Note: Descriptions are shown in the official language in which they were submitted.
WO 2014/035570
PCT/US2013/051886
SAFEGUARDING MEASURES FOR A CLOSED-LOOP INSULIN INFUSION SYSTEM
[0001]
TECHNICAL FIELD
100021 Embodiments of the subject matter described herein relate
generally to drug
delivery systems and more specifically to systems for controlling the infusion
rate of
insulin based on state variable feedback.
BACKGROUND
[0003] The pancreas of a normal healthy person produces and releases
insulin into the
blood stream in response to elevated blood plasma glucose levels. Beta cells
(I3-cells),
which reside in the pancreas, produce and secrete the insulin into the blood
stream, as it is
needed. If I3-cells become incapacitated or die, a condition known as Type I
diabetes
mellitus (or in some cases if I3-cells produce insufficient quantities of
insulin, Type II
diabetes), then insulin must be provided to the body from another source.
[0004] Traditionally, since insulin cannot be taken orally, insulin
has been injected
with a syringe. More recently, use of infusion pump therapy has been
increasing,
especially for delivering insulin for diabetics. For example, external
infusion pumps are
worn on a belt, in a pocket, or the like, and deliver insulin into the body
via an infusion
tube with a percutaneous needle or a cannula placed in the subcutaneous
tissue. As of
1995, less than 5% of Type I diabetics in the United States were using
infusion pump
therapy. Presently, over 7% of the more than 900,000 Type I diabetics in the
United
States are using infusion pump therapy, and the percentage of Type I diabetics
that use an
infusion pump is growing at an absolute rate of over 2% each year. Moreover,
the number
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of Type I diabetics is growing at 3% or more per year. In addition, growing
numbers of
insulin-using Type II diabetics are also using infusion pumps. Physicians have
recognized
that continuous infusion provides greater control of a diabetic's condition,
and are also
increasingly prescribing it for patients. Although offering control, pump
therapy can
suffer from several complications that make use of traditional external
infusion pumps
less desirable for the user.
[0005] In insulin pumps, it is common to use fast acting insulin as opposed
to the
slower acting insulin that is used for injections, because pumps allow
changing of insulin
profiles. As insulin companies develop faster acting insulin, the faster
acting insulin is
often adopted quickly. However, current pumps are still limited by the speed
of the
insulin they are using.
BRIEF SUMMARY
[0006] A processor-implemented method is presented here. The method can be
used
to control an insulin infusion device for a user. Certain embodiments of the
method
involve the operation of a processor architecture having at least one
processor device to
obtain a current insulin on board (JOB) value that represents an estimate of
active insulin
in the body of the user. The method continues by calculating, by the processor
architecture, an 10B rate based at least in part on the obtained current 10B
value. The
method continues by determining, by the processor architecture, an adjusted
insulin
infusion rate based at least in part on the calculated JOB rate and an
uncompensated
insulin infusion rate. The processor architecture selects a final insulin
infusion rate for the
insulin infusion device, wherein either the determined adjusted insulin
infusion rate, the
uncompensated insulin infusion rate, or a current basal rate is selected as
the final insulin
infusion rate.
[0007] Also presented here is a processor-implemented method of controlling
an
insulin infusion device for a user. Certain embodiments of the method begin by
generating a current IOB value that represents an estimate of active insulin
in the body of
the user. The method continues by calculating an JOB rate based at least in
part on the
generated current IOB value, obtaining an uncompensated insulin infusion rate,
and
determining an adjusted insulin infusion rate in accordance with the
expression
AdjustedRate(n)= max(0; PIDRate(n)¨ 10BRate(n)). The method continues by
selecting a final insulin infusion rate in accordance with the expression
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max(Basal; AdjustedRate(n)), P1DRate > Basal. In this
FinalRate(n) =
PID Rate(n), PIDRate < Basal
expression: AdjustedRate(n) is the determined adjusted insulin infusion rate;
PIDRate(n)
is the obtained uncompensated insulin infusion rate; IOBRate(n) is the
calculated LOB
rate; FinalRate(n) is the selected final insulin infusion rate; and Basal is a
current basal
rate maintained by the insulin infusion device for the user.
[0008] Also presented here is a tangible and non-transitory electronic
storage medium
having processor-executable instructions that, when executed by a processor
architecture
comprising at least one processor device, perform a method of controlling an
insulin
infusion device for a user. In certain embodiments, the method begins by
estimating a
current JOB value that indicates an amount of active insulin in the body of
the user. The
method continues by calculating an JOB rate based at least in part on the
estimated
current JOB value, determining an adjusted insulin infusion rate based at
least in part on
the calculated IOB rate and an uncompensated insulin infusion rate, and
selecting a final
insulin infusion rate for the insulin infusion device, wherein either the
determined
adjusted insulin infusion rate, the uncompensated insulin infusion rate, or a
current basal
rate is selected as the final insulin infusion rate. The method then provides
the selected
final insulin infusion rate to regulate delivery of insulin by the insulin
infusion device.
[0009] An electronic device is also presented here. Certain embodiments of
the
electronic device include a processor architecture and at least one memory
element
associated with the processor architecture. The at least one memory element
stores
processor-executable instructions that, when executed by the processor
architecture,
perform a method of controlling an insulin infusion device for a user. The
method
involves: computing a current IOB value that indicates an amount of active
insulin in the
body of the user; calculating an JOB rate based at least in part on the
computed JOB
value; determining an adjusted insulin infusion rate based at least in part on
the calculated
IOB rate and an uncompensated insulin infusion rate; and selecting a final
insulin
infusion rate for the insulin infusion device. The selecting step selects
either the
determined adjusted insulin infusion rate, the uncompensated insulin infusion
rate, or a
current basal rate as the final insulin infusion rate.
[OM An electronic controller for an insulin infusion device is also
presented here.
The electronic controller includes a processor architecture comprising at
least one
processor device, and at least one memory clement associated with the
processor
architecture. The at least one memory element stores processor-executable
instructions
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that, when executed by the processor architecture, provide an JOB compensation
module
that estimates a current JOB value that indicates an amount of active insulin
in the body
of the user, calculates an JOB rate based at least in part on the estimated
current JOB
value, and determines an adjusted insulin infusion rate based at least in part
on the
calculated JOB rate and an uncompensated insulin infusion rate. The JOB
compensation
module selects a final insulin infusion rate for the insulin infusion device,
wherein the
final insulin infusion rate is selected as either the determined adjusted
insulin infusion
rate, the uncompensated insulin infusion rate, or a current basal rate. The
JOB
compensation module then provides the selected final insulin infusion rate to
regulate
delivery of insulin by the insulin infusion device.
[0011] An exemplary embodiment of an electronic device is also provided
here. The
electronic device includes a processor architecture having at least one
processor device,
and at least one memory element associated with the processor architecture.
The at least
one memory element stores processor-executable instructions that, when
executed by the
processor architecture, perform a method of controlling an insulin infusion
device for a
user. The method operates the insulin infusion device in a closed-loop mode to
deliver
insulin to the body of the user, obtains current insulin-delivered data that
indicates an
amount of insulin delivered by the insulin infusion device during a most
recent sampling
period, obtains current sensor data that indicates a current sensor glucose
value for the
user corresponding to the most recent sampling period, and processes
historical insulin-
delivered data and historical sensor data, for a plurality of historical
sampling periods
prior to the most recent sampling period, to obtain predicted sensor glucose
values for a
historical time period. The method continues by calculating a difference
between the
current sensor glucose value and a predicted current sensor glucose value for
the most
recent sampling period, wherein the predicted sensor glucose values for the
historical
time period include the predicted current sensor glucose value. The method
continues by
generating an alert when the difference exceeds a threshold error amount.
[0012] The following detailed description also relates to a tangible and
non-transitory
electronic storage medium having processor executable instructions that, when
executed
by a processor architecture comprising at least one processor device, perform
a method of
controlling an insulin infusion device for a user. The method involves
operation of the
insulin infusion device in a closed-loop mode to deliver insulin to the body
of the user.
The method continues by identifying, from historical sensor glucose values for
the user, a
baseline historical sensor glucose value obtained during a begin-training
sampling period.
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The method calculates a plurality of candidate solutions to a sensor glucose
prediction
model, wherein each of the plurality of candidate solutions is calculated as a
function of a
bounded initial condition and historical insulin delivered data for the user,
and wherein
the bounded initial condition is influenced by the baseline sensor glucose
value. The
method continues by selecting a best-matched solution from the calculated
plurality of
candidate solutions, based on a comparison of predicted sensor glucose values
from the
calculated plurality of candidate solutions to a first portion of the
historical sensor glucose
values. The predicted sensor glucose values from the best-matched solution are
compared
to a second portion of the historical sensor glucose values, wherein the first
portion of the
historical sensor glucose values corresponds to a distant history period, the
second portion
of the historical sensor glucose values corresponds to a recent history
period, and the
distant history period occurred before the recent history period that data
samples. The
method continues by generating an alert, in response to the comparing, when
the second
portion of the historical sensor glucose values deviates from the best-matched
solution by
at least a threshold error amount.
100131 Also presented here
is an embodiment of an electronic controller for an insulin
infusion device. The electronic controller includes a processor architecture
comprising at
least one processor device, and at least one memory element associated with
the processor
architecture. The at least one memory element stores processor-executable
instructions
that, when executed by the processor architecture, provide a model supervisor
module to
obtain, during closed-loop operation of the insulin infusion device, insulin-
delivered data
that indicates an amount of insulin delivered by the insulin infusion device
during a most
recent sampling period, and current sensor data that indicates a current
sensor glucose
value for the user corresponding to the most recent sampling period. The model
supervisor module defines a model training period and a model prediction
period for a
historical period of time, and finds a best-matched solution to a sensor
glucose prediction
model, relative to historical sensor glucose values obtained during the model
training
period, wherein the best-matched solution is a function of a baseline sensor
glucose value
obtained during the model training period, and is a function of historical
insulin-delivered
data for the user obtained during the historical period of time. The model
supervisor
module compares at least one predicted sensor glucose value from the best-
matched
solution to at least one historical sensor glucose value corresponding only to
the model
prediction period, and generates an alert, in response to the comparing, when
the at least
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one historical sensor glucose value deviates from the at least one predicted
sensor glucose
value by at least a threshold error amount.
10014] Also included below is a detailed description of a processor-
implemented
method of controlling an insulin infusion device for a user. The method may
begin by
operating the insulin infusion device in a closed-loop mode to deliver insulin
to the body
of the user. The method continues by obtaining current insulin-delivered data
that
indicates an amount of insulin delivered by the insulin infusion device during
a most
recent sampling period, obtaining current sensor data that indicates a current
sensor
glucose value for the user corresponding to the most recent sampling period,
and
processing historical insulin-delivered data and historical sensor data, for a
plurality of
historical sampling periods prior to the most recent sampling period, to
obtain predicted
sensor glucose values for a historical time period. The method then calculates
a difference
between the current sensor glucose value and a predicted current sensor
glucose value for
the most recent sampling period, wherein the predicted sensor glucose values
for the
historical time period include the predicted current sensor glucose value. An
alert is
generated when the difference exceeds a threshold error amount.
100151 Also included below is a detailed description of a processor-
implemented
method of controlling an insulin infusion device for a user. The method may
begin by
operating the insulin infusion device in a closed-loop mode to deliver insulin
to the body
of the user. The method continues by identifying, from historical sensor
glucose values
for the user, a baseline historical sensor glucose value obtained during a
begin-training
sampling period. Next, a plurality of candidate solutions to a sensor glucose
prediction
model is calculated, wherein each of the plurality of candidate solutions is
calculated as a
function of a bounded initial condition and historical insulin delivered data
for the user,
and wherein the bounded initial condition is influenced by the baseline sensor
glucose
value. The method continues by selecting a best-matched solution from the
calculated
plurality of candidate solutions, based on a comparison of predicted sensor
glucose values
from the calculated plurality of candidate solutions to a first portion of the
historical
sensor glucose values. At least one predicted sensor glucose value from the
best-matched
solution is compared to a second portion of the historical sensor glucose
values, wherein
the first portion of the historical sensor glucose values corresponds to a
distant history
period, the second portion of the historical sensor glucose values corresponds
to a recent
history period, and the distant history period occurred before the recent
history period that
data samples. An alert is generated, in response to the comparing, when the
second
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portion of the historical sensor glucose values deviates from the best-matched
solution by
at least a threshold error amount.
[0016] Another embodiment of a processor-implemented method of controlling
an
insulin infusion device for a user is also presented below. The method
involves operating
the insulin infusion device in a closed-loop mode to deliver insulin to the
body of the
user, defining a model training period and a model prediction period for a
historical
period of time, and finding a best-matched solution to a sensor glucose
prediction model,
relative to historical sensor glucose values obtained during the model
training period,
wherein the best-matched solution is a function of a baseline sensor glucose
value
obtained during the model training period, and is a function of historical
insulin-delivered
data for the user obtained during the historical period of time. The method
continues by
comparing at least one predicted sensor glucose value from the best-matched
solution to
at least one historical sensor glucose value corresponding only to the model
prediction
period. An alert is generated, in response to the comparing, when the at least
one
historical sensor glucose value deviates from the at least one predicted
sensor glucose
value by at least a threshold error amount
[0017] This summary is provided to introduce a selection of concepts in a
simplified
form that are further described below in the detailed description. This
summary is not
intended to identify key features or essential features of the claimed subject
matter, nor is
it intended to be used as an aid in determining the scope of the claimed
subject matter.
BRIEF DESCRIPTION OF THE DRAWINGS
[0018] A more complete understanding of the subject matter may be derived
by
referring to the detailed description and claims when considered in
conjunction with the
following figures, wherein like reference numbers refer to similar elements
throughout
the figures.
[0019] FIG. 1 is a block diagram of a closed loop glucose control system in
accordance with an embodiment of the present invention.
[0020] FIG. 2 is a front view of closed loop hardware located on a body in
accordance
with an embodiment of the present invention.
[0021] FIG. 3A is a perspective view of a glucose sensor system for use in
an
embodiment of the present invention.
[0022] FIG. 3B is a side cross-sectional view of the glucose sensor system
of FIG.
3A.
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100231 FIG. 3C is a perspective view of a sensor set of the glucose sensor
system of
FIG. 3A for use in an embodiment of the present invention.
[0024] FIG. 3D is a side cross-sectional view of the sensor set of FIG. 3C.
[0025] FIG. 4 is a cross sectional view of a sensing end of the sensor of
FIG. 3D.
[0026] FIG. 5 is a top view of an infusion device with a reservoir door in
the open
position, for use in an embodiment of the present invention.
[0027] FIG. 6 is a side view of an infusion set with the insertion needle
pulled out, for
use in an embodiment of the present invention.
[0028] FIG. 7 is a circuit diagram of a sensor and its power supply in
accordance with
an embodiment of the present invention.
[0029] FIG. 8A is a diagram of a single device and its components in
accordance with
an embodiment of the present invention.
[0030] FIG. 8B is a diagram of two devices and their components in
accordance with
an embodiment of the present invention.
[0031] FIG. 8C is another diagram of two devices and their components in
accordance with an embodiment of the present invention.
[0032] FIG. 8D is a diagram of three devices and their components in
accordance
with an embodiment of the present invention.
[0033] FIG. 9 is a table listing the devices of FIGS. 8A-D and their
components.
[0034] FIG. 10 is a block diagram of the glucose sensor system of FIG. 3A.
[0035] FIG. 11A is a detailed block diagram of an A/D converter for the
glucose
sensor system of FIG. 10 in accordance with an embodiment of the present
invention.
100361 FIG. 11B is a detailed block diagram of the A/D converter for the
glucose
sensor system of FIG. 10 with a pulse duration output selection option in
accordance with
an embodiment of the present invention.
[0037] FIG. 12 is a circuit diagram of an I-F A/D converter of FIG. 10
accompanied
by charts of node signals in accordance with an embodiment of the present
invention.
[0038] FIG. 13 is another circuit diagram of an I-F A/D converter of FIG.
10
accompanied by charts of node signals in accordance with an embodiment of the
present
invention.
[0039] FIG. 14 is still another circuit diagram of an I-F A/D converter of
FIG. 10
accompanied by charts of node signals in accordance with an embodiment of the
present
invention.
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[0040] FIG. 15 is a circuit diagram of an I-V A/D converter of FIG. 10 in
accordance
with an embodiment of the present invention.
[0041] FIG. 16 is a block diagram of the glucose sensor system of FIG. 10
with a pre-
filter and a filter in accordance with an embodiment of the present invention.
[0042] FIG. 17 is a chart of an example of a pre-filter of FIG. 16 and its
effects on
digital sensor values Dsig in accordance with an embodiment of the present
invention.
[0043] FIG. 18 is frequency response chart for a filter of FIG. 16 in
accordance with
an embodiment of the present invention.
[0044] FIG. 19A is a plot of a filtered and an unfiltered sensor signal
over time in
accordance with an embodiment of the present invention.
[0045] FIG. 19B is close up of a section of the plot of FIG. 19A in
accordance with
an embodiment of the present invention.
[0046] FIG. 20 is a cross-sectional view of a sensor set and an infusion
set attached to
the body in accordance with an embodiment of the present invention.
[0047] FIG. 21 is a frequency response chart of a time delay correcting
Weiner filter
in accordance with an embodiment of the present invention.
[0048] FIG. 22 is a plot of a digital sensor values Dsig before and after
time delay
correction compared to actual glucose measurements over time in accordance
with an
embodiment of the present invention.
[0049] FIG. 23A is a diagram of a glucose clamp (glucose level with respect
to time).
[0050] FIG. 23B is a plot of insulin concentration in a normal glucose
tolerant (NGT)
individual in response to various magnitudes of glucose clamps of FIG. 23A.
100511 FIG. 24A is a diagram of a glucose clamp.
[0052] FIG. 24B is a diagram of a proportional insulin response to the
glucose clamp
of FIG. 24A in accordance with an embodiment of the present invention.
[0053] FIG. 24C is a diagram of an integral insulin response to the glucose
clamp of
FIG. 24A in accordance with an embodiment of the present invention.
[0054] FIG. 24D is a diagram of a derivative insulin response to the
glucose clamp of
FIG. 24A in accordance with an embodiment of the present invention.
[0055] FIG. 24E is a diagram of a combined proportional, integral, and
derivative
insulin response to the glucose clamp of FIG. 24A in accordance with an
embodiment of
the present invention.
[0056] FIG. 25A is a plot of insulin responses to a glucose clamp for
exercise trained
and normal individuals.
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100571 FIG. 25B is a bar chart of glucose uptake rates for exercise trained
and normal
individuals.
[0058] FIG. 26 is a block diagram of a closed loop system to control blood
glucose
levels through insulin infusion based on glucose level feedback in accordance
with an
embodiment of the present invention.
[0059] FIG. 27 is a detailed block diagram of the portion of the control
loop of FIG.
26 that is in the body in accordance with an embodiment of the present
invention.
[0060] FIGS. 28A and 28B are plots of measured insulin responses of two
different
normal glucose tolerant (NGT) individuals to a glucose clamp for use with an
embodiment of the present invention.
[0061] FIG. 29A is a plot of two different glucose sensor outputs compared
to glucose
meter readings during a glucose clamp in accordance with an embodiment of the
present
invention.
10062] FIG. 29B is a plot of actual insulin concentration in blood compared
to a
controller commanded insulin concentration in response to the glucose clamp of
FIG.
29A in accordance with an embodiment of the present invention.
[0063] FIG. 30 is a top view of an end of a multi-sensor for measuring both
glucose
concentration and pH in accordance with an embodiment of the present
invention.
[0064] FIG. 31A is a representative drawing of blood glucose compared to
sensor
measured blood glucose over time in accordance with an embodiment of the
present
invention.
[00651 FIG. 31B is a representative drawing of sensor sensitivity over the
same
period of time as FIG. 31A in accordance with an embodiment of the present
invention.
[0066] FIG. 31C is a representative drawing of sensor resistance over the
same period
of time as FIG. 31A in accordance with an embodiment of the present invention.
[0067] FIG. 32 is a block diagram using the derivative of sensor resistance
to
determine when to recalibrate or replace the sensor in accordance with an
embodiment of
the present invention.
[0068] FIG. 33A is a plot of an analog sensor signal Isig over time in
accordance with
an embodiment of the present invention.
10069] FIG. 33B is a plot of sensor resistance over the same period of time
as FIG.
32A in accordance with an embodiment of the present invention.
[0070] FIG. 33C is a plot of the derivative of the sensor resistance of
FIG. 32B in
accordance with an embodiment of the present invention.
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[0071] FIG. 34A is a bottom view of a telemetered characteristic monitor in
accordance with an embodiment of the present invention.
[0072] FIG. 34B is a bottom view of a different telemetered characteristic
monitor in
accordance with an embodiment of the present invention.
[0073] FIG. 35A is a drawing of a blood plasma insulin response to a
glucose clamp
in a normal glucose tolerant (NGT) individual in accordance with an embodiment
of the
present invention.
[0074] FIG. 35B is a drawing of the blood plasma insulin response of FIG.
35A when
delayed due to insulin being delivered to the subcutaneous tissue instead of
directly into
the blood stream in accordance with an embodiment of the present invention.
[0075] FIG. 36A is a drawing of blood plasma insulin concentration over
time after
an insulin bolus is delivered directly into the blood stream in accordance
with an
embodiment of the present invention.
[0076] FIG. 36B is a drawing of a blood plasma insulin concentration over
time after
an insulin bolus is delivered into the subcutaneous tissue in accordance with
an
embodiment of the present invention.
[0077] FIG. 37 is a block diagram of the closed loop system of FIG. 26 with
the
addition of a post-controller compensator and a derivative filter in
accordance with an
embodiment of the present invention.
[0078] FIG. 38A is a plot of sensor signal measurements and Via
measurements with
respect to time in accordance with an embodiment of the present invention.
[0079] FIG. 38B is a plot of a measured counter electrode voltage Vent with
respect
to time in accordance with an embodiment of the present invention.
[0080] FIG. 38C is a plot of calculated sensor sensitivity with respect to
time in
accordance with an embodiment of the present invention.
100811 FIG. 38D is a plot of a calculation of sensor resistance Rsi with
respect to time
in accordance with an embodiment of the present invention.
100821 FIG. 38E is a plot of another calculation of sensor resistance Rs2
with respect
to time in accordance with an embodiment of the present invention.
100831 FIG. 38F is a plot of the derivative of sensor resistance Rsi of
FIG. 38D with
respect to time in accordance with an embodiment of the present invention.
[0084] FIG. 38G is a plot of the derivative of the sensor resistance Rs2 of
FIG. 38E
with respect to time in accordance with an embodiment of the present
invention.
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[0085] FIG. 38H is a plot of when sensors were replaced with respect to
time in
accordance with an embodiment of the present invention.
[0086] FIGS. 39A and 39B are a block diagrams of a closed loop glucose
control
system in accordance with embodiments of the present invention.
[0087] FIG. 40 is a block diagram of auto blood withdrawal and return in
accordance
with an embodiment of the present invention.
100881 FIG. 41A is a plot actual blood glucose concentration in accordance
with an
embodiment of the present invention.
[0089] FIG. 41B is a plot of actual insulin concentration in blood compared
to a
controller commanded insulin concentration in response to the blood glucose in
FIG. 41A
in accordance with an embodiment of the present invention.
100901 FIG. 42 illustrates a control feedback block diagram of state
variable feedback
and in accordance with an embodiment of the present invention.
[0091] FIG. 43 is a plot of basal insulin delivery rate over time using
different control
gains in accordance with embodiments of the present invention.
[0092] FIG. 44 is a plot of subcutaneous insulin over time using different
control
gains in accordance with embodiments of the present invention.
[0093] FIG. 45 is a plot of plasma insulin over time using different
control gains in
accordance with embodiments of the present invention.
[0094] FIG. 46 is a plot of insulin effect over time using different
control gains in
accordance with embodiments of the present invention.
[0095] FIG. 47 is a plot of simulated glucose concentration over time using
a PID
controller with state variable feedback and a PID controller without state
variable
feedback in accordance with embodiments of the present invention.
[0096] FTG. 48 is a plot of simulated insulin delivery over time using a
PID controller
with state variable feedback and a PTD controller without state variable
feedback in
accordance with embodiments of the present invention.
[0097] FIG. 49 is a block diagram that illustrates processing modules and
algorithms
of an exemplary embodiment of a closed-loop system controller.
100981 FIG. 50 is a flow chart that illustrates an exemplary embodiment of
a control
process for an insulin infusion device.
[0099] FIG. 51 is a graph of integral clip value versus sensor glucose
levels.
[00100] FIG. 52 is a block diagram that schematically illustrates an exemplary
embodiment of an insulin on board (I0B) compensation module.
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100101] FIG. 53 is a flow chart that illustrates an exemplary embodiment of an
10B
compensation process.
[00102] FIG. 54 is a diagram that depicts certain time events associated with
the
operation of a model supervisor module.
[00103] FIG. 55 is a flow chart that illustrates an exemplary embodiment of a
sensor
model supervision process.
[00104] FIG. 56 is a flow chart that illustrates an exemplary embodiment of a
sensor
model training process, which may be performed in conjunction with the sensor
model
supervision process depicted in FIG. 55.
[00105] FIG. 57 is a diagram that illustrates two exemplary fault conditions
that can be
detected by the model supervisor module.
DETAILED DESCRIPTION
[00106] The following detailed description is merely illustrative in nature
and is not
intended to limit the embodiments of the subject matter or the application and
uses of
such embodiments. As used herein, the word "exemplary" means "serving as an
example,
instance, or illustration." Any implementation described herein as exemplary
is not
necessarily to be construed as preferred or advantageous over other
implementations.
Furthermore, there is no intention to be bound by any expressed or implied
theory
presented in the preceding technical field, background, brief summary or the
following
detailed description.
[00107] Techniques and technologies may be described herein in terms of
functional
and/or logical block components, and with reference to symbolic
representations of
operations, processing tasks, and functions that may be performed by various
computing
components or devices. Such operations, tasks, and functions are sometimes
referred to as
being computer-executed, computerized, software-implemented, or computer-
implemented. It should be appreciated that the various block components shown
in the
figures may be realized by any number of hardware, software, and/or firmware
components configured to perform the specified functions. For example, an
embodiment
of a system or a component may employ various integrated circuit components,
e.g.,
memory elements, digital signal processing elements, logic elements, look-up
tables, or
the like, which may carry out a variety of functions under the control of one
or more
microprocessors or other control devices.
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[00108] When implemented in software or firmware, various elements of the
systems
described herein are essentially the code segments or instructions that
perform the various
tasks. The program or code segments can be stored in any tangible and non-
transitory
processor-readable medium. The "processor-readable medium" or "machine-
readable
medium" may include any medium that can store or transfer information.
Examples of the
processor-readable medium include an electronic circuit, a semiconductor
memory
device, a ROM, a flash memory, an erasable ROM (EROM), a floppy diskette, a CD-
ROM, an optical disk, a hard disk, or the like.
1001091 The various tasks performed in connection with a process described
herein
may be performed by software, hardware, firmware, or any combination thereof.
It should
be appreciated that a described process may include any number of additional
or
alternative tasks, the tasks shown in a particular figure need not be
performed in the
illustrated order, and a described process may be incorporated into a more
comprehensive
procedure or process having additional functionality not described in detail
herein.
Moreover, one or more of the tasks shown in the figures could be omitted from
an
embodiment of a described process as long as the intended overall
functionality remains
intact.
1001101 As shown in the drawings for purposes of illustration, the invention
is
embodied in a closed loop infusion system for regulating the rate of fluid
infusion into a
body of a user based on feedback from an analyte concentration measurement
taken from
the body. In particular embodiments, the invention is embodied in a control
system for
regulating the rate of insulin infusion into the body of a user based on a
glucose
concentration measurement taken from the body. In preferred embodiments, the
system is
designed to model a pancreatic beta cell (0-cell). In other words, the system
controls an
infusion device to release insulin into a body of a user in a similar
concentration profile as
would be created by fully functioning human 0-cells when responding to changes
in
blood glucose concentrations in the body.
100111] Thus, the system simulates the body's natural insulin response to
blood
glucose levels and not only makes efficient use of insulin, but also accounts
for other
bodily functions as well since insulin has both metabolic and mitogcnic
effects. However,
the algorithms must model the 13-cells closely, since algorithms that are
designed to
minimize glucose excursions in the body, without regard for how much insulin
is
delivered, may cause excessive weight gain, hypertension, and atherosclerosis.
In
preferred embodiments of the present invention, the system is intended to
emulate the in
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vivo insulin secretion pattern and to adjust this pattern consistent with the
in vivo 13-cell
adaptation experienced by normal healthy individuals. The in vivo 3-cell
response in
subjects with normal glucose tolerance (NGT), with widely varying insulin
sensitivity
(SI), is the optimal insulin response for the maintenance of glucose
homeostasis.
1001121 Preferred embodiments include a glucose sensor system 10, a controller
12
and an insulin delivery system 14, as shown in FIG. 1. The glucose sensor
system 10
generates a sensor signal 16 representative of blood glucose levels 18 in the
body 20, and
provides the sensor signal 16 to the controller 12. The controller 12 receives
the sensor
signal 16 and generates commands 22 that are communicated to the insulin
delivery
system 14. The insulin delivery system 14 receives the commands 22 and infuses
insulin
24 into the body 20 in response to the commands 22.
100113] Generally, the glucose sensor system 10 includes a glucose sensor,
sensor
electrical components to provide power to the sensor and generate the sensor
signal 16, a
sensor communication system to carry the sensor signal 16 to the controller
12, and a
sensor system housing for the electrical components and the sensor
communication
system.
[00114] Typically, the controller 12 includes controller electrical components
and
software to generate commands for the insulin delivery system 14 based on the
sensor
signal 16, and a controller communication system to receive the sensor signal
16 and
carry commands to the insulin delivery system 14.
[00115] Generally, the insulin delivery system 14 includes an infusion device
and an
infusion tube to infuse insulin 24 into the body 20. In particular
embodiments, the
infusion device includes infusion electrical components to activate an
infusion motor
according to the commands 22, an infusion communication system to receive the
commands 22 from the controller 12, and an infusion device housing to hold the
infusion
device.
[00116] In preferred embodiments, the controller 12 is housed in the infusion
device
housing and the infusion communication system is an electrical trace or a wire
that carries
the commands 22 from the controller 12 to the infusion device. In alternative
embodiments, the controller 12 is housed in the sensor system housing and the
sensor
communication system is an electrical trace or a wire that carries the sensor
signal 16
from the sensor electrical components to the controller electrical components.
In other
alternative embodiments, the controller 12 has its own housing or is included
in a
supplemental device. In another alternative embodiment, the controller is
located with the
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infusion device and the sensor system all within one housing. In further
alternative
embodiments, the sensor, controller, and/or infusion communication systems may
utilize
a cable, a wire, fiber optic lines, RF, IR, or ultrasonic transmitters and
receivers, or the
like instead of the electrical traces.
[00117] System Overview
[00118] Preferred embodiments of the invention include a sensor 26, a sensor
set 28, a
telemetered characteristic monitor 30, a sensor cable 32, an infusion device
34, an
infusion tube 36, and an infusion set 38, all worn on the body 20 of a user,
as shown in
FIG. 2. The telemetered characteristic monitor 30 includes a monitor housing
31 that
supports a printed circuit board 33, batteries 35, antenna (not shown), and a
sensor cable
connector (not shown), as seen in FIGS. 3A and 3B. A sensing end 40 of the
sensor 26
has exposed electrodes 42 and is inserted through skin 46 into a subcutaneous
tissue 44 of
a user's body 20, as shown in FIGS. 3D and 4. The electrodes 42 are in contact
with
interstitial fluid (ISF) that is present throughout the subcutaneous tissue
44. The sensor 26
is held in place by the sensor set 28, which is adhesively secured to the
user's skin 46, as
shown in FIGS. 3C and 3D. The sensor set 28 provides for a connector end 27 of
the
sensor 26 to connect to a first end 29 of the sensor cable 32. A second end 37
of the
sensor cable 32 connects to the monitor housing 31. The batteries 35 included
in the
monitor housing 31 provide power for the sensor 26 and electrical components
39 on the
printed circuit board 33. The electrical components 39 sample the sensor
signal 16 and
store digital sensor values (Dsig) in a memory and then periodically transmit
the digital
sensor values Dsig from the memory to the controller 12, which is included in
the
infusion device.
[00119] The controller 12 processes the digital sensor values Dsig and
generates
commands 22 for the infusion device 34. Preferably, the infusion device 34
responds to
the commands 22 and actuates a plunger 48 that forces insulin 24 out of a
reservoir 50
located inside the infusion device 34, as shown in FIG. 5. In particular
embodiments, a
connector tip 54 of the reservoir 50 extends through the infusion device
housing 52 and a
first end 51 of the infusion tube 36 is attached to the connector tip 54. A
second end 53 of
the infusion tube 36 connects to the infusion set 38. Insulin 24 is forced
through the
infusion tube 36 into the infusion set 38 and into the body 20. The infusion
set 38 is
adhesively attached to the user's skin 46, as shown in FIG. 6. As part of the
infusion set
38, a cannula 56 extends through the skin 46 and terminates in the
subcutaneous tissue 44
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completing fluid communication between the reservoir 50 and the subcutaneous
tissue 44
of the user's body 20.
[00120] In alternative embodiments, the closed-loop system can be a part of a
hospital-
based glucose management system. Given that insulin therapy during intensive
care has
been shown to dramatically improve wound healing, reduce blood stream
infections, renal
failure, and polyneuropathy mortality, irrespective of whether subjects
previously had
diabetes (See Van den Berghe G. et al., NEJM 345: 1359-67, 2001),
the present invention can be used in this hospital setting to control
the blood glucose level of a patient in intensive care. In these alternative
embodiments,
since an intravenous (IV) hookup is typically implanted into a patient's arm
while the
patient is in an intensive care setting (e.g., ICU), a closed loop glucose
control can be
established which piggy-backs off the existing IV connection. Thus, in a
hospital based
system, IV catheters which are directly connected to a patient vascular system
for
purposes of quickly delivering IV fluids, can also be used to facilitate blood
sampling and
direct infusion of substances (e.g., insulin, anticoagulants) into the intra-
vascular space.
Moreover, glucose sensors may be inserted through the IV line to give real-
time glucose
levels from the blood stream. Therefore, depending on the type of hospital
based system,
the alternative embodiments would not necessarily need the described system
components
such as the sensor 26, the sensor set 28, the telemetered characteristic
monitor 30, the
sensor cable 32, the infusion tube 36, and the infusion set 38 as described in
the preferred
embodiments. Instead, standard blood glucose meters or vascular glucose
sensors as
described in provisional application entitled "Multi-lumen Catheter," filed
Sep. 27, 2002,
Ser. No. 60/414,248, can be used
to provide the blood glucose values to the infusion pump control and the
existing IV
connection can be used to administer the insulin to the patient.
