WO2000006017A1 - Oxymetre permettant de former une image d'un vaisseau sanguin - - Google Patents

Oxymetre permettant de former une image d'un vaisseau sanguin - Download PDF

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Publication number
WO2000006017A1
WO2000006017A1 PCT/US1999/017204 US9917204W WO0006017A1 WO 2000006017 A1 WO2000006017 A1 WO 2000006017A1 US 9917204 W US9917204 W US 9917204W WO 0006017 A1 WO0006017 A1 WO 0006017A1
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Prior art keywords
image
oxygen saturation
blood oxygen
values
determining
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Application number
PCT/US1999/017204
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English (en)
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WO2000006017A9 (fr
Inventor
James M. Beach
James S. Tiedeman
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University Of Virginia Patent Foundation
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Publication date
Application filed by University Of Virginia Patent Foundation filed Critical University Of Virginia Patent Foundation
Priority to AU55450/99A priority Critical patent/AU5545099A/en
Publication of WO2000006017A1 publication Critical patent/WO2000006017A1/fr
Publication of WO2000006017A9 publication Critical patent/WO2000006017A9/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/1455—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using optical sensors, e.g. spectral photometrical oximeters
    • A61B5/14551—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using optical sensors, e.g. spectral photometrical oximeters for measuring blood gases
    • A61B5/14555—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using optical sensors, e.g. spectral photometrical oximeters for measuring blood gases specially adapted for the eye fundus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B3/00—Apparatus for testing the eyes; Instruments for examining the eyes
    • A61B3/10—Objective types, i.e. instruments for examining the eyes independent of the patients' perceptions or reactions
    • A61B3/12—Objective types, i.e. instruments for examining the eyes independent of the patients' perceptions or reactions for looking at the eye fundus, e.g. ophthalmoscopes
    • A61B3/1225—Objective types, i.e. instruments for examining the eyes independent of the patients' perceptions or reactions for looking at the eye fundus, e.g. ophthalmoscopes using coherent radiation
    • A61B3/1233—Objective types, i.e. instruments for examining the eyes independent of the patients' perceptions or reactions for looking at the eye fundus, e.g. ophthalmoscopes using coherent radiation for measuring blood flow, e.g. at the retina

Definitions

  • the present invention relates to an apparatus and method for evaluating oxygen utilization in the posterior pole tissue of the eye. More particularly, the present
  • invention relates to a simple apparatus and method for measuring the hemoglobin oxygen saturation of retinal blood vessels using digital image analysis of reflectance at two specially
  • the blood supply to the inner retina is well-regulated to maintain an adequate
  • the inner retina may be the direct cause of many diseases, such as diabetic retinopathy,
  • papallopathy glaucoma, optic atrophy and macular degeneration, among others.
  • Diabetic retinopathy for example, is a progressively damaging eye disease
  • Diabetic retinopathy may create several
  • retinal disorders including swelling at the center of the retina, and reduction of retinal
  • diabetic retinopathy Like many eye diseases, diabetic retinopathy is preceded by early stage warning signs that can trigger severe damage if undetected. In diabetic retinopathy, such
  • BDR background diabetic retinopathy
  • Hickam, et al. and Laing, et al. investigated the use of photographic densitometry of large retinal vessels in vivo to monitor arterial and venous retinal blood
  • an apparatus for evaluating oxygen utilization in posterior pole tissue of an eye includes a fundus camera capable of generating an intermediate image of blood vessels in an eye, and a beam splitter assembly comprising a beam splitter, a first bandpass filter and a second bandpass filter.
  • beam splitter is capable of splitting the intermediate image generated by the fundus camera
  • a baffle is disposed between the first image and the
  • the apparatus of the present invention further includes an electronic imaging device capable
  • a digital imaging device may be of any known type, such as a digital imaging device, and preferably is a
  • apparatus of the present invention typically comprise separate but connected units, the fundus camera, beam splitter and electronic imaging device may comprise an integral unit.
  • the first and second images are passed through the first and second bandpass filters, respectively.
  • bandpass filter has a first wavelength and the second bandpass filter has a second wavelength
  • the first and second wavelengths being chosen to optimize the imaging capability of the first and second wavelengths
  • the wavelength of the first bandpass filter preferably is chosen to be an oxygen-sensitive wavelength of 600 nm ⁇ 2.5 nm
  • the second wavelength of the second bandpass filter preferably is chosen as 569 nm ⁇ 2.5 nm
  • the fundus in one embodiment of the apparatus of the present invention, the fundus
  • the camera has an imaging plane external to the body of the fundus camera.
  • other fundus cameras may be used which have an imaging plane internal to the body of the fundus camera.
  • the imaging plane is formed
  • the fundus camera may comprise a filter wheel
  • the beam splitter assembly may have a plurality of front surface mirrors to
  • a cover may be disposed over
  • the beam splitter assembly to protect it from contamination.
  • plurality of front surface mirrors is mounted so as to be adjustable, and the beam splitter
  • assembly comprises means for mounting the plurality of front surface mirrors in the beam
  • the splitter assembly may include a base plate.
  • the base plate may have a first side portion with a first plurality of rails, and a second side portion with a second plurality of rails. The first and
  • second pluralities of rails may be used to support first and second pluralities of mirror
  • a first portion of the front surface mirrors may be attached to the first
  • a first drive assembly may be selectively attached at least one of the first plurality of mirror mounts, wherein movement of the first drive assembly
  • a second drive assembly may be selectively attached to at least one of the second plurality of mirror mounts, wherein
  • the first drive assembly may comprise a first micrometer and the second
  • drive assembly may comprise a second micrometer.
  • the present invention is also drawn to a method for evaluating oxygen utilization in posterior pole tissue of an eye.
