EP1879494A2 - Procede et dispositif pour determiner la concentration de glucose dans du liquide tissulaire - Google Patents

Procede et dispositif pour determiner la concentration de glucose dans du liquide tissulaire

Info

Publication number
EP1879494A2
EP1879494A2 EP06742798A EP06742798A EP1879494A2 EP 1879494 A2 EP1879494 A2 EP 1879494A2 EP 06742798 A EP06742798 A EP 06742798A EP 06742798 A EP06742798 A EP 06742798A EP 1879494 A2 EP1879494 A2 EP 1879494A2
Authority
EP
European Patent Office
Prior art keywords
glucose
reference substance
measured value
concentration
lactate
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP06742798A
Other languages
German (de)
English (en)
Inventor
Stefano Ferrari
Ortrud Quarder
Peter Stephan
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
F Hoffmann La Roche AG
Original Assignee
F Hoffmann La Roche AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by F Hoffmann La Roche AG filed Critical F Hoffmann La Roche AG
Priority to EP06742798A priority Critical patent/EP1879494A2/fr
Publication of EP1879494A2 publication Critical patent/EP1879494A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/14532—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue for measuring glucose, e.g. by tissue impedance measurement
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/14525—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using microdialysis
    • A61B5/14528—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using microdialysis invasively
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/1468—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using chemical or electrochemical methods, e.g. by polarographic means
    • A61B5/1473—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue using chemical or electrochemical methods, e.g. by polarographic means invasive, e.g. introduced into the body by a catheter

