EP0955871A1 - Procede et appareil de determination non invasive de l'hematocrite - Google Patents

Procede et appareil de determination non invasive de l'hematocrite

Info

Publication number
EP0955871A1
EP0955871A1 EP96910716A EP96910716A EP0955871A1 EP 0955871 A1 EP0955871 A1 EP 0955871A1 EP 96910716 A EP96910716 A EP 96910716A EP 96910716 A EP96910716 A EP 96910716A EP 0955871 A1 EP0955871 A1 EP 0955871A1
Authority
EP
European Patent Office
Prior art keywords
signals
current
blood
body portion
voltage
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP96910716A
Other languages
German (de)
English (en)
Other versions
EP0955871A4 (fr
Inventor
Paul W. Ruben
Allan L. Kaminsky
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Microcor Inc
Original Assignee
Microcor Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US08/425,404 external-priority patent/US5526808A/en
Priority claimed from US08/602,700 external-priority patent/US5642734A/en
Application filed by Microcor Inc filed Critical Microcor Inc
Publication of EP0955871A1 publication Critical patent/EP0955871A1/fr
Publication of EP0955871A4 publication Critical patent/EP0955871A4/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/483—Physical analysis of biological material
    • G01N33/487—Physical analysis of biological material of liquid biological material
    • G01N33/49—Blood
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/14535—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue for measuring haematocrit
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/48—Other medical applications
    • A61B5/4869—Determining body composition
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/72—Signal processing specially adapted for physiological signals or for diagnostic purposes
    • A61B5/7235—Details of waveform analysis
    • A61B5/7264—Classification of physiological signals or data, e.g. using neural networks, statistical classifiers, expert systems or fuzzy systems

Definitions

  • the present invention relates generally to determination of the Packed Cell Volume or relative volume percent of erythrocytes (red blood corpuscles), also known as the hematocrit, of whole blood, and more specifically to a method and apparatus for making such determination noninvasively through coherent techniques.
  • Hematocrit is traditionally obtained by acquiring a patient blood sample from a vein via a syringe, or by use of a capillary tube from a finger stick, or puncture.
  • the blood contained in an elongated vessel, is then centrifuged and the height percentage of the column of blood in the vessel which is solid represents the hematocrit.
  • hematocrit has been obtained by the use of elaborate and expensive cell counting laboratory instruments which are also used to provide differentiations of white blood cells, platelets, etc.
  • the blood must be invasively removed from the patient for analysis.
  • the necessity of obtaining blood samples from patients and then centrifuging or otherwise analyzing the drawn blood presents no great inconvenience, as the volume of samples is large (warranting expensive automated equipment) and the time delay in obtaining results from a laboratory is generally acceptable.
  • the hematocrit determination apparatus and methodology of the prior art are markedly deficient.
  • impedance plethysmography A measurement technique termed "impedance plethysmography," or using impedance techniques to obtain a waveform, is conceptually rooted in biomedical antiquity. Medical literature abounds with vascular studies, respiration studies and attempts to determine cardiac output (the actual volume of blood flowing from the heart) by impedance techniques. None of these techniques has been proven to work particularly well, although there have been attempts at commercial instruments based on the concept.
  • a variant of impedance plethysmography electrically models intracellular as well as an extracellular tissue components and employs a comparison of measurements of tissue impedance responsive to applied electrical currents at two frequencies to quantify the intracellular and extracellular tissue components. While not directly related to the problem solved by the present invention, the electrical tissue model is useful to an understanding thereof.
  • Pulse oximetry relies upon the fact that the light absorbance of oxygenated hemoglobin and that of reduced hemoglobin differ at two wavelengths of light (generally red and near infrared) employed in an oximeter, and that the light absorbances at both frequencies have a pulsatile component which is attributable to the fluctuating volume of arterial blood in the patient body portion disposed between the light source and the detector of the oximeter.
  • two wavelengths of light generally red and near infrared
  • the pulsatile or AC absorbance response component attributable to pulsating arterial blood is determined for each wavelength, as is the baseline or DC component which represents the tissue bed absorbances, including venous blood, capillary blood, and nonpulsatile arterial blood.
  • the AC components are then divided by their respective DC components to obtain an absorbance that is independent of the incident light intensity, and the results divided to produce a ratio which may be empirically related to SaO 2 , or oxygen saturation of the patient's blood.
  • An excellent discussion of pulse oximetry may be found in "Pulse Oximetry," by K.K. Tremper et al., Anesthesiology. Vol. 70, No. 1 (1989) pp. 98-108.
  • the present invention provides a method and apparatus for noninvasive hematocrit determination.
  • impedance of blood is measured via application of stimulation and sensor electrodes to a portion of the body that contains a vascular compartment of arteries, capillaries, and veins.
  • the electrodes are usually applied to a finger.
  • the stimulation electrodes are driven with an alternating voltage over a range of frequencies.
  • the sensed voltage signals are amplified by a high input impedance voltage detector, converted to the digital domain by an analog-to-digital converter, and then demodulated via mixers into two complex waveforms, one representative of the stimulation current and another representative of the sense voltage at a selected frequency.
  • the waveforms are processed by a microcomputer to determine the tissue impedance scan indicia.
  • the blood volume is altered and another tissue impedance scan is made.
  • a pressure cuff is used to alter the blood volume.
  • Two tissue scans, one at one blood volume and one at another blood volume, are used to determine a blood impedance scan.
  • the impendance of the whole blood is seperated from the total impendance through a parallel model.
  • the whole blood impedance indicia is correlated to hematocrit by recognizing patterns in the blood impedance scan. It is also possible and contemplated as part of the invention to determine hematocrit using the preferred embodiment of the invention by analyzing the phase shift pattern with a neural network.
