U.S. patent application number 15/236831 was filed with the patent office on 2017-07-06 for fluid component analysis systems and methods for glucose monitoring and control.
The applicant listed for this patent is OptiScan Biomedical Corporation. Invention is credited to James R. Braig, Richard Keenan, Gil Rivas, Peter Rule, Mahesh Seetharaman.
Application Number | 20170188943 15/236831 |
Document ID | / |
Family ID | 40090132 |
Filed Date | 2017-07-06 |
United States Patent
Application |
20170188943 |
Kind Code |
A1 |
Braig; James R. ; et
al. |
July 6, 2017 |
FLUID COMPONENT ANALYSIS SYSTEMS AND METHODS FOR GLUCOSE MONITORING
AND CONTROL
Abstract
Disclosed are methods and apparatus for determining analyte
concentration in a sample such as bodily fluid. Systems and methods
disclosed herein can also include a treatment dosing system to
infuse or inject a treatment drug (e.g., insulin or glucose) and
provide glycemic control. The dose of the treatment drug may be
based on the concentration of the analyte or the average value for
the concentration of the analyte and/or the rate of change of the
value of the concentration of the analyte.
Inventors: |
Braig; James R.; (Piedmont,
NC) ; Keenan; Richard; (Livermore, CA) ; Rule;
Peter; (Los Altos Hills, CA) ; Rivas; Gil;
(Danville, CA) ; Seetharaman; Mahesh; (Danville,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
OptiScan Biomedical Corporation |
Hayward |
CA |
US |
|
|
Family ID: |
40090132 |
Appl. No.: |
15/236831 |
Filed: |
August 15, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13619825 |
Sep 14, 2012 |
9414782 |
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15236831 |
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13174610 |
Jun 30, 2011 |
8449524 |
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13619825 |
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12249831 |
Oct 10, 2008 |
7972296 |
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13174610 |
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60979044 |
Oct 10, 2007 |
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60979380 |
Oct 11, 2007 |
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61025260 |
Jan 31, 2008 |
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60979348 |
Oct 11, 2007 |
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61096461 |
Sep 12, 2008 |
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61099491 |
Sep 23, 2008 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61B 5/1427 20130101;
A61B 5/150786 20130101; A61M 2205/3303 20130101; A61M 2209/084
20130101; G06F 19/3468 20130101; A61M 5/16827 20130101; A61B
5/150992 20130101; A61B 5/1455 20130101; A61B 5/153 20130101; A61M
5/1723 20130101; A61B 5/14546 20130101; A61B 5/14557 20130101; A61M
2005/1726 20130101; A61B 5/1495 20130101; G16H 20/17 20180101; A61B
5/150755 20130101; A61M 2230/201 20130101; A61B 5/150229 20130101;
A61B 5/14532 20130101; A61B 5/4839 20130101; A61B 5/412 20130101;
A61B 5/157 20130101; A61M 2005/14208 20130101; A61B 5/15003
20130101; A61M 2005/1404 20130101; A61B 5/150267 20130101; A61M
2205/12 20130101; A61B 5/155 20130101; A61B 5/150221 20130101; A61B
5/7475 20130101; A61B 5/14535 20130101; A61B 5/150862 20130101 |
International
Class: |
A61B 5/00 20060101
A61B005/00; A61B 5/1455 20060101 A61B005/1455; A61B 5/1495 20060101
A61B005/1495; G06F 19/00 20060101 G06F019/00; A61B 5/155 20060101
A61B005/155; A61B 5/157 20060101 A61B005/157; A61M 5/168 20060101
A61M005/168; A61B 5/145 20060101 A61B005/145; A61B 5/15 20060101
A61B005/15 |
Claims
1.-53. (canceled)
54. A combined glucose monitoring and adjustment system comprising:
a fluid control device with pumps, valves, and fluid passageways
configured to automatically draw fluid from a patient multiple
times per hour and deliver a portion of that fluid to an analyte
monitoring system each time; the analyte monitoring system
comprising an optical glucose meter configured to irradiate the
fluid or a portion thereof and detect secondary radiation, either
transmitted or reflected, and determine, based on that secondary
radiation, a concentration of glucose in the fluid; and a glucose
adjustment system comprising: a repository of a treatment substance
selected from the group consisting of insulin and a sugar; a pump
configured to adjust the level of glucose in the patient by
infusing insulin and/or sugar; and a controller configured to
control the pump and provide signals to the pump multiple times per
hour, including signals to automatically stop infusion of insulin
if determination of concentration of glucose is below a first
threshold.
55. The analyte detection system of claim 54, wherein the body
fluid analyzer is configured for calibration no more than twice per
day.
56. The analyte detection system of claim 54, wherein the body
fluid analyzer is configured for calibration no more than once per
day.
57. The analyte detection system of claim 54, wherein the body
fluid analyzer is configured for calibration no more than once
every 36 hours.
58. The analyte detection system of claim 54, wherein the body
fluid analyzer is configured for calibration no more than once
every two days.
59. The analyte detection system of claim 54, wherein the body
fluid analyzer is configured for calibration no more than once
every three days.
60. The analyte detection system of claim 54, further comprising a
treatment dosing system configured to determine a dose of insulin
and/or sugar to be infused based on one or more determinations of
concentration of glucose.
61. The analyte detection system of claim 60, wherein the treatment
dosing system is configured to compare a determination of
concentration of glucose with a target glucose concentration to
determine a dose of insulin and/or sugar to be infused.
62. The analyte detection system of claim 60, wherein the treatment
dosing system is configured to determine a dose of insulin and/or
sugar to be infused based on at least one of: the patient's medical
conditions and medical history, an effectiveness of the dose,
presence or absence of other analytes in the fluid or other
medications being administered.
63. The analyte detection system of claim 54, wherein the
controller is further configured to provide signals to the pump or
a second pump to infuse an increased amount of sugar if
determination of concentration of glucose is below the first
threshold.
64. A method of glucose monitoring and adjusting a level of glucose
comprising: automatically withdrawing fluid from a patient multiple
times per hour and delivering a portion of the withdrawn fluid each
time to an analyte monitoring system via a fluid control device
with pumps, valves, and fluid passageways; determining a
concentration of glucose in the fluid using a glucose meter
adjusting an amount of glucose in the fluid using a glucose
adjustment system comprising: a repository of a treatment substance
selected from the group consisting of insulin and a sugar; a pump
configured to adjust the level of glucose in the patient by
infusing insulin and/or sugar; and a controller configured to
control the pump; and providing signals to the pump multiple times
per hour, including signals to automatically stop infusion of
insulin if determination of concentration of glucose is below a
first threshold.
65. The method of claim 64, further comprising determining a dose
of insulin and/or sugar to be infused based on one or more
determinations of concentration of glucose.
66. The method of claim 65, wherein the dose of insulin and/or
sugar to be infused is determined by comparing a determination of
concentration of glucose with a target glucose concentration to
determine.
67. The method of claim 65, wherein the dose of insulin and/or
sugar to be infused is determined based on at least one of: the
patient's medical conditions and medical history, an effectiveness
of the dose, presence or absence of other analytes in the fluid or
other medications being administered.
68. The method of claim 64, further comprising providing signals to
the pump or a second pump to infuse an increased amount of sugar if
determination of concentration of glucose is below the first
threshold.
69. The method of claim 64, wherein determining concentration of
glucose in the fluid comprises directing an optical radiation
towards the fluid or a portion thereof and detecting secondary
radiation, either transmitted or reflected.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional of U.S. patent application
Ser. No. 13/619,825, filed Sep. 14, 2012, entitled "FLUID COMPONENT
ANALYSIS SYSTEM AND METHOD FOR GLUCOSE MONITORING AND CONTROL,"
which is a continuation of U.S. patent application Ser. No.
13/174,610, filed Jun. 30, 2011, entitled "FLUID COMPONENT ANALYSIS
SYSTEM AND METHOD FOR GLUCOSE MONITORING AND CONTROL," now U.S.
Pat. No. 8,449,524, which is a divisional of U.S. patent
application Ser. No. 12/249,831, filed Oct. 10, 2008, entitled
"FLUID COMPONENT ANALYSIS SYSTEM AND METHOD FOR GLUCOSE MONITORING
AND CONTROL," now U.S. Pat. No. 7,972,296, which claims the benefit
under 35 U.S.C. .sctn.119(e) of U.S. Provisional Patent Application
No. 60/979,044, entitled "System and User Interface For Infusion
and Analysis," filed Oct. 10, 2007 (Atty. Docket No. Optis.197PR);
U.S. Provisional Patent Application No. 60/979,380, entitled "Fluid
Component Analysis System and Bolus Injection," filed Oct. 11, 2007
(Atty. Docket No. Optis.203PR); U.S. Provisional Patent Application
No. 61/025,260, entitled "Fluid Component Analysis System and
Method for Glucose Monitoring and Control," filed Jan. 31, 2008
(Atty. Docket No. Optis.203PR2); U.S. Provisional Patent
Application No. 60/979,348, entitled "System and Method for Glucose
Monitoring and Control," filed Oct. 11, 2007 (Atty. Docket No.
Optis.206PR); U.S. Provisional Patent Application No. 61/096,461,
entitled "Analyte Monitoring System and Treatment Dosing Protocol,"
filed Sep. 12, 2008 (Atty. Docket No. Optis.230PR); and U.S.
Provisional Patent Application No. 61/099,491, entitled "An Analyte
Monitoring System Including a Treatment Dosing Assistant," filed
Sep. 23, 2008 (Atty. Docket No. Optis.231PR). Each of the foregoing
applications, as well as U.S. Provisional Patent Application No.
60/978,385, entitled "Dilution Calibration for an Analyte Detection
System," filed Oct. 8, 2007 (Atty. Docket No. Optis.209PR), is
hereby incorporated by reference in its entirety and made part of
this specification.
BACKGROUND
[0002] Field
[0003] Some embodiments of the disclosure relate generally to
methods and devices for determining a concentration of an analyte
in a sample, such as an analyte in a sample of bodily fluid, as
well as methods and devices which can be used to support the making
of such determinations. This disclosure also relates generally to a
user interface for use with such apparatus. Some embodiments of
this disclosure also relate generally to bolus injection and basal
infusion systems and related apparatus. Some embodiments in this
disclosure also relate to an analyte detection system configured to
provide glycemic control and/or Tight Glycemic Control (TGC). Some
aspects of this disclosure relate to an analyte detection system
that is configured to determine a dosing protocol based on one or
more measurements of the concentration of an analyte. Some aspects
of this disclosure relate to a system and method that provides
feedback to a healthcare provider regarding the treatment dose
being administered to the patient. Some aspects of this disclosure
also relate generally to systems and methods for calibrating
analyte concentration when dilution of the sample has occurred.
[0004] Description of Related Art
[0005] It is advantageous to measure the levels of certain
analytes, such as glucose, in a bodily fluid, such as blood). This
can be done, for example, in a hospital or clinical setting when
there is a risk that the levels of certain analytes may move
outside a desired range, which in turn can jeopardize the health of
a patient. Systems for measuring analyte levels may include a user
interface (UI) that permits a user such as, for example, a patient,
a health care provider, and so forth, to interact with the system.
Currently known systems for analyte monitoring in a hospital or
clinical setting may suffer from various drawbacks.
SUMMARY
[0006] Example embodiments described herein have several features,
no single one of which is indispensable or solely responsible for
their desirable attributes. Without limiting the scope of the
claims, some of the advantageous features will now be
summarized.
[0007] Embodiments of an analyte detection and treatment dosing
system comprising a fluid transport network configured to provide
fluid communication with a body fluid in a patient through a
patient end are disclosed. The disclosed embodiments can further
comprise at least one pump system coupled to the fluid transport
network, the pump system having a sampling mode in which the pump
system is operable to withdraw a sample of bodily fluid from the
patient end and transport said sample of bodily fluid toward the
body fluid analyzer, and an infusion mode in which the pump system
is operable to transport an infusion fluid to the patient. The
disclosed embodiments can further comprise a body fluid analyzer
accessible via the fluid transport network, the body fluid analyzer
configured to measure a characteristic of at least one analyte in
the body fluid and determine the concentration of the at least one
analyte from the measured characteristic; and a treatment dosing
system in communication with the body fluid analyzer, said
treatment dosing system including a treatment dosing protocol
stored in a computer memory and configured to automatically
determine a recommended dose of an infusion substance configured to
provide glycemic control, wherein the body fluid analyzer
determines the recommended dose based at least in part on the
measured concentration of the analyte and the stored treatment
dosing protocol, wherein the treatment dosing system comprising a
treatment pump having a variable pump rate to deliver the
recommended dose of the infusion substance to the patient.
[0008] Embodiments of an analyte detection and treatment dosing
system comprising a fluid transport network configured to provide
fluid communication with a body fluid in a patient through a
patient end are disclosed. Disclosed embodiments comprise at least
one pump system coupled to the fluid transport network, the pump
system having a sampling mode in which the pump system is operable
to withdraw a sample of bodily fluid from the patient end and
transport said sample of bodily fluid towards the body fluid
analyzer, and an infusion mode in which the pump system is operable
to transport an infusion fluid to the patient. The disclosed
embodiments also comprise a body fluid analyzer accessible via the
fluid transport network, the body fluid analyzer configured to
measure a characteristic of at least one analyte in the body fluid
and determine the concentration of the at least one analyte from
the measured characteristic; and a treatment dosing system in
communication with the body fluid analyzer, said treatment dosing
system including a treatment dosing protocol stored in a computer
memory and configured to automatically determine a recommended dose
of an infusion substance configured to provide glycemic control,
wherein the recommended dose is determined based at least in part
on one or more determinations by the body fluid analyzer of the
concentration of the analyte and the treatment dosing protocol. In
some embodiments, the treatment dosing system comprises a basal
delivery system and a bolus injection system, both systems
configured to deliver infusion substances to the patient through
said patient end and through the same intravenous access line.
[0009] Embodiments of an analyte detection and control system to
determine and regulate the concentration of one or more analytes in
a sample of bodily fluid are disclosed. The disclosed embodiments,
can comprise a control system, an analyte detector configured to
measure a characteristic of at least one analyte in the sample of
bodily fluid and determine a concentration of the analyte in the
sample based on the measured characteristic, a fluid handling
system operatively coupled to the analyte detector, said fluid
handling system comprising a fluid passageway in communication with
a patient through a patient end, a pump unit configured to engage
the fluid handling system and draw a sample of bodily fluid from
the patient periodically at draw intervals of less than 1 hour for
analysis, a source of infusion fluid configured to adjust glycemic
levels in the patient, said infusion fluid source in fluid
communication with the fluid handling system and a treatment dosing
system in communication with the body fluid analyzer, said
treatment dosing system including a treatment dosing protocol and
configured to determine a recommended dose for the infusion fluid,
wherein the recommended dose is determined based at least in part
on one or more determinations by the body fluid analyzer of the
concentration of the analyte and the treatment dosing protocol.
[0010] An embodiment of a method of analyzing an analyte in the
body fluid of a patient is disclosed. The method comprises placing
a body fluid analyzer in fluid communication with the body fluid in
the patient; transporting a sample of the body fluid toward the
body fluid analyzer; with the body fluid analyzer, measuring a
characteristic of an analyte in the bodily fluid and determining
the concentration of the analyte in the body fluid, while the
analyzer is in fluid communication with the body fluid in the
patient; and with a treatment dosing system in communication with
the body fluid analyzer, determining a recommended dose for an
infusion fluid based at least in part on one or more determinations
by the body fluid analyzer of the concentration of the analyte and
a treatment dosing protocol.
[0011] An embodiment of a method of monitoring and regulating the
concentration of one or more analytes in a sample of bodily fluid
is disclosed. The method comprises providing a fluid connection to
a patient; periodically withdrawing a certain volume of bodily
fluid from the patient at draw intervals of less than 1 hour;
sensing a property of the withdrawn fluid using one or more
sensors; dividing the withdrawn volume of fluid into an analysis
portion and a return portion; measuring a characteristic of said
analysis portion to determine the concentration of an analyte in
said analysis portion; determining a recommended dose for an
infusion fluid for an infusion fluid based at least in part on one
or more determinations by the body fluid analyzer of the
concentration of the analyte and a treatment dosing protocol; and
providing an instruction to an infusion fluid system to infuse the
recommended dose of infusion fluid into the patient at a prescribed
infusion fluid delivery rate.
[0012] Embodiments of an analyte detection and treatment dosing
system are disclosed. Disclosed embodiments comprise a fluid
transport network configured to provide fluid communication with a
body fluid in a patient; a body fluid analyzer accessible via the
fluid transport network, the body fluid analyzer configured to
measure a characteristic of at least one analyte in the body fluid
and determine the concentration of the at least one analyte from
the measured characteristic; a treatment dosing system in
communication with the body fluid analyzer, said treatment dosing
system including a treatment dosing protocol and configured to
determine a recommended dose for an infusion fluid configured to
provide glycemic control, wherein the recommended dose is
determined based at least in part on one or more determinations by
the body fluid analyzer of the concentration of the analyte and the
treatment dosing protocol; a treatment pump coupled to the fluid
transport network, the treatment pump operable to transport the
infusion fluid to the patient through the patient end; and a fluid
system controller comprising a graphic user interface, said fluid
system controller configured to actuate the treatment pump and
control the pump rate of the pump, wherein the fluid system
controller and the body fluid analyzer are both included within a
single housing, the graphic user interface is located on the same
housing, and the graphic user interface is configured to display
the determined analyte concentration and the recommended dose. In
some embodiments, the graphic user interface includes an input
element configured to accept user input, the user interface further
configured to adjust the actual dose of the infusion fluid based at
least in part on the user input. In some embodiments the graphic
user interface is configured to display both the recommended dose
and the actual dose, where both the recommended dose and the actual
dose are expressed as infusion rates. In some embodiments, the
graphic user interface includes an input element configured to
accept user input, the user interface configured to actuate the
pump unit based at least in part on the user input.
[0013] Embodiments of an analyte monitoring system comprising a
fluidic system in fluid communication with a source of bodily
fluid, said fluidic system being configured to obtain a sample of
bodily fluid from the source; an analyte detection system
configured to analyze the sample of bodily fluid or a component of
the sample of bodily fluid; and a fluid infusion system are
disclosed. In some disclosed embodiments, the analyte detection
system is configured to determine the concentration of an analyte
in said sample of the bodily fluid or a component of the sample of
the bodily fluid. In some embodiments, the analyte detection system
is configured to access a measurement database and calculate an
average concentration of the analyte based on the determined
concentration and one or more previous values for the concentration
of the analyte stored in the measurement database.
[0014] Embodiments of an analyte monitoring system comprising a
fluidic system in fluid communication with a source of bodily
fluid, said fluidic system being configured to obtain a first
sample of bodily fluid from the source at a first time; an analyte
detection system configured to analyze the first sample of bodily
fluid or a component of the first sample of bodily fluid; and a
fluid infusion system are disclosed. In some embodiments, the
analyte detection system is configured to determine the
concentration of an analyte in said first sample of the bodily
fluid or a component of the first sample of the bodily fluid and
store the value of the determined concentration in a measurement
database. In some disclosed embodiments, the fluidic system further
obtains a second sample of the bodily fluid at a second time and
presents said second sample to the analyte detection system for
analysis. In the disclosed embodiments, the analyte detection
system analyzes the second sample or a component of the second
sample and determines the concentration of the analyte in the
second sample or the component of the second sample, calculates a
rate of change of the concentration of the analyte and determines a
treatment dose based on the rate of change of the concentration of
the analyte if the concentration of the analyte in the second
sample is not within a prescribed range. In some embodiments, the
analyte detection system communicates with the fluid infusion
system to deliver the determined treatment dose.
[0015] Embodiments of an analyte monitoring system comprising a
fluidic system in fluid communication with a source of bodily
fluid, said fluidic system being configured to obtain a sample of
bodily fluid from the source several times in a give time interval
are disclosed. Some disclosed embodiments can comprise an analyte
detection system configured to analyze the sample of bodily fluid
or a component of the sample of bodily fluid and determine the
concentration of an analyte in said sample of the bodily fluid or a
component of the sample of the bodily fluid, wherein the analyte
detection system is further configured to access a measurement
history and store the estimated concentration of the analyte in the
measurement history. Some disclosed embodiments comprise a feedback
system; and a user interface configured to accept an input from a
user; wherein the feedback system calculates a predicted value for
the concentration of the analyte at a future time based on the
input from the user and one or more previous values for the
concentration of the analyte stored in the measurement history, and
wherein the feedback system alerts the user through the user
interface if the predicted value for the concentration is not
within an acceptable range.
[0016] Embodiments of an analyte monitoring system comprising a
fluidic system in fluid communication with a source of bodily
fluid, said fluidic system being configured to obtain a sample of
bodily fluid from the source several times in a give time interval
are disclosed. The disclosed embodiments further comprise an
analyte detection system configured to analyze the sample of bodily
fluid or a component of the sample of bodily fluid and determine
the concentration of an analyte in said sample of the bodily fluid
or a component of the sample of the bodily fluid, wherein the
analyte detection system is further configured to access a
measurement history and store the estimated concentration of the
analyte in the measurement history. The disclosed embodiments can
also comprise a fluid infusion system comprising a plurality of
infusion fluid sources, each infusion fluid source configured to
provide one or more drugs or chemicals; a user feedback system; a
watch list comprising a catalog of spectra related to various known
substances that may present medical hazards, alone or in
combination, the watch list being electronically accessible to the
user feedback system; and a user interface configured to provide
information to a user and accept input from the user. In some
embodiments, the feedback system is configured to obtain one or
more spectroscopic measurements of the contents of the plurality of
infusion fluid sources, compare the spectroscopic measurements with
the watch list, and alert the user through the user interface if
any substance in the watch list is detected in the plurality of
infusion fluid sources.
[0017] Embodiments of a combined glucose monitoring and adjustment
system comprising a fluid control device with pumps, valves, and
fluid passageways configured to draw fluid from a fluid source and
deliver a portion of that fluid to an analyte monitoring system are
disclosed. The disclosed embodiments can further comprise an
optical glucose meter configured to irradiate the fluid or a
portion thereof and detect secondary radiation, either transmitted
or reflected, and determine, based on that secondary radiation, a
concentration of an analyte in the fluid. The disclosed embodiments
can further comprise a glucose adjustment system. In some
embodiments, the glucose adjustment system can comprise a
repository of a treatment substance selected from the group
consisting of insulin and a sugar; a pump configured to adjust the
level of glucose in the fluid source by infusing insulin and/or
sugar; and a controller configured to control the pump. In some
embodiments, the body fluid analyzer is configured for calibration
no more than twice per day. In some embodiments, the body fluid
analyzer is configured for calibration no more than once per day.
In some embodiments, the body fluid analyzer is configured for
calibration no more than once every 36 hours. In some embodiments,
the body fluid analyzer is configured for calibration no more than
once every two days. In some embodiments, the body fluid analyzer
is configured for calibration no more than once every three
days.
BRIEF DESCRIPTION OF THE DRAWINGS
[0018] The following drawings and the associated descriptions are
provided to illustrate embodiments of the present disclosure and do
not limit the scope of the claims.
[0019] FIG. 1 shows an embodiment of an apparatus for withdrawing
and analyzing fluid samples.
[0020] FIG. 2 illustrates how various other devices can be
supported on or near an embodiment of apparatus illustrated in FIG.
1.
[0021] FIG. 3 illustrates an embodiment of the apparatus in FIG. 1
configured to be connected to a patient.
[0022] FIG. 3A illustrates an embodiment of the apparatus in FIG. 1
that is not configured to be connected to a patient but which
receives a fluid sample from an extracorporeal fluid container such
as, for example, a test tube. This embodiment of the apparatus can
advantageously provide in vitro analysis of a fluid sample.
[0023] FIG. 4 is a block diagram of an embodiment of a system for
withdrawing and analyzing fluid samples.
[0024] FIG. 5 schematically illustrates an embodiment of a fluid
system that can be part of a system for withdrawing and analyzing
fluid samples.
[0025] FIG. 6 schematically illustrates another embodiment of a
fluid system that can be part of a system for withdrawing and
analyzing fluid samples.
[0026] FIG. 7 is an oblique schematic depiction of an embodiment of
a monitoring device.
[0027] FIG. 8 shows a cut-away side view of an embodiment of a
monitoring device.
[0028] FIG. 9 shows a cut-away perspective view of an embodiment of
a monitoring device.
[0029] FIG. 10 illustrates an embodiment of a removable cartridge
that can interface with a monitoring device.
[0030] FIG. 11 illustrates an embodiment of a fluid routing card
that can be part of the removable cartridge of FIG. 10.
[0031] FIG. 12 illustrates how non-disposable actuators can
interface with the fluid routing card of FIG. 11.
[0032] FIG. 13 illustrates a modular pump actuator connected to a
syringe housing that can form a portion of a removable
cartridge.
[0033] FIG. 14 shows a rear perspective view of internal
scaffolding and some pinch valve pump bodies.
[0034] FIG. 15 shows an underneath perspective view of a sample
cell holder attached to a centrifuge interface, with a view of an
interface with a sample injector.
[0035] FIG. 16 shows a plan view of a sample cell holder with
hidden and/or non-surface portions illustrated using dashed
lines.
[0036] FIG. 17 shows a top perspective view of the centrifuge
interface connected to the sample holder.
[0037] FIG. 18 shows a perspective view of an example optical
system.
[0038] FIG. 19 shows a filter wheel that can be part of the optical
system of FIG. 18.
[0039] FIG. 20 schematically illustrates an embodiment of an
optical system that comprises a spectroscopic analyzer adapted to
measure spectra of a fluid sample.
[0040] FIG. 21 is a flowchart that schematically illustrates an
embodiment of a method for estimating the concentration of an
analyte in the presence of interferents.
[0041] FIG. 22 is a flowchart that schematically illustrates an
embodiment of a method for performing a statistical comparison of
the absorption spectrum of a sample with the spectrum of a sample
population and combinations of individual library interferent
spectra.
[0042] FIG. 23 is a flowchart that schematically illustrates an
example embodiment of a method for estimating analyte concentration
in the presence of the possible interferents.
[0043] FIGS. 23A through 23D illustrate different examples of the
results obtained by using various algorithms to estimate the
concentration of an analyte in a sample.
[0044] FIGS. 24 and 25 schematically illustrate the visual
appearance of embodiments of a user interface for a system for
withdrawing and analyzing fluid samples.
[0045] FIG. 26 schematically depicts various components and/or
aspects of a patient monitoring system and the relationships among
the components and/or aspects.
[0046] FIG. 27 is a flowchart that schematically illustrates an
embodiment of a method of providing glycemic control.
[0047] FIG. 28A schematically illustrates the visual appearance of
an embodiment of a display graphic for providing information
related to suggested and actual insulin dose for a patient.
[0048] FIGS. 28B-28F schematically illustrate embodiments of a
display graphic comprising a graphic user interface and illustrate
examples of numerical display mode, trend display mode, suggested
and actual insulin dose information, and controls for delivery of
insulin.
[0049] FIG. 29 is a flowchart that schematically illustrates an
embodiment of a method of determining a treatment dose based on the
average concentration of an analyte.
[0050] FIG. 30 is a flowchart that schematically illustrates an
embodiment of a method of determining a treatment dose based on the
rate of change of the concentration of an analyte.
[0051] FIG. 31A is a flowchart that schematically illustrates an
embodiment of a method of determining a treatment dose based on the
average concentration of an analyte and the rate of change of the
concentration of the analyte.
[0052] FIG. 31B is a flowchart that schematically illustrates an
embodiment of a method of determining a treatment dose based on the
current concentration of an analyte and the rate of change of the
concentration of the analyte.
[0053] FIG. 32 schematically illustrates an embodiment of a history
that stores the previously determined values for the concentration
of an analyte and the values for a treatment dose previously
administered.
[0054] FIG. 33 is a flowchart that schematically illustrates steps
in a method of providing feedback regarding a treatment dose.
[0055] FIG. 34 schematically depicts a feedback system and the
relationship between the feedback system and the other components
and/or aspects of the patient monitoring system.
[0056] FIG. 35 schematically illustrates an embodiment of a fluid
system that can be part of a system for withdrawing and analyzing
fluid samples and calibrating the analyzed samples for sample
dilution;
[0057] FIG. 36 schematically illustrates another embodiment of a
fluid system that can be part of a system for withdrawing and
analyzing fluid samples and calibrating the analyzed samples for
sample dilution; and
[0058] FIG. 37 is a flowchart that schematically illustrates an
embodiment of a method for calibrating an analyte measurement in a
fluid sample for effects of dilution of the fluid sample.
[0059] These and other features will now be described with
reference to the drawings summarized above. The drawings and the
associated descriptions are provided to illustrate embodiments and
not to limit the scope of any claim. Throughout the drawings,
reference numbers may be reused to indicate correspondence between
referenced elements. In addition, where applicable, the first one
or two digits of a reference numeral for an element can frequently
indicate the figure number in which the element first appears.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
[0060] Although certain preferred embodiments and examples are
disclosed below, inventive subject matter extends beyond the
specifically disclosed embodiments to other alternative embodiments
and/or uses and to modifications and equivalents thereof. Thus, the
scope of the claims appended hereto is not limited by any of the
particular embodiments described below. For example, in any method
or process disclosed herein, the acts or operations of the method
or process may be performed in any suitable sequence and are not
necessarily limited to any particular disclosed sequence. Various
operations may be described as multiple discrete operations in
turn, in a manner that may be helpful in understanding certain
embodiments; however, the order of description should not be
construed to imply that these operations are order dependent.
Additionally, the structures, systems, and/or devices described
herein may be embodied as integrated components or as separate
components. For purposes of comparing various embodiments, certain
aspects and advantages of these embodiments are described. Not
necessarily all such aspects or advantages are achieved by any
particular embodiment. Thus, for example, various embodiments may
be carried out in a manner that achieves or optimizes one advantage
or group of advantages as taught herein without necessarily
achieving other aspects or advantages as may also be taught or
suggested herein.
[0061] The systems and methods discussed herein can be used
anywhere, including, for example, in laboratories, hospitals,
healthcare facilities, intensive care units (ICUs), or residences.
Moreover, the systems and methods discussed herein can be used for
invasive techniques, as well as non-invasive techniques or
techniques that do not involve a body or a patient such as, for
example, in vitro techniques.
Analyte Monitoring Apparatus
[0062] FIG. 1 shows an embodiment of an apparatus 100 for
withdrawing and analyzing fluid samples. The apparatus 100 includes
a monitoring device 102. In some embodiments, the monitoring device
102 can be an "OptiScanner.RTM." monitor available from OptiScan
Biomedical Corporation of Hayward, Calif. In some embodiments, the
device 102 can measure one or more physiological parameters, such
as the concentration of one or more substance(s) in a sample fluid.
The sample fluid can be, for example, whole blood from a patient
302 (see, e.g., FIG. 3) and/or a component of whole blood such as,
e.g., blood plasma. In some embodiments, the device 100 can also
deliver an infusion fluid to a patient.
[0063] In the illustrated embodiment, the monitoring device 102
includes a display 104 such as, for example, a touch-sensitive
liquid crystal display. The display 104 can provide an interface
that includes alerts, indicators, charts, and/or soft buttons. The
device 102 also can include one or more inputs and/or outputs 106
that provide connectivity and/or permit user interactivity.
[0064] In the embodiment shown in FIG. 1, the device 102 is mounted
on a stand 108. The stand 108 may comprise a cart such as, for
example, a wheeled cart 130 as shown in FIG. 1. In some
embodiments, the stand 108 is configured to roll on a wheeled
pedestal 240 (shown in FIG. 2). The stand 108 advantageously can be
easily moved and includes one or more poles 110 and/or hooks 112.
The poles 110 and hooks 112 can be configured to accommodate other
medical devices and/or implements, including, for example, infusion
pumps, saline bags, arterial pressure sensors, other monitors and
medical devices, and so forth. Some stands or carts may become
unstable if intravenous (IV) bags, IV pumps, and other medical
devices are hung too high on the stand or cart. In some
embodiments, the apparatus 100 can be configured to have a low
center of gravity, which may overcome possible instability. For
example, the stand 108 can be weighted at the bottom to at least
partially offset the weight of IV bags, IV pumps and medical
devices that may be attached to the hooks 112 that are placed above
the monitoring device 102. Adding weight toward the bottom (e.g.,
near the wheels) may help prevent the apparatus 100 from tipping
over.
