TY - JOUR
T1 - Positive End-expiratory Pressure Ventilation Induces Longitudinal Atrophy in Diaphragm Fibers
AU - Lindqvist, Johan
AU - van den Berg, Marloes
AU - van der Pijl, Robbert
AU - Hooijman, Pleuni E
AU - Beishuizen, Albertus
AU - Elshof, Judith
AU - de Waard, Monique
AU - Girbes, Armand
AU - Spoelstra-de Man, Angelique
AU - Shi, Zhong-Hua
AU - van den Brom, Charissa
AU - Bogaards, Sylvia
AU - Shen, Shengyi
AU - Strom, Joshua
AU - Granzier, Henk
AU - Kole, Jeroen
AU - Musters, René J P
AU - Paul, Marinus A
AU - Heunks, Leo M A
AU - Ottenheijm, Coen A C
PY - 2018
Y1 - 2018
N2 - 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.
AB - 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.
U2 - https://doi.org/10.1164/rccm.201709-1917OC
DO - https://doi.org/10.1164/rccm.201709-1917OC
M3 - Article
C2 - 29578749
SN - 1073-449X
VL - 198
SP - 472
EP - 485
JO - American journal of respiratory and critical care medicine
JF - American journal of respiratory and critical care medicine
IS - 4
ER -