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BACKGROUND OF THE INVENTION
Applicants herein are the inventors of U.S. Pat. No. 5,070,874, issued Dec.
10, 1991, for "Non-invasive Determination of Glucose Concentration in Body
of Patient."
This invention relates to the determination of the concentration of
analytes in the body of a mammal, and in particular to the determination
of the concentration of glucose in the blood of a patient who is suspected
of suffering from diabetes or to control the treatment or medication of
patients who already suffer from diabetes. It has particular relationship
to such determination without drawing blood from the patient, i.e., by a
non-invasive process and by non-invasive means.
There is widespread demand for non-invasive determination of glucose in
patients. In the United States there are approximately ten million
diabetics. Two million of these are Type 1 Diabetics, whose pancreas
secretes no insulin; and eight million of these are Type 2 Diabetics,
whose pancreas secretes insufficient insulin or secretes it too late. Most
of the Type 2 Diabetics can be controlled with proper diet and weight
control. Some of the Type 2 Diabetics and all of the Type 1 Diabetics
require one or more shots of insulin per day. Insulin controls the body's
utilization of glucose or sugar in the blood and, in the correct
concentrations, prevents hyperglycemia (excess glucose) which, if left
uncorrected, can lead to ketosis, coma and death. Glucose determination is
also indispensable for sufferers from hypoglycemia who must ingest glucose
containing fluids, such as orange juice, if the glucose in their blood
decreases to a low level.
Hyperglycemia in the diabetic is strongly suspected of being responsible
for the long-term effects of diabetes which include heart disease,
arteriosclerosis, blindness, stroke, hypertension, kidney failure, and
premature death. Severe hypoglycemia has similar drastic consequences. In
a normal person, the blood glucose level may vary between 60 and 130
milligrams per deciliter, a variance exceeding 100%; whereas, in a
diabetic, the levels may vary from time to time from 40 to 500 milligrams
per deciliter, a variance of 1150% for hyperglycemia. For hypoglycemia, 60
milligrams per deciliter indicates that treatment is necessary; the
glucose may reach a dangerous level of 20 milligrams per deciliter. These
large swings of glucose levels must be avoided to prevent the symptoms and
complications of the disease. To avoid the swings, the diabetic must be
able to conveniently monitor his blood glucose level, and then vary his
caloric intake, diet and insulin to control the level. For effective
control, frequent blood glucose monitoring is necessary.
The only practicable, reliable method currently available for monitoring
blood glucose is by means of blood sampling. The diabetic pricks his
epidermis with a needle or lance, usually in the finger, draws a drop of
blood, and absorbs the blood on a chemically treated strip of paper. He
can then read the glucose level by placing the strip in a glucometer (a
spectrophotometer which reads glucose concentrations); or he can compare
the color change of the strip with a calibrated color chart. The direct
reading instruments are more accurate. Other methods include measuring the
electrical resistance of the strip with a glucometer which is an ohmmeter
calibrated in milligrams per deciliter. For effective control, some
diabetics must utilize a finger prick four or more times a day.
It is desirable to dispense with the drawing and analyzing of blood and it
is an object of this invention to achieve this purpose, providing for
effective non-invasive determination of analyte concentration in the body
of a mammal, and in particular glucose concentration in a patient
suspected to suffer from, or already suffering from, diabetes.
European Publication 0 160 768, dated Nov. 13, 1985, to Clause Dahne and
Daniel Cross, discloses one prior art technique for the non-invasive
determination of glucose concentration. In Dahne, a beam of radiation in
selected bands, 1575, 1765, 2100 and 2270.+-.15 nanometers is impinged on
a portion of the patient's body, penetrating into the portion, and the
radiation resulting from the reaction within the body on the incident
radiation is analyzed photometrically for the presence quantitatively of
glucose. The resulting radiation which is analyzed may be scattered
radiation or the transmitted radiation which, in effect, is the incident
radiation less the predominant fraction of the scattered radiation and the
radiation absorbed by the portion of the body.
Dahne suffers from the disadvantage that its process lacks the precision
demanded for the effective monitoring of glucose concentration. The range
of concentration over which the glucose is in practice monitored for
effective control of the patient is between 40 and 500 milligrams per
deciliter, but even lower concentrations may be encountered in
hyperglycemia or hypoglycemia. A concentration appreciably greater than
120 milligrams per deciliter indicates a diabetic condition and treatment
by diet or insulin. In the actual practice of Dahne's process, the highest
concentration of glucose which was measured was one molar (1M) and the
lowest concentration of glucose which was measured was 0.05 molar (page
18). The chemical formula for glucose is C.sub.6 H.sub.12 O.sub.6. In a 1M
solution of glucose, there are 180.16 grams per liter or 18,000 milligrams
per deciliter. In 0.05 mole, there are 0.9 grams or 900 milligrams per
deciliter. This is far out of the range of glucose concentrations which
must be measured for effective control and, indeed, out of the range which
is compatible with life. There is no evidence in Dahne that its process is
more effective than is indicated by its tests.
