WO2014078101A1

WO2014078101A1 - System, method and computer program product for determining calibrant solution concentration

Info

Publication number: WO2014078101A1
Application number: PCT/US2013/068102
Authority: WO
Inventors: Paul S. VAN WIEREN; Jennifer L. WILBUR; Michael Higgins
Original assignee: Edwards Lifesciences Corporation
Priority date: 2012-11-15
Filing date: 2013-11-01
Publication date: 2014-05-22

Abstract

A system is provided for creating a diluted calibration solution out of a diluent supply and a calibrant supply. The system includes a restrictor, a flow controller, a pressure sensor and a processor having a module executable by the processor. The flow controller urges the calibrant supply through the restrictor toward the diluent supply. A pressure in the calibrant supply during urging is measured by the pressure sensor which is correlated by the processor to a concentration of the calibrant supply. Advantageously, calibration of the system can be avoided by using a draw of the diluent supply with a known concentration and comparing a ratio of the infusion and draw pressures to determine the calibrant supply concentration.

Description

SYSTEM, METHOD AND COMPUTER PROGRAM PRODUCT FOR DETERMINING CALIBRANT SOLUTION CONCENTRATION

Technical Field

[0001] This disclosure relates to systems for testing blood analytes, and more particularly, systems for testing blood analytes that include the use of a calibration fluid, such as a fluid containing a known concentration of dextrose.

BACKGROUND

[0002] Analyte testing in the home is fairly common and involves the use of finger stick glucometers that return blood glucose levels on an intermittent basis throughout a day. For patients in a hospital setting, however, these intermittent tests are not frequent enough to capture a patient' s (usually) more dynamically changing condition. Patients in critical care settings can experience especially high fluctuations in blood analytes such as glucose. Tracking such changes is better accomplished by more frequent sampling and reporting of analyte levels. To this end, companies have recently been developing continuous glucose monitoring systems for the hospital.

[0003] In continuous analyte monitoring the same sensor is repeatedly called upon over a series of hours or days to report sensed analyte parameters. During this time, it is advantageous to ensure that the sensor is correctly calibrated by using it to sense a calibration fluid with a known concentration of the analyte of interest, such as glucose. For example, a sensor system employed by Edwards Lifesciences Corporation (Irvine, CA) uses a glucose-oxidase sensor mounted in a catheter tube to sense patient glucose levels continuously for up to 72 hours. This analyte sensor is cycled continuously during this three-day period through alternating sample sensing and calibration cycles in alternation to ensure high accuracy.

[0004] During the calibration cycle, calibrant fluid is flowed through tubing by a flow control device over the sensor and the sensor reading is adjusted to match the known concentration of calibrant fluid. The calibrant fluid originates from a bag filled with a known amount of saline and dextrose. This calibrant fluid is created by taking a standard saline bag of known volume (or weight) and spiking the bag with an injection of a known volume (or weight) of dextrose. Unfortunately, this process can be a bit cumbersome and systems using calibration fluids could benefit from simpler, easier to use options for generating calibration fluids of known accuracy.

SUMMARY

[0005] In one embodiment, the present disclosure includes a system for creating a diluted calibration solution out of a diluent supply and a calibrant supply. Included in the system are a restrictor, a flow controller, a pressure sensor and a processor. The restrictor includes an inlet and an outlet. The flow controller generates head pressure configured to urge the calibrant supply through the inlet of the restrictor and out of the outlet toward the diluent supply. Pressures at the inlet of the restrictor are measured by the pressure sensor. The processor is configured to determine a concentration of the calibrant supply using the pressure measured by the pressure sensor.

[0006] In another aspect, the calibrant supply extends through the restrictor and mixes with the diluent supply to create the diluted calibration solution. And, the calibration solution is configured to calibrate a sensor, such as a glucose sensor, for measuring blood parameters.

[0007] In another aspect, the system includes a temperature sensor configured to measure a temperature of the calibrant supply. The processor is further configured to determine the concentration of the calibrant supply using the temperature of the calibrant supply. Also, the temperature sensor can measure a temperature of the diluent supply, with both temperatures being used to facilitate determination of the concentration of the calibrant supply.

[0008] The flow controller can also be configured, in another embodiment, to generate a vacuum pressure and draw the diluent supply back through the restrictor. The vacuum pressure is measured by the pressure sensor and this measurement is used to determine the concentration of the calibrant supply. For example, the processor is configured to determine a ratio of the vacuum and urged pressures to determine the concentration. Preferably, both urging and drawing are at the same flow rates which can help eliminate the impact of particular restrictor geometry and compliance of the system, thereby avoiding calibration. [0009] In another embodiment, the flow controller may be configured to apply a transient pressure pulse to the calibrant supply and a transient pressure response is measured by the pressure sensor. Similarly, the vacuum pressure may be applied to the diluent as a transient vacuum pressure pulse and the transient vacuum pressure response is measured by the pressure sensor. The processor is configured to determine an exponential decay time for the two responses and compare those responses to each other to determine the concentration of the calibrant supply. For example, a ratio of the two decay times may be compared to previously determined ratios to yield a concentration.

[0010] These and other features and advantages of the present disclosure will become more readily apparent to those skilled in the art upon consideration of the following detailed description and accompanying drawings, which describe both the preferred and alternative embodiments of the present disclosure.

