Method for determining the concentration of glucose in a body fluid with glucose-containing perfusate

• US 6,852,500 B1
• Filed: 07/20/2000
• Issued: 02/08/2005
• Est. Priority Date: 07/28/1999
• Status: Expired due to Fees

• Current Assignee: Roche Diagnostics GmbH (Roche Holding AG)
• Original Assignee: Roche Diagnostics GmbH (Roche Holding AG)
• Inventors: Fussgaenger, Rolf, Zieten, Hans-Ulrich, Hoss, Udo, Gessler, Ralf, Pfleiderer, Hans-Joerg
• Primary Examiner(s): GITOMER, RALPH J
• Application Number:
  US09/620,038
• Time in Patent Office: 1,664 Days
• Field of Search: 435/14, 600/315, 600/317, 600/365, 600/347, 600/345
• US Class Current: 435/14
• CPC Class Codes: A61B 5/14528 invasively
• CPC Class Codes: A61B 5/14532 for measuring glucose, e.g. by tissue impedance measurement
• CPC Class Codes: A61B 5/14865 invasive, e.g. introduced into the body by a catheter or needle or using implanted sensors

Abstract

The invention concerns a method and an arrangement for determining the concentration of glucose in a body fluid. In the microdialysis technology used for this purpose, perfusate containing glucose is transported in intermittent delivery pulses through a microdialysis probe (10) inserted into the body fluid and dialysate obtained in this process is passed to a measuring cell (16) to record the glucose content. In order to achieve an exact determination of glucose even with a reduced dialysis period, it is proposed that the starting content of glucose in the perfusate is adapted to the glucose content of the body fluid by means of a control device (18, 20) in accordance with a command variable derived from the measurement signals of the measuring cell (16). When the control deviation is negligible the momentary starting content of glucose in the perfusate can be determined as a measure for the glucose content of the body fluid.

Claims

1. A method for determining a glucose concentration in a body fluid with glucose-containing perfusate, the method comprising the steps of:

providing a microdialysis probe, a measuring cell having a sensor, and a control device,

inserting the microdialysis probe into the body fluid,

passing the perfusate having a pre-determined starting content of glucose through the microdialysis probe to obtain a dialysate,

transporting the dialysate to the measuring cell,

obtaining with the sensor measurement signals from the dialysate, the dialysate serving as an electrolyte and being used to continuously register a measuring current, which correlates with a glucose content of the dialysate in the measuring cell,

determining from the measurement signals a base line value corresponding to a starting concentration of glucose in the perfusate and the existence of a peak value, the peak value being present when there are differences in concentration between the starting concentration of glucose in the perfusate and the concentration of glucose in the body fluid,

adjusting the starting content of glucose in the perfusate to a glucose content of the body fluid with the control device in accordance with a command variable corresponding with the glucose concentration of the body fluid and being derived from the measurement signals of the measuring cell,

wherein the glucose concentration in the body fluid is determined by either using a momentary content of glucose in the perfusate as a measure for the glucose content of the body fluid when a deviation between the peak value and the base line value is negligible or by determining the glucose content of the body fluid directly from the obtained measurement signals.

2. The method of claim 1 wherein a value of the base line signal is a controlled variable and the adjusting step includes determining a momentary content of the glucose in the perfusate as a measure for the glucose content of the body fluid when a deviation of a controlled variable from the command variable is negligible.

3. The method of claim 2 wherein the control device includes an adjuster having an adjusting variable and the adjusting step includes initially determining the starting content of glucose in the perfusate by comparing the adjusting variable with corresponding normalized values of the glucose concentration in the body fluid.

4. The method of claim 2 further comprising the step of measuring the glucose content of the perfusate before it is passed into the microdialysis probe.

5. The method of claim 2 further comprising the step of flow mixing two perfusion liquids with different glucose concentrations provided in two separate reservoirs to influence the starting content of glucose in the perfusate.

6. The method of claim 2 wherein the perfusate is passed through the microdialysis probe in alternating intervals at different flow rates, the flow rate during one of the intervals being higher than during another of the intervals.

7. The method of claim 2 wherein the command variable is determined by integration or differentiation of the time course of the measurement signals.

8. The method of claim 1 wherein the control device includes an adjuster having an adjusting variable and the adjusting step includes initially determining the starting content of glucose in the perfusate by comparing the adjusting variable with corresponding normalized values of the glucose concentration in the body fluid.

9. The method of claim 8 further comprising the step of measuring the glucose content of the perfusate before it is passed into the microdialysis probe.

10. The method of claim 1 further comprising the step of measuring the glucose content of the perfusate before it is passed into the microdialysis probe.

