Intermittent hypoxemia and oxidative stress in preterm infants

Abstract

Intermittent hypoxemia events (IH) are common in extremely preterm infants and are associated with many poor outcomes including retinopathy or prematurity, wheezing, bronchopulmonary dysplasia, cognitive or language delays and motor impairment. More recent data in animal and rodent models have suggested that specific patterns of IH may increase the risk for morbidity. The pathway by which these high risk patterns of IH initiate a pathological cascade is unknown but animal models suggest that oxidative stress may play a role. This review describes early postnatal patterns of IH in preterm infants, their relationship with morbidity, oxidative stress biomarkers relevant to the newborn infant and the relationship between IH and reactive oxygen species.

Keywords: Hypoxia; Intermittent hypoxemia; Oxidative stress; Pulse oximetry.

Figure 1

-During reoxygenation following a hypoxemic event, stepwise reduction of oxygen generates superoxide anion (monovalent reduction) which either dismutates by the action of Superoxide Dismutases (Cu Zn SOD, Mn SOD, Ec SOD) to Hydrogen Peroxide, or reacts with nitric oxide to form peroxynitrite leading to DNA, protein and/or lipid damage. Hydrogen peroxide can be reduced to water by the action of Catalase (CAT), Glutathione Peroxidase (GPx) or Peroxiredoxin (PRx). Hydrogen peroxide acts as a potent cell signaling molecule regulating essential pathways related to cell physiology. However, in the presence of transition metals (ie. iron, copper, manganese, zinc) Fenton chemistry ensues converting hydrogen peroxide to hydroxyl radical, a highly reactive free radical capable of causing oxidative damage to cell components. Reduced glutathione (GSH) is the most potent cytosolic non-enzymatic antioxidant. The combination of two disulfide bonds (2GSH) in a disulfur bond leads to the formation of oxidized glutathione (GSSG) and the liberation of 2 electrons which are employed by GPx and CAT to neutralize hydrogen peroxide. Similar changes are experiences by reduced Thioredoxin and Cysteine when transformed into oxidized Thioredoxin (TRx) and Cystine (Cys). The switch from sulfur to disulfide bonds is an essential antioxidant mechanism. Moreover, the SH/S=S ratio in these three couples is essential for the maintenance of the redox status of the different cellular and extracellular compartments. An adequate redox status determines normal cell signaling such as cell division, growth, and differentiation, or in excess, activation of DNA, Protein and/or Lipid damage such as autophagy, apoptosis or necrosis. Note: open circles represent empty orbital loci without electrons; black circles represent orbital loci occupied by electrons.

Figure 2

-In preterm infants, the occurrence of IH in response to a respiratory pause may be enhanced by increased metabolic oxygen consumption and poor respiratory function (ie. decreased oxygen uptake by the alveoli, pulmonary oxygen stores, and total blood oxygen carrying capacity)

Figure 3

-The association between postnatal progression of intermittent hypoxemia events (IH) and poor outcomes in very low birthweight preterm infants. The average incidence of IH (solid line) during the first week of life is relatively low (Phase I), followed by a progressive increase during the second week of life (Phase II), peaking at approximately 4 weeks and decreasing thereafter (Phase III). A higher incidence of IH (dashed line) has been associated with multiple morbidities but current studies suggest that the timing of the increase in IH may be outcome dependent. For example, a higher incidence of IH during the first 3 days of life has been associated with an increased risk of asthma at 2yrs of age, while a higher frequency of IH after 3 to 5wks of age has been associated with retinopathy of prematurity (ROP). Transitional phases denoted by grey arrows. Significant associations between IH and individual morbidities are represented by grey boxes. Fading edges signify general postnatal windows as opposed to a fixed specific time. ^a use of asthma medications at 2 year follow up ^b 90-day survival ^c BPD-bronchopulmonary dysplasia defined as supplemental oxygen at 36 weeks corrected age ^d IVH-intraventricular hemorrhage during hospitalization ^e at a corrected age of 18 to 21 months ^f ROP-severe retinopathy of prematurity requiring intervention during ospitalization References: ¹ (Di Fiore et al., 2018) ² (Di Fiore et al., 2017) ³ (Fairchild et al., 2018) ⁴ (Raffay et al., 2018) ⁵ (Poets et al., 2015) ⁶ (Di Fiore et al., 2012)

Figure 4

-Reference range of urinary lipid peroxidation byproducts in preterm infants ≤28 weeks gestation with a clinical course free of oxidative stress-associated complications. Analytical determinations were performed using ultra-high performance liquid chromatography coupled to mass spectrometry. Straight line-mean values, dotted lines-Standard Deviations. Copyright, used with permission, Kuligowski J, et al. Antioxid Redox Signal. 2015

Figure 5

-In rodents, IH upregulates NADPH oxidase and pro-inflammatory cytokines leading to generation of reactive oxygen species (Yuan et al., 2008). IH also downregulates HIF-2α in carotid bodies and adrenal medullae leading to inhibition of SOD2 transcription (Nanduri et al., 2009). This increase in reactive oxygen species superimposed on decreased anti-oxidant signaling may result in overall increased oxidative stress inducing a pathological cascade.