WO2015051288A1 - Apparatus and method for automated blood analyte monitoring - Google Patents

Abstract

Automated blood analyte monitoring is provided by withdrawing a measured volume of blood from a patient by a reversible pump through a manifold; a similar volume of optimizing buffer is also metered through the dispense head to be mixed with the measured volume of blood. The mixture, forming a test sample, is provided through the dispense head to a selected electrochemical well. The analyte measurement under control of a processor provides a glucose measurement to a display; a flush solution is subsequently delivered through the system and a new electrochemical well is selected in alignment with the dispense head to permit subsequent blood samples, to be mixed with optimizing buffer, to be supplied to the newly selected well.

Description

APPARATUS AND METHOD FOR AUTOMATED

BLOOD ANALYTE MONITORING Related Applications

This application is related to and claims priority to a provisional application entitled "APPARATUS AND METHOD FOR AUTOMATED BLOOD

ANALYTE MONITORING" filed October 3, 2013, and assigned Serial No.

61/886,504.

Field of the Invention Automated monitoring of analytes found in human blood is critical to patient outcomes. Measurements are to be made employing electrochemical testing methods common in the point of care patient monitoring industry.

Background of the Invention

Tightly controlled glucose in hospitalized patients has been shown in numerous publications to provide better patient outcomes and lower hospital costs by reducing the number of complications associated with out of control blood glucose concentrations. Some regulations have mandated that preventable re- admissions are no longer to be reimbursed and that determinations regarding reimbursements will be based on an external assessment of patient outcomes. Providing a safe, sufficiently accurate, reliable, automated, and affordable measurement system that will allow medical professionals the timely and necessary information to maintain blood glucose close to the normal range of 80- 120mg/dL is the solution to be provided by the system of the present invention.

Current testing procedures are too labor intensive for overburdened medical staff, requiring the drawing of blood samples and administering blood droplets to the currently utilized monitoring systems. Currently available continuous blood glucose monitors require frequent calibration, employing the same labor intensive testing procedures described above. The measurement methods currently available have been developed for individual use, and have been shown to lack the required accuracy for making therapeutic decisions. The present acceptable testing techniques require laboratory testing systems that are too large, expensive, and cumbersome to be utilized in the normal patient setting. Alternatively, patient blood samples can be sent to the hospital laboratory, but the results are rarely provided to the healthcare professionals to make necessary and timely therapeutic decisions. Described herein are a method and apparatus that will provide sufficiently accurate real-time measurement of blood analytes (such as glucose) without adding labor or complexity and at a much lower cost.

The number of diabetics is growing rapidly, and required hospitalization is a significant factor in the need for automated analyte monitoring. Hospitalized diabetics have great difficulty maintaining their blood sugar during their stay in the hospital, and this leads to a host of complications including increased respiratory, urinary tract, and surgical site infections, slower healing, increased length of hospital stay, increased time on respirators, increased risk of re-admittance, loss of mental acuity, and generally poorer patient outcomes. This is a problem that also manifests itself in critical/intensive care patients undergoing major surgical procedures, recovering from heart attacks or strokes, in patients residing in general wards, dialysis, and rehabilitation hospitals. Several manufacturers have developed continuous glucose monitoring products. Unfortunately, their products require labor intensive fmgerstick calibration, as well as, fmgerstick testing for "out of bounds" readings, which add to the labor of medical care professionals that are already overburdened. In addition, there is a growing concern and belief that these products developed for individual users do not have the consistent accuracy required for making

therapeutic decisions.

Existing products have been labor intensive, unreliable, inaccurate, expensive, and/or highly complex, barring them from becoming viable solutions for use in the described environments.

Today nurses utilize existing fingerstick methods and draw blood from the patient, then deposit it on test strips that are read by common glucose meters.

Alternatively, blood samples are drawn in tubes, and these samples are taken to the hospital laboratory for testing in laboratory equipment Some of these laboratory analyzers have been reduced in size sufficiently to be moved to the hospital wards. However this does not remove the need for drawing blood, transporting it to the machine, setting up and running the tests, and waiting for results. In either event, the solution has not resolved the high cost of medical professionals drawing blood, or the labor burden added to these individuals who are already inundated with other patient care responsibilities. A device that provides automated results in a timely manner, with the increased accuracy required for therapeutic decisions, at low cost, is clearly needed.

