CA1288475C - Instrument and method for testing for fluid constituents - Google Patents
Instrument and method for testing for fluid constituentsInfo
- Publication number
- CA1288475C CA1288475C CA000548210A CA548210A CA1288475C CA 1288475 C CA1288475 C CA 1288475C CA 000548210 A CA000548210 A CA 000548210A CA 548210 A CA548210 A CA 548210A CA 1288475 C CA1288475 C CA 1288475C
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- sample
- constituent
- test
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Abstract
ABSTRACT OF THE DISCLOSURE
There is disclosed herein a nuclear magnetic resonance apparatus for testing body fluids for a constituent, for example, blood for glucose. The apparatus includes a principal magnet, a magnetizable coil, and a circuit for energizing the coil for energizing and realigning molecules and detecting changes resulting from relaxation of said field and analyzing said changes. The apparatus is compact and adapted to receive and test an extremity or vessel carrying a body fluid. The coil is constructed to be positioned adjacent the extremity or vessel to be tested. Circuit means are provided for energizing the coil to energize and realign molecules adjacent said coil, so as to permit molecules adjacent said coil to assume an aligned position and for sensing changes in position when the coil is deenergized, which is indicated by spectra having peaks corresponding to various molecular bonds. The circuit also includes means for comparing the actual value of a peak for a first constituent to A
predetermined value for the peak of said first constituent and determining the actual value of a second constituent from a predetermined relationship between the values of the peaks for the first and second constituents. Specifically, predetermined water and glucose peaks are compared with the measured water and glucose peaks for determining the measured glucose concentration.
There is disclosed herein a nuclear magnetic resonance apparatus for testing body fluids for a constituent, for example, blood for glucose. The apparatus includes a principal magnet, a magnetizable coil, and a circuit for energizing the coil for energizing and realigning molecules and detecting changes resulting from relaxation of said field and analyzing said changes. The apparatus is compact and adapted to receive and test an extremity or vessel carrying a body fluid. The coil is constructed to be positioned adjacent the extremity or vessel to be tested. Circuit means are provided for energizing the coil to energize and realign molecules adjacent said coil, so as to permit molecules adjacent said coil to assume an aligned position and for sensing changes in position when the coil is deenergized, which is indicated by spectra having peaks corresponding to various molecular bonds. The circuit also includes means for comparing the actual value of a peak for a first constituent to A
predetermined value for the peak of said first constituent and determining the actual value of a second constituent from a predetermined relationship between the values of the peaks for the first and second constituents. Specifically, predetermined water and glucose peaks are compared with the measured water and glucose peaks for determining the measured glucose concentration.
Description
3~;'Y5 INSTRUMENT AND METHOD FOR
TESTING FOR FLUID CONSTITUENTS
~ACKGROUND OF THE INVENTIOM - - -This inventlon primarily relates to a method and to an instrument for use in medical diagnosis, and in particu-lar, to detecting and determining glucose concentration in blood.
Diabetes $s a health problem affecting many indivi-duals and its prevalence is increasing. The usual treatment for diabetes is single or multiple insulin in~ections daily. Insulin is available in slowly or rapidly absorbed - . . : , , ~ , .. ... ..
forms, which may be injected alone or in combination. Such insulin in~ections have been effectlve in treating the ~
,, ., _ . . .
disease and in prolonging life.
. ,,. ., . . ., , : . , ~ ~:
Presently in order to determine if insul1n is needed, blood is withdrawn from a patient and is tested for -,, , ., , ~ . , . , .. . , .. . ,, ..,~ ... . ...
glucose concentration by a litmus-type indicator test. ~`lf- -indicated, insulin is taken by the patient.
This type of testing has several problems. For " : , , ,, ~ - - -~ -, example, the testing is periodLc, and thus the administra-tion of insulin is periodic, whioh can result in wide -~ -variations in glucose concentration over time and peaks inthe glucose concentration. Such variations can have physiological effects which may be adve~se to the patient.
, - , . , ,,- - . ~ - . - , , ,, ~ , . ~,; . . . -It has been reco~nized that it is desirable to -, . .
administer insulin periodically on demand and in'response to changes in glucose levels. One such system ~s disclosed in , ~ . ;
Albisser A, "Devices for the Control of Diabetes Melletus", Proc. IEEE 67 No. 9, 1308-1310 (19793 , wherein a servo ., . . ~ - .. . . .. .. .
system is employed which continuously withdraw~ 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, lnsulin 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 ls therefore an ob~ect of this invention to provide a glucose testing dsv~ce which can be used to monitor a patient's glucose level cont$nuously, if desired, so as to provide a more uniform administration of insulin and a more uniform glucose concentration in the bloDd.over time.
It is another ob~ect to provide a glucose moni-toring 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 ob;ect of this invention to provide a noninvasiave diagnosis apparatus for use in determining the concentratlon of various constituents of body fluids, such as glucose and alcohol and drugs.
Nuclear magnetlc resonance (NMR) ls a diagnostic technique which ls used widely for medical imaging and medical d$agnosis. In NMR, the test ob~ect is sub~ected to 4'7~i a first or blasing magnetic field to align previously randomly oriented 1H protons in the nuclei and a second field or burst of energy to lncrease the energy of a selected nuclsus. When the second magnetic field or energy source ls turned off, th~ return to the flrst alignment releases energy which is detected and analyzed. This release is analyzed or processed to form an lmage or spectrum. From the spectrum, the presence of particular molecular bonds can be observed and associated with various molecules or materials from which the concentration of that molecule or material can be determined.
NMR machines are most frequently used for imaging sections of a human body and require large magnets, for example, superconducting ma~nets. The machines are there-fore quite large and expenslve. Furthermore,-the NMR
testing of fluids has requ$red 1nvasive 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 lH 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 contalner and excited so as to yield the lH spectra, which is then analyzed.
Unfortunately, NMR testings are not common nor oonveniently available. The reason is believed to be that the equipment ls 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 34~75 b~dy fluid analysls as more convenient and less expensiYe alternatives are available.
Another disadvantage in preser,t N~R tests is that they are conducted on fluid samples which are withdrawn from the patient by the usual lnvasive techniques.
It is therefore an ob~ect o* this invention to provide a more convenient NMR instrument for use in analyzing body fluld samples.
It is a further object of this $nventlon to provide an NMR instrument for use ln analyzing body fluid for .
glucose.
It is yet another ob~ect 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 ob~ect to provide an NMR
instrument for use by a diabetic in noninvasively analyzing his blood serum for glucose concentration.
It is a still further ob~ect of the invention to ~,. . . . .
provida an NMR method and apparatus to test for other substances, for example, alcohol and drugs.
These and other cb~ects of this invention will become apparent from the followin~ disclosure and appended claims.
SUMMARY OF THE INVENTION - -. . : .
This lnvention provides a method and a portable NMR
instrument for use ~n noninvasively analyzing body fluids for the concentration of various constituents. Specifi-cally, a diabetic can use the instrument to noninvasively and substantially instantaneously analyze his blood for ~ ?~3847S
glucose, thereby eliminating the need to invasively obtain a blood sample which is then tested. Using the device dis-closed herein, a patient can periodically, frequently if necessary, and painlessly analyze hls blood for glucose concentration. This device may also be u~eful 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 pati~nt, such as a finger, and exposing the extremity to a first or biasin~ magnetic field and a second field or ener~y source. Sensors are provided for sensing the rates of relaxation or energy release so 85 to develop the spectrum. Analytical means are coupled to the sensors for recelving and analyzing the signals emitted, discriminating between various peaks, comparing the amplitude or hei~ht of various peaks, such as water and glucose, and normal~zing 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 th~ biasing magnet is physically much smaller than the magnet~ 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 sens~ng the energy released therefrom. A single coil or multiple coils can be used. Yet another important element of this invention is the electron~c clrcuit 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 detectlng and analyzing the spectra received from the sample when the field is relaxed. Operation o~ the microprocessor is disclosed herein.
