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ABSTRACT: BACKGROUND: The benefit of tight glucose control in the intensive care unit is controversial. Part of the debate is around the frequency of glucose measurements, and therefore, a continuous glucose monitoring system is needed. Previously, we have shown that intravenous microdialysis has the potential for this purpose but that the accuracy must be improved. The aim of this study was to investigate the effects of the microdialysis membrane length and the perfusion rate on improving the accuracy. METHODS: Two volunteer studies were performed, one comparing intravenous microdialysis catheters with different lengths (10 and 20 mm) and one comparing different perfusion rates (0.5, 1 and 2 μl/min) with plasma glucose reference levels. Median values of seven samples taken over 70-min periods were compared using Bland-Altman plots. RESULTS: When microdialysis membranes of 10 and 20 mm perfused at a rate of 1 μl/min were used, the differences with measured plasma glucose levels were 30% ± 21% and 14% ± 13%. In comparison, plasma glucose measured in two different veins gave a difference of 3% ± 3%. In the second study, the differences between measured plasma glucose and that estimated with a microdialysis membrane of 30 mm perfused at 0.5, 1 and 2 μl/min were 8% ± 7%, 25% ± 19% and 39% ± 28%. Bland-Altman analyses gave the best line of equality (-0.11 mM) and the lowest limits of agreement (1.13 and -1.35 mM) when using the 30-mm membrane perfused with 0.5 μl/min. CONCLUSION: The agreement of the intravenous microdialysis with plasma glucose levels improved significantly when increasing the microdialysis membrane length, and thereby the membrane area, and decreasing the perfusion rate.
Acta Anaesthesiologica Scandinavica 10/2012; · 2.19 Impact Factor
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Jan Wernerman,
T Kirketeig,
B Andersson,
H Berthelson,
A Ersson,
H Friberg,
A B Guttormsen,
S Hendrikx,
V Pettilä,
P Rossi,
F Sjöberg,
O Winsö
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ABSTRACT: Low plasma glutamine concentration is an independent prognostic factor for an unfavourable outcome in the intensive care unit (ICU). Intravenous (i.v.) supplementation with glutamine is reported to improve outcome. In a multi-centric, double-blinded, controlled, randomised, pragmatic clinical trial of i.v. glutamine supplementation for ICU patients, we investigated outcomes regarding sequential organ failure assessment (SOFA) scores and mortality. The hypothesis was that the change in the SOFA score would be improved by glutamine supplementation.
Patients (n=413) given nutrition by an enteral and/or a parenteral route with the aim of providing full nutrition were included within 72 h after ICU admission. Glutamine was supplemented as i.v. l-alanyl-l-glutamine, 0.283 g glutamine/kg body weight/24 h for the entire ICU stay. Placebo was saline in identical bottles. All included patients were considered as intention-to-treat patients. Patients given supplementation for >3 days were considered as predetermined per protocol (PP) patients.
There was a lower ICU mortality in the treatment arm as compared with the controls in the PP group, but not at 6 months. For change in the SOFA scores, no differences were seen, 1 (0,3) vs. 2 (0.4), P=0.792, for the glutamine group and the controls, respectively.
In summary, a reduced ICU mortality was observed during i.v. glutamine supplementation in the PP group. The pragmatic design of the study makes the results representative for a broad range of ICU patients.
Acta Anaesthesiologica Scandinavica 06/2011; 55(7):812-8. · 2.19 Impact Factor
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ABSTRACT: The conflicting results from studies over tight glucose control in intensive care unit (ICU) patients ask for a continuous on-line real-time glucose monitoring in future. Here, intravenous microdialysis was tested in ICU patients and healthy volunteers. Primary aims were technical feasibility and accuracy.
A microdialysis catheter was inserted into a peripheral vein. ICU patients (n=10) were studied for up to 5 days. Healthy volunteers (n=6) were studied on one occasion. Recordings were monitored during 70 min each 24-h period to allow for an estimate of variability over time. Microdialysis glucose and lactate were compared with plasma glucose and whole blood lactate. Results are presented as medians (quartiles) of the differences between microdialysis and plasma concentrations over each of the 70-min recording periods.