In nearly every case prior art fails to address either accuracy, reliability, or issues regarding labor and cost. Patient care providers who lack the time to draw fingerstick samples and test with a hand held meter, also do not have the time to be restarting IV *s, resetting equipment, performing fingerstick tests for calibration or verification of results, or learning to operate and maintain miniaturized laboratory equipment. In some cases, such as miniaturized blood analyzers, it is a. matter of cost and complexity. While it seems a good idea to move the lab closer to the patient, the need for someone draw blood samples, deliver them to the device, and to operate and maintain the measurement unit remains unresolved.

The variability of laboratory results of present laboratory analyzers has been attributed to a number of factors including physiological differences relating to time of day (morning vs. afternoon as much as 14% variation in fasting blood glucose depending on time of day that the sample is taken), differences in enzyme substrate measurement methods (glucose oxidase vs. hexokinase), timeliness of processing (glucose in whole blood decreases over time), and whether serum, plasma, or whole blood is tested.

Other devices utilize electrochemical measurement methods, and derive measurement from patient blood samples. None of these electrochemical methods and devices provide cost effective automated real-time measurement data with sufficient reliability or accuracy for use in making timely therapeutic decisions. Continuous glucose monitoring systems (CGM's) utilizing blood, plasma, serum, interstitial fluid, sweat, or implantable chemiluminscent sensors under development are unproven. Those CGM's that are currently available remain tied to calibration from alternative measurement methods that lack sufficient accuracy, reliability, and/or timeliness, and are labor intensive and costly.

Summary of the Invention

The apparatus and method of the present invention provides micro-tubes for delivery of a very low volume sample of a patient's fluid to a metering mixing dispenser; the dispense sample is mixed with an optimizing solution and delivered through a temperature controlling dispense head to electrochemically enhanced membrane-substrate matrix well. The chosen analyte is measured based on calibration utilizing chemical, temperature, and electrolyte optimized response for measurement of the analyte in a linear portion of the relevant response curve.

Measured blood glucose concentration is then provided to a display and wireless or wired stations such as nursing stations or patient electronic control records. The system is automatically flushed with a flush solution to clear the system and to establish electronic signal baseline as part of calibration. The dispense head is then repositioned over the next selected test well containing fresh membrane-substrate matrix for sample measurement.

Brief Description of the Drawings The present invention may more readily be described by reference to the accompanying drawings in which: Figure 1 is a functional block diagram of a system for automated blood analyte monitoring constructed in accordance with the teachings of the present invention.

Figure 2 is a schematic representation of an electrochemical sensor appropriate for use in the system of the present invention.

Figure 3 is an enlarged view of an electrochemical sensor of Figure 2 shown in greater detail.

Figure 4 is a schematic representation of an array of electrochemical sensors each incorporating the functional requirements of a sensor of the present invention.

Figure 5 is a schematic representation of microtubes illustrating multi-luman tubing utilized in the system of the present invention.

Figure 6 is a glucose response plot illustrating upper and lower portions that exhibit linearity showing measured responses to increasing glucose concentrations.

Figure 7 is a schematic representation of a system incorporating the teachings of the present invention useful for describing electronic signal

management.

Figure 8 is a schematic representation of the system incorporating the teachings of the present invention useful for describing fluid handling features of the present invention.

Detailed Description of the Invention

In Figure 1, Scanner 22 reads patient 1 barcode sending it wirelessly to processor 12, where all patient information is entered into patient file

electronically. The patient barcode is typically assigned to the patient upon entry/registration with the health facility and is placed on the patient's identifier bracelet. Blood is drawn from existing patient intravenous access (IV) or directly throug a newly placed IV. The blood sample is drawn by pump 3 through microtubule 2, manifold 48 and delivered to dispense head 4. Microtubule 2 comprises coated plastic tubing, potentially multiple lumen of some variety to bring blood from the patient through the pump and delivered to the test delivery head. Microtubes may also be utilized with some embodiments for return of fluids to the patient. See for example multi-lumen tubing 46 and dual lumen tubing 47 in Figure 5. Dispense head 4 deposits blood sample (typically 1.5 uL) on to an electrochemical sensor or sensor array 6. A signal 16 is generated by the electrochemical sensor or sensor array 6 and provided to the processor 12 where it is processed to provide the glucose concentration measurement and send signal 19 to the device display 15 and wirelessly 20 to electronic patient charting/record 21 after blood sample measurement is completed. Variations in the

current/impedance resulting from the patient samples positioned between sensors electrodes provides signals to the data processor to enable the production of glucose measurement values.