  • FIG. 1A comprises a circuit schematic for a first-order electrical model of whole blood in a large vessel
  • FIG. IB comprises a schematic representation of fluid and membrance cells in a large vessel corresponding to the electrical model of FIG. 1 A;
  • FIG. 2 A comprises a circuit schematic for a first-order electrical model of whole blood in a small vessel;
  • FIG. 2B comprises a schematic representation of fluid and membrance cells in a small vessel corresponding to the electrical model of FIG. 2A;
  • FIG. 3A shows a representation of the total impedance in a limb at a low blood volume
  • FIG. 3B shows a representation of the total impedance in a limb at high blood volume
  • FIG. 4 comprises a block diagram schematic of a preferred embodiment of a system of the present invention
  • FIG. 5 A comprises a bottom plan view of a limb to which electrodes are applied
  • FIG. 5B comprises a side view of the limb of FIG. 5A;
  • FIG. 6 comprises a more detailed block diagram schematic of the electrode pod of the system of FIG. 4;
  • FIG. 7 comprises a schematic representation of a wireless version of the signal generator and demodulator and electrode pod of FIG. 4;
  • FIG. 8 comprises a more detailed block diagram schematic of the signal generator and demodulator of FIG. 4;
  • FIG. 9 comprises a more detailed block diagram schematic of the air pump, solenoids, and pressure cuff of FIG. 4;
  • FIG. 10 comprises a more detailed schematic of the frequency generator of FIG. 4;
  • FIG. 11 comprises a combined diagram and schematic of a two-frequency embodiment of the present invention, with electrodes applied to a patient extremity;
  • FIG. 12 comprises a schematic of an embodiment of a constant current source as employed in the embodiment of FIG. 11;
  • FIG. 13 comprises a schematic of an embodiment of an AM detector as employed in the embodiment of FIG. 11;
  • FIG. 14 comprises a schematic of an embodiment of an A/D converter as employed in the embodiment of FIG. 11;
  • FIG. 15 comprises a graphic, not-to-scale depiction of an analog voltage signal representative of those measured in practicing the present invention showing the relatively small pulsatile component of the signal above the signal baseline;
  • FIG. 16 comprises a circuit schematic for a first-order electrical approximation of the impedance of a whole blood in a pulsatile vascular compartment in combination with that of the surrounding tissue in which the compartment is located.
  • FIG. 1A is an electrical circuit model that represents an approximation of the behavior of whole blood in a large vessel when subjected to an alternating electrical current I.
  • Resistor 10 in circuit path 12 represents the resistance R ⁇ E of the extracellular or plasma component.
  • a capacitor 16 and resistor 18 in a parallel circuit path 14 represent the capacitance C BC of the cell membrance and the resistance R BI of intercellular fluid of the erythrocyte or red blood corpuscles.
  • the impedance of whole blood e.g.
  • both paths 12 and 14 is attributable primarily to the extracellular blood component circuit path 12, while at higher frequencies (for example, 1 MHz), the capacitive nature of the cell membrane of the red blood corpuscles results in a more significant impedance contribution from circuit path 14, reducing the magnitude of the whole blood impedance.
  • FIG. IB illustrates a large vessel 20 containing many red blood cells 22 in plasma 24. As can be seen, there is a current path through plasma 24, even at low frequencies.
  • FIG. 2A is an electrical circuit model that represents an approximation of the behavior of whole blood in a small vessel when subjected to an alternating electrical current I.
  • FIG. 2B illustrates a small vessel 26 in which cells 22 are about as wide as vessel 26 preventing a plasma path between cells 22 and the wall of vessel 26.
  • the path for current I is through a capacitance C BC , in series with resistances R BI and Rr ⁇ .
  • the impedance of and the amount of current flowing through vessel 26 changes as the frequency of current I increases. While the ratio of small vessels to large vessels is not known, it is believed that the effect of small vessels may be significant in the overall limb impedance. (There are some vessels that are slightly or somewhat larger than a small vessel and allow a small path around the cells.)
  • the impedance Z represents the total limb impedance when blood flow through the limb is unrestricted.
  • Z B represents the impedance of the additional blood accumulated as a result of the restriction.
  • the total limb impedance during the restricted state is Z R .
  • a hematocrit measurement system 30 includes a signal generator and demodulator (SGD) 34 that sends a signal to an electrode pod 36 through conductor 38 and receives measured signals from electrode pod 36 through conductor 40.
  • SGD 34 provides to a personal computer (PC) 42 through conductors 32 and an RS-232 port, signals indicative of the current passing through the limb of a patient and the resulting voltage.
  • the voltage and current may be measured for various frequencies over, for example, a range from 10 kHz to 10 MHz.
  • the impedance from the blood alone is isolated from the total limb impedance from the blood, muscle, bone, etc. by measuring the limb impedance of different blood volumes.
  • an air pump, solenoid(s), and pressure cuff 28 may be used to cause a change in blood volume in the limb.
  • PC 42 determines the hematocrit.
  • the hematocrit may be determined from the signals from SGD 34 alone, or in combination with various other data regarding the particular patient such as age, sex, weight, temperature, illnesses, etc., or regarding patients in general.
  • a neural network may be useful.
  • a neural network may be executed in PC 42 or in a separate computer 52, shown in dashed lines.
  • electrode pod 36 provides an alternating electrical current signal to a limb 44 (such as a finger having a finger nail 46) of a patient through electrodes 48 A and 48B.
  • a limb 44 such as a finger having a finger nail 46
  • Fig. 5 A shows the underside of the two fingers next to the thumb of a left hand.
  • the resulting voltage drop across limb 44 is measured through electrodes 50 A and 50B.
  • the voltage between electrodes 48A and 48B may be about three volts.
  • Electrodes 48A, 48B, 50A, and 50B may be standard, commercially available electrodes. Electrodes 48A, 48B, 50A, and 50B may be conveniently held in place through a piece of tape 54 that covers both the electrodes and a portion of limb 44.
  • tape 54 preferably does not restrict blood flow. Tape 54 may extend 1/2 to 3/4 around the circumference of limb 44. In addition to holding the electrodes in place, tape 54 stiffens limb 44 which makes the measurement procedures more controlled. A splint or mylar may also be used.
  • electrode pod 36 includes a 50 ohm termination buffer 60 that receives a sine signal having frequency ⁇ on conductor 38 from SGD 34.
  • a sense resistor 64 is connected in series between buffer 64 and a conductor 66A, to which electrode 48A is connected. Electrodes 48A, 48B, 50A, and 50B are connected to electrode pod 36 through conductors 66A, 66B, 70A, and 70B, which are preferably as short as possible.
