Patent Application
20070060872
1. Field
Certain embodiments disclosed herein relate to methods and apparatus for determining the concentration of an analyte in a sample, such as an analyte in a sample of bodily fluid, as well as methods and apparatus which can be used to support the making of such determinations.
2. Description of the Related Art
It is a common practice to measure the levels of certain analytes, such as glucose, in a bodily fluid, such as blood. Often this is done 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. Certain currently known systems for analyte monitoring in a hospital or clinical setting suffer from various drawbacks.
In one embodiment, an apparatus for monitoring a predetermined parameter of a patient's body fluid and infusing the patient is disclosed. The apparatus comprises an infusion line having a patient end configured for fluid communication with a blood vessel of the patient, a source of an infusion fluid, the source being in fluid communication with the infusion line, and a reversible infusion pump coupled to the infusion line. The apparatus further comprises a body fluid sensor assembly mounted in fluid communication with the infusion line and including a first sensor. The first sensor comprises an optical sensor configured to provide a signal indicative of a predetermined parameter of fluid present in the infusion line near the first sensor. The apparatus further comprises a controller that is configured to operate the infusion pump in a forward direction, to pump the infusion fluid through the infusion line toward the patient end. The controller is configured to intermittently interrupt its operation of the infusion pump in the forward direction to operate the infusion pump in a rearward direction, to draw a body fluid sample from the patient through the patient end of the infusion line.
An embodiment of a method of extracting and analyzing bodily fluids from a patient at the point of care for the patient comprises establishing fluid communication between an analyte detection system, a sensor assembly, and a bodily fluid in the patient. The sensor assembly comprises a first sensor. The method further comprises drawing from the patient a portion of the bodily fluid and separating from the drawn portion a first component of the bodily fluid, while the analyte detection system and the sensor assembly remain in fluid communication with the patient. The method additionally comprises analyzing, with the analyte detection system, the first component to measure a concentration of an analyte. In certain other embodiments, the first sensor comprises an optical sensor.
One embodiment of an apparatus for extracting and analyzing bodily fluids from a patient at the point of care for the patient comprises an infusion line having a patient end configured for fluid communication with a blood vessel of the patient, a source of an infusion fluid, the source in fluid communication with the infusion line, and a reversible infusion pump coupled to the infusion line. The apparatus further comprises a body fluid sensor assembly mounted in fluid communication with the infusion line and including a first sensor. The first sensor is configured to provide a signal indicative of a predetermined parameter of fluid present in the infusion line near the first sensor. Additionally, the apparatus includes a controller that is configured to operate the infusion pump in a forward direction, to pump the infusion fluid through the infusion line toward the patient end. The controller is configured to intermittently interrupt its operation of the infusion pump in the forward direction to operate the infusion pump in a rearward direction, to draw a body fluid sample from the patient through the patient end of the infusion line. The apparatus also comprises a fluid component separator mounted in fluid communication with the infusion line and configured to separate from the body fluid sample a first component of the body fluid sample. In certain other embodiments, the first sensor comprises an optical sensor.
In one embodiment, an apparatus for monitoring a predetermined parameter of a patient's blood while infusing an infusion fluid into the patient is disclosed. The apparatus comprises an infusion line having a patient end configured for insertion into a blood vessel of the patient, a source of an infusion fluid, the source being in fluid communication with the infusion line, and a reversible infusion pump coupled to the infusion line. The apparatus also includes a blood chemistry sensor assembly mounted in fluid communication with the infusion line and including a first sensor that provides a signal indicative of a predetermined parameter of fluid present in the infusion line. The apparatus further comprises a device operatively connected to the apparatus to provide one or more anti-clotting agents to at least a portion of the infusion line. The apparatus further comprises a controller configured to operate the infusion pump in a forward direction, to pump the infusion fluid through the patient end of the infusion line for infusion into the patient. The controller is configured to intermittently interrupt its operation of the infusion pump in the forward direction to operate the infusion pump in a rearward direction, to draw a blood sample from the patient through the patient end of the infusion line into sensing contact with the first sensor of the blood chemistry sensor assembly. In certain other embodiments, the first sensor comprises an optical sensor.
In another embodiment, a patient status monitoring system is disclosed. The system comprises a first body fluid analyzer and a body fluid sensor assembly. The body fluid sensor assembly includes a first sensor that provides a signal indicative of a predetermined parameter of fluid present in the body fluid sensor assembly. The system includes a controller configured to monitor the signal from the body fluid sensor assembly and to detect a change in the signal indicative of an arrival of the fluid present in the body fluid sensor assembly at the first sensor. The system further comprises a fluid passageway configured to provide fluid communication among the first body fluid analyzer, the body fluid sensor assembly, and a body fluid in a patient. The first body fluid analyzer is configured to be in communication with a data network, which includes at least one data file. The first body fluid analyzer is configured to access the at least one data file via the data network. In certain other embodiments, the first sensor comprises an optical sensor.
An embodiment of an analyte detection system comprises a body fluid sensor assembly including a first sensor. The first sensor is configured to provide information relating to a measurement of at least one analyte in a body fluid sample that is in sensing contact with the first sensor. The system further comprises a processor and stored program instructions executable by the processor such that the system: (a) identifies, based on the measurement, one or more possible interferents to the measurement of the at least one analyte in the body fluid sample; (b) calculates a calibration which reduces error attributable to the one or more possible interferents; (c) applies the calibration to the measurement; and (d) estimates, based on the calibrated measurement, a concentration of the at least one analyte in the body fluid sample. In certain other embodiments, the first sensor comprises an optical sensor.
One embodiment of an apparatus for analyzing the composition of bodily fluid comprises a first fluid passageway having a patient end, which is configured to provide fluid communication with a bodily fluid within a patient, and at least one pump coupled to the first fluid passageway. The at least one pump is configured to have an infusion mode in which the pump is operable to deliver infusion fluid to the patient through the patient end and a sample draw mode in which the pump is operable to draw a sample of the bodily fluid from the patient through the patient end. The apparatus further comprises a controller that is configured to operate the at least one pump in the infusion mode and in the sample draw mode. The apparatus also comprises a spectroscopic analyte detection system accessible via the first fluid passageway such that the analyte detection system can receive at least one component of the drawn sample of bodily fluid and can determine a concentration of at least one analyte. The analyte detection system is spaced from the patient end of the first fluid passageway. The apparatus also includes a body fluid sensor assembly mounted in fluid communication with the first fluid passageway at or near the patient end and spaced from the analyte detection system. The body fluid sensor assembly includes a first sensor and a second sensor. The first sensor is configured to sense a first property indicative of the fluid within the first fluid passageway and to provide a first signal indicative of the first property. The second sensor is configured to sense a second property indicative of the fluid within the first fluid passageway and to provide a second signal indicative of the second property. The controller is configured to monitor the first signal provided by the first sensor and to detect a change in the first signal indicative of an arrival of the drawn sample of body fluid at the first sensor.
In some embodiments of the apparatus for analyzing the composition of bodily fluid, the first sensor is selected from the group consisting of a colorimetric sensor, a hemoglobin sensor, a hematocrit sensor, a pressure sensor, a dilution sensor, and a bubble sensor. In other embodiments, the second sensor comprises an electrochemical sensor or an optical sensor.
One embodiment of a fluid handling and analysis system comprises a fluid transport network comprising at least a first fluid passageway. The fluid transport network includes a patient end configured to maintain fluid communication with a bodily fluid in a patient and a sample analysis chamber and waste container, each accessible by the fluid transport network. The system also includes a bodily fluid sensor assembly in fluid communication with the fluid transport network. The bodily fluid sensor assembly includes a first sensor that provides a signal indicative of a predetermined parameter of fluid present in the first fluid passageway. Additionally, the system includes a pump unit in operative engagement with the fluid transport network and configured to have an infusion mode in which the pump unit delivers an infusion fluid to the patient through the patient end and a sample draw mode in which the pump unit draws a volume of the bodily fluid from the patient through the patient end, toward the sample analysis chamber. The fluid transport network and the pump unit are configured to draw a volume of the bodily fluid from the patient, isolate a fraction of the bodily fluid from the volume, and pass the fraction to the sample analysis chamber and then to the waste container. In certain other embodiments, the first sensor comprises an optical sensor.
An embodiment of an apparatus for monitoring a predetermined parameter of a patient's body fluid while infusing an infusion fluid into the patient is disclosed. The apparatus comprises an infusion line having a patient end configured for insertion into a blood vessel of the patient, a source of an infusion fluid, the source being in fluid communication with the infusion line, and a reversible infusion pump coupled to the infusion line. The apparatus also includes a body fluid sensor assembly mounted in fluid communication with the infusion line. The sensor assembly includes a temperature sensor that provides temperature information relating to fluid present in the body fluid sensor assembly. The sensor assembly also includes a first sensor that provides a signal indicative of a parameter of fluid present in the body fluid sensor assembly. The apparatus further comprises a controller configured to operate the infusion pump in a forward direction, to pump the infusion fluid through the infusion line for infusion into the patient. The controller is configured to intermittently interrupt its operation of the infusion pump in the forward direction to operate the infusion pump in a rearward direction, to draw a body fluid sample from the patient through the patient end of the infusion line into sensing contact with the first sensor and the temperature sensor of the body fluid sensor assembly. The controller further is configured to monitor the signal provided by the first sensor of the body fluid sensor assembly and to detect a change in the first signal indicative of an arrival of the body fluid sample at the first sensor. The signal produced by the first sensor provides an indication of a predetermined parameter of the patient's body fluid when the body fluid sample is in sensing contact with the first sensor. The controller is configured to acquire the temperature information and to use the temperature information when determining the predetermined parameter of the patient's body fluid. In certain other embodiments, the first sensor comprises an optical sensor.
In one embodiment, an apparatus is provided for monitoring a predetermined parameter of a patient's body fluid while infusing an infusion fluid into the patient. The apparatus comprises an infusion line and a catheter configured for insertion into a blood vessel of the patient, and a reversible infusion pump connected between a source of an infusion fluid and the infusion line and catheter. The apparatus further comprises a body fluid sensor assembly mounted in fluid communication with the infusion line and which includes a first sensor and a sample cell. The first sensor provides a signal indicative of a predetermined parameter of any fluid present in the infusion line. The sample cell is substantially transmissive to light comprising a wavelength λ. The apparatus further comprises a controller configured to operate the infusion pump in a forward direction so as to pump the infusion fluid through the infusion line and catheter for infusion into the patient. The controller is configured to intermittently interrupt its operating of the infusion pump in the forward direction to operate the infusion pump in a rearward direction so as to draw a body fluid sample from the patient through the catheter and infusion line. The body fluid sample drawn from the patient is disposed such that a first portion of the body fluid sample is in sensing contact with the first sensor of the body fluid sensor assembly, and a second portion of the body fluid sample is disposed within the sample cell of the body fluid sensor assembly. The controller further is configured to monitor the signal provided by the first sensor of the body fluid sensor assembly and to detect a change in the signal indicative of the arrival of the body fluid sample at the first sensor. The controller, in response to detecting the arrival of the body fluid sample at the first sensor, is configured to cease its operating of the infusion pump in the rearward direction. The signal produced by the first sensor provides an indication of a predetermined parameter of the patient's body fluid when the body fluid sample is in sensing contact with the first sensor.
In another embodiment, the apparatus further comprises a light source configured to produce light comprising the wavelength λ and a light detector configured to be responsive to light comprising the wavelength λ. An optical path is defined from the light source to the sample cell and from the sample cell to the light detector such that the light source, the light detector, and the sample cell are configured to be in optical communication along the optical path.
One embodiment of a method of extracting and analyzing bodily fluids from a patient at the point of care for the patient is disclosed. The method comprises establishing fluid communication between an analyte detection system, a sensor assembly, and a bodily fluid in the patient. The sensor assembly comprises a first sensor. The method further comprises drawing from the patient a portion of the bodily fluid and monitoring a signal produced by the first sensor of the sensor assembly and detecting a change in the signal indicative of an arrival of the bodily fluid at the first sensor. The method additionally comprises ceasing to draw the bodily fluid from the patient in response to detecting the arrival of the bodily fluid at the first sensor and separating from the drawn portion a first component of the bodily fluid, while the analyte detection system and the sensor assembly remain in fluid communication with the patient. Additionally, the analyte detection system is used for analyzing the first component to measure a concentration of an analyte.
An embodiment of an apparatus for monitoring a predetermined parameter of a patient's blood while infusing an infusion fluid into the patient is disclosed. The apparatus comprises an infusion line and a catheter configured for insertion into a blood vessel of the patient and a reversible infusion pump connected between a source of an infusion fluid and the infusion line and catheter. The apparatus also includes a blood chemistry sensor assembly mounted in fluid communication with the infusion line and which includes a first sensor that provides a signal indicative of a predetermined parameter of any fluid present in the infusion line. A device is operatively connected to provide one or more anti-clotting agents to at least a portion of the infusion line. The apparatus further comprises a controller that operates the infusion pump in a forward direction so as to pump the infusion fluid through the infusion line and catheter for infusion into the patient. The controller intermittently interrupts its operating of the infusion pump in the forward direction to operate the infusion pump in a rearward direction so as to draw a blood sample from the patient through the catheter and infusion line into sensing contact with the first sensor of the blood chemistry sensor assembly. The controller further is configured to monitor the signal provided by the first sensor of the blood chemistry sensor assembly and to detect a change in the signal indicative of the arrival of the blood sample at the first sensor. The controller, in response to detecting the arrival of the blood sample at the first sensor, ceases its operating of the infusion pump in the rearward direction. The signal that is produced by the first sensor provides an indication of a predetermined parameter of the patient's blood when the blood sample is in sensing contact with the first sensor.
In another embodiment of this apparatus, the one or more anti-clotting agents comprise a detergent, and the device provides the detergent within at least a portion of the infusion line. In yet another embodiment of the apparatus, the anti-clotting device comprises an ultrasound generator positionable to transmit an ultrasonic energy to the infusion line.
An embodiment of a patient status monitoring system comprises a body fluid analyzer, a body fluid sensor assembly including a first sensor that provides a signal indicative of a predetermined parameter of any fluid present in the body fluid sensor assembly, and a controller configured to monitor the signal from the body fluid sensor assembly and to detect a change in the signal indicative of an arrival of the body fluid sample at the first sensor. The system also comprises a fluid passageway configured to provide fluid communication among the body fluid analyzer, the body fluid sensor assembly, and a body fluid in a patient. The controller is configured to be in communication with a data network that is configured to include at least one data file. The controller is configured to access the at least one data file via the data network. In another embodiment, the controller is configured to update the at least one data file.
In another embodiment of the patient status monitoring system, the system further comprises an infusion line and a catheter configured for insertion into a blood vessel of the patient and a reversible infusion pump connected between a source of an infusion fluid and the infusion line and catheter. The controller is configured to operate the infusion pump in a forward direction so as to pump the infusion fluid through the infusion line and catheter for infusion into the patient. The controller is configured to intermittently interrupt its operating of the infusion pump in the forward direction to operate the infusion pump in a rearward direction so as to draw a body fluid sample from the patient through the catheter and infusion line into sensing contact with the first sensor of the body fluid sensor assembly. The controller, in response to detecting the arrival of the body fluid sample at the first sensor, ceases its operating of the infusion pump in the rearward direction. The signal produced by the first sensor provides an indication of a predetermined parameter of the patient's body fluid when the body fluid sample is in sensing contact with the first sensor.
An embodiment of an analyte detection system comprises a body fluid sensor assembly including a first sensor that is configured to provide information relating to a measurement of at least one analyte in a body fluid sample that is in sensing contact with the first sensor. The system includes a processor and stored program instructions executable by the processor. The stored program instructions are such that the system can identify, based on the measurement, one or more possible interferents to the measurement of the at least one analyte in the body fluid sample, calculate a calibration which reduces error attributable to the one or more possible interferents, apply the calibration to the measurement, and estimate, based on the calibrated measurement, a concentration of the at least one analyte in the body fluid sample.
Another embodiment of this analyte detection system further comprises an infusion line and a catheter configured for insertion into a blood vessel of a patient and a reversible infusion pump fluidly connected between a source of an infusion fluid and the infusion line and catheter. The infusion pump and the body fluid sensor assembly are configured to be in fluid communication with the infusion line. A controller operates the infusion pump in a forward direction so as to pump the infusion fluid through the infusion line and catheter for infusion into the patient. The controller intermittently interrupts its operating of the infusion pump in the forward direction to operate the infusion pump in a rearward direction so as to draw the body fluid sample from the patient through the catheter and infusion line into sensing contact with the first sensor of body fluid sensor assembly. The controller further is configured to monitor the signal provided by the first sensor of the body fluid sensor assembly and to detect a change in the signal indicative of the arrival of the body fluid sample at the first sensor. The controller, in response to detecting the arrival of the body fluid sample at the first sensor, ceases its operating of the infusion pump in the rearward direction.
An embodiment of an apparatus for analyzing the composition of bodily fluid comprises a first fluid passageway having a patient end which is configured to provide fluid communication with a bodily fluid within a patient and at least one pump coupled to the first fluid passageway. The at least one pump has an infusion mode in which the pump is operable to deliver infusion fluid to the patient through the patient end and a sample draw mode in which the pump is operable to draw a sample of the bodily fluid from the patient through the patient end. A controller is configured to operate the at least one pump in the infusion mode and in the sample draw mode. The apparatus includes a spectroscopic analyte detection system accessible via the first fluid passageway such that the analyte detection system can receive at least one component of the drawn sample of bodily fluid and can determine a concentration of at least one analyte. The analyte detection system is spaced from the patient end of the first fluid passageway. The apparatus also includes a body fluid sensor assembly mounted in fluid communication with the first fluid passageway at or near the patient end and spaced from the analyte detection system. The body fluid sensor assembly includes a first sensor configured to sense a property of the fluid within the first fluid passageway and configured to provide a signal indicative of the property. The controller is configured to monitor the signal provided by the first sensor of the body fluid sensor assembly and to detect a change in the signal indicative of an arrival of the body fluid at the first sensor.
In another embodiment of the apparatus for analyzing the composition of bodily fluid, the first sensor is selected from the group consisting of a calorimetric sensor, a hemoglobin sensor, a hematocrit sensor, a pressure sensor, a dilution sensor, and a bubble sensor
An embodiment of a fluid handling and analysis system is disclosed. The system comprises a fluid transport network, which comprises at least a first fluid passageway. The fluid transport network also includes a patient end configured to maintain fluid communication with a bodily fluid in a patient. The system includes a sample analysis chamber and waste container, which are each accessible by the fluid transport network. A bodily fluid sensor assembly is configured to be in fluid communication with the fluid transport network and includes a first sensor that provides a signal indicative of a predetermined parameter of any fluid present in the first fluid passageway. A pump unit is in operative engagement with the fluid transport network. The pump unit has an infusion mode in which the pump unit delivers an infusion fluid to the patient through the patient end and a sample draw mode in which the pump unit draws a volume of the bodily fluid from the patient through the patient end and toward the sample analysis chamber. A spectroscopic fluid analyzer is configured to analyze a sample of the bodily fluid while the sample is in the sample analysis chamber and to determine a concentration of at least one analyte. The fluid transport network and the pump unit are configured to draw a volume of the bodily fluid from the patient, isolate a fraction of the bodily fluid from the volume, and pass the fraction to the sample analysis chamber and then to the waste container.
An embodiment of an apparatus for monitoring a predetermined parameter of a patient's body fluid while infusing an infusion fluid into the patient is disclosed. The apparatus comprises an infusion line and a catheter configured for insertion into a blood vessel of the patient and a reversible infusion pump connected between a source of an infusion fluid and the infusion line and catheter. A body fluid sensor assembly is mounted in fluid communication with the infusion line and includes a first sensor that provides a signal indicative of a parameter of any fluid present in the body fluid sensor assembly. The body fluid sensor assembly further includes a thermal device. A controller operates the infusion pump in a forward direction so as to pump the infusion fluid through the infusion line and catheter for infusion into the patient. The controller intermittently interrupts its operating of the infusion pump in the forward direction to operate the infusion pump in a rearward direction so as to draw a body fluid sample from the patient through the catheter and infusion line into sensing contact with the first sensor and the thermal device of the body fluid sensor assembly. The controller further is configured to monitor the signal provided by the first sensor of the body fluid sensor assembly and to detect a change in the first signal indicative of an arrival of the body fluid sample at the first sensor. The controller, in response to detecting the arrival of the body fluid sample at the first sensor, ceases its operating of the infusion pump in the rearward direction. The signal that is produced by the first sensor provides an indication of a predetermined parameter of the patient's body fluid when the body fluid sample is in sensing contact with the first sensor. The controller is configured to communicate with the thermal device so as to regulate a temperature of the body fluid sample.
In other embodiments of the apparatus for monitoring a predetermined parameter of a patient's body fluid, the thermal device may comprise a thermoelectric device. In one embodiment, the thermoelectric device comprises a Peltier thermoelectric device.
Certain objects and advantages of the invention(s) are described herein. Of course, it is to be understood that not necessarily all such objects or advantages may be achieved in accordance with any particular embodiment. Thus, for example, those skilled in the art will recognize that the invention(s) may be embodied or carried out in a manner that achieves or optimizes one advantage or group of advantages as taught herein without necessarily achieving other objects or advantages as may be taught or suggested herein.
Certain embodiments are summarized above. However, despite the foregoing discussion of certain embodiments, only the appended claims (and not the present summary) are intended to define the invention(s). The summarized embodiments, and other embodiments, will become readily apparent to those skilled in the art from the following detailed description of the preferred embodiments having reference to the attached figures, the invention(s) not being limited to any particular embodiment(s) disclosed.
Reference symbols are used in the Figures to indicate certain components, aspects or features shown therein, with reference symbols common to more than one Figure indicating like components, aspects or features shown therein.
Although certain preferred embodiments and examples are disclosed below, it will be understood by those skilled in the art that the inventive subject matter extends beyond the specifically disclosed embodiments to other alternative embodiments and/or uses of the invention, and to obvious modifications and equivalents thereof. Thus it is intended that the scope of the inventions herein disclosed should not be limited by the particular disclosed embodiments described below. Thus, for example, in any method or process disclosed herein, the acts or operations making up the method/process may be performed in any suitable sequence, and are not necessarily limited to any particular disclosed sequence. For purposes of contrasting various embodiments with the prior art, certain aspects and advantages of these embodiments are described where appropriate herein. Of course, it is to be understood that not necessarily all such aspects or advantages may be achieved in accordance with any particular embodiment. Thus, for example, it should be recognized that the 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 be taught or suggested herein. While the systems and methods discussed herein can be used for invasive techniques, the systems and methods can also be used for non-invasive techniques or other suitable techniques, and can be used in hospitals, healthcare facilities, ICUs, or residences.
Overview of Embodiments of Fluid Handling Systems
Disclosed herein are fluid handling systems and various methods of analyzing sample fluids.
The fluid handling system 10 is located bedside and generally comprises a container 15 holding the infusion fluid 14 and a sampling system 100 which is in communication with both the container 15 and the patient P. In some embodiments, the fluid handling system 10 can be in fluid communication with an extracorporeal fluid conduit containing a volume of a bodily fluid. A tube 13 extends from the container 15 to the sampling system 100. A tube 12 extends from the sampling system 100 to the patient P. In some embodiments, in lieu of the depicted tube 12, any suitable extracorporeal fluid conduit, such as a catheter, IV tube or an IV network, can be connected to the sampling system 100 with a connector such as the depicted connector 110. The extracorporeal fluid conduit need not be attached to the patient P; for example, the extracorporeal fluid conduit can be in fluid communication with a container of the bodily fluid of interest (e.g. blood), or the extracorporeal fluid conduit can serve as a stand-alone volume of the bodily fluid of interest. In some embodiments, one or more components of the fluid handling system 10 can be located at another facility, room, or other suitable remote location. One or more components of the fluid handling system 10 can communicate with one or more other components of the fluid handling system 10 (or with other devices) by any suitable communication means, such as communication interfaces including, but not limited to, optical interfaces, electrical interfaces, and wireless interfaces. These interfaces can be part of a local network, internet, wireless network, or other suitable networks.
The infusion fluid 14 can comprise water, saline, dextrose, lactated Ringer's solution, drugs, insulin, mixtures thereof, or other suitable substances. The illustrated sampling system 100 allows the infusion fluid to pass to the patient P and/or uses the infusion fluid in the analysis. In some embodiments, the fluid handling system 10 may not employ infusion fluid. The fluid handling system 10 may thus draw samples without delivering any fluid to the patient P.
