CA1121243A

CA1121243A - Blood glucose control apparatus

Info

Publication number: CA1121243A
Application number: CA000315727A
Authority: CA
Inventors: Anton H. Clemens
Original assignee: Miles Laboratories Inc
Current assignee: Bayer Corp
Priority date: 1977-11-25
Filing date: 1978-11-02
Publication date: 1982-04-06
Also published as: SE7812146L; US4151845A; FR2409741B1; IT7852043A0; NL7811583A; JPS5717539B2; DE2849367B2; JPS5482885A; IT1106148B; FR2409741A1; GB2009460A; DE2849367A1; GB2009460B

Abstract

Docket No. 11771 BLOOD GLUCOSE CONTROL APPARATUS Abstract of the Disclosure Apparatus is described for controlling blood glucose concentration in a subject by selected infusion of insulin into the blood stream of such subject, depending upon the general blood glucose concentration. This apparatus com-prises in combination sensor means for determining the blood glucose concentration and for providing computer input signals based on such measurement, computer means for receiving such input signals and for providing output signals based upon such input signals, and pump means responsive to such computer output signals to supply insulin to such subject at a rate determined by such output signals. The computer means is programmed to derive the output signals in accordance with specific equations employing certain inde-pendently selected values relating to basal blood glucose concentrations and basal insulin infusion rates at such basal blood glucose concentrations.

Description

Fie~d_o~ the I-~v_ntion The present invention relates to glucose monitoring systems in general, and more particularly to apparatus for controlling blood glucose concentrations in a sub~ect by selected infusion of insulin.
' ~ ~
Baokqround o~the Invention ~, Insulin is a hormone produced in the pancreas which is essential for the proper metabolism of glucose in the blood.
The failure to produce insulin in appropriate quantities results in the onset of diabetes mellitusO
Since the early l900's diabetic conditions have been treated by periodic injections of insuIin, coupled with diet and exercise control. It was initiaIly felt that such treatment could be used to completely control a diabetic condition. It is difficult, however, to avoid over or under compensation since insulin injection generaIIy cannot be timed to coincide with carbohydrate intake. Situations thus exist in which the amount of insulin present lS either in `~
excess of or less than that required to handle the specific blood glucose level at any given time. Such situatlons are especially severe when an individual with a diabetic condition is under stress conditions, such as surgery or during :
.~ , .
childbirth.
It is generally recognized that individuals do not ~ `~
~5 respond uniformly to insulin treatments and that some patients ~
are better managed by short acting (regular or Semilente) ~` -insulin which requires several injections per day, whereas -~

-2~
. . .
' '~.

.2'~ Z~3 other patients are better managed with intermediate (globln, NPH or Lente) or longer ac~ing (protamine zinc or Ultralente) insulin which require less frequent injections. Nelther the short nor the longer acting varieties of insulin is capable of regulating a patient's blood glucose concentratlon accurately on a minute-to-minute basis because of varying demands created by food and exercise. Only by following a life of balanced diet and exercise can a patient prevent sudden and.excessive changes in the requirements for insulin.
Such a regimen will maintain the patient's blood glucose concentration below an acceptable upper level, thereby limiting the possibility of hyperglycemia~ and above a safe lower limitJ thereby.limiting the possibility of hypoglycemia, ,,- ,:
Unfortunately, a dangerously low.blood g.lucose concentration can also result from the use of larger infusions of insulin ~, ;,' :
~ , to counteract a rising concentration of blood glucoseO Tkis , ' is because there is an overshoot when the concentration of ~ :.
blood glucose ceases.to.increase,or actually:decreases and ' .-, the.presence of the insulin causes.a.rapid decline in blood .' .... :
glucose concent~ation to a.concentration below the safe ; ,~
limit. The resulting hypoglycemia can be fatal in some ,; `,'-~
cases.
,., ,:
Various systems and apparatus have been proposed to '`
analyze the,blood.glucose concentration and to infuse `' ., .
insulin.or glucose based.upon.such.analysis ln an effort to control the.blood glucose level wlthin desired rangesO One .
approach, referred to.as the.limit.approach7 continuously ,~.
monitors a patient's blood glucose concentration and regu- ,.''~
. lates this concentration by.administering insulin when the ~ '., concentration reaches an.upper limit and administering ','':`"., , ..... .
":-

-3~

dextrose when the blood glucose concentration reaches a lower limit~ The limit approach, however, has several difficulties because it is possible to overshoot both the upper and lower limits The system is not capable of controlling sudden changes.in blood glucose concentration~
Another approach is to use proportional regulation by solely matching the infusion rate of insulin to the blood glucose concentration according to a linear relationship.
Here again, hypoglycemia can result if there is a large .
requirement for insulin followed by a na~ural reduction in the blood glucose concentration.
. Still another approach is.described.in Diabetes 23(5), `:"~ ;
389-40`4 (1974) in which apparatus is described having a computer which operates an inusion pump to infuse insulin : .
or glucose based upon analytical blood glucose value~s~ The computer derives its output signal for pump operation from algorithms based on hyperbolic tangential functions... While ~:
this prior art computer control has advantages, it also has the distinct disadvantage.that.the responses obtained do not `.
always satisactorily.provide adequate controlO In.addi~
tion, the apparatus.provides only limited flexibility in the selection of specific operating sonditions for particular individuals whose blood glucose concentrations are.being .~
controlled by the.apparatus. .;
. .The.development o a rapid.glucose.~analyzer with a . ~.
total.response.time.of less than.two minutes has signi~
cantly affected the systems and apparatus being usedn It is no longer necessary to calculate and.use a predicted glucose value based on.an averaging of previous glucose values, ;.
~ whether the average is an arithmetic mean or weighted ~ :

f~'~3 ~;

average, in order to compensate for a long analyzer lag.
time because the response time of a rapid analyzer approxi-mates the physiological response of a healthy subject. Th1s fact has permitted improved apparatus for monitorlng and controlling.blood glucose le~els.to be developed~

