U.S. patent application number 16/878535 was filed with the patent office on 2020-12-10 for fluid analysis system.
The applicant listed for this patent is OptiScan Biomedical Corporation. Invention is credited to James R. Braig, Michael Butler, David N. Callicoat, Craig A. Johnson, Richard Keenan, Eugene Lim, Peter Rule, Roger Tong.
Application Number | 20200383620 16/878535 |
Document ID | / |
Family ID | 1000005039087 |
Filed Date | 2020-12-10 |
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United States Patent
Application |
20200383620 |
Kind Code |
A1 |
Lim; Eugene ; et
al. |
December 10, 2020 |
FLUID ANALYSIS SYSTEM
Abstract
Systems and method are disclosed for determining a concentration
of an analyte in a fluid (e.g., blood). The system can draw blood
from a patient and deliver the blood to a sample cell. A particular
component of the fluid (e.g., plasma) may be separated and/or
positioned such that the concentration of the analyte is measured
in the particular component of the fluid (e.g., plasma). The sample
cell can include a sample container that has two window pieces. The
system can have a fluid passage having a tip configured to mate
with a multi-lumen catheter without leaking. The multi-lumen
catheter can have proximal and distal ports. A fluid pressure
system can be configured to periodically draw fluid from
vasculature through a proximal intravascular opening and the
proximal port while maintaining a low pressure and/or flow rate to
thereby reduce risk of reversing the fluid flow in a vessel and
drawing infusates upstream into another intravascular opening.
Inventors: |
Lim; Eugene; (Lafayette,
CA) ; Tong; Roger; (Berkeley, CA) ; Rule;
Peter; (Los Altos Hills, CA) ; Braig; James R.;
(Piedmont, CA) ; Keenan; Richard; (Livermore,
CA) ; Callicoat; David N.; (Hayward, CA) ;
Butler; Michael; (Dublin, CA) ; Johnson; Craig
A.; (Dublin, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
OptiScan Biomedical Corporation |
Hayward |
CA |
US |
|
|
Family ID: |
1000005039087 |
Appl. No.: |
16/878535 |
Filed: |
May 19, 2020 |
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Application
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10660557 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61B 5/155 20130101;
G16H 20/17 20180101; A61M 39/1011 20130101; A61M 2205/128 20130101;
A61B 5/14546 20130101; A61B 5/15003 20130101; A61B 5/14552
20130101; A61M 2039/1033 20130101; A61M 5/16827 20130101; A61B
2562/0233 20130101; A61B 5/150992 20130101; A61B 5/150221 20130101;
G01N 33/491 20130101; A61B 5/157 20130101; A61B 5/14557 20130101;
A61M 5/1723 20130101; A61B 5/1455 20130101; A61B 5/412 20130101;
A61B 5/150229 20130101; A61B 5/153 20130101; A61B 5/150786
20130101; A61B 2560/0228 20130101; A61M 5/1415 20130101; A61B
2562/0238 20130101; A61B 5/6866 20130101; A61B 5/0059 20130101;
A61M 2005/14208 20130101; G01N 2021/0346 20130101; A61B 5/1427
20130101; G01N 21/35 20130101; A61B 5/14532 20130101; A61B 5/1459
20130101; A61M 39/10 20130101; A61B 5/150267 20130101; G01N 21/03
20130101; G01N 21/07 20130101; A61B 5/150236 20130101; A61M 2205/12
20130101; A61B 5/150755 20130101; A61M 5/142 20130101 |
International
Class: |
A61B 5/157 20060101
A61B005/157; A61B 5/00 20060101 A61B005/00; A61B 5/145 20060101
A61B005/145; A61B 5/1455 20060101 A61B005/1455; A61B 5/153 20060101
A61B005/153; A61B 5/155 20060101 A61B005/155; A61M 39/10 20060101
A61M039/10; A61B 5/15 20060101 A61B005/15; A61B 5/1459 20060101
A61B005/1459; A61M 5/172 20060101 A61M005/172; G01N 21/03 20060101
G01N021/03; G01N 21/07 20060101 G01N021/07; G01N 33/49 20060101
G01N033/49; G16H 20/17 20060101 G16H020/17 |
Claims
1.-18. (canceled)
19. A system comprising: an analyte measurement system configured
to measure the concentration of an analyte in at least a portion of
a fluid sample; a fluid handling system configured to receive the
fluid sample and to deliver at least a portion of the fluid sample
to the analyte measurement system; a fluid infusion system
configured to infuse fluid through a fluid infusion line to a
distal intravascular opening into a vessel having a flow of bodily
fluid in a patient; a fluid draw line configured to draw bodily
fluid from the vessel through a proximal intravascular opening,
wherein proximal intravascular opening is upstream from the distal
intravascular opening on the vessel; an accommodating medical
connector that couples the fluid draw line to the fluid handling
system, the connector comprising: a housing having a first side, a
second side, and an internal volume, wherein a fluid line of the
fluid handling system extends through the first side of the housing
and into the internal volume, wherein the second side of the
housing is removably coupled to a corresponding connector that is
coupled to the fluid draw line; a movable tube having a first
portion disposed inside the internal volume of the housing and a
second portion that extends past the second side of the housing and
into the corresponding connector, wherein the movable tube is
movable to adjust the amount of the movable tube that is inside the
internal volume of the housing and to adjust how far the movable
tube extends past the second side of the housing; a coupler inside
the internal volume of the housing, wherein the coupler couples the
fluid line to the movable tube so that movement of the movable tube
causes corresponding movement of the fluid line relative to the
housing, and wherein the coupler provides a fluid path between the
fluid line and the movable tube; and a biasing member disposed
inside the internal volume of the housing, wherein the biasing
member biases the movable tube toward the corresponding connector;
and a fluid pressure system configured to periodically draw bodily
fluid from the vessel through the proximal intravascular opening,
through the fluid draw line, through the connector, and to the
fluid handling system, wherein the fluid pressure system is
configured to draw the bodily fluid through the proximal
intravascular opening at a sufficiently low pressure and/or flow
rate to impede reversal of the flow of the bodily fluid in the
vessel.
20. The system of claim 19, wherein the fluid pressure system is
configured to draw the bodily fluid through the proximal
intravascular opening at a first flow rate when the fluid infusion
system is infusing fluid through the distal intravascular opening,
wherein the fluid pressure system is configured to draw the bodily
fluid through the proximal intravascular opening at a second flow
rate when the fluid infusion system is not infusing fluid through
the distal intravascular opening, and wherein the first flow rate
is lower than the second flow rate.
21. The system of claim 19, wherein the fluid pressure system is
configured to draw the bodily fluid at a flow rate between
approximately 1 mL per minute and approximately 10 mL per
minute.
22. The system of claim 19, wherein the fluid pressure system is
configured to draw the bodily fluid at a pressure between
approximately 1 psi and approximately 10 psi.
23. The system of claim 19, wherein the fluid pressure system is
configured to draw the bodily fluid at a sufficiently low pressure
and/or flow rate that the amount of the fluid infused through the
distal intravascular opening is less than 10 parts per million.
24. The system of claim 19, wherein the fluid pressure system
comprises a syringe pump.
25. The system of claim 19, wherein the movable tube has a tip at
one end that engages the fluid draw line.
26. The system of claim 25, wherein the tip of the movable tube has
a square cross-sectional shape.
27. The system of claim 25, wherein the tip of the movable tube is
tapered.
28. The system of claim 25, wherein the tip of the movable tube is
beveled.
29. The system of claim 25, wherein the tip of the movable tube is
stiffer than the fluid draw line.
30. The system of claim 19, wherein the tip of the movable tube
comprises polyimide.
31. The system of claim 19, wherein the accommodating medical
connector is configured to maintain substantially uniform velocity
of the bodily fluid across the accommodating connector.
32. The system of claim 19, wherein an inner diameter of the
movable tube of the accommodating medical connector is
approximately the same as an inner diameter of the fluid draw
line.
33. The system of claim 19, wherein the accommodating medical
connector is configured to restrict fluid flowing through the
accommodating medical connector to the fluid draw line, the
coupler, and the movable tube.
34. The system of claim 19, wherein the accommodating medical
connector is configured so that fluid flowing through the
accommodating medical connector does not contact the inside of the
housing.
35. The system of claim 19, wherein the biasing member comprises a
spring.
36. The system of claim 35, wherein the spring is compressed
between a interior surface of the housing and the coupler.
37. The system of claim 19, wherein the accommodating medical
connector provides a linear flow path through the accommodating
medical connector.
38. The system of claim 19, wherein the analyte measurement system
comprises an optical measurement system, and wherein the system
includes a cuvette that comprises: a first window piece that is
configured to be transparent to light emitted by the optical
measurement system; a second window piece that is configured to be
transparent to the light emitted by the optical measurement system;
a spacer positioned between the first window piece and the second
window piece to provide a gap between the first window piece and
the second window piece, wherein the gap forms a sample chamber
between the first window piece and the second window piece, and
wherein the sample chamber is configured to receive the at least a
portion of the fluid sample from the fluid handling system; a first
clamping element; and a second clamping element, wherein the first
and second clamping elements are positioned on opposite outer sides
of the first and second window pieces, wherein the first and second
clamping elements are secured to each other to provide support to
the first and second window pieces, wherein the first and second
clamping elements are configured to permit the light emitted by the
optical measurement system to pass through the sample chamber of
the cuvette.
Description
[0001] This application is a continuation of U.S. patent
application Ser. No. 16/271,653 (Attorney Docket No.
OPTIS.268P1D1), filed Feb. 8, 2019, and titled "FLUID ANALYSIS
CUVETTE WITH COUPLED TRANSPARENT WINDOWS", which is a divisional of
U.S. patent application Ser. No. 15/418,485 (Attorney Docket No.
OPTIS.268P1C1), filed Jan. 27, 2017, and titled "FLUID ANALYSIS
SYSTEM", which is a continuation of U.S. patent application Ser.
No. 14/589,867 (Attorney Docket No. OPTIS.268P1), filed Jan. 5,
2015, and titled "FLUID ANALYSIS SYSTEM," which is a
continuation-in-part of U.S. patent application Ser. No. 13/542,350
(Attorney Docket No. OPTIS.268A), filed on Jul. 5, 2012, and titled
"SAMPLE CELL FOR FLUID ANALYSIS SYSTEM," which claims the benefit
under 35 U.S.C. .sctn. 119(e) of U.S. Provisional Patent
Application No. 61/505,025 (Attorney Docket No. OPTIS.268PR), filed
on Jul. 6, 2011, and titled "SAMPLE CELL FOR FLUID ANALYSIS
SYSTEM."
[0002] The Ser. No. 14/589,867 application is a
continuation-in-part of U.S. patent application Ser. No. 13/552,542
(Attorney Docket No. OPTIS.267A), filed on Jul. 18, 2012, and
titled "METHOD AND APPARATUS FOR ANALYTE MEASUREMENTS USING
CALIBRATION SETS," which claims the benefit under 35 U.S.C. .sctn.
119(e) of U.S. Provisional Patent Application No. 61/509,487
(Attorney Docket No. OPTIS.267PR), filed on Jul. 19, 2011, and
titled "METHOD AND APPARATUS FOR ANALYTE MEASUREMENTS USING
MULTIPLE CALIBRATION SETS."
[0003] The Ser. No. 14/589,867 application is a
continuation-in-part of U.S. patent application Ser. No. 13/156,295
(Attorney Docket No. OPTIS.266A), filed on Jun. 8, 2011, and titled
"SYSTEMS AND METHODS FOR MEASURING MULTIPLE ANALYTES IN A SAMPLE,"
which claims the benefit under 35 U.S.C. .sctn. 119(e) of U.S.
Provisional Patent Application No. 61/353,186 (Attorney Docket No.
OPTIS.266PR), filed on Jun. 9, 2010, and titled "SYSTEMS AND
METHODS FOR MEASURING MULTIPLE ANALYTES IN A SAMPLE."
[0004] The Ser. No. 14/589,867 application is a
continuation-in-part of U.S. patent application Ser. No. 13/162,315
(Attorney Docket No. OPTIS.265A), filed on Jun. 16, 2011, and
titled "SYSTEMS AND METHODS TO REDUCE FLUID CONTAMINATION," which
claims the benefit under 35 U.S.C. .sctn. 119(e) of U.S.
Provisional Patent Application No. 61/355,982 (Attorney Docket No.
OPTIS.265PR), filed on Jun. 17, 2010, and titled "SYSTEMS AND
METHODS TO REDUCE FLUID CONTAMINATION."
[0005] The Ser. No. 14/589,867 application is a
continuation-in-part of U.S. patent application Ser. No. 14/259,940
(Attorney Docket No. OPTIS.263A2C1), filed on Apr. 23, 2014, and
titled "ADJUSTABLE CONNECTOR, IMPROVED FLUID FLOW AND REDUCED
CLOTTING RISK," which is a continuation of U.S. patent application
Ser. No. 13/068,121 (Attorney Docket No. OPTIS.263A2), filed on May
3, 2011, and titled "ADJUSTABLE CONNECTOR, IMPROVED FLUID FLOW AND
REDUCED CLOTTING RISK," which claims the benefit under 35 U.S.C.
.sctn. 119(e) of U.S. Provisional Patent Application No. 61/330,812
(Attorney Docket No. OPTIS.263PR), filed on May 3, 2010, and titled
"ADJUSTABLE CONNECTOR AND DEAD SPACE REDUCTION," and U.S. patent
application Ser. No. 13/068,121 (Attorney Docket No. OPTIS.263A2)
is a continuation-in-part of U.S. patent application Ser. No.
12/804,336 (Attorney Docket No. OPTIS.263A), filed on Jul. 20,
2010, and titled "ADJUSTABLE CONNECTOR AND DEAD SPACE REDUCTION,"
which claims the benefit under 35 U.S.C. .sctn. 119(e) of U.S.
Provisional Patent Application No. 61/330,812 (Attorney Docket No.
OPTIS.263PR), filed on May 3, 2010, and titled "ADJUSTABLE
CONNECTOR AND DEAD SPACE REDUCTION," and U.S. Provisional Patent
Application No. 61/227,040 (Attorney Docket No. OPTIS.248PR), filed
on Jul. 20, 2009, and titled "ANALYTE DETECTION SYSTEM WITH A FLOW
DIRECTOR."
[0006] The Ser. No. 14/589,867 application is a
continuation-in-part of U.S. patent application Ser. No. 14/257,920
(Attorney Docket No. OPTIS.263C1), filed on Apr. 21, 2014, and
titled "ADJUSTABLE CONNECTOR AND DEAD SPACE REDUCTION," which is a
continuation of U.S. patent application Ser. No. 12/804,336
(Attorney Docket No. OPTIS.263A), filed on Jul. 20, 2010, and
titled "ADJUSTABLE CONNECTOR AND DEAD SPACE REDUCTION," which
claims the benefit under 35 U.S.C. .sctn. 119(e) of U.S.
Provisional Patent Application No. 61/330,812 (Attorney Docket No.
OPTIS.263PR), filed on May 3, 2010, and titled "ADJUSTABLE
CONNECTOR AND DEAD SPACE REDUCTION," and U.S. Provisional Patent
Application No. 61/227,040 (Attorney Docket No. OPTIS.248PR), filed
on Jul. 20, 2009, and titled "ANALYTE DETECTION SYSTEM WITH A FLOW
DIRECTOR."
[0007] The entire contents of each of the above-identified
applications are hereby made part of this specification as if set
forth fully herein and incorporated by reference for all purposes,
for all that each contains. Additionally, the entirety of U.S.
Provisional Patent Application No. 61/954,530 (Attorney Docket No.
OPTIS.275PR), filed Mar. 17, 2014, and titled "AUTOMATING IN-LINE
OPTICAL MEASUREMENT IN MEDICAL FLUID SYSTEMS," is hereby made part
of this specification as if set forth fully herein and incorporated
by reference for all purposes, for all that it contains.
