USRE44875E1 - Active pulse blood constituent monitoring - Google Patents

Abstract

A blood constituent monitoring method for inducing an active pulse in the blood volume of a patient. The induction of an active pulse results in a cyclic, and periodic change in the flow of blood through a fleshy medium under test. By actively inducing a change of the blood volume, modulation of the volume of blood can be obtained to provide a greater signal to noise ratio. This allows for the detection of constituents in blood at concentration levels below those previously detectable in a non-invasive system. Radiation which passes through the fleshy medium is detected by a detector which generates a signal indicative of the intensity of the detected radiation. Signal processing is performed on the electrical signal to isolate those optical characteristics of the electrical signal due to the optical characteristics of the blood.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

Notice: More than one reissue application has been filed for the reissue of U.S. Pat. No. 7,239,905. The reissue applications are application Ser. No. 13/047,740 (the present application) and Ser. No. 12/497,517, both of which are reissues of U.S. Pat. No. 7,239,905.

This application is a continuation of U.S. patent application Ser. No. 09/706,965, filed Nov. 6, 2000, now U.S. Pat. No. 6,931,268, issued Aug. 16, 2005, which is a continuation of U.S. patent application Ser. No. 09/190,719, filed Nov. 12, 1998, now U.S. Pat. No. 6,151,516, issued Nov. 21, 2000, which is a continuation of U.S. patent application Ser. No. 08/843,863, filed Apr. 17, 1997, now U.S. Pat. No. 5,860,919, issued Jan. 19, 1999, which is a continuation of U.S. patent application Ser. No. 08/482,071, filed Jun. 7, 1995, now U.S. Pat. No. 5,638,816, issued Jun. 17, 1997. The present application incorporates the foregoing disclosures herein by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to noninvasive systems for monitoring blood glucose and other difficult to detect blood constituent concentrations, such as therapeutic drugs, drugs of abuse, carboxyhemoglobin, Methemoglobin, cholesterol.

2. Description of the Related Art

In the past, many systems have been developed for monitoring blood characteristics. For example, devices have been developed which are capable of determining such blood characteristics as blood oxygenation, glucose concentration, and other blood characteristics. However, significant difficulties have been encountered when attempting to determine blood glucose concentration accurately using noninvasive blood monitoring systems such as by means of spectroscopic measurement.

The difficulty in determining blood glucose concentration accurately may be attributed to several causes. One of the significant causes is that blood glucose is typically found in very low concentrations within the bloodstream (e.g., on the order of 100 to 1,000 times lower than hemoglobin) so that such low concentrations are difficult to detect noninvasively, and require a very high signal-to-noise ratio. Additionally, with spectroscopic methods, the optical characteristics of glucose are very similar to those of water which is found in a very high concentration within the blood. Thus, where optical monitoring systems are used, the optical characteristics of water tend to obscure the characteristics of optical signals due to glucose within the bloodstream. Furthermore, since each individual has tissue, bone and unique blood properties, each measurement typically requires calibration for the particular individual.

In an attempt to accurately measure blood glucose levels within the bloodstream, several methods have been used. For example, one method involves drawing blood from the patient and separating the glucose from the other constituents within the blood. Although fairly accurate, this method requires drawing the patient's blood, which is less desirable than noninvasive techniques, especially for patients such as small children or anemic patients. Furthermore, when blood glucose monitoring is used to control the blood glucose level, blood must be drawn three to six times per day, which may be both physically and psychologically traumatic for a patient. Other methods contemplate determining blood glucose concentration by means of urinalysis or some other method which involves pumping or diffusing body fluid from the body through vessel walls or using other body fluids such as tears or sweat. However, such an analysis tends to be less accurate than a direct measurement of glucose within the blood, since the urine, or other body fluid, has passed through the kidneys (or skin in the case of sweat). This problem is especially pronounced in diabetics. Furthermore, acquiring urine and other body fluid samples is often inconvenient.

As is well known in the art, different molecules, typically referred to as constituents, contained within the medium have different optical characteristics so that they are more or less absorbent at different wavelengths of light. Thus, by analyzing the characteristics of the fleshy medium containing blood at different wavelengths, an indication of the composition of the blood in the fleshy medium may be determined.

Spectroscopic analysis is based in part upon the Beer-Lambert law of optical characteristics for different elements. Briefly, Beer-Lambert's law states that the optical intensity of light through any medium comprising a single substance is proportional to the exponent of the product of path length through the medium times the concentration of the substance within the medium times the extinction coefficient of the substance. That is,
l=l_oe^−(pl*c*ε)  (1)
where pl represents the path length through the medium, c represents the concentration of the substance within, the medium, ε represents the absorbtion (extinction) coefficient of the substance and l_ois the initial intensity of the light from the light source. For optical media which have several constituents, the optical intensity of the light received from the illuminated medium is proportional to the exponent of the path length through the medium times the concentration of the first substance times the optical absorption coefficient associated with the first substance, plus the path length times the concentration of the second substance times the optical absorption coefficient associated with the second substance, etc. That is,
l=l_oe^{−(pl*c1*ε1+pl*c2*ε2+etc.)}  (2)
where ε_nrepresents the optical absorption (extinction) coefficient of the n^thconstituent and c_nrepresents the concentration of the n^thconstituent.

SUMMARY OF THE INVENTION

Due to the parameters required by the Beer-Lambert law, the difficulties in detecting glucose concentration arise from the difficulty in determining the exact path length through a medium (resulting from transforming the multi-path signal to an equivalent single-path signal), as well as difficulties encountered due to low signal strength resultant from a low concentration of blood glucose. Path length through a medium such as a fingertip or earlobe is very difficult to determine, because not only are optical wavelengths absorbed differently by the fleshy medium, but also the signals are scattered within the medium and transmitted through different paths. Furthermore, as indicated by the above equation (2), the measured signal intensity at a given wavelength does not vary linearly with respect to the path length. Therefore, variations in path length of multiple paths of light through the medium do not result in a linear averaging of the multiple path lengths. Thus, it is often very difficult to determine an exact path length through a fingertip or earlobe for each wavelength.

In conventional spectroscopic blood constituent measurements, such a blood oxygen saturation, light is transmitted at various wavelengths through the fleshy medium. The fleshy medium (containing blood) attenuates the incident light and the detected signal can be used to calculate certain saturation values. In conventional spectroscopic blood constituent measurements, the heart beat provides a minimal modulation to the detected attenuated signal in order to allow a computation based upon the AC portion of the detected signal with respect to the DC portion of the detected signal, as disclosed in U.S. Pat. No. 4,407,290. This AC/DC operation normalizes the signal and accounts for variations in the pathlengths, as well understood in the art.

However, the natural heart beat generally provides approximately a 1-10% modulation (AC portion of the total signal) of the detected signal when light is transmitted through a patient's digit or the like. That is, the variation in attenuation of the signal due to blood may be only 1% of the total attenuation (other attenuation being due to muscle, bone, flesh, etc.). In fact, diabetes patients typically have even lower modulation (e.g., 0.01-0.1%). Therefore, the attenuation variation (AC portion of the total attenuation) due to natural pulse can be extremely small. In addition, the portion of the pulse modulation which is due to glucose is roughly only 9% of the pulse (approximately 1/11) at a wavelength of 1330-1340 nm where glucose absorbs effectively. Furthermore, to resolve glucose from 5 mg/dl to 1005 mg/dl in increments or steps of 5 mg/dl, requires resolution of 1/200 of the 9% of the modulation which is due to glucose. Accordingly, by way of three different examples—one for a healthy individual, one for a diabetic with a strong pulse, and one for a diabetic with a weak pulse—for absorption at 1330 nm, the system would require resolution as follows.

EXAMPLE 1Healthy Individuals where Natural Pulse Provides Attenuation Modulation of 1% at 1330 nm

• • a. Natural modulation due to pulse is approximately 1% ( 1/100).
  • b. Portion of natural modulation due to glucose is approximately 9% ( 1/11).
  • c. To resolve glucose from 5-1005 mg/dl requires resolution of 1/200 (i.e., there are 200, 5 mg/dl steps between 5 and 1005 mg/dl).

Required Total Resolution is product of a-c: 1/100* 1/11* 1/200= 1/220,000

EXAMPLE 2Diabetic where Natural Pulse Provides Attenuation Modulation of 0.1% at 1330 nm

• • a. Natural modulation due to pulse approximately 0.1% ( 1/1000).
  • b. Portion of natural modulation due to glucose is approximately 9% ( 1/11)
  • c. To resolve glucose from 5-1005 mg/dl requires resolution of 1/200.

Required total resolution is product of a-c: 1/100* 1/11* 1/200= 1/220,000

EXAMPLE 3Diabetic where Natural Pulse Provides Attenuation Modulation of 0.01%

• • a. Natural modulation due to pulse approximately 0.01% ( 1/10,000).
  • b. Portion of natural modulation due to glucose is approximately 9% ( 1/11).
  • c. To resolve glucose from 5-1005 mg/dl requires resolution of 1/200.