[00121] It is important to appreciate that numerous combinations of devices in
the
hospital-based system can be used with the closed loop controller of the
present
invention. For example, as described in FIG. 39B compared to the preferred
system in
FIG. 39A, an auto blood glucose/intravenous insulin infusion system can
automatically
withdraw and analyze blood for glucose concentration at fixed intervals
(preferably 5-20
minutes), extrapolate the blood glucose values at a more frequent interval
(preferably 1
minute), and use the extrapolated signal for calculating an IV-insulin
infusion according
to the controller described below. The modified auto blood glucose/intravenous
insulin
infusion system would eliminate the need for subcutaneous sensor compensation
and
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subcutaneous insulin compensation (as described with regards to the lead-lag
compensator below). The automatic withdrawal of blood, and subsequent glucose
determination can be accomplished with existing technology (e.g. VIA or
Biostator like
blood glucose analyzer) or by the system described in FIG. 40. The system in
FIG. 40
uses a peristaltic pump 420 to withdraw blood across an amperometric sensor
410 (the
same technology as used in sensor 26) and then return the blood with added
flush (0.5 to
1.0 ml) from the reservoir 400. The flush can consist of any makeup of saline,
heparin,
glucose solution and/or the like. If the blood samples are obtained at
intervals longer than
1 minute but less than 20 minutes, the blood glucose determinations can be
extrapolated
on a minute-to-minute basis with extrapolation based on the present (n) and
previous
values (n-1) to work with the logic of the controller as described in detail
below. For
blood samples obtained at intervals greater than 20 minutes, a zero-order-hold
would be
used for the extrapolation. Based on these blood glucose values, the infusion
device can
administer insulin based on the closed loop controller described in greater
detail below.
[00122] In other modifications to the system, a manual blood
glucose/intravenous
insulin infusion system can be used where frequent manual entry of blood
glucose values
from a standard blood glucose meter (e.g., YSI, Beckman, etc.) and extrapolate
the values
at more frequent intervals (preferably 1 min) to create a surrogate signal for
calculating
IV-insulin infusion. Alternatively, a sensor blood glucose/intravenous insulin
infusion
system can use a continuous glucose sensor (e.g., vascular, subcutaneous,
etc.) for
frequent blood glucose determination. Moreover, the insulin infusion can be
administered
subcutaneously rather than intravenously in any one of the previous examples
according
to the controller described below.
[00123] In still further alternative embodiments, the system components may be
combined in a smaller or greater number of devices and/or the functions of
each device
may be allocated differently to suit the needs of the user.
[00124] Controller
[00125] Once the hardware for a closed loop system is configured, such as in
the
preferred embodiments described above, the effects of the hardware on a human
body are
determined by the controller. In preferred embodiments, the controller 12 is
designed to
model a pancreatic beta cell (P-cell). In other words, the controller 12
commands the
infusion device 34 to release insulin 24 into the body 20 at a rate that
causes the insulin
concentration in the blood to follow a similar concentration profile as would
be caused by
fully functioning human 13-cells responding to blood glucose concentrations in
the body
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20. In further embodiments, a "semi-closed-loop" system may be used, in which
the user
is prompted to confirm insulin delivery before any insulin is actually
delivered.
[00126] A controller that simulates the body's natural insulin response to
blood
glucose levels not only makes efficient use of insulin but also accounts for
other bodily
functions as well since insulin has both metabolic and mitogenic effects.
Controller
algorithms that are designed to minimize glucose excursions in the body
without regard
for how much insulin is delivered may cause excessive weight gain,
hypertension, and
atherosclerosis. In preferred embodiments, of the present invention, the
controller 12 is
intended to emulate the in vivo insulin secretion pattern and to adjust this
pattern to be
consistent with in vivo 13-cell adaptation. The in vivo 13-cell response in
subjects with
normal glucose tolerance (NGT), with widely varying insulin sensitivity (Si),
is the
optimal insulin response for the maintenance of glucose homeostasis.
[00127] The 13-Cell and PID Control
[00128] Generally, the in vivo 13-cell response to changes in glucose is
characterized by
"first" and "second" phase insulin responses. This biphasic insulin response
is clearly
seen during hyperglycemic clamps applied to NGT subjects, as shown in FIG.
23B.
During a hyperglycemic clamp the glucose level is rapidly increased from a
basal level
GB to a new higher level Gc and then held constant at the higher-level Gc as
shown in
FIG. 23A. The magnitude of the increase in glucose (AG) affects the insulin
response.
Four insulin response curves are shown for four different glucose clamp levels
in FIG.
23B.
[00129] The biphasic insulin response of a 13-cell can be modeled using
components of
a proportional, plus integral, plus derivative (PID) controller. A PID
controller is selected
since PID algorithms are stable for a wide variety of non-medical dynamic
systems, and
PID algorithms have been found to be stable over widely varying disturbances
and
changes in system dynamics.
[00130] The insulin response of13-cells during a hyperglycemic clamp is
diagrammed
in FIGS. 24A-E using the components of a PID controller to model the 13-cell.
A
proportional component Up and a derivative component Up of the ND controller
may be
combined to represent a first phase insulin response 440, which lasts several
minutes. An
integral component U1 of the PID controller represents a second phase insulin
response
442, which is a steady increase in insulin release under hyperglycemic clamp
conditions.
The magnitude of each component's contribution to the insulin response is
described by
the following equations:
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[00131] Proportional Component Response: Up = Kp(G ¨ GB)
[00132] Integral Component Response: U, itt (G ¨ GB) dt + 'B , and
[00133] Derivative Component Response: UD =
K D daGt
[00134] Where
1001351 Up is the proportional component of the command sent to the insulin
delivery
system,
[00136] Uf is the integral component of the command sent to the insulin
delivery
system,
1001371 Up is the derivative component of the command sent to the insulin
delivery
system,
[00138] Kp is a proportional gain coefficient,
[00139] K, is an integral gain coefficient,
1001401 Kp is a derivative gain coefficient,
[00141] G is a present blood glucose level,
[00142] GB is a desired basal glucose level,
[00143[ t is the time that has passed since the last sensor calibration,
[00144] to is the time of the last sensor calibration, and
[00145] IB is a basal insulin concentration at to, or can also be described as
U4I0).
[00146] The combination of the PID components that model the two phases of
insulin
response by a n-cell is shown in FIG. 24E as it responds to the hyperglycemic
clamp of
FIG. 24A. FIG. 24E shows that the magnitude of the first phase response 440 is
driven by
the derivative and proportional gains, Kp and Kp. And the magnitude of the
second phase
response 442 is driven by the integral gain 1(1.
[001471 The components of the PID controller can also be expressed in its
discrete
form:
[00148] Proportional Component Response: P
- conn = K p(SG7 ¨ G5p)
[00149] Integral Component Response: icõõn = icon (sGf n _ Lisp), i , con
=
[00150] Derivative Component Response: Dconn = KDdGdefl
[00151] Where Kp, K1, and Kp are the proportional, integral, and derivative
gain
coefficients, SGf and dGdtf are the filtered sensor glucose and derivative
respectively, and
the superscript n refers to discrete time.
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[00152] An acute insulin response is essential for preventing wide
postprandial
glycemic excursions. Generally, an early insulin response to a sudden increase
in glucose
level results in less total insulin being needed to bring the glucose level
back to a desired
basal glucose level. This is because the infusion of insulin increases the
percentage of
glucose that is taken up by the body. Infusing a large amount of insulin to
increase the
percentage of glucose uptake while the glucose concentration is high results
in an
efficient use of insulin. Conversely, infusing a large amount of insulin while
the glucose
concentration is low results in using a large amount of insulin to remove a
relatively small
amount of glucose. In other words, a larger percentage of a big number is more
than a
larger percentage of a small number. The infusion of less total insulin helps
to avoid
development of insulin resistance in the user. As well, first-phase insulin is
thought to
result in an early suppression of hepatic glucose output.
1001531 Insulin sensitivity is not fixed and can change dramatically in a body
depending on the amount of exercise by the body. In one study, for example,
insulin
responses in highly exercise-trained individuals (individuals who trained more
than 5
days a week) were compared to the insulin responses in subjects with normal
glucose
tolerance (NGT) during a hyperglycemic clamp. The insulin response in exercise-
trained
individuals 444 was about one-half of the insulin response of the NGT subjects
446, as
shown in FIG. 25A. But the glucose uptake rate for each of the individuals
(exercise-
trained 448 or normal 450) was virtually identical, as shown in FIG. 25B.
Thus, it can be
speculated that the exercise-trained individuals have twice the insulin
sensitivity and half
of the insulin response leading to the same glucose uptake as the NGT
individuals. Not
only is the first phase insulin response 440 reduced due to the effects of
exercise, but the
second phase insulin response 442 has also been shown to adjust to insulin
sensitivity, as
can be seen in FIG. 25A.
1001541 In preferred embodiments, a closed loop control system may be used for
delivering insulin to a body to compensate for 0-cells that perform
inadequately. There is
a desired basal blood glucose level GB for each body. The difference between
the desired
basal blood glucose level GB and an estimate of the present blood glucose
level G is the
glucose level error GE that must be corrected. The glucose level error GE is
provided as an
input to the controller 12, as shown in FIG. 26.
[00155] If the glucose level error GE is positive (meaning that the present
estimate of
the blood glucose level G is higher than the desired basal blood glucose level
GB) then the
controller 12 generates an insulin delivery command 22 to drive the infusion
device 34 to
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provide insulin 24 to the body 20. In terms of the control loop, glucose is
considered to be
positive, and therefore insulin is negative. The sensor 26 senses the 1SF
glucose level and
generates a sensor signal 16. The sensor signal 16 is filtered and calibrated
to create an
estimate of the present blood glucose level 452. In particular embodiments,
the estimate
of the present blood glucose level G is adjusted with correction algorithms
454 before it is
compared to the desired basal blood glucose level GB to calculate a new
glucose level
error GE to start the loop again.
[00156] If the glucose level error GE is negative (meaning that the present
estimate of
the blood glucose level is lower than the desired basal blood glucose level
GB) then the
controller 12 reduces or stops the insulin delivery depending on whether the
integral
component response of the glucose error GE is still positive.
1001571 If the glucose level error GE is zero, (meaning that the present
estimate of the
blood glucose level is equal to the desired basal blood glucose level GB) then
the
controller 12 may or may not issue commands to infuse insulin depending on the
derivative component (whether the glucose level is raising or falling) and the
integral
component (how long and by how much glucose level has been above or below the
basal
blood glucose level GB). In "semi-closed loop" embodiments, the user is
prompted before
the controller 12 issues the commands to infuse insulin. The prompts may be
displayed to
the user on a display, sounded to the user, or otherwise provide an indication
to the user
that the system is ready to deliver insulin, for example a vibration or other
tactile
indication. In addition, the amount of insulin to be delivered may be
displayed, with or
without other information, such as the total amount infused for the day or the
potential
effect on the user's blood glucose level by the insulin delivery. In response,
the user may
indicate that the insulin should or should not be delivered, for example by
selecting a
button, key, or other input. In further embodiments, there must be at least
two keystrokes
so that insulin is not delivered by accident.
[00158] To more clearly understand the effects that the body has on the
control loop, a
more detailed description of the physiological effects that insulin has on the
glucose
concentration in the interstitial fluid (ISF) is needed. In preferred
embodiments, the
infusion device 34 delivers insulin through the cannula 56 of the infusion set
38 into the
ISF of the subcutaneous tissue 44 of the body 20. And the insulin 24 diffuses
from the
local ISF surrounding the cannula into the blood plasma and then spreads
throughout the
body 20 in the main circulatory system, as described in the block diagram of
FIG. 27. The
insulin then diffuses from the blood plasma into the interstitial fluid ISF
substantially
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throughout the entire body. The insulin 24 binds with and activates membrane
receptor
proteins on cells of body tissues. This facilitates glucose permeation into
the activated
cells. In this way, the tissues of the body 20 take up the glucose from the
ISF. As the ISF
glucose level decreases, glucose diffuses from the blood plasma into the ISF
to maintain
glucose concentration equilibrium. Finally, the glucose in the ISF permeates
the sensor
membrane and affects the sensor signal 16.
[00159] In addition, insulin has direct and indirect effects on liver
glucose production.
Increased insulin concentration decreases liver glucose production. Therefore,
acute and
immediate insulin response not only helps the body to efficiently take up
glucose but also
substantially stops the liver from adding to the glucose in the blood stream.
In alternative
embodiments, insulin is delivered more directly into the blood stream instead
of into the
interstitial fluid, such as delivery into veins, arteries, the peritoneal
cavity, or the like.
And therefore, any time delay associated with moving the insulin from the
interstitial
fluid into the blood plasma is diminished. In other alternative embodiments,
the glucose
sensor is in contact with blood or body fluids other than interstitial fluid,
or the glucose
sensor is outside of the body and measures glucose through a non-invasive
means. The
embodiments that use alternative glucose sensors may have shorter or longer
delays
between the blood glucose level and the measured blood glucose level.
[00160] Selecting Controller Gains
[00161] In preferred embodiments, the controller gains Kp, lc, and KD, are
selected so
that the commands from the controller 12 cause the infusion device 34 to
release insulin
24 into the body 20 at a rate, that causes the insulin concentration in the
blood to follow a
similar concentration profile, as would be caused by fully functioning human
13-cells
responding to blood glucose concentrations in the body. In preferred
embodiments, the
gains may be selected by observing the insulin response of several normal
glucose
tolerant (NGT) individuals, with healthy normally functioning 13-cells. The
first step in
determining a set of controller gains is to take periodic measurements of
blood glucose
and blood insulin concentrations from the group of NGT individuals. Second,
each
individual in the group is subjected to a hyperglycemic clamp, while
continuing to
periodically measure and record the blood glucose and blood insulin
concentrations.
Third, a least squares curve fit is applied to the recorded blood insulin
concentrations
measured over time for each individual. The result is a set of curves
representing the
insulin responses to the hyperglycemic clamp for each individual of the group.
Fourth, the
curves are used to calculate the controller gains Kp, KJ, and KD, for each
individual. And
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finally, the proportional gains from each of the individuals are averaged
together to obtain
an average proportional gain, Kp, to be used in a controller 12. Similarly,
the integral
gains, K.1, and the derivative gains, KD, are averaged to obtain an average
integral gain,
Ict, and an average derivative gain, KD, for the controller 12. Alternatively,
other
statistical values may be used instead of averages such as, maximums,
minimums, the
high or low one, two or three sigma standard deviation values, or the like.
The gains
calculated for various individuals in a group may be filtered to remove
anomalous data
points before statistically calculating the gains to be used in a controller.
[00162] In an example, a least squares curve-fitting method is used to
generate
representative insulin response curves from two fasted individuals in a group,
as shown in
FIGS. 28A and B. Then the controller gains were calculated from the insulin
response
curves of the two representative individuals and are shown in Table 1. When
calculating
the controller gains, the insulin clearance rate (k), was assumed to be 10 (ml
of
insulin)/min/(kg. of body weight). The insulin clearance rate k is the rate
that insulin is
taken out of the blood stream in a body. Finally, the average value for each
type of gain is
calculated using the measurements from the group, as shown in Table 1.
Individuals Proportional Gain, Kp Integral Gain, K1 Derivative
Gain, KD
a 0.000406 0.005650 0.052672
0.000723 0.003397 0.040403
Average 0.000564 0.004523 0.046537
Table 1. MD Controller Gains Calculated From The Insulin Response Curves Of
Two
NGT Individuals
[00163] The controller gains may be expressed in various units and/or may be
modified by conversion factors depending on preferences for British or S. I.
Units,
floating-point or integer software implementation, the software memory
available, or the
like. The set of units for the controller gains in Table I is:
[00164] Kp: (mU of insulin)/min/(Kg of body weight) per (mg of glucose)/(d1 of
plasma);
[00165] Kr: (mU of insulin)/minl(Kg of body weight) per (mg of glucose)i(d1 of
plasma) min.; and
100166] KD: (mU of insulin)/min/(Kg of body weight) per (mg of glucose)/(d1 of
plasma)/min.
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1001671 In alternative embodiments, other curve fitting methods are used to
generate
the insulin response curves from the measurements of blood insulin
concentrations.
[00168] An estimate of an insulin clearance rate (k), the individual's body
weight (W),
and the insulin sensitivity SI are needed to calculate the controller gains
from the insulin
response curves for each NGT individual. The insulin clearance rate (k) is
generally
proportional to body weight and is well documented in literature. The
individual's insulin
sensitivity S1 may be measured using an intravenous glucose tolerance test, a
hyperinsulinemic clamp, or in the case of a diabetic, comparing the
individual's daily
insulin requirement to their daily carbohydrate intake.
[00169] In particular embodiments, two parameters, the insulin sensitivity Si
and the
insulin clearance rate k, arc measured for each individual. In other
embodiments, the
insulin clearance rate k is estimated from literature given the individual's
body weight. In
other particular embodiments, longer or shorter insulin clearance times are
used. In still
other embodiments, all of the parameters are estimated. In additional
embodiments, one
or more parameters are measured, while at least one parameter is estimated
from
literature.
[00170] In other alternative embodiments, the controller gains are calculated
using a
group of individuals with similar body types. For example, the insulin
response to a
hyperglycemic clamp may be measured for several tall, thin, NGT, males in
order to
calculate the controller insulin response gains for each individual in the
group. Then the
gains are statistically combined to generate a set of representative
controller gains for tall,
thin, NGT, males. The same could be done for other groups such as, but not
limited to,
short, heavy, NGT, females; medium height, medium weight, highly exercised
trained,
females; average height and weight 10 year olds; or the like. Then the
controller gains are
selected for each individual user based on the group that best represents
them. In further
alternative embodiments, controller gains are uniquely selected for each
individual user.
In particular embodiments, the controller gains for a user are selected based
on
measurements of insulin sensitivity, insulin clearing time, insulin appearance
time, insulin
concentration, body weight, body fat percentage, body metabolism, or other
body
characteristics such as pregnancy, age, heart conditions, or the like.
[00171] In other alternative embodiments, the controller gains are estimated
as a
function of a user's body weight W and insulin sensitivity S1. A series of
observations are
used to justify this method. The first observation is that the controller
gains are
proportional to each other. In other words, small changes in glucose
concentration cause a
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small derivative response UD, a small proportional response Up and a small
integral
response Ur. And larger changes in glucose concentration cause a
proportionally larger
derivative response UD, a proportionally larger proportional Up response and a
proportionally larger integral response Ur, as shown in FIG. 23B. Changes in
the glucose
concentration proportionally affect all three components of the controller
response UpLo.
The second observation is that the first phase insulin response (0) is
proportional to the
derivative gain KD. And the third observation is that two constants may be
readily
obtained from information in published literature or may be measured from a
cross-
section of the general population. The two constants are the insulin clearance
rate (k) for a
human given a body weight and the disposition index (DI) for a human given a
change in
glucose concentration.
[00172] While there are multiple sources for the information needed to
calculate the
insulin clearance rate k, one source is the article "Insulin clearance during
hypoglycemia
in patients with insulin-dependent diabetes mellitus", written by Kollind M et
al.,
published in Horm Metab Res, 1991 July; 23(7):333-5. The insulin clearance
rate k is
obtained from the insulin infused divided by the steady state plasma insulin
concentration. An insulin clearance constant Ak, which is independent of an
individual's
body weight, may be obtained by dividing the insulin clearance rate k
(measured from a
particular individual) by the individual's body weight. The insulin clearance
constant Ak
is generally the same for all humans, except under extenuating circumstances
such as
after an individual has contracted HIV, other metabolic affecting diseases, or
the like.
[00173] The disposition index (DI) for a human given a change in glucose
concentration is available from information presented in the article
"Quantification of the
relationship between insulin sensitivity and beta-cell function in human
subjects.
Evidence for a hyperbolic function", written by Khan S E et al., published in
Diabetes,
1993 November; 42(11):1663-72.
[00174] Both the disposition index DI and the insulin clearance rate k may be
measured directly from tests. The disposition index DI may be calculated given
the first
phase insulin response measured form a glucose clamp test and the individual's
insulin
sensitivity measured from an insulin sensitivity test. The insulin clearance
rate k may be
measured from an insulin clearance test. The glucose clamp test and the
insulin clearance
test are described in the above-mentioned articles and are well known in the
art. The
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insulin sensitivity S1 may be measured using an intravenous glucose tolerance
test or a
hyperinsulinemic clamp test.
[00175] Given these observations, then the following parameters may be
measured
from an NGT individual's insulin response to a glucose clamp: a desired first
phase
insulin response 4)1, the ratio of KD to Kp, and the ratio of KD to lc. Then
the derivative
gain KD may be calculated from the first phase insulin response 4)1 using the
constants k
and DI. And finally Kp and KI may be calculated using the ratios of KD to Kp
and KD to
K1.
[00176] The first phase insulin response 4)1 may be observed in a NGT
individual as
the area under the insulin response curve during approximately the first 10
minutes of a
glucose clamp. The increase in the glucose concentration during the glucose
clamp is
AG=(G¨GB), where G is equal to Gc, the glucose concentration during the clamp,
and GB
is the basal glucose concentration before the clamp.
[00177] The importance of the first phase insulin response 4)1 has been
emphasized by
studies indicating that, in subjects with normal glucose tolerance (NGT), the
product of
first phase insulin response 411 and insulin sensitivity (Si) is a constant
known as the
disposition index, DI=4)1S1. Therefore, 01 =
[00178] For a different AG there is a different (1)1 and therefore a different
DI. But, the
ratio DIIAG is substantially constant even for different individuals with
different insulin
sensitivities.
[00179] The insulin sensitivity SI is defined as the percentage of the glucose
concentration that the body tissues will take up for a given amount of
insulin. The 3-cell
naturally adapts to changes in insulin sensitivity by adjusting the amount of
insulin it
secretes during the first phase insulin response 4)1. This suggests that the
body naturally
seeks an optimal level of glucose tolerance. A controller that mimics this
characteristic of
the p-cell more accurately simulates the body's natural insulin response.
100180] The instantaneous insulin response (RI) may be calculated given the
insulin
clearance rate (k) and the first phase insulin response 4)1, RI=141.
[00181] The insulin clearance rate k is proportional to body weight (W),
therefore
substituting a proportional constant Ak and the user's body weight W fork and
replacing
DI
4)1 with the ratio of DI over S1 yields the following equation: R, =
St
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[00182] The instantaneous insulin response R1 may also be expressed as the
product of
the derivative gain KD and the change in glucose concentration AG, RI=KDAG.
[00183] Setting the two equations for R1 equal to each other and solving for
KD yields,
= w AkD1
KD
Si AG
[00184] As mentioned above, DI/AG and Ak are constants available or calculated
from
AkDi
data in published literature. Combining the constants into a single constant,
Q, Q
AG '
yields an equation for the derivative gain KD that is a function of the user's
body weight
W and the user's insulin sensitivity Si, KD = Q
[00185] Once the derivative gain KD is calculated, the proportional and
integral gains
arc calculated using ratios. The ratio of KD/Kp can be set to the dominant
time constant
for insulin action, ranging from 10-60 minutes, but more typically 20-40
minutes and
preferably 30 minutes. For example, calculating Kp given KD using a time
constant of 30
KD KD
minutes, yields the following relationship: ¨ = 30 Kp = ¨ . In a similar
fashion,
Kp 30
the ratio of K0/K.1 can be set to the average ratio measured from a population
of NGT
individuals. And K1can be calculated from KD.
[00186] In particular embodiments, the user enters their body weight W and
insulin
sensitivity Si into the device that contains the controller. Then the
controller gains are
automatically calculated and used by the controller. In alternative
embodiments, an
individual enters the user's body weight W and insulin sensitivity S1 into a
device and the
device provides the information to the controller to calculate the gains.
[00187] A study was conducted to confirm that the insulin response for an
individual
could be reproduced using the glucose sensor as an input. In the study,
glucose and
insulin measurements were taken while a hyperglycemic clamp was applied to a
NGT
individual. The glucose level measurements, shown in FIG. 29A, were used as
the inputs
to a mathematical model created to simulate a PID insulin response controller.
The insulin
dosing commanded by the controller in response to the glucose clamp very
closely
approximates the actual insulin appearance in the NGT individual, as shown in
FIG. 29B.
The insulin concentration measured from periodic blood samples 456 taken from
the
individual during the test are represented by dots in FIG. 29B. The output
from the
mathematical model simulating the insulin response commanded by the controller
is
shown as a solid line 458 in FIG. 29B.
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[00188] Three different devices were used to measure the individual's blood
glucose
during the study. Blood glucose meter readings 460 from periodic blood samples
taken
from the individual are represented by the dots in FIG, 29A. Two MiniMecl
sensors (such
as those described in the section entitled "sensor", below) were placed in the
individual's
subcutaneous tissue, and the sensor readings 462, 464 are shown as lines in
FIG. 29A.
The sensor readings 462, 464 are slightly delayed compared to the meter
readings 460.
The delay is most likely due to the delay between blood glucose and
interstitial fluid
(ISF) glucose and can be substantially corrected through the use of a filter
if needed. In
this study, the delay was not corrected by a filter and did not significantly
affect the
controller's ability to command an insulin response that matches the natural
response of
the NGT individual. This study indicates that the PID insulin response
controller model is
a good minimal model of insulin secretion that captures the biphasic response
of healthy
I3-cells. Correction of the delay is only expected to increase the accuracy of
the model.
[00189] Fuzzy Logic to Select Between Multiple Sets of Controller Gains
[00190] In preferred embodiments, one set of controller gains is used for a
particular
individual. In alternative embodiments, more than one set of controller gains
is used, and
fuzzy logic is used to select between sets of controller gains and to
determine when to
change from one set of controller gains to another. In particular alternative
embodiments,
the controller gains are different if the glucose level is above or below the
desired glucose
basal level. In other alternative embodiments, the controller gains are
different if the
glucose level is increasing or decreasing. A justification for different sets
of gains comes
from physiological studies that indicate that ft-cells turn off faster than
they turn on. In
still other alternative embodiments, the controller gains are different
depending on
whether the glucose level is above or below the desired glucose basal level
and whether
the glucose level is increasing or decreasing, which results in four sets of
controller gains.
In additional alternative embodiments, the controller gains change depending
on the
magnitude of the hypoglycemic excursion. In other words, the controller gains
for small
changes in glucose are different than those for large changes in glucose.
[00191] Self-Tuning Controller Gains
[00192] Further embodiments may include a controller that self-tunes one or
more the
gains, Kp, K1, KD to accommodate changes in insulin sensitivity. In particular
embodiments, previous measurements of glucose levels are compared to the
desired basal
glucose level GB. For example, the desired basal glucose level GB is
subtracted from the
previous glucose level measurements. Then any negative values, within a
predefined time
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window, are summed (in essence integrating the glucose level measurements that
were
below the basal glucose level GB). If the resulting sum is greater than a pre-
selected
hypoglycemic integral threshold, then the controller gains are increased by a
factor (1+a).
Conversely, if the integral of the glucose level measurements that were
measured above
the basal glucose level GB within the predefined time window is greater than a
pre-
selected hyperglycemic integral threshold, then the controller gains are
decreased by a
factor (1¨a).
[00193] In particular embodiments, the predefined time window over which the
glucose concentration integrals are evaluated is generally 24 hours, and the
controller
gains are adjusted if needed at the end of each predefined time window. In
alternative
embodiments, the integrals of the glucose level measurements are continuously
calculated
over a moving window of time, and if either integral exceeds a threshold, the
gains are
immediately adjusted. In particular embodiments, the moving time window is one
hour,
and the time window may be restarted whenever the gains are adjusted. In other
alternative embodiments, the time window is longer or shorter depending on the
sensor
accuracy, the rate at which an individual's insulin sensitivity changes, the
computational
capabilities of the hardware, or the like.
[00194] In particular embodiments, the adjustment amount (a) is 0.01. In
alternative
embodiments, the adjustment amount a is greater or smaller depending on the
sensor
accuracy, the rate at which an individual's insulin sensitivity changes, the
rate at which
the sensor sensitivity Si changes, or the like. In still other alternative
embodiments, the
adjustment amount a is made larger or smaller depending on the amount that the
integral
of the measured glucose levels exceeds a threshold. In this way, the gains are
adjusted by
greater amounts if the measured glucose level G is significantly deviating
from the
desired blood glucose level GB and less if the measured glucose level G is
closer to the
desired blood glucose level G. In additional alternative embodiments, the
controller
employs a Kalman filter.
[00195] State Variable Feedback
[00196] While the primary signal determining the 3-cell's insulin response
is glucose,
there also exists a putative effect of insulin per se to inhibit insulin
secretion. This effect
may be directly related to the concentration of insulin in plasma (IP(t)), or
mediated
through some signal proportional to insulin effect (IEFF(t)). The 13-cell can
likely directly
sense these signals (i.e., directly sense insulin concentration and secondary
signals
proportional to insulin effect such as free fatty acid). Feedback from these
intermediary
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signals is analogous to what is known as state variable feedback; that is
feedback,
whereby the variable being controlled (glucose in this case) is used together
with
feedback of each intermediary signal that affects the variable (insulin
concentration in
plasma and interstitial fluid). With this type of feedback, undesirable slow
kinetic process
can be made to appear much faster than they are. For example, if 13-cell
insulin secretion
were inhibited by a signal proportional to insulin concentration in the
interstitial fluid
where it acts, the delay between plasma and interstitial insulin could be made
to appear to
be shorter. For the artificial closed-loop algorithm, or for "semi-closed-
loop" algorithms,
this beneficial effect can be achieved by using "state observers"
(mathematical equations
that predict the insulin concentration in various parts of the body knowing
the history of
past insulin delivery). In "semi-closed loop" algorithms, the algorithms arc
the same as
for closed loop algorithms but there is a user confirmation step before any
insulin is
actually administered. By using state variable feedback, it is possible to
make the insulin
in an insulin pump act faster than the insulin actually is.
[00197] To estimate subcutaneous insulin concentration, plasma insulin
concentration,
and insulin effect, the following equations may be used:
1001981 ¨disc = ¨ isc)
dt
dlp
1001991 ¨ = a2(Jsc ¨ p)
at
dl
1002001 ¨ = a( 1p IEF)
dt
1002011 Wherein 'Sc is the estimate of normalized insulin concentration in the
subcutaneous space, Ip is the estimate of normalized insulin concentration in
the plasma,
IEF is the estimate of insulin effect on glucose, al is the rate constant
between insulin
delivery and the subcutaneous insulin compartment, a2 is the rate constant
between
subcutaneous insulin and plasma compartments, a3 is the rate constant between
the
plasma compartment and the insulin effect. ID is the delivered insulin, which
can be a
function of the three state variables OK, 1p, and
[00202] In particular embodiments, an open loop fixed base rate plus user
requested
bolus would result in the bolus being increased a certain amount and the basal
rate
subsequently decreased the same amount in accordance to the following formula:
[00203] /D' = (1 + +Y2 + y3)/D ¨
-sc Ygp Y3IEF
[00204] Wherein ID is the user requested basal (Ur%) plus bolus (U) profile
and ID' is
the state feedback adjusted profiles. Note that for a given kinetic excursion
the total
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amount of insulin requested (area under curve of ID) and delivered (area under
curve of
ID') is identical. Here, 71, 72, and y3 are state-feedback gains (scalars).
Careful choice of
these gains the pump to correct its delivery rate to compensate for delays
associated with
the dispersion of insulin from the bolus injection into the subcutaneous layer
of the
patient, to the plasma, and to its actual insulin effect/action on the body.
Thus, by
estimating how much insulin from a bolus is in the subcutaneous layer, the
plasma, or is
actually acting on the patient's glucose level (state variables Isc, Ip and
'SF), it is possible
to optimize delivery of insulin over time to the patient. Using state feedback
the bolus is
increased by an amount (1+y1+72+73) that is gradually taken away from future
insulin
delivery (-Ow - 72Ip - TtIH.). As a result, the apparent insulin
pharmolcinetic curve
appears faster. This is akin to developing a faster acting insulin, but it is
achieved
algorithmically by rearranging the distribution of the insulin delivery per
unit bolus by
delivering more upfront and removing the extra amount at a later time. The
three gains
can be chosen to move the time delays (Put, 1/02, and 1/03) to any arbitrary
locations. In
control theory, this is known as pole placement.
1002051 State feedback can be used in open loop and closed loop insulin
delivery
algorithms and with "semi-closed-loop" delivery algorithms. State feedback can
be used
in conjunction with a Proportional-Integral-Derivative (Pa) or any other type
of closed
loop controller. yl is the feedback gain multiplied to ISO, 72 is the feedback
gain multiplied
to Ip, and 73 is the feedback gain multiplied to IEF-
[00206] The physical state space form directly taken from the equations above
is:
{[iiscl = raa, ¨0a2 0 H,r1+,71
3] . ID
r 0 a3 -a3 i [/EF] [ 0 -I or (i. = Ax + Bu
i EF
'Sc [1 [y = Cx + du
ID = [0 0 01 = [ Ip + 1:11. ID
IEF 0
[00207] The finite difference form is calculated as follows (wherein cx
indicates an
exponential function):
Define: k1 = e'ir , k2 =. e-a2r, k3 = e-air
= (1 - ki)(4)(i - 1)) + k1/5(i - 1) (eq lb)
113(0 = (1¨ k 2)(1.5 c (0) + k 21 p(i ¨ 1) (eq 2b)
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47(0 = (1 ¨ k3)(4,(0) k3/EF(i ¨1) (eq 3b)
1002081 The Laplace Form is as follows, wherein s represents the Stackel
determinant
used in Laplace equations:
'Sc
- ¨ (eq 1c)
/D s+al
az
- = (eq 2c)
isc s-Faz
IEFF a3
(eq 3c)
1p s+a3
1p aia
=2
(eq 4)
ID (s+ai)(s+crz)
IEFF a1a2a3
(eq 5)
(s+ai)(s+ ce2)(s+ a3)
[00209] To obtain the transfer function of insulin delivery with state
feedback, the
control equation is as follows, wherein E represents the error between the
actual glucose
concentration and the desired glucose concentration (G¨G):
/D = PID=E¨Y
,i-sc Y2lp Y31EFF (eq 6)
Substituting equations (eq lc), (eq 4) and (eq 5) into (eq 6) and rearranging,
the following
transfer functions are obtained, wherein GM is a gain multiplier:
= (GM)(PID)(s+ai)(s+a2)(s+a3)
E (s+a1)(s+az)(s+a3)+a1ri(s+a2)(s+a3)+a1a2y2(s+a3)+a1a2a3y3 (eq 7)
'Sc (GM)(PID)a1(s+a2)(s+a3)
¨
E = (s+a1)(s+a2)(s+a3)+a1lt1 (s+a2)(s+a3)+aiazY2 (s+a3)+a1a2a3Y3 (eq 8)
p = (G WW1 D)ala2(s+a3)
E (s+a1)(s+a2)(s+a3)+a1n(s+a2)(s+a3)+a1a272 (s+a3)+a1a2 az Y3 (eq 9)
IEFF (GM)(PID)a1a2a3
¨ = (eq 10)
(s+a1)(s+a2)(s+a3)+a1r1(s+a2)(s+a3)+cr1a2Y2(s+a3)+a1a2(r3Y3
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[00210] The computation of the gain multiplier is also obtained in the state
variable
feedback method. When state variable feedback is used, the gain multiplier
(GM) is a
scalar that forces a step response to reach the same steady value whether
state feedback is
used or not. In other words, GM ensures that the total amount given per unit
of bolus will
be the same in both cases. In the case of state feedback, more insulin is
given up front, but
this extra insulin is taken away later. To calculate GM in particular
embodiments, the
"final value theorem" from control systems is used. The final value theorem
states that to
evaluate the steady state of any transfer function T(s) given any input X(s),
the steady
state output response to the input is given by:
Yss(t 00) = lims,o(sT(s)X(s))
1002111 The Laplace form of a step input is given by X(s) = is and the steady
state
solution of the final value theorem simplifies to:
Yss(t ¨" ) = lims-,o(T(s)).