BACKGROUND
Field
[0008] Some embodiments of the disclosure relate generally to
methods and devices for determining a concentration of an analyte
in a sample, such as an analyte in a sample of bodily fluid, as
well as methods and devices which can be used to support the making
of such determinations. Some embodiments of the disclosure relate
to a sample cell for holding a sample fluid. Various embodiments of
the disclosure also relate to systems and methods to withdraw
fluids (e.g. blood) through a port of a multi-lumen catheter such
that the contamination from other ports is reduced
Description of Related Art
[0009] 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. Currently known systems for analyte monitoring in a
hospital or clinical setting may suffer from various drawbacks. For
example, present fluid withdrawal techniques can result in fluid
(e.g. blood) being withdrawn at a fast rate and/or at high
pressures which can lead to contamination of the withdrawn blood
particularly in multi-lumen catheters, where fluids from the other
ports of the multi-lumen catheter can contaminate the withdrawn
blood. Systems and methods described herein can reduce the
contamination of the withdrawn fluid.
SUMMARY
[0010] Example embodiments described herein have several features,
no single one of which is indispensible or solely responsible for
their desirable attributes. Without limiting the scope of the
claims, some of the advantageous features will now be
summarized.
[0011] A cuvette is disclosed that includes a first window piece, a
second window piece, and a spacer positioned between the first
window piece and the second window piece to provide a gap between
the first window piece and the second window piece. The cuvette can
include a first clamshell piece and a second clamshell piece
positioned on opposite sides of the window pieces, and the first
and second clamshell pieces can be secured to each other to provide
support to the first and second window pieces.
[0012] In various embodiments, a system for reducing contamination
risk in drawing fluid from vasculature is described. The system
comprises a tube configured to connect to a multi-lumen catheter.
In various embodiments, the multi-lumen catheter can include a
proximal port comprising an independent lumen that provides a fluid
path between an extracorporeal opening and an intravascular opening
that is positioned upstream when the multi-lumen catheter is inside
a vessel having a fluid flow; a distal port comprising an
independent lumen that provides a fluid path between the
extracorporeal opening and the intravascular opening that is
positioned downstream from the proximal port when the multi-lumen
catheter is inside a vessel having a fluid flow; and a medial port
comprising an independent lumen that provides a fluid path between
the extracorporeal opening and the intravascular opening that is
positioned between the proximal port and the distal port. In
various embodiments, the distal and medial ports can each be
configured to allow infusion of an infusate into the vessel from
their intravascular openings downstream from the intravascular
opening of the proximal port. In various embodiments, the tube can
be configured to connect to the proximal port of the multi-lumen
catheter without leaking. In various embodiments, the tube can have
an inner lumen that is smaller than the inner lumen of the
independent lumen of the proximal port. For example, the diameter
of the inner lumen of the tube can be between approximately 0.01
inches and 0.04 inches. The system further comprises a fluid
pressure system in fluid communication with the inner lumen of the
tube that can be configured to create a pressure in the inner lumen
that is automatically controlled to be less than 10 psi and/or
provide a flow rate of between approximately 1 and 10 ml per minute
such that the amount of contaminating infusate that is drawn into
the intravascular opening of the proximal port is limited to less
than 10 parts per million. The fluid pressure system may be
configured to create a negative pressure in the inner lumen that is
between approximately 40% and approximately 99% of the pressure in
the vessel. The fluid pressure system may comprise a syringe
pump.
[0013] A method for reducing contamination risk in drawing fluid
from vasculature is described. The method comprises providing a
tube that is configured to connect to a multi-lumen catheter. In
various embodiments, the multi-lumen catheter can have a proximal
port comprising an independent lumen that provides a fluid path
between an extracorporeal opening and an intravascular opening that
is positioned upstream when the multi-lumen catheter is inside a
vessel having a fluid flow; a distal port comprising an independent
lumen that provides a fluid path between the extracorporeal opening
and the intravascular opening that is positioned downstream from
the proximal port when the multi-lumen catheter is inside a vessel
having a fluid flow; and a medial port comprising an independent
lumen that provides a fluid path between the extracorporeal opening
and the intravascular opening that is positioned between the
proximal port and the distal port. In various embodiments, the
distal and medial ports can each be configured to allow infusion of
an infusate into the vessel from their intravascular openings
downstream from the intravascular opening of the proximal port. In
various embodiments, the tube can be configured to connect to the
proximal port of the multi-lumen catheter without leaking. In
various embodiments, the tube can have an inner lumen that is
smaller than the inner lumen of the independent lumen of the
proximal port. For example, the diameter of the inner lumen of the
tube can be between approximately 0.01 inches and 0.04 inches. The
method further comprises providing a fluid pressure system in fluid
communication with the inner lumen of the tube and providing an
automated system that is configured to automatically control the
fluid pressure system and create a pressure in the inner lumen that
is less than 10 psi and/or provide a flow rate of between
approximately 1 and 10 ml per minute such that the amount of
contaminating infusate that is drawn into the intravascular opening
of the proximal port is limited to less than 10 parts per million.
The automated system may control the fluid pressure system to
create a negative pressure in the inner lumen that is between
approximately 40% and approximately 99% of the pressure in the
vessel. The fluid pressure system may comprise a syringe pump.
[0014] An apparatus for improving measurement accuracy in an
analyte monitoring system and reducing fluid contamination risk is
described. The apparatus may include a fluid passage with a tip
configured to mate with a multi-lumen catheter without leaking. The
mutli-lumen catheter may have a proximal port communicating with a
proximal port lumen that provides a fluid path to a proximal
intravascular opening that is configured to open into a vessel
having a fluid flow and a distal port communicating with a distal
port lumen that is independent from and not in fluid communication
with the proximal port lumen and that provides a fluid path to a
distal intravascular opening that is configured to open into the
vessel distal of and downstream from the proximal intravascular
opening to infuse infusates. The apparatus may include a fluid
pressure system in fluid communication with the fluid passage, the
fluid pressure system configured to periodically automatically draw
fluid from the vessel through the proximal intravascular opening
and the proximal port and through the tip back into the fluid
passage while maintaining a low pressure and/or flow rate to
thereby reduce risk of reversing the fluid flow in the vessel and
drawing infusates back upstream into the proximal intravascular
opening. The apparatus may also have an analyzer configured to
automatically analyze at least a portion of the drawn fluid,
automatically achieving higher accuracy analysis at least in part
as a result of the low pressure at which the fluid was drawn. The
apparatus may be configured to reduce dilution errors due to
withdrawal of infusates such that infusate does not cause more than
a 20% difference in accuracy of an analyte reading that uses fluid
drawn into the intravascular opening of the proximal port. The
fluid passage may have an inner diameter of between approximately
0.01 inches and approximately 0.04 inches. The fluid pressure
system may comprise a controller and a pressure monitor that
provides feedback to the controller, the controller configured to
maintain the withdrawal pressure below 99% of the pressure of blood
in the vessel. A patient blood pressure monitor may provide
feedback to the controller to allow a baseline for comparison to
the withdrawal pressure. The pressure monitor may be configured to
monitor the pressure at or near the proximal port. The fluid
pressure system may be configured to maintain a constant rate for
the majority of the time blood is being withdrawn through the
proximal port. The fluid pressure system may be configured to
adjust the withdrawal rate to be lower when infusates are being
infused through the distal port
[0015] A method for improving measurement accuracy in an analyte
monitoring system and reducing fluid contamination risk is
described. The method may comprise providing a tube configured to
connect to a multi-lumen catheter without leaking, the multi-lumen
catheter having an upstream port and a downstream port, each port
having an independent lumen not in fluid communication with the
other. The method may further comprise positioning the multi-lumen
catheter in a patient's vessel such that the lumen of the upstream
port opens into the vessel upstream of the lumen of the downstream
port, providing an automated fluid pressure system configured to
automatically maintain a low pressure and/or flow rate while
drawing blood, connecting the automated fluid pressure system to
the tube such that the system is in fluid communication with the
upstream port and blood flow in the patient's vessel, and using the
automated fluid pressure system to periodically draw blood in
through the lumen of the upstream port while maintaining a low
pressure and/or flow rate, thereby avoiding a reversal of blood
flow in the patient's vessel and reducing the risk of contamination
of a blood sample. The infusate may be infused into the vessel
through the downstream port, and the method further comprising
reducing the amount of infusate drawn into the lumen of the
upstream catheter so that infusate does not cause more than a 20%
difference in accuracy of an analyte reading of the blood drawn
into the tube as compared to a reading of blood drawn when no
infusate is being infused into the vessel. The automated fluid
pressure system may comprise a syringe pump. The infusate may be
periodically infused into the vessel through the downstream port,
the method further comprising using the automated fluid pressure
system to reduce the pressure and/or flow rate of withdrawn blood
when infusion of infusate and blood withdrawal occur
simultaneously. The method may also include determining the
patient's blood pressure and using the automated fluid pressure
system to maintain a withdrawal pressure that is less than the
patient's blood pressure, thereby avoiding reversal of blood flow
in the vessel.
BRIEF DESCRIPTION OF THE DRAWINGS
[0016] 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.
[0017] FIG. 1 shows an embodiment of an apparatus for withdrawing
and analyzing fluid samples.
[0018] FIG. 2 illustrates how various other devices can be
supported on or near an embodiment of apparatus illustrated in FIG.
1.
[0019] FIG. 3 illustrates an embodiment of the apparatus in FIG. 1
configured to be connected to a patient.
[0020] 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
advantageously provides in vitro analysis of a fluid sample.
[0021] FIG. 4 is a block diagram of an embodiment of a system for
withdrawing and analyzing fluid samples.
[0022] FIG. 5 schematically illustrates an embodiment of a fluid
system that can be part of a system for withdrawing and analyzing
fluid samples.
[0023] FIG. 6 schematically illustrates another embodiment of a
fluid system that can be part of a system for withdrawing and
analyzing fluid samples.
[0024] FIG. 6A schematically illustrates an embodiment of a fluid
system having tubes of different internal diameters that can be
part of a system for withdrawing and analyzing fluid samples.
[0025] FIG. 7 is an oblique schematic depiction of an embodiment of
a monitoring device.
[0026] FIG. 8 shows a cut-away side view of an embodiment of a
monitoring device.
[0027] FIG. 9 shows a cut-away perspective view of an embodiment of
a monitoring device.
[0028] FIG. 10 illustrates an embodiment of a removable cartridge
that can interface with a monitoring device.
[0029] FIG. 11 illustrates an embodiment of a fluid routing card
that can be part of the removable cartridge of FIG. 10.
[0030] FIG. 12 illustrates how non-disposable actuators can
interface with the fluid routing card of FIG. 11.
[0031] FIG. 13 illustrates a modular pump actuator connected to a
syringe housing that can form a portion of a removable
cartridge.
[0032] FIG. 14 shows a rear perspective view of internal
scaffolding and some pinch valve pump bodies.
[0033] 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.
[0034] FIG. 16 shows a plan view of a sample cell holder with
hidden and/or non-surface portions illustrated using dashed
lines.
[0035] FIG. 17 shows a top perspective view of the centrifuge
interface connected to the sample holder.
[0036] FIG. 18 shows a perspective view of an example optical
system.
[0037] FIG. 19 shows a filter wheel that can be part of the optical
system of FIG. 18.
[0038] FIG. 20 schematically illustrates an embodiment of an
optical system that comprises a spectroscopic analyzer adapted to
measure spectra of a fluid sample.
[0039] 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.
[0040] 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.
[0041] 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.
[0042] FIGS. 24 and 25 schematically illustrate the visual
appearance of embodiments of a user interface for a system for
withdrawing and analyzing fluid samples.
[0043] FIG. 26 schematically depicts various components and/or
aspects of a patient monitoring system and the relationships among
the components and/or aspects.
[0044] FIG. 27 is a flowchart that schematically illustrates an
embodiment of a method of providing glycemic control.
[0045] FIG. 28A illustrates an example embodiment of a sample cell
holder.
[0046] FIG. 28B is an exploded view of the sample cell holder of
FIG. 28A.
[0047] FIG. 29A illustrates an example embodiment of a cartridge
that includes the sample cell holder of FIG. 28A.
[0048] FIG. 29B is a close-up view of a portion of the cartridge of
FIG. 29A showing the fluid injectors.
[0049] FIG. 30 illustrates an example embodiment of a sample
cell.
[0050] FIG. 31 is a partial cross-sectional view of the sample cell
holder of FIG. 28A.
[0051] FIG. 32A illustrates an example embodiment of a cuvette for
use with the sample cell holder of FIG. 28A.
[0052] FIG. 32B is an exploded view of the cuvette of FIG. 32A.
[0053] FIG. 32C is an exploded view of the insert portion of the
cuvette of FIG. 32A.
[0054] FIG. 33 is an exploded view of another embodiment of a
cuvette.
[0055] FIGS. 34A-C illustrate the cuvette of FIG. 33 incorporated
into a rotor housing.
[0056] FIG. 35 illustrates an example embodiment of a juncture
between components in an analyte monitoring system.
[0057] FIG. 36 illustrates ends of fluid nipples for use with a
fluid interface in an analyte monitoring system.
[0058] FIG. 37 is a flowchart illustrating example methods for
measuring analytes in fluid samples.
[0059] FIGS. 38A-38D schematically illustrate various embodiments
of multi-lumen catheters.
[0060] FIG. 39 schematically illustrates an embodiment of a free
flow protection sub-system.
[0061] FIGS. 40A and 40B schematically illustrate embodiments of a
free flow protection device which is included in the free flow
protection system.
[0062] FIGS. 41A and 41B schematically illustrate embodiments of a
free flow protection system interfaced with a disposable.
[0063] FIGS. 42A-42C schematically illustrate embodiments of a free
flow protection system interfaced with an analyte monitoring
system.
[0064] 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
[0065] 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.
[0066] 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
[0067] 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.
[0068] 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.
[0069] 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.
[0070] 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.
[0071] 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.
[0072] 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 Alarms.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.
[0073] 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.
[0074] 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.
[0075] 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.
[0076] 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.
[0077] 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).
[0078] 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.
[0079] 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.
[0080] 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
[0081] 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.
[0082] 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.
[0083] 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.
[0084] 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). The sample can be optically measured both before and
after centrifugation (e.g., so that an analyte more readily
measurable in whole blood such as hemoglobin can be measured first,
and then an analyte readily measured in plasma such as glucose can
be measured). 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. In some
embodiments, the sample can be withdrawn continuously or
substantially continuously at certain time intervals (e.g., with a
given period). The time intervals at which the sample is withdrawn
can be periodic or aperiodic and range from approximately 1 minute
to approximately 15 minutes (e.g., the sample can be withdrawn at
time intervals of 1 minute, 5 minutes, 10 minutes or 15 minutes).
In some embodiments, the sample can be withdrawn at discrete time
intervals (e.g., once every 15 minutes, once every 30 minutes, once
every 45 minutes, once every hour, etc.).
[0085] The duration of time over which the sample of fluid is
withdrawn, referred to as "draw period", may be set to avoid
clinical drawbacks, and/or it can be varied according to a
health-care provider's wishes. For example, in some embodiments,
fluid may be continuously withdrawn into the sampling and analysis
system 400 over a draw period lasting approximately 10 seconds to
approximately 5 minutes.
[0086] In some embodiments, the amount of sample withdrawn from the
fluid source 402 can be small. For example, in some embodiments,
the volume of sample withdrawn from the fluid source can be between
approximately 1.0 ml and approximately 10.0 ml in a draw period
(e.g. 2.0 ml-6.0 ml or 2.0 ml-8.0 ml of sample can be withdrawn in
a draw period of approximately 1 minute). In some embodiments, the
amount of sample withdrawn can be in the range of approximately 20
ml/day to approximately 500 ml/day. In some embodiments, the amount
of sample withdrawn can be outside this range.
[0087] 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.
[0088] 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.
[0089] 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.
[0090] 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.
[0091] 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.
[0092] 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.
[0093] 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.
[0094] 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.
[0095] 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).
[0096] 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.
[0097] 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.
[0098] 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.).
[0099] 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.
[0100] 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.
[0101] 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.
[0102] 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
[0103] 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.
[0104] 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).
[0105] 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.
[0106] 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.
[0107] 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.
[0108] 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).
[0109] 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.
[0110] 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). In various embodiments,
the first pump 522 (pump #1) can be actuated at a rate such that
the flow of blood in the catheter attached to the patient is about
4.0-8.0 ml/minute on average. The sample is drawn 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 (Via), 533
(V3a), 542 (PV1), 559 (V7b), and 561 (V4b) can be closed and
therefore block (or substantially block) fluid flow by pinching the
tube.
