Variability in Skeletal Muscle Protein Synthesis Rates in Critically Ill Patients.

(1) Background: Muscle protein synthesis in critically ill patients is, on average, normal despite dramatic muscle loss, but the variation is much larger than in controls. Here, we evaluate if this variation is due to 1) heterogeneity in synthesis rates, 2) morphological variation or infiltrating cells, or 3) heterogeneity in the synthesis of different protein fractions. (2) Methods: Muscle biopsies were taken from both legs of critically ill patients (n = 17). Mixed and mitochondrial protein synthesis rates and morphologies were evaluated in both legs. Synthesis rates of myosin and actin were determined in combined biopsies and compared with controls. (3) Results: Muscle protein synthesis rates had a large variability in the patients (1.4-10.8%/day). No differences in mixed and mitochondrial protein synthesis rates between both legs were observed. A microscopic examination revealed no morphological differences between the two legs or any infiltrating inflammatory cells. The synthesis rates for myosin were lower and for actin they were higher in the muscles of critically ill patients, compared with the controls. (4) Conclusions: The large variation in muscle protein synthesis rates in critically ill patients is not the result of heterogeneity in synthesis rates, nor due to infiltrating cells. There are differences in the synthesis rates of different proteins, but these do not explain the larger variations.

Medical nutrition therapy and clinical outcomes in critically ill adults: a European multinational, prospective observational cohort study (EuroPN).

BACKGROUND: Medical nutrition therapy may be associated with clinical outcomes in critically ill patients with prolonged intensive care unit (ICU) stay. We wanted to assess nutrition practices in European intensive care units (ICU) and their importance for clinical outcomes. METHODS: Prospective multinational cohort study in patients staying in ICU ≥ 5 days with outcome recorded until day 90. Macronutrient intake from enteral and parenteral nutrition and non-nutritional sources during the first 15 days after ICU admission was compared with targets recommended by ESPEN guidelines. We modeled associations between three categories of daily calorie and protein intake (low: < 10 kcal/kg, < 0.8 g/kg; moderate: 10-20 kcal/kg, 0.8-1.2 g/kg, high: > 20 kcal/kg; > 1.2 g/kg) and the time-varying hazard rates of 90-day mortality or successful weaning from invasive mechanical ventilation (IMV). RESULTS: A total of 1172 patients with median [Q1;Q3] APACHE II score of 18.5 [13.0;26.0] were included, and 24% died within 90 days. Median length of ICU stay was 10.0 [7.0;16.0] days, and 74% of patients could be weaned from invasive mechanical ventilation. Patients reached on average 83% [59;107] and 65% [41;91] of ESPEN calorie and protein recommended targets, respectively. Whereas specific reasons for ICU admission (especially respiratory diseases requiring IMV) were associated with higher intakes (estimate 2.43 [95% CI: 1.60;3.25] for calorie intake, 0.14 [0.09;0.20] for protein intake), a lack of nutrition on the preceding day was associated with lower calorie and protein intakes (- 2.74 [- 3.28; - 2.21] and - 0.12 [- 0.15; - 0.09], respectively). Compared to a lower intake, a daily moderate intake was associated with higher probability of successful weaning (for calories: maximum HR 4.59 [95% CI: 1.5;14.09] on day 12; for protein: maximum HR 2.60 [1.09;6.23] on day 12), and with a lower hazard of death (for calories only: minimum HR 0.15, [0.05;0.39] on day 19). There was no evidence that a high calorie or protein intake was associated with further outcome improvements. CONCLUSIONS: Calorie intake was mainly provided according to the targets recommended by the active ESPEN guideline, but protein intake was lower. In patients staying in ICU ≥ 5 days, early moderate daily calorie and protein intakes were associated with improved clinical outcomes. Trial registration NCT04143503 , registered on October 25, 2019.

Plasma glutamine status at intensive care unit admission: an independent risk factor for mortality in critical illness.

