WO2011075711A1

WO2011075711A1 - System and method for maintaining glycemic control based on glucose activity measurements

Info

Publication number: WO2011075711A1
Application number: PCT/US2010/061173
Authority: WO
Inventors: Anthony P. Furnary; Soya Gamsey
Original assignee: Glumetrics, Inc.
Priority date: 2009-12-17
Filing date: 2010-12-17
Publication date: 2011-06-23

Abstract

A system and method for maintaining glycemic control based on glucose activity is described. Glucose activity is preferably measured directly using an optical, equilibrium, non-consuming glucose sensor configured to detect free, bioavailable glucose. The disclosed glycemic control systems can be used to monitor a patient's glucose activity level and trend, make treatment decisions based on the glucose activity level and trend, and automatically calculate and deliver appropriate doses of medications, such as insulin, to maintain glycemic control.

Description

SYSTEM AND METHOD FOR MAINTAINING GLYCEMIC CONTROL BASED ON GLUCOSE ACTIVITY MEASUREMENTS

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No. 61/287,643, filed December 17, 2009, the disclosure of which is hereby expressly incorporated by reference and hereby expressly made a portion of this application.

BACKGROUND OF THE INVENTION

Field of the Invention

[0002] Aspects of the present disclosure relate to systems and methods for maintaining glycemic control in patients using a glucose sensor that accurately measures, in near real-time, the amount of bioavailable glucose in the blood, wherein the glucose sensor is operably coupled to a means for delivering a glucose modifier, e.g., insulin or dextrose, etc., wherein delivery of the glucose modifier is titrated against the measured amount of bioavailable glucose (i.e., glucose activity).

Description of the Related Art

[0003] Types 1 and 2 diabetes are endocrine disorders characterized by abnormalities in the body's ability to regulate glucose metabolism. While the underlying pathology of these two illnesses differ, both are associated with significant complications including diabetic nephropathy, neuropathy, retinopathy, problems with wound healing, as well as an elevated risk of cerebrovascular and cardiovascular disease. While the mechanism of action is uncertain and likely varies with specific complication, it is believed that elevated glucose levels are associated with the release of various inflammatory mediators that produce vascular damage ultimately leading to many of these complications. In addition, elevated glucose levels in critically ill patients are associated with increased mortality and morbidity. Abnormally low glucose levels can also be problematic resulting in anxiety, weakness, and in extreme cases coma and death. Researchers and clinicians have increasingly become aware of the importance of maintaining tight control of glucose levels, particularly in acute care settings, so as to prevent or minimize the adverse complications.

[0004] While clinicians have used insulin for decades to regulate glucose levels in diabetics, determining precise dosages remains a problem. Insulin reduces circulating glucose levels through a series of complex interactions involving a number of hormones and cell types. Dosage protocols for insulin attempt to replicate the physiologic secretion of the hormone by the pancreas. However, administering according to fixed times and algorithms based on blood glucose measurements can only crudely approximate the ability of a healthy individual to continuously adjust insulin production in response to the amount of bioavailable glucose and the needs of the body. Thus, to determine the precise amount of insulin that should be administered to maintain a patient's blood glucose at an appropriate level, it is necessary to have near real-time, accurate measurements of the amount of bioavailable glucose circulating in blood.

[0005] Unfortunately, existing methods for determining blood glucose concentrations fail to provide near real-time, accurate measurements of the amount of bioavailable glucose. Clinicians and diabetic patients typically rely on point-of-care testing that seems to measure glucose concentration in plasma, e.g., using glucometers to read test strips that filter separate plasma from cells in a drop of whole blood. While the results can be available quickly, they vary depending on the patient's hematocrit, plasma protein and lipid profiles, etc., and can often be falsely elevated (See e.g., Chakravarthy et al., 2005 "Glucose determination from different vascular compartments by point-of-care testing in critically ill patients" Chest 128(4) October, 2005 Supplement: 220S-221S). More accurate determinations can be obtained by first separating the cellular components of whole blood. However, this requires separation of the plasma from the cellular components of blood, e.g., by centrifugation. Subsequently, isolated plasma must be stored and/or transported and/or diluted prior to analysis. Storage and processing conditions, e.g., temperature, dilution, etc., will almost certainly perturb the in vivo equilibrium between the bound and free (bioavailable) glucose. Consequently, regardless of the technology subsequently employed for measuring plasma glucose concentration (e.g., glucose oxidase, mass spectrometry, etc.), the measured glucose concentration is likely no longer reflective of the amount of bioavailable glucose in vivo. Therefore, it is not feasible to use plasma glucose measurements for near real-time monitoring and adjustment of a patient's glucose level.

[0006] Accordingly, there remain important and unmet needs to: (1) accurately measure in near real-time the amount of bioavailable glucose within a clinically relevant glucose activity range; and (2) utilize this measurement to manually or automatically adjust the glucose activity by administration of a glucose modulator (e.g., insulin) to accomplish glycemic control.

SUMMARY OF THE INVENTION

[0007] A method of maintaining glycemic control in a patient is disclosed. The method comprises determining glucose activity in or near real-time using an implanted glucose sensor and titrating the appropriate dosage of medications either manually or automatically using treatment protocols based on glucose activity.