11. The method of claim 10 further comprising the step of flow mixing two perfusion liquids with different glucose concentrations provided in two separate reservoirs to influence the starting content of glucose in the perfusate.

12. The method of claim 10 wherein the perfusate is passed through the microdialysis probe in alternating intervals at different flow rates, the flow rate during one of the intervals being higher than during another of the intervals.

13. The method of claim 10 wherein the command variable is determined by integration or differentiation of the time course of the measurement signals.

14. The method of claim 1 further comprising the step of flow mixing two perfusion liquids with different glucose concentrations provided in two separate reservoirs to influence the starting content of glucose in the perfusate.

15. The method of claim 14 wherein the perfusate is passed through the microdialysis in alternating intervals at different flow rates, the flow rate during one of the intervals being higher than during another of the intervals.

16. The method of claim 14 wherein the command variable is determined by integration or differentiation of the time course of the measurement signals.

17. The method of claim 1 wherein the perfusate is passed through the microdialysis probe in alternating intervals at different flow rates, the flow rate during one of the intervals being higher than during another of the intervals.

18. The method of claim 17 wherein the flow rate during one of the intervals is increased to such an extent that the starting content of glucose in the perfusate during passage through the microdialysis probe remains essentially constant and that during another of the intervals the transport is interrupted or at least the flow rate is reduced to such an extent that the glucose concentration of the dialysate approximates the glucose content of the body fluid.

19. The method of claim 17 wherein the command variable is determined by integration or differentiation of the time course of the measurement signals.

20. The method of claim 17 wherein the command variable is determined by comparing the actual signal curve of the measurement signals with calibrated signal patterns deposited in a storage medium.

21. The method of claim 17 wherein the command variable is determined from the peak value of the signal time course of the measurement signals during each transport interval.

22. The method of claim 17 wherein the command variable is determined according to the glucose content c of the body fluid according to the relationship $c=\lfloor$

SgSg·

(1-b)+b·

S0-1⌋

·

a·

c0+c0

in which S_g denotes a peak value of the measurement signal and S₀ denotes a base line value of the signals measured during a transport interval of the perfusate passing through the microdialysis probe and c₀ is the momentary content of glucose in the perfusate and a, b are empirically determined correction factors compensating for diffusion and mixing and remaining recovery effects during the transport interval.

23. The method of claim 1 wherein the command variable is determined by integration or differentiation of the time course of the measurement signals.

24. The method of claim 23 wherein the command variable is determined by qualitative detection of signal peaks in the time course of the measurement signals.

25. The method of claim 23 wherein the command variable is determined by comparing the actual signal curve of the measurement signals with calibrated signal patterns deposited in a storage medium.

26. The method of claim 23 wherein the command variable is determined from the peak value of the signal time course of the measurement signals during each transport interval.

27. The method of claim 23 wherein the command variable is determined according to the glucose content c of the body fluid according to the relationship $c=\lfloor$

SgSg·

(1-b)+b·

S0-1⌋

·

a·

c0+c0

in which S_g denotes a peak value of the measurement signal and S₀ denotes a base line value of the signals measured during a transport interval of the perfusate passing through the microdialysis probe and c₀ is the momentary content of glucose in the perfusate and a, b are empirically determined correction factors compensating for diffusion and mixing and remaining recovery effects during the transport interval.

28. The method of claim 1 further comprising a step of regulating discontinuously the starting content of glucose in the perfusate by a two-point control process in which the starting content of glucose in the perfusate is changed by a predetermined adjustment value when there is a control deviation.

29. A method for determining a glucose concentration in a body fluid with glucose-containing perfusate, the method comprising the steps of:

providing a microdialysis probe, a measuring cell having a sensor, and a control device,

inserting the microdialysis probe into the body fluid,

passing the perfusate having a pre-determined starting content of glucose through the microdialysis probe at different flow rates to obtain a dialysate,

transporting the dialysate to the measuring cell,

obtaining with the sensor measurement signals from the dialysate, the dialysate serving as an electrolyte and being used to continuously register as a measuring current, which correlates with a glucose content of the dialysate in the measuring cell,

determining from the measurement signals a base line value corresponding to a starting concentration of glucose in the perfusate and the existence of a peak value, the peak value being present when there are differences in concentration between the starting concentration of glucose in the perfusate and the concentration of glucose in the body fluid, and

adjusting the starting content of glucose in the perfusate to a glucose content of the body fluid with the control device in accordance with a command variable corresponding with the glucose concentration of the body fluid and begins derived from the measurement signals of the measuring cell,

wherein the glucose concentration in the body fluid is determined by either using a momentary content of glucose in the perfusate as a measure for the glucose content of the body fluid when a deviation between the peak value and the base line value is negligible or by determining the glucose content of the body fluid directly from the obtained measurement signals.