  • An embodiment of the apparatus of the present invention, or another apparatus, may be used to perform this method.
  • the method includes reflecting a light beam off of blood vessels in an eye to create an intermediate image of the
  • the method further comprises producing an
  • wavelength of the first image and the second wavelength of the second image are chosen to
  • I ⁇ n and I out ", respectively) may be determined from the first and second images of the blood vessel by scanning the first image and the second image. The path of minimum reflection inside the blood vessel may then be
  • the I values along with other data
  • O 2 SAT vein and O 2 SAT artery , respectively
  • O 2 SAT artery may also be determined for a given subject at different times after an
  • the direct reflectance method comprises determining values of arterial optical density ratio ("O ⁇ R ⁇ ”) for a subject using data contained in the electronic recording of the
  • the pigmentation correction method is used to reduce the influences of pigmentation on calculated values of O 2 SAT ve ⁇ n . Under this method, unless previously determined, the values of the variables required for determining O 2 SAT vess must first be
  • This comprises estimating, for a plurality
  • the reflectance at the second chosen wavelength, where pigment light absorption is strong using the reflectance at the first chosen wavelength where pigment light absorption is significantly less than that at the second wavelength.
  • ODR cor artery (“ODR cor artery ”) values are compared to values of systemic O 2 SAT corresponding therewith to determine a value for pigmentation corrected OS. Once a value for pigmentation corrected
  • OS is determined, a simple equation may be employed to obtain a value for O 2 SAT cor for an
  • the intravascular reflectance method permits the determination of O 2 SAT ve ⁇ n
  • O 2 SAT vess must first be obtained using the intravascular reflectance method. This method
  • value may be calculated independent of pigmentation for any subject at any time.
  • intravascular reflectance methods may also be corrected for vessel size. This is done by
  • the variables determined using the direct reflectance method are accurate for the subject from which the data used was obtained, but may not be as accurate for other
  • pigmentation correction and intravascular reflectance methods are determined using a
  • O 2 SAT vessel (or a change in O 2 SAT ve ⁇ n or O 2 SAT artery after an intervention) in
  • oximeter of the present invention is useful to diagnose eye diseases, including such diseases as diabetic retinopathy, papallopathy, glaucoma, retinal vein occlusion, optic atrophy and macular degeneration.
  • eye diseases including such diseases as diabetic retinopathy, papallopathy, glaucoma, retinal vein occlusion, optic atrophy and macular degeneration.
  • the determination of O 2 S AT values is automated using a
  • FIG. 1 is a schematic illustration of one embodiment of the imaging ocular
  • FIG. 2 is a schematic illustration of a commercially available fundus camera
  • FIG. 3a
  • FIG. 6a is an orthographic top view, full scale, of the mirror mount shown in
  • FIGS. 3a-3c the assembly of FIGS. 3a-3c;
  • FIG. 6b is an orthographic side view, full scale, of the mirror mount shown in FIGS. 3a-3c;
  • FIG. 7a is an orthographic top view, full scale, of the first drive block shown in the assembly of FIGS. 3a-3c;
  • FIG. 7b is an orthographic side view, full scale, of the first drive block shown in FIGS. 3a-3c;
  • FIG. 8a is an orthographic top view, full scale, of the second drive block shown in the assembly of FIGS. 3a-3c;
  • FIG. 8b is an orthographic side view, full scale, of the second drive block shown in FIGS. 3a-3c;
  • FIG. 10 is a side-by-side composite of two simultaneous, digitally recorded
  • FIG. 11 is a side-by-side composite of two computer-generated scans of simultaneous retinal images taken using bandpass filters having center wavelengths 600 nm
  • FIG. 12 is a schematic illustration of a breathing circuit used to collect data
  • FIG. 13 is a plot showing the relationship between ODR, calculated using the
  • FIG. 14 is a plot showing the relationship between ODR cor , calculated using the pigmentation correction method of the present invention, and O 2 SAT;
  • FIG. 15 is a plot showing the relationship between ODR cor calculated at 100%
  • FIG. 16 is a plot showing the relationship between ODR ⁇ , calculated using the intravascular reflectance method of the present invention, and systemic O 2 SAT artery .
  • the imaging ocular vessel oximeter of the present invention and the method of the present invention for measuring O 2 SAT and changes in O 2 SAT, will now be described
  • an imaging ocular vessel oximeter 8 made in accordance with the principles of the present invention includes a fundus camera 10, a beam splitter assembly 12, bandpass filters 14 and 15 and an imaging device 16.
  • FIG. 2 schematically in FIG. 2 is based upon a Kowa RC/W fundus camera, manufactured by Kowa
  • the Kowa RC/W fundus camera as provided by the manufacturer has a body 19 and an imaging plane external to the camera, beyond exit aperture 18.
  • a slit mask 28 is positioned at intermediate image plane 26 slightly off the optical axis to avoid central light artifacts produced by the fundus camera.
  • fundus camera 10 may be any conventional or specially designed fundus camera.
  • an internal xenon flash 30 is provided to fundus camera 10 of FIG. 2.
  • Flash energy is supplied in this embodiment by a Model 404 external strobe power supply (not shown), manufactured by Norman Co. of Burbank, California, at a setting of 200 Joules, providing a retinal exposure per flash of approximately
  • Flashes are synchronized with the operation of imaging device 16 in the conventional manner. Wavelengths above and below the wavelengths to be recorded are eliminated with a broadband illumination filter 32 which, in this embodiment, is a 580 nm center, 60 nm half-width filter. The light from the flash then passes through a condensing
  • lens 34 is redirected by mirrors 36, 38, and passes through an opthalmological lens 40 to the retina of a patient's eye. Reflected light returns back through opthalmological lens 40, through a mirror aperture 42, through a negative lens 44 contained in filter wheel 46, and through a variable focus objective lens 48, producing the intermediate image at slit mask 28 which projects past the backplate 50 of fundus camera 10.
