January 2013
Volume 54, Issue 1
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Retina  |   January 2013
Inner Retinal Oxygen Extraction Fraction in Rat
Author Notes
  • From the Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, Illinois. 
  • Corresponding author: Mahnaz Shahidi, Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, 1855 West Taylor Street, Chicago, IL 60612; mahnshah@uic.edu
Investigative Ophthalmology & Visual Science January 2013, Vol.54, 647-651. doi:10.1167/iovs.12-11305
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      Pang-yu Teng, Justin Wanek, Norman P. Blair, Mahnaz Shahidi; Inner Retinal Oxygen Extraction Fraction in Rat. Invest. Ophthalmol. Vis. Sci. 2013;54(1):647-651. doi: 10.1167/iovs.12-11305.

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Abstract

Purpose.: Oxygen extraction fraction (OEF), defined by the ratio of oxygen consumption to delivery, may be a useful parameter for assessing the retinal tissue status under impaired circulation. We report a method for measurement of inner retinal OEF in rats under normoxia and hypoxia based on vascular oxygen tension (PO2) imaging.

Methods.: Retinal vascular PO2 measurements were obtained in 10 rats, using our previously developed optical section phosphorescence lifetime imaging system. Inner retinal OEF was derived from retinal vascular PO2 measurements based on Fick's principle. Measurements of inner retinal OEF obtained under normoxia were compared between nasal and temporal retinal sectors and repeatability was determined. Inner retinal OEF measurements obtained under normoxia and hypoxia were compared.

Results.: Retinal vascular PO2 and inner retinal OEF measurements were repeatable (ICC ≥ 0.83). Inner retinal OEF measurements at nasal and temporal retinal sectors were correlated (R = 0.71; P = 0.02; n = 10). Under hypoxia, both retinal arterial and venous PO2 decreased significantly as compared with normoxia (P < 0.001; n = 10). Inner retinal OEF was 0.46 ± 0.13 under normoxia and increased significantly to 0.67 ± 0.16 under hypoxia (mean ± SD; P < 0.001; n = 10).

Conclusions.: Inner retinal OEF is a promising quantitative biomarker for the adequacy of oxygen supply for metabolism under physiologically and pathologically altered conditions.