[0065] In some embodiments, the apparatus 100 includes the cart
130, which has an upper shelf 131 on which the monitoring device
102 may be placed (or attached) and a bottom shelf 132 on which a
battery 134 may be placed (or attached). The battery 134 may be
used as a main or backup power supply for the monitoring device 102
(which may additionally or alternatively accept electrical power
from a wall socket). Two or more batteries are used in certain
embodiments. The apparatus 100 may be configured so that the upper
and lower shelves 131, 132 are close to ground level, and the
battery provides counterweight. Other types of counterweights may
be used. For example, in some embodiments, portions of the cart 130
near the floor (e.g., a lower shelf) are weighted, formed from a
substantial quantity of material (e.g., thick sheets of metal),
and/or formed from a relatively high-density metal (e.g., lead). In
some embodiments the bottom shelf 132 is approximately 6 inches to
1 foot above ground level, and the upper shelf 131 is approximately
2 feet to 4 feet above ground level. In some embodiments the upper
shelf 131 may be configured to support approximately 40 pounds
(lbs), and the bottom shelf 132 may be configured to support
approximately 20 lbs. One possible advantage of embodiments having
such a configuration is that IV pumps, bags containing saline,
blood and/or drugs, and other medical equipment weighing
approximately 60 lbs, collectively, can be hung on the hooks 112
above the shelves without making the apparatus 100 unstable. The
apparatus 100 may be moved by applying a horizontal force on the
apparatus 100, for example, by pushing and/or pulling the poles
110. In many cases, a user may exert force on an upper portion of
the apparatus 100, for example, close to shoulder-height. By
counterbalancing the weight as described above, the apparatus 100
may be moved in a reasonably stable manner.
[0066] In the illustrated embodiment, the cart 130 includes the
bottom shelf 132 and an intermediate shelf 133, which are enclosed
on three sides by walls and on a fourth side by a door 135. The
door 135 can be opened (as shown in FIG. 1) to provide access to
the shelves 132, 133. In other embodiments, the fourth side is not
enclosed (e.g., the door 135 is not used). Many cart variations are
possible. In some embodiments the battery 134 can be placed on the
bottom shelf 134 or the intermediate shelf 133.
[0067] FIG. 2 illustrates how various other devices can be
supported on or near the apparatus 100 illustrated in FIG. 1. For
example, the poles 110 of the stand 108 can be configured (e.g., of
sufficient size and strength) to accommodate multiple devices 202,
204, 206. In some embodiments, one or more COLLEAGUE.RTM.
volumetric infusion pumps available from Baxter International Inc.
of Deerfield, Ill. can be accommodated. In some embodiments, one or
more Alaris.RTM. PC units available from Cardinal Health, Inc. of
Dublin, Ohio can be accommodated. Furthermore, various other
medical devices (including the two examples mentioned here), can be
integrated with the disclosed monitoring device 102 such that
multiple devices function in concert for the benefit of one or
multiple patients without the devices interfering with each
other.
[0068] FIG. 3 illustrates the apparatus 100 of FIG. 1 as it can be
connected to a patient 302. The monitoring device 102 can be used
to determine the concentration of one or more substances in a
sample fluid. The sample fluid can come can come from the patient
302, as illustrated in FIG. 3, or the sample fluid can come from a
fluid container, as illustrated in FIG. 3A. In some preferred
embodiments, the sample fluid is whole blood.
[0069] In some embodiments (see, e.g., FIG. 3), the monitoring
device 102 can also deliver an infusion fluid to the patient 302.
An infusion fluid container 304 (e.g., a saline bag), which can
contain infusion fluid (e.g., saline and/or medication), can be
supported by the hook 112. The monitoring device 102 can be in
fluid communication with both the container 304 and the sample
fluid source (e.g., the patient 302), through tubes 306. The
infusion fluid can comprise any combination of fluids and/or
chemicals. Some advantageous examples include (but are not limited
to): water, saline, dextrose, lactated Ringer's solution, drugs,
and insulin.
[0070] The example monitoring device 102 schematically illustrated
in FIG. 3 allows the infusion fluid to pass to the patient 302
and/or uses the infusion fluid itself (e.g., as a flushing fluid or
a standard with known optical properties, as discussed further
below). In some embodiments, the monitoring device 102 may not
employ infusion fluid. The monitoring device 102 may thus draw
samples without delivering any additional fluid to the patient 302.
The monitoring device 102 can include, but is not limited to, fluid
handling and analysis apparatuses, connectors, passageways,
catheters, tubing, fluid control elements, valves, pumps, fluid
sensors, pressure sensors, temperature sensors, hematocrit sensors,
hemoglobin sensors, colorimetric sensors, gas (e.g., "bubble")
sensors, fluid conditioning elements, gas injectors, gas filters,
blood plasma separators, and/or communication devices (e.g.,
wireless devices) to permit the transfer of information within the
monitoring device 102 or between the monitoring device 102 and a
network.
[0071] In some embodiments, the apparatus 100 is not connected to a
patient and may receive fluid samples from a container such as a
decanter, flask, beaker, tube, cartridge, test strip, etc., or any
other extracorporeal fluid source. The container may include a
biological fluid sample such as, e.g., a body fluid sample. For
example, FIG. 3A schematically illustrates an embodiment of the
monitoring device 102 that is configured to receive a fluid sample
from one or more test tubes 350. This embodiment of the monitoring
device 102 is configured to perform in vitro analysis of a fluid
(or a fluid component) in the test tube 350. The test tube 350 may
comprise a tube, vial, bottle, or other suitable container or
vessel. The test tube 350 may include an opening disposed at one
end of the tube through which the fluid sample may be added prior
to delivery of the test tube to the monitoring device 102. In some
embodiments, the test tubes 350 may also include a cover adapted to
seal the opening of the tube. The cover may include an aperture
configured to permit a tube, nozzle, needle, pipette, or syringe to
dispense the fluid sample into the test tube 350. The test tubes
350 may comprise a material such as, for example, glass,
polyethylene, or polymeric compounds. In various embodiments, the
test tubes 350 may be re-usable units or may be disposable,
single-use units. In certain embodiments, the test tubes 350 may
comprise commercially available low pressure/vacuum sample bottles,
test bottles, or test tubes.
[0072] In the embodiment shown in FIG. 3A, the monitoring device
102 comprises a fluid delivery system 360 configured to receive a
container (e.g., the test tube 350) containing a fluid sample and
deliver the fluid sample to a fluid handling system (such as, e.g.,
fluid handling system 404 described below). In some embodiments,
the fluid handling system delivers a portion of the fluid sample to
an analyte detection system for in vitro measurement of one or more
physiological parameters (e.g., an analyte concentration). Prior to
measurement, the fluid handling system may, in some embodiments,
separate the fluid sample into components, and a measurement may be
performed on one or more of the components. For example, the fluid
sample in the test tube 350 may comprise whole blood, and the fluid
handling system may separate blood plasma from the sample (e.g., by
filtering and/or centrifuging).
[0073] In the embodiment illustrated in FIG. 3A, the fluid delivery
system 360 comprises a carousel 362 having one or more openings 364
adapted to receive the test tube 350. The carousel 362 may comprise
one, two, four, six, twelve, or more openings 364. In the
illustrated embodiment, the carousel 362 is configured to rotate
around a central axis or spindle 366 so that a test tube 350
inserted into one of the openings 364 is delivered to the
monitoring device 102. In certain embodiments, the fluid handling
system of the monitoring device 102 comprises a sampling probe that
is configured to collect a portion of the fluid sample from the
test tube 350 (e.g., by suction or aspiration). The collected
portion may then be transported in the device 102 as further
described below (see, e.g., FIGS. 4-7). For example, in one
embodiment suitable for use with whole blood, the collected portion
of the whole blood sample is transported to a centrifuge for
separation into blood plasma, a portion of the blood plasma is
transported to an infrared spectroscope for measurement of one or
more analytes (e.g., glucose), and the measured blood plasma is
then transported to a waste container for disposal.
[0074] In other embodiments of the apparatus 100 shown in FIG. 3A,
the fluid delivery system 360 may comprise a turntable, rack, or
caddy adapted to receive the test tube 350. In yet other
embodiments, the monitoring device 102 may comprise an inlet port
adapted to receive the test tube 350. Additionally, in other
embodiments, the fluid sample may be delivered to the apparatus 100
using a test cartridge, a test strip, or other suitable container.
Many variations are possible.
[0075] In some embodiments, one or more components of the apparatus
100 can be located at another facility, room, or other suitable
remote location. One or more components of the monitoring device
102 can communicate with one or more other components of the
monitoring device 102 (or with other devices) by communication
interface(s) such as, but not limited to, optical interfaces,
electrical interfaces, and/or wireless interfaces. These interfaces
can be part of a local network, internet, wireless network, or
other suitable networks.
System Overview
[0076] FIG. 4 is a block diagram of a system 400 for sampling and
analyzing fluid samples. The monitoring device 102 can comprise
such a system. The system 400 can include a fluid source 402
connected to a fluid-handling system 404. The fluid-handling system
404 includes fluid passageways and other components that direct
fluid samples. Samples can be withdrawn from the fluid source 402
and analyzed by an optical system 412. The fluid-handling system
404 can be controlled by a fluid system controller 405, and the
optical system 412 can be controlled by an optical system
controller 413. The sampling and analysis system 400 can also
include a display system 414 and an algorithm processor 416 that
assist in fluid sample analysis and presentation of data.
[0077] In some embodiments, the sampling and analysis system 400 is
a mobile point-of-care apparatus that monitors physiological
parameters such as, for example, blood glucose concentration.
Components within the system 400 that may contact fluid and/or a
patient, such as tubes and connectors, can be coated with an
antibacterial coating to reduce the risk of infection. Connectors
between at least some components of the system 400 can include a
self-sealing valve, such as a spring valve, in order to reduce the
risk of contact between port openings and fluids, and to guard
against fluid escaping from the system. Other components can also
be included in a system for sampling and analyzing fluid in
accordance with the described embodiments.
[0078] The sampling and analysis system 400 can include a fluid
source 402 (or more than one fluid source) that contain(s) fluid to
be sampled. The fluid-handling system 404 of the sampling and
analysis system 400 is connected to, and can draw fluid from, the
fluid source 402. The fluid source 402 can be, for example, a blood
vessel such as a vein or an artery, a container such as a decanter,
flask, beaker, tube, cartridge, test strip, etc., or any other
corporeal or extracorporeal fluid source. For example, in some
embodiments, the fluid source 402 may be a vein or artery in the
patient 302 (see, e.g., FIG. 3). In other embodiments, the fluid
source 402 may comprise an extracorporeal container 350 of fluid
delivered to the system 400 for analysis (see, e.g., FIG. 3B). The
fluid to be sampled can be, for example, blood, plasma,
interstitial fluid, lymphatic fluid, or another fluid. In some
embodiments, more than one fluid source can be present, and more
than one fluid and/or type of fluid can be provided.
[0079] In some embodiments, the fluid-handling system 404 withdraws
a sample of fluid from the fluid source 402 for analysis,
centrifuges at least a portion of the sample, and prepares at least
a portion of the sample for analysis by an optical sensor such as a
spectrophotometer (which can be part of an optical system 412, for
example). These functions can be controlled by a fluid system
controller 405, which can also be integrated into the
fluid-handling system 404. The fluid system controller 405 can also
control the additional functions described below.
[0080] In some embodiments, at least a portion of the sample is
returned to the fluid source 402. At least some of the sample, such
as portions of the sample that are mixed with other materials or
portions that are otherwise altered during the sampling and
analysis process, or portions that, for any reason, are not to be
returned to the fluid source 402, can also be placed in a waste
bladder (not shown in FIG. 4). The waste bladder can be integrated
into the fluid-handling system 404 or supplied by a user of the
system 400. The fluid-handling system 404 can also be connected to
a saline source, a detergent source, and/or an anticoagulant
source, each of which can be supplied by a user, attached to the
fluid-handling system 404 as additional fluid sources, and/or
integrated into the fluid-handling system 404.
[0081] Components of the fluid-handling system 404 can be
modularized into one or more non-disposable, disposable, and/or
replaceable subsystems. In the embodiment shown in FIG. 4,
components of the fluid-handling system 404 are separated into a
non-disposable subsystem 406, a first disposable subsystem 408, and
a second disposable subsystem 410.
[0082] The non-disposable subsystem 406 can include components
that, while they may be replaceable or adjustable, do not generally
require regular replacement during the useful lifetime of the
system 400. In some embodiments, the non-disposable subsystem 406
of the fluid-handling system 404 includes one or more reusable
valves and sensors. For example, the non-disposable subsystem 406
can include one or more valves (or non-disposable portions
thereof), (e.g., pinch-valves, rotary valves, etc.), sensors (e.g.,
ultrasonic bubble sensors, non-contact pressure sensors, optical
blood dilution sensors, etc). The non-disposable subsystem 406 can
also include one or more pumps (or non-disposable portions
thereof). For example, some embodiments can include pumps available
from Hospira. In some embodiments, the components of the
non-disposable subsystem 406 are not directly exposed to fluids
and/or are not readily susceptible to contamination.
[0083] The first and second disposable subsystems 408, 410 can
include components that are regularly replaced under certain
circumstances in order to facilitate the operation of the system
400. For example, the first disposable subsystem 408 can be
replaced after a certain period of use, such as a few days, has
elapsed. Replacement may be necessary, for example, when a bladder
within the first disposable subsystem 408 is filled to capacity.
Such replacement may mitigate fluid system performance degradation
associated with and/or contamination wear on system components.
[0084] In some embodiments, the first disposable subsystem 408
includes components that may contact fluids such as patient blood,
saline, flushing solutions, anticoagulants, and/or detergent
solutions. For example, the first disposable subsystem 408 can
include one or more tubes, fittings, cleaner pouches and/or waste
bladders. The components of the first disposable subsystem 408 can
be sterilized in order to decrease the risk of infection and can be
configured to be easily replaceable.
[0085] In some embodiments, the second disposable subsystem 410 can
be designed to be replaced under certain circumstances. For
example, the second disposable subsystem 410 can be replaced when
the patient being monitored by the system 400 is changed. The
components of the second disposable subsystem 410 may not need
replacement at the same intervals as the components of the first
disposable subsystem 408. For example, the second disposable
subsystem 410 can include a sample holder and/or at least some
components of a centrifuge, components that may not become filled
or quickly worn during operation of the system 400. Replacement of
the second disposable subsystem 410 can decrease or eliminate the
risk of transferring fluids from one patient to another during
operation of the system 400, enhance the measurement performance of
system 400, and/or reduce the risk of contamination or
infection.
[0086] In some embodiments, the sample holder of the second
disposable subsystem 410 receives the sample obtained from the
fluid source 402 via fluid passageways of the first disposable
subsystem 408. The sample holder is a container that can hold fluid
for the centrifuge and can include a window to the sample for
analysis by a spectrometer. In some embodiments, the sample holder
includes windows that are made of a material that is substantially
transparent to electromagnetic radiation in the mid-infrared range
of the spectrum. For example, the sample holder windows can be made
of calcium fluoride.
[0087] An injector can provide a fluid connection between the first
disposable subsystem 408 and the sample holder of the second
disposable subsystem 410. In some embodiments, the injector can be
removed from the sample holder to allow for free spinning of the
sample holder during centrifugation.
[0088] In some embodiments, the components of the sample are
separated by centrifuging for a period of time before measurements
are performed by the optical system 412. For example, a fluid
sample (e.g., a blood sample) can be centrifuged at a relatively
high speed. The sample can be spun at a certain number of
revolutions per minute (RPM) for a given length of time to separate
blood plasma for spectral analysis. In some embodiments, the fluid
sample is spun at about 7200 RPM. In some embodiments, the sample
is spun at about 5000 RPM. In some embodiments, the fluid sample is
spun at about 4500 RPM. In some embodiments, the fluid sample is
spun at more than one rate for successive time periods. The length
of time can be approximately 5 minutes. In some embodiments, the
length of time is approximately 2 minutes. Separation of a sample
into the components can permit measurement of solute (e.g.,
glucose) concentration in plasma, for example, without interference
from other blood components. This kind of post-separation
measurement, (sometimes referred to as a "direct measurement") has
advantages over a solute measurement taken from whole blood because
the proportions of plasma to other components need not be known or
estimated in order to infer plasma glucose concentration. In some
embodiments, the separated plasma can be analyzed electrically
using one or more electrodes instead of, or in addition to, being
analyzed optically. This analysis may occur within the same device,
or within a different device. For example, in certain embodiments,
an optical analysis device can separate blood into components,
analyze the components, and then allow the components to be
transported to another analysis device that can further analyze the
components (e.g., using electrical and/or electrochemical
measurements).
[0089] An anticoagulant, such as, for example, heparin can be added
to the sample before centrifugation to prevent clotting. The
fluid-handling system 404 can be used with a variety of
anticoagulants, including anticoagulants supplied by a hospital or
other user of the monitoring system 400. A detergent solution
formed by mixing detergent powder from a pouch connected to the
fluid-handling system 404 with saline can be used to periodically
clean residual protein and other sample remnants from one or more
components of the fluid-handling system 404, such as the sample
holder. Sample fluid to which anticoagulant has been added and used
detergent solution can be transferred into the waste bladder.
[0090] The system 400 shown in FIG. 4 includes an optical system
412 that can measure optical properties (e.g., transmission) of a
fluid sample (or a portion thereof). In some embodiments, the
optical system 412 measures transmission in the mid-infrared range
of the spectrum. In some embodiments, the optical system 412
includes a spectrometer that measures the transmission of broadband
infrared light through a portion of a sample holder filled with
fluid. The spectrometer need not come into direct contact with the
sample. As used herein, the term "sample holder" is a broad term
that carries its ordinary meaning as an object that can provide a
place for fluid. The fluid can enter the sample holder by
flowing.
[0091] In some embodiments, the optical system 412 includes a
filter wheel that contains one or more filters. In some
embodiments, more than ten filters can be included, for example
twelve or fifteen filters. In some embodiments, more than 20
filters (e.g., twenty-five filters) are mounted on the filter
wheel. The optical system 412 includes a light source that passes
light through a filter and the sample holder to a detector. In some
embodiments, a stepper motor moves the filter wheel in order to
position a selected filter in the path of the light. An optical
encoder can also be used to finely position one or more filters. In
some embodiments, one or more tunable filters may be used to filter
light into multiple wavelengths. The one or more tunable filters
may provide the multiple wavelengths of light at the same time or
at different times (e.g., sequentially). The light source included
in the optical system 412 may emit radiation in the ultraviolet,
visible, near-infrared, mid-infrared, and/or far-infrared regions
of the electromagnetic spectrum. In some embodiments, the light
source can be a broadband source that emits radiation in a broad
spectral region (e.g., from about 1500 nm to about 6000 nm). In
other embodiments, the light source may emit radiation at certain
specific wavelengths. The light source may comprise one or more
light emitting diodes (LEDs) emitting radiation at one or more
wavelengths in the radiation regions described herein. In other
embodiments, the light source may comprise one or more laser
modules emitting radiation at one or more wavelengths. The laser
modules may comprise a solid state laser (e.g., a Nd:YAG laser), a
semiconductor based laser (e.g., a GaAs and/or InGaAsP laser),
and/or a gas laser (e.g., an Ar-ion laser). In some embodiments,
the laser modules may comprise a fiber laser. The laser modules may
emit radiation at certain fixed wavelengths. In some embodiments,
the emission wavelength of the laser module(s) may be tunable over
a wide spectral range (e.g., about 30 nm to about 100 nm). In some
embodiments, the light source included in the optical system 412
may be a thermal infrared emitter. The light source can comprise a
resistive heating element, which, in some embodiments, may be
integrated on a thin dielectric membrane on a micromachined silicon
structure. In one embodiment the light source is generally similar
to the electrical modulated thermal infrared radiation source,
IRSource.TM., available from the Axetris Microsystems division of
Leister Technologies, LLC (Itasca, Ill.).
[0092] The optical system 412 can be controlled by an optical
system controller 413. The optical system controller can, in some
embodiments, be integrated into the optical system 412. In some
embodiments, the fluid system controller 405 and the optical system
controller 413 can communicate with each other as indicated by the
line 411. In some embodiments, the function of these two
controllers can be integrated and a single controller can control
both the fluid-handling system 404 and the optical system 412. Such
an integrated control can be advantageous because the two systems
are preferably integrated, and the optical system 412 is preferably
configured to analyze the very same fluid handled by the
fluid-handling system 404. Indeed, portions of the fluid-handling
system 404 (e.g., the sample holder described above with respect to
the second disposable subsystem 410 and/or at least some components
of a centrifuge) can also be components of the optical system 412.
Accordingly, the fluid-handling system 404 can be controlled to
obtain a fluid sample for analysis by optical system 412, when the
fluid sample arrives, the optical system 412 can be controlled to
analyze the sample, and when the analysis is complete (or before),
the fluid-handling system 404 can be controlled to return some of
the sample to the fluid source 402 and/or discard some of the
sample, as appropriate.
[0093] The system 400 shown in FIG. 4 includes a display system 414
that provides for communication of information to a user of the
system 400. In some embodiments, the display 414 can be replaced by
or supplemented with other communication devices that communicate
in non-visual ways. The display system 414 can include a display
processor that controls or produces an interface to communicate
information to the user. The display system 414 can include a
display screen. One or more parameters such as, for example, blood
glucose concentration, system 400 operating parameters, and/or
other operating parameters can be displayed on a monitor (not
shown) associated with the system 400. An example of one way such
information can be displayed is shown in FIGS. 24 and 25. In some
embodiments, the display system 414 can communicate measured
physiological parameters and/or operating parameters to a computer
system over a communications connection.
[0094] The system 400 shown in FIG. 4 includes an algorithm
processor 416 that can receive spectral information, such as
optical density (OD) values (or other analog or digital optical
data) from the optical system 412 and or the optical system
controller 413. In some embodiments, the algorithm processor 416
calculates one or more physiological parameters and can analyze the
spectral information. Thus, for example and without limitation, a
model can be used that determines, based on the spectral
information, physiological parameters of fluid from the fluid
source 402. The algorithm processor 416, a controller that may be
part of the display system 414, and any embedded controllers within
the system 400 can be connected to one another with a
communications bus.
[0095] Some embodiments of the systems described herein (e.g., the
system 400), as well as some embodiments of each method described
herein, can include a computer program accessible to and/or
executable by a processing system, e.g., a one or more processors
and memories that are part of an embedded system. Indeed, the
controllers may comprise one or more computers and/or may use
software. Thus, as will be appreciated by those skilled in the art,
various embodiments may be embodied as a method, an apparatus such
as a special purpose apparatus, an apparatus such as a data
processing system, or a carrier medium, e.g., a computer program
product. The carrier medium carries one or more computer readable
code segments for controlling a processing system to implement a
method. Accordingly, various embodiments may take the form of a
method, an entirely hardware embodiment, an entirely software
embodiment or an embodiment combining software and hardware
aspects. Furthermore, any one or more of the disclosed methods
(including but not limited to the disclosed methods of measurement
analysis, interferent determination, and/or calibration constant
generation) may be stored as one or more computer readable code
segments or data compilations on a carrier medium. Any suitable
computer readable carrier medium may be used including a magnetic
storage device such as a diskette or a hard disk; a memory
cartridge, module, card or chip (either alone or installed within a
larger device); or an optical storage device such as a CD or
DVD.
Fluid Handling System
[0096] The generalized fluid-handling system 404 can have various
configurations. In this context, FIG. 5 schematically illustrates
the layout of an example embodiment of a fluid system 510. In this
schematic representation, various components are depicted that may
be part of a non-disposable subsystem 406, a first disposable
subsystem 408, a second disposable subsystem 410, and/or an optical
system 412. The fluid system 510 is described practically to show
an example cycle as fluid is drawn and analyzed.
[0097] In addition to the reference numerals used below, the
various portions of the illustrated fluid system 510 are labeled
for convenience with letters to suggest their roles as follows: T#
indicates a section of tubing. C# indicates a connector that joins
multiple tubing sections. V# indicates a valve. BS# indicates a
bubble sensor or ultrasonic air detector. N# indicates a needle
(e.g., a needle that injects sample into a sample holder). PS#
indicates a pressure sensor (e.g., a reusable pressure sensor).
Pump# indicates a fluid pump (e.g., a syringe pump with a
disposable body and reusable drive). "Hb 12" indicates a sensor for
hemoglobin (e.g., a dilution sensor that can detect hemoglobin
optically).
[0098] The term "valve" as used herein is a broad term and is used,
in accordance with its ordinary meaning, to refer to any flow
regulating device. For example, the term "valve" can include,
without limitation, any device or system that can controllably
allow, prevent, or inhibit the flow of fluid through a fluid
passageway. The term "valve" can include some or all of the
following, alone or in combination: pinch valves, rotary valves,
stop cocks, pressure valves, shuttle valves, mechanical valves,
electrical valves, electro-mechanical flow regulators, etc. In some
embodiments, a valve can regulate flow using gravitational methods
or by applying electrical voltages or by both.
[0099] The term "pump" as used herein is a broad term and is used,
in accordance with its ordinary meaning, to refer to any device
that can urge fluid flow. For example, the term "pump" can include
any combination of the following: syringe pumps, peristaltic pumps,
vacuum pumps, electrical pumps, mechanical pumps, hydraulic pumps,
etc. Pumps and/or pump components that are suitable for use with
some embodiments can be obtained, for example, from or through
Hospira.
[0100] The function of the valves, pumps, actuators, drivers,
motors (e.g., the centrifuge motor), etc. described below is
controlled by one or more controllers (e.g., the fluid system
controller 405, the optical system controller 413, etc.) The
controllers can include software, computer memory, electrical and
mechanical connections to the controlled components, etc.
[0101] At the start of a measurement cycle, most lines, including a
patient tube 512 (T1), an Arrival sensor tube 528 (T4), an
anticoagulant valve tube 534 (T3), and a sample cell 548 can be
filled with saline that can be introduced into the system through
the infusion tube 514 and the saline tube 516, and which can come
from an infusion pump 518 and/or a saline bag 520. The infusion
pump 518 and the saline bag 520 can be provided separately from the
system 510. For example, a hospital can use existing saline bags
and infusion pumps to interface with the described system. The
infusion valve 521 can be open to allow saline to flow into the
tube 512 (T1).
[0102] Before drawing a sample, the saline in part of the system
510 can be replaced with air. Thus, for example, the following
valves can be closed: air valve 503 (PV0), the detergent tank valve
559 (V7b), 566 (V3b), 523 (V0), 529 (V7a), and 563 (V2b). At the
same time, the following valves can be open: valves 531 (V1a), 533
(V3a) and 577 (V4a). Simultaneously, a second pump 532 (pump #0)
pumps air through the system 510 (including tube 534 (T3), sample
cell 548, and tube 556 (T6)), pushing saline through tube 534 (T3)
and sample cell 548 into a waste bladder 554.
[0103] Next, a sample can be drawn. With the valves 542 (PV1), 559
(V7b), and 561 (V4b) closed, a first pump 522 (pump #1) is actuated
to draw sample fluid to be analyzed (e.g. blood) from a fluid
source (e.g., a laboratory sample container, a living patient,
etc.) up into the patient tube 512 (T1), through the tube past the
two flanking portions of the open pinch-valve 523 (V0), through the
first connector 524 (C1), into the looped tube 530, past the
arrival sensor 526 (Hb12), and into the arrival sensor tube 528
(T4). The arrival sensor 526 may be used to detect the presence of
blood in the tube 528 (T4). For example in some embodiments, the
arrival sensor 526 may comprise a hemoglobin sensor. In some other
embodiments, the arrival sensor 526 may comprise a color sensor
that detects the color of fluid flowing through the tube 528 (T4).
During this process, the valve 529 (V7a) and 523 (V0) are open to
fluid flow, and the valves 531 (V1a), 533 (V3a), 542 (PV1), 559
(V7b), and 561 (V4b) can be closed and therefore block (or
substantially block) fluid flow by pinching the tube.
[0104] Before drawing the sample, the tubes 512 (T1) and 528 (T4)
are filled with saline and the hemoglobin (Hb) level is zero. The
tubes that are filled with saline are in fluid communication with
the sample source (e.g., the fluid source 402). The sample source
can be the vessels of a living human or a pool of liquid in a
laboratory sample container, for example. When the saline is drawn
toward the first pump 522, fluid to be analyzed is also drawn into
the system because of the suction forces in the closed fluid
system. Thus, the first pump 522 draws a relatively continuous
column of fluid that first comprises generally nondiluted saline,
then a mixture of saline and sample fluid (e.g., blood), and then
eventually nondiluted sample fluid. In the example illustrated
here, the sample fluid is blood.
[0105] The arrival sensor 526 (Hb12) can detect and/or verify the
presence of blood in the tubes. For example, in some embodiments,
the arrival sensor 526 can determine the color of the fluid in the
tubes. In some embodiments, the arrival sensor 526 (Hb12) can
detect the level of Hemoglobin in the sample fluid. As blood starts
to arrive at the arrival sensor 526 (Hb12), the sensed hemoglobin
level rises. A hemoglobin level can be selected, and the system can
be pre-set to determine when that level is reached. A controller
such as the fluid system controller 405 of FIG. 4 can be used to
set and react to the pre-set value, for example. In some
embodiments, when the sensed hemoglobin level reaches the pre-set
value, substantially undiluted sample is present at the first
connector 524 (C1). The preset value can depend, in part, on the
length and diameter of any tubes and/or passages traversed by the
sample. In some embodiments, the pre-set value can be reached after
approximately 2 mL of fluid (e.g., blood) has been drawn from a
fluid source. A nondiluted sample can be, for example, a blood
sample that is not diluted with saline solution, but instead has
the characteristics of the rest of the blood flowing through a
patient's body. A loop of tubing 530 (e.g., a 1-mL loop) can be
advantageously positioned as illustrated to help insure that
undiluted fluid (e.g., undiluted blood) is present at the first
connector 524 (C1) when the arrival sensor 526 registers that the
preset Hb threshold is crossed. The loop of tubing 530 provides
additional length to the Arrival sensor tube 528 (T4) to make it
less likely that the portion of the fluid column in the tubing at
the first connector 524 (C1) has advanced all the way past the
mixture of saline and sample fluid, and the nondiluted blood
portion of that fluid has reached the first connector 524 (C1).
[0106] In some embodiments, when nondiluted blood is present at the
first connector 524 (C1), a sample is mixed with an anticoagulant
and is directed toward the sample cell 548. An amount of
anticoagulant (e.g., heparin) can be introduced into the tube 534
(T3), and then the undiluted blood is mixed with the anticoagulant.
A heparin vial 538 (e.g., an insertable vial provided independently
by the user of the system 510) can be connected to a tube 540. An
anticoagulant valve 541 (which can be a shuttle valve, for example)
can be configured to connect to both the tube 540 and the
anticoagulant valve tube 534 (T3). The valve can open the tube 540
to a suction force (e.g., created by the pump 532), allowing
heparin to be drawn from the vial 538 into the valve 541. Then, the
anticoagulant valve 541 can slide the heparin over into fluid
communication with the anticoagulant valve tube 534 (T3). The
anticoagulant valve 541 can then return to its previous position.
Thus, heparin can be shuttled from the tube 540 into the
anticoagulant valve tube 534 (T3) to provide a controlled amount of
heparin into the tube 534 (T3).
[0107] With the valves 542 (PV1), 559 (V7b), 561 (V4b), 523 (V0),
531 (V1a), 566 (V3b), and 563 (V2b) closed, and the valves 529
(V7a) and 553 (V3a) open, first pump 522 (pump #1) pushes the
sample from tube 528 (T4) into tube 534 (T3), where the sample
mixes with the heparin injected by the anticoagulant valve 541 as
it flows through the system 510. As the sample proceeds through the
tube 534 (T3), the air that was previously introduced into the tube
534 (T3) is displaced. The sample continues to flow until a bubble
sensor 535 (BS9) indicates a change from air to a liquid, and thus
the arrival of a sample at the bubble sensor. In some embodiments,
the volume of tube 534 (T3) from connector 524 (C1) to bubble
sensor 535 (BS9) is a known and/or engineered amount, and may be
approximately 500 .mu.L, 200 .mu.L or 100 .mu.L, for example.
[0108] When bubble sensor 535 (BS9) indicates the presence of a
sample, the remainder of the sampled blood can be returned to its
source (e.g., the patient veins or arteries). The first pump 522
(pump #1) pushes the blood out of the Arrival sensor tube 528 (T4)
and back to the patient by opening the valve 523 (V0), closing the
valves 531 (V1a) and 533 (V3a), and keeping the valve 529 (V7a)
open. The Arrival sensor tube 528 (T4) is preferably flushed with
approximately 2 mL of saline. This can be accomplished by closing
the valve 529 (V7a), opening the valve 542 (PV1), drawing saline
from the saline source 520 into the tube 544, closing the valve 542
(PV1), opening the valve 529 (V7a), and forcing the saline down the
Arrival sensor tube 528 (T4) with the pump 522. In some
embodiments, less than two minutes elapse between the time that
blood is drawn from the patient and the time that the blood is
returned to the patient.
[0109] Following return of the unused patient blood sample, the
sample is pushed up the anticoagulant valve tube 534 (T3), through
the second connector 546 (C2), and into the sample cell 548, which
can be located on the centrifuge rotor 550. This fluid movement is
facilitated by the coordinated action (either pushing or drawing
fluid) of the pump 522 (pump #1), the pump 532 (pump #0), and the
various illustrated valves. In particular, valve 531 (V1a) can be
opened, and valves 503 (PV0) and 559 (V7b) can be closed. Pump
movement and valve position corresponding to each stage of fluid
movement can be coordinated by one ore multiple controllers, such
as the fluid system controller 405 of FIG. 4.