Required total resolution is product of a-c: 1/10,000* 1/11* 1/200= 1/220,000

As seen from the above three examples which provide the range of modulation typically expected among human patients, the total resolution requirements range from 1 in 220,000 to 1 in 22,000,000 in order to detect the attenuation which is due to glucose based on the natural pulse for the three examples. This is such a small portion that accurate measurement is very difficult. In most cases, the noises accounts for a greater portion of the AC portion (natural modulation due to pulse) of the signal than the glucose, leaving glucose undetectable. Even with state of the art noise reduction processing as described in U.S. patent application Ser. No. 08/249,690, filed May 26, 1994, now U.S. Pat. No. 5,482,036, signals may be resolved to a level of approximately 1/250,000. This is for an 18-bit system. With a 16-bit system, resolution is approximately 1/65,000. In addition, LEDs are often noisy such that even if resolution in the system is available to 1/250,000, the noise from the LEDs leave glucose undetectable.

To overcome these obstacles, it has been determined that by actively inducing a change in the flow of blood in the medium under test such that the blood flow varies in a controlled manner periodically, modulation can be obtained such that the portion of the attenuated signal due to blood becomes a greater portion of the total signal than with modulation due to the natural pulse. This leads to the portion of total attenuation due to glucose in the blood being a greater portion of the total signal. In addition, the signal can be normalized to account for factors such as source brightness, detector responsiveness, tissue or bone variation. Changes in blood flow can be induced in several ways, such as physically perturbing the medium under test or changing the temperature of the medium under test. In the present embodiment, by actively inducing a pulse, a 10% modulation in attenuation ( 1/10 of the total attenuation) is obtained, regardless of the patient's natural pulse modulation (whether or not the patient is diabetic). Accordingly, at 1330 nm with actively induced changes in blood flow, the resolution required is 1/10* 1/11* 1/200 or 1/22,000 (where 1/10 is the active pulse attenuation modulation (the modulation obtained by induced blood flow changes), 1/11 is the portion of the modulation due to glucose, and 1/200 the resolution required to obtain glucose in 5 mg/dl increments from 5-1005 mg/dl). As will be understood from the discussion above, such resolution can be obtained, even in a 16 bit system. In addition, the resolution is obtainable beyond the noise floor, as described herein.

In conventional blood constituent measurement through spectroscopy, perturbation of the medium under test has been avoided because oxygen (the most commonly desired parameter) is not evenly dispersed in the arterial and venous blood. Therefore, perturbation obscures the ability to determine the arterial oxygen saturation because that venous and arterial blood become intermingled. However, glucose is evenly dispersed in blood fluids, so the mixing of venous and arterial blood and interstitial fluids should have no significant effect on the glucose measurements. It should be appreciated that this technique will be effective for any substance evenly dispersed in the body fluids (e.g., blood, interstitial fluids, etc.).

One aspect of the present invention involves a system for non-invasively monitoring a blood constituent concentration in a living subject. The system comprises a light source which emits radiation at a plurality of wavelengths and an active pulse inducement device which, independent of the natural flow of blood in the fleshy medium, causes a periodic change in the volume of blood in the fleshy medium. An optical detector positioned to detect light which has propagated through the fleshy medium is configured to generate an output signal indicative of the intensity of the radiation after attenuation through the fleshy medium. A signal processor responds to the output signal to analyze the output signal to extract portions of the signal due to optical characteristics of the blood to determine the concentration of the constituent within the subject's bloodstream.

In one embodiment, of the system further comprises a receptacle which receives the fleshy medium, the receptacle further having an inflatable bladder.

In one embodiment, the system has a temperature variation element in the receptacle, the temperature variation element varies (e.g., increases) the temperature of the fleshy medium in order to induce a change (e.g., increase) in the flow of blood in the fleshy medium.

Another aspect of the present invention involves a system for non-invasively monitoring blood glucose concentration within a patient's bloodstream. A light source emits optical radiation at a plurality of frequencies, and a sensor receives a fleshy medium of the patient, the fleshy medium having flowing blood. A fluid (e.g., blood and interstitial fluids) volume change inducement device causes a cyclic change in the volume of blood in the fleshy medium. An optical detector positioned to receive the optical radiation after transmission through a portion of the fleshy medium responds to the detection of the optical radiation to generate an output signal indicative of the intensity of the optical radiation. A signal processor coupled to the detector receives the output signal, and responds to the output signal to generate a value representative of the glucose concentration in the blood of the patient.

Yet another aspect of the present invention involves a method of non-invasively determining a concentration of a blood constituent. The method comprises a plurality of steps. Optical radiation is transmitted through a medium having flowing fluid, wherein the fluid has a concentration of the fluid constituent. A periodic change in the volume of the fluid in the medium is actively induced. The optical optical radiation after transmission through at least a portion of the medium is detected and a signal indicative of the optical characteristics of the medium is generated. The signal is analyzed to determine the concentration of the blood constituent. In one embodiment, the fluid constituent comprises blood glucose.

A further aspect of the present invention involves a method of actively varying the attenuation of optical radiation due to blood in a fleshy medium. The method comprises a plurality of steps. Optical radiation is transmitted through the fleshy medium. A periodic change in the volume of blood is actively influenced in the medium The optical radiation is detected after attenuation through the fleshy medium and an output signal indicative of the intensity of the attenuated signal is generated.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts an embodiment of a blood glucose monitor of the present invention.

FIG. 2 depicts an example of a physiological monitor in accordance with the teachings of the present invention.

FIG. 2A illustrates an example of a low noise emitter current driver with accompanying digital to analog converter.

FIG. 2B depicts an embodiment ofFIG. 2 with added function for normalizing instabilities in emitters ofFIG. 2.

FIG. 2C illustrates a comparison between instabilites in selected emitters.

FIG. 3 illustrates the front end analog signal conditioning circuitry and the analog to digital conversion circuitry of the physiological monitor ofFIG. 2.

FIG. 4 illustrates further detail of the digital signal processing circuitry ofFIG. 2.

FIG. 5 illustrates additional detail of the operations performed by the digital signal processing circuitry ofFIG. 2.

FIG. 6 illustrates additional detail regarding the demodulation module ofFIG. 5.

FIG. 7 illustrates additional detail regarding the decimation module ofFIG. 5. FIG.

FIG. 8 represents a more detailed block diagram of the operations of the glucose calculation module ofFIG. 5.

FIG. 9 illustrates the extinction coefficient versus wavelength for several blood constituents.

FIGS. 10-12 depict one embodiment of a probe which can be used to induce an active pulse in accordance with the principals of the present invention.

FIG. 13 depicts an example of the an active pulse signal where the modulation is 10% of the entire attenuation through the finger.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

FIG. 1 depicts one embodiment of a bloodglucose monitor system100 in accordance with the teachings of the present invention. The glucose monitor100 ofFIG. 1 has anemitter110 such as light emitting diodes or a light with a filter wheel as disclosed in U.S. patent application Ser. No. 08/479,164, now U.S. Pat. No. 5,743,262 Masimo. 014A) entitled Blood Glucose Monitoring System, filed on the same day as this application, and assigned to the assignee of this application, which application is incorporated by reference herein.

The filter wheel with a broadband light is depicted inFIG. 1. This arrangement comprises afilter wheel110A, amotor110B, and abroadband light source110C. Advantageously, this unit can be made relatively inexpensively as a replaceable unit. The filter wheel is advantageously made in accordance with U.S. patent application Ser. No. 08/486,798 now U.S. Pat. No. 5,760,910 entitled Optical Filter for Spectroscopic Measurement and Method of Producing the Optical Filter, filed on the same date as this application, and assigned to the assignee of this application, which application is incorporated herein by reference.

Themonitor system100 has adetector140, such as a photodetector. The blood glucose monitor100 also has apressure inducing cuff150 to physically squeeze adigit130 in order to periodically induce a “pulse” in the fluid (i.e., actively vary the flow of fluid) in adigit130. In other words, a device influences a change in the volume of blood in the digit or other fleshy medium. Awindow111 is positioned to allow light from theemitter110 to pass through the window11 and transmit through thedigit130. This intentional active perturbation of the blood in the digit or medium under test is further referred to herein as an “active pulse.” The blood glucose monitor also has adisplay160 which may be used to indicate such parameters as glucose concentration and signal quality. Advantageously, the blood glucose monitor also has apower switch154, astart switch156 and a trend data switch158.

Other methods of inducing a pulse are also possible. For instance, the fleshy medium under test, such as the patient's digit, could be perturbed with a pressure device152 (depicted in dotted lines inFIG. 1). Other methods of inducing a pulse could be utilized such as temperature fluctuations or other physiological changes which result in a fluctuation (modulation) of blood volume through the fleshy medium. All external methods (as opposed to the natural heart beat) actively vary the blood volume in the medium under test are collectively referred to herein as inducing an “active pulse.” In the present embodiment, 10% modulation in the total attenuation is obtained through the active induction of a pulse. The 10% modulation is selected as a level of minimal perturbation to the system. Too much perturbation of the medium will change the optical characteristics of the medium under test. For instance, with substantial modulation (e.g., 40-50%), the perturbation could impact scattering within the medium under test differently for different wavelengths, thus causing inacurate measurements.

