To date, it is known that inflammation and systemic and brain injuries are often triggered by ventilation-induced lung injury (VILI) [
4,
21]. Several studies demonstrated that ventilation may cause brain damage through two pathways: localized cerebral inflammatory response and hemodynamic instability. The first is due to the inflammatory pulmonary cascade that crosses the blood-brain barrier, causing pro-inflammatory cytokines overproduction and brain white matter injury [
22]. Already after 2 h of ventilation, an increase in the pro-inflammatory plasma cytokines of interleukin (IL) -8, IL-1β and TNF- α and a decrease IL-10 anti-inflammatory cytokines have been demonstrated [
7,
23]. An increase in pro-inflammatory cytokines can also compromise cerebral vascularization and reduce the integrity of the blood-brain barrier. The main reason of free radical overproduction is the use of pure oxygen during resuscitation in the delivery room. However, although there is evidence of an increase in OS when starting preterm infants in 100% oxygen, it is known that both hyperoxemia and hypoxemia should be avoided [
24]. Indeed, the combination of heart rate < 100 / min and SpO2 < 80% in the first 5 min is associated with death or intracranial hemorrhage [
25]. The second pathway is connected to the over-distension of the preterm alveoli, to the compression of the pulmonary capillaries and to the pulmonary hemodynamic instability which leads to an alteration of the pulmonary venous return and of the cardiac output and wide oscillations of the cerebral blood flow (CBF). Indeed, barotrauma caused by the application of intermittent positive pressure ventilation (IPPV) and Positive End-Expiratory Pressure (PEEP), induce the variability of intrathoracic pressure, which can affect preload, post-load, heart rate and myocardial contractility, altering the hemodynamic function of heart and brain. Moreover, some authors demonstrated that over-distention of the alveoli amplifies the pulmonary inflammatory response, which increase in the gene expression of pro-inflammatory cytokines in the brain of ventilated preterm lambs [
26]. These paths are amplified by duration of ventilation and high VT [
22,
27‐
29]. Indeed, concerning the volutrauma, some authors compared two groups of ventilated preterm infants with a VT < 5.8 ml/kg and > 5.8 ml/kg and described a higher incidence of intraventricular hemorrhage (IVH) in premature babies who received high VT compared to children who received lower VT in the delivery room (51% vs 13%) [
20,
30]. Three large VT breaths are sufficient to initiate an inflammatory response, while lower VT improves cerebral hemodynamic stability and reduces the inflammatory response [
28]. Finally, the increase in pro-inflammatory cytokines cause the widespread activation of microglia within the immature white matter, decrease the ability of cerebral vascularization to protect against abnormal CBF, as well as reduce the integrity of the blood-brain barrier, making it more prone to bleeding [
23,
28]. Histologically, the damage of the cerebral parenchyma is evident with an increase in the size and density of the microglial aggregations [
28].
Therefore, given the underlying risk of brain injury in premature babies, the need for ventilation further aggravates the likelihood of acute injury and chronic disability by suggesting the imperative that a premature baby receive the safest respiratory support possible from the delivery room.