U.S. patent application number 10/578479 was filed with the patent office on 2007-04-05 for method and system for non-invasive measurements in a human body.
This patent application is currently assigned to Orense Ltd.. Invention is credited to Boris Fikhte, Alexander Finarov, Ilya Fine, Iosef Gandelman.
Application Number | 20070078312 10/578479 |
Document ID | / |
Family ID | 34551580 |
Filed Date | 2007-04-05 |
United States Patent
Application |
20070078312 |
Kind Code |
A1 |
Fine; Ilya ; et al. |
April 5, 2007 |
Method and system for non-invasive measurements in a human body
Abstract
A method and system are presented for use in non-invasive
measurements in a patient's body. A condition of artificial blood
kinetics is created at a measurement location in a patient's blood
perfused fleshy medium, and this condition is maintained for a
certain time period. An external electromagnetic field is applied
to the measurement location while under the condition of artificial
blood kinetics. A time variation of a response of the blood
perfused fleshy medium to this external electromagnetic field is
detected, and measured data indicative thereof is generated. The
response of the medium can be a photo-acoustic signal obtained in
response to incident light, and/or impedance of the medium in
response to the applied ac electromagnetic field.
Inventors: |
Fine; Ilya; (Rehovot,
IL) ; Finarov; Alexander; (Rehovot, IL) ;
Gandelman; Iosef; (Ashdod, IL) ; Fikhte; Boris;
(Rehovot, IL) |
Correspondence
Address: |
BROWDY AND NEIMARK, P.L.L.C.;624 NINTH STREET, NW
SUITE 300
WASHINGTON
DC
20001-5303
US
|
Assignee: |
Orense Ltd.
5 Golda Meir St. 5th Floor Science Park
Ness Ziona
IL
74000
|
Family ID: |
34551580 |
Appl. No.: |
10/578479 |
Filed: |
May 8, 2006 |
PCT NO: |
PCT/IL04/01015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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10702044 |
Nov 6, 2003 |
7020506 |
|
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10578479 |
May 8, 2006 |
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Current U.S.
Class: |
600/316 ;
600/310; 600/322; 600/323; 600/324; 600/335; 600/407 |
Current CPC
Class: |
A61B 5/0053 20130101;
A61B 5/0095 20130101; G01N 29/2418 20130101; G01N 2291/02466
20130101; A61B 5/14532 20130101 |
Class at
Publication: |
600/316 ;
600/310; 600/335; 600/322; 600/323; 600/324; 600/407 |
International
Class: |
A61B 5/00 20060101
A61B005/00; A61B 5/05 20060101 A61B005/05 |
Claims
1. A method for use in non-invasive measurements in a patient's
body, the method comprising: (a) creating a condition of artificial
blood kinetics at a measurement location in a patient's blood
perfused fleshy medium and maintaining this condition for a certain
time period; (b) applying an external electromagnetic field to the
measurement location while under said condition of artificial blood
kinetics; (c) detecting a time response of the medium from at least
a portion of the measurement location to said external
electromagnetic field, and generating measured data indicative of
time evolutions of the response of the medium over at least a part
of said certain time period; the response to said external
electromagnetic field including at least one of the following: an
acoustic response to illuminating incident light having a
wavelength in a range where the scattering properties of blood are
sensitive to light, and an impedance of the portion of the
medium.
2. The method of claim 1 comprising: analyzing said measured data
for determining at least one characteristic parameter derived from
said time response of the medium; providing predetermined reference
data d indicative of a desired blood characteristic obtained by
other independent method as a function of said characteristic
parameter; and utilizing the determined characteristic parameter
derived from said time response of the medium and said
predetermined reference data for obtaining a value of the desired
blood characteristic of the patient.
3. The method of claim 1 comprising altering said condition of
artificial blood kinetics at the measurement location over a
predetermined time interval within said certain time period so as
to modulate properties of the blood affecting said time
response.
4. The method of claim 3 comprising: analyzing said measured data
for determining at least one characteristic parameter derived from
said response of the medium; providing predetermined reference data
indicative of a desired blood characteristic obtained by another
independent method as a function of said characteristic parameter;
and utilizing the determined characteristic parameter derived from
said response of the medium and said predetermined reference data
for obtaining a value of the desired blood characteristic of the
patient.
5. The method of claim 2 wherein said reference data is a
calibration curve defining a dependence of the characteristic
parameter on the desired blood characteristic.
6. The method of claim 4 wherein said reference data is a
calibration curve defining a dependence of the parameter on the
desired blood characteristic.
7. The method of claim 2 wherein said at least one characteristic
parameter is an actual value of the time response at a certain
moment during said certain time period.
8. The method of claim 7 wherein said certain moment is chosen when
the response attains its near asymptotic magnitude.
9. The method of claim 4 wherein said at least one characteristic
parameter is an actual value of the time response at a certain
moment during said certain time period.
10. The method of claim 9 wherein said certain moment is chosen
when the response attains its near asymptotic magnitude.
11. The method of claim 2 wherein said characteristic parameter is
a parametric slope defined as a ratio between a first function
depending on the time response of the medium corresponding to a
first frequency of the external electromagnetic field and a second
function depending on the time response of the medium corresponding
to a second frequency.
12. The method of claim 4 wherein said characteristic parameter is
a parametric slope defined as a ratio between a first function
depending on the time response of the medium corresponding to a
first frequency of the external electromagnetic field and a second
function depending on the time response of the medium corresponding
to a second frequency.
13. The method of claim 11 wherein said first and second functions
are logarithmic functions of the response corresponding to the
first and second frequencies, respectively.
14. The method of claim 12 wherein said first and second functions
are logarithmic functions of the response corresponding to the
first and second frequencies, respectively.
15. The method of claim 11 wherein said first and second functions
are a time rate of the changes of the response corresponding to the
first and second frequencies, respectively.
16. The method of claim 12 wherein said first and second functions
are a time rate of the changes of the response corresponding to the
first and second frequencies, respectively.
17. The method of claim 1 wherein said creating of the condition of
artificial blood kinetics comprises applying primary over-systolic
pressure to the medium 20 with a normal blood flow to create a
state of temporary blood flow cessation in the medium at the
measurement location.
18. The method of claim 17, wherein said creating of the state of
temporary blood flow cessation at the measurement location
comprises applying the primary over-systolic pressure to the medium
at a certain location upstream of the 25 measurement location.
19. The method of claim 1 wherein said certain time period is
insufficient for irreversible changes in the fleshy medium.
