Sveinn Hakon Hardarson

Regulation of retinal blood flow in health and disease

Optimal retinal neuronal cell function requires an appropriate, tightly regulated environment, provided by cellular barriers, which separate functional compartments, maintain their homeostasis, and control metabolic substrate transport. Correctly regulated hemodynamics and delivery of oxygen and metabolic substrates, as well as intact blood-retinal barriers are necessary requirements for the maintenance of retinal structure and function. Retinal blood flow is autoregulated by the interaction of myogenic and metabolic mechanisms through the release of vasoactive substances by the vascular endothelium and retinal tissue surrounding the arteriolar wall. Autoregulation is achieved by adaptation of the vascular tone of the resistance vessels (arterioles, capillaries) to changes in the perfusion pressure or metabolic needs of the tissue. This adaptation occurs through the interaction of multiple mechanisms affecting the arteriolar smooth muscle cells and capillary pericytes. Mechanical stretch and increases in arteriolar transmural pressure induce the endothelial cells to release contracting factors affecting the tone of arteriolar smooth muscle cells and pericytes. Close interaction between nitric oxide (NO), lactate, arachidonic acid metabolites, released by the neuronal and glial cells during neural activity and energy-generating reactions of the retina strive to optimize blood flow according to the metabolic needs of the tissue. NO, which plays a central role in neurovascular coupling, may exert its effect, by modulating glial cell function involved in such vasomotor responses. During the evolution of ischemic microangiopathies, impairment of structure and function of the retinal neural tissue and endothelium affect the interaction of these metabolic pathways, leading to a disturbed blood flow regulation. The resulting ischemia, tissue hypoxia and alterations in the blood barrier trigger the formation of macular edema and neovascularization. Hypoxia-related VEGF expression correlates with the formation of neovessels. The relief from hypoxia results in arteriolar constriction, decreases the hydrostatic pressure in the capillaries and venules, and relieves endothelial stretching. The reestablished oxygenation of the inner retina downregulates VEGF expression and thus inhibits neovascularization and macular edema. Correct control of the multiple pathways, such as retinal blood flow, tissue oxygenation and metabolic substrate support, aiming at restoring retinal cell metabolic interactions, may be effective in preventing damage occurring during the evolution of ischemic microangiopathies.

Retinal oxygen saturation is altered in diabetic retinopathy

Aim Retinal oxygen metabolism is thought to be affected in diabetic retinopathy. The aim of this study was to test whether retinal vessel oxygen saturation is different in patients with diabetic retinopathy from that in healthy controls. Methods The retinal oximeter is based on a fundus camera. It estimates retinal vessel oxygen saturation from light absorbance at 586 nm and 605 nm. Retinal vessel oxygen saturation was measured in one major temporal retinal arteriole and venule in healthy volunteers and in patients with diabetic retinopathy. Results Oxygen saturation in the retinal arterioles of healthy volunteers was 93±4% and 58±6% in venules (mean±SD, n=31). The corresponding values for all diabetic patients (n=20) were 101±5% and 68±7%. The difference between healthy volunteers and diabetic patients was statistically significant (p<0.001 for arterioles and venules). Three subgroups of diabetic patients (background retinopathy, macular oedema and pre-proliferative/proliferative retinopathy) all had higher saturation values than the healthy volunteers (p<0.05 for arterioles and venules). Conclusion Retinal vessel oxygen saturation is higher in patients with diabetic retinopathy than in healthy controls. Possible explanations include shunting of blood through preferential channels, bypassing non-perfused capillaries in the capillary network. Parts of the retinal tissue may be hypoxic while blood in larger vessels has high oxygen saturation.

Retinal vessel oxygen saturation in healthy individuals.

PURPOSE We measured oxygen saturation in retinal vessels of healthy eyes to determine the effects of age, sex, and cardiovascular parameters, as well as the reliability of the measurements and topographic differences. METHODS The Oxymap T1 retinal oximeter is based on a fundus camera. It simultaneously captures retinal images at two different wavelengths and estimates retinal vessel oxygen saturation. Mean saturation of main retinal arterioles and venules was measured in 120 healthy individuals aged 18-80 years (median 47 years). Of the 120 participants 44 (37%) were male (49 years) and 76 (63%) female (44 years). RESULTS Oxygen saturation was 92.2 ± 3.7% (mean ± SD) in retinal arterioles and 55.6 ± 6.3% in venules. No significant difference in oxygen saturation was found between left and right eyes. The inferotemporal quadrant had lower oxygen saturation in arterioles and venules (P < 0.0001). Arteriolar oxygen saturation was stable with age. Venular oxygen saturation in males decreased by 1.9 ± 0.6% (mean ± SEM) per 10 years of age (P = 0.003) and by 0.7 ± 0.4% in females (P = 0.068). Arteriovenous (AV) difference increased by 1.5 ± 0.5% per 10 years in males (P = 0.004) and 1.0 ± 0.4% (P = 0.007) in females. For every 10 mm Hg increase in ocular perfusion pressure, oxygen saturation in arterioles increased by 0.9 ± 0.4% (P = 0.024) and in venules by 1.2 ± 0.7% (P = 0.075). CONCLUSIONS Retinal arteriolar oxygen saturation is stable in healthy individuals, while there is a significant decrease in venular oxygen saturation with age in males and a similar trend in females. AV difference increases significantly with age for both sexes. Our study provided normative data for spectrophotometric retinal oximetry in the Caucasian population.