[0111] In some embodiments of fluid systems, for example those that
are used in the hospital environment to periodically monitor the
concentration of various analytes in a patient, the amount of
sample of fluid withdrawn from the patient can be greater than
approximately 600 ml/day. Withdrawing large blood sample volumes
can be disadvantageous in patients who are critically ill or have
significant blood loss. Thus it may be advantageous to provide
systems and methods that can reduce the amount of withdrawn sample
volume to between: approximately 500 ml/day-450 ml/day;
approximately 450 ml/day-approximately 400 ml/day; approximately
400 ml/day-approximately 350 ml/day; approximately 350
ml/day-approximately 300 ml/day; approximately 300
ml/day-approximately 250 ml/day; approximately 250
ml/day-approximately 200 ml/day; approximately 200
ml/day-approximately 150 ml/day; and lower.
[0112] In some embodiments of the fluid system described herein,
withdrawing low sample volumes (e.g. a few hundreds of milliliters
per day) can be achieved by a combination of bubble sensors, pinch
valves and low inner diameter tubing. For example, in some
embodiments, the patient tube 512 and/or tube T1 (see FIGS. 5, 6)
may comprise lower inner diameter tubing to allow reducing the
amount of withdrawn sample. In some embodiments, the inner diameter
of the patient tube 512 and/or tube T1 can be approximately 0.02
inches. In some embodiments, the inner diameter of the patient tube
512 and/or tube T1 can vary between 0.015 inches-0.02 inches. In
some embodiments, the inner diameter of the patient tube 512 and/or
tube T1 can vary between 0.02 inches-0.04 inches. Other values for
the inner diameter of the patient tube 512 and/or tube T1 between
0.015 inches-0.04 inches are also possible.
[0113] In some embodiments of fluid systems, e.g., those providing
continuous glucose monitoring, a sample of fluid is withdrawn
periodically at certain intervals within a given time period. The
duration of time over which the sample of fluid is withdrawn may be
set to avoid clinical drawbacks, and/or it can be varied according
to a health-care provider's wishes. In some embodiments, the
duration of time over which the sample is withdrawn can be reduced
and/or minimized. For example, in some embodiments, fluid may be
continuously withdrawn into a monitoring system over a period of
time lasting approximately 15 seconds to approximately 5 minutes,
and that continuous withdrawal can take place at intervals of, for
example, 15 minutes. In some embodiments, for every 15 minute time
period, sample withdrawal may be minimized to last for a small
fraction of that period (e.g., only 15 seconds to 5 minutes).
Alternatively, it may be desirable to withdraw fluid over a longer
period of time and/or at a lower flow rate, as discussed infra.
[0114] In continuous glucose monitoring systems where sample
withdrawal time is minimized and/or sample volume is minimized,
using a combination of low inner diameter tubing, pinch valves and
sensors (e.g. hemoglobin sensors, color sensors, bubble sensors,
etc.) can reduce the amount of sample withdrawn. For example,
whereas in some cases an additional amount of sample is
withdrawn--exceeding the bare minimum required for sample analysis
and/or measurement--to provide for a margin of error, increasing
precision can reduce the margin of error, thereby reducing a need
for an additional amount of sample. Thus, a system that creates a
more defined sample or more precisely detects the arrival of a
sample can reduce the likelihood of errors and diminish the need
for drawing additional sample fluid.
[0115] As described further below, injection of bubbles between
slugs of fluid (e.g., blood, saline, sample, etc.) can help provide
for greater accuracy and therefore smaller sample volumes. A bubble
sensor can be used to sense the arrival of a sample with increased
precision (e.g., by detecting the transition from air to liquid).
This can reduce the amount of sample that is withdrawn (e.g., by
reducing a need to draw additional sample volume as a precaution).
Use of such techniques, for example, can allow the volume of sample
fluid withdrawn to be in a range of between approximately 2 ml and
approximately 6 ml in a certain interval of time (e.g., that
interval can be the duration of a draw period, which can range from
approximately 15 seconds to approximately 5 minutes, in some
embodiments). In some embodiments the volume of sample withdrawn
can lie outside this range, and the timer interval can be greater
or lesser than the example provided.
[0116] 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.
[0117] 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).
[0118] 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).
[0119] With the valves 542 (PV1), 559 (V7b), 561 (V4b), 523 (V0),
531 (Via), 566 (V3b), and 563 (V2b) closed, and the valves 529
(V7a) and 533 (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. In
some embodiments, the volume of tube 534 (T3) from connector 524
(C1) to bubble sensor 535 (BS9) may be approximately less than 10
ml.
[0120] 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 (Via) 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.
[0121] 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 (Via) 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.
[0122] 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 533 (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).
[0123] In some embodiments, when the leading edge of the sample
reaches blood sensor 552 (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 566
(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.
[0124] 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.
[0125] A second slug can be prepared by opening the valve 533
(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 533 (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).
[0126] 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.
[0127] 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).
[0128] 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 (Via), 566 (V3b), 563 (V2b), and 561 (V4b).
[0129] 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.
[0130] 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 (Via), 566 (V3b), 563 (V2b), and 561
(V4b).
[0131] 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.
[0132] 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.
[0133] 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).
[0134] 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.
[0135] In some embodiments, various components of the fluid system
that may be part of a non-disposable (or less-frequently
disposable) subsystem (e.g. 406), a first disposable subsystem
(e.g. 408) or a second disposable subsystem (e.g. 410) may comprise
fluid passageways (e.g. tubes) having different inner diameters.
For example, in some embodiments of a fluid system that may be used
to withdraw a sample of fluid from a patient for analysis, the
inner diameter of the fluid passageway connected to the patient may
be appropriately sized to withdraw the sample by applying reduced
pressure and reduce the amount of sample withdrawn. For example,
the amount of sample withdrawn into a fluid passageway in a certain
interval of time depends on the cross-sectional area of the fluid
passageway and the pressure applied to draw the sample. The amount
of sample withdrawn in a certain interval of time in a fluid
passageway having a small inner diameter will be smaller than the
amount of sample withdrawn in a certain interval of time in a fluid
passageway having a larger inner diameter assuming that the fluid
flow speed of the sample is the same in both fluid passageways. The
pressure required to draw a volume of sample in a fluid passageway
having a small inner diameter is greater than the pressure required
to draw the same volume of sample in a fluid passageway having a
larger inner diameter in the same amount of time. Thus,
appropriately choosing the inner diameter of the fluid passageway
can strike a balance between the amount of sample withdrawn and the
pressure used to withdraw the sample.
[0136] In some embodiments, the fluid system may comprise fluid
passageways having a larger internal diameter. An advantage of
fluid passageways with large internal diameter is that they can be
used as a reservoir or a storage passageway for storing fluids
(e.g. infusion fluid, fluid sample, treatment fluid, etc.). In some
embodiments, a widened passage can allow an amount of fluid to be
drawn with reduced pressure or can allow application of non-reduced
pressure to draw the same amount of fluid more quickly.
[0137] In some embodiments, the fluid system may comprise fluid
passageways having small inner diameter. A small inner diameter
passageway has a smaller surface area which may be advantageous to
reduce the amount of fluid that tends to adhere to the inner walls
of the fluid passageways. In embodiments that use the same fluid
passageway to transport different fluids at different times,
reducing amount of fluid that tends to adhere to the inner walls of
the fluid passageways is advantageous to reduce the amount of
mixing between the different fluids. Fluid passageways with small
inner diameter can also advantageously reduce the amount of fluids
(e.g. infusion fluid, sample fluid or treatment fluid) that is used
in the fluid system. Fluid passageways with small inner diameter
can also advantageously reduce the flow rate of a fluid at the same
pressure. This may reduce the risk of contamination, as discussed
infra.
[0138] FIG. 6A schematically illustrates an embodiment of a fluid
system having tubes of different inner diameters that can be part
of a system for withdrawing and analyzing fluid samples. The outer
diameters of the various tubes (e.g. T1, T2, T3, etc.) in the
embodiment illustrated in FIG. 6A may vary between approximately
0.06 inches and approximately 0.07 inches, while the inner diameter
of the various tubes (e.g. T1, T2, T3, etc.) may vary between
approximately 0.02 inches and approximately 0.04 inches. The
various tubes (e.g. T1, T2, T3, etc.) in the embodiment illustrated
in FIG. 6A may comprise PVC.
[0139] In the embodiment illustrated in FIG. 6A, the patient tube
512 and/or tube T1 may have an inner diameter of approximately 0.03
inches and an outer diameter of approximately 0.06 inches. The
inner diameter of 0.03 inches is selected to withdraw a sample of
fluid from the patient in a short amount of time by applying a
reduced amount of pressure by the pump 522 (Pump 1) while still
maintaining a low draw volume between approximately 100 ml/day to
approximately 500 ml/day.
[0140] In the embodiment illustrated in FIG. 6A, the inner diameter
of tubing 528 or T4 is selected to be approximately 0.04 inches so
that the length of the loop 530 of the tubing 528 can be reduced,
compared to a length of the same general volume and storage
capacity having an inner diameter of less than approximately 0.04
inches. Indeed, altering the inner diameter of a tube in such a
system can effectively reduce lengths and provide for more
inexpensive manufacture, as well as reducing friction of fluid flow
in the system, reducing pressure in portions of the flow path, etc.
For example, increasing the inner diameter of the tubing 528 from
0.02 inches to 0.04 inches can allow the length of the loop 530
required to store approximately 1 ml of fluid to be reduced from
approximately 17 feet to approximately 4 feet. A reduction in the
length of the loop 530 provides space-saving and other
benefits.
[0141] The inner diameter of the tubing 536 or T2 and tubing 538 or
T3 is approximately 0.02 inches in the embodiment illustrated in
FIG. 6A. In some embodiments, tubings 536 and 538 may communicate
the sample to the sample cell 548 for analysis and may be
periodically flushed, e.g., with saline. Having small inner
diameters for tubings 536 and 538 can reduce the amount of mixing
between saline and the sample which can lead to less sample
dilution. Having smaller inner diameters for tubings 536 and 538
can also advantageously reduce the amount of saline required for
flushing and/or the amount of sample transferred to the sample cell
548.
Mechanical/Fluid System Interface
[0142] 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.
[0143] 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 710. A portion of the
non-disposable fluid-handling subsystem 708 can be located on or in
the moveable portion 706 (which can be a door having a slide or a
hinge, a detachable face portion, etc.).
[0144] 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 710.
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.
[0145] 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.
[0146] 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.
[0147] 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.
[0148] 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.
[0149] 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.
[0150] 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.
[0151] 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.
[0152] 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.
[0153] 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.
[0154] 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.
[0155] 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.
[0156] 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.
[0157] 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.
[0158] 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.
[0159] 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.
[0160] 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.
[0161] 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.
[0162] 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.
[0163] 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.
[0164] 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)
[0165] 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.
[0166] 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.
[0167] 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.
[0168] 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.
[0169] 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).
[0170] 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.
[0171] 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.
[0172] 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).
[0173] 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.
[0174] 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.
[0175] 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.
[0176] 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
[0177] 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 include, e.g., glucose and
lactate in whole blood or blood plasma.
[0178] 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.
[0179] 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.
[0180] 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.
[0181] 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.
[0182] 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.
[0183] 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.
[0184] 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.
[0185] 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.
[0186] 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.
[0187] 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. 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.
[0188] 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.
[0189] 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.
[0190] 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.
[0191] 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."
[0192] 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.
[0193] 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
[0194] 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.
[0195] 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.
[0196] 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.
[0197] 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.
[0198] 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.
[0199] 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
[0200] 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.
[0201] 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.
[0202] 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.
[0203] 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.
[0204] 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 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.
[0205] 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).
[0206] 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).
[0207] 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.
[0208] 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.
[0209] 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).
[0210] 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.
[0211] 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).
[0212] 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.
[0213] 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.
[0214] 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.
[0215] 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
[0216] 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.
[0217] 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.
[0218] 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.
[0219] 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.
[0220] 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(.andgate.)
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.
[0221] 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).
[0222] 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.
[0223] 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.
[0224] 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)!).
[0225] 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..
[0226] 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.
[0227] 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.
[0228] 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.
[0229] 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.
[0230] 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.
[0231] 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.
[0232] 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).
[0233] 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.
[0234] 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=E
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).
[0235] 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.
[0236] 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.
[0237] An example of an alternative embodiment of block 2130
includes the following steps and calculations.
[0238] 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.
[0239] 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.
[0240] 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 p=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.
[0241] 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.
[0242] 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.
[0243] 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.n=P.sup..perp..sub.n .alpha..sub.X/.alpha..sub.X
.sup.TP.sup..perp..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.TV.kappa..sub.n.
[0244] The steps 4-6 of this example are an embodiment of the HLA
technique.
[0245] 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.a 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
[0246] 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
[0247] 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."
Example Experiment 2
[0248] 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. 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 Hetastarch Pyruvate Sodium
Ampicillin Sulbactam Human Albumin Pyruvic Acid Azithromycin
Hydroxy Butyric Acid Salicylate Sodium Aztreonam Imipenem
Cilastatin Sodium Acetate Bacitracin Iohexol Sodium Bicarbonate
Benzyl Alcohol L_Arginine Sodium Chloride Calcium Chloride Lactate
Sodium Sodium Citrate Calcium Gluconate Magnesium Sulfate Sodium
Thiosulfate Cefazolin Maltose Sulfadiazine Cefoparazone Mannitol
Urea Cefotaxime Sodium Meropenem Uric Acid Ceftazidime Oxylate
Potassium Voriconazole Ceftriaxone Phenytoin Xylitol D_Sorbitol
Phosphates Potassium Xylose Dextran Piperacillin PC 1 of Saline
covariance Ertapenem Piperacillin Tazobactam PC 2 of Saline
covariance Ethanol PlasmaLyteA PC 3 of Saline covariance
Ethosuximide Procaine HCl PC 4 of Saline covariance Glycerol
Propylene Glycol ICU/Normal difference spectrum Heparin
Pyrazinamide
[0249] 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.
[0250] 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.
[0251] 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.
[0252] 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
[0253] 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.
[0254] 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 Example Average Standard Experiment Interferent
Sample Prediction Deviation No. Calibration Population Error
(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
[0255] 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
[0256] 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.
[0257] 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.
[0258] 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.
[0259] 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.
[0260] 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.
[0261] 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).
[0262] 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."
[0263] 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).
[0264] The button 2426 ("Dose History") may be actuated to bring up
a dosing history window that displays patient dosing history for an
analyte or medicament of interest. For example, in some
embodiments, the dosing history window displays insulin dosing
history of the patient and/or appropriate hospital dosing
protocols. A nurse attending the patient can actuate the dosing
history button 2426 to determine the time when the patient last
received an insulin dose, the last dosage amount, and/or the time
and amount of the next dosage. The system 400 may receive the
patient dosing history via wired or wireless communications from a
hospital information system.
[0265] 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.
[0266] Related Components
[0267] 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.
[0268] 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.
[0269] 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.
[0270] 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.
[0271] 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.
[0272] 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.
[0273] 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.
[0274] 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.
[0275] 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.
[0276] 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).
[0277] 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 that proper insulin doses are calculated.
Analyte Control and Monitoring
[0278] In some embodiments, it may 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 may be used
to monitor and/or control other analytes (e.g., lactate).
[0279] For example, diabetic individuals control their glucose
levels by administration of insulin. If a diabetic patient is
admitted to a hospital or ICU, the patient may be in a condition in
which he or she cannot self-administer insulin. Advantageously,
embodiments of the analyte detection systems disclosed herein may
be used to control the level of glucose in the patient.
Additionally, it has been found that a majority of patients
admitted to the ICU exhibit hyperglycemia without having diabetes.
In such patients it may be beneficial to monitor and control their
blood glucose level to be within a particular range of values.
Further, it has been shown that tightly controlling blood glucose
levels to be within a stringent range may be beneficial to patients
undergoing surgical procedures.
[0280] A patient admitted to the ICU or undergoing surgery may be
administered a variety of drugs and fluids such as Hetastarch,
intravenous antibiotics, intravenous glucose, intravenous insulin,
intravenous fluids such as saline, etc., which may act as
interferents and make it difficult to determine the blood glucose
level. Moreover, the presence of additional drugs and fluids in the
blood stream may require different methods for measuring and
controlling blood glucose level. Also, the patient may exhibit
significant changes in hematocrit levels due to blood loss or
internal hemorrhage, and there can be unexpected changes in the
blood gas level or a rise in the level of bilirubin and ammonia
levels in the event of an organ failure. Embodiments of the systems
and methods disclosed herein advantageously may be used to monitor
and control blood glucose (and/or other analytes) in the presence
of possible interferents to estimation of glucose and for patients
experiencing health problems.
