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Figure 1
Schematic diagram of intraretinal oxygen measurements. A double-barreled microelectrode is used as described elsewhere by Linsenmeier and Yancey and inserted into the vitreous through a 15-gauge needle mounted onto a manipulator that allows gonioscopic motion. A boot system is installed to maintain intraocular pressure and to prevent vitreal leakage. The microelectrode is then connected to a microdrive that controls movement in and out of the retina. One barrel, filled with isotonic sodium chloride solution and connected to an amplifier via a silver/silver chloride (Ag/AgCl) wire, measures voltages generated in the retina (the intraretinal electroretinogram and the transepithelial potential across the retinal pigment epithelium). The copper wire from the other barrel is connected to a polarizing voltage (−0.7 V) and a picoammeter to measure currents proportional to PO2.

Schematic diagram of intraretinal oxygen measurements. A double-barreled microelectrode is used as described elsewhere by Linsenmeier and Yancey20 and inserted into the vitreous through a 15-gauge needle mounted onto a manipulator that allows gonioscopic motion. A boot system is installed to maintain intraocular pressure and to prevent vitreal leakage. The microelectrode is then connected to a microdrive that controls movement in and out of the retina. One barrel, filled with isotonic sodium chloride solution and connected to an amplifier via a silver/silver chloride (Ag/AgCl) wire, measures voltages generated in the retina (the intraretinal electroretinogram and the transepithelial potential across the retinal pigment epithelium). The copper wire from the other barrel is connected to a polarizing voltage (−0.7 V) and a picoammeter to measure currents proportional to PO2.

Figure 2
Intraretinal oxygen profiles across cat retina during light and dark adaptations. The retina is shown schematically at the top. The 4 cell types shown are (from left to right) retinal pigment epithelial cells, rod photoreceptors, bipolar cells, and ganglion cells.

Intraretinal oxygen profiles across cat retina during light and dark adaptations. The retina is shown schematically at the top. The 4 cell types shown are (from left to right) retinal pigment epithelial cells, rod photoreceptors, bipolar cells, and ganglion cells.

Figure 3
Frequency histogram of the distribution of inner retinal PO2 in dark adaptation. The mean ± SD are 18.42 ± 12.52. Reproduced from The Journal of General Physiology (1992;99:177-197), by copyright permission from The Rockefeller University Press.

Frequency histogram of the distribution of inner retinal PO2 in dark adaptation. The mean ± SD are 18.42 ± 12.52. Reproduced from The Journal of General Physiology (1992;99:177-197), by copyright permission from The Rockefeller University Press.45

Figure 4
Intraretinal oxygen profiles recorded in dark during normoxia and hypoxemia. Reproduced from The Journal of General Physiology (1992;99:177-197), by copyright permission from The Rockefeller University Press.

Intraretinal oxygen profiles recorded in dark during normoxia and hypoxemia. Reproduced from The Journal of General Physiology (1992;99:177-197), by copyright permission from The Rockefeller University Press.45

Figure 5
Intraretinal oxygen profiles in dark during normoxia and hyperoxia.

Intraretinal oxygen profiles in dark during normoxia and hyperoxia.

Oxygen Consumption Rate Measured From Animals With Vascular Retinas, During Dark and Light Adaptation in Outer and Inner Retina*
Oxygen Consumption Rate Measured From Animals With Vascular Retinas, During Dark and Light Adaptation in Outer and Inner Retina*56,26,63,57,35
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Mechanisms of Ophthalmologic Disease
April 2003

Retinal OxygenFundamental and Clinical Aspects

Author Affiliations

From the Departments of Biomedical Engineering (Drs Wangsa-Wirawan and Linsenmeier) and Neurobiology and Physiology (Dr Linsenmeier) and the Institute for Neuroscience (Dr Linsenmeier), Northwestern University, Evanston, Ill. The authors have no relevant financial interest in this article..

 

LEONARD A.LEVINMD, PhD

Arch Ophthalmol. 2003;121(4):547-557. doi:10.1001/archopht.121.4.547
Abstract

We reviewed research on retinal oxygen (O2) distribution and use, focusing on O2 microelectrode studies in animals with circulatory patterns similar to those of humans. The inner and outer halves of the retina are different domains in terms of O2. Understanding their properties can suggest mechanisms of and therapies for retinal diseases. Inner retinal PO2 averages about 20 mmHg. Effective O2 autoregulation of the retinal circulation ensures that inner retinal PO2 is relatively uninfluenced by systemic hypoxia and hyperoxia and increased intraocular pressure in healthy animals. Failures of the retinal circulation lead to tissue hypoxia that underlies the vasoproliferation in diabetic retinopathy and retinopathy of prematurity. Choroidal blood flow is not regulated metabolically, so systemic hypoxia and elevated intraocular pressure lead to decreases in choroidal PO2 and photoreceptor O2 consumption. The same lack of regulation allows choroidal PO2 to increase dramatically during hyperoxia, offering the potential for O2 to be used therapeutically in retinal vascular occlusive diseases and retinal detachment.

