Hypoxic Oxygen Fluctuations Produce Less Severe Retinopathy than Hyperoxic Fluctuations in a Rat Model of Retinopathy of Prematurity

Abstract

The aim of this study was to investigate whether the mean around which arterial oxygen fluctuations take place was important in a unique animal model of oxygen-induced retinopathy. Retinopathy of prematurity (ROP) is associated with fluctuating arterial oxygen. A recent retrospective study suggested that management of high-risk preterm infants at lower oxygen saturations was associated with less severe ROP. Rat pups were raised in a variable oxygen environment around a high (24%), normal (21%) or low (17%) mean inspired oxygen for 14 d. Rat pups raised in the high (24%) mean variable oxygen environment had more retarded retinal vascular development than did rats raised in an environment that fluctuated around 21% mean oxygen. In contrast, rats raised in a lower mean (17%) but still variable oxygen environment had no discernible retinal differences from controls raised in constant room air. Rats raised in a relatively hypoxic but variable oxygen environment develop less severe retinal vascular abnormalities than those raised in variable oxygen around higher oxygen means. Abbreviations C, group raised in room air DAB, diaminobenzidine Hi, variable oxygen profile around 24% oxygen mean IQR, interquartile range Lo, variable oxygen profile around 17% oxygen mean N, variable oxygen profile around 21% oxygen mean PFA, paraformaldehyde ROP, retinopathy of prematurity TBS, Tris-buffered saline VEGF, vascular endothelial growth factor ROP is a leading cause of blindness among infants in developed (1) and middle-income countries (2). The role of high concentrations of supplemental oxygen was first recognized in the 1950s (3), and subsequent animal studies (4 -6) delineated the pathophysiology. Restrictions on oxygen use led to a reduction in the disease, but the technological advances in the 1970s and 1980s led to infants up to 16 wk preterm surviving. Even with strict oxygen control to prevent hyperoxia the disease incidence began to increase again. The cause of the current disease is generally considered multifactorial (7), however variations in oxygen have been shown important to the development of disease in humans (8, 9) and in animal models (10 -12).Current oxygen therapy for preterm neonates in our neonatal unit (Edinburgh, UK) provides a "safe" transcutaneous range of 6 -10 kPa (45-75 mm Hg). This is considered to minimize hyperoxia-associated ROP and to limit neurologic and pulmonary morbidity from associated hypoxia. However, there are few data to indicate whether these limits are appropriate. In "healthy" preterm infants (without lung disease) of 29 -34 wk gestation, Mok et al. (13) demonstrated a mean (range) of 9 kPa (4.7-10.9 kPa) [67.5 (35-82) mm Hg] over the first few months of life. However, no data are available for the gestations at risk for ROP currently (infants Ͻ 29 wk gestation).A recent retrospective case review suggested that babies Ͻ28 wk gestational age nursed in an oxygen saturation range of 70 -90% had a lower incidence of ROP (14) ABSTRACT107 dence of cerebral palsy or adverse pulmonary out...

Does the monitoring method influence stability of oxygenation in preterm infants? A randomised crossover study of saturation versus transcutaneous monitoring

“…Epidemiological studies and case series suggest that high oxygen tensions or saturations and increased variability of oxygenation may be harmful2 22 and that limiting these exposures may be associated with improved outcomes 4 5. The differences in oxygen tension variability observed in this study were large enough to be relevant to the risk of developing retinopathy of prematurity 2 5. Using only saturation monitoring as the basis for administering oxygen might not be the most effective clinical strategy.…”

“…Hyperoxia and variability of oxygenation have been linked with increased risk of morbidity in preterm infants 1 – 5. Oxygen saturation (Sp o 2 ) and transcutaneous oxygen tension (TcP o 2 ) monitors are used to monitor oxygen levels in preterm infants.…”

Oxygen and retinopathy of prematurity

“…Exposure to alternating hypoxia and hyperoxia causes severe proliferative retinopathy in the newborn rat, 18 and also when fluctuations occur at a relatively high level. 19 In animal models, both extreme fluctuations on an hourly basis and smaller but frequent swings as observed in the nursery, produced retinopathy. 20 One study measuring transcutaneous pO 2 showed that severe ROP was associated with greater oxygen tension variability in the first 2 weeks of life.…”

Optimum oxygen therapy in preterm babies

“…16 It was observed in animal studies on rat pups that fluctuations of inspired oxygen around higher fractional inspired oxygen levels (mean 24%) lead to more severe vascular abnormalities than around lower fractional inspired oxygen levels (means of 21% and 17%). 17 Oxygen and the brain The effects of oxygen on the brain may be, to some extent, similar to its effect on the retina, as the retina is a specialised part of the central nervous system and thus may share the same pathophysiological processes; cerebral and retinal damage have been suggested to share a common vasoreactive vascular origin. 18 The effect of exposure to pure oxygen on the brain was described as early as in 1959 by Gyllensten,19 who reported that rearing mice in pure oxygen for 20-30 days had a marked deleterious effect on subsequent cortical vascularisation and cellular differentiation.…”