U.S. patent application number 16/199510 was filed with the patent office on 2019-05-23 for obtaining cardiovascular parameters using arterioles related transient time.
The applicant listed for this patent is Reuven Gladshtein, Eilon Rahman. Invention is credited to Reuven Gladshtein, Eilon Rahman.
Application Number | 20190150763 16/199510 |
Document ID | / |
Family ID | 52746210 |
Filed Date | 2019-05-23 |
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United States Patent
Application |
20190150763 |
Kind Code |
A1 |
Gladshtein; Reuven ; et
al. |
May 23, 2019 |
OBTAINING CARDIOVASCULAR PARAMETERS USING ARTERIOLES RELATED
TRANSIENT TIME
Abstract
Methods, systems and apparatus for monitoring equivalent inner
diameter of arteriole-like blood vessels and related cardiovascular
parameters, where by measuring a time difference between signals
from larger blood vessels, like arteries (excluding arterioles),
and smaller blood vessels, similar to arterioles by their
physiologic properties, also taking concurrent heart rate value
into account. In case the signal from larger blood vessels is
measured geometrically relatively far from such a signal from
smaller, arteriole-like blood vessels, said measured time
difference may be evaluated by several ways in order to separate a
PWTT component of time differences, obtained from said measured
signals, from transient time component, including information about
changes of diameter in arteriole-like vessels. It also may be
effective defining more correctly the role of blood viscosity in
monitored vascular condition of patient.
Inventors: |
Gladshtein; Reuven;
(Netanya, IL) ; Rahman; Eilon; (Netanya,
IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Gladshtein; Reuven
Rahman; Eilon |
Netanya
Netanya |
|
IL
IL |
|
|
Family ID: |
52746210 |
Appl. No.: |
16/199510 |
Filed: |
November 26, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14612695 |
Feb 3, 2015 |
10165955 |
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16199510 |
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61936806 |
Feb 6, 2014 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61B 5/14503 20130101;
A61B 5/4255 20130101; A61B 5/026 20130101; A61B 5/02007 20130101;
A61B 5/02438 20130101; A61B 5/6823 20130101; F16L 33/30 20130101;
A61B 5/053 20130101; A61B 2560/0431 20130101; A61B 5/14542
20130101; A61B 5/4238 20130101; A61B 5/14555 20130101; A61B 5/6871
20130101; A61B 5/6824 20130101; A61B 5/01 20130101; A61B 3/1233
20130101; A61B 5/0295 20130101; A61B 3/1241 20130101; A61B 5/6873
20130101; A61B 5/02416 20130101; A61B 5/0261 20130101; A61B 5/6821
20130101; A61B 5/0245 20130101; A61B 5/0538 20130101; A61B 5/14556
20130101 |
International
Class: |
A61B 5/026 20060101
A61B005/026; A61B 3/12 20060101 A61B003/12; A61B 5/02 20060101
A61B005/02 |
Claims
1. A method for estimation of inner diameter of arterioles beneath
the skin of measured body part, the method comprising: obtaining a
first pressure wave signal from a first tissue volume beneath the
skin of a part of a subject's body, containing blood vessels;
wherein contribution in the first signal from artery-like blood
vessels predominates over contribution from arteriole-like blood
vessels; obtaining a second pressure wave signal from a second
tissue volume beneath the skin of the part of the subject's body,
containing blood vessels; wherein contribution in the second signal
from arteriole-like blood vessels predominates over contribution
from artery-like blood vessels; obtaining at least one concurrent
heart rate value; finding time delay values between the first
signal and the second signal; and using said at least one value of
the time delay values and said at least one heart rate value to
calculate an equivalent inner diameter of said arterioles.
2. The method according to claim 1, further comprising assessing
the presence or degree of damage to arterioles beneath the skin of
measured body part: obtaining a first equivalent inner diameter of
arterioles beneath the skin of a first part of a subject's body,
containing possibly damaged blood vessels; obtaining a second
equivalent inner diameter of arterioles beneath the skin of a
second part of a subject's body, containing possibly undamaged
blood vessels; comparing between the first and the second
equivalent inner diameters in order to assess the presence or
degree of damage to arterioles beneath the skin of said first part
of said subject's body.
3. The method according to claim 1, further comprising assessing
the presence or degree of damage to arterioles beneath the skin of
measured body part: obtaining a first equivalent inner diameter of
arterioles beneath the skin of a first part of a subject's body,
containing possibly damaged blood vessels; obtaining a second
equivalent inner diameter of arterioles beneath the skin of a
second part of a subject's body, containing possibly less damaged
blood vessels; comparing between the first and the second
equivalent inner diameters in order to assess the presence or
degree of damage to arterioles beneath the skin of said first part
of said subject's body.
4. The method according to claim 2, wherein obtaining equivalent
inner diameter of said arterioles from the subject's foot.
5. The method according to claim 3, wherein obtaining equivalent
inner diameter of said arterioles from the subject's foot.
6. The method according to claim 1, wherein obtaining said first
signal is from characteristic depth of more than 5 mm under the
skin of the subject's body.
7. The method according to claim 1, wherein obtaining said second
is from characteristic depth of less than 5 mm under the skin of
the subject's body.
8. The method according to claim 2, wherein said first and second
equivalent inner diameter of said arterioles are related to the
same peripheral body part.
9. The method according to claim 2, wherein assessing the presence
or degree of damage beneath the skin of measured body part
comprises one or more of a measure of damage to arterioles due to a
pathological condition, a change in damage to arterioles over time,
due to a pathological condition, and a difference in damage to
arterioles in different parts of the body.
10. The method according to claim 2, wherein assessing the presence
or degree of damageto arterioles beneath the skin of measured body
part comprises a difference in damage to arterioles in different
parts of the body, and the method also includes assessing damage
due to diabetes, from the difference in damage to arterioles
between a part of the body damaged by diabetes, and an undamaged
part of the body.
11. The method according to claim 1, wherein a characteristic depth
of said first tissue volume beneath the skin is at least 2 times as
great as a characteristic depth of said second tissue volume
beneath the skin.
12. The method according to claim 2, also comprising: obtaining
information about at least one physiologically influencing to
subject over time parameter; finding correlation between changes
over time of said at least one parameter and changes over time in
said assessing the presence or degree of damage of said
arterioles.
13. The method according to claim 12, wherein said parameter
represents a substance entering to subject body.
14. The method according to claim 13, wherein said substance is a
pharmaceutical substance.
15. The method according to claim 12, wherein said parameter is a
behavioral parameter of the subject.
16. The method according to claim 15, wherein said behavioral
parameter represents a subject's activity.
17. The method according to claim 2, wherein assessing the presence
or degree of damage to arterioles beneath the skin of measured body
part is further comprising: comparing an obtained value of
equivalent inner diameter of arterioles to predefined threshold
value; indicating when said obtained diameter value is below or
above said threshold value.
18. The method s according to claim 2, wherein multiple assessings
the presence or degree of damage to arterioles beneath the skin are
done at once over a general part of the subject's body.
19. The method according to claim 18, wherein said general part of
the subject's body is a foot.
20. The method according to claim 1, wherein: obtaining said first
signal is done by a first light source and first detector, adapted
to be placed a first distance apart on the skin of the subject's
body, light from the first light source scattering from beneath the
skin to the first detector to generate said first signal; and
obtaining said second signal is done by a second light source and a
second light detector, one or both of them different respectively
from the first light source and the first light detector, adapted
to be placed a second distance apart, smaller than the first
distance, light from the second light source scattering from
beneath the skin to the second detector to generate the second
signal.
21. The method according to claim 20, wherein said distance between
said first light source and detector is more than 5 mm.
22. The method according to claim 20, wherein said distance between
said second light source and detector is less than 5 mm.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application claims the benefit according to 35 U.S.C.
119(e) of a U.S. provisional patent application Ser. No.
61/936,806, filed on Feb. 6, 2014, the disclosure of which is
incorporated herein in its entirety by reference.
FIELD AND BACKGROUND OF THE INVENTION
[0002] The present invention, in some embodiments thereof, relates
to a system, method and apparatus for measuring vascular parameters
and, more particularly, but not exclusively, to a system, method
and apparatus for monitoring changes in the equivalent inner
diameter of small branching arteries and arterioles.
[0003] Many medical conditions are characterized by changes or
abnormalities and size and shape of arterioles. Vasoconstriction
and vasodilation are reversible changes in the diameters of
arterioles. Vasoconstriction and vasodilation also play a role in
regulating blood pressure, and in diseases characterized by
abnormal regulation of blood pressure (hypertension and
hypotension), general and peripheral blood flow impedance of
subject, systemic vascular resistance (SVR). Other diseases are
characterized by chronicle changes in the diameters and cross
sections of arterioles, including diabetes and atherosclerosis.
[0004] Generally, arterioles are too small to image, using such
imaging methods as ultrasound, MRI, and x-rays, including CT
scans.
[0005] Other techniques for examining the circulatory system are
known, for example. sphygmomanometry provides data on systolic and
diastolic blood pressure, and pulse oximetry provides data on blood
oxygen levels. Arterial line and central venous line sensors
provide data on blood pressure and blood flow rate inside large
blood vessels.
[0006] Josep Sola, Stefano F. Rimoldi, and Yves Allemann,
"Ambulatory Monitoring of the Cardiovascular System: the role of
Pulse Wave Velocity," in New Developments in Biomedical
Engineering, Chapter 21, p. 391-422, provides a review of
techniques for measuring pulse wave velocity, primarily in large
arteries over large distances, for example from the heart to the
extremities.
[0007] WO2007/097702 discusses a method for the generation,
detection and evaluation of a photoplethysmographic (PPG) signal to
monitor blood characteristics, in which the light source(s) are
spaced at particular distances from photodetector(s). U.S. Pat.
Nos. 6,123,719, 5,891,022, US2009/0306487 and EP1297784 discuss
photoplethysmographic measurement systems that have at least two
light emitters, each emitting light at different wavelengths and a
photodiode for detecting the intensity of light reflected from a
patient's tissue such as blood, finger, etc.
[0008] US2010/0331708 describes methods for monitoring
cardiovascular conditions, i.e., hyperblood flow related
circulation, vasodilation, vasoconstriction, or
central-to-peripheral arterial pressure decoupling conditions.
These methods involve measuring a central signal proportional to or
a function of the subject's heart activity and a peripheral signal
proportional to or a function of a signal related to central
signal. Then calculating a time or phase differences between
features in the central and peripheral signals representing the
same heart event. The cardiovascular condition is indicated if the
time or phase difference is greater or lower than a threshold value
over a specific period of time, or if there is a significant
statistical change in the times over the specific time period.
These methods can alert a user that a subject is experiencing some
cardiovascular conditions, which can enable a clinician to
appropriately provide treatment to the subject.
[0009] Said application provides methods, mostly suggesting
estimation of common vasoconstriction or vasodilation level, by
measurement between physiologically "central", heart-related point
and one of physiologically "peripheral" points of measured subject,
actually providing estimations of blood flow impedance change along
all branches of blood vessel tree, included between said two
points. Additional background art includes Reuven Gladshtein,
"Indications of cross-section of small branched blood vessels" WO
2012110955 A1, Minnan Xu, "Local Measurement of the Pulse Wave
Velocity Using Doppler Ultrasound," M.S. thesis, Dept. of
Electrical Engineering and Computer Science, M.I.T., May 24, 2002;
A. C. Fowler and M. J. McGuinness, "A Delay Recruitment Model of
the Cardiovascular Control System," submitted to Journal of
Mathematical Biology, June 2004, revised December 2004; John Allen,
"Photoplethysmography and its application in clinical physiological
measurement," Physiol. Meas. 28 (2007), R1-R39; H. S. Lim and G. Y.
H. Lip, "Arterial stiffness in diabetes and hypertension," Journal
of Human Hypertension (2004) 18, 467-468; and Emilie Franceschini,
Bruno Lombard, and Joel Piraux, "Ultrasound characterization of red
blood cells distribution: a wave scattering simulation study,"
Journal of Physics: Conference Series 269 (2011) 012014.
SUMMARY OF THE INVENTION
[0010] An aspect of some embodiments of the invention concerns
finding a measure of a blood flow proportional parameter in
arteries, and in arterioles that branch off them, and using
differences between them to find information about changes in
equivalent inner diameter of said arterioles. Present invention
describes a system, indicative or monitoring changes of equivalent
inner diameter value over time, the system comprising:
[0011] a multiplicity of at least one sensor adapted to obtain
signals, correlative to at least one changing over time blood flow
related parameter of blood circulation in a subject; [0012] wherein
said multiplicity of at least one sensor is adapted to be placed
relative to at least one body portion of said measured subject,
including branching blood vessels of blood circulation in subject;
[0013] wherein said multiplicity of at least one sensor is adapted
to obtain at least two signals concurrently, first and second, from
said at least one body portion;
[0014] wherein said multiplicity of at least one sensor is adapted
to obtain said at least two signals from said at least one body
portion of subject, wherein an artery-like blood vessels contribute
more, relative to an arteriole-like blood vessels, for the first
signal than for the second signal; [0015] at least one processor,
adapted to use differences between said first and second signals
coupled with a heart rate value in order to indicate or monitor
changes of equivalent inner diameter value of said arteriole-like
blood vessels. Present invention also describes an apparatus for
indication of changes in equivalent inner diameter value of
arteriole-like blood vessels or monitoring changes of said
equivalent inner diameter value over time, said apparatus
comprising:
[0016] multiplicity of at least one sensor, including at least one
transmitter and at least one receiver, geometrically adapted to
sample at least two non-identical volumes of a subject and wherein
each of said at least one receiver collects at least one signal,
transmitted to measured body portion from said at least one
transmitter; [0017] said multiplicity of at least one sensor,
adapted to obtain concurrent signals from said at least two
non-identical volumes, wherein artery-like blood vessels contribute
more, relative to arteriole-like blood vessels, to a signal from a
first volume than to a signal from a second volume;
[0018] and at least one processor, adapted to indicate changes of
equivalent inner diameter of said arteriole-like blood vessels by
using differences between said first and second signals coupled
with a heart rate value. [0019] Also a new method for estimation of
an equivalent inner diameter value of arteriole-like blood vessels
or monitoring changes of the equivalent inner diameter value over
time in a measured subject, the method for indication of changes in
an equivalent inner diameter value of arteriole-like blood vessels,
the method comprising: [0020] a) obtaining a first signal,
correlative to at least one changing over time blood flow related
parameter of blood circulation in artery-like blood vessels and in
arteriole-like blood vessels, belonging to a same branching tree of
blood circulation; [0021] b) concurrently obtaining a second
signal, correlative to at least one changing over time blood flow
related parameter of blood circulation in artery-like blood vessels
and in arteriole-like blood vessels, belong to the same said
branching tree of blood circulation, where said artery-like blood
vessels contributing more, relative to said arteriole-like blood
vessels, for the said first signal, than for the second signal;
[0022] c) obtaining an approximately concurrent heart rate value;
[0023] d) obtaining a time differences or phase differences between
said the first signal and the second signal; and [0024] e) using
said time differences or phase differences, coupled with said heart
rate value, to indicate changes in an equivalent inner diameter
value for the arterioles. Present invention describes a new system
for indication of at least one vascular or cardiovascular condition
or monitoring the same, said system comprising at least one
processor, configured to process plurality of image, movie or
scanned data from at least one body portion, including branching
blood vessels, wherein said at least one processor is adapted to
indicate from said plurality of images, movie or scanned data:
[0025] changes in at least one parameter, correlative to at least
one changing in time blood flow related process from at least one
artery-like blood vessel;
[0026] concurrent changes in at least one parameter, correlative to
at least one changing in time blood flow related process from at
least one arteriole-like blood vessel or artery-like blood vessel,
branched off from same said at least one artery-like blood
vessel;
[0027] differences between said first and second measured
parameters.
