Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B5/00—Measuring for diagnostic purposes; Identification of persons
  • A61B5/05—Detecting, measuring or recording for diagnosis by means of electric currents or magnetic fields; Measuring using microwaves or radio waves 
  • A61B5/053—Measuring electrical impedance or conductance of a portion of the body
  • A61B5/0531—Measuring skin impedance
• • 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
  • A61B5/14532—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 glucose, e.g. by tissue impedance measurement
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B5/00—Measuring for diagnostic purposes; Identification of persons
  • A61B5/05—Detecting, measuring or recording for diagnosis by means of electric currents or magnetic fields; Measuring using microwaves or radio waves 

Definitions

• the present invention relates to non-invasive methods and devices for determining the level of glucose in a body fluid of a subject.
• the person's skin is broken or lanced to cause an external flow of blood which is collected in some fashion for the glucose level determination.
• This can be both inconvenient and - 2 - distressful for a person and it is an object of the present invention to avoid the step of obtaining a blood sample directly, at least on a routine or daily basis.
• Radio frequency spectroscopy using spectral analysis for in vitro or in vivo environments is disclosed in WO 9739341 (published October 23, 1997) and WO 9504496 (published February 16, 1995). Measurement of a target chemical such as blood glucose is described. - 3 -
• the present invention is a method and apparatus for non- invasively monitoring levels of glucose in a body fluid of a subject.
• blood glucose levels are determined in a human subject.
• the invention is a method for non- invasively monitoring glucose in a body fluid of a subject in which the method includes steps of measuring impedance between two electrodes in conductive contact with a skin surface of the subject and determining the amount of glucose in the body fluid based upon the measured impedance.
• the body fluid in which it is desired to know the level of glucose is blood. In this way, the method can be used to assist in determining levels of insulin administration.
• the step of determining the amount of glucose can include comparing the measured impedance with a predetermined relationship between impedance and blood glucose level, further details of which are described below in connection with preferred embodiments.
• the step of determining the blood glucose level of a subject includes ascertaining the sum of a fraction of the magnitude of the measured impedance and a fraction of the phase of the measured impedance.
• impedance is measured at a plurality of frequencies
• the method includes determining the ratio of one or more pairs of measurements and determining the amount of glucose in the body fluid includes comparing the determined ratio(s) with corresponding predetermined ratio(s), i.e., that have been previously correlated with directly measured glucose levels.
• the method of the invention includes measuring impedance at two frequencies and determining the amount of glucose further includes determining a predetermined index, the index including a ratio of first and second numbers obtained from first and second of the impedance measurements.
• the first and second numbers can include a component of said first and second impedance measurements, respectively.
• the first number can be the real part of the complex electrical impedance at the first frequency and the second number can be the magnitude of the complex electrical impedance at the second frequency.
• the first number can be the imaginary part of the complex electrical impedance at the first frequency and the second number can be the magnitude of the complex electrical impedance at the second frequency.
• the first number can be the magnitude of the complex electrical impedance at the first frequency and the second number can be the magnitude of the complex electrical impedance at the second frequency.
• determining the amount of glucose further includes determining a predetermined index in which the index includes a difference between first and second numbers obtained from first and second of said impedance measurements.
• the first number can be the phase angle of the complex electrical impedance at the first frequency and said second number can be the phase angle of the complex electrical impedance at the second frequency.
• the skin site can be located on the volar forearm, down to the wrist, or it can be behind an ear of a human subject.
• the skin surface is treated with a saline solution prior to the measuring step.
• An electrically conductive gel can be applied to the skin to enhance the conductive contact of the electrodes with the skin surface during the measuring step.
• the electrodes can be in operative connection with a computer chip programmed to determine the amount of glucose in the body fluid based upon the measured impedance.
• the indicator can provide a visual display to the subject.
• the computer chip is operatively connected to an insulin pump and the computer chip is programmed to adjust the amount of insulin flow via the pump to the subject in response to the determined amount of glucose. Electrodes of a probe of the invention can be spaced between about 0.2 mm and about 2 cm from each other.
• the invention is an apparatus for non-invasive monitoring of glucose in a body fluid of a subject.
• the apparatus includes means for measuring impedance of skin tissue in response to a voltage applied thereto and a microprocessor operatively connected to the means for measuring impedance, for determining the amount of glucose in the body fluid based upon the impedance measurement(s).
