[Show abstract][Hide abstract] ABSTRACT: Age-related skeletal muscle loss is thought to stem from suboptimal nutrition and resistance to anabolic stimuli. Impaired microcirculatory (nutritive) blood flow may contribute to anabolic resistance by reducing delivery of amino acids to skeletal muscle. In this study, we employed contrast-enhanced ultrasound, microdialysis sampling of skeletal muscle interstitium, and stable isotope methodology, to assess hemodynamic and metabolic responses of older individuals to endurance type (walking) exercise during controlled amino acid provision. We hypothesized that older individuals would exhibit reduced microcirculatory blood flow, interstitial amino acid concentrations, and amino acid transport when compared with younger controls. We report for the first time that aging induces anabolic resistance following endurance exercise, manifested as reduced (by ∼40%) efficiency of muscle protein synthesis. Despite lower (by ∼40-45%) microcirculatory flow in the older than in the younger participants, circulating and interstitial amino acid concentrations and phenylalanine transport into skeletal muscle were all equal or higher in older individuals than in the young, comprehensively refuting our hypothesis that amino acid availability limits postexercise anabolism in older individuals. Our data point to alternative mediators of age-related anabolic resistance and importantly suggest correction of these impairments may reduce requirements for, and increase the efficacy of, dietary protein in older individuals.
The FASEB Journal 10/2010; 24(10):4117-27. DOI:10.1096/fj.09-150177 · 5.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
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).
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.
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.
[Show abstract][Hide abstract] ABSTRACT: Inadequate dietary protein intake has been implicated in sarcopenia.
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.
The study was performed at The University of Texas Medical Branch General Clinical Research Center.
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.
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.
The Journal of Clinical Endocrinology and Metabolism 02/2009; 94(5):1630-7. DOI:10.1210/jc.2008-1564 · 6.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Introduction: Early excision and closure is standard for severe burn management. Cadaver skin is generally used as temporary coverage if autograft donor sites are inadequate. However, it is associated with an inherent risk of antigenicity and infection and has a limited shelf life and availability. Use of Integra™, a dermal substitute, is well established for postburn reconstruction, but its efficacy as primary coverage for severe burns it is not well documented. Therefore the aim of the present study was to determine the short- and long-term efficacy of Integra™ as an acute cover.Method: Twenty children with >40 total body surface area (TBSA) burn, were randomized to be grafted with Integra™ or with the autograft-allograft technique. Short-term outcome measures such as length of hospital stay, mortality, incidence of infection/sepsis, cardiac, respiratory, and metabolic indexes were compared between and within groups before and after Integra™/graft application. Long-term outcome measures such as number of reconstructive procedures and blinded scar scoring were performed up to 2 years postinjury. Statistical analysis was performed using paired and unpaired t-test. Values are expressed as Mean ± SEM and significance accepted at p < 0.05.Results: There were no significant differences between groups, in burn size (Controls 74 ± 4% and Integra™ 70 ± 5%), mortality (Control 30%, Integra™ 40%), length of hospital stay (Control 39 ± 4 days, Integra™ 41 ± 4 days), and metabolic rates. In addition, there was no significant incidence of infection or sepsis in the Integra™ group compared to controls. Long-term follow-up (Integra n = 5, control n = 5) revealed a significantly improved scar, in terms of height, thickness, vascularity, and maturity, in the Integra™ group compared to the control group, at 12 months and 18–24 months postburn, (p < 0.01).Conclusion: Integra™ can be safely used for immediate wound coverage in children with severe burns, with better functional and aesthetic outcomes up to 2 years postinjury.
[Show abstract][Hide abstract] ABSTRACT: Cancer and oncological therapy are associated with a progressive physical deterioration, malnutrition, and enhanced inflammatory burden. Our considerable data showing the strong anabolic potential of amino acids (AA) led us to test whether AA can acutely stimulate muscle protein synthesis in cancer patients (CA) undergoing intense chemotherapy.
Mixed muscle fractional synthesis rate (FSR), rates of phenylalanine appearance and disappearance (Ra and Rd), and net phenylalanine balance (NB) were measured during a primed constant infusion of L-[ring-(2)H(5)]phenylalanine. Blood and muscle tissue samples were collected in the basal state and following ingestion of 40 g of AA given in 30 mL boluses every 10 min for 3h. Serum and tissue cytokines and NF-kappaB expression in skeletal muscle were measured and compared to normative, healthy older controls (OC).
Skeletal muscle TNF-alpha, IL-6, and NF-kappaB were elevated in CA. FSR and model-derived protein synthesis (Rd) increased significantly from basal to AA (FSR: 0.052+/-0.009 vs. 0.120+/-0.008%h(-1), P<0.001; Rd: 23.1+/-4.1 vs. 36.4+/-5.0 nmol min(-1) 100 mL leg(-1), P0.05). Model-derived protein breakdown (Ra) remained unchanged from basal to AA. Phenylalanine NB improved from a negative basal value (-16+/-2) to zero (0.8+/-6 nmol min(-1) 100 ml leg(-1), P0.05) following AA.
