Classifications

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  • A61M5/1723—Means for controlling media flow to the body or for metering media to the body, e.g. drip meters, counters ; Monitoring media flow to the body electrical or electronic using feedback of body parameters, e.g. blood-sugar, pressure
  • A61M2005/1726—Means for controlling media flow to the body or for metering media to the body, e.g. drip meters, counters ; Monitoring media flow to the body electrical or electronic using feedback of body parameters, e.g. blood-sugar, pressure the body parameters being measured at, or proximate to, the infusion site
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Definitions

• the present application relates to the field of automated blood glucose control systems, also called artificial pancreas.
• An artificial pancreas is a system that automatically controls the insulin intakes of a diabetic patient based on his blood glucose history, his meal history, and his history of insulin injection.
• MPC Model-based Predictive Control
• predictive control systems also known as predictive control systems, in which the regulation of the dose of insulin administered takes into account a prediction of the future evolution of the patient's blood glucose, made from a physiological model describing the insulin uptake by the patient's body and its impact on the patient's blood glucose. It would be desirable to be able to improve the performance of predictive-controlled artificial pancreas, and more particularly to be able to improve the quality of the prediction of the patient's future blood sugar, so that insulin inputs can be controlled with greater relevance. limit the risk of placing the patient in a situation of hyperglycemia or hypoglycaemia.
• an embodiment provides an automated system for regulating the glycemia of a patient, comprising:
• a treatment and control unit adapted to predict the future evolution of the patient's blood glucose from a physiological model and to control the insulin injection device taking into account this prediction
• the physiological model comprises a system of differential equations describing the evolution of a plurality of state variables as a function of time;
• the processing and control unit is adapted to implement an automatic calibration step of the physiological model comprising a step of estimating initial values of the state variables by minimizing a magnitude representative of the error, during a past observation period, between the glycemia estimated from the physiological model and the glucose measured by the sensor.
• the quantity is representative of the area between a first curve g representative of the temporal evolution of the glycemia estimated from the model over the observation period, and a second curve g representative of the temporal evolution of the glucose measured by the sensor over the period of observation.
• the magnitude is defined as follows:
• t is a discretized time variable
• t 0 is the start time of the observation phase
• t 0 + ⁇ T is the end time of the observation phase
• the calibration method further comprises a step of estimating parameters of the system of differential equations by minimizing said magnitude.
• the calibration method comprises a plurality of successive iterations of the following steps a) and b):
• the initial values of the state variables are determined analytically by assuming that all the derivatives of the system of differential equations are zero.
• the treatment and control unit takes into account the history of insulin injected into the patient by the injection device and the history of glucose ingested by the patient.
• the physiological model is the Hovorka model.
• Another embodiment provides a method for automated regulation of the blood glucose of a patient, comprising: a step of calculating, by means of a treatment and control unit, a prediction of the future evolution of the patient's blood glucose level from a physiological model comprising a system of differential equations describing the evolution of a plurality of state variables as a function of time;
• an automatic calibration step of the physiological model comprising a step of estimating initial values of the state variables by minimizing a magnitude representative of the error, during a past observation period, between the glycemia estimated from the model physiological and blood glucose measured on the patient by a blood glucose sensor.
• the method further comprises a step of estimating parameters of the system of differential equations by minimizing said magnitude.
• the calibration step comprises a plurality of successive iterations of the following steps a) and b):
• Another embodiment provides an automated system for regulating a patient's blood glucose, comprising:
• a treatment and control unit adapted to predict the future evolution of the patient's blood glucose from a physiological model and to control the insulin injection device taking into account this prediction
• processing and control unit is adapted to: a) implementing an automatic calibration step of the physiological model, taking into account a history of glucose measured by the sensor during a past observation period;
• the digital indicator comprises an indicator m representative of the area between a first curve g representative of the time evolution of the glycemia estimated from the model over the observation period, and a second curve g representative of the temporal evolution of the glucose measured by the sensor over the period of observation.
• the indicator m is defined as follows:
• t is a discretized time variable
• t 0 is the start time of the observation phase
• t 0 + ⁇ T is the end time of the observation phase
• the digital indicator comprises an indicator m 1 representative of the difference between the glycemia estimated from the model and the glucose measured by the sensor at a given moment.