Oxygen (O2) is essential for retinal function. As in other tissues, O2 diffuses through the tissue passively from the circulation and is consumed in the oxidative production of adenosine triphosphate. However, several features make retinal oxygenation unique, and these have an impact on the pathogenesis and treatment of retinal diseases. Among the unique features influencing retinal oxygenation are the presence of a dual circulation, lack of metabolic regulation of the choroid, presence of O2 regulation of the retinal circulation, and localization of mitochondria to photoreceptor inner segments. In most cases, it is useful to think of the retina as the following 2 domains: the avascular outer retina and the vascularized inner retina. The retina is also one of the most metabolically active tissues, consuming O2 more rapidly than many other tissues, 1 including the brain.2,3

Because the demand for O2 is high, and because it cannot be stored in the retina or other tissues, a continuous O2 supply is essential.4 This review focuses on vascularized retinas (eg, of the rat, cat, pig, monkey, and human) in which O2 is delivered by the retinal and choroidal circulations. In some species, retinal vasculature is nearly or completely absent (eg, the rabbit and guinea pig). These retinas rely on the choroid almost exclusively and the inner retina is strongly glycolytic.57 A review focusing on avascular and partially vascularized retina has been presented elsewhere.8

Retinal O2 tension (PO2) and other variables that provide an index of PO2 have been measured in several ways, which have recently been presented by Hogeboom van Buggenum et al.9 Hemoglobin saturation in retinal vessels has been measured by several groups.1012 Intravascular PO2 has been measured with a phosphorescent dye, for which decay is inversely proportional to the PO2.13 Berkowitz and coworkers14,15 have pioneered the development of magnetic resonance imaging techniques that measure absolute PO2 in the preretinal vitreous of animals and humans using the fluorine signal from perfluorocarbon droplets. They have also measured relative PO2 by using the dependence of the hydrogen signal on O2.16 However, only oxygen microelectrodes1720 have been able to map out O2 gradients within the retina with high spatial and temporal resolution. We will focus on these measurements in the first part of this review. In some of this work, a second barrel of the electrode has been used to record the local electroretinogram (ERG) and the transepithelial potential across the retinal pigment epithelium, which allows verification of the position of the intraretinal electrode.21,22 The invasive nature of the microelectrode is the major disadvantage of this technique, because the electrode may damage the tissue during measurement. Hence, this technique has limited clinical application. To date, microelectrodes have only been used in humans to measure O2 in the vitreous during intraocular surgery.23,24 Some authors have argued that O2 consumption by the microelectrode itself is another disadvantage.12 However, small recessed cathode microelectrodes17,20 do not significantly disturb the local O2 environment.25 Microelectrode O2 consumption (QO2) is about the same as that of a single small cell. An electrode producing a current of 2 pA, which is typical in our work, uses 5.2 × 10− 16 mol of O2 per second. This is the same as the O2 use of a 6.2-µm cube of tissue in a region with a modest QO2 of 3 mL O2 per 100 g of tissue per minute.

Oxygen recordings of the type presented herein are obtained as shown in Figure 1. The microelectrode is advanced with a microdrive through the retina in discrete (eg, 3-µm) steps until it reaches the choroid. The electrode is then withdrawn continuously, usually at a constant speed of 2 µm/s in our work. The map of PO2 across the retina, an O2 profile, can be recorded during microelectrode penetration or withdrawal, and these give similar results. Data obtained during withdrawals are preferable because one can be sure that the tissue and vasculature are not being compressed, and because a larger number of data points can be recorded than during penetration. In other experiments, the microelectrode has been left stationary at a point in the retina or vitreous to study responses to light, 22,26 effects of altered inspired gases, 2730 and spontaneous fluctuations in retinal PO2.31

