DD160212A3 - METHOD AND ARRANGEMENT FOR INDIVIDUAL-SPECIFIC CONTROL OF THE GLUCOSE-CONTROLLED INSULIN INFUSION - Google Patents

Abstract

The invention relates to a method and arrangement for individual-specific blood glucose-dependent insulin infusion in diabetics. Long-term normalization of the disordered metabolism is achieved by the implantable foreign-infusion blood glucose measurement device whose output signals for controlling the infusion device are equivalent insulin doses from the differences between the targeted blood glucose concentration and the current blood glucose concentration and the blood glucose concentration at which the insulin dosage becomes zero and the size and direction of change of the current to previously measured blood glucose concentration in a time interval after the linear non-recursive difference equation ID = FV.C times & a deep 1 times ((G deep B - G deep O) + (G deep t - G deep B)) + a deep 2 (G deep t - G deep t-delta t) & are determined. About the parameter adjustment circuit, the individual-specific parameters a deep i = a deep 1, a deep 2 in the case of signaling by the blood glucose meter over altered metabolic situations in diabetics according to the equation a'tief i = k deep i times a deep 1 adjusted, the correction factors k deep i can be determined from the difference of the signals of the blood glucose measuring device accumulated in the time interval t, tT in the blood circulation of the diabetic in a predetermined tolerance range of the blood glucose concentration.

Description

- / - 2 2 2 7 4 5

Title of the invention

Method and arrangement for individual-specific regulation of blood glucose-controlled insulin infusion

Field of application of the invention

The invention relates to a method and an arrangement for carrying out the method for the blood glucose-dependent regulation of the supply of foreign body insulin, which is adapted in the long term and continuously to the current insulin requirements of the patient with diabetes mellitus. The supply of insulin can be done both in the blood vessel system, in the body cavities and directly in the tissue of the patient.

Characteristic of the known technical solutions

Insulin is a hormone that is constantly released into the blood by the beta cells of the pancreas, the natural rate of delivery being controlled, inter alia, by the blood glucose concentration and the hormone in turn having the lowering of blood glucose concentration as a major function. Essential mechanism of disease in all forms of diabetes Mellitus is a variable insulin deficiency, which is counteracted by the traditional diabetes therapy by injections of foreign body insulin into the patient one to three times a day, whereby it can be kept alive and able to work over the years. However, this treatment can not adapt the body the blood glucose effective amount of insulin takes place at the changes in the insulin requirements of the glucose metabolism which change in the minute range

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The result is more or less pronounced morbid fluctuations in the blood glucose concentration in areas that are too low and / or too high, resulting in pathological changes in other metabolic processes coupled thereto, resulting in secondary damage to various organs and tissues such as blood vessels, kidneys, eyes throughout the years ultimately reduce the chance of survival of the diabetic far below the values of the rest of the population. This results in the demand for a kind of insulin administration, which over a longer period of time, the dose quasi-continuously adapts to the current needs of the diabetic. One way to do this is the artificial beta cell, a device provided with a processing unit for administering insulin due to constantly accumulating glucose-dependent signals.

There are known methods by means of which using hyperlinic hyperbolic tangent functions (Diabetes, Vol. 23 (1974), pp. 389-404), bi- or multi-exponential equations (Horm. Metab. Res., Suppl. Series, Volume 7 (FIG. 1977), pp. 23-33) or other polynomials (Aust.NZO Med., Volume 7 (1977), pp. 280-286; Acta endocrinologica, vol. 87 (1978), pp. 339-351) or control technology Functions (Medical World, Volume 30, (1979), pp 83-88) in selected diabetics for hours to a few days normal blood glucose profiles can be achieved and maintained. The arrangements based on these methods can only be due to the sometimes complicated mathematical algorithms for determining the current insulin demand and the resulting high technical complexity (Medizintechnik, Volume 99 (1979), pp. 67-70, La Nouvel-Ie Presse medicale, Vol 6 (1977), p. 2309-2313) can be realized by means of extracorporeal stationary appliances which force patients to bed rest or at least require hospital supervision. , '

By the DD-WP 141617 it became known that with a computer the plasma glucose measured values over functional units static non-

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linearity, extrapolation and averaging are fed via a mixing point to a PID control algorithm and processed there. The output signal is fed via an adjustment member of a metering device, whereby the individual patient's insulin needs largely automatic, timely and adequate to be supplied. However, all these known methods have the disadvantage that the function parameters of their mathematical algorithms are intuitively determined and fixed for the duration of the individual application, which is limited in time. The functional parameters of the control algorithms are not based on physiological bodily functions or individually predictable. This results in the application of these methods often unphysiologically high insulin doses and resulting from this diseased elevated insulin levels in the body fluids and in connection with the need for additional automatically controlled also infusions of glucose or glucagon to prevent dangerous blood glucose deviations in too low a range. Furthermore, the known methods also do not offer the possibility of a required for long-term application adjustment of the function parameters to the normal, z. B. changing physical and physiological stress, biological rhythms, pregnancy and. a. or pathological, z. B. Cold infection, digestive disorder u. a., Changing conditions for the effectiveness of the supplied insulin in the body of the patient.