• the digital indicator comprises an indicator m 2 representative of the difference between the derivative of the glycemia estimated from the model and the derivative of the glucose measured by the sensor at a given instant.
• the control of the insulin injection device is a predictive control based on a simplified physiological model.
• step c) the insulin injection device is controlled to deliver preprogrammed insulin doses corresponding to a baseline reference flow prescribed to the patient.
• the physiological model comprises a system of differential equations describing the evolution of a plurality of state variables as a function of time
• the automatic calibration step a) comprises a step of estimating parameters of the system of differential equations by minimizing a magnitude representative of the error, during a past observation period, between the glycemia estimated from the physiological model and the glucose measured by the sensor.
• the automatic calibration step a) of the model further comprises a step of determining initial values of the state variables.
• Another embodiment provides a method for automated regulation of the blood glucose of a patient, comprising:
• this method further comprising:
• a step of determining the quality of the physiological model from at least one numerical indicator representative of the error between the blood glucose estimated from the model and the actual blood glucose measured by the sensor;
• Figure 1 schematically shows, in block form, an example of an embodiment of an automated system for regulating a patient's blood glucose
• Figure 2 is a simplified representation of a physiological model used in the system of Figure 1 to predict the future evolution of the patient's blood glucose;
• Fig. 3 is a diagram showing in more detail an exemplary embodiment of the physiological model of Fig. 2;
• FIG. 4 is a diagram illustrating an example of an automated method for regulating glucose levels implemented by the system of FIG. 1;
• FIG. 5 is a diagram illustrating an example of an embodiment of an automated calibration method implemented by the system of FIG. 1;
• FIG. 6 is a diagram illustrating an example of an embodiment of an automated method for regulating glucose levels implemented by the system of FIG. 1.
• Figure 1 schematically shows, in block form, an example of an embodiment of an automated system for regulating a patient's blood glucose.
• the system of Figure 1 comprises a sensor 101 (CG) adapted to measure the blood glucose of the patient.
• the sensor 101 may be positioned permanently on or in the body of the patient, for example at the level of his abdomen.
• the sensor 101 is for example a CGM (Continuous Glucose Monitoring) sensor, that is to say a sensor adapted to measure continuously (for example at least once per year). minute) the patient's blood glucose.
• the sensor 101 is for example a subcutaneous blood glucose sensor.
• the system of Figure 1 further comprises an insulin injection device 103 (PMP), for example a subcutaneous injection device.
• the device 103 is for example an insulin pump-type automatic injection device, comprising an insulin reservoir connected to an injection needle implanted under the patient's skin, the pump being electrically controllable to automatically inject doses of insulin determined at specific times.
• the injection device 103 can be positioned permanently in or on the body of the patient, for example at its abdomen.
• the system of FIG. 1 further comprises a treatment and control unit 105 (CTRL) connected on the one hand to the glucose sensor 101, for example by wire connection or by radio link (wireless), and secondly to the injection device 103, for example by wire or radio link.
• CTRL treatment and control unit
• the processing and control unit 105 is adapted to receive the patient's blood glucose data measured by the sensor 101, and electrically control the device 103 to inject the patient insulin doses determined at specific times.
• the processing and control unit 105 is furthermore adapted to receive, via a non-detailed user interface, data echo (t) representative of the evolution, as a function of time, of the amount of glucose ingested by the patient.
• the treatment and control unit 105 is adapted to determine the doses of insulin to be injected into the patient, taking into account, in particular, the history of blood glucose measured by the sensor 101, the history of insulin injected by the device 103 , and the history of glucose ingestion by the patient.
• the processing and control unit 105 comprises a numerical calculation circuit (not detailed), comprising for example a microprocessor.
• the treatment and control unit 105 is for example a mobile device carried by the patient throughout the day and / or night, for example a smartphone-type device configured to implement a type of control method described below.
