Instrument and method for non-invasive in vivo testing for body fluid constituents

We claim:

1. In a nuclear magnetic resonance spectroscopy apparatus for testing body fluids for the presence of constituents, said apparatus being of the type in which a first magnetic field aligns .sup.1 H protons to an intial position, and in which a second magnetic field is cyclicly energized and deenergized to cause alignment of the .sup.1 H protons to a second position and realignment to said intial position, and in which the magnetic changes resulting during realignment are detected and analyzed, the improvement comprising:

first magnet means comprising a pair of permanent bar magnets each including a north pole and a south pole,

second magnet means for creating said second magnetic field;

mounting means for mounting said first magnet means,

said mounting means comprising a pair of spaced apart members for positioning said pair of bar magnets spaced apart with the north pole of each said bar magnet secured to one of said members and the south pole of each said bar magnet secured to the other of said members, said first magnet means, said second magnet means and said mounting means providing a cavity defining a test region therein for receiving a sample of the body fluid to be tested,

said first magnetic field being substantially uniform in field strength and direction throughout said test region;

said second magnet means being operatively disposed with respect to said test region for being magnetically coupled to the body fluid sample to be tested;

first and second members connecting said pair of spaced apart members, said first connecting member including an aperture therethrough for access of said body fluid sample into said test region;

circuit means for detecting and analyzing said magnetic changes;

said second connecting member having switch means operatively associated therewith for initiating operation of said circuit means;

a sample holder containing a standard sample of known concentrations of the constituents to be investigated;

said standard sample holder being intially disposed in said test region; and

means for biasing said sample holder to urge said sample holder toward said second connecting member and to initially locate said standard sample in said test region and capable of being operatively coupled to said second magnet means when said second magnet means is energized, said switch means being activated in response to the movement of said standard sample holder out of said test region to contact and operate said switch means when said body fluid sample to be tested is moved into said test region.

2. The improved nuclear magnetic resonance apparatus of claim 1, wherein:

each of said spaced apart members comprises a pole piece directed into said test region to concentrate the magnetic flux.

3. A portable nuclear magnetic resonance apparatus for spectroscopic testing of samples of body fluids for the presence of a constituent, said apparatus comprising:

principal magnet means partially defining a test region and having a pair of opposed magnetic poles establishing a substantially uniform magnetic field within the test region;

coil means; and

circuit means coupled to said coil means for producing an energization and realignment field within the test region and for detecting changes resulting from relaxation of said field and for analyzing said changes;

said principal magnet means being positioned to receive and test said body fluid samples in said test region;

said circuit means including means for energizing said coil means to resonate .sup.1 H protons adjacent said coil means, and means for sensing the change as indicated by spectra having peaks corresponding to various molecular bonds,

said circuit means also including means for comparing the actual amplitude of a peak for a first constituent in the body fluid sample being tested to a predetermined amplitude for a peak for a predetermined quantity of said first constituent contained in a separate, standard sample to determine the actual value of a second constituent

in said body fluid from a predetermined relationship between predetermined values of the peaks for the first and second constituents.

4. An apparatus as in claim 3, wherein the first constituent is water and the second constituent is glucose, and including means for calculating and displaying the actual concentration of glucose as determined from the following relationship: ##EQU4## wherein K=concentration of glucose in said standard sample expressed in mg/dl.

5. An apparatus as in claim 3, wherein the first constituent is water and the second constituent is alcohol, and including means for calculating and displaying the actual concentration of alcohol as determined from the following relationship: ##EQU5## wherein K=concentration of alcohol in said standard sample expressed in mg/dl.

6. An apparatus as in claim 3, wherein the coil means comprises at least one surface coil positioned adjacent the sample to be tested.

7. An apparatus as in claim 6, wherein said body fluid is blood, said test region is constructed to test said blood in vivo in a human finger in the area below the fingernail and the surface coil is arranged to be positioned in close proximity to the test region; and said apparatus also includes means for testing said standard sample for calibration of said apparatus after testing of the finger.

8. An apparatus as in claim 7, wherein the fluid to be tested is blood serum, and the first constituent is water and the second constituent is glucose, and said standard sample contains a mixture of water and glucose of known concentration.

