Patent Application
20190282141
Some embodiments of the disclosure relate generally to methods and devices for determining a concentration of an analyte in a sample, such as an analyte in a sample of bodily fluid, as well as methods and devices which can be used to support the making of such determinations. Some embodiments of the disclosure relate to a sample cell for measurements performed on a sample fluid.
It can be advantageous to measure the levels of certain analytes, such as glucose or lactate, in a bodily fluid such as blood. This can be done, for example, in a hospital or clinical setting when there is a risk that the levels of certain analytes may move outside a desired range, which in turn can jeopardize the health of a patient. Currently known systems for analyte monitoring in a hospital or clinical setting may suffer from various drawbacks.
The following drawings and the associated descriptions are provided to illustrate embodiments of the present disclosure and do not limit the scope of the claims.
These and other features will now be described with reference to the drawings summarized above. The drawings and the associated descriptions are provided to illustrate embodiments and not to limit the scope of any claim. Throughout the drawings, reference numbers may be reused to indicate correspondence between referenced elements. In addition, where applicable, the first one or two digits of a reference numeral for an element can frequently indicate the figure number in which the element first appears.
Although certain preferred embodiments and examples are disclosed below, inventive subject matter extends beyond the specifically disclosed embodiments to other alternative embodiments and/or uses and to modifications and equivalents thereof. Thus, the scope of the claims appended hereto is not limited by any of the particular embodiments described below. For example, in any method or process disclosed herein, the acts or operations of the method or process may be performed in any suitable sequence and are not necessarily limited to any particular disclosed sequence. Various operations may be described as multiple discrete operations in turn, in a manner that may be helpful in understanding certain embodiments; however, the order of description should not be construed to imply that these operations are order dependent. Additionally, the structures, systems, and/or devices described herein may be embodied as integrated components or as separate components. For purposes of comparing various embodiments, certain aspects and advantages of these embodiments are described. Not necessarily all such aspects or advantages are achieved by any particular embodiment. Thus, for example, various embodiments may be carried out in a manner that achieves or optimizes one advantage or group of advantages as taught herein without necessarily achieving other aspects or advantages as may also be taught or suggested herein.
The systems and methods discussed herein can be used anywhere, including, for example, in laboratories, hospitals, healthcare facilities, intensive care units (ICUs), or residences. Moreover, the systems and methods discussed herein can be used for invasive techniques, as well as non-invasive techniques or techniques that do not involve a body or a patient such as, for example, in vitro techniques.
In some embodiments, the sampling and analysis system 400 is a mobile point-of-care apparatus that monitors physiological parameters such as, for example, blood glucose concentration. Components within the system 400 that may contact fluid and/or a patient, such as tubes and connectors, can be coated with an antibacterial coating to reduce the risk of infection. Connectors between at least some components of the system 400 can include a self-sealing valve, such as a spring valve, in order to reduce the risk of contact between port openings and fluids, and to guard against fluid escaping from the system. Other components can also be included in a system for sampling and analyzing fluid in accordance with the described embodiments.
The sampling and analysis system 400 can include a fluid source 402 (or more than one fluid source) that contain(s) fluid to be sampled. The fluid-handling system 404 of the sampling and analysis system 400 is connected to, and can draw fluid from, the fluid source 402. The fluid source 402 can be, for example, a blood vessel such as a vein or an artery, a container such as a decanter, flask, beaker, tube, cartridge, test strip, etc., or any other corporeal or extracorporeal fluid source. For example, in some embodiments, the fluid source 402 may be a vein or artery in the patient 324 (see, e.g.,
In some embodiments, the fluid-handling system 404 withdraws a sample of fluid from the fluid source 402 for analysis, passes it through a flow cell having multiple measurement modalities (e.g., optical and electrochemical) and passes it back to the patient without disturbing the structure of the fluid components (e.g., blood cells). In some embodiments, the fluid-handling system 404 withdraws a sample of fluid from the fluid source 402 for analysis, centrifuges (or otherwise separates, for example, by lysing) at least a portion of the sample, and prepares at least a portion of the sample for analysis by an optical sensor such as a spectrophotometer (which can be part of an optical system 412, for example). In certain embodiments, the fluid drawn from the fluid source 402 can be analyzed using optical interrogation techniques, enzymatic sensors (see, e.g.,
The duration of time over which the sample of fluid is withdrawn, referred to as “draw period”, may be set to avoid clinical drawbacks, and/or it can be varied according to a health-care provider's wishes. For example, in some embodiments, fluid may be continuously withdrawn into the sampling and analysis system 400 over a draw period lasting approximately 10 seconds to approximately 5 minutes.
In some embodiments, the amount of sample withdrawn from the fluid source 402 can be small. For example, in some embodiments, the volume of sample withdrawn from the fluid source can be between approximately 1.0 ml and approximately 10.0 ml in a draw period (e.g. 2.0 ml-6.0 ml of sample can be withdrawn in a draw period of approximately 1 minute). In some embodiments, the amount of sample withdrawn can be in the range of approximately 20 ml/day to approximately 500 ml/day. In some embodiments, the amount of sample withdrawn can be outside this range.
In some embodiments, at least a portion of the sample is returned to the fluid source 402. At least some of the sample, such as portions of the sample that are mixed with other materials or portions that are otherwise altered during the sampling and analysis process, or portions that, for any reason, are not to be returned to the fluid source 402, can also be placed in a waste bladder (not shown in
Components of the fluid-handling system 404 can be modularized into one or more non-disposable, disposable, and/or replaceable subsystems. In the embodiment shown in
The non-disposable subsystem 406 can include components that, while they may be replaceable or adjustable, do not generally require regular replacement during the useful lifetime of the system 400. In some embodiments, the non-disposable subsystem 406 of the fluid-handling system 404 includes one or more reusable valves and sensors. For example, the non-disposable subsystem 406 can include one or more valves (or non-disposable portions thereof), (e.g., pinch-valves, rotary valves, etc.), sensors (e.g., ultrasonic bubble sensors, non-contact pressure sensors, optical blood dilution sensors, etc.). The non-disposable subsystem 406 can also include one or more pumps (or non-disposable portions thereof). For example, some embodiments can include pumps available from Hospira. In some embodiments, the components of the non-disposable subsystem 406 are not directly exposed to fluids and/or are not readily susceptible to contamination.
The first and/or second disposable subsystems 408, 410 can include components that are regularly replaced under certain circumstances in order to facilitate the operation of the system 400. For example, the first disposable subsystem 408 can be replaced after a certain period of use, such as a few days, has elapsed. Replacement may be necessary, for example, when a bladder within the first disposable subsystem 408 is filled to capacity. Such replacement may mitigate fluid system performance degradation associated with and/or contamination wear on system components.
In some embodiments, the first disposable subsystem 408 includes components that may contact fluids such as patient blood, saline, flushing solutions, anticoagulants, and/or detergent solutions. For example, the first disposable subsystem 408 can include one or more tubes, fittings, cleaner pouches and/or waste bladders. The components of the first disposable subsystem 408 can be sterilized in order to decrease the risk of infection and can be configured to be easily replaceable.
In some embodiments, the second disposable subsystem 410 can be designed to be replaced under certain circumstances. For example, in applicable embodiments, the second disposable subsystem 410 can be replaced when the patient being monitored by the system 400 is changed. The components of the second disposable subsystem 410 may not need replacement at the same intervals as the components of the first disposable subsystem 408. For example, the second disposable subsystem 410 can include a sample holder and/or at least some components of a centrifuge, components that may not become filled or quickly worn during operation of the system 400. Replacement of the second disposable subsystem 410 can decrease or eliminate the risk of transferring fluids from one patient to another during operation of the system 400, enhance the measurement performance of system 400, and/or reduce the risk of contamination or infection.
In some embodiments, the sample holder of the second disposable subsystem 410 receives the sample obtained from the fluid source 402 via fluid passageways of the first disposable subsystem 408. The sample holder is a container that can hold fluid for the centrifuge (and/or other sample conditioning element such as an ultrasonic lyser) and can include a window to the sample for analysis by a spectrometer. It can also or alternatively include access to the sample for enzymatic and/or electrochemical measurement. In some embodiments, the sample holder includes windows that are made of a material that is substantially transparent to electromagnetic radiation in the near and/or mid-infrared range of the spectrum. For example, the sample holder windows can be made of calcium fluoride. In some embodiments, a sample holder can include walls formed from injection moldable material such as plastic.
An injector can provide a fluid connection between the first disposable subsystem 408 and the sample holder of the second disposable subsystem 410. In some embodiments, the injector can be removed from the sample holder to allow for free spinning of the sample holder during centrifugation. In some advantageous embodiments, no injector is required because no centrifugation is necessary.
In some embodiments, blood (or other sample fluids) can be conditioned prior to or subsequent to measurement. For example, blood cells can be lysed, separated, etc. Some lysing can be performed chemically. Some lysing can be performed with an ultrasonic emitter. In some embodiments, the components of the sample are separated by centrifuging for a period of time before measurements are performed by the optical system 412. For example, a fluid sample (e.g., a blood sample) can be centrifuged at a relatively high speed. The sample can be spun at a certain number of revolutions per minute (RPM) for a given length of time to separate blood plasma for spectral analysis. In some embodiments, the fluid sample is spun at about 7200 RPM. In some embodiments, the sample is spun at about 5000 RPM. In some embodiments, the fluid sample is spun at about 4500 RPM. In some embodiments, the fluid sample is spun at more than one rate for successive time periods. The length of time can be approximately 5 minutes. In some embodiments, the length of time is approximately 2 minutes. Separation of a sample into the components (or other sample conditioning) can permit measurement of solute (e.g., glucose) concentration in plasma, for example, without interference from other blood components. Post-separation measurement can have advantages over a solute measurement taken from whole blood because the proportions of plasma to other components need not be known or estimated in order to infer plasma glucose concentration. In some embodiments, the separated plasma can be analyzed electrically using one or more electrodes instead of, or in addition to, being analyzed optically. This analysis may occur within the same device, or within a different device. For example, in certain embodiments, an optical analysis device can condition a sample (e.g., separate blood into components), analyze the sample, and then allow the sample and/or components thereof to be transported to another analysis device that can further analyze the sample and/or components (e.g., using electrical and/or electrochemical measurements).
Certain embodiments employ one or more enzymatic sensors to obtain measurements of one or more analytes within the fluid sample. In such embodiments a centrifuge and/or other means for plasma separation can be omitted. Fluid conditioning can include adding an anticoagulant, such as, for example, heparin, to the sample to prevent clotting. The fluid-handling system 404 can be used with a variety of anticoagulants, including anticoagulants supplied by a hospital or other user of the monitoring system 400. In some embodiments, no anticoagulant is necessary and is avoided such that blood can be returned to a patient after measurement. A detergent solution formed by mixing detergent powder from a pouch connected to the fluid-handling system 404 with saline can be used to periodically clean residual protein and other sample remnants from one or more components of the fluid-handling system 404, such as the sample holder. Sample fluid to which anticoagulant has been added and used detergent solution can be transferred into the waste bladder.
The system 400 shown in
In some embodiments, an optical system 412 includes a filter wheel that contains one or more filters. In some embodiments, more than ten filters can be included, for example twelve or fifteen filters. In some embodiments, more than 20 filters (e.g., twenty-five filters) are mounted on the filter wheel. The optical system 412 includes a light source that passes light through a filter and the sample holder to a detector. In some embodiments, a stepper motor moves the filter wheel in order to position a selected filter in the path of the light. An optical encoder can also be used to finely position one or more filters. In some embodiments, one or more tunable filters may be used to filter light into multiple wavelengths. The one or more tunable filters may provide the multiple wavelengths of light at the same time or at different times (e.g., sequentially). In some advantageous embodiments, no filters are needed because none, one, or very few wavelengths are required for analysis.
The light source included in the optical system 412 may emit radiation in the ultraviolet, visible, near-infrared, mid-infrared, and/or far-infrared regions of the electromagnetic spectrum. In some embodiments, the light source can be a broadband source that emits radiation in a broad spectral region (e.g., from about 1500 nm to about 6000 nm). In other embodiments, the light source may emit radiation at certain specific wavelengths. The light source may comprise one or more light emitting diodes (LEDs) emitting radiation at one or more wavelengths in the radiation regions described herein. In other embodiments, the light source may comprise one or more laser modules emitting radiation at one or more wavelengths. The laser modules may comprise a solid state laser (e.g., a Nd:YAG laser), a semiconductor based laser (e.g., a GaAs and/or InGaAsP laser), and/or a gas laser (e.g., an Ar-ion laser). In some embodiments, the laser modules may comprise a fiber laser. The laser modules may emit radiation at certain fixed wavelengths. In some embodiments, the emission wavelength of the laser module(s) may be tunable over a wide spectral range (e.g., about 30 nm to about 100 nm). In some embodiments, the light source included in the optical system 412 may be a thermal infrared emitter. The light source can comprise a resistive heating element, which, in some embodiments, may be integrated on a thin dielectric membrane on a micromachined silicon structure. In one embodiment the light source is generally similar to the electrical modulated thermal infrared radiation source, IRSource™, available from the Axetris Microsystems division of Leister Technologies, LLC (Itasca, Ill.).
The optical system 412 can be controlled by an optical system controller 413. The optical system controller can, in some embodiments, be integrated into the optical system 412. In some embodiments, the fluid system controller 405 and the optical system controller 413 can communicate with each other as indicated by the line 411. In some embodiments, the function of these two controllers can be integrated and a single controller can control both the fluid-handling system 404 and the optical system 412. Such an integrated control can be advantageous because the two systems are preferably integrated, and the optical system 412 is preferably configured to analyze the very same fluid handled by the fluid-handling system 404. Indeed, portions of the fluid-handling system 404 (e.g., the sample holder described above with respect to the second disposable subsystem 410 and/or at least some components of a centrifuge) can also be components of the optical system 412. Accordingly, the fluid-handling system 404 can be controlled to obtain a fluid sample for analysis by optical system 412, when the fluid sample arrives, the optical system 412 can be controlled to analyze the sample, and when the analysis is complete (or before), the fluid-handling system 404 can be controlled to return some or all of the sample to the fluid source 402 and/or discard some of the sample, as appropriate.
