Blood glucose control system

Abstract

Techniques are used for adaptation of drug-administration parameters that control insulin delivery in a blood glucose control system. One technique provides long-term adaptation of a nominal basal infusion rate, adapting to longer-term changes in a patient's needs due to growth, illness, hormonal fluctuations, physical activity, aging, etc. Another technique provides adaptation of priming dose size at mealtimes for overall better glycemic control and also adapting to longer-term changes in a patient's needs. Adaptation calculations use a receding-horizon window of recent values of the adapted parameter. doses of a counter-regulatory agent (e.g., glucagon) may also be delivered in response to information about estimated accumulation of exogenously infused insulin (subcutaneously, intramuscularly, intraperitoneally, or intravenously) and/or the effect insulin might have on glucose levels (blood glucose concentration or interstitial fluid glucose concentration).

Description

STATEMENT OF GOVERNMENT RIGHTS

This invention was made with Government Support under Contract No. DK085633 awarded by the National Institutes of Health. The US Government has certain rights in the invention.

where G_max is the maximum allowable glucagon dose (which may be infinite), t is in discrete time, k_p is the proportional gain, k_d is the derivative gain, T_s is the sampling period, i_e(t) is the estimated accumulation of exogenously infused insulin, and ƒ(i_e(t)) is some specified function of i_e(t) that has units of G_dose(t). An example ƒ(i_e(t)) might be a sigmoidal function that is near unity whenever i_e(t) is less than some factor times some estimated nominal or baseline value of the plasma insulin level and then begins to increase significantly as i_e(t) exceeds this nominal value. Alternatively, in another embodiment, the dependence of G_dose(t) on i_e(t) might appear in an additive way, by the introduction of an additional gain parameter, k_i, such that
G_dose(t)=k_p(β−y_t)+k_d(y_t-1−y_t)/T_s+k_di_e(t); 0≤G_dose(t)≤G_max,  (8)
where k_i might vanish whenever i_e(t) is less than some factor times some estimated nominal or baseline value of the plasma insulin level.

Variations on the above examples might include an additive term, G_pending(t), which is deducted from G_dose(t), and which represents an estimate of pending subcutaneous glucagon from recent doses. This could be computed, for example, with a function such as

$\begin{array}{cc}{G}_{\mathrm{pending}}\left(t\right)=\sum _{k=1}^{90/T_s}{G}_{\mathrm{dose}}\left(t-k\right){\left(\frac{1}{2}\right)}^{k{T}_s{G}_{1/2}}& \left(9\right)\end{array}$
where G_1/2 is an estimate of the average half life of subcutaneous doses of glucagon. Note that the estimate G_pending(t) limits unnecessary subcutaneous accumulation of glucagon. Thus, including G_pending(t) in Equations (7) and (8) could provide the alternate forms given by
G_dose(t)=ƒ(i_e(t)){k_p(β−y_t)+k_d(y_t-1−y_t)/T_s−G_pending(t)}; 0≤G_dose(t)≤G_max,  (10)
G_dose(t)=k_p(β−y_t)+k_d(y_t-1−y_t)/T_s+k_di_e(t)−G_pending(t); 0≤G_dose(t)≤G_max,  (11)
Alternatively, G_pending(t) might appear in an additive way, by the introduction of an additional gain parameter, k_g, such that G_pending(t) in Equations (10) and (11) might be replaced by k_gg_e(t), where g_e(t) is the estimated accumulation of exogenously infused glucagon.

In yet another embodiment, the control doses of glucagon, G_dose(t), may employ a model predictive control (MPC) strategy, where the modulation of glucagon doses due to the estimated accumulation of exogenously infused insulin, i_e(t), could be achieved using an outer scaling function (similar to the function ƒ(i_e(t)) in Equation (7)). For example, the control doses of glucagon may be computed as:
G_dose(t)=g(i_e(t))u_t; 0≤G_dose(t)≤G_max,  (12)
where u_t is the MPC glucagon dose signal and g(i_e(t)) is an outer scaling that is similar or identical to ƒ(i_e(t)) in that it is some function that is near unity whenever i_e(t) is less than some factor times some estimated nominal or baseline value of the plasma insulin level and is significantly higher when as i_e(t) exceeds this nominal value. One example for computing u_t is using an MPC cost function such as:

$\begin{array}{cc}J=\sum _{k=N_d}^{N_m}{\delta }_k{C\left(r_{t+k}-y_{t+k}\right)}^2+\sum _{k=0}^{N_u}{{\lambda }_k\left(\Delta u_{t+k}\right)}^2& \left(13\right)\end{array}$
where u_t denotes the MPC glucagon dose signal, y_t the glucose concentration signal, r_t the reference set point signal, N_d and N_m are respectively the minimum and maximum (output) prediction costing horizon limits, N_u the control horizon bound, m the weighting on prediction error, and λ_n the weighting on control signals. The glucose concentration, y_t, and the glucagon dose signal, u_t, could also be related by subject model. Upon solving Equation (13) for the MPC glucagon dose signal, u_t, the outer scaling with g(i_e(t)) could then be applied as per Equation (12) to compute the control doses of glucagon, G_dose(t). Alternatively, the control doses of glucagon, G_dose(t), could be based on the MPC glucagon dose signal, u_t, and an incorporation of the effect of i_e(t) in an additive way, by the introduction of a gain parameter, k_i, such that
G_dose(t)=u_t+k_ii_e)t); 0≤G_dose(t)≤G_max,  (14)
where k_i might vanish whenever i_e(t) is less than some factor times some estimated nominal or baseline value of the plasma insulin level.

Furthermore, the control doses of glucagon, G_dose(t), could also take into account the accumulation of glucagon from past glucagon doses. This could be handled by computing a quantity G_pending(t) similar to that described in Equation (9) and computing the control doses of glucagon as per
G_dose(t)=g(i_e(t)){u_t−G_pending(t)}; 0≤G_dose(t)≤G_max,  (15)
or
G_dose(t)=u_t+k_i(i_e(t))−G_pending(t); 0≤G_dose(t)≤G_max,  (16)
Alternatively, G_pending(t) might appear in an additive way, by the introduction of an additional gain parameter, k_g, such that G_pending(t) in Equations (15) and (16) might be replaced by k_gg_e(t), where g_e(t) is the estimated accumulation of exogenously infused glucagon.

Another option for accounting for the accumulation of glucagon from past doses is by augmenting the MPC cost function in Equation (13) with a mathematical formulation that estimates the accumulation of exogenous glucagon in a manner similar to that described in US patent publication 2008/0208113A1. Such an augmentation could take into account the accumulation of glucagon in both the administration site(s) as well as in plasma and could be based on pharmacokinetics of the administered glucagon pertaining to the method or route of administration as well as to the specific constituents present in the glucagon solution, including the type of glucagon or glucagon analog itself. With such an augmentation in effect, the MPC glucagon dose signal, u_t, becomes an augmented MPC glucagon dose signal, μ′_t. The augmented MPC glucagon dose signal, μ′_t, could replace the MPC glucagon dose signal, μ_t in both Equations (12) and (14) to provide the control doses of glucagon, G_dose(t).

Other control signals could replace the MPC glucagon dose signal, u_t, in Equations (12), (14), (15), or (16) and could be based on another algorithm such as a neural network, or a fuzzy logic, or a standard optimization algorithm.

In all the formulations above, the function i_e(t) may be computed by any manner by which the accumulation of exogenously infused insulin might be estimated.

It will be appreciated that the present invention may be embodied as an overall system such as shown in FIG. 1, as an overall method, as a controller such as shown in FIG. 2, and as methods performed by a controller such as shown in FIGS. 3-5. With respect to the methods performed by a controller, the methods may be performed by computer program instructions executed by generic controller hardware including memory, a processing or execution unit, and input/output circuitry. The instructions may be provided to the controller from a computer-readable medium such as semiconductor memory, magnetic memory (e.g. magnetic disk), optical memory (e.g. optical disk such as CD, DVD), etc.

While various embodiments of the invention have been particularly shown and described, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention as defined by the appended claims.