• the treatment and control unit 105 is adapted to determine the amount of insulin to be administered to the patient, taking into account a prediction of the future evolution of its blood glucose as a function of the time. More particularly, the processing and control unit
• the treatment and control unit 105 determines the doses of insulin to be injected into the patient during the coming period, so that the actual blood glucose (as opposed to the blood glucose level estimated from physiological model) of the patient remains within acceptable limits, and in particular to limit the risk of hyperglycemia or hypoglycemia.
• the actual blood glucose data measured by the sensor 101 are used primarily for calibration purposes of the physiological model.
• Figure 2 is a simplified representation of a MPC physiological model used in the system of Figure 1 to predict the future evolution of the patient's blood glucose.
• the model is represented in the form of a processing block comprising:
• the physiological model MPC is a compartmental model comprising, in addition to the input variables i (t) and cho (t) and the output variable G (t), a plurality of state variables corresponding to physiological variables of the patient, evolving with time.
• the temporal evolution of the state variables is governed by a system of differential equations comprising a plurality of parameters represented in FIG. 2 by a vector [PARAM] applied to an input p1 of the MPC block.
• the response of the physiological model is further conditioned by the initial states or initial values assigned to the state variables, represented in FIG. 2 by a vector [INIT] applied to an input P2 of the MPC block.
• FIG. 3 is a diagram showing in greater detail a non-limiting example of the MPC physiological model used in the system of FIG. 1 for predicting the future evolution of the patient's blood glucose.
• This sample template known as Hovorka's model is described in more detail in the article "Nonlinear model predictive control of glucose concentration in subjects with type 1 diabetes” by Roman Hovorka et al. (Physiol Meas., 2004; 25: 905-920), and in the article entitled “Partitioning glucose distribution / transport, disposal, and endogenous production during IVGTT", by Roman Hovorka et al. (Am J Physiol Endocrinol Metab 282: E992-E1007, 2002).
• the physiological model of Figure 3 includes a first bi-compartmental sub-model 301 describing the effect of a glucose uptake on the rate of glucose onset in blood plasma.
• the submodel 301 takes for input the amount of glucose ingested (ch), for example in mmol / min, and provides at its output a UQ rate of glucose absorption in the blood plasma, for example in mmol / min.
• Sub-model 301 comprises two state variables D 1 and D 2 corresponding respectively to glucose masses, for example in mmol, in first and second compartments.
• the model of FIG. 3 further comprises a second bi-compartmental sub-model 303 describing the absorption, in the blood plasma, of the insulin administered to the patient.
• the sub-model 303 takes as input the amount of insulin i (t) injected into the patient, for example in mU / min, and provided at its output a rate 1 U of insulin absorption into the blood plasma, example in mU / min.
• Sub-model 303 comprises two state variables S 1 and S 2 corresponding respectively to insulin masses, for example in mmol, in first and second compartments.
• the model of Figure 3 further comprises a third submodel 305 describing glucose regulation by the patient's body.
• Submodel 305 takes as input the u G uptake rates of glucose and U 1 insulin, and provided at its output blood glucose G (t), that is to say the concentration of glucose in the blood. blood plasma, for example in mmol / l.
• the submodel 305 comprises six state variables Q 1 , Q 2 , x 3 , x 1 , x 2 , I ⁇
• the variables Q 1 and Q 2 correspond respectively to glucose masses, for example in mmol, in first and second second compartments.
• the variables x 1 , x 2 , x 3 are unitless variables representing each of the actions of insulin on glucose kinetics.
• Variable I corresponds to insulinemia, ie the concentration of insulin in the blood plasma, for example in mU / l.
• the Hovorka model is governed by the following system of equations:
• EGP 0 , k b1 , k a1 , k b2 , k a2 , k b3 , k a3 , k a , V I , k e and t max are parameters.