, ...Su~ma~_ Q~ the Invent~on An object of the present in~ention is to provide :~
apparatus.for accurately.monitoring the blood.glucose level , in a subject.
Another object of the present in~ention is to provide apparatus.for.~ery accurately controlling.the amount of .-insulin supplied to a subiect based,upon an.algori~hm controlled computer signal.
Still another object.o.the present invention is to provide insulin infusion apparatus which has a high degree of flexibility in the selection.of specific operating conditions for the particular subject whose blood glucose concentrations are being controlled by the apparatus" ;~ ~
In accordance with.the.present.inventionJ apparatus is `,.. '.
provided or.controlling the.concentration o glucose in the `~
blood stream.of a subiect by controlled infusion of insulin ' ,.
to the subject dependent upon the concentration of glucose in the sub~ect's.blood.stream~.such apparatus comprising in .
combination,means or determining serial ~alues of blood ` ~-glucose,concen~ration in the.blood stream.of.a subject and for providing computer input.slgnals.corresponding to sald' ',.~,'.
serial values; computer means connected.to said first mentioned.means and operable to.p~ovide output signals in ~.Z ~2 ~ 3 response to the said input.signals; and infusion means connected.to said computer.means and to a source of insulin and responsive to said output signals for introducing . insulin from said.source to caid blood s~ream at.a rate determined by said ~utput.signals; said computer means being programmed to.pro~ide J in response to.said input : -signals, output signalc causin~.said infusion means to ~ ;
introduce insulin.to said.blood stream at a rate derived in accordance with.. the following-e~uation: :.

IR = ~ + l~n + K~
` .

wherein: IR = insulin infusion.rate, RI = required basal infusion rate at BI, . -.
G = the last.~lucose.value, BI = the desired basal or steady state glucose concentration, ;
QI = is a preselected.value dependent upon the subject, .
:., K = is a preselected value dependent upon the ., subject.and.whether or not the blood glucose `: i ... .. ..
. . concentration.~ the subject.is rising (KR) . ~-or falling ~KF), ~"
t = time, and n = a number ranging from 1 to 3 ~:.
'~
,' ':

,, . ,.. ~.. ~
-6- ~

~ ~.2~

Brief DescYi~tio~ o;~_the Dr ?~in~s Other and ~urther objects, advantages and,eatures of ~;:
the invention will be apparent to those skllled.ln the art '~
from the following detailed description thereof, taken ln conjunction with the accompanyi~g drawings, in which:
Fig.. 1 is a schematic view of apparatus according to the invention coupled to.a,diabetic subject;
Fig. 2 shows a family of curves representing operation ~
of the apparatus of.the present invention i~ a first ~. ,~,.
control mode contrasted to a cur~e illustrating insulin - ;~
infusion rate vs. blood glucose concentration.outside the ';
scope of claimed operation; ';
Figs. 3-5 show families of curves representing ~ ,.'.
operation of the apparatus o the'present inventlon in the . ;',' first control mode~ said curves illustrating~insulin infusion `~.
rate vs. blood glucose concentratlon for several basal or ,~
steady state glucose concentrations at.ualues of n equal to 1, 2 and 3, respectively; ''~
Figs. 6-8 show families of curves represen~ing operation ~ ~ ''...
of the apparatus.of the present invention.in the first .
control mode, said curves illustrating insulin in~usion ~`'';, rate vs. blood glucose concentration for~several required~
basal infusion rates at values of n.equal to 1, 2 and 3, ",,'.
respectively.
Figs. 9-11 show families of curves representlng ,:,.~'~
operation of the apparatus of the present~invention in the .. ~' first control mode, said curves lllustrating insulin lnfuslon rate vs. blood glucose:concentration for several values of "~'~
QI at values of n equal to 1, 2, and 3, respectively; and ',~ .

- 7 ~
~,. .

.. , . , ,: ~ , ~ : :;, ... . . .

Figs. 12-14 show families of curves representing operation of the apparatus of the present invention in the second control mode, said.curves illustrating insulin infusion rate V5r blood,glucose concentratLo~ for.several values of m at different.. values of KR and KF, as deflned herein~

. Descr*~t?.on_~ the Preferred Embodiment,s The apparatus forming the subject matter of the present invention for controlling the.concentration of glucose in '~ ' the blood stream of.a subject.by.controlled supply of '~`.
insulin to the.subject dependent.upon the rate of Fhange of glucose concentratio~ in.said.blood.stream~is.characterized ',-: ., by means for determining serial ualues of blood glucose .. ' ,':
concentration in the.blood.stream of a subject and for ; .
15 . . pro~iding computer.input.signals~.corresponding to said ,.
serial.values; computer.means.coupled to.said first mentioned ~'.
means and operable to pro~ide.output si~Dals in response to ~ ~
said input signals; and infusion means connected to said '. :`
computer.means.and to.a.source.of.insulin and responsive to . said output.signals for.introducing.insulin from said source to said.blood.stream at .a. rate.determined by said output ~"'`
signals; said.computer.means.being programmed:to.provide, in response.to.said.input signals,.output signals causing said infusion means.to.introduce.... insulin.to said.blood stream at 25 , .a rate deri~ed.in.accordance.. .with the ollowing equation:
.
I~ d R~ T__ + l)n , K~

