625
J Physiol 594.3 (2016) pp 625–640
Relationship between retinal blood flow and arterial oxygen Richard W. Cheng1,2,3 , Firdaus Yusof1,3,5 , Edmund Tsui1 , Monica Jong1,6 , James Duffin2,7,9 , John G. Flanagan1,4,8 , Joseph A. Fisher2,7,9 and Chris Hudson1,3,4 1
Department of Ophthalmology and Vision Sciences, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada Department of Physiology, University of Toronto, Toronto, ON, Canada 3 School of Optometry and Vision Science, University of Waterloo, Waterloo, Ontario, Canada 4 Institute of Medical Science, University of Toronto, Toronto, ON, Canada 5 Department of Optometry and Visual Science, International Islamic University of Malaysia, Bandar Indera Mahkota, Pahang, Malaysia 6 Brien Holden Vision Institute, University of New South Wales, Sydney, NSW, Australia 7 Thornhill Research Inc., Toronto, ON, Canada 8 School of Optometry, University of California Berkeley, Berkeley, CA, USA 9 Department of Anesthesiology, Toronto General Hospital, Toronto, ON, Canada
The Journal of Physiology
2
Key points
r Vascular reactivity, the response of the vessels to a vasoactive stimulus such as hypoxia and r
r r
hyperoxia, can be used to assess the vascular range of adjustment in which the vessels are able to compensate for changes in P O2 . Previous studies in the retina have not accurately quantified retinal vascular responses and precisely targeted multiple P aO2 stimuli at the same time as controlling the level of carbon dioxide, thus precluding them from modelling the relationship between retinal blood flow and oxygen. The present study modelled the relationship between retinal blood flow and P aO2 , showing them to be a combined linear and hyperbolic function. This model demonstrates that the resting tonus of the vessels is at the mid-point and that they have great vascular range of adjustment, compensating for decreases in oxygen above a P ETCO2 of 32–37 mmHg but being limited below this threshold.
Abstract Retinal blood flow (RBF) increases in response to a reduction in oxygen (hypoxia) but decreases in response to increased oxygen (hyperoxia). However, the relationship between blood flow and the arterial partial pressure of oxygen has not been quantified and modelled in the retina, particularly in the vascular reserve and resting tonus of the vessels. The present study aimed to determine the limitations of the retinal vasculature by modelling the relationship between RBF and oxygen. Retinal vascular responses were measured in 13 subjects for eight different blood gas conditions, with the end-tidal partial pressure of oxygen (P ETCO2 ) ranging from 40–500 mmHg. Retinal vascular response measurements were repeated twice; using the Canon laser blood flowmeter (Canon Inc., Tokyo, Japan) during the first visit and using Doppler spectral domain optical coherence tomography during the second visit. We determined that the relationship between RBF and P aO2 can be modelled as a combination of hyperbolic and linear functions. We concluded that RBF compensated for decreases in arterial oxygen content for all stages of hypoxia used in the present study but can no longer compensate below a P ETCO2 of 32–37 mmHg. These vessels have a great vascular range of adjustment, increasing diameter (8.5% arteriolar and 21% total venous area) with hypoxia (40 mmHg P ETCO2 ; P < 0.001) and decreasing diameter (6.9% arteriolar and 23% total venous area) with hyperoxia (500 mmHg P ETCO2 ; P < 0.001) to the same extent. This indicates that the resting tonus is near the mid-point of the adjustment ranges at resting P aO2 where sensitivity is maximum. C 2015 The Authors. The Journal of Physiology C 2015 The Physiological Society
DOI: 10.1113/JP271182
626
R. W. Cheng and others
J Physiol 594.3
(Resubmitted 24 June 2015; accepted after revision 19 November 2015; first published online 26 November 2015) Corresponding author C. Hudson: School of Optometry and Vision Science, University of Waterloo, 200 University Avenue West, Waterloo, Ontario N2L 3G1, Canada. Email: [email protected] Abbreviations CLBF, Canon laser blood flowmeter; MAP, mean arterial pressure; P aO2 , arterial oxygen tension; P aCO2 , arterial partial pressure of carbon dioxide; P ETO2 , end-tidal oxygen; P ETCO2 , end-tidal carbon dioxide; P O2 , partial pressure of oxygen; RBF, retinal blood flow; SaO2 , oxygen saturation.
