Late Ventilator-Induced Diaphragmatic Dysfunction After Extubation

Crit Care Med. 2020 Dec;48(12):e1300-e1305. doi: 10.1097/CCM.0000000000004569.

Abstract

Objectives: Mechanical ventilation is associated with primary diaphragmatic dysfunction, also termed ventilator-induced diaphragmatic dysfunction. Studies evaluating diaphragmatic function recovery after extubation are lacking. We evaluated early and late recoveries from ventilator-induced diaphragmatic dysfunction in a mouse model.

Design: Experimental randomized study.

Setting: Research laboratory.

Subjects: C57/BL6 mice.

Interventions: Six groups of C57/BL6 mice. Mice were ventilated for 6 hours and then euthanatized immediately (n = 18), or 1 (n = 18) or 10 days after extubation with (n = 5) and without S107 (n = 16) treatment. Mice euthanatized immediately after 6 hours of anesthesia (n = 15) or after 6 hours of anesthesia and 10 days of recovery (n = 5) served as controls.

Measurements and main results: For each group, diaphragm force production, posttranslational modification of ryanodine receptor, oxidative stress, proteolysis, and cross-sectional areas were evaluated. After 6 hours of mechanical ventilation, diaphragm force production was decreased by 25-30%, restored to the control levels 1 day after extubation, and secondarily decreased by 20% 10 days after extubation compared with controls. Ryanodine receptor was protein kinase A-hyperphosphorylated, S-nitrosylated, oxidized, and depleted of its stabilizing subunit calstabin-1 6 hours after the onset of the mechanical ventilation, 1 and 10 days after extubation. Post extubation treatment with S107, a Rycal drug that stabilizes the ryanodine complex, did reverse the loss of diaphragmatic force associated with mechanical ventilation. Total protein oxidation was restored to the control levels 1 day after extubation. Markers of proteolysis including calpain 1 and calpain 2 remained activated 10 days after extubation without significant changes in cross-sectional areas.

Conclusions: We report that mechanical ventilation is associated with a late diaphragmatic dysfunction related to a structural alteration of the ryanodine complex that is reversed with the S107 treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Airway Extubation / adverse effects*
  • Animals
  • Blotting, Western
  • Diaphragm* / pathology
  • Diaphragm* / physiopathology
  • Disease Models, Animal
  • Immunoprecipitation
  • Mice
  • Mice, Inbred C57BL
  • Oxidative Stress
  • Proteolysis
  • Respiration, Artificial / adverse effects*
  • Ryanodine Receptor Calcium Release Channel / metabolism

Substances

  • Ryanodine Receptor Calcium Release Channel