THE NORMAL O2 PROFILE IN LIGHT AND DARK
Outer Retina

In vivo O2 profiles have been recorded from pigs, 21,32 cats, 22,33 rats, 34 and monkeys.35 These studies have shown similar O2 profiles everywhere except in the monkey fovea. Under light-adapted conditions (ie, enough light to saturate rod responses), the PO2 falls steeply between the choriocapillaris(approximately 60 mmHg) and the photoreceptor inner segments and subsequently decreases more gradually through the outer retina, as shown in Figure 2. The direction of this gradient indicates that all of the O2 used by the photoreceptors comes from the choroid under light-adapted conditions. In darkness, the PO2 in the outer retina is considerably lower, 22,35 reaching 0 mmHg at the proximal side of the inner segments. Sometimes much of the outer nuclear layer in the cat has a PO2 of 0 mmHg (Figure 2). This low value leads to a reversal of the gradient of O2 proximal to the inner segment, so that in darkness, O2 also diffuses from the retinal circulation to the photoreceptors.

The steep drop of PO2 from the choroid reflects the high rate of O2 use by the photoreceptors.36,37 The high choroidal PO2 is maintained by the unusually high flow rate in the choroidal circulation, 3840 which is necessary for providing enough O2 to the retina.41

Inner Retina

One or more O2 peaks appear in the inner retina (Figure 2). These indicate O2 sources and, therefore, the presence of nearby retinal vessels. The preretinal PO2 in the vitreous is normally a good indicator of inner retinal PO2, 42,43 because the vitreous consumes very little O2, 44 and the inner retina is the source of vitreal O2.43,44 The average PO2 in the inner retina of the cat during dark adaptation was 18.5 mmHg, 45 which is in good agreement with the preretinal PO2 in cats of 18.9, 28 20 to 30, 44 15 to 20, 42 20.2, 33 and 19 mmHg.46 The similarity of retinal and vitreal PO2 may break down under some conditions, however, including diabetes mellitus.47

The values of inner retinal PO2 cover a relatively wide range(Figure 3). The average PO2 is a few millimeters of mercury lower in light adaptation.22,45 The O2 extraction from the retinal circulation is high relative to that in many tissues, about 8 mL O2 per 100 mL blood, 10 resulting in a low venous PO2 that contributes to making the average tissue PO2 in the retina lower than in many organs.48

OXYGEN METABOLISM

Oxygen consumption can be derived from material balances in vivo from blood arteriovenous differences49,50 or in vitro from reductions in PO2 in a closed chamber.3,51,52 Oxygen consumption can also be obtained by fitting mathematical models of O2 diffusion and consumption to PO2 profiles.22,26,53 The use of material balances does not provide information on the spatial distribution of consumption, but was the first method to show that QO2 was higher during dark than light adaptation in the whole retina.52,54 Further aspects of retinal energy metabolism, particularly the unusual amount of glycolytic metabolism, have been reviewed recently.3,55

Outer Retina

Absolute values of photoreceptor QO2 were computed by fitting a mathematical model of O2 diffusion in the outer retina to the O2 profiles.53 In the most satisfactory model, all the O2 use is confined to the inner segment layer. It is important to realize that even though QO2 is negligible in the outer segment and outer nuclear layers, linear gradients of O2 still remain throughout these regions (Figure 2, Figure 4, and Figure 5). The evidence of a nonzero QO2 is not the presence of a gradient but curvature in the profile, specifically a quadratic dependence of PO2 on distance.53

Table 1 shows that QO2 of the photoreceptors during steady illumination is 36% to 68% of the value in the dark. This agrees with the effect of light found by other methods in the rat, rabbit, and pig.6,56,58 Above rod saturation, which is below-normal room illumination, no further changes in QO2 are observed in the rod-dominated area centralis of the cat retina.22 Modeling also shows that the choroid is essential to photoreceptor metabolism, contributing approximately 90% of the O2 consumed by the photoreceptors in darkness, and all of the O2 consumed during light adaptation.45 Finally, the choroid contributes approximately 50% of the O2 consumed by the whole retina in dark adaptation, 26,56 which is consistent with earlier estimates based on choroidal arteriovenous O2 differences and blood flow.39

Table 1 gives values for QO2 as though the consumption were uniform across the whole outer retina. We have preferred to report the values this way, because it reduces the scatter in the measurements53 and makes values from modeling more comparable to those obtained by other methods. These values are somewhat misleading, however, since the QO2 is localized to the inner segments. The rod inner segments have an extremely high QO2 of 15 to 20 mL O2 (standard temperature and pressure) per 100 g of tissue per minute in the dark, consistent with the high density of mitochondria in this region.

