Glucose level control system with offline control based on preceding periods of online control

Abstract

Apparatus and methods calculate and deliver doses of insulin and optionally glucagon into a subject. Online operation controls delivery of correction doses of insulin automatically in response to regular glucose measurements from a sensor, and offline operation calculates and delivers correction doses based on isolated glucose measurements and information gathered autonomously during preceding online operation. In another aspect, offline operation includes automatically calculating and administering meal doses based on information gathered autonomously during preceding periods of online operation. Both methods include generating relevant control parameters tailored to the individual and continually converged upon and potentially modulated during online operation. The control parameters are employed in real time during periods of offline operation to regulate glucose level without the need for user-provided control parameters such as correction factors and insulin-to-carbohydrate ratios.

What is claimed is: 
     
       1. A glucose level control system, comprising:
 a glucose sensor operative to continually measure a 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 having online operation and offline operation to generate the insulin dose control signal to achieve and maintain euglycemia in the subject, online operation employing a control algorithm including (i) regular administration of correction doses of insulin based on control parameters of the control algorithm and regular periodic sampling of glucose levels via the glucose sensor, and (ii) autonomously adjusting the control parameters to tailor the control parameters to the subject, offline operation including (iii) evolving a state of the control algorithm over time without sampling of glucose levels and without automatic administration of the correction doses of insulin, and (iv) correction dosing operations each including administration of a correction dose of insulin in response to an isolated glucose measurement provided to the controller, the correction dose being calculated by the controller based on the isolated glucose measurement, the control parameters, and a state of the control algorithm as evolved at the time of the correction dosing operation. 
 
     
     
       2. A glucose level control system according to  claim 1 , wherein the control algorithm employs regular periodic sampling intervals, and wherein evolving the control algorithm during the offline operation includes updating time effects of insulin previously administered to the subject. 
     
     
       3. A glucose level control system according to  claim 2 , wherein each correction dose during the offline operation includes calculating estimated glucose levels for immediately preceding offline sampling intervals using interpolation between a current isolated glucose measurement and a sample of glucose level from a most recent period of online operation. 
     
     
       4. A glucose level control system according to  claim 1 , wherein the correction dose is calculated by the controller during the offline operation assuming a first target glucose level or range higher than a second target glucose level or range assumed during online operation. 
     
     
       5. A glucose level control system according to  claim 1 , wherein the isolated glucose measurement is provided to the controller via a user interface used by the subject, and wherein each correction dosing operation includes use of one or more user interface functions selected from (i) the subject confirming that the correction dose is to be delivered, (ii) displaying the value of the correction dose to the subject, and (iii) accepting a modified value from the subject for use as the correction dose instead of the correction dose calculated by the controller. 
     
     
       6. A glucose level control system according to  claim 1 , wherein online operation of the control algorithm further includes regular administration of correction doses of a counter-regulatory agent based on the control parameters of the control algorithm and the regular periodic sampling of glucose levels, and wherein the offline operation further includes counter-regulatory agent dosing operations each including administration of a dose of a counter-regulatory agent in response to a second isolated glucose measurement provided to the controller and calculated by the controller based on the second isolated glucose measurement, the control parameters, and the state of the control algorithm as evolved at the time of the counter-regulatory agent dosing operation. 
     
     
       7. A glucose level control system according to  claim 6 , wherein the correction dose of insulin is calculated by the controller during periods when a counter-regulatory delivery channel or device is unavailable and assuming a first target glucose level or range higher than a second target glucose level or range assumed when the counter-regulatory delivery channel or device is available. 
     
     
       8. A glucose level control system according to  claim 1 , wherein in both the online and offline operations, the control algorithm allows the subject to issue a microburst or rescue dose of counter-regulatory agent, a value of the microburst or rescue dose being calculated by the controller. 
     