Other specific features of the instrumen~ are disclosed herelnafter.
BRIEF DESCRIPTION OF THE DRAWINGS
FIGUR~ 1 is a vertical cross-sectional ~iew of an instrument according to this invention;
FIGURE 2 is a vert~cal cross-sectional view taken along line 2-2 of Fig. 1 and also showlng a housing and other components;
FIGURE 3 ~s a block-type schematic diagram for the circuitry to operate the instrument FIGURES 4a to 4c are flow charts showing the operation of the instrument;
FIGURES 5a and 5b are representative NMR spsctrums showing the water, glucose peaks and alcohol used for analysis;
FIGURE 6 is a schematic diagram showing a three-coil system for use in the instrument;
FIGURE 7 is a schematic diagram showing the electrical connections for the three-coil system of Fig. 6;
FIGURE 8 shows an NMR probe for implantation in a body;
~ IGURE 9 i5 a schematic block-type diagram of the electrical circuit for use with the implantable probe of Fig. 8;
FIGURE lO shows a human arm having a distended vein for NMR test$ng;
FIGURE ll is a fragmentary and sectional view of a magnetic probe for use in NMR analysis using a surface blood vessel; - -, FIGURE 12 is a schematic representa~ion of an alternative circuit arrangement for use with separate energizing and receiving coils; ~-~
FIGURE 13 is a schematic representation of the coil and magnet relationships which may be used ~n an arrangement .~-, of the type shown in Fig. 12; -- - ~~
-- FIGURE 14 1s a-schematic reprqsentation of a multl- --_."-,~
coil arrangement;
FIGURE 15 is a top view of the elements of Fig. 14;
and -FIGURE 16 is a side view of an alternativ~ C-shap~ed - -a magnet which ~ay replace the magnetic ~tructure of Figs. 1 --and ~
.
DESCRIPTION OF THE PREFERRED EMBODIMENT
Referring now to Figs. 1-3, a first embodiment of the test instrument is shown. Other em~odiments and c~
features will be discussed ~fter consideration of principal - -features of th~s invention by way o~ the first embodiment. --The test lnstrument 10 is ~hown as including 3 box- -^
shaped assembly which defines a finger-receiving recess 12 _.
therein. ~he assembly lncludes 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- _ ~ ~8475 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 p~ir 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 alignins magnetic field. It is to be noted that the poles of the respective magnets are aligned 50 that the field is additive and provide construc-tive lnterference, and the pole pieces or shoes shape themagnetic fleld in the finger-receiving recess 12. ~his alignment is shown by the "X" designation, wh~ch indicates that the magnetic field from the magnets passes through the secess 12 in the same direction, in Fig. 2, into the paper.
A sample holder or container:34 for a standard sample starting apparatus 30 is shown positioned in the recess.
The apparatus includes a compression blasing spring 32 pressing at one end against the back wall 24 and against 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 holdRr 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 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 hou~ing ad~acent one of the permanent magnets 26 and 28. The coil _ g _ 47~
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 coll and can thus be controlled.
The surface coil 38 may be a slngle coil for both energlzation and sensing. The co~1 can also be an assembly in which there are multiple coils, each of which are for energizatlon and 6ensing. 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 F~g.; 3 ) 80 that unauthorized vpening or removal of the cover will disable the electronics ,-described herelnafter, thereby prevent~ng unauthorized '--tampering or repair of the device which could destroy ' ' calibration and result in improper usage. - -' Physically the test is run by ~he patient inserting his finger into the instrumen~ and pushing the sample holder toward the back wall 24 and into engagement with the start switch 36 to start the analysis as describsd herelnafter.
It will be noted that the finger is positioned so that the fingernail i8 located adjacent the surface coil.
Thl~ positioning is chosen as the fingerna~l i5 dead t~ssue but has a bed of active blood vlessels pos~tioned ~ust below s the nail. These vessels are believ~d to provide an accurate testing site. In many other test sites, llve body tissue or bone must be penetrated in order to test blood in a vessel, which means that the tissue or bone will'émlt s~gnals due to testlng 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 ls believed that other body extremities can be tested, for example, the ear of either a human or other'~nimals. ' ''''' - ' The testing circuit 40'includes a battery power supply 42. In'a permanent installation, such as a doctor's-office, hosp~tal, 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 microproces~or 44. The microprocessor activates an RF generator and cyciically-operated gate 46, , which excites the surface coil~38 (or coil assembly) for applying the second fleld, raising the energy state and -realigning the nuclei.
At the appropriate time and under control of the' --microprocessor, the RF generator is deactivated, thereby ' permittin~ the nuclei (dipolesj to relax or return to the first alignment. The surface coil then detects the energy '' ' --released duriny relaxation and realignment. Those sisnals are received by receiver/gate 48, converted from analog signals to digital signals by the ~/D converter S0 and fed to the microprocessor 44. A rea~ only memory (ROM) 52 is provid~d for storing the program for use with the micro-~J
~ ~f~47~rj processor in calibrating the machine and analyzing and displaying test results. If separate coils are used, then the circuit ls chang0d so that the RF generator is connected to the energizing coil and the receiver is connscted to the sPnsing 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 ~s 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 ~ncludes a display 58, preferably digital, which is connectsd to the microprocessor and a group of status lamps (read 60, calibrate 62, display 64 and error 66), which indicate the status of the system1s operation.
The ROM 52 includes a program as represented by the flow chart of Figs. 4a-4c, whereby operation of the tester is controlled. In general, the operation of the tester is as follows:
1. A finger is inserted to depress the sample holder and activate the-start switch.
TESTING FOR FLUID CONSTITUENTS
~ACKGROUND OF THE INVENTIOM - - -This inventlon primarily relates to a method and to an instrument for use in medical diagnosis, and in particu-lar, to detecting and determining glucose concentration in blood.
Diabetes $s a health problem affecting many indivi-duals and its prevalence is increasing. The usual treatment for diabetes is single or multiple insulin in~ections daily. Insulin is available in slowly or rapidly absorbed - . . : , , ~ , .. ... ..
forms, which may be injected alone or in combination. Such insulin in~ections have been effectlve in treating the ~
,, ., _ . . .
disease and in prolonging life.
. ,,. ., . . ., , : . , ~ ~:
Presently in order to determine if insul1n is needed, blood is withdrawn from a patient and is tested for -,, , ., , ~ . , . , .. . , .. . ,, ..,~ ... . ...
glucose concentration by a litmus-type indicator test. ~`lf- -indicated, insulin is taken by the patient.
This type of testing has several problems. For " : , , ,, ~ - - -~ -, example, the testing is periodLc, and thus the administra-tion of insulin is periodic, whioh can result in wide -~ -variations in glucose concentration over time and peaks inthe glucose concentration. Such variations can have physiological effects which may be adve~se to the patient.
, - , . , ,,- - . ~ - . - , , ,, ~ , . ~,; . . . -It has been reco~nized that it is desirable to -, . .
administer insulin periodically on demand and in'response to changes in glucose levels. One such system ~s disclosed in , ~ . ;
Albisser A, "Devices for the Control of Diabetes Melletus", Proc. IEEE 67 No. 9, 1308-1310 (19793 , wherein a servo ., . . ~ - .. . . .. .. .
system is employed which continuously withdraw~ 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, lnsulin 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 ls therefore an ob~ect of this invention to provide a glucose testing dsv~ce which can be used to monitor a patient's glucose level cont$nuously, if desired, so as to provide a more uniform administration of insulin and a more uniform glucose concentration in the bloDd.over time.
