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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.

We developed a method to measure hemoglobin synthesis rate (SynHb) in humans, assuming that free glycine in the red blood cell (RBC) represents free glycine in bone marrow for hemoglobin synthesis. The present rat study examines this assumption of the method and quantifies SynHb in rats. Sprague-Dawley rats (n = 9) were studied, [2-(13)C]glycine was intravenously infused over 24 h (2.5 mg kg(-1) h(-1)), blood was drawn for glycine and heme isolation, and bone marrow was harvested for glycine isolation. Isotopic enrichments of glycine and heme were measured, fractional hemoglobin synthesis rate (fSynHb% day(-1)) was calculated, and from this a value for SynHb (mg g(-1) day(-1)) was derived. Mean body weight was 446 +/- 10 g (mean +/- SE) and hemoglobin concentration was 14 +/- 0.5 g dl(-1). At 24 h, the mean isotopic enrichment, atom percentage excess (APE), of the RBC free glycine (1.56 +/- 0.18 APE) was similar to the bone marrow (1.68 +/- 0.15 APE). The rate of incorporation of (13)C into heme increased over time from 0.0004 APE/h between 6 and 12 h, to 0.0014 APE/h between 12 and 18 h, and 0.0024 APE/h between 18 and 24 h. Consequently, fSynHb (1.19 +/- 0.32, 2.92 +/- 0.66, and 4.22 +/- 0.56% day(-1), respectively) and SynHb (0.11 +/- 0.03, 0.28 +/- 0.05, and 0.42 +/- 0.05 mg g(-1) day(-1), respectively) showed similar patterns over the 24-h study period. We conclude that (1) enrichment of free glycine in the circulating RBC approximates enrichment of bone marrow free glycine for heme formation and (2) this pattern of hemoglobin synthesis rate is reflecting the characteristic release and gradual maturation of reticulocytes in the circulation., (Copyright 2001 Academic Press.)

Objective: To determine which patient factors affect the degree of catabolism after severe burn., Summary Background Data: Catabolism is associated with severe burn and leads to erosion of lean mass, impaired wound healing, and delayed rehabilitation., Methods: From 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., Results: Increasing 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., Conclusions: Heavier, 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.

Background: In critically ill patients, elevation in the plasma lactate concentration has traditionally been interpreted as indicating a deficiency in oxygen availability and is often an impetus to increase oxygen delivery clinically. However, another possible basis for increased lactate concentrations may be simply a mass effect from increased pyruvate availability (i.e., accelerated glycolysis)., Methods: In six hypermetabolic burned patients, the rates of glucose production and oxidation were quantified using a tracer infusion of 6,6 d2 glucose combined with indirect calorimetry. Measurements were obtained after a 9-hour fast and after a 3-hour infusion of unlabeled glucose at 30 micromol/kg/min. No patient was overtly septic, hypoxic, or hypovolemic., Results: The infusion of glucose significantly increased the arterial glucose concentration and rate of glucose oxidation, with a corresponding increase in the arterial plasma concentration of lactate and pyruvate. Resting energy expenditure and oxygen consumption were not affected by the infusion of glucose., Conclusions: These findings show that elevations in plasma lactate in severely injured patients may, in part, be related to increases in glucose flux and not entirely a reflection of any deficit in oxygen availability. Such findings highlight a potential pitfall for interpreting plasma lactate concentrations as an index of tissue oxygen availability in hypermetabolic patients.

Contracture is a major detriment to functional recovery from large wounds. To determine the relative value of dermal replacement and epidermal coverage in inhibiting wound contraction, five full-thickness wounds (all 5 x 5 cm2) were placed on the back of 8 swine and treated in the following manner: (1) open wound, (2) porcine acellular dermis (analogous to AlloDerm for human use), (3) porcine acellular dermis with epidermal autograft placed 7 days postwounding, (4) porcine acellular dermis with immediate epidermal autograft, and (5) conventional-thickness autograft. Scar dimensions and punch biopsies were taken at days 14 and 30 postwounding. The planimetry results demonstrated that wound contraction was significantly greater with the open wounds (group 1) than all other wounds with a dermal substitute. Furthermore, wounds with initial epidermal coverage had significantly less contraction than unepithelialized wounds (14.8 +/- 1.1 cm2 at day 14 in wound group 2 vs. 20.4 +/- 0.6 cm2 in wound group 4; p < 0.05). Biopsy results revealed that wounds with initial epithelial coverage had the least amount of inflammation. These findings suggest that both dermal matrix and epidermal coverage contribute to an inhibition of wound contraction and that prompt epithelial coverage appears to impede contraction by reducing inflammation.