Little is known about cone QO2. Light does decrease the QO2 of monkey fovea.35 Cones in the monkey have a volume of mitochondria that is about 10 times that of rods, 59 but we have argued that QO2 of an individual cone could not be higher than that of a rod by a factor of 10, because the smaller number of mitochondria in rods already uses all the O2 available from the circulation.

Oxygen is used in photoreceptors for many processes, but the ones that appear to require the most energy are maintenance of the dark current, ie, pumping out the large load of sodium ion that enters through the light-dependent channels54,60,61 and generating guanosine triphosphate, from which cyclic guanosine monophosphate is produced.3,61 The dark current decreases dramatically during illumination, whereas the guanosine triphosphate turnover increases. These appear to be the only processes whose metabolic demands change significantly with illumination.61 The change in sodium ion pumping is larger, however, and, as a result, illumination causes a net decrease in photoreceptor QO2 in all species investigated to date.

Inner Retina

In the inner retina, the retinal circulation forms a 3-dimensional mesh, which makes mathematical modeling difficult. The retinal circulation must be occluded to allow the application of a diffusion model to the inner retina.26,62 Despite this limitation, various lines of evidence indicate that in the inner retina, no difference in QO2 exists between darkness and steady illumination26,56,63 (Table 1). The metabolism of the inner retina is higher when flickered light (4 Hz) is applied as opposed to steady light, 63 presumably because flickered light leads to greater neural activation. Unfortunately, this increase is difficult to quantify.

RETINAL OXYGENATION UNDER ALTERED CONDITIONS
Hypoxemia

Figure 3 shows intraretinal O2 profiles from the dark-adapted cat retina during normoxia and hypoxemia, induced by adding nitrogen to the inspired gas. In the inner retina, tissue PO2 is effectively regulated across a wide range of Pa O2. The decrease in preretinal PO2 is only 0.14 to 0.18 mm Hg/mm Hg PaO2 when the PaO2 is above 35 mmHg28,64 in the cat, and 0.2 mm Hg/mm Hg PaO2 in the miniature pig.65 When the PaO2 falls below 35 mmHg, PO2 in the inner retina decreases more steeply, approximately 0.62 mm Hg/mm Hg PaO2.64 The good regulation at PaO2 of greater than 35 mmHg results from vasodilation of the retinal circulation, 66,67 which in cats can increase blood flow by more than a factor of 3 during hypoxemia.68

In the outer retina, hypoxemia leads to a steep decrease in choroidal PO2 (Figure 4) of approximately 0.64 mm Hg/mm Hg PaO2.45 This occurs because the choroidal blood flow does not increase in hypoxemia69 (Melissa Pulfer, Jameel Ahmed, PhD, and R.A.L., unpublished data, June 2000). There would be little advantage of increasing choroidal blood flow, even if this were possible. The usual advantage of increasing blood flow to a tissue during hypoxemia is allowing the arteriovenous O2 difference to be reduced, which minimizes or prevents a decrease in venous PO2 during hypoxemia. In the choroid, the arteriovenous O2 difference is already very small, only about 1 volume percent, 28 due to the high rate of blood flow. In relatively mild hypoxemia, arterial PO2 drops below the normoxic choroidal venous PO2. Reducing the arteriovenous difference could not prevent this. Because photoreceptor metabolism is O2 limited under normoxic conditions in darkness, even mild hypoxemia (PaO2 of 60 mmHg) reduces the flux of O2 to the inner segments and, therefore, reduces photoreceptor QO2.45 When hypoxemia occurs during light adaptation, choroidal PO2 also falls, but in this case, metabolism is not O2 limited, so photoreceptor QO2 is not affected.

Elevated Intraocular Pressure

When the intraocular pressure (IOP) is elevated, the effects on retinal PO2 are similar to those observed during hypoxemia.70,71 Decreased perfusion pressure does not affect PO2 in the inner retina owing to effective autoregulation in the retinal circulation.39,72,73 In contrast, when the IOP is elevated, the choroidal blood flow decreases, 72,7476 which leads to a reduction of choroidal PO2 of approximately 0.5 mm Hg/mm Hg of perfusion pressure.70 This reduction leads to a reduction in photoreceptor QO2.70 An extension of this finding is that anything that decreases choroidal blood flow would be expected to have a negative impact on retinal oxygenation and on photoreceptors. There is evidence that human and experimental glaucomas affect photoreceptors, 77 possibly because they reduce photoreceptor O2 supply, and there is direct evidence of retinal damage by reduced choroidal blood flow in birds.78