The system 400 shown in
The system 400 shown in
The user interface 2400 can include an analyte concentration status graphic 2414 that indicates status of the patient's current analyte concentration compared with a reference standard. For example, the analyte may be glucose and/or lactate, and the reference standard may be a hospital ICU's tight glycemic control (TGC). In
In various implementations of the user interface 2400 a characteristic of the status graphic 2408 or 2412 displaying the concentration of the analyte can be varied (or otherwise emphasized) if the concentration of the analyte is predicted to be outside the acceptable bounds of the reference standard at a future time (e.g., less than or equal to about 5 minutes, less than or equal to about 10 minutes, less than or equal to about 15 minutes, less than or equal to about 20 minutes, less than or equal to about 30 minutes, less than or equal to about 45 minutes, less than or equal to about 60 minutes, less than or equal to about 90 minutes, less than or equal to about 120 minutes, etc.). The characteristic of the status graphic 2408 or 2412 can be a foreground and/or a background color. The characteristic of the status graphic 2408 or 2412 can be a visual state.
Various visual, auditory or other sensory approaches can be used to call attention to the display or a portion of the display. It can be advantageous to reduce anxiety of a patient while at the same time increasing awareness by a health-care provider. Such targeted but discrete emphasis can be accomplished, for example, by using visual cues that a health-care provider understands, but that do not add auditory alarms. Nevertheless, auditory alarms can be used for some particularly urgent circumstances. Visual emphasis effects can include foreground, background, or text colors, bright hues, increased color saturation or intensity, high contrast with surrounding visual colors, movement, animation, or dynamic displays, etc. Colors used can take advantage of existing or standardized cultural and/or medical meanings. For example, yellow can be a highly visual color that signifies caution but not an emergency. Red can signal something undesirable (or something that should be stopped), while green can signal something that is not dangerous or that is proceeding normally. These same colors can have other meanings in this or other contexts. Relative size or positioning of visual information can also be used for emphasis or de-emphasis. Larger symbols can call attention to more urgent or relevant information. In some embodiments, some colors (e.g., red and green) can be used for information about a current analyte value, while another color (e.g., yellow) can be used for information about a predicted or projected analyte value. Color, intensity, emphasis, etc. can change depending on the calculated certainty or uncertainty, and/or relative immediacy of a prediction, etc. These principles can apply to trend lines and other styles of data display (including tabular and bar graph displays, status graphics 2408 and 2412, etc. Three dimensional displays (with shading, contoured surfaces, multiple axes, movement into the screen to indicate forward movement in time, etc.) can be used and navigated using the user interface when multiple variables are being depicted.
For example, the status graphic 2408 or 2412 can have different foreground and/or background colors if the concentration of the analyte is predicted to be outside the acceptable bounds of the reference standard at a future time. For example, the status graphic 2408 or 2412 can have a yellow or an orange background color if the concentration of the analyte is predicted to be outside the acceptable bounds of the reference standard at a future time. The future time can be displayed, it can be adjustable, it can be modified through the display, and/or it can be set at a standard future time like 10 minutes, 30 minutes, 1 hour, 2 hours, etc. As another example, the status graphic 2408 or 2412 can have a green background or foreground color if the concentration of the analyte at the current measurement time and the predicted value for the concentration of the analyte at the future time is within the acceptable bounds of the reference standard. As yet another example, the status graphic 2408 or 2412 can be configured to blink and/or flash if the concentration of the analyte is predicted to be outside the acceptable bounds of the reference standard at a future time. Thus, for example, a nurse can be efficiently notified to change an insulin delivery rate based on measure glucose value and calculated or predicted rate of change.
For instance, the concentration of the analyte measured at the current measurement time may be within the acceptable bounds of the reference standard. However, if the value of the concentration of the analyte predicted to be outside the acceptable bounds of the reference standard at a future time (e.g., less than or equal to about 5 minutes, less than or equal to about 10 minutes, less than or equal to about 15 minutes, less than or equal to about 20 minutes, less than or equal to about 30 minutes, less than or equal to about 45 minutes, less than or equal to about 60 minutes, less than or equal to about 90 minutes, less than or equal to about 120 minutes, etc.), then the status graphic 2408 or 2412 can be emphasized according to the principles described herein (e.g., have a yellow or an orange background color and/or be configured to blink and/or flash, etc.) to indicate to the health care provider that the concentration of the analyte may be dangerous in the future, or outside an acceptable range of a reference standard. Accordingly, a health care provider (e.g., a doctor, a nurse or a care giver) can be alerted to change the dose of an infusion substance (e.g., insulin or dextrose) based on a dosing protocol to avoid concentration of the analyte from being outside the acceptable bounds of the reference standard at the future time. In various implementations, a patient monitoring system (e.g., system 400 of
The predicted value of the concentration of the analyte at a future time can be calculated using instructions stored in a processor (e.g., algorithm processor 416 of system 400 or the computer system 2646 of the system 2630) of a patient monitoring system (e.g., system 400 of
The predicted value of the concentration of the analyte at a future time can be determined from one or more previous measurements of the analyte concentration. For example, various systems and methods of determining the predicted value of the concentration of the analyte at a future time as described in U.S. patent application Ser. No. 12/249,831 (Atty. Docket No. OPTIS.203A) and Ser. No. 12/559,328 (Atty. Docket No. OPTIS.247A)—the entire disclosures of which are incorporated herein by reference, for all purposes—can be employed to determine predicted value of the concentration of the analyte at a future time.
As another example, the predicted value of the concentration of the analyte at a future time can be determined from a rate of change in the concentration of the analyte calculated based on one or more previous measurements of the analyte concentration. For instance, the average rate of change in the concentration of the analyte over a past certain period of time (e.g., about 10 minutes, about 20 minutes, about 30 minutes, about 45 minutes, about 1 hour, etc.) can be determined and the value of the concentration of the analyte in the next certain period of time (e.g., about 10 minutes, about 20 minutes, about 30 minutes, about 45 minutes, about 1 hour, etc.) can be calculated assuming a predicted rate of change of concentration that is proportional to the determined average rate of change in the concentration of the analyte. In various implementations, the predicted rate of change of concentration can depend on the average rate of change in the concentration of the analyte over a past certain period of time and a dose of the infusion substance (e.g., insulin or dextrose) in that period of time.
In various implementations, the predicted rate of change of concentration can be depend on a first average rate of change in the concentration of the analyte over a first time interval previous to the current measurement time, a second average rate of change in the concentration of the analyte over a second time interval previous to the current measurement time, a third average rate of change in the concentration of the analyte over a third time interval previous to the current measurement time and so on. Additionally, the predicted rate of change of concentration can be depend on a first dose of the infusion substance (e.g., insulin or dextrose) in the first time interval, a second dose of the infusion substance in the second time interval, a third dose of the infusion substance in the second time interval and so on.
As another example, the predicted value of the concentration of the analyte at a future time can be determined from a trend in the values of the concentration of the analyte obtained in one or more previous measurements of the analyte concentration. For instance, the predicted value of the concentration of the analyte at a future time can be determined from a slope of the curve of at least two values of the concentration of the analyte obtained at a time previous to the current measurement time.
In various implementations, the patient monitoring system can be configured to determine the concentration of the analyte at time t1 and rate of change of concentration of the analyte from a previous measurement time t0 and calculate the predicted value of the concentration at a future time tn. The patient monitoring system can be configured to subsequently determine the concentration of the analyte at time t2 and rate of change of concentration of the analyte from the previous measurement time t1 and refine the predicted value of the concentration at the future time tn. In this manner the predicted value of the concentration at the future time tn can be calculated and refined on a moving window basis based on the rate of change in the concentration of the analyte at the current measurement from a previous measurement time. Such a moving window can advantageously “move” in sync with the advance of actual time by having an initial window opening and final window closing time, each of which is prescribed to be a fixed amount of time into the future. The window's parameters (e.g., the width of the window, its distance into the future from the present time, statistical error associated with the data it displays, etc.) can be adjusted by a user, or they can be set (e.g., by a manufacturer) to avoid confusion.
Various embodiments and aspects of this disclosure can be combined, in particular those referring to a graphic user interface. Accordingly, the disclosure herein relating to visual emphasis of predicted future values can be combined with the disclosure relating to adding annotations to a computer memory using a touch-screen with bookmarks and visual flags indicating when a note has been entered by a user. Thus, a flashing yellow indicator can be annotated (and the time stamp of the annotation, the identity of the source of the note, etc. can be recorded) when a doctor or nurse wishes to record that the alert was noticed but ignored or overridden because of a factor that does not play a part in the automatic machine algorithm that led to the alert. Other synergies existing between various aspects of the disclosure herein relating to user interfaces, displays and interactions therewith, and the ability of a system to provide accurate analyte information and projections.
The user interface 2400 can include one or more trend indicators 2416 that provide a graphic indicating the time history of the concentration of an analyte of interest. In
The user interface 2400 can include one or more buttons 2420-2426 that can be actuated by a user to provide additional functionality or to bring up suitable context-sensitive menus and/or screens. For example, in the embodiments shown in
The button 2422 (“Pause”) may be actuated by the user if patient monitoring is to be interrupted but is not intended to end. For example, the “Pause” button 2422 may be actuated if the patient is to be temporarily disconnected from the system 400 (e.g., by disconnecting the tubes 306). After the patient is reconnected, the button 2422 may be pressed again to resume monitoring. In some embodiments, after the “Pause” button 2422 has been pressed, the button 2422 displays “Resume.”
The button 2424 (“Delay 5 Minutes”) causes the system 400 to delay the next measurement by a delay time period (e.g., 5 minutes in the depicted embodiments). Actuating the delay button 2424 may be advantageous if taking a reading would be temporarily inconvenient, for example, because a health care professional is attending to other needs of the patient. The delay button 2424 may be pressed repeatedly to provide longer delays. In some embodiments, pressing the delay button 2424 is ineffective if the accumulated delay exceeds a maximum threshold. The next-reading graphic 2410 automatically increases the displayed time until the next reading for every actuation of the delay button 2424 (up to the maximum delay).
The button 2426 (“Dose History”) may be actuated to bring up a dosing history window that displays patient dosing history for an analyte or medicament of interest. For example, in some embodiments, the dosing history window displays insulin dosing history of the patient and/or appropriate hospital dosing protocols. A nurse attending the patient can actuate the dosing history button 2426 to determine the time when the patient last received an insulin dose, the last dosage amount, and/or the time and amount of the next dosage. The system 400 may receive the patient dosing history via wired or wireless communications from a hospital information system.
In other embodiments, the user interface 2400 can include additional and/or different buttons, menus, screens, graphics, etc. that are used to implement additional and/or different functionalities.
Some embodiments of the systems described herein (e.g., the system 400), as well as some embodiments of each method described herein, can include a computer program accessible to and/or executable by a processing system, e.g., a one or more processors and memories that are part of an embedded system. Indeed, the controllers may comprise one or more computers and/or may use software. Thus, as will be appreciated by those skilled in the art, various embodiments may be embodied as a method, an apparatus such as a special purpose apparatus, an apparatus such as a data processing system, or a carrier medium, e.g., a computer program product. The carrier medium carries one or more computer readable code segments for controlling a processing system to implement a method. Accordingly, various embodiments may take the form of a method, an entirely hardware embodiment, an entirely software embodiment or an embodiment combining software and hardware aspects. Furthermore, any one or more of the disclosed methods (including but not limited to the disclosed methods of measurement analysis, interferent determination, and/or calibration constant generation) may be stored as one or more computer readable code segments or data compilations on a carrier medium. Any suitable computer readable carrier medium may be used including a magnetic storage device such as a diskette or a hard disk; a memory cartridge, module, card or chip (either alone or installed within a larger device); or an optical storage device such as a CD or DVD.
The fluid cell 312 can be in communication with a fluid network 316. The fluid network 316 can include one or more tubes, fittings, pumps, fluid interfaces, valves, sensors, connectors, cleaner pouches, and/or waste bladders. The components of the disposable system 304 may share one or more features with the first disposable subsystem 408 described above with reference to
The fluid cell 312 can include one or more sensors and/or optical cells. The one or more sensors may include one or more enzymatic sensors. For example, the enzymatic sensors may include glucose and/or lactate sensors. Glucose and lactate can serve as indicators of health within a patient 324. For example, the presence of lactate above a certain threshold may indicate that a patient 324 requires urgent assistance. The fluid cell 312 can be in electrical communication with a processor 332 via a processor interface 340. The processor interface 340 may be configured to receive electrical and/or electro-chemical signals from the one or more sensors (e.g., enzymatic sensors) in the fluid cell 312.
The fluid cell 312 may also be in optical communication with the optical system 328 via an optical interface 346. The optical interface 346 may include a transparent or translucent boundary between the fluid sample and a light source. The boundary may include a portion (e.g., a body) of the fluid cell 312. For example, the fluid cell 312 may comprise a transparent material configured to allow the transmission of light therethrough. In this way, the fluid cell 312 can allow the optical system 328 to optically interrogate the fluid sample. This can serve advantageously as a non-invasive approach to determining an amount of an interferent/analyte (e.g., hemoglobin) within the fluid sample. The optical system 328 may share one or more features of the optical system 412 described above with reference to
For example, with reference to
As illustrated in
In the embodiment of the analyzer 2010 shown in
The centrifuge wheel 2050 can be spun by a centrifuge motor 2026. In some embodiments of the analyzer 2010, the fluid sample (e.g., a whole blood sample) is spun at a certain number of revolutions per minute (RPM) for a given length of time to separate blood plasma for spectral analysis. In some embodiments, the fluid sample is spun at about 7200 RPM. In some embodiments, the fluid sample is spun at about 5000 RPM or 4500 RPM. In some embodiments, the fluid sample is spun at more than one rate for successive time periods. The length of time can be approximately 5 minutes. In some embodiments, the length of time is approximately 2 minutes. In some embodiments, an anti-clotting agent such as heparin may be added to the fluid sample before centrifuging to reduce clotting. With reference to
The embodiment of the analyzer 2010 illustrated in
In some embodiments, the reference detector 2036 and the sample detector 2030 comprise broadband pyroelectric detectors. As known in the art, some pyroelectric detectors are sensitive to vibrations. Thus, for example, the output of a pyroelectric infrared detector is the sum of the exposure to infrared radiation and to vibrations of the detector. The sensitivity to vibrations, also known as “microphonics,” can introduce a noise component to the measurement of the reference and sample energy beams Er, Es using some pyroelectric infrared detectors. Because it may be desirable for the analyzer 2010 to provide high signal-to-noise ratio measurements, such as, e.g., S/N in excess of 100 dB, some embodiments of the analyzer 2010 utilize one or more vibrational noise reduction apparatus or methods. For example, the analyzer 2010 may be mechanically isolated so that high S/N spectroscopic measurements can be obtained for vibrations below an acceleration of about 1.5 G.