In the case when there is no state feedback, (R, 72 and y3 = 0), the steady
state solution
may be obtained from equation (eq 7) to be as follows:
(t ¨> 00) = 1 (eq 11)
With state feedback without the gain correction factor, the steady state
solution is:
(eq 12)
1.-4-y1+),2+Y3
GM is then evaluated as the ratio of equation (eq 12) to equation (eq 11) to
obtain the
following: GM=1-1-71+72+y3.
[00212] Using state variable feedback, a closed loop control equation and
state
feedback gain are determined for pole placement. Specifically, the gains are
calculated for
the insulin delivery equation shown above. In particular embodiments, they are
determined as follows: First, with state feedback, the denominator of
equations (eq 7), (eq
8), (eq 9), and (eq 10) is:
D = s3 + (al + a2 + a3 + yial)s2 +
(a1a2 + (a1 + a2)a3 + y2a1a2 + (a2 + a3)y1 ai)s +
(a1a2a3 + y3ai a2 a3 + y2ai a2a3 + ai a2a3) (eq 14)
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100213] To get the poles of the system in the equations (eq 7), (eq 8), (eq
9), or (eq 10),
D may be set equal to zero yield the characteristic equation:
53 + (a1 + a2 + a3 + y1a1)s2 +
(a1a2 + (al + a2)a3 + y2a1a2 + (a2 + a3)y1a1)s +
(a1a2a3 + y3a1a2a3 + y2aia2a3 + ylaia2a3) = 0 (eq 16)
If the desired system poles or roots of (eq 16) are defined by eigenvalues ki,
kz and X3,
then the characteristic equation can be written as:
(s ¨ A1)(s ¨ A2)(s ¨ 23) = 0
Expanding and collecting like powers of s, (eq 16) can be written as:
¨(At + A2 +113)s2 +(111A2 +111113 + A2A3).3 A1/12A3 = 0 (eq 17)
[00214] Setting the coefficients of like powers of s equal to each other we
have the
system of equations:
al + a2 + a3 + yiai = ¨(A1 + 112+2.3) (eq 18)
a2 + a1a3 + a2a3 + na1a2 + al (a2 + a3) =
A.1.12 + A1.1.3 + A2A3 (eq 19)
a1a2a3 + y3a1a2a3 + y2a1a2a3 + y1a1a2a3 ¨ 111112113 (eq 20)
[00215] This results in three equations and three unknowns, 71, 72 and 73.
Therefore,
the unknown gains can be solved for in terms of the desired poles 2i,A.2, X3,
and system
time constants, al, az and al. These formulas enable us to control the desired
pharmacokinetics of insulin as it appears in the different compartments:
= ¨(Ai+A2+A,i-crii-a2-Fa3)
Yi al
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Ava2+Ai,13 +A22.3 -a1a2 -al a3-az a3 +(Ai +.12 +.13 +al +a2+er3)(a2+a3)
Y2 =
cri az
-111213 AiA2+AiA3+,12A3-aia2-aia3-a2a3+Gti +12 -F13+ai +a2 +a3)(a2 +a3)
y3¨ a1a2a3 a1a2
(11+12+13+a1+a2+(x3)
1
al
[00216] Thus, through the above calculations, the gains can be calculated and
used in
the control equation for insulin delivery of:
/D = PID=E¨v i-I
sc Y2IP Y3IEF
[00217] PID is the output of a PID controller of any other closed loop (or
"semi-
closed-loop") controller. The gains are generally calculated just once, but
could be
calculated more often if desired. The control equation may be calculated on a
repeated
basis, after predetermined periods of time or continuously. For example, and
without
limitation, it may be calculated every five, ten, thirty or sixty minutes.
Just the state
variable portion (v t-/
sc Ygp Y3-1EF) may be updated or the entire equation may be
updated. By updating the control equation, it is possible to continually
improve the
delivery of insulin to the patient.
[00218] A control feedback block diagram of an embodiment of a pump using
state
variable feedback is shown in FIG. 42. As shown, the desired glucose Go 600 of
the
patient is entered into the PID Controller 610. The output of the PID
controller is an
insulin delivery value ID 601. The block then calculates how much insulin
should actually
be delivered to the patient as a bolus in addition to the insulin delivery
value and how
much should be taken away from the basal rate, as discussed above. At each
discrete time
interval, Ti, (Ti 620, T2 630, and T3 640), the amount of insulin that has
entered into the
subcutaneous layer from the pump is calculated to provide Isc 602. That value
will be
multiplied (or otherwise factored by) 71 605 and subtracted from the output of
the PID
controller to provide an improved desired insulin value based on the
subcutaneous insulin
concentration (with the other calculations following). At each discrete time
interval Ti,
the amount of insulin that has entered into the plasma from the subcutaneous
compartment is calculated to provide Ip 603. That value will be multiplied (or
otherwise
factored by) 72 606 and subtracted from the output of the P1D controller to
determine an
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improved desired insulin value based on the plasma insulin concentration. At
each
discrete time interval Ti, the amount of insulin actually going into action or
the effective
insulin compartment from the insulin in the plasma is calculated to provide
IEF 604. That
value will be multiplied (or otherwise factored by) 73 607 and subtracted from
the output
of the PID controller to determine an improved desired insulin value based on
the
effective insulin. The insulin actually delivered to the subject 650 will then
change the
blood glucose G of the user 608, which will then be measured by the sensor 660
and
compared to the desired glucose 600.
1002191 FIGS. 43-46 show graphs with the effect of state feedback. FIG. 43
shows the
effect on the basal insulin delivery rate achieved using the algorithm
described above. A
bolus is given at time zero. Line 700 shows the insulin delivery when no state
feedback is
used. This line would be the same as a regular delivery of an insulin bolus
and is
indicated as 0.0000, because it does not change the amount of basal rate being
delivered.
The other three lines illustrate the change in insulin delivery rate over time
when all of the
state feedback is placed in one of the gains 71, 72, or 73. As can be seen, if
all the state
feedback is placed in the gain 71 (for the subcutaneous layer), the basal
insulin delivery
rate 701 (in relation to the standard basal rate) starts out low and gradually
moves to a
limit of zero, or the rate without state feedback, as steady state is reached.
If all of the
state feedback is placed in the gain 72 (for the plasma layer), the basal
insulin delivery
rate 702 starts at zero, dips lower, and then gradually returns up to a limit
of zero as
steady state is reached. If all of the state feedback is placed in the gain 73
(for the insulin
action/effect), the basal insulin delivery rate 703 starts at zero, dips
lower, but more
slowly than for the all 72 delivery rate, and then gradually returns up to a
limit of zero as
steady state is reached. In all cases, the total delivery of insulin is the
same.
1002201 FIG. 44 shows the effect of state feedback per unit bolus on the
subcutaneous
insulin. In other words, a bolus of insulin is given to a patient at time zero
and the figure
shows the rate in which the amount of insulin in the subcutaneous layer, from
that bolus,
decreases to zero. Line 705 shows the amount of insulin in the subcutaneous
layer over
time with no state feedback. Line 706 shows the amount of insulin in the
subcutaneous
layer over time when all of the state feedback is placed in gain 71. Line 707
shows the
amount of insulin in the subcutaneous layer over time when all of the state
feedback is
placed in gain 72. Line 708 shows the amount of insulin in the subcutaneous
layer over
time when all of the state feedback is placed in gain 73.
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[00221] FIG. 45 shows the effect of state feedback per unit bolus on the
plasma
insulin. In other words, a bolus of insulin is given to a patient at time zero
and the figure
shows the rate in which the amount of insulin in the plasma layer, from that
bolus,
increases from zero (there is a slight delay from injecting insulin to when
the insulin
moves into the plasma from the subcutaneous layer), reaches its peak and then
returns to
zero. Line 710 shows the amount of insulin in the plasma over time with no
state
feedback. Line 711 shows the amount of insulin in the plasma over time when
all of the
state feedback is placed in gain YI. Line 712 shows the amount of insulin in
the plasma
over time when all of the state feedback is placed in gain 72. Line 713 shows
the amount
of insulin in the plasma over time when all of the state feedback is placed in
gain 73.
[00222] FIG. 46 shows the effect of state feedback per unit bolus on the
insulin effect.
In other words, a bolus of insulin is given to a patient at time zero and the
figure shows
the rate in which the amount of insulin from that bolus creates the insulin
effect on the
body, starting at zero (there is a delay from the injection of insulin into
the subcutaneous
layer and through the plasma to the insulin effect), rising to its maximum
point, and
decreasing to zero. Line 715 shows the insulin effect over time with no state
feedback.
Line 716 shows the insulin effect over time when all of the state feedback is
placed in
gain 'yr. Line 717 shows the insulin effect over time when all of the state
feedback is
placed in gain 72. Line 718 shows the insulin effect over time when all of the
state
feedback is placed in gain 73.
[00223] FIGS. 47 and 48 compare insulin state variable feedback used in
conjunction
with a PID closed loop controller as opposed to use of a PID closed loop
controller alone
(with no insulin state variable feedback). FIG. 47 shows the simulated glucose
concentration of a patient over time. Meals are given at 8, 13, 18, 22, and 32
hours. The
glucose concentration using the PID with insulin state feedback is shown as
line 800. The
glucose concentration using the PID without insulin state feedback is shown as
line 801.
With glucose concentrations, it is always preferable to keep a patient's
concentrations
from being too high or too low, so the more that the closed loop program can
avoid high
and low values, the better. As can be seen in FIG. 47, as time goes on, the
glucose
concentration using the PID with insulin state feedback improves over time
(versus the
glucose concentration using the PID without insulin state feedback) in that it
varies less as
time goes on, keeping the patient with a more steady glucose level that will
greatly reduce
hyper- and hypoglycemic events. FIG. 48 shows average simulated insulin
delivery
profiles from the same system as FIG. 47. Line 810 represents the insulin
delivery using
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the PID with insulin state feedback. Line 811 represents the insulin delivery
using the
PID without insulin state feedback. As can be seen, the insulin delivery using
the PID
with insulin state feedback contains more spikes and dips, resulting from the
state
feedback.
[00224] Modifying the PID Controller to Incorporate an Integrator Leak
In preferred embodiments, the PID control response was described with constant
gain
components, Kp, K1, KD. Although the preferred control response guarantees
zero steady-
state error (i.e., steady state glucose minus a desired basal glucose (GB)41),
inherently,
the integral component Ul = K 5(G ¨ GB)dt + U1(t0) destabilizes feedback
control
because there is no temporal wind down of the insulin response while the
integral
component models the increase in the insulin response. Without any correction,
the
integral component has a tendency to over-estimate the increase in the insulin
response.
Since a small difference between steady-state glucose and GB is typically
acceptable in
insulin response control, an alternative modeling of the integral component
can
incorporate an integrator leak to reduce the magnitude of the destabilizing
effect.
Specifically, changes in WO can be described by a term proportional to the
error in
glucose and a term that leaks in proportion to the magnitude of U1. This can
be expressed
in the formula:
di
Ki(G ¨GB) ¨ KLEAK ;
dt
with initial condition Ui(to).
[00225] The parameter KLEAK is the reciprocal time constant of the rate of
leaking
(TT FAK in min=1/KLEAK), where TT PAK is a tuning parameter that can be set
based on
empirical data, and be tied with the other gain components Kp, K1, K0.
However, the
current realization of the artificial 13-cell has TLIAK as a user input. U1
can also be
expressed in discrete form by standard methods.
[00226] Post-Controller (Lead/Lag) Compensator
1002271 In preferred embodiments, commands are issued from the controller
without
regard to where in the body the insulin delivery system will infuse the
insulin. In essence,
the assumption is that the insulin is either delivered directly into the blood
stream for
immediate use by the body, or that any time delays caused by delivering the
insulin
somewhere in the body other than the blood stream can be compensated for by
adjusting
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Kp, K1, and KD. In this case, the commands generally model a13-cell insulin
secretion
profile, an example of which is shown in FIG. 35A. And since the 3-cells
secrete insulin
directly into the blood stream, thef3-cell insulin secretion profile is the
intended blood
plasma insulin concentration profile. However, an insulin delivery delay may
distort the
intended blood plasma insulin concentration profile, as shown in FIG. 35B. The
insulin
delivery delay is the amount of time between the instant that the command is
given to the
insulin delivery system to infuse insulin and the time that insulin reaches
the blood
plasma. An insulin delivery delay may be caused by a diffusion delay,
represented by a
circle with an arrow 528 in FIG. 20, which is the time required for insulin
that has been
infused into a tissue to diffuse into the blood stream. Other contributors to
insulin
delivery delay may include, time for the delivery system to deliver the
insulin to the body
after receiving a command to infuse insulin, time for the insulin to spread
throughout the
circulatory system once it has entered the blood stream, and/or by other
mechanical or
physiological causes. In addition, the body clears insulin even while an
insulin dose is
being delivered from the insulin delivery system into the body. Since insulin
is
continuously cleared from the blood plasma by the body, an insulin dose that
is delivered
to the blood plasma too slowly or is delayed is at least partially, if not
significantly,
cleared before the entire insulin dose fully reaches the blood plasma. And
therefore, the
insulin concentration profile in the blood plasma never achieves the same peak
(nor
follows the same profile) it would have achieved if there were no delay. Given
an insulin
dose delivered all at once into the blood plasma at time zero, the insulin
concentration in
the blood plasma is raised virtually instantaneously (not shown) and then
would decrease
exponentially over time as the body clears (uses or filters out) the insulin,
as shown in
FIG. 36A per equation: Cp = ,where:
Cp is is the concentration of insulin in the blood plasma,
To is a mass of the insulin dose delivered directly to the blood plasma at
time zero,
VP is a volume of the blood plasma in the body,
P1 is a reciprocal time constant for insulin clearance, and
t is the time that has passed since the delivery of the insulin dose directly
into the
blood plasma.
1002281 The time constant for insulin clearance Pi may be calculated using the
following equation: P1 = ¨, where:
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k is the volume insulin clearance rate, and
V, is a volume of the blood plasma in the body.
[00229] Or the time constant for insulin clearance Pi may be obtained by
providing
insulin to an individual that does not generate his own insulin, and then
periodically
testing blood samples from the individual for insulin concentration. Then,
using an
exponential curve fitting routine, generate a mathematical expression for a
best-fit curve
for the insulin concentration measurements, and observe the time constant in
the
mathematical expression.
[00230] Given the same insulin dose (delivered at time zero all at once) into
the
subcutaneous tissue, instead of directly into the blood plasma, the
concentration of insulin
in the blood plasma would begin to rise slowly as insulin diffuses from the
interstitial
fluid ISF into the blood plasma, as shown in FIG. 36B. At the same time that
insulin is
entering the blood plasma, the body is clearing insulin from the blood. While
the rate at
which insulin is entering the blood plasma exceeds the insulin clearance rate,
the insulin
concentration in the blood plasma continues to increase. When the insulin
clearance rate
exceeds the rate at which insulin is entering the blood plasma from the
interstitial fluid
ISF, the insulin concentration in the blood plasma begins to decrease. So, the
result of
delivering insulin into the interstitial fluid ISF instead of directly into
the blood stream is
that the insulin concentration in the blood plasma is spread over time rather
than
increased virtually instantaneously to a peak followed by a decay.
[00231] A bi-exponential equation may be used to model the insulin
concentration in
blood plasma given an insulin dose delivered to the subcutaneous tissue:
Cp = ______ 10D (e-'2t e-)3t) , where:
VpVISF(P3-P2)
Cp is the concentration of insulin in the blood plasma,
is the mass of the insulin dose delivered to the subcutaneous tissue at time
zero,
D is a diffusion coefficient (the rate at which insulin diffuses from the
interstitial fluid
ISF into the blood glucose)
V, is a volume of the blood plasma in the body,
VisF is a volume of interstitial fluid ISF that the insulin is delivered to,
P2 is a time constant,
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P3 is a time constant greater than or equal to P2, and
t is time since the delivery of the insulin dose into the interstitial fluid
ISF.
[00232] The time constants may be calculated using the quadratic formula:
al+ jai-4a0
P2/ P3 = __ 2 ,where:
D+K
al = ¨ ¨ , and
VP VISF
ao (D+x) D D2
VP !SF) V ISFVP
1002331 In alternative embodiments, a post-controller lead-lag compensator 522
is used
to modify the commands (Um)) to compensate for the insulin delivery delay
and/or the
insulin clearance rate k, as shown in FIG. 37. The post-controller lead-lag
compensator
522 is of the form Ucomp = ¨s+a where 1/a and 1/)' are the lead and lag
constants
UPID S-Fy
respectively, s is the Laplace variable, and UCOMP is the compensated commands
calculated by the lead-lag compensator 522.
[00234] The PID controller generates commands (Upm) for a desired insulin
delivery
rate into the blood plasma. The commands Um are calculated and issued
periodically
depending on the update rate for the control loop, which is selected based on
a maximum
anticipated rate of change of the blood glucose level, an insulin delivery
system minimum
insulin dosage, insulin sensitivity, a maximum and a minimum acceptable
glucose
concentration, or the like. The commands Um) are used as inputs to the post-
controller
lead-lag compensator 522.
[00235] In particular embodiments, the compensated commands (Ucomp) issued
from
the post-controller lead-lag compensator 522 uses more than one value from the
controller. In particular embodiments, post-controller lead-lag compensator
522 uses the
present command (UpiDn) and the previous command (Uppn-1) to calculate a
compensated
command 1.1comP per a compensation equation:
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UCOMPn = (1 Y)IICOMPn I UPIDn + (1 a)UPIDn-1 , where:
UnDn is the present command,
UpID"1 is the previous command,
Ucompn I is the previous compensated control output,
a is the reciprocal lead time constant in min I, and
is the reciprocal lag time constant in min-1.
1002361 This is a first forward difference equation. However, other forms can
be used
alternatively (e.g., first backward or bilinear), but all result in a
compensated control
output (Ucomp) that is comprised of a weighted history of both past MD outputs
(Um),
and past compensated outputs (UcomP).
1002371 An alternative method of modifying the commands (Upm) to compensate
for
the insulin delivery delay and/or the insulin clearance can be performed based
on a
weighted history of past insulin delivery. By giving the most recent delivery
history more
weight, the weighted history of the previous insulin delivered can then be
subtracted from
the present PID control output to yield a compensated control output.
Expressed in
Laplace domain this results in: Ucomp = PID E ¨aticoMP , where E is the
Laplace
transformed error signal (G¨GB), k determines how much the PID output is
reduce in
proportion to the weighted history of past control outputs, and a is the
reciprocal time
constant determining how long a history is weighted (the preferred value of a
would be
equal to the reciprocal dominant time constant or subcutaneous insulin
appearance, P2).
Solving the compensated signals as a function of the error results in:
u(s) s+avv s+aw
¨ = PID - = PID
E(s) s+(a+A) s+y
which is identical to the previously described lead-lag compensation.
1002381 In other alternative embodiments, additional previous command values
may be
used. In still other alternative embodiments, the compensation equation
compensates for
both time constants P2 and P3.
[00239] In still more alternative embodiments, the controller gains are
modified to
include the effects of the post-controller lead/lag compensator so that the
post-controller
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leadilag compensator is not needed to modify the commands to account for the
insulin
delivery delay.
[00240] In particular embodiments, the insulin delivery system provides finite
insulin
doses into the body in response to commands from the controller. The smallest
amount of
insulin that the insulin delivery system can deliver is the minimum finite
insulin dose.
The controller may generate commands for a dose of insulin to be delivered
that is not a
whole number multiple of the minimum finite insulin dose. Therefore, either
too much or
too little insulin is delivered by the insulin delivery system in response to
the commands.
In particular alternative embodiments, the post-controller lead-lag
compensator truncates
the command to the nearest whole number multiple of the minimum finite insulin
dose
and adds the remaining commanded volume of insulin to the next command. In
other
alternative embodiments, a compensator rounds the command to the nearest whole
number multiple of the minimum finite insulin dose. In still other alternative
embodiments, other methods are used to compensate for the difference between
the
commands and the nearest whole number multiple of the minimum finite insulin
dose. In
other embodiments, no compensation is needed.
[00241] Eliminating the Lead-Lag Compensator with Feedback of Predicted Plasma
Insulin
1002421 Yet in another alternative embodiment, the Pl D control commands may
be
modified to emulate the effect of plasma insulin on a 13-cell to determine
optimal insulin
administration by feeding back a predicted plasma insulin based on the
subcutaneous
insulin infusion. The net effect of such feedback is to replace an undesired
dynamic with
a more desirable one and achieve a plasma insulin profile that a I3-cell would
achieve.
This can be seen as follows (using Laplace transformed variables). Assume the
relation
between glucose above basal (G¨GB) and insulin delivery (ID) is described by a
linear
transfer function (s) = C(s)(G(s) ¨ GB) , where C(s) may be, but is not
necessarily,
described by the PID controller transfer function. If the 13-cell is using
peripheral insulin
(In(s)) levels to suppress insulin secretion the predicted rate of insulin
delivery would be
modified as: (s) = C(s)(G(s) ¨ GB) ¨ klp(s) .
[00243] For portal insulin delivery the relation between ID(s) and plasma
insulin Ip(s)
is known to be approximated by a single time delay:
I (s) = ¨I D (s) .
s+ct
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Substituting In(s) value into the previous formula and making k large results
in:
õ kk,
I D (s) ¨ C(s)(G(s)-GB) kk, C ¨ (tr( ) ¨ GB); 1 CC
1+¨ kki s+a
s+a
which would completely cancel the undesirable time constant I /a. In practice
a lower
value of k would be used resulting in:
I D (s) = C (s)(G (s) GB) _kki m(s) = G(s)_s+a (G(s) GB) ,
s+a s+y
where 7=a+kk1 (i.e., something greater than a). Thus, the effect for the 13-
cell, of adding a
plasma insulin feedback is to replace the portal insulin delivery time
constant (a) with a
faster time constant (7=a+kki; 7>a). In block diagram form:
s+a ID Ip
G ¨ GB ¨> C(S)'¨ ¨> ¨>
s+y s+a
which is equivalent to:
1 IP
G ¨ GB ¨> C(S) ¨ ¨>
S-Fy
[00244] To apply this mechanism to subcutaneous insulin delivery all that is
needed is
the transfer function between sc insulin delivery and plasma insulin. This
transfer
function is well approximated by a hi-exponential time course (bolus response)
or:
(s)
k2
ID(s) (s+a1)(s+a2)
thus,
kk,
I D (s) = C (s)(G (s) ¨ GB) I D (s)
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1
= C(S) kk2 (G (S) ¨ GB)
l+(s+a)(s+a,)
in the limiting case as kk2/(s+al)(s+a2)>>1 this is approximately equal to
I D (S) = (s)(s+ai)(s+a2)
(G (S) ¨ B)
k k2
where again, the undesirable time constants associated with subcutaneous
insulin delivery
have been eliminated. In practice they would just be replaced with more
desirable rate
constants (i.e., faster time constants).
1002451 Correction of Hypoglycemic Excursion Around -200 Minutes (Wind-Down)
1002461 Previous modeling of 13-cells using a PID controller gave excellent
predictability of the "first" and "second" phase insulin responses during
prolonged
periods of increased glucose appearance. However, if the periods of increased
glucose
appearance is followed by a rapid decrease in glucose appearance, the PID
controller
would not be able to correctly predict the wind down of the insulin response
to lower
glucose levels. FIG. 41B illustrates the insulin response to the blood glucose
level of FIG.
4IA based on the clinical data (shown as data points), the PID modeling (shown
as a solid
line), and correction of the PID for the hypoglycemic excursion (shown as a
dashed line).
1002471 In preferred embodiments, the hypoglycemic excursion is corrected by
modifying the PID controller to a PD control with Adaptive Proportional Gain
(or
Bilinear P1D controller), which is modified form of the original PID
equations. As
described previously, the discrete PID algorithm is as follows:
Proportional Component Response:
Pn ¨ G
con = Kp m)) ,
Integral Component Response:
icon= 1conn-1 KASGT ¨ G5p); I
-con = , and
Derivative Component Response:
Dconn = KDdGdel
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where Kp, K1, and Ko are the proportional, integral, and derivative gain
coefficients, SCif
and dGdtf are the filtered sensor glucose and derivative respectively, and the
superscript n
refers to discrete time.
[00248] In the Bilinear PID controller, the proportional gain Kp is based on
the
integrated error term. The magnitude of each component's contribution to the
insulin
response is described by the following equations:
= Kp n (SGF ¨ INT)
Pconn
= KDdGdtn
Dconn
Kpn = Kpn-1 Ki(sGp ¨ Gsp) , where Kp = Kpo
Where the proportional gain now integrates at rate K1(initial value Kpo) and
the
proportional component is related to an intercept value (INT) where (INT<Gsp).
The
modified formulation can be seen to fit the hypoglycemic glucose excursion
without
systematic error as the adaptive PD line shown as a dashed line in FIG. 39.
[00249] In additional embodiments, the Bilinear PID controller can also
incorporate an
integrator leak by modifying the formula to multiply the previous Kp with a
value such as
as follows:
Kpn = aKpn-1 KI(SGT ¨ G.,p) , where a 0.99
[00250] An alternative method of correcting the hypoglycemic glucose excursion
can
be performed by integrator clip into the PID control. PID controllers
generally have
integrator-reset rules that prevent excessive "winding" and such a rule can be
used to
correct the hypoglycemic glucose excursion. For example, the integrator can be
clipped as
follows:
If (SG < 60 mg/d1 AND /n-1 > Kp(SP-60)) then /n-1 = Kp(SP ¨ 60)
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This equation resets the integrator such that if the sensor glucose falls
below 60 mg/di the
insulin delivery is zero for all stable or falling sensor glucose signals. The
clipping limit
represents an absolute threshold, similar to the human counter regulatory
response.
[00251] However, other approaches that may emulate the 13-cell more accurately
include the use of piecewise continuous functions. For example, the following
function
allows for progressive clipping to be tuned:
y(SG) = yo + (1 ¨
u' r,-6o
if (SG T1 mgicil AND 4%1- > yKp (SP ¨ 60)) then
I gin" = K p (SP ¨ 60)
This equation introduces two additional tuning parameters (70 and Ti) and
starts to check
the integrator output at a higher threshold. For example, if 70=5 and T1=100
mg/di, the
integrator output would be clipped to 4 Kp60 if glucose fell to 90 mg/di, 3
Kp60 if glucose
fell to 80 mg/d1 and so forth until glucose reached 60 where it would be
clipped at Kp60.
Other functions than that proposed in the above equation (e.g. functions based
on the rate
of fall of glucose, or percent decrease in Ic.) may alternatively be used.
[00252] System Configurations
[00253] The following sections provide exemplary, but not limiting,
illustrations of
components that can be utilized with the controller described above. Various
changes in
components, layout of various components, combinations of elements, or the
like may be
made without departing from the scope of the embodiments of the invention.
[00254] Before it is provided as an input to the controller 12, the sensor
signal 16 is
generally subjected to signal conditioning such as pre-filtering, filtering,
calibrating, or
the like. Components such as a pre-filter, one or more filters, a calibrator
and the
controller 12 may be split up or physically located together, and may be
included with a
telemetered characteristic monitor transmitter 30, the infusion device 34, or
a
supplemental device. In preferred embodiments, the pre-filter, filters and the
calibrator
are included as part of the telemetered characteristic monitor transmitter 30,
and the
controller 12 is included with the infusion device 34, as shown in FIG. 8B. In
alternative
embodiments, the pre-filter is included with the telemetered characteristic
monitor
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transmitter 30 and the filter and calibrator are included with the controller
12 in the
infusion device, as shown in FIG. 8C. In other alternative embodiments, the
pre-filter
may be included with the telemetered characteristic monitor transmitter 30,
while the
filter and calibrator are included in the supplemental device 41, and the
controller is
included in the infusion device, as shown in FIG. 8D. To illustrate the
various
embodiments in another way, FIG. 9 shows a table of the groupings of
components (pre-
filter, filters, calibrator, and controller) in various devices (telemetered
characteristic
monitor transmitter, supplemental device, and infusion device) from FIGS. 8A-
D. In
other alternative embodiments, a supplemental device contains some of (or all
of) the
components.
[00255] In preferred embodiments, the sensor system generates a message that
includes information based on the sensor signal such as digital sensor values,
pre-filtered
digital sensor values, filtered digital sensor values, calibrated digital
sensor values,
commands, or the like. The message may include other types of information as
well such
as a serial number, an ID code, a check value, values for other sensed
parameters,
diagnostic signals, other signals, or the like. In particular embodiments, the
digital sensor
values Dsig may be filtered in the telemetered characteristic monitor
transmitter 30, and
then the filtered digital sensor values may be included in the message sent to
the infusion
device 34 where the filtered digital sensor values are calibrated and used in
the controller.
In other embodiments, the digital sensor values Dsig may be filtered and
calibrated before
being sent to the controller 12 in the infusion device 34. Alternatively, the
digital sensor
values Dsig may be filtered, and calibrated and used in the controller to
generate
commands 22 that are then sent from the telemetered characteristic monitor
transmitter 30
to the infusion device 34.
1002561 In further embodiments, additional optional components, such as a post-
calibration filter, a display, a recorder, and a blood glucose meter may be
included in the
devices with any of the other components or they may stand-alone. Generally,
if a blood
glucose meter is built into one of the devices, it will be co-located in the
device that
contains the calibrator. In alternative embodiments, one or more of the
components are
not used.
[00257] In preferred embodiments, RE telemetry is used to communicate between
devices, such as the telemetered characteristic monitor transmitter 30 and the
infusion
device 34, which contain groups of components. In alternative embodiments,
other
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communication mediums may be employed between devices such as wires, cables,
IR
signals, laser signals, fiber optics, ultrasonic signals, or the like.
1002581 Filtering
1002591 In preferred embodiments, the digital sensor values Dsig and/or the
derivative
of the digital sensor values are processed, filtered, modified, analyzed,
smoothed,
combined, averaged, clipped, scaled, calibrated, or the like, to minimize the
effects of
anomalous data points before they are provided as an input to the controller.
In particular
embodiments, the digital sensor values Dsig are passed through a pre-filter
400 and then a
filter 402 before they are passed to the transmitter 70, as shown in FIG. 16.
The filters are
used to detect and minimize the effects of anomalous digital sensor values
Dsig. Some
causes of anomalous digital sensor values Dsig may include temporary signal
transients
caused by sensor separation from the subcutaneous tissue, sensor noise, power
supply
noise, temporary disconnects or shorts, and the like. In particular
embodiments, each
individual digital sensor value Dsig is compared to maximum and minimum value-
thresholds. In other particular embodiments, the differences between
consecutive pairs of
digital sensor values Dsig are compared with rate-of-change-thresholds for
increasing or
decreasing values.
1002601 Pre-Filter
1002611 In particular embodiments, the pre-filter 400 uses fuzzy logic to
determine if
individual digital sensor values Dsig need to be adjusted. The pre-filter 400
uses a subset
of a group of digital sensor values Dsig to calculate a parameter and then
uses the
parameter to determine if individual digital sensor values Dsig need to be
adjusted in
comparison to the group as a whole. For example, the average of a subset of a
group of
digital sensor values Dsig may be calculated, and then noise thresholds may be
placed
above and below the average. Then individual digital sensor values Dsig within
the group
are compared to noise thresholds and eliminated or modified if they are
outside of the
noise thresholds.
1002621 A more detailed example is provided below to more clearly illustrate,
but not
limit, an embodiment of a pre-filter. A group of eight digital sensor values
Dsig are
shown in FIG. 17 including a most recently sampled value, labeled L, sampled
from the
analog sensor signal Tsig at time i, and the seven previous values K, H, G, F,
E, D, and C
sampled at times (i-1) through (i-7). An average value is calculated using the
four
temporally middle values in the group, H, G, F, and E sampled at times (i-2)
through
(i-5). The calculated average value is represented as a dashed/dotted average
line 404. A
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high noise threshold 406 is established at 100% above the average line 404. In
other
words, the magnitude of the high noise threshold 406 is two times the
magnitude of the =
average line 404. A negative noise threshold 408 is established at 50% below
the average
line 404. In other words, the magnitude of the negative noise threshold 408 is
one half of
the magnitude of the average line 404. The individual magnitudes of each of
the eight
values, L, K, H, G, F, E, D, and C are compared to the high and negative noise
thresholds
406 and 408. If a value is above the high noise threshold 406 or below the
negative noise
threshold 408 then the value is considered anomalous and the anomalous value
is
replaced with the magnitude of the average line 404. In the example shown in
FIG. 17,
the value K is above the high noise threshold 406 so it is replaced with the
average value
M. Also, the value D is below the negative noise threshold 408 so it is
replaced with the
average value N. In this way noisy signal spikes are reduced. Therefore, in
the example,
values L, K, H, G, F, E, D, and C are inputs to the pre-filter 400 and values
L, M, H, G, F,
E, N, and C are outputs from the pre-filter 400. In alternative embodiments,
other noise
threshold levels (or percentages) may be used. In other alternative
embodiments, values
outside of the thresholds may be replaced with values other than the average
value, such
as the previous value, the value of the closest threshold, a value calculated
by
extrapolating a trend line through previous data, a value that is calculated
by interpolation
between other values that are inside the thresholds, or the like.
[00263] In preferred embodiments, when any of a group's values are outside of
the
noise thresholds 406 or 408 then a warning flag is set. If one to three values
are outside of
the noise thresholds 406 or 408, a "noise" flag is set. If more than three
values are outside
of the noise thresholds 406 or 408, a "discard" flag is set which indicates
that the whole
group of values should be ignored and not used. In alternative embodiments,
more or less
values need be outside of the thresholds 406 or 408 to trigger the "noise"
flag or the
"discard" flag.