Objective: To evaluate the effect of gut gavage both alone and with enteral administration of monoclonal antibodies to endotoxin on the liberation of tumor necrosis factor (TNF)-alpha and subsequent hemodynamics after hemorrhage/resuscitation., Design: Dose response intervention, sham-controlled animal study., Setting: Research laboratory at a university medical center., Animals: Instrumented rats (250-325 g body weight) underwent standardized hemorrhage/resuscitation., Interventions: Animal groups received 4 hrs before hemorrhage/resuscitation: gastric gavage with Colyte alone (group 1), combined with E5 antiendotoxin at either 0.2 mg/100 g (group 2) or 2 mg/100 g body weight (group 3), or sham controls (group 4). There were six animals studied in each of the four groups., Measurements and Main Results: For animals receiving gut gavage and high-dose E5 antiendotoxin, plasma concentrations of TNF-alpha (pg/mL) at 120 mins after hemorrhage/resuscitation were significantly lower compared with sham controls (16+/-4 group 3; 65+/-36 group 4; mean +/- SD, p < .05). At 300 mins, this same treatment group had a significantly higher mean blood pressure (mm Hg) (110+/-6 group 3; 86+/-7 group 4: p < .05). Also at 300 mins after hemorrhage/resuscitation, plasma lactate concentrations (mmol/L) were significantly lower for all gut gavage treatment groups compared with sham control animals (1.9+/-0.2 group 1; 2.0+/-0.2 group 2; 1.8+/-0.2 group 3; 4.8+/-2.8 group 4, p < .05)., Conclusions: Prior treatment with gut gavage and enterally administered antiendotoxin antibodies reduces TNF-alpha liberation after hemorrhage/resuscitation and confers a subsequent improvement in hemodynamics and decreased plasma lactate concentrations. Such therapy may be efficacious in patients undergoing elective procedures where major hemorrhage is likely or in severely injured patients with continued or recurrent hemorrhage.

Purpose: To determine the roles of laparoscopic abdominal exploration (LE) and diagnostic peritoneal lavage (DPL) in the evaluation of abdominal stab wounds, we prospectively compared LE with mandatory celiotomy (MC) in 76 patients having anterior abdominal stab wounds penetrating the fascia over a 22-month period., Patients and Methods: Twenty-two patients underwent emergency celiotomy. The remaining patients were subjected to DPL and assigned to treatment by either celiotomy or initial LE with subsequent conversion to open exploration at the discretion of the attending surgeon., Results: Laparotomy was avoided in 55% of the 31 patients undergoing initial laparoscopy, and this group demonstrated a significant decrease in the incidence of nontherapeutic celiotomy, from 19% to 57% (P < 0.05), as well as decreased length of hospital stay (4 +/- 0.6 v 5.9 +/- 0.4 days; P < 0.05), and total hospital cost ($6119 +/- 756 v $8312 +/- 627; P < 0.05). There were no missed intraabdominal injuries or morbidity from laparoscopy identified in follow-up. The DPL (N = 36) was positive in 11 of the 12 patients with injury requiring surgical repair and was negative in 16 of the 25 patients not requiring repair. The sensitivity and specificity of DPL were 0.91 and 0.64 compared with 1.0 and 0.74 for laparoscopy., Conclusions: An algorithm to evaluate stable patients with anterior abdominal stab wounds and minimize overall costs of care, incidence of nontherapeutic celiotomy, and rate of missed injuries is suggested consisting of DPL followed by observation in patients with negative DPL and by laparoscopy in patients with positive DPL. Wounds to the thoracoabdominal region may be best evaluated by initial LE, as diaphragmatic wounds may result in a false-negative DPL.

Plasma glutamine levels decrease in association with severe injury, which suggests that the consumption of glutamine exceeds the production of glutamine or possibly represents a deficit in the release of glutamine from skeletal muscle. The goal of this study was to assess the peripheral glutamine kinetic response to prolonged stress in children with critical injuries. To accomplish this purpose, we quantitated peripheral glutamine kinetics in vivo with the use of 5N15 glutamine in 5 children with severe burns (total body surface area, 74%+/-14%; mean +/- SEM) and 3 children who underwent elective scar reconstruction. In the children with severe burns, leg blood flow was significantly elevated (16.2+/-2.1 vs 7.5 +/-0.3 mL/min/100 mL leg volume, P < .02) and the arterial concentration of glutamine was significantly reduced (0.31+/-0.04 vs 0.84+/-0.05 mmol/L, P < .001). The rate of glutamine turnover within the leg was significantly reduced in the patients with acute burns, whereas the net efflux of glutamine was similar between the 2 groups. These findings suggest that plasma glutamine concentrations decrease during severe stress as a result of a deficit in peripheral glutamine release in conjunction with an increased central consumption. This preliminary study supports the notion that exogenous glutamine supplementation in pediatric patients with severe injuries may be needed because of this inadequate skeletal muscle response.