BACKGROUND: A plasma glutamine concentration outside the normal range at Intensive Care Unit (ICU) admission has been reported to be associated with an increased mortality rate. Whereas hypoglutaminemia has been frequently reported, the number of patients with hyperglutaminemia has so far been quite few. Therefore, the association between hyperglutaminemia and mortality outcomes was studied in a prospective, observational study. PATIENTS AND METHODS: Consecutive admissions to a mixed general ICU were eligible. Exclusion criteria were < 18 years of age, readmissions, no informed consent, or a 'do not resuscitate' order at admission. A blood sample was saved within one hour from admission to be analysed by high-pressure liquid chromatography for glutamine concentration. Conventional risk scoring (Simplified Acute Physiology Score and Sequential Organ Failure Assessment) at admission, and mortality outcomes were recorded for all included patients. RESULTS: Out of 269 included patients, 26 were hyperglutaminemic (≥ 930 µmol/L) at admission. The six-month mortality rate for this subgroup was 46%, compared to 18% for patients with a plasma glutamine concentration < 930 µmol/L (P = 0.002). A regression analysis showed that hyperglutaminemia was an independent mortality predictor that added prediction value to conventional admission risk scoring and age. CONCLUSION: Hyperglutaminemia in critical illness at ICU admission was an independent mortality predictor, often but not always, associated with an acute liver condition. The mechanism behind a plasma glutamine concentration outside normal range, as well as the prognostic value of repeated measurements of plasma glutamine during ICU stay, remains to be investigated.

Endogenous production of glutamine and plasma glutamine concentration in critically ill patients.

BACKGROUND: Glutamine plasma concentrations outside the normal range at intensive care unit (ICU) admission are associated with unfavorable outcomes. Based on the hypothesis that hypoglutaminemia in the ICU is the result of an increased utilization of glutamine which cannot be fully met by endogenous production, extra glutamine supplementation has been advocated to ICU patients with hypoglutaminemia. However, it is still unclear whether there is a causal relation between hypo- and hyperglutaminemia and outcomes. Present guidelines advise against supplementation, although there is no evidence available for patients with hypoglutaminemia. The pathophysiology of abnormal glutamine levels and whether glutamine production or glutamine utilization is compromised is largely unknown. Therefore, the aim of this study was to elucidate the relationship between plasma glutamine levels and the endogenous glutamine production in ICU patients. METHOD: In this observational study, a technique using a small bolus of intravenous glutamine with an isotopic label was used to measure glutamine production. RESULTS: There was a statistically significant correlation between de novo endogenous production of glutamine (not emanating directly from protein breakdown) and plasma glutamine concentrations in the low and normal range in circulatory stabilized ICU patients (n = 19), R2 = 0.35 (P ≤ 0.01). CONCLUSION: The predictive value of a low plasma glutamine concentration at ICU admission on outcomes may thus be related to a low endogenous production, which may need to be supplemented in the best interest of this cohort of patients.

Serum selenium in critically ill patients: Profile and supplementation in a depleted region.

BACKGROUND: General selenium supplementation to intensive care unit (ICU) patients in regions with selenium-rich soil does not improve outcomes. Still selenium supplementation may reduce morbidity and mortality in patients with low-serum selenium concentration (S-Se) in selenium-poor areas who respond to treatment. The primary aim of this observational study was to investigate S-Se in a selenium-deficient region at time of intensive care admission, and in addition to monitor S-Se during high-dose selenium supplementation for safety. METHODS: We measured S-Se in 100 consecutive patients admitted to a tertiary general ICU. After initial sampling, high-dose intravenous (iv) selenium supplementation was administered up to 20 days. RESULTS: At admission, in 95% of the cases, S-Se was below the saturation level for selenoenzymes, in 91%, below the Swedish reference level, and in 71%, below the level where selenoenzyme function may be impaired. At day 5 of substitution, all patients still remaining in the ICU (n = 26) were within the range for enzyme function, 12% were below reference, and 24% did not reach full enzymatic saturation. At day 10 and forward, all patients were within target for treatment. No patients were at risk for toxic S-Se concentration. CONCLUSIONS: S-Se concentration was substantially lower compared to normal values at ICU admission in this cohort of unselected Swedish critical care patients. Selenium supplementation restituted S-Se to levels corresponding to enzymatic saturation and the Swedish reference interval for all subjects remaining in the ICU on day 5.

