Rapidly Progressive Diaphragmatic Weakness and Injury during Mechanical Ventilation in Humans

Rationale. Diaphragmatic function is a major determinant of the ability to successfully wean patients from mechanical ventilation (MV). Paradoxically, MV itself results in a rapid loss of diaphragmatic strength in animals. However, very little is known about the time course or mechanistic basis for such a phenomenon in humans. Objectives: To determine in a prospective fashion the time course for development of diaphragmatic weakness during MV; and the relationship between MV duration and diaphragmatic injury or atrophy, and the status of candidate cellular pathways implicated in these phenomena. Methods: Airway occlusion pressure (TwPtr) generated by the diaphragm during phrenic nerve stimulation was measured in short-term (0.5 h; n = 6) and long-term (>5 d; n = 6) MV groups. Diaphragmatic biopsies obtained during thoracic surgery (MV for 2-3 h; n = 10) and from brain-dead organ donors (MV for 24-249 h; n = 15) were analyzed for ultrastructural injury, atrophy, and expression of proteolysis-related proteins (ubiquitin, nuclear factor-kappa B, and calpains). Measurements and Main Results: TwPtr decreased progressively during MV, with a mean reduction of 32 +/- 6% after 6 days. Longer periods of MV were associated with significantly greater ultrastructural fiber injury (26.2 +/- 4.8 vs. 4.7 +/- 0.6% area), decreased cross-sectional area of muscle fibers (1,904 +/- 220 vs. 3,100 +/- 329 mu m(2)), an increase of ubiquitinated proteins (+19%), higher expression of p65 nuclear factor-kappa B (+77%), and greater levels of the calcium-activated proteases calpain-1, -2, and -3 (+104%, +432%, and +266%, respectively) in the diaphragm. Conclusions: Diaphragmatic weakness, injury, and atrophy occur rapidly in critically ill patients during MV, and are significantly correlated with the duration of ventilator support.