David W. Hart

Determinants of Skeletal Muscle Catabolism After Severe Burn

ObjectiveTo determine which patient factors affect the degree of catabolism after severe burn. Summary Background DataCatabolism is associated with severe burn and leads to erosion of lean mass, impaired wound healing, and delayed rehabilitation. MethodsFrom 1996 to 1999, 151 stable-isotope protein kinetic studies were performed in 102 pediatric and 21 adult subjects burned over 20–99.5% of their total body surface area (TBSA). Patient demographics, burn characteristics, and hospital course variables were correlated with the net balance of skeletal muscle protein synthesis and breakdown across the leg. Data were analyzed sequentially and cumulatively through univariate and cross-sectional multiple regression. ResultsIncreasing age, weight, and delay in definitive surgical treatment predict increased catabolism (P < .05). Body surface area burned increased catabolism until 40% TBSA was reached; catabolism did not consistently increase thereafter. Resting energy expenditure and sepsis were also strong predictors of net protein catabolism. Among factors that did not significantly correlate were burn type, pneumonia, wound contamination, and time after burn. From these results, the authors also infer that gross muscle mass correlates independently with protein wasting after burn. ConclusionsHeavier, more muscular subjects, and subjects whose definitive surgical treatment is delayed are at the greatest risk for excess catabolism after burn. Sepsis and excessive hypermetabolism are also associated with protein catabolism.

Anabolic effects of oxandrolone after severe burn

ObjectiveTo explore the hypothesis that oxandrolone may reverse muscle catabolism in cachectic, critically ill pediatric burn patients. Summary Background DataSevere burn causes exaggerated muscle protein catabolism, contributing to weakness and delayed healing. Oxandrolone is an anabolic steroid that has been used in cachectic hepatitis and AIDS patients. MethodsFourteen severely burned children were enrolled during a 5-month period in a prospective cohort analytic study. There was a prolonged delay in the arrival of these patients to the burn unit for definitive care. This neglect of skin grafting and nutritional support resulted in critically ill children with significant malnutrition. On arrival, all patients underwent excision and skin grafting and received similar clinical care. Subjects were studied 5 to 7 days after admission, and again after 1 week of oxandrolone treatment at 0.1 mg/kg by mouth twice daily or no pharmacologic treatment. Muscle protein kinetics were derived from femoral arterial and venous blood samples and vastus lateralis muscle biopsies during a stable isotope infusion. ResultsControl and oxandrolone subjects were similar in age, weight, and percentage of body surface area burned. Muscle protein net balance decreased in controls and improved in the oxandrolone group. The improvement in the oxandrolone group was associated with increased protein synthesis efficiency. Muscle protein breakdown was unchanged. ConclusionsIn burn victims, oxandrolone improves muscle protein metabolism through enhanced protein synthesis efficiency. These findings suggest the efficacy of oxandrolone in impeding muscle protein catabolism in cachectic, critically injured children.

Energy Expenditure and Caloric Balance After Burn: Increased Feeding Leads to Fat Rather Than Lean Mass Accretion

ObjectiveResting energy expenditure (REE) is commonly measured in critical illness to determine caloric “demands” and thus nutritive needs. Summary Background DataThe purpose of this study was to 1) determine whether REE is associated with clinical outcomes and 2) determine whether an optimal caloric delivery rate based on REE exists to offset erosion of lean mass after burn. MethodsFrom 1995 to 2001, REE was measured by indirect calorimetry in 250 survivors of 10 to 99%TBSA burns. Caloric intake and REE were correlated with muscle protein catabolism, length of stay, ventilator dependence, sepsis, and mortality. From 1998 to 2000, 42 patients (>60%TBSA burns) received continuous enteral nutrition at a spectrum of caloric balance between 1.0x REE kcal/d –1.8x REE kcal/d. Serial body composition was measured by dual energy x-ray absorptiometry. Lean mass, fat mass, morbidity, and mortality were determined. ResultsREE/predicted basal metabolic rate correlated directly with burn size, sepsis, ventilator dependence, and muscle protein catabolism (P < .05). Declining REE correlated with mortality (P < .05). 2) Erosion of lean body mass was not attenuated by increased caloric balance, however, fat mass increased with caloric supply (P < .05). ConclusionIn surviving burned patients, caloric delivery beyond 1.2 × REE results in increased fat mass without changes in lean body mass. Declining energy expenditure appears to be a harbinger of mortality in severely burned patients.

Effects of early excision and aggressive enteral feeding on hypermetabolism, catabolism, and sepsis after severe burn.