Also described a new method for indication of at least one vascular
or cardiovascular condition or monitoring the same, said method
comprising: a) transferring image, movie or scanned data collected
from body portion, including branching blood vessels, to at least
one processor, configured to process said data; b) extracting by
means of said at least one processor, at least one blood flow
related parameter, changing over time, said parameter correlative
to at least one blood flow related process occurring in at least
one artery-like blood vessel; c) extracting by means of said at
least one processor, at least one blood flow related parameter,
changing over time concurrently with said above parameter, said
parameter correlative to at least one blood flow related process
occurring in at least one arteriole-like blood vessel, branched off
directly or indirectly from same said at least one artery-like
blood vessel; d) finding differences between said at least first
and second measured parameters. Also described a new apparatus for
indication of changes in equivalent inner diameter value of
arteriole-like blood vessels or monitoring changes of said
equivalent inner diameter value over time, said apparatus
comprising:
[0028] plurality of sensors, adapted to obtain at least two signals
of a subject, wherein at least one of said at least two signals is
from peripheral part of blood circulation of subject body;
[0029] each of said plurality of sensors, adapted to obtain
concurrent signals, proportional to or indicative to heart activity
of subject;
[0030] and at least one processor, adapted to indicate changes,
related to peripheral vasculature by using time differences or
phase differences between said at least two signals, coupled with a
heart rate value.
[0031] Unless otherwise defined, all technical and/or scientific
terms used herein have the same meaning as commonly understood by
one of ordinary skill in the art to which the invention pertains.
Although methods and materials similar or equivalent to those
described herein can be used in the practice or testing of
embodiments of the invention, exemplary methods and/or materials
are described below. In case of conflict, the patent specification,
including definitions, will control. In addition, the materials,
methods, and examples are illustrative only and are not intended to
be necessarily limiting.
BRIEF DESCRIPTION OF THE DRAWINGS
[0032] Some embodiments of the invention are herein described, by
way of example only, with reference to the accompanying drawings.
With specific reference now to the drawings in detail, it is
stressed that the particulars shown are by way of example and for
purposes of illustrative discussion of embodiments of the
invention. In this regard, the description taken with the drawings
makes apparent to those skilled in the art how embodiments of the
invention may be practiced.
[0033] In the drawings:
[0034] FIG. 1 is a schematic drawing of an optical sensor system
being used on a surface of a subject's body to measure blood volume
or a related parameter as a function of time in small arteries, and
in arterioles branching off from said arteries, according to an
exemplary embodiment of the invention;
[0035] FIG. 2 is a schematic drawing of an ocular fundus imager,
according to an exemplary embodiment of the invention;
[0036] FIG. 3A is a schematic drawing of retinal artery, splitting
to two arteries of nearly same diameter.
[0037] FIG. 3B illustrates splitting of retinal arteriole from
retinal artery.
[0038] FIG. 4 is a schematic drawing of a laser Doppler system
being used to measure blood flow rate as a function of time in a
larger arteries, and in smaller arteries, like arterioles branching
off from said arteries, according to an exemplary embodiment of the
invention;
[0039] FIG. 5 is a flowchart for a method of finding the equivalent
inner diameter of smaller arteries, like arterioles branching off
from larger arteries, or changes in the said equivalent inner
diameter, for example using the systems shown in FIGS. 1,2 and 4,
using a time or phase shift in the pulse wave between said small
arteries and the arterioles, according to an exemplary embodiment
of the invention;
[0040] FIG. 6 A illustrate an initial phase of heart beat wave
propagation in small arteries, like arterioles, according to an
exemplary embodiment of the invention;
[0041] FIG. 6 B illustrate a final phase of heart beat wave
propagation in small arteries, like arterioles, according to an
exemplary embodiment of the invention;
[0042] FIG. 7 is a schematic drawing showing a pulse wave as a
function of time primarily in a larger arteries, and primarily in
smaller arteries, like arterioles, branching off from the said
larger arteries, for example using a photoplethysmography system
similar to the optical sensor systems shown in FIG. 1 or 4;
[0043] FIG. 8 is a flowchart for an exemplary method of evaluating
damage in arterioles that branch off small arteries, in patients
with pathological conditions such as diabetes, according to an
exemplary embodiment of the invention; and
[0044] FIG. 9 is a flowchart for a method of evaluating shock or
dehydration in a patient, by finding differences in the equivalent
inner diameter of arterioles branching off from small arteries, for
peripheral and central part of the patient's body, and optionally
monitoring changes in those differences over time, according to an
exemplary embodiment of the invention.
[0045] FIG. 10 A illustrates one-element Windkessel-type model of
arteriole.
[0046] FIG. 10 B illustrates three-element Windkessel-type model of
arteriole.
[0047] FIG. 10 C illustrates three-element Windkessel-type models
of arteriole and capillary drain.
[0048] FIG. 10 D illustrates Three-element Windkessel-type models
of arteriole with capillary drain and precapillary sphincter
correction.
[0049] FIG. 11 is an example of results by modeling of arteriole
with model, illustrated in FIG. 100.
[0050] FIG. 12 is a drawing, illustrating function of precapillary
sphincter, coupled to arteriole.
[0051] FIG. 13 is an example of results by modeling of arteriole
with model, illustrated in FIG. 10D.
[0052] FIG. 14 is a flowchart for an exemplary method of estimation
for equivalent inner diameter of retinal arteriole, branched off
from retinal artery, and optionally monitoring changes in value of
said diameter over time, by calculating from ophthalmoscopy data at
least one changing over time parameter of blood flow relative
process in said analyzed retinal artery and arteriole according to
an exemplary embodiment of the invention.
[0053] FIG. 15 is a flowchart for an exemplary method of estimation
for equivalent inner diameter of retinal arteriole, branched off
from retinal artery, and optionally monitoring changes in value of
said diameter over time, by calculating from ophthalmoscopy data at
least one changing over time parameter of pulse wave propagation
relative process in said analyzed retinal artery and arteriole
according to an exemplary embodiment of the invention.
[0054] FIG. 16 illustrates standard embodiment of transition
pulse-oximeter.
[0055] FIG. 17 illustrates a transition pulse-oximeter with ability
to monitor changes of arteriole's equivalent inner diameter in
measured region of tissue.
[0056] FIG. 18 illustrates a reflection pulse-oximeter embodiment
with ability to monitor changes of arteriole's equivalent inner
diameter in measured region of tissue.
[0057] FIG. 19 illustrates a reflection acoustic/ultrasonic
embodiment with ability to monitor changes of arteriole's
equivalent inner diameter in the region of kidney.
[0058] FIG. 20 illustrates an exemplary embodiment with ability to
monitor changes of arteriole's equivalent inner diameter also by
means of electrical sensors.
DESCRIPTION OF PRINCIPLES AND SPECIFIC EMBODIMENTS OF THE
INVENTION
[0059] The present invention, in some embodiments and principles
described thereof, relates to a system, method and apparatus for
measuring vascular parameters and, more particularly, but not
exclusively, to a system, method and apparatus for estimating
equivalent inner diameter and for monitoring changes in the
equivalent inner diameter of branching arteries and arterioles.
[0060] In order to monitor parameters mentioned above in the "Field
and Background of the Invention" section, as well as different
types of shock, which are characterized also by vasoconstriction or
vasodilatation of arterioles at peripheral regions of the body, and
in order to monitor their progression, it would be desirable to
have a convenient and inexpensive way to continuously monitor the
equivalent inner diameter, and changes in the equivalent inner
diameter, of arterioles and similar small blood vessels, but no
satisfactory technology for that purpose exists at present.
[0061] In principle, one could estimate the diameter of arterioles,
by combining an optical Doppler measurement of blood flow rate, a
photoplethysmography (PPG) sensor to measure blood volume, and an
accurate measurement of diastolic pressure inside the blood vessels
being examined. But it is difficult to obtain accurate measurements
of diastolic pressure in small blood vessels with only external
sensors, and besides, optical Doppler measurements of blood flow
rate may not be practical for continuous monitoring.
[0062] An aspect of some embodiments of the invention relates to
finding an estimation of changes in equivalent inner diameter value
of small arteries, like arterioles. Two sets of measurements are
made, of a physiological parameter that indicates a pressure wave
in blood flow of the larger arteries and smaller arteries, like
arterioles, the larger blood vessels, like arteries, contribute
more, relative to the smaller blood vessels, like arterioles, for
the first signal than for the second signal.
Thus said arterioles have higher blood flow impedance, then said
branching larger arteries; this difference of impedance causes to
time shift (phase shift) in propagation of pulsatile blood flow
from said arteries to branched arterioles. It is necessary to keep
in mind that physical nature of said time shift is similar to time
delay, described in patent applications like US2010/0331708. For
example, in US 2010/0331708 time delay is a composite value,
consisting from time of blood pressure wave propagation along
relatively long blood vessels (central signal) with relatively
large diameter and low flow impedance (aorta, big arteries and so
on) and characteristic time shift, caused by passing by said blood
pressure wave through circulatory branches with sufficiently
smaller diameters and lower stiffness (most types of arterioles).
Aorta and arteries have characteristic diameter from 10 mm and more
(Aorta) to about 0.4 mm (small arteries) and relatively low ability
to change their diameter due to changes of arterial muscle tone.
Arterioles have ability to change diameter commonly from 15 to 70
micrometers depends on type, which predefines changes of their flow
impedance in very wide range--relatively to flow impedance of
previous branching arteries. It is easy to understand, that
significant impedance differences are mainly predefined by
naturally existing difference in equivalent inner diameter for said
larger arteries and branched from them smaller arterioles
(equivalent inner diameter of arterioles are much smaller,
difference in equivalent inner diameter is localized at small space
of branching) taken into account with much lower stiffness of
arterioles, enable them to discover high volume capability,
compared to larger branching arteries with significantly higher
stiffness.
[0063] From other side, discussed here-before prevailing high flow
impedance of arterioles, is being connected in serial to said much
lower impedance of previous larger arteries in common artery tree
of body, make possible to conclude about dominant role of
arteriole's impedance on all impedances of larger arteries as
different components of common impedance for blood circulation.
(See [4], [17] etc.)
Thus it makes less important, which relatively big arteries of
branching artery tree were selected to measure said time shift
relatively to peripheral relatively small arteriole-like arteries.
Also changes of common blood flow impedance are mainly defined by
changes of impedance of same said arterioles--due to their
vasoconstriction or vasodilation, because their ability to change
their diameter is much higher that same ability of larger arteries.
Also such factors like number of branches or variation of branching
angles in any specific arteriole-like vessel are less significant
for complex measurements and analysis of common (averaged)
impedance value because influence of these factors to circulation
in any tissue region of size, applicable to Photoplethysmographic
measurements, is much smaller than same said impedance value and
may be neglected. These facts are well-known in common physiology
and physics of circulation and, for example, may be found from [4,
17-19 etc]. Following explanation is for short illustration of
ability for skilled in the art to measure signals from mainly
region of smaller arteries and mainly region of arterioles, belong
to same artery tree of blood circulation. For mammal blood
circulation in tissues we may see the following objects of
measurement: arteries, arterioles, capillary system, venules and
veins. For example, the green light (.about.530 nm) enables to
analyze blood peripheral perfusion mainly from capillary system and
arterioles, characterizing by relatively high blood flow impedance,
and characteristic to the tissue layer, close to skin surface.
These blood vessels are much less influenced by blood volume
changes caused by body movement and bring us information about
changes in Peripheral Blood perfusion, cause by arteriole's
activities. Opposite to relatively short visible light wavelengths,
using of NIR (Near Infra-Red) light radiation enables measurement
and monitoring of physiologic parameters from more deep layers of
physiologic tissue. For example, two transmitters of optical
radiation--of green light 530 nm and IR light 940 nm are placed
relatively to measured region of tissue by way, enabling to optical
receiver measurement of two non-identical physiologic layers of
tissue, one--closer to skin surface from green light source and
another region--deeper than the first one--from IR radiation
source. The relatively upper measured region includes the capillary
system and a part of arterioles and venules. The relatively deeper
region, measured by IR light, is mainly represented by small
arteries, including relatively much less blood volumes of
arterioles, venules and capillary. NIR is in use to analyze
physiologic signals of blood flow, modulated by Heart Rate, Breath
processes, Body Movement and so on. And all this because longer
wavelengths of light, penetrating biologic tissue deeper, enabling
to monitor blood flow processes, associated with relatively larger
and deeper blood vessels displaced in inner regions of biologic
tissue, such as arteries of various type. Achieving layers with
different depths of measured tissue may be described by other
way--using different distances between transmitter and detector of
light. Light energy propagation between emitter and detector within
highly scattering matter is deterministic and can be split into a
series of smaller "canoe" shaped envelops within which certain
fraction of light energy propagates through the matter. The shape
of this profile is a function of the source-detector separation,
the absorption coefficient, and the reduced scattering coefficient
within the tissue. Increases in both tissue scattering and
absorption act to reduce the amplitude of the detected signal and
reduce measurable the penetration depth. This approach to signal
sampling is an opposite of same approach that regularly is
realized, for example, in oxygen saturation measurement. Usually
oxygen saturation measurement needs for sampling of same tissue
volume in order to obtain numerical correlations of oxy- and
deoxyhemoglobin concentrations with oxygen saturation in blood.