[0008] In one embodiment, a system is disclosed for achieving glycemic control. The system comprises: (a) a sensor for detecting an amount of glucose activity in blood or interstitial fluid, comprising an optical fiber sized and configured to be deployed within a blood vessel or within an interstitial space, and capable of propagating light along a light path, and an equilibrium, non-consuming chemical indicator system disposed within the light path of the optical fiber, wherein the chemical indicator system is capable of generating a fluorescent emission signal in response to interrogation by an excitation light signal, wherein the fluorescent emission signal is related to the amount of glucose activity in the blood or interstitial fluid; (b) a controller operably coupled to the sensor, wherein the controller is configured to accept user input, and is programmed to convert the fluorescent emission signal into the glucose activity, correct the glucose activity for changes in pH and temperature, monitor rates and directions of changes in glucose activity, monitor sensor performance and calibration, and output information related to glucose activity; and (c) a glycemic control device operably coupled to the controller, wherein the glycemic control device is programmed and configured to deliver a selected dose of one or more compositions for modulating the amount of glucose activity in the blood or interstitial fluid, wherein the selected dose of one or more compositions is delivered based at least in part on the output information from the controller, thereby facilitating glycemic control.

[0009] In one variation, the system may further comprise a monitor for visually displaying at least some of the output information. In another variation, the system may further comprise a printer for printing at least some of the output information. In yet another variation, the system may further comprise a network connection for enabling viewing of at least some of the output information on a remote computer or other network interface device. In yet another variation, the system may further comprise an alarm for visually and/or audibly alerting a user that at least some of the output information has varied outside of a predetermined acceptable range.

[0010] A method for maintaining glycemic control based on measured glucose activity is also disclosed. The method may comprise: (a) providing the above-described system; (b) deploying the sensor within a blood vessel or interstitial space; (c) monitoring at least some of the output information; and (d) providing any user input to the controller needed to affect glycemic control.

[0011] A system is also disclosed for controlling an analyte activity. The system comprises: (a) a sensor capable of measuring the analyte activity level in blood or interstitial fluid and generating a signal related to the measured level; (b) a controller operably coupled to the sensor, wherein the controller is configured to accept user input, and is programmed to convert the signal into the analyte activity and output information related to analyte activity; and (c) an analyte control device operably coupled to the controller, wherein the analyte control device is programmed and configured to deliver a selected dose of one or more compositions for modulating the amount of analyte activity in the blood or interstitial fluid, wherein the selected dose of one or more compositions is delivered based at least in part on the output information from the controller, thereby facilitating control of analyte activity.

BRIEF DESCRIPTION OF THE DRAWINGS

[0012] FIG. 1 is a block diagram showing the components of a controller in accordance with one preferred embodiment of the glycemic control system. [0013] FIG. 2 shows aspects of the optical signal path in accordance with one embodiment of the present system.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

[0014] Embodiments of the present invention relate to measuring the activity of a particular analyte (e.g., glucose, potassium, etc.) in a physiologic fluid, e.g., blood or interstitial fluid, using a sensor configured to measure the amount of free, bioavailable analyte dissolved in the water compartment of the physiologic fluid, without significantly perturbing the equilibrium between free analyte in the water compartment and analyte that is otherwise bound or associated with molecules or cells. The phrases free and bioavailable analyte, or analyte activity, are used generally herein to refer to the amount of analyte (preferably expressed in mmoles) per unit of water (preferably expressed in kg). This measure of analyte activity focuses on the physiologically relevant amount of analyte (as opposed to the total concentration of analyte in the fluid/suspension). Preferably, analyte activity measurements minimize or exclude contributions from analyte that is not freely dissolved and bioavailable, such as e.g., analyte that may be aggregated, complexed with other molecules, bound to receptors, or associated with macromolecules, proteins, glycoproteins, lipids, glycolipids, etc., or sequestered within cells and organelles, etc.). In accordance with embodiments of the invention, the measured analyte activity is then utilized to adjust or maintain the physiologic analyte activity at a desired level, for example, by interfacing manually or automatically with means for raising or lowering the amount of analyte activity.

[0015] The broader concept of measuring the activity of an analyte and using the analyte activity to maintain certain desired analyte activity levels is illustrated herein by specific examples and description of sensors for measuring glucose activity in blood and systems and methods for using the measured glucose activity to adjust or maintain the glucose activity in blood within desired ranges. It should be understood, however, that the specific embodiments described and examples provided are not intended to limit the scope of the claimed inventions. Glucose Activity

[0016] Glucose activity is preferably expressed as millimoles of glucose per kilogram of water. This represents bioavailable glucose, that is, glucose that is readily available for use by the body. This is essentially what the beta cells of the pancreas measure to regulate insulin secretion in the body's own system of glycemic control. Through the use of near-real time implanted sensors, and by eliminating the measurement of glucose that is not available for physiologic use, such as protein-bound glucose, glucose activity provides a rapid and highly accurate method of quantifying a patient's glycemic status.

[0017] Glucose activity offers numerous advantages over existing methods of glucose quantification. This measure is not affected by the presence of red blood cells, lipids, protein concentration, pH nor oxygenation levels. By contrast, methods of quantifying glucose that require processing of the blood sample can cause the physiologically inactive glucose that is bound to these other blood constituents to enter the plasma and lead to an erroneous measurement of how much glucose is actually available for physiologic use. In addition, differences in how a given sample is handled or processed can affect the result. For example, the amount of blood cells hemolyzed during the collection, transport, or centrifugation of the sample can cause significant variation among different samples drawn simultaneously from the same patient. Finally, the temperature of sample can effect the plasma glucose measurement, therefore the results may change depending on how much an ex vivo sample has cooled since being extracted from the body. These sources of inaccuracy are largely eliminated through the use of an implanted glucose activity sensor that is capable of measuring bioavailable glucose in whole blood.

