P. Essén

A descriptive study of skeletal muscle metabolism in critically ill patients: Free amino acids, energy-rich phosphates, protein, nucleic acids, fat, water, and electrolytes

OBJECTIVE To characterize biochemical changes in skeletal muscle in critically ill patients. DESIGN Survey of critically ill patients. SETTING Intensive care unit (ICU) at a university hospital. PATIENTS Critically ill patients (n = 20) subjected to trauma, surgical complications, and/or bacteremia who were treated in the ICU and showed no risk of bleeding complications were included. Reference groups of metabolically healthy volunteers and patients served as the control/reference groups. INTERVENTIONS Percutaneous muscle biopsy was obtained from both patients and healthy volunteers. MEASUREMENTS AND MAIN RESULTS Total free amino acids in skeletal muscle decreased 59% (p < .001) and skeletal muscle glutamine concentration decreased 72% (p < .001) in the critically ill patients. Basic amino acids decreased 49% (p < .001). Branch-chain amino acids increased 39% (p < .01), and aromatic amino acids increased 88% (p < .001) in the patients. Adenosine triphosphate (ATP) was reduced by 12% (p < .01). Total creatine concentration increased by 26% (p < .001) due to an 80% increase in free creatine (p < .001). The phosphorylated creatine fraction of total creatine decreased 22% (p < .001) in the patients. Alkali-soluble protein/DNA decreased 24% (p < .01) and fat free solid/DNA decreased 21% (P <.01) in patients sampled on or after ICU day 5 compared with the reference group. Muscle water increased 10% due to a doubling of the extracellular water fraction. CONCLUSIONS Although critically ill patients are a very heterogeneous group from a clinical point of view, there is a remarkable homogeneity in many of the biochemical parameters regardless of the severity of illness and the length of the ICU admission. The three most consistent differences were the skeletal muscle low glutamine concentration, the decrease in protein content, and the increase in extracellular water in the patients.

Longitudinal changes of biochemical parameters in muscle during critical illness

The study was undertaken to characterize the time course of biochemical parameters in skeletal muscle during critical illness to gain information for the design of a suitable protocol for interventional studies using metabolic or nutritional manipulation. Critically ill patients in our intensive care unit ([ICU] N = 9) were investigated on two separate sampling occasions with percutaneous muscle biopsies for determination of protein, nucleic acids, free amino acids, energy-rich phosphates, fat, water, and electrolytes. The first biopsy specimen was taken 3 to 11 days after admission and the second biopsy specimen 3 to 7 days later. Protein concentration, expressed as alkali-soluble protein (ASP)/DNA, decreased by 12% (P < .02) between the two biopsies. The total free amino acid content was only 50% of normal, but remained unaltered over time. In particular, the concentration of glutamine remained low, approximately 25% of normal. In contrast, branched-chain amino acid (BCAA) increased by 25% (P < .05) and phenylalanine by 55% (P < .05) between biopsies. The fat content related to fat-free solid (FFS) increased by 130% (P < .001) between the two biopsies. Muscle water did not change during the study period. The extracellular portion was double the normal value when related to FFS. Intracellular water, on the other hand, was outside the 95% confidence interval for normal values in the second biopsy. The concentrations of adenosine triphosphate (ATP), creatine, phosphocreatine, and the phosphorylated fraction of total creatine remained at the same level between the two biopsies. We conclude that in critically ill patients, there is a decrease in protein content over time and increases in BCAA, phenylalanine, and fat content, while the low glutamine level and high extracellular water content remain unaltered. The temporal alterations were well characterized after a 5-day study period.

Tissue protein synthesis rates in critically ill patients

OBJECTIVES The aims of this study were to simultaneously determine the in vivo rates of protein synthesis in skeletal muscle, peripheral blood lymphocytes, and serum albumin in critically ill patients; to establish whether a relationship between the responses of these tissues could be observed; and to demonstrate if a protein synthesis pattern characteristic of critical illness exists. DESIGN Descriptive study. SETTING Intensive care unit of a 1000-bed university hospital. PATIENTS Fifteen patients treated in the intensive care unit. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Rates of tissue protein synthesis were determined in vivo once during the course of critical illness, using the flooding method with L-(2H5)phenylalanine. Protein synthesis in muscle was 1.49 +/- 0.16%/day; in circulating lymphocytes (i.e., mononuclear cells), protein synthesis was 11.10 +/- 1.82%/day. Albumin synthesis was 12.81 +/- 1.23%/day when expressed as the fractional rate, and was 184 +/- 19 mg/kg/day when expressed as the absolute rate. CONCLUSIONS The individual tissues responded differently to trauma, and showed a wide range of values. The responses were not significantly correlated with each other and no pattern of tissue protein synthesis characteristic of critical illness was observed. However, both muscle protein and albumin synthesis rates correlated with metabolic status and clinical indices of the severity of illness.

Protein-sparing effect in skeletal muscle of growth hormone treatment in critically ill patients.