9. An apparatus as in claim 8, wherein the apparatus includes means for resiliently biasing a standard sample holder into the test region adjacent said surface coil and for movement into a second position by movement of the finger to be tested into said test region.

10. An apparatus as in claim 9, wherein said coil energizing means includes means actuated responsive to the movement of the standard sample holder.

11. An apparatus as in claim 7, wherein the test apparatus is constructed to enclose and surround said test region.

12. An apparatus as in claim 3 for use in testing the body fluid in a blood vessel in vivo wherein the poles of the principal magnet are constructed to be positioned on opposite sides of the test region.

13. An apparatus as in claim 12, wherein the blood vessel is a surface blood vessel of an animal and said coil means is a surface coil.

14. An apparatus as in claim 12, wherein said apparatus is implantable and said coil means comprises a pair of coils adapted to be positioned on opposite sides of the test region.

15. An apparatus as in claim 3, wherein said coil means comprises a transmitting coil and a receiving coil.

16. An apparatus as in claim 3, wherein said coil means comprises three coil pairs arranged to be in a plane whose axes are equally spaced from each other and which intersect at a center so that their fields are at 120.degree. spacing, said test sample positionable at the center of said pairs.

17. An apparatus as in claim 3, wherein said circuit means includes RF generator and gate means for applying an exciting current to said coil means, a receiver and gate means for receiving signals sensed by said coil means, display means for displaying test results, memory means for storing an operational program and microprocessor means coupled to said generator and gate means, to said receiver and gate means, to said display means, and to said memory means, for selectively activating said coil means, for processing signals received by said coil means, for comparing actual test values of said body fluid sample with predetermined test values and for displaying test results in accordance with the stored program.

18. An apparatus as in claim 17, including disabling switch means for disabling said memory means in the event an unauthorized access to said apparatus is attempted.

19. The nuclear magnetic resonance apparatus of claim 3, wherein:

said coil means comprises a plurality of additively connected surface coils for both transmitting energization and sensing.

20. The nuclear magnetic resonance apparatus of claim 3, wherein:

said coil means comprises three coils phased at 120.degree. for both transmitting energization and sensing.

21. A method for non-invasively determining the value of a constituent in an aqueous body fluid of a patient using nuclear magnetic resonance spectroscopy, the method comprising the steps of:

analyzing a sample of said aqueous body fluid comprising the substeps of:

(a) exposing said body fluid sample to a biasing magnetic field, providing at least one magnetic field pulse to decrease a water peak reading obtained from said body fluid sample, resonating a magnetic field across said body fluid sample, sampling the field and recording data from the field and storing a spectrum of chemical shifts versus peak height as patient data;

(b) analyzing a standard sample having a known concentration of the constituent being tested for with the same fields as in substep (a), obtaining a standard sample pulse and recording data in memory and storing a spectrum of chemical shifts versus peak height as standard sample data;

(c) checking operation of the system, including the steps of comparing the standard sample data for the constituent being tested with an acceptable standard sample spectrum previously recorded for said constituent for error within a selected tolerance;

(d) normalizing the patient data and standard sample data for equal water peaks, including the steps of recalling the patient data and the standard sample data; adjusting the patient data peak height of water to match that of the standard data peak height of water; and

(e) calculating the body fluid sample constituent level comprising the substeps of obtaining a ratio of patient data constituent height to standard sample data constituent height and multiplying it by the concentration of said constituent in said standard sample to obtain a patient reading and displaying that reading.

22. The method set forth in claim 21, wherein the analysis in substep (b) is done in the same sequence as that in substep (a).