20. The method of claim 3 wherein said altering of the condition of
artificial blood kinetics includes applying a perturbation to the
medium by at least one secondary pressure pulse of a predetermined
value over said predetermined time interval.
21. The method of claim 20 wherein the predetermined value of the
secondary pressure is in the range of about 0-300 mmHg.
22. The method of claim 3 wherein said altering of the condition of
artificial blood kinetics includes applying a perturbation to the
medium by secondary pressure of a predetermined cyclic pattern over
said predetermined time interval.
23. The method of claim 22 wherein said predetermined cyclic
pattern is in the form of secondary pressure pulses having
amplitudes in the range of about 0-300 mmHg.
24. The method of claim 17, comprising altering said condition of
artificial blood kinetics at the measurement location over a
predetermined time interval within said certain time period so as
to modulate properties of the blood affecting said time
response.
25. The method of claim 24 wherein said altering of the condition
of artificial blood kinetics includes applying a perturbation to
the medium by at least one secondary pressure pulse of a
predetermined value over said predetermined time interval.
26. The method of claim 25 wherein the predetermined value of the
secondary pressure is in the range of about 0-300 mmHg.
27. The method of claim 24 wherein said altering of the condition
of artificial blood kinetics includes applying a perturbation to
the medium by secondary pressure of a predetermined cyclic pattern
over said predetermined time interval.
28. The method of claim 27 wherein said predetermined cyclic
pattern is in the form of secondary pressure pulses having
amplitudes in the range of about 0-300 mmHg.
29. The method of claim 1 wherein at least one desired
characteristic of the patient's blood to be measured is a
concentration of glucose therein.
30. A system for use in non-invasive measurements in a patient's
body for determining at least one desired characteristic of the
patient's body, the system comprising: (i) a pressurizing assembly
configured to be applied to the patient's body and operable for
creating a condition of artificial blood kinetics at a measurement
location in a patient's blood perfused fleshy medium and
maintaining this condition for a certain time period; (ii) a
measuring probe including a source of an external electromagnetic
field configured and operable for applying the electromagnetic
field to the measurement location, and a detecting module
configured for detecting a response of the medium from at least a
portion of the measurement location to said external
electromagnetic field, and generating measured data indicative of
the response as a function of time; and (iii) a control unit
connectable to said pressurizing assembly and measuring probe, said
control unit comprising a memory for storing reference data
indicative of the desired blood characteristic as a function of a
characteristic parameter derived from the time response; and a data
acquisition and processing utility configured to be response to the
measured data and to analyze the measured data utilizing the
reference data to determine said at least one desired blood
characteristic.
31. The system of claim 30 wherein said pressurizing assembly
comprises a primary occlusion cuff for applying a primary
over-systolic pressure to the fleshy medium at a primary pressure
location.
32. The system of claim 31 wherein said pressurizing assembly
comprises a secondary occlusion cuff for applying a secondary
pressure to the fleshy medium at a secondary pressure location,
thereby altering said condition of the artificial blood kinetics at
said secondary pressure location over a predetermined time interval
within said certain time period so as to modulate properties of the
blood affecting said time response.
33. The system of claim 32 wherein said primary pressure location
is selected upstream of the secondary pressure location with
respect to the normal blood flow direction in the medium, said
secondary pressure location being in the vicinity of the
measurement location.
34. The system of claim 30 wherein said measuring probe includes a
photo-acoustic system, where said source of the external
electromagnetic field is configured for generating light in the
wavelength range where the scattering or absorbing properties of
the patients blood are sensitive to provide an acoustic response,
and where said detecting module is an acoustic detector.
35. The system of claim 30 wherein said measurement probe includes
a photo-acoustic system and an optical system, where said detecting
module includes an acoustic radiation receiver and an optical
detector.
36. The system of claim 30 wherein said measuring probe includes a
system for measuring impedance of at least a portion of the medium
at the measurement location.
37. The system of claim 30 wherein said reference data comprises a
calibration curve defining a dependence of the characteristic
parameter on the desired blood characteristic.
38. The system of claim 37 wherein said at least one characteristic
parameter is an actual value of the time response at a certain
moment during said certain time period.
39. The system of claim 38 wherein said certain moment is chosen
when the response attains its near asymptotic magnitude.
40. The system of claim 30 wherein said characteristic parameter is
a parametric slope defined as a ratio between a first function
depending on the time response of the medium corresponding to a
first frequency of the external electromagnetic field and a second
function depending on the time response of the medium corresponding
to a second frequency.
41. The system of claim 40 wherein said first and second functions
are logarithmic functions of the response corresponding to the
first and second frequencies, respectively.
42. The system of claim 40 wherein said first and second functions
are a time rate of the changes of the response corresponding to the
first and second frequencies, respectively.
43. The system of claim 30 wherein said at least one desired
characteristic of the patient's blood is a concentration of glucose
therein.
Description
FIELD OF THE INVENTION
[0001] This invention relates to techniques for non-invasive
measurements in a human body, and in particular, to a method and
system for measuring blood characteristics by photo-acoustic and
electrical measurement techniques.
BACKGROUND OF THE INVENTION
[0002] Non-invasive techniques for measuring various blood
parameters, e.g. the concentration of glucose in blood, blood
oxygen saturation, etc. have become very popular, since they do not
require the withdrawal of a blood sample from a patient's body. One
approach for non-invasively determining the composition of blood
makes use of the interaction of electromagnetic radiation with the
blood under examination. It is known that electromagnetic radiation
having appropriate characteristics may interact with blood in two
primary ways. As it passes through a fleshy medium, the radiation
is scattered and a portion of it will be absorbed. Different
chemical species of the blood scatter and absorb to different
degrees at different wavelengths. The physical composition of the
fleshy medium will also effect its interaction with the
radiation.
[0003] A number of methods have been proposed that use optical
radiation to probe a patient's body (e.g., a finger) with the goal
of determining the concentration of a component of the
material.
[0004] For example, optical monitoring techniques can utilize the
detection of light transmitted or reflected from the location on
the patient's body under measurement, and are based on
spectrophotometric measurements enabling the indication of the
presence of various blood constituents based on known spectral
behaviors of these constituents. Usually, the optical monitoring
techniques utilize a measurement optical device or probe attached
to the patient's finger, and include an optical assembly for
irradiating the finger with light and detecting its light response.