It is another ob~ect to provide a glucose moni-toring 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 ob;ect of this invention to provide a noninvasiave diagnosis apparatus for use in determining the concentratlon of various constituents of body fluids, such as glucose and alcohol and drugs.
Nuclear magnetlc resonance (NMR) ls a diagnostic technique which ls used widely for medical imaging and medical d$agnosis. In NMR, the test ob~ect is sub~ected to 4'7~i a first or blasing magnetic field to align previously randomly oriented 1H protons in the nuclei and a second field or burst of energy to lncrease the energy of a selected nuclsus. When the second magnetic field or energy source ls turned off, th~ return to the flrst alignment releases energy which is detected and analyzed. This release is analyzed or processed to form an lmage or spectrum. From the spectrum, the presence of particular molecular bonds can be observed and associated with various molecules or materials from which the concentration of that molecule or material can be determined.
NMR machines are most frequently used for imaging sections of a human body and require large magnets, for example, superconducting ma~nets. The machines are there-fore quite large and expenslve. Furthermore,-the NMR
testing of fluids has requ$red 1nvasive 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 lH 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 contalner and excited so as to yield the lH spectra, which is then analyzed.
Unfortunately, NMR testings are not common nor oonveniently available. The reason is believed to be that the equipment ls 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 34~75 b~dy fluid analysls as more convenient and less expensiYe alternatives are available.
Another disadvantage in preser,t N~R tests is that they are conducted on fluid samples which are withdrawn from the patient by the usual lnvasive techniques.
It is therefore an ob~ect o* this invention to provide a more convenient NMR instrument for use in analyzing body fluld samples.
It is a further object of this $nventlon to provide an NMR instrument for use ln analyzing body fluid for .
glucose.
It is yet another ob~ect 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 ob~ect to provide an NMR
instrument for use by a diabetic in noninvasively analyzing his blood serum for glucose concentration.
It is a still further ob~ect of the invention to ~,. . . . .
provida an NMR method and apparatus to test for other substances, for example, alcohol and drugs.
These and other cb~ects of this invention will become apparent from the followin~ disclosure and appended claims.
SUMMARY OF THE INVENTION - -. . : .
This lnvention provides a method and a portable NMR
instrument for use ~n noninvasively analyzing body fluids for the concentration of various constituents. Specifi-cally, a diabetic can use the instrument to noninvasively and substantially instantaneously analyze his blood for ~ ?~3847S
glucose, thereby eliminating the need to invasively obtain a blood sample which is then tested. Using the device dis-closed herein, a patient can periodically, frequently if necessary, and painlessly analyze hls blood for glucose concentration. This device may also be u~eful 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 pati~nt, such as a finger, and exposing the extremity to a first or biasin~ magnetic field and a second field or ener~y source. Sensors are provided for sensing the rates of relaxation or energy release so 85 to develop the spectrum. Analytical means are coupled to the sensors for recelving and analyzing the signals emitted, discriminating between various peaks, comparing the amplitude or hei~ht of various peaks, such as water and glucose, and normal~zing 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 th~ biasing magnet is physically much smaller than the magnet~ 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 sens~ng the energy released therefrom. A single coil or multiple coils can be used. Yet another important element of this invention is the electron~c clrcuit 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 detectlng and analyzing the spectra received from the sample when the field is relaxed. Operation o~ the microprocessor is disclosed herein.
Other specific features of the instrumen~ are disclosed herelnafter.
BRIEF DESCRIPTION OF THE DRAWINGS
FIGUR~ 1 is a vertical cross-sectional ~iew of an instrument according to this invention;
FIGURE 2 is a vert~cal cross-sectional view taken along line 2-2 of Fig. 1 and also showlng a housing and other components;
FIGURE 3 ~s a block-type schematic diagram for the circuitry to operate the instrument FIGURES 4a to 4c are flow charts showing the operation of the instrument;
FIGURES 5a and 5b are representative NMR spsctrums showing the water, glucose peaks and alcohol used for analysis;
FIGURE 6 is a schematic diagram showing a three-coil system for use in the instrument;
FIGURE 7 is a schematic diagram showing the electrical connections for the three-coil system of Fig. 6;
FIGURE 8 shows an NMR probe for implantation in a body;
~ IGURE 9 i5 a schematic block-type diagram of the electrical circuit for use with the implantable probe of Fig. 8;
FIGURE lO shows a human arm having a distended vein for NMR test$ng;
FIGURE ll is a fragmentary and sectional view of a magnetic probe for use in NMR analysis using a surface blood vessel; - -, FIGURE 12 is a schematic representa~ion of an alternative circuit arrangement for use with separate energizing and receiving coils; ~-~
FIGURE 13 is a schematic representation of the coil and magnet relationships which may be used ~n an arrangement .~-, of the type shown in Fig. 12; -- - ~~
-- FIGURE 14 1s a-schematic reprqsentation of a multl- --_."-,~
coil arrangement;
FIGURE 15 is a top view of the elements of Fig. 14;
and -FIGURE 16 is a side view of an alternativ~ C-shap~ed - -a magnet which ~ay replace the magnetic ~tructure of Figs. 1 --and ~
.
DESCRIPTION OF THE PREFERRED EMBODIMENT
Referring now to Figs. 1-3, a first embodiment of the test instrument is shown. Other em~odiments and c~
features will be discussed ~fter consideration of principal - -features of th~s invention by way o~ the first embodiment. --The test lnstrument 10 is ~hown as including 3 box- -^
shaped assembly which defines a finger-receiving recess 12 _.
therein. ~he assembly lncludes 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- _ ~ ~8475 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 p~ir 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 alignins magnetic field. It is to be noted that the poles of the respective magnets are aligned 50 that the field is additive and provide construc-tive lnterference, and the pole pieces or shoes shape themagnetic fleld in the finger-receiving recess 12. ~his alignment is shown by the "X" designation, wh~ch indicates that the magnetic field from the magnets passes through the secess 12 in the same direction, in Fig. 2, into the paper.
A sample holder or container:34 for a standard sample starting apparatus 30 is shown positioned in the recess.
The apparatus includes a compression blasing spring 32 pressing at one end against the back wall 24 and against 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 holdRr 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 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 hou~ing ad~acent one of the permanent magnets 26 and 28. The coil _ g _ 47~
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 coll and can thus be controlled.
The surface coil 38 may be a slngle coil for both energlzation and sensing. The co~1 can also be an assembly in which there are multiple coils, each of which are for energizatlon and 6ensing. 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 F~g.; 3 ) 80 that unauthorized vpening or removal of the cover will disable the electronics ,-described herelnafter, thereby prevent~ng unauthorized '--tampering or repair of the device which could destroy ' ' calibration and result in improper usage. - -' Physically the test is run by ~he patient inserting his finger into the instrumen~ and pushing the sample holder toward the back wall 24 and into engagement with the start switch 36 to start the analysis as describsd herelnafter.
It will be noted that the finger is positioned so that the fingernail i8 located adjacent the surface coil.
Thl~ positioning is chosen as the fingerna~l i5 dead t~ssue but has a bed of active blood vlessels pos~tioned ~ust below s the nail. These vessels are believ~d to provide an accurate testing site. In many other test sites, llve body tissue or bone must be penetrated in order to test blood in a vessel, which means that the tissue or bone will'émlt s~gnals due to testlng 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 ls believed that other body extremities can be tested, for example, the ear of either a human or other'~nimals. ' ''''' - ' The testing circuit 40'includes a battery power supply 42. In'a permanent installation, such as a doctor's-office, hosp~tal, 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 microproces~or 44. The microprocessor activates an RF generator and cyciically-operated gate 46, , which excites the surface coil~38 (or coil assembly) for applying the second fleld, raising the energy state and -realigning the nuclei.
