WO1991016416A1

WO1991016416A1 - Wearable blood glucose monitor

Info

Publication number: WO1991016416A1
Application number: PCT/US1991/002911
Authority: WO
Inventors: Kevin L. Zamzow; Daniel G. Schmidt; Mark C. Shults; Stuart J. Updike
Original assignee: Markwell Medical Institute, Inc.
Priority date: 1990-04-26
Filing date: 1991-04-25
Publication date: 1991-10-31
Also published as: AU7854891A

Abstract

A wearable device (10) for continuously monitoring plasma glucose concentrations in samples of undiluted whole blood comprises an enzyme electrode assembly (34) and a plurality of interrelated pumps (20, 22, 24) which operate in a predetermined sequence to withdraw a blood sample from a patient for analysis and then return the entire volume of the blood sample to the patient. Methods are disclosed whereby glucose levels can be continuously determined in the plasma of undiluted whole blood sample without blood loss by the patient and whereby insulin can be infused in response to the determined glucose levels. Dilution of the blood sample caused by laminar flow during withdrawal of the blood sample is substantially eliminated.

Description

EARABLE BLOOD GLUCOSE MONITOR Technical Field

The present invention generally relates to a system for determining the amount of a substance in a biological fluid and, in particular, to a wearable device and a method for continuously monitoring glucose concentrations in blood. Background Of The Invention

Some medications must be administered at regular intervals to control a medical condition. Diabetes, for example, may be controlled by daily, or more frequent, injections of insulin to normalize blood glucose levels. It has been found in the treatment of certain conditions, including diabetes, that more effective treatment results from constant or repeated small doses of medication. This provides improved control of the medical condition and avoids the problems associated with under- and over- medication.

Systems have been developed in which a catheter is subcutaneously implanted in a patient, and a medication is supplied to the patient as desired through the catheter associated with a pumping apparatus. These systems, however, tend to be large and bulky and in some cases require a considerable power source. For example, an apparatus was manufactured at one time under the trade name BIOSTATOR (by the Life Science Division of Miles Laboratories) for monitoring glucose levels and infusing insulin. The apparatus, however, was relatively complicated to operate and is no longer commercially available. In particular, the apparatus included a glucose sensor, a system for infusing insulin and a microprocessor which, through an appropriate algorithm, transformed values for glucose levels into an adequate administration of insulin (or glucose) . A daily blood loss of about 50 illiliters, and the non-portability of the apparatus along with the brief service life (less than about 50 hours) of the glucose sensor were significant disadvantages of the system. Moreover, the apparatus subjected the blood sample to a continuous precision dilution before analysis, determined whole blood glucose rather than plasma glucose, required the use of a relatively large (18 gauge) cannula in a peripheral vein and weighed several hundred pounds. Furthermore, the accuracy of the apparatus was sensitive to changes in hematocrit.

Accordingly, there is need in the treatment of diabetes for a wearable and portable system having a reasonable cost that continuously monitors plasma glucose concentrations in undiluted whole blood samples and effectively administers insulin. The present invention satisfies that need. Summary of the Invention

The present invention relates to a system for determining the amount of a substance in a biological fluid. In particular, the invention relates to a programmable device and a method for withdrawing a sample of whole blood from a patient, determining the concentration of glucose in the plasma of the blood sample without dilution of the sample and returning the entire blood sample to the patient. The patient experiences no loss of blood in the process. Means is also provided for calibrating and flushing the device along with means for treating the patient with a medication, such as insulin, in response to the results of the analysis.

The device is portable and lightweight, and can be constructed as a wearable unit for bedside and ambulatory use. In particular, the device comprises a housing adapted for removable attachment to the patient. Means in communication with the housing is provided for withdrawing a blood sample from the patient for analysis and returning the entire blood sample to the patient after analysis. Sensing means connected to the withdrawing means determines the concentration of glucose in the plasma of the blood sample. First pump means, which is preferably bidirectional, has an inlet end operatively associated with a first channel of the sensing means and an outlet end in communication with a source of calibration solution. Second pump means, which is also preferably bidirectional, has an inlet end operatively associated with a second channel of the sensing means which is in communication with the first channel, and an outlet end in communication with a source of wash solution. In addition, means is provided for controlling the first and second pump means to withdraw and to return the blood sample in a predetermined sequence. The withdrawing means includes a catheter for withdrawing the blood sample from the patient. The catheter remains inserted in a blood vessel of the patient for the withdrawal of blood at frequent intervals (about every two- five minutes) for continuous monitoring of the blood glucose level of the patient.