For example, the conventional device of the kind specified, such as
a pulse oximeter, which is the generally accepted standard of
everyday clinical practice, provides for measuring enhanced optical
pulsatile signals caused by the changes in the volume of blood
flowing through a finger.
[0005] It is known that for some blood parameters other than oxygen
saturation, e.g., glucose concentration, significant difficulties
have been encountered, because their absorption spectral behavior
in red and near infrared regions is not as remarkable perceptible
as for the oxygenized hemoglobin. Hence, the main limitations of
the non-invasive optic techniques other than pulse oximetry are
associated with the limited selectivity of the absorption based
method.
[0006] Another optical technique is disclosed in U.S. Pat. No.
6,400,972, International Applications WO 01/45553 and WO 01/96872,
all assigned to the assignee of the present application. This is an
occlusion-based technique, according to which over-systolic
pressure is applied to the blood perfused fleshy medium with a
normal blood flow so as to create a state of temporary blood flow
cessation at the measurement location. The measurement with
different wavelengths of incident radiation and/or different
polarization states of detected light are carried out at sessions
which are separate in time and taken during a cessation time
period, i.e., when the state of blood flow cessation is maintained.
This technique utilizes the condition of "artificial blood
kinetics" rather than "natural blood kinetics" taking place when
the state of total blood cessation is not achieved. As a result of
the cessation of blood flow, a condition of artificial kinetics is
achieved with the optical characteristics of the blood associated
with the light response being different from those of natural blood
kinetics. Indeed, it is known that the scattering properties of
blood depend on the size and shape of scatterers (aggregates).
Thus, time changes of the light response at the condition of
artificial kinetics depend on the changes in the shape and average
size of the scattering centers in the medium, i.e., red blood cells
(RBC) aggregation (Rouleaux effect). It was found that owing to the
effect of artificial kinetics, the optical characteristics of blood
changes dramatically, such that they differ from those of the
fleshy medium with a normal blood flow by about 25 to 45%, and
sometimes even by 60%. Hence, the accuracy (i.e., signal-to-noise
ratio) of the technique based on artificial kinetics, as well as
selectivity of the optical measurements, can be substantially
better when compared with those based on measurements of blood
parameters at natural kinetics.
[0007] FIG. 1 illustrates an example showing a typical plot
representing light transmission/absorption characteristic (light
responses) of blood obtained over the time interval when the
condition of artificial kinetics is created, maintained during a
certain cessation time, and then released. In particular, the plot
shows how the light-transmitting characteristic of blood changes
under the application and release of the primary over-systolic
pressure. The transmitting characteristics are shown in FIG. 1 in
Transmission Arbitrary Units (T.A.U.).
[0008] The application of primary pressure to the fleshy medium
starts at a moment T.sub.start and is maintained for a period of
time so as not to cause irreversible changes in the medium (e.g.,
25 seconds). The pressure is released at the moment T.sub.release.
Measurements of the Relative Transmission are performed
continuously, starting prior to the application of the
over-systolic pressure. Different regions of light responses of the
medium, designated A, B, C, D and E, corresponding to the different
states of the blood flow are observed. Region A corresponds to a
state of normal blood flow before the over-systolic pressure is
applied. As shown, this region is characterized by a standard
fluctuating value of the relative light transmission of blood.
Region B starts at moment T.sub.start (when the pressure is
initially applied) and maintains over a short period of time
T.sub.B (about 0.5 sec) following the actual start of the condition
of artificial blood kinetics. Measurements taken over this time
period are not steady and can be disregarded, due to the
unavoidable influence of motional and/or other factors causing
non-monotonic fluctuations of the light transmission. Region C
corresponds to a state of the temporary cessation of blood flow,
which lasts within a cessation time T.sub.C between a moment
determined as (T.sub.start+T.sub.B) and the moment T.sub.release.
During this cessation time, T.sub.C, the ascending curve (as shown
in FIG. 1) or descending curve (not shown), depending on the
incident wavelength of relative light transmission of blood, can be
observed. It should be noted that this is the region where the
condition of artificial kinetics is maintained over T.sub.C.
Generally, the light transmission curve can reach an asymptotic
maximum over one second to several minutes. Region D corresponds to
a transitional state of blood flow, which takes place after
releasing the over-systolic pressure. This state starts with a
slight delay T.sub.d (approximately 0.5 sec), i.e., at the moment
determined as (T.sub.release+T.sub.d). During the time period
T.sub.D of the duration of region D, the relative transmission of
blood monotonously descends until it reaches values characteristic
of the normal blood flow. Such a moment is marked as T.sub.end in
the drawing. Usually, the end of region D, and the beginning of
region E, is detected when the changes of the light transmission
become periodic and minimal (about 2%). Region E corresponds to a
state of the normal blood flow, which is similar to that in region
A.
[0009] It has also been shown in the prior art that photo-acoustic
laser spectroscopy can be used for measuring glucose concentration
in blood. In this technique, a laser beam is used to rapidly heat a
sample generating an acoustic pressure wave produced in a sample,
where the excitation beam is absorbed, that can be measured by
high-sensitivity ultrasonic detectors such as piezo-electric
crystals, microphones, optical fiber sensors, laser interferometers
or diffraction sensors. Prior art techniques for non-invasive
measurement of blood glucose by photo-acoustic spectroscopy are
described, for example, in U.S. Pat. No. 5,348,002 to Caro; U.S.
Pat. No. 5,941,821 to Chou; and U.S. Pat. No. 6,466,806 to Geva,
et. al.
[0010] U.S. Pat. No. 5,348,002 to Caro discloses a technique for
measuring blood glucose which includes a light source for applying
electromagnetic radiation to patient's finger under analysis and a
transducer for detecting acoustic energy. The transducer is
positioned on one side of the finger and the incoming
electromagnetic wave impinges on the other side of the finger,
opposite the transducer.
[0011] The main disadvantage of this technique is that a tissue,
such as a body part, is optically thick. The impinging
electromagnetic energy is almost totally absorbed by the tissue.
Consequently, the measured acoustic wave will respond to the total
incident electromagnetic energy, rather than to the fraction
absorbed by the glucose.
[0012] Moreover, it is well known that the water content in skin or
blood can be more than 70%, making water the main absorbing
substance. The effect of strong water absorption is twofold. First,
because tissue has a high percentage of water, water absorption can
prevent a light beam from penetrating a sufficient depth through
tissue. Second, water absorption can yield an acoustic signal which
is overwhelming compared to that of glucose. The technique
disclosed in U.S. Pat. No. 5,348,002 fails to address the adverse
effects caused by the absorption of radiation by water, rather than
the medium to be measured, such as glucose.