Definitions

  • the invention relates to a method for determining the glucose concentration in tissue fluid in which measured values for glucose and for an endogenous reference substance are detected in a sample liquid obtained by microdialysis, microperfusion or ultrafiltration from a body tissue, and the measured value for glucose in accordance with the measured value for the reference substance is corrected.
  • the invention further relates to a corresponding device.
  • Body tissues consist of cells in a fluid environment in which metabolic products are transported between the cells and the blood vessels.
  • a probe can be used for extended periods in tissue in order to continuously collect ingredients from the tissue fluid via diffusion processes and to determine the glucose content in the tissue from the effusate. This can be closely correlated with blood glucose levels without requiring invasive access to the bloodstream.
  • the measurement can take place outside the body, wherein a sensor is supplied with the sample liquid.
  • an ionic reference technique is known in which an ionic reference value, in particular Na + , is detected by an ion-selective electrode simultaneously with glucose in order to calibrate the recovery of the glucose in the dialysate.
  • the object of the invention is to avoid the disadvantages which have arisen in the prior art and to provide a reference technique with which the actual body values can be determined and checked more accurately.
  • the invention is based on the idea of taking into account both local tissue effects and transport resistances as they occur due to the special probes in microdialysis, microperfusion or ultrafiltration. Accordingly, it is proposed according to a first variant of the invention that the concentration of lactate and / or pyruvate is determined as reference substance in the sample liquid. This makes it possible to use the specific metabolic pathways in glucose degradation in order to draw conclusions about effects caused by local tissue reactions for the correction of measured values.
  • a concentration ratio of lactate to pyruvate is formed in the sample liquid for correcting the measured value for glucose.
  • a concentration ratio of lactate to pyruvate in a selected middle range preferably between 10: 1 and 20: 1
  • a linear correction is carried out as a function of the concentration ratio, and in a higher above the selected range Range is preferably corrected from a concentration ratio of 20: 1, the measured value for glucose by a constant.
  • An analogous correction is conceivable even when lactate alone is used as reference substance.
  • the recovery rate (RGLU) for glucose from a nonlinear relationship to the recovery rate (RREF) for the ionic reference substance be determined and the glucose reading corrected therewith.
  • the recovery rate (RGLU) for glucose is determined according to the relationship
  • the value k as the ratio of the resistances for the transition of glucose and reference substance between the tissue and the sample liquid can preferably be determined empirically. It is further proposed that the retrieval rate (RREF) for the reference substance is determined as the ratio of the measured value for the reference substance in the sample fluid and a constant concentration value in the tissue fluid.
  • RREF retrieval rate
  • sodium is used as the body's own ionic reference substance.
  • a particularly effective and accurate compensation can be achieved by using sodium as reference substance for a correction of metrological deviations and lactate and / or pyruvate as a reference substance. for correction of locally induced deviations of the measured value for glucose in the sample fluid from the actual glucose concentration in the tissue of the organism.
  • the compensation described above can be used particularly advantageously in techniques in which the sample liquid is obtained by means of a probe located in the tissue by perfusion with rinsing liquid or by applying a negative pressure.
  • An additional functionality is achieved in that a malfunction is signaled when an upper and / or lower predetermined threshold of the measured value for the reference substance is exceeded.
  • the sensor unit is designed to determine the concentration of lactate and / or pyruvate as reference substance in the sample liquid.
  • the evaluation unit has an evaluation program which determines the recovery rate (RGLU) for glucose from a non-linear relationship with the recovery rate (RREF) for the ionic reference substance and thus corrects the glucose measurement value.
  • FIG. 1 shows a block diagram of a measuring arrangement for glucose determination
  • FIG. 2 is a schematic representation of a microdialysis system as a measuring arrangement
  • FIG. 3 shows a probe of the microdialysis system according to FIG. 2 in an enlarged view
  • Fig. 4 is a greatly simplified reaction scheme of
  • FIG. 7 is a measurement diagram corresponding to FIG. 5 for an investigation by ultrafiltration
  • the measuring arrangement according to FIG. 1 consists essentially of a probe 10 which can be used in the subcutaneous tissue for obtaining a sample liquid, a sensor 12 for detecting ingredients in the sample liquid, an evaluation and control unit 14 for processing the sensor signals and control of the measuring sequence and optionally one Output unit 16 and an interface 18 for displaying or forwarding the measurement results.
  • the probe 10 can be applied to obtain the sample liquid in a conventional manner with a perfusion liquid (microdialysis, microperfusion) or set to negative pressure (ultrafiltration).
  • the microdialysis probe 10 has a double-lumen membrane catheter 22 located in the tissue 20. This is flushable via a feed line 24 from a liquid reservoir 26 with a perfusion liquid 28.
  • the perfusion fluid 28 consists for example of physiological saline.
  • the return line 30 of the dialysis probe 10 leads via a peristaltic or roller metering pump 32 to a collecting container 34.
  • a measuring cell 36 of the probe 10 operating in the flow is arranged extracorporeally.
  • the measuring cell 36 detects, for example via an electrochemical measurement, the concentration of the desired analytes in the dialysate, especially glucose and a reference or control substance.
  • the catheter 22 has, in the region of its distal end, a dialysis membrane 38 which is embedded in the tissue 20, so that inflowing through the inflow channel 24 perfusate through the semi-permeable membrane is loaded with ingredients 40 from the intercellular tissue.
  • the porosity of the membrane 38 is dimensioned such that the metabolites to be determined, especially glucose, lactate and pyruvate can enter the perfusate almost without resistance, while larger molecules are retained.
