBSA burns of 88% (SD 1; full thickness 86% [SD 1]) were admitted. Mortality was 39.4% (13 of 30). When all variables were integrated into our final model, we predicted outcome with 97% accuracy. When we used a model based only on demographic characteristics of age, burn size, and presence of inhalation injury, outcome was correctly predicted in only 51% of patients. CONCLUSION We show prospectively that mortality in severely burned children can be reliably estimated at a burn centre, and that outcome cannot be reliably predicted on the basis of demographic and injury characteristics alone. These data suggest that all severely burned children should be given a course of treatment before consideration of treatment futility.

Influence of Metformin on Glucose Intolerance and Muscle Catabolism Following Severe Burn Injury

Summary Background Data:Hyperglycemia and accelerated muscle catabolism have been shown to adversely affect immune response and survival. The purpose of this study was to determine the effect of metformin on glucose kinetics and muscle protein metabolism in severely burned patients and assess any potential benefit of metformin in this clinical setting. Methods:In a double-blind, randomized manner, 8 adult burn patients received metformin (850 mg every 8 hours × 7 days), while 5 burn patients received placebo. Infusions of 6,6d2 glucose, d5 phenylalanine, sequential muscle biopsies, and femoral arterial, venous blood sampling allowed determination of glucose and muscle protein kinetics. Measurements were obtained immediately prior and at the conclusion of 7 days of treatment (metformin versus placebo). All patients received enteral feeds of comparable amounts during study. Results:Patients receiving metformin had a significant decrease in their plasma glucose concentration, the rate of glucose production, and an increase in glucose clearance. Metformin administration was also associated with a significant increase in the fractional synthetic rate of muscle protein and improvement in net muscle protein balance. Glucose kinetics and muscle protein metabolism were not significantly altered in the patients receiving placebo. Conclusions:Metformin attenuates hyperglycemia and increases muscle protein synthesis in severely burned patients, thereby indicating a metabolic link between hyperglycemia and muscle loss following severe injury. Therefore, therapies that improve glucose tolerance such as metformin may be of clinical value in ameliorating muscle catabolism in critically injured patients.