  • wireless communication could be used as shown in FIG. 7, which includes transmitters 76A, 76B, and 76C, and receivers 78A, 78B, and 78C. Wireless communication may be particularly useful in an operating room environment.
  • an instrumentation amplifier 68 provides to conductor 72, a signal A, sin( ⁇ t + 0,) indicative of the voltage drop across resistor 64, where "A,” is the amplitude, and 0, is a phase difference with respect to an original signal sin ⁇ t, described below.
  • Instrumentation amplifier 68 provides a high input impedance, rejects the common mode voltage at conductor 66A while amplifying the voltage drop across resistor 64.
  • Instrumentation amplifier 68 may comprise three operational amplifiers in a well known configuration.
  • An instrumentation amplifier 74 provides to a conductor 78, a signal A 2 sin( ⁇ t + 0 2 ) that is indicative of the voltage between electrodes 50A and 50B, where "A 2 " is the amplitude, and 0 2 is a phase with respect to the original signal, sin ⁇ t.
  • the difference in phase between ⁇ . and 0 2 is caused by the electrical capacitance in limb 44 between electrodes 48A and 50B, and differences in the speed and phase response of the instrumentation amplifiers 68 and 74.
  • instrumentation amplifiers 68 and 74 should be chosen and constructed to minimize differences in their phase responses.
  • the differences in speed and phase response of amplifiers 68 and 74 is calibrated out of the equipment using a dummy load. Thereafter, PC 42 stores the calibration information and substracts out any differences.
  • Instrumentation amplifier 74 rejects the common mode voltage between conductors 66B and 70B and amplifies the differential voltage between conductors 70A and 70B.
  • Instrumentation amplifier 74 may comprise three operational amplifiers in a well known configuration.
  • An RF switch 80 passes either the signal on conductor 72 or the signal on conductor 78 to conductor 40, under the control of a signal on conductor 84.
  • Signal Generator and Demodulator (SGD ⁇ Referring to FIG. 8, SGD 34 produces the signal on conductor 38 and demodulates and filters the signals on conductor 40.
  • SGD 34 may include a microprocessor 94 with an embedded EPROM, such as an HC6805.
  • Microprocessor 94 provides control signals to the various components of SGD 34 to RF switch 80 through conductor 84, and to solenoids of air pump, solenoids, and pressure cuff 28, through conductors 88A, 88B, and 88C, as described in connection with FIG. 9, below. Microprocessor 94 also communicates with PC 42 through conductors 32.
  • a frequency generator 100 produces to a digital sine signal FG srN shown in equation (1) below, to conductors 96:
  • FG S1N sin ⁇ t (1), where the amplitude is assumed to be unitary.
  • the signal sin ⁇ t is provided to mixer and filter 104, and to a DAC 110.
  • the analog sine signal from DAC 110 is provided through a buffer 112 to conductor 38.
  • the frequency of FG srN is controlled by a frequency control word provided by PC 42 to frequency generator 100.
  • Frequency generator 100 also produces a digital cosine signal FG COs shown in equation (2) below, to conductors 98:
  • the signals from electrode pod 36 on conductor 40 are received by a low pass filter 116 t rough a buffer 118.
  • Low pass filter 116 removes harmonic frequency components or aliasing.
  • the 22 MHz value was chosen to allow tissue impedance measurements with a sin ⁇ t at as high as 20 MHz.
  • the analog electronics may have difficulties maintaining the required phase tolerance above about 10 MHz. With the 10 MHz upper limit, low pass filter 116 may have a lower cut off frequency.
  • the filtered signals from low pass filter 116 are converted to digital signals through ADC 120, from which they are passed to mixer and filters 104 and 106.
  • DAC 110, ADC 120, and frequency generator 100 may be clocked at 60 MHz. However, if the maximum frequency of sin ⁇ t generated by frequency generator 100 is 10 MHz, then DAC 110, ADC 120, and frequency generator 100 may be clocked at, for example, 30 MHz.
  • Measured current indicating signals Me are provided by ADC 120 to conductors 90.
  • Signals Mc originate from conductor 72 in FIG. 6 and are processed through RF switch 80, buffer 118, low pass filter 116, and ADC 120.
  • Signals M c are shown in equation (3), below:
  • M c G A, sin( ⁇ t + 0, + ⁇ ) (3), where A, and 0, are the amplitude and phase of the signal at conductor 72, and G and ⁇ are the gain and phase shift caused by buffer 118, low pass filter 116, and ADC 120.
  • Measured voltage indicating signals M v are also provided by ADC 120 to conductors 90. Signals M v originate from conductor 78 in FIG. 6 and are processed through RF switch 80, buffer 118, low pass filter 116, and ADC 120. Signals M v are shown in equation (4), below:
  • M v G A 2 sin( ⁇ t + ⁇ 2 + ⁇ ) (4), where A- and 0 2 are the amplitude and phase of the signal at conductor 78, and G and ⁇ are the gain and phase shift caused by buffer 118, low pass filter 116, and ADC 120.
  • signals Mc and M v are merely examples of current indicating signals and voltage indicating signals, and other circuitry than is illustrated may be used to produce suitable current and voltage indicating signals.
  • a multiplier 124 multiplies sin ⁇ t on conductors 96 with the output of ADC 120. When RF switch 80 passes the signal on conductor 72, the output of multiplier 124 is the product P CT (current inphase), shown in equation (5), below:
  • a 60 Hz digital lowpass filter 128 filters out the ((G A,/2) sin(2 ⁇ t + 0, + ⁇ )) component as well as various noise, leaving only the DC component, ((G A,/2) cos ( j + ⁇ )).
  • the signal ((G A,/2) cos (0, + ⁇ )) is applied to conductors 134 and is referred to as , where "C” represents the current between electrodes 48A and 48B, and "I” stands for "in phase.”
  • Digital lowpass filter 128 may be constructed of multipliers and adders performing convolution in a well known manner.
  • 60 Hz digital lowpass filter 128 filters out the ((G Aj/2) sin(2 ⁇ t + 0 2 + ⁇ )) component as well as various noise, leaving only the DC component, ((G A 2 /2) cos (0 2 + ⁇ )).
