Inga Tjäder

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.).

Dysregulation of mitochondrial dynamics and the muscle transcriptome in ICU patients suffering from sepsis induced multiple organ failure.

Background Septic patients treated in the intensive care unit (ICU) often develop multiple organ failure including persistent skeletal muscle dysfunction which results in the patients protracted recovery process. We have demonstrated that muscle mitochondrial enzyme activities are impaired in septic ICU patients impairing cellular energy balance, which will interfere with muscle function and metabolism. Here we use detailed phenotyping and genomics to elucidate mechanisms leading to these impairments and the molecular consequences. Methodology/Principal Findings Utilising biopsy material from seventeen patients and ten age-matched controls we demonstrate that neither mitochondrial in vivo protein synthesis nor expression of mitochondrial genes are compromised. Indeed, there was partial activation of the mitochondrial biogenesis pathway involving NRF2α/GABP and its target genes TFAM, TFB1M and TFB2M yet clearly this failed to maintain mitochondrial function. We therefore utilised transcript profiling and pathway analysis of ICU patient skeletal muscle to generate insight into the molecular defects driving loss of muscle function and metabolic homeostasis. Gene ontology analysis of Affymetrix analysis demonstrated substantial loss of muscle specific genes, a global oxidative stress response related to most probably cytokine signalling, altered insulin related signalling and a substantial overlap between patients and muscle wasting/inflammatory animal models. MicroRNA 21 processing appeared defective suggesting that post-transcriptional protein synthesis regulation is altered by disruption of tissue microRNA expression. Finally, we were able to demonstrate that the phenotype of skeletal muscle in ICU patients is not merely one of inactivity, it appears to be an actively remodelling tissue, influenced by several mediators, all of which may be open to manipulation with the aim to improve clinical outcome. Conclusions/Significance This first combined protein and transcriptome based analysis of human skeletal muscle obtained from septic patients demonstrated that losses of mitochondria and muscle mass are accompanied by sustained protein synthesis (anabolic process) while dysregulation of transcription programmes appears to fail to compensate for increased damage and proteolysis. Our analysis identified both validated and novel clinically tractable targets to manipulate these failing processes and pursuit of these could lead to new potential treatments.

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.

Proteasome proteolytic activity in skeletal muscle is increased in patients with sepsis

Patients with sepsis in the ICU (intensive care unit) are characterized by skeletal muscle wasting. This leads to muscle dysfunction that also influences the respiratory capacity, resulting in prolonged mechanical ventilation. Catabolic conditions are associated with a general activation of the ubiquitin-proteasome pathway in skeletal muscle. The aim of the present study was to measure the proteasome proteolytic activity in both respiratory and leg muscles from ICU patients with sepsis and, in addition, to assess the variation of proteasome activity between individuals and between duplicate leg muscle biopsy specimens. When compared with a control group (n=10), patients with sepsis (n=10) had a 30% (P<0.05) and 45% (P<0.05) higher proteasome activity in the respiratory and leg muscles respectively. In a second experiment, ICU patients with sepsis (n=17) had a 55% (P<0.01) higher proteasome activity in the leg muscle compared with a control group (n=10). The inter-individual scatter of proteasome activity was larger between the patients with sepsis than the controls. We also observed a substantial intra-individual difference in activity between duplicate biopsies in several of the subjects. In conclusion, the proteolytic activity of the proteasome was higher in skeletal muscle from patients with sepsis and multiple organ failure compared with healthy controls. It was shown for the first time that respiratory and leg muscles were affected similarly. Furthermore, the variation in proteasome activity between individuals was more pronounced in the ICU patients for both muscle types, whereas the intra-individual variation between biopsies was similar for ICU patients and controls.

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.

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.

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.

Exogenous glutamine : Compensating a shortage?

There is still insufficient knowledge about in vivo glutamine metabolism and the regulation of glutamine homeostasis, particularly during metabolic stress. A shortage of glutamine is associated with a poor outcome, whereas for septic patients in the intensive care unit an increased availability of glutamine can prevent mortality and morbidity. Cellular defense mechanisms depend on normal glutamine availability to respond adequately to challenges presented. In clinical practice, treatment of plasma glutamine depletion improves outcome for the critically ill patient. An increased metabolic need for glutamine must be met with an increased consumption of glutamine. Ordinary food is not a sufficient supply of glutamine for the patient with multiple organ failure in the intensive care unit, but that is also true for several other nutrients. It is, therefore, debatable whether an exogenous supply of glutamine should be regarded as a pharmacologic treatment or whether this just represents physiology in stressed states. If a glutamine shortage requires substitution, supplementation to the normal concentration is compensation of a shortage, and the effect is physiological.

Muscle Protein Synthesis Rate Decreases 24 Hours After Abdominal Surgery Irrespective of Total Parenteral Nutrition

BACKGROUND Muscle protein synthesis rate is known to decrease postoperatively as a part of the catabolic response to trauma. Conventional total parenteral nutrition (TPN) in the postoperative period does not seem to counteract the decrease in protein synthesis. However, it is still unclear if ongoing TPN given continuously after surgery would inhibit this fall in muscle protein synthesis. METHODS The rate of protein synthesis in skeletal muscle was determined before and 24 hours after open cholecystectomy, used as a standardized human model of trauma. Patients (n = 14) were randomized to receive either TPN continuously throughout the postoperative period or saline as postoperative fluid therapy. The protein synthesis rate was calculated from the increase in enrichment of labeled phenylalanine in protein after an IV flooding dose of [2H5] phenylalanine, 45 mg/kg body weight. RESULTS The fractional synthesis rate decreased by 31% from 1.74 +/- 0.13% to 1.15 +/- 0.10% per 24 hours in the saline group (p < .02) and by 23% from 1.59 +/- 0.10% to 1.22 +/- 0.07% per 24 hours in the group receiving TPN (p < .01), showing no significant difference between the two groups. CONCLUSION A continuous and ongoing infusion of conventional TPN started immediately after surgery did not counteract the obligatory decline of muscle protein synthesis, observed 24 hours postoperatively.

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

BackgroundTransfusion 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/DesignThe 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.DiscussionThe 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.Trial registrationClinicalTrials.gov: NCT01485315. Registration date 30 November 2011. First patient was randomised 3 December 2011.