[0281] In some environments, Tight Glycemic Control (TGC) can
include: (1) substantially continuous monitoring (which can include
periodic monitoring, at relatively frequent intervals of every 1,
5, 15, 30, 45, and/or 60 minutes, for example) of glucose levels;
(2) determination of substances that tend to increase glucose
levels (e.g., sugars such as dextrose) and/or decrease glucose
levels (e.g., insulin); and/or (3) responsive delivery of one or
more of such substances, if appropriate under the controlling TGC
protocol. For example, one possible TGC protocol can be achieved by
controlling glucose within a relatively narrow range (for example
between 70 mg/dL to 110 mg/dL). As will be further described, in
some embodiments, TGC may be achieved by using an analyte
monitoring system to make continuous and/or periodic but frequent
measurements of glucose levels.
[0282] In some embodiments, the analyte detection system
schematically illustrated in FIGS. 4, 5, and 6 may 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 may
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 may be predetermined (e.g., according to a
hospital protocol or a physician's recommendation), or the range
may be adjusted as conditions change.
[0283] In an example of glycemic control, a system can be used to
determine and monitor the concentration of glucose in the sample.
If the concentration of glucose falls below a lower threshold,
glucose from an external source can be supplied. If the
concentration of glucose increases above an upper threshold,
insulin from an external source can be supplied. In some
embodiments, glucose or insulin may be infused in a patient
continuously over a certain time interval or may be injected in a
large quantity at once (referred to as "bolus injection").
[0284] In some embodiments, a glycemic control system may be
capable of delivering glucose, dextrose, glycogen, and/or glucagon
from an external source relatively quickly in the event of
hypoglycemia. As discussed, embodiments of the glycemic control
system may be capable of delivering insulin from an external source
relatively quickly in the event of hyperglycemia.
[0285] 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 may 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.
[0286] 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 may 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.
[0287] 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 for
infusion (or bolus injection) may be calculated based on one or
more detected concentration levels of glucose. The source 2782
advantageously may 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. 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.
[0288] 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 (or alternatively injected as
a bolus) into the patient. After a suitable amount of insulin has
been infused (or bolus injected) to the patient, the control system
can close the pinch valve 521 and open the pinch valves 542 and/or
2786 to allow flow of saline and/or glucose. The suitable amount of
insulin may be calculated based on one or more detected
concentration levels of glucose in the patient. The insulin source
518 advantageously may be located at a short enough fluidic
distance from the patient such that insulin can be delivered to the
patient within about one to about ten minutes. In other
embodiments, the insulin source 518 may be located at the site
where the patient tube 512 interfaces with the patient so that
insulin can be delivered to the patient within about one
minute.
[0289] In some embodiments, sampling bodily fluid from a patient
and providing medication to the patient may be achieved through the
same lines of the fluid handling system. For example, in some
embodiments, a port to a patient can be shared by alternately
drawing samples and medicating through the same line. In some
embodiments, a bolus can be provided to the patient at regular
intervals (in the same or different lines). For example, a bolus of
insulin can be provided to a patient after meals. In another
embodiment comprising a shared line, a bolus of medication can be
delivered when returning part of a body fluid sample back to the
patient. In some implementations, the bolus of medication is
delivered midway between samples (e.g., every 7.5 minutes if
samples are drawn every 15 minutes). In other embodiment, a dual
lumen tube can be used, wherein one lumen is used for the sample
and the other lumen to medicate. In yet another embodiment, an
analyte detection system (e.g., an "OptiScanner.RTM." monitor) may
provide suitable commands to a separate insulin pump (on a shared
port or different line).
[0290] Example Method for Glycemic Control
[0291] 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 may 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 may 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 may be made within about one to
about thirty minutes (e.g., every fifteen minutes).
[0292] 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 may 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. This calculation 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.
[0293] 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. 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.
[0294] In block 2765, the method 2700 returns to block 2705 to
await the start of the next measurement cycle, which may be within
about one to about thirty minutes (e.g., every fifteen minutes). 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.
[0295] Examples of Some Possible Additional or Alternative
Analytes
[0296] 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 may be particularly helpful in ICUs, which receive
patients experiencing trauma. 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.
[0297] 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.
[0298] 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.
[0299] 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 may be monitored and used to
provide information and/or warnings to a health care provider.
[0300] Sample Fluids
[0301] In many of the embodiments discussed herein, measurements
can be taken from a sample of bodily fluid. In some embodiments
whole blood can be used. For some analyte measurements,
characteristics of the sample can impede measurement. For example,
blood can include some analytes in the red blood cells and some
analytes in white blood cells. Some analytes can be present in the
blood and not present within either type of blood cell. Other,
non-analyte components in whole blood may have chemical bonds with
similar vibrational frequencies to those of the analyte. Analytes
can be unhelpfully shielded (optically, physically, or both) by
non-analyte components. Indeed, in some cases analytes can be
located within cell membranes and therefore more difficult to
measure or quantify, either because they are not evenly
distributed, because they are chemically bound, or for some other
reason. Other particles within a sample (e.g., blood) can interfere
with the measurement, thereby reducing accuracy of the system. For
example, in embodiments that use an optical measurement system
(e.g., 412) red blood cells, or other particles, can absorb,
reflect, scatter, or otherwise interfere with the light that is
transferred through the sample. Thus, in some embodiments, it can
be advantageous to remove these interfering particles or to
mitigate or suppress their adverse effects on the measurement.
Similarly, it can be advantageous to break down or adjust
biological or physiological structures in order to remove optical
or physical barriers to measurement, evenly distribute analytes, or
otherwise improve analyte detection and measurement. For example,
blood can be separated using a centrifuge or filter into components
that are organized by similar mass. Blood can also be separated
using a lysing process that breaks down the blood's structure on a
more fundamental level, breaking cell membranes and causing the
contents of cells to be released into a more general suspension.
Separation and/or lysing can occur using many mechanical and
chemical approaches. For example, cells can be broken down using
sonication, heat, lasers, ultrasound, physical shaking,
homogenization, freeze-thaw procedures, grinding, detergents or
other chemical approaches, enzymatic cell disruption, buffers,
bacterial or other biological cell lysates, etc. Separation into
components by mass can occur through settling, centrifugation, etc.
Separation by mass can occur before or after cell disruption (e.g.,
by lysing).
[0302] A fluid handling system (e.g., 404) can prepare a sample for
measurement. For example, a sample can be prepared by causing
interfering substances or particles to move away from an analyte.
In some embodiments, the fluid handling system can lyse the red
blood cells in a portion of bodily fluid that will be used for the
measurement, thereby releasing analytes from being confined within
cells. The fluid handling system can include an ultrasound source
configured to direct ultrasound energy into the bodily fluid to
lyse the red blood cells. The red blood cells can be lysed using
any other suitable manner as well, such as the mechanical, sonic,
chemical, or optical approaches listed above. Particles other than
red blood cells in the sample fluid can also be lysed or broken up
using the ultrasound energy or in another manner. In some
embodiments, the lysed red blood cells (or other particles)
interfere less with the measurement than in their whole state.
[0303] Once the red blood cells have been lysed, the cells'
cytoplasm and other contents can be released and intermingle with
other blood components (e.g., the blood plasma). In some
embodiments, the cytoplasm and other lysed components of the red
blood cells (or other lysed particles) can interfere with the
measurement. Thus, it can be advantageous in some embodiments to
remove the red blood cells, or other undesirable particles, from
the blood plasma (e.g., using filtering or centrifuging). In some
embodiments, the separation of the blood plasma can be performed by
the fluid handling system in lieu of lysing the particles as
discussed above. In other embodiments, the fluid handling system
can be configured to both lyse particles in the sample fluid and
also separate the sample into components (e.g., by centrifuging)
before or after lysing.
[0304] FIG. 37 is a flowchart showing example embodiments of
methods 3700 for measuring concentrations of analytes. The methods
3700 disclosed by FIG. 37 can be performed by an analyte (e.g.,
glucose) monitoring apparatus (e.g., the monitoring apparatus 2632
of FIG. 26), or by any other suitable device. At block 3702, a
sample of fluid is drawn. The fluid sample can be drawn from a
patient or other fluid source, and the fluid can be blood, for
example. At block 3704, an analysis portion of the fluid sample is
delivered to a sample preparation unit. At block 3706, the sample
preparation unit lyses cells (e.g., blood cells) in the analysis
portion of the fluid sample. And at block 3708, the monitoring
system measures the concentration of an analyte in the analysis
portion of the fluid sample. In some embodiments, additional steps
can be performed. For example, in block 3710, the sample
preparation unit can separate the analysis portion of the fluid
sample into components after the cells have been lysed. This can
provide the advantage of substantially isolating a component of the
fluid so that a measurement can be made in a component of the fluid
without other components influencing the measurement. If the lysed
cells are blood cells, for example, lysing can release cytoplasm
and other cell contents from the cell membranes into the blood
plasma. Then by centrifugation or filtering, one component of the
cells (e.g., the cytoplasm) can be substantially isolated, thereby
improving the ability to measure one component (e.g., the
cytoplasm) without being interference or obstruction from other
components (e.g., cell membranes). Centrifugation can stratify the
components into layers. However, centrifugation before lysing can
form different layers than centrifugation after lysing. For
example, centrifugation after lysing may involve additional
substances having their own distinct mass or other physical
qualities, resulting in additional strata containing particular
cell components of similar mass. In some embodiments, if the cells
are not lysed, the accuracy of measurements taken on components
inside the cells (e.g., cytoplasm) can be reduced by the cell
membranes or other cell components. By lysing the cells, a cell
component to be measured (e.g., cytoplasm) can be more easily
isolated and measured. In the flowchart, the lines leading to and
from the block 3710 are dotted lines to show that block 3710 is an
optional feature of the method 3700.
[0305] In some embodiments, the system can deliver a second
analysis portion of the fluid sample to the sample preparation unit
(block 3712). Then, at block 3714, the sample preparation unit can
separate the second analysis portion of the fluid sample into a
plurality of components (e.g., by centrifugation or filtering). At
block 3716, the concentration of a second analyte is measured in a
component of the second analysis portion of the fluid sample. Thus,
in some embodiments, a first analysis portion of the fluid sample
is prepared for analysis by lysing cells, and a second analysis
portion of the fluid sample is prepared for analysis by separating
the fluid into a plurality of components (e.g., by centrifugation,
filtering, or some other selective process based on mass, size,
magnetics, electrical qualities, etc.). In some embodiments, a
single analysis portion of the fluid sample can be prepared for
analysis by both lysing cells in the fluid and by separating the
fluid into a plurality of components. Thus, the lysing and the
component separating (e.g., by centrifuging) can be performed in
series on the same portion of the sample or in parallel on
different portions of the sample, or on different samples.
[0306] The line leading to block 3712 is dotted to indicate that
the features of blocks 3712, 3714, and 3716 are optional to the
method 3700. Although FIG. 37 shows a single flowchart, the method
3700 can follow several different possible paths. For example, the
method can include blocks 3702, 3704, 3706, and 3708. In some
embodiments, the method can include blocks, 3702, 3704, 3706, 3710,
and 3708. In some embodiments, the method can include blocks, 3702,
3704, 3706, 3710, 3708, 3712, 3714, and 3716. In some embodiments,
the method can include blocks, 3702, 3704, 3706, 3708, 3712, 3714,
and 3716.
[0307] Sample Cell Holder
[0308] FIG. 28A shows a sample cell holder 2820, which can be
similar to or the same as the sample cell holder 820, or any other
sample cell holder disclosed herein. FIG. 28B is an exploded view
of the sample cell holder 2820. The sample cell holder 2820 can
include a rotor housing 2834 that can be mounted (e.g., onto an
optical interface portion 1030 of a cartridge 1000) such that the
rotor housing 2834 can rotate about the axis 2824. A centrifuge
interface 2836 can be attached to the rotor housing 2834. In some
embodiments, posts 2837 formed on the centrifuge interface piece
2836 can mount into holes 2839 formed in the rotor housing 2834,
and can be secured thereto using an adhesive, a snap fit
connection, a friction fit connection, or any other suitable
fastening mechanism. The centrifuge interface 2836 can engage a
centrifuge motor (not shown) when the cartridge (e.g., 1000) is
inserted into the body of the monitoring system (e.g., 700). The
centrifuge motor can be configured to rotate the sample cell holder
2820 at least at about 7200 RPM, 5000 RPM, or 4500 RPM. Other
rotational speeds can also be used, such as 1000 RPM, 2000 RPM,
3000 RPM, or 4000 RPM. The rotational speed can be sufficiently
large to separate a sample fluid (e.g., blood) into a plurality of
components (e.g., plasma, red blood cells, buffy coat, etc.).
[0309] The rotor housing 2834 can include a sample cell 2848 that
includes a sample cell cover 2841, a recessed portion 2843 of the
rotor housing 2834, and a cuvette 2870. The cuvette 2870 can
provide a window 2856 configured to allow radiation from the
optical system (e.g., optical system 412) to pass through the
sample contained in the sample cell 2848. The sample cell cover
2841 can be secured to the rotor housing 2834 using an adhesive, a
snap fit connection, sonic welding, or any other suitable fastening
mechanism, and the cuvette 2870 can be sandwiched between the
sample cell cover 2841 and the rotor housing 2834. In some
embodiments, the cuvette 2870 can be secured directly to the rotor
housing 2834 and/or the sample cell cover 2841 using an adhesive or
sonic welding or any other suitable connection mechanism. The
cuvette 2870 can be positioned so as to be aligned with holes 2857,
2859 formed in the rotor housing 2834 and the sample cell cover
2841 so that radiation from the optical system can reach the window
and pass through the sample cell 2848.
[0310] The sample cell cover 2841 can include two receiving nubs
2812A that provide inlet and outlet fluid pathways for fluid to
enter and leave the sample cell 2848. The recessed portion 2843 of
the rotor housing 2834 can include channels 2850 to provide a fluid
flow path from an inlet point 2851 associated with the inlet
receiving nub 2812A, to the cuvette 2870, and to an outlet point
2853 associated with the outlet receiving nub 2812A. It will be
understood that the fluid pathway through the sample cell 2848 can
be provided by channels formed in the back of the sample cell
cover, or by tubing, or any other suitable manner. It will also be
understood that, in some cases, fluid may be directed into the
sample cell 2848 through the outlet and may exit the sample cell
2848 through the inlet (e.g., when flushing the sample cell 2848
with saline or cleaning solution). In some embodiments, the channel
2850 can include a wide portion 2855 located adjacent to the
cuvette 2870 such that the wide portion 2855 can collect particles
(e.g., red blood cells) that are isolated during centrifuging and
moved out of the optical pathway of the optical system.
[0311] The rotor housing 2834 can include an opening 2830
positioned generally at the opposite end of the rotor housing 2834
from the sample cell 2848. The opening 2830 can provide an
alternative optical pathway between a radiation source and a
radiation detector of the optical system. The alternate optical
pathway through the opening 2830 may be used, for example, for
obtaining a calibration measurement of the source and detector
without an intervening window or sample. The rotor housing 2834 can
include a shunt 2886, and a shunt cover 2887. The shunt cover 2887
can include two receiving nubs 2812B to provide an inlet and outlet
for fluid to enter and leave the shunt 2886.
[0312] With reference now to FIGS. 29A and 29B, the receiving nubs
2812A, 2812B of the sample cell colder 2820 can be configured to
engage or dock with fluid nipples 2914 of a fluid injector 2915 to
provide a fluid connection between tubes 2916 of the fluid handling
system and the sample cell 2848 or the shunt 2886. FIG. 29A is a
partial perspective view of a cartridge 2900 which can be similar
to or the same as the cartridge 1000 of FIG. 10 in many regards.
FIG. 29B is a partial view of the injector 2915 and receiving nubs
2812A in a disengaged configuration with the injector seal
omitted.
[0313] The cartridge 2900 can have an optical interface portion
2930 which can include the sample cell holder 2820 rotatably
mounted to an outer housing 2931. The fluid injector 2915 can
receive tubes 2916 that provide a fluid connection between the
fluid injector 2915 and the rest of the fluidics system (e.g., via
interface tubes 582 and 584). The fluid injector 2915 can be
movable between engaged and disengaged positions. The fluid
injector 2915 can be attached to the outer housing 2931 by an
injector seal 2917 that can be resiliently deformable and
configured to bias the injector 2915 to the disengaged position (as
shown in FIGS. 29A and 29B).