Retinal oximetry in primary open-angle glaucoma

PURPOSE. To determine whether retinal vessel oxygen saturation is affected in primary open-angle glaucoma (POAG) patients. METHODS. Retinal oxygen saturation in patients with POAG was measured in retinal vessels with a spectrophotometric retinal oximeter in darkness, and visual fields were obtained. Oxygen tension (Po(2)) was calculated from oxygen saturation values. Statistical analysis was performed using Pearsons correlation and Students t-test. RESULTS. Mean oxygen saturation in venules was higher in persons with poor visual fields (68% ± 4%, mean ± SD) than in those with good visual fields (62% ± 3%; P = 0.0018). The mean arteriovenous difference in oxygen saturation was lower in persons with poor visual fields (30% ± 4%, n = 9) than in those with good visual fields (37% ± 4%; P = 0.0003; n = 12). No correlation was found between saturation in retinal arterioles and visual field mean defect (n = 31; r = -0.16; P = 0.38). Oxygen saturation in retinal venules correlated positively with worsening visual field mean defect (r = 0.43; P = 0.015). Arteriovenous difference in oxygen saturation decreased significantly as the visual field mean defect worsened (r = -0.55; P = 0.0013). Mean Po(2) in venules was 38 ± 3 mm Hg. It was significantly higher in persons with poor visual field fields (40 ± 3 mm Hg) than in those with good visual fields (36 ± 2 mm Hg; P = 0.0016). CONCLUSIONS. Deeper glaucomatous visual field defects are associated with increased oxygen saturation in venules and decreased arteriovenous difference in retinal oxygen saturation. The data suggest that oxygen metabolism is affected in the glaucomatous retina, possibly related to tissue atrophy.

Oxygen saturation in human retinal vessels is higher in dark than in light

PURPOSE Animal studies have indicated that retinal oxygen consumption is greater in dark than light. In this study, oxygen saturation is measured in retinal vessels of healthy humans during dark and light. METHODS The oximeter consists of a fundus camera, a beam splitter, a digital camera and software, which calculates hemoglobin oxygen saturation in the retinal vessels. In the first experiment, 18 healthy individuals underwent oximetry measurements after 30 minutes in the dark, followed by alternating 5-minute periods of white light (80 cd/m(2)) and dark. In the second experiment, 23 volunteers underwent oximetry measurements after 30 minutes in the dark, followed by light at 1, 10, and 100 cd/m(2). Three subjects were excluded from analysis in the first experiment and four in the second experiment because of poor image quality. RESULTS In the first experiment, the arteriolar saturation decreased from 92% +/- 4% (n = 15; mean +/- SD) after 30 minutes in the dark to 89% +/- 5% after 5 minutes in the light (P = 0.008). Corresponding numbers for venules are 60% +/- 5% in the dark and 55% +/- 10% (P = 0.020) in the light. In the second experiment, the arteriolar saturation was 92% +/- 4% in the dark and 88% +/- 7% in 100 cd/m(2) light (n = 19, P = 0.012). The corresponding values for venules were 59% +/- 9% in the dark and 55% +/- 10% in 100 cd/m(2) light (P = 0.065). CONCLUSIONS Oxygen saturation in retinal blood vessels is higher in dark than in 80 or 100 cd/m(2) light in human retinal arterioles and venules. The authors propose that this is a consequence of increased oxygen demand in the outer retina in the dark.