     
       9. A glucose level control system according to  claim 1 , wherein online operation of the control algorithm includes (v) administration of meal doses of insulin in response to a meal dose control input and automatically calculated by the controller based on preceding meal doses and corresponding prandial and post-prandial responses of the subject as reflected in the sampling of glucose levels via the glucose sensor and (vi) autonomously adjusting control parameters used to determine meal dose size to tailor the control parameters to the subject, and wherein offline operation including meal dosing operations each including administration of a meal dose of insulin in response to the meal dose control input and calculated by the controller based on a second isolated glucose measurement, the control parameters, and the state of the control algorithm as evolved at the time of the meal dosing operation. 
     
     
       10. A method of operating a controller for a glucose level control system having a glucose sensor and an insulin delivery device, the glucose sensor being operative to continually measure a glucose level of a subject and generate a corresponding glucose level signal, the insulin delivery device being operative in response to an insulin dose control signal to infuse insulin into the subject, comprising:
 performing online operation employing a control algorithm including (i) regular administration of correction doses of insulin based on control parameters of the control algorithm and regular periodic sampling of glucose levels via the glucose sensor, and (ii) autonomously adjusting the control parameters to tailor the control parameters to the subject; and 
 performing offline operation including (iii) evolving a state of the control algorithm over time without sampling of glucose levels and without automatic administration of the correction doses of insulin, and (iv) correction dosing operations each including administration of a correction dose of insulin in response to an isolated glucose measurement provided to the controller, the correction dose being calculated by the controller based on the isolated glucose measurement, the control parameters, and the state of the control algorithm as evolved at the time of the correction dosing operation. 
 
     
     
       11. A method according to  claim 10 , wherein the control algorithm employs regular periodic sampling intervals, and wherein evolving the control algorithm during the offline operation includes updating time effects of insulin previously administered to the subject. 
     
     
       12. A method according to  claim 11 , wherein each correction dose during the offline operation includes calculating estimated glucose levels for immediately preceding offline sampling intervals using interpolation between a current isolated glucose measurement and a sample of glucose level from a most recent period of online operation. 
     
     
       13. A method according to  claim 10 , wherein the correction dose is calculated by the controller during the offline operation assuming a first target glucose level or range higher than a second target glucose level or range assumed during online operation. 
     
     
       14. A method according to  claim 10 , wherein the isolated glucose measurement is provided to the controller via a user interface used by the subject, and wherein each correction dosing operation includes use of one or more user interface functions selected from (i) the subject confirming that the correction dose is to be delivered, (ii) displaying a value of the correction dose to the subject, and (iii) accepting a modified value from the subject for use as the correction dose instead of the correction dose calculated by the controller. 
     
     
       15. A method according to  claim 10 , wherein online operation of the control algorithm further includes regular administration of correction doses of a counter-regulatory agent based on the control parameters of the control algorithm and the regular periodic sampling of glucose levels, and wherein the offline operation further includes counter-regulatory agent dosing operations each including administration of a correction dose of a counter-regulatory agent in response to a second isolated glucose measurement provided to the controller and calculated by the controller based on the second isolated glucose measurement, the control parameters, and the state of the control algorithm as evolved at the time of the counter-regulatory agent dosing operation. 
     
     
       16. A method according to  claim 15 , wherein the correction dose of insulin is calculated by the controller during periods when a counter-regulatory delivery channel or device is unavailable and assuming a first target glucose level or range higher than a second target glucose level or range assumed when the counter-regulatory delivery channel or device is available. 
     
     
       17. A method according to  claim 10 , wherein in both the online and offline operations, the control algorithm allows the subject to issue a microburst or rescue dose of counter-regulatory agent, a value of the microburst or rescue dose being calculated by the controller. 
     