At the appropriate time and under control of the' --microprocessor, the RF generator is deactivated, thereby ' permittin~ the nuclei (dipolesj to relax or return to the first alignment. The surface coil then detects the energy '' ' --released duriny relaxation and realignment. Those sisnals are received by receiver/gate 48, converted from analog signals to digital signals by the ~/D converter S0 and fed to the microprocessor 44. A rea~ only memory (ROM) 52 is provid~d for storing the program for use with the micro-~J
~ ~f~47~rj processor in calibrating the machine and analyzing and displaying test results. If separate coils are used, then the circuit ls chang0d so that the RF generator is connected to the energizing coil and the receiver is connscted to the sPnsing 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 ~s 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 ~ncludes a display 58, preferably digital, which is connectsd to the microprocessor and a group of status lamps (read 60, calibrate 62, display 64 and error 66), which indicate the status of the system1s operation.
The ROM 52 includes a program as represented by the flow chart of Figs. 4a-4c, whereby operation of the tester is controlled. In general, the operation of the tester is as follows:
1. A finger is inserted to depress the sample holder and activate the-start switch.
2. The ~inger ~s tested.
9 ~475 3. The finger test results are stored in the RAM
45.
9 ~475 3. The finger test results are stored in the RAM
45.
4. The finger is released and the standard sample moved to the test position.
5. The standard sample is tested.
6. The standard sample test results are stored in the RAM 45.
7. The standard sample test results are compared with predetermined calibration data previously entered in memory to determine if the standard sample data reading is still within preset and allowable tolerances.
8. Then the finger test results are compared with the sample standard test result data and the finger data is normalized and proportioned to determine glucose concentration.
Referring now to the flow diagrsm, Figs. 4a through 4c, tha various phases of the microprocessor and ROM are shown. These phases can considered as follows:
1. Patient reading cycle.
2. - Standard sample reading cycle.
3. Operational system check.
4. Calculation of normalized patient data and stan~ard sample for equal ~2 peak.
5. ~alculation of glucose level.
Within each one of these broad steps are a series of smaller steps.
Reerring first to Fig. 4a, the flow chart begins with depression of the starting switch 36, init~ation of the ~J
4~i program and activation of the read light 60. Next, a one second homodecoupling pulse (or a plur~lity of pulses~ to saturate the water peak is activated. A five microsecond sample pulse is taken, and the free induction deeay output from the A/D converter is noted. Next, th~ data points are stored in the memory 45 and the process is repeated (i.e,, looped) perhaps one hundred tlmes. In the right-hand column, there is shown a serles of diagrams representing the one second homodecoupling pulse, the five microsecond sampling pulse, the decay, and a Fourier transformation of the decay data points. The amplitude (Amp.) of the response is recorded along the Y-axis. After the samplings, the read lamp ~s deactivated, the accumulated responses are -- -multiplied by an exponent1al decay to provlde line broadeniny, a Fourier transformation is run, and a ~pectrum is stored as the chemical shifts versus the peak height as patient data.
Turning now to Fig. 4b, the standard sample reading cycle is next activated. Here the calibrate light is turned on, and the start switch is released. Once the switch is released, a one second homodecoupling puls0 (or plurality of pulses) is provided, a five mlcrosecond ~ampllng pulse is taken, the free lnduction decay ls recorded, and the data points are stored ln the memory 45. The system is then repeated again,-perhaps--one hundred times.~`As `i`n ~e ; `
patient reading cycle, the accumulated responses-are- --multiplied by an exponential decay to improve lina ~ ~-broadening, Fourler transforms are run and the spectrum of chemical sh~fts versus peak helght is stored as-sample~data.
The standard sample initially contains predeter-mined amounts of the constituent material or materials being tested for and acts as a reference level. In order to assure th~t there has been no significant change in these value(s), the next step is an operational check where the spectrum of chemical shifts versus peak height data for the standard sample is recalled and compared to the standard data previously taken within allowable tolerances. If the error is not within an ac~aptable tolerance, the~- error-display lamp 66 is lit and the operator notified. If thedata is with~n an allowable error, the system proceeds to the next step. lt is noted that on the right-hand side of Fig. 4c that a comparison is shown between the standard sample data and standard sample ~pectrum showing the allow-able shifts, peak height and frequency with amplitude plotted along the Y-axis. ~
The next step is to normalize the patient data and standard sample data for e~ual water heights. Here the patient data 18 recalled and the s~andard sample data is recalled. Next, the pati~nt data water peak height is scal~d to match the standard sample data water peak height.
The system then executes the next step whlch is to calculate the glucose 1PVe1. To do th~s a ratio is obtained of the patient data glucose peak height and ths standard sample data peak height. This ratio is then mult$plied by the known standard sample glucose to water ratio to obtain the patient reading and multiplied by a concentration factor (K) from the standard samplP and expressed in milligrams per deciliter or some other convenient unit. Then the patient glucose level is displayed in relation to plasma level.
Normal 91ucose concentration is ninety milligrams per deciliter.
This relationship is derived as follows:
1. The standard sample is prepared having a known glucose concentration expressed, ~or example, in milligram of glucose/deciliter of water (mg/dl) and is referred to as K.
2. A patient is tested and the water and glucose peak heights are obtained.
3. The standard sample ~s then tested for water and glucose peak heights.
4. The patient's water peak height is normalized by determining the ratio of water standard peak height/water patient peak height. ~his ratlo can be referred to as gain.
5. The patient's glucose peak height is normalized by multiply1ng the patient ~lucose peak height by the gainO The result is the normallzed patient glucose level. Expressed algebraically:
Glucose = (Water ~tandard) x glucsse pati~nt normalized (Water patient ) 6. In order to obtain the actual p~tient glucose concentration, expressed in units such as mg/dl, the normalized glucose now is divided by the glucose standard and the resulting ratio ls multiplied by the concentration factor K. In other words:
Patient glucose ~ Glucose normalized x K
concentrat1on Glucose standard ;,' ~ ~3847~
7. The entire expression which combines the 8tep8 of numbers 1-5 above can be stated as:
Patient glucose - ( m~ ) - K ( m~ ) -concentration ( dl ) ( dl ) -- -... . . . . .
(Glucose patient) (Water ~tandard) x ( peak height ) x ( peak height (Glucose standard) (Water patient ~
( peak height ) ~-peak height ) - - -In Fig. 5a, a 1~ typical blood spectrum is shown with the water (H20) and glucose peaks clearly shown. It 1s the ratio-of the peak heights as determined from the cali-bration and test samples that permit determination of the test sample glucose concentration. Fig. 5a shows the work~
of Jay Block, "Analysis of Serum by High Yield NMR", Clin.
Chem. 28/9, 1983, (1982) taksn from normal blood serum. ---- -Sample volume is 0.4 ml serum to which ~as been added D.l ml - - ---of 2H20 for field lock. In addltion, 10 mmol/l of TSP was - ~ _ added to the 2H20 to serve as a reference to assign chemical --shifts and peak area. The work was done on a WM 500 Bruker spectrometer. Samples were maintained at 30C and a 1 second homodecoupling pulse was applled before the S
mill~second sample pulse (45~ notation angle) to saturate and reduce the H20 peak. A total of 16k data points was ~eoorded in ~n ac~uisitlon time o~ 1.5 ssconds with B0 ~uch transients averaged for each spectrum (2 min per spectrum).
~ven with the water peak suppressed, ~t is still the most prominent feature, however, the glucose peak which is four orders of magnitude lower i8 still easily identified. The glucose concentration is in the normal range of 90 mgJdl as m~asured by the conventional glucose ox$dase procedure.
~, 347~
Lactate was also detectable. It is also interesting to look at the glucose peak at 5.25 in the otherwise peak free region.