The sensor array 6 may incorporate any of several sensor array designs, such as "lab on a chip", circular CD format, continuous tape of sensors or a plate with X-Y layout of sensor wells such as shown in Figures 7 and 8. Motion controller 13 is instructed by processor 12 to position sensor array, or dispense head 4 (or both) for delivery of patient sample 1 or calibration solution 9 to a selected well 6a

(Figure 3) of the electrochemical sensor (sensor array 6). After the patient sample measurement has been made pump 3 draws flush solution 8 through the manifold 48 and dispense head 4 and corresponding tubing 5 passing through to waste receptacle 7. Referring to Figures 2 and 3, each electrochemical sensor of the sensor array forms a well 6a incorporating a cathode 38 and anode 39 between which an optimum charge of .01 to 1.0 volts is imposed. Electrochemical analyte

measurement is achieved in the well laiown manner by detecting current variations resulting from conductivity changes of the analyte. The patient sample passes through a series of selective membranes including permeable membrane 35 to selectively remove particulates, permeable membrane 36 to remove confounding elements such as cholesterol with a binding affinity to Nation ^{1 M}, and permeable membrane 37 for removal of electro-active confounding elements such as ascorbic acid, acetaminophen, and others. Once it has passed through the membranes the patient sample interacts with an optimizing buffer including the enzyme substrate 41 comprising a glucose oxidase in an optimizing chemical matrix and a signal enhancing chemical in an optimum concentration between 0.001 and 0.005m that is embedded either in the optimizing chemical matrix or in the matrix of selectively permeable membranes 35, 36, and/or 37. The optimizing buffer may alternately be supplied by mixing with the patient blood sample as the blood is distributed to each well of the sensor array.

Optimizing buffer/compound matrix 62 (Figure 8) to be mixed with the patient's blood sample to form a test sample generally comprises or provides

0.001-0.005mM of an oxidizer from a group including benzodioxoborole, boronic acid, borinate esters, boronate esters, or other equivalent oxidizers. Said

"optimizer" also includes physiologically optimized electrolytes (including Na+, K+, Mg++, and Ca++) and in a preferred embodiment includes a known

concentration of glucose. Specific physiologic ranges for blood serum are: K+ - 3.6~4.8mEq/L: in our preferred embodiment (0.1 - 10.0 mEq/L) Na+ - 135-145 mEq/L: in our preferred embodiment (100 - 300 mEq/L) Mg++ - 1.5-2.4mEq/L: in our preferred embodiment (0.1 - 10.0 mEq L) Ca++ - lOmg/dL: in our preferred embodiment (1.0 - 25mg/dL)

Osmolality @ 280-310 mOsm/ g: in our prefeired embodiment

(100-500 mOsm/Kg)

The addition of both known glucose concentrations and signal enhancement from peroxide/oxygen donors (above) to form a test sample consistently provides signal measurement in one of two linear portions of the known glucose

electrochemistry. Analyzing measurements from a linear response allows for direct measurement without predictive algorithms. Also, utilizing optimized electrolytically tailored buffer for sample processing removes measurement variability due to oxygen saturation, increases response through oxygen/peroxide donor compound, and enhances conductivity via optimized electrolyte blend.

Using this optimizing buffer to "process" the sample for direct glucose measurement in one of two linear portions of the glucose measurement response curve for electrochemistry (hexokinase or glucose oxidase) based systems has not been addressed in prior ait.

The optimizing buffer may also include buffering compounds (Trizma or others to maintain pH range at or near 7. Buffer ("optimizer") can be delivered in aqueous form for automated clinical applications or in dried/lyophilized form incorporated in the enzyme substrate or layered between exclusion membranes. In either case it would be reconstituted by the blood sample.

These sensor(s) (Figures 2 & 3) can be arranged arrays such as

schematically shown in Figure 4 for the analysis of singular or multiple analytes utilizing enzyme substrates reactive with specific biomarkers of interest including but not limited to protein C, troponin, cholesterol, and others.