Really, said concentrations, being defined through their proportion
to amplitudes of heart rate wave, are measured at optical
wavelengths, specific to oxy- and deoxyhemoglobin absorption, may
be used in same formula of "ratio-of ratios", when being measured
from nearly same portion of blood vessels. Systems, methods and
devices, described in this invention, in opposite to described here
before, use non-identical measured volumes of tissues with
branching blood vessel or vessels in order to obtain any of blood
flow correlative data types from blood vessels of different size
contents. Thus by measuring a time difference between signals from
larger blood vessels, like arteries (excluding arterioles), and
smaller blood vessels, similar to arterioles by their physiologic
properties, which are related to same measured physiologic region,
it is possible to measure difference of local blood flow impedance
between said small arteries and arterioles, i.e. to estimate
changes in the equivalent inner diameter of said arterioles. In
case the signal from larger blood vessels is measured geometrically
relatively far from such a signal from smaller, arteriole-like
blood vessels, said measured time difference may be evaluated by
several ways as following: [0064] Additional sensor, adapted to
obtain arterial signal, may be placed close to sensor, measuring a
signal from local small arteries. In this case time difference,
measured between arterial signal of "far" sensor and arterial
signal of "close" sensor may be used to correct additional time
value, measured between "far" arterial signal sensor and sensor of
signal from arteriole-like blood vessels. Said measured time
difference, actually, is a well-known transit time of pulse wave
propagation (PWTT) between said "far" and "close" sensors of
signals from larger arteries. [0065] Another way of said time
correction may be done by computation, basing on known distance
between said "far" and "close" sensors of signals from larger
arteries and well-known average values of pulse wave propagation
velocity in relatively large arteries (9-12 m/sec, depends on
region). Such estimation may be less accurate for computation of
the equivalent inner diameter of measured arterioles, but still
effective to monitor and track changes of said diameter. [0066]
Thus by such a measurement we may separate a PWTT component of said
measured time difference from transient time component, including
information about changes of diameter in arteriole-like vessels.
[0067] It may be also effective in order to define more correctly
the role of blood viscosity in monitored vascular condition of
patient, for example, to correlate changes of viscosity value with
changes of PWTT component, separated from arteriole's transient
time etc. Here after we propose physical explanation, described by
two of possible physical models, which illustrates ability to
indicate characteristic diameter of arterioles and its changes by
use of measured time difference between blood flow wave,
propagating in said arterioles and larger arteries, locally
branching to said arterioles. Assuming that the vessel is rigid and
the flow is laminar, we may assume that in arteries with a radius
smaller than 0.2 cm pressure is proportional to flow [5]. The
circuit representing such a vessel (FIG. 10A) would simply contain
a resistance 1010 and no other elements. In other words, effects
due to inertia and elasticity may be ignored. Since smallest
arteries are typically not rigid (although there are exceptions),
but do provide resistance, it will be unnecessary to add a
capacitor to the model to account for elasticity. However, as shown
by Keener and Sneyd [6] it is possible to incorporate elasticity
using the two-element Windkessel model; that is, by adding a
capacitor 1070 to the circuit shown in (FIG. 10B). It should be
noted that the derivation by Keener and Sneyd is somewhat
artificial; it includes neither viscosity nor inertia [5]. Thus
achieving estimation, basing on Windkessel model with 3 elements,
which is widely in use [9,10], analyze small blood vessels with
high capability, applied to arteriole-like blood vessel with
capillary drain 1170, with the necessary changes having been made
(FIG. 10C). Here we have to keep in mind, that all analytical
estimations here-after are only to explain one of possible ways to
use value of time or phase shift between signals from larger blood
vessels, like small arteries (excluding arterioles), and smaller
blood vessels, similar to arterioles by their physiologic
properties, localized both at same measured region, but
physiologically displaced differently along said region, and
measured by skilled in the art in order to achieve correlative
estimation to their characteristic equivalent inner diameter value
and/or changes of said equivalent inner diameter value. Thus
current models are not described as an exact physical model of
blood pressure wave propagation in arteriole and may be modified by
skilled in the art mutatis mutandis to achieve physically more
exact results without any limitation to general ideas of the patent
(For example--[15,16]). Voltage, current, charge, resistance and
capacitance in the electronic circuit are respectively equivalent
to blood pressure, blood flow, volume, resistance and compliance in
the cardiovascular system. Ground potential of blood pressure
(reference for voltage measurements) is assumed to be zero as
usual. Following this analogy to electrical model on FIG. 10C, it
is possible to write linear equations of flow Q and pressure P
balance for arteriole. Said model means assumption that blood flow,
entering internal space of analyzed arteriole, passes through a
half of its viscous resistance before being accumulated in
arteriole's capacitance, i.e. before arteriole increases its
internal diameter due to its elasticity. Further process outlines
"discharging" of said capacity to capillary drain--through second
half of arteriole's resistance. Voltage, current, charge,
resistance and capacitance in the electronic circuit are
respectively equivalent to blood pressure, blood flow, volume,
resistance and compliance in the cardiovascular system. Ground
potential (reference for voltage measurements) is assumed to be
zero as usual. Analysis of the model is regular for skilled in the
art and is being made as usual, Windkessel model, combined
according to Kirchhoff's Lows, may be written as following
[0067] Q o = Q c + Q r ( 1 ) P = Q c R 2 + Q c - Q r jwC ( 2 ) Q r
- Q c jwC + Q r ( R 2 - r ) = 0 ( 3 ) ##EQU00001##
[0068] Here R--viscous resistance of arteriole to blood flow,
depended on radius of arteriole:
R=8*.eta.*L(.pi.*R.sub.a.sup.2).sup.2, (4)
where R.sub.a--radius of arteriole, .eta.--blood viscosity and
L--length of arteriole. C (1160)--capability parameter of
arteriole, primarily defined by mechanical elasticity of its walls,
depended on radius of arteriole:
C=4*Kart*.pi.*R.sub.a.sup.3*L, (5)
where R.sub.a--radius of arteriole, Kart--capacity coefficient for
arteriole and L--length of arteriole. r (1170)--viscous resistance
to blood flow of capillary, being branched off from said
arteriole,
r=8*.eta.*l/(.pi.*r.sub.0.sup.4), depended on radius of arteriole:
(6)
where .eta.--blood viscosity, r.sub.0--initial radius of branched
capillary and l--length of said capillary. Q.sub.o (1120)--income
blood flow to arteriole, Q.sub.c (1140)--component of blood flow,
participating in both first half of arteriole's resistance and
capacitance, Q.sub.r (1130)--blood flow through capillary, being
branched off from said arteriole. f.sub.hr--heart rate, where C and
R are parameters, strongly depended on diameter of arteriole. In
modern art there are several ways to estimate viscous resistance R
of arteriole to blood flow through arteriole's diameter (Equation
4), for example, by [7] or [8]. In same manner and from similar to
[7] or [8] sources viscous resistance r to blood flow in branched
capillary and capability parameter C of arteriole may be estimated
(Equation 5). Equations 1-3 are usually used to achieve transfer
function or complex impedance of described arteriole system. After
elementary manipulations we get
P = Q r R 2 ( R 2 - r ) jwC + R 2 Q r + Q r ( R 2 - r )
##EQU00002##
And finally bring Q.sub.r out of the brackets:
P = Q r [ R 2 ( R 2 - r ) jwC + R - r ] , ##EQU00003##
where P--is a blood pressure at the entrance of arteriole and
Q.sub.r is a drain of arteriole blood flow. Thus arteriole's flow
impedance relatively to Q.sub.r is:
Z a = R 2 ( R 2 - r ) jwC + R - r ##EQU00004##
Solving real and imaginary components of arteriole's impedance
Z.sub.a relatively to R and C and taking into account that time
shift tends to zero at big values of arteriole's diameter, we may
determine phase shift .THETA., being produced by complex parts of
said impedance. Time shift value of arteriole's blood flow may be
represented as:
.tau. = .THETA. w ( 7 ) ##EQU00005##
where w--radial frequency of pressure wave: w=.sup.2.pi.f.sub.hr.
On FIG. 11 we can see family of curves, where each one is
representing dependence of said time shift T on diameter of
arteriole for different values of heart rate. On FIG. 11 it is
shown that time shift increases, when value of arteriole's diameter
have decreased. Also we have to emphasize about very important fact
that time shift tends to increase, when heart rate gets slower,
even at same values of arteriole's diameter. It also describes very
understandable rule of frequency depended systems functioning:
value of heart rate influences significantly to blood flow
impedance value and its behavior. Unfortunately absence of this
factor in method descriptions and data processing algorithms is
characteristic for many applications in prior art, where possible
ways for measurement and/or indication of peripheral blood flow
impedance or vasoconstriction level is described. Mentioned in FIG.
100 model has predefined assumptions and some of them may be
changed by involving additional facts about physiology of
arterioles and capillary, branched off from them, into the model.
As it is possible to see from FIG. 12, at the point where each true
capillary 1204 originates from a metarteriole like 1202, a smooth
muscle fiber 1203 usually encircles the capillary. This is called
the precapillary sphincter. This sphincter can open and close the
entrance to the capillary. A precapillary sphincter encircles each
capillary branch at the point where it branches from the arteriole.
Contraction of the precapillary sphincter can close the arteriole
like 1202 off to blood flow. One of functions of precapillary
sphincter is by changes of its muscle tone to smooth oscillations
of blood pressure at the entrance of branched capillary from small
artery 1201 through aerterioles like 1202, when blood flow passes
from arteriole to said capillary, by equivalent rC-cuircuit,
including capacitance of precapillary sphincter and viscous
resistance of branched capillary. Thus one of possible model
interpretations for function of precapillary sphincter, proposed as
a final compartment of complex arteriole structure, may be
interpreted as capacitive impedance, coupled in parallel to second
part of arteriole resistance--before capillary resistance (FIG.
10D). Impedance of arteriole, describing by model, shown at FIG.
10D, may be written as following:
Z a = R 2 + ( C a ( C ps ( R 2 ) + r ) ) , ( 8 ) ##EQU00006##
Where C.sub.a (1160)--equivalent fluid capacitance of arteriole and
C.sub.ps (1180)--equivalent fluid capacitance of precapillary
sphincter. Sign .parallel. means parallel connection of equivalent
system components in analyzed model. After transformation of the
impedance (5) to its complex form and its evaluation in same manner
like in previous model, any skilled in the art may get phase shift
and time shift dependence on different values of arteriole's
diameter for different rates of heart beats. Parameters, adapted to
averaged physiological parameters of analyzed physiological
components of described model, bring same manner of time or phase
shift dependence from diameter of arteriole, but here it is
realized through hyperbolic-like form of curves. An example of
calculated results is shown at FIG. 13. At said figure, like at
FIG. 11, specifically time shift was selected to demonstrate
abilities of the model, because our working prototype estimates
equivalent inner diameter of arterioles by calculation of time
shift between signals from arterioles and larger arteries. Ability
to estimate equivalent inner diameter of arterioles enables to
determine Systemic Vascular Resistance of measured subject.
Systemic vascular resistance (SVR) refers to the resistance to
blood flow offered by all of the systemic vasculature, excluding
the pulmonary vasculature. This is sometimes referred as total
peripheral resistance (TPR). SVR is therefore determined by factors
that influence vascular resistance in individual vascular beds.
Mechanisms that cause vasoconstriction increase SVR, and those
mechanisms that cause vasodilation decrease SVR. Although SVR is
primarily determined by changes in blood vessel diameters, changes
in blood viscosity also affect SVR. [13] According to explained
here before we may conclude, that SVR may be mainly defined and/or
monitored by monitoring changes of diameter in blood vessels, which
diameter is able to sufficient changes. There are mostly arterioles
and some other types of small arteries. So, being able to monitor
diameter changes of arteriole-like blood vessels, we enable also to
estimate and monitor SVR.
[0069] Said US2010/0331708 describes methods involve measuring a
central signal proportional to or a function of the subject's heart
activity and a peripheral signal proportional to or a function of a
signal related to central signal. Then calculating a time
difference between features in the central and peripheral signals
representing the same heart event.
We have to emphasize about very important fact that time shift
tends to increase, when heart rate gets slower, even at same values
of arteriole's diameter.
[0070] It also describes very understandable rule of frequency
depended systems functioning: value of heart rate influences
significantly to blood flow impedance value and its behavior.
Unfortunately absence of this factor in method descriptions and
data processing algorithms is characteristic for many applications
in prior art, where possible ways for measurement and/or indication
of peripheral blood flow impedance or vasoconstriction level is
described.
[0071] Our method differs from invented in said patent by including
heart rate value, measured concurrently, in process of data
collection and processing. According to described in this
application, a combination of heart rate values and concurrently
measured time or phase differences between signals from larger and
smaller arteries, being processed by way, described here, may
provide an appropriate indication about said cardiovascular and
vascular conditions of subject.
[0072] At the same time said large blood vessels with their
relatively much lower flow resistance and relatively insufficient
ability to change their diameter (i.e. to change their resistance
to blood flow), influent SVR much less, than common plurality of
said smaller blood vessels in peripheral parts of systemic
circulation, thus in some cases may be excluded from SVR
measurements.
Without ability to monitor changes in blood vessel diameters SVR
may not be monitored directly, but can be calculated if cardiac
output (CO), mean arterial pressure (MAP), and central venous
pressure (CVP) are known.
