WO2014008288A1

WO2014008288A1 - Therapeutic agent delivery based on stored patient analyte values

Info

Publication number: WO2014008288A1
Application number: PCT/US2013/049124
Authority: WO
Inventors: Yaron Keidar; Michael Higgins
Original assignee: Edwards Lifesciences Corporation
Priority date: 2012-07-03
Filing date: 2013-07-02
Publication date: 2014-01-09

Abstract

A method and a system for therapeutic agent delivery based on stored patient analyte values are disclosed. The system can recommend a dosage and a caregiver can readily implement a conventional dosing scheme in response to the recommendation. Alternatively, the system can deliver the therapeutic agent automatically, either with or without additional user input. The patient analyte may be blood glucose as represented by an estimated glucose value (EGV), and the therapeutic agent may be insulin. The system can optionally include various refinements in calculating a dosage, for example, making use of confidence levels, a difference between an arterial EGV and a venous EGV, EGV rate of change, a difference between a core EGV and a peripheral EGV, and a determination of the level of sensor contamination.

Description

THERAPEUTIC AGENT DELIVERY BASED ON

STORED PATIENT ANALYTE VALUES

BACKGROUND

[0001] Devices for measuring various physiological parameters of a patient have been a standard part of medical care for many years. The vital signs of some patients typically are measured on a substantially continuous basis to enable physicians, nurses, and other healthcare providers to detect sudden changes in a patient's condition. Patient monitors are typically employed to display a variety of physiological patient data to physicians and other healthcare providers. Such patient data facilitates diagnosis of abnormalities or the patient' s current condition.

[0002] In some circumstances, a hospital subject is continuously tested for changes in a blood analyte level, test results are evaluated by a medical professional, and a therapeutic agent is administered based on these test results. For example, of importance for health care providers with some patients is measurement of the blood glucose levels of the subject, especially in a surgical or intensive care setting. Insulin is frequently delivered in hospitals to medical patients in order to control those patients' blood glucose levels and thereby to avoid hyperglycemia.

[0003] It is important to monitor blood glucose levels over time while insulin is being administered to avoid administering the insulin too rapidly or in quantities too great, as either may result in an undesirable or even dangerous hypoglycemic condition. Glucose levels are thus evaluated regularly to ensure appropriate quantities of insulin are being delivered at appropriate rates on an appropriate schedule, in order to keep the patient's blood glucose levels within the acceptable range.

SUMMARY

[0004] Embodiments of the invention provide for the use of various algorithms by which a patient analyte such as blood glucose can be measured and a therapeutic agent such as insulin can be delivered to the patent using an automated system. A system according to some embodiments of the invention can recommend a dosage and a caregiver can readily implement a conventional dosing scheme in response to the recommendation. In other embodiments, the system can deliver the therapeutic agent automatically. In still other embodiments of the invention, the system might calculate and deliver a recommended dose, which the caregiver could then accept or modify before instructing or allowing the system to deliver the therapeutic agent. In the case of insulin, the insulin can be delivered through the use of delivery device such as an electronically controlled insulin pump.

[0005] A processor-implemented method of facilitating delivery of a therapeutic agent to a patient according to some embodiments of the invention includes determining and storing a numerical value for a patient analyte and calculating, a dosage of the therapeutic agent based on the stored numerical value. In at least some embodiments, this recommended dosage of the therapeutic again is displayed on a display device. In some embodiments, the processor can then set or cause a delivery device to deliver the therapeutic agent to the patient. In some embodiments, user input triggers the delivery of the agent and in some embodiments the therapeutic agent is delivered automatically in response to the calculating of the dosage of the therapeutic agent by the system.

[0006] In some embodiments, the patient analyte is or includes glucose, the numerical value is or includes the estimated glucose value (EGV), and the therapeutic agent is or includes insulin. In some embodiments, the system, as part of calculating the dosage, estimate a confidence in the EGV. In some embodiments, the system, as part of calculating the dosage, determines a difference between an arterial EGV and a venous EGV. In some embodiments, the system stores and maintains historical estimated glucose values and, as part of calculating the dosage, the system determines an EGV rate of change for the patient from the most recent EGV and the historical estimated glucose values. In some embodiments, the system determines a difference between a core EGV and a peripheral EGV as part of calculating the dosage, and in some embodiments the system determines a sensor contamination level.

[0007] Embodiments of the invention can be implemented on a computer system, instruction execution platform, or a workstation with appropriate input and output capabilities. Embodiments of the invention may also be implemented on a patient monitoring and infusion system including a display device, a delivery device and a processor operatively connected to the display device and the delivery device and connected with a memory. The memory may be used to store historical numerical values for the patient analyte as well as non-transitory computer program code which, when executed, causes the processor to carry out all or a portion of the process of an embodiment of the invention. Such a system may also include an input/output (I/O) interface to connect sensors and the like, a network interface, and may include a graphics engine either on-chip with the principal microprocessor or controller, or in a dedicated graphics processor. This hardware along with a sensor interface and any other input and output components form at least some of the means to carry out the various process elements of embodiments of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

[0008] FIG. 1 is an illustration of a typical operating environment for example embodiments of the present invention.

