Timeline representation of the experimental protocol.

<p>First randomization: pressure-controlled ventilation (PCV) or pressure support ventilation (PSV). Second randomization: intra-abdominal hypertension (IAH) or normal intra-abdominal pressure (nIAP). Start: immediately after surgery (Sham) or IAH induction at PCV or PSV. V_T, tidal volume; PEEP, positive-end expiratory pressure; FiO₂, fraction of inspired oxygen. Mechanics and arterial blood gases were evaluated at Start and End (after 1 h of mechanical ventilation in PCV or PSV).</p

Real-time polymerase chain reaction analysis of biological markers associated with inflammation (interleukin [IL]-6), fibrogenesis (type III procollagen [PCIII]), pulmonary stretch (amphiregulin), type II epithelial cell damage (surfactant protein [SP]-B), and endothelial cell damage (vascular cellular adhesion molecule [VCAM-1]) in animals with normal intra-abdominal pressure (nIAP) or intra-abdominal hypertension (IAH) mechanically ventilated in pressure-controlled ventilation (PCV) or pressure support ventilation (PSV) mode.

<p>Values are given as medians, interquartile ranges, and minimum/maximum of 6 animals in each group. Relative gene expression was calculated as a ratio of average gene expression compared with the reference gene (<i>36B4</i>) and expressed as fold change relative to non-ventilated (NV) animals. *Significantly different from NV (p<0.05). #Significantly different from PCV (p<0.05).</p

Respiratory parameters at Start and End.

<p>Respiratory parameters at Start and End.</p

Arterial blood gases at Start and End.

<p>Arterial blood gases at Start and End.</p

Table3.PDF

<p>Tidal volume (V_T) has been considered the main determinant of ventilator-induced lung injury (VILI). Recently, experimental studies have suggested that mechanical power transferred from the ventilator to the lungs is the promoter of VILI. We hypothesized that, as long as mechanical power is kept below a safe threshold, high V_T should not be injurious. The present study aimed to investigate the impact of different V_T levels and respiratory rates (RR) on lung function, diffuse alveolar damage (DAD), alveolar ultrastructure, and expression of genes related to inflammation [interleukin (IL)-6], alveolar stretch (amphiregulin), epithelial [club cell secretory protein (CC)16] and endothelial [intercellular adhesion molecule (ICAM)-1] cell injury, and extracellular matrix damage [syndecan-1, decorin, and metalloproteinase (MMP)-9] in experimental acute respiratory distress syndrome (ARDS) under low-power mechanical ventilation. Twenty-eight Wistar rats received Escherichia coli lipopolysaccharide intratracheally. After 24 h, 21 animals were randomly assigned to ventilation (2 h) with low mechanical power at three different V_T levels (n = 7/group): (1) V_T = 6 mL/kg and RR adjusted to normocapnia; (2) V_T = 13 mL/kg; and 3) V_T = 22 mL/kg. In the second and third groups, RR was adjusted to yield low mechanical power comparable to that of the first group. Mechanical power was calculated as [(ΔP,L2/Est,_L)/2]× RR (ΔP,_L = transpulmonary driving pressure, Est,_L = static lung elastance). Seven rats were not mechanically ventilated (NV) and were used for molecular biology analysis. Mechanical power was comparable among groups, while V_T gradually increased. ΔP,_L and mechanical energy were higher in V_T = 22 mL/kg than V_T = 6 mL/kg and V_T = 13 mL/kg (p < 0.001 for both). Accordingly, DAD score increased in V_T = 22 mL/kg compared to V_T = 6 mL/kg and V_T = 13 mL/kg [23(18.5–24.75) vs. 16(12–17.75) and 16(13.25–18), p < 0.05, respectively]. V_T = 22 mL/kg was associated with higher IL-6, amphiregulin, CC16, MMP-9, and syndecan-1 mRNA expression and lower decorin expression than V_T = 6 mL/kg. Multiple linear regression analyses indicated that V_T was able to predict changes in IL-6 and CC16, whereas ΔP,_L predicted pHa, oxygenation, amphiregulin, and syndecan-1 expression. In the model of ARDS used herein, even at low mechanical power, high V_T resulted in VILI. V_T control seems to be more important than RR control to mitigate VILI.</p

Cumulative DAD score (scores arithmetically averaged from two independent investigators) representing injury from alveolar collapse, interstitial edema, and septal thickening in animals with normal intra-abdominal pressure (nIAP) or intra-abdominal hypertension (IAH) mechanically ventilated in pressure-controlled ventilation (PCV) or pressure support ventilation (PSV) mode.