SVR=(MAP-CVP)/CO (9)
Because CVP is normally near 0 mmHg, the calculation is sometimes
simplified to:
SVR=MAP/CO (10)
It is very important to note that SVR can be calculated from MAP
and CO, but it is not determined by either of these variables. A
more accurate way to view this relationship is that at a given CO,
if the MAP is very high, it is because SVR is high. Mathematically,
SVR here is the dependent variable in the above equations; however,
physiologically, SVR and CO are normally the independent variables
and MAP is the dependent variable. From other side, the systemic
vascular resistance is the resistance to blood flow throughout the
circulatory system of the body. It is controlled by three different
factors: length of the blood vessel (I), radius of the blood vessel
(r), and the viscosity of the blood (.eta.). The equation that
relates these three factors to resistance is known as Poiseuilles'
equation:
R.apprxeq.(.eta.x l)/r.sup.4 (11)
In the past and till today this formula was not in practical use
for SVR definition because direct monitoring of equivalent inner
diameter of small blood vessels, like arterioles, was impossible.
Really, for nearly same blood viscosity conditions and same common
length of blood vessels in subject's body systemic vascular
resistance is defined by equivalent inner diameters of small blood
vessels and changes of SVR are depended on changes of said
diameters, discussed in current invention, Thus we may conclude
that measuring of SVR and its changes is now possible through
estimation of equivalent inner diameter of arterioles, and, by
coupling it with measurements of Mean Arterial Pressure (MAP)
enable to define cardiac output of measured subject.
From (10):
[0073] CO=MAP/SVR (12)
In same manner it is easy to show, that, by coupling independent
measurements of SVR from (9) or (10) and equivalent inner diameter
of arterioles, it is possible to monitor changes of blood
viscosity. From (11):
.eta..apprxeq.SVR.times.r.sup.4/l, (13)
where l (common length of the blood vessels) is a constant and
2.times.r--equivalent inner diameter of arterioles. Or,
alternatively from (10) and (13):
.eta..apprxeq.MAP.times.r.sup.4/(CO.times.l) (14)
An estimation of q according to (13) or (14) may be done by use of
technology, estimating equivalent inner diameter of arterioles,
coupled with any other measuring system, estimating SVR or MAP and
CO independently. Also independent estimating SVR or MAP and CO may
be more effective and/or accurate using our invention. For example,
"Nihon Kohden" technology estimates stroke volume (SV) by principle
of esCCO, where an inverse correlation between stroke volume (SV)
and pulse wave transit time (PWTT) is found. [20] "Nihon Kohden"
describes PWTT as following: "PWTT as the time measured from the
ECG R-wave peak to the rise point of SpO.sub.2 pulse wave. PWTT
consists of the following three time components. [0074] 1. PEP:
Pre-ejection period including the electromechanical delay at the
start of systole and isometric contraction time, with the R wave of
ECG serving as the starting point. [0075] 2. T.sub.1: The time it
takes for pulse wave to travel from the aorta through the elastic
arteries to the muscular arteries [0076] 3. T.sub.2: The time it
takes for pulse wave to travel from the muscular artery to the
further distal peripheral site of SpO.sub.2 measurement." "Nihon
Kohden" further writes: "PEP is affected by cardiac contractility,
preload and afterload, and is reduced as stroke volume (SV)
increases. In peripheral vessels with small diameter, propagation
velocity of pulse wave is reduced because the impact of viscosity
becomes dominant. When there is no change in vascular diameter,
T.sub.2 is less affected by viscosity. However, viscosity can have
a dominant influence on T.sub.2 when vascular diameter is smaller,
so T.sub.2 is affected by vascular diameter. As vascular diameter
determines vascular resistance, we assume that T.sub.2 is affected
by vascular resistance. Considering the relationship between SV and
T.sub.2, T.sub.2 is reduced as SV is increased due to
vasodilatation with increased vascular diameter." Although
well-understood general conclusion regarding dependence manner
between SV and T2, authors were not correct regarding main factors
of influence on T.sub.2, relating it to viscosity factor only. It
is right that decreasing diameter of smallest arteries increases
role of viscosity when vascular resistance is determined. But
vasoconstriction of smallest arteries, like arterioles, causes also
changing (increasing) of arterioles transient time, a local
transient effect of blood wave propagation from significantly lower
impedance of muscular arteries to significantly larger impedance of
small arterioles, described in our invention here above. Taking
this transient time into account may define T.sub.2 transit phase
of PWTT more correctly, thus balancing relative weights of blood
viscosity and changes of diameter by small arteries in influencing
said T.sub.2. Due to unitary nature of human physiology,
characteristic diameter of healthy arterioles, their stiffness,
width of walls and other mechanical parameters in any predefined
region of each healthy humane with normal cardiovascular conditions
belongs to limited range of characteristic values (for example,
value of characteristic diameter of arterioles may be about 35
microns in some peripheral body regions), so estimations here above
are reasonable for each healthy human. Changes in some
physiological conditions of measured subject, like heart rate, have
been taken into account also, when such estimation is done, as was
explained there-before. Summarizing an issue of arterioles diameter
measurement, we have to emphasize, that invented here systems,
methods and devices, indirectly measuring changes in characteristic
diameter of arterioles or value of said diameter, may be proved
and/or calibrated by use any of existing absolute methods of
measurements, like in [11]. It may be done, for example, by same
way, like in pulse-oximetry, where computed from measured signals
values of oxygen saturation are corrected to more exact values by
means of initially prepared "Correction Table". Such a "Correction
Table" may be achieved, for example, by comparison of calculated
equivalent inner diameter values of arterioles for preselected
measurement conditions, like heart rate, to actually measured by
one of direct measurement methods, like in [11].
[0077] The measurements of the pressure wave may be, for example,
measurements of blood volume in tissue, for example optical
measurements, ultrasound measurements, or electrical impedance
measurements. The measurements may also be, for example,
measurements of blood flow rate, for example laser Doppler
measurements. The measurements may be measurements of oxygen or
carbon dioxide levels in blood or tissue, for example optical
measurements. The two sets of measurements may distinguish larger
blood vessels from the smaller blood vessels that branch off them,
by penetrating to different characteristic distances beneath the
surface of the body. Smaller blood vessels that branch off from
larger blood vessels typically extend closer to the surface than
the larger blood vessels they branch off from. For example, if
optical measurements are used, then larger blood vessels can be
measured using a wavelength of light that penetrates further into
the tissue, such as near infrared, while smaller blood vessels can
be measured using a wavelength of light that does not penetrate as
far, for example green light. Both near infrared light, and green
light, are suitable for measuring blood volume, because they are
both preferentially absorbed by blood over other tissue, and other
wavelengths can also be used for this reason. Wavelengths can also
be used even if they are not preferentially absorbed by blood, if
they provide an estimation of the pressure wave in a different way,
for example by providing a measure of blood oxygen level or carbon
dioxide level. Similarly, if ultrasound measurements are used to
measure blood volume, then lower frequencies, which penetrate
further into tissue, may be used to measure the larger blood
vessels, while higher frequencies are used to measure the smaller
blood vessels. In addition, for either optical or ultrasound
measurements, the large blood vessels can be measured using a
source (light source or ultrasound transducer) that is further
away, on the surface of the body, from the detector, while the
smaller blood vessels, closer to the surface of the body, can be
measured using a source that is closer, along the surface of the
body, to the detector, so that the signal is dominated by light or
ultrasound that has not penetrated very far beneath the surface.
Similarly, for electrical impedance measurements, electrodes can be
placed further from each other on the surface of the body, to
measure larger blood vessels, which are deeper in the body, and
closer to each on the surface of the body, to measure smaller blood
vessels, which are closer to the surface of the body.
[0078] In some embodiments of the invention, the first set of
measurements is made using a sensor placed relative to (aimed to)
blood vessels close to a surface, large enough to be visible to the
naked eye, or through an endoscope, and the second set of
measurements is made using a sensor placed in a nearby area of the
surface where there is no large blood vessel, visible to the naked
eye or through an endoscope, near the surface, so the measurements
will be dominated by smaller blood vessels that branch off the
larger blood vessel. This method may be particularly useful for
measurements made of the surfaces of internal organs, external
parts of eye and so on, for example by endoscope or during surgery,
for which relatively large blood vessels are likely to be visible
on the surface, for diagnostics of eye sclera or blood vessels
related investigations in small animals.
It is reasonable to use CCD-like sensors in such a cases.
[0079] Again, the measurements can comprise using optical,
ultrasound or electrical impedance measurements to measure blood
volume, or laser Doppler measurements to measure blood flow rate.
Optionally, the measurements are also made on larger blood vessels,
to provide a reference case, where the viscous drag is relatively
small, for comparison.
[0080] Either of these methods can be used to assess various
medical conditions. Vasoconstriction, which is a reversible
decrease in blood vessel diameter, specifically for arterioles, can
be an indication of shock, dehydration or blood pressure changes.
Pathological conditions such as diabetes, or atherosclerosis, can
cause long term irreversible narrowing of small blood vessels, or
changing of equivalent inner diameter value, and can be diagnosed
or monitored using these methods. For these pathological
conditions, narrowing of the blood vessels may be associated with a
change in time shift between larger and smaller blood vessels, or a
change in phase shift between larger and smaller blood vessels, if
the blood vessel walls also become stiffer due to the pathological
condition, but measuring these quantities can still be used to
distinguish damaged small blood vessels, from healthy ones.
[0081] Before explaining at least one embodiment of the invention
in detail, it is to be understood that the invention is not
necessarily limited in its application to the details set forth in
the following description or exemplified by the Examples. The
invention is capable of other embodiments or of being practiced or
carried out in various ways.
[0082] Referring now to the drawings, FIG. 1 illustrates an optical
sensor system 100, for example a photoplethysmography (PPG) system,
used to measure blood volume, or a related parameter such as blood
or tissue oxygen level or carbon dioxide level, as a function of
time in a region of a surface 102 of a subject's body, according to
an exemplary embodiment of the invention. Optionally, surface 102
is the subject's skin, and sensor system 100 is non-invasive.
Alternatively, system 100 can be used on an internal surface of the
subject's body, for example on a surface of an internal organ
during surgery, in an endoscopic procedure or during long term
internal monitoring or monitoring of internal organ, for example in
the nasal passage, in the gastrointestinal tract, in the ear, or in
the urethra. Blood vessels like 104, at some distance beneath
surface 102, has smaller blood vessels 106 branching off it. When
blood vessels have smaller blood vessels branching off it, the
smaller blood vessels often come closer to the surface than the
larger blood vessels, especially when the surface is the skin. For
example, blood vessels like 104 are a relatively small artery,
about 7 mm beneath the surface, and vessels 106 are arterioles,
which come closer to the surface than vessels like 104, for example
within 2 mm, 3 mm or 4 mm of the surface.
[0083] Light sources 108 and 110, being placed relatively to
measured tissue region, aimed into surface 102 and optionally in
contact with surface 102, illuminate the blood vessels, and light
scattered from the blood vessels is detected by detector 112. Light
source 108 produces light of a relatively long wavelength, for
example near infrared light, that can penetrate deeply enough into
body tissue to reach the depth of blood vessels like 104, while
light source 110 produces light of a shorter wavelength, for
example green light, which largely does not penetrate the tissue as
far as blood vessels like 104, but mainly illuminates smaller blood
vessels 106, that are closer to the surface. In this way, detector
112 can generate a first signal to which blood vessels like 104
make a substantial contribution, and a second signal to which blood
vessels like 104 make a smaller contribution, if any, and smaller
blood vessels 106 make a relatively larger contribution.
[0084] For example, the light from light source 108 penetrates to a
characteristic fall-off distance of 3 mm, or 5 mm, or 10 mm, or
more than 10 mm, or less than 3 mm, or an intermediate distance. A
characteristic fall-off distance in tissue for light from light
source 110 is smaller than the characteristic fall-off distance for
light from light source 108, for example by a factor of at least
1.3, or at least 1.5, or at least 2, or at least 3, or at least 5.
For example, the light from light source 110 penetrates to a
characteristic fall-off distance of 1 mm, or 2 mm, or 3 mm, or 5 mm
into the tissue, or a greater, smaller, or intermediate distance.
Optionally, one or both of light sources 108 and 110 is an LED, or
a laser diode. In some embodiments of the invention, light sources
108 and 110 comprise a single light source, which produces two
different wavelength bands of light, a longer wavelength band of
light which penetrates more deeply into the tissue, and a shorter
wavelength band of light which penetrates less deeply. In some
embodiments of the invention, the light source or separate light
sources produce three or more wavelength bands of light, which
penetrate into the tissue respectively a shorter distance, one or
more different intermediate distances, and a longer distance. Using
three or more wavelength bands may provide more accurate results
for time differences as a function of penetration distance, because
there is some redundancy. Additional wavelength bands may also be
used to measure different parameters, for example both blood
volume, and blood oxygenation level, which may provide more
accurate results.
[0085] In addition to, or instead of, using a wavelength range for
light source 108 that penetrates tissue more deeply than a
wavelength range used for light source 110, the light detected from
light source 108 will come from a deeper layer of tissue than the
light detected from light source 110, if light source 108 is
located further away from its detector than light source 110 is.
Light detector 112 is optionally positioned relatively to measured
region of tissue on surface 102, close enough to light source 108
that it can detect a substantial amount of light from light source
108 that scatters from tissue at the depth of blood vessels like
104, but not so close to light source 108 that light from light
source 108 scattering from a shallower depth in the tissue, for
example at the depth of blood vessels 106, overwhelms the light
scattered from tissue at the depth of blood vessels like 104. For
example, light detector 112 is located at a distance from light
source 108 equal to 0.5 times a characteristic fall-off distance in
tissue of the light from light source 108, or equal to the
characteristic fall-off distance, or equal to 2 times the
characteristic fall off distance, or 3 times the characteristic
fall off distance, or equal to 3 mm, or 5 mm, or 10 mm, or 20 mm,
or 30 mm, or equal to a smaller, greater, or immediate distance.
