627: Biological Findings From Respiratory Muscle Biopsies in Critical Illness: Systematic Review

Introduction: Respiratory muscle dysfunction is a major cause of weaning failure from mechanical ventilation. Revealing the mechanisms leading respiratory muscle dysfunction is essential to improve weaning outcomes. Therefore, the objective of this systematic review is to identify biological mechanisms of respiratory muscle dysfunction during critical illness. Methods: Six databases were electronically searched from inception to January 2025 examining original studies with muscle biopsy findings. Screening, data extraction, and quality assessment (Newcastle-Ottawa Scale) were performed by at least two reviewers using DistillerSR in accordance with PRISMA statement. The primary outcome was respiratory muscle size related variables in adults who required mechanical ventilation compared to controls. This review was registered in PROSPERO (No. CRD42024559279) and supported by NIH grants (No. R01AR081002/5K23AR079583). Results: From 22,035 titles screened, 78 studies comprised patients with critical illness (n=1,513) who underwent 1,832 biopsies. Respiratory muscle biopsies were reported in 11 studies (n=319 patients and n=201 human controls) published between 2001 and 2024 from European countries. Muscle biopsies were from diaphragm (n=160; 5 studies), intercostal (n=10; 1 study), rectus abdominis (n=196; 6 studies), and latissimus dorsi (n=3; 1 study). The combined diaphragmatic fiber cross-sectional area was 22–60% smaller than controls in five studies. The ubiquitin–proteasome system was higher in four studies. Five studies reported no major dysfunction in mitochondria, and mitophagy markers were either unaltered or lower in patients with critical illness. Gene expression changes included up-regulated oxidative stress pathways and altered NOS1/NOS3 responses in rectus abdominis. Extramyocellular parameters (such as extracellular matrix, satellite cells, and collagen) were not reported. Conclusions: Pooled data from respiratory muscle biopsies in critical illness reveal consistent atrophy and proteolytic activation, while mitochondrial and gene expression findings are heterogeneous and underexplored. Standardized studies targeting respiratory muscles are needed to clarify cellular and molecular mechanisms leading muscle dysfunction and guide ventilatory weaning interventions.