Method and apparatus for closed loop drug delivery

• US 5,733,259 A
• Filed: 12/22/1994
• Issued: 03/31/1998
• Est. Priority Date: 01/31/1992
• Status: Expired due to Fees

• Current Assignee: Gensia Pharmaceuticals, Inc. (Teva Pharmaceutical Industries Limited)
• Original Assignee: Gensia Pharmaceuticals, Inc. (Teva Pharmaceutical Industries Limited)
• Inventors: Valcke, Christian P., Bochenko, Walter J., Hillman, Robert S.
• Primary Examiner(s): Buiz, Michael
• Assistant Examiner(s): Mulcare, Nancy
• Application Number:
  US08/363,863
• Time in Patent Office: 1,195 Days
• Field of Search: 604/65-67, 128/DIG. 12, 128/DIG. 13
• US Class Current: 604/66
• CPC Class Codes: A61M 2230/005 Parameter used as control input for the apparatus
• CPC Class Codes: A61M 2230/06 Heartbeat rate only
• 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 20/17 delivered via infusion or injection
• CPC Class Codes: G16H 20/40 relating to mechanical, radiation or invasive therapies, e.g. surgery, laser therapy, dialysis or acupuncture
• CPC Class Codes: G16H 50/50 for simulation or modelling of medical disorders
• CPC Class Codes: Y10S 128/12 Pressure infusion
• CPC Class Codes: Y10S 128/13 Infusion monitoring

Abstract

A closed-loop drug delivery system uses patient response and rule based decision making methods to achieve operator specified responses for diagnostic purposes. In the preferred embodiment, cardiac diagnosis is performed by pharmacologically stressing the heart by administration of an exercise simulating agent drug. In the preferred method, a protocol is defined, which preferably includes a target for a physiologic variable, such as heart rate, and a plan to achieve that target value. Preferably, the plan includes a specification of the desired rate of increase in that variable, such as the rate of increase in the heart rate per minute. The plan comprises the desired changes in the physiologic variable as a function of time. While any desired function may be used, the more common modes include RAMP, HOLD, LEVEL and TARGET mode. In one aspect of this invention, the protocol may be varied by the operator after drug administration has begun. Further, in one embodiment, the protocol includes a definition of an acceptable zone of deviation from the plan, such that if the patient physiologic variable deviates from the permissible zone, alternate control rules are implemented. Preferably, saturation detection and avoidance is implemented.

Claims

1. A method for varying a patient heart rate using an exercise simulating drug in a closed-loop drug delivery system wherein the system has a processor that controls the delivery of the drug to the patient, comprising the steps of:

a) defining a protocol for implementation on the processor, the protocol including at least a target heart rate, a first plan to achieve the target heart rate, an alternate plan to achieve a second target heart rate, and transition conditions to cause the system to transition from the first plan to the alternate plan, where both first and alternate plans provide a non-zero amount of drug to the patient,

b) beginning the drug delivery to initiate the protocol,

c) monitoring the patient heart rate, wherein the monitored heart rate is received by the processor and

d) modifying the protocol implemented on the processor from the first plan to the alternate plan after the drug delivery begins and when the processor determines that the monitored heart rate satisfies the transition conditions wherein the modification changes the rate of the drug delivery.

2. The method for control of a patient heart rate of claim 1 where in step d the protocol is modified by varying the target heart rate.

3. The method for control of a patient heart rate of claim 1 where in step a the protocol further includes defining the desired rate of increase in patient heart rate during closed-loop drug delivery.

4. The method of claim 3 where in step d the protocol is modified by varying the desired rate of increase in the patient heart rate.

45. A method for detecting saturation in cardiac response to the drug delivery method of claim 1 further comprising the steps of:

monitoring for peak heart rate,

determining the length of time since the last heart rate peak was detected, and generating a signal indicative of the saturation when the length of time since the last heart rate peak was detected exceeds a pre-set time limit.

46. The method of claim 45 where in the pre-set time limit is 30 seconds.

5. A method for varying a patient physiological variable in a closed-loop drug delivery system wherein the system has a processor that controls the delivery of the drug to the patient, comprising the steps of:

a) defining a protocol for implementation on the processor including a first target value of the patient physiological variable and a first set of rules to achieve the first target value of the patient physiological variable,

b) defining an alternate set of rules to achieve a second target value of the patient physiological variable, where both the first and alternate sets of rules provide a non-zero amount of drug to the patient,

c) defining an acceptable zone of deviation from the first set of rules,

d) initiating drug delivery at a rate defined by the first set of rules,

e) monitoring the patient physiological variable to generate a monitored value wherein the monitored value is received by the processor, and

f) changing from the first set of rules to the alternate set of rules if the processor determines that the monitored value of the patient physiological variable is outside the acceptable zone of deviation from the first set of rules, thereby changing the rate of the drug delivery.