  • a second positive lens 52 a 2- element achromatic converging lens, is placed after slit mask 28 and before beam splitter
  • second positive lens 52 is manufactured by Edmund Scientific of Barrington, New Jersey.
  • beam splitter assembly 12 is mounted to fundus
  • beam splitter assembly 12 may be mounted another way or be manufactured as an integral unit with fundus camera 10 and/or
  • beam splitter assembly 12 is used to separate the light forming the intermediate image into first and second image paths of identical lengths, and ultimately into first and second laterally displaced, simultaneous images 13 and 17 at imaging device 16.
  • beam splitter assembly 12 is used to separate the light forming the intermediate image into first and second image paths of identical lengths, and ultimately into first and second laterally displaced, simultaneous images 13 and 17 at imaging device 16.
  • beam splitter assembly 12 of the embodiment illustrated in FIGS. 1 and 2 comprises a dichroic mirror 55, first bandpass filter 14 and a second bandpass filter 15 placed in each optical path emanating from dichroic mirror 55.
  • the beam splitter assembly 12 represented in FIG. 1 is manufactured by Optical Insights of
  • first and second bandpass filters 14 and 15 should be chosen to optimize the O 2 SAT signal, and therefore the
  • imaging capability of imaging device 16 with respect to O 2 SAT.
  • bandpass filter 14 should be chosen to have a wavelength that yields sufficient contrast to enable automatic computer vessel tracking, and the greatest degree of oxygen sensitivity.
  • the wavelength of second bandpass filter 15 should be chosen to be either completely
  • a 600 nm center wavelength (600 nm ⁇ 2.5 nm passband) was chosen for first bandpass filter 14 (light abso ⁇ tion of hemoglobin and deoxyhemoglobin at that wavelength differ by a large factor - approximately a factor of 4), and a 569 nm center wavelength (569 nm ⁇ 2.5 nm passband) was chosen for second bandpass filter 15 (it is an isosbestic wavelength for hemoglobin and oxyhemoglobin).
  • 600 nm and 569 nm bandpass filters used in connection with the embodiment of FIGS. 1 through 9 are manufactured by Omega Optical Co., and are side mounted, 5 nm halfwidth interference bandpass filters blocked for UV and IR out to 1100 nm.
  • a 586 nm ⁇ 2.5 nm wavelength could have been used, which, when paired with a 600 nm wavelength bandpass filter, would have the additional benefit of further decreasing the light scattering effect of the tissue because the two wavelengths are more closely matched.
  • a highly sensitive wavelength such as 558 nm ⁇ 2.5 nm could have been chosen for second bandpass filter 15, which would provide greater sensitivity when paired with a 600 nm wavelength bandpass filter because the change in light absorption
  • Figure 10 shows the effect of differing oxyhemoglobin content on reflected light from retinal vessels near the optic disk. Reflected light intensities from arteries A and veins V at the isosbestic wavelength (569 nm) (shown in second image 17 of FIG. 10) are
  • beam splitter assembly 12 also includes front surface mirrors 60, 62, 64, 66, 68, 70 and 72, which are used to effect a lateral displacement of first and second images 13 and 17.
  • front surface mirrors 60, 62, 64, 66, 68, 70 and 72 which are used to effect a lateral displacement of first and second images 13 and 17.
  • the 15 mm base TechSpec right angle mirror with enhanced aluminum coatings manufactured by Edmund Scientific Co. of Brunswick, New Jersey, has been found to be acceptable for use in connection with the present invention.
  • the positions of front surface mirrors 60 through 72 relative to first image 13 and second image 15 preferably are adjustable by any conventional means for adjustment, such as screws, bolts or other fasteners or other devices known in the art that would be useful for this purpose.
  • FIGS. 3-8 One design for selectively fixing and adjusting the positions of front surface mirrors 60 through 72 is illustrated in FIGS. 3-8. As shown in FIG.
  • mounting assembly 74 may be used to secure front surface mirrors 60 through 72 in place, and selectively permit adjustment of their positions.
  • Mounting assembly 74 includes a base plate 76, having a center portion 75, illustrated in FIG. 4, to which front surface mirrors 64, 66 and 72, dichroic mirror 55, and bandpass filters 14 and 15 are mounted to permit their 2° rotational adjustment about the optic axis.
  • Base plate 76 further includes side portions 77, illustrated in FIG. 5, to which front surface mirrors 60, 62, 68 and 70 are attached. As shown in FIG. 5, side portions 77 of base plate 76 have rails 78, 80, 82 and 84 on which mirror mounts 86, 88, 90 and 92 are disposed.
  • mirror mounts 86, 88, 90 and 92 are illustrated in FIG. 6 in isolation, and in FIG. 3 as contemplated for use in mounting assembly 74.
  • front surface mirror 68 is mounted to mirror mount 86 by a common vinyl doping compound, epoxy or another adhesive or
  • Mirror mount 86 is mounted on rail 82 and nominally held fixed in
  • first drive assembly 95 includes a first drive block 96 and a first micrometer assembly 98.
  • first drive block 96 has a first screw bore 98 and a second screw bore 100, matching screw bore 102 on mirror mount 86 and screw bore 104 on mirror mount 88.
  • First micrometer assembly 98 has a micrometer shaft 106 stabilized by a shaft support block 108 and aligned parallel to rails 82 and 84, and is designed to fit movably within a drive bore 110 of first drive block 96.
  • Drive bore 110 is intersected by a threaded set screw bore 112 such that when micrometer shaft 106 is positioned within drive bore 110, a set screw may be used to fix micrometer shaft 106 in place.