Thepressure device152, thecuff150 and the use of temperature to induce a pulse in the fleshy medium are advantageous in that they can be used with minimal or no movement of the fleshy medium in the area through which light is transmitted. This is possible through inducing the pulse at a location proximal or distal from the area receiving the incident light. The advantage of minimal movement is that movement in the area of the fleshy medium under test causes variation in the detected signal other than due to the varying fluid volume (e.g., blood and interstitial fluid) flow. For instance, physical perturbation in the area of light transmission can cause changes in the light coupling to the medium under test resulting in variations in attenuation which are not due to changes in fluid volume in the area of light transmission. These other variations comprise additional noise that should be removed for accurate measurement.

FIGS. 2-4 depict a schematic block diagram of the bloodglucose monitoring system100 in accordance with the teachings of the present invention.FIG. 2 illustrates a general hardware block diagram. Asensor300 has multiple light emitters301-305 such as LED's. In the present embodiment, each LED301-305 emits light at a different wavelength.

As well understood in the art, because Beer-Lambert's law contains a term for each constituent which attenuates the signal, one wavelength is provided for each constituent which is accounted for. For increased precision, the wavelengths are chosen at points where attenuation for each particular constituent is the greatest and attenuation by other constituents is less significant.FIG. 9 depicts the extinction coefficient on a log scale vs. wavelength for principal blood constituents. The curve162 represents the extinction coefficient for oxyhemoglobin; the curve164 represents the extinction coefficient for hemoglobin; the curve165 represents the extinction coefficient for carboxyhemoglobin; and the curve166 represents the extinction coefficient for water. Depicted on the same horizontal axis with a different vertical axis is a curve168 which represents the extinction coefficient for glucose in body fluids. It should be noted that the curve168 is placed above the other curves and is greatly amplified, and therefore is not to scale on the graph. If the glucose curve were graphed on the same scale as the other constituents, it would simply appear as flat line at ‘0’ on the vertical axis in the wavelength range from 900-1400 mm. The provision for a seperate vertical axis provides for amplification in order to illustrate at which wavelengths glucose attenuates the most in the range of interest. The vertical axis for the glucose curve168 also represents a different value. InFIG. 9, the vertical axis for the curve168 is in terms of the absolute transmission on the following log scale:
[log(log(average water))]−[log(log(6400 mg/dl glucose))]

However, for purposes of choosing appropriate wavelengths, the scale is of less significance that the points at which Glucose and the other constituents show good attenuation and the attenuation is not totally obscured by other constituents in the medium.

In the present embodiment, advantageous wavelengths for the emitters301-305 (or to obtain with the filter wheel and signal processing) are 660 nm (good attenuation hemoglobin), 905 nm (good attenuation from oxyhemoglobin), 1270 nm (good attenuation by water, and little attenuation by other constituents) 1330-1340 nm (good attenuation due to Glucose in the area of the graph labelled A ofFIG. 9, not totally obscured by the attenuation due to water), and 1050 nm (an additional point for good attenuation from Glucose). The use of two wavelengths to account for glucose attenuation provides overspecification of the equations. Overspecification of the equations discussed below increases resolution. Additional wavelengths to account for other constituents such as fats and proteins or others could also be included. For instance, an additional wavelength at 1100 nm could be added (good attenuation from-proteins) and 920 nm (good attenuation from fats). Another constituent often of interest is carboxyhemoglobin. A wavelength for carboxyhemoglobin is advantageously selected at 700-730 nm.

In addition to using multiple precise LEDs, an optical spectroscopic system for generating the optical characteristics over many wavelengths can be used. Such a device is disclosed in U.S. patent application Ser. No. 08/479,164, entitled Blood Glucose Monitoring System, filed on the same day as this application, and assigned to the assignee of this application.

Thesensor300 further comprises a detector320 (e.g., a photodetector), which produces an electrical signal corresponding to the attenuated light energy signals. Thedetector320 is located so as to receive the light from the emitters301-305 after it has propagated through at least a portion of the medium under test. In the embodiment depicted inFIG. 2, thedetector320 is located opposite the LED's301-305. Thedetector320 is coupled to front end analogsignal conditioning circuity330.

The front end analogsignal conditioning circuitry330 has outputs coupled to analog todigital conversion circuit332. The analog todigital conversion circuitry332 has outputs coupled to a digitalsignal processing system334. The digitalsignal processing system334 provides the desired parameter as an output for adisplay336. Thedisplay336 provides a reading of the blood glucose concentration.

The signal processing system also provides an emittercurrent control output337 to a digital-to-analog converter circuit338 which provides control information foremitter drivers340. Theemitter drivers340 couple to the emitters;301-305. The digitalsignal processing system334 also provides again control output342 for the front end analogsignal conditioning circuitry330.

FIG. 2A illustrates a preferred embodiment for theemitter drivers340 and the digital toanalog conversion circuit338. The driver depicted inFIG. 2a is depicted for two LEDs coupled back-to-back. However, additional LEDs (preferably coupled back-to-back to conserve connections) can be coupled to the D/A converter325 through additional multiplexing circuitry (not shown). As depicted inFIG. 2A, the driver comprises first and second input latches321,322, a synchronizinglatch323, avoltage reference324, a digital toanalog conversion circuit325, first andsecond switch banks326,327, first and second voltage tocurrent converters328,329 and theLED emitters301,302 corresponding to the LED emitters301-302 ofFIG. 2.

The preferred driver depicted inFIG. 2A is advantageous in that much of the noise in theblood glucose system100 ofFIG. 2 is caused by the LED emitters301-305. Therefore, the emitter driver circuit ofFIG. 2A is designed to minimize the noise from the emitters301-305. The first and second input latches321,324 are connected directly to the DSP bus. Therefore, these latches significantly minimize the bandwidth (resulting in noise) present on the DSP bus which passes through to the driver circuitry ofFIG. 2A. The output of the first and second input latches only changes when these latches detect their address on the DSP bus. The first input latch receives the setting for the digital toanalog converter circuit325. The second input latch receives switching control data for theswitch banks326,327. The synchronizing latch accepts the synchronizing pulses which maintain synchronization between the activation ofemitters301,302 (and the other emitters303-305 not depicted inFIG. 2a) and the analog todigital conversion circuit332.

The voltage reference is also chosen as a low noise DC voltage reference for the digital toanalog conversion circuit325. In addition, in the present embodiment, the voltage reference has an lowpass output filter with a very low corner frequency (e.g., 1 Hz in the present embodiment). The digital toanalog converter325 also has a lowpass filter at its output with a very low corner frequency (e.g., 1 Hz). The digital to analog converter provides signals for each of theemitters301,302 (and the remaining emitters303-305, not depicted inFIG. 2a).

In the present embodiment, the output of the voltage tocurrent converters328,329 are switched such that with theemitters301,302 connected in back-to-back configuration, only one emitter is active an any given time. A refusal position for theswitch326 is also provided to allow theemitters301 and302 to both be off when one of the other emitters303-305 is on with a similar switching circuit. In addition, the voltage to current converter for the inactive emitter is switched off at its input as well, such that it is completely deactivated. This reduces noise from the switching and voltage to current conversion circuitry. In the present embodiment, low noise voltage to current converters are selected (e.g., Op 27 Op Amps), and the feedback loop is configured to have a low pass filter to reduce noise. In the present embodiment, the low pass filtering function of the voltage tocurrent converter328,329 has a corner frequency just above the switching speed for the emitters. Accordingly, the preferred driver circuit ofFIG. 2a, minimizes the noise of theemitters301,302.

As represented inFIG. 2, the light emitters301-305 each emits energy which is absorbed by the finger310 and received by thedetector320. Thedetector320 produces an electrical signal which corresponds to the intensity of the light energy striking thephotodetector320. The front end analogsignal conditioning circuitry330 receives the intensity signals and filters and conditions these signals as further described below for further processing. The resultant signals are provided to the analog-to-digital conversion circuitry332 which converts the analog signals to digital signals for further processing by the digitalsignal processing system334. The digitalsignal processing system334 utilizes the signals in order to provide blood glucose concentration. In the present embodiment, the output of the digitalsignal processing system334 provides a value for glucose saturation to thedisplay336. Advantageously, thesignal processing system334 also store data over a period of time in order to generate trend data and perform other analysis on the data over time.

The digitalsignal processing system334 also provides control for driving the light emitters301-305 with an emitter current control signal on the emittercurrent control output337. This value is a digital value which is converted by the digital-to-analog conversion circuit338 which provides a control signal to the emittercurrent drivers340. The emittercurrent drivers340 provide the appropriate current drive for the emitters301-305.