[0009] FIG. 2 is an illustration of a typical operating environment for additional example embodiments of the present invention.

[0010] FIG. 3 is a block diagram of a system according to example embodiments of the invention.

[0011] FIG. 4 is a flowchart illustrating a process that can be carried out with example embodiments of the invention.

[0012] FIG. 5 is a flowchart illustrating a process that can be carried out with additional example embodiments of the invention.

[0013] FIG. 6 is a series of screen shots presented as FIGs. 6A-6N illustrating how a screen display might change over time in example embodiments of the invention. DETAILED DESCRIPTION OF EXAMPLE EMBODIMENTS

[0014] The following detailed description teaches specific example embodiments of the invention. Other embodiments do not depart from the scope of the present invention. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. It will be further understood that the terms

"includes" and/or "including" when used herein, specify the presence of stated features, integers, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof.

[0015] Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. It will be further understood that terms used herein should be interpreted as having a meaning that is consistent with their meaning in the context of this specification and the relevant art and will not be interpreted in an idealized or overly formal sense unless expressly so defined herein. Unless otherwise expressly stated, comparative, quantitative terms such as "less" and "greater", are intended to encompass the concept of equality. As an example, "less" can mean not only "less" in the strictest mathematical sense, but also, "less than or equal to."

[0016] As will be appreciated by one of skill in the art, the present invention may be embodied as a method, device, article, system, computer program product, or a combination of the foregoing. Any suitable computer usable or computer readable medium may be utilized for a computer program product including non-transitory computer program code to implement all or part of an embodiment of the invention. The computer usable or computer readable medium may be, for example but not limited to, a tangible electronic, magnetic, optical, electromagnetic, or semiconductor system, apparatus or device. More specific examples (a non-exhaustive list) of the computer readable medium would include the following: a portable computer diskette, a hard disk, a random access memory (RAM), a read-only memory (ROM), an erasable

programmable read-only memory (EPROM or Flash memory), a portable compact disc read-only memory (CD-ROM), or an optical storage device. The computer usable or computer readable medium may be one or more fixed disk drives or flash drives deployed in instruction execution platforms, such as servers or workstations, forming a "cloud" or network.

[0017] Computer program code for carrying out operations of the present invention or for assisting in the carrying out of a method according to an example embodiment of the invention may be written in an object oriented, scripted or unscripted programming language such as Java, Perl, Smalltalk, C++ or the like. However, the computer program code for carrying out operations of the present invention may also be written in conventional procedural programming languages, such as the "C" programming language or similar programming languages.

[0018] Computer program instructions may be provided to a processor of an instruction execution platform such as a general purpose computer, special purpose computer, server, workstation or other programmable data processing apparatus to produce a machine, such that the instructions, which execute via the processor of the computer or other programmable data processing apparatus, create means for implementing the functions/acts necessary to carry out an embodiment of the invention.

[0019] A processor used to implement an embodiment of the invention may be a general purpose digital signal processor, such as those commercially available from Texas Instruments, Inc., Analog Devices, Inc., or Freescale Semiconductor, Inc. It may also be a general purpose processor such as those typically provided for either workstation or embedded use by companies such as Advanced Micro Devices, Inc. or Intel Corporation. It could as well be a field programmable gate array (FPGA) as are available from Xilinx, Inc., Altera Corporation, or other vendors. The processor could also be a fully custom gate array or application specific integrated circuit (ASIC). Any combination of such processing elements may also be referred to as a processor, microprocessor, controller, or central processing unit (CPU). In some embodiments, firmware, software, or microcode can be stored in a non-transitory form on or in a tangible medium that is associated with the processor. Such a medium may be a memory integrated into the processor, or may be a memory chip that is addressed by the processor to perform various functions. Such firmware, software or microcode is executable by the processor and when executed, causes the processor to perform its display control and calculation functions. Such firmware or software could also be stored in or on a tangible medium such as an optical disk or traditional removable or fixed magnetic medium such as a disk drive used to load the firmware or software into a monitoring system according to embodiments of the present invention. [0020] The term "analyte" as used herein relates to a substance or chemical constituent in a biological sample (e.g., bodily fluids, including, blood, serum, plasma, interstitial fluid, cerebral spinal fluid, lymph fluid, ocular fluid, saliva, oral fluid, urine, excretions, or exudates). Analytes can include naturally occurring substances, artificial substances, metabolites, and/or reaction products. The analyte for measurement by the sensor, devices, and methods may include glucose. Any other physiological analyte or metabolite can be substituted or combined with the measurement of glucose. The term "subject" as used herein relates to mammals, inclusive of warm-blooded animals (domesticated and non-domesticated animals), and humans.

