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Increasing the inspiratory time and I:E ratio during mechanical ventilation aggravates ventilator-induced lung injury in mice.

Müller-Redetzky HC, Felten M, Hellwig K, Wienhold SM, Naujoks J, Opitz B, Kershaw O, Gruber AD, Suttorp N, Witzenrath M - Crit Care (2015)

Bottom Line: LVT 1:2 or LVT 1:1 did not result in VILI, and all individuals survived the ventilation period.In the HVT 1:1 group, significant mortality during mechanical ventilation was observed.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Infectious Diseases and Pulmonary Medicine, Charité - Universitätsmedizin Berlin, Berlin, Germany. holger.mueller-redetzky@charite.de.

ABSTRACT

Introduction: 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.

Conclusion: 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.

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Increasing the inspiratory time and I:E ratio increased the production of proinflammatory cytokines in VILI. Mice were mechanically ventilated for 4 hours with either low tidal volume (LVT 9 ml/kg) or high tidal volume (HVT 34 ml/kg) and an inspiratory/expiratory ratio of 1:2 or 1:1, respectively. An alternative end point was defined as decreasing of mean arterial blood pressure below 40 mm Hg, which predicts death with certainty in this model. Controls (ctr) were subjected to LVT 1:2 ventilation only during operation and were killed before the 4-hour ventilation protocol started. (A) mRNA levels of interleukin (IL)-1β, IL-6, macrophage chemotactic protein (MCP)-1, and keratinocyte-derived cytokine (KC) were measured with quantitative reverse transcription polymerase chain reaction in lung homogenates and normalized to GAPDH levels. (B) Protein levels of IL-1 β , IL-6, MCP-1, and KC were determined in lung homogenates by multiplex ELISA technique. n = 6 to 8 each group; *P < 0.05, **P < 0.01, ***P < 0.001.
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Fig8: Increasing the inspiratory time and I:E ratio increased the production of proinflammatory cytokines in VILI. Mice were mechanically ventilated for 4 hours with either low tidal volume (LVT 9 ml/kg) or high tidal volume (HVT 34 ml/kg) and an inspiratory/expiratory ratio of 1:2 or 1:1, respectively. An alternative end point was defined as decreasing of mean arterial blood pressure below 40 mm Hg, which predicts death with certainty in this model. Controls (ctr) were subjected to LVT 1:2 ventilation only during operation and were killed before the 4-hour ventilation protocol started. (A) mRNA levels of interleukin (IL)-1β, IL-6, macrophage chemotactic protein (MCP)-1, and keratinocyte-derived cytokine (KC) were measured with quantitative reverse transcription polymerase chain reaction in lung homogenates and normalized to GAPDH levels. (B) Protein levels of IL-1 β , IL-6, MCP-1, and KC were determined in lung homogenates by multiplex ELISA technique. n = 6 to 8 each group; *P < 0.05, **P < 0.01, ***P < 0.001.

Mentions: We measured transcription of the proinflammatory cytokines IL-1β, IL-6, KC, and MCP-1 (Figure 8A) and protein concentrations of IL-1β, IL-6, KC, and MCP-1 in lung homogenates (Figure 8B). HVT 1:2 increased IL-1β, IL-6, KC, and MCP-1 mRNA expression compared with ctr and LVT mice. Expression of most of these proinflammatory mediators was further increased in the HVT 1:1.Figure 8


Increasing the inspiratory time and I:E ratio during mechanical ventilation aggravates ventilator-induced lung injury in mice.

Müller-Redetzky HC, Felten M, Hellwig K, Wienhold SM, Naujoks J, Opitz B, Kershaw O, Gruber AD, Suttorp N, Witzenrath M - Crit Care (2015)

Increasing the inspiratory time and I:E ratio increased the production of proinflammatory cytokines in VILI. Mice were mechanically ventilated for 4 hours with either low tidal volume (LVT 9 ml/kg) or high tidal volume (HVT 34 ml/kg) and an inspiratory/expiratory ratio of 1:2 or 1:1, respectively. An alternative end point was defined as decreasing of mean arterial blood pressure below 40 mm Hg, which predicts death with certainty in this model. Controls (ctr) were subjected to LVT 1:2 ventilation only during operation and were killed before the 4-hour ventilation protocol started. (A) mRNA levels of interleukin (IL)-1β, IL-6, macrophage chemotactic protein (MCP)-1, and keratinocyte-derived cytokine (KC) were measured with quantitative reverse transcription polymerase chain reaction in lung homogenates and normalized to GAPDH levels. (B) Protein levels of IL-1 β , IL-6, MCP-1, and KC were determined in lung homogenates by multiplex ELISA technique. n = 6 to 8 each group; *P < 0.05, **P < 0.01, ***P < 0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4336519&req=5

Fig8: Increasing the inspiratory time and I:E ratio increased the production of proinflammatory cytokines in VILI. Mice were mechanically ventilated for 4 hours with either low tidal volume (LVT 9 ml/kg) or high tidal volume (HVT 34 ml/kg) and an inspiratory/expiratory ratio of 1:2 or 1:1, respectively. An alternative end point was defined as decreasing of mean arterial blood pressure below 40 mm Hg, which predicts death with certainty in this model. Controls (ctr) were subjected to LVT 1:2 ventilation only during operation and were killed before the 4-hour ventilation protocol started. (A) mRNA levels of interleukin (IL)-1β, IL-6, macrophage chemotactic protein (MCP)-1, and keratinocyte-derived cytokine (KC) were measured with quantitative reverse transcription polymerase chain reaction in lung homogenates and normalized to GAPDH levels. (B) Protein levels of IL-1 β , IL-6, MCP-1, and KC were determined in lung homogenates by multiplex ELISA technique. n = 6 to 8 each group; *P < 0.05, **P < 0.01, ***P < 0.001.
Mentions: We measured transcription of the proinflammatory cytokines IL-1β, IL-6, KC, and MCP-1 (Figure 8A) and protein concentrations of IL-1β, IL-6, KC, and MCP-1 in lung homogenates (Figure 8B). HVT 1:2 increased IL-1β, IL-6, KC, and MCP-1 mRNA expression compared with ctr and LVT mice. Expression of most of these proinflammatory mediators was further increased in the HVT 1:1.Figure 8

Bottom Line: LVT 1:2 or LVT 1:1 did not result in VILI, and all individuals survived the ventilation period.In the HVT 1:1 group, significant mortality during mechanical ventilation was observed.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Infectious Diseases and Pulmonary Medicine, Charité - Universitätsmedizin Berlin, Berlin, Germany. holger.mueller-redetzky@charite.de.

ABSTRACT

Introduction: 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.

Conclusion: 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.

Show MeSH
Related in: MedlinePlus