Fig. 5b is an enlarged portion of the 1H blood spectrum of Fig. 5a, showing the ethanol and water peaks, as also reported by Bock and showing the spectrum of serum obtained 30 minutes after ingesting 30 ml of vodka. The ethanol concentration measured by routine gaschromatographic method was only 30 mg/l, while the methyl resonance of ethanol at 1.20 ppm was detected with better -than 40:1 signal to noise ratio. The methylene resonance is buried in the glucose region. In addition, a large peak appears at 1.93 ppm, the position of acetate, presumably derived from the oxidation of ingested ethanol. In serum from intoxicated patients, the ethanol resonance had a much greater intensity and dominated the spectra.
Another smbodiment 70 of this lnvention is shown in Fig. 6. In this embodimentj three coil pairs 72, 74 and 76, a~e provided, whlch lie ln the same plane and are equally spaced, that is at egually spaced 60 intervals. The coils are arranged to provide constructive interference at the `
center of the coils where a sample ~such as a flnger or test tube) ls to be located. These coil pa$rs act as the energization ~r realignment coll ~nd as the sensor, in a 4~5 manner similar to the surface coil described hereinbefore.
This arrangement ls believed to provide better signal discrimination by ~ncreasing the signal-to-noise ratio. The coils are mounted in a housing similar to that shown in Figs. 1 and 2 and are controlled by a circuit and in the manner similar to that described in connection with Fig.
3. Physically, the standard and sample is inssrted into one of the coils, such as the test tu~e 78 into coil 72. The portion to be tested is located at the center of the coils as shown.
The test sample is then tested as described above with coils first acting as the energization or realignment magnets and then as sensors or receivers. In other regards, such as s$gnal pr~cess$ng and concentration analysis, this system operates in the same manner as above.
In those cases in which it may be desirable to implant a portion of the instrument, reference is made to Figs. e and 9.
A third embodiment 80 is shown in Fig. 8, which is constructed to surround a blood vessel which is internal of or within a body, for example, a vein or artery in the body.
The test device includes the principal magnet 82, which in this case is C-shaped and a palr o* RF coils 84.
The vein or artery 86 is positioned between the coil pa~rs and the poles of the magnet. By so doing, blood in the vein or artery is subjected to the first magnetic field, and the energization or realignment field and relaxatlon is ensed by coils 84.
In a fourth embodiment, the test instrument 90 ls constructed for surgical implantation as shown in Fig. 9.
847~
Such a device has two component parts: one part is the internal or implanted portion 92 and the oth~r part is th~
external or power supply and sensing part 94. The two parts are electronically coupled by transformer-like members as described herein.
In the fourth embodiment 90 an external AC power supply 96 is induct~vely coupled to an internal pow~r supply 98. The internal power supply 98 powers the NMR unit 100, which is conneeted to probe snd magnet unit 102. Signals from the probe and magnet are received by the receiver 104, which is inductively coupled to the microprocessor 106, through the coil element 108. The microprocessor then provides an output to the digital display 110 of the glucose concentration.
The magnet and probe assembly 102 is in the same form as that in Fig. 8 and is positioned to surround an artery. The signal processing is performed by the micro-processor in the same manner as with the other embodiments, particularly Fig. 3.
In a fifth embodiment, a surface blood vessel, usually a vein, is distended and used to analyzs for glucose concentration. Such an embodiment is shown in Figs. 10 and lI, where a patient's arm 120 is shown surrounded by a pressurizable cuff 122 for causing a vein 124 to protrude or distend from the skin surface. In that situation, the NMR
unit is fitted on either side of the protruding vsssel at the surface of the arm. In this embodiment a C-shaped permanent magnet 126 is arranged so that its north and south poles (~ & S) are on opposite sides ~f the vessel. A
surface coil 128, like that ln Figs. 1-2, is employed for f .
i,~ j, f347~
en0rgization and realignment and sensing. Testing circuitry of the type shown in Fig. 3 is also employed in the embodi-ment of Figs. lO snd 11.
A principal advantage of the test instrument shown herein is that the device is smaller than the large ~R test instruments now used at hospitals, etc. The reason is that the present instruments include a large principal magnet for surrounding the body of a patient. Here, since the tested portion is a finger or other extremity, the principal magnet may be smaller 50 that the instrument may be mounted on a table top, carried in a brief case, or be even smaller. In order to achieve such a device, the m~gnet must be small in size, be of a comparatively light we~ght, such as one pound, - -~
ana still exhibit an adequate field strength. ~deq~ate - --strengths ~hould be on the order of at least five to s1x ~:
kilogauss. One particularly suitable material containing .',,7 Neodynium is manufactured by General Motors Corporation.
Fig. 12 shows the generator and gate 46 and the receiver 46 and gate 48, respectively, connected to separate transmit and recelve coils 38', 38". - ~--~
Fiy. 13 shows an embodiment of the coils 38' and- ---~
33" along with the field directions, including the bias ~ ~~ r' field Ho, at 9O with respect to one another.
Figs. 14 and 15 illustrate the u~e of a plurality of surface coils 38''', which are connected for addltive fields, as a single transmitJreceive arrangement. --Fig. 16 shows an alternate bias magnet, similar to that shown in Fig. 11. The magnet 138 comprises a pair of spaced pole pieces 132, 134, which define a gap for ---receiving; in this example, a finger.
Although the invention has been described with respect to preferred embodiments, it is not to be so limited, as changes and modiflcations can be made which are within the full intended scope of the invention as defined by the appended claims.
: - - - - --
Referring now to the flow diagrsm, Figs. 4a through 4c, tha various phases of the microprocessor and ROM are shown. These phases can considered as follows:
1. Patient reading cycle.
2. - Standard sample reading cycle.
3. Operational system check.
4. Calculation of normalized patient data and stan~ard sample for equal ~2 peak.
5. ~alculation of glucose level.
Within each one of these broad steps are a series of smaller steps.
Reerring first to Fig. 4a, the flow chart begins with depression of the starting switch 36, init~ation of the ~J
4~i program and activation of the read light 60. Next, a one second homodecoupling pulse (or a plur~lity of pulses~ to saturate the water peak is activated. A five microsecond sample pulse is taken, and the free induction deeay output from the A/D converter is noted. Next, th~ data points are stored in the memory 45 and the process is repeated (i.e,, looped) perhaps one hundred tlmes. In the right-hand column, there is shown a serles of diagrams representing the one second homodecoupling pulse, the five microsecond sampling pulse, the decay, and a Fourier transformation of the decay data points. The amplitude (Amp.) of the response is recorded along the Y-axis. After the samplings, the read lamp ~s deactivated, the accumulated responses are -- -multiplied by an exponent1al decay to provlde line broadeniny, a Fourier transformation is run, and a ~pectrum is stored as the chemical shifts versus the peak height as patient data.
Turning now to Fig. 4b, the standard sample reading cycle is next activated. Here the calibrate light is turned on, and the start switch is released. Once the switch is released, a one second homodecoupling puls0 (or plurality of pulses) is provided, a five mlcrosecond ~ampllng pulse is taken, the free lnduction decay ls recorded, and the data points are stored ln the memory 45. The system is then repeated again,-perhaps--one hundred times.~`As `i`n ~e ; `
patient reading cycle, the accumulated responses-are- --multiplied by an exponential decay to improve lina ~ ~-broadening, Fourler transforms are run and the spectrum of chemical sh~fts versus peak helght is stored as-sample~data.