The calibration solution contains a predetermined amount of glucose and, along with the wash solution, includes an anti-coagulant (such as heparin or urokinase) in an amount sufficient to prevent the blood from clotting in the device but without significantly effecting the coagulating properties of the blood in vivo. The sensing means comprises a flow cell which is disposable and can be releasably mounted on the housing. The flow cell includes a body portion having a first channel in communication with a second channel. An enzyme electrode assembly is operatively associated with the second channel.

The juncture of the first and second channels provides an anti-convection barrier to prevent the blood sample or the calibration solution from entering the flow cell prematurely.

In particular, the cross-sectional area of the second channel is preferably less than the cross-sectional area of the first channel whereby the blood sample can flow through the first channel without flowing through the second channel. In an alternative embodiment, the second channel is substantially non-linear and is configured so that the blood sample can flow through the first channel without flowing through the second channel. A third pump means can also be provided having an inlet end operatively associated with the first or the second channel of the sensing means and an outlet end in communication with a source of insulin. This pump means need not be bidirectional. The device can also include means for detecting air (for example, an optical bubble detector) and for detecting hematocrit (for example, by electrical conductivity) in the device and thereupon providing a signal to the controlling means. The controlling means generally comprises electronic circuit means associated with the housing and operably associated with the enzyme electrode assembly for processing a signal from the electrodes of the enzyme electrode assembly. Display means operably associated with the electronic circuit means can also be provided for displaying a result.

The present invention also relates to a method of continuously determining the amount of glucose in the plasma of a sample of undiluted whole blood comprising the steps of: withdrawing a blood sample from a patient utilizing catheter means including tubing in communication with sensing means which includes a first channel, a second channel in communication with the first channel and an enzyme electrode assembly operatively associated with the second channel; pumping the blood sample through the tubing and through the first channel of the sensing means using a first pump having a plurality of rollers which fully occlude the tubing as the rollers rotate; pumping the blood sample through the tubing and through the second channel of the sensing means using a second pump having a plurality of rollers which fully occlude the tubing as the rollers rotate; determining the concentration of glucose in the plasma of the blood sample as the blood sample flows through the enzyme electrode assembly; and infusing the entire blood sample into the patient after the amount of glucose in the blood sample has been determined.

The glucose determinations are made on an intermittent basis at frequent intervals to continuously monitor the blood glucose level of the patient.

Additional embodiments of the method include the step of pumping a calibration solution or a wash solution through the apparatus thereby flushing the apparatus and returning the entire blood sample to the patient; and the step of infusing a predetermined amount of insulin into the patient based on the amount of glucose in the blood sample.

The relatively compact device of the present invention is particularly well-suited for the controlled administration of insulin in managing the abnormal glucose metabolism which characterizes diabetes. Either a continuous slow injection or a series of small injections over a period of time can be provided to avoid the problems of over- and under-medication. Thus, the diabetic patient can be provided with a lightweight wearable unit for monitoring blood glucose levels which includes a readily infusible source of insulin.

Numerous other advantages and features of the present invention will become readily apparent from the following claims, drawings and detailed description. Brief Description of the Drawings

In the accompanying drawings, which comprise a portion of this disclosure: FIGURE 1 is a perspective view of one embodiment of the present device being removably secured to the forearm of a patient;

FIGURE 2 is a plan view of the device of FIGURE 1;

FIGURES 3a-d are schematic diagrams of the analysis sequence of the device;

FIGURES 4a-b are schematic diagrams of the calibration sequence of the device; and

FIGURE 5 is a schematic view of an alternative embodiment of the device. Description of the Preferred Embodiments

The device of this invention can be assembled and used in many different forms. This detailed description and the accompanying drawings disclose only specific forms which provide examples of the preferred embodiments. The particular shapes and the sizes of the components described herein are not essential to the invention unless otherwise indicated. Moreover, the invention is not intended to be limited to the embodiments illustrated.

