title: Rapidly progressive diaphragmatic weakness and injury during mechanical ventilation in humans.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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).
  
  
  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.
authors.affiliation: Department of Clinical Physiology, Arnaud de Villeneuve University Hospital, CHU de Montpellier, France. s-matecki@chu-montpellier.fr
authors.forename: Samir
authors.initials: S
authors.lastname: Jaber
authors.forename: Basil J
authors.initials: BJ
authors.lastname: Petrof
authors.forename: Boris
authors.initials: B
authors.lastname: Jung
authors.forename: Gérald
authors.initials: G
authors.lastname: Chanques
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Berthet
authors.forename: Christophe
authors.initials: C
authors.lastname: Rabuel
authors.forename: Hassan
authors.initials: H
authors.lastname: Bouyabrine
authors.forename: Patricia
authors.initials: P
authors.lastname: Courouble
authors.forename: Christelle
authors.initials: C
authors.lastname: Koechlin-Ramonatxo
authors.forename: Mustapha
authors.initials: M
authors.lastname: Sebbane
authors.forename: Thomas
authors.initials: T
authors.lastname: Similowski
authors.forename: Valérie
authors.initials: V
authors.lastname: Scheuermann
authors.forename: Alexandre
authors.initials: A
authors.lastname: Mebazaa
authors.forename: Xavier
authors.initials: X
authors.lastname: Capdevila
authors.forename: Dominique
authors.initials: D
authors.lastname: Mornet
authors.forename: Jacques
authors.initials: J
authors.lastname: Mercier
authors.forename: Alain
authors.initials: A
authors.lastname: Lacampagne
authors.forename: Alexandre
authors.initials: A
authors.lastname: Philips
authors.forename: Stefan
authors.initials: S
authors.lastname: Matecki
mesh_terms: D000328:Adult; D002154:Calpain / Q000032:analysis; D003964:Diaphragm / Q000737:chemistry / Q000293:injuries* / Q000473:pathology / Q000503:physiopathology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D018908:Muscle Weakness / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D009133:Muscular Atrophy / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D012121:Respiration, Artificial / Q000009:adverse effects*; D013997:Time Factors; D051996:Transcription Factor RelA / Q000032:analysis; D057149:Ubiquitinated Proteins / Q000032:analysis; D055815:Young Adult
chemical_list: D051996:Transcription Factor RelA; D057149:Ubiquitinated Proteins; D002154:Calpain