23. A method for non-invasively determining the value of a constituent in a sample of an aqueous body fluid of a patient using nuclear magnetic resonance spectroscopy, said method comprising the steps of:

applying a biasing magnetic field to said sample to align at least the

.sup.1 H protons in the body fluid sample to an initial orientation;

applying a resonating field to flip the .sup.1 H protons between a further position and the initial position;

sensing, as analog signals, magnetic changes as the bonds flip from the further position to the initial position;

converting the analog signals into digital signals;

storing the digital signals as patient data in a memory;

multiplying the accumulated responses in the memory by an exponential decay to improve line broadening;

transforming the multiplied data with a fast Fourier transform;

repeating the above steps for a standard sample which includes water and a predetermined amount of the constituent being tested for;

comparing the spectrum of chemical shifts versus peak height of the standard sample to stored data of a previous predetermined spectrum of the standard sample for allowable error;

scaling the patient data peak height of water to match the peak height of water of the standard sample data;

forming a ratio of the patient constituent peak height to the standard sample data constituent peak height;

multiplying the ratio by the known standard sample constituent/water ratio to obtain a patient constituent reading in designated units; and

displaying the patient constituent level in such designated units.

24. The method set forth in claims 21 or 23, wherein the body fluid is blood.

25. The method set forth in claims 21 or 23, wherein the body fluid is blood and the constituent being tested for is glucose or alcohol.

26. The method set forth in claims 21 or 23 wherein said in vivo testing is performed by applying said biasing magnetic field and said resonating magnetic field to a selected portion of the body of said patient.

27. The method set forth in claim 26 wherein said selected portion of said patient's body is a finger.

28. The method set forth in claim 26 wherein said selected portion of said patient's body is a blood vessel of said body.

29. A self-contained portable apparatus for performing in vivo nuclear magnetic resonance spectroscopy testing of body fluids for the presence of certain constituents therein, said apparatus comprising:

wall means defining a housing;

a permanent magnet assembly disposed within said housing,

said permanent magnet assembly at least partially defining a test region within said housing;

means for defining a relatively narrow access opening in said housing enabling access to said test region for the placement therein of a test sample of the body fluid to be tested,

said test region being slightly larger than said test sample,

said permanent magnet assembly creating a permanent magnetic field sufficiently effective to align to a first position .sup.1 H protons of said test sample located in said test region;

said permanent magnetic field being substantially uniform in field strength and direction throughout said test region;

a generator and first means for producing gated radio frequency pulses;

coil means positioned within said housing and in close proximity to said test region, said coil means being connected to said generator, and being cyclicly energized by the gated radio frequency pulses for cyclicly flipping the .sup.1 H protons from said first position to a second aligned position, and for sensing the magnetic changes as analog data signals during realignment of said .sup.1 H protons from said second position to said first position;

second gate means connected to said coil means for receiving the analog data signals during realignment of said .sup.1 H protons from said second position to said first position;

an analog/digital converter connected to said second gate means for converting the analog data signals into digital data signals;

control means connected to said generator and said first gate means for receiving data from said analog/digital converter, said control means comprising means for storing and analyzing said digital data signals; and

display means for displaying the results of said analysis to a user.

30. The apparatus of claim 29, wherein said control means comprises:

a program memory storing an operating program;

a random access memory in said analysis means for storing and emitting the digital data signals; and

a microprocessor means connected to said generator and first gate means, to said program memory, to said random access memory, and to said analog/digital converter for controlling said apparatus in accordance with the stored program.

31. The apparatus of claim 30, and further comprising:

said housing surrounding and enclosing said program memory and said sample holding means, said housing including a housing cover;

a power supply for said program memory and

said housing having means to disable said program memory responsive to the removal of said housing cover,

said disabling means including switch means connecting said power supply to said program memory and operated by the removal of said housing cover to cause disruption of the stored program.

Description Submit all comments and votes

BACKGROUND OF THE INVENTION

This invention primarily relates to a method and to an instrument for use in medical diagnosis, and in particular, to detecting and determining glucose concentration in blood.

Diabetes is a health problem affecting many individuals and its prevalence is increasing. The usual treatment for diabetes is single or multiple insulin injections daily. Insulin is available in slowly or rapidly absorbed forms, which may be injected alone or in combination. Such insulin injections have been effective in treating the disease and in prolonging life.

Presently in order to determine if insulin is needed, blood is withdrawn from a patient and is tested for glucose concentration by a litmus-type indicator test. If indicated, insulin is taken by the patient.