6. The method of claim 5 wherein the patient physiological variable is the heart rate.

7. The method of claim 5 or 6 where in step b the alternate set of rules include an alert or alarm condition.

8. The method of claim 5 or 6 where in step b the alternate set of rules includes open-loop administration of the drug.

9. The method of claim 5 or 6 where the alternate set of rules affects the administration of drug delivery and includes a proportional-integral control rule that has i) a proportionality error component proportional to the difference between the second target value and the monitored value of the physiological variable and ii) an integral error term that is an integral over time of the proportionality error component.

10. The method of claim 5 or 6 where in step b the alternate set of rules affects the administration of drug delivery and includes a proportional-integral-derivative control rule that has i) a proportionality error component that is proportional to the difference between the second target value and the monitored value of the physiological variable, ii) an integral over time of the proportionality error component, and iii) a derivative over time of the proportionality error component.

11. The method of claim 5 or 6 where in step c the acceptable zone of deviation from the first set of rules includes definition of a maximum acceptable value for the patient physiological variable.

12. The method of claim 5 or 6 where in step c the acceptable zone of deviation from the first set of rules includes a maximum acceptable rate of increase in the patient physiological variable.

13. The method of claim 5 or 6 where in step a the first set of rules affects the administration of drug delivery and includes a proportional-integral control rule that has:

i) a proportionality error component proportional to the difference between the second target value and the monitored value of the physiological variable; and

ii) an integral error term that is an integral over time of the proportionality error component.

14. The method of claims 5 or 6 where in step a the first set of rules affects the administration of drug delivery and includes a proportional-integral-derivative control rule that has i) a proportionality error component proportional to the difference between the second target value and the monitored value of the physiological variable, ii) an integral over time of the proportionality error component, and iii) a derivative over time of the proportionality error component.

15. A method for closed-loop drug delivery to a patient for varying a patient physiological variable, the method using a system wherein the system has a processor that controls the delivery of the drug to the patient, the method comprising the steps of:

a) administering the drug to the patient,

b) determining the individual patient response, including an onset delay, to the administered drug, wherein the onset delay is the interval between the time drug administration begins and a change in the patient physiological variable is measured, and

c) adjusting the administration of the drug with closed-loop control of drug delivery wherein the processor adjusts drug delivery by utilizing the individual patient response information, including the onset delay, in the patient response to the drug.

16. The method of claim 15 where the individual patient response information includes the heart rate gain per unit drug infusion.

17. The method of claim 15 wherein step b further includes determining an estimation of a time constant for drug response for the patient.

18. The method of claim 15 wherein the drug is an exercise simulation agent.

19. A method for using closed-loop drug delivery to vary a patient physiological variable, the method using a system wherein the system has a processor that controls the delivery of the drug to the patient, the method comprising the steps of:

a) specifying a first desired rate of change in the patient physiological variable, a second desired rate of change in the patient physiological variable, and transition conditions to indicate when to switch from the first desired rate of change to the second desired rate of change, where both the first and second desired rates of change provide a non-zero amount of drug to the patient,

b) administering the drug which causes variation in the patient'"'"'s physiological variable,

c) monitoring the patient physiological variable wherein the monitored value is received by the processor,

d) determining a determined rate of change in the patient physiological variable, and

e) controlling the drug delivery in the closed-loop system whereby the determined rate of change in the patient physiological variable is adjusted by the processor toward the first desired rate of change in the patient physiological variable, and when the monitored patient physiological variable satisfies the transition conditions, the determined rate of change is adjusted by the processor toward the second desired rate of change of the patient physiological variable.

20. The method of claim 19 wherein the patient physiological variable is the heart rate.

21. The method of claim 19 wherein the desired rate of change in the patient physiological variable is a positive number.

47. The method of claim 19 for using closed-loop drug delivery to vary a patient physiological variable further comprising the steps:

f) comparing the determined rate of change with a threshold rate of change, and

g) generating a signal indicative of a saturation condition if the determined rate of change is less than the threshold rate of change.

22. A method for closed-loop drug delivery using an exercising simulating agent drug for adjusting a heart rate, the method using a system wherein the system has a processor that controls the delivery of the drug to the patient, the method comprising the steps of:

a) specifying for implementation on the processor i) a first protocol that includes a first target heart rate, ii) an alternate protocol that includes a second target heart rate and, iii) transition conditions for indicating whether to switch from the first protocol to the second protocol,

b) establishing a baseline heart rate approximately equal to the patient'"'"'s average heart rate at the initial start of drug administration,

c) determining the individual patient response to the drug, including, monitoring the heart rate to find a monitored heart rate, wherein the monitored heart rate is received by the processor,

d) adjusting the ad ministration of the drug based upon;

i) the first protocol, or the second protocol when transition conditions are met, ii) the baseline heart rate, iii) the monitored heart rate, and iv) the individual patient response,

e) collecting patient specific data about the patient response to the drug, and

f) outputting the patient specific data about the patient response to the drug.