Introduction The retinal circulation forms a closed circuit such that the central retinal artery, which penetrates the optic nerve, passes blood through the arterioles and into the superior capillary plexus or deep capillary plexus, eventually draining into the venules surrounding the optic nerve head. The inner retinal vasculature is uniquely situated in that imaging through the eye permits non-invasive investigation of vascular reactivity, comprising the response of these vessels to a vasoactive stimulus. By examining total flow through all the venules surrounding the optic nerve head or by investigating flow through a specific arteriole, and assuming the arterioles all respond similarly, we can evaluate the response of the retinal vasculature to a stimulus. The retinal vessels, much like the rest of the brain vasculature, respond to increases in oxygen (hyperoxia) by constricting the vessels to decrease blood flow (Eperon et al. 1975; Kiss et al. 2002; Wimpissinger et al. 2005; Sehi et al. 2012; Werkmeister et al. 2012; Tsui et al. 2013) and respond to reductions in oxygen (hypoxia) by dilating the vessels to increase blood flow (Hickam & Frayser, 1966; Frayser et al. 1971; Fallon et al. 1985). Measurements of retinal vascular reactivity may be used to investigate vascular dysregulation in ocular diseases such as diabetic retinopathy (Gilmore et al. 2007) and primary open angle glaucoma (Venkataraman et al. 2010). Indeed, using vascular reactivity assessment to determine retinal vasculature dysfunction will enhance the comprehension of pathophysiology. However, first, the retinal vascular reactivity in healthy young individuals must be characterized. The relationship between retinal blood flow and oxygen for healthy participants has been only loosely defined in previous studies. When examining the acute effects of hypoxia, Hickam & Frayser (1966) and Fallon et al. (1985) demonstrated that retinal vessels in healthy individuals dilate by 10% and increase blood flow by 16–38% for an arterial oxygen saturation (SaO2 ) of 70–80%. However, studies at altitude (Frayser et al. 1971; Rennie & Morrissey, 1975; Bosch et al. 2009) appear to indicate that the vessels can dilate by as much as 20–40%. Vascular reactivity to hyperoxia (100% oxygen) has generally shown that retinal vessels constrict by 10–15%, whereas flow decreases by as much as 40–50% (Eperon et al. 1975; Kiss et al. 2002; Wimpissinger et al. 2005; Sehi et al. 2012; Werkmeister et al. 2012; Tsui et al. 2013). These previous studies
(Hickam & Frayser, 1966; Frayser et al. 1971; Fallon et al. 1985; Brinchmann-Hansen & Myhre, 1990; Wimpissinger et al. 2005; Sehi et al. 2012; Werkmeister et al. 2012; Tsui et al. 2013) have generally investigated only one hypoxic or hyperoxic stimulus, which precludes modelling the entire relationship between retinal blood flow and oxygen, as well as determining the vascular reserve and resting tonus of the retinal vessels. The methodologies employed probably resulted in large inter-individual variability not only because of instrument inaccuracies, but also as a result of the imprecision of the gas provocation method used to target a given arterial partial pressure of oxygen (P aO2 ). Breath to breath fluctuations in end-tidal partial pressures of oxygen (P ETCO2 ) and an inability to maintain isocapnia have therefore limited previous investigations (Hickam & Frayser, 1966; Frayser et al. 1971; Fallon et al. 1985; Brinchmann-Hansen et al. 1989). The retinal vascular responses to oxygen can also be used to determine the vascular adjustment reserve of the vessels, which is the maximal amount by which the vessels can dilate and constrict, as well as the resting tonus, which is the tone of the vessels at resting P aO2 . Measurements of the vascular reserve and resting tonus of the retinal vessels will demonstrate the extent of the ability of the vasculature to compensate for changes in oxygen. Studies