[0110] After the unused sample is returned to the patient, the
sample can be divided into separate slugs before being delivered
into the sample cell 548. Thus, for example, valve 553 (V3a) is
opened, valves 566 (V3b), 523 (V0) and 529 (V7a) are closed, and
the pump 532 (pump #0) uses air to push the sample toward sample
cell 548. In some embodiments, the sample (for example, 200 .mu.L
or 100 .mu.L) is divided into multiple (e.g., more than two, five,
or four) "slugs" of sample, each separated by a small amount of
air. As used herein, the term "slug" refers to a continuous column
of fluid that can be relatively short. Slugs can be separated from
one another by small amounts of air (or bubbles) that can be
present at intervals in the tube. In some embodiments, the slugs
are formed by injecting or drawing air into fluid in the first
connector 546 (C2).
[0111] In some embodiments, when the leading edge of the sample
reaches blood sensor 553 (BS14), a small amount of air (the first
"bubble") is injected at a connector C6. This bubble helps define
the first "slug" of liquid, which extends from the bubble sensor to
the first bubble. In some embodiments, the valves 533 (V3a) and 556
(V3b) are alternately opened and closed to form a bubble at
connector C6, and the sample is pushed toward the sample cell 548.
Thus, for example, with pump 532 actuated, valve 566 V(3b) is
briefly opened and valve 533 (V3a) is briefly closed to inject a
first air bubble into the sample.
[0112] In some embodiments, the volume of the tube 534 (T3) from
the connector 546 (C2) to the bubble sensor 552 (BS14) is less than
the volume of tube 534 (T3) from the connector 524 (C1) to the
bubble sensor 535 (BS9). Thus, for example and without limitation,
the volume of the tube 534 (T3) from the connector 524 (C1) to the
bubble sensor 535 (BS9) can be in the range of approximately 80
.mu.L to approximately 120 .mu.L, (e.g., 100 .mu.L) and the volume
of the tube 534 (T3) from the connector 546 (C2) to the bubble
sensor 552 (BS14) can be in the range of approximately 5 .mu.L to
approximately 25 .mu.L (e.g., 15 .mu.L). In some embodiments,
multiple blood slugs are created. For example, more than two blood
slugs can be created, each having a different volume. In some
embodiments, five blood slugs are created, each having
approximately the same volume of approximately 20 .mu.L each. In
some embodiments, three blood slugs are created, the first two
having a volume of 10 .mu.L and the last having a volume of 20
.mu.L. In some embodiments, four blood slugs are created; the first
three blood slugs can have a volume of approximately 15 .mu.L, and
the fourth can have a volume of approximately 35 .mu.L.
[0113] A second slug can be prepared by opening the valve 553
(V3a), closing the valve 566 (V3b), with pump 532 (pump #0)
operating to push the first slug through a first sample cell holder
interface tube 582 (N1), through the sample cell 548, through a
second sample cell holder interface tube 584 (N2), and toward the
waste bladder 554. When the first bubble reaches the bubble sensor
552 (BS 14), the open/closed configurations of valves 553 (V3a) and
566 (V3b) are reversed, and a second bubble is injected into the
sample, as before. A third slug can be prepared in the same manner
as the second (pushing the second bubble to bubble sensor 552 (BS
14) and injecting a third bubble). After the injection of the third
air bubble, the sample can be pushed through system 510 until the
end of the sample is detected by bubble sensor 552 (BS 14). The
system can be designed such that when the end of the sample reaches
this point, the last portion of the sample (a fourth slug) is
within the sample cell 548, and the pump 532 can stop forcing the
fluid column through the anticoagulant valve tube 534 (T3) so that
the fourth slug remains within the sample cell 548. Thus, the first
three blood slugs can serve to flush any residual saline out the
sample cell 548. The three leading slugs can be deposited in the
waste bladder 554 by passing through the tube 556 (T6) and past the
tube-flanking portions of the open pinch valve 557 (V4a).
[0114] In some embodiments, the fourth blood slug is centrifuged
for a given length of time (e.g., more than 1 minute, five minutes,
or 2 minutes, to take three advantageous examples) at a relatively
fast speed (e.g., 7200 RPM, 5000 RPM, or 4500 RPM, to take three
examples). Thus, for example, the sample cell holder interface
tubes 582 (N1) and 584 (N2) disconnect the sample cell 548 from the
tubes 534 (T3) and 562 (T7), permitting the centrifuge rotor 550
and the sample cell 548 to spin together. Spinning separates a
sample (e.g., blood) into its components, isolates the plasma, and
positions the plasma in the sample cell 548 for measurement. The
centrifuge 550 can be stopped with the sample cell 548 in a beam of
radiation (not shown) for analysis. The radiation, a detector, and
logic can be used to analyze a portion of the sample (e.g., the
plasma) spectroscopically (e.g., for glucose, lactate, or other
analyte concentration). In some embodiments, some or all of the
separated components (e.g., the isolated plasma) may be transported
to a different analysis chamber. For example, another analysis
chamber can have one or more electrodes in electrical communication
with the chamber's contents, and the separated components may be
analyzed electrically. At any suitable point, one or more of the
separated components can be transported to the waste bladder 554
when no longer needed. In some chemical analysis systems and
apparatus, the separated components are analyzed electrically.
Analysis devices may be connected serially, for example, so that
the analyzed substance from an optical analysis system (e.g., an
"OptiScanner.RTM." fluid analyzer) can be transferred to an
independent analysis device (e.g., a chemical analysis device) for
subsequent analysis. In certain embodiments, the analysis devices
are integrated into a single system. Many variations are
possible.
[0115] In some embodiments, portions of the system 510 that contain
blood after the sample cell 548 has been provided with a sample are
cleaned to prevent blood from clotting. Accordingly, the centrifuge
rotor 550 can include two passageways for fluid that may be
connected to the sample cell holder interface tubes 582 (N1) and
584 (N2). One passageway is sample cell 548, and a second
passageway is a shunt 586. An embodiment of the shunt 586 is
illustrated in more detail in FIG. 16 (see reference numeral
1586).
[0116] The shunt 586 can allow cleaner (e.g., a detergent such as
tergazyme A) to flow through and clean the sample cell holder
interface tubes without flowing through the sample cell 548. After
the sample cell 548 is provided with a sample, the interface tubes
582 (N1) and 584 (N2) are disconnected from the sample cell 548,
the centrifuge rotor 550 is rotated to align the shunt 586 with the
interface tubes 582 (N1) and 584 (N2), and the interface tubes are
connected with the shunt. With the shunt in place, the detergent
tank 559 is pressurized by the second pump 532 (pump #0) with
valves 561 (V4b) and 563 (V2b) open and valves 557 (V4a) and 533
(V3a) closed to flush the cleaning solution back through the
interface tubes 582 (N1) and 584 (N2) and into the waste bladder
554. Subsequently, saline can be drawn from the saline bag 520 for
a saline flush. This flush pushes saline through the Arrival sensor
tube 528 (T4), the anticoagulant valve tube 534 (T3), the sample
cell 548, and the waste tube 556 (T6). Thus, in some embodiments,
the following valves are open for this flush: 529 (V7a), 533 (V3a),
557 (V4a), and the following valves are closed: 542 (PV1), 523
(V0), 531 (V1a), 566 (V3b), 563 (V2b), and 561 (V4b).
[0117] Following analysis, the second pump 532 (pump #0) flushes
the sample cell 548 and sends the flushed contents to the waste
bladder 554. This flush can be done with a cleaning solution from
the detergent tank 558. In some embodiments, the detergent tank
valve 559 (V7b) is open, providing fluid communication between the
second pump 532 and the detergent tank 558. The second pump 532
forces cleaning solution from the detergent tank 558 between the
tube-flanking portions of the open pinch valve 561 and through the
tube 562 (T7). The cleaning flush can pass through the sample cell
548, through the second connector 546, through the tube 564 (T5)
and the open valve 563 (V2b), and into the waste bladder 554.
[0118] Subsequently, the first pump 522 (pump #1) can flush the
cleaning solution out of the sample cell 548 using saline in drawn
from the saline bag 520. This flush pushes saline through the
Arrival sensor tube 528 (T4), the anticoagulant valve tube 534
(T3), the sample cell 548, and the waste tube 556 (T6). Thus, in
some embodiments, the following valves are open for this flush: 529
(V7a), 533 (V3a), 557 (V4a), and the following valves are closed:
542 (PV1), 523 (V0), 531 (V1a), 566 (V3b), 563 (V2b), and 561
(V4b).
[0119] When the fluid source is a living entity such as a patient,
a low flow of saline (e.g., 1-5 mL/hr) is preferably moved through
the patient tube 512 (T1) and into the patient to keep the
patient's vessel open (e.g., to establish a keep vessel open, or
"KVO" flow). This KVO flow can be temporarily interrupted when
fluid is drawn into the fluid system 510. The source of this KVO
flow can be the infusion pump 518, the third pump 568 (pump #3), or
the first pump 522 (pump #1). In some embodiments, the infusion
pump 518 can run continuously throughout the measurement cycle
described above. This continuous flow can advantageously avoid any
alarms that may be triggered if the infusion pump 518 senses that
the flow has stopped or changed in some other way. In some
embodiments, when the infusion valve 521 closes to allow pump 522
(pump #1) to withdraw fluid from a fluid source (e.g., a patient),
the third pump 568 (pump #3) can withdraw fluid through the
connector 570, thus allowing the infusion pump 518 to continue
pumping normally as if the fluid path was not blocked by the
infusion valve 521. If the measurement cycle is about two minutes
long, this withdrawal by the third pump 568 can continue for
approximately two minutes. Once the infusion valve 521 is open
again, the third pump 568 (pump #3) can reverse and insert the
saline back into the system at a low flow rate. Preferably, the
time between measurement cycles is longer than the measurement
cycle itself (for example, the time interval can be longer than ten
minutes, shorter than ten minutes, shorter than five minutes,
longer than two minutes, longer than one minute, etc.).
Accordingly, the third pump 568 can insert fluid back into the
system at a lower rate than it withdrew that fluid. This can help
prevent an alarm by the infusion pump.
[0120] FIG. 6 schematically illustrates another embodiment of a
fluid system that can be part of a system for withdrawing and
analyzing fluid samples. In this embodiment, the anticoagulant
valve 541 has been replaced with a syringe-style pump 588 (Pump
Heparin) and a series of pinch valves around a junction between
tubes. For example, a heparin pinch valve 589 (Vhep) can be closed
to prevent flow from or to the pump 588, and a heparin waste pinch
valve 590 can be closed to prevent flow from or to the waste
container from this junction through the heparin waste tube 591.
This embodiment also illustrates the shunt 592 schematically. Other
differences from FIG. 5 include the check valve 593 located near
the detergent tank 558 and the patient loop 594. The reference
letters D, for example, the one indicated at 595, refer to
components that are advantageously located on the door. The
reference letters M, for example, the one indicated at 596, refer
to components that are advantageously located on the monitor. The
reference letters B, for example, the one indicated at 597, refer
to components that can be advantageously located on both the door
and the monitor.
[0121] In some embodiments, the system 400 (see FIG. 4), the
apparatus 100 (see FIG. 1), or even the monitoring device 102 (see
FIG. 1) itself can also actively function not only to monitor
analyte levels (e.g., glucose), but also to change and/or control
analyte levels. Thus, the monitoring device 102 can be both a
monitoring and an infusing device. In some embodiments, the fluid
handling system 510 can include an optional analyte control
subsystem 2780 that will be further described below (see discussion
of analyte control).
[0122] In certain embodiments, analyte levels in a patient can be
adjusted directly (e.g., by infusing or extracting glucose) or
indirectly (e.g., by infusing or extracting insulin). FIG. 6
illustrates one way of providing this function. The infusion pinch
valve 598 (V8) can allow the port sharing pump 599 (compare to the
third pump 568 (pump #3) in FIG. 5) to serve two roles. In the
first role, it can serve as a "port sharing" pump. The port sharing
function is described with respect to the third pump 568 (pump #3)
of FIG. 5, where the third pump 568 (pump #3) can withdraw fluid
through the connector 570, thus allowing the infusion pump 518 to
continue pumping normally as if the fluid path was not blocked by
the infusion valve 521. In the second role, the port sharing pump
599 can serve as an infusion pump. The infusion pump role allows
the port sharing pump 599 to draw a substance (e.g., glucose,
saline, etc.) from another source when the infusion pinch valve 598
is open, and then to infuse that substance into the system or the
patient when the infusion pinch valve 598 is closed. This can
occur, for example, in order to change the level of a substance in
a patient in response to a reading by the monitor that the
substance is too low. In some embodiments, one or more of the pumps
may comprise a reversible infusion pump configured to interrupt the
flow of the infusion fluid and draw a sample of blood for
analysis.
Mechanical/Fluid System Interface
[0123] FIG. 7 is an oblique schematic depiction of a modular
monitoring device 700, which can correspond to the monitoring
device 102. The modular monitoring device 700 includes a body
portion 702 having a receptacle 704, which can be accessed by
moving a movable portion 706. The receptacle 704 can include
connectors (e.g., rails, slots, protrusions, resting surfaces,
etc.) with which a removable portion 710 can interface. In some
embodiments, portions of a fluidic system that directly contact
fluid are incorporated into one or more removable portions (e.g.,
one or more disposable cassettes, sample holders, tubing cards,
etc.). For example, a removable portion 710 can house at least a
portion of the fluid system 510 described previously, including
portions that contact sample fluids, saline, detergent solution,
and/or anticoagulant.
[0124] In some embodiments, a non-disposable fluid-handling
subsystem 708 is disposed within the body portion 702 of the
monitoring device 700. The first removable portion 710 can include
one or more openings that allow portions of the non-disposable
fluid-handling subsystem 708 to interface with the removable
portion 710. For example, the non-disposable fluid-handling
subsystem 708 can include one or more pinch valves that are
designed to extend through such openings to engage one or more
sections of tubing. When the first removable portion 710 is present
in a corresponding first receptacle 704, actuation of the pinch
valves can selectively close sections of tubing within the
removable portion. The non-disposable fluid-handling subsystem 708
can also include one or more sensors that interface with
connectors, tubing sections, or pumps located within the first
removable portion 710. The non-disposable fluid-handling subsystem
708 can also include one or more actuators (e.g., motors) that can
actuate moveable portions (e.g., the plunger of a syringe) that may
be located in the removable portion F10. A portion of the
non-disposable fluid-handling subsystem 708 can be located on or in
the moveable portion F06 (which can be a door having a slide or a
hinge, a detachable face portion, etc.).
[0125] In the embodiment shown in FIG. 7, the monitoring device 700
includes an optical system 714 disposed within the body portion
702. The optical system 714 can include a light source and a
detector that are adapted to perform measurements on fluids within
a sample holder (not shown). The light source may comprise a fixed
wavelength light source and/or a tunable light source. The light
source may comprise one or more sources including, for example,
broadband sources, LEDs, and lasers. In some embodiments, the
sample holder comprises a removable portion, which can be
associated with or disassociated from the removable portion F10.
The sample holder can include an optical window through which the
optical system 714 can emit radiation for measuring properties of a
fluid in the sample holder. The optical system 714 can include
other components such as, for example, a power supply, a centrifuge
motor, a filter wheel, and/or a beam splitter.
[0126] In some embodiments, the removable portion 710 and the
sample holder are adapted to be in fluid communication with each
other. For example, the removable portion 710 can include a
retractable injector that injects fluids into a sample holder. In
some embodiments, the sample holder can comprise or be disposed in
a second removable portion (not shown). In some embodiments, the
injector can be retracted to allow the centrifuge to rotate the
sample holder freely.
[0127] The body portion 702 of the monitoring device 700 can also
include one or more connectors for an external battery (not shown).
The external battery can serve as a backup emergency power source
in the event that a primary emergency power source such as, for
example, an internal battery (not shown) is exhausted.
[0128] FIG. 7 shows an embodiment of a system having subcomponents
illustrated schematically. By way of a more detailed (but
nevertheless non-limiting) example, FIG. 8 and FIG. 9 show more
details of the shape and physical configuration of a sample
embodiment.
[0129] FIG. 8 shows a cut-away side view of a monitoring device 800
(which can correspond, for example, to the device 102 shown in FIG.
1). The device 800 includes a casing 802. The monitoring device 800
can have a fluid system. For example, the fluid system can have
subsystems, and a portion or portions thereof can be disposable, as
schematically depicted in FIG. 4. As depicted in FIG. 8, the fluid
system is generally located at the left-hand portion of the casing
802, as indicated by the reference 801. The monitoring device 800
can also have an optical system. In the illustrated embodiment, the
optical system is generally located in the upper portion of the
casing 802, as indicated by the reference 803. Advantageously,
however, the fluid system 801 and the optical system 803 can both
be integrated together such that fluid flows generally through a
portion of the optical system 803, and such that radiation flows
generally through a portion of the fluid system 801.
[0130] Depicted in FIG. 8 are examples of ways in which components
of the device 800 mounted within the casing 802 can interface with
components of the device 800 that comprise disposable portions. Not
all components of the device 800 are shown in FIG. 8. A disposable
portion 804 having a variety of components is shown in the casing
802. In some embodiments, one or more actuators 808 housed within
the casing 802, operate syringe bodies 810 located within a
disposable portion 804. The syringe bodies 810 are connected to
sections of tubing 816 that move fluid among various components of
the system. The movement of fluid is at least partially controlled
by the action of one or more pinch valves 812 positioned within the
casing 802. The pinch valves 812 have arms 814 that extend within
the disposable portion 804. Movement of the arms 814 can constrict
a section of tubing 816.
[0131] In some embodiments, a sample cell holder 820 can engage a
centrifuge motor 818 mounted within the casing 802 of the device
800. A filter wheel motor 822 disposed within the housing 802
rotates a filter wheel 824, and in some embodiments, aligns one or
more filters with an optical path. An optical path can originate at
a source 826 within the housing 802 that can be configured to emit
a beam of radiation (e.g., infrared radiation, visible radiation,
ultraviolet radiation, etc.) through the filter and the sample cell
holder 820 and to a detector 828. A detector 828 can measure the
optical density of the light when it reaches the detector.
[0132] FIG. 9 shows a cut-away perspective view of an alternative
embodiment of a monitoring device 900. Many features similar to
those illustrated in FIG. 8 are depicted in this illustration of an
alternative embodiment. A fluid system 901 can be partially seen.
The disposable portion 904 is shown in an operative position within
the device. One of the actuators 808 can be seen next to a syringe
body 910 that is located within the disposable portion 904. Some
pinch valves 912 are shown next to a fluid-handling portion of the
disposable portion 904. In this figure, an optical system 903 can
also be partially seen. The sample holder 920 is located underneath
the centrifuge motor 918. The filter wheel motor 922 is positioned
near the radiation source 926, and the detector 928 is also
illustrated.
[0133] FIG. 10 illustrates two views of a cartridge 1000 that can
interface with a fluid system such as the fluid system 510 of FIG.
5. The cartridge 1000 can be configured for insertion into a
receptacle of the device 800 of FIG. 8 and/or the device 900 shown
in FIG. 9. In some embodiments, the cartridge 1000 can comprise a
portion that is disposable and a portion that is reusable. In some
embodiments, the cartridge 1000 can be disposable. The cartridge
1000 can fill the role of the removable portion 710 of FIG. 7, for
example. In some embodiments, the cartridge 1000 can be used for a
system having only one disposable subsystem, making it a simple
matter for a health care provider to replace and/or track usage
time of the disposable portion. In some embodiments, the cartridge
1000 includes one or more features that facilitate insertion of the
cartridge 1000 into a corresponding receptacle. For example, the
cartridge 1000 can be shaped so as to promote insertion of the
cartridge 1000 in the correct orientation. The cartridge 1000 can
also include labeling or coloring affixed to or integrated with the
cartridge's exterior casing that help a handler insert the
cartridge 1000 into a receptacle properly.
[0134] The cartridge 1000 can include one or more ports for
connecting to material sources or receptacles. Such ports can be
provided to connect to, for example, a saline source, an infusion
pump, a sample source, and/or a source of gas (e.g., air, nitrogen,
etc.). The ports can be connected to sections of tubing within the
cartridge 1000. In some embodiments, the sections of tubing are
opaque or covered so that fluids within the tubing cannot be seen,
and in some embodiments, sections of tubing are transparent to
allow interior contents (e.g., fluid) to be seen from outside.
[0135] The cartridge 1000 shown in FIG. 10 can include a sample
injector 1006. The sample injector 1006 can be configured to inject
at least a portion of a sample into a sample holder (see, e.g., the
sample cell 548), which can also be incorporated into the cartridge
1000. The sample injector 1006 can include, for example, the sample
cell holder interface tubes 582 (N1) and 584 (N2) of FIG. 5,
embodiments of which are also illustrated in FIG. 15.
[0136] The housing of the cartridge 1000 can include a tubing
portion 1008 containing within it a card having one or more
sections of tubing. In some embodiments, the body of the cartridge
1000 includes one or more apertures 1009 through which various
components, such as, for example, pinch valves and sensors, can
interface with the fluid-handling portion contained in the
cartridge 1000. The sections of tubing found in the tubing portion
1008 can be aligned with the apertures 1009 in order to implement
at least some of the functionality shown in the fluid system 510 of
FIG. 5.
[0137] The cartridge 1000 can include a pouch space (not shown)
that can comprise one or more components of the fluid system 510.
For example, one or more pouches and/or bladders can be disposed in
the pouch space (not shown). In some embodiments, a cleaner pouch
and/or a waste bladder can be housed in a pouch space. The waste
bladder can be placed under the cleaner pouch such that, as
detergent is removed from the cleaner pouch, the waste bladder has
more room to fill. The components placed in the pouch space (not
shown) can also be placed side-by-side or in any other suitable
configuration.
[0138] The cartridge 1000 can include one or more pumps 1016 that
facilitate movement of fluid within the fluid system 510. Each of
the pump housings 1016 can contain, for example, a syringe pump
having a plunger. The plunger can be configured to interface with
an actuator outside the cartridge 1000. For example, a portion of
the pump that interfaces with an actuator can be exposed to the
exterior of the cartridge 1000 housing by one or more apertures
1018 in the housing.
[0139] The cartridge 1000 can have an optical interface portion
1030 that is configured to interface with (or comprise a portion
of) an optical system. In the illustrated embodiment, the optical
interface portion 1030 can pivot around a pivot structure 1032. The
optical interface portion 1030 can house a sample holder (not
shown) in a chamber that can allow the sample holder to rotate. The
sample holder can be held by a centrifuge interface 1036 that can
be configured to engage a centrifuge motor (not shown). When the
cartridge 1000 is being inserted into a system, the orientation of
the optical interface portion 1030 can be different than when it is
functioning within the system.
[0140] In some embodiments, the cartridge 1000 is designed for
single patient use. The cartridge 1000 may also be disposable
and/or designed for replacement after a period of operation. For
example, in some embodiments, if the cartridge 1000 is installed in
a continuously operating monitoring device that performs four
measurements per hour, the waste bladder may become filled or the
detergent in the cleaner pouch depleted after about three days. The
cartridge 1000 can be replaced before the detergent and waste
bladder are exhausted. In some embodiments, a portion of the
cartridge 1000 can be disposable while another portion of the
cartridge 1000 is disposable, but lasts longer before being
discarded. In some embodiments, a portion of the cartridge 1000 may
not be disposable at all. For example, a portion thereof may be
configured to be cleaned thoroughly and reused for different
patients. Various combinations of disposable and less- or
non-disposable portions are possible.
[0141] The cartridge 1000 can be configured for easy replacement.
For example, in some embodiments, the cartridge 1000 is designed to
have an installation time of only minutes. For example, the
cartridge can be designed to be installed in less than about five
minutes, or less than two minutes. During installation, various
fluid lines contained in the cartridge 1000 can be primed by
automatically filling the fluid lines with saline. The saline can
be mixed with detergent powder from the cleaner pouch in order to
create a cleaning solution.
[0142] The cartridge 1000 can also be designed to have a relatively
brief shut down time. For example, the shut down process can be
configured to take less than about fifteen minutes, or less than
about ten minutes, or less than about five minutes. The shut down
process can include flushing the patient line; sealing off the
insulin pump connection, the saline source connection, and the
sample source connection; and taking other steps to decrease the
risk that fluids within the used cartridge 1000 will leak after
disconnection from the monitoring device.
[0143] Some embodiments of the cartridge 1000 can comprise a flat
package to facilitate packaging, shipping, sterilizing, etc.
Advantageously, however, some embodiments can further comprise a
hinge or other pivot structure. Thus, as illustrated, an optical
interface portion 1030 can be pivoted around a pivot structure 1032
to generally align with the other portions of the cartridge 1000.
The cartridge can be provided to a medical provider sealed in a
removable wrapper, for example.
[0144] In some embodiments, the cartridge 1000 is designed to fit
within standard waste containers found in a hospital, such as a
standard biohazard container. For example, the cartridge 1000 can
be less than one foot long, less than one foot wide, and less than
two inches thick. In some embodiments, the cartridge 1000 is
designed to withstand a substantial impact, such as that caused by
hitting the ground after a four foot drop, without damage to the
housing or internal components. In some embodiments, the cartridge
1000 is designed to withstand significant clamping force applied to
its casing. For example, the cartridge 1000 can be built to
withstand five pounds per square inch of force without damage. In
some embodiments, the cartridge 1000 can be designed to be less
sturdy and more biodegradable. In some embodiments, the cartridge
1000 can be formed and configured to withstand more or less than
five pounds of force per square inch without damage. In some
embodiments, the cartridge 1000 is non pyrogenic and/or latex
free.
[0145] FIG. 11 illustrates an embodiment of a fluid-routing card
1038 that can be part of the removable cartridge of FIG. 10. For
example, the fluid-routing card 1038 can be located generally
within the tubing portion 1008 of the cartridge 1000. The
fluid-routing card 1038 can contain various passages and/or tubes
through which fluid can flow as described with respect to FIG. 5
and/or FIG. 6, for example. Thus, the illustrated tube opening
openings can be in fluid communication with the following fluidic
components, for example:
TABLE-US-00001 Tube Opening Reference Numeral Can Be In Fluid
Communication With 1142 third pump 568 (pump #3) 1144 infusion pump
518 1146 Presx 1148 air pump 1150 Vent 1152 detergent (e.g.,
tergazyme) source or waste tube 1154 Presx 1156 detergent (e.g.,
tergazyme) source or waste tube 1158 waste receptacle 1160 first
pump 522 (pump #1) (e.g., a saline pump) 1162 saline source or
waste tube 1164 anticoagulant (e.g., heparin) pump (see FIG. 6)
and/or shuttle valve 1166 detergent (e.g., tergazyme) source or
waste tube 1167 Presx 1168 Arrival sensor tube 528 (T4) 1169 tube
536 (T2) 1170 Arrival sensor tube 528 (T4) 1171 Arrival sensor tube
528 (T4) 1172 anticoagulant (e.g., heparin) pump 1173 T17 (see FIG.
6) 1174 Sample cell holder interface tube 582 (N1) 1176
anticoagulant valve tube 534 (T3) 1178 Sample cell holder interface
tube 584 (N2) 1180 T17 (see FIG. 6) 1182 anticoagulant valve tube
534 (T3) 1184 Arrival sensor tube 528 (T4) 1186 tube 536 (T2) 1188
anticoagulant valve tube 534 (T3) 1190 anticoagulant valve tube 534
(T3)
[0146] The depicted fluid-routing card 1038 can have additional
openings that allow operative portions of actuators and/or valves
to protrude through the fluid-routing card 1038 and interface with
the tubes.
[0147] FIG. 12 illustrates how actuators, which can sandwich the
fluid-routing card 1038 between them, can interface with the
fluid-routing card 1038 of FIG. 11. Pinch valves 812 can have an
actuator portion that protrudes away from the fluid-routing card
1038 containing a motor. Each motor can correspond to a pinch
platen 1202, which can be inserted into a pinch platen receiving
hole 1204. Similarly, sensors, such as a bubble sensor 1206 can be
inserted into receiving holes (e.g., the bubble sensor receiving
hole 1208). Movement of the pinch valves 812 can be detected by the
position sensors 1210.
[0148] FIG. 13 illustrates an actuator 808 that is connected to a
corresponding syringe body 810. The actuator 808 is an example of
one of the actuators 808 that is illustrated in FIG. 8 and in FIG.
9, and the syringe body 810 is an example of one of the syringe
bodies 810 that are visible in FIG. 8 and in FIG. 9. A ledge
portion 1212 of the syringe body 810 can be engaged (e.g., slid
into) a corresponding receiving portion 1214 in the actuator 808.
In some embodiments, the receiving portion 1214 can slide outward
to engage the stationary ledge portion 1212 after the disposable
cartridge 804 is in place. Similarly, a receiving tube 1222 in the
syringe plunger 1223 can be slide onto (or can receive) a
protruding portion 1224 of the actuator 808. The protruding portion
1224 can slide along a track 1226 under the influence of a motor
inside the actuator 808, thus actuating the syringe plunger 1223
and causing fluid to flow into or out of the syringe tip 1230.
[0149] FIG. 14 shows a rear perspective view of internal
scaffolding 1231 and the protruding bodies of some pinch valves
812. The internal scaffolding 1231 can be formed from metal and can
provide structural rigidity and support for other components. The
scaffolding 1231 can have holes 1232 into which screws can be
screwed or other connectors can be inserted. In some embodiments, a
pair of sliding rails 1234 can allow relative movement between
portions of an analyzer. For example, a slidable portion 1236
(which can correspond to the movable portion 706, for example) can
be temporarily slid away from the scaffolding 1231 of a main unit
in order to allow an insertable portion (e.g., the cartridge 804)
to be inserted.
[0150] FIG. 15 shows an underneath perspective view of the sample
cell holder 820, which is attached to the centrifuge interface
1036. The sample cell holder 820 can have an opposite side (see
FIG. 17) that allows it to slide into a receiving portion of the
centrifuge interface 1036. The sample cell holder 820 can also have
receiving nubs 1512A that provide a pathway into a sample cell 1548
held by the sample cell holder 820. Receiving nubs 1512B can
provide access to a shunt 1586 (see FIG. 16) inside the sample cell
holder 820. The receiving nubs 1512A and 1512B can receive and or
dock with fluid nipples 1514. The fluid nipples 1514 can protrude
at an angle from the sample injector 1006, which can in turn
protrude from the cartridge 1000 (see FIG. 10). The tubes 1516
shown protruding from the other end of the sample injector 1006 can
be in fluid communication with the sample cell holder interface
tubes 582 (N1) and 584 (N2) (see FIG. 5 and FIG. 6), as well as
1074 and 1078 (see FIG. 11).
[0151] FIG. 16 shows a plan view of the sample cell holder 820 with
hidden and/or non-surface portions illustrated using dashed lines.
The receiving nubs 1512A communicate with passages 1550 inside the
sample cell 1548 (which can correspond, for example to the sample
cell 548 of FIG. 5). The passages widen out into a wider portion
1552 that corresponds to a window 1556. The window 1556 and the
wider portion 1552 can be configured to house the sample when
radiation is emitted along a pathlength that is generally
non-parallel to the sample cell 1548. The window 1556 can allow
calibration of the instrument with the sample cell 1548 in place,
even before a sample has arrived in the wider portion 1552.
[0152] An opposite opening 1530 can provide an alternative optical
pathway between a radiation source and a radiation detector (e.g.,
the radiation source 826 of FIG. 18) and may be used, for example,
for obtaining a calibration measurement of the source and detector
without an intervening window or sample. Thus, the opposite opening
1530 can be located generally at the same radial distance from the
axis of rotation as the window 1556.
[0153] The receiving nubs 1512B communicate with a shunt passage
1586 inside the sample cell holder 820 (which can correspond, for
example to the shunt 586 of FIG. 5).
[0154] Other features of the sample cell holder 820 can provide
balancing properties for even rotation of the sample cell holder
820. For example, the wide trough 1562 and the narrower trough 1564
can be sized or otherwise configured so that the weight and/or mass
of the sample cell holder 820 is evenly distributed from left to
right in the view of FIG. 16, and/or from top to bottom in this
view of FIG. 16.
[0155] FIG. 17 shows a top perspective view of the centrifuge
interface 1036 connected to the sample cell holder 820. The
centrifuge interface 1036 can have a bulkhead 1520 with a rounded
slot 1522 into which an actuating portion of a centrifuge can be
slid from the side. The centrifuge interface 1036 can thus be spun
about an axis 1524, along with the sample cell holder 820, causing
fluid (e.g., whole blood) within the sample cell 1548 to separate
into concentric strata, according to relative density of the fluid
components (e.g., plasma, red blood cells, buffy coat, etc.),
within the sample cell 1548. The sample cell holder 820 can be
transparent, or it can at least have transparent portions (e.g.,
the window 1556 and/or the opposite opening 1530) through which
radiation can pass, and which can be aligned with an optical
pathway between a radiation source and a radiation detector (see,
e.g., FIG. 20). In addition, a round opening 1530 through
centrifuge rotor 1520 provides an optical pathway between the
radiation source and radiation detector and may be used, for
example, for obtaining a calibration measurement of the source and
detector without an intervening window or sample.