  • the signal ((G A 2 /2) cos (0 2 + ⁇ )) is applied to conductors 134 and is referred to as V f , where "V" represents the current between electrodes 50A and 50B, and "I” stands for "in phase.”
  • a multiplier (not shown) multiplies cos ⁇ t on conductors 98 with the output of ADC 120.
  • a 60 Hz digital lowpass filter 128 filters out the ((G A,/2) sin(2 ⁇ t + 0, -1- ⁇ )) component as well as various noise, leaving only the DC component, ((G A j /2) sin (0j + ⁇ )).
  • the signal ((G A,/2) sin ( ⁇ , + ⁇ )) is applied to conductors 136 and is referred to as C Q , where "C” represents the current between electrodes 48A and 48B, and "Q" stands for "quadrature.”
  • 60 Hz digital lowpass filter 128 filters out the ((G Aj/2) sin(2 ⁇ t + 0 2 + ⁇ )) component as well as various noise, leaving only the DC component, ((G Aj/2) sin (0. + ⁇ ))-
  • the signal ((G A 2 /2) sin (0 2 + ⁇ )) is applied to conductors 136 and is referred to as V Q , where "V" represents the voltage between electrodes 50A and 50B, and "Q" stands for "quadrature.”
  • Signals C, and C Q provide information regarding the amplitude and phase of the current between electrodes 48 A and 48B.
  • Signals V, and V Q provide information regarding the amplitude and phase of the voltage electrodes 50A and 50B.
  • Signals V and C are complex (i.e.. they have inphase components V, and C, and quadrature components V Q and C Q ).
  • the signals V,, V Q , C and C Q may be analyzed as follows.
  • the magnitude C MA0 of the current components is determined through equation (9), below: where C, and C Q are the signals on conductors 134 and 136 from mixer and filters 104 and 106.
  • phase C ⁇ of the current components is determined through equation (10), below:
  • V MAO Cv? + V Q 2 )* (11), where V, and V Q on conductors 134 and 136 from mixer and filters 104 and 106.
  • V ⁇ tan "1 (V Q /V,) (12).
  • the impedance Z is the ratio of complex numbers V and C.
  • the magnitude component of the impedance is determined through equation (13), below:
  • phase component of the impedance is determined through equation (14), below:
  • the impedance from the blood alone is isolated from the total impedance from the blood, tissue, bone, etc. This isolation may be performed as follows. At each frequency in a scan, the limb impedance is determined by calculating V,, V Q , C Compute and C Q when blood flow through limb 44 is unrestricted and, therefore, the limb has a normal or unrestricted blood volume. Then, another scan is performed over the same frequencies when blood flow through limb 44 is restricted and, therefore, the limb has a restricted blood volume (which may be higher or lower than the unrestricted blood volume). Methods of restriction are discussed below.
  • FIGS. 3 A and 3B illustrate the situation in which restriction causes an increase in blood volume.
  • the total limb impedance at lower blood volume when the limb is unrestricted is Z ⁇ , illustrated in FIG. 3A.
  • the total limb impedance at higher blood volume when the limb is restricted is Z R , illustrated in FIG. 3A.
  • Impedance Z R is the equivalent to impedance Z ⁇ in parallel with the impedance Z B , where Z B is the blood present at higher volume that is not present at lower volume. (This model assumes that the extra blood has the same hematocrit as all other blood passing through the limb.)
  • Impedance Z R is calculated through equation (15), below:
  • Zy is equivalent to Z R in parallel with Z B , where Z B is the blood present at higher volume that is not present at lower volume.
  • impedance Z R is calculated through equation (17), below:
  • Z B (Zu x Z R )/(Z R - Zu) (18), for the case in which restriction causes a decrease in blood volume.
  • blood impedance Z B includes both a magnitude and phase, the phase appears to be the stronger indicator of hematocrit.
  • both phase and magnitude of Z B may be used in pattern analysis in a neural network.
  • the processes of determining Z B are repeated for various frequencies over a range from about 10 kHz to about 10 MHz.
  • Various steps may be used. In the current embodiment, there may be from 3 steps per octave to 10 steps per octave, where octaves are 10 kHz, 20 kHz, 40 kHz, 80 kHz, 160 kHz, etc.
  • a large number of steps may be used to average out arterial pulsation noise, but takes more time and, therefore, there is a greater risk that the blood volume will undesirably and unpredictably change over time with a longer measurement. It has been found by the inventors t at the phase change increases (as a negative number) from about 10 kHz to in the region of 1.6 MHz and then begins to decrease (although there may be an inflection point at well below 1.6 MHz), (de Vries, P.M.J.M., et al., "Implications of the dielectrical behavior of human blood for continuous on-line measurement of hematocrit", Med. Biol. Eng.
  • a "scan” refers to the process of applying signals of various frequencies in steps between a lower and upper frequency limit to electrode 48A. As described above, this creates a current between electrodes 48A and 48B, and a voltage between electrodes 50A and 50B. It takes about one 55th of a second to gather V,, V Q , , and C Q signals at each frequency. Digital filter 128 requires about 9 milliseconds to achieve the desired 60 Hz bandwidth.
  • digital filter 128 processes P ⁇ for 9 milliseconds and then processes Pyj for 9 milliseconds at one frequency. The processes is then repeated for 9 milliseconds for P CT and then 9 milliseconds for Py, at another frequency.
  • the corresponding digital filter in mixer and filter 106 similarly processes P CQ and P VQ .
  • a "repetition” refers to the number of "scans" that are performed in quick succession before changing the blood volume.
  • the software is written so there may be between 1 and 10 repetitions. The reason to perform multiple repetitions is as follows. Arterial pulsations cause a small alternating fluctuation in blood volume. The pulsations can affect the phase. If multiple repetitions are made, the variations in phase caused by arterial pulsations can be averaged and the effect reduced.
  • a “measurement” refers to the completion of a specified number of scan repetitions at a particular blood volume.
  • the software is written to make any number of measurements up to 25. For example, a first measurement is at unrestricted blood volume. A second measurement is at restricted blood volume. A third measurement may be at the unrestricted blood volume or some other blood volume, and so forth.