Claims

1. A sensor-driven glucose control system, comprising:

an insulin delivery device operative in response to an insulin dose control signal to infuse insulin into the subject; and

a controller operative to generate the insulin dose control signal by:

(1) continually administering priming doses of insulin at respective times, each priming dose being of a respective amount and having a prescribed interval of action;

(2) receiving information regarding total amounts of insulin administered during the prescribed intervals of action, each total amount including an aggregation of total doses administered in response to a glucose level signal; and

(3) automatically adapting the amounts of the priming doses in response to a mathematical relationship, over respective periods each spanning multiple prescribed intervals of action, between the amounts of the priming doses and the total amounts of insulin administered during the prescribed intervals of action.

2. A sensor-driven glucose control system according to claim 1, wherein the mathematical relationship includes a target ratio of the amount of each priming dose to the total amount of insulin administered in each prescribed interval of action.

3. A sensor-driven glucose control system according to claim 2, wherein the target ratio has different values over respective time periods of a day, or over different prescribed intervals of action, or both.

4. A sensor-driven glucose control system according to claim 3, wherein the time periods have a regularity associated with timing of food consumption.

5. A sensor-driven glucose control system according to claim 1, wherein each period is defined by a receding-horizon time window extending back from a present time by a predetermined amount of time.

6. A sensor-driven glucose control system according to claim 1, being an autonomous or semi-autonomous control system in which the controller includes a corrective insulin controller that generates the insulin dose control signal in response to the glucose level signal to administer corrective doses of insulin so as to regulate the glucose level signal.

7. A sensor-driven glucose control systemaccording to claim 1,, comprising:

an insulin delivery device configured to receive an insulin dose control signal and operative in response to the insulin dose control signal to infuse priming doses of insulin to a subject; and

a controller configured and operative to generate the insulin dose control signal and send it to the insulin delivery device to:

(1) continually administer the priming doses of insulin at respective times, each priming dose being of a respective amount and having a prescribed interval of action;

(2) receive information regarding total amounts of insulin administered during the prescribed intervals of action, each total amount including an aggregation of total doses administered in response to a glucose level signal; and

(3) automatically adapt the amounts of the priming doses in response to a mathematical relationship, over respective periods each spanning multiple prescribed intervals of action, between the amounts of the priming doses and the total amounts of insulin administered during the prescribed intervals of action,

and further comprising a counter-regulatory agent delivery device configured to receive a counter-regulatory agent dose control signal and operative to infuse a counter-regulatory agent into the subject in response to a the counter-regulatory agent dose control signal, and wherein the controller is operative to generate the counter-regulatory agent dose control signal and send it to the counter-regulatory agent delivery device by performing a calculation generating (1) a raw dose control value based on the glucose level signal, and (2) the counter-regulatory agent dose control signal as a modification of the raw dose control value based on an estimation of an effect of insulin infused into the subject by the insulin delivery device.

8. A method of operating a controller for a sensor-driven glucose control system including an insulin delivery device configured to receive an insulin dose control signal and operative in response to an the insulin dose control signal to infuse insulin into the a subject, comprising:

generating the insulin dose control signal and sending it to the insulin delivery device to continually administer priming doses of insulin at respective times, each priming dose being of a respective amount and having a prescribed interval of action;

receiving information regarding total amounts of insulin administered during the prescribed intervals of action, each total amount including an aggregation of total doses administered in response to a glucose level signal; and

automatically adapting the amounts of the priming doses in response to a mathematical relationship, over respective periods each spanning multiple prescribed intervals of action, between the amounts of the priming doses and the total amounts of insulin administered during the prescribed intervals of action.

9. A method according to claim 8, wherein the mathematical relationship includes a target ratio of the amount of each priming dose the priming doses to the total amount amounts of insulin administered in each prescribed interval during the prescribed intervals of action.

10. A method according to claim 9, wherein the target ratio has different values over respective time periods of a day, or over different prescribed intervals of action, or both.

11. A method according to claim 10, wherein the time periods have a regularity associated with timing of food consumption.