In the present embodiment, the emitters301-305 are driven via the emittercurrent driver340 to provide light transmission with digital modulation at 625 Hz. In the present embodiment, the light emitters301-305 are driven at a power level which provides an acceptable intensity for detection by the detector and for conditioning by the front end analogsignal conditioning circuitry330. Once this energy level is determined for a given patient by the digitalsignal processing system334, the current level for the emitters is maintained constant. It should be understood, however, that the current could be adjusted for changes in the ambient room light and other changes which would effect the voltage input to the front end analogsignal conditioning circuitry330. In the present invention, light emitters are modulated as follows: for one complete 625 Hz cycle for the first wavelength, thefirst emitter301 is activated for the first tenth of the cycle, and off for the remaining nine-tenths of the cycle; for one complete 625 Hz second wavelength cycle, thesecond light emitter302 is activated for the one tenth of the cycle and off for the remaining nine-tenths cycle; for one 625 Hz third wavelength cycle, the thirdlight emitter303 is activated for one tenth cycle and is off for the remaining nine-tenths cycle; for one 625 Hz fourth wavelength cycle, thefourth light emitter304 is activated for one tenth cycle and is off for the remaining nine-tenths cycle; and for one 625 Hz fifth wavelength cycle, thefifth light emitter305 is activated for one tenth cycle and is off for the remaining nine-tenths cycle. In order to receive only one signal at a time, the emitters are cycled on and off alternatively, in sequence, with each only active for a tenth cycle per 625 Hz cycle and a tenth cycle separating the active times.

The light signal is attenuated (amplitude modulated) by the blood (with the volume of blood changing through cyclic active pulse in the present embodiment) through the finger310 (or other sample medium). In the present embodiment, thefingertip130 is physiologically altered on a periodic basis by the pressure device150 (or the active pulse device) so that approximately 10% amplitude modulation is achieved. That is, enough-pressure is applied to the fingertip310 to evacuate a volume of body fluid such that the variation in the overall difference in optical attenuation observed between the finger tip310 when full of blood and the finger tip310 when blood is evacuated, is approximately 10%. For example, if the transmission of optical radiation through the fingertip310 is approximately 0.4%, then the fingertip310 would have to be physiologically altered to evacuate enough blood so that the attenuation of the fingertip having fluid evacuated would be on the order to 0.36%.FIG. 13 depicts an example of the an active pulse signal where the modulation is 10% of the entire attenuation through the finger. The 10% is obtained by varying the volume of blood enough to obtain the cyclic modulation depicted inFIG. 13. As explained above, the 10% modulation is chosen as sufficient to obtain information regarding glucose concentrations, yet cause minimal perturbation to the system. Minimal perturbation is advantageous due to the optical variations caused by perturbing the system. The level of perturbation is advantageously below a level that causes significant variations in optical properties in the system, which variations affect different wavelengths differently.

In one advantageous embodiment, physiological altering of the fingertip310 is accomplished by the application of periodic gentle pressure to the patient's finger310 with the pressure cuff150 (FIG. 1). The finger310 could also be perturbed by the pressure device152 (FIG. 1) or with temperature.

The modulation is performed at a selected rate. A narrow band pass filter may then be employed to isolate the frequency of interest. In the present embodiment, the modulation obtained through influencing an active pulse preferably occurs at a rate just above the normal heart rate (for instance, 4 Hz). In one embodiment, the system checks the heart rate and sets the active pulse rate such that it is above the natural heart rate, and also away from harmonics of the natural pulse rate. This allows for easy filtering with a very narrow band-pass filter with a center frequency of at the selected active pulse rate (e.g., 4 Hz or the rate automatically selected by the system to be away from the fundamental natural heart rate frequency and any harmonics to the fundamental frequency). However, a frequency in or below the range of normal heart rate could also be used. Indeed, in one embodiment, the frequency tracks the heart rate, in which case the active pulse operates in conjunction with the natural pulse to increase the change in volume of flow with each heart beat.

The attenuated (amplitude modulated) signal is detected by thephotodetector320 at the 625 Hz carrier frequency for each emitter. Because only a single photodetector is used, thephotodetector320 receives all the emitter signals to form a composite time division signal. In the present embodiment, a photodetector is provided which is a sandwich-type photodetector with a first layer which is transparent to infrared wavelengths but detects red wavelengths and a second layer which detects infrared wavelengths. One suitable photodetector is a K1713-05 photodiode made by Hamamatsu Corp. This photodetector provides for detection by the infrared layer of a relatively large spectrum of infrared wavelengths, as well as detection of a large spectrum of wavelengths in the red range by the layer which detects red wavelengths, with a single photodetector. Alternatively, multiple photodetectors could be utilized for the wavelengths in the system.

The composite time division signal is provided to the front analogsignal conditioning circuitry330. Additional detail regarding the front end analogsignal conditioning circuitry330 and the analog todigital converter circuit332 is illustrated inFIG. 3. As depicted inFIG. 3, thefront end circuity300 has apreamplifier342, ahigh pass filter344, anamplifier346, aprogrammable gain amplifier348, and a low pass filter350. Thepreamplifier342 is a transimpedance amplifier that converts the composite current signal from thephotodetector320 to a corresponding voltage signal, and amplifies the signal. In the present embodiments, the preamplifier has a predetermined gain to boost the signal amplitude for ease of processing. In the present embodiment, the source voltages for thepreamplifier342 are −15 VDC and +15 VDC. As will be understood, the attenuated signal contains a component representing ambient light as well as the component representing the light at each wavelength transmitted by each emitter301-305 as the case may be in time. If there is light in the vicinity of thesensor300 other than from the emitters301-305, this ambient light is detected by thephotodetector320. Accordingly, the gain of the preamplifier is selected in order to prevent the ambient light in the signal from saturating the preamplifier under normal and reasonable operating conditions.

The output of thepreamplifier342 couples as an input to thehigh pass filter344. The output of the preamplifier also provides afirst input347 to the analog todigital conversion circuit332. In the present embodiment, the high pass filter is a single-pole filter with a corner frequency of about ½-1 Hz. However, the corner frequency is readily raised to about 90 Hz in one embodiment. As will be understood; the 625 Hz carrier frequency of the emitter signals is well above a 90 Hz corner frequency. The high-pass filter344 has an output coupled as an input to anamplifier346. In the present embodiment, theamplifier346 comprises a unity gain transimpedance amplifier. However, the gain of theamplifier346 is adjustable by the variation of a single resistor. The gain of theamplifier346 would be increased if the gain of thepreamplifier342 is decreased to compensate for the effects of ambient light.

The output of theamplifier346 provides an input to aprogrammable gain amplifier348. Theprogrammable gain amplifier348 also accepts a programming input from the digitalsignal processing system334 on a gaincontrol signal line343. The gain of theprogrammable gain amplifier348 is digitally programmable. The gain is adjusted dynamically at initialization or sensor placement for changes in the medium under test from patient to patient. For example, the signal from different fingers differs somewhat. Therefore, a dynamically adjustable amplifier is provided by theprogrammable gain amplifier348 in order to obtain a signal suitable for processing.

The output of theprogrammable gain amplifier348 couples as an input to a low-pass filter350. Advantageously, the low pass filter350 is a single-pole filter with a corner frequency of approximately 10 Khz in the present embodiment. This low pass filter provides antialiasing in the present embodiment.

The output of the low-pass filter350 provides asecond S input352 to the analog-to-digital conversion circuit332.FIG. 3 also depicts additional details of the analog-to-digital conversion circuit. In the present embodiment, the analog-to-digital conversion circuit332 comprises a first analog-to-digital converter354 and a second analog-to-digital converter356. Advantageously, the first analog-to-digital converter354 accepts signals from thefirst input347 to the analog-to-digital conversion circuit332, and the second analog todigital converter356 accepts signals on thesecond input352 to the analog-to-digital conversion circuitry332.

In one advantageous embodiment, the first analog-to-digital converter354 is a diagnostic analog-to-digital converter. The diagnostic task (performed by the digital signal processing system) is to read the output of the detector as amplified by thepreamplifier342 in order to determine if the signal is saturating the input to the high-pass filter344. In the present embodiment, if the input to thehigh pass filter344 becomes saturated, the front end analogsignal conditioning circuits330 provides a ‘0’ output. Alternatively, the first analog-to-digital converter354 remains unused.

The second analog-to-digital converter352 accepts the conditioned composite analog signal from the front endsignal conditioning circuitry330 and converts the signal to digital form. In the present embodiment, the second analog todigital converter356 comprises a single-channel, delta-sigma converter. This converter is advantageous in that it is low cost, and exhibits low noise characteristics. In addition, by using a single-channel converter, there is no need to tune two or more channels to each other. The delta-sigma converter is also advantageous in that it exhibits noise shaping, for improved noise control. An exemplary analog to digital converter is an Analog Devices AD1877JR. In the present embodiment; the second analog todigital converter356 samples the signal at a 50 Khz sample rate. The output of the second analog todigital converter356 provides data samples at 50 Khz to the digital signal processing system334 (FIG. 2).