In addition, the present device utilizes certain conventional analysis and control means, the type and operation of which will be apparent to those skilled in the art. The choice of materials is somewhat dependent on the particular application and other variables as will be appreciated by those having an understanding of the operation and use of electronic instrumentation.

Referring to Figures 1 and 2, the present device 10 includes a main housing 12 which can be removably secured, for example, to the forearm of a patient to provide a wearable, portable analysis and infusion apparatus. In particular, the main housing 12 can be secured to support means comprising a cradle member 14 which wraps around the forearm and is removably secured thereto, as by Velcro straps 16.

The main housing 12 includes means for withdrawing and infusing a biological fluid, means for determining the amount of a substance in the biological fluid and means for treating the fluid. The following description relates to the determination of the concentration of glucose in the plasma of a sample of undiluted whole blood, and the treatment of the patient by infusing insulin to maintain desired blood glucose levels. However, it will be understood that the invention can be modified to determine the presence and the amount of other substances in biological fluids.

The withdrawing and infusing means include tubing 18 (with an associated catheter/needle) and pump means comprising a plurality of interrelated pumps 20, 22 and 24 which can be standard peristaltic or roller pumps of the type frequently used in blood treatment systems. One acceptable type of pump, which employs spring-loaded rollers, is Model SARA manufactured by SARNS of Ann Arbor, Michigan. The tubing 18 is preferably a flexible plastic material of the type ordinarily used in blood treatment systems which is compatible with the pump means. Such tubing is typically from about 0.01-0.06 inches in diameter depending on the application and flow rate demands. Heparin-bonded tubing may be used for the end portions of the tubing to prevent clotting which otherwise might occur. In addition, urokinase can be used in controlled amounts to prevent fibrin formation in the tubing. In a preferred embodiment, the withdrawing means, which comprises a catheter and associated tubing 18, withdraws a sample of undiluted whole blood from the patient for analysis and infuses the entire volume of the blood sample back into the patient so the patient does not experience any loss of blood.

Operatively associated with the withdrawing and infusing means is means for determining the amount of a substance in the biological fluid. Means including the pump 24 can also be provided for treating the fluid (for example, with insulin) , although this is optional.

The means for determining the amount of a substance in a biological fluid comprises sensing means 26 in the form of a sensor and flow cell 28. The flow cell is preferably disposable in the form of a removable cartridge member; and comprises first and second channels 30 and 32, respectively, for the passage of a fluid and an enzyme electrode assembly 34 operatively associated with the second channel 32. The enzyme electrode assembly 34 is capable of sensing glucose accurately and precisely in the plasma of samples of undiluted whole blood.

In the illustrated embodiment, pumps 20, 22 and 24 are identical so the following description with regard to pump 20 relates to the construction of each pump. In particular, pump 20 comprises a platen member 36 which can be removably secured and accurately aligned to the main housing 12 by a convenient, easy-to-use latching mechanism 38. The platen member 36 includes an arcuate-shaped surface 40 on one side thereof. A portion of flexible tubing 18 through which the blood, a calibration solution or a wash solution can flow is positioned adjacent the arcuate-shaped surface 40 of the platen member 36. A rotatable member 42 mounted on the main housing 12 includes a plurality of equally-spaced rollers 44 (preferably four) and is operatively connected to a DC motor (not shown) .

When the rotatable member 42 is rotated by the motor, the rollers 44 squeeze the tubing 18 against the arcuate-shaped surface 40 of the platen member 36 to collapse the tubing and thus displace the fluid in the tubing. The rollers 44 occlude the tubing fully so the pump, when stopped, blocks the flow of fluid in either direction. After a roller 44 has collapsed a portion of the tubing 18, the tubing re-expands to draw the appropriate fluid. The rotatable member 42 can rotate clockwise or counter-clockwise so the pump is bidirectional.

