title: Hypercapnic acidosis in ventilator-induced lung injury.
abstract: BACKGROUND
  Permissive hypercapnia is established in lung injury management. Therapeutic hypercapnia causes benefit or harm, depending on the context. Ventilator-associated lung injury has a wide spectrum of candidate mechanisms, affording multiple opportunities for intervention such as hypercapnia to exert benefit or harm.
  
  
  OBJECTIVE
  To confirm (1) that hypercapnia attenuates in vivo ventilator-induced lung injury (VILI); (2) biological plausibility of such protection (e.g., dose-response, time series, inflammatory profile); and (3) that the associated biochemical events are consistently beneficial.
  
  
  METHODS
  A mouse model of VILI was established in vivo. Injurious ventilation was established, hypercapnia applied and markers of inflammation measured.
  
  
  METHODS
  Lung injury was quantified by gas exchange, elastance, microvascular leak, histology and levels of cytokines and eicosanoids, cyclooxygenase and tissue nitrotyrosine.
  
  
  RESULTS
  Injurious ventilation caused significant lung injury (mechanics, microvascular leak, histology) and release of inflammatory cytokines, chemokines and eicosanoids. Hypercapnia attenuated these responses, with dose-response and time-dependent effects. No adverse effects of hypercapnia were observed in controls. Hypercapnia suppressed the transcription (mRNA) and translation (protein) of the major inducible prostanoid-generating enzyme (COX-2), but the effects on the downstream eicosanoids were modest. However, hypercapnia significantly increased lung tissue nitrotyrosine-at PaCO(2) levels that were protective.
  
  
  CONCLUSIONS
  Hypercapnia provided consistent and biologically plausible in vivo protection against VILI, but elevated lung tissue levels of nitro-tyrosine as previously described in sepsis. Clinicians and those designing clinical trials need to be aware of the potential for detrimental effects when using hypercapnia in order to balance benefits versus harm with this approach.
authors.affiliation: Physiology and Experimental Medicine, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
authors.forename: Vanya
authors.initials: V
authors.lastname: Peltekova
authors.forename: Doreen
authors.initials: D
authors.lastname: Engelberts
authors.forename: Gail
authors.initials: G
authors.lastname: Otulakowski
authors.forename: Satoko
authors.initials: S
authors.lastname: Uematsu
authors.forename: Martin
authors.initials: M
authors.lastname: Post
authors.forename: Brian P
authors.initials: BP
authors.lastname: Kavanagh
mesh_terms: D000142:Acidosis, Respiratory / Q000378:metabolism* / Q000517:prevention & control; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006935:Hypercapnia / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D011659:Pulmonary Gas Exchange; D055397:Ventilator-Induced Lung Injury / Q000378:metabolism* / Q000517:prevention & control
chemical_list: D016207:Cytokines