The digitalsignal processing system334 is illustrated in additional detail inFIG. 4. In the present embodiment, the digital signal processing system comprises amicrocontroller360, adigital signal processor362, aprogram memory364, asample buffer366, adata memory368, a read onlymemory370 and communication registers372. In the present embodiment, thedigital signal processor362 is an Analog Devices AD21020. In the present embodiment, themicrocontroller360 comprises a Motorola 68HC05, with built in program memory. In the present embodiment, thesample buffer366 is a buffer which accepts the 50 Khz sample data from the analog todigital conversion circuit332 for storage in thedata memory368. In the present embodiment, thedata memory368 comprises 32 KWords (words being 40 bits in the present embodiment) of dynamic random access memory.

Themicrocontroller360 is connected to theDSP362 via a conventional JTAG Tap line. Themicrocontroller360 transmits the boot loader for theDSP362 to theprogram memory364 via the Tap line, and then allows theDSP362 to boot from theprogram memory364. The boot loader inprogram memory364 then causes the transfer of the operating instructions for theDSP362 from the read onlymemory370 to theprogram memory364. Advantageously, theprogram memory364 is a very high speed memory for theDSP362.

Themicrocontroller360 provides the emitter current control and gain control signals via the communications register372.

FIGS. 5-8 depict functional block diagrams of the operations of the glucose monitoring system carried out by the digitalsignal processing system334. The signal processing functions described below are carried out by theDSP362 in the present embodiment with themicrocontroller360 providing system management. In the present embodiment, the operation is software/firmware controlled.FIG. 5 depicts a generalized functional block diagram for the operations performed on the 50 Khz sample data entering the digitalsignal processing system334. As illustrated inFIG. 5, a demodulation, as represented in ademodulation module400, is first performed. Decimation, as represented in adecimation module402 is then performed on the resulting data. Then, the glucose concentration is determined, as represented in aGlucose Calculation module408.

In general, the demodulation operation separates each emitter signal from the composite signal and removes the 625 Hz carrier frequency, leaving raw data points. The raw data points are provided at 625 Hz intervals to the decimation operation which reduces the samples by an order of 10 to samples at 62.5 Hz. The decimation operation also provides some filtering on the samples. The resulting data is subjected to normalization (which essentially generates a normalized AC/DC signal) and then glucose concentration is determined in theGlucose Calculation module408.

FIG. 6 illustrates the operation of thedemodulation module400. The modulated signal format is depicted inFIG. 6. The pulses for the first three wavelengths of one full 625 Hz cycle of the composite signal is depicted inFIG. 6 with the first tenth cycle being the active first emitter light plus ambient light signal, the second tenth cycle being an ambient light signal, the third tenth cycle being the active second emitter light plus ambient light signal, and the fourth tenth cycle being an ambient light signal, and so forth for each emitter. The sampling frequency is selected at 50 Khz so that the single full cycle at 625 Hz described above comprises 80 samples of data, eight samples relating to the first emitter wavelength plus ambient light, eight samples relating to ambient light, eight samples relating to the second emitter wavelength plus ambient light, eight more samples related to ambient light and so forth until there are eight samples of each emitter wavelength followed by eight samples of ambient light.

Because thesignal processing system334 controls the activation of the light emitters301-305, the entire system is synchronous. The data is synchronously divided (and thereby demodulated) into the eight-sample packets, with a time division demultiplexing operation as represented in ademultiplexing module421. One eight-sample packet422 represents the first emitter wavelength plus ambient light signal; a second eight-sample packet424 represents an ambient light signal; a third eight-sample packet426 represents the attenuated second emitter wavelength light plus ambient light signal; and a fourth eight-sample packet428 represents the ambient light signal. Again, this continues until there is a eight-sample packet for each emitter active period with an accompanying eight-sample packet for the corresponding ambient light period. A select signal synchronously controls the demultiplexing operation so as to divide the time-division multiplexed composite signal at the input of thedemultiplexer421 into its representative subparts or packets.

A sum of the four last samples from each packet is then calculated, as represented in the summingoperations430,432,434,436 ofFIG. 6. It should be noted that similar operations are performed on the remaining wavelengths. In other words, at the output of the demodulation operation, five channels are provided in the present embodiment. However, only two channels for two wavelengths are depicted inFIG. 6 for simplicity in illustration. The last four samples are used from each packet because a low pass filter in the analog todigital converter356 of the present embodiment has a settling time. Thus, collecting the last four samples from each eight-sample packet allows the previous signal to clear. The summingoperations430,432,434,436 provide integration which enhances noise immunity. The sum of the respective ambient light samples is then subtracted from the sum of the emitter samples, as represented in thesubtraction modules438,440. The subtraction operation provides some attenuation of the ambient light signal present in the data. In the present embodiment, it has been found that approximately 20 dB attenuation of the ambient light is provided by the operations of thesubtraction modules438,440. The resultant emitter wavelength sum values are divided by four, as represented in the divide by fourmodules442,444. Each resultant value provides one sample each of the emitter wavelength signals at 625 Hz.

It should be understood that the 625 Hz carrier frequency has been removed by thedemodulation operation400. The 625 Hz sample data at the output of thedemodulation operation400 is sample data without the carrier frequency. In order to satisfy Nyquist sampling requirements, less than 10 Hz is needed (with an active pulse of about 4 Hz in the present embodiment). Accordingly, the 625 Hz resolution is reduced to 62.5 Hz in the decimation operation.

FIG. 7 illustrates the operations of thedecimation module402 for the first two wavelengths. The same operations are also performed on the other wavelength data. Each emitter's sample data is provided at 625 Hz to respective buffer/filters450,452. In the present embodiment, the buffer/filters are 519 samples deep. Advantageously, the buffer filters450,452 function as continuous first-in, first-out buffers. The 519 samples are subjected to low-pass filtering. Preferably, the low-pass filtering has a cutoff frequency of approximately 7.5 Hz with attenuation of approximately −110 dB. The buffer/filters450,452 form a Finite Impulse Response (FIR) filter with coefficients for 519 taps. In order to reduce the sample frequency by ten, the low-pass filter calculation is performed every ten samples, as represented in respective wavelength decimation by 10modules454,456. In other words, with the transfer of each new ten samples into the buffer/filters450,452, a new low pass filter calculation is performed by multiplying the impulse response (coefficients) by the 519 filter taps. Each filter calculation provides one output sample for each respective emitterwavelength output buffers458,460. In the present embodiment, the output buffers458,460 are also continuous FIFO buffers that hold 570 samples of data. The 570 samples provide respective samples or packets (also denoted “snapshot” herein) of samples. As depicted inFIG. 5, the output buffers provide sample data forGlucose Calculation Module408 for two wavelengths.

FIG. 8 illustrates additional functional operation details of theGlucose Calculation module408. As represented inFIG. 8, the Glucose Calculation operation accepts packets of samples for each wavelength (e.g., 570 samples at 62.5 Hz in the present embodiment) representing the attenuated wavelength signals, with the carrier frequency removed. The respective packets for each wavelength signal are normalized with a log function, as represented in thelog modules480,482. Again, at this point, only two channels are illustrated inFIG. 8. However, in the present embodiment, five channels are provided, one for each wavelength. The normalization effectively creates an AC/DC normalized signal, this normalization is followed by removal of the DC portion of the signals, as represented in theDC Removal modules484,486. In the present embodiment, the DC removal involves ascertaining the DC value of the first one of the samples (or the mean of the first several or the mean of an entire snapshot) from each of the respective wavelength snapshots, and removing this DC value from all samples in the respective packets.

Once the DC signal is removed, the signals are subjected to bandpass filtering, as represented inBandpass Filter modules488,490. In the present embodiment, with 570 samples in each packet, the bandpass filters are configured with 301 taps to provide a FIR filter with a linear phase response and little or no distortion. In the present embodiment, the bandpass filter has a narrow passband from 3.7-4.3 Hz. This provides a narrow passband which eliminates most noise and leaves the portion of the signal due to the active pulse. The 301 taps slide over the 570 samples in order to obtain 270 filtered samples representing the filtered signal of the first emitter wavelength and 270 filtered samples representing the filtered signal of the second emitter wavelength, continuing for each emitter wavelength. In an ideal case, thebandpass filters488,490 assist in removing the DC in the signal. However, theDC removal operation484,486 also assists in DC removal in the present embodiment.

After filtering, the last 120 samples from each packet (of now 270 samples in the present embodiment) are selected for further processing as represented inSelect Last 120Samples modules492,494. The last 120 samples are selected in order to provide settling time for the system.

The RMS for the samples is then determined for each of the 120-sample packets (for each wavelength). The process to obtain the overall RMS values is represented in the RMS modules495-499.