[0021] The term "calibration" as used herein refers to one or more process of determining the relationship between sensor data and a corresponding reference data. A continuous analyte sensor can be initially calibrated, calibration can be updated or recalibrated over time (whether or not if changes in the relationship between the sensor data and reference data occur), for example, due to changes in

disconnection/reconnection, sensitivity, baseline, analyte transport, metabolism, and the like. The sensed values produced by a calibrated sensor can be referred to as "calibrated values."

[0022] The phrases "operatively connected" and "operably connected" as used herein relate to one or more components linked to one or more other components, such that a function is enabled. The terms can refer to a mechanical connection, an electrical connection, or any connection that allows transmission of signals between the components. For example, one or more electrodes can be used to detect the amount of analyte in a sample and to convert that information into a signal; the signal can then be transmitted to a circuit. In such an example, the electrode is "operably connected" to the electronic circuitry. The terms include wired and wireless connections, and situations where there is are or may be intervening components.

[0023] The term "sensor" as used herein relates to a device, component, or region of a device capable of detecting and/or quantifying and/or qualifying an analyte in the intravascular and/or subcutaneous space of a subject. The phrase "sensor system" as used herein relates to a device, or combination of devices operating at least in part in a cooperative manner, that is inclusive of the sensor. In preferred aspects, sensor relates to a device, component, or region of a device capable of detecting and/or quantifying and/or qualifying an analyte in the intravascular and/or subcutaneous space in vivo.

[0024] FIG. 1 depicts a system that incorporates aspects of some embodiments of the invention. As shown in that figure, the system 10 is configured to monitor and display blood glucose levels in a hospitalized medical patient. The system is built around a monitor and control unit 12, which comprises programmed electronic circuitry to control the functioning of the system, and a display panel configured to communicate information regarding the system and its functions, as well as the condition of the patient, to a user of the system. The display panel may also serve as a touch screen interface through which a user can enter information and commands for controlling the system's operations. An access point 14 provides access for the system to the patient's body. The access point may provide an entry site for a catheter placed in the vein or another vessel in the vasculature of the patient, access to interstitial fluid located under the patient's skin, or to any other site through which access can be provided to fluids or materials bearing glucose or otherwise providing a reliable indicator of blood glucose levels or corresponding information relevant to the patient.

[0025] FIG. 1 illustrates a configuration in which an intravascular catheter is disposed inside a vein of the patient, and through which blood can be drawn over an electronic sensor to measure directly glucose levels in the patient' s blood. The sensor in this configuration can be a glucose oxidase sensor configured to produce a current or voltage proportional to the patient's blood glucose level.

[0026] The system of FIG. 1 further includes a supply of infusion fluid 16 contained inside an infusion bag 32 and in fluid communication with the sensor and the access point 14 through a fluid line 22 between the infusion bag and the access point. A fluid pump 20 controls the flow of fluids back and forth through the fluid line between the access point and the fluid bag. Under control of the pump, blood may be drawn from the patient's vein over the sensor. At other times, infusion fluid may be directed from the bag to flow over and rinse the sensor, or to be infused into the patient. Various other devices can be used in place of the pump, including piezoelectric and impeller-based devices, and any other device that can serve as a fluid controller. The infusion fluid may include normal medical saline solution. The infusion fluid may further include glucose at a known concentration, which may be directed over the sensor from time-to-time in order to calibrate the sensor by reading the resultant current or voltage from the sensor at times when the known-concentration glucose solution in the infusion bag is being directed over and in contact with the sensor. [0027] The elements of system 10 are mounted on and supported by a wheeled, movable stand 34, so that the system can be moved as needed with the patient. A signal line 36 provides electrical communication between the sensor near the access point 14 and the monitor and control unit 12. Electrical communication is similarly provided between the monitor and control unit and the fluid pump 20 through a first data and control cable 38.

[0028] The system 10 of FIG. 1 is an "open-loop" system configured to monitor the patient's blood glucose level, as determined under the control of software and circuitry of the monitor and control unit 12. The visual display and touch-screen control of the monitor and control unit communicate information including the patient' s measured blood glucose level, and other information regarding the system's operations, to a user of the system. The user may input commands to the system through that same visual display and touch-screen control. In some embodiments, the system may

programmatically and automatically determine an appropriate insulin infusion rate or dosage to be administered in the normal manner to keep the patient's blood glucose level in the appropriate range. A caregiver may observe this recommendation and act accordingly, or administer insulin at a different rate or dosage according to the caregiver's judgment and training.