[0013] Another photo-acoustic method for non-invasive monitoring of
glucose is described in U.S. Pat. No. 5,941,821 to Chou, in which
an excitation source provides electromagnetic energy at a
wavelength corresponding to the absorption characteristics of the
analysis. Upon irradiation, acoustic energy is generated in a is
relatively thin layer of the sample to be measured, characterized
by a heat-diffusing length. The acoustic emission is detected with
a differential microphone, one end of which is positioned in a
measuring cell and the other end of which is positioned in a
reference cell. A processor determines the concentration of the
substance being measured based upon the detected acoustic signal.
In order to determine the concentration of glucose in the
bloodstream, the excitation source is preferably tuned to the
absorption bands of glucose in spectral ranges from about 1520-1850
nm and about 2050-2340 nm to induce a strong photo-acoustic
emission. In these wavelength ranges, water absorption is
relatively weak and glucose absorption is relatively strong. Thus,
even though a tissue may have a high percentage of water at the
above-specified wavelength ranges, the electromagnetic radiation is
able to penetrate through the tissue to a sufficient depth to allow
for measurements.
[0014] U.S. Pat. No. 6,466,806 to Geva, et. al describes a method
and apparatus of resonant photo-acoustic spectroscopy (RPAS) for
determining a concentration of an interest component in a medium.
The method comprises irradiating a surface of the medium with a
light pulse-train comprising equidistant short pulses having
variable duration, frequency, number, and power. The frequency of
the light short pulses is chosen equal to a natural acoustic
oscillation frequency in a medium for resonant light-excitation of
acoustic modes. The wavelength of the light pulses is selected so
as to excite resonant acoustic oscillation in the medium due to the
absorption of light by the interest component and subsequent
adiabatic temperature rise in the testing area of the medium.
[0015] Some of the non-invasive methods of determining the
concentration of the chemical of interest (e.g., glucose) in blood
are based on measuring impedance (total electrical resistance) or a
component of the impedance of a body part of a patient. For
example, U.S. Pat. No. 5,792,668 to Fuller, et al., describes a
technique in which two electrodes are brought into direct contact
with the human body and real and imaginary components of reflected
and/or transmitted electromagnetic signals are spectrally examined
as a function of frequency to identify the concentration of the
chemical of interest The examination can include the analysis of
the effective complex impedance presented by the human body, and/or
the effective phase shift between the transmitted and reflected
signal at the human body.
[0016] It is known that the total electrical impedance of a human
body, as well as the components of the total electrical impedance,
depend not only on the actual value of the concentration of glucose
in blood, but also on the temporal rate of change of that
concentration. The rate of change of the glucose concentration is
specific to each individual and varies within certain limits
depending on a number of reasons and factors, such as, for example,
environmental, psycho-physiological, nutritional, specific
metabolic factors and others.
[0017] International Publication No. WO02069791 to Schrepfer, et.
al. discloses a technique for determining the concentration of a
substance in body liquid. In one of the embodiments, WO02069791
describes a device suited for in-vivo measurements of the human
body. The device comprises an elongate electrode having a width
much smaller than its length. A holder is provided to mount the
electrode to an arm or a leg with the longitudinal axis of the
electrode extending parallel thereto. In this way, a large
interaction space is established, which allows to measure the
desired concentration with a higher level of accuracy. The method
of determining the glucose concentration comprises the steps of
arranging a first electrode, which is electrically insulated from
the specimen, applying a modulated electrical voltage having a
frequency between 10 MHz and 2 GHz to the first electrode for
generating a modulated field in the specimen and measuring
parameters that depend on the electrical impedance of the
specimen.
[0018] U.S. Patent Application Publication No. 2002/0155615A1 to
Novikov, et. al. describes a method of non-invasive determination
of a glucose concentration in blood based on the measurements of
the total impedance of the skin of a patient taking into account
the rate of change of the glucose concentration. The method is
based on a linear model of a first order correlation between the
glucose concentration and the total impedance. The determination of
the concentration of glucose G(t) in blood comprises measuring the
total impedance N(x) or a component of the total impedance of the
skin, and then determining the concentration of glucose in
accordance with the following approximating equation: G .function.
( t ) = G 1 .times. exp .function. ( - a 0 .times. t ) + q + a 1
.times. exp .function. ( - a 0 .times. t ) .times. .intg. 0 t
.times. N .function. ( x ) .times. exp .function. ( a 0 .times. t )
.times. d x , .times. where .times. .times. G 1 = G 0 - q ;
##EQU1## G.sub.0 is the initial concentration of glucose in blood
at the beginning of the measurement process, q is a parameter that
characterizes the ability of a human organism to maintain
homeostasis relative to the glucose concentration in blood,
.alpha..sub.0 is a coefficient that characterizes the correlation
between a total electrical impedance (or its components) of the
skin and a concentration of glucose in blood of a specific
individual, and .alpha..sub.1 is a coefficient taking into account
the variability of the external factors and specific
characteristics of an individual. The coefficients q, .alpha..sub.0
and .alpha..sub.1 used in an approximating function are determined
at the preliminary stage measurements by an invasive method.
SUMMARY OF THE INVENTION
[0019] Despite their potential, the known photo-acoustic and
impedance methods suffer from limited accuracy. The present
invention facilitates non-invasive measurements in a human body by
providing a novel method and device for measuring time variations
of a response of the blood perfused fleshy medium (e.g., finger) to
an external electromagnetic field. It should be understood that
measuring of the response from blood may be aimned at determining
blood-related parameter(s), or may be aimed at determining
tissue-related parameter(s) in which case "blood" response presents
a "noise" part and is determined to be extracted from the entire
measured signal.
[0020] According to one embodiment, the response to the external
electromagnetic field is a photo-acoustic signal obtained in
response to the exciting light. According to another embodiment,
the response to the external field is the impedance of the medium
in response to the applied ac electromagnetic field.
[0021] It should be noted that in the present description, the term
"impedance" hereinafter will, for brevity, include not only total
electrical resistance, but also each component of the impedance.
The measured components of the impedance of the medium can, for
example, be as follows: an active component, a reactive component,
a phase angle between the active and reactive components of the
impedance, as well as parameters that can be derived from the
impedance and its components. These parameters include, inter alia,
dielectric permittivity, dielectric losses and conductivity of the
medium.