The sampling system 100 can be removably or permanently coupled to the tube 13 and tube 12 via connectors 110, 120. The patient connector 110 can selectively control the flow of fluid through a bundle 130, which includes a patient connection passageway 112 and a sampling passageway 113, as shown in
The illustrated fluid handling and analysis apparatus 140 has a display 141 and input devices 143. The illustrated fluid handling and analysis apparatus 140 can also have a sampling unit 200 configured to analyze the drawn fluid sample. The sampling unit 200 can thus receive a sample, prepare the sample, and/or subject the sample (prepared or unprepared) to one or more tests. The sampling unit 200 can then analyze results from the tests. The sampling unit 200 can include, but is not limited to, separators, filters, centrifuges, sample elements, and/or detection systems, as described in detail below. The sampling unit 200 (see
With continued reference to
In some embodiments, the fluid handling system 10 can draw and analyze body fluid sample(s) from the patient P to provide real-time or near-real-time measurement of glucose levels. Body fluid samples can be drawn from the patient P continuously, at regular intervals (e.g., every 5, 10, 15, 20, 30 or 60 minutes), at irregular intervals, or at any time or sequence for desired measurements. These measurements can be displayed bedside with the display 141 for convenient monitoring of the patient P.
The illustrated fluid handling system 10 is mounted to a stand 16 and can be used in hospitals, ICUs, residences, healthcare facilities, and the like. In some embodiments, the fluid handling system 10 can be transportable or portable for an ambulatory patient. The ambulatory fluid handling system 10 can be coupled (e.g., strapped, adhered, etc.) to a patient, and may be smaller than the bedside fluid handling system 10 illustrated in
In some embodiments, the fluid handling system 10 is a disposable fluid handling system and/or has one or more disposable components. As used herein, the term “disposable” when applied to a system or component (or combination of components), such as a cassette or sample element, is a broad term and means, without limitation, that the component in question is used a finite number of times and then discarded. Some disposable components are used only once and then discarded. Other disposable components are used more than once and then discarded. For example, the fluid handling and analysis apparatus 140 can have a main instrument and a disposable cassette that can be installed onto the main instrument, as discussed below. The disposable cassette can be used for predetermined length of time, to prepare a predetermined amount of sample fluid for analysis, etc. In some embodiments, the cassette can be used to prepare a plurality of samples for subsequent analyses by the main instrument. The reusable main instrument can be used with any number of cassettes as desired. Additionally or alternatively, the cassette can be a portable, handheld cassette for convenient transport. In these embodiments, the cassette can be manually mounted to or removed from the main instrument. In some embodiments, the cassette may be a non disposable cassette which can be permanently coupled to the main instrument, as discussed below.
Disclosed herein are a number of embodiments of fluid handling systems, sampling systems, fluid handling and analysis apparatuses, analyte detection systems, and methods of using the same. Section I below discloses various embodiments of the fluid handling system that may be used to transport fluid from a patient for analysis. Section II below discloses several embodiments of fluid handling methods that may be used with the apparatus discussed in Section I. Section III below discloses several embodiments of a sampling system that may be used with the apparatus of Section I or the methods of Section II. Section IV below discloses various embodiments of a sample analysis system that may be used to detect the concentration of one or more analytes in a material sample. Section V below discloses methods for determining analyte concentrations from sample spectra.
Section I—Fluid Handling System
More specifically,
As used herein, the term “passageway” is a broad term and is used in its ordinary sense and includes, without limitation except as explicitly stated, as any opening through a material through which a fluid, such as a liquid or a gas, may pass so as to act as a conduit. Passageways include, but are not limited to, flexible, inflexible or partially flexible tubes, laminated structures having openings, bores through materials, or any other structure that can act as a conduit and any combination or connections thereof. The internal surfaces of passageways that provide fluid to a patient or that are used to transport blood are preferably biocompatible materials, including but not limited to silicone, polyetheretherketone (PEEK), or polyethylene (PE). One type of preferred passageway is a flexible tube having a fluid contacting surface formed from a biocompatible material. A passageway, as used herein, also includes separable portions that, when connected, form a passageway.
The inner passageway surfaces may include coatings of various sorts to enhance certain properties of the conduit, such as coatings that affect the ability of blood to clot or to reduce friction resulting from fluid flow. Coatings include, but are not limited to, molecular or ionic treatments.
As used herein, the term “connected” is a broad term and is used in its ordinary sense and includes, without limitation except as explicitly stated, with respect to two or more things (e.g., elements, devices, patients, etc.): a condition of physical contact or attachment, whether direct, indirect (via, e.g., intervening member(s)), continuous, selective, or intermittent; and/or a condition of being in fluid, electrical, or optical-signal communication, whether direct, indirect, continuous, selective (e.g., where there exist one or more intervening valves, fluid handling components, switches, loads, or the like), or intermittent. A condition of fluid communication is considered to exist whether or not there exists a continuous or contiguous liquid or fluid column extending between or among the two or more things in question. Various types of connectors can connect components of the fluid handling system described herein. As used herein, the term “connector” is a broad term and is used in its ordinary sense and includes, without limitation except as explicitly stated, as a device that connects passageways or electrical wires to provide communication (whether direct, indirect, continuous, selective, or intermittent) on either side of the connector. Connectors contemplated herein include a device for connecting any opening through which a fluid may pass. These connectors may have intervening valves, switches, fluid handling devices, and the like for affecting fluid flow. In some embodiments, a connector may also house devices for the measurement, control, and preparation of fluid, as described in several of the embodiments.
Fluid handling and analysis apparatus 140 may control the flow of fluids through passageways 20 and the analysis of samples drawn from a patient P, as described subsequently. Fluid handling and analysis apparatus 140 includes the display 141 and input devices, such as buttons 143. Display 141 provides information on the operation or results of an analysis performed by fluid handling and analysis apparatus 140. In one embodiment, display 141 indicates the function of buttons 143, which are used to input information into fluid handling and analysis apparatus 140. Information that may be input into or obtained by fluid handling and analysis apparatus 140 includes, but is not limited to, a required infusion or dosage rate, sampling rate, or patient specific information which may include, but is not limited to, a patient identification number or medical information. In an other alternative embodiment, fluid handling and analysis apparatus 140 obtains information on patient P over a communications network, for example an hospital communication network having patient specific information which may include, but is not limited to, medical conditions, medications being administered, laboratory blood reports, gender, and weight. As one example of the use of fluid handling system 10, which is not meant to limit the scope of the present invention,
As discussed subsequently, fluid handling system 10 may catheterize a patient's vein or artery. Sampling system 100 is releasably connectable to container 15 and catheter 11. Thus, for example,
Patient connector 110 may also include one or more devices that control, direct, process, or otherwise affect the flow through passageways 112 and 113. In some embodiments, one or more lines 114 are provided to exchange signals between patient connector 110 and fluid handling and analysis apparatus 140. The lines 114 can be electrical lines, optical communicators, wireless communication channels, or other means for communication. As shown in
In various embodiments, fluid handling and analysis apparatus 140 and/or patient connector 110, includes other elements (not shown in
In one embodiment, patient connector 110 includes devices to determine when blood has displaced fluid 14 at the connector end, and thus provides an indication of when a sample is available for being drawn through passageway 113 for sampling. The presence of such a device at patient connector 110 allows for the operation of fluid handling system 10 for analyzing samples without regard to the actual length of tube 12. Accordingly, bundle 130 may include elements to provide fluids, including air, or information communication between patient connector 110 and fluid handling and analysis apparatus 140 including, but not limited to, one or more other passageways and/or wires.
In one embodiment of sampling system 100, the passageways and lines of bundle 130 are sufficiently long to permit locating patient connector 110 near patient P, for example with tube 12 having a length of less than 0.1 to 0.5 meters, or preferably approximately 0.15 meters and with fluid handling and analysis apparatus 140 located at a convenient distance, for example on a nearby stand 16. Thus, for example, bundle 130 is from 0.3 to 3 meters, or more preferably from 1.5 to 2.0 meters in length. It is preferred, though not required, that patient connector 110 and connector 120 include removable connectors adapted for fitting to tubes 12 and 13, respectively. Thus, in one embodiment, container 15/tube 13 and catheter 11/tube 12 are both standard medical components, and sampling system 100 allows for the easy connection and disconnection of one or both of the container and catheter from fluid handling system 10.
In another embodiment of sampling system 100, tubes 12 and 13 and a substantial portion of passageways 111 and 112 have approximately the same internal cross-sectional area. It is preferred, though not required, that the internal cross-sectional area of passageway 113 is less than that of passageways 111 and 112 (see
Thus, for example, in one embodiment passageways 111 and 112 are formed from a tube having an inner diameter from 0.3 millimeter to 1.50 millimeter, or more preferably having a diameter from 0.60 millimeter to 1.2 millimeter. Passageway 113 is formed from a tube having an inner diameter from 0.3 millimeter to 1.5 millimeter, or more preferably having an inner diameter of from 0.6 millimeter to 1.2 millimeter.
While
In
As described subsequently in several embodiments, sampling unit 200 may include one or more passageways, pumps and/or valves, and sampling assembly 220 may include passageways, sensors, valves, and/or sample detection devices. Controller 210 collects information from sensors and devices within sampling assembly 220, from sensors and analytical equipment within sampling unit 200, and provides coordinated signals to control pump 203 and pumps and valves, if present, in sampling assembly 220.
Fluid handling and analysis apparatus 140 includes the ability to pump in a forward direction (towards the patient) and in a reverse direction (away from the patient). Thus, for example, pump 203 may direct fluid 14 into patient P or draw a sample, such as a blood sample from patient P, from catheter 11 to sampling assembly 220, where it is further directed through passageway 113 to sampling unit 200 for analysis. Preferably, pump 203 provides a forward flow rate at least sufficient to keep the patient vascular line open. In one embodiment, the forward flow rate is from 1 to 5 ml/hr. In some embodiments, the flow rate of fluid is about 0.05 ml/hr, 0.1 ml/hr, 0.2 ml/hr, 0.4 ml/hr, 0.6 ml/hr, 0.8 ml/hr, 1.0 ml/hr, and ranges encompassing such flow rates. In some embodiments, for example, the flow rate of fluid is less than about 1.0 ml/hr. In certain embodiments, the flow rate of fluid may be about 0.1 ml/hr or less. When operated in a reverse direction, fluid handling and analysis apparatus 140 includes the ability to draw a sample from the patient to sampling assembly 220 and through passageway 113. In one embodiment, pump 203 provides a reverse flow to draw blood to sampling assembly 220, preferably by a sufficient distance past the sampling assembly to ensure that the sampling assembly contains an undiluted blood sample. In one embodiment, passageway 113 has an inside diameter of from 25 to 200 microns, or more preferably from 50 to 100 microns. Sampling unit 200 extracts a small sample, for example from 10 to 100 microliters of blood, or more preferably approximately 40 microliters volume of blood, from sampling assembly 220.
In one embodiment, pump 203 is a directionally controllable pump that acts on a flexible portion of passageway 111. Examples of a single, directionally controllable pump include, but are not limited to a reversible peristaltic pump or two unidirectional pumps that work in concert with valves to provide flow in two directions. In an alternative embodiment, pump 203 includes a combination of pumps, including but not limited to displacement pumps, such as a syringe, and/or valve to provide bi-directional flow control through passageway 111.
Controller 210 includes one or more processors for controlling the operation of fluid handling system 10 and for analyzing sample measurements from fluid handling and analysis apparatus 140. Controller 210 also accepts input from buttons 143 and provides information on display 141. Optionally, controller 210 is in bi-directional communication with a wired or wireless communication system, for example a hospital network for patient information. The one or more processors comprising controller 210 may include one or more processors that are located either within fluid handling and analysis apparatus 140 or that are networked to the unit.
The control of fluid handling system 10 by controller 210 may include, but is not limited to, controlling fluid flow to infuse a patient and to sample, prepare, and analyze samples. The analysis of measurements obtained by fluid handling and analysis apparatus 140 of may include, but is not limited to, analyzing samples based on inputted patient specific information, from information obtained from a database regarding patient specific information, or from information provided over a network to controller 210 used in the analysis of measurements by apparatus 140.
Fluid handling system 10 provides for the infusion and sampling of a patient blood as follows. With fluid handling system 10 connected to bag 15 having fluid 14 and to a patient P, controller 210 infuses a patient by operating pump 203 to direct the fluid into the patient. Thus, for example, in one embodiment, the controller directs that samples be obtained from a patient by operating pump 203 to draw a sample. In one embodiment, pump 203 draws a predetermined sample volume, sufficient to provide a sample to sampling assembly 220. In another embodiment, pump 203 draws a sample until a device within sampling assembly 220 indicates that the sample has reached the patient connector 110. As an example which is not meant to limit the scope of the present invention, one such indication is provided by a sensor that detects changes in the color of the sample. Another example is the use of a device that indicates changes in the material within passageway 111 including, but not limited to, a decrease in the amount of fluid 14, a change with time in the amount of fluid, a measure of the amount of hemoglobin, or an indication of a change from fluid to blood in the passageway.
When the sample reaches sampling assembly 220, controller 210 provides an operating signal to valves and/or pumps in sampling system 100 (not shown) to draw the sample from sampling assembly 220 into sampling unit 200. After a sample is drawn towards sampling unit 200, controller 210 then provides signals to pump 203 to resume infusing the patient. In one embodiment, controller 210 provides signals to pump 203 to resume infusing the patient while the sample is being drawn from sampling assembly 220. In an alternative embodiment, controller 210 provides signals to pump 203 to stop infusing the patient while the sample is being drawn from sampling assembly 220. In another alternative embodiment, controller 210 provides signals to pump 203 to slow the drawing of blood from the patient while the sample is being drawn from sampling assembly 220.
In another alternative embodiment, controller 210 monitors indications of obstructions in passageways or catheterized blood vessels during reverse pumping and moderates the pumping rate and/or direction of pump 203 accordingly. Thus, for example, obstructed flow from an obstructed or kinked passageway or of a collapsing or collapsed catheterized blood vessel that is being pumped will result in a lower pressure than an unobstructed flow. In one embodiment, obstructions are monitored using a pressure sensor in sampling assembly 220 or along passageways 20. If the pressure begins to decrease during pumping, or reaches a value that is lower than a predetermined value then controller 210 directs pump 203 to decrease the reverse pumping rate, stop pumping, or pump in the forward direction in an effort to reestablish unobstructed pumping.
It is preferred, though not necessary, that the sensors of sampling system 100 are adapted to accept a passageway through which a sample may flow and that sense through the walls of the passageway. As described subsequently, this arrangement allows for the sensors to be reusable and for the passageways to be disposable. It is also preferred, though not necessary, that the passageway is smooth and without abrupt dimensional changes which may damage blood or prevent smooth flow of blood. In addition, is also preferred that the passageways that deliver blood from the patient to the analyzer not contain gaps or size changes that permit fluid to stagnate and not be transported through the passageway.
In one embodiment, the respective passageways on which valves 312, 313, 316, and 323 are situated along passageways that are flexible tubes, and valves 312, 313, 316, and 323 are “pinch valves,” in which one or more movable surfaces compress the tube to restrict or stop flow therethrough. In one embodiment, the pinch valves include one or more moving surfaces that are actuated to move together and “pinch” a flexible passageway to stop flow therethrough. Examples of a pinch valve include, for example, Model PV256 Low Power Pinch Valve (Instech Laboratories, Inc., Plymouth Meeting, Pa.). Alternatively, one or more of valves 312, 313, 316, and 323 may be other valves for controlling the flow through their respective passageways.
Colorimetric sensor 311 accepts or forms a portion of passageway 111 and provides an indication of the presence or absence of blood within the passageway. In one embodiment, colorimetric sensor 311 permits controller 210 to differentiate between fluid 14 and blood. Preferably, colorimetric sensor 311 is adapted to receive a tube or other passageway for detecting blood. This permits, for example, a disposable tube to be placed into or through a reusable colorimetric sensor. In an alternative embodiment, colorimetric sensor 311 is located adjacent to bubble sensor 314b. Examples of a colorimetric sensor include, for example, an Optical Blood Leak/Blood vs. Saline Detector available from Introtek International (Edgewood, N.J.).
As described subsequently, sampling system 300 injects a gas—referred to herein and without limitation as a “bubble”—into passageway 113. Sampling system 300 includes gas injector manifold 315 at or near junction 318 to inject one or more bubbles, each separated by liquid, into passageway 113. The use of bubbles is useful in preventing longitudinal mixing of liquids as they flow through passageways both in the delivery of a sample for analysis with dilution and for cleaning passageways between samples. Thus, for example the fluid in passageway 113 includes, in one embodiment of the invention, two volumes of liquids, such as sample S or fluid 14 separated by a bubble, or multiple volumes of liquid each separated by a bubble therebetween.
Bubble sensors 314a, 314b and 321 each accept or form a portion of passageway 112 or 113 and provide an indication of the presence of air, or the change between the flow of a fluid and the flow of air, through the passageway. Examples of bubble sensors include, but are not limited to ultrasonic or optical sensors, that can detect the difference between small bubbles or foam from liquid in the passageway. Once such bubble detector is an MEC Series Air Bubble/Liquid Detection Sensor (Introtek International, Edgewood, N.Y.). Preferably, bubble sensor 314a, 314b, and 321 are each adapted to receive a tube or other passageway for detecting bubbles. This permits, for example, a disposable tube to be placed through a reusable bubble sensor.
Pressure sensor 317 accepts or forms a portion of passageway 111 and provides an indication or measurement of a fluid within the passageway. When all valves between pressure sensor 317 and catheter 11 are open, pressure sensor 317 provides an indication or measurement of the pressure within the patient's catheterized blood vessel. In one embodiment, the output of pressure sensor 317 is provided to controller 210 to regulate the operation of pump 203. Thus, for example, a pressure measured by pressure sensor 317 above a predetermined value is taken as indicative of a properly working system, and a pressure below the predetermined value is taken as indicative of excessive pumping due to, for example, a blocked passageway or blood vessel. Thus, for example, with pump 203 operating to draw blood from patient P, if the pressure as measured by pressure sensor 317 is within a range of normal blood pressures, it may be assumed that blood is being drawn from the patient and pumping continues. However, if the pressure as measured by pressure sensor 317 falls below some level, then controller 210 instructs pump 203 to slow or to be operated in a forward direction to reopen the blood vessel. One such pressure sensor is a Deltran IV part number DPT-412 (Utah Medical Products, Midvale, Utah).
Sample analysis device 330 receives a sample and performs an analysis. In several embodiments, device 330 is configured to prepare of the sample for analysis. Thus, for example, device 330 may include a sample preparation unit 332 and an analyte detection system 334, where the sample preparation unit is located between the patient and the analyte detection system. In general, sample preparation occurs between sampling and analysis. Thus, for example, sample preparation unit 332 may take place removed from analyte detection, for example within sampling assembly 220, or may take place adjacent or within analyte detection system 334.
As used herein, the term “analyte” is a broad term and is used in its ordinary sense and includes, without limitation, any chemical species the presence or concentration of which is sought in the material sample by an analyte detection system. For example, the analyte(s) include, but not are limited to, glucose, ethanol, insulin, water, carbon dioxide, blood oxygen, cholesterol, bilirubin, ketones, fatty acids, lipoproteins, albumin, urea, creatinine, white blood cells, red blood cells, hemoglobin, oxygenated hemoglobin, carboxyhemoglobin, organic molecules, inorganic molecules, pharmaceuticals, cytochrome, various proteins and chromophores, microcalcifications, electrolytes, sodium, potassium, chloride, bicarbonate, and hormones. As used herein, the term “material sample” (or, alternatively, “sample”) is a broad term and is used in its ordinary sense and includes, without limitation, any collection of material which is suitable for analysis. For example, a material sample may comprise whole blood, blood components (e.g., plasma or serum), interstitial fluid, intercellular fluid, saliva, urine, sweat and/or other organic or inorganic materials, or derivatives of any of these materials. In one embodiment, whole blood or blood components may be drawn from a patient's capillaries.
In one embodiment, sample preparation unit 332 separates blood plasma from a whole blood sample or removes contaminants from a blood sample and thus comprises one or more devices including, but not limited to, a filter, membrane, centrifuge, or some combination thereof. In alternative embodiments, analyte detection system 334 is adapted to analyze the sample directly and sample preparation unit 332 is not required.
Generally, sampling assembly 220 and sampling unit 200 direct the fluid drawn from sampling assembly 220 into passageway 113 into sample analysis device 330.
With reference to
Sampling unit 510 includes valves 501, 326a, and 326b under the control of controller 210. Valve 501 provides additional liquid flow control between sampling unit 200 and sampling unit 510. Pump 328 is preferably a bi-directional pump that can draw fluid from and into passageway 113. Fluid may either be drawn from and returned to passageway 501, or may be routed to waste receptacle 325. Valves 326a and 326b are situated on either side of pump 328. Fluid can be drawn through passageway 113 and into return line 503 by the coordinated control of pump 328 and valves 326a and 326b. Directing flow from return line 503 can be used to prime sampling system 500 with fluid. Thus, for example, liquid may be pulled into sampling unit 510 by operating pump 328 to pull liquid from passageway 113 while valve 326a is open and valve 326b is closed. Liquid may then be pumped back into passageway 113 by operating pump 328 to push liquid into passageway 113 while valve 326a is closed and valve 326b is open.
Importantly, gas injected into passageways 20 should be prevented from reaching catheter 11. As a safety precaution, one embodiment prevents gas from flowing towards catheter 11 by the use of bubble sensor 314a as shown, for example, in
Section II—Fluid Handling Methods
One embodiment of a method of using fluid handling system 10, including sampling assembly 220 and sampling unit 200 of
F = Forward (fluid into patient),
R = Reverse (fluid from patient),
O = Open,
C = Closed
The next nine figures (
The last step shown in
Section III—Sampling System
More specifically, as shown in
As shown in
Passageway portions of cassette 820 contact various components of instrument 810 to form sampling system 800. With reference to
In addition to placement of interface 811 against interface 821, the assembly of apparatus 800 includes assembling sampling assembly 220. More specifically, an opening 815a and 815b are adapted to receive passageways 111 and 113, respectively, with junction 829 within sampling assembly instrument portion 813. Thus, for example, with reference to
In operation, the assembled main instrument 810 and cassette 820 of
When it is time to conduct a measurement, air is first drawn into the system to clear liquid from a portion of the passageways 112, 113, in a manner similar to that shown in
From this point the pumps 905, 1005, valves 1007e, 1007f, 1007g, 1007h, bubble sensors 1001b, 1001c and/or hemoglobin sensor 1003 can be operated to move a series of air bubbles and sample-fluid columns into the passageway 113, in a manner similar to that shown in
Once a portion of the bodily fluid sample and any desired bubbles have moved into the passageway 113, the valve 1007h can be closed, and the remainder of the initial drawn sample or volume of bodily fluid in the passageway 112 can be returned to the patient, by operating the pump 1005 in the forward or infusion direction until the passageway 112 is again filled with infusion fluid.
With appropriate operation of the valves 1007a-1007h, and the pump(s) 905 and/or 1005, at least a portion of the bodily fluid sample in the passageway 113 (which is 10-100 microliters in volume, or 20, 30, 40, 50 or 60 microliters, in various embodiments) is moved through the sample preparation unit 332 (in the depicted embodiment a filter or membrane; alternatively a centrifuge as discussed in greater detail below). Thus, only one or more components of the bodily fluid (e.g., only the plasma of a blood sample) passes through the unit 332 or filter/membrane and enters the sample chamber or cell 903. Alternatively, where the unit 332 is omitted, the “whole” fluid moves into the sample chamber 903 for analysis.
Once the component(s) or whole fluid is in the sample chamber 903, the analysis is conducted to determine a level or concentration of one or more analytes, such as glucose, lactate, carbon dioxide, blood urea nitrogen, hemoglobin, and/or any other suitable analytes as discussed elsewhere herein. Where the analyte detection system 1700 is spectroscopic (e.g. the system 1700 of FIGS. 17 or 44-46), a spectroscopic analysis of the component(s) or whole fluid is conducted.
After the analysis, the body fluid sample within the passageway 113 is moved into the waste receptacle 325. Preferably, the pump 905 is operated via the actuator 1009 to push the body fluid, behind a column of saline or infusion fluid obtained via the passageway 909, back through the sample chamber 903 and sample preparation unit 332, and into the receptacle 325. Thus, the chamber 903 and unit 332 are back-flushed and filled with saline or infusion fluid while the bodily fluid is delivered to the waste receptacle. Following this flush a second analysis can be made on the saline or infusion fluid now in the chamber 903, to provide a “zero” or background reading. At this point, the fluid handling network of
In some embodiments of the apparatus 140, a pair of pinch valve pinchers acts to switch flow between one of two branches of a passageway.
As an example of the use of pinch valve 1300,
As an example of the use of pinch valve 1300 in sampling system 300, pinchers 1320 and 1330 are positioned to act as valve 323 and 326, respectively.