Autophagy flux in critical illness, a translational approach.

Recent clinical trials suggest that early nutritional support might block the induction of autophagy in critically ill patients leading to the development of organ failure. However, the regulation of autophagy, especially by nutrients, in critical illness is largely unclear. The autophagy flux (AF) in relation to critical illness and nutrition was investigated by using an in vitro model of human primary myotubes incubated with serum from critically ill patients (ICU). AF was calculated as the difference of p62 expression in the presence and absence of chloroquine (50 µM, 6 h), in primary myotubes incubated for 24 h with serum from healthy volunteers (n = 10) and ICU patients (n = 93). We observed 3 different phenotypes in AF, non-altered (ICU non-responder group), increased (ICU inducer group) or blocked (ICU blocker group). This block was not associate with a change in amino acids serum levels and was located at the accumulation of autophagosomes. The increase in the AF was associated with lower serum levels of non-essential amino acids. Thus, early nutrition during critical illness might not block autophagy but could attenuate the beneficial effect of starvation on reactivation of the autophagy process. This could be of clinical importance in the individual patients in whom this process is inhibited by the critical illness insult.

A supplemental intravenous amino acid infusion sustains a positive protein balance for 24 hours in critically ill patients.

BACKGROUND: Providing supplemental amino acids to ICU patients during a 3-h period results in improved whole-body net protein balance, without an increase in amino acid oxidation. The primary objective was to investigate if a 24-h intravenous amino acid infusion in critically ill patients has a sustained effect on whole-body protein balance as was seen after 3 h. Secondary objectives were monitoring of amino acid oxidation rate, urea and free amino acid plasma concentrations. METHODS: An infusion of [1-13C]-phenylalanine was added to ongoing enteral nutrition to quantify the enteral uptake of amino acids. Primed intravenous infusions of [ring-2H5]-phenylalanine and [3,3-2H2]-tyrosine were used to assess whole-body protein synthesis and breakdown, to calculate net protein balance and to assess amino acid oxidation at baseline and at 3 and 24 hours. An intravenous amino acid infusion was added to nutrition at a rate of 1 g/kg/day and continued for 24 h. RESULTS: Eight patients were studied. The amino acid infusion resulted in improved net protein balance over time, from -1.6 ± 7.9 µmol phe/kg/h at 0 h to 6.0 ± 8.8 at 3 h and 7.5 ± 5.1 at 24 h (p = 0.0016). The sum of free amino acids in plasma increased from 3.1 ± 0.6 mmol/L at 0 h to 3.2 ± 0.3 at 3 h and 3.6 ± 0.5 at 24 h (p = 0.038). Amino acid oxidation and plasma urea were not altered significantly. CONCLUSION: We demonstrated that the improvement in whole-body net protein balance from a supplemental intravenous amino acid infusion seen after 3 h was sustained after 24 h in critically ill patients. TRIAL REGISTRATION: This trial was prospectively registered at Australian New Zealand Clinical Trials Registry. ACTRN, 12615001314516 . Registered on 1 December 2015.

Approximation of Resting Energy Expenditure in Intensive Care Unit Patients Using the SenseWear Bracelet: A Comparison With Indirect Calorimetry.

BACKGROUND AND AIMS: Indirect calorimetry (IC) is the gold standard for determining energy expenditure in patients requiring mechanical ventilation. Metabolic armbands using data derived from dermal measurements have been proposed as an alternative to IC in healthy subjects, but their utility during critical illness is unclear. The aim of this study was to determine the level of agreement between the SenseWear armband and the Deltatrac Metabolic Monitor in mechanically ventilated intensive care unit (ICU) patients. METHODS: Adult ICU patients requiring invasive ventilator therapy were eligible for inclusion. Simultaneous measurements were performed with the SenseWear Armband and Deltatrac under stable conditions. Resting energy expenditure (REE) values were registered for both instruments and compared with Bland-Altman plots. RESULTS: Forty-two measurements were performed in 30 patients. The SenseWear Armband measured significantly higher REE values as compared with IC (mean bias, 85 kcal/24 h; P = .027). Less variability was noted between individual SenseWear measurements and REE as predicted by the Harris-Benedict equation (2 SD, ±327 kcal/24 h) than when IC was compared with SenseWear and Harris-Benedict (2 SD, ±473 and ±543 kcal/24 h, respectively). CONCLUSIONS: The systematic bias and large variability of the SenseWear armband when compared with gas exchange measurements confer limited benefits over the Harris Benedict equation in determining caloric requirements of ICU patients.