:

~':
wherein: IR = insulin infusion rate, RI = required basal infusion ~ate at BI, G = the last.glucose.value, ~ :
B~ = the desired.basal or steady state ~lucose concent.ration, QI = is a preselec~ed.value depe~dent upon ~ -the subject, K = is a preselected.~alue dependent upon the `: :
subject and whether.or not the blood.glucose .-concentration.of the subject is.rising (KR) or falling (KF) 3 .`' t = time, and ~ .
n = a number ranging.from 1 to:3 ~;
'' ;`:
., .
As shown schematical.ly in Figo 1, blood is removed from the blood.stream of subject lO.by.suitable:means~,~such as ~ .
through a.double.lumen.catheter (not shown) r .~hich also .:, .
introduces an anticoagulant:such~.as heparin,. in line 12, which .~.
is mixed with the blood as it lea~es the.subject, thereby . ~-diluting the blood passing~throu~h.llne 13~ The antico~
agulant.is stored in.reservoir.l4 and.is pumped to the~
cstheter.throu~h lines 16 and.12~by suitable.means, such as~
peristaltic pump 18,.which also pumps diluted blood from the `~-catheter through line.l3..i~.the opposite direction. Pump 18 runs continuously to drive the.diluted blood..rom llne 13 into glucose analyzer:22.
Glucose.analyzer 22 can..take.a ~ariety of forms. For .
example, using a.colorimeter approach7 diluted blood enters analyzer 22.and is diluted.urther.with a physiol.ogical , . ~ . :-, . .
. g - .;,'' ~ ~

,.

: -:
.

~ 3 saline solution before being segmented with al~ into dls-crete bits to be dialy7ed a~ainst a ~lucose oxidase-peroxidase-chromogen reagent. The presence of blood gluco~e specifically alters the color of the reagent and the opt1ca density of the resulting color is measured by a colorlmeter which generates a corresponding output signal. The resu~t-ing signal is then fed to analog-to-dlgltal converter 26 which prepares the input signal fo~ dlgltal computer 28.
In a preferred embodiment glucose analyzer 22 is a membrane type polarographic assembly which measures the glucose level of the diluted blood and generates a corre- .
sponding signal which is supplied to analog-to-dlgltal :
converter 26 which prepares the input signal for digltal computer 28. Suitable membrane type polarographlc apparatus is described, for example, ln U.S. Patent ~o. 4,092,233 issued M~y 30,197~. In this U.S. application a membrane lS
disclosed containing glucose oxidase which converts glucose ~ `~
to hydrogen peToxide which is detected in the po1arograph1c assembly by a difference in electrlcal potentia1 Analog-to~digital converter 26 feeds the dlgltal lnput signal corresponding to the blood glucose level to computer 28, which is programmed according to an algorithm whlch Wl11 -~""` `
be discussed later. Responsive to the signals from analyzer 22, the computer determines t~e infusion rate of insulln for ~5 the subject by use of the algorithm programmed lnto the computer. Once the infusion rate requlred by the subject has been determined, digital signals are fed from computer 28 to pump interface 32 which controls the infuslon pump1ng wh1ch `~
will no~ be described. Pump 34 connected to 1nterface 32 receives insulin from reservoir 36 b~ way of line 38 and ~.Z~ 2 ~ ~

feeds the insulin into lines 39 and 400 Line 42 receives saline solutîon from pump 44, whïch draws said solution from :~
reservoir 46. Accordingly, insulin from reservoir 36 is mixed with saline solutlon as lt lS fed into 11ne 40, and the resulting solution is introduced into the blood stream of subject 10 through a suitable catheter (not shown). A
closed loop is therefore provided which includes subject 10.
It will be understood that while the use of a digital computer is preferred, converter 26 and computer 28 can be replaced by an analog computer, if desired~ Pump 34 would then be driven in analog fashion rather than in digital fashion. :.
- As will be apparent, the regulation afforded by the structure described with reference to Fig~ 1 depends on computer algorithms programmable into computer 28 ldeally, `:
the algorithms should be capable of interpreting requirements for insulin to the point where the blood glucose concentra~
tion of a subject ls maintained substantially constant at a level which is considered normal for the subject 1n questlon. -~0 An insulin dependent diabetic requlres a static lnsulln ~ ` :
release supplemented by a dynamic control function.
Algorithms have been developed which allow investi-gators to use the present system for:
- .,:
(1) Static control - a control mode of operatlon in which insulin release is dependent upon the statlc value of ~;
the blood glucose level;
(2) Dynamic control - a control mode in which lnsulln:
infusion is controlled solely by the rate of change of blood glucose levels; and .: - ., . ~ , . . . ..

