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We here attempt to improve quantification of the ischemic retinal insult, that is, what is imposed on the retinal tissue by ischemia, especially in experimental models of ischemia. The ischemic retinal insult initiates the ischemic retinal injury (or outcome). Accordingly, it is reasonable to assume that the better the quantification of the insult, the better the correlation with, and thereby estimation of, the injury. The insult seldom has been quantified in terms of the relevant physiological factors, especially in connection with the rate of oxygen delivery (DO 2 ). We here propose the accumulated oxygen deficit (AO 2 D) as an indicator of the ischemic retinal insult. We hypothesized that AO 2 D is correlated with the rate of oxygen metabolism measured 1 h after reperfusion following an episode of ischemia (MO 2 _1_Hr). Previously, we showed that MO 2 _1_Hr is related to the electroretinogram amplitude and the retinal thickness when they are measured seven days after reperfusion. We studied 27 rats, as well as 26 rats from our published data on retinal ischemia in which we had measurements of DO 2 and duration of ischemia (T) of various levels and durations. We also measured DO 2 in 29 rats treated with sham surgery. Ischemia was induced by either ipsilateral or bilateral common carotid artery occlusion or by ophthalmic artery occlusion, which gave a wide range of DO 2 . DO 2 and MO 2 _1_Hr were evaluated based on three types of images: 1) red-free images to measure vessel diameters, 2) fluorescence images to estimate blood velocities by the displacement of intravascular fluorescent microspheres over time, and 3) phosphorescence images to quantify vascular oxygen tension from the phosphorescence lifetime of an intravascular oxygen sensitive phosphor. Loss of oxygen delivery (DO 2 L) was calculated as the difference between DO 2 under normal/sham condition and DO 2 during ischemia. AO 2 D, a volume of oxygen, was calculated as the product DO 2 L and T. Including all data, the linear relationship between AO 2 D and MO 2 _1_Hr was significant (R 2  = 0.261, P = 0.0003). Limiting data to that in which T or DO 2 L was maximal also yielded significant relationships, and revealed that DO 2 L at a long duration of ischemia contributed disproportionately more than T to MO 2 _1_Hr. We discuss the potential of AO 2 D for quantifying the ischemic retinal insult, predicting the ischemic retinal injury and evaluating the likelihood of infarction., Competing Interests: Declaration of competing interest M. Shahidi holds a patent for the oxygen imaging technology. The other authors have no interests to declare., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

After total retinal ischemia induced experimentally by ophthalmic vessel occlusion followed by reperfusion, studies have reported alterations in retinal oxygen metabolism (MO 2 ), delivery (DO 2 ), and extraction fraction (OEF), as well as visual dysfunction and cell loss. In the current study, under variable durations of ischemia/reperfusion, changes in these oxygen metrics, visual function, retinal thickness, and degeneration markers (gliosis and apoptosis) were assessed and related. Additionally, the prognostic value of MO 2 for predicting visual function and retinal thickness outcomes was reported. Sixty-one rats were divided into 5 groups of ischemia duration (0 [sham], 60, 90, 120, or 180 min) and 2 reperfusion durations (1 h, 7 days). Phosphorescence lifetime and blood flow imaging, electroretinography, and optical coherence tomography were performed. MO 2 reduction was related to visual dysfunction, retinal thinning, increased gliosis and apoptosis after 7-days reperfusion. Impairment in MO 2 after 1-h reperfusion predicted visual function and retinal thickness outcomes after 7-days reperfusion. Since MO 2 can be measured in humans, findings from analogous studies may find value in the clinical setting., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The retinal degeneration 1 (rd1) mouse is a well-established model of inherited retinal degeneration, displaying photoreceptor degeneration and retinal vasculature damage. The purpose of the current study was to determine alterations in the rate of oxygen delivery from retinal circulation (DO 2 ), the rate of oxygen extraction from the retinal circulation for metabolism (MO 2 ), and oxygen extraction fraction (OEF) in rd1 mice. The study was performed in a total of 18 wild type (WT) and 10 rd1 mice at both 3-weeks and 12-weeks of age. Retinal arterial and venous oxygen contents (O 2A and O 2V ) were measured using phosphorescence lifetime imaging. Total retinal blood flow (TRBF) was determined by fluorescence and red-free imaging. DO 2 and MO 2 were determined as TRBF × O 2A and TRBF × (O 2A -O 2V ), respectively. OEF was calculated as MO 2 /DO 2 . The thickness of individual retinal layers was measured from histology sections and inner retina (IR) and total retina (TR) thickness were calculated. TRBF, DO 2 and MO 2 were lower in rd1 mice compared to WT mice (P ≤ 0.001), whereas OEF was not significantly different between rd1 and WT mice (P = 0.4). TRBF and DO 2 were lower at 3-weeks of age compared to 12-weeks of age (P ≤ 0.01), while MO 2 was not significantly different between age groups (P = 0.4) and OEF was higher at 3-weeks of age compared to 12-weeks of age (P = 0.003). Additionally, the outer and inner retinal cell layer thicknesses were decreased in rd1 mice at 12-weeks of age compared to both age-matched WT mice and rd1 mice at 3-weeks of age (P ≤ 0.02). MO 2 was directly correlated with both IR and TR thickness (R ≥ 0.50; P ≤ 0.03, N = 20). The findings indicate that the rate oxygen is supplied by the retinal circulation is decreased and the reduction in oxygen extracted for metabolism is related to retinal cell layer thinning in rd1 mice., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Studies in experimental ischemia models by permanent bilateral common carotid artery occlusion (BCCAO) have reported reduced retinal electrophysiological function, coupled with inner retinal degeneration and gliosis. In the current study, we tested the hypothesis that long-term (up to 14 days) BCCAO impairs oxygen delivery (DO 2 ), which affects oxygen metabolism (MO 2 ) and extraction fraction (OEF), electrophysiological function, morphology, and biochemical pathways. Twenty-one rats underwent BCCAO (N = 12) or sham surgery (N = 9) and were evaluated in separate groups after 3, 7, or 14 days. Electroretinography (ERG), optical coherence tomography, blood flow and vascular oxygen tension imaging, and morphological and biochemical evaluations were performed in both eyes. Reduced ERG b-wave amplitudes and delayed implicit times were reported at 3, 7, and 14 days following BCCAO. Total retinal blood flow, MO 2 , and DO 2 were reduced in all BCCAO groups. OEF was increased in both 3- and 7-day groups, while no significant difference was observed in OEF at 14 days compared to the sham group. At 14 days following BCCAO, total and inner retinal layer thickness was reduced, while the outer nuclear layer thickness and gliosis were increased. There was an increase in nuclei containing fragmented DNA at 3 days following BCCAO. The compensatory elevation in OEF following BCCAO did not meet the tissue demand, resulting in the subsequent reduction of MO 2 . The associations between retinal MO 2 , DO 2 , and retinal function were shown to be significant in the sequelae of persistent ischemia. In sum, measurements of DO 2 , MO 2 , and OEF may become useful for characterizing salvageable tissue in vision-threatening pathologies.