     
       18. A method according to  claim 10 , wherein online operation of the control algorithm includes (v) administration of meal doses of insulin in response to a meal dose control input and automatically calculated by the controller based on preceding meal doses and corresponding prandial and post-prandial responses of the subject as reflected in the sampling of glucose levels via the glucose sensor and (vi) autonomously adjusting control parameters used to determine meal dose size to tailor the control parameters to the subject, and wherein offline operation including meal dosing operations each including administration of a meal dose of insulin in response to the meal dose control input and calculated by the controller based on a second isolated glucose measurement, the control parameters, and a state of the control algorithm as evolved at the time of the meal dosing operation. 
     
     
       19. A glucose level 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 having online operation and offline operation to generate the insulin dose control signal to achieve and maintain euglycemia in the subject, online operation employing a control algorithm including (i) administration of meal doses of insulin in response to a meal dose control input and automatically calculated by the controller based on preceding meal doses and corresponding prandial and post-prandial responses of the subject as reflected in sampling of glucose levels via the glucose sensor and (ii) autonomously adjusting control parameters used to determine meal dose size to tailor the control parameters to the subject, offline operation including (iii) evolving a state of the control algorithm over time without sampling of glucose levels, and (iv) meal dosing operations each including administration of a meal dose of insulin in response to the meal dose control input and calculated by the controller based on an isolated glucose measurement, the control parameters, and a state of the control algorithm as evolved at the time of the meal dosing operation. 
 
     
     
       20. A glucose level control system according to  claim 19 , wherein online operation of the control algorithm further includes (i) regular administration of correction doses of insulin based on control parameters of the control algorithm and regular periodic sampling of glucose levels via the glucose sensor, and (ii) autonomously adjusting the control parameters to tailor the control parameters to the subject, and wherein the offline operation further includes (iii) evolving the state of the control algorithm over time without sampling of glucose levels and without automatic administration of the correction doses of insulin, and (iv) correction dosing operations each including administration of a correction dose of insulin in response to a second isolated glucose measurement provided to the controller, the correction dose being calculated by the controller based on the second isolated glucose measurement, the control parameters, and the state of the control algorithm as evolved at the time of the correction dosing operation. 
     
     
       21. A controller for use in a glucose level control system having an insulin delivery device and a glucose sensor, the controller comprising:
 processing circuitry including one or more processors;   memory; and   input/output circuitry,   the input/output circuitry providing respective interfaces to the insulin delivery device and the glucose sensor (1) to convey an insulin dose control signal to the insulin delivery device for controlling infusion of insulin into a subject, and (2) to receive a glucose level signal from the glucose sensor indicating a glucose level of the subject,   the memory storing computer program instructions executed by the processors to provide online operation and offline operation of the glucose level control system to generate the insulin dose control signal to achieve and maintain euglycemia in the subject, the online operation employing a control algorithm including (i) regular administration of correction doses of insulin based on control parameters of the control algorithm and regular periodic sampling of glucose levels via the glucose sensor, and (ii) autonomously adjusting the control parameters to tailor the control parameters to the subject, offline operation including (iii) evolving a state of the control algorithm over time without sampling of glucose levels and without automatic administration of the correction doses of insulin, and (iv) correction dosing operations each including administration of a correction dose of insulin in response to an isolated glucose measurement provided to the controller, the correction dose being calculated by the controller based on (i) the isolated glucose measurement, (ii) the control parameters, and (iii) the state of the control algorithm as evolved at the time of the correction dosing operation.   
     
     
       22. The controller of  claim 21 , wherein the control algorithm employs regular periodic sampling intervals, and wherein evolving the control algorithm during the offline operation includes updating time effects of insulin previously administered to the subject. 
     
     
       23. The controller of  claim 22 , wherein each correction dose during the offline operation includes calculating estimated glucose levels for immediately preceding offline sampling intervals using interpolation between a current isolated glucose measurement and a sample of glucose level from a most recent period of online operation. 
     
     
       24. The controller of  claim 21 , wherein the correction dose is calculated by the controller during the offline operation assuming a first target glucose level or range higher than a second target glucose level or range assumed during online operation. 
     