Alternative embodiment of pinch valves includes 2, 3, 4, or more passageway segments that meet at a common junction, with pinchers located at one or more passageways near the junction.
As shown in
Section IV—Sample Analysis System
In several embodiments, analysis is performed on blood plasma. For such embodiments, the blood plasma must be separated from the whole blood obtained from the patient. In general, blood plasma may be obtained from whole blood at any point in fluid handling system 10 between when the blood is drawn, for example at patient connector 110 or along passageway 113, and when it is analyzed. For systems where measurements are preformed on whole blood, it may not be necessary to separate the blood at the point of or before the measurements is performed.
For illustrative purposes, this section describes several embodiments of separators and analyte detection systems which may form part of system 10. The separators discussed in the present specification can, in certain embodiments, comprise fluid component separators. As used herein, the term “fluid component separator” is a broad term and is used in its ordinary sense and includes, without limitation, any device that is operable to separate one or more components of a fluid to generate two or more unlike substances. For example, a fluid component separator can be operable to separate a sample of whole blood into plasma and non- plasma components, and/or to separate a solid-liquid mix (e.g. a solids-contaminated liquid) into solid and liquid components. A fluid component separator need not achieve complete separation between or among the generated unlike substances. Examples of fluid component separators include filters, membranes, centrifuges, electrolytic devices, or components of any of the foregoing. Fluid component separators can be “active” in that they are operable to separate a fluid more quickly than is possible through the action of gravity on a static, “standing” fluid. Section IV.A below discloses a filter which can be used as a blood separator in certain embodiments of the apparatus disclosed herein. Section IV.B below discloses an analyte detection system which can be used in certain embodiments of the apparatus disclosed herein. Section IV.C below discloses a sample element which can be used in certain embodiments of the apparatus disclosed herein. Section IV.D below discloses a centrifuge and sample chamber which can be used in certain embodiments of the apparatus disclosed herein.
Section IV.A—Blood Filter
Without limitation as to the scope of the present invention, one embodiment of sample preparation unit 332 is shown as a blood filter 1500, as illustrated in
As shown in the embodiment of
Filter 1500 provides for a continuous filtering of blood plasma from whole blood. Thus, for example, when a flow of whole blood is provided at inlet 1503 and a slight vacuum is applied to the second volume 1504 side of membrane 1509, the membrane filters blood cells and blood plasma passes through second outlet 1507. Preferably, there is transverse blood flow across the surface of membrane 1509 to prevent blood cells from clogging filter 1500. Accordingly, in one embodiment of the inlet 1503 and first outlet 1505 may be configured to provide the transverse flow across membrane 1509.
In one embodiment, membrane 1509 is a thin and strong polymer film. For example, the membrane filter may be a 10 micron thick polyester or polycarbonate film. Preferably, the membrane filter has a smooth glass-like surface, and the holes are uniform, precisely sized, and clearly defined. The material of the film may be chemically inert and have low protein binding characteristics.
One way to manufacture membrane 1509 is with a Track Etching process. Preferably, the “raw” film is exposed to charged particles in a nuclear reactor, which leaves “tracks” in the film. The tracks may then be etched through the film, which results in holes that are precisely sized and uniformly cylindrical. For example, GE Osmonics, Inc. (4636 Somerton Rd. Trevose, Pa. 19053-6783) utilizes a similar process to manufacture a material that adequately serves as the membrane filter. The surface the membrane filter depicted above is a GE Osmonics Polycarbonate TE film.
As one example of the use of filter 1500, the plasma from 3 cc of blood may be extracted using a polycarbonate track etch film (“PCTE”) as the membrane filter. The PCTE may have a pore size of 2 μm and an effective area of 170 millimeter2. Preferably, the tubing connected to the supply, exhaust and plasma ports has an internal diameter of 1 millimeter. In one embodiment of a method employed with this configuration, 100 μl of plasma can be initially extracted from the blood. After saline is used to rinse the supply side of the cell, another 100 μl of clear plasma can be extracted. The rate of plasma extraction in this method and configuration can be about 15-25 μl/min.
Using a continuous flow mechanism to extract plasma may provide several benefits. In one preferred embodiment, the continuous flow mechanism is reusable with multiple samples, and there is negligible sample carryover to contaminate subsequent samples. One embodiment may also eliminate most situations in which plugging may occur. Additionally, a preferred configuration provides for a low internal volume.
Additional information on filters, methods of use thereof, and related technologies may be found in U.S. Patent Application Publication No. 2005/0038357, published on Feb. 17, 2005, titled SAMPLE ELEMENT WITH BARRIER MATERIAL; and U.S. patent application Ser. No. 11/122,794, filed on May 5, 2005, titled SAMPLE ELEMENT WITH SEPARATOR. The entire contents of the above noted publication and patent application are hereby incorporated by reference herein and made a part of this specification.
Section IV.B—Analyte Detection System
One embodiment of analyte detection system 334, which is not meant to limit the scope of the present invention, is shown in
Analyte detection system 1700 comprises an energy source 1720 disposed along a major axis X of system 1700. When activated, the energy source 1720 generates an energy beam E which advances from the energy source 1720 along the major axis X. In one embodiment, the energy source 1720 comprises an infrared source and the energy beam E comprises an infrared energy beam.
The energy beam E passes through an optical filter 1725 also situated on the major axis X, before reaching a probe region 1710. Probe region 1710 is portion of apparatus 322 in the path of an energized beam E that is adapted to accept a material sample S. In one embodiment, as shown in
As used herein, “sample element” is a broad term and is used in its ordinary sense and includes, without limitation, structures that have a sample chamber and at least one sample chamber wall, but more generally includes any of a number of structures that can hold, support or contain a material sample and that allow electromagnetic radiation to pass through a sample held, supported or contained thereby; e.g., a cuvette, test strip, etc.
In one embodiment of the present invention, sample element 1730 forms a disposable portion of cassette 820, and the remaining portions of system 1700 form portions of instrument 810, and probe region 1710 is probe region 1002.
With further reference to
In the embodiment shown in
In one embodiment detection system 1700, filter 1725 comprises a varying-passband filter, to facilitate changing, over time and/or during a measurement taken with the detection system 1700, the wavelength or wavelength band of the energy beam E that may pass the filter 25 for use in analyzing the sample S. When the energy beam E is filtered with a varying-passband filter, the absorption/transmittance characteristics of the sample S can be analyzed at a number of wavelengths or wavelength bands in a separate, sequential manner. As an example, assume that it is desired to analyze the sample S at N separate wavelengths (Wavelength 1 through Wavelength N). The varying-passband filter is first operated or tuned to permit the energy beam E to pass at Wavelength 1, while substantially blocking the beam E at most or all other wavelengths to which the detector 1745 is sensitive (including Wavelengths 2-N). The absorption/transmittance properties of the sample S are then measured at Wavelength 1, based on the beam E that passes through the sample S and reaches the detector 1745. The varying-passband filter is then operated or tuned to permit the energy beam E to pass at Wavelength 2, while substantially blocking other wavelengths as discussed above; the sample S is then analyzed at Wavelength 2 as was done at Wavelength 1. This process is repeated until all of the wavelengths of interest have been employed to analyze the sample S. The collected absorptiori/transmittance data can then be analyzed by the processor 210 to determine the concentration of the analyte(s) of interest in the material sample S. The measured spectra of sample S is referred to herein in general as Cs(λi), that is, a wavelength dependent spectra in which Cs is, for example, a transmittance, an absorbance, an optical density, or some other measure of the optical properties of sample S having values at or about a number of wavelengths λi, where i ranges over the number of measurements taken. The measurement Cs(λi) is a linear array of measurements that is alternatively written as Csi.
The spectral region of system 1700 depends on the analysis technique and the analyte and mixtures of interest. For example, one useful spectral region for the measurement of glucose in blood using absorption spectroscopy is the mid-IR (for example, about 4 microns to about 11 microns). In one embodiment system 1700, energy source 1720 produces a beam E having an output in the range of about 4 microns to about 11 microns. Although water is the main contributor to the total absorption across this spectral region, the peaks and other structures present in the blood spectrum from about 6.8 microns to 10.5 microns are due to the absorption spectra of other blood components. The 4 to 11 micron region has been found advantageous because glucose has a strong absorption peak structure from about 8.5 to 10 microns, whereas most other blood constituents have a low and flat absorption spectrum in the 8.5 to 10 micron range. The main exceptions are water and hemoglobin, both of which are interferents in this region.
The amount of spectral detail provided by system 1700 depends on the analysis technique and the analyte and mixture of interest. For example, the measurement of glucose in blood by mid-IR absorption spectroscopy is accomplished with from 11 to 25 filters within a spectral region. In one embodiment system 1700, energy source 1720 produces a beam E having an output in the range of about 4 microns to about 11 microns, and filter 1725 include a number of narrow band filters within this range, each allowing only energy of a certain wavelength or wavelength band to pass therethrough. Thus, for example, one embodiment filter 1725 includes a filter wheel having 11 filters with a nominal wavelength approximately equal to one of the following: 3 μm, 4.06 μm, 4.6 μm, 4.9 μm, 5.25 μm, 6.12 μm, 6.47 μm, 7.98 μm, 8.35 μm, 9.65 μm, and 12.2 μm.
In one embodiment, individual infrared filters of the filter wheel are multi-cavity, narrow band dielectric stacks on germanium or sapphire substrates, manufactured by either OCLI (JDS Uniphase, San Jose, Calif.) or Spectrogon US, Inc. (Parsippany, N.J.). Thus, for example, each filter may nominally be 1 millimeter thick and 10 millimeter square. The peak transmission of the filter stack is typically between 50% and 70%, and the bandwidths are typically between 150 nm and 350 nm with center wavelengths between 4 and 10 μm. Alternatively, a second blocking IR filter is also provided in front of the individual filters. The temperature sensitivity is preferably <0.01% per degree C to assist in maintaining nearly constant measurements over environmental conditions.
In one embodiment, the detection system 1700 computes an analyte concentration reading by first measuring the electromagnetic radiation detected by the detector 1745 at each center wavelength, or wavelength band, without the sample element 1730 present on the major axis X (this is known as an “air” reading). Second, the system 1700 measures the electromagnetic radiation detected by the detector 1745 for each center wavelength, or wavelength band, with the material sample S present in the sample element 1730, and the sample element and sample S in position on the major axis X (i.e., a “wet” reading). Finally, the processor 210 computes the concentration(s), absorbance(s) and/or transmittances relating to the sample S based on these compiled readings.
In one embodiment, the plurality of air and wet readings are used to generate a pathlength corrected spectrum as follows. First, the measurements are normalized to give the transmission of the sample at each wavelength. Using both a signal and reference measurement at each wavelength, and letting Si represent the signal of detector 1745 at wavelength i and Ri represent the signal of the detector at wavelength i, the transmittance, Ti at wavelength i may computed as Ti=Si(wet) /Si(air). Optionally, the spectra may be calculated as the optical density, ODi, as −Log(Ti). Next, the transmission over the wavelength range of approximately 4.5 μm to approximately 5.5 μm is analyzed to determine the pathlength. Specifically, since water is the primary absorbing species of blood over this wavelength region, and since the optical density is the product of the optical pathlength and the known absorption coefficient of water (OD=L σ, where L is the optical pathlength and σ is the absorption coefficient), any one of a number of standard curve fitting procedures may be used to determine the optical pathlength, L from the measured OD. The pathlength may then be used to determine the absorption coefficient of the sample at each wavelength. Alternatively, the optical pathlength may be used in further calculations to convert absorption coefficients to optical density.
Blood samples may be prepared and analyzed by system 1700 in a variety of configurations. In one embodiment, sample S is obtained by drawing blood, either using a syringe or as part of a blood flow system, and transferring the blood into sample chamber 903. In another embodiment, sample S is drawn into a sample container that is a sample chamber 903 adapted for insertion into system 1700.
The detection system 1700 shown in
As shown in
With further reference to
The primary filter 40 is preferably configured to substantially maintain its operating characteristics (center wavelength, passband width) where some or all of the energy beam E deviates from normal incidence by a cone angle of up to about twelve degrees relative to the major axis X. In further embodiments, this cone angle may be up to about 15 to 35 degrees, or from about 15 degrees or 20 degrees. The primary filter 40 may be said to “substantially maintain” its operating characteristics where any changes therein are insufficient to affect the performance or operation of the detection system 1700 in a manner that would raise significant concerns for the user(s) of the system in the context in which the system 1700 is employed.
In the embodiment illustrated in
Optical filter wheel 50 is employed as a varying-passband filter, to selectively position the secondary filter(s) 60 on the major axis X and/or in the energy beam E. The filter wheel 50 can therefore selectively tune the wavelength(s) of the energy beam E downstream of the wheel 50. These wavelength(s) vary according to the characteristics of the secondary filter(s) 60 mounted in the filter wheel 50. The filter wheel 50 positions the secondary filter(s) 60 in the energy beam E in a “one-at-a-time” fashion to sequentially vary, as discussed above, the wavelengths or wavelength bands employed to analyze the material sample S. An alternative to filter wheel 50 is a linear filter translated by a motor (not shown). The linear filter may be, for example, a linear array of separate filters or a single filter with filter properties that change in a linear dimension.
In alternative arrangements, the single primary filter 40 depicted in
The filter wheel 50, in the embodiment depicted in
In one embodiment, the wheel body 52 can be formed from molded plastic, with each of the secondary filters 60 having, for example a thickness of 1 mm and a 10 mm×10 mm or a 5 mm×5 mm square configuration. Each of the filters 60, in this embodiment of the wheel body, is axially aligned with a circular aperture of 4 mm diameter, and the aperture centers define a circle of about 1.70 inches diameter, which circle is concentric with the wheel body 52. The body 52 itself is circular, with an outside diameter of 2.00 inches.
Each of the secondary filter(s) 60 is preferably configured to operate as a narrow band filter, allowing only a selected energy wavelength or wavelength band (i.e., a filtered energy beam (Ef) to pass therethrough. As the filter wheel 50 rotates about its rotational center RC, each of the secondary filter(s) 60 is, in turn, disposed along the major axis X for a selected dwell time corresponding to each of the secondary filter(s) 60.
The “dwell time” for a given secondary filter 60 is the time interval, in an individual measurement run of the system 1700, during which both of the following conditions are true: (i) the filter is disposed on the major axis X; and (ii) the source 1720 is energized. The dwell time for a given filter may be greater than or equal to the time during which the filter is disposed on the major axis X during an individual measurement run. In one embodiment of the analyte detection system 1700, the dwell time corresponding to each of the secondary filter(s) 60 is less than about 1 second. However, the secondary filter(s) 60 can have other dwell times, and each of the filter(s) 60 may have a different dwell time during a given measurement run.
From the secondary filter 60, the filtered energy beam (Ef) passes through a beam sampling optics 90, which includes a beam splitter 4400 disposed along the major axis X and having a face 4400a disposed at an included angle θ relative to the major axis X. The splitter 4400 preferably separates the filtered energy beam (Ef) into a sample beam (Es) and a reference beam (Er).
With further reference to
At least a fraction of the sample beam (Es) is transmitted through the sample S and continues onto a second lens 4440 disposed along the major axis X. The second lens 4440 is configured to focus the sample beam (Es) onto a sample detector 150, thus increasing the flux density of the sample beam (Es) incident upon the sample detector 150. The sample detector 150 is configured to generate a signal corresponding to the detected sample beam (Es) and to pass the signal to a processor 210, as discussed in more detail below.
Beam sampling optics 90 further includes a third lens 160 and a reference detector 170. The reference beam (Er) is directed by beam sampling optics 90 from the beam splitter 4400 to a third lens 160 disposed along a minor axis Y generally orthogonal to the major axis X. The third lens 160 is configured to focus the reference beam (Er) onto reference detector 170, thus increasing the flux density of the reference beam (Er) incident upon the reference detector 170. In one embodiment, the lenses 4410, 4440, 160 may be formed from a material which is highly transmissive of infrared radiation, for example germanium or silicon. In addition, any of the lenses 4410, 4440 and 160 may be implemented as a system of lenses, depending on the desired optical performance. The reference detector 170 is also configured to generate a signal corresponding to the detected reference beam (Er) and to pass the signal to the processor 210, as discussed in more detail below. Except as noted below, the sample and reference detectors 150, 170 may be generally similar to the detector 1745 illustrated in
In further variations of the detection system 1700 depicted in
The energy source 1720 of the embodiment of
The energy source 1720 is preferably configured to selectably operate at a modulation frequency between about 1 Hz and 30 Hz and have a peak operating temperature of between about 1070 degrees Kelvin and 1170 degrees Kelvin. Additionally, the source 1720 preferably operates with a modulation depth greater than about 80% at all modulation frequencies. The energy source 1720 preferably emits electromagnetic radiation in any of a number of spectral ranges, e.g., within infrared wavelengths; in the mid-infrared wavelengths; above about 0.8 μm; between about 5.0 μm and about 20.0 μm; and/or between about 5.25 μm and about 12.0 μm. However, in other embodiments, the detection system 1700 may employ an energy source 1720 which is unmodulated and/or which emits in wavelengths found anywhere from the visible spectrum through the microwave spectrum, for example anywhere from about 0.4 μm to greater than about 100 μm. In still other embodiments, the energy source 1720 can emit electromagnetic radiation in wavelengths between about 3.5 μm and about 14 μm, or between about 0.8 μm and about 2.5 μm, or between about 2.5 μm and 20 μm, or between about 20 μm and about 100 μm, or between about 6.85 μm and about 10.10 μm. In yet other embodiments, the energy source 1720 can emit electromagnetic radiation within the radio frequency (RF) range or the terahertz range. All of the above-recited operating characteristics are merely exemplary, and the source 1720 may have any operating characteristics suitable for use with the analyte detection system 1700.
A power supply (not shown) for the energy source 1720 is preferably configured to selectably operate with a duty cycle of between about 30% and about 70%. Additionally, the power supply is preferably configured to selectably operate at a modulation frequency of about 10 Hz, or between about 1 Hz and about 30 Hz. The operation of the power supply can be in the form of a square wave, a sine wave, or any other waveform defined by a user.
With further reference to
As illustrated in
The inner surfaces 32 of the collimator 30 cause the rays making up the energy beam E to straighten (i.e., propagate at angles increasingly parallel to the major axis X) as the beam E advances downstream, so that the energy beam E becomes increasingly or substantially cylindrical and oriented substantially parallel to the major axis X. Accordingly, the inner surfaces 32 are highly reflective and minimally absorptive in the wavelengths of interest, such as infrared wavelengths.
The tube 30a itself may be fabricated from a rigid material such as aluminum, steel, or any other suitable material, as long as the inner surfaces 32 are coated or otherwise treated to be highly reflective in the wavelengths of interest. For example, a polished gold coating may be employed. Preferably, the inner surface(s) 32 of the collimator 30 define a circular cross-section when viewed orthogonal to the major axis X; however, other cross-sectional shapes, such as a square or other polygonal shapes, parabolic or elliptical shapes may be employed in alternative embodiments.
As noted above, the filter wheel 50 shown in
In another embodiment, the filter wheel 50 comprises twenty secondary filters 60, each of which is configured to allow a filtered energy beam (Ef) to travel therethrough with a nominal center wavelengths of: 4.275 μm, 4.5 μm, 4.7 μm, 5.0 μm, 5.3 μm, 6.056 μm, 7.15 μm, 7.3 μm, 7.55 μm, 7.67 μm, 8.06 μm, 8.4 μm, 8.56 μm, 8.87 μm, 9.15 μm, 9.27 μm, 9.68 μm, 9.82 μm, and 10.06 μm. (This set of wavelengths may also be employed with or in any of the embodiments of the analyte detection system 1700 disclosed herein.) In still another embodiment, the secondary filters 60 may conform to any one or combination of the following specifications: center wavelength tolerance of ±0.01 μm; half-power bandwidth tolerance of ±0.01 μm; peak transmission greater than or equal to 75%; cut-on/cut-off slope less than 2%; center-wavelength temperature coefficient less than 0.01% per degree Celsius; out of band attenuation greater than OD 5 from 3 μm to 12 μm; flatness less than 1.0 waves at 0.6328 μm; surface quality of E-E per Mil-F-48616; and overall thickness of about 1 mm.
In still another embodiment, the secondary filters mentioned above may conform to any one or combination of the following half-power bandwidth (“HPBW”) specifications:
In still further embodiments, the secondary filters may have a center wavelength tolerance of ±0.5% and a half-power bandwidth tolerance of ±0.02 μm.
Of course, the number of secondary filters employed, and the center wavelengths and other characteristics thereof, may vary in further embodiments of the system 1700, whether such further embodiments are employed to detect glucose, or other analytes instead of or in addition to glucose. For example, in another embodiment, the filter wheel 50 can have fewer than fifty secondary filters 60. In still another embodiment, the filter wheel 50 can have fewer than twenty secondary filters 60. In yet another embodiment, the filter wheel 50 can have fewer than ten secondary filters 60.
In one embodiment, the secondary filters 60 each measure about 10 mm long by 10 mm wide in a plane orthogonal to the major axis X, with a thickness of about 1 mm. However, the secondary filters 60 can have any other (e.g., smaller) dimensions suitable for operation of the analyte detection system 1700. Additionally, the secondary filters 60 are preferably configured to operate at a temperature of between about 5° C. and about 35° C. and to allow transmission of more than about 75% of the energy beam E therethrough in the wavelength(s) which the filter is configured to pass.
According to the embodiment illustrated in
A reflector tube 98 is preferably positioned to receive the filtered energy beam (Ef) as it advances from the secondary filter(s) 60. The reflector tube 98 is preferably secured with respect to the secondary filter(s) 60 to substantially prevent introduction of stray electromagnetic radiation, such as stray light, into the reflector tube 98 from outside of the detection system 1700. The inner surfaces of the reflector tube 98 are highly reflective in the relevant wavelengths and preferably have a cylindrical shape with a generally circular cross-section orthogonal to the major and/or minor axis X, Y. However, the inner surface of the tube 98 can have a cross-section of any suitable shape, such as oval, square, rectangular, etc. Like the collimator 30, the reflector tube 98 may be formed from a rigid material such as aluminum, steel, etc., as long as the inner surfaces are coated or otherwise treated to be highly reflective in the wavelengths of interest. For example, a polished gold coating may be employed.
According to the embodiment illustrated in
The major section 98a conducts the filtered energy beam (Ef) from the first end 98c to the beam splitter 4400, which is housed in the major section 98a at the intersection of the major and minor axes X, Y. The major section 98a also conducts the sample beam (Es) from the beam splitter 4400, through the first lens 4410 and to the second end 98d. From the second end 98d the sample beam (Es) proceeds through the sample element 1730, holder 4430 and second lens 4440, and to the sample detector 150. Similarly, the minor section 98b conducts the reference beam (Er) through beam sampling optics 90 from the beam splitter 4400, through the third lens 160 and to the third end 98e. From the third end 98e the reference beam (Er) proceeds to the reference detector 170.
The sample beam (Es) preferably comprises from about 75% to about 85% of the energy of the filtered energy beam (Ef). More preferably, the sample beam (Es) comprises about 80% of the energy of the filtered energy beam (Es). The reference beam (Er) preferably comprises from about 10% and about 50% of the energy of the filtered energy beam (Es). More preferably, the reference beam (Er) comprises about 20% of the energy of the filtered energy beam (Ef). Of course, the sample and reference beams may take on any suitable proportions of the energy beam E.
The reflector tube 98 also houses the first lens 4410 and the third lens 160. As illustrated in
The sample element 1730 is retained within the holder 4430, which is preferably oriented along a plane generally orthogonal to the major axis X. The holder 4430 is configured to be slidably displaced between a loading position and a measurement position within the analyte detection system 1700. In the measurement position, the holder 4430 contacts a stop edge 136 which is located to orient the sample element 1730 and the sample S contained therein on the major axis X.
The structural details of the holder 4430 depicted in
As with the embodiment depicted in
The receiving portion 152a houses the second lens 4440 in the lens chamber 152d proximal to the aperture 152c. The sample detector 150 is also disposed in the lens chamber 152d downstream of the second lens 4440 such that a detection plane 154 of the detector 150 is substantially orthogonal to the major axis X. The second lens 4440 is positioned such that a plane 142 of the lens 4440 is substantially orthogonal to the major axis X. The second lens 4440 is configured, and is preferably disposed relative to the holder 4430 and the sample detector 150, to focus substantially all of the sample beam (Es) onto the detection plane 154, thereby increasing the flux density of the sample beam (Es) incident upon the detection plane 154.
