Metabolic intervention in surgical patients. An assessment of the effect of somatostatin, ranitidine, naloxone, diclophenac, dipyridamole, or salbutamol infusion on energy and protein kinetics in surgical patients using stable and radioisotopes.

We have assessed the effect of a variety of forms of metabolic intervention on both energy and protein metabolism in 44 severely ill surgical patients. The patients were studied either in the basal state or while receiving total parenteral nutrition (TPN), and the metabolic effects were assessed using the primed-constant infusion of a combination of stable isotopes and radioisotopes. Somatostatin infusion, either in the basal state or in the TPN, did not change glucose kinetics, but there was a significant decrease in the rate of net protein catabolism (NPC). In the basal studies the rate of NPC decreased from 3.4 +/- 0.7 g/kg/d to 2.9 +/- 0.7 g/kg/d (p less than 0.002), while in the TPN patients the corresponding values were 1.48 +/- 0.61 g/kg/d and 1.10 +/- 0.50 g/kg/d, respectively (p less than 0.005). Histamine type 2 blockade with ranitidine did not significantly alter glucose kinetics, but in both the TPN patients and in the basal state ranitidine was associated with a significant decrease in the rate of NPC. In the basal state rate of NPC was 2.44 +/- 0.53 g/kg/d and during ranitidine infusion the value was 2.08 +/- 0.42 g/kg/d (p less than 0.04). Naloxone infusion did not alter glucose kinetics, but there was a significant decrease in the rate of NPC from a basal value of 2.6 +/- 0.6 g/kg/d to 2.3 +/- 0.5 g/kg/d (p less than 0.04). The infusion of the prostaglandin antagonists diclofenac or dipyridamole resulted in increases in the plasma insulin level, and as a result glucose turnover decreased in both groups. In the diclofenac group the rate of glucose turnover decreased from 14.4 +/- 1.7 mumol/kg/min to 12.6 +/- 1.3 mumol/kg/min (p less than 0.02). Neither prostaglandin antagonist resulted in any significant change in the rate of NPC. Beta-adrenergic stimulation with salbutamol resulted in a significant increase in glucose turnover from 12.1 +/- 1.1 mumol/kg/min to 13.4 +/- 0.9 mumol/kg/min (p less than 0.02), and the rates of appearance (Ra) of both alanine and free fatty acids (FFAs) also increased. Alanine Ra increased from 11.7 +/- 2.5 mumol/kg/min to 12.8 +/- 3.0 mumol/kg/min, and the corresponding values for FFA turnover were 7.6 +/- 1.1 mumol/kg/min and 10.3 +/- 2.1 mumol/kg/min (p less than 0.03), respectively. Salbutamol infusion did not result in any significant change in the rate of NPC.(ABSTRACT TRUNCATED AT 400 WORDS)     

Ligation of a patent ductus arteriosus under fentanyl anesthesia improves protein metabolism in premature neonates

BACKGROUND/PURPOSE: Although surgical ligation effectively reverses the cardiopulmonary failure associated with patent ductus arteriosus (PDA), previous findings have suggested that such surgery itself elicits a catabolic response in premature neonates. Therefore, the authors sought to quantitatively assess whether PDA ligation under fentanyl anesthesia aggravated or improved the protein metabolism of premature neonates. METHODS: Seven ventilated, premature neonates (birth weight 815 +/- 69 g) underwent PDA ligation with standardized fentanyl anesthesia (15 microg/kg) on day-of-life 8.4 +/- 1.2 and were studied immediately pre- and 16 to 24 hours postoperatively while receiving continuous total parenteral nutrition (TPN). Whole-body protein kinetics were calculated using intravenous 1-[13C]leucine, and skeletal muscle protein breakdown was measured from the urinary 3-methylhistidine to creatinine ratio (MH:Cr). RESULTS: Whole-body protein breakdown (10.9 +/- 1.2 v8.9 +/- 0.8 g/kg/d, P < .05), turnover (17.4 +/- 1.2 v 15.4 +/- 0.8 g/kg/d, P< .05), and MH:Cr (1.95 +/- 0.20 v 1.71 +/- 0.16 micromol:mg, P< .05) decreased significantly after operation. This resulted in a 60% improvement in protein balance (1.6 +/- 0.8 v 2.6 +/- 0.6 g/kg/d, P = 0.08) postoperatively. CONCLUSIONS: Because of decreased whole-body protein breakdown, whole-body protein turnover, skeletal muscle protein breakdown, and increased protein accrual, surgical PDA ligation under fentanyl anesthesia promptly improves the protein metabolism of premature neonates enduring the stress of a PDA.     

