METHOD OF DETECTING PRESENCE OR ABSENCE OF A CLOT IN A LIQUID SAMPLE ANALYZER

Abstract

The disclosure relates to a method of detecting a clot in a measurement chamber of a liquid sample analyzer, wherein the liquid sample analyzer comprises at least two analyte sensors, a first analyte sensor, for measuring a first analyte in a liquid sample, and one or more second analyte sensors, for measuring one or more second analytes in the liquid sample in the measurement chamber, the method comprising the steps of, (a) at least partly filling the measurement chamber with a known solution having a composition comprising the first analyte at a pre-determined level, and the second one or more analytes at pre-determined levels, (b) obtaining a first sequence of measurement results by the first analyte sensor, and simultaneously obtaining a second sequence of measurement results by the second, one or more analyte sensors, (c) determining a change of the first sequence of measurement results, (d) determining a change of the second or more sequence of measurement results, and (e) comparing the change of the first sequence of measurement results with the second sequence of measurement results.

Claims

1. A method of detecting a clot in a measurement chamber of a liquid sample analyzer, wherein the liquid sample analyzer comprises at least two analyte sensors, a first analyte sensor, for measuring a first analyte in a liquid sample, and one or more second analyte sensors, for measuring one or more second analytes in the liquid sample in the measurement chamber, the method comprising the steps of; a. at least partly filling the measurement chamber with a known solution having a composition comprising the first analyte at a pre-determined level, and the second one or more analytes at pre-determined levels, b. obtaining a first sequence of measurement results by the first analyte sensor, and simultaneously obtaining a second sequence of measurement results by the second, one or more analyte sensors; c. determining a change of the first sequence of measurement results; d. determining a change of the second or more sequence of measurement results; e. comparing the change of the first sequence of measurement results with the second sequence of measurement results.

2. The method according to claim 1, wherein presence of a clot is determined if the difference between the change over time of the first sequence of measurement results, and the second sequence of measurement results is above a threshold.

3. The method according to claim 1, wherein presence of a clot is determined if the difference between the actual change of the first sequence of measurement results, and the second sequence of measurement results is above a threshold.

4. The method according to claim 2, wherein absence of a clot is determined if the difference between the change between the first sequence of measurement results and the second sequence of measurement results is below a threshold.

5. The method according to claim 1, wherein the first and second analyte sensors are located at different locations along the measurement chamber.

6. The method according to claim 1, wherein the first and/or second measurement results are used for maintaining a calibration of the respective analyte sensors for subsequent measurements.

7. The method according claim 1, wherein the one or more physical parameters are one or more of the types of analyte concentration, partial pressure of a gas in liquid, and pH-value.

8. The method according to claim 1, wherein the first and second analyte sensors are adapted for measuring the same type of physical parameters.

9. The method according to claim 1, wherein the first and second analyte sensors are adapted for measuring the same type of physical parameters for different analytes.

10. The method according to claim 1, wherein the first and second analyte sensors are electrochemical sensors, each sensor comprising an ion selective electrode.

11. The method according to claim 1, wherein the electrochemical sensor includes an electrode device with a solid state inner reference system.

12. The method according to claim 1, wherein the first and second analyte sensors are optical sensors.

13. The method according to claim 1, wherein the liquid sample analyzer comprises at least three analyte sensors, for further determining which of the sensors are affected by a clot in the measurement chamber by cross comparing the change in analyzer response, wherein the clot is affecting the analyte sensor where the change is deviating from the change on the two other sensors.

14. A liquid sample analyzer adapted for performing a method of clot detection according to any of the preceding claims, the liquid sample analyzer comprising a measurement chamber with inlet for feeding a liquid sample to the measurement chamber, and outlet for discharging a liquid sample from the measurement chamber, a first analyte sensor ans one or more second analyte sensors facing the measurement chamber, the analyte sensors being arranged for measuring an analyte in the liquid sample in the measurement chamber, and a signal processor configured for receiving signals from the analyte sensors as an input, for performing a comparison between the change over time of the measurement results of the first and second analyte sensors in a first sequence of measurements and a second sequence of measurements, based on that input, and for determining presence or absence of a clot in the measurement chamber based on the comparison.