One problem that is common to all types of blood treatment systems is the need to prime the system before initial use. A common safety device in such systems is a bubble detector that monitors the blood or other fluids flowing through the tubing for the presence of air or other gases which could harm the patient.

In the present device, a detector 46 is positioned adjacent the flow cell 28 at the point where the blood from the patient enters the device. The detector ultrasonically or optically monitors the presence of an abnormal amount of air or foam in the fluid passing through the tubing 18, whether the fluid is the blood sample, the calibration solution, the wash solution or insulin. The detector 46, in association with the controlling means, responds to the occurrence of such an abnormal condition by deactivating the appropriate pump to prevent delivery of the air bubbles or foam to the patient. The detector 46 can also monitor the passage of the blood sample to and from the device by sensing the passage of the interface between the blood sample and the wash or calibration solution.

The detector 46 can also measure the electrical conductance through a short segment of tubing and thus also monitor hematocrit which is known to those skilled in the art to be transducable by monitoring conductance. If the cannulated vein should become thrombosed or obstructed downstream, then the fluid withdrawn from the vein would show a decrease in hematocrit and signal that inadequate blood sampling is occurring.

The controlling means can include a central processor having both communication hardware and operational hardware. The communication hardware transmits information between the central processor and the individual wearing or operating the device. The communication hardware can include display means and an input device such as a keyboard having a plurality of input and output keys which determine the sequence and mode of operation of the device. The display means can include an electronic alphanumeric display which can both prompt the operator for input and display relevant operating parameters.

In a particularly preferred embodiment, a 200 icroliter sample of venous blood is withdrawn from a patient (preferably from an arm vein) through a 22 gauge single lumen cannula or catheter with associated tubing 18. The blood is drawn through the tubing 18 and passes through the flow cell 28. A rate determination is completed in about 20 seconds or less, and the entire sample of whole blood is returned to the arm vein followed by a heparin- containing saline wash or calibration solution. No blood loss or significant systemic heparinization occurs. The total cycle time is preferably about 1-5 minutes depending on the clinical situation.

Serial rate determinations of glucose are preferably made about every 1-5 minutes. After each glucose determination, the entire blood sample is flushed back into the patient with the heparin-containing wash solution. The wash solution comprises a physiologically acceptable saline solution without glucose and serves to determine the baseline zero glucose concentration signal which is needed for a drift-free rate determination. This is performed promptly to lessen the risk of blood clotting in the tubing after the analysis.

Moreover, in addition to providing a means for calibrating the device between readings, the calibration solution can also serve as a wash solution to flush the device and return the blood sample to the patient. The calibration solution comprises a saline solution including a predetermined concentration of glucose (for example, 200 mg/dl) . The method is linear to about 800 milligrams/deciliter glucose, is independent of hematocrit or physiological p0₂ and is free of interferences from blood constituents. The coefficient of variation is less than about 4 percent between calibrations. Moreover, the enzyme electrode assembly 34 has a service life of over one month. This wearable blood glucose analyzer is a significant improvement in the evaluation and treatment of diabetes.

An enzyme electrode assembly suitable for use in this invention is described in U.S. Patent No. 4,757,022 which issued to Shults et al. on July 12, 1988 and which is incorporated herein by reference. Other suitable enzyme electrode assemblies are disclosed in copending application Serial No. 216,683, which was filed on July 7, 1988 and which is also incorporated herein by reference.

In particular, the enzyme electrode assembly comprises at least two electrodes carried by the main housing. A membrane associated with the second channel 32 of flow cell 28 is adapted to contact the electrodes when the flow cell is mounted on the housing. The membrane is a multilayered structure including layers formed of materials such as polyethylene, polyvinylchloride, tetrafluorethylene, polypropylene, cellophane, polyacrylamide, polymethyl methacrylate, silicone polymers, polycarbonate, cuprophane, collagen, polyurethanes and block copolymers thereof. The membrane prevents direct contact of the fluid sample with the electrodes, but permits selected substances of the fluid to pass through the membrane for electrochemical reaction with the electrodes. To ensure electrochemical reaction, the surface of the membrane layer nearest the electrode is preferably coated with a water-swellable film to maintain electrolyte at the electrode-membrane interface, and thereby improve the sensitivity of the measurement.

