BLOOD GLUCOSE CONTROL SYSTEM

• US 20130245547A1
• Filed: 04/25/2013
• Published: 09/19/2013
• Est. Priority Date: 10/31/2010
• Status: Active Grant

• Current Assignee: The General Hospital Corporation (Mass General Brigham, Inc.), Trustees of Boston University
• Original Assignee: Trustees of Boston University
• Inventors: El-Khatib, Firas, Damiano, Edward
• Granted Patent: US 9,833,570 B2
• Time in Patent Office: Days
• US Class Current: 604/66
• CPC Class Codes: A61M 2005/1402 Priming
• CPC Class Codes: A61M 2005/14208 with a programmable infusion control system, characterised by the infusion program
• CPC Class Codes: A61M 2202/07 Proteins
• CPC Class Codes: A61M 2205/52 with memories providing a history of measured variating parameters of apparatus or patient
• CPC Class Codes: A61M 2230/201 Glucose concentration
• CPC Class Codes: A61M 5/14244 adapted to be carried by the patient, e.g. portable on the body
• CPC Class Codes: A61M 5/14248 of the skin patch type
• CPC Class Codes: A61M 5/1723 using feedback of body parameters, e.g. blood-sugar, pressure measurement of body parameters A61B5/00
• CPC Class Codes: G16H 20/13 delivered from dispensers
• CPC Class Codes: G16H 20/17 delivered via infusion or injection
• CPC Class Codes: G16H 40/63 for local operation
• CPC Class Codes: G16H 50/50 for simulation or modelling of medical disorders
• CPC Class Codes: G16Z 99/00 Subject matter not provided for in other main groups of this subclass

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).

Claims

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

a glucose sensor operative to continually measure glucose level of a subject and generate a corresponding glucose level signal;

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 in response to the glucose level signal by;

(1) modulating a basal infusion rate of insulin about a nominal basal infusion rate in response to short-term variations of glucose level occurring on the order of seconds to minutes; and

(2) continually adjusting the nominal basal infusion rate based on a mathematical relationship between the basal infusion rate as modulated and the nominal basal infusion rate over a longer term than a short term associated with modulating the basal infusion rate.

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

3. 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.

4. A sensor-driven glucose control system according to claim 1, wherein the modulation of the basal infusion rate of insulin is limited to a range between predetermined minimum and maximum limit values that determine actual modulation of the basal infusion rate when a calculated raw modulation value falls outside the range.

5. A sensor-driven glucose control system according to claim 4, wherein the maximum limit value has a predetermined mathematical relationship to the nominal basal infusion rate.

6. A sensor-driven glucose control system according to claim 1, wherein continually adjusting the nominal basal infusion rate includes calculating a moving integral or summed average of the modulated basal infusion rate over the longer term.

7. A sensor-driven glucose control system according to claim 1, wherein continually adjusting the nominal basal infusion rate includes calculating a ratio of the modulated basal infusion rate to the nominal basal infusion rate over the longer term.

8. A sensor-driven glucose control system according to claim 7, wherein continually adjusting the nominal basal infusion rate includes calculating the ratio of the modulated basal infusion rate to the nominal basal infusion rate as a moving integral or summed average of ratios of the corresponding instantaneous values of each rate over the longer term.

9. A sensor-driven glucose control system according to claim 7, wherein continually adjusting the nominal basal infusion rate includes calculating the ratio of the modulated basal infusion rate to the nominal basal infusion rate as a moving integral or summed average of weighted ratios of the corresponding instantaneous values of each rate over the longer term.

10. A sensor-driven glucose control system according to claim 1, wherein the controller is further operative to generate the insulin dose control signal in response to the glucose level signal by:

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

(4) 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 the glucose level signal; and

(5) 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.

11. A sensor-driven glucose control system according to claim 1, further comprising a counter-regulatory agent delivery device operative to infuse a counter-regulatory agent into the subject in response to a counter-regulatory agent dose control signal, and wherein the controller is operative to generate the counter-regulatory agent dose control signal by performing a calculation generating (3) a raw dose control value based on the glucose level signal, and (4) 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.

12. 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.

13. A sensor-driven glucose control system according to claim 12, 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.

14. A sensor-driven glucose control system according to claim 13, wherein the target ratio has different values over respective time periods of a day, or over different prescribed intervals of action, or both.

15. A sensor-driven glucose control system according to claim 14, wherein the time periods have a regularity associated with timing of food consumption.

16. A sensor-driven glucose control system according to claim 12, wherein each period is defined by a receding-horizon time window extending back from a present time by a predetermined amount of time.

17. A sensor-driven glucose control system according to claim 12, 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.

18. A sensor-driven glucose control system according to claim 12, further comprising a counter-regulatory agent delivery device operative to infuse a counter-regulatory agent into the subject in response to a counter-regulatory agent dose control signal, and wherein the controller is operative to generate the counter-regulatory agent dose control signal 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.

