Mechanical ventilation (MV) is intimately linked with the daily care of critically ill children and has added significantly to survival. It is used to ensure oxygenation and ventilation and to decrease patient respiratory effort during the period in which the underlying (non-) pulmonary disorders can (partially) resolve. However, MV is also linked to the initiation or even aggravation of lung injury, termed ventilator-induced lung injury (VILI) The inflammation is not limited to the lung; inflammatory mediators can enter the systemic circulation and lead to organ failure and multiple system organ failure (MSOF) linked to VILI [1–3]. Several mechanisms have been attributed to play a role in VILI, including ventilating at high lung volumes following the delivery of inappropriately sized tidal volumes (Vt) in relation to the amount of inflatable lung volume (i.e. the “baby lung”), and ventilating at low lung volumes leading to repetitive alveolar opening and closure (also known as atelectrauma) [4, 5]. A better understanding of these mechanisms led to the concept of lung and diaphragm protective ventilation (LPV), a strategy that focuses on the delivery of small Vt to avoid excessive lung strain (the changes in volume in relation to its resting volume) and a certain level of positive end-expiratory pressure (PEEP) to maintain alveolar patency [6, 7]. When conventional mechanical ventilation (CMV) fails, high-frequency oscillatory ventilation (HFOV) and airway pressure release ventilation (APRV) can be considered alternative modes of ventilation as they are, at least theoretically, justifiable modes to be used in the context of LPV because they target the two major determinants of VILI.