     
       25. The controller of  claim 21 , wherein the isolated glucose measurement is provided to the controller via a user interface used by the subject, and wherein each correction dosing operation includes use of one or more user interface functions selected from (i) the subject confirming that the correction dose is to be delivered, (ii) displaying a value of the correction dose to the subject, and (iii) accepting a modified value from the subject for use as the correction dose instead of the correction dose calculated by the controller. 
     
     
       26. The controller of  claim 21 , wherein online operation of the control algorithm further includes regular administration of correction doses of a counter-regulatory agent based on the control parameters of the control algorithm and the regular periodic sampling of glucose levels, and wherein the offline operation further includes counter-regulatory agent dosing operations each including administration of a dose of a counter-regulatory agent in response to a second isolated glucose measurement provided to the controller and calculated by the controller based on the second isolated glucose measurement, the control parameters, and the state of the control algorithm as evolved at the time of the counter-regulatory agent dosing operation. 
     
     
       27. The controller of  claim 26 , wherein the correction dose of insulin is calculated by the controller during periods when a counter-regulatory delivery channel or device is unavailable and assuming a first target glucose level or range higher than a second target glucose level or range assumed when the counter-regulatory delivery channel or device is available. 
     
     
       28. The controller of  claim 21 , wherein in both the online and offline operations, the control algorithm allows the subject to issue a microburst or rescue dose of counter-regulatory agent, a value of the microburst or rescue dose being calculated by the controller. 
     
     
       29. The controller of  claim 21 , wherein online operation of the control algorithm includes (v) administration of meal doses of insulin in response to a meal dose control input and automatically calculated by the controller based on preceding meal doses and corresponding prandial and post-prandial responses of the subject as reflected in the sampling of glucose levels via the glucose sensor and (vi) autonomously adjusting control parameters used to determine meal dose size to tailor the control parameters to the subject, and wherein offline operation including meal dosing operations each including administration of a meal dose of insulin in response to the meal dose control input and calculated by the controller based on the control parameters and the state of the control algorithm as evolved at the time of the meal dosing operation. 
     
     
       30. A method of operating a controller in a glucose level control system having a glucose sensor and an insulin delivery device, the controller having respective interfaces to the insulin delivery device and the glucose sensor (1) to convey an insulin dose control signal to the insulin delivery device for controlling infusion of insulin into a subject, and (2) to receive a glucose level signal from the glucose sensor indicating a glucose level of the subject, the method comprising:
 performing online operation employing a control algorithm including (i) regularly administering correction doses of insulin based on control parameters of the control algorithm and regular periodic sampling of glucose levels of the subject via the glucose sensor, and (ii) autonomously adjusting the control parameters to tailor the control parameters to the subject; and   performing offline operation including (iii) evolving a state of the control algorithm over time without sampling of glucose levels and without automatic administration of the correction doses of insulin, and (iv) correction dosing operations each including administration of a correction dose of insulin in response to an isolated glucose measurement provided to the controller, the correction dose being calculated by the controller based on (i) the isolated glucose measurement, (ii) the control parameters, and (iii) the state of the control algorithm as evolved at the time of the correction dosing operation.   
     
     
       31. The method of  claim 30 , wherein the control algorithm employs regular periodic sampling intervals, and wherein evolving the control algorithm during the offline operation includes updating time effects of insulin previously administered to the subject. 
     
     
       32. The method of  claim 31 , wherein each correction dose during the offline operation includes calculating estimated glucose levels for immediately preceding offline sampling intervals using interpolation between a current isolated glucose measurement and a sample of glucose level from a most recent period of online operation. 
     
     
       33. The method of  claim 30 , wherein the correction dose is calculated by the controller during the offline operation assuming a first target glucose level or range higher than a second target glucose level or range assumed during online operation. 
     
