Mechanical ventilation is the centrepiece of life support therapy for patients requiring intensive care and an essential tool for anaesthesiologist in the perioperative setting. Despite its fundamental role to assure adequate gas exchange for patients, mechanical ventilation can induce morphological changes in the lung parenchyma and alter physiological processes that can potentially lead to the development of ventilator-induced lung injury (VILI). Over the past decades, a substantial effort has been made by clinicians and scientists together to investigate the underlying mechanisms leading to VILI and to develop novel ventilation strategies to protect the lungs during mechanical ventilation.

Early descriptions focused on the structural lung damage caused by excessive airway pressures, and the harm resulting from alveolar overdistension due to large tidal volumes. Later, attention turned towards the importance of preserving the alveolar structure describing the repetitive opening and closing of unstable lung units as a signalling pathway that can induce inflammation. Most recently, the total mechanical energy delivered by the ventilator to the lungs has been proposed as a unifying outcome for these injury mechanisms.

This thesis describes these evolving concepts in detail to summarize our current knowledge while placing it into a historical context. Building on scientific and clinical advancement combined with technological innovation we will explore the potential of novel ventilation strategies in order to minimize the potentially harmful effect of mechanical ventilation. The experimental work presented here not only underscores how technological advances combined with translational research can change ventilatory management but also provides evidence for the protective potential of emerging ventilation modalities. Specifically, the implementation of physiological variability into the breathing pattern, precise flow control for expiratory ventilation assistance, and the combination of positive-pressure with negative extrathoracic pressure ventilation were studied as promising approaches to reduce ventilation-associated morbidity and mortality.

Future strategies should build on these results to develop individually tailored ventilation approaches specific to every patient and pathological condition to improve ventilation efficiency while protecting from the potential injury to improve patient care and respiratory outcome.