  • micrometer shaft 106 will effect movement of micrometer shaft 106 and one or both of first and second mirror mounts 86 and 88, depending upon whether one or both of the set screws of mirror mounts 86 and 88 have been tightened. Movement of first and second
  • mirror mounts 86 and 88 effects movement of front surface mirrors 68 and 70 along rails 82 and 84, respectively. Movement of one or both front surface mirrors 68 and 70 changes the path length through beam splitter assembly 12, causing a change in magnification.
  • FIGS. 1 and 8 a similar arrangement exists for the positioning and selective adjustment of mirror mounts 90 and 92 and front surface mirrors 60 and 62 using rails 78 and 80 and a second drive assembly 114, including a second drive block 116 and a second micrometer assembly 118.
  • a cover 120 as illustrated in
  • FIG. 9 may be used to protect beam splitter assembly 12 from contamination, and to ensure that excess light is not introduced.
  • Cover 120 includes openings 122 and 124 for permitting micrometer shafts and set screws to extend into beam splitter assembly 12 and be externally adjusted. Openings 122 and 124 may be insulated using gaskets, diaphragms, baffles or other protective devices to preclude excess light from entering the assembly. Similarly, light- absorbing surface coatings may be used inside the assembly to eliminate any excess noise that would otherwise be created.
  • an opaque light baffle 53 is used to block stray light between first image 13 and second image 17 emerging from beam splitter assembly 12 and to produce a line of dark pixels separating simultaneous first and second images 13 and 17 as recorded by imaging device 16 (i.e., line "L" in FIG. 10).
  • Opaque light baffle 53 may be constructed of any suitable material that is generally opaque and nonreflective, and in the present embodiment is made of aluminum covered by electrical insulating tape and further
  • imaging device 16 which is mounted to beam splitter assembly 12 using the
  • Imaging device mounting bracket 126 provided with the imaging device used.
  • Imaging device 16 may comprise any high-quality custom or commercially available electronic imaging system. In the embodiment of FIGS. 1 and 2, imaging device 16 is a Model OMA
  • the Model OMA camera is an 18 bit air-cooled digital camera equipped with a 1024 xl024 pixel charge-coupled device detector 128. Where another type of imaging system is used for imaging device 16, the resolution preferably will be 12 bit or greater. When a EG&G Park Model OMA imaging device is used as imaging device 16, it may be controlled using the manufacturer's "HIDRIS" software or its equivalent.
  • the imaging retinal oximeter 8 of the embodiment shown in FIGS. 1 through 9 is inexpensive, compact and easy to use, and is appropriate for use in clinical and other
  • FIGS. 1 though 9 illustrate only
  • imaging ocular vessel oximeter 8 of the present invention one potential embodiment of the imaging ocular vessel oximeter 8 of the present invention, and other obvious variations of the apparatus are contemplated.
  • virtually any commercially available fundus camera could be used for fundus camera 10, and the remaining components of the system adjusted accordingly.
  • fundus camera could be used for fundus camera 10
  • imaging device 16 may comprise two separate imaging systems, both preferably being digital systems, each such system being positioned directly after first and second bandpass filters 14 and 15, eliminating the need and cost of front surface mirrors 60 through 72 and mounting assembly 74.
  • First and second bandpass filters 14 and 15 could also be selected to have an oxygen-sensitive wavelength other than 600 nm, and an oxygen-insensitive wavelength other
  • the image acquisition step of the present invention is complete once first and second images 13 and 17 of a patient's retinal blood vessels are obtained using imaging device 16.
  • the image acquisition step is followed by a scanning step in which a search algorithm embedded in a computer software program is used to scan first and second images 13 and 17 and obtain I values from identical vessel segments in first and second images 13 and 17.
  • a search algorithm embedded in a computer software program is used to scan first and second images 13 and 17 and obtain I values from identical vessel segments in first and second images 13 and 17.
  • first image 13 is a scan of a 600 nm image
  • second image 17 is a scan of a 569 nm image.
  • the search algorithm tracks the path 130 of the minimum reflection inside vessels V to determine a value of average reflected light intensity I in within the vessel V and the path 132 of the extravascular reflection at a fixed distance from the minimum reflection to determine a value of average reflected light intensity I out outside the vessel V, in both first and second images 13 and 17.
  • the initial x-y coordinate of the vessel segment is identified in second image 17 (the 569 nm image), where vessel contrast is greater than in first image 13 (the 600 nm image), and x- and y- offsets to the same anatomic point on first image 13 are determined. If light reflex artifacts are present in the center of the vessel, the starting point is chosen to lie to the side of the reflex. Typically, between 30 and 120 rows or columns of elements in second image
  • Edges of the blood column may be identified using gradient detection filters (Sobel operators) embedded in the computer code. The edge is identified at pixels for which the sum of filter responses peaks. Accordingly, this procedure will not mistake smaller light gradients of the central vessel reflection for the edge
  • first image 13 Similar measurements are obtained from first image 13 by adding the x- and y- offsets to the vessel path determined from second image 17. Contrast in the first image also aids in correctly scanning the vessel path. Similarly, dark pixel values from an area of the charge-coupled device detector 128 outside the fundus image (i.e. the dark line denoted as
  • the acquired data may be used to calculate O 2 SAT vessel . This may be done simply and automatically, preferably using a computer program. Before a subject's hemoglobin saturation level can be quantified using this system, however, empirical values required for such quantification must be calculated, preferably using data acquired in a statistically relevant study of a wide range of individuals such that the values will be relevant for any subject for which hemoglobin oxygen saturation is to be measured. Significantly, under two approaches of the method of the present invention, such an initial calibration need only be done once in order to measure O 2 S AT vesse , for any of an unlimited number and variety of individuals (although separate calibrations would likely be
  • Direct Reflectance Method In accordance with the direct reflectance method, a direct calculation of the apparent vessel optical densities OD 569 and OD 600 is obtained for a given subject from I in and
  • 0D vessel l ⁇ g 10 (I out / LJ where OD vessel is the optical density of a vessel, I out is the average intensity outside the vessel, and I in is the average intensity inside the vessel. The values of ODR ⁇ ,., are then determined
  • ⁇ vessel OL» vessel,600 / OD v ⁇ e
  • O 2 SAT vessel may be calculated using the slope, OS, and intercept, Int, of the regression line as follows:
  • O 2 SAT vessel - Inty OS Regression coefficients will need to be obtained for each new vessel by a separate calibration.