• V Q corresponds to the volume of distribution of glucose, for example in liters
• F 01 corresponds to a non-insulin-dependent glucose transfer rate, for example in mmol / min
• k 12 corresponds to a transfer rate constant between the two compartments of submodel 305, for example in min -1
• k a1 , k a2 , k a3 correspond to insulin deactivation rate constants, for example in min -1
• FR corresponds to urinary excretion of glucose, for example in mmol / min
• EGP 0 corresponds to an endogenous production of glucose, for example in min -1
• k b1 , k b2 and k b3 correspond to constants of insulin activation rate
• k a corresponds to a constant absorption rate of insulin injected subcutaneously
• Vj corresponds to the insulin distribution volume, for example in liters
• k e corresponds a removal rate of insulin from plasma
• the vector [INIT] comprises for its part ten values corresponding to the initial values (at a time t 0 of the beginning of a simulation phase of the patient's behavior from the model) assigned to the ten state variables D] _, D 2 , S 1 , S 2 , Q 1 , Q 2 , x 1 , x 2 , x 1 _ and I of the model.
• cert can be considered constant for a given patient. This is for example the parameters k 12, k a1, k a2, a3 k, k a, k e, V I, V and G t max.
• Other parameters hereinafter referred to as time-dependent parameters, are however capable of changing over time, for example the parameters k b1 , k b2 k b3 , E GP 0 , F 01 and F. Due to this variability of certain parameters of the system, it is in practice necessary to recalibrate or re- Regularly calibrate the model in use, for example every 1 to 20 minutes, to ensure that model predictions remain relevant. This update of the model, also called model customization, must be able to be performed automatically by the system of FIG. 1, that is to say without it being necessary to physically measure the time-dependent parameters of the model. system on the patient and then transmit them to the processing and control unit 105.
• FIG. 4 is a diagram illustrating an example of an automated method for regulating glucose levels implemented by the system of FIG. 1.
• This method comprises a step 401 for recalibration or updating of the model, which may for example be repeated at regular intervals, for example every 1 to 20 minutes.
• the processing and control unit 105 implements a method for re-estimating the time-dependent parameters of the model, taking into account the insulin data actually injected by the device 103 and actual blood glucose data. measured by the sensor 101 during a past observation period, for example a period of 1 to 10 hours preceding the calibration step. More particularly, during the calibration step, the treatment and control unit 105 simulates the behavior of the patient over the observation period passed from the physiological model (taking into account possible glucose ingestions and injections of insulin during this period), and compares the model's estimated blood glucose curve to the actual blood glucose curve measured by the sensor during that time.
• the processing and control unit 105 searches for, for the time-dependent parameters of the model, a set of values leading to minimize a magnitude representative of the error between the glycemic curve estimated by the model and the actual blood glucose curve. during the observation period.
• the treatment and control unit seeks a set of parameters leading to minimize an indicator m representative of the area between the blood glucose curve. estimated by the model and the actual blood glucose curve during the observation period, for example defined as:
• t is the discretized time variable
• t 0 corresponds to the start time of the past observation phase
• t 0 + ⁇ T corresponds to the end time of the past observation phase (corresponding, for example, to the start time of the model calibration step)
• g is the time evolution curve of the actual blood glucose measured by the sensor 101 during the period [t 0 , tg + ⁇ T]
• g is the estimated blood glucose curve from the model during the period [tg, tg + ⁇ T].
• the optimal parameter search algorithm used during this step is not detailed in the present application, the described embodiments being compatible with the usual algorithms used in various fields to solve problems of parameter optimization by minimization. a cost function.
• the method of FIG. 4 further comprises, after step 401, a step 403 of prediction, by the treatment and control unit 105, of the temporal evolution of the patient's blood glucose level over a future period, at from the physiological model updated in step 401 and taking into account the history of insulin injected into the patient and the history of glucose ingested by the patient.
• the process of FIG. 4 further comprises, after the step
• the treatment and control unit 105 can program the injection device 103 to administer the determined doses during the coming period.
• the steps 403 for predicting blood glucose and 405 and determining the future doses of insulin to be administered may, for example, be repeated each time the physiological model is updated (that is to say after each iteration of step 401). at each new ingestion of glucose reported by the patient, and / or at each new administration of a dose of insulin by the injection device 103.
• a problem that arises in the operation described above is that, during the updating of the physiological model in step 401, the processing and control unit 105 must define a vector [INIT] of initial states. (states to tg) model state variables, to be able to simulate the behavior of the patient from the model. These initial states are necessary not only in order to predict the future evolution of the patient's blood glucose (step 403), but also during the updating step of the model itself (step 401), in order to be able to simulate the evolution the patient's blood glucose level during the observation period, so that the simulated glucose level can be compared to the measured blood glucose level.