We investigated whether the normal anabolic effects of acute hyperaminoacidemia were maintained after 5 days of oxandrolone (Oxandrin, Ox)-induced anabolism. Five healthy men [22 +/- 3 (SD) yr] were studied before and after 5 days of oral Ox (15 mg/day). In each study, a 5-h basal period was followed by a 3-h primed-continuous infusion of a commercial amino acid mixture (10% Travasol). Stable isotopic data from blood and muscle sampling were analyzed using a three-compartment model to calculate muscle protein synthesis and breakdown. Model-derived muscle protein synthesis increased after amino acid infusion in both the control [basal control (BC) vs. control + amino acids (C+AA); P < 0.001] and Ox study [basal Ox (BOx) vs. Ox + amino acids (Ox+AA); P < 0.01], whereas protein breakdown was unchanged. Fractional synthetic rates of muscle protein increased 94% (BC vs. C+AA; P = 0.01) and 53% (BOx vs. Ox+AA; P < 0.01), respectively. We conclude that the normal anabolic effects of acute hyperaminoacidemia are maintained in skeletal muscle undergoing oxandrolone-induced anabolism.

Androstenedione is the immediate precursor of testosterone. Androstenedione intake has been speculated to increase plasma testosterone levels and muscle anabolism. Thus, androstenedione supplements have become widely popular in the sport community to improve performance. This study was designed to determine whether 5 days of oral androstenedione (100 mg/day) supplementation increases skeletal muscle anabolism. Six healthy young men were studied before the treatment period and after 5 days of oral androstenedione supplementation. Muscle protein turnover parameters were compared to those of a control group studied twice as well and receiving no treatment. We measured muscle protein kinetics using a three-compartment model involving infusion of L-[ring-2H5]phenylalanine, blood sampling from femoral artery and vein, and muscle biopsies. Plasma testosterone, androstenedione, LH, and estradiol concentrations were determined by RIA. After ingestion of oral androstenedione, plasma testosterone and LH concentrations did not change from basal, whereas plasma androstenedione and estradiol concentrations were significantly increased (P<0.05). Compared to a control group, androstenedione did not affect muscle protein synthesis and breakdown, or phenylalanine net balance across the leg. We conclude that oral androstenedione does not increase plasma testosterone concentrations and has no anabolic effect on muscle protein metabolism in young eugonadal men.

Objective: Bronchoscopy and lavage are used to confirm diagnosis and can be therapeutic in patients suffering inhalation injury. Lavage is traditionally performed using saline, which is unfortunately associated with profound transient hypoxemia. Perfluorocarbons, having a high gas solubility for oxygen and carbon dioxide, increase oxygenation when instilled into the airway. We hypothesized that the use of perfluorocarbons for bronchoscopic lavage would attenuate this transient hypoxemia., Methods: Sheep were prepared for chronic study. They were insufflated with cotton smoke and then randomized to receive a lavage with 200 mL of perfluorocarbon or saline at 2, 6, 12, and 24 hours after injury., Results: All animals had a steady and significant decline in their pre- to post-PaO2/FiO2 (P/F) ratio. At 2, 6, and 12 hours, the saline lavage group had a significant decrease in their P/F ratio (485+/-32 to 212+/-37 mm Hg, 439+/-22 to 170+/-40 mm Hg, and 381+/-48 to 184+/-59 mm Hg). This decrease in P/F ratio was not observed in the perfluorocarbon group (474+/-19 to 459+/-29 mm Hg, 424+/-32 to 387+/-43 mm Hg, and 366+/-50 to 357+/-67 mm Hg)., Conclusion: These findings indicate that perfluorocarbons attenuate the transient hypoxemia associated with saline bronchoscopic lavage and thus may be considered safer for patients with acute lung injury.

Background: Increasing the percentage of inspiratory time during mechanical ventilation (i.e., inverse inspiratory-expiratory (I:E) ventilation) is frequently used to improve oxygenation in patients with acute respiratory distress syndrome; however, an optimal I:E ratio is unknown., Methods: To assess for an optimal I:E ratio, hemodynamic, ventilatory, and oxygenation parameters were determined in eight adult trauma patients with acute respiratory distress syndrome supported with pressure-control ventilation. An indwelling pulmonary artery catheter facilitated the extensive measurements as I:E ratios were randomly changed between 1:1 and 3:1. Measurements were determined 30 minutes after each change in the I:E ratio., Results: Increasing the percentage of inspiratory time resulted in a progressive increase in arterial oxygenation (p < 0.05) in conjunction with elevations in mean airway pressure (p < 0.05) and a decrease in alveolar-arterial oxygen difference (p < 0.05). Furthermore, progressive reversal of the I:E ratio significantly diminished alveolar ventilation (p < 0.01), with worsening dynamic compliance (p < 0.01). There were no demonstrable changes in hemodynamics., Conclusion: These findings demonstrate the effectiveness of increasing inspiratory time to improve oxygenation, yet to the detriment of ventilation. This suggests that within the parameter confines of this study, the preferential I:E ratio is a balance between oxygen demands and ventilatory requirements.