  • the linear response of the oximeter has been established with the direct reflectance method, it may be impractical to use this method to study a large number of subjects, as is needed in clinical evaluations and research investigations.
  • the present invention contemplates that the amount of pigment contained in extravascular structures will vary from subject to subject, and will have an effect on measured OD vessel values which influence the relationship between ODR, ⁇ , and O 2 SAT vessel . It is noted that presence of extravascular pigment causes
  • the vessel diameters differ by a large factor.
  • the pigmentation correction method of the present invention overcomes the disadvantages of the direct reflectance method.
  • the pigmentation correction method significantly reduces influence of pigmentation upon the relationship between ODR,,,. ⁇ , and O 2 SAT vessel .
  • the pigmentation correction method of the present invention provides such a correction, as well as a correction for the vessel diameter.
  • the pigmentation correction method of the present invention assumes that extravascular light reflectance at the first wavelength (e.g., 600 nm) is influenced to a significantly lesser degree by pigment light abso ⁇ tion than is the reflectance at the second wavelength (e.g... 569nm), where pigment light abso ⁇ tion is strong.
  • a corrected value for OD vessel at 569 nm (“OD cor 569 ") is calculated using the following formula for each artery and vein pair in each subject:
  • OD cor, 569 1 Og ⁇ o ( ⁇ Iout, 600 I in, 569) where ⁇ is the ratio of transmission from the light source to each of the images inherent in the image splitter and camera.
  • ⁇ is the ratio of transmission from the light source to each of the images inherent in the image splitter and camera.
  • ODR cor OD 600 / OD cor 569 .
  • the ODR cor values are plotted against systemic O 2 SAT, values of which are known from pulse oximeter measurements as described previously. A linear regression analysis may then be performed between these variables, and slopes of regression may be found in the conventional manner.
  • the variance of linear regression coefficients between subjects is significantly reduced with respect to those obtained using uncorrected ODR values ( " e.g. using the direct reflectance method). Therefore, it has been found that the mean value of regression slopes can serve to represent the oxygen sensitivity, OS, which is inherent in the oximeter response.
  • Plots of regression lines from several subjects document the degree of agreement between regression slopes obtained in a group of subjects having skin pigmentation varying from fair to dark, and iris pigmentation of blue and brown.
  • the generation of the data represented in FIG. 14 is discussed in the example presented below.
  • the degree of improvement is noticeable by comparing this plot with that of the direct reflectance method shown in FIG. 13.
  • the pigmentation correction method reduces, but does not eliminate, the range of vertical offsets between the regression lines.
  • the invention anticipates that by measurement of the vessel ODR cor during breathing of 100% oxygen, the correct amount of vertical offset can be ascertained.
  • the vertical offset is first determined during oxygen breathing, and the value of O 2 SAT is then determined under desired conditions by a second measurement.
  • OS which is determined from the mean of regression slopes determined earlier from calibration measurements, is applied to make the particular desired measurement of O 2 SAT in the desired vessel.
  • O 2 S AT vessel 100% - (ODR corjartery - ODR cor ⁇ Vessel - ( ⁇ D x C)) / OS
  • ⁇ D the difference in diameters of the vessels
  • C the slope of the line fit between ODR cor artery at 100% oxygen and diameter as shown in FIG. 15 (upper panel), e., vessel diameter sensitivity.
  • This equation takes into account the vertical offsets in measurements of ODR cor at 100% O 2 SAT by adjusting the ODR ⁇ ,.,.,,, value according to the relationship between ODR at 100% O 2 SAT and vessel diameter ("D"). The equation therefore corrects the measurement for any effects caused by differences in vessel diameter.
  • the value of ⁇ D is difference in the value of D for two vessels, in particular for one artery for which measurement was made with 100% breathing oxygen, and for a second vessel for which measurement is made under desired conditions.
  • Correction for D is thus based on measurement of the vessel diameters and upon the linear regression fit between the ODR cor at 100% O 2 SAT and vessel diameter, and this correction is included in the equation as a factor which adjusts the value of the ODR cor by an amount predicted by the relationship established through the regression fit between the value of ODR cor measured in the artery at 100% and vessel diameter.
  • This method of pigmentation correction provides means to utilize the oximeter for measurement of O 2 SAT in arteries and veins of the general population under desired measurement conditions, which include those presented by experimental means and those presented by disease conditions.
  • Intravascular Reflectance Method Another method for calibrating the system to avoid the effects of pigmentation and vessel diameter is the intravascular reflectance method. This approach involves comparing reflectance from only within blood vessels at the two chosen wavelengths, and replacing measured reflectance outside vessels with an estimate of reflectance from unpigmented fundus.
  • UR unpigmented reflectance
  • ODR, ⁇ m% is an ODR value obtained using the intravascular reflectance method
  • UR is unpigmented reflectance
  • I ⁇ n 600 100% and I ⁇ n 569 100 o /o are average intensities obtained inside blood vessels in the 600 nm and 569 nm wavelength images, respectively, and obtained from images recorded during 100% oxygen breathing
  • e ⁇ 600 and ⁇ m02, 569 are extinction coefficients of blood which are measured using first and second bandpass filters employed for wavelength selection at 600 and 569 nm.