Introduction
The maintenance of retinal tissue requires adequate delivery of oxygen by the retinal and choroidal circulations. Indeed, under a severe hypoxic or ischemic insult, retinal function is compromised 13 and irreversible functional loss can occur shortly following retinal vascular nonperfusion. 2,4,5 Consequently, it would be advantageous to assess the status of the retina when impaired circulation is suspected. 
Oxygen extraction fraction (OEF) is a parameter defined by the ratio of oxygen consumption (MO2) to oxygen delivery (DO2). Cerebral OEF measured by positron emission tomography and magnetic resonance imaging has been widely accepted as a valuable parameter for assessing tissue ischemia. 613 In fact, increased cerebral OEF, also termed “misery perfusion,” has been reported in subjects with acute ischemic stroke 1012 and carotid occlusion. 7,8 Moreover, an increase in cerebral OEF has been shown to be an independent predictor of stroke. 9,13  
Due to similarities between cerebral and retinal tissues, measurement of OEF may also be useful for assessment of ischemia that occurs in many retinal diseases; however, currently available brain imaging modalities lack adequate resolution to quantify OEF in the retinal tissue. Alternatively, OEF can be expressed as the ratio of the arteriovenous oxygen content difference to the arterial oxygen content based on Fick's principle, 14 as shown by the following equation.  Therefore, inner retinal OEF can be derived without direct measurements of MO2 and DO2.  
In the current study, we report a method for quantitative measurement of inner retinal OEF based on retinal vascular oxygen tension (PO2) imaging. 15 The repeatability, spatial variation, and hypoxia-induced alterations of inner retinal OEF measurements were determined. 
Methods
Animals
Ten Long Evans pigmented rats (weight 444 ± 99 g, mean ± SD) were used in this study. The rats were treated in compliance with the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research. Anesthesia was induced by intraperitoneal injections of ketamine (100 mg·kg−1) and xylazine (5 mg·kg−1), and maintained with supplemental injections of ketamine (20 mg·kg−1) and xylazine (1 mg·kg−1), as needed. The body temperatures of the rats were maintained at 37°C using an animal holder with a copper tubing water heater. A catheter was placed in a femoral artery and connected to a pressure transducer. Blood pressure and heart rate of the rats were monitored with a data acquisition system (Biopac Systems, Goleta, CA) linked to a pressure transducer connected to the catheter. 
The rats were mechanically ventilated with room air (21% O2, normoxia) and then with 10% oxygen (hypoxia) through an endotracheal tube connected to a small animal ventilator (Harvard Apparatus, Inc., South Natick, MA). To verify the physiological condition, arterial blood was drawn from the femoral arterial catheter to measure systemic arterial oxygen tension (PaO2), carbon dioxide tension (PaCO2), and pH with a blood gas analyzer (Radiometer, Westlake, OH) and also hemoglobin concentration with a hematology system (Siemens, Tarrytown, NY). Animals were maintained normocapnic by adjusting the respiratory minute volume and performing blood gas analysis 5 minutes after each adjustment until PaCO2 was within the range of 35 to 45 mm Hg. An oxygen-sensitive molecular probe (Pd-porphine; Frontier Scientific, Logan, UT) was dissolved (12 mg·mL−1) in bovine serum albumin solution (60 mg·mL−1) and administered (20 mg·kg−1) through the femoral arterial catheter, typically 10 minutes prior to imaging. The probe binds to albumin and does not permeate from the normal vasculature to the retinal tissue. The pupils were dilated with 2.5% phenylephrine and 1% tropicamide. Glass cover slips and 1% hydroxypropyl methylcellulose were applied to the corneas to eliminate the refractive power and to prevent dehydration. 
Retinal Vascular Oxygen Tension Imaging
Retinal vascular PO2 was measured with our custom optical section phosphorescence lifetime imaging system. 15 In short, a laser beam was focused to a vertical line, and projected at an oblique angle on the retina. An optical section phosphorescence image of the retinal vasculature was acquired with an intensified charge-coupled device camera attached to a slit lamp biomicroscope. Since the incident laser beam was at an angle with respect to the imaging path, phosphorescence emissions of the Pd-porphine from the retinal vessels were depth-resolved. Phosphorescence lifetime was determined using a frequency-domain approach and converted to PO2 measurements using the Stern-Volmer relationship defined by PO2 = (1/κ Q) · (1/τ − 1/τ 0), where κ Q (mm Hg−1·μs−1) is the quenching constant for the triplet-state of Pd-porphine, τ (μs) is the phosphorescence lifetime, and τ 0 (μs) is the lifetime in a zero-oxygen environment. 16,17 Measurements of PO2 were obtained in a retinal sector, defined by a zone bounded by two major retinal arteries (PO2A), with a major retinal vein (PO2V) between the two arteries (Fig. 1). Three repeated measurements were obtained at nasal and temporal retinal sectors, within three optic disc diameters (∼600 μm) from the edge of the optic nerve head. A red-free retinal image was acquired for documenting the locations of the PO2 measurements. Under both ventilation conditions, the laser power incident on the cornea was approximately 40 μW, which is safe for 1 hour of continuous viewing according to the American National Standard Institute for Safety Standards. 18  
Figure 1. 
 
Examples of cross-sectional vascular PO2 maps (shaded rectangles) superimposed on red-free retinal images in a rat under normoxia (A) and hypoxia (B). Maps depict PO2 in retinal arteries (a) and veins (v) in the temporal (left) and nasal (right) sides of the optic disc. Color bar displays PO2 in mm Hg.
Figure 1. 
 
