Ventilator-induced lung injury (VILI) caused by excessive lung stretch during mechanical ventilation, is an important determinant of intensive care mortality. In recent years the mouse has increasingly become the pre-clinical model of choice, and studies using mice have identified numerous pathways and mediators all apparently vital during VILI. However, findings have not translated into clinical benefit, and it is conceptually extremely difficult to reconcile this plethora of mediators into a single paradigm. We propose that this confused situation has arisen from a somewhat naïve belief that the wide variety of tidal volumes (VT) used within such studies all induce over-stretching of the lungs.Methods
Anaesthetised mice were ventilated (3 cm H2O positive end-expiratory pressure, using air ±CO2 to regulate pH) with a variety of VT ranging from “clinically relevant” (10 ml/kg) to “very high” (40 ml/kg) for up to 3 h.Results
Both 10 ml/kg and 40 ml/kg VT evoked deterioration in arterial pO2 and mean arterial blood pressure (BP), although intermediate VT (20–30 ml/kg) did not (see Abstract S75 table 1). Lung wet:dry weight ratio and lavage fluid total protein were both marginally increased by 10–20 ml/kg VT compared to non-ventilated controls (NVC). However, raising the VT to 30 ml/kg did not further enhance these, suggesting that any increases following 10–20 ml/kg were not due to over-stretching the lungs. Only 40 ml/kg induced substantial increases compared to other groups. Both 40 ml/kg and 30 ml/kg upregulated lavage fluid IL-6, while soluble receptor for advanced glycation end-products (sRAGE) tended to be increased with 10–20 ml/kg but not 30 ml/kg (compared to NVC). Again, only 40 ml/kg VT induced significant upregulation.Conclusions
These data demonstrate that only the highest VT used (40 ml/kg) induced major changes in physiological and inflammatory markers consistent with development of VILI. Signs of injury/inflammation using VT 10–20 ml/kg are likely to result not from substantial lung over-stretch but from other factors, particularly epithelial shear stress secondary to alveolar derecruitment and atelectasis. While such VT may themselves be considered to be “clinically relevant”, whether they induce a “clinically relevant” pathophysiology in healthy mice is questionable.