<p>NV: non-ventilated animals. Values are given as medians, interquartile ranges, and minimum/maximum of 6 animals in each group. Statistical significance was accepted at p < 0.05. *Significantly different from NV.</p

Image1.PDF

<p>Tidal volume (V_T) has been considered the main determinant of ventilator-induced lung injury (VILI). Recently, experimental studies have suggested that mechanical power transferred from the ventilator to the lungs is the promoter of VILI. We hypothesized that, as long as mechanical power is kept below a safe threshold, high V_T should not be injurious. The present study aimed to investigate the impact of different V_T levels and respiratory rates (RR) on lung function, diffuse alveolar damage (DAD), alveolar ultrastructure, and expression of genes related to inflammation [interleukin (IL)-6], alveolar stretch (amphiregulin), epithelial [club cell secretory protein (CC)16] and endothelial [intercellular adhesion molecule (ICAM)-1] cell injury, and extracellular matrix damage [syndecan-1, decorin, and metalloproteinase (MMP)-9] in experimental acute respiratory distress syndrome (ARDS) under low-power mechanical ventilation. Twenty-eight Wistar rats received Escherichia coli lipopolysaccharide intratracheally. After 24 h, 21 animals were randomly assigned to ventilation (2 h) with low mechanical power at three different V_T levels (n = 7/group): (1) V_T = 6 mL/kg and RR adjusted to normocapnia; (2) V_T = 13 mL/kg; and 3) V_T = 22 mL/kg. In the second and third groups, RR was adjusted to yield low mechanical power comparable to that of the first group. Mechanical power was calculated as [(ΔP,L2/Est,_L)/2]× RR (ΔP,_L = transpulmonary driving pressure, Est,_L = static lung elastance). Seven rats were not mechanically ventilated (NV) and were used for molecular biology analysis. Mechanical power was comparable among groups, while V_T gradually increased. ΔP,_L and mechanical energy were higher in V_T = 22 mL/kg than V_T = 6 mL/kg and V_T = 13 mL/kg (p < 0.001 for both). Accordingly, DAD score increased in V_T = 22 mL/kg compared to V_T = 6 mL/kg and V_T = 13 mL/kg [23(18.5–24.75) vs. 16(12–17.75) and 16(13.25–18), p < 0.05, respectively]. V_T = 22 mL/kg was associated with higher IL-6, amphiregulin, CC16, MMP-9, and syndecan-1 mRNA expression and lower decorin expression than V_T = 6 mL/kg. Multiple linear regression analyses indicated that V_T was able to predict changes in IL-6 and CC16, whereas ΔP,_L predicted pHa, oxygenation, amphiregulin, and syndecan-1 expression. In the model of ARDS used herein, even at low mechanical power, high V_T resulted in VILI. V_T control seems to be more important than RR control to mitigate VILI.</p

Table2.PDF

<p>Tidal volume (V_T) has been considered the main determinant of ventilator-induced lung injury (VILI). Recently, experimental studies have suggested that mechanical power transferred from the ventilator to the lungs is the promoter of VILI. We hypothesized that, as long as mechanical power is kept below a safe threshold, high V_T should not be injurious. The present study aimed to investigate the impact of different V_T levels and respiratory rates (RR) on lung function, diffuse alveolar damage (DAD), alveolar ultrastructure, and expression of genes related to inflammation [interleukin (IL)-6], alveolar stretch (amphiregulin), epithelial [club cell secretory protein (CC)16] and endothelial [intercellular adhesion molecule (ICAM)-1] cell injury, and extracellular matrix damage [syndecan-1, decorin, and metalloproteinase (MMP)-9] in experimental acute respiratory distress syndrome (ARDS) under low-power mechanical ventilation. Twenty-eight Wistar rats received Escherichia coli lipopolysaccharide intratracheally. After 24 h, 21 animals were randomly assigned to ventilation (2 h) with low mechanical power at three different V_T levels (n = 7/group): (1) V_T = 6 mL/kg and RR adjusted to normocapnia; (2) V_T = 13 mL/kg; and 3) V_T = 22 mL/kg. In the second and third groups, RR was adjusted to yield low mechanical power comparable to that of the first group. Mechanical power was calculated as [(ΔP,L2/Est,_L)/2]× RR (ΔP,_L = transpulmonary driving pressure, Est,_L = static lung elastance). Seven rats were not mechanically ventilated (NV) and were used for molecular biology analysis. Mechanical power was comparable among groups, while V_T gradually increased. ΔP,_L and mechanical energy were higher in V_T = 22 mL/kg than V_T = 6 mL/kg and V_T = 13 mL/kg (p < 0.001 for both). Accordingly, DAD score increased in V_T = 22 mL/kg compared to V_T = 6 mL/kg and V_T = 13 mL/kg [23(18.5–24.75) vs. 16(12–17.75) and 16(13.25–18), p < 0.05, respectively]. V_T = 22 mL/kg was associated with higher IL-6, amphiregulin, CC16, MMP-9, and syndecan-1 mRNA expression and lower decorin expression than V_T = 6 mL/kg. Multiple linear regression analyses indicated that V_T was able to predict changes in IL-6 and CC16, whereas ΔP,_L predicted pHa, oxygenation, amphiregulin, and syndecan-1 expression. In the model of ARDS used herein, even at low mechanical power, high V_T resulted in VILI. V_T control seems to be more important than RR control to mitigate VILI.</p