~3) Static plus Dynamic Control - a control mode 1n which dynamic control and static control are combined for controlling insulin infuslon Durîng the development of the control algorithms the static control has been optimized so that an elevated glucose level can be reduced asymptotically into the normal range without overshooting into the hypoglycemic state~
Furthermore, the static control alogrithm allows control `
constants to be selected directly for the area of physio^
logical significance, such as the basal insulin infuslon rate, the glucose level at which the basal rate should occur, and the "gain" of the control function, as expressed by the expression:
RI (-~T-__ + l)n ~ ;~
Thus, in contrast to earlie~ control algorithms uslng the '`tangens hyperbolicus", the static control algorithm of the present invention does not have control constants selected "
primarily to relate to the central portion of the control curve and only secondarily to the critical control region around and slightly above the physi~ogical range. Moreover, instead of maintaining fixed relationships for the dynamlc control conditions, the present system utilizes separate control constants during dynamic control for increasing and ;;
decreasing blood glucose levelsO `
In the past, simple averaging of the most recent blood glucose concentration value (BG) readings was used to predict the next BG valueO Simple averaging, however, has not provided satisfactory results. Unsatisfactory results have also been obtained when attempts have been made to ".

`,.

predict a BG value by using a weighted scale in whlch a number of previous BG signals received by the computer are weighted with the greatest weight being applied to the last reading As indicated, the apparatus of the present in~ention lS
capable of operatlng in several modes at the choice of the :
operator. In the first or so-called static control mode 9 : `
insulin is infused into the blood stream of a subject at a - -~
rate dependent upon the static value of the blood glucose . .
concentration. In this first mode o operation the computer ~-is programmed to provide, in response to the serial input signals, output signals causing infusion of insulln at a ` .
rate derived in accordance with the equation~
IR = RI ~ T- + l~n wherein IR = the insulin infusion:rate, RI = the required basal insulin infusion rate at BI, G = the last glucose value, :
BI = the desired basal (steady state) glucose concentration, QI = a preselected value depending upon the subject, :~
and ~ ~
n = a number ranging from l to 3 ::
-.
In order to obtain an accurate value and simultaneously to avoid the "noise" due to small minute-to-minute analyzer . . .
output fluctuations, a preferred algorithm of the present :~
invention has been developed using a least squares regres-sion line~ For this preferred embodiment the slope (m) for five co~secutive glucose values Go to G4, with Go belng the most recent glucose value, becomes:
m = 0 1 3._ 4 ,, '~ '' '':" ' ' ' ;~"'' ~ 2 ~ ~

and the value of the last glucose value ~Gy), corrected to fit the regression line, becomes:
Gy = 2m ~ Go _Gl G2 G3 G4 Substituting Gy for G the preferred equation for the flrst `~
mode becomes: -.
IR = RI (GY - BI + l)n In the second or dynamic control mode of operation, insulin is infused at a rate dependent solely upon the rate of change of blood glucose levels, and the computer ls pro-grammed to provide, in response to the serial input signals, ~ -output signals causing infusion of insulin at a rate derived in accordance with the equation: --.~-IR = K
wherein IR = the insulin infusion rate, K = a preselected value dependent upon the sub~ct and whether or not the blood glucose concen-.,-.: ,. .
- tration of the subject is rising (KR) or falling ~KF), ~. .
G = the last glucose value, and t ~ time :.

. j .

This equation is modified in a preferred embodiment to ~ .
incorporate the slope of the least squares regression llne ~.
fit for the most recent blood glucose values to become~
IR = K~
'` ~; `
-14- ~ :

" ~i 3 :.
-When this equation is modified to incorporate a factor proportional to the difference between the actual and desired glucose level the equation becomes IR=Km(G - BI) except when G is less than BI, in whîch event IR equals ~ `~
zero. Using Gy instead of G the final preferred equation for the second mode becomes:
IR = Km ~Gy - BI) ~`
except when Gy is less than BI, in which event IR equals zero. For computational convenience this equation can be written as follows: . `
IR = ~ (Gy-BI) by also increasing the values of K by a factor of 10.
In the third or static plus dynamic control mode of ~
operation, insulin is infused at a rate dependent upon both - .
the first and second modes and the computer is programmed to provide, in response to the serial input signals, output signals causing infusion of insulin at a rate derived in .
accordance with the equation: ~
IR = RI (GQI Bl + l)n ~ K~
and preferably:
IR = RI (GyQ~ BI ~ l)n ~ Km (Gy - Bl) .~;
except when Gy is less than BI, in which event said rate is :~
derived in accordance with the equation: -IR = RI (Gy QIRI + l)n . . ;;
wherein: IR = insulin infusion rate, -RI ~ required basal infusion rate at BI, Gy ~ the last glucose value, corrected to flt -a least squares regression line, ~ :
BI = the desired basal (steady state) glucose concentration, `''' '~
-I5~
' ' QI = is a preselected value dependent upon the subject, K = is a preselected value dependent upon the subject and whether or not the blood glucose concentration of the subject is rislng (KR) or falling (KF), m = is the slope of the least squares regression line fit for the most recent consecutive blood glucose values, such as~the last five blood glucose vaiues, and n = a number ranging from 1 to 3 In the above equations IR and RI are expressed in milliunits of insulin per minute of infuslonO Bl and QI are expressed in milligram percent of glucose. This can also be ~-expressed as milligrams per deciliter (mg/dl~. Bl represen~s i a selected or desired basal blood glucose concentratlon which typically would be present in a normal subject under ` i resting conditionsO RI represents the require~d basal insulin infusion rate provided by the body of~a normal subject under such conditions and is typically about 10 milliunits per minute for a person having 50 kilograms of body weight~ ~ i Thus, when the apparatus of the present inventlon is used i~ `
with a 70 kilogram human subject, for example, Rl is typl-cally about 14 milliunits of insulin per minute~ Bl is .
about 80 milligram per deciliter glucoseO A nomlnal Ql is .
about 30 mg/dl of glucose with Ql values ranging from about 5 to about 30. K will have a nominal value (KR) of approxi- ~ ~
mately 30 when the blood glucose level is rislng and a `
nominal value (KF) of approximately 8 when the glucose level is falling, if the expresslon T~ (Gy - BI) is used.