In one embodiment the dispense head and sensor array are housed in an environmentally controlled enclosure 59a (Figure 7) that maintains an optimum temperature for the activity of the glucose oxidase enzyme substrate at or near body temperature of 37 Centigrade. A heater and/or cooling coil is imposed on the dispense head and/or prior to the dispense head to maintain the temperature of the patient sample and or the calibration solution 9 to be applied to the electrochemical sensor(s). Thermo-electric cooler/heater 59 (Figure 7) is utilized in a preferred embodiment to maintain optimum temperature of sensor/substrate and fluid dispense head.

Referring to Figure 8, blood is removed from the patient 1 via a patient access catheter 2 equipped with a pressure sensor to prevent venous/arterial collapse and drawn by the pump 3 through a manifold 48 that delivers the sample through a metered/mixing dispense head 4 that delivers a diluted and/or augmented (to be described) patient sample to the measurement sensor array 6 for

measurement. When patient draw is completed the reversible pump 3 draws or pushes flush solution 8 (physiological buffer) back through the catheter to clear blood products, and simultaneously or separately through the movable dispense head 4 that has now been positioned by the processor 12 and dispense head motion controller 13 for delivery to a waste reservoir 7. In a calibration sequence for the proposed device embodiment in Figure 8 the pump 3 would draw calibration fluid 9 and optimizing buffer 62 through the manifold 48 to the metered mixing dispense head 4 and deliver it to the electrochemical measurement sensor array 6. This would be followed by a flush cycle that would draw/deliver flush solution 8 through the fluid delivery system flushing the tubing and metered mixing dispense head 4 and exiting into the waste reservoir 7.

Referring to Figure 7, the data processor 12, operating under program control, receives and sends electronic signals to and from system components to monitor and control the operation of the system of the present invention. The data processor receives signals 51 from the patient return line bubble sensor 50, signals 31 from the patient return line pressure sensor 28, and signals 32 from the pressure sensor 29 for the nitric-oxide stimulating eluting system. These signals are received by the data processor 12 in combination with signals 30 from the pressure sensor 27 for fluids exiting the patient. Control signals 60 and 61 to and from a thermoelectric cooler/heater 59 permit the data processor to control the

temperature of a reaction chamber 59a that includes the sensor array 6, pump 3 and delivery head 4 (see Figure 1) as well as fluids delivered to the sensor array. In accordance with the program control within the data processor 12, signals 54 are provided to the pump 56 for nitric-oxide stimulating buffer as well as signals 26 for the reversible pump 3, signals 49 for the manifold 48, and signals 17 for the motion controller 13 for controlling the relative motion of the sensor array and the dispensing head. The data processor also provides signals 40 to the motion control unit 25 for the sensor array and receives feedback signals 16 therefrom to permit the appropriate timing and positioning of the sensor array and dispensing head for the dispensing of fluids.

The data processor provides signals 19 to a display 15 and makes available signals 20 to the patient electronic charting system 21 and updating signals 23 to the barcode scanner 22. Connections between the data processor 12 and the charting system 21, as well as connections between the data processor 12 and the barcode scanner 22 may be hard wired or wireless. The sequence of events in a "measurement cycle" in the proposed

embodiment begins with a signal to the reversible pump 3 to draw blood through patient access system 45. During the draw, signals 30 from the patient access pressure sensor 27 are delivered to the processor 12 which manages the pump 3 to avoid venous/arterial collapse. A measured volume of blood from the patient is drawn by the reversible pump 3 through the manifold 48 along with a metered volume of optimizing buffer 62 (Figure 8) into the metered mixing dispense head 4. The processor 12 provides signals to the motion controller 13 either for the dispense head 4 or to the motion control unit 25 (or both) that will align the dispense head 4 with the electrochemical well or wells to be utilized. Signals 16 from the electrochemical sensor array 6 are processed by the processor 12 and operating software to provide a glucose measurement to the display 15 and for wireless delivery to the electronic patient record 21. The remainder of the cycle includes flush sequence signals from the processor 12 to the pump 3 and manifold 48 to access flush buffer from the flush reservoir 8 (Figure 8) and flush patient access system 45, metered mixing dispense head 4, and corresponding tubing.

Patient access is again monitored via the catheter pressure sensor 28 and optionally a bubble sensor 50.