In a preferred embodiment, the membrane is a semi- permeable multilayered membrane having at least one layer formed of a nonporous block copolymer having hydrophobic segments and hydrophilic segments that limits the amount of a substance passing therethrough and a second layer including an enzyme that reacts with the substance to form a product.

In a more preferred embodiment, the electrode assembly comprises an electrode, a first (outer) layer of a block copolymer that limits the amount of a hydrophilic substance passing therethrough, a second (intermediate) layer of a block copolymer including an enzyme bound to the first layer and a third (inner) layer of a block copolymer bound to the second layer and covering the surface of the electrode. The third layer is permeable to relatively low molecular weight substances, such as hydrogen peroxide, but restricts the passage of higher molecular weight substances. It is generally accepted that a linear relationship between the concentration of the glucose analyte and the signal generated by the reaction product, ^H2°₂' ^^s desirable. Such a linear relationship exists for glucose at a concentration well below its Michaelis-Menten rate constant expressed quantitatively as K_m. This linearity, however, is outside the range of milligrams per deciliter that is generally of clinical interest.

The present enzyme electrode assembly avoids the problem of the non-linear relationship existing between the glucose analyte and the signal generated from the hydrogen peroxide reaction product within a clinically useful concentration range of from about 40 to about 400 milligrams glucose per deciliter. This is accomplished by (a) using a glucose oxidase enzyme electrode in which the enzyme immobilization technology used allows the electrode to measure plasma glucose in whole blood in the useful clinical range directly from an undiluted blood sample, and to do so independently of changes in hematocrit (hematocrit is well- recognized in the art as the volume percentage of red blood cells (RBC) in whole blood and indicates the ratio of RBC volume to plasma volume) ; (b) conducting the analysis so rapidly that the analytical result is not influenced by intracellular glucose (RBC glucose is always less than plasma glucose) and thus is indeed independent of hematocrit; and (c) using a multilayered, polyurethane-based polymer membrane matrix to entrap the enzyme which is (i) sufficiently hydrophobic to allow adequate transport of oxygen to be non-rate limiting with respect to oxygen, and (ii) sufficiently hydrophilic to selectively allow the transport of water-soluble substances like glucose by preferential diffusion and (iii) sufficiently strong to stabilize the diffusion path length. The operation of an enzyme electrode that is suitable for use in this invention is described in Updike et al., Diabetes Care, 11, 801-807 (1988) which is incorporated herein by reference. As demonstrated in that article, the glucose determination is independent of hematocrit. This feature was not previously demonstrated in any glucose detection method that utilizes a whole blood sample.

This linearity is achieved because the enzyme is immobilized in such a way that the rate-limiting step involves partitioning and diffusion of a substance such as glucose through the surrounding non-porous multilayered polymer membrane matrix. On the other hand, the porous membranes disclosed in the prior art use size exclusion filtration to control diffusion without achieving linearity in the physiological range. The polyurethane-based membrane of the present enzyme electrode assembly not only selectively limits the amount of substance diffusing therethrough, it also provides an unusually strong and durable membrane. The strength and durability of the membrane allows the membrane to maintain a constant cross-sectional dimension for the diffusion path of glucose through the membrane to the electrode and thereby avoids calibration problems caused by variable or inconsistent path lengths seen with conventional porous membranes used in prior commercially available analyzers. An additional problem associated with blood treatment and analysis systems relates to the accuracy of readings or determinations when a fluid flows through tubing, or a similar passage having a relatively small cross-sectional area. In particular, when a Newtonian fluid passes through a tube, the portion of the fluid closest to the sidewall of the tube moves at a substantially slower rate than the portion of the fluid at the center portion of the tube (i.e., due to laminar flow). In fact, the maximum velocity of the fluid at the coaxial center of the tube is approximately twice the mean velocity of the fluid.

Thus, when a blood sample is withdrawn from the patient via the catheter and tubing 18 for passage through the flow cell 28 for analysis by the enzyme electrode assembly 34, the leading portion of the blood sample is diluted to some extent. This is because laminar flow causes the sample to partially mix with any fluid (e.g., a wash or calibration solution) that may remain in the tubing from a previous operational step involving the same patient.