Out of the included ICU patients, no exclusions or early terminations were due to failure of the microdialysis catheter. The concordance was highly variable. The difference of medians over the recording periods differed by -34% (-40, -16) in patients and -22% (-31, -15) for the volunteers. In contrast, the overall variability within the individual measurement periods was low.
Technical feasibility was good, but the accuracy was not sufficient and the variability between the recording periods was high without calibrations. The non-availability of suitable peripheral veins was a problem in many patients screened but not included in the study. Intravenous microdialysis to obtain continuous on-line real-time glucose monitoring is technically feasible, but accuracy needs to be improved.
Acta Anaesthesiologica Scandinavica 08/2010; 54(7):841-7. · 2.19 Impact Factor
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ABSTRACT: Glutathione is a major antioxidant, and, in the present study, we investigated whether a clinical model of short warm ischaemia and reperfusion of the human liver during surgery would influence glutathione and amino acid metabolism. Previous studies in humans have demonstrated that ischaemia and reperfusion in skeletal muscle for up to 120 min have no major effect on muscle glutathione concentrations. Liver ischaemia and reperfusion in animals have demonstrated diverging results concerning glutathione metabolism. In the present study, six patients with liver malignancies, undergoing liver resection during warm ischaemia, were included. Liver biopsies were obtained from healthy appearing liver tissue from both lobes before ischaemia and at maximal ischaemia, and from the remaining liver lobe after 5, 10, 15, 20, 25 and 30 min of reperfusion. The biopsies were analysed for glutathione, amino acids and lactate. Median ischaemia time was 28 (range, 15-36) min. Lactate increased 266% at maximal ischaemia (P<0.05). No alterations in glutathione concentrations or the redox status of glutathione (GSH/total glutathione) were observed. Glutamate decreased 22% (P<0.05) at maximal ischaemia and increased thereafter 72% at 30 min of reperfusion (P<0.05). Alanine increased 105% at maximal ischaemia (P<0.05) and was normalized during reperfusion. BCAAs (branched-chain amino acids) increased 67% at maximal ischaemia (P<0.05). In conclusion, short-time ischaemia and reperfusion in the human liver did not affect glutathione concentrations, whereas changes were observed in amino acid concentrations during both ischaemia and reperfusion.
Clinical Science 04/2009; 117(9):339-44. · 4.61 Impact Factor
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ABSTRACT: Mitochondrial derangements in muscle of patients suffering from sepsis have been established in several studies and have been related to muscle dysfunction and organ failure. It is not possible to study the early phase of sepsis in patients; therefore, we used a human endotoxaemia model to study the effect of early sepsis on muscle mitochondria.
Seven healthy male volunteers received a standardised endotoxin challenge. Muscle biopsies were obtained immediately before the challenge, and at 2 and 4 h following the endotoxin challenge. The muscle biopsies were analysed for maximal activities of citrate synthase and complexes I and IV of the respiratory chain. In addition, total and mitochondrial superoxide dismutase (SOD) activities were analysed. The concentrations of ATP, creatine phosphate and lactate were analysed to assess the cellular energy status. Total and phosphorylated AMP-activated protein kinase (AMPK-P), a key regulator in intracellular energy metabolism, was measured.
Activities of citrate synthase and complex I were significantly increased 2 h after the endotoxin challenge. SOD activities were unaffected by the endotoxin challenge. No changes in ATP, creatine phosphate or lactate were observed. Neither total nor AMPK-P changed.
An endotoxin challenge given to healthy volunteers rapidly increases mitochondrial enzyme activity in skeletal muscle. The results of this human model indicate that possibly early during sepsis, mitochondrial activity might be increased in contrast to what has been shown in the later phases of sepsis. It is possible that this early activation leads to exhaustion of the mitochondria and a decreased function later during sepsis.