With further reference to
The receiving portion 152a preferably also houses a printed circuit board 158 disposed between the gasket 157 and the sample detector 150. The board 158 connects to the sample detector 150 through at least one connecting member 150a. The sample detector 150 is configured to generate a detection signal corresponding to the sample beam (Es) incident on the detection plane 154. The sample detector 150 communicates the detection signal to the circuit board 158 through the connecting member 150a, and the board 158 transmits the detection signal to the processor 210.
In one embodiment, the sample detector 150 comprises a generally cylindrical housing 150a, e.g. a type TO-39 “metal can” package, which defines a generally circular housing aperture 150b at its “upstream” end. In one embodiment, the housing 150a has a diameter of about 0.323 inches and a depth of about 0.248 inches, and the aperture 150b may have a diameter of about 0.197 inches.
A detector window 150c is disposed adjacent the aperture 150b, with its upstream surface preferably about 0.078 inches (+/−0.004 inches) from the detection plane 154. (The detection plane 154 is located about 0.088 inches (+/−0.004 inches) from the upstream edge of the housing 150a, where the housing has a thickness of about 0.010 inches.) The detector window 150c is preferably transmissive of infrared energy in at least a 3-12 micron passband; accordingly, one suitable material for the window 150c is germanium. The endpoints of the passband may be “spread” further to less than 2.5 microns, and/or greater than 12.5 microns, to avoid unnecessary absorbance in the wavelengths of interest. Preferably, the transmittance of the detector window 150c does not vary by more than 2% across its passband. The window 150c is preferably about 0.020 inches in thickness. The sample detector 150 preferably substantially retains its operating characteristics across a temperature range of −20 to +60 degrees Celsius.
The receiving portion 172a houses the reference detector 170 in the chamber 172d proximal to the aperture 172c. The reference detector 170 is disposed in the chamber 172d such that a detection plane 174 of the reference detector 170 is substantially orthogonal to the minor axis Y. The third lens 160 is configured to substantially focus the reference beam (Er) so that substantially the entire reference beam (Er) impinges onto the detection plane 174, thus increasing the flux density of the reference beam (Er) incident upon the detection plane 174.
With further reference to
The receiving portion 172a preferably also houses a printed circuit board 178 disposed between the gasket 177 and the reference detector 170. The board 178 connects to the reference detector 170 through at least one connecting member 170a. The reference detector 170 is configured to generate a detection signal corresponding to the reference beam (Er) incident on the detection plane 174. The reference detector 170 communicates the detection signal to the circuit board 178 through the connecting member 170a, and the board 178 transmits the detection signal to the processor 210.
In one embodiment, the construction of the reference detector 170 is generally similar to that described above with regard to the sample detector 150.
In one embodiment, the sample and reference detectors 150, 170 are both configured to detect electromagnetic radiation in a spectral wavelength range of between about 0.8 μm and about 25 μm. However, any suitable subset of the foregoing set of wavelengths can be selected. In another embodiment, the detectors 150, 170 are configured to detect electromagnetic radiation in the wavelength range of between about 4 μm and about 12 μm. The detection planes 154, 174 of the detectors 150, 170 may each define an active area about 2 mm by 2 mm or from about 1 mm by 1 mm to about 5 mm by 5 mm; of course, any other suitable dimensions and proportions may be employed. Additionally, the detectors 150, 170 may be configured to detect electromagnetic radiation directed thereto within a cone angle of about 45 degrees from the major axis X.
In one embodiment, the sample and reference detector subsystems 150, 170 may further comprise a system (not shown) for regulating the temperature of the detectors. Such a temperature-regulation system may comprise a suitable electrical heat source, thermistor, and a proportional-plus-integral-plus-derivative (PID) control. These components may be used to regulate the temperature of the detectors 150, 170 at about 35 ° C. The detectors 150, 170 can also optionally be operated at other desired temperatures. Additionally, the PED control preferably has a control rate of about 60 Hz and, along with the heat source and thermistor, maintains the temperature of the detectors 150, 170 within about 0.1 ° C. of the desired temperature.
The detectors 150, 170 can operate in either a voltage mode or a current mode, wherein either mode of operation preferably includes the use of a pre-amp module. Suitable voltage mode detectors for use with the analyte detection system 1700 disclosed herein include: models LIE 302 and 312 by InfraTec of Dresden, Germany; model L2002 by BAE Systems of Rockville, Md.; and model LTS-1 by Dias of Dresden, Germany. Suitable current mode detectors include: InfraTec models LIE 301, 315, 345 and 355; and 2×2 current-mode detectors available from Dias.
In one embodiment, one or both of the detectors 150, 170 may meet the following specifications, when assuming an incident radiation intensity of about 9.26×10−4 watts (rms) per cm2, at 10 Hz modulation and within a cone angle of about 15 degrees: detector area of 0.040 cm2 (2 mm×2 mm square); detector input of 3.70×10−5 watts (rms) at 10 Hz; detector sensitivity of 360 volts per watt at 10 Hz; detector output of 1.333×10−2 volts (rms) at 10 Hz; noise of 8.00×10−8 volts/sqrtHz at 10 Hz; and signal-to-noise ratios of 1.67×105 rms/sqrtHz and 104.4 dB/sqrtHz; and detectivity of 1.00×109 cm sqrtHz/watt.
In alternative embodiments, the detectors 150, 170 may comprise microphones and/or other sensors suitable for operation of the detection system 1700 in a photoacoustic mode.
The components of any of the embodiments of the analyte detection system 1700 may be partially or completely contained in an enclosure or casing (not shown) to prevent stray electromagnetic radiation, such as stray light, from contaminating the energy beam E. Any suitable casing may be used. Similarly, the components of the detection system 1700 may be mounted on any suitable frame or chassis (not shown) to maintain their operative alignment as depicted in
In one method of operation, the analyte detection system 1700 shown in FIGS. 44 or 46 measures the concentration of one or more analytes in the material sample S, in part, by comparing the electromagnetic radiation detected by the sample and reference detectors 150, 170. During operation of the detection system 1700, each of the secondary filter(s) 60 is sequentially aligned with the major axis X for a dwell time corresponding to the secondary filter 60. (Of course, where an electronically tunable filter or Fabry-Perot interferometer is used in place of the filter wheel 50, the tunable filter or interferometer is sequentially tuned to each of a set of desired wavelengths or wavelength bands in lieu of the sequential alignment of each of the secondary filters with the major axis X.) The energy source 1720 is then operated at (any) modulation frequency, as discussed above, during the dwell time period. The dwell time may be different for each secondary filter 60 (or each wavelength or band to which the tunable filter or interferometer is tuned). In one embodiment of the detection system 1700, the dwell time for each secondary filter 60 is less than about 1 second. Use of a dwell time specific to each secondary filter 60 advantageously allows the detection system 1700 to operate for a longer period of time at wavelengths where errors can have a greater effect on the computation of the analyte concentration in the material sample S. Correspondingly, the detection system 1700 can operate for a shorter period of time at wavelengths where errors have less effect on the computed analyte concentration. The dwell times may otherwise be nonuniform among the filters/wavelengths/bands employed in the detection system.
For each secondary filter 60 selectively aligned with the major axis X, the sample detector 150 detects the portion of the sample beam (Es), at the wavelength or wavelength band corresponding to the secondary filter 60, that is transmitted through the material sample S. The sample detector 150 generates a detection signal corresponding to the detected electromagnetic radiation and passes the signal to the processor 210. Simultaneously, the reference detector 170 detects the reference beam (Er) transmitted at the wavelength or wavelength band corresponding to the secondary filter 60. The reference detector 170 generates a detection signal corresponding to the detected electromagnetic radiation and passes the signal to the processor 210. Based on the signals passed to it by the detectors 150, 170, the processor 210 computes the concentration of the analyte(s) of interest in the sample S, and/or the absorbance/transmittance characteristics of the sample S at one or more wavelengths or wavelength bands employed to analyze the sample. The processor 210 computes the concentration(s), absorbance(s), transmittance(s), etc. by executing a data processing algorithm or program instructions residing within the memory 212 accessible by the processor 210.
The signal generated by the reference detector may be used to monitor fluctuations in the intensity of the energy beam emitted by the source 1720, which fluctuations often arise due to drift effects, aging, wear or other imperfections in the source itself. This enables the processor 210 to identify changes in intensity of the sample beam (Es) that are attributable to changes in the emission intensity of the source 1720, and not to the composition of the sample S. By so doing, a potential source of error in computations of concentration, absorbance, etc. is minimized or eliminated.
In one embodiment, the detection system 1700 computes an analyte concentration reading by first measuring the electromagnetic radiation detected by the detectors 150, 170 at each center wavelength, or wavelength band, without the sample element 1730 present on the major axis X (this is known as an “air” reading). Second, the system 1700 measures the electromagnetic radiation detected by the detectors 150, 170 for each center wavelength, or wavelength band, with the material sample S present in the sample element 1730, and the sample element 1730 and sample S in position on the major axis X (i.e., a “wet” reading). Finally, the processor 180 computes the concentration(s), absorbance(s) and/or transmittances relating to the sample S based on these compiled readings.
In one embodiment, the plurality of air and wet readings are used to generate a pathlength corrected spectrum as follows. First, the measurements are normalized to give the transmission of the sample at each wavelength. Using both a signal and reference measurement at each wavelength, and letting Si represent the signal of detector 150 at wavelength i and Ri represent the signal of detector 170 at wavelength i, the transmission, τi is computed as τi=Si(wet)/Ri(wet)/Si(air)/Ri(air). Optionally, the spectra may be calculated as the optical density, ODi, as −Log(Ti).
Next, the transmission over the wavelength range of approximately 4.5 μm to approximately 5.5 μm is analyzed to determine the pathlength. Specifically, since water is the primary absorbing species of blood over this wavelength region, and since the optical density is the product of the optical pathlength and the known absorption coefficient of water (OD=L σ, where L is the optical pathlength and σ is the absorption coefficient), any one of a number of standard curve fitting procedures may be used to determine the optical pathlength, L from the measured OD. The pathlength may then be used to determine the absorption coefficient of the sample at each wavelength. Alternatively, the optical pathlength may be used in further calculations to convert absorption coefficients to optical density.
Additional information on analyte detection systems, methods of use thereof, and related technologies may be found in the above-mentioned and incorporated U.S. Patent Application Publication No. 2005/0038357, published on Feb. 17, 2005, titled SAMPLE ELEMENT WITH BARRIER MATERIAL.
Section IV.C—Sample Element
In the embodiment illustrated in
In various embodiments, the material that makes up the window(s) of the sample element 1730 is completely transmissive, i.e., it does not absorb any of the electromagnetic radiation from the source 1720 and filters 1725 that is incident upon it. In another embodiment, the material of the window(s) has some absorption in the electromagnetic range of interest, but its absorption is negligible. In yet another embodiment, the absorption of the material of the window(s) is not negligible, but it is stable for a relatively long period of time. In another embodiment, the absorption of the window(s) is stable for only a relatively short period of time, but sample analysis apparatus 322 is configured to observe the absorption of the material and eliminate it from the analyte measurement before the material properties can change measurably. Materials suitable for forming the window(s) of the sample element 1730 include, but are not limited to, calcium fluoride, barium fluoride, germanium, silicon, polypropylene, polyethylene, or any polymer with suitable transmissivity (i.e., transmittance per unit thickness) in the relevant wavelength(s). Where the window(s) are formed from a polymer, the selected polymer can be isotactic, atactic or syndiotactic in structure, so as to enhance the flow of the sample between the window(s). One type of polyethylene suitable for constructing the sample element 1730 is type 220, extruded or blow molded, available from KUBE Ltd. of Staefa, Switzerland.
In one embodiment, the sample element 1730 is configured to allow sufficient transmission of electromagnetic energy having a wavelength of between about 4 μm and about 10.5 μm through the window(s) thereof. However, the sample element 1730 can be configured to allow transmission of wavelengths in any spectral range emitted by the energy source 1720. In another embodiment, the sample element 1730 is configured to receive an optical power of more than about 1.0 MW/cm2 from the sample beam (Es) incident thereon for any electromagnetic radiation wavelength transmitted through the filter 1725. Preferably, the sample chamber 903 of the sample element 1730 is configured to allow a sample beam (Es) advancing toward the material sample S within a cone angle of 45 degrees from the major axis X (see
In the embodiment illustrated in
In operation, the supply opening 1806 of the sample element 1730 is placed in contact with the material sample S, such as a fluid flowing from a patient. The fluid is then transported through the sample supply passage 1804 and into the sample chamber 903 via an external pump or by capillary action.
Where the upper and lower chamber walls 1802c, 1802d comprise windows, the distance T (measured along an axis substantially orthogonal to the sample chamber 903 and/or windows 1802a, 1802b, or, alternatively, measured along an axis of an energy beam (such as but not limited to the energy beam E discussed above) passed through the sample chamber 903) between them comprises an optical pathlength. In various embodiments, the pathlength is between about 1 μm and about 300 μm, between about 1 μm and about 100 μm, between about 25 μm and about 40 μm, between about 10 μm and about 40 μm, between about 25 μm and about 60 μm, or between about 30 μm and about 50 μm. In still other embodiments, the optical pathlength is about 50 μm, or about 25 μm. In some instances, it is desirable to hold the pathlength T to within about plus or minus 1 μm from any pathlength specified by the analyte detection system with which the sample element 1730 is to be employed. Likewise, it may be desirable to orient the walls 1802c, 1802d with respect to each other within plus or minus 1 μm of parallel, and/or to maintain each of the walls 1802c, 1802d to within plus or minus 1 μm of planar (flat), depending on the analyte detection system with which the sample element 1730 is to be used. In alternative embodiments, walls 1802c, 1802d are flat, textured, angled, or some combination thereof.
In one embodiment, the transverse size of the sample chamber 903 (i.e., the size defined by the lateral chamber walls 1802a, 1802b) is about equal to the size of the active surface of the sample detector 1745. Accordingly, in a further embodiment the sample chamber 903 is round with a diameter of about 4 millimeter to about 12 millimeter, and more preferably from about 6 millimeter to about 8 millimeter.
The sample element 1730 shown in
The sample element 1730 is preferably sized to receive a material sample S having a volume less than or equal to about 15 μL (or less than or equal to about 10 μL, or less than or equal to about 5 μL) and more preferably a material sample S having a volume less than or equal to about 2 μL. Of course, the volume of the sample element 1730, the volume of the sample chamber 903, etc. can vary, depending on many variables, such as the size and sensitivity of the sample detector 1745, the intensity of the radiation emitted by the energy source 1720, the expected flow properties of the sample, and whether flow enhancers are incorporated into the sample element 1730. The transport of fluid to the sample chamber 903 is achieved preferably through capillary action, but may also be achieved through wicking or vacuum action, or a combination of wicking, capillary action, peristaltic, pumping, and/or vacuum action.
With further reference to
The sample chamber 903 preferably comprises a reagentless chamber. In other words, the internal volume of the sample chamber 903 and/or the wall(s) 1802 defining the chamber 903 are preferably inert with respect to the sample to be drawn into the chamber for analysis. As used herein, “inert” is a broad term and is used in its ordinary sense and includes, without limitation, substances which will not react with the sample in a manner which will significantly affect any measurement made of the concentration of analyte(s) in the sample with sample analysis apparatus 322 or any other suitable system, for a sufficient time (e.g., about 1-30 minutes) following entry of the sample into the chamber 903, to permit measurement of the concentration of such analyte(s). Alternatively, the sample chamber 903 may contain one or more reagents to facilitate use of the sample element in sample assay techniques which involve reaction of the sample with a reagent.
In one embodiment of the present invention, sample element 1730 is used for a limited number of measurements and is disposable. Thus, for example, with reference to
Additional information on sample elements, methods of use thereof, and related technologies may be found in the above-mentioned and incorporated U.S. Patent Application Publication No. 2005/0038357, published on Feb. 17, 2005, titled SAMPLE ELEMENT WITH BARRIER MATERIAL; and in the above-mentioned and incorporated U.S. patent application Ser. No. 11/122,794, filed on May 5, 2005, titled SAMPLE ELEMENT WITH SEPARATOR.
Section IV.D—Centrifuge
In some embodiments, the fluid interface 2120 selectively controls the transfer of a sample from the passageway 113 and into the sample element 2112 to permit centrifuging of the sample. In another embodiment, the fluid interface 2120 also permits a fluid to flow though the sample element 2112 to cleanse or otherwise prepare the sample element for obtaining an analyte measurement. Thus, the fluid interface 2120 can be used to flush and fill the sample element 2112.
As shown in
As is further shown in
One position that the sample element 2112 may be rotated through or to is a sample measurement location 2140. The location 2140 may coincide with a region of an analysis system, such as an optical analyte detection system. For example, the location 2140 may coincide with a probe region 1002, or with a measurement location of another apparatus.
The rotor 2111 may be driven in a direction indicated by arrow R, resulting in a centrifugal force on sample(s) within sample element 2112. The rotation of a sample(s) located a distance from the center of rotation creates centrifugal force. In some embodiments, the sample element 2112 holds whole blood. The centrifugal force may cause the denser parts of the whole blood sample to move further out from the center of rotation than lighter parts of the blood sample. As such, one or more components of the whole blood can be separated from each other. Other fluids or samples can also be removed by centrifugal forces. In one embodiment, the sample element 2112 is a disposable container that is mounted on to a disposable rotor 2111. Preferably, the container is plastic, reusable and flushable. In other embodiments, the sample element 2112 is a non-disposable container that is permanently attached to the rotor 2111.
The illustrated rotor 2111 is a generally circular plate that is fixedly coupled to the axle 2113. The rotor 2111 can alternatively have other shapes. The rotor 2111 preferably comprises a material that has a low density to keep the rotational inertia low and that is sufficiently strong and stable to maintain shape under operating loads to maintain close optical alignment. For example, the rotor 2111 can be comprised of GE brand ULTEM(™) polyetherimide (PEI). This material is available in a plate form that is stable but can be readily machined. Other materials having similar properties can also be used.
The size of the rotor 2111 can be selected to achieve the desired centrifugal force. In some embodiments, the diameter of rotor 2111 is from about 75 millimeters to about 125 millimeters, or more preferably from about 100 millimeters to about 125 millimeters. The thickness of rotor 2111 is preferably just thick enough to support the centrifugal forces and can be, for example, from about 1.0 to 2.0 millimeter thick.
In an alternative embodiment, the fluid interface 2120 selectively removes blood plasma from the sample element 2112 after centrifuging. The blood plasma is then delivered to an analyte detection system for analysis. In one embodiment, the separated fluids are removed from the sample element 2112 through the bottom connector. Preferably, the location and orientation of the bottom connector and the container allow the red blood cells to be removed first. One embodiment may be configured with a red blood cell detector. The red blood cell detector may detect when most of the red blood cells have exited the container by determining the haemostatic level. The plasma remaining in the container may then be diverted into the analysis chamber. After the fluids have been removed from the container, the top connector may inject fluid (e.g., saline) into the container to flush the system and prepare it for the next sample.
The removable fluid handling cassette 820 can be removably engaged with a main analysis instrument 810. When the fluid handling cassette 820 is coupled to the main instrument 810, a drive system 2030 of the main instrument 810 mates with the rotor assembly 2016 of the cassette 820 (
In some embodiments, the rotor assembly 2016 includes a rotor 2020 sample element 2448 (
The main instrument 810 includes both the centrifuge drive system 2030 and an analyte detection system 1700, a portion of which protrudes from a housing 2049 of the main instrument 810. The drive system 2030 is configured to releasably couple with the rotor assembly 2016, and can impart rotary motion to the rotor assembly 2016 to rotate the rotor 2020 at a desired speed. After the centrifuging process, the analyte detection system 1700 can analyze one or more components separated from the sample carried by the rotor 2020. The projecting portion of the illustrated detection system 1700 forms a slot 2074 for receiving a portion of the rotor 2020 carrying the sample element 2448 so that the detection system 1700 can analyze the sample or component(s) carried in the sample element 2448.
To assemble the fluid handling and analysis apparatus 140 as shown in
After the centrifuging process, the rotor 2020 is rotated to an analysis position (see
With reference to
In some embodiments, the cassette 820 is a disposable fluid handling cassette. The reusable main instrument 810 can be used with any number of cassettes 820 as desired. Additionally or alternatively, the cassette 820 can be a portable, handheld cassette for convenient transport. In these embodiments, the cassette 820 can be manually mounted to or removed from the main instrument 810. In some embodiments, the cassette 820 may be a non disposable cassette which can be permanently coupled to the main instrument 810.
The illustrated rotor body 2446 can be a generally planar member that defines a mounting aperture 2447 for coupling to the drive system 2030. The illustrated rotor 2020 has a somewhat rectangular shape. In alternative embodiments, the rotor 2020 is generally circular, polygonal, elliptical, or can have any other shape as desired. The illustrated shape can facilitate loading when positioned horizontally to accommodate the analyte detection system 1700.
With reference to
With continued reference to
One or more windows 2460a, 2460b can be provided for optical access through the rotor 2020. A window 2460a proximate the bypass element 2452 can be a through-hole (see
Various fabrication techniques can be used to form the rotor 2020. In some embodiments, the rotor 2020 can be formed by molding (e.g., compression or injection molding), machining, or a similar production process or combination of production processes. In some embodiments, the rotor 2020 is comprised of plastic. The compliance of the plastic material can be selected to create the seal with the ends of pins 2542, 2544 of a fluid interface 2028 (discussed in further detail below). Non-limiting exemplary plastics for forming the ports (e.g., ports 2572, 2574, 2472, 2474) can be relatively chemically inert and can be injection molded or machined. These plastics include, but are not limited to, PEEK and polyphenylenesulfide (PPS). Although both of these plastics have high modulus, a fluidic seal can be made if sealing surfaces are produced with smooth finish and the sealing zone is a small area where high contact pressure is created in a very small zone. Accordingly, the materials used to form the rotor 2020 and pins 2542, 2544 can be selected to achieve the desired interaction between the rotor 2020 and the pins 2542, 2544, as described in detail below.
The illustrated rotor assembly 2016 of
With reference again to
The sample element 2448 comprises a sample chamber 2464 that holds a sample for centrifuging, and fluid channels 2466, 2468, which provide fluid communication between the chamber 2464 and the channels 2512, 2510, respectively, of the rotor 2020. Thus, the fluid channels 2512, 2466 define a first flow path between the port 2474 and the chamber 2464, and the channels 2510, 2468 define a second flow path between the port 2472 and the chamber 2464. Depending on the direction of fluid flow into the sample element 2448, either of the first or second flow paths can serve as an input flow path, and the other can serve as a return flow path.
A portion of the sample chamber 2464 can be considered an interrogation region 2091, which is the portion of the sample chamber through which electromagnetic radiation passes during analysis by the detection system 1700 of fluid contained in the chamber 2464. Accordingly, the interrogation region 2091 is aligned with the window 2460b when the sample element 2448 is coupled to the rotor 2020. The illustrated interrogation region 2091 comprises a radially inward portion (i.e., relatively close to the axis of rotation 2024 of the rotor 2020) of the chamber 2464, to facilitate spectroscopic analysis of the lower density portion(s) of the body fluid sample (e.g., the plasma of a whole blood sample) after centrifuging, as will be discussed in greater detail below. Where the higher-density portions of the body fluid sample are of interest for spectroscopic analysis, the interrogation region 2091 can be located in a radially outward (i.e., further from the axis of rotation 2024 of the rotor 2020) portion of the chamber 2464.
The rotor 2020 can temporarily or permanently hold the sample element 2448. As shown in
The sample element 2448 can be used for a predetermined length of time, to prepare a predetermined amount of sample fluid, to perform a number of analyses, etc. If desired, the sample element 2448 can be removed from the rotor 2020 and then discarded. Another sample element 2448 can then be placed into the recess 2502. Thus, even if the cassette 820 is disposable, a plurality of disposable sample elements 2448 can be used with a single cassette 820. Accordingly, a single cassette 820 can be used with any number of sample elements as desired. Alternatively, the cassette 820 can have a sample element 2448 that is permanently coupled to the rotor 2020. In some embodiments, at least a portion of the sample element 2448 is integrally or monolithically formed with the rotor body 2446. Additionally or alternatively, the rotor 2020 can comprise a plurality of sample elements (e.g., with a record sample element in place of the bypass 2452). In this embodiment, a plurality of samples (e.g., bodily fluid) can be prepared simultaneously to reduce sample preparation time.
The second layer 2475 can be formed by die-cutting a substantially uniform-thickness sheet of a material to form the lateral wall pattern shown in
However constructed, the second layer 2475 is preferably of uniform thickness to define a substantially uniform thickness or path length of the sample chamber 2464 and/or interrogation region 2091. This path length (and therefore the thickness of the second layer 2475 as well) is preferably between 10 microns and 100 microns, or is 20, 40, 50, 60, or 80 microns, in various embodiments.