Validation of a point-of-care instrument for bedside glutamine screening in the intensive care unit.

BACKGROUND: A point-of-care instrument developed for measuring glutamine levels in cell cultures was validated for bedside use in the ICU setting and compared with a standard HPLC technique to measure plasma glutamine. The aim was to evaluate the instrument for absolute measurements and for screening purposes. METHODS: Consecutive blood samples were obtained from one hundred adult ICU patients 3-5 days apart during their ICU stay. Each sample was divided into 3 aliquots, out of which two were used for analyses of plasma and whole blood glutamine by the point-of-care instrument, and one was used for analysis of plasma glutamine concentration by the gold standard HPLC technique. Comparisons were performed by Bland-Altman analyses. RESULTS: Comparison of the initial plasma sample of each subject (n = 100), between the point of care instrument and HPLC analysis revealed a systematic bias of -221 µmol/L. Comparisons between plasma and whole blood on the point-of-care instrument revealed comparable results. After pragmatic adjustments for the measured bias and hematocrit, whole blood analyses during ICU stay (n = 316) compared with HPLC plasma analyses showed a line of identity of -34 µmol/L and limits of agreement between 288 and -355 µmol/L. CONCLUSION: When compared to the HPLC gold standard in particular, the lines of agreement indicate that the point-of-care instrument is not suitable for quantitative plasma or whole blood glutamine concentration measurements. For screening purposes the instrument may be useful in order to identify patients with hypoglutaminemia and hyperglutaminemia and the tested accuracy was high enough for safe supplementation of glutamine to patients with low plasma values measured with the device. The point-of-care instrument may also serve as a screening tool for scientific studies.

Measuring energy expenditure in the intensive care unit: a comparison of indirect calorimetry by E-sCOVX and Quark RMR with Deltatrac II in mechanically ventilated critically ill patients.

BACKGROUND: Indirect calorimetry allows the determination of energy expenditure in critically ill patients by measuring oxygen consumption (VO2) and carbon dioxide production (VCO2). Recent studies have demonstrated variable performance of "breath-by-breath" instruments compared to mixing chamber technology. The aim of this study was to validate two modern devices (E-sCOVX and Quark RMR) against a reference method (Deltatrac II). METHOD: Measurements of VO2/VCO2 with the test and reference devices were performed simultaneously over a 20-min period in mechanically ventilated adult intensive care unit patients. Accuracy and precision of instruments were analyzed using Bland-Altman plots. RESULTS: Forty-eight measurements in 22 patients were included for analysis. Both E-sCOVX and Quark RMR overestimated VO2 and VCO2 compared to Deltatrac II, corresponding to a 10% higher mean resting energy expenditure. Limits of agreement of resting energy expenditure within ± 2 standard deviations were ± 461 kcal/24 h (± 21% expressed as percentage error) for ΔE-sCOVX-Deltatrac II and ± 465 kcal/24 h (± 22%) for ΔQuark RMR-Deltatrac II. CONCLUSION: Both test devices overestimate VO2 and VCO2 compared to Deltatrac II. The observed limits of agreement are comparable to those commonly accepted in evaluations of circulatory monitoring, and significantly less than results from predictive equations. We hypothesize that the discrepancy between methods is due to patient/ventilator-related factors that affect the synchronization of gas and spirometry waveforms. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, Trial ID ACTRN12615000205538. Date registered 3 March 2015.

Plasma Glutamine Concentrations in Liver Failure.