This type of testing has several problems. For example, the testing is periodic, and thus the administration of insulin is periodic, which can result in wide variations in glucose concentration over time and peaks in the glucose concentration. Such variations can have physiological effects which may be adverse to the patient.

It has been recognized that it is desirable to administer insulin periodically on demand and in response to changes in glucose levels. One such system is disclosed in Albisser A, "Devices for the Control of Diabetes Melletus", Proc. IEEE 67 No. 9, 1308-1310 (1979) , wherein a servo system is employed which continuously withdraws blood from a patient and analyzes the same for glucose. Using a computer or microprocessor, calculations are made from the withdrawn sample as to the need for insulin, and in response thereto, insulin is administered. This system has only been used for short periods and has a disadvantage in that the system is invasive (i.e., the patient is catheterized continuously for withdrawing blood samples).

The litmus-type system has the disadvantage in that it is invasive and the patient is periodically and repeatedly pricked for blood samples.

It is therefore an object of this invention to provide a glucose testing device which can be used to monitor a patient's glucose level continuously, if desired, so as to provide a more uniform administration of insulin and a more uniform glucose concentration in the blood over time.

It is another object to provide a glucose monitoring system which is noninvasive and does not require periodic blood withdrawal to determine glucose levels.

It is sometimes desirable to test body fluids for other constituents. For example, law enforcement officers test individuals for alcohol content of their blood using a breathalyzer. However, breathalyzer tests may be inaccurate in that non-ingested alcohol, such as in mouthwashes, will provide false results.

It is another object of this invention to provide a non-invasive diagnosis apparatus for use in determining the concentration of various constituents of body fluids, such as glucose and alcohol and drugs.

Nuclear magnetic resonance (NMR) is a diagnostic technique which is used widely for medical imaging and medical diagnosis. In NMR, the test object is subjected to a first or biasing magnetic field to align previously randomly oriented .sup.1 H protons in the nuclei and a second field or burst of energy to increase the energy of a selected nucleus. When the second magnetic field or energy source is turned off, the return to the first alignment releases energy which is detected and analyzed. This release is analyzed or processed to form an image or spectrum. From the spectrum, the presence of particular molecular bonds can be observed and associated with various molecules or materials from which the concentration of that molecule or material can be determined.

NMR machines are most frequently used for imaging sections of a human body and require large magnets, for example, superconducting magnets. The machines are therefore quite large and expensive. Furthermore, the NMR testing of fluids has required invasive sample withdrawal techniques, which sample was then tested in the larger machines.

Using such NMR machines, blood serum has been analyzed and a spectra of the .sup.1 H resonance developed. In such spectra, identifiable peaks are obtained for water, glucose and ethanol. In reported tests, blood serum has been taken from animals, placed in a container and excited so as to yield the .sup.1 H spectra, which is then analyzed. Unfortunately, NMR testings are not common nor conveniently available. The reason is believed to be that the equipment is generally large, complex and expensive, and is therefore available only at selected centers, such as hospitals, universities, and other similar research and test sites. The equipment therefore is not normally used for blood or body fluid analysis as more convenient and less expensive alternatives are available.

Another disadvantage in present NMR tests is that they are conducted on fluid samples which are withdrawn from the patient by the usual invasive techniques.

It is therefore an object of this invention to provide a more convenient NMR instrument for use in analyzing body fluid samples.

It is a further object of this invention to provide an NMR instrument for use in analyzing body fluid for glucose.

It is yet another object to provide a portable NMR instrument for use by a person having diabetes to analyze his blood for glucose concentration.

It is yet a further object to provide an NMR instrument for use by a diabetic in noninvasively analyzing his blood serum for glucose concentration.

It is a still further object of the invention to provide an NMR method and apparatus to test for other substances, for example, alcohol and drugs.

These and other objects of this invention will become apparent from the following disclosure and appended claims.

SUMMARY OF THE INVENTION

This invention provides a method and a portable NMR instrument for use in noninvasively analyzing body fluids for the concentration of various constituents. Specifically, a diabetic can use the instrument to noninvasively and substantially instantaneously analyze his blood for glucose, thereby eliminating the need to invasively obtain a blood sample which is then tested. Using the device disclosed herein, a patient can periodically, frequently if necessary, and painlessly analyze his blood for glucose concentration. This device may also be useful in analyzing body fluids for alcohol or drugs.