[0314] FIG. 29B shows the fluid injector 2915 in the disengaged
position, and the injector seal 1917 is omitted to allow a view
into the inside of the outer housing 2931. The receiving numbs
2812A can include a number of guide posts (e.g., four posts each)
configured to guide the fluid nipples 2914 of the fluid injector
2915 as it transitions from the disengaged position to the engaged
position. In some embodiments, an actuator (not shown) can be
driven by a motor to press against the fluid injector 2915 and
drive the fluid nipples 2914 toward the receiving nubs 2812A until
a fluid connection is established between the fluid nipples 2914
and the receiving nubs 2812A. When the actuator (not shown) is
retracted, the injector seal 2917 can resiliently return the fluid
injector 2915 to the disengaged position, pulling the fluid nipples
2914 away from, and breaking the fluid connection with, the
receiving nubs 2912A. Thus, the fluid injector 2915 can be
retracted to a position that is clear from contact with the sample
cell holder 2820 when the centrifuge motor spins the sample cell
holder 2820. It will be understood that the sample cell holder 2820
can be rotated to a position in which the receiving nubs 2812B
associated with the shunt 2886 can aligned with the fluid injector
2915 so that the fluid nipples 2914 can engage the receiving nubs
2912B to provide a fluid connection to the shunt 2886.
[0315] FIG. 30 shows a perspective cross-sectional view of another
embodiment of a sample cell holder 3020 that can include a sample
cell 3048, a rotor housing 3034, and a centrifuge interface 3036.
In the embodiment shown in FIG. 30, the centrifuge interface piece
3036 can be laser welded to the rotor housing 3034. The centrifuge
interface 3036 can include posts 3037 (e.g., four posts) that are
configured to engage holes 3039 formed in the rotor housing 3034.
The posts 3037 can include studs 3021 that form a step 3023 at the
periphery of the posts 3037. The studs 3021 can be configured to
fit into the holes 3039 such that the steps 3023 engage the
shoulders 3025 of the holes 3039. The studs 3021 can be laser
welded to the rotor housing 3034, and the stress on the connection
between the rotor housing 3034 and the centrifuge interface 3036
that is caused by the centrifuge motor (not shown) rotating the
sample cell holder 3020 are kept generally localized to the
locations that are laser welded together, thereby preventing
warping or other deformation that can occur as a result of the
force introduced by the centrifuge motor. The portions where the
centrifuging stress is focused can be fortified to prevent
deformation, or they can located where minor deformation does not
significantly affect the positioning of the sample cell 3048 or
otherwise adversely affect the operation of the monitoring
system.
[0316] FIG. 31 is a partial cross-sectional view of the sample cell
holder 2820 that includes the sample cell 2848. Fluid can enter the
sample cell 2848 via the inlet receiving nub 2812A and travel
toward the cuvette 2870 via the channel 2850. When the sample cell
holder 2820 is rotated by the centrifuge motor, the fluid sample
contained in the sample cell 2848 can be separated such that
heavier particles (e.g., red blood cells) are pulled radially
outwardly (toward the right in FIG. 31) into the bloodtrap 2855 and
lighter particles (e.g., blood plasma) remain in the cuvette 2870
aligned with the window 2856.
[0317] A beam of light 3127 can be directed from a light source to
an optical detector such that the beam of light 3127 passes through
the window 2856 and through the fluid (e.g., plasma) contained in
the sample portion 3129 of the sample cell 2848. The sample portion
3129 can be significantly thinner than the channels 2850 that lead
to and from the cuvette 2870. In some embodiments, the path length
of the light through the fluid sample contained in the sample
portion 3129 is at least about 0.001 inches and/or no more than
about 0.003 inches, and can be about 0.002 inches, although path
lengths outside these ranges can also be used. The window 2856 can
provide an aperture 3131 for the light beam 3127 that is at least
about 0.25 inches wide and/or no more than about 0.50 inches wide,
and can be about 0.31 inches wide, although widths outside these
ranges can also be used. The aperture 3131 size can be larger than
the beam of light 3127 that passes through the sample portion 3129.
In some embodiments, the use of laser welding for features on the
rotor can widen the process window.
[0318] Cuvette
[0319] FIG. 32A is a perspective view of the cuvette 2870, FIG. 32B
is an exploded view of the cuvette 2870, and FIG. 32C is an
exploded view of the insert portion 3272 of the cuvette. The insert
portion 3272 includes an upper window piece 3274 and a lower window
piece 3276 sandwiched together with an adhesive layer 3278 formed
therebetween to secure the upper window piece 3274 to the lower
window piece 3276. The window pieces 3274, 3276 can be made from
Calcium Fluoride or other suitably transparent material. As can be
seen in FIG. 32B, in some cases, the loser window piece 3276 can be
somewhat longer than the upper window piece 3274. In some
embodiments, the lower window piece 3276 can be longer than the
upper window piece 3274 by a distance of at least about 0.25 mm
and/or by less than or equal to about 2.0 mm, although distances
outside these ranges can also be used. In some embodiments, the
lower window piece 3276 can be longer than the upper window piece
3274 by a distance of about 1.0 mm. The window pieces 3274, 3276
can be relatively thin to conserve on the cost of Calcium Fluoride.
The window pieces 3274, 3276 can be at least about 0.015 inches
thick, and or no more than about 0.025 inches thick, and can be
about 0.02 inches thick, although other thicknesses outside these
ranges can be used.
[0320] The adhesive 3278 can be positioned at the sides of the
insert portion 3272, such that a generally round aperture portion
3280 of the insert portion 3272 does not contain any adhesive
between the window pieces 3274, 3276, thereby forming a gap between
the window pieces 3274 at the aperture portion 3280. The gap
provides the thin sample portion 3129 discussed above in connection
with FIG. 31. The thickness of the adhesive layer 3278 can set the
width of the gap (and the sample portion 3129) between the window
pieces 3274, 3276. Thus, the adhesive layer can have a thickness of
at least about 0.001 inches and/or no more than about 0.003 inches,
and can be about 0.002 inches, although thicknesses outside these
ranges can also be used. The adhesive 3278 can substantially
completely cover two opposing sides of the insert portion 3272. The
other two sides of the insert portion 3272 can be partially covered
by the adhesive 3278, forming an inlet 3282 at one end of the
insert portion 3272 and an outlet 3284 at the opposing side of the
insert portion 3272. In some embodiments, the outlet 3284 can be
wider than the inlet 3282. The width of the outlet 3284 can be at
least about 2 times the width of the inlet 3282 and/or no more than
about 3 times the width of the inlet 3282, and can be about 2.5
times the width of the inlet 3282. Other dimensions may also be
used for the inlet 3282 and outlet 3284. The adhesive can be an
epoxy resin, such as Delo-Monopox 1197 provided by Delo Industrial
Adhesives LLC of Hauppauge, N.Y.
[0321] The insert portion 3272 can be sandwiched between an upper
clamshell piece 3286 and a lower clamshell piece 3288. The
clamshell pieces 3286, 3288 can be injection molded rigid plastic
pieces and may be formed of polycarbonate or any other suitably
rigid material. The upper clamshell 3286 and lower clamshell 3288
can include holes 3285 and 3287 configured to align with the
aperture portion 3280 of the insert portion 3272 such that light
from the optical system can pass through the cuvette 3270. The
upper clamshell piece 3286 can include arms 3290 that extend toward
the lower clamshell piece 3288 and are configured to engage the
lower clamshell piece 3288 so as to secure the upper clamshell
piece 3286 to the lower clamshell piece 3288 with the insert
portion 3272 sandwiched therebetween. The lower clamshell piece
3288 can include tapered walls 3292 that are configured to engage
the arms 3290 to maintain a pressure exerted on the insert portion
3272. In some embodiments, the upper clamshell piece 3286 can be
secured to the lower clamshell piece 3288 using an adhesive. In
some cases, no adhesive is used. The clamshell pieces 3286, 3288
can provide additional support to the cuvette 3270 so as to
maintain the cuvette's 3270 integrity during repeated centrifuging,
for example, at about 5000 RPM (or other speeds disclosed herein).
The clamshell pieces 3286, 3288 can also stabilize the spacing
between the window pieces 3274, 3276 so as to maintain a
substantially constant optical path length through the sample
portion of the cuvette 3270. In some embodiments, the clamshell
pieces 3286, 3288 can be made from a glass-filled material (e.g., a
polymer or other plastic material), such as glass-filled nylon or
glass-filled polypropylene. In some embodiments, the material can
be 30% glass-filled. In some embodiments, the material can be at
least about 10% glass-filled and/or less than or equal to about 50%
glass filled, although values outside these ranges may also be
used.
[0322] FIG. 33 is an exploded view of another embodiment of a
cuvette 3370 that can be similar to or the same as the cuvette
2870, or any other cuvette described herein, in many regards. The
cuvette 3370 includes an insert portion 3372 that can have two
window pieces 3374, 3376 sandwiched together with an adhesive
formed therebetween, similar to the cuvette 2870 described above.
The window pieces 3374, 3376 can be made from Calcium Fluoride. The
windows pieces 3374, 3376 can be of the same size, and can be
square or rectangular in shape. In some embodiments, the window
pieces 3374, 3376 can have side lengths between about 8 mm and 15
mm, and can have dimensions of about 11 mm by 11 mm, although other
dimensions can be used. The window pieces 3374, 3376 can be at
least about 0.015 inches thick, and or no more than about 0.025
inches thick, and can be about 0.02 inches thick, although other
thicknesses outside these ranges can be used. An aperture portion
3380 can be formed in the center where no adhesive is present and
there is a gap between the window pieces 3374, 3376. In some
embodiments, an insert 3375 can be positioned between the window
pieces 3374, 3376 when the window pieces 3374, 3376 are adhered to
each other to maintain a constant gap size and form a precise
optical path length through the sample portion. The insert 3375 can
be removed from the insert portion 3372 once the adhesive
cures.
[0323] In some embodiments, no adhesive is applied between the
window pieces 3374, 3376. A spacer (not shown) can be positioned
between the upper window piece 3374 and the lower window piece 3376
such that a thin gap is maintained therebetween. The spacer can
have a thickness that is configured to provide a path length
between the window pieces of at least about 0.001 inches and/or no
more than about 0.003 inches, and in some cases of about 0.002
inches, although other path lengths can be used. The spacer can be
made from Teflon or other suitable material. Thus, the window
pieces 3374, 3376 are not directly adhered or otherwise secured to
each other, but are pressed together by the two clamshell pieces
3386, 3388 which are secured to each other. This can simplify the
construction of the cuvette since no hand application of the epoxy
resin to the window pieces is required. In some cases, the
clamshell pieces can be secured using an adhesive, but application
of the adhesive to the clamshell pieces can simpler than gluing the
window pieces directly.
[0324] The insert portion 3372 can be sandwiched between the upper
clamshell piece 3386 and the lower clamshell piece 3388, which can
each include an opening 3385, 3387 that aligns with the aperture
portion 3380 of the insert portion 3372. The lower clamshell piece
3388 can include raised sidewalls 3390 that extend substantially
around the entire periphery except for an inlet gap 3391 and an
outlet gap 3392. The sidewalls 3390 can extend around each of the
corners of the lower clamshell piece 3388. This can provide
rigidity to the cuvette 3370 and aid in maintaining the integrity
of the cuvette 3370 when it spins at high speeds during repeated
centrifuging. Thus, the same cuvette 3370 can be used for many
different samples, where the cuvette 3370 is subjected to
centrifuging stresses for each sample. It will be understood that
although the cuvette illustrated in FIG. 33 is generally
square-shaped and has four corners, a cuvette having a different
number of corners and sides can be used.
[0325] In some embodiments, the top clamshell piece 3386 can be
secured to the lower clamshell piece 3388 using an adhesive that
extends substantially around the entire periphery of the cuvette
3370, except for the inlet and outlet. The seal formed between
polycarbonate and the epoxy resin adhesive can be significantly
stronger than the seal formed between Calcium Fluoride and the
adhesive. Thus, by providing a polycarbonate to adhesive seal
surrounding substantially the entire periphery of the insert
portion 3372 except at the inlet and outlet, the cuvette 3370 can
prevent fluid from leaking out of the cuvette 3370 more effectively
than a cuvette in which the boarders of the cuvette are sealed
using a Calcium Fluoride to epoxy resin bond. This is especially
the case since gamma sterilization or electromagnetic radiation
that passes through the cuvette can break adhesive bonds to Calcium
Fluoride causing delamination.
[0326] FIG. 34A is a partial perspective view of the cuvette 3370
incorporated into a rotor housing 3434 which can be similar to the
rotor housing 2834 discussed above in many regards. FIG. 34B is a
partial plan view of the cuvette 3370 incorporated into the rotor
housing 3434. FIG. 34C is a partial cross-sectional view of the
cuvette 3370 incorporated into the rotor housing 3434. In FIGS.
34A-34C, the rotor housing 3434 is shown as being partially
transparent such that feature of the rotor housing 3434 are visible
that would otherwise be hidden from view.
[0327] In some embodiments, the sample cell cover 3441 and the
rotor housing 3434 contact the clamshell pieces 3386, 3388 to
secure the cuvette 3370 in place, and they do not directly apply
pressure to the window pieces 3374, 3376. This reduces the
occurrence of occlusion in the sample portion between the window
pieces 3374, 3376 and aids in maintaining a constant optical path
length through the sample portion.
[0328] Dead Space and Sealing Mass
[0329] Analyte monitoring systems can be connected to a source of
bodily fluid (e.g., blood) that may be susceptible to clotting. If
clotting occurs in the analyte monitoring system, a fluid pathway
may be obstructed or otherwise compromised. In some instances, if
clotting occurs, the disposable cartridge must be replaced. Thus,
by reducing the occurrence of clotting, the cartridge may be used
for a longer period of time before replacement, thereby reducing
cost, reducing waste, reducing time required of the medical
professionals, and reducing agitation of the patient. Blood
clotting risk can be reduced, for example, by employing coatings in
or on portions of the Analyte monitoring system and/or by reducing
dead space volume. As used herein, the term "dead space" is a broad
term and is used in accordance with its ordinary meaning to refer
to any unwanted or unproductive areas that do not allow efficient
and/or smooth fluid flow. For example, a widened portion, a
peripheral opening or cavity that is located out of a main fluid
flow path can be "dead space" because fluid can get caught in that
space and either form eddy currents, turbulence, or stagnation,
which can increase the risk of clotting. Also, in some instances, a
portion of the fluid being transferred can remain trapped in the
dead space, thereby preventing the desired volume of fluid from
reaching the desired destination, and possibly contaminating later
samples of fluid that come into contact with the fluid retained in
the dead space. The problems presented by dead space can be
exaggerated in a low volume system (e.g., the analyte monitoring
system) because even a small amount of fluid that is diverted or
unintentionally mixed can compromise a fluid sample and the
resulting analyte measurements. Also, in a small volume system,
tubes having small diameters can more easily be occluded by clots
of small sizes.
[0330] In medical systems and devices used in hospitals it can be
useful to use anticoagulants (e.g. heparin) to help prevent
deposits from building up in fluid systems, especially those that
contain bodily fluids such as blood. In some medical devices
connected to the vasculature of a patient, anticoagulants (e.g.,
heparin) can be used to prevent blood clotting in a patient and/or
to keep the fluid lines open (e.g., by preventing fluids from
coagulating in dead spaces of connectors). However, if excessive
amounts of these anticoagulants are infused into a patient--for
example, when the line is flushed--the patient may lose some
clotting capability and Heparin Induced Thrombocytopenia (HIT) can
result in many or all heparin-sensitive patients. HIT can be a very
dangerous condition, and may lead to loss of vision, loss of a
limb, or even death. Systems and methods of preventing accidental
injection into the patient are described in U.S. Patent Publication
No. 2009/0036764, published on Feb. 5, 2009, which corresponds to
U.S. patent application Ser. No. 12/123,422, filed on May 19, 2008
(Atty. Docket No. OPTIS.194A), and which is hereby incorporated by
reference herein in its entirety and made a part of this
specification. Another approach of preventing infusion of heparin
into a patient is to avoid the use of anticoagulants (e.g. heparin)
in portions of devices that may be connected to or in fluid
communication with a patient's vasculature. However, not using
anticoagulants can result in fluid pathways that are attached to a
patient's vasculature being blocked over time due to clotting
and/or accumulation of deposits.
