Jan Wernerman

A prospective randomised multi-centre controlled trial on tight glucose control by intensive insulin therapy in adult intensive care units: the Glucontrol study

PurposeAn optimal target for glucose control in ICU patients remains unclear. This prospective randomized controlled trial compared the effects on ICU mortality of intensive insulin therapy (IIT) with an intermediate glucose control.MethodsAdult patients admitted to the 21 participating medico-surgical ICUs were randomized to group 1 (target BG 7.8–10.0xa0mmol/L) or to group 2 (target BG 4.4–6.1xa0mmol/L).ResultsWhile the required sample size was 1,750 per group, the trial was stopped early due to a high rate of unintended protocol violations. From 1,101 admissions, the outcomes of 542 patients assigned to group 1 and 536 of group 2 were analysed. The groups were well balanced. BG levels averaged in group 1 8.0xa0mmol/L (IQR 7.1–9.0) (median of all values) and 7.7xa0mmol/L (IQR 6.7–8.8) (median of morning BG) versus 6.5xa0mmol/L (IQR 6.0–7.2) and 6.1xa0mmol/L (IQR 5.5–6.8) for group 2 (pxa0<xa00.0001 for both comparisons). The percentage of patients treated with insulin averaged 66.2 and 96.3%, respectively. Proportion of time spent in target BG was similar, averaging 39.5% and 45.1% (median (IQR) 34.3 (18.5–50.0) and 39.3 (26.2–53.6)%) in the groups 1 and 2, respectively. The rate of hypoglycaemia was higher in the group 2 (8.7%) than in group 1 (2.7%, pxa0<xa00.0001). ICU mortality was similar in the two groups (15.3 vs. 17.2%).ConclusionsIn this prematurely stopped and therefore underpowered study, there was a lack of clinical benefit of intensive insulin therapy (target 4.4–6.1xa0mmol/L), associated with an increased incidence of hypoglycaemia, as compared to a 7.8–10.0xa0mmol/L target. (ClinicalTrials.gov # NCT00107601, EUDRA-CT Number: 200400391440).

Reduced oxidative power but unchanged antioxidative capacity in skeletal muscle from aged humans

The hypothesis that the aging process is associated with mitochondrial dysfunction and oxidative stress has been investigated in human skeletal muscle. Muscle biopsy samples were taken from seven old male subjects [OS; 75 (range 61–86)xa0years] and eight young male subjects [YS; 25 (22–31)xa0years]. Oxidative function was measured both in permeabilised muscle fibres and isolated mitochondria. Despite matching the degree of physical activity, OS had a lower training status than YS as judged from pulmonary maximal O2 consumption (V̇O2max, −36%) and handgrip strength (−20%). Both maximal respiration and creatine-stimulated respiration were reduced in muscle fibres from OS (−32 and −34%, respectively). In contrast, respiration in isolated mitochondria was similar in OS and YS. The discrepancy might be explained by a biased harvest of healthy mitochondria and/or disruption of structural components during the process of isolation. Cytochrome C oxidase was reduced (−40%, P<0.01), whereas UCP3 protein tended to be elevated in OS (P=0.09). Generation of reactive oxygen species by isolated mitochondria and measures of antioxidative defence (muscle content of glutathione, glutathione redox status, antioxidative enzymes activity) were not significantly different between OS and YS. It is concluded that aging is associated with mitochondrial dysfunction, which appears to be unrelated to reduced physical activity. The hypothesis of increased oxidative stress in aged muscle could not be confirmed in this study.

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.

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.

Effects on skeletal muscle of intravenous glutamine supplementation to ICU patients

Objective: To evaluate the effect of four doses of intravenous glutamine supplementation on skeletal muscle metabolism. Design: A prospective, blinded, randomized study. Setting: The general Intensive Care Unit (ICU) of a university hospital. Patients: ICU patients with multiple organ failure (n=40), who were expected to stay in the unit for more than five days. Intervention: Patients received 0, 0.28, 0.57 or 0.86 g of glutamine per kg bodyweight per day intravenously for five days as part of an isocaloric, isonitrogenous and isovolumetric diet. Results: Plasma glutamine concentration responded to glutamine supplementation with normalization of plasma levels in a dose-dependent way, while free muscle glutamine concentration, as well as muscle protein synthesis and muscle protein content, did not change significantly. Conclusion: Intravenous glutamine supplementation to ICU patients for a period of five days resulted in normalization of plasma glutamine concentrations in a dose-dependent way whereas muscle glutamine concentrations were unaffected.

