Respiratory Muscle Dysfunction in Mechanical Ventilation: A Systematic Review and Meta-Analysis of Biological Mechanisms

Revealing biological mechanisms leading to respiratory muscle dysfunction is essential to improve clinical outcomes in patients with critical illness. The purpose was to identify biological mechanisms associated with respiratory muscle dysfunction in patients with critical illness during mechanical ventilation or sepsis. Six databases were electronically searched from inception to January 2025 examining studies with muscle biopsies. Screening, data collection, and risk-of-bias were conducted in duplicate by two independent assessors. Meta-analysis was performed to determine differences in muscle biological parameters of patients with critical illness requiring mechanical ventilation compared to controls. From 22,036 titles screened, eight studies (n=187 patients and n=161 controls) published between 2000-2024 met eligibility criteria. Muscle biopsies were taken between days 1-7 in the intensive care unit from diaphragm (n=110; 3 studies), rectus abdominis (n=68; 5 studies), external intercostal (n=10; 1 study), and latissimus dorsi (n=3; 1 study). Diaphragmatic fiber cross-sectional area was 30% smaller (mean difference 95% confidence interval =–629 –876, –382 μm²), with lower proportion of type II fibers (–1.94 –3.40, –0.49 %) compared with controls. Diaphragmatic fiber force of patients was more than two standard deviations lower (Standardized mean difference=–2.49 –3.84, –1.14) and ubiquitinated protein levels were higher (2.09 –0.14, 4.32) than controls. Extramyocellular, mitochondrial, and gene expression parameters were assessed in some studies, but low sample size and high heterogeneity prevented meta-analyses. In conclusion, muscle biopsies from ventilated patients revealed atrophy, contractile weakness, and proteolysis markers. Standardized methodologies assessing respiratory muscles are needed to clarify biological mechanisms leading to muscle dysfunction and to guide respiratory muscle interventions.