Background: To reduce cost, outpatient surgery is advocated when feasible; however, the potential of compromising outcome is a concern. The purpose of this review is to assess patient outcome and cost for managing operative burn injuries without hospitalization., Methods: During the past 18 months, 54 patients were identified with burns amenable to operative debridement and skin grafting without hospitalization. Twenty patients chose to be hospitalized and underwent prompt skin grafting. Operative skin grafting as an outpatient was chosen by the remaining 34 patients. Of these, four patients were subsequently hospitalized postoperatively (two for pain, one for cellulitis, and one for vomiting)., Results: Hospitalized patients and outpatients were similar in age and extent of burn; however, those hospitalized underwent skin grafting sooner after injury (2.1 +/- 0.4 days for inpatients vs. 11.5 +/- 0.8 days for outpatients; mean +/- SEM). Inpatients also had a significantly larger area skin-grafted (286 +/- 24 cm2 for inpatients vs. 178 +/- 14 cm2 for outpatients). Graft take was very good in each group. Cost, as indexed by patient charge, was substantially less for outpatients ($2,397 +/- $222) than for inpatients ($17,220 +/- $410)., Conclusion: These results demonstrate a significant cost reduction with nonhospitalized operative care of burn injuries without any overt detriment in outcome, thus endorsing outpatient skin grafting when amenable. This review also illustrates that delaying operative intervention reduces the burn area required for grafting.

Background: Malignancies enlarge because protein synthesis exceeds the rate of breakdown; however, the specific protein kinetic pattern remains unknown. Determining in vivo protein kinetic rates for a tumor may be useful for quantifying individual responses to a specific therapy. The aim of this study was to assess whether the growth of tumors is related to an increase in protein synthesis or an inhibition of protein breakdown., Methods: Five patients (age, 59 +/- 3 years) with adenocarcinoma of the colon undergoing colonoscopy were studied. Tissue protein synthesis and breakdown rates were measured in vivo for both segments of colon cancer and adjacent normal-appearing colonic mucosa by using a primed, continuous infusion of 1(13)C leucine with tissue biopsy and quantitation of regional blood flow by laser Doppler flowmetry., Results: Segments of colon cancer had a significantly (p < 0.05) greater rate of protein synthesis as quantitated by both the fractional rate of protein synthesis (Ca 45.4% +/- 5.0%/day versus nl mucosa 35.7% +/- 3.1%/day; mean +/- SEM) and by the tissue synthesis rate (Ca 69.4 +/- 9.0 versus nl mucosa 51.6 +/- 5.2 mumol/L leucine/day/100 gm tissue). Regional blood flow was significantly elevated in the cancer (Ca 110.9 +/- 5.8 versus nl mucosa 91.2 +/- 2.9 ml/min/100 gm), which contributed to commensurate rates of tissue breakdown (Ca 28.6 +/- 2.0 versus nl mucosa 28.2 +/- 2.4 mumol/L leucine/day/100 gm)., Conclusions: These results illustrate that human colon cancers grow in vivo as a result of increases in protein synthesis. Furthermore, increases in regional blood flow limit the rate of tissue protein breakdown of colon cancer, thereby contributing to growth of the malignancy. These findings support the contention that therapeutic strategies aimed at negating this inherent increase in protein synthesis or limiting blood flow may effectively limit the growth of malignancies. This methodology may also provide an index for evaluating the effectiveness of future therapies aimed at reducing tumor growth for individual patients.

Background: Hypothermia exacerbates coagulopathy and is thus a potentially devastating morbidity during operative debridement of burn wounds. Current techniques for maintaining body temperature include warming intravenous fluids at 38 degrees C. The purpose of this study was to assess the safety of infusing saline heated to 55-60 degrees C., Methods: Using a modified fluid warmer, saline heated to 60 degrees C was infused through central venous access in eight adult patients undergoing debridement of burn wounds. The temperature of the saline actually entering the patient was measured by a thermocouple attached at the connection to the central line catheter., Results: The actual infusate temperature was 54.0 +/- 1.2 degrees C. Over the first hour, 1,100 mL of hot saline was given, thus delivering 17.6 kcal more heat than fluid warmed to the traditional 38 degrees C. Core temperature measured via esophageal and Foley catheters had an insignificant trend toward increase during the operative procedure. There was no evidence of intravascular hemolysis or coagulopathy., Conclusion: This pilot study suggests that infusion of hot crystalloids given via central venous access is safe and may be an acceptable adjuvant in attenuating hypothermia during operative procedures.

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.

