Dennis C. Gore

Association of hyperglycemia with increased mortality after severe burn injury.

BACKGROUND Hyperglycemia is commonly associated with the hypermetabolic stress response. However, persistent hyperglycemia may adversely affect wound healing and immunity. The purpose of this study was to assess any relationship between hyperglycemia and clinical outcome after severe burn injury. METHODS Survey of the medical records from January 1996 to July 1999 identified 58 pediatric patients with burns > or = 60% body surface. Patients were categorized as having poor glucose control (n = 33) if > or = 40% of all plasma glucose determinations were > or = 7.8 mmol/L (140 mg/dL) and compared with patients deemed to have adequate glucose control (n = 25) in whom > or = 40% of all glucose values were > or = 7.8 mmol/L. RESULTS Despite similar age, burn size, caloric intake, and frequency of wound infection, patients categorized with poor glucose control had a significantly greater incidence of positive blood cultures (positive blood cultures/length of stay days, 0.42 +/- 0.04 for hyperglycemia patients vs. 0.30 +/- 0.03 for normoglycemia patients; mean +/- SEM, p > or = 0.05). This finding was especially prominent for blood cultures positive for yeast. Hyperglycemia patients had significantly less percentage of skin graft take than did the normoglycemic patients (percent take/operative procedure, 64 +/- 9 for hyperglycemia patients vs. 88 +/- 5 for normoglycemia patients; p < 0.05). Nine patients (27%) with persistent hyperglycemia died compared with only one death (4%) in patients with adequate glucose control (p > or = 0.05). CONCLUSION This association between poor glucose control, bacteremia/fungemia, reduced skin graft take, and subsequent mortality in severely burned children may be related to a hyperglycemia-induced detriment in antimicrobial defense. Although this report fails to establish cause and effect, these findings suggest that aggressive maneuvers to normalize plasma glucose in critically injured patients may be warranted.

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.

Lactic acidosis during sepsis is related to increased pyruvate production, not deficits in tissue oxygen availability.

OBJECTIVE The purpose of this study was to quantitate the derangements in intermediary carbohydrate metabolism and oxygen use in severely septic patients in comparison with healthy volunteers. SUMMARY BACKGROUND DATA It commonly has been assumed that the development of lactic acidosis during sepsis results from a deficit in tissue oxygen availability. Dichloroacetate (DCA), which is known to increase pyruvate oxidation but only when tissue oxygen is available, provides a means to assess the role of hypoxia in lactate production. METHODS Stable isotope tracer methodology and indirect calorimetry was used to determine the rates of intermediary carbohydrate metabolism and oxygen use in five severely septic patients with lactic acidosis and six healthy volunteers before and after administration of DCA. RESULTS Oxygen consumption and the rates of glucose and pyruvate production and oxidation were substantially greater (p < 0.05) in the septic patient compared with healthy volunteers. Administration of DCA resulted in a further increase in oxygen consumption and the percentage of glucose and pyruvate directed toward oxidation. Dichloroacetate also decreased glucose and pyruvate production, with a corresponding decrease in plasma lactate concentration. CONCLUSIONS These findings clearly indicate that the accumulation of lactate during sepsis is not the result of limitations in tissue oxygenation, but is a sequelae to the markedly increased rate of pyruvate production. Furthermore, the substantially higher rate of pyruvate oxidation in the septic patients refutes the notion of a sepsis-induced impairment in pyruvate dehydrogenase activity.

Superiority of oral ketamine as an analgesic and sedative for wound care procedures in the pediatric patient with burns.

The management of pain and anxiety in pediatric patients with burns includes the challenge of striking a balance between inadequate versus excessive medication. Ketamine provides effective sedative, analgesic, and amnestic properties for children and has been used intravenously with good results. With its recent availability as an elixir, we speculated that ketamine given orally may provide effective analgesia and sedation during wound care procedures with a wide safety margin. To test this hypothesis, 19 pediatric patients with burns undergoing a wound care procedure were randomized to receive either ketamine oral suspension or 300 mg acetaminophen with codeine phosphate and diphenhydramine, our prior standard for analgesia and sedation. Intensity of pain was determined with use of a color slide algometer and demonstrated more than 400% reduction in pain with the use of ketamine (p < 0.05). The Ramsey scale was used to quantitate sedation and demonstrated that ketamine improved sedation by 360% (p < 0.05). These results substantiate improved analgesia and sedation with oral ketamine as compared to a commonly used narcotic and sedative in facilitating wound care procedures in pediatric patients with burns. These findings suggest that expanded use of ketamine oral suspension may be.

The Quality of Life after Major Thermal Injury in Children: An Analysis of 12 Survivors with 80% Total Body, 70% Third-degree Burns

Twenty-one children admitted between December 1981 and May 1985, with greater than 80% total body surface area burn (TBSAB), underwent total excision and grafting of all of their wounds within 72 hours of injury. Twelve survivors (with an average TBSAB of 89%, 82% third degree) were studied in detai

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.