  • restrictive pressure such as from a cuff
  • the vascular circulation it can take between about 10 seconds to 45 seconds for blood volume of limb 44 to reach a new equilibrium after the restrictive pressure is changed.
  • a neural network may analyze very complex noisy data and find patterns (or combinations of data) that can be used to determine underlying parameters. These patterns are usually not apparent to human observers. In a statistical sense, neural networks are capable of performing non-linear non-parametric regression.
  • Finding neural network solutions to complex data analysis problems may be as much art as science.
  • the search for a systematic neural network design approach is a very active area of research within the field of Artificial Intelligence.
  • the particular paradigms of interest in the present invention are believed to be those that produce continuous-valued outputs and that undergo supervised training.
  • This is a technique of shaping the neural network in which the network is repeatedly exposed to both the data and the right answer. This allows the net to structure itself internally so that it extracts the features in the data that we have identified as being important to the present invention.
  • Clinical data collection could be gathered from several runs on each patient or subject.
  • the runs could be performed with certain varying conditions (such as different height of the limb under test, applied heat to the limb, etc.). Thereby, several different environments could be produced with different patterns of data for the same hematocrit.
  • blood could be drawn to accurately determine the actual hematocrit using the "gold standard" technique of centrifuging capillary tubes containing the subjects whole blood.
  • the neural nets will be trained to determine the underlying parameter of hematocrit.
  • Neural network 52 may be in PC 42 or an adjacent PC or other computer. Accordingly, in FIG. 4, neural network 52 is shown in dashed lines.
  • the neural network could consider parameters including frequency, magnitude, phase, and derivations thereof.
  • the neural network could consider parametes including the patient's age, weight, sex, temperature, illiness, heat applied to the limb, blood pressure, and arm elevation and position. Of course, it is not necessary that the neural network consider each of these parameters.
  • the neural network would also consider the hematocrit measurements from centrifuging capillary tubes corresponding to the patient from which the other factors were obtained.
  • the neural network is used in two manners. First, it is used to derive a group of patterns and/or other data from a large amount of the parameters regarding patients and waveforms. Second, once the patterns and/or other data are derived, the neural network is used in determining the hematocrit of a particular patient
  • the neural network is able to process out the small vessel effect and produce the hematocrit value due to blood contained in large vessels.
  • the term "patient” includes both those persons from whom the data is originally obtain to create the group of patterns or data, and those persons whose hematocrit is later determined from the group of patterns or data. Look up tables may be used, although it is expected that many of the patterns (such as equations) may be too complicated to make look-up tables practical for most purposes.
  • Air pump, solenoid(s'). and pressure cuff 28 There are various methods of changing the blood volume. For example, if limb 44 is a finger, blood volume may be change through venous restriction about the upper arm of the patient, or arterial occlusion of the wrist of the patient.
  • the cuff create less than diastolic pressure so that arteries can pump blood in, but blood does not flow out under the cuff until pressure in limb 44 equals the cuff pressure.
  • arterial occlusion arterial blood is blocked from entering limb 44 and blood drains out of limb 44 through the veins to create a lower blood volume. It has been found that the phase change detected during venous restriction may be different from that detected during arterial occlusion. It is believed to be easier to implement venous restriction with a blood pressure cuff than it is to perform arterial occlusion. To obtain restriction through occlusion, the ulna and radial arteries should be occluded, which may be difficult.
  • air pump, solenoid(s), and pressure cuff 28 may work as follows.
  • An air pump 152 provides increased air pressure to a tube 154.
  • microprocessor 94 activates a solenoid 160 which allows the increased pressure in tube 154 to flow to tube 162.
  • Microprocessor 94 is informed of the pressure in tube 162 through pressure transducer 164.
  • microprocessor 94 When it is time to decrease the pressure in cuff 156, microprocessor 94 activates solenoid 168 through which tube 162 is connected to an exhaust. Air pump 152 may be turned on under separate switch or under the control of micro-processor 94. The volume change should be maximized by adjusting the tilt and height of the patient's arm.
  • limb movement may significantly change the impedance.
  • Frequency generator 100 may be constructed according to a well known practice shown in FIG. 10.
  • a 16-bit frequency word FW is received on conductor 112 by an adder 180 that produces a phase word PW in response to the FW.
  • the desired sinusoidal frequency FW X clock frequency/ 2 16 .
  • the clock frequency may be, for example, 30 MHz or 60 MHz.
  • the phase word PW is received by a sine/cosine look-up table PROM 182 that produces sine and cosine signals.
  • the sine signal may be 127.5 x sin (PW x 2x)/2048 and the cosine signal may be 127.5 cos (PW x 2 ⁇ )/2048.
  • the preceding is merely an example and various other well known techniques could be used.
  • current is injected into limb 44 between electrodes 48 A and 48B, and voltage is measured between electrodes 50 A and 50B.
  • current could injected between electrodes 50 A and 50B, and voltage measured between electrodes 48 A and 48B.
  • both the current injected by electrode 50A and the current received by electrode 50B would be measured to account for any current that may pass to another part of the body.
  • it may also be desirable to bring electrodes 50B and 48B closer to electrodes 48A and 50A, and to make the electrodes narrower.
  • the out-of-phase signals on conductors 98 from signal generator 100 are cosine signals, which are 90 degrees (or 270 degrees) out of phase with the sine signal on conductors 96 (sometimes called a quadrature signal).
  • the output-of-phase signals could have some other relationship than 90 degrees out of phase with respect sine signals on conductors 96. In that case, it may be necessary and/or desirable to have three or more signals rather than only two signals.
  • frequency generator 100 low pass filters 116 and 128, and mixer and filters 104 and 106 are performed in hardware (including programmed dedicated hardware with, for example, adders, multipliers, and gate arrays) as opposed to a microprocessor.
  • some or all of the functions may be performed in PC 42, in another microprocessor system, or otherwise in software.
  • PC 42 does not have to be a "personal computer” but may be any of various other computers, such as a Macintosh, Sun Microsystems, etc.
  • a "conductor” may actual comprise multiple wires, such as in the case of a parallel digital transmission. In another words, digital data may be transmitted in parallel or in series. There may also be a ground wire. Conductors 38 and 40 each may be a 50 ohm coaxial cable.