Objective: Colloids are used clinically to minimize edema yet may have detrimental consequences on glomerular filtration. The purpose of this study is to assess the renal and hormonal effects of colloid supplementation in the fluid resuscitation of burn victims., Design: Analytic cohort study., Material and Methods: Immediately following their 24 hour post-burn fluid resuscitation with Ringer's lactate, six burn patients (% total body surface area burn 30-57%) were given primed, continuous infusions of inulin and p-aminohippuric acid for 6 hours. Albumin (25% solution, 3 mL/kg/h) was given for the final 4 hours of study., Measurements and Main Results: Albumin infusion increased plasma volume by 37%; however, glomerular filtration rate decreased by 32% (p < 0.05). There was no significant change in urine output, sodium excretion, or effective renal plasma flow. Plasma volume expansion with albumin normalized elevated basal levels of aldosterone and plasma renin activity., Conclusions: These findings illustrate that despite substantially increasing plasma volume, colloid infusions reduce glomerular filtration and may limit any associated diuresis. Furthermore, this study demonstrates that hormonal regulation of blood volume remains intact after moderate burn injury.

Hyperglycemia is common in severely ill patients and is related principally to an increase in glucose production. Dichloroacetate (DCA), which is known to increase the rate of pyruvate oxidation, has been shown to lower plasma glucose concentrations in normal fasting subjects and in diabetics and thus may be efficacious in treating stress induced hyperglycemia. However, the mechanism by which DCA lowers the plasma glucose concentration in humans has not been elucidated. To examine the human in vivo metabolic alterations induced by DCA, six fasting volunteers were infused with 6,6-D2-glucose and indirect calorimetry was performed prior to and following DCA administration. Glucose, lactate, and alanine net balance across the leg were also quantitated. Following DCA administration, plasma glucose concentrations decreased by 9% due to a proportional decrease in the rate of glucose production (P < 0.05). DCA had no affect on glucose clearance or leg net balance; however, the rate of glucose oxidation increased by 24% from baseline (P < 0.05). This increase in glucose oxidation without a compensatory change in peripheral glucose consumption suggests an improved efficiency in peripheral glucose utilization induced by DCA. Plasma concentrations of lactate and alanine were also lowered by DCA (56% for lactate, 66% for alanine, P < 0.05) without a significant alteration in leg net balance. These results suggest that DCA may decrease gluconeogenesis by limiting the availability of the precursor substrates lactate and alanine. Thus dichloroacetate may be an appropriate alternative to insulin in correcting mild elevations in plasma glucose concentrations. Furthermore, DCA may be especially effective in severely ill patients where hyperglycemia is largely due to increases in gluconeogenesis.

Objective: To assess any relationship between hyperglycemia and muscle protein catabolism associated with critical illness., Design: Cohort analytic study., Setting: Clinical research center and intensive care unit of a university hospital., Participants: Six healthy volunteers and five patients with severe sepsis., Interventions: Study subjects were given infusions of 6,6,d2 glucose and 15N lysine for 6 hours. After infusion of the stable isotopes for 2 hours (basal period), dichloroacetate, which accelerates pyruvate oxidation, was given (dichloroacetate period). Leg blood flow was measured by indocyanine green dye dilution, and femoral artery and vein substrate concentrations were quantitated., Main Outcome Measures: The metabolic rates of glucose production, oxidation, and clearance; the whole-body protein breakdown rate; and the net efflux of amino acids from the leg were determined., Results: In comparison with the healthy volunteers, septic patients had significant elevations in glucose production, oxidation, and clearance, accelerated protein catabolism, and greater net peripheral efflux of amino acids. Dichloroacetate significantly decreased glucose production and increased the percentage of glucose directed toward oxidation in both healthy volunteers and septic patients. However, this dichloroacetate-induced perturbation of glucose utilization had no significant effect on whole-body protein breakdown or the efflux of specific amino acids from the leg except for alanine, whose net efflux doubled (P < or = .05)., Conclusions: The findings of this study demonstrate a universal acceleration in the metabolic rates of both intermediary glucose metabolism and protein/amino acid catabolism during sepsis. Except for alanine, however, there appears to be no coupling between these two physiologic responses to sepsis.