[00264] In preferred embodiments, each digital sensor value Dsig is checked
for
saturation and disconnection. To continue with the example of FIG. 17, each
individual
value is compared to a saturation threshold 410. If a value is equal to or
above the
saturation threshold 410 then a "saturation" flag is set. In particular
embodiments, when
the "saturation" flag is set, a warning is provided to the user that the
sensor 26 may need
calibration or replacement. In further particular embodiments, if an
individual digital
sensor value Dsig is at or above the saturation threshold 410, the individual
digital sensor
value Dsig may be ignored, changed to a value equal to the average line 404,
or the entire
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group of values associated with the individual digital sensor value Dsig may
be ignored.
In preferred embodiments, the saturation threshold 410 is set at about 16%
below the
maximum value of the range of digital sensor values that may be generated. In
preferred
embodiments, the maximum digital sensor value represents a glucose
concentration
greater than 150 mg/d1. In alternative embodiments, the maximum digital sensor
value
may represent larger or smaller a glucose concentrations depending on the
range of
expected glucose concentrations to be measured, the sensor accuracy, the
sensor system
resolution needed for closed loop control, or the like. The full range of
values is the
difference between the maximum and the minimum digital sensor value that may
be
generated. Higher or lower saturation threshold levels may be used depending
on an
expected signal range of the sensor, sensor noise, sensor gains, or the like.
[00265] Similarly, in preferred embodiments, if a digital signal value Dsig is
below a
disconnect threshold 412, then a "disconnect" flag is set indicating to a user
that the
sensor is not properly connected to the power supply and that the power supply
or sensor
may need replacement or recalibration. In further particular embodiments, if a
digital
sensor value Dsig is below the disconnect threshold 412, the individual value
may be
ignored, changed to a value equal to the average line 404, or the entire group
of values
associated with the individual digital sensor value Dsig may be ignored. In
preferred
embodiments, the disconnect threshold 410 is set at about 20% of the full
range of values.
Higher or lower disconnect threshold levels may be used depending on an
expected signal
range of the sensor, sensor system noise, sensor gains, or the like.
[00266] In alternative embodiments, other methods are used to pre-filter the
digital
sensor values Dsig such as rate-of-change thresholds, rate-of-change squared
thresholds,
noise thresholds about a least squares fit line rather than about the average
of a subset of a
group's values, higher or lower noise threshold lines, or the like.
[00267] Noise Filter
[00268] After the digital sensor values Dsig are evaluated, and if necessary,
modified
by the pre-filter 400, the digital sensor values Dsig are passed to the filter
402. The filter
402 may be used to reduce noise in particular frequency bands. Generally the
body's
blood glucose level 18 changes relatively slowly compared to a rate at which
digital
sensor values Dsig are collected. Therefore, high frequency signal components
are
typically noise, and a low pass filter may be used to improve the signal to
noise ratio.
[00269] In preferred embodiments, the filter 402 is a finite impulse response
(FIR)
filter used to reduce noise. In particular embodiments, the FIR filter is a
7th order filter
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tuned with a pass band for frequencies from zero to 3 cycles per hour (c/hr)
and a stop
band for frequencies greater than about 6 c/hr, as shown in an example
frequency
response curve 414 in FIG. 18. However, typically FIR filters tuned with a
pass band for
frequencies from zero up to between about 2 c/hr and 5 c/hr and a stop band
beginning at
1.2 to three times the selected pass band frequency will sufficiently reduce
noise while
passing the sensor signal. In particular embodiments, FIR filters tuned with a
pass band
for frequencies from zero up to between about 2 c/hr and 10 c/hr and a stop
band
beginning at 1.2 to three times the selected pass band frequency will
sufficiently reduce
noise. In the 7th order filter, unique weighting factors are applied to each
of eight digital
sensor values Dsig. The digital sensor values Dsig include the most recently
sampled
value and the seven previous values. The effects of a low pass filter on a
digital sensor
values collected at one minute intervals is shown in FIGS. 19A and B. An
unfiltered
sensor signal curve 416 of digital sensor values is contrasted with a curve of
the same
signal after the effects of a 7th order FIR filter 418. The filtered signal
curve 418 is
delayed and the peaks are smoother compared to the unfiltered sensor signal
curve 416. In
other particular embodiments, higher or lower order filters may be used. In
still other
particular embodiments, filter weighting coefficients may be applied to
digital sensor
values Dsig collected at time intervals shorter or longer than one minute
depending on the
desired sensor sample rate based on the body's physiology, the computational
capabilities
of the telemetered characteristic monitor transmitter 30, the sensor's
response time, or the
like. In alternative embodiments, filters with other frequency responses may
be used to
eliminate other noise frequencies depending on the type of sensor, noise from
the power
supply or other electronics, the sensor's interaction with the body, the
effects of body
motion on the sensor signal, or the like. In still other alternative
embodiments, the filter is
an infinite impulse response (IIR) filter.
1002701 In alternative embodiments, other methods are used to pre-filter the
digital
sensor values Dsig such as rate-of-change thresholds, rate-of-change squared
thresholds,
noise thresholds about a least squares fit line rather than about the average
of a subset of a
group's values, higher or lower noise threshold lines, or the like.
1002711 Delay Compensation Filter
[00272] Aside from noise reduction, a filter may be used to compensate for
time
delays. Ideally, a sensor would provide a real time, noise-free measurement of
a
parameter that a control system is intended to control, such as a blood
glucose
measurement. However, realistically there are physiological, chemical,
electrical, and
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algorithmic sources of time delays that cause the sensor measurement to lag
behind the
present value of blood glucose.
1002731 A physiological delay 422 is due to the time required for glucose to
move
between blood plasma 420 and interstitial fluid (ISF). The delay is
represented by the
circled double headed arrow 422 in FIG. 20. Generally, as discussed above, the
sensor 26
is inserted into the subcutaneous tissue 44 of the body 20 and the electrodes
42 near the
tip of the sensor 40 are in contact with interstitial fluid (ISF). But the
desired parameter to
bc measured is the concentration of blood glucose. Glucose is carried
throughout the body
in blood plasma 420. Through the process of diffusion, glucose moves from the
blood
plasma 420 into the ISF of the subcutaneous tissue 44 and vice versa. As the
blood
glucose level 18 changes so does the glucose level in the ISF. But the glucose
level in the
ISF lags behind the blood glucose level 18 due to the time required for the
body to
achieve glucose concentration equilibrium between the blood plasma 420 and the
ISF.
Studies show the glucose lag times between blood plasma 420 and ISF vary
between 0 to
30 minutes. Some parameters that may affect the glucose lag time between blood
plasma
420 and 1SF are the individual's metabolism, the current blood glucose level,
whether the
glucose level is rising, or falling, or the like.
[00274] A chemical reaction delay 424 is introduced by the sensor response
time,
represented by the circle 424 surrounding the tip of the sensor 26 in FIG. 20.
The sensor
electrodes 42 are coated with protective membranes that keep the electrodes 42
wetted
with ISF, attenuate the glucose concentration, and reduce glucose
concentration
fluctuations on the electrode surface. As glucose levels change, the
protective membranes
slow the rate of glucose exchange between the ISF and the electrode surface.
In addition,
there is a chemical reaction delay simply due to the reaction time for glucose
to react with
glucose oxidase GOX to generate hydrogen peroxide, and the reaction time for a
secondary reaction, the reduction of hydrogen peroxide to water, oxygen and
free
electrons.
[00275] There is also a processing delay as the analog sensor signal Isig is
converted to
digital sensor values Dsig. In preferred embodiments, the analog sensor signal
Isig is
integrated over one-minute intervals and then converted to a number of counts.
In essence
an A/D conversion time results in an average delay of 30 seconds. In
particular
embodiments, the one-minute values are averaged into 5-minute values before
they are
sent to the controller. The resulting average delay is two and one half
minutes. In
alternative embodiments, longer or shorter integration times are used
resulting in longer
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or shorter delay times. In other embodiments the analog sensor signal current
Isig is
continuously converted to an analog voltage Vsig and a AID converter samples
the
voltage Vsig every 10 seconds. Then six 10-second values are pre-filtered and
averaged
to create a one-minute value. Finally, five 1-minute values are filtered and
then averaged
creating a five-minute value resulting in an average delay of two and one half
minutes.
Other embodiments use other electrical components or other sampling rates and
result in
other delay periods.
1002761 Filters also introduce a delay due to the time required to acquire
a sufficient
number of digital sensor values Dsig to operate the filter. Higher order
filters, by
definition, require more digital sensor values Dsig. Aside from the most
recent digital
sensor value Dsig, FIR filters use a number of previous values equal to the
order of the
filter. For example, a 7th order filter uses 8 digital sensor values Dsig.
There is a time
interval between each digital sensor value Dsig. To continue with the example,
if the time
interval between digital sensor values Dsig is one minute, then the oldest
digital sensor
value Dsig used in a 7th order FIR filter would be seven minutes old.
Therefore, the
average time delay for all of the values used in the filter is three and a
half minutes.
However, if the weighting factors associated with each of the values are not
equal then
the time delay may be longer or shorter than three and one half minutes
depending on the
effects of the coefficients.
[00277] Preferred embodiments of the invention include a FIR filter that
compensates
for both the various time delays, of up to about 30 minutes as discussed
above, and high
frequency noise, greater than about 10 c/hr also discussed above. Particular
embodiments
employ a 7th order Weiner type FIR filter. The coefficients for the filter are
selected to
correct for time lags while simultaneously reducing high frequency noise. An
example of
a frequency response curve 426 is shown in FIG. 21. The example frequency
response
curve 416 is generated for a Weiner filter with a pass band for frequencies
from zero up
to about 8 c/hr and a stop band for frequencies greater than about 15 c/hr for
a sensor with
a sensitivity of about 20 pA/100 mg/d1. A study conducted with sensors in dogs
demonstrates that a FIR filter may be used to compensate for time delays.
During the
study a filter was used to compensate for a time delay of about 12 minutes.
The results,
presented in FIG. 22, show dots 428 representing actual blood plasma glucose
levels
measured with a blood glucose meter, a broken line 430 representing sensor
measurements without delay compensation, and a solid line 432 representing
sensor
measurements with delay compensation. The sensor in the test was abnormally
low in
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sensitivity. Studies with average sensitivity sensors in humans are indicating
a time delay
of about 3 to 10 minutes is more normal. Other filter coefficients and other
orders of
filters may be used to compensate for the time delay and/or noise.
[00278] In alternative embodiments, other types of filters may be used as long
as they
remove a sufficient portion of the noise from the sensor signal. In other
alternative
embodiments, no time compensation is used if the rate of change in the blood
glucose
level is slow compared to the time delay. For example, a five-minute delay
between blood
plasma glucose and a sensor measurement does not have to be corrected for a
closed loop
glucose control system to function.
[002791 Derivative Filter
[00280] Further embodiments may include a filter to remove noise from the
derivative
of the sensor signal before the controller uses it. A derivative is taken from
the digital
sensor values Dsig, which results in digital derivative sensor values
(dDsig/dt). The
digital derivative sensor values dDsig/dt are passed through a FIR filter. In
particular
embodiments, the derivative filter is at least a 7th order FIR filter tuned to
remove high
frequency noise. In alternative embodiments, higher or lower order filters may
be used
and the filters may be tuned to remove various frequencies of noise. In other
alternative
embodiments, a derivative is taken from the glucose level error GE values and
then passed
through a derivative filter 526, as shown in FIG. 37. In further alternative
embodiments, a
derivative is taken of an analog sensor signal Isig and a hardware filter is
used to remove
noise.
100281] Calibration
[00282] In preferred embodiments, after filtering, the digital sensor values
Dsig are
calibrated with respect to one or more glucose reference values. The glucose
reference
values are entered into the calibrator and compared to the digital sensor
values Dsig. The
calibrator applies a calibration algorithm to convert the digital sensor
values Dsig, which
are typically in counts into blood glucose values. In particular embodiments,
the
calibration method is of the type described in U.S. patent application Ser.
No. 09/511,580,
filed on Feb. 23, 2000, entitled "GLUCOSE MONITOR CALIBRATION METHODS".
In particular embodiments, the calibrator is
included as part of the infusion device 34 and the glucose reference values
are entered by
the user into the infusion device 34. In other embodiments, the glucose
reference values
are entered into the telemetered characteristic monitor transmitter 30 and the
calibrator
calibrates the digital sensor values Dsig and transmits calibrated digital
sensor values to
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the infusion device 34. In further embodiments, the glucose reference values
are entered
into a supplemental device where the calibration is executed. In alternative
embodiments,
a blood glucose meter is in communication with the infusion device 34,
telemetered
characteristic monitor transmittcr 30 or supplemental device so that glucose
reference
values may be transmitted directly into the device that the blood glucose
meter is in
communication with. In additional alternative embodiments, the blood glucose
meter is
part of the infusion device 34, telemetered characteristic monitor transmitter
30 or
supplemental device such as that shown in U.S. patent application Ser. No.
09/334,996,
filed on Jun. 17, 1999, entitled "CHARACTERISTIC MONITOR WITH A
CHARACTERISTIC METER AND METHOD OF USING THE SAME".
[00283] In preferred embodiments, to obtain blood glucose reference values,
one or
more blood samples are extracted from the body 20, and a common, over-the-
counter,
blood glucose meter is used to measure the blood plasma glucose concentration
of the
samples. Then a digital sensor value Dsig is compared to the blood glucose
measurement
from the meter and a mathematical correction is applied to convert the digital
sensor
values Dsig to blood glucose values. In alternative embodiments, a solution of
a known
glucose concentration is introduced into the subcutaneous tissue surrounding
the sensor
26 by using methods and apparatus such as described in U.S. patent application
Ser. No.
09/395,530, filed on Sep. 14, 1999, entitled "METHOD AND KIT FOR SUPPLYING A
FLUID TO A SUBCUTANEOUS PLACEMENT SITE",
or by using injection, infusion, jet pressure, introduction through a
lumen, or the like. A digital sensor value Dsig is collected while the sensor
26 is bathed in
the solution of known glucose concentration. A mathematical formula such as a
factor, an
offset, an equation, or the like, is derived to convert the digital sensor
value Dsig to the
known glucose concentration. The mathematical formula is then applied to
subsequent
digital sensors values Dsig to obtain blood glucose values. In alternative
embodiments,
the digital sensor values Dsig are calibrated before filtering. In additional
alternative
embodiments, the digital sensor values Dsig are calibrated after pre-filtering
and before
filtering. In other alternative embodiments, the sensors are calibrated before
they are used
in the body or do not require calibration at all.
[00284] Sensor Signal Processing Systems
[00285] Before filtering and calibrating, generally the sensor signal
is processed to
convert the sensor signal from a raw form into a form acceptable for use in
the filters
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and/or calibrator. In preferred embodiments, as shown in FIG. 10, an analog
sensor signal
Isig is digitally quantified through an A/D converter 68 resulting in digital
sensor values
Dsig that are transmitted by a transmitter 70 from the telemetered
characteristic monitor
transmitter 30 to another device. In particular embodiments, the analog sensor
signal Isig
is an analog current value that is converted to a digital sensor value Dsig in
the form of a
digital frequency measurement, as shown in FIG. 11(a). The general circuit
includes an
integrator 72, a comparator 74, a counter 76, a buffer 78, a clock 80 and the
transmitter
70. The integrator 72 generates a substantially ramped voltage signal (A), and
the
instantaneous slope of the ramped voltage signal is proportional to the
magnitude of the
instantaneous analog sensor signal Isig. The comparator 74 converts the ramped
voltage
signal (A) from the integrator 72 into square wave pulses (B). Each pulse from
the
comparator 74 increments the counter 76 and also resets the integrator 72. The
clock 80
periodically triggers the buffer 78 to store the present value from the
counter 76 and then
resets the counter 76. The values stored in the buffer 78 are the digital
sensor values Dsig.
The clock 80 may also periodically signal the transmitter 70 to send a value
from the
buffer 78. In preferred embodiments, the clock period is one minute. However,
in
alternative embodiments, the clock period may be adjusted based on how often
measurements are needed, sensor signal noise, sensor sensitivity, required
measurement
resolution, the type of signal to be transmitted, or the like. In alternative
embodiments, a
buffer is not used.
[00286] A/D Converters
[00287] Various A/D converter designs may be used in embodiments of the
present
invention. The following examples are illustrative, and not limiting, since
other AID
converters may be used.
[00288] Ito F (Current to Frequency (Counts)), Single Capacitor, Quick
Discharge
1002891 In preferred embodiments, the integrator 72 consists of a first Op-Amp
92 and
a capacitor 82, shown in FIG. 12. The integrator 72 sums the analog sensor
signal Isig
current by charging the capacitor 82 until the capacitor voltage (A') achieves
a high
reference voltage (Vreft-I). The capacitor voltage (A') is measured at the
output of the first
Op-Amp 92. A second Op-Amp 94 is used as a comparator. When the capacitor
voltage
(A') reaches VrefH, the comparator output (B') changes from low to high. The
high
comparator output (B') closes a reset switch 84 that discharges the capacitor
82 through a
voltage source (V+). The high comparator output (B') also triggers a reference
voltage
switch 88 to close, while substantially simultaneously an inverter 86 inverts
the
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comparator output (B'). And the inverter output (C') triggers a reference
voltage switch 90
to open. The result is that the reference voltage of the comparator is changed
from VrefH
to the low reference voltage (VrefL).
[00290] When the capacitor voltage (A') is discharged to VrefL, the comparator
output
(B') returns to low, thus forming a pulse. The low comparator output (B')
opens the reset
switch 84 allowing the capacitor 82 to begin charging again.
[00291] Virtually simultaneously, the low comparator output (B') also triggers
the
reference voltage switch 88 to open and the inverter output (C') triggers
reference voltage
switch 90 to close resulting in changing the comparator reference voltage from
VrefL
back to VrefH.
1002921 Ito F, Single Reversible Capacitor
[00293] In alternative embodiments, two or more integrator switches are used
to
control the polarity of one or more capacitors. A particular embodiment is
shown in FIG.
13. Generally, only one of the two integrator-switches 110 and 112 is closed
and the other
integrator switch is open. When the first integrator switch 110 is closed, the
second
integrator switch 112 is open and an integrator Op-Amp 114 sums the analog
sensor
signal Isig current by charging a capacitor 116 until the capacitor voltage
(A") achieves a
high reference voltage (VrefH). The comparator 120 compares the integrator
output (A")
to the reference voltage VrefH. And when the capacitor voltage (A") reaches
VrefH, the
comparator output (B") shifts from low to high, initiating a pulse.
[00294] The high comparator output (B") pulse causes the capacitor polarity to
reverse
using the following method. The high comparator output (B") triggers the
second
integrator switch 112 to close while virtually simultaneously the inverter 118
inverts the
comparator output (B"). And the low inverter output (C") pulse triggers the
first integrator
switch 110 to open. Once the capacitor's polarity is reversed, the capacitor
116 discharges
at a rate proportional to the analog sensor signal Isig. The high comparator
output (B")
pulse also triggers the reference voltage of the comparator to change form
VrefH the low
reference voltage (VrefL). When the capacitor voltage (A") is discharged to
VrefL, the
comparator output (B") returns to low. The low comparator output (B") opens
the second
integrator switch 112 and virtually simultaneously the high inverter output
(C") closes the
first integrator switch 110 allowing the capacitor 116 to begin charging
again. The low
comparator output (B") also triggers the comparator reference voltage to
change from
VrefL back to Vreft-1.
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[00295] An advantage of this embodiment is that sensor signal errors, which
may be
created due to capacitor discharge time, are reduced since the magnitude of
the analog
sensor signal Isig drives both the charging and the discharging rates of the
capacitor 116.
[00296] Ito F, Dual Capacitor
[00297] In further alternative embodiments, more than one capacitor is used
such that
as one capacitor is charging, at a rate proportional to the magnitude of the
analog sensor
signal Isig, another capacitor is discharging. An example of this embodiment
is shown in
FIG. 14. A series of three switches are used for each capacitor. A first group
of switches
210 is controlled by a latch voltage C", and a second group of switches 212
are
controlled by voltage D", which is the inverse of C". Substantially, only one
group of
switches is closed at a time. When the first group of switches 210 is closed,
the voltage
across a first capacitor 216 increases at a rate proportional to the analog
sensor signal Isig
until the integrator voltage (A") at the output of Op-Amp 214 achieves a
reference
voltage (Vref). At the same time one of the switches shorts the circuit across
a second
capacitor 222 causing it to discharge. A comparator 220 compares the
integrator output
(A") to the reference voltage Vref. And when the integrator output (A")
reaches Vref,
the comparator output (Fr) generates a pulse. The comparator output pulse
increments a
counter 76, and triggers the latch output voltage C" from a latch 221 to
toggle from a low
voltage to a high voltage. The change in the latch voltage C' causes the
second group of
switches 212 to close and the first group of switches 210 to open. One of the
switches
from the second group of switches 212 shorts the circuit across the first
capacitor 216
causing it to discharge. At the same time the voltage across the second
capacitor 222
increases at a rate proportional to the analog sensor signal Isig until the
integrator voltage
(A") at the output of Op-Amp 214 achieves a reference voltage (Vref). Again,
the
comparator 220 compares the integrator output (A") to the reference voltage
Vref. And
when the integrator output (A') reaches Vref, the comparator output (B'")
generates a
pulse. The comparator output pulse increments the counter 76, and triggers the
latch
output voltage C'" to toggle from a high voltage to a low voltage, which
causes the
switches to return to their initial position with the first group of switches
210 closed and
the second group of switches 212 to open.
[00298] In summary, as the blood glucose level 18 increases, the analog sensor
signal
Isig increases, which causes the voltage coming out of the integrator 72 to
ramp up faster
to the high reference voltage VrefH, which causes the comparator 74 to
generate pulses
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more often, which adds counts to the counter 76 faster. Therefore, higher
blood glucose
levels generate more counts per minute.
[00299] The charge storage capacity for the capacitors used in the integrator
72, and
the reference voltages VrefH, and VrefL are selected such that the count
resolution for
counts collected in a one-minute period at a glucose level of 200 mg/d1
represents a blood
glucose measurement error of less than 1 mg/d1. In particular embodiments,
VrefH is 1.1
volts and VrefL is 0.1 volts. Higher or lower reference voltages may be
selected based on
the magnitude of the analog sensor signal Isig, the capacity of the
capacitors, and the
desired measurement resolution. The source voltage V+ is set to a voltage
sufficiently
high to discharge one or more capacitors quickly enough that the discharge
times do not
significantly reduce the number of counts per minute at a blood glucose level
of 200
[00300] Pulse Duration Output Feature
[00301] In preferred embodiments, the transmitter 70 transmits the digital
sensor
values Dsig from the buffer 78 whenever triggered by the clock 80. However, in
particular embodiments, the user or another individual may use a selector 96
to choose
other outputs to be transmitted from the transmitter 70, as shown in FIG. 11B.
In
preferred embodiments, the selector 96 is in the form of a menu displayed on a
screen that
is accessed by the user or another individual by using buttons on the surface
of the
telemetered characteristic monitor transmitter 30. In other embodiments, a
dial selector,
dedicated buttons, a touch screen, a signal transmitted to the telemetered
characteristic
monitor transmitter 30, or the like, may be used. Signals that may be selected
to be
transmitted, other than the digital sensor values Dsig, include, but are not
limited to, a
single pulse duration, digital sensor values before pre-filtering, digital
sensor values after
pre-filtering but before filtering, digital sensor values after filtering, or
the like.
[00302] In particular embodiments, a pulse duration counter 98 counts clock
pulses
from a pulse duration clock 100 until the pulse duration counter 98 is reset
by a rising or
falling edge of a pulse from the comparator 74, as shown in FIG. 11B. The
accumulated
count at the time that the pulse duration counter 98 is reset represents the
pulse duration
for a portion of a single pulse from the comparator 74. The accumulated count
from the
pulse duration counter 98 is stored in the single pulse buffer 102 when
triggered by the
reset signal. When an individual selects the single pulse output, the
transmitter 70
transmits the values from the single pulse buffer 102. The pulse duration
clock 100 period
must be sufficiently shorter than the period between individual pulse edges
from the
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comparator 74 given a high analog sensor signal Isig to have sufficient
resolution to
quantify different pulse durations from the comparator 74.
[00303] Ito V (Current to Voltage), Voltage AID
[00304] Alternative methods may be used to convert the analog sensor signal
Isig from
an analog current signal to a digital voltage signal. The analog sensor signal
Isig is
converted to an analog voltage Vsig using an Op Amp 302 and a resistor 304, as
shown in
FIG. 15. And then periodically a clock 308 triggers an AID converter 306 to
take a
sample value from the analog voltage Vsig and convert it to a digital signal
representing
the magnitude of the voltage. The output values of the AID converter 306 are
digital
sensor values Dsig. The digital sensor values Dsig are sent to a buffer 310
and then to the
transmitter 70. In particular embodiments, the resistor 304 may be adjusted to
scale the
Vsig to use a significant portion of the range of the voltage AID converter
306 depending
on the sensor sensitivity, the maximum glucose concentration to be measured,
the desired
resolution from the voltage AID converter 306, or the like.
[00305] In alternative embodiments, a buffer 310 is not needed and the digital
sensor
values Dsig are sent from the AiD converter directly to the transmitter 70. In
other
alternative embodiments, the digital sensor values Dsig are processed,
filtered, modified,
analyzed, smoothed, combined, averaged, clipped, scaled, calibrated, or the
like, before
being sent to the transmitter 70. In preferred embodiments, the clock 308
triggers a
measurement every 10 seconds. Ti alternative embodiments, the clock 308 runs
faster or
slower triggering measurements more or less frequently depending on how
quickly the
blood glucose level can change, the sensor sensitivity, how often new
measurements are
needed to control the delivery system 14, or the like.
[00306] Finally, in other alternative embodiments, other sensor signals from
other
types of sensors, as discussed in the section "Sensor and Sensor Set" below,
are converted
to digital sensor values Dsig if necessary before transmitting the digital
sensor values
Dsig to another device.
[00307] Additional Controller Inputs
[00308] Generally, the proportional plus, integral plus, derivative (PID)
insulin
response controller uses only glucose (digital sensor values Dsig) as an
input. Conversely,
in a normally glucose tolerant human body, healthy 13-cells benefit from
additional inputs
such as neural stimulation, gut hormone stimulation, changes in free fatty
acid (FFA) and
protein stimulation etc. Thus in other alternative embodiments, the PID
controller, as
discussed above, can be augmented with one or more additional inputs. In
particular
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alternative embodiments, the user may manually input supplemental information
such as
a start of a meal, an anticipated carbohydrate content of the meal, a start of
a sleep cycle,
an anticipated sleep duration, a start of an exercise period, an anticipated
exercise
duration, an exercise intensity estimation, or the like. Then, a model
predictive control
feature assists the controller to use the supplemental information to
anticipate changes in
glucose concentration and modify the output commands accordingly. For example,
in a
NOT individual, neural stimulation triggers the I3-cells to begin to secrete
insulin into the
blood stream before a meal begins, which is well before the blood glucose
concentration
begins to rise. So, in alternative embodiments, the user can tell the
controller that a meal
is beginning and the controller will begin to secrete insulin in anticipation
of the meal.
[00309] In other alternative embodiments, the user or another individual may
manually
override the control system or select a different controller algorithm. For
instance, in
particular alternative embodiments, an individual may select to normalize to a
basal
glucose level immediately, and instead of using the 13-cell emulating PID
controller
another controller would take over such as a PID controller with different
gains, a PD
controller for rapid glucose adjustment, or the like. Additional alternative
embodiments
allow an individual to turn off the integral component of the PID controller
once the
glucose level is normalized and no meals are anticipated. In other particular
alternative
embodiments, the user may select to turn off the controller entirely,
therefore disengaging
the closed loop system. Once the closed loop system is not controlling insulin
dosing, the
user may program the infusion device with a basal rate, variable basal rates,
boluses, or
the like, or the user may manually enter each individual dosage when it is
needed.
1003101 In still other alternative embodiments, more than one body
characteristic is
measured, and the measurements are provided as inputs to a controller.
Measured body
characteristics that may be used by the controller include, but are not
limited to, the blood
glucose level, blood and/or ISF pH, body temperature, the concentration of
amino acids in
blood (including arginine and/or lysine, and the like), the concentration of
gastrointestinal
hormones in blood or ISF (including gastrin, secretin, cholecystokinin, and/or
gastro
inhibitory peptide, and the like), the concentration of other hormones in
blood or ISF
(including glucagons, growth hormone, cortisol, progesterone and/or estrogen,
and the
like), blood pressure, body motion, respiratory rate, heart rate, and other
parameters.
[00311] In NOT individuals, the glucose-induced secretion of insulin by
healthy P-
eens may be as much as doubled in the presence of excess amino acids. Yet, the
presence
of excess amino acids alone, without elevated blood glucose, only mildly
increases
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insulin secretions according to the Textbook of Medical Physiology, Eighth
Edition,
written by Arthur C. Guyton, published by W. B. Saunders Company, 1991, Ch.
78, pg.
861, section "Other Factors That Stimulate Insulin Secretion". In particular
alternative
embodiments, amino acid concentrations are estimated or measured, and the
controller's
insulin response increases when amino acid concentrations are sufficiently
high.
[00312] In NGT individuals, the presence of sufficient quantities of
gastrointestinal
hormones in the blood causes an anticipatory increase in blood insulin, which
suggests
that 13-cells release insulin before increases in blood glucose due to an
individual's
anticipation of a meal. In particular alternative embodiments, the
concentration of
gastrointestinal hormones is measured or estimated, and when concentrations
are high
enough to indicate that a meal is anticipated, the controller commands are
adjusted to
cause insulin introduction into the body even before the blood glucose level
changes. In
other alternative embodiments, the controller uses measurements or estimates
of other
hormones to modify the rate of insulin secretion.
[00313] In NGT individuals, the body's cells take up glucose during periods of
heavy
exercise with significantly lower levels of insulin. In alternative
embodiments,
physiologic parameters such as body motion, blood pressure, pulse rate,
respiratory rate,
or the like, are used to detect periods of heavy exercise by the body and
therefore provide
inputs to the controller that decreases (or eliminates) the amount of insulin
infused into
the body to compensate for glucose concentrations.
[00314] Sensor Compensation and End-of-Life Detection
[00315] In particular embodiments, the sensor sensitivity 510 may degrade over
time,
as shown in FIG. 31B. As the sensor sensitivity 510 changes the sensor signal
accuracy
degrades. If the sensor sensitivity 510 changes significantly then the sensor
must be
recalibrated or replaced. A diagnostic signal may be used to evaluate whether
sensor
signal accuracy has changed and/or may be used to adjust the signal or to
indicate when
to recalibrate or replace the sensor. As the sensor sensitivity 510 decreases,
the measured
glucose level 512 using the sensor signal underestimates the actual blood
glucose level
514, and the measurement error 516 between the measured glucose level 512 and
the
actual blood glucose level 514 becomes greater over time, as shown in FIG.
31A. The
sensor sensitivity 510 decreases due to increases in sensor resistance Rs, as
shown in FIG.
3 IC. The sensor resistance Rs is the resistance provided by the body between
the working
electrode WRK and the counter electrode CNT, shown as the sum or RI and R2 in
the
circuit diagram of FIG. 7. The sensor resistance Rs can be obtained indirectly
by
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measuring the analog sensor signal Isig and the counter electrode voltage Vent
and then
calculating the resistance, Rs=Vent/Isig.
[00316] As the sensor resistance Rs increases, the analog sensor signal Isig
response to
a given glucose concentration decreases. In preferred embodiments, the
decrease in the
analog sensor signal Isig may be compensated for by identifying the amount
that the
sensor resistance Rs has changed since the last calibration and then using the
change in
resistance in a correction algorithm 454 to adjust the analog sensor signal
value. A
compensation value calculated by the correction algorithm 454 is used to
increase the
sensor analog signal value. The compensation value increases over time as the
sensor
resistance Rs increases. The correction algorithm 454 includes at least one
value that
varies with changes in sensor resistance Rs. In particular embodiments, a low
pass filter is
applied to the sensor resistance Rs measurement to decrease high frequency
noise before
evaluating how much the sensor resistance Rs has changed since the last
calibration.
[00317] In alternative embodiments, the sensor resistance Rs may be calculated
using
different equations. For instance, a sensor resistance Rs2 may be calculated
as:
Rs2 = (V0 ¨ Vcntlisig)
[00318] In particular embodiments, Vo is the same voltage as Vset. An
advantage of
this approach is that it accounts for the voltage level Vset, which can vary
from sensor to
sensor and/or monitor to monitor, and/or as the analog sensor signal changes.
This
removes the noise and/or offset associated with variations in Vset, and can
provide a
more accurate indication of sensor resistance. In other particular
embodiments, Vo is set
at ¨0.535 volts, which is a commonly used voltage for Vset. In further
embodiments, Vo
is calculated from paired measurements of Vent and Isig. Using least squares
or another
curve fitting method, a mathematical equation representing the curve
(typically a straight
line equation) is derived from the relationship between Vent and Isig. Then,
Vo is
obtained by extrapolating the curve to find the value for Vent when Isig is
zero.
[00319] FIGS. 38A-H show a comparison between calculating the sensor
resistance
with Vo and without Vo. The plot of the derivative of Rs2 shown in FIG. 38G is
cleaner
and indicates the sensor failure more clearly than the plot of the derivative
of Rs shown in
FIG. 38F. Hence sensor resistance Rs2 may be used instead of, or in
conjunction with,
sensor resistance Rs described above.
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[00320] In preferred embodiments, the sensor is recalibrated or replaced when
the
change in the sensor resistance Rs since the last calibration exceeds a
threshold, or the
rate of change of the sensor resistance dRs/dt exceeds another threshold. In
particular
embodiments, the rate of change of the sensor resistance dRs/dt may be
compared to two
thresholds as shown in FIG. 32. If dRs/dt exceeds a "replacement" threshold
then a
warning is provided to the user to replace the sensor. If dRs/dt exceeds a
"recalibrate"
threshold then a warning is provided to the user to recalibrate the sensor.
[00321] In an example shown in FIGS. 33A-C, the analog sensor signal Isig
decreases
dramatically at approximately 0.3 days, as seen in FIG. 33A. Given only the
analog
sensor signal Isig, the user would believe that the decrease in the analog
sensor signal Isig
is due to a decrease in blood glucose. But in reality the drop in the analog
sensor signal
Isig is due to a sudden change in sensor sensitivity. The sensor resistance
Rs, shown in
FIG. 33A increases as the analog sensor signal Isig drops at about 0.3 days.
The
derivative of the sensor resistance dRs/dt, shown in FIG. 33C, clearly shows a
spike 522
at about 0.3 days when the analog sensor signal Isig dropped. The spike 522 in
the change
in sensor resistance dRs/dt indicates a sensor anomaly rather than a realistic
drop in blood
glucose. If a threshold were placed at +/-4 on the dRs/dt, the user would have
received a
warning to replace the sensor at about 0.3 days. As seen in FIG. 33A, the
sensor was not
replaced until about 1.4 days. The analog sensor signal lsig was under
estimating the true
glucose level from about 0.3 days until the sensor was replaced at about 1.4
days.