• a first possibility is to assume that, in the period preceding the observation period [t 0 , tg + ⁇ T] on which the calibration of the model is based, the patient was in a steady state, with constant injected insulin delivery, and no food intake of glucose. Under this assumption, all the derivatives of the system of differential equations can be considered as zero at the initial moment t 0 ⁇ The values at t 0 of the state variables of the system can then be calculated analytically.
• the output of the model (the estimated glycemia) is not constrained.
• the estimated blood glucose at time t 0 may be different from the actual blood glucose measured at time t g.
• the algorithm used in step 401 for searching the time-dependent parameters of the model by Minimizing the error between simulated glucose and measured blood glucose may be difficult to converge.
• a second possibility consists in making the same hypotheses as before, but by constraining the variable Q 1 (t 0 ) so that the glycemia estimated at time t 0 is equal to the real blood glucose measured by the sensor. This makes it possible to improve the relevance of the initialization at time t 0 .
• the derivative of the estimated blood glucose and the derivative of the actual blood glucose may diverge.
• the search algorithm for the time-dependent parameters of the system can again find it difficult to converge.
• the initial states [INIT] of the model are considered to be random variables.
• a search for an optimal set of initial state values by minimizing a magnitude representative of the error between the estimated blood glucose curve from the model and the actual blood glucose curve during the observation period on which the calibration is based.
• the optimal values of the time-dependent parameters and the initial states of the state variables can be determined simultaneously, in the same step model optimization by minimizing the error between the estimated blood glucose and the actual blood glucose over the past observation period.
• the cumulative number of time-dependent parameters and 'states is relatively large, which can lead to numerical instability during the search phase of optimal values. In other words, some values can be difficult or impossible to estimate in a single search, the number of unknowns is too important.
• the problem can be decomposed into two sub-problems, respectively corresponding to the estimation of the time-dependent parameters of the model and to the estimation of the initial states of the model, as will now be described in connection with FIG. 5.
• FIG. 5 is a diagram illustrating an example of an embodiment of an automated method for calibrating or updating the system of FIG. 1, corresponding to an exemplary implementation of step 401 of FIG. 4.
• This method comprises a step 501 during which the parameter vector [PARAM] (here reduced to only the time-dependent parameters of the model) is initialized to a first set of values P1.
• the set PI corresponds for example to the values taken by the [PARAM] parameters before the start of the model update phase.
• the set of values PI is a predetermined reference set corresponding, for example, to the average values taken by the parameters [PARAM] over a reference period.
• the initial state vector [INIT] of the state variables is further initialized to a first set of value II.
• the set of values II is, for example, determined analytically as described above, by assuming a stationary state of the patient in the period preceding the calibration phase, and by making the estimated blood glucose coincide at time t 0 and the actual blood glucose measured at that moment.
• the processing and control unit 105 searches, by fixing the set of initial states [INIT] to its current state, a set of values of the time-dependent parameters of the model leading to minimizing a magnitude representative of the error between the estimated glucose curve from the model and the actual blood glucose curve during the observation period, for example the indicator m defined above.
• the vector [PARAM] is updated with the new estimated values.
• step 505 subsequent to step 503, the processing and control unit 105 searches, by setting the parameter set [PARAM] to its current state, a set of initial state values of the variables of a condition leading to minimizing a magnitude representative of the error between the estimated glucose curve from the model and the actual blood glucose curve during the observation period, for example the indicator m defined above, or any other representative indicator the error between the two curves, for example an indicator based on the standard L1.
• the vector [INIT] is updated with the new estimated values.
• the steps 503 and 505 are repeated a predetermined number N N, where N is an integer greater than 1.
• the values of the time-dependent parameters and initial states of the updated model then correspond to the values of the vectors [ PARAM] and [INIT] at the end of the Nth iteration of the steps 503 and 505.
