Variable cell stretching and mechanical ventilation: A comprehensive investigation on the mechanisms and long-term effects of a new ventilatory strategy
Final Report Abstract
The project added new relevant information to the field of mechanical ventilation and, more specifically, to variable mechanical ventilation. We could show, for the first time, that variable stretch of type-I alveolar epithelial cells challenged with an inflammatory hit respond with a reduced release of pro-inflammatory cytokines, as compared to non-variable stretch. Thus, besides macro-structural mechanisms (e.g. lung recruitment, redistribution of perfusion), variable ventilation seems to have also exerts cellular effects, from which the main pathway (ERK1/2 signaling) was identified. It seems, however, that in severe lung injury, the beneficial effects of long-lasting variable ventilation are less pronounced, but the choice of inappropriate levels of PEEP might have been responsible for this observation. Importantly, once lungs have been stabilized with variable ventilation, variability should not be decreased in an attempt to avoid sporadic increases in airway pressure that are inherent to this ventilation strategy. Such reduction, may lead namely to the loss of the beneficial effects. The findings of this project open a variety of perspectives in the field of mechanical ventilation, and possibly also outside of it. The mechano-transduction and signaling during variable stretch of alveolar epithelial cells deserves further investigation in more depth. It is worth of note that the response to mechanical stress is influenced not only by the amplitude or rate of stretch, but also the variability. Such finding might find application in other areas, for example the response of endothelial cells to cyclic variability in blood pressure. In the long term, possible beneficial effects of variable ventilation might be better coupled with lung stabilization of lung units with appropriate PEEP values. We hypothesize that these effects would be then pronounced, and might be guided by online measurements of the elastance of the respiratory system. Given that we accumulated experience and know-how with long-term variable ventilation during this project, as well as small animal experiments, we intend to investigate the hypothesis that PEEP should be titrated according to the elastic properties of lungs in variable ventilation using a closed-loop system.