  • the equation set forth above is used with measurements of I jn obtained from images recorded during 100% oxygen breathing to calculate UR for each subject.
  • the above equation is again employed for a given subject, using the UR value obtained for that subject, to obtain values of ODR ⁇ for systemic O 2 SAT artery values other than 100% O ⁇ AT ⁇ ,. This is done for each subject, and a plot of ODR j ⁇ ,, vs. O 2 SAT artery is obtained for each. A line of best fit is determined for each of these plots.
  • a value of oximeter response OS is then determined from the simple mean of best fit line slopes.
  • correction for vessel diameter is obtained by adjusting the value of the slope according to the relationship between regression slopes and diameter.
  • the other difference between the pigmentation correction method and this method is that the second measurement using 100% oxygen breathing is not necessary.
  • This step is instead included in the model assumption and, as can be seen from the regression lines obtained by this method in FIG. 16, all the lines converge to the value of the ODR predicted by the model at 100% O 2 SAT artery .
  • the effect of vessel diameter upon the slope of the lines is readily apparent (FIG. 16).
  • the process of using the intravascular reflectance method involves first establishing the mean value for OS and the value for C.
  • the value of O 2 SAT in a particular vessel under desired measurement conditions may then be found by first measuring the ODR j ⁇ for the vessel and locating this value on the y axis of a plot with respect to systemic
  • O 2 SAT O 2 SAT.
  • the diameter of the vessel is measured as described above for the pigmentation correction method.
  • This value of D is used to correct the mean value of the slope obtained during calibration measurements in different subjects.
  • the intravascular reflectance method thus also enables measurement of O 2 SAT vessel from the general population once initial calibrations with the oximeter are performed. This method has advantages of requiring only reflectance readings from within the blood vessels, which simplified the process of scanning the image. Exclusion of measurements from extravascular areas also reduces spurious influence upon the measurement from specular reflections outside vessels, such as from nerve fibers near the surface of the tissue.
  • the empirical value OS derived from the pigmentation correction method or intravascular reflectance method need only be obtained once using a statistically significant population and appropriate scientific methods to ensure accuracy.
  • This value along with the forgoing formula for calculating O 2 SAT vein or ⁇ O 2 SAT vem , may then be embedded in a computer program for generating a result for research or diagnostic pu ⁇ oses evaluating the oxygen utilization (e.g., oxygen supply, delivery, consumption, and gradients of O 2 SAT along vasculature) in the tissue of the retina or other portions of the posterior pole of the eye.
  • a device of the type described above is used to perform the image acquisition step of the present invention, obtaining simultaneous first and second images 13 and 17 of a patient's retinal blood vessels using imaging device 16, which preferably is a digital camera.
  • a search algorithm embedded in the computer program may then be used to perform the scanning step of the invention, in which first and second images 13 and 17 are scanned and I in and I out values obtained. If the requisite OS value has not yet been obtained, the computer program may then be further used to calculate ODR values using the direct reflectance, pigment correction or intravascular reflectance methods, or another calibration method which preferably corrects for pigmentation and/or vessel size.
  • the computer program may also be programmed to calculate a value for O 2 SAT vem using data collected for a subject. In a clinical setting, this value may be compared to available data concerning diseases affecting the posterior pole of the eye, and a diagnosis made.
  • the present approach differs from those previously employed in several important respects, including the use of an image splitter and digital image method of reflectance at two carefully wavelengths to determine empirical relationships between ODR and O 2 SAT values, avoiding assumptions about the optical path through a vessel.
  • the system is compact, low-cost, and simple to use.
  • the present approach uniquely features the ability to compensate for the variability in fundus pigmentation among different individuals, as well as for vessel diameter, using a device and method that are simpler in theory and practice and require less complex instrumentation than those previously described.
  • This approach yields reasonable estimates of O 2 SAT in both the larger retinal arteries and veins, and should be applicable to vessel sizes of between about 50 ⁇ m and 200 ⁇ m.
  • the present invention also makes possible understanding the effects of metabolism or blood flow changes on retinal function by enabling the determination of changes in vessels occurring before and after interventions, a change which is made straightforward to obtain since many variables potentially affecting absolute measures of O 2 SAT will cancel.
  • the values derived from the empirical relationships disclosed and utilized in the present invention will vary somewhat depending upon the size and composition of the pool of subjects from which data is collected, an adequate sample size and inclusion of light and dark pigmented subjects will ensure the validity of these empirical relationships. The following provides an example of the calculation of such values.
  • Oximetry data was collected in a study often volunteers using the imaging ocular oximeter illustrated in FIGS. 1-9.
  • the volunteers were healthy, non-smoking males aged 18-40 years and having no history of dyshemoglobinemia.
  • One subject was unable to complete the oximetry portion of the study.
  • Two subjects were excluded from the oximetry portion of the study because images obtained from one of these subjects revealed sclerosis of the arterial wall, and in the other subject the artery demonstrated extreme instability of caliber during measurements.
  • an Ohmeda 3700 version J
  • a finger probe could have been used instead, an ear probe was chosen because of its ability to respond accurately and quickly to a changing systemic O 2 SAT artery .
  • the Ohmeda 3700 in particular features a graphic display of waveform and signal strength to aid in minimizing inaccurate readings. As illustrated schematically in FIG.
  • a Mapleson C breathing circuit 134 and face mask 136 was modified by inserting an inspiratory valve 138 just proximal to the mask, allowing all exhaled gas to be vented through an expiratory valve 140 placed just distal to face mask 136.
  • This arrangement of components kept rebreathing of alveolar gas and dead space to a minimum.
  • a polarographic inspired oxygen analyzer 142 with a Clark electrode (Critikon Oxychek model 2000) was calibrated to room air and inserted just proximal to inspiratory valve 138.