Whole-body protein kinetics in patients with early and advanced gastrointestinal cancer: the response to glucose infusion and total parenteral nutrition

We have isotopically determined rates of whole-body protein synthesis and catabolism in a group of normal volunteers and in two groups of cancer patients: 20 patients with advanced weight-loss (AWL) upper gastrointestinal cancer and 7 patients with early non-weight-loss (ENWL) lower gastrointestinal cancer. In both patients and volunteers we determined protein kinetics in the basal state and during glucose infusion at 4 mg/kg/min. In addition, in the AWL patients the effect of total parenteral nutrition (TPN) on protein dynamics was also assessed. The rate of net protein breakdown was determined with the primed constant infusion of either 15N-urea or 14C-urea, the rate of whole-body protein catabolism was measured with the primed constant infusion of 15N-lysine, and the rate of whole-body protein synthesis was deduced from the above two values. The basal rates of net protein catabolism, whole-body protein catabolism, and whole-body protein synthesis were similar in the volunteers and ENWL cancer patients. The basal values for net protein catabolism in the volunteers and ENWL patients were 1.46 +/- 0.18 and 1.34 +/- 0.08 gm/kg/min, respectively. In both volunteers and ENWL patients glucose infusion resulted in a significant decrease in net protein catabolism. In the ENWL patients this decrease was due to a significant decrease in whole-body protein catabolism (p less than 0.05); the rate of whole-body protein synthesis did not change significantly. In the AWL cancer patients the rate of net protein catabolism was significantly higher than in either the volunteer or ENWL group (p less than 0.05), and glucose infusion did not result in a decrease in net protein catabolism. However, when the AWL group was studied during TPN there was a significant decrease in net protein catabolism from 2.24 +/- 0.30 to 0.17 +/- 0.09 gm/kg/day (p less than 0.01). This decrease was due to the combined effect of a significant decrease in whole-body protein catabolism coupled with an increase in whole-body protein synthesis. From these studies we conclude the following: (1) ENWL cancer patients and normal volunteers have similar protein dynamics, and in both groups glucose infusion resulted in a significant decrease in protein loss. (2) AWL cancer patients have an elevated rate of net protein catabolism, and this is not sensitive to glucose infusion.(ABSTRACT TRUNCATED AT 400 WORDS)     

Branched chain amino acids as the protein component of parenteral nutrition in cancer cachexia

A prospective randomized trial was conducted to determine the effects of branched chain amino acids (BCAA) as the protein component of total parenteral nutrition (TPN) on protein kinetics in patients with intraabdominal adenocarcinoma. Nine malnourished patients were given both conventional TPN containing 19 per cent BCAA (AA) and isocaloric, isonitrogenous TPN containing 50 per cent BCAA (BCAA-TPN), in random order. Both [13C]leucine and [14C]tyrosine were employed as tracers to avoid the potential bias due to the different amino acid composition of the two TPN solutions. With BCAA-TPN, leucine and tyrosine flux increased significantly from (mean +/- s.d.) 158.0 +/- 37.2 to 243.5 +/- 75.8 mumol kg-1 h-1 (P less than 0.025) and from 35.0 +/- 8.4 to 42.6 +/- 11.0 mumol kg-1 h-1 (P less than 0.05) respectively. Leucine oxidation was significantly higher on BCAA-TPN (24.1 +/- 6.3 on AA versus 68.3 +/- 37.1 mumol kg-1 h-1, P less than 0.025) while tyrosine oxidation was significantly lower (3.7 +/- 1.8 mumol kg-1 h-1 on AA versus 2.5 +/- 2.0 mumol kg-1 h-1 on BCAA-TPN, P less than 0.05). Whole body protein synthesis and breakdown was significantly higher on BCAA-TPN by the tyrosine tracer (31.3 +/- 7.3 on AA versus 40.1 +/- 9.3 mumol kg-1 h-1, P less than 0.025 and 33.0 +/- 8.4 on AA versus 41.3 +/- 11.1 mumol kg-1 h-1, P less than 0.05) respectively. Using the leucine tracers both synthesis and breakdown were increased, but not significantly, from 133.8 +/- 40.0 to 175.3 +/- 65.1 mumol kg-1 h-1 and from 127.9 +/- 33.6 to 167.7 +/- 71.2 mumol kg-1 h-1 respectively. The fractional albumin synthetic rate increased significantly on BCAA-TPN from 4.3 +/- 2.9 on AA to 8.0 +/- 5.1 per cent per day (P less than 0.05). The reduction in tyrosine oxidation, suggesting improved protein utilization, coupled with an increase in protein and albumin synthesis, strongly support a positive benefit from BCAA-TPN in cancer cachexia.     