Hyperoxia

Figure 5 compares a normoxic profile to one obtained during hyperoxia (inspiration of 100% O2).Vitreal PO228 and inner retinal PO229,30,32,57,79 are well regulated during hyperoxia in the cat, pig, and rat and presumably in humans. This regulation is due to constriction of retinal vessels10,66,80 and reduction of retinal blood flow.10,66,81 In the miniature pig, PO2 in the inner retina has been reported to be perfectly regulated during hyperoxia in intervascular zones, 29,32 but it increases by an average of approximately 40 mmHg in juxta-arteriolar zones, the same value observed in cats.30,57 Adding 5% carbon dioxide to the inspired gas leads to larger increases in inner retinal PO2 during hyperoxia.16 The most striking change during hyperoxia is the increase in choroidal PO2 to about 250 mmHg in cats30 and 220 mmHg in miniature pigs.32 This increase is a consequence of the lack of metabolic regulation of choroidal blood flow.82

It is sometimes thought that hyperoxic therapy has a limited potential for treating retinal disease. This is based on the idea that the blood is nearly saturated with O2 during normoxia, so that the small additional O2 content during hyperoxia should be of little benefit. The fundamental misconception is that the O2 supply to the tissue relies on O2 saturation, whereas, in reality, O2 moves into tissue by simple diffusion, which is driven by gradients of PO2, not saturation. The PO2 gradient from the choroid is much steeper during hyperoxia, and a greater portion of the retina can be supplied by the choroid during hyperoxia than during normoxia, 30,32 as shown in Figure 5.

Despite an abundance of O2, higher photoreceptor QO2 was not found in cat retina during hyperoxia.30,57 Pournaras and coworkers32,83 argued that QO2 increased during hyperoxia in healthy retinas of the miniature pig, but not in retinas with a branch vein occlusion. Their conclusions were not based on calculations of QO2, however, but only on the steepness of gradients, which cannot be used to infer values for QO2. The gradient through the outer segments is steeper during hyperoxia, so the flux across them is larger, but they never use any O2.

For a few hours, at least, hyperoxia does not impair retinal electrical function in animals, 57 but the issue of O2 toxicity to the retina has not been fully addressed. It is clear that O2 can be damaging to photoreceptors if combined with high levels of illumination.84,85

CLINICAL ISSUES
Diabetic Retinopathy

Diabetic retinopathy is a disease predominantly of the retinal vasculature, leading first to capillary occlusion and then to vascular proliferation. For many years, tissue hypoxia has been suggested to be involved in the progression of diabetic retinopathy86 and retinal neovascularization in general.87 By the time that capillary nonperfusion is clinically observable, tissue hypoxia has likely occurred, but the exact time when hypoxia begins is as yet unknown. Retinal tissue hypoxia was not found in the early stage of diabetic retinopathy in animal models.46,88,89 However, intraretinal O2 measurements on cats with long-term (6-7 years) diabetes mellitus showed an abnormally low average inner retinal PO2 of 7.7 mmHg(compared with 16.4 mmHg in normal cats).47 This report, the only one to provide intraretinal measurements, stressed that tissue hypoxia was present in the diabetic retina before capillary dropout was evident and when only a few microaneurysms were present. Further evidence of hypoxia relatively early in the disease was provided by the observation that hyperoxia reversed early contrast sensitivity deficits90 and oscillatory potential reductions.91 In addition, Arden et al92 provided evidence of altered dark adaptation in diabetes mellitus, which was also suggested to be an effect of hypoxia.

Hypoxia may occur during diabetic retinopathy due to capillary occlusion. Leukocytes have been reported to be present in greater number and are less deformable in diabetic cats.93 Increased levels of endothelial cell/leukocyte adhesion molecules (intercellular adhesion molecule 1 and P-selectin) have also been observed in humans with diabetes mellitus(hereafter referred to as diabetic humans).94 These findings may explain the increase of leukocyte activation and adhesion in diabetic humans95 and rats, 96 which are known to increase vascular resistance97,98 as capillaries become plugged. In addition, a hyperglycemic (hyperosmotic) environment increases the adhesion of leukocytes to retinal endothelial cells.99

The findings of tissue hypoxia and occlusion of retinal capillaries by leukocytes are consistent with observations that retinal blood flow is reduced before and in the early stages of diabetic retinopathy.100103 A subsequent increase in retinal blood flow occurs, 102,103 possibly because lower-resistance shunt pathways develop and carry some of the flow102 and/or because vascular endothelial growth factor(VEGF) dilates vessels.103 The flow is reduced again in proliferative retinopathy.104,105 Complete consensus on this sequence of events has not been achieved, but they seem to explain most of the observations.

