Skeletal muscle metabolism in critically ill patients

The loss of skeletal muscle mass is of importance for the length of the hospital stay and recovery in critically ill patients admitted to the intensive care unit (ICU). In the acute illness, the export of amino acids from skeletal muscle provides substrates for vital functions and thus enhances survival. As there is no inactive store of protein in the body, the protein being depleted represents functional tissue. Eventually the role of muscle tissue as an exporter of substrates as well as the functional proprerties of muscle may become impaired. Hence, in long term ICU patients the muscle depletion may become a limiting factor for survival. The aims of this project were to evaluate efforts to limit skeletal muscle wasting in ICU patients staying for a prolonged time in the unit and also to develop a protocol for interventional studies on this group of patients. These aims were approached by characterising the biochemical markers of muscle protein depletion and then investigating the effects of interventions. The changes in the biochemical markers for muscle protein catabolism were established early on in the course of the critical illness and there was a characteristic pattern of changes in relation to the length of stay for several markers. Despite the heterogeneity of the acute clinical appearance of the patients, muscle biochemistry shows similarities in the long-term critically ill patients. Furthermore the scatters of several of the markers do not differ from the scatter in a reference population. The results made it possible to design a protocol to be used in ICU patients, as well as in healthy volunteers to evaluate interventions. The protein content was lower in patients sampled on day 5 or later of the ICU stay in comparison with the patients sampled earlier. In paired samples, the decrease over time was found to be 10 % per 5 days. Muscle protein synthesis was not different in ICU patients compared to an age matched reference group, however, the scatter was large with outliers in the high as well as the low range. The persisting catabolism leading to loss of muscle tissue is presumably of great importance for the prognosis of the disease and for the length of hospital stay and recovery. The free glutamine concentration in muscle decreased down to 25% of reference levels, with all values outside the 95% confidence interval of the reference group. The decrease was established already in the biopsies taken at the earliest time point of ICU stay, and there was no further change detected in relation to length of stay. Branced chain and aromatic amino acids concentrations in muscle were high compared to the reference group, but no further increase over time was observed. In the total patient series the concentrations remained at the same level and no further increase over time was observed. The total muscle water content was elevated in the ICU patients due to doubling of the extracellular water. In addition the intracellular water content decreased between the paired biopsies. Growth hormone treatment was shown to increase the intracellular water by 6 %. Among the energy-rich phosphates the ATP and phosphorylated creatine concentrations were low as compared to the levels in the reference group with no relation to length of stay demonstrated. The effect of treatment with growth hormone, 0.3 U /kg/day, was marginal on protein content but increased muscle protein synthesis by 33 % (p< 0.01) and the free glutamine concentration by 100% (p< 0.05). Supplementation with glutamine or [alpha] -ketoglutarate (0.28g/ kg bw/24 h) on the other hand, was not shown not affect protein content and showed a marginal effect on muscle protein synthesis and the free glutamine concentration. The statistical correlation between the free glutamine and muscle protein synthesis was very weak but attained statistical significance, r 2 = 0.09 (p< 0.05). Immobilization by unloading of one leg for 10 days in healthy volunteers resulted in a decrease of the RNA concentration and an increase in the concentration of branched chain amino acids indicative of muscle protein catabolism. In summary changes in biochemical markers for muscle protein catabolism are established early in the course of critical illness and there is a characteristic pattern of changes with a relation to the length of stay for several markers. Despite the heterogeneity of the acute clinical appearance of the patients, muscle biochemistry show similarities in long-term patients in the ICU. Growth hormone was shown to affect muscle metabolism with an increase in protein synthesis rate and glutamine concentration and in addition a decrease of intracellular water content. Supplementation with glutamine or [alpha] -ketoglutarate was shown to increase protein synthesis rate and glutamine concentration only marginally. These results indicate a potential to save muscle proteins in long term ICU patients

An attenuated rate of leg muscle protein depletion and leg free amino acid efflux over time is seen in ICU long-stayers

Abstract Background There is extensive documentation on skeletal muscle protein depletion during the initial phase of critical illness. However, for intensive care unit (ICU) long-stayers, objective data are very limited. In this study, we examined skeletal muscle protein and amino acid turnover in patients with a prolonged ICU stay. Methods Patients (n = 20) were studied serially every 8–12 days between days 10 and 40 of their ICU stay as long as patients stayed in the ICU. Leg muscle protein turnover was assessed by measurements of phenylalanine kinetics, for which we employed a stable isotope-labeled phenylalanine together with two-pool and three-pool models for calculations, and results were expressed per 100 ml of leg volume. In addition, leg muscle amino acid flux was studied. Results The negative leg muscle protein net balance seen on days 10–20 of the ICU stay disappeared by days 30–40 (p = 0.012). This was attributable mainly to an increase in the de novo protein synthesis rate (p = 0.007). It was accompanied by an attenuated efflux of free amino acids from the leg. Leg muscle protein breakdown rates stayed unaltered (p = 0.48), as did the efflux of 3-methylhistidine. The arterial plasma concentrations of free amino acids did not change over the course of the study. Conclusions In critically ill patients with sustained organ failure and in need of a prolonged ICU stay, the initial high rate of skeletal muscle protein depletion was attenuated over time. The distinction between the acute phase and a more prolonged and more stable phase concerning skeletal muscle protein turnover must be considered in study protocols as well as in clinical practice. Trial registration Australian New Zealand Trial Registry, ACTRN12616001012460 . Retrospectively registered on 1 August 2016

Additional file 1: of An attenuated rate of leg muscle protein depletion and leg free amino acid efflux over time is seen in ICU long-stayers

Table S1. Individual patients characteristics. Table S2. Patient characteristics at the two measurement points. Figure S1. Longitudinal presentation of plasma flow. Figure S2. Longitudinal presentation of phenylalanine turnover using the two-pool model. Figure S3. Longitudinal presentation of SOFA scores and nutrition. Figure S4. Longitudinal presentation of all amino acid fluxes. Figure S5. Amino acid concentrations. (PDF 185 kb