Variable ventilation (VV), characterized by breath-to-breath variation of tidal volume (Vt) and breathing rate (f), has been shown to improve lung mechanics and blood oxygenation during acute lung injury in many species compared with conventional ventilation (CV), characterized by constant Vt and f. During CV as well as VV, the lungs of mice tend to collapse over time; therefore, the goal of this study was to develop a new VV mode (VV(N)) with an optimized distribution of Vt to maximize recruitment. Groups of normal and HCl-injured mice were subjected to 1 h of CV, original VV (VV(O)), CV with periodic large breaths (CV(LB)), and VV(N), and the effects of ventilation modes on respiratory mechanics, airway pressure, blood oxygenation, and IL-1beta were assessed. During CV and VV(O), normal and injured mice showed regional lung collapse with increased airway pressures and poor oxygenation. CV(LB) and VV(N) resulted in a stable dynamic equilibrium with significantly improved respiratory mechanics and oxygenation. Nevertheless, VV(N) provided a consistently better physiological response. In injured mice, VV(O) and VV(N), but not CV(LB), were able to reduce the IL-1beta-related inflammatory response compared with CV. In conclusion, our results suggest that application of higher Vt values than the single Vt currently used in clinical situations helps stabilize lung function. In addition, variable stretch patterns delivered to the lung by VV can reduce the progression of lung injury due to ventilation in injured mice.

The accepted protocol to ventilate patients with acute lung injury is to use low tidal volume (VT) in combination with recruitment maneuvers or positive end-expiratory pressure (PEEP). However, an important aspect of mechanical ventilation has not been considered: the combined effects of PEEP and ventilation modes on the integrity of the epithelium. Additionally, it is implicitly assumed that the best PEEP-VT combination also protects the epithelium. We aimed to investigate the effects of ventilation mode and PEEP on respiratory mechanics, peak airway pressures and gas exchange as well as on lung surfactant and epithelial cell integrity in mice with acute lung injury. HCl-injured mice were ventilated at PEEPs of 3 and 6 cmH2O with conventional ventilation (CV), CV with intermittent large breaths (CVLB) to promote recruitment, and a new mode, variable ventilation, optimized for mice (VVN). Mechanics and gas exchange were measured during ventilation and surfactant protein (SP)-B, proSP-B and E-cadherin levels were determined from lavage and lung homogenate. PEEP had a significant effect on mechanics, gas exchange and the epithelium. The higher PEEP reduced lung collapse and improved mechanics and gas exchange but it also down regulated surfactant release and production and increased epithelial cell injury. While CVLB was better than CV, VVN outperformed CVLB in recruitment, reduced epithelial injury and, via a dynamic mechanotransduction, it also triggered increased release and production of surfactant. For long-term outcome, selection of optimal PEEP and ventilation mode may be based on balancing lung physiology with epithelial injury.

We investigated the influence of load impedance on ventilator performance and the resulting effects of reduced tidal volume (Vt) on lung physiology during a 30-min ventilation of normal mice and 10 min of additional ventilation following lavage-induced injury at two positive end-expiratory pressure (PEEP) levels. Respiratory mechanics were regularly monitored, and the lavage fluid was tested for the soluble E-cadherin, an epithelial cell adhesion molecule, and surfactant protein (SP) B. The results showed that, due to the load dependence of the delivered Vt from the small-animal ventilator: 1) uncontrolled ventilation in normal mice resulted in a lower delivered Vt (6 ml/kg at 3-cmH(2)O PEEP and 7 ml/kg at 6-cmH(2)O PEEP) than the prescribed Vt (8 ml/kg); 2) at 3-cmH(2)O PEEP, uncontrolled ventilation in normal mice led to an increase in lung parenchymal functional heterogeneity, a reduction of SP-B, and an increase in E-cadherin; 3) at 6-cmH(2)O PEEP, ventilation mode had less influence on these parameters; and 4) in a lavage model of acute respiratory distress syndrome, delivered Vt decreased to 4 ml/kg from the prescribed 8 ml/kg, which resulted in severely compromised lung function characterized by increases in lung elastance, airway resistance, and alveolar tissue heterogeneity. Furthermore, the low Vt ventilation also resulted in poor survival rate independent of PEEP. These results highlight the importance of delivering appropriate Vt to both the normal and injured lungs. By leaving the Vt uncompensated, it can significantly alter physiological and biological responses in mice.

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