  • connection As used in the claims, the term “connect,” “connectable,” or “connected to” are not necessarily limited to a direct connection.
  • resistance 10 in circuit path 12 representing the response of the extracellular or plasma component
  • the parallel circuit path 14 representative of the erythrocyte or red blood coipuscle component
  • whole blood impedance is attributable primarily to the extracellular blood component circuit path 12, while at higher frequencies (for example, 1 MHz) the capacitive nature of the cell membrane of the red blood corpuscles results in a more significant impedance contribution from circuit path 14, reducing the magnitude of the whole blood impedance.
  • the ratio of a low-frequency impedance to a high-frequency impedance is representative of the relative volume percent of red blood corpuscles, or hematocrit.
  • the impedance magnitude differential due to the frequency response characteristics of blood below and above the aforementioned transition zone enables the practitioner employing the present invention to utilize electrical stimulation of the patient to determine hematocrit in a noninvasive manner.
  • FIG. 15 of the drawings comprises a representative sector of a demodulated voltage signal envelope over a period of time as measured by sensors attached to an electrically-stimulated extremity of a patient according to the present invention, the measured voltage being directly proportional to and therefore representative of the total impedance of the whole blood plus the surrounding tissue.
  • the signal envelope includes a dominant DC or baseline component and a small AC or pulsatile component.
  • the DC component is generated by the patient's tissue, non- pulsatile arterial blood, and venous and capillary blood of the stimulated body portion.
  • the AC component is attributable only to the pulsatile blood, and is therefore truly representative of whole blood impedance for a given frequency.
  • AC components at different frequencies will have substantially identical voltage envelope shapes, differing only in magnitude due to the aforementioned frequency-dependent nature of the whole blood impedance response.
  • the impedance effects of the patient's extravascular tissue are eliminated and a hematocrit determination may be made using the ratio of a low-frequency pulsatile impedance to a high-frequency pulsatile impedance.
  • FIG. 11 which is illustrative of a two-frequency embodiment of the invention, shows a patient body portion 220 containing an artery (which may also be referred to as a pulsatile vascular compartment) on the exterior of which have been placed outer stimulation electrodes 222 and inner sensor electrodes 224, all of which are preferably ring electrodes so as to envelop the body portion 220.
  • the four-electrode method is a standard engineering technique which helps to eliminate errors attributable to contact resistance and, except insofar as it is employed in the present invention, does not constitute a part thereof.
  • Power or stimulation electrodes 222 are driven with a constant current composite carrier waveform consisting of two frequencies A and B provided by current sources 226 and 228. It is preferred that the applied constant current be of a peak-to-peak magnitude of 2 mA or less.
  • Frequencies A and B should differ sufficiently to provide a significantly different blood impedance response to each frequency due to the capacitive component of the patient's blood, and thus an impedance differential useful in practicing the present invention. It has been found that a low frequency A of 50 kHz and a high frequency B of 1 MHz provide a usable differential response, in that they are, respectively, sufficiently far below and above the frequency transition zone wherein the capacitive component of the response becomes significant.
  • each frequency excites the tissue of body portion 220 with a constant current, and the resulting voltage signal at each frequency is measured from inner sensor electrodes 224. Since the current excitation is constant, the envelope of the measured voltage at each frequency is directly proportional to the tissue impedance at that frequency.
  • AM Detectors 230 and 232 measure the envelope of the voltage signals, and transmit the resulting signals to A/D Converter 234, which converts the signals to the digital domain for isolation of the pulsatile component of the signal and further processing by a programmed processing unit, preferably general purpose Microcomputer 236, in response to commands from Keyboard 238.
  • Microcomputer 236 repeatedly extracts time-matched converted pulsatile signal component segments at each frequency, normalizes them against the voltage baseline of the respective carrier waveforms and then creates a series of segment ratios of the normalized pulsatile signal components.
  • ratios are averaged, preferably using a weighted averaging methodology which more heavily weights more significant ratios, being those comprised of pulsatile component segments exhibiting the greatest change in voltage magnitude over time.
  • the weighted average of the ratios is representative of the hematocrit, the latter being extracted from an internal look-up table of corresponding ratio and hematocrit values by Microcomputer 236, and displayed to the practitioner via Display 240, which may comprise a graphic screen display, a numerical display, or both.
  • An embodiment of current sources 226 and 228 of FIG. 11, as depicted in FIG. 12, uses transistor 300 as an approximation of a current source, which is driven by oscillator 302 through automatic gain control (AGC) multiplier 322 at the desired frequency, the resulting output signal driving power transformer 304 which in turn outputs to patient stimulation electrodes 222. Isolation of each current source using transformer coupling via power transformer 304 and pickoff transformer 306 is used for patient safety. It should be noted that, as is well known in the art, transformers 304 and 306 should be wound to maximize their response at the frequencies of interest and minimize sensitivity to artifact.
  • AGC automatic gain control
  • phase lock loop synchronous AM detector 317 which includes detector multiplier 310, phase lock loop 312, quadrature amplifier 314 and low pass filter 316.
  • Phase lock loops are well known in the art, as are AM synchronous detectors incorporating same, and therefore their structure and function will not be further described herein. However, a brief but excellent description of phase lock loops, their operation, versatility and applications, specifically in the fabrication of an AM synchronous detector suitable for use with the present invention, appears in the 1987 EXAR Databook. pp. 6-62 through 65 and 11-68 through 71, published by EXAR Corporation, 2222 Qume Drive, San Jose, California 95131. Detector 317 outputs the envelope of the sensed current drive signal to difference amplifier 318 for comparison to the input signal from reference 32883 PC17US96/04547
  • the AM Detectors 230 and 232 used in the embodiment of FIG. 11 of the present invention, as depicted in FIG. 13, are AM synchronous detectors built around a phase lock loop.
  • the measured voltage signal from the sensor or patient measurement electrodes 224 which is quite minute, is amplified by instrumentation amplifier 400 and sent to detector multiplier 402 and phase lock loop 404 of each AM Detector 230 and 232, the output of the phase lock loops being filtered by low pass filters 408.
  • the outputs of Detectors 230 and 232 are thus the envelopes of the measured voltage waveforms at low and high frequencies, respectively, and inherently representative of impedance at those frequencies.
