Journal
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
Volume 198, Issue 4, Pages 472-485Publisher
AMER THORACIC SOC
DOI: 10.1164/rccm.201709-1917OC
Keywords
mechanical ventilation; PEEP; diaphragm; critically ill
Categories
Funding
- NHLBI [HL-121500]
- MSCA-RISE-2014 (Marie Sklodowska-Curie Actions - Research and Innovation Staff Exchange) grant [645648]
- National Institute of Arthritis and Musculoskeletal and Skin Diseases grant [R01AR053897]
- Marie Curie Actions (MSCA) [645648] Funding Source: Marie Curie Actions (MSCA)
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Rationale: Diaphragm weakness in critically ill patients prolongs ventilator dependency and duration of hospital stay and increases mortality and healthcare costs. Themechanisms 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 the 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: PEEP causes a caudal movement of the diaphragm, both in critically ill patients and in rats, and this caudal movement reduces fiber length. Diaphragm fibers of 18-hour mechanically ventilated rats (PEEP of 2.5 cm H-2 O) adapt to the reduced length by absorbing serially linked sarcomeres, the smallest contractile units in muscle (i. e., longitudinal atrophy). Increasing the compliance of titin molecules reduces longitudinal atrophy. Conclusions: Mechanical ventilation with PEEP results in longitudinal atrophy of diaphragm fibers, a response that 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.
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