Rapidly Progressive Diaphragmatic Weakness and Injury during Mechanical Ventilation in Humans

TLDR

Diaphragmatic function is critical for successful weaning from mechanical ventilation, yet ventilation itself can rapidly diminish diaphragm strength, as shown in animal studies. This prospective study aimed to chart the time course of diaphragm weakness during mechanical ventilation and to examine how ventilator duration relates to diaphragm injury, atrophy, and activation of proteolytic pathways. Researchers measured diaphragm-generated airway occlusion pressure during phrenic nerve stimulation in short‑ and long‑term ventilation groups and analyzed diaphragm biopsies from patients and organ donors for ultrastructural damage, atrophy, and expression of ubiquitin, NF‑κB, and calpains. Diaphragm strength fell by 32 % after six days of ventilation, with prolonged support producing marked fiber injury, reduced cross‑sectional area, and elevated ubiquitinated proteins, NF‑κB, and calpain levels, demonstrating that weakness, injury, and atrophy develop rapidly and correlate with ventilator duration.

Abstract

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-κB, 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 μm2), an increase of ubiquitinated proteins (+19%), higher expression of p65 nuclear factor-κB (+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.