Acute response of human muscle protein to catabolic hormones

OBJECTIVE The purpose of this study was to determine the acute in vivo response of human muscle protein to stress. SUMMARY BACKGROUND DATA Prior animal and human in vitro studies have suggested that physiologic stress increases muscle protein turnover. In contrast, recent publications using a polyribosomal methodology have demonstrated a reduction in human muscle protein synthesis in vivo after surgery. METHODS Five healthy volunteers were given a stable isotopic infusion of 1,2(13)C leucine that allowed for determination of the fractional rate of muscle protein synthesis by measuring the rate of incorporation of 13C label into vastus lateralis muscle biopsies. Simultaneous infusion of 15N lysine and quantitation of leg blood flow by indocyanine green dye dilution allowed for estimation of leg muscle protein breakdown rate (Lys Ra) and synthesis rate (Lys Rd). These measurements were performed before and then at the conclusion of a 4-hour femoral arterial infusion of the catabolic hormones epinephrine, cortisol, and glucagon. RESULTS The catabolic hormone infusion elicited a significant (65%) increase in the leg muscle protein breakdown rate and a significant but less marked increase in the rate of muscle protein synthesis, as assessed by both an increase in the fractional rate of muscle protein synthesis of 48.5% and in lysine uptake within the leg of 32%. CONCLUSIONS This study conclusively demonstrates that a hormonally induced stress results in a net catabolism of human muscle protein by increasing the rate of protein breakdown in excess of an increased protein synthetic rate.

Metformin blunts stress-induced hyperglycemia after thermal injury

BACKGROUND Hyperglycemia is associated with detriments in immune function and impaired wound healing. The purpose of this study was to assess the effect of metformin, an oral antihyperglycemic agent approved for patients with diabetes mellitus, on glucose metabolism in severely burned patients. METHODS Metformin was given in a double-blind, placebo-controlled fashion to 10 patients, all with burns > 60% body surface area (age, 36 +/- 4 years; weight, 92 +/- 3 kg; mean +/- SEM). After 8 days of metformin or placebo, glucose kinetics were quantitated using isotopic dilution with 6,6-d glucose and indirect calorimetry. Measurements were made during fasting; during an intravenous glucose infusion (30 micromol/kg/min); and during a hyperinsulinemic (500 mIU/m2/h), euglycemic clamp (mean plasma glucose concentration, 6.5 +/- 0.3 mmol/L). RESULTS During fasting, metformin-treated subjects had a significantly lower rate of endogenous glucose production (met. 9.6) and glucose oxidation than placebo control subjects. With the administration of intravenous glucose, metformin treatment significantly accelerated glucose clearance, thereby attenuating hyperglycemia. During hyperinsulinemia, glucose uptake was significantly greater in metformin-treated patients. Patients receiving metformin also had a significantly higher plasma concentration of insulin. CONCLUSION These findings suggest a potential clinical efficacy of metformin to reduce stress-induced hyperglycemia by increasing glucose clearance. This effect may be mediated by either a metformin-induced augmentation of insulin sensitivity or by increasing insulin availability.

Accelerated Glutamine Synthesis in Critically III Patients Cannot Maintain Normal Intramuscular Free Glutamine Concentration

BACKGROUND Muscle glutamine is severely depleted in critically ill patients (by approximately 50% to 80% of normal). Because muscle protein breakdown, and thus the release of glutamine from muscle protein, is enhanced in response to metabolic stress, the depletion of intramuscular glutamine could be due to its impaired synthesis or accelerated outward transport or both. METHODS To distinguish these possibilities, we measured skeletal muscle glutamine metabolism in five critically ill patients by means of primed, continuous infusions of 5-15N-glutamine and ring-2H5-phenylalanine and compared them to values we previously reported for healthy volunteers. RESULTS The intramuscular free glutamine concentration in patients was approximately 70% of that in healthy volunteers (5.8 +/- 0.6 mmol/L intracellular free water vs 21.5 +/- 2.8 mmol/L). Whole-body glutamine rate of appearance was 5.8 +/- 1.0 micromol x kg (-1) body wt x min (-1), and whole-body clearance was 19.3 +/- 3.3 mL x kg(-1) x min (-1). Despite the low intramuscular glutamine concentration in the patients, the rate of unidirectional outward transport from skeletal muscle into venous blood (1.1. +/- 0.2 micromol x 100 mL x leg(-1) x min(-1)) was similar to that observed in healthy volunteers (1.6 +/- 0.2 mol x 100 mL x leg(-1) x min(-1)); intramuscular synthesis was 2.7 +/- 0.9 micromol x 100 mL x leg(-1) x min(-1) compared with a normal value of 0.6 +/- 0.06 micromol x 100 mL x leg(-1) x min(-1). Net balance across the leg was normal. CONCLUSIONS The depletion of intramuscular glutamine in critically ill patients is not due to an impairment of the rate of synthesis. In fact, accelerated glutamine production cannot maintain normal intramuscular glutamine levels because of accelerated outward transport.

Effect of exogenous growth hormone on glucose utilization in burn patients

The treatment of burn patients with recombinantly derived human growth hormone (rHGH) appears effective in counteracting protein catabolism. However, exogenous growth hormone is frequently associated with hyperglycemia, an aspect which may limit its usefulness. Therefore, to assess the affect of rHGH on glucose utilization, 13 severely burned patients (65% +/- 4 TBSA burn; mean +/- SEM) began receiving on admission either placebo or rHGH (0.2 mg/kg.d) in a double-blind randomized fashion. While hypermetabolic (percentage REE/predicted REE 1.41 +/- 0.11) fasting oxygen consumption and CO2 production were measured using indirect calorimetry prior to and then during a hyperinsulinemic euglycemic clamp. This experiment demonstrated that rHGH significantly reduced glucose uptake and inhibited glucose oxidation compared to the placebo patients. Since the decreases in glucose oxidation and uptake were proportional, glucose utilization (percentage glucose uptake oxidized) remained similar in both patient groups. Furthermore, the hyperinsulinemic clamp lowered the plasma amino acid concentrations in the control patients while rHGH-treated patients had no significant alterations. In conclusion, exogenous growth hormone therapy induces an insulin resistance in burn patients. Furthermore, since the glucose utilization did not change, it is likely that the mechanism of insulin resistance is due to a deficiency in glucose transport.