BRIEF DESCRIPTION OF THE DRAWINGS

[0011] FIG. 1 is a perspective view of a blood glucose sensing system of one embodiment of the present disclosure;

[0012] FIG. 2 is a schematic of a calibration fluid injection system of the blood glucose sensing system shown in FIG. 1 ;

[0013] FIG. 3 is an enlarged view of a restrictor of the calibration fluid injection system of FIG. 2;

[0014] FIG. 4 is a z-site sampling port of another embodiment of the present disclosure;

[0015] FIG. 5 is a flow chart of a process of another embodiment of the present disclosure that uses a steady-state pressure response to determine a calibrant concentration;

[0016] FIG. 6 is a graph of steady-state pressure ratio data collected for use with the process of FIG. 5 ;

[0017] FIG. 7 is a flow chart of a process of another embodiment of the present disclosure that uses a transient pressure response to determine a calibrant fluid concentration; [0018] FIG. 8 are graphs of transient pressure response data collected and processed using the process of FIG. 7;

[0019] FIG. 9 is a graph of the transient pressure response ratios collected using the embodiment of FIG. 7; and

[0020] FIG. 10 is a schematic of another embodiment of a blood glucose sensing system of the present disclosure including actuated valves for priming of a syringe.

DETAILED DESCRIPTION

[0021] The present disclosure overcomes the problems of the prior art by providing a system for creating a diluted calibration solution out of a diluent supply and a calibrant supply. The system includes a restrictor, a flow controller, a pressure sensor and some kind of processor (e.g., a computer system) with a module that executes code. The flow controller urges the calibrant supply through the restrictor toward the diluent supply. A pressure in the calibrant supply is measured by the pressure sensor which is correlated by the module to a concentration of the calibrant supply. Advantageously, calibration of the system can be avoided by using a draw of the diluent supply with a known concentration and comparing a ratio of the infusion and draw pressures to determine the calibrant supply concentration.

[0022] The disclosure now will be described more fully hereinafter with reference to specific embodiments. This disclosure can be embodied in many different forms, though, and thus should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements. As used in the specification, and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. The term "comprising" and variations thereof as used herein is used synonymously with the term "including" and variations thereof and are open, non- limiting terms.

[0023] An improvement to ad hoc creation of bags with known amounts of calibration solution for continuous analyte sensing systems is to have supplied to the end-user off- the-shelf options for calibration. For example, pre-packaged dextrose solutions could be supplied to the user for connection to the fluid pathway of the analyte sensing system. A problem with such a scenario, however, is that a healthcare worker might erroneously deploy or enter into the sensing system's computer processor module incorrect information corresponding to the wrong solution due to inattention. Or, because it is much harder to control the composition of a calibrant solution than to measure its concentration after the fact, the supplied calibrant solution might have inaccuracies great enough to materially affect the glucose levels determined and reported to the healthcare worker. It is therefore advantageous to measure (or re-measure) the concentration of the calibrant at the time of testing of the analyte.

[0024] There are many ways to measure glucose concentration of an aqueous dextrose solution, including both electrochemical and optical methods. Both electrochemical and optical techniques themselves must often be calibrated, so their use is not generally an optimal solution. Electrochemical methods also require the use of expensive one-time use sensors. Optical systems are generally quite expensive and require special (and possibly expensive) disposable designs in order to interface the durable optics portions with the disposable portions. It is theoretically possible, however, to measure high concentrations of a pure aqueous dextrose solution using viscosity measurements. Most conventional viscometers (such as tall glass units), however, are large and expensive bench-top units that require large amounts of fluid (>30mL) and are thus not optimal for use with high volume disposables. In addition, conventional viscometers must also be occasionally recalibrated to ensure accuracy.

[0025] Embodiments described in this disclosure include a blood glucose sensing system 10 that includes a solution fluid 12, a flow controller 14, a calibration fluid injection system 16 and a sensor assembly 18, as shown in FIG. 1. Included in the calibration fluid injection system 16 is a calibrant source fluid 20, a flow controller 22, a pressure sensor 24 and a restrictor 26, as shown in FIG. 2 and FIG. 3. Generally, injection system 16 is configured to measure pressures associated with moving the calibrant source fluid 20 and the solution fluid 12, to correlate those pressures to a relative viscosity, and to determine a concentration of the calibrant source fluid 20 prior to its mixture with the solution fluid 12 and delivery to a glucose sensor 28 of the sensor assembly 18 for calibration. [0026] The solution fluid 12 is supplied, in this embodiment, from a bag 30 mounted on a pole 32. The solution fluid is preferably off-the-shelf and/or not inconvenient to employ in a hospital setting and includes attributes that help with function of the sensing system 10. For example, the solution in the bag may be a plasmalyte or conventional saline with selected amounts of buffers and anti-thrombogenic compounds such as heparin that help with flushing the sensor assembly 18 to keep it clear of clots and thrombosis. The buffers also help to optimize sensor performance. The solution in the bag 30 may also include various nutrients to keep fluid and nutrition at appropriate levels for the patient. Preferably, however, the solution fluid 12 is easily and conveniently obtained by the healthcare worker charged with having to track the patient's blood glucose or other analytes.

[0027] Although the illustrated embodiment employs a fluid bag 30, it should be noted that the solution fluid 12 could come from several sources, including several sources at one time, and have varying compositions, as long as it effectively acts as a diluent of some sort for the compound (such as dextrose) being used to calibrate the analyte sensor. For example, a pressurized canister or a reservoir may be employed. It is also possible that the solution fluid 12 is entirely done away with in favor of a single calibrant source fluid 20 of appropriate concentration in a pre-mixed state. However, generally, the calibrant source fluid is likely to have relatively low concentrations (e.g., 50 to 200 mg/dL) that, if known with a high degree of accuracy (e.g. 3%), provide advantages for sensing glucose concentration. Since the relative viscosity differences between solutions of - for example — 100 mg/dL and 103 mg/dL are very small, it is challenging to achieve a usable resolution for measurement of a pre-mixed calibration solution using only solution viscosity.