Optionally, light detector 112 is also used to detect light from
light source 110 that scatters from tissue at a shallower depth, or
a separate light detector is used for that purpose. Light detector
112, or a separate light detector if one is used, is located close
enough to light source 110 so that it detects a substantial amount
of light from light source 110 that scatters from tissue at the
depth of blood vessels 106, but not so close that light scattered
from a shallower depths overwhelms the light scattered from tissue
at the depth of blood vessels 106. For example, light detector 112,
or a separate light detector used for light source 110, is located
relatively to light source 110 at distance equal to 0.5 times a
characteristic fall-off distance in tissue of the light from light
source 110, or equal to the characteristic fall-off distance, or
equal to 2 times the characteristic fall off distance, or 3 times
the characteristic fall off distance, or equal to 0.5 mm, or 1 mm,
or 2 mm, or 5 mm, or 10 mm, or equal to 1 times, 1.5 times, 2
times, 3 times, 5 times or 10 times the distance between light
source 108 and light detector 112, or equal to a smaller, greater,
or immediate distance. If there are three or more light sources
producing light of different wavelengths which penetrate to other
distances into the tissue, then the light sources producing the
more deeply penetrating light are optionally located further from
the detector, or their individual detector, than the light sources
producing the less deeply penetrating light.
[0086] When system 100 operates, light source 108 produces light
114, directed into the tissue beneath surface 102, which scatters
relatively more from blood vessels like 104, and relatively less
from smaller blood vessels 106, and is detected by detector 112,
while light source 110 produces light 116, directed into the tissue
beneath surface 102, which scatters relatively more from smaller
blood vessels 106, and relatively less from blood vessels like 104,
and is detected by light detector 112, or by a different light
detector as noted above. It should be understood that "relatively
more" and "relatively less," mean that the ratio of light scattered
from blood vessels like 104 to light scattered from blood vessels
106 is greater for light produced by light source 108 and detected
by light detector 112, than it is for light produced by light
source 110 and detected by light detector 112. Optionally, the
ratio is 1.2 times as great, or 1.5 times as great, or 2 times as
great, or 5 times and great, or 10 times as great, or a smaller,
greater, or intermediate number of times as great. Optionally, more
of the light produced by light source 108 and detected by light
detector 112 is scattered by blood vessels like 104 than by blood
vessels 106, for example 1.2 times as much, or 1.5 times as much,
or 2 times as much, or 5 times as much, or 10 times as much, or a
smaller, greater, or intermediate number of times as much.
Optionally, more of the light produced by light source 110 and
detected by light detector 112 is scattered by blood vessels 106
than by blood vessels like 104, for example 1.2 times as much, or
1.5 times as much, or 2 times as much, or 5 times as much, or 10
times as much, or a smaller, greater, or intermediate number of
times as much.
[0087] Optionally, light sources 108 and 110 placed relatively to
measured tissue region such way, that illuminate the tissue beneath
surface 102 simultaneously, and light detector 112 distinguishes
between light from light source 108 and light from light source 110
by using filters, or using two detectors that are each sensitive to
wavelengths from a different one of the light sources.
Alternatively, light coming from light source 108 is distinguished
from light coming from light source 110 by multiplexing, i.e. the
light sources are alternately turned on and off, with only one of
the light sources on at a given time. However, if such multiplexing
is used, it may be advantageous to do it rapidly enough, for
example with on and off times of several milliseconds or less, so
that a time shift between signals from the two light sources, that
is only a few tens of milliseconds, can be accurately measured, as
will be explained below.
[0088] The light from light source 108 detected by light detector
112, scattered relatively more from blood vessels like 104 and less
from smaller blood vessels 106 than the light from light source 110
is, provides a measure of the volume of blood or a related
parameter in blood vessels like 104, in the vicinity of the light
sources and detector, as a function of time. The light from light
source 110 detected by light source 112, scattered relatively more
from blood vessels 106, and less from blood vessel 104, provides a
measure of the volume of blood or a related parameter in blood
vessels 106, in the vicinity of the light sources and detector, as
a function of time. Two signals produced by detector 112, one of
light produced by light source 108 and one of light produced by
light source 110, are sent to a controller 118, for example a
computer or dedicated circuitry. Controller 118 compares the two
signals, and, as will be described below in the description of FIG.
5, uses the signals to obtain information about the equivalent
inner diameter of blood vessels 106, or about a change in the
equivalent inner diameter of blood vessels 106, or a difference in
the equivalent inner diameter in different parts of the body. As it
was shown in theoretical part of this description, proper
estimation of equivalent inner diameter needs of heart rate value
taken into account. Said heart rate value has to be obtained at
same time, when detector 112 produces said signals. In current
embodiment the heart rate value may be calculated from at least one
of measured said signals, or, alternatively, may be obtained from
any other sensor or any other device.
[0089] Alternatively or additionally, other parameters of the blood
vessels may be found, for example the mean arterial pressure may be
found if there is other information about heart stroke
parameter.
[0090] Even if the signals from light produced by light source 108
and light produced by light source 110 are not dominated
respectively by scattering from blood vessels like 104 and
scattering from blood vessels 106, in some embodiments of the
invention due to different relative contributions to the signals
from scattering from blood vessels like 104 and scattering from
blood vessels 106, controller 118 is able to separate the
contribution from blood vessels like 104 from the contribution from
blood vessels 106, and to create two output signals that, subject
to noise and other limitations of the data, represent only or
primarily scattering from blood vessels like 104 and blood vessels
106 respectively. Optionally, controller 118 uses those two output
signals, instead of or in addition to the two signals of light
produced by light source 108 and light produced by light source
110, to find the information about the equivalent inner diameter or
change or difference in equivalent inner diameter of blood vessels
106.
[0091] Optionally, controller 118 is connected to an I/O device
120, such as a display screen, a printer, a touch screen, a
keyboard, and/or a mouse, that allows users to see the results of
calculations done by controller 118. Optionally, controller 118
also controls and/or detects when light sources 108 and 110 are
turned on. Optionally, a user can use the input features of I/O
device 120 to turn system 100 on, and/or to control parameters used
by controller 118 in analyzing the signals from light detector 112,
optionally using a graphic user interface. Controller 118, I/O
device 120, and the light sources and detector need not be
physically located in the same room, but may be remote from each
other, connected by communications links. For example, I/O device
may be a cell phone or a Bluetooth device, used to monitor a
patient remotely. I/O device 120 may also be located next to the
patient, or even on a device worn by the patient, such as a
bracelet with a display screen, so medical personnel can easily
read off data from it when examining the patient.
[0092] It should be understood that elements with a function
attributed to controller 118, for example A/D converters, or CPUs,
may also be located in detector 112, and this is true also for the
system shown in FIG. 4, and the detectors or receivers, and
controllers, in the system. Alternatively, such elements may be
considered part of controller 118, even if they are housed in a
same physical unit as detector 112. In general, controller 118, and
the other controller in FIG. 4, need not be a single physical unit,
but are optionally distributed in a plurality of different places
or combined with different pieces of hardware.
[0093] It should also be understood that more than one system such
as system 100, or elements of more than one such system, may be
used on a same subject. For example, different types of sensors,
such as those in FIG. 1 or 4, may be used together, with different
controllers, or with a single controller that performs the control
functions for all of the sensors.
[0094] Light scattered from tissue provides a measure of the blood
volume in the scattering region, if the light is of a wavelength or
band of wavelengths that is absorbed and/or scattered at a rate
different from the rest of the tissue, and this is true of the
light produced by light sources 108 and 110. For example, the light
produced by light source 110 is optionally in an absorption band of
oxyhemoglobin, if system 100 is designed to be used for arteries,
or deoxyhemoglobin if system 100 is designed to be used for veins.
The light produced by light source 108 is optionally in a
wavelength range, in the near infrared, that is absorbed by water
with an absorption length on the order of 1 cm or a few cm, for
example between 0.9 and 1.4 so would be preferentially absorbed by
blood, which has a higher percentage of water than the surrounding
tissue, but would not be almost completely absorbed before it
reaches blood vessels like 104.
[0095] In some embodiments of the invention, light sources 108 and
110 use wavelengths that are not preferentially absorbed by blood
over other tissue, but that are preferentially absorbed by
oxyhemoglobin over deoxyhemoglobin, or vice versa, or that are
absorbed by carbon dioxide, for example in the infrared at 2.15
.mu.m or 4.2 .mu.m. Such wavelengths are used by optical pulse
oximeters, and by optical capnometers. In this case, the signal
produced need not be a measure of blood volume, but may be a
measure of oxygen level or carbon dioxide level in the blood, and
in tissue. Since oxygen levels and carbon dioxide levels in the
blood, and in tissue, may vary periodically over the cardiac cycle
and over the breathing cycle, they may be used, as an alternative
to blood volume, to find a time differences between the signals, as
described in FIG. 5.
[0096] In some embodiments of the invention, there are a plurality
of different light sources 108 located at different distances from
detector 112, and/or a plurality of different light sources 110
located at different distances from detector 112, and/or a
plurality of different detectors 112 located at different distances
from light sources 108 and 110. The distance between light source
108 and detector 112, and/or the distance between light source 110
and detector 112, can then be optimized, by looking at the signal
for each distance between the light sources and the detector, and
optionally only using the signals that work best. Optionally, there
are also a plurality of light source and detectors pairs at the
same separation distance, but located at different places, and the
location can be optimized by looking at the signal from each pair,
and optionally only using the signal that works best. Some
locations may work better than other locations because, for
example, the light source and detector are positioned better with
respect to blood vessels that are suitable for measuring
vasoconstriction, or that are suitable for detecting narrowing of
blood vessels due to a pathological condition, such as diabetes,
that may only affect blood vessels in some locations.
[0097] From description of the embodiment, discussed above, we may
see, that it is possible to achieve different separation levels
between measured signal from artery-like and arteriole-like blood
vessels. In theory, obtaining at least two signals, wherein the
first one includes not significantly more from artery-like blood
vessels, then the second one, we are able to calculate the
difference between them and, according to known anatomy of measured
body portion, estimate equivalent inner diameter of arteriole-like
blood vessels by appropriate numerical correction.
[0098] But much better the situation, where said different
separation levels between measured signal from artery-like and
arteriole-like blood vessels is sufficient, thus enabling to
estimate equivalent inner diameter of arteriole-like blood vessels
without significant numerical corrections.
[0099] An ideal is the case, wherein we obtain at least two signals
from artery-like and arteriole-like blood vessels, being fully or
almost fully separated.
[0100] Here after an example embodiment of modified pulse-oximeter
is described and this is also to example of almost full separation
between signaling from artery-like and arteriole-like blood
vessels.
[0101] We see much reason also to reflect here an additional
possibility for estimation of arteriole's equivalent inner
diameter, where the analyzed blood vessels are observed visually or
may be observed by different optical magnification or optical
scanning means. This possibility enables finding different blood
flow related processes in each artery-like or arteriole-like blood
vessel by digital processing of data, obtained from their imaging
or scanning examinations, in separate.
[0102] Calculated here time or phase differences are represented in
their optimal conditions, thus performing the best correlation to
different vascular or cardiovascular conditions in measured
subject. Traditionally there is well developed technique, enables
to image retinal blood vessels with resolution and accuracy, good
enough to quantitative analysis.
The technique is related to fundus ophthalmoscopy and fundus
photography. Ophthalmoscopy (also called fundoscopy) is a test that
allows to see inside the back of the eye (called the fundus) and
other structures using a magnifying instrument (ophthalmoscope) and
a light source. Usually it is done as part of an eye exam and may
be done as part of a routine physical exam. The fundus contains a
lining of nerve cells (the retina), which detects images seen by
the clear, outer covering of the eye (cornea). The fundus also
contains blood vessels and the optic nerve Compared to
ophthalmoscopy, fundus photography generally needs a considerably
larger instrument, but has the advantage of availing the image to
be examined by a specialist at another location and/or time, as
well as providing photo documentation for future reference. Modern
fundus photographs generally recreate considerably larger areas of
the fundus than what can be seen at any one time with handheld
ophthalmoscopes. Both types of these retinal monitoring techniques
enable to observe different sizes of retinal vessels, being
recognized there separately one from another. Thus here we may
speak about comparison of two separate arterial vessels of
different sizes. As it was described for previous embodiment, in
this invention we find from measured blood vessels proportion or
correlation blood flow related process, changing over time. It
means that instead of one image of retinal blood vessels we have to
collect a number of different images in any of data formats (image
data)--in order to be able to calculate some parameters, said about
changes in measured blood vessels due to blood flow propagation
over time. During its collection or after being collected, said
image data has to be transferred to processor unit for further
analysis. FIG. 2 illustrates a system of said ocular fundus imager,
which may be used for estimating of equivalent inner diameter of
retinal arterioles. The system includes ophthalmoscopic device 202,
irradiating light 208 to retinal surface 206 of eye 204. The
portion of light 210 comes back to ophthalmoscopic device and,
being optically prepared to focused retinal image 216, is collected
by image sensor 212, which is able to collect images with proper
rate. Transformed from images by image sensor 212 image data in its
digital form is transferred to local or remote processor unit 214
for immediate or further analysis. As it was done in previous
embodiment, estimation of arteriole's equivalent inner diameter in
eye's retina is possible by at least partial separation between
blood flow related signals from larger retinal arteries and blood
flow signals from smaller retinal arteries, like arterioles. Basic
properties of focused image enable to separate between said signals
through using object analysis from said image data. Each branching
blood vessel has its unique place in collected image, thus enabling
to analyze it separately. Being identified by image data, said
blood vessel may be analyzed by its configuration and brightness
parameters and their changes over time in order to estimate their
proportion or correlation to at least one of blood flow related
processes. FIG. 3 A illustrates splitting of two smaller retinal
arteries 330 and 360 of nearly same diameter from larger retinal
artery. 320. When processor 214 performs analyzing of image data,
including, for example an image portion with illustrated by FIG.
3A, at least one analysis area may be selected for each blood
vessel. On FIG. 3A is shown analysis area 340 for branching retinal
artery 320 and analysis area 360 for branched smaller retinal
artery 330. Blood flow proportional or correlative process from
vessel-related portions of said areas may be achieved by separate
or combined analysis of their brightness and geometric properties.
