Rapidly progressive diaphragmatic weakness and injury during mechanical ventilation in humans.
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.
Jaber
Samir
S
Department of Clinical Physiology, Arnaud de Villeneuve University Hospital, CHU de Montpellier, France. s-matecki@chu-montpellier.fr
Petrof
Basil J
BJ
Jung
Boris
B
Chanques
Gérald
G
Berthet
Jean-Philippe
JP
Rabuel
Christophe
C
Bouyabrine
Hassan
H
Courouble
Patricia
P
Koechlin-Ramonatxo
Christelle
C
Sebbane
Mustapha
M
Similowski
Thomas
T
Scheuermann
Valérie
V
Mebazaa
Alexandre
A
Capdevila
Xavier
X
Mornet
Dominique
D
Mercier
Jacques
J
Lacampagne
Alain
A
Philips
Alexandre
A
Matecki
Stefan
S
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
D051996:Transcription Factor RelA; D057149:Ubiquitinated Proteins; D002154:Calpain