Despite advanced cancer, ongoing therapy, and an enhanced inflammatory burden, AA were capable of acutely stimulating muscle protein synthesis in these patients.
[Show abstract][Hide abstract] ABSTRACT: Given the contention that survival is to be expected from even the most severely burned child, then, intuitively, at least some pediatric burn victims die because of suboptimal care. The purpose of this study is to assess the impact of any adverse events that may have contributed to the death of burned children.
Four surgeons with specialty training in pediatric burn care reviewed the clinical course and autopsy findings of 71 burned children who died after admission to a burn center during a 10-year interval. Reviewers were asked to determine the predominant factor or factors contributing to each child's demise and to assess the significance of any deviations from optimal care.
For the 10 years under review, overall mortality for all pediatric burns was 2.4%. Of these deaths, 25% had burns encompassing less than 50% body surface area. The reviewers identified lung damage as the most frequent cause of death, which was deemed largely unpreventable. Conversely, hypovolemia related to inadequate prehospital fluid resuscitation and failure to obtain and maintain a patent airway were considered the second and third most common factors in a child's death and deemed preventable under ideal circumstances.
This review implies that deficiencies in health care contribute to the demise of many burned children. The most notable areas for improvement are in fluid resuscitation and airway control. This suggests that quality assurance and educational initiatives to improve these aspects of care may have the greatest impact on further improving survival of burned children.
The Journal of trauma 11/2007; 63(4):814-8. DOI:10.1097/TA.0b013e31811f3574 · 2.96 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Growth hormone (GH) improves wound healing and ameliorates pediatric postburn tissue catabolism associated with deficient endogenous GH/IGF-1 levels. Expense, parenteral administration, and compliance have limited widespread usage. Gammahydroxybutyrate (GHB), an upstream neuromodulatory gamma-amino butyric acid (GABA) derivative, is known to increase slow wave sleep and stimulate endogenous GH secretion. In this study, improvement in GH levels in turn has been shown to accelerate wound healing.
Body composition in male Sprague-Dawley rats with > or =40% total body surface area scald burn, receiving incremental GHB doses orally, was assessed by Dual Energy X-Ray Absorptiometry. Serum GH and IGF-1 levels were measured. Wound cross sections were scored semiquantitatively for wound healing variables.
Incremental elevation in GH and IGF-1 were associated with significantly improved wound edge epithelialization and cell-layer thickness at high doses (p < 0.005). However, body composition was similar to that of burned controls.
GHB sufficiently elevated serum GH and IGF-1 levels to significantly improve epithelialization rates and layer thickness at high doses. Substantially greater elevations of serum GH and IGF-1 levels are required in the rat burn model than for humans. GHB may improve postburn hypermetabolism in humans by elevating endogenous GH levels, though only improved epithelialization was demonstrated in this study.
The Journal of trauma 11/2007; 63(5):1099-107. DOI:10.1097/TA.0b013e318157d9d0 · 2.96 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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.
Integra can be used for immediate wound coverage in children with severe burns without the associated risks of cadaver skin.
Critical Care Medicine 11/2007; 35(11):2615-23. DOI:10.1097/01.CCM.0000285991.36698.E2 · 6.31 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To determine some of the mechanisms involved in insulin resistance immediately following burn trauma, and to determine the efficacy of PPAR-alpha agonism for alleviating insulin resistance in this population.
Hyperglycemia following trauma, especially burns, is well documented. However, the underlying insulin resistance is not well understood, and there are limited treatment options.
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 approximately 2 weeks of either placebo (PLA) or 5 mg/kg of PPAR-alpha agonist fenofibrate (FEN) treatment, within 3 weeks of injury.
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).
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.
Annals of Surgery 03/2007; 245(2):214-21. DOI:10.1097/01.sla.0000250409.51289.ca · 8.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Timing of nutrient ingestion has been demonstrated to influence the anabolic response of muscle following exercise. Previously, we demonstrated that net amino acid uptake was greater when free essential amino acids plus carbohydrates were ingested before resistance exercise rather than following exercise. However, it is unclear if ingestion of whole proteins before exercise would stimulate a superior response compared with following exercise. This study was designed to examine the response of muscle protein balance to ingestion of whey proteins both before and following resistance exercise. Healthy volunteers were randomly assigned to one of two groups. A solution of whey proteins was consumed either immediately before exercise (PRE; n = 8) or immediately following exercise (POST; n = 9). Each subject performed 10 sets of 8 repetitions of leg extension exercise. Phenylalanine concentrations were measured in femoral arteriovenous samples to determine balance across the leg. Arterial amino acid concentrations were elevated by approximately 50%, and net amino acid balance switched from negative to positive following ingestion of proteins at either time. Amino acid uptake was not significantly different between PRE and POST when calculated from the beginning of exercise (67 +/- 22 and 27 +/- 10 for PRE and POST, respectively) or from the ingestion of each drink (60 +/- 17 and 63 +/- 15 for PRE and POST, respectively). Thus the response of net muscle protein balance to timing of intact protein ingestion does not respond as does that of the combination of free amino acids and carbohydrate.