At all times while the patient access system is inserted in the patient the designated "soaker" pump will provide slow and steady delivery of the endothelial nitric oxide synthase stimulating buffer to the catheter "soaker" coating. This delivery will be based on pressure sensor 29 incorporated in the "soaker" sheath. The implementation of the present system including controlled operation of the processor enables the system to provide an innovative accurate method for providing on-demand automated real time patient blood analyte measurements. The electrochemical based measurements of numerous analytes that are utilized to guide therapeutic treatment of patients are collected and provided to caregivers in critical care environments. The method includes the insertion of a patient access device, or the connection to an already existing access device that may use the above described innovative access catheter. A very low volume sample of the patient's fluid is derived through micro-tubes wherein blood is delivered to metered/mixing/pump/dispenser in a programmed controlled sequence and environment. The dispense sample is mixed with an optimizing solution through a temperature controlling dispense head. The temperature controlled sample is delivered to electrochemically enhanced membrane-substrate matrix under temperature control and signal enhancing matrix. The chosen analyte is measured based on an automated calibration technique utilizing an integrated approach to chemical, temperature, and electrolyte optimized response for measurement in a linear portion of a chosen response curve. The measured blood glucose

concentration is sent to a display and wireless or wired appropriate stations such as nursing stations or patient electronic control records. The system is automatically flushed with a flush solution to clear the system and to establish electronic signal baseline as part of calibration. The dispense head is then repositioned over the next selected test well with fresh membrane-substrate matrix for sample

measurement or calibration, or the test well is repositioned under the dispense head - - or a combination of movement of both to provide accurate and rapid

repositioning in preparation for subsequent tests. Venous and arterial access systems often suffer from signal degradation over time due to deposition of biological and cellular components found in human blood. They have a tendency to become encapsulated over time when implanted in the human body. The improvement incorporated in the present system provides an eluting/" stimulating" outer layer covering the catheter needle releasing milli-molar (niM) concentrations of a proprietary mixture of naturally occurring amino acids (such as 1-arginine and 1-citrulline), calcium, magnesium, and other electrolytes within optimal physiological ranges. In one embodiment the generation of endothelial nitric oxide is stimulated through a bioabsorbable coating that releases the amino acid mixture at a controlled rate as it is dissolved into the bloodstream. In an another embodiment an aqueous solution is intermittently released in microliter volumes bathing the outer surface of the implanted catheter and surrounding venous endothelial cells and stimulating the activity of endothelial nitric oxide synthase bound to the cell membranes of the venous or arterial endothelium. A separate reservoir 55 (Figure 1) contained within a disposable package contains the endothelial nitric oxide synthase (eNOS) stimulating solution and it will be delivered to the to the patie t catheter system by the reversible pump 3 or a separate dedicated pump responding to signals 32 from the pressure sensor 29 and sent from catheter sheath 44 (Figure 5) to the device's microprocessor 12. Patient access system 45 (Figure 1 ) may be included within the present system or as a standalone product to be utilized for IV 's, fistulas, dialysis catheter

placements, central lines (such as peripherally inserted central catheters "PICC's" or long-arm catheters "LAC's"), and with other devices providing or utilizing venous or arterial patient access.

In a preferred embodiment the device will utilize a disposable kit in Figure 1 containing the flush 8, calibration 9, eNOS stimulating solution 55, a waste reservoir 7, coiTesponding tubing, venous access catheter, and a sensor array 6 in one of several formats, and in some embodiments a reservoir and delivery system for a reaction optimizing buffer 62 (Figure 8) to be added to the patient sample or calibration fluid at the delivery head 4. These formats include X-Y plates, printed microchip, spooled roll of sensors, sensors laid out on or in the shape of CD, and others. With each format a corresponding means for positioning the dispense head 4 via dispense head motion controller 13, and/or the sensor(s) 6 via sensor motion controller 25 as shown in Figures 1 and 7 to optimize sample delivery and economies of space, power, and cost. The proposed disposable package is designed to provide testing sensors and solutions for testing as frequently as eveiy 10 minutes for 72 hours with sufficient additional tests to accommodate hourly calibration.