  • a membrane is dispensed with and the probe interior is coupled directly to the tissue via wall openings. In both cases, the sample liquid 42 obtained is sucked off via the mouth of the return channel 30 which is set back proximally with respect to the outlet opening of the feed line 24.
  • the glucose concentration in the dialysate or effusate is not equivalent to the glucose content of the tissue fluid.
  • the sensor unit 10 in conjunction with the evaluation unit 14 for additional concentration determination of an endogenous reference or control substance designed so as to be able to perform a compensation of the measurement falsifying effects.
  • the "golden standard” here is the glucose concentration in the capillary blood, which can be determined by means of known tests by spot measurements.
  • One aspect relates to the correction of the measured value for glucose on the basis of the concentration ratio of lactate to pyruvate in the sample liquid.
  • Background is the glucose processing in the tissue cells, as shown in Fig. 4 simplistic.
  • glucose is degraded to pyruvate, which in turn can be utilized in an aerobic process with high energy yield, where as many H atoms (in the form of NADH / H + and FADH 2 ) are obtained, which react with oxygen to water and ATP make (citrate cycle).
  • H atoms in the form of NADH / H + and FADH 2
  • pyruvate is broken down to lactate in a competing metabolic pathway. This process provides less energy so cells need to process more glucose locally to meet their energy needs.
  • the compensation method explained in more detail below is based on the idea that there is an exceptional case of a lactate increase, which indicates that the general glucose concentration in the body is greater than the local concentration in the vicinity of the probe.
  • Such local changes could be caused, for example, by the introduction of the probe or by probe movements in the tissue.
  • Fig. 5 shows a measurement diagram in conjunction with a proposed compensation curve.
  • the deviation or difference of the parallel measured glucose values for sample fluid and blood over the ratio of lactate to pyruvate in the sample fluid is plotted.
  • the aim of the compensation is to minimize the deviation from the values in the blood.
  • a correction calculation is carried out in the evaluation unit in that at a concentration ratio lactate / pyruvate between 10: 1 and 20: 1 a linear correction is carried out (curve section 44), and that from a concentration ratio of 20: 1 the measured value for glucose is corrected by a constant (curve section 46). This constant is shown in FIG. 5 directly by the magnitude of the abscissa value of the section 46.
  • FIG. 6 shows a measurement diagram in conjunction with a proposed compensation curve using only lactate as reference substance.
  • the deviation or difference between the glucose values measured in parallel for the sample liquid and blood over the lactate content in the sample liquid is plotted.
  • a linear correction is carried out at a lactate content between 1, 3 and 2.5 millimoles per liter, whereas at higher lactate contents above this selected middle range the measured value for glucose is corrected by a constant.
  • This constant is again obtained from FIG. 6 by the absolute value of the abscissa value of the compensation straight line in the higher range.
  • a negative pressure is applied to a membrane probe 10 by means of a suction pump or suction syringe without supply of perfusion fluid, whereby interstitial tissue fluid enters the suction line and is transported to a sensor 12.
  • the semi-permeable membrane of the catheter only allows small molecules to diffuse with the fluid, thus forming a sample fluid separate from the tissue fluid. In this case too, injury-induced tissue reactions can take place which lead to local changes in the glucose concentration and can be corrected by means of lactate / pyruvate measurements in the sample fluid.
  • the dashed correction curve 48 corresponds to the compensation explained above with reference to FIG. 5. It is also possible that By means of the solid line 50, only a linear correction is carried out, for example, in a concentration range between 10: 1 and 30: 1 lactate / pyruvate, the slope of the compensation curve being obtained by an adaptation to the measured values.
  • measured values for ions which are kept very constant in the tissue, especially nations, are also detected as endogenous ionic reference substance. It is assumed that Na + remains largely constant in the tissue fluid independent of the glucose processing, and that with a simultaneous measurement of glucose and sodium ions in the sample liquid thus conclusions on the transport or flow resistance can be made in the sample collection.
  • the recovery rate is defined as the concentration ratio of the respective substance in the tissue and the sample fluid.
  • the evaluation unit 14 has an evaluation routine 52, which determines the recovery rate RGLU for glucose from a nonlinear relationship to the recovery rate RREF for the ionic reference substance (Na + ) and thus corrects the glucose measurement value.
  • the evaluation program 52 determines the recovery rate RGLU for glucose from the relationship
  • the recovery rate RREF for the reference substance is determined as a ratio of the measurement value for the reference substance in the sample liquid and a known constant concentration value in the tissue fluid.
  • the basis for equation (1) provides a non-linear model for recovery:
  • This factor k can be estimated by quotient formation using in vivo studies and in vitro data from equation (3).
  • the factor k is a function of the resistances, ie practically a function of the flow rate, membrane and interstitial properties:
  • FIG. 8 is a graph showing glucose recovery rate readings over the Na + recovery rate.
  • FIG. 8 a proportional relationship of the recovery rates (curve 54) and the compensation curve 56 according to equation (1) is shown in the diagram. It can be clearly seen that the proportional or linear curve 54 is not confirmed by the measured values, while the compensation curve 56 runs completely curved positively below the bisecting line and thus describes the empirical measurements correctly.
  • the compensation curve 56 can thus compensate for a fluctuation of the recovery by also correcting the value for glucose based on a changing Na + recovery.
  • the compensation curve 56 could be upset by an additional factor, taking into account that due to high throughput, 100% recovery can not be achieved.
  • Na + is used as a reference substance for a correction of technical deviations
  • lactate / pyruvate as a reference substance for a correction of locally induced deviations of the measured value for glucose in the sample fluid from the actual glucose concentration in the tissue.
  • a further improvement of the functionality can also be achieved by signaling a malfunction of the measurement arrangement when a threshold value of the measured value for the reference substance is exceeded by a signal generator.