The mechanism of the reduction of protein catabolism following trauma and during sepsis using xylitol

Total parenteral nutrition (TPN) after trauma and sepsis has two major goals. One is the reduction of enhanced protein catabolism; the second is the avoidance of enhancement of whole-body glucose turnover. Glucose and xylitol differ in their quantitative utilization rate after trauma and sepsis. Maximal glucose utilization is reduced during such states, while the utilization of xylitol is more than doubled. In order to investigate whether these differences are associated with beneficial effects with regard to whole-body glucose turnover rate of gluconeogenesis and protein sparing, we conducted two studies using animal models and two clinical studies. METHODS. For the determination of glucose and protein turnover, radioactive and stable isotope techniques were applied. In an animal model a primed constant infusion of 3-H-6-glucose, 14-C-1-alanine and 13-C-3-alanine and 14-C-U-acetate was used to determine total glucose appearance, gluconeogenesis from 3-C-precursors and alanine flux. In the human studies hepatic glucose production was determined by using a primed constant infusion of 6.6-D-2-glucose and urea synthesis rate was determined by a primed constant infusion of 2-N-15-urea. RESULTS. In the first rat model we were able to show that hypocaloric xylitol compared to glucose significantly reduced whole-body glucose turnover from 1741 +/- 232 mumol/h during glucose infusion to 449 +/- 49 mumol/h during xylitol infusion and gluconeogenesis from C-3 carbons form 382 +/- 24 mumol/h during glucose infusion to 155 +/- 39 mumol/h during xylitol infusion after a burn trauma. In a second septic rat model the exchange of glucose calories by xylitol in a proportion of 1:1 was associated with a significantly ameliorated N-balance from +144 +/- 90 mgN/kg body weight per day during glucose infusion to +699 +/- 80 mgN/kg body weight per day during glucose-xylitol infusion and a reduced 3-methyl-histidine excretion from 7.14 +/- 0.61 mumol/kg body wt. per day during glucose infusion to 4.10 +/- 0.56 mumol/kg per day during glucose-xylitol infusion, respectively. In two studies with surgical intensive care patients we were able to confirm the nitrogen-sparing properties of xylitol infusion, together with amino acids during hypocaloric feeding or during TPN with a glucose/xylitol mixture in a proportion of 1:1. From a basal urea production rate of 9.2 +/- 1.6 mumol/kg min. xylitol led to a significant reduction with 6.4 +/- 1.5 mumol/kg per min. Hepatic glucose production was significantly reduced during xylitol infusion from basal 4.8 +/- 0.6 mg/kg per min to 3.1 +/- 0.7 mg/kg per min, respectively. Equicaloric glucose in a dosage of 3 g/kg per day had no effect. During TPN glucose/xylitol, in a proportion of 1:1 at a total dosage of 0.24 g/kg per h, significantly reduced whole-body glucose turnover, endogenous glucose production and lactate concentrations compared to an isocaloric glucose infusion. DISCUSSION. In animal as well as in human studies hypocaloric xylitol as well as a glucose-xylitol mixture were more efficient in preserving body protein than glucose alone. Whole-body glucose turnover was significantly reduced during hypocaloric xylitol or glucose-xylitol infusion compared to isocaloric glucose infusion. During the acute phase after trauma we therefore recommend a carbohydrate supplementation of 3 g/kg body wt. per day using xylitol. During long-term TPN, a glucose-xylitol mixture in a proportion of 1:1 in a dosage of 3 g/kg body wt. per day each is recommended as energy source, together with amino acids and, if necessary, lipids.     

The effects of atrial natriuretic peptide on urinary protein excretion in patients with renal parenchymal disease and those with diabetic mellitus

The effects of atrial natriuretic peptide (ANP) on urinary protein excretion were examined in patients with renal parenchymal diseases (RPD, n = 18) and those with diabetes mellitus (DM, n = 12). Before and 30 min after intravenous injection of ANP (50 micrograms), urine samples were collected. ANP injection increased urinary volume and urinary sodium excretion in both groups. In RPD, urinary protein excretion (UprV) increased by 87% (1.5 +/- 0.7 [SEM] to 2.8 +/- 1.1 mg/min, p less than 0.05). ANP also increased UprV in patients with diabetic nephropathy [N(+); 1.7 +/- 0.8 to 5.0 +/- 2.5 mg/min, p less than 0.05] and those without nephropathy [N(-); 0.10 +/- 0.02 to 0.22 +/- 0.07 mg/min, p less than 0.05]. Since ANP increased creatinin clearance in both groups (+9.4 +/- 2.5 ml/min in RPD and +24.1 +/- 3.5 ml/min in DM, p less than 0.01 for both), urinary protein to creatinine excretion ratios (UprV/UcrV) were determined, which should be a parameter of glomerular protein permeability. The UprV/UcrV ratio increased by 48% (p less than 0.01) and 24% (p less than 0.05) in RPD and in DM, respectively. ANP did not change urinary composition of albumin and globulin. In RPD, increases in UprV by ANP were positively related to the basal serum creatinin levels (r = 0.57, p less than 0.01). In DM group, ANP-induced increases in the UprV/UcrV ratio were higher in the N(+) subgroup than in the N(-) subgroup (+0.8 +/- 0.4 vs +0.09 +/- 0.04, p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Urinary excretion of inorganic pyrophosphate by normal subjects and patients with renal calculi in north-western India and the effect of diclofenac sodium upon urinary excretion of pyrophosphate in stone formers.