It is accordingly an object of this invention to overcome the disadvantages
and drawbacks of the prior art and to provide for the precise effective
non-invasive determination of the concentration of blood analytes in a
mammal, and particularly glucose in a human patient, taking into
consideration the concentrations actually involved in such determination.
SUMMARY OF THE INVENTION
This invention arises from the realization that in any expression, for
example, in a graph, of the concentration of glucose in blood as a
function of the wavelengths over which an analysis is carried out, the
measure of the maximum concentration, which must be precisely determined,
is often obscured by the presence of other chemical species. It has been
realized in arriving at this invention that the specific spectral features
associated with species which must be measured may be emphasized and
readily determined by appropriate mathematical techniques. In particular,
such mathematical techniques may involve a step of pretreatment, followed
by a step of multivariate analysis. The step of pretreatment serves to
eliminate or minimize the effects of detector offset and optical
scattering drift. In particular, the step of pretreatment may also include
deriving a new function, the nth derivative with respect to wavelength of
the expression defining the concentration of glucose as a function of
wavelength, over a defined region of this nth derivative. The nth
derivative with respect to wavelength is then used as an input for
multivariate analysis. Using multivariate analysis techniques, the glucose
concentration is then determined. As is conventional in the use of
multivariate techniques in chemical analysis, the multivariate analysis
uses a model developed by comparing predicted concentrations of the
species to be measured in specimens to the known concentrations of the
species in that specimen.
Specifically, the non-invasive measurement of the concentration of glucose
in blood is performed with a near-infrared radiation source, a probe, a
spectrum analyzer with a detector and a data processor. The probe may
include a dual fiber-optic conductor of near infrared radiation which is
used in either the transmission or scattering mode. Radiation from the
near infrared source is transmitted through one of the dual conductors,
the end of which is placed near or in contact with a portion of the
patient's body. The radiation transmitted into the body undergoes
scattering and characteristic absorption depending on the identity of the
species present. A portion of the radiation having undergone scattering
and absorption is back scattered from the body and collected and
transmitted back to the spectral analyzer/detector system by the other
fiber-optic conductor, which is referred to as the sensing or pick-up
conductor. The end of the sensing or pick-up fiber-optic conductor, placed
near or in contact with the body, is arranged so that either a
transmission or a scattering measurement is performed. In the transmission
mode, the end of the pick-up fiber-optic conductor is arranged so that the
near infrared radiation from the source can be passed through the portion
of the body, which may be the ear lobe, tongue or webbing between the
fingers or toes, and its spectral absorption characteristics measured.
This is accomplished by placing the body section between the ends of the
dual conductor so that radiation from the fiber-optic conductor connected
to the near infrared source passes through the body section to the pick-up
fiber-optic conductor which transmits the attenuated radiation to the
spectral analyzer/detector. In the scattering mode, a bifurcated
fiberoptic probe is preferably used. The bifurcated probe includes two
separate bundles of fibers, one bundle being connected to the near
infrared source, and the other bundle being connected to the spectral
analyzer/detector system. The pick-up bundle may be, for example,
centrally located and the source conductor bundle may be disposed in any
configuration surrounding the central bundle. Alternatively, individual
pick-up fibers may be disposed at selected locations in a bundle of
conductors connected to the source. To measure blood glucose, the sensing
end of the probe is placed near or in direct contact with an outer surface
of the body. Near infrared radiation from the fibers connected to the
source is transmitted through that portion of the body undergoing both
characteristic spectral absorption and scattering. Some of the scattered
radiation which has traveled through the body experiencing absorption is
collected by the pick-up fibers in this configuration and then transmitted
to the spectrum analyzer/detector.
The spectrum analyzer for this application can include a dispersive
spectrometer with a prism or diffraction grating, a spectrometer in a
Czerny-Turner configuration, a set of optical filters, a scanning
interferometer, a stationary interferometer, or it may include a Hadamard
transform spectrometer. Hadamard transform spectroscopy is described in a
paper by Hammaker et al. in Vibrational Spectra and Structure, Vol. 15,
Nov. 1986, edited by J. R. Durig, Elsevier Press, Amsterdam, Holland. The
purpose of the spectrum analyzer is to disperse the near infrared
radiation passing through the body into its spectral components. Selected
wavelength ranges are focused on detector cells, which provide an analog
signal proportional to the intensity of radiation in the selected
wavelength ranges.
The data processor receives the output signal from the spectral analyzer.
This output signal may be a reflected light intensity as a function of
wavelength. The reflectance, R, is given by
R=.sub.I.sbsb.O /.sup.I
where I.sub.0 is the intensity of the radiation incident on the portion of
the patient's body and I is the resulting radiation reflected back or
scattered by the portion. When the reflectance is graphically presented,
the quantity log (1/R) is customarily presented and called absorbance.
The data processor then calculates the concentration of blood glucose, and
formats the output to a display or recording device giving blood glucose
concentration in selected units. Preferably, a microprocessor in the data
processor is used to perform data processing and control the operation of
the spectral analyzer.
To investigate and demonstrate the practical utility of the invention, near
infrared measurements were performed in different concentrations of
glucose in rabbit ears. It was found that the intensity of the reflected
radiation as a function of wavelength in the near infrared band of glucose
between 1100 and 1900 nm. yielded effective data from which glucose
concentrations could be derived. In the practice of this invention, in its
broad aspects, measurements are made over the range of wavelengths from
700 to 3000 nm.