BACKGROUND: Higher than normal plasma glutamine concentration at admission to an intensive care unit is associated with an unfavorable outcome. Very high plasma glutamine levels are sometimes seen in both acute and chronic liver failure. We aimed to systematically explore the relation between different types of liver failure and plasma glutamine concentrations. METHODS: Four different groups of patients were studies; chronic liver failure (n = 40), acute on chronic liver failure (n = 20), acute fulminant liver failure (n = 20), and post-hepatectomy liver failure (n = 20). Child-Pugh and Model for End-stage Liver Disease (MELD) scores were assessed as indices of liver function. All groups except the chronic liver failure group were followed longitudinally during hospitalisation. Outcomes were recorded up to 48 months after study inclusion. RESULTS: All groups had individuals with very high plasma glutamine concentrations. In the total group of patients (n = 100), severity of liver failure correlated significantly with plasma glutamine concentration, but the correlation was not strong. CONCLUSION: Liver failure, regardless of severity and course of illness, may be associated with a high plasma glutamine concentration. Further studies are needed to understand whether high glutamine levels should be regarded as a biomarker or as a contributor to symptomatology in liver failure.

Nutritional needs for the critically ill in relation to inflammation.

PURPOSE OF REVIEW: This review focuses on nutritional needs in critically ill patients. The inflammation corresponding to acute stress is highlighted. Simultaneously, we try to avoid limiting the perspective to only the acute phase. RECENT FINDINGS: During the last year, a number of important studies on nutritional needs in the critically ill have been published, including large randomized controlled trials. In particular studies addressing the needs for energy and proteins in the critically ill have imparted new knowledge in this field. However, there are few studies concerning the rehabilitation phase after critical illness. SUMMARY: Although the recent findings and publications contribute to a more nuanced understanding of nutrition during critical illness, the implications for clinical practice are not in discord with the current recommendations of guidelines.

Whole body protein turnover in critically ill patients with multiple organ failure.

BACKGROUND & AIMS: To evaluate the effect of nutrition therapy on protein turnover in critically ill patients isotopically labeled amino acids can be used. Here parallel measurements using (13)C-leucine and (2)H5-phenylalanine were performed to evaluate if one tracer was to be preferred. METHODS: As a reference group, healthy volunteers (n = 8) were studied in the postabsorptive state and during parenteral nutrition delivery. ICU patients with multiple organ failure (n = 8) were studied during parenteral nutrition delivery only. RESULTS: For the volunteers, the net protein balances changed from negative to positive during parenteral nutrition delivery (compared to the postabsorptive state) when evaluated with leucine and phenylalanine (P < 0.0001). For phenylalanine this change was attributable to an increased protein synthesis (P < 0.0001), while for leucine the change was attributable to a decreased protein degradation (P < 0.0001). For the patients, only measured during parenteral nutrition delivery, the estimates by the two amino acid tracers agreed, showing a protein balance not statistically significantly different from zero. The whole body protein turnover was higher than that of the healthy volunteers during parenteral nutrition delivery. In the patients, the net protein balance correlated positively to the amount of amino acids given. CONCLUSIONS: Critically ill patients with multiple organ failure have an increased protein turnover. The findings in the healthy volunteers indicate that the use of the two different amino acid tracers in parallel in future studies should be considered.

Lower versus higher hemoglobin threshold for transfusion in septic shock.

BACKGROUND: Blood transfusions are frequently given to patients with septic shock. However, the benefits and harms of different hemoglobin thresholds for transfusion have not been established. METHODS: In this multicenter, parallel-group trial, we randomly assigned patients in the intensive care unit (ICU) who had septic shock and a hemoglobin concentration of 9 g per deciliter or less to receive 1 unit of leukoreduced red cells when the hemoglobin level was 7 g per deciliter or less (lower threshold) or when the level was 9 g per deciliter or less (higher threshold) during the ICU stay. The primary outcome measure was death by 90 days after randomization. RESULTS: We analyzed data from 998 of 1005 patients (99.3%) who underwent randomization. The two intervention groups had similar baseline characteristics. In the ICU, the lower-threshold group received a median of 1 unit of blood (interquartile range, 0 to 3) and the higher-threshold group received a median of 4 units (interquartile range, 2 to 7). At 90 days after randomization, 216 of 502 patients (43.0%) assigned to the lower-threshold group, as compared with 223 of 496 (45.0%) assigned to the higher-threshold group, had died (relative risk, 0.94; 95% confidence interval, 0.78 to 1.09; P=0.44). The results were similar in analyses adjusted for risk factors at baseline and in analyses of the per-protocol populations. The numbers of patients who had ischemic events, who had severe adverse reactions, and who required life support were similar in the two intervention groups. CONCLUSIONS: Among patients with septic shock, mortality at 90 days and rates of ischemic events and use of life support were similar among those assigned to blood transfusion at a higher hemoglobin threshold and those assigned to blood transfusion at a lower threshold; the latter group received fewer transfusions. (Funded by the Danish Strategic Research Council and others; TRISS ClinicalTrials.gov number, NCT01485315.).