12. A method according to claim 8, wherein each period is defined by a receding-horizon time window extending back from a present time by a predetermined amount of time.

13. A method according to claim 8, wherein the sensor-driven glucose control system is an autonomous or semi-autonomous control system in which the controller includes a corrective insulin controller that generates the insulin dose control signal in response to the glucose level signal to administer corrective doses of insulin so as to regulate the glucose level signal.

14. A method according to claim 8, wherein the sensor-driven glucose control system further includes a counter-regulatory agent delivery device configured to receive a counter-regulatory agent dose control signal and operative to infuse a counter-regulatory agent into the subject in response to a the counter-regulatory agent dose control signal, and wherein the method further includes generating the counter-regulatory agent dose control signal and sending it to the counter-regulatory agent delivery device by performing a calculation generating (1) a raw dose control value based on the glucose level signal, and (2) the counter-regulatory agent dose control signal as a modification of the raw dose control value based on an estimation of an effect of insulin infused into the subject by the insulin delivery device.

15. A sensor-driven glucose control system, comprising:

a controller configured and operative to generate an insulin dose control signal and send it to an insulin delivery device to:

(1) continually administer priming doses of insulin at respective times, each priming dose being of a respective amount and having a prescribed interval of action;

(2) receive information regarding total amounts of insulin administered during the prescribed intervals of action, each total amount including an aggregation of total doses administered in response to a glucose level signal; and

(3) automatically adapt the amounts of the priming doses in response to a mathematical relationship, over respective periods each spanning multiple prescribed intervals of action, between the amounts of the priming doses and the total amounts of insulin administered during the prescribed intervals of action,

wherein the controller is operative to generate a counter-regulatory agent dose control signal and send it to a counter-regulatory agent delivery device to cause the counter-regulatory agent delivery device to infuse a counter-regulatory agent into the subject, by performing a calculation generating (1) a raw dose control value based on the glucose level signal, and (2) the counter-regulatory agent dose control signal as a modification of the raw dose control value based on an estimation of an effect of insulin infused into the subject.

16. A method of operating a controller for a sensor-driven glucose control system having an insulin delivery device configured to receive an insulin dose control signal and operative in response to the insulin dose control signal to infuse insulin into a subject, comprising:

generating the insulin dose control signal and sending it to the insulin delivery device to cause the insulin delivery device to continually administer priming doses of insulin at respective times, each priming dose being of a respective amount and having a prescribed interval of action;

receiving information regarding total amounts of insulin administered during the prescribed intervals of action, each total amount including an aggregation of total doses administered in response to a glucose level signal; and

automatically adapting the amounts of the priming doses in response to a mathematical relationship, over respective periods each spanning multiple prescribed intervals of action, between the amounts of the priming doses and the total amounts of insulin administered during the prescribed intervals of action.

17. A method according to claim 16, wherein the mathematical relationship includes a target ratio of the amounts of the priming doses to the total amounts of insulin administered during the prescribed intervals of action.

18. A method according to claim 17, wherein the target ratio has different values over respective time periods of a day, or over different prescribed intervals of action, or both.

19. A method according to claim 18, wherein the time periods have a regularity associated with timing of food consumption.

20. A method according to claim 16, wherein each period is defined by a receding-horizon time window extending back from a present time by a predetermined amount of time.

21. A method according to claim 16, wherein the sensor-driven glucose control system is an autonomous or semi-autonomous control system in which the controller includes a corrective insulin controller that generates the insulin dose control signal in response to the glucose level signal to administer corrective doses of insulin so as to regulate the glucose level signal.

22. A method according to claim 16, wherein the sensor-driven glucose control system further includes a counter-regulatory agent delivery device configured to receive a counter-regulatory agent dose control signal and operative to infuse a counter-regulatory agent into the subject in response to the counter-regulatory agent dose control signal, and wherein the method further includes generating the counter-regulatory agent dose control signal and sending it to the counter-regulatory agent delivery device by performing a calculation generating (1) a raw dose control value based on the glucose level signal, and (2) the counter-regulatory agent dose control signal as a modification of the raw dose control value based on an estimation of an effect of insulin infused into the subject.