Folke Hammarqvist

Addition of glutamine to total parenteral nutrition after elective abdominal surgery spares free glutamine in muscle, counteracts the fall in muscle protein synthesis, and improves nitrogen balance.

Twenty-two patients undergoing elective abdominal surgery were given total parenteral nutrition (TPN) after the operation. The TPN contained either a conventional amino acid solution supplemented with glutamine or a conventional amino acid solution without supplementation. To study amino acid and protein metabolism, muscle biopsy specimens were taken before surgery and on the third postoperative day. The postoperative decrease in the intracellular concentration of free glutamine was less pronounced in the glutamine group (21.8 +/- 5.5%) than in the control group (38.7 +/- 5.1%; p less than 0.05). The protein synthesis was reflected in the concentration and size distribution of ribosomes. No significant changes in these parameters were seen in the glutamine group after the operation. In the control group, the total concentration of ribosomes fell by 27.2 +/- 8.5% (p less than 0.05), and the relative proportion of polyribosomes fell by 10.6 +/- 2.9% (p less than 0.01). Although there were significant changes in the control group, no significant differences in the changes of these parameters between the two groups were detected. The cumulative nitrogen loss was significantly less in the glutamine group as compared to the control group during the period studied--2.3 +/- 1.4 g versus 8.5 +/- 1.5 g, respectively (p less than 0.01). Administration of glutamine to catabolic patients is advocated.

A Carbohydrate-Rich Drink Reduces Preoperative Discomfort in Elective Surgery Patients

We studied the effects of different preoperative oral fluid protocols on preoperative discomfort, residual gastric fluid volumes, and gastric acidity. Two-hundred-fifty-two elective abdominal surgery patients (ASA physical status I–II) were randomized to preparation with a 12.5% carbohydrate drink (CHO), placebo (flavored water), or overnight fasting. The CHO and Placebo groups were double-blinded and were given 800 mL to drink on the evening before and 400 mL on the morning of surgery. Visual analog scales were used to score 11 different discomfort variables. CHO did not increase gastric fluid volumes or affect acidity, and there were no adverse events. The visual analog scale scores in a control situation were not different between groups. During the waiting period before surgery, the CHO-treated group was less hungry and less anxious than both the other groups (P ≤ 0.05). CHO reduced thirst as effectively as placebo (P < 0.0001 versus Fasted). Trend analysis showed consistently decreasing thirst, hunger, anxiety, malaise, and unfitness in the CHO group (P < 0.05). The Placebo group experienced decreasing unfitness and malaise, whereas nausea, tiredness, and inability to concentrate increased (P < 0.05). In the Fasted group, hunger, thirst, tiredness, weakness, and inability to concentrate increased (P < 0.05). In conclusion, CHO significantly reduces preoperative discomfort without adversely affecting gastric contents.

Skeletal muscle glutathione is depleted in critically ill patients.

OBJECTIVE To investigate the concentrations of reduced and total glutathione in relation to the muscle free amino acid pattern in critically ill patients and matched healthy controls. DESIGN Prospective case control. SETTING University hospital intensive care unit (ICU). PATIENTS Eleven critically ill patients in the intensive care unit were studied after a stay of at least 4 days. Eleven age- and gender-matched metabolically healthy patients undergoing elective surgical procedures served as controls. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Reduced and total glutathione concentrations were determined in skeletal muscle, in plasma, and in whole blood, together with muscle free amino acid concentrations. In the ICU group, reduced and total glutathione values were 57% and 62%, respectively, of the values seen in the control group (p < .001). In addition, a decreased ratio between reduced and total glutathione compared with the controls was seen (0.80 as compared with 0.91, p < .001). The glutamine concentration in skeletal muscle in the ICU group was 72% lower compared with that value seen in healthy controls (p < .001). Correlations were found between the concentrations of glutamine and the total muscle glutathione (r2 = .46, p < .001), as well as between glutamine and the ratio of reduced and total glutathione (r2 = .45, p < .001) in skeletal muscle, suggesting that the redox status of glutathione and the glutamine status of the tissue are related. CONCLUSIONS Critical illness is associated with alterations in muscle glutathione metabolism. The muscle-reduced glutathione concentrations decrease and, in addition, the ratio between reduced and total glutathione decreases, indicating a situation of oxidative stress in this tissue. This decrease may impair the defense of muscle against oxygen free radicals and influence amino acid transport, thus contributing to the loss of balance between protein synthesis and protein degradation that is characteristic of protein catabolism.

Biosynthetic human growth hormone preserves both muscle protein synthesis and the decrease in muscle-free glutamine, and improves whole-body nitrogen economy after operation.