A tracer bolus method for investigating glutamine kinetics in humans.

Glutamine transport between tissues is important for the outcome of critically ill patients. Investigation of glutamine kinetics is, therefore, necessary to understand glutamine metabolism in these patients in order to improve future intervention studies. Endogenous glutamine production can be measured by continuous infusion of a glutamine tracer, which necessitates a minimum measurement time period. In order to reduce this problem, we used and validated a tracer bolus injection method. Furthermore, this method was used to measure the glutamine production in healthy volunteers in the post-absorptive state, with extra alanine and with glutamine supplementation and parenteral nutrition. Healthy volunteers received a bolus injection of [1-13C] glutamine, and blood was collected from the radial artery to measure tracer enrichment over 90 minutes. Endogenous rate of appearance (endoRa) of glutamine was calculated from the enrichment decay curve and corrected for the extra glutamine supplementation. The glutamine endoRa of healthy volunteers was 6.1±0.9 µmol/kg/min in the post-absorptive state, 6.9±1.0 µmol/kg/min with extra alanyl-glutamine (p = 0.29 versus control), 6.1±0.4 µmol/kg/min with extra alanine only (p = 0.32 versus control), and 7.5±0.9 µmol/kg/min with extra alanyl-glutamine and parenteral nutrition (p = 0.049 versus control). In conclusion, a tracer bolus injection method to measure glutamine endoRa showed good reproducibility and small variation at baseline as well as during parenteral nutrition. Additionally, we showed that parenteral nutrition including alanyl-glutamine increased glutamine endoRa in healthy volunteers, which was not attributable to the alanine part of the dipeptide.

Endogenous glutamine production in critically ill patients: the effect of exogenous glutamine supplementation.

INTRODUCTION: Glutamine rate of appearance (Ra) may be used as an estimate of endogenous glutamine production. Recently a technique employing a bolus injection of isotopically labeled glutamine was introduced, with the potential to allow for multiple assessments of the glutamine Ra over time in critically ill patients, who may not be as metabolically stable as healthy individuals. Here the technique was used to evaluate the endogenous glutamine production in critically ill patients in the fed state with and without exogenous glutamine supplementation intravenously. METHODS: Mechanically ventilated patients (n = 11) in the intensive care unit (ICU) were studied on two consecutive days during continuous parenteral feeding. To allow the patients to be used as their own controls, they were randomized for the reference measurement during basal feeding without supplementation, before or after the supplementation period. Glutamine Ra was determined by a bolus injection of 13C-glutamine followed by a period of frequent sampling to establish the decay-curve for the glutamine tracer. Exogenous glutamine supplementation was given by intravenous infusion of a glutamine containing dipeptide, L-alanyl-L-glutamine, 0.28 g/kg during 20 hours. RESULTS: A 14% increase of endogenous glutamine Ra was seen at the end of the intravenous supplementation period as compared to the basal measurements (P = 0.009). CONCLUSIONS: The bolus injection technique to measure glutamine Ra to estimate the endogenous production of glutamine in critically ill patients was demonstrated to be useful for repetitive measurements. The hypothesized attenuation of endogenous glutamine production during L-alanyl-L-glutamine infusion given as a part of full nutrition was not seen.

Transfusion requirements in septic shock (TRISS) trial - comparing the effects and safety of liberal versus restrictive red blood cell transfusion in septic shock patients in the ICU: protocol for a randomised controlled trial.