• the means for measuring impedance of skin tissue can include a pair of spaced apart electrodes for electrically conductive contact with a skin surface.
• the microprocessor can be programmed to compare the measured impedance with a predetermined correlation between impedance and blood glucose level.
• the apparatus can include means for measuring impedance at a plurality frequencies of the applied voltage and the programme can include means for determining the ratio of one or more pairs of the impedance measurements and means for comparing the determined ratio(s) with corresponding predetermined ratio(s) to determine the amount of glucose in the body fluid.
• the apparatus preferably includes an indicator operatively connected to the microprocessor for indication of the determined amount of glucose.
• the indicator can provide a visual display for the subject to read the determined amount of glucose. It is possible that the indicator would indicate if the glucose level is outside of an acceptable range.
• the microprocessor is operatively connected to an insulin pump and the apparatus includes means to adjust the amount of insulin flow via the pump to the subject in response to the determined amount of glucose. - 6 -
• the apparatus can include a case having means for mounting the apparatus on the forearm of a human subject with the electrodes in electrically conductive contact with a skin surface of the subject.
• the apparatus includes means for calibrating the apparatus against a directly measured glucose level of a said subject.
• the apparatus can thus include means for inputting the value of the directly measured glucose level in conjunction with impedance measured about the same time, for use by the programme to determine the blood glucose level of that subject at a later time based solely on subsequent impedance measurements.
• a microprocessor of the apparatus can be programmed to determine the glucose level of a subject based on the sum of a fraction of the magnitude of the measured impedance and a fraction of the phase of the measured impedance.
• Figure 1 shows plots of various indices as a function of time and glucose concentration based on impedance measurements taken on the skin (SCIM) of a first diabetic subject.
• Figure 1 (a) shows MIX versus measurement number, the timing of the measurements being given in Table 1.
• Figure 1(b) shows PIX versus measurement number.
• Figure 1 (c) shows RIX versus measurement number.
• Figure 1 (d) shows IMIX versus measurement number. The determinations of MIX, PIX, RIX and IMIX are described in the text.
• Figures 2(a), 2(b), 2(c) and 2(d) are similar to Figures 1(a) to 1(d), respectively, but are based on impedance measurement taken on the skin of a second diabetic subject. - 7 -
• Figure 3 is a plot showing the reading (average of ten readings) of a dermal phase meter as a function of directly determined blood glucose concentration. Measurements were taken on a site on the left forearm (•) and right forearm (+); and Figure 4 is similar to Figure 3, but readings were taken at a finger.
• a preferred method of the invention involves directly contacting a subject's skin with an electrode, taking one or more impedance measurements and determining the subject's blood glucose level based on the impedance measurement(s).
• a computer programmed to make the determination based on the impedance measurement(s).
• the invention includes deriving a number of indices from one or more measurements of impedence between poles of the electrode. The value(s) of the one or more indices is an indicator of, i.e. correlates with, the subject's blood glucose level.
• the invention is illustrated below by laboratory feasibility tests to establish that a correlation between one or more such index values based on impedance measurement(s) and a subject's blood glucose level exists.
• the tests were conducted using particular parameters, for example impedance measurements obtained at a certain frequency or certain frequencies, and particular indices were dervied therefrom. It will be understood that other and/or additional frequencies may be found to be more optimal and that other indicies may well be found to be more optimal.
• Impedance measurements were taken at the volar forearm using the "SCIM" apparatus described below. Impedance measurements were taken at thirty- one frequencies and four different indices were determined using two of the - 8 - frequencies: 20 and 500 kHz. Directly measured blood glucose levels of each subject are indicated in Table 1.
• Figures 1 and 2 are based were obtained using a Surface Characterizing Impedance Monitor (SCIM) developed by Ollmar (United States Patent No. 5,353,802, issued October 11 , 1994; "Instrument evaluation of skin irritation", P.Y. Rizvi, B.M. Morrison, Jr., M.J. Grove and G.L. Grove, Cosmetics & Toiletries., 111: 39, 1996; "Electrical impedance index in human skin: Measurements after occlusion, in 5 anatomical regions and in mild irritant contact dermatitis", L. Emtestam and S. Ollmar, Cont. Derm. 28: 337, 1975; "Electrical impedance for estimation of irritation in oral mucosa and skin", S.