~ 3 It has been determined that in order to prevent any excess infusion of insulin in hyperglycemic condltions the infusion rates for insulin should have a controlled maximum value. A maximum însulin infusion rate of about 500 m~ unlts per minute or less has been found suitablen Typical operating conditions for computer calculated insulin infusion rates (IR) vsO measured serial blood glucose concentrations tG) for the first mode of operation are shown in Figure 2 and controlled with operating conditions outside the scope of claimed operation. Rl and BI are kept constant at typical values of lO milliunits per minute and 80 mg/dl respectivelyO QI is maintained at values of 7, 30, 57 and 85 mg/dl for values of n equal to 1, 2, 3 and 4, respectively.
The calculated IR is then obtained from the appropriate curve depending on the measured blood glucose readlng (G) , and the value of n selected by the operator. Comparable curves can also be obtained for different values of n.
Typical operating conditions or computer calculated i~nsulin infusion rates (IR) vs. measured serial blood glucose concentrations (G) for the first mode of operation are shown in Figures 3-5. RI is kept constant at a typical value of 10 mu/min. QI is maintained at 7 mg/dl for n equal to l, 30 mg/dl for n equal to 2 and 57 mg/dl for n equal to 3. BI is shown for three typical values of 60 9 80 9 and 100 mg/dl. ;';
The calculated IR is then obtained rom the appropriate curve depending on the measured blood glucose reading (G) and the appropriate BI selected by the operator~ Comparable curves can also be obtained for diferent values of BI.
Typical operating conditions for computer calculated insulin infusion rates (IR) vs. measured serlal blood ;`

z~

glucose concentrations (G) for the first mode of operatlon are shown in Figures 6-8. BI is kept cons~ant at 80 mg/dl.
QI is maintained at 7 mg/dl for n equal to 1, 30 mg/dl for n equal to 2 and 57 mgldl for n equal to 3. RI ïs shown for three values. The calculated IR is ~hen obtained from the appropriate curve depending on the measured blood glucose reading (G) and the appropriate RI selected by the operator.
Comparable curves can also be obtained for different values of RI.
Typical operating conditîons for computer calculated insulin infusion rates (IR) vs. measured serial blood glucose -~
concentrations ~G) for the first mode of operation are also shown in Figure 9-11. BI and RI are kept constant at ` `
typical values of 80 mg/dl and 10 milliunits per minute, ~ ;
respectively. QI is shown for values of 5, 7 and 9 mg/dl for n equal to 1, 20, 30 and 40 mg/dl for n equal to 2 and 47, 57 and 67 mg/dl for n equal to 3. The calculated IR ~
is then obtained from the appropriate curve depending on the ` ~;
m~asured blood glucose reading (G) and the appToprlate QI
selected by the operatorO Comparable curves can also be ` ``;
obtained for different values of QI.
Typical operating conditions for computer calculated insulin infusion rates ~IR) vsO measured serial blood glucose ~
concentrations ~G) for the second mode of operation plotted ; ``
for various values of m are shown in Figures 12-14. BI lS
kept constant at 80 mg/dl. The calculated IR is obtained from the appropriate curve depending on the measured blood - `
glucose reading (G) for different values of KR and KF. ;;~

. ;, ~z~

Using the third mode, as described herein, ~he insulin infusion rate was determined for a human subjectu Table I
illustrates calculated IR values based on the glucose levels obtained from the human subjectO The following preselected values were used:

RI = l8 mu/min, BI = 80 mg/dl, QI = 30 mg/dl, KR = 30 when the blood glucose concen-tration of the subject was rising, KF = 8 when the blood glucose concen-tration of the subject was falling.
based on the expression ~ (Gy -:BI) ." ..~.,.

,:
. ,~ .

: .'^.
'` ;~
"' , - 19 - .,,~ .
.. .;, ~, i - . .
Ta~ble I

G IR : :

102 84 `:: -101 85 : ~ . .
101 58 ~-.:
101 50 :

102 59 ~:
102 ~ 60 103 83 :
, .

lS 104 : : ~ 85 107: ~ ~ 147 : ; `~
1 0 8 ~ 1 9 1 .
- ......................... ... .... ......... ... ... ... ... ... .......... .......... ... .... ... ..... ... ... ... .. ~
1 0 7 ~ 1 8 ~ 7 109 ~ 156 2 0 I 12 ~ 19 0 1 1 4 ~ : ~ 2 5 5 , ~ i :, 114 ~ 218 1 1 3 1 4 3 ;
~ . ,.,; .

116 ~ 126 116 : 162 :., , 117 ~ 201 . , :. ~. . :
- 2 0 - . ; i , .;, : ~ .', ~ .Z~2 G (cont ' d. ) IR (cont ' d. ) 106 19 ~ `
107 29 ~:

lO0 17 ~:
100 22 :
' `-100 48 .
. ...
lO0 50 . : ~ ~
100 48 - ~ ~.
96 31 ~ "
.. ...

: . :, i .

.-. ::;-94 : 36 ~`
.~.-.

93 35 :

.
- 21 - : ~ ::
..
,: ~
:. ~` `.