In some embodiments of the analyzer 2010, vibrational noise can be reduced by using a temporally modulated energy source 2012 combined with an output filter. In some embodiments, the energy source 2012 is modulated at a known source frequency, and measurements made by the detectors 2036 and 2030 are filtered using a narrowband filter centered at the source frequency. For example, in some embodiments, the energy output of the source 2012 is sinusoidally modulated at 10 Hz, and outputs of the detectors 2036 and 2030 are filtered using a narrow bandpass filter of less than about 1 Hz centered at 10 Hz. Accordingly, microphonic signals that are not at 10 Hz are significantly attenuated. In some embodiments, the modulation depth of the energy beam E may be greater than 50% such as, for example, 80%. The duty cycle of the beam may be between about 30% and 70%. The temporal modulation may be sinusoidal or any other waveform. In embodiments utilizing temporally modulated energy sources, detector output may be filtered using a synchronous demodulator and digital filter. The demodulator and filter are software components that may be digitally implemented in a processor such as the algorithm processor 416. Synchronous demodulators, coupled with low pass filters, are often referred to as “lock in amplifiers.”
The analyzer 2010 may also include a vibration sensor 2032 (e.g., one or more accelerometers) disposed near one (or both) of the detectors 2036 and 2030. The output of the vibration sensor 2032 is monitored, and suitable actions are taken if the measured vibration exceeds a vibration threshold. For example, in some embodiments, if the vibration sensor 2032 detects above-threshold vibrations, the system discards any ongoing measurement and “holds off” on performing further measurements until the vibrations drop below the threshold. Discarded measurements may be repeated after the vibrations drop below the vibration threshold. In some embodiments, if the duration of the “hold off” is sufficiently long, the fluid in the sample cell 2030 is flushed, and a new fluid sample is delivered to the cell 2030 for measurement. The vibration threshold may be selected so that the error in analyte measurement is at an acceptable level for vibrations below the threshold. In some embodiments, the threshold corresponds to an error in glucose concentration of 5 mg/dL. The vibration threshold may be determined individually for each filter 2015.
Certain embodiments of the analyzer 2010 include a temperature system (not shown in
The reference detector can be used to perform a check on the optical measurement path, for example, when saline, or another reference fluid is in the flow cell. For example, if a window on the flow cell were to become dirty, or light along the optical measurement path were otherwise obstructed, the measurement detector would see a reduced amount of light transmitted, while the reference detector would detect no reduction in light intensity. When the difference between light received by the measurement detector and the reference detector is different than an expected amount, the system can indicate that that optical system may have a problem. The reference detector can be used to perform a check on the light source. For example, if the reference detector detects a light intensity below a threshold value, or above a threshold value, or different than an expected value or range, or if the detected light intensity changes, the system can indicate that the light source may have a problem. In some embodiments, the system can use information from both the measurement detector and the reference detector in making the analyte concentration determinations. This can compensate for variations in the light source output. For example, if the light source outputs a reduced light intensity, the measurement detector can detect a corresponding reduced light intensity. If the system did not use information from the reference detector, the reduced light intensity measured by the measurement detector could result in an inaccurate analyte concentration determination. The reference detector can also detect a reduced light intensity, and the system can use make the analyte concentration determination based at least in part on the information from both detectors. In some cases a ratio or comparison between the light intensities detected by the measurement detector and the reference detector can be used in making the analyte concentration determination.
A fluid network interface 344 may allow the disposable system 304 to communicate with the network controller 336. This may allow one or more sensors within the fluid analysis system 300 to determine one or more measurements associated with the fluid sample. For example, the patient connector 320 may include a temperature sensor that identifies a temperature of the fluid sample near the source. In this way, for example, the fluid analysis system 300 can monitor (e.g., continuously, periodically, or intermittently) the temperature of the fluid in the patient 324. In some cases, a wire or wires can be embedded in a wall or walls of the tube, which can enable communication (or other electrical transfer) between the temperature sensor and the main system 308 (e.g., via the network or other controller). The system can monitor the temperature of the fluid (e.g., being drawn through the connector 320). Incorporating electrical leads, wires, or other elements configured for electrical power or other signal transmission can assist in allowing various fluidly-connected elements to also be electrically connected. Thus, a fluid connector that interfaces with a patient-connected line (e.g., a central-venous catheter or peripheral intravenous catheter) can be employed as (or can incorporate) a temperature sensor because it is closer to a patient's body and receives blood most directly and immediately from a patient when blood is drawn. After blood has been drawn for a given amount of time, it can have a warming effect on the connector or other surrounding structure. Initially, the monitored temperature can rise as fluid is drawn from the patient, and the temperature change can slow or stop after a time, indicating that the measurement temperature is approximately the same as the patient's body temperature. It can be helpful to insulate any electrical leads, metal, or other electrically conductive components from blood or fluid within a tube, to reduce risk that electrical current flows to or through a patient in harmful ways. It can also be useful to use low voltages and/or currents for safety and conservation reasons.
Additionally or alternatively, the network controller 336 may receive input from one or more bubble sensors and/or pressure sensors. These and other sensors described herein can be located in the disposable system 304, in the main system 308, or they can include components in both systems. In advantageous embodiments, a more expensive and long-lasting portion of such a sensor is located in the main system and less-expensive portions (and/or those configured for fluid contact) are positioned in the disposable system 304. In many cases The one or more bubble sensors can indicate whether a bubble has arrived within the fluid network 316. The one or more pressure sensors may provide a pressure reading at one or more points within the fluid network 316 (e.g., at tube junctions/intersections). Any bubble and/or pressure sensors included in the fluid analysis system 300 may share one or more features with those described above with reference to
The fluid analysis system 300 may be configured to measure the pressure in the fluid network 316 periodically, e.g., by using one or more pressure sensors in fluid communication with the fluid network 316. The at least one pressure sensor can monitor the pressure by measuring the pressure in the fluid handling network regularly (e.g., once every minute, once every thirty seconds, once every fifteen seconds, once every five seconds, once every two seconds, once every second, twice per second, three times per second, five times per second, ten times per second, etc.), on a substantially continuous basis, or by a single measurement.
A system interface 348 may be included in the fluid analysis system 300 to allow for communication between the disposable system 304 and the permanent system 308. For example, electrical communication may be initiated and maintained between the systems. Other types of communication (e.g., mechanical) are contemplated. For example, the system interface 348 may include various attachment mechanisms (e.g., snap fits, friction fits, locking features, adhesives, etc.). Electrical contact points for transferring or conveying current associated with an enzymatic sensor can be engineered to create a consistent, snug, reproducible, electrically sound connection. For example, these contact points can include one or more resilient members that exert force against other surfaces or objects. Sufficient electrical contact can be confirmed using a test current and an alarm can notify a user when electrical contact is inadequate. Mechanical resilience can be provided using metal springs or members biased using resilient rubber, plastic, composite, or other materials. Sliding or hinging contact can be created such that closing of a door, drawer, latch provides electrical contact. Any component (not just an enzymatic sensor) can be configured to incorporate electrical current such that electrical connection can benefit its function, for example, for diagnostic, control, monitoring, or troubleshooting purposes.
Fluid (e.g., blood) may be received through a patient connector 512 into the fluid analysis system 500. One or more pumps (e.g., a saline pump 535) may provide negative pressure within the fluid analysis system 500 to promote the intake of the fluid. The saline pump 535 may provide negative pressure in conjunction with the opening and closing of certain valves. For example, to draw fluid through the patient connector 512, a valve 540 (V6) may be closed while a valve 542 (V5) may remain open. Other valves 528, 532 (V1, V3) may be closed while the valves 526, 530 (V2, V4) may be opened. Each discrete fluid sample may be relatively small in order that a total volume of blood drawn may be reduced, thus preventing a need for blood transfusions into the patient. For example, the fluid analysis system 500 can be configured to draw between about 50 μL and 800 μL. The fluid analysis system 500 may preferably draw between about 100 μL and 350 μL in each sample. In some embodiments, the fluid analysis system 500 is configured to draw about 170 μL in each sample.
Advantageously the fluid analysis system 500 can be configured to return some or all of the sample to the patient. This can mitigate the need for blood transfusions to replace lost blood during the operation of the fluid analysis system 500. Moreover, this can reduce the need for disposing of the fluid, e.g., in a waste bladder or some other waste container. Hospitals can benefit from reducing costs and risks of biohazardous material disposal. Returning a larger portion of drawn blood can also allow for more frequent, or even steady or continuous blood withdrawal and analysis because the net blood loss may be zero or negligible. Advantageously the fluid analysis system 500 can be configured to return the fluid to the patient within a threshold time. The threshold time may be between about 20 seconds and 160 seconds. The fluid analysis system 500 may preferably return the fluid to the patient within a threshold time of between 45 seconds and 60 seconds. Fluid return to a patient can be especially useful if the fluid (e.g., blood) is treated gently while it is outside a patient. This can include limiting any additives (e.g., using innocuous substances such as saline) and avoiding inclusion of potentially harmful substances such as heparin. This can also include avoiding lysing, separation, coagulation, stacking, and the like. Gentle treatment can also include structures that reduce or minimize turbulence and improve laminar flow. The dimensions of any flow passages and/or flow cells can be large enough to allow blood particles to flow smoothly and avoid occlusions. Fluid flow can be generally steady to avoid stagnation and clotting, for example. In embodiments that do not centrifuge or lyse blood cells, for example, but rather filter, apply glucose-oxidase reactions, and/or apply electric voltages, the blood and any by-products of the measurement process can be returned to a patient.
The fluid sample may be returned to the patient in a number of ways. For example, the fluid analysis system 500 may be configured to close one or more valves, such as the valve 532, the valve 528, and the valve 540. A pump (e.g., the saline pump 535) may be configured to create a positive pressure on the fluid to push it back to the patient. The bubble sensor 516 and/or bubble sensor 517 may be configured to identify when the fluid sample has been successfully been returned to the patient or when it has successfully exited an apparatus en route to a patient. Saline solution may be injected into the patient between each sampling of the fluid. This can maintain an opening in a fluid source within the patient (e.g., the blood vessel).
However, in some embodiments, portions of the sample that may be mixed with other materials or portions that are otherwise altered during the sampling and analysis process, or portions that, for any reason, are not to be returned to the patient, can also be placed in a waste bladder (not shown in
The optical cell 566 can be configured to interact with an optical interrogation device, not shown (e.g., in the optical system 328). The optical interrogation device can be configured to detect a presence of an interferent (e.g., hemoglobin (Hb)). The optical cell 566 can be configured to receive radiation (e.g., white light) therethrough. The fluid (e.g., blood) may absorb some of that radiation. The optical interrogation device can be configured to detect a transmission of radiation through the flow cell 560. The optical interrogation device can be configured to detect multiple aspects related to the interferent. For example, the optical interrogation device can be configured to detect various variants of hemoglobin or related interferents (e.g., oxyhemoglobin, deoxyhemoglobin, methemoglobin, carboxyhemoglobin, sulfhemoglobin, etc.). Absorption data can be obtained for one or more of the interferents and submitted to a processor (e.g., the processor 332). In some embodiments, the system can be configured to display one or more of these absorption data, such as in one or more absorption spectra. Other data may be displayed as well, such as one or more levels of the analytes detected as described herein. Some embodiments allow for measurement of Hemoglobin (Hb) in whole blood (blood that has not been separated, e.g., by centrifugation or lysing). Such measurement can occur using optical systems and methods, for example, with a device that measures red wavelengths and/or a wavelength corresponding to Hb. For example, a full spectrum spectrometer can be used with a broadband light source and absorption at multiple wavelengths can be used to determine an amount of total hemoglobin (tHb). For example, absorption at multiple wavelengths corresponding to different types of hemoglobin (e.g., oxyhemoglobin, deoxyhemoglobin, methemoglobin, carboxyhemoglobin, sulfhemoglobin, etc.) can be added combined or processed (optically and/or algorithmically) to determine tHb.
It may be advantageous to cause the flow of the fluid to occur at a particular rate. Exertion of fluid pressure on a system using a syringe pump, for example, can assist in achieving steady, rapid fluid flow. These conditions are often preferred to rapidly varying and/or slower flow rates. For example, optical measurements may be more reliable if the fluid flows at a rate that will allow the fluid (e.g., blood) to prevent non-ideal fluid conditions (e.g., nonlinear fluid effects, stacking of red blood cells). These effects can cause undue scatter and/or transmission of the radiation and result in unreliable or inaccurate measurement data. For example, the system can be configured to move fluid through the flow cell at a flow rate of 0.05 feet per second, 0.1 feet per second, 0.25 feet per second, 0.5 feet per second, 0.75 feet per second, 1 feet per second, 1.25 feet per second, 1.5 feet per second, 1.75 feet per second, 2 feet per second, or any values therebetween, or any ranges bounded by any combination of these values, although other flow rates can be used in some implementations. The system can be configured to provide a flow rate that varies by no more than 0.1 feet per second, 0.2 feet per second, 0.3 feet per second, 0.4 feet per second, 0.5 feet per second, 0.6 feet per second, 0.7 feet per second.