[00322] In particular embodiments, the amount of time dt over which the
derivative of
the sensor resistance Rs is taken is the entire time since the last
calibration. In other
embodiments, the amount of time dt over which the derivative is taken is
fixed, for
example over the last hour, 90 minutes, 2 hours, or the like.
1003231 In alternative embodiments, the sensor is recalibrated or replaced
when the
integral of the sensor resistance Rs over a predetermined time window (5 Rs
d/dt)
exceeds a predetermined resistance integral threshold. An advantage to this
approach is
that it tends to filter out potential noise that could be encountered from a
signal that
includes occasional spikes, sudden variations in voltage levels, or the like.
Preferably, the
integral of the sensor resistance Rs is calculated over a time window (such as
15 minutes,
or the like) based on Rs measurements obtained at set rates (such as 1 minute,
5 minutes,
or the like) during the time window. In alternative embodiments, the time
windows may
be longer or shorter and different sampling rates may be used, with the
selection being
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dependent on noise, response of the system, sampling rate used in the
controller, or the
like. In further embodiments, the time windows and sampling rates may change
over
time, such as when approaching the end of the expected sensor life, or as the
equations
indicate that the sensor is degrading, or the like.
[00324] Like above, multiple thresholds may be used. For instance, if IRs d/dt
exceeds
a "replacement" threshold then a warning is provided to the user to replace
the sensor.
And Wilts didt exceeds a "recalibrate" threshold then a warning is provided to
the user to
recalibrate the sensor. In further alternative embodiments, the counter
electrode voltage
Vcnt is used to evaluate other characteristics such as, sensor accuracy,
sensor bio-fouling,
sensor function, sensor voltage operating range, sensor attachment, or the
like.
[00325] pH Controller Input
[00326] In alternative embodiments, the controller uses measurements of both
the
interstitial fluid (ISF) glucose level and a local pH in the ISF surrounding
the sensor to
generate commands for the infusion device. In particular alternative
embodiments, a
single multi-sensor 508 located in the subcutaneous tissue is used to measure
both the
glucose level and the pH. The tip of the multi-sensor 508 that is placed into
the
subcutaneous tissue with three electrodes is shown in FIG. 30. The working
electrode 502
is plated with platinum black and coated with glucose oxidase (GOX). The
reference
electrode 506 is coated with silver-silver chloride. And the counter electrode
504 is
coated with iridium oxide (Jr Ox). The analog sensor signal Isig is generated
at the
working electrode 502 due to the reaction between glucose oxidase GOX and the
ISF
glucose as described with the preferred sensor embodiment. In this alternative
embodiment however, as glucose in the ISF reacts with the glucose oxidase GOX
on the
working electrode and gluconic acid is generated, the local pH in the ISF
surrounding the
sensor decreases, which changes the potential of the iridium oxide on the
counter
electrode 504, with respect to the reference electrode REF. So, as the pH
decreases, the
voltage at the counter electrode 504 increases. Therefore, as the glucose
concentration
increases, the local pH decreases, which causes the counter electrode voltage
to increase.
So, the glucose concentration may be estimated based on the counter electrode
voltage.
The counter electrode voltage estimate of glucose concentration can be
compared to the
estimate of glucose level from the analog sensor signal Isig. The two
estimates of the
glucose level may be combined by a weighted average or one estimate may simply
be
used as a check to verify that the other sensing method is functioning
properly. For
example, if the difference between the two estimates is 10% for a period of
time and then
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suddenly the difference increased to 50%, a warning would be issued indicating
to the
user that the sensor may need to be replaced or recalibrated.
1003271 In additional alternative embodiments, the pH level near the sensor
may be
used to detect infection. By tracking trends in the pH over time, a dramatic
change in pH
may be used to identify that an infection has developed in proximity to the
sensor. A
warning is used to notify the user to replace the sensor.
[00328] The pH sensor may be used in other embodiments. When insulin is not
available to assist the body to use glucose, the body shifts to consuming fat
for energy. As
the body shifts from using glucose to using almost exclusively fat for energy,
concentrations of keto acids (acetoacetic acid and fl-hydroxybutyric acid)
increase from
about 1 mEq/liter to as high as 10 mEceliter. In particular alternative
embodiments, the
pH level is measured to detect increases in keto acids in the body. In
embodiments of the
present invention, a warning is provided to the user when the ISF pH level is
too low.
[00329] A side effect of the increased of keto acid concentrations is that
sodium is
drawn from the body's extra cellular fluid to combine with the acids so that
the body can
excrete the acids. This leads to increased quantities of hydrogen ions, which
greatly
increases the acidosis. Severe cases lead to rapid deep breathing, acidotic
coma and even
death. In other alternative embodiments, an ion-selective electrode (ISE) is
used to detect
changes in sodium concentration. A special membrane is used to coat the ISE so
that it
only senses changes in sodium concentration. In particular alternative
embodiments, the
ISE is a fourth electrode added to the glucose sensor. hi another alternative
embodiment,
a three-electrode system is used with a silver-silver chloride reference
electrode REF, an
Jr Ox counter electrode CNT, and a sodium ion-selective (Na ISE) working
electrode
WRK.
[00330] While pH measurements, end-of-life measurements, hormone measurements,
or the like, add inputs to the controller that can significantly affect the
accuracy of insulin
delivery, the basic input to the controller is generally a glucose
measurement. The glucose
measurement is provided by the sensor system. And once the controller uses the
glucose
measurement to generate commands, the delivery system executes the commands.
The
following is a detailed description of several apparatus embodiments for the
sensor
system and the delivery system.
[00331] Sensor System
[00332] The sensor system provides the glucose measurements used by the
controller.
The sensor system includes a sensor, a sensor set to hold the sensor if
needed, a
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telemetered characteristic monitor transmitter, and a cable if needed to carry
power and/or
the sensor signal between the sensor and the telemetered characteristic
monitor
transmitter.
[00333] Sensor and Sensor Set
[00334] In preferred embodiments, the glucose sensor system 10 includes a thin
film
electrochemical sensor such as the type disclosed in U.S. Pat. No. 5,391,250,
entitled
"METHOD OF FABRICATING THIN FILM SENSORS"; U.S. patent application Ser.
No. 09/502,204, filed on Feb. 10, 2000, entitled "IMPROVED ANALYTE SENSOR
AND METHOD OF MAKING THE SAME"; or other typical thin film sensors such as
described in commonly assigned U.S. Pat. Nos. 5,390,671; 5,482,473; and
5,586,553.
See also U.S. Pat. No. 5,299,571.
[00335] The glucose sensor system 10 also includes a sensor set 28 to support
the
sensor 26 such as described in U.S. Pat. No. 5,586,553, entitled
"TRANSCUTANEOUS
SENSOR INSERTION SET" (published as PCT Application WO 96/25088); and U.S.
Pat. No. 5,954,643, entitled "INSERTION SET FOR A TRANSCUTANEOUS
SENSOR" (published as PCT Application WO 98/56293); and U.S. Pat. No.
5,951,521,
entitled "A SUBCUTANEOUS IMPLANTABLE SENSOR SET HAVING. THE
CAPABILITY TO REMOVE OR DELIVER FLUIDS TO AN INSERTION SITE".
[00336] In preferred embodiments, the sensor 26 is inserted through the user's
skin 46
using an insertion needle 58, which is removed and disposed of once the sensor
is
positioned in the subcutaneous tissue 44. The insertion needle 58 has a
sharpened tip 59
and an open slot 60 to hold the sensor during insertion into the skin 46, as
shown in FIGS.
3C and D and FIG. 4. Further description of the needle 58 and the sensor set
28 are found
in U.S. Pat. No. 5,586,553, entitled "TRANSCUTANEOUS SENSOR INSERTION
SET" (published as PCT Application WO 96/25088); and U.S. Pat. No. 5,954,643,
entitled "INSERTION SET FOR A TRANSCUTANEOUS SENSOR" (published as PCT
Application WO 98/5629).
[00337] In preferred embodiments, the sensor 26 has three electrodes 42 that
are
exposed to the interstitial fluid (ISF) in the subcutaneous tissue 44 as shown
in FIGS. 3D
and 4. A working electrode WRK, a reference electrode REF and a counter
electrode
CNT are used to form a circuit, as shown in FIG. 7. When an appropriate
voltage is
supplied across the working electrode WRK and the reference electrode REF, the
ISF
provides impedance (R1 and R2) between the electrodes 42. And an analog
current signal
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Isig flows from the working electrode WRK through the body (RI and R2, which
sum to
Rs) and to the counter electrode CNT. Preferably, the working electrode WRK is
plated
with platinum black and coated with glucose oxidase (GOX), the reference
electrode REF
is coated with silver-silver chloride, and the counter electrode is plated
with platinum
black. The voltage at the working electrode WRK is generally held to ground,
and the
voltage at the reference electrode REF is substantially held at a set voltage
Vset. Vset is
between 300 and 700 mV, and preferably to about 535 mV.
[00338] The most prominent reaction stimulated by the voltage difference
between the
electrodes is the reduction of glucose as it first reacts with GOX to generate
gluconic acid
and hydrogen peroxide (H202). Then the H202 is reduced to water (H20) and (01
at the
surface of the working electrode WRK. The 0- draws a positive charge from the
sensor
electrical components, thus repelling an electron and causing an electrical
current flow.
This results in the analog current signal Isig being proportional to the
concentration of
glucose in the ISF that is in contact with the sensor electrodes 42. The
analog current
signal Isig flows from the working electrode WRK, to the counter electrode
CNT,
typically through a filter and back to the low rail of an op-amp 66. An input
to the op-amp
66 is the set voltage Vset. The output of the op-amp 66 adjusts the counter
voltage Vent at
the counter electrode CNT as Isig changes with glucose concentration. The
voltage at the
working electrode WRK is generally held to ground, the voltage at the
reference electrode
REF is generally equal to Vset, and the voltage Vent at the counter electrode
CNT varies
as needed.
[00339] In alternative embodiments, more than one sensor is used to measure
blood
glucose. In particular embodiments, redundant sensors are used. The user is
notified when
a sensor fails by the telemetered characteristic monitor transmitter
electronics. An
indicator may also inform the user of which sensors are still functioning
and/or the
number of sensors still functioning. In other particular embodiments, sensor
signals are
combined through averaging or other means. If the difference between the
sensor signals
exceeds a threshold then the user is warned to recalibrate or replace at least
one sensor. In
other alternative embodiments, more than one glucose sensor is used, and the
glucose
sensors are not of the same design. For example, an internal glucose sensor
and an
external glucose sensor may be used to measure blood glucose at the same time.
1003401 In alternative embodiments, other continuous blood glucose sensors and
sensor sets may be used. In particular alternative embodiments, the sensor
system is a
micro needle analyte sampling device such as described in U.S. patent
application Ser.
WO 2014/035570
PCT/US2013/051886
No. 09/460,121, filed on Dec. 13, 1999, entitled "INSERTION SET WITH
MTCROPTERCING MEMBERS AND METHODS OF USING THE SAME",
or an internal glucose sensor as described in U.S. Pat.
Nos. 5,497,772; 5,660,163; 5,791,344; and 5,569,186, and/or a glucose sensor
that uses
florescence such as described in U.S. Pat. No. 6,011,984.
In other alternative embodiments, the sensor system uses other sensing
technologies such as described in Patent Cooperation Treaty publication No. WO
99/29230, light beams, conductivity, jet sampling, micro dialysis, micro-
poration, ultra
sonic sampling, reverse iontophoresis, or the like. In still other alternative
embodiments,
only the working electrode WRK is located in the subcutaneous tissue and in
contact with
the ISF, and the counter CNT and reference REF electrodes are located external
to the
body and in contact with the skin. In particular embodiments, the counter
electrode CNT
and the reference electrode REF are located on the surface of a monitor
housing 518 and
are held to the skin as part of the telemetered characteristic monitor, as
shown in FIG.
34A. In other particular embodiments, the counter electrode CNT and the
reference
electrode REF are held to the skin using other devices such as running a wire
to the
electrodes and taping the electrodes to the skin, incorporating the electrodes
on the
underside of a watch touching the skin, or the like. In more alternative
embodiments,
more than one working electrode WRK is placed into the subcutaneous tissue for
redundancy. In additional alternative embodiments, a counter electrode is not
used, a
reference electrode REF is located outside of the body in contact with the
skin, and one or
more working electrodes WRK are located in the ISF. An example of this
embodiment
implemented by locating the reference electrode REF on a monitor housing 520
is shown
in FIG. 34B. In other embodiments, ISF is harvested from the body of an
individual and
flowed over an external sensor that is not implanted in the body.
[00341] Sensor Cable
[00342] In preferred embodiments, the sensor cable 32 is of the type described
in U.S.
patent application Ser. No. 60/121,656, filed on Feb. 25, 1999, entitled "TEST
PLUG
AND CABLE FOR A GLUCOSE MONITOR".
In other embodiments, other cables may be used such as shielded, low noise
cables for carrying nA currents, fiber optic cables, or the like. In
alternative embodiments,
a short cable may be used or the sensor may be directly connected to a device
without the
need of a cable.
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[00343] Telemetered Characteristic Monitor Transmitter
[00344] In preferred embodiments, the telemetered characteristic monitor
transmitter
30 is of the type described in U.S. patent application Ser. No. 09/465,715,
filed on Dec.
17, 1999, entitled "TELEMETERED CHARACTERISTIC MONITOR SYSTEM AND
METHOD OF USING THE SAME" (published as PCT Application WO 00/19887 and
entitled, "TELEMETERED CHARACTERISTIC MONITOR SYSTEM"),
and is connected to the sensor set 28 as shown in FIGS.
3A and B.
[003451 In alternative embodiments, the sensor cable 32 is connected directly
to the
infusion device housing, as shown in FIG. 8A, which eliminates the need for a
telemetered characteristic monitor transmitter 30. The infusion device
contains a power
supply and electrical components to operate the sensor 26 and store sensor
signal values.
[00346] In other alternative embodiments, the telemetered characteristic
monitor
transmitter includes a receiver to receive updates or requests for additional
sensor data or
to receive a confirmation (a hand-shake signal) indicating that information
has been
received correctly. Specifically, if the telemetered characteristic monitor
transmitter does
not receive a confirmation signal from the infusion device, then it re-sends
the
information. In particular alternative embodiments, the infusion device
anticipates
receiving blood glucose values or other information on a periodic basis. If
the expected
information is not supplied when required, the infusion device sends a "wake-
up" signal
to the telemetered characteristic monitor transmitter to cause it to re-send
the information.
[00347] Insulin Delivery System
[00348] Infusion device
[00349] Once a sensor signal 16 is received and processed through the
controller 12,
commands 22 are generated to operate the infusion device 34. In preferred
embodiments,
semi-automated medication infusion devices of the external type are used, as
generally
described in U.S. Pat. Nos. 4,562,751; 4,678,408; 4,685,903; and U.S. patent
application
Ser. No. 09/334,858, filed on Jun. 17, 1999, entitled "EXTERNAL INFUSION
DEVICE
WITH REMOTE PROGRAMMING, BOLUS ESTIMATOR AND/OR VIBRATION
CAPABILITIES" (published as PCT application WO 00/10628).
In alternative embodiments, automated implantable medication
infusion devices, as generally described in U.S. Pat. Nos. 4,373,527 and
4,573,994, are
used.
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[00350] Insulin
[00351] In preferred embodiments, the infusion device reservoir 50 contains
HUMALOG lispro insulin to be infused into the body 20. Alternatively, other
forms of
insulin may be used such as HUMALINg, human insulin, bovine insulin, porcine
insulin,
analogs, or other insulins such as insulin types described in U.S. Pat. No.
5,807,315,
entitled "METHOD AND COMPOSITIONS FOR THE DELIVERY OF MONOMERIC
PROTEINS", and U.S. Patent Application Ser. No. 60/177,897, filed on Jan. 24,
2000,
entitled "MIXED BUFFER SYSTEM FOR STABILIZING POLYPEPTIDE
FORMULATIONS", or the like. In further
alternative embodiments, other components are added to the insulin such as
polypeptides
described in U.S. patent application Ser. No. 09/334,676, filed on Jun. 25,
1999, entitled
"MULTIPLE AGENT DIABETES THERAPY", small molecule insulin mimetic
materials such as described in U.S. patent application Ser. No. 09/566,877,
filed on May
8,2000, entitled "DEVICE AND METHOD FOR INFUSION OF SMALL MOLECULE
INSULIN MIMETIC MATERIALS",
or the like.
[00352] Infusion Tube
[00353] In preferred embodiments, an infusion tube 36 is used to carry the
insulin 24
from the infusion device 34 to the infusion set 38. In alternative
embodiments, the
infusion tube carries the insulin 24 from infusion device 34 directly into the
body 20. in
further alternative embodiments, no infusion tube is needed, for example if
the infusion
device is attached directly to the skin and the insulin 24 flows from the
infusion device,
through a cannula or needle directly into the body. In other alternative
embodiments, the
infusion device is internal to the body and an infusion tube may or may not be
used to
carry insulin away from the infusion device location.
[00354] Infusion Set
[00355] In preferred embodiments, the infusion set 38 is of the type described
in U.S.
Pat. No. 4,755,173, entitled "SOFT CANNULA SUBCUTANEOUS INJECTION SET".
In alternative embodiments, other infusion
sets, such described in U.S. Pat. Nos. 4,373,527 and 4,573,994, are used.
In alternative embodiments, other infusion sets, such as
the Rapidlet from Disetronic, the Silhouedetrom MiniMed, or the like, may be
used. In
further alternative embodiments, no infusion set is required, for example if
the infusion
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device is an internal infusion device or if the infusion device is attached
directly to the
skin.
1003561 Configurations With Supplemental Devices
1003571 In further alternative embodiments, the pre-filter,
filters, calibrator and/or
= controller 12 are located in a supplemental device that is in
communication with both the
telemetered characteristic monitor transmitter 30 and the infusion device 34.
Examples of
supplemental devices include, a hand held personal digital assistant such as
described in
U.S. patent application Ser. No. 09/487,423, filed on Jan. 20, 2000, entitled
"HANDHELD PERSONAL DATA ASSISTANT (PDA) WITH A MEDICAL DEVICE
AND METHOD OF USING THE SAME", a
computer, a module that may be attached to the telemetered characteristic
monitor
transmitter 30, a module that may be attached to the infusion device 34, a RF
programmer
such as described in U.S. patent application Ser. No. 09/334,858, filed on
Jun. 17, 1999,
entitled EXTERNAL INFUSION DEVICE WITH REMOTE PROGRAMMING,
BOLUS ESTIMATOR AND/OR VIBRATION CAPABILITIES (published as PCT
application WO 00/10628), or the like. In
particular embodiments, the supplemental device includes a post-calibration
filter, a
display, a recorder, and/or a blood glucose meter. In further alternative
embodiments, the
supplemental device includes a method for a user to add or modify information
to be
communicated to the infusion device 34 and/or the telemetered characteristic
monitor
transmitter 30 such as buttons, a keyboard, a touch screen, and the like.
[00358] In particular alternative embodiments, the supplemental device is a
computer
in combination with an analyte monitor and a RF programmer. The analyte
monitor
receives RF signals from the telemetered characteristic monitor transmitter
30, stores the
signals and down loads them to a computer when needed. The RF programmer sends
control signals to the infusion device 34 to reprogram the rate of insulin
infusion. Both
the analyte monitor and the RF programmer are placed into separate
communication
stations. The communication stations include IR transmitters and IR receivers
to
communicate with the analyte monitor and the RF programmer. The sensor signal
values
are transmitted via the telemetered characteristic monitor transmitter 30 to
the analyte
monitor located in one of the communication stations. Then the sensor signal
values are
communicated through the IR receiver in a first communication station and to
the
computer. The computer processes the sensor signal values through one or more
filters,
calibrators, and controllers to generate commands 22. The commands arc sent to
a second
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communication station and sent to an RF programmer by the IR transmitter in
the
communication station. Finally the RF programmer transmits the commands 22 to
the
infusion device 34. The communication station, analyte monitor and infusion
device 34
may be of the type described in U.S. patent application Ser. No. 09/409,014,
filed on Sep.
29, 1999 entitled COMMUNICATION STATION FOR INTERFACING WITH AN
INFUSION PUMP, ANALYTE MONITOR, ANALYTE METER OR THE LIKE
(published as a PCT application WO 00/18449).
Alternatively, the RF programmer may be omitted and the infusion device may be
placed in a communication station, or the infusion device may receive the
commands
without the use of an RF programmer and/or a communication station.
[00359] Overnight Closed-Loop System
[00360] A closed-loop insulin delivery system of the type described herein may
utilize
a variety of control algorithms to regulate the delivery of insulin to the
body of the patient
in a safe and predictable manner. Overnight operation of a closed-loop insulin
infusion
system should be carefully controlled in an automated way that need not depend
on
patient, user, or caregiver interaction. In this regard, a number of
safeguards can be
implemented with the system. These safeguards are intended to provide
actionable sensor
glucose readings, assess the accuracy of sensor readings, and constrain
insulin delivery
based upon possible sensor over-read conditions. These safeguards will alert
the user and
allow the patient to take appropriate actions. Therefore, these safeguards
will mitigate the
potential risks of overnight closed-loop control.
[00361] The control algorithm utilized by the system may be considered to be
one type
of safeguard in that it emulates the effect of insulin inhibiting insulin
secretion. The
system may also implement sensor performance safeguards. For example, a closed-
loop
initiation algorithm determines if the system can enter the closed-loop mode
by
calculating a recent calibration factor. The initiation algorithm checks the
time between
recent and prior calibration factors and determines the relative sensor error
between the
readings. As another example of a sensor safeguard, the system may employ a
model
supervisor during the closed-loop mode. The model supervisor checks that the
sensor
glucose readings are adequate for use during overnight closed-loop mode by
comparing
model-predicted sensor glucose values in real-time against actual sensor
glucose values.
If the model-predicted glucose values and the actual values differ
significantly, the
system triggers a fail-safe alert indicating a faulty sensor. This fail-safe
alert can be
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generated in response to a number of sensor issues, such as sensor drift,
sensor
dislodgement, sensor compression artifact, etc.
1003621 The system may also implement a target glucose level safeguard. In
this
regard, a start-up algorithm can be deployed to provide a smooth transition
between the
open-loop mode and the closed-loop mode by gradually adjusting the target
glucose level
while in the closed-loop mode. The adjusted target glucose is used by the
closed-loop
control algorithm until the adjusted target glucose converges to a particular
setpoint. At
that time, the setpoint can be used for future dosing calculations during the
closed-loop
mode.
1003631 The system may also utilize at least one insulin limit as an insulin
delivery and
sensor performance safeguard. In this context, the insulin limit constrains
the maximum
amount of insulin delivered to the patient at any time in order to avoid over-
delivery of
insulin by the closed-loop control system due to potential sensor faults. In
practice, the
insulin limit is a value that is specific to each patient and is calculated
based on the
patient's basal rate, fasting blood glucose, and insulin sensitivity.
1003641 The system may also employ one or more insulin delivery safeguards.
For
example, an insulin delivery timeout continuously monitors (during closed-loop
operation) if the patient is receiving insulin at the insulin limit for a
prolonged period of
time and, if so, triggers a fail-safe alert. This safeguard also monitors if
the system is not
delivering insulin for a prolonged period of time and, if so, triggers a fail-
safe alert. A
correction bolus is another insulin delivery safeguard. The system calculates
an insulin
bolus dosage for mitigating hyperglycemia at the commencement of closed-loop
mode if
the patient is above a designated blood glucose threshold. The determination
can be
achieved by acquiring a blood glucose meter reading at the initiation of
closed-loop
mode. The correction bolus is calculated based on the patient's insulin
sensitivity, the
amount of insulin on board, and a glucose target. Insulin on board (I013)
compensation is
yet another insulin delivery safeguard. IOB compensation estimates the amount
of insulin
on board based on manual boluses administered, such that the system can
effectively
account for the JOB. In this regard, the manual boluses may be subtracted from
the
insulin dose that is calculated by the PID-IFB control algorithm.
1003651 The system may also implement one or more communication safeguards.
For
example, a "missed sensor transmission" feature continuously monitors data
being
received by the controller. For missed data packets totaling less than 15
minutes of
operating time, the system remains in closed-loop mode. During this time,
however, the
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system continues to calculate the insulin dose using the closed loop control
algorithm
based on the last valid sensor glucose value. For missed data packets totaling
15-60
minutes, the safeguard will switch to a pre-programmed safe basal rate,
defined as half
the patient's night time basal rate. If the controller starts receiving data
packets during the
safe basal rate timeframe, the system will again switch to the closed-loop
mode. For
missed data packets totaling more than 60 minutes, the system will switch to
the open-
loop mode where it will deliver a pre-programmed basal rate (which may be set
by a
caregiver).
1003661 The exemplary closed-loop control algorithms, methodologies, and
techniques
described in more detail below may be based around a PID control algorithm of
the type
presented in the preceding sections of this disclosure. In certain
embodiments, the closed-
loop control algorithms utilize a PID insulin feedback (PID-IFB) control
algorithm. More
specifically, the PID-IFB control algorithm cooperates with other algorithms,
processes,
and controls that represent additional safeguards that may apply during
overnight use
(and/or during other periods of use). These additional safeguards may include,
without
limitation: the use of an "Insulin Limits" parameter; a closed-loop initiation
circuit that is
based on glucose sensor calibration; an insulin on board (JOB) compensation
algorithm;
monitoring missed transmissions; and monitoring sensor glucose against
predicted sensor
glucose.
1003671 In practice, optimal or desired settings for the Insulin Limits
parameter should
be determined. In this regard, the Insulin Limits parameter serves as an input
to the
controller logic for each patient, and it imposes an upper limit to the
insulin delivery rate
as an additional safety feature to avoid over-delivery of insulin by the
controller due to
potential sensor error. In certain embodiments, the Insulin Limits parameter
is calculated
from the patient's basal rate, fasting blood glucose, and insulin sensitivity.
[00368] Referring again to FIG. 1, a closed-loop system generally includes a
glucose
sensor system 10, a controller 12, and an insulin delivery system 14. Although
FIG. 1
depicts these primary elements as separate blocks, embodiments of the system
may
combine two or more of the illustrated blocks into a single physical
component. For
example, an investigational test configuration of the closed-loop system may
include a
traditional patient-worn infusion pump (corresponding to the insulin delivery
system 14),
a conventional continuous glucose sensor/transmitter assembly (corresponding
to the
glucose sensor system 10), and a mobile computing device with a suitably
written
software application installed thereon (corresponding to the controller 12).
The mobile
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computing device may be, for example: a smartphone; a tablet computer; a
netbook
computer; a digital media player; a handheld video game device; or the like.
It should be
appreciated that the desired closed-loop control functionality can be carried
out by way of
one or more computer-executable programs or applications designed to run on
the mobile
computing device. An investigational test configuration may also include a
translator
device that serves as a data communication interface between the mobile
computing
device (which may utilize standard wireless data communication technologies
such as the
Wi-Fi or BLUETOOTH data communication protocol) and the glucose sensor system
10
(which may use a proprietary data communication protocol that is usually
incompatible
with the mobile computing device).
100369] In other embodiments, the functionality of the glucose sensor system
10 could
be integrated into the insulin delivery system 14, perhaps as an
interchangeable
disposable module that attaches to the housing of the insulin delivery system
14. In yet
other embodiments, the functionality of the controller 12 could be
incorporated into the
insulin delivery system 14 such that a separate and distinct controller device
need not be
carried by the patient. Indeed, the control software utilized by the
controller 12 can be
ported for installation in an insulin infusion pump, a pump monitor device, or
the like to
implement the functionality of the controller 12 in those devices if so
desired. In further
embodiments, a single hardware device platform could be suitably designed to
accommodate the functionality of the insulin delivery system 14, the glucose
sensor
system 10, and the controller 12. These and other possible implementations are
contemplated by this disclosure, and the particular manner in which the closed-
loop
system is configured and deployed is not intended to limit or otherwise
restrict the scope
or application of the closed-loop control techniques described herein.
[00370] Although not shown in FIG. 1, the closed-loop system may include or
cooperate with a conventional blood glucose meter (e.g., a finger stick
device) that
provides measured BG values to the controller 12 and/or to the insulin
delivery system
14, such that the glucose sensor system 10 can be calibrated. In certain
embodiments, the
measured BG values are sent to the insulin delivery system 14, which in turn
sends the
BG value, sensor calibration factor, and calibration time to the controller
12. The
controller 12 can process and analyze the received information to determine
whether or
not the system can enter the closed-loop operating mode. In this regard, the
controller 12
may check to ensure that the calibration of the glucose sensor system 10 is
within an
acceptable range before allowing the system to enter the closed-loop mode.
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1003711 After entering the closed-loop mode, the insulin delivery system 14
sends
sensor glucose (SG) values, sensor Isig values, calibration factors, "insulin
delivered"
values, and other data as needed to the controller 12 in accordance with a
predetermined
schedule, e.g., at five minute intervals. The controller 12 determines the
desired insulin
dose based on the closed-loop algorithm to maintain the patient at a target
glucose
setpoint, and communicates suitable control data and instructions to the
insulin delivery
system 14. The insulin delivery system 14 responds to deliver the insulin dose
specified
by the controller 12 to the user.
1003721 FIG. 49 is a block diagram that illustrates processing modules and
algorithms
of an exemplary embodiment of a closed-loop system controller 900, and FIG. 50
is a
flow chart that illustrates an exemplary embodiment of a control process 1000
that may
be performed at least in part by the controller 900 to control the insulin
delivery system
14. The controller 12 shown in FIG. 1 may be configured in accordance with
that shown
in FIG. 49. FIG. 49 schematically depicts certain inputs and outputs of the
controller 900,
where the parallelograms represent the inputs, the ovals represent the
outputs, and the
rectangles represent the various functional modules of the controller 900. In
the context of
this description, a "functional module" may be any process, technique, method,
algorithm, computer-executable program logic, or the like. In this regard, the
controller
900 could be realized as any electronic device having a processor architecture
with at
least one processor device, and at least one memory element that is
cooperatively
associated with the processor architecture. The processor architecture is
suitably
configured to execute processor-executable instructions stored in the at least
one memory
element such that the controller 900 can perform the various control
operations and
methods described in detail herein.
[00373] The host electronic device that implements the controller 900 may be
realized
as a monitor device for an insulin infusion device, where the monitor device
and the
insulin infusion device are two physically distinct hardware devices. In
another
embodiment of the system, the host electronic device that implements the
controller 900
may be realized as a portable wireless device, where the portable wireless
device and the
insulin infusion device are two physically distinct hardware devices. The
portable
wireless device in this context may be, without limitation: a mobile telephone
device; a
tablet computer device; a laptop computer device; a portable video game
device; a digital
media player device; a portable medical device; or the like. In yet other
system
embodiments, the host electronic device and the insulin infusion device are
physically
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and functionally integrated into a single hardware device. In such
embodiments, the
insulin infusion device will include the functionality of the controller 900
as presented
here.
[00374] Certain embodiments of the controller 900 include a plurality of
cooperating
functional modules that are designed and configured to determine the insulin
dose to be
delivered to keep the patient at the target glucose setpoint during an
overnight closed-loop
operating mode. In this regard, the illustrated embodiment of the controller
900 may
include the following functional modules, without limitation: a closed-loop
initiation
module 902; a start-up module 904; a proportional integral derivative insulin
feedback
(PID-IFB) control module 906; an insulin limit module 908; an insulin on board
(I0B)
compensation module 910; an insulin delivery timeout module 912; a model
supervisor
module 914; and a missed transmission module 916.
[00375] Referring to FIG. 50, the control process 1000 may begin at any time
when it
is desired to enter the closed-loop operating mode. Accordingly, the control
process 1000
may begin in response to a user-initiated command, automatically in response
to the
detection of operating conditions that are usually indicative of closed-loop
operation (e.g.,
sleeping), or the like. Certain embodiments of the control process 1000 may
begin with
one or more system checks (task 1002) to confirm whether or not the system is
allowed to
enter the closed-loop operating mode. This particular example employs a sensor
calibration check before allowing the system to proceed to the closed-loop
mode.
Referring to FIG. 49, the closed-loop initiation module 902 may be involved
during task
1002.
[00376] In some embodiments, the closed-loop initiation module 902 may
consider
certain sensor performance criteria that prevents closed-loop initiation. Such
criteria may
include, without limitation: (1) during start-up when the calibration is not
stable; (2) when
the sensor sensitivity changes significantly; (3) when sensors may be
calibrated with a
potentially invalid meter reading thereby changing the sensor sensitivity
significantly; (4)
any other situation that could cause a mismatch between the sensor and meter
for a
number of most recent calibrations spaced over a designated period of time
(e.g., the two
most recent calibrations).
[00377] The illustrated embodiment of the closed-loop initiation module 902
receives
at least the following items as inputs: a meter (measured) BG value 920; at
least one
sensor calibration factor 922 (i.e., calibration measurements, calibration
data, etc.); the
current sensor lsig value 924; and timestamp data 926 that indicates the
calibration time
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associated with the BG value 920 and the sensor calibration factor 922. Some
or all of
this input data may be provided directly or indirectly by the insulin delivery
system 14
(see FIG. 1), a translator device, a monitor device, or any device in the
closed-loop
system. This description assumes that a new sensor calibration factor 922 and
new
timestamp data 926 is generated for each measured BG value 920, wherein the
sensor
calibration factor 922 is associated with the calibration of the glucose
sensor system 10
(see FIG. 1) that is being used to monitor the patient. In particular, the
sensor calibration
factor may be based on the meter BG value 920 and the corresponding sensor
Isig value
924.
[00378] The closed-loop initiation module 902 analyzes the input data (both
current
values and historical values) to determine whether or not the system is
allowed to enter
into the closed-loop mode. For example, the closed-loop initiation module 902
may:
check the period between two consecutive calibration timestamp values; compare
recent
and prior calibration factor values; and the like. The "outputs" of the closed-
loop
initiation module 902 correspond to two operating modes of the system. More
specifically, the closed-loop initiation module 902 controls whether the
system remains
operating in the open-loop mode 928 or whether the system starts the closed-
loop mode
930.
1003791 Referring to FIG. 50, if the closed-loop mode is not permitted (the
"No"
branch of query task 1004), then the control process 1000 operates the system
such that it
remains in the open-loop mode (task 1006). On the other hand, if the closed-
loop mode is
permitted (the "Yes" branch of query task 1004), then the control process 1000
can
initiate and start the closed-loop mode in an appropriate manner (task 1008).
Referring
again to FIG. 49, a correction bolus 932 can be calculated and delivered (if
needed) to
mitigate hyperglycemia at the commencement of the closed-loop mode. This
correction
bolus 932 serves as an additional safeguard to achieve a target blood glucose
level if a
measured meter reading is greater than a threshold value. If the control
process 1000
determines that a correction bolus is required, then an appropriate insulin
dose instruction
is generated for execution by the insulin delivery system at the outset of the
closed-loop
mode.