[0028] A first fluid line 34 connects the fluid bag 30 to the flow controller 14, as shown in FIG. 1. The flow controller 14 in one embodiment of the present disclosure includes some type of hardware, software, firmware, or combinations thereof that electromechanically controls one or more valves or other mechanical flow control devices to selectively allow, push, pull, reverse, or prevent flow through the first fluid line 34. In the illustrated embodiment, the mechanical aspect of the flow controller 14 includes a rotary head with rollers configured to compress the line, with the first fluid line 34 extending through the rotary head. This rotary head with rollers pinches the fluid line to stop flow and, by sliding along a short length of the fluid line, can advance the solution fluid 12 or retract the solution fluid in a column extending down a second fluid line 36 all the way to the sensor assembly 18. The effects of this operation will be described in more detail below for the illustrated embodiment.

[0029] Notably, the flow controller 14 of the illustrated embodiment employs a combination of the head pressure generated (primarily, except for the short draw and infusion by pinch point advancement) by the elevation of the fluid bag 30 on the pole 32 and the on-off regulation of the flow induced by the head pressure. The flow controller 14, however, could also include a combination of an actual powered pump and a programmable controller, so as to eliminate the need for the pole 32. This pump could be combined with the aforementioned solution fluid 12 reservoir. One advantage, however, of the illustrated embodiment is that the gravity feed of the fluid bag 30 on the pole 32 is well-understood and mediated to control the amount of fluid administered to the patient. Use of active pumps should be controlled in some manner to avoid administration of excess fluid and its side-effects. Regardless, the role of the flow controller 14 can be met flexibly with various combinations of technology and the present disclosure should thus not be considered limited to any one particular configuration. The flow controller 14 in the illustrated embodiment also includes a display for displaying information such as the measured glucose signals and the flow control signals.

[0030] The sensor assembly 18 includes a catheter within which is mounted the glucose sensor 28. The catheter is connected to the end of the second fluid line 36 and includes a lumen connected in fluid communication with the second fluid line's lumen. The catheter lumen opens into the blood stream within the patient's vasculature at the distal tip of the catheter. Alternatively, the sensor assembly 18 may be employed with an existing multiple lumen catheter, such as in the proximal lumen of a three-lumen catheter, about 5 cm or so from the distal end. In this manner, a fluid column extends up from the distal tip of the catheter in the patient's blood stream all the way to the flow controller 14. [0031] The sensor assembly 18 may also include a patient cable 19 that couples the flow controller 14 in electrical communication with the glucose sensor, as shown in FIG. 1.

[0032] When the flow controller 14 is operated such that its rollers are not pinching off the fluid line, solution from the bag 30 is gravity fed down through the first and second fluid lines 34, 36, through the catheter, over the sensor mounted in the catheter, and finally into the patient. Alternatively, the flow controller 14 could advance the head and rollers in the direction of the catheter and drive the solution to flush the glucose sensor 28 and catheter. If the solution from the bag 30 includes heparin or another anti- thrombogenic agent, or if it includes anti-thrombogenic mechanical qualities, this flush step clears the catheter and cleans the glucose sensor 28.

[0033] In a draw step, the head and rollers are reversed by the flow controller 14 forming a vacuum and drawing a blood sample up into the catheter from the patient's vasculature. The glucose sensor 28, during or after this step, can then be activated to sense the glucose concentration in the drawn blood sample. After sufficient time has elapsed to take one or more analyte measurements, the flush cycle is then run, typically in 5 to 10 minute cycles, as described above. This process of flush-and-draw is repeated over the life of the sensing system 10, or at least the life of the glucose sensor 28.

[0034] If the calibration fluid injection system 16 of an embodiment of the present disclosure is employed, the flush step described above can also include a calibration function. The fluid calibration injection system includes the calibrant source fluid 20, flow controller 22, pressure sensor 24 and restrictor 26. The calibration fluid injection system 16 may be positioned above or below (i.e., in fluid communication with the first fluid line 34 or second fluid line 36) the flow controller 14, as long as (in this embodiment) the fluid column extending down from the solution fluid 12 is available. As mentioned below, though, there are possible embodiments where the system 16 measures the concentration of the already-mixed glucose solution.

[0035] The calibrant source fluid 20 includes some type of a relatively high concentration dextrose solution (or, for other analyte sensing systems, a different analyte solution), such as D5W, D30W or D50W that exhibits viscosity substantially different from those of water, saline or other solution fluids 12. Alternatively, the calibrant source fluid 20 may have a viscosity similar to the solution fluid 12, but different than those of less desired fluids not suited for calibration. In this latter embodiment, the differences in viscosity would enable detection of undesired compositions being used for the calibrant source fluid 20. Regardless, the source fluid 20 may be in some type of reservoir, a second bag, or some type of pressurized container. Or, alternatively, it can be created on the spot by mixing dextrose with saline or another solute as it passes on its way to the flow controller 22. As is evident from these alternatives, there is a wide range of suitable calibrant source fluid 20 embodiments. This is enabled by the calibration fluid injection system 16 in that it determines the concentration of the calibrant source fluid 20 on the spot, which is a much easier task than accurately controlling the composition of the fluid 20.

[0036] The flow controller 22 controls the flow rate of the calibrant source fluid 20 by varying the head urging the calibrant source fluid in the direction of the restrictor 26. The pump 22 is configured to generate the head pressure and can include various methods and devices for doing so, such as a volumetric infusion pump, a peristaltic pump or a piston pump. The pump 22 (because the term "pump" should be broadly construed in this context) could also be a combination of a fluid bag to generate head pressure, along with one or more valves to control the application of the gravity-generated head pressure, somewhat similar to the flow controller 14 and bag 30 described above for the sensing system 10.

