Hylke Salverda

15 1 General introduction and outline of this thesis Supplemental oxygen and effects on morbidity Supplemental oxygen is one of the most common therapies for preterm infants on respiratory support. Oxygen is fundamental for generating intracellular energy and is therefore essential to human life. A deficit of oxygen in the blood, or hypoxaemia, is common in preterm infants due to the immaturity of their lungs and respiratory centre, and can lead to oxygen shortage in the mitochondria which will eventually lead to cell death.1 Oxygen supplementation is therefore used to avert cell death and subsequent effects of hypoxaemia on the central nervous system, lungs, vasculature and other organs. As development of the respiratory system occurs until after term age,2 supplemental oxygen for preterm infants is often given for long periods of time. However, as with any drug, too much of it can lead to toxicity. The higher oxygen tension present in the extra-uterine atmosphere can harm a preterm infants’ organs, even without supplemental oxygen. The immaturity of a preterm infants’ anti-oxidant system renders them vulnerable to free radicals, also known as reactive oxygen and nitrogen intermediates, formed under the influence of excess oxygen in the blood. These free radicals cause membrane disruption and activate inflammatory pathways through lipid peroxidation.3 Indeed, infants developing a chronic lung condition called bronchopulmonary dysplasia were found to have elevated lipid peroxidation products.4 Causal evidence on the effect of hyperoxia is scarce for preterm infants, but plenty of evidence from animal experiments exists. Neonatal mice demonstrated that exposure of the lung to hyperoxia decreased the alveolarization, changed the vasculature of the lung, and increased lung fibrosis.5 Furthermore, intestinal histology of rat pups was markedly changed in pups continuously exposed to hyperoxia immediately after birth.6 Finally, hyperoxia has been shown to alter cerebral blood flow in mice, induce neuronal apoptosis and inflammation.7, 8 The first morbidity attributed to hyperoxaemia in preterm infants was retinopathy of prematurity (ROP), a neurovascular disease leading to blindness.9 The aetiology is not fully understood. Initially not enough retinal blood vessels are formed due to insufficient nutrition, insufficient growth factors, sepsis and a fluctuating oxygenation of the blood. The vasculogenesis of the retina is further reduced by iatrogenic hyperoxaemia inhibiting the formation of vascular endothelial growth factor. In this initial phase the retina is particularly susceptible to damage from intermittent hypoxia due to the scarce blood supply. After this phase uncontrolled blood vessel formation occurs under the influence of vascular endothelial growth factor eventually leading to retinal detachment.10 Given this aetiology, it is not surprising both intermittent