Positive end-expiratory pressure ventilation induces longitudinal atrophy in diaphragm fibers

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, René J.P. Musters, Marinus A. Paul, Leo M.A. Heunks, Coen A.C. Ottenheijm

Research output: Contribution to journalArticlepeer-review

44 Scopus citations


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 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. 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.

Original languageEnglish (US)
Pages (from-to)472-485
Number of pages14
JournalAmerican journal of respiratory and critical care medicine
Issue number4
StatePublished - Aug 15 2018


  • Critically ill
  • Diaphragm
  • Mechanical ventilation
  • PEEP

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine


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