The upper chamber wall 2482, lower chamber wall 2484, and lateral wall 2490 cooperate to form the chamber 2464. The upper chamber wall 2482 and/or the lower chamber wall 2484 can permit the passage of electromagnetic energy therethrough. Accordingly, one or both of the first and third layers 2473, 2478 comprises a sheet or layer of material which is relatively or highly transmissive of electromagnetic radiation (preferably infrared radiation or mid-infrared radiation) such as barium fluoride, silicon, polyethylene or polypropylene. If only one of the layers 2473, 2478 is so transmissive, the other of the layers is preferably reflective, to back-reflect the incoming radiation beam for detection on the same side of the sample element 2448 as it was emitted. Thus the upper chamber wall 2482 and/or lower chamber wall 2484 can be considered optical window(s). These window(s) are disposed on one or both sides of the interrogation region 2091 of the sample element 2448.
In one embodiment, sample element 2448 has opposing sides that are transmissive of infrared radiation and suitable for making optical measurements as described, for example, in U.S. Patent Application Publication No. 2005/0036146, published Feb. 17, 2005, titled SAMPLE ELEMENT QUALIFICATION, and hereby incorporated by reference and made a part of this specification. Except as further described herein, the embodiments, features, systems, devices, materials, methods and techniques described herein may, in some embodiments, be similar to any one or more of the embodiments, features, systems, devices, materials, methods and techniques described in U.S. Patent Application Publication No. 2003/0090649, published on May 15, 2003, titled REAGENT-LESS WHOLE-BLOOD GLUCOSE METER; or in U.S. Patent Application Publication No. 2003/0086075, published on May 8, 2003, titled DEVICE AND METHOD FOR IN VITRO DETERMINATION OF ANALYTE CONCENTRATIONS WITHIN BODY FLUIDS; or in U.S. Patent Application Publication No. 2004/0019431, published on Jan. 29, 2004, titled METHOD OF DETERMINING AN ANALYTE CONCENTRATION IN A SAMPLE FROM AN ABSORPTION SPECTRUM, or in U.S. Pat. No. 6,652,136, issued on Nov. 25, 2003 to Marziali, titled METHOD OF SIMULTANEOUS MIXING OF SAMPLES. In addition, the embodiments, features, systems, devices, materials, methods and techniques described herein may, in certain embodiments, be applied to or used in connection with any one or more of the embodiments, features, systems, devices, materials, methods and techniques disclosed in the above-mentioned U.S. Patent Applications Publications Nos. 2003/0090649; 2003/0086075; 2004/0019431; or U.S. Pat. No. 6,652,136. All of the above-mentioned publications and patent are hereby incorporated by reference herein and made a part of this specification.
With reference to
With continued reference to
The fluid interface 2028 of
The fluid pins 2542, 2544 extend outwardly from the main body 2580 and can engage the rotor 2020 to deliver and/or remove sample fluid to or from the rotor 2020. The fluid pins 2542, 2544 have respective pin bodies 2561, 2563 and pin ends 2571, 2573. The pin ends 2571, 2573 are sized to fit within corresponding ports 2472, 2474 of the fluid connector 2027 and/or the ports 2572, 2574 of the fluid connector 2029, of the rotor 2020. The pin ends 2571, 2573 can be slightly chamfered at their tips to enhance the sealing between the pin ends 2571, 2573 and rotor ports. In some embodiments, the outer diameters of the pin ends 2573, 2571 are slightly larger than the inner diameters of the ports of the rotor 2020 to ensure a tight seal, and the inner diameters of the pins 2542, 2544 are preferably identical or very close to the inner diameters of the channels 2510, 2512 leading from the ports. In other embodiments, the outer diameter of the pin ends 2571, 2573 are equal to or less than the inner diameters of the ports of the rotor 2020.
The connections between the pins 2542, 2544 and the corresponding portions of the rotor 2020, either the ports 2472, 2474 leading to the sample element 2448 or the ports 2572, 2574 leading to the bypass element 2452, can be relatively simple and inexpensive. At least a portion of the rotor 2020 can be somewhat compliant to help ensure a seal is formed with the pins 2542, 2544. Alternatively or additionally, sealing members (e.g., gaskets, O-rings, and the like) can be used to inhibit leaking between the pin ends 2571, 2573 and corresponding ports 2472, 2474, 2572, 2574.
The illustrated cassette 820 has a pair of opposing side walls 2041, 2043, top 2053, and a notch 2408 for mating with the detection system 1700. A front wall 2045 and rear wall 2047 extend between the side walls 2041, 2043. The rotor assembly 2016 is mounted to the inner surface of the rear wall 2047. The front wall 2045 is configured to mate with the main instrument 810 while providing the drive system 2030 with access to the rotor assembly 2016.
The illustrated front wall 2045 has the opening 2404 that provides access to the rotor assembly 2016. The drive system 2030 can be passed through the opening 2404 into the interior of the cassette 820 until it operatively engages the rotor assembly 2016. The opening 2404 of
The notch 2408 of the housing 2400 can at least partially surround the projecting portion of the analyte detection system 1700 when the cassette 820 is loaded onto the main instrument 810. The illustrated notch 2408 defines a cassette slot 2410 (
Although not illustrated, fasteners, clips, mechanical fastening assemblies, snaps, or other coupling means can be used to ensure that the cassette 820 remains coupled to the main instrument 810 during operation. Alternatively, the interaction between the housing 2400 and the components of the main instrument 810 can secure the cassette 820 to the main instrument 810.
The illustrated centrifuge drive system 2030 of
The centrifuge drive motor 2038 of
The drive motor 2038 can be the type of motor typically used in personal computer hard drives that is capable of rotating at about 7,200 RPM on precision bearings, such as a motor of a Seagate Model ST380011A hard drive (Seagate Technology, Scotts Valley, Calif.) or similar motor. In one embodiment, the drive spindle 2034 may be rotated at 6,000 rpm, which yields approximately 2,000 G's for a rotor having a 2.5 inch (64 millimeter) radius. In another embodiment, the drive spindle 2034 may be rotated at speeds of approximately 7,200 rpm. The rotational speed of the drive spindle 2034 can be selected to achieve the desired centrifugal force applied to a sample carried by the rotor 2020.
The main instrument 810 includes a main housing 2049 that defines a chamber sized to accommodate a filter wheel assembly 2300 including a filter drive motor 2320 and filter wheel 2310 of the analyte detection system 1700. The main housing 2049 defines a detection system opening 3001 configured to receive an analyte detection system housing 2070. The illustrated analyte detection system housing 2070 extends or projects outwardly from the housing 2049.
The main instrument 810 of
With continued reference to
The analyte detection system 1700 can be a spectroscopic bodily fluid analyzer that preferably comprises an energy source 1720. The energy source 1720 can generate an energy beam directed along a major optical axis X that passes through the slot 2074 towards a sample detector 1745. The slot 2074 thus permits at least a portion of the rotor (e.g., the interrogation region 2091 or sample chamber 2464 of the sample element 2448) to be positioned on the optical axis X. To analyze a sample carried by the sample element 2448, the sample element and sample can be positioned in the detection region 2080 on the optical axis X such that light emitted from the source 1720 passes through the slot 2074 and the sample disposed within the sample element 2448.
The analyte detection system 1700 can also comprise one or more lenses positioned to transmit energy outputted from the energy source 1720. The illustrated analyte detection system 1700 of
The analyte detection system 1700 can be used to determine the analyte concentration in the sample carried by the rotor 2020. Other types of detection or analysis systems can be used with the illustrated centrifuge apparatus or sample preparation unit. The fluid handling and analysis apparatus 140 is shown for illustrative purposes as being used in conjunction with the analyte detection system 1700, but neither the sample preparation unit nor analyte detection system are intended to be limited to the illustrated configuration, or to be limited to being used together.
To assemble the fluid handling and analysis apparatus 140, the cassette 820 can be moved towards and installed onto the main instrument 810, as indicated by the arrow 2007 in
After the cassette 820 is assembled with the main instrument 810, a sample can be added to the sample element 2448. The cassette 820 can be connected to an infusion source and a patient to place the system in fluid communication with a bodily fluid to be analyzed. Once the cassette 820 is connected to a patient, a bodily fluid may be drawn from the patient into the cassette 820. The rotor 2020 is rotated to a vertical loading position wherein the sample element 2448 is near the fluid interface 2028 and the bypass element 2452 is positioned within the slot 2074 of the detection system 1700. Once the rotor 2020 is in the vertical loading position, the pins 2542, 2544 of the fluid interface 2028 are positioned to mate with the ports 2472, 2474 of the rotor 2020. The fluid interface 2028 is then rotated upwardly until the ends 2571, 2573 of the pins 2542, 2544 are inserted into the ports 2472, 2474.
When the fluid interface 2028 and the sample element 2448 are thus engaged, sample fluid (e.g., whole blood) is pumped into the sample element 2448. The sample can flow through the pin 2544 into and through the rotor channel 2512 and the sample element channel 2466, and into the sample chamber 2464. As shown in
The centrifuge drive system 2030 can then spin the rotor 2020 and associated sample element 2448 as needed to separate one or more components of the sample. The separated component(s) of the sample may collect or be segregated in a section of the sample element for analysis. In the illustrated embodiment, the sample element 2448 of
The rotor 2020 can then be moved to a vertical analysis position wherein the sample element 2448 is disposed within the slot 2074 and aligned with the source 1720 and the sample detector 1745 on the major optical axis X. When the rotor 2020 is in the analysis position, the interrogation portion 2091 is preferably aligned with the major optical axis X of the detection system 1700. The analyte detection system 1700 can analyze the sample in the sample element 2448 using spectroscopic analysis techniques as discussed elsewhere herein.
After the sample has been analyzed, the sample can be removed from the sample element 2448. The sample may be transported to a waste receptacle so that the sample element 2448 can be reused for successive sample draws and analyses. The rotor 2020 is rotated from the analysis position back to the vertical loading position. To empty the sample element 2448, the fluid interface 2028 can again engage the sample element 2448 to flush the sample element 2448 with fresh fluid (either a new sample of body fluid, or infusion fluid). The fluid interface 2028 can be rotated to mate the pins 2542, 2544 with the ports 2472, 2474 of the rotor 2020. The fluid interface 2028 can pump a fluid through one of the pins 2542, 2544 until the sample is flushed from the sample element 2448. Various types of fluids, such as infusion liquid, air, water, and the like, can be used to flush the sample element 2448. After the sample element 2448 has been flushed, the sample element 2448 can once again be filled with another sample.
In an alternative embodiment, the sample element 2448 may be removed from the rotor 2020 and replaced after each separate analysis, or after a certain number of analyses. Once the patient care has terminated, the fluid passageways or conduits may be disconnected from the patient and the sample cassette 820 which has come into fluid contact with the patient's bodily fluid may be disposed of or sterilized for reuse. The main instrument 810, however, has not come into contact with the patient's bodily fluid at any point during the analysis and therefore can readily be connected to a new fluid handling cassette 820 and used for the analysis of a subsequent patient.
The rotor 2020 can be used to provide a fluid flow bypass. To facilitate a bypass flow, the rotor 2020 is first rotated to the vertical analysis/bypass position wherein the bypass element 2452 is near the fluid interface 2028 and the sample element 2448 is in the slot 2074 of the analyte detection system 1700. Once the rotor 2020 is in the vertical analysis/bypass position, the pins 2542, 2544 can mate with the ports 2572, 2574 of the rotor 2020. In the illustrated embodiment, the fluid interface 2028 is rotated upwardly until the ends 2571, 2573 of the pins 2542, 2544 are inserted into the ports 2572, 2574. The bypass element 2452 can then provide a completed fluid circuit so that fluid can flow through one of the pins 2542, 2544 into the bypass element 2452, through the bypass element 2452, and then through the other pin 2542, 2544. The bypass element 2452 can be utilized in this manner to facilitate the flushing or sterilizing of a fluid system connected to the cassette 820.
As shown in
The fluid handling network 2600 of the fluid handling and analysis apparatus 140 includes the passageway 111 which extends from the connector 120 toward and through the cassette 820 until it becomes the passageway 112, which extends from the cassette 820 to the patient connector 110. A portion 111a of the passageway 111 extends across an opening 2613 in the front face 2045 of the cassette 820. When the cassette 820 is installed on the main instrument 810, the roller pump 2619 engages the portion 111a, which becomes situated between the impeller 2620a and the impeller support 2620b (see
The fluid handling network 2600 also includes passageway 113 which extends from the patient connector 110 towards and into the cassette 820. After entering the cassette 820, the passageway 113 extends across an opening 2615 in the front face 2045 to allow engagement of the passageway 113 with a bubble sensor 321 of the main instrument 810, when the cassette 820 is installed on the main instrument 810. The passageway 113 then proceeds to the connector 2532 of the fluid interface 2028, which extends the passageway 113 to the pin 2544. Fluid drawn from the patient into the passageway 113 can thus flow into and through the fluid interface 2028, to the pin 2544. The drawn body fluid can further flow from the pin 2544 and into the sample element 2448, as detailed above.
A passage 2609 extends from the connector 2530 of the fluid interface 2028 and is thus in fluid communication with the pin 2542. The passageway 2609 branches to form the waste line 324 and the pump line 327. The waste line 324 passes across an opening 2617 in the front face 2045 and extends to the waste receptacle 325. The pump line 327 passes across an opening 2619 in the front face 2045 and extends to the pump 328. When the cassette 820 is installed on the main instrument 810, the pinch valves 323a, 323b extend through the openings 2617, 2619 to engage the lines 324, 327, respectively.
The waste receptacle 325 is mounted to the front face 2045. Waste fluid passing from the fluid interface 2028 can flow through the passageways 2609, 324 and into the waste receptacle 325. Once the waste receptacle 325 is filled, the cassette 820 can be removed from the main instrument 810 and discarded. Alternatively, the filled waste receptacle 325 can be replaced with an empty waste receptacle 325.
The pump 328 can be a displacement pump (e.g., a syringe pump). A piston control 2645 can extend over at least a portion of an opening 2621 in the cassette face 2045 to allow engagement with an actuator 2652 when the cassette 820 is installed on the main instrument 810. When the cassette 820 is installed, the actuator 2652 (
It will be appreciated that, upon installing the cassette 820 of
The illustrated fluid handling network 2700 also includes a passageway 2723 which extends between the passageway 111 and a passageway 2727, which in turn extends between the passageway 2723 and the fluid interface 2028. The passageway 2727 extends across an opening 2733 in the front face 2745. A pump line 2139 extends from a pump 328 to the passageways 2723, 2727. When the cassette 820 is installed on the main instrument 810, the pinch valves 2716, 2718 extend through the openings 2725, 2733 in the front face 2745 to engage the passageways 2723, 2727, respectively.
It will be appreciated that, upon installing the cassette 820 on the main instrument 810 (as shown in
In view of the foregoing, it will be further appreciated that the various embodiments of the fluid handling and analysis apparatus 140 (comprising a main instrument 810 and cassette 820) depicted in
Section V—Methods for Determining Analyte Concentrations from Sample Spectra
This section discusses a number of computational methods or algorithms which may be used to calculate the concentration of the analyte(s) of interest in the sample S, and/or to compute other measures that may be used in support of calculations of analyte concentrations. Any one or combination of the algorithms disclosed in this section may reside as program instructions stored in the memory 212 so as to be accessible for execution by the processor 210 of the fluid handling and analysis apparatus 140 or analyte detection system 334 to compute the concentration of the analyte(s) of interest in the sample, or other relevant measures.
Several disclosed embodiments are devices and methods for analyzing material sample measurements and for quantifying one or more analytes in the presence of interferents. Interferents can comprise components of a material sample being analyzed for an analyte, where the presence of the interferent affects the quantification of the analyte. Thus, for example, in the spectroscopic analysis of a sample to determine an analyte concentration, an interferent could be a compound having spectroscopic features that overlap with those of the analyte. The presence of such an interferent can introduce errors in the quantification of the analyte. More specifically, the presence of interferents can affect the sensitivity of a measurement technique to the concentration of analytes of interest in a material sample, especially when the system is calibrated in the absence of, or with an unknown amount of, the interferent.
Independently of or in combination with the attributes of interferents described above, interferents can be classified as being endogenous (i.e., originating within the body) or exogenous (i.e., introduced from or produced outside the body). As example of these classes of interferents, consider the analysis of a blood sample (or a blood component sample or a blood plasma sample) for the analyte glucose. Endogenous interferents include those blood components having origins within the body that affect the quantification of glucose, and may include water, hemoglobin, blood cells, and any other component that naturally occurs in blood. Exogenous interferents include those blood components having origins outside of the body that affect the quantification of glucose, and can include items administered to a person, such as medicaments, drugs, foods or herbs, whether administered orally, intravenously, topically, etc.
Independently of or in combination with the attributes of interferents described above, interferents can comprise components which are possibly but not necessarily present in the sample type under analysis. In the example of analyzing samples of blood or blood plasma drawn from patients who are receiving medical treatment, a medicament such as acetaminophen is possibly, but not necessarily present in this sample type. In contrast, water is necessarily present in such blood or plasma samples.
To facilitate an understanding of the inventions, embodiments are discussed herein where one or more analyte concentrations are obtained using spectroscopic measurements of a sample at wavelengths including one or more wavelengths that are identified with the analyte(s). The embodiments disclosed herein are not meant to limit, except as claimed, the scope of certain disclosed inventions which are directed to the analysis of measurements in general.
As an example, certain disclosed methods are used to quantitatively estimate the concentration of one specific compound (an analyte) in a mixture from a measurement, where the mixture contains compounds (interferents) that affect the measurement. Certain disclosed embodiments are particularly effective if each analyte and interferent component has a characteristic signature in the measurement, and if the measurement is approximately affine (i.e., includes a linear component and an offset) with respect to the concentration of each analyte and interferent. In one embodiment, a method includes a calibration process including an algorithm for estimating a set of coefficients and an offset value that permits the quantitative estimation of an analyte. In another embodiment, there is provided a method for modifying hybrid linear algorithm (HLA) methods to accommodate a random set of interferents, while retaining a high degree of sensitivity to the desired component. The data employed to accommodate the random set of interferents are (a) the signatures of each of the members of the family of potential additional components and (b) the typical quantitative level at which each additional component, if present, is likely to appear.
Certain methods disclosed herein are directed to the estimation of analyte concentrations in a material sample in the possible presence of an interferent. In certain embodiments, any one or combination of the methods disclosed herein may be accessible and executable processor 210 of system 334. Processor 210 may be connected to a computer network, and data obtained from system 334 can be transmitted over the network to one or more separate computers that implement the methods. The disclosed methods can include the manipulation of data related to sample measurements and other information supplied to the methods (including, but not limited to, interferent spectra, sample population models, and threshold values, as described subsequently). Any or all of this information, as well as specific algorithms, may be updated or changed to improve the method or provide additional information, such as additional analytes or interferents.
Certain disclosed methods generate a “calibration constant” that, when multiplied by a measurement, produces an estimate of an analyte concentration. Both the calibration constant and measurement can comprise arrays of numbers. The calibration constant is calculated to minimize or reduce the sensitivity of the calibration to the presence of interferents that are identified as possibly being present in the sample. Certain methods described herein generate a calibration constant by: 1) identifying the presence of possible interferents; and 2) using information related to the identified interferents to generate the calibration constant. These certain methods do not require that the information related to the interferents includes an estimate of the interferent concentration—they merely require that the interferents be identified as possibly present. In one embodiment, the method uses a set of training spectra each having known analyte concentration(s) and produces a calibration that minimizes the variation in estimated analyte concentration with interferent concentration. The resulting calibration constant is proportional to analyte concentration(s) and, on average, is not responsive to interferent concentrations.
In one embodiment, it is not required (though not prohibited either) that the training spectra include any spectrum from the individual whose analyte concentration is to be determined. That is, the term “training” when used in reference to the disclosed methods does not require training using measurements from the individual whose analyte concentration will be estimated (e.g., by analyzing a bodily fluid sample drawn from the individual).
Several terms are used herein to describe the estimation process. As used herein, the term “Sample Population” is a broad term and includes, without limitation, a large number of samples having measurements that are used in the computation of a calibration—in other words, used to train the method of generating a calibration. For an embodiment involving the spectroscopic determination of glucose concentration, the Sample Population measurements can each include a spectrum (analysis measurement) and a glucose concentration (analyte measurement). In one embodiment, the Sample Population measurements are stored in a database, referred to herein as a “Population Database.”
The Sample Population may or may not be derived from measurements of material samples that contain interferents to the measurement of the analyte(s) of interest. One distinction made herein between different interferents is based on whether the interferent is present in both the Sample Population and the sample being measured, or only in the sample. As used herein, the term “Type-A interferent” refers to an interferent that is present in both the Sample Population and in the material sample being measured to determine an analyte concentration. In certain methods it is assumed that the Sample Population includes only interferents that are endogenous, and does not include any exogenous interferents, and thus Type-A interferents are endogenous. The number of Type-A interferents depends on the measurement and analyte(s) of interest, and may number, in general, from zero to a very large number. The material sample being measured, for example sample S, may also include interferents that are not present in the Sample Population. As used herein, the term “Type-B interferent” refers to an interferent that is either: 1) not found in the Sample Population but that is found in the material sample being measured (e.g., an exogenous interferent), or 2) is found naturally in the Sample Population, but is at abnormally high concentrations in the material sample (e.g., an endogenous interferent). Examples of a Type-B exogenous interferent may include medications, and examples of Type-B endogenous interferents may include urea in persons suffering from renal failure. In the example of mid-IR spectroscopic absorption measurement of glucose in blood, water is found in all blood samples, and is thus a Type-A interferent. For a Sample Population made up of individuals who are not taking intravenous drugs, and a material sample taken from a hospital patient who is being administered a selected intravenous drug, the selected drug is a Type-B interferent.
In one embodiment, a list of one or more possible Type-B Interferents is referred to herein as forming a “Library of Interferents,” and each interferent in the library is referred to as a “Library Interferent.” The Library Interferents include exogenous interferents and endogenous interferents that may be present in a material sample due, for example, to a medical condition causing abnormally high concentrations of the endogenous interferent.
In addition to components naturally found in the blood, the ingestion or injection of some medicines or illicit drugs can result in very high and rapidly changing concentrations of exogenous interferents. This results in problems in measuring analytes in blood of hospital or emergency room patients. An example of overlapping spectra of blood components and medicines is illustrated in
One method for estimating the concentration of an analyte in the presence of interferents is presented in flowchart 3100 of
The method Blocks 3110, 3120, 3130, and 3140 may be repeatedly performed for each analyte whose concentration is required. If one measurement is sensitive to two or more analytes, then the methods of Blocks 3120, 3130, and 3140 may be repeated for each analyte. If each analyte has a separate measurement, then the methods of Blocks 3110, 3120, 3130, and 3140 may be repeated for each analyte.
An embodiment of the method of flowchart 3100 for the determination of an analyte from spectroscopic measurements will now be discussed. Further, this embodiment will estimate the amount of glucose concentration in blood sample S, without limit to the scope of the inventions disclosed herein. In one embodiment, the measurement of Block 3110 is an absorbance spectrum, Cs(λi), of a measurement sample S that has, in general, one analyte of interest, glucose, and one or more interferents. In one embodiment, the methods include generating a calibration constant κ(λi) that, when multiplied by the absorbance spectrum Cs(λi), provides an estimate, gest, of the glucose concentration gs.
As described subsequently, one embodiment of Block 3120 includes a statistical comparison of the absorbance spectrum of sample S with a spectrum of the Sample Population and combinations of individual Library Interferent spectra. After the analysis of Block 3120, a list of Library Interferents that are possibly contained in sample S has been identified and includes, depending on the outcome of the analysis of Block 3120, either no Library Interferents, or one or more Library Interferents. Block 3130 then generates a large number of spectra using the large number of spectra of the Sample Population and their respective known analyte concentrations and known spectra of the identified Library Interferents. Block 3130 then uses the generated spectra to generate a calibration constant matrix to convert a measured spectrum to an analyte concentration that is the least sensitive to the presence of the identified Library Interferents. Block 3140 then applies the generated calibration constant to predict the glucose concentration in sample S.
As indicated in Block 3110, a measurement of a sample is obtained. For illustrative purposes, the measurement, Cs(λi), is assumed to be a plurality of measurements at different wavelengths, or analyzed measurements, on a sample indicating the intensity of light that is absorbed by sample S. It is to be understood that spectroscopic measurements and computations may be performed in one or more domains including, but not limited to, the transmittance, absorbance and/or optical density domains. The measurement Cs(λi) is an absorption, transmittance, optical density or other spectroscopic measurement of the sample at selected wavelength or wavelength bands. Such measurements may be obtained, for example, using analyte detection system 334. In general, sample S contains Type-A interferents, at concentrations preferably within the range of those found in the Sample Population.