Object of the invention

The aim of the invention is to keep the blood glucose of the patient suffering from diabetes mellitus both under rest and under load condition within physiological limits and to achieve long-term normalization of his disturbed metabolism with an implantable and out-of-hospital applicable Blutglukosemeßwertseinheit with insulin infusion device.

Explanation of the essence of the invention

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The object of the invention is to develop a method for the long-term treatment of diabetics by a glucose-controlled on-demand administration of insulin without additional glucose or glucagon infusion by means of a miniaturized Meßwertverarbeitungseinheit using microelectronics, wherein the parameters of the blood glucose Meßwertverarbeitungseinheit underlying mathematical algorithm can be derived individually and adapted automatically to the current requirements of the metabolism of the patient. According to the invention, this object is achieved in that the determination of the demand-based administration of insulin on the basis of a linear mathematical algorithm proportional to the current blood glucose concentration and differentially to their rate of change and direction, wherein the parameter values of the equation in non-insulin deficiency state by multiple regression analysis between the calculated from insulin concentration measurements normal Insulin secretion rates and the current blood glucose concentrations and their rates of change and directions are determined individually. In the insulin deficient state, the individual-specific determination of the parameters of the algorithm is preferably carried out by applying standardized parameter values of a group of healthy individuals to a diabetic with insulin deficiency, determining the metabolic situation of this diabetic, and determining the parameter values from the comparison with the blood glucose concentration behavior of the group of healthy individuals This diabetic is done. The application of the method according to the invention is achieved in that by a measuring device for determining the blood glucose concentration successively measured values of a preferably equipped with digital frequency-controlled counters miniaturized Meßwertverarbeitungseinheit be supplied from the input signals time-coded output signals for direct

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Derives from the control of an insulin infusion device and which, when used over a long period of time, ie implanted in the patient's body, automatically adapts the parameters of the mathematical algorithm to altered metabolic situations of the patient, preferably by comparison with a mean normal blood glucose concentration.

Execution Example

The invention will be explained in more detail using an exemplary embodiment according to FIGS. 1 and 2.

Fig. 1 shows schematically the control circuit of the invention process

FIG. 2 shows the arrangement according to the invention for blood glucose-controlled insulin infusion.

The method for individual-specific control of the blood glucose-controlled insulin infusion according to FIG. 1 provides that signals from the blood glucose meter 2 in the circulatory system of the individual suffering from diabetes mellitus are fed to the measured value processing unit 3 analogously to the blood glucose values in a time-sequential manner from the input signals Deriving from the differences between the target blood glucose concentration G _Q and the current blood glucose concentration G _t and the blood glucose concentration G _Q , at which the Insulindosierung to zero, and the size and direction of the change of the current to the previously measured blood glucosity concentrate G.-G ₄ . Be determined in a time interval At after the linear non-recursive difference adjustment.

ID «FV.C ^ a _a [(G _B -G ₀ ) + (G _t -G _B )] ♦ e ₂ (G _t -G _t _ _{Δ t} ) I (1) In the equation (1) ID s insulin dosage FV s delivery rate of the insulin infusion device 5 C s concentration of insulin solution

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^a i # Qp ^a individual-pacific parameters a.

G _t "current blood glucose concentration

G _Q "aspired blood glucose concentration

G ₀ = blood glucose concentration at which the

sulphin dosage becomes zero

G = change in the instantaneous blood glucose

^τ " ^Δτ concentration in the time interval At ·

Above the parameter adjustment circuit 4 are the individual-specific parameters a. the individual 1 afflicted with diabetes, with long-term use of the control device, which is advantageously implanted in the body of the individual 1, in the case of signaling by the blood glucose measuring device 2 via changed metabolism situations in the individual 1 according to the equation,