The resultant RMS values for each wavelength provide normalized intensity values for forming equations according to Beer-Lambert's law. In other words, for Beer-Lambert equation
l=l_oe^{−(pl*c1*ε1+pl*c2*ε2+etc.)}  (3)

then taking the log of operations480-482:
ln(I)=ln(l_o)−(pl*c₁*ε₁+pl*c₂*ε₂+etc.)  (4)

Then performing DC removal though theDC removal operations484,486 and Bandpass filter operations488,490, the the normalized equation becomes:
l_nonλ=−(pl*c₁*ε₁+pl*c₂*ε₂+etc.)  (5)

The RMS values (blocks495-499) for each wavelength provide l_normλ for the left side of Equation (7). The extinction coefficients are known for the selected wavelengths.

As will be understood, each equation has a plurality of unknowns. Specifically, each equation will have an unknown term which is the product of concentration and pathlength for each of the constituents of concern (hemoglobin, oxyhemoglobin, glucose and water in the present embodiment). Once a normalized Beer-Lambert equation is formed for each wavelength RMS value (the RMS value representing the normalized intensity for that wavelength), a matrix is formed as follows:
l_nomλ1=−(ε_1λ1c₁+ε_2λ1c₂+ε_3λ1c₃+ε_4λ1c₄+ε_5λ1c₅)pl  (6)
l_nomλ2=−(ε_1λ2c₁+ε_2λ2c₂+ε_3λ2c₃+ε_4λ2c₄+ε_5λ2c₅)pl  (7)
l_nomλ3=−(ε_1λ3c₁+ε_2λ3c₂+ε_3λ3c₃+ε_4λ3c₄+ε_5λ3c₅)pl  (8)
l_nomλ4=−(ε_1λ4c₁+ε_2λ4c₂+ε_3λ4c₃+ε_4λ4c₄+ε_5λ4c₅)pl  (9)
l_nomλ5=−(ε_1λ5c₁+ε_2λ5c₂+ε_3λ5c₃+ε_4λ5c₄+ε_5λ5c₅)pl  (10)
where

C₁=concentration of water

C₂=concentration of hemoglobin

C₃=concentration of oxyhemoglobin

C₄=concentration of Glucose

C₅=concentration of Glucose

and

ε_1λn=extinction coefficient for water at λ_n

ε_2λn=extinction coefficient for hemoglobin at λ_n

ε_3λn=extinction coefficient for oxyhemoglobin at λ_n

ε_4λn=extinction coefficient for Glucose at λ_n

ε_5λn=extinction coefficient for Glucose at λ_n

The equations are solved using conventional matrix algebra in order to solve for the product of concentration times pathlength for each constituent, as represented in theMatrix block489.

In order to remove the path length term, in the present embodiment where glucose is desired, a ratio is performed of the product of pathlength times concentration for glucose to the product of pathlength times the concentration of water as represented in aratio block487. Since the pathlength is substantially the same for each wavelength due to normalization (i.e., taking AC/DC) and due to minimal perturbation (e.g., 10%), the pathlength terms cancel, and the ratio indicates the concentration of glucose to water (preferably, this is scaled to mg/dL). The glucose concentration is provided to thedisplay336.

It should be noted that it may also be possible to create an empirical table by way of experiment which correlates ratios of one or more of the concentration times path length terms to blood glucose concentration.

Even with the emitter driver circuit ofFIG. 2A discussed above, infrared LEDs with the longer wavelengths are also inherently unstable with respect to their power transmission. Accordingly, in one advantageous embodiment, the instabilities for the source LEDs can be corrected to accommodate for the instabilities depicted inFIG. 2C. As illustrated inFIG. 2C, two curves are depicted representing transmitted power over time. A first curve labelled AA represents power transmission from LEDs having wavelengths of 660 nm and 905 nm. As illustrated, these emitters have relatively stable power transmission over time. A second curve labelled BB represents power transmission from an emitter with a wavelength of approximately 1330 nm. As illustrated, typical emitters of this wavelength have unstable power transmission over time.

Accordingly, in one embodiment, the emitters in the 1300 nm range are selected as with an integrated photodetector. An appropriate laser diode is an SCW-1300-CD made by Laser Diode, Inc. An appropriate LED is an Apitaxx ETX1300T. With such an emitter, a configuration as depicted inFIG. 2B can be used, whereby the internal photodiode in the emitter is also sampled to detect the initial intensity l_otimes a constant (α). In general, the signal detected after transmission through the finger is divided by the α_osignal. In this manner, the instability can be normalized because the instability present in the attenuated signal due to instability in the emitter will also be present in the measured α_osignal.

FIG. 2B depicts such an embodiment illustrating only one emitter301 (of the emitters301-305). However, all or several of the emitters301-305 could be emitters having an internal photodiode. As depicted inFIG. 2B, theemitter301 has an internal photodiode301a and its LED301b. As depicted inFIG. 2B, light emitted from the LED301b in theemitter301 is detected by a photodiode301a. The signal from the photodiode301a is provided to front end analogsignal conditioning circuitry330A. The analogsignal conditioning circuitry330A similar to the analogsignal conditioning circuitry330. However, because the photodiode301a detects a much stronger intensity compared to the detector320 (due to attenuation by tissue), different amplification may be required.

After analog signal conditioning in the front end anaologsignal conditioning circuity330A, the signal from the photodiode301a is converted to digital form with an analog to digital conversion circuit332a. Again, it should be understood that the analog to digital conversion circuit332a can be the same configuration as the analog todigital conversion circuit332. However, because the signal from the photodiode301a and thedetector320 appear at the same time, two channels are required.

The attenuated light signal through the finger is detected with thedetector320 and passed through front end analogsignal conditioning circuit330 and is converted-to-digital form in analog todigital conversion circuit332, as described in further detail below. The signal representing the intensity of the light transmitted through the finger310 is divided as represented by the division block333 by the signal which represents the intensity of light from the LED301b detected by the photodiode301a.

In this manner, the variations or instability in the initial intensity l_ocancel through the division leaving a corrected intensity which is divided by the constant α. When the log is performed as discussed below, and bandpass filtering is performed, the constant .alpha. term is removed leaving a clean signal.

Mathmatically, this can be understood by representing the attenuated signal under Beer-Lambert's Law and the signal from the photodiode301a as αl_oas discussed above:

Thus, the signal emerging from the analog todigital conversion circuit332 is as follows:
l=l_oe^{Σ(−ε*pl*c)}

Dividing Equation 3 by α*l_oand simplifying provides the signal after the division operation333:
=(e^{Σ(−ε*pl*c)})/α

Thus providing a normalized intensity signal for the input to the digitalsignal processing circuit334.

FIG. 10 depicts a perspective view of one alternative embodiment of aninflatable bladder sensor500 which can be used to induce an active pulse in accordance with the teachings of the present invention. Thisinflatable bladder sensor500 is for a bed-side blood glucose monitor. Theinflatable bladder sensor500 haselectrical connections502 for coupling the device to the blood glucose system299.

Typically, theelectrical connection502 carries sufficient conductors to power the emitters301-305 and to receive a detector signal from thedetector320.

Theinflatable bladder sensor500 has a curvedupper surface504 andvertical sides506. Theinflatable bladder sensor500 also has an fluidpressure supply tube508. In one advantageous embodiment, the supply tube cycles air into and out of an inflatable bladder within theinflatable bladder sensor500. Thefluid supply tube508 couples to the bedside glucose monitoring system which is equipped with a cycling pump to induce pressure and remove pressure from thesupply tube508. In one embodiment, apressure relief valve510 is located on theupper surface504 to allow release of pressure in the inflatable bladder.

FIG. 11 depicts a cross-sectional view along theinflatable bladder sensor500 ofFIG. 10. As depicted inFIG. 11, a human digit orfinger512 is positioned inside thesensor500. Thefinger512 is positioned is supported by apad514 in the area of light transmission. A flexibleinflatable bladder516 surrounds the finger proximally from the area of light transmission. The pad has an anaperture518 to enable emitters301-305 to provide unobstructed optical transmission to the surface offinger512.

Surrounded by thepadding514 and opposite the emitters301-305 is thedetector320. Thedetector320 is positioned within anaperture520 in thepad514 to ensure that photodetector is separated from thefinger512. A serpentine arrow is shown extending from the light emitters301-305 to thedetector320 to illustrate the direction of propagation of light energy through thefinger512.

Relief valve510 enables manual and automatic release of pressure in theinflatable bladder516.Relief valve510 has avalve plate522 which is spring biased to seal anaperture524 usingspring532. The valve plate is connected torelief valve shaft526. Avalve button530 is coupled to the valve shaft. The valve shaft extends through a valve housing531 which forms a cylindrical sleeve shape. The valve housing is coupled to theupper surface504 ofsensor500. The valve housing has anaperture523 which allows air to readily escape from the relief valve. Preferably, the relief valve is designed to ensure that the pressure is not high enough to cause damage to nerves. Accordingly, if the pressure increases beyond a certain point, the relief valve allows the excess fluid to escape, thereby reducing the pressure to the maximum allowable limit. Such pressure relief valves are well understood in the art.Relief valve510 could also be a spring-loaded needle-type valve.