An optical system can be used for detection of blockages or abnormalities within a flowing system. An optical signal from a system trained on a flowing passage can typically fluctuate—for example, if the materials within the flowing fluid have varying shapes, densities, concentrations, and/or other optical properties. However, if this normal range of fluctuation stops and the signal becomes steady, this can indicate that a blockage has occurred and flow has slowed or stopped. A detected optical signal can also increase, which can indicate that red blood cells are stacking or otherwise clumping in a biological process such as clotting. Thus, optical outputs can be useful in diagnosing and assessing fluid flow in systems such as those described here. Thus, presence of an optical system can reduce the number of other sensors needed in an overall system because algorithms can be employed to accomplish more than one assessment function based on a single stream of data, for example. In
The glucose sensor 568 can be configured to detect a presence and/or level of glucose within the fluid. The glucose sensor 568 may comprise a glucose membrane and/or a glucose enzyme (e.g., glucose oxidase (GOx)15). The glucose membrane and/or glucose enzyme may be housed in a slot or receptacle within the flow cell 560. The slot can be configured to allow the fluid to pass over the glucose sensor 568 for a sufficient time to get an accurate reading of the glucose level in the fluid. However, it may also be advantageous to avoid allowing the fluid to slow or stop for too long in order to avoid negative effects in the fluid, such as clotting of blood. For example, the fluid analysis system 500 may be configured to allow the fluid sample to pass over the glucose sensor 568 for between about 1 and 8 seconds. In some embodiments, the fluid analysis system 500 is configured to allow the fluid sample to pass over the glucose sensor 568 for between 2 and 4 seconds. Sensors can have different times for saturation or other reading thresholds to be achieved. The glucose sensor 568 can be configured to allow plasma and glucose to pass through a membrane. Additionally or alternatively, the glucose sensor 568 can be configured to gather reliable measurements of a level of glucose within the fluid within a threshold time. The threshold time may be between 30 seconds and 90 seconds. In some embodiments, the threshold is one minute, such that measurements can be obtained in under one minute.
The lactate sensor 564 may be configured to detect a presence and/or level of lactate within the fluid. The detection and indication of lactate levels can provide many benefits for health care providers. Lactate levels may indicate whether a patient requires urgent medical attention. For example, higher than normal lactate levels can indicate the presence of a serious (even life-threatening) problem needing immediate intervention. The lactate sensor 564 may comprise a lactate membrane and/or a lactate enzyme (e.g., lactate oxidase (LOx)). The lactate membrane and/or lactate enzyme may be housed in a slot or receptacle within the flow cell 560. The slot can be configured to allow the fluid to pass over the lactate sensor 564 for a sufficient time to get an accurate reading of the glucose level in the fluid. The fluid analysis system 500 may be configured to allow the fluid sample to pass over the lactate sensor 564 for between about 1 and 8 seconds. In some embodiments, the fluid analysis system 500 is configured to allow the fluid sample to pass over the lactate sensor 564 for between 2 and 4 seconds (or within another acceptable range). The lactate sensor 564 can be configured to allow plasma and lactate to pass through the glucose membrane. Additionally or alternatively, the lactate sensor 564 can be configured to gather reliable measurements of a level of glucose within the fluid within a threshold time. The threshold time may be between 20 seconds and 120 seconds. In some embodiments, the threshold is one minute, such that measurements can be obtained in under one minute.
The flow cell 560 may comprise an optically transmissive portion. The flow cell 560 may be formed of an optically transmissive material, such as a plastic or other polymer (e.g., TOPAS® COC plastic). The flow cell 560 may comprise a portion that can be in optical communication with an optical interrogation system (e.g., the optical system 328 of
The fluid analysis system 500 can include a blood sample detection sensor 554. The blood sample detection sensor 554 can be disposed in fluid series with the flow cell 560. As shown, the blood sample detection sensor 554 is disposed such that the fluid reaches the blood sample detection sensor 554 after it passes through the flow cell 560.
Advantageously the enzymatic fluid analysis system 500 can include a flow path extension 550. The flow path extension 550 can allow the enzymatic fluid analysis system 500 to draw fluid steadily and/or continuously. This can help prevent various problems during sampling of the fluid (e.g., blood clotting, nonlinear fluid dynamic issues). Additionally or alternatively, the flow path extension 550 can permit the steady draw of the fluid without allowing the fluid sample to flow beyond a valve 542 and/or a connector C2. This can prevent blood from entering a tube configured only for saline (e.g., saline pump tube 580). The flow path extension 550 can comprise tubing of a threshold length. The threshold length can be between about 5 feet and 45 feet. In some embodiments, the threshold length is about 20 feet. For example, 20 feet has been found to be particularly advantageous in certain embodiments to allow for the benefits described above while minimizing excess tubing. The inner diameter of the tubing can be between 500 μm and 1800 μm. In some embodiments, the inner diameter is about 1000 μm.
The fluid analysis system 500 may further include a saline source 546 and/or a saline pump 535. At the start of a measurement cycle, various lines, including a saline source tube 578, a flow cell tube 582, the flow cell 560, a delivery tube 584, and an intake tube 536 can be filled with saline that can be introduced into the system through the saline source tube 578, and which can come from the saline source 546 and/or drawn using a saline pump 535. The saline pump 535 and/or the saline source 546 can be provided separately from the fluid analysis system 500. For example, a hospital can use existing saline bags and infusion pumps to interface with the described system. Alternatively, the saline pump 535, for example, may be formed as part of the fluid analysis system 500.
In some embodiments, it may be advantageous to control a level of an analyte (e.g., glucose) in a patient using an embodiment of the fluid analysis system 500 described herein. Although certain examples of glucose control are described below, embodiments of the systems and methods disclosed herein may be used to monitor and/or control other analytes (e.g., lactate).
For example, diabetic individuals control their glucose levels by administration of insulin. If a diabetic patient is admitted to a hospital or ICU, the patient may be in a condition in which he or she cannot self-administer insulin. Advantageously, embodiments of the analyte detection systems disclosed herein may be used to control the level of glucose in the patient. Additionally, it has been found that a majority of patients admitted to the ICU exhibit hyperglycemia without having diabetes. In such patients it may be beneficial to monitor and control their blood glucose level to be within a particular range of values. Further, it has been shown that tightly controlling blood glucose levels to be within a stringent range may be beneficial to patients undergoing surgical procedures.
A patient admitted to the ICU or undergoing surgery may be administered a variety of drugs and fluids such as Hetastarch, intravenous antibiotics, intravenous glucose, intravenous insulin, intravenous fluids such as saline, etc., which may act as interferents and make it difficult to determine the blood glucose level. Moreover, the presence of additional drugs and fluids in the blood stream may require different methods for measuring and controlling blood glucose level. Also, the patient may exhibit significant changes in hematocrit levels due to blood loss or internal hemorrhage, and there can be unexpected changes in the blood gas level or a rise in the level of bilirubin and ammonia levels in the event of an organ failure. Embodiments of the systems and methods disclosed herein advantageously may be used to monitor and control blood glucose (and/or other analytes) in the presence of possible interferents to estimation of glucose and for patients experiencing health problems.
In some environments, Tight Glycemic Control (TGC) can include: (1) substantially continuous monitoring (which can include periodic monitoring, at relatively frequent intervals of every 1, 5, 15, 30, 45, and/or 60 minutes, for example) of glucose levels; (2) determination of substances that tend to increase glucose levels (e.g., sugars such as dextrose) and/or decrease glucose levels (e.g., insulin); and/or (3) responsive delivery of one or more of such substances, if appropriate under the controlling TGC protocol. For example, one possible TGC protocol can be achieved by controlling glucose within a relatively narrow range (for example between 70 mg/dL to 110 mg/dL). As will be further described, in some embodiments, TGC may be achieved by using an analyte monitoring system to make continuous and/or periodic but frequent measurements of glucose levels.
In some embodiments, the analyte detection system schematically illustrated in
In an example of glycemic control, a system can be used to determine and monitor the concentration of glucose in the sample. If the concentration of glucose falls below a lower threshold, glucose from an external source can be supplied. If the concentration of glucose increases above an upper threshold, insulin from an external source can be supplied. In some embodiments, glucose or insulin may be infused in a patient continuously over a certain time interval or may be injected in a large quantity at once (referred to as “bolus injection”).
In some embodiments, a glycemic control system may be capable of delivering glucose, dextrose, glycogen, and/or glucagon from an external source relatively quickly in the event of hypoglycemia. As discussed, embodiments of the glycemic control system may be capable of delivering insulin from an external source relatively quickly in the event of hyperglycemia.
Returning to
As schematically illustrated in
In an example implementation for glycemic control, if the analyte detection system determines that the level of glucose has fallen below a lower threshold value (e.g., the patient is hypoglycemic), a control system (e.g., the fluid system controller 405 in some embodiments) controlling an infusion delivery system may close the pinch valve to prevent infusion of insulin and/or saline into the patient. The control system may open the pinch valve 2786 and insulin solution from the insulin source 548 can be infused (or alternatively injected as a bolus) into the patient. After a suitable amount of solution has been infused to the patient, the pinch valve can be closed. In some systems, the amount of solution for infusion (or bolus injection) may be calculated based on one or more detected concentration levels of glucose. [0276] If the analyte detection system determines that the level of glucose in the fluid (e.g., by detection by the flow cell 560) has increased above an upper threshold value (e.g., the patient is hyperglycemic), the control system may prevent infusion of saline into the patient. The control system may open the pinch valve (e.g., the valve 528), and insulin can be infused (or alternatively injected as a bolus) into the patient. After a suitable amount of insulin has been infused (or bolus injected) to the patient, the control system can close the pinch valve and open the valve 526 and/or the valve 530 to allow flow of saline. The suitable amount of insulin may be calculated based on one or more detected concentration levels of glucose in the patient. The insulin source 548 advantageously may be located at a short enough fluidic distance from the patient such that insulin can be delivered to the patient within about one to about ten minutes. In other embodiments, the insulin source 518 may be located at the site where the patient tube 512 interfaces with the patient so that insulin can be delivered to the patient within about one minute.
In some embodiments, sampling bodily fluid from a patient and providing medication to the patient may be achieved through the same lines of the fluid handling system. For example, in some embodiments, a port to a patient can be shared by alternately drawing samples and medicating through the same line. In some embodiments, a bolus can be provided to the patient at regular intervals (in the same or different lines). For example, a bolus of insulin can be provided to a patient after meals. In embodiments comprising a shared line, a bolus of medication can be delivered when returning part of a body fluid sample back to the patient. In some implementations, the bolus of medication is delivered midway between samples (e.g., every 7.5 minutes if samples are drawn every 15 minutes). In other embodiment, a dual lumen tube can be used, wherein one lumen is used for the sample and the other lumen to medicate. In yet another embodiment, an analyte detection system (e.g., an “OptiScanner®” monitor) may provide suitable commands to a separate insulin pump (on a shared port or different line).
The fluid cell component 600 can define an axis A as shown. The axis A may run from a first end 612 to a second end 616. The fluid cell component 600 can include a first approach 624 and a second approach 628 opposite the first approach 624. The approaches 628, 624 may include an inner radius (as measured perpendicular to the axis A) that is greater than an inner radius of corresponding inlets/outlets 632, 636. Fluid may flow from the first approach 624 into the first inlet/outlet 632. From the first inlet/outlet 632, the fluid sample may pass through a first transition portion 640 into a main cell chamber 648. The main cell chamber 648 may include a first slot 652. As described in more detail herein, the first slot 652 may be configured to house an enzymatic sensor (e.g., glucose sensor, lactate sensor).
The fluid cell component 600 can include various features to aid in assembling the final flow cell. For example, a protruding portion 604 can be included within a body of the flow cell and/or outside a portion where fluid may be configure to flow. The protruding portion 604 can be configured to be inserted into a corresponding receiving portion 608 of a second fluid cell component 600. This connection may be a friction attachment, an adhesive attachment, a snap fit, and/or other means for attaching the two fluid cell components 600 together. A first adhesive inlet 620 can be configured to allow for the insertion of adhesive between two fluid cell components 600, as is discussed in more detail below. The fluid cell component 600 can be molded and/or may comprise an optically transmissive material (e.g., plastic or other compound).
The assembled fluid cell 660 can be configured to receive the fluid sample through the fluid inlet 670. An inner diameter of the fluid inlet 670 can be configured to be the same as an inner diameter of one or more tubes in the system (e.g., the flow cell tube 582, the delivery tube 584 of
Flow of the fluid can pass from the fluid inlet 670 to the first fluid profile modifier 676. The first fluid profile modifier 676 can have a constant cross-sectional area at one or more points along axis A. In some cases, the first fluid profile modifier 676 can have a constant cross-sectional area along a majority of, or along the full length of, the profile modifier 676. A constant cross-sectional area as described can mitigate irregular flow patterns (e.g., turbulent flow, clotting, stacking of red blood cells) as the fluid transitions in to the main cell chamber 648. The fluid outlet 672 may include one or more features common with the fluid inlet 670 described above. Additionally or alternatively, the second fluid profile modifier 678 may include one or more features common with the first fluid profile modifier 676 described above.
The main cell chamber 648 may include two enzymatic sensors (e.g., the glucose sensor 568, the lactate sensor 564). Each of the enzymatic sensors may be disposed within corresponding slots 652, 656. These slots may be configured to allow fluid flow over each sensor. The sensors can be disposed to allow passage of fluid (e.g., blood plasma, the fluid sample) to pass (e.g., diffuse) along a direction perpendicular to the axis A and/or perpendicular to a direction of fluid flow through the assembled fluid cell 660. The main cell chamber 648 can also include an optical investigation portion 664. In some embodiments, the optical investigation portion 664 comprises a body of the assembled fluid cell 660 through which radiation (e.g., white light) can pass. In some designs, the optical investigation portion 664 comprises an optically transparent and/or rigid material. The cross-sectional area of the main cell chamber 648 can the same cross-sectional area as the inlet 670, and/or as the profile modifier 676. An interior of the flow cell 660 can have a constant cross-sectional area along a majority of, or along the full length of, the flow cell 660 along the axis A. The main cell chamber 648 can height of 50 microns, 75 microns, 100 microns, 125 microns, 150 microns, 175 microns, 200 microns, 225 microns, 250 microns, or any values therebetween, or any ranges bounded by any combination of these values, although other heights can also be used. The main cell chamber 648 can have a width of 1000 microns, 2000 microns, 3000 microns, 4000 microns, 5000 microns, 6000 microns, 7000 microns, 8000 microns, 9000 microns, or 10,000 microns, or any values therebetween, or any ranges bounded by any combination of these values, although others could be used. The flow cell 660 can have features that are the same as or similar to the flow cell embodiments disclosed herein.