^a i ^{B k} i ^a i < ² )

the correction factors k ^ are determined from the difference of the signals of the blood glucose measuring device 2 accumulated in the time interval t ₍ tT) from a predetermined lower and upper limit of the blood glucose concentration. The electronic circuit arrangement according to FIG. 2 for carrying out the method according to the invention for individual-specific, automatic Regulation of blood glucose-dependent insulin infusion in the individual suffering from diabetes mellitus consists of the blood glucose measuring device 2 in the blood circulation of the individual 1, the measured value processing unit 3 with the register 3 · 1, the preset counter 3 * 2 «the up / down counter 3 * 3, the comparator 3 · 4, the sequence control circuit 3 * 5 and the timer 3 * 6 for the pump of the insulin infusion device 5 and the Pararaeteranpassungsschal-tung 4 with the sum of counter 4 · 1, the _/ comparator 4 * 2, the clock control circuit for adapting 4 # 3 and the threshold comparison scarf device 4 · 4 ·

The electronic control provides that measured values of the blood glucose measuring device 2 are analog in the form of digital signals

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the instantaneous blood glucose concentration G _{t of} the individual 1 consecutively on the data input of the register 3.1 ·, which stores these signals and are delivered to the input of the backward counting preset counter 3.2 to the sampling time .DELTA.t · The register 3.1 and the preset counter 3.2 of the sequence control circuit via the control line a clocked. At the beginning of the blood glucose-controlled insulin infusion, the up / down counter 3.3 is adjusted once to the count analogous to the instantaneous blood glucose.

LO kosekonzentration G. set. The register 3.1 and the up / down counter 3 * 3 are connected on the output side respectively to an input of the comparator 3.4, which contains the greater-lesser comparison between the signal G. of the register 3.1 and the signal G of the signal In front-

down / counter 3.3. If the comparison in the comparator 3.4 yields the result G _t & G _t and this information is given via the control line b from the output of the comparator 3.4 to the sequence control circuit 3.5, then this sets via the control line c the up / down counter 3.3 on up-counting and at the same time, the preset counter begins to 3.2 Vorwahlzählwert G _Q with the counting frequency ^ aI * ^{by the valley <t} 9 ^{enera1: or} d ^it is produced sequencer circuit 3.5 and supplied via the control line d the preset counter 3.2 to expire. During the countdown of the preselection counter 3.2, the timer is 3.6. opened on the sequence control circuit 3.5 and the pump of the insulin infusion device 5 is turned on · The insulin infusion at the individual 1 begins · After reaching the preset value G _Q , the preset counter 3 * 2 is stopped and the forward / backward counter 3.3 with the control line e from the output of the preset counter 3.2 via the sequence control circuit 3.5 for counting up started · During its counting process with the also provided via the control line f from the clock generator of the sequence control circuit 3.5 counting frequency f _Q2

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from counter reading G. "to the counter reading G ₁ . is the

t tt Δ

sulininfusionsvorrichtung 5 on the timer 3.6 by means of sequence control circuit 3.5 continues to operate «After reaching the tie G _t « G _t _ _{Δ t} at the comparator 3.4 is closed via the control line b by means of sequence control circuit 3 * 5, the timer 3 · 6 and the operation of Insulininfueionsvorrichtung. 5 stopped ·

However, if the comparison in the comparator 3.4, the result G <G. _t, then the forward / reverse-counter is set 3.3von the sequence control circuit 3.5 via the control line c at down counting and is started simultaneously with the preset counters 3.2 counts at the preset value G ₀ to run until the comparator 3.4 the tie between G and G. is reached. In this case, the pump of the insulin infusion device 5 does not run as long as the counters 3 # 2 and 3.3 are simultaneously in the state of the teeth. The expiration times of the two counters 3 * 2 and 3 * 3 correspond to the multiplications of the individual-specific parameters of a. With

[(Gg-G ₀ ) + (G _t - <3 _B ) j and a ₂ with (G _t -G _{t- Δ t} ) according to equation (1) and the sequence of the two counters 3.2 and 3.3 of the addition or subtraction the summands to be determined ^a l '[( ^G B " ^G o) ⁺ ( ^G t" ^G s)] ^{and a} 2 ^ t " ^G t-4 ^ ^{the Gleichun} 9 C ¹ ) · Parallel to the register 3.1 and preset counter 3.2 of Meßwertverarbeitungseinheit 3, the measured values G _{t of} the Blutgluko semeßeinrichtung 2 are counted into the sum counter 4.1 of the parameter adjustment circuit 4 and successively over periods T »λ t added, the sum counter 4.1 from the sequence control circuit 3.5 via the control line a to the clock control circuit for the adjustment 4.3 and there is clocked via the control line e $. the sum value calculated in the totalizer 4.1 ~ G ~ j. is compared to the time T with the predetermined sum value "" G ₈₀ H by the comparator 4 · 2, the parameter adjustment circuit 4 ·