Examples of cross-sectional vascular PO2 maps (shaded rectangles) superimposed on red-free retinal images in a rat under normoxia (A) and hypoxia (B). Maps depict PO2 in retinal arteries (a) and veins (v) in the temporal (left) and nasal (right) sides of the optic disc. Color bar displays PO2 in mm Hg.
Quantification of OEF
Based on retinal vascular PO2 measurements, the O2 content of blood was estimated as follows:  where O2max is the maximum oxygen carrying capacity of hemoglobin (1.39 mLO2·g−1), 19 Hgb is the measured hemoglobin concentration of arterial blood (13.9 ± 0.5 g·dL−1; n = 10), k is the oxygen solubility in blood (0.003 mLO2·dL−1·mm Hg−1), 19 and SO2 is the oxygen saturation. Based on vascular PO2 and arterial blood pH measurements, SO2 was calculated from the Hill equation, which models the oxygen dissociation curve and is defined as SO2 = (PO2/P50)n/(1 + [PO2/P50]n), where n is an empirical constant taken to be 2.6 in rat, 20 and P50 is the PO2 when SO2 is 0.5 at a given pH, based on the Bohr effect. 21  
Inner retinal OEF was quantified in a retinal sector as follows,  where mO2A is the mean arterial O2 content of the two major arteries, and O2V is the venous O2 content. The mean arterial PO2 of the two major arteries (mPO2A) was also calculated.  
Data Analysis
Repeatability of mPO2A, PO2V, and OEF was determined by calculating the intraclass correlation coefficients (ICCs) and the SDs of three repeated measurements obtained under normoxia at a retinal sector nasal to the optic disc. Repeated measurements of mPO2A, PO2V, and OEF at each retinal sector were averaged, and spatial variation was assessed by relating OEF measurements at nasal and temporal sectors using Pearson's correlation. In each rat, measurements of mPO2A, PO2V, and OEF at nasal and temporal retinal sectors were averaged, and the mean values under normoxia and hypoxia were compared with paired Student's t-test. Statistical significance was accepted at P less than 0.05. 
Results
Repeatability and Spatial Variation
The ICCs and mean SDs (averaged over data in 10 rats) obtained from three repeated mPO2A, PO2V, and OEF measurements in nasal retinal sectors under normoxia are shown in Table 1. Measurements of mPO2A and PO2V were repeatable, with ICCs greater than or equal to 0.86 and mean SDs less than or equal to 3 mm Hg. Similarly, inner retinal OEF measurements were also repeatable (ICC = 0.83 and mean SD = 0.08). As anticipated, measurements of OEF at nasal and temporal retinal sectors were correlated under normoxia (R = 0.71; P = 0.02; n = 10). 
Table 1. 
 
ICCs and mean SDs, Averaged over Data in 10 Rats, Based on Three Repeated mPO2A, PO2V, and OEF Measurements in the Nasal Sectors under Normoxia
Table 1. 
 
ICCs and mean SDs, Averaged over Data in 10 Rats, Based on Three Repeated mPO2A, PO2V, and OEF Measurements in the Nasal Sectors under Normoxia
ICC SD
mPO2A 0.86 3 mm Hg
PO2V 0.89 2 mm Hg
OEF 0.83 0.08
Systemic Physiological Status
The systemic physiological status of the rats under normoxia and hypoxia is presented in Table 2. PaO2 under hypoxia (34 ± 4 mm Hg) was significantly lower as compared with normoxia (93 ± 8 mm Hg) (P < 0.001; n = 10). Due to controlled ventilation, PaCO2 under normoxia and hypoxia were similar (P = 0.76). Arterial blood pH, blood pressure, and heart rate decreased significantly under hypoxia (P ≤ 0.001). 
Table 2. 
 
The Systemic Physiologic Status and Retinal Vascular PO2 Measurements under Normoxia and Hypoxia
Table 2. 
 
The Systemic Physiologic Status and Retinal Vascular PO2 Measurements under Normoxia and Hypoxia
Normoxia Hypoxia P Value
Systemic physiologic status
 PaO2, mm Hg 93 ± 8 34 ± 4 <0.001*
 PaCO2, mm Hg 40 ± 5 41 ± 5 0.76
 pH 7.38 ± 0.05 7.31 ± 0.05 <0.001*
 Blood pressure, mm Hg 113 ± 17 78 ± 22 0.001*
 Heart rate, beats·min−1 214 ± 36 162 ± 45 0.002*
Retinal vascular PO2
 mPO2A, mm Hg 44 ± 4 20 ± 4 <0.001*
 PO2V, mm Hg 28 ± 5 11 ± 4 <0.001*
Retinal Vascular PO2 and OEF
Examples of cross-sectional vascular PO2 maps obtained in the same rat under normoxia and hypoxia are shown overlaid on the corresponding red-free retinal images in Figure 1. As expected, in both nasal and temporal sectors, mPO2A was higher than PO2V under both normoxia and hypoxia. Both mPO2A and PO2V decreased under hypoxia as compared with normoxia. 
Measurements of mPO2A and PO2V averaged over all rats under normoxia and hypoxia are listed in Table 2. Under normoxia, mPO2A and PO2V were 44 ± 4 and 28 ± 5 mm Hg, respectively (n = 10). Under hypoxia, both mPO2A (20 ± 4 mm Hg) and PO2V (11 ± 4 mm Hg) decreased significantly as compared with normoxia (P < 0.001). Mean measurements of inner retinal OEF under normoxia and hypoxia are shown in Figure 2. Mean inner retinal OEF was 0.46 ± 0.13 under normoxia and increased significantly to 0.67 ± 0.16 under hypoxia (P < 0.001; n = 10). 
Figure 2. 
 