[0037] In the illustrated embodiment of FIG. 2, the calibration fluid injection system 16 includes a syringe pump 40 connected to a syringe 42. The syringe pump 40 is generally an electromechanical motor (e.g., a solenoid) that drives a plunger of the syringe 42 in and out of the syringe housing. A needle 44 extends from the syringe through an injection site 46 mounted into the second fluid line 36. Advantageously, the syringe 42 is a relatively low cost, disposable component that can be replaced with a new sterile syringe along with a new glucose sensor 28 for a new patient. The syringe pump 40 would likely be retained longer-term (such as 5 years) and configured for easy exchange of new syringes. An exemplary needle 44 has a relatively small orifice diameter (approximately 0.007 inches) and a short length (approximately 1 cm) that, when combined with the syringe pump 40, pumps at a flow rate of about 50 mL/hr to achieve a good signal-to-noise ratio. This generates pressure measurements of roughly 5 psi with an aim to reduce the tolerance of off-the-shelf D50W by 50%.

[0038] In embodiments of the present disclosure, the restrictor 26 may include any reduced area constrictor of flow or frictional challenge that resists movement of the calibrant source fluid 20 so as to generate, at a relatively low flow rate, an increased pressure reading by the pressure sensor 24, which can be correlated to a viscosity and a concentration for the calibrant source fluid. For example, the restrictor 26 could be a plate with one or more orifices defined through it, or a narrow length of tubing, or a tube with a roughened internal surface, or a venturi shaped tube, or a frustoconical taper, a needle, etc.

[0039] Another advantage of the syringe 42, however, is that it also includes a frustoconical shape 48 and an annular needle mount 50, as shown in FIG. 3, that, along with the restricted diameter of the needle 44, function as the restrictor 26 of the illustrated embodiment. The majority of the resistance in the system, however, is provided by the needle, because the resistance is inversely proportional to the fourth power of the restrictor (i.e., the inner diameter of the needle) radius.

[0040] The injection site 46 is configured to allow fluid coupling of the calibrant source fluid 20 with the column of solution fluid 12 extending down from the bag 30. In this manner, the calibration fluid injection system 16 can pump the calibrant source fluid at higher concentrations into the solution fluid 12, which then acts as a diluent to produce a lower-concentration calibration solution in desired physiological ranges appropriate for calibration for commercial settings, which is then flushed over the glucose sensor 28. In FIG. 3, the injection site is a T-junction with the leg of the T having a valve 52 mounted in it and configured to guard against leakage of the solution fluid 12 while allowing easy insertion of the needle 44 of the syringe 42. Notably, these components could be collectively molded together into a portion of a pump cassette. The arms of the T are connected to opposing ends of a break in the second fluid line 36 or the first fluid line 34, depending upon the location of the calibration fluid injection system 16 with respect to the flow controller 14.

[0041] As an alternative to the T-junction, a Z-SITE needleless sampling port (Edwards Lifesciences, Irvine, CA) can be configured to receive a blunt tipped cannula, as shown in FIG. 4, mounted at the end of the syringe 42. The needleless sampling port includes a compressed cylindrical elastomer valve that has a pre-slit injection site that can be urged open by the blunt tipped cannula. This has the advantage of avoiding an accidental piercing of the second fluid line 36, a healthcare worker, or another component of the sensing system 10. The Z-SITE also advantageously has a small chamber that provides an offset between the inlet and outlet connectors (thereby forming a "Z" shape in an elevation view). This configuration promotes mixing of the injected calibrant source fluid 20 and the solution fluid 12.

[0042] Other configurations could also be used to connect the flows of the two fluids, the solution fluid 12 and the calibrant source fluid 20 exiting the restrictor 26, such as by using various tubing junctions (to avoid a needle), pumping of the calibrant source fluid 20 into a bag or reservoir that uses further gravity feed to generate a pressure head, etc. Generally, however, it is desirable that this connection be sterile, low cost, and easy-to- use. Also, multiple junctions or tubes might be employed for higher flow rates, or multiple calibration fluid injection systems 16. Parts of these connection systems may also function as part of the restrictor 26 depending on their resistance to flow.

[0043] As yet another alternative embodiment, the calibration fluid injection system 16 may stand alone and supply a calibrant source fluid 20 not in need of additional dilution to serve as a calibrant solution. In this instance, the second fluid line 36, for example, may originate at the end of the syringe from the annular needle mount 50 and go straight to the sensor assembly 18. Generally, however, physiological analyte concentrations of interest are very low and their viscosity differences (i.e., S/N ratio) harder to detect and correlate to concentration. A higher-concentration source fluid may thus be used in preferred embodiments.

[0044] Flanking the injection site 46 may be two three-way stopcocks, an upstream stopcock 54 and a downstream stopcock 56. Optionally, the stopcocks could be replaced by other flow control components configured to isolate the viscometer from the upstream bag pressure or the downstream central venous pressure. As another option, depending upon system pressures, these flow control elements may not be needed at all. The downstream stopcock 56 can be closed off to isolate, as will be described below in more detail, the injection site 46 from the continuously varying blood pressure of the patient's vasculature. The upstream stopcock 54 can isolate the injection site 46 from the solution fluid 12 during changing of the syringe 42 or other attachments of the calibrant fluid injection system 16.

[0045] Referring to FIG. 3, the calibrant fluid injection system 16 includes the pressure sensor 24 mounted in or at the distal end of the syringe 42 very near the annular needle mount 50. This positioning is advantageously as close to the narrowest orifice of the needle 44 (the lumen of the annular needle mount) as possible for fidelity in measuring the pressure of the restrictor 26 aspect of the calibrant fluid injection system 16.

