RATIONALE: Diaphragm weakness in critically ill patients prolongs ventilator dependency and duration of hospital stay, and increases mortality and health care costs. The mechanisms underlying diaphragm weakness include cross-sectional fiber atrophy and contractile protein dysfunction, but whether additional mechanisms are at play is unknown.
OBJECTIVES: To test the hypothesis that mechanical ventilation with positive end-expiratory pressure (PEEP) induces longitudinal atrophy by displacing the diaphragm in caudal direction and reducing the length of fibers.
METHODS: We studied structure and function of diaphragm fibers of mechanically ventilated critically ill patients, and mechanically ventilated rats with normal and increased titin compliance.
MEASUREMENTS AND MAIN RESULTS: (1) PEEP causes a caudal movement of the diaphragm, both in critically ill patients and in rats, and this caudal movement reduces fiber length; (2) diaphragm fibers of 18h mechanically ventilated rats (PEEP: 2.5 cmH2O) adapt to the reduced length by absorbing serially-linked sarcomeres, the smallest contractile units in muscle (i.e. longitudinal atrophy); (3) increasing the compliance of titin molecules reduces longitudinal atrophy.
CONCLUSION: Mechanical ventilation with PEEP results in longitudinal atrophy of diaphragm fibers, a response which is modulated by the elasticity of the giant sarcomeric protein titin. We postulate that longitudinal atrophy, in concert with the aforementioned cross-sectional atrophy, hampers spontaneous breathing trials in critically ill patients: during these efforts end-expiratory lung volume is reduced, and the shortened diaphragm fibers are stretched to excessive sarcomere lengths. At these lengths, muscle fibers generate less force and diaphragm weakness ensues.
|Number of pages||15|
|Journal||American Journal of Respiratory and Critical Care Medicine|
|Early online date||26 Mar 2018|
|Publication status||Published - 2018|