Inner retinal oxygen extraction fraction (OEF) under hypoxia (0.67 ± 0.16) was significantly higher than under normoxia (0.46 ± 0.13) (mean ± SD; P < 0.001; n = 10).
Figure 2. 
 
Inner retinal oxygen extraction fraction (OEF) under hypoxia (0.67 ± 0.16) was significantly higher than under normoxia (0.46 ± 0.13) (mean ± SD; P < 0.001; n = 10).
Discussion
Retinal ischemia is implicated in many retinal diseases that lead to visual impairment; however, methods that can quantitatively assess the retinal tissue status in vivo under ischemia are limited. One potential parameter is OEF, which indicates the adequacy of oxygen supply relative to the tissue's metabolic demand. In the current study, we report for the first time to our knowledge, quantitative measurements of inner retinal OEF in rats based on retinal vascular PO2 imaging, and demonstrate a significant increase in inner retinal OEF under systemic hypoxia. 
Inner retinal OEF measurements in the current study were compared with calculated retinal and measured cerebral OEFs due to a lack of published retinal data. Based on oximetry studies in healthy subjects, 2224 we computed the inner retinal OEF to be 0.40, which is comparable to our measurements of 0.46 in rats under normoxia. Additionally, inner retinal OEF measured under normoxia in the current study was in agreement with published cerebral OEFs (0.37 to 0.57). 2530 Our finding of increased inner retinal OEF under systemic hypoxia was similar to elevated inner retinal OEF in chronic systemic hypoxia 31 and central retinal vein occlusion, 32 calculated from oximetry data in humans. Moreover, this finding was also consistent with the response of cerebral OEF under hypoxia. 25,27,30  
An increase in inner retinal OEF can occur due to either an increase in retinal MO2 or a decrease in DO2. Under hypoxia, because MO2 is unlikely to increase, the observed increase in inner retinal OEF would occur due to a decrease in DO2 that can result from reductions in retinal blood flow and/or arterial blood oxygen content. Although retinal blood flow in principle could be affected by systemic blood pressure and/or blood pH, it was not likely influenced by these factors under our experimental conditions. Blood pressure remained within the autoregulatory range, 33 even though it was reduced during hypoxia. Likewise, a change in blood pH was not expected to alter blood flow, according to findings in the brain. 34,35 On the other hand, hypoxia has been reported to increase retinal blood flow, 3639 which would tend to maintain DO2. Nevertheless, the compensatory increase in blood flow may not be adequate to maintain DO2, if the hypoxia is severe enough. In that case, because of reductions in retinal arterial blood oxygen content, DO2 decreases, thereby causing an increase in inner retinal OEF. 
One factor that likely affected our results was that oxygen contents in retinal veins were estimated from the oxygen dissociation curve using the arterial blood pH. Because blood pH is expected to be lower in veins than in arteries, 40,41 the actual venous oxygen contents were likely lower due to a right shift of the oxygen dissociation curve. As a result, the actual inner retinal OEF should have been higher than the reported values under normoxia. The right shift of the oxygen dissociation curve would be expected to be even more prominent during hypoxia due to increased anaerobic metabolism. Because OEF was underestimated under both ventilation conditions, this limitation likely did not affect our finding of increased inner retinal OEF under hypoxia. 
Measurements of inner retinal OEF may provide information about the retinal tissue status during ischemic insult complementary to retinal blood flow measurements or conventional diagnostic tests, such as fundus photography and fluorescein angiography. An acute increase in retinal OEF indicates a state of misery perfusion, in which DO2 declines, and thereby support for MO2 becomes precarious. If DO2 remains reduced chronically, irreversible anoxic damage may develop, leading to decreases in retinal MO2 and OEF. Therefore, while OEF is elevated, retinal tissue may still remain viable, 42 thus potentially providing a window of opportunity for successful intervention, as has been demonstrated in cerebral tissue. 4345 In the current study, we evaluated inner retinal OEF under two ventilation conditions to establish a normal baseline and demonstrate a response to a severe hypoxic challenge. Additional studies that assess inner retinal OEF in response to varying levels of inspired oxygen may help establish a threshold at which OEF begins to increase due to maximized blood flow compensation. Furthermore, future studies are needed to provide knowledge of OEF response in experimental animal models of retinal vascular deficiency that may eventually be translated for clinical management of patients. 
In summary, we established a method for quantitative measurement of inner retinal OEF in rats and demonstrated an increase in OEF under acute systemic hypoxia. The method can be extended to provide a global assessment of inner retinal OEF by measuring O2 contents in all major retinal blood vessels. Quantification of inner retinal OEF has potential value for providing information about the retinal energy metabolism under challenged physiological and pathological conditions. 
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Footnotes
 Supported by the National Eye Institute, Bethesda, Maryland, EY17918 (MS) and EY01792 (University of Illinois at Chicago), and Research to Prevent Blindness, New York, New York, senior scientific investigator award (MS), and an unrestricted departmental award.
Footnotes
 Disclosure: P.-Y. Teng, None; J. Wanek, None; N.P. Blair, None; M. Shahidi, P
Figure 1. 
 