[0156] FIG. 18 shows a perspective view of an example optical
system 803. Such a system can be integrated with other systems as
shown in FIG. 9, for example. The optical system 803 can fill the
role of the optical system 412, and it can be integrated with
and/or adjacent to a fluid system (e.g., the fluid-handling system
404 or the fluid system 801). The sample cell holder 820 can be
seen attached to the centrifuge interface 1036, which is in turn
connected to, and rotatable by the centrifuge motor 818. A filter
wheel housing 1812 is attached to the filter wheel motor 822 and
encloses a filter wheel 1814. A protruding shaft assembly 1816 can
be connected to the filter wheel 1814. The filter wheel 1814 can
have multiple filters (see FIG. 19). The radiation source 826 is
aligned to transmit radiation through a filter in the filter wheel
1814 and then through a portion of the sample cell holder 820.
Transmitted and/or reflected and/or scattered radiation can then be
detected by a radiation detector.
[0157] FIG. 19 shows a view of the filter wheel 1814 when it is not
located within the filter wheel housing 1812 of the optical system
803. Additional features of the protruding shaft assembly 1816 can
be seen, along with multiple filters 1820. In some embodiments, the
filters 1820 can be removably and/or replaceably inserted into the
filter wheel 1814.
Spectroscopic System
[0158] As described above with reference to FIG. 4, the system 400
comprises the optical system 412 for analysis of a fluid sample. In
various embodiments, the optical system 412 comprises one or more
optical components including, for example, a spectrometer, a
photometer, a reflectometer, or any other suitable device for
measuring optical properties of the fluid sample. The optical
system 412 may perform one or more optical measurements on the
fluid sample including, for example, measurements of transmittance,
absorbance, reflectance, scattering, and/or polarization. The
optical measurements may be performed in one or more wavelength
ranges including, for example, infrared (IR) and/or optical
wavelengths. As described with reference to FIG. 4 (and further
described below), the measurements from the optical system 412 are
communicated to the algorithm processor 416 for analysis. For
example, in some embodiments the algorithm processor 416 computes
concentration of analyte(s) (and/or interferent(s)) of interest in
the fluid sample. Analytes of interest can include, for example,
glucose and/or lactate in whole blood and/or in blood plasma. In
some embodiments the algorithm processor 416 can advantageously
calibrate a measured analyte concentration for some or all of the
effects of sample dilution. In some embodiments, the algorithm
processor 416 may correct a measured analyte concentration for
dilution to provide an estimate of analyte concentration that is
more representative of the concentration in the patient's body than
would otherwise be the case without correcting for dilution.
[0159] FIG. 20 schematically illustrates an embodiment of the
optical system 412 that comprises a spectroscopic analyzer 2010
adapted to measure spectra of a fluid sample such as, for example,
blood or blood plasma. The analyzer 2010 comprises an energy source
2012 disposed along an optical axis X of the analyzer 2010. When
activated, the energy source 2012 generates an electromagnetic
energy beam E, which advances from the energy source 2012 along the
optical axis X In some embodiments, the energy source 2012
comprises an infrared energy source, and the energy beam E
comprises an infrared beam. In some embodiments, the infrared
energy beam E comprises a mid-infrared energy beam or a
near-infrared energy beam. In some embodiments, the energy beam E
can include optical and/or radio frequency wavelengths.
[0160] The energy source 2012 may comprise a broad-band and/or a
narrow-band source of electromagnetic energy. In some embodiments,
the energy source 2012 comprises optical elements such as, e.g.,
filters, collimators, lenses, mirrors, etc., that are adapted to
produce a desired energy beam E. For example, in some embodiments,
the energy beam E is an infrared beam in a wavelength range between
about 2 .mu.m and 20 .mu.m. In some embodiments, the energy beam E
comprises an infrared beam in a wavelength range between about 4
.mu.m and 10 .mu.m. In the infrared wavelength range, water
generally is the main contributor to the total absorption together
with features from absorption of other blood components,
particularly in the 6 .mu.m-10 .mu.m range. The 4 .mu.m to 10 .mu.m
wavelength band has been found to be advantageous for determining
glucose concentration, because glucose has a strong absorption peak
structure from about 8.5 .mu.m to 10 .mu.m, whereas most other
blood components have a relatively low and flat absorption spectrum
in the 8.5 .mu.m to 10 .mu.m range. Two exceptions are water and
hemoglobin, which are interferents in this range.
[0161] The energy beam E may be temporally modulated to provide
increased signal-to-noise ratio (S/N) of the measurements provided
by the analyzer 2010 as further described below. For example, in
some embodiments, the beam E is modulated at a frequency of about
10 Hz or in a range from about 1 Hz to about 30 Hz. A suitable
energy source 2012 may be an electrically modulated thin-film
thermoresistive element such as the HawkEye IR-50 available from
Hawkeye Technologies of Milford, Conn.
[0162] As depicted in FIG. 20, the energy beam E propagates along
the optical axis X and passes through an aperture 2014 and a filter
2015 thereby providing a filtered energy beam E.sub.f. The aperture
2014 helps collimate the energy beam E and can include one or more
filters adapted to reduce the filtering burden of the filter 2015.
For example, the aperture 2014 may comprise a broadband filter that
substantially attenuates beam energy outside a wavelength band
between about 4 .mu.m to about 10 .mu.m. The filter 2015 may
comprise a narrow-band filter that substantially attenuates beam
energy having wavelengths outside of a filter passband (which may
be tunable or user-selectable in some embodiments). The filter
passband may be specified by a half-power bandwidth ("HPBW"). In
some embodiments, the filter 2015 may have an HPBW in a range from
about 0.1 .mu.m to about 2 .mu.m, or 0.01 .mu.m to about 1 .mu.m.
In some embodiments, the bandwidths are in a range from about 0.2
.mu.m to 0.5 .mu.m, or 0.1 .mu.m to 0.35 .mu.m. Other filter
bandwidths may be used. The filter 2015 may comprise a
varying-passband filter, an electronically tunable filter, a liquid
crystal filter, an interference filter, and/or a gradient filter.
In some embodiments, the filter 2015 comprises one or a combination
of a grating, a prism, a monochrometer, a Fabry-Perot etalon,
and/or a polarizer. Other optical elements may be utilized as
well.
[0163] In the embodiment shown in FIG. 20, the analyzer 2010
comprises a filter wheel assembly 2021 configured to dispose one or
more filters 2015 along the optical axis X The filter wheel
assembly 2021 comprises a filter wheel 2018, a filter wheel motor
2016, and a position sensor 2020. The filter wheel 2018 may be
substantially circular and have one or more filters 2015 or other
optical elements (e.g., apertures, gratings, polarizers, mirrors,
etc.) disposed around the circumference of the wheel 2018. In some
embodiments, the number of filters 2015 in the filter wheel 2016
may be, for example, 1, 2, 5, 10, 15, 20, 25, or more. The motor
2016 is configured to rotate the filter wheel 2018 to dispose a
desired filter 2015 (or other optical element) in the energy beam E
so as to produce the filtered beam E.sub.f. In some embodiments,
the motor 2016 comprises a stepper motor. The position sensor 2020
determines the angular position of the filter wheel 2016, and
communicates a corresponding filter wheel position signal to the
algorithm processor 416, thereby indicating which filter 2015 is in
position on the optical axis X In various embodiments, the position
sensor 2020 may be a mechanical, optical, and/or magnetic encoder.
An alternative to the filter wheel 2018 is a linear filter
translated by a motor. The linear filter can include an array of
separate filters or a single filter with properties that change
along a linear dimension.
[0164] The filter wheel motor 2016 rotates the filter wheel 2018 to
position the filters 2015 in the energy beam E to sequentially vary
the wavelengths or the wavelength bands used to analyze the fluid
sample. In some embodiments, each individual filter 2015 is
disposed in the energy beam E for a dwell time during which optical
properties in the passband of the filter are measured for the
sample. The filter wheel motor 2016 then rotates the filter wheel
2018 to position another filter 2015 in the beam E. In some
embodiments, 25 narrow-band filters are used in the filter wheel
2018, and the dwell time is about 2 seconds for each filter 2015. A
set of optical measurements for all the filters can be taken in
about 2 minutes, including sampling time and filter wheel movement.
In some embodiments, the dwell time may be different for different
filters 2015, for example, to provide a substantially similar S/N
ratio for each filter measurement. Accordingly, the filter wheel
assembly 2021 functions as a varying-passband filter that allows
optical properties of the sample to be analyzed at a number of
wavelengths or wavelength bands in a sequential manner.
[0165] In some embodiments of the analyzer 2010, the filter wheel
2018 includes 25 finite-bandwidth infrared filters having a
Gaussian transmission profile and full-width half-maximum (FWHM)
bandwidth of 28 cm.sup.-1 corresponding to a bandwidth that varies
from 0.14 .mu.m at 7.08 .mu.m to 0.28 .mu.m at 10 .mu.m. The
central wavelength of the filters are, in microns: 7.082, 7.158,
7.241, 7.331, 7.424, 7.513, 7.605, 7.704, 7.800, 7.905, 8.019,
8.150, 8.271, 8.598, 8.718, 8.834, 8.969, 9.099, 9.217, 9.346,
9.461, 9.579, 9.718, 9.862, and 9.990.
[0166] With further reference to FIG. 20, the filtered energy beam
E.sub.f propagates to a beamsplitter 2022 disposed along the
optical axis X The beamsplitter 2022 separates the filtered energy
beam E.sub.f into a sample beam E.sub.s and a reference beam
E.sub.r. The reference beam E.sub.r propagates along a minor
optical axis Y, which in this embodiment is substantially
orthogonal to the optical axis X The energies in the sample beam
E.sub.s and the reference beam E.sub.r may comprise any suitable
fraction of the energy in the filtered beam E.sub.f. For example,
in some embodiments, the sample beam E.sub.s comprises about 80%,
and the reference beam E.sub.r comprises about 20%, of the filtered
beam energy E.sub.f. A reference detector 2036 is positioned along
the minor optical axis Y. An optical element 2034, such as a lens,
may be used to focus or collimate the reference beam E.sub.r onto
the reference detector 2036. The reference detector 2036 provides a
reference signal, which can be used to monitor fluctuations in the
intensity of the energy beam E emitted by the source 2012. Such
fluctuations may be due to drift effects, aging, wear, or other
imperfections in the source 2012. The algorithm processor 416 may
utilize the reference signal to identify changes in properties of
the sample beam E.sub.s that are attributable to changes in the
emission from the source 2012 and not to the properties of the
fluid sample. By so doing, the analyzer 2010 may advantageously
reduce possible sources of error in the calculated properties of
the fluid sample (e.g., concentration). In other embodiments of the
analyzer 2010, the beamsplitter 2022 is not used, and substantially
all of the filtered energy beam E.sub.f propagates to the fluid
sample.
[0167] As illustrated in FIG. 20, the sample beam E.sub.s
propagates along the optical axis X, and a relay lens 2024
transmits the sample beam E.sub.s into a sample cell 2048 so that
at least a fraction of the sample beam E.sub.s is transmitted
through at least a portion of the fluid sample in the sample cell
2048. A sample detector 2030 is positioned along the optical axis X
to measure the sample beam E.sub.s that has passed through the
portion of the fluid sample. An optical element 2028, such as a
lens, may be used to focus or collimate the sample beam E.sub.s
onto the sample detector 2030. The sample detector 2030 provides a
sample signal that can be used by the algorithm processor 416 as
part of the sample analysis.
[0168] In the embodiment of the analyzer 2010 shown in FIG. 20, the
sample cell 2048 is located toward the outer circumference of the
centrifuge wheel 2050 (which can correspond, for example, to the
sample cell holder 820 described herein). The sample cell 2048
preferably comprises windows that are substantially transmissive to
energy in the sample beam E.sub.s. For example, in implementations
using mid-infrared energy, the windows may comprise calcium
fluoride. As described herein with reference to FIG. 5, the sample
cell 2048 is in fluid communication with an injector system that
permits filling the sample cell 2048 with a fluid sample (e.g.,
whole blood) and flushing the sample cell 2048 (e.g., with saline
or a detergent). The injector system may disconnect after filling
the sample cell 2048 with the fluid sample to permit free spinning
of the centrifuge wheel 2050.
[0169] The centrifuge wheel 2050 can be spun by a centrifuge motor
2026. In some embodiments of the analyzer 2010, the fluid sample
(e.g., a whole blood sample) is spun at a certain number of
revolutions per minute (RPM) for a given length of time to separate
blood plasma for spectral analysis. In some embodiments, the fluid
sample is spun at about 7200 RPM. In some embodiments, the fluid
sample is spun at about 5000 RPM or 4500 RPM. In some embodiments,
the fluid sample is spun at more than one rate for successive time
periods. The length of time can be approximately 5 minutes. In some
embodiments, the length of time is approximately 2 minutes. In some
embodiments, an anti-clotting agent such as heparin may be added to
the fluid sample before centrifuging to reduce clotting. With
reference to FIG. 20, the centrifuge wheel 2050 is rotated to a
position where the sample cell 2048 intercepts the sample beam
E.sub.s, allowing energy to pass through the sample cell 2048 to
the sample detector 2030.
[0170] The embodiment of the analyzer 2010 illustrated in FIG. 20
advantageously permits direct measurement of the concentration of
analytes in the plasma sample rather than by inference of the
concentration from measurements of a whole blood sample. An
additional advantage is that relatively small volumes of fluid may
be spectroscopically analyzed. For example, in some embodiments the
fluid sample volume is between about 1 .mu.L and 80 .mu.L and is
about 25 .mu.L in some embodiments. In some embodiments, the sample
cell 2048 is disposable and is intended for use with a single
patient or for a single measurement.
[0171] In some embodiments, the reference detector 2036 and the
sample detector 2030 comprise broadband pyroelectric detectors. As
known in the art, some pyroelectric detectors are sensitive to
vibrations. Thus, for example, the output of a pyroelectric
infrared detector is the sum of the exposure to infrared radiation
and to vibrations of the detector. The sensitivity to vibrations,
also known as "microphonics," can introduce a noise component to
the measurement of the reference and sample energy beams E.sub.r,
E.sub.s using some pyroelectric infrared detectors. Because it may
be desirable for the analyzer 2010 to provide high signal-to-noise
ratio measurements, such as, e.g., S/N in excess of 100 dB, some
embodiments of the analyzer 2010 utilize one or more vibrational
noise reduction apparatus or methods. For example, the analyzer
2010 may be mechanically isolated so that high S/N spectroscopic
measurements can be obtained for vibrations below an acceleration
of about 1.5 G.
[0172] In some embodiments of the analyzer 2010, vibrational noise
can be reduced by using a temporally modulated energy source 2012
combined with an output filter. In some embodiments, the energy
source 2012 is modulated at a known source frequency, and
measurements made by the detectors 2036 and 2030 are filtered using
a narrowband filter centered at the source frequency. For example,
in some embodiments, the energy output of the source 2012 is
sinusoidally modulated at 10 Hz, and outputs of the detectors 2036
and 2030 are filtered using a narrow bandpass filter of less than
about 1 Hz centered at 10 Hz. Accordingly, microphonic signals that
are not at 10 Hz are significantly attenuated. In some embodiments,
the modulation depth of the energy beam E may be greater than 50%
such as, for example, 80%. The duty cycle of the beam may be
between about 30% and 70%. The temporal modulation may be
sinusoidal or any other waveform. In embodiments utilizing
temporally modulated energy sources, detector output may be
filtered using a synchronous demodulator and digital filter. The
demodulator and filter are software components that may be
digitally implemented in a processor such as the algorithm
processor 416. Synchronous demodulators, coupled with low pass
filters, are often referred to as "lock in amplifiers."
[0173] The analyzer 2010 may also include a vibration sensor 2032
(e.g., one or more accelerometers) disposed near one (or both) of
the detectors 2036 and 2030. The output of the vibration sensor
2032 is monitored, and suitable actions are taken if the measured
vibration exceeds a vibration threshold. For example, in some
embodiments, if the vibration sensor 2032 detects above-threshold
vibrations, the system discards any ongoing measurement and "holds
off" on performing further measurements until the vibrations drop
below the threshold. Discarded measurements may be repeated after
the vibrations drop below the vibration threshold. In some
embodiments, if the duration of the "hold off" is sufficiently
long, the fluid in the sample cell 2030 is flushed, and a new fluid
sample is delivered to the cell 2030 for measurement. The vibration
threshold may be selected so that the error in analyte measurement
is at an acceptable level for vibrations below the threshold. In
some embodiments, the threshold corresponds to an error in glucose
concentration of 5 mg/dL. The vibration threshold may be determined
individually for each filter 2015.
[0174] Certain embodiments of the analyzer 2010 include a
temperature system (not shown in FIG. 20) for monitoring and/or
regulating the temperature of system components (such as the
detectors 2036, 2030) and/or the fluid sample. Such a temperature
system can include temperature sensors, thermoelectrical heat pumps
(e.g., a Peltier device), and/or thermistors, as well as a control
system for monitoring and/or regulating temperature. In some
embodiments, the control system comprises a
proportional-plus-integral-plus-derivative (PID) control. For
example, in some embodiments, the temperature system is used to
regulate the temperature of the detectors 2030, 2036 to a desired
operating temperature, such as 35 degrees Celsius.
Optical Measurement
[0175] The analyzer 2010 illustrated in FIG. 20 can be used to
determine optical properties of a substance in the sample cell
2048. The substance can include whole blood, plasma, saline, water,
air or other substances. In some embodiments, the optical
properties include measurements of an absorbance, transmittance,
and/or optical density in the wavelength passbands of some or all
of the filters 2015 disposed in the filter wheel 2018. As described
above, a measurement cycle comprises disposing one or more filters
2015 in the energy beam E for a dwell time and measuring a
reference signal with the reference detector 2036 and a sample
signal with the sample detector 2030. The number of filters 2015
used in the measurement cycle will be denoted by N, and each filter
2015 passes energy in a passband around a center wavelength
.lamda..sub.i, where i is an index ranging over the number of
filters (e.g., from 1 to N). The set of optical measurements from
the sample detector 2036 in the passbands of the N filters 2015
provide a wavelength-dependent spectrum of the substance in the
sample cell 2048. The spectrum will be denoted by
C.sub.s(.lamda..sub.i), where C.sub.s may be a transmittance,
absorbance, optical density, or some other measure of an optical
property of the substance. In some embodiments, the spectrum is
normalized with respect to one or more of the reference signals
measured by the reference detector 2030 and/or with respect to
spectra of a reference substance (e.g., air or saline). The
measured spectra are communicated to the algorithm processor 416
for calculation of the concentration of the analyte(s) of interest
in the fluid sample.
[0176] In some embodiments, the analyzer 2010 performs
spectroscopic measurements on the fluid sample (known as a "wet"
reading) and on one or more reference samples. For example, an
"air" reading occurs when the sample detector 2036 measures the
sample signal without the sample cell 2048 in place along the
optical axis X. (This can occur, for example, when the opposite
opening 1530 is aligned with the optical axis X). A "water" or
"saline" reading occurs when the sample cell 2048 is filled with
water or saline, respectively. The algorithm processor 416 may be
programmed to calculate analyte concentration using a combination
of these spectral measurements. In some embodiments, an advantage
of combining the "wet reading" with at least the "water" or
"saline" reading is to calibrate a measured analyte concentration
for some or all of the effects of dilution.
[0177] In some embodiments, a pathlength corrected spectrum is
calculated using wet, air, and reference readings. For example, the
transmittance at wavelength .lamda..sub.i, denoted by T.sub.i, may
be calculated according to
T.sub.i=(S.sub.i(wet)/R.sub.i(wet))/(S.sub.i(air)/R.sub.i(air)),
where S.sub.i denotes the sample signal from the sample detector
2036 and R.sub.i denotes the corresponding reference signal from
the reference detector 2030. In some embodiments, the algorithm
processor 416 calculates the optical density, OD.sub.i, as a
logarithm of the transmittance, e.g., according to
OD.sub.i=-Log(T.sub.i). In one implementation, the analyzer 2010
takes a set of wet readings in each of the N filter passbands and
then takes a set of air readings in each of the N filter passbands.
In other embodiments, the analyzer 2010 may take an air reading
before (or after) the corresponding wet reading.
[0178] The optical density OD.sub.i is the product of the
absorption coefficient at wavelength .lamda..sub.i, .alpha..sub.i,
times the pathlength L over which the sample energy beam E.sub.s
interacts with the substance in the sample cell 2048, e.g.,
OD.sub.i=.alpha..sub.i L. The absorption coefficient .alpha..sub.i
of a substance may be written as the product of an absorptivity per
mole times a molar concentration of the substance. FIG. 20
schematically illustrates the pathlength L of the sample cell 2048.
The pathlength L may be determined from spectral measurements made
when the sample cell 2048 is filled with a reference substance. For
example, because the absorption coefficient for water (or saline)
is known, one or more water (or saline) readings can be used to
determine the pathlength L from measurements of the transmittance
(or optical density) through the cell 2048. In some embodiments,
several readings are taken in different wavelength passbands, and a
curve-fitting procedure is used to estimate a best-fit pathlength
L. The pathlength L may be estimated using other methods including,
for example, measuring interference fringes of light passing
through an empty sample cell 2048.
[0179] The pathlength L may be used to determine the absorption
coefficients of the fluid sample at each wavelength. Molar
concentration of an analyte of interest can be determined from the
absorption coefficient and the known molar absorptivity of the
analyte. In some embodiments, a sample measurement cycle comprises
a saline reading (at one or more wavelengths), a set of N wet
readings (taken, for example, through a sample cell 2048 containing
saline solution), followed by a set of N air readings (taken, for
example, through the opposite opening 1530). As discussed above,
the sample measurement cycle can be performed in a given length of
time that may depend, at least in part, on filter dwell times. For
example, the measurement cycle may take five minutes when the
filter dwell times are about five seconds. In some embodiments, the
measurement cycle may take about two minutes when the filter dwell
times are about two seconds. After the sample measurement cycle is
completed, a detergent cleaner may be flushed through the sample
cell 2048 to reduce buildup of organic matter (e.g., proteins) on
the windows of the sample cell 2048. The detergent is then flushed
to a waste bladder.
[0180] In some embodiments, the system stores information related
to the spectral measurements so that the information is readily
available for recall by a user. The stored information can include
wavelength-dependent spectral measurements (including fluid sample,
air, and/or saline readings), computed analyte values, system
temperatures and electrical properties (e.g., voltages and
currents), and any other data related to use of the system (e.g.,
system alerts, vibration readings, S/N ratios, etc.). The stored
information may be retained in the system for a time period such
as, for example, 30 days. After this time period, the stored
information may be communicated to an archival data storage system
and then deleted from the system. In some embodiments, the stored
information is communicated to the archival data storage system via
wired or wireless methods, e.g., over a hospital information system
(HIS).
Analyte Analysis
[0181] The algorithm processor 416 (FIG. 4) (or any other suitable
processor or processors) may be configured to receive from the
analyzer 2010 the wavelength-dependent optical measurements
Cs(.lamda..sub.i) of the fluid sample. In some embodiments, the
optical measurements comprise spectra such as, for example, optical
densities OD.sub.i measured in each of the N filter passbands
centered around wavelengths .lamda..sub.i. The optical measurements
Cs(.lamda..sub.i) are communicated to the processor 416, which
analyzes the optical measurements to detect and quantify one or
more analytes in the presence of interferents. In some embodiments,
one or more poor quality optical measurements Cs(.lamda..sub.i) are
rejected (e.g., as having a S/N ratio that is too low), and the
analysis performed on the remaining, sufficiently high-quality
measurements. In another embodiment, additional optical
measurements of the fluid sample are taken by the analyzer 2010 to
replace one or more of the poor quality measurements.
[0182] 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, in
at least a portion of the wavelength range of the measurements. The
presence of such an interferent can introduce errors in the
quantification of the analyte. More specifically, the presence of
one or more 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.
[0183] 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 an 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 can 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.
[0184] 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.
[0185] Certain disclosed analysis methods are particularly
effective if each analyte and interferent has a characteristic
signature in the measurement (e.g., a characteristic spectroscopic
feature), and if the measurement is approximately affine (e.g.,
includes a linear term and an offset) with respect to the
concentration of each analyte and interferent. In such methods, a
calibration process is used to determine a set of one or more
calibration coefficients and a set of one or more optional offset
values that permit the quantitative estimation of an analyte. For
example, the calibration coefficients and the offsets may be used
to calculate an analyte concentration from spectroscopic
measurements of a material sample (e.g., the concentration of
glucose in blood plasma). In some of these methods, the
concentration of the analyte is estimated by multiplying the
calibration coefficient by a measurement value (e.g., an optical
density) to estimate the concentration of the analyte. Both the
calibration coefficient and measurement can comprise arrays of
numbers. For example, in some embodiments, the measurement
comprises spectra C.sub.s(.lamda..sub.i) measured at the
wavelengths .lamda..sub.i, and the calibration coefficient and
optional offset comprise an array of values corresponding to each
wavelength .lamda..sub.i. In some embodiments, as further described
below, a hybrid linear analysis (HLA) technique is used to estimate
analyte concentration in the presence of a set of interferents,
while retaining a high degree of sensitivity to the desired
analyte. The data used to accommodate the set of possible
interferents can include (a) signatures of each of the members of
the family of potential additional substances and (b) a typical
quantitative level at which each additional substance, if present,
is likely to appear. In some embodiments, the calibration
coefficient (and optional offset) are adjusted to minimize or
reduce the sensitivity of the calibration to the presence of
interferents that are identified as possibly being present in the
fluid sample.
[0186] In some embodiments, the analyte analysis method uses a set
of training spectra each having known analyte concentration and
produces a calibration that minimizes the variation in estimated
analyte concentration with interferent concentration. The resulting
calibration coefficient indicates sensitivity of the measurement to
analyte concentration. The training spectra need not include a
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).
[0187] Several terms are used herein to describe the analyte
analysis process. 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 calibration values
(e.g., calibration coefficients and optional offsets). In some
embodiments, the term Sample Population comprises measurements
(such as, e.g., spectra) from individuals and may comprise one or
more analyte measurements determined from those same individuals.
Additional demographic information may be available for the
individuals whose sample measurements are included in the Sample
Population. For an embodiment involving the spectroscopic
determination of glucose concentration, the Sample Population
measurements may include a spectrum (measurement) and a glucose
concentration (analyte measurement).
[0188] Various embodiments of Sample Populations may be used in
various embodiments of the systems and methods described herein.
Several examples of Sample Populations will now be described. These
examples are intended to illustrate certain aspects of possible
Sample Population embodiments but are not intended to limit the
types of Sample Populations that may be generated. In certain
embodiments, a Sample Population may include samples from one or
more of the example Sample Populations described below.
[0189] In some embodiments of the systems and methods described
herein, one or more Sample Populations are included in a
"Population Database." The Population Database may be implemented
and/or stored on a computer-readable medium. In certain
embodiments, the systems and methods may access the Population
Database using wired and/or wireless techniques. Certain
embodiments may utilize several different Population Databases that
are accessible locally and/or remotely. In some embodiments, the
Population Database includes one or more of the example Sample
Populations described below. In some embodiments, two or more
databases can be combined into a single database, and in other
embodiments, any one database can be divided into multiple
databases.
[0190] An example Sample Population may comprise samples from
individuals belonging to one or more demographic groups including,
for example, ethnicity, nationality, gender, age, etc. Demographic
groups may be established for any suitable set of one or more
distinctive factors for the group including, for example, medical,
cultural, behavioral, biological, geographical, religious, and
genealogical traits. For example, in certain embodiments, a Sample
Population includes samples from individuals from a specific ethnic
group (e.g., Caucasians, Hispanics, Asians, African Americans,
etc.). In another embodiment, a Sample Population includes samples
from individuals of a specific gender or a specific race. In some
embodiments, a Sample Population includes samples from individuals
belonging to more than one demographic group (e.g., samples from
Caucasian women).
[0191] Another example Sample Population can comprise samples from
individuals having one or more medical conditions. For example, a
Sample Population may include samples from individuals who are
healthy and unmedicated (sometimes referred to as a Normal
Population). In some embodiments, the Sample Population includes
samples from individuals having one or more health conditions
(e.g., diabetes). In some embodiments, the Sample Population
includes samples from individuals taking one or more medications.
In certain embodiments, Sample Population includes samples from
individuals diagnosed to have a certain medical condition or from
individuals being treated for certain medical conditions or some
combination thereof. The Sample Population may include samples from
individuals such as, for example, ICU patients, maternity patients,
and so forth.
[0192] An example Sample Population may comprise samples that have
the same interferent or the same type of interferents. In some
embodiments, a Sample Population can comprise multiple samples, all
lacking an interferent or a type of interferent. For example, a
Sample Population may comprise samples that have no exogenous
interferents, that have one or more exogenous interferents of
either known or unknown concentration, and so forth. The number of
interferents in a sample depends on the measurement and analyte(s)
of interest, and may number, in general, from zero to a very large
number (e.g., greater than 300). All of the interferents typically
are not expected to be present in a particular material sample, and
in many cases, a smaller number of interferents (e.g., 0, 1, 2, 5,
10, 15, 20, or 25) may be used in an analysis. In certain
embodiments, the number of interferents used in the analysis is
less than or equal to the number of wavelength-dependent
measurements N in the spectrum Cs(.lamda..sub.i).
[0193] Certain embodiments of the systems and methods described
herein are capable of analyzing a material sample using one or more
Sample Populations (e.g., accessed from the Population Database).
Certain such embodiments may use information regarding some or all
of the interferents which may or may not be present in the material
sample. In some embodiments, a list of one or more possible
interferents, referred to herein as forming a "Library of
Interferents," can be compiled. Each interferent in the Library can
be referred to as a "Library Interferent." The Library Interferents
may include exogenous interferents and endogenous interferents that
may be present in a material sample. For example, an interferent
may be present due to a medical condition causing abnormally high
concentrations of the exogenous and endogenous interferents. In
some embodiments, the Library of Interferents may not include one
or more interferents that are known to be present in all samples.
Thus, for example, water, which is a glucose interferent for many
spectroscopic measurements, may not be included in the Library of
Interferents. In certain embodiments, the systems and methods use
samples in the Sample Population to train calibration methods.
[0194] The material sample being measured, for example a fluid
sample in the sample cell 2048, may also include one or more
Library Interferents which may include, but is not limited to, an
exogenous interferent or an endogenous interferent. Examples of
exogenous interferent can include medications, and examples of
endogenous interferents can include urea in persons suffering from
renal failure. 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.
[0195] In some embodiments, measurements of a material sample
(e.g., a bodily fluid sample), samples in a Sample Population, and
the Library Interferents comprise spectra (e.g., infrared spectra).
The spectra obtained from a sample and/or an interferent may be
temperature dependent. In some embodiments, it may be beneficial to
calibrate for temperatures of the individual samples in the Sample
Population or the interferents in the Library of Interferents. In
some embodiments, a temperature calibration procedure is used to
generate a temperature calibration factor that substantially
accounts for the sample temperature. For example, the sample
temperature can be measured, and the temperature calibration factor
can be applied to the Sample Population and/or the Library
Interferent spectral data. In some embodiments, a water or saline
spectrum is subtracted from the sample spectrum to account for
temperature effects of water in the sample.
[0196] In other embodiments, temperature calibration may not be
used. For example, if Library Interferent spectra, Sample
Population spectra, and sample spectra are obtained at
approximately the same temperature, an error in a predicted analyte
concentration may be within an acceptable tolerance. If the
temperature at which a material sample spectrum is measured is
within, or near, a temperature range (e.g., several degrees
Celsius) at which the plurality of Sample Population spectra are
obtained, then some analysis methods may be relatively insensitive
to temperature variations. Temperature calibration may optionally
be used in such analysis methods.
Systems and Methods for Estimating Analyte Concentration in the
Presence of Interferents
[0197] FIG. 21 is a flowchart that schematically illustrates an
embodiment of a method 2100 for estimating the concentration of an
analyte in the presence of interferents. In block 2110, a
measurement of a sample is obtained, and in block 2120 data
relating to the obtained measurement is analyzed to identify
possible interferents to the analyte. In block 2130, a model is
generated for predicting the analyte concentration in the presence
of the identified possible interferents, and in block 2140 the
model is used to estimate the analyte concentration in the sample
from the measurement. In certain embodiments of the method 2100,
the model generated in block 2130 is selected to reduce or minimize
the effect of identified interferents that are not present in a
general population of which the sample is a member.
