Protective ventilation is a cornerstone of perioperative management during lung transplantation. However, its current clinical approach is mainly based on literature from intensive care and elective surgery with one-lung ventilation. This review summarizes the pathophysiology of each of the four main end-stage lung diseases and how mechanical power affects the energy exerted on the lungs during the different surgical steps, first on the host and then on the grafts. Each pathology presents specific parenchymal characteristics, and there is great heterogeneity in pulmonary compliance within and between patients. Recognizing these regional heterogeneities in compliance is fundamental to personalizing ventilator settings and avoiding increasing ventilator-induced lung injury.

Furthermore, we explored the concept of the multiple-hits model of lung allograft injury. It highlights the consequences over time (additive or synergic) of all the risk factors cumulated on allograft injury, from the donor before harvesting, to the transport, and finally after implantation. Additionally, we discussed the novel opportunity that ex-vivo lung perfusion offers in the assessment of graft quality using various parameters, as well as mechanical power to guide different modes and settings to optimize ventilation. This experimental model could be used to develop new specific ventilation strategies to optimize the mechanical energy exerted on the lungs without a chest wall. Finally, we advocate for early extubation to reduce ventilation-induced lung injury and promote early rehabilitation.