in monkeys report conflicting results, with one study (Tsacopoulos & David, 1973) finding the resting tonus at the mid-point of the adjustment range, and another (Eperon et al. 1975) showing that it is closer to the vasoconstrictive limit. In humans, the resting tonus of the vessels remains to be determined (Hickam & Frayser, 1966; Eperon et al. 1975; Fallon et al. 1985; Gilmore et al. 2005). In the brain, the relationship between blood flow and hypoxia was previously shown to be modelled as a rectangular hyperbolic function (Mardimae et al. 2012). However, its relationship in the retina has not been accurately characterized (Hickam & Frayser, 1966; Frayser et al. 1971; Eperon et al. 1975; Rennie & Morrissey, 1975; Fallon et al. 1985; Brinchmann-Hansen & Myhre, 1990; Gilmore et al. 2005). The present study used innovative instrumentation that allowed us not only to accurately quantify retinal vascular responses, but also to precisely target the P aO2 stimulus at the same time as controlling the level of carbon dioxide. We aimed to characterize the limitations of the retinal vasculature by modelling the relationship between retinal blood flow and oxygen, C 2015 The Authors. The Journal of Physiology C 2015 The Physiological Society
J Physiol 594.3
Relationship between retinal blood flow and arterial oxygen
thereby simultaneously defining the vascular reserve and resting tonus of the vessels. Methods Ethical approval and subjects
Thirteen healthy non-smoking individuals (age 26.4 ± 4.5 years) participated in the present study. Informed consent was obtained for all thirteen participants. There was no history of ocular, cardiovascular or respiratory disorders for any participant. The study was approved by the Research Ethics Board of the University Health Network, University of Toronto and followed the recent guidelines set by the Declaration of Helsinki. All participants had a logMAR visual acuity of 0.0 or better and a refractive error of
J Physiol 594.3 (2016) pp 625–640
Relationship between retinal blood flow and arterial oxygen Richard W. Cheng1,2,3 , Firdaus Yusof1,3,5 , Edmund Tsui1 , Monica Jong1,6 , James Duffin2,7,9 , John G. Flanagan1,4,8 , Joseph A. Fisher2,7,9 and Chris Hudson1,3,4 1
Department of Ophthalmology and Vision Sciences, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada Department of Physiology, University of Toronto, Toronto, ON, Canada 3 School of Optometry and Vision Science, University of Waterloo, Waterloo, Ontario, Canada 4 Institute of Medical Science, University of Toronto, Toronto, ON, Canada 5 Department of Optometry and Visual Science, International Islamic University of Malaysia, Bandar Indera Mahkota, Pahang, Malaysia 6 Brien Holden Vision Institute, University of New South Wales, Sydney, NSW, Australia 7 Thornhill Research Inc., Toronto, ON, Canada 8 School of Optometry, University of California Berkeley, Berkeley, CA, USA 9 Department of Anesthesiology, Toronto General Hospital, Toronto, ON, Canada
The Journal of Physiology
2
Key points
r Vascular reactivity, the response of the vessels to a vasoactive stimulus such as hypoxia and r
r r
hyperoxia, can be used to assess the vascular range of adjustment in which the vessels are able to compensate for changes in P O2 . Previous studies in the retina have not accurately quantified retinal vascular responses and precisely targeted multiple P aO2 stimuli at the same time as controlling the level of carbon dioxide, thus precluding them from modelling the relationship between retinal blood flow and oxygen. The present study modelled the relationship between retinal blood flow and P aO2 , showing them to be a combined linear and hyperbolic function. This model demonstrates that the resting tonus of the vessels is at the mid-point and that they have great vascular range of adjustment, compensating for decreases in oxygen above a P ETCO2 of 32–37 mmHg but being limited below this threshold.