[0198] An example embodiment of the method 2100 of FIG. 21 for the
determination of an analyte (e.g., glucose) in a blood sample will
now be described. This example embodiment is intended to illustrate
various aspects of the method 2100 but is not intended as a
limitation on the scope of the method 2100 or on the range of
possible analytes. In this example, the sample measurement in block
2110 is an absorption spectrum, Cs(.lamda..sub.i), of a measurement
sample S that has, in general, one analyte of interest, glucose,
and one or more interferents.
[0199] In block 2120, a statistical comparison of the absorption
spectrum of the sample S with a spectrum of the Sample Population
and combinations of individual Library Interferent spectra is
performed. The statistical comparison provides a list of Library
Interferents that are possibly contained in sample S and can
include either no Library Interferents or one or more Library
Interferents. In this example, in block 2130, one or more sets of
spectra are generated from spectra of the Sample Population and
their respective known analyte concentrations and known spectra of
the Library Interferents identified in block 2120. In block 2130,
the generated spectra are used to calculate a model for predicting
the analyte concentration from the obtained measurement. In some
embodiments, the model comprises one or more calibration
coefficients .kappa.(.lamda..sub.i) that can be used with the
sample measurements Cs(.lamda..sub.i) to provide an estimate of the
analyte concentration, g.sub.est. In block 2140, the estimated
analyte concentration is determined form the model generated in
block 2130. For example, in some embodiments of HLA, the estimated
analyte concentration is calculated according to a linear formula:
g.sub.est=.kappa.(.lamda..sub.i)C.sub.s(.lamda..sub.i). Because the
absorption measurements and calibration coefficients may represent
arrays of numbers, the multiplication operation indicated in the
preceding formula may comprise a sum of the products of the
measurements and coefficients (e.g., an inner product or a matrix
product). In some embodiments, the calibration coefficient is
determined so as to have reduced or minimal sensitivity to the
presence of the identified Library Interferents.
[0200] An example embodiment of block 2120 of the method 2100 will
now be described with reference to FIG. 22. In this example, block
2120 includes forming a statistical Sample Population model (block
2210), assembling a library of interferent data (block 2220),
assembling all subsets of size K of the library interferents (block
2225), comparing the obtained measurement and statistical Sample
Population model with data for each set of interferents from an
interferent library (block 2230), performing a statistical test for
the presence of each interferent from the interferent library
(block 2240), and identifying possible interferents that pass the
statistical test (block 2250). The size K of the subsets may be an
integer such as, for example, 1, 2, 3, 4, 5, 6, 10, 16, or more.
The acts of block 2220 can be performed once or can be updated as
necessary. In certain embodiments, the acts of blocks 2230, 2240,
and 2250 are performed sequentially for all subsets of Library
Interferents that pass the statistical test (block 2240). In this
example, in block 2210, a Sample Population Database is formed that
includes a statistically large Sample Population of individual
spectra taken over the same wavelength range as the sample
spectrum, C.sub.s(.lamda..sub.i). The Database also includes an
analyte concentration corresponding to each spectrum. For example,
if there are P Sample Population spectra, then the spectra in the
Database can be represented as C={C.sub.1, C.sub.2, . . . ,
C.sub.P}, and the analyte concentration corresponding to each
spectrum can be represented as g={g.sub.1, g.sub.2, . . . ,
g.sub.P}. In some embodiments, the Sample Population does not have
any of the Library Interferents present, and the material sample
has interferents contained in the Sample Population and one or more
of the Library Interferents.
[0201] In some embodiments of block 2210, the statistical sample
model comprises a mean spectrum and a covariance matrix calculated
for the Sample Population. For example, if each spectrum measured
at N wavelengths .lamda..sub.i is represented by an N.times.1
array, C, then the mean spectrum, .mu., is an N.times.1 array
having values at each wavelength averaged over the range of spectra
in the Sample Population. The covariance matrix, V, is calculated
as the expected value of the deviation between C and .mu. and can
be written as V=E((C-.mu.) (C-.mu.).sup.T) where E(.cndot.)
represents the expected value and the superscript T denotes
transpose. In other embodiments, additional statistical parameters
may be included in the statistical model of the Sample Population
spectra.
[0202] Additionally, a Library of Interferents may be assembled in
block 2220. A number of possible interferents can be identified,
for example, as a list of possible medications or foods that might
be ingested by the population of patients at issue. Spectra of
these interferents can be obtained, and a range of expected
interferent concentrations in the blood, or other expected sample
material, can be estimated. In certain embodiments, the Library of
Interferents includes, for each of "M" interferents, the absorption
spectrum normalized to unit interferent concentration of each
interferent, IF={IF.sub.1, IF.sub.2, . . . , IF.sub.M}, and a range
of concentrations for each interferent from Tmax={Tmax.sub.1,
Tmax.sub.2, . . . , Tmax.sub.M) to Tmin={Tmin.sub.1, Tmin.sub.2, .
. . , Tmin.sub.M). Information in the Library may be assembled once
and accessed as needed. For example, the Library and the
statistical model of the Sample Population may be stored in a
storage device associated with the algorithm processor 416 (see,
FIG. 4).
[0203] Continuing in block 2225, the algorithm processor 416
assembles one or more subsets comprising a number K of spectra
taken from the Library of Interferents. The number K may be an
integer such as, for example, 1, 2, 3, 4, 5, 6, 10, 16, or more. In
some embodiments, the subsets comprise all combinations of the M
Library spectra taken K at a time. In these embodiments, the number
of subsets having K spectra is M!/(K!(M-K)!), where ! represents
the factorial function.
[0204] Continuing in block 2230, the obtained measurement data
(e.g., the sample spectrum) and the statistical Sample Population
model (e.g., the mean spectrum and the covariance matrix) are
compared with data for each subset of interferents determined in
block 2225 in order to determine the presence of possible
interferents in the sample (block 2240). In some embodiments, the
statistical test for the presence of an interferent subset in block
2240 comprises determining the concentrations of each subset of
interferences that minimize a statistical measure of "distance"
between a modified spectrum of the material sample and the
statistical model of the Sample Population (e.g., the mean .mu. and
the covariance V). The term "concentration" used in this context
refers to a computed value, and, in some embodiments, that computed
value may not correspond to an actual concentration. The
concentrations may be calculated numerically. In some embodiments,
the concentrations are calculated by algebraically solving a set of
linear equations. The statistical measure of distance may comprise
the well-known Mahalanobis distance (or square of the Mahalanobis
distance) and/or some other suitable statistical distance metric
(e.g., Hotelling's T-square statistic). In certain implementations,
the modified spectrum is given by C'.sub.s(T)=C.sub.s-IFT where
T=(T.sub.1, T.sub.2, . . . T.sub.K).sup.T is a K-dimensional column
vector of interferent concentrations and IF={IF.sub.1, IF.sub.2, .
. . IF.sub.K} represents the K interferent absorption spectra of
the subset. In some embodiments, concentration of the i.sup.th
interferent is assumed to be in a range from a minimum value,
Tmin.sub.i, to a maximum value, Tmax.sub.i. The value of Tmin.sub.i
may be zero, or may be a value between zero and Tmax.sub.i, such as
a fraction of Tmax.sub.i, or may be a negative value. Negative
values represent interferent concentrations that are smaller than
baseline interferent values in the Sample Population.
[0205] In block 2250, a list of a number N.sub.S of possible
interferent subsets .xi. may be identified as the particular
subsets that pass one or more statistical tests (in block 2240) for
being present in the material sample. One or more statistical tests
may be used, alone or in combination, to identify the possible
interferents. For example, if a statistical test indicates that an
i.sup.th interferent is present in a concentration outside the
range Tmin.sub.i to Tmax.sub.i, then this result may be used to
exclude the i.sup.th interferent from the list of possible
interferents. In some embodiments, only the single most probable
interferent subset is included on the list, for example, the subset
having the smallest statistical distance (e.g., Mahalanobis
distance). In an embodiment, the list includes the subsets .xi.
having statistical distances smaller than a threshold value. In
certain embodiments, the list includes a number N.sub.S of subsets
having the smallest statistical distances, e.g., the list comprises
the "best" candidate subsets. The number N.sub.S may be any
suitable integer such as 10, 20, 50, 100, 200, or more. An
advantage of selecting the "best" N.sub.S subsets is reduced
computational burden on the algorithm processor 416. In some
embodiments, the list includes all the Library Interferents. In
certain such embodiments, the list is selected to comprise
combinations of the N.sub.S subsets taken L at a time. For example,
in some embodiments, pairs of subsets are taken (e.g., L=2). An
advantage of selecting pairs of subsets is that pairing captures
the most likely combinations of interferents and the "best"
candidates are included multiple times in the list of possible
interferents. In embodiments in which combinations of L subsets are
selected, the number of combinations of subsets in the list of
possible interferent subsets is N.sub.S!/(L!(N.sub.S-L)!).
[0206] In other embodiments, the list of possible interferent
subsets .xi. is determined using a combination of some or all of
the above criteria. In another embodiment, the list of possible
interferent subsets .xi. includes each of the subsets assembled in
block 2225. Many selection criteria are possible for the list of
possible interferent subsets .xi..
[0207] Returning to FIG. 21, the method 2100 continues in block
2130 where analyte concentration is estimated in the presence of
the possible interferent subsets .xi. determined in block 2250.
FIG. 23 is a flowchart that schematically illustrates an example
embodiment of the acts of block 2130. In block 2310, synthesized
Sample Population measurements are generated to form an Interferent
Enhanced Spectral Database (IESD). In block 2360, the IESD and
known analyte concentrations are used to generate calibration
coefficients for the selected interferent subset. As indicated in
block 2365, blocks 2310 and 2360 may be repeated for each
interferent subset .xi. identified in the list of possible
interferent subsets (e.g., in block 2250 of FIG. 22). In this
example embodiment, when all the interferent subsets .xi. have been
processed, the method continues in block 2370, wherein an average
calibration coefficient is applied to the measured spectra to
determine a set of analyte concentrations.
[0208] In one example embodiment for block 2310, synthesized Sample
Population spectra are generated by adding random concentrations of
each interferent in one of the possible interferent subsets .xi..
These spectra are referred to herein as an Interferent-Enhanced
Spectral Database or IESD. In one example method, the IESD is
formed as follows. A plurality of Randomly-Scaled Single
Interferent Spectra (RSIS) are formed for each interferent in the
interferent subset .xi.. Each RSIS is formed by combinations of the
interferent having spectrum IF multiplied by the maximum
concentration Tmax, which is scaled by a random factor between zero
and one. In certain embodiments, the scaling places the maximum
concentration at the 95.sup.th percentile of a log-normal
distribution in order to generate a wide range of concentrations.
In some embodiments, the log-normal distribution has a standard
deviation equal to half of its mean value.
[0209] In this example method, individual RSIS are then combined
independently and in random combinations to form a large family of
Combination Interferent Spectra (CIS), with each spectrum in the
CIS comprising a random combination of RSIS, selected from the full
set of identified Library Interferents. An advantage of this method
of selecting the CIS is that it produces adequate variability with
respect to each interferent, independently across separate
interferents.
[0210] The CIS and replicates of the Sample Population spectra are
combined to form the IESD. Since the interferent spectra and the
Sample Population spectra may have been obtained from measurements
having different optical pathlengths, the CIS may be scaled to the
same pathlength as the Sample Population spectra. The Sample
Population Database is then replicated R times, where R depends on
factors including the size of the Database and the number of
interferents. The IESD includes R copies of each of the Sample
Population spectra, where one copy is the original Sample
Population Data, and the remaining R-1 copies each have one
randomly chosen CIS spectra added. Accordingly, each of the IESD
spectra has an associated analyte concentration from the Sample
Population spectra used to form the particular IESD spectrum. In
some embodiments, 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. A smaller
replication factor may be used if there is greater spectral variety
among the Library Interferent spectra, and a larger replication
factor may be used if there is a greater number of Library
Interferents.
[0211] After the IESD is generated in block 2310, in block 2360,
the IESD spectra and the known, random concentrations of the subset
interferents are used to generate a calibration coefficient for
estimating the analyte concentration from a sample measurement. The
calibration coefficient is calculated in some embodiments using a
hybrid linear analysis (HLA) technique. In certain embodiments, the
HLA technique uses a reference analyte spectrum to construct a set
of spectra that are free of the desired analyte, projecting the
analyte's spectrum orthogonally away from the space spanned by the
analyte-free calibration spectra, and normalizing the result to
produce a unit response. Further description of embodiments of HLA
techniques may be found in, for example, "Measurement of Analytes
in Human Serum and Whole Blood Samples by Near-Infrared Raman
Spectroscopy," Chapter 4, Andrew J. Berger, Ph. D. thesis,
Massachusetts Institute of Technology, 1998, and "An Enhanced
Algorithm for Linear Multivariate Calibration," by Andrew J.
Berger, et al., Analytical Chemistry, Vol. 70, No. 3, Feb. 1, 1998,
pp. 623-627, the entirety of each of which is hereby incorporated
by reference herein. In other embodiments, the calibration
coefficients may be calculated using other techniques including,
for example, regression techniques such as, for example, ordinary
least squares (OLS), partial least squares (PLS), and/or principal
component analysis.
[0212] In block 2365, the processor 416 determines whether
additional interferent subsets .xi. remain in the list of possible
interferent subsets. If another subset is present in the list, the
acts in blocks 2310-2360 are repeated for the next subset of
interferents using different random concentrations. In some
embodiments, blocks 2310-2360 are performed for only the most
probable subset on the list.
[0213] The calibration coefficient determined in block 2360
corresponds to a single interferent subset .xi. from the list of
possible interferent subsets and is denoted herein as a
single-interferent-subset calibration coefficient
.kappa..sub.avg(.xi.). In this example method, after all subsets
.xi. have been processed, the method continues in block 2370, in
which the single-interferent-subset calibration coefficient is
applied to the measured spectra C.sub.s to determine an estimated,
single-interferent-subset analyte concentration,
g(.xi.)=.kappa..sub.avg(.xi.)C.sub.s, for the interferent subset
.xi.. The set of the estimated, single-interferent-subset analyte
concentrations g(.xi.) for all subsets in the list may be assembled
into an array of single-interferent-subset concentrations. As noted
above, in some embodiments the blocks 2310-2370 are performed once
for the most probable single-interferent-subset on the list (e.g.,
the array of single-interferent analyte concentrations has a single
member).
[0214] Returning to block 2140 of FIG. 21, the array of
single-interferent-subset concentrations, g(.xi.), is combined to
determine an estimated analyte concentration, g.sub.est, for the
material sample. In certain embodiments, a weighting function
p(.xi.) is determined for each of the interferent subsets .xi. on
the list of possible interferent subsets. The weighting functions
may be normalized such that .SIGMA.p(.xi.)=1, where the sum is over
all subsets .xi. that have been processed from the list of possible
interferent subsets. In some embodiments, the weighting functions
can be related to the minimum Mahalanobis distance or an optimal
concentration. In certain embodiments, the weighting function
p(.xi.), for each subset .xi., is selected to be a constant, e.g.,
1/N.sub.S where N.sub.S is the number of subsets processed from the
list of possible interferent subsets. In other embodiments, other
weighting functions p(.xi.) can be selected.
[0215] In certain embodiments, the estimated analyte concentration,
g.sub.est, is determined (in block 2140) by combining the
single-interferent-subset estimates, g(.xi.), and the weighting
functions, p(.xi.), to generate an average analyte concentration.
The average concentration may be computed according to
g.sub.est=.SIGMA. g(.xi.) p(.xi.), where the sum is over the
interferent subsets processed from the list of possible interferent
subsets. In some embodiments, the weighting function p(.xi.) is a
constant value for each subset (e.g., a standard arithmetic average
is used for determining average analyte concentration). By testing
the above described example method on simulated data, it has been
found that the average analyte concentration advantageously has
errors that may be reduced in comparison to other methods (e.g.,
methods using only a single most probable interferent).
[0216] Although the flowchart in FIG. 21 schematically illustrates
an embodiment of the method 2100 performed with reference to the
blocks 2110-2140 described herein, in other embodiments, the method
2100 can be performed differently. For example, some or all of the
blocks 2110-2140 can be combined, performed in a different order
than shown, and/or the functions of particular blocks may be
reallocated to other blocks and/or to different blocks. Embodiments
of the method 2100 may utilize different blocks than are shown in
FIG. 21.
[0217] For example, in some embodiments of the method 2100, the
calibration coefficient is computed without synthesizing spectra
and/or partitioning the data into calibration sets and test sets.
Such embodiments are referred to herein as "Parameter-Free
Interferent Rejection" (PFIR) methods. In one example embodiment
using PFIR, for each of the possible interferent subsets .xi., the
following calculations may be performed to compute an estimate of a
calibration coefficient for each subset .xi.. An average
concentration may be estimated according to g.sub.est=.SIGMA.
g(.xi.) p(.xi.), where the sum is over the interferent subsets
processed from the list of possible interferent subsets.
[0218] An example of an alternative embodiment of block 2130
includes the following steps and calculations.
[0219] Step 1: For a subset's N.sub.IF interferents, form a scaled
interferent spectra matrix. In certain embodiments, the scaled
interferent spectra matrix is the product of an interferent
spectral matrix, IF, multiplied by an interferent concentration
matrix, T.sub.max, and can be written as: IF T.sub.max. In certain
such embodiments, the interferent concentration matrix T.sub.max is
a diagonal matrix having entries given by the maximum plasma
concentrations for the various interferents.
[0220] Step 2: Calculate a covariance for the interferent
component. If X denotes the IESD, the covariance of X, cov(X), is
defined as the expectation E((X-mean(X))(X-mean(X)).sup.T) and
is
cov(X).apprxeq.X X.sup.T/(N-1)-mean(X)mean(X).sup.T.
As described above, the IESD (e.g., X) is obtained as a combination
of Sample Population Spectra, C, with Combination Interferent
Spectra (CIS): X.sub.j=C.sub.j+IF.sub.j.xi..sub.j, therefore the
covariance is:
cov(X).apprxeq.C
C.sup.T/(N-1)+IF.XI..XI..sup.TIF.sup.T/(N-1)-mean(X)mean(X).sup.T,
which can be written as,
cov(X).apprxeq.cov(C)+IF cov(.XI.)IF.sup.T.
If the weights in the weighting matrix .XI. are independent and
identically distributed, the covariance of .XI., cov(.XI.), is a
diagonal matrix having along the diagonal the variance, v, of the
samples in .XI.. The last equation may be written as
cov(X).apprxeq.V.sub.0+v.PHI.,
where V.sub.0 is the covariance of the original sample population
and .PHI. is the covariance of the IF spectral set.
[0221] Step 3: The group's covariance may be at least partially
corrected for the presence of a single replicate of the Sample
Population spectra with the IESD as formed from N.sub.IF replicates
of the Sample Population Spectra with Combined Interferent Spectra.
This partial correction may be achieved by multiplying the second
term in the covariance formula given above by a correction factor
.rho.:
V=V.sub.0+.rho.v.PHI.,
where .rho. is a scalar weighting function that depends on the
number of interferents in the group. In some embodiments, the
scalar weighting function is .rho.=N.sub.IF/(N.sub.IF+1). In
certain embodiments, the variance v of the weights is assumed to be
the variance of a log-normal random variable having a 95th
percentile at a value of 1.0, and a standard deviation equal to
half of the mean value.
[0222] Step 4: The eigenvectors and the corresponding eigenvalues
of the covariance matrix V are determined using any suitable linear
algebraic methods. The number of eigenvectors (and eigenvalues) is
equal to the number of wavelengths L in the spectral measurements.
The eigenvectors may be sorted based on decreasing order of their
corresponding eigenvalues.
[0223] Step 5: The matrix of eigenvectors is decomposed so as to
provide an orthogonal matrix Q. For example, in some embodiments, a
QR-decomposition is performed, thereby yielding the matrix Q having
orthonormal columns and rows.
[0224] Step 6: The following matrix operations are performed on the
orthogonal matrix Q. For n=2 to L-1, the product
P.sup..parallel..sub.n=Q(:,1:n) Q(:,1:n).sup.T is calculated, where
Q(:,1:n) denotes the submatrix comprising the first n columns of
the full matrix Q. The orthogonal projection, P.sup..perp..sub.n,
away from the space spanned by Q(:,1:n) is determined by
subtracting P.sup..parallel..sub.n from the L.times.L identity
matrix I. The n.sup.th calibration vector is then determined from
.kappa..sub.nP.sup..perp..sub.n=.alpha..sub.X/.alpha..sub.X.sup.TP.sup..p-
erp..sub.n.alpha..sub.X, and the n.sup.th error variance E.sub.n is
determined as the projection of the full covariance V onto the
subspace spanned by .kappa..sub.n as follows:
E.sub.n=.kappa..sub.n.sup.T V .kappa..sub.n.
[0225] The steps 4-6 of this example are an embodiment of the HLA
technique.
[0226] In some embodiments, the calibration coefficient .kappa. is
selected as the calibration vector corresponding to the minimum
error variance E.sub.n. Thus, for example, the average group
calibration coefficient .kappa. may be found by searching among all
the error variances for the error variance E.sub.n that has the
minimum value. The calibration coefficient is then selected as the
n.sup.th calibration vector .kappa..sub.n corresponding to the
minimum error variance E.sub.n. In other embodiments, the
calibration coefficient is determined by averaging some or all of
the calibration vectors .kappa..sub.n.
Examples of Algorithm Results and Effects of Sample Population
[0227] Embodiments of the above-described methods have been used to
estimate blood plasma glucose concentrations in humans. Four
example experiments will now be described. The population of
individuals from whom samples were obtained for analysis
(estimation of glucose concentration) will be referred to as the
"target population." Infrared spectra obtained from the target
population will be referred to as the "target spectra." In the four
example experiments, the target population included 41 intensive
care unit (ICU) patients. Fifty-five samples were obtained from the
target population.
Example Experiment 1
[0228] In this example experiment, a partial least squares (PLS)
regression method was applied to the infrared target spectra of the
target patients' blood plasma to obtain the glucose estimates. In
example experiment 1, estimated glucose concentration was not
corrected for effects of interferents. The Sample Population used
for the analysis included infrared spectra and independently
measured glucose concentrations for 92 individuals selected from
the general population. This Sample Population will be referred to
as a "Normal Population."
[0229] FIG. 23A plots predicted versus measured glucose
measurements for 55 measurements taken from 41 intensive care unit
(ICU) patients. PLS regression method was applied to the infrared
spectra of the patients' blood plasma to obtain the glucose
measurements. In the example depicted in FIG. 23A, the Sample
Population measurements include infrared spectra measurements and
independently measured glucose concentrations for 92 individuals
selected from the general population. This Sample Population is
referred to herein, without limitation, as a "Normal Population."
Some embodiments of a method can calculate the calibration
constants that correspond to the infrared spectra of the Normal
Population to obtain the predicted value of the glucose
concentration. The population whose infrared spectra are intended
to be analyzed by the analysis device and whose glucose
concentration is intended to be predicted therefrom will be
referred to herein as a "target population." The infrared spectra
of that target population are referred to herein as the "target
spectra".
[0230] From FIG. 23A it is observed that the estimated glucose
values in the blood plasma of ICU patients do not always correspond
to the measured glucose values. If the estimated glucose values
matched the measured glucose values then all the dots would lie on
the straight line 2380. The estimated or predicted glucose values
have an average prediction error of 126 mg/dl and a standard
deviation of prediction error of 164 mg/dl. Possible reasons for
the high average prediction error and high standard deviation of
prediction error could be a result of using a Sample Population
that includes only the Normal Population and the fact that the
predicted values were not corrected for possible interferents.
Example Experiment 2
[0231] In example experiment 2, an embodiment of the Parameter-Free
Interferent Rejection (PFIR) method was used to estimate glucose
concentration for the same target population of patients in example
experiment 1. To achieve better correlation between the predicted
glucose value and the measured glucose value, a PFIR method can be
applied to infrared spectra of the patient's blood plasma and the
prediction can be corrected for interfering substances (e.g., those
present in a library of interferents). FIG. 23B plots the predicted
versus independently measured glucose values for the same patients
as those of FIG. 23A, except that this time, the predicted glucose
values are obtained using a PFIR method, and the prediction is
corrected for interfering substances. The Sample Population was the
Normal Population. In this example, calibration for Library
Interferents was applied to the measured target spectra. The
Library of Interferents included spectra of the 59 substances
listed below:
TABLE-US-00002 Acetylsalicylic Acid Ampicillin Sulbactam
Azithromycin Aztreonam Bacitracin Benzyl Alcohol Calcium Chloride
Calcium Gluconate Cefazolin Cefoparazone Cefotaxime Sodium
Ceftazidime Ceftriaxone D_Sorbitol Dextran Ertapenem Ethanol
Ethosuximide Glycerol Heparin Hetastarch Human Albumin Hydroxy
Butyric Acid Imipenem Cilastatin Iohexol L_Arginine Lactate Sodium
Magnesium Sulfate Maltose Mannitol Meropenem Oxylate Potassium
Phenytoin Phosphates Potassium Piperacillin Piperacillin Tazobactam
PlasmaLyteA Procaine HCl Propylene Glycol Pyrazinamide Pyruvate
Sodium Pyruvic Acid Salicylate Sodium Sodium Acetate Sodium
Bicarbonate Sodium Chloride Sodium Citrate Sodium Thiosulfate
Sulfadiazine Urea Uric Acid Voriconazole Xylitol Xylose PC 1 of
Saline covariance PC 2 of Saline covariance PC 3 of Saline
covariance PC 4 of Saline covariance ICU/Normal difference
spectrum
[0232] In some embodiments, the calibration data set is determined
according to two criteria: the calibration method itself (e.g.,
HLA, PLS, OLS, PFIR) and the intended application of the method.
The calibration data set may comprise spectra and corresponding
analyte levels derived from a set of plasma samples from the Sample
Population. In some embodiments, e.g., those where an HLA
calibration method is used, the calibration data set may also
include spectra of the analyte of interest.
[0233] From FIG. 23B it is observed that by including the spectral
effects of the interferents in the above table, the predicted
glucose values are closer to the measured glucose values. The
average prediction error in this case is approximately -6.8 mg/dL
and the standard deviation of the prediction error is approximately
23.2 mg/dL. The difference in the average prediction error and the
standard deviation of prediction error between FIG. 23A and FIG.
23B illustrates that the prediction is greatly improved when the
model includes the effects of possible interferents.
[0234] In the example experiments 1 and 2, the Sample Population
was the Normal Population. Thus, samples were drawn from a
population of normal individuals who did not have identifiable
medical conditions that might affect the spectra of their plasma
samples. For example, the sample plasma spectra typically did not
show effects of high levels of medications or other substances
(e.g., ethanol), or effects of chemicals that are indicative of
kidney or liver malfunction. Similarly, in the data presented in
FIGS. 23A and 23B, the Sample Population samples are drawn from a
population of normal individuals. These individuals do not have
identifiable medical conditions that might affect the spectra of
their plasma, for example, the spectra of their plasma may not
exhibit high plasma levels of medications or other substances such
as ethanol, or other chemicals that are indicative of kidney or
liver malfunction.
[0235] In some embodiments, an analysis method may calibrate for
deviations from the distribution defined by the calibration plasma
spectra by identifying a "base" set of interferent spectra likely
to be responsible for the deviation. The analysis method may then
recalibrate with respect to an enhanced spectral data set. In some
embodiments, the enhancement can be achieved by including the
identified interferent spectra into the calibration plasma spectra.
When it is anticipated that the target population may have been
administered significant amounts of substances not present in the
samples of the calibration set, or when the target population have
many distinct interferents, estimation of the interferents present
in the target spectrum may be subject to a large degree of
uncertainty. In some cases, this may cause analyte estimation to be
subject to errors.
[0236] Accordingly, in certain embodiments, the calibration data
set may be enhanced beyond the base of "normal" samples to include
a population of samples intended to be more representative of the
target population. The enhancement of the calibration set may be
generated, in some embodiments, by including samples from a
sufficiently diverse range of individuals in order to represent the
range of likely interferents (both in type and in concentration)
and/or the normal variability in underlying plasma characteristics.
The enhancement may, additionally or alternatively, be generated by
synthesizing interferent spectra having a range of concentrations
as described above (see, e.g., discussion of block 2310 in FIG.
23). Using the enhanced calibration set may reduce the error in
estimating the analyte concentration in the target spectra.
Example Experiments 3 and 4
[0237] Example experiments 3 and 4 use the analysis methods of
example experiments 1 and 2, respectively (PLS without interferent
correction and PFIR with interferent correction). However, example
experiments 3 and 4 use a Sample Population having blood plasma
spectral characteristics different from the Normal Population used
in example experiments 1 and 2. In example experiments 3 and 4, the
Sample Population was modified to include spectra of both the
Normal Population and spectra of an additional population of 55 ICU
patients. These spectra will be referred to as the "Normal+Target
Spectra." In experiments 3 and 4, the ICU patients included
Surgical ICU patients, Medical ICU patients as well as victims of
severe trauma, including a large proportion of patients who had
suffered major blood loss. Major blood loss may necessitate
replacement of the patient's total blood volume multiple times
during a single day and subsequent treatment of the patient via
electrolyte and/or fluid replacement therapies. Major blood loss
may also require administration of plasma-expanding medications.
Major blood loss may lead to significant deviations from the blood
plasma spectra representative of a Normal Population. The
population of 55 ICU patients (who provided the Target Spectra) has
some similarities to the individuals for whom the analyses in
experiments 1-4 were performed (e.g., all were ICU patients), but
in these experiments, target spectra from individuals in the target
population were not included in the Target Spectra.
[0238] FIG. 23C and FIG. 23D illustrate the principles discussed
with respect to Experiments 3 and 4. Specifically, to obtain the
data presented in FIG. 23C, the method used to obtain the data of
FIG. 23A is modified to include spectra of both Normal Population
members and spectra of 55 ICU patients. (The target population, for
such a method, can advantageously comprise ICU patients. For
example, the spectra obtained from a target population of ICU
patients can be similar in many ways to the spectra obtained from
the 55 ICU patients.) This combined set of Spectra is referred to
herein as the "Normal+Target Spectra." In this particular study,
the ICU was a major trauma center, and the ICU patients were all
victims of severe trauma, including a large proportion of patients
who had suffered major blood loss. In such cases, researchers
generally agree that this degree of blood loss--which may
necessitate replacement of the patient's total blood volume
multiple times during a single day and subsequent treatment of the
patient via electrolyte/fluid replacement and the administration of
plasma-expanding medications--can lead to significant spectral
deviations from the blood plasma spectra of a Normal Population. A
comparison of FIG. 23A and FIG. 23C shows that the predicted
glucose values match the measured glucose values to a greater
extent in FIG. 23C than in FIG. 23A. Statistical analysis of the
data presented in FIG. 23C shows that the average prediction error
of the predicted glucose value is approximately 8.2 mg/dl and the
standard deviation of the prediction error is approximately 16.9
mg/dl. It should be noted that in predicting the glucose value in
FIG. 23C, the presence of interferents was not taken into
account.
[0239] The data shown in FIG. 23D, is obtained by modifying the
method used to obtain the data for FIG. 23B (which included
correction for possible interferents) to include spectra of the
"Normal+Target Spectra." A comparison of FIG. 23B and FIG. 23D
shows that the predicted glucose values match the measured glucose
values to a greater extent in FIG. 23D than in FIG. 23B.
Statistical analysis of the data presented in FIG. 23D shows that
in this example, the average prediction error of the predicted
glucose value is approximately 1.32 mg/dl and the standard
deviation of the prediction error is approximately 12.6 mg/dl. It
can be concluded from this example that determining calibration
constants from a population that includes both normal spectra and
spectra derived from individuals similar to those of the target
population, and also correcting for possible interferents, provides
a good match between the estimated value and the measured
value.
[0240] Results of example experiments 1-4 are shown in the
following table. The glucose concentrations estimated from the
analysis method were compared to independently determined glucose
measurements to provide an average prediction error and a standard
deviation of the average prediction error. The table demonstrates
that independent of the Sample Population used (e.g., either the
Normal Population or the Normal+Target Population), calibrating for
interferents reduces both the average prediction error and the
standard deviation (e.g., compare the results for experiment 2 to
the results for experiment 1 and compare the results for experiment
4 to the results for experiment 3). The table further demonstrates
that independent of the analysis method used (e.g., either PLS or
PFIR), using a Sample Population with more similarity to the target
population (e.g., the Normal+Target Population) reduces both the
average prediction error and the standard deviation (e.g., compare
the results for experiment 3 to the results for experiment 1 and
compare the results for experiment 4 to the results for experiment
2).
