Robust accurate non-invasive analyte monitor

Details Robust accurate non-invasive analyte monitor Robust accurate non-invasive analyte monitor

1999-09-30

2001-08-21

Nasser, Robert L. (Department: 3736)

Surgery

Diagnostic testing

Measuring or detecting nonradioactive constituent of body...

C600S323000

Reexamination Certificate

active

06278889

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a robust, accurate non-invasive analyte monitor, particularly to a reliable instrument (and associated methodology) for the measurement of glucose levels in a human in both clinical and at home situations. Other analytes which can also be measured include alcohol, BUN (blood urea nitrogen), bilirubin, hemoglobin, creatine, cholesterol, and electrolytes.
BACKGROUND OF THE INVENTION
A major limitation to the clinical goal of achieving ideal diabetic glucose control is the unavailability of unlimited and/or continuous glucose monitoring. Despite the non-invasive advances described in U.S. Pat. No. 4,975,581 to Robinson, et al., a lancet cut into the finger is still necessary for all present forms of home glucose monitoring. This is so compromising to the diabetic patient that the most effective use of any form of diabetic management is rarely achieved, including multiple insulin shots, continuous subcutaneous pump delivery, intraperitoneal or intravascular implanted pump delivery, or oral diabetic pharmaceutical agents. It is possible that diabetic glycemia could be controlled with conventional treatment, external pumps, or implanted insulin delivery devices, if on-line or continuous glucose levels were known by the patient or by a monitoring system. Such information would enable development of a closed loop insulin delivery system.
The theoretical basis for non-invasive glucose determination is based upon quantitative infrared spectroscopy. Infrared spectroscopy measures the electromagnetic radiation (0.7-25 &mgr;m) a substance absorbs at various wavelengths. Molecules do not maintain fixed positions with respect to each other but vibrate back and forth about an average distance. Absorption of light at the appropriate energy causes the molecule to become excited to a higher vibrational level. The excitation of the molecule to an excited state occurs only at certain discrete energy levels, which are characteristic for that particular molecule. Most primary vibrational states occur in the mid-infrared frequency region (i.e., 2.5-25 &mgr;m). However, noninvasive analyte determination in this region is problematic, if not impossible, due to the absorption of the light by water. The problem is overcome through the use of shorter wavelengths of light which are not as attenuated by water. Overtones of the primary vibrational states exist at shorter wavelengths and enable quantitative determination at these wavelengths. Overtones of the primary vibrations occur at ½, ⅓, ¼ . . . and so on of the wavelength of the fundamental mode. Additionally, combination bands also exist. A combination band occurs when the radiation has the correct energy to excite two vibrations at once.
Although glucose absorbs at multiple frequencies in both the mid and near infrared, there are other infrared active analytes in the blood which also absorb at similar frequencies. Due to the overlapping nature of these absorption bands no single or specific frequency can be used for reliable noninvasive glucose measurement. Analysis of spectral data for glucose measurement thus requires evaluation of many spectral intensities over a wide spectral range to achieve the sensitivity, precision, accuracy, and reliability necessary for quantitative determination. This is also true for other blood analytes. In addition to overlapping absorption bands, measurement of glucose is further complicated by the fact that glucose is a minor component by weight in blood and that the resulting spectral data may exhibit a nonlinear response due to both the properties of the substance being examined and/or inherent nonlinearities in optical instrumentation.
The difficulty of modeling the spectral response requires, as set forth in U.S. Pat. No. 4,975,581, the use of multivariate statistical methods rather than univariate methods. These techniques allow information to be extracted from data which cannot be obtained by other data analysis routines. The methods previously disclosed in U.S. Pat. No. 4,975,581, increase analytical precision to the point where the spectroscopic methods become useful for clinical determinations.
Using expensive optical instrumentation, the technology disclosed in U.S. Pat. No. 4,975,581 has been applied for the quantitative measurement of analytes in biological fluids. The focus of this effort has been in the area of noninvasive glucose measurement, portions of which are described in: (1) “Post-Prandial Blood Glucose Determination by Quantitative Mid-Infrared Spectroscopy”, K. J. Ward, D. M. Haaland, M. R. Robinson and R. P. Eaton,
Applied Spectroscopy, Vol.
46, No. 6, 1992, pages 959-965, (2) “Reagentless Near-Infrared Determination of Glucose In Whole Blood Using Multivariate Calibration”, D. M. Haaland, M. R. Robinson, G. W. Koepp, E. V. Thomas, and R. P. Eaton,
Applied Spectroscopy,
Vol. 46, No. 10, 1992, pages 1575-1578, and (3) “Noninvasive Glucose Monitoring in Diabetic Patients: a Preliminary Evaluation”, M. R. Robinson, R. P. Eaton, D. M. Haaland, G. W. Koepp, E. V. Thomas, B. R. Stallard and P. L. Robinson,
Clinical Chemistry,
Vol. 38, No. 9, 1992, pages 1618-1622.
In addition to the body of glucose research disclosed by the foregoing papers, M. K. Alam, R. P. Eaton, D. M. Haaland, M. R. Robinson, P. L. Robinson and E. V. Thomas (hereinafter Alam, et. al.) have worked extensively in the near infrared from 700 to 1400 nm. This spectral region allows transmission of the infrared light through the finger and contains meaningful glucose information. With type-I diabetic volunteers, three representative instrument configurations were investigated. In the first, as disclosed in
Clinical Chemistry,
Vol. 38, No. 9, a Nicolet 800 FTIR instrument equipped with a InSb detector was used. The second system utilized a SPEX grating spectrometer equipped with a germanium array detector. In the third configuration, the SPEX grating spectrometer equipped with the germanium array detector was coupled with fiber optics, which transmitted the light from the instrument to the finger and from the finger back to the instrument. The clinical protocol and method for evaluation of IR spectroscopy for the in vitro determination of blood glucose is described in more detail in the above identified patent and published papers. Work on the second and third configurations has not been published.
With a Nicolet 800 Fourier transform infrared spectrometer (FTIR) equipped with an InSb detector, a diabetic patient undergoing a meal tolerance test was examined using near-infrared transmission measurements through his finger. The patient's blood glucose levels varied between 48 mg/dl and 481 mg/dl, with 41 samples obtained. The average absolute error of prediction on all samples was 19.8 mg/dl. The data are plotted in FIG.
1
.
The feasibility of non-invasive glucose determination was next investigated on a grating spectrometer equipped with a germanium array detector. The optical sampling method was transmission of light (800-1330 nm) through the patient's index finger. The patient's blood glucose level varied between 92 mg/dl and 434 mg/dl, with 29 samples obtained. The average absolute error of prediction for this data was approximately 24.3 mg/dl. The data are plotted in FIG.
2
.
In the final instrument configuration, the grating spectrometer-germanium detector instrument was outfitted with a fiber optic sampling configuration. Fiber optics were used both to transmit light to the finger and to collect light from the opposite side of the finger. The patient's blood glucose level varied from 83 mg/dl and 399 mg/dl, with 21 samples obtained. Analysis of the data yielded an average absolute error of 11.9 mg/dl. The data are plotted in FIG.
3
. The accuracy of this non-invasive determination is comparable to the accuracy of existing invasive home glucose monitors. The results from the fiber optic study were, vis-a-vis the first two configurations, improved due to the ability to repeatedly position the finger between the fiber bundles.

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