One of the puzzles about diabetic retinopathy has always been why it affects the microvasculature of the retina more than that of the brain.106 Arden et al92 suggested that dark adaptation aggravates hypoxia by depriving the inner retina of the small amount of O2 that diffuses from the choroid during light adaptation. They suggested further that avoiding a long period of dark adaptation(eg, during sleeping at night) could be an alternative therapy for diabetic retinopathy.

Hypoxia is thought to induce the synthesis of VEGF, 107,108 which is present in higher levels during proliferative diabetic retinopathy.109,110 Vascular endothelial growth factor has also been found in eyes with no retinopathy or only early signs of retinopathy.111113 This initially suggested that factors besides hypoxia may induce the production of VEGF, 112 but we now know that the retina is hypoxic early in the disease.47 Although VEGF is important, other angiogenic114118 and antiangiogenic119,120 factors may also be involved. A detailed discussion on factors involved in intraocular neovascularization is available elsewhere.121 A competing theory of vasoproliferation implicated the mechanical aspect of vasodilation resulting from hypoxia or hyperglycemia.122 This theory has received little attention recently, but it seems prudent to recognize that mechanical factors could play a role in angiogenesis.

The QO2 of the retina in diabetes mellitus has been a subject of controversy. In the intact cat retina, photoreceptor QO2 was lower on average in subjects with diabetes than in healthy subjects, 47 but QO2 has a strong positive correlation with choroidal PO2, and the choroidal PO2 values tended to be lower in diabetic cats. Whether lower choroidal PO2 is a general feature in diabetes could not be determined with the number of animals available in that study. In vitro studies in rabbits suggested that the QO2 decreased in diabetes.123,124 In contrast, one study reported that QO2 in diabetic rats125 was greater. Little work has been done on the QO2 of the inner retina. Tiedeman et al12 found that retinal venous O2 saturation was lower than normal in diabetic humans, and concluded on that basis that QO2 of the inner retina must be greater in subjects with diabetes. If blood flow increased or was unchanged, this would be a reasonable conclusion, but blood flow was not measured in that study. Increased QO2 is difficult to reconcile with capillary dropout and inner retinal damage.

On the theory that one of the major problems in diabetic retinopathy is lack of O2 in the inner retina, therapies have been designed to improve the O2 supply. Panretinal photocoagulation is effective in treating proliferative retinopathy.126130 Studies on animal models46,131134 and in humans24 showed that PO2 in the preretinal vitreous is higher over photocoagulated regions than over normal regions. These measurements provided little detail about O2 gradients in the retina, and were obtained mainly during hyperoxia, which is not the condition in which diabetic retinopathy develops or progresses. Nevertheless, they provide some evidence that photocoagulation reduces the QO2 of the photoreceptors, allowing more O2 to diffuse from the choroid to the inner retina.135,136

At present, no treatment stops retinopathy apart from panretinal photocoagulation, but it seems reasonable that if early retinal circulatory changes preceding VEGF up-regulation could be detected clinically, then interfering with leukocyte adhesion or using other pharmacological techniques to increase retinal blood flow might be effective in preventing retinopathy.

Retinopathy of Prematurity

Retinopathy of prematurity (ROP), previously known as retrolental fibroplasia, 137 develops in 3 distinct stages.138 First, the retina of premature infants is exposed to excess O2 as a result of breathing O2-enriched gas, which causes constriction and irreversible closure of retinal vessels and prevents new vessels from developing normally.139,140 As a result, hypoxia is thought to develop in the inner retina when the infant is returned to breathing air, and the extra supply of O2 from the choroid is lost. Finally, this hypoxic condition induces vascularization to counteract the hypoxia, but for some reason this vascularization is abnormal.140142

The current therapy for prevention of the disease is generally to titrate the infant's blood to an adequate PaO2 but to prevent systemic hyperoxia. Moderate supplemental O2 with a target arterial saturation of 99% and a PaO2 of less than 100 mmHg was found to decrease prethreshold ROP.143145 Vitamin E supplementation may also be useful in decreasing the severity of ROP, 146148 possibly by minimizing auto-oxidative reactions that arrest the growth of normal blood vessels.148 Other therapies, such as gradual reduction in O2 level (oxygen weaning) appear less promising.149151