  • phase lock loops and synchronous AM detectors their structure and function are well known in the art, and the reader is again referred to the above-referenced pages of the 1987 EXAR Databook for a more detailed description thereof.
  • A/D Converter 234 depicted in its preferred embodiment in FIG. 14, A/D Converter 234 including a pair of level shifters 500, each driven by level set commands from Microcomputer 236 via digital-to-analog (D/A) convenors 502 to extend the range of high resolution analog-to-digital (A/D) converter unit 504 to accommodate the fact that the variable (pulsatile) component of the impedance being measured typically constitutes only about one percent (1 %) of the total measured impedance.
  • Analog multiplexor 506 selects the appropriate signals from either AM Detector 230 or 232 responsive to channel select commands from Microcomputer 236, and feeds the selected signal to analog-to-digital converter unit 504 for conversion to the digital domain.
  • One preferred means of obtaining the pulsatile waveform component of interest in the practice of the present invention is to utilize a high resolution A/D converter unit 504, that is to say one which has a 20-22 bit resolution capability, and digitize the entire waveform, including both the small AC (pulsatile) and much larger DC (baseline) components.
  • A/D converter unit 504 that is to say one which has a 20-22 bit resolution capability
  • digitize the entire waveform including both the small AC (pulsatile) and much larger DC (baseline) components.
  • This provides a sufficiently large dynamic range so that the pulsatile, or AC component, of the waveform at each frequency can be isolated to provide meaningful data.
  • this approach requires a relatively expensive A/D converter unit, and an alternative approach is to set a voltage clamp level at the magnitude of the DC component, subtract this from the waveform and magnify the remaining signal.
  • the voltage clamp approach is less expensive as it requires fewer bits of resolution capability in the A/D converter unit.
  • Segments of the converted analog values from Detectors 230 and 232 are then repeatedly extracted over identical time periods by Microcomputer 236, correlated to further reduce noise effects, and then normalized by dividing by the voltage baseline of their respective carrier waveforms before a series of ratios of the time-matched digitized pulsatile component signal segments at frequencies A and B are calculated.
  • the ratios are averaged in a preferred embodiment using weighted averaging techniques well known in the art, relative weighting being based upon the change in voltage magnitude versus time for the time period over which the digitized signals are extracted. Stated another way, the greater the ⁇ V per _U for a pair of time-matched component segments, the more significant the resulting ratio and the more heavily the ratio is weighted in the averaging process.
  • the weighted ratio average which is representative of hematocrit, is correlated to a hematocrit value by Microcomputer 36 via a look-up table of corresponding ratio and hematocrit values constructed a priori from clinical studies and depicted numerically and or graphically to the practitioner on Display 240.
  • a look-up table of corresponding ratio and hematocrit values constructed a priori from clinical studies and depicted numerically and or graphically to the practitioner on Display 240.
  • the foregoing process from measurement of voltage across the patient body portion 220 to ultimate output of patient hematocrit on Display 240 is performed repeatedly and substantially continuously, so that variations and trends in hematocrit will be immediately apparent.
  • the use of empirical data for the look-up table is due to the fact that the electrical approximation employed for the whole blood model is first- order, and a rigorous derivation of the response of the model will be inaccurate. Moreover, any such derivations will yield calibration results which vary with the two frequencies chosen, as well as the gain
  • the frequency range of greatest interest previously believed to lie between 50 kHz and 1 MHz, has been proven to be somewhat different and expanded at the high frequency end.
  • the preferred frequency range has subsequently been established to he substantially between 100 kHz and 10 MHz to 20 MHz.
  • the electrical performance characteristics of blood according to the FIG. 1 model over this latter frequency range have been confirmed by the inventor on numerous occasions with a specially prepared test cell.
  • the test cell was fabricated by taking a cylindrical glass tube 1 cm in diameter. One end was sealed with an insulator containing an embedded electrode.
  • the blood sample was then introduced into the test cell, together with a very small quantity of heparin, to prevent the sample from coagulating in the test cell.
  • a removable stopper of an insulating material was then inserted in the open end of the test cell; the stopper also had an embedded electrode that descended into the blood, when the stopper was properly positioned.
  • the impedance characteristic of the blood were then measured in a straight-forward manner (in this configuration, the test cell operates as a two-terminal electrical device) by doing a frequency sweep over the range of interest and measuring the response.
  • C TM Cell Membrane Capacitance of Tissue
  • the Two-Frequency Technique addresses the problem (hematocrit determination) from the point of view of impedance magnitude. Since the equivalent electrical circuits used to model the pertinent physiology contain reactive components (capacitors), the impedance across the frequency spectrum is complex; i.e., magnitude and phase are both pertinent (or, equivalently, real and imaginary parts). However, as noted immediately above, by using measurement frequencies that are sufficiently low and sufficiently high, the capacitive components are either respectively open or closed. Thus, the phase at the measurement frequencies would be expected to be at or near zero.
  • phase angle (phase shift) of a detected waveform relative to the input signal is related to the amount of cell membrane present, and thus to hematocrit.
  • the phase reaches a maximum response in the vicinity of 1.6 MHz (also confirmed by de Vries, et al, previously cited). This is the frequency region approximately corresponding to the point of inflection of the reverse S-shaped impedance/frequency curve.
  • the noninvasive hematocrit determination problem can be solved with a two frequency measurement employing the phase of the detected signals in combination with impedance magnitude, wherein the high frequency is significantly lower than 20 MHz. d.
  • the pulsatile component (known as the plethysmographic signal) is a very small percentage of the baseline DC signal.
  • this plethysmographic signal is 0.05 % - 0.1 % of the magnitude of the baseline. This in itself requires very rigorously designed instrumentation, as heretofore noted, because of the necessary dynamic range.
  • This modified small signal approach is effected by applying a mechanical "assist" to the limb under measurement. To understand the basis for this "assist,” consider what happens when a blood pressure cuff is applied to a limb and taken through an inflation- deflation cycle.
  • the tiny fraction of blood that is able to completely traverse the occlusion zone is nearly pure plasma, because plasma is less viscous than whole blood and the resistance of the nearly totally occluded artery is very high. As the cuff pressure continues to decrease, the resistance presented to the blood also decreases, and more cellular components are able to flow.
