Understanding skeletal muscle wasting in critically ill patients

Background Survivors of critical illness demonstrate skeletal muscle wasting with associated functional impairment. Methods Objective: The objective was to perform a comprehensive prospective characterization of skeletal muscle wasting, defining the pathogenic roles of altered protein synthesis and breakdown. Design: Prospective observational study. Setting: Patients were recruited from a university and community hospital in England. Subjects: The study involved 63 critically ill patients > 18 years old who were anticipated to be intubated > 48 hours and to spend > 7 days in the ICU and to survive their ICU stay. Subjects were enrolled within 24 hours of admission. Outcomes: Muscle loss was determined through serial ultrasound measurement of the rectus femoris cross-sectional area (CSA) on days 1, 3, 7, and 10. In a subset of patients, the fiber CSA area was quantified along with the ratio of protein to DNA on days 1 and 7. Histopathological analysis was performed. In addition, muscle protein synthesis, breakdown rates, and respective signaling pathways were characterized. Results There were significant reductions in the rectus femoris CSA observed at day 10 (-17.7%; 95% confidence interval (CI), -25.9 to 8.1%; P < 0.001). In the 28 patients assessed by all three measurement methods on days 1 and 7, the rectus femoris CSA decreased by 10.3% (95% CI, 6.1 to 14.5%), the fiber CSA by 17.5% (95% CI, 5.8 to 29.3%), and the ratio of protein to DNA by 29.5% (95% CI, 13.4 to 45.6%). Decrease in the rectus femoris CSA was greater in patients who experienced multiorgan failure by day 7 (-15.7%; 95% CI, -27.7 to 11.4%) compared with single organ failure (-3.0%; 95% CI, -5.3 to 2.1%; P < 0.001), even by day 3 (-8.7%; 95% CI, -59.3 to 50.6% versus -1.8%; 95% CI, -12.3 to 10.5%, respectively; P = 0.03). Myofiber necrosis occurred in 20 of 37 patients (54.1%). Protein synthesis measured by the muscle protein fractional synthetic rate was depressed in patients on day 1 (0.035%/hour; 95% CI, 0.023 to 0.047%/hour) compared with rates observed in fasted healthy controls (0.039%/hour; 95% CI, 0.029 to 0.048%/hour; P = 0.57) and increased by day 7 (0.076%; 95% CI, 0.032 to 0.120%/hour; P = 0.03) to rates associated with fed controls (0.065%/hour; 95% CI, 0.049 to 0.080%/hour; P = 0.30), independent of nutritional load. Leg protein breakdown remained elevated throughout the study (8.5; 95% CI, 4.7 to 12.3 mu mol phenylalanine/minute/ideal body weight x 100 to 10.6; 95% CI, 6.8 to 14.4 mu mol phenylalanine/minute/ideal body weight x 100; P = 0.40). The pattern of intracellular signaling supported increased breakdown (n = 9, r = -0.83, P = 0.005) and decreased synthesis (n = 9, r = -0.69, P = 0.04). Conclusions Among these critically ill patients, muscle wasting occurred early and rapidly during the first week of critical illness and was more severe among those with multiorgan failure compared with single organ failure. These findings may provide insights into skeletal muscle wasting and critical illness.