In order to circumvent this unwanted and somewhat variable dilution, a volume of blood sample that is greater than that needed for the analysis must be withdrawn to completely flush the fluid (usually the wash or calibration solution) from the tubing 18 and the flow cell 34. As a result, the enzyme electrode assembly begins its analysis on a blood sample which has undergone an unwanted dilution. The precision of the readings obtained during use of such a system is substantially unaffected, but the accuracy of the readings can vary considerably.

Figures 3a-d are schematic diagrams of a representative analysis sequence using the present device. As shown in Figure 3a, blood is withdrawn from the patient through the single lumen catheter and associated flexible tubing 18 by a first roller pump 20. The rollers 44 of the pump fully occlude the flexible tubing 18 thereby allowing fluid to flow only when the pump is activated. At this point, heparin-containing wash solution is contained within the tubing 18 associated with the second pump 22 and the enzyme electrode assembly 34.

Referring to Figure 3b, blood is drawn by the second pump 22 through the flow cell 28 immediately after the first pump 20 is stopped. Blood fills the tubing 18 associated with the first and second pumps and the flow cell, and the determination of the amount of glucose in the blood is performed.

As shown in Figure 3c, after the glucose determination is made, the blood is flushed or washed from the flow cell 28 and is infused into the patient along with a relatively small volume of the heparin-containing wash solution upon activation of the second pump 22. At this point, the catheter connected to the patient contains the wash solution as do the flow cell and the tubing associated with the second pump 22. However, the tubing positioned between the flow cell and the first pump 20 still contains a portion of the blood sample.

The step shown in Figure 3d is then performed to wash the device of the remaining portion of the blood sample. In particular, the first pump 20 is reactivated to infuse the remaining blood sample along with a relatively small volume of the heparin-containing calibration solution. In this manner, the entire volume of blood that was initially withdrawn from the patient is infused back to the patient. In a variation of this scheme, reinfusion of all blood may be done simultaneously by pumps 20 and 22.

Figures 4a-b are schematic diagrams of a representative calibration sequence using the device. Figure 4a is identical to Figure 3d because the last step of the analysis sequence is the same as the first step of the calibration sequence. In particular, the device has been washed free of the blood sample; the catheter and the tubing 18 between the patient and the first pump 20 contains the calibration solution; and the flow cell 28 along with the second pump 22 contain the wash solution.

As shown in Figure 4b, the enzyme electrode of the flow cell is then calibrated by activating the second pump 22 to draw the calibration solution into and through the flow cell.

Because the device can be supported on the forearm of the patient near the point where the blood sample is withdrawn, the hold-up volume within the tubing is minimized. This reduces the volume of blood necessary for the analysis. Moreover, the problem relating to the laminar flow and potential for dilution of the blood sample is reduced. To further reduce the hold-up volume, the device, as shown in Figure 5, can embody a more comprehensive intravenous cannula that includes the sensor itself, and which thus eliminates the hold-up volume contained in tubing 18. The assembly comprises a cannula 48 having a distal or extracorporeal portion 50 which includes a housing 52 for supporting both the flow cell 28 and the enzyme electrode sensor 34. The cannula 48 preferably includes a plurality of openings 54 in the sidewall thereof to improve blood withdrawal characteristics. A flexible gasket 56 is provided to seal the electrical connections from the flow cell and housing. The housing 52 comprises a small, lightweight arm module which can be Luer-lok compatible with an associated catheter/needle assembly. A preamplifier can be supported by the housing which is operatively associated (preferably by a small umbilicus) with the source of calibration solution, the source of wash solution and the controlling means (which can be wearable or pole mounted) . This assembly avoids use of tubing 18 between the catheter/needle and the sensor.

The foregoing description is only illustrative of the principles of this invention. Since numerous modifications and changes will readily occur to those skilled in the art, it is not desired to limit the invention to the particular construction and mode of operation described herein. Accordingly, all suitable modifications and equivalents are intended to fall within the scope of this invention.