OBJECTIVE To investigate the effect of growth hormone (GH) treatment on skeletal muscle protein catabolism in patients with multiple organ failure in the intensive care unit (ICU). SUMMARY BACKGROUND DATA Skeletal muscle depletion affects the incidence of complications and the length of hospital stay. A protein-sparing effect of GH treatment in skeletal muscle of long-term ICU patients was hypothesized. METHODS Twenty critically ill ICU patients were randomized to treatment with GH (0.3 U/kg/day) or as controls. Percutaneous muscle biopsy samples were taken before and after a 5-day treatment period starting on day 3 to 42 of the patients ICU stay. Protein content, protein synthesis, water, nucleic acids, and free amino acids in muscle were analyzed. RESULTS The protein content decreased by 8% +/- 11% in the control patients, with no significant change in the GH group. The fractional synthesis rate of muscle proteins increased in the GH group by 33% +/- 48%, and muscle free glutamine increased by 207% +/- 327% in the GH group. Total intramuscular water increased by 12% +/- 14% in the control group as a result of an increase in extracellular water of 67% +/- 86%; these increases were not seen in the GH group. In contrast, the intracellular water increased by 6% +/- 8% in the GH group. CONCLUSION Treatment with GH for 5 days in patients with multiple organ failure stimulated muscle protein synthesis, increased muscle free glutamine, and increased intracellular muscle water.

Laparoscopic cholecystectomy does not prevent the postoperative protein catabolic response in muscle

ObjectiveThe authors determined the effect of laparoscopic cholecystectomy on protein synthesis in skeletal muscle. In addition to a decrease in muscle protein synthesis, after open cholecystectomy, the authors previously demonstrated a decrease in insulin sensitivity. This study on patients undergoing laparoscopic and open surgery, therefore, included simultaneous measurements of protein synthesis and insulin sensitivity. Summary Background DataLaparoscopy has become a routine technique for several operations because of postoperative benefits that allow rapid recovery. However, its effect on postoperative protein catabolism has not been characterized. Conventional laparotomy induces a drop in muscle protein synthesis, whereas degradation is unaffected. MethodsPatients were randomized to laparoscopic or open cholecystectomy, and the rate of protein synthesis in sketetal muscle was determined 24 hours postoperatively by the flooding technique using L- (2H5)phenylalanine, during a hyperinsulnemic nomoglycemic clamp to assess insulin sensitivity. ResultsThe protein synthesis rate decreased by 28% (1.77 ± 0.11 %/day vs. 1.26 ± 0.08%/day, p < 0.01) in the laparoscopic group and by 20% (1.97 ± 0.15%/day vs. 1.57 ± 0.15%/day, p < 0.01) In the open cholecystectomy group. In contrast, the fall in insulin sensitivity after surgery was lower with laparoscopic (22 ± 2%) compared with open surgery (49 ± 5%). ConclusionsLaparoscopic cholecystectomy did not avoid a substantial decline in muscle protein synthesis, despite improved insulin sensitivity. The change in the two parameters occurred independently, indicating different mechanisms controlling insulin sensitivity and muscle protein synthesis.

Response of in vivo protein synthesis in T lymphocytes and leucocytes to an endotoxin challenge in healthy volunteers

In vivo determination of protein synthesis in immune cells reflects metabolic activity and immunological activation. An intravenous injection of endotoxin to healthy volunteers was used as a human sepsis model, and in vivo protein synthesis of T lymphocytes and leucocytes was measured. The results were related to plasma concentrations of selected cytokines, peripheral cell counts and subpopulations of immune cells. The subjects (n = 8 + 8) were randomized to an endotoxin (4 ng/kg) or a saline group. In vivo protein synthesis was determined twice: before and 1–2·5 h after the endotoxin/saline injection. Protein synthesis decreased in isolated T lymphocytes, but increased in leucocytes. Plasma levels of TNF‐α, IL‐8, IL‐6, IL‐1 ra and IL‐10 were elevated, whereas IL‐2 and IFN‐γ, produced predominantly by T lymphocytes, did not change in response to endotoxin. Neutrophils increased, whereas lymphocytes and monocytes decreased 2·5 h after the endotoxin injection. Flow cytometry revealed a drop in total CD3+ T lymphocytes and CD56+ natural killer cells, accompanied by an increase in CD15+ granulocytes. In summary, in vivo protein synthesis decreased in T lymphocytes, while the total leucocyte population showed a concomitant increase immediately after the endotoxin challenge. The changes in protein synthesis were accompanied by alterations in immune cell subpopulations and in plasma cytokine levels.

Depression of liver protein synthesis during surgery is prevented by growth hormone.