24 h urinary pyrophosphate excretion was studied in 20 normal healthy subjects and 75 idiopathic stone formers from north-western regions of India. The mean 24-hour urinary excretion of pyrophosphate was significantly low in stone formers (50.67 +/- 2.16 mumol/24 h) as compared to that of normal subjects (71.46 +/- 5.46 mumol/24 h) (p less than 0.01). Diclofenac sodium, a non-steroidal anti-inflammatory agent, was administered 50 mg thrice daily for 1 week to 18 stone formers and 24-hour urinary pyrophosphate excretion was studied before and after drug therapy. The 24-hour urinary excretion of pyrophosphate increased from 54.32 +/- 21.40 to 78.31 +/- 28.03 mumol subsequent to diclofenac sodium therapy (p less than 0.01).     

Glucose and urea kinetics in patients with early and advanced gastrointestinal cancer: the response to glucose infusion, parenteral feeding, and surgical resection

We isotopically determined rates of glucose turnover, urea turnover, and glucose oxidation in normal volunteers (n = 16), patients with early gastrointestinal (EGI) cancer (n = 6), and patients with advanced gastrointestinal (AGI) cancer (n = 10). Studies were performed in the basal state, during glucose infusion (4 mg/kg/min), and during total parenteral feeding (patients with AGI cancer only). Patients with early stages of the disease were also studied 2 to 3 months after resection of the cancer. Basal rates of glucose turnover were similar in volunteers and in patients with EGI cancer (13.9 +/- 0.3 mumol/kg/min and 13.3 +/- 0.2 mumol/kg/min, respectively) but were significantly higher in patients with AGI cancer (17.6 +/- 1.4 mumol/kg/min). Glucose infusion resulted in significantly less suppression of endogenous production in both patient groups than that seen in the volunteers (76% +/- 6% for EGI group, 69% +/- 7% for AGI group, and 94% +/- 4% for volunteers). The rate of glucose oxidation increased progressively in proportion to the tumor bulk. In the volunteers the percent of VCO2 from glucose oxidation was 23.9% +/- 0.7%, and in EGI and AGI groups the values were 32.8% +/- 2.0% and 43.0% +/- 3.0%, respectively. After curative resection of the cancer, glucose utilization decreased significantly (p less than 0.05). The rate of urea turnover was significantly higher in the AGI group (8.4 +/- 1.0 mumol/kg/min) in comparison with the volunteer group value of 5.9 +/- 0.6 mumol/kg/min (p less than 0.03). Glucose infusion resulted in a significant suppression of urea turnover in the volunteers (p less than 0.02), but in the AGI group glucose infusion did not induce a statistically significant decrease. We conclude from these studies that the presence of even a small, potentially curable gastrointestinal cancer is associated with a loss of the normal host-regulatory mechanisms designed to conserve body resources; this effect is more marked as the tumor bulk increases; increasing tumor bulk effects a progressive increase in glucose utilization and in protein breakdown.     

Demonstration of a reduction in postoperative body protein breakdown using the Clinitron fluidized bed with an ambient temperature of 32 degrees C

Patients managed at an elevated ambient temperature after major surgery have a less pronounced rise in postoperative urinary nitrogen excretion. To investigate the mechanism involved, body protein breakdown was assessed, using a tracer dose of labelled amino acid, in patients following aorto-bifemoral bypass surgery nursed on either a Clinitron fluidized bed at 32 degrees C or a hospital bed at 22 degrees C and correlated with urinary total nitrogen excretion. Results showed a small reduction in measured body protein breakdown on the second postoperative day in patients managed on the Clinitron fluidized bed at 32 degrees C (2.92 +/- 0.91 versus 3.23 +/- 0.84 g protein kg-1 day-1; mean +/- s.d.), which was equivalent to the mean protein sparing (0.29g protein kg-1 day-1) demonstrated by the significant improvement in urinary total nitrogen excretion (9.20 +/- 2.0 versus 12.48 +/- 3.9 g N day-1; mean +/- s.d.: P less than 0.05). Urinary total nitrogen excretion (N) and body protein breakdown (B) showed a weak though significant positive correlation (B = 1.25 + 13.13N; r = +0.55: P = 0.05), whereas no correlation existed between urinary total nitrogen excretion and the derived rate of body protein synthesis. There was also a significant decrease in postoperative stress, measured during the isotope infusion, in patients managed on the Clinitron fluidized bed at 32 degrees C (12.3 +/- 2.2 versus 16.1 +/- 3.2 per cent activity incorporated into plasma proteins; mean +/- s.d.: P less than 0.05). These results show the beneficial effect of managing postoperative patients on a Clinitron fluidized bed at 32 degrees C in conserving body nitrogen through a reduction in body protein breakdown, probably as a consequence of decreased postoperative stress.     