Mechanistically, the disease is not as straightforward as the above discussion would suggest. As in diabetic retinopathy, it has been impossible to determine exactly what the oxygenation status of the human retina is at any time during the disease progression, and difficult even in the animal models. Ernest and Goldstick152 used O2 microelectrodes in the vitreous humor of kittens after O2 supplementation(80%-90% O2) and found that preretinal PO2 over the avascular retina was close to 0 mmHg, but normal over the vascular retina. These remain the only direct measurements of PO2 in an ROP model. More recently, attention has shifted to a rodent model of ROP called ischemia-induced or O2-induced retinopathy.153,154 Retinopathy is produced most effectively by a regimen that cycles the inspired gas between a relatively hyperoxic one and a relatively hypoxic or normoxic one for at least several days during retinal vascular maturation.154 Surprisingly, well-controlled hyperoxia followed by normoxia produces ROP-like symptoms with less certainty than does O2 cycling. In O2-induced retinopathy, some evidence from novel magnetic resonance imaging measurements suggests that hypoxia plays a role early in the disease.155 Berkowitz and Penn155 based this conclusion on a blunted response of retinal oxygenation to breathing of carbogen (a mixture of 95% O2 and 5% carbon dioxide) in animals in which histological signs of the disease developed, rather than a direct demonstration of tissue hypoxia.

As in diabetic retinopathy, it is thought that hypoxia does not directly affect vessel growth, but instead influences the production of angiogenic factors in the retina, 138 with the probable involvement of hypoxia-inducible factor 1 as an intermediate.156

Vascular Occlusive Diseases

Work on complete ocular ischemia, produced in general with elevation of IOP, and work on the effects of anoxia on the retina in vitro have a long history. Although they are relevant to ocular ischemic syndrome, in which the retinal and choroidal circulations are compromised by carotid artery obstruction, 157 they will not be reviewed herein. Of more interest from a clinical standpoint is the role of O2 in central and branch venous and arterial occlusions of the retinal circulation. Experimental venous occlusion in pigs leads to decreased inner retinal PO2, which can be followed by neovascularization.158 Work on cats shows that retinal arterial occlusion makes the entire inner retina anoxic, 57,61 and this causes a rapid failure of the ERG b wave in cats and monkeys.57,159,160 Even when the animal breathes air, the retina is reasonably tolerant to occlusion, surviving episodes of 100 to 120 minutes with full recovery of the ERG159,160 after the occlusion is reversed. Several studies have shown that retinal oxygenation can be partially or completely restored during the arterial occlusion by making animals hyperoxic.57,61,161,162 It is clear from O2 profiles that this effect relies on an increased O2 supply from the choroid during hyperoxia. Corroborating the importance of O2 as the limiting factor during occlusion are a few studies that have used a model of total ischemia. Anderson and Saltzman2 have shown that if human subjects breathed O2 before IOP elevation, their vision was sustained longer than if they breathed air. Blair and coworkers163 have shown that perfusing the vitreous with an oxygenated solution after total occlusion can maintain the structural integrity of the retina and the ERG. Despite this positive experimental data, the clinical experience with hyperoxia has been mixed, with only a few studies recommending hyperoxia as a treatment for vascular occlusion.164,165 Unfortunately, most clinical attempts to provide hyperoxia during occlusion have not adequately considered that it must be provided for large blocks of time and as soon as possible because O2 is not stored and is used so rapidly. In addition, there have been two fears of using hyperoxic therapy. First, hyperoxia constricts retinal vessels, and this might impede the clearance of emboli. This may be an unnecessary concern, because the inner retina is acidic during occlusion(Gulnur Birol, PhD, N.D.W.-W., Ewa Budzynski, MS, and R.A.L., unpublished data, October 2002), which would tend to counteract hyperoxic vasoconstriction. In addition, carbon dioxide can be added to the inspired gas to induce vasodilation.164,165 Second, extended O2 breathing can be toxic, but this should not prevent hyperoxic therapy, because it is possible to breathe 60% to 70% O2 for hours without toxic effects.166

Other Diseases

Oxygen undoubtedly plays a role in other diseases. Several studies report that cystoid macular edema can be ameliorated by hyperbaric O2 therapy.167170 No clear theoretical reason for this exists. Depending on the mechanism of this effect, hyperoxia at normal atmospheric pressure may do just as well. This has not been tested, but should be, because it would allow application of the therapy to more patients.