Objectives: To quantitate duplex Doppler measurements of splanchnic perfusion to determine if these measurements are reproducible in euvolemic humans and if such measurements are sensitive to mild degrees of systemic hypovolemia., Design: Prospective, nonrandomized, controlled trial., Setting: Clinical research center., Participants: Seven fasting, healthy male and female volunteers, ranging in age from 25 to 37 yrs and weighing 60 to 90 kg., Interventions: Pulse, blood pressure, hematocrit, and duplex Doppler measurements of the peak systolic velocity and time averaged velocity of the subdiaphragmatic aorta, celiac artery, and superior mesenteric artery were obtained at four time points. Time points I and II were on separate days before hemorrhage and consisted of routine blood donation of 450 mL. Time point III was immediately after blood donation. Time point IV was 24 hrs after donation. Estimated blood flow was calculated from time averaged velocity (estimated blood flow = 60[vessel cross-sectional area][time averaged velocity])., Measurements and Main Results: Vital signs and hematocrit remained without significant change at all time points. Peak systolic velocity, time averaged velocity, and estimated blood flow were also unchanged between measurements at time points I and II. However, after a mean reduction of 9.1% of total blood volume, duplex ultrasound detected significant decreases of 14.5% in celiac artery and superior mesenteric artery peak systolic velocity, as well as 15.1%, 17.3%, and 20.2% decreases in aorta, celiac artery and superior mesenteric artery time averaged velocity and estimated blood flow, respectively (all values p < .05 vs. baseline, Duncan's multiple range test). All measured variables returned to baseline 24 hrs after hemorrhage., Conclusions: Noninvasive duplex Doppler measurements of splanchnic peak systolic velocity, time averaged velocity, and estimated blood flow are reproducible and sensitive to small changes in intravascular volume. These data suggest a potential clinical role for duplex imaging in the treatment of critically ill patients to guide therapy to optimize splanchnic perfusion.

Objective: To assess the acute and protracted adaptive response of peripheral glutamine kinetics to a severe injury., Design: Comparison study., Setting: Clinical research center at a university-affiliated hospital., Patients: Six severely burned men and five young healthy men., Interventions: The catabolic hormones epinephrine, cortisol, and glucagon were infused simultaneously into the femoral artery of five healthy volunteers, thus acutely simulating the hormonal milieu associated with a severe injury., Main Outcome Measures: Whole-body glutamine flux and peripheral glutamine kinetics were determined using glutamine labeled with nitrogen 15 and net balance measurements in patients 2 weeks following a severe burn injury. Identical measurements were made in the healthy volunteers before and following 4 hours of catabolic hormone infusion., Results: Whole-body glutamine flux increased to a similar extent in both the burn patients and in volunteers following catabolic hormone infusion. In comparison with their basal kinetics, the hormonally simulated acute stress in the volunteers induced a significant efflux of glutamine from the leg by greatly increasing the rate of glutamine appearance. In contrast, burn patients had a significant decrease in their rate of glutamine appearance and achieved a similar net loss of glutamine from the leg only by a compensatory decrease in peripheral glutamine consumption., Conclusions: These findings suggest that in the acute stress response, skeletal muscle preferentially releases glutamine from its free intracellular pool. As this reserve becomes depleted, net glutamine efflux is maintained by decreasing its rate of muscle glutamine utilization. These results suggest a failure of muscle to augment de novo glutamine synthesis and support the conclusion that glutamine is a conditionally essential amino acid during critical illness.

Objective: The effect of insulin-like growth factor-1 (IGF-1) on energy expenditure and protein and glucose metabolism in a group of patients with thermal injury was determined., Summary Background Data: Accelerated protein catabolism is a constant feature of the hypermetabolic response to thermal injury. Insulin-like growth factor-1 has been reported to minimize protein catabolism and normalize energy expenditure in animal models of thermal injury., Methods: To determine the efficacy of IGF-1 in human burn patients, resting energy expenditure (metabolic cart), whole body protein kinetics (N15 Lysine), and glucose disposal (glucose tolerance test) were assessed in eight burn patients before and after a 3-day infusion of IGF-1 (20 micrograms/kg/hr). All patients were fluid-resuscitated uneventfully and were without obvious infection at the time of study. Enteral nutrition was administered at a constant rate before and during the IGF-1 infusion., Results: Resting energy expenditure was not altered by IGF-1 (40.3 +/- 2.2 vs. 39.1 +/- 2.3 kcal/kg/day). However, glucose uptake was promoted, and protein oxidation decreased significantly (0.118 +/- 0.029 vs. 0.087 +/- 0.021 g/kg/d, p < 0.05) by IGF-1. In addition, insulin secretion, in response to a glucose challenge, was blunted., Conclusions: Insulin-like growth factor-1 therapy has a beneficial effect in preserving lean body mass during severe stress conditions by minimizing the flux of amino acids toward oxidation.

Objective: To determine the impact of catabolic hormones on the pattern of amino acid efflux from human skeletal muscle during stress., Design: Cohort analytical study., Setting: Burn intensive care unit and clinical research facility at a university hospital., Patients: Five patients with severe burns and five healthy volunteers of similar size and age., Interventions and Measurements: The net balance of amino acids across the leg was determined in five healthy volunteers prior to and following a 2-hour infusion of the catabolic hormones epinephrine, cortisol, and glucagon into the femoral artery. These results were compared with amino acid net balance measurements in five severely burned patients., Results: Hormonal simulation of stress in the normal volunteers increased glutamine efflux from the leg to an extent similar to that of the burn patients. Alanine efflux, however, was not affected by the hormonal infusion. Because alanine efflux constituted a major proportion of the total peripheral amino acid catabolism in the burn patients, there was significantly less total amino acid nitrogen loss from the healthy volunteers receiving the stress hormones., Conclusions: Catabolic hormones alone fail to reproduce the stress-induced pattern and quantity of amino acid efflux from human skeletal muscle. This discrepancy is largely due to an unresponsiveness of alanine to hormonally induced muscle protein catabolism.