In some cases, variations in manufacturing can cause slight differences in dimensions or other attributes of the system. In some embodiments, the system can include an attribute indicator that is indicative of an attribute of the system. The attribute can include an optical path length, one or more dimension of the flow cell, a measured height of the main cell chamber of the flow cell, etc. The attribute indicator can include a Quick Response Code (QR code), a bar code, an Radio-frequency identification (RFID), etc.
The assembled fluid cell 660 may be included as part of a disposable system described above. This process may include supplying adhesive (e.g., glue) to a portion of the assembled fluid cell 660 and/or attaching one or more tubes thereto.
Various embodiments disclosed hereby can relate to the electrochemical, enzymatic, spectroscopic (e.g., near infrared) or other measurement of one or more analytes in a bodily fluid (e.g., blood) of a patient. The bodily fluid can be drawn out of the patient and positioned within the system for processing and/or analysis as discussed herein.
An analyte sensor can be used in a fluid-handling system with various configurations.
At the start of a measurement cycle, most tubing can be filled with saline that can come from a saline bag 1846. The saline bag 1846 can be provided separately from the system 1810. For example, a hospital can use existing saline bags and/or saline pumps to interface with the described system. Before drawing a bodily fluid sample, the saline in part of the system 1810 can be replaced with air 1822. Thus, for example, the following valves can be closed: valve 1844 (PV0), 1840 (PV1), 1826 (V0a), 1860 (Vhep), and 1874 (V2b). At the same time, the following valves can be open: valves 1832 (V1a), 1828 (V2a), 1854 (V3a), 1858 (V0b), 1824 (V3b), and 1872 (V4a). An air pump 1818 pumps air through the system, pushing saline through the system into a waste bag 1864.
Next, a sample can be drawn. With valves 1832 (V1a), 1840 (PV1), 1844 (PV0), and 1828 (V2a) closed, a saline pump 1835 is actuated to draw sample fluid to be analyzed (e.g., blood) from a fluid source (e.g., a laboratory sample container, a living patient, etc.). The sample fluid is drawn up into the patient tubing, though the tube past the two flanking portions of the open pinch-valve 1826 (V0a), through the first connector C1, into the looped tube 1834, and past the arrival sensor 1836 (Hb12). The arrival sensor 1836 (Hb12) may be used to detect the presence of blood in the tube.
The system 1810 can measure the pressure in the fluid-handling network, e.g., by using one or more pressure sensors, such as pressure sensor 1842 (PS9) and/or pressure sensor 1820 (PS10). The one or more pressure sensors can be in fluid communication with the fluid-handling network. The at least one pressure sensor can monitor the pressure, e.g., by measuring the pressure in the fluid handling network periodically (e.g., once every minute, once every thirty seconds, once every fifteen seconds, once every five seconds, once every two seconds, once every second, twice per second, three times per second, five times per second, ten times per second, etc.), on a substantially continuous basis, or by a single measurement.
Before drawing the sample, the tubes can be filled with saline and the hemoglobin level (Hb) is zero. The tubes that are filled with saline are in fluid communication with the sample source at 1812. When the saline is drawn toward the saline pump 1835, the fluid meant to be analyzed is also drawn into the system because of suction forces in the closed fluid system. The saline pump 1835 draws a relatively continuous column of fluid through the system, from tubing loop 1814, past bubble sensor 1816 (BS11), past first connection C1, and past arrival sensor 1836 (Hb12). The fluid column first comprises generally nondiluted saline, then a mixture of saline and sample fluid, then eventually minimally diluted and/or nondiluted sample fluid. The arrival sensor 1836 (Hb12) can detect and/or verify the presence of blood in the tubes. In some embodiments, when the sensed hemoglobin level reaches some pre-set value, substantially undiluted blood is present at first connection C1. The loop of tubing 1834 can provide additional length to the tubing. The additional length makes it more likely that a sufficient nondiluted portion of the fluid has reached the tubing. The system can include a plurality of arrival sensors (e.g., bubble sensor 1816 (BS11), bubble sensor 1848 (BS19), arrival sensor 1862 (BS8), bubble sensor 1878 (BS14), and arrival sensor 1836 (HB12), which can be configured to detect the arrival of a fluid (e.g., bodily fluid such as blood) at a plurality of locations in the fluid handling network.
If nondiluted and/or minimally diluted blood is present at the first connector C1, a sample can be directed toward a measurement portion. Bubble sensor 1848 (BS19) can detect the arrival of the sample. The sample can be directed into a flow cell, which can comprise part of an analysis portion 1899, which can comprise one or more sample conditioning devices (e.g., a lysing apparatus) and one or more sample measurement devices (e.g., an optical and/or enzymatic sensor or series of sensors). The sample can start out as a whole blood sample. A series of pinch valves, valves 1854 (V3a) and 1828 (V2a), can be closed in order to a channel which can form part of the analysis portion 1899. The analysis portion can include a flow cell 560 similar to the one described with respect to
A flow cell can be used in conjunction with a near and/or mid infrared light source and a near and/or mid infrared spectrometer. The spectrometer can measure a variety of parameters. For example, the near infrared spectrometer may measure oxygen, hemoglobin, CO2, pH, lactate, fluid flow rate, presence of fluid, color of fluid, etc. Energy from the infrared source can pass through the center of a flow cell before being measured by the near infrared spectrometer.
Before or after the near infrared spectrometer has taken measurements of the sample, the sample can be heparinized. An amount of anticoagulant (e.g., heparin) can be introduced by the syringe-style heparin pump 1852. A series of pinch valves, valves 1860 (Vhep) and 1858 (V0b) can be open, while valve 1854 (V3a) can be closed to prevent anticoagulant from mixing with the unused fluid. The heparin components may be separate from the fluid system 1810. Heparin pinch valve 1860 (Vhep) can be closed to prevent flow from or to the heparin pump 1852, and a heparin waste pinch valve 1856 (V1b) can be closed to prevent flow from or to the waste container 1864 from this junction. When bubble sensor 1862 (BS8) indicates the presence of a sample, the unused bodily fluid can be returned to its source. The saline pump 1835 pushes the fluid back to the patient by opening the valve 1826 (V0a), closing the valves 1832 (V1a) and 1828 (V2a), and keeping the valve 1830 (V7a) open. Saline from the saline bag 1846 may then flush the tubing.
Following the return of the unused fluid, the heparinized sample can be pushed through connector C2 into a sample cell (which can be part of an analysis portion 1899). Pump movement and valve position corresponding to each stage of fluid movement can be coordinated by one or more multiple controllers, such as the fluid system controller 405 of
In some embodiments, following analysis of the sample, the sample may be flushed by air pump 1818 (or a saline pump) and sent to the waste container 1864. Cleaner (e.g., a detergent such as tergazyme A) may flow through and clean the tubing surrounding the sample cell. Detergent tank 1868 may provide cleaner that is flushed through the tubing leading to and from the analysis portion 1899 and into the waste container 1864. Check valve 1866 prevents cleaner from flowing from the detergent tank toward the saline bag 1846 and saline pump 1835. Following the cleansing flush, saline can be drawn from the saline bag 1846 for a second flush. The saline pump 1836 can flush the cleaning solution out using the saline. This saline flush pushes saline through the tubing past the arrival sensor 1836 (Hb12), the heparin pump 1852, the analysis portion 1899 and into the waste container 1864. In some embodiments, the following valves are open for this flush: 1830 (V7a), 1828 (V2a), 1872 (V4a), and the following valves are closed: 1826 (V0a), 1832 (V1a), 1874 (V2b), and 1876 (V4b).
When the fluid source is a living entity such as a patient, a low flow of saline (e.g., 1-5 mL/hr) is preferably moved through the tubing 1812 and 1814 and into the patient to keep the patient's vessel open (e.g., to establish a keep vessel open, or “KVO” flow). This KVO flow can be temporarily interrupted when fluid is drawn into the fluid system 1810. The source of this KVO flow can be the saline pump 1835 or the air pump 1818. Preferably, the time between measurement cycles is longer than the measurement cycle itself (for example, the time interval can be longer than ten minutes, shorter than ten minutes, shorter than five minutes, longer than two minutes, longer than one minute, etc.).
Numerous sensors, fluid lines, pinch valves, junctions, pumps, fluid sources, and fluid receptacles are shown, largely consistent with the disclosure herein describing other fluidics diagrams (e.g.,
In many of the embodiments discussed herein, measurements can be taken from a sample of bodily fluid. In some embodiments whole blood can be used. For some analyte measurements, characteristics of the sample can impede measurement. For example, blood can include some analytes in the red blood cells and some analytes in white blood cells. Some analytes can be present in the blood and not present within either type of blood cell. Other, non-analyte components in whole blood may have chemical bonds with similar vibrational frequencies to those of the analyte. Analytes can be unhelpfully shielded (optically, physically, or both) by non-analyte components. Indeed, in some cases analytes can be located within cell membranes and therefore more difficult to measure or quantify, either because they are not evenly distributed, because they are chemically bound, or for some other reason. Other particles within a sample (e.g., blood) can interfere with the measurement, thereby reducing accuracy of the system. For example, in embodiments that use an optical measurement system, red blood cells, or other particles, can absorb, reflect, scatter, or otherwise interfere with the light that is transferred through the sample. Thus, in some embodiments, it can be advantageous to remove these interfering particles or to mitigate or suppress their adverse effects on the measurement. Similarly, it can be advantageous to break down or adjust biological or physiological structures in order to remove optical or physical barriers to measurement, evenly distribute analytes, or otherwise improve analyte detection and measurement. For example, blood can be separated using a centrifuge or filter into components that are organized by similar mass. Blood can also be separated using a lysing process that breaks down the blood's structure on a more fundamental level, breaking cell membranes and causing the contents of cells to be released into a more general suspension. Separation and/or lysing can occur using many mechanical and chemical approaches. For example, cells can be broken down using sonication, heat, lasers, ultrasound, physical shaking (e.g., using a piezoelectric vibrator), homogenization, freeze-thaw procedures, grinding, detergents or other chemical approaches, enzymatic cell disruption, buffers, bacterial or other biological cell lysates, etc. An ultrasound source can focus its energy on a portion of the fluid network to accomplish the lysing function. The ultrasound source can be incorporated into a permanent instrument and aim for a flow cell or other fluid repository contained within a disposable portion configured to interface therewith. Separation into components by mass can occur through settling, centrifugation, etc. Separation by mass can occur before or after cell disruption (e.g., by lysing). The system can include an ultrasound bubble detector. In some cases an ultrasound device can contact the flow cell, and can be used to clean the flow cell. If an ultrasound device is employed for one purpose, it may also be used for one or more purposes. For example, an ultrasound device may help clean fluid passages and may also be used for lysing fluid components prior to measurement.
A fluid handling system (e.g., that shown in
Once the red blood cells have been lysed, the cells' cytoplasm and other contents can be released and intermingle with other blood components (e.g., the blood plasma). In some embodiments, the cytoplasm and other lysed components of the red blood cells (or other lysed particles) can interfere with the measurement. Thus, it can be advantageous in some embodiments to remove the red blood cells, or other undesirable particles, from the blood plasma (e.g., using filtering or centrifuging). In some embodiments, the separation of the blood plasma can be performed by the fluid handling system in lieu of lysing the particles as discussed above. In other embodiments, the fluid handling system can be configured to both lyse particles in the sample fluid and also separate the sample into components (e.g., by centrifuging) before or after lysing.
Lysing or another type of separation can provide the advantage of substantially isolating a component of the fluid so that a measurement can be made in a component of the fluid without other components influencing the measurement. If the lysed cells are blood cells, for example, lysing can release cytoplasm and other cell contents from the cell membranes into the blood plasma. Then by centrifugation or filtering, one component of the cells (e.g., the cytoplasm) can be substantially isolated, thereby improving the ability to measure one component (e.g., the cytoplasm) without being interference or obstruction from other components (e.g., cell membranes). Centrifugation can stratify the components into layers. However, centrifugation before lysing can form different layers than centrifugation after lysing. For example, centrifugation after lysing may involve additional substances having their own distinct mass or other physical qualities, resulting in additional strata containing particular cell components of similar mass. In some embodiments, if the cells are not lysed, the accuracy of measurements taken on components inside the cells (e.g., cytoplasm) can be reduced by the cell membranes or other cell components. By lysing the cells, a cell component to be measured (e.g., cytoplasm) can be more easily isolated and measured.
Thus, in some embodiments, a first analysis portion of the fluid sample is prepared for analysis by lysing cells, and a second analysis portion of the fluid sample is prepared for analysis by separating the fluid into a plurality of components (e.g., by centrifugation, filtering, or some other selective process based on mass, size, magnetics, electrical qualities, etc.). In some embodiments, a single analysis portion of the fluid sample can be prepared for analysis by both lysing cells in the fluid and by separating the fluid into a plurality of components. Lysing and/or component separating (e.g., by centrifuging), if warranted, can be performed in series on the same portion of the sample or in parallel on different portions of the sample, or on different samples.
A sample measurement device can include various electrochemical measurement structures described above with respect to
Use of Systems with EMR and Big Data, Artificial Intelligence
This disclosure refers to the “OptiScanner.” This is a general term used to refer to the analyte systems for analyte measurement featured in this disclosure. A specific example of an OptiScanner is the “OptiScanner 5000 Glucose Monitoring System,” an automated, bedside glucose monitoring device indicated for detecting trends and tracking patterns in persons (age 18 and older) in the surgical intensive care unit. The system collects a venous whole blood sample via connection to a central venous catheter, centrifuges the sample, and measures the plasma glucose concentration. It is not intended for the screening or diagnosis of diabetes mellitus but is indicated for use in determining dysglycemia. The OptiScanner 5000 Glucose Monitoring System is for in vitro diagnostic use. As noted above, the analysis systems (e.g., the OptiScanner) described herein can be especially useful for “detecting trends and tracking patterns.”