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If the comparison G _t \ ^G soll * ^{then the} totalizer 4.1 is started by the ⁿ comparator 4.2 via control line g via the clock control circuit for the adaptation 4 * 3 and from there by means of control line h * The totalizer 4.1 runs at the count frequency f ^, the provided by the clock generator of the timing control circuit for the adaptation 4.3 via the control line i, on the predetermined count gPji on and thus forms the difference between the counts ^ ₀ Jj and 7 »7 · The generated by the totalizer 4.1

mean difference aG becomes ^{n of} the threshold comparison circuit

4.4, in which the factor K is formed in accordance with equation (2). The factor k, which is generated via the control line j from the limit comparison circuit 4 * 4 of the sequence control circuit

3.5 multiplicatively affects the count frequencies f, formed in the sequencer circuit 3 * 5, and the counter 3 * 2 and 3.3 · If there is no difference A ~ &gt; G ₈₀ ; q and G _t at the comparator 4.2, the sum counter becomes 4.1 ⁿ not started via the control line g between comparator 4 * 2 and clock control circuit for the adaptation and via the control line h between clock control circuit for the adjustment 4.3 and totalizer 4 * 1 and a limit comparison is omitted.

Claims (2)

-ίο »222745 Invention claims 1 · A method for individual control of blood glucose-controlled insulin infusion, characterized in that from a Blutglukosemeßeinrichtung (2) in the circulatory system of an individual suffering from diabetes tnellitus (1) signals analogous to the blood glucose value temporally successively a Meßwertverarbeitungseinheit (3) are supplied, the time discrete from the input signals Deriving output signals for controlling an insulin infusion device (5), wherein the insulin dosages corresponding to the output signals are the differences between target blood glucose concentration and current blood glucose concentration and blood glucose concentration at which the insulin dosage becomes zero, and the magnitude and direction of the change from the instantaneous to the previously measured blood glucose concentration in one Time interval, preferably after the linear non-recursive difference equation are determined, where ID = insulin dosage FV = delivery rate of the infusion device C = concentration of insulin solution ^a <L * ^a 2 ⁼ individual-specific parameters a _i G _t = instantaneous blood glucose concentration Gg = desired blood glucose concentration Gq = blood glucose concentration at which the insulin dosage becomes zero G. β Change in current blood glucose concentration ^Δ tration in the time interval ^ t mean, and that via a parameter adjustment circuit (4) individual-specific parameters (a. ^) with long-term use of the control device in the case of signaling by the blood 2 2 2 7 U 5 glucose measuring device on changed metabolic situations in the individual according to the equation B ₁ '- K ₁ . e _± be adapted, wherein the correction factors (k ^) from the difference of the time interval (t, t-T) summed up signals of the blood glucose meter are to be determined in a predetermined tolerance range of the blood glucose concentration. 2. Arrangement for carrying out the method according to item 1, characterized in that the known Blutglukosemeßein-direction in the bloodstream of the individual output side to the input of the Meßwertverarbeitungseinheit,> consisting of a register (3 * 1), a preselection counter (3.2), a forward / Reverse counter (3.3), a first comparator (3,4), a sequencer circuit (3 * 5) and a timer (3 * 6) for controlling the insulin infusion device, and at the input of the parameter adjustment circuit, consisting of a sum counter (4.1), a second comparator (4.2), a timing adjustment circuit (4.3) and a threshold comparison circuit (4.4) connected to the input of the measurement processing unit from the register and the preset counter clocked by the scheduler via a first control line (a) are formed, that the data output of the register and the up / down counter with the inputs of the first connected comparator that the output of the first comparator via a second control line (b) to the first input of the sequence control circuit and the second output of the sequence control circuit via a third control line (c) with the first input of the up / down counter linked »that in Clock generator of the Ablaufsteue- tion generated count frequencies via a fourth or fifth control line (d; f) the preset counter and the forward / backward counter supplied that the output of the preset counter - 12 -, 2 2 2 7 4 5 connected via the sequence control circuit by means of a sixth control line (e) to the third input of the up / down counter that the sequence control circuit connected at its sixth output via the timer with the Insulininfusiebvorrichtung, which is arranged in a known manner to the individual, that the the totalizer forming the input of the parameter adjustment circuit is also clocked via the first control line (a) to the input of the timing control circuit for adaptation and from the output thereof via the continuation control line (a ^) and its counting frequency generated in the timing control circuit and from there a seventh control line (i) receives "that the first oatenausgang of the sum counter to the first input of the second comparator, to whose second input a setpoint signal applied connected, that the output of the second comparator via the clock control circuit by means of eighth and ninth Steuerle connected to the fourth input of the summation counter, that the second data input of the summation counter is connected to the input of the limit value switching circuit and this on the output side via a tenth control line (^ j) to the third input of the sequence control circuit. For this! Page Zelchnungon