  • the desirable effect being sought is one where the artery remains occluded for at least a small portion of the cardiac cycle and where the blood traversing the occlusion zone is representative of whole blood, at least over time.
  • the plethysmographic signal is representative of the total volume of blood in the artery, rather than the small portion of additional volume due to cardiac ejection. Additionally, if the blood traversing the occlusion zone is representative of whole blood over time, then the plethysmographic waveform can be integrated to solve the problem.
  • the cuff pressure is in the region of mean arterial pressure.
  • This pressure zone is non-critical and corresponds to the pressure region where the amplitude of the plethysmographic component of the signal becomes a maximum.
  • the cuff is applied to the body portion (limb) in question proximate the stimulation and sensor electrodes. It is feasible to place the cuff either proximally, distally or over the electrodes, there at present being no identified preferred location for the cuff relative to the electrodes.
  • Pressure in the cuff and inflation and deflation thereof may be controlled via a pump, bleed valve and sensor (pressure transducer) as known in the art, which devices are preferably under control of the microcomputer of the hematocrit determination apparatus.
  • the modified small signal approach should be employed with simultaneous stimulation of the body portion in question at the two selected frequencies, due to the importance of fairly precise synchronization of sampling with the timing of the cuff inflation/deflation cycle.
  • the Large Signal Approach The multi-frequency approach described in connection with FIGS. 3-10 is referred to as a large signal approach.
  • the two-frequency approach is referred to as a small signal approach.
  • An underlying impedance effect has been discovered and verified that allows the determination of hematocrit using electrical measurements. The concept is extended to the noninvasive realm by observing blood plus background tissue and focusing in on the component that is due to blood; i.e., subtracting out the portion of the effect that is due to the background tissue.
  • a large shift in blood is effected by the system and method described in connection with FIGS. 3-10.
  • the nature of the method is such that blood flow artifact is eliminated.
  • the same concept of subtracting out the background tissue impedance is employed, using the equations that result from solving the parallel model.
  • the procedure requires that an initial measurement of the background be taken with the limb under examination at rest, a blood pressure cuff having been previously applied.
  • the cuff is then inflated to a point that is just below diastolic blood pressure. This pressure level allows blood flow during the complete cardiac cycle through the arteries; however, the cuff pressure is sufficient to provide venous occlusion.
  • a vein may also be referred to as a non- pulsatile vascular compartment.
  • the operation of the blood pressure cuff to effectuate the large signal approach is preferably controlled, as with the small signal approach, by the microcomputer of the hematocrit determination apparatus.
  • the apparatus may also be used to provide for the measurement of blood pressure using a different technique than that which is commonly employed in present day noninvasive automatic blood pressure monitors.
  • the blood pressure determination technique of the invention involves the connection of additional interfaces to the patient, this is already being done to obtain the hematocrit noninvasively. Therefore, it is attractive to use the apparatus of the invention to also obtain a blood pressure reading that is, in fact, more accurate than that afforded by the oscillometric technique.
  • the measurement points of interest using a blood pressure cuff and impedance determination electrodes and circuitry are found as follows: the cuff is inflated initially to suppress the plethysmographic signal; as the cuff is deflated, systolic pressure is the point at which the plethysmographic waveform reappears; as cuff deflation continues, mean arterial pressure is the point of maximum intensity of the plethysmographic signal; as cuff deflation continues still further, diastolic pressure is that at which the morphology of the plethysmographic waveform ceases to undergo further change with continued cuff deflation. D.

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Abstract

Procédé et appareil de détermination non invasive de l'hématocrite, fondés sur les caractéristiques d'impédance électrique dépendant de la fréquence du sang entier. Selon ledit procédé, on stimule électriquement une partie du corps d'un patient contenant un compartiment vasculaire à l'aide d'une source de courant sur une gamme de fréquences. Un système de mesure de l'hématocrite comporte un générateur et démodulateur de signaux (SGD) (34) qui envoie un signal appliqué à un ensemble électrodes (36) servant à appliquer un courant sur le membre d'un patient. Ledit ensemble électrodes (36) reçoit les signaux de tension mesurés résultants et les envoie au SGD. Le SGD envoie à un ordinateur personnel (PC) (42) des signaux indicateurs du courant qui passe dans le membre du patient et de la tension obtenue. La tension et le courant peuvent être mesurés pour des fréquences diverses, par exemple sur une gamme allant de 10 kHz à environ 10 MHz. L'impédance électrique du sang seul est isolée de l'impédance totale du membre fournie par le sang, les tissus, les os, etc. par détermination de la différence entre les mesures pour des volumes sanguins différents. L'hématocrite est déterminée par le PC sur la base de données en phase et en quadrature fournies par le SGD. Un réseau neuronal (52) peut être utile pour déterminer l'hématocrite à partir des schémas d'impédance sanguine.
EP96910716A 1995-04-20 1996-04-03 Procede et appareil de determination non invasive de l'hematocrite Withdrawn EP0955871A4 (fr)

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
US425404 1995-04-20
US08/425,404 US5526808A (en) 1990-10-04 1995-04-20 Method and apparatus for noninvasively determining hematocrit
US48449095A 1995-06-07 1995-06-07
US484490 1995-06-07
US602700 1996-02-16
US08/602,700 US5642734A (en) 1990-10-04 1996-02-16 Method and apparatus for noninvasively determining hematocrit
PCT/US1996/004547 WO1996032883A1 (fr) 1995-04-20 1996-04-03 Procede et appareil de determination non invasive de l'hematocrite

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EP0955871A4 EP0955871A4 (fr) 2000-03-22

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JPH0788105A (ja) * 1993-09-22 1995-04-04 Kowa Co 脈波分光計
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JP2001500392A (ja) 2001-01-16
CA2218281A1 (fr) 1996-10-24
WO1996032883A1 (fr) 1996-10-24
EP0955871A4 (fr) 2000-03-22
CA2218281C (fr) 2004-08-17
JP3844779B2 (ja) 2006-11-15
CN1244779A (zh) 2000-02-16
AU5383796A (en) 1996-11-07

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