Inflammation and altered metabolism impede efficacy of functional electrical stimulation in critically ill patients
Abstrakt
BACKGROUND: Critically ill patients suffer from acute muscle wasting, which is associated with significant physical functional impairment. We describe data from nested muscle biopsy studies from two trials of functional electrical stimulation (FES) that did not shown improvements in physical function.
METHODS: Primary cohort: single-centre randomized controlled trial. Additional healthy volunteer data from patients undergoing elective hip arthroplasty.
Validation cohort: Four-centre randomized controlled trial. INTERVENTION: FES cycling for 60-90min/day.
ANALYSES: Skeletal muscle mRNA expression of 223 genes underwent hierarchal clustering for targeted analysis and validation. RESULTS: Positively enriched pathways between healthy volunteers and ICU participants were "stress response", "response to stimuli" and "protein metabolism", in keeping with published data.
Positively enriched pathways between admission and day 7 ICU participants were "FOXO-mediated transcription" (admission = 0.48 +- 0.94, day 7 = - 0.47 +- 1.04 mean log(2) fold change; P = 0.042), "Fatty acid metabolism" (admission = 0.50 +- 0.67, day 7 = 0.07 +- 1.65 mean log(2) fold change; P = 0.042) and "Interleukin-1 processing" (admission = 0.88 +- 0.50, day 7 = 0.97 +- 0.76 mean log(2) fold change; P = 0.054). Muscle mRNA expression of UCP3 (P = 0.030) and DGKD (P = 0.040) decreased in both cohorts with no between group differences.
Changes in IL-18 were not observed in the validation cohort (P = 0.268). Targeted analyses related to intramuscular mitochondrial substrate oxidation, fatty acid oxidation and intramuscular inflammation showed PPARγ-C1α; (P 0.05).
CONCLUSIONS: Intramuscular inflammation and altered substrate utilization are persistent in skeletal muscle during first week of critical illness and are not improved by the application of Functional Electrical Stimulation-assisted exercise. Future trials of exercise to prevent muscle wasting and physical impairment are unlikely to be successful unless these processes are addressed by other means than exercise alone.