In one embodiment, absorbance measurements are converted to pathlength normalized measurements. Thus, for example, the absorbance is converted to optical density by dividing the absorbance by the optical pathlength, L, of the measurement. In one embodiment, the pathlength L is measured from one or more absorption measurements on known compounds. Thus, in one embodiment, one or more measurements of the absorption through a sample S of water or saline solutions of known concentration are made and the pathlength, L, is computed from the resulting absorption measurement(s). In another embodiment, absorption measurements are also obtained at portions of the spectrum that are not appreciably affected by the analytes and interferents, and the analyte measurement is supplemented with an absorption measurement at those wavelengths.
Some methods are “pathlength insensitive,” in that they can be used even when the precise pathlength is not known beforehand. The sample can be placed in the sample chamber 903 or 2464, sample element 1730 or 2448, or in a cuvette or other sample container. Electromagnetic radiation (in the mid-infrared range, for example) can be emitted from a radiation source so that the radiation travels through the sample chamber. A detector can be positioned where the radiation emerges, on the other side of the sample chamber from the radiation source, for example. The distance the radiation travels through the sample can be referred to as a “pathlength.” In some embodiments, the radiation detector can be located on the same side of the sample chamber as the radiation source, and the radiation can reflect off one or more internal walls of the sample chamber before reaching the detector.
As discussed above, various substances can be inserted into the sample chamber. For example, a reference fluid such as water or saline solution can be inserted, in addition to a sample or samples containing an analyte or analytes. In some embodiments, a saline reference fluid is inserted into the sample chamber and radiation is emitted through that reference fluid. The detector measures the amount and/or characteristics of the radiation that passes through the sample chamber and reference fluid without being absorbed or reflected. The measurement taken using the reference fluid can provide information relating to the pathlength traveled by the radiation. For example, data may already exist from previous measurements that have been taken under similar circumstances. That is, radiation can be emitted previously through sample chambers with various known pathlengths to establish reference data that can be arranged in a “look-up table,” for example. With reference fluid in the sample chamber, a one- to-one correspondence can be experimentally established between various detector readings and various pathlengths, respectively. This correspondence can be recorded in the look-up table, which can be recorded in a computer database or in electronic memory, for example.
One method of determining the radiation pathlength can be accomplished with a thin, empty sample chamber. In particular, this approach can determine the thickness of a narrow sample chamber or cell with two reflective walls. (Because the chamber will be filled with a sample, this same thickness corresponds to the “pathlength” radiation will travel through the sample). A range of radiation wavelengths can be emitted in a continuous manner through the cell or sample chamber. The radiation can enter the cell and reflect off the interior cell walls, bouncing back and forth between those walls one or multiple times before exiting the cell and passing into the radiation detector. This can create a periodic interference pattern or “fringe” with repeating maxima and minima. This periodic pattern can be plotted where the horizontal axis is a range of wavelengths and the vertical axis is a range of transmittance, measured as a percentage of total transmittance, for example. The maxima occur when the radiation reflected off of the two internal surfaces of the cell has traveled a distance that is an integral multiple N of the wavelength of the radiation that was transmitted without reflection. Constructive interference occurs whenever the wavelength is equal to 2b/N, where “b” is the thickness (or pathlength) of the cell. Thus, if ΔN is the number of maxima in this fringe pattern for a given range of wavelengths λ1-λ2, then the thickness of the cell b is provided by the following relation: b=ΔN/2(λ1-λ2). This approach can be especially useful when the refractive index of the material within the sample chamber or fluid cell is not the same as the refractive index of the walls of the cell, because this condition improves reflection.
Once the pathlength has been determined, it can be used to calculate or determine a reference value or a reference spectrum for the interferents (such as protein or water) that may be present in a sample. For example, both an analyte such as glucose and an interferent such as water may absorb radiation at a given wavelength. When the source emits radiation of that wavelength and the radiation passes through a sample containing both the analyte and the interferent, both the analyte and the interferent absorb the radiation. The total absorption reading of the detector is thus fully attributable to neither the analyte nor the interferent, but a combination of the two. However, if data exists relating to how much radiation of a given wavelength is absorbed by a given interferent when the radiation passes through a sample with a given pathlength, the contribution of the interferent can be subtracted from the total reading of the detector and the remaining value can provide information regarding concentration of the analyte in the sample. A similar approach can be taken for a whole spectrum of wavelengths. If data exists relating to how much radiation is absorbed by an interferent over a range of wavelengths when the radiation passes through a sample with a given pathlength, the interferent absorbance spectrum can be subtracted from the total absorbance spectrum, leaving only the analyte's absorbance spectrum for that range of wavelengths. If the interferent absorption data is taken for a range of possible pathlengths, it can be helpful to determine the pathlength of a particular sample chamber first so that the correct data can be found for samples measured in that sample chamber.
This same process can be applied iteratively or simultaneously for multiple interferents and/or multiple analytes. For example, the water absorbance spectrum and the protein absorbance spectrum can both be subtracted to leave behind the glucose absorbance spectrum.
The pathlength can also be calculated using an isosbestic wavelength. An isosbestic wavelength is one at which all components of a sample have the same absorbance. If the components (and their absorption coefficients) in a particular sample are known, and one or multiple isosbestic wavelengths are known for those particular components, the absorption data collected by the radiation detector at those isosbestic wavelengths can be used to calculate the pathlength. This can be advantageous because the needed information can be obtained from multiple readings of the absorption detector that are taken at approximately the same time, with the same sample in place in the sample chamber. The isosbestic wavelength readings are used to determine pathlength, and other selected wavelength readings are used to determine interferent and/or analyte concentration. Thus, this approach is efficient and does not require insertion of a reference fluid in the sample chamber.
In some embodiments, a method of determining concentration of an analyte in a sample can include inserting a fluid sample into a sample container, emitting radiation from a source through the container and the fluid sample, obtaining total sample absorbance data by measuring the amount of radiation that reaches the detector, subtracting the correct interferent absorbance value or spectrum from the total sample absorbance data, and using the remaining absorbance value or spectrum to determine concentration of an analyte in the fluid sample. The correct interferent absorbance value can be determined using the calculated pathlength.
The concentration of an analyte in a sample can be calculated using the Beer-Lambert law (or Beer's Law) as follows: If T is transmittance, A is absorbance, P0 is initial radiant power directed toward a sample, and P is the power that emerges from the sample and reaches a detector, then T=P/P0, and A=−log T =log(P0/P). Absorbance is directly proportional to the concentration (c) of the light-absorbing species in the sample, also known as an analyte or an interferent. Thus, if e is the molar absorptivity (1/M 1/cm), b is the path length (cm), and c is the concentration (M), Beer's Law can be expressed as follows: A=e b c. Thus, c=A/(e b).
Referring once again to flowchart 3100, the next step is to determine which Library Interferents are present in the sample. In particular, Block 3120 indicates that the measurements are analyzed to identify possible interferents. For spectroscopic measurements, it is preferred that the determination is made by comparing the obtained measurement to interferent spectra in the optical density domain. The results of this step provide a list of interferents that may, or are likely to, be present in the sample. In one embodiment, several input parameters are used to estimate a glucose concentration gest from a measured spectrum, Cs. The input parameters include previously gathered spectrum measurement of samples that, like the measurement sample, include the analyte and combinations of possible interferents from the interferent library; and spectrum and concentration ranges for each possible interferent. More specifically, the input parameters are:
Preferably, the Sample Population does not have any of the M interferents present, and the material sample has interferents contained in the Sample Population and none or more of the Library Interferents. Stated in terms of Type-A and Type-B interferents, the Sample Population has Type-A interferents and the material sample has Type-A and may have Type-B interferents. The Sample Population Data are used to statistically quantify an expected range of spectra and analyte concentrations. Thus, for example, for a system 10 or 334 used to determine glucose in blood of a person having unknown spectral characteristics, the spectral measurements are preferably obtained from a statistical sample of the population.
The following discussion, which is not meant to limit the scope of the present disclosure, illustrates embodiments for measuring more than one analyte using spectroscopic techniques. If two or more analytes have non-overlapping spectral features, then a first embodiment is to obtain a spectrum corresponding to each analyte. The measurements may then be analyzed for each analyte according to the method of flowchart 3100. An alternative embodiment for analytes having non-overlapping features, or an embodiment for analytes having overlapping features, is to make one measurement comprising the spectral features of the two or more analytes. The measurement may then be analyzed for each analyte according to the method of flowchart 3100. That is, the measurement is analyzed for each analyte, with the other analytes considered to be interferents to the analyte being analyzed for.
Interferent Determination
One embodiment of the method of Block 3120 is shown in greater detail with reference to the flowchart of
One embodiment of each of the methods of Blocks 3210, 3220, 3230, 3240, and 3250 are now described for the example of identifying Library Interferents in a sample from a spectroscopic measurement using Sample Population Data and a Library of Interferent Data, as discussed previously. Each Sample Population spectrum includes measurements (e.g., of optical density) taken on a sample in the absence of any Library Interferents and has an associated known analyte concentration. A statistical Sample Population model is formed (Block 3210) for the range of analyte concentrations by combining all Sample Population spectra to obtain a mean matrix and a covariance matrix for the Sample Population. Thus, for example, if each spectrum at n different wavelengths is represented by an n×1 matrix, C, then the mean spectrum, μ, is a n×1 matrix with the (e.g., optical density) value at each wavelength averaged over the range of spectra, and the covariance matrix, V, is the expected value of the deviation between C and μ as V=E((C−μ) (C−μ)T). The matrices μ and V are one model that describes the statistical distribution of the Sample Population spectra.
In another step, Library Interferent information is assembled (Block 3220). A number of possible interferents are identified, for example as a list of possible medications or foods that might be ingested by the population of patients at issue or measured by system 10 or 334, and their spectra (in the absorbance, optical density, or transmission domains) are obtained. In addition, a range of expected interferent concentrations in the blood, or other expected sample material, are estimated. Thus, each of M interferents has spectrum IF and maximum concentration Tmax. This information is preferably assembled once and is accessed as needed.
The obtained measurement data and statistical Sample Population model are next compared with data for each interferent from the interferent library (Block 3230) to perform a statistical test (Block 3240) to determine the identity of any interferent in the mixture (Block 3250). This interferent test will first be shown in a rigorous mathematical formulation, followed by a discussion of
Mathematically, the test of the presence of an interferent in a measurement proceeds as follows. The measured optical density spectrum, Cs, is modified for each interferent of the library by analytically subtracting the effect of the interferent, if present, on the measured spectrum. More specifically, the measured optical density spectrum, Cs, is modified, wavelength-by-wavelength, by subtracting an interferent optical density spectrum. For an interferent, M, having an absorption spectrum per unit of interferent concentration, IFM, a modified spectrum is given by C′s(T)=Cs−IFM T, where T is the interferent concentration, which ranges from a minimum value, Tmin, to a maximum value Tmax. The value of Tmin may be zero or, alternatively, be a value between zero and Tmax, such as some fraction of Tmax.
Next, the Mahalanobis distance (MD) between the modified spectrum C′s (T) and the statistical model (μ, V) of the Sample Population spectra is calculated as:
MD2(Cs−(T t),μ; ρs)=(Cs−(T IFm)−μ)TV−1(Cs−(T IFm)−μ) Eq.(1)
The test for the presence of interferent IF is to vary T from Tmin to Tmax (i.e., evaluate C′s (T) over a range of values of T) and determine whether the minimum MD in this interval is in a predetermined range. Thus for example, one could determine whether the minimum MD in the interval is sufficiently small relative to the quantiles of a χ2 random variable with L degrees of freedom (L=number of wavelengths).
Referring to
In one embodiment, a threshold level of MD2 is set as an indication of the presence of a particular interferent. Thus, for example,
As described subsequently, information related to the identified interferents is used in generating a calibration constant that is relatively insensitive to a likely range of concentration of the identified interferents. In addition to being used in certain methods described subsequently, the identification of the interferents may be of interest and may be provided in a manner that would be useful. Thus, for example, for a hospital based glucose monitor, identified interferents may be reported on display 141 or be transmitted to a hospital computer via communications link 216.
Calibration Constant Generation Embodiments
Once Library Interferents are identified as being possibly present in the sample under analysis, a calibration constant for estimating the concentration of analytes in the presence of the identified interferents is generated (Block 3130). More specifically, after Block 3120, a list of possible Library Interferents is identified as being present. One embodiment of the steps of Block 3120 are shown in the flowchart of
One embodiment of each of the methods of Blocks 3410, 3420, 3430, 3440, 3450, and 3460 are now described for the example of using identifying interferents in a sample for generating an average calibration constant. As indicated in Block 3410, one step is to generate synthesized Sample Population spectra, by adding a random concentration of possible Library Interferents to each Sample Population spectrum. The spectra generated by the method of Block 3410 are referred to herein as an Interferent-Enhanced Spectral Database, or IESD. The IESD can be formed by the steps illustrated in
The first step in Block 3410 is shown in
Once the individual Library Interferent spectra have been multiplied by the random concentrations to produce the RSIS, the RSIS are combined to produce a large population of interferent-only spectra, the CIS, as illustrated in
The next step combines the CIS and replicates of the Sample Population spectra to form the IESD, as illustrated in
In one embodiment, a 10-fold replication of the Sample Population database is used for 130 Sample Population spectra obtained from 58 different individuals and 18 Library Interferents. Greater spectral variety among the Library Interferent spectra requires a smaller replication factor, and a greater number of Library Interferents requires a larger replication factor.
The steps of Blocks 3420, 3430, 3440, and 3450 are executed to repeatedly combine different ones of the spectra of the IESD to statistically average out the effect of the identified Library Interferents. First, as noted in Block 3420, the IESD is partitioned into two subsets: a calibration set and a test set. As described subsequently, the repeated partitioning of the IESD into different calibration and test sets improves the statistical significance of the calibration constant. In one embodiment, the calibration set is a random selection of some of the IESD spectra and the test set are the unselected IESD spectra. In a preferred embodiment, the calibration set includes approximately two-thirds of the IESD spectra.
In an alternative embodiment, the steps of Blocks 3420, 3430, 3440, and 3450 are replaced with a single calculation of an average calibration constant using all available data.
Next, as indicted in Block 3430, the calibration set is used to generate a calibration constant for predicting the analyte concentration from a sample measurement. First an analyte spectrum is obtained. For the embodiment of glucose determined from absorption measurements, a glucose absorption spectrum is indicated as aG. The calibration constant is then generated as follows. Using the calibration set having calibration spectra C={c1, c2, . . . , cn} and corresponding glucose concentration values G={g1, g2, . . . , gn}, then glucose-free spectra C={c′1, c′2, . . . , c′n} can be calculated as: c′j=cj−aGgj. Next, the calibration constant, κ, is calculated from C′ and aG, according to the following 5 steps:
Next, the calibration constant is used to estimate the analyte concentration in the test set (Block 3440). Specifically, each spectrum of the test set (each spectrum having an associated glucose concentration from the Sample Population spectra used to generate the test set) is multiplied by the calibration vector κ from Block 3430 to calculate an estimated glucose concentration. The error between the calculated and known glucose concentration is then calculated (Block 3450). Specifically, the measure of the error can include a weighted value averaged over the entire test set according to 1/rms2.
Blocks 3420, 3430, 3440, and 3450 are repeated for many different random combinations of calibration sets. Preferably, Blocks 3420, 3430, 3440, and 3450 are repeated are repeated hundreds to thousands of times. Finally, an average calibration constant is calculated from the calibration and error from the many calibration and test sets (Block 3460). Specifically, the average calibration is computed as weighted average calibration vector. In one embodiment the weighting is in proportion to a normalized rms, such as the κave=κ*rms2/Σ(rms2) for all tests.
With the last of Block 3130 executed according to
Accordingly, one embodiment of a method of computing a calibration constant based on identified interferents can be summarized as follows:
One example of certain methods disclosed herein is illustrated with reference to the detection of glucose in blood using mid-IR absorption spectroscopy. Table 2 lists 10 Library Interferents (each having absorption features that overlap with glucose) and the corresponding maximum concentration of each Library Interferent. Table 2 also lists a Glucose Sensitivity to Interferent without and with training. The Glucose Sensitivity to Interferent is the calculated change in estimated glucose concentration for a unit change in interferent concentration. For a highly glucose selective analyte detection technique, this value is zero. The Glucose Sensitivity to Interferent without training is the Glucose Sensitivity to Interferent where the calibration has been determined using the methods above without any identified interferents. The Glucose Sensitivity to Interferent with training is the Glucose Sensitivity to Interferent where the calibration has been determined using the methods above with the appropriately identified interferents. In this case, least improvement (in terms of reduction in sensitivity to an interferent) occurs for urea, seeing a factor of 6.4 lower sensitivity, followed by three with ratios from 60 to 80 in improvement. The remaining six all have seen sensitivity factors reduced by over 100, up to over 1600. The decreased Glucose Sensitivity to Interferent with training indicates that the methods are effective at producing a calibration constant that is selective to glucose in the presence of interferents.
Another example illustrates the effect of the methods for 18 interferents. Table 3 lists of 18 interferents and maximum concentrations that were modeled for this example, and the glucose sensitivity to the interferent without and with training. The table summarizes the results of a series of 1000 calibration and test simulations that were performed both in the absence of the interferents, and with all interferents present.
In a third example, certain methods disclosed herein were tested for measuring glucose in blood using mid-IR absorption spectroscopy in the presence of four interferents not normally found in blood (Type-B interferents) and that may be common for patients in hospital intensive care units (ICUs). The four Type-B interferents are mannitol, dextran, n-acetyl L cysteine, and procainamide.
Of the four Type-B interferents, mannitol and dextran have the potential to interfere substantially with the estimation of glucose: both are spectrally similar to glucose (see
The central wavelength of the data obtained using filter is indicated in
Next, random amounts of each Type-B interferent of this Example are added to the spectra to produce mixtures that, for example could make up an Interferent Enhanced Spectral. Each of the Sample Population spectra was combined with a random amount of a single interferent added, as indicated in Table 4, which lists an index number N, the Donor, the glucose concentration (GLU), interferent concentration (conc(IF)), and the interferent for each of 54 spectra. The conditions of Table 4 were used to form combined spectra including each of the 6 plasma spectra was combined with 2 levels of each of the 4 interferents.
Next, calibration vectors were generated using the spectra of
The calibration vectors are shown in
The similarity of the calibration vectors obtained for minimizing the effects of the two interferents n-acetyl L cysteine and procainamide, to that obtained for pure plasma, is a reflection of the fact that these two interferents are spectrally quite distinct from the glucose spectrum; the large differences seen between the calibration vectors for minimizing the effects of dextran and mannitol, and the calibration obtained for pure plasma, are conversely representative of the large degree of similarity between the spectra of these substances and that of glucose. For those cases in which the interfering spectrum is similar to the glucose spectrum (that is, mannitol and dextran), the greatest change in the calibration vector. For those cases in which the interfering spectrum is different from the glucose spectrum (that is, n-acetyl L cysteine and procainamide), it is difficult to detect the difference between the calibration vectors obtained with and without the interferent.
It will be understood that the steps of methods discussed are performed in one embodiment by an appropriate processor (or processors) of a processing (i.e., computer) system executing instructions (code segments) stored in appropriate storage. It will also be understood that the disclosed methods and apparatus are not limited to any particular implementation or programming technique and that the methods and apparatus may be implemented using any appropriate techniques for implementing the functionality described herein. The methods and apparatus are not limited to any particular programming language or operating system. In addition, the various components of the apparatus may be included in a single housing or in multiple housings that communication by wire or wireless communication.
Further, the interferent, analyte, or population data used in the method may be updated, changed, added, removed, or otherwise modified as needed. Thus, for example, spectral information and/or concentrations of interferents that are accessible to the methods may be updated or changed by updating or changing a database of a program implementing the method. The updating may occur by providing new computer readable media or over a computer network. Other changes that may be made to the methods or apparatus include, but are not limited to, the adding of additional analytes or the changing of population spectral information.
One embodiment of each of the methods described herein may 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. Thus, as will be appreciated by those skilled in the art, embodiments of the disclosed inventions 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 ones of the disclosed inventions 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.
Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. 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.
Similarly, it should be appreciated that in the above description of embodiments, various features of the inventions 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, as the following claims reflect, inventive aspects lie in a combination of fewer than all features of any single foregoing disclosed embodiment. Thus, the claims following the Detailed Description are hereby expressly incorporated into this Detailed Description, with each claim standing on its own as a separate embodiment.
Further information on analyte detection systems, sample elements, algorithms and methods for computing analyte concentrations, and other related apparatus and methods can be found in U.S. Patent Application Publication No. 2003/0090649, published May 15, 2003, titled REAGENT-LESS WHOLE BLOOD GLUCOSE METER; U.S. Patent Application Publication No. 2003/0178569, published Sep. 25, 2003, titled PATHLENGTH-INDEPENDENT METHODS FOR OPTICALLY DETERMINING MATERIAL COMPOSITION; U.S. Patent Application Publication No. 2004/0019431, published Jan. 29, 2004, titled METHOD OF DETERMINING AN ANALYTE CONCENTRATION IN A SAMPLE FROM AN ABSORPTION SPECTRUM; U.S. Patent Application Publication No. 2005/0036147, published Feb. 17, 2005, titled METHOD OF DETERMINING ANALYTE CONCENTRATION IN A SAMPLE USING INFRARED TRANSMISSION DATA; and U.S. Patent Application Publication No. 2005/0038357, published on Feb. 17, 2005, titled SAMPLE ELEMENT WITH BARRIER MATERIAL. The entire contents of each of the above-mentioned publications are hereby incorporated by reference herein and are made a part of this specification.
A number of applications, publications and external documents are incorporated by reference herein. Any conflict or contradiction between a statement in the bodily text of this specification and a statement in any of the incorporated documents is to be resolved in favor of the statement in the bodily text.
Infusion and Monitoring System
With reference to the drawings, for purposes of illustration, and particularly to
At appropriate times, a system controller 6023 causes the infusion pump 6013 to reverse its direction, and instead to draw blood from the patient 6011 through the catheter 6021 and into the sensor assembly 6019. This reversal of the pump's direction may occur at predetermined time intervals, or upon receipt by the controller of a manual command issued by a caregiver.
One suitable blood chemistry sensor assembly 6019 is depicted in
To perform the desired analysis, a sample of the patient's blood may be drawn into a position where it contacts or otherwise engages one or more of the analytical sensors of the sensor assembly 6019. In addition, sufficient additional blood preferably is drawn to minimize the effects of any dilution of the blood by the adjacent infusion fluid.
After the patient's blood sample has been drawn to the appropriate position, signals from the various analytical sensors are read and analyzed by an analyzer 6025 (
In some embodiments, one or more of the analytical sensors comprises an optical sensor. The optical sensor may enable spectroscopic or photometric measurements of the properties or characteristics of the blood sample and may utilize the visible, near-infrared, mid-infrared, or other portions of the electromagnetic spectrum.
After a blood sample has been drawn into the sensor assembly 6019, it is preferred, but not necessary, that a brief period of time, such as about 8 seconds, be allowed to elapse before the sensors are read so that a stable sensor output is achieved. The analyzer 6025 converts electrical signals from one or more electrical sensors, if present, into corresponding indications of the presence or concentrations of one or more components, or of other parameters, of the patient's blood. Similarly, the analyzer 6025 converts optical signals from one or more optical sensors into corresponding indications of the presence or concentrations of one or more components, or other parameters, of the patient's blood. These indications can be read by a caregiver monitoring the patient.
Thereafter, after the analysis has been completed, the controller 6023 again operates the pump 6013 in its forward direction, to flush the blood sample out of the sensor assembly 6019 and back into the patient 6011. Pumping of the infusion fluid into the patient then resumes. This pumping can occur at a relatively low flow rate of about 1 to 10 milliliters per hour.
When the infusion pump 6013 is operated in its rearward direction, it draws the patient's blood at a substantially constant flow rate. However, because the length and internal volume of the catheter 6021 located between the sensor assembly 6019 and the patient 6011 can vary, merely drawing the blood for a fixed time duration cannot ensure that the blood will reach its desired position in the sensor assembly without a possibly large draw of blood from the patient. Some means for sensing the arrival of the blood sample at its desired position, therefore, is required. If necessary, a dedicated sensor may be provided within the sensor assembly 6019, for sensing the arrival of the blood sample at its desired position. For example, some embodiments may use a sensor that detects changes in the color of the fluid, such as a color sensor, e.g., the calorimetric sensor 311 (
In some embodiments, the need for such a dedicated sensor within the sensor assembly 6019, for detecting the arrival of the blood sample at its desired position within the assembly, may be obviated by configuring the controller 6023 to monitor the signal from one or more of the analytical sensors that already are present within the assembly. In response to detecting a predetermined signal or change in signal from the sensor or sensors being monitored, the controller ceases operating the pump 6013 in the rearward direction.