Claims

WHAT IS CLAIMED IS:

1. A wearable device suitable for continuously determining the plasma glucose concentration in a sample of undiluted whole blood from a patient comprising: a) a housing adapted for removable attachment to the patient; b) means in communication with the housing for withdrawing the blood sample from the patient for analysis and returning the entire blood sample to the patient after analysis; c) means connected to the withdrawing means for sensing the concentration of glucose in the blood sample; d) first pump means having an inlet end operatively associated with a first channel of the sensing means and an outlet end in communication with a source of calibration solution; e) second pump means having an inlet end operatively associated with a second channel of the sensing means which is in communication with the first channel, and an outlet end in communication with a source of wash solution; and f) means for controlling the first and second pump means to withdraw and to return the blood sample in a predetermined sequence.

2. The device according to claim 1 wherein the withdrawing means includes a catheter for withdrawing the blood sample from the patient, the catheter remaining inserted in a blood vessel of the patient for the withdrawal of blood at frequent intervals for continuous monitoring of the blood glucose level of the patient.

3. The device according to claim 1 wherein the calibration solution contains a predetermined amount of glucose and an anti-coagulant in an amount sufficient to prevent the blood from clotting in the apparatus but without significantly effecting the coagulating properties of the blood in vivo.

4. The device according to claim 3 wherein the anti-coagulant is heparin.

5. The device according to claim 1 wherein the wash solution contains an anti-coagulant in an amount sufficient to prevent the blood from clotting in the apparatus but without significantly effecting the coagulating properties of the blood in vivo.

6. The device according to claim 5 wherein the anti-coagulant is heparin.

7. The device according to claim 1 wherein the cross-sectional area of the second channel is less than the cross-sectional area of the first channel whereby the blood sample can flow through the first channel without flowing through the second channel.

8. The device according to claim 1 wherein the second channel is substantially non-linear and is configured so that the blood sample can flow through the first channel without flowing through the second channel.

9. The device according to claim 1 wherein the sensing means comprises a flow cell including an enzyme electrode assembly, and the second channel is operatively associated with the enzyme electrode assembly for determining the concentration of glucose in the blood sample.

10. The device according to claim 1 including means for releasably mounting the sensing means on the housing.

11. The device according to claim 1 wherein the sensing means comprises a disposable cartridge.

12. The device according to claim 11 wherein the cartridge comprises a body portion for supporting an enzyme electrode assembly and means for removably mounting and aligning the cartridge on the electrodes associated with the housing.

13. The device according to claim 1 wherein the first and second pump means are bidirectional.

14. The device according to claim 1 including third pump means having an inlet end operatively associated with the first channel of the sensing means and an outlet end in communication with a source of insulin.

15. The device according to claim 1 including third pump means having an inlet end operatively associated with the second channel of the sensing means and an outlet end in communication with a source of insulin.

16. The device according to claim 1 including means for detecting air and changes in hematocrit in the device and thereupon providing a signal to the controlling means.

17. The device according to claim 1 wherein the controlling means includes electronic circuit means associated with the housing and operably associated with the enzyme electrode assembly for processing a signal from the electrodes of the enzyme electrode assembly.

18. The device according to claim 17 further including display means operably associated with the electronic circuit means for displaying a result.

19. The device according to claim 2 wherein the catheter has a distal portion which includes the flow cell and the enzyme electrode assembly.

20. A wearable device suitable for continuously determining the plasma glucose concentration in a sample of undiluted whole blood from a patient comprising: a) a housing adapted for removable attachment to the patient; b) means in communication with the housing for withdrawing the blood sample from the patient for analysis and returning the blood sample to the patient after analysis; c) means connected to the withdrawing means for sensing the concentration of glucose in the blood sample, the sensing means comprising a first channel, a second channel in communication with the first channel and an enzyme electrode assembly operatively associated with the second channel for determining the presence of glucose; d) first pump means having an inlet end operatively associated with the first channel of the sensing means and an outlet end in communication with a source of calibration solution; e) second pump means having an inlet end operatively associated with the second channel of the sensing means which is in communication with the first channel, and an outlet end in communication with a source of wash solution; and f) means for controlling the first and second pump means to withdraw and to return the blood sample in a predetermined sequence.