Acta Anaesthesiologica Scandinavica 04/2009; 53(3):299-304. · 2.19 Impact Factor
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ABSTRACT: Patients with septic shock have high plasma glutathione concentrations, whereas intracellular concentrations in erythrocytes and muscle are low. In the present study, we investigated the temporal pattern of glutathione status and glutathione kinetics in healthy volunteers during the initial phase of sepsis using a human endotoxin model. The present study was a descriptive pilot study in healthy male volunteers (n=8) before and after an endotoxin challenge. The glutathione status was determined in plasma and whole blood at baseline and hourly for 4 h after intravenous endotoxin injection and in skeletal muscle at baseline and at 2 and 4 h after endotoxin injection. In plasma, the concentration of total glutathione decreased 24% (P<0.05) at 3 h after endotoxin injection and 32% (P<0.001) at 4 h. In whole blood and skeletal muscle, the concentrations of both GSH and total glutathione as well as the redox status remained unaltered during the initial 4 h after the endotoxin challenge. The FSR (fractional synthesis rate) of glutathione in whole blood was 38+/-20%/day before and 59+/-22%/day 4 h after the endotoxin challenge (P=0.088) and in skeletal muscle this was 41+/-25 and 46+/-18%/day (P=0.68) respectively. During the initial phase of sepsis, as represented by an intravenous endotoxin challenge to healthy volunteers, plasma concentrations of total glutathione decreased, whereas glutathione status and synthesis rate in skeletal muscle and whole blood remained unaltered. However, due to the variation in the synthesis measurements, larger studies are needed to confirm these findings.
Clinical Science 03/2009; 117(9):313-9. · 4.61 Impact Factor
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ABSTRACT: Glutamine is a non-essential amino acid with a special role in metabolism and nutrition. The depletion of glutamine is reported
to be a predictor of a poor outcome in particular for intensive care unit (ICU) patients [1]. Consequently, supplementation of intravenous nutrition with glutamine improves outcome in terms of mortality and morbidity
in ICU patients [2–4]. A number of questions have been raised concerning the handling of glutamine-supplemented nutrition in ICU patients, including
the vascular and metabolic tolerance of the dipeptide infusions, the handling of glutamine during renal replacement therapy
in ICU patients, and the safety of glutamine administration in head trauma patients. These issues will be dealt with in this
short chapter.
12/2008: pages 705-715;
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ABSTRACT: Glutathione, a tripeptide (L-γ-glutamyl-L-cysteinyl-glycine) with antioxidant properties, is present at high concentrations
(mmol) in most tissues in man. Its major functions are to scavenge toxic reactive oxidant species (ROS), to detoxify exogenous
toxic compounds, including drugs, and to regulate protein metabolism. The ubiquitous cytoprotective effects of glutathione
are well established [1]. In skeletal muscle from intensive care unit (ICU) patients, low glutathione concentrations are seen, which correlates with
glutamine depletion [2] and with mortality [3]. The consequences of glutathione deplertion are not fully understood. In this chapter, new insights into the glutathione
status of ICU patients are presented including the temporal pattern [4, 5], the effect of exogenous glutamine supplementation [6], and the relation between glutathione status in different tissues [7].
12/2007: pages 444-453;
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ABSTRACT: To investigate glutamine kinetics during continuous renal replacement therapy (CRRT) in multiple organ failure (MOF) patients with and without exogenous intravenous glutamine supplementation.
In a pragmatic clinical study 12 patients without urine production receiving CRRT were prospectively randomized in a cross-over design to receive glutamine intravenously for 20 h before placebo or placebo before glutamine on two consecutive days. Alanyl-glutamine or placebo (saline) was infused.
Plasma glutamine concentration was measured in artery, femoral vein, and filtration fluid. Blood flow across the leg was measured and the efflux of glutamine calculated. The rate of appearance of glutamine was calculated from the plasma decay curve of glutamine concentration on the day of treatment.
Glutamine supplementation increased plasma concentrations from 570+/-252 to 831+/-367 micromol l(-1). Glutamine losses into the filtration fluids were similar during treatment and control days: 25+/-13 vs. 24+/-11 mmol 24 h(-1), corresponding to 3.6+/-1.9 and 3.5+/-1.6 g 24 h(-1), respectively. Net glutamine balance across the leg was also similar on treatment and control days: 150+/-138 and 188+/-205 nmol min(-1) 100 ml(-1), respectively. The rate of appearance of glutamine was 54+/-17 g 24 h(-1).