[0018] The ability to monitor glucose activity using an implanted sensor also offers a number of advantages. Glucose activity can be measured rapidly and made available for use in or near real-time. Obviously this offers an advantage of speed over methods of glucose concentration measurement that require the processing of an ex vivo sample that must be drawn from the patient (often with some patient discomfort), transported to the processing site, and processed before the analysis can take place. Even if the patient or facility is using simple blood glucose concentration analysis, while rapid, this still involves patient discomfort and can produce results that are ultimately prone to inaccuracy. Glucose activity measurements using an implanted sensor device can also be performed at nearly any frequency desired by the operator. For example, if particularly intensive glucose control is desired, such as when the glucose activity sensor is operably coupled to insulin dispensing glycemic control device, testing can take place every few minutes, several times per minute, or in some embodiments, continuously or nearly continuously.

Glucose Activity Sensors

[0019] The glucose sensors in accordance with some exemplary embodiments of the present invention can be utilized under a variety of conditions. The particular configuration of a sensor may depend on the use for which it is intended and the conditions under which it will operate. One embodiment includes a sensor configured for implantation into a patient or user. For example, implantation of the sensor may be made in the arterial or venous systems for direct testing of glucose activity in blood. Alternatively, a glucose activity sensor may be implanted in the interstitial tissue for determining the glucose activity in interstitial fluid. The site and depth of implantation may affect the particular shape, components, and configuration of the sensor.

[0020] In preferred embodiments, glucose activity can be directly measured using an optical detector system designed to detect and quantify glucose activity. In one such embodiment, glucose activity is measured using a sensor comprising a light sensitive chemical indicator system disposed within the light path of an optical fiber, which is sized and configured to be deployed within a blood vessel or within the interstitial space. The chemical indicator system is configured to interact with free, unbound glucose dissolved within the aqueous compartment of the plasma.

[0021] Examples of such chemical indicator systems and sensor configurations for intravascular or interstitial glucose monitoring include the optical sensors disclosed in U.S. Patent Nos. 5,137,033, 5,512,246, 5,503,770, 6,627,177, 7,417,164 and 7,470,420, and U.S. Patent Publ. Nos. 2008/0188722, 2008/0188725, 2008/0187655, 2008/0305009, 2009/0018426, 2009/0018418, and co-pending U.S. Patent Appl. Nos. 1 1/296,898, 12/187,248, 12/172,059, 12/274,617 and 12/424,902; each of which is incorporated herein in its entirety by reference thereto. [0022] In certain preferred embodiments, the chemical indicator system comprises a fluorophore (or fluorescent dye) capable of absorbing light at an excitation wavelength and generating a detectable fluorescent signal at an emission wavelength. In certain preferred embodiments, the chemical indicator system also comprises a glucose binding moiety capable of reversibly binding glucose and interacting with the fluorophore in a manner related to the amount of glucose binding. In certain preferred embodiments, the fluorophore is operably coupled to the glucose binding moiety, such that the detectable fluorescent signal generated by the fluorophore is modulated by the interaction between the fluorophore and the glucose binding moiety. Preferably, the intensity of the emission wavelength is modulated. The operable coupling between the fluorophore and glucose binding moiety may be a direct covalent coupling, an indirect covalent coupling (e.g., via a linker), or a non-covalent association (e.g., an electrostatic attraction). Various embodiments may include more than one fluorophore and more than one glucose binding moiety. Further, some fluorophores that may be useful in such a chemical indicator system may be capable of absorbing light at more than one excitation wavelength and generating detectable signals at more than one emission wavelength.

[0023] In some embodiments, the above described chemical indicator system also comprises a polymer matrix that is permeable to glucose, wherein the fluorophore and the glucose binding moiety are immobilized therein and capable of sufficient molecular interaction to facilitate glucose-dependent modulation of the detectable fluorescent signal. In various embodiments, the fluorophore and glucose binding moiety may be covalently or non- covalently associated with the polymer matrix.

[0024] In one preferred embodiment of the glucose activity sensor of the present invention, the chemical indicator system comprises HPTS-triCys-MA (fluorophore) and 3,3'- oBBV (glucose binding moiety) immobilized within a glucose permeable polymer matrix and disposed within a cavity in the distal end region of an optical fiber. The opening to the cavity is preferably covered by a semipermeable membrane which is permeable to free dissolved glucose, but not macromolecular or cell associated glucose. The preferred HTPS-tri-Cys-MA fluorophore and the benzylboronic acid substituted viologen (3,3'-oBBV) are described in US Patent No. 7,417,164, entitled FLUORESCENT DYES FOR USE IN GLUCOSE SENSING, the entire disclosure of which is incorporated herein by reference thereto. In such glucose activity sensors, the 3,3'-oBBV glucose-binding moiety associates with the HPTS-triCys-MA fluorophore through electrostatic attraction in the absence of free glucose, wherein the viologen acts as a quencher, suppressing the emission signal of the dye in response to interrogation by an excitation light signal. As free glucose diffuses through the semipermeable membrane and the polymer matrix and binds to the aromatic boronic acid groups on the 3,3'-oBBV, the charge is altered, and the glucose binding moiety (sometimes referred to hereinafter as the "quencher") dissociates from the fluorophore, thereby allowing fluorescent emission in response to the excitation light. The intensity of the fluorescent emission signal in this preferred embodiment of the glucose activity sensor is therefore proportional to the concentration of free, bioavailable glucose.