~ 2~2~3 , G (cont ' d. ) IR (cont ' d . ) 92 37 :

' " , `'~:
: `:
, ~, ',' ,~
~'.' ..~,~`' :::~ .~: .
~,, ;. ~
:;.; :, ' '~','" ~, . .
:

-~
"`,-"~ , ,, ,~, "
- 2 2 - : :

4~

In the apparatus of Fi~ure 1 anv suitable sensor means can be employed to measure the blood glucose concentration of the blood samples obtained from the patient. Like-:ise an~
suitable pump can be used in the insulin infusion means. The particular details of sensor 22, compùter 2& or pumps 18, 34 and 44 do not form a part of the present invention.
Although not part of ~he present invention, it will be understood that the apparatus employed to infuse insulin can be used to also infuse glucose when glucose infuslon is necessary in order to maintain the desired blood glucose -concentration. A suitable algori~hm controlling the input of glucose is disclosed in U.S. Patent No. 4,055,175 `"
issued October 25, 1977. ~ ~
; The present apparatus can be designed to provide an ~ -alarm when physiological levels have been exceeded. FOT
example, the alarm can function to indicate hypoglycemia or hyperglycemia in a subject. Safeguards, such as means for automatically stopping infusion of insulin under.prede-termined conditionsj can likewise be incorporated~ if desired. ¦
From the foregoing, it will be seen that this invention -is well adapted to attain all of the ends and objects hereinabove set forth, together with other advantages which are obvious and which are inherent to the system. It can be seen from the above discussion that the apparatus of the present invention provides considerable flexibilit!t to the operator to select not only the specific desired mode of operation, but also to selected desired control ~talues in ¦
the computer operating equation for the selected operating ¦;
mode. The significance of the separation of the Yarious control modes 1, 2 and 3 is especially apparent in the I ~ .

-23- ~
.~ .

~ ~Jz~z~
:

research field. While it is true that ~he insulin-dependent :
diabetic requires operating mode 3, the avaïlability of a -"pure" derivative control, such as operating mode 2, helps to clarify an important question as to whether "maturi~y- -onset" diabetes is the result of a lacking "first phase"
release or a consequence of a reduced number or sensitivity of insulin receptors, or bothO
Unlike previous bi-quadratic function algorithms for .:~
"static control" mode l utilizes an exponential function wherein the exponent can va~y from l to 3. One advantage of havin~ the algorithm for "static" control as an exponential function in which the exponent varys from 1 to 3 rather than :`;
a bi-quadratic function is a reduction in the static gain .;~ :
for the elevated glucose range, an increase in gain in the range immediately above the BI level and a reduction in gain below the BI glucose level. This results in an Increase in glucose stabilizing effect of the static control algorithm about the BI glucose level, whlle concurrently reducing the ~.
; static insulin release at substantially elevated glucose :
levels, like severe hyperglycemic conditions. Moreover, the -~
.
algorithms used avoid one serious shortcoming of ear.lier algorithms, namely the sensitivity of feedback control output to a "noisy" input signal, particularly noise due to small minute-by-minute analyzer output fluctuationsO It will be understood that while preferably the letter "n" in the ,. ..
algorithms of the present invention is the integer l, 2 or :: .
3, and most preferably 1 or 2, "n" can be any decimal number ~ ~ ;
between 1 and 3.
Obviously, many other modifications and varlations of 30the invention as hereinbeore set forth may be made without ; ~-~
departing from the spiri~ and scope thereof.
~.
-Z4- ~ ~
~ ,,

Claims

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. Apparatus for controlling the concentration of glucose in the blood stream of a subject by controlled supply of insulin to such blood stream dependent upon both the concentration of glucose and the rate of change thereof in said blood stream, said apparatus comprising means for determining serial values of blood glucose concentration in the blood steam of a subject and for providing computer input signals corresponding to said serial values; computer means connected to said first-mentioned means and operable to provide output signals in response to said input signals;
and infusion means connected to said computer means and to a source of insulin and responsive to said output signals for introducing insulin from said source to said blood stream at a rate determined by said output signals; said computer means being programmed to provide, in response to said input signals, output signals causing said infusion means to introduce insulin to said blood stream at a rate derived in accordance with the equation:
wherein: IR = insulin infusion rate, RI = required basal infusion rate at BI, G = the last glucose value, BI = the desired basal or steady state glucose concentration, QI = is a preselected value dependent upon the subject, K = is a preselected value dependent upon the subject and whether or not the blood glucose concentration of the subject is rising (KR) or falling (KF), t = time; and n = a number ranging from 1 to 3.

2. Apparatus for controlling the concentration of glucose in the blood stream of a subject by controlled supply of insulin to such blood stream dependent upon both the concentration of glucose and the rate of change thereof in said blood stream, said apparatus comprising means for determining serial values of blood glucose concentration in the blood stream of a subject and for providing computer input signals corresponding to said serial values; computer means connected to said first-mentioned means and operable to provide output signals in response to said input signals;
and infusion means connected to said computer means and to a source of insulin and responsive to said output signals for introducing insulin from said source to said blood stream at a rate determined by said out signals; said computer means being programmed to provide, in response to said input signals, output signals causing said infusion means to introduce insulin to said blood stream at a rate derived in accordance with the equation:
except when Gy is less than BI, in which event said rate is derived in accordance with the equation:
wherein: IR = insulin infusion rate, RI = required basal infusion rate at BI, Gy = the last glucose value, corrected to fit a least squares regression line, BI = the desired basal or steady state glucose concentration, QI = is a preselected value dependent upon the subject, K = is a preselected value dependent upon the the subject and whether or not the blood glucose concentration of the subject is rising (KR) or falling; (KF), m = is the slope of the least squares regression line fit for the most recent consecutive blood glucose values; and n = a number ranging from 1 to 3.