[0331] For at least these reasons there is a need for fluid
transfer/handling systems that can provide a continuous flow path
with minimized change in the cross-sectional area of various points
along the flow path and with reduced dead space. Such fluid
transfer systems can promote smooth flow and reduce unwanted
turbulence and stagnation in fluid systems, leading to reduced
medical risk. Such systems may have coatings on the inner or outer
walls of the connecting tubes or other components. The coatings can
be designed to provide various benefits such as delivering
therapeutic compounds or other additives to the fluid flowing
through the system, reducing friction and improving fluid flow,
protecting sidewall materials from prolonged contact with the
fluid; and/or decreasing the occurrence of blood clotting and
lengthening the useful life of the fluid transfer/handling system
such as may be included in a removable cartridge.
[0332] One way to reduce dead space is to include a sealing mass at
or near an interface where fluid flows across a junction between
two components. For example, a sealing mass can be placed on a tube
so that it partially or fully surrounds the tube. The sealing mass
may be placed at specific locations along the tube where it may be
most effective in reducing dead space. For example, the sealing
mass may be placed such that it encircles a connecting tube near
the tip of the tube that is inserted into, or otherwise interface
with, a connector or other component to help reduce dead space at
the connection between the tube and the connector or other
component. The sealing mass can resiliently deform to fill cavities
or crevices that may otherwise allow fluid pooling, stagnation,
eddy currents, etc. a sealing mass can be used in various locations
in the analyte detection system.
[0333] A sealing mass may be made out of any type of material. The
material used for a sealing mass may be chosen based upon any
number of desirable characteristics, such as biological neutrality
(or biological activity), affinity for the fluid in the fluid path
(or lack of affinity), impermeability, resilience, compressibility,
cost, ease of manufacture, ease of attaching to a tube, or other
reasons. Various approaches can improve the sealing ability of a
sealing mass. For example, a sealing mass may be made from the same
type of material as the tube it surrounds. This can allow the mass
and the tube to resiliently abut or conform to other surfaces and
to each other in a similar manner. A sealing mass may be joined to
the tube it surrounds. This can reduce the likelihood of fluid
leakage between the sealing mass and the tube and also assist in
urging the sealing mass against a mating component. A sealing mass
may be a unitary piece with the tube that it surrounds for similar
reasons. It can be beneficial to make a sealing mass from a
resilient or compressible material, as these materials may be
useful to more effectively fill dead space and thereby reduce
turbulence in a fluid path. These materials may be used to form a
fluid-tight seal around the fluid path between the tubing and a
mating component. In one particularly useful example, a sealing
mass may be a plug or roughly frustoconical body made out of
silicone.
[0334] If a sealing mass is placed such that it encircles a tube
near a tip, a resilient or compressible material can help to create
a seal between the connecting tube and another component.
Compressible or resilient material may be preferable because such
material may be able to form a tighter or larger seal near the
connection between the connecting tube and the other component.
This tighter or larger seal may restrict a fluid traveling through
the tube from entering dead space that may otherwise be present
near the connection between the connecting tube and the other
component. A resilient or compressible sealing mass placed near the
tip of a connecting tube may be especially effective in forming a
tight, large seal in the presence of a force-exerting or an
actuating member. A force-exerting member may be designed to apply
pressure to firmly seat the connecting tube and the other
component. Such pressure may be sufficient to partially compress a
resilient or compressible sealing mass that encircles the tip of
the connecting tube.
[0335] A sealing mass that is placed around a tube may be any
shape. The shape of the sealing mass may depend upon what type of
material is used, where it is placed, and the anticipated use of
the sealing mass. For example, if a sealing mass is placed
encircling the tip of a tube which will connect to another tube,
this may make some shapes more advantageous. A sealing mass with a
radially symmetric shape may be desirable in order to create a
larger or better seal. This can be especially helpful in a common
medical setting where the component receiving the tubing or other
piece that has the sealing mass is radially symmetric. Thus, the
shape, surface angles, and symmetries of the sealing mass can be
made compatible with a wide variety of interfaces. If it is known
what type of interface a tube will connect to, the shape of the
sealing mass may be based upon the shape of the corresponding
interface. Additional details relating to the structure and
functionality of the sealing mass are disclosed in U.S. Patent
Application Publication No. 2011/0313317, published on Dec. 22,
2011, which corresponds to U.S. patent application Ser. No.
13/068,121, filed on May 3, 2011 (Attorney Docket No. OPTIS.263A2),
the entirety of which is hereby incorporated herein by reference
and made a part of this disclosure.
[0336] A sealing mass can be used at various different positions in
the analyte monitoring system. For example, with reference to FIG.
5, the fluid handling network can include various junctions (e.g.,
at connectors C1, C2, C3, etc.) between portions of fluid transport
tubing. FIG. 35 shows an example embodiment of a junction (which
can be similar to, or the same as the connector C1) between tubing
elements 3512, 3528, 3534, and 3536. The connector 3524 can be a
rigid plastic connector with through holes to provide fluid
pathways for fluid to pass through the connector. In the
illustrated embodiment, the connector 3524 can be a 4-way
connector, but other configurations (e.g., 3-way connectors) are
possible. The end of the tubing 3512 can be inserted into the
corresponding hole in the connector 3524. In some embodiments, the
through hole can include a wide portion configured to receive the
end of the tubing 3512 therein so that the inner surface of the
through hole generally aligns with the inner surface of the tubing
3512, thereby providing a substantially linear non-turbulent flow
path through from the tubing 3512 to the connector 3524. A sealing
mass can be positioned near the tip of the tubing 3512 and/or on
the inside of the through hole. The sealing mass can be configured
to expand to fill area that would otherwise be dead space, thereby
reducing turbulence in the flow of fluid and reducing the amount of
fluid that can be retained stagnant in dead space. The other tubing
elements, 3528, 3534, and 3536 can be connected to the connector
3512 in a similar manner.
[0337] If the sealing mass is placed near the tip of a connecting
tube 3512, it may be desirable to minimize the distance between the
sealing mass and the tip of the connecting tube 3512 because fluid
may be more likely to leak out of the tip, so stopping the flow of
leaked fluid advantageously occurs close to the original leak. For
example, it may be advantageous to place a sealing mass within
0.001, 0.005, 0.01, 0.05 or 0.1 inches from, or completely flush
with, the tip of a connecting tube 3512.
[0338] A sealing mass may be especially useful on connections which
are intended to be engaged and disengaged multiple times. For
example, with reference to FIG. 29B, the fluid nipples 2914 of a
fluid injector 2915 can be configured to interface with the two
receiving nubs 2812A (as well as the receiving nubs 2812B in
similar manner). The fluid nipples 2914 can disengage from the
receiving nubs 2812A (as shown in the configuration illustrated in
FIG. 29B), for example, to allow the rotor to spin without
contacting the fluid nipples 2914. The fluid injector 2915 can be
moved forward by an actuator to engage the receiving nubs 2812A,
thereby forming a fluid connecting that allows fluid to flow
between the tubing 2916 and a flow cell by passing through the
interface between the fluid nipples 2914 and the receiving nubs
2812A. The fluid nipples 2914 and/or the receiving nubs 2812A can
include one or more sealing masses configured to occupy area at the
interface that would otherwise result in dead space.
[0339] FIG. 36 is a close up view of two fluid nipples 3619A, 3619B
that include sealing masses 3620A, 3620B and tubing ends 3622A,
3622B. In the fluid nipple, 3619A, the edge of the sealing mass
3620A is space back from the end of the tubing 3622A by a distance
3624A, and in the fluid nipple 3619B, the edge of the sealing mass
3620B is space back from the end of the tubing 3622B by a distance
3624B. The distances 3624A, 3624B can cause dead space in the
interface between the fluid nipples 3619A and 3629B and the
corresponding receiving nubs. It may be desirable to minimize the
distances 3624A, 3624B between the sealing masses 3620A, 3620B and
the ends of the tubing 3622A, 3622B to prevent dead space from
forming. For example, it may be advantageous to place the sealing
masses 3620A, 3620B within 0.001, 0.005, 0.01, 0.05 or 0.1 inches
from, or completely flush with, the edge of a connecting tubing
3622A, 3622B. The sealing masses 3620A, 3620B can be shaped and
configured to interface with the receiving nubs (e.g., 2812A or
2812B) to reduce dead space and form substantially linear
non-turbulent flow paths between the fluid nipples 3619A and 3619B
and the corresponding receiving nubs.
[0340] Coatings
[0341] One or more coatings may be applied to any surface of an
analyte monitoring system. For example, coatings may be applied to
the inner or outer walls of a sample cell, of connecting tubes, of
a sealing mass, or of other connecting structures in the analyte
monitoring system. Such coatings may serve any number of purposes,
such as making the components last longer, preventing materials
used in the tubing or other components from entering the fluid
contained in a fluid path, increasing the accuracy of an analyte
measurement, allowing for more flexibility in which materials are
used in the components, or reducing blood clotting. The purpose of
a coating may determine where on an analyte monitoring system the
coating is applied. For example, if a coating is designed to reduce
or eliminate blood clotting, it may be advantageous to apply the
coating to the inner and outer walls of a connecting tube, to a
sealing mass placed near the tip of the connecting tube, and/or to
any other surface that blood may come into contact with. A coating
that is designed to reduce or eliminate blood clotting may be
applied to any surface in an analyte monitoring system that may
come into contact with blood. For example, a coating may be applied
to an analyte monitoring system that is situated outside the body,
either in the analyte monitoring system or in a tube that leads to
the analyte monitoring system.
[0342] There are a number of ways that a coating may assist in
reducing or eliminating blood clotting in an analyte monitoring
system. For example, lubricious coatings can be used to reduce
friction between the flowing fluid and the side-walls of the tubing
or other components. Therapeutic drug delivery coatings can also be
used (e.g., drug-eluting coatings). Some useful coatings include
those that comprise heparin, which can be designed to reduce blood
clotting against the side-walls of the connector by acting as an
anticoagulant. A coating may be applied to the inner or outer walls
of various components. A reduction in friction may reduce the shear
stress on blood that flows in a boundary area near the side-walls
of the connector. The blood coagulation cascade is a very delicate
process, and a reduction in shear stress can decrease the tendency
for blood to begin to coagulate by reducing the turbulence in blood
passing through the tubing or other components. Any number of
lubricating agents may be suitable to form a lubricious coating on
the inner or outer walls of the connecting tubes and other
components. A number of companies provide a wide array of active or
inactive haemocompatible coatings that can be used in this context.
Such companies include: AdvanSource biomaterials (e.g., HydroMed);
AorTech Biomaterials; Applied Membrane Technology (e.g., Silglide,
Fluorocarb); AST Products Inc. (LubriLAST); Bayer (e.g., Baymedix
CL); Biocoat, Inc. (e.g., HYDAK); BioInteractions Ltd. (e.g.,
Assist); Cadence Inc.; Carmeda (e.g., CBAS); Coatings2Go LLC;
Covalon Technologies Ltd.; Demax Medical; DSM Biomedical (e.g.,
ComfortCoat); Hemoteq (e.g., Lubriteq); Medkote; Merit Medical
Systems Inc. (e.g., Endotek); SurModics Inc. (e.g., Rejoice,
Harmony); and Tegra Medical. Lubricious coatings can be used to
coat the inner or outer walls of the connecting tubes or other
components. Lubricious coatings such as this can dramatically
reduce the friction between blood and the inner walls of the
connecting tubes, and therefore reduce the shear stress on the
blood. Lubricious coatings may be advantageous because they are
less likely than some other coatings to interfere with analyte
detection and measurement. Lubricious coatings may also be easier
to apply to the inner and outer walls of a connecting tube, and may
be more cost-effective than other types of coatings. Lubricious
coatings may also present less danger than some types of
drug-eluting coatings, and therefore be easier to work with or more
desirable than other types of coatings. Lubricious coatings can
work with interfaces between components in the analyte monitoring
system that are configured to minimize dead space to reduce the
incidents of clotting on the inner walls of the connecting
interfaces. In some embodiments, such a coating can be applied to
surfaces of components of the analyte monitoring system as one of
the later steps in their production, as coatings may be somewhat
more sensitive to temperatures encountered during manufacturing.
For example, it maybe desirable to apply a coating to a component
as a final step in manufacturing the component, to ensure that heat
used to shape the component does not adversely affect the coating
and inhibit its function.
[0343] Coatings may reduce the need for detergent and/or heparin to
flush the fluid system between draws and may allow for more
frequent measurements. For example, a lubricious coating may cause
less blood or other fluid to remain in the fluid system after blood
is drawn. If less blood remains in the fluid system after blood is
drawn, this may reduce the amount of detergent (such as tergazyme
A) and/or heparin that are needed to flush the system between blood
draws, or may even eliminate the need to use detergent and/or
heparin during flushing. This may simplify the design of the
system, may create less waste, and/or may make the system less
expensive to create and to operate. Coatings may also allow for
more frequent measurements, as less time may be needed between
measurements to flush the system.
[0344] Coating (e.g., lubricious coatings) can be applied at
transitions and junctures between components in the analyte
monitoring system. For example, a coating may be applied near an
intersection, such as the juncture shown in FIG. 35. As discussed
above, the connector 3524 can be the same as, or similar to, the
first connector 524 (C1) as illustrated in FIG. 5. A coating can be
applied to the inner walls and/or the ends of the tubes 3512, 3528,
3534, and 3536 as well as to the portions of the connector 3524
that are configured to receive the tubes 3512, 3528, 3534, and
3536. It may also be beneficial to apply a coating to sealing
masses that can be positioned at the interface between the
connector 3524 and the tubes 3512, 3528, 3534, and 3536. Thus, in
some embodiments, as fluid flows from a tube (e.g., 3512) and into
the connector 3524, each surface that the fluid contacts can have a
coating (e.g., a lubricious coating) applied thereto, thereby
reducing the likelihood that blood will start to clot at the
interface between the tube (e.g., 3512) and the connector 3524. An
intersection such the one shown in FIG. 35 may be especially prone
to turbulence because fluid flowing through the connector 3524 may
be required to make a sharp 90-degree turn. Thus, in some
embodiments, all the inner walls of the connector 3524 can have a
coating applied thereto to reduce clotting. Also, fluid that flows
through the connector 3524 (e.g., from tube 3512 to tube 3534) may
be especially prone to turbulence when a neighboring valve (e.g.,
pinch valves 3529 and/or 3531) is closed, if the valve is some
distance away from the connector 3524. For example, when the valve
(e.g., pinch valve 3531, or a rotary valve, shuttle valve, etc.) is
placed some distance from the connector 3524, fluid that passes
through connector (e.g., from tube 3512 to tube 3534) and fluid
that is in the tube 3536 leading to the closed valve 3531 may be
more likely to be turbulent. Therefore, to avoid such turbulence,
it may be useful to apply a coating to some or all of the surfaces
of the intersection, especially when a valve is placed further away
from the connector 3524. For example, a coating can be applied to
some or all of the internal surfaces of the fluid pathways through
the connector 3524, and to the internal walls of the tubing 3512,
3528, 3534, and 3536 between the connector 3524 and the valves
3523, 3529, 3531, 3533. In some embodiments, coating can be applied
to the full inner surfaces of the tubing 3512, 3528, 3534, and 3536
(or other tubing in the system).
[0345] A coating may be applied to an analyte monitoring system
that is designed to take multiple readings of analyte levels. Such
a coating may be applied to components that are used during
multiple readings from a medical device, and over multiple fluid
withdrawal cycles. A coating may also be applied to an analyte
monitoring system that is situated at least partly inside the
patient's body to reduce or prevent the formation of clots thereon.
A coating may also be applied to other systems that may come into
contact with blood where it is desired to reduce friction and/or
avoid blood clotting.
[0346] For example, in some embodiments, the sample cell 2848 can
have a coating (e.g., a lubricious coating) applied thereto. The
sample cell 2848 can be flushed (e.g., between measurements). In
some embodiments, saline can be used to flush the sample cell 2848.