30. The method of claim 29 wherein a value of the base line signal is a controlled variable and the adjusting step includes determining a momentary content of the glucose in the perfusate as a measure for the glucose content of the body fluid when a deviation of a controlled variable from the command variable is negligible.

31. The method of claim 30 wherein the control unit includes an adjuster having an adjusting variable and the adjusting step includes initially determining the starting content of glucose in the perfusate by comparing the adjusting variable with corresponding normalized values of the glucose concentration in the body fluid.

32. The method of claim 29 further comprising the step of measuring the glucose content of the perfusate before the perfusate is passed into the microdialysis probe.

33. The method of claim 29 further comprising the step of flow mixing two perfusion liquids with different glucose concentrations provided in two separate reservoirs to influence the starting content of glucose in the perfusate.

34. The method of claim 29 wherein the perfusate flows through the microdialysis probe during transport intervals and dialysis intervals, the flow rate during the transport intervals is greater than the flow rate during the dialysis intervals and is such that the starting content of glucose in the perfusate during passage through the microdialysis probe remains essentially constant and that during the dialysis intervals the transport of the perfusate is interrupted or at least the flow rate is reduced to such an extent that the glucose concentration of the dialysate approximates the glucose content of the body fluid.

35. The method of claim 34 wherein the command variable is determined from a peak value of a signal time course of the measurement signals during each transport interval.

36. The method of claim 29 wherein the command variable is determined from a peak value of a signal time course of the measurement signals.

37. The method of claim 29 wherein the command variable is determined according to the glucose content c of the body fluid according to the relationship $c=\lfloor$

SgSg·

(1-b)+b·

S0-1⌋

·

a·

c0+c0

in which S_g denotes a peak value of the measurement signal and S₀ denotes a base line value of the signals measured during a transport interval of the perfusate passing through the microdialysis probe and c₀ is the momentary content of glucose in the perfusate and a, b are empirically determined correction factors compensating for diffusion and mixing and remaining recovery effects during the transport interval.

38. The method of claim 29 wherein the command variable is determined by integration or differentiation of a time course of the measurement signals.

39. The method of claim 29 wherein the command variable is determined by comparing an actual signal curve of the measurement signals with calibrated signal patterns deposited in a storage medium.

40. The method of claim 29 further comprising a step of regulating discontinuously the starting content of glucose in the perfusate by a two-point control process in which the starting content of glucose in the perfusate is changed by a predetermined adjustment value when there is a control deviation.

41. A method for determining a glucose concentration in a body fluid with glucose-containing perfusate, the method comprising the steps of:

providing a microdialysis probe, a measuring cell having a sensor, and a control device,

inserting the microdialysis probe into the body fluid,

passing the perfusate having a pre-determined starting content of glucose through the microdialysis probe to obtain a dialysate,

transporting the dialysate to the measuring cell,

obtaining with the sensor measurement signals from the dialysate, the dialysate serving as an electrolyte and being used to continuously register a measuring current, which correlates with a glucose content of the dialysate in the measuring cell, and

adjusting the starting content of glucose in the perfusate to a glucose content of the body fluid with the control device in accordance with a command variable corresponding with the glucose concentration of the body fluid and being derived from the measurement signals of the measuring cell, wherein the glucose concentration in the body fluid is determined by either using a momentary content of glucose in the perfusate as a measure for the glucose content of the body fluid or by determining the glucose content of the body fluid directly from the obtained measurement signals.

42. The method of claim 41 further comprising the step of measuring the glucose content of the perfusate before it is passed into the microdialysis probe.

43. The method of claim 41 further comprising the step of flow mixing two perfusion liquids with different glucose concentrations provided in two separate reservoirs to influence the starting content of glucose in the perfusate.

44. The method of claim 41 wherein the perfusate is passed through the microdialysis probe in alternating intervals at different flow rates, the flow rate during one of the intervals being higher than during one of the other intervals.

45. The method of claim 41 wherein the control device includes an adjuster having an adjusting variable and the adjusting step includes initially determining the starting content of glucose in the perfusate by comparing the adjusting variable with corresponding normalized values of the glucose concentration in the body fluid.

46. The method of claim 41 wherein the perfusate is passed through the microdialysis probe in alternating intervals at different flow rates, the flow rate during one of the intervals being higher than during another of the intervals.

47. The method of claim 41 wherein the command variable is determined by integration or differentiation of the time course of the measurement signals.

48. The method of claim 41 wherein the command variable is determined by comparing the actual signal curve of the measurement signals with calibrated signal patterns deposited in a storage medium.