[Show abstract][Hide abstract] ABSTRACT: In response to injury, muscle catabolism can be extensive, and in theory, the wound consumes amino acids to support healing. The purpose of this study is to assess a technique by which in vivo protein kinetics of muscle, wound, and normal skin can be quantified in burn-injured patients.
Study protocol consisting of infusion of d5 phenylalanine; biopsies of skeletal muscle, skin, and donor-site wound on the leg; quantification of blood flow to total leg, wound, and skin; and sequential blood sampling from the femoral artery and vein. Five-compartment modeling was used to quantify the rates of protein synthesis, breakdown, and phenylalanine transport between muscle, wound, and skin.
The study results demonstrated a net release of phenylalanine from muscle yet a net consumption of phenylalanine by the wound. Compared with skin, the wound had a substantially increased rate of protein synthesis and a reduced rate of protein breakdown (p < .01). Transport rates into and out of muscle were significantly higher than those for wound (p < .01).
This novel methodology enables in vivo quantification of the integrated response of muscle, wound, and skin protein/amino acid metabolism and confirms the long-held theory of a net catabolism of muscle and a net anabolism of wound protein in patients after injury. This methodology can be used to assess the metabolic impact of such measures as nutrition, pharmacologic agents, and surgical procedures.
Journal of Parenteral and Enteral Nutrition 07/2006; 30(4):331-8. DOI:10.1177/0148607106030004331 · 3.15 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Major trauma and burns are associated with whole body catabolism which can persist for 1 or more years after injury. This study investigates body composition in massively burned children for up to 2 years.
Twenty-five pediatric patients with greater than 40% total body surface area burns were studied. At discharge, 6, 12, 18, and 24 months after burn height, weight, body composition, resting energy expenditure (REE), serum growth hormone, insulin-like growth factor-I (IGF-I), IGF binding protein-3 (IGFBP-3), insulin, cortisol, parathyroid hormone, and thyroid hormones were measured. Tukey's test was used for analysis. Significance was accepted at p < 0.05.
Lean body mass, fat mass, bone mineral content, height, and weight increased significantly during the second year after burn. Percent predicted REE decreased significantly, whereas IGFBP-3 and parathyroid hormone levels increased significantly over time. Insulin and T3 uptake were significantly higher at discharge.
Body composition of severely burned children significantly improved in the second year compared with the first year after injury. This demonstrates a need for long-term rehabilitation in these burn patients.
The Journal of trauma 06/2006; 60(5):968-71; discussion 971. DOI:10.1097/01.ta.0000214580.27501.19 · 2.96 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Previous studies have examined the response of muscle protein to resistance exercise and nutrient ingestion. Net muscle protein synthesis results from the combination of resistance exercise and amino acid intake. No study has examined the response of muscle protein to ingestion of protein in the context of a food. This study was designed to determine the response of net muscle protein balance following resistance exercise to ingestion of nutrients as components of milk.
Three groups of volunteers ingested one of three milk drinks each: 237 g of fat-free milk (FM), 237 g of whole milk (WM), and 393 g of fat-free milk isocaloric with the WM (IM). Milk was ingested 1 h following a leg resistance exercise routine. Net muscle protein balance was determined by measuring amino acid balance across the leg.
Arterial concentrations of representative amino acids increased in response to milk ingestion. Threonine balance and phenylalanine balance were both > 0 following milk ingestion. Net amino acid uptake for threonine was 2.8-fold greater (P < 0.05) for WM than for FM. Mean uptake of phenylalanine was 80 and 85% greater for WM and IM, respectively, than for FM, but not statistically different. Threonine uptake relative to ingested was significantly (P < 0.05) higher for WM (21 +/- 6%) than FM (11 +/- 5%), but not IM (12 +/- 3%). Mean phenylalanine uptake/ingested also was greatest for WM, but not significantly.
Ingestion of milk following resistance exercise results in phenylalanine and threonine uptake, representative of net muscle protein synthesis. These results suggest that whole milk may have increased utilization of available amino acids for protein synthesis.
Medicine & Science in Sports & Exercise 05/2006; 38(4):667-74. DOI:10.1249/01.mss.0000210190.64458.25 · 3.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
Journal of burn care & research: official publication of the American Burn Association 03/2006; 27(2):131-9; discussion 140-1. DOI:10.1097/01.BCR.0000202620.55751.4F · 1.43 Impact Factor