This study was undertaken to elucidate the specific effects of growth hormone (GH) on liver protein metabolism in humans during surgery. Otherwise healthy patients scheduled for elective laparoscopic cholecystectomy were randomized into controls (n = 9) or pretreatment with 12 units of GH for 1 day (GH 1, n = 9) or daily for 5 days (GH 5, n = 10). The fractional synthesis rate of liver proteins, as assessed by flooding with [2H5]phenylalanine, was higher in the GH 5 group (22.0 +/- 6.9%/day, mean +/- SD, P < 0.05) than in the control (16.1 +/- 3.1%/day) and GH 1 (16.5 +/- 5.5%/day) groups. During surgery, the fraction of polyribosomes in the liver, as assessed by ribosome analysis, decreased in the control group by approximately 12% (P < 0.01) but did not decrease in the GH-treated groups. In addition, the concentrations of the essential amino acids and aspartate in the liver decreased in response to GH treatment. In conclusion, GH pretreatment decreases hepatic free amino acid concentrations and preserves liver protein synthesis during surgery.This study was undertaken to elucidate the specific effects of growth hormone (GH) on liver protein metabolism in humans during surgery. Otherwise healthy patients scheduled for elective laparoscopic cholecystectomy were randomized into controls ( n = 9) or pretreatment with 12 units of GH for 1 day (GH 1, n = 9) or daily for 5 days (GH 5, n = 10). The fractional synthesis rate of liver proteins, as assessed by flooding with [2H5]phenylalanine, was higher in the GH 5 group (22.0 ± 6.9%/day, mean ± SD, P < 0.05) than in the control (16.1 ± 3.1%/day) and GH 1 (16.5 ± 5.5%/day) groups. During surgery, the fraction of polyribosomes in the liver, as assessed by ribosome analysis, decreased in the control group by ∼12% ( P < 0.01) but did not decrease in the GH-treated groups. In addition, the concentrations of the essential amino acids and aspartate in the liver decreased in response to GH treatment. In conclusion, GH pretreatment decreases hepatic free amino acid concentrations and preserves liver protein synthesis during surgery.

The synthesis rate of albumin decreases during laparoscopic surgery

In previous studies, a decline in total liver protein synthesis during elective laparoscopic surgery has been observed. However, when albumin synthesis was measured in parallel no apparent influence of the procedure was detected. The aim of the present study was to specifically investigate the effect of a laparoscopic procedure on albumin synthesis. Female (n = 9) patients scheduled for elective laparoscopic cholecystectomy as a consequence of cholecystolithiasis were investigated. The fractional synthesis rate (FSR) of albumin was investigated twice in each patient, before and during surgery (2–3 h apart), employing l‐[2H5]phenylalanine and gas chromatography mass spectrometry. The FSR of albumin decreased from 7·3 ± 1·2% per day before surgery to 6·2 ± 1·4% per day during the procedure (P<0·01), whereas the corresponding absolute synthesis rates of albumin decreased from 114 ± 24 to 86 ± 16 mg kg−1 day−1, respectively (P<0·001). In conclusion, the synthesis rate of albumin decreased during a laparoscopic surgery procedure. However, the characteristics for this decrease differ from those previously observed for total liver protein synthesis.

The Effects of Short-Term Parenteral Nutrition on Human Liver Protein and Amino Acid Metabolism During Laparoscopic Surgery

BACKGROUND This study was undertaken to elucidate the specific effects of short-term artificial nutrition on human liver protein metabolism. METHODS Thirty patients undergoing elective laparoscopic cholecystectomy were studied: a control group (n = 16) and a group that received total parenteral nutrition (TPN; n = 14). The nutrition consisted of a balanced i.v. solution of nutrients (17.5 nonprotein kcal/kg body wt, 50% fat, 50% carbohydrates, and 0.1 gN/kg) that was discontinued when the investigation was finished, after a total infusion time of 8.6 +/- 1.0 hours. A liver biopsy specimen was taken as soon as possible after surgery was started, for the determination of the free hepatic amino acid concentrations. In 16 of the patients, L[2H5]phenylalanine was given by i.v. to determine the fractional synthesis rate of total liver protein in a second liver biopsy specimen taken approximately 30 minutes later. RESULTS The fractional synthesis rate of total liver protein was 15.2% +/- 4.7%/d in the TPN group (n = 7), which was not different from that of the control group (17.7% +/- 3.8%/d, n = 9). However, the free hepatic concentrations of alanine (p < .05) and the essential amino acids increased (p < .001) in the TPN group, whereas the total hepatic amino acid concentrations were comparable between the groups. CONCLUSION Thus short-term TPN induced specific changes of the free hepatic amino acid concentrations, whereas total liver protein synthesis remained unaffected by the nutrition.

In vivo protein synthesis of circulating human T lymphocytes does not respond to a cortisol challenge within 24 h

Background: Although immunocompetence is often measured by assessing responsiveness of lymphocytes to mitogenic stimulation in vitro, this approach may not reflect the in vivo situation. The aim of this investigation was to determine in vivo the protein synthesis rate (FSR) in isolated T lymphocytes and to study the effect of a short‐term cortisol infusion on FSR.