[00380] Referring to FIG. 49, the start-up module 904 may be called in
response to a
determination that the system can proceed to the closed-loop operating mode.
Once the
system is in the closed-loop mode, the controller retrieves historical data
that can be
processed and used as described in more detail below. In certain embodiments,
for
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example, the controller obtains data for the last 24 hours (from the insulin
delivery
system, from a monitor, or the like). Thereafter, the controller retrieves
data packets once
every sampling period to obtain, without limitation: sensor glucose (SG)
values; sensor
Isig values; sensor calibration factors; information related to the amount of
insulin
delivered; information related to manual boluses delivered; and sensor
calibration factors.
As explained in more detail below, the received information can be used in the
various
safeguards, and to determine the final insulin dose.
1003811 The start-up module 904 receives sensor glucose (SG) values 940 as an
input,
and the functionality of the start-up module 904 may be initiated in response
to the start
of the closed-loop mode 930 (this trigger mechanism is represented by the
dashed arrow
942 in FIG. 49). The SG values 940 may be provided directly by the glucose
sensor
system 10 or indirectly via the insulin delivery system 14, a translator
device, or any
device in the closed-loop system (see FIG. 1). This description assumes that
SG values
940 are received by the start-up module 904 in an ongoing manner as they
become
available. The start-up module 904 may also utilize a target glucose setpoint
value 944,
which may be internally maintained, generated, andior provided by the
controller 900.
For the implementation presented here, the target glucose setpoint value 944
represents a
fixed (constant) value that the user can specify (FIG. 49 depicts the target
glucose
setpoint value 944 in dashed lines to indicate that the value is a user-
specified parameter
rather than a functional module or data received by the system).
1003821 In certain embodiments, the start-up module 904 calculates a final
target
glucose value 946, which serves as an input to the PID-IFB control module 906.
The final
target glucose value 946 enables the system to make a smoother transition
between open-
loop and closed-loop modes (by gradually adjusting the final target glucose
value 946).
The start-up module 904 may utilize the target glucose setpoint value 944 to
calculate the
final target glucose value 946. In this regard, the start-up module 904
elevates the final
target glucose value 946 to the same level as the sensor glucose value at the
start of the
closed-loop mode, provided the sensor glucose is above a certain threshold. As
time
progresses, the final target glucose value 946 gradually decreases back to the
target
glucose setpoint value 944 (usually in approximately two hours). Referring to
FIG. 50,
the control process 1000 calculates the final target glucose value (task 1010)
and
continues by calculating an uncompensated insulin infusion rate, PIDRate(n),
based at
least in part on the final target glucose value (task 1012). For this example,
the start-up
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module 904 may be involved during task 1010, and the PID-IFB control module
906 may
be involved during task 1012.
[00383] As an additional safeguard, the insulin limit module 908 cooperates
with the
PID-IFB control module 906 to provide an upper insulin limit that is
calculated based on
the patient's basal rate, fasting blood glucose, and insulin sensitivity. This
upper insulin
limit imposes an upper limit to the insulin delivery rate to avoid over-
delivery of insulin
by the system due to potential sensor error.
[00384] The PID-IFB control module 906 may be configured to carry out the
control
processes described in more detail above with reference to FIGS. 1-48. In some
embodiments, the PID-IFB control module 906 receives at least the following
items as
inputs: the SG value 940 (which may be used to calculate a rate of change
value that
indicates the rate of change of the SG value); the current sensor Isig value
950; the
current sensor calibration factor 952; and an amount of insulin delivered 954.
The inputs
to the PID-IFB control module 906 may be provided directly or indirectly by
the insulin
delivery system 14, the glucose sensor system 10, a translator device, a
monitor device,
and/or any device in the closed-loop system (see FIG. 1). The PID-IFB control
module
906 is suitably configured to calculate the insulin infusion rate based on the
current and
past SG values 940, the SG rate of change, the sensor Isig value 950, the
sensor
calibration factor 952, the final target glucose value 946, and the insulin
delivered 954 in
order to achieve euglycemia. These (and possibly other) values may be received
by the
P1D-IFB control module 906 in an ongoing manner as they become available,
e.g., in five
minute intervals or in accordance with any desired schedule.
[00385] The insulin delivered 954 is a parameter or value that indicates the
amount of
insulin that has been delivered to the patient by the insulin delivery system.
Thus, the
insulin delivered 954 may indicate recent boluses (typically by Units)
delivered over a
period of time. In certain implementations, the insulin delivered 954
corresponds to the
amount of insulin delivered in the last sampling time, which may be, without
limitation:
one minute; five minutes; thirty seconds; or any designated sampling time. The
insulin
delivered 954 may also indicate the amount of insulin delivered by the
delivery system as
basal or boluses in any defined period of time in the past (e.g., the last N
hours) or the
amount of insulin delivered by the system in the last sampling cycle. In
practice, the PID-
IFB control module 906 (and the JOB compensation module 910) may be
"initialized" to
collect and save historical values for the insulin delivered 954 as needed.
Thereafter, the
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insulin delivered 954 can simply indicate an amount of insulin administered by
the
system during the last sampling time period if by a bolus or basal channels.
[003861 As mentioned above, the PID-IFB control module 906 may utilize an
upper
insulin limit, which is a patient-specific parameter. In certain embodiments,
the upper
insulin limit may be entered by the user, a caregiver, or the like.
Alternatively, the insulin
limit module 908 may be responsible for calculating or otherwise managing the
upper
insulin limit if so desired. The upper insulin limit imposes an upper limit to
the insulin
delivery rate as an additional safety feature to avoid over-delivery of
insulin by the
controller 900 due to potential sensor error. Thus, if the PID-IFB control
module 906
recommends a dose higher than the insulin limit, the insulin limit will
constrain the
insulin delivered to the insulin limit value. In addition, the insulin limit
will "freeze" the
integral component of the PID to its previous value to prevent integral
windup, which can
cause continuous integrating of the glucose error until it reaches maximum
values. In
certain embodiments, the upper insulin limit has a default value set at five
times the
patient's basal rate. Hence, if the maximum value is reached, the PID-IFB
control
algorithm will be fairly aggressive in calculating an insulin dose.
Accordingly, to
minimize integral windup, the insulin limit is fed back to the PID-IFB control
module 906
(as depicted in FIG. 49) for use in the next insulin dose calculation.
1003871 The PID-IFB control module 906 operates as described previously to
calculate
a current insulin dose 958 as an output value (the current insulin dose 958 is
also referred
to herein as the uncompensated insulin infusion rate, PIDRate(n)). Tn
practice, the current
insulin dose 958 is typically expressed as an infusion rate (Units/Hour). In
the context of
this description, the current insulin dose 958 represents a baseline closed-
loop infusion
rate, which may be subjected to further adjustment or compensation by the JOB
compensation module 910. Referring again to FIG. 50, the control process 1000
may
compensate for the insulin "on board" the patient by calculating an adjusted
insulin
infusion rate, AdjustedRate(n), based at least in part on the uncompensated
insulin
infusion rate (task 1014). For this example, the JOB compensation module 910
may be
involved during task 1014.
1003881 The 10B compensation module 910 receives at least the following items
as
inputs: the current insulin dose 958; and information regarding manual boluses
delivered
960. The manual boluses delivered 960 may be provided directly or indirectly
by the
insulin delivery system 14, a translator device, a monitor device, and/or any
device in the
closed-loop system (see FIG. 1). This description assumes that the manual
boluses
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delivered 960 is received by the 10B compensation module 910 in an ongoing
manner as
it becomes available, e.g., in five minute intervals or in accordance with any
desired
schedule. The JOB compensation module 910 is suitably configured to estimate
insulin on
board based on manual boluses delivered, before or during closed-loop
operation, in order
to compensate the final infusion rate to help avoid over-delivery of insulin
by the
controller 900. Accordingly, the output of the 10B compensation module 910 may
be a
final insulin dose 962 expressed as a final infusion rate (Units/Hour). The
final insulin
dose 962 is also referred to herein as the adjusted insulin infusion rate,
AdjustedRate(n).
[00389] Referring to FIG. 50, the control process 1000 uses the adjusted
insulin
infusion rate, AdjustedRate(n), to control the insulin infusion device, which
in turn
regulates the delivery of insulin to the body of the user (task 1016). In
certain
embodiments, the adjusted insulin infusion rate is communicated to the insulin
infusion
device in an appropriate manner (such as wireless data communication). The
control
process 1000 may continue as described above in an iterative and ongoing
manner to
monitor the condition of the user and deliver insulin as needed without user
involvement.
That said, if the control process 1000 determines that the closed-loop
operating mode
should be terminated (the "Yes" branch of query task 1018), then the control
process
1000 causes the system to switch back to the open-loop mode (task 1020). The
closed-
loop mode may be ended in response to a user-initiated command, automatically
in
response to the detection of operating conditions that are usually indicative
of open-loop
operation, or the like.
[00390] If query task 1018 determines that the closed-loop mode should
continue (the
"No" branch of query task 1018), then the control process 1000 may check
whether it is
time to perform another iteration of the control routine. In other words, the
control
process 1000 may check for the next sampling time (query task 1022). If it is
time for the
next iteration, then the control process 1000 may return to task 1010 and
repeat the
computations with the next set of data values. For example, the next iteration
of the
control routine may obtain and process the current values of some or all of
the following
parameters, without limitation: the SG value 940; the SG rate of change; the
sensor Isig
value 924; the amount of insulin delivered 954; and the manual boluses
delivered 960.
This allows the control process 1000 to adjust the final insulin infusion rate
in an ongoing
manner in accordance with a predetermined schedule, a designated sampling
rate, or the
like.
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[00391] The insulin delivery timeout module 912 monitors if the patient is
receiving
continuous delivery of insulin at the maximum insulin limit or the minimum
allowable
infusion of zero Units/Hour for a time specified by the controller.
Accordingly, the
insulin delivery timeout module 912 may receive the insulin delivered 954 as
an input. If
the specified time is exceeded, the system will trigger a fail-safe alert 966.
Otherwise, the
system remains in the closed-loop operating mode 968.
[00392] Referring back to FIG. 49, the model supervisor module 914 receives at
least
the following as inputs: the insulin delivered 954; sensor Isig values 950;
and one or more
sensor calibration factors 952. The inputs to the model supervisor module 914
may be
provided directly or indirectly by the insulin delivery system 14, the glucose
sensor
system 10, a translator device, a monitor device, and/or any device in the
closed-loop
system (sec FIG. 1). The model supervisor module 914 is suitably designed and
configured to estimate the user's glucose concentration in real time (or
substantially real
time) based on the insulin delivered 954, the sensor Isig values 950, and the
sensor
calibration factors 952. The sensor calibration factors 952 used by the model
supervisor
module 914 are equal to the sensor calibration factors 922 used by the closed-
loop
initiation module 902. That said, the closed-loop initiation module 902
utilizes the sensor
calibration factors 922 at one particular time, whereas the model supervisor
module 914
considers the sensor calibration factors 952 in an ongoing and continuous
manner during
operation in the closed-loop mode. Should the model-predicted glucose and the
sensor
glucose values differ significantly, the system will exit closed loop mode.
Accordingly,
the model supervisor module 914 regulates whether the system remains in the
closed-loop
mode 974 or switches to the open-loop mode 976.
[00393] The missed transmission module 916 is suitably configured to monitor
the
following, without limitation: the sensor Isig values 950; the SG values 940;
and the
sensor calibration factors 952. More particularly, the missed transmission
module 916
continuously monitors to check whether the system is receiving data packets
that convey
the necessary information and input values. For missed data packets totaling
less than a
lower threshold of time (e.g., 15 minutes), the system remains in the closed-
loop mode, as
indicated by block 980 in FIG. 49. During this time, the system will continue
to calculate
the insulin dose using the closed-loop control methodology based on the last
valid sensor
glucose value. For missed data packets totaling a time longer than the lower
threshold and
shorter than an upper threshold of time (e.g., 60 minutes), the missed
transmission
module 916 will switch the system to a pre-programmed safe basal rate, as
indicated by
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block 982 in FIG. 49. In certain embodiments, this safe basal rate is defined
as half the
patient's overnight basal rate, and this parameter may be programmed by a
caregiver or
physician. If the missed transmission module 916 starts receiving data packets
while the
safe basal rate is being administered, the system will switch back to the
closed-loop
mode. For missed data packets totaling more than the upper threshold of time,
the system
will switch to the open-loop mode, as indicated by block 984 in FIG. 49. At
this point, the
system will be controlled to deliver a pre-programmed open-loop overnight
basal rate.
[00394] To summarize, the controller 900 determines whether to enter into the
closed-
loop mode in response to at least the recent meter BG values 920, the sensor
calibration
factors 922, and the calibration timestamp data 926. The controller 900
utilizes the
closed-loop initiation module 902 to check if the sensor calibration time
between the last
two calibration values is within an acceptable range, and whether any change
between the
two calibration values (recent and prior value) is acceptable. If so, the
controller 900 will
switch the system into the closed-loop mode. Once the system is in the closed-
loop mode,
the controller 900 will periodically receive data packets (e.g., every five
minutes) that
include the current SG value 940, the current sensor lsig values 950, the
insulin delivered
954, the sensor calibration factors 952, and manual boluses delivered 960. In
certain
embodiments, each of the data packets received by the controller 900 includes
data
collected during the previous 24-hour period.
[00395] The start-up module 904 utilizes the SG values 940 and the target
glucose
setpoint value 944 to calculate the final target glucose value 946. In some
embodiments,
the target glucose setpoint value 944 is set to 120 mg/dL, although other
settings could be
used if so desired (a typical range of settings may be, for example 70-300
mg/dL). This
results in a smoother transition between open-loop and closed-loop modes by
gradually
adjusting the final target glucose value 946. The final target glucose value
946 is sent to
the PID-IFB control module 906 for use as one input to calculate the final
insulin dose
962.
[00396] The PID-IFB control module 906 utilizes the final target glucose value
946,
the current and past SG values 940, the SG rate of change values, and the
insulin
delivered 954 to determine the insulin infusion rate (final insulin dose 962)
in order to
achieve euglycemia. As an additional safeguard, the upper insulin limit
(calculated based
on the patient's basal rate, fasting blood glucose, and insulin sensitivity)
from the insulin
limit module 908 is input into the controller 900 for each patient to impose
an upper limit
to the insulin delivery rate to avoid over-delivery of insulin by the
controller 900. The
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PID-IFB control module 906 considers the upper insulin limit before sending
the final
insulin dose 962 to the 10B compensation module 910, which estimates insulin
on board
from manual boluses, before or during closed-loop operation, in order to
calculate the
final insulin dose 962. The final insulin dose 962 may be communicated from
the
controller 900 directly or indirectly to the insulin delivery system 14 such
that the final
insulin dose 962 can be delivered to the patient during closed-loop operation.
[00397] Additional safeguards could be implemented to monitor the system
during
closed-loop operation, such that the system exits the closed-loop mode when
certain
criteria are not met. For example, the controller 900 may cause the system to
exit the
closed-loop mode if more than a designated number of consecutive data packets
are
missed. This assumes that the controller 900 usually receives data packets
(from the
insulin delivery system 14, from a monitor, from a translation device, or the
like) in a
continuous manner during closed-loop operation. Thus, if the controller 900
detects that
more than a threshold number of consecutive data packets are not received as
expected,
the system will be commanded to exit the closed-loop mode. This functionality
is
associated with the missed transmission module 916, as described previously.
[00398] Moreover, the model supervisor module 914 estimates the user's glucose
concentration in an ongoing manner, based on the insulin delivered 954, the
sensor Isig
values 950, and the sensor calibration factors 952. If the difference between
the model-
predicted glucose and the sensor glucose value is greater than a stated
threshold, the
controller 900 may cause the system to exit the closed-loop mode.
1003991 As summarized above, the controller 900 employs a number of modules or
functions that cooperate to regulate the delivery of insulin during closed-
loop operation:
the closed-loop initiation module 902; the start-up module 904; the PID-IFB
control
module 906; the insulin limit module 908; and the 10B compensation module 910.
Moreover, the controller 900 may employ a number of modules that perform
various
safeguarding functions during closed-loop operation. These safeguarding
modules may
include: the insulin delivery timeout module 912; the model supervisor module
914; and
the missed transmission module 916.
[00400] Closed-Loop Initiation Module: First Representation
[00401] The closed-loop initiation module 902 checks for changes in sensor
sensitivity
and determines whether or not the system is allowed to enter the closed-loop
mode.
Referring again to FIG. 49, the inputs to the closed-loop initiation module
902 include the
meter BG value 920, the sensor calibration factor 922, and the calibration
timestamp data
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926. The closed-loop initiation module 902 checks for a series of conditions
pertaining to
the sensor calibration factor values 922 and the times when the sensor
calibration factor
values 922 were obtained. If all the conditions are met, the controller 900
initiates the
closed-loop operating mode. If this criteria is not met, the system remains in
the open-
loop operating mode and the controller 900 requests a new sensor calibration.
[00402] Certain embodiments of the closed-loop initiation module 902 execute
one or
more functions, algorithms, or methods to determine whether or not the system
can
proceed to the closed-loop mode. The following are the parameters and
variables used by
an exemplary embodiment of the closed-loop initiation module 902:
t = time when attempting to enter the closed-loop mode;
Recent Calibration Factor (CFR) = the most recent sensor calibration factor
(CF) value;
tR = the time when the CFR was obtained;
Prior Calibration Factor (CFP) = the last CF value before the CFR;
tP = the time when the CFP was obtained;
CFchange = percentage change in CF from a previous CF to a current CF, for
any pair of CFs. The CFchange can be calculated according to the following
equation:
CFchange = (abs(CFcurrent ¨ CFprevious)/CFprevious)* 100 (eq 50)
tRecent = time window for the most recent calibration before attempting to
start closed-loop mode (minutes)
tDiffmin = minimum time difference between the recent calibration and the
calibration prior to the recent calibration (minutes)
tDiffmax = maximum time difference between the recent calibration and the
prior calibration (minutes)
CFmin = minimum acceptable CF (mg/dL per nA)
CFmax = maximum acceptable CF (mg/dL per nA)
CFprevious = the CF value before CFcurrent in the pair of CF values
CFchangeTh = threshold for acceptable CFchange in % (mg/dL per nA)
[00403] In some embodiments, the closed-loop initiation module 902 is
implemented
in the form of a series of processing steps. Using the logic described below,
the closed-
loop initiation module 902 decides whether to let the system enter the closed-
loop mode.
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100404.1 Case A
If (tP is not in the time window (tR-tDiffmin : tR)), the following logic is
checked.
If (CFmin < CFR < CFmax)
If (t-tRecent < tR < t)
If (tR-tDiffmax < tP < tR-tDiffmin)
If (CFmax < CFP < CFmax)
Calculate CFchange with CFR as the CFcurrent and
with CFP as the CFprevious in Equation 50 stated
above
If (CFchange < CFchangeTh)
Enter Closed Loop
Else Cannot enter closed loop at that time
Else Cannot enter closed loop at that time
Else Cannot enter closed loop at that time
Else Cannot enter closed loop at that time
Else Cannot Enter Closed Loop
1004051 If any of the above conditions is not met, the system remains in the
open-loop
mode. Thus, in order to enter the closed-loop mode, new calibration(s) that
satisfy all of
the conditions in Case A (or Case B as described below) will be required.
1004061 Case B
If (tP is in the time window (tR-tDiffmin : tR)),
CFV = most recent CF value in the time window of tR-tDiffmax : tR-tDiffmin
tV = time when CFV was obtained
If (CFmin < CFR < CFmax)
if there is a CFV available
Calculate CFchange with CFR as the CFcurrent and with CFV
as the CFprevious in Equation 50 stated above
If (CFV, CFR and all CF values between times tV and tR lie in
the range of (CFmin:CFmax) AND CFchange between CFV
and CFR is < CFchangeTh)
Enter closed loop
Else Cannot enter closed loop at that time
Else Cannot enter closed loop at that time
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Else Cannot enter closed loop at that time
Else Cannot Enter Closed Loop
1004071 If any of the above conditions is not met, the system remains in the
open-loop
mode. Thus, in order to enter the closed-loop mode, new calibration(s) that
satisfy all of
the conditions in Case A or Case B will be required.
100408] In accordance with certain variations of the closed-loop initiation
module 902,
the system requests a meter BG and related calibration when entering the
closed-loop
mode. In such alternative embodiments, therefore, the closed-loop initiation
module 902
uses the meter BG and Isig to calculate CFR. Thus, in such an implementation,
the sensor
current would also be an input to the closed-loop initiation module 902.
Accordingly,
because CFR is now being calculated by the closed-loop initiation module 902
itself, the
conditions in Case A and Case B (i.e., checking whether t-tRecent < tR < t)
will always
be met.
[00409] In particular implementations, some of the parameters mentioned above
can be
fixed. In this regard, the following values may be utilized in an exemplary
embodiment. It
should be appreciated that these values are provided here for illustrative
purposes only,
and that an implementation of the closed-loop initiation module 902 may
utilize different
values if so desired.
tRecent =120 minutes
tDiffmin = 120 minutes
tDiffmax = 480 minutes
CFmin = 2.5 mg/dL per nA
CFmax =6 mg/dL per nA
1004101 Closed-Loop initiation Module: Second Representation
[00411] In accordance with some embodiments, the functionality of the closed-
loop
initiation module 902 can be represented as follows. The closed-loop
initiation module
902 may be implemented in the form of a series of case steps. In this regard,
the closed-
loop initiation module 902 first calculates the recent calibration factor
value (CFR) using
the most recent meter BG and Isig values as shown in the following Equation
Al:
CFR = meterBGI(Isig ¨2) (eq Al)
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Here, CFR is the recent calibration factor value, meterBG is the meter BG
value, and Isig
is the sensor Isig value. The "-2" in Equation Al represents a constant offset
that is used
by the calibration algorithm when calculating calibration factors and sensor
glucose.
[00412] Using the logic described below for Case C or Case D, the closed-loop
initiation module 902 decides whether to let the system enter the closed-loop
mode. Each
case condition is dependent upon the time at which the most recent prior
calibration factor
(CFP) was obtained.
[00413] Case C
[00414] Case C corresponds to a scenario where the time of prior calibration
is greater
than 120 minutes before the most recent calibration. In addition, the recent
calibration
factor (CFR) and the prior calibration factor (CFP) are within limits as shown
in the
following logical expressions.
CFmin < CFR < CFmax (eq A2)
CFmin < CFP < CFmax (eq A3)
Here, CFR is the recent calibration factor value, CFP is the prior calibration
value,
CFmin is the minimum value for the calibration factor that is set as 2.5 mg/dL
per nA,
and CFmax is the maximum value for the calibration factor that is set as 6
mg/dL per nA.
[00415] For Case C, the time of recent calibration (tR) is within two hours of
the start
of closed-loop initiation as shown in the following logical expression.
t ¨ tRecent < tR < t (eq A4)
Here, tR is the time of recent calibration, t is the time when attempting to
enter the
closed-loop mode, and tRecent is the time window for the most recent
calibration before
attempting to start the closed-loop mode (which is set to 120 minutes).
[00416] For Case C, the time of prior calibration (tP) occurs between two and
eight
hours before time of recent calibration factor as shown in the following
logical
expression.
tR ¨ tDif fmax < tP tR ¨ tDif fmin (eq A5)
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Here, tP is the time of prior calibration, tR is the time when CFR was
obtained, tDiffmax
is the maximum time difference between the recent calibration and the prior
calibration
(which is set as 480 minutes (8 hours)), and tDiffmin is the minimum time
difference
between the recent calibration and the calibration prior to the recent
calibration (which is
set as 120 minutes (2 hours)).
1004171 For Case C, the calibration change (CFchange) is less than 35% as
shown in
the following logical expression, where CFchange is calculated according to
Equation
A6.
CFchange = (abs(CFR ¨ CFP)ICFP) x 100 (eq A6)
CFchange CFchangeTh (eq A7)
Here, CFchange is the percentage change in calibration factor from the
previous
calibration factor to a current calibration factor for any pair of calibration
factors,
CFchangeTh is the threshold for acceptable CFchange, (which is set to 35% for
this
example), CFR is the most recent calibration factor value, and CFP is the last
calibration
factor value before CFR.
[00418] If all of the foregoing conditions are met for Case C (Equations A2-
A7), the
closed-loop initiation module 902 can initiate the methodology for calculating
the
correction bolus (if needed). If, however, any condition is not met, the
controller 900
remains in the open-loop mode. Thus, in order to enter the closed-loop mode,
new
calibration(s) that satisfy all of the conditions in Case C or Case D will be
required.
[00419] Case D
[004201 Case D corresponds to a scenario where the time of prior calibration
is less
than 120 minutes before the most recent calibration. If the prior calibration
is less than
two hours before the recent calibration, an additional prior calibration
factor (CFP2) is
included in the analysis. This allows the closed-loop initiation module 902 to
evaluate
sensor sensitivity that has at least a two hour time span.
[00421] For Case D, the closed-loop initiation module 902 finds an earlier
second prior
calibration factor (CFP2) that occurs within two to eight hours before the
time of the
recent calibration factor (CFR) as shown in the following logical expression.
tR ¨ tDif fmax < tP2 tR ¨ tDif fmin (eq A8)
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Here, tP2 is the time when the second prior calibration factor (CFP2) is
obtained, tR is the
time when CFR was obtained, tDiffmax is the maximum time difference between
tP2 and
tR (which is set as 480 minutes (8 hours) for this example), and tDiffinin is
the minimum
time difference between tP2 and tR (which is set as 120 minutes (2 hours) for
this
example).
[00422] For Case D, the closed-loop initiation module 902 also determines if
more
than one calibration factor (CF1...CFn) is available between the time of the
second prior
calibration factor (CFP2) and the time of the recent calibration factor (CFR),
as shown in
the following logical expression.
tP2 < t1 ...tn < tR (eq A9)
Here, ii... In is the time when more calibration factors (CF1...CFn) are
observed, tR is the
time when CFR was obtained, and tP2 is the time when CFP2 is obtained.
1004231 For Case D, the time of recent calibration (tR) is within two hours of
the start
of closed-loop initiation, as shown in the following logical expression.
t ¨ tRecent < tR < t (eq A10)
Here, tR is the time of recent calibration, t is time when attempting to enter
the
closed-loop mode, and tRecent is the time window for the most recent
calibration before
attempting to start the closed-loop mode (which is set to 120 minutes for this
example).
[00424] For Case D, all calibration factors including recent calibration
factor (CFR),
prior calibration factor (CFP), second prior calibration factor (CFP2) and CFI
...CFn are
within limits as shown in the following logical expressions.
CFmin < CFR < CFmax (eq A11)
CFmin < CFP < CFmax (eq Al2)
CFmin < CFP2 < CFmax (eq A13)
CFmin < CF1 ...CFn < CFmax (eq A14)
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Here, CFR is the recent calibration factor, CEP is the prior calibration
factor, CFP2 is the
second prior calibration factor, CFI CFn are calibration factors obtained
between tP2
and tR, CFmin is the minimum value for the calibration factor (which is set as
2.5 mg/dL
per nA for this example), and CFmax is the maximum value for the calibration
factor
(which is set as 6 mg/dL per nA for this example).
[00425] For Case D, the calibration change (CFchange) between CFR and CFP2 is
less
than 35%, as shown in the following logical expression where CFchange is
calculated
according to Equation A15.
CFchange = (abs(CFR ¨ CFP2)/CFP2) X 100 (eq A15)
CFchange CFchangeTh (eq A16)
Here, CFchange is the percentage change in calibration factor from the
previous
calibration factor to a current calibration factor for any pair of calibration
factors,
CFchangeTh is the threshold for acceptable CFchange (which is set to 35% for
this
example), CFR is the most recent calibration factor value, and CFP2 is the
most recent
calibration factor value in the time range described in Equation A8.
[00426] If all of the foregoing conditions are met for Case D (Equations A8-
A16), the
closed-loop initiation module 902 can initiate the methodology for calculating
the
correction bolus (if needed). If, however, any condition is not met, the
controller 900
remains in the open-loop mode. Thus, in order to enter the closed-loop mode,
new
calibration(s) that satisfy all of the conditions in Case C or Case D will be
required.
[00427] Correction Bolus With JOB Compensation
[00428] As described above, a correction bolus 932 may be commanded at the
beginning of the closed-loop mode. The purpose of the correction bolus is to
provide an
insulin dose for mitigating hyperglycemia at the initiation of the closed-loop
mode. This
can be achieved by first acquiring a blood glucose meter reading value
immediately prior
to closed-loop initiation. If that BG meter reading value is above a certain
correction
threshold (CTH, which is 180 mg/dL for this example), the controller 900 will
deliver an
insulin dose based on the patient's insulin sensitivity (ISF, mg/dL/Units),
insulin on
board, and the desired target glucose level (TG, mg/dL) in order to bring the
subject's
glucose level to the target glucose level.
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1004291 In accordance with certain implementations, the correction bolus
(CB) is
delivered based on the meter BG value (in mg/dL) acquired at the start of the
closed-loop
mode, as shown below:
BG-TG
I0B(n), if (BG > CTH)
CB ={ IsF (eq A17)
0, if (BG 5_ CTH)
Here, CB is the correction bolus, BG is the blood glucose meter value (mg/dL),
TG is the
target glucose (mg/dL), ISF (see Equation A18) is the patient's adjusted
insulin
sensitivity factor (mg/dLUnits), CTI-I is the correction threshold for blood
glucose
beyond which a correction bolus will be delivered (mg/dL), and I0B(n) is the
active
insulin on board from manual boluses (Units) where n is the current sampling
point as
described previously.
ISF = !SF factor x ISF0 (eq A18)
Here, ISF is the patient's adjusted insulin sensitivity factor (mg/dL/Units),
/SF0 is the
patient's established insulin sensitivity factor (mg/dLIUnits) and ISFfactor
is an ISF
adjusting factor (unit less). The default value for ISFfactor is set to one,
which makes ISF
= ISF0. However, for this particular example, ISFfactor has been assigned as
an
adjustable parameter with a range of 0.5 to 2 in order to provide greater
flexibility for
optimizing the patient's insulin sensitivity factor.
CB_ 1CB, if (CB 0) A19
0, if (CB <0) (eq )
Here, CB is the correction bolus expressed in Units. It should be appreciated
that
Equation A19 is utilized because the controller 900 can only deliver positive
boluses.
1004301 Start-Up Module
[00431] The start-up module 904 processes sensor glucose (SG) values 940 and
the
target glucose setpoint value 944 (which is set to 120 mg/dL in certain
embodiments) to
calculate the final target glucose value 946, which in turn serves as an input
to the PID-
IFB control module 906. Accordingly, the final target glucose value 946 is
sent to the
PID-IFB control module 90610 calculate the final insulin dose 962. Referring
again to
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FIG. 49, the start-up module 904 is "activated" or initiated in response to
the starting of
the closed-loop mode.
1[004321 At the beginning of the closed-loop operating mode, the start-up
module 904
calculates the difference between the current SG value 940 and the target
glucose setpoint
value 944, as indicated by Equation 51 below.
= 1SG (n) ¨ Setpoint, m = 1
DeltaGlu(n) (eq 51)
(0, m > 1
In Equation 51, SG is the sensor glucose value, n is the current sampling
point, Setpoint is
the target glucose setpoint value defined by user, and m is the sampling time
during
closed-loop operation (m=1 indicates the start of the closed-loop mode, and m
increases
with each sample received during the closed-loop mode). DeltaGlu(n) is forced
to zero
when m> 1 as well as in the following situation described in Equation 52.
[00433] Force DeltaGlu to zero if it is less than a certain threshold set in
the controller
900 (referred to as MinDeltaGlu). Otherwise, it remains as DeltaGlu(n) if it
is more than
the threshold set in the controller 900, as described in Equation 52:
DeltaGlu < MinDeltaGlu
DeltaGlu(n) = (eq 52)
DeltaGlu(n), DeltaGlu > MinDeltaGlu
Here DeltaGlu is the difference between the current SG value 940 and the
defined target
glucose setpoint value 944, calculated from Equation 51 above, and MinDeltaGlu
is the
minimum difference (set in the controller 900) allowable between the current
SG value
940 and the target glucose setpoint value 944.
[00434] The dynamic setpoint (DynSP) is calculated based on a discretized
second
order transfer function model as indicated in Equation 53:
DynSP(n) = cdi = DynSP(n ¨ 1) + c d2 = DynSP(n ¨ 2) + en = DeltaGlu(n) +
cni = DeltaGlu(n ¨ 1) (eq 53)
Here, DynSP is the dynamic setpoint value, n is the current sampling point, n-
1 is the last
sampling point, and n-2 is the second to last sampling point. The parameters
ccli, cd2, cno,
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and cni are the coefficients of the setpoint model. These parameters are
calculated based
on the two time constants (1õ1 and isp2) of the setpoint model, as indicated
below:
cdi = eaxxl + eaxx2
cd2 = ¨eaxxl x eaxx2
cno = 1
(axxixeaxxl-axx2xeaxx2)
cni =
daxx2i
Where:
axxl =
axx2 = 1 It sp2
eaxxl = e-axxl=Ts
eaxx2 = e-axx2.7'5
daxx21 = axx2 ¨ axxl
In the above equations 7's indicates the sampling interval in minutes, and -
Espi and Tsp2 are
the time constants of the setpoint model. Moreover, axxl is the reciprocal of
the time
constant rspi, axx2 is the reciprocal of the time constant zsp2, eaxxl is the
exponential
decay factor for rspi, eaxx2 is the exponential decay factor for 1,2, and
da;cx21 is the
difference between the reciprocal of tspi and isp2.
100435] The final target glucose value 946 is obtained by adding the dynamic
setpoint
value (calculated in Equation 53) with the target glucose setpoint value 944
as shown in
Equation 54:
Final Target = Setpoint + DynSP(n) (eq 54)
100436] In particular implementations, some of the parameters mentioned above
for
the start-up module 904 can be fixed. In this regard, the following values may
be utilized
in an exemplary embodiment. It should be appreciated that these values are
provided here
for illustrative purposes only, and that an implementation of the start-up
module 904 may
utilize different values if so desired.
Setpoint = 120 mg/dL
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MinDeltaGlu = 30 mg/dL (nominal); 0 mg/dL (lower bound); 600 mg/dL (upper
bound)
Tv' =25 minutes (nominal); 0.1 minute (lower bound); 250 minutes (upper bound)
Tsp2 =30 minutes (nominal); 0.1 minute (lower bound); 250 minutes (upper
bound)
1004371 PID-IFB Control Module
1004381 The PID-IFB control module 906 calculates the insulin infusion rate
(final
insulin dose 962) based on the current and past sensor glucose values 940, the
sensor Isig
values 950, the rate of change of the sensor glucose values, the sensor
calibration factor
952, the final target glucose value 946, the target glucose setpoint value
944, insulin
limits such as the upper insulin limit, and the insulin delivered 954 in order
to achieve
euglycemia. In certain embodiments, the PID-IFB control module 906 receives
its inputs
every five minutes, therefore the calculation of the insulin feedback
components
considers how often the input data is being received by the controller 900.