Examples of cross-sectional vascular PO2 maps (shaded rectangles) superimposed on red-free retinal images in a rat under normoxia (A) and hypoxia (B). Maps depict PO2 in retinal arteries (a) and veins (v) in the temporal (left) and nasal (right) sides of the optic disc. Color bar displays PO2 in mm Hg.
Figure 1. 
 
Examples of cross-sectional vascular PO2 maps (shaded rectangles) superimposed on red-free retinal images in a rat under normoxia (A) and hypoxia (B). Maps depict PO2 in retinal arteries (a) and veins (v) in the temporal (left) and nasal (right) sides of the optic disc. Color bar displays PO2 in mm Hg.
Figure 2. 
 
Inner retinal oxygen extraction fraction (OEF) under hypoxia (0.67 ± 0.16) was significantly higher than under normoxia (0.46 ± 0.13) (mean ± SD; P < 0.001; n = 10).
Figure 2. 
 
Inner retinal oxygen extraction fraction (OEF) under hypoxia (0.67 ± 0.16) was significantly higher than under normoxia (0.46 ± 0.13) (mean ± SD; P < 0.001; n = 10).
Table 1. 
 
ICCs and mean SDs, Averaged over Data in 10 Rats, Based on Three Repeated mPO2A, PO2V, and OEF Measurements in the Nasal Sectors under Normoxia
Table 1. 
 
ICCs and mean SDs, Averaged over Data in 10 Rats, Based on Three Repeated mPO2A, PO2V, and OEF Measurements in the Nasal Sectors under Normoxia
ICC SD
mPO2A 0.86 3 mm Hg
PO2V 0.89 2 mm Hg
OEF 0.83 0.08
Table 2. 
 
The Systemic Physiologic Status and Retinal Vascular PO2 Measurements under Normoxia and Hypoxia
Table 2. 
 
The Systemic Physiologic Status and Retinal Vascular PO2 Measurements under Normoxia and Hypoxia
Normoxia Hypoxia P Value
Systemic physiologic status
 PaO2, mm Hg 93 ± 8 34 ± 4 <0.001*
 PaCO2, mm Hg 40 ± 5 41 ± 5 0.76
 pH 7.38 ± 0.05 7.31 ± 0.05 <0.001*
 Blood pressure, mm Hg 113 ± 17 78 ± 22 0.001*
 Heart rate, beats·min−1 214 ± 36 162 ± 45 0.002*
Retinal vascular PO2
 mPO2A, mm Hg 44 ± 4 20 ± 4 <0.001*
 PO2V, mm Hg 28 ± 5 11 ± 4 <0.001*
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