3. Apparatus for controlling the concentration of glucose in the blood stream of a subject by controlled supply of insulin to such blood stream dependent upon both the concentration of glucose and the rate of change thereof in said blood stream, said apparatus comprising means for determining serial values of blood glucose concentration in the blood steam of a subject and for providing computer input signals corresponding to said serial values; computer means connected to said first-mentioned means and operable to provide output signals in response to said input signals;
and infusion means connected to said computer means and to a source of insulin and responsive to said output signals for introducing insulin from said source to said blood stream at a rate determined by said output signals; said computer means being programmed to provide, in response to said input signals, output signals causing said infusion means to introduce insulin to said blood stream at a rate derived in accordance with the equation:
wherein: IR = insulin infusion rate, RI = required basal infusion rate at BI, G = the last glucose value, BI = the desired basal or steady state glucose concentration, QI = is a preselected value dependent upon the subject, K = is a preselected value dependent upon the subject and whether or not the blood glucose concentration of the subject is rising (KR) or falling (KF), and t = time.

4. Apparatus for controlling the concentration of glucose in the blood stream of a subject by controlled supply of insulin to such blood stream dependent upon both the concentration of glucose and the rate of change thereof in said blood stream, said apparatus comprising means for determining serial values of blood glucose concentration in the blood stream of a subject and for providing computer input signals corresponding to said serial values; computer means connected to said first-mentioned means and operable to provide output signals in response to said input signals;
and infusion means connected to said computer means and to a source of insulin and responsive to said output signals for introducing insulin from said source to said blood stream at a rate determined by said out signals; said computer means being programmed to provide, in response to said input signals, output signals causing said infusion means to introduce insulin to said blood stream at a rate derived in accordance with the equation:
except when Gy is less than BI, in which event said rate is derived in accordance with the equation:
wherein: IR = insulin infusion rate, RI = required basal infusion rate at BI, Gy = the last glucose value, corrected to fit a least squares regression line, BI = the desired basal or steady state glucose concentration, QI = is a preselected value dependent upon the subject, K = is a preselected value dependent upon the the subject and whether or not the blood glucose concentration of the subject is rising (KR) or falling (KF); and m = is the slope of the least squares regression line fit for the most recent consecutive blood glucose values.

5. Apparatus for controlling the concentration of glucose in the blood stream of a subject by controlled supply of insulin to such blood stream dependent upon the concentration of glucose in said blood stream, said apparatus comprising means for determining serial values of blood glucose concentrations in the blood stream of a subject and for providing computer input signals corresponding to said serial values, computer means connected to said first mentioned means and operable to provide output signals in response to said input signals; and infusion means connected to said computer means and to a source of insulin and responsive to said output signals for introducing insulin from said course to said blood stream at a rate determined by said output signals; said computer means being programmed to provide, in response to said input signals, output signals causing said infusion means to introduce insulin to said blood stream at a rate derived in accordance with the equation:
wherein: IR = the insulin infusion rate, RI = the desired basal insulin infusion rate at BI, G = the last glucose value, BI = the desired basal or steady state glucose concentration, and QI = a preselected value depending upon the subject.

6. Apparatus for controlling the concentration of glucose in the blood stream of a subject by controlled supply of insulin to such blood stream dependent upon the concentration of glucose in said blood stream, said apparatus comprising means for determining serial values of blood glucose concentrations in the blood stream of a subject and for providing computer input signals corresponding to said serial values, computer means connected to said first mentioned means and operable to provide output signals in response to said input signals; and infusion means connected to said computer means and to a source of insulin and responsive to said output signals for introducing insulin from said source to said blood stream at a rate determined by said output signals; said computer means being programmed to provide, in response to said input signals, output signals causing said infusion means to introduce Insulin to said blood stream at a rate derived in accordance with the equation:
wherein:
wherein: IR = the insulin infusion rate, RI = the required basal insulin infusion rate at BI, G = the last glucose value, BI = the desired basal or steady state glucose concentration, and QI = a preselected value depending upon the subject.

7. Apparatus for controlling the concentration of glucose in the blood stream of a subject by controlled supply of insulin to such blood stream dependent upon the concentration of glucose in said blood stream, said apparatus comprising means for determining serial values of blood glucose concentrations in the blood stream of a subject and for providing computer input signals corresponding to said serial values, computer means connected to said first mentioned means and operable to provide output signals in response to said input signals; and infusion means connected to said computer means and to a source of insulin and responsive to said output signals for introducing insulin from said source to said blood stream at a rate determined by said output signals; said computer means being programmed to provide, in response to said input signals, output signals causing said infusion means to introduce insulin to said blood stream at a rate derived in accordance with the equation:
wherein: IR = the insulin infusion rate, RI = the required basal insulin infusion rate at BI, G = the last glucose value, BI = the desired basal or steady state glucose concentration, and QI = a preselected value depending upon the subject

8. Apparatus for controlling the concentration of glucose in the blood stream of a subject by controlled supply of insulin to such blood stream dependent upon the concentration of glucose in said blood stream, said apparatus comprising means for determining serial values of blood glucose concentration in the blood stream of a subject and for providing computer input signals corresponding to said serial values; computer means connected to said first mentioned means and operable to provide output signals in response to said input signals; and infusion means connected to said computer means and to a source of insulin and responsive to said output signals for introducing insulin from said source to said blood stream at a rate determined by said output signals; said computer means being programmed to provide, in response to said input signals, output signals causing said infusion means to introduce insulin to said blood stream at a rate derived in accordance with the equation:
wherein: IR = the insulin infusion rate, RI = the required basal insulin infusion rate at BI, Gy = the last glucose value, corrected to fit a least squares regression line, BI = the desired basal or steady state glucose concentration, and QI = a preselected value depending upon the subject.

