Prolonged mechanical ventilation worsens sepsis-induced diaphragmatic dysfunction in the rat

PLoS One. 2018 Aug 1;13(8):e0200429. doi: 10.1371/journal.pone.0200429. eCollection 2018.

Abstract

Background: Short-term mechanical ventilation (MV) protects against sepsis-induced diaphragmatic dysfunction. Prolonged MV induces diaphragmatic dysfunction in non-septic animals, but few reports describe the effects of prolonged MV in sepsis. We hypothesized that prolonged MV is not protective but worsens the diaphragmatic dysfunction induced by a mild sepsis, because MV and sepsis share key signaling mechanisms, such as cytokine upregulation.

Method: We studied the impact of prolonged MV (12 h) in four groups (n = 8) of male Wistar rats: 1) endotoxemia induced by intraperitoneal injection of Escherichia coli lipopolysaccharide, 2) MV without endotoxemia, 3) combination of endotoxemia and MV and 4) sham control. Diaphragm mechanical performance, pro-inflammatory cytokine concentrations (Tumor Necrosis Factor-α, Interleukin-1β, Interleukin-6) in plasma were measured.

Results: Prolonged MV and sepsis independtly reduced maximum diaphragm force (-27%, P = 0.003; -37%, P<0.001; respectively). MV and sepsis acted additively to further decrease diaphragm force (-62%, P<0.001). Similar results were observed for diaphragm kinetics (maximum lengthening velocity -47%, P<0.001). Sepsis and MV reduced diaphragm cross sectional area of type I and IIx fibers, which was further increased by the combination of sepsis and MV (all P<0.05). Sepsis and MV were individually associated with the presence of a robust perimysial inflammatory infiltrate, which was more marked when sepsis and MV were both present (all P<0.05). Sepsis and, to a lesser extent, MV increased proinflammatory cytokine production in plasma and diaphragm (all P<0.05); proinflammatory cytokine expression in plasma was increased further by the combination of sepsis and MV (all P<0.05). Maximum diaphragm force correlated negatively with plasma and diaphragmatic cytokine production (all p<0.05).

Conclusions: Prolonged (12 h) MV exacerbated sepsis-induced decrease in diaphragm performance. Systemic and diaphragmatic overproduction of pro-inflammatory cytokines may contribute to diaphragm weakness.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Diaphragm / metabolism
  • Diaphragm / pathology
  • Diaphragm / physiopathology*
  • Endotoxemia / etiology
  • Escherichia coli / metabolism
  • Injections, Intraperitoneal
  • Interleukin-1beta / blood
  • Interleukin-6 / blood
  • Lipopolysaccharides / toxicity
  • Male
  • Myosin Heavy Chains / metabolism
  • Protein Isoforms / metabolism
  • Rats
  • Rats, Wistar
  • Respiration, Artificial
  • Sepsis / etiology
  • Sepsis / pathology*
  • Sepsis / veterinary
  • Tumor Necrosis Factor-alpha / blood

Substances

  • Interleukin-1beta
  • Interleukin-6
  • Lipopolysaccharides
  • Protein Isoforms
  • Tumor Necrosis Factor-alpha
  • Myosin Heavy Chains

Grants and funding

This study was supported by research grants from Chancellerie des Universités de Paris, Legs Poix 2011 (Paris, France), and Institut Fédératif de Recherche 14-INSERM annual research prize 2011 (Paris, France). Serge Carreira was supported by the Formation Médicale Continue des Hôpitaux de Paris, APHP (Paris, France). Alexandre Demoule was supported by the Société de Réanimation de Langue Française (Paris, France) and CARDIF – L’Assistance Respiratoire (Paris, France).