As a reproducible human trauma model, patients (n = 17) undergoing elective cholecystectomy were studied for 3 postoperative days. They were randomly allocated to receive either recombinant human growth hormone (hGH; 0.3 U/kg/24 hours) or placebo together with total parenteral nutrition, including 0.2 gN/kg/24 hours and 135 kJ/kg/24 hours. Before operation and on the third postoperative day, percutaneous muscle biopsies were performed to determine the concentration and size distribution of ribosomes and the free amino acid concentrations. The significant postoperative decrease in the total ribosome concentration (15.3 ± 6.4%) and the polyribosome concentration (20.9 ± 6.5%) in the control group was impeded in the group receiving synthetic hGH. Muscle free glutamine decreased by 35.6 ± 4.2% in the control group and to a lesser extent in the group that was given hGH after operation (p < 0.05). The protein content of skeletal muscle was unchanged. The cumulated nitrogen balance for the study period was negative in the control group (-7.09 ± 0.71 gN), but was not different from zero in the hGH group (-2.32 ± 1.66 gN). It is concluded that synthetic hGH administered after operation has beneficial effects on the whole-body nitrogen economy, as indicated by the unchanged capacity for protein synthesis in skeletal muscle, the preserved levels of muscle free glutamine, and improvement in the whole-body nitrogen balance. The effects of hGH on skeletal muscle protein and amino acid metabolism can explain the postoperative nitrogen-sparing effect attributed to hGH.

α-ketoglutarate and postoperative muscle catabolism

The hypothesis that muscle protein catabolism after trauma is associated with a shortage of alpha-ketoglutarate, rather than glutamine, was tested. Addition of alpha-ketoglutarate to postoperative total parenteral nutrition prevented the decrease in muscle protein synthesis and free glutamine that usually occurs after surgery. alpha-ketoglutarate supplementation may improve recovery after trauma.

Alanyl-glutamine counteracts the depletion of free glutamine and the postoperative decline in protein synthesis in skeletal muscle.

Skeletal muscle protein and amino acid metabolism change after surgical trauma during a period characterized by skeletal muscle protein catabolism. Available total parenteral nutrition (TPN) not containing glutamine does not prevent these changes, while TPN enriched with glutamine has been shown to have beneficial effects on postoperative skeletal muscle protein metabolism. Glutamine, in the form of a dipeptide, alanyl-glutamine, was added to TPN. Patients undergoing elective cholecystectomy were given postoperative TPN. Two groups received isocaloric and isonitrogenous conventional TPN, one group with (n = 8) and the other without an addition of alanyl-glutamine (n = 8). Skeletal muscle protein metabolism was studied in muscle biopsy specimens from which the muscle free amino acid pattern and the concentration and size distribution of ribosomes, serving as a measure of protein synthesis, were determined. In the control group, muscle free glutamine decreased by 38.8% +/- 6.6% and the polyribosome concentration per mg of DNA decreased by 21% +/- 5.2% after operation. In the group given TPN supplemented with alanyl-glutamine, these two parameters of muscle protein and amino acid metabolism did not change significantly. Compared to the control group, whole-body nitrogen balance was improved after operation by the addition of alanyl-glutamine to TPN (p less than 0.01). Muscle free glutamine and muscle protein synthesis were preserved after operation and the whole-body nitrogen balance was improved by adding glutamine in the form of alanyl-glutamine to TPN. The dipeptide alanyl-glutamine seems to be a suitable means of providing glutamine in a stable form.

Role of Glutamine and Its Analogs in Posttraumatic Muscle Protein and Amino Acid Metabolism

Skeletal muscle protein catabolism following trauma has until recently not been possible to counteract by intravenous nutritional means. The obligatory loss of nitrogen with concomitant reduction of skeletal muscle protein synthesis is also accompanied by a decrease of muscle free glutamine, the extent of which is proportional to the muscle protein catabolism. Serving as a human model of surgical trauma, patients undergoing elective cholecystectomy were given total parenteral nutrition including additions of either glutamine or its analogs (ornithine-alpha-ketoglutarate, alpha-ketoglutarate, or alanylglutamine) during 3 postoperative days. The polyribosome concentration and the intracellular glutamine concentration in skeletal muscle, as well as nitrogen balance, showed a less pronounced skeletal muscle catabolism in these groups than when conventional total parenteral nutrition was given. It is concluded that a support of either glutamine or its carbon skeleton, alpha-ketoglutarate, counteracts the postoperative fall of muscle free glutamine and of muscle protein synthesis. Furthermore, statistical correlations could be shown between the changes of muscle glutamine and muscle protein synthesis and the postoperative nitrogen losses.