U.S. Pat. No. 6,931,328 and U.S. Patent Pub. No. 2007/0083160 are incorporated herein by reference for all purposes, for all that they contain. The former describes an analyte monitoring instrument having network connectivity and the latter describes how data can be incorporated into patient Electronic Medical Records (EMR), for example. The above-described analyte detection and analysis systems can be similarly connected to a network. The described systems collect data frequently and provide beneficial accuracy for the analytes they detect and analyze. For example, some embodiments obtain glucose, lactate, hemoglobin, and/or other data multiple times per hour. This can result in highly valuable data inputs for an artificial intelligence system or other big data analysis server. These data can be collected and analyzed to identify medical or environmental issues that might not be immediately clear to a doctor reviewing a trend of data points for a single variable.
Referring to
Because the noninvasive system 10 is depicted in the embodiment of
Data is communicated over the network 520 as determined by the configuration of the system 500 and the state and condition of the measurement being performed. Measurement data may accordingly be communicated to the remote station(s) 524, 528 at the time the measurement is performed, or it may be retained within the system 500 and sent to the remote station(s) according to a schedule or other selection criterion. The system 500 and/or remote station(s) 524, 284 may be capable of comparing each measurement with a set of limits and providing alerts to a supervisory authority regarding excursions therefrom.
In
Furthermore, the centralized computer 524 may simultaneously transfer or route the data (e.g., measurements, system status, etc.) via connection 526 to a computer 528 in the office of a medical practitioner over the network 520. Instead of or in addition to the medical practitioner computer 528, the network may include connections to a computer 528′ located at the manufacturer of the analyte detection system 500, to a computer 528″ located at the patient's home, and/or to a computer 528′″ located at the home or place of business of a parent of the patient. Alternatively, the data may be directly sent over the network 520 to the medical practitioner 528/manufacturer 528′/patient's home 528″/patient's parent 528′″ from the signal processing system 516; in this instance the centralized computer 524 is not necessary and may be omitted from the network 520. Where the centralized computer 524 is omitted, any of the computer(s) 528/528′/528″/528′″ (hereinafter, collectively “528”) may be capable of checking the data received from the system 500 for emergency conditions, logging the data for later use, and/or monitoring the status of the system 500 for proper operation and calibration. It will be appreciated that the foregoing data routing is provided as an example, and not as a limitation, of the data routing utilized to provide the network services in support of a patient's use of the system 500.
In one embodiment, the system 500 includes a panic button 530 which permits the patient to alert a medical practitioner should an important concern arise. In addition, sound and/or visual output may be provided by the system 500 for signaling the patient when the time arrives to perform a measurement, or of a directive from a supervisory authority as received over the network 520.
In another embodiment, the system 500 includes a location button 531 which permits the patient to signal his or her location (as well as the location of the system 500) to any of the remote station(s) 524, 528. When so signaled, a remote user at a remote station 524/528 can direct emergency assistance to the location of the patient/system, should the remote user discover that the patient's condition merits immediate medical attention. In one embodiment, the location information is generated via GPS (Global Positioning System) equipment built into the system 500 and accessible by the processing element(s) 519. In another embodiment, the system 500 continually, intermittently or otherwise automatically transmits its location to any or all of the remote station(s) 524, 528, and the location button 531 may be omitted. In still another embodiment, the system 500 is configured to transmit its location to remote station(s) 524, 528 in response to a query sent from the remote station(s) to the system 500.
In another embodiment, the GPS equipment is supplemented by storage, within appropriate memory accessible by the processing element(s) 519 and/or the GPS equipment, of favorite locations frequented by the patient. Examples of favorite locations include Home, Work, School, etc. and/or a widely recognizable expression thereof, such as the associated street address, nearest cross streets, ZIP or postal code, and/or longitude and latitude. The purpose of such storage is to counteract the tendency of GPS equipment to lose contact with the GPS satellite(s) when the GPS device in question is located inside of a building or other large structure.
Accordingly, when the system 500 loses contact with the GPS satellite(s) and a need arises, under any of the circumstances discussed herein, to transmit the location of the patient/system to a remote user, the system 500 recognizes the loss of contact with the GPS satellite(s) and selects for transmission one of the patient's favorite locations based on the last GPS-computed position of the user/system prior to loss of contact with the GPS satellite(s). In one embodiment, the system 500 selects and transmits whichever favorite location is nearest the last GPS-computed position of the system 500. In another embodiment, the system 500 selects and transmits this nearest favorite location only when the nearest favorite location is within a given minimum distance (e.g., 10 miles, 5 miles, 1 mile, 0.5 miles) from the last GPS-computed position of the system 500. In still another embodiment, the system 500 displays a list of the patient's stored favorite locations on a suitable display, and the patient can select, using an appropriate input device (keypad, button, touchscreen, mouse, voice recognition system, etc.) built into or connected to the system 500, his or her present location from a list of favorites and prompt the system 500 to transmit the selected location.
Any of the location-transmission processes discussed above may be implemented in an algorithm or program instructions executable by, and residing within memory accessible by, the processing element(s) 519 of the system 500 (in particular, by the signal processor 74/260 where the system 500 comprises the noninvasive system 10 or the whole-blood system 200, respectively).
In any of the embodiments discussed herein, the system 500 and/or one or more of the remote station(s) 524, 528 may be configured to encrypt any or all of the data that it transmits over the network 520. Where the user of any of the system 500 and the remote station(s) 524, 528 (or the system/remote station itself) is authorized to receive, read and/or otherwise use the encrypted data, the recipient system 500/remote station 524, 528 is configured to decrypt the encrypted data, to make the data available to the device and/or the user thereof. By encrypting the data, physician-patient confidentiality, or any physician-patient privilege may be preserved, preventing unauthorized reading or use of the data. Encryption also permits transmission of data over wireless networks or public networks such as the Internet while preserving confidentiality of the transmitted data.
It is contemplated that the encryption and decryption may be performed in any suitable manner, with any suitable methods, software and/or hardware presently known or hereafter developed. In the system 500, the encryption and/or decryption processes may be implemented in an algorithm or program instructions executable by, and residing within memory accessible by, the processing element(s) 519 of the system 500 (in particular, by the signal processor 74/260 where the system 500 comprises the noninvasive system 10 or the whole-blood system 200, respectively). In the remote station(s) 524, 528, the encryption and/or decryption processes may be implemented in an algorithm or program instructions executable by, and residing within memory accessible by, processing element(s) (not shown) of the remote station 524/528 in question.
The connection of the system 500 to the network 520, provides either a direct or indirect link from the patient to the practitioner. The practitioner is thereby accorded an ability to monitor the status of the patient and may elect to be alerted should deviations in the measurement values the or timeliness thereof arise. The system may be configured to transmit measurement data at predetermined intervals, or at the time each measurement is performed. The measurements can be transmitted using various network protocols which include standard internet protocols, encrypted protocols, or email protocols.
In one embodiment, the signal processing system 516 is additionally capable of providing visual or audible cues to the patient when the time arrives to conduct a measurement. These alerts may be augmented by requests, transmitted over the network 520 to the instrument, from the practitioner. Errors introduced within measurements and recordation within a manual system can thereby be eliminated with the electronically logged measurements. It will be appreciated that the system provides enhanced utility and measurement credibility in comparison to the use of an instrument that requires manual logging of the measurements and permits no practitioner interaction therewith.
Secretive non-compliance may also be eliminated as the patient is not conferred the responsibility of manually logging measurements. In using the system 500, the measurements collected within the instrument by the patient are capable of being transmitted to a practitioner, or a centralized computer, such that if a patient is not being diligent in conducting measurements, the practitioner may immediately contact the patient to reinforce the need for compliance. In addition, the information provided over the network can be used to warn the practitioner when measurement readings appear abnormal, so that the practitioner may then investigate the situation and verify the status of the patient.
It will be appreciated that the invention has particular utility for patients preferring to receive direct guidance from a practitioner. The information that flows between the patient and the practitioner increases the ability of the practitioner to provide knowledgeable patient guidance.
The network link provides a mechanism to facilitate performing and recording analyte measurements under supervision, while it additionally provides for periodic instrument calibration, and the ability to assure both measurement and calibration compliance. Calibration data can be communicated from systems 500 in the field to the system manufacturer, or a service organization, so that the systems 500 and their calibrations may be logged. The disclosed network link can be utilized to provide various mechanisms for assuring calibration compliance. Generally the mechanisms are of two categories, those that provide information or a warning about calibration, and those that prevent use of an instrument which is out of calibration. In one embodiment, systems 500 which have exceeded their calibration interval, or schedule, are to be locked out from further use until recalibration is performed. For example, the system 500 may be set to operate for thirteen months for a given calibration interval of twelve months. The system 500 may issue warnings prior to the expiration of calibration, and warnings of increased severity after the expiration of the calibration interval. If the system 500, however, is not properly calibrated by the end of the thirteen months, normal operation ceases, thereby locking out the user after providing an appropriate error message in regard to the expired calibration. Upon recalibration, the calibrated operation interval is restored to provide for another thirteen month period of calibrated operation.
Alternatively, or in addition thereto, a “lockout command” can be sent to the system 500 over the network 520 from the manufacturer, practitioner or system maintenance organization, thereby engaging a lockout mode of the system 500, so that operation may not be continued until the system 500 has been serviced. The lockout command could also be sent in the event that the patient has not paid his or her bills, or be sent under other circumstances warranting lockout of the system 500.
Another mode is that of locking out normal system use after the expiration of calibration, and allowing limited use thereafter only after a code, or token, has been downloaded from a supervisory site. Although many variations are possible, the code could for instance be provided when a calibration appointment is made for the system 500. To provide continued service and minimize cost, the patient may be allowed to perform calibration checks of the system 500. The patient is supplied with a small set of analyte calibration standards which are read by the system 500 once it is put into a calibration mode and preferably connected to a remote site for supervising the process. Should the calibration check pass, wherein the instrument readings fall within normal levels, or be capable of being automatically adjusted thereto, the calibration interval may be extended. Failure of the calibration check would typically necessitate returning the system 500 for service.
It will be appreciated that the present invention provides functionality beyond that which can be provided by a stand-alone analyte detection system, as the practitioner, or practitioner's office, is involved in the analyte measurement process to confer a portion of the benefits normally associated with an office visit. The aforesaid description illustrates how these features provide the capability for two-way data flow which facilitates the conducting and recording of correct measurements while encouraging compliance in regard to both measurements and instrument calibration. Furthermore, the data collected by the system may be utilized by others in addition to the practitioner, such as pharmaceutical companies which may be provided data access to alter or administer medication programs, and insurance companies which may require data regarding patient diligence according to the specified treatment program.
As used herein, the term “computer” is a broad term and is used in its ordinary sense and refers, without limitation, to any programmable electronic device that can store, retrieve and process data. Examples of computers include terminal devices, such as personal computers, workstations, servers, mini computers, main-frame computers, laptop computers, a network of individual computers, mobile computers, palm top computers, hand held computers, set top for a TV, an interactive television, an interactive kiosk, a personal digital assistant (“PDA”), an interactive wireless communications device, or a combination thereof. The computers may further possess storage devices, input devices such as a keyboard, mouse or scanner, and output devices such as a computer screen or a speaker. Furthermore, the computers may serve as clients, servers, or a combination thereof.
As used herein, the term “network” is a broad term and is used in its ordinary sense and refers, without limitation, to a series of points or nodes interconnected by communication paths, such as a group of interconnected computers. Examples of networks are the Internet, storage networks, local area networks and wide area networks.
Further to
As used herein, the term “processor” is a broad term and is used in its ordinary sense and refers, without limitation, to the part of a computer that operates on data. Examples of processors are central processing units (“CPU”) and microprocessors.
As used herein, the term “software” is a broad term and is used in its ordinary sense and refers, without limitation, to instructions executable by a computer or related device. Examples of software include computer programs and operating systems.
As used herein, the term “software update” or “update” is a broad term and is used in its ordinary sense and refers, without limitation, to information used by a computer to modify software. A software update may be, for example, data, algorithms or programs.
A process flow diagram of a preferred software update process 700 is shown in
Further to the act 702, the analyte detection system 602 detects analytes in a material sample and calculates an analyte concentration in accordance to the analyte detection system's software 612. Additionally, the analyte detection system may issue alerts to the user, for example, in response to exceeded tolerances defined in the software 612. The alerts may be visually displayed to the user and/or audibly sounded to the user. For instance, the analyte detection system 602 may issue an alert in response to an elapsed calibration time tolerance defined in the software 612. Other alerts may be issued when the software or analyte-concentration calculation algorithm is out of date, or when the analyte concentration reading made by the detection system 602 are higher or lower than defined safe limits or ranges.
In one embodiment, the software 612 is contained in the analyte detection system 602 internally. In another embodiment, the software 612 is retained external to the analyte detection system 602.
Next, in an act 704, the analyte detection system 602 is connected to the centralized computer 604 via the network 606. Advantageously, the network interface 608 readily connects the analyte detection system 602 to the network 606. Furthermore, once the analyte measuring device 602 is connected to the network 606, the analyte measuring device 602 is, in one embodiment, in two-way communication with the centralized computer 604. In one embodiment, the communication between the analyte measuring device 602 and the centralized computer 604 is established without any intervention from a user.
The process 700 then proceeds to a decision act 706 where the centralized computer 604 determines an update status for the analyte measuring device's software 612. Various conditions may trigger the centralized computer 604 to update the software 612. In one embodiment, a condition for updating the software 612 is the presence of a new drug in the material sample (e.g., a new drug taken by the user) that alters the analyte calculations. Specifically, the centralized computer 604 determines whether the software 612 currently in use accounts for the use of the new drug. If the current software does not account for the new drug, the centralized computer 604 sends a software update 614 over the network 706 that does account for the new drug, and as a result, corrects future analyte calculations performed by the analyte measuring device 602. In another embodiment, a condition for updating the software 612 is where a new analyte-detection algorithm is developed. For example, the new algorithm may improve the accuracy or speed of the analyte detection system 602 over the software 612 currently in use. In another embodiment, a condition for updating the software 612 is where the analyte detection system 602 should display a new warning or where the monitoring device should display an existing warning in response to new or different events. The existing warning or the new warning may be displayed, for instance, in response to new information learned from a subset of a customer population. Advantageously, other conditions not specifically mentioned herein may also trigger the centralized computer 604 to update the software 612.