A cleaning solution, such as a detergent (e.g., tergazyme), can be
used to flush the sample cell 2848 and can facilitate the removal
of blood or blood components from the sample cell 2848. In some
embodiments in which the sample cell 2848 is coated with the
lubricious coating, no detergent or other cleaning solution is
used, or a reduced amount of detergent or other cleaning solution
can be used. The coating can prevent the blood or blood components
or other substances from sticking to the sample cell 2848, thereby
facilitating the flushing with a reduce amount of, or without, a
cleaning solution. In some embodiments, saline or water can be
used. Various portions of the sample cell 2848 can be coated. For
example, the sample portion 3129, the channels 2850, the inlet,
and/or the outlet have the coating applied thereto. Also, tubing or
other portions of the system can be coated (e.g., with a lubricant)
to facilitate flushing.
[0347] With reference again to FIG. 36, the fluid nipples 3619A,
3619B can have a coating (e.g., a lubricious coating) applied
thereto. For example, the inner and/or outer surfaces of the tube
ends 3622A, 3622B and/or the sealing masses 3620A, 3620B can be
coated with a lubricious coating to reduce or prevent the formation
of clots at the interface between the fluid nipples 3619A, 3619B
and the receiving nubs (e.g., 2812A or 2812B). Various other
coatings can also be used, as discussed herein.
[0348] An analyte monitoring apparatus can be usefully configured
to draw blood from the body and analyze a portion of that blood.
One useful assumption to make is that the drawn and analyzed blood
is representative of the other blood that remains in the body and
is not analyzed. This can be a valid assumption in many cases
because blood flow in the body is a turbulent process, with the
heart urging the blood through vessels and organs and tissue having
various diameters and various levels of flow resistance. Indeed,
there can be a great amount of variation in the flow rate of blood
as it passes through the many regions of the body. This turbulence
and variation of flow rates will tend to mix blood within the body,
which will prevent blood in one part of the body from having a
substantially different composition than blood in other parts of
the body.
[0349] An analyte monitoring apparatus can also be usefully
configured to be inserted into the body, and, for example, into the
blood stream. This can have the advantage of eliminating any need
to transport the blood out of the body; it can also introduce other
potential risks. However, even if a monitoring device is inserted
into the body, at any given time the device is likely only capable
of measuring an analyte in a limited portion of the blood--for
example, the blood that is in contact with (or within the view of)
a sensor in the device. Thus, even in this case it is useful to
assume that this limited portion of the blood is representative of
the other blood in the body.
[0350] Some systems do not measure over a fixed amount of blood,
but instead assume a constant relationship between the analyte in
local blood and the amount of blood overall in the body. Such a
constant relationship can be referred to as a stoichiometric
relationship. If this assumption is inaccurate, results of the
analysis can be inaccurate. This potential problem can be amplified
when measurements are taken, for example, in a portion of the blood
flow that has a varying rate of the analyte (e.g., for
physiological reasons). For example, measurement of oxygen in the
blood inside the lungs can be difficult over time because the lungs
introduce blood into the oxygen periodically but at relatively
short intervals. An indwelling system that is constantly measuring
the glucose level of the blood that flows by and/or through its
sensors may provide a reading that is too local and not provide a
consistently useful overview of the amount of analyte generally
present in the body as a whole. One way to avoid inaccuracies due
to failures of this assumption is to measure an amount of analyte
in a fixed amount of blood, drawn from a portion of the bloodstream
that is physiologically likely to maintain a relatively constant
level of the analyte in question. In many cases, the larger the
blood sample, the less likely it will be to reflect misleading
and/or temporary local distortions in an analyte level.
Accordingly, ex-vivo systems that withdraw blood can have some
advantages over systems with sensors that are inserted into the
body notwithstanding the potential difficulties of repeatedly
withdrawing blood out of the body and reducing clot risk in ex-vivo
fluid systems.
Reducing Fluid Contamination During Withdrawal
[0351] As discussed above, various embodiments of analyte
monitoring systems such as the analyte monitoring system 100 (e.g.
an "OptiScanner.RTM.") can be attached or connected to a patient.
In various embodiments, a patient connection can be achieved
through a patient tube (e.g. patient tube 512) having an inner
lumen which is configured to be connected to a patient catheter. In
various embodiments, the inner lumen of the patient tube can have a
small inner diameter--e.g., without limitation, a diameter in the
range of approximately 0.01 inches to approximately 0.04 inches. In
various embodiments, the outer diameter of the patient tube can be
less than or equal to approximately 0.06 inches. In a hospital or
an ICU setting, the analyte monitoring system can be connected to a
patient through a variety of patient catheters such as, for
example, a central venous catheter (CVC), a peripherally inserted
central catheter (PICC), and/or other central or peripheral IV
catheters. Other catheters not described herein can also be used to
connect patients to devices such as an analyte monitoring system
(e.g., the system(s) described herein). CVCs can generally be used
when fluid is desired to be regularly inserted into a patient
and/or the vascular access is compromised or unavailable for
repeated insertions (e.g. if peripheral veins are collapsed,
difficult to find, not available in sufficient quantity, etc.).
[0352] FIGS. 38A-38D illustrate various embodiments of multi-lumen
catheters 3800 that can be used to attach analyte monitoring
systems to patients. The multi-lumen catheter 3800 can be
representative of any of the patient catheters described above. The
multi-lumen catheter 3800 can in general include multiple lumina
(e.g. 2 lumina, 3 lumina, 5 lumina, etc.). Often, one of the lumina
of the catheter is longer than another; accordingly, the lumina do
not open into a blood vessel directly adjacent to one another. As
illustrated, the multi-lumen catheter 3800 comprises an elongated
tubular structure 3802 that comprises three lumina 3802a, 3802b and
3802c, and multiple external ports 3804, 3806 and 3808 that connect
to the elongated tubular structure 3802 through a fitting or a hub
3805. The elongated tubular structure 3802 can be much longer than
shown in FIG. 38A, as indicated schematically with a break.
[0353] The elongated tubular structure 3802 can comprise a
bio-compatible material and include a proximal end (closer to the
fitting 3805) and a distal end (at the right in FIG. 38A) that is
configured to be inserted into a blood vessel (e.g. an artery or a
vein) or a body portion of the patient. In various embodiments, the
elongated tubular structure 3802 can be flexible. In some
embodiments, the elongated tubular structure 3802 can comprise a
stiff material that provides structural stability to the elongated
tubular structure 3802. In various embodiments, the diameter of the
proximal end of the elongated tubular structure 3802 can be
approximately equal to the diameter of the distal end. In contrast,
in some embodiments the diameter of the proximal end of the
elongated tubular structure 3802 can be larger or smaller than the
diameter of the distal end. In some embodiments, the distal end of
the elongated tubular structure 3802 can be tapered. In some
embodiments, the lumina of the elongated tubular structure can have
different lengths such that each internal tube terminates at a
different position to create the staggered effect illustrated in
FIG. 38A with the openings 3814, 3816, and 3818. In some
embodiments, the lumina of the elongated tubular structure can have
the same lengths (not shown).
[0354] The multiple lumina 3802a, 3802b and 3802c may be separated
from each other by an internal partition or membrane such that
fluid integrity and separation is maintained within the multi-lumen
catheter. In various embodiments, the internal partition or
membrane may comprise materials that generally prevent the mixing
of the different fluids flowing through the multiple lumina. Each
of the multiple (e.g., three) ports can be configured to be in
fluid communication with one of the lumina of the elongated tubular
structure 3802. For example, in the illustrated embodiment, the
proximal port 3804 is configured to be in fluid communication with
the lumen 3802a, which in turn corresponds to the proximal opening
3814. The medial port 3806 is configured to be in fluid
communication with the lumen 3802b, which in turn corresponds to
the medial opening 3816, and the port 3808 is configured to be in
fluid communication with the lumen 3802c, which in turn corresponds
to the distal opening 3818. The proximal port is referred to in
this way because a health care provider often can determine, using
a color code, for example, which external port corresponds to the
internal opening that is "proximal" of (or nearer to the health
care provider than) the openings corresponding to the other ports.
In many cases, this type of staggered internal port arrangement is
configured by users such that the "proximal" port (e.g., the
proximal opening 3814) is upstream from the other ports (e.g.,
medial opening 3816 and distal opening 3818) relative to the
expected or typical flow of body fluid (e.g., blood). This
convention can be useful because a "distal" port can be used to
administer therapeutic compounds to the blood stream, for example,
which carries those compounds further downstream, thus reducing the
risk that those compounds will flow upstream into the other ports.
Because of the useful convention assuming that these staggered
catheters place the proximal port upstream and the distal port
downstream, in this description, it will be generally assumed that
this convention is followed.
[0355] At the generally distal end of the elongated tubular
structure 3802, the openings of the various lumina can be staggered
and/or configured such that a certain minimum distance is
maintained between the three in-patient openings. In various
embodiments, the proximal port can be the port that communicates
with an outlet (here illustrated as the opening 3814) for infusate
is the closest of the in-patient openings to the caregiver or
medical practitioner. In some embodiments, the proximal port can be
the port wherein the outlet of the infusate is farthest from the
extreme tip of the catheter 3800 that is typically configured to
enter the patient first. As illustrated in FIG. 38A, this extreme
tip corresponds to the distal opening 3818.
[0356] In various embodiments, the analyte monitoring system
described above can be connected to the proximal port 3804 of the
multi-lumen catheter 3800. In various embodiments, an advantage of
using the proximal port 3804 of the catheter is that under many
hospital protocols, this port can be reserved for a dedicated
connection to a device (such as an analyte monitor that also
infuses substances such as insulin, dextrose, saline, etc.), but no
non-controlled medications or drugs--other than those controlled
and tracked by the analyte monitor and infusion system--are infused
through this port. In some embodiments, it may be advantageous to
use the "proximal" port of a CVC to withdraw blood because that
port typically has an opening into a patient's bloodstream that is
upstream (with respect to blood flow in a vein, for example) from
the openings into the bloodstream of any other ports. Accordingly,
and because the blood flow rate can be relatively high (e.g. 4-6
liters/minute), downstream infusions (entering the blood stream
from the medial or the distal port) are unlikely to flow upstream
and substantially mix with the blood in the area of the proximal
port. Thus the withdrawn blood from the proximal port can be
substantially undiluted (or "uncontaminated" by other infusates).
This can be advantageous because it can reduce the likelihood that
recently-infused compounds are sucked into the proximal port and
lead to inaccuracies in measurements of analytes present in the
withdrawn fluid (e.g., blood). These and other advantages will be
described further below.
[0357] For the reasons described above, it is wise for health care
practitioners to withdraw from the proximal port when drawing blood
for analysis. It may also be advisable to clamp the other ports of
the CVC (e.g. distal or medial ports) while blood is being drawn
from the proximal port. However, this can be cumbersome and
impractical. Accordingly, in various embodiments of the apparatus,
systems and methods described herein, fluid can be withdrawn from
one port (e.g., the proximal port of the CVC) while other ports
(e.g., the medial or distal ports) are still in use, while still
reducing likelihood of contamination in the withdrawn fluid. As
used in this context, the term "contamination" can refer to
inclusion of any unwanted or unexpected substance in a withdrawn
sample, the inclusion of which may lead to an inaccurate analysis
and false measurement of analyte levels in a body fluid (e.g., in
the blood flow). One useful aspect includes the described push/pull
fluidics systems, which can use gravity systems, valves, fine
motors and/or precision controls to enable withdrawal of a sample
at a slow, steady rate (e.g., a slower, steadier rate than that
achievable through manual withdrawal by a health care
practitioner).
[0358] Ordinarily, the human heart pumps the blood around the
vascular system such that the rate of flow of blood is
approximately 5-6 liters/minute. The blood flow rate can be higher
or lower depending on the physical condition of the human. For
example, during or after a period vigorous cardio-vascular activity
the blood flow rate may be higher. To take another example, a human
who is critically ill or has suffered significant blood loss can
have a blood flow rate as low as 2 liters/minute. The pressure in
the vascular system can be between approximately 1-3 psi.
[0359] As discussed above, the different lumina of a multi-lumen
catheter may be separated internally--e.g., by walls or
membrane(s)--such that the fluids introduced in each of the
multiple lumina are kept separated from each other and do not mix
as they flow through the lumina. In certain embodiments, it may be
beneficial to reduce the likelihood of inter-mixing between the
different fluids even after they are introduced into a patient's
vasculature. The ordinary rate of flow of blood--about 5-6
liters/minute--in the patient's vasculature can be sufficient to
prevent or substantially reduce mixing of the different fluids
(e.g. medications, drugs, saline, control fluids, etc.) that are
being infused through the various lumina of the multi-lumen even
after they are introduced into the patient's vasculature because
the "current" of the blood flow sweeps away infusates so quickly
downstream that they are often rapidly well dispersed into the
bloodstream before they have a chance to directly intermix with
other infusates that may be coming through catheter ports into the
blood stream. For example, generally, fluids can be introduced into
the patient's vasculature at a rate of between approximately 300
ml/hour to approximately 1 liter/hour--rates that are substantially
lower than the typical rates of flow of blood in the patient's
vasculature.
[0360] In some embodiments, as illustrated in FIG. 38D, each of the
lumina of the multi-lumen catheter can be further configured to
have different lengths (and possibly even different diameters) such
that the fluids are introduced in different regions of the
patient's vasculature--some farther upstream, and some farther
downstream--to further reduce the possibility of inter-mixing
between the different fluids. In FIG. 38D, the proximal port is
3804 because the opening 3814 is located proximally when compared
to the more distal openings 3816 and 3818. Another method to reduce
or prevent intermixing between the different fluids that can be
used instead of or in addition to having lumina with different
lengths can be to control the pressure and/or the flow rate at
which the different fluids are introduced into the patient's
vasculature.
[0361] Various blood withdrawal techniques can require high
pressures (e.g. as high as 3000 psi) and/or high flow rates to
withdraw blood from a patient's vasculature. Systems comprising a
multi-lumen catheter may be configured such that blood can be
withdrawn through one of the ports (e.g. the proximal port 3804)
while infusates/infusion fluids can be infused through the other
ports (e.g., medial port 3806 and distal port 3808). Withdrawing
blood using high pressures and/or high flow rates can cause some of
the infusates/infusion fluid to be drawn or pulled into a
withdrawal port along with the withdrawn blood. This can
"contaminate" the withdrawn blood. In a system where the withdrawn
blood is used to determine the presence and/or the concentration of
various analytes, contamination of the withdrawn blood with the
infusate/infusion fluid can affect the measurement results. Thus,
it may be advantageous to clamp the infusion ports (e.g. medial
3806 and distal 3808 ports) while blood is being withdrawn from the
proximal port 3804 under high pressure and/or at a high flow rate
since such a technique can advantageously prevent or substantially
reduce the risk of contamination or mixing of the withdrawn blood
with the fluids being infused.
[0362] But even clamping may not minimize or avoid undesired
reversal of flow and withdrawal of substances that were located
downstream of the withdrawal port (e.g., substances present in or
near the infusion ports). Moreover, it may be advantageous to avoid
clamping the infusion ports while blood is being withdrawn. Methods
of and systems for preventing or substantially reducing the
inter-mixing between the different fluids introduced into the
patients' vasculature can be also useful in preventing or
substantially reducing the contamination of the withdrawn blood
without clamping the infusion ports.
[0363] For example, blood can be withdrawn through one of the ports
of the multi-lumen catheter using an automated blood withdrawal
system (e.g. an "OptiScanner.RTM.") at a controlled flow rate. For
example, the system may control the flow rate such that a low flow
rate and/or low pressure is used to withdraw blood. The automated
blood withdrawal system can be configured to withdraw blood using a
pressure between approximately 1 psi and approximately 10 psi or
lower. The automated blood withdrawal system can be configured to
create a pressure in the proximal port of the catheter (through
which blood is withdrawn) that is between approximately 40% to
approximately 99% of the pressure of blood in the vasculature
thereby allowing withdrawal of blood under negative pressure. This
pressure may be monitored in order to gauge whether blood or other
fluids are being withdrawn at a low flow rate. A pressure sensor
may be attached at various points in the system, to determine the
pressure in the system and assist in maintaining it at desirable
levels. The automated system can be configured to withdraw blood at
a rate that is between approximately 1 mL/minute and approximately
10 mL/minute. These flow rates may be monitored directly or
indirectly. Flow parameters (e.g., a pump setting) can be adjusted
accordingly to allow the system to withdraw fluid at the desired
rate. The automated blood withdrawal system may also use other
methods to ensure blood is withdrawn at the desired flow rate
and/or pressure. As discussed above, withdrawing blood rapidly at
relatively high pressures (e.g. 1000-3000 psi) and/or relatively
high flow rates (e.g. >10 mL/minute) from the proximal
port--which is often configured to be upstream of the other
port(s)--can draw the fluids being infused through the other--often
downstream--ports. This can be especially likely if the rapid blood
withdrawal is fast enough to cause a temporary flow reversal in the
local blood stream and/or if any infusion ports are in the process
of infusing (or are at least open or not clamped, for example).