• SCIM Surface Characterizing Impedance Monitor
• the instrument is basically an AC-bridge fabricated from standard laboratory instruments: a function generator, a digital oscilloscope, impedance references, and a driver for the probe.
• the indices plotted in Figures 1 and 2 were determined as follows: - 11 -
• MIX (magnitude index) aos(Z 20kHz )/abs(Z 500kHz )
• phase index arg * (Z 20kH2 ) - arg(Z 500kH2 )
• RIX (real part index) Re(Z 20kH2 )/a )s(Z 500kHz )
• IMIX (imaginary part index) /m(Z 20kHz )/a ⁇ s(Z 500kHz ) where abs ⁇ Z,) is the magnitude (modulus) of the complex electrical impedance at the frequency /, arg(Z,) the argument (phase angle) in degrees, Re(Z,) the real part of the complex electrical impedance, and /t77(Z,) the imaginary part of the complex electrical impedance.
• the RIX reflects changes mainly in conductivity; the IMIX reflects mainly reactance changes, which are of capacitive nature; the MIX reflects changes along the length of the vector describing the impedance in complex space, which will be emphasized if the real and imaginary parts change in the same direction and proportion; the PIX will be emphasized if the real and imaginary parts change in different directions and/or in different proportions.
• the skin Prior to contacting a subject's skin with the electrode, the skin is treated with a 0.9% saline solution by holding a soaked gauze against the measurement site for about a minute and then wiping the site with a dry cloth.
• the purpose of this step is to ensure adequate electrical coupling between the skin and the probe (electrode) in order to reduce variability that may introduced into the measurements by stratum corneum.
• a person skilled in the art would understand that variations are possible, and more optimal pre- treatment conditions may be obtainable.
• Blood glucose levels were determined directly from a blood sample using a lancet prick and measuring the blood glucose concentration with an Elite Glucometer according to manufacturer's instructions (Elite Glucometer, Miles Canada, Diagnostics Division, Division of Bayer). In a second set of experiments, 31 subjects were tested using the
• the multiple R for the prediction was 0.33.
• the SCIM instrument was used to measure impedance measured at 31 different frequencies logarithmically distributed in the range of 1 kHz to 1 Mhz (10 frequencies per decade). Subsequent determinations were based, in the first set of experiments, on two of the frequencies: 20 and 500kHz; and in the second set of experiments, 20 kHz only. It may be found in the future that there is a more optimal frequency or frequencies. It is quite possible, in a commercially acceptable instrument that impedance will be determined at at least two frequencies, rather than only one. For practical reasons of instrumentation, the upper frequency at which impedance is measured is likely to be about 500 kHz, but higher frequencies, even has high as 5 MHz or higher are possible and are considered to be within the scope of this invention. Relationships may be established using data obtained at one, two or more frequencies.
• a preferred instrument specifically for determining glucose levels of a subject, includes a 2-pole measurement configuration that measures impedance at multiple frequencies, preferably two well spaced apart frequencies.
• the instrument includes a computer which also calculates the index or indices that correlate with blood glucose levels and determines the glucose levels based on the corrlelation(s).
• the invention is also illustrated by experiments that were carried out with a dermal phase meter (DPM) available from NovaTM Technology - 13 -
• DPM dermal phase meter
• electrodes of a device are placed in conductive contact with a subject's skin in order to measure impedance (Z) at various frequencies (f) in a range from a few Hertz (hz) (say 10 hz) to about 5 Mhz. A more typical range would be between 1 kHz and 1 Mhz, and more likely between 5 kHz and 500 kHz.
• Electrodes of the device are electrically - 14 - connected to a metering device which indicates the impedance at a selected frequency of applied voltage, as understood by a person skilled in the art. In a particular embodiment, the device is programmed to operate at the selected frequencies in rapid sequence.
• the voltage can be rapidly increased with time and Fourier transformation carried out to obtain a frequency spectrum.
• Ratios of impedance measured at various frequencies are determined and the blood glucose level of the subject is measured directly. This process is repeated at different times so as to make the determination at a number of different glucose levels.
• ratios of impedance determined at particular frequencies which are found to reproducibly reflect a person's blood glucose levels over a range of glucose levels are determined.
