A conceptual framework: The early and late phases of skeletal muscle dysfunction in the acute respiratory distress syndrome

D. Clark Files, Michael A. Sanchez, Peter E. Morris

Research output: Contribution to journalReview articlepeer-review

28 Scopus citations

Abstract

Patients with acute respiratory distress syndrome (ARDS) often develop severe diaphragmatic and limb skeletal muscle dysfunction. Impaired muscle function in ARDS is associated with increased mortality, increased duration of mechanical ventilation, and functional disability in survivors. In this review, we propose that muscle dysfunction in ARDS can be categorized into an early and a late phase. These early and late phases are based on the timing in relationship to lung injury and the underlying mechanisms. The early phase occurs temporally with the onset of lung injury, is driven by inflammation and disuse, and is marked predominantly by muscle atrophy from increased protein degradation. The ubiquitin-proteasome, autophagy, and calpain-caspase pathways have all been implicated in early-phase muscle dysfunction. Late-phase muscle weakness persists in many patients despite resolution of lung injury and cessation of ongoing acute inflammation-driven muscle atrophy. The clinical characteristics and mechanisms underlying late-phase muscle dysfunction do not involve the massive protein degradation and atrophy of the early phase and may reflect a failure of the musculoskeletal system to regain homeostatic balance. Owing to these underlying mechanistic differences, therapeutic interventions for treating muscle dysfunction in ARDS may differ during the early and late phases. Here, we review clinical and translational investigations of muscle dysfunction in ARDS, placing them in the conceptual framework of the early and late phases. We hypothesize that this conceptual model will aid in the design of future mechanistic and clinical investigations of the skeletal muscle system in ARDS and other critical illnesses.

Original languageEnglish
Article number266
JournalCritical Care
Volume19
Issue number1
DOIs
StatePublished - Jul 2 2015

Bibliographical note

Funding Information:
DCF would like to thank his mentors, Michael T Crow and Landon S King, without whom none of this work would be possible. The authors thank Karen Klein for editorial assistance and Nick Weir at Creative Communications for the illustrations. This work was supported by institutional funds from the Wake Forest School of Medicine, the Department of Medicine (DCF), the Claude D. Pepper Older Americans Independence Center (grant P30-AG21332), the Parker B. Francis Foundation (DCF), the American Thoracic Society Foundation (DCF), the National Institutes of Health (grant 1R01NR011186-01 to PEM), and the Department of the Army (ERMS #12340010 to PEM).

Publisher Copyright:
© 2015 Files et al.

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine

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