Indeed, rapid blood withdrawal can often result in the
"contamination" of the withdrawn fluid--by inclusion of higher
concentrations of the substances being infused, by unwanted
dilution, etc. In contrast, the ability of the automated blood
withdrawal systems described herein to withdraw blood at low
pressures and/or flow rates can substantially reduce the
possibility that the withdrawn blood will be "contaminated," for
example by an infused fluid. Withdrawing fluid at a lower flow rate
may also improve the accuracy of analyte readings if the amount of
analyte in the blood at one point is not representative of the
total amount of analyte in the body (e.g., for physiological
reasons), as discussed supra.
[0364] In some embodiments, it may be advantageous to use a
multi-lumen catheter wherein the multiple lumina can be further
configured to have different lengths and different diameters such
that in combination with low withdrawal pressures and/or withdrawal
rates, a small negative pressure can be created in the proximal
port and/or region surrounding the proximal port which can further
reduce or eliminate the contamination of the withdrawn fluid from
the fluids infused in the other lumina of the catheter.
[0365] It can be advantageous to measure dilution of withdrawn
fluids in order to determine the effectiveness of systems and
methods for minimizing dilution. For example, the systems and
methods described herein can reduce dilution to 20%, to 10%, to 5%,
or, in some embodiments, to approximately 0%, effectively
eliminating dilution. These results can be achieved by withdrawing
blood at a location far from an infusion port, or by
controlling--usually by lowering--the rate of withdrawal. Automated
blood withdrawal systems can be especially helpful in achieving
steady, low flow rates and/or pressures at the proximal port
(through which blood is withdrawn), since a motor controlling a
pump, for example, can be more precisely and systematically
controlled than the movements of a nurse's muscles in withdrawing
fluids into a syringe. Accordingly, the automated systems described
herein can reduce the risk that infusate contaminants from the
medial and/or distal ports are included in withdrawn blood.
[0366] Automated fluid withdrawal may be measured, controlled, or
described according to flow rate. Withdrawal can be achieved at a
constant rate, where the rate of withdrawing blood is low enough to
reduce the presence of infusate contaminants being withdrawn
through the proximal port. The withdrawal of blood may also be done
at a variable rate to reduce the presence of infusate contaminants
being withdrawn through the proximal port. The rate at which blood
is withdrawn may be controlled to correspond to activity at other
lumina of a multi-lumen catheter. For example, a system may reduce
the rate of blood withdrawal when large amounts of infusates are
being infused into the blood stream at another port. A system may
also adjust the rate at which blood is withdrawn based upon the
type of infusates that are being infused at other ports. For
example, the system may withdraw blood at a lower rate when
infusates that are more likely to affect the accuracy of an analyte
measurement are being infused.
[0367] Automated fluid withdrawal may be measured, controlled, or
described according to pressure. For example, blood withdrawal can
be achieved at a constant pressure. The pressure at the proximal
port or within an inner lumen of a tube attached to the proximal
port may be maintained at some fixed pressure, where the pressure
is low enough to reduce the presence of infusate contaminants being
withdrawn through the proximal port. A pressure monitor may be used
to help maintain pressure at a desirable level. Blood may also be
withdrawn at variable pressures to reduce the presence of infusate
contaminants being withdrawn through the proximal port. For
example, the pressure at which blood is withdrawn may be
automatically controlled to correspond to activity at other lumina
of a multi-lumen catheter. It may be useful to use a system that is
able to adjust the pressure that blood is withdrawn according to
the rate that infusates are being infused into the blood stream
from other lumina. A system may also adjust the pressure at which
blood is withdrawn based upon the type of infusates that are being
infused at other ports. For example, the system may withdraw blood
at a lower pressure when infusates that are more likely to affect
the accuracy of an analyte measurement are being infused.
[0368] Controlling the rate and/or pressure at which fluid is
withdrawn may reduce or avoid contamination, and thereby reduce any
effect that potential infusate contaminants may have on an analyte
reading taken on withdrawn fluid. Infusate contaminants can be
especially troublesome in a system where the infused substance is,
or directly affects, the analyzed substance. For example, a glucose
measurement system drawing blood from a withdrawal port can be
produce very inaccurate readings if nearby infusion ports are
concurrently infusing glucose, dextrose, insulin, etc. Accordingly,
it can be very advantageous to lower the effect of such
contamination and achieve a 20% difference in the accuracy of the
analyte reading due to contamination effects. It can be even more
advantageous to achieve even better accuracy and reduce
contamination effects further yet. For example, the infusate
contaminants may cause only a 2, 4, 5, 10, 15, or 20% difference in
the accuracy of the analyte reading from the withdrawn fluid.
[0369] The flow rate and/or pressure that is needed to achieve a
certain difference in the accuracy of the analyte reading from the
withdrawn fluid may depend upon numerous factors. For example, the
distance between the proximal port and the other ports may impact
the flow rate and/or pressure needed to achieve a certain accuracy
of the analyte reading. If the proximal port is further away from
the other ports, a somewhat higher pressure and/or flow rate may be
used to withdraw fluid without creating excessive infusate
contamination. The analyte that is being measured may affect the
flow rate and/or pressure needed to maintain a certain accuracy in
analyte readings. Some analytes may be more or less prone to
inaccurate analyte measurements due to the presence of
contaminants. The type of infusates being infused may impact the
flow rate and/or pressure that fluid may be withdrawn at. Certain
infusates may be more likely to promote inaccurate analyte readings
than others. For example, if the analyte that is being measured is
the same as an infusate that is being infused in another port, it
may be necessary to use even lower flow rates and/or pressures than
normal in order to achieve analyte readings with a desired level of
accuracy. For example, if the analyte to be measured is glucose,
and if glucose is being infused at a downstream port, it may be
useful to withdraw fluid at a very low pressure and/or flow rate
because if the withdrawn fluid contains infused glucose, the
glucose reading may be too high. The amount of infusate being
infused may affect the flow rate and/or pressure needed to maintain
a certain accuracy in analyte readings. For example, if a
relatively large amount of infusate is being infused at a high
rate, it may be necessary to withdraw fluid at a lower pressure
and/or flow rate than if a smaller amount of infusate is being
infused at a lower rate. The flow rate of the fluid may also affect
the flow rate and/or pressure that fluid may be withdrawn at. If a
fluid has a high flow rate, infusates that enter at a downstream
port may be carried away from the proximal port more quickly and
effectively, and therefore, a slightly higher flow rate and/or
pressure may be used to withdraw fluid without adversely affecting
the accuracy of the analyte reading.
[0370] The expected level of the analyte to be measured may also
affect the flow rate and/or pressure at which fluid may with
withdrawn. If the levels of an analyte in the bloodstream is
extremely low, for example 50 ppm, then in may be more important to
avoid infusate contamination in the withdrawn fluid. This may be
especially true when the infusate is the same chemical as the
analyte to be measured. In this instance, if even a small amount of
infusate from a downstream port traveled to the proximal port and
into the withdrawn fluid, it could dramatically alter the accuracy
of the analyte reading. In this situation, infusate contamination
is a much more serious problem, as it will cause a much higher
error in the analyte measurement than would be caused when the
infusate is merely diluting the withdrawn fluid (which may slightly
decrease the analyte reading). Thus, if an analyte level is very
low, it may be useful to use a very low flow rate and/or pressure
when withdrawing fluid from the proximal port. For example, if the
infusate and the analyte being measured are glucose, and if the
level of glucose in a blood stream is extremely low, it can be
vitally important to be able to accurately measure glucose levels
as discussed above under the heading ANALYTE CONTROL AND
MONITORING. Therefore, it may be necessary in this situation to
withdraw fluid at a very low flow rate and/or pressure, to minimize
contamination in the withdrawn fluid. There may also be other
factors that affect the pressure and/or flow rate that fluid should
be withdrawn at in order to achieve the desired level of accuracy
in an analyte reading.
[0371] In various methods and systems as described herein, it can
be observed that by using the fluid withdrawal techniques discussed
herein, the amount of infusate contaminants in the withdrawn blood
can be very low--for example in the range of 10, 20, 30, 100, or
1000 parts per million. However, such volumetric expressions of
contamination reduction can be less useful than percentage
expressions, since, as noted above, some contaminants affect an
analyte measurement more directly (e.g., if glucose is the analyte
and glucose, dextrose, and/or insulin are the contaminant, for
example). Thus, one useful measure of the advantages of the
described systems and methods is by how they improve the accuracy
of an analyte measurement itself. The systems and methods described
herein can reduce the effects of contaminants in the withdrawn
fluid such that there is only a 20%, 15%, 10%, 5%, 4%, 2%, and/or
0% difference in the underlying analyte measurement.
[0372] The relative sizes of adjoining tubular structures can be
used to provide desired changes in fluid velocity and/or pressure.
For example, a tube with a small inner diameter may have a lower
flow rate than a larger tube at the same pressure. A system may be
designed which uses a variety of diameters of tubes in order to
achieve desirable flow rates. In some cases, however, the relative
sizes of adjoining tubular structures can introduce factors that
must be overcome or compensated for using other aspects of the
device, method, or system. For example, if a tube to which a fluid
pump is immediately attached later communicates with a tube having
a smaller diameter, a pumping action can cause a pressure in the
immediately attached tube that is lower than the pressure in the
more distant tube. Indeed, if the proper conditions are met (e.g.,
laminar flow, presence or absence of other flow paths, etc.), the
relative fluid velocities, pressures, etc. in connected tubes can
be determined using Bernoulli's equations, in a similar fashion as
flow in a Venturi tube is calculated and modeled using principles
of hydraulic systems. The practical consequence of this can be that
a system of tubes having a greater diameter at the in-patient
opening than at the immediate pump interface can have a lower
pressure at the in-patient opening than at the immediate pump
interface. In this way, system design having a larger opening in
the patient can allow even lower pressures at that point than may
otherwise be possible using the same pump. On the other hand, a
system of tubes having a smaller diameter at the in-patient opening
than at the immediate pump interface can have a higher pressure at
the in-patient opening than at the immediate pump interface. Thus,
in order to have a low pressure for fluid intake at a relatively
very small in-patient opening, the pump may need to operate at an
even lower pressure than would be called for if the tube had the
same diameter at the pump and at the in-patient opening.
Free Flow Protection Subsystem
[0373] As discussed above, various embodiments of analyte
monitoring systems such as the analyte monitoring system 100 (e.g.
an "OptiScanner.RTM.") can be attached or connected to a patient.
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) of FIG. 5 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 illustrated in FIG. 5. The
source of this KVO flow can be the infusion pump 518 shown in FIG.
5, the third pump 568 (pump #3) shown in FIG. 5, or the first pump
522 (pump #1) shown in FIG. 5. In various embodiments, a flow of an
infusion fluid including infusates such as glucose, insulin or
other medications can be also provided to the patient through the
patient tube 512 of FIG. 5. The flow of the KVO fluid and/or the
infusion fluid can be controlled by various valves e.g. pinch valve
521 and 542 shown in FIG. 5. As discussed above with reference to
FIG. 6, in some embodiments, the pinch valves 521 and 542 may be
located on the door of the analyte monitoring system. In some
embodiments, when the door of the analyte monitoring system is
open, the pinch valves may not be capable of controlling the flow
of the KVO and/or the infusion fluid. In such instances, to prevent
the free flow of the KVO and/or the infusion fluid into the
patient, a free flow protection sub-system may be provided. The
free flow protection sub-system is further described below with
reference to FIGS. 39-42.
[0374] The free flow protection (FFP) sub-system 3900 illustrated
in FIG. 39 comprises a motor 3901 which moves a pin 3903 that
pushes on a FFP device 3905. In various embodiments, the FFP device
3905 may interface with a disposable (e.g. disposable system 408 of
FIG. 4, removable portion 710 of FIG. 7, disposable portion 804 of
FIG. 8, etc.) and be configured to pinch off or control the flow of
fluids through the patient tube 3907 (which can be similar to the
patient tube 512(T1) of FIG. 5). In various embodiments, the FFP
device 3905 can be configured to shut-off or control the flow of
KVO and/or infusion fluids through the patient and thus avoid or
substantially reduce free flow of infusion fluids.
[0375] FIGS. 40A and 40B schematically illustrate an embodiment of
the FFP device 3905. The FFP device 3905 can include a widened
portion 4001 and a narrowed portion 4003. In the normal,
non-actuated or load position of the FFP device 3905, the pin 3903
(also referred to as the trigger pin) is configured to slide
underneath the FFP device 3905 as shown in FIG. 40B and the patient
tube 3907 (e.g. tube 512 of FIG. 5) runs through the widened
portion 4001 of the FFP device such that the flow through the tube
is not restricted as shown in FIGS. 40 A and 40 B.
[0376] When the FFP device is actuated (e.g. when the door is
opened), the pin 3903 is configured to move upwards to an actuated
position and pushes the FFP device 3905 upwards, such that the
patient tube 3907 is crimped by the narrowed portion 4003 of the
FFP device 3905 thus restricting the flow of fluid through the
patient tube 3907. When the door is closed the pin 3903 goes back
to its normal, non-actuated position.
[0377] FIGS. 41A and 41B schematically illustrate an embodiment of
the FFP sub-system 3900 interfaced with a disposable 4100. The FFP
sub-system interfaces with the disposable 4100 such that the FFP
device 3905 is located in the tubing carrier portion of the
disposable that interfaces or includes the patient tube 3907 (e.g.
tube 512 of FIG. 5). As illustrated in FIGS. 41A and 41B, the pin
3903 of the FFP sub-system 3900 is configured to move between two
positions: a load position and an actuated position. In various
embodiments, the difference between the load and the actuated
positions can be approximately 0.1 inches to approximately 0.15
inches. As described above, in its normal position, non-actuated or
load position the FFP device 3905 does not interfere with the
disposable the loading process. While it is in its actuated
position, the FFP device is configured to pinch the patient tube
3907. Upon loading, the tube sections in the tubing carrier portion
of the disposable align with (e.g., can register off of) the pins
in the pinch zone assembly of the analyte monitoring system.
[0378] FIGS. 42A-42C schematically illustrate a FFP sub-system
mounted to the analyte monitoring system. As illustrated in FIG.
42A, in some embodiments, the FFP sub-system comprises a variety of
mounting points 3909 which are used to mount the FFP sub-system to
a side of the analyte monitoring system by using bolts. In various
embodiments, as illustrated in FIG. 42A, Teflon tape 3911 may be
provided between the FFP device 3905 and the surface of the analyte
monitoring system to prevent from wearing the FFP device down by
the rough surface of the analyte monitoring system. In some
embodiments, the FFP subsystem may comprise optical sensors 3913 as
shown in FIG. 42C which are located at the load and the actuated
positions of the FFP device 3905. The optical sensors can be used
to control the movement of the FFP device 3905 between the load and
the actuated positions. For example, in some embodiments, the FFP
device 3905 moves from the load position to the actuated position
and/or from the actuated position to the load position until one of
the optical sensors is tripped (or changes state).
[0379] Reference throughout this specification to "some
embodiments" or "an embodiment" means that a particular feature,
structure or characteristic described in connection with the
embodiment is included in at least some embodiments. Thus,
appearances of the phrases "in some embodiments" or "in an
embodiment" in various places throughout this specification are not
necessarily all referring to the same embodiment and may refer to
one or more of the same or different embodiments. Furthermore, the
particular features, structures or characteristics may be combined
in any suitable manner, as would be apparent to one of ordinary
skill in the art from this disclosure, in one or more
embodiments.
[0380] 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.
[0381] 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.
[0382] Embodiments of the disclosed systems and methods may be used
and/or implemented with local and/or remote devices, components,
and/or modules. The term "remote" may include devices, components,
and/or modules not stored locally, for example, not accessible via
a local bus. Thus, a remote device may include a device which is
physically located in the same room and connected via a device such
as a switch or a local area network. In other situations, a remote
device may also be located in a separate geographic area, such as,
for example, in a different location, building, city, country, and
so forth.
[0383] 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.
[0384] 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.
[0385] 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.
[0386] 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.
* * * * *