In one form, the device is portable and provided with means for receiving an extremity of the patient, such as a finger, and exposing the extremity to a first or biasing magnetic field and a second field or energy source. Sensors are provided for sensing the rates of relaxation or energy release so as to develop the spectrum. Analytical means are coupled to the sensors for receiving and analyzing the signals emitted, discriminating between various peaks, comparing the amplitude or height of various peaks, such as water and glucose, and normalizing the analysis by reference to a standard sample so as to obtain the concentration of constituents in the tested materials.

One of the principal components of the NMR instrument is the first or biasing magnet for providing the first magnetic field. In this device the biasing magnet is physically much smaller than the magnets used in standard NMR machines. For example, the magnet may be one pound in weight and may exhibit a field strength of at least five to six kilogauss. Another component is a coil apparatus for applying a second field or energy to the test sample and sensing the energy released therefrom. A single coil or multiple coils can be used. Yet another important element of this invention is the electronic circuit used for the analysis. This circuit is controlled by a microprocessor that is programmed to control the application of the second field or energy source and cooperates in detecting and analyzing the spectra received from the sample when the field is relaxed. Operation of the microprocessor is disclosed herein.

Other specific features of the instrument are disclosed hereinafter.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a vertical cross-sectional view of an instrument according to this invention;

FIG. 2 is a vertical cross-sectional view taken along line 2--2 of FIG. 1 and also showing a housing and other components;

FIG. 3 is a block-type schematic diagram for the circuitry to operate the instrument;

FIGS. 4a to 4c are flow charts showing the operation of the instrument;

FIGS. 5a and 5b are representative NMR spectrums showing the water, glucose peaks and alcohol used for analysis;

FIG. 6 is a schematic diagram showing a three-coil system for use in the instrument;

FIG. 7 is a schematic diagram showing the electrical connections for the three-coil system of FIG. 6;

FIG. 8 shows an NMR probe for implantation in a body;

FIG. 9 is a schematic block-type diagram of the electrical circuit for use with the implantable probe of FIG. 8;

FIG. 10 shows a human arm having a distended vein for NMR testing;

FIG. 11 is a fragmentary and sectional view of a magnetic probe for use in NMR analysis using a surface blood vessel;

FIG. 12 is a schematic representation of an alternative circuit arrangement for use with separate energizing and receiving coils;

FIG. 13 is a schematic representation of the coil and magnet relationships which may be used in an arrangement of the type shown in FIG. 12;

FIG. 14 is a schematic representation of a multi-coil arrangement;

FIG. 15 is a top view of the elements of FIG. 14; and

FIG. 16 is a side view of an alternative C-shaped magnet which may replace the magnetic structure of FIGS. 1 and 2.

DESCRIPTION OF THE PREFERRED EMBODIMENT

Referring now to FIGS. 1-3, a first embodiment of the test instrument is shown. Other embodiments and features will be discussed after consideration of principal features of this invention by way of the first embodiment.

The test instrument 10 is shown as including a box-shaped assembly which defines a finger-receiving recess 12 therein. The assembly includes a body section 14 defined by the top, bottom and elongated side walls 16, 18, 20 and 22 and the back wall 24. The assembly is enclosed in a two-piece cover or housing 25A and 25B within which the electronic components discussed hereinafter are also enclosed. Alternatively, the electronics can be enclosed in a separate housing connected to the body section. A pair of first or biasing permanent magnets 26 and 28 form the top and bottom walls 18 and 22, are positioned opposite one another and provide the first aligning magnetic field. It is to be noted that the poles of the respective magnets are aligned so that the field is additive and provide constructive interference, and the pole pieces or shoes shape the magnetic field in the finger-receiving recess 12. This alignment is shown by the "X" designation, which indicates that the magnetic field from the magnets passes through the recess 12 in the same direction, in FIG. 2, into the paper.