TABLE-US-00003 Average Example Prediction Standard Experiment
Interferent Sample Error Deviation No. Calibration Population
(mg/dL) (mg/dL) 1 NO Normal 126 164 2 YES Normal -6.8 23.2 3 NO
Normal + Target 8.2 16.9 4 YES Normal + Target 1.32 12.6
[0241] Accordingly, embodiments of analysis methods that use a
Sample Population that includes both normal spectra and spectra
from individuals similar to those of the target population and that
calibrate for possible interferents provide a good match between
the estimated glucose concentration and the measured glucose
concentration. As discussed above, a suitable Sample Population may
be assembled from the Population Database in order to include
normal spectra plus suitable target spectra from individuals that
match a desired target population including, for example, ICU
patients, trauma patients, a particular demographic group, a group
having a common medical condition (e.g., diabetes), and so
forth.
User Interface
[0242] The system 400 can include a display system 414, for
example, as depicted in FIG. 4. The display system 414 may comprise
an input device including, for example, a keypad or a keyboard, a
mouse, a touchscreen display, and/or any other suitable device for
inputting commands and/or information. The display system 414 may
also include an output device including, for example, an LCD
monitor, a CRT monitor, a touchscreen display, a printer, and/or
any other suitable device for outputting text, graphics, images,
videos, etc. In some embodiments, a touchscreen display is
advantageously used for both input and output.
[0243] The display system 414 can include a user interface 2400 by
which users can conveniently and efficiently interact with the
system 400. The user interface 2400 may be displayed on the output
device of the system 400 (e.g., the touchscreen display). In some
embodiments, the user interface 2400 is implemented and/or stored
as one or more code modules, which may be embodied in hardware,
firmware, and/or software.
[0244] FIGS. 24 and 25 schematically illustrate the visual
appearance of embodiments of the user interface 2400. The user
interface 2400 may show patient identification information 2402,
which can include patient name and/or a patient ID number. The user
interface 2400 also can include the current date and time 2404. An
operating graphic 2406 shows the operating status of the system
400. For example, as shown in FIGS. 24 and 25, the operating status
is "Running," which indicates that the system 400 is fluidly
connected to the patient ("Jill Doe") and performing normal system
functions such as infusing fluid and/or drawing blood. The user
interface 2400 can include one or more analyte concentration
graphics 2408, 2412, which may show the name of the analyte and its
last measured concentration. For example, the graphic 2408 in FIG.
24 shows "Glucose" concentration of 150 mg/dL, while the graphic
2412 shows "Lactate" concentration of 0.5 mmol/L. The particular
analytes displayed and their measurement units (e.g., mg/dL,
mmol/L, or other suitable unit) may be selected by the user. The
size of the graphics 2408, 2412 may be selected to be easily
readable out to a distance such as, e.g., 30 feet. The user
interface 2400 may also include a next-reading graphic 2410 that
indicates the time until the next analyte measurement is to be
taken. In FIG. 24, the time until next reading is 3 minutes,
whereas in FIG. 25, the time is 6 minutes, 13 seconds.
[0245] The user interface 2400 can include an analyte concentration
status graphic 2414 that indicates status of the patient's current
analyte concentration compared with a reference standard. For
example, the analyte may be glucose, and the reference standard may
be a hospital ICU's tight glycemic control (TGC). In FIG. 24, the
status graphic 2414 displays "High Glucose," because the glucose
concentration (150 mg/dL) exceeds the maximum value of the
reference standard. In FIG. 25, the status graphic 2414 displays
"Low Glucose," because the current glucose concentration (79 mg/dL)
is below the minimum reference standard. If the analyte
concentration is within bounds of the reference standard, the
status graphic 2414 may indicate normal (e.g., "Normal Glucose"),
or it may not be displayed at all. The status graphic 2414 may have
a background color (e.g., red) when the analyte concentration
exceeds the acceptable bounds of the reference standard.
[0246] The user interface 2400 can include one or more trend
indicators 2416 that provide a graphic indicating the time history
of the concentration of an analyte of interest. In FIGS. 24 and 25,
the trend indicator 2416 comprises a graph of the glucose
concentration (in mg/dL) versus elapsed time (in hours) since the
measurements started. The graph includes a trend line 2418
indicating the time-dependent glucose concentration. In other
embodiments, the trend line 2418 can include measurement error bars
and may be displayed as a series of individual data points. In FIG.
25, the glucose trend indicator 2416 is shown as well as a trend
indicator 2430 and trend line 2432 for the lactate concentration.
In some embodiments, a user may select whether none, one, or both
trend indicators 2416, 2418 are displayed. In some embodiments, one
or both of the trend indicators 2416, 2418 may appear only when the
corresponding analyte is in a range of interest such as, for
example, above or below the bounds of a reference standard.
[0247] The user interface 2400 can include one or more buttons
2420-2426 that can be actuated by a user to provide additional
functionality or to bring up suitable context-sensitive menus
and/or screens. For example, in the embodiments shown in FIG. 24
and FIG. 25, four buttons 2420-2426 are shown, although fewer or
more buttons are used in other embodiments. The button 2420 ("End
Monitoring") may be pressed when one or more removable portions
(see, e.g., 710 of FIG. 7) are to be removed. In many embodiments,
because the removable portions 710, 712 are not reusable, a
confirmation window appears when the button 2420 is pressed. If the
user is certain that monitoring should stop, the user can confirm
this by actuating an affirmative button in the confirmation window.
If the button 2420 were pushed by mistake, the user can select a
negative button in the confirmation window. If "End Monitoring" is
confirmed, the system 400 performs appropriate actions to cease
fluid infusion and blood draw and to permit ejection of a removable
portion (e.g., the removable portion 710).
[0248] The button 2422 ("Pause") may be actuated by the user if
patient monitoring is to be interrupted but is not intended to end.
For example, the "Pause" button 2422 may be actuated if the patient
is to be temporarily disconnected from the system 400 (e.g., by
disconnecting the tubes 306). After the patient is reconnected, the
button 2422 may be pressed again to resume monitoring. In some
embodiments, after the "Pause" button 2422 has been pressed, the
button 2422 displays "Resume."
[0249] The button 2424 ("Delay 5 Minutes") causes the system 400 to
delay the next measurement by a delay time period (e.g., 5 minutes
in the depicted embodiments). Actuating the delay button 2424 may
be advantageous if taking a reading would be temporarily
inconvenient, for example, because a health care professional is
attending to other needs of the patient. The delay button 2424 may
be pressed repeatedly to provide longer delays. In some
embodiments, pressing the delay button 2424 is ineffective if the
accumulated delay exceeds a maximum threshold. The next-reading
graphic 2410 automatically increases the displayed time until the
next reading for every actuation of the delay button 2424 (up to
the maximum delay).
[0250] The button 2426 ("Dose History") may be actuated to bring up
a dosing history window that displays patient dosing history for an
analyte or medicament of interest. For example, in some
embodiments, the dosing history window displays insulin dosing
history of the patient and/or appropriate hospital dosing
protocols. A nurse attending the patient can actuate the dosing
history button 2426 to determine the time when the patient last
received an insulin dose, the last dose amount, and/or the time and
amount of the next dose. The system 400 may receive the patient
dosing history via wired or wireless communications from a hospital
information system.
[0251] In other embodiments, the user interface 2400 can include
additional and/or different buttons, menus, screens, graphics, etc.
that are used to implement additional and/or different
functionalities.
[0252] Related Components
[0253] FIG. 26 schematically depicts various components and/or
aspects of a patient monitoring system 2630 and how those
components and/or aspects relate to each other. In some
embodiments, the monitoring system 2630 can be the apparatus 100
for withdrawing and analyzing fluid samples. Some of the depicted
components can be included in a kit containing a plurality of
components. Some of the depicted components, including, for
example, the components represented within the dashed rounded
rectangle 2640 of FIG. 26, are optional and/or can be sold
separately from other components.
[0254] The patient monitoring system 2630 shown in FIG. 26 includes
a monitoring apparatus 2632. The monitoring apparatus 2632 can be
the monitoring device 102, shown in FIG. 1 and/or the system 400 of
FIG. 4. The monitoring apparatus 2632 can provide monitoring of
physiological parameters of a patient. In some embodiments, the
monitoring apparatus 2632 measures glucose and/or lactate
concentrations in the patient's blood. In some embodiments, the
measurement of such physiological parameters is substantially
continuous. The monitoring apparatus 2632 may also measure other
physiological parameters of the patient. In some embodiments, the
monitoring apparatus 2632 is used in an intensive care unit (ICU)
environment. In some embodiments, one monitoring apparatus 2632 is
allocated to each patient room in an ICU.
[0255] The patient monitoring system 2630 can include an optional
interface cable 2642. In some embodiments, the interface cable 2642
connects the monitoring apparatus 2632 to a patient monitor (not
shown). The interface cable 2642 can be used to transfer data from
the monitoring apparatus 2632 to the patient monitor for display.
In some embodiments, the patient monitor is a bedside cardiac
monitor having a display that is located in the patient room (see,
e.g., the user interface 2400 shown in FIG. 24 and FIG. 25.) In
some embodiments, the interface cable 2642 transfers data from the
monitoring apparatus 2632 to a central station monitor and/or to a
hospital information system (HIS). The ability to transfer data to
a central station monitor and/or to a HIS may depend on the
capabilities of the patient monitor system.
[0256] In the embodiment shown in FIG. 26, an optional bar code
scanner 2644 is connected to the monitoring apparatus 2632. In some
embodiments, the bar code scanner 2644 is used to enter patient
identification codes, nurse identification codes, and/or other
identifiers into the monitoring apparatus 2632. In some
embodiments, the bar code scanner 2644 contains no moving parts.
The bar code scanner 2644 can be operated by manually sweeping the
scanner 2644 across a printed bar code or by any other suitable
means. In some embodiments, the bar code scanner 2644 includes an
elongated housing in the shape of a wand.
[0257] The patient monitoring system 2630 includes a fluid system
kit 2634 connected to the monitoring apparatus 2632. In some
embodiments, the fluid system kit 2634 includes fluidic tubes that
connect a fluid source to an analytic subsystem. For example, the
fluidic tubes can facilitate fluid communication between a blood
source or a saline source and an assembly including a sample holder
and/or a centrifuge. In some embodiments, the fluid system kit 2634
includes many of the components that enable operation of the
monitoring apparatus 2632. In some embodiments, the fluid system
kit 2634 can be used with anti-clotting agents (such as heparin),
saline, a saline infusion set, a patient catheter, a port sharing
IV infusion pump, and/or an infusion set for an IV infusion pump,
any or all of which may be made by a variety of manufacturers. In
some embodiments, the fluid system kit 2634 includes a monolithic
housing that is sterile and disposable. In some embodiments, at
least a portion of the fluid system kit 2634 is designed for single
patient use. For example, the fluid system kit 2634 can be
constructed such that it can be economically discarded and replaced
with a new fluid system kit 2634 for every new patient to which the
patient monitoring system 2630 is connected. In addition, at least
a portion of the fluid system kit 2634 can be designed to be
discarded after a certain period of use, such as a day, several
days, several hours, three days, a combination of hours and days
such as, for example, three days and two hours, or some other
period of time. Limiting the period of use of the fluid system kit
2634 may decrease the risk of malfunction, infection, or other
conditions that can result from use of a medical apparatus for an
extended period of time.
[0258] In some embodiments, the fluid system kit 2634 includes a
connector with a luer fitting for connection to a saline source.
The connector may be, for example, a three-inch pigtail connector.
In some embodiments, the fluid system kit 2634 can be used with a
variety of spikes and/or IV sets used to connect to a saline bag.
In some embodiments, the fluid system kit 2634 also includes a
three-inch pigtail connector with a luer fitting for connection to
one or more IV pumps. In some embodiments, the fluid system kit
2634 can be used with one or more IV sets made by a variety of
manufacturers, including IV sets obtained by a user of the fluid
system kit 2634 for use with an infusion pump. In some embodiments,
the fluid system kit 2634 includes a tube with a low dead volume
luer connector for attachment to a patient vascular access point.
For example, the tube can be approximately seven feet in length and
can be configured to connect to a proximal port of a cardiovascular
catheter. In some embodiments, the fluid system kit 2634 can be
used with a variety of cardiovascular catheters, which can be
supplied, for example, by a user of the fluid system kit 2634.
[0259] As shown in FIG. 26, the monitoring apparatus 2632 is
connected to a support apparatus 2636, such as an IV pole. The
support apparatus 2636 can be customized for use with the
monitoring apparatus 2632. A vendor of the monitoring apparatus
2632 may choose to bundle the monitoring apparatus 2632 with a
custom support apparatus 2636. In some embodiments, the support
apparatus 2636 includes a mounting platform for the monitoring
apparatus 2632. The mounting platform can include mounts that are
adapted to engage threaded inserts in the monitoring apparatus
2632. The support apparatus 2636 can also include one or more
cylindrical sections having a diameter of a standard IV pole, for
example, so that other medical devices, such as IV pumps, can be
mounted to the support apparatus. The support apparatus 2636 can
also include a clamp adapted to secure the apparatus to a hospital
bed, an ICU bed, or another variety of patient conveyance
device.
[0260] In the embodiment shown in FIG. 26, the monitoring apparatus
2632 is electrically connected to an optional computer system 2646.
The computer system 2646 can comprise one or multiple computers,
and it can be used to communicate with one or more monitoring
devices. In an ICU environment, the computer system 2646 can be
connected to at least some of the monitoring devices in the ICU.
The computer system 2646 can be used to control configurations and
settings for multiple monitoring devices (for example, the system
can be used to keep configurations and settings of a group of
monitoring devices common). The computer system 2646 can also run
optional software, such as data analysis software 2648, HIS
interface software 2650, and insulin dosing software 2652.
[0261] In some embodiments, the computer system 2646 runs optional
data analysis software 2648 that organizes and presents information
obtained from one or more monitoring devices. In some embodiments,
the data analysis software 2648 collects and analyzes data from the
monitoring devices in an ICU. The data analysis software 2648 can
also present charts, graphs, and statistics to a user of the
computer system 2646.
[0262] In some embodiments, the computer system 2646 runs optional
hospital information system (HIS) interface software 2650 that
provides an interface point between one or more monitoring devices
and an HIS. The HIS interface software 2650 may also be capable of
communicating data between one or more monitoring devices and a
laboratory information system (LIS).
[0263] In some embodiments, the computer system 2646 runs optional
insulin dosing software 2652 that provides a platform for
implementation of an insulin dosing regimen. In some embodiments,
the hospital tight glycemic control protocol is included in the
software. The protocol allows computation of proper insulin doses
for a patient connected to a monitoring device 2646. The insulin
dosing software 2652 can communicate with the monitoring device
2646 to ensure (or at least improve the likelihood) that proper
insulin doses are calculated. For example, the insulin dosing
software 2652 can communicate with the computer system 2646 to
perform the dosing calculations. The user interface 2400 can be
used to communicate relevant information such as, for example, rate
of dose and/or infusion, type of dose and/or infusion (e.g., bolus
injection, basal infusion, steady state dose, treatment dose,
etc.), to a health care practitioner so that the infusion rate and
type of dose can be provided to the patient. The insulin dosing
software 2652 and user interface can be implemented with the
monitoring system 102 (FIG. 1), the system 400 (FIG. 4), or any
other suitable patient monitoring system.
Analyte Control and Monitoring
[0264] In some embodiments, it can be advantageous to control a
level of an analyte (e.g., glucose) in a patient using an
embodiment of an analyte detection system described herein.
Although certain examples of glucose control are described below,
embodiments of the systems and methods disclosed herein can be used
to monitor and/or control other analytes (e.g., lactate).
[0265] For example, diabetic individuals control their glucose
levels by administration of insulin. If a diabetic patient is
admitted to a hospital or ICU, the patient may be in a condition in
which he or she cannot self-administer insulin. Advantageously,
embodiments of the analyte detection systems disclosed herein can
be used to control the level of glucose in the patient.
Additionally, it has been found that a majority of patients
admitted to the ICU exhibit hyperglycemia without having diabetes.
In such patients it may be beneficial to monitor and control their
blood glucose level to be within a particular range of values.
Further, it has been shown that tightly controlling blood glucose
levels to be within a stringent range may be beneficial to patients
undergoing surgical procedures.
[0266] A patient admitted to the ICU or undergoing surgery can be
administered a variety of drugs and fluids such as Hetastarch,
intravenous antibiotics, intravenous glucose, intravenous insulin,
intravenous fluids such as saline, etc., which may act as
interferents and make it difficult to determine the blood glucose
level. Moreover, the presence of additional drugs and fluids in the
blood stream may require different methods for measuring and
controlling blood glucose level. Also, the patient may exhibit
significant changes in hematocrit levels due to blood loss or
internal hemorrhage, and there can be unexpected changes in the
blood gas level or a rise in the level of bilirubin and ammonia
levels in the event of an organ failure. Embodiments of the systems
and methods disclosed herein advantageously can be used to monitor
and control blood glucose (and/or other analytes) in the presence
of possible interferents to estimation of glucose and for patients
experiencing health problems.
[0267] In some environments, Tight Glycemic Control (TGC) can
include: (1) substantially continuous monitoring (which can include
periodic monitoring, at relatively frequent intervals of every 15,
30, 45, and/or 60 minutes, for example) of glucose levels; (2)
determination of substances that tend to increase glucose levels
(e.g., sugars such as dextrose) and/or decrease glucose levels
(e.g., insulin); and/or (3) responsive delivery of one or more of
such substances, if appropriate under the controlling TGC protocol.
For example, one possible TGC protocol can be achieved by
controlling glucose within a relatively narrow range (for example
between 70 mg/dL to 110 mg/dL). As will be further described, in
some embodiments, TGC can be achieved by using an analyte
monitoring system to make continuous and/or periodic but frequent
measurements of glucose levels.
[0268] In some embodiments, the analyte detection system
schematically illustrated in FIGS. 4, 5, and 6 can be used to
regulate the concentration of one or more analytes in the sample in
addition to determining and monitoring the concentration of the one
or more analytes. In some cases, the analyte detection system can
be used in an ICU to monitor (and/or control) analytes that may be
present in patients experiencing trauma. In some implementations,
the concentration of the analytes is regulated to be within a
certain range. The range can be predetermined (e.g., according to a
hospital protocol or a physician's recommendation), or the range
can be adjusted as conditions change.
[0269] In an example of glycemic control, a system can be used to
determine and monitor the concentration of glucose in the sample.
If the concentration of glucose falls below a lower threshold,
glucose from an external source can be supplied and/or delivery of
insulin can be scaled back or halted altogether. If the
concentration of glucose exceeds an upper threshold, insulin from
an external source can be supplied and/or delivery of glucose can
be scaled back or halted altogether. A treatment dose of glucose
and/or insulin can be infused into a patient continuously over a
certain time interval or can be injected in a relatively large
quantity at once (referred to as "bolus injection"). Moreover, a
steady-state or baseline (as opposed to a treatment) can be
achieved as glucose and/or insulin can be infused into a patient
relatively continuously at a low delivery rate (referred to as
"basal infusion") to maintain the concentration of one or more
analytes within a predetermined range. For example, in some cases a
basal infusion can comprise a series of discrete doses designed to
maintain a concentration of one or more analytes in a patient
(e.g., concentration of glucose in a patient's blood stream). Such
a serial infusion of discrete packets or doses can be referred to
as "pulsatile" infusion. In some cases, instead of a series of
discrete doses, a steady stream of infusion substance can be
provided. The automatic and/or recommended basal infusion rate of
glucose or insulin can be determined on the basis of one or more
factors. For example, body weight, medical condition, medical
history, presence or absence of other drugs and chemicals in the
patient, etc. can all be factors that contribute to such a
determination. Without contradicting the use of the term "basal"
set forth above, the "basal infusion rate" can also refer to the
rate of insulin needed to cover the "basal" metabolic functions
(e.g. breathing, maintaining heart rate and other metabolic
processes).
[0270] Various dosing protocols can be used to determine a dose of
a treatment substance (e.g., a drug, glucose, dextrose, insulin,
etc.). For example, in some embodiments, the dosing protocol used
by personnel at a hospital is integrated into the glucose
monitoring system to automatically determine the delivery rate of
the treatment drug. In some embodiments, the system and method for
recommending insulin bolus quantities to an insulin user disclosed
in U.S. Pat. No. 7,291,107 B2 titled "INSULIN BOLUS RECOMMENDATION
SYSTEM", by Hellwig et. al. can be used with the above described
glucose monitoring system to determine the bolus dose of insulin to
be delivered to the patient in the event of hyperglycemia or
hypoglycemia. The entire content of U.S. Pat. No. 7,291,107 B2 is
hereby incorporated by reference herein and is made a part of this
specification.
[0271] In some embodiments, a hospital dosing protocol can be
integrated into a glucose monitoring and control system. For
example, the protocol instructions for a nurse can be accomplished
automatically by the system rather than by the nurse. In some
embodiments, a hospital or other health care provider can use its
own protocol and program a monitoring system to incorporate the
specific protocol. The procedure outline and corresponding tables
below are an example of such a dosing protocol (the example
provided can be referred to as the "Atlanta Protocol" and related
information publically available at the following web address:
"http://www.gha.org/pha/health/diabetes/Toolkit/guidelines/IVins80110/80--
110chart_col1-16.pdf"). The following protocol can also be modified
and incorporated into a monitoring system:
TABLE-US-00004 START infusion using the drip rate (ml/hr) shown in
Column 2 for the current Blood Glucose Range. To determine the new
drip rate for each hourly measurement, compare the latest BG Range
to the previous BG Range If latest BG Range has decreased: Stay in
the same column If latest BG Range has not changed or increased:
Move 1 column to the right When hourly BG 80-110, stay in the same
column to determine the new drip rate. (Do Not Change Columns) When
BG <80, move one column to the left and treat for hypoglycemia
Blood 2 Glucose 1 (ml/hr) 3 4 5 6 7 8 9 10 Ranges (ml/hr) START
(ml/hr) (ml/hr) (ml/hr) (ml/hr) (ml/hr) (ml/hr) (ml/hr) (ml/hr)
>450 4.4 8.8 13.2 17.6 22.0 26.4 30.8 35.2 39.6 44.0 385-450 3.6
7.2 10.8 14.4 18.0 21.6 25.2 28.8 32.4 36.0 326-384 3.0 6.0 9.0
12.0 15.0 18.0 21.0 24.0 27.0 30.0 290-333 2.5 5.0 7.5 10.0 12.5
15.0 17.5 20.0 22.5 25.0 251-289 2.1 4.2 6.3 8.4 10.5 12.6 14.7
16.8 18.9 21.0 217-250 1.7 3.4 5.1 7.2 8.5 10.2 11.9 13.6 15.3 17.0
188-216 1.4 2.8 4.2 5.6 7.0 8.4 9.8 11.2 12.6 14.0 163-187 1.2 2.4
3.6 4.8 6.0 7.2 8.4 9.6 10.8 12.0 141-162 1.0 2.0 3.0 4.0 5.0 6.0
7.0 8.0 9.0 10.0 119-140 0.8 1.6 2.4 3.2 4.0 4.8 5.6 6.4 7.2 8.0
111-120 0.6 1.2 1.8 2.4 3.0 3.6 4.2 4.8 5.4 6.0 106-110 0.5 1.0 1.5
2.0 2.5 3.0 3.5 4.0 4.5 5.0 101-105 0.4 0.9 1.3 1.8 2.2 2.7 3.1 3.6
4.0 4.5 96-100 0.4 0.8 1.2 1.6 2.0 2.4 2.8 3.2 3.6 4.0 91-95 0.3
0.7 1.0 1.4 1.7 2.1 2.4 2.8 3.2 3.5 86-90 0.3 0.6 0.9 1.2 1.5 1.8
2.1 2.4 2.7 3.0 80-85 0.2 0.5 0.7 1.0 1.2 1.5 1.7 2.0 2.3 2.5 75-79
0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 70-74 0.1 0.3 0.4 0.6 0.7
0.9 1.0 1.2 1.3 1.5 60-70 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0
<60 0 0 0 0 0 0 0 0 0 0 BG D50W ACTION 70-79 10.0 ml IV push
Move 1 column to the left 60-69 15.0 ml IV push Recheck BG in 15
minutes Repeat as necessary 50-59 20.0 ml IV push Move 1 column to
the left 30-49 25.0 ml IV push Recheck BG in 15 minutes <30 30.0
ml IV push Repeat as necessary Contact Physician if BG <60 for 2
consecutive BG measurements Notify Physician If: BG is less <60
for 2 consecutive BG measurements BG reverts to >200 for 2
consecutive BG measurements Insulin requirement exceeds 24
units/hour If the K+ level drops to <4 If drip rate (ml/hr) is
0.5 or less If continuous enteral feeding, TPN, or IV insulin
infusion is stopped or interrupted
[0272] In some embodiments, a glycemic control system is capable of
delivering glucose, dextrose, glycogen, and/or glucagon from an
external source relatively quickly in the event of hypoglycemia. As
discussed herein, embodiments of the glycemic control system are
capable of delivering insulin from an external source relatively
quickly in the event of hyperglycemia.
[0273] Returning to FIGS. 5 and 6, these figures schematically
illustrate embodiments of a fluid handling system that comprise
optional analyte control subsystems 2780. The analyte control
subsystem 2780 can be used for providing control of an analyte such
as, e.g., glucose, and may provide delivery of the analyte and/or
related substances (e.g., dextrose solution and/or insulin in the
case of glucose). The analyte control subsystem 2780 comprises a
source 2782 such as, for example, the analyte (or a suitable
compound related to the analyte) dissolved in water or saline. For
example, if the analyte is glucose, the source 2782 may comprise a
bag of dextrose solution (e.g., Dextrose or Dextrose 50%). The
source 2782 can be coupled to an infusion pump (not shown). The
source 2782 and the infusion pump can be provided separately from
the analyte control subsystem 2780. For example, a hospital
advantageously can use existing dextrose bags and infusion pumps
with the subsystem 2780.
[0274] As schematically illustrated in FIGS. 5 and 6, the source
2782 is in fluid communication with the patient tube 512 via a tube
2784 and suitable connectors. A pinch valve 2786 can be disposed
adjacent the tube 2784 to regulate the flow of fluid from the
source 2782. A patient injection port can be located at a short
distance from the proximal port of the central venous catheter or
some other catheter connected to the patient.
[0275] In an example implementation for glycemic control, if the
analyte detection system determines that the level of glucose has
fallen below a lower threshold value (e.g., the patient is
hypoglycemic), a control system (e.g., the fluid system controller
405 in some embodiments) controlling an infusion delivery system
may close the pinch valves 521 and/or 542 to prevent infusion of
insulin and/or saline into the patient. The control system may open
the pinch valve 2786 and dextrose solution from the source 2782 can
be infused (or alternatively injected as a bolus) into the patient.
After a suitable amount of dextrose solution has been infused to
the patient, the pinch valve 2786 can be closed, and the pinch
valves 521 and/or 542 can be opened to allow flow of insulin and/or
saline. In some systems, the amount of dextrose solution to be
delivered as a basal infusion or as a bolus injection can be
calculated based on one or more detected concentration levels of
glucose. The source 2782 advantageously can be located at a short
enough fluidic distance from the patient such that dextrose can be
delivered to the patient within a time period of about one to about
ten minutes of receiving an instruction (e.g. from a control system
or a health care provider). In other embodiments, the source 2782
can be located at the site where the patient tube 512 interfaces
with the patient so that dextrose can be delivered within about one
minute of receiving an instruction (e.g. from a control system or a
health care provider).
[0276] If the analyte detection system determines that the level of
glucose has increased above an upper threshold value (e.g., the
patient is hyperglycemic), the control system may close the pinch
valves 542 and/or 2786 to prevent infusion of saline and/or
dextrose into the patient. The control system may open the pinch
valve 521, and insulin can be infused at a basal infusion rate
(and/or injected as a bolus) into the patient. After a suitable
amount of insulin has been infused (or bolus injected) to the
patient, the control system can close the pinch valve 521 and open
the pinch valves 542 and/or 2786 to allow flow of saline and/or
glucose. The suitable amount of insulin can be calculated based on
one or more detected concentration levels of glucose in the
patient. In some embodiments, the insulin source can be connected
to the infusion pump 518 which advantageously can be located at a
short enough fluidic distance from the patient such that insulin
can be delivered to the patient rapidly, e.g., within about one to
about ten minutes. In some embodiments, the insulin source can be
located at the site where the patient tube 512 interfaces with the
patient so that insulin can be delivered to the patient rapidly,
e.g., within about one minute.
[0277] In some embodiments, sampling bodily fluid from a patient
and providing medication to the patient can be achieved through the
same lines of the fluid handling system. For example, in some
embodiments, a port to a patient can be shared by alternately
drawing samples and medicating through the same line. In some
embodiments, insulin can be provided to the patient at regular
intervals (in the same or different lines). For example, insulin
can be provided to a patient after meals. In some embodiments, the
medication can be delivered to the patient continuously at a basal
infusion rate combined with intermittent bolus injections (e.g.
after meals). In some embodiments, the medication can be delivered
through a fluid passageway connected to the patient (e.g. patient
tube 512 of FIG. 5). Intermittent injections can be provided to the
patient by the same fluid passageway (e.g. patient tube 512 of FIG.
5). In some embodiments, a separate delivery system comprising a
delivery pump can be used to provide the medication. In some
embodiments comprising a shared line, medication can be delivered
when returning part of a body fluid sample back to the patient. In
some implementations, medication is delivered midway between
samples (e.g., every 7.5 minutes if samples are drawn every 15
minutes). In some embodiments, a dual lumen tube can be used,
wherein one lumen is used for the sample and the other lumen to
medicate. In some embodiments, an analyte detection system (e.g.,
an "OptiScanner.RTM." monitor) may provide suitable commands to a
separate insulin pump (on a shared port or different line) to
provide the recommended dose of insulin.
[0278] Example Method for Glycemic Control
[0279] FIG. 27 is a flowchart that schematically illustrates an
example embodiment of a method 2700 of providing analyte control.
The example embodiment is directed toward one possible
implementation for glycemic control (including but not limited to
tight glycemic control) and is intended to illustrate certain
aspects of the method 2700 and is not intended to limit the scope
of possible analyte control methods. In block 2705, a glucose
monitoring apparatus (e.g., the monitoring apparatus 2632 of FIG.
26) draws a sample (e.g., a blood or blood plasma sample) from a
sample source (e.g., a patient) and obtains a measurement from the
sample (e.g., a portion of the drawn sample). The measurement may
comprise an optical measurement such as, for example, an infrared
spectrum of the sample. In block 2710, the measurement sample is
analyzed to identify possible interferents to an estimation of the
glucose concentration in the measurement sample. In block 2715, a
model is generated for estimating the glucose concentration from
the obtained measurement. In some embodiments, models developed
from the algorithms describe above with reference to FIGS. 21-23
are used. The generated model may reduce or minimize effects of the
identified interferents on the estimated glucose concentration, in
certain embodiments. In block 2720, an estimated glucose
concentration is determined from the model and the obtained
measurement. In block 2725, the estimated glucose concentration in
the sample is compared to an acceptable range of concentrations.
The acceptable range can be determined according to a suitable
glycemic control protocol such as, for example, a TGC protocol. For
example, in certain TGC protocols the acceptable range can be a
glucose concentration in a range from about 70 mg/dL to about 110
mg/dL. If the estimated glucose concentration lies within the
acceptable range, the method 2700 returns to block 2705 to obtain
the next sample measurement, which can be made after a relatively
short or a relatively long time period has elapsed since the last
measurement. For example, the next measurement can be taken within
about one minute. In another example, the succeeding measurement
can be taken after about one hour. In other examples, measurements
are taken every fifteen minutes or less, every thirty minutes or
less, ever forty-five minutes or less, etc. In some embodiments, a
treatment substance (e.g. insulin or glucose) or drug can be
continuously infused through the patient even if the estimated
glucose concentration is already within the predetermined range.
This can be advantageous when it is determined, for example, that
without such a basal injection, the glucose concentration may drift
outside the range, or when it is predicted that the glucose
concentration would preferably be within another range.
[0280] In block 2725, if the estimated glucose concentration is
outside the acceptable range of concentrations, then the method
2700 proceeds to block 2740 in which the estimated glucose
concentration is compared with a desired glucose concentration. The
desired glucose concentration can be based on, for example, the
acceptable range of glucose concentrations, the parameters of the
particular glycemic protocol, the patient's estimated glucose
concentration, and so forth. If the estimated glucose concentration
is below the desired concentration (e.g., the patient is
hypoglycemic), a dose of dextrose to be delivered to the patient is
calculated in block 2745. In some embodiments, this dose of
dextrose can be delivered in addition to a low dose of the
treatment substance (e.g. a drug, insulin, glucose, etc.) being
delivered to the patient continuously at a steady rate. The
calculation of the dose of dextrose may take into account various
factors including, for example, one or more estimated glucose
concentrations, presence of additional drugs in the patient's
system, time taken for dextrose to be assimilated by the patient,
and the delivery method (e.g., continuous infusion or bolus
injection). In block 2750, a fluid delivery system (e.g., a system
such as the optional subsystem 2780 shown in FIGS. 5 and 6)
delivers the calculated dose of dextrose to the patient.