FIG. 12 depicts a sectional view alongline12—12 ofFIG. 11 to illustrate the state of thesensor500 when theinflatable bladder516 is deflated.FIG. 12a depicts the same sectional view asFIG. 12 with thebladder516 inflated.

With this configuration, the blood glucose system can cycle fluid into and out of theinflatable bladder516 at the selected rate to actively induce a pulse of sufficient magnitude as discussed above.

Additional Application of Active Pulse

As discussed in the co-pending U.S. patent application Ser. No. 08/320,154 filed Oct. 7, 1994, now U.S. Pat. No. 5,632,272 which is incorporated herein by reference, a saturation transform may be applied to each 120 sample packet. It has been found that a second maxima representing venous oxygen saturation exists in the Master Power Curve during motion of the patient. In view of this, it is possible to utilize the inducement of a pulse disclosed herein through physically perturbing the medium under test in order to obtain the second maxima in the Master Power Curve, and thereby obtain the venous oxygen saturation if desired. The modulation may be lower than 10% because hemoglobin and oxyhemoglobin concentrations are higher than glucose and absorbtion at 660 nm and 905 nm are relatively strong. Thus, modulation from 1-5% may provide adequate results.

Although the preferred embodiment of the present invention has been described and illustrated above, those skilled in the art will appreciate that various changes and modifications to the present invention do not depart from the spirit of the invention. For example, the principles and method of the present invention could be used to detect trace elements within the bloodstream (e.g., for drug testing, etc.). Accordingly, the scope of the present invention is limited only by the scope of the following appended claims.

Claims (49)

What is claimed is:

1. A system for non-invasively monitoring concentrations of blood constituents in a living subject, said system comprising:

a light source configured to be positioned at a measurement site and further configured to irradiate a fleshy medium of a living subject with radiation at a plurality of wavelengths selected for attenuation sensitivity to at least one of a plurality of blood constituent concentrations, said plurality of blood constituent concentrations including a glucose concentration;

an optical detector configured to be positioned at said measurement site to detect only light which has been attenuated by said fleshy medium at said measurement site, said optical detector configured to generate an output signal indicative of an intensity of said radiation after attenuation through said fleshy medium;

a pressure application device configured to be positioned at a location different from said measurement site to avoid applying direct pressure to said measurement site while causing a change in a volume of blood in the fleshy medium at said measurement site sufficient to alter said output signal to increase a likelihood of determining at least said glucose concentration, said pressure application device configured to modulate pressure on the fleshy medium at a rate above a normal heart rate range; and

a signal processor responsive to said output signal to analyze said output signal to extract portions of said signal due to optical characteristics of said blood and to determine a concentration of at least one selected constituent within said subject's bloodstream; and a pressure application device configured to be positioned at a location different from said measurement site to avoid applying direct pressure to said measurement site while causing a change in a volume of blood in the fleshy medium at said measurement site sufficient to alter said output signal to increase a likelihood that said signal processor can determine at least said glucose concentration. by analyzing an effect of the modulated pressure on the output signal.

2. The system ofclaim 1, wherein said change in said volume of blood alters said output signal such that a difference in said output signal at a full blood volume and said output signal at said changed output volume comprises about 1 to about 10 percent.

3. The system ofclaim 2, wherein said difference comprises about 10 percent.

4. The system ofclaim 1, wherein at least one of said plurality of wavelengths comprises about 660 nanometers (nm).

5. The system of claim4 1, wherein said at least one wavelength of said plurality of wavelengths is selected for attenuation sensitivity to a hemoglobin concentration.

6. The method system ofclaim 1, wherein said light source comprises two or more light emitting diodes.

7. A method of non-invasively monitoring concentrations of blood constituents in a living subject, said method comprising:

irradiating a fleshy medium of a living subject at a measurement site with radiation at a plurality of wavelengths selected for attenuation sensitivity to at least one of a plurality of blood constituent concentrations, said plurality, of blood constituent concentrations including a glucose concentration;

detecting at said measurement site only light which has been attenuated by said fleshy medium;

outputting a signal indicative of the intensity of said radiation after attenuation through said fleshy medium;

using a device external to said fleshy medium, changing a volume of blood in the fleshy medium at said measurement site sufficient to alter said output signal to increase a likelihood that at least said glucose concentration can be determined without applying direct mechanical pressure to said fleshy medium at said measurement site, said device external to said fleshy medium configured to modulate pressure on the fleshy medium at a rate above a normal heart rate range;

extracting portions of said signal due to optical characteristics of said blood to determine a concentration of at least one selected constituent within said subject's bloodstream based on an effect of the modulated pressure on the output signal; and

using a device external to said fleshy medium, changing a volume of blood in the fleshy medium at said measurement site sufficient to alter said output signal to increase a likelihood that at least said glucose concentration can be determined without applying direct mechanical pressure to said fleshy medium at said measurement site; and

causing said glucose concentration to be displayed.

8. A method of non-invasively monitoring glucose concentrations in a living subject, said method comprising:

applying pressure at a first location to a fleshy medium to increase a likelihood of determining a glucose concentration in a living subject, said pressure applied to said fleshy medium at a modulated rate above a normal heart rate range;

detecting only light attenuated by said fleshy medium at a second location different from said first location, wherein said applying pressure does not apply direct mechanical pressure to said second location;

outputting a signal indicative of said detected attenuated light, wherein said signal includes information about said glucose concentration at a resolution differentiable from noise or other blood constituents;

determining at least said glucose concentration by analyzing an effect of the pressure on said output signal; and

causing said glucose concentration to be displayed.

9. A system for non-invasively monitoring concentrations of blood constituents in a living subject, said system comprising:

a light source configured to be positioned at a measurement site and further configured to irradiate a fleshy medium of a living subject with radiation at a plurality of wavelengths selected for attenuation sensitivity to at least one of a plurality of blood constituent concentrations, said plurality of blood constituent concentrations including a glucose concentration, wherein said light source comprises two or more light emitting diodes;

an optical detector configured to be positioned at said measurement site to detect light which has been attenuated by said fleshy medium, said optical detector configured to generate an output signal indicative of the intensity of said radiation after attenuation through said fleshy medium;

a pressure application device configured to be positioned at a location different from said measurement site to avoid applying direct pressure to said measurement site while causing a change in a volume of blood in the fleshy medium at said measurement site sufficient to alter said output signal to increase a likelihood of determining at least said glucose concentration, said pressure application device configured to modulate pressure on the fleshy medium at a rate above a normal heart rate range; and

a signal processor responsive to said output signal to analyze said output signal to extract portions of said signal due to optical characteristics of said blood and to determine a concentration of at least one selected constituent within said subject's bloodstream; and a pressure application device configured to be positioned at a location different from said measurement site to avoid applying direct pressure to said measurement site while causing a change in a volume of blood in the fleshy medium at said measurement site sufficient to alter said output signal to increase a likelihood that said signal processor can determine at least said glucose concentration by analyzing an effect of the modulated pressure on the output signal.

10. The system ofclaim 9, wherein said optical detector detects light which has been attenuated by said fleshy medium at one location.

11. The system ofclaim 9, wherein the pressure application device comprises an inflatable bladder.

12. The system ofclaim 9, further comprising a temperature variation element.

13. The system ofclaim 12, wherein said temperature variation element cyclically varies the temperature of said fleshy medium in order to induce a change in the flow of blood in said fleshy medium.

14. The system ofclaim 9, wherein said two or more light emitting diodes are configured to produce light at a plurality of wavelengths, each wavelength selected for attenuation sensitivity to determine a concentration of said at least one selected constituent.

15. A method of non-invasively monitoring concentrations of blood constituents in a living subject, said method comprising:

irradiating a fleshy medium of a living subject at a measurement site with radiation at a plurality of wavelengths selected for attenuation sensitivity to at least one of a plurality of blood constituent concentrations, said plurality of blood constituent concentrations including a glucose concentration, wherein irradiating comprises using two or more light emitting diodes;

detecting at said measurement site light which has been attenuated by said fleshy medium;

outputting a signal indicative of the detected light;

using a device external to said fleshy medium, changing a volume of blood in the fleshy medium sufficient to alter said output signal to increase a likelihood that at least said glucose concentration can be determined without applying direct mechanical pressure to said fleshy medium at said measurement site, said device external to said fleshy medium configured to modulate pressure on the fleshy medium at a rate above a normal heart rate range;

extracting portions of said signal due to optical characteristics of said blood to determine a concentration of at least one selected constituent within said subject's bloodstream by analyzing an effect of the modulated pressure on the output signal; and

using a device external to said fleshy medium, changing a volume of blood in the fleshy medium at said measurement site sufficient to alter said output signal to increase a likelihood that at least said glucose concentration can be determined without applying direct mechanical pressure to said fleshy medium at said measurement site; and

causing said glucose concentration to be displayed.