The standard sample initially contains predeter-mined amounts of the constituent material or materials being tested for and acts as a reference level. In order to assure th~t there has been no significant change in these value(s), the next step is an operational check where the spectrum of chemical shifts versus peak height data for the standard sample is recalled and compared to the standard data previously taken within allowable tolerances. If the error is not within an ac~aptable tolerance, the~- error-display lamp 66 is lit and the operator notified. If thedata is with~n an allowable error, the system proceeds to the next step. lt is noted that on the right-hand side of Fig. 4c that a comparison is shown between the standard sample data and standard sample ~pectrum showing the allow-able shifts, peak height and frequency with amplitude plotted along the Y-axis. ~
The next step is to normalize the patient data and standard sample data for e~ual water heights. Here the patient data 18 recalled and the s~andard sample data is recalled. Next, the pati~nt data water peak height is scal~d to match the standard sample data water peak height.
The system then executes the next step whlch is to calculate the glucose 1PVe1. To do th~s a ratio is obtained of the patient data glucose peak height and ths standard sample data peak height. This ratio is then mult$plied by the known standard sample glucose to water ratio to obtain the patient reading and multiplied by a concentration factor (K) from the standard samplP and expressed in milligrams per deciliter or some other convenient unit. Then the patient glucose level is displayed in relation to plasma level.
Normal 91ucose concentration is ninety milligrams per deciliter.
This relationship is derived as follows:
1. The standard sample is prepared having a known glucose concentration expressed, ~or example, in milligram of glucose/deciliter of water (mg/dl) and is referred to as K.
2. A patient is tested and the water and glucose peak heights are obtained.
3. The standard sample ~s then tested for water and glucose peak heights.
4. The patient's water peak height is normalized by determining the ratio of water standard peak height/water patient peak height. ~his ratlo can be referred to as gain.
5. The patient's glucose peak height is normalized by multiply1ng the patient ~lucose peak height by the gainO The result is the normallzed patient glucose level. Expressed algebraically:
Glucose = (Water ~tandard) x glucsse pati~nt normalized (Water patient ) 6. In order to obtain the actual p~tient glucose concentration, expressed in units such as mg/dl, the normalized glucose now is divided by the glucose standard and the resulting ratio ls multiplied by the concentration factor K. In other words:
Patient glucose ~ Glucose normalized x K
concentrat1on Glucose standard ;,' ~ ~3847~
7. The entire expression which combines the 8tep8 of numbers 1-5 above can be stated as:
Patient glucose - ( m~ ) - K ( m~ ) -concentration ( dl ) ( dl ) -- -... . . . . .
(Glucose patient) (Water ~tandard) x ( peak height ) x ( peak height (Glucose standard) (Water patient ~
( peak height ) ~-peak height ) - - -In Fig. 5a, a 1~ typical blood spectrum is shown with the water (H20) and glucose peaks clearly shown. It 1s the ratio-of the peak heights as determined from the cali-bration and test samples that permit determination of the test sample glucose concentration. Fig. 5a shows the work~
of Jay Block, "Analysis of Serum by High Yield NMR", Clin.
Chem. 28/9, 1983, (1982) taksn from normal blood serum. ---- -Sample volume is 0.4 ml serum to which ~as been added D.l ml - - ---of 2H20 for field lock. In addltion, 10 mmol/l of TSP was - ~ _ added to the 2H20 to serve as a reference to assign chemical --shifts and peak area. The work was done on a WM 500 Bruker spectrometer. Samples were maintained at 30C and a 1 second homodecoupling pulse was applled before the S
mill~second sample pulse (45~ notation angle) to saturate and reduce the H20 peak. A total of 16k data points was ~eoorded in ~n ac~uisitlon time o~ 1.5 ssconds with B0 ~uch transients averaged for each spectrum (2 min per spectrum).
~ven with the water peak suppressed, ~t is still the most prominent feature, however, the glucose peak which is four orders of magnitude lower i8 still easily identified. The glucose concentration is in the normal range of 90 mgJdl as m~asured by the conventional glucose ox$dase procedure.
~, 347~
Lactate was also detectable. It is also interesting to look at the glucose peak at 5.25 in the otherwise peak free region.
Fig. 5b is an enlarged portion of the 1H blood spectrum of Fig. 5a, showing the ethanol and water peaks, as also reported by Bock and showing the spectrum of serum obtained 30 minutes after ingesting 30 ml of vodka. The ethanol concentration measured by routine gaschromatographic method was only 30 mg/l, while the methyl resonance of ethanol at 1.20 ppm was detected with better -than 40:1 signal to noise ratio. The methylene resonance is buried in the glucose region. In addition, a large peak appears at 1.93 ppm, the position of acetate, presumably derived from the oxidation of ingested ethanol. In serum from intoxicated patients, the ethanol resonance had a much greater intensity and dominated the spectra.
Another smbodiment 70 of this lnvention is shown in Fig. 6. In this embodimentj three coil pairs 72, 74 and 76, a~e provided, whlch lie ln the same plane and are equally spaced, that is at egually spaced 60 intervals. The coils are arranged to provide constructive interference at the `
center of the coils where a sample ~such as a flnger or test tube) ls to be located. These coil pa$rs act as the energization ~r realignment coll ~nd as the sensor, in a 4~5 manner similar to the surface coil described hereinbefore.
This arrangement ls believed to provide better signal discrimination by ~ncreasing the signal-to-noise ratio. The coils are mounted in a housing similar to that shown in Figs. 1 and 2 and are controlled by a circuit and in the manner similar to that described in connection with Fig.
3. Physically, the standard and sample is inssrted into one of the coils, such as the test tu~e 78 into coil 72. The portion to be tested is located at the center of the coils as shown.
The test sample is then tested as described above with coils first acting as the energization or realignment magnets and then as sensors or receivers. In other regards, such as s$gnal pr~cess$ng and concentration analysis, this system operates in the same manner as above.
In those cases in which it may be desirable to implant a portion of the instrument, reference is made to Figs. e and 9.
A third embodiment 80 is shown in Fig. 8, which is constructed to surround a blood vessel which is internal of or within a body, for example, a vein or artery in the body.
The test device includes the principal magnet 82, which in this case is C-shaped and a palr o* RF coils 84.
The vein or artery 86 is positioned between the coil pa~rs and the poles of the magnet. By so doing, blood in the vein or artery is subjected to the first magnetic field, and the energization or realignment field and relaxatlon is ensed by coils 84.
In a fourth embodiment, the test instrument 90 ls constructed for surgical implantation as shown in Fig. 9.
847~
Such a device has two component parts: one part is the internal or implanted portion 92 and the oth~r part is th~
external or power supply and sensing part 94. The two parts are electronically coupled by transformer-like members as described herein.
In the fourth embodiment 90 an external AC power supply 96 is induct~vely coupled to an internal pow~r supply 98. The internal power supply 98 powers the NMR unit 100, which is conneeted to probe snd magnet unit 102. Signals from the probe and magnet are received by the receiver 104, which is inductively coupled to the microprocessor 106, through the coil element 108. The microprocessor then provides an output to the digital display 110 of the glucose concentration.
The magnet and probe assembly 102 is in the same form as that in Fig. 8 and is positioned to surround an artery. The signal processing is performed by the micro-processor in the same manner as with the other embodiments, particularly Fig. 3.
In a fifth embodiment, a surface blood vessel, usually a vein, is distended and used to analyzs for glucose concentration. Such an embodiment is shown in Figs. 10 and lI, where a patient's arm 120 is shown surrounded by a pressurizable cuff 122 for causing a vein 124 to protrude or distend from the skin surface. In that situation, the NMR
unit is fitted on either side of the protruding vsssel at the surface of the arm. In this embodiment a C-shaped permanent magnet 126 is arranged so that its north and south poles (~ & S) are on opposite sides ~f the vessel. A
surface coil 128, like that ln Figs. 1-2, is employed for f .
i,~ j, f347~
en0rgization and realignment and sensing. Testing circuitry of the type shown in Fig. 3 is also employed in the embodi-ment of Figs. lO snd 11.