15. The liquid sample analyzer according to claim 14, wherein the liquid sample analyzer is adapted for measurement of blood parameters in a whole blood sample.

16. The liquid sample analyzer according to claim 14, wherein the first and second analyte sensors are located at different locations along the measurement chamber.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0059] Preferred embodiments of the invention will be described in more detail in connection with the appended drawings, which show in

[0060] FIG. 1 a diagram of a blood analyzer according to one embodiment,

[0061] FIG. 2 a graph plotting the rate of change as a function of time for a set of three analyte sensors, the data indicating presence of a clot in the measurement chamber, and in

[0062] FIG. 3 a further graph plotting the rate of change as a function of time for a further set of three analyte sensors, the data indicating absence of a clot in the measurement chamber.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[0063] FIG. 1 shows schematically a liquid sample analyzer 1 with an analyzer part having a signal processor 8, one or more analyte sensors 3(a-i), 4, a measurement chamber 2, and fluid handling infrastructure 20. For performing measurements, the user may provide a liquid sample at an input port 12a/b of the analyzer 1. The liquid sample is transferred through an inlet port 6 to the measurement chamber 2 comprising a plurality of analyte sensors 3, 4. The analyte sensors 3, 4 are arranged to provide essentially simultaneous measurements on analyte parameters in a liquid sample, e.g. a whole blood sample. Preferably, the required sample amount for obtaining precise and reliable data is as small as possible. A detailed example of a sensor assembly design that is particularly suitable for simultaneously measuring a plurality of different parameters in bodily fluids, particularly in whole blood, and its use in a blood analyzer is e.g. found in EP 2 147 307 B1. Following pre-programmed instructions loaded in a signal processor 8 and/or user input, measurements are performed using the analyte sensors 3, 4. The analyte sensors 3, 4 generate signals that are representative of a physical parameter for the respective analyte and provide the signals to the signal processor 8 of the analyzer part. The signal processor 8 is adapted to receive and process signals from the analyte sensors 3, 4, and present the processed signals as output to a user or to a subsequent/further data analysis. After measurement, the liquid sample is discharged, and the measurement chamber 2 is prepared for the next measurement. The embodiment of the analyzer shown in FIG. 1 is particularly adapted for the measurement of blood parameters, and further comprises an optional oximetry measurement device 9 downstream of the measurement chamber 2. Performing the measurements, calibration tasks, and quality control procedures thus typically involves the loading, unloading, rinsing, cleaning and re-loading of different liquids, which may be done by the fluid handling infrastructure 20. The fluid handling may be controlled in an automated way by the signal processor 8 according to pre-programmed instructions and/or user input. The fluid handling infrastructure 20 includes a number of reservoirs 21 pre-filled with process liquids (RINSE/CAL1, CAL2, QC1, QC2, QC3) for rinsing/wash-out, calibration and quality control tasks. The process liquids (RINSE/CAL1, CAL2, QC1, QC2, QC3) have a known composition. The exact composition of a given batch may be stored in a chip 25 that may be attached to a cassette comprising the reservoirs 21, wherein the chip 25 may be read by the signal processor 8. The process liquid (RINSE/CAL1, CAL2, QC1, QC2, QC3) for a given process step may be selected by a fluid selector valve 22, and via feed line 12c transferred through the inlet port 6 to the measurement chamber 2. Correct filling of the measurement chamber 2 may be monitored and verified by visual inspection or according to known procedures by observing the propagation of a liquid interface through the system by means of liquid sensors 10a, 10b, 10c located upstream and downstream of the measurement chamber, such as at the inlet 6 (“LS inlet” 10a), at the outlet 7 (“LS BG” 10b), and just after the oximetry measurement device 9 (“LS OXI” 10c), respectively. The fluid flow through the analyzer is driven by a pump 23, here a peristaltic hose-pump arranged downstream of the measurement chamber 2 and the oximetry measurement device 9 and connected thereto via fluid line 13. The discharged fluids are finally transported through fluid line 14 to the waste reservoir 24.

