Samir Jaber1,2,6, Basil J. Petrof3, Boris Jung1,2, Gérald Chanques1,2, Jean-Philippe Berthet4, Christophe Rabuel5, Hassan Bouyabrine6, Patricia Courouble1,2, Christelle Koechlin-Ramonatxo7, Mustapha Sebbane1,2, Thomas Similowski8, Valérie Scheuermann9, Alexandre Mebazaa5, Xavier Capdevila1,2, Dominique Mornet2, Jacques Mercier2,10, Alain Lacampagne9, Alexandre Philips2 and Stefan Matecki2,10. American Journal of Respiratory and Critical Care Medicine Vol 183. pp. 364-371, (2011). Published ahead of print on September 2, 2010, doi:10.1164/rccm.201004-0670OC
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-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 µm2), an increase of ubiquitinated proteins (+19%), higher expression of p65 nuclear factor-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.

Key Words: diaphragm disuse • atrophy • calpain • weaning • ventilator-induced diaphragmatic dysfunction

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