At least some of these properties tend to vary over time according
to blood flow propagation there. Really, physical parameters of
blood flow in said vessels, like changes of blood pressure, blood
volume or blood velocity over time, cause to blood vessel with
finite stiffness to change its diameter and, sometimes, also its
geometrical position in retinal space (vasomotion). Being
illuminated by external light 208, such a vessel varies its
reflectance properties that cause to changes in geometric and
brightness parameters of collected over time image data. Taking
into account, that larger artery is much rigid, than branched
smaller arteries and much more rigid than its brunched arterioles,
we may conclude, that diameter changes, caused by blood flow
propagation to said artery, will be much less, than for its
branched arterioles. Said difference has also to be taken into
account for proper use of processor unit 214. FIG. 3B illustrates
splitting of retinal arteriole 380 from larger retinal artery 370,
when selected area of analysis 340 for said artery and selected
area of analysis 350 for said arteriole may be analyzed by
different ways. Due to sufficient diameter of artery 370 it may be
useful to analyze, for example, changes in brightness in margins of
its internal area. For smaller arteriole 380 internal variations of
brightness may be insufficient for detailed analysis, but, because
of its higher elasticity, changes of its diameter may be recognized
much easier that in case of larger and relatively rigid retinal
artery 370. On FIG. 14 a flowchart illustrates an example for an
exemplary method of estimation for equivalent inner diameter of
retinal arteriole, branched off from retinal artery, and optionally
monitoring changes in value of said diameter over time, by
calculating from image data at least one changing over time
parameter of blood flow relative process in said analyzed retinal
artery and arteriole according to an exemplary embodiment of the
invention. Here the first stage 1410 comprises obtaining of retinal
movie data from fundus imager. Said data at the following step 1420
is being transferred to preconfigured processor for further
process. Said processor extracts blood flow proportional
parameters, changing over time, from at least one larger retinal
artery (1430) and from at least one smaller retinal artery, belongs
to same artery tree, like said larger artery (1440). It may be
arteriole, branched directly from said larger artery. Also it may
be at least one smaller artery, branched from same said larger
artery and so on. Optionally it may be extraction of blood flow
proportional parameters, changing over time, from all arteries,
branching from said larger artery. Said processor calculates time
or phase shift between said time-dependent parameters, extracted
from larger and smaller retinal vessels (1450) in order to
estimate, coupling this data with heart rate value, obtained at the
time period of image data collection, equivalent inner diameter
value of said smaller retinal blood vessels (1460). Heart rate
value, used for estimation of equivalent inner diameter of smaller
retinal vessel, may be obtained from analysis of same said blood
flow proportional or correlative over time parameter, extracted
from said image data, Optionally or alternatively heart rate value
may be obtained from independent measurement, performed at a time
of collecting same said image data by same ophthalmologic device or
by any other device, intended for this measurement. Following
potential ability of retinal image technology also to collect
retinal images at relatively high rate, we may illustrate a way of
estimation for heart beat wave propagation velocity by means of
analysis, described before. On FIGS. 6 A and B two different phases
of heart beat wave propagation from branching retinal artery 620 to
smaller retinal arteriole 630 are illustrated. On FIG. 6A the
frontal part 660 of current heart beat wave widens initially small
diameter of said arteriole 630 and this widening may be analyzed in
selected area of analysis 650. On FIG. 6B, by using appropriate
rate of image collecting after some time we may recognize similar
widening 670 in other place of selected area of analysis 650,
distanced from its initial place on FIG. 6A. Said measurable
distance between positions of said frontal part 660 on FIG. 6A and
on FIG. 6B, in couple with known time range between collecting
their appropriate image data, enables to calculate heart beat wave
propagation velocity in said retinal arteriole. On FIG. 15 a
flowchart illustrates an example of method for estimation of
equivalent inner diameter of retinal arteriole, branched off from
retinal artery, and optionally monitoring changes in value of said
diameter over time, by calculating from ophthalmoscopy data at
least one changing over time parameter of pulse wave propagation
relative process in said analyzed retinal artery and arteriole
according to an exemplary embodiment of the invention. Here the
first stage 1510 comprises obtaining of retinal movie data from
fundus imager. Said data at the following step 1520 is being
transferred to preconfigured processor for further process. Said
processor extracts time of pulse wave propagation trough said
larger (1530) and smaller (1540) retinal arteries. It may be
arteriole, branched directly from said larger artery. Also it may
be at least one smaller artery, branched from same said larger
artery or any other possible branch. Optionally this extraction may
be performed by analysis of geometrical changes in blood vessel
configurations of collected image data or in changes of their
brightness. Said processor estimates equivalent inner diameter
value by use of said extracts time of pulse wave propagation trough
said larger (1530) and smaller (1540) retinal arteries, in coupling
this data with heart rate value, obtained at the time period of
image data collection, equivalent inner diameter value of said
smaller retinal blood vessels (1560). Heart rate value, used for
estimation of equivalent inner diameter of smaller retinal vessel,
may be obtained from analysis of same said blood flow proportional
or correlative over time parameter, extracted from said image data,
Also here optionally or alternatively heart rate value may be
obtained from independent measurement, performed at a time of
collecting same said image data by same ophthalmologic device or by
any other device, intended for this measurement. Ophthalmologic
fundus imaging is also based on Doppler-based optical scanning (See
[13,14] and more). Doppler fundus imaging in its various
implementations enables to reach parameter, proportional to or
correlative to velocity of blood in measured arteries and
arterioles of retina. It also may be a parameter for estimation of
equivalent inner diameter of retinal arterioles by use of its time
or phase differences in scanned retinal arteries and arterioles
over time. It is necessary to remind regarding two widespread
diagnostic methods in fundus ophthalmology, where an option for
direct measurement of blood velocity is possible without use of
Doppler Effect. In Fluorescentic Fundus Ophthalmology a mixture
with fluorescent dye is injected into circulation and enables to
observe it flow in retinal imaging without application of external
illumination. By imaging of fluorescent dye components moving in
retinal blood vessel tree it is also possible to estimate
characteristic velocity of blood in each of imaged blood vessels
over time. Same principle of blood velocity estimation may be
applied in case of autofluorescense retinal imaging, where for
example, illuminated by specific wavelengths red blood cells (RBC)
of blood in retinal blood vessels irradiate their own fluorescent
light, which is imaged by ophthalmologic device. Generally,
estimated by methods, illustrated in FIGS. 14 and 15, results may
be represented at different numerical and graphical forms,
including also retinal mapping in case of said image data
processing, applied to one or several sectors of retinal image.
[0103] FIG. 4 shows a system 400 that uses laser Doppler
measurements to measure a blood flow rate in blood vessels like
104, and in one or more of blood vessels 106. A laser Doppler
system 408 scatters one or more laser beams from moving
erythrocytes in blood vessels like 104, which are received by a
detector 412. A laser Doppler system 410 scatters one or more laser
beams from moving erythrocytes in one or more of blood vessels 106,
which are received by detector 412, or by a separate detector.
Optionally, laser Doppler system 408 uses a wavelength of light
that penetrates further into the tissue beneath surface 102, so it
can reach blood vessels like 104 while remaining coherent, than the
light of laser Doppler system 410, which only has to penetrate as
far as blood vessels 106. Alternatively, they use the same
wavelength. Detector 412 optionally uses the different wavelengths
to distinguish the signals from the two laser Doppler systems.
Alternatively, detector 412 uses multiplexing to distinguish the
signals.
[0104] Detector 412 sends signals from the two laser Doppler
systems to a controller 418, which uses the signals to calculate a
flow rate of blood in blood vessels like 104, and a flow rate of
blood in one or more of blood vessels 106, as a function of time.
Optionally, because there may be many blood vessels 106 oriented in
many different directions, and it may be difficult to determine the
direction of orientation of a particular blood vessels 106 that is
being measured, laser Doppler system 410 makes a 2D or 3D
measurement of blood vessels 106, so that the flow rate can be
found as a function of time, by controller 418, even if the
orientation of the vessel is not known. Optionally this is also
done by laser Doppler system 408 for blood vessels like 104.
[0105] Because blood flow rate, like blood volume, varies in blood
vessels like 104 and 106 over time, depending on the pressure, the
signals of blood flow rate, like the signals of blood volume, can
be used to measure the pressure wave in blood vessels like 104 and
106, and hence can be used by controller 418 to find information
about the equivalent inner diameter, change in equivalent inner
diameter or difference in equivalent inner diameter of blood
vessels 106, in coupling with obtained at the same time value of
heart rate, as will be described below in the description of FIG.
5. In some embodiments of the invention, as noted above, only the
signal from blood vessels 106 is needed, and for those embodiments,
the flow speed or velocity in blood vessels like 104 need not be
measured.
[0106] FIG. 5 shows a flowchart 500, for a method of using
measurements for one or more larger blood vessels and for smaller
blood vessels that branch off the larger vessels, to find
information about the equivalent inner diameter of the smaller
vessels, and/or about changes in the equivalent inner diameter over
time, and/or about differences in the equivalent inner diameter
between different parts of the body. The measurements can be any
measurement in the larger and smaller blood vessels, as a function
of time, that depends on the pressure, and provides an indication
of a pressure wave in those blood vessels, for example blood
volume, flow rate, or oxygen level or carbon dioxide level in blood
or tissue. The term "pressure wave" as used herein includes the
variation in blood pressure in arteries due to the cardiac cycle,
as well as a variation in blood pressure in veins due to motion of
the subject's body, or any other cause of short-term temporal
variation of pressure in blood vessels.
[0107] At 502, a measurement is made of blood volume or blood flow
as a function of time in the smaller blood vessels, and at 504,
simultaneously with 502, or with a known time shift, a measurement
is made of blood volume or blood flow rate as a function of time in
the larger blood vessels, using any of the methods described in
FIGS. 1 and 4, for example. At 506, the signal from the smaller
vessels is optionally filtered to remove noise, optionally by
low-pass filtering, and at 508 the signal from the larger blood
vessels is optionally filtered to remove noise, optionally by
low-pass filtering. The low-pass filtering removes high frequency
noise from the signals, but optionally the filtering is not so
strong that the overall shape of the signal on the time scale of
the pressure wave is greatly distorted. In particular, the
filtering is not so strong as to introduce substantial errors in a
time or phase shift calculation between the two signals. For
example, frequencies up to 5 times the heart beat frequency, or up
to 10 times the heart beat frequencies, are not filtered very much,
but higher frequencies are. Optionally, very low frequency
components, for example at frequencies below the frequency of the
heart beat, are also filtered out, to detrend the data, or the data
is detrended in another way. At 510, the two signals are compared,
and time or phase differences are found between them, for example
by finding a time shift that maximizes their equivalent inner
diameter value. The time shift, coupling with heart rate value at
the time of measurement, provides information about the diameter of
the smaller vessels.
[0108] At 512, the equivalent inner diameter valueis optionally
compared to an equivalent inner diameter value found at other times
or in other parts of the body, optionally in the same way as this
time shift. At 514, conclusions are drawn about the equivalent
inner diameter of the small blood vessels. These conclusions need
not involve absolute measures of the equivalent inner diameter
value, but could involve only changes in the equivalent inner
diameter over time, possibly only about the direction of change.
Additionally or alternatively, the conclusions could involve
differences in the equivalent inner diameter, possibly only the
sign of the difference, between this part of the body and other
parts of the body.
[0109] In some embodiments of the invention, conclusions are drawn
about the equivalent inner diameter of small blood vessels, based
on whether or not the equivalent inner diameter is smaller than a
threshold value. For example, the threshold value is between 20 and
50 micrometer and if the equivalent inner diameter exceeds the
threshold value, then conclusions are drawn that small blood
vessels being measured exhibit vasoconstriction or vasodilation.
Optionally, the threshold is specific for a patient, and/or for a
particular method of measurement. Optionally, the threshold is
determined by earlier testing of that patient, and is stored in a
controller, such as controllers 118, or 418 of FIGS. 1 and 4
respectively, that performs the step of drawing conclusions about
the equivalent inner diameter of the small blood vessels at
514.
[0110] In general, a larger time or phase shift means smaller
equivalent inner diameter of the smaller blood vessels, at least if
the smaller blood vessel walls are not also becoming more rigid
when the diameter gets smaller. That seems to be the case with
normal, reversible vasoconstriction in healthy subjects, as
indicated by the observations described below under "Examples."
That data was obtained by inducing vasoconstriction by cooling part
of the body. But vasoconstriction can also be sign of such
dangerous medical conditions as shock and dehydration, and the
method of flowchart 500 can be used to help diagnose such
conditions, as will be described in more detail in the description
of FIG. 9. In those cases, vasoconstriction occurs first in
peripheral parts of the body, and can work its way closer to the
central parts of the body, i.e. closer to the trunk, as the
condition gets more severe. Monitoring vasoconstriction in such
circumstances can be clinically useful, and it is not necessary to
be able to calibrate the equivalent inner diameter to the exact
diameter of the smaller blood vessels. It may be enough to observe
qualitatively that the small blood vessel equivalent inner diameter
is decreasing in time, more severely in peripheral parts of the
body.
[0111] The method of flowchart 500 can also be used to measure
changes in the equivalent inner diameter s of small blood vessels
due to causes other than vasoconstriction. For example, pathologies
such as diabetes, and atherosclerosis, may cause a narrowing of
smaller arteries, and it can be clinically useful to monitor such
changes over time, for example over months or years. In general, it
may not be known, from first principles, whether progression of
diabetes or atherosclerosis would be expected to lead to an
increase or decrease in equivalent inner diameter value in smaller
arteries, and it may not even be the same for all patients. Even in
these circumstances, measuring equivalent inner diameter value
repeatedly at different times can be useful, just by showing a
change in equivalent inner diameter value, in either direction.
Also, particularly in the case of diabetic patients, there may be
parts of the body where it is clear, from clinical indications,
that small arteries have not yet been affect adversely by the
disease, and these parts of the body may provide a reference for
comparison, that can be used to evaluate the direction of change in
equivalent inner diameter value in smaller arteries in areas that
are affected. Further details on using this method to evaluate
patients with pathologies such as diabetes, are provided in the
description of FIG. 8, below.