BRIEF DESCRIPTION OF THE DRAWINGS
For a better understanding of this invention, both as to its organization
and as to its method of operation, together with additional objects and
advantages thereof, reference is made to the following description, taken
in connection with the accompanying drawings, in which:
FIG. 1 is a block diagram showing an embodiment of this invention with
which the method of invention is practiced;
FIG. 2 is a graph presenting 31 spectra of the log of the reciprocal of the
reflectance of radiation from a rabbit used as a test subject, i.e., the
absorption for the subject, as a function of the wavelength in the near
infrared;
FIG. 3 is a graph presenting the functions shown in FIG. 2 as a function of
wavelength after a step of data pretreatment;
FIG. 4A through 4F are graphs showing six factors in a multivariate
analysis model developed using the data of FIG. 2 and 3.
FIG. 5 is a graph in which concentrations of glucose in rabbit blood were
determined in vivo and non-invasively in the practice of this invention
from the data derived from the graphs shown in FIGS. 2 and 3, using the
model of FIGS. 4A-4F, is plotted against the corresponding known
concentrations;
FIG. 6 is a graph in which the model of FIGS. 4A-4F is plotted on a single
graph.
DETAILED DESCRIPTION OF A PREFERRED EMBODIMENT
FIG. 1 shows apparatus 11 for the non-invasive determination of the glucose
concentration in a patient. This apparatus includes a source 13 of
near-infrared radiation, a first lens system 15, a dual conductor
fiber-optic probe 17, a second lens system 19, a spectrum
analyzer/detector 21, a data processor and controller 23, an output
display device 25 and an output recorder 27. As stated the source may
produce radiation over the range from 700 to 3000 nm. The data presented
in this application were produced using a Model 6500 System Near Infrared
Spectrometer acquired from Pacific Scientific Instrument Division of
Pacific Scientific, Ltd. The address of this Instrument Division is 2431
Linden Lane, Silver Spring, Md. 20910. The source may be an appropriate
tungsten filament bulb, with an infrared filter disposed intermediate the
bulb and the input radiation conductor 29. The intensity of the radiation
of the source over the wavelengths of interest must be maintained
constant. This may be achieved, for example, by thermally isolating the
bulb from its surroundings and maintaining the current through the
filament constant. The lens systems 15 and 19 are represented by
single-lens symbols. In actual practice, they are appropriate combinations
of lenses including focusing lenses and collimators on the outlet side.
The fiber-optic probe 17 includes an input radiation conductor 29 for
transmitting radiation to a portion 31, for example, an ear lobe or wrist,
of the patient's body and pickup or sensing radiation conductor 33 for
receiving the resulting radiation from the portion 31. The output end of
the input conductor 29 and the input or sensing end of the pickup
conductor 33 are preferably in firm contact with the outer surface of the
portion 31 of the subject's body. While each conductor 29 and 33 is
represented by a symbol for a single conductor, each radiation conductor,
in actual practice of this invention, includes bundles of optical fibers.
Radiation from the source 13 is directed by the lens system 15 into
conductor 29 and, at its outlet, is projected into the portion 31. This
incident radiation induces scattered radiation within the body portion 31,
some of which passes through the end of conductor 33 and through the
conductor and is directed by lens system 19 into the spectrum
analyzer/detector. While FIG. 1 discloses apparatus in which scattered
radiation is analyzed, the analysis of transmitted radiation, i.e., the
input radiation less the back scattered and absorbed radiation, plus any
forward scattered radiation, is within the scope of equivalents of this
invention. In this case, the ends of conductors 29 and 33, instead of
being side-by-side in contact with adjacent surfaces of the body portion
31, would be in contact with the outer surfaces on opposite sides of the
body portion 31, for example, with opposite surfaces of the ear lobe. The
radiation, which is in this case passed through conductor 33, is
predominantly the radiation from the source 13 less the radiation
scattered and absorbed by the molecules of the water in the blood, the
glucose and other constituents of the blood. The skin also contributes to
the scattering and absorption.
With the apparatus as shown in FIG. 1, the resulting back scattered
radiation emitted by the body portion 31 is passed by pickup conductor 33
and lens system 19 to the spectrum analyzer/detector 21 where this
radiation is spread into a spectrum. The spectrum is focused on an array
of optical detectors. A selected wavelength range is focused on each
detector. For example, a range of 15 nanometers may be focused on each
detector. The detectors may be lead-sulfide detectors, which are
well-known in the field of infrared spectroscopy of grains and other
agricultural products. Each detector converts the radiation in the
corresponding selected wavelength range to electrical signals which are
transmitted to the data processor 23. In a preferred embodiment,
intermediate each detector and the data processor, there is a
pre-amplifier, an amplifier, and an analog-to-digital converter. It should
be noted that, to reduce noise effects, a chopper is preferably provided
before the spectrometer to modulate the infrared beam. The amplifier is a
lock-in amplifier, so that only the portion of the s | | |