[0029] FIG. 2 depicts an operating environment and a system that incorporates aspects of some embodiments of the invention. In this example, analyte information display system 11 is configured to monitor blood glucose levels in a subject. The subject in this case is a hospitalized medical patient. The system is built around a monitor and control unit 13, which comprises programmed processor to control the functioning of the system, and a display device including a visible panel configured to communicate information regarding the system and its functions, as well as the condition of the patient, to a user of the system. The display panel may also serve as a touch screen interface through which a user can enter information and commands for controlling the system's operations. Like reference numbers in the system of FIG. 2 indicate like structures and elements relative to the system of FIG. 1.

[0030] In FIG. 2, an access point 14 provides access for the system to the patient's body. The access point may provide an entry site for a catheter placed in the vein or another vessel in the vasculature of the patient, access to interstitial fluid located under the patient's skin, or to any other sight through which access can be provided to fluids or materials bearing glucose or otherwise providing a reliable indicator of blood glucose levels or corresponding information relevant to the subject. FIG. 2 illustrates a configuration in which an intravascular catheter is disposed inside a vein of the patient, and through which blood can be drawn over an electronic sensor to measure directly glucose levels in the patient's blood. The sensor in this configuration again can be a glucose oxidase sensor configured to produce a current or voltage proportional to the patient's blood glucose level. It cannot be overemphasized that this arrangement is an example. Other mechanisms can be used to monitor blood glucose, and a system according to embodiments of the invention can be devised to measure other analytes. Some sensor systems that can be used with embodiments of the invention are described in U.S. Patent Publication No. 2007/0027385, the entire disclosure of which is incorporated herein by reference. [0031] Unlike the system of FIG. 1, the system 11 of FIG. 2 includes a delivery device 18, an insulin supply controller configured to supply insulin in a controlled fashion through an insulin supply line 19 to the fluid line 22 and from there into the body of the patient. It should be noted that the term "system" may be used herein to refer to the entire arrangement of electronic elements and connection cables described in either or both of FIG. 1 and FIG. 2. However, the term system may also be used to refer only to the monitor and control unit including installed software and/or firmware that together direct and execute the functions described herein.

[0032] Continuing to refer to FIG. 2, as before, a signal line 36 provides electrical communication between the sensor near the access point 14 and the monitor and control unit 13. Electrical communication is similarly provided between the monitor and control unit and the fluid pump 20 through a first data and control cable 38, and similarly between the monitor and control unit and the delivery device 18 through a second data and control cable 39. The system 11 of Fig. 2 is thus a "closed- loop" system in which the delivery of insulin to the patient is controlled more or less automatically by the system itself, with perhaps little or no intervention by the caregiver user of the system beyond the initial setup, and with perhaps periodic checks to make sure that the system continues to function properly.

[0033] Intermediate or hybrid systems, which combine aspects of open-loop and closed-loop systems, may find use as well. Such systems may, for example, measure the patient's blood glucose level, calculate a recommended or default insulin dosing level or scheme, display that recommendation to the user, and then await the user's input before adjusting or implementing the actual amount and timing of insulin delivery to the patient by addressing the insulin supply controller. Any of these systems described thus far may also be expected to include various alerts, alarms, and similar messages for conveying relevant information clearly to the systems' users.

[0034] FIG. 3 is an enlarged view, schematically illustrating detail of the monitor and control unit 13 of FIG. 2. The insulin supply portions (other than the controller) of FIG. 2 are omitted. The system includes I/O interface 302, which may in turn include an appropriate connector, and circuitry to monitor signals from the sensor system. This circuitry may include analog-to-digital converters, encoders, decoders, and the like. I/O interface 302 is coupled to a central processing unit (CPU) 304, which controls the operation of the entire system. The I/O interface receives sensor signals and may also send signals to control the supply of insulin to the subject with some embodiments of the invention. CPU 304 is further operatively connected to memory 306. Memory 306 stores all of the information needed for the system to operate. Such information may be stored in a temporary fashion, or may be stored more permanently. This memory may include a single, or multiple types of memory. For example, a portion of the memory connected with CPU 304 may be "flash" memory, which stores information semipermanently for use by the system. In either event memory 306 of FIG. 2 in this example embodiment includes computer program code 308 which, when executed by CPU 304, causes the system to carry out the various processes to graphically display information according to example embodiments of the invention. Memory 306 also stores data 310, which in example embodiments includes historical numerical values for the analyte being measured, for example, blood glucose. [0035] Still referring to FIG. 3, monitoring and control unit 13 may also include a network interface 313. This network interface can allow the system to be connected to a wired or wireless network to allow monitoring on a remote display (not shown). For example, the remote display could duplicate, or be used in place of the local display panel. Network interface 313 could also be simply used to trigger an alarm at a nurse's station or on a mobile device. In the embodiment of FIG. 3, a local display device, 317, is connected with CPU 304 via a graphics engine 324. The local display device may be an LCD panel, plasma panel, or any other type of display component and accompanying circuitry to interface the display device to graphics engine 324. Graphics engine 324 may be on its own chip, or in some embodiments it may be on the same chip as CPU 304. Note that display device 317 may include user input functionality, for example an optical or capacitive touchscreen over the display screen. In such a case, monitoring control unit 13 may include additional circuitry to process such input. Alternatively, such circuitry may be included in the display device itself, the graphics engine, or the CPU 304.