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.

Position paper of the ESICM Working Group on Nutrition and Metabolism

The metabolic changes associated with critical illness involve several pathways acting at different steps of the utilization of nutritive substrates. The understanding of the role of these pathways and of their complex regulation has led to the development of new strategies for the metabolic and nutritional management of critically ill patients, including the development of new products for nutritional support. The rationale for changing the profile of nutritional support solutions by adding novel substrates is also discussed. This review focuses on the metabolic specificities of critically ill patients and also includes an analysis of the adequacy of tools to monitor the metabolic status and the adequacy of the nutritional support.

GLUTATHIONE STATUS IN CRITICALLY-ILL PATIENTS : POSSIBILITY OF MODULATION BY ANTIOXIDANTS

Muscle tissue serves as a protein reservoir which is mobilized to meet the specific metabolic needs associated with various catabolic conditions in human subjects, such as trauma and critical illness. Glutathione is one of the most abundant short-chain peptides and a major source of non-protein thiol in the body, and tissue glutathione concentration is related to its oxidative capacity. Skeletal muscle is relatively unique with respect to a variety of metabolic properties, such as oxidative potential, patterns of amino acid utilization, and antioxidant enzyme activity. The glutathione concentration is not influenced by food intake, or by food deprivation. Moreover, there is no diurnal variation on muscle glutathione levels. Following elective surgery the muscle concentration of GSH (the reduced form) decreases by 40% 24 h post-operatively, while the concentration of GSSG (the oxidized form) remains unaltered. During critical illness a similar decrease in the GSH concentration is seen, but in addition a change in the redox status indicative of an elevated GSSG level occurs. Furthermore, correlations between the concentrations of glutamine as well as glutamate and GSH exist in these patients. From available evidence accumulated it is clear that glutathione plays a pivotal role in the maintenance of the intracellular redox status, the antioxidant vitamin levels, and the antioxidant enzyme functions under various metabolic conditions. The effectiveness of glutathione protection in the individual tissue depends on the tissue concentration of glutathione as well as the capacity of the tissue to import GSH and to export GSSG. The mechanisms by which catabolism regulates tissue glutathione levels and the enzyme activities associated with the gamma-glutamyl cycle are not completely understood and further studies need to be conducted.

Intravenous glutamine supplementation to head trauma patients leaves cerebral glutamate concentration unaffected.

ObjectiveThere is reluctance to use glutamine-containing i.u202fv. nutrition for neurosurgical patients, as this may result in elevated intracerebral glutamate levels, which are thought to be associated with neuronal injury and cell swelling, causing an increase in ICP and an unfavourable outcome. As general ICU patients benefit from i.u202fv. glutamine supplementation in terms of reduced mortality and morbidity, neurosurgical patients might also be candidates for such treatment, if the possible relation between i.u202fv. glutamine supplementation and axa0possible increase in cerebral glutamate could be sorted out.Design and settingThe study protocol had axa0crossover design with axa024u202fh treatment period and axa024u202fh placebo period in random order. Treatment was axa0glutamine containing dipeptide, L-alanyl-L-glutamine 200u202fmg/ml, for 20u202fh; placebo was saline. The rate of infusion was 0.125u202fml/kg/h, which is equal to 0.34u202fg/kg of glutamine over the 20u202fh period. Microdialysate was collected for analysis in 120u202fmin portions. The flow through the microdialysis catheter was 0.3u202fμu202fl/min.SubjectsPatients with severe head trauma (GCSu202f≤u202f8; nu202f=u202f15) on routine monitoring, including intracerebral microdialysis, were randomly assigned to treatment followed by placebo or placebo followed by treatment.Measurements and resultsGlutamine infusion increased plasma glutamine concentration by 30%, but not plasma glutamate concentration. Intracerebral glutamate was unaffected in median values and in all individual patients.ConclusionIntravenous glutamine in clinically relevant doses leaves cerebral glutamate unaffected. This opens the possibility of evaluating the effects of i.u202fv. glutamine supplementation upon outcome for neurosurgical ICU patients.