Lung injury is demonstrated to be caused directly by ROS production in response to hyperoxia and indirectly by ROS due to phagocyte activation and inflammation. The two mechanisms seem to be integrated In vitro and in vivo exposures to hyperoxia result in downregulation of peroxisome proliferators-activated receptor gamma and in increase transdifferentiation of pulmonary protective lipofibroblasts to myofibroblasts MYFs 50 , Epithelial cell growth and differentiation is not adequately supported by MYFs.
This results in a disturbed alveolarization, characterizing bronchopulmonary dysplasia BPD High level of neutrophils, IL-8, and leukotrienes in alveolar fluid of BPD infants clearly support the role of inflammation and ROS in the development of this oxidative damage The exposure to hyperoxia is also associated with higher risk for severe retinopathy of prematurity ROP , due to susceptibility of the phospholipid-rich retina to ROS The peripheral temporal portion of the retina is the last to be vascularized, and it is still immature even at term These mechanisms finally lead to abnormal retinal vascular proliferation and the formation of a ridge, which places traction on the retina and increases the risk of detachment, as seen in ROP Newborn erythrocytes are more prone to damaging effects of oxidative stress and to have higher content of free iron than those of adults.
In this context, free radical damage is involved in neonatal hemolytic anemia and particularly of the preterm 58 , Furthermore, prolonged exposure to hyperbaric oxygen leads to changes of erythrocytes shape, as a consequence of toxic effects of oxygen on the erythrocyte membranes.
In an animal model, various forms of abnormal red blood cells are observed after exposure to high oxygen concentration, and in particular echinocyte shape was dominated Exposure to hyperoxia at birth can also be related to long-term pathological effects. Furthermore, the exposure of newborn mice to hyperoxia may lead to long-term cardiac abnormalities, such as left ventricular dysfunctions 63 , and neurodevelopmental impairments in adult life, as demonstrated by abnormal behavior, deficits in spatial and recognition memory, small hippocampal dimensions, in the absence of intracranial pathology such as intraventricular hemorrhage or periventricular leukomalacia in the neonatal period In conclusion, experimental studies and clinical observations demonstrated high susceptibility of the fetus and newborn to oxidative stress.
Increased release and decreased detoxification in the newborn appear to be negatively correlated with the gestational age. Avoidance of conditions, such as infections, asphyxia, retinal light exposure, iron supplementation, and, in particular, hyperoxia, reduces oxidative stress. Recent studies, that have been accomplished, have revised the concept of the optimal oxygenation in newborns, children, and adults.
Chow et al. They found a decrease of incidence of ROP in the group treated with lower O 2 saturation without any differences in mortality and morbidity Neonatal outcomes showed that newborns treated with higher level of oxygen had more cognitive disabilities than those treated with lower oxygen, after 10 years But, as secondary outcome, they showed an increased incidence of chronic lung disease and a longer duration of hospitalization, both in the higher group.
Thanks to these data, it was possible to conduct a prospective meta-analysis, NeOProM 73 study, with a primary outcome defined as a composite of death and disability at 18—24 months of corrected age. The study showed no significant differences in the primary outcome, but the use of a lower range of oxygen saturation results in a decrease of occurrence of severe ROP and an increase of death before the discharge. The COT study, with a primary outcome defined as death before 18 months of corrected age or survival with one or more disability, do not showed significant differences in the mortality or other outcome, but only a reduction of duration of O 2 therapy.
However, there are more unanswered questions and the optimal oxygen saturation range for low birth weight preterm infants remains elusive. This is mainly due to the several different clinical conditions of preterm newborns. Some authors indicate that 50 and 70 mmHg 75 is the optimal oxygen tension, but it is noteworthy that pulse oximetry ability remains controversial. In clinical practice, the continuous monitoring of oxygen saturation is mandatory to titrate oxygen therapy as better as possible and the routine use of pulse oximetry systems can be considered a very useful approach for the neonatologists, in order to reach this goal.
However, the optimal target range for oxygen saturation in the sick newborns and, above all, in the extremely preterm babies is not clear. The challenge for the clinicians is reaching a balance in the oxygen administration, to avoid the damage and negative outcomes, associated with either hyperoxemia or hypoxemia.
Based on all the actually available evidence and considering the lack of evidence about the influence of many factors such as transfusional status, different gestational ages and underlying diseases, the most careful approach is to avoid both hypoxia and hyperoxia in infants requiring oxygen supplementation.
It is essential to control the low limit as well as the upper limit to prevent excessive fluctuations of oxygen saturation 78 , Hyperoxia and hypoxia are deeply involved in the development of several neonatal diseases, and the mechanisms are complex and not yet fully understood. However, evidences suggest that both the generation of oxidant species i.
Hyperoxia and inflammation as well as the episode of hypoxia—reoxygenation and free iron appear to be sources of increased ROS release, which may cause tissue injury either by direct effect or as consequences of endothelium dysfunction and gene alteration, particularly in preterm newborns. Understanding the effects of O 2 administration is important for the management of oxygen therapy in newborns, in order to prevent inadvertent cellular and tissue damage caused by hyperoxia, in the patients requiring supplemental oxygenation.
SP: wrote a draft and supervised the final manuscript; CB: assisted with preparation of manuscript; NV: assisted with preparation of manuscript; GB: conceived the idea and supervised the final manuscript. The authors declare that there is no commercial or financial relationship that could be constructed as a potential conflict of interest.
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