[0046] The pressure sensor 24 could also be mounted in other places in fluid communication downstream of the pump 22 without appreciable loss of fidelity unless the calibrant fluid injection system 16 has varied or high compliance and/or the calibrant fluid has some compressibility. In the embodiment employing the syringe pump 40, for example, one or more pressure sensors 24 may be mounted downstream of a plunger 58 of the syringe 42. As another alternative, depending upon the pliability of various components of the calibrant fluid injection system 16, the pressure sensor 24 could be externally mounted and sense shape change or flex of a component of the system and correlate this to pressure and viscosity.

[0047] In a preferred embodiment, the pressure sensor 24 preferably should be configured for the wet, sterile operating environment and for a relatively small size, depending upon the size of the pump 22 and/or restrictor 26. For example, the pressure sensor 24 could be a dynamic pressure transducer sold under the mark TRUWAVE (Edwards Lifesciences, Irvine, CA). Alternatively, the pressure sensor 24 could be an ultra-miniature, solid-state pressure sensor used on mice and manufactured by Scisense (London, Ontario, Canada) which can be mounted inside a tube as small as 1.2 French. Advantageously, the Scisense pressure transducer has a recessed membrane and is customized for hemodynamic environments and has a smooth profile for minimizing interference with fluid flow.

[0048] In another embodiment, the syringe pump 40 could be modified to further accommodate the pressure sensor 24 by having a recess cut within its internal passageway which should promote smoother flow of the calibrant source fluid 20. As an alternative to an off-the-shelf pressure transducer, the pressure sensor 24 may be built into the syringe by covering the recess with a membrane with a stress/strain detector or piezoelectric component attached thereto to measure pressure variations.

[0049] Also, although small size is an advantage, it should be noted that the present disclosure could be employed with a range of different pressure sensing technologies. For example, there are optical pressure sensors that use fiber optics with a miniature pressure sensor on a distal end. As another alternative, a strain gauge could be affixed to a particularly flexible wall of a syringe pump 40 (or other type of pump/restrictor assembly) and correlated to pressure changes.

[0050] The pressure sensor 24 and the pump 22, as well as other components of the system, such as the sensor assembly 18, are connected in communication (wired or wirelessly) to some type of a computer processor. For example, as shown in FIG. 2, the pressure sensor 24 and the pump 22 are connected by communication lines 60 to a computer 62 that includes its own processor with a module executable by the processor. As will be explained below in more detail, the computer 62 includes various hardware, software and firmware modules that are configured to operate the system 10 of the present disclosure. These functions include collecting data from the pressure sensor 24 and the glucose (or other analyte) sensor 28 and controlling operation of the flow controller 14 and pump 22.

[0051] Referring again to FIG. 2, the calibration fluid injection system 16 may also include one or more temperature probes or sensors 64 that are associated with the calibrant source fluid 20 and the solution fluid 12. These temperature sensors, similar to the pressure sensor 24, are preferably positioned to sense temperature of the fluids near the inlet and outlets of the restrictor 26. The temperature sensors 64 are connected in communication with the computer 62 and continuously communicate temperature information to the computer. As is described in more detail below, this temperature information is used to adjust the viscosity comparisons for the two fluids 12, 20.

[0052] In another embodiment, the pump 22 is configured to be self-priming with dextrose solution. For example, the syringe 40 could include actuated valves on either side that selectively open for the ingress of the dextrose solution, such as D5, D30, D40 or D50. For example, as shown in FIG. 10, during normal operation where calibrant source fluid 20 is dispensed in cycles, a top actuated valve 300 is closed and a bottom actuated valve 302 is open. To prime or refill the syringe, the bottom valve 302 is closed and the top valve 300 opened to allow the syringe to draw in calibrant source fluid 20. Another alternative would be to use a peristaltic pump connected in fluid communication with a reservoir of the calibrant source fluid 20.

[0053] Referring to a process of an embodiment of the calibration fluid injection system 16 as shown in FIG. 5, the downstream stopcock 56 is closed 96 to isolate the calibrant fluid injection system 16 from the effects of varying blood pressure from the patient. Conversely, if not already open, the upstream stopcock 54 is opened 98 to provide a supply of the solution fluid 12 from the bag 30 or other reservoir. Also, the head and roller of the flow controller 14 may be opened to allow free access of the solution fluid 12 in the bag 30 through its column down to the syringe 42.

[0054] In a first calibration phase, the solution fluid 12 is drawn 100 from the second fluid line 36 through the needle 44 and into the syringe 42 by the computer 62 instructing the syringe pump 40 to pull the plunger 58 back within its housing to generate a negative pressure. As the solution fluid is drawn, pressure data is collected 102, preferably continuously, by the pressure sensor 24 communicating with the computer 62. Also, temperature data may be collected 104 at the same time by the temperature sensor 64 communicating with the computer 62. After the draw pressures are recorded, the solution fluid is injected 106 back into the second fluid line 36.

[0055] In an injection phase, the calibrant source fluid 20 is loaded 108 into the syringe 42. This can be done, for example, by opening an inlet valve that fills the syringe 42 with D30, D40, D50, etc., or a cartridge with such fluid may be inserted into an opening of the syringe 42. Or, the syringe 42 may be detached from its connection to the second fluid line 36 and connected to a reservoir of the calibrant source fluid 20 and the fluid drawn into the syringe.