The loss of glutamine into the ultrafiltrate during CRRT in MOF patients suggests a greater need for exogenous glutamine than in patients without renal failure. The leg efflux and the filtration losses of glutamine were not affected in response to intravenous glutamine supplementation.
Intensive Care Medicine 05/2007; 33(4):660-6. · 5.40 Impact Factor
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ABSTRACT: The understanding of sepsis-induced organ dysfunction has advanced considerably over the last few years. The interaction between
signaling systems and metabolic pathways is a particularly ‘hot’ area of ongoing research. Energy production and the availability
of substrates in the acute phase seem to have a crucial impact on the course of sepsis and on mortality and morbidity. Later
on, during MOF, the same metabolic pathways determine outcome, but the mechanisms and clinical picture are different. Knowledge
of these mechanisms is, therefore, necessary for optimal clinical practice.
12/2006: pages 311-320;
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ABSTRACT: There is reluctance to use glutamine-containing i.v. 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.v. glutamine supplementation in terms of reduced mortality and morbidity, neurosurgical patients might also be candidates for such treatment, if the possible relation between i.v. glutamine supplementation and a possible increase in cerebral glutamate could be sorted out.
The study protocol had a crossover design with a 24h treatment period and a 24h placebo period in random order. Treatment was a glutamine containing dipeptide, L-alanyl-L-glutamine 200mg/ml, for 20h; placebo was saline. The rate of infusion was 0.125ml/kg/h, which is equal to 0.34g/kg of glutamine over the 20h period. Microdialysate was collected for analysis in 120min portions. The flow through the microdialysis catheter was 0.3microl/min.
Patients with severe head trauma (GCS<or=8; n=15) on routine monitoring, including intracerebral microdialysis, were randomly assigned to treatment followed by placebo or placebo followed by treatment.
Glutamine infusion increased plasma glutamine concentration by 30%, but not plasma glutamate concentration. Intracerebral glutamate was unaffected in median values and in all individual patients.
Intravenous glutamine in clinically relevant doses leaves cerebral glutamate unaffected. This opens the possibility of evaluating the effects of i.[Symbol: see text]v. glutamine supplementation upon outcome for neurosurgical ICU patients.
Intensive Care Medicine 12/2006; 32(11):1741-6. · 5.40 Impact Factor
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ABSTRACT: After an ischemia time of 1 h during aortic aneurysm surgery, muscle glutathione redox-status is not altered, indicating that this ischemic insult is well within the scavenging capacity of muscle glutathione, the most important endogenous scavenger. In the present study, the impact of elective aorto-bifemoral bypass surgery, involving a longer ischemia time, on muscle glutathione and its redox-status was investigated.
Leg muscle biopsies were obtained pre-operatively, at maximal ischemia, after 10 min and 24 h of reperfusion from 12 patients undergoing aorto-bifemoral bypass surgery. Muscle glutathione, free amino acids and energy-rich compounds were determined.
Clamping times were 113 (99-120 min); median (quartiles). At maximal ischemia, muscle lactate increased by 7.5 (4.0-10.7) mmol/kg dry weight (dw) (P < 0.001) and phosphocreatine (PCr) decreased by 14.6 (8.9-23.3) mmol/kg dw (P < 0.001). At maximal ischemia, reduced glutathione (GSH) was unaltered but muscle glutamate decreased by 0.51 (0.30-0.85) mmol/kg wet weight (ww) (P < 0.001). At 24 h post-operatively, the reduced glutathione decreased by 0.47 (0.34-0.65) mmol/kg (ww) (P < 0.001) without changes in oxidized glutathione (GSSG) or in glutathione redox-status. Cysteine and glycine, the two other constituent amino acids to glutathione, did not change during the study period.
Ischemia of 2 h during aorto-bifemoral bypass was associated with changes in muscle energy-rich compounds but without any changes in glutathione redox-status. A decreased antioxidative capacity, as reflected by a decrease in muscle glutathione concentrations, was seen 24 h post-operatively, still without changes in glutathione redox-status. This is not different from the changes seen after abdominal surgery not involving ischemia-reperfusion.