[0025] Other indicator chemistries, such as those disclosed in U.S. Patent Nos. 5,176,882 to Gray et al. and 5,137,833 to Russell, can also be used in accordance with embodiments of the present invention; both of which are incorporated herein in their entireties by reference thereto. In some embodiments, an indicator system may comprise an analyte binding protein operably coupled to a fluorophore, such as the indicator systems and glucose binding proteins disclosed in U.S. Patent Nos. 6,197,534, 6,227,627, 6,521,447, 6,855,556, 7,064,103, 7,316,909, 7,326,538, 7,345,160, and 7,496,392, U.S. Patent Application Publication Nos. 2003/0232383, 2005/0059097, 2005/0282225, 2009/0104714, 2008/0311675, 2008/0261255, 2007/0136825, 2007/0207498, and 2009/0048430, and PCT International Publication Nos. WO 2009/021052, WO 2009/036070, WO 2009/021026, WO 2009/021039, WO 2003/060464, and WO 2008/072338 which are hereby incorporated by reference herein in their entireties.

[0026] In further preferred embodiments, the glucose activity sensor is adapted to facilitate fatiometric correction of glucose activity measurements for optical artifacts of the system as disclosed in co-pending US Publication No 2008-0188725 Al and US Application No. 12/612,602; incorporated herein in its entirety by reference.

[0027] An embodiment is directed to an optical sensor capable of measuring two analytes with a single indicator system. More particularly, the preferred sensor employs a single fluorophore (e.g., a fluorescent dye) to: (1) determine the concentration of a first analyte, e.g., H⁺ (pH), by a ratiometric method, wherein such determination is independent of the concentration of the fluorophore; and (2) determine the concentration of a second analyte, e.g., a polyhydroxyl compounds (e.g., preferably glucose) by measuring the apparent fluorophore concentration (e.g., emission intensity of the fluorophore upon excitation), wherein the apparent fluorophore concentration is dependent on the concentration of the second analyte. Further, where measurement of the second analyte concentration is dependent on the first analyte concentration (e.g., in optical systems in which glucose measurement varies with pH— a common problem in this field), then in accordance with a preferred embodiment of the present invention, the measured second analyte concentration may be corrected for the contribution of the first analyte concentration. The sensor is preferably stable in aqueous media (e.g., physiological media, blood, interstitial fluid, etc.), and more preferably, the sensor is configured to be inserted into a blood vessel where it can remain indwelling for a period of time. Thus, in accordance with a preferred embodiment of the present invention, an optical sensor configured for intravascular placement is disclosed, which sensor is capable of measuring two analytes (preferably pH and glucose) with a single indicator system and correcting the glucose measurement for any contributions of pH.

[0028] Although preferred embodiments of the sensor are directed inter alia to ratiometric pH sensing, other first analyte concentrations may be determined in accordance with the broader scope of the present invention, as long as the indicator system comprises a fluorophore that exists in at least two forms the concentration of which are associated with the concentration of the first analyte and the emission ratio of which is independent of the fluorophore concentration. Likewise, although glucose is used as a second analyte example herein, it is understood that the concentration of other polyhydroxyl-containing organic compounds (carbohydrates, 1,2-diols, 1,3-diols and the like) in a solution may be determined using embodiments of this invention, as long as the indicator system comprises a fluorophore that is operably coupled to a binding moiety that binds the second analyte, wherein the signal intensity of the fluorophore varies with the concentration of second analyte. In some embodiments, the concentration of second analytes may including non-carbohydrates. Further details of the simultaneous measurement of glucose and pH are disclosed in US Patent No. 7,751,863, which is hereby incorporated by reference herein in its entirety. [0029] Preferred sensor configurations are described in co-pending US Application No. 12/612,602, entitled IMPROVED OPTICAL SENSOR CONFIGURATION FOR RATIOMETRIC CORRECTION OF BLOOD GLUCOSE MEASUREMENT; incorporated herein in its entirety by reference.

Glucose Activity Sensors Operably Coupled to a Controller

[0030] In some embodiments, the glucose activity sensor described above is further incorporated into a system whereby optical information (fluorescent emission signal) about a patient's glucose activity can be converted to an electrical (analog or digital) signal and communicated to a user programmable (or pre-programmed) controller. The controller may comprise an integral visual and/or audio output device, such as a conventional computer monitor/display, alarm, speaker, and/or an integral or operably coupled printer. Preferably, the controller comprises a visual display that indicates the present glucose activity level (millimoles glucose/kg water), the trend (steady, rising or falling), and the relative rate of change.

[0031] In some embodiments, where controller output of conventional blood glucose concentration (i.e., mg/dL) is desired, the glucose activity may be converted to blood glucose concentration (as long as the hematocrit (HCT) is known) by the equation: glucose cone. = glucose act. x (HCT x .7029) + [(1-HCT) x 0.939394]

[0032] Thus, in some embodiments, the controller may comprise the necessary algorithms and program instructions to convert direct measurements of glucose activity, along with HCT input, into conventional glucose concentration values, and further comprise a user selectable switch or other actuator to allow toggling between the measured glucose activity and the calculated glucose concentration values (See e.g., co-pending US Provisional Application entitled: Glucose Sensor And Controller With User Selectable Output, filed on the same date herewith).