The effect of major thermal injury and carbohydrate-free intake on serum triglycerides, insulin, and 3-methylhistidine excretion.

The severely burned patient responds differently to starvation ketosis in the early stage of injury as compared to the normal individual. A similar response has been observed in the patient after skeletal trauma and sepsis. In order to determine the extent of muscle protein contribution and the mechanism(s) involved, 11 burn patients with 35% to 80% BSA burn were resuscitated using carbohydrate-free solutions for 3 days followed by unrestricted intake. Blood was drawn daily and 24-hour urinary nitrogens were determined. Controls consisted of 10 preoperative elective surgical patients and two normal volunteers. The burned patients lost a mean +/- SEM of 17.1 +/- 1.72 g nitrogen per day on the third day. The mean +/- SEM ketone body response on the third day for burned patients was 385 +/- 77 mumol/l compared to 727 +/- 81 mumol/l for control patients. The mean +/- SEM 3-methylhistidine loss for burned patients on the third day was 9.83 +/- 0.82 mumol/kg compared to 3.6 mol/kg for control patients. Insulin levels on the third day of fast were three times the normal group. This insulin increase may be the modulating factor that suppresses excessive fat mobilization. This metabolic response causes a lower plasma ketone level, which may then necessitate the need for continued protein catabolism for glucose production for certain tissues. The protein contribution to the hypercatabolic response as assessed by increased urinary nitrogen losses is in part supported by an increased muscle protein breakdown as indicated by increased 3-methylhistidine excretion.     

The effect of human growth hormone on protein metabolism in the surgically stressed state]

The effects of human growth hormone (HGH) on protein metabolism were investigated. In the experimental study, thirty one male SD rats receiving TPN were divided into 2 groups (control group & HGH group). Cumulative nitrogen balance after burn in HGH group was significantly higher than in control group. (p less than 0.05) Rates of whole body protein turnover (Q), together with those of synthesis (S) and breakdown (B) were significantly higher in HGH group than in control group. (p less than 0.01) Nitrogen balance significantly correlated with urinary total catecholamine excretion in both groups. (p less than 0.01) The difference of correlations of nitrogen balance to urinary total catecholamine excretion between two groups was statistically significant (p less than 0.01) when compared by analysis of covariance. In the clinical study, 12 patients after sub-total esophagectomy receiving TPN were divided into 2 groups (control group & HGH group). Cumulative nitrogen balance after operation in HGH group was significantly higher than in control group. (p less than 0.01) Q,S, and B were higher in HGH group than in control group. Increase of S was statistically significant. (p less than 0.01). These results indicate that HGH may be greatly beneficial in improving protein metabolism in the surgically stressed state.     

An integrated analysis of glucose, fat, and protein metabolism in severely traumatized patients. Studies in the basal state and the response to total parenteral nutrition.

A series of isotopic infusions were performed in 43 severely ill patients suffering from blunt trauma (mean injury severity score of 31). The patient data have been compared with data obtained from 32 normal volunteers, and in addition the metabolic response of the trauma patient to total nutritional support (TPN) has been assessed. The rate of VO2 was elevated in the trauma patients compared with that of the volunteers (160 mumol/kg/minute vs. 103 mumol/kg/minute). Glucose production was significantly increased in the patients compared with the volunteers (21 +/- 2 mumol/kg/minute vs. 14 +/- 1 mumol/kg/minute), but the trauma patients had an impaired capacity to directly oxidize plasma glucose. The percentage of glucose uptake oxidized in the volunteers was 36 +/- 2%, and the percentage of glucose uptake recycled was 10 +/- 1%. By contrast, in the trauma patients, 23 +/- 4% of the glucose uptake was directly oxidized, and 29 +/- 11% was recycled. The rate of glycerol turnover in the trauma patients (5.3 +/- 0.3 mumol/kg/minute) was significantly elevated compared with the volunteer value (2.2 +/- 0.1 mumol/kg/minute), and the basal rate of fat oxidation was twice as high in the patients as in the volunteers (2 mg/kg/minute vs. 1 mg/kg/minute). The rate of whole body protein catabolism was significantly higher in the patients (5.8 +/- 0.7 g/kg/day vs. 4.3 +/- 0.3 g/kg/day), and as a result, the rate of net protein catabolism was significantly elevated in the patients. The response to TPN (amino acids and a 50:50 mixture of glucose and fat) included an increase in the percentage of glucose uptake oxidized (up to 45 +/- 12%), a decrease in the oxidation of fat (up to 0.8 mg/kg/minute), and a significant increase in whole body protein synthesis (up to 6.1 +/- 1.1 g/kg/day) so that the rate of net protein loss was minimized but not prevented. (The rate of net protein catabolism during TPN was 1.3 +/- 0.5 g/kg/day.) There was no correlation between the injury severity score (ISS) and the degree of metabolic abnormality. The rate of NPC in the patients with ISS less than 20 was higher than in the volunteers (ISS = 0), but the values for NPC in patients with ISS 21-40, and ISS greater than 40 were virtually identical to the corresponding values in patients with ISS less than 20. It is concluded from these studies that: 1) Trauma patients have a high rate of VO2.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of intermittent muscle stimulation on muscle catabolism in patients immobilized in the ICU