Acta Anaesthesiologica Scandinavica 07/2006; 50(6):699-705. · 2.19 Impact Factor
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ABSTRACT: The presence of correlations between the in vivo rates of protein synthesis and relevant clinical parameters suggests that determination of the ongoing metabolic activity
in immune competent cells reflects changes in the functional activity of the immune system, being of importance for the severity
and time course of the critical illness. Our results encourage future studies, in order to characterize the alterations in
the in vivo metabolic activity in immune competent cells in later phases of the ICU stay, characterized by a general anti-inflammatory
activity and decreased resistance to opportunistic infections.
12/2005: pages 52-67;
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ABSTRACT: A randomised, double blind, placebo-controlled study was performed giving 0.5 g x kg(-1) x day(-1) of undiluted alanyl-glutamine (20%) or saline in a peripheral vein during 4 hours in ICU patients (n = 20). During the infusion period a steady state in plasma concentration was reached for alanyl-glutamine, but not for alanine, glutamine or glutamate. On the other hand there was no accumulation of any of the amino acids, as the pre-infusion concentrations were reached within 8 hours after the end of infusion. The half-life of the dipeptide was 0.26 hours (range, 0.15-0.63 h). The distribution volume of alanyl-glutamine was larger than the extracellular water volume, indicating a rapid hydrolysis of the dipeptide. There was no detectable alanyl-glutamine in the urine of any of the patients. All patients had excretion of small amounts of amino acids in urine, but the renal clearance of alanine, glutamine and glutamate were not different between the two groups.
Amino Acids 12/2005; 29(3):221-8. · 3.25 Impact Factor
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ABSTRACT: This study investigated the temporal changes in whole-blood and plasma glutathione in ICU patients with multiple organ failure.
Prospective and descriptive pilot study performed in an ICU with eight beds at a university hospital.
Critically ill patients (n=11) with multiple organ failure and ICU stay of at least 6 days were consecutively included. Patients with chronic obstructive pulmonary disease (n=21) and healthy volunteers (n=10) were used as reference groups.
Whole-blood and plasma glutathione were measured every 72 h. Total glutathione and the reduced fraction were determined in whole blood. The oxidized fraction and the redox status were calculated from these values. In plasma only the total concentration was determined. Patients were studied for 6-15 days. Nutrition was supplied according to routines supplying basal needs including glutamine. Both total and reduced glutathione was found to be depleted in whole blood compared to the reference groups. Redox status indicated continuing oxidative stress. Plasma glutathione showed higher values in total concentrations than the reference groups.
This study demonstrates that glutathione remains depleted in whole blood. This contrasts to what has previously been shown in skeletal muscle where a restitution of glutathione concentration is seen.
Intensive Care Medicine 09/2005; 31(8):1072-8. · 5.40 Impact Factor
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ABSTRACT: 3-Methylhistidine urinary excretion and net balances across the leg or forearm have been used as markers of contractile protein breakdown in muscle tissue. Here we investigate whether infusion of labeled 3-methylhistidine and the measurement of the arteriovenous dilution of the tracer with unlabeled 3-methylhistidine will result in more consistent and precise measurements of 3-methylhistidine rates of appearance and consequently muscle contractile protein breakdown rates in comparison with conventional arteriovenous concentration difference measurements. Six healthy volunteers were studied in the postabsorptive state and received a primed continuous infusion of 3-[2H3-methyl]- methylhistidine and L-[ring-2H5]-phenylalanine for 4 hours. 2H3-3-methylhistidine reached an isotopic steady state after 210 minutes in all subjects. Arteriovenous differences of 3-methylhistidine, measured by high-performance liquid chromatography (HPLC), showed both uptake and release from skeletal muscle, which is theoretically not likely to occur. The enrichment of 2H3-3-methylhistidine was consistently lower in the femoral vein than in the artery, and therefore a constant net release of 3-methylhistidine from the leg was observed. The mean rates of appearance for 3-methylhistidine and phenylalanine were 0.44 +/- 0.30 nmol x min(-1) x 100 mL(-1) and 11.2 +/- 5.7 nmol x min(-1) x 100 mL(-1), respectively. In summary, arteriovenous difference measurement of 2H3-3-methylhistidine enrichment is more reliable than measurement of arteriovenous difference of unlabeled 3-methylhistidine. Consequently, measuring rates of appearance from leg muscle using labeled 3-methylhistidine resulted in more consistent and accurate values of contractile protein degradation rates in human skeletal muscle.