In one preferred embodiment the proposed device is calibrated using a single calibration solution of a known glucose concentration that will automatically adjust the device's internal algorithm for measurements made within the physiologically significant range of 40-400mg/dL, This calibration solution will be part of the disposable kit supplied for each patient. In the proposed device embodiment an optimizing buffer will be utilized to dilute samples or increase sample

electrochemical signals via the addition of known concentrations of glucose to make measurements in the recognized linear portions 57 or 58 (Figure 6) of the generally recognized electrochemical glucose response curve. Typical analyses of response plots from readings at concentrations ranging from 25-400mg/dL result in response curves that are not linear. However, the upper and lower portions of the individual plots exhibit linearity; therefore, utilizing the linear portions of the glucose response plot avoids the use of significant mathematical processing and the introduction of predictive algorithms as the curvature of the plot shifts in response to temperature, pressure, oxygen concentration, electrolyte balance and pH. The present invention minimizes reliance on complex predictive algorithms and allows for more straight forward data processing; specifically, the glucose concentration in the patient's sample utilized to make measurements is limited to one of the two linear portions 57 and 58 of the response plot shown in Figure 6. In a preferred embodiment, glucose would be added to the work sample in the upper range commencing at about 200mg/dL. As a result, the glucose response is directed to two linear portions of the glucose response plot thus avoiding the significant mathematical processing.

In another embodiment a secondary sensor well is utilized to provide a background signal based solely on the optimizing buffer. In this embodiment the background signal is removed from the patient sample signal to provide a direct differential measure. The glucose measurement would in this embodiment be derived from a calibration signal generated in the same manner, whereby the calibration standard would be measured with the addition of the optimizing buffer and the optimizing buffer would be measured separately providing a direct differential response. This calibration response would then be utilized to update the systems reporting algorithm for glucose measurement.

The present invention has been described in terms of selected specific embodiments of the apparatus and method incorporating details to facilitate the understanding of the principles of construction and operation of the invention. Such reference herein to a specific embodiment and details thereof is not intended to limit the scope of the claims appended hereto. It will be apparent to those skilled in the art that modifications may be made in the embodiments chosen for illustration without departing from the spirit and scope of the invention.

Claims

What is Claimed:

1. A method for blood analyte monitoring comprising:

(a) drawing a measured volume of blood from a patient;

(b) mixing a measured volume of optimizing buffer with said measured volume of blood to form a test sample; and

(c) eiectrochemically measuring the analyte concentration in said test sample.

2. The method of Claim 1 wherein said measured volume of optimizing buffer includes an oxidizer, and an analyte concentration of the analyte being measured to render the test sample's analyte measurement response within a linear portion of a corresponding analyte response plot.

3. The method of Claim 2 wherein said oxidizer is from a group consisting of benzodioxoborole, boronic acid, borinate esters and boronate esters.

4. The method of Claim 2 wherein said optimizing buffer includes physiologically optimized electrolytes to provide said test sample with the following ranges of electrolytes:

K+ - 3.6-4.8mEq/L

Na+ - 135-145 mEq L

Mg++ - 1.5-2.4mEq/L

Ca++ - lOmg/dL

5. The method of Claim 2 including maintaining a temperature of said test sample at or near 37° centigrade.

6. A method for blood glucose monitoring comprising:

(a) drawing a measured volume of blood from a patient;

(b) mixing a measured volume of optimizing buffer with said measured volume of blood to form a test sample; and

(c) electrochemically measuring the glucose concentration in said test sample.

7. The method of Claim 6 wherein said measured volume of optimizing buffer includes an oxidizer, and a glucose concentration of the analyte being measured to render the test sample's glucose measurement response within a linear portion of a glucose response plot.

8. The method of Claim 7 wherein said oxidizer is from a group consisting of benzodioxoborole, boronic acid, borinate esters and boronate esters.

9. The method of Claim 7 wherein said optimizing buffer includes physiologically optimized electrolytes to provide said test sample with the following ranges of electrolytes:

K+ - 3.6-4.8mEq/L

Na+ - 135-145 mEq/L

Mg++ - 1.5-2.4mEq/L

Ca++ - l Omg/dL

10. The method of Claim 7 including maintaining a temperature of said test sample at or near 37° centigrade.

1 1. Apparatus for automated blood analyte monitoring comprising:

(a) a manifold for connection to a patient catheter for obtaining a patient blood sample;

(b) a reservoir connected to said manifold containing an optimizing buffer;

(c) a pump connected to said manifold for receiving a patient blood sample and to said optimizing buffer for receiving said optimizing buffer to form a test sample;

(d) a dispense head connected to said manifold for dispensing said test sample;

(e) a sensor array comprising a plurality of test wells each positionable with respect to said dispense head to receive test samples therefrom; and

(f) each test well including electrodes therein for connection to a voltage source for creating an electric current in said test samples contained in the test well to provide a measurement of analyte concentration.