[0036] The system shown in FIG. 3 can deliver insulin to a patient based on blood glucose levels measured by the system. The system can programmatically implement a conventional dosing scheme (closed-loop), or programmatically make a recommendation on which a caregiver can act independently (open-loop). A hybrid or "semi-closed loop" system might calculate and deliver a recommended insulin dose, which the caregiver could then accept or modify before the system to delivers the insulin appropriately. In either a closed loop or semi-closed loop system, the insulin can be delivered through the use of an electronically controlled insulin pump as shown in FIG. 2 as the delivery device. Other delivery devices can be used.

[0037] In addition to automating traditional insulin protocols, such systems can improve therapeutic effectiveness. This is especially so because systems like those disclosed herein can produce much more frequent and higher quality measurements than have so far been readily available with conventional equipment. With conventional human monitoring, as an example, blood glucose may be measured once every hour for patients receiving IV insulin, and perhaps once every four hours otherwise. A system of the type described above, in contrast, may draw a small quantity of blood automatically from the patient and measure an estimated glucose value (EGV) as frequently as once every five minutes - 12 times every hour. Such a system, moreover, includes automatic data storage and processing capable of storing historical estimated blood glucose values, and thereafter performing a vast range of calculations, processing, recommendations, and controls based on that historical data, examples of some of which are disclosed herein. Such blood glucose level data may be processed in combination with stored data that reflects insulin delivery, particularly but not necessarily exclusively in closed-loop systems where the delivery of the insulin is directly controlled by the system itself.

[0038] FIG. 4 is a flowchart illustrating the details of a process for measuring a patient analyte and determining a dosing and/or infusion rate for a therapeutic agent as executed by a system like that shown in FIG. 2 and FIG. 3. Like most flowcharts, FIG. 3 illustrates process 400 as a series of process or sub-process blocks. At block 402, the process begins. Block 402 may correspond to the initiation of monitoring of a patient by s witching on or resetting the monitor and control unit. At block 404, the system obtains readings from the sensor, calculates, and stores numerical values for the patient analyte, for example blood glucose, over time. In the case of blood glucose, each of these values may be referred to as an estimated glucose value (EGV) since it is calculated based on an electronic property read from the sensor. Block 406 includes the determining and storing of the most recent numerical value based on the most recent sensor reading. At block 408, the recent numerical value and historical numerical values for the patient analyte are graphically and persistently displayed.

[0039] Still referring to FIG. 4, at block 410, the therapeutic dosage of the therapeutic agent is calculated based on at least the latest numerical value for the patient analyte, which is stored in memory. At block 412, a determination is made as to whether the infusion rate or other form of dosage needs to change based on the calculation. If yes, at block 414 the new dosage is displayed on the display device in or associated with the monitor and control unit. Dosages as well as EGVs can also be remotely displayed. Optionally, at block 416, a user may adjust the dosage rate of the therapeutic agent so that the dosage administered by the delivery device is set in response to user input. Otherwise, or if there is no input, the dosage can be set automatically once this system calculates the dosage. If the dosage rate displayed needs to be updated, it is updated at block 418 and the process is continuously repeated.

[0040] FIG. 5 is a flowchart illustrating sub-process 410 from FIG. 4 in further detail. FIG. 5 shows a number of optional enhancements to the calculation of dosage by the monitor and control unit of the system of FIGs. 2 and 3. These enhancements may all be used together as shown, none may be used, or a subset of these may be used by a system according to example embodiments of the invention. In this example, it can be assumed that blood glucose is the analyte being monitored by the system, an EGV is stored to represent a measured blood glucose value, and insulin is the therapeutic agent being administered. At block 502 the sub-process begins. At block 504, the CPU obtains current and/or historical EGVs as needed from memory. At block 506, the system estimates a statistical confidence level in the value for the current or possibly some other EGV. For example change in value or statistical average value techniques can be used so that statistical outlying values can be discounted in the calculation of the insulin dosage.