As mentioned above, an additional amount of blood is drawn from the patient 6011 after the sample first reaches the analytical sensor being monitored, to minimize the dilution effects of the adjacent infusion fluid. The amount of additional blood required to minimize dilution effects depends, in part, on the dimension of the passageway through which the blood is drawn. Although several milliliters would be required to reduce any such dilution effects in a passageway having an inside diameter of about one millimeter and a length of about 0.25 meters, for example, the effects can be reduced to an acceptably small, and repeatable, level by drawing merely about 0.1-1.0 milliliters of additional blood after the blood has been detected to have arrived at the sensor being monitored. The controller 6023, therefore, is programmed to continue drawing blood for whatever time duration is required after detecting the arrival of the blood sample at the sensor before switching off the pump 6013.
Additionally, the controller 6023 preferably is programmed to actuate an alarm and to switch off the infusion pump 6013 if the arrival of the patient's blood sample has not been detected within a predetermined maximum time duration following initiation of pump's reversal and also if the arrival is detected to have occurred before a predetermined minimum time duration. This ensures that the pump is not operated indefinitely to draw blood from the patient in case of a sensor failure or other system failure, and it also ensures that the caregiver is alerted to a possible sensor failure, a blockage in the infusion tube 6017 or catheter 6021, or other system failure.
With reference again to
In the embodiment illustrated in
One optical sensor 6040 is illustrated in the embodiment shown in
In one embodiment, the optical sensor 6040 may comprise a sensor similar to the colorimetric sensor 311 (see
The optical sensor 6040 may be employed in addition to sensors 6027-6039, as shown in the embodiment depicted in
The optical sensor 6040 may be used to determine the presence and/or concentration of more than one analyte. For example, the optical sensor 6040 may transmit an optical signal to the analyzer 6025 that represents or otherwise conveys spectroscopic or non-spectroscopic characteristics of a group of analytes or interferents. Accordingly, one embodiment of the sensor assembly 6019 may comprise the temperature sensor 6033, the pH sensor 6039, and a single optical sensor 6040 configured to transmit information about the concentrations of a group of analytes, such as, for example, oxygen, carbon dioxide, sodium, potassium, calcium, and other suitable characteristics such as, for example, hematocrit.
Embodiments of the sensor assembly 6019 may include one or more non-optical sensors to measure fluid properties and characteristics such as, for example, temperature, pH, pressure, salinity, electrical conductivity, and the like. Some embodiments may omit such sensors. It will be apparent to one of ordinary skill in the art that embodiments of the sensor assembly 6019 may include a selection of sensors, including optical and non-optical sensors, such that the blood analysis system may measure desired properties and characteristics of the fluid in within the system.
The incident energy beam Ei propagates along the optical line 6070 until it reaches the second chamber 6045. An optical coupler 6076, which may comprise a lens, may be used to focus or direct the energy beam E into the chamber 6045. The energy beam E passes through a first window 6080 that forms at least a portion of a side of the chamber 6045. The energy beam E is transmitted through the fluid sample 6090 within the chamber 6045. In the embodiment shown in
The returned energy beam Er comprises an optical signal that carries information about the properties and characteristics of fluid sample 6090 in the chamber 6045. The analyzer 6025 may measure spectroscopic or non-spectroscopic properties of the returned energy beam Er and may comprise a spectrometer, a photometer, a calorimeter, a filter, and/or other optical devices. The analyzer 6025 may comprise an analyte detection system similar to any of the embodiments of the analyte detection system 1700 depicted in
In some embodiments, the energy beam E may comprise different wavelength ranges of the electromagnetic spectrum at different times. For example, the energy source may be selectively tunable by the system controller 6023 so as to emit an energy beam Ei comprising a desired wavelength range. Alternatively, the energy beam Es from the energy source may pass through a filter wheel similar to the embodiment shown in
In the embodiment shown in
The optical sensor 6040 may have additional features. For example, one or both of the windows 6080 or 6082 may comprise a filter to selectively pass only predetermined wavelength regions of the energy beam E. Additionally, one or both of the windows 6080 or 6082 may comprise etalons so that the optical sensor 6040 functions as a Fabry-Perot interferometer. In some embodiments, one or more piezoelectric devices may be used to vary the distance between the etalons.
In the embodiment shown in
In the embodiment shown in
After activation of the timer, the analyzer 6025 begins monitoring the signal produced by the calcium sensor 6035. That signal should show a similar rise above its baseline level after activation of the timer. This is because blood ordinarily carries substantially more ionized calcium than does the infusion fluid being used. If the expected rise in the calcium sensor signal does in fact occur within this time period, it may be concluded that the blood sample has reached both the carbon dioxide sensor 6027 and the calcium sensor 6035. In some embodiments, the calcium sensor signal may show a rise above its baseline level within seven to ten seconds after activation of the timer.
After the analyzer has detected a rise in the level of the signal from the calcium sensor 6035, the controller 6023 continues to operate the infusion pump 6013 in the rearward direction for a time sufficient to draw about an additional 0.1 to 1.0 milliliters of blood from the patient 6011. The internal construction of the sensor assembly 6019 is such that the leading edge of the blood sample thereby is drawn nearly all of the way up the length of the tubing 6049 located within the assembly housing. In this position, the blood sample should be in sensing contact with the analytical sensors 6027-6040 included in the sensor assembly 6019. The leading edge of the drawn blood preferably remains within the assembly housing both for cosmetic reasons and also to avoid undue delays caused by drawing excessive amounts of blood.
At the point where the prescribed additional amount of blood has been drawn from the patient 6011, readings can be taken from any or all of the analytical sensors 6027-6040. The analyzer 6025 reads the various signals from these sensors and converts them into indications of conditions of the patient's blood chemistry. The analyzer 6025 may then communicate these blood conditions to the caregiver via a printed record, an optical display, digital data transmission, or any other suitable means.
The blood chemistry analysis system may also include safety/alarm features that alert the caregiver if a fault or other failure condition is detected. For example, if a predetermined maximum time period elapses after reversal of the infusion pump 6013 without the analyzer 6025 detecting the expected rise in the signals from the carbon dioxide sensor 6027 and/or the calcium sensor 6035, it may be determined that a failure condition is present. This could be due, for example, to an obstruction in the line or a failure of one or both of the sensors. When this occurs, the controller 6023 may cease operating the pump and may activate an alarm 6050 (
It is apparent to those of skill in the art that alternative embodiments of the sensor assembly 6019 may use sensors other than the carbon dioxide sensor 6027 and/or the calcium sensor 6035 to determine when the blood sample has reached a predetermined position within the sensor assembly 6019. For example, some embodiments may use the sodium 6037 or the hematocrit sensor 6047a-6047c instead of the carbon dioxide sensor 6027 or the calcium sensor 6035. In other embodiments, the optical sensor 6040 may comprise a colorimetric sensor, generally similar to the sensor 311 (
With reference now to
The glucose sensor 6051 may operate using electrochemical techniques and/or optical techniques and may transmit an electrical signal, an optical signal, or both indicating the concentration of glucose in the fluid sample adjacent to the sensor. An optical glucose sensor 6051 may in one embodiment be generally similar to the optical sensor 6040 depicted in
Electrically conductive sleeves 6055a and 6055b may be located at the inlet and outlet of the chamber 6053, respectively, and may be used to sense the arrival of a drawn blood sample. The conductive sleeves 6055a and 6055b may be comprised of a metal and preferably may be comprised of stainless steel. As was the case with the electrically conductive sleeves 6047a, 6047b and 6047c in the sensor assembly 6019 of
In the sensor assembly 6019′ of
It should be appreciated from the foregoing description that the blood analysis system of
Preferred embodiments of a fluid infusion and blood testing system incorporating the invention have been described in detail for purposes of understanding and illustration. Various additions and modifications will no doubt occur to those skilled in the art. For example, the layout, number, and type of sensors used may be varied considerably. Other modifications may be made as well.
Certain embodiments disclosed herein include an improved method and apparatus for precisely and repeatably controlling the drawing of a patient's blood sample to a prescribed position within a blood chemistry sensor assembly. This method and apparatus ensures that the blood sample reaches all of the sensor assembly's individual sensors and that sufficient additional blood is drawn to minimize the dilution effects of an adjacent infusion fluid. The method and apparatus have particular use as part of an infusion system that substantially continuously infuses an infusion fluid into patient, while intermittently reversing itself and drawing blood samples from the patient, for chemical analysis.
More particularly, one embodiment of the apparatus can include a reversible infusion pump that, under the control of a controller, normally pumps an infusion fluid in a forward direction from a fluid source into the patient via an infusion tube and a catheter. Intermittently, the controller operates the pump in a rearward direction, to draw a blood sample from the patient into the blood chemistry sensor assembly, which is connected to the infusion tube. The controller monitors the signal produced by a sensor of the sensor assembly, to detect the arrival of the blood at the sensor, after which time it ceases operating the pump in the rearward direction. The sensor signal then is monitored, to provide an indication of a predetermined parameter of the patient's blood.
In another optional feature, the sensor whose signal is monitored in the detecting of the arrival of the patient's blood sample is selected from the group consisting of carbon dioxide sensors, oxygen sensors, potassium sensors, calcium sensors, sodium sensors, hematocrit sensors, temperature sensors, glucose sensors, and pH sensors. In a preferred form of the apparatus, the controller detects the arrival of the blood sample in response to a predetermined combination of signals generated by both a carbon dioxide sensor and a calcium sensor.
In another optional feature, the apparatus actuates an alarm in response to a predetermined signal received from one or more of the sensor assembly's sensors. An alarm also is actuated in response to a failure to detect the arrival of the blood sample within a predetermined time period after operation of the infusion pump in the rearward direction is initiated and in response to detecting the arrival of the blood sample at a time too soon after operation of the infusion pump in the rearward direction is initiated.
In yet another optional feature, the controller ceases operation of the infusion pump in the rearward direction a prescribed time after the arrival of the blood sample has been detected. Preferably, this occurs after a prescribed additional volume of blood has been drawn from the patient.
Additional information related to a method and apparatus for monitoring blood chemistry may be found in U.S. Pat. No. 5,758,643, titled “METHOD AND APPARATUS FOR MONITORING BLOOD CHEMISTRY,” issued Jun. 2, 1998, which is hereby incorporated by reference herein and made a part of this specification in its entirety.
Patient Specific Plasma Separation
In certain embodiments, the extraction and analysis of a patient's bodily fluid, for example blood plasma, may be performed entirely at the patient's point of care or bedside, and/or with a device attached or connected to a patient. Prior art methods of analyzing bodily fluid from a hospital patient involved taking a sample of a bodily fluid, transporting the sample to a central processing and analysis lab and periodically batch processing a group of samples collected from several patients using a common, central device, for example a centrifuge and bodily fluid analyzer. Here, methods of analysis are disclosed wherein a fluid handling system or sampling system is attached to a single patient, for example at the patients bedside or point of care, and is capable of extracting a bodily fluid sample from the patient, preparing the sample for analysis and analyzing the sample all at the patient's bedside.
At a first step, a fluid handling system, sampling system, analyte detection system or other suitable apparatus is connected to a patient so that the system is placed in fluid communication with a bodily fluid of the patient. Since the system is only associated with a single patient, the connector between the system and patient may be of a type to establish a sustained connection to the patient such as through an IV tube or a catheter inserted into the patient's vasculature.
At a second step, once fluid communication has been established with the patient's bodily fluid, a sample of the bodily fluid may be drawn into the system. The sample may then be transported through one or more passageways in the system to a sample preparation unit located with in the system. At a third step, the sample preparation unit prepares the sample for analysis. Depending on the bodily fluid to be analyzed, the preparation of the sample may involve diverting or isolating of a fraction of the drawn portion of fluid for analysis, filtering the sample through a filter or membrane to remove impurities, or separating a first component from the whole sample, for example separating plasma from a sample of whole blood, to analyze only the first component. Since the sample preparation unit is co-located with the sample draw apparatus, the sample may be analyzed almost immediately after it has been drawn. Once the sample has been prepared, it may be transferred to a chamber, a sample cell or any other location accessible by an analyte detection system for analysis. Alternatively, the sample preparation unit itself may be configured to hold the sample of component for analysis by the analyte detection system.
At a fourth step, after the sample has been prepared, the analyte detection system which is preferably located within the fluid handling system or sampling system connected to the patient determines the concentration of one or more analytes based on or within the prepared sample. The concentration of the measured analyte(s) and/or values of other suitable characteristics may then be reported to a display or operator's console located at the patient's bedside or point of care, and/or uploaded to a data network such as a Hospital Information System (HIS), shortly after the sample was drawn from the patient.
At a fifth step, once the sample has been drawn, prepared, and analyzed the fluid handling system or sampling system may shift to infusing the patient with an infusion fluid, such as saline, lactated Ringer's solution, water or any other suitable infusion liquid. In shifting to the infusion mode, the system may return at least a portion of the drawn portion or sample of bodily fluid to the patient. In addition, since the system is dedicated to a single patient use and continuously connected to the patient, the system may further be automated to periodically draw, prepare, and measure a sample of bodily fluid from the patient. In an alternative embodiment where the fluid handling system or sampling system includes an alarm system, the determined analyte concentration(s) may then be compared to a predetermined range of acceptable concentrations and if the determined concentration(s) fall outside the range, an indicator may be triggered, for example an alarm may be sounded, to alert the hospital staff.
Embodiments of the above described method and apparatus as used to prepare a plasma sample from a patient's whole blood and analyze the plasma sample at the patient's bedside or point of care are further described herein in reference to
In use, the patient sampling system 100 of
Once the system 100 is connected to a patient, a sample of whole blood from the patient may be periodically withdrawn from the patient's vasculature through connector 110 and passageway 112. The whole blood sample may then be transported to the co-located fluid handling and analysis apparatus 140 where it may be processed and analyzed. Such a system and method of analysis is advantageous over the prior methods because it permits the sample to be processed in a much shorter timeframe. Since the sample does not have to be transported to a central facility and is not batch processed with a group of samples from other hospital patients, but rather is drawn and analyzed at the patient's bedside via a dedicated machine, the sample can be processed and analyzed almost without delay. In addition, such a system and method of analysis permits the system to use a smaller sample size to perform the analysis, since multiple transfers (and the associated incidental fluid loss) from a separate sampling device to a separate processing device to a separate analysis device are no longer necessary.
Once the sample of whole blood has been drawn from the patient, at least a portion of the sample may be transported through passageway 112 to the fluid component separator or sample preparation unit 332, for example a centrifuge or filter membrane, located in the fluid handling and analysis apparatus 140. Here, the sample may be separated into at least one component for analysis and a remainder portion, for example a whole blood sample may be separated into a plasma sample and a remainder. Again, because the fluid component separator is co-located with the sampling system at the patient's bedside, the sample may be separated almost without delay, for example in less than 5 minutes from drawing, alternatively less than 2 minutes from drawing, alternatively immediately after drawing from the patient. In an alternative embodiment, for example analysis of whole blood, separation into components may not be required and the sample may simply be filtered to remove impurities. Once the sample has been processed into a first component, the first component may then be almost immediately analyzed by the analyte detection system 334 co-located in the fluid handling and analysis apparatus 140.
This is especially advantageous when the sample is whole blood and the component desired is blood plasma. For example, the glucose levels in plasma are an important indicator of patient health. However, since blood typically clots in less than two minutes, the delay in prior art systems where the samples are transported to a central lab for batch processing often complicate separation of plasma from whole blood. Under certain prior art methods, an anticoagulant is added to the whole blood sample to prevent clotting prior to processing and separation of the plasma. Under other prior art methods, a coagulant is added to the whole blood sample, serum is separated from the sample and analyzed in lieu of the plasma, and finally blood glucose level in the plasma is extrapolated from the levels in the serum. With regard to certain embodiments of the presently disclosed method and apparatus, because the samples are processed shortly after they are drawn, it is possible to separate the plasma from the whole blood without the addition of anti-coagulants and thus it is possible to get an accurate measurement of the plasma glucose level.
In addition, as shown in
Certain alternative embodiments, shown in
The methods for extracting and analyzing a bodily fluid from a hospital patient at the patient's bedside or point of care described herein may also be used with embodiments of the patient infusion and monitoring system illustrated in
A sample of whole blood from the patient 6011 may be drawn at various times. The sampling times may be spaced periodically or they may be intermittent or subject to the control of an attending health care provider. To draw a sample of whole blood, the controller 6023 directs the pump 6013 to operate in the reverse direction so as to draw whole blood from the patient 6011. An advantage of the system shown in
Once the sample of whole blood has been drawn from the patient 6011, at least a portion of the sample may be transported into the sensor assembly 6019 through the tubing 6049. In certain embodiments, the sensor assembly 6019 comprises a fluid component separator such as a filter, which may be generally similar to the blood filter 1500 or membrane 1509 shown in
Again, because the fluid component separator is co-located with the sampling system at the patient's bedside, the sample may be separated almost without delay, for example in less than 5 minutes from drawing, alternatively less than 2 minutes from drawing, alternatively immediately after drawing from the patient. In an alternative embodiment, for example analysis of whole blood, separation into components may not be required and the sample may simply be filtered to remove impurities. Once the sample has been processed into a blood plasma component, the blood plasma component may then be almost immediately analyzed by any or all of the sensors 6031-6040 disposed within the sensor assembly 6019. For example, in certain embodiments, the blood plasma component is analyzed by the optical sensor 6040 (as shown, e.g., in
In other embodiments, the fluid component separator comprises a centrifuge in place of, or in addition to, a filter. The centrifuge may be generally similar to the centrifuge 2110 illustrated in
Inside the sensor assembly 6019, the blood plasma component can be analyzed by any or all of the sensors 6031-6040. In particular, the blood plasma component can be promptly analyzed via the spectroscopic methods of
In other embodiments, the fluid component separator may be disposed in other locations in the infusion and monitoring system. For example, in some embodiments, the analyzer 6025 comprises the fluid component separator. In such embodiments, additional passageways, valves, and pumps may direct a portion of a drawn whole blood sample into the analyzer 6025 wherein the whole blood sample is separated into a blood plasma component. The separation may be performed by one or more filters and/or one or more centrifuges.
Variations of the infusion and monitoring system shown in
Clot Inhibition
The coagulation of blood may affect the operation of extracorporeal blood systems. In general, coagulation proceeds according to a series of complex chemical reactions within the blood. In extracorporeal systems, coagulation may begin upon the contact of blood with most types of surfaces, and may collect on surfaces or within crevices or changes in surface type or flow conditions. Thus, for example, blood flowing through passageways may build up on the passageway walls or may form clots that restrict or block the flow of blood, hindering the operation of the system. Accordingly, it is advantageous for embodiments of the fluid handling system 10 illustrated in
One method for inhibiting and/or removing blood clots comprises intermittently providing one or more anti-clotting agents and/or clot disrupting or dissolving agents to a passageway of the extracorporeal blood flow system. In embodiments of the system 10 shown in
In some embodiments of the blood clot inhibition method and apparatus, the agents may comprise a cleaning solution S, such as a detergent, which may be delivered through the flow passageways. In one embodiment, the cleaning solution S is effective in removing blood, blood components, and/or clotted blood from the surfaces of the passageways, sample elements, or other blood contacting surfaces. In one embodiment, the solution S may be thermally stable at room temperatures. Suitable solutions S include solutions commonly used for cleaning hospital and laboratory instruments. In one embodiment, the solution S may include nonspecific protease enzymes for digesting blood. In another embodiment, the cleaning solution S may comprise a mixture of approximately 1% TERGAZYME™ (manufactured by Alconox, Inc., White Planes, N.Y.) in saline. In yet another embodiment, a mixture of more than one cleaning solution S may be utilized.
The system 10 in
In some embodiments of the system 10 in
In embodiments of the infusion and monitoring system shown in
In one embodiment of an anti-clotting procedure, the system controller 6023 directs the pump 6013 to close valves permitting the infusion fluid to flow from the infusion source 6015 and to open valves permitting the cleaning solution S to flow through the pump 6013, into the infusion line 6017, and thereby into the sensor assembly 6019 and/or the catheter 6021. After a time sufficient for the cleaning solution S to clean the passageways, the system controller 6023 directs the pump 6013 to close the valves permitting the cleaning solution S to flow into the infusion tube 6017 and to re-open the valves permitting infusion fluid to be pumped into the patient 6011.
In other embodiments of the anti-clotting or clot disrupting device, the container 6092 is fluidly coupled to the infusion tube 6017 at a “T” junction. Additional pumps and/or valves may be included in the anti-clotting device in order to transfer the cleaning solution S through the “T” junction into the infusion tube 6017 and thereby into the sensor assembly 6019. In certain embodiments, the anti-clotting device is disposed within the sensor assembly 6019. For example, in certain such embodiments, the container 6092 storing the cleaning solution S is disposed within the sensor assembly 6019 so that it is in fluid communication with the tubing 6049 and/or the sensing chambers 6043 and 6045. In other embodiments, more than one anti-clotting device may be used. For example, a first anti-clotting device can be disposed within the sensor assembly 6019, and a second anti-clotting device can be put into fluid communication with the pump 6013 as shown in
In some embodiments, the pump 8030 and the valves 8020a-8020d are operated by a controller disposed within the sensor assembly 6019, while in other embodiments, these devices are controlled by the system controller 6023. The anti-clotting device may be intermittently operated so as to flush the system with cleaning solution S in order to keep the system free from clots. In one embodiment, the flushing action may be a backflow—that is the flow may be in the reverse direction of the normal flow of the system. Some embodiments permit the cleaning solution S to remain in the flow passageways for a time period sufficient to allow effective cleaning of the passageways. In certain embodiments, the system is configured to permit an attending health care professional to actuate the anti-clotting device so as to advantageously clean the system if the health care professional visually observes signs of clot formation.
In certain embodiments, residual blood, infusion fluid, cleaning solution S, or other fluids may be pumped into the waste receptacle 8035 or into other waste receptacles disposed within the system (e.g., the waste receptacle 325 shown in
Additional embodiments of the anti-clotting or clot disrupting agents are possible. For example, it has been found by the inventors that the application of vibrations to an extracorporeal system inhibits the formation of blood clots within the system and disrupts clots already formed in the system and facilitates flushing of the passageways and chambers. The vibrations may be at frequencies above the range of human hearing such as, for example, greater than 15 kHz, and are referred to herein and without limitation as ultrasonic vibrations or ultrasonic waves, or as “ultrasound.” Accordingly, certain embodiments of the anti-clotting or clot disrupting system comprise ultrasound units or devices. The ultrasonic unit may be positioned adjacent to or otherwise in sonic transmission engagement with one or more fluid flow passageways and/or the sensor assembly 6019.
The ultrasonic controller 8054 is coupled to the ultrasonic transducer 8050 and controls characteristics of the ultrasonic vibrations transmitted by the transducer 8050 into portions of the infusion and sampling system. The ultrasound characteristics include, for example, amplitude, frequency, power, and duration of the ultrasonic vibrations. In some embodiments, the ultrasound may be transmitted continuously, or it may be pulsed, or a combination of continuous and pulsed ultrasound may be used. A single frequency or a range of frequencies may be used in various embodiments.
In the embodiment shown in
In some preferred embodiments, the ultrasonic transducer 8050 is disposed adjacent to a chamber or cell holding a fluid sample such as, for example, the sample element or cuvette 1730 (
In certain embodiments, the frequency transmitted through the ultrasonic transducer is from about 15 kHz to about 60 kHz, and the power transmitted through the transducer is from about 2 Watts to 200 Watts. In one preferred embodiment, a model VC24 ultrasonic system obtained from Sonics & Materials, Inc (Newtown, Conn.) is operated at a frequency of 40 kHz and 25 Watts of power. The ultrasonic transducer may be operated to provide one or more pulses of ultrasonic energy to the system. In one preferred embodiment, the pulse duration is about 10 seconds and is delivered between fluid fillings of a sample chamber or a passageway. In this preferred embodiment, the fluid filling and providing of ultrasound is repeated every 30 minutes over a time period of 69 hours, after which there is typically very little evidence of clotting, as observed either visually or by measuring the inhibition of blood flowing through the passageway.
Some embodiments of the ultrasound anti-clotting or clot disrupting system comprise ultrasound comprising different frequencies, powers, pulse durations, and/or application times. In other embodiments, the ultrasound generator may drive two or more ultrasound transducers, which may be suitably disposed within the fluid handling system. In still other embodiments, the anti-clotting agent may comprise additional ultrasound generators. Other variations of ultrasound units or devices are possible.
