Oxygen Supplementation to Stabilize Preterm Infants in the Fetal to Neonatal Transition: No Satisfactory Answer

Abstract

Fetal life elapses in a relatively low oxygen environment. Immediately after birth with the initiation of breathing, the lung expands and oxygen availability to tissue rises by twofold, generating a physiologic oxidative stress. However, both lung anatomy and function and the antioxidant defense system do not mature until late in gestation, and therefore, very preterm infants often need respiratory support and oxygen supplementation in the delivery room to achieve postnatal stabilization. Notably, interventions in the first minutes of life can have long-lasting consequences. Recent trials have aimed to assess what initial inspiratory fraction of oxygen and what oxygen targets during this transitional period are best for extremely preterm infants based on the available nomogram. However, oxygen saturation nomogram informs only of term and late preterm infants but not on extremely preterm infants. Therefore, the solution to this conundrum may still have to wait before a satisfactory answer is available.

Keywords: biomarkers; free radicals; oxidative stress; oxygen; oxygen saturation; prematurity; pulse oximetry.

Figure 1

Acetyl-coA is the merging metabolite derived from basic nutrients. Entering into the inner mitochondrial space acetyl-coA will undergo a metabolic transformation in the tricarboxylic cycle (Kreb’s cycle). During this process, highly energized electrons are liberated and transported by specific electron transporters to the electron transport chain (ETC). Energy is used to extrude protons and thus establish a transmembrane potential (Ψ_m). In the final step, ATP synthase will again intrude protons in the inner mitochondrial space. The energy provided by Ψ_m will be employed to synthesize adenosine triphosphate (ATP) from adenosin diphosphate (ADP). Oxygen will be reduced with four electrons and combined with two protons to form water. This process is known as oxidative phosphorylation.

Figure 2

Oxygen (1) is stepwise reduced by just one electron leading to the formation of anion superoxide (2). Anion superoxide is dismutated by superoxide dismutases (SODs) to hydrogen peroxide (3), which in turn is transformed into water and oxygen by the action of catalases (CATs) and glutathione peroxidase (GPX). In the presence of transition metals (e.g., iron and copper), hydrogen peroxide can be transformed into hydroxyl radical (4). Moreover, in the presence of nitric oxide (NO), anion superoxide can also be transformed into peroxynitrite (5). Anion superoxide, hydroxyl radical, and peroxynitrite are highly reactive free radicals that will cause structural and functional damage to nearby standing molecules. Hydrogen peroxide will act as a cell-signaling molecule. Reduced glutathione (GSH) is the most relevant non-enzymatic antioxidant in the cell cytoplasm and an essential determinant of cell’s redox balance.

Figure 3

Oxygenation of the fetus is clearly dependent on the partial pressure gradients between maternal blood, placental tissue, fetal blood, and tissue. The level of intervillous oxygen concentration varies along gestation. Studies performed in human fetuses have shown that before the 12th week of gestation, the intervillous partial pressure of oxygen (PIVO₂) has a median value around 18–20 mmHg, presumably to protect the embryo, which is highly sensitive to ROS. However, PIVO₂ rises in the following weeks reaching a peak value (60 mmHg) around 14–16 weeks of gestation. Thenceforth, PIVO₂ decreases slowly, reaching values of 45–48 mmHg at 36 weeks of gestation (9).

Figure 4

Correlation between amniotic fluid levels of erythropoietin (EPO) and meta-tyrosine, a biomarker of oxidative damage to protein in diabetic type 2 pregnancies treated with insulin (23).

Figure 5

(A) Under normal circumstances, nitric oxide produced by the action of NO synthase activates guanylate cyclase, which catalyzes the formation of cGMP and subsequently lung vessel vasodilatation. In addition, superoxide anion, derived from air-borne oxygen by the action of superoxide dismutases, is catalyzed to hydrogen peroxide, which acts also as lung vessel vasodilator. (B) In the presence of oxygen in excess (resuscitation and ventilation), anion superoxide will sequester nitric oxide and produce highly reactive peroxynitrite. The amount of available cGMP is reduced and also the production of hydrogen peroxide. Under these circumstances, there is a potent tendency toward vasoconstriction (17, 25, 27).