12. The apparatus of Claim 11 including a thermo-electric

controller/heater programmed to control the temperature of the sensor array, pump and dispense head to maintain the temperature of said test sample at or near body temperature of 37°C.

13. The apparatus of Claim 1 1 wherein each of said test wells includes permeable membranes for filtering test samples deposited therein by said dispense head.

14. The apparatus of Claim 13 wherein said membranes include a membrane for removing particulates, a permeable membrane to remove elements such as cholesterol with a binding affinity to Nation™ and a membrane for removal of electro-active confounding elements such as ascorbic acid and acetaminophen.

15. Apparatus for automated blood analyte monitoring comprising:

(a) a manifold for connection to a patient catheter for obtaining a patient blood sample;

(b) a pump connected to said manifold for receiving a patient blood sample to form a test sample;

(c) a dispense head connected to said manifold for dispensing said test sample;

(d) a sensor array comprising a plurality of test wells each positionable with respect to said dispense head to receive test samples therefrom;

(e) each test well including electrodes therein for connection to a voltage source for creating an electrical current in test samples containing in the test well; and

(f) each test well including an enzyme substrate comprising a glucose oxidase in an optimizing chemical matrix and a signal enhancing chemical in an optimum concentration between 0.001 and 0.005mM imbedded in the optimizing chemical matrix.

16. The apparatus of Claim 15 including a thermoelectric cooler/heater programmed to control the temperature of the sensor array, pump and dispenser head to maintain the temperature of said test sample at or near body temperature of 37°C.

17. The apparatus of Claim 15 wherein each test cell includes permeable membranes for filtering test samples deposited therein by said dispense head.

18. The apparatus of Claim 17 wherein said permeable membranes include a membrane for removing particulates, a permeable membrane to remove elements such as cholesterol with a binding affinity to Nafion™ and a membrane for removal of electro-active confounding elements such as ascorbic acid and acetaminophen,

19. Apparatus for automated blood glucose monitoring comprising:

(a) a manifold for connection to a patient catheter for obtaining a patient blood sample;

(b) a reservoir connected to said manifold containing an optimizing buffer;

(c) a pump connected to said manifold for receiving a patient blood sample and to said optimizing buffer for receiving said optimizing buffer to form a test sample;

(d) a dispense head connected to said manifold for dispensing said test sample;

(e) a sensor array comprising a plurality of test wells each positionable with respect to said dispense head to receive test samples therefrom; and (f) each test well including electrodes therein for connection to a voltage source for creating an electric current in said test samples contained in the test well to provide a measurement of glucose concentration.

20. The apparatus of Claim 19 including a thermo-electric

controller/heater programmed to control the temperature of the sensor array, pump and dispense head to maintain the temperature of said test sample at or near body temperature of 37°C.

21. The apparatus of Claim 19 wherein each of said test wells includes permeable membranes for filtering test samples deposited therein by said dispense head.

22. The apparatus of Claim 21 wherein said membranes include a membrane for removing particulates, a permeable membrane to remove elements such as cholesterol with a binding affinity to Nation™ and a membrane for removal of electro-active confounding elements such as ascorbic acid and acetaminophen.

23. Apparatus for automated blood glucose monitoring comprising:

(a) a manifold for connection to a patient catheter for obtaining a patient blood sample;

(b) a pump connected to said manifold for receiving a patient blood sample to form a test sample;

(c) a dispense head connected to said manifold for dispensing said test sample; (d) a sensor array comprising a plurality of test wells each positionable with respect to said dispense head to receive test samples therefrom;

(e) each test well including electrodes therein for connection to a voltage source for creating an electrical current in test samples containing in the test well; and

(f) each test well including an enzyme substrate comprising a glucose oxidase in an optimizing chemical matrix and a signal enhancing chemical in an optimum concentration between 0.001 and O.OOSmM imbedded in the optimizing chemical matrix.

24. The apparatus of Claim 23 including a thermoelectric cooler/heater programmed to control the temperature of the sensor array, pump and dispenser head to maintain the temperature of said test sample at or near body temperature of 37°C.

25. The apparatus of Claim 23 wherein each test cell includes permeable membranes for filtering test samples deposited therein by said dispense head.

26. The apparatus of Claim 25 wherein said permeable membranes include a membrane for removing particulates, a permeable membrane to remove elements such as cholesterol with a binding affinity to Nafion™ and a membrane for removal of electro-active confounding elements such as ascorbic acid and acetaminophen.