[0112] FIG. 7 shows a plot 700 of photoplethysmographic (PPG)
signals for green and near infrared light, for the same location on
the body of a test subject, to illustrate how the time differences
may be found from the signals. The signals were obtained with a PPG
system similar to system 100 shown in FIG. 1. The amplitude of the
signal is plotted on a vertical axis 702, in arbitrary units, and
the time is shown on a horizontal axis 704, also in arbitrary
units. Curve 706 is the PPG signal using green light, which is
sensitive primarily to the blood volume in the arterioles, while
curve 708 is the PPG signal using near infrared light, which is
sensitive primarily to the blood volume in the artery or arteries
that the arterioles are branching off from. The signals have been
low-pass filtered to remove noise, but still show the general shape
of pressure waves in the artery and the arterioles. The signals
have been inverted so that a more positive value of the signal
indicates a greater volume of blood, even though a greater volume
of blood results in a lower intensity of light scattered from the
tissue, since the green light used for signal 706 and the near
infrared light used for signal 708 are both absorbed more by blood
than the surrounding tissue. Optionally, signals 706 and 708 are
de-trended before finding the time differences, to remove drift in
the signal from one cardiac period to the next that can distort the
shape of the signal, although that was not done with signals 706
and 708 shown in FIG. 7.
[0113] To find a time delay between signal 706 and signal 708, a
time difference is found for corresponding points on curve 706 and
curve 708. For example, minima of the two signals, for the same
cardiac cycle, may be used to find the time difference. Time 710 is
a minimum of curve 708, and time 712 is the minimum of curve 706
for the same cardiac cycle. A difference 714 between time 712 and
time 710 is optionally used as the time shift for these two
signals. Alternatively, maxima of the two signals, for the same
cardiac cycle, may be used to find the time shift. Time 716 is a
maximum of curve 708, and time 718 is a maximum of curve 706 for
the same cardiac cycle. A difference 720 between time 718 and time
716 is optionally used as the time shift between these two signals.
Although time shift 714 is different from time shift 720, due to
the different shape of curves 706 and 708, the time shift may be
meaningfully compared at different times, and/or at different parts
of the body, if the time shift is defined consistently. Still other
procedures for measuring time shift include looking at the time
difference of an inflection point, for example the time of greatest
rate of rise, or the time of greatest rate of fall, for the two
signals, or looking at the time difference between points that are
half-way between the local minimum and local maximum in amplitude,
or in time, for the two signals. The time difference can also be
found by finding a time shift that maximizes a cross-correlation
between the two signals. Optionally, the time shift, however it is
found, is averaged over multiple cardiac periods, for example to
reduce noise.
[0114] Optionally, before finding the time difference, the signal
is examined to make sure that it is a good signal. For example, if
the signal comes from arteries, it is examined to verify that its
dominant component is at a reasonable cardiac frequency, optionally
between 0.5 and 3 Hz.
[0115] FIG. 8 is a flowchart for a method of assessing or
monitoring damage to small blood vessels due a pathological
condition such as diabetes, using the method of FIG. 5. At 802, a
quantity that serves as an indication of a pressure wave in blood
vessels, such as blood volume or blood flow rate, is measured in a
larger branching blood vessels and in the smaller blood vessels
that belong to same peripheral part of systemic circulation, for
example using one of the systems shown in FIGS. 1, 2 and 4, in a
part of a body of a patient that is believed to have damage from a
disease, such as diabetes, that can damage small blood vessels.
Signals from these measurements are optionally low-pass filtered,
at 804, and optionally detrended. A time or phase difference
between the two signals, for the larger and smaller blood vessels,
is found at 806. At 808, measurements are made, similar to the
measurements made at 802, but for a part of the body where the
small blood vessels are believed to be undamaged, or less damaged,
by the pathological condition. The signals from these measurements
are optionally filtered at 810, and a time or phase difference
between the larger and smaller blood vessels is found at 812, and,
being coupled with obtained heart rata value related to said
measuring time, fn equivalent inner diameter value may be
estimated.
[0116] At 814, the equivalent inner diameter values from the region
believed to be damaged, and the region believed to be undamaged or
less damaged, are compared, and results of the comparison are used,
at 816, to assess the presence or degree of damage to small blood
vessels, in the region believed to be damaged.
[0117] Optionally, if the method is being used to monitor a patient
with diabetes, which often effects small blood vessels only in
scattered localized regions of tissue without affecting other
regions as much or at all, then an array of sets of sensors and
detectors, each set similar to those shown in FIG. 1 is used over a
large area on a general part of the body, for example the foot,
that is likely to be affected in some locations, in order to
monitor the whole area at once.
[0118] The method of flowchart 800 may be particular suited for
assessing damage to small blood vessels due to diabetes (for
example, in foot or Retina), since diabetes typically causes such
damage to small blood vessels in some parts of the body and not in
others, so it is usually possible to find regions, known to be
relatively undamaged by diabetes, which can be used as a reference.
The method of flowchart 800 may be less suited for assessing damage
to small blood vessels due to atherosclerosis, since such damage
may be more widespread throughout the body, and it may be difficult
to find undamaged areas for comparison, but it may still be
possible to use the method of flowchart 800 for assessing damage to
small blood vessels due to atherosclerosis.
[0119] FIG. 9 shows a flowchart 900, for a method of assessing
shock or dehydration in a patient, from their vasoconstrictive
effect, using the method of FIG. 5. Shock can be an indication of
hidden internal bleeding in a trauma patient, and having a way to
detect it early or to continuously monitor for it in a non-invasive
way, using inexpensive equipment that could be carried in an
ambulance or used routinely in an emergency room, could potentially
save lives. The method of flowchart 900 uses the fact that, in
shock or in dehydration, peripheral blood vessels tend to undergo
vasoconstriction first, in order to preserve the volume of blood in
the central region of the body, and the area of vasoconstriction
increases, towards the center of the body, the trunk, if shock or
dehydration persists. Using the method of FIG. 5 to detect a trend
in vasoconstriction, in time and in different parts of the body,
may be easier than using the method of FIG. 5 to assess a degree of
vasoconstriction absolutely, at only one time and one part of the
body.
[0120] At 902, a quantity that serves as an indication of a
pressure wave in blood vessels, such as blood volume or blood flow
rate, is measured in a larger branching blood vessels and in the
smaller blood vessels that branch off from it, for example using
one of the systems shown in FIG. 1 or 4, in a central part of the
body of a patient. Signals from these measurements are optionally
low-pass filtered, at 904, and optionally detrended. A time
difference between the two signals, for the larger and smaller
blood vessels, is found at 906 and, being coupled with obtained at
the same time heart rate value, enables to estimate an equivalent
inner diameter value of smaller blood vessels. At 908, measurements
are made, similar to the measurements made at 902, but for one or
more peripheral parts of the body. The signals from these
measurements are optionally filtered at 910, and a time difference
between the larger and smaller blood vessels is found at 912 and,
being coupled with obtained at the same time heart rate value, also
enables to estimate an equivalent inner diameter value of smaller
blood vessels from other peripheral part of body. Optionally,
similar measurements are made and an equivalent inner diameter
values are found for several different peripheral parts of the body
that are at increasing distances from the central part of the body,
in order to determine whether vasoconstriction increases with
distance from the central part of the body, as would be expected in
a patient exhibiting shock of dehydration. Measurements at multiple
locations can also be made to reduce error.
[0121] At 914, the equivalent inner diameter values are compared in
the central part of the body and in the one or more peripheral
parts. Optionally, an estimation is made from these measurements at
a single time as to whether the patient is exhibiting increasing
vasoconstriction going further out from the central part of the
body. At 916, the measurements are repeated, and the equivalent
inner diameter values found, at a later time. If, at 918, it is
found that the equivalent inner diameter value is decreasing with
time, indicating increased vasoconstriction, in peripheral regions
of the body more than in the central part of the body, and
especially if this trend is strongest in the most peripheral
regions, this is an indication that the patient may be suffering
from shock or dehydration, which are diagnosed, at least
tentatively, at 920. Optionally, if the patient is being monitored
for these conditions, then medical personnel are alerted at this
time, for example through a cell phone or Bluetooth device, or by
sounding an alarm in a room where the patient is located. If no
such trend of increasing vasoconstriction in peripheral parts of
the body is found, and if patient is judged to be out of danger at
922, then the procedure is ended at 924. If the patient is not
judged to be out of danger, then measurements continue to be made,
and equivalent inner diameter values found, at later times, at
916.
Sometimes it may be useful or necessary to measure changes in
diameter of arterioles at same time with measurement of other
important physiologic parameter. As an example, we will describe
embodiment, combining properties of standard pulse-oximeter with
ability to measure changes in diameter of arterioles at same
measurement region. Said embodiment is based on principle of
standard transmittance pulse-oximeter (see FIG. 16). Here optical
module, including, as usual, infrared optical transmitter 1746, red
light optical transmitter 1745 and photodetector 1747 are placed at
two sides of finger before fingertip, where photodetector 1747 is
placed upon nail 1741 and two said optical transmitters are placed
at an opposite side of finger. Digital artery 1743 does not come to
same part of finger, being branched there to small arterioles. So
as digital vein 1742 is represent before also. Optical beams 1750
and 1749, irradiating by said optical transmitters 1746 and 1745
consequently, are collected at photodetector 1747 after direct
diffusive drift through vascular bath 44, consisting mainly of
arterioles, venules and capillary. Waveforms of both signals,
collected on photodetector 1747, are processed by well-known
principle of "ratio of ratios" and, after calibration by predefined
numerical table, final result of oxygen saturation is provided. On
FIG. 17 additional photodetector 1748 is placed at same side as
optical transmitters, at a distance from infrared transmitter
enough to have diffusion "canoe" arc 1751 between said
photodetector 1748 and infrared optical transmitter 1746, that
passing inside finger tissue and reaching digital artery 1742. It
is easy to see that waveform, collected by said photodetector 1748,
is not collected from same measurement region, like waveforms,
collected by photodetector 1747. Here measurements of blood flow
from different types of vessels are achieved from different parts
of body organ (finger), and might be even from different fingers of
same palm, but still related to same peripheral part of blood
vessel tree (hand region here), as it was claimed in present
invention. From FIG. 17 we may provide both blood oxygen saturation
and peripheral vasoconstriction level measuring functions in one
device. It is easy to understand that same result may be achieved
on basis of reflective pulse-oximeter, where, for example, one only
photodetector enables to collect waveform signal from two optical
transmitters, providing oximetric measurements from same region of
small arterioles and from an additional optical transmitter, placed
to distance from said photodetector, adapted to build the "canoe"
arc with depth for measurement of artery from same blood vessel
tree. Such a configuration is illustrated by an example device on
FIG. 18, where optical signals from light sources 1803 and 1804
with wavelengths, adapted for measurements of oxygen saturation in
blood, placed at nearly same place and same distance from light
detector 1805 close to the surface of tissue 1806 so, that their
trajectory in measured tissue passes through region, including
mainly arterioles 1809, branched off from small arteries 1810,
displaced deeper, then said arterioles. Thus controller 1801
enables to collect biological signals, which may be used to find
oxygen saturation value in blood of measured region. Additional
light source 1808 is places at longer distance from light detector
1805, then said light sources 1803 and 1804. Said longer distance
enables to light detector 1805 to collect optical signal from said
additional light source 1808 through deeper optical arc trajectory
1811, that passes mainly through said small arteries 1810, thus
blood volume of said small arteries prevails on blood volume of
arterioles 1809, branched off from them. Being also collected by
controller 1801 from same light detector 1805, this additional
signal may be compared by processing unit 1802 to at least one of
signals, initiated by light sources 1803 and 1804 in order to find
time difference between them and, in coupling with obtained at the
same time heart rate value to estimate equivalent inner diameter of
arterioles.
[0122] Wide range of perspective measurements, related to
indicating or monitoring changes for equivalent inner diameter
value of arterioles, may be done in same principle manner also for
internal organs, by mean, for example, of acoustic/ultrasonic
techniques.
An exemplary configuration for such measurements is illustrated in
FIG. 19, where acoustic or ultrasonic signals 1980 from sensor 1970
propagates on predefined distance in human body 1900 to tissues of
kidney 1940 and their scattered energy, being modulated by periodic
blood flow pulsations in small arteries and arterioles of said
kidney, is registered by said sensor. The sensor 1970 may comprise
a preference of Doppler measurements. Sensor 1970 is non-invasive.
Alternatively, sensor 1970 can be used on an internal surface of
the subject's body, for example on a surface of an internal organ
during surgery, in an endoscopic procedure or during long term
internal monitoring or monitoring of internal organ, for example in
transplantation of kidney, inside nasal passage, in the
gastrointestinal tract, in the ear, or in the urethra, or on the
kidney. Alternatively, sensors like 1970 and described here-after
1950 can combine non-invasive and invasive parts. The kidney 1940
is being supplied by Renal artery 1990, branched from Celiac artery
1920. Celiac artery is a continuation artery of Aortic Arch 1930,
providing heart pressure waves of blood. In order to measure time
or phase differences between blood flow of said big arteries and
small arteries of kidney 1940, it may be reasonable to measure the
second signal from region of Aortic Arch 1930. The sensor 1950,
which is intended for it, may be of active or passive type. I.e. it
may be an ultrasonic sensor, irradiating acoustic energy to the
measured region 1930 and the scattered part of said energy, being
modulated by periodic blood flow pulsations in Aortic Arch, will
registered by said sensor. By another way, the sensor 1950 of
passive type may, for example, simply register natural acoustic
signals 1960 of heart contractions, thus providing same
time-dependent data for the second signal as well. A general
principle of this invention may be embodied also by means of
sensors, based on measurement of electrical signals or electrical
impedance. Really, conductivity of larger blood vessels and smaller
blood vessels, like arterioles, branching off of them is changing
proportional to propagation process of blood pressure waves there.