Are muscular contractions obtained by electrical stimulation able to reduce muscle catabolism in immobilized patients? Ten patients (65 to 79 yr old), hospitalized in an intensive care unit for postoperative failure or cerebral infarction, were studied during nine days. Artificial nutrition was the same for each patient during the study. Two periods of four days where defined and randomized for each patient, separated by one day; during the stimulation period (S), intermittent electrical stimulation of the muscles of the legs (external electrodes) was performed daily 2 X 30 min; during the non-stimulation period (NS), muscular stimulation was not performed. Urinary excretion of nitrogen (micro-Kjeldhal digestion and Nessler procedure), creatinine (Jaffé reaction) and 3-methylhistidine were measured every day. Results (X +/- SD) are as follows: the nitrogen balance (g/d) was -1.29 +/- 1.26 during the NS period and 1.43 +/- 1.10 during the S period (NS); 3-methylhistidine (mumol/kg/d) was 3.78 +/- 0.37 during the NS period and 3.15 +/- 0.32 during the S period (p less than 0.01); creatinine (mumol/kg/d) was 92.9 +/- 6.8 during the NS period and 72.9 +/- 25 during the S period (p less than 0.01). It is concluded that a significant decrease in 3-methylhistidine and creatinine excretions is observed during the S period. In intensive care unit patients, muscle protein breakdown may be influenced by intermittent electrical muscle stimulation.     

Whole body protein turnover, synthesis and breakdown in patients receiving total parenteral nutrition (TPN) before and after recovery from surgical stress

This study was conducted to clarify the mechanisms underlying the loss of body nitrogen after trauma. Six patients who underwent abdominal surgery and six for control were studied. The measurement of whole body protein turnover was made on the third and tenth postoperative day during TPN with constant infusion of [15N] glycine according to Picou and Taylor-Roberts. The measurement was also made on six control patients during TPN in non-stressed state. The rates of whole body protein turnover (Q), synthesis (S) and breakdown (B) were calculated from the plateau 15N enrichment of urinary total N, which was analyzed with a mass spectrometer. The values were compared with control and the changes in the individual patients were examined by a paired t-test. Immediately after operation, Q and B were significantly elevated (p less than 0.05 and p less than 0.02, respectively), and reduced with the improvement of N-balance after recovery from stress by 0.95 +/- 0.21 and 0.61 +/- 0.13 g X protein/kg X day, respectively. The changes in Q and B were statistically significant (p less than 0.005 and p less than 0.005, respectively). Whereas, no tendency of alteration in S was found throughout the study. It is concluded that protein turnover rate increases in surgical stress, and that the increased protein catabolism rather than the alteration in synthesis could account for the postoperative nitrogen losses.     

Comparative study of the circadian rhythmicity in the urinary concentration of glycosaminoglycans in patients of calcium oxalate nephrolithiasis and in healthy adults