[0033] Controller electronics are well known. In one embodiment, the controller may comprise electronics and receiver/display unit configurations such as those described in US Patent Appl. No. 2009/0188054 Al, the entire disclosure of which is incorporated herein by reference.

[0034] The controller may also be in communication with other devices, including e.g., data processing device(s), storage devices, and/or networks; in some embodiments these additional devices/functionalities may be integral with the controller while in other embodiments, these additional devices/functionalities may be remote and operably coupled to the controller. In some other embodiments, the patient's glucose activity level can be transmitted to a data network for viewing via a computer or other network interface device. Embodiments that transmit information in this manner are disclosed in U.S. Patent Numbers 6,024,699, 6,168,563, 6,645,142, 6,976,958 and 7,156,809, the disclosures of which are incorporated herein in their entirety by reference thereto. In yet other embodiments, information about the patient's glucose activity level can be transmitted through voice synthesizer or earcon. An example of a system that transmits information to the user via auditory output is disclosed in U.S. Patent Number 7,440,786 the disclosure of which are incorporated herein in their entirety by reference thereto.

[0035] In many embodiments, the controller can be configured to alert the user if the measured glucose activity level rises above or falls below a certain threshold. Examples of such devices that are capable of alerting the user of abnormal glucose levels are described in U.S. Patent Numbers 5,497,772 and 5,791,344, and US Patent Publication No. 2009/0177054A1; the disclosures of which are incorporated herein in their entirety by reference thereto. Such an alarm function may also desirably be initiated based on rates of glucose activity change, e.g., if the glucose activity is dropping rapidly, then an alarm may alert medical personnel that rapid intervention (infusion of glucose) may avert a critical condition before a programmed threshold is reached and thereby facilitate desired glycemic control. Of course, in some preferred embodiments discussed in greater detail below, the glucose activity level and/or rate of change thereof is communicated from the controller to a blood glucose modulating unit (e.g., an insulin and glucose infusion pump). Although medical practitioners do not necessary agree at this time on the stringency of glycemic control (e.g., some studies suggest better clinical outcomes with tight glycemic control in the critically ill, whereas others suggest that moderate glycemic control may be preferred), embodiments of the invention provide systems and methods for facilitating any desired stringency of glycemic control.

[0036] Besides receiving information from the sensor, the controller preferably also controls the light interrogation of the sensor chemistry, e.g., by actuating LED's to provide the excitation light and/or reference light. Of course other light sources, e.g., laser light, may be employed in some embodiments depending on the sensor optics and the indicator chemistry. In some preferred embodiments, the frequency of light interrogation can be controlled based on the blood glucose activity. For example, where the glucose activity level is steady, interrogation rate may be relatively slow/infrequent, thereby conserving energy (battery life in portable controllers) and minimizing any photo-bleaching effect on the indicator chemistry. However, where the glucose activity level is increasing or decreasing the interrogation rate may be increased. This is especially desirable, where glucose activity is dropping and establishing real-time or near real-time glucose monitoring may have greater clinical relevance.

Example of Controller/Monitor

[0037] In one preferred embodiment, the controller enables a number of functions to be described herein; primarily, however, its fundamental purpose is to "interrogate" (illuminate) the sensor chemistry and to respond to the resultant fluorescent signals which are proportional to the glucose concentration present, and to convert the signal into a glucose value for display and trending. Preferably, it also measures the temperature of the sensor tip and uses the temperature to correct for the glucose concentration as a function of sensed temperature. Preferably, the glucose concentration is also corrected by an indirect measurement of pH which is derived from the same signals fluorescent signals as used for the glucose concentration measurement (algorithmically as described for example in 2008- 0188722 Al).

[0038] In preferred embodiments, the controller connects to the optical sensor and makes the measurements of signal intensity and temperature to produce a glucose value based on the modulation of the fluorescent chemistry. Preferably, it includes a User Interface which is comprised of a LCD and simple keypad, which enables the user to input various parameters e.g., alarm limits, values for the in-vivo adjustment, set the display mode, confirmation of pre-patient insertion calibration of the sensor, etc. Likewise, in preferred embodiments, it will also produce error codes and advise the User via the LCD and built-in alarm buzzer when errant conditions or situations are detected.

[0039] The controller may communicate to an external PC via an IrDA port, for the purpose of programming specific parameters prior to any use, and also for downloading data after use to the PC for further display, printing and report generation.

[0040] The major functional blocks of the controller are itemized in Table 1, although it is to be understood that these are illustrative of one preferred embodiment of a controller useful in the systems described herein. Any of the specific functional blocks may be substituted with art-recognized equivalents or alternatives. Likewise, in some embodiments of the controller, not all of these functional blocks be included.

TABLE 1

[0041] With reference to FIG. 1, the microcontroller 1 is at the core of the controller. It and all other circuitry is powered by the Power Supply circuit 14, which obtains its input power from 4 x AA NiMH batteries 13. Microcontroller 1 monitors the Power Supply voltage via Battery Monitor Circuit 12.