• the number of iterations of the steps 503 and 505 may not be predetermined, and be adjusted taking into account the evolution the m error indicator between the estimated blood glucose from the model and the actual blood glucose over the observation period.
• An object of another embodiment is to limit the risks to the patient related to a possible failure of the physiological model used to predict the patient's future blood glucose.
• control and processing device 105 of the regulation system is adapted, after each update or re-calibration of the physiological model (step 401), to estimate the quality of the physiological model updated with one or more quality numeric indicators and, if the quality of the model is considered unsatisfactory, to stop using the model to regulate the patient's blood glucose.
• FIG. 6 is a diagram illustrating an example of an embodiment of an automated method for regulating glucose levels implemented by the system of FIG. 1.
• This method comprises the same steps 401, 403 and 405 as in the example of FIG. 4.
• the method of FIG. 6 further comprises, after each step 401 of updating the physiological model operated by the regulation system and before the implementation of the following steps 403 for predicting the patient's future blood glucose from the model and 405 for controlling the delivery of insulin from the prediction of blood glucose, a step 601 of verifying the quality of the model set up to date.
• step 601 the processing and control unit 105 determines one or more digital indicators of the quality of the model updated at step 401.
• the treatment and control unit calculates a quality digital indicator representative of the area between the blood glucose curve estimated from the model and the actual glucose curve measured by the sensor 101 during a past observation period. This indicator corresponds for example to the magnitude m defined above.
• the processing and control unit 105 may calculate the one and / or or the other of the following quality indicators m 1 and m 2 :
• g corresponds to the time evolution function of the actual glucose measured by the sensor 101
• g corresponds to the function of temporal evolution of the simulated glycemia from the model
• g ' corresponds to the derivative of the temporal evolution function of the real blood glucose
• g' corresponds to the derivative of the time evolution function of the simulated glycemia.
• the quality of the model can be considered satisfactory by the processing and control unit 105 when the values m, m 1 and m 2 are lower than predefined thresholds. More generally, any other quality criterion or combination of quality criteria may be used in step 601 to determine whether the physiological model re-calibrated at step 401 can be considered reliable.
• steps 403 and 405 may be implemented in a manner similar to that described above, ie, the processing and control 105 continues to be based on the predictions made by the model physiological to regulate the administration of insulin to the patient.
• the processing and control unit 105 ceases to use this model to regulate the administration of insulin to the patient, and implements a method of substitution control during a step 603.
• the processing and control unit 105 uses a simplified physiological model, for example a compartmental model comprising a number of state variables and a reduced number of parameters with respect to the initial model, to predict the evolution of the patient's blood glucose and regulate the insulin injection accordingly.
• a simplified physiological model for example a compartmental model comprising a number of state variables and a reduced number of parameters with respect to the initial model
• the processing and control unit 105 ceases to implement predictive control, i.e., it ceases to use a physiological model to predict the the patient's future blood glucose and regulate the insulin injection accordingly.
• the treatment and control unit 105 controls, for example, the insulin injection device 103 to administer pre-programmed doses of insulin, corresponding for example to a baseline reference flow prescribed to the patient.
• Such a substitution method may for example be used for a predetermined period of time.
• the calibration steps 401 of the main physiological model and 601 of the estimation of the quality of the main physiological model can be reiterated, for, if the quality of the main physiological model is judged satisfactory, reactivate the use of this model to regulate the administration of insulin to the patient.
• the method of FIG. 6 is not limited to the embodiment described with reference to FIGS. 4 and 5, in which the calibration of the physiological model comprises a step of determining the initial values of the state variables of the model by minimization of a representative magnitude the error between the measured blood glucose data and the estimated blood glucose during an observation period, but can be used regardless of the chosen method of determining the initial values of the model state variables.
• the embodiments described are not limited to the particular example of a physiological model detailed in the present description, namely the Hovorka model, but are compatible with any physiological model describing the assimilation of insulin by the patient. body of a patient and its effect on the patient's blood glucose, for example the so-called Cobelli model, described in the article "A System Model of Oral Glucose Absorption: Validation on Gold Standard Data” by Chiara Dalla Man et al . (IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING, VOL 53, NO.12, DECEMBER 2006).

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