BACKGROUND: Transfusion of red blood cells (RBC) is recommended in septic shock and the majority of these patients receive RBC transfusion in the intensive care unit (ICU). However, benefit and harm of RBCs have not been established in this group of high-risk patients. METHODS/DESIGN: The Transfusion Requirements in Septic Shock (TRISS) trial is a multicenter trial with assessor-blinded outcome assessment, randomising 1,000 patients with septic shock in 30 Scandinavian ICUs to receive transfusion with pre-storage leuko-depleted RBC suspended in saline-adenine-glucose and mannitol (SAGM) at haemoglobin level (Hb) of 7 g/dl or 9 g/dl, stratified by the presence of haematological malignancy and centre. The primary outcome measure is 90-day mortality. Secondary outcome measures are organ failure, ischaemic events, severe adverse reactions (SARs: anaphylactic reaction, acute haemolytic reaction and transfusion-related circulatory overload, and acute lung injury) and mortality at 28 days, 6 months and 1 year.The sample size will enable us to detect a 9% absolute difference in 90-day mortality assuming a 45% event rate with a type 1 error rate of 5% and power of 80%. An interim analysis will be performed after 500 patients, and the Data Monitoring and Safety Committee will recommend the trial be stopped if a group difference in 90-day mortality with P ≤0.001 is present at this point. DISCUSSION: The TRISS trial may bridge the gap between clinical practice and the lack of efficacy and safety data on RBC transfusion in septic shock patients. The effect of restrictive versus liberal RBC transfusion strategy on mortality, organ failure, ischaemic events and SARs will be evaluated.

Indirect calorimetry in mechanically ventilated patients. A systematic comparison of three instruments.

BACKGROUND & AIMS: Indirect calorimetry is the gold standard in determining energy expenditure to dose nutritional therapy for critically ill patients. The most commonly used system for indirect calorimetry in the ICU setting (Deltatrac Metabolic Monitor) is no longer in production. The aim of this study was to compare two new instruments for IC (Quark RMR, CCM Express) to the Deltatrac in mechanically ventilated patients. METHODS: Sequential measurements with all three instruments were performed in randomized order on 24 mechanically ventilated ICU patients. Resting energy expenditure (REE), respiratory quotient (RQ), oxygen consumption and carbon dioxide production were recorded during a stable 10-30 min period. RESULTS: There was no difference in mean REE measurements between Deltatrac, 1749 ± 389 kcal/24 h and Quark RMR, 1788 ± 494 kcal/24 h (P = 0.166). CCM Express produced 64% higher mean REE values (2876 ± 656 kcal/24 h) than Deltatrac (P < 0.0001). All instruments registered different values for RQ and expiratory minute volume. CONCLUSION: Available instruments for indirect calorimetry give conflicting estimates of energy expenditure in mechanically ventilated patients. Whilst the Quark RMR compares better with the Deltatrac than CCM Express, the mechanisms behind this difference needs to be further explored.

Protein metabolism and gene expression in skeletal muscle of critically ill patients with sepsis.

Muscle wasting negatively affects morbidity and mortality in critically ill patients. This progressive wasting is accompanied by, in general, a normal muscle PS (protein synthesis) rate. In the present study, we investigated whether muscle protein degradation is increased in critically ill patients with sepsis and which proteolytic enzyme systems are involved in this degradation. Eight patients and seven healthy volunteers were studied. In vivo muscle protein kinetics was measured using arteriovenous balance techniques with stable isotope tracers. The activities of the major proteolytic enzyme systems were analysed in combination with mRNA expression of genes related to these proteolytic systems. Results show that critically ill patients with sepsis have a variable but normal muscle PS rate, whereas protein degradation rates are dramatically increased (up to 160%). Of the major proteolytic enzyme systems both the proteasome and the lysosomal systems had higher activities in the patients, whereas calpain and caspase activities were not changed. Gene expression of several genes related to the proteasome system was increased in the patients. mRNA levels of the two main lysosomal enzymes (cathepsin B and L) were not changed but, conversely, genes related to calpain and caspase had a higher expression in the muscles of the patients. In conclusion, the dramatic muscle wasting seen in critically ill patients with sepsis is due to increased protein degradation. This is facilitated by increased activities of both the proteasome and lysosomal proteolytic systems.