• Johan Lindqvist, Marloes van den Berg, Robbert van der Pijl, Pleuni E Hooijman, Albertus Beishuizen, Judith Elshof, Monique de Waard, Armand Girbes, Angelique Spoelstra-de Man, Zhong-Hua Shi, Charissa van den Brom, Sylvia Bogaards, Shengyi Shen, Joshua Strom, Henk Granzier, Jeroen Kole, MustersRené J PRJP2 Department of Physiology., Marinus A Paul, HeunksLeo M ALMA4 Department of Intensive Care., and OttenheijmCoen A CCAC1 Cellular and Molecular Medicine, University of Arizona, Tucson, Arizona.2 Department of Physiology..
• 1 Cellular and Molecular Medicine, University of Arizona, Tucson, Arizona.
• Am. J. Respir. Crit. Care Med. 2018 Aug 15; 198 (4): 472485472-485.

RationaleDiaphragm weakness in critically ill patients prolongs ventilator dependency and duration of hospital stay and increases mortality and healthcare costs. The mechanisms underlying diaphragm weakness include cross-sectional fiber atrophy and contractile protein dysfunction, but whether additional mechanisms are at play is unknown.ObjectivesTo 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.MethodsWe 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 ResultsPEEP 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 H2O) 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.ConclusionsMechanical 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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