Metabolism 09/2004; 53(8):1076-80. · 2.66 Impact Factor
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ABSTRACT: This study investigated the changes over time in glutathione and its constituent amino acids in skeletal muscle of ICU patients with multiple organ failure.
Prospective and descriptive pilot study in two medium-sized ICUs with ten beds.
Critically ill patients ( n=10) with multiple organ failure and with an expected ICU stay longer than 6 days were included during their initial 3 days after admission to the ICU.
Muscle biopsy and blood samples were taken on days 0, 3, and 6 after inclusion and total, reduced, and oxidized glutathione and the related amino acids were determined. During the study period both total and reduced glutathione increased and was in the normal range on day 6. The constituent amino acids normalized during the study period as well.
This pilot study demonstrates a recovery of muscle glutathione concentrations in critically ill patients with ongoing multiple organ failure within 1 week. Restoration of muscle glutathione seems to be a biological process of high priority in this group of patients.
Intensive Care Medicine 01/2004; 29(12):2193-8. · 5.40 Impact Factor
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Clinical Nutrition 09/2003; 22(4):423. · 3.73 Impact Factor
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ABSTRACT: Glutathione is quantitatively the most important endogenous scavenger system. Glutathione depletion in skeletal muscle is pronounced following major trauma and sepsis in intensive care unit patients. Also, following elective surgery, glutathione depletion occurs in parallel with a progressive decline in muscle glutamine concentration. The present study was designed to test the hypothesis that glutamine supplementation may counteract glutathione depletion in a human trauma model. A homogeneous group of patients (n = 17) undergoing a standardized surgical procedure were prospectively randomly allocated to receive glutamine (0.56 g x day(-1) x kg(-1)) or placebo as part of isonitrogenous and isocaloric nutrition. Percutaneous muscle biopsies and blood samples were taken pre-operatively and at 24 and 72 h after surgery. The concentrations of muscle glutathione and related amino acids were determined in muscle tissue and plasma. In the control (unsupplemented) subjects, total muscle glutathione had decreased by 47+/-8% and 37+/-11% and reduced glutathione had decreased by 53+/-10% and 45+/-16% respectively at 24 and 72 h after surgery (P < 0.05). In contrast, in the glutamine-supplemented group, no significant post-operative decreases in total or reduced glutathione were seen following surgery. Muscle free glutamine had decreased at 72 h after surgery in both groups, by 41.4+/-14.8% (P < 0.05) in the glutamine-supplemented group and by 46.0+/-14.3% (P < 0.05) in the control group. In conclusion, the present study demonstrates that intravenous glutamine supplementation attenuates glutathione depletion in skeletal muscle in humans following standardized surgical trauma.
Clinical Science 03/2003; 104(3):275-82. · 4.61 Impact Factor
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ABSTRACT: ObjectiveThis study investigated the changes over time in glutathione and its constituent amino acids in skeletal muscle of ICU patients with multiple organ failure.Design and settingProspective and descriptive pilot study in two medium-sized ICUs with ten beds.PatientsCritically ill patients (n=10) with multiple organ failure and with an expected ICU stay longer than 6days were included during their initial 3days after admission to the ICU.Measurements and resultsMuscle biopsy and blood samples were taken on days 0, 3, and 6 after inclusion and total, reduced, and oxidized glutathione and the related amino acids were determined. During the study period both total and reduced glutathione increased and was in the normal range on day 6. The constituent amino acids normalized during the study period as well.ConclusionsThis pilot study demonstrates a recovery of muscle glutathione concentrations in critically ill patients with ongoing multiple organ failure within 1week. Restoration of muscle glutathione seems to be a biological process of high priority in this group of patients.
Intensive Care Medicine 01/2003; 29(12):2193-2198. · 5.40 Impact Factor