Glycosaminoglycans (GAGs) are potent inhibitors of calcium oxalate crystallisation and/or crystal aggregation. Urinary concentration of GAGs has been shown to vary during 24 h; therefore, circadian rhythmicity in urinary concentration of GAGs was investigated in 33 healthy male adults in the age group of 20-40 years and in 27 male patients of a similar age group with calcium nephrolithiasis. Three-hourly urine samples were collected for 24 h beginning from 00.00 h for estimation of urinary concentration of GAGs. The data of each patient was analysed by single cosinor rhythmometry and population mean-cosinor rhythmometry was then applied to each group. Twenty-four-hour urinary excretion of GAGs was significantly less in renal calculus patients (16.867 +/- 5.89 mumol) than in healthy subjects (22.588 +/- 5.32 mumol; p less than 0.001). A statistically validated circadian rhythm in urinary concentration of GAGs was demonstrated in both the groups. However, the amplitude-acrophase test revealed a significant difference between the two groups (F2,57 = 8.305; p less than 0.001); the amplitude was 2.354 mumol/l in patients with nephrolithiasis, whereas the amplitude was 7.028 mumol/l in healthy adults. The mesor test also revealed a significant difference in the 3-hour urinary concentration of GAGs between the two groups (18.536 mumol/l in healthy adults vs. 9.728 mumol/l in patients with nephrolithiasis). Thus in patients with nephrolithiasis, not only is the 24-hour urinary excretion of GAGs significantly low but the 3-hourly urinary concentration of GAGs is also significantly decreased as compared to healthy subjects.(ABSTRACT TRUNCATED AT 250 WORDS)     

The inefficiency of total parenteral nutrition to stimulate protein synthesis in moderately malnourished patients.

The acute whole-body and peripheral tissue protein response to total parenteral nutrition (TPN) was evaluated before surgery in moderately malnourished patients with stable disease. A primed constant infusion of (U-14C) tyrosine was used in combination with simultaneous measurements of the leg exchange of amino acids, glucose, glycerol, and free fatty acids (FFA). Energy expenditure was measured by indirect calorimetry. Sixteen patients with stable disease and in need of nutritional support were randomized to receive TPN at rates either corresponding to resting requirements (nonprotein calories at 120% of REE with 0.2 g of N/kg/d) or at increased rates (200% of REE with 0.33 g of N/kg/d). Energy expenditure was not affected by the low rate of TPN, but increased with the high rate, with a thermic effect corresponding to 16% of basal levels. Tyrosine flux and incorporation rate into whole-body proteins (protein synthesis) were not altered by the low TPN rate, but increased with the high rate. Estimates of protein breakdown decreased, and tyrosine oxidation increased significantly with both rates of TPN. Protein synthesis was stimulated at the high dose rate only. However, a positive whole-body tyrosine balance (net protein synthesis) measured by the 14C tyrosine technique was associated with a continued negative tyrosine balance across the skeletal muscle compartment in the leg. The results demonstrate that TPN given at rates corresponding to resting needs of 0.2 g of N/kg/day is insufficient to promote protein synthesis in the majority of body proteins. Skeletal muscles may remain in negative protein balance even at high TPN loads. Our results reflect the difficulties of expanding lean body mass through intravenous nutrition in moderately malnourished patients--even those with stable disease.     

A controlled, randomized trial evaluating the effects of enteral and parenteral nutrition on protein metabolism in cancer-bearing man

To characterize the effects of enteral versus parenteral nutritional support on protein metabolism in the cancer patient, patients with localized, squamous cell carcinoma of the distal esophagus were randomized to receive nutritional support as follows: (1) if there was a loss of less than 20% of the preillness body weight, patients were randomized to continue eating ad libitum (group I) versus receiving total parenteral nutrition (TPN) (group II); (2) if there was a loss greater than 20% of the preillness body weight and/or the patient was unable to swallow, patients were randomized to jejunostomy feedings (group III) versus TPN (group IV). Patients were initially studied in the postabsorptive state and again 2 weeks after beginning, and while receiving, enteral or parenteral feedings. Stable isotopic tracer methods utilizing constant infusion of [15N]glycine were used to determine whole-body protein turnover (flux), synthesis, and catabolism. Skeletal muscle catabolism was determined by measuring the urinary excretion of 3-methylhistidine and lean tissue mass was evaluated by determining total-body potassium by 40K whole-body scanning. Positive nitrogen balance was obtained in groups II and IV associated with significant weight gain in both; the changes in weight were not significant in groups I and III. Whole-body protein flux increased in all groups, but significantly only in group II. Synthesis increased in groups II and IV and decreased in I and III, but not significantly. Catabolism tended to decrease in all groups but group I. Urinary 3-methylhistidine excretion decreased in groups II and IV signifying decreased skeletal muscle catabolism, but increased in groups I and III. Total body potassium tended to increase in groups II and IV. In this group of patients with localized squamous cell carcinoma of the esophagus, both TPN and jejunal feedings tended to stabilize nutritional status and whole-body protein economics. TPN appeared to be slightly more efficacious, although the differences between enteral and parenteral nutritional support in this study were slight.     

