Exposure to variable hyperoxia has recently been shown to be much more effective at producing proliferative retinopathy in the newborn rat than exposure to constant hyperoxia. To incorporate a more clinically relevant oxygen-exposure paradigm in our studies, we have now used a cycle between 50 and 10% oxygen and have compared its effects with those found using new exposures to the previously used 80140% cycle. Starting at birth and continuing for 14 d, rats were exposed to environments that cycled between 50 and 10% oxygen or 80 and 40% oxygen every 24 h. After exposure, some rats were killed for assessment of retinal vascular development. Others were removed to room air for 4 d before killing and evaluation for the presence of abnormal neovascularization-a clinical consequence believed to be promoted by termination of oxygen therapy. The 50110% cycle resulted in greater retardation of retinal blood vessel development during oxygen than that found in the 80140% exposure group. After 4 d postexposure in room air, the incidence of preretinal neovascularization was 97% in the 50110% rats and 72% in the 80140% group. Clearly, the overall amount of oxygen the subject receives is less critical than other parameters of its administration in producing proliferative retinopathy. Also, the range of variation (40% in both cases) is not the controlling characteristic. Our results suggest that consistency of oxygen level and avoidance of hypoxic levels should be important concerns in neonatal oxygen therapy. ROP is a complex disease involving multiple factors. Oxygen was first recognized as a critical factor in the early 1950s (1-3), but the potential for prolonged hyperoxia alone to cause or exacerbate ROP is still not clearly defined. The disease persists despite the attention now placed on careful monitoring and limited oxygen delivery. Additional doubt about the role of hyperoxia in the pathogenesis of ROP has been raised with the finding that cyanotic premature infants can develop ROP in the absence of oxygen therapy (4). The theory (5) that the developing retina is highly sensitive to any disruption of its oxygen supply, whether hyperoxemic or hypoxemic, warrants consideration. Recent studies in animals (6, 7) have addressed this issue.Exposure to variable hyperoxia has been shown to be a much more effective stimulus of proliferative retinopathy in the newborn rat than exposure to constant hyperoxia (6). This previous study compared the effect of a cyclic variation of oxygen between 80 and 40% with that of a constant 80% exposure. An exposure paradigm that incorporates fluctuations in oxygen level is clearly more representative of the neonatal setting than the constant exposures typical of animal studies. Still, variations in inspired oxygen (FiO,) between 80 and 40% do not accu- rately reflect the therapeutic levels received by prema-

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Rearing neonatal rats in hyperoxia induces the development of retinal hemorrhages and retinal dysplasia. Albino rats were placed in 80% oxygen immediately after birth and were exposed for either 5, 10, or 14 days, followed by sacrifice or exposure to normoxia for an additional 2, 4, 5, 7, 8, 10, 38, 45 or 56 days. Control rats were simultaneously raised in room air and sacrificed at the same times. All animals were enucleated and their eyes processed for light and electron microscopy. Eyecups were trimmed to facilitate cross-sectioning of the retina in the vertical meridian. No control rats showed signs of retinal hemorrhages or of dysplastic folds or rosettes. Nor did the retinas of rats killed immediately after oxygen exposure contain hemorrhages, but the incidence of retinal folds or rosettes in this group was 54%. For rats exposed to combinations of hyperoxia and brief normoxia (10 days or less), 40% suffered hemorrhages and 50% developed retinal folds or rosettes. Although hemorrhages were more prominent in rats subjected to longer periods of oxygen (73% of all rats exposed for 14 days followed by brief normoxia vs. 6% of those exposed for 5 days followed by brief normoxia), the incidence decreased with time post-exposure in room air. Hemorrhages occurred in 100% of the rats raised in oxygen for 14 days followed by 2 days in room air, and decreased to 50% by 7 days in room air and to 0% by 38 days, indicating a spontaneous resolution with time. In each case, the blood appeared to leak from the newly-forming vessels of the deep capillary net, with most of the red blood cells migrating to the subretinal space. Retinal fold or rosette formation, indicative of developmental dysplasia, occurred in a fraction of virtually all groups of exposed rats, and persisted at the longest post-exposure periods. These two manifestations of oxygen-induced retinopathy are emphasized because they lead to an abnormal separation of the retina from the epithelial layer, which may increase the likelihood of the most serious consequence of ROP--retinal detachment. In fact, all rats that endured post-exposure periods of 38 days or longer before sacrifice exhibited retinal detachment.

We have developed a rat model of ROP using an exposure protocol designed to create systemic oxygen levels that approximate those of premature infants. This model does not demonstrate the complete resolution of vessel abnormalities that historically has limited animal models of ROP.

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