If the centralized computer 604 decides that the software 612 does not need to be updated in the decision act 706, then the update process 700 proceeds via the “No” path to an act 708. In the act 708, the user disconnects the analyte detection system 602 from the network and the software 612 is not updated. Thus, the analyte detection system 602 operates in the same manner as the analyte detection system 602 previously operated in the act 702.
If the centralized computer 604 decides that the software 612 needs to be updated in the decision act 706, then the update process 700 proceeds via the “Yes” path to an act 710. In the act 710, the centralized computer 604 sends a software update 614 to the analyte detection system 602. In one embodiment, the centralized computer 604 contains a database of various software updates 614, and consequently, the centralized computer 604 selects the appropriate software update 614 from the database and then sends the software update 614 to the analyte detection system 602.
Next, in an act 712, the analyte detection system 602 receives (e.g. downloads) the software update 614. The analyte detection system 602 then preferably modifies the software 612 to an updated version of the software 612. The process then proceeds to an act 714.
In the act 714, the user performs analyte measurements in accordance with the updated software 612. Thus, depending upon the software update 614, the analyte measuring device 602 operates differently than the manner in which the analyte measuring device 602 previously operated in act 702. One example is that the analyte detection system 602 may calculate analyte concentrations differently. Another example is that the analyte detection system 602 may displays new warnings to the user. A further example is that the analyte detection system 602 may display the same warnings, but the warnings are triggered by different events.
In any of the embodiments of the software update system 600 discussed herein, the analyte detection system 602 and/or the centralized computer 604 (or, where applicable, the computer(s) 528) may be configured to encrypt any or all of the data that it transmits over the network 606. Where the user of any of the analyte detection system 602 and the centralized computer 604 (or the analyte detection system/centralized computer itself) is authorized to receive, read and/or otherwise use the encrypted data, the recipient system 602/computer 604 is configured to decrypt the encrypted data, to make the data available to the device and/or the user thereof. By encrypting the data, physician-patient confidentiality, or any physician-patient privilege may be preserved, preventing unauthorized reading or use of the data. Encryption also permits transmission of data over wireless networks or public networks such as the Internet while preserving confidentiality of the transmitted data.
It is contemplated that the encryption and decryption may be performed in any suitable manner, with any suitable methods, software and/or hardware presently known or hereafter developed. In the analyte detection system 602, the encryption and/or decryption processes may be implemented in an algorithm or program instructions executable by, and residing within the memory accessible by, the processor 610 of the analyte detection system 602 (in particular, by the signal processor 74/260 where the analyte detection system 602 comprises the noninvasive system 10 or the whole-blood system 200, respectively). In the centralized computer 604 (or, where applicable, the computer(s) 528), the encryption and/or decryption processes may be implemented in an algorithm or program instructions executable by, and residing within memory accessible by, processing element(s) (not shown) of the computer 604/528 in question.
The software update process 700 has many advantages. One advantage is that the software 612 of the analyte measuring device 602 may be updated without requiring significant user participation. Another advantage is that the software 612 may be quickly and conveniently updated at a remote location (e.g., the user's home) rather than requiring the user to travel to, for example, a doctor's office or other administrative center.
There are many challenges and risks involved with the naïve use of Big Data in medical settings without accompanying knowledge of medicine, focusing on issues in critical care. For example, there is a challenge of transforming the large amount of data into usable and useful medical knowledge. The system described here helps address these challenges in several ways. First, it provides very useful, frequent, accurate inputs to a big data analysis. Second, it can provide a window into this specific, timely information for doctors directly in the critical care environment. The described analyte detection system itself does not suffer from the risks of big data discussed in the article because its outputs are specific and depend on analysis and algorithms that are well understood. By integrating this described system into a Big Data system, it can help anchor big data algorithmic or predictive outputs in reliable hard data. By comparing, contrasting, or juxtaposing data from a single analyte measurement system (e.g., an “OptiScanner,” which can refer to a device having features disclosed herein) connected to a single patient, for example, with output from a large number of analyte measurement systems (e.g., OptiScanners), system administrators and doctors can identify medical and/or technical issues.
The principles discussed above can be used, for example, in Intensive Care Unit (ICU) scoring systems such as APACHE (Acute Physiology and Chronic Health Evaluation), MPM (Mortality Probability Model), and SAPS (Simplified Acute Physiology Score). These systems have use as short-hand indicators of patient acuity. Because the described analyte measuring systems improve data accuracy (and increase data volume and resolution greatly by using periodic measurements), these systems can greatly improve these scoring system values. Another database that can be improved with the described analyte monitor is the Multiparameter Intelligent Monitoring in Intensive Care (MIMIC) database and the like. For example, the described analyte measurements systems can provide“dynamic clinical data mining” (DCDM). Thus, they can assist in a process where users of EMR can be automatically presented with prior interventions and outcomes of similar patients to support medical decisions.
Another benefit of providing network connectivity and access to big data algorithms and outputs is that the described systems provide an interface to doctors with the knowledge to weigh risks and who are present to act quickly on big data outputs, in view of analyte system outputs. For example, in some embodiments, a portion of an analyte measurement system (e.g., OptiScanner or similar analysis instrument having features disclosed herein and using enzymatic technology, sometimes referred to as an “OptiZymer” device) can provide visual outputs to a medical professional through a graphic user interface, or GUI. Example GUIs are described, for example, in U.S. Publication No. 2015/0045641 and in U.S. Publication No. 2008/0077073. The entire contents of these publications are incorporated herein for all purposes, for all that they contain. Some embodiments have the benefit of receiving user input, where a doctor can annotate a visual display to indicate and record where or when a patient received a dose of medication, when a medical event occurred that may affect the data, a prediction based on an emerging trend, a warning to disregard an outlier data point, etc. A portion of the GUI (or an alternative or additional GUI view that is readily accessible therefrom) can be provided to show output or results from a big data algorithm or to display results from a different source outside of the main instrument. Thus, a doctor can be alerted to an issue or a trend among other similarly-situated patients, or an issue or trend with similar instruments. Making such additional information available readily, in close association with hard data specific to the patient, can allow a doctor to identify relevant actions to be taken, thereby alleviating some of the problems with pure big data applications that do not involve medical knowledge or do not involve the context of accurate data readings.
As more robust big data outputs are developed, the described GUI and system can be incorporated as an alert system not only for outputs from the device itself, but also for outputs from trusted big data sources. For example, if medical professionals determine as a group that a specific lactate level or trend should be investigated immediately based on common patient morbidity after those levels or trends are analyte measurement system (e.g., OptiScanner) GUI can incorporate this big data output into a visual warning sign for a doctor in the hospital room of such a patient. This warning can be based on both the actual readings from the local analysis instrument, as well as the latest trend or level warning data available from big data sources, which can communicate such big data information over an internet connection to an analyte measurement system (e.g., OptiScanner or OptiZymer, for example). The GUI can rapidly indicate the source of a warning to medical professionals. For example, one portion of the interface can be designated for display of data sourced purely from the instrument itself, and another portion can be designated for display of outputs from external algorithms (which may include inputs from the device). To reduce screen size, these portions can be alternatively accessible based on user input. To avoid mistakes, the GUI can have a starkly different appearance based on the source of the information displayed (different colors, fonts, arrangement of information, numerical values, etc.)
An example of how big data outputs can be enhanced using the systems described herein is described with respect to
As can be seen from the table, in this illustrative example the subpopulation having sepsis (with or without any complicating factors) was broken into two further subpopulations: those without organ failure and those without indication of hetastarch (a plasma expander commonly administered to patients after trauma, blood loss, or serious injury). The disease states shown in the table are intended to be illustrative and not to limit the scope of the disclosed systems and methods for diagnosing disease states. In other examples, a population of sample data may be classified into additional and/or different disease states for analysis. For example, a population of patients having the sepsis disease state may be broken into subpopulations corresponding to bacterial infection, fungal infection, or both types of infection. Other disease states and sample populations may be used with other embodiments of the disclosed systems and methods.
In one example of the method 2800, collections of spectra (for both the ICU population and the normal population) were obtained from patient blood plasma samples using a Fourier Transform Infrared (FTIR) spectrometer sensitive to the mid-infrared spectral region between about 7 microns and about 10 microns. In other examples, a different spectral region may be used (e.g., near-infrared, far-infrared, visible, etc.). Other types of spectral data (e.g., narrow-band and/or broad-band spectra) and/or spectroscopic instruments may be used in other embodiments. For example, in some implementations, spectral data taken at one or more discrete wavelength passbands may be used (see, e.g., the description of the spectroscopic analyzer 2010 shown in
In the embodiment of the method 2800 shown in
Continuing with the embodiment of the method 2800, in block 2840, the difference spectra are analyzed to determine a set of basis spectra that span the space of the difference spectra Do. For example, in some embodiments, a non-parametric method such as principle component analysis (PCA) can be used to determine the basis spectra. In some such embodiments, a singular value decomposition (SVD) of the matrix of difference spectra is performed (typically after subtraction of the mean) according to:
D0=A B CT,
where A and C are orthogonal matrices and B is a diagonal matrix. The columns of the matrix A are called the principal components (PC) of the difference spectra Do, and they form a set of orthonormal basis spectra that can be used to parameterize the space of differences between the (mean-centered) glucose-free sample spectra So and the (mean-centered) glucose-free normal spectra N0. In some embodiments, a commercially-available mathematical analysis package such as, e.g., MATLAB®, is used for the PCA computations.
In other embodiments of the method 2800, the basis spectra can be determined (in block 2840) by other statistical techniques including, but not limited to, factor analysis, kernel methods (e.g., kernel PCA), independent component analysis, and/or other techniques from pattern analysis.
Without subscribing to or requiring any particular theory or interpretation, the example graphs 2910-2940 illustrate some of the following features, which may or may not be present (or present to the same degree) in examples based on different sample populations or for different disease states. In this example, the first principal components 2912-2918 for the populations with the different disease states are relatively similar in shape and magnitude across the wavelength range shown in
In certain embodiments, this “normal” variation seen in the first principle component (e.g., possibly due to normal blood protein variation) may be reduced by using signal processing techniques that reduce the variation in the difference spectra due to this “unwanted” component. For example, in certain such embodiments, the normal variation is treated as a “noise” component that is removed by signal processing techniques such as, e.g., filtering, Fourier analysis, etc. By accounting for and removing some or all of the normal variation found in plasma spectra, such embodiments may better extract the underlying signal corresponding to disease-state specific features of the principal components. Further, such embodiments may provide increased contrast between features in one or more principal components that correspond to different disease states (e.g., the contrast between a sepsis-specific feature and a kidney-failure-specific feature).
Returning to the embodiment of the method 2800 shown in
In some embodiments, the basis spectra are rank-ordered from 1 to NB. For example, it is common in PCA to rank order the principle components in descending order of their associated variances (obtainable from the diagonal matrix B). For example, the principle components shown in
In block 2850 of the method 2800 shown in
In certain embodiments, the patient spectrum is initially processed to provide a glucose-free, mean-subtracted patient spectrum for comparison with the difference spectra (determined in block 2830). The correction for glucose in the patient spectrum may be determined using the same or similar techniques as for the glucose-free spectra in the Sample and Normal populations. For example, a scaled, reference glucose spectrum may be subtracted from the patient spectrum to provide a glucose-free patient spectrum. In other embodiments, the glucose-free patient spectrum may be determined using embodiments of the methods for analyte determination described above. For example, in some implementations, an embodiment of the method 2100 described above with reference to
In block 2860, the likelihood of the presence (and/or severity) of one or more disease states is determined using one or more statistical tests based at least in part on a comparison of the patient spectrum and the subset that includes ND of the basis spectra. As described above, in some embodiments, a glucose-free, mean-subtracted patient spectrum may be used for the comparison.
In some embodiments, the statistical test includes convolving a probability density function (PDF) of a statistical distribution function of the “distance” between the patient spectrum and a linear combination of the subset of basis vector with a PDF for the basis spectra. For example, the distance may be measured according to the Mahalanobis distance (or distance squared) or some other suitable statistical distance metric (e.g., Hotelling's T-square statistic). In some such embodiments, the statistical test includes calculating the following integral over the subspace spanned by the subset ND of the basis spectra (represented by the ND-dimensional variable v):
∫PDF[MD2(X−A□v)]PDF[v]dv.
In this convolution integral, MD2 represents the square of the Mahalanobis distance. The argument of MD2 is the difference between the patient spectrum X and the inner (dot) product between the first ND columns of the orthogonal matrix A (obtained from the SVD of the difference spectra) and the vector v . The PDF of MD2 is multiplied by the PDF of the basis spectra PDF[v] and integrated over the subspace spanned by the subset of basis spectra. In some embodiments, PDF[v] is an ND dimensional Gaussian PDF having mean and variance obtainable from the PCA analysis (e.g., the variances for the basis spectra are found from the diagonal matrix B).
In some embodiments of the method, the convolution integral is evaluated using the basis spectra corresponding to a specific disease state (e.g., sepsis). The value of the convolution integral can be used to determine the likelihood of the presence and/or severity of the disease state. For example, in some implementations, a binary statistical test is performed such that if the value of the convolution integral exceeds a threshold, then the patient is diagnosed with the disease state. If the value of the convolution integral is below the threshold, the patient is not diagnosed with the disease state. In some such implementations, an amount by which the convolution value exceeds the threshold is used to provide an indication of the severity of the disease state in the patient. In some embodiments, the convolution integral is evaluated for each of several disease states (e.g., sepsis, organ failure, etc.). As discussed, a binary statistical test may be used to diagnose the presence (and/or severity) of each of the disease states. In some implementations, the values for the convolution integrals for each of the disease states are rank ordered, and a relative likelihood of the presence (and/or severity) of the disease states is provided. For example, some such implementations may provide information that it is more likely that sepsis is present than is kidney failure and so forth.