  • Velcro straps (not shown) were used to fix face mask 136 tightly over a subject's mouth and nose.
  • a fresh gas flow port 144 was positioned between oxygen analyzer 142 and a reservoir bag 146. Reservoir bag 146 was inflated with the gas mixture before breathing started.
  • Subjects were allowed to breathe room air during the first series of fundus image recordings.
  • Various oxygen/nitrogen mixtures size H gas cylinders
  • subjects breathed either a gas mixture containing 14% oxygen, which corresponds to an arterial hemoglobin O 2 SAT of approximately 94%, or a mixture of 10%) oxygen, which corresponds to a hemoglobin O 2 SAT of approximately 84%.
  • the 14% oxygen mixture was given followed by the 10% oxygen mixture.
  • a mixture containing 8% oxygen was then given, which corresponds to a hemoglobin O 2 SAT of approximately 80%.
  • the pulse oximeter systemic O 2 SAT reading was noted.
  • the eyes of each subject were dilated with topical tropicamide 1% and phenylephrine 2.5%. After the pupil diameter stabilized, the room was darkened and the subject's fundus was illuminated using the tungsten aiming light (not shown) of fundus camera 10. The eye gaze was positioned to enable imaging the retinal area of interest using a movable illuminated fixation target against a dark background. Optimal focus was also achieved using the aiming light. The actual image recording at each breathing gas mixture was made using xenon flash 30.
  • Three to five dual wavelength images (comprising first and second images 13 and 17) were recorded at each gas mixture and stored to the disc memory of a computer.
  • Each image element formed by imaging device 16 was formed with 3x3 pixels, with the camera temperature maintained at -60°C.
  • the scanning step of the invention was performed as described previously using the computer program set forth in full in Appendix A hereto.
  • a pigmentation correction method was used to correct for pigmentation among the various subjects, as well as for vessel diameter.
  • ⁇ was calculated to be 1.79 for the embodiment of the imaging retinal oximeter system described in FIGS. 1 through 9.
  • Figure 14 shows ODR cor points from the same seven subjects (each type of symbol represents a different subject) with line fits (dotted lines), along with the oxygen sensitivity OS (solid line "OS”) averaged from individual slopes and intercepts. Results of a regression analysis are shown in Table III below:
  • the device and method of the present invention have applicability as tools for medical research, _g ⁇ , in studies of oxygen utilization in the human retina, and as a diagnostic tool for humans or animals with respect to many eye diseases. Its potential clinical applications are particularly important, as a uniquely noninvasive system for evaluating oxygen metabolism in human patients during eye examinations and screening for the risk of eye diseases.
  • the invention will be particularly applicable for clinical tests for assessing the risk for onset of diabetic retinopathy, and for tests evaluating the effects of topical medications on blood flow and oxygen delivery in the retina.
  • the present ocular vessel oximeter and method will be thus useful in any research or clinical application where hemoglobin O 2 S AT must be determined in the larger (approximately 50 ⁇ m to 200 ⁇ m) range of retinal blood vessels.
  • ves_array array [1..341] of word; var avg3,avg4,evavg6,evavg5,minsum5,minsum6:ves_array; od569,od600,r,pr,pod569:real; di,vw,offset: integer;
  • ⁇ init_textfiles ⁇ procedure scanartery_vertical(var infile:file;var x600,x569,y600,y569,dx,scanlength:longint;p:char; vw,offset: integer; var avg3,avg4,evavg5,evavg6,minsum5,minsum6:ves_array;var result:text);
  • gx5: (read569[l,k-l]*sobelx[l,l]+read569[l,k]*sobelx[l,2]+read569[l,k+l]*sobelx [l,3]+read569[2,k-l]*sobelx[2,l]+read569[2,k]*sobelx[2,2]+read569[2,k+l]*sobelx[ 2,3]
  • gx5: (read569[l,k-l]*sobelx[l,l]+read569[l,k]*sobelx[l,2]+read569[l,k+l]*sobelx [l,3]+read569[2,k-l]*sobelx[2,l]+read569[2,k]*sobelx[2,2]+read569[2,k+l]*sobelx[ 2,3]+read569[3,k-l]*sobelx[3,l]+read569[3,k]*sobelx[3,2]+read569[3,k+l]*sobelx[3,k+l]*sobelx[[3,k+l]*sobelx[[3,k+l]*sobelx[[3,k+l]*sobelx[[3,k+l]*sobelx[[3,k+l]*sobelx[[3,k+l]*sobel
  • gx6: (read600[l,k-l]*sobelx[l,l]+read600[l,k]*sobelx[l,2]+read600[l,k+l]*sobelx [l,3]+read600[2,k-l]*sobelx[2,l]+read600[2,k]*sobelx[2,2]+read600[2,k+l]*sobelx[ 2,3]+read600[3,k-l]*sobelx[3,l]+read600[3,k]*sobelx[3,2]+read600[3,k+l]*sobelx[[
  • Competed (evavg5,evavg6,avg3,avg4,minsum5,minsum6,scanlength,di,evi569,evi600, od569,od600,r,pr,pod569); print(vi600,vi569,evi569,evi600,di,od569,od600,r,pr,pod569,result); end.