[0041] Because automated systems of the type described above collect much more data much more frequently than is currently typical with conventional methods, much more analysis can be performed on that data in order to determine or estimate a degree of confidence that might legitimately be placed on that data. Real blood glucose levels inside a patient's body should change relatively slowly, as it takes some time for the body to process blood glucose and insulin, and thus for changes in blood glucose levels actually to occur in the patient's blood. If, then, the system detects rapid fluctuations or variations between measured blood glucose levels generated at points close in time, the system may legitimately infer that the quality of the individual measurements is not likely to be high, as real blood glucose levels would not be expected to vary so rapidly. This would be the case especially where a single data point was either much higher or much lower than other points near it in time. That point would be thought simply to be an outlier, reflective of some measurement error and thus not subject to a great deal of confidence. [0042] Insulin dosing has historically been calculated based on measurements taken at one-hour intervals, any single one of which might be substantially in error. With some embodiments of the invention, measurements are taken 12 times per hour. Confidence can be improved substantially simply by averaging the previous 12 measurements and calculating the new dose based on that calculated average. The insulin dosing algorithm could also be refined by incorporating estimated levels of confidence in the measured data into the determinations of how much insulin to deliver. Outliers can be given relatively little weight in dosing calculations, adjustments could be made in part based on the variance or standard deviations of multiple data points in a data set consisting of a series of measurements, and so forth.

[0043] Returning to FIG. 5, at block 508 a rate of change of EGV is determined and compared to an estimated target value or values 510 if glucose is being measured at more than one place. Systems like those described above take measurements more frequently than is currently the case, and because those systems include means for storing historical data reflecting past measured blood glucose levels (and insulin deliveries), they offer much expanded opportunities for programming. A system according to example embodiments takes into account a difference between a current, measured blood glucose level and a desired, target blood glucose level, in combination with a calculated rate of change in the measured blood glucose level. If blood glucose is nearing an acceptable upper bound, for example, then insulin delivery can be scaled back to avoid overshooting the target and putting the patient's blood glucose below an acceptable hypoglycemic threshold. Similarly, if it were to be determined that the patient' s blood glucose was high but falling very slowly, then insulin delivery can be stepped up in an attempt to prompt a faster rate of change. Such determinations can also be used to deliver insulin of different types, or according to different modes of delivery. Measured and calculated rates of change in a patient's blood glucose level can provide bases, for example, for delivering insulin of "fast-acting" or "slow acting" types, alone or in various mixtures - or intravenously (rapid- acting) or subcutaneously (slower-acting), or in appropriate combinations. In any of such insulin delivery schemes, the availability of near real-time, near continuous blood glucose measurement data, allows one to deliver therapies reflective of the changing conditions and needs in the bodies of a variety of individual patients.

[0044] Still referring to FIG. 5, at block 512, a difference between an arterial EGV and a venous EGV is calculated so that it can be used to improve calculation of the insulin dosage. Similarly, at block 514 the processor in the system determines the difference between a core EGV and a peripheral EGV in the patient's body. Blood glucose is frequently measured in blood in an artery of the patient. Such arterial blood glucose measurements are thought to be useful because they provide a measurement reflective of glucose supply to the body's organs. Arterial glucose concentrations, though, are often higher than those sampled in the same patient at a venous location. This difference may be particularly pronounced, moreover, at times shortly after a patient eats or after nutrition is supplied otherwise to the patient. If insulin is dosed and delivered based on arterial blood glucose measurements, there is some risk of venous hypoglycemia. Insulin therapy conducted based on venous glucose measurements, on the other hand, may incur increased "times to target" in comparison with optimal or desired arterial conditions. In some embodiments of the invention insulin dosing protocols or algorithms are designed to take such conditions into account by taking into account the difference between arterial and venous EG Vs.

[0045] For example, dosing protocols based solely on arterial or solely on venous blood glucose measurements can be adjusted to provide insulin in higher or lower quantities, or at higher or lower rates, based on the location of the measurement and the known differences in blood glucose quantities typically seen at alternate sites. Optimal or improved therapies might be devised, moreover, that would utilize arterial and venous measurements in conjunction with one another, including through the use of multiple sensors positioned to measure blood glucose at both an arterial and a venous location.

[0046] The differences between core and peripheral EGVs can be handled in a similar fashion according to some embodiments of the invention. The human body has the capability to pull blood selectively to its core with a concomitant reduction of blood flow in and supply to the body's periphery. This redirection of blood flow may occur, moreover, particularly when the body is under stress, and thus may be particularly significant in medical patients in hospital settings. A possible consequence of this is that blood glucose concentrations measured at peripheral sites may be low in comparison with blood glucose levels in the body's core, with the latter being possibly more relevant to the delivery of optimal therapies for overall glucose control. This difference might delay or interfere with the achievement of optimal or desired blood glucose levels at the body core, when therapies are devised or adjusted based on measurements taken from sites at peripheral vessels. [0047] Differences in EGVs based on measurements at varied locations of the body or measured in arterial blood and venous blood can also be based on or include

measurements of other types of blood and other fluids. Also, arterial blood can include subcutaneous blood and/or fluids. EGVs taken from interstitial fluids by interstitial fluid sampling can be used with arterial and venous sampling to calculate doses of insulin or other therapeutic agents.