Abstract Retinal blood flow (RBF) increases in response to a reduction in oxygen (hypoxia) but decreases in response to increased oxygen (hyperoxia). However, the relationship between blood flow and the arterial partial pressure of oxygen has not been quantified and modelled in the retina, particularly in the vascular reserve and resting tonus of the vessels. The present study aimed to determine the limitations of the retinal vasculature by modelling the relationship between RBF and oxygen. Retinal vascular responses were measured in 13 subjects for eight different blood gas conditions, with the end-tidal partial pressure of oxygen (P ETCO2 ) ranging from 40–500 mmHg. Retinal vascular response measurements were repeated twice; using the Canon laser blood flowmeter (Canon Inc., Tokyo, Japan) during the first visit and using Doppler spectral domain optical coherence tomography during the second visit. We determined that the relationship between RBF and P aO2 can be modelled as a combination of hyperbolic and linear functions. We concluded that RBF compensated for decreases in arterial oxygen content for all stages of hypoxia used in the present study but can no longer compensate below a P ETCO2 of 32–37 mmHg. These vessels have a great vascular range of adjustment, increasing diameter (8.5% arteriolar and 21% total venous area) with hypoxia (40 mmHg P ETCO2 ; P < 0.001) and decreasing diameter (6.9% arteriolar and 23% total venous area) with hyperoxia (500 mmHg P ETCO2 ; P < 0.001) to the same extent. This indicates that the resting tonus is near the mid-point of the adjustment ranges at resting P aO2 where sensitivity is maximum. C 2015 The Authors. The Journal of Physiology C 2015 The Physiological Society
DOI: 10.1113/JP271182
626
R. W. Cheng and others
J Physiol 594.3
(Resubmitted 24 June 2015; accepted after revision 19 November 2015; first published online 26 November 2015) Corresponding author C. Hudson: School of Optometry and Vision Science, University of Waterloo, 200 University Avenue West, Waterloo, Ontario N2L 3G1, Canada. Email: [email protected] Abbreviations CLBF, Canon laser blood flowmeter; MAP, mean arterial pressure; P aO2 , arterial oxygen tension; P aCO2 , arterial partial pressure of carbon dioxide; P ETO2 , end-tidal oxygen; P ETCO2 , end-tidal carbon dioxide; P O2 , partial pressure of oxygen; RBF, retinal blood flow; SaO2 , oxygen saturation.
Introduction The retinal circulation forms a closed circuit such that the central retinal artery, which penetrates the optic nerve, passes blood through the arterioles and into the superior capillary plexus or deep capillary plexus, eventually draining into the venules surrounding the optic nerve head. The inner retinal vasculature is uniquely situated in that imaging through the eye permits non-invasive investigation of vascular reactivity, comprising the response of these vessels to a vasoactive stimulus. By examining total flow through all the venules surrounding the optic nerve head or by investigating flow through a specific arteriole, and assuming the arterioles all respond similarly, we can evaluate the response of the retinal vasculature to a stimulus. The retinal vessels, much like the rest of the brain vasculature, respond to increases in oxygen (hyperoxia) by constricting the vessels to decrease blood flow (Eperon et al. 1975; Kiss et al. 2002; Wimpissinger et al. 2005; Sehi et al. 2012; Werkmeister et al. 2012; Tsui et al. 2013) and respond to reductions in oxygen (hypoxia) by dilating the vessels to increase blood flow (Hickam & Frayser, 1966; Frayser et al. 1971; Fallon et al. 1985). Measurements of retinal vascular reactivity may be used to investigate vascular dysregulation in ocular diseases such as diabetic retinopathy (Gilmore et al. 2007) and primary open angle glaucoma (Venkataraman et al. 2010). Indeed, using vascular reactivity assessment to determine retinal vasculature dysfunction will enhance the comprehension of pathophysiology. However, first, the retinal vascular reactivity in healthy young individuals must be characterized. The relationship between retinal blood flow and oxygen for healthy participants