[0022] For both techniques (photo-acoustic and impedance
measurements), the invention utilizes the benefits of
occlusion-based measurements described above in connection with
optical measurement techniques. Namely, the measurement of time
variations of the response of the blood perfused fleshy medium by
occlusion-based techniques is based on creating and controlling the
artificial blood kinetics in the medium. The condition of
artificial kinetics is created and maintained for a certain time
period by applying primary over-systolic pressure to a certain
location at the medium with a normal blood flow so as to achieve a
state of temporary blood flow cessation at the medium downstream of
the certain location or adjacent to the location if applied
pressure. When required, the control of the condition of the
artificial kinetics can be further achieved by applying a
perturbation of a secondary pressure to the fleshy medium.
[0023] There is thus provided according to one broad aspect of the
invention a method for use in non-invasive measurements in a
patient's body, the method comprising: [0024] (a) creating a
condition of artificial blood kinetics at a measurement location in
a patient's blood perfused fleshy medium and maintaining this
condition for a certain time period; [0025] (b) applying an
external electromagnetic field to the measurement location while
under said condition of artificial blood kinetics; [0026] (c)
detecting a time response of the medium from at least a portion of
the measurement location to said external electromagnetic field,
and generating measured data indicative of time evolutions of the
response of the medium over at least a part of said certain time
period;
[0027] the response to said external electromagnetic field
including at least one of the following: an acoustic response to
illuminating incident light having a wavelength in a range where
the scattering properties of blood are sensitive to light, and an
impedance of the portion of the medium.
[0028] The measured data may be then analyzed for determining at
least one characteristic parameter derived from the time response
of the medium. To this end, predetermined reference data,
indicative of the desired blood characteristic as a function of the
characteristic parameter, is provided being obtained by another
independent method. The determined characteristic parameter derived
from the time response of the medium and the predetermined
reference data may then be utilized for obtaining a value of the
desired blood characteristic.
[0029] According to another broad aspect of the invention there is
provided a system for use in non-invasive measurements in a
patient's body for determining at least one desired characteristic
of the patient's body, the system comprising: [0030] (i) a
pressurizing assembly configured to be applied to the patient's
body and operable for creating a condition of artificial blood
kinetics at a measurement location in a patient's blood perfused
fleshy medium and maintaining this condition for a certain time
period; [0031] (ii) a measuring probe including [0032] a source of
an external electromagnetic field configured and operable for
applying the electromagnetic field to the measurement location, and
a detecting module configured for detecting a response of the
medium from at least a portion of the measurement location to said
external electromagnetic field, and generating measured data
indicative of the response as a function of time; and [0033] (iii)
a control unit connectable to said pressurizing assembly and
measuring probe, said control unit comprising a memory for storing
reference data sensitive to patient individuality and indicative of
the desired blood characteristic as a function of a characteristic
parameter derived from the time response; and a data acquisition
and processing utility configured to be response to the measured
data and to analyze the measured data utilizing the reference data
to determine said at least one desired blood characteristic.
[0034] Preferably, the pressurizing assembly includes a primary
occlusion cuff for applying primary up to over-systolic pressure to
the fleshy medium at a primary pressure location; and optionally
also a secondary occlusion cuff for applying secondary pressure to
the fleshy medium at a secondary pressure location, thereby
altering the condition of the artificial blood kinetics at the
secondary pressure location over a predetermined time interval
within said certain time period, so as to modulate properties of
the blood affecting the time response.
[0035] The primary pressure location can be selected upstream of
the secondary pressure location with respect to the normal blood
flow direction in the medium or adjacent to measurement location.
The secondary pressure location can be in the vicinity of the
measurement location.
[0036] According to one embodiment, the measuring probe is a
photo-acoustic system, where the source of the external
electromagnetic field can be configured for generating light in the
wavelength range where the scattering or absorbing properties of
the patients blood are sensitive to provide an acoustic response,
and the detecting module is an acoustic detector. According to
another embodiment, the measuring probe can be a system for
measuring impedance of at least a portion of the medium at the
measurement location.
[0037] According to one embodiment, the reference data includes a
calibration curve defining a dependence of the characteristic
parameter on the desired blood characteristic. The characteristic
parameter can, for example, be an actual value of the time response
at a certain moment during said certain time period. The certain
moment can be chosen when the response attains its near asymptotic
magnitude.
[0038] According to another embodiment, the characteristic
parameter is a parametric slope defined as a ratio between a first
function depending on a time response of the medium corresponding
to a first frequency of the external electromagnetic field and a
second function depending on the time response of the medium
corresponding to a second frequency. According to one example, the
first and second functions are logarithmic functions of the
response corresponding to the first and second frequencies,
respectively. According to another example, the first and second
functions present a time rate of the changes of the response
corresponding to the first and second frequencies,
respectively.
[0039] There has thus been outlined, rather broadly, the features
of the invention in order that the detailed description thereof
that follows hereinafter may be better understood. Additional
details and advantages of the invention will be set forth in the
detailed description, and in part will be appreciated from the
description, or may be learned by practice of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0040] In order to understand the invention and to see how it may
be carried out in practice, a preferred embodiment will now be
described, by way of non-limiting example only, with reference to
the accompanying drawings, in which:
[0041] FIG. 1 illustrates a typical plot representing light
transmission characteristics of blood obtained when the condition
of artificial kinetics is created and changed;
[0042] FIG. 2 illustrates an example of the simulation of the light
absorption changes of the blood versus the light scattering changes
during the condition of the artificial kinetics;
[0043] FIG. 3 illustrates time behavior of light absorption in the
above computer simulation caused by the artificial blood
kinetics;
[0044] FIG. 4 illustrates time dependence of a typical PA signal
(normalized value) obtainable during the condition of artificial
blood kinetics in vitro;
[0045] FIG. 5 illustrates an example of the simulation of a time
dependence of a typical impedance signal obtainable during the
condition of artificial blood kinetics; and
[0046] FIG. 6 illustrates a schematic block diagram of a measuring
system for carrying out the method of the present invention,
according to one embodiment of the invention.
DETAILED DESCRIPTION OF THE INVENTION
[0047] The principles and operation of the system and method for
non-invasive measurement of blood parameters according to the
present invention may be better understood with reference to the
drawings and the accompanying description, it being understood that
these drawings and examples in the description are given for
illustrative purposes only and are not meant to be limiting. The
same reference Roman numerals and alphabetic characters will be
utilized for identifying those components which are common in the
system for non-invasive measurement of blood parameters shown in
the drawings throughout the present description of the
invention.