23. The method of claim 22 wherein the first protocol specifies the desired rate of increase in the heart rate.

24. The method of claim 22 wherein the first protocol specifies the time that the monitored heart rate is to be held at the target heart rate.

25. The method of claim 22 wherein the first protocol utilizes patient specific information to affect drug delivery.

26. The method of claim 22 further including the step of establishing a baseline blood pressure equal to the patient'"'"'s average blood pressure at the initial start of drug administration.

27. The method of claim 22 where in step c, the individual patient response is determined in response to an open loop administration of the drug.

28. The method of claim 22 wherein step c, the determination of individual patient response includes the gain in the patient heart rate per unit drug infusion.

29. The method of claim 22 wherein step c the determination of individual patient response includes determination of the time required for the patient response to respond measurably to the drug.

30. The method of claim 22 wherein the monitored heart rate of step d uses an average of the monitored heart rates.

31. The method of claim 22 further including the step of monitoring the patient blood pressure and wherein the administering of the drug in step d is also adjusted based upon the monitored blood pressure.

32. The method of claim 22 further including the step of monitoring for saturation of the patient response to the drug wherein saturation occurs when the patient heart rate does not change sufficiently with drug administration.

33. The method of claim 22 where in step d the first protocol includes a ramp mode whereby increased administering of the drug causes the patient response to the drug to increase.

34. The method of claim 22 where in step d the first protocol includes an initialization mode whereby the first protocol is initialized to the patient'"'"'s particular response to the drug.

35. The method of claim 22 where in step d the first protocol includes a level mode whereby the drug is administered such that the patient response to the drug is kept constant.

36. The method of claim 22 where in step d the first protocol affects the administration of drug delivery and includes a proportional-integral control rule that has a proportionality error component proportional to the difference between the second target value and the monitored value of the physiological variable and an integral error term that is an integral over time of the proportionality error component.

37. The method of claim 22 where in step e, the output includes a plot of trends in the patient response to the drug.

38. The method of claim 22 where in step e, the output includes real time data.

39. The method of claim 22 further including the step of issuing alerts or alarms if a hazardous or unexpected patient response to the drug is detected.

40. The method of claim 22 further including the step of filtering the monitored heart rate.

41. The method of claim 22 where in step d the first protocol includes a HOLD mode whereby the drug is administered such that the patient monitored heart rate is held at the target heart rate.

42. A method for achieving a HOLD mode in a closed-loop drug delivery system wherein the system has a processor that controls rates of drug delivery to a patient and where the rate of drug delivery affects a physiological parameter of the patient, comprising the steps of:

setting a desired value for the physiological parameter, reducing initially the rate of drug delivery, increasing the rate of drug delivery, and measuring the physiological parameter wherein the measured physiological parameter is used by the processor to control the rate of drug delivery such that at the end of the increase, the rate of drug delivery results in maintenance of the physiological parameter at the desired value.

43. The reducing step of claim 42 wherein the initial reduction in the rate of drug delivery is to a zero rate of infusion.

44. The increasing step of claim 42 in which the rate of drug delivery is increased exponentially.

48. In a closed-loop drug delivery method implemented on a closed-loop control system having a processor, the method administering an exercising simulating agent to elicit stress, where the patient heart rate is monitored in response to the administration of the drug and the patient heart rate is used in the closed-loop control system to adjust the drug delivery, the improvement in the method comprising:

a) monitoring the drug administration and the patient heart rate for a saturation level of the drug wherein the monitored values are received by the processor and where the saturation level is reached when the processor determines that the patient heart rate changes insufficiently with drug administration, and

b) adjusting the drug administration in response to the saturation level.

49. A method for determining when a target heart rate has been achieved in a closed-loop drug delivery system wherein the system has a processor that controls the delivery of the drug to the patient, comprising the steps of:

initiate drug delivery,

monitor the patient heart rate wherein the monitored heart is received by the processor,

determine the slope of the patient heart rate,

generate a threshold to target value based in part on the heart rate slope, wherein the threshold to target value represents an acceptable deviation from the target heart rate, and

terminate drug delivery when the processor determines that the patient heart rate exceeds the target heart rate minus the threshold to target value.

50. The method for determining when a target heart rate has been achieved in claim 49 where the threshold to target value is generated based upon the heart slope and desired heart rate slope.

51. The method for determining when a target heart rate has been achieved of claim 50 where the threshold to target value is generated based upon the average of the heart rate slope and the desired slope.