21. The device according to claim 20 wherein the withdrawing means includes a catheter for withdrawing the blood sample from the patient, the catheter remaining inserted in a blood vessel of the patient for the withdrawal of blood at frequent intervals for continuous monitoring of the blood glucose level of the patient.

22. The device according to claim 20 wherein the calibration solution contains a predetermined amount of glucose and an anti-coagulant in an amount sufficient to prevent the blood from clotting in the apparatus but without significantly effecting the coagulating properties of the blood in vivo.

23. The device according to claim 22 wherein the anti-coagulant is heparin.

24. The device according to claim 20 wherein the wash solution contains an anti-coagulant in an amount sufficient to prevent the blood from clotting in the apparatus but without significantly effecting the coagulating properties of the blood in vivo.

25. The device according to claim 24 wherein the anti-coagulant in heparin.

26. The device according to claim 20 wherein the cross-sectional area of the second channel is less than the cross-sectional area of the first channel whereby the blood sample can flow through the first channel without flowing through the second channel.

27. The device according to claim 20 wherein the second channel is substantially non-linear and is configured so that the blood sample can flow through the first channel without flowing through the second channel.

28. The device according to claim 20 including means for releasably mounting the sensing means on the housing.

29. The device according to claim 20 wherein the sensing means comprises a removable cartridge.

30. The device according to claim 29 wherein the cartridge comprises a body portion for supporting an enzyme electrode assembly and means for removably mounting the cartridge on the housing.

31. The device according to claim 20 wherein the first and second pump means are bidirectional.

32. The device according to claim 20 wherein the entire volume of the blood sample is returned to the patient after analysis.

33. The device according to claim 20 including third pump means having an inlet end operatively associated with the first channel of the sensing means and an outlet end in communication with a source of insulin.

34. The device according to claim 20 including third pump means having an inlet end operatively associated with the second channel of the sensing means and an outlet end in communication with a source of insulin.

35. The device according to claim 20 including means for detecting air and changes in hematocrit in the device and thereupon providing a signal to the controlling means.

36. The device according to claim 20 wherein the controlling means includes electronic circuit means associated with the housing and operably associated with the enzyme electrode assembly for processing a signal from the electrodes of the enzyme electrode assembly.

37. The device according to claim 36 further including display means operably associated with the electronic circuit means for displaying a result.

38. The device according to claim 20 wherein the catheter has a distal portion which includes the flow cell and the enzyme electrode assembly.

39. A method of continuously determining the plasma glucose concentration in a sample of undiluted whole blood comprising the steps of: a) withdrawing a blood sample from a patient utilizing catheter means including tubing in communication with sensing means which includes a first channel, a second channel in communication with the first channel and an enzyme electrode assembly operatively associated with the second channel; b) pumping the blood sample through the tubing and through the first channel of the sensing means using a first pump having a plurality of rollers which fully occlude the tubing as the rollers rotate; c) pumping the blood sample through the tubing and through the second channel of the sensing means using a second pump having a plurality of rollers which fully occlude the tubing as the rollers rotate; d) determining the concentration of glucose in the blood sample as the blood sample flows through the enzyme electrode assembly; and e) infusing the entire blood sample into the patient after the concentration of glucose in the blood sample has been determined.

40. The method according to claim 39 wherein determinations are made on an intermittent basis at frequent intervals to continuously monitor the blood glucose level of the patient.

41. The method according to claim 39 including the step of pumping a calibration solution through the apparatus thereby flushing the apparatus and returning the entire blood sample to the patient.

42. The method according to claim 39 including the step of pumping a wash solution through the apparatus thereby flushing the apparatus and returning the entire blood sample to the patient.

43. The method according to claim 39 wherein cross-sectional area of the second channel is less than the cross-sectional area of the first channel whereby the blood sample can flow through the first channel without flowing through the second channel.

44. The method according to claim 39 wherein the second channel is substantially non-linear and is configured so that the blood sample can flow through the first channel without flowing through the second channel.

45. The method according to claim 39 further including the step of infusing a predetermined amount of insulin into the patient based on the concentration of glucose in the blood sample.