16. The method ofclaim 15, wherein the step of detecting further comprise comprises detecting at said measurement site light which has been attenuated by said fleshy medium at one location.

17. A method of non-invasively monitoring glucose concentrations in a living subject, said method comprising:

irradiating a fleshy medium of a living subject using two or more light emitting diodes;

applying pressure at a first location to a fleshy medium to increase a likelihood of determining a glucose concentration in a living subject, said pressure applied to said fleshy medium at a modulated rate above a normal heart rate range;

detecting light attenuated by said fleshy medium at a second location different from said first location, wherein said applying pressure does not apply direct mechanical pressure to said fleshy medium at said second location;

outputting a signal indicative of said detected attenuated light, wherein said signal includes information about said glucose concentration at a resolution differentiable from noise or other blood constituents;

determining at least said glucose concentration by analyzing an effect of the pressure on the output signal; and

causing glucose concentration to be displayed.

18. The method ofclaim 17, wherein the step of detecting further comprises detecting light attenuated through a single location of said fleshy medium.

19. The method ofclaim 17, wherein applying pressure comprises inflating a bladder.

20. The method ofclaim 17, further comprising cyclically varying the temperature of said fleshy medium in order to induce a change in the flow of blood in said fleshy medium.

21. A system for non-invasively monitoring a blood constituent in a living subject, said system comprising:

a light source configured to be positioned at a measurement site and further configured to irradiate a fleshy medium of a living subject with radiation at a plurality of wavelengths selected for attenuation sensitivity to at least one of a plurality of blood constituents;

an optical detector configured to be positioned at said measurement site to detect light which has been attenuated by said fleshy medium at said measurement site, said optical detector configured to generate an output signal indicative of an intensity of said radiation after attenuation through said fleshy medium;

a pressure application device configured to be positioned at a location proximal to said measurement site but different from said measurement site to avoid applying direct pressure to said measurement site while causing a change in a volume of blood in the fleshy medium at said measurement site sufficient to alter said output signal to increase a likelihood of determining a level of at least one selected constituent within said subject's bloodstream, said pressure application device configured to modulate pressure on the fleshy medium at a rate above a normal heart rate range; and

a signal processor responsive to said output signal to analyze said output signal to extract portions of said signal due to optical characteristics of said blood and to determine said level by analyzing an effect of the modulated pressure on the output signal.

22. The system of claim 21, wherein said change in said volume of blood comprises causing evacuation of said volume of blood at said measurement site.

23. The system of claim 22, wherein said evacuation causes an overall difference in optical attenuation from a full blood state of approximately 10%.

24. The system of claim 21, wherein said at least one selected constituent within said subject's bloodstream comprises glucose.

25. A system of claim 21, wherein said at least one selected constituent within said subject's bloodstream comprises hemoglobin.

26. A system of claim 21, wherein said at least one selected constituent within said subject's bloodstream comprises oxyhemoglobin.

27. A system of claim 21, wherein said at least one selected constituent within said subject's bloodstream comprises carboxyhemoglobin.

28. A system of claim 21, wherein said at least one selected constituent within said subject's bloodstream comprises oxygen saturation.

29. A system of claim 21, wherein said at least one selected constituent within said subject's bloodstream comprises venous oxygen saturation.

30. A system of claim 21, wherein said at least one selected constituent within said subject's bloodstream comprises protein.

31. A system of claim 21, wherein said at least one selected constituent within said subject's bloodstream comprises fat.

32. A system of claim 21, wherein said at least one selected constituent within said subject's bloodstream comprises cholesterol.

33. A system of claim 21, wherein said at least one selected constituent within said subject's bloodstream comprises a therapeutic drug.

34. A system of claim 21, wherein said at least one selected constituent within said subject's bloodstream comprises a drug of abuse.

35. A method of non-invasively monitoring a blood constituent in a living subject, said method comprising:

applying pressure at a first location to a fleshy medium to increase a likelihood of determining a level of said blood constituent, said pressure applied to said fleshy medium at a modulated rate above a normal heart rate range;

detecting light attenuated by said fleshy medium at a second location distal to said first location, wherein said applying pressure does not apply direct mechanical pressure to said second location;

electronically outputting a signal indicative of said detected attenuated light, wherein said signal includes information about said level at a resolution differentiable from noise or other blood constituents, and wherein said signal is affected by the modulation from said application of pressure at said first location; and

electronically determining at least said level using said signal and analyzing an effect of the modulation on said signal.

36. The method of claim 35, wherein applying a first pressure comprises causing an evacuation of a volume of blood at said first location.

37. The method of claim 36, wherein said evacuation causes an overall difference in optical attenuation from a full blood state of approximately 10%.

38. The method of claim 35, further comprising displaying an indication of said level.

39. The method of claim 35, wherein said blood constituent is one or more of glucose, hemoglobin, oxyhemoglobin, carboxyhemoglobin, oxygen saturation, venous oxygen saturation, protein, fat, cholesterol, therapeutic drug, drug of abuse, and water.

40. A method of non-invasively monitoring a blood constituent in a living subject, said method comprising:

irradiating a fleshy medium of a living subject at a measurement site with radiation at a plurality of wavelengths selected for attenuation sensitivity to at least one of a plurality of blood constituents, wherein irradiating comprises using two or more light emitting diodes;

detecting at said measurement site light which has been attenuated by said fleshy medium;

electronically outputting a signal indicative of the detected light;

using a device external to said fleshy medium proximal to said measurement site, changing a volume of blood in the fleshy medium sufficient to alter said output signal to increase a likelihood that at least a level of at least one selected constituent within said subject's bloodstream can be determined without applying direct mechanical pressure to said fleshy medium at said measurement site, said device external to said fleshy medium configured to modulate pressure on the fleshy medium at a rate above a normal heart rate range; and

electronically extracting portions of said signal due to optical characteristics of said blood and determining said level by analyzing an effect of the modulated pressure on the output signal.

41. The method of claim 40, further comprising displaying an indication of said level.

42. The method of claim 40, wherein said at least one selected constituent is one or more of glucose, hemoglobin, oxyhemoglobin, carboxyhemoglobin, oxygen saturation, venous oxygen saturation, protein, fat, cholesterol, therapeutic drug, drug of abuse, and water.

43. A method of non-invasively monitoring a blood constituent in a living subject, said method comprising:

irradiating a fleshy medium of a living subject using two or more light emitting diodes;

applying pressure at a first location to a fleshy medium to increase a likelihood of determining a level of said blood constituent, said pressure applied to said fleshy medium at a modulated rate above a normal heart rate range;

detecting light attenuated by said fleshy medium at a second location distal to said first location, the first location substantially in the region about the second location, wherein said applying pressure does not apply direct mechanical pressure to said fleshy medium at said second location;

electronically outputting a signal indicative of said detected attenuated light, wherein said signal includes information about said level at a resolution differentiable from noise or other blood constituents, and wherein said signal is affected by the modulation from said application of pressure at said first location; and

electronically determining at least said level using said signal.

44. The method of claim 43, further comprising displaying an indication of said level.

45. The method of claim 43, wherein said blood constituent is one or more of glucose, hemoglobin, oxyhemoglobin, carboxyhemoglobin, oxygen saturation, venous oxygen saturation, protein, fat, cholesterol, therapeutic drug, drug of abuse, and water.

46. A system for non-invasively monitoring concentrations of blood constituents in a living subject, said system comprising:

a light source configured to be positioned at a measurement site and further configured to irradiate a fleshy medium of a living subject with radiation at a plurality of wavelengths selected for attenuation sensitivity to at least one of a plurality of blood constituent concentrations, said plurality of blood constituent concentrations including a glucose concentration;

an optical detector configured to be positioned at said measurement site to detect light which has been attenuated by said fleshy medium at said measurement site, said optical detector configured to generate an output signal indicative of an intensity of said radiation after attenuation through said fleshy medium;

a pressure application device configured cause a change in a volume of blood in the fleshy medium at said measurement site sufficient to alter said output signal to increase a likelihood of determining at least said glucose concentration, said pressure application device configured to modulate pressure on the fleshy medium at a rate above a normal heart rate range; and

a signal processor responsive to said output signal to analyze at least an effect of the modulated pressure on the fleshy medium on said output signal and to extract portions of said signal due to optical characteristics of said blood to determine a concentration of at least one selected constituent within said subject's bloodstream by analyzing an effect of the modulated pressure on the output signal.

47. The system of claim 46, wherein at least one of said plurality of wavelengths comprises about 660 nanometers (nm).

48. The system of claim 46, wherein said at least one wavelength is selected for attenuation sensitivity to a hemoglobin concentration.

49. The system of claim 46, wherein said light source comprises two or more light emitting diodes.

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