The role of leucine in hepatic ketogenesis

Isolated hepatocyte studies demonstrated that leucine can be a precursor of ketone bodies. In this study we examine the relative contribution of leucine to hepatic ketogenesis in vivo. Three groups of conscious dogs with long-term indwelling catheters in the femoral artery, hepatic vein, and portal vein were studied. Group I (n = 3) animals were fasted overnight for 24 hours, and those in groups II and III (n = 4, each) were fasted for 62 to 68 hours (designated 3-day fast). Groups I and III received intravenous saline solution (0.9%) and served as controls. In group II selective acute insulin deficiency (SAID) was induced by a peripheral intravenous somatostatin (SRIF) infusion and intraportal glucagon (0.55 ng/body weight/min). Net hepatic production (NHP) of ketone bodies (kb) and leucine (leu) was measured by the arteriovenous difference technique. Hepatic conversion of leucine to ketone bodies was measured by continuous infusion of L-U-[14C]-leucine and by determination of the appearance of [14C]-ketone bodies across the liver. In the group fasted overnight NHPleu was 0.02 +/- 0.01 mumol/kg/min, a value not different from zero. NHPkb was 3.1 +/- 0.1 mumol/kg/min and hepatic conversion of leucine to ketone bodies accounted for 3.5% of NHPkb. Insulin deficiency after 3 day's fasting resulted in a near 70% increase in NHPleu (from basal values of 0.31 +/- 0.1 mumol/kg/min to 0.52 +/- 0.06 mumol/kg/min during SAID, p less than 0.01). NHPkb increased from 11.0 +/- 1.0 to 15.5 mumol/kg/min (p less than 0.05). The rate of leucine conversion to ketone bodies (L-C) increased from 1.1 +/- 0.25 to 2.4 +/- 0.3 mumol/kg/min (p less than 0.01) with SAID. We conclude that as the dog progresses to fasting, the contribution of leucine carbon to hepatic production of ketone bodies increases from 3.5% to 10% (p less than 0.01), and this value increases to 15% (p less than 0.01 versus groups I and II) after SAID. Furthermore, the amount of leucine carbon taken up by the liver was not sufficient to account for all [14C]-labeled leucine to ketone bodies. The data suggest that the leucine carbon converted to ketone bodies must have been derived from intrahepatic protein sources of possibly from the keto acids of leucine, which are derived by the breakdown of leucine at distant sites, such as skeletal muscle or adipose tissue.     

Urinary histamine excretion in proteinuric states

The kidney possesses the enzymatic steps required for the biosynthesis of histamine and this autocoid may play a role in modulating renal hemodynamics and the local inflammatory response to immunologic injury. We, therefore, measured urinary histamine. N-methylhistamine and N-methylimidazole acetic acid concentrations in patients with proteinuria due to a variety of disease states-idiopathic nephrotic syndrome (n = 19), systemic lupus erythematosus (n = 10), refractory focal segmental glomerulosclerosis (n = 10) and control patients (n = 16). Urinary histamine concentration was significantly reduced in treatment-responsive idiopathic nephrotic syndrome during disease relapse compared to remission (16.6 +/- 3.6 vs. 28.4 +/- 4.8 mumol/mol creatinine, p less than 0.02). The levels were also depressed in children with other causes of persistent proteinuria, including systemic lupus erythematosus (10.3 +/- 4.0 mumol/mol creatinine) and focal segmental glomerulosclerosis (14.6 +/- 2.8 mumol/mol creatinine) compared to normal controls (31.4 +/- 4.7 mumol/mol creatinine). The decreased urinary excretion of histamine and its metabolites in patients with proteinuria may be a result of immunologically mediated mesangial cell injury or represent a compensatory hemodynamic response to limit urinary protein losses.     

Fluoride metabolites after prolonged exposure of volunteers and patients to desflurane.

We examined the metabolism of desflurane in 13 healthy volunteers given 7.35 +/- 0.81 MAC-hours (mean +/- SD) of desflurane and 26 surgical patients given 3.08 +/- 1.84 MAC-hours (mean +/- SD). Markers of desflurane metabolism included fluoride ion measured via an ion-specific electrode, nonvolatile organic fluoride measured after sodium fusion of urine samples, and trifluoroacetic acid determined by a gas chromatographic-mass spectrometric method. In both volunteer and patient groups, postanesthesia serum fluoride ion concentrations did not differ from background fluoride ion concentrations. Similarly, postanesthesia urinary excretion of fluoride ion and organic fluoride in volunteers was comparable to preanesthesia excretion rates. However, small but significant levels of trifluoroacetic acid were found in both serum and urine from volunteers after exposure to desflurane. A peak serum concentration of 0.38 +/- 0.17 mumol/L of trifluoroacetic acid and a peak urinary excretion rate of 0.169 +/- 0.107 mumol/h were detected in volunteers at 24 h after desflurane exposure. Although these increases in trifluoroacetic acid after exposure to desflurane were statistically significant, they are approximately 10-fold less than levels seen after exposure to isoflurane. Thus, desflurane strongly resists biodegradation, but a small amount is metabolized in humans.