• the ratios of measured impedance at the selected frequencies can thus be correlated with directly measured glucose levels, that is, a plot in which log(Z 1 /Z 2 ) vs log (f) is a linear correlation, or an approximately linear correlation, is determined.
• Impedance includes both resistance and reactance. It may be found for a proportion of the population that there is a universal set of impedance frequency ratios, thus avoiding the necessity of determining individual correlations.
• an appropriate skin site is chosen.
• an undamaged skin site and one that is not heavily scarred would be chosen.
• a skin site having a stratum corneum which is less likely to deleteriously interfere with the measurements is chosen.
• a likely possibility is the volar forearm, down to the - 15 - wrist, or behind an ear.
• the skin surface can be treated just prior to measurement in order to render the stratum corneum more electrically transparent by application, for example, of a physiological saline dressing for about a minute. Excess liquid should be removed before application of the probe.
• the invention be used only in circumstances in which it is known that the approach described herein reliably indicates glucose levels of a subject. It is possible that the invention would not be suitable for use with a given proportion of the population or 100% of the time with a given individual. For example, an individual may have a skin condition which deleteriously interferes with impedance measurements, making it difficult to assume that impedance measurements can reliably indicate a person's blood glucose level. For such a person, a different approach to glucose level determination would be more suitable.
• An apparatus that utilizes a neural network to carry out analyses based on impedance could be trained for a specific subject, or possibly a group of subjects.
• An example of such a group of subjects might be subjects of the same sex, belonging to a particular age group and within particular height and weight ranges.
• - t may be advantageous to optimize the spacing of the electrodes of the probe. That is, it may found that the electrodes of a SCIM probe are too close to each other to provide maximally reproducible results.
• An object of a suitable probe is to have electrodes spaced from each other to obtain optimal penetration of current into tissue containing glucose in its interstitial spaces. It is expected that electrodes spaced somewhere between about 0.2 mm and about 2 cm are suitable.
• a gel can improve skin-probe contact to more reliably produce useful measurements, as would be known to a person skilled in the art, e.g., a gel comprising mostly water in combination with a - 16 - thickener such as Cellusize, glycerin or propylene glycol as a moisturizer, and a suitable preservative.
• a gel comprising mostly water in combination with a - 16 - thickener such as Cellusize, glycerin or propylene glycol as a moisturizer, and a suitable preservative.
• An apparatus for non-invasive monitoring of glucose in a body fluid of a subject includes means for measuring impedance of skin tissue in response to a voltage applied thereto, i.e. a probe.
• a computer processor operatively connected to the means for measuring impedance for determining the blood glucose level based upon one or more impedance measurements.
• the microprocessor is programmed to calculate the blood glucose level of a subject based upon impedance measurements taken at one or more frequencies.
• a calcuation based upon impedance at a single frequency, along the lines of that shown in relationship (1 ) is carried out by the processor.
• the calculation includes determining MIX and/or IMIX.
• the calculation might include determining PIX.
• the calculation might include determining RIX. It might be necessary to calibrate an individual apparatus for use with a particular subject.
• the apparatus includes means for calibrating the apparatus against a directly measured glucose level of that subject.
• the apparatus could thus include means for inputting the value of the directly measured glucose level in conjunction with impedance measured about the same time, for use by the programme to determine the blood glucose level of that subject at a later time based solely on subsequent impedance measurements.
• a meter is worn in which a probe is continuously in contact with the skin and moisture buildup between occlusive electrodes and the skin is sufficient to obtain useful measurements.
• the device can be mountable on a person's forearm, much like a wristwatch. Such an embodiment might not prove to be useful for all subjects.
• a - 17 - preferred monitoring device of the invention includes means for calibrating the relationship between a directly measured blood glucose level and an index or indices of interest.
• blood glucose level determinations of the present invention are non-invasive and relatively painless it is possible to make such determinations with a greater frequency than with a conventional pin-prick method.
• blood glucose levels are monitored quite frequently, say every fifteen or five, or even one minute or less, and an insulin pump is interfaced with the meter to provide continual control of blood glucose in response to variations of blood glucose levels ascertained by means of the meter.

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• 1998
  • 1998-02-04 AU AU61421/98A patent/AU762922B2/en not_active Ceased
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