Although C3H/HeJ mice, characterized by a genetic deficiency in macrophage cytokine release in response to endotoxin, have been studied extensively to gain insight into the possible role of various cytokines in sepsis, few past studies have examined the physiologic response to hemorrhagic shock in this "endotoxin-resistant" strain. We utilized a fixed-volume model of hemorrhagic shock and two different levels of hemorrhage severity (50 and 67% blood volume) to compare C3H/HeJ mice to normal C3H/HeN mice. An additional group of endotoxin-sensitive C3H/HeN mice were treated with 2.5 mg/kg of anti-tumor necrosis factor (TNF) antibody to define the possible role of TNF in shock physiology. Hematocrit, circulating neutrophils, and plasma glucose and lactate concentrations were measured following hemorrhage. TNF increased significantly following hemorrhage in normal mice but did not increase in C3H/HeJ mice or in C3H/HeN mice treated with anti-TNF antibody. No difference between groups was identified in hematocrit, circulating neutrophils, or glucose. Whereas plasma lactate increased significantly by 30 min in all groups, lactate returned to baseline levels in C3H/HeJ mice at 60 min, but remained persistently elevated in C3H/HeN mice and in C3H/HeN mice treated with anti-TNF antibody. The data demonstrate attenuated lactate accumulation in C3H/HeJ mice following hemorrhage. Inhibition of circulating TNF activity with anti-TNF antibody failed to reproduce this late decrease in plasma lactate in normal mice. The data suggest that macrophage products other than TNF known to be deficient in C3H/HeJ mice contribute to anaerobic metabolism in hemorrhagic shock.

Objective: To assess if the derangements in peripheral glucose, lactate, and oxygen utilization that are observed in severely injured patients are due to the hormonal response to injury or are related to the extent of the wound., Design: Comparison study., Interventions: The catabolic hormones epinephrine, cortisol, and glucagon were infused simultaneously into the femoral artery of six healthy volunteers, thus simulating the hormonal milieu associated with severe trauma in an uninjured leg., Setting: Clinical research center at a university-affiliated hospital., Patients: Young, adult males deemed healthy by screening medical history, physical examination, and blood chemistries., Measurements and Main Results: Substrate net balance and indirect calorimetry measurements were performed before and then at the completion of 2 hrs of catabolic hormone infusion. Catabolic hormones elicited significant increases in leg glucose uptake and oxidation, and an increased net efflux from the leg of lactate and alanine. While leg oxygen delivery also increased, catabolic hormones failed to alter peripheral oxygen consumption., Conclusions: Catabolic hormones can elicit a similar peripheral metabolic response in an uninjured leg as that reported previously by Wilmore et al. in severely burned extremities. This finding suggests that the hormonal milieu associated with severe injury is influential in regulating peripheral glucose and oxygen utilization and that wound inflammation is not an essential component of this response.

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.

The purpose of this study was to examine the relationship of peripheral metabolism of glucose, lactate, alanine, and muscle protein catabolism to pyruvate availability during stress. Peripheral catabolic stress was simulated by the infusion of epinephrine, cortisol, and glucagon into the femoral artery of 12 healthy volunteers, 6 of whom received prior treatment with dichloroacetate while 6 served as controls. The catabolic hormone infusion reproduced the peripheral stress response in which glucose consumption increased and the efflux of lactate, alanine, and total amino acid nitrogen (i.e., net muscle protein catabolism) from the leg increased. Dichloroacetate (DCA), which is known to increase pyruvate oxidation, reduced the hormonally stimulated efflux of pyruvate and alanine from the leg and decreased the rate of extremity glucose consumption. DCA had no effect on the rate of lactate efflux and except for alanine had no effect on the stimulated rate of total amino acid nitrogen loss. These results demonstrate the dependence of alanine efflux on pyruvate availability during stress and suggest that the rate of glycolysis within peripheral tissues is a major factor in regulating the quantity of alanine efflux. This study further illustrates that except for alanine, pyruvate kinetics are not salient in the regulation of muscle protein catabolism and elucidates the dichotomy between alanine kinetics and true muscle protein breakdown.

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.