Skeletal muscle glutathione after surgical trauma

OBJECTIVE The authors investigate the effect of surgical trauma on skeletal muscle concentrations of glutathione in patients undergoing selective abdominal surgery. SUMMARY BACKGROUND DATA The posttraumatic state is accompanied by characteristic changes in the pattern of free amino acids and a decline of protein synthesis in human skeletal muscle. Glutathione has multiple metabolic functions that are involved in cellular homeostasis. It is unknown how surgical trauma affects the glutathione metabolism of skeletal muscle in surgical patients. METHODS Eight patients undergoing elective abdominal surgery were investigated. Percutaneous muscle biopsies and blood samples were taken before operation and at 6, 24, and 48 hours after operation. The concentrations of glutathione were determined in muscle tissue, plasma, and whole blood, as well as the concentrations of the related amino acids in muscle and plasma. RESULTS In skeletal muscle, the levels of both reduced and total glutathione decreased by 40% (p<0.01) at 24 hours and remained low at 48 hours after operation compared with the preoperative values. The glutathione concentration in plasma was 20% lower after operation compared with the concentration before operation (p<0.05). There were no changes at the whole blood levels of glutathione. Tissue glutamate and glutamine decreased significantly after operation (p<0.001), whereas intracellular cysteine and glycine remained unchanged. CONCLUSIONS Skeletal muscle glutathione deficiency occurs after surgical trauma. This may lead to an increase in the susceptibility to intracellular oxidative injury.

Glutamine and α-ketoglutarate prevent the decrease in muscle free glutamine concentration and influence protein synthesis after total hip replacement

After surgical trauma, protein synthesis, as well as the concentration of free glutamine in muscle, decreases. Total parenteral nutrition (TPN) alone does not prevent the decrease of glutamine in muscle, but TPN supplemented with glutamine or its precursor, alpha-ketoglutarate, maintains amino acid concentration in muscle and preserves protein synthesis. The aim of this study was to characterize a human trauma model using patients undergoing total hip replacement, and furthermore to investigate whether glutamine or alpha-ketoglutarate alone without TPN can prevent the postoperative decrease in muscle free glutamine. Metabolically healthy patients undergoing total hip replacement were randomized into three groups. The control group (n = 13) received glucose 2 g/kg body weight (BW) during surgery and the first 24 postoperative hours. The glutamine group (n = 10) received glucose 2 g/kg BW and glutamine 0.28 g/kg BW, and the alpha-ketoglutarate group (n = 10) received glucose 2 g/kg BW and alpha-ketoglutarate 0.28 g/kg BW. Muscle biopsies were performed before surgery and 24 hours postoperatively. Free glutamine concentration in muscle decreased from 11.62 +/- 0.67 to 9.80 +/- 0.36 mmol/kg wet weight in the control group (P < .01), whereas it remained unchanged in both the glutamine group and alpha-ketoglutarate group. Protein synthesis, as reflected by the concentration of total ribosomes, decreased significantly in the control group, but not in glutamine and alpha-ketoglutarate groups. Polyribosome concentration decreased significantly in both the control and alpha-ketoglutarate groups. Total hip replacement can be used as a reproducible trauma model, with characteristic changes in the muscle amino acid pattern and protein synthesis 24 hours postoperatively.(ABSTRACT TRUNCATED AT 250 WORDS)

Determination of intracellular glutathione in human skeletal muscle by reversed-phase high-performance liquid chromatography

A chromatographic method for the specific determination of cellular low molecular mass thiols has been applied to human muscle tissue. The method is based on the derivatisation of thiols using monobromobimane, which is a specific reagent for the sulphydryl group. The glutathione and cysteine bimane adducts were separated by reversed-phase HPLC, whilst quantitation of the cysteine and glutathione adducts was achieved by fluorescence spectroscopy. The method was found to yield a quantitative recovery of glutathione (ca. 96%), to be sensitive (down to 20 pmol glutathione/per injection) and reveal a low intra-individual coefficient of variation (C.V. < 5%) of the glutathione concentrations in human skeletal muscle. The concentrations of reduced and total glutathione were 1320 +/- 37 mumol/kg wet weight (mean +/- S.E.M.) and 1525 +/- 66 mumol/kg wet weight, respectively. The method was also applied to tissues from nine healthy volunteers to determine if fluctuations in glutathione level occurred over a 24-h period. No diurnal variation of glutathione level in human skeletal muscle was observed.