BACKGROUND Severe burn induces a systemic hypermetabolic response, which includes increased energy expenditure, protein catabolism, and diminished immunity. We hypothesized that early burn excision and aggressive enteral feeding diminish hypermetabolism. METHODS Forty-six burned children were enrolled into a cohort analytic study. Cohorts were segregated according to time from burn to transfer to our institution for excision, grafting, and nutritional support. No subject had undergone wound excision or continuous nutritional support before transfer. Resting energy expenditure, skeletal muscle protein kinetics, the degree of bacterial colonization from quantitative cultures, and the incidence of burn sepsis were measured as outcome variables. RESULTS Early, aggressive treatment did not decrease energy expenditure; however, it did markedly attenuate muscle protein catabolism when compared with delay in aggressive treatment. Wound colonization and sepsis were diminished in the early treatment group as well. CONCLUSION Early excision and concurrent aggressive feeding attenuate muscle catabolism and improve infectious outcomes after burn.

Efficacy of a high-carbohydrate diet in catabolic illness

ObjectiveTo determine within the setting of isocaloric, isonitrogenous enteral diets whether a diet that supplies most of its calories from fat or carbohydrate would be most beneficial at limiting muscle protein wasting in catabolic illness. DesignProspective, randomized, crossover trial. SettingAcademic pediatric burn unit in tertiary medical center. PatientsFourteen severely burned (>40% total body surface area) children underwent systemic metabolic and cross-leg muscle protein kinetic studies. InterventionsAll were treated clinically in a similar manner, including early excision and grafting, antimicrobial therapy, and isocaloric, isonitrogenous enteral nutritional support. Subjects randomly received either a high-carbohydrate enteral diet (3% fat, 82% carbohydrate, 15% protein), or a high-fat enteral diet (44% fat, 42% carbohydrates, 14% protein) for 1 week and then crossed over to the other diet for a second week. Measurements and Main Results On day 5 of each diet, muscle protein kinetics were determined from femoral arterial and venous blood samples during a primed-constant d5-phenylalanine infusion. Indirect calorimetry was used to determine systemic resting energy expenditure and respiratory quotient. The seven boys and seven girls were 7.1 ± 1.1 (mean ± sem) years old and suffered burns over 65 ± 4% of their bodies, with 52 ± 6% being third-degree burns. Muscle protein degradation markedly decreased (p < .01) with administration of the high-carbohydrate diet. Protein synthesis was unaltered. Endogenous insulin concentrations increased during the high-carbohydrate feeding period. No differences in energy expenditure were seen between study diets. ConclusionsIn severely burned pediatric patients, enteral nutrition supplied predominantly as carbohydrate rather than fat improves the net balance of skeletal muscle protein across the leg. This is attributable to decreased protein breakdown, suggesting a protein-sparing effect of high-carbohydrate feedings.

Biobrane® Improves Wound Healing In Burned Children Without Increased Risk Of Infection

A synthetic bilaminar membrane used as a skin substitute (Biobrane) has been shown to decrease pain and hospitalization in superficial second-degree burns. Despite these benefits, it has not been utilized universally, particularly in young children, due to a perceived increase in related infections. We propose that when this synthetic membrane is applied to superficial scald burns <25% of the total body surface area (TBSA), decreased healing times are expected without increased risk of infection. Between 1994-1999, 89 children treated within 48 h after receiving superficial partial thickness scald burns covering 5-25% TBSA with no indication of infection were seen at our hospital. Forty-one were assigned randomly to receive treatment with the skin substitute Biobrane and 48 to receive conservative treatment with topical antimicrobials and dressing changes. Comparisons of treatment were made between groups for length of hospitalization, wound healing times, and infectious complications. Children treated with Biobrane or topical antimicrobials were similar in age, race, sex, %TBSA burned, and location of burn. Those receiving Biobrane had shorter hospitalizations and healing times, which was significant for both infants and toddlers and older children. Treatment groups were not different in the use of systemic antibiotics or readmissions for infectious complications. Biobrane was removed in 5.9% of cases for non-adherence. The application of Biobrane within 48 h of superficial burns provides for shorter hospitalizations and faster healing times in children of all ages without increased risk of infection.

β-Blockade and Growth Hormone After Burn

Objective To determine whether propranolol and growth hormone (GH) have additive effects to combat burn-induced catabolism. Background Data Both GH and propranolol have been attributed anabolic properties after severe trauma and burn. It is conceivable that the two in combination would have additive effects. Methods Fifty-six children with more than 40% TBSA burns were randomized to one of four anabolic regimens: untreated control, GH treatment, propranolol treatment, or combination GH plus propranolol therapy. Clinical treatment was identical for all groups. Resting energy expenditure was determined by indirect calorimetry and skeletal muscle protein kinetics were measured using stable amino acid isotope infusions before and after each anabolic regimen. Results There were no differences in age, sex, or burn size between groups. Tachycardia and energy expenditure were decreased during propranolol treatment (P <.05). The net balance of muscle protein synthesis and breakdown was improved during proprandol and GH plus propranolol treatment (P <.05). There was no significant benefit of GH alone. No additive effect of combination therapy was seen. Conclusions Propranolol is a strongly anabolic drug during the early, hypercatabolic period after burn. No synergistic effect between propranolol and GH was identified.