Thus time or phase differences between signals may be measured by
sensors of said type also. An exemplary configuration of such
embodiment is described on FIG. 20. Here ECG-like electrical
sensors 2010 are attached to heart region of the human body 2000
and measure electrical signals, concurrent to heart contraction
activity. Said sensors 2010 may optionally or alternatively measure
changes in conductivity of Aortic Arch region due to blood pressure
wave propagation there. The sensor 2020 may measure electric
conductivity of peripheral blood circulation, changing because
pulsation of peripheral blood pressure, or may be, for example, of
photoplethysmographic type, thus measuring signal, proportional to
changes of blood volume in preselected region of peripheral
tissues. And additional sensor 2040 may be placed relatively close
to sensor 2020 to measure a signal from local small arteries. It
enables to obtain time difference (PWTT, transit time) between
arterial signals from sensor 2010 and from sensor 2040, which will
be separated here from influence of artery-arteriole's transient
time. Said obtained transit time optionally may be used, for
example, to get additional information about parameters or possible
pathologies, relating to functionality of arterial system, locating
between said sensors 2010 and 2040, or, optionally or alternatively
relating to common cardiovascular conditions of measured subject.
Said separation of between time differences of PWTT type from
common time/phase differences, measured from signals of sensors
2010 and 2020, thus may improve estimation of arterioles transient
time and equivalent inner diameter of arterioles in measured region
2020. As it was explained in previous embodiments, processing of
time or phase differences (arterioles transient time) between these
signals by processor 2030, together with concurrently measured
value of heart rate of the subject enables to indicate changes in
equivalent inner diameter of peripheral arterioles and, optionally
or alternatively, changes of blood viscosity in measured
region.
[0123] Various embodiments and aspects of the present invention as
delineated hereinabove and as claimed in the claims section below
find experimental support in the following examples.
[0124] The term "equivalent inner diameter" means for blood vessel
an equivalent diameter of inner duct of blood vessel, where
"equivalent inner diameter" of blood vessels in measured region
means the inner diameter of equal non-branched circular ducts or
blood vessels plurality in measured region that gives the same
pressure loss as a numerically equal plurality of real,
non-circular ducts or blood vessels with natural dispersion of
their geometric, branching and physiologic parameters in a live
biologic tissue.
[0125] The term "systemic circulation" means the general
circulation, carrying oxygenated blood from the left ventricle to
the body tissues, and returning venous blood to the right
atrium.
[0126] "Peripheral part of systemic circulation" means here
peripheral blood vessels and blood vessels, supplying tissues of
internal organs i.e. hand, arm, finger, foot, leg, kidney, lever,
intestine, eye, brain, lungs and so on and being branched from same
larger artery from central part of the systemic circulation.
[0127] "Peripheral blood vessels" means those which are not in the
core of the body and not those which supply skeletal muscles and
the most common example is the blood vessels of the skin.
[0128] The term "Blood flow" means the continuous and pulsate
running of blood in the cardiovascular system.
[0129] The term "transient time" means time difference between at
least two pulse wave related signals, which is mainly created
during pulse wave propagation from a lower flow impedance of
artery-like blood vessels to a higher flow impedance of
arteriole-like blood vessels.
[0130] The terms "branching", "branching from", "branching off
from" mean branching off of one blood vessel directly or indirectly
from another.
[0131] The terms "branching directly", "branching directly from",
"directly branching off from" mean direct branching off of one
blood vessel from another. The term "correlative to" means
"proportional to or a function of".
[0132] The terms "comprises", "comprising", "includes",
"including", "having" and their conjugates mean "including but not
limited to".
[0133] The term "consisting of" means "including and limited
to".
[0134] The term "concurrently" includes at least one of means
"operating or occurring at the same time", "running parallel",
"meeting or intersecting in a point" and "acting in
conjunction".
[0135] As used herein, the singular form "a", "an" and "the"
include plural references unless the context clearly dictates
otherwise. For example, the term "a compound" or "at least one
compound" may include a plurality of compounds, including mixtures
thereof.
[0136] Throughout this application, various embodiments of this
invention may be presented in a range format. It should be
understood that the description in range format is merely for
convenience and brevity and should not be construed as an
inflexible limitation on the scope of the invention. Accordingly,
the description of a range should be considered to have
specifically disclosed all the possible subranges as well as
individual numerical values within that range. For example,
description of a range such as from 1 to 6 should be considered to
have specifically disclosed subranges such as from 1 to 3, from 1
to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as
well as individual numbers within that range, for example, 1, 2, 3,
4, 5, and 6. This applies regardless of the breadth of the
range.
[0137] Whenever a numerical range is indicated herein, it is meant
to include any cited numeral (fractional or integral) within the
indicated range. The phrases "ranging/ranges between" a first
indicate number and a second indicate number and "ranging/ranges
from" a first indicate number "to" a second indicate number are
used herein interchangeably and are meant to include the first and
second indicated numbers and all the fractional and integral
numerals there-between.
[0138] As used herein the term "method" refers to manners, means,
techniques and procedures for accomplishing a given task including,
but not limited to, those manners, means, techniques and procedures
either known to, or readily developed from known manners, means,
techniques and procedures by practitioners of the chemical,
pharmacological, biological, biochemical and medical arts.
[0139] It is appreciated that certain features of the invention,
which are, for clarity, described in the context of separate
embodiments, may also be provided in combination in a single
embodiment. Conversely, various features of the invention, which
are, for brevity, described in the context of a single embodiment,
may also be provided separately or in any suitable sub combination
or as suitable in any other described embodiment of the invention.
Certain features described in the context of various embodiments
are not to be considered essential features of those embodiments,
unless the embodiment is inoperative without those elements.
EXAMPLES
[0140] Reference is now made to the following example from
physiological trials, which together with the above descriptions
illustrates a sample from series of experiments for experimental
confirmation of current invention in a non-limiting fashion.
[0141] A test was made, using a PPG system similar to that
described in FIG. 1, and the method of FIG. 5, on the forearm of
subjects, before and after immersing the arm in cold water. The
measurements were performed according to the following
protocol:
[0142] 1. The time difference was measured between green and near
infrared PPG signals with measuring depth of 3-4 mm and 8-9 mm
under the skin consequently, on the forearm of the subject closer
to the wrist, for 20 seconds, before immersing the subject's arm in
cold water.
[0143] 2. The subject's forearm was immersed in cold water with
temperature of 18 degrees C., and the surface temperature of the
forearm was measured once a minute with a non-contact IR sensor
approved by the FDA for measuring body temperature, until it had
fallen to 22 degrees C.
[0144] 3. The area of the forearm to be measured was quickly dried,
and the time difference was measured again for 20 seconds.
[0145] 4. The surface temperature of the forearm, the time
difference, and the uncertainty in the time difference, were
recorded before and after cooling, and the room temperature was
recorded.
[0146] 5. The procedure was repeated at intervals of at least 24
hours with approximately same values of Heart Rate.
[0147] 6. Heart Rate was measured around 105 BPM during all
represented measurements. Several results from the experiment are
shown below in Table 1:
TABLE-US-00001 TABLE 1 Test data for time delay before and after
cooling subject's arm Data before cooling Data after cooling Tw =
18.degree. C. Temp., .degree. C. Time Delay Temp., .degree. C. Time
Delay Room # Time Before Before, ms After After, ms Temperature, C.
1 06:35:00 PM 34.9 56.9 24.0-25.6 80.53 19 2 08:14:00 PM 35.2 38.8
23.5-25.5 91.11 18 3 06:15:00 PM 35.1 26.84 23.8-25.1 84.56 18 4
03:25:00 PM 34.9 32.14 23.2-24.2 83.45 18 5 05:22:00 PM 35.6 34
24.5-25.1 73.73 18 6 05:34:00 PM 35.2 19.47 23.8-25.2 82.37 18
The time shift before the arm was cooled had a mean value of 34
milliseconds and a standard deviation of 14 milliseconds, with most
of that standard deviation due to uncertainty in the measured
value. After the arm was cooled, the time shift had a mean value 83
milliseconds, with a standard deviation of 6 milliseconds.
[0148] The difference in time shift before and after cooling the
arm is very statistically significant, and shows that the effect of
narrowing the blood vessels, which would increase the time shift,
is most powerful reason of time shift changes.
[0149] By relating measured data about time differences and heart
rate value to plot on FIG. 13, we may find initial inner diameter
of arteriole as varied from 26 to 30 micrometers before local
cooling and after local cooling was decreased to about 18
micrometers that is reasonable change of reasonable values.
[0150] Here well-known physiological phenomena of thermal
vasoconstriction was demonstrated directly, without involving any
other measuring equipment, regularly used by skilled in the art in
such a case (1 D or 2D Doppler Flowmeter ets).
[0151] Although the invention has been described in conjunction
with specific embodiments thereof, it is evident that many
alternatives, modifications and variations will be apparent to
those skilled in the art. Accordingly, it is intended to embrace
all such alternatives, modifications and variations that fall
within the spirit and broad scope of the appended claims.
[0152] All publications, patents and patent applications mentioned
in this specification are herein incorporated in their entirety by
reference into the specification, to the same extent as if each
individual publication, patent or patent application was
specifically and individually indicated to be incorporated herein
by reference. In addition, citation or identification of any
reference in this application shall not be construed as an
admission that such reference is available as prior art to the
present invention. To the extent that section headings are used,
they should not be construed as necessarily limiting.
REFERENCES
[0153] 1. Vitaly A. Kalion, Ivan V. Kazachkov, and Yuri I. Shmakov
Rheology of Complex Fluids and Blood Flows, Stockholm 2004. [0154]
2. David Elad and Shmuel Einav, PHYSICAL AND FLOW PROPERTIES OF
BLOOD. Standard Handbook Of Biomedical Engineering And Design
[0155] 3. Mette S. Olufsen ON DERIVING LUMPED MODELS FOR BLOOD FLOW
AND PRESSURE IN THE SYSTEMIC ARTERIES. MATHEMATICAL BIOSCIENCES AND
ENGINEERING Volume 1, Number 1, June 2004 [0156] 4. Alan C. Burton
Physiology and Biophysics of Circulation. 2-nd Edition, 1972 [0157]
5. Mette S. Olufsen, Ali Nadim MATHEMATICAL BIOSCIENCES AND
ENGINEERING Volume 1, Number 1, June 2004 [0158] 6. J. Keener and
J. Sneyd, Mathematical Physiology, vol. 8.sup.th of
Interdisciplinary Applied Mathematics New York, N.Y.: Springer
Verlag, 1998. [0159] 7. Simulating of Human Cardiovascular System
and Blood Vessel Obstruction Using Lumped Method, Mohammad Reza
Mirzaee, Omid Ghasemalizadeh, and Bahar Firoozabadi, World Academy
of Science, Engineering and Technology 41 2008 [0160] 8. A
multi-compartment vascular model for inferring arteriole dilation
and cerebral metabolic changes during functional activation
Theodore J. Huppert1,2, Monica S. Allen3, Heval Benav1, Anna
Devor1,4, Phil Jones1, Anders Dale4, and David A. Boas1,5 1
Athinoula A. Martinos Center for Biomedical Imaging Massachusetts
General Hospital, Charlestown, Mass. 02129, USA [0161] 9. Pulse
pressure and arterial elasticity S. E. GREENWALD From the
Department of Histopathology and Morbid Anatomy, Barts and The
London Queen Mary's School of Medicine and Dentistry, Royal London
Hospital, London, UK [0162] 10. WINDKESSEL MODEL ANALYSIS IN MATLAB
Ing. Martin HLAV , Doctoral Degree Programme (3) Dept. of
Biomedical Engineering, FEEC, BUT [0163] 11. A new method for
assessing arteriolar diameter and hemodynamic resistance using
image analysis of vessel lumen Karel Tyml, 1,2 Donald Anderson,2
Darcy Lidington,1,2 and Hanif M. Ladak Am J Physiol Heart Circ
Physiol 284: H1721-H1728, 2003 [0164] 12. Cardiovascular Physiology
Concepts, Richard E. Klabunde, PhD, Revised Apr. 1, 2007,
http://cvphysiology.com/Blood %20Pressure/BP021.htm [0165] 13.
Fundus camera-based retinal laser doppler velocimeter, U.S. Pat.
No. 4,402,601 [0166] 14. Holographic laser Doppler ophthalmoscopy,
M. Simonutti, M. Paques, J. A. Sahel, M. Gross, B. Samson, C.
Magnain,4 and M. Atlan4, 1 Institut de la Vision, Institut National
de la Sante et de la Recherche Medicale (INSERM)-101, UMR-S 968,
rue de Tolbiac, 75654 Paris Cedex 13, France [0167] 15. Combined
effects of pulsatile flow and dynamic curvature on wall shear
stress in a coronary artery bifurcation model, I. V. Pivkinl, P. D.
Richardson2, D. H. Laidlaw3 and G. E. Karniadakis1.sup..quadrature.
Brown University Oct. 29, 2003 [0168] 16. Validation of a
one-dimensional model of the systemic arterial tree, Philippe
Reymond, Fabrice Merenda, Fabienne Perren, Daniel Rufenacht and
Nikos Stergiopulos, Am J Physiol Heart Circ Physiol 297:H208-H222,
2009. First published 8 May 2009; [0169] 17. Evidence of a
Cerebrovascular Postarteriole Windkessel With Delayed Compliance
Joseph B Mandeville.sup.*, .dagger., John J A Marota.sup.*,
.dagger-dbl., C Ayata.sup..sctn. , Greg Zaharchuk.sup.*, .dagger.,
Michael A Moskowitz.sup..sctn. , Bruce R Rosen.sup.*, .dagger. and
Robert M Weisskoff.sup.*, .dagger.Journal of Cerebral Blood Flow
& Metabolism (1999) 19, 679-689; [0170] 18. A multi-compartment
vascular model for inferring arteriole dilation and cerebral
metabolic changes during functional activation Theodore J.
Huppert1,2, Monica S. Allen3, Heval Benav1, Anna Devor1,4, Phil
Jones1, Anders Dale4, and David A. Boas1,5 J Cereb Blood Flow
Metab. 2007 June; 27(6): 1262-1279. doi:10.1038/sj.jcbfm.9600435.
[0171] 19. A vascular anatomical network model of the
spatio-temporal response to brain activation David A. Boas,
Stephanie R. Jones, Anna Devor, Theodore J. Huppert, and Anders M.
Dale Neuroimage. Author manuscript; available in PMC Apr. 15,2009.
[0172] 20.
http://www.nihonkohden.com/tech/escco/principle.html#principle
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References