Skeletal muscle metabolism in critically ill patients

Abstract: 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.