Oxygen is likely to play a role in the dramatic vasoattenuation of the retinal circulation that is associated with photoreceptor degenerations in humans and animals.171 This role can be understood on the basis of the normal gradients. When photoreceptors are lost, O2 derived from the choroid that was once used by photoreceptors now diffuses all the way to the inner retina.172,173 In addition to the reduced size of the major vessels, capillaries in the inner retina are permanently lost174 in animals with photoreceptor degeneration. This capillary loss can be prevented by maintaining the animals under hypoxic conditions, which probably reduce the flux of O2 from the choroid to the inner retina. Evidence also exists that O2 can modulate the survival of photoreceptors early in the Royal College of Surgeons rat model of retinal degeneration. Hyperoxia is protective at early stages, whereas hypoxia induces death of photoreceptors.175 Up-regulation of basic fibroblast growth factor by hypoxia is not sufficient to prevent photoreceptor death, 176 and later stages of the photoreceptor loss may not be caused by hypoxia.

Although a focus on mechanical causes of ganglion cell loss in glaucoma continues, many lines of evidence indicate that reduced ocular blood flow, and by implication reduced O2, is a contributing factor in the retinal damage in glaucoma.177,178 This is a complex area in which most of the evidence is indirect, but support for a vascular hypothesis continues to accumulate. First, hyperbaric O2, which does not change IOP, can improve visual fields in glaucomatous subjects.179 Second, photocoagulation, which destroys photoreceptors and presumably increases the inner retinal O2 supply from the choroid, promotes survival of ganglion cells in glaucomatous monkeys.180 Third, cones, which should not be affected directly by mechanical stresses at the optic nerve, are swollen in eyes of humans with glaucoma and in primates with experimental glaucoma.181 Finally, systemic vascular variables, which have been known to be risk factors for glaucoma, help predict the degree of visual dysfunction in glaucoma.182

Oxygen may also play a role in vision loss in retinal detachment. A recent argument has been made on a theoretical basis that hyperoxia may be useful in preventing photoreceptor damage.41 Detachment separates the inner segments from their O2 supply, and although no consuming tissue is found under the retina, the increased distance reduces the flux of O2 from the choroid to the photoreceptor inner segments. Hyperoxia should restore this flux, at least for detachments of moderate height, because increased choroidal PO2 can compensate for the increased distance. For large detachments, the photoreceptors may benefit more from increased amounts of O2 in the retinal circulation than in the choroidal circulation. The protective effect of hyperoxia on detached photoreceptors has been shown experimentally in cats, in which hyperoxia was able to save photoreceptors and prevent the activation of retinal glia normally caused by detachment.183,184

CONCLUSIONS

Most of the important features of normal retinal oxygenation are now known, and the status of retinal oxygenation in some prevalent diseases has been partially elucidated. Tissue hypoxia is believed to be important in regulating vascular growth factors, particularly in the vasoproliferation observed in diabetes mellitus and ROP. Hypoxia is also involved in the loss of photoreceptors during a retinal detachment and the loss of inner retinal neurons in retinal arterial occlusions. Evidence is emerging that hypoxia may damage photoreceptors and possibly other cells in glaucoma, and that O2 modulates the survival of photoreceptors in photoreceptor degenerations. One of the most interesting aspects of retinal oxygenation is the important metabolic role of the choroidal circulation. Lack of regulation of the choroid by O2 may be detrimental to the photoreceptors under conditions when choroidal PO2 or choroidal blood flow decrease (eg, glaucoma), but this same lack of regulation provides an opportunity to use the choroid therapeutically in treating cystoid macular edema, retinal arterial occlusions, and retinal detachment. Oxygen therapy only has a chance of working if it is sustained, however, and this has generally not been the mode in which it has been used.

The difficulty of measuring O2 intraretinally in humans or in animal models of human diseases has prevented a more complete understanding of the role of O2 in retinal diseases. Measuring retinal O2 would be far better than measuring blood flow, because tissue PO2 is the variable that is directly relevant to metabolism and presumably to visual function. Noninvasive measurements have been difficult, because of the spatial heterogeneity of PO2 in the retina and the difficulty of accessing the choroid, but these techniques are important and need to be developed. Development of noninvasive optical techniques would allow one to study the timing of hypoxia with respect to biochemical and histological changes, and would serve as a way to follow disease progression and evaluate treatments.

Corresponding author and reprints: Robert A. Linsenmeier, PhD, Department of Biomedical Engineering, Northwestern University, 2145 Sheridan Rd, Evanston, IL 60208-3107 (e-mail: r-linsenmeier@northwestern.edu).

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Article Information

Submitted for publication January 4, 2002; final revision received November 15, 2002; accepted December 6, 2002.

This study was supported by grant EY05034 from the National Institutes of Health, Bethesda, Md.

We thank Lissa Padnick-Silver, PhD, for useful feedback.

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