[0048] According to one general aspect, the present invention
provides a novel method for non-invasive electromagnetic scattering
determination of glucose. It should be understood that the present
invention is not limited to the measurement of blood glucose
levels, but may also be utilized to measure other blood
characteristics. Examples of the blood characteristics include, but
are not limited to the concentration of a substance in patient's
blood (e.g., glucose, hemoglobin), oxygen saturation, Erythrocyte
Sedimentation Rate (ESR) and Erytirocyte Aggregation Rate
(EAR).
[0049] The method is based on creating and, when required,
controlling the artificial blood kinetics in a patient's blood
perfused fleshy medium, e.g., his finger, and applying
photo-acoustic and impedance measurements thereto. The condition of
artificial kinetics is created and maintained for a certain time
period. The creation of the condition of artificial kinetics is
preferably made by applying a primary over-systolic pressure to a
certain location at the medium with a normal blood flow so as to
achieve a state of temporary blood flow cessation, as described
above in the background section.
[0050] According to the invention, when required, control of the
condition of the artificial kinetics can be carried out by applying
a perturbation of a secondary pressure to the fleshy medium, as
will be described in detail hereinbelow.
[0051] According to one embodiment of the invention, the
controllable altering of the condition of the artificial blood
kinetics is performed by applying a perturbation to the medium by a
secondary pressure pulse of a predetermined value over the
predetermined time interval so as to modulate scattering/absorbing
properties of blood. According to one example, the secondary
pressure can be applied to the medium (e.g., patient's finger) at
the location of the main occlusion providing the over-systolic
pressure. According to another example, the secondary pressure can
be applied to the medium at a certain location selected downstream
of the main occlusion with respect to the blood flow direction. It
should be noted that the location of the application of the
secondary pressure may either coincide with the location of a
response signal detector or slightly differ frorn it, depending on
the kind of measured medium and/or design of the measurement probe.
The physical effect of the secondary pressure results, inter alia,
in the modification of the aggregates of red blood cells (RBC).
Therefore, the location of the application of the secondary
pressure has to be in the vicinity of the measurement place.
[0052] The altering of the condition of artificial blood knetics
includes applying a perturbation to the medium by at least one
secondary pressure pulse of a predetermined value over a certain
time period which is insufficient for irreversible changes in the
fleshy medium. The predet ed value of the secondary pressure pulse
can, for example, be in the range of about 0-300 mmHg. It was also
found by the inventors that one can obtain some more useful
information about the patient's blood characteristics by means of
manipulating the magnitude of the secondary pressure pulse. In
particular, in the case when the magnitude of the secondary
pressure pulse is small and does not exceed a certain relatively
small value P.sub.1, all tree main components of the blood (venous,
capillary and arterial blood components) can contribute to the
measurements. However, in the case when the magnitude of the
secondary pressure exceeds the value of P.sub.1 the venous blood
component can be excluded from the consideration. Likewise, in
order to exclude from the consideration also the capillary blood
component, the secondary pressure should exceed the value of
P.sub.2 (where P.sub.2>P.sub.1). In other words, when the
magnitude of the secondary pressure is over P.sub.2 venous and
capillary blood becomes forced out of the measurement location,
while arterial blood remains at the measurement location, and
measurements in this case would be applied to arterial blood only.
It should be understood that the values of P.sub.1 and P.sub.2,
depend on the person's physiology, and should be selected
individually for each patient.
[0053] A modification of RBC clusters resulting in the altering of
the artificial kinetics can be caused by many different ways. Thus,
other than the single secondary pulse described above, the altering
of the condition of artificial blood kinetics can be carried out by
applying a perturbation to the medium by means of the secondary
pressure of a predetermined cyclic pattern over the predetermined
time interval. The predetermined cyclic pattern can, for example,
be in the form of a train of short secondary pressure pulses having
a duration of about 0.5-2 seconds and amplitude in the range of
about 0-300 mmHg.
[0054] According to one embodiment of the invention, the
non-invasive measurements are carried out by illuminating a
measurement location on the medium at the state of temporary blood
flow cessation with an incident light beam, and detecting acoustic
energy as a response to the incident electromagnetic energy (light
in this case). The light beam is usually a pulsed laser signal
having the wavelength selected from a range where the scattering or
absorbing properties of blood are sensitive to provide an acoustic
response (e.g., 600-1000 nm).
[0055] According to Beer's law, the optical absorption coefficient,
and consequently the corresponding photo-acoustic signal, are
proportional to the concentration of the component of interest in
the medium being tested. Moreover, changes of the
absorption/scattering properties of the blood due to the altering
of the artificial kinetics will also be reflected on the
corresponding photo-acoustic response.
[0056] FIG. 2 illustrates an example of the computer simulation of
the light absorption changes versus the scattering coefficient of
the blood, when the condition of the artificial kinetics changes
over time, for example, due to the cessation of blood flow (caused
by the described above occlusion maneuver). The computer
simulations were carried out for a blood layer of 1 mm thickness,
with Hematocrit 0.4 and a light wavelength of 900 nm. It was
assumed that at the beginning of the aggregation process, the red
blood cells (RBC) were all in a non-aggregated state (e.g.,
individual red blood cells) that corresponds in this example to the
scattering coefficient of single red blood cells, viz. 100
mm.sup.-1. As can be seen, the changes of the artificial blood
kinetics results in the decrease of absorption, due to the
diminishing of the optical path.
[0057] FIG. 3 illustrates the time behavior of light absorption in
the above computer simulation caused by changes in the artificial
blood kinetics. As can be appreciated, the diminishing of the
optical path, owing to the RBC aggregation, consequently, causes
the reduction of light absorption.
[0058] In turn, a photo-acoustic response is proportional to the
light absorption and the scattering coefficient of blood. FIG. 4
illustrates a time dependence of a typical PA signal (normalized
value) obtainable in vitro during the condition of artificial blood
kinetics (i.e., RBC aggregation process). The wavelength of the
illumination light for this simulation corresponds to 900 nm. In
consistence with the prediction, the measured photoacoustic signal,
which is proportional to the light absorption, actually decreases
with evolvement of aggregation process.
[0059] It should be appreciated that a curve of the corresponding
time dependence can also be obtained for a photo-acoustic signal
when the condition of the artificial blood kinetics is controllably
altered by applying a perturbation to the flesh medium by a
predetermined secondary pulse, as described above. In particular,
the measured data of the photo-acoustic signal over a certain time
interval selected from the intervals when the secondary pressure is
applied can be used. Moreover, the measured data over a certain
interval selected from the time intervals after the release of the
secondary pressure can also be utilized for determining blood
characteristics.