A sample holder or container 34 for a standard sample is shown positioned in the recess. The apparatus includes a compression biasing spring 32 pressing at one end against the back wall 24 and against a the rear wall 30 of sample holder 34 at the other end. The holder 34 is mounted on a post-like member 35, which is guided through an aperture 37. A start switch 36 is mounted to the back wall offset from the member 35 so that when the sample holder 34 is pushed against the spring toward the back wall, the holder will depress the start switch to start operation of the instrument. Release of the standard sample holder will release the switch. The switch may also be mounted outside, say beneath the head 39, and operated upon movement of the head 39.

A surface coil 38 is mounted in the housing adjacent one of the permanent magnets 26 and 28. The coil produces the second field and acts as a source of energy for realignment and for sensing purposes. As seen in FIG. 1, the second field produced by the surface coil is transverse to the first or permanent magnet field. The surface coil has been selected for this embodiment because the depth of magnetization (i.e., extent of penetration of the field) is related to the diameter of the coil and can thus be controlled.

The surface coil 38 may be a single coil for both energization and sensing. The coil can also be an assembly in which there are multiple coils, each of which are for energization and sensing. Furthermore, the coil may be an assembly of at least two coils, where at least one is for energization and at least one other coil is for sensing. These alternatives are shown in FIGS. 13, 14 and 15.

The cover or housing 25A and 25B for the electronics is provided with an electronic interlock system (schematically shown as 56 in FIG. 3) so that unauthorized opening or removal of the cover will disable the electronics described hereinafter, thereby preventing unauthorized tampering or repair of the device which could destroy calibration and result in improper usage.

Physically the test is run by the patient inserting his finger into the instrument and pushing the sample holder toward the back wall 24 and into engagement with the start switch 36 to start the analysis as described hereinafter.

It will be noted that the finger is positioned so that the fingernail is located adjacent the surface coil. This positioning is chosen as the fingernail is dead tissue but has a bed of active blood vessels positioned just below the nail. These vessels are believed to provide an accurate testing site. In many other test sites, live body tissue or bone must be penetrated in order to test blood in a vessel, which means that the tissue or bone will emit signals due to testing which act as noise and may interfere with analysis of the blood for glucose concentration. The finger region is preferable, since the nail is essentially dead material and produces little, if any, interfering noise, thereby increasing the signal to noise ratio. It is believed that other body extremities can be tested, for example, the ear of either a human or other animals.

The testing circuit 40 includes a battery power supply 42. In a permanent installation, such as a doctor's office, hospital, etc., a commercial AC power supply and battery charger may be used to supply energy to the battery. Depression of the start switch activates the circuit and, thereby the microprocessor 44. The microprocessor activates an RF generator and cyclically-operated gate 46, which excites the surface coil 38 (or coil assembly) for applying the second field, raising the energy state and realigning the nuclei.

At the appropriate time and under control of the microprocessor, the RF generator is deactivated, thereby permitting the nuclei (dipoles) to relax or return to the first alignment. The surface coil then detects the energy released during relaxation and realignment. Those signals are received by receiver/gate 48, converted from analog signals to digital signals by the A/D converter 50 and fed to the microprocessor 44. A read only memory (ROM) 52 is provided for storing the program for use with the microprocessor in calibrating the machine and analyzing and displaying test results. If separate coils are used, then the circuit is changed so that the RF generator is connected to the energizing coil and the receiver is connected to the sensing coil as shown in FIG. 12.

The ROM is continuously energized by the battery 54. A cover interlock switch 56 is provided between the ROM 52 and battery 54 to deenergize the ROM in the event the electronics cover 25A or 25B is opened, removed or tampered with. In such an event, the switch 56 is opened and the program in the ROM is erased. In this instance, the ROM may be selected from the well-known classes of electrically erasable or alterable ROM's. The specific function of the ROM-cover interlock arrangement may be selected as desired, i.e., to generate an error message on the panel display, or simply to disable the apparatus from operating or exhibiting any panel display. Various other forms of electronic-type interlocks are well-known in the computer art.

The testing circuit 40 also includes a display 58, preferably digital, which is connected to the microprocessor and a group of status lamps (read 60, calibrate 62, display 64 and error 66), which indicate the status of the system's operation.

The ROM 52 includes a program as represented by the