[0056] Regardless, once the calibrant source fluid 20 is loaded 108, the plunger 58 of the syringe 42 is advanced to inject or infuse 110 the calibrant source fluid into the second fluid line 36 to be diluted by the solution fluid 12. During infusion 110, pressure data is (preferably continuously) collected 112 and temperature data is also collected 114.

[0057] Preferably, the rate of infusion 110 of the calibrant source fluid 20 is the same as the rate of draw 100 of the solution fluid 12. This allows elimination of a calibration for variations in the geometry of the restrictor 26. In addition, for both stages, the flow rate is preferably large enough to allow an ample signal-to-noise ratio on the pressure sensor 24. And, the time for the draw 100 and/or infuse 110 should be long enough to allow the calibration fluid injection system 16 to reach a steady-state equilibrium to account for the mechanical compliance of the system.

[0058] Despite the preference for using identical flow rates, it should be noted that this is not a fundamental constraint of the system. Differences in flow rates may be accounted for if the relationship between these flow rates is known. For example, at equilibrium, if the draw is at half the flow rate of the infusant, the draw pressure could be doubled before use in determining relative viscosity.

[0059] Once the data has been collected, the steady-state portion of the pressure measurements, as shown in FIG. 5, for the draw 100 and infuse 110 are compared 116 by the computer 62 to a baseline pressure value taken at the beginning of the process. Next, a ratio calculation 118 is performed by the computer 62 to determine a ratio of the draw 100 and infuse 110 equilibrium pressure values. This ratio is representative of the relative viscosity of the calibrant source fluid 20 to the solution fluid 12, the latter of which has a known viscosity. And, advantageously, this relative comparison is calibrated with respect to the geometry of the restrictor 26 and the gain of the pressure sensor 24 since those same components are employed for both measurements.

[0060] Optionally, one of the previous steps could be modified by a temperature adjustment 120 wherein the relative temperature difference determined by the temperature sensor 64 could be applied to the draw 100 and infuse 110 pressure values. This would be helpful when either the solution fluid 12 or calibrant source fluid 20 have different temperatures, such as when dextrose has been refrigerated right up until use as a calibrant source.

[0061] As shown in FIG. 6, a relationship of steady-state infusion/calibration draw pressure ratios to dextrose concentration allows determination of the dextrose concentration when the pressure ratio is known. The ratio calculation 118 could thus then be compared 122 to a curve fit to the data of FIG. 6 to yield the glucose concentration in the calibrant source fluid 20.

[0062] Notably, this ratio calculation 118 could depend on the composition of the solution fluid 12 (e.g., saline, heparin and buffer concentration) if components were employed that affect viscosity. In this instance, there could be an additional adjustment by the computer 62 for the effect of the components and/or the ratio comparison 122 could search out different data sets generated for that particular calibrant source fluid 20 composition. Or, a fluid could also be employed purely for calibration, as opposed to the calibrant source fluid 20, and have a known composition for which robust ratio comparisons have been previously generated and stored in a memory of the computer 62.

[0063] Referring again to FIG. 5, this glucose concentration could then be employed in either an error check 124 in which the glucose concentration is displayed for user comparison to expected glucose concentration and/or compared by the computer 62 to an expected or entered dextrose concentration. If the difference is large, an alarm or other preventive measure could be employed. Advantageously, this step guards against manufacturer variability and/or user error in the calibrant source fluid 20 concentration.

[0064] As another option, the newly determined calibrant source fluid 20 concentration could be used to adjust an amount of solution fluid 12 sent by the flow controller 14 to mix with the calibrant source fluid 20. Thus, if a known volume of calibrant source fluid 20 is infused 110 by syringe pump 40 at a higher concentration, a proportionately larger amount of solution fluid 12 could be sent to compensate for the difference and arrive at the same expected concentration. Conversely, the amount of calibrant source fluid 20 could be modulated to compensate for concentration differences. This would ensure that the correct concentration of calibration fluid reaches the sensor assembly 18 during the calibration cycle. Alternatively, instead controlling the calibration fluid concentration, the more accurate concentration information from the ratio comparison 122 could be used to adjust 126 the calibration of the glucose sensor 28. If the concentration of the calibrant source fluid 20 is off significantly, both of these steps could be combined to achieve an improved calibration cycle.

[0065] In another embodiment, the calibration fluid injection system 16 may be employed to determine concentration of the calibrant source fluid using a transient response. For example, as shown in FIG. 7, the syringe pump 40 may be configured to apply a draw impulse 200 in a draw direction to load the needle 44 with the solution fluid 12 and soak up any plunger 58 free travel. The system 16 is then allowed a rest period 210 so that it can approach equilibrium. A second draw impulse 220 is applied to collect pressure data using the pressure sensor 24. A second rest period 230 to allow equilibrium is applied.

[0066] An infusion 240 is performed by reversing the plunger 58, which preferably injects more (such as twice) of the solution fluid 12 than was drawn in the first and second 200, 220 impulse steps. This step loads the needle with clean calibrant source fluid 20 and soaks up any plunger 58 free travel. A third rest period 250 allows the system 16 to once again approach equilibrium. Another, second infusion 260 applies a delta impulse and pressure response data is collected by the pressure sensor 24. This is followed by a fourth rest period 270 wherein the system 16 is again allowed to approach equilibrium.