[0042] Microcontroller 1 controls all of the elements of the system including the User Interface devices (Keypad 9, LCD 5 and the Audible alarm 6) and provides all control for the Optical Subassembly 7. The Optical Subassembly 7 includes LEDs 7a for illuminating the Sensor 17 and detectors 7b for receiving the fluorescent and reference signals. The Optical Subassembly communicates with the Sensor 17 and the Microcontroller 1. In a preferred embodiment, the Optical Subassembly 7 is comprised of two LEDs 7a of two different wavelengths, and two photodiode detectors 7b. The LEDs may be controlled by signals from Microcontroller 1 and an interface circuit (not shown), and via embedded software, can be set to pulse periodically and sequentially e.g., 1/min, 5/min, etc. and at any pulse width between 1 ms to 100 ms. The amplitude of the LED drive current is also adjustable by the Microcontroller 1 up to about 50 ma from virtually 0 ma.

[0043] Synchronous with the LED pulse, the two photodiode detectors 7b receive the "green" and or "blue" signals; green being the result of the fluorescent response of the chemistry and blue being the "reflected" or reference signal. It should be noted that other sensor embodiments could utilize other referencing signals, and that "blue" is just an illustration for the current design embodiment.

[0044] The photodiode detectors 7b are configured in a fairly typical, but highly optimized "transimpedance amplifier" configuration which converts the sensed photodiode current to a voltage. Signal currents are typically in the low picoampere range, from perhaps a few picoamps to a few hundred picoamps. The detected pulses - from each detector - are then amplified and the signals digitized via dual A/D convertors within the Dual Detector Circuit. The A/D convertors enable the digital voltages to be read and stored by the Microcontroller 1.

[0045] It should be noted that the variable parameters at which the LEDs are excited (pulse rate, amplitude, and pulse width) can be adjusted in response to conditions of the patient. For example, the rate could be adjusted to be more frequent at lower glucose levels, and/or when the glucose values are changing rapidly to provide a higher density of information which could be relevant for clinical decision making. Likewise, at higher glucose levels, the excitation values (pulse rate, pulse width) might be reduced in order to reduce the power consumption and extend the overall use time if needed.

[0046] The Thermocouple Measurement circuitry 8 measures the sensor temperature via thermocouple embedded within the sensor itself. Likewise, the heater temperature of the separate Calibration Chamber heater is controlled by Heater Controller 4.

[0047] The User Interface 5 is preferably a graphical LCD (e.g., configured as 240 x 160 pixels) which provides all of the controller's information including the calculated (and pH/temperature corrected) glucose value, trend information, rate of change, alarms and alerts, and in conjunction with Keypad 9 enables the User to input and adjust parameters.

[0048] With reference to FIG. 2, an aspect of the optical signal path is the actual transmission of the optical signals from the monitor Optical Subassembly 7 to the sensor (the efferent path) and from the Sensor 17 to the Optical Subassembly 7 (the afferent path). The optical signal transmission is accomplished with the use of a bundled fiber optic cable, which contains a mix of fibers for the efferent and afferent signals. The orientation of the fibers is such that specific fibers are mapped for the efferent blue signals and likewise a number of fibers mapped for the afferent green and blue signals. This particular fiber mapping is an example of one mapping format; other mappings may be used to match new sensor designs which require more or less light or different wavelengths of light for enhanced functionality.

Integration with a Glycemic Control Device

[0049] Just as the pancreas of a healthy individual measures glucose activity and titrates insulin secretion to maintain normal physiologic glycemic control, any artificial pancreas, comprising a closed system for maintaining glycemic control, will function optimally if the adjustments (e.g., insulin infusion) are made in response to measured glucose activity (rather than some non-physiologic approximation of glucose concentration). Accordingly, in some preferred embodiments, a treatment device designed to regulate glucose levels through the administration of medications can be operably coupled to the controller. This treatment device will be hereafter referred to as a glycemic control device. In many embodiments, the device can comprise a housing, one or more drug reservoirs, an optional processing device capable of directing the delivery of a specific quantity of medications to the patient, as well as a means of delivering the medications to the patient. In many embodiments, the means of delivering medications can be through tubes implanted subcutaneously or intravascularly. An example of such a glycemic control device, albeit one utilizing blood and plasma glucose concentration measurements, can be found in U.S. Patent No. 6,544,212 the disclosure of which is incorporated herein in its entirety by reference thereto. Other examples include, but are not limited to the Paradigm® Pump from the Medtronic Corporation, or the Accu-Chek Spirit® Insulin Pump System from Roche, the as well as the Smiths Medical Deltec Cozmo® Insulin Pump, or any similar commercially available glycemic control devices.

[0050] In many embodiments, the glycemic control device can be operably coupled to the controller that is, in turn, operably coupled to the glucose activity sensor for use in maintaining glycemic control. Systems comprising this combination of components will hereafter be referred to as a glycemic control system. In preferred embodiments, the controller is capable of calculating an appropriate insulin treatment regimen based on the measured glucose activity level in accordance with a treatment algorithm.

[0051] Standard glycemic control protocols, such as The Portland Protocol (http://www.providence.org/Oregon/Programs and Services/Heart/portlandprotocol/default. htm), are well known and provide detailed guidance for the skilled practitioner broken down for different target blood sugar ranges, including 70-110, 80-120, 100-150, 125-175, and 150- 200. For example, in ICU patients for target blood glucose concentrations of 70-110 mg/dl, Regular Human Insulin is reconstituted in 0.9% Normal Saline and IV infused via pump if the blood glucose concentration exceeds 125 mg/dl (including in non-diabetic patients) in accordance with the Portland Protocol shown in Table 2.