Additionally, in certain preferred embodiments, the anti-clotting or clot disrupting system may comprise one or more cleaning solutions and one or more ultrasound units. Other variations are possible.
Network Connected Data for Verification/Calibration
In certain embodiments, the body fluid analyzing system 5000 comprises the infusion and monitoring system shown in, for example,
The data system 5120 may comprise one or more data-containing devices (e.g., computers, servers, storage devices) in communication with the system 5000 via one or more data links. In certain embodiments, the data system 5120 comprises a single data-containing device in communication with the analyzer 6025 or the sensor assembly 6019 via one or more data links. In certain such embodiments, the analyzer 6025 or the sensor assembly 6019 communicates directly with the data-containing device via the communication interface 5110. In certain other embodiments, the data system 5120 comprises a plurality of data-containing devices in communication with the analyzer 6025 or the sensor assembly 6019, and in certain embodiments with one another, via a network comprising one or more data links. In certain embodiments, the one or more data links can comprise wireless data links (e.g., electromagnetic radiation such as radio frequency or infrared), hardwired data links, fiber optic data links, or any other suitable data links, or the one or more data links can comprise a combination of wireless, hardwired, fiber optic, or other suitable links, and/or the Internet.
In some configurations, the data system 5120 comprises one or more storage devices, processing devices, memory devices, input and/or output devices, computers, servers, and/or medical devices, which are interlinked by the one or more data links. Additional devices other than those listed above can be connected to the data system. In some embodiments, the data system 5120 comprises a local network and covers a limited region, such as a hospital building or a portion thereof, such as a floor, unit, or ward. In other configurations, the data system 5120 is more wide-ranging, and, in some instances, is connected to additional networks such as the Internet. In some embodiments, the data system 5120 can comprise a Hospital Information System (HIS). In certain embodiments, the communication interface 5110 comprises a CAT5 connection and communicates with the data system using the POCT-1A communication protocol standard.
In certain embodiments, the at least one data file 5115 is stored in one or more components of the data system 5120. The at least one data file 5115 can be stored in any suitable medium, such as, for example, a hard drive, a flash drive, a DVD drive, a CD drive, or RAM. In certain embodiments, the at least one data file 5115 contains calibration information for calibrating the analyzer 6025 or the sensor assembly 6019. In other embodiments, the data file 5115 comprises an electronic medical record pertaining to the patient 6011. Various programs for creating and updating electronic medical records are available, such as, for example, Enterprise Medical Record™ available from Meditech (Westwood, Mass.) and RALS® available from Medical Automated Systems (Charlottesville, Va.).
In certain embodiments, the analyzer 6025 or the sensor assembly 6019 may be in continuous or selective communication with the data system 5120 via the communication interface 5110 and can thereby access the electronic medical record pertaining to the patient 6011. The electronic medical record can contain such information as the name, age, height, weight, blood type, medicine dosing history, other treatment dosing history, analyte level history, treatment response history, general medical history, etc. of the patient 6011. In certain embodiments, a single electronic medical record contains all the relevant information regarding the patient 6011, while in other embodiments, the relevant information is parsed among a plurality of electronic medical records corresponding to the patient 6011.
After determining one or more levels or concentrations of desired analytes, drugs, or compounds, the analyzer 6025, or in some embodiments, the sensor assembly 6019, can upload and record the determined one or more levels or concentrations onto the electronic medical record via the data system 5120. These recorded levels/concentrations can include a time stamp to indicate the time at which the analysis was performed. Because the body fluid analyzer 6025 (or the sensor assembly 6019) is simultaneously in communication with the patient 6011 and the data system 5120, it can provide a real-time flow of one or more current analyte levels and other data for recording in electronic medical record. The analyzer 6025 or the sensor assembly 6019 can also use information obtained on the one or more levels of analytes, drugs, or compounds as inputs or data to assist in determining the one or more levels of other analytes, drugs, or compounds. The analyzer 6025 or the sensor assembly 6019 can obtain this information directly (e.g., by analyzing a body fluid sample), or by accessing data stored in the electronic medical record.
For example, in one implementation of the patient infusion and monitoring system shown in
Based on such patient treatment information in the electronic medical record (e.g., an indication that drug A is being administered to the patient 6011), the analyzer 6025 or the sensor assembly 6019 can be prompted to estimate the level of drug A in addition to estimating the level of the “usual” one or more analytes of interest. This prompting can take the form of a command issued to the analyzer 6025 or the sensor assembly 6019 from another device on the data system 5120 (such as a computer, server or processor, based on a review or analysis of the patient's electronic medical record 5130), or self-prompting by the analyzer 6025 (or the sensor assembly 6019) itself, after receiving or accessing the patient's electronic medical record. However prompted, the analyzer 6025 or the sensor assembly 6019 analyzes a sample of the patient's body fluid, estimates based on this analysis the level of the drug A (or other interfering compound, as explained above), and makes an initial estimate of the level of one or more analytes of interest. The analyzer 6025 (and/or other appropriate device on the data system 5120) can then correct or adjust the initial estimate according to the known interfering tendency of drug A. For example, if a given level of drug A is known to affect the estimation of an analyte level by a given amount, the initial estimate is corrected or adjusted to eliminate or account for this effect. Alternatively, an indication in the electronic medical record (or a determination by the analyzer 6025 or the sensor assembly 6019 based on a body fluid analysis) that an interferent, such as drug A, is present can trigger execution of an algorithm by the analyzer 6025 (and/or other appropriate device on the data system 5120) for determining the desired analyte concentration in the presence of interferents. (See, e.g., any of the methods discussed with reference to the flowcharts illustrated in
Other variations are possible. In one embodiment, the sensor assembly 6019 communicates with the analyzer 6025, and the analyzer 6025 communicates with the data system 5120. The communication interface 5110 may be disposed in the analyzer 6025, or in the sensor assembly 6019, or in both. In other embodiments of the system, the communications interface 5110 may be disposed within the system controller 6023 instead of or in addition to a communications interface 5110 disposed within the analyzer 6025 or the sensor assembly 6019.
In certain embodiments, the body fluid analyzing system 5000 comprises the infusion and monitoring system shown in, for example,
Where the second analyzer 5200 comprises a hand-held analyzer, a sample of body fluid may be taken from the patient via a finger-stick or other percutaneous sampling techniques, or by accessing a port provided in the I.V. tubing connected to the patient. Suitable hand-held analyzers include electrochemical test-strip-based meters, such as the Accu-Chek™ available from Roche Diagnostics Corp. (Indianapolis, Ind.), or other hand-held electrochemical analyzers such as the I-STAT™ available from Abbott Laboratories (Abbott Park, Ill.). Suitable laboratory meters include “bench-top” devices like the 2300 STAT Plus™ available from Yellow Springs Instruments (YSI, Inc., Yellow Springs, Ohio), and the BioProfile™ available from Nova Biomedical Corp. (Waltham, Mass.).
The patient monitoring system 5000 advantageously permits comparison of the analyte-concentration estimates made by the body fluid analyzer 5100 (e.g., the analyzer 6025 or the sensor assembly 6019) with the analyte-concentration estimates made by the second analyzer 5200 (e.g., a handheld or bench-top device), to facilitate, for example, verification that analyzer 5100 or second analyzer 5200 is functioning properly. After the body fluid analyzer 5100 analyzes a sample of the body fluid of the patient P and makes an estimate of analyte concentration, the analyzer 5100 (and/or any other suitable device of the data system 5120, such as the second analyzer 5200 or a computer or server) can compare that estimate to one or more (preferably recent) analyte-concentration estimates made by the second analyzer 5200 based on its analysis of the body fluid of the patient P. Performing the comparison can involve accessing one or more of the (subsequently) compared analyte-concentration estimates from the electronic medical record 5130 of the patient P. These accessed estimates can include, e.g., periodic laboratory-based measurements of one or more analytes of interest in the body fluid of the patient P, which are stored in the electronic medical record 5130.
In some preferred embodiments, the estimates made by second analyzer 5200 and used in this comparison must be made within a short time before or after the compared estimates are made by body fluid analyzer 5100. For example, estimates made by the second analyzer 5200 that serve as a basis for comparison can be made within a maximum of 1 day, 12 hours, 6 hours, 3 hours, 2 hours, 1 hour, or 30 minutes before or after the time of the corresponding estimate made by body fluid analyzer 5100.
If the comparison of estimates indicates that estimates made by body fluid analyzer 5100 unacceptably differ from estimates made by second analyzer 5200, an alert can be issued by the body fluid analyzer 5100, the second analyzer 5200, and/or other devices of data system 5120. Various forms of alerts can be issued; for example, an audible and/or visible alarm can be issued by the body fluid analyzer 5100 itself or by a hospital public address system or messaging system, a notation can be made in the electronic medical record 5130, and/or a message such as electronic mail can be sent to one or more devices of the data system 5120, such as a computer or other device discussed above. For example, in embodiments in which the body fluid analyzing system 5000 comprises the infusion and monitoring system shown, e.g., in
Instead of or in addition to an alert, the body fluid analyzing system 5000 can activate a stop based on the comparison (e.g., a lock out or shutdown of body fluid analyzer 5100 can be triggered by body fluid analyzer 5100 itself, or second analyzer 5200, and/or other devices of the data system 5120).
The electronic medical record 5130 can include treatment information pertaining to patient P, such as analytes, drugs, or compounds that have been prescribed to the patient. The body fluid analyzer 5100, the second analyzer 5200, or other devices of the data system 5120 can issue one or more alerts when a comparison between treatment information and data from the body fluid analyzer 5100 indicates an unexpected result. For example, one or more alerts can signal when analytes, drugs, or compounds that have not been prescribed to patient P or are otherwise undesirable are present in the body fluid of patient P, or when a drug that has been prescribed for patient P (e.g., as shown in the medical record 5130) is not found in the body fluid of patient P. The one or more alerts can take any of the forms mentioned above. In response to the one or more alerts, hospital staff can take appropriate steps, such as administering particular compounds to patient P, to reestablish a desirable composition of the body fluid.
In a clinical or hospital environment, there may be several patients each fluidly coupled to a body fluid analyzing system. In some embodiments, each of the body fluid analyzing systems comprises an infusion and monitoring system as shown, for example, in
The body fluid analyzing systems fluidly coupled to each of the patients may be configured to access and/or update the electronic medical records of the patients, respectively. In certain embodiments, the laboratory analyzer is used to analyze a body fluid or other sample from the patients and to update their respective electronic medical records via communication interface. In some embodiments, there may be two patients, while in further embodiments, additional patients and body fluid analyzing systems may be used to communicate with the data system and to access and/or update an electronic medical record for each patient that resides on data system.
Measurement of Multiple Aanlytes
In some of the embodiments of the infusion and monitoring system disclosed herein, an optical sensor 6040 may be disposed within the sensor assembly 6019 (
In some embodiments, the analyzer 6025 may also determine the presence or concentrations of one or more analytes of interest in the fluid under analysis. For example, the analyzer 6025 may be configured to quantify one or more analytes in the presence of interferents using embodiments of the spectroscopic methods disclosed herein. In certain embodiments, some of the disclosed spectroscopic methods are used to quantitatively estimate the concentration of one or more analyte in a mixture from a measurement, where the mixture contains one or more interferents that affect the measurement. In certain preferred embodiments, the measurement comprises one or more spectroscopic measurements of the mixture. Certain disclosed embodiments are particularly effective if each analyte and interferent component has a characteristic signature in the measurement, and if the measurement is approximately affine (i.e., includes a linear component and an offset) with respect to the concentration of each analyte and interferent. In one embodiment, a method includes a calibration process including an algorithm for estimating a set of coefficients and an offset value that permits the quantitative estimation of an analyte.
One method for estimating the concentration of an analyte in the presence of interferents is presented in flowchart 3100 of
An embodiment of the method of flowchart 3100 for the determination of an analyte from spectroscopic measurements is further discussed herein with reference to
Once interferents are identified as being possibly present in the sample under analysis, a calibration constant, κ, for estimating the concentration of analytes in the presence of the identified interferents is generated (Block 3130 in flowchart 3100 of
For example, in one embodiment of the method of flowchart 3100 (
The methods described with reference to
Additional embodiments of methods for measuring more than one analyte using spectroscopic techniques may be used. If two or more analytes have non-overlapping spectral features, then a first embodiment of the method is to obtain a spectrum corresponding to each analyte. The spectra may be analyzed serially for each analyte concentration according to the method of flowchart 3100 (
A second embodiment of the method may be suitable for analytes having non-overlapping features or for two or more analytes having overlapping features. In the second embodiment, one measurement is made that comprises the spectral features of the two or more analytes. The measurement may then be analyzed for each analyte according to the method of flowchart 3100 (
An alternative embodiment of a method for calculating analyte concentrations includes obtaining a sequence of measurements of an analyte and mathematically manipulating these measurements. The measurements may be combined to yield an analyte concentration parameter such as, for example, a best estimate of an analyte concentration, or an average analyte concentration, or a trend in analyte concentration, or some combination thereof. An example where this alternative embodiment may be advantageous includes, but is not limited to, conditions where there are temporal variations in the fluid being analyzed such as, for example, variations in analyte or interferent concentration.
The determination of an average concentration from several previous measurements may provide a more useful indication of the analyte concentration. In cases where there is a variation in the average concentration, the measurements may be analyzed for the determination of a temporal trend in a concentration—for example a rate of change of a concentration of an analyte. Another example of a situation where this alterative embodiment may be useful is in systems where averaging measurements results in a more accurate estimate as, for example, where the measurement is subject to random noise. One illustrative example is a spectroscopic analysis system having random noise. There are other situations where the alternative embodiment may be useful.
In one embodiment of a method for calculating analyte concentrations from a sequence of measurements, a sample may be provided, for example, to sample analysis device 330 (
In some embodiments, the controller 210 (
The sequence of estimates may be analyzed according to any one of a number of techniques for averaging measurements. In an embodiment involving performing a sequence of measurements on a single sample, an average of the measurements may be determined. In an embodiment involving performing a sequence of measurements obtained on a series of different samples, the sequence may be analyzed to determine an average. Averaging methods include, but are not limited to, providing an average of several of the most recent measurements, providing a weighted average of the most recent measurements that favors the most recent over the more distant measurements in time, or a statistical analysis that factors in the most statistically relevant measurements. Many other averaging methods may be used. Other embodiments may analyze the measurements for quantities in addition to an average such as, for example, a standard deviation, a variance, a median, a mode, or any other statistical parameter of interest. Still other embodiments may perform additional mathematical operations on the sequence of measurements.
Embodiments of the system disclosed herein that measure the concentration of a broader range of analytes may give a more complete status report of the parameters, characteristics, and chemistry of the body fluid sample. A further benefit is that a more accurate status report can be generated by using all the measured analytes to correct for interferences among them.
It will be understood that the steps of methods discussed herein are performed in one embodiment by an appropriate processor (or processors) of a processing (i.e., computer) system executing instructions (code segments) stored in appropriate storage. It will also be understood that the disclosed methods and apparatus are not limited to any particular implementation or programming technique and that the methods and apparatus may be implemented using any appropriate techniques for implementing the functionality described herein. The methods and apparatus are not limited to any particular programming language or operating system. In addition, the various components of the apparatus may be included in a single housing or in multiple housings that communication by wire or wireless communication.
Further, the interferent, analyte, or population data used in the method may be updated, changed, added, removed, or otherwise modified as needed. Thus, for example, spectral information and/or concentrations of interferents that are accessible to the methods may be updated or changed by updating or changing a database of a program implementing the method. The updating may occur by providing new computer readable media or over a computer network. Other changes that may be made to the methods or apparatus include, but are not limited to, the adding of additional analytes or the changing of population spectral information.
One embodiment of each of the methods described herein may 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. Thus, as will be appreciated by those skilled in the art, embodiments of the disclosed inventions 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 ones of the disclosed inventions 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.
Apparatus and Methods for Distributed Sensing
In one embodiment, the color sensor 7001 comprises an optical colorimetric sensor, such as, for example, an Optical Blood Leak/Blood vs. Saline Detector available from Introtek International (Edgewood, N.J.). Other devices may be used as well. For example, in some embodiments, the color sensor 7001 may detect the concentration of hemoglobin or the hematocrit in the fluid sample.
The color sensor 7001 advantageously may be used in a procedure in which a blood sample is drawn from the patient 6011. In an example of this procedure utilizing the embodiment shown in
When the leading edge of the blood sample reaches the position of the color sensor 7001, the color sensor 7001 may detect the presence of blood by measuring the fluid color or a rate of change thereof. If the color sensor 7001 detects a sufficient change in the color properties of the fluid or a stable “plateau” of a color of reference (e.g., red), the sensor 7001 may signal the system controller 6023 to cease operation of the infusion pump 6013. The analytical sensors 6027-6040 may then be read to determine the desired properties and characteristics of the blood sample. Accordingly, by monitoring the color sensor 7011 to ascertain the presence of an undiluted or minimally diluted blood sample, the blood analysis system may reduce the effects of dilution of the blood by adjacent infusion fluid.
One or more color sensors 7001 may be included in the sensor assembly 6019, or positioned along the catheter 6021 or the infusion tube 6017. For example, in addition to the color sensor 7001 shown in
In the preferred embodiment shown and described with reference to
Accordingly, the sensor 7001 in
In certain preferred embodiments of the systems illustrated in
The color sensor 7025 advantageously may be used in a procedure in which a blood sample is drawn from the patient 6011. In an example of this procedure utilizing the embodiments shown in
Blood Sample Separation
The valves 7020a and 7020b may comprise “pinch valves,” in which one or more movable surfaces compress the tube to restrict or stop flow therethrough. In one embodiment, the pinch valves include one or more moving surfaces that are actuated to move together and “pinch” a flexible passageway to stop flow therethrough. Examples of a pinch valve include, for example, Model PV256 Low Power Pinch Valve (Instech Laboratories, Inc., Plymouth Meeting, Pa.). Embodiments of suitable pinch valves are illustrated in
In one embodiment, pump 7030 is a directionally controllable pump that acts on a flexible portion of passageway 6049. Examples of a single, directionally controllable pump include, but are not limited to a reversible peristaltic pump or two unidirectional pumps that work in concert with valves to provide flow in two directions. In an alternative embodiment, pump 7030 includes a combination of pumps, including but not limited to displacement pumps, such as a syringe, and/or valve to provide bi-directional flow control through passageway 6049.
The embodiment illustrated in
During a blood sampling process, the fluid handling system in
Some embodiments of the blood sampling system shown in
Additionally, in some embodiments, the volume of the drawn blood used for sampling and analysis (e.g., the first portion moved into the sensor assembly 6019) is reduced, for example, by decreasing the volume of the passageway between the infusion tubing 7017 and the sensor assembly 6019, and by decreasing the fluid volume within the sensor assembly 6019. In some embodiments, the internal diameters of the passageway 6049 and the passageway between the tubing 7017 and the sensor assembly 6019 are smaller than the internal diameter of the infusion tubing 7017. In other embodiments, the lengths of the passageway 6049 within the sensor assembly 6019 and the passageway between the tubing 7017 and the sensor assembly 6019 are reduced. In certain embodiments, the chambers 6043, 6045 are configured to have a volume large enough to provide a sufficient blood sample for the analytical sensors 6027-6041 to take measurements but without additional, unnecessary volume. Certain preferred embodiments are configured to use some or all of these techniques for reducing the volume of blood drawn from the patient 6011 and used for sampling and analysis.
After sampling and analysis is complete, some embodiments may return the first portion of the blood sample from the sensor assembly 6019 to the patient 6011. In these embodiments, the system controller 6023 signals the first valve 7020a to close, the second valve 7020b to open, and the pump 7030 to operate in the forward direction to return the first portion back into the patient 6011. These embodiments may use an additional color sensor positioned along tubing 7017 (not shown) to signal the system controller 6023 when the first portion has reached the patient 6011.
In other embodiments, the sensor assembly 6019 may include additional pumps, valves, and sensors configured to direct the first portion of the blood sample into a waste receptacle (not shown), which may be generally similar to the waste receptacle 325 illustrated and described with reference to
In different embodiments, the passageways, valves, and pumps may be configured differently. For example,
In one embodiment of a procedure to draw a blood sample into the analyzer 6025, the system controller 6023 signals the first valve 7020a to close, the second, third, and fourth valves 7020b-7020d to open, and the pump 7030 to operate in the rearward direction. After a sufficient blood sample has been drawn from the patient 6011, the system controller 6023 signals the third valve 7020c to close. The controller 6023 may then signal the first valve 7020a to open such that infusion fluid may flow behind a trailing edge of the drawn blood sample. The pump 7030 may then direct the blood sample through the passageway 7018 into the analyzer 6025. Optionally, the infusion pump 6013 may be operated in the forward direction to assist the pump 7030 in directing the fluid sample into the analyzer 6025.
Sensors may be included in the analyzer 6025 to signal the system controller 6023 when the blood sample has reached the analyzer 6025 at which time the pump 7030 may cease operation. Suitable sensors include, for example, color sensors generally similar to color sensor 7001. In one embodiment, the system may restart the infusion process by closing the second valve 7020b, opening the third valve 7020c, and signaling the infusion pump 6013 to operate in the forward direction to direct infusion fluid into the patient 6011.
Analysis of the blood sample within the analyzer 6025 may proceed using any of the methods and apparatuses disclosed herein. In one embodiment, after reaching the analyzer 6025, the blood sample may pass through the sample preparation unit 332 for analysis by the analyte detection system 334 as illustrated in
Other embodiments of the blood analysis and fluid handling system illustrated in
Temperature Monitoring and Regulation
Some of the parameters and characteristics of the fluid sample 6090 sensed by the optical sensor 6040 may depend on the temperature of the fluid within the chamber 6045 (
The temperature sensitivity of some fluid parameters may depend on the wavelengths being probed by the optical sensor 6040, and thus the measurement and/or control of the sample temperature may provide for improved fluid parameter estimation. For example, analyte concentrations determined using near-infrared optical methods may need correction based on the fluid temperature at the time of measurement of the fluid sample 6090. Accordingly, it may be preferred, although not necessary, for the sensor assembly 6019 to regulate the temperature of the fluid sample in one or both of the chambers 6043, 6045. In some embodiments, the sensor assembly 6019 includes a suitable thermal device disposed within the sensor assembly 6019. The thermal device may comprise, for example, a thermoelectric heating/cooling device coupled to a proportional-plus-integral-plus-derivative (PID) controller. In one embodiment, the thermoelectric device may comprise a Peltier thermoelectric device. The thermal device may be used to regulate the temperature of the fluid sample 6090 to a suitable reference or baseline value such as, for example, 95 degrees Fahrenheit, or to a suitable body temperature of the patient, or to a temperature suitable for performing the analyte detections, or to any other appropriate temperature. In some embodiments, the thermal device may be controlled by the system controller 6023. In other embodiments, the thermal device may be disposed elsewhere in the system, for example, along the infusion tube 6017. Still other embodiments may include additional thermal devices or temperature sensors.
Although the invention(s) presented herein have been disclosed in the context of certain preferred embodiments and examples, it will be understood by those skilled in the art that the invention(s) extend beyond the specifically disclosed embodiments to other alternative embodiments and/or uses of the invention(s) and obvious modifications and equivalents thereof. Thus, it is intended that the scope of the invention(s) herein disclosed should not be limited by the particular embodiments described above, but should be determined only by a fair reading of the claims that follow.
This application is a continuation-in-part of U.S. patent application Ser. No. 11/316,407, filed Dec. 21, 2005, titled APPARATUS AND METHODS FOR ANALYZING BODY FLUID SAMPLES, which claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Application No. 60/652,660, filed Feb. 14, 2005, titled ANALYTE DETECTION SYSTEM; U.S. Provisional Application No. 60/724,199, filed Oct. 6, 2005, titled INTENSIVE CARE UNIT BLOOD ANALYSIS SYSTEM AND METHOD; U.S. Provisional Application No. 60/658,001, filed Mar. 2, 2005, titled SEPARATING BLOOD SAMPLE FOR ANALYTE DETECTION SYSTEM; and of U.S. Provisional Application No. 60/673,551, filed Apr. 21, 2005, titled APPARATUS AND METHODS FOR SEPARATING SAMPLE FOR ANALYTE DETECTION SYSTEM. The entire contents of each of the above-listed nonprovisional and provisional applications are hereby incorporated by reference herein and made part of this specification.
| Number | Date | Country | |
|---|---|---|---|
| 60652660 | Feb 2005 | US | |
| 60724199 | Oct 2005 | US | |
| 60658001 | Mar 2005 | US | |
| 60673551 | Apr 2005 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 11316407 | Dec 2005 | US |
| Child | 11352956 | Feb 2006 | US |