[0060] According to another embodiment of the invention, the
response to the external electromagnetic field is the impedance of
the medium in response to the applied ac electromagnetic field. For
example, the basic principles of Time Reflection Spectroscopy or
Time Domain Dielectric Spectroscopy (see, for example, Yu. Feldman
etc., "Time Domain Dielectric Spectroscopy: An Advanced Measuring
System." Rev. Sci. Instrum., 1996, V 67, (9), P. 3208-3216) can be
used for determination of the impedance.
[0061] It should be noted that components of the impedance or
parameters that can be derived from the impedance or its components
also can be utilized as a response to the external electromagnetic
field. The measured components of the impedance of the medium can
be the following: an active component, a reactive component, or a
phase angle between the active and reactive components of the
impedance. These components allow deriving, inter alia, such
parameters as dielectric permittivity, dielectric losses and
conductivity of the medium.
[0062] It is well known that dielectric properties of RBC depend on
the glucose concentration. In particular, it was measured that
impedance of the blood can increase by 0.25 ohm when the glucose
level increases by 10 mg/dl. Since this effect is mainly related to
the cellular membranes, then the change of the RBC's membranes
surface during the aggregation caused by the artificial kinetics
should lead to a change in the measured impedance signal. It can be
assumed that the impedance signal is proportional to the free
surface of RBCs. Thus, the aggregation of N RBCs will approximately
reduce the free surface by factor (N+r/h)/(1+r/h), where r and h
are the radius of the RBC and the RBC's membrane thickness,
respectively. In calculations, r and h can, for example, be set to
4 micron and 1 micron, respectively. Accordingly, the measured
entire blood impedance should be varied due to the aggregation
process. An example of a dependence of a typical impedance signal
versus Number of RBC in an aggregate obtainable during the
condition of artificial blood kinetics (i.e., RBC aggregation
process) is shown in FIG. 5.
[0063] The rate of change of the impedance during the state of the
artificial kinetics is specific to each individual and can be used
for obtaining the corresponding glucose concentration. Hence, the
accuracy (i.e., signal-to-noise ratio) of the technique based on
the artificial kinetics can be substantially better when compared
to those based on measurements of the blood parameters at natural
kinetics.
[0064] Moreover, when required to further increase the sensitivity,
the altering component of the impedance (associated with the
aggregation) can be easily extracted from the total blood impedance
that includes also the components of impedance which are
insensitive to the aggregation process, e.g., the components
related to skin, water, swear, etc.
[0065] It should be appreciated that a certain curve of the
corresponding time dependence can also be obtained for impedance
when the condition of the artificial blood kinetics is controllably
altered by applying a perturbation to the flesh medium by a
predetermined secondary pulse, as described above. In particular,
for determining blood characteristics the entire impedance or its
component (measured data) can be used measured over a certain
interval selected from the intervals when the secondary pressure
perturbations are applied. Moreover, the measured data over a
certain interval selected from the time intervals after the release
of the secondary pressure perturbations can also be utilized.
[0066] According to the invention, for the determination of blood
characteristics, a characteristic parameter should be used derived
from the time variations of the response (photo-acoustic signal
and/or impedance) of the medium during either the condition of the
artificial blood kinetics or when this condition is altered by the
secondary pressure perturbations. Since the determination of this
parameter does not depend on the details of the employed technique
and is similar for the response obtained from either photo-acoustic
or impedance measurement techniques, the examples of the procedures
for determination of blood characteristics (e.g., glucose
concentration) will be shown herebelow for the response
corresponding to the generalized case.
[0067] According to one example, this characteristic parameter can
be the actual value of the time response of the medium to an
external electromagnetic field at a certain moment in time during
the state of the artificial kinetics. For example, this time moment
can be chosen when the response attains its asymptotic or almost
asymptotic magnitude of the time response, e.g., at the moment of 1
minute after applying the external electromagnetic field. For
instance, for the photo-acoustic measurements, the external
electromagnetic field can be light, having the wavelengths selected
from the range of 500-1700 nm; while for the impedance
measurements, the external electromagnetic field can be ac
electromagnetic field having the frequency selected from the range
of 1-200 MHz.
[0068] According to another example, this characteristic parameter
can be a parametric slope (PS) defined as the ratio between a first
function depending on a response of the medium corresponding to one
wavelength (frequency) of the external electromagnetic field and a
second function depending on the response of the medium
corresponding to another wavelength (frequency). For instance, one
of the wavelengths (frequencies) can always be selected in the
glucose sensitive range, e.g. between 700-780 nm for the
photo-acoustic measurements, and 1-200 MHz for impedance
measurements; while the other wavelength (frequency) can be taken
either from the glucose sensitive range or outside of this
range.
[0069] According to one embodiment, the first and second functions
can be logarithmic functions log(T.sub.1) and log(T.sub.2) of the
responses T.sub.1, and T.sub.2, corresponding to the two different
wavelengths (frequencies). According to another embodiment, the
first and second functions can be functions of the time rate of the
changes of the light response signal, i.e., .DELTA.T/.DELTA.t (or
.DELTA.logT/.DELTA.t), where At can be any part of the time
interval during which the condition of artificial kinetics is
maintained or altered.
[0070] It should be appreciated that the characteristic parameter
utilized for calculation of the blood characteristics can be
calculated as a function of various parameters obtained from more
than one technique. For example, the characteristic parameter can
be calculated as a predetermined relationship between the
parameters obtained from photo-acoustic measurements in combination
with impedance measurements, and optical measurements as well.
[0071] According to the invention, for determining a desired blood
characteristic, certain reference data should be provided. The
reference data should be indicative of the desired blood
characteristic (e.g., glucose concentration) as a function of the
characteristic parameter derived as described above. Such reference
data can, for example, be a calibration curve defining the
dependence of the characteristic parameter on the desired blood
characteristic. The calibration curve can be created by plotting a
dependence of the characteristic parameter versus the desired blood
characteristic that can be obtained for the particular individual
or various patients by any other known invasive or non-invasive
method which is independent of the current measurements. It should
be appreciated that for different blood characteristics such
independent methods may also be different. For example, a
calibration curve to be used for determining the glucose
concentration may be constructed by measuring the concentration of
glucose in the blood by an invasive method simultaneously with the
method of the present invention. Such measurements for constructing
the calibration curve can be carried out either for a specific
patient during a certain time period, sufficient to observe changes
of the concentration of his glucose, or by applying measurements to
various patients having different glucose concentration. It should
be appreciated that when required (e.g., for increasing accuracy of
the measurement), a combination of several techniques can be used
for obtaining a calibration curve.