[00439] The PID-IFB control module 906 calculates the final insulin dose 962
in
accordance with Equation 55:
u(n) = P (n) + 1(n) + D (n) ¨ Y ilsc ¨Y2lp Y3IEFF (eq 55)
Note that P I D Rate (n) E u(n). In Equation 55, the insulin infusion rate
u(n) represents
the final insulin dose 962 shown in FIG. 49. In Equation 55, P (n) , I (n) ,
and D (n) are,
respectively, the proportional, integral, and derivative components of the PID
controller.
The insulin feedback components correspond to the remaining terms. The
variables 71, 72,
and 73 represent tuning coefficients. In accordance with some embodiments,
yoD.64935,
72=0.34128, and =y3=0.0093667, although other values may be used. The
parameters
/õ(n), i,,(n), and IEFF(n) correspond to the states of the insulin
pharmacokinetic model
corresponding to, respectively, the subcutaneous, plasma, and effective site
compartments. Therefore, the amount of insulin delivered is reduced in
proportion to the
predicted insulin concentration in the different compartments.
[00440] The exemplary implementation of the control algorithm employed by the
PID-
IFB control module 906 is implemented in discrete (sampled) time. In the
notation used, n
is the current time step, where = nT, , and t is the continuous time (in
minutes) when
using a sampling period of Tõ.
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[00441] The proportional component P(n) is calculated as follows:
P(n) Kp[SG(n) ¨ Final Target(n)] (eq 56)
Here, Kp is the overall controller gain (expressed in Units/hour per mg/dL),
SG(n) is the
current sensor glucose, n indicates the current sampling point, and Final
Target(n) is the
calculated final target glucose setpoint from Equation 54. It should be
appreciated that Kp
is a patient-specific value and, therefore, the actual value of Kp will vary
from one person
to another. Although the range can vary depending upon the patient, in most
typical
scenarios, the value of Kp may be within the range of 0.008 to 0.200.
[00442] The integral component 1(n) can be calculated as follows:
1(n) = 1(n ¨ 1) + [SG(n) ¨ Final Target(n)] (eq 57)
Here, 1(n-1) is the integral component from the previous sampling point, n
indicates the
current sampling point, n-1 indicates the previous sampling point, Kp is the
overall
controller gain, Ts is the sampling period, T1 is the integral time constant,
SG(n) is the
current sensor glucose, and Final Target(n) is the calculated final target
glucose setpoint
from Equation 54.
[00443] The derivative component D (n) can be calculated as follows:
D(n) = Kp X TD X dSGdt(n) (eq 58)
Here, Kp is the overall controller gain, TD is the derivative time constant,
dSGdt(n) is
derivative of the sensor glucose value (pre-filtered to remove noise), and n
indicates the
current sampling point.
[00444] The parameters that need to be set (tuned) for the controller 900 are:
Kp, 17,
and Tr) (see Equations 56, 57, and 58). For the first three PID parameters,
they will be
calculated in accordance with the previous studies mentioned below (these
previous
approaches have resulted in good controller performance). The nominal (i.e.,
for the case
with no insulin feedback) controller gain Kpg is calculated based on the
subject's insulin
total daily dose IIDD, (in Units/day), as indicated in Equation 59:
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60
Kpo =
(90)(1500) ITDD (eq 59)
Here, Kpo is the default controller gain, and bap is the subject's insulin
total daily dose in
Units/Day.
[00445] The purpose of insulin feedback is to allow the controller 900 to
deliver more
insulin up-front (e.g., at the onset of a meal disturbance), but to prevent
over-infusion of
insulin, in a similar fashion to the bolus estimator calculations used in
existing insulin
pumps to prevent the stacking of boluses. Therefore, when insulin feedback is
used, the
controller gain Kp can be adjusted so that at steady state (i.e., basal
delivery conditions)
the insulin delivery system will deliver the same amount of insulin as in the
nominal case.
This is accomplished by multiplying the nominal controller gain KpO
(calculated for no
insulin feedback) by (1 + 71 + 72 + 73) as indicated below:
Kp = Kp factor = KR) = (1 + yi + y2 + y3) (eq 60)
Here, Kp is the overall controller gain, KpfaCtor is the gain factor for Kp,
Kpo is the default
controller gain, 71 (0.64935) is a tuning coefficient for the subcutaneous
insulin
concentration, 72 (0.34128) is a tuning coefficient for plasma insulin
concentration, and
73 (0.0093667) is a tuning coefficient for effective insulin concentration.
[00446] The integral component 1(n) is also equipped with anti-windup and
saturation
constraints to address integral windup issues. This is achieved by calculating
an integral
clip value (upper limit for the integral component, 'Clip) as indicated by the
following
equations:
Imax(n), (SG(n) > UnwindHigh)
!Clip(n) = Iramp(n), (SG(n) > UnwindLow) and (SG(n) < UnwindH Oh)
1
I low(n), (SG(n) < UnwindLow) (eq 61)
Imax(n) = Imax f actor X Basal X (1 + yi + Y2 + Y3) (eq 61a)
Here, Imaxfactor is the gain factor for Imax, and Basal is the subject's night
time basal
rate. In accordance with these expressions, /Clip becomes equal to the lmax
(which is a
constant value) when the sensor glucose value is greater than an upper
threshold
(UnwindHigh). In certain embodiments, the value of (expressed in
Units/hour) may
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reach about 15. In a typical case, Imax may have a default value of 5Ø When
the sensor
glucose value is between the upper and lower threshold (UnwindLow), then IClip
becomes equal to Iramp(n), which is calculated as indicated in Equation 62.
Iramp(n) = Kp = [SG(n) ¨ UnwindLow] ( SG(n)-UnwindLow ("max Kp
Unw indH igh-UnwindLow 1
retpoint(n) ¨ UnwindLow]) (eq 62)
Here, Kp is is the overall controller gain, SG(n) is the current sensor
glucose, UnwindLow
is the sensor glucose lower threshold, UnwindHigh is the sensor glucose upper
threshold,
Imax is a constant value, and Setpoint(n) is a user-defined target glucose
setpoint.
[00447] Finally, if sensor glucose is below the UnwindLow threshold, IClip
assumes
the value of Ilow(n), which can be calculated by Equation 61:
flow(n) = Kp[Setpoint(n) ¨ Unwindlow] (eq 63)
Here, Kp is the overall controller gain, Setpoint is the target glucose
defined by the user,
and UnwindLow is the sensor glucose lower threshold.
[00448] FIG. 51 is a graph of 'cup (in Units/Hour) versus sensor glucose level
(in
mg/dL) in accordance with one example. FIG. 51 depicts the relationships
between Imax,
UnwindLow, and UnvvindHigh for this particular example.
[00449] The integral component /(n) as calculated in Equation 57 must be less
than or
equal to the IClip value as shown in Equation 64:
1( ) EIClip(n), 1(n) > IClip(n) n = (eq 64)
/ (n), I(n) 1Clip(n)
[00450] The insulin feedback components correspond to the remaining terms. As
mentioned above, for this particular example yM).64935, y2=0.34128, and
73=0.0093667
(the tuning coefficients), while the parameters 'Sc (n), Ip(n), and IEFF(71)
correspond to
the states of the insulin pharmacokinetic model corresponding to,
respectively, the
subcutaneous, plasma, and effective site compartments. Therefore, the amount
of insulin
delivered is reduced in proportion to the predicted insulin concentration in
the different
compartments.
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1004511 The model describing the insulin pharmacokinetics (insulin PK) is
given by
the following expressions:
isc(n) = an X isc(n ¨1) + A x (n) (eq 65)
where:
= exp (¨ ¨Ts)
(eq 65a)
(eq 65b)
ks
Here, Ts is the sampling time (which is five minutes for this example), and
zs. is the
time constant for estimated subcutaneous insulin level in minutes (which is
set to 50
minutes for this example).
f(n) = a21 x /sc(n ¨1) + a22 x /p(rt ¨1) + fl2 x ID (n) (eq 65c)
where:
s Tp)
an = Ts = [exp(-7-1) ¨ exp (_ L)1 (Ts (eq 65d)
Ts Tp
a22 = exp --Ts
(eq 65e)
/60 \ TS
P2 = ) = (ts = 11 exp VI ¨ Tp = {1 exp(--
Z)1)1(7-5. ¨ rp) (eq 65f)
Here, Ts is the sampling time, which is five minutes for this example, ts is
the time
constant for estimated subcutaneous insulin level in minutes, which is set to
50 for this
example, and ri, is the time constant for estimated plasma insulin level in
minutes, which
is set to 70 for this example.
/EFF(n) = a31 x isc(n ¨ 1) + a32 x ip(n ¨ 1) + a33 X IEFF(n ¨1) x 1 D (71)
(eq 66)
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For Equation 66:
Ls Ts
a31 = Ts = [Ts = (Tp ¨ re) = exp(_) Tr (Tp ¨ T e) = exp(--)+ Te = (Ts ¨ Tp) =
\ rs / Tp
exp (--
Ts)1/[(Ts Tp). (Ts Te) (Tv Te)] (eq 66a)
re
Ts s
a32 = rp = [exp exp (_!)]/(T T e) (eq 66b)
Ty
TS)
a33 = exp /--) (eq 66c)
Te
P3 = (-61)' (F4 ' (Tp ¨ re ) = (1 exp (¨ ¨Z))1¨ Tf, = (Ts ¨ re) = [1 ¨
exp (_)1+
4 .(r-
rp) [1 exp (¨ ¨
Ts)i) Ars _ Tp) (Ts _ re) (Tp Te)
rp Te)/
(eq 66d)
Here, Ts is the sampling time, which is five minutes for this example, rs is
the time
constant for estimated subcutaneous insulin level in minutes, which is set to
50 for this
example, Tr, is the time constant for estimated plasma insulin level in
minutes, which is set
to 70 for this example, and Te is the time constant for estimated interstitial
insulin level in
minutes, which is set to 55 for this example.
1004521 ID(n) is the calculated and administered insulin infusion.
1004531 The notation (n-1) indicates values at the previous time step.
[00454] /sc is the subcutaneous insulin model estimate/prediction.
[00455] Ip is the plasma insulin model estimate/prediction.
1004561 JEFF is the effective site insulin model estimate/prediction.
[00457] For this particular example, the insulin PK model parameters all,
azt, ot,z, cc31,
11-32, 033, pi, 132, and 133 are set to 0.9802, 0.014043, 0.98582, 0.000127,
0.017889, 0.98198,
1.1881, 0.0084741, and 0.00005, respectively. These values were calculated
from PK-PD
data for insulin as part of an empirical study and investigation. It should be
appreciated
that the specific values presented here merely reflect one possible set of
suitable values,
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and that any one or more of these values may be adjusted as appropriate for
the particular
embodiment.
[00458] Insulin Limit
[00459) The final infusion rate as calculated by Equation 55 is limited such
that is does
not exceed the maximum upper insulin limit (Umax) as indicated below in
Equation 67:
u(n) = I/ max , u(n) > Umax
u(n) Umax (eq 67)
Umax is calculated as indicated by Equation 68:
BGLBL¨FBG0
Umax = I +
basa1,0 K1 (eq 68)
Here, Umax is the upper insulin limit bounded at BGLBL (see Equation 68a
below), and
ibasai3O is the basal rate defined for the user to bring the patient to a
Fasting Blood Glucose
(FBG) of the value FBG0 mg/dL. BGLBL (mg/dL) is the lower buffer limit BG when
reaching Umax, FBG0 is the estimated blood glucose using meter blood glucose
readings
at the end of the night period, and IC/ is insulin gain as calculated by
Equation 69 below.
BGLBL = Setpoint ¨ ILL? (eq 68a)
Here, BGLBL (mg/dL) is the lower buffer limit BG when reaching Umax, Setpoint
is the
target glucose setpoint value 944 (FIG. 49) that is defined by the user, and
ILB is the
insulin limit buffer, which is an amount (in mg/dL) that the system allows as
an additional
buffer to handle higher insulin needs. For example, an ILB of 50 allows the
system to
deliver additional insulin to lower by 50 mg/dL from the Setpoint.
KI = ¨IS * 3 (n21 per ¨u) (eq 69)
dL
Here, K/ is insulin gain, and IS is the insulin sensitivity estimated by the
1800 rule as
IS = 1800/TD/ (Total Daily Insulin). In certain embodiments, the value of Umax
may
reach 150 Units/hour. In a typical implementation, the value of Umax is
calculated on a
per-patient basis, and the typical range for Umax is between 0.5 to 3.0
Units/hour.
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1004601 Moreover, if the insulin limit is active, then the integral component
of the PID
algorithm is frozen to its previous value. This feature can be employed to
assist in the
prevention of integral wind up. This information is passed back to the PID-IFB
control
module 906 for use during the next PID calculation.
1 1(n ¨ 1), u(n) = Umax
1(n) =
/(n), u(n) < Umax (cq 70)
[00461] As mentioned above, previous studies may be leveraged for purposes of
configuring and/or operating the PID-IFB control module 906. A first study
(Study 1;
Panteleon et al., 2006) looked at the effect of changing the controller gain
in a study on
eight diabetic dogs. The nominal gain was calculated based on the total daily
dose of
insulin for one experiment; in duplicate experiments this nominal gain was
increased and
decreased by fifty percent. Insulin delivery in the six-hour postprandial
period tended to
increase with increasing gain, but this did not achieve statistical
significance. This was
due to feedback, with lower insulin delivered as glucose levels fell. In
essence, the higher
gains tended to give more insulin earlier (achieving much better glucose
regulation), and
reducing the infusion later, whereas the lower gains tended to keep insulin
infusion above
basal for a longer period of time due to the glucose levels remaining
significantly above
target. Note that the controller gain affects all of the components of the P1D
algorithm,
including the integral and derivative terms.
1004621 A second study (Study 2; Steil et al., 2006) applied a PID controller
to ten
human subjects. In this study the nominal controller gain was about 42 percent
higher
than that proposed here, with the integral time constants the same (therefore
also a higher
integral response), but slightly lower derivative time constants (defined in
terms of rising
or falling blood glucose, instead of day or night response). In the proposed
embodiment
presented here, the night-time derivative time constant is just slightly lower
than that used
in Study 2.
[00463] A third study (Study 3; Weinzimer et al., 2008) applied a PID
controller to
seventeen human subjects. For a subset of eight subjects, no pre-meal bolus
was given,
while in the remaining nine subjects about 50 percent of the standard meal
bolus was
given about fifteen minutes before the meal. The controller tuning was the
same as that
proposed herein. In both cases, performance was acceptable, with the pre-meal
bolus
helping to lower the postprandial peak glucose excursion. When compared with
home
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treatment using standard pump therapy, both closed-loop algorithms were
superior,
reducing both glucose excursions above 180 mg/di and below 70 mg/d1.
100464] One of the observations from Study 3 was that the meal-related insulin
infusion persisted above pre-meal levels for at least four hours after the
meal. This result
led to the introduction of insulin feedback to the algorithm, which serves to
compensate
for insulin already delivered, while at the same time allowing for more
aggressive action
at the start of meals, where it is needed.
1004651 In particular implementations, some of the parameters mentioned above
for
the PID-IFB control module 906 can be fixed. In this regard, the following
values may be
utilized in an exemplary embodiment. It should be appreciated that these
values are
provided here for illustrative purposes only, and that an implementation of
the PID-IFB
control module 906 may utilize different values if so desired.
i= 0.64935
72= 0.34128
-y3= 0.0093667
= 0.90483741803596
0,21 = 0.065563404170158
a22 = 0.931062779704023
a31 = 0.00297495042963571
0.32 = 0.083822962634882
o.33 = 0.083822962634882
= 5.70975491784243
132 = 0.202428967549153
133 = 0.202428967549153
[00466] The values of the PID parameters mentioned above (Kp, rj, and ID) are
not
expected to change, but it may be desirable to adjust them if doing so would
improve the
response of the glucose excursion. The nominal values for these P1D
parameters, together
with exemplary allowable ranges, are shown in Table 2.
Parameter Nominal Value Lower Bound Upper Bound
Controller gain: x x (1 + + Y2 0.05 x X (1+ y,
+ yi 20 x Kõ X (1+ + Y2
Kp +3) +3) +3)
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Integral time 250 min 10 min 1500 min
constant: r1
Derivative time 75 min 10 min 500 min
constant: VD
UnwindLow 80 0 200
(mg/dL)
Unwindifigh 100 0 200
(mg/dL)
Imax 2.5 x (1 + y, + y, + y3) 0 10 x (1 + y, +
y2 + y3)
x Basal Rate x Basal Rate
Table 2: Adjustable Parameters For the PID-IFB Control Module
1004671 The lower bound for the controller gain Kpo would lower it by 95
percent from
the nominal, resulting in an overall less aggressive response of the
controller 900, and
resulting in less insulin delivered for the same glucose level and trend. The
upper bound
allows this gain to be increased up to 20 times from the nominal. Although
this would
result in more insulin being given, this is always with respect to the actual
glucose level
and its derivative, rapidly falling blood glucose, even with an elevated blood
glucose
level, results in a decreased delivery of insulin due to the derivative
component.
[00468] The integral time constant ri determines how fast a deviation in the
blood
glucose from the desired glucose target accumulates. A higher value results in
a slower
response to persistent deviations in glucose from target. Lastly, the
derivative time
constant JD can safely be decreased all the way to zero, as the lower it is
the less insulin
will be delivered. Anything much higher than the upper bound of 500 minutes
would
make the controller too sensitive to small changes in the rate of change of
the sensor
glucose, which even though it is not necessarily dangerous, is still
undesirable in terms of
overall performance.
[00469] IOB Compensation Module
[00470] FIG. 52 is a block diagram that schematically depicts one suitable
embodiment
of the JOB compensation module 910 in additional detail. As mentioned briefly
above,
the JOB compensation module 910 adjusts the current insulin dose 958 (i.e.,
the insulin
infusion rate as computed by the PID-IFB control module 906) as needed to
generate the
final insulin dose 962 (i.e., the final adjusted infusion rate used by the
insulin infusion
device). The 10B compensation module 910 may also receive basal rate data 990
and the
information related to the manual boluses delivered 960 as input for purposes
of
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calculating the current value of the final insulin dose 962 and/or for
purposes of
calculating future values of the final insulin dose 962. The basal rate data
990 may
indicate the current basal rate of insulin being delivered to the user, and
the manual
boluses delivered 960 may indicate the amount for each bolus administered to
the user,
along with timestamp data corresponding to the delivery date/time of each
bolus. In this
regard, the manual boluses delivered 960 may include information for any
number of
boluses delivered in the past, and the manual boluses delivered 960 can be
updated as
needed in response to each bolus that is delivered going forward. Moreover,
the basal rate
could be dynamically adjusted if needed or desired (automatically by the
system, by the
user, by a caregiver, etc.).
[00471] The manual boluses delivered 960 may be collected and saved in
association
with the JOB compensation module 910 for use as bolus history 992. In this
regard, the
bolus history 992 may include any number of past bolus amounts administered
during a
given period of time. The JOB compensation module 910 may also use a number of
constants, parameters, coefficients, configuration settings, gain values, or
the like (for
simplicity, the constants 994 shown in FIG. 52 are intended to encompass these
and any
other quantities that might be used by the IOB compensation module 910 to
calculate the
final insulin dose 962. FIG. 52 also depicts JOB history 996, which represents
previously
calculated 10B values (i.e., historical 10B values calculated for past
sampling times). As
explained in more detail below, the JOB history 996 and the bolus history 992
may
influence the determination of the final insulin dose 962. It should be
appreciated that the
bolus history 992, the constants 994, and the IOB history 996 can be stored
and
maintained in one or more memory storage elements of the host system. FIG. 52
shows
these data items "inside" the JOB compensation module 910 for simplicity and
ease of
description.
[00472] The 10B compensation module 910 provides an additional safeguard that
estimates the insulin on board the body of the patient from manual boluses
that were
delivered prior to activation of the closed-loop mode, to compensate the final
insulin dose
962 and help avoid over-delivery of insulin. When the system initially enters
the closed-
loop mode, the IOB compensation module 910 considers the manual boluses
delivered
960 that have been administered over a defined period of time (e.g., the last
eight hours),
and subtracts the manual boluses. Thereafter, during the closed-loop mode, the
JOB
compensation module adjusts for manual boluses that were delivered during each
sampling period (e.g., every five minutes).
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1004731 FIG. 53 is a flow chart that illustrates an exemplary embodiment of an
10B
compensation process 1100, which may be performed by the JOB compensation
module
910. The process 1100 represents one iteration that is performed for a current
sampling
point or time, n. Accordingly, the process 1100 receives, obtains, or accesses
a variety of
inputs that may have an influence on the output of the JOB compensation module
(task
1102). For example, the process 1100 may utilize the current value of the
uncompensated
insulin infusion rate, PIDRate(n), as generated by the PID-IFB control module
906. The
process 1100 may also use the current basal rate (provided with the basal rate
data 990),
some of the bolus history 992, and/or some of the 10B history 996 as needed.
[00474] In the context of the process 1100, the JOB compensation module 910
calculates insulin on board from manual boluses at each cycle and compensates
the
controller output rate (insulin infusion rate) if active JOB is greater than a
certain
threshold. Accordingly, the process 1100 calculates, generates, or otherwise
obtains a
current JOB value (task 1104) that represents an estimate of active insulin in
the body of
the user. In certain embodiments, the active IOB is estimated in accordance
with a
discretized three-compartment insulin pharrnacolcinetic (PK) model, as
indicated below:
108(n) = ci1= 10B(n¨ 1) + c12 = 10B(n ¨ 2) + c13= 10B(n¨ 3) + cbo =
Ubolus(n) + cb, = Ubolus(n ¨ 1) + cb2 = Ubolus(n ¨2) (eq 71)
[00475] Here, JOB is the active insulin on board, Ubolus is the amount of
manual
bolus delivered in units per sample, n is the current sampling point, n-1 is
the last
sampling point, n-2 is the second to last sampling point, and n-3 is the third
to last
sampling point. Accordingly, the process 1100 obtains the current JOB value,
10B(n),
based at least in part on historical bolus delivery data for the user (see the
manual boluses
delivered 960 and the bolus history 992 in FIG. 52). The parameters cii, ci2,
ci3, cbo,
and cb2 are the coefficients of the insulin absorption model. These parameters
are
calculated based on the three time constants (r(., rp, and 7-cif) of the
insulin
pharmacokinetic model, as indicated below:
= eaxx3 + eaxx4 + eaxx5 (eq 71a)
ci2 =--(eaxx3 X eaxx4 + (eaxx3 + eaxx4)x eaxx5) (eq 71b)
ci3 = eaxx3 X eaxx4 X eaxx5 (eq 71c)
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cbo = 1
cb, = dprod x (¨(daxx22 X eaxx3 + daxx22 x eaxx4) x axx3 x axx4 +
(daxx31 X eaxx3 + daxx31 X eaxx5) X axx3 x axx5 ¨ (daxx32 x eaxx4 +
daxx32 x eaxx5) X axx4 X axx5) (eq 71d)
cb2 = dprod x (daxx22 X eaxx3 x eaxx4 x axx3 x axx4 + daxx32 X eaxx4 x
eaxx5 x axx4 x axx5 ¨ daxx31 X eaxx3 x eaxx5 X axx3 X axx5) (eq 71e)
Where:
axx3 = 1/z5c (cq 71f)
axx4 = 1/zp (eq 71g)
axx5 = ltreff (eq 71h)
eaxx3 = e'xx3=TsC (eq 71i)
eaxx4 = e-axx+TsC (eq 71j)
eaxx5 = e-axx5=T5C (eq 71k)
daxx22 = axx4 ¨ axx3 (eq 711)
daxx31 = axx5 ¨ axx3 (eq 71m)
daxx32 = axx5 ¨axx4 (eq 71n)
dprod = ¨1/(daxx22 x daxx31 x daxx32) (eq 710)
In the above equations TsC indicates a modified sampling interval in minutes,
which can
be calculated as TsC = Ts * 6/CurveSpeed , where Ts is the sampling interval
and
CurveSpeed is the insulin on board decay speed rate in hours. zs( , zp, and
Tell are the
respective time constants of the subcutaneous, plasma, and effective
compartments of the
insulin PK model.
[00476] JOB (in Units) as calculated by Equation 71 represents the residual
active
insulin in the body from manual boluses (that may have been administered
before the start
of the closed-loop mode or during closed-loop operation) which must be taken
into
account for calculation of the final insulin delivery rate. This is achieved
by first
calculating the JOB rate (task 1106) and then deducting the 1013 rate from the
PID-IFB
calculated infusion rate, as indicated below, Accordingly, in certain
situations the process
1100 determines an adjusted insulin infusion rate (task 1108) based at least
in part on the
calculated 10B rate and the uncompensated insulin infusion rate, PIDRate(n):
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r0ainlOB X 10B(n), 10B(n)> MinlOB
10BRate(n)= (eq 72)
, 10B(n)< MinlOB
AdjustedRate(n)=max(0, PIDRate(n)-10BRate(n)) (eq 73)
Note that the process 1100 calculates the JOB rate, IOBRate(n), based at least
in part on
the current JOB value, I0B(n). The JOB rate, which is expressed in Units per
hour (IA),
represents the amount of active insulin accumulated from manual boluses in the
body per
unit of time. Hence, this additional insulin which is already present in the
body is
deducted from the controller delivery rate (PIDRate). This accounts for all
the manual
boluses that have been administered by the user, and minimizes the possibility
of
over-delivery by the controller. Here, GainIOB is the IOB decay rate in h-1,
and MinlOB
is the minimum JOB required to compensate the P1DRate (where MinlOB is
expressed in
Units). Thus, the JOB rate is calculated to be equal to the current 10B value
multiplied by
an IOB decay rate when the current JOB value is greater than a minimum IOB
value, and
is calculated to be equal to zero when the current JOB value is less than or
equal to the
minimum JOB value. In this regard, MinlOB is a minimum threshold for JOB,
below
which the effect of JOB on glucose is considered to be negligible; hence not
needed to be
compensated.
1004771 As reflected in Equation 73, the process 1100 selects the adjusted
insulin
infusion rate to be the maximum of zero or the difference between the
uncompensated
insulin infusion rate and the calculated JOB rate (from task 1106). Note that
the
difference between PIDRate and 10BRate could be negative, as these values are
calculated from different sources. PIDRate is the controller calculated
infusion rate and
IOBRate is the accumulated active insulin in the body obtained from manual
boluses.
Accordingly, Equation 73 ensures that the AdjustedRate does not fall below
zero.
1004781 Next, the process 1100 may calculate, select, or otherwise
determine a final
insulin infusion rate (task 1110). In certain embodiments, the final insulin
infusion rate
(the final insulin dose 962 in FIG. 49) is calculated as indicated below:
FinalRate(n)=_ max(Basal,AdjustedRate(n)), PIDRate > Basal
(eq 74)
PIDRate(n), PIDRate <Basal
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As indicated by this expression, the process 1100 selects either the adjusted
insulin
infusion rate (AdjustedRate(n)), the uncompensated insulin infusion rate
(PIDRate(n)), or
the current basal rate (Basal) to serve as the final insulin infusion rate
(FinalRate(n)) for
the insulin infusion device. Here, PIDRate is the insulin infusion rate as
calculated by the
PID-IFB control module 906 and Basal is the current pre-programmed pump basal
rate.
Accordingly, task 1110 selects the final insulin infusion rate to be equal to
the
uncompensated insulin infusion rate when the current basal rate is greater
than or equal to
the uncompensated insulin infusion rate. In contrast, when the current basal
rate is less
than the uncompensated insulin infusion rate, task 1110 selects the final
insulin infusion
rate to be either the current basal rate or the adjusted insulin infusion
rate, whichever is
higher.
1004791 In the context of task 1110, the PIDRate is used as the FinalRate
(when
PIDRate is less than or equal to Basal) to allow the controller to "apply
brakes" (in other
words, suppress insulin delivery rate) in order to prevent any potential
hypoglycemia. On
the other hand, when PIDRate is greater than Basal, the FinalRate will be the
maximum
of Basal or AdjustedRate, which ensures that the insulin adjustment only
accounts for the
insulin coming from boluses, and not the basal. A lower bound (i.e., the value
of Basal) is
applied to the FinalRate when PIDRate is greater than Basal; this lower bound
is utilized
to prevent over-compensation of insulin on board under these circumstances.
1004801 The process 1100 may continue by communicating or otherwise providing
the
final insulin infusion rate, FinalRate(n), to the insulin infusion device
(task 1112). For
embodiments where the process 1100 is executed natively by the insulin
infusion device
itself, then the process 1100 may simply provide the final insulin infusion
rate to the
processing logic or fluid delivery control module of the infusion device. In
turn, the
insulin infusion device responds by regulating delivery of insulin in
accordance with the
final insulin infusion rate.
1004811 This description assumes that the process 1100 is repeated for each
sampling
time. For the next sampling time, therefore, the value of 17 may be
incremented by one (or
by any desired amount) to establish an index for the next iteration of the
process 1100
(task 1114). Thereafter, the process 1100 may return to task 1102 to obtain
the newest
input data values and to repeat the various tasks described above.
Accordingly, the
process 1100 facilitates regulation of insulin delivery to the body of the
user in a
controlled and ongoing manner by continuously adjusting the final insulin
infusion rate
while the system is operating in the closed-loop mode.
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[00482] In certain embodiments, it may be desirable to adjust some of the
parameters
utilized by the JOB compensation module 910 if doing so would improve
performance.
The nominal values for these parameters, together with exemplary allowable
ranges, are
shown in Table 3.
Parameter Nominal Value Lower Bound Upper Bound
CurveSpeed 6 1 8
GainlOB 1.25 0 5
MinIOB 1 0 500
Table 3: Adjustable Parameters For the IOB Compensation Module
[00483] Insulin Delivery Timeout Module
[00484] The insulin delivery timeout module 912 is suitably designed and
configured
to continuously monitor (during the closed-loop mode) if the patient is
receiving insulin
at the insulin limit (Umax) or no insulin (Urn/n, which may be defined as
insulin delivery
at little to no Units/Hour) for a prolonged period of time. If one of these
insulin delivery
conditions is detected, the system will issue a warning and continue operating
under the
closed-loop mode. As mentioned previously, the insulin delivery timeout module
912
may process the insulin delivered 960 as an input.
[00485] Accordingly, the insulin delivery timeout module 912 introduces an
additional
safeguard that checks for a series of steps as described below for the
delivery of insulin at
the insulin limit (Um ax Timeout) or no insulin (Umin Timeout) for a prolonged
period of
time. This is achieved by calculating the total amount of insulin delivered by
the system
during the closed-loop mode in a pre-specified moving window that is
identified as the
insulin time window.
[00486] Regarding the Umin Timeout condition, once the insulin time window for
Umin (which may be defined as delivering insulin at zero Units/Hour) has been
reached
from the start of the closed-loop mode, the system will monitor the amount of
insulin
being delivered at the user specified insulin time window and compare it with
the amount
that could have been delivered if operating at the patient's basal rate for
the same time
span, as shown in the following logical expression.
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Pump Delivery Rate =
FinalRate, if nmin > (MinDeliveryTo11100) x Urals%lin f 14
Alert, if tq,iinmin < (MinDeliveryTo1/100)x Urasinar (eq 75)
Here, Pump Delivery Rate (Units/Hour) is the infusion rate, which is either
equal to the
FinalRate from Equation 74 (i.e., the infusion rate calculated by the
controller during the
closed-loop mode), or a pre-programmed overnight basal rate that is used
during open-
loop operation. The quantity UrZmin is the total amount of insulin delivered
(in Units)
by the closed-loop control algorithm in a user-specified insulin time window
for Umin,
and the quantity Csnaftlin is the total amount of insulin that could be
delivered if
operating at a pre-programmed overnight basal rate in the same insulin time
window for
Urn/n. The parameter MinDeliveryTol is a user-specified tolerance, in
percentage of
U 1Bgaisnal i n , that the system has to deliver in order to stay in the
closed-loop mode.
[00487] In accordance with this particular example, closed-loop control
continues as
long as the total amount of insulin delivered during the insulin time window
(which is set
to 120 minutes for this example) by the system is greater than the total
amount of insulin
that might have been delivered if operating at five percent (which is the
default minimum
tolerance for this example) of basal. Moreover, a fail-safe alert is triggered
once the total
amount of insulin delivered during the insulin time window (120 minutes) by
the system
is less than five percent of basal.
[00488] Regarding the Umax Timeout condition, once the insulin time window for
Umax has been reached from the start of the closed-loop mode, the system will
monitor
the amount of insulin being delivered at the user specified insulin time
window and
compare it with the amount that might be delivered if operating at the Unica
rate for the
same time span, as shown in the following logical expression.
Pump Delivery Rate =
{ .- FinalRate, if U71/Yoirkfax -
(MaxDeliveryTo11100) x 14,tr"
(MaxDeliveryTo1/100) x UAlax (eq 76)
Alert, if uroitnmax >
Here, Pump Delivery Rate is the infusion rate, which is equal to either the
FinalRate or a
pre-programmed overnight basal rate that is used during operation in the open-
loop mode.
i
The quantity UrWnMaxot is the total amount of insulin delivered (in Units)
by the closed-
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loop control algorithm in a user-specified insulin time window for Umax, and
the quantity
UwinaXmax is the total amount of insulin that could have been delivered in the
M
user-specified moving window for Umax if operating at a calculated Umax rate.
The
parameter MaxDelivegTol is a user-specified tolerance, in percentage of
Umwainxmax, that
the system must adhere to in order to stay in the closed-loop mode.
[00489] In accordance with this particular example, closed-loop control
continues as
long as the total amount of insulin delivered during the insulin time window
(which is set
to 600 minutes for this example) by the system is less than the total amount
of insulin that
might have been delivered if operating at 95% (which is the default maximum
tolerance
for this example) of Umax. Moreover, a fail-safe alert is triggered once the
total amount
of insulin delivered during the insulin time window (600 minutes) by the
system is greater
than the total amount that might have been delivered if operating at 95% of
Umax.
[00490] In certain embodiments, it may be desirable to adjust some of the
parameters
utilized by the insulin delivery timeout module 912 if doing so would improve
performance. The nominal values for these parameters, together with exemplary
allowable ranges, are shown in Table 4.