19. A system for control of blood glucose level of a subject receiving exogenously infused insulin, comprising:

a glucose sensor operative to continually sense a glucose level of the subject and generate a corresponding glucose level signal;

a delivery device operative to infuse a counter-regulatory agent into the subject in response to a counter-regulatory agent dose control signal; and

a controller operative to generate the counter-regulatory agent dose control signal 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 the exogenously infused insulin.

20. A system according to claim 19, wherein the estimation of the effect of the exogenously infused insulin includes an estimation of an amount of insulin in the subject that will have a future effect.

21. A system according to claim 20, wherein the estimation of the amount of insulin in the subject includes an estimation of the accumulated amount due to a finite utilization rate in the subject.

22. A system according to claim 19, wherein performing the calculation includes performing a proportional-derivative or proportional-integral-derivative control strategy to generate the raw dose control signal.

23. A system according to claim 19, wherein performing the calculation to generate the modification of the raw dose control value includes scaling the raw dose control value using a function of an estimated accumulation of the exogenously infused insulin.

24. A system according to claim 19, wherein performing the calculation to generate the modification of the raw dose control value includes adding the raw dose control value to a mathematical expression based on an estimated accumulation of the exogenously infused insulin.

25. A system according to claim 19, wherein performing the modification of the raw dose control value is further based on an estimation of an effect of previously delivered doses of the counter-regulatory agent based on a finite utilization rate in the subject.

26. A system according to claim 19, wherein the counter-regulatory agent includes glucagon.

27. A system according to claim 19, wherein the counter-regulatory agent includes intravenously administered dextrose.

28. A system according to claim 19, including autonomous, semi-autonomous, or non-autonomous control over the exogenously infused insulin, the non-autonomous control being user control and not sensor-driven.

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

a glucose sensor operative to continually measure glucose level of a subject and generate a corresponding glucose level signal;

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

counter-regulatory agent delivery device operative to infuse a counter-regulatory agent into the subject in response to a counter-regulatory agent dose control signal; and

a controller operative to generate the insulin dose control signal and counter-regulatory agent dose control signal in response to the glucose level signal by;

(1) modulating a basal infusion rate of insulin about a nominal basal infusion rate in response to short-term variations of glucose level occurring on the order of seconds to minutes;

(2) continually adjusting the nominal basal infusion rate based on a mathematical relationship between the basal infusion rate as modulated and the nominal basal infusion rate over a longer term than a short term associated with modulating the basal infusion rate;

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

(4) maintaining 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 the glucose level signal;

(5) 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; and

(6) generating the counter-regulatory agent dose control signal by performing a calculation generating (a) a raw dose control value based on the glucose level signal, and (b) 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.

30. A sensor-driven glucose control system according to claim 29, 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.

31. A method of operating a controller for a sensor-driven glucose control system including a glucose sensor and an insulin delivery device, the glucose sensor operative to continually measure glucose level of a subject and generate a corresponding glucose level signal, the insulin delivery device operative in response to an insulin dose control signal to infuse insulin into the subject, comprising:

modulating a basal infusion rate of insulin about a nominal basal infusion rate in response to short-term variations of glucose level occurring on the order of seconds to minutes as indicated by the glucose level signal;

continually adjusting the nominal basal infusion rate based on a mathematical relationship between the basal infusion rate as modulated and the nominal basal infusion rate over a longer term than a short term associated with modulating the basal infusion rate; and

generating the insulin dose control signal in accordance with the modulated basal infusion rate.

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

generating the insulin dose control signal 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.

33. A method of operating a controller for a system for control of blood glucose level of a subject receiving exogenously infused insulin, the system including a glucose sensor and a delivery device, the glucose sensor operative to continually sense a glucose level of the subject and generate a corresponding glucose level signal, the delivery device operative to infuse a counter-regulatory agent into the subject in response to a counter-regulatory agent dose control signal, comprising:

performing a calculation generating (1) a raw dose control value based on the glucose level signal, and (2) a counter-regulatory agent dose control value as a modification of the raw dose control value based on an estimation of an effect of the exogenously infused insulin; and

generating the counter-regulatory agent dose control signal in accordance with the counter-regulatory agent dose control value.

34. A method of operating a controller for a sensor-driven glucose control system including a glucose sensor, an insulin delivery device, and a counter-regulatory agent delivery device, the glucose sensor being operative to continually measure glucose level of a subject and generate a corresponding glucose level signal, the insulin delivery device operative in response to an insulin dose control signal to infuse insulin into the subject, and the counter-regulatory agent delivery device operative to infuse a counter-regulatory agent into the subject in response to a counter-regulatory agent dose control signal, comprising:

generating the insulin dose control signal in response to the glucose level signal by;

modulating a basal infusion rate of insulin about a nominal basal infusion rate in response to short-term variations of glucose level occurring on the order of seconds to minutes;

continually adjusting the nominal basal infusion rate based on a mathematical relationship between the basal infusion rate as modulated and the nominal basal infusion rate over a longer term than a short term associated with modulating the basal infusion rate;

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

maintaining 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 the 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; and

generating the counter-regulatory agent dose control signal by performing a calculation generating (a) a raw dose control value based on the glucose level signal, and (b) 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.