A principal advantage of the test instrument shown herein is that the device is smaller than the large ~R test instruments now used at hospitals, etc. The reason is that the present instruments include a large principal magnet for surrounding the body of a patient. Here, since the tested portion is a finger or other extremity, the principal magnet may be smaller 50 that the instrument may be mounted on a table top, carried in a brief case, or be even smaller. In order to achieve such a device, the m~gnet must be small in size, be of a comparatively light we~ght, such as one pound, - -~
ana still exhibit an adequate field strength. ~deq~ate - --strengths ~hould be on the order of at least five to s1x ~:
kilogauss. One particularly suitable material containing .',,7 Neodynium is manufactured by General Motors Corporation.
Fig. 12 shows the generator and gate 46 and the receiver 46 and gate 48, respectively, connected to separate transmit and recelve coils 38', 38". - ~--~
Fiy. 13 shows an embodiment of the coils 38' and- ---~
33" along with the field directions, including the bias ~ ~~ r' field Ho, at 9O with respect to one another.
Figs. 14 and 15 illustrate the u~e of a plurality of surface coils 38''', which are connected for addltive fields, as a single transmitJreceive arrangement. --Fig. 16 shows an alternate bias magnet, similar to that shown in Fig. 11. The magnet 138 comprises a pair of spaced pole pieces 132, 134, which define a gap for ---receiving; in this example, a finger.
Although the invention has been described with respect to preferred embodiments, it is not to be so limited, as changes and modiflcations can be made which are within the full intended scope of the invention as defined by the appended claims.
: - - - - --
Claims (49)
1. A nuclear magnetic resonance apparatus for in vitro spectroscopic testing of fluid samples for the presence of a constituent, said apparatus comprising:
principal magnet means partially defining a test region and having a pair of opposed magnet poles establishing a substantially uniform field within the test region;
coil means;
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 fluid samples;
said coil means constructed to be positioned adjacent the fluid sample to be tested; and said circuit means including means for energizing said coil means to resonate 1H 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 said sample being tested to a predetermined amplitude for a peak for a predetermined quantity of said first constituent contained in a separate standard sample and to determine the actual value of a second constituent in said test sample from a predetermined relationship between predetermined values of the peaks for the first and second constituents.
principal magnet means partially defining a test region and having a pair of opposed magnet poles establishing a substantially uniform field within the test region;
coil means;
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 fluid samples;
said coil means constructed to be positioned adjacent the fluid sample to be tested; and said circuit means including means for energizing said coil means to resonate 1H 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 said sample being tested to a predetermined amplitude for a peak for a predetermined quantity of said first constituent contained in a separate standard sample and to determine the actual value of a second constituent in said test sample from a predetermined relationship between predetermined values of the peaks for the first and second constituents.
2. In a nuclear magnetic resonance spectroscopy apparatus for testing fluids for the presence of constituents, said apparatus being of the type in which a first magnetic field aligns 1H protons to an initial position, and in which a second magnetic field is cyclicly energized and deenergized to cause alignment of the 1H
protons to a second position and realignment to said initial 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 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 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 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 initially 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 fluid sample to be tested is moved into said test region.
protons to a second position and realignment to said initial 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 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 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 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 initially 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 fluid sample to be tested is moved into said test region.
3. A self-contained portable apparatus for performing in vitro nuclear magnetic resonance spectroscopy testing of 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 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 1H 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 1H protons from said first position to a second aligned position, and for sensing the magnetic changes as analog data signals during realignment of said 1H protons from said second positon to said first position;
second gate means connected to said coil means for receiving the analog data signals during realignment of said 1H 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.
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 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 1H 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 1H protons from said first position to a second aligned position, and for sensing the magnetic changes as analog data signals during realignment of said 1H protons from said second positon to said first position;
second gate means connected to said coil means for receiving the analog data signals during realignment of said 1H 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.
4. The improved nuclear magnetic resonance apparatus of claim 1, wherein:
said coil means comprises three coils phased at 120°
for both transmitting energization and sensing.
said coil means comprises three coils phased at 120°
for both transmitting energization and sensing.
5. The improved nuclear magnetic resonance apparatus of claim 2, wherein:
each of said spaced apart members comprises a pole piece directed into said test region to concentrate the magnetic flux.
each of said spaced apart members comprises a pole piece directed into said test region to concentrate the magnetic flux.
6. The improved nuclear magnetic resonance apparatus of claim 2, wherein:
said second magnet means comprises a plurality of additively connected surface coils for both transmitting energization and sensing.
said second magnet means comprises a plurality of additively connected surface coils for both transmitting energization and sensing.
7. The apparatus of claim 3, 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.
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.
8. The apparatus of claim 7, and further comprising:
a 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;
said housing having means to disable said apparatus 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 erasure of the stored program.
a 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;
said housing having means to disable said apparatus 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 erasure of the stored program.
9. An apparatus as in claim 1, 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:
Glucose concentration = K (mg/dl) (mg/dl) x (Glucose patient peak height) (Glucose standard peak height) x (Water standard peak height) (Water patient peak height) wherein K = concentration of glucose in said standard sample expressed in mg/dl.
Glucose concentration = K (mg/dl) (mg/dl) x (Glucose patient peak height) (Glucose standard peak height) x (Water standard peak height) (Water patient peak height) wherein K = concentration of glucose in said standard sample expressed in mg/dl.
10. An apparatus as in claim 1, 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:
Alcohol concentration = K (mg/dl) (mg/dl) x (Alcohol patient peak height) (Alcohol standard peak height) x (Water standard peak height) (Water patient peak height) wherein K = concentration of alcohol in said standard sample expressed in mg/dl.
Alcohol concentration = K (mg/dl) (mg/dl) x (Alcohol patient peak height) (Alcohol standard peak height) x (Water standard peak height) (Water patient peak height) wherein K = concentration of alcohol in said standard sample expressed in mg/dl.
11. An apparatus as in claim 1, wherein the coil means comprises at least one surface coil positioned adjacent the sample to be tested.
12. An apparatus as in claim 1, 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 spacing, said test sample adapted to be positioned at the center of said pairs.
13. An apparatus as in claim 12, 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 test sample with predetermined test values and for displaying test results in accordance with the stored program.
14. An apparatus as in claim 13, including disabling switch means for disabling said memory means in the event an unauthorized access to said apparatus is attempted.
15. A method for determining in vitro the value of a constituent in a fluid sample using nuclear magnetic resonance spectroscopy comprising the steps of:
analyzing the sample comprising the substeps of:
(a) exposing said fluid sample to a biasing magnetic field, providing at least one magnetic field pulse to decrease a water peak reading in said sample, resonating a magnetic field across said sample, sampling the field and recording data from the field and storing spectrum of chemical shifts versus peak height as test sample 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 sample pulse and recording data in memory and storing 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 error within a normal tolerance;
(d) normalizing the test sample data and standard sample data for equal water peaks, including the steps of recalling the test sample data and standard sample data;
adjusting the test sample data peak height of water to match that of the standard data peak height; and (e) calculating the test sample constituent level comprising the substeps of obtaining a ratio of test sample constituent height to standard sample data constituent height and multiplying it by the concentration of said constituent in said standard sample to obtain a test sample reading and displaying that reading.
analyzing the sample comprising the substeps of:
(a) exposing said fluid sample to a biasing magnetic field, providing at least one magnetic field pulse to decrease a water peak reading in said sample, resonating a magnetic field across said sample, sampling the field and recording data from the field and storing spectrum of chemical shifts versus peak height as test sample 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 sample pulse and recording data in memory and storing 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 error within a normal tolerance;
(d) normalizing the test sample data and standard sample data for equal water peaks, including the steps of recalling the test sample data and standard sample data;
adjusting the test sample data peak height of water to match that of the standard data peak height; and (e) calculating the test sample constituent level comprising the substeps of obtaining a ratio of test sample constituent height to standard sample data constituent height and multiplying it by the concentration of said constituent in said standard sample to obtain a test sample reading and displaying that reading.