TABLE 2*

Blood Glucose IV Regular Insulin Initial Regular Insulin Rate

Units/Hour

125 - 150 mg/dl 2 (for DM pts only) 1 Unit/hr 2 Units/hr

151 - 180 mg/dl 4 Units 2 Units/hr 3.5 Units/hr

181 - 240 mg/dl 6 Units 3.5 Units/hr 5 Units/hr

241 - 300 mg/dl 8 Units 5 Units/hr 6.5 Units/hr

301 - 360 mg/dl 12 Units 6.5 Units/hr 8 Units/hr

> 360 mg/dl 16 Units 8 Units/hr 10 Units/hr

* Further details of the protocol are provided at the above-referenced Portland Protocol website.

[0052] It is noted that this example of a treatment protocol is one of many options that the skilled practitioner may select. Regardless of the protocol, the systems and methods disclosed herein in accordance with aspects of the present invention, will allow programming of the controller to calculate an appropriate insulin treatment regimen based on the measured glucose activity level. Initially, before specific treatment protocols are designed based on measured glucose activity, it may be desirable to convert the measured glucose activity (mmoles/kg water) to the conventional blood glucose concentration (mg/dl), to facilitate controller programming with standard treatment protocols, e.g., the Portland Protocol. The conversion is disclosed above, with input of the patient's HCT.

[0053] After calculating the appropriate insulin dosage, or other intervention, based on the measured glucose activity (and/or rates of change, and/or trends), the controller can then transmit a command to the glycemic control device to administer the appropriate quantity of insulin or other blood sugar modulator to the patient thereby facilitating the maintenance of glycemic control. The function of monitoring glucose activity levels, rates of change and trends, and then calculating an appropriate glycemic control response (e.g., infusion of insulin or glucose, etc.) can be carried out by the microcontroller unit of the above-described controller, or this functionality can be embodied in a separate processor or may be integral to the glycemic control device itself. Examples of glycemic control systems are disclosed in U.S. Patent Nos. 4,515,584, 5,109,866, 6,544,212 and 6,572,545; the disclosures of which are incorporated herein in their entirety by reference thereto.

[0054] In some embodiments, the glycemic control system can administer predetermined standing dosages of short and or long acting insulin or other drugs with a similar physiological effect as insulin. This can be used to maintain a certain baseline level of insulin or insulin-like activity. In some embodiments, the glycemic control system can further monitor the patient's response to a given dosage of insulin, and adjust the dosing parameters to maintain glycemic control based on an individual patient's insulin response. Some embodiments can automatically adjust the testing interval if closer monitoring and more aggressive intervention is desirable. For example, if a patient is prone to particularly large or frequent glucose activity fluctuations, the testing interval can be shortened and treatments likewise administered on a more frequent basis. In some embodiments, the user can manually direct the glycemic control system to monitor and treat on a more or less frequent basis and/or adjust the desired maximum and minimum glucose levels that trigger interventions.

[0055] In addition to providing standing dosages of insulin or other medications, some embodiments of the glycemic control system can be configured to automatically treat abnormal variations in the patient's glucose level. If excessively high glucose activity levels are detected, the processing device can direct the glycemic control device to administer additional dosages of medication as necessary in accordance with a treatment algorithm such as that of a standard insulin sliding scale algorithm. If glucose activity levels are chronically elevated necessitating repeated additional dosage of medications, some embodiments of the glycemic control system may be able to modify standing dosages of insulin or other medications so as to maintain better glycemic control. Examples of devices capable of calculating and automatically executing an appropriate medication regimen in response to measured physiologic parameters can be found in U.S. Patent Nos, 4,515,584, 5,109,866, 6,544,212, 6,572,545, 6,582,366, 6,668,272, and 6,835,175, the disclosures of which are incorporated herein in their entirety by reference thereto. Commercially available examples of glycemic control systems include, but are not limited to, the Guardian® Real-Time Continuous Glucose Monitoring System and the Paradigm® Real-Time Insulin Pump and Continuous Glucose Monitoring System from the Medtronic Corporation.

[0056] In some embodiments, the glycemic control system can have additional functions, such as correcting for abnormally low levels of glucose activity. In many embodiments, the processing device can command the glycemic control device to withhold dosages of insulin or other medications if the measured level of glucose activity is below a certain threshold value or trending toward a lower value. If glucose activity levels are chronically low, some embodiments can modify the standing dosages of insulin or other medications so as to maintain better glycemic control. Some embodiments of the glycemic control system can correct for excessively low glucose activity through the administration of carbohydrate solutions, glucagon, or other compounds capable of raising blood glucose levels. Examples of glycemic control systems capable of automatically dispensing such medications to treat hypoglycemic conditions can be found in U.S. Patent Nos. 5,807,375 and 5,820,622, the disclosures of which are incorporated herein in their entirety by reference thereto.