[0064] By way of example, a kit of process fluids may include the following compositions with approximate concentrations of different substances contained in these compositions as given in Table 1 below.

TABLE-US-00001 TABLE 1 Concentration RINSE/CAL1 CAL2 CAL3 Substance Unit S1920 S1930 S1940 pH 7.30 6.8 NA pCO.sub.2 mmHg 35 NA 80 pO.sub.2 mmHg 180 NA NA cNa.sup.+ mmol/L 150 70 NA cK.sup.+ mmol/L 4 10 NA cCl.sup.− mmol/L 95 50 NA cCa.sup.2+ mmol/L 0.5 2.3 NA cGlu mmol/L 0 NA 10 cLac mmol/L 0 NA 10 ctHb g/dL NA NA 0

[0065] Upon start-up and, in an ongoing manner, during uptime, the analyzer 1 performs self-control routines. If any abnormality is detected, the analyzer 1 indicates the deviation to a user, and may further indicate ways of overcoming an error state. On the other hand, when the analyzer indicates normal operation, measurements can be performed immediately. Advantageously according to some embodiments, the self-control routines may be performed during idle times, i.e. when the analyzer is in an idle state, where it is not used for performing actual measurements on a user's sample. The self-control control routines may include continued repetitive measurements performed on a calibration-grade process liquid with a precisely known composition, as e.g. stored on chip 25. A suitable liquid is for example the process liquid RINSE/CAL1, labelled S1920 in the Table 1 above. The signals obtained for each of the different analyte sensors on the well-known composition may then be used to continuously update the reference for the respective analyte measurements.

[0066] Such data from continued idle state measurements on the RINSE/CAL1 process liquid over a period of operation of 24 hrs are shown in FIGS. 2 and 3. FIGS. 2 and 3 show graphs plotting for a set of three analyte sensors a representative value that may be used as a discrimination criterion for determining presence or absence of a clot in the measurement chamber of a blood analyzer. The three sensors of FIGS. 2 and 3 are all electrochemical sensors adapted to measure concentration of Ca.sup.2+-ions (crosses), K.sup.+-ions (stars), and Na.sup.+-ions (circles), respectively. In the graphs of FIGS. 2 and 3, the representative value reflecting the synchronized status of the three sensors is a relative idle slope, wherein the relative idle slope is determined from the continued idle state updating measurements described above. The relative idle slope for each electrode is here determined as the slope obtained from a regression to a time sequence of measurements for each of the analyte sensors included in the clot detection procedure, and referring the respective slope to the ensemble of all the analyte sensors included in the clot detection procedure by subtracting the average of the slopes of all said sensors. Alternatively, the average slope subtracted from the slope of a given analyte sensor may be taken over the slopes for all sensors included in the clot detection procedure, except for the given sensor.

[0067] The data in FIG. 3, and in FIG. 2 up to about 14:00 hrs, behave “normal”, i.e. the data do not indicate the presence of any contaminant in the measurement chamber 2 that would significantly affect the result of a measurement on a user sample. The synchronized status slopes for the idle measurements of all three analyte sensors tend to stabilize around zero. Only small characteristic recovery decays are observed after a user's measurement, a calibration routine, or a quality control procedure has perturbed the state of the analyte sensors, until the sensor signal stabilizes again around zero.