Image2.PDF

<p>Tidal volume (V_T) has been considered the main determinant of ventilator-induced lung injury (VILI). Recently, experimental studies have suggested that mechanical power transferred from the ventilator to the lungs is the promoter of VILI. We hypothesized that, as long as mechanical power is kept below a safe threshold, high V_T should not be injurious. The present study aimed to investigate the impact of different V_T levels and respiratory rates (RR) on lung function, diffuse alveolar damage (DAD), alveolar ultrastructure, and expression of genes related to inflammation [interleukin (IL)-6], alveolar stretch (amphiregulin), epithelial [club cell secretory protein (CC)16] and endothelial [intercellular adhesion molecule (ICAM)-1] cell injury, and extracellular matrix damage [syndecan-1, decorin, and metalloproteinase (MMP)-9] in experimental acute respiratory distress syndrome (ARDS) under low-power mechanical ventilation. Twenty-eight Wistar rats received Escherichia coli lipopolysaccharide intratracheally. After 24 h, 21 animals were randomly assigned to ventilation (2 h) with low mechanical power at three different V_T levels (n = 7/group): (1) V_T = 6 mL/kg and RR adjusted to normocapnia; (2) V_T = 13 mL/kg; and 3) V_T = 22 mL/kg. In the second and third groups, RR was adjusted to yield low mechanical power comparable to that of the first group. Mechanical power was calculated as [(ΔP,L2/Est,_L)/2]× RR (ΔP,_L = transpulmonary driving pressure, Est,_L = static lung elastance). Seven rats were not mechanically ventilated (NV) and were used for molecular biology analysis. Mechanical power was comparable among groups, while V_T gradually increased. ΔP,_L and mechanical energy were higher in V_T = 22 mL/kg than V_T = 6 mL/kg and V_T = 13 mL/kg (p < 0.001 for both). Accordingly, DAD score increased in V_T = 22 mL/kg compared to V_T = 6 mL/kg and V_T = 13 mL/kg [23(18.5–24.75) vs. 16(12–17.75) and 16(13.25–18), p < 0.05, respectively]. V_T = 22 mL/kg was associated with higher IL-6, amphiregulin, CC16, MMP-9, and syndecan-1 mRNA expression and lower decorin expression than V_T = 6 mL/kg. Multiple linear regression analyses indicated that V_T was able to predict changes in IL-6 and CC16, whereas ΔP,_L predicted pHa, oxygenation, amphiregulin, and syndecan-1 expression. In the model of ARDS used herein, even at low mechanical power, high V_T resulted in VILI. V_T control seems to be more important than RR control to mitigate VILI.</p

Table1.PDF

<p>Tidal volume (V_T) has been considered the main determinant of ventilator-induced lung injury (VILI). Recently, experimental studies have suggested that mechanical power transferred from the ventilator to the lungs is the promoter of VILI. We hypothesized that, as long as mechanical power is kept below a safe threshold, high V_T should not be injurious. The present study aimed to investigate the impact of different V_T levels and respiratory rates (RR) on lung function, diffuse alveolar damage (DAD), alveolar ultrastructure, and expression of genes related to inflammation [interleukin (IL)-6], alveolar stretch (amphiregulin), epithelial [club cell secretory protein (CC)16] and endothelial [intercellular adhesion molecule (ICAM)-1] cell injury, and extracellular matrix damage [syndecan-1, decorin, and metalloproteinase (MMP)-9] in experimental acute respiratory distress syndrome (ARDS) under low-power mechanical ventilation. Twenty-eight Wistar rats received Escherichia coli lipopolysaccharide intratracheally. After 24 h, 21 animals were randomly assigned to ventilation (2 h) with low mechanical power at three different V_T levels (n = 7/group): (1) V_T = 6 mL/kg and RR adjusted to normocapnia; (2) V_T = 13 mL/kg; and 3) V_T = 22 mL/kg. In the second and third groups, RR was adjusted to yield low mechanical power comparable to that of the first group. Mechanical power was calculated as [(ΔP,L2/Est,_L)/2]× RR (ΔP,_L = transpulmonary driving pressure, Est,_L = static lung elastance). Seven rats were not mechanically ventilated (NV) and were used for molecular biology analysis. Mechanical power was comparable among groups, while V_T gradually increased. ΔP,_L and mechanical energy were higher in V_T = 22 mL/kg than V_T = 6 mL/kg and V_T = 13 mL/kg (p < 0.001 for both). Accordingly, DAD score increased in V_T = 22 mL/kg compared to V_T = 6 mL/kg and V_T = 13 mL/kg [23(18.5–24.75) vs. 16(12–17.75) and 16(13.25–18), p < 0.05, respectively]. V_T = 22 mL/kg was associated with higher IL-6, amphiregulin, CC16, MMP-9, and syndecan-1 mRNA expression and lower decorin expression than V_T = 6 mL/kg. Multiple linear regression analyses indicated that V_T was able to predict changes in IL-6 and CC16, whereas ΔP,_L predicted pHa, oxygenation, amphiregulin, and syndecan-1 expression. In the model of ARDS used herein, even at low mechanical power, high V_T resulted in VILI. V_T control seems to be more important than RR control to mitigate VILI.</p