[0072] Referring to FIG. 6, a schematic block diagram of a
measuring system 60 applied to a patient's finger F for carrying
out the method of the present invention is illustrated. It should
be noted that the blocks in FIG. 6 are intended as functional
entities only, such that the functional relationships between the
entities are shown, rather than any physical connections and/or
physical relationships. Although the application of the measuring
system to the patient's finger F will be illustrated below, it
should be understood that other parts of the patient's body, e.g.,
a toe, a wrist, an elbow and/or a knee, can also be used, mutatis
mutandis, as a medium for the light transmission measurements. The
system 60 comprises such main constructional parts as a measuring
probe 61, a pressurizing assembly 62 (occluder), and a control unit
63. The measuring probe 61 includes a source 611 of an external
electromagnetic field configured for applying this field to the
blood perfused fleshy medium (i.e., finger F), and a detecting
module 612 configured for measuring the response of the medium to
the external field.
[0073] According to one embodiment of the invention, the measuring
probe 61 can be a photo-acoustic system that may be any known
photo-acoustic system configured for irradiating the medium and
detecting the generated acoustic energy. According to another
embodiment of the invention, the measuring probe 61 can be any
conventional system for measuring impedance of the medium and/or
components of the impedance. According to a further embodiment of
the invention, the measuring probe 61 includes a combination of a
photo-acoustic system and a system for measuring impedance of the
medium. According to yet another embodiment of the invention, the
measuring probe 61 includes a combination of a photo-acoustic
system, a system for measuring impedance of the medium and any
other system. Examples of such other systems include, but are not
limited to, an optical system described in U.S. Pat. No. 6,400,972,
International Publications WO 01/45553 and WO 01/96872, all
assigned to the assignee of the present application. It should be
understood that if a combination of photo-acoustic and all-optical
measurements is used, the detecting module 612 is appropriately
designed for detecting both acoustic and light response, namely
includes acoustic transducer (at least acoustic receiver) and a
photodetector.
[0074] The principles of photo-acoustic and impedance based
techniques are known per se. Numerous examples of the
photo-acoustic and impedance measuring systems are known in the art
(see, for example, EP 0 282 234; U.S. Pat. Nos. 6,466,806;
6,049,728; 5,792,668; WO 00/43759; WO 02/069791), and therefore the
detail of these systems will not be expounded herein below.
[0075] The pressurizing assembly 62 includes a primary occlusion
cuff 621 operable for applying the primary over-systolic pressure
to the patient's finger F at a location L.sub.1 and, when required,
a secondary occlusion cuff 622 operable for applying the secondary
pressure to the patient's finger at a location L.sub.2 in the
vicinity of a measurement location ML. The pressurizing assembly 62
further includes a pressure driver 623 actuated by the control unit
64 for operating the squeezing of the cuff 621 and, when required,
the cuff 622. The primary occlusion cuff 621 and the secondary
occlusion cuff 622 may be of any known suitable type. It should be
noted that the primary occlusion cuff 621 may, for example, be
accommodated on the patient's wrist or palm, while the secondary
occlusion cuff 622 and the detecting module 612 of the probe 61
(measuring either an acoustic response or impedance of the medium)
may be located on the patient's finger.
[0076] In the present example, the location L.sub.2 of the
secondary pressure is selected downstream of the main occlusion
(location L.sub.1) with respect to the normal blood flow direction.
The locations to which the pressure and measurements are applied
may be aligned along the direction of the normal blood flow; or the
measurement location ML may substantially coincide or be adjacent
to the location of the secondary pressure and/or the location of
the primary pressure, depending on the kind of measured medium
and/or design of the measuring probe 61.
[0077] A signal detected by the measuring probe 61 is fed to the
control unit 63 through a suitable electronic interface block,
typically including an analog-to-digital (A/D) converter (not
shown) configured for generating measured data indicative of time
evolutions of the response of the medium. The control unit 63 is
interconnected between the measuring probe 61 and the pressurizing
assembly 62 for synchronizing the operation of the source 611 of
the external field and the pressure driver 623 so as to apply
primary over-systolic pressure to a certain location on the medium
for creating a condition of artificial blood kinetics in the medium
at the measurement location and maintaining this condition for a
certain time period. Likewise, when required, the control unit 63
can provide synchronization for applying secondary pressure to the
fleshy medium in the vicinity of or at the measurement location so
as to alter the condition of artificial blood kinetics over a
predetermined time interval within the certain time period, and
thereby modulate the properties of blood affecting the time
response. The control unit 63 is coupled to the output of the
detecting module 612 for applying the measurements synchronously
while maintaining and/or altering the condition of the artificial
blood kenetics.
[0078] The control unit 63 includes a computer system having inter
alia a memory utility 631 for storing reference data indicative of
the desired blood characteristic(s) as a function of a
characteristic parameter derived, as have been described above,
from the response of the medium. The control unit 63 further
includes a processor 632 (data acquisition and processing utility),
and a monitor 633 configured for presenting the measurement
results. The processor 632 is preprogrammed by a suitable software
model capable of analyzing the received output of the detecting
module 612 (measured data) and determining one or more desired
characteristics of the patient's blood by utilizing the reference
data, as have been described above.
[0079] Those skilled in the art to which the present invention
pertains, can appreciate that while the present invention has been
described in terms of preferred embodiments, the concept upon which
this disclosure is based may readily be utilized as a basis for the
designing of other structures, systems and processes for carrying
out the several purposes of the present invention.
[0080] Also, it is to be understood that the phraseology and
terminology employed herein are for the purpose of description and
should not be regarded as limiting.
[0081] In the method claims that follow, alphabetic characters
numerals used to designate claim steps are provided for convenience
only and do not imply any particular order of performing the
steps.
[0082] Finally, it should be noted that the word "comprising" as
used throughout the appended claims is to be interpreted to mean
"including but not limited to".
[0083] It is important, therefore, that the scope of the invention
is not construed as being limited by the illustrative embodiments
set forth herein. Other variations are possible within the scope of
the present invention as defined in the appended claims and their
equivalents.
* * * * *