To evaluate the role of solvent-processed human cadaveric dura in experimental tracheal reconstruction, anesthetized piglets underwent an elliptical excision of a four-ring segment of the trachea. Twelve animals were randomly divided into two equal groups: in group I, the resected trachea was rotated 180 degrees and sutured into position; in group II, the resected trachea was replaced with dura. The animals were extubated after the operation, and endotracheal stents were not used. Tracheal dimensions were recorded, and tissues were evaluated for mechanical compliance (percent elongation/displacement). Histology of the grafts was characterized by fibrosis and granulation tissue, and there were no distinguishing features between groups. The data suggest that solvent-processed human dura has compliance and patency comparable to those of autologous free-grafted trachea and that it may prove useful as an adjunct to reconstructive tracheal surgery in infants.

To evaluate the effects of ibuprofen on gram-negative septic shock, immature piglets were subjected to fecal-Escherichia coli peritonitis. Group I (n = 5) received a 12.5 mg/kg bolus of ibuprofen in 0.9% benzyl alcohol, followed by a continuous infusion of 6.25 mg/kg/h. Group II (n = 5) received the vehicle, benzyl alcohol, and Group III (n = 5) received lactated Ringer's solution. Mean survival times among the three groups were not significantly different. Ibuprofen-treated animals had a mean survival time (+/- S.E.M.) of 17.1 +/- 2 h vs. 19.2 +/- 2.4 h in the benzyl alcohol group and 15.7 +/- 2.7 h in the animals receiving lactated Ringer's solution. Thromboxane B2 levels were not significantly different in the treatment vs. non-treatment groups while 6-keto-PGF1a levels were significantly lower in the ibuprofen-treated animals. Neutropenia and thrombocytopenia were not prevented by treatment with ibuprofen.

Beta adrenergic blockade diminishes the catecholamine-mediated elevations in heart rate and myocardial contractility that characterize postburn hypermetabolism. To examine how these alterations in cardiac performance affect peripheral perfusion, indirect calorimetry and leg blood flow were measured before and then after a 2-hour intravenous propranolol infusion. Five severely burned patients (55% + 7% total burn surface area), given propranolol at 8 micrograms/kg/minute, had a significant reduction in cardiac index and heart rate with an increased leg vascular resistance resulting in a decrease in extremity perfusion. Four healthy volunteers were given propranolol at 5 micrograms/kg/minute, resulting in a comparable decrease in heart rate, yet there was no change in leg vascular resistance or extremity perfusion. In both patient groups, propranolol decreased the plasma lactate concentration. This suggests that in hypermetabolic patients, beta adrenergic blockade reduces peripheral perfusion and that peripheral perfusion is not a principal determinate of plasma lactate levels. Rather adrenergic blockade appears to decrease lactate concentration as a consequence of the inhibition of lipolysis.

The effect of growth hormone on protein kinetics was assessed in burned patients during the hyperdynamic phase using N15 lysine and balance data across the leg. Levels of resting energy expenditure and cardiac index were comparably elevated in all patients, but leg blood flow was greater in the patients receiving growth hormone. Growth hormone therapy (0.2 mg/kg per day) significantly stimulated protein synthesis in the whole body and in the studied leg. A hyperinsulinemic clamp, which raised the insulin concentration to more than 1435 pmol/L of blood, caused comparable stimulation of leg protein synthesis in patients not receiving growth hormone, but did not further increase protein synthesis in the growth hormone-treated patients. These results suggest that administration of exogenous growth hormone may limit the peripheral protein wasting in severely injured patients by a mechanism similar to that of insulin.

Nutritional support is provided to children after severe burn injuries in amounts derived from empirical formulas or measurements of resting energy expenditure. To scrutinize these methods, indirect calorimetry measurements were performed on 74 survivors of burns (greater than or equal to 40% total body surface area) and compared to their actual caloric intake, percent weight change, and optimal caloric requirements formulated from the Curreri and Shriners' equations. These parameters showed that in spite of an initial deficit in actual caloric intake as compared to formulated goals, weight was maintained, whereas resting energy expenditures ranged from 30% to 40% below the actual caloric intake. Furthermore, a subgroup of patients (n = 42) who met +/- 20% of their formulated needs were stratified by extent of burn; this illustrated a significant weight gain in the more severely burned children. In conclusion, nutritional formulas in popular use overestimate caloric requirements in severe burns, whereas resting energy expenditure measurements require an additional factor of 30% to maintain body weight.

To evaluate the effects of heparin on gram-negative septic shock, immature piglets were subjected to fecal Escherichia coli peritonitis. One group of animals received a continuous infusion of heparin 25 units/kg/hr, while the control animals were given an equivalent volume of lactated Ringer's solution. Heparin-treated animals (n = 5) had a mean survival time (+/- SEM) of 18.8 +/- 2.2 hr vs. 11.9 +/- 2.8 (P less than 0.05) in controls (n = 5). Animals receiving heparin tended to have improved hemodynamic profiles and less leukopenia than controls.