The range of PaO2 variation determines the severity of oxygen-induced retinopathy in newborn rats

This study was conducted to determine the potential influence of PaO2 fluctuation on the retinal neovascular response known to occur in newborn rats exposed to hyperoxic conditions. As an inherent corollary, the authors also defined the relationship between the fraction of inspired oxygen (FiO2) and the arterial blood oxygen tension (PaO2) in newborn rats.

Experiment 1 was composed of several oxygen-exposure protocols in which atmospheres of 10% oxygen concentration were alternated with different higher levels of ambient oxygen (50%, 40%, 30%, and room air). In experiment 2, two alternating oxygen concentrations were made to converge toward room air (20.9% oxygen) with each successive group of four treatment groups. These included another group exposed to alternating 50% and 10% oxygen, a group exposed to alternating 45% and 12.5% oxygen concentrations, one exposed to alternating concentrations of 40% and 15% oxygen, and a final group exposed to 35% and room air oxygen concentrations. In each case, oxygen was alternated between the two exposure concentrations every 24 hours. The term delta FiO2 is used to designate the difference in the two oxygen concentrations to which a treatment group was subjected, applying the units of fraction of inspired oxygen (i.e., delta FiO2 = 0.4 for the exposure to alternating 50% and 10% oxygen). At birth, litters of albino rats were placed in each of these environments for 13 or 14 days, after which PaO2 and retinal vascular development were assessed in some rats. The remainder were removed to room air for 4 days before the incidence and severity of abnormal neovascularization were measured.

PaO2 and FiO2 were directly and linearly correlated (r2 = 0.998). In experiment 1, the extent of retinal vascular development on removal from oxygen was a linear function of delta FiO2. Retinal neovascularization subsequently occurred in all rats exposed to alternating 50% and 10% or 40% and 10% oxygen concentrations, but only a third of the 30% and 10% exposure group, indicating a minimum threshold for proliferative disease at delta FiO2 = 0.2. In experiment 2, retinal avascularity also increased linearly with increasing delta FiO2. There was a threshold for neovascularization between the exposure to alternating 45% and 12.5% oxygen and the 40% and 15% oxygen exposure (100% versus 4.8% incidence of neovascularization), indicating a requirement of < or = 12.5% oxygen episodes to stimulate a consistent proliferative response.

These results suggest that PaO2 fluctuation and degree of hypoxia may have more influence on proliferative retinal disease in newborn rats than the extended hyperoxia that has historically received greater attention. Experimental designs that address the inherent differences in pulmonary function between intrinsically healthy animals and compromised premature infants are of substantial value to our understanding of the pathogenesis of retinopathy of prematurity.