has been only loosely defined in previous studies. When examining the acute effects of hypoxia, Hickam & Frayser (1966) and Fallon et al. (1985) demonstrated that retinal vessels in healthy individuals dilate by 10% and increase blood flow by 16–38% for an arterial oxygen saturation (SaO2 ) of 70–80%. However, studies at altitude (Frayser et al. 1971; Rennie & Morrissey, 1975; Bosch et al. 2009) appear to indicate that the vessels can dilate by as much as 20–40%. Vascular reactivity to hyperoxia (100% oxygen) has generally shown that retinal vessels constrict by 10–15%, whereas flow decreases by as much as 40–50% (Eperon et al. 1975; Kiss et al. 2002; Wimpissinger et al. 2005; Sehi et al. 2012; Werkmeister et al. 2012; Tsui et al. 2013). These previous studies
(Hickam & Frayser, 1966; Frayser et al. 1971; Fallon et al. 1985; Brinchmann-Hansen & Myhre, 1990; Wimpissinger et al. 2005; Sehi et al. 2012; Werkmeister et al. 2012; Tsui et al. 2013) have generally investigated only one hypoxic or hyperoxic stimulus, which precludes modelling the entire relationship between retinal blood flow and oxygen, as well as determining the vascular reserve and resting tonus of the retinal vessels. The methodologies employed probably resulted in large inter-individual variability not only because of instrument inaccuracies, but also as a result of the imprecision of the gas provocation method used to target a given arterial partial pressure of oxygen (P aO2 ). Breath to breath fluctuations in end-tidal partial pressures of oxygen (P ETCO2 ) and an inability to maintain isocapnia have therefore limited previous investigations (Hickam & Frayser, 1966; Frayser et al. 1971; Fallon et al. 1985; Brinchmann-Hansen et al. 1989). The retinal vascular responses to oxygen can also be used to determine the vascular adjustment reserve of the vessels, which is the maximal amount by which the vessels can dilate and constrict, as well as the resting tonus, which is the tone of the vessels at resting P aO2 . Measurements of the vascular reserve and resting tonus of the retinal vessels will demonstrate the extent of the ability of the vasculature to compensate for changes in oxygen. Studies in monkeys report conflicting results, with one study (Tsacopoulos & David, 1973) finding the resting tonus at the mid-point of the adjustment range, and another (Eperon et al. 1975) showing that it is closer to the vasoconstrictive limit. In humans, the resting tonus of the vessels remains to be determined (Hickam & Frayser, 1966; Eperon et al. 1975; Fallon et al. 1985; Gilmore et al. 2005). In the brain, the relationship between blood flow and hypoxia was previously shown to be modelled as a rectangular hyperbolic function (Mardimae et al. 2012). However, its relationship in the retina has not been accurately characterized (Hickam & Frayser, 1966; Frayser et al. 1971; Eperon et al. 1975; Rennie & Morrissey, 1975; Fallon et al. 1985; Brinchmann-Hansen & Myhre, 1990; Gilmore et al. 2005). The present study used innovative instrumentation that allowed us not only to accurately quantify retinal vascular responses, but also to precisely target the P aO2 stimulus at the same time as controlling the level of carbon dioxide. We aimed to characterize the limitations of the retinal vasculature by modelling the relationship between retinal blood flow and oxygen, C 2015 The Authors. The Journal of Physiology C 2015 The Physiological Society
J Physiol 594.3
Relationship between retinal blood flow and arterial oxygen
thereby simultaneously defining the vascular reserve and resting tonus of the vessels. Methods Ethical approval and subjects
Thirteen healthy non-smoking individuals (age 26.4 ± 4.5 years) participated in the present study. Informed consent was obtained for all thirteen participants. There was no history of ocular, cardiovascular or respiratory disorders for any participant. The study was approved by the Research Ethics Board of the University Health Network, University of Toronto and followed the recent guidelines set by the Declaration of Helsinki. All participants had a logMAR visual acuity of 0.0 or better and a refractive error of