[0068] However, between 14 hrs and 16 hrs (at about 15 hrs towards positive values) in the graph of FIG. 2, a dramatic change of the signal from the Calcium ion sensor is observed—here expressed by a dramatic increase in the relative idle slope for the Ca.sup.2+-sensor, and a corresponding rapid decrease of the relative idle slope values for the remaining two analyte sensors. This pronounced deviation is the signature of the presence of a clot in the measurement chamber, acting as a reservoir for the delayed up-take and emission of analytes. If un-detected and if not removed, the clot may cause contamination/pollution of subsequent samples in the measurement chamber and/or distortion of the measurement values for at least some of the analytes of a given sample. In the event between 14 hrs and 16 hrs in FIG. 2, apparently the clot contributes with a delayed excessive emission of Ca.sup.2+ into the RINSE/CAL1 solution of the idle measurement. An appropriate threshold value may be chosen as a discrimination criterion for determining the presence (or absence) of a clot. For example, in FIGS. 2 and 3, a threshold of e.g. (+/−0.3) has been defined for the deviation of the relative idle slope from its stabilized state around zero. The threshold is marked in the graph by two horizontal lines. Presence of a clot may then be determined if at least one analyte sensor exceeds the threshold, and absence of a clot may be concluded if none of the analyte sensors exceeds the threshold. In addition to the event at about 15 hrs, in FIG. 2 two further events of exceeding the threshold indicated by the horizontal lines at (+/−0.3) are observed between 16 hrs and 18 hrs (at about 17 hrs towards positive values), and between 20 hrs and 22 hrs (at about 21 hrs towards negative values), respectively. In fact, after the first event at about 15 hrs, the analyte signals do not really seem to properly stabilize in a manner as before the event, or in a manner as seen in FIG. 3 throughout the entire period of operation shown. Any measurement performed on a user sample after about 15 hrs would have to be discarded retrospectively.

[0069] By using the method of the invention, presence of a clot would be determined already at the first event, and an alarm/error state would be presented to a user of the analyzer. Furthermore, measures for clot removal and/or replacement of the measurement chamber by a new one may be initiated. Thereby, loss of data, loss of time for obtaining useless data, and in particular the loss of valuable samples is successfully avoided. Note also that a flow-based detection, such as by liquid sensors would not report any problem from a point of view of the fluidic behavior during filling and discharge of the measurement chamber 2, whereas the inventive method allows for a very sensitive detection of this type of clot.

[0070] In a specific embodiment of the invention the slope used for determining a clot on a specific sensor in a three sensor system (Ca, K, Na) is calculated as follows.

[00001]$C{a}_{{\mathrm{rinse}}_{-}\mathrm{syncSlope}}=\left({\mathrm{Ca}}_{{\mathrm{rinse}}_{\mathrm{syncSlope}}}-\frac{K_{{\mathrm{rinse}}_{\mathrm{syncSlope}}}+N{a}_{{\mathrm{rinse}}_{\mathrm{syncSlope}}}}{2}\right)*t$$K_{{\mathrm{rinse}}_{-}\mathrm{syncSlope}}=\left(K_{{\mathrm{rinse}}_{\mathrm{syncSlope}}}-\frac{C{a}_{{\mathrm{rinse}}_{\mathrm{syncSlope}}}+N{a}_{{\mathrm{rinse}}_{\mathrm{syncSlope}}}}{2}\right)*t$$N{a}_{{\mathrm{rinse}}_{-}\mathrm{syncSlope}}=\left({\mathrm{Na}}_{{\mathrm{rinse}}_{\mathrm{syncSlope}}}-\frac{K_{{\mathrm{rinse}}_{\mathrm{SyncSlope}}}+C{a}_{{\mathrm{rinse}}_{\mathrm{syncSlope}}}}{2}\right)*t$

[0071] In a perfect situation where the different sensors would have the exact same response, and there is not clot, and the amount of each analyte in the rinse solution is the same, the result for each of the above equations should be zero. However the sensors do respond different to the rinse solution. Whether the analyzer should flag the result as indicating an error on the sensor, that could imply the sensor being covered by a clot, would thus depend on whether the calculated value is above or below a threshold value. The table below shows the threshold limits in a given set-up.

TABLE-US-00002 Parameter lo [mV] Hi [mV] Ca.sub.rinse_syncSlope −0.3 0.3 K.sub.rinse_syncSlope −0.3 0.3 Na.sub.rinse.sub.syncSlope −0.3 0.3