Oxygen Saturation in Central Retinal Vein Occlusion

PURPOSE To test whether oxygen saturation is affected in retinal blood vessels in patients with central retinal vein occlusion (CRVO). DESIGN Prospective observational case series. METHODS Oxygen saturation of hemoglobin was measured in retinal blood vessels in 10 patients with unilateral CRVO. The duration of CRVO before measurement was from 1 day to about 6 months. Two patients were excluded because of poor quality of oximetry images. The spectrophotometric retinal oximeter is based on a fundus camera. It simultaneously captures images of the retina at 605 nm and 586 nm and calculates optical density (absorbance) of retinal vessels at both wavelengths. The ratio of the 2 optical densities is approximately linearly related to hemoglobin oxygen saturation. Mean oxygen saturation was calculated for first- and second-degree arterioles and venules in both eyes of each patient. RESULTS The mean oxygen saturation of hemoglobin in retinal venules was 49% ± 12% (mean ± SD, n = 8) in eyes affected by CRVO and 65% ± 6% in unaffected fellow eyes (P = .003). The mean arteriolar oxygen saturation was 99% ± 3% in CRVO eyes and 99% ± 6% in the fellow eyes. Venular oxygen saturation was variable within and between CRVO eyes. CONCLUSIONS Oxygen saturation in retinal venules is lower in eyes with CRVO than in fellow eyes and there is considerable variability within and between CRVO eyes. Arteriolar saturation is the same in CRVO and fellow eyes. Retinal oxygenation is disturbed in CRVO.

The oxygen saturation in retinal vessels from diabetic patients depends on the severity and type of vision-threatening retinopathy.

Diabetic retinopathy is characterized by morphological lesions in the retina secondary to disturbances in retinal blood flow which may influence the supply of oxygen to the retinal metabolism. Using retinal oximetry, it has been shown that the oxygen saturation is increased in retinal arterioles and venules from diabetic patients with retinopathy, but oxygenation before the development of retinopathy and possible differences in retinal oxygenation between diabetic maculopathy and proliferative diabetic retinopathy patients have not been evaluated.

Oxygen saturation in branch retinal vein occlusion.

Purpose:  The aim of this study was to test whether oxygen saturation in retinal blood vessels is affected by branch retinal vein occlusion (BRVO).

Glaucoma Filtration Surgery and Retinal Oxygen Saturation

PURPOSE Glaucoma may involve disturbances in retinal oxygenation and blood flow. The purpose of this study was to measure the effect of glaucoma filtration surgery on retinal vessel oxygen saturation. METHODS A noninvasive spectrophotometric retinal oximeter was used to measure hemoglobin oxygen saturation in retinal arterioles and venules before and after glaucoma filtration surgery. Twenty-five consecutive patients were recruited, and 19 had adequate image quality. Fourteen underwent trabeculectomy and five glaucoma tube surgery. Twelve had primary open-angle glaucoma and seven had exfoliative glaucoma. IOP decreased from 23 +/- 7 to 10 +/- 4 mm Hg (mean +/- SD, P = 0.0001). RESULTS Oxygen saturation increased in retinal arterioles from 97% +/- 4% to 99% +/- 6% (n = 19; P = 0.046) after surgery and was unchanged in venules (63% +/- 5% before surgery and 64% +/- 6% after, P = 0.76). There were no significant changes in saturation in the fellow eyes (P > 0.60). The arteriovenous difference was 34% before and 36% after surgery (P = 0.35). CONCLUSIONS Glaucoma filtration surgery had almost no effect on retinal vessel oxygen saturation.

Dorzolamide-Timolol Combination and Retinal Vessel Oxygen Saturation in Patients with Glaucoma or Ocular Hypertension

Aims: To examine whether the addition of dorzolamide to timolol monotherapy influences oxygen saturation in the human retina. Methods: Non-invasive spectrophotometric retinal oximetry was used to measure oxygen saturation in retinal vessels. Twenty patients with open-angle glaucoma (11) and ocular hypertension (9) were recruited. The patients were randomised into receiving timolol monotherapy or dorzolamide–timolol combination for an 8-month test period, followed by a second test period, before which the patients switched treatments. Oximetry measurements were performed at 2-month intervals during each period. Of the 20 patients, 13 followed the study protocol into the second test period, and 10 managed all study visits. Results: The oxygen saturation in retinal vessels was stable within the test periods. The mean arteriolar saturation was 96 (2)% (mean (SD)) during timolol monotherapy and 97 (2)% during dorzolamide–timolol combination therapy (p = 0.17, all patients pooled, n = 13). Corresponding values in venules were 66 (5)% during timolol monotherapy and 65 (6)% during dorzolamide–timolol therapy (p = 0.13). Patients who started on dorzolamide–timolol combination showed a significant reduction in arteriolar (98 (2)% to 95 (2)%, p<0.01) and venular saturation (69 (5)% to 66 (6)%, p<0.05) when changing to timolol monotherapy. Conclusion: Adding dorzolamide to timolol monotherapy has a minimal effect, but going from dorzolamide–timolol combination to timolol alone lowered arteriolar and venular oxygen saturation. The retinal oxygen saturation measurements show a high degree of stability over an extended period of time. Previous studies have suggested increased retinal and optic nerve blood flow with dorzolamide. Unchanged oxygen saturation and increased blood flow would indicate increased oxygen delivery to the retina.