Gut epithelial apoptosis after Severe burn : Effects of gut hypoperfusion

BACKGROUND Severe cutaneous burn causes transient mesenteric vasoconstriction and altered gut mucosal integrity. We recently showed that burn also increases gut epithelial cell death by apoptosis. The goal of this study was to determine whether changes in gut perfusion after burn contribute to burn-associated gut apoptosis. STUDY DESIGN We first correlated superior mesenteric artery blood flow with measurement of gut perfusion at the tissue level by laser doppler in four nonburned rats before, during, and after arterial clamping to validate our measurements of gut perfusion. We then characterized gut perfusion sequentially over time after burn; gut perfusion was measured 3 cm from the ligament of Treitz before burn and hourly for 6 hours. A group of control rats underwent the exact same protocol without the burn to exclude effects of anesthesia and laparotomy on tissue perfusion (n = 4). We studied a third group of rats with hypoperfusion of the same duration and magnitude induced mechanically without burn (n = 7). Sections of the proximal gut from all three groups (control without burn, burn, and hypoperfusion without burn) were examined for epithelial apoptosis. RESULTS Linear regression analysis demonstrated a strong correlation between superior mesenteric artery blood flow and intestinal tissue perfusion measured by laser doppler under both low and high flow conditions (r = 0.85). Laser doppler measurements of gut perfusion after burn showed deceased gut perfusion that was maximal at 2 hours postburn (p < 0.05), and that persisted for 4 hours (p < 0.05). By 6 hours, gut perfusion returned to baseline. Apoptosis increased significantly in the burn group (2.11 +/- 0.17%) compared with control (0.52 +/- 0.2%) and the mechanically decreased perfusion group (0.51 +/- .03) (p < 0.001). CONCLUSIONS We conclude that burn-induced gut hypoperfusion is insufficient to cause burn-related increased gut epithelial apoptosis. We speculate that the signal for increased gut epithelial apoptosis is primarily related to proinflammatory mediators induced by the burn wound.

Sepsis-induced failure of hepatic energy metabolism

HYPOTHESIS Recent evidence suggests that sepsis may induce an uncoupling of oxidative phosphorylation. The purpose of this study was to quantify temporal changes in hepatic oxygen consumption and cellular energy state with increasing severity of sepsis and thus assess the interrelationship of these parameters as either primary defect or compensatory response. MAIN OUTCOME MEASURES Pseudomonas aeruginosa was infused intravenously in eight instrumented anesthetized swine inducing a progressive severity of sepsis to shock. Eight other animals served as instrumented controls. Hepatic blood flow, oxygen use, and concentrations of ATP, ADP, AMP, NAD(+), and NADH were measured at baseline and then sequentially during the study. RESULTS Except for an increase in heart rate, there were no temporal changes in measured values for the control animals. For swine receiving P. aeruginosa, hepatic oxygen delivery and consumption increased with early sepsis whereas there were no alterations in the concentrations of adenine nucleotides or NAD(+)/NADH within liver. Septic shock was notable for a decrease in oxygen delivery yet oxygen consumption remained elevated because of an increase in percent oxygen extraction. The hepatic concentrations of ATP and NADH decreased during septic shock. CONCLUSIONS These findings suggest that any sepsis-induced limitation in phosphorylation may be initially compensated by an increase in oxygen use. This study also suggests that decreases in NADH availability may be a principal factor in the decompensation of sepsis to shock.

Increased tissue oxygen extraction and acidosis with progressive severity of sepsis

BACKGROUND Lactic acidosis and increased production of CO(2) are common in septic shock. Presumably, both acidosis and CO(2) enhance the release of oxygen from hemoglobin. The purpose of this study was to assess the relationship of oxygen utilization, CO(2) production, acidosis, and hemoglobin oxygen (Hgb-O(2)) dissociation with progressive severity of sepsis to shock. MATERIALS AND METHODS Femoral arterial and vein, hepatic vein, portal vein, and pulmonary artery catheters were placed in 16 anesthetized swine. Organ blood flow was determined by timed injections of colored microspheres. After baseline measurements, Pseudomonas aeruginosa was infused in eight animals. This bacterial slurry was continued inciting a progression of sepsis to shock. Eight animals served as instrumented controls. RESULTS With sepsis and shock, there was a progressive decrease in pH and an increase in pCO(2) in plasma with all sampling sites (P < 0.01 septic shock versus baseline versus control). Blood flow to the liver and intestines increased with sepsis (P < 0.01) but then returned to near baseline control values during shock. VO(2) and/or percent O(2) extraction increased with sepsis and septic shock for the whole body and for the liver, intestine and leg (P < 0.01). There was a strong correlation between venous O(2) saturation, acidosis, and pCO(2) to percent O(2) extraction (r > 60; P < 0.0001). However, calculated P(50) values for Hgb-O(2) dissociation remained unchanged. CONCLUSIONS This study demonstrates that increased oxygen extraction in severe sepsis is related to a fall in tissue oxygen availability and not related to any allosteric change in Hgb-O(2) dissociation. Therefore, acidosis and hypercapnia do not have a demonstrable effect on altering oxygen availability during sepsis.