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Abstract

L'invention concerne un appareil permettant de mesurer le degré d'oxygénation dans un tissu polaire postérieur d'un oeil, comprenant un rétinographe (10) capable de produire une image intermédiaire des vaisseaux sanguins d'un oeil, un ensemble diviseur (12) de faisceau pourvu d'un premier filtre passe-bande (14), d'un second filtre passe-bande (15), et d'un diviseur de faisceau (55) capable de diviser l'image intermédiaire produite par le rétiniscope en une première et une seconde images, et un dispositif électronique (16) de formation d'image capable d'enregistrer électroniquement la première et la seconde images, après leur passage à travers le premier et le second filtres passe-bande. Les premier et second filtres passe-bande, possèdent une première et une seconde longueurs d'onde respectives, choisies afin d'optimiser la capacité de formation d'image représentant la saturation du sang en oxygène du dispositif électronique de formation d'image. Un procédé permettant d'évaluer le degré d'oxygénation d'un tissu polaire postérieur d'un oeil, consiste à réfléchir un rayon lumineux sur les vaisseaux sanguins d'un oeil, afin de créer une image intermédiaire, et à diviser cette image en une première et une seconde images qui traversent un filtre, de sorte que celles-ci présentent une première et une seconde longueurs d'onde respectives, choisies afin d'optimiser l'enregistrement électronique représentant la saturation du sang en oxygène. On utilise un rapport empirique entre O2SAT et OD afin d'obtenir des valeurs de O2SAT pour un sujet donné.
PCT/US1999/017204 1998-07-30 1999-07-28 Oxymetre permettant de former une image d'un vaisseau sanguin - WO2000006017A1 (fr)

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Cited By (8)

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GB2375679A (en) * 2001-04-09 2002-11-20 Patrick Kerr Retinal function camera using plural light wavelengths to produce a retinal function image showing haemoglobin oxygenation.
WO2004112599A1 (fr) * 2003-06-20 2004-12-29 Lions Eye Institute Limited Camera ophtalmique, adaptateur de camera ophtalmique et procedes de determination du taux d'hemoglobine et de glucose d'un patient
WO2005094671A1 (fr) * 2004-03-31 2005-10-13 Imedos Gmbh Procede pour determiner par photometrie spectrale, la saturation en oxygene du sang dans des vaisseaux sanguins accessibles d'un point de vue optique
US7774036B2 (en) * 2005-06-07 2010-08-10 Oxymap Ehf Automatic registration of images
CN104997519A (zh) * 2015-08-13 2015-10-28 中国科学院光电技术研究所 基于眼底相机的双波长视网膜血管血氧测量系统
EP2989977A4 (fr) * 2013-04-23 2016-06-01 Softcare Co Ltd Dispositif de diagnostic par imagerie du flux sanguin et procédé de diagnostic
WO2017094010A1 (fr) * 2015-11-30 2017-06-08 Technion Research & Development Foundation Limited Mesure d'hémoglobine à partir d'un vaisseau sanguin unique
WO2019147135A1 (fr) * 2018-01-29 2019-08-01 Stichting Vu Oxymétrie rétinienne à précision améliorée

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US4877322A (en) * 1987-04-30 1989-10-31 Eyedentify, Inc. Method and apparatus for measuring blood oxygen levels in selected areas of the eye fundus
US5240006A (en) * 1990-05-24 1993-08-31 Hitoshi Fujii Apparatus for displaying a bloodstream state
US5308919A (en) * 1992-04-27 1994-05-03 Minnich Thomas E Method and apparatus for monitoring the arteriovenous oxygen difference from the ocular fundus

Patent Citations (3)

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Publication number Priority date Publication date Assignee Title
US4877322A (en) * 1987-04-30 1989-10-31 Eyedentify, Inc. Method and apparatus for measuring blood oxygen levels in selected areas of the eye fundus
US5240006A (en) * 1990-05-24 1993-08-31 Hitoshi Fujii Apparatus for displaying a bloodstream state
US5308919A (en) * 1992-04-27 1994-05-03 Minnich Thomas E Method and apparatus for monitoring the arteriovenous oxygen difference from the ocular fundus

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7134754B2 (en) 2001-04-09 2006-11-14 Patrick Kerr Retinal function camera
GB2375679A (en) * 2001-04-09 2002-11-20 Patrick Kerr Retinal function camera using plural light wavelengths to produce a retinal function image showing haemoglobin oxygenation.
WO2004112599A1 (fr) * 2003-06-20 2004-12-29 Lions Eye Institute Limited Camera ophtalmique, adaptateur de camera ophtalmique et procedes de determination du taux d'hemoglobine et de glucose d'un patient
US7499634B2 (en) 2003-06-20 2009-03-03 The Lions Eye Institute Ltd. Ophthalmic camera, ophthalmic camera adaptor and methods for determining a haemoglobin and glucose level of a patient
WO2005094671A1 (fr) * 2004-03-31 2005-10-13 Imedos Gmbh Procede pour determiner par photometrie spectrale, la saturation en oxygene du sang dans des vaisseaux sanguins accessibles d'un point de vue optique
US7774036B2 (en) * 2005-06-07 2010-08-10 Oxymap Ehf Automatic registration of images
EP2989977A4 (fr) * 2013-04-23 2016-06-01 Softcare Co Ltd Dispositif de diagnostic par imagerie du flux sanguin et procédé de diagnostic
CN104997519A (zh) * 2015-08-13 2015-10-28 中国科学院光电技术研究所 基于眼底相机的双波长视网膜血管血氧测量系统
WO2017094010A1 (fr) * 2015-11-30 2017-06-08 Technion Research & Development Foundation Limited Mesure d'hémoglobine à partir d'un vaisseau sanguin unique
US11033209B2 (en) 2015-11-30 2021-06-15 Technion Research & Development Foundation Limited Hemoglobin measurement from a single vessel
US11779246B2 (en) 2015-11-30 2023-10-10 Technion Research & Development Foundation Limited Hemoglobin measurement from a single vessel
WO2019147135A1 (fr) * 2018-01-29 2019-08-01 Stichting Vu Oxymétrie rétinienne à précision améliorée
NL2020341B1 (en) * 2018-01-29 2019-08-02 Stichting Vu Retinal oximetry with improved accuracy

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