Abstract

L'invention concerne un procédé et un dispositif servant à déterminer la concentration de glucose dans du liquide tissulaire (40). Des valeurs de mesure pour le glucose et pour une substance de référence endogène sont détectées (capteur 12) dans un échantillon liquide (42) obtenu par microdialyse, microperfusion ou ultrafiltration (sonde 10) et la valeur de glucose est corrigée en fonction de la valeur mesurée pour la substance de référence. Selon l'invention, le taux de récupération pour le glucose est déterminé à partir d'une relation non linéaire au taux de récupération pour la substance de référence ionique et la valeur de mesure de glucose est corrigée au moyen de ce taux, la concentration en lactate et/ou en pyruvate en tant qu'autre substance de référence dans l'échantillon liquide étant également utilisée pour parfaire la correction.
EP06742798A 2005-05-07 2006-05-04 Procede et dispositif pour determiner la concentration de glucose dans du liquide tissulaire Withdrawn EP1879494A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP06742798A EP1879494A2 (fr) 2005-05-07 2006-05-04 Procede et dispositif pour determiner la concentration de glucose dans du liquide tissulaire

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP05009986A EP1719447A1 (fr) 2005-05-07 2005-05-07 Méthode et dispositif pour la détermination de la concentration de glucose dans la lymphe
PCT/EP2006/004179 WO2006119914A2 (fr) 2005-05-07 2006-05-04 Procede et dispositif pour determiner la concentration de glucose dans du liquide tissulaire
EP06742798A EP1879494A2 (fr) 2005-05-07 2006-05-04 Procede et dispositif pour determiner la concentration de glucose dans du liquide tissulaire

Publications (1)

Publication Number Publication Date
EP1879494A2 true EP1879494A2 (fr) 2008-01-23

Family

ID=35455901

Family Applications (2)

Application Number Title Priority Date Filing Date
EP05009986A Withdrawn EP1719447A1 (fr) 2005-05-07 2005-05-07 Méthode et dispositif pour la détermination de la concentration de glucose dans la lymphe
EP06742798A Withdrawn EP1879494A2 (fr) 2005-05-07 2006-05-04 Procede et dispositif pour determiner la concentration de glucose dans du liquide tissulaire

Family Applications Before (1)

Application Number Title Priority Date Filing Date
EP05009986A Withdrawn EP1719447A1 (fr) 2005-05-07 2005-05-07 Méthode et dispositif pour la détermination de la concentration de glucose dans la lymphe

Country Status (6)

Country Link
US (1) US8114623B2 (fr)
EP (2) EP1719447A1 (fr)
JP (1) JP2008541028A (fr)
CN (1) CN101170942A (fr)
CA (1) CA2607396A1 (fr)
WO (1) WO2006119914A2 (fr)

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2416700A4 (fr) 2009-04-07 2012-12-05 Univ Carnegie Mellon Système de micro-dialyse en temps réel
AU2010337426B2 (en) * 2009-12-30 2015-05-07 Maquet Critical Care Ab System for continuous monitoring of glucose and lactate levels
JP5735773B2 (ja) * 2010-03-29 2015-06-17 シスメックス株式会社 生体成分分析方法及び生体成分分析装置
EP2436311A1 (fr) * 2010-10-04 2012-04-04 PharmaSens AG Dispositif de diagnostic
JP5792517B2 (ja) * 2011-06-02 2015-10-14 国立大学法人長岡技術科学大学 ストレスの評価方法
DE102017110269A1 (de) * 2017-05-11 2018-11-15 B. Braun Avitum Ag Online Linearisierung eines optischen Sensors
US11766510B2 (en) * 2020-05-11 2023-09-26 Covidien Lp Wearable microdialysis device for early detection of anastomotic leaks

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ATE97791T1 (de) * 1988-10-31 1993-12-15 Avl Medical Instr Ag Vorrichtung zur bestimmung der konzentration von zumindest einer in organischem gewebe vorliegenden substanz.
US5118473A (en) * 1989-09-18 1992-06-02 Nova Biomedical Corporation Apparatus for determining the concentration of water soluble species in biological fluid
AT398694B (de) 1990-07-19 1995-01-25 Avl Verbrennungskraft Messtech Vorrichtung zur bestimmung der konzentration von zumindest einer in organischem gewebe vorliegenden substanz
DE69221040T2 (de) * 1991-01-10 1997-11-13 Amylin Pharmaceuticals Inc Aktivätsmessungen des amylin
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See references of WO2006119914A3 *

Also Published As

Publication number Publication date
JP2008541028A (ja) 2008-11-20
CA2607396A1 (fr) 2006-11-16
US20080153118A1 (en) 2008-06-26
WO2006119914A2 (fr) 2006-11-16
EP1719447A1 (fr) 2006-11-08
CN101170942A (zh) 2008-04-30
WO2006119914A3 (fr) 2007-02-01
US8114623B2 (en) 2012-02-14

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