[0048] With the sensor types and placements previously described, where blood is withdrawn automatically through a catheter over a sensor that produces an electrical signal to indicate a measured blood glucose concentration, reduced blood flow in the peripheral vessels in which the catheter is typically located may lead to a failure of the sensor to measure accurately the most relevant blood glucose levels as they actually exist in the body of the patient. Improved insulin dosing protocols result from embodiments of the invention that take these phenomena into account.

[0049] Continuing with FIG. 5, at block 516 the system can determine whether sensor contamination is likely, and also determine the level of sensor contamination in order to use this level in dosing calculations. At block 518 the process for the current dosing calculation ends, meaning processing returns to FIG. 4. A potential exists for inaccurate blood glucose measurements, especially where nutritional therapy is being delivered to the patient simultaneously or near in time to the blood glucose measurement. This contamination of the blood samples with the nutritional glucose can lead to artificially high measurements of blood glucose concentration, which can in turn lead to the physician' s believing falsely that the patient is in a persistent state of hyperglycemia. In some embodiments of the invention, such contamination can be detected or its possibility can otherwise be programmatically accounted for. Upon the detection of such a condition, an adjustment can be made to the dosing, or an alert can be provided to the caregiver.

[0050] Some of the statistical refinements described above can make use of multi-site glucose measurements. There is currently substantial literature that describes significant differences between, for example, venous and arterial glucose and relevant levels of glucose in those two portions of the vasculature. Despite this, such distinctions are currently not well defined, and current clinical practice tends to consider hypoglycemia and hyperglycemia as global states, more or less uniform throughout the patient's body. However, blood glucose can be measured simultaneously at both arterial and venous locations. These simultaneous measurements can lead to the ability to measure or estimate body glucose consumption. Such measurements or estimates may lead in turn to improved insulin dosing algorithms and to the improvement in other treatment decisions, since insulin delivery protocols might be improved if insulin were to be delivered based in part on an individual patient's ability to use that insulin effectively. This patient's ability can be determined, for example, by measuring blood glucose at different sites within the patient's body, and then determining insulin dosing based at least in part on the differences in blood glucose levels measured at those different sites.

[0051] One might measure blood glucose, for example, in a first blood vessel situated to deliver blood to the patient's brain, and at the same or nearly the same time, in a second blood vessel situated to carry blood away from the patient's brain. A substantial difference in those two levels - blood glucose in the vessel upstream of the brain being higher than blood glucose downstream of the brain - would then indicate that the patient' s brain was consuming that glucose effectively, and thus making good use of the insulin being delivered to the patient. A small difference, on the other hand, would indicate that the patient's brain was not using glucose effectively, thus that the current delivery of insulin was not having a good effect, and therefore that an alternative rate insulin delivery or another mode of treatment would be more appropriate.

[0052] The goal of such a scheme would be to deliver insulin to increase the patient' s consumption of glucose as long as the patient is hypoglycemic. If it is determined on the other hand, that increasing the level of insulin does not increase glucose consumption, then the delivery of insulin should not be increased further, because the patient would experience no benefit from such an increase. Insulin would thus be delivered only to the extent that it would be determined currently to be having a substantial positive effect in that particular patient. Similar measurements could be made, for example, both in the patient's blood and the patient's urine, with dosing algorithms or other treatment decisions based appropriately on differences between the two measured levels, rates of change of those levels or their differences, or similar values measured by the system.

[0053] FIG. 6 presents multiple views, FIGs. 6A-6N showing a screen of the display device of the system previously described, and how the display screen may change over time. The screen shows chart 600, a readout for EGV 602, a readout and a "touch" adjustment panel 604 for insulin levels, and a touch menu button 606. In these screens estimated glucose values are shown graphically as points 608. Historical and the most current insulin levels are shown with solid line 610, and recommended insulin levels are shown with dotted line 612. In addition, time is shown on horizontal axis 620 and glucose level is shown on vertical axis 640. The display also shows glucose limit lines defining the acceptable range of values for this patent, a high limit line 650 and a low limit line 660. In FIGs. 6A, 6B, 6C and 6D, the insulin dosage is set to 5.0 units per hour and the EGV for the patient is gradually dropping.

[0054] In FIG. 6E, the system has increased the recommended insulin dose to 5.5 units per hour. In this particular example embodiment, a caregiver must confirm this new recommended dose for the processor to cause the delivery device to change the infusion rate. The caregiver confirms the dose in FIG. 6F by pressing a soft key with a finger 680. A pointing device such as a mouse could also be used to position and activate a "virtual" finger or otherwise provide input to the system. As can be seen in FIGs. 6G and 6H, the dose has increased to the recommended level of 5.5 units per hour.

[0055] In FIGs. 61 and 6J, the recommended insulin dose has changed to 4.5 and then 4.0 units per hour, respectively. In FIG. 6K the recommended dose has now been calculated at 3.5 units per hour, and a caregiver has confirmed this dose and it is being administered in FIG. 6L and 6M. In FIG. 6N, the recommended does has now been calculated to be 4.0 units per hour.