[0067] As shown in FIG. 8, the raw impulse response data has a pressure spike and then asymptotic drop off afterwards. The computer 62 is configured to process 280 (FIG. 7) the raw data, including correcting for offset, scaling, trimming of data to improve the shape of the resultant curve, etc., with an automated algorithm until two comparable time-domain exponential pressure decay curves are generated, as shown in FIG. 8. For example, program takes the data, adjusts it for offset and scales it down to peak-to-peak magnitude of 1, and trims some of the data out to isolate the middle of the exponential decay curve. [0068] A natural logarithm 290 is applied to the two curves to generate two linear data sets and linear regression is applied to get the slopes, as shown in FIG. 7. A ratio calculation 118 and comparison 122, such as from the process of FIG. 5, can be applied to these two slopes to determine the viscosity and dextrose (or analyte) concentration of the calibrant source fluid 20 relative to the test solution, such as by using the data shown in the graph of FIG. 9.

[0069] Viewed from a different perspective, the process 280 can calculate a RC time constant of each exponential decay by log-transforming and determining the slope. The capacitance (C) part of the time constant is the system's mechanical compliance, which should be about the same in this dynamic embodiment for the test and calibration solutions. The resistance (R) part of the time constant is the fluid resistance of the restrictor that the test or calibration solution is being pushed through. Generally, without being wed to theory, it is believed that the resistance is dependent on both the geometry of the restrictor (which is the same for both test and calibration solutions), and on the viscosity of the solution. Therefore, the ratio of the two RC time constants should theoretically cancel out the C term and the geometric part of the R term, resulting in a ratio of the test solution viscosity to the calibration solution viscosity.

[0070] In another embodiment, the computer 62 may be configured to transform both a pump input flow function and a pressure sensor output function into the frequency domain, such as by using a fast Fourier transform. The output frequency spectrum and input frequency spectrum could be compared between the draw of the solution fluid 12 and infusion of the calibrant source fluid 20. This ratio could be compared to known values similar to the processes described above. Also, different aspects of the frequency response could be compared as ratios, such as peak frequency or cutoff frequency.

[0071] It will be understood that each step of the flowchart of FIGs. 5 and 7, and combinations of the steps in the flowchart, can be implemented by computer program instructions. These computer program instructions may be loaded onto a computer or other programmable apparatus to produce a machine, such that the instructions which execute on the computer or other programmable apparatus create means for implementing the functions specified in the flowchart step(s). These computer program instructions may also be stored in a computer-readable memory that can direct a computer or other programmable apparatus to function in a particular manner, such that the instructions stored in the computer-readable memory produce an article of manufacture including instruction means which implement the function specified in the flowchart step(s). The computer program instructions may also be loaded onto a computer or other programmable apparatus to cause a series of operational steps to be performed on the computer or other programmable apparatus to produce a computer implemented process such that the instructions which execute on the computer or other programmable apparatus provide steps for implementing the functions specified in the flowchart step(s).

[0072] Accordingly, steps of the flowchart support combinations of means for performing the specified functions, combinations of steps for performing the specified functions and program instruction means for performing the specified functions. It will also be understood that each step of the flowchart, and combinations of steps in the flowchart, can be implemented by special purpose hardware-based computer systems which perform the specified functions or steps, or combinations of special purpose hardware and computer instructions.

[0073] In some embodiments, the computer 62 includes a microprocessor, however a computer system other than a microprocessor can be used to process data as described herein, for example an application-specific integrated circuit (ASIC) can be used for some or all of the sensor's central processing. The processor typically provides semipermanent storage of data, for example, storing data such as sensor identifier (ID) and programming to process data streams (for example, programming for data smoothing and/or replacement of signal artifacts). The processor additionally can be used for the system's cache memory, for example for temporarily storing recent sensor data. In some embodiments, the processor module comprises memory storage components such as ROM, RAM, dynamic-RAM, static-RAM, non-static RAM, EEPROM, rewritable ROMs, flash memory, and the like.

[0074] Many modifications and other embodiments of the present disclosure set forth herein will come to mind to one skilled in the art to which this present disclosure pertains having the benefit of the teachings presented in the foregoing description. Therefore, it is to be understood that the present disclosure is not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended claims. Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

Claims

THAT WHICH IS CLAIMED:

1. A system for creating a diluted calibration solution out of a diluent supply and a calibrant supply, the system comprising:

a restrictor with an inlet and an outlet;

a pump for generating head pressure configured to urge the calibrant supply through the inlet of the restrictor and out the outlet of the restrictor toward the diluent supply;

a pressure sensor configured to measure a pressure of the calibrant supply between the pump and the restrictor;

a processor; and

at least one module, executable by the processor, and configured to determine a concentration of the calibrant supply using the pressure measured by the pressure sensor.

2. A system of Claim 1, wherein the calibrant supply extends through the restrictor and mixes with the diluent supply to create the diluted calibration solution.

3. A system of Claim 2, wherein the diluted calibration solution is configured to calibrate a sensor for sensing blood parameters.

4. A system of Claim 1, further comprising a temperature sensor configured to measure a temperature of the calibrant supply and wherein the module is further configured to determine the concentration of the calibrant supply using the temperature of the calibrant supply.

5. A system of Claim 4, wherein the temperature sensor is further configured to measure a temperature of the diluent supply and wherein the module is further configured to determine the concentration of the calibrant supply using the temperature of the diluent supply.

6. A system of Claim 1, wherein the pump is further configured to generate a vacuum pressure and draw the diluent supply in the outlet of the restrictor, the pressure sensor is further configured to measure the vacuum pressure and the module is further configured to determine a concentration of the calibrant supply using the vacuum pressure.

7. A system of Claim 6, wherein the module is further configured to compare the pressure to the vacuum pressure to determine the concentration of the calibrant supply.

8. A system of Claim 7, wherein the pump is configured to urge the calibrant supply at a same flow rate as the pump is configured to draw the diluent supply.

9. A system of Claim 8, wherein the module is further configured to determine a ratio of the pressure to the vacuum pressure to determine the concentration of the calibrant supply.