[0281] In block 2740, if the estimated glucose concentration is
greater than the desired concentration (e.g., the patient is
hyperglycemic), a dose of insulin to be delivered is calculated in
block 2755. In some embodiments, this dose of insulin can be
delivered in addition to a low dose of the treatment substance
(e.g. a drug, insulin, glucose, etc.) being delivered to the
patient continuously at a steady rate. The calculation of the dose
of insulin may depend on various factors including, for example,
one or more estimated glucose concentrations in the patient,
presence of other drugs, type of insulin used, time taken for
insulin to be assimilated by the patient, method of delivery (e.g.,
continuous infusion or bolus injection), etc. In block 2750, a
fluid delivery system (e.g., the optional subsystem 2780 shown in
FIGS. 5 and 6) delivers the calculated dose of insulin to the
patient.
[0282] In block 2765, the method 2700 returns to block 2705 to
await the start of the next measurement cycle, which can be within
about one minute to about one hour (e.g., every fifteen minutes or
less, every 30 minutes or less, every 45 minutes or less, etc.). In
some embodiments, the next measurement cycle begins at a different
time than normally scheduled in cases in which the estimated
glucose concentration lies outside the acceptable range of
concentrations under the glycemic protocol. Such embodiments
advantageously allow the system to monitor response of the patient
to the delivered dose of dextrose (or insulin). In some such
embodiments, the time between measurement cycles is reduced so the
system can more accurately monitor analyte levels in the
patient.
[0283] Examples of Some Possible Additional or Alternative
Analytes
[0284] Although examples of control and/or monitoring has been
described in the illustrative context of glycemic control,
embodiments of the systems and methods can be configured for
control and/or monitoring of one or more of many possible analytes,
in addition to or instead of glucose. Monitor and/or control of
analytes can be particularly helpful in ICUs, which receive trauma
patients. For example, another parameter that can be monitored is
level of Hemoglobin (Hb). If the Hb level of a patient goes down
without an apparent external reason, the patient could be suffering
from internal bleeding. Indeed, many ICU patients (some estimate as
many as 10%) suffer from what appears to be spontaneous internal
bleeding that may not be otherwise detectable until the
consequences are too drastic to easily overcome. In some
embodiments, level of Hb can be measured indirectly, because its
relationship to oxygen in the veins and arteries (at different
points in the vasculature with respect to the heart and lungs) is
understood. In some embodiments, the apparatus, systems and methods
described herein can be useful for measuring a level of Hb.
[0285] Another parameter that can be monitored is lactate level,
which can be related to sepsis or toxic shock. Indeed, high levels
and/or rapid rise in lactate levels can be correlated to organ
failure and oxygenation problems in the blood and organs. However,
other direct measures of the biological effects related to lactate
level problems can be difficult to measure, for example, only
becoming measurable with a delay (e.g., 2-6 hours later). Thus,
measurement of lactate level can help provide a valuable early
warning of other medical problems. Indeed, if a problem with
lactate levels is detected, a nurse or doctor may be able to
prevent the correlated problems by providing more fluids.
[0286] Another parameter that can be monitored is central venous
oxygen saturation (ScvO2). It can be advantageous to try to
maintain an ScvO2 of 65-70% or greater in ICU patients (to help
avoid sepsis, for example). In some embodiments, the apparatus,
systems, and methods described herein can be useful for measuring a
level of ScvO2.
[0287] Levels of lactate and ScvO2 in a patient can be used
together to provide information and/or warnings to a health care
provider, which can be especially useful in an ICU setting. For
example, if lactate and ScvO2 are both high, a warning can be
provided (e.g., automatically using an alarm). If lactate is high,
but ScvO2 is low, a patient may benefit from additional fluids. If
ScvO2 is high, but lactate is low, a cardiac problem may be
indicated. Thus, a system that provides information about both
lactate and ScvO2 can be very beneficial to a patient, especially,
for example, in the ICU environment. Although lactate and ScvO2
have been used as an illustrative example, in other embodiments
different combinations of analytes can be monitored and used to
provide information and/or warnings (e.g., to a patient and/or
health care provider).
Treatment Dosing System
[0288] Some implementations of a hospital's TGC protocol suffer
from disadvantages. For example, in some healthcare environments
(e.g., an ICU) healthcare providers such as nurses may not have
readily available a paper insulin protocol that is sometimes used
with IV insulin drips as part of the TGC protocol. As a result,
such healthcare providers may have to "estimate" the next required
insulin dose adjustment or may have to leave the patient's care in
order to find the appropriate protocol. Further, when a new insulin
dose is estimated, there is a risk that there may be a
transcription error if the healthcare provider incorrectly inputs a
new dose rate into an IV delivery pump. In such examples, an
"estimated" rate is typically considered to be a deviation from the
hospital's TGC protocol. Hospitals refine their insulin protocols
and generally seek "high compliance" with the insulin protocol in
order, for example, to improve quality of care. Accordingly, in
some embodiments, the patient monitoring system (e.g. 2630 of FIG.
26) advantageously is configured to determine insulin doses in
compliance with the TGC protocol.
[0289] In some embodiments, the insulin dose rate adjustments are
determined from one or more previously-made glucose readings and
the current glucose reading. One or both glucose readings can be
determined by the patient monitoring system (e.g., by the
monitoring apparatus 2632 of FIG. 26) and/or can be input to the
patient monitoring system (e.g., via the HIS interface software
2650). Possible advantages of determining glucose readings with the
system patient monitoring system include increased precision,
reduced transcription errors, and near real-time access to the most
current patient readings.
[0290] In some embodiments, the patient monitoring system may
comprise a treatment dosing system including a treatment dosing
software (e.g. insulin dosing software 2652 of FIG. 26). In some
embodiments, the dosing software is configured to include a
treatment dosing protocol (e.g. an insulin protocol and/or TGC
protocol). For example, the dosing software may include the
hospital's current, approved, local insulin protocol. If an
adjustment to a patient's insulin dose should be made because of
the patient's current glucose values, the patient monitoring system
can be configured to calculate the next recommended (or suggested)
treatment dose. The calculation of the next recommended treatment
dose can be made at least in part based on the insulin dosing
protocol for the particular hospital. In some embodiments,
information related to the recommended treatment dose is output on
the user interface (e.g., the user interface 2400 and/or a display
graphic as shown in FIGS. 28A-F). For example, the user interface
may display the current rate of dose and/or infusion, the dose type
(e.g., bolus or steady (basal) rate), and the recommended dose. A
healthcare provider may use the information output by the user
interface to adjust the actual dose value, as needed by a specific
patient condition, and may initiate infusion. In some embodiments,
the patient monitoring system performs the calculation of
recommended dose, makes the adjustments to the actual dose value,
and provides this dose value to the patient, for example, by
infusion with the fluid system kit 2634 of FIG. 26. In some
embodiments, a control system (e.g. fluid system controller 405 of
FIG. 4) in communication with the patient monitoring system can be
configured to provide instructions to an infusion pump fluidically
connected to the source of infusion fluid to start infusion. The
control system may also be configured to adjust the pump rate of
the infusion fluid to deliver the recommended dose to the patient
at a basal rate or as a bolus injection.
[0291] FIG. 28A schematically illustrates an example of a display
graphic 2800 for use with an embodiment of the user interface 2400.
The display graphic 2800 can be output by, for example, a
touchscreen display device so that a user can view the information
on the display graphic 2800 and actuate suitable insulin dosing
controls. In other embodiments, buttons, keys, a mouse, or other
input device can be used instead of (or in addition to) touchscreen
buttons. The embodiment of the display graphic 2800 shown in FIG.
28A includes a suggested dose graphic 2804, an actual dose graphic
2808, dose decrement and increment buttons 2812a and 2812b, and
dosing control buttons 2816, and 2820. In other embodiments, the
graphics and buttons schematically illustrated in FIG. 28A can be
arranged differently, and the display graphic 2800 may include
additional and/or different information and controls.
[0292] In this embodiment, the suggested dose graphic 2804 includes
a suggested dose rate (e.g., 4 ml/hr) and a title graphic ("Insulin
Dose"). As described above, the suggested dose rate can be
calculated using the dosing software. The actual dose graphic 2708
includes a graphic representation of the current, actual dose
(e.g., 4 ml/hr). In this embodiment, the suggested dose graphic
2808 and the actual dose graphic 2808 use alphanumeric graphics to
output dose information. In other embodiments, the graphics 2804,
2808 may output dose information using, for example, trend graphs,
bar or pie charts, symbols, and so forth. Advantageously, the
values for the suggested and actual doses are displayed in a
sufficiently large graphic font that a user can readily read the
values, which reduces potential error in dosing the patient. In the
example shown in FIG. 28A, a steady (basal) infusion rate (e.g., 4
ml/hr) is shown. In other embodiments, the display graphic 2800 may
show a suggested bolus dose in addition to, or instead of, a steady
state (basal) dose.
[0293] In this illustrative example, the actual dose and the
recommended dose are the same (e.g., 4 ml/hr), but this is not a
limitation. In a typical implementation, if the actual dose differs
from the suggested dose, a user may adjust the actual dose value by
actuating (e.g., pressing on a touchscreen) a decrement button
2812a and/or an increment button 2812b until the actual dose equals
the suggested dose. The decrement and increment buttons 2812a and
2812b can be graduated in any suitable dose fractions (e.g., 0.1
ml/hr or some other amount).
[0294] The dosing control buttons include a cancel button 2816 and
an infuse button 2820. The cancel button 2816 can be used to stop,
and the infuse button 2820 can be used to actuate an infusion pump
coupled to the infusion fluid source and start, infusion of the
insulin dose. In other embodiments, additional or different
infusion control buttons can be used.
[0295] In some embodiments, a control system (e.g. fluid system
controller 405 of FIG. 4) configured to provide instructions to an
infusion pump fluidically connected to a source of infusion fluid
may comprise the display graphic 2800. A health care provider or a
user may actuate the infusion pump or control the pump rate through
the display graphic 2800 and the control system. Moreover, the
patient monitoring system can allow a user to control delivery of
infusion fluids using controls on a graphic user interface of the
monitoring system, even if the infusion fluids are pumped by a
separate system that is not contained within the same housing as
the patient monitoring system. For example, the monitoring system
can have built in wireless connectivity that can locate infusion
pumps (e.g., those that have wireless capabilities) in the vicinity
and establish communication with them. The monitoring system can
allow a user to control those external infusion pumps through its
own control interface (e.g., through its display graphic described
herein). In some embodiments, the monitoring system can wirelessly
search for an infusion pump delivering total parenteral nutrition
(TPN), for example, and, with a handshake protocol, query that
infusion pump for its hourly rate. This information can affect
various outputs from the system (including, for example, a dose or
rate suggested by the insulin dosing algorithm). The monitoring
system can do the same with an infusion pump that is delivering
insulin, and provide remote control of that pump through the
monitoring system's graphic user interface, for example.
[0296] The display graphic 2800 can be output on to any suitable
monitor or output device (e.g., a touchscreen display). For
example, in some embodiments, the display graphic 2800 is displayed
on the user interface 2400, e.g., adjacent an outer boundary of the
example UI graphic shown in FIGS. 24 and 25. In other embodiments,
the display graphic 2800 is shown instead of the trend indicators
2816. In yet other embodiments, the display graphic 2800 is output
with optional patient identification information. Many variations
are possible.
[0297] Accordingly, certain embodiments of the patient monitoring
system (e.g. system 2630 of FIG. 26) can be used as an infusion
pump, actuatable using an embodiment of the display graphic 2800.
In certain such embodiments, a healthcare provider advantageously
will be able to control insulin delivery through the same patient
IV access line. Embodiments of patient monitoring system that are
configured to include a treatment dosing protocol (e.g. insulin
protocol and/or a TGC protocol), to determine a patient treatment
dose based on patient glucose reading(s), and to deliver a
recommended treatment dose to the patient via a fluidic system
(e.g. the fluid system kit 26134 of FIG. 26 or via an infusion
pump, for example, infusion pump 518 of FIG. 5) may have one or
more of the following potential benefits: increased compliance with
a treatment dosing protocol, reduction in treatment dosing errors,
time savings for healthcare providers, and greater IV access
efficiency by delivery of some or all TGC-related medicaments
through a common IV line (e.g., a proximal port of a central venous
catheter or a lumen of a peripherally inserted central
catheter).
[0298] FIGS. 28B-28F schematically illustrate embodiments of a
display graphic comprising a graphic user interface. These figures
illustrate how an analyte detection system can be configured to
have a numerical display mode (see, e.g., 2822) and a trend display
mode (see, e.g., 2824) to display the present and/or historical
concentration of one or more analytes (e.g. glucose, ScvO2,
lactate, etc.). Similar to the embodiment illustrated in FIG. 28A,
the embodiments illustrated in FIGS. 28B-28F can also provide
information related to suggested and/or actual insulin dose and
enable the user or health care provider to control (e.g., start,
cancel, increase, decrease, etc.) delivery of insulin.
[0299] FIG. 28B shows an example of an embodiment of the display
graphic 2800. In this example, the concentrations of three
analytes; glucose, ScvO2 and lactate are displayed on a screen of
the display graphic 2800. The concentration can be displayed as a
number (see, e.g., 2822) or as a trend line (see, e.g., 2824), or
both. In some embodiments, the concentration can be displayed as a
trend graph of the concentration versus time. The embodiments
illustrated in FIG. 28B can also display the rate at which an
infusion substance (e.g. insulin) is being delivered to the
patient. For example reference numeral 2808 indicates that the
amount of insulin being infused is 0.5 units/hr. In some
embodiments, the display can be refreshed periodically to display
the most current measured and/or stored values. The display can
indicate when the last measurement was taken and/or the last time
the display was refreshed (see, e.g., the text "rate confirmation
at: 01:35").
[0300] The example illustrated in FIG. 28B also illustrates a
button 2812 that can be used to modify the rate at which insulin is
being infused or otherwise control an analyte level. The display
graphic, 2800 of FIG. 28B can comprise additional buttons such as
the Menu button 2828, which can provide additional
functionalities.
[0301] A user or a health care provider can activate the button
2812 of FIG. 28B to control infusion (e.g., modify the rate at
which insulin or another infusion substance is delivered). In some
embodiments, activating the button 2812 can display a secondary
screen as illustrated in FIG. 28C. The secondary screen may display
the current rate at which insulin is being infused and the
suggested rate at which insulin should be infused. The secondary
screen may comprise a dose increment button 2812a and a dose
decrement button 2812b to increase or decrease the rate at which
insulin is being infused. In some embodiments, a keypad may be
provided so that the user or health care provider can input the
value for the insulin infusion rate. The secondary screen may
comprise controls (e.g. cancel button 2816 or confirm button 2836)
to cancel or confirm the change in the insulin infusion rate. In
the example embodiments illustrated in FIGS. 28C and 28D, a bolus
dose button 2832 can be provided to program a bolus dose that can
be delivered to the patient. If the user or the health care
provider activates the bolus dose button 2832, the display graphic
can display a bolus dose screen which displays a value for the
bolus dose as illustrated in FIG. 28E. In some embodiments, the
bolus dose screen may display the remaining supply of insulin as
illustrated in FIG. 28E. The user or the health care provider can
change the amount of insulin bolus to be delivered and instruct the
system to deliver the bolus amount by activating the button 2820. A
confirmation screen 2840 may be displayed on the display graphic
2800 as illustrated in FIG. 28F to confirm that the user or health
care provider wished to proceed with the bolus delivery. The
embodiments illustrated in FIGS. 28B-28F can comprise a touch
screen to accept instructions and input from the user or the health
care provider.
[0302] Although the insulin dosing software 2652 schematically
illustrated in FIG. 26 and the display graphic 2800 schematically
illustrated in FIGS. 28A-28F are shown and described with respect
to delivery of an insulin dose, this is not a limitation, and in
other embodiments, the dosing software 2652 and the display graphic
2800 can be used to provide suitable doses and information related
thereto for any suitable item or items administered to a person,
such as medicaments, drugs, foods or herbs, whether administered
orally, intravenously, topically, etc. The dosing software 2652 of
FIG. 26 may calculate a recommended dose based (at least in part)
on readings of suitable analyte(s) of interest in the patient
(e.g., glucose in the case of insulin dosing). The readings can be
performed by the system 2630 (e.g., with the monitoring apparatus
2632) and/or by other analyte detection systems.
Examples of Calculating Treatment Dose
[0303] In the method for providing glycemic control schematically
illustrated in FIG. 27, the dextrose or insulin dose can be
determined by a treatment dosing protocol. In some embodiments, the
treatment dosing protocol may determine the amount of dextrose or
insulin to be delivered by comparing the currently estimated value
of glucose concentration with a target or desired value of glucose
concentration. In some embodiments, the treatment dosing protocol
may determine the treatment dose based on one or more of the
following factors: the patient's medical condition and medical
history, the effectiveness of the treatment dose, the presence or
absence of other analytes, other drugs being administered, etc.
[0304] For example, in some embodiments, different types of
insulin, listed in the table below, having different activation
properties can be used to control the concentration of glucose in
patients with hyperglycemia.
TABLE-US-00005 Quick-acting, such as the insulin analog lispro
starts working: 5 to 15 mins; active: 3 to 4 hrs. Short-acting,
such as regular insulin starts working: 30 mins; active: 5 to 8
hrs. Intermediate-acting, such as NPH insulin, or lente insulin
starts working: 1 to 3 hrs; active: 16 to 24 hrs. Long-acting, such
as ultralente insulin starts working: 4 to 6 hrs; active: 24 to 28
hrs. Insulin glargine and Insulin detemir start working: 1 to 2
hrs; active, w/o peaks or dips: 24 hrs. A mixture of NPH and
regular insulin starts working: 30 mins; active: 16 to 24 hrs.
[0305] In these embodiments, the insulin delivery rate can be
calculated based on factors such as the type of insulin, the time
taken by the insulin to start working, the time it remains active
in the body, etc. In some embodiments the amount of treatment dose
provided to control the analyte concentration can be adjusted no
more frequently than once every hour. In these embodiments,
determining the treatment dose only on the basis of the comparison
of the currently estimated value of glucose concentration with a
desired value of glucose concentration and a few other factors may
be insufficient to accurately determine the treatment dose required
to provide TGC. Thus treatment dosing protocols that determine the
treatment dose by taking an average of two or more sequential
glucose values or by calculating a rate of change of the glucose
concentration over a period of time or both may be effective in
providing glycemic control.
[0306] FIG. 29 is a flowchart that schematically illustrates an
embodiment of a method 2900 of determining the treatment dose based
on the average concentration of an analyte (e.g. glucose). In block
2905, an analyte monitoring system (e.g., the monitoring apparatus
2632 of FIG. 26) comprising a fluidic system (e.g. the fluid system
kit 2634 of FIG. 26) obtains a sample of bodily fluid (e.g., a
blood or blood plasma sample) from a source of bodily fluid (e.g.,
a patient) at an initial time T.sub.initial. In some embodiments,
the analyte monitoring system may further comprise an analyte
detection system that spectroscopically analyzes the sample and
obtains a measurement from the sample. The measurement may comprise
an optical measurement such as, for example, an infrared spectrum
of the sample. In block 2910, the initial concentration
(C.sub.initial) of an analyte (e.g. glucose) in the sample is
estimated from the measurement by using any of the methods
described above. In block 2915, the initial concentration
C.sub.initial at time T.sub.initial is stored in an internal or an
external database.
[0307] In some embodiments, the database can be located in a
processing system (e.g. a computer system 2646 of FIG. 26) in
electrical communication with the monitoring system. In some
embodiments, the initial concentration C.sub.initial at time
T.sub.initial can be stored in a memory location of a memory
device. The memory device can be located in the monitoring system
or the processing system. In some embodiments, the memory device
can be located external to the monitoring system and be in
electrical communication with the monitoring system. In some
embodiments, an initial treatment dose D.sub.initial can be
determined and delivered to the patient if the initial
concentration C.sub.initial of the analyte is not within a
predetermined range. The initial treatment dose D.sub.initial may
also be stored in the database or the memory location.
[0308] At a later time T.sub.i, a subsequent sample measurement is
obtained as shown in block 2920. The time T.sub.i may occur after a
time interval .DELTA.T from time T.sub.i-1 when a sample
measurement was previously obtained. For example, a first sample
measurement can be obtained at a first time T.sub.1 which occurs
after a time interval .DELTA.T from the initial time T.sub.initial
and a second sample measurement can be obtained at a second time
T.sub.2 which occurs after a time interval .DELTA.T from the first
time T.sub.1 and so on. The time interval .DELTA.T may range
anywhere from 5 minutes to 15 minutes. In some embodiments, the
time interval .DELTA.T may be less than 5 minutes or greater than
15 minutes. In block 2930, the concentration C.sub.i of the same
analyte at time T.sub.i is estimated from the obtained sample
measurement. The method 2900 then proceeds to block 2940 wherein
the estimated concentration C.sub.i of the analyte is compared to a
predetermined range. The predetermined range can be determined by
taking into account various factors such as a patient's medical
condition, the medications and drugs being administered to the
patient, etc. In some embodiments, the predetermined range is a
glucose concentration in a range from about 70 mg/dL to about 110
mg/dL. If in block 2940, the concentration C.sub.i of the analyte
is within the predetermined range, then the method 2900 moves to
block 2950 where the value of the estimated concentration C.sub.i
of the analyte at time T.sub.i is stored in the database or the
memory location. The method 2900 then returns to block 2920 to
obtain a next sample measurement after a time interval
.DELTA.T.
[0309] However, if in block 2940, the estimated concentration of
the analyte C.sub.i is determined to be not within the
predetermined range, then the method 2900 proceeds to block 2960
wherein an average concentration C.sub.avg of the analyte is
calculated. In some embodiments, the average concentration
C.sub.avg can be calculated by taking an arithmetic mean of the
estimated concentration C.sub.i and one or more previous
concentration values stored in the database or the memory location
and is given by the equation:
C avg = C i + k = 1 n C i - k n + 1 , ##EQU00001##
where n is an integer greater than or equal to 1.
[0310] In the above equation, the variable C.sub.i corresponds to
the currently estimated concentration value and the variables
C.sub.i-1, C.sub.i-2, . . . , C.sub.i-n correspond to the
concentration values previously obtained. In some embodiments, the
average concentration C.sub.avg can be calculated by taking a
weighted average of the estimated concentration C.sub.i and one or
more previous concentration values and is given by the
equation:
C avg = w i C i + k = 1 n w i - k C i - k w i + k = 1 n w i - k ,
##EQU00002##
where n can be an integer greater than or equal to 1.
[0311] The weights w.sub.i and w.sub.i-k can be determined in a
variety of ways. For example, in some embodiments the weight
w.sub.i associated with the current estimated concentration value
C.sub.i may be greater than the weights w.sub.i-k associated with
the previous concentration values. In some embodiments, a greater
weight can be assigned to a concentration value that is either
abnormally high or abnormally low. In some embodiments, by contrast
a smaller weight can be assigned to a concentration value that is
either abnormally high or abnormally low.
[0312] The method 2900 then proceeds to block 2970 where a
treatment dose of dextrose or insulin can be determined according
to a glycemic control protocol based at least in part on the
calculated average concentration C.sub.avg. In some embodiments,
the treatment dose of dextrose or insulin can be determined
according to a glycemic control protocol based on the calculated
average concentration C.sub.avg and variety of factors such as
patient's sensitivity to the treatment drug (e.g. insulin), the
treatment dosing history, the effectiveness of the treatment dose,
the presence or absence of other analytes, other drugs being
administered, etc. In some embodiments, the determined treatment
dose can be displayed to a health care provider on a display
graphic (e.g. display graphic 2800 of FIG. 28). In block 2980 the
determined treatment dose can be delivered to the patient by a
fluid delivery system or a fluid infusion system (e.g., a system
such as the subsystem 2780 shown in FIGS. 5 and 6). In some
embodiments, a control system (e.g. fluid system controller 405 of
FIG. 4) can be configured to provide instructions to an infusion
pump fluidically connected to a source of infusion fluid to start
infusion. The control system may also be configured to adjust the
pump rate of the infusion fluid to deliver the recommended
treatment dose to the patient at a basal rate or as a bolus
injection. In some embodiments, the treatment dose can be delivered
to the patient in addition to a low dose of the treatment drug
(e.g. insulin or glucose) being delivered to the patient
continuously at a steady rate. In some embodiments, the healthcare
provider may actuate the infusion pump fluidically connected to a
source of infusion fluid through a graphic user interface (e.g.
display graphic 2800 of FIG. 28). In some embodiments, the health
care provider may provide instructions regarding the pump rate to
the infusion pump through a graphic user interface (e.g. display
graphic 2800 of FIG. 28). In block 2990 the method 2900 returns to
block 2950 where the value of the estimated concentration C.sub.i
of the analyte at time T.sub.i is stored in the database or the
memory location.
[0313] FIG. 30 is a flowchart that schematically illustrates an
embodiment of a method 3000 of determining the treatment dose based
on the rate of change of the concentration of an analyte (e.g.
glucose). The method 3000 differs from the method 2900 in that if
in block 2940, the estimated concentration of the analyte C.sub.i
is determined to be not within the predetermined range, then the
method 3000 proceeds to block 3060 where a rate of change of the
concentration R.sub.c of the analyte is calculated. The rate of
change of the concentration of the analyte R.sub.c can be
calculated in a variety of ways. In some embodiments, the rate
R.sub.c can be calculated from the current estimated concentration
of the analyte C.sub.i at time T.sub.i and the previously
determined concentration of the analyte C.sub.i-1 at time T.sub.i-1
stored in the database or memory location and is given by the
following equation:
R c = C i - C i - 1 T i - T i - 1 ##EQU00003##
[0314] In some embodiments, the rate R.sub.c can be calculated from
the currently estimated concentration of the analyte C.sub.i at
time T.sub.i and several previously determined values for the
concentration of the analyte stored in the database or memory
location. In the method 3000, the treatment dose is determined
using a glycemic control protocol based at least in part on the
rate of change R.sub.c of the concentration of the analyte as shown
in block 3070. In some embodiments, determining the treatment dose
based on the rate of change R.sub.c of the concentration of the
analyte can ensure that the treatment dosing protocol responds to
certain extreme conditions such as rapid change in the
concentration of the analyte (e.g. glucose). In some embodiments,
such rapid change in the concentration of the analyte can indicate
that the patient's medical condition is unstable or critical. In
some embodiments, the rapid change in the concentration can be an
indicator of a failure of the measurement system or a part
thereof.
[0315] FIG. 31A is a flowchart that schematically illustrates an
embodiment of a method 3100 of determining the treatment dose based
on the current estimated concentration or the average concentration
of an analyte (e.g. glucose) and the rate of change of the
concentration of the analyte. The method 3100 determines the
treatment dose using a glycemic control protocol based at least in
part on the average concentration C.sub.avg of the analyte and the
rate of change of the concentration R.sub.c of the analyte as shown
in block 3170. The average concentration C.sub.avg and the rate of
change of the concentration R.sub.c can be calculated by one or
more of the methods described above. In some embodiments, as
illustrated in FIG. 31B, the treatment dose can be determined using
a glycemic control protocol based at least in part on the currently
estimated concentration C.sub.i and the rate of change of the
concentration R.sub.c of the analyte.
Treatment Dose Feedback System
[0316] As described above, in some embodiments, the analyte
monitoring system can be configured to control the concentration of
one or more analyte by infusing a treatment dose calculated by a
treatment dosing protocol. However, the analyte monitoring system
or the healthcare provider may not have feedback regarding the
effectiveness of the treatment dose suggested by the treatment
dosing protocol. Thus it may be advantageous to have a system that
can both: (i) predict the concentration of an analyte (e.g.
glucose) at a future time based on the treatment dose suggested by
the treatment dosing protocol; and (ii) provide feedback to the
healthcare provider.
[0317] As described above, an analyte monitoring apparatus
comprising a fluidic system (e.g. the fluid system kit 2634 of FIG.
26) can obtain a sample of bodily fluid (e.g., a blood or blood
plasma sample) from a source of bodily fluid (e.g., a patient) and
estimate the concentration of one or more analytes in the sample
several times during an hour. The concentration of the one or more
analytes can be stored in a measurement history that can be
accessed later. The measurement history may comprise one or more
stored databases or memory locations.
[0318] In some embodiments, the measurement history can be located
in a processing system (e.g. a computer system 2646 of FIG. 26) in
electrical communication with the monitoring system. In some
embodiments, the concentration of the one or more analytes can be
stored in a memory location of a memory device. The memory device
can be located in the monitoring system or the processing system.
In some embodiments, the memory device can be located external to
the monitoring system and be in electrical communication with the
monitoring system. FIG. 32 illustrates an embodiment of a
measurement history 3200 that stores the time of measurement
T.sub.i, the estimated or measured concentration of an analyte
(e.g. glucose) C.sub.i and the treatment dose D.sub.i (of insulin
or sugar, for example) administered to the patient. In some
embodiments, the measurement history 3200 may store information
regarding estimated or measured concentration of other analytes.
Other embodiments of the measurement history are also possible.
[0319] If the estimated or measured concentration of an analyte
(e.g. glucose) is not within an acceptable range, then a healthcare
provider may administer a treatment dose based on a treatment
dosing protocol to bring the concentration of the analyte within
the acceptable range. FIG. 33 schematically illustrates steps in a
method to provide feedback to the monitoring and/or dosing system
(and, e.g., the healthcare provider) regarding the effectiveness of
the treatment dose suggested by the treatment dosing protocol.
Feedback can be provided by a feedback system 3405 illustrated in
FIG. 34 which is in electronic communication with the analyte
monitoring apparatus 2632 and/or the computer system 2646 of FIG.
34. Referring to FIG. 33, in block 3305 the feedback system 3405
reads the treatment dose input by the healthcare provider or
determined by the treatment dosing software. The treatment dose can
be put in to the system in a variety of ways. For example, in one
embodiment, the healthcare provider may input the treatment dose
using a keyboard. In some embodiments, the healthcare provider may
input the treatment dose using a touch screen. In some embodiments,
the treatment dose can be provided automatically (e.g. by
computer).
[0320] In block 3315 the feedback system 3405 accesses the
measurement history (e.g. the measurement history 3200 illustrated
in FIG. 32) that stores the previously determined values for the
concentration of the analyte and the values for a treatment dose
previously administered. The method 3300 then proceeds to block
3320 where the feedback system 3405 calculates a predicted value
for the concentration of the analyte at a future time (e.g. in the
next hour) based on the previously determined values for the
concentration of the analyte and the treatment dosing history. In
some embodiments, the calculation may predict the value for the
concentration of the analyte at a future time by extrapolating the
concentration of the analyte assuming that the patient's
sensitivity to the treatment drug (e.g. insulin) remains the same
and by further assuming that the amount of medications and drugs
being administered to the patient remain the same. For example, in
some embodiments, the feedback system 3405 may assume that
treatment dose input by the healthcare provider will not change
over the next several time durations.
[0321] In block 3330, the predicted value for the concentration of
the analyte is compared with a predetermined range. The
predetermined range can be determined by taking into account
various factors such as a patient's medical condition, the
medications and drugs being administered to the patient, etc. In
some embodiments, the predetermined range may be a glucose
concentration in a range from about 70 mg/dL to about 110 mg/dL. If
in block 3330, the predicted concentration of the analyte is
determined to be within the predetermined range, then the method
3300 moves to block 3340 where the treatment dose input by the
healthcare provider is stored in the measurement history.
[0322] However, if in block 3330, the predicted concentration of
the analyte is determined to be not within the predetermined range,
then the method 3300 proceeds to block 3360 where feedback is
provided (e.g. to the healthcare provider or analyte monitoring
system) that the predicted concentration of the analyte at a future
time may be outside the predetermined range if the treatment dose
input to the system is delivered to the patient. The system or the
healthcare provider may change the treatment dose based on the
feedback. In some embodiments, the feedback system 3405 can be
configured to automatically stop the flow of the infusion fluid
(e.g. glucose or insulin) based on the trend or a value of the
concentration of one or more analytes. For example, in the case
where the analyte of interest is glucose and the infusion fluid is
insulin, the feedback system 3405 may stop the flow of insulin if
the concentration of glucose is low enough to be life threatening
or if the trend of successive glucose measurements indicated that
the concentration of glucose may drop to levels that may to harmful
to the patient.
[0323] In some embodiments, the feedback system 3405 can provide
feedback regarding one or more drugs being administered to the
patient without requiring an input from the healthcare provider. In
some embodiments the feedback system 3405 can spectroscopically
analyze the infusion fluid as it flows out of the infusion pump
and/or source of infusion fluid (e.g. 518, 520 or 2782 of FIG. 5)
through the infusion fluid tubes (e.g. 514, 516 or 2784 of FIG. 5)
to determine the contents of the infusion fluid. For example, in
some embodiments the feedback system 3405 may irradiate the
infusion fluid with three or more wavelengths. In some embodiments,
the wavelengths can be selected from the wavelength range of
approximately 275 nm to 310 nm. In some embodiments, the
wavelengths can be selected from the near infrared or infrared
range of wavelengths. The feedback system 3405 can then obtain one
or more spectra from the radiation reflected, transmitted and/or
scattered by the infusion fluid to determine the contents of the
infusion fluid. The spectra obtained by the feedback system 3405
can be compared with a catalog of drug or chemical spectra to
identify the contents of the infusion fluid. In some embodiments,
the spectra can be further analyzed to determine the concentration
of the various contents of the infusion fluid.