In some embodiments of the method, other statistical tests may be used. For example, Baye's law may be used to interpret the results of the convolution analysis. In some embodiments, Baye's law may provide an indication of the likelihood of the presence (and/or severity) of a disease state, given the prior information corresponding to the patient spectrum. In other embodiments, the results of the statistical analysis may be combined with information on concentrations of one or more analytes. For example, results of the statistical analysis for the kidney failure disease state may be combined with information on concentration of creatinine (and/or urea) in a patient fluid sample to provide an improved diagnosis of the presence (and/or severity) of kidney failure and/or renal dysfunction.
In some embodiments, the apparatus 100 shown in
In some embodiments, the display system 414 (
In some implementations, if the disease state is determined to be sufficiently severe, an alert may be communicated to appropriate health care providers. For example, the alert may comprise an audible and/or visible signal. The alert may comprise an alert message communicated to an attending physician via a suitable network (e.g., the hospital information system). Some embodiments of the apparatus 100 may be configured to take other actions in response to the diagnosis of a disease state. For example, the apparatus 100 may initiate (or change the rate of) infusion of an appropriate infusion fluid or medicament to the patient.
In other embodiments, other processors or computer systems (e.g., the computer system 2646) may be configured to perform some or all of the analysis for disease states. In some such embodiments, the monitoring apparatus 104 is configured to take the patient spectrum (e.g., an infrared spectrum) and communicate information related to the patient spectrum to other processors for analysis. In some such embodiments, the other processors may store the information related to the subset of basis spectra and so forth. Many variations are possible and the above examples of possible system implementations are intended to be illustrative.
This describes how spectra or other data can be obtained from sample populations with and without a disease state. Such disease states can include sepsis, organ failure, kidney failure, and liver failure, for example. The data can be evaluated algorithmically (e.g., a glucose-free spectrum can be obtained, and a difference calculated between the spectra or other data for the two populations). Statistical methods such as component analysis (using linear algebra to develop basis sets, etc.) can be used to determine a likelihood of the presence of a disease state. This type of statistical analysis can be an input into a big data network. The systems described herein can both deliver and receive input for (or results from) analyses such as this. Another example of how the system can provide data for important medical analysis, diagnosis, and treatment is provided herein. This describes how data taken from the described systems, and potentially related systems, can be combined to determine important parameters such as cardiac output.
In some embodiments, an apparatus such as those described herein can assist in warning a physician (or patient, nurse, or other user) regarding one or more danger signs of a harmful medical condition. An example of such a condition is sepsis. Because many of the described embodiments are configured to be located close to (and indeed connected to) a patient in an intensive care setting and have access to a patient's vital biological information, it can be a useful tool for such warnings. In addition to measuring glucose and lactate levels, for example, such a device can also measure core body temperature (e.g., using a temperature sensor in a patient connector that is exposed to or otherwise measures patient blood soon after it exits a patient's central vein, for example, as described elsewhere herein). In the cases of sepsis, data regarding respiration rate, heart rate, and core temperature can be received by (or generated by sensors or other apparatus within) a device. Sepsis can be predicted and/or imminent when respiration and hear rates both increase, in connection with changes in core temperature of a patient. Thus, when data between devices and/or portions of a device are shared and such a medical event is present or recorded, a doctor may be warned, e.g., using a GUI such as those referred to above.
In 1st Example, an analyte detection system comprises: a fluid passageway having a patient end, the fluid passageway configured to provide fluid communication with a bodily fluid in a patient via the patient end; a pump in fluid communication with the fluid passageway, the pump configured to withdraw bodily fluid from the patient via the patient end of the fluid passageway; and a flow cell in fluid communication with the fluid passageway and the pump, the flow cell configured to receive the bodily fluid withdrawn from the patient, the flow cell comprising: a first opening proximal to the patient end and in fluidic communication with the fluid passageway; a second opening distal to the patient end and in fluidic communication with the pump; a flow cell chamber in communication with the first opening and the second opening, the flow cell chamber comprising: an analysis region configured to detect presence of at least one analyte in the withdrawn bodily fluid, wherein the analysis region comprises at least one enzymatic sensor configured to detect presence of the at least one analyte; and an optical investigation region transmissive to visible light, the optical investigation region configured to be in optical communication with an optical system comprising a visible light source and an optical detector.
In a 2nd example, the analyte detection system of Example 1, wherein the at least one enzymatic sensor comprises a glucose sensor or a lactate sensor.
In a 3rd example, the analyte detection system of any of Examples 1-2, wherein the at least one analyte comprises glucose or lactate.
In a 4th example, the analyte detection system of any of Examples 1-3, wherein the withdrawn bodily fluid comprises whole blood.
In a 5th example, the analyte detection system of Example 4, wherein the optical investigation region is configured to measure a level of Hemoglobin in the whole blood.
In a 6th example, the analyte detection system of any of Examples 1-5, wherein the optical system is configured to inclusion in the flow of the withdrawn bodily fluid.
In a 7th example, the analyte detection system of any of Examples 1-6, wherein the analysis region comprises at least one membrane configured to allow diffusion of the at least one analyte from the withdrawn bodily fluid towards the enzymatic sensor.
In a 8th example, the analyte detection system of Example 7, wherein the at least one membrane is configured to allow diffusion of the at least one analyte from the withdrawn bodily fluid towards the enzymatic sensor such that an electrical output of the enzymatic sensor reaches a saturation level in a time interval less than or equal to about 1 minute.
In a 9th example, the analyte detection system of any of Examples 1-8, wherein the cross-sectional area of the flow cell chamber is approximately equal to the cross-sectional area of the first or the second opening.
In a 10th example, the analyte detection system of any of Examples 1-9, further comprising a length of tubing greater than five feet disposed between the second opening of the flow cell and the pump, the length of tubing configured to prevent flow of the withdrawn bodily fluid into the pump.
In a 11th example, the analyte detection system of any of Examples 1-10, wherein the withdrawn fluid is returned to the patient after analysis.
In a 12th example, a method of measuring concentration of at least one analyte in a bodily fluid comprises: withdrawing a sample of bodily fluid from a patient via a patient end of a fluid passageway; drawing the sample of withdrawn bodily fluid into a flow cell, the flow cell comprising a region transmissive to visible light; measuring the concentration of at least one analyte in the sample of withdrawn bodily fluid using an enzymatic sensor provided within the flow cell; measuring the concentration of hemoglobin in the sample of withdrawn bodily fluid using an optical system configured to transmit visible light through the region of the flow cell transmissive to visible light; and returning the sample of withdrawn bodily fluid to the patient.
In a 13th example, the method of Example 12, wherein the sample of bodily fluid is withdrawn using a pump.
In a 14th example, the method of any of Examples 12-13, wherein the concentration of the at least one analyte in the sample of withdrawn bodily fluid using an enzymatic sensor is measured in a time interval less than or equal to 1 minute.
In a 15th example, the method of any of Examples 12-14, wherein the optical system comprises a photodetector configured to detect light scattered or transmitted through the sample of withdrawn bodily fluid.
In a 16th example, a flow cell configured to analyze bodily fluid and determine concentration of at least one analyte in the bodily fluid comprises: an inlet configured to allow flow of a sample of the bodily fluid therethrough; an outlet configured to allow flow of the sample of the bodily fluid therethrough; a flow cell chamber in fluid communication with the inlet and the outlet, the flow cell chamber comprising: an analysis region configured to detect presence of at least one analyte in the withdrawn bodily fluid, wherein the analysis region comprises at least one enzymatic sensor configured to detect presence of the at least one analyte; and an optical investigation region transmissive to visible light, the optical investigation region configured to be in optical communication with an optical system comprising a visible light source and an optical detector.
In a 17th example, the flow cell of Example 16, comprising a moldable material.
In a 18th example, the flow cell of any of Examples 16-17, wherein the analysis region comprises at least one membrane configured to allow diffusion of the at least one analyte from the withdrawn bodily fluid towards the enzymatic sensor.
In a 19th example, the flow cell of any of Examples 16-18, wherein the at least one membrane is configured to allow fast diffusion of the at least one analyte from the withdrawn bodily fluid towards the enzymatic sensor such that an electrical output of the enzymatic sensor reaches a saturation level in a time interval less than or equal to about 1 minute.
In a 20th example, the flow cell of any of Examples 16-19, wherein the enzymatic sensor comprises at least one of a glucose sensor or a lactate sensor.
In a 21th example, the flow cell of any of Examples 16-20, wherein at least one enzymatic sensor configured to detect presence of the at least one analyte comprises both an enzymatic lactate sensor and an enzymatic glucose sensor.
In a 22nd example, the flow cell of any of Examples 16-21, wherein a cross-sectional area of the flow chamber is substantially equal to a cross-sectional area of the first inlet/outlet or the second inlet/outlet.
In a 23rd example, a method of manufacturing a flow cell comprises: providing a first section comprising: a first semi-cylindrical opening at a first end of the first section and a second semi-cylindrical opening at a second end of the first section; and a widened region connected to the first and the second semi-cylindrical openings, the widened region comprising a slot for receiving an enzymatic sensor, at least a portion of the widened region comprising a material transmissive to visible light; providing a second section comprising: a first semi-cylindrical opening at a first end of the second section and a second semi-cylindrical opening at a second end of the second section; and a widened region connected to the first and the second semi-cylindrical openings, the widened region comprising a slot for receiving an enzymatic sensor, at least a portion of the widened region comprising a material transmissive to visible light; and attaching the first section and the second section such that: the first semi-cylindrical openings of the first and the section sections form a first tubular opening, the second semi-cylindrical openings of the first and the section sections form a second tubular opening, and the widened regions of the first and the section sections form a widened chamber, wherein a cross-sectional area of the widened chamber is substantially equal to the cross-sectional areas of the first and the second tubular openings.
In a 24th example, the method of manufacturing the flow cell of Example 23, wherein attaching the first section and the second section comprises laser welding the first and the second sections.
In a 25th example, the method of manufacturing the flow cell of any of Examples 23-24, wherein a dimension of the widened region is less than 250 microns.
Reference throughout this specification to “some embodiments” or “an embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least some embodiments. Thus, appearances of the phrases “in some embodiments” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment and may refer to one or more of the same or different embodiments. Furthermore, the particular features, structures or characteristics may be combined in any suitable manner, as would be apparent to one of ordinary skill in the art from this disclosure, in one or more embodiments.
As used in this application, the terms “comprising,” “including,” “having,” and the like are synonymous and are used inclusively, in an open-ended fashion, and do not exclude additional elements, features, acts, operations, and so forth. Also, the term “or” is used in its inclusive sense (and not in its exclusive sense) so that when used, for example, to connect a list of elements, the term “or” means one, some, or all of the elements in the list.
Similarly, it should be appreciated that in the above description of embodiments, various features are sometimes grouped together in a single embodiment, figure, or description thereof for the purpose of streamlining the disclosure and aiding in the understanding of one or more of the various inventive aspects. This method of disclosure, however, is not to be interpreted as reflecting an intention that any claim require more features than are expressly recited in that claim. Rather, inventive aspects lie in a combination of fewer than all features of any single foregoing disclosed embodiment.
Embodiments of the disclosed systems and methods may be used and/or implemented with local and/or remote devices, components, and/or modules. The term “remote” may include devices, components, and/or modules not stored locally, for example, not accessible via a local bus. Thus, a remote device may include a device which is physically located in the same room and connected via a device such as a switch or a local area network. In other situations, a remote device may also be located in a separate geographic area, such as, for example, in a different location, building, city, country, and so forth.
Methods and processes described herein may be embodied in, and partially or fully automated via, software code modules executed by one or more general and/or special purpose computers. The word “module” refers to logic embodied in hardware and/or firmware, or to a collection of software instructions, possibly having entry and exit points, written in a programming language, such as, for example, C or C++. A software module may be compiled and linked into an executable program, installed in a dynamically linked library, or may be written in an interpreted programming language such as, for example, BASIC, Perl, or Python. It will be appreciated that software modules may be callable from other modules or from themselves, and/or may be invoked in response to detected events or interrupts. Software instructions may be embedded in firmware, such as an erasable programmable read-only memory (EPROM). It will be further appreciated that hardware modules may be comprised of connected logic units, such as gates and flip-flops, and/or may be comprised of programmable units, such as programmable gate arrays, application specific integrated circuits, and/or processors. The modules described herein are preferably implemented as software modules, but may be represented in hardware and/or firmware. Moreover, although in some embodiments a module may be separately compiled, in other embodiments a module may represent a subset of instructions of a separately compiled program, and may not have an interface available to other logical program units.
In certain embodiments, code modules may be implemented and/or stored in any type of computer-readable medium or other computer storage device. In some systems, data (and/or metadata) input to the system, data generated by the system, and/or data used by the system can be stored in any type of computer data repository, such as a relational database and/or flat file system. Any of the systems, methods, and processes described herein may include an interface configured to permit interaction with patients, health care practitioners, administrators, other systems, components, programs, and so forth.
A number of applications, publications, and external documents may be incorporated by reference herein. Any conflict or contradiction between a statement in the body text of this specification and a statement in any of the incorporated documents is to be resolved in favor of the statement in the body text.
Although described in the illustrative context of certain preferred embodiments and examples, it will be understood by those skilled in the art that the disclosure extends beyond the specifically described embodiments to other alternative embodiments and/or uses and obvious modifications and equivalents. Thus, it is intended that the scope of the claims which follow should not be limited by the particular embodiments described above.
This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Application No. 62/642,561 (Atty. Docket No. OPTIS.280PR), titled “FLUID ANALYTE DETECTION SYSTEMS AND METHODS,” filed on Mar. 13, 2018. The entire disclosure of each of the above-identified applications is incorporated by reference herein and made part of this specification.
| Number | Date | Country | |
|---|---|---|---|
| 62642561 | Mar 2018 | US |