10. A system of Claim 9, wherein the ratio of the pressure to the vacuum pressure is equivalent to a ratio of viscosities of the calibrant supply and diluent concentrations.

11. A system of Claim 9, wherein the flow controller is configured to urge the calibrant supply and draw the diluent supply for a time sufficient for the system to reach equilibrium.

12. A system of Claim 11, wherein the pressure sensor is configured to measure pressure continuously while the flow controller urges the calibrant supply and draws the diluent supply.

13. A system of Claim 11, wherein the flow controller is configured to draw the diluent supply before urging the calibrant supply.

14. A system of Claim 13, wherein the pump is configured to urge a known amount of the calibrant supply through the restrictor and into a known amount of the diluent supply and wherein the module is configured to determine, using the concentration and known amounts of the calibrant supply and diluent supply, a concentration of the diluted calibration solution.

15. A system of Claim 14, wherein the module is configured to control the known amounts of the calibrant supply and diluent supply.

16. A system of Claim 8, wherein the flow rate is sufficiently high to have a signal to noise ratio of greater than 1.

17. A system of Claim 1, wherein the module is configured to generate an alert if the concentration of the calibrant supply falls outside of a range.

18. A system of Claim 1, wherein the module is configured to record an assumed concentration of the calibrant supply and generate an alert if the assumed concentration is sufficiently different from the determined concentration of the calibrant supply.

19. A system of Claim 1, wherein the pressure sensor is configured to measure a baseline pressure value when the flow controller is not generating head pressure.

20. A system of Claim 1 , wherein the flow controller is configured to apply a transient pressure pulse to the calibrant supply and wherein the pressure measured by the pressure sensor is a transient pressure.

21. A system of Claim 20, wherein module is configured to compare an input function of the flow controller to an output function of the pressure sensor to determine the concentration of the calibrant supply.

22. A system of Claim 21, wherein the module is configured to determine a frequency spectrum of the input function and a frequency spectrum of the output function to determine a frequency domain transfer function for the calibrant solution.

23. A system of Claim 22, wherein the flow controller is further configured to generate a vacuum pressure and draw the diluent supply in the outlet of the restrictor, the pressure sensor is further configured to measure the vacuum pressure and the module is further configured to determine a frequency domain transfer function for the diluent supply and compare the domain transfer functions of the calibrant supply and the diluent supply to determine the concentration of the calibrant supply.

24. A system of Claim 20, wherein the module is configured to determine a time domain exponential decay of the pressure and a time domain exponential decay of the vacuum pressure, and determine the concentration of the calibrant supply using a ratio of the exponential decay time constants.

25. A system of Claim 20, wherein the module is configured to determine a time domain exponential pressure decay of the pressure and determine the concentration of the calibrant supply using the time domain exponential pressure decay.

26. A method for creating a diluted calibration solution out of a diluent supply and a calibrant supply, the system comprising:

urging the calibrant supply through a restrictor toward the diluent supply; measuring a pressure in the calibrant supply; and

determining a concentration of the calibrant supply using the pressure.

27. A method of Claim 26, further comprising mixing the calibrant supply with the diluent supply to create the diluted calibration solution.

28. A method of Claim 27, further comprising calibrating a sensor for sensing blood parameters using the diluted calibration solution.

29. A method of Claim 26, further comprising measuring a temperature of the calibrant supply and further determining or validating the concentration of the calibrant supply using the temperature of the calibrant supply.

30. A method of Claim 29, further comprising measuring a temperature of the diluent supply and further determining or validating the concentration of the calibrant supply using the temperature of the diluent supply.

31. A method of Claim 26, further comprising generating a vacuum pressure and drawing the diluent supply through the restrictor and measuring the vacuum pressure and further determining or validating the concentration of the calibrant supply using the vacuum pressure.

32. A method of Claim 31, further comprising comparing the pressure to the vacuum pressure to determine the concentration of the calibrant supply.

33. A method of Claim 32, further comprising urging the calibrant supply at a same flow rate as drawing the diluent supply.

34. A method of Claim 33, further comprising determining a ratio of the pressure to the vacuum pressure to determine the concentration of the calibrant supply.

35. A method of Claim 33, wherein urging and drawing are for a sufficient time to allow equilibrium.

36. A method of Claim 32, further comprising urging a known amount of the calibrant supply through the restrictor and into a known amount of the diluent supply and determining a concentration of the diluted calibration solution.

37. A method of Claim 36, further comprising controlling the known amounts.

38. A method of Claim 26, further comprising generating an alert if the concentration of the calibrant supply falls outside of a range.

39. A method of Claim 26, further comprising measuring a baseline pressure for adjusting the measured pressure.

40. A method of Claim 31, wherein urging includes applying a transient pressure pulse to the calibrant supply and wherein measuring the pressure includes measuring a transient pressure response of the calibrant supply.

41. A method of Claim 40, wherein generating a vacuum pressure includes generating a transient draw pressure and wherein measuring the vacuum pressure includes measuring a transient vacuum pressure response of the diluent supply.

42. A method of Claim 41, further comprising determining a time domain exponential decay of the transient pressure response and the transient vacuum pressure response and using the time domain exponential decays to determine the concentration of the calibrant supply.

43. A method of Claim 42, wherein determining the concentration of the calibrant supply includes using a ratio of the time domain exponential decays.

44. A computer program product for determining the concentration of a calibrant solution, the computer program product comprising:

a non-transitory computer-readable medium comprising a set of codes for causing a computer to:

receive one or more signals associated with a pressure of a source of calibrant supply;

determine the concentration of the calibrant supply based on the one or more signals associated with the pressure of the calibrant supply.