16. A method for determining in vitro the value of a constituent in a fluid sample using nuclear magnetic resonance spectroscopy, comprising the steps of:
applying a biasing magnetic field to said sample to align at least the 1H protons in the sample to an initial orientation;
applying a resonating field to flip the 1H protons between a further position and the initial position;
sensing magnetic changes as the bonds flip from the further position to the initial position as analog signals;
converting the analog signals into digital signals;
storing the digital signals as test sample 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 test sample data peak height of water to match the peak height of water of the standard sample data;
forming a ratio of the test sample constituent peak height to the standard sample data peak height;
multiplying the ratio by the known standard sample constituent/water ratio to obtain a test sample constituent reading in designated units; and displaying the test sample constituent level in the designated units.
applying a biasing magnetic field to said sample to align at least the 1H protons in the sample to an initial orientation;
applying a resonating field to flip the 1H protons between a further position and the initial position;
sensing magnetic changes as the bonds flip from the further position to the initial position as analog signals;
converting the analog signals into digital signals;
storing the digital signals as test sample 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 test sample data peak height of water to match the peak height of water of the standard sample data;
forming a ratio of the test sample constituent peak height to the standard sample data peak height;
multiplying the ratio by the known standard sample constituent/water ratio to obtain a test sample constituent reading in designated units; and displaying the test sample constituent level in the designated units.
17. The method of claim 15 wherein the fluid sample comprises blood.
18. The method of claim 16 wherein the fluid sample comprises blood.
19. 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 1H protons to an intial position, and in which a second magnetic field is cyclicly energized and deenergized to cause alignment of the 1H
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 investi-gated;
said standard sample holder being initially 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.
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 investi-gated;
said standard sample holder being initially 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.
20. The improved nuclear magnetic resonance apparatus of claim 19, wherein;
each of said spaced apart members comprises a pole piece directed into said test region to concentrate the magnetic flux.
each of said spaced apart members comprises a pole piece directed into said test region to concentrate the magnetic flux.
21. 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 1H 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.
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 1H 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.
22. An apparatus as in claim 21, 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:
Glucose concentration (mg/dl) = K (mg/dl) X
( Glucose patient peak height ) ( Glucose standard peak height ) X
( Water standard peak height ) ( Water patient peak height ) wherein K=concentration of glucose in said standard sample expressed in mg/dl.
Glucose concentration (mg/dl) = K (mg/dl) X
( Glucose patient peak height ) ( Glucose standard peak height ) X
( Water standard peak height ) ( Water patient peak height ) wherein K=concentration of glucose in said standard sample expressed in mg/dl.
23. An apparatus as in claim 21, 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:
Alcohol concentration (mg/dl) = K (mg/dl) X
( Alcohol patient peak height ) X
( Alcohol standard peak height ) ( Water standard peak height ) ( Water patient peak height ) wherein K=concentration of alcohol in said standard sample expressed in mg/dl.
Alcohol concentration (mg/dl) = K (mg/dl) X
( Alcohol patient peak height ) X
( Alcohol standard peak height ) ( Water standard peak height ) ( Water patient peak height ) wherein K=concentration of alcohol in said standard sample expressed in mg/dl.
24. An apparatus as in claim 21, wherein the coil means comprises at least one surface coil positioned adjacent the sample to be tested.
25. An apparatus as in claim 24, 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.
26. An apparatus as in claim 25, 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.
27. An apparatus as in claim 26, 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.
28. An apparatus as in claim 27, wherein said coil energizing means includes means actuated responsive to the movement of the standard sample holder.
29. An apparatus as in claim 25, wherein the test apparatus is constructed to enclose and surround said test region.
30. An apparatus as in claim 21 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.
31. An apparatus as in claim 30, wherein the blood vessel is a surface blood vessel of an animal and said coil means is a surface coil.
32. An apparatus as in claim 30, 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.
33. An apparatus as in claim 21, wherein said coil means comprises a transmitting coil and a receiving coil.
34. An apparatus as in claim 21, 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°
spacing, said test sample positionable at the center of said pairs.
spacing, said test sample positionable at the center of said pairs.
35. An apparatus as in claim 21, 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.
36. An apparatus as in claim 35, including disabling switch means for disabling said memory means in the event an unauthorized access to said apparatus is attempted.
37. The nuclear magnet resonance apparatus of claim 21, wherein:
said coil means comprises a plurality of additively connected surface coils for both transmitting energization and sensing.
said coil means comprises a plurality of additively connected surface coils for both transmitting energization and sensing.
38. The nuclear magnetic resonance apparatus of claim 21, wherein:
said coil means comprises three coils phased at 120°
for both transmitting energization and sensing.
said coil means comprises three coils phased at 120°
for both transmitting energization and sensing.
39. 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.
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.
40. The method set forth in claim 39, wherein the analysis in substep (b) is done in the same sequence as that in substep (a).
41. 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 1H protons in the body fluid sample to an initial orientation;
applying a resonating field to flip the 1H 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.
applying a biasing magnetic field to said sample to align at least the 1H protons in the body fluid sample to an initial orientation;
applying a resonating field to flip the 1H 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.
42. The method set forth in claims 39 or 41, wherein the body fluid is blood.
43. The method set forth in claims 39 or 41, wherein the body fluid is blood and the constituent being tested for is glucose or alcohol.
44. The method set forth in claims 39 or 41 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.
45. The method set forth in claim 44 wherein said selected portion of said patient's body is a finger.
46. The method set forth in claim 44 wherein said selected portion of said patient's body is a blood vessel of said body.
47. A self-contained portable apparatus for performing in vivo nuclear magnetic resonance spectroscopy testing of body fluids for the presennce 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 1H 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 1H protons from said first position to a second aligned position, and for sensing the magnetic changes as analog data signals during realignment of said 1H protons from said second positon to said first position;
second gate means connected to said coil means for receiving the analog data signals during realignment of said 1H 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.
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 1H 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 1H protons from said first position to a second aligned position, and for sensing the magnetic changes as analog data signals during realignment of said 1H protons from said second positon to said first position;
second gate means connected to said coil means for receiving the analog data signals during realignment of said 1H 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.
48. The apparatus of claim 47, 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.
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.
49. The apparatus of claim 48, 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.
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.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000548210A CA1288475C (en) | 1987-09-30 | 1987-09-30 | Instrument and method for testing for fluid constituents |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000548210A CA1288475C (en) | 1987-09-30 | 1987-09-30 | Instrument and method for testing for fluid constituents |
| EP88306345A EP0350546A3 (en) | 1986-09-04 | 1988-07-12 | Instrument and method for noninvasive testing for glucose and other body fluid constituents |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1288475C true CA1288475C (en) | 1991-09-03 |
Family
ID=25671529
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000548210A Expired - Lifetime CA1288475C (en) | 1987-09-30 | 1987-09-30 | Instrument and method for testing for fluid constituents |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1288475C (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014096411A1 (en) * | 2012-12-21 | 2014-06-26 | Diehl Bernd | Method for determining blood-alcohol concentration using quantitative nmr spectroscopy |
-
1987
- 1987-09-30 CA CA000548210A patent/CA1288475C/en not_active Expired - Lifetime
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014096411A1 (en) * | 2012-12-21 | 2014-06-26 | Diehl Bernd | Method for determining blood-alcohol concentration using quantitative nmr spectroscopy |
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