Androstenedione does not stimulate muscle protein anabolism in young healthy men.

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.

Assessment of human colon cancer protein kinetics in vivo.

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.

Glutamine kinetics in burn patients. Comparison with hormonally induced stress in volunteers.

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.

Catabolic hormones alone fail to reproduce the stress-induced efflux of amino acids.

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.

Except for alanine, muscle protein catabolism is not influenced by alterations in glucose metabolism during sepsis.

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.

Effect of exogenous growth hormone on whole-body and isolated-limb protein kinetics in burned patients.

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.

Ibuprofen therapy in experimental porcine gram-negative septic shock.

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.

Accelerated glutamine synthesis in critically ill 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.

Segmental adenomyomatosis of the gallbladder. A radiologic, sonographic, and pathologic correlation.

Adenomyomatosis is a hyperplastic condition that is occasionally symptomatic. The segmental form of adenomyomatosis can result in marked wall thickening in the waist of the gallbladder, giving a characteristic "hourglass" deformity in both the oral cholecystogram and the ultrasound examination.

The application of solvent-processed human dura in experimental tracheal reconstruction.

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.

Deficiency in peripheral glutamine production in pediatric patients with burns.

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.

Comparison of resting energy expenditures and caloric intake in children with severe burns.

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.

Complementary roles of laparoscopic abdominal exploration and diagnostic peritoneal lavage for evaluating abdominal stab wounds: a prospective study.

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.

Outcome and cost analysis for outpatient skin grafting.

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.

Hemodynamic and ventilatory effects associated with increasing inverse inspiratory-expiratory ventilation.

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.

Infusion of hot crystalloid during operative burn wound debridement.

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.

In vivo metabolic response of glucose to dichloroacetate in humans.

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.

Gut gavage with antiendotoxin antibodies reduces the liberation of tumor necrosis factor-alpha after hemorrhage/resuscitation.

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.