[0057] In some embodiments, the glycemic control system can be relatively large. Such embodiments would generally be for use in an inpatient setting, particularly in critical care situations where glycemic control is particularly desirable. In other embodiments, the glycemic control system can comprise a small, portable unit capable of being worn by an ambulatory patient. In some embodiments, these units can be partially implanted into the patient's body. In some such embodiments, the glucose sensor and the output from the glycemic control device can be implanted subcutaneously, whereas the other components are carried outside of the patient. In other embodiments, all or nearly all of the components of the glycemic control system can be surgically implanted in the patient. Examples of such portable devices are disclosed in U.S. Patent Nos. 4,146,029, 4,871,351, 5,062,841, 5,109,850, and 7,135,964, as well as in U.S. Patent Publication No. 2004/0158232A1; the disclosures of each of which are incorporated herein in their entirety by reference thereto.

[0058] In many such embodiments, the glycemic control system can be operably coupled to a display or other means of providing data regarding the status and function of the device. In some embodiments, the display will also be operably coupled to the data processing unit and can display information regarding the patient's glucose activity. In many embodiments, the glycemic control system can be operably coupled to controls enabling an operator to command the processing device to adjust the desired treatment algorithm and/or override the existing treatment plan if a change in the medication regimen is desirable. In some embodiments these controls can be on a housing of the system itself. In some embodiments, the glycemic control system can be programmed remotely via a network connection. An example may be found in U.S. Patent No. 5,665,065 the disclosure of which is incorporated herein in its entirety by reference thereto.

Claims

WHAT IS CLAIMED IS:

1. A system for achieving glycemic control, comprising:

a sensor for detecting an amount of glucose activity in blood or interstitial fluid, comprising

an optical fiber sized and configured to be deployed within a blood vessel or within an interstitial space, and capable of propagating light along a light path, and

an equilibrium, non-consuming chemical indicator system disposed within the light path of the optical fiber, wherein the chemical indicator system is capable of generating a fluorescent emission signal in response to interrogation by an excitation light signal, wherein the fluorescent emission signal is related to the amount of glucose activity in the blood or interstitial fluid;

a controller operably coupled to the sensor, wherein the controller is configured to accept user input, and is configured to convert the fluorescent emission signal into the amount of glucose activity, to correct the amount of glucose activity for changes in pH and temperature, to monitor rates and directions of changes in the amount of glucose activity, to monitor sensor performance and calibration, and to output information related to the amount of glucose activity; and

a glycemic control device operably coupled to the controller, wherein the glycemic control device is configured to deliver a selected dose of one or more compositions for modulating the amount of glucose activity in the blood or interstitial fluid, wherein the selected dose of one or more compositions is delivered based at least in part on the output information from the controller, thereby facilitating glycemic control.

2. The system of Claim 1 , further comprising a monitor for visually displaying at least some of the output information.

3. The system of Claim 1, further comprising a printer for printing at least some of the output information.

4. The system of Claim 1, further comprising a network connection for enabling viewing of at least some of the output information on a remote computer or other network interface device.

5. The system of Claim 1, further comprising an alarm for visually and/or audibly alerting a user that at least some of the output information has varied outside of a predetermined acceptable range.

6. The system of Claim 1, further comprising a pH sensor configured to detect a pH signal related to the pH of the blood or interstitial fluid and a temperature sensor configured to detect a temperature signal related to the temperature of the blood or interstitial fluid.

7. The system of Claim 1, wherein the chemical indicator system comprises a fluorophore that exists in at least first and second different forms depending on the pH of the blood or interstitial fluid, wherein the different forms can be distinguished based on their respective first and second emissions and wherein a ratio of the first and second emissions is independent of the concentration of glucose.

8. A method for maintaining glycemic control based on measured glucose activity, comprising:

providing the system of Claim 1 ;

deploying the sensor within a blood vessel or interstitial space; monitoring at least some of the output information; and

providing one or more user input to the controller needed to affect glycemic control.

9. A method for maintaining glycemic control in a subject comprising:

providing a glucose sensor configured to detect in near real-time an amount of glucose activity in blood or interstitial fluid, wherein the amount of glucose detected is independent of the subject's hematocrit, plasma protein, or lipid profile, the glucose sensor comprising

an optical fiber sized and configured to be deployed within a blood vessel or within an interstitial space, and capable of propagating light along a light path, and an equilibrium, non-consuming chemical indicator system disposed within the light path of the optical fiber, wherein the chemical indicator system is capable of generating a fluorescent emission signal in response to interrogation by an excitation light signal;

deploying the glucose sensor within a blood vessel or interstitial space;

interrogating the chemical indicator system with the excitation light signal in a predetermined rate,

detecting the fluorescent emission signal generated in response to the excitation light signal;

calculating the amount of glucose activity based on the fluorescent emission signal;

recording the amount of glucose activity;

monitoring a trend of the amount of glucose activity, the trend comprising data indicative of a rate of change of the amount of glucose activity over time; and

providing an ouput data comprising information of the amount of glucose activity and the trend of the amount of glucose activity, to a glycemic control device configured to deliver a selected dose of one or more compositions for modulating the amount of glucose activity in the blood or interstitial fluid, wherein the selected dose of one or more compositions is delivered based at least in part on the output data, thereby facilitating glycemic control.

10. The method of Claim 9, wherein the predetermined rate is between 1 second and 2 minutes.

1 1. The method of Claim 9, wherein the predetermined rate is between 1 second and 30 seconds.

12. The method of Claim 9, wherein the predetermined rate is between 1 second and 6 seconds.

13. The method of Claim 9, further comprising automatically calculating and delivering appropriate doses of medications to maintain glycemic control.