[0056] References cited herein, including but not limited to published and unpublished applications, patents, and literature references, are incorporated herein by reference in their entirety and are hereby made a part of this specification. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification; the present specification supersedes and/or takes precedence over any such contradictory material of the incorporated reference.

[0057] All numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification are to be understood as being modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth herein are approximations that may vary depending upon the desired properties sought to be obtained. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of any claims in any application claiming priority to the present application, each numerical parameter should be construed in light of the number of significant digits and ordinary rounding approaches.

[0058] Although specific embodiments have been illustrated and described herein, those of ordinary skill in the art appreciate that any arrangement which is calculated to achieve the same purpose may be substituted for the specific embodiments shown and that the invention has other applications in other environments. This application is intended to cover any adaptations or variations of the present invention. The following claims are in no way intended to limit the scope of the invention to the specific embodiments described herein.

Claims

WHAT IS CLAIMED IS:

1. A method of facilitating delivery of a therapeutic agent to a patient, the method comprising:

determining by a processor, a numerical value for a patient analyte; storing the numerical value for the patient analyte in a memory;

calculating, by the processor, a dosage of the therapeutic agent based on the numerical value stored in the memory; and

displaying the dosage of the therapeutic agent on a display device.

2. The method of claim 1 further comprising setting a delivery device by the processor to deliver the dosage of the therapeutic agent.

3. The method of claim 2 wherein the setting of the delivery device is accomplished in response to user input.

4. The method of claim 2 wherein the setting of the delivery device is accomplished in response to the calculating of the dosage of the therapeutic agent.

5. The method of claim 2 wherein the patient analyte comprises glucose, the numerical value comprises an estimated glucose value (EGV), and the therapeutic agent comprises insulin.

6. The method of claim 5 wherein the calculating of the dosage of the insulin further comprises estimating a confidence in the EGV.

7. The method of claim 5 wherein the calculating of the dosage of the insulin further comprises determining a difference between an arterial EGV and a venous EGV.

8. The method of claim 5 wherein the calculating of the dosage of the insulin further comprises:

determining by the processor and storing in the memory a plurality of historical estimated glucose values; and

determining by the processor of an EGV rate of change for the patient from the EGV and the historical estimated glucose values.

9. The method of claim 5 wherein the calculating of the dosage of the insulin further comprises determining a difference between a core EGV and a peripheral EGV.

10. The method of claim 5 wherein the calculating of the dosage of the insulin further comprises determining a sensor contamination level.

11. A system for delivering a therapeutic agent to a patient, the system comprising:

a display device;

a delivery device;

a processor operably connected to the display device and the delivery device; and

a memory operably connected with the processor to store a numerical value for a patient analyte, the memory also operable to store computer program code which, when executed, causes the processor to calculate a dosage of the therapeutic agent based on the numerical value and to deliver the dosage of the therapeutic agent.

12. The system of claim 11 wherein the patient analyte comprises glucose, the numerical value comprises an estimated glucose value (EGV), and the therapeutic agent comprises insulin.

13. The system of claim 12 wherein the computer program code causes the processor to deliver the dosage in response to user input.

14. The system of claim 12 wherein the computer program code causes the processor to deliver the dosage in response to calculating the dosage.

15. The system of claim 14 wherein the computer program code causes the processor to estimate a confidence in the EGV as part of calculating the dosage.

16. The system of claim 14 wherein the computer program code causes the processor to determine a difference between an arterial EGV and a venous EGV as part of calculating the dosage.

17. The system of claim 14 wherein the computer program code causes the processor to determine a plurality of historical estimated glucose values and to determine an EGV rate of change for the patient from the EGV and the historical estimated glucose values as part of calculating the dosage.

18. The system of claim 14 wherein the computer program code causes the processor to determine a difference between a core EGV and a peripheral EGV as part of calculating the dosage.

19. The system of claim 14 wherein the computer program code causes the processor to determine a sensor contamination level as part of calculating the dosage.

20. Apparatus for delivering insulin to a patient, the apparatus comprising: means for determining an estimate glucose value (EGV) for the patient; means for calculating a dosage of insulin based on the EGV; means for displaying the dosage of insulin to a user; and

means for delivering the dosage of insulin to the patient.

21. The apparatus of claim 20 further comprising means for determining a difference between an arterial EGV and a venous EGV.

22. The apparatus of claim 20 further comprising:

means for storing a plurality of historical estimated glucose values; and means for determining an EGV rate of change for the patient from the EGV and the historical estimated glucose values.

23. The apparatus of claim 20 further comprising means for determining a difference between a core EGV and a peripheral EGV.

24. The apparatus of claim 20 further comprising means for determining a sensor contamination level.