Parameter Nominal Value Lower Bound Upper Bound
Insulin Time Window for Untin 120 minutes 30 minutes 600
minutes
Insulin Time Window for Umax 600 minutes 30 minutes 600
minutes
MinDeliveryTol 5% 0% 100%
MaxDeliveryTol 95% 0% 100%
Table 4: Adjustable Parameters For the Insulin Delivery Timeout Module
[00491] Model Supervisor Module
1004921 The model supervisor module 914 is similar to the insulin delivery
timeout
module 912 in that it monitors and polices the system during closed-loop
operation. In
practice, closed-loop systems are only aware of signals (inputs) that are
being provided by
the measurement device(s). If measurements deviate from true values, the
control system
may react to the deviation. When using continuous glucose sensors for
diabetes, the
sensors provide the measurements to the closed-loop control system and, based
on these
measurements, insulin is delivered to the subject. Accordingly, sensor
performance and
integrity should be closely monitored. Fortunately, there is a relationship
between the
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insulin and meal intake to the glycemic response. This relationship can be
translated into
a mathematical model that is able to predict the sensor glucose response based
upon the
insulin delivered. The sensitivity of sensor glucose to insulin delivered is
patient-specific
(the sensitivity can usually be learned over a period of three to six days for
each patient).
[00493] The model supervisor module 914 uses a mathematical model that enables
individualization of a patient's unique blood glucose time-dependent response.
The model
describes the sensor glucose time-dependent response as a function of insulin
and meal
intake. The exemplary mathematical model described herein has a number of
benefits and
advantages: it is linear, physiologically-based, and includes only parameters
that have
direct connection to measurable data (sensor glucose and insulin delivered).
These
features are important because a linear model is easy to analyze and predict.
Moreover, a
physiological-based model facilitates an understanding of the origin of the
predictions
(e.g., insulin sensitivity, meal intake, etc.), and use of measureable data
reduces the need
to estimate unobserved variables (e.g., metabolism, cell activity, etc.).
[00494] FIG. 54 is a diagram that defines certain time events for the model
supervision. The label "present" indicates the most recent sampling time or
sampling
period 1120, and k is equal to the present sampling time minus a period
corresponding to
a length of prediction horizon (LPH) in sampling times. FIG. 54 also indicates
a period
corresponding to a length of training horizon (LTH) in sampling times, which
refers to a
model training period. Insulin history is defined as the length of data needed
to estimate
the plasma insulin. In order for the model supervisor module 914 to be able to
estimate a
fault, it considers the records of the insulin delivered over the past insulin
history plus the
LTH and the LPH sampling periods, and at least 80 percent of the Isig
(electrical signal)
measurements from k-LTH and k.
[00495] As described in more detail below, the model supervisor module 914
considers
a "moving window" that includes a historical time period 1122 that is defined
from the
present (most recent sampling period 1120) back to the beginning of the LTH.
The
moving window considered by the model supervisor module 914 may also include
insulin
history that precedes the LTH, as depicted in FIG. 54. Data obtained during
each window
of time is processed and analyzed at or near the present time and preferably
before the
next sampling period has ended. Thus, at the end of each new sampling period,
the
"moving window" shifts by one sampling period such that the model supervisor
module
914 can consider the most recently obtained data for the current sampling
period while
disregarding the data that no longer appears within the updated window of time
(i.e., the
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oldest data is no longer considered). The historical time period 1122 may be
defined by
the LTH and the LPH, which for this example immediately follows the LTH (as
shown in
FIG. 54). The LPH may also be referred to herein as the "recent history
period" or the
"model prediction period" for reasons that will become apparent from the
following
description. The LTH may also be referred to herein as the "distant history
period" or the
"model training period" for reasons that will become apparent from the
following
description. In this regard, the LTH (distant history period) corresponds to a
period of
time from a begin-training sampling period 1124 to an end-training sampling
period
1126, inclusive, while the LPH (recent history period) corresponds to a period
of time
from a begin-prediction sampling period 1128 to the most recent sampling
period 1120,
inclusive. Accordingly, by definition the current sampling period (i.e., the
most recent
sampling period 1120) resides within the LPH. For this particular example, the
begin-
prediction sampling period 1128 corresponds to the end-training sampling
period 1126.
Alternatively, the begin-prediction sampling period 1128 may immediately
follow the
end-training sampling period 1126.
[00496] FIG. 55 is a flow chart that illustrates an exemplary embodiment of a
sensor
model supervision process 1150, which may be performed by the model supervisor
module 914. The process 1150 is shown and described in a simplified manner
that
focuses on functionality for ease of understanding. Certain aspects of the
process 1150 arc
addressed in more detail below with reference to particular representations of
the model
supervisor module 914.
[00497] The process 1150 represents one iteration that is performed for a
current
sampling point or time, which corresponds to the most recent sampling period.
This
example assumes that the insulin infusion device is already operating in the
closed-loop
mode (task 1152) to deliver insulin to the body of the user, and that the
process 1150
receives relevant data in accordance with a predetermined schedule (e.g., a
sampling
period of five minutes). Accordingly, the process 1150 receives, obtains, or
accesses a
variety of inputs that may have an influence on the operation of the model
supervisor
module 914 (task 1154). For example, the process 1150 may receive at least the
following
data for the current sampling period: current insulin-delivered data that
indicates an
amount of insulin delivered by the insulin infusion device during the most
recent
sampling period; current sensor data that indicates a current sensor glucose
value for the
user, which corresponds to the most recent sampling period; and a current
sensor
calibration factor, which may be needed to compensate for recent meter-based
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calibrations. Any amount of historical data could also be received during task
1154 if so
desired. Thus, some amount of redundancy may be built into the system (which
may be
desirable to account for missed transmissions, lost packets, or the like). The
sensor data
may be received and processed in any suitable form. For example, a continuous
glucose
sensor may generate Isig (electrical current) values that can be mapped to
sensor glucose
values. The model supervisor module 914 may be suitably configured to process
Isig
values directly, or it could translate or map the raw big values into any
desired
representation.
1004981 The process 1150 may also access or retrieve historical data that was
received
for past sampling periods (task 1156). Task 1156 may represent an
initialization routine
that populates a grid, matrix, or other type of database structure as needed
to prepare the
model supervisor module 914 for the various calculations, analyses, and
functions
described in more detail below. It should be appreciated that subsequent
iterations of the
process 1150 (which are performed in an ongoing manner during the closed-loop
mode)
need not repeat the initialization of the historical data. Rather, task 1156
may simply
adjust the data history to reflect newly received data. For the embodiments
described
here, the following historical data may be processed by the model supervisor
module 914,
without limitation: historical insulin-delivered data for the user; and
historical sensor
glucose values for the user. The historical insulin-delivered data may
correspond to
amounts of insulin delivered by the insulin infusion device during each
historical
sampling period of interest, and the historical sensor glucose values may
correspond to
respective sensor glucose measurements obtained during each historical
sampling period
of interest. In certain implementations, each historical sensor glucose value
may be
associated with or derived from a historical Isig value and a sensor
calibration factor.
[00499] The process 1150 is iterative in nature, and each iteration considers
data
associated with the defined historical period of time (see FIG. 54).
Accordingly, the
process 1150 may define the model training period and the model prediction
period for
the historical period of time (task 1158). In this regard, task 1158 may
identify or
designate which data samples fall within the model training period (the LTH in
FIG. 54)
and/or which data samples fall within the model prediction period (the LPH in
FIG. 54).
Task 1158 may also serve to identify or designate "stale" data samples that
need not be
considered going forward. In practice, if data for the oldest sampling period
is missing for
some reason, then the process 1150 can make appropriate adjustments (e.g.,
search for the
closest available data sample, wait for the next sampling period, or the
like).
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1005001 Next, the process 1150 processes at least some of the historical data
to
determine a best-matched solution to a sensor glucose prediction model (task
1160). Task
1160 may be considered to be a training procedure that finds the best-fitting
sensor
glucose prediction function, which in turn can be used to check (predict) the
integrity and
quality of the glucose sensor. In certain embodiments, the sensor glucose
prediction
model is expressed as a fourth order ordinary differential equation that, when
solved
given the initial conditions, provides model-predicted sensor glucose values.
Notably,
task 1160 uses the actual sensor glucose values obtained during the model
training period
(and does not use any of the actual sensor glucose values obtained during the
model
prediction period) to determine which candidate solution will be selected as
the best-
matched solution. Conceptually, task 1160 generates a plurality of curves (or
discrete
values that may be used to visualize curves for purposes of this explanation)
and
compares the portion of the curves within the model training period to the
actual sensor
glucose values obtained during the model training period. In an ideal scenario
with a
perfect match, one of the generated curves will precisely track the actual
sensor glucose
values within the model training period. In practice, however, the generated
curves will
deviate from the actual sensor glucose values. Accordingly, task 1160
identifies the
calculated curve that best matches the actual sensor values. It should be
appreciated that
this best-matching curve also includes model-predicted sensor glucose values
that extend
beyond the model training period and into the model prediction period.
[00501] The process 1150 may continue by comparing at least one historical
sensor
glucose value obtained during the model prediction period to at least one
corresponding
predicted sensor glucose value of the best-matched solution (task 1162). In
certain
embodiments, task 1162 checks only one actual sensor glucose value: the
current sensor
glucose value obtained for the most recent sampling period. In other
embodiments, any or
all of the sensor glucose values obtained during the model prediction period
could be
analyzed during task 1162. The straightforward example described here only
considers
the current sensor glucose value such that the comparison in task 1162 is
simple and
straightforward. In this regard, task 1162 may calculate a difference between
the current
sensor glucose value (i.e., the most recent historical value) and the
predicted current
glucose value for the most recent sampling period (the difference may be
expressed as an
absolute value), and the process 1150 may continue by comparing the calculated
difference to a threshold error amount (query task 1164). In other
embodiments, the
comparison performed during task 1162 may involve a more advanced methodology,
e.g.,
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curve-fitting that considers more than one sampling point in the model
prediction period,
statistical analyses, or the like. For example, rather than calculating error
on a
point-by-point basis, the process 1150 could utilize any appropriate
methodology to
determine whether or not the historical sensor glucose values in the model
prediction
period deviate (by at least a threshold amount) from the corresponding model-
predicted
values in the best-matched solution.
[00502] If the calculated error between the model-predicted glucose value(s)
and the
corresponding actual historical sensor glucose value(s) is less than or equal
to the error
threshold, or otherwise satisfies the predetermined criteria monitored by the
model
supervisor module 914, then the "No" branch of query task 1164 is followed and
the
process 1150 continues to the next sampling period (task 1166). At this point,
the process
1150 returns to task 1152 such that the core of the process 1150 can be
repeated to
consider the data received for the next sampling period. Thus, the oldest data
considered
by the previous iteration of the process 1150 is disregarded, the newly
received data is
designated as the "most recent" data, and the historical time period or
"analysis window"
for the current iteration of the process 1150 shifts by one sampling period
(see FIG. 54).
[00503] If the calculated error exceeds the threshold error amount (the "Yes"
branch of
query task 1164), then the process 1150 may generate an alert, an alarm,
and/or a message
(task 1168). In practice, an alert, alarm, or message can be initiated by the
model
supervisor module 914 for rendering, annunciation, delivery, playback, etc.
For example,
an alert could be presented at the insulin infusion device, at a remote
monitoring station,
at a handheld controller device, or the like. In certain embodiments, the
process 1150
switches from the closed-loop mode to the open-loop mode (or to some type of
safe
operating mode with reduced insulin delivery) when the threshold error amount
is
exceeded (task 1170).
[00504] One important aspect of the process 1150 relates to the manner in
which the
best-matched sensor glucose prediction model is chosen (see task 1160). In
this regard,
FIG. 56 is a flow chart that illustrates an exemplary embodiment of a sensor
model
training process 1180, which may be performed in conjunction with the sensor
model
supervision process 1150 depicted in FIG. 55. The process 1180 is shown and
described
in a simplified manner for ease of understanding. Certain aspects of the
process 1180 are
addressed in more detail below with reference to particular implementations of
the model
supervisor module 914.
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[00505] As mentioned previously, the exemplary sensor glucose prediction model
utilized here is expressed as a fourth order ordinary differential equation.
In accordance
with conventional mathematics, the model-predicted sensor glucose values (G)
in time are
calculated as a function of the two model prediction initial conditions Go and
dGo. Here,
Go is the estimated sensor glucose value for the begin-training sampling
period 1124 (the
start of LTH in FIG. 54), and dG0 is the derivative of Go. Therefore,
different initial
condition values result in different solutions to the sensor glucose
prediction model; each
distinct set of initial conditions corresponds to a different prediction
model. For the sake
of processing efficiency, the model supervisor module 914 imposes limits and
boundaries
on the initial condition values to calculate and analyze a manageable number
of candidate
solutions. In this regard, the sensor model training process 1180 may begin by
calculating
a range or boundary for each bounded initial condition (task 1182).
[00506] For the exemplary embodiment presented here, the initial condition dG0
is
bounded in a simple manner that is based on a predetermined parameter (which
may be
adjustable): dG0 = +grad_bound. In contrast, the boundary for the initial
condition Go
is based on (or is otherwise influenced by) a baseline historical sensor
glucose value
obtained during the model training period, such as the sensor glucose value
that was
obtained during the begin-training sampling period 1124. Thus, the process
1180 may
identify, from the historical sensor glucose values, the baseline sensor
glucose value to be
used for purposes of calculating the boundary for the initial condition Go: Go
=
SG k-LTH + 0.14 = SG k_LTH, where SG k-LTH is the baseline sensor glucose
value obtained
for the earliest sampling period in the historical time period under analysis
(see FIG. 54).
Notably, the boundary for Go is a function of the baseline sensor glucose
value, which
may vary in an ongoing manner during operation of the system, and which may
vary from
one iteration of the process 1180 to another. In practice, if the sensor
glucose data is
missing for the begin-training sampling period 1124, then the process 1180 can
take
appropriate measures, e.g., search for the nearest available sensor glucose
data point, wait
for the next sampling period, etc.
[00507] The process 1180 may then continue by determining, calculating, or
otherwise
obtaining the next set of initial conditions (task 1184). The manner in which
the process
1180 selects and steps through the different initial conditions is unimportant
in this
context. The current set of initial conditions is used to calculate a
candidate solution to the
sensor glucose prediction model (task 1186). As mentioned above, each
candidate
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solution is calculated as a function of the two bounded initial conditions.
Moreover, each
candidate solution is calculated as a function of estimated plasma insulin for
the user,
which in turn is calculated as a function of an amount of insulin delivered to
the user.
Accordingly, task 1186 may estimate plasma insulin for the user based on: the
current
insulin-delivered data (obtained for the most recent sampling period); the
historical
insulin-delivered data; and an insulin basal rate for the user. In practice,
task 1186
considers the total insulin (basal, bolus, and any other insulin delivered)
for all sampling
periods. This allows the process 1180 to obtain the candidate solution to the
sensor
glucose prediction model based at least in part on the estimated plasma
insulin and based
at least in part on the baseline sensor glucose value obtained at the earliest
sampling
period under analysis.
1005081 The process 1180 may continue by generating a training error value,
quantity,
or function for the candidate solution (task 1188). The training error may be
calculated by
comparing predicted sensor glucose values from the candidate solution to the
corresponding historical sensor glucose values, to obtain a metric that
indicates how
closely the predicted values match the actual values. In certain embodiments,
the training
error is based only on predicted values and actual values for the model
training period
(LTH in FIG. 54), and, therefore, task 1188 does not consider any predicted or
actual
values for the model prediction period (LPH in FIG. 54).
[00509] If the process 1180 has considered all of the initial condition
combinations
(the "Yes" branch of query task 1190), then the process 1180 may proceed to a
task 1192.
If more sets of initial conditions remain (the "No" branch of query task
1190), then the
process 1180 may return to task 1184, retrieve the next set of initial
conditions, and
continue as described above. Task 1192 is performed after a plurality of
different
candidate solutions have been calculated, using the different sets of initial
conditions.
Task 1192 may be performed to select the best-matching candidate solution from
the
plurality of calculated solutions. For this particular embodiment, the
selection is based on
the training errors generated during task 1188. For example, the candidate
solution having
the lowest training error may be selected as the best-matching solution.
[00510] It should be appreciated that the process 1180 need not be performed
in the
illustrated sequence, and that some tasks could be performed in parallel. For
example, the
calculation of the training errors (task 1188) may instead be performed after
all of the
candidate solutions have been obtained and saved. Moreover, the process 1180
could be
designed to immediately eliminate candidate solutions (following completion of
task
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1188) that have a training error that exceeds a predetermined error threshold.
As another
option, the process 1180 could be designed to immediately designate a
candidate solution
as the best-matched solution if the associated training error satisfies
certain criteria.
[00511] The foregoing concepts and methodologies may be implemented in a
practical
embodiment of the model supervisor module 914. The following description
relates to
two possible embodiments that implement the general concepts presented above.
It should
be appreciated that the particular embodiments described below are not
exhaustive, and
that the description of the embodiments is not intended to limit or restrict
the scope or
application of the subject matter presented here.
[00512] Model Supervisor Module: First Representation
[00513] The model supervisor module 914 is suitably designed and configured to
detect potentially faulty sensor measurements. The model supervisor module 914
may
utilize a mathematical model that is trained offline. For example, parameters
that could be
estimated offline estimated include, without limitation: K1 (insulin gain in
mg/dL per U/h;
ri (first insulin time constant, in minutes); r2 (second insulin time
constant, in minutes);
Masai (basal insulin, in U/h); and SGbase (blood glucose (BG) at fasting, in
mg/dL, when
Masai insulin is delivered.
[00514] The model supervisor module 914 trains the model prediction initial
conditions, Go and dGo every sampling time. Go and dGo represent the BG
(mg/dL) and
BG derivative (mg/dUmin) estimate values at k-LTH (see FIG. 54), where LTH is
the
length of the training data (sampling times) and k is equal to the present
sampling time
minus LPH. In this context, LPH is the length of the prediction horizon in
sampling times.
Go and dGo estimations are bounded as formulated by the expressions
collectively
identified below as Equation 77. Note that these initial conditions and their
boundaries
were also described above with reference to task 1182 of the sensor model
training
process 1180.
Go = CG k _LTH 0.14 = CG Mk_LTH
(eq 77)
dG0 = + grad_bound
For Equation 77, CGAlk-mi is the CGM measurement at sampling time k-LTH, and
grad bound is a predefined absolute maximum BG derivative in time (mg/dL/min).
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1005151 The model supervisor module 914 estimates plasma insulin, 4õ at k-LTH
using
the insulin history records from k-LTH-insulin history and k-LTH (see FIG. 54)
in
accordance with Equation 81. Having the estimated /p, Go, and dGo, a model
prediction is
generated from present-LTH-LPH, until present (as described above for task
1186 of the
sensor model training process 1180). The model prediction enables the
calculation of two
values: Terr and Perr. Terr is defined as the mean sum square of errors
between the
model prediction and the CGM records from k-LTH and k (Equation 78). Perr is
defined
as the absolute mean error between the model prediction and the CGM records
from k and '
present (Equation 79). Note that Terr is one type of training error, which was
described
above for task 1188 of the process 1180, and Perr is one type of prediction
error, as
described above for task 1162 and query task 1164 of the sensor model
supervision
process 1150. A fault is defined when Perr < err] and Terr > err2 (Equation
80).
Elic=k_LTH(Modeli¨CGMi) 2
Terr = _________________________________________ (eq 78)
LTH
EI-FLPH Modeli¨CGMi)
Perr = abs( E¨k LPH (eq 79)
1, if Terr < err1 and Perr > err2
Fault = 0, else if Terr < err2 or Perr > err1
1
¨1, if not enough data records available (eq 80)
In Equation 80, Fault 1 indicates a faulty sensor, Fault 0 indicates a non-
faulty sensor,
and Fault -1 indicates that there is not enough information to decide.
Referring again to
FIG. 55, Fault 1 corresponds to the "Yes" branch of query task 1164.
1005161 In certain embodiments, some of the parameters used by the model
supervisor
module 914 may be adjustable. Table 5 identifies the adjustable parameters,
along with
some exemplary values for the parameters.
Parameter Symbol Typical Starting
Minimum Value Maximum Value
Value
Insulin gain K1 -100 -500 -1
Insulin time ri 30 0.1 150
constant
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Insulin time r2 150 0.1 150
constant
Fasting BG SGbase 120 50 300
Basal insulin at lbasal 1 0.1 3
fasting BG
Training data err! 5 1 100
error
Prediction data err2 20 1 100
error
Length of LTH 8 5 30
training data
Length of LP!! 3 1 20
prediction data
Length of insulin Insulin History 48 30 60
data
BG maximum grad bound 5 1 8
absolute
derivative
Table 5: Adjustable Parameters For the Model Supervisor Module
[00517] The following equations describe the mathematical model equations in
Laplace transform form:
In(s) ¨ (50s+1)(7os-1-1) ipos a a + dlpofl) (eq
81)
In this expression, cc=3500, 3-120, and fp is the /p in deviation form. ipo
and dip are the
ip and derivative initial conditions, respectively.
[00518] All the insulin states are formulated in deviation form from the given
insulin
value lbasal as it is expressed by the following Equation 82:
ix = ¨ Ibasal (eq 82)
In Equation 82, x represents D, in, or P.
1005191 The following Equation 83 expresses BG in deviation form from SGbase.
Note that Equation 83 represents one suitable expression for the sensor
glucose prediction
model, which is a fourth order ordinary differential equation.
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6(S) ¨ __________ (Ki = ip ____ (60 = a + (6o = s + A) = fl +
(ris+1)2s+1) (50s+1)(70s+1) -
(k) = S2 CI60 = S) = X + (60 = s3 + d60 = s2) = 8)) (eq 83)
In Equation 83, the following relationships hold:
a = 120 + r1 + T2
= 3500+ 120Ti +120r2 + TiT2
x = 3500Ti + 3500T2 + 120T1T2
6 = 3500T1T2
Moreover, in Equation 78, d, Kb do, dGo, rj, and 1-2 are the BG in deviation
form from
SGbase, the insulin gain, the BG initial conditions in deviation form, the BG
derivative
initial conditions, and two time constants, respectively.
[00520] Model Supervisor Module: Second Representation
[00521] In accordance with some embodiments, the functionality of the model
supervisor module 914 can be represented as follows. As mentioned above, the
model
supervisor module 914 estimates the user's glucose concentration in real-time
based on
the insulin delivered, the sensor Isig values, and sensor calibration factors.
If the
model-predicted sensor glucose value (SG) and the actual SG value differ
significantly,
the system will trigger a fail-safe alert that indicates that the collected
data contains
unexplained behavior, which may in turn be associated with a faulty sensor
and/or insulin
delivery, or an unannounced meal intake.
[005221 The time frames and reference time periods for the model supervisor
module
914 are defined as shown in FIG. 54. The methodology performed by the model
supervisor module 914 uses data packets received for past time frames to
estimate plasma
insulin and model-predicted glucose in order to estimate the fault conditions.
The
sampling time is the time interval between two consecutive data packets, which
for this
particular example is five minutes. The insulin history in FIG. 54 corresponds
to a defined
past time frame that is needed to estimate plasma insulin (for this example,
the insulin
history corresponds to four hours or 48 sampling periods). The length training
horizon
(LTII) for this example includes 24 data packets, which corresponds to a past
time frame
of 120 minutes. The length of predicted horizon (LH?) for this example
includes 24 data
packets, which corresponds to a past time frame of 120 minutes. In FIG. 54, k
is equal to
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the present number of data packets minus LPH, and "present" indicates the most
recent
sampling time.
[00523] The following equations describe the mathematical model in Laplace
transform form. Equation 84 provides an estimate of the plasma insulin, and
Equation 85
provides the model-predicted SG values. Accordingly, the model supervisor
module 914
in accordance with this particular embodiment estimates the plasma insulin as
follows:
In(s) ¨ (sasi i)(7os+1) (ID + ipoS E dipoy) (eq 84)
For this example, c = 3500, y = 120, ip is the estimated plasma insulin in
deviation form,
(s) refers to Laplace transform form, and ID is the insulin delivered from the
system in
deviation form. Moreover, ipo is the estimated plasma insulin in deviation
form for the
sampling time identified as k-LTH (see FIG. 54), dip is the derivative of the
estimated
plasma insulin, and a and 13 are constants.
[00524] The insulin states described above are formulated in deviation form
from a
given insulin value Ibasal as it is expressed by the following equation:
ix =I - Ibasal (eq 85)
In Equation 85, x represents D or P (where D refers to insulin delivered and P
refers to
plasma insulin), and hasai,o is the estimated basal rate defined for each user
to bring the
patient to a fasting blood glucose (FBG) of the value FBG0 (in mg/dL).
[00525] For this second embodiment, the model-predicted sensor glucose value,
d, in
time is calculated in accordance with Equation 83 and the associated
relationships, as
described for the first embodiment of the model supervisor module 914. In this
regard, d
is the model-predicted SG value in deviation form from FBG0 (estimated blood
glucose
using meter blood glucose readings at the end of the night period), (s) refers
to Laplace
transform form, il, and I are the two insulin time constants identified for
each patient,
which are related to how fast a patient reacts to insulin, k is the insulin
gain, and ip is the
estimated plasma insulin in deviation form. Moreover, a is the estimated SG
value (in
mg/dL) in deviation form for the sampling time of k-LTH (see FIG. 54), as
calculated in
accordance with Equation 86 below, and dGo (calculated by Equation 87 below)
is the
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derivative of the estimated SG value (in mg/dL/min) for the sampling time of k-
LTH. The
constants a, 13, x, and 8 are calculated as set forth above in the context of
Equation 83.
[00526] The estimated blood glucose values are calculated as a function of the
model
prediction initial conditions, Go and dGo. For this particular embodiment, the
estimations
for Go and dGo are bounded as formulated by the following equations. Note that
these
initial conditions and their boundaries were also described above with
reference to task
1182 of the sensor model training process 1180.
Go = SGk¨LTH 0.14 = SGk_LTH (eq 86)
dGo = + grad_bound (eq 87)
Here, Go is the estimated SG value (in mg/dL) value for the sampling time of k-
LTH,
SGk_LTH is the SG measurement for the sampling time of k-LTH, dG 0 is the
derivative of
the estimated SG value (in mg/dL/min) for the sampling time of k-LTH, and
grad_bound
is a predefined absolute maximum SG derivative in time (mg/dL/min). For
certain
embodiments, grad_bound is a fixed parameter. For the example presented here,
grad_bound has a value of 5 mg/dL/min.
[00527] The model prediction facilitates the calculation of two values: Terr
and Perr.
Terr is defined as the mean absolute error between the model predicted SG
values and the
actual SG records for the sampling time identified as k-LTH and k as
calculated by
Equation 88 below. Perr is defined as the mean absolute error between the
model
predicted SG values and the actual SG records for sampling times identified as
k to
present (see FIG. 54) as calculated by Equation 89 below.
abs(Modeli-SGi)
t=k-LTH
Terr (eq 88)
LTH
Here, Terr is defined as the mean absolute error between the model predicted
SG values
(Model) and the SG records (SG) for the sampling time identified as k-LTH and
k.
abs(Modelpresent¨SGpresent)
Perr = = 100% (eq 89)
SGpresent
Here, Perr is defined as the percentage of error between the model prediction
and the SG
measurement at the present (most recent) sampling time.
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[00528] In accordance with this particular implementation, the model
supervisor
module 914 estimates the fault scenario based on Equation 90, where Fault 1
signifies a
faulty sensor, Fault 0 indicates a non-faulty sensor, Fault 3 indicates a
training error, and
Fault -1 indicates that there is not enough data available to make a
determination.
1, if Terr < err1 and Perr > err2
0, if Perr err2 or Terr err1
Fault = (eq 90)
3, if Terr > err3
k. ¨1, if not enough data available
In Equation 90, err] is the upper threshold for the mean absolute error (see
Equation 88).
Thus, if the training error is above this threshold, a fault cannot be
triggered because the
credibility of the training is suspect. The err2 is the lower threshold for
Equation 89. If
the prediction value of the model and the sensor measurement at present are
above this
threshold and the training error is less than err], then a fault will be
triggered. The err3
defines a lower threshold for the training period. If Equation 88 indicates a
value that is
above this threshold, then a warning associated with poor training can be
triggered.
[00529] FIG. 57 is a diagram that illustrates exemplary sensor conditions
corresponding to a non-faulty sensor (Fault 0) and a faulty sensor (Fault 1).
The common
horizontal axis indicates the present sampling time at the far right, along
with the time
periods identified by LPH and LTH. The sampling time 1202 corresponds to the
oldest
data considered by the model supervisor module 914 at the present time.
Accordingly,
historical data 1204 for sampling times that occurred before the sampling time
1202 is
disregarded.
[00530] The top plot 1206 in FIG. 57 is indicative of a non-faulty sensor
(Fault 0), the
middle plot 1208 is indicative of a faulty sensor (Fault 1), and the bottom
plot 1210
depicts the insulin administered, which is needed in order to estimate the
plasma insulin
and to generate the model predicted SG values. In the plots 1206, 1208, the
solid line
1212 represents the model-predicted SG values, and the dots represent the
actual SG
measurements. The dashed vertical line 1214 represents the demarcation between
the
LTH time frame and the LPH time frame. The lines between the solid line 1212
and the
dots represent the difference (error) between the model-predicted SG values
and the
actual SG measurements. Dashed lines are utilized in the LPH time frame, which
corresponds to fifteen minutes or three sampling periods for this example.
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[00531] Referring to the top plot 1206, there is good agreement between the
model
predicted SG values (represented by the solid line 1212) and the actual SG
measurements
(represented by the dots). In other words, the actual measurements do not
deviate
significantly from the predicted values. In certain embodiments, the model
supervisor
module 914 only compares actual measurement values that are within the LPH
time
frame. In accordance with one exemplary embodiment, the model supervisor
module 914
determines the fault status based solely on the most recently obtained data,
i.e., the
information received for the last sampling time. For this example depicted in
FIG. 55,
Perr is less than or equal to err2. Thus, in accordance with Equation 90, the
model
supervisor module 914 returns Fault 1 and the system is commanded to remain in
the
closed-loop mode.
[00532] Referring to the middle plot 1208, of FIG. 57, there is good agreement
between the model predicted SG values and the actual SG measurements in the
LTH time
period (for this period, Terr is less than err] in Equation 90). Note,
however, that there is
a significant difference observed between the model predicted SG last value
and the
actual last SG measurement 1218 (Perr is greater than err2 in Equation 90). In
this
scenario, therefore, the model supervisor module 914 will issue a fail-safe
alert and/or
take other appropriate measures.
1005331 In certain embodiments, some of the parameters used by the model
supervisor
module 914 may be adjustable. Table 6 identifies some adjustable parameters
for this
embodiment, along with some exemplary values for the parameters.
Parameter Default Value Lower Bound Upper Bound
(mgidL/U/H) -100 -360 -49
FBGo (mat) 120 50 300
lbasal (U/H) 1 0.1 3
errl (mg/dL) 5 1 30
err2 (%) 50 20 100
err3 (mg/dL) 10 1 30
LTH (sampling times) 24 4 48
LPH (sampling times) 24 1 48
Table 6: Adjustable Parameters For the Model Supervisor Module
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[00534] Missed Transmission Module
[00535] The missed transmission module 916 continuously checks whether the
controller receiving data packets (including SG values) for processing. The
missed
transmission module 916 keeps the system operating in the closed-loop mode for
when
less than a stated number of data packets are missed (e.g., less than four
data packets in a
row, a total number of data packets that represent a timespan of less than 15
minutes, or
the like). During this time, the system will continue to calculate the insulin
dose using the
closed-loop control algorithm based on the last valid sensor glucose value or
sensor big
value. For missed data packets that represent a time longer than a lower time
threshold
and longer than an upper time threshold (e.g., between 15 and 60 minutes), the
missed
transmission module 916 switches the system to a pre-programmed safe basal
rate, which
may be defined as half the patient's nighttime basal rate. If the controller
starts receiving
data packets during the safe basal rate timeframe, the system will switch back
to the
closed-loop mode. For missed data packets that represent a time longer than
the upper
time threshold, however, the missed transmission module 916 switches the
system to the
open-loop mode to deliver a pre-programmed nighttime basal rate, which may be
set by a
healthcare provider or a caregiver.
[00536] The missed transmission module 916 cheeks for different scenarios
pertaining
to when and what kind of packet is lost during transmission. Different steps
are executed
depending on the type of lost transmission. The details of four different
scenarios are
described below.
[00537] Case 1
[00538] If the sensor Isig value and the SG value are both received by the
controller,
then:
(a) the sensor Isig is saved by the controller;
(b) the SG value is saved by the controller;
(c) a Zero Order Hold (ZOH) count is set to zero; and
(d) the system remains in the closed-loop mode as described previously.
[00539] Case 2
1005401 If the sensor Isig value is not received, but the SG value is received
by the
controller, then:
(a) the ZOH count is set to zero;
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(b) Isig is calculated by Equation 91 (see below) using the SG value and the
sensor
calibration factor; and
(c) the system remains in the closed-loop mode.
isigccac = (SG/CF') + 2 (eq 91)
[00541] Case 3
[00542] If the sensor Isig value is received, but the SG value is not received
by the
controller, then:
(a) the ZOH count is set to zero;
(b) SG is calculated by Equation 92 (see below) using the Isig value and the
sensor
calibration factor; and
(c) the system remains in the closed-loop mode.
SGcaic = (Isig ¨ 2) x CF' (eq 92)
[00543] Case 4a
1005441 If neither the sensor Isig value nor the SG value are received by the
controller
(i.e., both values are not received), and if:
ZOH Count < ZOH Count Max
then:
(a) the ZOH count for the sensor Isig and SG is calculated based on previous
values;
(b) ZOH Count = ZOH Count +1;
(c) TimeoutCount = 0; and
(d) the system remains in the closed-loop mode.
[00545] Case 4b
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1005461 If neither the sensor lsig value nor the SG value are received by the
controller
(i.e., both values are not received), and if:
ZOH Count > ZOH Count Max
then:
(a) an "invalid" place holder for the sensor lsig and SG value is saved;
(b) the system remains in the closed-loop mode, but switches to a temporary
safe
basal rate, which is half the patient's night time basal rate when in the open-
loop mode;
(c) if a packet is received by the system while it is delivering the safe
basal rate, the
system will transition back to the closed-loop mode;
(d) for every minute that the system is delivering the safe basal rate, a
TimeoutCount
is incremented: TimeoutCount = TimeoutCount + /;
(e) if TimeoutCount > Timeout Count Max, then the system switches to the open-
loop
mode.
1005471 In accordance with certain embodiments, ZOH Count Max has a fixed
value of
two, and Timeout Count Max has a fixed value of 45, although different values
may be
used as appropriate to the particular implementation. Moreover, the safe basal
rate used
by the missed transmission module 916 may be adjustable. In this regard, the
safe basal
rate may be adjustable within a range of about zero to five Units/Hour.
1005481 While at least one exemplary embodiment has been presented in the
foregoing
detailed description, it should be appreciated that a vast number of
variations exist. It
should also be appreciated that the exemplary embodiment or embodiments
described
herein are not intended to limit the scope, applicability, or configuration of
the claimed
subject matter in any way. Rather, the foregoing detailed description will
provide those
skilled in the art with a convenient road map for implementing the described
embodiment
or embodiments. It should be understood that various changes can be made in
the
function and arrangement of elements without departing from the scope defined
by the
claims, which includes known equivalents and foreseeable equivalents at the
time of
filing this patent application.
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