     
       34. The method of  claim 30 , wherein the isolated glucose measurement is provided to the controller via a user interface used by the subject, and wherein each correction dosing operation includes use of one or more user interface functions selected from (i) the subject confirming that the correction dose is to be delivered, (ii) displaying a value of the correction dose to the subject, and (iii) accepting a modified value from the subject for use as the correction dose instead of the correction dose calculated by the controller. 
     
     
       35. The method of  claim 30 , wherein online operation of the control algorithm further includes regular administration of correction doses of a counter-regulatory agent based on the control parameters of the control algorithm and the regular periodic sampling of glucose levels, and wherein the offline operation further includes counter-regulatory agent dosing operations each including administration of a correction dose of a counter-regulatory agent in response to a second isolated glucose measurement provided to the controller and calculated by the controller based on the second isolated glucose measurement, the control parameters, and the state of the control algorithm as evolved at the time of the counter-regulatory agent dosing operation. 
     
     
       36. The method of  claim 35 , wherein the correction dose of insulin is calculated by the controller during periods when a counter-regulatory delivery channel or device is unavailable and assuming a first target glucose level or range higher than a second target glucose level or range assumed when the counter-regulatory delivery channel or device is available. 
     
     
       37. The method of  claim 30 , wherein in both the online and offline operations, the control algorithm allows the subject to issue a microburst or rescue dose of counter-regulatory agent, a value of the microburst or rescue dose being calculated by the controller. 
     
     
       38. The method of  claim 30 , wherein online operation of the control algorithm includes (v) administration of meal doses of insulin in response to a meal dose control input and automatically calculated by the controller based on preceding meal doses and corresponding prandial and post-prandial responses of the subject as reflected in the sampling of glucose levels via the glucose sensor and (vi) autonomously adjusting control parameters used to determine meal dose size to tailor the control parameters to the subject, and wherein offline operation including meal dosing operations each including administration of a meal dose of insulin in response to the meal dose control input and calculated by the controller based on a second isolated glucose measurement, the control parameters, and the state of the control algorithm as evolved at the time of the meal dosing operation. 
     
     
       39. A controller for use in a glucose level control system having an insulin delivery device and a glucose sensor, the controller comprising:
 processing circuitry including one or more processors;   memory; and   input/output circuitry,   the input/output circuitry providing respective interfaces to the insulin delivery device and the glucose sensor (1) to convey an insulin dose control signal to the insulin delivery device for controlling infusion of insulin into a subject, and (2) to receive a glucose level signal from the glucose sensor indicating a glucose level of the subject,   the memory storing computer program instructions executed by the processors to provide online operation and offline operation of the glucose level control system to generate the insulin dose control signal to achieve and maintain euglycemia in the subject, online operation employing a control algorithm including (i) administration of meal doses of insulin in response to a meal dose control input and automatically calculated by the controller based on preceding meal doses and corresponding prandial and post-prandial responses of the subject as reflected in sampling of glucose levels via the glucose sensor and (ii) autonomously adjusting control parameters used to determine meal dose size to tailor the control parameters to the subject, offline operation including (iii) evolving a state of the control algorithm over time without sampling of glucose levels, and (iv) meal dosing operations each including administration of a meal dose of insulin in response to the meal dose control input and calculated by the controller based on the control parameters and the state of the control algorithm as evolved at the time of the meal dosing operation.   
     
     
       40. The controller of  claim 39 , wherein online operation of the control algorithm further includes (i) regular administration of correction doses of insulin based on control parameters of the control algorithm and regular periodic sampling of glucose levels via the glucose sensor, and (ii) autonomously adjusting the control parameters to tailor the control parameters to the subject, and wherein the offline operation further includes (iii) evolving the state of the control algorithm over time without sampling of glucose levels and without automatic administration of the correction doses of insulin, and (iv) correction dosing operations each including administration of a correction dose of insulin in response to an isolated glucose measurement provided to the controller, the correction dose being calculated by the controller based on the isolated glucose measurement, the control parameters, and the state of the control algorithm as evolved at the time of the correction dosing operation.