9. Apparatus for controlling the concentration of glucose in the blood stream of a subject by controlled supply of insulin to such blood stream dependent upon the concentration of glucose in said blood stream, said apparatus comprising means for determining serial values of blood glucose concentration in the blood stream of a subject and for providing computer input signals corresponding to said serial values; computer means connected to said first mentioned means and operable to provide output signals in response to said input signals; and infusion means connected to said computer means and to a source of insulin and responsive to said output signals for introducing insulin from said source to said blood stream at a rate determined by said output signals; said computer means being programmed to provide, in response to said input signals, output signals causing said infusion means to introduce insulin to said blood stream at a rate derived in accordance with the equation:
wherein:
wherein: IR = the insulin infusion rate, RI = the required basal insulin infusion rate at BI, Gy = the last glucose value, corrected to fit a least squares regression line, BI = the desired basal or steady state glucose concentration, and QI = a preselected value depending upon the subject.

. -36-

10. Apparatus for controlling the concentration of glucose in the blood stream of a subject by controlled supply of insulin to such blood stream dependent upon the concentration of glucose in said blood stream, said apparatus comprising means for determining serial values of blood glucose concentration in the blood stream of a subject and for providing computer input signals corresponding to said serial values; computer means connected to said first mentioned means and operable to provide output signals in response to said input signals; and infusion means connected to said computer means and to a source of insulin and responsive to said output signals for introducing insulin from said source to said blood stream at a rate determined by said output signals; said computer means being programmed to provide, in response to said input signals, output signals causing said infusion means to introduce insulin to said blood stream at a rate derived in accordance with the equation:
wherein: IR = a the insulin infusion rate, RI = a the required basal insulin infusion rate at BI, Gy = the last glucose value, corrected to fit a least squares regression line, BI = the desired basal or steady state glucose concentration, and QI = the preselected value depending upon the subject.

11. Apparatus for controlling the concentration of glucose in the blood stream of a subject by controlled supply of insulin to such blood stream dependent upon the rate of change of glucose concentration in said blood stream, said apparatus comprising means for determining serial values of blood glucose concentration in the blood stream of a subject and for providing computer input signals corresponding to said serial values; computer means connected to said first-mentioned means and operable to provide output signals in response to said input signals; and infusion means con-nected to said computer means and to a source of insulin and responsive to said output signals for introducing insulin from said source to said blood stream at a rate determined by said output signals; said computer means being programmed to provide, in response to said input signals, output signals causing said infusion means to introduce insulin to said blood stream at a rate derived in accordance with the equation:
wherein: IR = the insulin infusion rate, K = a preselected value dependent upon the subject and whether or not the blood glucose concentration of the subject is rising (KR) or falling (KF), G = the last glucose value, and t = time.

12. Apparatus for controlling the concentration of glucose in the blood stream of a subject by controlled supply of insulin to such blood stream dependent upon the rate of change of glucose concentration in said blood stream said apparatus comprising means for determining serial values of blood glucose concentration in the blood stream of a subject and for providing computer input signals corre-sponding to said serial values; computer means connected to said first-mentioned means and operable to provide output signals in response to said input signals; and infusion means connected to said computer means and to a source of insulin and responsive to said output signals for intro-ducing insulin from said source to said blood stream at a rate determined by said output signals; said computer means being programmed to provide, in response to said input signals, output signals causing said infusion means to introduce insulin to said blood stream at a rate derived in accordance with the equation:
IR = Km wherein: IR = the insulin infusion rate, K = a preselected value dependent upon the subject and whether or not the blood glucose concentration of the subject is rising (KR) or falling (KF), and m = the slope of the least squares regression line fit for the most recent consecutive blood glucose values.

13. Apparatus for controlling the concentration of glucose in the blood stream of a subject by controlled supply of insulin to such blood stream dependent upon the rate of change of glucose concentration in said blood stream said apparatus comprising means for determining serial values of blood glucose concentration in the blood stream of a subject and for providing computer input signals corre-sponding to said serial values; computer means connected to said first-mentioned means and operable to provide output signals in response to said input signals; and infusion means connected to said computer means and to a source of insulin and responsive to said out signals for introducing insulin from said source to said blood stream at a rate determined by said output signals; said computer means being programmed to provide, in response to said input signals, output signals causing said infusion means to introduce insulin to said blood stream at a rate derived in accordance with the equation:
IR = Km (Gy - BI) except when Gy is less than BI, in which event IR equals zero, wherein: IR = the insulin infusion rate, K = a preselected value dependent upon the subject and whether or not the blood glucose concentration of the subject is rising (KR) or falling (KF), m = the slope of the least squares regression line fit for the most recent consecutive blood glucose values, Gy = the last glucose value, corrected to fit a least squares regression line, and BI = the desired basal or steady state glucose concentration