[0324] The feedback system 3405 can comprise a watch list including
the drugs or chemicals that may be detrimental to the health of the
patient. The identified contents of the infusion fluid can be
compared with the watch list. If a particular drug or chemical
present in the watch list is detected in the infusion fluid, then
the feedback system 3405 can be configured to shut off the infusion
system delivering that particular drug or chemical to the patient.
In addition, the feedback system 3405 may provide alerts or
warnings to the healthcare provider and request confirmation from
the healthcare provider before resuming the flow of that particular
drug or chemical. In some embodiments, the feedback system 3405 can
be configured to prevent the flow of a drug or chemical if the
concentration of that drug or chemical in the infusion fluid is
determined to be outside an acceptable range. For example, the
system can issue an alert or warning to the healthcare
provider.
Dilution Calibration
[0325] As described above, in certain embodiments, the systems and
methods determine a concentration of an analyte such as, for
example, glucose, in a bodily fluid sample such as, for example,
whole blood or blood plasma. In some cases, the concentration of a
blood plasma analyte can be affected by dilution of the whole blood
sample from which the plasma is obtained. Dilution of a sample may
occur during processing of the sample (e.g., by addition of a
diluent to the sample), during operation of the sampling apparatus
(e.g., by mixing of the sample with diluents in the apparatus), and
so forth. For example, dilution may occur if an anticoagulant
(e.g., heparin) is added to a blood sample to prevent clotting.
Also, dilution may occur as a fluid sample travels through the
apparatus, for example, through accumulation of residual diluent
fluids (e.g., saline solution) in tubing.
[0326] Generally, dilution of a bodily fluid sample will result in
the analyte concentration measured from the diluted sample being
less than the analyte concentration present in the patient's body.
Because diluents are more likely to reside in the plasma portion of
the blood, dilution effects may be greater for analyte
concentrations measured in blood plasma. Accordingly, it may be
advantageous to calibrate a measured analyte concentration for some
or all of the effects of dilution. In some embodiments, a measured
analyte concentration is corrected for dilution to provide an
estimate of analyte concentration that is more representative of
the concentration in the patient's body.
[0327] As described above, certain embodiments of the disclosed
systems and methods are directed to the measurement of blood plasma
analytes in samples of whole blood. Since fluid diluents typically
reside in blood plasma rather than in non-plasma components, it may
be advantageous to determine the relative amounts of plasma and
non-plasma components in a whole blood sample.
[0328] Whole blood includes fluid components (e.g., blood plasma)
and non-fluid components (e.g., red blood cells, white blood cells,
platelets, etc.). In a typical sample of whole human blood, red
blood cells constitute approximately 45% of the blood volume, and
white blood cells constitute approximately 1% of the blood of the
blood volume. Platelets are small, non-fluid blood components that
typically remain in the plasma, even after the plasma is separated
(e.g., via centrifuging). Consequently, blood plasma typically
constitutes approximately 54% of the blood volume.
[0329] The relative amounts of plasma and corpuscles in a whole
blood sample can be determined in many ways, for example, by using
a hematocrit, which is an instrument that separates a blood sample
by centrifugation. The hematocrit value (commonly referred to as
"Ht" or "HCT") is the percentage of red blood cells in whole blood.
The hematocrit value can be determined by centrifuging a sample of
whole blood in a graduated tube, a process which packs the red
blood cells into the bottom of the tube. Values of the volume of
packed red blood cells and the total volume of the blood sample are
measured, and the percentage of red blood cells in the total
sample, Ht, is calculated as the ratio of these values. As noted
above, red blood cells form the bulk of the non-plasma component of
blood. Accordingly, the fraction of blood plasma in whole blood is
approximately 1-Ht.
[0330] The hematocrit value can be estimated without separating red
blood cells from whole blood in a centrifuge. One method for
estimating Ht uses the fact that hemoglobin predominantly resides
in the red blood cells. The concentration of hemoglobin in whole
blood can be determined, for example, by optical spectroscopy of
the blood sample. Apparatus and methods for optical measurements of
blood are described, for example, in U.S. Pat. No. 5,385,539,
issued Jan. 31, 1995, entitled "APPARATUS FOR MONITORING HEMATOCRIT
LEVELS OF BLOOD," the entire disclosure of which is hereby
incorporated by reference herein. The hematocrit, Ht, has been
found to be related to the concentration of hemoglobin in whole
blood, Hb, as follows:
Ht(%)=3Hb/(g/dL) (1)
Accordingly, a measurement of hemoglobin concentration, Hb, can be
converted into a measurement of hematocrit, Ht, (and vice versa) by
application of Equation (1). Therefore, embodiments of analyte
detection systems can be configured with hematocrit sensors,
hemoglobin sensors, or a combination thereof to determine, as
appropriate, hematocrit and/or hemoglobin concentration.
[0331] Hematocrit (and/or hemoglobin concentration) can be measured
via other techniques as well. For example, one example method for
estimating Ht uses changes in the electrical conductivity through
whole blood, where blood cells act as electrical insulators.
Electrical conductivity apparatus and methods are described, for
example, in U.S. Pat. No. 6,058,934, issued May 9, 2000, entitled
"PLANAR HEMATOCRIT SENSOR INCORPORATING A SEVEN-ELECTRODE
CONDUCTIVITY MEASUREMENT CELL," the entire disclosure of which is
hereby incorporated by reference herein. Another example method for
estimating Ht uses acoustic ultrasound measurements to determine
Ht, for example, as described in U.S. Pat. No. 4,854,170, issued
Aug. 8, 1989, entitled "APPARATUS AND METHOD FOR USING ULTRASOUND
TO DETERMINE HEMATOCRIT," the entire disclosure of which is hereby
incorporated by reference herein. In other techniques, hematocrit
and/or hemoglobin concentration can be measured using a combination
of approaches such as, for example, optical and acoustic techniques
as described in U.S. Pat. No. 6,751,490, issued Jun. 15, 2004,
entitled "CONTINUOUS OPTOACOUSTIC MONITORING OF HEMOGLOBIN
CONCENTRATION AND HEMATOCRIT," the entire disclosure of which is
hereby incorporated by reference herein. Embodiments of the systems
and methods disclosed herein may use one or more of the
above-described example approaches (or other approaches) to measure
hematocrit and/or hemoglobin concentration in a fluid sample.
[0332] In certain embodiments, an analyte concentration, g, is
calibrated for the effects of dilution by determining or inferring
a volume of diluent fluid added to the bodily fluid sample during
processing of the sample, operation of the analyte detection
system, and so forth. The estimated analyte concentration can be
calibrated to account for the added diluent volume. For example, in
some embodiments, one or more measurements of hematocrit (and/or
hemoglobin concentration) in the fluid sample are made before and
after dilution, and these measurements are used to at least
partially correct an estimated analyte concentration for the
effects of dilution. Examples of dilution calibration methods and
systems will now be described.
Example Dilution Calibration Systems
[0333] Any of the example analyte detection systems (and/or fluid
handling systems) described herein can be used to provide dilution
calibration. For example, FIGS. 35 and 36 schematically illustrate
embodiments suitable for using hematocrit and/or hemoglobin
concentration measurements to at least partially correct for
dilution. Many of the components shown in FIGS. 35 and 36 have been
described above with reference to FIGS. 5 and 6. In the embodiments
depicted in FIGS. 35 and 36, the bubble sensor BS14 shown in FIG. 5
(reference numeral 552) and FIG. 6 has been interchanged with a
hemoglobin sensor Hb14 (reference numeral 3504 in FIG. 35). In some
embodiments, the hemoglobin sensor Hb14 is generally similar to the
hemoglobin sensor 526 (Hb12) described above with reference to
FIGS. 5 and 6. As will be described below, in these embodiments,
the hemoglobin sensor Hb12 is used to measure hemoglobin
concentration of the fluid sample after drawing from the body (and
before substantial dilution has occurred). The hemoglobin sensor
Hb14 is used to measure hemoglobin concentration after the fluid
sample has traveled through the tubing to the vicinity of the
centrifuge (and therefore after dilution may have occurred). These
"before dilution" and "after dilution" measurements of hemoglobin
concentration can be used to at least partially correct for the
effects, if present, of dilution.
[0334] Although the embodiments shown in FIGS. 35 and 36 utilize a
hemoglobin concentration sensor Hb14, in other embodiments either
(or both) of the hemoglobin concentration sensors Hb12 and Hb14 may
be hematocrit sensors. Further, although the bubble sensor BS14
(shown in FIGS. 5 and 6) has been interchanged with the hematocrit
sensor Hb14 in the embodiments shown in FIGS. 35 and 36, in other
embodiments, the hematocrit sensor Hb14 is provided in addition to
the bubble sensor BS 14. Also, in other embodiments the sensors
Hb12 and Hb14 can be disposed at locations in the fluid handling
network that are different than shown in FIGS. 5, 6, 35, and 36.
For example, the sensor Hb12 can be located closer to the patient
tube 512 (T1), and the sensor Hb14 can be located closer to (but
downstream of) the anticoagulant valve 541. It is advantageous for
the sensors Hb12 and Hb14 to be disposed at locations in the fluid
handling network such that substantially all the dilution of the
fluid sample can be accounted for. Although two sensors Hb12 and
Hb14 are shown in FIGS. 35 and 36, in other embodiments three,
four, five, six, or more sensors can be used to measure dilution of
the fluid sample. For example, in some embodiments, sensors are
positioned upstream and downstream of the location where an
anticoagulant (e.g., heparin) is added to the fluid sample. Such
embodiments advantageously can be used to calibrate for dilution by
the anticoagulant.
[0335] An example of collection of a fluid sample will now be
described with reference to FIG. 35. With the valves 542 (PV1), 559
(V7b), and 561 (V4b) closed, a first pump 522 (pump #1) is actuated
to draw sample fluid to be analyzed (e.g. blood) from a fluid
source (e.g., a laboratory sample container, a living patient,
etc.) up into the patient tube 512 (T1), through the tube past the
two flanking portions of the open pinch-valve 523 (V0), through the
first connector 524 (C1), into the looped tube 530, past the
hemoglobin sensor 526 (Hb12), and into the Hb sensor tube 528 (T4).
During this process, the valve 529 (V7a) and 523 (V0) are open to
fluid flow, and the valves 531 (V1a), 533 (V3a), 542 (PV1), 559
(V7b), and 561 (V4b) can be closed and therefore block (or
substantially block) fluid flow by pinching the tube.
[0336] Before drawing the sample, the tubes 512 (T1) and 528 (T4)
are filled with saline and the hemoglobin (Hb) level is zero. The
tubes that are filled with saline are in fluid communication with
the sample source (e.g., the fluid source 402). The sample source
can be the vessels of a living human or a pool of liquid in a
laboratory sample container, for example. When the saline is drawn
toward the first pump 522, fluid to be analyzed is also drawn into
the system because of the suction forces in the closed fluid
system. Thus, the first pump 522 draws a relatively continuous
column of fluid that first comprises generally nondiluted saline,
then a mixture of saline and sample fluid (e.g., blood), and then
eventually a nondiluted sample fluid.
[0337] The hemoglobin sensor 526 (Hb12) detects the concentration
of hemoglobin in the sample fluid. As blood starts to arrive at the
hemoglobin sensor 526 (Hb12), the hemoglobin level rises. A
hemoglobin level can be selected, and the system can be pre-set to
determine when that level is reached. A controller such as the
fluid system controller 405 of FIG. 4 can be used to set and react
to the pre-set value, for example. In some embodiments, when the
sensed hemoglobin level reaches the pre-set value, a substantially
undiluted sample is present at the first connector 524 (C1). The
preset value can depend, in part, on the length and diameter of any
tubes and/or passages traversed by the sample. A nondiluted sample
can be, for example, a blood sample that is not diluted with saline
solution, but instead has the characteristics of the rest of the
blood flowing through a patient's body. The hemoglobin sensor 526
(Hb12) can measure the hemoglobin concentration of this "before
dilution" blood sample. A loop of tubing 530 (e.g., a 1-mL can be
advantageously positioned as illustrated to help insure that
undiluted fluid (e.g., undiluted blood) is present at the first
connector 524 (C1) when the hemoglobin sensor 526 (Hb12) registers
that the preset Hb threshold is crossed. The loop of tubing 530
provides additional length to the Hb sensor tube 528 (T4) to make
it less likely that the portion of the fluid column in the tubing
at the first connector 524 (C1) has advanced all the way past the
mixture of saline and sample fluid, and the nondiluted blood
portion of that fluid has reached the first connector 524 (C1).
Accordingly, a possible advantage of embodiments using the loop of
tubing 530 is that the "before dilution" hemoglobin concentration
measured by the sensor 526 (Hb12) is representative of the
(non-diluted) hemoglobin concentration of the patient's body.
[0338] When sufficiently nondiluted blood is present at the first
connector 524 (C1), the fluid sample can be directed through the
tube 534 (T3), past the connectors C6 and C2, and to the sample
cell 548 for analysis. While traveling through this tubing, the
fluid sample can be diluted by accumulation of saline solution,
cleaning solution, etc. that has been left behind on the tube walls
after cleaning or purging. Additionally, in some embodiments, an
amount of anticoagulant (e.g., heparin) can be introduced into the
tube 534 (T3), and then the fluid sample is mixed with the
anticoagulant. As described above, the anticoagulant can be
shuttled from the tube 540 into the anticoagulant valve tube 534
(T3) to provide a controlled amount of anticoagulant into the tube
534 (T3), which thereby additionally dilutes the fluid sample.
After addition of the anticoagulant (if desired), the fluid sample
is pushed up the anticoagulant valve tube 534 (T3), through the
connector C6, and through the second connector 546 (C2). Along this
path, the fluid sample may experience further dilution from
accumulation of fluids on the tube walls. After passing the
connector C2, the sample comes into sensing contact with the
hemoglobin sensor 3404 (Hb14), which determines an "after-dilution"
hemoglobin concentration of the sample. The sample is then pushed
into the sample cell 548, which can be located on the centrifuge
rotor 550. The fluid in the sample cell is centrifuged, which
separates blood corpuscles from the blood plasma and any diluents
present in the plasma (e.g., heparin, saline, cleaning fluid,
etc.). Concentration of analytes in the diluted blood plasma can be
measured as described above.
[0339] An example of the collection of a fluid sample in the fluid
handling embodiment schematically illustrated in FIG. 36 will be
described. Collection of the fluid sample may be generally similar
to the collection described above with reference to FIG. 35. For
example, blood is drawn from a patient (or from a suitable
extracorporeal conduit), through the tubes T1, T22, and T4 and into
the loop. When the hemoglobin sensor Hb12 determines, via a "before
dilution" hemoglobin measurement, that the loop contains undiluted
blood, the blood sample is directed to connector C1 and into line
T2. If desired, as the blood sample passes the connector C6 an
anticoagulant (e.g., heparin) can be injected, which dilutes the
blood sample. The blood sample is then directed through the tubes
T3 and T17 and passes the connector C2, where the hemoglobin sensor
Hb14 performs an "after dilution" hemoglobin measurement. The blood
sample is then directed into the sample cell of the centrifuge,
where the blood corpuscles are separated from a diluted volume of
blood plasma. A measurement of analyte concentration may then be
performed on the diluted plasma sample. As discussed above, as the
blood sample travels from the sensor Hb12 to the sensor Hb14, the
blood sample can be diluted due to 1) accumulation of fluids (e.g.,
saline, cleaning solution, etc.) left behind on the tube walls from
a previous tube purging/cleaning, and/or 2) injection, if desired,
of an amount of a anticoagulant at the connector C6.
Example Dilution Calibration Methods
[0340] FIG. 37 is a flowchart illustrating an example method 3700
for calibrating an analyte measurement in a fluid sample for
dilution of the fluid sample. In block 3704, a fluid sample is
obtained for measurement. The fluid sample may comprise whole
blood, blood plasma, interstitial body fluid, and so forth. The
fluid sample can be obtained from a suitable fluid source (e.g., a
laboratory sample container, a living patient, etc.). In many of
the illustrative examples described herein, the fluid sample is a
whole blood sample drawn from a patient, but this is not intended
to be a limitation to embodiments of the calibration methods.
[0341] In block 3708, a first property of the fluid sample is
measured. Advantageously, the first property may be sensitive to
dilution of the sample. For example, in some embodiments the first
property is hematocrit and/or hemoglobin concentration, and the
first property is measured by a blood sensor such as, e.g., a
hematocrit sensor and/or a hemoglobin sensor. In other embodiments,
the first property may be a concentration of a particular
component, analyte, or species in the fluid sample. Properties such
as, for example, density and/or volume of the fluid sample can be
measured. The first property may be a measurement of a single
parameter or characteristic of the fluid sample or may include a
group of measurements.
[0342] In block 3712, the obtained fluid sample is transported to a
measurement site capable of providing a measurement of an analyte
in the fluid sample. For example, the obtained fluid sample can be
transported by a fluid handling network in an analyte detection
system, such as, e.g., the fluid handling networks schematically
depicted in FIGS. 35 and 36. While being transported, the fluid
sample may experience dilution caused by, for example, processing
of the fluid sample (e.g., addition of one or more diluents) and/or
through routine operation of the fluid transport network (e.g.,
accumulation in the sample of diluents present in tubing in the
fluid handling network). The amount of dilution can be known and/or
unknown. For example, the amount (e.g., volume) of an anticoagulant
added to the sample can be known (or determinable), while the
amount of diluent accumulated from the fluid handling network can
be unknown (and dependent on how the system has been operated prior
to transport of the sample).
[0343] In block 3716, a second property of the fluid sample is
measured. Advantageously, the second property may be sensitive to
dilution of the sample such that the amount of dilution can be
determined from comparison of the first property and the second
property. As discussed above for the first property, the second
property may include hematocrit, hemoglobin concentration,
concentration of a particular component, analyte, or species in the
fluid sample, density, and/or volume of the fluid sample. The
second property may be a measurement of a single parameter or
characteristic of the fluid sample or may include a group of
measurements. The second property may be the same as the first
property (e.g., both the first and the second property may be
hematocrit), or the second property may be different from the first
property (e.g., the first property may be hematocrit and the second
property may be hemoglobin concentration).
[0344] In block 3720, a measuring apparatus performs a measurement
of an analyte concentration in a portion of the fluid sample. For
example, the measuring apparatus may comprise a spectroscopic
analyte detection system configured to measure the concentration of
an analyte (e.g., glucose) in plasma separated from a blood sample.
The measuring apparatus may perform the analyte measurement on the
fluid sample (e.g., a whole blood sample) and/or a component of the
fluid sample (e.g., blood plasma separated from whole blood).
Because of the possible effects of dilution of the fluid sample
during transport in block 3712, the measured analyte concentration
may not represent the analyte concentration in the nondiluted fluid
sample obtained in block 3704. Accordingly, in blocks 3724 and
3728, the measured analyte concentration is calibrated for dilution
of the fluid during transport. In some embodiments, the calibration
at least partially corrects the measured analyte concentration for
the dilution. For example, in block 3724 a calibration is
determined based at least in part on the first property and the
second property. Illustrative, non-limiting examples of the
calculation of the calibration will be presented below. In block
3728, the calibration is applied to the analyte concentration
measured in block 3720 to provide an at least partially
dilution-calibrated estimate for analyte concentration.
[0345] In some embodiments, one or more general purpose and/or
special purpose computers can be used to implement embodiments of
the method 3700. Embodiments of the method 3700 can be represented
as computer-executable instructions on a computer-readable medium.
For example, the fluid system controller 405 may control the
measurements of the first and second properties in blocks 3708 and
3716 (e.g., using measurement of hematocrit and/or hemoglobin
concentration), and the algorithm processor 416 may control the
measurement and calibration of the analyte concentration in blocks
3720-3728. In other embodiments, portions of the method 3700 can be
executed by processors that are remote from analyte detection
system. In certain embodiments, some (or all) of the blocks
3604-3728 can be combined or can be performed differently (or in
different orders) than shown in the example method 3700 shown in
FIG. 37. Many variations are possible.
[0346] An example procedure for calibrating an analyte measurement
for the effects of dilution will now be described. This example is
intended to be illustrative and not to limit the scope of the
dilution calibration methods. In this example, a measurement of
hematocrit and/or hemoglobin in a blood sample is performed "before
dilution" (e.g., in block 3708) and another hematocrit and/or
hemoglobin measurement is performed "after dilution" (e.g., in
block 3716). For example, in the fluid system embodiments shown in
FIGS. 35 and 36, the "before dilution" measurement can be provided
by the hemoglobin sensor Hb12 and the "after dilution" measurement
can be provided by the hemoglobin sensor Hb14. As described above,
in other embodiments, additional hematocrit and/or hemoglobin
measurements can be obtained. In such embodiments, the additional
measurements can be used to improve accuracy and/or precision of
the dilution calibration according to any suitable statistical
techniques (e.g., regression, least squares, maximum likelihood,
outlier analysis, etc.).
[0347] In this example procedure, "before dilution" measurements
are indicated with a subscript "0," and "after dilution"
measurements are indicated with a subscript "1." Further, in this
example, the blood sample will be considered to include corpuscles,
e.g., red and white blood cells, (subscript "c") and plasma
(subscript "p"). In a volume of blood denoted by V, a volume
V.sub.c contains corpuscles, and the remaining volume
V.sub.p=V-V.sub.c contains plasma. Thus, hematocrit, Ht, can be
written as
Ht = V c V = 1 - V p V ( 2 ) ##EQU00004##
If hemoglobin concentration, Hb, is used to estimate Ht, Equation
(1) can be used to convert Hb to Ht (or vice versa).
[0348] The total amount of glucose in the plasma is denoted by G,
and equals the plasma glucose concentration, g, multiplied by the
plasma volume
G=g V.sub.p (3)
In this example, assume that as the blood sample is transported, it
is diluted with a volume .DELTA.V of fluid having no glucose and no
solids. For example, .DELTA.V may represent the controlled amount
of anticoagulant mixed with the blood sample at the tube 534 (T3,
shown in FIG. 35). Because no glucose and no solids are assumed to
be added to the blood sample, the values of G and V.sub.c do not
change during dilution. Consequently,
G.sub.0=G.sub.1=G (4)
V.sub.c0=V.sub.c1=V.sub.c. (5)
[0349] The total blood volume and the plasma volume after dilution
are related to the volumes before dilution and the dilution volume
.DELTA.V by
V.sub.1=V.sub.0+.DELTA.V (6)
V.sub.p1=V.sub.p0+.DELTA.V. (7)
[0350] The plasma glucose concentration after dilution, g.sub.1, is
determined by the analyte detection system (e.g., in block 3720 of
FIG. 37) and is thus a measured (known) quantity. Because the total
amount of glucose, G, in the blood sample is assumed to be constant
(no glucose is added by the diluent fluid), the value of the plasma
glucose concentration before dilution, g.sub.0, is unknown but may
be related to g.sub.1 from Equations (3) and (4):
G=g.sub.0V.sub.p0=g.sub.1V.sub.p1. Combining this relationship with
Equation (7) yields
g 0 g 1 - 1 = .DELTA. V V p 0 , ( 8 ) ##EQU00005##
hence, the calibration of the plasma glucose measurement is related
to the amount of dilution, .DELTA.V, of the blood sample. The
"before dilution" plasma volume V.sub.p0 can be replaced with the
"before dilution" hematocrit, Ht.sub.0, by using Equation (2),
which yields
g 0 g 1 - 1 = .DELTA. V / V 0 1 - Ht 0 , ( 9 ) ##EQU00006##
where V.sub.0 is the total blood volume before dilution.
[0351] In embodiments in which hemoglobin concentration, Hb, is
measured instead of hematocrit, Ht, Equation (1) can be used in
Equation (9) to yield
g 0 g 1 - 1 = .DELTA. V / V 0 1 - 3 Hb 0 , ( 10 ) ##EQU00007##
where Hb.sub.0 is measured in g/dL.
[0352] In some embodiments, the volumes .DELTA.V and V.sub.0 (or
the ratio .DELTA.V/V.sub.0) and the value Hb.sub.0 are measured,
and Equation (10) is used to adjust the measured plasma glucose
concentration, g.sub.1, to yield an estimate of the undiluted
plasma glucose concentration, g.sub.0. For example, in
implementations where addition of an anticoagulant predominates
dilution of the sample, the amount .DELTA.V of the added
anticoagulant can be measured (or otherwise know) and used in
Equation (10) to calibrate the analyte concentration
measurement.
[0353] In other embodiments, the diluted hematocrit, Ht.sub.1
(and/or the diluted hemoglobin concentration Hb.sub.1) is measured,
and the volumes in Equation (10) are replaced with measured blood
sample values. For example, because no solids are assumed to be
added by the fluid diluent, the volume of corpuscles in the sample,
V.sub.c, is constant, and Equations (2) and (5) can be combined as
V.sub.c=V.sub.0Ht.sub.0=V.sub.1 Ht.sub.1. Equation (6) can be used
eliminate V.sub.1 to yield
.DELTA. V V 0 = Ht 0 Ht 1 - 1. ( 11 ) ##EQU00008##
Consequently, measurements of hematocrit (and/or hemoglobin
concentration) "before dilution" and "after dilution" can be used
to provide an estimate of fractional sample dilution,
.DELTA.V/V.sub.0.
[0354] Substituting Equation (11) into Equation (9) provides
another relationship that can be used to calibrate an "after
dilution" glucose measurement to yield an estimate for the "before
dilution" glucose measurement:
g 0 g 1 - 1 = Ht 0 / Ht 1 - 1 1 - Ht 0 , ( 12 ) ##EQU00009##
or if hemoglobin concentration Hb is measured (see, Eq. (1)),
g 0 g 1 - 1 = Hb 0 / Hb 1 - 1 1 - 3 Hb 0 . ( 13 ) ##EQU00010##
Equations (12) and (13) can be rewritten to show how the estimate
for the "before dilution" analyte concentration g.sub.0 is related
to the measured "after dilution" analyte concentration g.sub.1:
g 0 = g 1 [ Ht 0 Ht 1 ( 1 - Ht 1 ) ( 1 - Ht 0 ) ] , ( 14 ) g 0 = g
1 [ Hb 0 Hb 1 ( 1 - 3 Hb 1 ) ( 1 - 3 Hb 0 ) ] . ( 15 )
##EQU00011##
If there is no measurable dilution of the sample, the "before
dilution" and the "after dilution" Ht and/or Hb measurements will
be substantially the same (e.g., the factors in square brackets
will be approximately equal to one), and Equations (14) and (15)
demonstrate that, as expected, g.sub.0.apprxeq.g.sub.1. In some
embodiments, the calibration shown in Equation (14) or (15) is not
applied if the change between Ht.sub.1 and Ht.sub.0 (or Hb.sub.1
and Hb.sub.0) is more representative of measurement errors by
hematocrit (and/or hemoglobin) sensors than dilution of the sample.
If measurable dilution of the sample occurs, the "before dilution"
and "after dilution" values for Ht (and/or Hb) will be different,
and the factors in square brackets in Equations (14) and (15)
provide an approximate correction factor that at least partially
accounts for the dilution.
[0355] Thus, for example, in an embodiment in which Hb.sub.0,
Hb.sub.1, and g.sub.1 are measured (e.g., the embodiments shown in
FIGS. 35 and 36), Equation (13) (or Eq. (15)) provides a
relationship that can be used to estimate the "before dilution"
analyte concentration g.sub.0. Although the above example has been
described in terms of glucose concentration, this is not a
limitation, and the example procedure described herein can be used
to calibrate concentration of any analyte measured in blood plasma.
Further, Equations (2)-(15) can be readily modified if various
assumptions that went into their derivation are relaxed. For
example, an appropriate calibration for an analyte concentration
can be derived if the diluent fluid added to the blood sample
contains a known amount (or concentration) of the analyte of
interest and/or blood solids. Also, Equations (12)-(15) can be
modified if more than two hematocrit (and/or hemoglobin
concentration) measurements are made while the blood sample is
being transported between the patient (or an extracorporeal fluid
container) and the analyte measurement apparatus (e.g., the
centrifuge and spectroscopic analyzer). Many variations are
contemplated, and an appropriate calibration may readily be
determined for each such variation using the teachings herein. For
example, in many implementations, the calibration will be a linear
(e.g., affine) relationship, thus the "before dilution"
concentration estimate will be related to the "after dilution"
concentration measurement according to g.sub.0=C g.sub.1+D, where C
is a calibration factor and D is a calibration offset. In the
example calibration procedure described above, the calibration
offset D=0, and the calibration factor C is the quantity in the
square brackets in Equation (14) (if hematocrit is measured) or
Equation (15) (if hemoglobin concentration is measured). In other
embodiments, the calibration offset is non-zero. For example, the
calibration offset may at least partially correct for a diluent
fluid that also includes the analyte of interest.
[0356] Reference throughout this specification to "some
embodiments" or "an embodiment" means that a particular feature,
structure or characteristic described in connection with the
embodiment is included in at least some embodiments. Thus,
appearances of the phrases "in some embodiments" or "in an
embodiment" in various places throughout this specification are not
necessarily all referring to the same embodiment and may refer to
one or more of the same or different embodiments. Furthermore, the
particular features, structures or characteristics can 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.
[0357] As used in this application, the terms "comprising,"
"including," "having," and the like are synonymous and are used
inclusively, in an open-ended fashion, and do not exclude
additional elements, features, acts, operations, and so forth.
Also, the term "or" is used in its inclusive sense (and not in its
exclusive sense) so that when used, for example, to connect a list
of elements, the term "or" means one, some, or all of the elements
in the list.
[0358] Similarly, it should be appreciated that in the above
description of embodiments, various features are sometimes grouped
together in a single embodiment, figure, or description thereof for
the purpose of streamlining the disclosure and aiding in the
understanding of one or more of the various inventive aspects. This
method of disclosure, however, is not to be interpreted as
reflecting an intention that any claim require more features than
are expressly recited in that claim. Rather, inventive aspects lie
in a combination of fewer than all features of any single foregoing
disclosed embodiment.
[0359] Embodiments of the disclosed systems and methods can be used
and/or implemented with local and/or remote devices, components,
and/or modules. The term "remote" may include devices, components,
and/or modules not stored locally, for example, not accessible via
a local bus. Thus, a remote device may include a device which is
physically located in the same room and connected via a device such
as a switch or a local area network. In other situations, a remote
device may also be located in a separate geographic area, such as,
for example, in a different location, building, city, country, and
so forth.
[0360] Methods and processes described herein may be embodied in,
and partially or fully automated via, software code modules
executed by one or more general and/or special purpose computers.
The word "module" refers to logic embodied in hardware and/or
firmware, or to a collection of software instructions, possibly
having entry and exit points, written in a programming language,
such as, for example, C or C++. A software module may be compiled
and linked into an executable program, installed in a dynamically
linked library, or may be written in an interpreted programming
language such as, for example, BASIC, Perl, or Python. It will be
appreciated that software modules may be callable from other
modules or from themselves, and/or may be invoked in response to
detected events or interrupts. Software instructions may be
embedded in firmware, such as an erasable programmable read-only
memory (EPROM). It will be further appreciated that hardware
modules may be comprised of connected logic units, such as gates
and flip-flops, and/or may be comprised of programmable units, such
as programmable gate arrays, application specific integrated
circuits, and/or processors. The modules described herein are
preferably implemented as software modules, but may be represented
in hardware and/or firmware. Moreover, although in some embodiments
a module may be separately compiled, in other embodiments a module
may represent a subset of instructions of a separately compiled
program, and may not have an interface available to other logical
program units.
[0361] In certain embodiments, code modules may be implemented
and/or stored in any type of computer-readable medium or other
computer storage device. In some systems, data (and/or metadata)
input to the system, data generated by the system, and/or data used
by the system can be stored in any type of computer data
repository, such as a relational database and/or flat file system.
Any of the systems, methods, and processes described herein may
include an interface configured to permit interaction with
patients, health care practitioners, administrators, other systems,
components, programs, and so forth.
[0362] A number of applications, publications, and external
documents may be incorporated by reference herein. Any conflict or
contradiction between a statement in the body text of this
specification and a statement in any of the incorporated documents
is to be resolved in favor of the statement in the body text.
[0363] Although described in the illustrative context of certain
preferred embodiments and examples, it will be understood by those
skilled in the art that the disclosure extends beyond the
specifically described embodiments to other alternative embodiments
and/or uses and obvious modifications and equivalents. Thus, it is
intended that the scope of the claims which follow should not be
limited by the particular embodiments described above.
* * * * *
References