title: Increasing the inspiratory time and I:E ratio during mechanical ventilation aggravates ventilator-induced lung injury in mice.
abstract: BACKGROUND
  Lung-protective ventilation reduced acute respiratory distress syndrome (ARDS) mortality. To minimize ventilator-induced lung injury (VILI), tidal volume is limited, high plateau pressures are avoided, and positive end-expiratory pressure (PEEP) is applied. However, the impact of specific ventilatory patterns on VILI is not well defined. Increasing inspiratory time and thereby the inspiratory/expiratory ratio (I:E ratio) may improve oxygenation, but may also be harmful as the absolute stress and strain over time increase. We thus hypothesized that increasing inspiratory time and I:E ratio aggravates VILI.
  
  
  METHODS
  VILI was induced in mice by high tidal-volume ventilation (HVT 34 ml/kg). Low tidal-volume ventilation (LVT 9 ml/kg) was used in control groups. PEEP was set to 2 cm H2O, FiO2 was 0.5 in all groups. HVT and LVT mice were ventilated with either I:E of 1:2 (LVT 1:2, HVT 1:2) or 1:1 (LVT 1:1, HVT 1:1) for 4 hours or until an alternative end point, defined as mean arterial blood pressure below 40 mm Hg. Dynamic hyperinflation due to the increased I:E ratio was excluded in a separate group of animals. Survival, lung compliance, oxygenation, pulmonary permeability, markers of pulmonary and systemic inflammation (leukocyte differentiation in lung and blood, analyses of pulmonary interleukin-6, interleukin-1β, keratinocyte-derived chemokine, monocyte chemoattractant protein-1), and histopathologic pulmonary changes were analyzed.
  
  
  RESULTS
  LVT 1:2 or LVT 1:1 did not result in VILI, and all individuals survived the ventilation period. HVT 1:2 decreased lung compliance, increased pulmonary neutrophils and cytokine expression, and evoked marked histologic signs of lung injury. All animals survived. HVT 1:1 caused further significant worsening of oxygenation, compliance and increased pulmonary proinflammatory cytokine expression, and pulmonary and blood neutrophils. In the HVT 1:1 group, significant mortality during mechanical ventilation was observed.
  
  
  CONCLUSIONS
  According to the "baby lung" concept, mechanical ventilation-associated stress and strain in overinflated regions of ARDS lungs was simulated by using high tidal-volume ventilation. Increase of inspiratory time and I:E ratio significantly aggravated VILI in mice, suggesting an impact of a "stress/strain × time product" for the pathogenesis of VILI. Thus increasing the inspiratory time and I:E ratio should be critically considered.
authors.affiliation: Department of Infectious Diseases and Pulmonary Medicine, Charité - Universitätsmedizin Berlin, Berlin, Germany. holger.mueller-redetzky@charite.de.
authors.forename: Holger C
authors.initials: HC
authors.lastname: Müller-Redetzky
authors.affiliation: Department of Infectious Diseases and Pulmonary Medicine, Charité - Universitätsmedizin Berlin, Berlin, Germany. matthias.felten@charite.de.
authors.forename: Matthias
authors.initials: M
authors.lastname: Felten
authors.affiliation: Department of Infectious Diseases and Pulmonary Medicine, Charité - Universitätsmedizin Berlin, Berlin, Germany. katharina.hellwig@charite.de.
authors.forename: Katharina
authors.initials: K
authors.lastname: Hellwig
authors.affiliation: Department of Infectious Diseases and Pulmonary Medicine, Charité - Universitätsmedizin Berlin, Berlin, Germany. sandra.wienhold@charite.de.
authors.forename: Sandra-Maria
authors.initials: SM
authors.lastname: Wienhold
authors.affiliation: Department of Infectious Diseases and Pulmonary Medicine, Charité - Universitätsmedizin Berlin, Berlin, Germany. jan.naujoks@charite.de.
authors.forename: Jan
authors.initials: J
authors.lastname: Naujoks
authors.affiliation: Department of Infectious Diseases and Pulmonary Medicine, Charité - Universitätsmedizin Berlin, Berlin, Germany. bastian.opitz@charite.de.
authors.forename: Bastian
authors.initials: B
authors.lastname: Opitz
authors.affiliation: Department of Veterinary Pathology, Freie Universität Berlin, Berlin, Germany. olivia.kershaw@fu-berlin.de.
authors.forename: Olivia
authors.initials: O
authors.lastname: Kershaw
authors.affiliation: Department of Veterinary Pathology, Freie Universität Berlin, Berlin, Germany. achim.gruber@fu-berlin.de.
authors.forename: Achim D
authors.initials: AD
authors.lastname: Gruber
authors.affiliation: Department of Infectious Diseases and Pulmonary Medicine, Charité - Universitätsmedizin Berlin, Berlin, Germany. norbert.suttorp@charite.de.
authors.forename: Norbert
authors.initials: N
authors.lastname: Suttorp
authors.affiliation: Department of Infectious Diseases and Pulmonary Medicine, Charité - Universitätsmedizin Berlin, Berlin, Germany. martin.witzenrath@charite.de.
authors.forename: Martin
authors.initials: M
authors.lastname: Witzenrath
mesh_terms: D000818:Animals; D045853:Exhalation; D005260:Female; D001239:Inhalation; D008168:Lung / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D012121:Respiration, Artificial / Q000009:adverse effects* / Q000379:methods; D012128:Respiratory Distress Syndrome / Q000150:complications / Q000503:physiopathology; D013990:Tidal Volume; D055397:Ventilator-Induced Lung Injury / Q000150:complications / Q000473:pathology / Q000503:physiopathology*